Clinical Review

Fatigue is defined as “an overwhelming, sustained sense of exhaustion and decreased capacity for physical and mental work,”¹ and it is experienced by most patients with chronic disease. There are 2 types of fatigue: acute and chronic.² Acute fatigue typically is caused by an identified insult (ie, injury), is self-limited, and is relieved by rest. Chronic fatigue, which may have multiple unknown causes, may accompany chronic illness and lasts longer than 6 months.² In chronic disease, fatigue can originate peripherally (neu romuscular dysfunction outside of the central nervous system) or centrally (neurotransmitter activity within the central nervous system). Generally, central fatigue is more relevant in patients with chronic disease; however, both central and peripheral fatigue frequently coexist.

Fatigue, even with its accepted definition, is a nonspecific symptom, making it difficult to measure. Because of its subjective nature and the lack of effective therapies, clinicians often ignore fatigue. Still, patients with chronic disease continue to cite fatigue as one of the most challenging aspects of their disease that frequently decreases their quality of life (QOL).²

Fatigue has been well recognized in a number of chronic inflammatory diseases such as rheumatoid arthritis,^3,4 systemic lupus erythematosus,⁵ fibromyalgia,⁶ and primary Sjögren syndrome.⁷ Similarly, fatigue is a frequent concern among patients with psoriasis and psoriatic arthritis.⁸ Given the prevalence and significance of psoriasis-associated fatigue,⁹ new efforts are needed to understand its pathophysiology, to develop new metrics for its evaluation, and to investigate therapeutic strategies to target it clinically. The following discussion provides an overview of the association between fatigue and psoriatic disease as well as the commonly used metrics for evaluating fatigue. Possible therapeutic agents with which to manage fatigue in this patient population also are provided.

Pathogenesis of Psoriasis-Associated Fatigue

Immunologic/Molecular Basis for Psoriasis-Associated Fatigue

Several theories aim to explain the pathophysiology of fatigue in patients with psoriatic disease. Psoriasis is a chronic inflammatory disease characterized by sharply demarcated erythematous plaques with adherent scale (Figure 1). Many in vitro studies have demonstrated the complex cytokine network that underlies the histopathologic alterations we observe in psoriatic lesions.^10,11 Until recently, psoriasis was considered a type I autoimmune disease with strong T_H1 signaling, influenced by IFN-γ, IL-2, and IL-12.¹² T_H1-producing proinflammatory cytokines, tumor necrosis factor α (TNF-α), and IFN-γ are elevated in psoriatic lesions.¹³ Studies on the efficacy of ustekinumab, a monoclonal antibody targeting IL-12 and IL-23, demonstrate the integral role of the immune system in psoriasis pathogenesis as the production of IL-12 polarizes T cells into T_H1 cells.^14,15 However, in recent years, T_H17 cells have been linked to autoimmune inflammation¹⁶ and have been localized to the dermis in psoriatic lesions.¹⁷

Among a milieu of inflammatory cytokines, IL-1 is crucial for the early differentiation of T_H17 cells.¹⁸ The IL-1 family of cytokines serve as primary mediators of inflammation with members including the IL-1 agonists (IL-1α, IL-1β),¹⁹ IL-1 receptor antagonist (IL-1RA),²⁰ and IL-1 receptor type II (IL-1RII).²⁰ The latter two inhibit IL-1 agonists from binding to their receptor (IL-1RI).^19,20 A study by Yoshinaga et al²¹ investigated the level of inflammatory cytokines within lesional and nonlesional psoriatic skin, finding elevated levels of IL-1β in lesional skin. Another study found that IL-1β expression was increased 357% within biopsied psoriasiform lesions from flaky-skin mice, a useful model to examine the hyperproliferative alterations in the skin. This same study revealed that in vivo IL-1β neutralization alleviated the psoriasiform features in these same mice, suggesting IL-1β is integral to psoriasis pathogenesis.²²

Evidence indicates that the aforementioned inflammatory mediators may contribute to psoriasis-associated fatigue. When the peripheral immune system is continuously activated, such as in psoriasis, the peripherally produced proinflammatory cytokines and subsequent immune signaling are monitored by the brain via afferent nerves, cytokine transporters at the blood-brain barrier, and IL-1 receptors on macrophages and endothelial cells of brain venules.²³ For example, subseptic doses of lipopolysaccharide injected into rats induced messenger RNA expression of IL-1β in the choroid plexus, circumventricular organs, and the meninges,²⁴ sites where cytokines can enter the blood-brain barrier via diffusion or cytokine transporters.²³ These results may suggest a pathway that relays the peripheral immune signals that underlie psoriatic disease to the brain, resulting in activation of brain circuitry that mediates various negative behavioral responses, including fatigue.²³ Following a central IL-1β infusion in mice, investigators found a significant decrease in the running performance (P<.01)²⁵; the same infusion increased lethargy, malaise, and fatigue in rats.²⁶ Interestingly, administration of IL-1RA significantly increased run time to fatigue (P<.05), supporting the hypothesis that IL-1β plays an important role in fatigue.²⁵ Other investigators found that administration of many cytokines (IL-1β, IL-6, TNF-α) into rats induced depressivelike behaviors²⁷ and suppressed locomotor activity.²⁸ Lastly, another investigation found that IL-1RI knockout mice were resistant to symptoms of sickness, such as social exploration, anorexia, immobility, and weight loss, following IL-1β injections.²⁹ Although the translatability of these studies to humans is not entirely clear, one study found that the proinflammatory cytokines IL-1 and TNF-α were elevated in patients with chronic fatigue syndrome.³⁰ Furthermore, a 2013 systematic review found that several serum inflammatory markers including IL-6 and TNF-α were elevated in patients with severe plaque psoriasis compared to healthy controls.³¹ Therefore, these shared inflammatory cytokines may contribute to and explain the pathogenesis of both fatigue and psoriasis.

Confounding Factors

Although fatigue may be partially explained by the joint effect of inflammatory mediators on both the skin and the brain, there is evidence to suggest that other confounding factors may modify this association and affect its clinical presentation. The pathophysiology of fatigue in psoriasis may not be strictly immunologic; the environmental, psychological, and physical effects of psoriasis may all contribute to and perpetuate fatigue.^9,32,33 Interestingly, the pathophysiology of psoriasis involves many cytokines also known to contribute to features of the metabolic syndrome.³⁴ For example, elevated levels of free fatty acids, TNF-α, and IL-6 act in concert to promote inflammation, alter glucose metabolism, and dysregulate endothelial cell function, contributing to dyslipidemia, insulin resistance, and cardiovascular disease.³⁵ A systematic review found a high prevalence of metabolic syndrome in patients with psoriasis and have found that those with more severe disease have an even greater risk for developing metabolic syndrome.³⁴

Numerous studies have documented that upward of 80% of patients consider psoriasis to have a major impact on their QOL.^36-38 The National Psoriasis Foundation assessed patients’ perspectives on the social, physical, and psychological aspects of their disease, finding that health-related QOL is impaired in patients with psoriatic disease.^36,39 Patients reported their disease interfered with overall emotional well-being and life enjoyment and cited feelings of anger, frustration, helplessness, embarrassment, and self-consciousness, all of which can influence fatigue.^36,39 Pain and pruritus (Figure 2) can interrupt sleep and thus may also contribute to symptoms of fatigue.⁴⁰ Patients with psoriatic disease have a higher incidence of both depression and anxiety compared with the general population. Another study found that patient-reported factors of disability, pain, and fatigue were associated with clinical depression and anxiety; however, these factors are commonly observed in this cohort of patients and thus it is unclear whether they are predictors of or the result of depression.³⁸

Furthermore, psoriatic disease leads to considerable economic burdens; one study (N=5604) found that among respondents who were not employed, 92% reported they were unemployed solely due to their psoriatic disease.³⁶ One study explored the relationship between fatigue, work disability, and psoriatic arthritis, finding that the association between fatigue and work productivity loss persisted after controlling for cutaneous/musculoskeletal activity.⁴¹ However, another investigation revealed contradicting results, finding that improvements in fatigue correlated with improvements in joint and skin pain.⁹

Therefore, we can conclude that the pathogenesis of psoriasis-associated fatigue is the result of a multifactorial immunologic, psychologic, and physiologic pathway that triggers symptoms of exhaustion and lethargy. Fatigue is a complex multidimensional symptom activated by psoriatic disease, directly by shared inflammatory cytokines and indirectly by factors of disease activity and psychiatric distress that inherently influence somatic manifestations of fatigue. Regardless of its pathogenesis, these data and observations highlight the importance of fatigue symptoms and the need for new therapeutics to target this debilitating disease.

Measurement of Fatigue in Psoriasis

A patient’s level of fatigue is not objectively quantifiable. For this reason, clinicians and investigators have relied on self-report instruments to gauge fatigue (Table).^{9,38,40,42-53} These survey instruments each have distinct advantages and disadvantages, though all are subject to common difficulties. Many rely on the literacy of patients and their interpretation of each item, which can make completing the survey difficult and yield variability between subjects. Patients are inaccurate in self-reporting even measurable characteristics such as height and weight,⁵⁴ which introduces an element of uncertainty in the reporting of subjective symptoms (ie, fatigue). Lastly, there are several biases implicit in self-reporting including recall bias, selective recall, and digit preference.⁵⁵

When analyzing fatigue due to a chronic disease, several symptoms may be misconstrued or interfere with the interpretation of fatigue. For instance, patients with multiple sclerosis may confuse neuropathy-associated muscle weakness with fatigue. These interactions can be controlled for in self-report instruments and validated through careful study of many patients. Disease-specific questionnaires have been validated for use in several diseases,^56-58 though none have been validated for cutaneous psoriasis in the absence of psoriatic arthritis. The need for validated instruments in psoriasis is great, as symptoms such as sleep disturbance and arthralgia may confound metrics of fatigue.

Thus far, 4 self-report instruments have been used to study fatigue in psoriasis: the medical outcomes 36-item short-form health survey (SF-36), the functional assessment of chronic illness therapy-fatigue, the fatigue severity scale (FSS), and the visual analog scale (VAS) for fatigue.

The SF-36 is a 36-item survey designed to measure 8 dimensions of health status in patients with chronic disease.⁵⁹ Items are answered using a 3- to 6-point Likert scale, or in a yes/no format. Although the SF-36 is typically administered by a trained interviewer, it relies on a patient’s interpretation of language that must be used to describe their level of fatigue, which may not capture the full range of symptoms. Also, the length of the survey makes it impractical for use in clinical practice.

The functional assessment of chronic illness therapy-fatigue survey is validated for use in psoriatic arthritis. It is similar to the SF-36 in its use of a 5-point Likert scale to answer each of 13 items. It improves on the SF-36 model by including questions about associated symptoms (ie, pain, medication side effects) that may interfere with the measurement of fatigue. It also investigates the impact of fatigue on several areas of functioning. However, it is subject to the same pitfalls of interpretation and a rigid scale with which to answer questions.

The FSS is another Likert scale–based instrument that gauges both level of fatigue and its impact using 9 items and a 7-point scale. Investigators used the FSS to uncover an association between increasing fatigue scores and depression in patients with psoriatic disease.³⁸

The VAS overcomes many of the language and interpretation issues inherent in Likert scale–based instruments. Patients are presented with a single item in which they are asked to plot their level of fatigue on a continuous line, with one end representing no fatigue and the other end the worst possible fatigue. Although VAS adds simplicity of response and removes some ambiguity from surveying, it provides no information about the functional impact of fatigue on patients. It also does not provide a method to control for other symptoms.

Treatment of Psoriasis-Associated Fatigue

Much of our understanding of psoriasis-associated fatigue arises from therapeutic clinical trials. Because increased concentrations of proinflammatory cytokines are associated with fatigue, it has been suggested that blocking these cytokines with biologic agents may relieve fatigue symptoms. For example, investigators found that patients treated with etanercept, a soluble TNF-α receptor fusion protein, had clinically meaningful improvement in fatigue compared to those receiving placebo, with sustained improvements at 96 weeks.^9,47 We must note, however, that the decrease in fatigue correlated with improvements in cutaneous/arthritic pain. Nevertheless, another study found that treatment with the same drug decreased fatigue in patients with psoriasis, even after controlling for improvements in the psoriasis area severity index score.⁴⁰ Adalimumab is another monoclonal antibody for TNF-α that has caused a notable decline in fatigue symptoms.⁴⁹

These data suggest that biologic agents are useful in the treatment of fatigue. Biologic agents are frequently administered to patients with moderate to severe psoriasis in whom more conservative treatments previously failed. However, cutaneous/arthritic disease severity is not always correlated with fatigue, so these data may urge clinicians to lower their threshold for treatment with biologics in patients with substantial fatigue symptoms. Although further investigations are necessary, we may even consider using a biologic therapy for severe fatigue in those without severe psoriatic disease.

Conclusion

Fatigue is a multidimensional symptom, impacted both directly and indirectly by psoriasis pathophysiology. The prevalence of fatigue within this patient population suggests that clinicians need to recognize the symptom as a core domain in psoriasis evaluation. Although a host of metrics have been used to quantify/qualify fatigue, there remains a need for a validated instrument for assessing fatigue in patients with psoriatic disease.

Biologic agents have proven useful in the treatment of psoriasis-associated fatigue. The central role of proinflammatory cytokines to both fatigue and psoriasis pathogenesis provide insight into potential treatment targets. Understanding the overlapping pathophysiology of psoriasis and fatigue provides an avenue for developing innovative strategies to target molecules implicated in the activation of the immune system. In the future, it may be possible to predict the severity of fatigue by measuring the levels of serum inflammatory cytokines; in fact, a new study aims to identify a panel of soluble biomarkers that can predict joint damage in psoriatic arthritis.⁶⁰ Taken together, the findings described suggest that further study is needed to characterize, measure, and treat psoriasis-associated fatigue.

Fatigue is defined as “an overwhelming, sustained sense of exhaustion and decreased capacity for physical and mental work,”¹ and it is experienced by most patients with chronic disease. There are 2 types of fatigue: acute and chronic.² Acute fatigue typically is caused by an identified insult (ie, injury), is self-limited, and is relieved by rest. Chronic fatigue, which may have multiple unknown causes, may accompany chronic illness and lasts longer than 6 months.² In chronic disease, fatigue can originate peripherally (neu romuscular dysfunction outside of the central nervous system) or centrally (neurotransmitter activity within the central nervous system). Generally, central fatigue is more relevant in patients with chronic disease; however, both central and peripheral fatigue frequently coexist.

Fatigue, even with its accepted definition, is a nonspecific symptom, making it difficult to measure. Because of its subjective nature and the lack of effective therapies, clinicians often ignore fatigue. Still, patients with chronic disease continue to cite fatigue as one of the most challenging aspects of their disease that frequently decreases their quality of life (QOL).²

Fatigue has been well recognized in a number of chronic inflammatory diseases such as rheumatoid arthritis,^3,4 systemic lupus erythematosus,⁵ fibromyalgia,⁶ and primary Sjögren syndrome.⁷ Similarly, fatigue is a frequent concern among patients with psoriasis and psoriatic arthritis.⁸ Given the prevalence and significance of psoriasis-associated fatigue,⁹ new efforts are needed to understand its pathophysiology, to develop new metrics for its evaluation, and to investigate therapeutic strategies to target it clinically. The following discussion provides an overview of the association between fatigue and psoriatic disease as well as the commonly used metrics for evaluating fatigue. Possible therapeutic agents with which to manage fatigue in this patient population also are provided.

Pathogenesis of Psoriasis-Associated Fatigue

Immunologic/Molecular Basis for Psoriasis-Associated Fatigue

Several theories aim to explain the pathophysiology of fatigue in patients with psoriatic disease. Psoriasis is a chronic inflammatory disease characterized by sharply demarcated erythematous plaques with adherent scale (Figure 1). Many in vitro studies have demonstrated the complex cytokine network that underlies the histopathologic alterations we observe in psoriatic lesions.^10,11 Until recently, psoriasis was considered a type I autoimmune disease with strong T_H1 signaling, influenced by IFN-γ, IL-2, and IL-12.¹² T_H1-producing proinflammatory cytokines, tumor necrosis factor α (TNF-α), and IFN-γ are elevated in psoriatic lesions.¹³ Studies on the efficacy of ustekinumab, a monoclonal antibody targeting IL-12 and IL-23, demonstrate the integral role of the immune system in psoriasis pathogenesis as the production of IL-12 polarizes T cells into T_H1 cells.^14,15 However, in recent years, T_H17 cells have been linked to autoimmune inflammation¹⁶ and have been localized to the dermis in psoriatic lesions.¹⁷

Among a milieu of inflammatory cytokines, IL-1 is crucial for the early differentiation of T_H17 cells.¹⁸ The IL-1 family of cytokines serve as primary mediators of inflammation with members including the IL-1 agonists (IL-1α, IL-1β),¹⁹ IL-1 receptor antagonist (IL-1RA),²⁰ and IL-1 receptor type II (IL-1RII).²⁰ The latter two inhibit IL-1 agonists from binding to their receptor (IL-1RI).^19,20 A study by Yoshinaga et al²¹ investigated the level of inflammatory cytokines within lesional and nonlesional psoriatic skin, finding elevated levels of IL-1β in lesional skin. Another study found that IL-1β expression was increased 357% within biopsied psoriasiform lesions from flaky-skin mice, a useful model to examine the hyperproliferative alterations in the skin. This same study revealed that in vivo IL-1β neutralization alleviated the psoriasiform features in these same mice, suggesting IL-1β is integral to psoriasis pathogenesis.²²

Evidence indicates that the aforementioned inflammatory mediators may contribute to psoriasis-associated fatigue. When the peripheral immune system is continuously activated, such as in psoriasis, the peripherally produced proinflammatory cytokines and subsequent immune signaling are monitored by the brain via afferent nerves, cytokine transporters at the blood-brain barrier, and IL-1 receptors on macrophages and endothelial cells of brain venules.²³ For example, subseptic doses of lipopolysaccharide injected into rats induced messenger RNA expression of IL-1β in the choroid plexus, circumventricular organs, and the meninges,²⁴ sites where cytokines can enter the blood-brain barrier via diffusion or cytokine transporters.²³ These results may suggest a pathway that relays the peripheral immune signals that underlie psoriatic disease to the brain, resulting in activation of brain circuitry that mediates various negative behavioral responses, including fatigue.²³ Following a central IL-1β infusion in mice, investigators found a significant decrease in the running performance (P<.01)²⁵; the same infusion increased lethargy, malaise, and fatigue in rats.²⁶ Interestingly, administration of IL-1RA significantly increased run time to fatigue (P<.05), supporting the hypothesis that IL-1β plays an important role in fatigue.²⁵ Other investigators found that administration of many cytokines (IL-1β, IL-6, TNF-α) into rats induced depressivelike behaviors²⁷ and suppressed locomotor activity.²⁸ Lastly, another investigation found that IL-1RI knockout mice were resistant to symptoms of sickness, such as social exploration, anorexia, immobility, and weight loss, following IL-1β injections.²⁹ Although the translatability of these studies to humans is not entirely clear, one study found that the proinflammatory cytokines IL-1 and TNF-α were elevated in patients with chronic fatigue syndrome.³⁰ Furthermore, a 2013 systematic review found that several serum inflammatory markers including IL-6 and TNF-α were elevated in patients with severe plaque psoriasis compared to healthy controls.³¹ Therefore, these shared inflammatory cytokines may contribute to and explain the pathogenesis of both fatigue and psoriasis.

Confounding Factors

Although fatigue may be partially explained by the joint effect of inflammatory mediators on both the skin and the brain, there is evidence to suggest that other confounding factors may modify this association and affect its clinical presentation. The pathophysiology of fatigue in psoriasis may not be strictly immunologic; the environmental, psychological, and physical effects of psoriasis may all contribute to and perpetuate fatigue.^9,32,33 Interestingly, the pathophysiology of psoriasis involves many cytokines also known to contribute to features of the metabolic syndrome.³⁴ For example, elevated levels of free fatty acids, TNF-α, and IL-6 act in concert to promote inflammation, alter glucose metabolism, and dysregulate endothelial cell function, contributing to dyslipidemia, insulin resistance, and cardiovascular disease.³⁵ A systematic review found a high prevalence of metabolic syndrome in patients with psoriasis and have found that those with more severe disease have an even greater risk for developing metabolic syndrome.³⁴

Numerous studies have documented that upward of 80% of patients consider psoriasis to have a major impact on their QOL.^36-38 The National Psoriasis Foundation assessed patients’ perspectives on the social, physical, and psychological aspects of their disease, finding that health-related QOL is impaired in patients with psoriatic disease.^36,39 Patients reported their disease interfered with overall emotional well-being and life enjoyment and cited feelings of anger, frustration, helplessness, embarrassment, and self-consciousness, all of which can influence fatigue.^36,39 Pain and pruritus (Figure 2) can interrupt sleep and thus may also contribute to symptoms of fatigue.⁴⁰ Patients with psoriatic disease have a higher incidence of both depression and anxiety compared with the general population. Another study found that patient-reported factors of disability, pain, and fatigue were associated with clinical depression and anxiety; however, these factors are commonly observed in this cohort of patients and thus it is unclear whether they are predictors of or the result of depression.³⁸

Furthermore, psoriatic disease leads to considerable economic burdens; one study (N=5604) found that among respondents who were not employed, 92% reported they were unemployed solely due to their psoriatic disease.³⁶ One study explored the relationship between fatigue, work disability, and psoriatic arthritis, finding that the association between fatigue and work productivity loss persisted after controlling for cutaneous/musculoskeletal activity.⁴¹ However, another investigation revealed contradicting results, finding that improvements in fatigue correlated with improvements in joint and skin pain.⁹

Therefore, we can conclude that the pathogenesis of psoriasis-associated fatigue is the result of a multifactorial immunologic, psychologic, and physiologic pathway that triggers symptoms of exhaustion and lethargy. Fatigue is a complex multidimensional symptom activated by psoriatic disease, directly by shared inflammatory cytokines and indirectly by factors of disease activity and psychiatric distress that inherently influence somatic manifestations of fatigue. Regardless of its pathogenesis, these data and observations highlight the importance of fatigue symptoms and the need for new therapeutics to target this debilitating disease.

Measurement of Fatigue in Psoriasis

A patient’s level of fatigue is not objectively quantifiable. For this reason, clinicians and investigators have relied on self-report instruments to gauge fatigue (Table).^{9,38,40,42-53} These survey instruments each have distinct advantages and disadvantages, though all are subject to common difficulties. Many rely on the literacy of patients and their interpretation of each item, which can make completing the survey difficult and yield variability between subjects. Patients are inaccurate in self-reporting even measurable characteristics such as height and weight,⁵⁴ which introduces an element of uncertainty in the reporting of subjective symptoms (ie, fatigue). Lastly, there are several biases implicit in self-reporting including recall bias, selective recall, and digit preference.⁵⁵

When analyzing fatigue due to a chronic disease, several symptoms may be misconstrued or interfere with the interpretation of fatigue. For instance, patients with multiple sclerosis may confuse neuropathy-associated muscle weakness with fatigue. These interactions can be controlled for in self-report instruments and validated through careful study of many patients. Disease-specific questionnaires have been validated for use in several diseases,^56-58 though none have been validated for cutaneous psoriasis in the absence of psoriatic arthritis. The need for validated instruments in psoriasis is great, as symptoms such as sleep disturbance and arthralgia may confound metrics of fatigue.

Thus far, 4 self-report instruments have been used to study fatigue in psoriasis: the medical outcomes 36-item short-form health survey (SF-36), the functional assessment of chronic illness therapy-fatigue, the fatigue severity scale (FSS), and the visual analog scale (VAS) for fatigue.

The SF-36 is a 36-item survey designed to measure 8 dimensions of health status in patients with chronic disease.⁵⁹ Items are answered using a 3- to 6-point Likert scale, or in a yes/no format. Although the SF-36 is typically administered by a trained interviewer, it relies on a patient’s interpretation of language that must be used to describe their level of fatigue, which may not capture the full range of symptoms. Also, the length of the survey makes it impractical for use in clinical practice.

The functional assessment of chronic illness therapy-fatigue survey is validated for use in psoriatic arthritis. It is similar to the SF-36 in its use of a 5-point Likert scale to answer each of 13 items. It improves on the SF-36 model by including questions about associated symptoms (ie, pain, medication side effects) that may interfere with the measurement of fatigue. It also investigates the impact of fatigue on several areas of functioning. However, it is subject to the same pitfalls of interpretation and a rigid scale with which to answer questions.

The FSS is another Likert scale–based instrument that gauges both level of fatigue and its impact using 9 items and a 7-point scale. Investigators used the FSS to uncover an association between increasing fatigue scores and depression in patients with psoriatic disease.³⁸

The VAS overcomes many of the language and interpretation issues inherent in Likert scale–based instruments. Patients are presented with a single item in which they are asked to plot their level of fatigue on a continuous line, with one end representing no fatigue and the other end the worst possible fatigue. Although VAS adds simplicity of response and removes some ambiguity from surveying, it provides no information about the functional impact of fatigue on patients. It also does not provide a method to control for other symptoms.

Treatment of Psoriasis-Associated Fatigue

Much of our understanding of psoriasis-associated fatigue arises from therapeutic clinical trials. Because increased concentrations of proinflammatory cytokines are associated with fatigue, it has been suggested that blocking these cytokines with biologic agents may relieve fatigue symptoms. For example, investigators found that patients treated with etanercept, a soluble TNF-α receptor fusion protein, had clinically meaningful improvement in fatigue compared to those receiving placebo, with sustained improvements at 96 weeks.^9,47 We must note, however, that the decrease in fatigue correlated with improvements in cutaneous/arthritic pain. Nevertheless, another study found that treatment with the same drug decreased fatigue in patients with psoriasis, even after controlling for improvements in the psoriasis area severity index score.⁴⁰ Adalimumab is another monoclonal antibody for TNF-α that has caused a notable decline in fatigue symptoms.⁴⁹

These data suggest that biologic agents are useful in the treatment of fatigue. Biologic agents are frequently administered to patients with moderate to severe psoriasis in whom more conservative treatments previously failed. However, cutaneous/arthritic disease severity is not always correlated with fatigue, so these data may urge clinicians to lower their threshold for treatment with biologics in patients with substantial fatigue symptoms. Although further investigations are necessary, we may even consider using a biologic therapy for severe fatigue in those without severe psoriatic disease.

Conclusion

Fatigue is a multidimensional symptom, impacted both directly and indirectly by psoriasis pathophysiology. The prevalence of fatigue within this patient population suggests that clinicians need to recognize the symptom as a core domain in psoriasis evaluation. Although a host of metrics have been used to quantify/qualify fatigue, there remains a need for a validated instrument for assessing fatigue in patients with psoriatic disease.

Biologic agents have proven useful in the treatment of psoriasis-associated fatigue. The central role of proinflammatory cytokines to both fatigue and psoriasis pathogenesis provide insight into potential treatment targets. Understanding the overlapping pathophysiology of psoriasis and fatigue provides an avenue for developing innovative strategies to target molecules implicated in the activation of the immune system. In the future, it may be possible to predict the severity of fatigue by measuring the levels of serum inflammatory cytokines; in fact, a new study aims to identify a panel of soluble biomarkers that can predict joint damage in psoriatic arthritis.⁶⁰ Taken together, the findings described suggest that further study is needed to characterize, measure, and treat psoriasis-associated fatigue.

Fatigue is defined as “an overwhelming, sustained sense of exhaustion and decreased capacity for physical and mental work,”¹ and it is experienced by most patients with chronic disease. There are 2 types of fatigue: acute and chronic.² Acute fatigue typically is caused by an identified insult (ie, injury), is self-limited, and is relieved by rest. Chronic fatigue, which may have multiple unknown causes, may accompany chronic illness and lasts longer than 6 months.² In chronic disease, fatigue can originate peripherally (neu romuscular dysfunction outside of the central nervous system) or centrally (neurotransmitter activity within the central nervous system). Generally, central fatigue is more relevant in patients with chronic disease; however, both central and peripheral fatigue frequently coexist.

Fatigue, even with its accepted definition, is a nonspecific symptom, making it difficult to measure. Because of its subjective nature and the lack of effective therapies, clinicians often ignore fatigue. Still, patients with chronic disease continue to cite fatigue as one of the most challenging aspects of their disease that frequently decreases their quality of life (QOL).²

Fatigue has been well recognized in a number of chronic inflammatory diseases such as rheumatoid arthritis,^3,4 systemic lupus erythematosus,⁵ fibromyalgia,⁶ and primary Sjögren syndrome.⁷ Similarly, fatigue is a frequent concern among patients with psoriasis and psoriatic arthritis.⁸ Given the prevalence and significance of psoriasis-associated fatigue,⁹ new efforts are needed to understand its pathophysiology, to develop new metrics for its evaluation, and to investigate therapeutic strategies to target it clinically. The following discussion provides an overview of the association between fatigue and psoriatic disease as well as the commonly used metrics for evaluating fatigue. Possible therapeutic agents with which to manage fatigue in this patient population also are provided.

Pathogenesis of Psoriasis-Associated Fatigue

Immunologic/Molecular Basis for Psoriasis-Associated Fatigue

Several theories aim to explain the pathophysiology of fatigue in patients with psoriatic disease. Psoriasis is a chronic inflammatory disease characterized by sharply demarcated erythematous plaques with adherent scale (Figure 1). Many in vitro studies have demonstrated the complex cytokine network that underlies the histopathologic alterations we observe in psoriatic lesions.^10,11 Until recently, psoriasis was considered a type I autoimmune disease with strong T_H1 signaling, influenced by IFN-γ, IL-2, and IL-12.¹² T_H1-producing proinflammatory cytokines, tumor necrosis factor α (TNF-α), and IFN-γ are elevated in psoriatic lesions.¹³ Studies on the efficacy of ustekinumab, a monoclonal antibody targeting IL-12 and IL-23, demonstrate the integral role of the immune system in psoriasis pathogenesis as the production of IL-12 polarizes T cells into T_H1 cells.^14,15 However, in recent years, T_H17 cells have been linked to autoimmune inflammation¹⁶ and have been localized to the dermis in psoriatic lesions.¹⁷

Among a milieu of inflammatory cytokines, IL-1 is crucial for the early differentiation of T_H17 cells.¹⁸ The IL-1 family of cytokines serve as primary mediators of inflammation with members including the IL-1 agonists (IL-1α, IL-1β),¹⁹ IL-1 receptor antagonist (IL-1RA),²⁰ and IL-1 receptor type II (IL-1RII).²⁰ The latter two inhibit IL-1 agonists from binding to their receptor (IL-1RI).^19,20 A study by Yoshinaga et al²¹ investigated the level of inflammatory cytokines within lesional and nonlesional psoriatic skin, finding elevated levels of IL-1β in lesional skin. Another study found that IL-1β expression was increased 357% within biopsied psoriasiform lesions from flaky-skin mice, a useful model to examine the hyperproliferative alterations in the skin. This same study revealed that in vivo IL-1β neutralization alleviated the psoriasiform features in these same mice, suggesting IL-1β is integral to psoriasis pathogenesis.²²

Evidence indicates that the aforementioned inflammatory mediators may contribute to psoriasis-associated fatigue. When the peripheral immune system is continuously activated, such as in psoriasis, the peripherally produced proinflammatory cytokines and subsequent immune signaling are monitored by the brain via afferent nerves, cytokine transporters at the blood-brain barrier, and IL-1 receptors on macrophages and endothelial cells of brain venules.²³ For example, subseptic doses of lipopolysaccharide injected into rats induced messenger RNA expression of IL-1β in the choroid plexus, circumventricular organs, and the meninges,²⁴ sites where cytokines can enter the blood-brain barrier via diffusion or cytokine transporters.²³ These results may suggest a pathway that relays the peripheral immune signals that underlie psoriatic disease to the brain, resulting in activation of brain circuitry that mediates various negative behavioral responses, including fatigue.²³ Following a central IL-1β infusion in mice, investigators found a significant decrease in the running performance (P<.01)²⁵; the same infusion increased lethargy, malaise, and fatigue in rats.²⁶ Interestingly, administration of IL-1RA significantly increased run time to fatigue (P<.05), supporting the hypothesis that IL-1β plays an important role in fatigue.²⁵ Other investigators found that administration of many cytokines (IL-1β, IL-6, TNF-α) into rats induced depressivelike behaviors²⁷ and suppressed locomotor activity.²⁸ Lastly, another investigation found that IL-1RI knockout mice were resistant to symptoms of sickness, such as social exploration, anorexia, immobility, and weight loss, following IL-1β injections.²⁹ Although the translatability of these studies to humans is not entirely clear, one study found that the proinflammatory cytokines IL-1 and TNF-α were elevated in patients with chronic fatigue syndrome.³⁰ Furthermore, a 2013 systematic review found that several serum inflammatory markers including IL-6 and TNF-α were elevated in patients with severe plaque psoriasis compared to healthy controls.³¹ Therefore, these shared inflammatory cytokines may contribute to and explain the pathogenesis of both fatigue and psoriasis.

Confounding Factors

Although fatigue may be partially explained by the joint effect of inflammatory mediators on both the skin and the brain, there is evidence to suggest that other confounding factors may modify this association and affect its clinical presentation. The pathophysiology of fatigue in psoriasis may not be strictly immunologic; the environmental, psychological, and physical effects of psoriasis may all contribute to and perpetuate fatigue.^9,32,33 Interestingly, the pathophysiology of psoriasis involves many cytokines also known to contribute to features of the metabolic syndrome.³⁴ For example, elevated levels of free fatty acids, TNF-α, and IL-6 act in concert to promote inflammation, alter glucose metabolism, and dysregulate endothelial cell function, contributing to dyslipidemia, insulin resistance, and cardiovascular disease.³⁵ A systematic review found a high prevalence of metabolic syndrome in patients with psoriasis and have found that those with more severe disease have an even greater risk for developing metabolic syndrome.³⁴

Numerous studies have documented that upward of 80% of patients consider psoriasis to have a major impact on their QOL.^36-38 The National Psoriasis Foundation assessed patients’ perspectives on the social, physical, and psychological aspects of their disease, finding that health-related QOL is impaired in patients with psoriatic disease.^36,39 Patients reported their disease interfered with overall emotional well-being and life enjoyment and cited feelings of anger, frustration, helplessness, embarrassment, and self-consciousness, all of which can influence fatigue.^36,39 Pain and pruritus (Figure 2) can interrupt sleep and thus may also contribute to symptoms of fatigue.⁴⁰ Patients with psoriatic disease have a higher incidence of both depression and anxiety compared with the general population. Another study found that patient-reported factors of disability, pain, and fatigue were associated with clinical depression and anxiety; however, these factors are commonly observed in this cohort of patients and thus it is unclear whether they are predictors of or the result of depression.³⁸

Furthermore, psoriatic disease leads to considerable economic burdens; one study (N=5604) found that among respondents who were not employed, 92% reported they were unemployed solely due to their psoriatic disease.³⁶ One study explored the relationship between fatigue, work disability, and psoriatic arthritis, finding that the association between fatigue and work productivity loss persisted after controlling for cutaneous/musculoskeletal activity.⁴¹ However, another investigation revealed contradicting results, finding that improvements in fatigue correlated with improvements in joint and skin pain.⁹

Therefore, we can conclude that the pathogenesis of psoriasis-associated fatigue is the result of a multifactorial immunologic, psychologic, and physiologic pathway that triggers symptoms of exhaustion and lethargy. Fatigue is a complex multidimensional symptom activated by psoriatic disease, directly by shared inflammatory cytokines and indirectly by factors of disease activity and psychiatric distress that inherently influence somatic manifestations of fatigue. Regardless of its pathogenesis, these data and observations highlight the importance of fatigue symptoms and the need for new therapeutics to target this debilitating disease.

Measurement of Fatigue in Psoriasis

A patient’s level of fatigue is not objectively quantifiable. For this reason, clinicians and investigators have relied on self-report instruments to gauge fatigue (Table).^{9,38,40,42-53} These survey instruments each have distinct advantages and disadvantages, though all are subject to common difficulties. Many rely on the literacy of patients and their interpretation of each item, which can make completing the survey difficult and yield variability between subjects. Patients are inaccurate in self-reporting even measurable characteristics such as height and weight,⁵⁴ which introduces an element of uncertainty in the reporting of subjective symptoms (ie, fatigue). Lastly, there are several biases implicit in self-reporting including recall bias, selective recall, and digit preference.⁵⁵

When analyzing fatigue due to a chronic disease, several symptoms may be misconstrued or interfere with the interpretation of fatigue. For instance, patients with multiple sclerosis may confuse neuropathy-associated muscle weakness with fatigue. These interactions can be controlled for in self-report instruments and validated through careful study of many patients. Disease-specific questionnaires have been validated for use in several diseases,^56-58 though none have been validated for cutaneous psoriasis in the absence of psoriatic arthritis. The need for validated instruments in psoriasis is great, as symptoms such as sleep disturbance and arthralgia may confound metrics of fatigue.

Thus far, 4 self-report instruments have been used to study fatigue in psoriasis: the medical outcomes 36-item short-form health survey (SF-36), the functional assessment of chronic illness therapy-fatigue, the fatigue severity scale (FSS), and the visual analog scale (VAS) for fatigue.

The SF-36 is a 36-item survey designed to measure 8 dimensions of health status in patients with chronic disease.⁵⁹ Items are answered using a 3- to 6-point Likert scale, or in a yes/no format. Although the SF-36 is typically administered by a trained interviewer, it relies on a patient’s interpretation of language that must be used to describe their level of fatigue, which may not capture the full range of symptoms. Also, the length of the survey makes it impractical for use in clinical practice.

The functional assessment of chronic illness therapy-fatigue survey is validated for use in psoriatic arthritis. It is similar to the SF-36 in its use of a 5-point Likert scale to answer each of 13 items. It improves on the SF-36 model by including questions about associated symptoms (ie, pain, medication side effects) that may interfere with the measurement of fatigue. It also investigates the impact of fatigue on several areas of functioning. However, it is subject to the same pitfalls of interpretation and a rigid scale with which to answer questions.

The FSS is another Likert scale–based instrument that gauges both level of fatigue and its impact using 9 items and a 7-point scale. Investigators used the FSS to uncover an association between increasing fatigue scores and depression in patients with psoriatic disease.³⁸

The VAS overcomes many of the language and interpretation issues inherent in Likert scale–based instruments. Patients are presented with a single item in which they are asked to plot their level of fatigue on a continuous line, with one end representing no fatigue and the other end the worst possible fatigue. Although VAS adds simplicity of response and removes some ambiguity from surveying, it provides no information about the functional impact of fatigue on patients. It also does not provide a method to control for other symptoms.

Treatment of Psoriasis-Associated Fatigue

Much of our understanding of psoriasis-associated fatigue arises from therapeutic clinical trials. Because increased concentrations of proinflammatory cytokines are associated with fatigue, it has been suggested that blocking these cytokines with biologic agents may relieve fatigue symptoms. For example, investigators found that patients treated with etanercept, a soluble TNF-α receptor fusion protein, had clinically meaningful improvement in fatigue compared to those receiving placebo, with sustained improvements at 96 weeks.^9,47 We must note, however, that the decrease in fatigue correlated with improvements in cutaneous/arthritic pain. Nevertheless, another study found that treatment with the same drug decreased fatigue in patients with psoriasis, even after controlling for improvements in the psoriasis area severity index score.⁴⁰ Adalimumab is another monoclonal antibody for TNF-α that has caused a notable decline in fatigue symptoms.⁴⁹

These data suggest that biologic agents are useful in the treatment of fatigue. Biologic agents are frequently administered to patients with moderate to severe psoriasis in whom more conservative treatments previously failed. However, cutaneous/arthritic disease severity is not always correlated with fatigue, so these data may urge clinicians to lower their threshold for treatment with biologics in patients with substantial fatigue symptoms. Although further investigations are necessary, we may even consider using a biologic therapy for severe fatigue in those without severe psoriatic disease.

Conclusion

Fatigue is a multidimensional symptom, impacted both directly and indirectly by psoriasis pathophysiology. The prevalence of fatigue within this patient population suggests that clinicians need to recognize the symptom as a core domain in psoriasis evaluation. Although a host of metrics have been used to quantify/qualify fatigue, there remains a need for a validated instrument for assessing fatigue in patients with psoriatic disease.

Biologic agents have proven useful in the treatment of psoriasis-associated fatigue. The central role of proinflammatory cytokines to both fatigue and psoriasis pathogenesis provide insight into potential treatment targets. Understanding the overlapping pathophysiology of psoriasis and fatigue provides an avenue for developing innovative strategies to target molecules implicated in the activation of the immune system. In the future, it may be possible to predict the severity of fatigue by measuring the levels of serum inflammatory cytokines; in fact, a new study aims to identify a panel of soluble biomarkers that can predict joint damage in psoriatic arthritis.⁶⁰ Taken together, the findings described suggest that further study is needed to characterize, measure, and treat psoriasis-associated fatigue.

In 1983 the Brazilian Ministry of Health launched the Program for Integrated Women’s Health Care following a worldwide trend to adopt multidisciplinary approaches that consider the complexity of women’s health.¹ Although menopause may have the greatest impact on women’s health among all the stages of life, research on this topic is limited.² Due to the aging general population, both the proportion of women who are menopausal and the total population of menopausal women have increased.² On average, women in developed countries spend one-third of their lives in menopause; thus, the physiology of menopause has become a matter of public health. In a survey of 87 women attending a specialist menopause clinic, more than 64% reported prior skin problems.³ Despite the high frequency of dermatologic signs and symptoms associated with menopause, few studies have been conducted on the subject.^3,4 In this article, we review some of the common skin disorders that occur during menopause and assess possible therapeutic and preventive skin care approaches.

Stages of Menopause

During perimenopause, irregular menstrual cycles and a series of clinical manifestations occur⁵ that may precede menopause by 2 to 8 years.⁶ The term menopausal transition is used by the World Health Organization to describe the phase of perimenopause prior to the end of menstrual periods.⁷ The World Health Organization also suggests that the term climacterium should be substituted for perimenopause in the period ranging from just before the onset of menopause to 1 year after menopause. Climacterium is the period of transition between the last years of the reproductive stage and postreproductive life, which begins with the gradual disappearance of ovarian function.⁸

Menopause is the cessation of menstrual periods due to the loss of ovarian function and is a normal physiologic process in women when it occurs after the fifth decade of life. The mean age at menopause is 51 years, and the clinical criterion used to establish the diagnosis is complete absence of menstrual periods for 12 months.⁶

Throughout a woman’s life, the total number of primordial ovarian follicles decreases and most become refractory to the actions of pituitary gonadotropins. As a result, the circulating level of estradiol progressively decreases and progesterone production by the corpus luteum becomes irregular and subsequently ceases.⁸ Increased production of follicle-stimulating hormone and luteinizing hormone occurs as a consequence. Conversely, the changes in circulating androgens are more complex and controversial.⁹ It has been documented that testosterone production is lower in postmenopausal patients and that sex hormone–binding globulin decreases and the free androgen index increases.Dehydroepiandrosterone sulfate linearly declines as a function of age, but it lacks an obvious relationship with ovarian function.¹⁰

The Importance of Hormones on the Skin

Ovarian failure and the resulting hormonal changes during menopause affect almost all aspects of women’s health and may present with signs and symptoms in nearly every body system.⁵ Symptoms are experienced differently according to ethnic, educational, and sociocultural variability. Asian American women report a low frequency of physical, psychological, and psychosomatic symptoms compared with black women.¹¹ Brazilian women have a higher prevalence of vasomotor symptoms compared to women in other developed Western countries.¹² Also, medications used during perimenopause to prevent and treat osteoporosis are capable of inducing hot flashes.¹³

Estrogens are essential for skin hydration because they increase production of glycosaminoglycans, promote an increased production of sebum, increase water retention, improve barrier function of the stratum corneum, and optimize the surface area of corneocytes. As a result, concerns about dry skin are more frequent among menopausal women who are not taking hormone replacement therapy (HRT).² Decreased estrogen reduces the polymerization of glycosaminoglycans, while elastin experiences granular degeneration and fragmentation, forming cystic spaces. In addition, there is a reduction in the microvasculature and thinning of the epidermis.^14,15

Albright et al¹⁶ noted that the skin of menopausal women with osteoporosis showed considerable atrophy, a finding subsequently supported by a study from Brincat et al.¹⁷ In menopausal women, the decrease in estrogen promotes a reduction in type I and type III collagen and a reduction in the type III collagen to type I collagen ratio compared with nonmenopausal women.¹⁸ Healthy skin is made up of type I collagen (80%, responsible for strength) to type III collagen (15%, responsible for elasticity).² However, a decrease in androgens is partially responsible for the reduction in sebum secretion, xerosis, and skin thinning or atrophy, accompanied by a reduction in blood vessels, oxygenation, and nutrition of the skin, as well as increased transepidermal water loss.^19,20 Regarding skin annexes, the decrease in estrogen causes a reduction in axillary and pubic hair. The reduction in elastic fibers results in a loss of firmness and elasticity. Moreover, with a relative predominance of androgenic hormones, vellus hair may be replaced by thicker hair.²¹

Anagen hairs have estrogen receptors in both sexes. In contrast to the α-receptor, the β-receptor largely is expressed in the papillary dermis and the hair’s bulb region; this expression could account for the occurrence of androgenetic alopecia in menopausal women. These receptors are not expressed in telogen hairs, and their role in regulating the hair cycle is unknown.²⁰ The aging of the follicular unit, resulting from the reduction of active melanocytes, promotes the appearance of gray hair. It is estimated that in 50% of men and women, half of their hair will be gray by 50 years of age.²¹ The age of onset for graying hair appears to be influenced by heredity and ethnicity. Unlike the skin, hair aging is more affected by intrinsic than extrinsic factors.^22,23

In women, hormonal changes during menopause are the main source of alterations in hair characteristics.²⁴ The identification of high concentrations of hydrogen peroxide and low levels of catalase in the stems of gray hairs have shed light on the biochemistry of hair whitening and opened new possibilities for its prevention and treatment. A change in the balance of oxidation/reduction reactions may lead to DNA damage and melanocyte apoptosis.^22,25

Osteoporosis and Vitamin D

Concerns about the worsening of or induction of osteoporosis after menopause due to the excessive use of sunscreens and vitamin D (VD) deficiency are controversial. Middle-aged women with low serum 25-hydroxyvitamin D levels (<20 ng/mL) have an increased risk of fracture during menopausal transition.²⁶ A study that measured the UV index in São Paulo, Brazil, demonstrated that environmental levels ensure sufficient production of VD from unintentional sun exposure throughout the course of the year.²⁷ Thus, concerns about the use of sunscreen affecting VD levels are not justified.^27,28

In a study that specifically focused on postmenopausal women in Recife, Brazil (which is located 10º south of the equator), a considerable prevalence of VD deficiency was found, ranging from 30% to 83% depending on age. Despite the abundance of sunlight, the researchers emphasized that the VD prevalence rates found in the study were similar to those observed in nontropical countries, such as the United States and Canada; however, the period of intentional exposure to the sun was not assessed.²⁹ Moreover, the lack of consensus on the appropriate levels of sun exposure makes it difficult to compare different countries, and thus it is recommended that minimum normal limits be regionally established.^29,30

Although it has been suggested that the use of sun protection factor 15 could, in theory, promote a 99% reduction in the synthesis of VD, other studies have failed to identify such an insufficiency.^31,32 In practice, the disparity may be explained by the large variation in the amount of sunscreen applied, by the body areas to which it is applied, and by the fact that duration of sun exposure usually is greater when using sunscreen.³¹

Considering all the evidence and taking into account that the safe limit for sun exposure that allows maximum synthesis of VD without an increased risk for skin cancer remains unknown, the American Academy of Dermatology states that intentional exposure to the sun should not be considered a main source of sun exposure and the use of sunscreen should not be discouraged. Instead, the Academy recommends using dietary sources of VD or artificial VD supplementation at doses that vary by age: between 1 and 70 years, a dose of 600 IU daily is recommended; older than 70 years, 800 IU daily.³³

Primary Skin Disorders of Menopause

Pruritus

Pruritus is the primary skin concern in women older than 65 years. Given that xerosis is the most prominent cause of pruritus, consider the possible role of menopause-related transepidermal water loss.^19,34 Regardless of the underlying cause, however, some general measures are recommended for managing pruritus in menopausal women such as using low-pH moisturizers daily, preferably after bathing; keeping nails short; wearing loose and light clothing; maintaining a comfortable ambient temperature; using humidifiers or air-conditioning devices; restricting bathing time; and avoiding hot water and high-pH sanitizers.³⁴

Hyperhidrosis

Night sweats, hyperhidrosis, and hot flashes (flushing) are common concerns in 35% to 50% of perimenopausal women and in 30% to 80% of postmenopausal women.Menopausal hyperhidrosis is classified as secondary hyperhidrosis, the symptoms of which may be alleviated by HRT, suggesting that the cause is decreasing levels of estrogen.³⁵

In addition to HRT, other treatments such as gabapentin, serotonin-norepinephrine reuptake inhibitors, and acupuncture are used to treat menopausal hyperhidrosis. One study evaluated the use of oxybutynin for 3 months in 21 patients with menopausal hyperhidrosis, and the authors concluded that the drug was effective and well tolerated in women who were nonresponsive to HRT.³⁶

Senile Alopecia

Starting at 50 years of age, scalp hairs show varying degrees of change in pigmentation, growth, and diameter. Despite the normal ratio of telogen to anagen hair, there may be a considerable reduction in follicular density. The clinical distinction between senile alopecia and androgenetic alopecia can be challenging, and the conditions may coexist.²⁴

Androgenetic Alopecia

Up to 50% of women experience androgenetic alopecia, or female pattern hair loss (FPHL), during their lives.²⁴ It is the main cause of hair loss in women, and women in perimenopause are the most affected. Hair regrowth is difficult when treatment is not instituted early in perimenopausal FPHL.²⁴ The pathogenesis involves a progressive reduction in the hair cycle, resulting in shrinkage of the hair follicles.³⁷ Unlike the pathogenesis of androgenetic alopecia in men, little is known about the role of androgens in FPHL.³⁷ The measurement of androgen levels is not recommended in the absence of symptoms of virilization or in the absence of abnormal clinical patterns or progression.²⁴

Three clinical forms of FPHL have been described: (1) Ludwig classification (diffuse central thinning concentrated in the parieto-occipital region with the frontal hairline intact), (2) Olsen classification (thinning of the central line and a consequent Christmas tree pattern), and (3) Hamilton classification (frontotemporal or vertex recession, which is seen less often than the other 2 forms). Female pattern hair loss primarily is treated with a 2% to 5% minoxidil solution,³⁸ which is able to interrupt hair loss or induce mild to moderate regrowth in 60% of patients with FPHL.³⁷ The effectiveness of the treatment should only be assessed after 1 year of use.³⁷ Contact dermatitis is the main adverse effect, but its incidence may be reduced by up to 82% by using vehicles that do not contain propylene glycol.³⁹ If the use of minoxidil solution is not possible, good results also have been reported with antiandrogen medications, such as spironolactone.⁴⁰ These drugs are especially useful in cases of hyperandrogenism.³⁷

Conventional doses of finasteride 1 mg daily, as used in men, have shown discrepant results in menopausal women.^41-45 Improvement of FPHL has been shown in studies using doses of 2.5 mg or higher for a minimum of 12 months.^42-45 The use of dutasteride, an inhibitor of 5α-reductases I and II, promotes greater inhibition (100%) of dihydrotestosterone activity than finasteride (70%) in men; however, it has not yet been approved by the US Food and Drug Administration for treatment in women.⁴⁶

Impaired Wound Healing

Wound healing also is affected by aging. Delays in healing may be more closely related to the decrease in estrogen levels than to intrinsic aging. A comparison between the expression of genes associated with healing in young and elderly men showed that most of the genes are regulated exclusively by estrogen, which could explain the higher incidence of chronic ulcers in elderly men compared to women.⁴⁷ However, menopausal women also are at risk for development of chronic ulcers.⁴⁸ Ashcroft et al⁴⁹ showed that the use of topical estrogen accelerates the healing of acute incisional wounds by increasing transforming growth factor β.

Healing of the oral mucosa is associated with a higher rate of complications and longer recovery time in women than in men. Estrogens produce anti-inflammatory effects, whereas progesterone demonstrates a proinflammatory effect. Testosterone has anti-inflammatory effects and is able to modify the proinflammatory state in the oral mucosae of menopausal women. Wound healing in menopausal women who are not receiving HRT tends to be slower than in those who are receiving HRT. Age is not necessarily an important factor in wound healing. Premenopausal and younger women have shown no notable differences in healing. Nevertheless, after menopause, differences in wound healing have been found, indicating that hormonal status may be more crucial to wound healing than age.⁵⁰

Common Dermatoses With No Hormonal Associations

Brittle Nail Syndrome

Brittle nail syndrome (BNS) affects 20% of the population with a female-to-male ratio of 2:1.The pathogenesis of BNS involves factors that affect the adhesion of corneocytes to the nail plate and alter nail formation from its matrix; the former process produces onychoschizia, whereas the latter leads to onychorrhexis.⁵¹

The normal nail contains approximately 18% water, and nails with less than 16% water content are more likely to develop weakness.⁵² Nail water content appears to be negatively influenced by repetitive occupational exposure to water, and its increase is proportional to the frequency of moisturizer use. The use of certain nail polishes and cuticle removers is considered one of the main reasons for nail weakness in those who have frequent manicures.⁵³

Management of BNS requires the correction of the precipitating cause by hydration of the nail blade, cuticle, and proximal nail folds, preferably under occlusion. Supplementation with biotin is considered highly effective by many researchers.^54,55 In a retrospective study, the use of biotin for 6 months improved BNS in 63% (22/35) of patients.⁵⁶ Recommended doses generally are more than 2.5 mg daily.⁵⁷ The use of 10% urea in nail polish once or twice daily showed that both regimens improved the morphology, consistency, and reflectiveness of the nail plate.⁵²

The use of nail polish containing hydroxypropyl chitosan, Equisetum arvense extract, and methylsulfonylmethane has been reported as a treatment of dystrophic and fragile fingernails. The treatment was evaluated in patients with nail psoriasis and it was shown to be effective in decreasing dystrophy.⁵⁸

Although women are affected twice as frequently as men,⁵¹ there are no known studies comparing the prevalence of BNS in premenopausal versus menopausal women, despite the fact that the ratio of women to men affected has been shown to increase with age.^51,52 In our clinical practice, BNS predominates among menopausal women. We believe that low estrogen levels may lead to dehydration of the nail plate.

Frontal Fibrosing Alopecia

Frontal fibrosing alopecia has a tendency to affect menopausal women.⁵⁹ Frontal fibrosing alopecia is a slow, progressive, lymphocytic cicatricial alopecia that produces symmetrical frontal or temporal recession but rarely affects other areas of the scalp. It often is associated with nonscarring alopecia of body hair or eyebrows. The cicatricial area is atrophic, pale, and surrounded by hyperpigmented skin due to long-term sun damage.^60,61

Many investigators believe it is a variant of lichen planopilaris.^62,63 Others suggest the possibility that hormonal changes characteristic of perimenopause contribute to triggering the disease. Some cases show a partial response to finasteride or dutasteride.⁶⁴ Furthermore, the lymphocytic inflammatory component of the disorder has been treated with immunomodulators, topical and intralesional corticosteroids, and hydroxychloroquine.^60,63

Telogen Effluvium

Telogen effluvium (TE) is the premature transformation of hair from the anagen phase to the telogen phase. Considered a symptom of an underlying condition (eg, endocrine, nutritional, and autoimmune disorders) rather than a full diagnosis in itself,⁶⁵ TE is characterized by diffuse hair loss confirmed by a pull test in which more than 5 hairs are removed from the scalp on tugging a section of 25 to 50 hairs.⁶⁶ If there is concurrent TE in women with androgenetic alopecia, more severe hair loss has been reported.^24,66 There may be concerns of dysesthesia of the scalp (trichodynia), especially in patients with emotional stress.⁶⁶

Most often diagnosed in women, TE in its acute form is even more common in menopausal women and lasts less than 6 months.²⁴ The acute form of TE is secondary to hemorrhage, high fever, surgery, drug use, systemic diseases, diet, or great psychological stress and typically occurs 1 to 3 months after the primary event.^24,66 The most common cause of iron deficiency at menopausal transition is malabsorption or chronic gastrointestinal bleeding. Ferritin levels below 40 µg/L are associated withhair loss with a 98% specificity and sensitivity.²⁴ Low serum levels of vitamin B₁₂ or VD also are considered important factors.^24,65,66

Chronic TE (ie, lasting more than 6 months) predominantly occurs in women aged 40 to 60 years, and its onset is abrupt. Chronic TE is considered a diagnosis of exclusion.²⁴ In 30% of cases of chronic diffuse hair loss lasting longer than 6 months, the cause is unknown.⁶⁷ The pathogenesis is poorly understood, though it is assumed to result from a reduced duration of the anagen growth phase in the absence of shrinking hair follicles.^37,68

Patient education is the most important aspect of TE management. The aim of treatment is to reduce hair loss and correct the precipitating factors. Even if the underlying cause is corrected, hair loss may continue for up to 6 months with the desired cosmetic regrowth occurring after only 12 to 18 months.^37,65 In acute secondary TE, the course of the disease is self-limited, and correction of the causal factor is sufficient. In chronic diffuse loss, identification of causal factors is more difficult and treatment involves adequate nutrition (ie, at least 1200 calories daily including 9.8 mg/kg body weight of protein) and multivitamin supplementation, minoxidil, and even antiandrogen medications.^37,65-67

Trichotillomania

Trichotillomania is the compulsive behavior of plucking strands of hair and is considered to be a poor adaptive response to stress. Although trichotillomania most commonly occurs in children, adolescents, and young adults, in older adults it is more often associated with psychopathology and is markedly more common in women.⁶⁹ The condition usually is refractory to treatment, and although the scalp usually is the primary focus of the behavior, eventually patients may pluck body hair. Menopausal women also may present with trichoteiromania in which hair loss is secondary to repeated friction that has fractured the hair shaft; this condition often is associated with scalp dysesthesia.²⁴ Trichotillomania is considered an obsessive-compulsive disorder, whereas trichoteiromania needs further investigation because it can occur secondary to many psychiatric disorders. The specific psychotherapeutic and pharmacologic treatments likely will depend on the underlying cause of the disease.⁷⁰

Treatment of Skin Disorders in Menopausal Women

Classic HRT

Several studies have used histologic analysis or ultrasonography to show that estrogens used in HRT thicken the skin or increase collagen content, whether given orally, topically, or transdermally.^71-75 In a randomized, double-blind study comparing topical estrogen versus glycolic acid, 6 months of estrogen use on only one side of the face promoted a 23% increase in epidermal thickness (P=.00458), and the use of glycolic acid stimulated a 27% increase (P=.00467). The combined use of estrogen and glycolic acid prompted a 38% increase in epidermal thickness (P=.000181), with significant differences observed for all groups compared with the controls for the reversal of histologic markers of skin aging.⁷⁶

Finally, collagen synthesis also is increased as inferred by the increase in procollagen type I and II terminal peptides.⁷⁵ Hormone replacement therapy also affects the skin’s ability to retain water and leads to a reduction in skin wrinkling; however, the effects of HRT on dyschromic alterations have not been well studied.⁷⁷ The numerous adverse effects of HRT, such as an increased incidence of cancer and cardiovascular morbidity, limit its use.

Isoflavones

Estrogen use is capable of causing morphologic changes in the aged skin of menopausal women.^19,77 Given that HRT is contraindicated for some women and can cause adverse effects or pose unacceptable risks for others, Accorsi-Neto et al¹⁵ studied the possibility of achieving the beneficial effects of estrogen with plant hormones. Oral isoflavones given to rats that had been irradiated with UV light inhibited the increased expression of UV-induced metalloproteinases, reducing collagen degradation.⁷⁸

Among the phytoestrogens, genistein, an isoflavone, is notable for its selectivity, with a high affinity for estrogen receptor β and low affinity for estrogen receptor α, which is found in the uterus and breasts. Accorsi-Neto et al¹⁵ assessed whether soy isoflavones also would reduce skin aging in women, as observed in the aforementioned rat study. After 6 months of using 100 mg of concentrated soy extract daily, the investigators noted increased thickness of the dermis and epidermis, increased dermal vasculature, an increased number of collagen and elastic fibers, and an increased papillary index. In rats, genistein increases antioxidant enzymes, such as superoxide dismutase, catalase, and glutathione.^78,79 Topical phytoestrogens also were evaluated, with promising results for increased skin thickness. In animals, the use of isoflavones also offers protection against carcinogenesis in sun-damaged skin.¹⁵

Some investigators believe that a better understanding of the mechanism of action and possible side effects of phytoestrogens is essential to allow their use as a promising antiaging alternative.⁸⁰ There is no evidence that estrogens (eg, HRT) possess antioxidant or photoprotective properties.⁷⁸ Moreover, it is possible that new selective estrogen receptor modulators will specifically affect the skin without the expected systemic effects of existing estrogens.⁸⁰

Conclusion

Although often overlooked, skin disorders are quite common during menopause. Understanding the physiology of this important period in a woman’s life is essential for developing an early and effective preventive therapeutic approach. Use of sunscreens has been questioned due to a concern about osteoporosis, but studies have not shown a connection between sunscreen use and reduced VD levels. Intentional sun exposure should not be considered a source of VD; instead, recommend dietary or artificial supplementation. Although studies have shown HRT to positively affect wound healing, reduce signs of aging, increase hydration, and yield other benefits, its use is not recommended for treating skin disorders. Isoflavones could be promising alternatives to estrogen; however, further studies are needed before their use can be recommended.

In 1983 the Brazilian Ministry of Health launched the Program for Integrated Women’s Health Care following a worldwide trend to adopt multidisciplinary approaches that consider the complexity of women’s health.¹ Although menopause may have the greatest impact on women’s health among all the stages of life, research on this topic is limited.² Due to the aging general population, both the proportion of women who are menopausal and the total population of menopausal women have increased.² On average, women in developed countries spend one-third of their lives in menopause; thus, the physiology of menopause has become a matter of public health. In a survey of 87 women attending a specialist menopause clinic, more than 64% reported prior skin problems.³ Despite the high frequency of dermatologic signs and symptoms associated with menopause, few studies have been conducted on the subject.^3,4 In this article, we review some of the common skin disorders that occur during menopause and assess possible therapeutic and preventive skin care approaches.

Stages of Menopause

During perimenopause, irregular menstrual cycles and a series of clinical manifestations occur⁵ that may precede menopause by 2 to 8 years.⁶ The term menopausal transition is used by the World Health Organization to describe the phase of perimenopause prior to the end of menstrual periods.⁷ The World Health Organization also suggests that the term climacterium should be substituted for perimenopause in the period ranging from just before the onset of menopause to 1 year after menopause. Climacterium is the period of transition between the last years of the reproductive stage and postreproductive life, which begins with the gradual disappearance of ovarian function.⁸

Menopause is the cessation of menstrual periods due to the loss of ovarian function and is a normal physiologic process in women when it occurs after the fifth decade of life. The mean age at menopause is 51 years, and the clinical criterion used to establish the diagnosis is complete absence of menstrual periods for 12 months.⁶

Throughout a woman’s life, the total number of primordial ovarian follicles decreases and most become refractory to the actions of pituitary gonadotropins. As a result, the circulating level of estradiol progressively decreases and progesterone production by the corpus luteum becomes irregular and subsequently ceases.⁸ Increased production of follicle-stimulating hormone and luteinizing hormone occurs as a consequence. Conversely, the changes in circulating androgens are more complex and controversial.⁹ It has been documented that testosterone production is lower in postmenopausal patients and that sex hormone–binding globulin decreases and the free androgen index increases.Dehydroepiandrosterone sulfate linearly declines as a function of age, but it lacks an obvious relationship with ovarian function.¹⁰

The Importance of Hormones on the Skin

Ovarian failure and the resulting hormonal changes during menopause affect almost all aspects of women’s health and may present with signs and symptoms in nearly every body system.⁵ Symptoms are experienced differently according to ethnic, educational, and sociocultural variability. Asian American women report a low frequency of physical, psychological, and psychosomatic symptoms compared with black women.¹¹ Brazilian women have a higher prevalence of vasomotor symptoms compared to women in other developed Western countries.¹² Also, medications used during perimenopause to prevent and treat osteoporosis are capable of inducing hot flashes.¹³

Estrogens are essential for skin hydration because they increase production of glycosaminoglycans, promote an increased production of sebum, increase water retention, improve barrier function of the stratum corneum, and optimize the surface area of corneocytes. As a result, concerns about dry skin are more frequent among menopausal women who are not taking hormone replacement therapy (HRT).² Decreased estrogen reduces the polymerization of glycosaminoglycans, while elastin experiences granular degeneration and fragmentation, forming cystic spaces. In addition, there is a reduction in the microvasculature and thinning of the epidermis.^14,15

Albright et al¹⁶ noted that the skin of menopausal women with osteoporosis showed considerable atrophy, a finding subsequently supported by a study from Brincat et al.¹⁷ In menopausal women, the decrease in estrogen promotes a reduction in type I and type III collagen and a reduction in the type III collagen to type I collagen ratio compared with nonmenopausal women.¹⁸ Healthy skin is made up of type I collagen (80%, responsible for strength) to type III collagen (15%, responsible for elasticity).² However, a decrease in androgens is partially responsible for the reduction in sebum secretion, xerosis, and skin thinning or atrophy, accompanied by a reduction in blood vessels, oxygenation, and nutrition of the skin, as well as increased transepidermal water loss.^19,20 Regarding skin annexes, the decrease in estrogen causes a reduction in axillary and pubic hair. The reduction in elastic fibers results in a loss of firmness and elasticity. Moreover, with a relative predominance of androgenic hormones, vellus hair may be replaced by thicker hair.²¹

Anagen hairs have estrogen receptors in both sexes. In contrast to the α-receptor, the β-receptor largely is expressed in the papillary dermis and the hair’s bulb region; this expression could account for the occurrence of androgenetic alopecia in menopausal women. These receptors are not expressed in telogen hairs, and their role in regulating the hair cycle is unknown.²⁰ The aging of the follicular unit, resulting from the reduction of active melanocytes, promotes the appearance of gray hair. It is estimated that in 50% of men and women, half of their hair will be gray by 50 years of age.²¹ The age of onset for graying hair appears to be influenced by heredity and ethnicity. Unlike the skin, hair aging is more affected by intrinsic than extrinsic factors.^22,23

In women, hormonal changes during menopause are the main source of alterations in hair characteristics.²⁴ The identification of high concentrations of hydrogen peroxide and low levels of catalase in the stems of gray hairs have shed light on the biochemistry of hair whitening and opened new possibilities for its prevention and treatment. A change in the balance of oxidation/reduction reactions may lead to DNA damage and melanocyte apoptosis.^22,25

Osteoporosis and Vitamin D

Concerns about the worsening of or induction of osteoporosis after menopause due to the excessive use of sunscreens and vitamin D (VD) deficiency are controversial. Middle-aged women with low serum 25-hydroxyvitamin D levels (<20 ng/mL) have an increased risk of fracture during menopausal transition.²⁶ A study that measured the UV index in São Paulo, Brazil, demonstrated that environmental levels ensure sufficient production of VD from unintentional sun exposure throughout the course of the year.²⁷ Thus, concerns about the use of sunscreen affecting VD levels are not justified.^27,28

In a study that specifically focused on postmenopausal women in Recife, Brazil (which is located 10º south of the equator), a considerable prevalence of VD deficiency was found, ranging from 30% to 83% depending on age. Despite the abundance of sunlight, the researchers emphasized that the VD prevalence rates found in the study were similar to those observed in nontropical countries, such as the United States and Canada; however, the period of intentional exposure to the sun was not assessed.²⁹ Moreover, the lack of consensus on the appropriate levels of sun exposure makes it difficult to compare different countries, and thus it is recommended that minimum normal limits be regionally established.^29,30

Although it has been suggested that the use of sun protection factor 15 could, in theory, promote a 99% reduction in the synthesis of VD, other studies have failed to identify such an insufficiency.^31,32 In practice, the disparity may be explained by the large variation in the amount of sunscreen applied, by the body areas to which it is applied, and by the fact that duration of sun exposure usually is greater when using sunscreen.³¹

Considering all the evidence and taking into account that the safe limit for sun exposure that allows maximum synthesis of VD without an increased risk for skin cancer remains unknown, the American Academy of Dermatology states that intentional exposure to the sun should not be considered a main source of sun exposure and the use of sunscreen should not be discouraged. Instead, the Academy recommends using dietary sources of VD or artificial VD supplementation at doses that vary by age: between 1 and 70 years, a dose of 600 IU daily is recommended; older than 70 years, 800 IU daily.³³

Primary Skin Disorders of Menopause

Pruritus

Pruritus is the primary skin concern in women older than 65 years. Given that xerosis is the most prominent cause of pruritus, consider the possible role of menopause-related transepidermal water loss.^19,34 Regardless of the underlying cause, however, some general measures are recommended for managing pruritus in menopausal women such as using low-pH moisturizers daily, preferably after bathing; keeping nails short; wearing loose and light clothing; maintaining a comfortable ambient temperature; using humidifiers or air-conditioning devices; restricting bathing time; and avoiding hot water and high-pH sanitizers.³⁴

Hyperhidrosis

Night sweats, hyperhidrosis, and hot flashes (flushing) are common concerns in 35% to 50% of perimenopausal women and in 30% to 80% of postmenopausal women.Menopausal hyperhidrosis is classified as secondary hyperhidrosis, the symptoms of which may be alleviated by HRT, suggesting that the cause is decreasing levels of estrogen.³⁵

In addition to HRT, other treatments such as gabapentin, serotonin-norepinephrine reuptake inhibitors, and acupuncture are used to treat menopausal hyperhidrosis. One study evaluated the use of oxybutynin for 3 months in 21 patients with menopausal hyperhidrosis, and the authors concluded that the drug was effective and well tolerated in women who were nonresponsive to HRT.³⁶

Senile Alopecia

Starting at 50 years of age, scalp hairs show varying degrees of change in pigmentation, growth, and diameter. Despite the normal ratio of telogen to anagen hair, there may be a considerable reduction in follicular density. The clinical distinction between senile alopecia and androgenetic alopecia can be challenging, and the conditions may coexist.²⁴

Androgenetic Alopecia

Up to 50% of women experience androgenetic alopecia, or female pattern hair loss (FPHL), during their lives.²⁴ It is the main cause of hair loss in women, and women in perimenopause are the most affected. Hair regrowth is difficult when treatment is not instituted early in perimenopausal FPHL.²⁴ The pathogenesis involves a progressive reduction in the hair cycle, resulting in shrinkage of the hair follicles.³⁷ Unlike the pathogenesis of androgenetic alopecia in men, little is known about the role of androgens in FPHL.³⁷ The measurement of androgen levels is not recommended in the absence of symptoms of virilization or in the absence of abnormal clinical patterns or progression.²⁴

Three clinical forms of FPHL have been described: (1) Ludwig classification (diffuse central thinning concentrated in the parieto-occipital region with the frontal hairline intact), (2) Olsen classification (thinning of the central line and a consequent Christmas tree pattern), and (3) Hamilton classification (frontotemporal or vertex recession, which is seen less often than the other 2 forms). Female pattern hair loss primarily is treated with a 2% to 5% minoxidil solution,³⁸ which is able to interrupt hair loss or induce mild to moderate regrowth in 60% of patients with FPHL.³⁷ The effectiveness of the treatment should only be assessed after 1 year of use.³⁷ Contact dermatitis is the main adverse effect, but its incidence may be reduced by up to 82% by using vehicles that do not contain propylene glycol.³⁹ If the use of minoxidil solution is not possible, good results also have been reported with antiandrogen medications, such as spironolactone.⁴⁰ These drugs are especially useful in cases of hyperandrogenism.³⁷

Conventional doses of finasteride 1 mg daily, as used in men, have shown discrepant results in menopausal women.^41-45 Improvement of FPHL has been shown in studies using doses of 2.5 mg or higher for a minimum of 12 months.^42-45 The use of dutasteride, an inhibitor of 5α-reductases I and II, promotes greater inhibition (100%) of dihydrotestosterone activity than finasteride (70%) in men; however, it has not yet been approved by the US Food and Drug Administration for treatment in women.⁴⁶

Impaired Wound Healing

Wound healing also is affected by aging. Delays in healing may be more closely related to the decrease in estrogen levels than to intrinsic aging. A comparison between the expression of genes associated with healing in young and elderly men showed that most of the genes are regulated exclusively by estrogen, which could explain the higher incidence of chronic ulcers in elderly men compared to women.⁴⁷ However, menopausal women also are at risk for development of chronic ulcers.⁴⁸ Ashcroft et al⁴⁹ showed that the use of topical estrogen accelerates the healing of acute incisional wounds by increasing transforming growth factor β.

Healing of the oral mucosa is associated with a higher rate of complications and longer recovery time in women than in men. Estrogens produce anti-inflammatory effects, whereas progesterone demonstrates a proinflammatory effect. Testosterone has anti-inflammatory effects and is able to modify the proinflammatory state in the oral mucosae of menopausal women. Wound healing in menopausal women who are not receiving HRT tends to be slower than in those who are receiving HRT. Age is not necessarily an important factor in wound healing. Premenopausal and younger women have shown no notable differences in healing. Nevertheless, after menopause, differences in wound healing have been found, indicating that hormonal status may be more crucial to wound healing than age.⁵⁰

Common Dermatoses With No Hormonal Associations

Brittle Nail Syndrome

Brittle nail syndrome (BNS) affects 20% of the population with a female-to-male ratio of 2:1.The pathogenesis of BNS involves factors that affect the adhesion of corneocytes to the nail plate and alter nail formation from its matrix; the former process produces onychoschizia, whereas the latter leads to onychorrhexis.⁵¹

The normal nail contains approximately 18% water, and nails with less than 16% water content are more likely to develop weakness.⁵² Nail water content appears to be negatively influenced by repetitive occupational exposure to water, and its increase is proportional to the frequency of moisturizer use. The use of certain nail polishes and cuticle removers is considered one of the main reasons for nail weakness in those who have frequent manicures.⁵³

Management of BNS requires the correction of the precipitating cause by hydration of the nail blade, cuticle, and proximal nail folds, preferably under occlusion. Supplementation with biotin is considered highly effective by many researchers.^54,55 In a retrospective study, the use of biotin for 6 months improved BNS in 63% (22/35) of patients.⁵⁶ Recommended doses generally are more than 2.5 mg daily.⁵⁷ The use of 10% urea in nail polish once or twice daily showed that both regimens improved the morphology, consistency, and reflectiveness of the nail plate.⁵²

The use of nail polish containing hydroxypropyl chitosan, Equisetum arvense extract, and methylsulfonylmethane has been reported as a treatment of dystrophic and fragile fingernails. The treatment was evaluated in patients with nail psoriasis and it was shown to be effective in decreasing dystrophy.⁵⁸

Although women are affected twice as frequently as men,⁵¹ there are no known studies comparing the prevalence of BNS in premenopausal versus menopausal women, despite the fact that the ratio of women to men affected has been shown to increase with age.^51,52 In our clinical practice, BNS predominates among menopausal women. We believe that low estrogen levels may lead to dehydration of the nail plate.

Frontal Fibrosing Alopecia

Frontal fibrosing alopecia has a tendency to affect menopausal women.⁵⁹ Frontal fibrosing alopecia is a slow, progressive, lymphocytic cicatricial alopecia that produces symmetrical frontal or temporal recession but rarely affects other areas of the scalp. It often is associated with nonscarring alopecia of body hair or eyebrows. The cicatricial area is atrophic, pale, and surrounded by hyperpigmented skin due to long-term sun damage.^60,61

Many investigators believe it is a variant of lichen planopilaris.^62,63 Others suggest the possibility that hormonal changes characteristic of perimenopause contribute to triggering the disease. Some cases show a partial response to finasteride or dutasteride.⁶⁴ Furthermore, the lymphocytic inflammatory component of the disorder has been treated with immunomodulators, topical and intralesional corticosteroids, and hydroxychloroquine.^60,63

Telogen Effluvium

Telogen effluvium (TE) is the premature transformation of hair from the anagen phase to the telogen phase. Considered a symptom of an underlying condition (eg, endocrine, nutritional, and autoimmune disorders) rather than a full diagnosis in itself,⁶⁵ TE is characterized by diffuse hair loss confirmed by a pull test in which more than 5 hairs are removed from the scalp on tugging a section of 25 to 50 hairs.⁶⁶ If there is concurrent TE in women with androgenetic alopecia, more severe hair loss has been reported.^24,66 There may be concerns of dysesthesia of the scalp (trichodynia), especially in patients with emotional stress.⁶⁶

Most often diagnosed in women, TE in its acute form is even more common in menopausal women and lasts less than 6 months.²⁴ The acute form of TE is secondary to hemorrhage, high fever, surgery, drug use, systemic diseases, diet, or great psychological stress and typically occurs 1 to 3 months after the primary event.^24,66 The most common cause of iron deficiency at menopausal transition is malabsorption or chronic gastrointestinal bleeding. Ferritin levels below 40 µg/L are associated withhair loss with a 98% specificity and sensitivity.²⁴ Low serum levels of vitamin B₁₂ or VD also are considered important factors.^24,65,66

Chronic TE (ie, lasting more than 6 months) predominantly occurs in women aged 40 to 60 years, and its onset is abrupt. Chronic TE is considered a diagnosis of exclusion.²⁴ In 30% of cases of chronic diffuse hair loss lasting longer than 6 months, the cause is unknown.⁶⁷ The pathogenesis is poorly understood, though it is assumed to result from a reduced duration of the anagen growth phase in the absence of shrinking hair follicles.^37,68

Patient education is the most important aspect of TE management. The aim of treatment is to reduce hair loss and correct the precipitating factors. Even if the underlying cause is corrected, hair loss may continue for up to 6 months with the desired cosmetic regrowth occurring after only 12 to 18 months.^37,65 In acute secondary TE, the course of the disease is self-limited, and correction of the causal factor is sufficient. In chronic diffuse loss, identification of causal factors is more difficult and treatment involves adequate nutrition (ie, at least 1200 calories daily including 9.8 mg/kg body weight of protein) and multivitamin supplementation, minoxidil, and even antiandrogen medications.^37,65-67

Trichotillomania

Trichotillomania is the compulsive behavior of plucking strands of hair and is considered to be a poor adaptive response to stress. Although trichotillomania most commonly occurs in children, adolescents, and young adults, in older adults it is more often associated with psychopathology and is markedly more common in women.⁶⁹ The condition usually is refractory to treatment, and although the scalp usually is the primary focus of the behavior, eventually patients may pluck body hair. Menopausal women also may present with trichoteiromania in which hair loss is secondary to repeated friction that has fractured the hair shaft; this condition often is associated with scalp dysesthesia.²⁴ Trichotillomania is considered an obsessive-compulsive disorder, whereas trichoteiromania needs further investigation because it can occur secondary to many psychiatric disorders. The specific psychotherapeutic and pharmacologic treatments likely will depend on the underlying cause of the disease.⁷⁰

Treatment of Skin Disorders in Menopausal Women

Classic HRT

Several studies have used histologic analysis or ultrasonography to show that estrogens used in HRT thicken the skin or increase collagen content, whether given orally, topically, or transdermally.^71-75 In a randomized, double-blind study comparing topical estrogen versus glycolic acid, 6 months of estrogen use on only one side of the face promoted a 23% increase in epidermal thickness (P=.00458), and the use of glycolic acid stimulated a 27% increase (P=.00467). The combined use of estrogen and glycolic acid prompted a 38% increase in epidermal thickness (P=.000181), with significant differences observed for all groups compared with the controls for the reversal of histologic markers of skin aging.⁷⁶

Finally, collagen synthesis also is increased as inferred by the increase in procollagen type I and II terminal peptides.⁷⁵ Hormone replacement therapy also affects the skin’s ability to retain water and leads to a reduction in skin wrinkling; however, the effects of HRT on dyschromic alterations have not been well studied.⁷⁷ The numerous adverse effects of HRT, such as an increased incidence of cancer and cardiovascular morbidity, limit its use.

Isoflavones

Estrogen use is capable of causing morphologic changes in the aged skin of menopausal women.^19,77 Given that HRT is contraindicated for some women and can cause adverse effects or pose unacceptable risks for others, Accorsi-Neto et al¹⁵ studied the possibility of achieving the beneficial effects of estrogen with plant hormones. Oral isoflavones given to rats that had been irradiated with UV light inhibited the increased expression of UV-induced metalloproteinases, reducing collagen degradation.⁷⁸

Among the phytoestrogens, genistein, an isoflavone, is notable for its selectivity, with a high affinity for estrogen receptor β and low affinity for estrogen receptor α, which is found in the uterus and breasts. Accorsi-Neto et al¹⁵ assessed whether soy isoflavones also would reduce skin aging in women, as observed in the aforementioned rat study. After 6 months of using 100 mg of concentrated soy extract daily, the investigators noted increased thickness of the dermis and epidermis, increased dermal vasculature, an increased number of collagen and elastic fibers, and an increased papillary index. In rats, genistein increases antioxidant enzymes, such as superoxide dismutase, catalase, and glutathione.^78,79 Topical phytoestrogens also were evaluated, with promising results for increased skin thickness. In animals, the use of isoflavones also offers protection against carcinogenesis in sun-damaged skin.¹⁵

Some investigators believe that a better understanding of the mechanism of action and possible side effects of phytoestrogens is essential to allow their use as a promising antiaging alternative.⁸⁰ There is no evidence that estrogens (eg, HRT) possess antioxidant or photoprotective properties.⁷⁸ Moreover, it is possible that new selective estrogen receptor modulators will specifically affect the skin without the expected systemic effects of existing estrogens.⁸⁰

Conclusion

Although often overlooked, skin disorders are quite common during menopause. Understanding the physiology of this important period in a woman’s life is essential for developing an early and effective preventive therapeutic approach. Use of sunscreens has been questioned due to a concern about osteoporosis, but studies have not shown a connection between sunscreen use and reduced VD levels. Intentional sun exposure should not be considered a source of VD; instead, recommend dietary or artificial supplementation. Although studies have shown HRT to positively affect wound healing, reduce signs of aging, increase hydration, and yield other benefits, its use is not recommended for treating skin disorders. Isoflavones could be promising alternatives to estrogen; however, further studies are needed before their use can be recommended.

In 1983 the Brazilian Ministry of Health launched the Program for Integrated Women’s Health Care following a worldwide trend to adopt multidisciplinary approaches that consider the complexity of women’s health.¹ Although menopause may have the greatest impact on women’s health among all the stages of life, research on this topic is limited.² Due to the aging general population, both the proportion of women who are menopausal and the total population of menopausal women have increased.² On average, women in developed countries spend one-third of their lives in menopause; thus, the physiology of menopause has become a matter of public health. In a survey of 87 women attending a specialist menopause clinic, more than 64% reported prior skin problems.³ Despite the high frequency of dermatologic signs and symptoms associated with menopause, few studies have been conducted on the subject.^3,4 In this article, we review some of the common skin disorders that occur during menopause and assess possible therapeutic and preventive skin care approaches.

Stages of Menopause

During perimenopause, irregular menstrual cycles and a series of clinical manifestations occur⁵ that may precede menopause by 2 to 8 years.⁶ The term menopausal transition is used by the World Health Organization to describe the phase of perimenopause prior to the end of menstrual periods.⁷ The World Health Organization also suggests that the term climacterium should be substituted for perimenopause in the period ranging from just before the onset of menopause to 1 year after menopause. Climacterium is the period of transition between the last years of the reproductive stage and postreproductive life, which begins with the gradual disappearance of ovarian function.⁸

Menopause is the cessation of menstrual periods due to the loss of ovarian function and is a normal physiologic process in women when it occurs after the fifth decade of life. The mean age at menopause is 51 years, and the clinical criterion used to establish the diagnosis is complete absence of menstrual periods for 12 months.⁶

Throughout a woman’s life, the total number of primordial ovarian follicles decreases and most become refractory to the actions of pituitary gonadotropins. As a result, the circulating level of estradiol progressively decreases and progesterone production by the corpus luteum becomes irregular and subsequently ceases.⁸ Increased production of follicle-stimulating hormone and luteinizing hormone occurs as a consequence. Conversely, the changes in circulating androgens are more complex and controversial.⁹ It has been documented that testosterone production is lower in postmenopausal patients and that sex hormone–binding globulin decreases and the free androgen index increases.Dehydroepiandrosterone sulfate linearly declines as a function of age, but it lacks an obvious relationship with ovarian function.¹⁰

The Importance of Hormones on the Skin

Ovarian failure and the resulting hormonal changes during menopause affect almost all aspects of women’s health and may present with signs and symptoms in nearly every body system.⁵ Symptoms are experienced differently according to ethnic, educational, and sociocultural variability. Asian American women report a low frequency of physical, psychological, and psychosomatic symptoms compared with black women.¹¹ Brazilian women have a higher prevalence of vasomotor symptoms compared to women in other developed Western countries.¹² Also, medications used during perimenopause to prevent and treat osteoporosis are capable of inducing hot flashes.¹³

Estrogens are essential for skin hydration because they increase production of glycosaminoglycans, promote an increased production of sebum, increase water retention, improve barrier function of the stratum corneum, and optimize the surface area of corneocytes. As a result, concerns about dry skin are more frequent among menopausal women who are not taking hormone replacement therapy (HRT).² Decreased estrogen reduces the polymerization of glycosaminoglycans, while elastin experiences granular degeneration and fragmentation, forming cystic spaces. In addition, there is a reduction in the microvasculature and thinning of the epidermis.^14,15

Albright et al¹⁶ noted that the skin of menopausal women with osteoporosis showed considerable atrophy, a finding subsequently supported by a study from Brincat et al.¹⁷ In menopausal women, the decrease in estrogen promotes a reduction in type I and type III collagen and a reduction in the type III collagen to type I collagen ratio compared with nonmenopausal women.¹⁸ Healthy skin is made up of type I collagen (80%, responsible for strength) to type III collagen (15%, responsible for elasticity).² However, a decrease in androgens is partially responsible for the reduction in sebum secretion, xerosis, and skin thinning or atrophy, accompanied by a reduction in blood vessels, oxygenation, and nutrition of the skin, as well as increased transepidermal water loss.^19,20 Regarding skin annexes, the decrease in estrogen causes a reduction in axillary and pubic hair. The reduction in elastic fibers results in a loss of firmness and elasticity. Moreover, with a relative predominance of androgenic hormones, vellus hair may be replaced by thicker hair.²¹

Anagen hairs have estrogen receptors in both sexes. In contrast to the α-receptor, the β-receptor largely is expressed in the papillary dermis and the hair’s bulb region; this expression could account for the occurrence of androgenetic alopecia in menopausal women. These receptors are not expressed in telogen hairs, and their role in regulating the hair cycle is unknown.²⁰ The aging of the follicular unit, resulting from the reduction of active melanocytes, promotes the appearance of gray hair. It is estimated that in 50% of men and women, half of their hair will be gray by 50 years of age.²¹ The age of onset for graying hair appears to be influenced by heredity and ethnicity. Unlike the skin, hair aging is more affected by intrinsic than extrinsic factors.^22,23

In women, hormonal changes during menopause are the main source of alterations in hair characteristics.²⁴ The identification of high concentrations of hydrogen peroxide and low levels of catalase in the stems of gray hairs have shed light on the biochemistry of hair whitening and opened new possibilities for its prevention and treatment. A change in the balance of oxidation/reduction reactions may lead to DNA damage and melanocyte apoptosis.^22,25

Osteoporosis and Vitamin D

Concerns about the worsening of or induction of osteoporosis after menopause due to the excessive use of sunscreens and vitamin D (VD) deficiency are controversial. Middle-aged women with low serum 25-hydroxyvitamin D levels (<20 ng/mL) have an increased risk of fracture during menopausal transition.²⁶ A study that measured the UV index in São Paulo, Brazil, demonstrated that environmental levels ensure sufficient production of VD from unintentional sun exposure throughout the course of the year.²⁷ Thus, concerns about the use of sunscreen affecting VD levels are not justified.^27,28

In a study that specifically focused on postmenopausal women in Recife, Brazil (which is located 10º south of the equator), a considerable prevalence of VD deficiency was found, ranging from 30% to 83% depending on age. Despite the abundance of sunlight, the researchers emphasized that the VD prevalence rates found in the study were similar to those observed in nontropical countries, such as the United States and Canada; however, the period of intentional exposure to the sun was not assessed.²⁹ Moreover, the lack of consensus on the appropriate levels of sun exposure makes it difficult to compare different countries, and thus it is recommended that minimum normal limits be regionally established.^29,30

Although it has been suggested that the use of sun protection factor 15 could, in theory, promote a 99% reduction in the synthesis of VD, other studies have failed to identify such an insufficiency.^31,32 In practice, the disparity may be explained by the large variation in the amount of sunscreen applied, by the body areas to which it is applied, and by the fact that duration of sun exposure usually is greater when using sunscreen.³¹

Considering all the evidence and taking into account that the safe limit for sun exposure that allows maximum synthesis of VD without an increased risk for skin cancer remains unknown, the American Academy of Dermatology states that intentional exposure to the sun should not be considered a main source of sun exposure and the use of sunscreen should not be discouraged. Instead, the Academy recommends using dietary sources of VD or artificial VD supplementation at doses that vary by age: between 1 and 70 years, a dose of 600 IU daily is recommended; older than 70 years, 800 IU daily.³³

Primary Skin Disorders of Menopause

Pruritus

Pruritus is the primary skin concern in women older than 65 years. Given that xerosis is the most prominent cause of pruritus, consider the possible role of menopause-related transepidermal water loss.^19,34 Regardless of the underlying cause, however, some general measures are recommended for managing pruritus in menopausal women such as using low-pH moisturizers daily, preferably after bathing; keeping nails short; wearing loose and light clothing; maintaining a comfortable ambient temperature; using humidifiers or air-conditioning devices; restricting bathing time; and avoiding hot water and high-pH sanitizers.³⁴

Hyperhidrosis

Night sweats, hyperhidrosis, and hot flashes (flushing) are common concerns in 35% to 50% of perimenopausal women and in 30% to 80% of postmenopausal women.Menopausal hyperhidrosis is classified as secondary hyperhidrosis, the symptoms of which may be alleviated by HRT, suggesting that the cause is decreasing levels of estrogen.³⁵

In addition to HRT, other treatments such as gabapentin, serotonin-norepinephrine reuptake inhibitors, and acupuncture are used to treat menopausal hyperhidrosis. One study evaluated the use of oxybutynin for 3 months in 21 patients with menopausal hyperhidrosis, and the authors concluded that the drug was effective and well tolerated in women who were nonresponsive to HRT.³⁶

Senile Alopecia

Starting at 50 years of age, scalp hairs show varying degrees of change in pigmentation, growth, and diameter. Despite the normal ratio of telogen to anagen hair, there may be a considerable reduction in follicular density. The clinical distinction between senile alopecia and androgenetic alopecia can be challenging, and the conditions may coexist.²⁴

Androgenetic Alopecia

Up to 50% of women experience androgenetic alopecia, or female pattern hair loss (FPHL), during their lives.²⁴ It is the main cause of hair loss in women, and women in perimenopause are the most affected. Hair regrowth is difficult when treatment is not instituted early in perimenopausal FPHL.²⁴ The pathogenesis involves a progressive reduction in the hair cycle, resulting in shrinkage of the hair follicles.³⁷ Unlike the pathogenesis of androgenetic alopecia in men, little is known about the role of androgens in FPHL.³⁷ The measurement of androgen levels is not recommended in the absence of symptoms of virilization or in the absence of abnormal clinical patterns or progression.²⁴

Three clinical forms of FPHL have been described: (1) Ludwig classification (diffuse central thinning concentrated in the parieto-occipital region with the frontal hairline intact), (2) Olsen classification (thinning of the central line and a consequent Christmas tree pattern), and (3) Hamilton classification (frontotemporal or vertex recession, which is seen less often than the other 2 forms). Female pattern hair loss primarily is treated with a 2% to 5% minoxidil solution,³⁸ which is able to interrupt hair loss or induce mild to moderate regrowth in 60% of patients with FPHL.³⁷ The effectiveness of the treatment should only be assessed after 1 year of use.³⁷ Contact dermatitis is the main adverse effect, but its incidence may be reduced by up to 82% by using vehicles that do not contain propylene glycol.³⁹ If the use of minoxidil solution is not possible, good results also have been reported with antiandrogen medications, such as spironolactone.⁴⁰ These drugs are especially useful in cases of hyperandrogenism.³⁷

Conventional doses of finasteride 1 mg daily, as used in men, have shown discrepant results in menopausal women.^41-45 Improvement of FPHL has been shown in studies using doses of 2.5 mg or higher for a minimum of 12 months.^42-45 The use of dutasteride, an inhibitor of 5α-reductases I and II, promotes greater inhibition (100%) of dihydrotestosterone activity than finasteride (70%) in men; however, it has not yet been approved by the US Food and Drug Administration for treatment in women.⁴⁶

Impaired Wound Healing

Wound healing also is affected by aging. Delays in healing may be more closely related to the decrease in estrogen levels than to intrinsic aging. A comparison between the expression of genes associated with healing in young and elderly men showed that most of the genes are regulated exclusively by estrogen, which could explain the higher incidence of chronic ulcers in elderly men compared to women.⁴⁷ However, menopausal women also are at risk for development of chronic ulcers.⁴⁸ Ashcroft et al⁴⁹ showed that the use of topical estrogen accelerates the healing of acute incisional wounds by increasing transforming growth factor β.

Healing of the oral mucosa is associated with a higher rate of complications and longer recovery time in women than in men. Estrogens produce anti-inflammatory effects, whereas progesterone demonstrates a proinflammatory effect. Testosterone has anti-inflammatory effects and is able to modify the proinflammatory state in the oral mucosae of menopausal women. Wound healing in menopausal women who are not receiving HRT tends to be slower than in those who are receiving HRT. Age is not necessarily an important factor in wound healing. Premenopausal and younger women have shown no notable differences in healing. Nevertheless, after menopause, differences in wound healing have been found, indicating that hormonal status may be more crucial to wound healing than age.⁵⁰

Common Dermatoses With No Hormonal Associations

Brittle Nail Syndrome

Brittle nail syndrome (BNS) affects 20% of the population with a female-to-male ratio of 2:1.The pathogenesis of BNS involves factors that affect the adhesion of corneocytes to the nail plate and alter nail formation from its matrix; the former process produces onychoschizia, whereas the latter leads to onychorrhexis.⁵¹

The normal nail contains approximately 18% water, and nails with less than 16% water content are more likely to develop weakness.⁵² Nail water content appears to be negatively influenced by repetitive occupational exposure to water, and its increase is proportional to the frequency of moisturizer use. The use of certain nail polishes and cuticle removers is considered one of the main reasons for nail weakness in those who have frequent manicures.⁵³

Management of BNS requires the correction of the precipitating cause by hydration of the nail blade, cuticle, and proximal nail folds, preferably under occlusion. Supplementation with biotin is considered highly effective by many researchers.^54,55 In a retrospective study, the use of biotin for 6 months improved BNS in 63% (22/35) of patients.⁵⁶ Recommended doses generally are more than 2.5 mg daily.⁵⁷ The use of 10% urea in nail polish once or twice daily showed that both regimens improved the morphology, consistency, and reflectiveness of the nail plate.⁵²

The use of nail polish containing hydroxypropyl chitosan, Equisetum arvense extract, and methylsulfonylmethane has been reported as a treatment of dystrophic and fragile fingernails. The treatment was evaluated in patients with nail psoriasis and it was shown to be effective in decreasing dystrophy.⁵⁸

Although women are affected twice as frequently as men,⁵¹ there are no known studies comparing the prevalence of BNS in premenopausal versus menopausal women, despite the fact that the ratio of women to men affected has been shown to increase with age.^51,52 In our clinical practice, BNS predominates among menopausal women. We believe that low estrogen levels may lead to dehydration of the nail plate.

Frontal Fibrosing Alopecia

Frontal fibrosing alopecia has a tendency to affect menopausal women.⁵⁹ Frontal fibrosing alopecia is a slow, progressive, lymphocytic cicatricial alopecia that produces symmetrical frontal or temporal recession but rarely affects other areas of the scalp. It often is associated with nonscarring alopecia of body hair or eyebrows. The cicatricial area is atrophic, pale, and surrounded by hyperpigmented skin due to long-term sun damage.^60,61

Many investigators believe it is a variant of lichen planopilaris.^62,63 Others suggest the possibility that hormonal changes characteristic of perimenopause contribute to triggering the disease. Some cases show a partial response to finasteride or dutasteride.⁶⁴ Furthermore, the lymphocytic inflammatory component of the disorder has been treated with immunomodulators, topical and intralesional corticosteroids, and hydroxychloroquine.^60,63

Telogen Effluvium

Telogen effluvium (TE) is the premature transformation of hair from the anagen phase to the telogen phase. Considered a symptom of an underlying condition (eg, endocrine, nutritional, and autoimmune disorders) rather than a full diagnosis in itself,⁶⁵ TE is characterized by diffuse hair loss confirmed by a pull test in which more than 5 hairs are removed from the scalp on tugging a section of 25 to 50 hairs.⁶⁶ If there is concurrent TE in women with androgenetic alopecia, more severe hair loss has been reported.^24,66 There may be concerns of dysesthesia of the scalp (trichodynia), especially in patients with emotional stress.⁶⁶

Most often diagnosed in women, TE in its acute form is even more common in menopausal women and lasts less than 6 months.²⁴ The acute form of TE is secondary to hemorrhage, high fever, surgery, drug use, systemic diseases, diet, or great psychological stress and typically occurs 1 to 3 months after the primary event.^24,66 The most common cause of iron deficiency at menopausal transition is malabsorption or chronic gastrointestinal bleeding. Ferritin levels below 40 µg/L are associated withhair loss with a 98% specificity and sensitivity.²⁴ Low serum levels of vitamin B₁₂ or VD also are considered important factors.^24,65,66

Chronic TE (ie, lasting more than 6 months) predominantly occurs in women aged 40 to 60 years, and its onset is abrupt. Chronic TE is considered a diagnosis of exclusion.²⁴ In 30% of cases of chronic diffuse hair loss lasting longer than 6 months, the cause is unknown.⁶⁷ The pathogenesis is poorly understood, though it is assumed to result from a reduced duration of the anagen growth phase in the absence of shrinking hair follicles.^37,68

Patient education is the most important aspect of TE management. The aim of treatment is to reduce hair loss and correct the precipitating factors. Even if the underlying cause is corrected, hair loss may continue for up to 6 months with the desired cosmetic regrowth occurring after only 12 to 18 months.^37,65 In acute secondary TE, the course of the disease is self-limited, and correction of the causal factor is sufficient. In chronic diffuse loss, identification of causal factors is more difficult and treatment involves adequate nutrition (ie, at least 1200 calories daily including 9.8 mg/kg body weight of protein) and multivitamin supplementation, minoxidil, and even antiandrogen medications.^37,65-67

Trichotillomania

Trichotillomania is the compulsive behavior of plucking strands of hair and is considered to be a poor adaptive response to stress. Although trichotillomania most commonly occurs in children, adolescents, and young adults, in older adults it is more often associated with psychopathology and is markedly more common in women.⁶⁹ The condition usually is refractory to treatment, and although the scalp usually is the primary focus of the behavior, eventually patients may pluck body hair. Menopausal women also may present with trichoteiromania in which hair loss is secondary to repeated friction that has fractured the hair shaft; this condition often is associated with scalp dysesthesia.²⁴ Trichotillomania is considered an obsessive-compulsive disorder, whereas trichoteiromania needs further investigation because it can occur secondary to many psychiatric disorders. The specific psychotherapeutic and pharmacologic treatments likely will depend on the underlying cause of the disease.⁷⁰

Treatment of Skin Disorders in Menopausal Women

Classic HRT

Several studies have used histologic analysis or ultrasonography to show that estrogens used in HRT thicken the skin or increase collagen content, whether given orally, topically, or transdermally.^71-75 In a randomized, double-blind study comparing topical estrogen versus glycolic acid, 6 months of estrogen use on only one side of the face promoted a 23% increase in epidermal thickness (P=.00458), and the use of glycolic acid stimulated a 27% increase (P=.00467). The combined use of estrogen and glycolic acid prompted a 38% increase in epidermal thickness (P=.000181), with significant differences observed for all groups compared with the controls for the reversal of histologic markers of skin aging.⁷⁶

Finally, collagen synthesis also is increased as inferred by the increase in procollagen type I and II terminal peptides.⁷⁵ Hormone replacement therapy also affects the skin’s ability to retain water and leads to a reduction in skin wrinkling; however, the effects of HRT on dyschromic alterations have not been well studied.⁷⁷ The numerous adverse effects of HRT, such as an increased incidence of cancer and cardiovascular morbidity, limit its use.

Isoflavones

Estrogen use is capable of causing morphologic changes in the aged skin of menopausal women.^19,77 Given that HRT is contraindicated for some women and can cause adverse effects or pose unacceptable risks for others, Accorsi-Neto et al¹⁵ studied the possibility of achieving the beneficial effects of estrogen with plant hormones. Oral isoflavones given to rats that had been irradiated with UV light inhibited the increased expression of UV-induced metalloproteinases, reducing collagen degradation.⁷⁸

Among the phytoestrogens, genistein, an isoflavone, is notable for its selectivity, with a high affinity for estrogen receptor β and low affinity for estrogen receptor α, which is found in the uterus and breasts. Accorsi-Neto et al¹⁵ assessed whether soy isoflavones also would reduce skin aging in women, as observed in the aforementioned rat study. After 6 months of using 100 mg of concentrated soy extract daily, the investigators noted increased thickness of the dermis and epidermis, increased dermal vasculature, an increased number of collagen and elastic fibers, and an increased papillary index. In rats, genistein increases antioxidant enzymes, such as superoxide dismutase, catalase, and glutathione.^78,79 Topical phytoestrogens also were evaluated, with promising results for increased skin thickness. In animals, the use of isoflavones also offers protection against carcinogenesis in sun-damaged skin.¹⁵

Some investigators believe that a better understanding of the mechanism of action and possible side effects of phytoestrogens is essential to allow their use as a promising antiaging alternative.⁸⁰ There is no evidence that estrogens (eg, HRT) possess antioxidant or photoprotective properties.⁷⁸ Moreover, it is possible that new selective estrogen receptor modulators will specifically affect the skin without the expected systemic effects of existing estrogens.⁸⁰

Conclusion

Although often overlooked, skin disorders are quite common during menopause. Understanding the physiology of this important period in a woman’s life is essential for developing an early and effective preventive therapeutic approach. Use of sunscreens has been questioned due to a concern about osteoporosis, but studies have not shown a connection between sunscreen use and reduced VD levels. Intentional sun exposure should not be considered a source of VD; instead, recommend dietary or artificial supplementation. Although studies have shown HRT to positively affect wound healing, reduce signs of aging, increase hydration, and yield other benefits, its use is not recommended for treating skin disorders. Isoflavones could be promising alternatives to estrogen; however, further studies are needed before their use can be recommended.

The prevalence of diabetes mellitus (DM) is growing at epidemic proportions in the U.S. and has been reported as the most common reason for hospital admissions in western countries.¹ There continues to be an alarmingly steady increase in the incidence of type 2 DM (T2DM), especially among the young and obese. Long-term diabetes-related complications also are likely to rise in prevalence. In particular, the diabetic foot is associated with morbidity and disability, leading to a significant impairment of quality of life.² People with DM develop foot ulcers because of neuropathy (sensory, motor, and autonomic deficits), ischemia, or both.³ The initiating injury may be from acute mechanical or thermal trauma or from repetitively or continuously applied mechanical stress.⁴

From foot ulcerations to neuropathy to peripheral vascular disease, the challenges are significant and can result in amputations and even premature death. To address these challenges, early diagnosis and a multidisciplinary team approach should be employed. Managing the numerous comorbidities is essential for treatment.^1,2,5

Due to the longevity of patients with DM, diabetes-associated complications are expected to rise in prevalence.⁶ The American Diabetes Association recently reported that T2DM accounts for about 90% to 95% of all persons with DM.^7,8 Today, many hospitalizations for patients with DM are for lower extremity conditions, such as ulceration, infection, or gangrene. Diabetic foot ulcerations (DFUs) are painful and costly for both the patient and the health care system. Every year, more than 1 million people with DM worldwide lose a leg as a consequence of this disease.⁹ Most DM-related amputations are preceded by a foot ulcer.

Diabetic foot ulcerations are the most common foot condition leading to lower extremity amputation (Figure 1).¹⁰ About 14 million individuals in the U.S. with diagnosed and undiagnosed DM will experience pathologic changes of their lower extremities that, when combined with minor trauma and infection, may lead to serious foot problems.¹¹ Although the triad of vasculopathy, neuropathy, and susceptibility to infection are the primary permissive factors in its pathogenesis, DFU can also be attributed to other important risk factors. The presence of peripheral neuropathy and peripheral arterial disease (PAD) are considered to be the most significant risk factors for all types of diabetic foot complications.¹²

Related: A Combined Treatment Protocol for Patients With Diabetic Peripheral Neuropathy

Optimal care of foot ulceration depends on the treating physician’s understanding of the pathophysiology involved, familiarity with accepted principles of treatment, and the knowledge that a coordinated, multidisciplinary team approach will best accomplish the goal of limb salvage. All efforts should be made to prevent foot lesions, and when present, existing ulcers should be treated promptly and aggressively, which can often prevent an exacerbation of the problem and decrease the incidence of amputations. Even when ulcers have healed, patients with DM and a history of a lower extremity ulcer should consider it a lifelong condition that requires monitoring to prevent recurrence.^13,14

This review provides a brief overview of DFU, including etiology, evaluation, treatment, and prevention, to provide clinicians with the clinical markers, evidence, and DFU treatment recommendations.

Etiologies

Multiple risk factors contribute to the development and pathogenesis of DFUs.^5,6,15,16 Neuropathy and PAD are major factors in the pathogenesis of diabetic foot ulcers.¹⁷ However, there are several additional factors leading to the occurrence of foot complications. Reiber and colleagues have determined that 63% of their patients’ ulcers were attributed to the critical triad of peripheral sensory neuropathy, trauma, and deformity.¹⁵

Other factors also implicated in the causal pathway to ulceration were ischemia, callus, and edema. Infection was rarely implicated in the etiology of these lesions, although once an ulcer has developed, infection and PAD were found to be the major causes for amputation.^10,18,19 Many of the risk factors for foot ulcer are also predisposing factors for amputation, because ulcers are primary antecedent events leading to amputation.^20-23

Evaluation

The clinical evaluation must include a thorough and systematic lower extremity examination when starting DFU treatment. It is important to have a thorough assessment of the ulcer’s size and depth, and the evaluation should include a description of its appearance and measurement of its diameter at each visit. Evaluation for the presence of local and systemic infection and potential for osteomyelitis, using a small sterile blunt probe, is critical in determining depth of penetration and tracking along tendon sheaths (Figure 2).

Peripheral arterial disease is directly linked to lower extremity disorders, such as intermittent claudication, pain on exertion, pain at rest, and, in severe cases, critical limb ischemia and gangrene.¹ Bilateral lower extremity pulses should routinely be palpated. When dorsalis pedis or posterior tibial artery pulses are absent or diminished, Doppler segmental pressures to the toes, pulse volume recording, skin perfusion pressure, or transcutaneous oxygen evaluation is indicated, and vascular consultation should be sought.³ Ischemia is caused by peripheral arterial occlusive disease of larger vessels, not by microangiopathy.¹³ Poor arterial inflow is associated not only with impaired ulcer healing, but also subsequent infection, gangrene, and amputation.¹³

Diabetic peripheral neuropathy is characterized by loss of protective sensation, allowing ulceration in areas of high pressure. Peripheral sensory neuropathy as measured by vibration perception thresholds can impart a 3.4-fold to 32-fold risk of ulceration.^19,21 Patients insensitive to a 10-g monofilament, commonly used to assess peripheral neuropathy, has been shown in several studies to convey a 2.2-fold to18-fold risk of ulceration.^6,19,27,28 In the large, population-based North-West Diabetes Foot Care Study, loss of protective sensation to the 10-g monofilament increased the risk of ulceration 80%, whereas abnormal ankle reflexes increased this risk 55%.²⁹

Peripheral neuropathy has been demonstrated as a strong risk factor for foot ulceration in many cross-sectional studies and is present in > 80% of affected patients.²⁹ Recent studies suggested that impaired sensation makes the foot increasingly vulnerable to damage caused by mechanical, thermal, or pressure-related injury.³⁰ Autonomic neuropathy by virtue of subsequent anhidrosis causes dryness of the skin and, therefore, vulnerability to fissuring.¹³

Unhealed cracks in the skin can easily lead to infection, especially in the presence of PAD. Neuropathy has an insidious and nonhomogeneous manifestation, making it difficult to identify its onset and a challenge for patients and clinicians.^31,32

Sacco and colleagues reviewed current literature and the International Consensus on the Diabetic Foot recommendation and concluded that most attention is given to patients with imminent foot ulceration rather than attempting to develop and improve assessment techniques that detect early impairments.^31,33 They propose that effort should be made that detect patients at risk of developing diabetic polyneuropathy. Although the 10-g monofilament pressure perception threshold is a common screening technique for early detection, tests of the vibration perception threshold may be more sensitive.

The authors propose that different monofilament sizes could probably better help determine the disease status, as the vibration tests do. In addition to the considerable subjectivity of both methods of assessing sensitivity, they are unquestionably clinical resources that can contribute to early detection of DPN. Future studies should focus on developing assessment strategies and tools that better detect early neuropathic changes. Early diagnosis of impending problems will aid in preventing further limb-threatening complications.

Treatment

The management of diabetic foot disease is focused primarily on avoiding lower extremity amputation and should be carried out through 3 main strategies: identification of the at risk foot, treatment of the acutely diseased foot, and prevention of further complications.³⁴ The primary goal in the treatment of DFUs is to obtain wound closure. Prompt, aggressive treatment of DFUs can often prevent an exacerbation of the problem and the potential need for amputation. The aim of therapy, therefore, should be early intervention to allow prompt healing of the lesion and, once healed, prevent its recurrence.^3,20,25,35

Management of the foot ulcer is largely determined by its severity (grade), vascularity, and presence of infection.^3,14,36 A multidisciplinary team approach should be used due to the multifaceted nature of foot ulcers, as well as for managing the numerous comorbidities attendant with these patients. The choice of treatment methods is determined by patient and ulcer characteristics. Equally important is the ability of patients to comply with the treatment as well as with the location and severity of the ulcer.⁴

Rest, elevation, and removal of pressure (off-loading) are essential components of treatment and should be initiated at first presentation. Recent studies provided evidence that indicated proper off-loading promotes more rapid DFU healing.^37,38 Ill-fitting footwear should be discarded and replaced with an appropriate off-loading device for mitigating pressure at the site of the ulceration. Although many off-loading modalities are currently in use, only a few studies describe the frequency and rate of wound healing associated with their use.

The total contact cast (TCC) is considered the superior standard therapy in management for neuropathic ulcers due to its proven ability to redistribute pressure, thereby promoting expeditious wound closure. Another inherent benefit is to ensure patient adherence with off-loading as well as reducing activity levels.^24,39 Previous randomized controlled trials have demonstrated that patients treated with TCC healed a higher percentage of plantar ulcers at a faster rate than did patients in the control groups. One unique study demonstrated histologic evidence of more rapid angiogenesis with formation of granulation tissue in the casted group compared with the standard treatment group.^40,41

Potential disadvantages of the TCC include the need for expertise in its proper application, the need for weekly cast changes, and related costs.^24,35 Although a number of new devices have been introduced as alternatives to the TCC, only several clinical studies demonstrating their efficacy have been published.^5,14,25,36 If nonweight bearing with crutches, wheelchair, or more effective devices are not feasible, even a pressure-attenuating insert can be used in a simple postoperative shoe until specialty referral is made.

Debridement of necrotic, callus, fibrous, and senescent tissues is a mainstay of ulcer therapy.^42,43 It is considered the first and the most important therapeutic step leading to wound closure in patients with DFU.^42-44 Unhealthy tissue must be sharply debrided back to bleeding tissue to fully visualize the extent of the ulcer as well as to detect any underlying abscesses or sinuses. It has been reported that regular (weekly) sharp debridement is associated with more rapid healing of ulcers compared with less frequent debridement.^45-47 Wilcox and colleagues indicated that frequent debridement healed more wounds in a shorter time (P < .001).⁴⁶ The more frequent the debridement, the better the healing outcome. There are different types of debridement methods, including surgical, enzymatic, autolytic, mechanical, and biologic.⁴⁸ Surgical or sharp debridement can convert a chronic ulcer into an acute wound that is more likely to heal.²⁴ Adequate debridement must always precede the application of topical wound healing agents, dressings, or wound closure procedures.²⁴ Conversely, a wound that does not receive the necessary debridement is one that has not been adequately treated.

There are numerous types of dressings that have been developed over the past decade that promote wound healing. Few have undergone any formal clinical studies to determine efficacy or effectiveness to help guide clinicians in their use.

Yazdanpanah and colleagues argued that dressings should confer moisture balance, protease sequestration, growth factor stimulation, antimicrobial activity, oxygen permeability, and the capacity to promote autolytic debridement to facilitate the production of granulation tissues and the re-epithelialization process.²⁴ In addition, it should have a prolonged time of action, high efficiency, and protection against contamination or infection.¹⁷ The group noted that no single dressing fulfills all the requirements of a diabetic patient with a foot ulcer. The choice of dressing is largely determined by the causes of DFU, wound location, depth, amount of scar or slough, exudates, condition of wound margins, presence of infection and pain, need for adhesiveness, and conformability of the dressing (Table 2).

Advanced Therapies

In 2003, Sheehan and colleagues reported that a 50% change in foot ulcer area after 4 weeks of observation is a robust predictor of healing at 12 weeks.⁴⁹ In addition, wounds failing to achieve a 50% reduction in area after 4 weeks need to be reassessed and considered for advanced treatment modalities if there are no otherwise identified impediments to wound healing.^6,9,38 These findings have served as a pivotal clinical decision point in the care of DFUs over the past several years for early identification of patients who may not respond to the standard of care. Today, most wound care protocols advocate use of standard therapies for at least 4 weeks before advanced therapies are considered.

Significant improvements have been achieved in the treatment of ulcerations, and today clinicians have several advanced therapeutic options for management of chronic DFUs. These new technologies have been shown to increase the probability of complete wound closure in difficult-to-heal foot ulcerations in patients with diabetes. Among these are recombinant platelet-derived growth factors, a human living skin equivalent, and a human fibroblast-derived dermal substitute.^49-51 Tissue-engineered skin equivalent (Apligraf) and human dermis (Dermagraft) are types of biologically active dressings that are derived from fibroblasts of neonatal foreskins.

The most recent advancements for wound care therapies is that of stem cell therapies, primarily bone marrow-derived and, most recently, placental-derived stem cells, including dehydrated human amnion chorion (Epifix) and amniotic matrix with mesenchymal stem cells (Grafix).^52,53 Because of the expense of these products, they cannot be used universally in the treatment of DFUs but rather are used and reserved for difficult-to-heal wounds. In addition, negative pressure therapy has assumed a major role in the management of traumatic, acute, and chronic wounds and has shown efficacy in healing DFUs.^54-57 Hyperbaric oxygen therapy and several biophysical modalities have been studied and found to be efficacious in healing a wide variety of chronic wounds over the past decade as well, although results vary by study, and no advanced modality has become universal in its application.^58-64

Table 3 lists most of the wound care technologies commonly used in current clinical practice. Although randomized controlled trials have been published supporting the use of most of these modalities, a lack of strong data proving efficacy for use of such treatment options remains.

Treatment of any underlying ischemia is critical in achieving a successful outcome. Vascular surgical consultation should be obtained on presentation of an ischemic wound and in cases where ulcers show no sign of progress despite appropriate management.^4,13 Revascularization is commonly performed in patients with critical limb ischemia and DFUs but is also performed in patients with less severe arteriopathy. The goal is to restore a palpable pulse on the affected foot.⁶⁵ The postrevascularization ulcer-healing rate ranges from 46% to 91% at 1 year and seems to be improved in those patients with distal arterial reconstruction and restoration of pulsatile flow.⁶⁶

Endovascular approaches are becoming increasingly common in patients whose arterial disease is more limited or morbidity is a significant concern.^67,68 Studies report that the exact role of isolated endovascular procedures is still to be determined, although such interventions are frequently performed in concert with angiography preceding vascular reconstructive procedures.^69,70 However, in many such studies, healing was often a secondary criterion, and there was no description of the initial wound or its management.⁷¹

Challenges

Within the VA setting there is a wide range of patient comorbidities that frequently present clinicians with unique challenges. Often these patients are older with many social and mental health conditions, including self-abuse, drug-abuse, nonadherence, psychological issues and lack of financial and/or educational resources or support. Many of these patients have comorbidities associated with diabetes that can delay healing of their ulcerations.

Systemwide VA mandates have implemented multidisciplinary foot care teams. The teams identify veterans at risk for lower limb complications; provide preventive care; track high-risk foot care across the continuum of outpatient, inpatient, and rehabilitative care; and provide education, orthoses, and social support.^72,73 In the late 1990s, the VHA implemented a national program of foot risk screening and referral, conducted largely in primary care.²⁹ By 1998 as determined from medical record reviews, 95% of veterans had a visual examination, 84% had palpation of pulses, and 78% had undergone a sensory examination. In addition, about 83% of patients had a monofilament examination, and 85% of individuals with risk factors were referred to foot specialists in 2004.^72,74 Veterans at higher risk for lower extremity complications routinely receive subsequent preventive foot care, such as education or prescription of therapeutic shoes in the VHA.

Tseng and colleagues evaluated risk-adjusted trends in amputations among veterans with diabetes during a 5-year period and reported a decrease in amputation rates observed for all types of lower extremity amputations (LEA) and among all racial groups.⁷⁴ Implementation of such universal programs for foot screening, tracked through performance measures, may have contributed to a decrease in LEAs and improved outcomes in the VA patient population.

Prevention

A healthy, intact diabetic foot is best maintained by a consistent and recurrent preventive treatment strategy. Prevention of ulcer recurrence remains to be a major clinical challenge. Andrews and colleagues demonstrated that recurrence rates range from 28% at 12 months to 100% at 40 months.⁷⁵ They report that the highest incidence of reulceration is in the site of a previous ulceration, noting that a newly healed ulcer is covered with fragile skin and after complete healing, there is an area of higher density tissue (scar). Shearing between the different tissue densities often contributes to new ulcers.

After the ulcer heals, the patient and their caregivers must incorporate preventative measures in care plans to reduce the risk of wound reoccurrence. A study reported by Barshes and colleagues demonstrated that a majority of people with diabetes do not receive guideline-recommended foot care, including regular foot examinations.⁷⁶ Identifying the patients with diabetes at risk for ulceration requires foot examination,including the vascular and neurologic systems, skin conditions, and foot structure.⁷⁷ Among the complications of diabetes, lower limb amputation is considered to be preventable.^78,79 Because there is a great beneficial effect of patient education on reducing LEAs, a flexible schedule for diabetes education, that offers education at any time for the maximum convenience of patients rather than focusing on health care provider’s convenience is critical.^79,80 Conservative management of foot problems also has reduced the risk of amputation by simple procedures, such as appropriate foot wear, cleanliness, aggressive surgical debridement, and evidence-based ulcer management.³⁴ This is best accomplished through a multidisciplinary approach involving a team of specialists and personnel who provide a coordinated process of care, including a patient motivated to ensure its success.⁶

Conclusions

The authors have described the components of assessment and treatment that can help ensure successful healing of foot ulcers in diabetic patients. These approaches should be used whenever feasible to reduce the high morbidity and risk of serious complications resulting from foot ulcers. Advances in treating chronic diabetic wounds are promising; however, the intrinsic pathophysiologic abnormalities that lead to ulcers in the first place cannot be ignored. No known therapy will be effective without concomitant management of ischemia, infection, and adequate off-loading.^6,75

Not all diabetic foot complications can be prevented, but it is possible to dramatically reduce their incidence through appropriate management and prevention programs. The multidisciplinary team approach that combines the expertise of many types of health care providers for diabetic foot disorders has been demonstrated as the optimal method to achieve favorable rates of limb salvage in the high-risk diabetic patient.

The prevalence of diabetes mellitus (DM) is growing at epidemic proportions in the U.S. and has been reported as the most common reason for hospital admissions in western countries.¹ There continues to be an alarmingly steady increase in the incidence of type 2 DM (T2DM), especially among the young and obese. Long-term diabetes-related complications also are likely to rise in prevalence. In particular, the diabetic foot is associated with morbidity and disability, leading to a significant impairment of quality of life.² People with DM develop foot ulcers because of neuropathy (sensory, motor, and autonomic deficits), ischemia, or both.³ The initiating injury may be from acute mechanical or thermal trauma or from repetitively or continuously applied mechanical stress.⁴

From foot ulcerations to neuropathy to peripheral vascular disease, the challenges are significant and can result in amputations and even premature death. To address these challenges, early diagnosis and a multidisciplinary team approach should be employed. Managing the numerous comorbidities is essential for treatment.^1,2,5

Due to the longevity of patients with DM, diabetes-associated complications are expected to rise in prevalence.⁶ The American Diabetes Association recently reported that T2DM accounts for about 90% to 95% of all persons with DM.^7,8 Today, many hospitalizations for patients with DM are for lower extremity conditions, such as ulceration, infection, or gangrene. Diabetic foot ulcerations (DFUs) are painful and costly for both the patient and the health care system. Every year, more than 1 million people with DM worldwide lose a leg as a consequence of this disease.⁹ Most DM-related amputations are preceded by a foot ulcer.

Diabetic foot ulcerations are the most common foot condition leading to lower extremity amputation (Figure 1).¹⁰ About 14 million individuals in the U.S. with diagnosed and undiagnosed DM will experience pathologic changes of their lower extremities that, when combined with minor trauma and infection, may lead to serious foot problems.¹¹ Although the triad of vasculopathy, neuropathy, and susceptibility to infection are the primary permissive factors in its pathogenesis, DFU can also be attributed to other important risk factors. The presence of peripheral neuropathy and peripheral arterial disease (PAD) are considered to be the most significant risk factors for all types of diabetic foot complications.¹²

Related: A Combined Treatment Protocol for Patients With Diabetic Peripheral Neuropathy

Optimal care of foot ulceration depends on the treating physician’s understanding of the pathophysiology involved, familiarity with accepted principles of treatment, and the knowledge that a coordinated, multidisciplinary team approach will best accomplish the goal of limb salvage. All efforts should be made to prevent foot lesions, and when present, existing ulcers should be treated promptly and aggressively, which can often prevent an exacerbation of the problem and decrease the incidence of amputations. Even when ulcers have healed, patients with DM and a history of a lower extremity ulcer should consider it a lifelong condition that requires monitoring to prevent recurrence.^13,14

This review provides a brief overview of DFU, including etiology, evaluation, treatment, and prevention, to provide clinicians with the clinical markers, evidence, and DFU treatment recommendations.

Etiologies

Multiple risk factors contribute to the development and pathogenesis of DFUs.^5,6,15,16 Neuropathy and PAD are major factors in the pathogenesis of diabetic foot ulcers.¹⁷ However, there are several additional factors leading to the occurrence of foot complications. Reiber and colleagues have determined that 63% of their patients’ ulcers were attributed to the critical triad of peripheral sensory neuropathy, trauma, and deformity.¹⁵

Other factors also implicated in the causal pathway to ulceration were ischemia, callus, and edema. Infection was rarely implicated in the etiology of these lesions, although once an ulcer has developed, infection and PAD were found to be the major causes for amputation.^10,18,19 Many of the risk factors for foot ulcer are also predisposing factors for amputation, because ulcers are primary antecedent events leading to amputation.^20-23

Evaluation

The clinical evaluation must include a thorough and systematic lower extremity examination when starting DFU treatment. It is important to have a thorough assessment of the ulcer’s size and depth, and the evaluation should include a description of its appearance and measurement of its diameter at each visit. Evaluation for the presence of local and systemic infection and potential for osteomyelitis, using a small sterile blunt probe, is critical in determining depth of penetration and tracking along tendon sheaths (Figure 2).

Peripheral arterial disease is directly linked to lower extremity disorders, such as intermittent claudication, pain on exertion, pain at rest, and, in severe cases, critical limb ischemia and gangrene.¹ Bilateral lower extremity pulses should routinely be palpated. When dorsalis pedis or posterior tibial artery pulses are absent or diminished, Doppler segmental pressures to the toes, pulse volume recording, skin perfusion pressure, or transcutaneous oxygen evaluation is indicated, and vascular consultation should be sought.³ Ischemia is caused by peripheral arterial occlusive disease of larger vessels, not by microangiopathy.¹³ Poor arterial inflow is associated not only with impaired ulcer healing, but also subsequent infection, gangrene, and amputation.¹³

Diabetic peripheral neuropathy is characterized by loss of protective sensation, allowing ulceration in areas of high pressure. Peripheral sensory neuropathy as measured by vibration perception thresholds can impart a 3.4-fold to 32-fold risk of ulceration.^19,21 Patients insensitive to a 10-g monofilament, commonly used to assess peripheral neuropathy, has been shown in several studies to convey a 2.2-fold to18-fold risk of ulceration.^6,19,27,28 In the large, population-based North-West Diabetes Foot Care Study, loss of protective sensation to the 10-g monofilament increased the risk of ulceration 80%, whereas abnormal ankle reflexes increased this risk 55%.²⁹

Peripheral neuropathy has been demonstrated as a strong risk factor for foot ulceration in many cross-sectional studies and is present in > 80% of affected patients.²⁹ Recent studies suggested that impaired sensation makes the foot increasingly vulnerable to damage caused by mechanical, thermal, or pressure-related injury.³⁰ Autonomic neuropathy by virtue of subsequent anhidrosis causes dryness of the skin and, therefore, vulnerability to fissuring.¹³

Unhealed cracks in the skin can easily lead to infection, especially in the presence of PAD. Neuropathy has an insidious and nonhomogeneous manifestation, making it difficult to identify its onset and a challenge for patients and clinicians.^31,32

Sacco and colleagues reviewed current literature and the International Consensus on the Diabetic Foot recommendation and concluded that most attention is given to patients with imminent foot ulceration rather than attempting to develop and improve assessment techniques that detect early impairments.^31,33 They propose that effort should be made that detect patients at risk of developing diabetic polyneuropathy. Although the 10-g monofilament pressure perception threshold is a common screening technique for early detection, tests of the vibration perception threshold may be more sensitive.

The authors propose that different monofilament sizes could probably better help determine the disease status, as the vibration tests do. In addition to the considerable subjectivity of both methods of assessing sensitivity, they are unquestionably clinical resources that can contribute to early detection of DPN. Future studies should focus on developing assessment strategies and tools that better detect early neuropathic changes. Early diagnosis of impending problems will aid in preventing further limb-threatening complications.

Treatment

The management of diabetic foot disease is focused primarily on avoiding lower extremity amputation and should be carried out through 3 main strategies: identification of the at risk foot, treatment of the acutely diseased foot, and prevention of further complications.³⁴ The primary goal in the treatment of DFUs is to obtain wound closure. Prompt, aggressive treatment of DFUs can often prevent an exacerbation of the problem and the potential need for amputation. The aim of therapy, therefore, should be early intervention to allow prompt healing of the lesion and, once healed, prevent its recurrence.^3,20,25,35

Management of the foot ulcer is largely determined by its severity (grade), vascularity, and presence of infection.^3,14,36 A multidisciplinary team approach should be used due to the multifaceted nature of foot ulcers, as well as for managing the numerous comorbidities attendant with these patients. The choice of treatment methods is determined by patient and ulcer characteristics. Equally important is the ability of patients to comply with the treatment as well as with the location and severity of the ulcer.⁴

Rest, elevation, and removal of pressure (off-loading) are essential components of treatment and should be initiated at first presentation. Recent studies provided evidence that indicated proper off-loading promotes more rapid DFU healing.^37,38 Ill-fitting footwear should be discarded and replaced with an appropriate off-loading device for mitigating pressure at the site of the ulceration. Although many off-loading modalities are currently in use, only a few studies describe the frequency and rate of wound healing associated with their use.

The total contact cast (TCC) is considered the superior standard therapy in management for neuropathic ulcers due to its proven ability to redistribute pressure, thereby promoting expeditious wound closure. Another inherent benefit is to ensure patient adherence with off-loading as well as reducing activity levels.^24,39 Previous randomized controlled trials have demonstrated that patients treated with TCC healed a higher percentage of plantar ulcers at a faster rate than did patients in the control groups. One unique study demonstrated histologic evidence of more rapid angiogenesis with formation of granulation tissue in the casted group compared with the standard treatment group.^40,41

Potential disadvantages of the TCC include the need for expertise in its proper application, the need for weekly cast changes, and related costs.^24,35 Although a number of new devices have been introduced as alternatives to the TCC, only several clinical studies demonstrating their efficacy have been published.^5,14,25,36 If nonweight bearing with crutches, wheelchair, or more effective devices are not feasible, even a pressure-attenuating insert can be used in a simple postoperative shoe until specialty referral is made.

Debridement of necrotic, callus, fibrous, and senescent tissues is a mainstay of ulcer therapy.^42,43 It is considered the first and the most important therapeutic step leading to wound closure in patients with DFU.^42-44 Unhealthy tissue must be sharply debrided back to bleeding tissue to fully visualize the extent of the ulcer as well as to detect any underlying abscesses or sinuses. It has been reported that regular (weekly) sharp debridement is associated with more rapid healing of ulcers compared with less frequent debridement.^45-47 Wilcox and colleagues indicated that frequent debridement healed more wounds in a shorter time (P < .001).⁴⁶ The more frequent the debridement, the better the healing outcome. There are different types of debridement methods, including surgical, enzymatic, autolytic, mechanical, and biologic.⁴⁸ Surgical or sharp debridement can convert a chronic ulcer into an acute wound that is more likely to heal.²⁴ Adequate debridement must always precede the application of topical wound healing agents, dressings, or wound closure procedures.²⁴ Conversely, a wound that does not receive the necessary debridement is one that has not been adequately treated.

There are numerous types of dressings that have been developed over the past decade that promote wound healing. Few have undergone any formal clinical studies to determine efficacy or effectiveness to help guide clinicians in their use.

Yazdanpanah and colleagues argued that dressings should confer moisture balance, protease sequestration, growth factor stimulation, antimicrobial activity, oxygen permeability, and the capacity to promote autolytic debridement to facilitate the production of granulation tissues and the re-epithelialization process.²⁴ In addition, it should have a prolonged time of action, high efficiency, and protection against contamination or infection.¹⁷ The group noted that no single dressing fulfills all the requirements of a diabetic patient with a foot ulcer. The choice of dressing is largely determined by the causes of DFU, wound location, depth, amount of scar or slough, exudates, condition of wound margins, presence of infection and pain, need for adhesiveness, and conformability of the dressing (Table 2).

Advanced Therapies

In 2003, Sheehan and colleagues reported that a 50% change in foot ulcer area after 4 weeks of observation is a robust predictor of healing at 12 weeks.⁴⁹ In addition, wounds failing to achieve a 50% reduction in area after 4 weeks need to be reassessed and considered for advanced treatment modalities if there are no otherwise identified impediments to wound healing.^6,9,38 These findings have served as a pivotal clinical decision point in the care of DFUs over the past several years for early identification of patients who may not respond to the standard of care. Today, most wound care protocols advocate use of standard therapies for at least 4 weeks before advanced therapies are considered.

Significant improvements have been achieved in the treatment of ulcerations, and today clinicians have several advanced therapeutic options for management of chronic DFUs. These new technologies have been shown to increase the probability of complete wound closure in difficult-to-heal foot ulcerations in patients with diabetes. Among these are recombinant platelet-derived growth factors, a human living skin equivalent, and a human fibroblast-derived dermal substitute.^49-51 Tissue-engineered skin equivalent (Apligraf) and human dermis (Dermagraft) are types of biologically active dressings that are derived from fibroblasts of neonatal foreskins.

The most recent advancements for wound care therapies is that of stem cell therapies, primarily bone marrow-derived and, most recently, placental-derived stem cells, including dehydrated human amnion chorion (Epifix) and amniotic matrix with mesenchymal stem cells (Grafix).^52,53 Because of the expense of these products, they cannot be used universally in the treatment of DFUs but rather are used and reserved for difficult-to-heal wounds. In addition, negative pressure therapy has assumed a major role in the management of traumatic, acute, and chronic wounds and has shown efficacy in healing DFUs.^54-57 Hyperbaric oxygen therapy and several biophysical modalities have been studied and found to be efficacious in healing a wide variety of chronic wounds over the past decade as well, although results vary by study, and no advanced modality has become universal in its application.^58-64

Table 3 lists most of the wound care technologies commonly used in current clinical practice. Although randomized controlled trials have been published supporting the use of most of these modalities, a lack of strong data proving efficacy for use of such treatment options remains.

Treatment of any underlying ischemia is critical in achieving a successful outcome. Vascular surgical consultation should be obtained on presentation of an ischemic wound and in cases where ulcers show no sign of progress despite appropriate management.^4,13 Revascularization is commonly performed in patients with critical limb ischemia and DFUs but is also performed in patients with less severe arteriopathy. The goal is to restore a palpable pulse on the affected foot.⁶⁵ The postrevascularization ulcer-healing rate ranges from 46% to 91% at 1 year and seems to be improved in those patients with distal arterial reconstruction and restoration of pulsatile flow.⁶⁶

Endovascular approaches are becoming increasingly common in patients whose arterial disease is more limited or morbidity is a significant concern.^67,68 Studies report that the exact role of isolated endovascular procedures is still to be determined, although such interventions are frequently performed in concert with angiography preceding vascular reconstructive procedures.^69,70 However, in many such studies, healing was often a secondary criterion, and there was no description of the initial wound or its management.⁷¹

Challenges

Within the VA setting there is a wide range of patient comorbidities that frequently present clinicians with unique challenges. Often these patients are older with many social and mental health conditions, including self-abuse, drug-abuse, nonadherence, psychological issues and lack of financial and/or educational resources or support. Many of these patients have comorbidities associated with diabetes that can delay healing of their ulcerations.

Systemwide VA mandates have implemented multidisciplinary foot care teams. The teams identify veterans at risk for lower limb complications; provide preventive care; track high-risk foot care across the continuum of outpatient, inpatient, and rehabilitative care; and provide education, orthoses, and social support.^72,73 In the late 1990s, the VHA implemented a national program of foot risk screening and referral, conducted largely in primary care.²⁹ By 1998 as determined from medical record reviews, 95% of veterans had a visual examination, 84% had palpation of pulses, and 78% had undergone a sensory examination. In addition, about 83% of patients had a monofilament examination, and 85% of individuals with risk factors were referred to foot specialists in 2004.^72,74 Veterans at higher risk for lower extremity complications routinely receive subsequent preventive foot care, such as education or prescription of therapeutic shoes in the VHA.

Tseng and colleagues evaluated risk-adjusted trends in amputations among veterans with diabetes during a 5-year period and reported a decrease in amputation rates observed for all types of lower extremity amputations (LEA) and among all racial groups.⁷⁴ Implementation of such universal programs for foot screening, tracked through performance measures, may have contributed to a decrease in LEAs and improved outcomes in the VA patient population.

Prevention

A healthy, intact diabetic foot is best maintained by a consistent and recurrent preventive treatment strategy. Prevention of ulcer recurrence remains to be a major clinical challenge. Andrews and colleagues demonstrated that recurrence rates range from 28% at 12 months to 100% at 40 months.⁷⁵ They report that the highest incidence of reulceration is in the site of a previous ulceration, noting that a newly healed ulcer is covered with fragile skin and after complete healing, there is an area of higher density tissue (scar). Shearing between the different tissue densities often contributes to new ulcers.

After the ulcer heals, the patient and their caregivers must incorporate preventative measures in care plans to reduce the risk of wound reoccurrence. A study reported by Barshes and colleagues demonstrated that a majority of people with diabetes do not receive guideline-recommended foot care, including regular foot examinations.⁷⁶ Identifying the patients with diabetes at risk for ulceration requires foot examination,including the vascular and neurologic systems, skin conditions, and foot structure.⁷⁷ Among the complications of diabetes, lower limb amputation is considered to be preventable.^78,79 Because there is a great beneficial effect of patient education on reducing LEAs, a flexible schedule for diabetes education, that offers education at any time for the maximum convenience of patients rather than focusing on health care provider’s convenience is critical.^79,80 Conservative management of foot problems also has reduced the risk of amputation by simple procedures, such as appropriate foot wear, cleanliness, aggressive surgical debridement, and evidence-based ulcer management.³⁴ This is best accomplished through a multidisciplinary approach involving a team of specialists and personnel who provide a coordinated process of care, including a patient motivated to ensure its success.⁶

Conclusions

The authors have described the components of assessment and treatment that can help ensure successful healing of foot ulcers in diabetic patients. These approaches should be used whenever feasible to reduce the high morbidity and risk of serious complications resulting from foot ulcers. Advances in treating chronic diabetic wounds are promising; however, the intrinsic pathophysiologic abnormalities that lead to ulcers in the first place cannot be ignored. No known therapy will be effective without concomitant management of ischemia, infection, and adequate off-loading.^6,75

Not all diabetic foot complications can be prevented, but it is possible to dramatically reduce their incidence through appropriate management and prevention programs. The multidisciplinary team approach that combines the expertise of many types of health care providers for diabetic foot disorders has been demonstrated as the optimal method to achieve favorable rates of limb salvage in the high-risk diabetic patient.

The prevalence of diabetes mellitus (DM) is growing at epidemic proportions in the U.S. and has been reported as the most common reason for hospital admissions in western countries.¹ There continues to be an alarmingly steady increase in the incidence of type 2 DM (T2DM), especially among the young and obese. Long-term diabetes-related complications also are likely to rise in prevalence. In particular, the diabetic foot is associated with morbidity and disability, leading to a significant impairment of quality of life.² People with DM develop foot ulcers because of neuropathy (sensory, motor, and autonomic deficits), ischemia, or both.³ The initiating injury may be from acute mechanical or thermal trauma or from repetitively or continuously applied mechanical stress.⁴

From foot ulcerations to neuropathy to peripheral vascular disease, the challenges are significant and can result in amputations and even premature death. To address these challenges, early diagnosis and a multidisciplinary team approach should be employed. Managing the numerous comorbidities is essential for treatment.^1,2,5

Due to the longevity of patients with DM, diabetes-associated complications are expected to rise in prevalence.⁶ The American Diabetes Association recently reported that T2DM accounts for about 90% to 95% of all persons with DM.^7,8 Today, many hospitalizations for patients with DM are for lower extremity conditions, such as ulceration, infection, or gangrene. Diabetic foot ulcerations (DFUs) are painful and costly for both the patient and the health care system. Every year, more than 1 million people with DM worldwide lose a leg as a consequence of this disease.⁹ Most DM-related amputations are preceded by a foot ulcer.

Diabetic foot ulcerations are the most common foot condition leading to lower extremity amputation (Figure 1).¹⁰ About 14 million individuals in the U.S. with diagnosed and undiagnosed DM will experience pathologic changes of their lower extremities that, when combined with minor trauma and infection, may lead to serious foot problems.¹¹ Although the triad of vasculopathy, neuropathy, and susceptibility to infection are the primary permissive factors in its pathogenesis, DFU can also be attributed to other important risk factors. The presence of peripheral neuropathy and peripheral arterial disease (PAD) are considered to be the most significant risk factors for all types of diabetic foot complications.¹²

Related: A Combined Treatment Protocol for Patients With Diabetic Peripheral Neuropathy

Optimal care of foot ulceration depends on the treating physician’s understanding of the pathophysiology involved, familiarity with accepted principles of treatment, and the knowledge that a coordinated, multidisciplinary team approach will best accomplish the goal of limb salvage. All efforts should be made to prevent foot lesions, and when present, existing ulcers should be treated promptly and aggressively, which can often prevent an exacerbation of the problem and decrease the incidence of amputations. Even when ulcers have healed, patients with DM and a history of a lower extremity ulcer should consider it a lifelong condition that requires monitoring to prevent recurrence.^13,14

This review provides a brief overview of DFU, including etiology, evaluation, treatment, and prevention, to provide clinicians with the clinical markers, evidence, and DFU treatment recommendations.

Etiologies

Multiple risk factors contribute to the development and pathogenesis of DFUs.^5,6,15,16 Neuropathy and PAD are major factors in the pathogenesis of diabetic foot ulcers.¹⁷ However, there are several additional factors leading to the occurrence of foot complications. Reiber and colleagues have determined that 63% of their patients’ ulcers were attributed to the critical triad of peripheral sensory neuropathy, trauma, and deformity.¹⁵

Other factors also implicated in the causal pathway to ulceration were ischemia, callus, and edema. Infection was rarely implicated in the etiology of these lesions, although once an ulcer has developed, infection and PAD were found to be the major causes for amputation.^10,18,19 Many of the risk factors for foot ulcer are also predisposing factors for amputation, because ulcers are primary antecedent events leading to amputation.^20-23

Evaluation

The clinical evaluation must include a thorough and systematic lower extremity examination when starting DFU treatment. It is important to have a thorough assessment of the ulcer’s size and depth, and the evaluation should include a description of its appearance and measurement of its diameter at each visit. Evaluation for the presence of local and systemic infection and potential for osteomyelitis, using a small sterile blunt probe, is critical in determining depth of penetration and tracking along tendon sheaths (Figure 2).

Peripheral arterial disease is directly linked to lower extremity disorders, such as intermittent claudication, pain on exertion, pain at rest, and, in severe cases, critical limb ischemia and gangrene.¹ Bilateral lower extremity pulses should routinely be palpated. When dorsalis pedis or posterior tibial artery pulses are absent or diminished, Doppler segmental pressures to the toes, pulse volume recording, skin perfusion pressure, or transcutaneous oxygen evaluation is indicated, and vascular consultation should be sought.³ Ischemia is caused by peripheral arterial occlusive disease of larger vessels, not by microangiopathy.¹³ Poor arterial inflow is associated not only with impaired ulcer healing, but also subsequent infection, gangrene, and amputation.¹³

Diabetic peripheral neuropathy is characterized by loss of protective sensation, allowing ulceration in areas of high pressure. Peripheral sensory neuropathy as measured by vibration perception thresholds can impart a 3.4-fold to 32-fold risk of ulceration.^19,21 Patients insensitive to a 10-g monofilament, commonly used to assess peripheral neuropathy, has been shown in several studies to convey a 2.2-fold to18-fold risk of ulceration.^6,19,27,28 In the large, population-based North-West Diabetes Foot Care Study, loss of protective sensation to the 10-g monofilament increased the risk of ulceration 80%, whereas abnormal ankle reflexes increased this risk 55%.²⁹

Peripheral neuropathy has been demonstrated as a strong risk factor for foot ulceration in many cross-sectional studies and is present in > 80% of affected patients.²⁹ Recent studies suggested that impaired sensation makes the foot increasingly vulnerable to damage caused by mechanical, thermal, or pressure-related injury.³⁰ Autonomic neuropathy by virtue of subsequent anhidrosis causes dryness of the skin and, therefore, vulnerability to fissuring.¹³

Unhealed cracks in the skin can easily lead to infection, especially in the presence of PAD. Neuropathy has an insidious and nonhomogeneous manifestation, making it difficult to identify its onset and a challenge for patients and clinicians.^31,32

Sacco and colleagues reviewed current literature and the International Consensus on the Diabetic Foot recommendation and concluded that most attention is given to patients with imminent foot ulceration rather than attempting to develop and improve assessment techniques that detect early impairments.^31,33 They propose that effort should be made that detect patients at risk of developing diabetic polyneuropathy. Although the 10-g monofilament pressure perception threshold is a common screening technique for early detection, tests of the vibration perception threshold may be more sensitive.

The authors propose that different monofilament sizes could probably better help determine the disease status, as the vibration tests do. In addition to the considerable subjectivity of both methods of assessing sensitivity, they are unquestionably clinical resources that can contribute to early detection of DPN. Future studies should focus on developing assessment strategies and tools that better detect early neuropathic changes. Early diagnosis of impending problems will aid in preventing further limb-threatening complications.

Treatment

The management of diabetic foot disease is focused primarily on avoiding lower extremity amputation and should be carried out through 3 main strategies: identification of the at risk foot, treatment of the acutely diseased foot, and prevention of further complications.³⁴ The primary goal in the treatment of DFUs is to obtain wound closure. Prompt, aggressive treatment of DFUs can often prevent an exacerbation of the problem and the potential need for amputation. The aim of therapy, therefore, should be early intervention to allow prompt healing of the lesion and, once healed, prevent its recurrence.^3,20,25,35

Management of the foot ulcer is largely determined by its severity (grade), vascularity, and presence of infection.^3,14,36 A multidisciplinary team approach should be used due to the multifaceted nature of foot ulcers, as well as for managing the numerous comorbidities attendant with these patients. The choice of treatment methods is determined by patient and ulcer characteristics. Equally important is the ability of patients to comply with the treatment as well as with the location and severity of the ulcer.⁴

Rest, elevation, and removal of pressure (off-loading) are essential components of treatment and should be initiated at first presentation. Recent studies provided evidence that indicated proper off-loading promotes more rapid DFU healing.^37,38 Ill-fitting footwear should be discarded and replaced with an appropriate off-loading device for mitigating pressure at the site of the ulceration. Although many off-loading modalities are currently in use, only a few studies describe the frequency and rate of wound healing associated with their use.

The total contact cast (TCC) is considered the superior standard therapy in management for neuropathic ulcers due to its proven ability to redistribute pressure, thereby promoting expeditious wound closure. Another inherent benefit is to ensure patient adherence with off-loading as well as reducing activity levels.^24,39 Previous randomized controlled trials have demonstrated that patients treated with TCC healed a higher percentage of plantar ulcers at a faster rate than did patients in the control groups. One unique study demonstrated histologic evidence of more rapid angiogenesis with formation of granulation tissue in the casted group compared with the standard treatment group.^40,41

Potential disadvantages of the TCC include the need for expertise in its proper application, the need for weekly cast changes, and related costs.^24,35 Although a number of new devices have been introduced as alternatives to the TCC, only several clinical studies demonstrating their efficacy have been published.^5,14,25,36 If nonweight bearing with crutches, wheelchair, or more effective devices are not feasible, even a pressure-attenuating insert can be used in a simple postoperative shoe until specialty referral is made.

Debridement of necrotic, callus, fibrous, and senescent tissues is a mainstay of ulcer therapy.^42,43 It is considered the first and the most important therapeutic step leading to wound closure in patients with DFU.^42-44 Unhealthy tissue must be sharply debrided back to bleeding tissue to fully visualize the extent of the ulcer as well as to detect any underlying abscesses or sinuses. It has been reported that regular (weekly) sharp debridement is associated with more rapid healing of ulcers compared with less frequent debridement.^45-47 Wilcox and colleagues indicated that frequent debridement healed more wounds in a shorter time (P < .001).⁴⁶ The more frequent the debridement, the better the healing outcome. There are different types of debridement methods, including surgical, enzymatic, autolytic, mechanical, and biologic.⁴⁸ Surgical or sharp debridement can convert a chronic ulcer into an acute wound that is more likely to heal.²⁴ Adequate debridement must always precede the application of topical wound healing agents, dressings, or wound closure procedures.²⁴ Conversely, a wound that does not receive the necessary debridement is one that has not been adequately treated.

There are numerous types of dressings that have been developed over the past decade that promote wound healing. Few have undergone any formal clinical studies to determine efficacy or effectiveness to help guide clinicians in their use.

Yazdanpanah and colleagues argued that dressings should confer moisture balance, protease sequestration, growth factor stimulation, antimicrobial activity, oxygen permeability, and the capacity to promote autolytic debridement to facilitate the production of granulation tissues and the re-epithelialization process.²⁴ In addition, it should have a prolonged time of action, high efficiency, and protection against contamination or infection.¹⁷ The group noted that no single dressing fulfills all the requirements of a diabetic patient with a foot ulcer. The choice of dressing is largely determined by the causes of DFU, wound location, depth, amount of scar or slough, exudates, condition of wound margins, presence of infection and pain, need for adhesiveness, and conformability of the dressing (Table 2).

Advanced Therapies

In 2003, Sheehan and colleagues reported that a 50% change in foot ulcer area after 4 weeks of observation is a robust predictor of healing at 12 weeks.⁴⁹ In addition, wounds failing to achieve a 50% reduction in area after 4 weeks need to be reassessed and considered for advanced treatment modalities if there are no otherwise identified impediments to wound healing.^6,9,38 These findings have served as a pivotal clinical decision point in the care of DFUs over the past several years for early identification of patients who may not respond to the standard of care. Today, most wound care protocols advocate use of standard therapies for at least 4 weeks before advanced therapies are considered.

Significant improvements have been achieved in the treatment of ulcerations, and today clinicians have several advanced therapeutic options for management of chronic DFUs. These new technologies have been shown to increase the probability of complete wound closure in difficult-to-heal foot ulcerations in patients with diabetes. Among these are recombinant platelet-derived growth factors, a human living skin equivalent, and a human fibroblast-derived dermal substitute.^49-51 Tissue-engineered skin equivalent (Apligraf) and human dermis (Dermagraft) are types of biologically active dressings that are derived from fibroblasts of neonatal foreskins.

The most recent advancements for wound care therapies is that of stem cell therapies, primarily bone marrow-derived and, most recently, placental-derived stem cells, including dehydrated human amnion chorion (Epifix) and amniotic matrix with mesenchymal stem cells (Grafix).^52,53 Because of the expense of these products, they cannot be used universally in the treatment of DFUs but rather are used and reserved for difficult-to-heal wounds. In addition, negative pressure therapy has assumed a major role in the management of traumatic, acute, and chronic wounds and has shown efficacy in healing DFUs.^54-57 Hyperbaric oxygen therapy and several biophysical modalities have been studied and found to be efficacious in healing a wide variety of chronic wounds over the past decade as well, although results vary by study, and no advanced modality has become universal in its application.^58-64

Table 3 lists most of the wound care technologies commonly used in current clinical practice. Although randomized controlled trials have been published supporting the use of most of these modalities, a lack of strong data proving efficacy for use of such treatment options remains.

Treatment of any underlying ischemia is critical in achieving a successful outcome. Vascular surgical consultation should be obtained on presentation of an ischemic wound and in cases where ulcers show no sign of progress despite appropriate management.^4,13 Revascularization is commonly performed in patients with critical limb ischemia and DFUs but is also performed in patients with less severe arteriopathy. The goal is to restore a palpable pulse on the affected foot.⁶⁵ The postrevascularization ulcer-healing rate ranges from 46% to 91% at 1 year and seems to be improved in those patients with distal arterial reconstruction and restoration of pulsatile flow.⁶⁶

Endovascular approaches are becoming increasingly common in patients whose arterial disease is more limited or morbidity is a significant concern.^67,68 Studies report that the exact role of isolated endovascular procedures is still to be determined, although such interventions are frequently performed in concert with angiography preceding vascular reconstructive procedures.^69,70 However, in many such studies, healing was often a secondary criterion, and there was no description of the initial wound or its management.⁷¹

Challenges

Within the VA setting there is a wide range of patient comorbidities that frequently present clinicians with unique challenges. Often these patients are older with many social and mental health conditions, including self-abuse, drug-abuse, nonadherence, psychological issues and lack of financial and/or educational resources or support. Many of these patients have comorbidities associated with diabetes that can delay healing of their ulcerations.

Systemwide VA mandates have implemented multidisciplinary foot care teams. The teams identify veterans at risk for lower limb complications; provide preventive care; track high-risk foot care across the continuum of outpatient, inpatient, and rehabilitative care; and provide education, orthoses, and social support.^72,73 In the late 1990s, the VHA implemented a national program of foot risk screening and referral, conducted largely in primary care.²⁹ By 1998 as determined from medical record reviews, 95% of veterans had a visual examination, 84% had palpation of pulses, and 78% had undergone a sensory examination. In addition, about 83% of patients had a monofilament examination, and 85% of individuals with risk factors were referred to foot specialists in 2004.^72,74 Veterans at higher risk for lower extremity complications routinely receive subsequent preventive foot care, such as education or prescription of therapeutic shoes in the VHA.

Tseng and colleagues evaluated risk-adjusted trends in amputations among veterans with diabetes during a 5-year period and reported a decrease in amputation rates observed for all types of lower extremity amputations (LEA) and among all racial groups.⁷⁴ Implementation of such universal programs for foot screening, tracked through performance measures, may have contributed to a decrease in LEAs and improved outcomes in the VA patient population.

Prevention

A healthy, intact diabetic foot is best maintained by a consistent and recurrent preventive treatment strategy. Prevention of ulcer recurrence remains to be a major clinical challenge. Andrews and colleagues demonstrated that recurrence rates range from 28% at 12 months to 100% at 40 months.⁷⁵ They report that the highest incidence of reulceration is in the site of a previous ulceration, noting that a newly healed ulcer is covered with fragile skin and after complete healing, there is an area of higher density tissue (scar). Shearing between the different tissue densities often contributes to new ulcers.

After the ulcer heals, the patient and their caregivers must incorporate preventative measures in care plans to reduce the risk of wound reoccurrence. A study reported by Barshes and colleagues demonstrated that a majority of people with diabetes do not receive guideline-recommended foot care, including regular foot examinations.⁷⁶ Identifying the patients with diabetes at risk for ulceration requires foot examination,including the vascular and neurologic systems, skin conditions, and foot structure.⁷⁷ Among the complications of diabetes, lower limb amputation is considered to be preventable.^78,79 Because there is a great beneficial effect of patient education on reducing LEAs, a flexible schedule for diabetes education, that offers education at any time for the maximum convenience of patients rather than focusing on health care provider’s convenience is critical.^79,80 Conservative management of foot problems also has reduced the risk of amputation by simple procedures, such as appropriate foot wear, cleanliness, aggressive surgical debridement, and evidence-based ulcer management.³⁴ This is best accomplished through a multidisciplinary approach involving a team of specialists and personnel who provide a coordinated process of care, including a patient motivated to ensure its success.⁶

Conclusions

The authors have described the components of assessment and treatment that can help ensure successful healing of foot ulcers in diabetic patients. These approaches should be used whenever feasible to reduce the high morbidity and risk of serious complications resulting from foot ulcers. Advances in treating chronic diabetic wounds are promising; however, the intrinsic pathophysiologic abnormalities that lead to ulcers in the first place cannot be ignored. No known therapy will be effective without concomitant management of ischemia, infection, and adequate off-loading.^6,75

Not all diabetic foot complications can be prevented, but it is possible to dramatically reduce their incidence through appropriate management and prevention programs. The multidisciplinary team approach that combines the expertise of many types of health care providers for diabetic foot disorders has been demonstrated as the optimal method to achieve favorable rates of limb salvage in the high-risk diabetic patient.

Heat injuries are a major problem worldwide. In a study chronicling heat deaths in the U.S. from 1979 to 1999, a total of 8,015 deaths were associated with excessive heat exposure.¹ Weather conditions caused 3,829 (48%) deaths, and manmade conditions (kitchens, vehicles, boiler rooms, etc) caused 377 (5%) deaths, particularly for those wearing protective clothing.¹

Military members who wear combat gear are especially vulnerable to heat injuries, but none more so than members who wear personal protective equipment (PPE). In this review, PPE is defined as self-contained breathing apparatus protective equipment (SCBA) levels B or C. The challenge of PPE is the inability of the individual to dispel heat through radiation, convection, and evaporation. The only close approximation of the PPE environment is combat and football protective equipment. In 2011, CDC reported that football players in uniforms, which resemble PPE for the purpose of this discussion, experienced heat injury at a rate 10 times higher than the average rate for other sports.² These heat injuries in football players occurred most often during August.² The injuries could be due to the application of protective clothing and the lack of the participants’ acclimatization. Protective clothing impedes the wearer’s ability to balance heat production with heat dissipation.

In 2010, Armstrong and colleagues suggested that the weight of a football uniform increases heat production.³ And the insulation provided by a football uniform reduces heat dissipation to the surrounding air, decreasing heat loss.³ Additionally, this same study indicated that the more protective gear the subject used, the greater the heat stress.³ The most challenging environment for heat injury is PPE due to the inability to facilitate any heat loss. In 2011, Caldwell and colleagues observed that wearing torso armor increased body temperature 10.8% faster than that of the control group, and those wearing full armor increased body temperature 38% faster than that of the control group.⁴ And it was proposed that 60% of this heat effect was from wearing the combat helmet.⁴

The inability to dissipate heat, particularly in protective gear, results in degradation of the effectiveness of the individual and, if left unchecked, may lead to death. Methods exist for health care providers to assess, intervene, and treat populations with heat injuries. These methods include but are not limited to vital signs (blood pressure [BP], body temperature, respiration rate), history of previous heat injury, medications (over-the-counter and prescription), and mental status.

Heat Injuries

Heat injuries are generally divided into 3 categories defined by their severity: heat stress, heat exhaustion, and heat stroke. Heat injuries are due to the individual’s inability to dissipate heat. As the severity of the heat exposure continues, the individual will experience heat stress, and if decompensation continues, the individual will progress to heat exhaustion and finally heat stroke.

If the individual’s physiology is limited or if compensatory mechanisms are compromised, heat stress may occur. Heat compensation can be retarded by any number of the following (including but not limited to): humidity, previous heat injury, lack of sleep, medications, sedentary lifestyle, obesity, caffeinated energy drinks, and dehydration.

In the early phases of heat stress, an individual’s vital signs will increase to compensate for the increase in body heat. Heat exchange is dependent on gradients of temperature and humidity, and as temperature and humidity increase, the ability to transfer heat decreases and becomes less efficient. Failure to accommodate for the increased heat generated and transferred will inevitably result in heat injury.

Working in a hazmat environment in PPE is the worst possible heat transfer scenario due to the inability to use evaporation, the primary means by which heat is released from the body. In this scenario, heat injuries can become dangerous and even fatal if monitoring of vital signs and uncompensated heat production is allowed to continue. As the heat insult progresses from heat stress to heat exhaustion and heat stroke, the core temperature, heart rate, and BP continue to increase. Also, during the progression of heat injury, mental status changes often begin to occur. In 2012, Morley and colleagues found that firefighters wearing protective clothing demonstrated a neurocognitive decline after 50 minutes of treadmill exercise, but these performance declines were not noted until 1 hour or more following the exercise.⁵

Mental status change is a key diagnostic factor that indicates the progression of the patient from heat stress to heat exhaustion and from heat exhaustion to heat stroke. As the hyperthermia progresses, vital signs increase, and the patient’s mental status will begin to deteriorate. If the hyperthermia advances from heat exhaustion to heat stroke, hospitalization is required to reverse the condition. If homeostasis is not restored, the patient may die.

Mental status changes are usually described as fatigue, lethargy, disorientation, headache, seizure and coma. Indeed, mental status changes may be one of the most important factors that can assist the clinician in the identification, mitigation, and treatment of heat injury before it reaches a critical stage. Clinical familiarity with and diagnosis of delirium resulting from heat injury could prove beneficial in protecting an individual exposed to severe heat environments.

In 2011, Becker and Stewart suggested that in the absence of hyperthermia, the presence of central nervous system (CNS) symptoms should prompt the clinician to pursue another diagnosis.⁶ However, a core temperature of 104°F with associated CNS changes and anhydrosis should be defined as heat stroke and is a medical emergency.⁶

Death rates from excessive heat are documented as high as 31%.⁷ Signs of CNS dysfunction such as irritability, ataxia, headache, nausea, vomiting, anhydrosis, confusion, and decreased cognitive function are essential to the diagnosis of heat stroke. Classic heat stroke will present as a triad of hyperpyrexia, anhydrosis, and mental status changes.⁸ However, making the diagnosis of heat stroke based on anhydrosis could be dangerous, because in exertional heat stroke, many patients continue to sweat. Overlooking the diagnosis of heat stroke based on anhydrosis could lead to a delay in treatment and severe complications.⁸ These complications may include hyperkalemia, hyperphosphatemia, hypocalcemia, and myoglobinuria.

Once heat stroke has occurred, coagulopathies may manifest as epistaxis, and endothelial damage may present as peripheral or pulmonary edema. Additionally, a core temperature of above 104°F may trigger a cascade of events that may include systemic inflammatory response resulting in increased cell wall permeability and release of endotoxins. These events can lead to tissue hypoxia, metabolic acidosis, and organ failure. Sequalae from heat stroke can result in multisystem failure. A 1998 study of Chicago heat wave victims reported that the degree of functional disability predicted survival at 1 year.⁹ Although hospital mortality was 21%, severe functional impairment at discharge was 33%, with an additional 28% mortality at 1 year.⁹ And the 1-year mortality from heat stroke is similar to that of cerebral vascular accidents.¹⁰ Within 24 hours, heat stroke victims often will display evidence of muscle, kidney, and cardiac dysfunction. Delay in intervention raises the risk of fatalities associated with hyperthermia.^11,12 Tissue destruction due to uncompensated heat may lead to rhabdomyolysis and subsequent myoglobinuria and renal injury. Damaged hepatocytes may lead to coagulopathies and hepatitis. Injured heart muscle may lead to arrhythmias and cardiac arrest.

The CNS symptoms may be difficult to ascertain in an intense working environment. The CNS system dysfunction is indicative of progression from heat injury to heat stroke and thus a medical emergency. It is imperative that the clinician be able to assess the individual quickly and accurately.

Delirium

Along with physical problems associated with it, heat injury can also lead to relatively abrupt mental status changes. In 2005, Glazer reported that even with minimally elevated core temperatures, CNS system changes can present with altered mental status, convulsions, and coma.¹³ This qualifies as a medical emergency known as delirium. Patients with delirium may present with a history of abrupt and fluctuating levels of consciousness. This fluctuation in symptoms that resemble sepsis could confuse medical providers.¹³ Thus, it is imperative that there be continuity of care of the patient with the ability to compare states of consciousness longitudinally over time.

In 1984, Pérez reported that nurses, perhaps because of their familiarity with and proximity to the patient, recorded delirium in 93% of patients, whereas psychiatric consultants recorded delirium only 34% of the time.¹⁴ Delirium manifests with several neurologic signs and symptoms; these include but are not limited to tremor, myoclonus, difficulty reading and writing, and visuoconstructive deficits, such as copying designs and problem solving.¹⁵ No matter the method to discover the delirium, the definitive treatment is to identify and treat the underlying medical condition.¹⁵ The CNS system dysfunction consistent with delirium such as irritability, ataxia, and confusion are essential to the diagnosis of heat stroke.¹³ Coma and seizures may occur, and retarded recovery of functional ability is an indication of a poor prognosis.⁹

Objective

The authors propose that in addition to vital signs, an assessment of a patient’s mental status through the use of a mental status exam could be a tool that identifies the problem early and avoids the progression of symptoms from heat stress to heat exhaustion and heat stroke. Early intervention in the progression of symptoms of hyperthermia can save lives, decrease suffering, and maintain a more robust mission-ready posture for the individual and the unit.

Study

During the fall of 2014, the Chemical, Biological, Radiological, Nuclear, and Explosive (CBRNE) unit of the Utah Air and Army National Guard participated in exercises using 2,159 patient encounters that were in PPE (full hazmat and SCBA) also known as level C protective clothing. Temperatures ranged from a minimum of 29°F to a high of 56°F. A mock disaster was practiced for 5 days, and of those 2,159 iterations, 43 were disqualified (2%) for any reason. Two individuals presented with altered mental status and disrupted vital signs and were disqualified for heat injuries with cognitive symptoms (0.00092%). These members were excused from duty, monitored in the medical work/rest tent until mental status and vital signs returned to baseline.

The tool used in the study was the Micro-Mental Test. This is a mental status exam that is more than a simple gestalt of how the patient is performing cognitively but less than a full Mini-Mental State Examination (MMSE). This abbreviated mental status exam provides a field expedient measurement of the individual’s ability to function cognitively. It is important to realize that this exam is most effective when repeated over time to assess the patients’ mental status longitudinally. It would be cavalier to propose that an abbreviated mental status exam would be sufficient to diagnose heat stroke, but a mental status exam—however brief—along with symptoms of hyperpyrexia, abnormal vital signs, and anhydrosis can be a useful tool to make the diagnostic transition from heat exhaustion to heat stroke.

Micro-Mental Status Exam

The traditional mental status measures are appearance, behavior, speech, mood, affect, thought process, thought content, cognition, insight, and judgment. Rapidly assessing mental status is crucial for the assessment of heat injuries, because increased vital signs coupled with neurologic changes indicate a medical emergency. The MMSE is painstaking and a somewhat cumbersome tool to use in the field. Therefore, the authors suggest a micro-mental status exam (Table). This abbreviated mental status exam is performed before the individual is placed in the PPE and enters the working environment.

The individual is then assessed after every rotation exiting the PPE and allowed to rest under supervision. Assessing the individual with vital signs and mental status longitudinally allows the provider to rapidly assess and intervene if the patient begins to exhibit mental status changes along with increased vital signs. The patient is assessed for ataxia, confusion, irritability, and lack of coordination. Patients are asked to find from a file drawer their individual prescreen checklist. This test assesses fine motor skills and cognition. Following this, self-identifying personal information from a precheck sheet is verified, and finally, simple questions regarding orientation to person, place, date, and time are posed.

Assessing Executive Function

Examples of measures of thought processes include assessing executive function by having participants find their paperwork, identifying their platoon leader, and correctly responding to questions, such as, “Where exactly were you working in the emergency area and what exactly were you doing?” This assesses executive function and thought process. Thought content could be assessed with inquiries such as, “Anything troubling about your work?” or “Would you tell me honestly if there were anything troubling or unsafe about the work you have performed?” Cognition could be assessed by questions regarding chain of command (both officer and enlisted), 3 suggestions to improve, 3 suggestions to maintain, and knowledge of the rotation schedule for the rest of the day.

The abbreviated mental status exam should in no way replace the robust and accurate mental status exam. However, in a rapidly changing, austere, or asymmetrical environment, a simple gestalt of the patient is ineffective, and the full mental status evaluation may be too time consuming. The authors propose the Micro-Mental Exam as an alternative. It is imperative that the exam be compared with the baseline assessment of the individual during the prescreening of vital signs before the individual enters the exercise.

This Micro-Mental Exam provides a quick, easy, nonintrusive, and stress-free assessment of the patient. The clarity of cognition and ability to perform simple mental tasks could serve to reassure the provider that the patient has not progressed into the dangerous area of delirium secondary to heat exposure.

Use of this simple tool during the CBRNE exercise resulted in the disqualification of 2 individuals for probable heat injury; additionally, it gave the providers a rapid assessment tool to quickly identify and treat individuals with progressive heat stress to heat stroke.

Discussion

Compared with studies of heat injuries in military and football equipment, the expected heat injury in PPE gear is very low.^2-4 The low number of disqualifications during the CBRNE exercise could be due to the extensive measures in place to assist individuals under heat stress. These measures include strict adherence to the work/rest cycles mandated by the DoD, competent leadership in evaluating and treating individuals participating in the exercise, and paying close attention not only to the vital signs, but also participants’ mental status.

A study in 2002 suggested that spending time in an air-conditioned area is the strongest factor in preventing heat-related deaths.¹⁶ The study also recommended prevention measures if heat exposure cannot be avoided: working in the cooler part of the day, plenty of water or nonalcoholic drinks, cool showers, lightweight light-colored clothing, and avoiding direct sunshine.¹⁶

A study in 2013 suggested that heat injuries are a significant threat to the effectiveness of military operations in general and to the youngest (the most inexperienced soldiers) specifically.¹⁷ The study further suggested that it is imperative that leaders be aware of adequate hydration on the one hand and excessive water intake on the other and enforce effective countermeasures against all types of heat injuries.¹⁷

Hyponatremia

Hyponatremia is a possible complication of heat exposure and can be divided into categories according to volume: hypovolemia, euvolemia, and hypervolemia.¹⁸ Hyponatremia is associated with excessive water consumption and excessive sodium losses via sweat during prolonged physical exertion. Symptoms of hyponatremia are related to the severity of sodium deficit and the rate of sodium decline.¹⁸ These symptoms include but are not limited to polydipsia, muscle cramps, headache, altered mental status, coma, and status epilepticus.

Hypovolemic hyponatremia usually will have signs of volume depletion, and sodium levels < 20 mEq/L. Treatment typically consists of volume replenishment with isotonic saline (0.9%), treatment of the underlying condition, and correction of the factors causing hypovolemia.

Euvolemic hyponatremia is typically due to the syndrome of inappropriate antidiuretic hormone (SIADH) and spot urinary sodium is > 20 mEq/L. Correction consists of fluid restriction and correction of the underlying cause.¹⁸

Hypervolemic hyponatremia occurs when the kidneys are overwhelmed and cannot excrete water effectively. It is commonly caused by heart failure, cirrhosis, or renal injury. Treatment consists of correction of the underlying cause, sodium and fluid restriction, and diuretic therapy.¹⁸ In severe cases of hyponatremia, sodium levels usually have decreased rapidly—typically in less than 24 hours.

Hyponatremia is defined as plasma sodium levels < 135 mEq/L, and severe symptoms often occur when the sodium level reaches 120 mEq/L. Treatment must be initiated quickly to avoid cerebral edema, respiratory failure, brain stem herniation, and death. Correction includes hypertonic 3% saline infusion at a rate of 0.5 to 2 mL/kg per hour until symptoms resolve. Two separate studies in 2014 and 2013 suggested that the rate of sodium correction should be 6 to 12 mEq/L in the first 24 hours and 18 mEq/L or less in 48 hours.^19,20

In 2009, Sterns and colleagues suggested that for the treatment of hyponatremia the therapeutic goals for serum sodium concentrations should be 6 to 8 mmol/L in 24 hours, 12 to 14 mmol/L in 48 hours, and 14 to 16 mmol/L in 72 hours.²¹ To exceed these parameters in the correction of hyponatremia risks overcorrection and iatrogenic brain damage.²¹

Care must be taken not to overcorrect sodium levels. In 2013, Sood and colleagues reported that in severe hyponatremia, a combination of 3% saline and 1 to 2 µg of desmopressin every 6 to 8 hours achieved a predictable correction of 3 to 7 mEq/L per hour with no overcorrection.²²

In the spring of 1998, U.S. Army guidelines were revised not only to protect service members from heat injury, but also from hyponatremia caused by excessive sodium loss due to exertion combined with excessive water consumption. There were fewer hospitalizations of soldiers for hyponatremia due to excessive water consumption after the guidelines were implemented.²³ Potential hyponatremia in PPE is even greater due to the strenuous environment. The potential injury due to heat injury on the one hand and hyponatremia on the other demands tailored scrutiny by experienced providers and commanders who can make appropriate changes to the work-rest cycle as needed.

Quick recognition and treatment of exercise-induced hyponatremia is essential to avoid altered mental status, seizures, coma, and death. Current guidelines for the correction of exercise-induced hyponatremia suggest rapid correction of hyponatremia with up to three 100 mL boluses of 3% NaCl in 10-minute intervals. A 2012 case study by Elsaesser and colleagues reported that a severely dehydrated marathon runner with exercise-induced hyponatremic encephalopathy achieved a resolution of symptoms with rapid correction with 100 mL boluses of 3% NaCl spaced in 10-minute intervals. An additional volume of 650 mL of 3% NaCl given over 2 hours for a total volume of 950 mL was needed to resolve the exercise-induced hyponatremia.²⁴ It seems that a 4- to 6-mmol/L increase in serum (Na+) is adequate to reverse most serious clinical manifestations of acute hyponatremia.²¹

When hyponatremia is corrected too rapidly, the brain’s ability to absorb the metabolites is overwhelmed, resulting in osmotic demyelination.²¹ Demyelination was produced in animal models by the rapid induction of hypernatremia and can occur in patients who are overcorrected to a hypernatremic state.²⁰ When individuals with chronic hyponatremia are corrected to normal sodium levels, an initial improvement may occur followed by new and often progressive neurologic deficits.²⁰

In 2012, Elsaesser and colleagues suggested that concern regarding overcorrection of hyponatremia might be exaggerated in the setting of exercise-induced hyponatremia. Indeed, the only cases of death associated with exercise-induced hyponatremia have been in the setting of no treatment or slow correction of hyponatremia with normal saline.²⁴

Conclusions

The issue of heat injury in athletic and military environments plagues participants and leaders alike. This article has sought to shed light on mechanisms that are helpful in mitigating heat injury. Football equipment and military protective gear that diminishes that ability to dissipate heat through the retardation of evaporation, convection, and radiation is a key factor in the development of heat injury.

Personal protective equipment is the most hazardous environment for the development of heat injury. This protective gear along with increased environmental humidity, elevated temperature, and increased workload create a dangerous environment for the individuals involved. Careful monitoring of vital signs is an important factor in avoiding heat injuries.

This article proposes that vital signs along with strict monitoring of mental status through (1) orientation; (2) simple task completion; (3) thought processes; and (4) cognitive ability over time combine to be a powerful deterrent to heat injury in an austere and dangerous working environment. It would be cavalier to propose that all heat injuries in any environment could be avoided by following these guidelines, and more tools to avoid heat injury will be developed. But medical providers trained not only to use vital signs, but also monitor and respond to mental status changes in the patient can mitigate heat injuries more effectively. Finally, careful attention should be placed on correcting hypo- and hypernatremia when rehydrating individuals in this challenging environment.

Acknowledgements
The authors wish to thank the following for their contribution to this manuscript: Sarah M. Paulsen, REB Smith, and the entire CERF-P leadership of the Utah National Guard.

Heat injuries are a major problem worldwide. In a study chronicling heat deaths in the U.S. from 1979 to 1999, a total of 8,015 deaths were associated with excessive heat exposure.¹ Weather conditions caused 3,829 (48%) deaths, and manmade conditions (kitchens, vehicles, boiler rooms, etc) caused 377 (5%) deaths, particularly for those wearing protective clothing.¹

Military members who wear combat gear are especially vulnerable to heat injuries, but none more so than members who wear personal protective equipment (PPE). In this review, PPE is defined as self-contained breathing apparatus protective equipment (SCBA) levels B or C. The challenge of PPE is the inability of the individual to dispel heat through radiation, convection, and evaporation. The only close approximation of the PPE environment is combat and football protective equipment. In 2011, CDC reported that football players in uniforms, which resemble PPE for the purpose of this discussion, experienced heat injury at a rate 10 times higher than the average rate for other sports.² These heat injuries in football players occurred most often during August.² The injuries could be due to the application of protective clothing and the lack of the participants’ acclimatization. Protective clothing impedes the wearer’s ability to balance heat production with heat dissipation.

In 2010, Armstrong and colleagues suggested that the weight of a football uniform increases heat production.³ And the insulation provided by a football uniform reduces heat dissipation to the surrounding air, decreasing heat loss.³ Additionally, this same study indicated that the more protective gear the subject used, the greater the heat stress.³ The most challenging environment for heat injury is PPE due to the inability to facilitate any heat loss. In 2011, Caldwell and colleagues observed that wearing torso armor increased body temperature 10.8% faster than that of the control group, and those wearing full armor increased body temperature 38% faster than that of the control group.⁴ And it was proposed that 60% of this heat effect was from wearing the combat helmet.⁴

The inability to dissipate heat, particularly in protective gear, results in degradation of the effectiveness of the individual and, if left unchecked, may lead to death. Methods exist for health care providers to assess, intervene, and treat populations with heat injuries. These methods include but are not limited to vital signs (blood pressure [BP], body temperature, respiration rate), history of previous heat injury, medications (over-the-counter and prescription), and mental status.

Heat Injuries

Heat injuries are generally divided into 3 categories defined by their severity: heat stress, heat exhaustion, and heat stroke. Heat injuries are due to the individual’s inability to dissipate heat. As the severity of the heat exposure continues, the individual will experience heat stress, and if decompensation continues, the individual will progress to heat exhaustion and finally heat stroke.

If the individual’s physiology is limited or if compensatory mechanisms are compromised, heat stress may occur. Heat compensation can be retarded by any number of the following (including but not limited to): humidity, previous heat injury, lack of sleep, medications, sedentary lifestyle, obesity, caffeinated energy drinks, and dehydration.

In the early phases of heat stress, an individual’s vital signs will increase to compensate for the increase in body heat. Heat exchange is dependent on gradients of temperature and humidity, and as temperature and humidity increase, the ability to transfer heat decreases and becomes less efficient. Failure to accommodate for the increased heat generated and transferred will inevitably result in heat injury.

Working in a hazmat environment in PPE is the worst possible heat transfer scenario due to the inability to use evaporation, the primary means by which heat is released from the body. In this scenario, heat injuries can become dangerous and even fatal if monitoring of vital signs and uncompensated heat production is allowed to continue. As the heat insult progresses from heat stress to heat exhaustion and heat stroke, the core temperature, heart rate, and BP continue to increase. Also, during the progression of heat injury, mental status changes often begin to occur. In 2012, Morley and colleagues found that firefighters wearing protective clothing demonstrated a neurocognitive decline after 50 minutes of treadmill exercise, but these performance declines were not noted until 1 hour or more following the exercise.⁵

Mental status change is a key diagnostic factor that indicates the progression of the patient from heat stress to heat exhaustion and from heat exhaustion to heat stroke. As the hyperthermia progresses, vital signs increase, and the patient’s mental status will begin to deteriorate. If the hyperthermia advances from heat exhaustion to heat stroke, hospitalization is required to reverse the condition. If homeostasis is not restored, the patient may die.

Mental status changes are usually described as fatigue, lethargy, disorientation, headache, seizure and coma. Indeed, mental status changes may be one of the most important factors that can assist the clinician in the identification, mitigation, and treatment of heat injury before it reaches a critical stage. Clinical familiarity with and diagnosis of delirium resulting from heat injury could prove beneficial in protecting an individual exposed to severe heat environments.

In 2011, Becker and Stewart suggested that in the absence of hyperthermia, the presence of central nervous system (CNS) symptoms should prompt the clinician to pursue another diagnosis.⁶ However, a core temperature of 104°F with associated CNS changes and anhydrosis should be defined as heat stroke and is a medical emergency.⁶

Death rates from excessive heat are documented as high as 31%.⁷ Signs of CNS dysfunction such as irritability, ataxia, headache, nausea, vomiting, anhydrosis, confusion, and decreased cognitive function are essential to the diagnosis of heat stroke. Classic heat stroke will present as a triad of hyperpyrexia, anhydrosis, and mental status changes.⁸ However, making the diagnosis of heat stroke based on anhydrosis could be dangerous, because in exertional heat stroke, many patients continue to sweat. Overlooking the diagnosis of heat stroke based on anhydrosis could lead to a delay in treatment and severe complications.⁸ These complications may include hyperkalemia, hyperphosphatemia, hypocalcemia, and myoglobinuria.

Once heat stroke has occurred, coagulopathies may manifest as epistaxis, and endothelial damage may present as peripheral or pulmonary edema. Additionally, a core temperature of above 104°F may trigger a cascade of events that may include systemic inflammatory response resulting in increased cell wall permeability and release of endotoxins. These events can lead to tissue hypoxia, metabolic acidosis, and organ failure. Sequalae from heat stroke can result in multisystem failure. A 1998 study of Chicago heat wave victims reported that the degree of functional disability predicted survival at 1 year.⁹ Although hospital mortality was 21%, severe functional impairment at discharge was 33%, with an additional 28% mortality at 1 year.⁹ And the 1-year mortality from heat stroke is similar to that of cerebral vascular accidents.¹⁰ Within 24 hours, heat stroke victims often will display evidence of muscle, kidney, and cardiac dysfunction. Delay in intervention raises the risk of fatalities associated with hyperthermia.^11,12 Tissue destruction due to uncompensated heat may lead to rhabdomyolysis and subsequent myoglobinuria and renal injury. Damaged hepatocytes may lead to coagulopathies and hepatitis. Injured heart muscle may lead to arrhythmias and cardiac arrest.

The CNS symptoms may be difficult to ascertain in an intense working environment. The CNS system dysfunction is indicative of progression from heat injury to heat stroke and thus a medical emergency. It is imperative that the clinician be able to assess the individual quickly and accurately.

Delirium

Along with physical problems associated with it, heat injury can also lead to relatively abrupt mental status changes. In 2005, Glazer reported that even with minimally elevated core temperatures, CNS system changes can present with altered mental status, convulsions, and coma.¹³ This qualifies as a medical emergency known as delirium. Patients with delirium may present with a history of abrupt and fluctuating levels of consciousness. This fluctuation in symptoms that resemble sepsis could confuse medical providers.¹³ Thus, it is imperative that there be continuity of care of the patient with the ability to compare states of consciousness longitudinally over time.

In 1984, Pérez reported that nurses, perhaps because of their familiarity with and proximity to the patient, recorded delirium in 93% of patients, whereas psychiatric consultants recorded delirium only 34% of the time.¹⁴ Delirium manifests with several neurologic signs and symptoms; these include but are not limited to tremor, myoclonus, difficulty reading and writing, and visuoconstructive deficits, such as copying designs and problem solving.¹⁵ No matter the method to discover the delirium, the definitive treatment is to identify and treat the underlying medical condition.¹⁵ The CNS system dysfunction consistent with delirium such as irritability, ataxia, and confusion are essential to the diagnosis of heat stroke.¹³ Coma and seizures may occur, and retarded recovery of functional ability is an indication of a poor prognosis.⁹

Objective

The authors propose that in addition to vital signs, an assessment of a patient’s mental status through the use of a mental status exam could be a tool that identifies the problem early and avoids the progression of symptoms from heat stress to heat exhaustion and heat stroke. Early intervention in the progression of symptoms of hyperthermia can save lives, decrease suffering, and maintain a more robust mission-ready posture for the individual and the unit.

Study

During the fall of 2014, the Chemical, Biological, Radiological, Nuclear, and Explosive (CBRNE) unit of the Utah Air and Army National Guard participated in exercises using 2,159 patient encounters that were in PPE (full hazmat and SCBA) also known as level C protective clothing. Temperatures ranged from a minimum of 29°F to a high of 56°F. A mock disaster was practiced for 5 days, and of those 2,159 iterations, 43 were disqualified (2%) for any reason. Two individuals presented with altered mental status and disrupted vital signs and were disqualified for heat injuries with cognitive symptoms (0.00092%). These members were excused from duty, monitored in the medical work/rest tent until mental status and vital signs returned to baseline.

The tool used in the study was the Micro-Mental Test. This is a mental status exam that is more than a simple gestalt of how the patient is performing cognitively but less than a full Mini-Mental State Examination (MMSE). This abbreviated mental status exam provides a field expedient measurement of the individual’s ability to function cognitively. It is important to realize that this exam is most effective when repeated over time to assess the patients’ mental status longitudinally. It would be cavalier to propose that an abbreviated mental status exam would be sufficient to diagnose heat stroke, but a mental status exam—however brief—along with symptoms of hyperpyrexia, abnormal vital signs, and anhydrosis can be a useful tool to make the diagnostic transition from heat exhaustion to heat stroke.

Micro-Mental Status Exam

The traditional mental status measures are appearance, behavior, speech, mood, affect, thought process, thought content, cognition, insight, and judgment. Rapidly assessing mental status is crucial for the assessment of heat injuries, because increased vital signs coupled with neurologic changes indicate a medical emergency. The MMSE is painstaking and a somewhat cumbersome tool to use in the field. Therefore, the authors suggest a micro-mental status exam (Table). This abbreviated mental status exam is performed before the individual is placed in the PPE and enters the working environment.

The individual is then assessed after every rotation exiting the PPE and allowed to rest under supervision. Assessing the individual with vital signs and mental status longitudinally allows the provider to rapidly assess and intervene if the patient begins to exhibit mental status changes along with increased vital signs. The patient is assessed for ataxia, confusion, irritability, and lack of coordination. Patients are asked to find from a file drawer their individual prescreen checklist. This test assesses fine motor skills and cognition. Following this, self-identifying personal information from a precheck sheet is verified, and finally, simple questions regarding orientation to person, place, date, and time are posed.

Assessing Executive Function

Examples of measures of thought processes include assessing executive function by having participants find their paperwork, identifying their platoon leader, and correctly responding to questions, such as, “Where exactly were you working in the emergency area and what exactly were you doing?” This assesses executive function and thought process. Thought content could be assessed with inquiries such as, “Anything troubling about your work?” or “Would you tell me honestly if there were anything troubling or unsafe about the work you have performed?” Cognition could be assessed by questions regarding chain of command (both officer and enlisted), 3 suggestions to improve, 3 suggestions to maintain, and knowledge of the rotation schedule for the rest of the day.

The abbreviated mental status exam should in no way replace the robust and accurate mental status exam. However, in a rapidly changing, austere, or asymmetrical environment, a simple gestalt of the patient is ineffective, and the full mental status evaluation may be too time consuming. The authors propose the Micro-Mental Exam as an alternative. It is imperative that the exam be compared with the baseline assessment of the individual during the prescreening of vital signs before the individual enters the exercise.

This Micro-Mental Exam provides a quick, easy, nonintrusive, and stress-free assessment of the patient. The clarity of cognition and ability to perform simple mental tasks could serve to reassure the provider that the patient has not progressed into the dangerous area of delirium secondary to heat exposure.

Use of this simple tool during the CBRNE exercise resulted in the disqualification of 2 individuals for probable heat injury; additionally, it gave the providers a rapid assessment tool to quickly identify and treat individuals with progressive heat stress to heat stroke.

Discussion

Compared with studies of heat injuries in military and football equipment, the expected heat injury in PPE gear is very low.^2-4 The low number of disqualifications during the CBRNE exercise could be due to the extensive measures in place to assist individuals under heat stress. These measures include strict adherence to the work/rest cycles mandated by the DoD, competent leadership in evaluating and treating individuals participating in the exercise, and paying close attention not only to the vital signs, but also participants’ mental status.

A study in 2002 suggested that spending time in an air-conditioned area is the strongest factor in preventing heat-related deaths.¹⁶ The study also recommended prevention measures if heat exposure cannot be avoided: working in the cooler part of the day, plenty of water or nonalcoholic drinks, cool showers, lightweight light-colored clothing, and avoiding direct sunshine.¹⁶

A study in 2013 suggested that heat injuries are a significant threat to the effectiveness of military operations in general and to the youngest (the most inexperienced soldiers) specifically.¹⁷ The study further suggested that it is imperative that leaders be aware of adequate hydration on the one hand and excessive water intake on the other and enforce effective countermeasures against all types of heat injuries.¹⁷

Hyponatremia

Hyponatremia is a possible complication of heat exposure and can be divided into categories according to volume: hypovolemia, euvolemia, and hypervolemia.¹⁸ Hyponatremia is associated with excessive water consumption and excessive sodium losses via sweat during prolonged physical exertion. Symptoms of hyponatremia are related to the severity of sodium deficit and the rate of sodium decline.¹⁸ These symptoms include but are not limited to polydipsia, muscle cramps, headache, altered mental status, coma, and status epilepticus.

Hypovolemic hyponatremia usually will have signs of volume depletion, and sodium levels < 20 mEq/L. Treatment typically consists of volume replenishment with isotonic saline (0.9%), treatment of the underlying condition, and correction of the factors causing hypovolemia.

Euvolemic hyponatremia is typically due to the syndrome of inappropriate antidiuretic hormone (SIADH) and spot urinary sodium is > 20 mEq/L. Correction consists of fluid restriction and correction of the underlying cause.¹⁸

Hypervolemic hyponatremia occurs when the kidneys are overwhelmed and cannot excrete water effectively. It is commonly caused by heart failure, cirrhosis, or renal injury. Treatment consists of correction of the underlying cause, sodium and fluid restriction, and diuretic therapy.¹⁸ In severe cases of hyponatremia, sodium levels usually have decreased rapidly—typically in less than 24 hours.

Hyponatremia is defined as plasma sodium levels < 135 mEq/L, and severe symptoms often occur when the sodium level reaches 120 mEq/L. Treatment must be initiated quickly to avoid cerebral edema, respiratory failure, brain stem herniation, and death. Correction includes hypertonic 3% saline infusion at a rate of 0.5 to 2 mL/kg per hour until symptoms resolve. Two separate studies in 2014 and 2013 suggested that the rate of sodium correction should be 6 to 12 mEq/L in the first 24 hours and 18 mEq/L or less in 48 hours.^19,20

In 2009, Sterns and colleagues suggested that for the treatment of hyponatremia the therapeutic goals for serum sodium concentrations should be 6 to 8 mmol/L in 24 hours, 12 to 14 mmol/L in 48 hours, and 14 to 16 mmol/L in 72 hours.²¹ To exceed these parameters in the correction of hyponatremia risks overcorrection and iatrogenic brain damage.²¹

Care must be taken not to overcorrect sodium levels. In 2013, Sood and colleagues reported that in severe hyponatremia, a combination of 3% saline and 1 to 2 µg of desmopressin every 6 to 8 hours achieved a predictable correction of 3 to 7 mEq/L per hour with no overcorrection.²²

In the spring of 1998, U.S. Army guidelines were revised not only to protect service members from heat injury, but also from hyponatremia caused by excessive sodium loss due to exertion combined with excessive water consumption. There were fewer hospitalizations of soldiers for hyponatremia due to excessive water consumption after the guidelines were implemented.²³ Potential hyponatremia in PPE is even greater due to the strenuous environment. The potential injury due to heat injury on the one hand and hyponatremia on the other demands tailored scrutiny by experienced providers and commanders who can make appropriate changes to the work-rest cycle as needed.

Quick recognition and treatment of exercise-induced hyponatremia is essential to avoid altered mental status, seizures, coma, and death. Current guidelines for the correction of exercise-induced hyponatremia suggest rapid correction of hyponatremia with up to three 100 mL boluses of 3% NaCl in 10-minute intervals. A 2012 case study by Elsaesser and colleagues reported that a severely dehydrated marathon runner with exercise-induced hyponatremic encephalopathy achieved a resolution of symptoms with rapid correction with 100 mL boluses of 3% NaCl spaced in 10-minute intervals. An additional volume of 650 mL of 3% NaCl given over 2 hours for a total volume of 950 mL was needed to resolve the exercise-induced hyponatremia.²⁴ It seems that a 4- to 6-mmol/L increase in serum (Na+) is adequate to reverse most serious clinical manifestations of acute hyponatremia.²¹

When hyponatremia is corrected too rapidly, the brain’s ability to absorb the metabolites is overwhelmed, resulting in osmotic demyelination.²¹ Demyelination was produced in animal models by the rapid induction of hypernatremia and can occur in patients who are overcorrected to a hypernatremic state.²⁰ When individuals with chronic hyponatremia are corrected to normal sodium levels, an initial improvement may occur followed by new and often progressive neurologic deficits.²⁰

In 2012, Elsaesser and colleagues suggested that concern regarding overcorrection of hyponatremia might be exaggerated in the setting of exercise-induced hyponatremia. Indeed, the only cases of death associated with exercise-induced hyponatremia have been in the setting of no treatment or slow correction of hyponatremia with normal saline.²⁴

Conclusions

The issue of heat injury in athletic and military environments plagues participants and leaders alike. This article has sought to shed light on mechanisms that are helpful in mitigating heat injury. Football equipment and military protective gear that diminishes that ability to dissipate heat through the retardation of evaporation, convection, and radiation is a key factor in the development of heat injury.

Personal protective equipment is the most hazardous environment for the development of heat injury. This protective gear along with increased environmental humidity, elevated temperature, and increased workload create a dangerous environment for the individuals involved. Careful monitoring of vital signs is an important factor in avoiding heat injuries.

This article proposes that vital signs along with strict monitoring of mental status through (1) orientation; (2) simple task completion; (3) thought processes; and (4) cognitive ability over time combine to be a powerful deterrent to heat injury in an austere and dangerous working environment. It would be cavalier to propose that all heat injuries in any environment could be avoided by following these guidelines, and more tools to avoid heat injury will be developed. But medical providers trained not only to use vital signs, but also monitor and respond to mental status changes in the patient can mitigate heat injuries more effectively. Finally, careful attention should be placed on correcting hypo- and hypernatremia when rehydrating individuals in this challenging environment.

Acknowledgements
The authors wish to thank the following for their contribution to this manuscript: Sarah M. Paulsen, REB Smith, and the entire CERF-P leadership of the Utah National Guard.

Heat injuries are a major problem worldwide. In a study chronicling heat deaths in the U.S. from 1979 to 1999, a total of 8,015 deaths were associated with excessive heat exposure.¹ Weather conditions caused 3,829 (48%) deaths, and manmade conditions (kitchens, vehicles, boiler rooms, etc) caused 377 (5%) deaths, particularly for those wearing protective clothing.¹

Military members who wear combat gear are especially vulnerable to heat injuries, but none more so than members who wear personal protective equipment (PPE). In this review, PPE is defined as self-contained breathing apparatus protective equipment (SCBA) levels B or C. The challenge of PPE is the inability of the individual to dispel heat through radiation, convection, and evaporation. The only close approximation of the PPE environment is combat and football protective equipment. In 2011, CDC reported that football players in uniforms, which resemble PPE for the purpose of this discussion, experienced heat injury at a rate 10 times higher than the average rate for other sports.² These heat injuries in football players occurred most often during August.² The injuries could be due to the application of protective clothing and the lack of the participants’ acclimatization. Protective clothing impedes the wearer’s ability to balance heat production with heat dissipation.

In 2010, Armstrong and colleagues suggested that the weight of a football uniform increases heat production.³ And the insulation provided by a football uniform reduces heat dissipation to the surrounding air, decreasing heat loss.³ Additionally, this same study indicated that the more protective gear the subject used, the greater the heat stress.³ The most challenging environment for heat injury is PPE due to the inability to facilitate any heat loss. In 2011, Caldwell and colleagues observed that wearing torso armor increased body temperature 10.8% faster than that of the control group, and those wearing full armor increased body temperature 38% faster than that of the control group.⁴ And it was proposed that 60% of this heat effect was from wearing the combat helmet.⁴

The inability to dissipate heat, particularly in protective gear, results in degradation of the effectiveness of the individual and, if left unchecked, may lead to death. Methods exist for health care providers to assess, intervene, and treat populations with heat injuries. These methods include but are not limited to vital signs (blood pressure [BP], body temperature, respiration rate), history of previous heat injury, medications (over-the-counter and prescription), and mental status.

Heat Injuries

Heat injuries are generally divided into 3 categories defined by their severity: heat stress, heat exhaustion, and heat stroke. Heat injuries are due to the individual’s inability to dissipate heat. As the severity of the heat exposure continues, the individual will experience heat stress, and if decompensation continues, the individual will progress to heat exhaustion and finally heat stroke.

If the individual’s physiology is limited or if compensatory mechanisms are compromised, heat stress may occur. Heat compensation can be retarded by any number of the following (including but not limited to): humidity, previous heat injury, lack of sleep, medications, sedentary lifestyle, obesity, caffeinated energy drinks, and dehydration.

In the early phases of heat stress, an individual’s vital signs will increase to compensate for the increase in body heat. Heat exchange is dependent on gradients of temperature and humidity, and as temperature and humidity increase, the ability to transfer heat decreases and becomes less efficient. Failure to accommodate for the increased heat generated and transferred will inevitably result in heat injury.

Working in a hazmat environment in PPE is the worst possible heat transfer scenario due to the inability to use evaporation, the primary means by which heat is released from the body. In this scenario, heat injuries can become dangerous and even fatal if monitoring of vital signs and uncompensated heat production is allowed to continue. As the heat insult progresses from heat stress to heat exhaustion and heat stroke, the core temperature, heart rate, and BP continue to increase. Also, during the progression of heat injury, mental status changes often begin to occur. In 2012, Morley and colleagues found that firefighters wearing protective clothing demonstrated a neurocognitive decline after 50 minutes of treadmill exercise, but these performance declines were not noted until 1 hour or more following the exercise.⁵

Mental status change is a key diagnostic factor that indicates the progression of the patient from heat stress to heat exhaustion and from heat exhaustion to heat stroke. As the hyperthermia progresses, vital signs increase, and the patient’s mental status will begin to deteriorate. If the hyperthermia advances from heat exhaustion to heat stroke, hospitalization is required to reverse the condition. If homeostasis is not restored, the patient may die.

Mental status changes are usually described as fatigue, lethargy, disorientation, headache, seizure and coma. Indeed, mental status changes may be one of the most important factors that can assist the clinician in the identification, mitigation, and treatment of heat injury before it reaches a critical stage. Clinical familiarity with and diagnosis of delirium resulting from heat injury could prove beneficial in protecting an individual exposed to severe heat environments.

In 2011, Becker and Stewart suggested that in the absence of hyperthermia, the presence of central nervous system (CNS) symptoms should prompt the clinician to pursue another diagnosis.⁶ However, a core temperature of 104°F with associated CNS changes and anhydrosis should be defined as heat stroke and is a medical emergency.⁶

Death rates from excessive heat are documented as high as 31%.⁷ Signs of CNS dysfunction such as irritability, ataxia, headache, nausea, vomiting, anhydrosis, confusion, and decreased cognitive function are essential to the diagnosis of heat stroke. Classic heat stroke will present as a triad of hyperpyrexia, anhydrosis, and mental status changes.⁸ However, making the diagnosis of heat stroke based on anhydrosis could be dangerous, because in exertional heat stroke, many patients continue to sweat. Overlooking the diagnosis of heat stroke based on anhydrosis could lead to a delay in treatment and severe complications.⁸ These complications may include hyperkalemia, hyperphosphatemia, hypocalcemia, and myoglobinuria.

Once heat stroke has occurred, coagulopathies may manifest as epistaxis, and endothelial damage may present as peripheral or pulmonary edema. Additionally, a core temperature of above 104°F may trigger a cascade of events that may include systemic inflammatory response resulting in increased cell wall permeability and release of endotoxins. These events can lead to tissue hypoxia, metabolic acidosis, and organ failure. Sequalae from heat stroke can result in multisystem failure. A 1998 study of Chicago heat wave victims reported that the degree of functional disability predicted survival at 1 year.⁹ Although hospital mortality was 21%, severe functional impairment at discharge was 33%, with an additional 28% mortality at 1 year.⁹ And the 1-year mortality from heat stroke is similar to that of cerebral vascular accidents.¹⁰ Within 24 hours, heat stroke victims often will display evidence of muscle, kidney, and cardiac dysfunction. Delay in intervention raises the risk of fatalities associated with hyperthermia.^11,12 Tissue destruction due to uncompensated heat may lead to rhabdomyolysis and subsequent myoglobinuria and renal injury. Damaged hepatocytes may lead to coagulopathies and hepatitis. Injured heart muscle may lead to arrhythmias and cardiac arrest.

The CNS symptoms may be difficult to ascertain in an intense working environment. The CNS system dysfunction is indicative of progression from heat injury to heat stroke and thus a medical emergency. It is imperative that the clinician be able to assess the individual quickly and accurately.

Delirium

Along with physical problems associated with it, heat injury can also lead to relatively abrupt mental status changes. In 2005, Glazer reported that even with minimally elevated core temperatures, CNS system changes can present with altered mental status, convulsions, and coma.¹³ This qualifies as a medical emergency known as delirium. Patients with delirium may present with a history of abrupt and fluctuating levels of consciousness. This fluctuation in symptoms that resemble sepsis could confuse medical providers.¹³ Thus, it is imperative that there be continuity of care of the patient with the ability to compare states of consciousness longitudinally over time.

In 1984, Pérez reported that nurses, perhaps because of their familiarity with and proximity to the patient, recorded delirium in 93% of patients, whereas psychiatric consultants recorded delirium only 34% of the time.¹⁴ Delirium manifests with several neurologic signs and symptoms; these include but are not limited to tremor, myoclonus, difficulty reading and writing, and visuoconstructive deficits, such as copying designs and problem solving.¹⁵ No matter the method to discover the delirium, the definitive treatment is to identify and treat the underlying medical condition.¹⁵ The CNS system dysfunction consistent with delirium such as irritability, ataxia, and confusion are essential to the diagnosis of heat stroke.¹³ Coma and seizures may occur, and retarded recovery of functional ability is an indication of a poor prognosis.⁹

Objective

The authors propose that in addition to vital signs, an assessment of a patient’s mental status through the use of a mental status exam could be a tool that identifies the problem early and avoids the progression of symptoms from heat stress to heat exhaustion and heat stroke. Early intervention in the progression of symptoms of hyperthermia can save lives, decrease suffering, and maintain a more robust mission-ready posture for the individual and the unit.

Study

During the fall of 2014, the Chemical, Biological, Radiological, Nuclear, and Explosive (CBRNE) unit of the Utah Air and Army National Guard participated in exercises using 2,159 patient encounters that were in PPE (full hazmat and SCBA) also known as level C protective clothing. Temperatures ranged from a minimum of 29°F to a high of 56°F. A mock disaster was practiced for 5 days, and of those 2,159 iterations, 43 were disqualified (2%) for any reason. Two individuals presented with altered mental status and disrupted vital signs and were disqualified for heat injuries with cognitive symptoms (0.00092%). These members were excused from duty, monitored in the medical work/rest tent until mental status and vital signs returned to baseline.

The tool used in the study was the Micro-Mental Test. This is a mental status exam that is more than a simple gestalt of how the patient is performing cognitively but less than a full Mini-Mental State Examination (MMSE). This abbreviated mental status exam provides a field expedient measurement of the individual’s ability to function cognitively. It is important to realize that this exam is most effective when repeated over time to assess the patients’ mental status longitudinally. It would be cavalier to propose that an abbreviated mental status exam would be sufficient to diagnose heat stroke, but a mental status exam—however brief—along with symptoms of hyperpyrexia, abnormal vital signs, and anhydrosis can be a useful tool to make the diagnostic transition from heat exhaustion to heat stroke.

Micro-Mental Status Exam

The traditional mental status measures are appearance, behavior, speech, mood, affect, thought process, thought content, cognition, insight, and judgment. Rapidly assessing mental status is crucial for the assessment of heat injuries, because increased vital signs coupled with neurologic changes indicate a medical emergency. The MMSE is painstaking and a somewhat cumbersome tool to use in the field. Therefore, the authors suggest a micro-mental status exam (Table). This abbreviated mental status exam is performed before the individual is placed in the PPE and enters the working environment.

The individual is then assessed after every rotation exiting the PPE and allowed to rest under supervision. Assessing the individual with vital signs and mental status longitudinally allows the provider to rapidly assess and intervene if the patient begins to exhibit mental status changes along with increased vital signs. The patient is assessed for ataxia, confusion, irritability, and lack of coordination. Patients are asked to find from a file drawer their individual prescreen checklist. This test assesses fine motor skills and cognition. Following this, self-identifying personal information from a precheck sheet is verified, and finally, simple questions regarding orientation to person, place, date, and time are posed.

Assessing Executive Function

Examples of measures of thought processes include assessing executive function by having participants find their paperwork, identifying their platoon leader, and correctly responding to questions, such as, “Where exactly were you working in the emergency area and what exactly were you doing?” This assesses executive function and thought process. Thought content could be assessed with inquiries such as, “Anything troubling about your work?” or “Would you tell me honestly if there were anything troubling or unsafe about the work you have performed?” Cognition could be assessed by questions regarding chain of command (both officer and enlisted), 3 suggestions to improve, 3 suggestions to maintain, and knowledge of the rotation schedule for the rest of the day.

The abbreviated mental status exam should in no way replace the robust and accurate mental status exam. However, in a rapidly changing, austere, or asymmetrical environment, a simple gestalt of the patient is ineffective, and the full mental status evaluation may be too time consuming. The authors propose the Micro-Mental Exam as an alternative. It is imperative that the exam be compared with the baseline assessment of the individual during the prescreening of vital signs before the individual enters the exercise.

This Micro-Mental Exam provides a quick, easy, nonintrusive, and stress-free assessment of the patient. The clarity of cognition and ability to perform simple mental tasks could serve to reassure the provider that the patient has not progressed into the dangerous area of delirium secondary to heat exposure.

Use of this simple tool during the CBRNE exercise resulted in the disqualification of 2 individuals for probable heat injury; additionally, it gave the providers a rapid assessment tool to quickly identify and treat individuals with progressive heat stress to heat stroke.

Discussion

Compared with studies of heat injuries in military and football equipment, the expected heat injury in PPE gear is very low.^2-4 The low number of disqualifications during the CBRNE exercise could be due to the extensive measures in place to assist individuals under heat stress. These measures include strict adherence to the work/rest cycles mandated by the DoD, competent leadership in evaluating and treating individuals participating in the exercise, and paying close attention not only to the vital signs, but also participants’ mental status.

A study in 2002 suggested that spending time in an air-conditioned area is the strongest factor in preventing heat-related deaths.¹⁶ The study also recommended prevention measures if heat exposure cannot be avoided: working in the cooler part of the day, plenty of water or nonalcoholic drinks, cool showers, lightweight light-colored clothing, and avoiding direct sunshine.¹⁶

A study in 2013 suggested that heat injuries are a significant threat to the effectiveness of military operations in general and to the youngest (the most inexperienced soldiers) specifically.¹⁷ The study further suggested that it is imperative that leaders be aware of adequate hydration on the one hand and excessive water intake on the other and enforce effective countermeasures against all types of heat injuries.¹⁷

Hyponatremia

Hyponatremia is a possible complication of heat exposure and can be divided into categories according to volume: hypovolemia, euvolemia, and hypervolemia.¹⁸ Hyponatremia is associated with excessive water consumption and excessive sodium losses via sweat during prolonged physical exertion. Symptoms of hyponatremia are related to the severity of sodium deficit and the rate of sodium decline.¹⁸ These symptoms include but are not limited to polydipsia, muscle cramps, headache, altered mental status, coma, and status epilepticus.

Hypovolemic hyponatremia usually will have signs of volume depletion, and sodium levels < 20 mEq/L. Treatment typically consists of volume replenishment with isotonic saline (0.9%), treatment of the underlying condition, and correction of the factors causing hypovolemia.

Euvolemic hyponatremia is typically due to the syndrome of inappropriate antidiuretic hormone (SIADH) and spot urinary sodium is > 20 mEq/L. Correction consists of fluid restriction and correction of the underlying cause.¹⁸

Hypervolemic hyponatremia occurs when the kidneys are overwhelmed and cannot excrete water effectively. It is commonly caused by heart failure, cirrhosis, or renal injury. Treatment consists of correction of the underlying cause, sodium and fluid restriction, and diuretic therapy.¹⁸ In severe cases of hyponatremia, sodium levels usually have decreased rapidly—typically in less than 24 hours.

Hyponatremia is defined as plasma sodium levels < 135 mEq/L, and severe symptoms often occur when the sodium level reaches 120 mEq/L. Treatment must be initiated quickly to avoid cerebral edema, respiratory failure, brain stem herniation, and death. Correction includes hypertonic 3% saline infusion at a rate of 0.5 to 2 mL/kg per hour until symptoms resolve. Two separate studies in 2014 and 2013 suggested that the rate of sodium correction should be 6 to 12 mEq/L in the first 24 hours and 18 mEq/L or less in 48 hours.^19,20

In 2009, Sterns and colleagues suggested that for the treatment of hyponatremia the therapeutic goals for serum sodium concentrations should be 6 to 8 mmol/L in 24 hours, 12 to 14 mmol/L in 48 hours, and 14 to 16 mmol/L in 72 hours.²¹ To exceed these parameters in the correction of hyponatremia risks overcorrection and iatrogenic brain damage.²¹

Care must be taken not to overcorrect sodium levels. In 2013, Sood and colleagues reported that in severe hyponatremia, a combination of 3% saline and 1 to 2 µg of desmopressin every 6 to 8 hours achieved a predictable correction of 3 to 7 mEq/L per hour with no overcorrection.²²

In the spring of 1998, U.S. Army guidelines were revised not only to protect service members from heat injury, but also from hyponatremia caused by excessive sodium loss due to exertion combined with excessive water consumption. There were fewer hospitalizations of soldiers for hyponatremia due to excessive water consumption after the guidelines were implemented.²³ Potential hyponatremia in PPE is even greater due to the strenuous environment. The potential injury due to heat injury on the one hand and hyponatremia on the other demands tailored scrutiny by experienced providers and commanders who can make appropriate changes to the work-rest cycle as needed.

Quick recognition and treatment of exercise-induced hyponatremia is essential to avoid altered mental status, seizures, coma, and death. Current guidelines for the correction of exercise-induced hyponatremia suggest rapid correction of hyponatremia with up to three 100 mL boluses of 3% NaCl in 10-minute intervals. A 2012 case study by Elsaesser and colleagues reported that a severely dehydrated marathon runner with exercise-induced hyponatremic encephalopathy achieved a resolution of symptoms with rapid correction with 100 mL boluses of 3% NaCl spaced in 10-minute intervals. An additional volume of 650 mL of 3% NaCl given over 2 hours for a total volume of 950 mL was needed to resolve the exercise-induced hyponatremia.²⁴ It seems that a 4- to 6-mmol/L increase in serum (Na+) is adequate to reverse most serious clinical manifestations of acute hyponatremia.²¹

When hyponatremia is corrected too rapidly, the brain’s ability to absorb the metabolites is overwhelmed, resulting in osmotic demyelination.²¹ Demyelination was produced in animal models by the rapid induction of hypernatremia and can occur in patients who are overcorrected to a hypernatremic state.²⁰ When individuals with chronic hyponatremia are corrected to normal sodium levels, an initial improvement may occur followed by new and often progressive neurologic deficits.²⁰

In 2012, Elsaesser and colleagues suggested that concern regarding overcorrection of hyponatremia might be exaggerated in the setting of exercise-induced hyponatremia. Indeed, the only cases of death associated with exercise-induced hyponatremia have been in the setting of no treatment or slow correction of hyponatremia with normal saline.²⁴

Conclusions

The issue of heat injury in athletic and military environments plagues participants and leaders alike. This article has sought to shed light on mechanisms that are helpful in mitigating heat injury. Football equipment and military protective gear that diminishes that ability to dissipate heat through the retardation of evaporation, convection, and radiation is a key factor in the development of heat injury.

Personal protective equipment is the most hazardous environment for the development of heat injury. This protective gear along with increased environmental humidity, elevated temperature, and increased workload create a dangerous environment for the individuals involved. Careful monitoring of vital signs is an important factor in avoiding heat injuries.

This article proposes that vital signs along with strict monitoring of mental status through (1) orientation; (2) simple task completion; (3) thought processes; and (4) cognitive ability over time combine to be a powerful deterrent to heat injury in an austere and dangerous working environment. It would be cavalier to propose that all heat injuries in any environment could be avoided by following these guidelines, and more tools to avoid heat injury will be developed. But medical providers trained not only to use vital signs, but also monitor and respond to mental status changes in the patient can mitigate heat injuries more effectively. Finally, careful attention should be placed on correcting hypo- and hypernatremia when rehydrating individuals in this challenging environment.

Acknowledgements
The authors wish to thank the following for their contribution to this manuscript: Sarah M. Paulsen, REB Smith, and the entire CERF-P leadership of the Utah National Guard.

Angiotensin-converting enzyme (ACE) inhibitors are commonly used medications in the treatment of hypertension in the ambulatory care setting. Serum sodium concentrations are not usually affected in the majority of patients treated with ACE inhibitors. Nonetheless, hyponatremia, defined as serum sodium level < 135 mEq/L, has been reported in patients taking ACE inhibitors.^1,2 The authors report a case of hyponatremia attributed to the use of lisinopril.

Case Presentation

In 2012, a 49-year-old man with a past medical history significant for polysubstance abuse, alcohol use, and hypertension was referred to the pharmacy clinic by his primary care physician (PCP) for management of hypertension. At the PCP visit, the patient’s blood pressure (BP) was above the goal of < 140/90 mm Hg and hydrochlorothiazide (HCTZ) 12.5 mg by mouth daily monotherapy was initiated. At the follow-up pharmacy appointment 6 weeks later, his BP remained uncontrolled, and HCTZ was increased to 25 mg daily. Of note, at that time the patient reported drinking about 6 beers per week. His electrolytes—serum sodium, potassium, chloride, carbon dioxide (CO₂), blood urea nitrogen (BUN), and serum creatinine (SCr)—were all within normal limits and stable to previous baseline results after taking HCTZ for about 2 weeks.

The patient returned to the pharmacy clinic at week 11, and his BP was controlled (136/83 mm Hg) on HCTZ 25 mg daily. His electrolytes, BUN, and SCr continued to be stable. The patient requested another appointment 8 weeks later to continue to monitor his BP.

The patient did not return to the pharmacy clinic until week 31, when he reported that he was told his BP was very high when attempting to donate plasma. The patient reported drinking a “6 pack of beer per day” at that visit. Two BP readings were taken in the clinic. The first of systolic blood pressure (SBP) was 144 mm Hg and the second was below the patient’s goal (< 140 mm Hg). His pulse (94 bpm) was also noted to be higher than baseline range (66-84 bpm). Atenolol 25 mg daily by mouth was added to the patient’s regimen of HCTZ 25 mg daily.

The patient returned at week 38, and his BP of 149/101 mm Hg was elevated above goal range. Lisinopril was added to HCTZ 25 mg in a combination formulation of lisinopril/HCTZ 20 mg/25 mg by mouth daily. The patient reported drinking 4 beers on days he worked (5 days per week) and 6 beers on days he was off (2 days per week). A repeated electrolyte, BUN, and SCr panel 1 month later (week 42) revealed a drop in the patient’s sodium level from 136 mEq/L (baseline) to 130 mEq/L (Table 1). Other measured electrolytes remained within normal limits with the exception of a slight decrease in serum chloride to 93 mEq/L (Table 2). No symptoms of hyponatremia were noted.

The patient was instructed to cut the lisinopril/HCTZ tablet in half and take it daily, then repeat blood work in 5 days. The patient’s repeated laboratory work noted an increase in sodium level to 134 mEq/L. All other measured electrolytes, including serum chloride, were within normal limits. During his follow-up visit, the patient reported stopping lisinopril/HCTZ altogether and resuming HCTZ 25 mg daily for the 5 days prior, in lieu of taking the reduced lisinopril/HCTZ dose as instructed. The patient continued to report drinking 6 beers daily.

Medication was changed to HCTZ 25 mg daily, with lisinopril discontinued, and atenolol increased to 50 mg daily. At week 46, the patient repeated electrolytes, BUN, and SCr laboratory work while on HCTZ 25 mg and atenolol 50 mg daily, and the serum sodium level increased to 139 mEq/L. After the laboratory work at week 49, he noted a reduction in alcohol to 4 beers daily at the pharmacy appointment. The patient’s BP was controlled to below the < 140/90 mm Hg goal. Medications were not changed. He was instructed to follow up with his PCP and return to the pharmacy clinic as needed for BP control.

Of note, serum magnesium levels are not included in the standard electrolyte panel and must be ordered separately. Additionally, serum magnesium levels are not monitored routinely with thiazide and ACE inhibitor therapy. In this case, serum magnesium levels were not drawn at baseline or in subsequent laboratory monitoring.

Discussion

This case demonstrates a potential link between administration of lisinopril and the development of hyponatremia. Adverse effects (AEs) of ACE inhibitors frequently include elevation in SCr, hyperkalemia, and/or a dry cough. Hyponatremia, although not commonly associated with ACE inhibitors, has been reported in the literature.^1,2

Although the mechanism is not completely understood, previous case reports hypothesized that ACE inhibitor therapy can lead to Syndrome of Inappropriate Antidiuretic Hormone (SIADH).^1,3 Angiotensin I is not converted to angiotensin II peripherally with ACE inhibitor therapy. This elevated circulating level of angiotensin I is available to cross the blood-brain barrier where it is converted to angiotensin II. Angiotensin can then stimulate vasopressin release, which, in turn, increases thirst and leads to decreased amounts of concentrated urine.⁴ The combination of increased thirst and concentrated urine can lead to hyponatremia.

The clinical manifestations of hyponatremia can vary. In patients with ACE inhibitor-induced hyponatremia, an early sign may be polydipsia. Once hyponatremia develops, patients may experience nausea, muscle spasms or weakness, and general malaise. Additionally, lethargy, a decreased level of consciousness, and headaches may occur. In the most severe cases, hyponatremia may lead to seizures, coma, and eventually death.

Several case reports involving various ACE inhibitors, such as captopril, enalapril, and lisinopril, have been reported over the past 30 years, citing the connection linking these medications to SIADH and symptomatic hyponatremia. A large number of cases involved patients with established congestive heart failure for whom ACE inhibitors were added because of their beneficial impact on improved survival and reduced left ventricular dysfunction.⁵ Angiotensin converting enzyme inhibitor-induced hyponatremia may be confounded by heart failure, due to the complex disease pathophysiology.¹ Therefore, case reports of ACE inhibitors use in patients treated for indications other than heart failure, such as hypertension, provide a clearer picture of ACE inhibitor-induced hyponatremia.

One such striking case report involved a 63-year-old woman taking lisinopril 10 mg daily as monotherapy (no other medications) for mild hypertension with a baseline serum sodium level within normal limits.⁶ One month later, the patient was admitted a with serum sodium level of 101 mEq/L and symptomatic with altered mental status and generalized tonic-clonic seizures. Once the serum sodium was corrected, the patient’s mental status improved, and her 1-year follow-up examination was unremarkable. This case report is significant for its findings that there may be a cause-and-effect relationship between lisinopril monotherapy and symptomatic hyponatremia that occurred within a month. There are cases of hyponatremia in patients receiving ACE inhibitor therapy in addition to established diuretic therapy. For example, a woman aged 71 years was admitted for elevated BP with an initial medication regimen that included HCTZ and other antihypertensive medications.⁷ She was given captopril at increasing doses up to 150 mg daily. The patient’s serum sodium levels dropped correspondingly with titrated doses of captopril. The patient reported feeling confusion, and her serum sodium levels dropped to 114 mEq/L. Once captopril was discontinued and serum sodium corrected with IV fluids, the patient’s confusion subsided. The patient was discharged on a medication regimen that continued HCTZ but not the ACE inhibitor, with no clinical consequences and normal serum sodium levels over the following year. Similarly, the patient in this case study had established HCTZ therapy with normal serum sodium that declined upon addition of an ACE inhibitor.

Other factors that could contribute to hyponatremia, such as beer potomania, confound the current case of hyponatremia. This patient reported chronic beer ingestion, which can lead to hyponatremia and may have aggravated the hyponatremia upon initiation of lisinopril. Additionally, the patient was taking HCTZ, an agent known to cause hyponatremia, prior to initiation of the ACE inhibitor. Another limiting factor noted was that serum magnesium levels were not measured to assess for potential hypomagnesemia, which may affect other electrolytes.

Using the Naranjo Assessment scale, a score of 3 was calculated, indicating a possible link to lisinopril as the cause of hyponatremia.⁸ Although the patient had the aforementioned risk factors, the notable drop of serum sodium level correlated with the lisinopril administration, which was previously stable despite HCTZ treatment and alcohol consumption. The time line of events led the authors to believe that hyponatremia was strongly related to lisinopril. This patient was fortunate that he experienced no neurologic complications, which have been reported in other cases of ACE inhibitor-induced hyponatremia, manifested from the drop in serum sodium.

Conclusion

Though rarely occurring, hyponatremia should be considered a potentially serious AE associated with ACE inhibitor therapy. Timely monitoring of electrolytes, BUN, and SCr should continue to assess for more common AEs of elevated SCr and hyperkalemia, but clinicians should be aware of the potential for ACE inhibitor-induced hyponatremia.

Angiotensin-converting enzyme (ACE) inhibitors are commonly used medications in the treatment of hypertension in the ambulatory care setting. Serum sodium concentrations are not usually affected in the majority of patients treated with ACE inhibitors. Nonetheless, hyponatremia, defined as serum sodium level < 135 mEq/L, has been reported in patients taking ACE inhibitors.^1,2 The authors report a case of hyponatremia attributed to the use of lisinopril.

Case Presentation

In 2012, a 49-year-old man with a past medical history significant for polysubstance abuse, alcohol use, and hypertension was referred to the pharmacy clinic by his primary care physician (PCP) for management of hypertension. At the PCP visit, the patient’s blood pressure (BP) was above the goal of < 140/90 mm Hg and hydrochlorothiazide (HCTZ) 12.5 mg by mouth daily monotherapy was initiated. At the follow-up pharmacy appointment 6 weeks later, his BP remained uncontrolled, and HCTZ was increased to 25 mg daily. Of note, at that time the patient reported drinking about 6 beers per week. His electrolytes—serum sodium, potassium, chloride, carbon dioxide (CO₂), blood urea nitrogen (BUN), and serum creatinine (SCr)—were all within normal limits and stable to previous baseline results after taking HCTZ for about 2 weeks.

The patient returned to the pharmacy clinic at week 11, and his BP was controlled (136/83 mm Hg) on HCTZ 25 mg daily. His electrolytes, BUN, and SCr continued to be stable. The patient requested another appointment 8 weeks later to continue to monitor his BP.

The patient did not return to the pharmacy clinic until week 31, when he reported that he was told his BP was very high when attempting to donate plasma. The patient reported drinking a “6 pack of beer per day” at that visit. Two BP readings were taken in the clinic. The first of systolic blood pressure (SBP) was 144 mm Hg and the second was below the patient’s goal (< 140 mm Hg). His pulse (94 bpm) was also noted to be higher than baseline range (66-84 bpm). Atenolol 25 mg daily by mouth was added to the patient’s regimen of HCTZ 25 mg daily.

The patient returned at week 38, and his BP of 149/101 mm Hg was elevated above goal range. Lisinopril was added to HCTZ 25 mg in a combination formulation of lisinopril/HCTZ 20 mg/25 mg by mouth daily. The patient reported drinking 4 beers on days he worked (5 days per week) and 6 beers on days he was off (2 days per week). A repeated electrolyte, BUN, and SCr panel 1 month later (week 42) revealed a drop in the patient’s sodium level from 136 mEq/L (baseline) to 130 mEq/L (Table 1). Other measured electrolytes remained within normal limits with the exception of a slight decrease in serum chloride to 93 mEq/L (Table 2). No symptoms of hyponatremia were noted.

The patient was instructed to cut the lisinopril/HCTZ tablet in half and take it daily, then repeat blood work in 5 days. The patient’s repeated laboratory work noted an increase in sodium level to 134 mEq/L. All other measured electrolytes, including serum chloride, were within normal limits. During his follow-up visit, the patient reported stopping lisinopril/HCTZ altogether and resuming HCTZ 25 mg daily for the 5 days prior, in lieu of taking the reduced lisinopril/HCTZ dose as instructed. The patient continued to report drinking 6 beers daily.

Medication was changed to HCTZ 25 mg daily, with lisinopril discontinued, and atenolol increased to 50 mg daily. At week 46, the patient repeated electrolytes, BUN, and SCr laboratory work while on HCTZ 25 mg and atenolol 50 mg daily, and the serum sodium level increased to 139 mEq/L. After the laboratory work at week 49, he noted a reduction in alcohol to 4 beers daily at the pharmacy appointment. The patient’s BP was controlled to below the < 140/90 mm Hg goal. Medications were not changed. He was instructed to follow up with his PCP and return to the pharmacy clinic as needed for BP control.

Of note, serum magnesium levels are not included in the standard electrolyte panel and must be ordered separately. Additionally, serum magnesium levels are not monitored routinely with thiazide and ACE inhibitor therapy. In this case, serum magnesium levels were not drawn at baseline or in subsequent laboratory monitoring.

Discussion

This case demonstrates a potential link between administration of lisinopril and the development of hyponatremia. Adverse effects (AEs) of ACE inhibitors frequently include elevation in SCr, hyperkalemia, and/or a dry cough. Hyponatremia, although not commonly associated with ACE inhibitors, has been reported in the literature.^1,2

Although the mechanism is not completely understood, previous case reports hypothesized that ACE inhibitor therapy can lead to Syndrome of Inappropriate Antidiuretic Hormone (SIADH).^1,3 Angiotensin I is not converted to angiotensin II peripherally with ACE inhibitor therapy. This elevated circulating level of angiotensin I is available to cross the blood-brain barrier where it is converted to angiotensin II. Angiotensin can then stimulate vasopressin release, which, in turn, increases thirst and leads to decreased amounts of concentrated urine.⁴ The combination of increased thirst and concentrated urine can lead to hyponatremia.

The clinical manifestations of hyponatremia can vary. In patients with ACE inhibitor-induced hyponatremia, an early sign may be polydipsia. Once hyponatremia develops, patients may experience nausea, muscle spasms or weakness, and general malaise. Additionally, lethargy, a decreased level of consciousness, and headaches may occur. In the most severe cases, hyponatremia may lead to seizures, coma, and eventually death.

Several case reports involving various ACE inhibitors, such as captopril, enalapril, and lisinopril, have been reported over the past 30 years, citing the connection linking these medications to SIADH and symptomatic hyponatremia. A large number of cases involved patients with established congestive heart failure for whom ACE inhibitors were added because of their beneficial impact on improved survival and reduced left ventricular dysfunction.⁵ Angiotensin converting enzyme inhibitor-induced hyponatremia may be confounded by heart failure, due to the complex disease pathophysiology.¹ Therefore, case reports of ACE inhibitors use in patients treated for indications other than heart failure, such as hypertension, provide a clearer picture of ACE inhibitor-induced hyponatremia.

One such striking case report involved a 63-year-old woman taking lisinopril 10 mg daily as monotherapy (no other medications) for mild hypertension with a baseline serum sodium level within normal limits.⁶ One month later, the patient was admitted a with serum sodium level of 101 mEq/L and symptomatic with altered mental status and generalized tonic-clonic seizures. Once the serum sodium was corrected, the patient’s mental status improved, and her 1-year follow-up examination was unremarkable. This case report is significant for its findings that there may be a cause-and-effect relationship between lisinopril monotherapy and symptomatic hyponatremia that occurred within a month. There are cases of hyponatremia in patients receiving ACE inhibitor therapy in addition to established diuretic therapy. For example, a woman aged 71 years was admitted for elevated BP with an initial medication regimen that included HCTZ and other antihypertensive medications.⁷ She was given captopril at increasing doses up to 150 mg daily. The patient’s serum sodium levels dropped correspondingly with titrated doses of captopril. The patient reported feeling confusion, and her serum sodium levels dropped to 114 mEq/L. Once captopril was discontinued and serum sodium corrected with IV fluids, the patient’s confusion subsided. The patient was discharged on a medication regimen that continued HCTZ but not the ACE inhibitor, with no clinical consequences and normal serum sodium levels over the following year. Similarly, the patient in this case study had established HCTZ therapy with normal serum sodium that declined upon addition of an ACE inhibitor.

Other factors that could contribute to hyponatremia, such as beer potomania, confound the current case of hyponatremia. This patient reported chronic beer ingestion, which can lead to hyponatremia and may have aggravated the hyponatremia upon initiation of lisinopril. Additionally, the patient was taking HCTZ, an agent known to cause hyponatremia, prior to initiation of the ACE inhibitor. Another limiting factor noted was that serum magnesium levels were not measured to assess for potential hypomagnesemia, which may affect other electrolytes.

Using the Naranjo Assessment scale, a score of 3 was calculated, indicating a possible link to lisinopril as the cause of hyponatremia.⁸ Although the patient had the aforementioned risk factors, the notable drop of serum sodium level correlated with the lisinopril administration, which was previously stable despite HCTZ treatment and alcohol consumption. The time line of events led the authors to believe that hyponatremia was strongly related to lisinopril. This patient was fortunate that he experienced no neurologic complications, which have been reported in other cases of ACE inhibitor-induced hyponatremia, manifested from the drop in serum sodium.

Conclusion

Though rarely occurring, hyponatremia should be considered a potentially serious AE associated with ACE inhibitor therapy. Timely monitoring of electrolytes, BUN, and SCr should continue to assess for more common AEs of elevated SCr and hyperkalemia, but clinicians should be aware of the potential for ACE inhibitor-induced hyponatremia.

Angiotensin-converting enzyme (ACE) inhibitors are commonly used medications in the treatment of hypertension in the ambulatory care setting. Serum sodium concentrations are not usually affected in the majority of patients treated with ACE inhibitors. Nonetheless, hyponatremia, defined as serum sodium level < 135 mEq/L, has been reported in patients taking ACE inhibitors.^1,2 The authors report a case of hyponatremia attributed to the use of lisinopril.

Case Presentation

In 2012, a 49-year-old man with a past medical history significant for polysubstance abuse, alcohol use, and hypertension was referred to the pharmacy clinic by his primary care physician (PCP) for management of hypertension. At the PCP visit, the patient’s blood pressure (BP) was above the goal of < 140/90 mm Hg and hydrochlorothiazide (HCTZ) 12.5 mg by mouth daily monotherapy was initiated. At the follow-up pharmacy appointment 6 weeks later, his BP remained uncontrolled, and HCTZ was increased to 25 mg daily. Of note, at that time the patient reported drinking about 6 beers per week. His electrolytes—serum sodium, potassium, chloride, carbon dioxide (CO₂), blood urea nitrogen (BUN), and serum creatinine (SCr)—were all within normal limits and stable to previous baseline results after taking HCTZ for about 2 weeks.

The patient returned to the pharmacy clinic at week 11, and his BP was controlled (136/83 mm Hg) on HCTZ 25 mg daily. His electrolytes, BUN, and SCr continued to be stable. The patient requested another appointment 8 weeks later to continue to monitor his BP.

The patient did not return to the pharmacy clinic until week 31, when he reported that he was told his BP was very high when attempting to donate plasma. The patient reported drinking a “6 pack of beer per day” at that visit. Two BP readings were taken in the clinic. The first of systolic blood pressure (SBP) was 144 mm Hg and the second was below the patient’s goal (< 140 mm Hg). His pulse (94 bpm) was also noted to be higher than baseline range (66-84 bpm). Atenolol 25 mg daily by mouth was added to the patient’s regimen of HCTZ 25 mg daily.

The patient returned at week 38, and his BP of 149/101 mm Hg was elevated above goal range. Lisinopril was added to HCTZ 25 mg in a combination formulation of lisinopril/HCTZ 20 mg/25 mg by mouth daily. The patient reported drinking 4 beers on days he worked (5 days per week) and 6 beers on days he was off (2 days per week). A repeated electrolyte, BUN, and SCr panel 1 month later (week 42) revealed a drop in the patient’s sodium level from 136 mEq/L (baseline) to 130 mEq/L (Table 1). Other measured electrolytes remained within normal limits with the exception of a slight decrease in serum chloride to 93 mEq/L (Table 2). No symptoms of hyponatremia were noted.

The patient was instructed to cut the lisinopril/HCTZ tablet in half and take it daily, then repeat blood work in 5 days. The patient’s repeated laboratory work noted an increase in sodium level to 134 mEq/L. All other measured electrolytes, including serum chloride, were within normal limits. During his follow-up visit, the patient reported stopping lisinopril/HCTZ altogether and resuming HCTZ 25 mg daily for the 5 days prior, in lieu of taking the reduced lisinopril/HCTZ dose as instructed. The patient continued to report drinking 6 beers daily.

Medication was changed to HCTZ 25 mg daily, with lisinopril discontinued, and atenolol increased to 50 mg daily. At week 46, the patient repeated electrolytes, BUN, and SCr laboratory work while on HCTZ 25 mg and atenolol 50 mg daily, and the serum sodium level increased to 139 mEq/L. After the laboratory work at week 49, he noted a reduction in alcohol to 4 beers daily at the pharmacy appointment. The patient’s BP was controlled to below the < 140/90 mm Hg goal. Medications were not changed. He was instructed to follow up with his PCP and return to the pharmacy clinic as needed for BP control.

Of note, serum magnesium levels are not included in the standard electrolyte panel and must be ordered separately. Additionally, serum magnesium levels are not monitored routinely with thiazide and ACE inhibitor therapy. In this case, serum magnesium levels were not drawn at baseline or in subsequent laboratory monitoring.

Discussion

This case demonstrates a potential link between administration of lisinopril and the development of hyponatremia. Adverse effects (AEs) of ACE inhibitors frequently include elevation in SCr, hyperkalemia, and/or a dry cough. Hyponatremia, although not commonly associated with ACE inhibitors, has been reported in the literature.^1,2

Although the mechanism is not completely understood, previous case reports hypothesized that ACE inhibitor therapy can lead to Syndrome of Inappropriate Antidiuretic Hormone (SIADH).^1,3 Angiotensin I is not converted to angiotensin II peripherally with ACE inhibitor therapy. This elevated circulating level of angiotensin I is available to cross the blood-brain barrier where it is converted to angiotensin II. Angiotensin can then stimulate vasopressin release, which, in turn, increases thirst and leads to decreased amounts of concentrated urine.⁴ The combination of increased thirst and concentrated urine can lead to hyponatremia.

The clinical manifestations of hyponatremia can vary. In patients with ACE inhibitor-induced hyponatremia, an early sign may be polydipsia. Once hyponatremia develops, patients may experience nausea, muscle spasms or weakness, and general malaise. Additionally, lethargy, a decreased level of consciousness, and headaches may occur. In the most severe cases, hyponatremia may lead to seizures, coma, and eventually death.

Several case reports involving various ACE inhibitors, such as captopril, enalapril, and lisinopril, have been reported over the past 30 years, citing the connection linking these medications to SIADH and symptomatic hyponatremia. A large number of cases involved patients with established congestive heart failure for whom ACE inhibitors were added because of their beneficial impact on improved survival and reduced left ventricular dysfunction.⁵ Angiotensin converting enzyme inhibitor-induced hyponatremia may be confounded by heart failure, due to the complex disease pathophysiology.¹ Therefore, case reports of ACE inhibitors use in patients treated for indications other than heart failure, such as hypertension, provide a clearer picture of ACE inhibitor-induced hyponatremia.

One such striking case report involved a 63-year-old woman taking lisinopril 10 mg daily as monotherapy (no other medications) for mild hypertension with a baseline serum sodium level within normal limits.⁶ One month later, the patient was admitted a with serum sodium level of 101 mEq/L and symptomatic with altered mental status and generalized tonic-clonic seizures. Once the serum sodium was corrected, the patient’s mental status improved, and her 1-year follow-up examination was unremarkable. This case report is significant for its findings that there may be a cause-and-effect relationship between lisinopril monotherapy and symptomatic hyponatremia that occurred within a month. There are cases of hyponatremia in patients receiving ACE inhibitor therapy in addition to established diuretic therapy. For example, a woman aged 71 years was admitted for elevated BP with an initial medication regimen that included HCTZ and other antihypertensive medications.⁷ She was given captopril at increasing doses up to 150 mg daily. The patient’s serum sodium levels dropped correspondingly with titrated doses of captopril. The patient reported feeling confusion, and her serum sodium levels dropped to 114 mEq/L. Once captopril was discontinued and serum sodium corrected with IV fluids, the patient’s confusion subsided. The patient was discharged on a medication regimen that continued HCTZ but not the ACE inhibitor, with no clinical consequences and normal serum sodium levels over the following year. Similarly, the patient in this case study had established HCTZ therapy with normal serum sodium that declined upon addition of an ACE inhibitor.

Other factors that could contribute to hyponatremia, such as beer potomania, confound the current case of hyponatremia. This patient reported chronic beer ingestion, which can lead to hyponatremia and may have aggravated the hyponatremia upon initiation of lisinopril. Additionally, the patient was taking HCTZ, an agent known to cause hyponatremia, prior to initiation of the ACE inhibitor. Another limiting factor noted was that serum magnesium levels were not measured to assess for potential hypomagnesemia, which may affect other electrolytes.

Using the Naranjo Assessment scale, a score of 3 was calculated, indicating a possible link to lisinopril as the cause of hyponatremia.⁸ Although the patient had the aforementioned risk factors, the notable drop of serum sodium level correlated with the lisinopril administration, which was previously stable despite HCTZ treatment and alcohol consumption. The time line of events led the authors to believe that hyponatremia was strongly related to lisinopril. This patient was fortunate that he experienced no neurologic complications, which have been reported in other cases of ACE inhibitor-induced hyponatremia, manifested from the drop in serum sodium.

Conclusion

Though rarely occurring, hyponatremia should be considered a potentially serious AE associated with ACE inhibitor therapy. Timely monitoring of electrolytes, BUN, and SCr should continue to assess for more common AEs of elevated SCr and hyperkalemia, but clinicians should be aware of the potential for ACE inhibitor-induced hyponatremia.

Total hip arthroplasty (THA) is considered to be one of the most successful orthopedic interventions of its generation.¹ In 2010, 332,000 THAs were performed in the U.S.² Although used to correct advanced joint diseases in the elderly, the THA procedure has become increasingly common in a younger population for posttraumatic fractures and conditions that lead to early onset secondary arthritis such as avascular necrosis, juvenile rheumatoid arthritis, hip dysplasia, Perthes disease, and femoro-acetabular impingement.

Current hip replacements are expected to function at least 10 to 20 years in 90% of patients.³ As increasing numbers of young patients have these procedures and as seniors continue to live longer, patients will outlast their implants. Younger and more active patients have a higher rate of revision, because the longevity of the prosthesis is usually a function of usage.³ The number of revision THAs is projected to increase 137% by 2030.⁴

Hip resurfacing has been developed as a bone preserving surgical alternative to THA. The first system for use in the U.S. received FDA approval in 2006, but concerns about the metal on metal bearing surfaces, high failure and revision rates, and early catastrophic modes of failure compared with THAs has resulted in the recall of many of these devices. Hip resurfacing may offer some advantages compared with those of a THA in a carefully selected population, but its use will not be further discussed in this case study.⁵ Periprosthetic osteolysis and aseptic loosening are 2 of the long-term consequences of THA.⁶ Bone loss is felt to be secondary to a biologic reaction to particulate debris from implants.⁶ Some patients, especially those with loosening, complete wear, or fracture, will be symptomatic with pain. However, wear and osteolysis is a silent disease unless there is mechanical failure. Other patients may not experience discomfort. Radiographic studies may reveal significant changes, which warrant the recommendation for a hip revision.

Hip revision surgery has 3 major purposes: relieving pain in the affected joint, restoring the patient’s mobility, and removing a loose or damaged prosthesis before irreversible harm is done to the joint. It’s anticipated that most primary care providers (PCPs) will encounter patients who seek advice on the need for a revision hip arthroplasty.

This case will present an asymptomatic patient who underwent a THA in 1997 at age 37, to address developmental dysplasia of the hip (DDH) and was advised to undergo a revision hip arthroplasty due to abnormal radiographic findings at age 55 years. A discussion will follow that includes a brief review of the history of THA, the materials and bearings commonly used, the presenting symptoms or radiographic changes that signal the need for a revision, and the current options available for a patient such as this.

Case Report

A man aged 55 years presented to a new orthopedic surgeon for his first orthopedic appointment in 10 years. The patient had a left metal-on-polyethylene (M-on-PE) THA 18 years prior due to early onset secondary degenerative joint disease from DDH. The patient’s M-on-PE THA was a titanium acetabular socket and femoral stem with a cobalt-chromium alloy femoral head and a polyethylene liner. The patient remained physically active with an exercise routine consisting of walking, swimming, and weight training.

The patient’s orthopedic history was notable for a right knee arthroscopy for intervention due to a torn medial and lateral meniscus, and birth history was noteworthy for a breech presentation. The physical exam was unremarkable except for a slight leg length discrepancy, but the patient did not exhibit a Trendelenburg gait.

Plain X-rays and a computed tomography (CT) scan showed eccentric PE wear and superior migration of the femoral head, which was indicative of significant PE liner wear. No significant osteolysis or periprosthetic loosening was observed on the X-rays or CT scan. He was advised that a hip revision procedure would need to be done, optimally, within the next 6 months to a year.

Discussion

Hip dysplasia represents a broad group of disorders and generally means abnormal development of the hip joint. The term is most commonly used to refer to DDH with inadequate coverage of the femoral head. In one study, 25% of hip replacements performed in patients aged ≤ 40 years were due to underlying hip dysplasia.⁷

Developmental dysplasia of the hip occurs more often in children who present in the breech position.⁸ One theory argues that packaging issues in utero may account for the increased incidence of DDH.⁹ The earliest recorded attempts at hip replacement occurred in Germany, in 1891, when ivory was used to replace the femoral heads of patients whose hip joints had been destroyed by tuberculosis.¹

The orthopedic surgeon Sir John Charnley, who worked at the Manchester Royal Infirmary, is considered the father of the modern THA.¹ His low friction arthroplasty, designed in the early 1960s is identical, in principle, to the M-on-PE prosthesis used today.¹ The PE liner used was ultrahigh molecular weight polyethylene (UHMWPE).¹

Due to the early success of the Charnley prosthesis, the M-on-PE prosthesis became the most widely used. Although PE is the most studied and understood of all acetabular liner materials, it will eventually wear and shed debris. Acetabular cup wear is the most frequent reason for mid-to-long-term revisions, especially in young and active patients.¹⁰ More active patients shed more debris.³ The PE debris instigates the release of inflammatory mediators, which results in chronic inflammation and tissue damage that erodes the supporting bone and can lead to implant loosening or fracture.⁶ Ongoing studies seek to optimize and improve properties of the UHMWPE and to develop alternative bearings. After FDA approval in 1999, highly cross-linked polyethylene liners (HXLPE) rapidly became the standard of care for THAs, at least in the U.S.¹¹ Highly cross-linked polyethylene liners are created from UHMWPE through a process of cross-linking by exposure to gamma radiation, and subsequent heat treatment to neutralize free radicals and limit oxidative degradation.¹²

In one study, the 5-year annual linear wear rate for a HXLPE liner was only 45% of that seen with the UHMWPE liner, although the qualitative wear pattern was the same.¹³ In a study that followed patients for 7 years postoperatively, the mean steady-state wear rate of the HXLPE was 0.005 mm/y compared with 0.037 mm/y for UHMWPE.¹⁴ In a long-term study (a minimum follow-up of 10 years) of 50 patients who were aged < 50 years and underwent THA using HXLPE liners, there was no radiographic evidence of osteolysis or component loosening, and liner wear was 0.020 ± 0.0047 mm/y.¹² In 2005, second-generation HXLPE liners were introduced clinically and have been shown to further reduce wear in vitro compared with both UHMWPE and first-generation HXLPE liners. Callary and colleagues calculated that the wear rates between 1 year and 5 years were all < 0.001 mm/y.¹⁵

The use of ceramic for THAs began in 1970, and ceramic heads on polyethylene (C-on-PE) liners and ceramic-on-ceramic (C-on-C) bearings have been in continual use for > 30 years in Europe. Premarket FDA approval based on European data was granted in 1983; however, the manufacturer voluntarily removed it from the market because of a high incidence of stem loosening (> 30% within 3 years in some series).¹⁶ FDA approvals came much later for C-on-PE (1989) and C-on-C (2003) bearings.

Ceramic is the hardest implant material used, and it can be concluded from many clinical and laboratory reports that C-on-PE and C-on-C combinations confer a potentially significant reduction in wear on THA bearings.¹⁶ Ceramic hips initially had 2 concerns: catastrophic shattering and squeaking. Current ceramic hips have been substantially improved, and some experts feel shattering has been essentially eliminated.¹⁶ Other experts note that ceramic brittleness remains a major concern.¹⁷ Squeaking remains a problem for some, but it usually abates over time. No study has correlated squeaking with impending failure or increased pain or disability.

While C-on-C bearings are now felt to be a good implant for young active patients, these bearings have generally not resulted in significantly lower wear rates and fewer revisions.¹⁸ High rates of wear and osteolysis have been sporadically documented over the 35-year history of ceramic implants.¹⁶ The FDA approved the first ceramic-on-metal total hip replacement system on June 13, 2011.

Metal-on-metal (M-on-M) implants have been used by some for decades, although they were not approved by the FDA until the late 1990s. However, some device recalls have brought negative attention to M-on-M implants.¹⁹ It was felt that they would generate less wear debris than PE, but reports of pseudotumors (from inflammatory mediators) and metallosis have significantly tempered enthusiasm for these products.^20,21 The wear rates are very low, estimated to be only 0.01 mm/y, but concerns about the carcinogenetic potential of systemically increased metal ions remains a possible and much debated concern.^19,22,23 In January 2013, FDA issued a safety communication on M-on-M implants.

Many experts feel that modern ceramic or metal on second-generation HXLPE represents the gold standard and the most predictable bearing choice for young, active patients.¹⁸ Others feel that the optimal choice of bearing surfaces in THA, particularly in the younger and more active patient, remains controversial.²⁴

Follow-Up

Intermittent orthopedic monitoring is recommended for all patients who have undergone a THA. The frequency of hip X-rays on follow-up appointments is left to the orthopedic surgeon. After the initial recovery, serial images every 2 to 5 years can identify progressive failure, and annual X-rays may be used for closer follow-up in high-risk patients.

Patients who experience dislocations, fractures, infections, or pain usually maintain close orthopedic follow-up. Significant wear of the prosthesis damages the socket; osteolysis can cause irreversible bone loss, fracture, and loosening. Massive acetabular bone loss is very difficult to reverse and creates major reconstruction challenges.

Figure 1A is a 2009 X-ray of a woman aged 44 years who underwent a THA after a motor vehicle accident in 1997 and who was advised to have a revision THA when seen in 2009.

Figure 3A is an X-ray of a man aged 71 years who had undergone THA 21 years earlier and had complied with routine follow-up. When his X-rays showed significant wear of the liner and some osteolysis, he was able to undergo a simple revision (Figure 3B).

Three-dimensional CT is useful for quantifying the presence and severity of osteolytic lesions, because plain radiographs may underestimate the amount of bone loss that is present.²⁵ The CT in Figure 3C shows the magnitude of osteolysis that was underestimated by the preoperative plain X-rays (Figure 3A). Computed tomography scans are crucial for surgical planning in the setting of severe acetabular bone loss.

There is a wide spectrum of signs and symptoms that can occur in the setting of acetabular component failure. Pain is a common presenting symptom. Groin pain can represent acetabular failure; thigh pain may be correlated to femoral component failure.²⁵ The clinical patient presentation ultimately depends on the underlying cause: an infection, polyethylene wear, instability, or aseptic loosening.²⁵ Leg-length discrepancy, joint deformity, location of prior incisions, functional status, and baseline neurologic status should be evaluated and documented during the preoperative evaluation as well.²⁵

Case Study Revision Options

The X-rays and CT scans for this case study patient showed that he was a possible candidate for the simplest revision surgery; an isolated liner exchange and replacement of the femoral head. When the original surgery was performed (1997), the only FDA approved PE liner was UHMWPE. To justify isolated liner exchange, the modular acetabular metallic shell also should be well-fixed and appropriately oriented.²⁶ This is evaluated both preoperatively and intraoperatively.

If found to be well fixed with an appropriate orientation and locking mechanism, the UHMWPE liner could be replaced with a HXLPE liner and a larger metal femoral head for improved wear and stability. Acetabular revision is indicted for an asymptomatic patient who has progressive osteolysis, severe wear, or bone loss that would compromise future reconstruction.

Conclusions

Over the past several decades, THA has become recognized as an effective treatment option for the reduction of pain and disability associated with hip joint disease and is associated with successful clinical outcomes. The most frequently noted recommendations for trying to increase the life expectancy of an artificial hip replacement include maintaining a normal weight, keeping leg muscles strong, and avoiding repetitive squatting and kneeling.

As the number of primary THAs has increased and the average age of those undergoing a primary THA has decreased, the need for revisions has risen. Reviews have demonstrated that the most common causes for early total hip revision, regardless of component, included infection, instability/dislocation, and fracture, whereas wear is the most common reason for mid to late revisions.

The wear of all materials used has been shown to be greatest in the most active patients.

Studies continue to identify ways to potentially prevent or reverse osteolysis from wear debris. Alendronate therapy has been shown to prevent and treat PE debris-induced periprosthetic bone loss in rats.²⁷ It also was successfully used in a case report of an asymptomatic woman aged 39 years who had rapid PE wear and aggressive periprosthetic osteolysis within just 2 years of a bilateral THA.²⁸ Other areas of research on decreasing osteolysis in THA recipients include trials with mesenchymal stem cells, bone morphogenic proteins, and gene therapy.⁶

In the U.S., 46,000 revisions were performed in 2004 and this number is expected to more than double by 2030.⁴ Primary care providers are sure to encounter patients who will be in need of a hip revision procedure. It’s important for them to make sure that their patients who have undergone a THA are periodically seen for orthopedic follow-up. Despite the long history of primary THAs, there is still not a single technique and material to suit all patient characteristics.¹ Unfortunately, the same currently applies to hip revision procedures.

Total hip arthroplasty (THA) is considered to be one of the most successful orthopedic interventions of its generation.¹ In 2010, 332,000 THAs were performed in the U.S.² Although used to correct advanced joint diseases in the elderly, the THA procedure has become increasingly common in a younger population for posttraumatic fractures and conditions that lead to early onset secondary arthritis such as avascular necrosis, juvenile rheumatoid arthritis, hip dysplasia, Perthes disease, and femoro-acetabular impingement.

Current hip replacements are expected to function at least 10 to 20 years in 90% of patients.³ As increasing numbers of young patients have these procedures and as seniors continue to live longer, patients will outlast their implants. Younger and more active patients have a higher rate of revision, because the longevity of the prosthesis is usually a function of usage.³ The number of revision THAs is projected to increase 137% by 2030.⁴

Hip resurfacing has been developed as a bone preserving surgical alternative to THA. The first system for use in the U.S. received FDA approval in 2006, but concerns about the metal on metal bearing surfaces, high failure and revision rates, and early catastrophic modes of failure compared with THAs has resulted in the recall of many of these devices. Hip resurfacing may offer some advantages compared with those of a THA in a carefully selected population, but its use will not be further discussed in this case study.⁵ Periprosthetic osteolysis and aseptic loosening are 2 of the long-term consequences of THA.⁶ Bone loss is felt to be secondary to a biologic reaction to particulate debris from implants.⁶ Some patients, especially those with loosening, complete wear, or fracture, will be symptomatic with pain. However, wear and osteolysis is a silent disease unless there is mechanical failure. Other patients may not experience discomfort. Radiographic studies may reveal significant changes, which warrant the recommendation for a hip revision.

Hip revision surgery has 3 major purposes: relieving pain in the affected joint, restoring the patient’s mobility, and removing a loose or damaged prosthesis before irreversible harm is done to the joint. It’s anticipated that most primary care providers (PCPs) will encounter patients who seek advice on the need for a revision hip arthroplasty.

This case will present an asymptomatic patient who underwent a THA in 1997 at age 37, to address developmental dysplasia of the hip (DDH) and was advised to undergo a revision hip arthroplasty due to abnormal radiographic findings at age 55 years. A discussion will follow that includes a brief review of the history of THA, the materials and bearings commonly used, the presenting symptoms or radiographic changes that signal the need for a revision, and the current options available for a patient such as this.

Case Report

A man aged 55 years presented to a new orthopedic surgeon for his first orthopedic appointment in 10 years. The patient had a left metal-on-polyethylene (M-on-PE) THA 18 years prior due to early onset secondary degenerative joint disease from DDH. The patient’s M-on-PE THA was a titanium acetabular socket and femoral stem with a cobalt-chromium alloy femoral head and a polyethylene liner. The patient remained physically active with an exercise routine consisting of walking, swimming, and weight training.

The patient’s orthopedic history was notable for a right knee arthroscopy for intervention due to a torn medial and lateral meniscus, and birth history was noteworthy for a breech presentation. The physical exam was unremarkable except for a slight leg length discrepancy, but the patient did not exhibit a Trendelenburg gait.

Plain X-rays and a computed tomography (CT) scan showed eccentric PE wear and superior migration of the femoral head, which was indicative of significant PE liner wear. No significant osteolysis or periprosthetic loosening was observed on the X-rays or CT scan. He was advised that a hip revision procedure would need to be done, optimally, within the next 6 months to a year.

Discussion

Hip dysplasia represents a broad group of disorders and generally means abnormal development of the hip joint. The term is most commonly used to refer to DDH with inadequate coverage of the femoral head. In one study, 25% of hip replacements performed in patients aged ≤ 40 years were due to underlying hip dysplasia.⁷

Developmental dysplasia of the hip occurs more often in children who present in the breech position.⁸ One theory argues that packaging issues in utero may account for the increased incidence of DDH.⁹ The earliest recorded attempts at hip replacement occurred in Germany, in 1891, when ivory was used to replace the femoral heads of patients whose hip joints had been destroyed by tuberculosis.¹

The orthopedic surgeon Sir John Charnley, who worked at the Manchester Royal Infirmary, is considered the father of the modern THA.¹ His low friction arthroplasty, designed in the early 1960s is identical, in principle, to the M-on-PE prosthesis used today.¹ The PE liner used was ultrahigh molecular weight polyethylene (UHMWPE).¹

Due to the early success of the Charnley prosthesis, the M-on-PE prosthesis became the most widely used. Although PE is the most studied and understood of all acetabular liner materials, it will eventually wear and shed debris. Acetabular cup wear is the most frequent reason for mid-to-long-term revisions, especially in young and active patients.¹⁰ More active patients shed more debris.³ The PE debris instigates the release of inflammatory mediators, which results in chronic inflammation and tissue damage that erodes the supporting bone and can lead to implant loosening or fracture.⁶ Ongoing studies seek to optimize and improve properties of the UHMWPE and to develop alternative bearings. After FDA approval in 1999, highly cross-linked polyethylene liners (HXLPE) rapidly became the standard of care for THAs, at least in the U.S.¹¹ Highly cross-linked polyethylene liners are created from UHMWPE through a process of cross-linking by exposure to gamma radiation, and subsequent heat treatment to neutralize free radicals and limit oxidative degradation.¹²

In one study, the 5-year annual linear wear rate for a HXLPE liner was only 45% of that seen with the UHMWPE liner, although the qualitative wear pattern was the same.¹³ In a study that followed patients for 7 years postoperatively, the mean steady-state wear rate of the HXLPE was 0.005 mm/y compared with 0.037 mm/y for UHMWPE.¹⁴ In a long-term study (a minimum follow-up of 10 years) of 50 patients who were aged < 50 years and underwent THA using HXLPE liners, there was no radiographic evidence of osteolysis or component loosening, and liner wear was 0.020 ± 0.0047 mm/y.¹² In 2005, second-generation HXLPE liners were introduced clinically and have been shown to further reduce wear in vitro compared with both UHMWPE and first-generation HXLPE liners. Callary and colleagues calculated that the wear rates between 1 year and 5 years were all < 0.001 mm/y.¹⁵

The use of ceramic for THAs began in 1970, and ceramic heads on polyethylene (C-on-PE) liners and ceramic-on-ceramic (C-on-C) bearings have been in continual use for > 30 years in Europe. Premarket FDA approval based on European data was granted in 1983; however, the manufacturer voluntarily removed it from the market because of a high incidence of stem loosening (> 30% within 3 years in some series).¹⁶ FDA approvals came much later for C-on-PE (1989) and C-on-C (2003) bearings.

Ceramic is the hardest implant material used, and it can be concluded from many clinical and laboratory reports that C-on-PE and C-on-C combinations confer a potentially significant reduction in wear on THA bearings.¹⁶ Ceramic hips initially had 2 concerns: catastrophic shattering and squeaking. Current ceramic hips have been substantially improved, and some experts feel shattering has been essentially eliminated.¹⁶ Other experts note that ceramic brittleness remains a major concern.¹⁷ Squeaking remains a problem for some, but it usually abates over time. No study has correlated squeaking with impending failure or increased pain or disability.

While C-on-C bearings are now felt to be a good implant for young active patients, these bearings have generally not resulted in significantly lower wear rates and fewer revisions.¹⁸ High rates of wear and osteolysis have been sporadically documented over the 35-year history of ceramic implants.¹⁶ The FDA approved the first ceramic-on-metal total hip replacement system on June 13, 2011.

Metal-on-metal (M-on-M) implants have been used by some for decades, although they were not approved by the FDA until the late 1990s. However, some device recalls have brought negative attention to M-on-M implants.¹⁹ It was felt that they would generate less wear debris than PE, but reports of pseudotumors (from inflammatory mediators) and metallosis have significantly tempered enthusiasm for these products.^20,21 The wear rates are very low, estimated to be only 0.01 mm/y, but concerns about the carcinogenetic potential of systemically increased metal ions remains a possible and much debated concern.^19,22,23 In January 2013, FDA issued a safety communication on M-on-M implants.

Many experts feel that modern ceramic or metal on second-generation HXLPE represents the gold standard and the most predictable bearing choice for young, active patients.¹⁸ Others feel that the optimal choice of bearing surfaces in THA, particularly in the younger and more active patient, remains controversial.²⁴

Follow-Up

Intermittent orthopedic monitoring is recommended for all patients who have undergone a THA. The frequency of hip X-rays on follow-up appointments is left to the orthopedic surgeon. After the initial recovery, serial images every 2 to 5 years can identify progressive failure, and annual X-rays may be used for closer follow-up in high-risk patients.

Patients who experience dislocations, fractures, infections, or pain usually maintain close orthopedic follow-up. Significant wear of the prosthesis damages the socket; osteolysis can cause irreversible bone loss, fracture, and loosening. Massive acetabular bone loss is very difficult to reverse and creates major reconstruction challenges.

Figure 1A is a 2009 X-ray of a woman aged 44 years who underwent a THA after a motor vehicle accident in 1997 and who was advised to have a revision THA when seen in 2009.

Figure 3A is an X-ray of a man aged 71 years who had undergone THA 21 years earlier and had complied with routine follow-up. When his X-rays showed significant wear of the liner and some osteolysis, he was able to undergo a simple revision (Figure 3B).

Three-dimensional CT is useful for quantifying the presence and severity of osteolytic lesions, because plain radiographs may underestimate the amount of bone loss that is present.²⁵ The CT in Figure 3C shows the magnitude of osteolysis that was underestimated by the preoperative plain X-rays (Figure 3A). Computed tomography scans are crucial for surgical planning in the setting of severe acetabular bone loss.

There is a wide spectrum of signs and symptoms that can occur in the setting of acetabular component failure. Pain is a common presenting symptom. Groin pain can represent acetabular failure; thigh pain may be correlated to femoral component failure.²⁵ The clinical patient presentation ultimately depends on the underlying cause: an infection, polyethylene wear, instability, or aseptic loosening.²⁵ Leg-length discrepancy, joint deformity, location of prior incisions, functional status, and baseline neurologic status should be evaluated and documented during the preoperative evaluation as well.²⁵

Case Study Revision Options

The X-rays and CT scans for this case study patient showed that he was a possible candidate for the simplest revision surgery; an isolated liner exchange and replacement of the femoral head. When the original surgery was performed (1997), the only FDA approved PE liner was UHMWPE. To justify isolated liner exchange, the modular acetabular metallic shell also should be well-fixed and appropriately oriented.²⁶ This is evaluated both preoperatively and intraoperatively.

If found to be well fixed with an appropriate orientation and locking mechanism, the UHMWPE liner could be replaced with a HXLPE liner and a larger metal femoral head for improved wear and stability. Acetabular revision is indicted for an asymptomatic patient who has progressive osteolysis, severe wear, or bone loss that would compromise future reconstruction.

Conclusions

Over the past several decades, THA has become recognized as an effective treatment option for the reduction of pain and disability associated with hip joint disease and is associated with successful clinical outcomes. The most frequently noted recommendations for trying to increase the life expectancy of an artificial hip replacement include maintaining a normal weight, keeping leg muscles strong, and avoiding repetitive squatting and kneeling.

As the number of primary THAs has increased and the average age of those undergoing a primary THA has decreased, the need for revisions has risen. Reviews have demonstrated that the most common causes for early total hip revision, regardless of component, included infection, instability/dislocation, and fracture, whereas wear is the most common reason for mid to late revisions.

The wear of all materials used has been shown to be greatest in the most active patients.

Studies continue to identify ways to potentially prevent or reverse osteolysis from wear debris. Alendronate therapy has been shown to prevent and treat PE debris-induced periprosthetic bone loss in rats.²⁷ It also was successfully used in a case report of an asymptomatic woman aged 39 years who had rapid PE wear and aggressive periprosthetic osteolysis within just 2 years of a bilateral THA.²⁸ Other areas of research on decreasing osteolysis in THA recipients include trials with mesenchymal stem cells, bone morphogenic proteins, and gene therapy.⁶

In the U.S., 46,000 revisions were performed in 2004 and this number is expected to more than double by 2030.⁴ Primary care providers are sure to encounter patients who will be in need of a hip revision procedure. It’s important for them to make sure that their patients who have undergone a THA are periodically seen for orthopedic follow-up. Despite the long history of primary THAs, there is still not a single technique and material to suit all patient characteristics.¹ Unfortunately, the same currently applies to hip revision procedures.

Total hip arthroplasty (THA) is considered to be one of the most successful orthopedic interventions of its generation.¹ In 2010, 332,000 THAs were performed in the U.S.² Although used to correct advanced joint diseases in the elderly, the THA procedure has become increasingly common in a younger population for posttraumatic fractures and conditions that lead to early onset secondary arthritis such as avascular necrosis, juvenile rheumatoid arthritis, hip dysplasia, Perthes disease, and femoro-acetabular impingement.

Current hip replacements are expected to function at least 10 to 20 years in 90% of patients.³ As increasing numbers of young patients have these procedures and as seniors continue to live longer, patients will outlast their implants. Younger and more active patients have a higher rate of revision, because the longevity of the prosthesis is usually a function of usage.³ The number of revision THAs is projected to increase 137% by 2030.⁴

Hip resurfacing has been developed as a bone preserving surgical alternative to THA. The first system for use in the U.S. received FDA approval in 2006, but concerns about the metal on metal bearing surfaces, high failure and revision rates, and early catastrophic modes of failure compared with THAs has resulted in the recall of many of these devices. Hip resurfacing may offer some advantages compared with those of a THA in a carefully selected population, but its use will not be further discussed in this case study.⁵ Periprosthetic osteolysis and aseptic loosening are 2 of the long-term consequences of THA.⁶ Bone loss is felt to be secondary to a biologic reaction to particulate debris from implants.⁶ Some patients, especially those with loosening, complete wear, or fracture, will be symptomatic with pain. However, wear and osteolysis is a silent disease unless there is mechanical failure. Other patients may not experience discomfort. Radiographic studies may reveal significant changes, which warrant the recommendation for a hip revision.

Hip revision surgery has 3 major purposes: relieving pain in the affected joint, restoring the patient’s mobility, and removing a loose or damaged prosthesis before irreversible harm is done to the joint. It’s anticipated that most primary care providers (PCPs) will encounter patients who seek advice on the need for a revision hip arthroplasty.

This case will present an asymptomatic patient who underwent a THA in 1997 at age 37, to address developmental dysplasia of the hip (DDH) and was advised to undergo a revision hip arthroplasty due to abnormal radiographic findings at age 55 years. A discussion will follow that includes a brief review of the history of THA, the materials and bearings commonly used, the presenting symptoms or radiographic changes that signal the need for a revision, and the current options available for a patient such as this.

Case Report

A man aged 55 years presented to a new orthopedic surgeon for his first orthopedic appointment in 10 years. The patient had a left metal-on-polyethylene (M-on-PE) THA 18 years prior due to early onset secondary degenerative joint disease from DDH. The patient’s M-on-PE THA was a titanium acetabular socket and femoral stem with a cobalt-chromium alloy femoral head and a polyethylene liner. The patient remained physically active with an exercise routine consisting of walking, swimming, and weight training.

The patient’s orthopedic history was notable for a right knee arthroscopy for intervention due to a torn medial and lateral meniscus, and birth history was noteworthy for a breech presentation. The physical exam was unremarkable except for a slight leg length discrepancy, but the patient did not exhibit a Trendelenburg gait.

Plain X-rays and a computed tomography (CT) scan showed eccentric PE wear and superior migration of the femoral head, which was indicative of significant PE liner wear. No significant osteolysis or periprosthetic loosening was observed on the X-rays or CT scan. He was advised that a hip revision procedure would need to be done, optimally, within the next 6 months to a year.

Discussion

Hip dysplasia represents a broad group of disorders and generally means abnormal development of the hip joint. The term is most commonly used to refer to DDH with inadequate coverage of the femoral head. In one study, 25% of hip replacements performed in patients aged ≤ 40 years were due to underlying hip dysplasia.⁷

Developmental dysplasia of the hip occurs more often in children who present in the breech position.⁸ One theory argues that packaging issues in utero may account for the increased incidence of DDH.⁹ The earliest recorded attempts at hip replacement occurred in Germany, in 1891, when ivory was used to replace the femoral heads of patients whose hip joints had been destroyed by tuberculosis.¹

The orthopedic surgeon Sir John Charnley, who worked at the Manchester Royal Infirmary, is considered the father of the modern THA.¹ His low friction arthroplasty, designed in the early 1960s is identical, in principle, to the M-on-PE prosthesis used today.¹ The PE liner used was ultrahigh molecular weight polyethylene (UHMWPE).¹

Due to the early success of the Charnley prosthesis, the M-on-PE prosthesis became the most widely used. Although PE is the most studied and understood of all acetabular liner materials, it will eventually wear and shed debris. Acetabular cup wear is the most frequent reason for mid-to-long-term revisions, especially in young and active patients.¹⁰ More active patients shed more debris.³ The PE debris instigates the release of inflammatory mediators, which results in chronic inflammation and tissue damage that erodes the supporting bone and can lead to implant loosening or fracture.⁶ Ongoing studies seek to optimize and improve properties of the UHMWPE and to develop alternative bearings. After FDA approval in 1999, highly cross-linked polyethylene liners (HXLPE) rapidly became the standard of care for THAs, at least in the U.S.¹¹ Highly cross-linked polyethylene liners are created from UHMWPE through a process of cross-linking by exposure to gamma radiation, and subsequent heat treatment to neutralize free radicals and limit oxidative degradation.¹²

In one study, the 5-year annual linear wear rate for a HXLPE liner was only 45% of that seen with the UHMWPE liner, although the qualitative wear pattern was the same.¹³ In a study that followed patients for 7 years postoperatively, the mean steady-state wear rate of the HXLPE was 0.005 mm/y compared with 0.037 mm/y for UHMWPE.¹⁴ In a long-term study (a minimum follow-up of 10 years) of 50 patients who were aged < 50 years and underwent THA using HXLPE liners, there was no radiographic evidence of osteolysis or component loosening, and liner wear was 0.020 ± 0.0047 mm/y.¹² In 2005, second-generation HXLPE liners were introduced clinically and have been shown to further reduce wear in vitro compared with both UHMWPE and first-generation HXLPE liners. Callary and colleagues calculated that the wear rates between 1 year and 5 years were all < 0.001 mm/y.¹⁵

The use of ceramic for THAs began in 1970, and ceramic heads on polyethylene (C-on-PE) liners and ceramic-on-ceramic (C-on-C) bearings have been in continual use for > 30 years in Europe. Premarket FDA approval based on European data was granted in 1983; however, the manufacturer voluntarily removed it from the market because of a high incidence of stem loosening (> 30% within 3 years in some series).¹⁶ FDA approvals came much later for C-on-PE (1989) and C-on-C (2003) bearings.

Ceramic is the hardest implant material used, and it can be concluded from many clinical and laboratory reports that C-on-PE and C-on-C combinations confer a potentially significant reduction in wear on THA bearings.¹⁶ Ceramic hips initially had 2 concerns: catastrophic shattering and squeaking. Current ceramic hips have been substantially improved, and some experts feel shattering has been essentially eliminated.¹⁶ Other experts note that ceramic brittleness remains a major concern.¹⁷ Squeaking remains a problem for some, but it usually abates over time. No study has correlated squeaking with impending failure or increased pain or disability.

While C-on-C bearings are now felt to be a good implant for young active patients, these bearings have generally not resulted in significantly lower wear rates and fewer revisions.¹⁸ High rates of wear and osteolysis have been sporadically documented over the 35-year history of ceramic implants.¹⁶ The FDA approved the first ceramic-on-metal total hip replacement system on June 13, 2011.

Metal-on-metal (M-on-M) implants have been used by some for decades, although they were not approved by the FDA until the late 1990s. However, some device recalls have brought negative attention to M-on-M implants.¹⁹ It was felt that they would generate less wear debris than PE, but reports of pseudotumors (from inflammatory mediators) and metallosis have significantly tempered enthusiasm for these products.^20,21 The wear rates are very low, estimated to be only 0.01 mm/y, but concerns about the carcinogenetic potential of systemically increased metal ions remains a possible and much debated concern.^19,22,23 In January 2013, FDA issued a safety communication on M-on-M implants.

Many experts feel that modern ceramic or metal on second-generation HXLPE represents the gold standard and the most predictable bearing choice for young, active patients.¹⁸ Others feel that the optimal choice of bearing surfaces in THA, particularly in the younger and more active patient, remains controversial.²⁴

Follow-Up

Intermittent orthopedic monitoring is recommended for all patients who have undergone a THA. The frequency of hip X-rays on follow-up appointments is left to the orthopedic surgeon. After the initial recovery, serial images every 2 to 5 years can identify progressive failure, and annual X-rays may be used for closer follow-up in high-risk patients.

Patients who experience dislocations, fractures, infections, or pain usually maintain close orthopedic follow-up. Significant wear of the prosthesis damages the socket; osteolysis can cause irreversible bone loss, fracture, and loosening. Massive acetabular bone loss is very difficult to reverse and creates major reconstruction challenges.

Figure 1A is a 2009 X-ray of a woman aged 44 years who underwent a THA after a motor vehicle accident in 1997 and who was advised to have a revision THA when seen in 2009.

Figure 3A is an X-ray of a man aged 71 years who had undergone THA 21 years earlier and had complied with routine follow-up. When his X-rays showed significant wear of the liner and some osteolysis, he was able to undergo a simple revision (Figure 3B).

Three-dimensional CT is useful for quantifying the presence and severity of osteolytic lesions, because plain radiographs may underestimate the amount of bone loss that is present.²⁵ The CT in Figure 3C shows the magnitude of osteolysis that was underestimated by the preoperative plain X-rays (Figure 3A). Computed tomography scans are crucial for surgical planning in the setting of severe acetabular bone loss.

There is a wide spectrum of signs and symptoms that can occur in the setting of acetabular component failure. Pain is a common presenting symptom. Groin pain can represent acetabular failure; thigh pain may be correlated to femoral component failure.²⁵ The clinical patient presentation ultimately depends on the underlying cause: an infection, polyethylene wear, instability, or aseptic loosening.²⁵ Leg-length discrepancy, joint deformity, location of prior incisions, functional status, and baseline neurologic status should be evaluated and documented during the preoperative evaluation as well.²⁵

Case Study Revision Options

The X-rays and CT scans for this case study patient showed that he was a possible candidate for the simplest revision surgery; an isolated liner exchange and replacement of the femoral head. When the original surgery was performed (1997), the only FDA approved PE liner was UHMWPE. To justify isolated liner exchange, the modular acetabular metallic shell also should be well-fixed and appropriately oriented.²⁶ This is evaluated both preoperatively and intraoperatively.

If found to be well fixed with an appropriate orientation and locking mechanism, the UHMWPE liner could be replaced with a HXLPE liner and a larger metal femoral head for improved wear and stability. Acetabular revision is indicted for an asymptomatic patient who has progressive osteolysis, severe wear, or bone loss that would compromise future reconstruction.

Conclusions

Over the past several decades, THA has become recognized as an effective treatment option for the reduction of pain and disability associated with hip joint disease and is associated with successful clinical outcomes. The most frequently noted recommendations for trying to increase the life expectancy of an artificial hip replacement include maintaining a normal weight, keeping leg muscles strong, and avoiding repetitive squatting and kneeling.

As the number of primary THAs has increased and the average age of those undergoing a primary THA has decreased, the need for revisions has risen. Reviews have demonstrated that the most common causes for early total hip revision, regardless of component, included infection, instability/dislocation, and fracture, whereas wear is the most common reason for mid to late revisions.

The wear of all materials used has been shown to be greatest in the most active patients.

Studies continue to identify ways to potentially prevent or reverse osteolysis from wear debris. Alendronate therapy has been shown to prevent and treat PE debris-induced periprosthetic bone loss in rats.²⁷ It also was successfully used in a case report of an asymptomatic woman aged 39 years who had rapid PE wear and aggressive periprosthetic osteolysis within just 2 years of a bilateral THA.²⁸ Other areas of research on decreasing osteolysis in THA recipients include trials with mesenchymal stem cells, bone morphogenic proteins, and gene therapy.⁶

In the U.S., 46,000 revisions were performed in 2004 and this number is expected to more than double by 2030.⁴ Primary care providers are sure to encounter patients who will be in need of a hip revision procedure. It’s important for them to make sure that their patients who have undergone a THA are periodically seen for orthopedic follow-up. Despite the long history of primary THAs, there is still not a single technique and material to suit all patient characteristics.¹ Unfortunately, the same currently applies to hip revision procedures.

Chronic conditions contribute to increasing health care expenditures, and a small number of patients with chronic medical conditions consume a disproportionately larger amount of health care resources.^1,2 Naessens and colleagues showed that 2.6% of adult patients accounted for 20.7% of all primary care clinic visits during a calendar year.² These high-risk patients may be using much of the health care resources but have unmet needs even with the increased amount of health care services they receive.

The impact of interprofessional forms of chronic disease management on patient outcomes is unclear.^3-5 Definitions for high-risk patients and interprofessional care are broad, making comparison of studies difficult. In a team setting, it is difficult to discern the exact contributions of a single member of the team. Katon and colleagues concluded in a randomized, controlled trial that a nurse care manager collaborative treatment program added additional depression-free days and quality-adjusted life-years in adults with depression and poorly controlled diabetes mellitus (DM), coronary artery disease, or both.³ The intervention also resulted in improvements in a composite outcome of hemoglobin A_1c (A_1c), low-densitylipoprotein cholesterol, systolic blood pressure (BP) levels, and depression symptoms at 12 months, but these improvements were not sustained at 24 months.^3,4

A study looked at interprofessional team care provided by primary care internal medicine residents, nurse practitioner students, and pharmacy students, compared with usual care by only internal medicine residents. The study showed improvements in patient assessments and a trend toward the decreased use of urgent care in patients with type 2 DM over 18 months but no significant improvements in A_1c or BP values.⁵ The impact of pharmacists participating in team-based care and patient-centered medical home models has also been shown to be positive regarding metabolic parameters.^6,7Patient aligned care teams (PACT), the VA patient-centered medical home model initiative, seek to optimize patient care through provision of interprofessional, team-based care. At the Boise VAMC in Idaho, PACT training occurs at a primary care academic training clinic that includes 40 primary care providers, supervisors, and trainees in internal medicine, nurse practitioner programs, pharmacy, and behavioral health.

The Boise VAMC is also 1 of 5 VA Centers of Excellence in Primary Care Education (CoEPCE), institutions that prepare health care trainees from many disciplines to participate in interprofessional PACTs, provide patient-centered, team-based care, and learn and understand the roles of other team members.⁸ This VAMC CoEPCE, implemented in 2010, is an academic partnership with area professional schools of medicine, nursing, and pharmacy.

Team-Based Care

At the Boise VAMC CoEPCE, primary care trainees are taught a team-based approach to providing more effective care for high-risk patients through a complex curriculum that includes interprofessional case conferences called PACT interprofessional care updates (ICU). During these case conferences, high-risk patients on a primary care trainee’s panel are presented to an interprofessional group of health care professionals (HCPs) for recommendations to improve care. Trainees from the various disciplines participate in these PACT ICU presentations during time spent rotating through the institution’s academic clinic.

The CoEPCE activities include PACT ICU, interprofessional didactic sessions, and provision of primary care to patients in an interprofessional clinic. Physician trainees participate in one-half day per week of ambulatory didactics and conferences during a 2-week clinic block, which occurs every 2 months. Other health care disciplines participate in PACT ICU during longitudinal experiences (ranging from 4 to 12 months) in the primary care training clinic throughout the academic year.

The PACT ICU case conferences occur weekly at the academic clinic with 2 patient cases presented and discussed at each meeting. Prior to each conference, a primary care trainee, generally an internal medicine resident, is given a list of the top 5 high-risk patients from their panel, determined by a care assessment needs score that is based on high health care use and risk of hospitalization or death within 90 days. To determine care assessment needs scores, patient electronic health records (EHRs) are scanned weekly to review more than 150 data elements, including vital signs; recent clinic, urgent care, and emergency department (ED) visits; medications; laboratory values; and the number and types of illnesses. Statistical analyses are run on the EHR data to provide up-to-date estimates of likelihood of hospital admission or death.

Trainees may also select any patient on their panel whose health care they feel would benefit from a case conference discussion. The trainee presents all medical and social problems related to the selected patient to a team of HCPs, including other trainees and their supervisors, from multiple different disciplines, such as medicine, nursing, pharmacy, behavioral health, and social work. The interprofessional team then provides recommendations.

A care plan is developed by the group to implement as appropriate. The care plan may consist of various recommendations from the different disciplines, such as consults to a pharmacist for medication review or medication management, referrals to social work to coordinate care with home health services, or asking the nurse care manager to follow up with a patient by phone on a more regular basis. Trainees are encouraged to use alternate forms of care, including team-based care from other health care disciplines as well as other methods of communication, such as secure electronic messaging to increase access.

Interprofessional patient case conferences could offer another tool for HCPs to improve the care of high-risk patients through team-based efforts if the effect on patient outcomes or health care use is beneficial. The objective of this study was to evaluate the relationship of interprofessional case conferences and A_1c levels in high-risk patients with DM and BP measurements in patients with hypertension whose case was discussed at PACT ICU case conferences at the Boise VAMC. The authors hypothesized that the PACT ICU presentation intervention would lead to improved metabolic parameters as care plans were implemented. This evaluation is a subset of a larger study assessing the impact of PACT ICU presentation on various patient, trainee, and team level outcomes.

Methods

This study was a retrospective, observational analysis of patients seen at the Boise VAMC academic clinic whose cases were discussed at PACT ICU case conferences from January 2013 to April 2014. For the analysis of A_1c values, patients must have been discussed at a PACT ICU presentation during the study time period and had a diagnosis of DM in the EHR. Those included must have A_1c results in the EHR before and after the patient case presentation. The most recent A_1c measured prior to presentation was chosen as the prepresentation value. The next measured value 2 to 6 months after the case presentation date was chosen as the postpresentation value. This was chosen as the postpresentation value because it may be more indicative of the impact of the PACT ICU care plan. An A_1c measured at least 2 months following the case conference intervention was chosen to allow all possible measurements to be included in the analysis, according to usual care for measuring A_1c at the clinic. The primary outcome was the mean change in A_1c values pre- and post-PACT ICU presentation.

Blood pressure analyses were included if patients had a diagnosis of hypertension in the EHR as well as recorded BP values measured during the 6 months prior to PACT ICU presentation and 1 to 6 months after presentation. Blood pressure values were limited to 1 to 6 months after presentation to be more suggestive of the case conference care plan impact. Blood pressure measured during hospitalizations, urgent care, or ED visits were excluded from the analysis. The primary outcome in the BP analysis was the mean change in systolic and diastolic BP pre- and post-PACT ICU presentation. The mean of all in-clinic BP measurements was calculated as the prepresentation value and compared with the mean of all postpresentation BP measurements in the designated time period.

Assessment of DM or hypertension control was not a factor for inclusion in the study. The types of interventions and recommendations resulting from the case conferences were not evaluated.

Results

During the study period, 65 patients were discussed at a PACT ICU case conferences (Figure). The average age was 67 years, and 89% of patients were male. Of these patients, 32 had a DM diagnosis. A total of 12 patients had A_1c values within the parameters specified for this study and were included in the final analysis for the A_1c group.

Of all patients discussed at a PACT ICU case conference, 52 had a diagnosis of hypertension (Table 2).

Discussion

High-risk patients with DM enrolled in this primary care academic clinic and discussed at interprofessional case conferences did not have a statistically significant change in A_1c values following the case conferences. There was also no statistically significant change in systolic and diastolic BP measurements following PACT ICU case conferences in high-risk patients with hypertension. The relationship between PACT ICU presentations and patient outcomes may not be direct, but the potential to decrease A_1c values by 0.6% may be of clinical benefit to patients enrolled at the Boise VAMC academic clinic.

The results of this study are comparable with other studies where the impact of interprofessional forms of care on patient outcomes such as A_1c and BP is not as apparent.^3-5 The patients included in this study were high-risk compared with other patients, and patient outcome goals for DM and hypertension management according to clinical practice guidelines may be less stringent for these patients.^9-11

Interprofessional case conferences are being used at the Boise VAMC academic clinic to teach primary care trainees how to improve care for patients by working on teams, with a goal of promoting alternate forms of health care. Referrals of patients to pharmacy services for chronic disease management may result from these case conferences, and patients could benefit from pharmacy review and management of medications for the treatment of DM and hypertension. There may be other advantages to patients and to the health system in the form of more appropriate health care use, increased contact with providers, and use of other health care resources to decrease costs and medication burden, although these are speculative at this time.

Limitations

This study had several limitations. The patients included in this study were high-risk patients seen by primary care trainees at the Boise VAMC academic clinic, and a small number of patients were included in the final analysis, limiting the generalizability of the results to other patient populations. Finding a difference in A_1c and BP values before and after PACT ICU case conferences was also limited by the small number of patients who met inclusion criteria. Many patients included in the study also had reasonably controlled A_1c and BP levels prior to PACT ICU case conferences; therefore, a difference would be more difficult to determine.

The PACT ICU case conferences occur at one point in time, but the impact of the intervention and recommendations may take longer to appreciate. A longer study duration may be needed to determine differences in A_1c and BP values over time. Regression to the mean is also a possibility given the type of data collected. As each primary care trainee selects the patient to be discussed at a PACT ICU case conference, bias could also be present, because the provider may focus on patients with recent clinic visits or on patients who are the most difficult for the provider to manage or contact.

The Boise VAMC PACTs include many different health care disciplines; therefore, the institution may foster interprofessional, team-based care more easily compared with that of other health care systems. Trainees in the CoEPCE also are aware of other team members’ roles, and clinical pharmacists are currently part of PACTs at the institution. The idea of interprofessional case conferences may be simple, but the process at this institution requires time and effort from a nurse care manager who coordinates patient selection and information distribution and an attending physician supervisor who facilitates each case conference. The Boise VAMC also supports pharmacy chronic disease management services, and several of these patients with uncontrolled DM or resistant hypertension may have been seen by the pharmacy-managed insulin titration or hypertension clinics. Finally, there is also limited documentation of whether DM or hypertension management was discussed at the case conferences.

Despite the medical complexities seen in these patients, discussions during PACT ICU presentations may involve many social and behavioral interventions, and DM and hypertension issues may not be significant enough for review at a case conference. However, the intervention of PACT ICU case conferences encompassed a variety of care plans, and this study evaluated the impact of the entire discussion and recommendations and not any individual component. Other recommendations were not evaluated due to the wide variety of interventions that were potentially discussed, and a process for tracking these was not in place.

The results of this study did not show that the care plans that develop at PACT ICU case conferences impacted high-risk patients with DM or hypertension, likely due to small sample sizes (2 patient cases were discussed per week). The impact could be better determined through a larger sample size, longer duration, or assessment of patients whose disease was not controlled. The impact may also be more significant for individuals who benefit from the increased review and assessment of their chronic medical conditions and increased access to care.

Seeing a possible trend toward benefit in A_1c values in this short time frame helps support continuing and expanding case conferences at the Boise VAMC. The goals of these interprofessional case conferences include developing a proactive approach to identify high-risk patients to improve the care of these patients and increase use of more appropriate health care resources. Other outcomes currently being studied include the impact of PACT ICU presentations on health care use, the impact on alternate health care consult patterns, and trainee participant opinions. Future directions for the interprofessional case conferences include expansion to other nonacademic primary care teams. The benefit of PACT ICU case conferences also extends to the primary care trainees as they continue to learn how to best work with other HCPs as part of a team and how to use the resources available through these other health care disciplines.

Conclusions

Presentation at an interprofessional case conference was not associated with a statistically significant change in mean A_1c or BP values in a small group of high-risk patients at the Boise VAMC PACT academic clinic. Although there was a trend toward a decrease in A_1c values, it is difficult to determine whether there is a relation to the interprofessional case conferences. Interprofessional case conferences are still occurring at the Boise VAMC with efforts in place to incorporate concurrent PACT ICU outcomes data collection and further the educational goals of primary care trainees.

Acknowledgments
The authors would like to express their appreciation to Rick Tivis, MPH, and Tim Gordon, MA, MPH, MS, for their assistance in the analysis and collection of data for this study.

Chronic conditions contribute to increasing health care expenditures, and a small number of patients with chronic medical conditions consume a disproportionately larger amount of health care resources.^1,2 Naessens and colleagues showed that 2.6% of adult patients accounted for 20.7% of all primary care clinic visits during a calendar year.² These high-risk patients may be using much of the health care resources but have unmet needs even with the increased amount of health care services they receive.

The impact of interprofessional forms of chronic disease management on patient outcomes is unclear.^3-5 Definitions for high-risk patients and interprofessional care are broad, making comparison of studies difficult. In a team setting, it is difficult to discern the exact contributions of a single member of the team. Katon and colleagues concluded in a randomized, controlled trial that a nurse care manager collaborative treatment program added additional depression-free days and quality-adjusted life-years in adults with depression and poorly controlled diabetes mellitus (DM), coronary artery disease, or both.³ The intervention also resulted in improvements in a composite outcome of hemoglobin A_1c (A_1c), low-densitylipoprotein cholesterol, systolic blood pressure (BP) levels, and depression symptoms at 12 months, but these improvements were not sustained at 24 months.^3,4

A study looked at interprofessional team care provided by primary care internal medicine residents, nurse practitioner students, and pharmacy students, compared with usual care by only internal medicine residents. The study showed improvements in patient assessments and a trend toward the decreased use of urgent care in patients with type 2 DM over 18 months but no significant improvements in A_1c or BP values.⁵ The impact of pharmacists participating in team-based care and patient-centered medical home models has also been shown to be positive regarding metabolic parameters.^6,7Patient aligned care teams (PACT), the VA patient-centered medical home model initiative, seek to optimize patient care through provision of interprofessional, team-based care. At the Boise VAMC in Idaho, PACT training occurs at a primary care academic training clinic that includes 40 primary care providers, supervisors, and trainees in internal medicine, nurse practitioner programs, pharmacy, and behavioral health.

The Boise VAMC is also 1 of 5 VA Centers of Excellence in Primary Care Education (CoEPCE), institutions that prepare health care trainees from many disciplines to participate in interprofessional PACTs, provide patient-centered, team-based care, and learn and understand the roles of other team members.⁸ This VAMC CoEPCE, implemented in 2010, is an academic partnership with area professional schools of medicine, nursing, and pharmacy.

Team-Based Care

At the Boise VAMC CoEPCE, primary care trainees are taught a team-based approach to providing more effective care for high-risk patients through a complex curriculum that includes interprofessional case conferences called PACT interprofessional care updates (ICU). During these case conferences, high-risk patients on a primary care trainee’s panel are presented to an interprofessional group of health care professionals (HCPs) for recommendations to improve care. Trainees from the various disciplines participate in these PACT ICU presentations during time spent rotating through the institution’s academic clinic.

The CoEPCE activities include PACT ICU, interprofessional didactic sessions, and provision of primary care to patients in an interprofessional clinic. Physician trainees participate in one-half day per week of ambulatory didactics and conferences during a 2-week clinic block, which occurs every 2 months. Other health care disciplines participate in PACT ICU during longitudinal experiences (ranging from 4 to 12 months) in the primary care training clinic throughout the academic year.

The PACT ICU case conferences occur weekly at the academic clinic with 2 patient cases presented and discussed at each meeting. Prior to each conference, a primary care trainee, generally an internal medicine resident, is given a list of the top 5 high-risk patients from their panel, determined by a care assessment needs score that is based on high health care use and risk of hospitalization or death within 90 days. To determine care assessment needs scores, patient electronic health records (EHRs) are scanned weekly to review more than 150 data elements, including vital signs; recent clinic, urgent care, and emergency department (ED) visits; medications; laboratory values; and the number and types of illnesses. Statistical analyses are run on the EHR data to provide up-to-date estimates of likelihood of hospital admission or death.

Trainees may also select any patient on their panel whose health care they feel would benefit from a case conference discussion. The trainee presents all medical and social problems related to the selected patient to a team of HCPs, including other trainees and their supervisors, from multiple different disciplines, such as medicine, nursing, pharmacy, behavioral health, and social work. The interprofessional team then provides recommendations.

A care plan is developed by the group to implement as appropriate. The care plan may consist of various recommendations from the different disciplines, such as consults to a pharmacist for medication review or medication management, referrals to social work to coordinate care with home health services, or asking the nurse care manager to follow up with a patient by phone on a more regular basis. Trainees are encouraged to use alternate forms of care, including team-based care from other health care disciplines as well as other methods of communication, such as secure electronic messaging to increase access.

Interprofessional patient case conferences could offer another tool for HCPs to improve the care of high-risk patients through team-based efforts if the effect on patient outcomes or health care use is beneficial. The objective of this study was to evaluate the relationship of interprofessional case conferences and A_1c levels in high-risk patients with DM and BP measurements in patients with hypertension whose case was discussed at PACT ICU case conferences at the Boise VAMC. The authors hypothesized that the PACT ICU presentation intervention would lead to improved metabolic parameters as care plans were implemented. This evaluation is a subset of a larger study assessing the impact of PACT ICU presentation on various patient, trainee, and team level outcomes.

Methods

This study was a retrospective, observational analysis of patients seen at the Boise VAMC academic clinic whose cases were discussed at PACT ICU case conferences from January 2013 to April 2014. For the analysis of A_1c values, patients must have been discussed at a PACT ICU presentation during the study time period and had a diagnosis of DM in the EHR. Those included must have A_1c results in the EHR before and after the patient case presentation. The most recent A_1c measured prior to presentation was chosen as the prepresentation value. The next measured value 2 to 6 months after the case presentation date was chosen as the postpresentation value. This was chosen as the postpresentation value because it may be more indicative of the impact of the PACT ICU care plan. An A_1c measured at least 2 months following the case conference intervention was chosen to allow all possible measurements to be included in the analysis, according to usual care for measuring A_1c at the clinic. The primary outcome was the mean change in A_1c values pre- and post-PACT ICU presentation.