Admission to a hospital can be a stressful event,^1,2 and patients report having many concerns at the time of hospital admission.³ Over the last 20 years, the United States has widely adopted the hospitalist model of inpatient care. Although this model has clear benefits, it also has the potential to contribute to patient stress, as hospitalized patients generally lack preexisting relationships with their inpatient physicians.^4,5 In this changing hospital environment, defining and promoting effective medical communication has become an essential goal of both individual practitioners and medical centers.

Successful communication and strong therapeutic relationships with physicians support patients’ coping with illness-associated stress^6,7 as well as promote adherence to medical treatment plans.⁸ Empathy serves as an important building block of patient-centered communication and encourages a strong therapeutic alliance.⁹ Studies from primary care, oncology, and intensive care unit (ICU) settings indicate that physician empathy is associated with decreased emotional distress,^10,11 improved ratings of communication,¹² and even better medical outcomes.¹³

Prior work has shown that hospitalists, like other clinicians, underutilize empathy as a tool in their daily interactions with patients.^14-16 Our prior qualitative analysis of audio-recorded hospitalist-patient admission encounters indicated that how hospitalists respond to patient expressions of negative emotion influences relationships with patients and alignment around care plans.¹⁷ To determine whether empathic communication is associated with patient-reported outcomes in the hospitalist model, we quantitatively analyzed coded admission encounters and survey data to examine the association between hospitalists’ responses to patient expressions of negative emotion (anxiety, sadness, and anger) and patient anxiety and ratings of communication. Given the often-limited time hospitalists have to complete admission encounters, we also examined the association between response to emotion and encounter length.

We analyzed data collected as part of an observational study of hospitalist-patient communication during hospital admission encounters¹⁴ to assess the association between the way physicians responded to patient expressions of negative emotion and patient anxiety, ratings of communication in the encounter, and encounter length. We collected data between August 2008 and March 2009 on the general medical service at 2 urban hospitals that are part of an academic medical center. Participants were attending hospitalists (not physician trainees), and patients admitted under participating hospitalists’ care who were able to communicate verbally in English and provide informed consent for the study. The institutional review board at the University of California, San Francisco approved the study; physician and patient participants provided written informed consent.

Enrollment and data collection has been described previously.¹⁷ Our cohort for this analysis included 76 patients of 27 physicians who completed encounter audio recordings and pre- and postencounter surveys. Following enrollment, patients completed a preencounter survey to collect demographic information and to measure their baseline anxiety via the State Anxiety Scale (STAI-S), which assesses transient anxious mood using 20 items answered on a 4-point scale for a final score range of 20 to 80.^10,18,19 We timed and audio-recorded admission encounters. Encounter recordings were obtained solely from patient interactions with attending hospitalists and did not take into account the time patients may have spent with other physicians, including trainees. After the encounter, patients completed postencounter surveys, which included the STAI-S and patients’ ratings of communication during the encounter. To rate communication, patients responded to 7 items on a 0- to 10-point scale that were derived from previous work (Table 1)^12,20,21; the anchors were “not at all” and “completely.” To identify patients with serious illness, which we used as a covariate in regression models, we asked physicians on a postencounter survey whether or not they “would be surprised by this patient’s death or admission to the ICU in the next year.”²²

We analyzed data from admission encounters with 76 patients (consent rate 63%) and 27 hospitalists (consent rate 91%). Their characteristics are shown in Table 3. Median encounter length was 19 minutes (mean 21 minutes, range 3-68). Patients expressed negative emotion in 190 instances across all encounters; median number of expressions per encounter was 1 (range 0-14). Hospitalists responded empathically to 32% (n = 61) of the patient expressions, neutrally to 43% (n = 81), and nonempathically to 25% (n = 48).

The STAI-S was normally distributed. The mean preencounter STAI-S score was 39 (standard deviation [SD] 8.9). Mean postencounter STAI-S score was 38 (SD 10.7). Mean change in anxiety over the course of the encounter, calculated as the postencounter minus preencounter mean was −1.2 (SD 7.6). Table 1 shows summary statistics for the patient ratings of communication items. All items were rated highly. Across the items, between 51% and 78% of patients rated the highest score of 10.

Across the range of frequencies of emotional expressions per encounter in our data set (0-14 expressions), each additional empathic hospitalist response was associated with a 1.65-point decrease in the STAI-S (95% confidence interval [CI], 0.48-2.82). We did not find significant associations between changes in the STAI-S and the number of neutral hospitalist responses (−0.65 per response; 95% CI, −1.67-0.37) or nonempathic hospitalist responses (0.61 per response; 95% CI, −0.88-2.10).

Our study set out to measure how hospitalists responded to expressions of negative emotion during admission encounters with patients and how those responses correlated with patient anxiety, ratings of communication, and encounter length. We found that empathic responses were associated with diminishing patient anxiety after the visit, as well as with better ratings of several domains of hospitalist communication. Moreover, nonempathic responses to negative emotion were associated with more strongly negative ratings of hospitalist communication. Finally, while clinicians may worry that encouraging patients to speak further about emotion will result in excessive visit lengths, we did not find a statistical association between empathic responses and encounter duration. To our knowledge, this is the first study to indicate an association between empathy and patient anxiety and communication ratings within the hospitalist model, which is rapidly becoming the predominant model for providing inpatient care in the United States.^4,5

As in oncologic care, anxiety is an emotion commonly confronted by clinicians meeting admitted medical patients for the first time. Studies show that not only do patient anxiety levels remain high throughout a hospital course, patients who experience higher levels of anxiety tend to stay longer in the hospital.^1,2,27-30 But unlike oncologic care or other therapy provided in an outpatient setting, the hospitalist model does not facilitate “continuity” of care, or the ability to care for the same patients over a long period of time. This reality of inpatient care makes rapid, effective rapport-building critical to establishing strong physician-patient relationships. In this setting, a simple communication tool that is potentially able to reduce inpatients’ anxiety could have a meaningful impact on hospitalist-provided care and patient outcomes.

In terms of the magnitude of the effect of empathic responses, the clinical significance of a 1.65-point decrease in the STAI-S anxiety score is not precisely clear. A prior study that examined the effect of music therapy on anxiety levels in patients with cancer found an average anxiety reduction of approximately 9.5 units on the STAIS-S scale after sensitivity analysis, suggesting a rather large meaningful effect size.³¹ Given we found a reduction of 1.65 points for each empathic response, however, with a range of 0-14 negative emotions expressed over a median 19-minute encounter, there is opportunity for hospitalists to achieve a clinically significant decrease in patient anxiety during an admission encounter. The potential to reduce anxiety is extended further when we consider that the impact of an empathic response may apply not just to the admission encounter alone but also to numerous other patient-clinician interactions over the course of a hospitalization.

A healthy body of communication research supports the associations we found in our study between empathy and patient ratings of communication and physicians. Families in ICU conferences rate communication more positively when physicians express empathy,¹² and a number of studies indicate an association between empathy and patient satisfaction in outpatient settings.⁸ Given the associations we found with negative ratings on the items in our study, promoting empathic responses to expressions of emotion and, more importantly, stressing avoidance of nonempathic responses may be relevant efforts in working to improve patient satisfaction scores on surveys reporting “top box” percentages, such as Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS). More notably, evidence indicates that empathy has positive impacts beyond satisfaction surveys, such as adherence, better diagnostic and clinical outcomes, and strengthening of patient enablement.⁸Not all hospitalist responses to emotion were associated with patient ratings across the 7 communication items we assessed. For example, we did not find an association between how physicians responded to patient expressions of negative emotion and patient perception that enough time was spent in the visit or the degree to which talking with the doctor met a patient’s overall needs. It follows logically, and other research supports, that empathy would influence patient ratings of physician caring and trust,³² whereas other communication factors we were unable to measure (eg, physician body language, tone, and use of jargon and patient health literacy and primary language) may have a more significant association with patient ratings of the other items we assessed.

In considering the clinical application of our results, it is important to note that communication skills, including responding empathically to patient expressions of negative emotion, can be imparted through training in the same way as abdominal examination or electrocardiogram interpretation skills.^33-35 However, training of hospitalists in communication skills requires time and some financial investment on the part of the physician, their hospital or group, or, ideally, both. Effective training methods, like those for other skill acquisition, involve learner-centered teaching and practicing skills with role-play and feedback.³⁶ Given the importance of a learner-centered approach, learning would likely be better received and more effective if it was tailored to the specific needs and patient scenarios commonly encountered by hospitalist physicians. As these programs are developed, it will be important to assess the impact of any training on the patient-reported outcomes we assessed in this observational study, along with clinical outcomes.

Our study has several limitations. First, we were only able to evaluate whether hospitalists verbally responded to patient emotion and were thus not able to account for nonverbal empathy such as facial expressions, body language, or voice tone. Second, given our patient consent rate of 63%, patients who agreed to participate in the study may have had different opinions than those who declined to participate. Also, hospitalists and patients may have behaved differently as a result of being audio recorded. We only included patients who spoke English, and our patient population was predominately non-Hispanic white. Patients who spoke other languages or came from other cultural backgrounds may have had different responses. Third, we did not use a single validated scale for patient ratings of communication, and multiple analyses increase our risk of finding statistically significant associations by chance. The skewing of the communication rating items toward high scores may also have led to our results being driven by outliers, although the model we chose for analysis does penalize for this. Furthermore, our sample size was small, leading to wide CIs and potential for lack of statistical associations due to insufficient power. Our findings warrant replication in larger studies. Fourth, the setting of our study in an academic center may affect generalizability. Finally, the age of our data (collected between 2008 and 2009) is also a limitation. Given a recent focus on communication and patient experience since the initiation of HCAHPS feedback, a similar analysis of empathy and communication methods now may result in different outcomes.

In conclusion, our results suggest that enhancing hospitalists’ empathic responses to patient expressions of negative emotion could decrease patient anxiety and improve patients’ perceptions of (and thus possibly their relationships with) hospitalists, without sacrificing efficiency. Future work should focus on tailoring and implementing communication skills training programs for hospitalists and evaluating the impact of training on patient outcomes.

Acknowledgments

The authors extend their sincere thanks to the patients and physicians who participated in this study. Dr. Anderson was funded by the National Palliative Care Research Center and the University of California, San Francisco Clinical and Translational Science Institute Career Development Program, National Institutes of Health (NIH) grant number 5 KL2 RR024130-04. Project costs were funded by a grant from the University of California, San Francisco Academic Senate.

Disclosure

 All coauthors have seen and agree with the contents of this manuscript. This submission is not under review by any other publication. Wendy Anderson received funding for this project from the National Palliative Care Research Center, University of California San Francisco Clinical and Translational Science Institute (NIH grant number 5KL2RR024130-04), and the University of San Francisco Academic Senate [From Section 2 of Author Disclosure Form]. Andy Auerbach has a Patient-Centered Outcomes Research Institute research grant in development [From Section 3 of the Author Disclosure Form].

Admission to a hospital can be a stressful event,^1,2 and patients report having many concerns at the time of hospital admission.³ Over the last 20 years, the United States has widely adopted the hospitalist model of inpatient care. Although this model has clear benefits, it also has the potential to contribute to patient stress, as hospitalized patients generally lack preexisting relationships with their inpatient physicians.^4,5 In this changing hospital environment, defining and promoting effective medical communication has become an essential goal of both individual practitioners and medical centers.

Successful communication and strong therapeutic relationships with physicians support patients’ coping with illness-associated stress^6,7 as well as promote adherence to medical treatment plans.⁸ Empathy serves as an important building block of patient-centered communication and encourages a strong therapeutic alliance.⁹ Studies from primary care, oncology, and intensive care unit (ICU) settings indicate that physician empathy is associated with decreased emotional distress,^10,11 improved ratings of communication,¹² and even better medical outcomes.¹³

Prior work has shown that hospitalists, like other clinicians, underutilize empathy as a tool in their daily interactions with patients.^14-16 Our prior qualitative analysis of audio-recorded hospitalist-patient admission encounters indicated that how hospitalists respond to patient expressions of negative emotion influences relationships with patients and alignment around care plans.¹⁷ To determine whether empathic communication is associated with patient-reported outcomes in the hospitalist model, we quantitatively analyzed coded admission encounters and survey data to examine the association between hospitalists’ responses to patient expressions of negative emotion (anxiety, sadness, and anger) and patient anxiety and ratings of communication. Given the often-limited time hospitalists have to complete admission encounters, we also examined the association between response to emotion and encounter length.

We analyzed data collected as part of an observational study of hospitalist-patient communication during hospital admission encounters¹⁴ to assess the association between the way physicians responded to patient expressions of negative emotion and patient anxiety, ratings of communication in the encounter, and encounter length. We collected data between August 2008 and March 2009 on the general medical service at 2 urban hospitals that are part of an academic medical center. Participants were attending hospitalists (not physician trainees), and patients admitted under participating hospitalists’ care who were able to communicate verbally in English and provide informed consent for the study. The institutional review board at the University of California, San Francisco approved the study; physician and patient participants provided written informed consent.

Enrollment and data collection has been described previously.¹⁷ Our cohort for this analysis included 76 patients of 27 physicians who completed encounter audio recordings and pre- and postencounter surveys. Following enrollment, patients completed a preencounter survey to collect demographic information and to measure their baseline anxiety via the State Anxiety Scale (STAI-S), which assesses transient anxious mood using 20 items answered on a 4-point scale for a final score range of 20 to 80.^10,18,19 We timed and audio-recorded admission encounters. Encounter recordings were obtained solely from patient interactions with attending hospitalists and did not take into account the time patients may have spent with other physicians, including trainees. After the encounter, patients completed postencounter surveys, which included the STAI-S and patients’ ratings of communication during the encounter. To rate communication, patients responded to 7 items on a 0- to 10-point scale that were derived from previous work (Table 1)^12,20,21; the anchors were “not at all” and “completely.” To identify patients with serious illness, which we used as a covariate in regression models, we asked physicians on a postencounter survey whether or not they “would be surprised by this patient’s death or admission to the ICU in the next year.”²²

We analyzed data from admission encounters with 76 patients (consent rate 63%) and 27 hospitalists (consent rate 91%). Their characteristics are shown in Table 3. Median encounter length was 19 minutes (mean 21 minutes, range 3-68). Patients expressed negative emotion in 190 instances across all encounters; median number of expressions per encounter was 1 (range 0-14). Hospitalists responded empathically to 32% (n = 61) of the patient expressions, neutrally to 43% (n = 81), and nonempathically to 25% (n = 48).

The STAI-S was normally distributed. The mean preencounter STAI-S score was 39 (standard deviation [SD] 8.9). Mean postencounter STAI-S score was 38 (SD 10.7). Mean change in anxiety over the course of the encounter, calculated as the postencounter minus preencounter mean was −1.2 (SD 7.6). Table 1 shows summary statistics for the patient ratings of communication items. All items were rated highly. Across the items, between 51% and 78% of patients rated the highest score of 10.

Across the range of frequencies of emotional expressions per encounter in our data set (0-14 expressions), each additional empathic hospitalist response was associated with a 1.65-point decrease in the STAI-S (95% confidence interval [CI], 0.48-2.82). We did not find significant associations between changes in the STAI-S and the number of neutral hospitalist responses (−0.65 per response; 95% CI, −1.67-0.37) or nonempathic hospitalist responses (0.61 per response; 95% CI, −0.88-2.10).

Our study set out to measure how hospitalists responded to expressions of negative emotion during admission encounters with patients and how those responses correlated with patient anxiety, ratings of communication, and encounter length. We found that empathic responses were associated with diminishing patient anxiety after the visit, as well as with better ratings of several domains of hospitalist communication. Moreover, nonempathic responses to negative emotion were associated with more strongly negative ratings of hospitalist communication. Finally, while clinicians may worry that encouraging patients to speak further about emotion will result in excessive visit lengths, we did not find a statistical association between empathic responses and encounter duration. To our knowledge, this is the first study to indicate an association between empathy and patient anxiety and communication ratings within the hospitalist model, which is rapidly becoming the predominant model for providing inpatient care in the United States.^4,5

As in oncologic care, anxiety is an emotion commonly confronted by clinicians meeting admitted medical patients for the first time. Studies show that not only do patient anxiety levels remain high throughout a hospital course, patients who experience higher levels of anxiety tend to stay longer in the hospital.^1,2,27-30 But unlike oncologic care or other therapy provided in an outpatient setting, the hospitalist model does not facilitate “continuity” of care, or the ability to care for the same patients over a long period of time. This reality of inpatient care makes rapid, effective rapport-building critical to establishing strong physician-patient relationships. In this setting, a simple communication tool that is potentially able to reduce inpatients’ anxiety could have a meaningful impact on hospitalist-provided care and patient outcomes.

In terms of the magnitude of the effect of empathic responses, the clinical significance of a 1.65-point decrease in the STAI-S anxiety score is not precisely clear. A prior study that examined the effect of music therapy on anxiety levels in patients with cancer found an average anxiety reduction of approximately 9.5 units on the STAIS-S scale after sensitivity analysis, suggesting a rather large meaningful effect size.³¹ Given we found a reduction of 1.65 points for each empathic response, however, with a range of 0-14 negative emotions expressed over a median 19-minute encounter, there is opportunity for hospitalists to achieve a clinically significant decrease in patient anxiety during an admission encounter. The potential to reduce anxiety is extended further when we consider that the impact of an empathic response may apply not just to the admission encounter alone but also to numerous other patient-clinician interactions over the course of a hospitalization.

A healthy body of communication research supports the associations we found in our study between empathy and patient ratings of communication and physicians. Families in ICU conferences rate communication more positively when physicians express empathy,¹² and a number of studies indicate an association between empathy and patient satisfaction in outpatient settings.⁸ Given the associations we found with negative ratings on the items in our study, promoting empathic responses to expressions of emotion and, more importantly, stressing avoidance of nonempathic responses may be relevant efforts in working to improve patient satisfaction scores on surveys reporting “top box” percentages, such as Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS). More notably, evidence indicates that empathy has positive impacts beyond satisfaction surveys, such as adherence, better diagnostic and clinical outcomes, and strengthening of patient enablement.⁸Not all hospitalist responses to emotion were associated with patient ratings across the 7 communication items we assessed. For example, we did not find an association between how physicians responded to patient expressions of negative emotion and patient perception that enough time was spent in the visit or the degree to which talking with the doctor met a patient’s overall needs. It follows logically, and other research supports, that empathy would influence patient ratings of physician caring and trust,³² whereas other communication factors we were unable to measure (eg, physician body language, tone, and use of jargon and patient health literacy and primary language) may have a more significant association with patient ratings of the other items we assessed.

In considering the clinical application of our results, it is important to note that communication skills, including responding empathically to patient expressions of negative emotion, can be imparted through training in the same way as abdominal examination or electrocardiogram interpretation skills.^33-35 However, training of hospitalists in communication skills requires time and some financial investment on the part of the physician, their hospital or group, or, ideally, both. Effective training methods, like those for other skill acquisition, involve learner-centered teaching and practicing skills with role-play and feedback.³⁶ Given the importance of a learner-centered approach, learning would likely be better received and more effective if it was tailored to the specific needs and patient scenarios commonly encountered by hospitalist physicians. As these programs are developed, it will be important to assess the impact of any training on the patient-reported outcomes we assessed in this observational study, along with clinical outcomes.

Our study has several limitations. First, we were only able to evaluate whether hospitalists verbally responded to patient emotion and were thus not able to account for nonverbal empathy such as facial expressions, body language, or voice tone. Second, given our patient consent rate of 63%, patients who agreed to participate in the study may have had different opinions than those who declined to participate. Also, hospitalists and patients may have behaved differently as a result of being audio recorded. We only included patients who spoke English, and our patient population was predominately non-Hispanic white. Patients who spoke other languages or came from other cultural backgrounds may have had different responses. Third, we did not use a single validated scale for patient ratings of communication, and multiple analyses increase our risk of finding statistically significant associations by chance. The skewing of the communication rating items toward high scores may also have led to our results being driven by outliers, although the model we chose for analysis does penalize for this. Furthermore, our sample size was small, leading to wide CIs and potential for lack of statistical associations due to insufficient power. Our findings warrant replication in larger studies. Fourth, the setting of our study in an academic center may affect generalizability. Finally, the age of our data (collected between 2008 and 2009) is also a limitation. Given a recent focus on communication and patient experience since the initiation of HCAHPS feedback, a similar analysis of empathy and communication methods now may result in different outcomes.

In conclusion, our results suggest that enhancing hospitalists’ empathic responses to patient expressions of negative emotion could decrease patient anxiety and improve patients’ perceptions of (and thus possibly their relationships with) hospitalists, without sacrificing efficiency. Future work should focus on tailoring and implementing communication skills training programs for hospitalists and evaluating the impact of training on patient outcomes.

Acknowledgments

The authors extend their sincere thanks to the patients and physicians who participated in this study. Dr. Anderson was funded by the National Palliative Care Research Center and the University of California, San Francisco Clinical and Translational Science Institute Career Development Program, National Institutes of Health (NIH) grant number 5 KL2 RR024130-04. Project costs were funded by a grant from the University of California, San Francisco Academic Senate.

Disclosure

 All coauthors have seen and agree with the contents of this manuscript. This submission is not under review by any other publication. Wendy Anderson received funding for this project from the National Palliative Care Research Center, University of California San Francisco Clinical and Translational Science Institute (NIH grant number 5KL2RR024130-04), and the University of San Francisco Academic Senate [From Section 2 of Author Disclosure Form]. Andy Auerbach has a Patient-Centered Outcomes Research Institute research grant in development [From Section 3 of the Author Disclosure Form].

Admission to a hospital can be a stressful event,^1,2 and patients report having many concerns at the time of hospital admission.³ Over the last 20 years, the United States has widely adopted the hospitalist model of inpatient care. Although this model has clear benefits, it also has the potential to contribute to patient stress, as hospitalized patients generally lack preexisting relationships with their inpatient physicians.^4,5 In this changing hospital environment, defining and promoting effective medical communication has become an essential goal of both individual practitioners and medical centers.

Successful communication and strong therapeutic relationships with physicians support patients’ coping with illness-associated stress^6,7 as well as promote adherence to medical treatment plans.⁸ Empathy serves as an important building block of patient-centered communication and encourages a strong therapeutic alliance.⁹ Studies from primary care, oncology, and intensive care unit (ICU) settings indicate that physician empathy is associated with decreased emotional distress,^10,11 improved ratings of communication,¹² and even better medical outcomes.¹³

Prior work has shown that hospitalists, like other clinicians, underutilize empathy as a tool in their daily interactions with patients.^14-16 Our prior qualitative analysis of audio-recorded hospitalist-patient admission encounters indicated that how hospitalists respond to patient expressions of negative emotion influences relationships with patients and alignment around care plans.¹⁷ To determine whether empathic communication is associated with patient-reported outcomes in the hospitalist model, we quantitatively analyzed coded admission encounters and survey data to examine the association between hospitalists’ responses to patient expressions of negative emotion (anxiety, sadness, and anger) and patient anxiety and ratings of communication. Given the often-limited time hospitalists have to complete admission encounters, we also examined the association between response to emotion and encounter length.

We analyzed data collected as part of an observational study of hospitalist-patient communication during hospital admission encounters¹⁴ to assess the association between the way physicians responded to patient expressions of negative emotion and patient anxiety, ratings of communication in the encounter, and encounter length. We collected data between August 2008 and March 2009 on the general medical service at 2 urban hospitals that are part of an academic medical center. Participants were attending hospitalists (not physician trainees), and patients admitted under participating hospitalists’ care who were able to communicate verbally in English and provide informed consent for the study. The institutional review board at the University of California, San Francisco approved the study; physician and patient participants provided written informed consent.

Enrollment and data collection has been described previously.¹⁷ Our cohort for this analysis included 76 patients of 27 physicians who completed encounter audio recordings and pre- and postencounter surveys. Following enrollment, patients completed a preencounter survey to collect demographic information and to measure their baseline anxiety via the State Anxiety Scale (STAI-S), which assesses transient anxious mood using 20 items answered on a 4-point scale for a final score range of 20 to 80.^10,18,19 We timed and audio-recorded admission encounters. Encounter recordings were obtained solely from patient interactions with attending hospitalists and did not take into account the time patients may have spent with other physicians, including trainees. After the encounter, patients completed postencounter surveys, which included the STAI-S and patients’ ratings of communication during the encounter. To rate communication, patients responded to 7 items on a 0- to 10-point scale that were derived from previous work (Table 1)^12,20,21; the anchors were “not at all” and “completely.” To identify patients with serious illness, which we used as a covariate in regression models, we asked physicians on a postencounter survey whether or not they “would be surprised by this patient’s death or admission to the ICU in the next year.”²²

We analyzed data from admission encounters with 76 patients (consent rate 63%) and 27 hospitalists (consent rate 91%). Their characteristics are shown in Table 3. Median encounter length was 19 minutes (mean 21 minutes, range 3-68). Patients expressed negative emotion in 190 instances across all encounters; median number of expressions per encounter was 1 (range 0-14). Hospitalists responded empathically to 32% (n = 61) of the patient expressions, neutrally to 43% (n = 81), and nonempathically to 25% (n = 48).

The STAI-S was normally distributed. The mean preencounter STAI-S score was 39 (standard deviation [SD] 8.9). Mean postencounter STAI-S score was 38 (SD 10.7). Mean change in anxiety over the course of the encounter, calculated as the postencounter minus preencounter mean was −1.2 (SD 7.6). Table 1 shows summary statistics for the patient ratings of communication items. All items were rated highly. Across the items, between 51% and 78% of patients rated the highest score of 10.

Across the range of frequencies of emotional expressions per encounter in our data set (0-14 expressions), each additional empathic hospitalist response was associated with a 1.65-point decrease in the STAI-S (95% confidence interval [CI], 0.48-2.82). We did not find significant associations between changes in the STAI-S and the number of neutral hospitalist responses (−0.65 per response; 95% CI, −1.67-0.37) or nonempathic hospitalist responses (0.61 per response; 95% CI, −0.88-2.10).

Our study set out to measure how hospitalists responded to expressions of negative emotion during admission encounters with patients and how those responses correlated with patient anxiety, ratings of communication, and encounter length. We found that empathic responses were associated with diminishing patient anxiety after the visit, as well as with better ratings of several domains of hospitalist communication. Moreover, nonempathic responses to negative emotion were associated with more strongly negative ratings of hospitalist communication. Finally, while clinicians may worry that encouraging patients to speak further about emotion will result in excessive visit lengths, we did not find a statistical association between empathic responses and encounter duration. To our knowledge, this is the first study to indicate an association between empathy and patient anxiety and communication ratings within the hospitalist model, which is rapidly becoming the predominant model for providing inpatient care in the United States.^4,5

As in oncologic care, anxiety is an emotion commonly confronted by clinicians meeting admitted medical patients for the first time. Studies show that not only do patient anxiety levels remain high throughout a hospital course, patients who experience higher levels of anxiety tend to stay longer in the hospital.^1,2,27-30 But unlike oncologic care or other therapy provided in an outpatient setting, the hospitalist model does not facilitate “continuity” of care, or the ability to care for the same patients over a long period of time. This reality of inpatient care makes rapid, effective rapport-building critical to establishing strong physician-patient relationships. In this setting, a simple communication tool that is potentially able to reduce inpatients’ anxiety could have a meaningful impact on hospitalist-provided care and patient outcomes.

In terms of the magnitude of the effect of empathic responses, the clinical significance of a 1.65-point decrease in the STAI-S anxiety score is not precisely clear. A prior study that examined the effect of music therapy on anxiety levels in patients with cancer found an average anxiety reduction of approximately 9.5 units on the STAIS-S scale after sensitivity analysis, suggesting a rather large meaningful effect size.³¹ Given we found a reduction of 1.65 points for each empathic response, however, with a range of 0-14 negative emotions expressed over a median 19-minute encounter, there is opportunity for hospitalists to achieve a clinically significant decrease in patient anxiety during an admission encounter. The potential to reduce anxiety is extended further when we consider that the impact of an empathic response may apply not just to the admission encounter alone but also to numerous other patient-clinician interactions over the course of a hospitalization.

A healthy body of communication research supports the associations we found in our study between empathy and patient ratings of communication and physicians. Families in ICU conferences rate communication more positively when physicians express empathy,¹² and a number of studies indicate an association between empathy and patient satisfaction in outpatient settings.⁸ Given the associations we found with negative ratings on the items in our study, promoting empathic responses to expressions of emotion and, more importantly, stressing avoidance of nonempathic responses may be relevant efforts in working to improve patient satisfaction scores on surveys reporting “top box” percentages, such as Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS). More notably, evidence indicates that empathy has positive impacts beyond satisfaction surveys, such as adherence, better diagnostic and clinical outcomes, and strengthening of patient enablement.⁸Not all hospitalist responses to emotion were associated with patient ratings across the 7 communication items we assessed. For example, we did not find an association between how physicians responded to patient expressions of negative emotion and patient perception that enough time was spent in the visit or the degree to which talking with the doctor met a patient’s overall needs. It follows logically, and other research supports, that empathy would influence patient ratings of physician caring and trust,³² whereas other communication factors we were unable to measure (eg, physician body language, tone, and use of jargon and patient health literacy and primary language) may have a more significant association with patient ratings of the other items we assessed.

In considering the clinical application of our results, it is important to note that communication skills, including responding empathically to patient expressions of negative emotion, can be imparted through training in the same way as abdominal examination or electrocardiogram interpretation skills.^33-35 However, training of hospitalists in communication skills requires time and some financial investment on the part of the physician, their hospital or group, or, ideally, both. Effective training methods, like those for other skill acquisition, involve learner-centered teaching and practicing skills with role-play and feedback.³⁶ Given the importance of a learner-centered approach, learning would likely be better received and more effective if it was tailored to the specific needs and patient scenarios commonly encountered by hospitalist physicians. As these programs are developed, it will be important to assess the impact of any training on the patient-reported outcomes we assessed in this observational study, along with clinical outcomes.

Our study has several limitations. First, we were only able to evaluate whether hospitalists verbally responded to patient emotion and were thus not able to account for nonverbal empathy such as facial expressions, body language, or voice tone. Second, given our patient consent rate of 63%, patients who agreed to participate in the study may have had different opinions than those who declined to participate. Also, hospitalists and patients may have behaved differently as a result of being audio recorded. We only included patients who spoke English, and our patient population was predominately non-Hispanic white. Patients who spoke other languages or came from other cultural backgrounds may have had different responses. Third, we did not use a single validated scale for patient ratings of communication, and multiple analyses increase our risk of finding statistically significant associations by chance. The skewing of the communication rating items toward high scores may also have led to our results being driven by outliers, although the model we chose for analysis does penalize for this. Furthermore, our sample size was small, leading to wide CIs and potential for lack of statistical associations due to insufficient power. Our findings warrant replication in larger studies. Fourth, the setting of our study in an academic center may affect generalizability. Finally, the age of our data (collected between 2008 and 2009) is also a limitation. Given a recent focus on communication and patient experience since the initiation of HCAHPS feedback, a similar analysis of empathy and communication methods now may result in different outcomes.

In conclusion, our results suggest that enhancing hospitalists’ empathic responses to patient expressions of negative emotion could decrease patient anxiety and improve patients’ perceptions of (and thus possibly their relationships with) hospitalists, without sacrificing efficiency. Future work should focus on tailoring and implementing communication skills training programs for hospitalists and evaluating the impact of training on patient outcomes.

Acknowledgments

The authors extend their sincere thanks to the patients and physicians who participated in this study. Dr. Anderson was funded by the National Palliative Care Research Center and the University of California, San Francisco Clinical and Translational Science Institute Career Development Program, National Institutes of Health (NIH) grant number 5 KL2 RR024130-04. Project costs were funded by a grant from the University of California, San Francisco Academic Senate.

Disclosure

 All coauthors have seen and agree with the contents of this manuscript. This submission is not under review by any other publication. Wendy Anderson received funding for this project from the National Palliative Care Research Center, University of California San Francisco Clinical and Translational Science Institute (NIH grant number 5KL2RR024130-04), and the University of San Francisco Academic Senate [From Section 2 of Author Disclosure Form]. Andy Auerbach has a Patient-Centered Outcomes Research Institute research grant in development [From Section 3 of the Author Disclosure Form].

The hospital environment fails to promote adequate sleep for acutely or critically ill patients. Intensive care units (ICUs) have received the most scrutiny, because critically ill patients suffer from severely fragmented sleep as well as a lack of deeper, more restorative sleep.^1-4 ICU survivors frequently cite sleep deprivation, contributed to by ambient noise, as a major stressor while receiving care.^5,6 Importantly, efforts to modify the ICU environment to promote sleep have been associated with reductions in delirium.^7,8 However, sleep deprivation and delirium in the hospital are not limited to ICU patients.

Sleep in the non-ICU setting is also notoriously poor, with 50%-80% of patients reporting sleep as “unsound” or otherwise subjectively poor.^9-11 Additionally, patients frequently ask for and/or receive pharmacological sleeping aids¹² despite little evidence of efficacy¹³ and increasing evidence of harm.¹⁴ Here too, efforts to improve sleep seems to attenuate risk of delirium,¹⁵ which remains a substantial problem on general wards, with incidence reported as high as 20%-30%. The reasons for poor sleep in the hospital are multifactorial, but data suggest that the inpatient environment, including noise and light levels, which are measurable and modifiable entities, contribute significantly to the problem.¹⁶

The World Health Organization (WHO) recommends that nighttime baseline noise levels do not exceed 30 decibels (dB) and that nighttime noise peaks (ie, loud noises) do not exceed 40 dB¹⁷; most studies suggest that ICU and general ward rooms are above this range on average.^10,18 Others have also demonstrated an association between loud noises and patients’ subjective perception of poor sleep.^10,19 However, when considering clinically important noise, peak and average noise levels may not be the key factor in causing arousals from sleep. Buxton and colleagues²⁰ found that noise quality affects arousal probability; for example, electronic alarms and conversational noise are more likely to cause awakenings compared with the opening or closing of doors and ice machines. Importantly, peak and average noise levels may also matter less for sleep than do sound level changes (SLCs), which are defined as the difference between background/baseline noise and peak noise. Using healthy subjects exposed to simulated ICU noise, Stanchina et al.²¹ found that SLCs >17.5 dB were more likely to cause polysomnographic arousals from sleep regardless of peak noise level. This sound pressure change of approximately 20 dB would be perceived as 4 times louder, or, as an example, would be the difference between normal conversation between 2 people (~40 dB) that is then interrupted by the start of a vacuum cleaner (~60 dB). To our knowledge, no other studies have closely examined SLCs in different hospital environments.

Ambient light also likely affects sleep quality in the hospital. The circadian rhythm system, which controls the human sleep–wake cycle as well as multiple other physiologic functions, depends on ambient light as the primary external factor for regulating the internal clock.^22,23 Insufficient and inappropriately timed light exposure can desynchronize the biological clock, thereby negatively affecting sleep quality.^24,25 Conversely, patients exposed to early-morning bright light may sleep better while in the hospital.¹⁶ In addition to sleep patterns, ambient light affects other aspects of patient care; for example, lower light levels in the hospital have recently been associated with higher levels of fatigue and mood disturbance.²⁶A growing body of data has investigated the ambient environment in the ICU, but fewer studies have focused on sound and light analysis in other inpatient areas such as the general ward and telemetry floors. We examined sound and light levels in the ICU and non-ICU environment, hypothesizing that average sound levels would be higher in the ICU than on non-ICU floors but that the number of SLCs >17.5 dB would be similar. Additionally, we expected that average light levels would be higher in the ICU than on non-ICU floors.

This was an observational study of the sound and light environment in the inpatient setting. Per our Institutional Review Board, no consent was required. Battery-operated sound-level (SDL600, Extech Instruments, Nashua, NH) and light-level (SDL400, Extech Instruments, Nashua, NH) meters were placed in 24 patient rooms in our tertiary-care adult hospital in La Jolla, CA. Recordings were obtained in randomly selected, single-patient occupied rooms that were from 3 different hospital units and included 8 general ward rooms, 8 telemetry floor rooms, and 8 ICU rooms. We recorded for approximately 24-72 hours. Depending on the geographic layout of the room, meters were placed as close to the head of the patient’s bed as possible and were generally not placed farther than 2 meters away from the patient’s head of bed; all rooms contained a window.

Sound Measurements

Sound meters measured ambient noise in dB every 2 seconds and were set for A-weighted frequency measurements. We averaged individual data points to obtain hourly averages for ICU and non-ICU rooms. For hourly sound averages, we further separated the data to compare the general ward telemetry floors (both non-ICU), the latter of which has more patient monitoring and a lower nurse-to-patient ratio compared with the general ward floor.

Data from ICU versus non-ICU rooms were analyzed for the number of sound peaks throughout the 24-hour day and for sound peak over the nighttime, defined as the number of times sound levels exceeded 65 dB, 70 dB, or 80 dB, which were averaged over 24 hours and over the nighttime (10 PM to 6 AM). We also calculated the number of average SLCs ≥17.5 dB observed over 24 hours and over the nighttime.

Light Measurements

Light meters measured luminescence in lux at a frequency of 120 seconds. We averaged individual data points to obtain hourly averages for ICU and non-ICU rooms. In addition to hourly averages, light-level data were analyzed for maximum levels throughout the day and night.

Statistical Analysis

Hourly sound-level averages between the 3 floors were evaluated using a 1-way analysis of variance (ANOVA); sound averages from the general ward and telemetry floor were also compared at each hour using a Student t test. Light-level data, sound-level peak data, as well as SLC data were also evaluated using a Student t test.

Sound Measurements

Examples of the raw data distribution for individual sound recordings in an ICU and non-ICU room are shown in Figure 1A and 1B. Sound-level analysis with specific average values and significance levels between ICU and non-ICU rooms (with non-ICU rooms further divided between telemetry and general ward floors for purposes of hourly averages) are shown in Table 1. The average hourly values in all 3 locations were always above the 30-35 dB level (nighttime and daytime, respectively) recommended by the WHO (Figure 1C). A 1-way ANOVA analysis revealed significant differences between the 3 floors at all time points except for 10 AM. An analysis of the means at each time point between the telemetry floor and the general ward floor showed that the telemetry floor had significantly higher sound averages compared with the general ward floor at 10 PM, 11 PM, and 12 AM. Sound levels dropped during the nighttime on both non-ICU wards but remained fairly constant throughout the day and night in the ICU.

Light Measurements

Examples of light levels over a 24-hour period in an ICU and non-ICU room are shown in Figure 2A and 2B, respectively. Maximum average light levels (reported here as average value ± standard deviation to demonstrate variability within the data) in the ICU were 169.7 ± 127.1 lux and occurred at 1 PM, while maximum average light levels in the non-ICU rooms were 213.5 ± 341.6 lux and occurred at 5 PM (Figure 2C). Average light levels in the morning hours remained low and ranged from 15.9 ± 12.7 lux to 38.9 ± 43.4 lux in the ICU and from 22.3 ± 17.5 lux to 100.7 ± 92.0 lux on the non-ICU floors. The maximum measured level from any of the recordings was 2530 lux and occurred in a general ward room in the 5 PM hour. Overall, light averages remained low, but this particular room had light levels that were significantly higher than the others. A t test analysis of the hourly averages revealed only 1 time point of significant difference between the 2 floors; at 7 AM, the general ward floor had a higher lux level of 49.9 ± 27.5 versus 19.2 ± 10.7 in the ICU (P = 0.038). Otherwise, there were no differences between light levels in ICU rooms versus non-ICU rooms. Evaluation of the data revealed a substantial amount of variability in light levels throughout the daytime hours. Light levels during the nighttime remained low and were not significantly different between the 2 groups.

To our knowledge, this is the first study to directly compare the ICU and non-ICU environment for its potential impact on sleep and circadian alignment. Our study adds to the literature with several novel findings. First, average sound levels on non-ICU wards are lower than in the ICU. Second, although quieter on average, SLCs >17.5 dB occurred an equivalent number of times for both the ICU and non-ICU wards. Third, average daytime light levels in both the ICU and non-ICU environment are low. Lastly, peak light levels for both ICU and non-ICU wards occur later in the day instead of in the morning. All of the above have potential impact for optimizing the ward environment to better aid in sleep for patients.

Sound-Level Findings

Data on sound levels for non-ICU floors are limited but mostly consistent with our findings; sound averages in our study ranged from 44.6 to 55.1 dB in non-ICU rooms, while others report averages ranging from 48 dB¹⁹ to 63.5 dB,¹⁰ although the latter measurement includes rooms occupied with 4 to 6 patients, which we expect would increase the noise levels. Others report average noise levels in the ICU similar to our values, which ranged from 56.1 to 60.3 dB.^18,27 Here, we show that average and peak sound levels on non-ICU wards are consistently lower than in the ICU. However, sound levels on the general ward and telemetry floors still remain quite high and potentially disruptive to patients, with average nighttime sound levels reaching the range of light outdoor traffic. The sleep environment could play an even larger role in sleep quality for non-ICU patients, as they do not typically receive sedation (though pharmacological sleeping-aid use is quite high, despite the risks)²⁸ and thus may be more sensitive to environmental factors that impact sleep.

Average and peak sound levels contribute to the ambient noise experienced by patients but may not be the source of sleep disruptions. Using polysomnography in healthy subjects exposed to recordings of ICU noise, Stanchina et al.²¹ showed that SLCs from baseline and not peak sound levels determined whether a subject was aroused from sleep by sound. Accordingly, they also found that increasing baseline sound levels by using white noise reduced the number of arousals that subjects experienced. To our knowledge, other studies have not quantified and compared SLCs in the ICU and non-ICU environments. Our data show that patients on non-ICU floors experience at least the same number of SLCs, and thereby the same potential for arousals from sleep, when compared with ICU patients. The higher baseline level of noise in the ICU likely explains the relatively lower number of SLCs when compared with the non-ICU floors. Although decreasing overall noise to promote sleep in the hospital seems like the obvious solution, the treatment for noise pollution in the hospital may actually be more background noise, not less.

Recent studies support the clinical implications of our findings. First, decreasing overall noise levels is difficult to accomplish.²⁹ Second, recent studies utilized white noise in different hospital settings with some success in improving patients’ subjective sleep quality, although more studies using objective data measurements are needed to further understand the impact of white noise on sleep in hospitalized patients.^30,31 Third, efforts at reducing interruptions—which likely will decrease the number of SLCs—such as clustering nursing care or reducing intermittent alarms may be more beneficial in improving sleep than efforts at decreasing average sound levels. For example, Bartick et al. reduced the number of patient interruptions at night by eliminating routine vital signs and clustering medication administration. Although they included other interventions as well, we note that this approach likely reduced SLCs and was associated with a reduction in the use of sedative medications.³² Ultimately, our data show that a focus on reducing SLCs will be one necessary component of a multipronged solution to improving inpatient sleep.³³

Light-Level Findings

Because of its effect on circadian rhythms, the daily light-dark cycle has a powerful impact on human physiology and behavior, which includes sleep.³⁴ Little is understood about how light affects sleep and other circadian-related functions in general ward patients, as it is not commonly measured. Our findings suggest that patients admitted to the hospital are exposed to light levels and patterns that may not optimally promote wake and sleep. Encouragingly, we did not find excessive average light levels during the nighttime in either ICU or non-ICU environment of our hospital, although others have described intrusive nighttime light in the hospital setting.^35,36 Even short bursts of low or moderate light during the nighttime can cause circadian phase delay,³⁷ and efforts to maintain darkness in patient rooms at night should continue.

Our measurements show that average daytime light levels did not exceed 250 lux, which corresponds to low, office-level lighting, while the brightest average light levels occurred in the afternoon for both environments. These levels are consistent with other reports^26,35,36 as is the light-level variability noted throughout the day (which is not unexpected given room positioning, patient preference, curtains, etc). The level and amount of daytime light needed to maintain circadian rhythms in humans is still unknown.³⁸ Brighter light is generally more effective at influencing the circadian pacemaker in a dose-dependent manner.³⁹ Although entrainment (synchronization of the body’s biological rhythm with environmental cues such as ambient light) of the human circadian rhythm has been shown with low light levels (eg, <100 lux), these studies included healthy volunteers in a carefully controlled, constant, routine environment.²³ How these data apply to acutely ill subjects in the hospital environment is not clear. We note that low to moderate levels of light (50-1000 lux) are less effective for entrainment of the circadian rhythm in older people (age >65 years, the majority of our admissions) compared with younger people. Thus, older, hospitalized patients may require greater light levels for regulation of the sleep-wake cycle.⁴⁰ These data are important when designing interventions to improve light for and maintain circadian rhythms in hospitalized patients. For example, Simons et al. found that dynamic light-application therapy, which achieved a maximum average lux level of <800 lux, did not reduce rates of delirium in critically ill patients (mean age ~65). One interpretation of these results, though there are many others, is that the light levels achieved were not high enough to influence circadian timing in hospitalized, mostly elderly patients. The physiological impact of light on the circadian rhythm in hospitalized patients still remains to be measured.

Our study does have a few limitations. We did not assess sound quality, which is another determinant of arousal potential.²⁰ Also, a shorter measurement interval might be useful in determining sharper sound increases. It may also be important to consider A- versus C-weighted measurements of sound levels, as A-weighted measurements usually reflect higher-frequency sound while C-weighted measurements usually reflect low-frequency noise¹⁸; we obtained only A-weighted measurements in our study. However, A-weighted measurements are generally considered more reflective of what the human ear considers noise and are used more standardly than C-weighted measurements.

Regarding light measurements, we recorded from rooms facing different cardinal directions and during different times of the year, which likely contributed to some of the variability in the daytime light levels on both floors. Additionally, light levels were not measured directly at the patient’s eye level. However, given that overhead fluorescent lighting was the primary source of lighting, it is doubtful that we substantially underestimated optic-nerve light levels. In the future, it may also be important to measure the different wavelengths of lights, as blue light may have a greater impact on sleep than other wavelengths.⁴¹ Although our findings align with others’, we note that this was a single-center study, which could limit the generalizability of our findings given inter-hospital variations in patient volume, interior layout and structure, and geographic location.

Overall, our study suggests that the light and sound environment for sleep in the inpatient setting, including both the ICU and non-ICU wards, has multiple areas for improvement. Our data also suggest specific directions for future clinical efforts at improvement. For example, efforts to decrease average sound levels may worsen sleep fragmentation. Similarly, more light during the day may be more helpful than further attempts to limit light during the night.

Disclosure

This research was funded in part by a NIH/NCATS flagship Clinical and Translational Science Award Grant (5KL2TR001112). None of the authors report any conflict of interest, financial or otherwise, in the preparation of this article.

The hospital environment fails to promote adequate sleep for acutely or critically ill patients. Intensive care units (ICUs) have received the most scrutiny, because critically ill patients suffer from severely fragmented sleep as well as a lack of deeper, more restorative sleep.^1-4 ICU survivors frequently cite sleep deprivation, contributed to by ambient noise, as a major stressor while receiving care.^5,6 Importantly, efforts to modify the ICU environment to promote sleep have been associated with reductions in delirium.^7,8 However, sleep deprivation and delirium in the hospital are not limited to ICU patients.

Sleep in the non-ICU setting is also notoriously poor, with 50%-80% of patients reporting sleep as “unsound” or otherwise subjectively poor.^9-11 Additionally, patients frequently ask for and/or receive pharmacological sleeping aids¹² despite little evidence of efficacy¹³ and increasing evidence of harm.¹⁴ Here too, efforts to improve sleep seems to attenuate risk of delirium,¹⁵ which remains a substantial problem on general wards, with incidence reported as high as 20%-30%. The reasons for poor sleep in the hospital are multifactorial, but data suggest that the inpatient environment, including noise and light levels, which are measurable and modifiable entities, contribute significantly to the problem.¹⁶

The World Health Organization (WHO) recommends that nighttime baseline noise levels do not exceed 30 decibels (dB) and that nighttime noise peaks (ie, loud noises) do not exceed 40 dB¹⁷; most studies suggest that ICU and general ward rooms are above this range on average.^10,18 Others have also demonstrated an association between loud noises and patients’ subjective perception of poor sleep.^10,19 However, when considering clinically important noise, peak and average noise levels may not be the key factor in causing arousals from sleep. Buxton and colleagues²⁰ found that noise quality affects arousal probability; for example, electronic alarms and conversational noise are more likely to cause awakenings compared with the opening or closing of doors and ice machines. Importantly, peak and average noise levels may also matter less for sleep than do sound level changes (SLCs), which are defined as the difference between background/baseline noise and peak noise. Using healthy subjects exposed to simulated ICU noise, Stanchina et al.²¹ found that SLCs >17.5 dB were more likely to cause polysomnographic arousals from sleep regardless of peak noise level. This sound pressure change of approximately 20 dB would be perceived as 4 times louder, or, as an example, would be the difference between normal conversation between 2 people (~40 dB) that is then interrupted by the start of a vacuum cleaner (~60 dB). To our knowledge, no other studies have closely examined SLCs in different hospital environments.

Ambient light also likely affects sleep quality in the hospital. The circadian rhythm system, which controls the human sleep–wake cycle as well as multiple other physiologic functions, depends on ambient light as the primary external factor for regulating the internal clock.^22,23 Insufficient and inappropriately timed light exposure can desynchronize the biological clock, thereby negatively affecting sleep quality.^24,25 Conversely, patients exposed to early-morning bright light may sleep better while in the hospital.¹⁶ In addition to sleep patterns, ambient light affects other aspects of patient care; for example, lower light levels in the hospital have recently been associated with higher levels of fatigue and mood disturbance.²⁶A growing body of data has investigated the ambient environment in the ICU, but fewer studies have focused on sound and light analysis in other inpatient areas such as the general ward and telemetry floors. We examined sound and light levels in the ICU and non-ICU environment, hypothesizing that average sound levels would be higher in the ICU than on non-ICU floors but that the number of SLCs >17.5 dB would be similar. Additionally, we expected that average light levels would be higher in the ICU than on non-ICU floors.

This was an observational study of the sound and light environment in the inpatient setting. Per our Institutional Review Board, no consent was required. Battery-operated sound-level (SDL600, Extech Instruments, Nashua, NH) and light-level (SDL400, Extech Instruments, Nashua, NH) meters were placed in 24 patient rooms in our tertiary-care adult hospital in La Jolla, CA. Recordings were obtained in randomly selected, single-patient occupied rooms that were from 3 different hospital units and included 8 general ward rooms, 8 telemetry floor rooms, and 8 ICU rooms. We recorded for approximately 24-72 hours. Depending on the geographic layout of the room, meters were placed as close to the head of the patient’s bed as possible and were generally not placed farther than 2 meters away from the patient’s head of bed; all rooms contained a window.

Sound Measurements

Sound meters measured ambient noise in dB every 2 seconds and were set for A-weighted frequency measurements. We averaged individual data points to obtain hourly averages for ICU and non-ICU rooms. For hourly sound averages, we further separated the data to compare the general ward telemetry floors (both non-ICU), the latter of which has more patient monitoring and a lower nurse-to-patient ratio compared with the general ward floor.

Data from ICU versus non-ICU rooms were analyzed for the number of sound peaks throughout the 24-hour day and for sound peak over the nighttime, defined as the number of times sound levels exceeded 65 dB, 70 dB, or 80 dB, which were averaged over 24 hours and over the nighttime (10 PM to 6 AM). We also calculated the number of average SLCs ≥17.5 dB observed over 24 hours and over the nighttime.

Light Measurements

Light meters measured luminescence in lux at a frequency of 120 seconds. We averaged individual data points to obtain hourly averages for ICU and non-ICU rooms. In addition to hourly averages, light-level data were analyzed for maximum levels throughout the day and night.

Statistical Analysis

Hourly sound-level averages between the 3 floors were evaluated using a 1-way analysis of variance (ANOVA); sound averages from the general ward and telemetry floor were also compared at each hour using a Student t test. Light-level data, sound-level peak data, as well as SLC data were also evaluated using a Student t test.

Sound Measurements

Examples of the raw data distribution for individual sound recordings in an ICU and non-ICU room are shown in Figure 1A and 1B. Sound-level analysis with specific average values and significance levels between ICU and non-ICU rooms (with non-ICU rooms further divided between telemetry and general ward floors for purposes of hourly averages) are shown in Table 1. The average hourly values in all 3 locations were always above the 30-35 dB level (nighttime and daytime, respectively) recommended by the WHO (Figure 1C). A 1-way ANOVA analysis revealed significant differences between the 3 floors at all time points except for 10 AM. An analysis of the means at each time point between the telemetry floor and the general ward floor showed that the telemetry floor had significantly higher sound averages compared with the general ward floor at 10 PM, 11 PM, and 12 AM. Sound levels dropped during the nighttime on both non-ICU wards but remained fairly constant throughout the day and night in the ICU.

Light Measurements

Examples of light levels over a 24-hour period in an ICU and non-ICU room are shown in Figure 2A and 2B, respectively. Maximum average light levels (reported here as average value ± standard deviation to demonstrate variability within the data) in the ICU were 169.7 ± 127.1 lux and occurred at 1 PM, while maximum average light levels in the non-ICU rooms were 213.5 ± 341.6 lux and occurred at 5 PM (Figure 2C). Average light levels in the morning hours remained low and ranged from 15.9 ± 12.7 lux to 38.9 ± 43.4 lux in the ICU and from 22.3 ± 17.5 lux to 100.7 ± 92.0 lux on the non-ICU floors. The maximum measured level from any of the recordings was 2530 lux and occurred in a general ward room in the 5 PM hour. Overall, light averages remained low, but this particular room had light levels that were significantly higher than the others. A t test analysis of the hourly averages revealed only 1 time point of significant difference between the 2 floors; at 7 AM, the general ward floor had a higher lux level of 49.9 ± 27.5 versus 19.2 ± 10.7 in the ICU (P = 0.038). Otherwise, there were no differences between light levels in ICU rooms versus non-ICU rooms. Evaluation of the data revealed a substantial amount of variability in light levels throughout the daytime hours. Light levels during the nighttime remained low and were not significantly different between the 2 groups.

To our knowledge, this is the first study to directly compare the ICU and non-ICU environment for its potential impact on sleep and circadian alignment. Our study adds to the literature with several novel findings. First, average sound levels on non-ICU wards are lower than in the ICU. Second, although quieter on average, SLCs >17.5 dB occurred an equivalent number of times for both the ICU and non-ICU wards. Third, average daytime light levels in both the ICU and non-ICU environment are low. Lastly, peak light levels for both ICU and non-ICU wards occur later in the day instead of in the morning. All of the above have potential impact for optimizing the ward environment to better aid in sleep for patients.

Sound-Level Findings

Data on sound levels for non-ICU floors are limited but mostly consistent with our findings; sound averages in our study ranged from 44.6 to 55.1 dB in non-ICU rooms, while others report averages ranging from 48 dB¹⁹ to 63.5 dB,¹⁰ although the latter measurement includes rooms occupied with 4 to 6 patients, which we expect would increase the noise levels. Others report average noise levels in the ICU similar to our values, which ranged from 56.1 to 60.3 dB.^18,27 Here, we show that average and peak sound levels on non-ICU wards are consistently lower than in the ICU. However, sound levels on the general ward and telemetry floors still remain quite high and potentially disruptive to patients, with average nighttime sound levels reaching the range of light outdoor traffic. The sleep environment could play an even larger role in sleep quality for non-ICU patients, as they do not typically receive sedation (though pharmacological sleeping-aid use is quite high, despite the risks)²⁸ and thus may be more sensitive to environmental factors that impact sleep.

Average and peak sound levels contribute to the ambient noise experienced by patients but may not be the source of sleep disruptions. Using polysomnography in healthy subjects exposed to recordings of ICU noise, Stanchina et al.²¹ showed that SLCs from baseline and not peak sound levels determined whether a subject was aroused from sleep by sound. Accordingly, they also found that increasing baseline sound levels by using white noise reduced the number of arousals that subjects experienced. To our knowledge, other studies have not quantified and compared SLCs in the ICU and non-ICU environments. Our data show that patients on non-ICU floors experience at least the same number of SLCs, and thereby the same potential for arousals from sleep, when compared with ICU patients. The higher baseline level of noise in the ICU likely explains the relatively lower number of SLCs when compared with the non-ICU floors. Although decreasing overall noise to promote sleep in the hospital seems like the obvious solution, the treatment for noise pollution in the hospital may actually be more background noise, not less.

Recent studies support the clinical implications of our findings. First, decreasing overall noise levels is difficult to accomplish.²⁹ Second, recent studies utilized white noise in different hospital settings with some success in improving patients’ subjective sleep quality, although more studies using objective data measurements are needed to further understand the impact of white noise on sleep in hospitalized patients.^30,31 Third, efforts at reducing interruptions—which likely will decrease the number of SLCs—such as clustering nursing care or reducing intermittent alarms may be more beneficial in improving sleep than efforts at decreasing average sound levels. For example, Bartick et al. reduced the number of patient interruptions at night by eliminating routine vital signs and clustering medication administration. Although they included other interventions as well, we note that this approach likely reduced SLCs and was associated with a reduction in the use of sedative medications.³² Ultimately, our data show that a focus on reducing SLCs will be one necessary component of a multipronged solution to improving inpatient sleep.³³

Light-Level Findings

Because of its effect on circadian rhythms, the daily light-dark cycle has a powerful impact on human physiology and behavior, which includes sleep.³⁴ Little is understood about how light affects sleep and other circadian-related functions in general ward patients, as it is not commonly measured. Our findings suggest that patients admitted to the hospital are exposed to light levels and patterns that may not optimally promote wake and sleep. Encouragingly, we did not find excessive average light levels during the nighttime in either ICU or non-ICU environment of our hospital, although others have described intrusive nighttime light in the hospital setting.^35,36 Even short bursts of low or moderate light during the nighttime can cause circadian phase delay,³⁷ and efforts to maintain darkness in patient rooms at night should continue.

Our measurements show that average daytime light levels did not exceed 250 lux, which corresponds to low, office-level lighting, while the brightest average light levels occurred in the afternoon for both environments. These levels are consistent with other reports^26,35,36 as is the light-level variability noted throughout the day (which is not unexpected given room positioning, patient preference, curtains, etc). The level and amount of daytime light needed to maintain circadian rhythms in humans is still unknown.³⁸ Brighter light is generally more effective at influencing the circadian pacemaker in a dose-dependent manner.³⁹ Although entrainment (synchronization of the body’s biological rhythm with environmental cues such as ambient light) of the human circadian rhythm has been shown with low light levels (eg, <100 lux), these studies included healthy volunteers in a carefully controlled, constant, routine environment.²³ How these data apply to acutely ill subjects in the hospital environment is not clear. We note that low to moderate levels of light (50-1000 lux) are less effective for entrainment of the circadian rhythm in older people (age >65 years, the majority of our admissions) compared with younger people. Thus, older, hospitalized patients may require greater light levels for regulation of the sleep-wake cycle.⁴⁰ These data are important when designing interventions to improve light for and maintain circadian rhythms in hospitalized patients. For example, Simons et al. found that dynamic light-application therapy, which achieved a maximum average lux level of <800 lux, did not reduce rates of delirium in critically ill patients (mean age ~65). One interpretation of these results, though there are many others, is that the light levels achieved were not high enough to influence circadian timing in hospitalized, mostly elderly patients. The physiological impact of light on the circadian rhythm in hospitalized patients still remains to be measured.

Our study does have a few limitations. We did not assess sound quality, which is another determinant of arousal potential.²⁰ Also, a shorter measurement interval might be useful in determining sharper sound increases. It may also be important to consider A- versus C-weighted measurements of sound levels, as A-weighted measurements usually reflect higher-frequency sound while C-weighted measurements usually reflect low-frequency noise¹⁸; we obtained only A-weighted measurements in our study. However, A-weighted measurements are generally considered more reflective of what the human ear considers noise and are used more standardly than C-weighted measurements.

Regarding light measurements, we recorded from rooms facing different cardinal directions and during different times of the year, which likely contributed to some of the variability in the daytime light levels on both floors. Additionally, light levels were not measured directly at the patient’s eye level. However, given that overhead fluorescent lighting was the primary source of lighting, it is doubtful that we substantially underestimated optic-nerve light levels. In the future, it may also be important to measure the different wavelengths of lights, as blue light may have a greater impact on sleep than other wavelengths.⁴¹ Although our findings align with others’, we note that this was a single-center study, which could limit the generalizability of our findings given inter-hospital variations in patient volume, interior layout and structure, and geographic location.

Overall, our study suggests that the light and sound environment for sleep in the inpatient setting, including both the ICU and non-ICU wards, has multiple areas for improvement. Our data also suggest specific directions for future clinical efforts at improvement. For example, efforts to decrease average sound levels may worsen sleep fragmentation. Similarly, more light during the day may be more helpful than further attempts to limit light during the night.

Disclosure

This research was funded in part by a NIH/NCATS flagship Clinical and Translational Science Award Grant (5KL2TR001112). None of the authors report any conflict of interest, financial or otherwise, in the preparation of this article.

The hospital environment fails to promote adequate sleep for acutely or critically ill patients. Intensive care units (ICUs) have received the most scrutiny, because critically ill patients suffer from severely fragmented sleep as well as a lack of deeper, more restorative sleep.^1-4 ICU survivors frequently cite sleep deprivation, contributed to by ambient noise, as a major stressor while receiving care.^5,6 Importantly, efforts to modify the ICU environment to promote sleep have been associated with reductions in delirium.^7,8 However, sleep deprivation and delirium in the hospital are not limited to ICU patients.

Sleep in the non-ICU setting is also notoriously poor, with 50%-80% of patients reporting sleep as “unsound” or otherwise subjectively poor.^9-11 Additionally, patients frequently ask for and/or receive pharmacological sleeping aids¹² despite little evidence of efficacy¹³ and increasing evidence of harm.¹⁴ Here too, efforts to improve sleep seems to attenuate risk of delirium,¹⁵ which remains a substantial problem on general wards, with incidence reported as high as 20%-30%. The reasons for poor sleep in the hospital are multifactorial, but data suggest that the inpatient environment, including noise and light levels, which are measurable and modifiable entities, contribute significantly to the problem.¹⁶

The World Health Organization (WHO) recommends that nighttime baseline noise levels do not exceed 30 decibels (dB) and that nighttime noise peaks (ie, loud noises) do not exceed 40 dB¹⁷; most studies suggest that ICU and general ward rooms are above this range on average.^10,18 Others have also demonstrated an association between loud noises and patients’ subjective perception of poor sleep.^10,19 However, when considering clinically important noise, peak and average noise levels may not be the key factor in causing arousals from sleep. Buxton and colleagues²⁰ found that noise quality affects arousal probability; for example, electronic alarms and conversational noise are more likely to cause awakenings compared with the opening or closing of doors and ice machines. Importantly, peak and average noise levels may also matter less for sleep than do sound level changes (SLCs), which are defined as the difference between background/baseline noise and peak noise. Using healthy subjects exposed to simulated ICU noise, Stanchina et al.²¹ found that SLCs >17.5 dB were more likely to cause polysomnographic arousals from sleep regardless of peak noise level. This sound pressure change of approximately 20 dB would be perceived as 4 times louder, or, as an example, would be the difference between normal conversation between 2 people (~40 dB) that is then interrupted by the start of a vacuum cleaner (~60 dB). To our knowledge, no other studies have closely examined SLCs in different hospital environments.

Ambient light also likely affects sleep quality in the hospital. The circadian rhythm system, which controls the human sleep–wake cycle as well as multiple other physiologic functions, depends on ambient light as the primary external factor for regulating the internal clock.^22,23 Insufficient and inappropriately timed light exposure can desynchronize the biological clock, thereby negatively affecting sleep quality.^24,25 Conversely, patients exposed to early-morning bright light may sleep better while in the hospital.¹⁶ In addition to sleep patterns, ambient light affects other aspects of patient care; for example, lower light levels in the hospital have recently been associated with higher levels of fatigue and mood disturbance.²⁶A growing body of data has investigated the ambient environment in the ICU, but fewer studies have focused on sound and light analysis in other inpatient areas such as the general ward and telemetry floors. We examined sound and light levels in the ICU and non-ICU environment, hypothesizing that average sound levels would be higher in the ICU than on non-ICU floors but that the number of SLCs >17.5 dB would be similar. Additionally, we expected that average light levels would be higher in the ICU than on non-ICU floors.

This was an observational study of the sound and light environment in the inpatient setting. Per our Institutional Review Board, no consent was required. Battery-operated sound-level (SDL600, Extech Instruments, Nashua, NH) and light-level (SDL400, Extech Instruments, Nashua, NH) meters were placed in 24 patient rooms in our tertiary-care adult hospital in La Jolla, CA. Recordings were obtained in randomly selected, single-patient occupied rooms that were from 3 different hospital units and included 8 general ward rooms, 8 telemetry floor rooms, and 8 ICU rooms. We recorded for approximately 24-72 hours. Depending on the geographic layout of the room, meters were placed as close to the head of the patient’s bed as possible and were generally not placed farther than 2 meters away from the patient’s head of bed; all rooms contained a window.

Sound Measurements

Sound meters measured ambient noise in dB every 2 seconds and were set for A-weighted frequency measurements. We averaged individual data points to obtain hourly averages for ICU and non-ICU rooms. For hourly sound averages, we further separated the data to compare the general ward telemetry floors (both non-ICU), the latter of which has more patient monitoring and a lower nurse-to-patient ratio compared with the general ward floor.

Data from ICU versus non-ICU rooms were analyzed for the number of sound peaks throughout the 24-hour day and for sound peak over the nighttime, defined as the number of times sound levels exceeded 65 dB, 70 dB, or 80 dB, which were averaged over 24 hours and over the nighttime (10 PM to 6 AM). We also calculated the number of average SLCs ≥17.5 dB observed over 24 hours and over the nighttime.

Light Measurements

Light meters measured luminescence in lux at a frequency of 120 seconds. We averaged individual data points to obtain hourly averages for ICU and non-ICU rooms. In addition to hourly averages, light-level data were analyzed for maximum levels throughout the day and night.

Statistical Analysis

Hourly sound-level averages between the 3 floors were evaluated using a 1-way analysis of variance (ANOVA); sound averages from the general ward and telemetry floor were also compared at each hour using a Student t test. Light-level data, sound-level peak data, as well as SLC data were also evaluated using a Student t test.

Sound Measurements

Examples of the raw data distribution for individual sound recordings in an ICU and non-ICU room are shown in Figure 1A and 1B. Sound-level analysis with specific average values and significance levels between ICU and non-ICU rooms (with non-ICU rooms further divided between telemetry and general ward floors for purposes of hourly averages) are shown in Table 1. The average hourly values in all 3 locations were always above the 30-35 dB level (nighttime and daytime, respectively) recommended by the WHO (Figure 1C). A 1-way ANOVA analysis revealed significant differences between the 3 floors at all time points except for 10 AM. An analysis of the means at each time point between the telemetry floor and the general ward floor showed that the telemetry floor had significantly higher sound averages compared with the general ward floor at 10 PM, 11 PM, and 12 AM. Sound levels dropped during the nighttime on both non-ICU wards but remained fairly constant throughout the day and night in the ICU.

Light Measurements

Examples of light levels over a 24-hour period in an ICU and non-ICU room are shown in Figure 2A and 2B, respectively. Maximum average light levels (reported here as average value ± standard deviation to demonstrate variability within the data) in the ICU were 169.7 ± 127.1 lux and occurred at 1 PM, while maximum average light levels in the non-ICU rooms were 213.5 ± 341.6 lux and occurred at 5 PM (Figure 2C). Average light levels in the morning hours remained low and ranged from 15.9 ± 12.7 lux to 38.9 ± 43.4 lux in the ICU and from 22.3 ± 17.5 lux to 100.7 ± 92.0 lux on the non-ICU floors. The maximum measured level from any of the recordings was 2530 lux and occurred in a general ward room in the 5 PM hour. Overall, light averages remained low, but this particular room had light levels that were significantly higher than the others. A t test analysis of the hourly averages revealed only 1 time point of significant difference between the 2 floors; at 7 AM, the general ward floor had a higher lux level of 49.9 ± 27.5 versus 19.2 ± 10.7 in the ICU (P = 0.038). Otherwise, there were no differences between light levels in ICU rooms versus non-ICU rooms. Evaluation of the data revealed a substantial amount of variability in light levels throughout the daytime hours. Light levels during the nighttime remained low and were not significantly different between the 2 groups.

To our knowledge, this is the first study to directly compare the ICU and non-ICU environment for its potential impact on sleep and circadian alignment. Our study adds to the literature with several novel findings. First, average sound levels on non-ICU wards are lower than in the ICU. Second, although quieter on average, SLCs >17.5 dB occurred an equivalent number of times for both the ICU and non-ICU wards. Third, average daytime light levels in both the ICU and non-ICU environment are low. Lastly, peak light levels for both ICU and non-ICU wards occur later in the day instead of in the morning. All of the above have potential impact for optimizing the ward environment to better aid in sleep for patients.

Sound-Level Findings

Data on sound levels for non-ICU floors are limited but mostly consistent with our findings; sound averages in our study ranged from 44.6 to 55.1 dB in non-ICU rooms, while others report averages ranging from 48 dB¹⁹ to 63.5 dB,¹⁰ although the latter measurement includes rooms occupied with 4 to 6 patients, which we expect would increase the noise levels. Others report average noise levels in the ICU similar to our values, which ranged from 56.1 to 60.3 dB.^18,27 Here, we show that average and peak sound levels on non-ICU wards are consistently lower than in the ICU. However, sound levels on the general ward and telemetry floors still remain quite high and potentially disruptive to patients, with average nighttime sound levels reaching the range of light outdoor traffic. The sleep environment could play an even larger role in sleep quality for non-ICU patients, as they do not typically receive sedation (though pharmacological sleeping-aid use is quite high, despite the risks)²⁸ and thus may be more sensitive to environmental factors that impact sleep.

Average and peak sound levels contribute to the ambient noise experienced by patients but may not be the source of sleep disruptions. Using polysomnography in healthy subjects exposed to recordings of ICU noise, Stanchina et al.²¹ showed that SLCs from baseline and not peak sound levels determined whether a subject was aroused from sleep by sound. Accordingly, they also found that increasing baseline sound levels by using white noise reduced the number of arousals that subjects experienced. To our knowledge, other studies have not quantified and compared SLCs in the ICU and non-ICU environments. Our data show that patients on non-ICU floors experience at least the same number of SLCs, and thereby the same potential for arousals from sleep, when compared with ICU patients. The higher baseline level of noise in the ICU likely explains the relatively lower number of SLCs when compared with the non-ICU floors. Although decreasing overall noise to promote sleep in the hospital seems like the obvious solution, the treatment for noise pollution in the hospital may actually be more background noise, not less.

Recent studies support the clinical implications of our findings. First, decreasing overall noise levels is difficult to accomplish.²⁹ Second, recent studies utilized white noise in different hospital settings with some success in improving patients’ subjective sleep quality, although more studies using objective data measurements are needed to further understand the impact of white noise on sleep in hospitalized patients.^30,31 Third, efforts at reducing interruptions—which likely will decrease the number of SLCs—such as clustering nursing care or reducing intermittent alarms may be more beneficial in improving sleep than efforts at decreasing average sound levels. For example, Bartick et al. reduced the number of patient interruptions at night by eliminating routine vital signs and clustering medication administration. Although they included other interventions as well, we note that this approach likely reduced SLCs and was associated with a reduction in the use of sedative medications.³² Ultimately, our data show that a focus on reducing SLCs will be one necessary component of a multipronged solution to improving inpatient sleep.³³

Light-Level Findings

Because of its effect on circadian rhythms, the daily light-dark cycle has a powerful impact on human physiology and behavior, which includes sleep.³⁴ Little is understood about how light affects sleep and other circadian-related functions in general ward patients, as it is not commonly measured. Our findings suggest that patients admitted to the hospital are exposed to light levels and patterns that may not optimally promote wake and sleep. Encouragingly, we did not find excessive average light levels during the nighttime in either ICU or non-ICU environment of our hospital, although others have described intrusive nighttime light in the hospital setting.^35,36 Even short bursts of low or moderate light during the nighttime can cause circadian phase delay,³⁷ and efforts to maintain darkness in patient rooms at night should continue.

Our measurements show that average daytime light levels did not exceed 250 lux, which corresponds to low, office-level lighting, while the brightest average light levels occurred in the afternoon for both environments. These levels are consistent with other reports^26,35,36 as is the light-level variability noted throughout the day (which is not unexpected given room positioning, patient preference, curtains, etc). The level and amount of daytime light needed to maintain circadian rhythms in humans is still unknown.³⁸ Brighter light is generally more effective at influencing the circadian pacemaker in a dose-dependent manner.³⁹ Although entrainment (synchronization of the body’s biological rhythm with environmental cues such as ambient light) of the human circadian rhythm has been shown with low light levels (eg, <100 lux), these studies included healthy volunteers in a carefully controlled, constant, routine environment.²³ How these data apply to acutely ill subjects in the hospital environment is not clear. We note that low to moderate levels of light (50-1000 lux) are less effective for entrainment of the circadian rhythm in older people (age >65 years, the majority of our admissions) compared with younger people. Thus, older, hospitalized patients may require greater light levels for regulation of the sleep-wake cycle.⁴⁰ These data are important when designing interventions to improve light for and maintain circadian rhythms in hospitalized patients. For example, Simons et al. found that dynamic light-application therapy, which achieved a maximum average lux level of <800 lux, did not reduce rates of delirium in critically ill patients (mean age ~65). One interpretation of these results, though there are many others, is that the light levels achieved were not high enough to influence circadian timing in hospitalized, mostly elderly patients. The physiological impact of light on the circadian rhythm in hospitalized patients still remains to be measured.

Our study does have a few limitations. We did not assess sound quality, which is another determinant of arousal potential.²⁰ Also, a shorter measurement interval might be useful in determining sharper sound increases. It may also be important to consider A- versus C-weighted measurements of sound levels, as A-weighted measurements usually reflect higher-frequency sound while C-weighted measurements usually reflect low-frequency noise¹⁸; we obtained only A-weighted measurements in our study. However, A-weighted measurements are generally considered more reflective of what the human ear considers noise and are used more standardly than C-weighted measurements.

Regarding light measurements, we recorded from rooms facing different cardinal directions and during different times of the year, which likely contributed to some of the variability in the daytime light levels on both floors. Additionally, light levels were not measured directly at the patient’s eye level. However, given that overhead fluorescent lighting was the primary source of lighting, it is doubtful that we substantially underestimated optic-nerve light levels. In the future, it may also be important to measure the different wavelengths of lights, as blue light may have a greater impact on sleep than other wavelengths.⁴¹ Although our findings align with others’, we note that this was a single-center study, which could limit the generalizability of our findings given inter-hospital variations in patient volume, interior layout and structure, and geographic location.

Overall, our study suggests that the light and sound environment for sleep in the inpatient setting, including both the ICU and non-ICU wards, has multiple areas for improvement. Our data also suggest specific directions for future clinical efforts at improvement. For example, efforts to decrease average sound levels may worsen sleep fragmentation. Similarly, more light during the day may be more helpful than further attempts to limit light during the night.

Disclosure

This research was funded in part by a NIH/NCATS flagship Clinical and Translational Science Award Grant (5KL2TR001112). None of the authors report any conflict of interest, financial or otherwise, in the preparation of this article.

A treatment for cancer is finding a new purpose in treating another life-threatening condition. The FDA expanded approval of Ibrutinib for treatment of adults with chronic graft versus host disease (cGVHD) after ≥ 1 treatments have failed. Ibrutinib was previously approved for certain indications in treating chronic lymphocytic leukemia, Waldenström macroglobulinemia, and marginal zone lymphoma.

An estimated 30% to 70% of patients who receive hematopoietic stem cell transplantation for blood or bone marrow cancer develop cGVHD.

Ibrutinib , a kinase inhibitor, was tested in a single-arm trial of 42 patients with cGVHD. Most had mouth ulcers and skin rashes; > 50% had ≥ 2 organs affected. Their symptoms had persisted despite standard treatment with corticosteroids. In the study, cGVHD symptoms improved in 67%. For nearly half (48%), the improvements lasted for 5 months or longer.

Common adverse effects include fatigue, bruising, diarrhea, and thrombocytopenia. Serious adverse effects include severe bleeding, infections, and cytopenia.

A treatment for cancer is finding a new purpose in treating another life-threatening condition. The FDA expanded approval of Ibrutinib for treatment of adults with chronic graft versus host disease (cGVHD) after ≥ 1 treatments have failed. Ibrutinib was previously approved for certain indications in treating chronic lymphocytic leukemia, Waldenström macroglobulinemia, and marginal zone lymphoma.

An estimated 30% to 70% of patients who receive hematopoietic stem cell transplantation for blood or bone marrow cancer develop cGVHD.

Ibrutinib , a kinase inhibitor, was tested in a single-arm trial of 42 patients with cGVHD. Most had mouth ulcers and skin rashes; > 50% had ≥ 2 organs affected. Their symptoms had persisted despite standard treatment with corticosteroids. In the study, cGVHD symptoms improved in 67%. For nearly half (48%), the improvements lasted for 5 months or longer.

Common adverse effects include fatigue, bruising, diarrhea, and thrombocytopenia. Serious adverse effects include severe bleeding, infections, and cytopenia.

A treatment for cancer is finding a new purpose in treating another life-threatening condition. The FDA expanded approval of Ibrutinib for treatment of adults with chronic graft versus host disease (cGVHD) after ≥ 1 treatments have failed. Ibrutinib was previously approved for certain indications in treating chronic lymphocytic leukemia, Waldenström macroglobulinemia, and marginal zone lymphoma.

An estimated 30% to 70% of patients who receive hematopoietic stem cell transplantation for blood or bone marrow cancer develop cGVHD.

Ibrutinib , a kinase inhibitor, was tested in a single-arm trial of 42 patients with cGVHD. Most had mouth ulcers and skin rashes; > 50% had ≥ 2 organs affected. Their symptoms had persisted despite standard treatment with corticosteroids. In the study, cGVHD symptoms improved in 67%. For nearly half (48%), the improvements lasted for 5 months or longer.

Common adverse effects include fatigue, bruising, diarrhea, and thrombocytopenia. Serious adverse effects include severe bleeding, infections, and cytopenia.

Photo by Rhoda Baer

A new study suggests cancer patients may be open to using marijuana, but healthcare providers may be falling short in educating patients on marijuana use.

This single-center study included more than 900 cancer patients in a US state with legalized medicinal and recreational marijuana.

More than 90% of the patients surveyed said they were interested in learning more about marijuana use in the context of cancer, and nearly three-quarters of the patients wanted their cancer care providers to supply information on the topic.

However, less than 15% of patients received such information from providers. Instead, patients learned about marijuana use from sources such as the Internet or other patients.

“Cancer patients desire but are not receiving information from their cancer doctors about marijuana use during their treatment, so many of them are seeking information from alternate, non-scientific sources,” said Steven Pergam, MD, of the Fred Hutchinson Cancer Research Center in Seattle, Washington.

Dr Pergam and his colleagues reported this finding in the journal Cancer.

Eight US states and the District of Columbia have legalized recreational marijuana, and more than half of states have passed laws allowing for medical marijuana in some form. Marijuana is purported to alleviate symptoms related to cancer treatment, but patterns of use among cancer patients are not well known.

To investigate, Dr Pergam and his colleagues surveyed 926 patients at the Seattle Cancer Center Alliance. The patients’ median age was 58, 52% were male, and 59% had at least a college degree. Thirty-four percent of patients had hematologic malignancies.

Results

Sixty-six percent of patients said they had used marijuana in the past, 24% used in the last year, and 21% used in the last month.

A random analysis of patient urine samples showed that 14% of patients had evidence of recent marijuana use, similar to the 18% of users who reported at least weekly marijuana use.

When compared to patients who never used marijuana and those who previously used marijuana but quit, patients currently using marijuana said they were more likely to do so because the drug had been legalized. Women were more likely than men to use because of legalization.

Current marijuana users were younger, had less education, and were less likely to have undergone hematopoietic stem cell transplant. There was no difference in marijuana use according to a patient’s cancer type.

Most patients said they used marijuana to relieve physical symptoms (75%) and neuropsychiatric symptoms (63%), though some also used it recreationally (35%).

In addition, 26% of current marijuana users said they believed the drug was helping to treat their cancer. And 5% of these users said this was their only reason for marijuana use.

Most patients (92%) said they wanted to learn more about marijuana and cancer. However, the level of interest varied with age, with younger patients expressing the most interest.

Seventy-four percent of patients said they would prefer to get information on marijuana use from their cancer team, but less than 15% received such information from their cancer physician or nurse.

Patients said they received information on marijuana and cancer from friends and family, newspaper and magazine articles, websites and blogs, or another cancer patient.

More than a third of patients said they had not received any information on marijuana and cancer.

“We hope that this study helps to open up the door for more studies aimed at evaluating the risks and benefits of marijuana in this population,” Dr Pergam said. “This is important because if we do not educate our patients about marijuana, they will continue to get their information elsewhere.”

Photo by Rhoda Baer

A new study suggests cancer patients may be open to using marijuana, but healthcare providers may be falling short in educating patients on marijuana use.

This single-center study included more than 900 cancer patients in a US state with legalized medicinal and recreational marijuana.

More than 90% of the patients surveyed said they were interested in learning more about marijuana use in the context of cancer, and nearly three-quarters of the patients wanted their cancer care providers to supply information on the topic.

However, less than 15% of patients received such information from providers. Instead, patients learned about marijuana use from sources such as the Internet or other patients.

“Cancer patients desire but are not receiving information from their cancer doctors about marijuana use during their treatment, so many of them are seeking information from alternate, non-scientific sources,” said Steven Pergam, MD, of the Fred Hutchinson Cancer Research Center in Seattle, Washington.

Dr Pergam and his colleagues reported this finding in the journal Cancer.

Eight US states and the District of Columbia have legalized recreational marijuana, and more than half of states have passed laws allowing for medical marijuana in some form. Marijuana is purported to alleviate symptoms related to cancer treatment, but patterns of use among cancer patients are not well known.

To investigate, Dr Pergam and his colleagues surveyed 926 patients at the Seattle Cancer Center Alliance. The patients’ median age was 58, 52% were male, and 59% had at least a college degree. Thirty-four percent of patients had hematologic malignancies.

Results

Sixty-six percent of patients said they had used marijuana in the past, 24% used in the last year, and 21% used in the last month.

A random analysis of patient urine samples showed that 14% of patients had evidence of recent marijuana use, similar to the 18% of users who reported at least weekly marijuana use.

When compared to patients who never used marijuana and those who previously used marijuana but quit, patients currently using marijuana said they were more likely to do so because the drug had been legalized. Women were more likely than men to use because of legalization.

Current marijuana users were younger, had less education, and were less likely to have undergone hematopoietic stem cell transplant. There was no difference in marijuana use according to a patient’s cancer type.

Most patients said they used marijuana to relieve physical symptoms (75%) and neuropsychiatric symptoms (63%), though some also used it recreationally (35%).

In addition, 26% of current marijuana users said they believed the drug was helping to treat their cancer. And 5% of these users said this was their only reason for marijuana use.

Most patients (92%) said they wanted to learn more about marijuana and cancer. However, the level of interest varied with age, with younger patients expressing the most interest.

Seventy-four percent of patients said they would prefer to get information on marijuana use from their cancer team, but less than 15% received such information from their cancer physician or nurse.

Patients said they received information on marijuana and cancer from friends and family, newspaper and magazine articles, websites and blogs, or another cancer patient.

More than a third of patients said they had not received any information on marijuana and cancer.

“We hope that this study helps to open up the door for more studies aimed at evaluating the risks and benefits of marijuana in this population,” Dr Pergam said. “This is important because if we do not educate our patients about marijuana, they will continue to get their information elsewhere.”

Photo by Rhoda Baer

A new study suggests cancer patients may be open to using marijuana, but healthcare providers may be falling short in educating patients on marijuana use.

This single-center study included more than 900 cancer patients in a US state with legalized medicinal and recreational marijuana.

More than 90% of the patients surveyed said they were interested in learning more about marijuana use in the context of cancer, and nearly three-quarters of the patients wanted their cancer care providers to supply information on the topic.

However, less than 15% of patients received such information from providers. Instead, patients learned about marijuana use from sources such as the Internet or other patients.

“Cancer patients desire but are not receiving information from their cancer doctors about marijuana use during their treatment, so many of them are seeking information from alternate, non-scientific sources,” said Steven Pergam, MD, of the Fred Hutchinson Cancer Research Center in Seattle, Washington.

Dr Pergam and his colleagues reported this finding in the journal Cancer.

Eight US states and the District of Columbia have legalized recreational marijuana, and more than half of states have passed laws allowing for medical marijuana in some form. Marijuana is purported to alleviate symptoms related to cancer treatment, but patterns of use among cancer patients are not well known.

To investigate, Dr Pergam and his colleagues surveyed 926 patients at the Seattle Cancer Center Alliance. The patients’ median age was 58, 52% were male, and 59% had at least a college degree. Thirty-four percent of patients had hematologic malignancies.

Results

Sixty-six percent of patients said they had used marijuana in the past, 24% used in the last year, and 21% used in the last month.

A random analysis of patient urine samples showed that 14% of patients had evidence of recent marijuana use, similar to the 18% of users who reported at least weekly marijuana use.

When compared to patients who never used marijuana and those who previously used marijuana but quit, patients currently using marijuana said they were more likely to do so because the drug had been legalized. Women were more likely than men to use because of legalization.

Current marijuana users were younger, had less education, and were less likely to have undergone hematopoietic stem cell transplant. There was no difference in marijuana use according to a patient’s cancer type.

Most patients said they used marijuana to relieve physical symptoms (75%) and neuropsychiatric symptoms (63%), though some also used it recreationally (35%).

In addition, 26% of current marijuana users said they believed the drug was helping to treat their cancer. And 5% of these users said this was their only reason for marijuana use.

Most patients (92%) said they wanted to learn more about marijuana and cancer. However, the level of interest varied with age, with younger patients expressing the most interest.

Seventy-four percent of patients said they would prefer to get information on marijuana use from their cancer team, but less than 15% received such information from their cancer physician or nurse.

Patients said they received information on marijuana and cancer from friends and family, newspaper and magazine articles, websites and blogs, or another cancer patient.

More than a third of patients said they had not received any information on marijuana and cancer.

“We hope that this study helps to open up the door for more studies aimed at evaluating the risks and benefits of marijuana in this population,” Dr Pergam said. “This is important because if we do not educate our patients about marijuana, they will continue to get their information elsewhere.”

Micrograph showing MF

Results of the SIMPLIFY-1 study revealed how 2 JAK inhibitors—momelotinib and ruxolitinib—compared to one another in myelofibrosis (MF) patients who were previously JAK-inhibitor-naïve.

Momelotinib proved noninferior to ruxolitinib when it came to spleen reduction but not symptom response.

On the other hand, momelotinib was more effective than ruxolitinib in reducing transfusion dependence.

The overall incidence of adverse events (AEs) was similar between the treatment arms.

However, patients receiving momelotinib were more likely to experience AEs leading to treatment discontinuation.

Ruben A. Mesa, MD, of Mayo Clinic Cancer Center in Phoenix, Arizona, and his colleagues reported these results in the Journal of Clinical Oncology. The study was sponsored by Gilead Sciences.

SIMPLIFY-1 was a phase 3, double-blind, active-controlled study. It enrolled 432 patients with symptomatic intermediate-1-risk MF, intermediate-2-risk MF, or high-risk MF.

These JAK-inhibitor-naïve patients were randomized to receive 24 weeks of treatment with momelotinib (n=215, 200 mg once daily) or ruxolitinib (n=217, 20 mg twice a day or per label). After that, all patients could receive open-label momelotinib.

The researchers said baseline characteristics were similar between the treatment arms. In the overall cohort, most patients were white (82.6%), male (56.5%), 65 or older (57.2%), and had primary MF (56.5%).

In all, 376 patients completed 24 weeks of treatment—175 in the momelotinib arm and 201 in the ruxolitinib arm. And 368 patients proceeded to the open-label phase of the study—171 from the momelotinib arm and 197 from the ruxolitinib arm (who switched to momelotinib).

Efficacy

The primary efficacy endpoint was spleen response rate at 24 weeks, which was defined as the proportion of patients achieving at least a 35% reduction in spleen volume.

This endpoint was achieved by a similar proportion of patients in both treatment arms—26.5% in the momelotinib arm and 29% in the ruxolitinib arm. This met the criteria for noninferiority (P=0.011).

On the other hand, noninferiority was not met for total symptom score, which was the proportion of patients achieving at least a 50% reduction in MF symptoms. This endpoint was achieved by 28.4% in the momelotinib arm and 42.2% in the ruxolitinib arm (P=0.98 for noninferiority).

A greater proportion of patients were transfusion-independent at week 24 in the momelotinib arm than the ruxolitinib arm—66.5% and 49.3%, respectively (nominal P<0.001).

The median rate of red blood cell transfusion was 0 units per month in the momelotinib arm and 0.4 units per month in the ruxolitinib arm (nominal P<0.001).

Safety

Most patients had at least 1 AE—92.1% in the momelotinib arm and 95.4% in the ruxolitinib arm. Grade 3 or higher AEs occurred in 35.5% and 43.5%, respectively.

Serious AEs occurred in 22.9% and 18.1%, respectively. AEs leading to treatment discontinuation occurred in 13.1% and 5.6%, respectively.

Treatment-emergent AEs occurring in at least 10% of patients in either treatment arm (momelotinib and ruxolitinib, respectively) were thrombocytopenia (18.7% and 29.2%), diarrhea (17.8% and 19.9%), headache (17.3% and 19.9%), dizziness (15.9% and 11.6%), nausea (15.9% and 3.7%), fatigue (14.5% and 12.0%), anemia (13.6% and 38%), abdominal pain (10.3% and 11.1%), and peripheral neuropathy (10.3% and 4.6%).

The most common grade 3/4 AEs in the momelotinib arm were thrombocytopenia (7.0%), anemia (5.6%), diarrhea (2.8%), hypertension (2.8%), and neutropenia (2.8%).

The most common grade 3/4 AEs in the ruxolitinib arm were anemia (23.1%), neutropenia (4.6%), thrombocytopenia (4.6%), and hypertension (4.2%).

There were 7 deaths in the momelotinib arm. The causes of death were listed as enteritis, mesenteric vein thrombosis, death, sudden death, sepsis, renal failure, and aortic dissection.

There were 7 deaths in the ruxolitinib arm as well. The causes of death were melena, sepsis, pneumonia, head injury, acute myeloid leukemia, recurrent mantle cell lymphoma, and coma.

Transformation to acute myeloid leukemia occurred in 1 patient in the momelotinib arm (grade 4) and 2 patients in the ruxolitinib arm (grade 3 and grade 5).

Micrograph showing MF

Results of the SIMPLIFY-1 study revealed how 2 JAK inhibitors—momelotinib and ruxolitinib—compared to one another in myelofibrosis (MF) patients who were previously JAK-inhibitor-naïve.

Momelotinib proved noninferior to ruxolitinib when it came to spleen reduction but not symptom response.

On the other hand, momelotinib was more effective than ruxolitinib in reducing transfusion dependence.

The overall incidence of adverse events (AEs) was similar between the treatment arms.

However, patients receiving momelotinib were more likely to experience AEs leading to treatment discontinuation.

Ruben A. Mesa, MD, of Mayo Clinic Cancer Center in Phoenix, Arizona, and his colleagues reported these results in the Journal of Clinical Oncology. The study was sponsored by Gilead Sciences.

SIMPLIFY-1 was a phase 3, double-blind, active-controlled study. It enrolled 432 patients with symptomatic intermediate-1-risk MF, intermediate-2-risk MF, or high-risk MF.

These JAK-inhibitor-naïve patients were randomized to receive 24 weeks of treatment with momelotinib (n=215, 200 mg once daily) or ruxolitinib (n=217, 20 mg twice a day or per label). After that, all patients could receive open-label momelotinib.

The researchers said baseline characteristics were similar between the treatment arms. In the overall cohort, most patients were white (82.6%), male (56.5%), 65 or older (57.2%), and had primary MF (56.5%).

In all, 376 patients completed 24 weeks of treatment—175 in the momelotinib arm and 201 in the ruxolitinib arm. And 368 patients proceeded to the open-label phase of the study—171 from the momelotinib arm and 197 from the ruxolitinib arm (who switched to momelotinib).

Efficacy

The primary efficacy endpoint was spleen response rate at 24 weeks, which was defined as the proportion of patients achieving at least a 35% reduction in spleen volume.

This endpoint was achieved by a similar proportion of patients in both treatment arms—26.5% in the momelotinib arm and 29% in the ruxolitinib arm. This met the criteria for noninferiority (P=0.011).

On the other hand, noninferiority was not met for total symptom score, which was the proportion of patients achieving at least a 50% reduction in MF symptoms. This endpoint was achieved by 28.4% in the momelotinib arm and 42.2% in the ruxolitinib arm (P=0.98 for noninferiority).

A greater proportion of patients were transfusion-independent at week 24 in the momelotinib arm than the ruxolitinib arm—66.5% and 49.3%, respectively (nominal P<0.001).

The median rate of red blood cell transfusion was 0 units per month in the momelotinib arm and 0.4 units per month in the ruxolitinib arm (nominal P<0.001).

Safety

Most patients had at least 1 AE—92.1% in the momelotinib arm and 95.4% in the ruxolitinib arm. Grade 3 or higher AEs occurred in 35.5% and 43.5%, respectively.

Serious AEs occurred in 22.9% and 18.1%, respectively. AEs leading to treatment discontinuation occurred in 13.1% and 5.6%, respectively.

Treatment-emergent AEs occurring in at least 10% of patients in either treatment arm (momelotinib and ruxolitinib, respectively) were thrombocytopenia (18.7% and 29.2%), diarrhea (17.8% and 19.9%), headache (17.3% and 19.9%), dizziness (15.9% and 11.6%), nausea (15.9% and 3.7%), fatigue (14.5% and 12.0%), anemia (13.6% and 38%), abdominal pain (10.3% and 11.1%), and peripheral neuropathy (10.3% and 4.6%).

The most common grade 3/4 AEs in the momelotinib arm were thrombocytopenia (7.0%), anemia (5.6%), diarrhea (2.8%), hypertension (2.8%), and neutropenia (2.8%).

The most common grade 3/4 AEs in the ruxolitinib arm were anemia (23.1%), neutropenia (4.6%), thrombocytopenia (4.6%), and hypertension (4.2%).

There were 7 deaths in the momelotinib arm. The causes of death were listed as enteritis, mesenteric vein thrombosis, death, sudden death, sepsis, renal failure, and aortic dissection.

There were 7 deaths in the ruxolitinib arm as well. The causes of death were melena, sepsis, pneumonia, head injury, acute myeloid leukemia, recurrent mantle cell lymphoma, and coma.

Transformation to acute myeloid leukemia occurred in 1 patient in the momelotinib arm (grade 4) and 2 patients in the ruxolitinib arm (grade 3 and grade 5).

Micrograph showing MF

Results of the SIMPLIFY-1 study revealed how 2 JAK inhibitors—momelotinib and ruxolitinib—compared to one another in myelofibrosis (MF) patients who were previously JAK-inhibitor-naïve.

Momelotinib proved noninferior to ruxolitinib when it came to spleen reduction but not symptom response.

On the other hand, momelotinib was more effective than ruxolitinib in reducing transfusion dependence.

The overall incidence of adverse events (AEs) was similar between the treatment arms.

However, patients receiving momelotinib were more likely to experience AEs leading to treatment discontinuation.

Ruben A. Mesa, MD, of Mayo Clinic Cancer Center in Phoenix, Arizona, and his colleagues reported these results in the Journal of Clinical Oncology. The study was sponsored by Gilead Sciences.

SIMPLIFY-1 was a phase 3, double-blind, active-controlled study. It enrolled 432 patients with symptomatic intermediate-1-risk MF, intermediate-2-risk MF, or high-risk MF.

These JAK-inhibitor-naïve patients were randomized to receive 24 weeks of treatment with momelotinib (n=215, 200 mg once daily) or ruxolitinib (n=217, 20 mg twice a day or per label). After that, all patients could receive open-label momelotinib.

The researchers said baseline characteristics were similar between the treatment arms. In the overall cohort, most patients were white (82.6%), male (56.5%), 65 or older (57.2%), and had primary MF (56.5%).

In all, 376 patients completed 24 weeks of treatment—175 in the momelotinib arm and 201 in the ruxolitinib arm. And 368 patients proceeded to the open-label phase of the study—171 from the momelotinib arm and 197 from the ruxolitinib arm (who switched to momelotinib).

Efficacy

The primary efficacy endpoint was spleen response rate at 24 weeks, which was defined as the proportion of patients achieving at least a 35% reduction in spleen volume.

This endpoint was achieved by a similar proportion of patients in both treatment arms—26.5% in the momelotinib arm and 29% in the ruxolitinib arm. This met the criteria for noninferiority (P=0.011).

On the other hand, noninferiority was not met for total symptom score, which was the proportion of patients achieving at least a 50% reduction in MF symptoms. This endpoint was achieved by 28.4% in the momelotinib arm and 42.2% in the ruxolitinib arm (P=0.98 for noninferiority).

A greater proportion of patients were transfusion-independent at week 24 in the momelotinib arm than the ruxolitinib arm—66.5% and 49.3%, respectively (nominal P<0.001).

The median rate of red blood cell transfusion was 0 units per month in the momelotinib arm and 0.4 units per month in the ruxolitinib arm (nominal P<0.001).

Safety

Most patients had at least 1 AE—92.1% in the momelotinib arm and 95.4% in the ruxolitinib arm. Grade 3 or higher AEs occurred in 35.5% and 43.5%, respectively.

Serious AEs occurred in 22.9% and 18.1%, respectively. AEs leading to treatment discontinuation occurred in 13.1% and 5.6%, respectively.

Treatment-emergent AEs occurring in at least 10% of patients in either treatment arm (momelotinib and ruxolitinib, respectively) were thrombocytopenia (18.7% and 29.2%), diarrhea (17.8% and 19.9%), headache (17.3% and 19.9%), dizziness (15.9% and 11.6%), nausea (15.9% and 3.7%), fatigue (14.5% and 12.0%), anemia (13.6% and 38%), abdominal pain (10.3% and 11.1%), and peripheral neuropathy (10.3% and 4.6%).

The most common grade 3/4 AEs in the momelotinib arm were thrombocytopenia (7.0%), anemia (5.6%), diarrhea (2.8%), hypertension (2.8%), and neutropenia (2.8%).

The most common grade 3/4 AEs in the ruxolitinib arm were anemia (23.1%), neutropenia (4.6%), thrombocytopenia (4.6%), and hypertension (4.2%).

There were 7 deaths in the momelotinib arm. The causes of death were listed as enteritis, mesenteric vein thrombosis, death, sudden death, sepsis, renal failure, and aortic dissection.

There were 7 deaths in the ruxolitinib arm as well. The causes of death were melena, sepsis, pneumonia, head injury, acute myeloid leukemia, recurrent mantle cell lymphoma, and coma.

Transformation to acute myeloid leukemia occurred in 1 patient in the momelotinib arm (grade 4) and 2 patients in the ruxolitinib arm (grade 3 and grade 5).

of Medical Research

Carbohydrates on the surface of malaria parasites play a critical role in the parasites’ ability to infect mosquito and human hosts, according to research published in Nature Communications.

Researchers found that Plasmodium falciparum “tags” its proteins with carbohydrates in order to stabilize and transport them.

And this process is crucial to completing the parasite’s life cycle.

“Malaria parasites have a complex life cycle that involves constant shape-shifting to evade detection and infect humans and, subsequently, mosquitoes,” said study author Justin Boddey, PhD, of The Walter and Eliza Hall Institute of Medical Research in Parkville, Victoria, Australia.

“We found that the parasite’s ability to ‘tag’ key proteins with carbohydrates is important for 2 stages of the malaria life cycle. It is critical for the earliest stages of human infection, when the parasite migrates through the body and invades in the liver, and later, when it is transmitted back to the mosquito from an infected human, enabling the parasite to be spread between people.”

“Interfering with the parasite’s ability to attach these carbohydrates to its proteins hinders liver infection and transmission to the mosquito and weakens the parasite to the point that it cannot survive in the host.”

Dr Boddey and his colleagues said this research suggests steps that may improve the efficacy of the malaria vaccine RTS,S/AS01 (Mosquirix).

“The protein used in the RTS,S vaccine mimics one of the proteins we’ve been studying on the surface of the malaria parasite that is readily recognized by the immune system,” said study author Ethan D. Goddard-Borger, PhD, of The Walter and Eliza Hall Institute of Medical Research.

“It was hoped that the vaccine would generate a good antibody response that protected against the parasite. However, it has, unfortunately, not been as effective at evoking protective immunity as hoped.”

“With this study, we’ve shown that the parasite protein is tagged with carbohydrates, making it slightly different to the vaccine, so the antibodies produced may not be optimal for recognizing target parasites.”

Dr Goddard-Borger said there were many documented cases where attaching carbohydrates to a protein improved its efficacy as a vaccine.

“It may be that a version of RTS,S with added carbohydrates will perform better than the current vaccine,” he said. “Now that we know how important these carbohydrates are to the parasite, we can be confident that the malaria parasite cannot ‘escape’ vaccination pressure by doing away with its carbohydrates.”

of Medical Research

Carbohydrates on the surface of malaria parasites play a critical role in the parasites’ ability to infect mosquito and human hosts, according to research published in Nature Communications.

Researchers found that Plasmodium falciparum “tags” its proteins with carbohydrates in order to stabilize and transport them.

And this process is crucial to completing the parasite’s life cycle.

“Malaria parasites have a complex life cycle that involves constant shape-shifting to evade detection and infect humans and, subsequently, mosquitoes,” said study author Justin Boddey, PhD, of The Walter and Eliza Hall Institute of Medical Research in Parkville, Victoria, Australia.

“We found that the parasite’s ability to ‘tag’ key proteins with carbohydrates is important for 2 stages of the malaria life cycle. It is critical for the earliest stages of human infection, when the parasite migrates through the body and invades in the liver, and later, when it is transmitted back to the mosquito from an infected human, enabling the parasite to be spread between people.”

“Interfering with the parasite’s ability to attach these carbohydrates to its proteins hinders liver infection and transmission to the mosquito and weakens the parasite to the point that it cannot survive in the host.”

Dr Boddey and his colleagues said this research suggests steps that may improve the efficacy of the malaria vaccine RTS,S/AS01 (Mosquirix).

“The protein used in the RTS,S vaccine mimics one of the proteins we’ve been studying on the surface of the malaria parasite that is readily recognized by the immune system,” said study author Ethan D. Goddard-Borger, PhD, of The Walter and Eliza Hall Institute of Medical Research.

“It was hoped that the vaccine would generate a good antibody response that protected against the parasite. However, it has, unfortunately, not been as effective at evoking protective immunity as hoped.”

“With this study, we’ve shown that the parasite protein is tagged with carbohydrates, making it slightly different to the vaccine, so the antibodies produced may not be optimal for recognizing target parasites.”

Dr Goddard-Borger said there were many documented cases where attaching carbohydrates to a protein improved its efficacy as a vaccine.

“It may be that a version of RTS,S with added carbohydrates will perform better than the current vaccine,” he said. “Now that we know how important these carbohydrates are to the parasite, we can be confident that the malaria parasite cannot ‘escape’ vaccination pressure by doing away with its carbohydrates.”

of Medical Research

Carbohydrates on the surface of malaria parasites play a critical role in the parasites’ ability to infect mosquito and human hosts, according to research published in Nature Communications.

Researchers found that Plasmodium falciparum “tags” its proteins with carbohydrates in order to stabilize and transport them.

And this process is crucial to completing the parasite’s life cycle.

“Malaria parasites have a complex life cycle that involves constant shape-shifting to evade detection and infect humans and, subsequently, mosquitoes,” said study author Justin Boddey, PhD, of The Walter and Eliza Hall Institute of Medical Research in Parkville, Victoria, Australia.

“We found that the parasite’s ability to ‘tag’ key proteins with carbohydrates is important for 2 stages of the malaria life cycle. It is critical for the earliest stages of human infection, when the parasite migrates through the body and invades in the liver, and later, when it is transmitted back to the mosquito from an infected human, enabling the parasite to be spread between people.”

“Interfering with the parasite’s ability to attach these carbohydrates to its proteins hinders liver infection and transmission to the mosquito and weakens the parasite to the point that it cannot survive in the host.”

Dr Boddey and his colleagues said this research suggests steps that may improve the efficacy of the malaria vaccine RTS,S/AS01 (Mosquirix).

“The protein used in the RTS,S vaccine mimics one of the proteins we’ve been studying on the surface of the malaria parasite that is readily recognized by the immune system,” said study author Ethan D. Goddard-Borger, PhD, of The Walter and Eliza Hall Institute of Medical Research.

“It was hoped that the vaccine would generate a good antibody response that protected against the parasite. However, it has, unfortunately, not been as effective at evoking protective immunity as hoped.”

“With this study, we’ve shown that the parasite protein is tagged with carbohydrates, making it slightly different to the vaccine, so the antibodies produced may not be optimal for recognizing target parasites.”

Dr Goddard-Borger said there were many documented cases where attaching carbohydrates to a protein improved its efficacy as a vaccine.

“It may be that a version of RTS,S with added carbohydrates will perform better than the current vaccine,” he said. “Now that we know how important these carbohydrates are to the parasite, we can be confident that the malaria parasite cannot ‘escape’ vaccination pressure by doing away with its carbohydrates.”

The U.S. Supreme Court will not hear oral arguments over President Trump’s controversial travel ban in light of new travel restrictions issued by the Trump administration that may render the case moot.

President Trump released new regulations Sept. 24 that prohibit travel to the United States from seven countries, most of which were covered in his original travel ban. Those include citizens of Iran, Libya, Syria, Yemen, Somalia, Chad, and North Korea. In addition, citizens of Iraq and certain citizens of Venezuela will face restrictions or heightened scrutiny when traveling to the United States.

Gage Skidmore/Wikimedia Commons/CC BY-SA 2.0

[email protected]

On Twitter @legal_med

The U.S. Supreme Court will not hear oral arguments over President Trump’s controversial travel ban in light of new travel restrictions issued by the Trump administration that may render the case moot.

President Trump released new regulations Sept. 24 that prohibit travel to the United States from seven countries, most of which were covered in his original travel ban. Those include citizens of Iran, Libya, Syria, Yemen, Somalia, Chad, and North Korea. In addition, citizens of Iraq and certain citizens of Venezuela will face restrictions or heightened scrutiny when traveling to the United States.

Gage Skidmore/Wikimedia Commons/CC BY-SA 2.0

[email protected]

On Twitter @legal_med

The U.S. Supreme Court will not hear oral arguments over President Trump’s controversial travel ban in light of new travel restrictions issued by the Trump administration that may render the case moot.

President Trump released new regulations Sept. 24 that prohibit travel to the United States from seven countries, most of which were covered in his original travel ban. Those include citizens of Iran, Libya, Syria, Yemen, Somalia, Chad, and North Korea. In addition, citizens of Iraq and certain citizens of Venezuela will face restrictions or heightened scrutiny when traveling to the United States.

Gage Skidmore/Wikimedia Commons/CC BY-SA 2.0

[email protected]

On Twitter @legal_med

The Food and Drug Administration has granted accelerated approval to nivolumab (Optivo) for the treatment of patients with hepatocellular carcinoma (HCC) who have been treated previously with sorafenib.

Approval was based on tumor response rate and durability of response from the phase 1/2 Checkmate 040 trial. Of 154 patients with HCC in the trial who received nivolumab following progression on sorafenib, 3 experienced complete response, and 19 experienced partial response. Median time to response was 2.8 months, and 91% of patients who responded to treatment had a response length longer than 6 months, with 55% of patients having a response length longer than 1 year.

Courtesy Wikimedia Commons/FitzColinGerald/Creative Commons License

[email protected]

The Food and Drug Administration has granted accelerated approval to nivolumab (Optivo) for the treatment of patients with hepatocellular carcinoma (HCC) who have been treated previously with sorafenib.

Approval was based on tumor response rate and durability of response from the phase 1/2 Checkmate 040 trial. Of 154 patients with HCC in the trial who received nivolumab following progression on sorafenib, 3 experienced complete response, and 19 experienced partial response. Median time to response was 2.8 months, and 91% of patients who responded to treatment had a response length longer than 6 months, with 55% of patients having a response length longer than 1 year.

Courtesy Wikimedia Commons/FitzColinGerald/Creative Commons License

[email protected]

The Food and Drug Administration has granted accelerated approval to nivolumab (Optivo) for the treatment of patients with hepatocellular carcinoma (HCC) who have been treated previously with sorafenib.

Approval was based on tumor response rate and durability of response from the phase 1/2 Checkmate 040 trial. Of 154 patients with HCC in the trial who received nivolumab following progression on sorafenib, 3 experienced complete response, and 19 experienced partial response. Median time to response was 2.8 months, and 91% of patients who responded to treatment had a response length longer than 6 months, with 55% of patients having a response length longer than 1 year.

Courtesy Wikimedia Commons/FitzColinGerald/Creative Commons License

[email protected]

INTRODUCTION

In the normal person, the process of coagulation is finely controlled at many levels to ensure the appropriate amount of hemostasis at the appropriate location. Broadly defined, disseminated intravascular coagulation (DIC) is the name given to any process that disrupts this fine tuning, leading to unregulated coagulation. Defined this way, DIC may be found in a variety of patients with a variety of disease states, and can present with a spectrum of findings ranging from asymptomatic abnormal laboratory results to florid bleeding or thrombosis. It is important to remember that DIC is always a consequence of an underlying pathological process and not a disease in and of itself. This article first reviews concepts common to all forms of DIC, and then reviews the more common disease states that lead to DIC.

PATHOGENESIS

At the most basic level, DIC is the clinical manifestation of inappropriate thrombin activation.^1–5 Inappropriate thrombin activation can be due to underlying conditions such as sepsis and obstetric disasters. The activation of thrombin leads to (1) conversion of fibrinogen to fibrin, (2) activation of platelets (and their consumption), (3) activation of factors V and VIII, (4) activation of protein C (and degradation of factors Va and VIIIa), (5) activation of endothelial cells, and (6) activation of fibrinolysis (Table 1). 

1. Conversion of fibrinogen to fibrin, which leads to the formation of fibrin monomers and excessive thrombus formation. These thrombi are rapidly dissolved by excessive fibrinolysis in most patients. In certain clinical situations, especially cancer, excessive thrombosis will occur. In patients with cancer, this is most often a deep venous thrombosis. Rare patients, especially those with pancreatic cancer, may have severe DIC with multiple arterial and venous thromboses. Nonbacterial thrombotic endocarditis can also be seen in these patients, leading to widespread embolic complications.

2. Activation of platelets and their consumption. Thrombin is the most potent physiologic activator of platelets, so in DIC there is increased activation of platelets. These activated platelets are consumed, resulting in thrombocytopenia. Platelet dysfunction is also present. Platelets that have been activated and have released their contents but still circulate are known as “exhausted” platelets; these cells can no longer function to support coagulation. The fibrin degradation products (FDP) in DIC can also bind to GP IIb/IIIa and inhibit further platelet aggregation.

3. Activation of factors V, VIII, XI, and XIII. Activation of these factors can promote thrombosis, but they are then rapidly cleared by antithrombin (XI) or activated protein C (V and VIII) or by binding to the fibrin clot (XIII). This can lead to depletion of all the prothrombotic clotting factors and antithrombin, which in turn can lead to both thrombosis and bleeding.

4. Activation of protein C further promotes degradation of factors Va and VIIIa, enhances fibrinolysis, and decreases protein C levels.

5. Activation of endothelial cells, especially in the skin, may lead to thrombosis, and in certain patients, especially those with meningococcemia, purpura fulminans. Endothelial damage will down-regulate thrombomodulin, preventing activation of protein C and leading to further reductions in levels of activated protein C.⁵6. Activation of fibrinolysis leads to the breakdown of fibrin monomers, formation of fibrin thrombi, and increased circulating fibrinogen. In most patients with DIC, the fibrinolytic response is brisk.⁶ This is why most patients with DIC present with bleeding and prolonged clotting times.

PATTERNS OF DIC

The clinical manifestations of DIC in a given patient depend on the balance of thrombin activation and secondary fibrinolysis plus the patient’s ability to compensate for the DIC. Patients with DIC can present in 1 of 4 patterns:^1–3

1. Asymptomatic. Patients can present with laboratory evidence of DIC but no bleeding or thrombosis. This is often seen in patients with sepsis or cancer. However, with further progression of the underlying disease, these patients can rapidly become symptomatic.

2. Bleeding. The bleeding is due to a combination of factor depletion, platelet dysfunction, thrombocytopenia, and excessive fibrinolysis.¹ These patients may present with diffuse bleeding from multiple sites (eg, intravenous sites, areas of instrumentation).

3. Thrombosis. Despite the general activation of the coagulation process, thrombosis is unusual in most patients with acute DIC. The exceptions include patients with cancer, trauma patients, and certain obstetrical patients. Most often the thrombosis is venous, but arterial thrombosis and nonbacterial thrombotic endocarditis have been reported.⁷

4. Purpura fulminans. This form of DIC is discussed in more detail later (see Specific DIC Syndromes section).

DIAGNOSIS

There is no one test that will diagnose DIC; one must match the test to the clinical situation (Table 2).⁸ 

SCREENING TESTS

The prothrombin time-INR and activated thromboplastin time (aPPT) are usually elevated in severe DIC but may be normal or shortened in chronic forms.⁹ One may also see a shortened aPTT in severe acute DIC due to large amounts of activated thrombin and factor X “bypassing” the contact pathway. An aPTT as short as 10 seconds has been seen in acute DIC. The platelet count is usually reduced but may be normal in chronic DIC. Serum fibrinogen and platelets are decreased in acute DIC but again may be in the “normal” range in chronic DIC.¹⁰ The most sensitive screening test for DIC is a fall in the platelet count, with low counts seen in 98% of patients and counts under 50,000 cells/μL in 50%.^9,11 The least specific test is fibrinogen, which tends to fall below normal only in severe acute DIC.⁹

SPECIFIC TESTS

This group of tests allows one to deduce that abnormally high concentrations of thrombin are present.

Ethanol Gel and Protamine Tests

Both of these older tests detected circulating fibrin monomers, whose appearance is an early sign of DIC. Circulating fibrin monomers are seen when thrombin acts on fibrinogen. Usually the monomer polymerizes with the fibrin clot, but when there is excess thrombin these monomers can circulate. Detection of circulating fibrin monomer means there is too much IIa and, ergo, DIC is present.

Fibrin(ogen) Degradation Products

Plasmin acts on the fibrin/fibrinogen molecule to cleave the molecule in specific places. The resulting degradation product levels will be elevated in situations of increased fibrin/fibrinogen destruction (DIC and fibrinolysis). The FDP are typically mildly elevated in renal and liver disease due to reduced clearance.

D-Dimers

When fibrin monomers bind to form a thrombus, factor XIII acts to bind their “D” domains together. This bond is resistant to plasmin and thus this degradation fragment is known as the “D-dimer.” High levels of D-dimer indicate that (1) IIa has acted on fibrinogen to form a fibrin monomer that bonded to another fibrin monomer, and (2) this thrombus was lysed by plasmin. Because D-dimers can be elevated (eg, with exercise, after surgery), an elevated D-dimer needs to be interpreted in the context of the clinical situation.¹¹ Currently, this is the most common specific test for DIC performed.

Other Tests

Several other tests are sometimes helpful in diagnosing DIC.

Thrombin time. This test is performed by adding thrombin to plasma. Thrombin times are elevated in DIC (FDPs interfere with polymerization), in the presence of low fibrinogen levels, in dysfibrinogenemia, and in the presence of heparin (very sensitive).

Reptilase time is the same as thrombin time but is performed with a snake venom that is insensitive to heparin. Reptilase time is elevated in the same conditions as the thrombin time, with the exception of the presence of heparin. Thrombin time and reptilase time are most useful in evaluation of dysfibrinogenemia.

Prothrombin fragment 1.2 (F_1.2). F_1.2 is a small peptide cleaved off when prothrombin is activated to thrombin. Thus, high levels of F_1.2 are found in DIC but can be seen in other thrombotic disorders. This test is still of limited clinical value.

DIC scoring system. A scoring system to both diagnose and quantify DIC has been proposed (Figure).^11,12 

MIMICKERS OF DIC

It is important to recognize coagulation syndromes that are not DIC, especially those that have specific other therapies. The syndromes most frequently encountered are thrombotic thrombocytopenic purpura (TTP) and catastrophic antiphospholipid antibody syndrome (CAPS). One important clue to both of these syndromes is that, unlike DIC, there is no primary disorder (cancer, sepsis) that is driving the coagulation abnormalities.

TTP should be suspected when any patient presents with any combination of thrombo­cytopenia, microangiopathic hemolytic anemia (schistocytes and signs of hemolysis) plus end-organ damage.^15–18 Patients with TTP most often present with intractable seizures, strokes, or sequelae of renal insufficiency. Many patients who present with TTP have been misdiagnosed as having sepsis, “lupus flare,” or vasculitis. The key diagnostic differentiator between TTP and DIC is the lack of activation of coagulation with TTP—fibrinogen is normal and D-dimers are minimally or not elevated. In TTP, lactate dehydrogenase is invariably elevated, often 2 to 3 times normal.¹⁹ The importance of identifying TTP is that untreated TTP is rapidly fatal. Mortality in the pre–plasma exchange era ranged from 95% to 100%. Today plasma exchange therapy is the foundation of TTP treatment and has reduced mortality to less than 20%.^16,20–23Rarely patients with antiphospholipid antibody syndrome can present with fulminant multiorgan system failure.^24–28 CAPS is caused by widespread microthrombi in multiple vascular fields. These patients will develop renal failure, encephalopathy, adult respiratory distress syndrome (often with pulmonary hemorrhage), cardiac failure, dramatic livedo reticularis, and worsening thrombocytopenia. Many of these patients have pre-existing autoimmune disorders and high-titer anticardiolipin antibodies. It appears that the best therapy for these patients is aggressive immunosuppression with steroids plus plasmapheresis, followed by rituximab or, if in the setting of lupus, intravenous cyclophosphamide monthly.^27,29 Early recognition of CAPS can lead to quick therapy and resolution of the multiorgan system failure.

GENERAL THERAPY

The best way to treat DIC is to treat the underlying cause that is driving the thrombin generation.^1,2,4,30,31 Fully addressing the underlying cause may not be possible or may take time, and in the meantime it is necessary to disrupt the cycle of thrombosis and/or hemorrhage. In the past, there was concern about using factor replacement due to fears of “feeding the fire,” or perpetuating the cycle of thrombosis. However, these concerns are not supported by evidence, and factors must be replaced if depletion occurs and bleeding ensues.³²

Transfusion therapy of the patient with DIC is guided by the 5 laboratory tests that reflect the basic parameters essential for both hemostasis and blood volume status:^33,34 hematocrit, platelet count, prothrombin time-INR, aPTT, and fibrinogen level. Decisions regarding replacement therapy are based on the results of these laboratory tests and the clinical situation of the patient (Table 3). 

SPECIFIC DIC SYNDROMES

SEPSIS/INFECTIOUS DISEASE

Any overwhelming infection can lead to DIC.⁴⁵ Classically, it was believed that gram-negative bacteria can lead tissue factor exposure via production of endotoxin, but recent studies indicate that DIC can be seen with any overwhelming infection.^46,47 There are several potential avenues by which infections can lead to DIC. As mentioned, gram-negative bacteria produce endotoxin that can directly lead to tissue factor exposure, resulting in excess thrombin generation. In addition, any infection can lead to expression of inflammatory cytokines that induce tissue-factor expression by endothelium and monocytes. Some viruses and Rickettsia species can directly infect the vascular endothelium, converting it from an antithrombotic to a prothrombotic phenotype.⁴⁸ When fighting infections, neutrophils can extrude their contents, including DNA, to help trap organisms. These neutrophil extracellular traps (NETS) may play an important role in promoting coagulopathy.^49,50 The hypotension produced by sepsis leads to tissue hypoxia, which results in more DIC. The coagulopathy in sepsis can range from subtle abnormalities of testing to purpura fulminans. Thrombocytopenia is worsened by cytokine-induced hemophagocytic syndrome.

As with all forms of DIC, empiric therapy targeting the most likely source of infection and maintaining hemodynamic stability is the key to therapy. As discussed below, heparin and other forms of coagulation replacement appear to be of no benefit in therapy.

PURPURA FULMINANS

DIC in association with necrosis of the skin is seen in primary and secondary purpura fulminans.^51,52 Primary purpura fulminans is most often seen after a viral infection.⁵³ In these patients, the purpura fulminans starts with a painful red area on an extremity that rapidly progresses to a black ischemic area. In many patients, acquired deficiency of protein S is found.^51,54,55 Secondary purpura fulminans is most often associated with meningococcemia infections but can be seen in any patient with overwhelming infection.^56–58 Post-splenectomy sepsis syndrome patients and those with functional hyposplenism due to chronic liver diseases are also at risk.⁵⁹ Patients present with signs of sepsis, and the skin lesions often involve the extremities and may lead to amputations. As opposed to primary purpura fulminans, those with the secondary form will have symmetrical ischemia distally (toes and fingers) that ascends as the process progresses. Rarely, adrenal infarction (Waterhouse-Friderichsen syndrome) occurs, which leads to severe hypotension.⁴⁵

Recently, Warkenten has reported on limb gangrene in critically ill patients complicating sepsis or cardiogenic shock.^60,61 These patients have DIC that is complicated by shock liver. Deep venous thrombosis with ischemic gangrene then develops, which can result in tissue loss and even amputation. The pathogenesis is hypothesized to be hepatic dysfunction leading to sudden drops in protein C and S plasma levels, which then leads to thrombophilia with widespread microvascular thrombosis. Therapy for purpura fulminans is controversial. Primary purpura fulminans, especially in those with postvaricella autoimmune protein S deficiency, has responded to plasma infusion titrated to keep the protein S level above 25%.⁵¹ Intravenous immunoglobulin has also been reported to help decrease the anti-protein S antibodies. Heparin has been reported to control the DIC and extent of necrosis.⁶² The starting dose in these patients is 5 to 8 units/kg/hr.²

Sick patients with secondary purpura fulminans have been treated with plasma drips, plasmapheresis, and continuous plasma ultrafiltration.^62–66 Heparin therapy alone has not been shown to improve survival.⁶⁶ Much attention has been given to replacement of natural anticoagulants such as protein C and antithrombin as therapy for purpura fulminans, but unfortunately randomized trials using antithrombin have shown mostly negative results.^{51,55,67–69} Trials using protein C concentrates have shown more promise in controlling the coagulopathy of purpura fulminans, but this is not widely available.^63,70–72 Unfortunately, many patients will need debridement and amputation for their necrotic limbs, with one review showing approximately 66% of patients needing amputations.⁵²

TRAUMA

Currently, the most common cause of acute DIC is trauma. The coagulation defects that occur in trauma patients are complex in origin and still controversial (including if even calling it DIC is appropriate!).^73–76 The most common etiologies are

• Generation of excess activated protein C leading to increased consumption of factor V and VIII and increased fibrinolysis;
• Tissue damage leading to generation of excess thrombin generation;
• Dilution of hemostatic factors by blood or fluid resuscitation; and
• Activation of endothelial cells leading to generation of a prothrombotic surface and shedding of glycocalyx with antithrombotic properties.

Trauma patients are prone to hypothermia, and this can be the major complicating factor in their bleeding.^77,78 Patients may be out “in the field” for a prolonged period of time and be hypothermic on arrival.⁷⁹ Packed red cells are stored at 4°C, and the infusion of 1 unit can lower the body temperature by 0.16°C.⁸⁰ Hypothermia has profound effects on the coagulation system that are associated with clinical bleeding.^77,81,82 Even modest hypothermia can greatly augment bleeding and needs to be treated or prevented.

The initial management of the bleeding trauma patient is administration of red cells and plasma (FFP) in a 1:1 ratio. This has been shown by clinical studies to lessen the risk of exsanguination in the first 24 hours and to be associated with improved clinical outcomes.^83,84 The basic set of coagulation tests should also be obtained to guide product replacement, especially as the bleeding is brought under control. Hypothermia can be prevented by several measures, including transfusing the blood through blood warmers. Devices are available that can warm 1 unit of blood per minute. An increasingly used technique is to perform “damage control” surgery. Patients are initially stabilized with control of damaged vessels and packing of oozing sites.⁸⁵ Then the patient is taken to the intensive care unit to be warmed and have coagulation defects corrected.

For trauma patients at risk of serious bleeding, the use of tranexamic acid reduced all- cause mortality (relative risk 0.91), with death due to bleeding also being reduced (relative risk 0.85).⁸⁶ There was no increase in thrombosis, but benefit was restricted to patients treated within 3 hours of the trauma. The dose of tranexamic acid was a 1-g bolus followed by a 1-g continuous infusion over 8 hours.

PREGNANCY-RELATED DIC SYNDROMES

Acute DIC of Pregnancy

Pregnancy can be associated with the rapid onset of severe DIC in 2 situations, abruption and amniotic fluid embolism.^87,88 The separation of the placenta from the uterine wall creates a space for blood to occupy. Given the richness of the placenta in tissue factor, this leads to activation of coagulation both locally and systemically. Release of blood when this space reaches the vaginal opening can lead to rapid hemorrhage, further augmenting the coagulation abnormalities. Placental insufficiency can lead to fetal demise, which can also worsen the DIC. Management depends on the size of the abruption and the clinical status of both mother and fetus.⁸⁷ For severe bleeding and DIC, blood product support is crucial to allow safe delivery. In pregnancy, the fibrinogen goal needs to be higher—200 mg/dL.⁸⁹ For smaller abruption, close observation with early delivery is indicated.

Amniotic fluid embolism is sudden, with the vascular collapse of the woman soon after delivery. Due to the presence of procoagulant rich fluid in the circulatory system, there is often overwhelming DIC. Therapy is directed at both supporting blood volume and correcting hemostatic defects.

HELLP

The acronym HELLP (hemolysis, elevated liver tests, low platelets) describes a variant of preeclampsia.⁹⁰ Classically, HELLP syndrome occurs after 28 weeks of gestation in a patient with preeclampsia, but can occur as early as 22 weeks in patients with antiphospholipid antibody syndrome.^91–93 The preeclampsia need not be severe. The first sign of HELLP is a decrease in the platelet count followed by abnormal liver function tests. Signs of hemolysis are present with abundant schistocytes on the smear and a high lactate dehydrogenase level. HELLP can progress to liver failure, and deaths are also reported due to hepatic rupture. Unlike TTP, fetal involvement is present in the HELLP syndrome, with fetal thrombocytopenia reported in 30% of cases. In severe cases, elevated D-dimers consistent with DIC are also found. Delivery of the child will most often result in cessation of the HELLP syndrome, but refractory cases will require dexamethasone and plasma exchange.⁹⁴ Patients should be closely observed for 1 to 2 days after delivery as the hematologic picture can transiently worsen before improving.⁹⁵

Acute Fatty Liver of Pregnancy

Fatty liver of pregnancy also occurs late in pregnancy and is only associated with preeclampsia in 50% of cases.^96,97 Patients first present with nonspecific symptoms of nausea and vomiting but can progress to fulminant liver failure. Patients develop thrombocytopenia early in the course, but in the later stages can develop DIC and very low fibrinogen levels. Mortality rates without therapy can be as high as 90%. Low blood glucose and high ammonia levels can help distinguish fatty liver from other pregnancy complications.⁹⁸ Treatment consists of prompt delivery of the child and aggressive blood product support.

Retained Dead Fetus Syndrome

Becoming rarer in modern practices, the presence of a dead fetus for many weeks (usually ≥ 5) can result in a chronic DIC state with fibrinogen depletion and coagulopathy. In some women, this is worsened at delivery. In a stable patient, a short trial of heparin prior to planning delivery can control the DIC to allow the coagulopathy to stabilize.

DRUG-INDUCED HEMOLYTIC-DIC SYNDROMES

A severe variant of the drug-induced immune complex hemolysis associated with DIC has been recognized. Rare patients who receive certain second- and third-generation cephalosporins (especially cefotetan and ceftriaxone) have developed this syndrome.^99–104 The clinical syndrome starts 7 to 10 days after the drug is administered. Often the patient has only received the antibiotic for surgical prophylaxis. The patient will develop severe Coombs’-positive hemolysis with hypotension and DIC. The patients are often believed to have sepsis and in the management of the supposed sepsis often are re-exposed to the cephalosporin, resulting in worsening of the clinical picture. The outcome is often fatal due to massive hemolysis and thrombosis.^{101,105–107}

Quinine is associated with a unique syndrome of drug-induced DIC.^108–111 Approximately 24 to 96 hours after quinine exposure, the patient becomes acutely ill with nausea and vomiting. The patient then develops a microangiopathic hemolytic anemia, DIC, and renal failure. Some patients, besides having antiplatelet antibodies, also have antibodies binding to red cells and neutrophils, which may lead to the more severe syndrome. Despite therapy, patients with quinine-induced TTP have a high incidence of chronic renal failure.

Treatment of the drug-induced hemolytic-DIC syndrome is anecdotal. Patients have responded to aggressive therapy, including plasma exchange, dialysis, and prednisone. Early recognition of the hemolytic anemia and the suspicion it is drug related is important for early diagnosis so that the incriminated drug can be discontinued.

CANCER

Cancers, primarily adenocarcinomas, can result in DIC. The classic Trousseau syndrome referred to the association of migratory superficial thrombophlebitis with cancer¹¹² but now refers to cancer associated with thrombotic DIC.^113,114 Highly vascular tumor cells are known to express tissue factor.^114,115 In addition, some tumor cells can express a direct activator of factor X (“cancer procoagulant”). Unlike many DIC states, cancer presents with thrombosis instead of bleeding. This may be due to the inflammatory state which accompanies cancer, or it may be a unique part of the chronic nature of cancer DIC biology that allows time for the body to compensate for loss of coagulation factors. In some patients, thrombosis is the first sign of an underlying cancer, sometimes predating the cancer diagnosis by months.¹¹⁵ Rarely, the DIC can result in nonthrombotic endocarditis with micro-emboli leading to widespread small-vessel thrombosis.¹¹³

Since effective antineoplastic therapy is lacking for many tumors associated with Trousseau syndrome, DIC therapy is aimed at suppressing thrombosis. An exception is prostate cancer, where hormonal therapy can markedly decrease the DIC.¹¹⁶ Due to the tumor directly activating coagulation factors, inhibition of active enzymes via heparin has been shown to reduce rates of recurrence compared with warfarin.^114,115 Clinical trials have demonstrated that heparin therapy is associated with a lower thrombosis recurrence rate than warfarin.^117,118 In some patients, the thrombotic process is so vigorous that new thrombosis can be seen within hours of stopping heparin.¹¹²

ACUTE PROMYELOCYTIC LEUKEMIA

There are multiple hemostatic defects in patients with acute promyelocytic leukemia (APL).¹¹⁹ Most, if not all, patients with APL have evidence of DIC at the time of diagnosis. Patients with APL have a higher risk of death during induction therapy as compared with patients with other forms of leukemia, with death most often due to bleeding. Once in remission, APL patients have a higher cure rate than most patients with leukemia. APL is also unique among leukemias in that biologic therapy with retinoic acid or arsenic is effective in inducing remission and cure in most patients. Although effective therapy is available, early death rates due to bleeding have not changed.¹¹⁹

APL patients can present with pancytopenia due to leukemic marrow replacement or with diffuse bleeding due to DIC and thrombocytopenia. Life-threatening bleeding such as intracranial hemorrhage may occur at any time until the leukemia is put into remission. The etiology of the hemostatic defects in APL is complex and is thought to be the result of DIC, fibrinolysis, and the release of prothrombotic extracellular chromatin and other procoagulant enzymes.^119,120 The diagnosis of APL can be straightforward when the leukemic cells are promyelocytes with abundant Auer rods, although some patients have the microgranular form without obvious Auer rods. The precise diagnosis requires molecular methods, including obtaining FISH for detecting the t(15;17) in PML/RARA fusion. Upon diagnosis of APL, one should obtain a complete coagulation profile, including INR, aPTT, fibrinogen, platelet count, and D-dimers. Change in fibrinogen levels tends to be a good marker of progress in treating the coagulation defects.

Therapy of APL involves treating both the leukemia and the coagulopathy. Currently, the standard treatment for APL is trans-retinoic acid (ATRA) in combination with chemotherapy or arsenic.^121,122 This approach will induce remission in more than 90% of patients, and a sizable majority of these patients will be cured of their APL. ATRA therapy will also lead to early correction of the coagulation defects, often within the first week of therapy.¹²³ This is in stark contrast to the chemotherapy era when the coagulation defects would become worse with therapy. Given the marked beneficial effect of ATRA on the coagulopathy of APL and its low toxicity profile, it should be empirically started for any patients suspected of having APL while genetic testing is being performed. Rare reports of massive thrombosis complicating therapy with ATRA exist, but the relationship to either the APL or ATRA is unknown.

Therapy for the coagulation defects consists of aggressive transfusion therapy support and possible use of other pharmacologic agents to control DIC.^124,125 The fibrinogen level should be maintained at over 150 mg/dL and the platelet count at over 50,000 cells/µL.¹²⁶ Controversy still exists over the role of heparin in therapy of APL.¹⁰⁴ Although attractive for its ability to quench thrombin, heparin use can lead to profound bleeding and its use in treating APL has fallen out of favor.

SNAKEBITES

Snake envenomation can lead to direct activation of multiple coagulation enzymes, including factors V, X, thrombin, and protein C, and lead to cleavage of fibrinogen.^127,128 Envenomation can also activate coagulation and damage vascular endothelium. The DIC can be enhanced by widespread tissue necrosis and hypotension. The key to management of snake bites is administration of specific antivenom. The role of prophylactic factor replacement is controversial, but this therapy is indicated if there is clinical bleeding.¹²⁹ One confounder is that some snake venoms, especially rattlesnake, can induce reversible platelet aggregation, which corrects with antivenom.

LOCAL VASCULAR ABNORMALITIES

Abnormal vascular structures, such as vascular tumors, vascular malformations, and aneurysms, can lead to localized areas of thrombin generation that can “spill-over” into the general circulation, leading to DIC. The diagnosis Kasabach-Merritt phenomenon should be reserved for children with vascular tumors such as angioma or hemangioendothelioma.¹³⁰ Therapy depends on the lesion. Embolization to reduce blood flow of vascular malformations can either be definitive therapy or stabilize the patient for surgery. Aneurysms can be repaired by surgery or stenting. Rare patients with aneurysms with significant coagulopathy may require heparin to raise the fibrinogen level before surgery. Kasabach-Merritt disease can respond to steroids or therapy such as vincristine or interferon.¹³⁰ Increasing data shows that use of the mTOR inhibitor sirolimus can shrink these vascular abnormalities leading to lessening of the coagulopathy.¹³¹

CONCLUSION

At the most basic level, DIC is the excess activity of thrombin. However, the clinical presentation and therapy can differ greatly depending on the primary cause. Both diagnosis and therapy involve close coordination of laboratory data and clinical assessment.

INTRODUCTION

In the normal person, the process of coagulation is finely controlled at many levels to ensure the appropriate amount of hemostasis at the appropriate location. Broadly defined, disseminated intravascular coagulation (DIC) is the name given to any process that disrupts this fine tuning, leading to unregulated coagulation. Defined this way, DIC may be found in a variety of patients with a variety of disease states, and can present with a spectrum of findings ranging from asymptomatic abnormal laboratory results to florid bleeding or thrombosis. It is important to remember that DIC is always a consequence of an underlying pathological process and not a disease in and of itself. This article first reviews concepts common to all forms of DIC, and then reviews the more common disease states that lead to DIC.

PATHOGENESIS

At the most basic level, DIC is the clinical manifestation of inappropriate thrombin activation.^1–5 Inappropriate thrombin activation can be due to underlying conditions such as sepsis and obstetric disasters. The activation of thrombin leads to (1) conversion of fibrinogen to fibrin, (2) activation of platelets (and their consumption), (3) activation of factors V and VIII, (4) activation of protein C (and degradation of factors Va and VIIIa), (5) activation of endothelial cells, and (6) activation of fibrinolysis (Table 1). 

1. Conversion of fibrinogen to fibrin, which leads to the formation of fibrin monomers and excessive thrombus formation. These thrombi are rapidly dissolved by excessive fibrinolysis in most patients. In certain clinical situations, especially cancer, excessive thrombosis will occur. In patients with cancer, this is most often a deep venous thrombosis. Rare patients, especially those with pancreatic cancer, may have severe DIC with multiple arterial and venous thromboses. Nonbacterial thrombotic endocarditis can also be seen in these patients, leading to widespread embolic complications.

2. Activation of platelets and their consumption. Thrombin is the most potent physiologic activator of platelets, so in DIC there is increased activation of platelets. These activated platelets are consumed, resulting in thrombocytopenia. Platelet dysfunction is also present. Platelets that have been activated and have released their contents but still circulate are known as “exhausted” platelets; these cells can no longer function to support coagulation. The fibrin degradation products (FDP) in DIC can also bind to GP IIb/IIIa and inhibit further platelet aggregation.

3. Activation of factors V, VIII, XI, and XIII. Activation of these factors can promote thrombosis, but they are then rapidly cleared by antithrombin (XI) or activated protein C (V and VIII) or by binding to the fibrin clot (XIII). This can lead to depletion of all the prothrombotic clotting factors and antithrombin, which in turn can lead to both thrombosis and bleeding.

4. Activation of protein C further promotes degradation of factors Va and VIIIa, enhances fibrinolysis, and decreases protein C levels.

5. Activation of endothelial cells, especially in the skin, may lead to thrombosis, and in certain patients, especially those with meningococcemia, purpura fulminans. Endothelial damage will down-regulate thrombomodulin, preventing activation of protein C and leading to further reductions in levels of activated protein C.⁵6. Activation of fibrinolysis leads to the breakdown of fibrin monomers, formation of fibrin thrombi, and increased circulating fibrinogen. In most patients with DIC, the fibrinolytic response is brisk.⁶ This is why most patients with DIC present with bleeding and prolonged clotting times.

PATTERNS OF DIC

The clinical manifestations of DIC in a given patient depend on the balance of thrombin activation and secondary fibrinolysis plus the patient’s ability to compensate for the DIC. Patients with DIC can present in 1 of 4 patterns:^1–3

1. Asymptomatic. Patients can present with laboratory evidence of DIC but no bleeding or thrombosis. This is often seen in patients with sepsis or cancer. However, with further progression of the underlying disease, these patients can rapidly become symptomatic.

2. Bleeding. The bleeding is due to a combination of factor depletion, platelet dysfunction, thrombocytopenia, and excessive fibrinolysis.¹ These patients may present with diffuse bleeding from multiple sites (eg, intravenous sites, areas of instrumentation).

3. Thrombosis. Despite the general activation of the coagulation process, thrombosis is unusual in most patients with acute DIC. The exceptions include patients with cancer, trauma patients, and certain obstetrical patients. Most often the thrombosis is venous, but arterial thrombosis and nonbacterial thrombotic endocarditis have been reported.⁷

4. Purpura fulminans. This form of DIC is discussed in more detail later (see Specific DIC Syndromes section).

DIAGNOSIS

There is no one test that will diagnose DIC; one must match the test to the clinical situation (Table 2).⁸ 

SCREENING TESTS

The prothrombin time-INR and activated thromboplastin time (aPPT) are usually elevated in severe DIC but may be normal or shortened in chronic forms.⁹ One may also see a shortened aPTT in severe acute DIC due to large amounts of activated thrombin and factor X “bypassing” the contact pathway. An aPTT as short as 10 seconds has been seen in acute DIC. The platelet count is usually reduced but may be normal in chronic DIC. Serum fibrinogen and platelets are decreased in acute DIC but again may be in the “normal” range in chronic DIC.¹⁰ The most sensitive screening test for DIC is a fall in the platelet count, with low counts seen in 98% of patients and counts under 50,000 cells/μL in 50%.^9,11 The least specific test is fibrinogen, which tends to fall below normal only in severe acute DIC.⁹

SPECIFIC TESTS

This group of tests allows one to deduce that abnormally high concentrations of thrombin are present.

Ethanol Gel and Protamine Tests

Both of these older tests detected circulating fibrin monomers, whose appearance is an early sign of DIC. Circulating fibrin monomers are seen when thrombin acts on fibrinogen. Usually the monomer polymerizes with the fibrin clot, but when there is excess thrombin these monomers can circulate. Detection of circulating fibrin monomer means there is too much IIa and, ergo, DIC is present.

Fibrin(ogen) Degradation Products

Plasmin acts on the fibrin/fibrinogen molecule to cleave the molecule in specific places. The resulting degradation product levels will be elevated in situations of increased fibrin/fibrinogen destruction (DIC and fibrinolysis). The FDP are typically mildly elevated in renal and liver disease due to reduced clearance.

D-Dimers

When fibrin monomers bind to form a thrombus, factor XIII acts to bind their “D” domains together. This bond is resistant to plasmin and thus this degradation fragment is known as the “D-dimer.” High levels of D-dimer indicate that (1) IIa has acted on fibrinogen to form a fibrin monomer that bonded to another fibrin monomer, and (2) this thrombus was lysed by plasmin. Because D-dimers can be elevated (eg, with exercise, after surgery), an elevated D-dimer needs to be interpreted in the context of the clinical situation.¹¹ Currently, this is the most common specific test for DIC performed.

Other Tests

Several other tests are sometimes helpful in diagnosing DIC.

Thrombin time. This test is performed by adding thrombin to plasma. Thrombin times are elevated in DIC (FDPs interfere with polymerization), in the presence of low fibrinogen levels, in dysfibrinogenemia, and in the presence of heparin (very sensitive).

Reptilase time is the same as thrombin time but is performed with a snake venom that is insensitive to heparin. Reptilase time is elevated in the same conditions as the thrombin time, with the exception of the presence of heparin. Thrombin time and reptilase time are most useful in evaluation of dysfibrinogenemia.

Prothrombin fragment 1.2 (F_1.2). F_1.2 is a small peptide cleaved off when prothrombin is activated to thrombin. Thus, high levels of F_1.2 are found in DIC but can be seen in other thrombotic disorders. This test is still of limited clinical value.

DIC scoring system. A scoring system to both diagnose and quantify DIC has been proposed (Figure).^11,12 

MIMICKERS OF DIC

It is important to recognize coagulation syndromes that are not DIC, especially those that have specific other therapies. The syndromes most frequently encountered are thrombotic thrombocytopenic purpura (TTP) and catastrophic antiphospholipid antibody syndrome (CAPS). One important clue to both of these syndromes is that, unlike DIC, there is no primary disorder (cancer, sepsis) that is driving the coagulation abnormalities.

TTP should be suspected when any patient presents with any combination of thrombo­cytopenia, microangiopathic hemolytic anemia (schistocytes and signs of hemolysis) plus end-organ damage.^15–18 Patients with TTP most often present with intractable seizures, strokes, or sequelae of renal insufficiency. Many patients who present with TTP have been misdiagnosed as having sepsis, “lupus flare,” or vasculitis. The key diagnostic differentiator between TTP and DIC is the lack of activation of coagulation with TTP—fibrinogen is normal and D-dimers are minimally or not elevated. In TTP, lactate dehydrogenase is invariably elevated, often 2 to 3 times normal.¹⁹ The importance of identifying TTP is that untreated TTP is rapidly fatal. Mortality in the pre–plasma exchange era ranged from 95% to 100%. Today plasma exchange therapy is the foundation of TTP treatment and has reduced mortality to less than 20%.^16,20–23Rarely patients with antiphospholipid antibody syndrome can present with fulminant multiorgan system failure.^24–28 CAPS is caused by widespread microthrombi in multiple vascular fields. These patients will develop renal failure, encephalopathy, adult respiratory distress syndrome (often with pulmonary hemorrhage), cardiac failure, dramatic livedo reticularis, and worsening thrombocytopenia. Many of these patients have pre-existing autoimmune disorders and high-titer anticardiolipin antibodies. It appears that the best therapy for these patients is aggressive immunosuppression with steroids plus plasmapheresis, followed by rituximab or, if in the setting of lupus, intravenous cyclophosphamide monthly.^27,29 Early recognition of CAPS can lead to quick therapy and resolution of the multiorgan system failure.

GENERAL THERAPY

The best way to treat DIC is to treat the underlying cause that is driving the thrombin generation.^1,2,4,30,31 Fully addressing the underlying cause may not be possible or may take time, and in the meantime it is necessary to disrupt the cycle of thrombosis and/or hemorrhage. In the past, there was concern about using factor replacement due to fears of “feeding the fire,” or perpetuating the cycle of thrombosis. However, these concerns are not supported by evidence, and factors must be replaced if depletion occurs and bleeding ensues.³²

Transfusion therapy of the patient with DIC is guided by the 5 laboratory tests that reflect the basic parameters essential for both hemostasis and blood volume status:^33,34 hematocrit, platelet count, prothrombin time-INR, aPTT, and fibrinogen level. Decisions regarding replacement therapy are based on the results of these laboratory tests and the clinical situation of the patient (Table 3). 

SPECIFIC DIC SYNDROMES

SEPSIS/INFECTIOUS DISEASE

Any overwhelming infection can lead to DIC.⁴⁵ Classically, it was believed that gram-negative bacteria can lead tissue factor exposure via production of endotoxin, but recent studies indicate that DIC can be seen with any overwhelming infection.^46,47 There are several potential avenues by which infections can lead to DIC. As mentioned, gram-negative bacteria produce endotoxin that can directly lead to tissue factor exposure, resulting in excess thrombin generation. In addition, any infection can lead to expression of inflammatory cytokines that induce tissue-factor expression by endothelium and monocytes. Some viruses and Rickettsia species can directly infect the vascular endothelium, converting it from an antithrombotic to a prothrombotic phenotype.⁴⁸ When fighting infections, neutrophils can extrude their contents, including DNA, to help trap organisms. These neutrophil extracellular traps (NETS) may play an important role in promoting coagulopathy.^49,50 The hypotension produced by sepsis leads to tissue hypoxia, which results in more DIC. The coagulopathy in sepsis can range from subtle abnormalities of testing to purpura fulminans. Thrombocytopenia is worsened by cytokine-induced hemophagocytic syndrome.

As with all forms of DIC, empiric therapy targeting the most likely source of infection and maintaining hemodynamic stability is the key to therapy. As discussed below, heparin and other forms of coagulation replacement appear to be of no benefit in therapy.

PURPURA FULMINANS

DIC in association with necrosis of the skin is seen in primary and secondary purpura fulminans.^51,52 Primary purpura fulminans is most often seen after a viral infection.⁵³ In these patients, the purpura fulminans starts with a painful red area on an extremity that rapidly progresses to a black ischemic area. In many patients, acquired deficiency of protein S is found.^51,54,55 Secondary purpura fulminans is most often associated with meningococcemia infections but can be seen in any patient with overwhelming infection.^56–58 Post-splenectomy sepsis syndrome patients and those with functional hyposplenism due to chronic liver diseases are also at risk.⁵⁹ Patients present with signs of sepsis, and the skin lesions often involve the extremities and may lead to amputations. As opposed to primary purpura fulminans, those with the secondary form will have symmetrical ischemia distally (toes and fingers) that ascends as the process progresses. Rarely, adrenal infarction (Waterhouse-Friderichsen syndrome) occurs, which leads to severe hypotension.⁴⁵

Recently, Warkenten has reported on limb gangrene in critically ill patients complicating sepsis or cardiogenic shock.^60,61 These patients have DIC that is complicated by shock liver. Deep venous thrombosis with ischemic gangrene then develops, which can result in tissue loss and even amputation. The pathogenesis is hypothesized to be hepatic dysfunction leading to sudden drops in protein C and S plasma levels, which then leads to thrombophilia with widespread microvascular thrombosis. Therapy for purpura fulminans is controversial. Primary purpura fulminans, especially in those with postvaricella autoimmune protein S deficiency, has responded to plasma infusion titrated to keep the protein S level above 25%.⁵¹ Intravenous immunoglobulin has also been reported to help decrease the anti-protein S antibodies. Heparin has been reported to control the DIC and extent of necrosis.⁶² The starting dose in these patients is 5 to 8 units/kg/hr.²

Sick patients with secondary purpura fulminans have been treated with plasma drips, plasmapheresis, and continuous plasma ultrafiltration.^62–66 Heparin therapy alone has not been shown to improve survival.⁶⁶ Much attention has been given to replacement of natural anticoagulants such as protein C and antithrombin as therapy for purpura fulminans, but unfortunately randomized trials using antithrombin have shown mostly negative results.^{51,55,67–69} Trials using protein C concentrates have shown more promise in controlling the coagulopathy of purpura fulminans, but this is not widely available.^63,70–72 Unfortunately, many patients will need debridement and amputation for their necrotic limbs, with one review showing approximately 66% of patients needing amputations.⁵²

TRAUMA

Currently, the most common cause of acute DIC is trauma. The coagulation defects that occur in trauma patients are complex in origin and still controversial (including if even calling it DIC is appropriate!).^73–76 The most common etiologies are

• Generation of excess activated protein C leading to increased consumption of factor V and VIII and increased fibrinolysis;
• Tissue damage leading to generation of excess thrombin generation;
• Dilution of hemostatic factors by blood or fluid resuscitation; and
• Activation of endothelial cells leading to generation of a prothrombotic surface and shedding of glycocalyx with antithrombotic properties.

Trauma patients are prone to hypothermia, and this can be the major complicating factor in their bleeding.^77,78 Patients may be out “in the field” for a prolonged period of time and be hypothermic on arrival.⁷⁹ Packed red cells are stored at 4°C, and the infusion of 1 unit can lower the body temperature by 0.16°C.⁸⁰ Hypothermia has profound effects on the coagulation system that are associated with clinical bleeding.^77,81,82 Even modest hypothermia can greatly augment bleeding and needs to be treated or prevented.

The initial management of the bleeding trauma patient is administration of red cells and plasma (FFP) in a 1:1 ratio. This has been shown by clinical studies to lessen the risk of exsanguination in the first 24 hours and to be associated with improved clinical outcomes.^83,84 The basic set of coagulation tests should also be obtained to guide product replacement, especially as the bleeding is brought under control. Hypothermia can be prevented by several measures, including transfusing the blood through blood warmers. Devices are available that can warm 1 unit of blood per minute. An increasingly used technique is to perform “damage control” surgery. Patients are initially stabilized with control of damaged vessels and packing of oozing sites.⁸⁵ Then the patient is taken to the intensive care unit to be warmed and have coagulation defects corrected.

For trauma patients at risk of serious bleeding, the use of tranexamic acid reduced all- cause mortality (relative risk 0.91), with death due to bleeding also being reduced (relative risk 0.85).⁸⁶ There was no increase in thrombosis, but benefit was restricted to patients treated within 3 hours of the trauma. The dose of tranexamic acid was a 1-g bolus followed by a 1-g continuous infusion over 8 hours.

PREGNANCY-RELATED DIC SYNDROMES

Acute DIC of Pregnancy

Pregnancy can be associated with the rapid onset of severe DIC in 2 situations, abruption and amniotic fluid embolism.^87,88 The separation of the placenta from the uterine wall creates a space for blood to occupy. Given the richness of the placenta in tissue factor, this leads to activation of coagulation both locally and systemically. Release of blood when this space reaches the vaginal opening can lead to rapid hemorrhage, further augmenting the coagulation abnormalities. Placental insufficiency can lead to fetal demise, which can also worsen the DIC. Management depends on the size of the abruption and the clinical status of both mother and fetus.⁸⁷ For severe bleeding and DIC, blood product support is crucial to allow safe delivery. In pregnancy, the fibrinogen goal needs to be higher—200 mg/dL.⁸⁹ For smaller abruption, close observation with early delivery is indicated.

Amniotic fluid embolism is sudden, with the vascular collapse of the woman soon after delivery. Due to the presence of procoagulant rich fluid in the circulatory system, there is often overwhelming DIC. Therapy is directed at both supporting blood volume and correcting hemostatic defects.

HELLP

The acronym HELLP (hemolysis, elevated liver tests, low platelets) describes a variant of preeclampsia.⁹⁰ Classically, HELLP syndrome occurs after 28 weeks of gestation in a patient with preeclampsia, but can occur as early as 22 weeks in patients with antiphospholipid antibody syndrome.^91–93 The preeclampsia need not be severe. The first sign of HELLP is a decrease in the platelet count followed by abnormal liver function tests. Signs of hemolysis are present with abundant schistocytes on the smear and a high lactate dehydrogenase level. HELLP can progress to liver failure, and deaths are also reported due to hepatic rupture. Unlike TTP, fetal involvement is present in the HELLP syndrome, with fetal thrombocytopenia reported in 30% of cases. In severe cases, elevated D-dimers consistent with DIC are also found. Delivery of the child will most often result in cessation of the HELLP syndrome, but refractory cases will require dexamethasone and plasma exchange.⁹⁴ Patients should be closely observed for 1 to 2 days after delivery as the hematologic picture can transiently worsen before improving.⁹⁵

Acute Fatty Liver of Pregnancy

Fatty liver of pregnancy also occurs late in pregnancy and is only associated with preeclampsia in 50% of cases.^96,97 Patients first present with nonspecific symptoms of nausea and vomiting but can progress to fulminant liver failure. Patients develop thrombocytopenia early in the course, but in the later stages can develop DIC and very low fibrinogen levels. Mortality rates without therapy can be as high as 90%. Low blood glucose and high ammonia levels can help distinguish fatty liver from other pregnancy complications.⁹⁸ Treatment consists of prompt delivery of the child and aggressive blood product support.

Retained Dead Fetus Syndrome

Becoming rarer in modern practices, the presence of a dead fetus for many weeks (usually ≥ 5) can result in a chronic DIC state with fibrinogen depletion and coagulopathy. In some women, this is worsened at delivery. In a stable patient, a short trial of heparin prior to planning delivery can control the DIC to allow the coagulopathy to stabilize.

DRUG-INDUCED HEMOLYTIC-DIC SYNDROMES

A severe variant of the drug-induced immune complex hemolysis associated with DIC has been recognized. Rare patients who receive certain second- and third-generation cephalosporins (especially cefotetan and ceftriaxone) have developed this syndrome.^99–104 The clinical syndrome starts 7 to 10 days after the drug is administered. Often the patient has only received the antibiotic for surgical prophylaxis. The patient will develop severe Coombs’-positive hemolysis with hypotension and DIC. The patients are often believed to have sepsis and in the management of the supposed sepsis often are re-exposed to the cephalosporin, resulting in worsening of the clinical picture. The outcome is often fatal due to massive hemolysis and thrombosis.^{101,105–107}

Quinine is associated with a unique syndrome of drug-induced DIC.^108–111 Approximately 24 to 96 hours after quinine exposure, the patient becomes acutely ill with nausea and vomiting. The patient then develops a microangiopathic hemolytic anemia, DIC, and renal failure. Some patients, besides having antiplatelet antibodies, also have antibodies binding to red cells and neutrophils, which may lead to the more severe syndrome. Despite therapy, patients with quinine-induced TTP have a high incidence of chronic renal failure.

Treatment of the drug-induced hemolytic-DIC syndrome is anecdotal. Patients have responded to aggressive therapy, including plasma exchange, dialysis, and prednisone. Early recognition of the hemolytic anemia and the suspicion it is drug related is important for early diagnosis so that the incriminated drug can be discontinued.

CANCER

Cancers, primarily adenocarcinomas, can result in DIC. The classic Trousseau syndrome referred to the association of migratory superficial thrombophlebitis with cancer¹¹² but now refers to cancer associated with thrombotic DIC.^113,114 Highly vascular tumor cells are known to express tissue factor.^114,115 In addition, some tumor cells can express a direct activator of factor X (“cancer procoagulant”). Unlike many DIC states, cancer presents with thrombosis instead of bleeding. This may be due to the inflammatory state which accompanies cancer, or it may be a unique part of the chronic nature of cancer DIC biology that allows time for the body to compensate for loss of coagulation factors. In some patients, thrombosis is the first sign of an underlying cancer, sometimes predating the cancer diagnosis by months.¹¹⁵ Rarely, the DIC can result in nonthrombotic endocarditis with micro-emboli leading to widespread small-vessel thrombosis.¹¹³

Since effective antineoplastic therapy is lacking for many tumors associated with Trousseau syndrome, DIC therapy is aimed at suppressing thrombosis. An exception is prostate cancer, where hormonal therapy can markedly decrease the DIC.¹¹⁶ Due to the tumor directly activating coagulation factors, inhibition of active enzymes via heparin has been shown to reduce rates of recurrence compared with warfarin.^114,115 Clinical trials have demonstrated that heparin therapy is associated with a lower thrombosis recurrence rate than warfarin.^117,118 In some patients, the thrombotic process is so vigorous that new thrombosis can be seen within hours of stopping heparin.¹¹²

ACUTE PROMYELOCYTIC LEUKEMIA

There are multiple hemostatic defects in patients with acute promyelocytic leukemia (APL).¹¹⁹ Most, if not all, patients with APL have evidence of DIC at the time of diagnosis. Patients with APL have a higher risk of death during induction therapy as compared with patients with other forms of leukemia, with death most often due to bleeding. Once in remission, APL patients have a higher cure rate than most patients with leukemia. APL is also unique among leukemias in that biologic therapy with retinoic acid or arsenic is effective in inducing remission and cure in most patients. Although effective therapy is available, early death rates due to bleeding have not changed.¹¹⁹

APL patients can present with pancytopenia due to leukemic marrow replacement or with diffuse bleeding due to DIC and thrombocytopenia. Life-threatening bleeding such as intracranial hemorrhage may occur at any time until the leukemia is put into remission. The etiology of the hemostatic defects in APL is complex and is thought to be the result of DIC, fibrinolysis, and the release of prothrombotic extracellular chromatin and other procoagulant enzymes.^119,120 The diagnosis of APL can be straightforward when the leukemic cells are promyelocytes with abundant Auer rods, although some patients have the microgranular form without obvious Auer rods. The precise diagnosis requires molecular methods, including obtaining FISH for detecting the t(15;17) in PML/RARA fusion. Upon diagnosis of APL, one should obtain a complete coagulation profile, including INR, aPTT, fibrinogen, platelet count, and D-dimers. Change in fibrinogen levels tends to be a good marker of progress in treating the coagulation defects.

Therapy of APL involves treating both the leukemia and the coagulopathy. Currently, the standard treatment for APL is trans-retinoic acid (ATRA) in combination with chemotherapy or arsenic.^121,122 This approach will induce remission in more than 90% of patients, and a sizable majority of these patients will be cured of their APL. ATRA therapy will also lead to early correction of the coagulation defects, often within the first week of therapy.¹²³ This is in stark contrast to the chemotherapy era when the coagulation defects would become worse with therapy. Given the marked beneficial effect of ATRA on the coagulopathy of APL and its low toxicity profile, it should be empirically started for any patients suspected of having APL while genetic testing is being performed. Rare reports of massive thrombosis complicating therapy with ATRA exist, but the relationship to either the APL or ATRA is unknown.

Therapy for the coagulation defects consists of aggressive transfusion therapy support and possible use of other pharmacologic agents to control DIC.^124,125 The fibrinogen level should be maintained at over 150 mg/dL and the platelet count at over 50,000 cells/µL.¹²⁶ Controversy still exists over the role of heparin in therapy of APL.¹⁰⁴ Although attractive for its ability to quench thrombin, heparin use can lead to profound bleeding and its use in treating APL has fallen out of favor.

SNAKEBITES

Snake envenomation can lead to direct activation of multiple coagulation enzymes, including factors V, X, thrombin, and protein C, and lead to cleavage of fibrinogen.^127,128 Envenomation can also activate coagulation and damage vascular endothelium. The DIC can be enhanced by widespread tissue necrosis and hypotension. The key to management of snake bites is administration of specific antivenom. The role of prophylactic factor replacement is controversial, but this therapy is indicated if there is clinical bleeding.¹²⁹ One confounder is that some snake venoms, especially rattlesnake, can induce reversible platelet aggregation, which corrects with antivenom.

LOCAL VASCULAR ABNORMALITIES

Abnormal vascular structures, such as vascular tumors, vascular malformations, and aneurysms, can lead to localized areas of thrombin generation that can “spill-over” into the general circulation, leading to DIC. The diagnosis Kasabach-Merritt phenomenon should be reserved for children with vascular tumors such as angioma or hemangioendothelioma.¹³⁰ Therapy depends on the lesion. Embolization to reduce blood flow of vascular malformations can either be definitive therapy or stabilize the patient for surgery. Aneurysms can be repaired by surgery or stenting. Rare patients with aneurysms with significant coagulopathy may require heparin to raise the fibrinogen level before surgery. Kasabach-Merritt disease can respond to steroids or therapy such as vincristine or interferon.¹³⁰ Increasing data shows that use of the mTOR inhibitor sirolimus can shrink these vascular abnormalities leading to lessening of the coagulopathy.¹³¹

CONCLUSION

At the most basic level, DIC is the excess activity of thrombin. However, the clinical presentation and therapy can differ greatly depending on the primary cause. Both diagnosis and therapy involve close coordination of laboratory data and clinical assessment.

INTRODUCTION

In the normal person, the process of coagulation is finely controlled at many levels to ensure the appropriate amount of hemostasis at the appropriate location. Broadly defined, disseminated intravascular coagulation (DIC) is the name given to any process that disrupts this fine tuning, leading to unregulated coagulation. Defined this way, DIC may be found in a variety of patients with a variety of disease states, and can present with a spectrum of findings ranging from asymptomatic abnormal laboratory results to florid bleeding or thrombosis. It is important to remember that DIC is always a consequence of an underlying pathological process and not a disease in and of itself. This article first reviews concepts common to all forms of DIC, and then reviews the more common disease states that lead to DIC.

PATHOGENESIS

At the most basic level, DIC is the clinical manifestation of inappropriate thrombin activation.^1–5 Inappropriate thrombin activation can be due to underlying conditions such as sepsis and obstetric disasters. The activation of thrombin leads to (1) conversion of fibrinogen to fibrin, (2) activation of platelets (and their consumption), (3) activation of factors V and VIII, (4) activation of protein C (and degradation of factors Va and VIIIa), (5) activation of endothelial cells, and (6) activation of fibrinolysis (Table 1). 

1. Conversion of fibrinogen to fibrin, which leads to the formation of fibrin monomers and excessive thrombus formation. These thrombi are rapidly dissolved by excessive fibrinolysis in most patients. In certain clinical situations, especially cancer, excessive thrombosis will occur. In patients with cancer, this is most often a deep venous thrombosis. Rare patients, especially those with pancreatic cancer, may have severe DIC with multiple arterial and venous thromboses. Nonbacterial thrombotic endocarditis can also be seen in these patients, leading to widespread embolic complications.

2. Activation of platelets and their consumption. Thrombin is the most potent physiologic activator of platelets, so in DIC there is increased activation of platelets. These activated platelets are consumed, resulting in thrombocytopenia. Platelet dysfunction is also present. Platelets that have been activated and have released their contents but still circulate are known as “exhausted” platelets; these cells can no longer function to support coagulation. The fibrin degradation products (FDP) in DIC can also bind to GP IIb/IIIa and inhibit further platelet aggregation.

3. Activation of factors V, VIII, XI, and XIII. Activation of these factors can promote thrombosis, but they are then rapidly cleared by antithrombin (XI) or activated protein C (V and VIII) or by binding to the fibrin clot (XIII). This can lead to depletion of all the prothrombotic clotting factors and antithrombin, which in turn can lead to both thrombosis and bleeding.

4. Activation of protein C further promotes degradation of factors Va and VIIIa, enhances fibrinolysis, and decreases protein C levels.

5. Activation of endothelial cells, especially in the skin, may lead to thrombosis, and in certain patients, especially those with meningococcemia, purpura fulminans. Endothelial damage will down-regulate thrombomodulin, preventing activation of protein C and leading to further reductions in levels of activated protein C.⁵6. Activation of fibrinolysis leads to the breakdown of fibrin monomers, formation of fibrin thrombi, and increased circulating fibrinogen. In most patients with DIC, the fibrinolytic response is brisk.⁶ This is why most patients with DIC present with bleeding and prolonged clotting times.

PATTERNS OF DIC

The clinical manifestations of DIC in a given patient depend on the balance of thrombin activation and secondary fibrinolysis plus the patient’s ability to compensate for the DIC. Patients with DIC can present in 1 of 4 patterns:^1–3

1. Asymptomatic. Patients can present with laboratory evidence of DIC but no bleeding or thrombosis. This is often seen in patients with sepsis or cancer. However, with further progression of the underlying disease, these patients can rapidly become symptomatic.

2. Bleeding. The bleeding is due to a combination of factor depletion, platelet dysfunction, thrombocytopenia, and excessive fibrinolysis.¹ These patients may present with diffuse bleeding from multiple sites (eg, intravenous sites, areas of instrumentation).

3. Thrombosis. Despite the general activation of the coagulation process, thrombosis is unusual in most patients with acute DIC. The exceptions include patients with cancer, trauma patients, and certain obstetrical patients. Most often the thrombosis is venous, but arterial thrombosis and nonbacterial thrombotic endocarditis have been reported.⁷

4. Purpura fulminans. This form of DIC is discussed in more detail later (see Specific DIC Syndromes section).

DIAGNOSIS

There is no one test that will diagnose DIC; one must match the test to the clinical situation (Table 2).⁸ 

SCREENING TESTS

The prothrombin time-INR and activated thromboplastin time (aPPT) are usually elevated in severe DIC but may be normal or shortened in chronic forms.⁹ One may also see a shortened aPTT in severe acute DIC due to large amounts of activated thrombin and factor X “bypassing” the contact pathway. An aPTT as short as 10 seconds has been seen in acute DIC. The platelet count is usually reduced but may be normal in chronic DIC. Serum fibrinogen and platelets are decreased in acute DIC but again may be in the “normal” range in chronic DIC.¹⁰ The most sensitive screening test for DIC is a fall in the platelet count, with low counts seen in 98% of patients and counts under 50,000 cells/μL in 50%.^9,11 The least specific test is fibrinogen, which tends to fall below normal only in severe acute DIC.⁹

SPECIFIC TESTS

This group of tests allows one to deduce that abnormally high concentrations of thrombin are present.

Ethanol Gel and Protamine Tests

Both of these older tests detected circulating fibrin monomers, whose appearance is an early sign of DIC. Circulating fibrin monomers are seen when thrombin acts on fibrinogen. Usually the monomer polymerizes with the fibrin clot, but when there is excess thrombin these monomers can circulate. Detection of circulating fibrin monomer means there is too much IIa and, ergo, DIC is present.

Fibrin(ogen) Degradation Products

Plasmin acts on the fibrin/fibrinogen molecule to cleave the molecule in specific places. The resulting degradation product levels will be elevated in situations of increased fibrin/fibrinogen destruction (DIC and fibrinolysis). The FDP are typically mildly elevated in renal and liver disease due to reduced clearance.

D-Dimers

When fibrin monomers bind to form a thrombus, factor XIII acts to bind their “D” domains together. This bond is resistant to plasmin and thus this degradation fragment is known as the “D-dimer.” High levels of D-dimer indicate that (1) IIa has acted on fibrinogen to form a fibrin monomer that bonded to another fibrin monomer, and (2) this thrombus was lysed by plasmin. Because D-dimers can be elevated (eg, with exercise, after surgery), an elevated D-dimer needs to be interpreted in the context of the clinical situation.¹¹ Currently, this is the most common specific test for DIC performed.

Other Tests

Several other tests are sometimes helpful in diagnosing DIC.

Thrombin time. This test is performed by adding thrombin to plasma. Thrombin times are elevated in DIC (FDPs interfere with polymerization), in the presence of low fibrinogen levels, in dysfibrinogenemia, and in the presence of heparin (very sensitive).

Reptilase time is the same as thrombin time but is performed with a snake venom that is insensitive to heparin. Reptilase time is elevated in the same conditions as the thrombin time, with the exception of the presence of heparin. Thrombin time and reptilase time are most useful in evaluation of dysfibrinogenemia.

Prothrombin fragment 1.2 (F_1.2). F_1.2 is a small peptide cleaved off when prothrombin is activated to thrombin. Thus, high levels of F_1.2 are found in DIC but can be seen in other thrombotic disorders. This test is still of limited clinical value.

DIC scoring system. A scoring system to both diagnose and quantify DIC has been proposed (Figure).^11,12 

MIMICKERS OF DIC

It is important to recognize coagulation syndromes that are not DIC, especially those that have specific other therapies. The syndromes most frequently encountered are thrombotic thrombocytopenic purpura (TTP) and catastrophic antiphospholipid antibody syndrome (CAPS). One important clue to both of these syndromes is that, unlike DIC, there is no primary disorder (cancer, sepsis) that is driving the coagulation abnormalities.

TTP should be suspected when any patient presents with any combination of thrombo­cytopenia, microangiopathic hemolytic anemia (schistocytes and signs of hemolysis) plus end-organ damage.^15–18 Patients with TTP most often present with intractable seizures, strokes, or sequelae of renal insufficiency. Many patients who present with TTP have been misdiagnosed as having sepsis, “lupus flare,” or vasculitis. The key diagnostic differentiator between TTP and DIC is the lack of activation of coagulation with TTP—fibrinogen is normal and D-dimers are minimally or not elevated. In TTP, lactate dehydrogenase is invariably elevated, often 2 to 3 times normal.¹⁹ The importance of identifying TTP is that untreated TTP is rapidly fatal. Mortality in the pre–plasma exchange era ranged from 95% to 100%. Today plasma exchange therapy is the foundation of TTP treatment and has reduced mortality to less than 20%.^16,20–23Rarely patients with antiphospholipid antibody syndrome can present with fulminant multiorgan system failure.^24–28 CAPS is caused by widespread microthrombi in multiple vascular fields. These patients will develop renal failure, encephalopathy, adult respiratory distress syndrome (often with pulmonary hemorrhage), cardiac failure, dramatic livedo reticularis, and worsening thrombocytopenia. Many of these patients have pre-existing autoimmune disorders and high-titer anticardiolipin antibodies. It appears that the best therapy for these patients is aggressive immunosuppression with steroids plus plasmapheresis, followed by rituximab or, if in the setting of lupus, intravenous cyclophosphamide monthly.^27,29 Early recognition of CAPS can lead to quick therapy and resolution of the multiorgan system failure.

GENERAL THERAPY

The best way to treat DIC is to treat the underlying cause that is driving the thrombin generation.^1,2,4,30,31 Fully addressing the underlying cause may not be possible or may take time, and in the meantime it is necessary to disrupt the cycle of thrombosis and/or hemorrhage. In the past, there was concern about using factor replacement due to fears of “feeding the fire,” or perpetuating the cycle of thrombosis. However, these concerns are not supported by evidence, and factors must be replaced if depletion occurs and bleeding ensues.³²

Transfusion therapy of the patient with DIC is guided by the 5 laboratory tests that reflect the basic parameters essential for both hemostasis and blood volume status:^33,34 hematocrit, platelet count, prothrombin time-INR, aPTT, and fibrinogen level. Decisions regarding replacement therapy are based on the results of these laboratory tests and the clinical situation of the patient (Table 3). 

SPECIFIC DIC SYNDROMES

SEPSIS/INFECTIOUS DISEASE

Any overwhelming infection can lead to DIC.⁴⁵ Classically, it was believed that gram-negative bacteria can lead tissue factor exposure via production of endotoxin, but recent studies indicate that DIC can be seen with any overwhelming infection.^46,47 There are several potential avenues by which infections can lead to DIC. As mentioned, gram-negative bacteria produce endotoxin that can directly lead to tissue factor exposure, resulting in excess thrombin generation. In addition, any infection can lead to expression of inflammatory cytokines that induce tissue-factor expression by endothelium and monocytes. Some viruses and Rickettsia species can directly infect the vascular endothelium, converting it from an antithrombotic to a prothrombotic phenotype.⁴⁸ When fighting infections, neutrophils can extrude their contents, including DNA, to help trap organisms. These neutrophil extracellular traps (NETS) may play an important role in promoting coagulopathy.^49,50 The hypotension produced by sepsis leads to tissue hypoxia, which results in more DIC. The coagulopathy in sepsis can range from subtle abnormalities of testing to purpura fulminans. Thrombocytopenia is worsened by cytokine-induced hemophagocytic syndrome.

As with all forms of DIC, empiric therapy targeting the most likely source of infection and maintaining hemodynamic stability is the key to therapy. As discussed below, heparin and other forms of coagulation replacement appear to be of no benefit in therapy.

PURPURA FULMINANS

DIC in association with necrosis of the skin is seen in primary and secondary purpura fulminans.^51,52 Primary purpura fulminans is most often seen after a viral infection.⁵³ In these patients, the purpura fulminans starts with a painful red area on an extremity that rapidly progresses to a black ischemic area. In many patients, acquired deficiency of protein S is found.^51,54,55 Secondary purpura fulminans is most often associated with meningococcemia infections but can be seen in any patient with overwhelming infection.^56–58 Post-splenectomy sepsis syndrome patients and those with functional hyposplenism due to chronic liver diseases are also at risk.⁵⁹ Patients present with signs of sepsis, and the skin lesions often involve the extremities and may lead to amputations. As opposed to primary purpura fulminans, those with the secondary form will have symmetrical ischemia distally (toes and fingers) that ascends as the process progresses. Rarely, adrenal infarction (Waterhouse-Friderichsen syndrome) occurs, which leads to severe hypotension.⁴⁵

Recently, Warkenten has reported on limb gangrene in critically ill patients complicating sepsis or cardiogenic shock.^60,61 These patients have DIC that is complicated by shock liver. Deep venous thrombosis with ischemic gangrene then develops, which can result in tissue loss and even amputation. The pathogenesis is hypothesized to be hepatic dysfunction leading to sudden drops in protein C and S plasma levels, which then leads to thrombophilia with widespread microvascular thrombosis. Therapy for purpura fulminans is controversial. Primary purpura fulminans, especially in those with postvaricella autoimmune protein S deficiency, has responded to plasma infusion titrated to keep the protein S level above 25%.⁵¹ Intravenous immunoglobulin has also been reported to help decrease the anti-protein S antibodies. Heparin has been reported to control the DIC and extent of necrosis.⁶² The starting dose in these patients is 5 to 8 units/kg/hr.²

Sick patients with secondary purpura fulminans have been treated with plasma drips, plasmapheresis, and continuous plasma ultrafiltration.^62–66 Heparin therapy alone has not been shown to improve survival.⁶⁶ Much attention has been given to replacement of natural anticoagulants such as protein C and antithrombin as therapy for purpura fulminans, but unfortunately randomized trials using antithrombin have shown mostly negative results.^{51,55,67–69} Trials using protein C concentrates have shown more promise in controlling the coagulopathy of purpura fulminans, but this is not widely available.^63,70–72 Unfortunately, many patients will need debridement and amputation for their necrotic limbs, with one review showing approximately 66% of patients needing amputations.⁵²

TRAUMA

Currently, the most common cause of acute DIC is trauma. The coagulation defects that occur in trauma patients are complex in origin and still controversial (including if even calling it DIC is appropriate!).^73–76 The most common etiologies are

• Generation of excess activated protein C leading to increased consumption of factor V and VIII and increased fibrinolysis;
• Tissue damage leading to generation of excess thrombin generation;
• Dilution of hemostatic factors by blood or fluid resuscitation; and
• Activation of endothelial cells leading to generation of a prothrombotic surface and shedding of glycocalyx with antithrombotic properties.

Trauma patients are prone to hypothermia, and this can be the major complicating factor in their bleeding.^77,78 Patients may be out “in the field” for a prolonged period of time and be hypothermic on arrival.⁷⁹ Packed red cells are stored at 4°C, and the infusion of 1 unit can lower the body temperature by 0.16°C.⁸⁰ Hypothermia has profound effects on the coagulation system that are associated with clinical bleeding.^77,81,82 Even modest hypothermia can greatly augment bleeding and needs to be treated or prevented.

The initial management of the bleeding trauma patient is administration of red cells and plasma (FFP) in a 1:1 ratio. This has been shown by clinical studies to lessen the risk of exsanguination in the first 24 hours and to be associated with improved clinical outcomes.^83,84 The basic set of coagulation tests should also be obtained to guide product replacement, especially as the bleeding is brought under control. Hypothermia can be prevented by several measures, including transfusing the blood through blood warmers. Devices are available that can warm 1 unit of blood per minute. An increasingly used technique is to perform “damage control” surgery. Patients are initially stabilized with control of damaged vessels and packing of oozing sites.⁸⁵ Then the patient is taken to the intensive care unit to be warmed and have coagulation defects corrected.

For trauma patients at risk of serious bleeding, the use of tranexamic acid reduced all- cause mortality (relative risk 0.91), with death due to bleeding also being reduced (relative risk 0.85).⁸⁶ There was no increase in thrombosis, but benefit was restricted to patients treated within 3 hours of the trauma. The dose of tranexamic acid was a 1-g bolus followed by a 1-g continuous infusion over 8 hours.

PREGNANCY-RELATED DIC SYNDROMES

Acute DIC of Pregnancy

Pregnancy can be associated with the rapid onset of severe DIC in 2 situations, abruption and amniotic fluid embolism.^87,88 The separation of the placenta from the uterine wall creates a space for blood to occupy. Given the richness of the placenta in tissue factor, this leads to activation of coagulation both locally and systemically. Release of blood when this space reaches the vaginal opening can lead to rapid hemorrhage, further augmenting the coagulation abnormalities. Placental insufficiency can lead to fetal demise, which can also worsen the DIC. Management depends on the size of the abruption and the clinical status of both mother and fetus.⁸⁷ For severe bleeding and DIC, blood product support is crucial to allow safe delivery. In pregnancy, the fibrinogen goal needs to be higher—200 mg/dL.⁸⁹ For smaller abruption, close observation with early delivery is indicated.

Amniotic fluid embolism is sudden, with the vascular collapse of the woman soon after delivery. Due to the presence of procoagulant rich fluid in the circulatory system, there is often overwhelming DIC. Therapy is directed at both supporting blood volume and correcting hemostatic defects.

HELLP

The acronym HELLP (hemolysis, elevated liver tests, low platelets) describes a variant of preeclampsia.⁹⁰ Classically, HELLP syndrome occurs after 28 weeks of gestation in a patient with preeclampsia, but can occur as early as 22 weeks in patients with antiphospholipid antibody syndrome.^91–93 The preeclampsia need not be severe. The first sign of HELLP is a decrease in the platelet count followed by abnormal liver function tests. Signs of hemolysis are present with abundant schistocytes on the smear and a high lactate dehydrogenase level. HELLP can progress to liver failure, and deaths are also reported due to hepatic rupture. Unlike TTP, fetal involvement is present in the HELLP syndrome, with fetal thrombocytopenia reported in 30% of cases. In severe cases, elevated D-dimers consistent with DIC are also found. Delivery of the child will most often result in cessation of the HELLP syndrome, but refractory cases will require dexamethasone and plasma exchange.⁹⁴ Patients should be closely observed for 1 to 2 days after delivery as the hematologic picture can transiently worsen before improving.⁹⁵

Acute Fatty Liver of Pregnancy

Fatty liver of pregnancy also occurs late in pregnancy and is only associated with preeclampsia in 50% of cases.^96,97 Patients first present with nonspecific symptoms of nausea and vomiting but can progress to fulminant liver failure. Patients develop thrombocytopenia early in the course, but in the later stages can develop DIC and very low fibrinogen levels. Mortality rates without therapy can be as high as 90%. Low blood glucose and high ammonia levels can help distinguish fatty liver from other pregnancy complications.⁹⁸ Treatment consists of prompt delivery of the child and aggressive blood product support.

Retained Dead Fetus Syndrome

Becoming rarer in modern practices, the presence of a dead fetus for many weeks (usually ≥ 5) can result in a chronic DIC state with fibrinogen depletion and coagulopathy. In some women, this is worsened at delivery. In a stable patient, a short trial of heparin prior to planning delivery can control the DIC to allow the coagulopathy to stabilize.

DRUG-INDUCED HEMOLYTIC-DIC SYNDROMES

A severe variant of the drug-induced immune complex hemolysis associated with DIC has been recognized. Rare patients who receive certain second- and third-generation cephalosporins (especially cefotetan and ceftriaxone) have developed this syndrome.^99–104 The clinical syndrome starts 7 to 10 days after the drug is administered. Often the patient has only received the antibiotic for surgical prophylaxis. The patient will develop severe Coombs’-positive hemolysis with hypotension and DIC. The patients are often believed to have sepsis and in the management of the supposed sepsis often are re-exposed to the cephalosporin, resulting in worsening of the clinical picture. The outcome is often fatal due to massive hemolysis and thrombosis.^{101,105–107}

Quinine is associated with a unique syndrome of drug-induced DIC.^108–111 Approximately 24 to 96 hours after quinine exposure, the patient becomes acutely ill with nausea and vomiting. The patient then develops a microangiopathic hemolytic anemia, DIC, and renal failure. Some patients, besides having antiplatelet antibodies, also have antibodies binding to red cells and neutrophils, which may lead to the more severe syndrome. Despite therapy, patients with quinine-induced TTP have a high incidence of chronic renal failure.

Treatment of the drug-induced hemolytic-DIC syndrome is anecdotal. Patients have responded to aggressive therapy, including plasma exchange, dialysis, and prednisone. Early recognition of the hemolytic anemia and the suspicion it is drug related is important for early diagnosis so that the incriminated drug can be discontinued.

CANCER

Cancers, primarily adenocarcinomas, can result in DIC. The classic Trousseau syndrome referred to the association of migratory superficial thrombophlebitis with cancer¹¹² but now refers to cancer associated with thrombotic DIC.^113,114 Highly vascular tumor cells are known to express tissue factor.^114,115 In addition, some tumor cells can express a direct activator of factor X (“cancer procoagulant”). Unlike many DIC states, cancer presents with thrombosis instead of bleeding. This may be due to the inflammatory state which accompanies cancer, or it may be a unique part of the chronic nature of cancer DIC biology that allows time for the body to compensate for loss of coagulation factors. In some patients, thrombosis is the first sign of an underlying cancer, sometimes predating the cancer diagnosis by months.¹¹⁵ Rarely, the DIC can result in nonthrombotic endocarditis with micro-emboli leading to widespread small-vessel thrombosis.¹¹³

Since effective antineoplastic therapy is lacking for many tumors associated with Trousseau syndrome, DIC therapy is aimed at suppressing thrombosis. An exception is prostate cancer, where hormonal therapy can markedly decrease the DIC.¹¹⁶ Due to the tumor directly activating coagulation factors, inhibition of active enzymes via heparin has been shown to reduce rates of recurrence compared with warfarin.^114,115 Clinical trials have demonstrated that heparin therapy is associated with a lower thrombosis recurrence rate than warfarin.^117,118 In some patients, the thrombotic process is so vigorous that new thrombosis can be seen within hours of stopping heparin.¹¹²

ACUTE PROMYELOCYTIC LEUKEMIA

There are multiple hemostatic defects in patients with acute promyelocytic leukemia (APL).¹¹⁹ Most, if not all, patients with APL have evidence of DIC at the time of diagnosis. Patients with APL have a higher risk of death during induction therapy as compared with patients with other forms of leukemia, with death most often due to bleeding. Once in remission, APL patients have a higher cure rate than most patients with leukemia. APL is also unique among leukemias in that biologic therapy with retinoic acid or arsenic is effective in inducing remission and cure in most patients. Although effective therapy is available, early death rates due to bleeding have not changed.¹¹⁹

APL patients can present with pancytopenia due to leukemic marrow replacement or with diffuse bleeding due to DIC and thrombocytopenia. Life-threatening bleeding such as intracranial hemorrhage may occur at any time until the leukemia is put into remission. The etiology of the hemostatic defects in APL is complex and is thought to be the result of DIC, fibrinolysis, and the release of prothrombotic extracellular chromatin and other procoagulant enzymes.^119,120 The diagnosis of APL can be straightforward when the leukemic cells are promyelocytes with abundant Auer rods, although some patients have the microgranular form without obvious Auer rods. The precise diagnosis requires molecular methods, including obtaining FISH for detecting the t(15;17) in PML/RARA fusion. Upon diagnosis of APL, one should obtain a complete coagulation profile, including INR, aPTT, fibrinogen, platelet count, and D-dimers. Change in fibrinogen levels tends to be a good marker of progress in treating the coagulation defects.

Therapy of APL involves treating both the leukemia and the coagulopathy. Currently, the standard treatment for APL is trans-retinoic acid (ATRA) in combination with chemotherapy or arsenic.^121,122 This approach will induce remission in more than 90% of patients, and a sizable majority of these patients will be cured of their APL. ATRA therapy will also lead to early correction of the coagulation defects, often within the first week of therapy.¹²³ This is in stark contrast to the chemotherapy era when the coagulation defects would become worse with therapy. Given the marked beneficial effect of ATRA on the coagulopathy of APL and its low toxicity profile, it should be empirically started for any patients suspected of having APL while genetic testing is being performed. Rare reports of massive thrombosis complicating therapy with ATRA exist, but the relationship to either the APL or ATRA is unknown.

Therapy for the coagulation defects consists of aggressive transfusion therapy support and possible use of other pharmacologic agents to control DIC.^124,125 The fibrinogen level should be maintained at over 150 mg/dL and the platelet count at over 50,000 cells/µL.¹²⁶ Controversy still exists over the role of heparin in therapy of APL.¹⁰⁴ Although attractive for its ability to quench thrombin, heparin use can lead to profound bleeding and its use in treating APL has fallen out of favor.

SNAKEBITES

Snake envenomation can lead to direct activation of multiple coagulation enzymes, including factors V, X, thrombin, and protein C, and lead to cleavage of fibrinogen.^127,128 Envenomation can also activate coagulation and damage vascular endothelium. The DIC can be enhanced by widespread tissue necrosis and hypotension. The key to management of snake bites is administration of specific antivenom. The role of prophylactic factor replacement is controversial, but this therapy is indicated if there is clinical bleeding.¹²⁹ One confounder is that some snake venoms, especially rattlesnake, can induce reversible platelet aggregation, which corrects with antivenom.

LOCAL VASCULAR ABNORMALITIES

Abnormal vascular structures, such as vascular tumors, vascular malformations, and aneurysms, can lead to localized areas of thrombin generation that can “spill-over” into the general circulation, leading to DIC. The diagnosis Kasabach-Merritt phenomenon should be reserved for children with vascular tumors such as angioma or hemangioendothelioma.¹³⁰ Therapy depends on the lesion. Embolization to reduce blood flow of vascular malformations can either be definitive therapy or stabilize the patient for surgery. Aneurysms can be repaired by surgery or stenting. Rare patients with aneurysms with significant coagulopathy may require heparin to raise the fibrinogen level before surgery. Kasabach-Merritt disease can respond to steroids or therapy such as vincristine or interferon.¹³⁰ Increasing data shows that use of the mTOR inhibitor sirolimus can shrink these vascular abnormalities leading to lessening of the coagulopathy.¹³¹

CONCLUSION

At the most basic level, DIC is the excess activity of thrombin. However, the clinical presentation and therapy can differ greatly depending on the primary cause. Both diagnosis and therapy involve close coordination of laboratory data and clinical assessment.

SAN FRANCISCO – Hypertensive patients averaged about a 10-mm Hg drop in 24-hour ambulatory systolic blood pressure and about a 12-mm Hg drop in office systolic blood pressure, 2 years after treatment with Medtronic’s new Symplicity Spyral renal artery denervation catheter, according to a review of the company’s renal artery denervation registry.

No major safety issues were reported, but there was no reduction from baseline in the number of antihypertensive drugs that patients were prescribed, which averaged more than four.

[email protected]

SAN FRANCISCO – Hypertensive patients averaged about a 10-mm Hg drop in 24-hour ambulatory systolic blood pressure and about a 12-mm Hg drop in office systolic blood pressure, 2 years after treatment with Medtronic’s new Symplicity Spyral renal artery denervation catheter, according to a review of the company’s renal artery denervation registry.

No major safety issues were reported, but there was no reduction from baseline in the number of antihypertensive drugs that patients were prescribed, which averaged more than four.

[email protected]

SAN FRANCISCO – Hypertensive patients averaged about a 10-mm Hg drop in 24-hour ambulatory systolic blood pressure and about a 12-mm Hg drop in office systolic blood pressure, 2 years after treatment with Medtronic’s new Symplicity Spyral renal artery denervation catheter, according to a review of the company’s renal artery denervation registry.

No major safety issues were reported, but there was no reduction from baseline in the number of antihypertensive drugs that patients were prescribed, which averaged more than four.

[email protected]