Letters To The Editor

To the Editor: I read with great interest the article “Resuming anticoagulation after hemorrhage: A practical approach.”¹ The article was very well written and thorough, and the authors did a great job discussing such a controversial topic.

For the sake of completeness, I would like to point out another available option when it comes to warfarin-related bleeding. We have two studies so far. Although the results were contradicting in some ways, the Prevention of Recurrent Venous Thromboembolism (PREVENT)² and Extended Low-Intensity Anticoagulation for Thromboembolism (ELATE)³ trials shed light on the possible value of low-intensity anticoagulation (international normalized ratio 1.5–2.0) beyond the conventional treatment period for prevention of recurrent venous thromboembolism. While the PREVENT trial found a lower rate of venous thromboembolism with low-intensity anticoagulation than with placebo without increasing the risk of major bleeding, the ELATE trial found no difference in bleeding rates between low-intensity and conventional treatment.

To put this in perspective, I believe that low-intensity anticoagulation is still an option for patients with moderate-risk indications and low to moderate bleeding risk.

It will be interesting to see how lower-intensity dosing of the newer anticoagulants will perform in a similar setting.

To the Editor: I read with great interest the article “Resuming anticoagulation after hemorrhage: A practical approach.”¹ The article was very well written and thorough, and the authors did a great job discussing such a controversial topic.

For the sake of completeness, I would like to point out another available option when it comes to warfarin-related bleeding. We have two studies so far. Although the results were contradicting in some ways, the Prevention of Recurrent Venous Thromboembolism (PREVENT)² and Extended Low-Intensity Anticoagulation for Thromboembolism (ELATE)³ trials shed light on the possible value of low-intensity anticoagulation (international normalized ratio 1.5–2.0) beyond the conventional treatment period for prevention of recurrent venous thromboembolism. While the PREVENT trial found a lower rate of venous thromboembolism with low-intensity anticoagulation than with placebo without increasing the risk of major bleeding, the ELATE trial found no difference in bleeding rates between low-intensity and conventional treatment.

To put this in perspective, I believe that low-intensity anticoagulation is still an option for patients with moderate-risk indications and low to moderate bleeding risk.

It will be interesting to see how lower-intensity dosing of the newer anticoagulants will perform in a similar setting.

To the Editor: I read with great interest the article “Resuming anticoagulation after hemorrhage: A practical approach.”¹ The article was very well written and thorough, and the authors did a great job discussing such a controversial topic.

For the sake of completeness, I would like to point out another available option when it comes to warfarin-related bleeding. We have two studies so far. Although the results were contradicting in some ways, the Prevention of Recurrent Venous Thromboembolism (PREVENT)² and Extended Low-Intensity Anticoagulation for Thromboembolism (ELATE)³ trials shed light on the possible value of low-intensity anticoagulation (international normalized ratio 1.5–2.0) beyond the conventional treatment period for prevention of recurrent venous thromboembolism. While the PREVENT trial found a lower rate of venous thromboembolism with low-intensity anticoagulation than with placebo without increasing the risk of major bleeding, the ELATE trial found no difference in bleeding rates between low-intensity and conventional treatment.

To put this in perspective, I believe that low-intensity anticoagulation is still an option for patients with moderate-risk indications and low to moderate bleeding risk.

It will be interesting to see how lower-intensity dosing of the newer anticoagulants will perform in a similar setting.

In Reply: We thank Dr. Jandali for his thoughtful comments on our article. We acknowledge that there may be a small subset of patients in whom low-intensity warfarin may be worth trying—such as patients with a history of idiopathic or recurrent venous thromboembolism in whom problematic (but not life-threatening) bleeding recurs—but only when the international normalized ratio (INR) is at the high end of the therapeutic range or slightly above it. However, when attempting to apply the results from PREVENT¹ and ELATE² to clinical practice and the management of anticoagulation after hemorrhage, it is important to note that in ELATE there was a higher incidence of recurrent thromboembolism in patients on lower-intensity anticoagulation than in those on conventional treatment, and no significant difference in major bleeding was noted between the high- and low-intensity groups.

We acknowledge, though, that the rates of major bleeding were surprisingly low in the high-intensity group in this study relative to historical controls and so may not apply to all patients.

It is also important to recognize that several studies have evaluated low-intensity dosing for stroke prophylaxis in atrial fibrillation with generally disappointing results, and at present, expert opinion continues to support a therapeutic INR goal of 2.0 to 3.0.³

Therefore, we believe that low-intensity warfarin treatment is only appropriate to try in a very small subset of carefully selected patients with a history of venous thromboembolism who have proven that they cannot tolerate full-dose warfarin and in whom a trial of low-dose warfarin treatment carries acceptable risk.

In Reply: We thank Dr. Jandali for his thoughtful comments on our article. We acknowledge that there may be a small subset of patients in whom low-intensity warfarin may be worth trying—such as patients with a history of idiopathic or recurrent venous thromboembolism in whom problematic (but not life-threatening) bleeding recurs—but only when the international normalized ratio (INR) is at the high end of the therapeutic range or slightly above it. However, when attempting to apply the results from PREVENT¹ and ELATE² to clinical practice and the management of anticoagulation after hemorrhage, it is important to note that in ELATE there was a higher incidence of recurrent thromboembolism in patients on lower-intensity anticoagulation than in those on conventional treatment, and no significant difference in major bleeding was noted between the high- and low-intensity groups.

We acknowledge, though, that the rates of major bleeding were surprisingly low in the high-intensity group in this study relative to historical controls and so may not apply to all patients.

It is also important to recognize that several studies have evaluated low-intensity dosing for stroke prophylaxis in atrial fibrillation with generally disappointing results, and at present, expert opinion continues to support a therapeutic INR goal of 2.0 to 3.0.³

Therefore, we believe that low-intensity warfarin treatment is only appropriate to try in a very small subset of carefully selected patients with a history of venous thromboembolism who have proven that they cannot tolerate full-dose warfarin and in whom a trial of low-dose warfarin treatment carries acceptable risk.

In Reply: We thank Dr. Jandali for his thoughtful comments on our article. We acknowledge that there may be a small subset of patients in whom low-intensity warfarin may be worth trying—such as patients with a history of idiopathic or recurrent venous thromboembolism in whom problematic (but not life-threatening) bleeding recurs—but only when the international normalized ratio (INR) is at the high end of the therapeutic range or slightly above it. However, when attempting to apply the results from PREVENT¹ and ELATE² to clinical practice and the management of anticoagulation after hemorrhage, it is important to note that in ELATE there was a higher incidence of recurrent thromboembolism in patients on lower-intensity anticoagulation than in those on conventional treatment, and no significant difference in major bleeding was noted between the high- and low-intensity groups.

We acknowledge, though, that the rates of major bleeding were surprisingly low in the high-intensity group in this study relative to historical controls and so may not apply to all patients.

It is also important to recognize that several studies have evaluated low-intensity dosing for stroke prophylaxis in atrial fibrillation with generally disappointing results, and at present, expert opinion continues to support a therapeutic INR goal of 2.0 to 3.0.³

Therefore, we believe that low-intensity warfarin treatment is only appropriate to try in a very small subset of carefully selected patients with a history of venous thromboembolism who have proven that they cannot tolerate full-dose warfarin and in whom a trial of low-dose warfarin treatment carries acceptable risk.

To the Editor: I would like to add two points to the excellent review on starting insulin in patients with type 2 diabetes by Brateanu et al in the August 2015 issue.¹

First, in my practice, I review glucose patterns and recommend that mealtime insulin be started early after basal insulin is started and not simply wait for the next hemoglobin A_1c result. In my experience, basal insulin is often mindlessly up-titrated, month after month, to fix a high fasting glucose. During the first 2 to 3 weeks of basal insulin titration, I ask patients to test before breakfast, dinner, and bedtime, not just fasting. In so doing, I detect, in most patients, significant bedtime hyperglycemia arising from dinner, usually their largest meal. Then I prescribe dinnertime rapid-acting insulin to correct the bedtime hyperglycemia, and this in turn ameliorates the fasting hyperglycemia. Additional mealtime doses can be added if necessary.²

After all, why should we ignore hyperglycemia occurring at other times and focus only on fasting glucose? With blood glucose pattern review, we can detect those glucose elevations that need to be targeted regardless of when they occur. It has been repeatedly shown that up to almost 50% of patients will fail to reach a hemoglobin A_1c below 7%, even after months of up-titration of basal insulin.^3,4 Most patients will benefit by starting mealtime rapid-acting insulin early on.

And second, when adjusting mealtime rapid-acting injected insulin, there is no need to measure postprandial glucose in most patients with type 2 diabetes. A rigorous clinical trial⁵ showed that testing before the next meal or, in the case of dinner, before bedtime worked as well as or better than postprandial testing. By implementing the above steps, I think we all can provide better, more individualized therapy for our patients.

To the Editor: I would like to add two points to the excellent review on starting insulin in patients with type 2 diabetes by Brateanu et al in the August 2015 issue.¹

First, in my practice, I review glucose patterns and recommend that mealtime insulin be started early after basal insulin is started and not simply wait for the next hemoglobin A_1c result. In my experience, basal insulin is often mindlessly up-titrated, month after month, to fix a high fasting glucose. During the first 2 to 3 weeks of basal insulin titration, I ask patients to test before breakfast, dinner, and bedtime, not just fasting. In so doing, I detect, in most patients, significant bedtime hyperglycemia arising from dinner, usually their largest meal. Then I prescribe dinnertime rapid-acting insulin to correct the bedtime hyperglycemia, and this in turn ameliorates the fasting hyperglycemia. Additional mealtime doses can be added if necessary.²

After all, why should we ignore hyperglycemia occurring at other times and focus only on fasting glucose? With blood glucose pattern review, we can detect those glucose elevations that need to be targeted regardless of when they occur. It has been repeatedly shown that up to almost 50% of patients will fail to reach a hemoglobin A_1c below 7%, even after months of up-titration of basal insulin.^3,4 Most patients will benefit by starting mealtime rapid-acting insulin early on.

And second, when adjusting mealtime rapid-acting injected insulin, there is no need to measure postprandial glucose in most patients with type 2 diabetes. A rigorous clinical trial⁵ showed that testing before the next meal or, in the case of dinner, before bedtime worked as well as or better than postprandial testing. By implementing the above steps, I think we all can provide better, more individualized therapy for our patients.

To the Editor: I would like to add two points to the excellent review on starting insulin in patients with type 2 diabetes by Brateanu et al in the August 2015 issue.¹

First, in my practice, I review glucose patterns and recommend that mealtime insulin be started early after basal insulin is started and not simply wait for the next hemoglobin A_1c result. In my experience, basal insulin is often mindlessly up-titrated, month after month, to fix a high fasting glucose. During the first 2 to 3 weeks of basal insulin titration, I ask patients to test before breakfast, dinner, and bedtime, not just fasting. In so doing, I detect, in most patients, significant bedtime hyperglycemia arising from dinner, usually their largest meal. Then I prescribe dinnertime rapid-acting insulin to correct the bedtime hyperglycemia, and this in turn ameliorates the fasting hyperglycemia. Additional mealtime doses can be added if necessary.²

After all, why should we ignore hyperglycemia occurring at other times and focus only on fasting glucose? With blood glucose pattern review, we can detect those glucose elevations that need to be targeted regardless of when they occur. It has been repeatedly shown that up to almost 50% of patients will fail to reach a hemoglobin A_1c below 7%, even after months of up-titration of basal insulin.^3,4 Most patients will benefit by starting mealtime rapid-acting insulin early on.

And second, when adjusting mealtime rapid-acting injected insulin, there is no need to measure postprandial glucose in most patients with type 2 diabetes. A rigorous clinical trial⁵ showed that testing before the next meal or, in the case of dinner, before bedtime worked as well as or better than postprandial testing. By implementing the above steps, I think we all can provide better, more individualized therapy for our patients.

In Reply: We thank Dr. Weiss for his insightful comments and for the opportunity to clarify a number of points from our article.

We agree that controlling the fasting glucose should not take months. As mentioned in our article, adjusting the basal insulin dose should be done with 2 to 4 units every 2 to 3 days in order to reach the fasting glycemic goal. Applying this approach and systematically titrating the NPH, glargine, or detemir insulin will smoothly decrease the fasting glucose within 12 weeks, as described in the 24-week¹ and 52-week² treat-to-target trials in which basal insulin was added to the oral therapy in patients with type 2 diabetes.

When basal insulin is no longer sufficient to reach a target hemoglobin A_1c, a glucagon-like peptide-1 receptor agonist or prandial insulin can be used. The basal-bolus or twice-daily premixed insulin analogues can also be considered as the initial therapy, depending on the patient, disease, and drug characteristics.³ We agree that once a prandial insulin regimen is initiated, the dose titration can be done based on preprandial or postprandial blood glucose measurements, as shown in Table 2 in our article. However, adding the prandial insulin without first optimizing the basal therapy was considered a limitation of the Orals Plus Apidra and Lantus (OPAL) study,⁴ which investigated the addition of one prandial insulin injection to basal glargine insulin.⁵ As a consequence, the subsequent studies investigating the effects of initiating and titrating the preprandial rapid-acting insulin (as a single dose or using a stepwise approach) in patients inadequately controlled with once-daily basal insulin and oral antidiabetic drugs had run-in periods of 12 to 14 weeks, in order to optimize the basal insulin dosage and achieve target fasting blood glucose levels of 110 mg/dL or less. This approach had the additional benefit of achieving a target hemoglobin A_1c level of less than 7% in a significant number of patients (up to 37%),⁶ before starting the preprandial insulin.^6–8

Regardless of the regimen selected, titration of the insulin doses can only be achieved with understanding the pharmacodynamic characteristics of each type of insulin used.⁹

In Reply: We thank Dr. Weiss for his insightful comments and for the opportunity to clarify a number of points from our article.

We agree that controlling the fasting glucose should not take months. As mentioned in our article, adjusting the basal insulin dose should be done with 2 to 4 units every 2 to 3 days in order to reach the fasting glycemic goal. Applying this approach and systematically titrating the NPH, glargine, or detemir insulin will smoothly decrease the fasting glucose within 12 weeks, as described in the 24-week¹ and 52-week² treat-to-target trials in which basal insulin was added to the oral therapy in patients with type 2 diabetes.

When basal insulin is no longer sufficient to reach a target hemoglobin A_1c, a glucagon-like peptide-1 receptor agonist or prandial insulin can be used. The basal-bolus or twice-daily premixed insulin analogues can also be considered as the initial therapy, depending on the patient, disease, and drug characteristics.³ We agree that once a prandial insulin regimen is initiated, the dose titration can be done based on preprandial or postprandial blood glucose measurements, as shown in Table 2 in our article. However, adding the prandial insulin without first optimizing the basal therapy was considered a limitation of the Orals Plus Apidra and Lantus (OPAL) study,⁴ which investigated the addition of one prandial insulin injection to basal glargine insulin.⁵ As a consequence, the subsequent studies investigating the effects of initiating and titrating the preprandial rapid-acting insulin (as a single dose or using a stepwise approach) in patients inadequately controlled with once-daily basal insulin and oral antidiabetic drugs had run-in periods of 12 to 14 weeks, in order to optimize the basal insulin dosage and achieve target fasting blood glucose levels of 110 mg/dL or less. This approach had the additional benefit of achieving a target hemoglobin A_1c level of less than 7% in a significant number of patients (up to 37%),⁶ before starting the preprandial insulin.^6–8

Regardless of the regimen selected, titration of the insulin doses can only be achieved with understanding the pharmacodynamic characteristics of each type of insulin used.⁹

In Reply: We thank Dr. Weiss for his insightful comments and for the opportunity to clarify a number of points from our article.

We agree that controlling the fasting glucose should not take months. As mentioned in our article, adjusting the basal insulin dose should be done with 2 to 4 units every 2 to 3 days in order to reach the fasting glycemic goal. Applying this approach and systematically titrating the NPH, glargine, or detemir insulin will smoothly decrease the fasting glucose within 12 weeks, as described in the 24-week¹ and 52-week² treat-to-target trials in which basal insulin was added to the oral therapy in patients with type 2 diabetes.

When basal insulin is no longer sufficient to reach a target hemoglobin A_1c, a glucagon-like peptide-1 receptor agonist or prandial insulin can be used. The basal-bolus or twice-daily premixed insulin analogues can also be considered as the initial therapy, depending on the patient, disease, and drug characteristics.³ We agree that once a prandial insulin regimen is initiated, the dose titration can be done based on preprandial or postprandial blood glucose measurements, as shown in Table 2 in our article. However, adding the prandial insulin without first optimizing the basal therapy was considered a limitation of the Orals Plus Apidra and Lantus (OPAL) study,⁴ which investigated the addition of one prandial insulin injection to basal glargine insulin.⁵ As a consequence, the subsequent studies investigating the effects of initiating and titrating the preprandial rapid-acting insulin (as a single dose or using a stepwise approach) in patients inadequately controlled with once-daily basal insulin and oral antidiabetic drugs had run-in periods of 12 to 14 weeks, in order to optimize the basal insulin dosage and achieve target fasting blood glucose levels of 110 mg/dL or less. This approach had the additional benefit of achieving a target hemoglobin A_1c level of less than 7% in a significant number of patients (up to 37%),⁶ before starting the preprandial insulin.^6–8

Regardless of the regimen selected, titration of the insulin doses can only be achieved with understanding the pharmacodynamic characteristics of each type of insulin used.⁹

To the Editor: Dr. Venkat¹ was spot on when he identified the need for electronic medical records to communicate and educate, rather than document. Short and actionable notes are best. But with the focus on billing and compliance, annotated, informative assessments are actually discouraged. Our billing and coding department performs periodic chart audits and considers the note “out of compliance” if there is a difference between the list of free text assessments and the International Classification of Diseases, Ninth Revision (ICD-9) codes chosen. Therefore, many physicians just use the billing codes as their assessment and skip the free text assessment section of a SOAP (subjective-objective-assessment-plan) note, which means the notes convey even less of what the physician is thinking. A classic example is the note of a patient whom I knew had pernio, yet the assessment blandly reported “circulatory disorder.” The plan likewise is often reduced to the imported structured text of the tests and medications ordered rather than a rich discussion of the differential diagnosis and medical reasoning.

Imagine the notes we might write if their primary purpose was communication to ourselves and the others involved in our patients’ care. Imagine if the notes made us more knowledgeable about the uniqueness of this particular patient and also contributed to a continuous learning environment. More meaning, less filler. The notes would be shorter and sweeter, as Dr. Venkat suggested.

To the Editor: Dr. Venkat¹ was spot on when he identified the need for electronic medical records to communicate and educate, rather than document. Short and actionable notes are best. But with the focus on billing and compliance, annotated, informative assessments are actually discouraged. Our billing and coding department performs periodic chart audits and considers the note “out of compliance” if there is a difference between the list of free text assessments and the International Classification of Diseases, Ninth Revision (ICD-9) codes chosen. Therefore, many physicians just use the billing codes as their assessment and skip the free text assessment section of a SOAP (subjective-objective-assessment-plan) note, which means the notes convey even less of what the physician is thinking. A classic example is the note of a patient whom I knew had pernio, yet the assessment blandly reported “circulatory disorder.” The plan likewise is often reduced to the imported structured text of the tests and medications ordered rather than a rich discussion of the differential diagnosis and medical reasoning.

Imagine the notes we might write if their primary purpose was communication to ourselves and the others involved in our patients’ care. Imagine if the notes made us more knowledgeable about the uniqueness of this particular patient and also contributed to a continuous learning environment. More meaning, less filler. The notes would be shorter and sweeter, as Dr. Venkat suggested.

To the Editor: Dr. Venkat¹ was spot on when he identified the need for electronic medical records to communicate and educate, rather than document. Short and actionable notes are best. But with the focus on billing and compliance, annotated, informative assessments are actually discouraged. Our billing and coding department performs periodic chart audits and considers the note “out of compliance” if there is a difference between the list of free text assessments and the International Classification of Diseases, Ninth Revision (ICD-9) codes chosen. Therefore, many physicians just use the billing codes as their assessment and skip the free text assessment section of a SOAP (subjective-objective-assessment-plan) note, which means the notes convey even less of what the physician is thinking. A classic example is the note of a patient whom I knew had pernio, yet the assessment blandly reported “circulatory disorder.” The plan likewise is often reduced to the imported structured text of the tests and medications ordered rather than a rich discussion of the differential diagnosis and medical reasoning.

Imagine the notes we might write if their primary purpose was communication to ourselves and the others involved in our patients’ care. Imagine if the notes made us more knowledgeable about the uniqueness of this particular patient and also contributed to a continuous learning environment. More meaning, less filler. The notes would be shorter and sweeter, as Dr. Venkat suggested.

To the Editor: We read with interest the paper by Dr. Reena Mehra,“Sleep apnea ABCs: Airway, breathing, circulation.”¹ It was very consistent and informative. However, we feel that some considerations on the pathogenesis warrant more discussion.

The pathophysiologic heterogeneity of sympathetic nervous system activity enhancement is complex and involves both intermittent hypoxia and arousal. We agree with Dr. Mehra about the importance of intermittent hypoxia in sympathetic activation, and we would like to point out the importance of effects of arousal from sleep on autonomic outflow. In some patients with obstructive sleep apnea (OSA) in whom respiratory events are not followed by oxygen desaturation, sympathetic activation cannot be explained by intermittent hypoxia. Arousal has been reported to be associated with an acute increase in sympathetic activity in the absence of hypercapnia or hypoxia.² Cortical arousals from sleep have been historically assumed to be important in restoring airflow at the end of OSA breathing events.³ Furthermore, arousals often precede upper-airway opening in patients with OSA.⁴

Reprinted from Mehra R. Sleep apnea ABCs: airway, breathing, circulation. Cleve Clin J Med 2014; 81:479–489.

In Figure 1 of Dr. Mehra’s paper, all the respiratory events were associated with microarousals. According to the conventional definition, cortical arousal is an abrupt shift in the electroencephalogram lasting more than 3 seconds. In Figure 1, the beginning of arousals must be scored a few seconds before breathing recovery, just at the beginning of electroencephalogram acceleration. The second respiratory event was scored as obstructive apnea, or the apnea started out as central apnea, where all respiratory channels are flat and then the chest and abdominal belts start moving, making it look like typical mixed apnea.

In the title of the paper, the “A” of ABCs referred to airway and, more specifically, to the collapse of the upper airway in sleep, which is the cause of OSA. We think that the “A” can be attributed to arousal, which is specific to sleep and contributes to the pathogenesis of OSA.

To the Editor: We read with interest the paper by Dr. Reena Mehra,“Sleep apnea ABCs: Airway, breathing, circulation.”¹ It was very consistent and informative. However, we feel that some considerations on the pathogenesis warrant more discussion.

The pathophysiologic heterogeneity of sympathetic nervous system activity enhancement is complex and involves both intermittent hypoxia and arousal. We agree with Dr. Mehra about the importance of intermittent hypoxia in sympathetic activation, and we would like to point out the importance of effects of arousal from sleep on autonomic outflow. In some patients with obstructive sleep apnea (OSA) in whom respiratory events are not followed by oxygen desaturation, sympathetic activation cannot be explained by intermittent hypoxia. Arousal has been reported to be associated with an acute increase in sympathetic activity in the absence of hypercapnia or hypoxia.² Cortical arousals from sleep have been historically assumed to be important in restoring airflow at the end of OSA breathing events.³ Furthermore, arousals often precede upper-airway opening in patients with OSA.⁴

Reprinted from Mehra R. Sleep apnea ABCs: airway, breathing, circulation. Cleve Clin J Med 2014; 81:479–489.

In Figure 1 of Dr. Mehra’s paper, all the respiratory events were associated with microarousals. According to the conventional definition, cortical arousal is an abrupt shift in the electroencephalogram lasting more than 3 seconds. In Figure 1, the beginning of arousals must be scored a few seconds before breathing recovery, just at the beginning of electroencephalogram acceleration. The second respiratory event was scored as obstructive apnea, or the apnea started out as central apnea, where all respiratory channels are flat and then the chest and abdominal belts start moving, making it look like typical mixed apnea.

In the title of the paper, the “A” of ABCs referred to airway and, more specifically, to the collapse of the upper airway in sleep, which is the cause of OSA. We think that the “A” can be attributed to arousal, which is specific to sleep and contributes to the pathogenesis of OSA.

To the Editor: We read with interest the paper by Dr. Reena Mehra,“Sleep apnea ABCs: Airway, breathing, circulation.”¹ It was very consistent and informative. However, we feel that some considerations on the pathogenesis warrant more discussion.

The pathophysiologic heterogeneity of sympathetic nervous system activity enhancement is complex and involves both intermittent hypoxia and arousal. We agree with Dr. Mehra about the importance of intermittent hypoxia in sympathetic activation, and we would like to point out the importance of effects of arousal from sleep on autonomic outflow. In some patients with obstructive sleep apnea (OSA) in whom respiratory events are not followed by oxygen desaturation, sympathetic activation cannot be explained by intermittent hypoxia. Arousal has been reported to be associated with an acute increase in sympathetic activity in the absence of hypercapnia or hypoxia.² Cortical arousals from sleep have been historically assumed to be important in restoring airflow at the end of OSA breathing events.³ Furthermore, arousals often precede upper-airway opening in patients with OSA.⁴

Reprinted from Mehra R. Sleep apnea ABCs: airway, breathing, circulation. Cleve Clin J Med 2014; 81:479–489.

In Figure 1 of Dr. Mehra’s paper, all the respiratory events were associated with microarousals. According to the conventional definition, cortical arousal is an abrupt shift in the electroencephalogram lasting more than 3 seconds. In Figure 1, the beginning of arousals must be scored a few seconds before breathing recovery, just at the beginning of electroencephalogram acceleration. The second respiratory event was scored as obstructive apnea, or the apnea started out as central apnea, where all respiratory channels are flat and then the chest and abdominal belts start moving, making it look like typical mixed apnea.

In the title of the paper, the “A” of ABCs referred to airway and, more specifically, to the collapse of the upper airway in sleep, which is the cause of OSA. We think that the “A” can be attributed to arousal, which is specific to sleep and contributes to the pathogenesis of OSA.

In Reply: We thank Dr. Abouda for underscoring the role of arousals in the pathophysiology of obstructive sleep apnea (OSA). Although the focus of the referenced article was to provide a general overview of the epidemiology, diagnostic testing, and cardiovascular ramifications of untreated OSA and not a detailed summary of the underlying pathophysiology, we welcome the comments from Dr. Abouda to highlight the importance of cortical or microarousals in OSA.

Whether cortical arousal during sleep is bad or good is controversial. During the development of the American Academy of Sleep Medicine respiratory event guidelines, the assignment of detriment or benefit to the arousal when considering defining and scoring of a hypopnea event was a topic of much discussion.^1,2 Supporters of including arousal in the hypopnea definition cite data that sleep fragmentation without attendant hypoxia is associated with symptoms such as excessive daytime somnolence, which is recognized to be effectively addressed with OSA treatment.^3,4 Moreover, experimental data indicate that arousals lead to activation of the sympathetic nervous system.⁵ On the other hand, those who question the inclusion of cortical arousal in the hypopnea definition cite large-scale epidemiologic studies that have failed to find a significantly increased cardiovascular risk in relation to increasing arousal index, as well as the enhanced potential to introduce measurement variability.¹

The effects of cortical arousals as a purported source of sympathetic activation may operate in concert with hypoxic influences, the latter resulting in sustained increases in blood pressure in both animal models and human studies.^6,7 Gottlieb et al⁸ examined the effect of supplemental oxygen vs continuous positive airway pressure (CPAP) on 24-hour mean arterial pressure in a multicenter randomized controlled trial. Although CPAP reduced blood pressure, as expected, the somewhat unanticipated finding that supplemental oxygen did not suggests that other factors such as hypercapnia and cortical arousals with attendant sympathetic activation may represent potential culprits. Along these lines, in patients with OSA and increased loop gain, benefit in response to sedative hypnotics has been shown to reduce ventilatory instability through an increase in arousal threshold.⁹ A genetic predisposition may influence the intensity of cortical arousals and accompanying cardiovascular influences that appear to be consistent within individuals but that are heterogeneous within populations.¹⁰

Few studies have identified increased cortical arousals as a cardiovascular risk factor. In the Cleveland Family Study, an elevated arousal index was associated with hypertension, but respiratory event-specific arousals was not specifically examined.¹¹ Not only have large-scale epidemiologic studies failed to identify an association between arousal index and cardiovascular outcomes, existing data appear to support the contrary. For example, the extent of incident white matter disease identified on brain magnetic resonance imaging was inversely related to the arousal index in a subset of participants of the Sleep Heart Health Study, a large population-based study focused on sleep and cardiovascular outcomes.¹² Furthermore, elevated arousal indices in women were associated with reduced incidence of stroke in the Sleep Heart Health Study.¹³ These data suggest that arousals may represent beneficial, protective biomarkers reflecting truncation of respiratory events translating into reduced duration of hypoxic exposure and decreased work of breathing.

Needed is further investigation dedicated to understanding the impact of cortical arousals on health outcomes in population-based studies and elucidating the mechanistic role of cortical arousals in the autonomic nervous system physiology in various subtypes of sleep-disordered breathing (eg, obstructive vs central sleep apnea) as well as periodic limb movements.

As the upper Airway is central to the pathophysiology of OSA leading to compromise in Breathing and Circulatory or Cardiovascular ramifications, we think it logical that the “A” in ABCs should stand for “airway.” Hopefully, future research will allow us to better understand the associated benefit vs detriment of cortical arousals as they pertain to subgroup susceptibilities and enhance our ability to tailor a personalized medicine approach to the treatment of sleep disorders.

In Reply: We thank Dr. Abouda for underscoring the role of arousals in the pathophysiology of obstructive sleep apnea (OSA). Although the focus of the referenced article was to provide a general overview of the epidemiology, diagnostic testing, and cardiovascular ramifications of untreated OSA and not a detailed summary of the underlying pathophysiology, we welcome the comments from Dr. Abouda to highlight the importance of cortical or microarousals in OSA.

Whether cortical arousal during sleep is bad or good is controversial. During the development of the American Academy of Sleep Medicine respiratory event guidelines, the assignment of detriment or benefit to the arousal when considering defining and scoring of a hypopnea event was a topic of much discussion.^1,2 Supporters of including arousal in the hypopnea definition cite data that sleep fragmentation without attendant hypoxia is associated with symptoms such as excessive daytime somnolence, which is recognized to be effectively addressed with OSA treatment.^3,4 Moreover, experimental data indicate that arousals lead to activation of the sympathetic nervous system.⁵ On the other hand, those who question the inclusion of cortical arousal in the hypopnea definition cite large-scale epidemiologic studies that have failed to find a significantly increased cardiovascular risk in relation to increasing arousal index, as well as the enhanced potential to introduce measurement variability.¹

The effects of cortical arousals as a purported source of sympathetic activation may operate in concert with hypoxic influences, the latter resulting in sustained increases in blood pressure in both animal models and human studies.^6,7 Gottlieb et al⁸ examined the effect of supplemental oxygen vs continuous positive airway pressure (CPAP) on 24-hour mean arterial pressure in a multicenter randomized controlled trial. Although CPAP reduced blood pressure, as expected, the somewhat unanticipated finding that supplemental oxygen did not suggests that other factors such as hypercapnia and cortical arousals with attendant sympathetic activation may represent potential culprits. Along these lines, in patients with OSA and increased loop gain, benefit in response to sedative hypnotics has been shown to reduce ventilatory instability through an increase in arousal threshold.⁹ A genetic predisposition may influence the intensity of cortical arousals and accompanying cardiovascular influences that appear to be consistent within individuals but that are heterogeneous within populations.¹⁰

Few studies have identified increased cortical arousals as a cardiovascular risk factor. In the Cleveland Family Study, an elevated arousal index was associated with hypertension, but respiratory event-specific arousals was not specifically examined.¹¹ Not only have large-scale epidemiologic studies failed to identify an association between arousal index and cardiovascular outcomes, existing data appear to support the contrary. For example, the extent of incident white matter disease identified on brain magnetic resonance imaging was inversely related to the arousal index in a subset of participants of the Sleep Heart Health Study, a large population-based study focused on sleep and cardiovascular outcomes.¹² Furthermore, elevated arousal indices in women were associated with reduced incidence of stroke in the Sleep Heart Health Study.¹³ These data suggest that arousals may represent beneficial, protective biomarkers reflecting truncation of respiratory events translating into reduced duration of hypoxic exposure and decreased work of breathing.

Needed is further investigation dedicated to understanding the impact of cortical arousals on health outcomes in population-based studies and elucidating the mechanistic role of cortical arousals in the autonomic nervous system physiology in various subtypes of sleep-disordered breathing (eg, obstructive vs central sleep apnea) as well as periodic limb movements.

As the upper Airway is central to the pathophysiology of OSA leading to compromise in Breathing and Circulatory or Cardiovascular ramifications, we think it logical that the “A” in ABCs should stand for “airway.” Hopefully, future research will allow us to better understand the associated benefit vs detriment of cortical arousals as they pertain to subgroup susceptibilities and enhance our ability to tailor a personalized medicine approach to the treatment of sleep disorders.

In Reply: We thank Dr. Abouda for underscoring the role of arousals in the pathophysiology of obstructive sleep apnea (OSA). Although the focus of the referenced article was to provide a general overview of the epidemiology, diagnostic testing, and cardiovascular ramifications of untreated OSA and not a detailed summary of the underlying pathophysiology, we welcome the comments from Dr. Abouda to highlight the importance of cortical or microarousals in OSA.

Whether cortical arousal during sleep is bad or good is controversial. During the development of the American Academy of Sleep Medicine respiratory event guidelines, the assignment of detriment or benefit to the arousal when considering defining and scoring of a hypopnea event was a topic of much discussion.^1,2 Supporters of including arousal in the hypopnea definition cite data that sleep fragmentation without attendant hypoxia is associated with symptoms such as excessive daytime somnolence, which is recognized to be effectively addressed with OSA treatment.^3,4 Moreover, experimental data indicate that arousals lead to activation of the sympathetic nervous system.⁵ On the other hand, those who question the inclusion of cortical arousal in the hypopnea definition cite large-scale epidemiologic studies that have failed to find a significantly increased cardiovascular risk in relation to increasing arousal index, as well as the enhanced potential to introduce measurement variability.¹

The effects of cortical arousals as a purported source of sympathetic activation may operate in concert with hypoxic influences, the latter resulting in sustained increases in blood pressure in both animal models and human studies.^6,7 Gottlieb et al⁸ examined the effect of supplemental oxygen vs continuous positive airway pressure (CPAP) on 24-hour mean arterial pressure in a multicenter randomized controlled trial. Although CPAP reduced blood pressure, as expected, the somewhat unanticipated finding that supplemental oxygen did not suggests that other factors such as hypercapnia and cortical arousals with attendant sympathetic activation may represent potential culprits. Along these lines, in patients with OSA and increased loop gain, benefit in response to sedative hypnotics has been shown to reduce ventilatory instability through an increase in arousal threshold.⁹ A genetic predisposition may influence the intensity of cortical arousals and accompanying cardiovascular influences that appear to be consistent within individuals but that are heterogeneous within populations.¹⁰

Few studies have identified increased cortical arousals as a cardiovascular risk factor. In the Cleveland Family Study, an elevated arousal index was associated with hypertension, but respiratory event-specific arousals was not specifically examined.¹¹ Not only have large-scale epidemiologic studies failed to identify an association between arousal index and cardiovascular outcomes, existing data appear to support the contrary. For example, the extent of incident white matter disease identified on brain magnetic resonance imaging was inversely related to the arousal index in a subset of participants of the Sleep Heart Health Study, a large population-based study focused on sleep and cardiovascular outcomes.¹² Furthermore, elevated arousal indices in women were associated with reduced incidence of stroke in the Sleep Heart Health Study.¹³ These data suggest that arousals may represent beneficial, protective biomarkers reflecting truncation of respiratory events translating into reduced duration of hypoxic exposure and decreased work of breathing.

Needed is further investigation dedicated to understanding the impact of cortical arousals on health outcomes in population-based studies and elucidating the mechanistic role of cortical arousals in the autonomic nervous system physiology in various subtypes of sleep-disordered breathing (eg, obstructive vs central sleep apnea) as well as periodic limb movements.

As the upper Airway is central to the pathophysiology of OSA leading to compromise in Breathing and Circulatory or Cardiovascular ramifications, we think it logical that the “A” in ABCs should stand for “airway.” Hopefully, future research will allow us to better understand the associated benefit vs detriment of cortical arousals as they pertain to subgroup susceptibilities and enhance our ability to tailor a personalized medicine approach to the treatment of sleep disorders.