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Symptom-Triggered Therapy for Alcohol Withdrawal Syndrome in Medical Inpatients
Mayo Clin Proc, December 2001, Vol 76
Letters to the Editor 1275
Letters to the Editor
Midodrine is one of the most effective vasoconstrictor drugs available.3,4 The example of our patient, to our knowledge the first of its kind, suggests that the drug should be administered with caution, particularly when it is reintroduced at its former dose. Paola Sandroni, MD, PhD Eduardo E. Benarroch, MD Eelco F. M. Wijdicks, MD Mayo Clinic Rochester, Minn
Caudate Hemorrhage as a Possible Complication of Midodrine-Induced Supine Hypertension To the Editor: Midodrine is an α1-adrenergic prodrug used widely to treat postural hypotension. Midodrine is well tolerated, but supine hypertension is a potentially serious adverse effect.1 We report caudate hemorrhage as a possible complication of midodrine-induced supine hypertension. Report of a Case.—A 66-year-old man presented with an 8-year history of impotence, constipation, and heat intolerance.. A tilt-table study revealed orthostatic hypotension (OH). Midodrine, 2.5 mg 3 times a day, was prescribed with good clinical response. Nine months later his hypotensive symptoms recurred. Midodrine was gradually titrated up to 10 mg 3 times a day because of its progressively shorter duration of effect. Fludrocortisone, 0.5 mg twice a day, was added to his treatment regimen. Supine hypertension was never documented despite frequent measurements with use of a portable device. Prior to autonomic testing, midodrine and fludrocortisone were discontinued for 48 hours, with worsening of OH. During testing, supine blood pressure (BP) was 156/74 mm Hg, and heart rate (HR) was 74 beats/min; on tilt, BP was 116/70 mm Hg, and HR, 82 beats/min. Test results indicated diffuse autonomic failure. Three hours later, at home, he complained of lightheadedness and nausea; subsequently, he vomited and collapsed for a few minutes. Assuming this event represented one of his usual hypotensive spells, his wife gave him 10 mg of midodrine, and within 30 minutes, he experienced a similar episode. On arrival at the emergency department, his supine BP was 210/96 mm Hg. His evaluation, including computed tomographic (CT) scan of the head, was unremarkable, and he was discharged to home. The next day he appeared “confused.” He restarted his medication regimen of midodrine, 10 mg 3 times a day, and fludrocortisone, 0.5 mg twice a day. Approximately 1 hour after his evening meal, he collapsed and remained drowsy, confused, and agitated with no focal signs. When he again arrived at the emergency department, his BP was 156/96 mm Hg. A CT scan showed a caudate hemorrhage. He recovered and again displayed OH. After administration of only 2.5 mg of midodrine, BP was 168/83 mm Hg in the sitting position. Comment.—This patient had been taking 10 mg of midodrine 3 times a day for 3 months without known supine hypertension. The progressive decrease in efficacy of midodrine may reflect α1-receptor desensitization.2 After resumption, midodrine may have acted on α 1-receptors resensitized after 48 hours of drug discontinuation, thus eliciting hypertension. Baroreflex failure may also have predisposed to this event, despite near-normal BP throughout the day. The location of the hemorrhage would fit this mechanism, but we acknowledge that the relationship remains uncertain. Mayo Clin Proc. 2001;76:1275-1279
1. 2. 3. 4.
Jacob G, Shannon JR, Black B, et al. Effects of volume loading and pressor agents in idiopathic orthostatic tachycardia. Circulation. 1997;96:575-580. Polinsky RJ, Kopin IJ, Ebert MH, Weise V. Pharmacologic distinction of different orthostatic hypotension syndromes. Neurology. 1981;31:1-7. Wright RA, Kaufmann HC, Perera R, et al. A double-blind, doseresponse study of midodrine in neurogenic orthostatic hypotension. Neurology. 1998;51:120-124. Low PA, Gilden JL, Freeman R, Sheng KN, McElligott MA, Midodrine Study Group. Efficacy of midodrine vs placebo in neurogenic orthostatic hypotension: a randomized, double-blind multicenter study [published correction appears in JAMA. 1997;278:388]. JAMA. 1997;277:1046-1051.
Symptom-Triggered Therapy for Alcohol Withdrawal Syndrome in Medical Inpatients To the Editor: We read with interest the recent article by Jaeger et al1 on alcohol withdrawal syndrome (AWS) in medical inpatients. Since treatment of alcohol withdrawal is a daily concern for many urban clinicians, the ramifications of this study are extensive.2 Although we agree with the authors’ conclusion that symptom-triggered therapy (STT) is effective for AWS, we are concerned that the study contains several methodologic flaws. Outcome measures in the study groups were compared from a retrospective chart review. The authors conclude that STT is effective because the postimplementation group had fewer complications and a decreased incidence of delirium tremens. However, the postimplementation group was monitored very closely, and the hospital staff was trained extensively in evaluating and treating AWS patients. Compared with the preimplementation group, the postimplementation group most likely received better benzodiazepine therapy in addition to all other aspects of care (intravenous fluids, antibiotics, etc). Furthermore, without the documentation of autonomic hyperactivity, the definition of delirium tremens used by the authors of “alcohol withdrawal accompanied by disorientation, agitation, and hallucinations” appears to be less than ideal and may have led to some inclusion bias. Their Table 1 attempts to equate varying doses and routes of administration of different benzodiazepines based on 1275
© 2001 Mayo Foundation for Medical Education and Research
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
1276
Letters to the Editor
lorazepam equivalents. All benzodiazepines vary in onset of action, anticonvulsant effect, duration of action, bioavailability (depending on route of administration), and presence of active metabolites.3 Are the benzodiazepine equivalents in the table based on plasma level of the drug, drug half-life, or simply clinical effect? There is no mention of whether this table takes into consideration any of these factors and if it is the foundation of the authors’ premise. Before a conclusion can be drawn with regard to the outcome differences in the preimplementation and postimplementation groups, a more accurate comparison of benzodiazepine equivalence must be established. We believe that STT is the best approach to the management of AWS and is previously well described.4,5 Based on the literature and our experience, we routinely recommend intravenous diazepam as the sole initial benzodiazepine for the treatment of AWS.6,7 Intravenous diazepam has a rapid onset of action, prolonged duration of effect due to presence of active metabolites, and guaranteed absorption. All other benzodiazepines lack a similar pharmacokinetic profile and should thus be considered inferior. The successful treatment of AWS requires intensive pharmacotherapy, monitoring, nutritional supplementation, and awareness of the precipitating event(s). As a result of this study, Jaeger et al demonstrate only that patients have better outcomes when they are frequently evaluated, receive medication, and have their medical issues addressed promptly. Because of the potential flaws in the study’s methods, it fails to provide sufficient evidence to justify the authors’ conclusion that symptomatic benzodiazepine therapy alone accounts for their important findings. Doodnauth Hiraman, MD New York University Bellevue Hospital Center New York, NY Mark Su, MD New York University Bellevue Hospital Center New York City Poison Control Center Mary Ann Howland, PharmD St John’s University College of Pharmacy Jamaica, NY Robert S. Hoffman, MD New York University Bellevue Hospital Center New York City Poison Control Center 1. 2. 3.
Jaeger TM, Lohr RH, Pankratz VS. Symptom-triggered therapy for alcohol withdrawal syndrome in medical inpatients. Mayo Clin Proc. 2001;76:695-701. Whiteman PJ, Hoffman RS, Goldfrank LR. Alcoholism in the emergency department: an epidemiologic study. Acad Emerg Med. 2000; 7:14-20. Hobbs WR, Rall TW, Verdoorn TA. Hypnotics and sedatives: ethanol. In: Hardman JG, Limbird LE, Molinoff PB, Ruddon RW,
Mayo Clin Proc, December 2001, Vol 76
4. 5. 6.
7.
Gilman AG, eds. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill; 1996:361396. Wasilewski D, Matsumoto H, Kur E, et al. Assessment of diazepam loading dose therapy of delirium tremens. Alcohol Alcohol. 1996; 31:273-278. Manikant S, Tripathi BM, Chavan BS. Loading dose diazepam therapy for alcohol withdrawal state. Indian J Med Res. 1993;98:170173. Saitz R, Mayo-Smith MF, Roberts MS, Redmond HA, Bernard DR, Calkins DR. Individualized treatment for alcohol withdrawal: a randomized double-blind controlled trial. JAMA. 1994;272:519523. Mayo-Smith MF, American Society of Addiction Medicine Working Group on Pharmacologic Management of Alcohol Withdrawal. Pharmacological management of alcohol withdrawal: a meta-analysis and evidence-based practice guideline. JAMA. 1997;278:144151.
In reply: Dr Hiraman and colleagues raise questions about the validity of our conclusions because of concerns about difference in care delivered to the pre- and postimplementation cohorts, the different types of benzodiazepines used, and the retrospective nature of the study. Symptom-triggered therapy involves much more than frequent dosing of benzodiazepines for patients experiencing AWS. Regular and frequent assessment of patient symptoms with use of validated symptom scoring tools, dosage of benzodiazepine based on symptoms, and careful attention to the overall medical condition of the patient by nursing and physician staff certainly contribute to the efficacy of STT. We agree that the postimplementation cohort received close monitoring as prescribed by a protocol of STT. Our hypothesis was that this regimen could benefit medical inpatients as has been shown in chemical dependency units.1 The data we presented supported our hypothesis given the limitations of a retrospective study. For ease of data collection, we defined dosage of benzodiazepine in terms of lorazepam equivalents. All benzodiazepine doses were equated to 1 mg of oral lorazepam; eg, 1 mg of oral lorazepam would be considered equivalent to 10 mg of oral diazepam. Our hospital pharmacy assisted us with these calculations and the table in question. The clinical effects of these dosage equivalents should be similar. As stated in our article, 97% of all doses in the preimplementation cohort and 99% of doses in the postimplementation cohort were chlordiazepoxide or lorazepam. The majority of the doses were orally administered although some patients received intravenous lorazepam. Hiraman et al correctly point out several potential flaws in our study inherent in any retrospective study. We attempted to state carefully that our conclusions were based on retrospective data and that any further conclusions about STT for AWS will require more study, ideally in a prospective, randomized fashion. Finally, Hiraman et al advocate use of intravenous diazepam for AWS as a preferred treatment. All benzodiazepines are considered appropriate treatment for AWS.1 Some authors advocate long-acting preparations to the exclusion of the
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
Letters to the Editor 1275
Letters to the Editor
Midodrine is one of the most effective vasoconstrictor drugs available.3,4 The example of our patient, to our knowledge the first of its kind, suggests that the drug should be administered with caution, particularly when it is reintroduced at its former dose. Paola Sandroni, MD, PhD Eduardo E. Benarroch, MD Eelco F. M. Wijdicks, MD Mayo Clinic Rochester, Minn
Caudate Hemorrhage as a Possible Complication of Midodrine-Induced Supine Hypertension To the Editor: Midodrine is an α1-adrenergic prodrug used widely to treat postural hypotension. Midodrine is well tolerated, but supine hypertension is a potentially serious adverse effect.1 We report caudate hemorrhage as a possible complication of midodrine-induced supine hypertension. Report of a Case.—A 66-year-old man presented with an 8-year history of impotence, constipation, and heat intolerance.. A tilt-table study revealed orthostatic hypotension (OH). Midodrine, 2.5 mg 3 times a day, was prescribed with good clinical response. Nine months later his hypotensive symptoms recurred. Midodrine was gradually titrated up to 10 mg 3 times a day because of its progressively shorter duration of effect. Fludrocortisone, 0.5 mg twice a day, was added to his treatment regimen. Supine hypertension was never documented despite frequent measurements with use of a portable device. Prior to autonomic testing, midodrine and fludrocortisone were discontinued for 48 hours, with worsening of OH. During testing, supine blood pressure (BP) was 156/74 mm Hg, and heart rate (HR) was 74 beats/min; on tilt, BP was 116/70 mm Hg, and HR, 82 beats/min. Test results indicated diffuse autonomic failure. Three hours later, at home, he complained of lightheadedness and nausea; subsequently, he vomited and collapsed for a few minutes. Assuming this event represented one of his usual hypotensive spells, his wife gave him 10 mg of midodrine, and within 30 minutes, he experienced a similar episode. On arrival at the emergency department, his supine BP was 210/96 mm Hg. His evaluation, including computed tomographic (CT) scan of the head, was unremarkable, and he was discharged to home. The next day he appeared “confused.” He restarted his medication regimen of midodrine, 10 mg 3 times a day, and fludrocortisone, 0.5 mg twice a day. Approximately 1 hour after his evening meal, he collapsed and remained drowsy, confused, and agitated with no focal signs. When he again arrived at the emergency department, his BP was 156/96 mm Hg. A CT scan showed a caudate hemorrhage. He recovered and again displayed OH. After administration of only 2.5 mg of midodrine, BP was 168/83 mm Hg in the sitting position. Comment.—This patient had been taking 10 mg of midodrine 3 times a day for 3 months without known supine hypertension. The progressive decrease in efficacy of midodrine may reflect α1-receptor desensitization.2 After resumption, midodrine may have acted on α 1-receptors resensitized after 48 hours of drug discontinuation, thus eliciting hypertension. Baroreflex failure may also have predisposed to this event, despite near-normal BP throughout the day. The location of the hemorrhage would fit this mechanism, but we acknowledge that the relationship remains uncertain. Mayo Clin Proc. 2001;76:1275-1279
1. 2. 3. 4.
Jacob G, Shannon JR, Black B, et al. Effects of volume loading and pressor agents in idiopathic orthostatic tachycardia. Circulation. 1997;96:575-580. Polinsky RJ, Kopin IJ, Ebert MH, Weise V. Pharmacologic distinction of different orthostatic hypotension syndromes. Neurology. 1981;31:1-7. Wright RA, Kaufmann HC, Perera R, et al. A double-blind, doseresponse study of midodrine in neurogenic orthostatic hypotension. Neurology. 1998;51:120-124. Low PA, Gilden JL, Freeman R, Sheng KN, McElligott MA, Midodrine Study Group. Efficacy of midodrine vs placebo in neurogenic orthostatic hypotension: a randomized, double-blind multicenter study [published correction appears in JAMA. 1997;278:388]. JAMA. 1997;277:1046-1051.
Symptom-Triggered Therapy for Alcohol Withdrawal Syndrome in Medical Inpatients To the Editor: We read with interest the recent article by Jaeger et al1 on alcohol withdrawal syndrome (AWS) in medical inpatients. Since treatment of alcohol withdrawal is a daily concern for many urban clinicians, the ramifications of this study are extensive.2 Although we agree with the authors’ conclusion that symptom-triggered therapy (STT) is effective for AWS, we are concerned that the study contains several methodologic flaws. Outcome measures in the study groups were compared from a retrospective chart review. The authors conclude that STT is effective because the postimplementation group had fewer complications and a decreased incidence of delirium tremens. However, the postimplementation group was monitored very closely, and the hospital staff was trained extensively in evaluating and treating AWS patients. Compared with the preimplementation group, the postimplementation group most likely received better benzodiazepine therapy in addition to all other aspects of care (intravenous fluids, antibiotics, etc). Furthermore, without the documentation of autonomic hyperactivity, the definition of delirium tremens used by the authors of “alcohol withdrawal accompanied by disorientation, agitation, and hallucinations” appears to be less than ideal and may have led to some inclusion bias. Their Table 1 attempts to equate varying doses and routes of administration of different benzodiazepines based on 1275
© 2001 Mayo Foundation for Medical Education and Research
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
1276
Letters to the Editor
lorazepam equivalents. All benzodiazepines vary in onset of action, anticonvulsant effect, duration of action, bioavailability (depending on route of administration), and presence of active metabolites.3 Are the benzodiazepine equivalents in the table based on plasma level of the drug, drug half-life, or simply clinical effect? There is no mention of whether this table takes into consideration any of these factors and if it is the foundation of the authors’ premise. Before a conclusion can be drawn with regard to the outcome differences in the preimplementation and postimplementation groups, a more accurate comparison of benzodiazepine equivalence must be established. We believe that STT is the best approach to the management of AWS and is previously well described.4,5 Based on the literature and our experience, we routinely recommend intravenous diazepam as the sole initial benzodiazepine for the treatment of AWS.6,7 Intravenous diazepam has a rapid onset of action, prolonged duration of effect due to presence of active metabolites, and guaranteed absorption. All other benzodiazepines lack a similar pharmacokinetic profile and should thus be considered inferior. The successful treatment of AWS requires intensive pharmacotherapy, monitoring, nutritional supplementation, and awareness of the precipitating event(s). As a result of this study, Jaeger et al demonstrate only that patients have better outcomes when they are frequently evaluated, receive medication, and have their medical issues addressed promptly. Because of the potential flaws in the study’s methods, it fails to provide sufficient evidence to justify the authors’ conclusion that symptomatic benzodiazepine therapy alone accounts for their important findings. Doodnauth Hiraman, MD New York University Bellevue Hospital Center New York, NY Mark Su, MD New York University Bellevue Hospital Center New York City Poison Control Center Mary Ann Howland, PharmD St John’s University College of Pharmacy Jamaica, NY Robert S. Hoffman, MD New York University Bellevue Hospital Center New York City Poison Control Center 1. 2. 3.
Jaeger TM, Lohr RH, Pankratz VS. Symptom-triggered therapy for alcohol withdrawal syndrome in medical inpatients. Mayo Clin Proc. 2001;76:695-701. Whiteman PJ, Hoffman RS, Goldfrank LR. Alcoholism in the emergency department: an epidemiologic study. Acad Emerg Med. 2000; 7:14-20. Hobbs WR, Rall TW, Verdoorn TA. Hypnotics and sedatives: ethanol. In: Hardman JG, Limbird LE, Molinoff PB, Ruddon RW,
Mayo Clin Proc, December 2001, Vol 76
4. 5. 6.
7.
Gilman AG, eds. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill; 1996:361396. Wasilewski D, Matsumoto H, Kur E, et al. Assessment of diazepam loading dose therapy of delirium tremens. Alcohol Alcohol. 1996; 31:273-278. Manikant S, Tripathi BM, Chavan BS. Loading dose diazepam therapy for alcohol withdrawal state. Indian J Med Res. 1993;98:170173. Saitz R, Mayo-Smith MF, Roberts MS, Redmond HA, Bernard DR, Calkins DR. Individualized treatment for alcohol withdrawal: a randomized double-blind controlled trial. JAMA. 1994;272:519523. Mayo-Smith MF, American Society of Addiction Medicine Working Group on Pharmacologic Management of Alcohol Withdrawal. Pharmacological management of alcohol withdrawal: a meta-analysis and evidence-based practice guideline. JAMA. 1997;278:144151.
In reply: Dr Hiraman and colleagues raise questions about the validity of our conclusions because of concerns about difference in care delivered to the pre- and postimplementation cohorts, the different types of benzodiazepines used, and the retrospective nature of the study. Symptom-triggered therapy involves much more than frequent dosing of benzodiazepines for patients experiencing AWS. Regular and frequent assessment of patient symptoms with use of validated symptom scoring tools, dosage of benzodiazepine based on symptoms, and careful attention to the overall medical condition of the patient by nursing and physician staff certainly contribute to the efficacy of STT. We agree that the postimplementation cohort received close monitoring as prescribed by a protocol of STT. Our hypothesis was that this regimen could benefit medical inpatients as has been shown in chemical dependency units.1 The data we presented supported our hypothesis given the limitations of a retrospective study. For ease of data collection, we defined dosage of benzodiazepine in terms of lorazepam equivalents. All benzodiazepine doses were equated to 1 mg of oral lorazepam; eg, 1 mg of oral lorazepam would be considered equivalent to 10 mg of oral diazepam. Our hospital pharmacy assisted us with these calculations and the table in question. The clinical effects of these dosage equivalents should be similar. As stated in our article, 97% of all doses in the preimplementation cohort and 99% of doses in the postimplementation cohort were chlordiazepoxide or lorazepam. The majority of the doses were orally administered although some patients received intravenous lorazepam. Hiraman et al correctly point out several potential flaws in our study inherent in any retrospective study. We attempted to state carefully that our conclusions were based on retrospective data and that any further conclusions about STT for AWS will require more study, ideally in a prospective, randomized fashion. Finally, Hiraman et al advocate use of intravenous diazepam for AWS as a preferred treatment. All benzodiazepines are considered appropriate treatment for AWS.1 Some authors advocate long-acting preparations to the exclusion of the
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.