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Pharmacologic Prevention for Acute Mountain Sickness—Lack of Appropriate Inclusion of the Available Evidence
Correspondence 1. Menditto VG, Lucci M, Polonara S, et al. Management of minor head injury in patients receiving oral anticoagulant therapy: a prospective study of a 24-hour observation protocol. Ann Emerg Med. 2012;59:451-455. 2. Kaen A, Jimenez-Roldan L, Arrese I, et al. The value of sequential computed tomography scanning in anticoagulated patients suffering from minor head injury. J Trauma. 2010;68:895-898. 3. Peck KA, Sise CB, Shackford SR, et al. Delayed intracranial hemorrhage after blunt trauma: are patients on preinjury anticoagulants and prescription antiplatelet agents at risk? J Trauma. 2011;71:1600-1604. 4. Itshayek E, Rosenthal G, Fraifeld S, et al. Delayed posttraumatic acute subdural hematoma in elderly patients on anticoagulation. Neurosurgery. 2006;58:E851-856; discussion E851– 856. 5. Volans AP. The risks of minor head injury in the warfarinised patient. J Accid Emerg Med. 1998;15:159-161.
In reply: Shah et al1 emphasize that the number of patients needed to observe, admit, and reimage to identify 1 patient requiring neurosurgical intervention was high in our study (97), limiting the clinical significance and influence of our results. However, only 33 patients had to undergo this process. Moreover, even if less clinically relevant, 19 subjects had to be evaluated to identify 1 patient with any delayed intracranial hemorrhage. Regardless, the number needed to treat, harm, or observe is just a number. According to Plato,2 mathematical entities are “intermediate” between the intelligible and sensible world. Thus, it is the clinician’s responsibility to integrate the numbers coming from scientific articles into daily medical practice. We believe that in an age of growing litigation, knowing whether our patients have an intracranial hemorrhage, even a minor one, is of paramount importance. Emergency clinicians face a similar situation every day when they treat patients with chest pain. Serial troponin measurements have been evaluated as part of an algorithm for early discharge after ruling out acute coronary syndrome in the emergency department.3 These studies show that a second level increased the sensitivity of the test from 95% to 96%, to 97% to 98% in identifying patients with “minor” infarctions.2 Whether this marginal advantage for patients (and clinicians) is worth the cost is going to be an endless debate. In the same way, our protocol could be used to rule out early and delayed, and sometimes “minor,” intracranial hemorrhage after head injury in anticoagulated patients. In our work, we identified 6 patients with delayed intracranial bleeding without indication for immediate neurosurgical intervention. The optimal management of these patients is still unclear.4 The majority of studies suggest that early follow-up computed tomography (CT) imaging is not routinely indicated, even in presence of intracranial hemorrhage.5 However, there are no data about the long-term follow-up of these patients, particularly if anticoagulated. Therefore, in our opinion, the observation that our 6 patients remained well 30 days after head injury is of interest. It would not have been possible to extract these data if a second CT scan not been performed for all our patients. 538 Annals of Emergency Medicine
We think that our study shed some light into the grey area of guidelines on minor head injury, and it has highlighted some aspects about management of minor head injury in anticoagulated patients, in particular identifying a subset of patients who are at high risk of delayed intracranial bleeding (initial international normalized ratio ⱖ3). These results have been recently confirmed.6 We believe that further investigations are needed to better characterize high-risk patients who could benefit from a more intensive algorithm, including 24-hour observation, a repeated CT scan before discharge, and a repeated visit 3 days after the trauma. Vincenzo G. Menditto, MD Stefano Polonara, MD Emergency Department Ospedali Riuniti di Ancona Ancona, Italy Moira Lucci, MD Giovanni Pomponio, MD Armando Gabrielli, MD Department of Internal Medicine Università Politecnica delle Marche Ancona, Italy doi:10.1016/j.annemergmed.2012.03.010
Funding and support: By Annals policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article as per ICMJE conflict of interest guidelines (see www.icmje.org). The authors have stated that no such relationships exist. 1. Kaushal HS, Ali SR, Newman DH. Repeat CTs – Let’s use our heads. Ann Emerg Med. 2012;60:537-538. ´ ⌸␣ ´ ). 2. (Plato) The Republic (⌸␣ 3. Aldous SJ, Richards M, Cullen L, et al. Diagnostic and prognostic utility of early measurement with high-sensitivity troponin T assay in patients presenting with chest pain. CMAJ. 2012 Jan 30. [Epub ahead of print]. 4. Wang MC, Linnau KF, Tirschwell DL, et al. Utility of repeat head computed tomography after blunt head trauma: a systematic review. J Trauma. 2006;61:226-233. 5. Smith JS, Chang EF, Rosenthal G, et al. The role of early follow-up computed tomography imaging in the management of traumatic brain injury patients with intracranial hemorrhage. J Trauma. 2007; 63:75-82. 6. Claudia C, Claudia R, Agostino O, et al. Minor head injury in warfarinized patients: indicators of risk for intracranial hemorrhage. J Trauma. 2011;70:906-909.
Pharmacologic Prevention for Acute Mountain Sickness—Lack of Appropriate Inclusion of the Available Evidence To the Editor: The Seupaul et al1 systematic shortcut review of pharmacologic prophylaxis for acute mountain sickness is a timely literature Volume , . : October
Correspondence review, and we applaud the authors’ support of expert consensus2,3 advocating lower-dose acetazolamide for acute mountain sickness (AMS) prevention. However, there are inconsistencies in study selection and several interpretation errors that need addressing. First, we disagree with the authors’ depiction of the Headache Evaluation at Altitude Trial (HEAT)4 methodology as “significantly flawed.” Enrollment in the placebo arm was limited by minimizing the number of placebo allotments because efficacy of acetazolamide relative to placebo had been established at identical altitudes. In the setting of a prospective, randomized, double-blind, placebo-controlled trial, a deleterious “effect on randomization or concealment” would be negligible. Furthermore, the results were analyzed to exclude anyone who may have consumed crossover medications; refer to Table 3 in the HEAT article, where this analysis resulted in significance for both primary and secondary outcomes. Participants did not “receive” nonprotocol medications; rather, this clinical study enrolled trekkers in a high-altitude environment who chose to receive medicines on their own recognizance. Second, high-altitude headache is the cornerstone of AMS symptomatology, occurring with enough frequency that it has been defined as a separate entity. HEAT was powered to detect differences between preventive treatments as small as 12% to prevent high-altitude headache, the primary outcome. The primary outcome is defined by the World Health Organization as “the outcome used to determine the effects of the intervention.”5 Similarly, the Jafarian et al study had headache at high altitude, not AMS, as its primary outcome. Including a study’s secondary outcome in a systematic review of studies powered for primary outcomes is inconsistent and, without clarification, could lead to inappropriate conclusions. If studies with secondary outcomes were to be included, HEAT had the largest cohort (N⫽97) of any of the studies evaluating lower-dose acetazolamide (⬇250 mg daily), resulting in 15.4% incidence of AMS versus 34.1% in the placebo group, which was statistically significant and contributes to the reviewers’ conclusions. Last, when comparing AMS prevention studies with differing methodologies, there is inherent heterogeneity and an important limitation, the ascent rate. The rate of ascent to high altitude is arguably the greatest risk factor in determining AMS susceptibility. Comparison between studies with ascent rates ranging from 354 to 1,900 m/day will have disparate penetrance of disease, and implying similar efficacy between medications may be misleading. A critic of this approach stated, “if the rate of ascent is not controlled between studies then the comparisons are not valid.”2 Although we welcome critical reviews of wilderness medicine and fully support lower-dose acetazolamide for AMS prevention, caution is warranted in translating systematic review recommendations to the clinical milieu of high-altitude travel. Grant S. Lipman, MD Division of Emergency Medicine Stanford University School of Medicine Stanford, CA Volume , . : October
Jeffrey H. Gertsch, MD Department of Neurosciences University of California San Diego School of Medicine San Diego, CA http://dx.doi.org/10.1016/j.annemergmed.2012.03.034
Funding and support: By Annals policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article as per ICMJE conflict of interest guidelines (see www.icmje.org). The authors have stated that no such relationships exist. 1. Seupaul RA, Welch JL, Malka ST, et al. Pharmacologic prophylaxis for acute mountain sickness: a systematic shortcut review. Ann Emerg Med. 2012;59:307. 2. Hackett P. Pharmacologic prevention of acute mountain sickness. BMJ. 2001;322:48. 3. Luks AM, McIntosh SE, Grissom CK, et al. Wilderness Medical Society consensus guidelines for the prevention and treatment of acute altitude illness. Wilderness Environ Med. 2010;21:146-155. 4. Gertsch JH, Lipman GS, Holck PS, et al. Prospective, double blind, randomized, placebo controlled comparison of acetazolamide versus ibuprofen for prophylaxis against high altitude headache: the Headache Evaluation at Altitude Trial (HEAT). Wilderness Environ Med. 2010;21:236-243. 5. International Clinical Trials Registry Platform. Available at: http:// www.who.int/ictrp/network/trds/en/index.html. Accessed March 18, 2012.
Ethylene Glycol Elimination Kinetics and Outcomes in Patients Managed Without Hemodialysis To the Editor: In the article by Levine et al,1 the authors used retrospective data to determine the elimination half-life of ethylene glycol, as well as report mortality and the development of renal failure when fomepizole was used as monotherapy, without hemodialysis. They stated that an average of 4 doses of fomepizole was administered per patient and calculated a mean elimination half-life of 14.2 hours. It is unclear whether the elimination half-life of serum ethylene glycol was calculated with serum assay samples taken after fomepizole was discontinued. If this were the case, this would have reduced the calculated half-life. In their work, the authors defined renal failure as a serum creatinine level greater than an absolute value of 1.6 mg/dL. This definition is problematic because the patients’ baseline renal function was either unknown or never stated. Also, this definition may miss patients with significant relative increases in baseline serum creatinine level if their final creatinine level is less than 1.6 mg/dL. In addition, the authors stated that 1 patient developed renal “insufficiency,” with a creatinine level of 2.1 mg/dL, whereas they defined renal “failure” as a creatinine level greater than 1.5 mg/dL. They further stated that this patient recovered without Annals of Emergency Medicine 539
In reply: Shah et al1 emphasize that the number of patients needed to observe, admit, and reimage to identify 1 patient requiring neurosurgical intervention was high in our study (97), limiting the clinical significance and influence of our results. However, only 33 patients had to undergo this process. Moreover, even if less clinically relevant, 19 subjects had to be evaluated to identify 1 patient with any delayed intracranial hemorrhage. Regardless, the number needed to treat, harm, or observe is just a number. According to Plato,2 mathematical entities are “intermediate” between the intelligible and sensible world. Thus, it is the clinician’s responsibility to integrate the numbers coming from scientific articles into daily medical practice. We believe that in an age of growing litigation, knowing whether our patients have an intracranial hemorrhage, even a minor one, is of paramount importance. Emergency clinicians face a similar situation every day when they treat patients with chest pain. Serial troponin measurements have been evaluated as part of an algorithm for early discharge after ruling out acute coronary syndrome in the emergency department.3 These studies show that a second level increased the sensitivity of the test from 95% to 96%, to 97% to 98% in identifying patients with “minor” infarctions.2 Whether this marginal advantage for patients (and clinicians) is worth the cost is going to be an endless debate. In the same way, our protocol could be used to rule out early and delayed, and sometimes “minor,” intracranial hemorrhage after head injury in anticoagulated patients. In our work, we identified 6 patients with delayed intracranial bleeding without indication for immediate neurosurgical intervention. The optimal management of these patients is still unclear.4 The majority of studies suggest that early follow-up computed tomography (CT) imaging is not routinely indicated, even in presence of intracranial hemorrhage.5 However, there are no data about the long-term follow-up of these patients, particularly if anticoagulated. Therefore, in our opinion, the observation that our 6 patients remained well 30 days after head injury is of interest. It would not have been possible to extract these data if a second CT scan not been performed for all our patients. 538 Annals of Emergency Medicine
We think that our study shed some light into the grey area of guidelines on minor head injury, and it has highlighted some aspects about management of minor head injury in anticoagulated patients, in particular identifying a subset of patients who are at high risk of delayed intracranial bleeding (initial international normalized ratio ⱖ3). These results have been recently confirmed.6 We believe that further investigations are needed to better characterize high-risk patients who could benefit from a more intensive algorithm, including 24-hour observation, a repeated CT scan before discharge, and a repeated visit 3 days after the trauma. Vincenzo G. Menditto, MD Stefano Polonara, MD Emergency Department Ospedali Riuniti di Ancona Ancona, Italy Moira Lucci, MD Giovanni Pomponio, MD Armando Gabrielli, MD Department of Internal Medicine Università Politecnica delle Marche Ancona, Italy doi:10.1016/j.annemergmed.2012.03.010
Funding and support: By Annals policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article as per ICMJE conflict of interest guidelines (see www.icmje.org). The authors have stated that no such relationships exist. 1. Kaushal HS, Ali SR, Newman DH. Repeat CTs – Let’s use our heads. Ann Emerg Med. 2012;60:537-538. ´ ⌸␣ ´ ). 2. (Plato) The Republic (⌸␣ 3. Aldous SJ, Richards M, Cullen L, et al. Diagnostic and prognostic utility of early measurement with high-sensitivity troponin T assay in patients presenting with chest pain. CMAJ. 2012 Jan 30. [Epub ahead of print]. 4. Wang MC, Linnau KF, Tirschwell DL, et al. Utility of repeat head computed tomography after blunt head trauma: a systematic review. J Trauma. 2006;61:226-233. 5. Smith JS, Chang EF, Rosenthal G, et al. The role of early follow-up computed tomography imaging in the management of traumatic brain injury patients with intracranial hemorrhage. J Trauma. 2007; 63:75-82. 6. Claudia C, Claudia R, Agostino O, et al. Minor head injury in warfarinized patients: indicators of risk for intracranial hemorrhage. J Trauma. 2011;70:906-909.
Pharmacologic Prevention for Acute Mountain Sickness—Lack of Appropriate Inclusion of the Available Evidence To the Editor: The Seupaul et al1 systematic shortcut review of pharmacologic prophylaxis for acute mountain sickness is a timely literature Volume , . : October
Correspondence review, and we applaud the authors’ support of expert consensus2,3 advocating lower-dose acetazolamide for acute mountain sickness (AMS) prevention. However, there are inconsistencies in study selection and several interpretation errors that need addressing. First, we disagree with the authors’ depiction of the Headache Evaluation at Altitude Trial (HEAT)4 methodology as “significantly flawed.” Enrollment in the placebo arm was limited by minimizing the number of placebo allotments because efficacy of acetazolamide relative to placebo had been established at identical altitudes. In the setting of a prospective, randomized, double-blind, placebo-controlled trial, a deleterious “effect on randomization or concealment” would be negligible. Furthermore, the results were analyzed to exclude anyone who may have consumed crossover medications; refer to Table 3 in the HEAT article, where this analysis resulted in significance for both primary and secondary outcomes. Participants did not “receive” nonprotocol medications; rather, this clinical study enrolled trekkers in a high-altitude environment who chose to receive medicines on their own recognizance. Second, high-altitude headache is the cornerstone of AMS symptomatology, occurring with enough frequency that it has been defined as a separate entity. HEAT was powered to detect differences between preventive treatments as small as 12% to prevent high-altitude headache, the primary outcome. The primary outcome is defined by the World Health Organization as “the outcome used to determine the effects of the intervention.”5 Similarly, the Jafarian et al study had headache at high altitude, not AMS, as its primary outcome. Including a study’s secondary outcome in a systematic review of studies powered for primary outcomes is inconsistent and, without clarification, could lead to inappropriate conclusions. If studies with secondary outcomes were to be included, HEAT had the largest cohort (N⫽97) of any of the studies evaluating lower-dose acetazolamide (⬇250 mg daily), resulting in 15.4% incidence of AMS versus 34.1% in the placebo group, which was statistically significant and contributes to the reviewers’ conclusions. Last, when comparing AMS prevention studies with differing methodologies, there is inherent heterogeneity and an important limitation, the ascent rate. The rate of ascent to high altitude is arguably the greatest risk factor in determining AMS susceptibility. Comparison between studies with ascent rates ranging from 354 to 1,900 m/day will have disparate penetrance of disease, and implying similar efficacy between medications may be misleading. A critic of this approach stated, “if the rate of ascent is not controlled between studies then the comparisons are not valid.”2 Although we welcome critical reviews of wilderness medicine and fully support lower-dose acetazolamide for AMS prevention, caution is warranted in translating systematic review recommendations to the clinical milieu of high-altitude travel. Grant S. Lipman, MD Division of Emergency Medicine Stanford University School of Medicine Stanford, CA Volume , . : October
Jeffrey H. Gertsch, MD Department of Neurosciences University of California San Diego School of Medicine San Diego, CA http://dx.doi.org/10.1016/j.annemergmed.2012.03.034
Funding and support: By Annals policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article as per ICMJE conflict of interest guidelines (see www.icmje.org). The authors have stated that no such relationships exist. 1. Seupaul RA, Welch JL, Malka ST, et al. Pharmacologic prophylaxis for acute mountain sickness: a systematic shortcut review. Ann Emerg Med. 2012;59:307. 2. Hackett P. Pharmacologic prevention of acute mountain sickness. BMJ. 2001;322:48. 3. Luks AM, McIntosh SE, Grissom CK, et al. Wilderness Medical Society consensus guidelines for the prevention and treatment of acute altitude illness. Wilderness Environ Med. 2010;21:146-155. 4. Gertsch JH, Lipman GS, Holck PS, et al. Prospective, double blind, randomized, placebo controlled comparison of acetazolamide versus ibuprofen for prophylaxis against high altitude headache: the Headache Evaluation at Altitude Trial (HEAT). Wilderness Environ Med. 2010;21:236-243. 5. International Clinical Trials Registry Platform. Available at: http:// www.who.int/ictrp/network/trds/en/index.html. Accessed March 18, 2012.
Ethylene Glycol Elimination Kinetics and Outcomes in Patients Managed Without Hemodialysis To the Editor: In the article by Levine et al,1 the authors used retrospective data to determine the elimination half-life of ethylene glycol, as well as report mortality and the development of renal failure when fomepizole was used as monotherapy, without hemodialysis. They stated that an average of 4 doses of fomepizole was administered per patient and calculated a mean elimination half-life of 14.2 hours. It is unclear whether the elimination half-life of serum ethylene glycol was calculated with serum assay samples taken after fomepizole was discontinued. If this were the case, this would have reduced the calculated half-life. In their work, the authors defined renal failure as a serum creatinine level greater than an absolute value of 1.6 mg/dL. This definition is problematic because the patients’ baseline renal function was either unknown or never stated. Also, this definition may miss patients with significant relative increases in baseline serum creatinine level if their final creatinine level is less than 1.6 mg/dL. In addition, the authors stated that 1 patient developed renal “insufficiency,” with a creatinine level of 2.1 mg/dL, whereas they defined renal “failure” as a creatinine level greater than 1.5 mg/dL. They further stated that this patient recovered without Annals of Emergency Medicine 539