Abstracts of Current Literature

Annals of Emergency Medicine

Acute Hypersensitivity Reactions Associated with Administration of Crotalidae Polyvalent Immune Fab Antivenom

Sheep-derived crotalidae polyvalent immune Fab (FabAV, CroFab™, Protherics, London) was approved by the United States Food and Drug Administration in 2000 as a safer alternative to the long used horse-serum-derived polyvalent antivenom. Multiple studies have shown its effectiveness; however, there has not been a randomized controlled trial showing its side effect profile since 2001. ¹ The earlier trial reported a 19% incidence of acute hypersensitivity reactions in all patients. The current study describes the incidence of hypersensitivity reactions now that CroFab™ is in mainstream use.

This nonconcurrent observational cohort study was conducted at Banner Good Samaritan Medical Center and Phoenix Children's Hospital from 2000 to 2004. Only those patients that received CroFab™ were included. The criteria for acute hypersensitivity included pruritic rash, urticaria, dyspnea, wheezing, angioedema, or hypotension that occurred with administration of antivenom. Ninety-three patients (including 20 pediatric patients) were included in the study. Only 5 patients (5.4%) had reported hypersensitivity reactions and 1 patient had a severe enough reaction that CroFab™ could not be restarted after treatment for allergic reaction and further dilution. Of the 5 patients, several received other medications, such as meperidine and morphine, that may have contributed to the hypersensitivity reactions but were included in the study for completeness.

This study is limited by its method of data collection and size. Undoubtedly, a retrospective chart review may miss some reactions that were not appropriately documented. In addition, at least 17 patients were pretreated with antihistamines, which possibly prevented some reactions. As well, a larger population of patients might show more severe reactions than were found in this relatively small population. However, this study does suggest that the number of hypersensitivity reactions with CroFab™ is smaller than previously reported and that they are uncommonly severe.

(Ann Emerg Med. 2008;51:407–411) R Cannon, A Ruha, J Kashani.

Prepared by Karen Nolan Kuehl, MD, FACEP

Carilion Emergency Medicine, Roanoke, VA, USA

Shock

HSD Is a Better Resuscitation Fluid for Hemorrhagic Shock with Pulmonary Edema at High Altitude

Most research concerning fluid resuscitation for traumatic shock has been completed at sea level and findings show that shock patients can typically handle threefold to fourfold volumes of crystalloid infusion during the resuscitation process. The same authors of this study have previously completed research showing that trauma patients at high altitudes can tolerate much less fluid resuscitation than at sea level, thought to be secondary to hypoxia and its resultant physiologic changes (higher pulmonary pressures, increased capillary permeability, and increased systemic inflammatory responses). ² The findings from the prior study indicated that 1 to 1.5 volumes of lactated Ringer's (LR) did somewhat resuscitate patients, but more than 2 volumes of LR actually would worsen the outcome. In the current study, the authors expanded their previous research to see if the use of hypertonic saline/6% dextran (HSD) would be a more effective resuscitative fluid in an animal model of hemorrhagic shock with pulmonary edema (HSPE).

In this animal study, 196 rats were transported to Lhasa, Tibet, at 3760 m above sea level. Part I of the experimental protocol included 77 rats that were divided into 11 groups of 7 rats: 3 control groups, groups with induced HSPE resuscitated by 0.5-, 1.0-, 1.5-, 2.0-, or 3.0-fold volumes of LR, and groups with induced HSPE resuscitated by 4, 6, and 8 mL/kg of HSD. Hemodynamic parameters, arterial blood gases, and water content of lung and brain were then followed in these groups. In part II of the protocol, 99 rats were divided into 11 groups of 9 rats with the same distribution of control and experimental groups as above. These rats were then followed for survival times.

Hemodynamic parameters, including mean arterial pressures, were slightly improved in those rats receiving 0.5 and 1.0 volumes of LR. However, all hemodynamic parameters were worsened in those rats receiving 1.5, 2.0, and 3.0 volumes of LR. Those HSPE rats receiving HSD had improved parameters, with 6 mL/kg having the best effects. Blood gases were not affected by 0.5 and 1.0 volumes of LR but were worsened by greater LR infusion. HSD in 4- and 6-mL/kg doses improved blood gases while 8 mL/kg increased acidosis. More than 1.0 volume of LR aggravated pulmonary edema exemplified by increased lung weights. HSD significantly decreased water content of the lung in HSPE rats (P < .01). Survival times were slightly improved with 0.5 volume LR, were not changed with 1 volume LR, and were worsened by more LR resuscitation. Four and 6 mL/kg of HSD significantly prolonged survival times.

This study is the first of its kind to show how much fluid can be tolerated by a patient with hemorrhagic shock and pulmonary edema. The data show that minimal resuscitation with LR may be somewhat helpful, but that amounts of LR typically used in resuscitation of hemorrhagic shock may be extremely harmful in patients at high altitude. HSD may be a much better alternative to LR in trauma patients at high altitude. Further guidelines will have to be developed for human use, but 4 to 6 mL/kg seems to be a reasonable starting point for resuscitation. The findings of this study will undoubtedly be helpful in high altitude medicine in the future, which will have implications for both mountaineers and the military.

(Shock. 2008;May 2:Epub ahead of print) LM Liu, DY Hu, XW Zhou, et al.

Prepared by Karen Nolan Kuehl, MD, FACEP

Carilion Emergency Medicine, Roanoke, VA, USA

Surgical Neurology

Barometric Changes in Patients with Intracranial Lesions: Can They Dive and Fly?

This short article developed as the result of a case study in which barometric changes might have led to focal neurologic changes and increased intracranial pressure. In the case study, a previously healthy 36-year-old male was diagnosed with a high-grade glioma after developing neurologic deficits after scuba diving to 18 m and flying in a commercial aircraft on a transatlantic flight. After encountering this case, the authors reviewed the literature on the possible risks of sudden changes in barometric pressure on cerebral pathology, such as tumors, aneurysms, colloid cysts, and multiple sclerosis.

Upon reviewing the literature, the authors were able to find 14 reported cases of neurological decompensation in patients with both diagnosed and undiagnosed neurosurgical conditions, including glioma, colloid cyst, meningioma, metastatic melanoma, multiple sclerosis, and hydrocephalus that had undergone the barometric stress of diving and/or flying. The subsequent signs and symptoms varied from headache and vomiting to coma and death and occurred soon after the patient underwent changes in barometric pressure.

Based on these cases, the authors recommend that those individuals with known cerebral lesions should be generally discouraged from activities such as flying, diving, and climbing because of the risk of decompensation. The conclusions are admittedly generic, and the authors state that individualized recommendations could be made based on an individual patient. An experimental model would be necessary to further delineate how these neurological conditions are specifically affected by barometric changes.

(Surg Neurol. 2008;January 18:Epub ahead of print) A Perin, F Larosa, P Longatti.

Prepared by Karen Nolan Kuehl, MD, FACEP

Carilion Emergency Medicine, Roanoke, VA, USA

Chest

Medication and Dosage Considerations in the Prophylaxis and Treatment of High-Altitude Illness

This article completes a thorough review of the current recommendations for pharmacologic management of high altitude illness. Importantly, the use of acetazolamide, dexamethasone, nifedipine, tadalafil, sildenafil, and salmeterol is considered in both healthy individuals and in those with renal insufficiency, hepatic insufficiency, pregnancy, and other serious medical conditions. In addition, these authors include possible interactions of these medications with commonly prescribed antimalarials and antibiotics used for traveler's diarrhea. Although this article is summarized below, many important details can be found in the article.

Acetazolamide (a carbonic anhydrase inhibitor) is currently recommended for the treatment and prevention of acute mountain sickness (AMS) and high altitude cerebral edema (HACE). Dosing for treatment is 250 mg twice daily, while dosing for prevention is 125 to 250 mg twice daily in healthy individuals. Patients with a glomerular filtration rate (GFR) of 10 to 50 mL/min should not take the medication more often than every 12 hours and those with a GFR of <10 mL/min should not use acetazolamide due to its renal clearance. In addition, acetazolamide should not be used in those with liver disease, with preexisting metabolic acidosis, with hypercalcemia or hyperphosphatemia, or with a history of nephrolithiasis. Caution should be used in those with chronic obstructive pulmonary disease or other ventilatory limitation, with a sulfa allergy, and in pregnant women (teratogenic in first trimester and can cause neonatal jaundice after 36 weeks of pregnancy). Due to impairment of elimination, acetazolamide should not be used in those receiving long-term high doses of aspirin. Significant interactions can occur with topiramate, carbemazepine, diuretics, and digoxin.

Dexamethasone is recommended as an alternative to acetazolamide in the treatment and prevention of AMS and is the primary treatment of HACE. Dexamethasone does not facilitate acclimatization. Recommended dosing for prevention of AMS is 2 mg every 6 hours or 4 mg every 12 hours. Treatment dosing for AMS is 4 mg every 6 hours and 8 mg initially followed by 4 mg every 6 hours for HACE. Dexamethasone is a good alternative to acetazolamide for patients with renal and hepatic insufficiency and does not require dose adjustment in these individuals. However, dexamethasone must be used carefully in those with diabetes (risk of hyperglycemia), those with amebiasis or strongyloidiasis, and in those with active peptic ulcer disease or recent gastrointestinal bleeding. Effectiveness of dexamethasone can be decreased in those on carbemazepine, phenytoin, or phenobarbital due to increased corticosteroid metabolism. There is theoretical risk of tendon rupture with the concomitant use of corticosteroids and fluoroquinolones (commonly used in treatment of traveler's diarrhea).

Nifedipine is a calcium-channel antagonist used to treat high altitude pulmonary edema (HAPE). Dosing for prevention and treatment of HAPE is 20 to 30 mg of sustained-release nifedipine every 12 hours. It can be used without dose adjustment in those with renal insufficiency. Due to the potential for accumulation of the medication in those with hepatic insufficiency, it is recommended to half the dose to 10 mg every 12 hours. Based on new data, nifedipine can be used in those with stable coronary artery disease, but the authors recommend thorough evaluation of these patients prior to ascent to altitude. Nifedipine does have significant drug interactions, including reduced effectiveness when combined with any inducers of the P450 pathway (rifampin, phenobarbital, phenytoin, carbemazepine) and increased concentrations when used with any inhibitors of the P450 pathway (protease inhibitors, doxycycline, macrolide antibiotics). The combined effect of nifedipine and beta-blockers may be hypotension, and users of nifedipine should avoid grapefruit juice. Ginkgo biloba should not be used with nifedipine, and anti-inflammatories should be minimized to reduce the risk of gastrointestinal bleeding.

The phosphodiesterase inhibitors, tadalafil and sildenafil, have been suggested in the prevention but not treatment of HAPE. Dosing for tadalafil is 10 mg twice daily and for sildenafil is 50 mg every 8 hours for the prevention of HAPE. Patients with creatinine clearance of 30 to 50 mL/min should receive no more than 5 mg/day. The pharmacokinetics of sildenafil are similar. The overall recommendation is limited use of these medications in those with moderate to severe renal insufficiency. Although the phosphodiesterase inhibitors can be used in patients with hepatic insufficiency, close consultation with a physician should occur due to the potential risk of variceal hemorrhage in these patients. Those with a history of coronary artery disease who take nitrates should not use these medications. There is a risk of postural hypotension when combined with alpha-blocker medications such as doxazosin, terazosin, or prazosin.

Finally, salmeterol has been used in combination with nifedipine to prevent HAPE in known susceptible individuals. Dosing is 125 mg twice daily (inhaled). There are no dose adjustments suggested for those with renal insufficiency, but salmeterol should not be used in those with hepatic insufficiency. Salmeterol should not be used in those with a history of cardiac disease or those with a history of tachyarrhythmias. Potentially dangerous drug interactions can occur with monoamine oxidase inhibitors and tricyclic antidepressants.

This article is a solid review of the common pharmacologic treatments for high altitude illness. Not only does it provide important dosing recommendations, but it also reminds the reader that slow ascent is important, as is medical clearance for all individuals with disease planning to travel to altitude.

(Chest. 2008;133:744–755) AM Luks, ER Swenson.

Prepared by Karen Nolan Kuehl, MD, FACEP

Carilion Emergency Medicine, Roanoke, VA, USA

Cardiology

High Altitude Arrhythmias

Between 1826 and 1834 on the crest of the Peruvian Cordilileras, the explorer D’Orbigny is quoted in this article as saying “at the least movement, I felt violent palpitations.” Since that time, the studies that have attempted to provide evidence regarding risk of ischemia and arrhythmia at high altitude have not been congruent with the rate of sudden cardiac death at altitude. The authors of this study sought to establish the previously undetermined nature of palpitations at high altitude and incidence of ischemia and arrhythmia using an implantable electrocardiogram (ECG) recorder during ascent to high altitude.

Nine healthy male volunteers, who were not experienced climbers, aged 29.9 ± 5.2 years, had normal cardiovascular examinations, 12-lead ECG, 2-dimensional cardiac echocardiogram, and achieved at least stage 5 of the Bruce protocol without abnormality pre-expedition. Implantable loop recorders (ILR) were used to record any episode of palpitations during exercise, rest, and sleep. Arterial oxygen saturation was assessed and altitude was measured concomitant with ILR activation. Participants flew to Kathmandu (elevation 1250 m) and then to the town of Lukla (elevation 2800 m) before immediately commencing identical ascent and descent profiles. The volunteers acted as their own controls in this study in 2 ways. First, prior to ascent volunteers exerted themselves to exhaustion at sea level during an exercise test and none demonstrated arrhythmias on continuous ECG monitoring. Second, after insertion of the ILRs and prior to departure for Nepal, the volunteers underwent severe exertion at minor altitude (978–1344 m) with no arrhythmias recorded.

Two hundred sixty-three ECG recordings were made, 29.2 ± 2.6 per volunteer. Among the findings, all volunteers experienced palpitations above 5000 m, with 2 symptomatic episodes at rest (5600 m and 6300 m). All symptomatic recordings were found to correlate with sinus tachycardia. One volunteer had an episode of asymptomatic atria flutter with 2:1 conduction for 8.5 minutes following severe exertion at 4500 m (SaO₂ 76%). All volunteers had sinus arrhythmias with non-conducted entopic p-waves during sleep recordings. During exercise at 6300 m, 1 volunteer had dramatic ST segment depression (SaO₂ 59%), consistent with cardiac ischemia. In general, the quality of the ECG tracings obtained was excellent, with clear morphological discrimination of all components of the ECG.

This study demonstrated the feasibility of using an ILR to record ECGs at altitude. In this series, 99.2% of the tracings obtained could be reliably interpreted, even during adverse conditions such as extreme altitude, extreme temperature, and during exercise. Previous findings demonstrated at altitude were corroborated by this study. Heart rate at altitude increases progressively at rest and during exercise, likely a consequence of hypoxic pulmonary hypertension combined with neurohumoral mechanisms such as sympathetic stimulation resulting from hypoxia and exertion. While sinus arrhythmias have been previously demonstrated during sleep at altitude, this is the first observation during exercise. Previous studies have demonstrated periodic breathing causing sinus arrhythmia during sleep at altitude, and this may be the cause of the sinus arrhythmia observed in the 1 volunteer during exercise. Though it is not possible to identify the mechanism triggering the 1 episode of atrial tachycardia observed in this study, it is possible that atrial myocardial ischemia (SaO₂ as low as 59%) with increased sympathetic activity may have precipitated the event. The authors propose that those with underlying coronary artery disease may be at risk for a potentially life-threatening ventricular arrhythmia due to ventricular myocardial ischemia and pulmonary hypertension at altitude. There is a recognized association between ventricular arrhythmias and sympathetic activation at altitude, especially in patients with known cardiac disease. Since the elderly account for 15% of the 100 million visitors to altitude annually, the authors recommend further evaluation.

(Cardiology. 2008;111:239–246) DR Woods, S Allen, TR Betts, et al.

Prepared by Adrian Flores, MS3M

Louisiana State University Health Sciences Center, New Orleans, LA, USA