Abstract
American Journal of Respiratory and Critical Care Medicine
Acetazolamide: A Treatment for Chronic Mountain Sickness
Chronic mountain sickness (CMS), also known as Monge disease, is characterized by excessive polycythemia with hemoglobin greater than 21 g·dL−1. According to this study, CMS is found in 5% to 18% of high-altitude dwellers who live higher than 3200 m. Clinical signs and symptoms include fatigue, headache, dyspnea, and digestive problems and can eventually result in heart failure and neurologic disorders such as stroke. Although 3 drugs (medroxyprogesterone, enalapril, and almitrine) have been used to treat the disorder, the only truly effective treatments are blood letting or moving to lower altitudes. The pathophysiology of the disorder is thought to be a decreased ventilatory response to hypoxia resulting in hypoventilation, which leads to excessive hypoxemia and resultant exaggerated erythropoiesis. This study examined the use of acetazolamide in CMS patients with the hypothesis that acetazolamide would decrease erythropoietin (EPO) by stimulation of ventilation, as well as by indirect effect of the medication on EPO production in the renal tubule.
The double-blind, placebo-controlled study included 30 high-altitude patients, with 10 receiving acetazolamide 250 mg daily, 10 receiving acetazolamide 500 mg daily, and 10 receiving daily placebo. Baseline hematocrit was a minimum of 60%. A group of 10 subjects without CMS served as controls. Patients wore a nighttime recording system that measured ventilation, episodes of apneas and hypopneas, and oxygen saturation. Blood samples were taken each morning to follow hematocrit, transferrin receptors, ferritin, and EPO levels.
At the minimum dose, acetazolamide increased nocturnal arterial oxygen saturation by 5% (P < .05) and decreased the number of apnea-hypopnea episodes by 74% (P < .05). Acetazolamide 250 mg and 500 mg decreased hematocrit by 7.1% (P < .001) and 6.7% (P < .001), serum EPO by 67% (P < .01) and 50% (P < .001), and serum transferrin receptors by 11.1% (P < .05) and 3.4% (P < .001) and increased serum ferritin by 540% (P < .001) and 134% (P < .001). There was no improved effect with the larger dose of acetazolamide. The side effect profile was minimal, with adverse effects including diuresis, paresthesias, and altered taste of carbonated beverages.
Chronic mountain sickness may affect up to 50 000 individuals in the areas around La Paz alone and is also a significant problem for other areas in South America and the Himalayan region. A low-cost alternative to phlebotomy or moving to lower altitude would be a welcome addition to the medical community of these regions. This study showed a significant improvement in hematocrit and EPO levels after only 3 weeks of treatment and is the first study to suggest that acetazolamide could be used to treat CMS, after being used for years as a treatment for acute mountain sickness.
(Am J Respir Crit Care Med. 2005;172:1427–1433) J Richalet, M Rivera, P Bouchet, et al. Prepared by Karen Nolan Kuehl, MD, FACEP, Oregon Health & Science University, Portland, OR, USA
The Journal of Trauma
An Open-Label Study to Evaluate the Safety and Efficacy of Tissue Plasminogen Activator in Treatment of Severe Frostbite
Severe frostbite causes limb and digit loss by the direct mechanism of ice crystallization within cells as well as indirect damage caused by thrombosis of damaged vasculature. Standard treatment of frostbite is rapid rewarming and elevation and padding of the damaged limbs and digits. Although rapid rewarming may reverse ice formation within cells, it does not effectively prevent or reverse the damage secondary to thrombosis. In this study, physicians in Minnesota hypothesized that the addition of thrombolytic therapy with tissue plasminogen activator (tPA) followed by heparin might effectively preserve limbs and digits injured by severe frostbite.
Sixteen patients with severe frostbite of 22 feet and 14 hands from 1985 to 1989 served as historical controls and did not receive thrombolytics (they received only standard, conservative care). These patients underwent Tc-99m MDP triple-phase bone scintiscans, which included blood flow studies and delayed images. Between 1989 and 1997, a total of 19 patients were included in the study if they met the following inclusion criteria: no improvement with rapid rewarming in tepid water, absent Doppler pulses in limbs or digits, and no perfusion on Tc-99m triple-phase bone scan. Exclusion criteria included severe hypertension, pregnancy, recent trauma or bleeding, recent stroke, mental incapacity, drug or alcohol intoxication, repeated freeze-thaw cycles, or more than 48 hours of exposure. The first 6 frostbite patients, from 1989 to 1994, received intra-arterial tPA at a dosage of 0.075 mg kg−1·h−1 for 6 hours. The dosage was repeated once in those who had no improvement seen on repeat scintiscan. The next 13 patients, from 1995 to 2003, received intravenous tPA with an initial 0.15 mg·kg−1 intravenous bolus followed by 0.15 mg kg−1·h−1 over 6 hours (up to 100 mg). After the infusion, the intravenous patients received heparin until PTT was twice the control and then took warfarin for 4 weeks.
Seven of the 16 control patients who had minimal or no perfusion distal to a vascular cutoff point on the delayed scintiscan images required subsequent amputation at that vascular cutoff point. On the basis of these early cases, the physicians theorized that scintiscans were accurate predictors of the future amputation level and that routine frostbite care did not seem to alter the predicted level of amputation. However, 16 of 19 patients given tPA either intra-arterially or intravenously responded to treatment, and only 33 of 174 severely frostbitten digits required amputation (10 digits were from 1 patient who required bilateral below-the-knee amputations, and another patient lost multiple digits). Two of the 6 intra-arterial patients did have bleeding complications that included bleeding from an arterial puncture site and hematuria. There were no reported complications in the group receiving intravenous heparin.
On the basis of the above results, the authors published a suggested treatment algorithm: 1) rapid rewarming, 2) assess clinical appearance, 3) early phase Tc-99m scintiscan to assess distal circulation, 4) patients with digits or limbs showing no flow are candidates for intravenous tPA (if no contraindications), 5) tPA at 0.15 mg·kg−1 intravenous bolus followed by 0.15 mg·kg−1·h−1 to maximum dose 100 mg over 4 to 6 hours, 6) therapeutic heparin for 3 to 5 days, 7) warfarin to INR 2 times control for 4 weeks, 8) pain management as needed, 9) ibuprofen 400 to 600 mg orally 4 times daily, 10) light dressings with topical antimicrobials, and 11) no ambulation on frostbitten feet. Additional studies are planned with aspirin as opposed to ibuprofen and warfarin.
(J Trauma. 2005;59:1350–1355) JA Twomey, GL Peltier, and RT Zera. Prepared by Karen Nolan Kuehl, MD, FACEP, Oregon Health & Science University, Portland, OR, USA
Pediatrics
Effect of Altitude on Hospitalizations for Respiratory Syncytial Virus Infection
Respiratory syncytial virus (RSV) is a common respiratory pathogen that annually infects 64 million people around the world, leading to 160 000 deaths. An adult infected with RSV will usually experience only a mild “coldlike” illness, with rare lingering effects. On the other hand, RSV is much more serious in children and is known to cause myriad respiratory disorders; in fact, RSV is the number-one cause of pneumonia and bronchiolitis in pediatric populations. Numerous medical, social, and environmental risk factors for RSV have been elucidated. Much remains unknown, however, including the effect of high altitude on the severity of RSV infections. The authors hypothesize that physiological responses to altitude will predispose children to more severe illness from RSV infections than infants, leading to more RSV hospitalizations at higher altitudes.
This retrospective case control study extracted hospitalization data for children younger than 5 years old residing in the state of Colorado. Patients’ ages, home zip codes, and ICD-9 codes were collected. Only patients under 5 years with RSV-related admission codes during the 1998 to 2002 seasons were used as cases in this study. Cases were then stratified by age into 2 groups: less than 1 year vs 1 to 4 years. These data were overlaid by Geographical Information System calculations of patients’ home zip code altitudes. Three categories of residential altitude were used: low (<1500 m), moderate (1500–2500 m), and high (>2500 m). Potential confounders related to differences in population demographics were identified and addressed by adjusted statistical models.
The highest rate of hospitalization for RSV diagnosis was seen with infants; this population represented 70% of admissions during the study period (median age 3 months), which resulted in 4847 in-patient stays. Children between 1 and 4 years accounted for the other 2129 admissions (median age 22 months). For every 1000-m increase in altitude, unadjusted models showed a 25% increase in infants and a 53% increase in children admitted for RSV-related diagnoses. Although adjusted models also hinted at a positive linear relationship between rates of RSV hospitalization and zip code elevation, closer examination revealed that the increased risk occurred only in the high-altitude category (>2500 m). There were significant increases in rates of RSV hospitalization in both groups at high altitude when compared with moderate and low altitudes individually. No significant difference was noted between hospitalization rates of patients at moderate altitude and of those living at low altitude. The cutoff above which rates of hospitalization began to markedly increase appeared to be 2500 m; moreover, the highest rates of RSV hospitalization in infants and children were in zip codes with altitudes greater than 2750 m.
With infants, there existed less difference in rate of hospitalization among altitudes, which is likely an artifact of parents and providers having a lower threshold for admitting a sick infant to the hospital as compared with an older child. As such, there was a more robust altitude effect on RSV hospitalizations for children. The authors also surmised that altitudes less than 2500 m may not provide enough physiological stress to influence the course or severity of RSV infections, for hospitalization rates did not begin to increase markedly until above this cutoff. Although many confounding factors were statistically minimized during the analysis of the data, other confounders existed that may have affected the results. These included differences in physician admitting practices, household and air pollutants, and preexisting conditions. Finally, the authors did not seek to confirm RSV diagnoses; thus, their data were based on ICD-9 codes alone.
In conclusion, this study demonstrates that infants and children living at altitudes greater than 2500 m are at increased risk for more severe RSV infections, as illustrated by higher rates of hospitalization. Considering that RSV is an exceptionally common viral infection, physicians who treat pediatric patients should keep RSV near the top of the differential when working up a respiratory illness. At altitude, the physician should not only have a higher index of suspicion for RSV, but should also be more vigilant when observing and treating the child with the virus. As with many other childhood illnesses, whether on top of a mountain or at sea level, prevention of RSV through community education and prophylaxis in appropriate circumstances remains a key element to the health of pediatric populations.
(Pediatrics. 2006;117:349–356) JA Choudhuri, LG Ogden, AJ Ruttenber, et al. Prepared by Preston J. Fedor, MSII, Oregon Health & Science University, Portland, OR, USA
Journal of Travel Medicine
Drugs and Drug Administration in Extreme Environments
In emergency, travel, and expedition medicine, pharmaceutical agents must often be used or stored in conditions that vary markedly from an idealized, stable environment. Extremes and significant oscillations of temperature, ultraviolet exposure, and other similar outdoor conditions might be expected to significantly alter the stability and efficacy of drugs. In addition, alternatives to the normal route of drug administration may often prove necessary in emergent situations. By combining literature research and extensive personal correspondence with the safety department heads of drug companies, the authors summarize the information for many drugs used in medical emergencies.
Most drugs are meant to be stored and used at a range between 8°C and 25°C, which reflects the model of kinetic average room temperature. Expiration dates are based on tests of stability within this temperature range over a period of time, at the end of which the amount of active drug must have decreased less than 5%. Although some drugs (eg, atropine, lidocaine, and naloxone) are temperature resistant over an enormous range (−20°C to 70°C), others are much more sensitive. Freezing may affect the substance itself, solvents, or stabilizers, and any resulting disintegration may cause significant alteration that creates doubt whether some drugs can be used after cold stress. Common methods of transport place drugs at risk of extreme changes in temperature, and insulated bags have limited effectiveness, for within hours the internal temperature equals that of the ambient environment. Extreme temperatures cause degradation of several drugs by chemical reactions such as oxygenation, hydrolysis, or decarboxylation, which decreases the drugs’ efficacy.
The authors evaluate data relating to the stability of drugs that are recommended to be carried in emergency bags within multiple western European countries and in the United States. Hot climate was defined as exposure to 60°C for several hours, and cold was defined as the temperature at which the ampoule contents were frozen, with the actual freezing point existing as an individual value for each drug and differing over a wide range of temperatures. Furthermore, the authors evaluated how alternative routes of administration (sublingual, oral, or via tracheal tube) of the drugs might be useful when it is impossible to establish an intravenous line.
In general, any frozen ampoule should be evaluated by visual inspection to ensure that hairline cracks have not caused contamination or oxidation of the drug. Any frozen ampoule should be melted carefully—without excessive heat—or replaced as soon as an opportunity arises. Under any environmental condition, the contents should be clear and their color should be normal. Any drug that contains proteins (eg, insulin) and any emulsion will disintegrate by freezing, and intravenous administration of frozen emulsions after rewarming is very dangerous because conglomerates of the lipophilic phase may embolize to the pulmonary arteries. Neither emulsions nor protein-containing drugs should be used after exposure to temperatures below 4°C to 5°C to exclude freezing. Capsules are very fragile if they are frozen, whereas lyophilisates are very temperature resistant if they are not dissolved. Exposure of any ampoule to sunlight longer than necessary should be avoided. Nifedipine and many other drugs (eg, theophylline, nitroglyceride, chloral hydrate, and insulin) show significant sensitivity to ultraviolet light.
Research data about alternative routes of drug administration are scant. If a drug is administered by tracheal tube, 5 to 10 mL NaCl 0.9% should be added, and moderate hyperventilation should be performed for some minutes. In most cases, the interval between administration and clinical effect will be longer than in intravenous administration, and it is difficult to estimate the extent of the effect. Spray and powder applicator systems provide constant doses and are cold resistant, whereas heat resistance depends on the substance itself. Most suppositories melt above 25°C and are solid as glass when frozen, making administration difficult.
Without recounting the specific effects of environmental exposure on each of the drugs, some general principles can be described. Most drugs can be used after temperature stress of limited duration. It should be recommended that they be replaced at least once per year or after exposure to extreme heat. The expiration periods will be diminished and are of limited value for travel, expedition, and emergency medicine. The authors suggest the inclusion of stability tests at 50°C, freezing and oscillating temperatures, and ultraviolet exposure in the postregistration procedure of drugs to simulate storage under outdoor conditions. Any drug must be used with caution in extreme environmental conditions, and further investigation is needed to evaluate drug safety and altered characteristics in wilderness settings.
(J Travel Med. 2006;13:35–47) TE Küpper, S Bettina, R Burkhard, et al. Prepared by Brandon R. Peters, MSII, Oregon Health & Science University, Portland, OR, USA
The Journal of Allergy and Clinical Immunology
Multicenter Study of Emergency Department Visits for Insect Sting Allergies
Insect sting allergies vary from localized reactions to anaphylactoid reactions. Local reactions are defined by redness, swelling, and hives within the immediate area of the sting. Mild systemic reactions are characterized as having some generalized toxicity. Anaphylaxis does not have a single definition but is classically thought of as involving 2 or more organ systems (skin, respiratory, cardiovascular, and gastrointestinal) or the single defining sign of hypotension. Because of the wide spectrum of presentations from insect stings, these researchers hoped to better define the actual frequency of insect envenomations and to describe clinical presentations, emergency management, patient outcomes, and discharge treatment of these patients.
The Multicenter Airway Research Collaboration completed a chart review of 1523 patients in 15 North American emergency departments. These patients were identified by ICD-9 codes for “toxic effect of venom,” “other anaphylactic shock,” and “allergy, unspecified” and were collected during the study period. Chart review included demographics, medical history, presentation, clinical course, signs and symptoms, positive findings on examination, and discharge instructions. Localized reactions were defined as rash, hives, and swelling at the area of envenomation. Mild systemic reactions involved skin and cutaneous tissue without involvement of other systems. Moderate reactions were defined as anaphylaxis with 2 organ systems involved and systolic blood pressure between 90 and 100 mm Hg. Severe anaphylaxis was defined as systolic blood pressure less than 90 mm Hg or neurologic symptoms such as confusion, collapse, or coma.
A cohort of 617 patients was identified (42% female, 61% white, mean age 36 ± 19 years). The study group had localized reactions (58%), mild systemic reactions (11%), and anaphylactoid reactions (31%). Over three quarters of patients presented within 6 hours of envenomation, and over 95% were discharged to home from the emergency department. The treatment of all patients varied widely: antihistamines were given in half of patients with local reactions, in 94% of those with mild systemic reactions, and in 70% of those with anaphylaxis. Systemic steroids were given in one quarter of patients with local reactions and in only half of those with mild systemic reactions and anaphylaxis. Of patients with anaphylaxis, 16% had received epinephrine within the 3 hours before arrival and 13% received epinephrine in the emergency department. Of patients with anaphylaxis, only 31% were prescribed self-injectable epinephrine (Epi-pen) and only 21% received a referral to an allergist. The emergency department treatment and discharge of anaphylaxis patients was obviously disconcordant with current guidelines advocating steroids and epinephrine as standard of care for these patients.
According to this study, between 35% and 60% of patients with a history of severe systemic reactions will have anaphylaxis if stung again. Therefore, a history of envenomation should be obtained from each patient to help assess risk for current and future anaphylactoid reactions. For serious reactions, steroids and epinephrine are widely available and administered. Also, there is plenty of room for improvement during the discharge process for patients with allergic reactions. All patients with moderate to severe reactions to insect stings should be prescribed an epinephrine self-administration kit and should be taught how to use it correctly. In addition, these patients should be referred to an allergist for further testing.
(J Allergy Clin Immunol. 2005;116:643–649) S Clark, AA Long, TJ Gaeta, and CA Camargo. Prepared by Karen Nolan Kuehl, MD, FACEP, Oregon Health & Science University, Portland, OR, USA
Jama: The Journal of the American Medical Association
Helmet Use and Risk of Head Injuries in Alpine Skiers and Snowboarders
Proponents of helmet use by skiers and snowboarders argue that helmets should offer the same protection that they have been proven to offer to bicyclists and inline skaters. Opponents suggest that helmet use may impair visual fields, could limit hearing, or might increase the risk of cervical spine injuries by the increased weight on the head. In addition, some opponents suggest that the increased sense of security offered by wearing a helmet might lead skiers and snowboarders to take more risks than they would otherwise. Recent epidemiologic studies have shown that helmets decrease head injuries at ski resorts, but the study by Macnab et al 1 was small and did not control for confounders, and the study by Hagel et al 2 used injured patients without head injuries as controls. The authors of this Norwegian study set out to definitively show that helmets reduce both head and neck injuries. Their methods differ from recent studies by using uninjured but appropriate controls and by adjusting for confounders such as age, ability, gender, and equipment.
This study was completed with data compiled at 8 Norwegian ski resorts during the 2002 ski season. Injured skiers were entered into the study if seen in the first-aid rooms or examined by the ski patrol on scene. Standardized forms summarized injuries and provided demographic information such as age, gender, nationality, equipment type, use of helmet, any ski-school attendance, rented vs owned equipment, self-reported skiing ability, and geographical location of the injury (groomed runs, out-of-boundary, ski lift, or snowboard park). Controls consisted of 2992 uninjured skiers and snowboarders sampled at the bottom of the busiest lifts during the busiest hours of operation (interviews were completed on every 10th skier or snowboarder waiting in the lift line at these times). In addition, 700 additional controls (obtained by the same mechanism) were interviewed about risk-taking behavior (cautious vs risk taking). Univariate analyses were completed on relationships between head injuries and risk factors as well as helmet use and risk factors.
A total of 3277 injured patients were entered, with 18% (n = 578) having head injuries. There was equal prevalence of head injuries in alpine skiers, snowboarders, and telemark skiers. When compared with injured controls, and after adjustment for confounders, the use of a helmet reduced the risk of head injury by 60% (odds ratio [OR] = 0.40). This effect was slightly lessened in patients with other injuries (OR = 0.45). Of those requiring transport to a hospital, the adjusted OR was 0.43. Snowboarders were more likely than skiers to have head injuries (OR = 1.53). After adjusting for confounders, helmets did protect from neck injuries, but the protection was not statistically significant. Helmets were more likely to be worn by the risk takers than by the cautious individuals.
This larger study did replicate the results of the Hagel et al 2 study in that helmets did protect skiers from head injuries in accidents causing other injuries (reduction of 29%–56%). This study showed an overall 60% reduction in head injury risk after adjusting for confounders such as age, gender, and ability. Evaluation of the numbers showed an increased chance of head injuries in beginners, in males, in those younger than 13 years, and in snowboarders, but the protective effect of helmets was present in these groups as well. This study suggests that helmets do not increase the risk of cervical spine injury in wearers, but, like other studies, this study is unable to provide adequate statistical evidence to support this claim.
(JAMA. 2006;295:919–924) S Sulheim, I Holme, A Ekeland, and R Bahr. Prepared by Karen Nolan Kuehl, MD, FACEP, Oregon Health & Science University, Portland, OR, USA