Abstract
Archives of Dermatology
Comparison of Colchicine, Dapsone, Triamcinolone, and Diphenhydramine Therapy for the Treatment of Brown Recluse Spider Envenomation
Brown spiders (genus Loxosceles) are found throughout the United States, particularly in the south-central states. Envenomation by these spiders is feared because of potential resultant severe skin necrosis and permanent disfigurement. In this animal study, the authors compared the efficacy of dapsone, diphenhydramine, colchicine, and intralesional triamcinolone in prevention of both dermonecrotic and systemic effects of Loxosceles envenomation.
This double-blind, controlled study was completed with 60 rabbits separated into 5 groups of 12 (1 control and 4 test groups). On day 1, each rabbit was injected with highly concentrated brown recluse (L reclusa) venom. Two hours after envenomation, treatment with each protocol began: dapsone once daily for 14 days, diphenhydramine twice daily for 7 days, colchicine twice daily for 7 days, and intralesional triamcinolone once. Eschar size was monitored for 14 days by digital photography, and at the end of the study the eschars were examined for depth, vasculitis, thrombosis, and extent of neutrophil infiltration. All rabbits also underwent coagulation studies at 72 hours after envenomation.
Eschars reached a remarkable size of 28 to 38 cm during the 14-day study period. There were no significant differences in any of the groups in final eschar size except for the diphenhydramine group, which did slightly worse than the others (P = .003). Triamcinolone offered some protection in subsequent thrombosis, but there was no associated decrease in eschar size. All rabbits developed coagulopathies, but these were reversed with normal rabbit plasma.
None of the drugs studied had any clinically relevant effect after envenomation by a Loxosceles spider. Specific antivenom and hyperbaric oxygen treatments have been shown to have variable benefit but are not usually immediately available. In addition, victims bitten by brown spiders tend to present in a delayed fashion, making antivenom less helpful as a treatment. Future treatments, particularly those focused on prevention of cell lysis and neutrophil aggregation, are needed.
(Arch Dermatol. 2005;141:595–597) DM Elston, et al. Prepared by Karen Nolan Kuehl, MD, FACEP Oregon Health & Science University, Portland, OR, USA
Annals of Emergency Medicine
Pressure-Immobilization Bandages Delay Toxicity in a Porcine Model of Eastern Coral Snake (Micrurus fulvius fulvius) Envenomation
The pressure-immobilization technique has been shown to sequester snake venom near the bite site via prevention of lymphatic drainage to the central circulation. These splints are advocated for use after envenomation by the elapids—many of which have neurotoxic venoms—but have been shown to increase local tissue damage after envenomation by the crotalids, which have greater local proteolytic effects. Coral snakes (Micrurus fulvius) are found in the southeastern United States and cause respiratory depression by blockage of acetylcholine receptors with very little local effects. Current treatment consists of supportive care until respiratory muscle paralysis has ceased. Although antivenom is still available, it is difficult to find, and future production in the United States is in question. This study was designed to evaluate pressure immobilization as a temporizing measure to prevent systemic envenomation until definitive medical care has been reached.
This randomized, unblinded, controlled trial was completed in an animal laboratory with 12 anesthetized pigs (6 study animals and 6 control animals). Each animal was given a lethal dose of M fulvius venom in the subcutaneous tissue of 1 foreleg. One minute after envenomation, the study animals had pressure-immobilization splints placed on the affected extremity by the same individual with an elastic bandage and accompanying splint in the same way that placement has been prescribed for field treatment: wrap is applied “as tightly as one would wrap an acute sprain.” Vital signs were then recorded in both groups every 10 minutes until obvious respiratory distress developed or the study endpoint of 8 hours. Systemic toxicity was defined as respiratory distress, with falling oxygen saturations, agonal respirations, or apnea.
One pig from each group, study and control, died from preexisting pulmonary infections found after death. Four of 5 study animals survived 480 minutes, whereas none of the control animals lived longer than 200 minutes, with a median time to death of 182 minutes (P = .0036). No animal had any evidence of ischemic or pressure injuries at the envenomation sites, although all animals had some minor localized hemorrhage.
Although this study was small and animal based, it does suggest the protective effect of pressure immobilization after envenomation by Micrurus species and also showed no increased local damage resulting from the technique. Because the device is easy to apply and to carry in backcountry kits and is relatively inexpensive, pressure immobilization should be considered in areas endemic for coral snakes, particularly when advanced medical care is not immediately available.
(Ann Emerg Med. 2005;45:603–608) BT German, JB Hack, K Brewer, and WJ Meggs. Prepared by Karen Nolan Kuehl, MD, FACEP Oregon Health & Science University, Portland, OR, USA
British Medical Journal
Effectiveness of Helmets in Skiers and Snowboarders: Case-Control and Case Crossover Study
Helmet use in skiers and snowboarders has continued to increase as evidence of a helmet's ability to protect against head injuries continues to accumulate. Some of this evidence is based on assumptions adopted from other sports (eg, cycling) and studies that have been criticized for methodological flaws. Reservations about widespread recommendation of helmet use for skiing and snowboarding also come from the concern that wearing a helmet might increase the risk of neck injuries. Children, with their larger ratio of head to body mass, may be particularly susceptible to the hypothesized larger forces of bending and twisting exerted on the head when it is covered with a helmet. This mechanism might turn what would have been an otherwise uneventful fall into a cervical injury. In this study, the authors attempt to answer 2 questions: are helmets protective against head injury, and does helmet use increase the risk for neck injury?
This was a case-control study but also included a case crossover design. The study population consisted of 4377 skiers or snowboarders who received medical attention at 19 different ski areas in Quebec. Cases (n = 1082) were patients who had injuries that included head or neck trauma. Injuries were classified as severe if there was an isolated head or neck injury that required evacuation. Controls were defined as patients who were injured but did not sustain head or neck injuries. For patients whose injuries were only to the head, the researchers also used a case crossover design. (This is similar to the case control, but the chosen cases serve as their own controls. This is done by comparing the circumstances of the skiing cases on the day of the injury with the most recent previous day on the slope.) Baseline characteristics, experience levels, mechanisms of the fall, and other factors were collected via questionnaire.
The adjusted odds ratio for helmet use in patients with any head injury was 0.71 (95% CI 0.55–0.92) and equaled a 29% reduction in the risk of head injury. Similarly, wearing a helmet reduced the risk of severe head injury by 56% (95% CI 0.24–0.81). The case crossover design had a similar odds ratio (0.43) but a wider CI (0.09–1.83). The adjusted odds ratio for helmet use was 0.62 (CI 0.33–1.19) for patients with any neck injury and 1.29 (CI 0.41–4.04) for patients who required evacuation by ambulance for neck injuries.
This well-designed study found a reduction in risk from head injuries that is similar to other studies and adds additional evidence to support helmet use. Whether helmets increase risk of neck injury is, however, left unanswered. The number of cervical injuries did not provide statistically meaningful results. Given the relatively rare event of a serious cervical spine injury or head injury, a case-control study was the only viable option to answer the questions posed by the authors. After reviewing the results of this study, limitations of case-control design in certain areas bear further mention. First, persons who strike their heads might be more likely to seek medical attention if they were not wearing helmets. Similarly, persons wearing helmets may be less likely to report potentially severe head injuries, believing they are fine because they wore helmets. Also, despite baseline characteristics and ability levels, persons who voluntarily choose to wear helmets are different from persons who choose not to. Such wearers may take more risks and hence have more severe accidents and be less likely to report minor ones. It would then seem that the helmets prevented head injuries when, in fact, it was merely the more risk-averse personality type that was protective. This study tries to combat these problems by using patients as their own perfectly matched controls. However, the case crossover portion of the study gives extremely wide CIs. Even larger case series will have to be studied to definitively answer whether helmets increase the risk of cervical spine injuries. The benefits from helmet use in preventing head injuries, however, appear to be clear.
(BMJ. 2005;330:281) BE Hagel, et al. Prepared by Damon Kuehl, MD Oregon Health & Science University, Portland, OR, USA
Emergency Medicine Journal
Predictors of Multi-Organ Dysfunction in Heatstroke
Although heatstroke incidence reporting is imprecise and varies regionally and seasonally (between 17.6 and 26.5 cases per 100 000 persons per year in the United States and between 22 and 250 cases per 100 000 persons per year in desert countries such as Saudi Arabia), the crude mortality rate associated with heatstroke approaches 50%. The morbidity and mortality associated with heatstroke results from multi-organ dysfunction (MOD) and eventual organ failure from complications, including disseminated intravascular coagulation, rhabdomyolysis, hepatic dysfunction, cerebral edema, seizures, and coma. These complications, in addition to multi-organ injury, have been shown to be mediated by an exaggerated acute-phase response leading to local and systemic inflammation. Thermoregulatory failure and heatstroke soon follow. Previous studies have characterized MOD by a combination of clinical and laboratory findings indicating coagulopathy, azotemia, transaminase elevation, elevated creatine kinase (CPK), and leukocytosis in patients with heatstroke. However, until this study, there were no studies looking at these clinical and laboratory findings as possible predictors of MOD in patients with heatstroke.
This retrospective cohort study, conducted by a southern Indian teaching hospital between 1998 and 2001, identified 28 adult patients with heatstroke, which was defined as a core body temperature >40.6°C with associated central nervous system dysfunction during periods of sustained high ambient temperature. Exclusionary criteria consisted of adult patients with proven central nervous system infection, systemic sepsis, malaria, neuroleptic malignant syndrome, and malignant hyperthermia secondary to anesthetic agents. Clinical data were recorded on predesigned forms and included demographic characteristics, known premorbid illness, temperature at admission, maximum temperature, Glascow coma score, clinical features at presentation, vital signs, laboratory results (serum CPK, lactate dehydrogenase, bicarbonate, leukocyte count, creatinine, liver function tests), chest radiograph findings, length of stay in an intensive care unit, length of stay in a hospital, condition at discharge, and outcome. Organ-system dysfunction was assessed by using a combination of clinical and laboratory parameters, including CPK >1000 IU/L, lactate dehydrogenase >500 U/L, aspartate aminotranserase–alanine aminotransferase >80 U/L, presence of metabolic acidosis (H
Overall case fatality rate for 28 patients with heatstroke was 71.4%. Multi-organ dysfunction was found in 78.6% of patients, with a mortality rate of 86%. The most common organ dysfunction was respiratory failure (85.7% of patients, with 78.6% requiring ventilator support), followed by central nervous system dysfunction (60.7% of patients). Cardiovascular and renal dysfunction were noted in 53.6% and 50% of patients. Among the selected predictors, metabolic acidosis (14 of 16 patients, 87.5%; P = .011), elevated CPK of 1000 IU/ L (17 of 19 patients, 89.5%; P = .005), and elevated liver transaminases >80 U/L (11 of 13 patients, 84.6%; P = .02) had the highest correlation with MOD. Leukocytosis and high lactate dehydrogenase had no statistically significant association with MOD.
Although this study shows that metabolic acidosis, elevated CPK, and elevated transaminases at hospital admission are predictive indicators of MOD in this study population, the small patient sample size and the incomplete laboratory data collection weaken the study's conclusions. Despite these weaknesses, this study provides a basis for further research in the early detection of impending MOD, and it is hoped that it will lead to earlier interventions to improve the current dismal outcomes of MOD in patients with heatstroke.
(Emerg Med J. 2005;22:185–187) GM Varghese, et al. Prepared by Bradley A. Dreifuss Oregon Health & Science University, Portland, OR, USA
Low Dose of Snake Antivenom Is as Effective as High Dose in Patients With Severe Neurotoxic Snake Envenoming
Snake envenomation resulting in neurotoxicity is a common occurrence in the Indian subcontinent and is frequently caused by members of the Elapid family, including cobras (Naja spp) and kraits (Bungarus spp). Neurotoxic venom causes paralysis of the respiratory, bulbar, ocular, and limb muscles, and care is typically supportive, with victims surviving after spending time on a ventilator. Snake antivenom (SAV) has traditionally been used in these patients, though there is no current consensus on dosing or length of treatment. In theory, SAV should be given until free venom concentrations in serum are undetectable; however, this approach is rarely used. Snake antivenom is expensive, is increasingly difficult to obtain, and has a large adverse-effect profile, including anaphylactoid reactions; therefore, the use of a smaller amount of SAV is preferable.
This study was a retrospective analysis of 55 patients treated in the intensive care unit in an Indian hospital during a 4-year period. Inclusion criteria included ventilatory failure after a presumed neurotoxic snakebite (patient had neurotoxic manifestations and evidence of snakebite, such as fang marks, blister formation, or the dead snake itself that was brought to the hospital). Analysis was based on the prevailing treatment in the intensive care unit at the time. Group 1 consisted of 27 patients before June 2002 who received high-dose SAV (100 mL of polyvalent SAV at presentation with repeat dosing every 6 hours until patient improvement or death). Group 2 consisted of 28 patients treated between July 2002 and July 2004 who received low-dose SAV (100 mL of polyvalent SAV at presentation with a second dose of 50 mL 6 hours after presentation). Outcome measurements included number of hours on a ventilator and length of stay in the intensive care unit.
Only 3 snakes were brought in for identification (2 kraits and 1 cobra). Further analysis of species by laboratory assay was not completed on any patient. All 55 patients presented with obvious neurotoxicity, including respiratory failure (Pa
The authors concluded that high-dose SAV (repeated dosing designed to capture any residual circulating venom) was not effective in reducing time on the ventilator or time in the intensive care unit when compared with low-dose SAV in “unselected” neurotoxic envenomations. The design of this study did not allow differentiation among snake types: at a minimum, 2 types of snake envenomations (cobra and krait) were included in the study, and there is no differentiation of which victims were bitten by which type of snake. The mechanism of action of the 2 venoms is different (cobra venom typically acts on the postsynaptic neuron, and krait venom acts mostly on the presynaptic neuron), even though the clinical manifestations are similar. More research is needed to further define dosing regimens for each specific type of venom.
(Emerg Med J. 2005;22:397–399) R Agarwal, et al. Prepared by Karen Nolan Kuehl, MD, FACEP Oregon Health & Science University, Portland, OR, USA
Clinical Toxicology
Use of Amifostine, a Novel Cytoprotective Agent, in α-Amanitin Poisoning
Amanita phalloides, also known by its less endearing alias, the “death cap” mushroom, is responsible for approximately 1 death per year in the United States. According to the American Association of Poison Control Centers, there are approximately 40 to 50 exposures per year, with 13 to 16 cases of ingestion of the Amanita mushroom resulting in moderate to major toxicity. In Europe, Amanita ingestions are more prominent, accounting for 50 to 100 fatalities per year. Mortality from ingestions of A phalloides remains as high as 20% to 40%, with many surviving patients requiring liver transplantation because of the hepatatoxic effect of α-amanitin, the primary lethal toxin of A phalloides. The Amanita species are responsible for 90% of fatal mushroom poisonings worldwide. Even experts can mistake A phalloides for similar nontoxic mushrooms. The mushroom has no characteristic odor. It is large with a hemispherical cap 5 to 15 cm in diameter located on a central stem 8 to 15 cm long and 1 to 2 cm in diameter. The cap is usually dry and shiny with a light green-yellow darkening toward the center. Gills are located under the cap and are not attached to the stem. In the United States, Amanita species are most commonly found in the Pacific Northwest and the Blue Ridge Mountains of the Northeast. They tend to grow near filbert (hazelnut), chestnut, or oak trees. Their peak season is late summer into fall; however, mushrooms can be found in early winter.
A variety of treatments for Amanita ingestion have been evaluated (including ethanol, cimetidine, silibinin, N-acetylcysteine, thioctic acid, and benzyl penicillin), but other than supportive measures, no effective treatment has been identified. In addition, patients poisoned from cyclopeptide-containing mushrooms typically present 8 to 10 hours postingestion, at which time decontamination or antidotal therapy may be ineffective. Because of late presentation, the authors believe that cytoprotective agents have greater potential for treatment success. This study aimed to determine whether amifostine, an organic thiophosphate pro-drug that functions as a free-radical scavenger, is an effective postexposure therapy for α-amanitin poisoning,
Swiss mice (n = 30 in all groups) were given an approximate LD75 dose of intraperitoneal α-amanitin. Amifostine was administered intraperitoneal 6 hours after poisoning in 3 cumulative dose groups: 250 mg·kg−1, 500 mg·kg−1, and 1600 mg·kg−1. Controls received equal volumes of intraperitoneal sterile saline. Mice were monitored and time of death recorded with survival assumed at day 7. Qualitative histologic comparisons of hepatic and renal toxicity were also performed.
Results of the study showed there is no statistically significant survival benefit with cumulative-dose amifostine administration after α-amanitin poisoning; however, higher doses may result in subsequent toxicity and decreased survival. At day 7, only 3 (10%) of the control mice survived, whereas for the amifostine-treated mice, 6 (20%) survived in the 250 mg·kg−1 treatment group, 6 (20%) survived in the 500 mg·kg−1 treatment group, and 1 (3%) survived in the 1600 mg·kg−1 treatment group. There were no statistically significant differences detected in Kaplan-Meier survival between mice in the control group and those receiving 250 or 500 mg·kg−1. There was a statistically significant decrease in survival in the group receiving 1600 mg·kg−1 (P = .0002). In addition, there was no evidence of direct hepatic or renal injury attributed to amifostine administration alone, leading the authors to postulate a possible cumulative toxicity of either amifostine or α-amanitin or both.
The authors conclude that amifostine cannot be recommended for cyclopeptide poisoning. Additional studies would need to be completed to show that amifostine had any cytoprotective effects at alternative doses, or if it could be used successfully in other toxic exposures.
(Clin Toxicol. 2005;43:261–267) BK Wills, NA Haller, D Peter, LJ White. Prepared by Damian Flowers Oregon Health & Science University, Portland, OR, USA