e2 45 Lavonas EJ, Khatri V, Daugherty C, Bucher Bartelson B, King T, Dart RC Medically significant late bleeding after treated crotaline envenomation a systematic review Ann Emerg Med 2014;63(1) 71 78[.]
e2 45 Lavonas EJ, Khatri V, Daugherty C, Bucher-Bartelson B, King T, Dart RC Medically significant late bleeding after treated crotaline envenomation: a systematic review Ann Emerg Med 2014;63(1): 71-78.e1 46 de Silva HA, Pathmeswaran A, Ranasinha CD, et al Low-dose adrenaline, promethazine, and hydrocortisone in the prevention of acute adverse reactions to antivenom following snakebite: a randomised, double-blind, placebo-controlled trial PLoS Med 2011; 8(5):e1000435 47 Premawardhena AP, de Silva CE, Fonseka MM, Gunatilake SB, de Silva HJ Low dose subcutaneous adrenaline to prevent acute adverse reactions to antivenom serum in people bitten by snakes: randomised, placebo controlled trial BMJ 1999;318(7190):1041-1043 48 Vetter RS Spider envenomation in North America Crit Care Nurs Clin North Am 2013;25(2):205-223 49 Glatstein M, Carbell G, Scolnik D, Rimon A, Hoyte C Treatment of pediatric black widow spider envenomation: A national poison center’s experience Am J Emerg Med 2018;36(6):998-1002 50 Monte AA, Bucher-Bartelson B, Heard KJ A US perspective of symptomatic Latrodectus spp envenomation and treatment: a National Poison Data System review Ann Pharmacother 2011;45(12): 1491-1498 51 Vetter RS Seasonality of brown recluse spiders, Loxosceles reclusa, submitted by the general public: implications for physicians regarding loxoscelism diagnoses Toxicon 2011;58(8):623-625 52 Hubbard JJ, James LP Complications and outcomes of brown recluse spider bites in children Clin Pediatr (Phila) 2011;50(3):252-258 53 Isbister GK, Fan HW Spider bite Lancet 2011;378(9808): 2039-2047 54 Vetter RS, Isbister GK Medical aspects of spider bites Annu Rev Entomol 2008;53:409-429 55 Clark RF, Wethern-Kestner S, Vance MV, Gerkin R Clinical presentation and treatment of black widow spider envenomation: a review of 163 cases Ann Emerg Med 1992;21(7):782-787 56 Bush SP Black widow spider envenomation mimicking cholecystitis Am J Emerg Med 1999;17(3):315 57 Alexakis LC, Arapi S, Stefanou I, Gargalianos P, Astriti M Transient reverse takotsubo cardiomyopathy following a spider bite in Greece: a case report Medicine (Baltimore) 2015;94(5):e457 58 Cohen J, Bush S Case report: compartment syndrome after a suspected black widow spider bite Ann Emerg Med 2005;45(4):414-416 59 Goel SC, Yabrodi M, Fortenberry J Recognition and successful treatment of priapism and suspected black widow spider bite with antivenin Pediatr Emerg Care 2014;30(10):723-724 60 Pneumatikos IA, Galiatsou E, Goe D, Kitsakos A, Nakos G, Vougiouklakis TG Acute fatal toxic myocarditis after black widow spider envenomation Ann Emerg Med 2003;41(1):158 61 Dart RC, Bogdan G, Heard K, et al A randomized, double-blind, placebo-controlled trial of a highly purified equine F(ab)2 antibody black widow spider antivenom Ann Emerg Med 2013;61(4): 458-467 62 Isbister GK, Page CB, Buckley NA, et al Randomized controlled trial of intravenous antivenom versus placebo for latrodectism: the second Redback Antivenom Evaluation (RAVE-II) study Ann Emerg Med 2014;64(6):620-628.e2 63 Murphy CM, Hong JJ, Beuhler MC Anaphylaxis with Latrodectus antivenin resulting in cardiac arrest J Med Toxicol 2011;7(4): 317-321 64 Hoyte CO, Cushing TA, Heard KJ Anaphylaxis to black widow spider antivenom Am J Emerg Med 2012;30(5):836.e1-2 65 Gomez HF, Krywko DM, Stoecker WV A new assay for the detection of Loxosceles species (brown recluse) spider venom Ann Emerg Med 2002;39(5):469-474 66 Skolnik AB, Ewald MB Pediatric scorpion envenomation in the United States: morbidity, mortality, and therapeutic innovations Pediatr Emerg Care 2013;29(1):98-103; quiz 104-105 67 Santos MS, Silva CG, Neto BS, et al Clinical and Epidemiological Aspects of Scorpionism in the World: A Systematic Review Wilderness Environ Med 2016;27(4):504-518 68 Kang AM, Brooks DE Geographic distribution of scorpion exposures in the United States, 2010-2015 Am J Public Health 2017; 107(12):1958-1963 69 Isbister GK, Bawaskar HS Scorpion envenomation N Engl J Med 2014;371(5):457-463 70 Boyer LV, Theodorou AA, Berg RA, et al Antivenom for critically ill children with neurotoxicity from scorpion stings N Engl J Med 2009;360(20):2090-2098 71 Fitzgerald KT, Flood AA Hymenoptera stings Clin Tech Small Anim Pract 2006;21(4):194-204 72 West PL, McKeown NJ, Hendrickson RG Massive hymenoptera envenomation in a 3-year-old Pediatr Emerg Care 2011;27(1):46-48 73 Vetter RS, Visscher PK, Camazine S Mass envenomations by honey bees and wasps West J Med 1999;170(4):223-227 74 Betten DP, Richardson WH, Tong TC, Clark RF Massive honey bee envenomation-induced rhabdomyolysis in an adolescent Pediatrics 2006;117(1):231-235 75 Kolecki P Delayed toxic reaction following massive bee envenomation Ann Emerg Med 1999;33(1):114-116 76 Bresolin NL, Carvalho LC, Goes EC, Fernandes R, Barotto AM Acute renal failure following massive attack by Africanized bee stings Pediatr Nephrol 2002;17(8):625-627 77 Stack K, Pryor L Significant traumatic intracranial hemorrhage in the setting of massive bee venom-induced coagulopathy: a case report Wilderness Environ Med 2016;27(3):405-408 e3 Abstract: Snake and spider bites, as well as scorpion and massive Hymenoptera stings, can lead to clinically significant envenomation syndromes in children Pediatric intensivists must maintain a high index of suspicion to prevent morbidity and mortality Treatment may require intensive care unit admission and involves supportive measures as well as antivenin administration in some cases This chapter discusses the epidemiology, clinical presentation, and management of common envenomation syndromes in the United States Key words: Snakebite, envenomation, antivenin, spider bite, latrodectism, loxoscelism, scorpion, Hymenoptera, stings 113 Hyperthermic Injury JASON A CLAYTON AND PHILIP TOLTZIS PEARLS • According to the Centers for Disease Control and Prevention, from 1999 to 2010, 7415 deaths were attributable to excessive heat exposure or hyperthermia in the United States With an increased occurrence of heat waves, even in temperate areas, the risk of heat-related illness is rapidly increasing After the onset of heat stroke, the systemic inflammatory response is induced and may continue despite adequate control of body temperature Coagulopathy and progression to multipleorgan failure may ensue Maintaining organ perfusion and rapid cooling are the major initial treatment goals for patients with heat stroke • • • The interest in heat-related illnesses has grown substantially, largely because of the effects of climate change and an increased frequency of heat waves.1,2 According to the Centers for Disease Control and Prevention, from 1999 to 2010, excessive heat exposure caused 7415 deaths in the United States.3,4 During this period, more people died of heat-related illness than all other natural disasters combined.5,6 Among the pediatric population, neonates and infants are at highest risk, mainly because of poorly developed thermoregulatory mechanisms and complete dependence on caregivers to provide adequate protection from excessive heat Children with comorbid conditions, such as developmental delay and various chronic diseases, are also at high risk Adolescents also may be affected by heat-related injury due to sports-related exertion, poor judgment, or intoxication Over the past decades, the understanding of the cellular and molecular responses to heat stress has improved dramatically At its most severe, heat-related injury produces multiorgan dysfunction through a complex interplay between the cytotoxic effect of the heat and inflammatory and coagulation responses of the host.7 Despite better understanding of heat injury pathophysiology, treatment remains supportive, with emphasis on immediate cooling Prevention and education are still the best tools available in the hands of healthcare providers to minimize heat-related morbidity and death • • The central nervous system is particularly vulnerable to heat, with the cerebellum being most susceptible Pyramidal dysfunction, dysphagia, cognitive changes (ranging from impaired judgment to delirium and coma), quadriparesis, extrapyramidal syndrome, and neuropathy have all been described Extraneurologic organ dysfunction, including the heart, lungs, kidneys, liver, and blood, may evolve even after the patient has been cooled Definitions Heat-related illnesses are best regarded as a spectrum of disorders that should be seen as a continuum of increasing severity Heat cramps are painful sustained muscle contractions, most often in the legs or abdominal wall, primarily due to inadequate circulation, dehydration, hyponatremia, and muscle fatigue Heat has not been shown to directly trigger cramping, and body temperature is usually normal.8 Heat exhaustion is a mild-to-moderate illness due to water or salt depletion from excessive sweating resulting from exposure to high environmental heat or strenuous physical exercise The patient may have headache, intense thirst, muscle weakness, dizziness, fainting, nausea, and visual disturbances Core temperature may be normal or elevated but is less than 40°C Postural hypotension may occur Heat stroke is a life-threatening emergency that occurs when the core temperature exceeds 40°C Physical manifestations essentially always include central nervous system abnormalities, such as delirium, convulsions, or coma The pathophysiology of heat stroke is driven by the induction of the systemic inflammatory response syndrome (SIRS) Untreated, heat stroke leads to a syndrome of multiorgan dysfunction.7 Traditionally, heat stroke has been divided into two types Exertional heat stroke develops in the setting of recreational or occupational exercise It results from heat production by muscular work, which exceeds the body’s ability to dissipate heat Classic (or nonexertional) heat stroke develops in the setting of high ambient temperature in the absence of exertion Classic heat stroke can occur at any age but is particularly prevalent in the very young and in the elderly, the latter of whom frequently possess comorbidities—such as poor mobility, hypertension, and congestive heart failure—that may interfere with the dissipation of body heat 1327 1328 S E C T I O N X I I Pediatric Critical Care: Environmental Injury and Trauma Epidemiology Excessive heat is a leading contributor to death by natural events in the United States.9 From 1999 to 2010, an annual average of 674 deaths in the United States was attributable to “excessive heat exposure.” Because death rates from other causes (e.g., cardiovascular and respiratory disease) increase during heat waves, deaths classified as caused by hyperthermia represent only a portion of heat-related death.10 Persons aged 15 years and younger accounted for 7% of deaths caused by weather conditions.3 There is a significant increase in heat-related death rate during heat waves (defined as or more consecutive days of air temperature 90°F or greater (32.2°C) For example, in 1980, a year with a record heat wave, the death rate was more than three times higher than that for any other year during the 19-year period of 1979 to 1997.11 Chicago experienced heat waves in 1990 and 1995 in which there were 103 and 485 heat-related deaths, respectively.12 Data on heat-related death are imprecise because this condition is misdiagnosed or underdiagnosed, its definition varies,7 and many patients with near-fatal heat stroke who survive the acute hospitalization have a high 1-year death rate.13 There is a statistically significant correlation between the number of heat-related illness hospitalizations and the average monthly maximum temperature or heat index (a statistic that combines temperature and humidity).14 In Saudi Arabia, where the temperature is extremely high, the incidence of heat stroke varies seasonally, from 22 to 250 cases per 100,000 population.15 Heat-related illness is reported from subtropical and cold parts of the world as well In Taiwan, a subtropical country without any history of heat waves, a cluster of heat stroke cases was reported during periods of sustained hotterthan-average temperatures.16 In an observational study in which cold and hot areas in Europe were compared, heat-related death occurred in both types of climates but at higher temperatures in the hot regions,17 suggesting that the former populations had accommodated to their hotter environments over time Within the pediatric population, children younger than years are at higher risk, with specific factors such as diarrheal disease, sweat gland dysfunction, child neglect, and underlying chronic or febrile illness contributing Children left unattended in parked vehicles remain a principal preventable cause, with an average of 38 fatalities per year in the United States.18 The majority of cases are male children younger than years One-quarter of the children were playing and gained access to unlocked vehicles, while the remainder were either intentionally left in the vehicle or forgotten by a caregiver.19 Additionally, student athletes are at risk of death and disability due to heat-related illness during practice or competition.20,21 The frequency of emergency department visits for athletes with heat illness increased by 133% from 1997 to 2006,22 and the number of deaths from heat stroke doubled.23 Heat-related injuries among athletes are particularly frequent in American football, especially during preseason training, which typically occurs at the end of the summer Obesity and sicklecell trait may place student athletes at particular risk Sports associations—specifically, the National Athletic Trainers Association and the National Collegiate Athletic Association—have published guidelines to prevent heat-related injuries in high school and college students,24 including strong recommendations for a minimum 2-week period of heat acclimation at the start of preseason football practice and limitation on the duration of continuous exercise and protective-equipment use These are not mandatory, however, and their adoption by state athletic associations is variable.25,26 Alcohol and drug abuse—as well as neuroleptic drugs such as phenothiazines, tricyclic antidepressants, lithium, and fluoxetine taken for medical indications, alone or in conjunction with athletics—may all exacerbate heat-related illness in adolescents.27–29 Pathophysiology of Heat-Related Illnesses Understanding the systemic and cellular pathophysiology of heatrelated illnesses involves an appreciation of thermoregulation, physiologic alterations directly related to hyperthermia, acutephase response, and production of heat shock proteins (HSPs) For normal enzymatic and cellular function, it is essential that body core temperature be maintained within a narrow range of 37°C 0.5 to 0.9°C.29,30 The thermoregulation system, controlled by the preoptic area of the anterior hypothalamus, receives input from thermosensitive receptors in the skin and body core, compares the data with a reference level (the set point), and responds to an elevation of 0.3°C29,31 with activation of heat loss mechanisms.7,29,32 Heat dissipation occurs by means of four mechanisms: (1) conduction (i.e., the transmission of heat through direct contact with a cooler surface); (2) convection (i.e., the transfer of heat to moving air or liquid); (3) radiation of heat energy via emanation of electromagnetic energy; and (4) evaporation Once activated by the hypothalamus, the efferent heat response is both autonomic and behavioral Blood delivery to the body surface is increased by sympathetic discharge, causing cutaneous vasodilation Blood flow may increase 8- to 16-fold, up to L/min.33 Thermal sweating, in response to parasympathetic discharge, can produce approximately L/h per square meter of body surface of sweat Per liter of evaporated sweat, 588 kCal are lost Secondary to cutaneous vasodilation and sweating, blood is shunted toward the periphery and visceral perfusion is reduced, especially to the liver, kidneys, and intestines.31 Rising core temperature will also lead to tachycardia independent of fluid loss, a high cardiac output state, and an increase in minute ventilation Losses of salt and water through sweating may lead to dehydration and salt depletion, resulting in impaired thermoregulation When ambient temperature equals or exceeds body temperature, conduction, convection, and radiation cease to be effective A combination of high ambient humidity and temperature creates a particularly dangerous situation, since at humidity of 90% to 95%, evaporation of sweat stops; under these conditions, the body can no longer eliminate heat by any of its normal mechanisms Hyperthermia directly induces cellular injury by causing damage to macromolecules, including proteins, membrane lipids, and deoxyribonucleic acid (DNA).34–36 The accumulation of damaged macromolecules triggers the cell to transcribe HSPs, a family of molecules that facilitate stabilization and repair of cellular homeostasis in response to a variety of stressors.35,36 The severity of injury is cumulative; thus, exposure to a high temperature for a brief period of time may cause similar injury to an exposure to a lower temperature for a longer period of time.37 Cell death is mainly due to apoptosis.38 Acclimatization Prolonged exposure to a hot environment results in adaptation and tolerance to higher temperature levels Acclimatization to heat may take several weeks and involves multiple organs Sweat glands develop increased capacity to secrete sweat, plasma volume is increased, and the renin-angiotensin-aldosterone axis is activated, CHAPTER 113 Hyperthermic Injury leading to improved salt conservation The adaptability of the cardiovascular system is probably the most important single determinant of a person’s ability to tolerate heat stress.7,39 Acclimatization is thought to be at least partially mediated by induction of HSP 72.40 Even acclimatized people have definite limitations for heat tolerance Once driven beyond a critical level, progression to heat stroke and death may result Acute-Phase Response A variety of cytokines are produced in the acute phase of heat stress Plasma levels of both proinflammatory cytokines (tumor necrosis factor–a [TNF-a], interleukin [IL]-1, and interferon-g) and antiinflammatory cytokines (IL-6, IL-10, TNF receptors p55 and p75) are elevated in patients with heat stroke.41–47 Soluble TNF, IL-2, and IL-6 receptors are also elevated in heat stroke.48,49 It has been shown that the severity of symptoms during heat stroke correlates with IL-1 and IL-6 levels.41 The acute-phase response may continue after the patient is cooled Onset of inflammation may be local, with systemic progression7,46 involving endothelial cell activation, release of endothelial vasoactive factors, and endothelial cell injury.50–52 The gastrointestinal tract may also play a role in the exaggeration of the inflammatory response Vascular congestion, hemorrhage, thrombosis, and massive loss of surface epithelium in the jejunum were observed in a baboon model of heat stroke.52 These changes facilitate bacterial and endotoxin translocation and release of mitochondrial DNA fragments, which contribute significantly to SIRS and multiple-organ dysfunction syndrome (MODS).53–55 Endothelial cell injury activates both the coagulation and fibrinolytic systems.56 Microvascular thrombosis is found in many organs of deceased heat stroke patients Heat stress by itself is a procoagulation condition because it causes platelet clumping in small vessels Injured endothelium plays an important role in producing and releasing both procoagulant and anticoagulant substances (e.g., von Willebrand factor antigen [vWF-Ag], tissue plasminogen activator, and plasminogen activator inhibitor).50,51 Circulating vWF-Ag, thrombomodulin, endothelin-1, nitric oxide (NO) metabolites, soluble E-selectin, and intercellular adhesion molecule-1 (ICAM-1) are elevated in heat-related illness, creating a clinical picture of disseminated intravascular coagulation (DIC).50,57–59 Cooling patients with heat stroke reverses only part of these coagulation abnormalities.56 In some animal models of heat stroke, inhibiting the inflammatory response by administering corticosteroids, IL-1 receptor antagonist, or recombinant activated protein C prevented organ damage.60–62 In contrast, studies using a baboon model of heat stroke demonstrated that corticosteroids given before or at the onset of induced heat stroke exacerbated tissue injury and accelerated progression to MODS.63 In addition, in mouse studies in which TNF receptor or IL-6 was knocked out, animals with heat stroke had higher mortality.64 The promotion of endogenous mediators by heat thus appears to be protective in some contexts and harmful in others More recent studies in rodents suggests that the inflammatory response is mediated by the high-mobility group box (HMGB1) proteins that are released by heat-injured cells.65,66 These molecules act on toll-like receptor and initiate a proinflammatory cascade mediated by nuclear factor-kB (NF-kB) Further characterization of these molecular pathways may help us to better understand the pathophysiologic and adaptive role of the host immune response to heat stress 1329 Clinical Features of Heat Stroke Heat exhaustion may produce relatively mild dysfunction of multiple organs, but heat stroke typically is associated with severe MODS Recognition and support of these multifarious manifestations is critical to a successful outcome Central Nervous System Neurologic dysfunction is a cardinal feature of heat stroke Brain dysfunction is usually severe but may be subtle, manifesting only as inappropriate behavior or impaired judgment More often, patients present with delirium or coma.32 Seizures may occur, especially during cooling The central nervous system is particularly vulnerable to heat, the cerebellum being most susceptible.67 Proton magnetic resonance imaging is a useful tool for evaluating major metabolic changes in the cerebellum after heat stroke.68 Pyramidal dysfunction, dysphagia, mental status changes, quadriparesis, extrapyramidal syndrome, and peripheral neuropathy have all been described.32,69 No data regarding long-term neurologic outcome in children have been reported Cardiovascular Cardiovascular dysfunction is common in heat stroke.70 Hypotension and shock may result from splanchnic vasoconstriction and cutaneous vasodilation aimed to facilitate heat dissipation Dehydration, combined with redistribution of blood volume, leads to reduction in venous pressure and diastolic filling.32,70 Circulation is hyperdynamic in these patients, with tachycardia and high cardiac output.71 Vasomotor tone may remain abnormally low, even after normal temperature and intravascular volume have been restored Electrocardiographic changes are common in heat stroke but are nonspecific and include QT segment prolongation and ST-T wave changes Less frequently, the patient may experience multiform premature ventricular contractions, ventricular tachycardia, and other dysrhythmias.72 The electrocardiographic abnormalities are transient, typically subsiding with cooling and correction of potassium, magnesium, and calcium abnormalities.73 Pulmonary The pulmonary system is not involved in early stages of heat-related illnesses However, approximately 25% of adults with heat stroke acquire acute respiratory distress syndrome (ARDS).74 Patients with ARDS have poor prognosis, with up to 75% mortality rate Lung involvement frequently occurs as part of MODS.74 Renal Elevated blood urea nitrogen and creatinine levels are seen even in mild heat-related disease such as heat cramps.75 Incidence of acute kidney injury ranges from 5% in classic heat stroke to 25% in exertional heat stroke.70 Direct thermal injury, hypoperfusion, rhabdomyolysis with myoglobinuria, release of vasoactive mediators, and DIC may all contribute to renal injury.7,32,76,77 Gastrointestinal Gastrointestinal involvement in heat stroke occurs secondary to splanchnic vasoconstriction and gut hypoperfusion.7,78,79 Jejunal ... variable.25,26 Alcohol and drug abuse—as well as neuroleptic drugs such as phenothiazines, tricyclic antidepressants, lithium, and fluoxetine taken for medical indications, alone or in conjunction... Prevention, from 1999 to 2010, excessive heat exposure caused 7415 deaths in the United States.3,4 During this period, more people died of heat-related illness than all other natural disasters combined.5,6... to high environmental heat or strenuous physical exercise The patient may have headache, intense thirst, muscle weakness, dizziness, fainting, nausea, and visual disturbances Core temperature may