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1414 SECTION 16: Environmental Injuries TABLE 221-3 Plant-Induced Dermatitis Dermatitis Classification Mechanism of Injury Specific Plants Mechanical injury Calcium oxalate Dumbcane (Diffenbachia maculate) Philodendron (Philodendron spp.) Raphides and trichomes Stinging nettles (Urtica dioica) Velvet bean or cowhage (Mucuna pruriens) Pineapple (Bromeliaceae spp.) Irritant dermatitis Phorbol esters Cow’s horn (Euphorbia grandicornis) Poinsettia (Euphorbia pulcherrima) Manchineel tree (Hippomane mancinella) Other chemical irritants Stinging nettles (Urtica dioica) Velvet bean or cowhage (M. pruriens) Pineapple (Bromeliaceae spp.) Contact dermatitis

Calcium oxalate Dumbcane (Diffenbachia maculate) Philodendron (Philodendron spp.) Raphides and trichomes Stinging nettles (Urtica dioica) Velvet bean or cowhage (Mucuna pruriens) Pineapple (Bromeliaceae spp.) Irritant dermatitis Phorbol esters Cow’s horn (Euphorbia grandicornis) Poinsettia (Euphorbia pulcherrima) Manchineel tree (Hippomane mancinella) Other chemical irritants Stinging nettles (Urtica dioica) Velvet bean or cowhage (M. pruriens) Pineapple (Bromeliaceae spp.) Contact dermatitis Urushiol oleoresins Gingko (Ginkgoaceae) Poison ivy, oak, and sumac (Toxicodendron spp.) Mango (Mangifera indica) Pistachio (Pistacia vera) Cashew (Anacardium occidentale) Miscellaneous antigens Peruvian lily (Alstroemeria spp.) Narcissus and daffodils (Narcissus spp.) Tulips (Tulipa spp.) Primroses (Primula spp.) Phytophotodermatitis Furocoumarins Cow parsnip (Heracleum lanatum) Wild parsnip (Pastinaca sativa) Lime (Citrus aurantiifolia) Poison ivy, poison oak , and poison sumac (Toxicodendron spp.) are ubiquitous sources of the antigenic resin urushiol. Ginkgo (Ginkgoaceae), mango (Mangifera indica), pistachio (Pistacia vera), and cashew (Anacardium occidentale) are common foods with urushiol-like compounds. In sensitized individuals, reexposure can result in urticaria and pruritus. Over 12 to 48 hours, symptoms may progress to varying degrees of vesiculobullous formation. Treatment usually consists of drying agents and local topical steroids, but systemic steroids may be necessary in severe cases. Some exposures can result in type I hypersensitivity or anaphylaxis. See Chapter 253, “Skin Disorders: Extremities. ” Tulips ( Tulipa spp.) and daffodils ( Narcissus spp.) contain the glycoside tuliposide A. After hydrolysis, an allergen causes tulip fin gers or daffodil itch with chronic reexposure, a painful and pruritic condition.  PHYTOPHOTODERMATITIS Phytophotodermatitis occurs when furocoumarins are activated by sunlight and produce symptoms that resemble sunburn in the acute phase; erythema and bullae are common. When these symptoms heal, hyperpigmentation persists for months. The mechanism is unknown. Exposure can be directly through the dermis, or furocoumarins can be deposited in the skin following ingestion and subsequent systemic circulation. Many plants, including common foods, can cause phytophotodermatitis, including numerous citrus fruits, celery, carrots, and herbs. REFERENCES The complete reference list is available online at www.TintinalliEM.com. crystal bundles, are found in a number of common plants, including dumbcane (Dieffenbachia spp.) and philodendron (Philodendron spp.). Needles of pineapples (Bromeliaceae spp.) and the hairs of stinging nettles (Urtica dioica) directly pierce the dermis, and chemical irritants in these structures cause further dermal injury (see next section).  IRRITANT DERMATITIS Phorbol esters found in the sap of plants of the Euphorbiaceae (spurge) can cause dermal irritation following contact. The phorbol esters can penetrate the dermis upon contact. Symptoms such as erythema and bullae may develop shortly after direct contact. Ocular injuries and GI injury can also occur upon exposure or ingestion. Occasionally, aerosolized irritants can cause dermatitis or respiratory distress. Expo sures to poinsettia (Euphorbia pulcherrima) are typically well tolerated despite the widespread belief that poinsettia ingestion is potentially life threatening. Occasionally, these plants cause hypersensitivity reac tions because several members of the Euphorbia family carry common allergens, including trees that produce natural latex. 21 Pineapples (Bromeliaceae spp.), stinging nettles ( U. dioica ), and dumbcane (Dieffenbachia spp.) all introduce irritants such as proteolytic enzymes and other proinflammatory chemicals such as histamine, acetylcholine, and 5-hydroxytryptamine.  ALLERGIC CONTACT DERMATITIS Many plants can cause allergic contact dermatitis after repeat expo sure.

.), stinging nettles ( U. dioica ), and dumbcane (Dieffenbachia spp.) all introduce irritants such as proteolytic enzymes and other proinflammatory chemicals such as histamine, acetylcholine, and 5-hydroxytryptamine.  ALLERGIC CONTACT DERMATITIS Many plants can cause allergic contact dermatitis after repeat expo sure. Sensitization occurs after a resin binds to skin proteins and forms an antigen. Reexposure then stimulates a T-cell–mediated immune response. Carbon Monoxide Gerald E. Maloney INTRODUCTION AND EPIDEMIOLOGY Carbon monoxide (CO) is one of the most common toxic exposures that emergency physicians will encounter. It is the second most common cause of fatal poisoning, either intentional (suicidal) or accidental, in the United States, 1 and is suspected to be the most common cause of fatal poisoning worldwide. Despite a great deal of clinical experience and several randomized trials, there is no clear consensus on the best approach to managing CO exposures. Exact statistics for CO poisoning are difficult to determine, mainly due to incomplete reporting. In 2016, the American Association of Poison Control Centers Toxic Exposure Surveillance System reported 13,620 exposures, with 48 deaths. 3 Deaths in the United States from both intentional and accidental exposures are over 1200 per year. 4 Decades ago, vehicular emissions were the major source of CO poisoning in U.S. adults. Currently, nonvehicular sources, such as heating systems, are more common, as modern exhaust systems reduce CO emissions. 5 Table 222-1 lists the most common sources of CO exposures.3,6-8 Peak incidence occurs in the fall and winter months, generally due to use of space heaters, wood-burning stoves, charcoal burning for heat, or portable generators without adequate ventilation. 4 It is not uncom mon for whole families to be affected. Exposures have been reported in persons riding in the back of pickup trucks, as well as persons riding in vehicles with exhaust pipes occluded by snow. It is believed that CO poisoning is probably the most pressing danger from smoke inhalation and is a major contributor to fire-related deaths. An unusual source of CO is methylene chloride, which is found in varnishes and paint strippers and bubbling fluid in Christmas orna ments. Routes of exposure are inhalational or by ingestion. Methylene CHAPTER Tintinalli_Sec16_p1333-1418.indd 1414 8/2/19 8:23 PM

lation and is a major contributor to fire-related deaths. An unusual source of CO is methylene chloride, which is found in varnishes and paint strippers and bubbling fluid in Christmas orna ments. Routes of exposure are inhalational or by ingestion. Methylene CHAPTER Tintinalli_Sec16_p1333-1418.indd 1414 8/2/19 8:23 PM CHAPTER 222:  Carbon Monoxide      1415 chloride is metabolized in the liver to CO. As a result of ongoing metabolism, persistent elevation of carboxyhemoglobin occurs despite oxygen therapy.9 Time to peak CO levels may be ≥8 hours. PATHOPHYSIOLOGY CO is typically described as a colorless, odorless gas. It is normally present in air at 10 ppm or less, perhaps higher in urban areas. CO is also an endogenous substance, with production occurring in the body during normal breakdown of heme. Normal physiologic CO levels (as carboxyhemoglobin) from this process are approximately 1% in healthy nonsmokers. Physiologic production can be increased in hemolysis or sepsis. CO toxicity causes profound tissue hypoxia and activation of inflammatory mediators that may lead to permanent injury of the heart, the CNS, 8,10-14 and less commonly, the peripheral nervous system.15  TISSUE HYPOXIA The most easily quantified physiologic effect is binding to hemoglobin to form carboxyhemoglobin (COHb). The binding affinity of normal adult hemoglobin for carbon monoxide is over 200 times that for oxygen (Figure 222-1). 8 CO affinity is higher for fetal hemoglobin, which may account for potentially severe fetal toxicity.8 Approximately 85% of CO is bound to hemoglobin, with the rest dissolved in plasma or bound intracellularly, often to myoglobin. CO shifts the oxyhemoglobin dissociation curve to the left, impairing oxygen release to the tissues. The half-life of COHb on room air at normal atmospheric pressure ranges from 249 to 320 minutes. 8 On 100% oxygen at atmospheric pressure, half-life is about 74 to 80 minutes. 8 The exception to this is COHb generated by methylene chloride exposure, which can have a half-life of ≥8 hours due to ongoing metabolic production.  MITOCHONDRIAL INHIBITION CO binds as ferrous heme a 3, disabling oxidative phosphorylation. Inhibition is more profound under the hypoxic conditions resulting from CO binding of hemoglobin. The net effect is decreased adenosine triphosphate production and production of free radicals, compromising tissues with the highest metabolic demand, the brain and heart, and generating lactic acidosis.  INFLAMMATORY AND PLATELET EFFECTS CO activates platelets by displacing nitric oxide (NO) from platelet surface proteins; the displaced NO reacts with superoxide released from the effects of CO on the mitochondria to yield peroxynitrite, which further compromises mitochondrial function and stimulates platelet activation. 8,10 These combined effects stimulate neutrophils to degranulate, releasing myeloperoxidase and amplifying further degranulation and platelet adhesion. 14 The proinflammatory mediators catalyze lipid peroxidation of myelin basic proteins of nerve tissues, triggering lymphocyte and microglia activation in the brain 16 and causing neurologic injury and dysfunction, primarily of the CNS. 8,10 Cells in the basal ganglia are particularly sensitive to this neurotoxic effect and may be demonstrated by the globus pallidus lesions evident on CT or MRI. Platelet activation, endothelial injury, and cell apop tosis combine to yield several types of cardiac injury or dysfunction, including myocardial infarction, cardiomyopathy, and myocardial fibrosis. 8,10,11 CARBOXYHEMOGLOBIN MEASUREMENT Co-oximetry, which measures total hemoglobin as well as oxyhemo globin, methemoglobin, and COHb saturation, is the only accurate measurement tool.

bine to yield several types of cardiac injury or dysfunction, including myocardial infarction, cardiomyopathy, and myocardial fibrosis. 8,10,11 CARBOXYHEMOGLOBIN MEASUREMENT Co-oximetry, which measures total hemoglobin as well as oxyhemo globin, methemoglobin, and COHb saturation, is the only accurate measurement tool. There is excellent correlation between arterial and venous COHb levels, and so a venous blood gas with co-oximetry is sufficient in most cases. 17,18 Standard pulse oximetry is unreliable in the diagnosis of CO poisoning. Routine arterial blood gas analyzers without co-oximetry calculate, rather than measure, saturation and add the contribution of dyshemoglobinemias to total oxygen saturation. The wavelengths for COHb fall into the same range as those for oxyhemoglobin, so stan dard pulse oximetry does not differentiate the two. As a result, in CO poisoning, the oxygen saturation obtained by standard pulse oximetry may appear artificially high 19,20 (Figure 222-1). When the pulse oximetry values, without co-oximetry, are compared to the oxygen saturation on an arterial blood gas, the oxygen saturation on the pulse oximeter will be higher than the saturation on the arterial blood gas. This is termed the pulse oximetry gap. CLINICAL FEATURES The clinical presentation of CO poisoning varies widely, leading to misdiagnosis in many cases ( Table 222-2). An unconscious patient pulled from a house fire or from a running car in a closed garage does not represent a diagnostic dilemma; the patient with “flulike” symptoms, or the elderly person with syncope and ischemic ECG changes is difficult to correctly diagnose. TABLE 222-1 Sources of Carbon Monoxide •  Wood  or coal-burning stoves or heaters •  Propane-fueled  heaters •  Structure  fires •  Natural  gas–powered heaters/furnaces/generators •  Automotive  exhaust •  Motorboat  exhaust •  Gasoline-powered  generators or motors •  Forklifts/ice  resurfacing machines •  Methylene  chloride Oxygen tension (b) sigmoid curve HbO (a) asymptotic curve“CO HbO 2” HbO2 % sat 100% 150 mm Hg FIGURE 222-1. Carboxyhemoglobin “shift to the left” reshaping of the oxyhemoglobin (HbO2) dissociation curve. (a) Carbon monoxide (CO)–affected HbO2 dissociation curve (asymptotic) and (b) normal HbO2 dissociation curve (sigmoid). TABLE 222-2 Symptoms and Signs of Acute Carbon Monoxide Poisoning Headache Visual disturbances Nausea/vomiting Focal neurologic deficit Ataxia Dyspnea/tachypnea Seizure Bullous skin lesions Syncope Retinal hemorrhage Chest pain/shortness of breath ECG changes/dysrhythmias Confusion Cardiac arrest Tintinalli_Sec16_p1333-1418.indd 1415 8/2/19 8:23 PM

of Acute Carbon Monoxide Poisoning Headache Visual disturbances Nausea/vomiting Focal neurologic deficit Ataxia Dyspnea/tachypnea Seizure Bullous skin lesions Syncope Retinal hemorrhage Chest pain/shortness of breath ECG changes/dysrhythmias Confusion Cardiac arrest Tintinalli_Sec16_p1333-1418.indd 1415 8/2/19 8:23 PM 1416 SECTION 16: Environmental Injuries  HISTORY History may be obviously suggestive, such as headache related to home propane heater use, with headache relief when leaving the home environment. Other situations, such as new-onset seizure, syncope, myocardial infarction, or cardiac arrest, are not as obvious. Concurrent symptoms in other members of the household, or even pets, may be a clue. However, even within a household, different persons may manifest symptoms differently, depending on age, comorbid disease, and prox imity to the CO source. Occupational history may help, particularly in cases due to less common causes such as methylene chloride exposure. Exposure to any gas, propane-powered motors, or fumes from methy lene chloride, especially if in a closed environment, may serve as a clue in nonspecific presentations. Consider CO poisoning in the differential diagnosis of coma, mental status changes, and elevated anion gap metabolic acidosis or lactic acidosis.  PHYSICAL EXAM The classically touted finding of cherry red oral mucosa is rarely seen in living patients. Vital signs may reveal mild fever, tachycardia, tachypnea, hypertension, or hypotension. Severe poisoning can cause respiratory or cardiac arrest. Neurologic findings are variable, ranging from mild headache and confusion to irritability, seizures, focal neurologic deficits, ataxia, and coma. Retinal hemorrhages have been reported with severe poisoning. Skin findings include bullous lesions, generally seen in patients with prolonged immobility from pressure necrosis, although a direct toxic effect of CO on epidermal tissue is possible. Signs and symptoms of CO poisoning may be obscured by trauma or burns. A comatose patient removed from a fire scene should be assumed to have CO poisoning until proven otherwise, even in the absence of cutaneous or airway burns. Although most discussions focus on an acute exposure, chronic poi soning, generally from occupational sources, also must be considered. Symptoms are usually more insidious, such as trouble concentrating, personality changes, neuropsychiatric problems, or memory loss, and can be difficult to diagnose.  INTERPRETING CARBOXYHEMOGLOBIN LEVELS COHb levels are typically <1% to 2% in the nonsmoker and 4% to 10% in the active smoker. 21 Therefore, the diagnosis of CO poisoning is clinical: an elevated COHb level along with a history of exposure and compatible symptoms or signs. The COHb level is not an absolute indicator of clinical severity, nor is rapid clearance of an elevated level evidence of clinical improvement. When interpreting COHb levels, consider time and duration of exposure, time from exposure to presentation, treatment (such as high-flow oxygen) rendered in route, and clinical symptoms. Although a markedly elevated COHb level, such as 50%, is a clear indi cator of severe intoxication, a level of 10% in a patient with symptoms a few hours earlier can still be a marker of CO intoxication. In one series, 30% of 163 patients with CO poisoning had a normal COHb level at ED presentation. 22 Even in the absence of an elevated COHb level, the diagnosis is still made by history of exposure and compatible symptoms or signs.  ANCILLARY TESTS Obtain arterial blood gases and serum lactate levels.

CO intoxication. In one series, 30% of 163 patients with CO poisoning had a normal COHb level at ED presentation. 22 Even in the absence of an elevated COHb level, the diagnosis is still made by history of exposure and compatible symptoms or signs.  ANCILLARY TESTS Obtain arterial blood gases and serum lactate levels. Elevated lactate from the interference in the electron transport chain, an unexplained elevated anion gap metabolic acidosis, elevated creatine phosphokinase, or elevated troponin may trigger an investigation for CO poisoning. Consider concomitant cyanide poisoning. Also consider additional toxicology testing for intentional CO poisoning. ECG findings may range from entirely normal to ST-segment eleva tion myocardial infarction. There does not appear to be any classic CO ECG pattern. Of note, few patients with acute myocardial infarction due to CO poisoning have occlusive arterial lesions demonstrated by cardiac catheterization. 23 Patients diagnosed with CO poisoning have been reported to have an increased risk of subsequent myocardial infarction,24 but this is controversial.17 Poisoned patients appear to have an increased risk of future ischemic stroke.25  IMAGING Radiographic imaging is generally more helpful in establishing an alternative diagnosis. However, CO poisoning is associated with one specific radiographic finding, globus pallidus lesions (Figure 222-2). Lesions are generally bilateral, symmetric, and more common in severely poisoned patients. TREATMENT Initial resuscitation is no different from initial resuscitation of any other critically ill patient. If CO poisoning is suspected, start 100% oxygen immediately. Identify risks for possible referral for hyperbaric oxygen treatment (Table 222-3).  ED TREATMENT OF CARBOXYHEMOGLOBIN WITH NO HIGH-RISK FEATURES If there are no high-risk features and the patient has only mild symp toms such as headache, dizziness, or nausea/vomiting, continue 100% oxygen until symptoms have resolved and COHb is normal (<3%). An ED observation period of 6 hours, with 100% oxygen, is recommended FIGURE 222-2. The  scan  shows  characteristic  bilateral  symmetrical  lucencies  of  the globus pallidus (arrowheads). [Reproduced with permission from Knoop KJ, Stack LB, Storrow AB, Thurman RJ (eds): The Atlas of Emergency Medicine , 4th ed. McGraw-Hill Education, Inc., 2016. Fig 17.53, p. 613. Photo contributor: Lawrence B. Stack, MD.] TABLE 222-3 Common Indications for Referral for Hyperbaric Oxygen Treatment Loss of consciousness/syncope Altered mental status/confusion Seizure Coma Focal neurologic deficit Pregnancy carboxyhemoglobin level ≥15% Acute myocardial ischemia Cardiovascular dysfunction/dysrhythmia Hypotension Severe metabolic acidosis Carboxyhemoglobin level ≥25% Tintinalli_Sec16_p1333-1418.indd 1416 8/2/19 8:23 PM

s of consciousness/syncope Altered mental status/confusion Seizure Coma Focal neurologic deficit Pregnancy carboxyhemoglobin level ≥15% Acute myocardial ischemia Cardiovascular dysfunction/dysrhythmia Hypotension Severe metabolic acidosis Carboxyhemoglobin level ≥25% Tintinalli_Sec16_p1333-1418.indd 1416 8/2/19 8:23 PM CHAPTER 222:  Carbon Monoxide      1417 by Hampson and colleagues 26 for those with mild symptoms. Methy lene chloride exposure requires ≥8 hours of observation and oxygen treatment.  TREATMENT OF CARBOXYHEMOGLOBIN WITH HIGH-RISK FEATURES American College of Emergency Physicians guidelines recommend that emergency providers “should use HBO 2 [hyperbaric oxygen] therapy or high-flow normobaric therapy for acute CO-poisoned patients. ” 20 However, two expert societies, the Undersea and Hyperbaric Medicine Society and the Tenth European Consensus Conference on Hyper baric Medicine, recommend hyperbaric oxygen for the treatment of symptomatic CO poisoning . 27,28 The indications for hyperbaric oxygen therapy listed in Table 222-3 are based on these two sources.27,28 A Cochrane review from 2011 examined six clinical trials; two were positive trials showing decreased neurologic sequelae, and the remain ing four trials failed to demonstrate a benefit. 29 However, all of the studies suffered from various degrees of methodologic flaws, and it was unclear whether hyperbaric oxygen improves long-term neurocognitive outcomes. 29 Two additional trials published since the Cochrane review were negative.30,31 Taking into consideration the evidence, as well as the recommendations from experts, the clinician should review the sever ity of the patient’s symptoms, the COHb level, the comorbid conditions (including pregnancy), and the location of the nearest center with emergency hyperbaric capabilities and consult with the referral center when considering the need for hyperbaric oxygen therapy. DISPOSITION Those without any high-risk features of CO intoxication may be discharged from the ED after symptom resolution and normalization of COHb as long as the exposure is not considered to be a suicide attempt and patients are returning to a safe environment. If there is a suspected source of environmental CO, other potentially exposed persons should be contacted and evaluated in the ED. Notify the fire department to measure ambient levels of CO at the source site. Once the safety of the discharge destination is established, the patient may be discharged. Patients with accidental or inadvertent CO exposure should be referred for cognitive follow-up in 4 to 6 weeks. 26 Intentional CO poisoning requires emergency psychiatric consultation in the ED and eventual follow-up for cognitive dysfunction. For those with high-risk features of CO intoxication, prior to referral or transport for hyperbaric oxygen, secure the airway, stabilize vital signs, continue 100% oxygen, and identify and treat trauma or acute surgical or medical issues. Fulfill Emergency Medical Treatment and Labor Act requirements prior to transfer. Given the limitations in space inside a hyperbaric chamber, as well as the difficulties in rapidly extricating the patient once a “dive” has commenced, most hyperbaric specialists are hesitant to accept an unstable patient. See Chapter 21, “Hyperbaric Oxygen Therapy, ” for additional information. SPECIAL SITUATIONS  DELAYED NEUROLOGIC SEQUELAE (OR ENCEPHALOPATHY) Delayed neurologic sequelae can occur 4 days to 5 weeks after CO exposure. There are no widely established diagnostic criteria for delayed injury, so the reported incidence varies widely, from 3% to 40% of patients. 32 In a series of 347 patients diagnosed with CO exposure, 24% were diagnosed with delayed neurologic sequelae.

neurologic sequelae can occur 4 days to 5 weeks after CO exposure. There are no widely established diagnostic criteria for delayed injury, so the reported incidence varies widely, from 3% to 40% of patients. 32 In a series of 347 patients diagnosed with CO exposure, 24% were diagnosed with delayed neurologic sequelae. 22 Risks include pro longed CO exposure (>6 hours), Glasgow Coma Scale score <9, seizures at the time of initial presentation, and leukocytosis. Reported neurologic effects include cognitive impairments and affective disorders. 22 The precise neuropathology is not known, but proposed mechanisms supported primarily by animal studies include apoptosis, immune-mediated injury, and delayed inflammation. 12,13,33,34 Hyperbaric oxygen has been used anecdotally with success for the treatment of delayed neurologic sequelae of CO 35; however, it has not been tested in a trial. A bundle therapy has been suggested for this indication using temperature control, hyperbaric oxygen, steroids, antioxidants, and sympatholytics. 36 The success of these therapies and the individual contribution of each component are yet to be determined.  INFANTS, PREGNANT WOMEN, AND THE ELDERLY Infants may be more susceptible to the effects of CO due to the persis tence of fetal hemoglobin for the first 6 months of life, as well as higher metabolic rates. 8 The indications for referral of children for hyperbaric oxygen therapy are similar to those for adults. Hyperbaric oxygen has been used in children with a good safety profile. There are no data on optimal therapy for exposure in neonates or young infants. Obtain consultation for this age group. Pregnant women should be considered for referral or discussed with the admitting physician at a hyperbaric center at CO levels of 15% to 20% because fetal morbidity has been demonstrated at lower levels than usual due to the high affinity of CO for fetal hemoglobin. The elderly, particularly those with serious comorbid disease, are also at higher risk from CO poisoning. In patients with known coronary artery disease, even low levels of COHb (4% to 6%) can cause ECG changes and myocardial ischemia. 8 Some elderly may also be at risk due to use of alternative heating sources, particularly during the winter. REFERENCES The complete reference list is available online at www.TintinalliEM.com. Tintinalli_Sec16_p1333-1418.indd 1417 8/2/19 8:23 PM

levels of COHb (4% to 6%) can cause ECG changes and myocardial ischemia. 8 Some elderly may also be at risk due to use of alternative heating sources, particularly during the winter. REFERENCES The complete reference list is available online at www.TintinalliEM.com. Tintinalli_Sec16_p1333-1418.indd 1417 8/2/19 8:23 PM Tintinalli_Sec16_p1333-1418.indd 1418 8/2/19 8:23 PM This page intentionally left blank