Epidemiology

Accidental hypothermia continues to be a public health problem. The Centers for Disease Control and Prevention (CDC) reports that between 1979 and 2002, a total of 16,555 deaths in the United States (average of 689 per year, range 417-1021) were attributed to excessive natural cold.²

Approximately 50% of all hypothermia-related deaths occur in persons older than 65. The age-adjusted mortality rate is three times higher for men than it is for women. In blacks and other races, the mortality rate is higher than that of whites.2,3 Blacks have decreased heat production and lower rectal temperatures in response to cold exposure.⁴ Other populations at risk include the elderly, people with preexisting chronic medical conditions, and people suffering from alcoholism and drug intoxication.^2,3,5 Emerging populations include wilderness enthusiasts and winter sport participants.⁶

Despite advances in medical care, hypothermia remains a challenge to health care providers, with in-hospital mortality rate reaching 40%,⁷ and an overall mortality rate ranging from 17% to 80%.⁸ The prompt recognition and appropriate management play a key role in improving outcomes.

Definition

Hypothermia is defined as a core body temperature lower than 35° C (<95° F). It has been further classified by severity according to the degree by which the core temperature has decreased from baseline into mild, moderate, and severe. Mild hypothermia is defined by a core body temperature of 32° to 35° C (90-95° F). Moderate hypothermia reflects a core body temperature of 28° to 32° C (82-90° F). Severe hypothermia is a core body temperature of less than 28° C (less than 82° F). Some reports refer to severe hypothermia below 30° C. In trauma patients, hypothermia carries a poorer prognosis. In this case, the definition is even more conservative, with severe hypothermia starting below 32° C. This subclassification has important implications regarding the anticipated physiologic changes and subsequently the use of appropriate therapeutic modalities.9,10

Heat Regulation

Body temperature is regulated through a balance between heat production and heat dissipation.¹¹ Heat production occurs mostly from the metabolic activity of energy-consuming processes within the viscera, namely, the heart, liver, and brain. Heat production in these organs is estimated to be between 40 and 60 kcal/m²/hour. Normally heat production is increased by food intake and muscle activity. Different stresses such as fever, infection, and cold exposure also increase heat production.

Heat loss occurs through different forms. Radiation cooling (infrared emissions) accounts for approximately 60% of heat loss. It occurs primarily from the head and unisolated parts of the body. Conduction (direct transfer of heat to an adjacent cooler object) and convection (direct transfer of heat to convective air currents) account for around 10% to 15% of heat loss. Evaporation from the skin and respiratory tract accounts for 25% to 30%. Conduction is an important mechanism in immersion accidents because thermal conduction of water is 30 times that of air. Convection is important in windy conditions by removing the warm isolating layer of air around the body.6,10,11

Upon cold exposure, the hypothalamus initiates mechanisms for heat conservation and heat production. Heat conservation is achieved by peripheral vasoconstriction, reducing heat conduction to the skin, and behavioral responses such as wearing more clothes and seeking a warmer environment. Heat production is achieved through stimulation of muscular activity via shivering, which can increase the basal metabolic rate by two to five times. A nonshivering thermogenesis occurs via increased levels of catecholamines and thyroxine.¹²

This coordinated physiologic response occurs typically for temperatures between 32° and 35° C. It only lasts for few hours, after which muscle fatigue and glycogen depletion ensue. As the core temperature drops below 32° C (90° F), shivering thermogenesis abates, and nonshivering thermogenesis slows down. By temperatures below 20° to 24° C, the different mechanisms of heat production completely fail.¹³

Clinical Presentation

Laboratory Evaluation

Laboratory evaluations should be obtained to assess metabolic status and organ dysfunction. The following are common laboratory findings during hypothermia. They usually change with rewarming and require frequent monitoring.

Management (see Fig. 69.2)

The severity of hypothermia, clinical findings, and comorbid conditions of the patient are important factors for determining the aggressiveness of resuscitation techniques. Once hypothermia is confirmed, assessment and treatment of the critically ill patient should take place simultaneously. Some patients with hypothermia and cardiac arrest achieved an almost complete recovery despite prolonged resuscitation with a temperature as low as 13.7° C. Patients with moderate or severe hypothermia should be resuscitated until adequate rewarming is achieved before declaring efforts as unsuccessful.33–35

Prognosis

Different reports on the outcome of moderate to severe hypothermic patients have been variable. Multiple confounding factors exist that make it difficult to predict survival. Older age, lower core body temperature, indoor exposure, submersion, trauma, toxin ingestion, prehospital hemodynamic status, BUN and potassium levels, the need for intubation, and presence or absence of asphyxiation are significant predictors of outcome. For patients undergoing CPB for hypothermia and hemodynamic instability, favorable factors for survival are associated with younger age, higher arterial pH, lower PaCO₂, lower serum potassium levels, and the absence of asphyxia and suffocation.¹⁸ Many patients die even after achieving adequate rewarming secondary to multiorgan failure. Knowing its detrimental outcome, an important approach should pursue prevention. In general, hypothermia is a preventable condition. Public health education and preparedness should be directed toward populations at risk.

History and Incidence

Innumerable military campaigns throughout history were lost as a result of heat illness, long before the enemy ever raised a weapon. In modern times, the Israeli Six-Day War during the late 1960s provides the best example of the ravages of heat illness. The Israeli army had forced water consumption policies, by the clock, including strict disciplinary measures for evidence of heat injury due to negligence. By contrast, the Egyptian army did not have well-enforced policies. In the end, the Israeli army’s heat injury statistics were negligible, but more than 50% of the Egyptian soldiers in the same locale suffered from heat illnesses that rendered them unable to effectively perform their expected tasks.

Heatstroke and hyperthermia have been identified as the environmental diseases least frequently monitored by epidemiology systems in the United States. Serious heat illness has received considerable recent attention owing to catastrophic heat waves in the United States and Europe, the deaths of high-profile athletes, and military deployments. The exact incidence of heatstroke in the United States is unknown. The CDC reported that between the years 1987 and 1988, 1092 death certificates listed excessive heat as either a primary or a secondary cause.⁴⁷ It is suspected that a number of other heat-related severe illnesses and deaths occur each year that are attributed to other causes. Guidelines from the National Association of Medical Examiners suggest that in cases in which the measured antemortem body temperature at the time of collapse was 105° F (40.6° C) or higher, the cause of death should be certified as heatstroke or hyperthermia. Deaths also may be certified as heatstroke or hyperthermia with lower body temperatures when cooling has been attempted before arrival at the hospital or when the clinical history includes mental status changes and elevated liver and muscle enzymes.⁴⁸

Pathogenesis

Heatstroke is a complex syndrome of end-organ dysfunction initiated by hyperthermia that occurs when heat accumulation in the body overwhelms heat-dissipating mechanisms. The diagnosis of heatstroke should be considered in patients with core body temperatures greater than 41° C, or in patients with a core temperature of 40.6° C and concomitant mental status changes. Because anhidrosis is a late finding and sweating may be observed in severely hyperthermic patients, diaphoresis should not be considered a discriminatory finding. Heatstroke traditionally is subdivided into exertional and nonexertional causes. Box 69.1 outlines examples of diseases and conditions within each of these categories. To understand the pathogenesis of heatstroke, the systemic and cellular responses to heat stress must be appreciated. These responses include thermoregulation (with acclimatization), an acute-phase response, and a response that involves the production of heat shock proteins.

Predisposing Factors

The epidemiology of heatstroke parallels that of hypothermia—nonexertional heatstroke is seen in elderly, alcoholic, or otherwise debilitated patients in urban areas. By contrast, exertional heatstroke develops in otherwise healthy people who overexert themselves in exceedingly hot or humid conditions. Like hypothermia, heatstroke most often develops in patients with impaired thermoregulation. Antidopaminergic drugs, alcohol, and primary central nervous system (CNS) disorders are common denominators in many patients.⁴⁹ A number of environmental and socioeconomic conditions have been associated in recent years with heatstroke.^50,51 A lack of air conditioning and a lack of trees or shrubbery around homes are commonly observed in patients presenting with heatstroke. People who are apartment bound, particularly those on higher floors, also appear to be at higher risk during summer heat waves. Finally, elderly patients not only have diminished temperature perception but also do not produce the same volume of sweat, placing them at higher risk for the development of heatstroke.

Many drugs, “recreational” and prescription, are associated with an increased risk of hyperthermia and deserve further emphasis. Cocaine causes generalized sympathetic activation and loss of response to environmental cues. It is rapidly becoming a leading cause of heatstroke in many urban emergency departments. Beta blockers, on the other hand, have been implicated in heatstroke through a drug-mediated direct decrease in sweat gland production. Diuretics decrease baseline circulating plasma volume, leading to decreased sweat production. Hypokalemia decreases sweat gland output as well, and barbiturates can even cause sweat gland necrosis. When a heat wave arrives in an urban area, any one or several of the foregoing factors combined can lead to outbreaks of heat injury.

Presentation and Clinical Manifestations

Nonexertional heatstroke may manifest insidiously.⁵² An urban setting and the recognized presence of a heat wave may be the best available diagnostic clues. Some form of CNS dysfunction is nearly universal in patients with nonexertional heatstroke. The spectrum of dysfunction ranges from increased irritability and confusion to stupor and coma. Hyperpyrexia often is the most specific physical finding. In many cases, the presentation of an elderly patient with an altered mental status, irritability, and a high fever suggests sepsis. However, epidemiologic associations, concurrent debilitating disease, and the impact of medications that limit thermoregulation should be considered before limiting therapy to empiric antibiotics and antipyretic medications.

Exertional heatstroke typically occurs more suddenly and with a more self-evident clinical history.⁵³ Severe dehydration, anhidrosis, and extreme hyperpyrexia are common in external heatstroke. Affected persons appear hyperdynamic, with tachycardia, increased cardiac output, and peripheral arterial vasodilation. CNS dysfunction is somewhat less common in this patient subset. Initially, thermoregulation is intact in patients with exertional hyperthermia. At high core body temperatures, however, metabolic activity overwhelms normal heat dissipation mechanisms, and clear-cut disruption of normal thermoregulation may then appear. Hyperthermia is further accelerated by the loss of effective sweating for evaporative heat dissipation. Myocardial dysfunction with depression of left ventricular ejection fraction also has been described after heatstroke, which resolves with treatment.⁵⁴

In addition to alterations of consciousness, hallucinations, focal neurologic deficits, various cranial nerve abnormalities, and opisthotonos are well described. Seizures occur in greater than half of these patients and may be related strictly to core body temperature or to concomitant disorders of free water-electrolyte balance. Decerebrate posturing also is rarely observed in some patients without other known mechanisms of acute brain injury. Many patients may suffer residual defects such as dementia, personality changes, focal deficits, cerebellar changes, or pyramidal findings. Nevertheless, many patients also proceed to complete recovery, suggesting that early findings should not deter acute management.⁵¹

Diagnostic Approach

In addition to CNS dysfunction, rhabdomyolysis is a frequent feature of exertional hyperthermia. Manifestations sometimes include tender, edematous muscles and “cola-colored” urine, but the condition more commonly is defined by elevation in total creatine kinase (CK), serum aldolase, uric acid, or serum potassium (alone or in combination). Hyperkalemia in this situation may be life-threatening.

Acute renal failure occurs in up to one third of patients with heatstroke.⁵⁵ It is considerably more common in patients in whom rhabdomyolysis is a feature (i.e., with myoglobinuria or urate nephropathy). However, direct heat injury and renal hypoperfusion also may contribute. Acute tubular necrosis in heatstroke typically manifests with oliguria, non-nephrotic range proteinuria, and abundant granular cast formation.

Evidence of hepatocellular injury is present to some degree in essentially all patients with heatstroke and is attributed principally to a direct toxic effect of hyperthermia on hepatocytes.⁵⁶ Elevation of serum transaminases is a cardinal feature of this toxicity and often is observed within 30 minutes of syndrome onset. So prevalent is this finding that the absence of transaminitis should cast serious doubt on the diagnosis of heatstroke. Histologic changes including centrilobular necrosis have been observed within 24 hours of heat injury and evolve over the ensuing days. Transaminase and lactate dehydrogenase levels typically peak on the third or fourth hospital day, and depending upon the extent of injury, these changes may be accompanied by increased alkaline phosphatase levels, hyperbilirubinemia, and a prolonged prothrombin time. Overall, fulminant hepatic necrosis is rare; however, hepatic insufficiency contributes to late morbidity and death in patients who survive the initial resuscitation.⁵⁷ Prolongation of coagulation times also may be due to disseminated intravascular coagulation (DIC). Although DIC also is rare, it is a marker of poor prognosis when present. Clinical manifestations of DIC range from isolated laboratory abnormalities to generalized bleeding. In patients with heatstroke, DIC may exacerbate hepatic injury and is associated with the development of acute respiratory distress syndrome (ARDS). In fact, the codevelopment of DIC and ARDS in patients with heatstroke is predictive of a high mortality rate (>75%). Qualitative coagulation function (including platelet function) also may be impaired by heat injury. The clinical effects of these impairments are variable.

A range of electrolyte abnormalities related to renal failure and dehydration in heatstroke victims has been well described and includes hyponatremia, hypocalcemia, hypokalemia (hyperkalemia in patients with acute tubular necrosis or rhabdomyolysis), hypophosphatemia, and hypomagnesemia. Of these, hyponatremia and free water excess may produce severe neurologic effects including central pontine myelinolysis (CPM). CPM has been reported in patients with heatstroke who receive aggressive prehospital resuscitation with hypotonic solutions. Serum osmolality should be carefully monitored during volume resuscitation, and intravenous solutions should be modified accordingly. Severe lactic acidosis is especially common in patients with exertional heat injury.⁵⁸ Finally, arterial blood gas results are influenced by temperature in a fashion opposite that described with hypothermia (Box 69.2).

Specific Hyperthermic Syndromes

Malignant hyperthermia (MH) and NMS deserve special emphasis because of their potentially catastrophic impact on critically ill patients, particularly when they are not promptly recognized. MH is associated with use of certain anesthetic agents and can lead to profound skeletal muscle contraction and the subsequent development of life-threatening hyperthermia and other complications. NMS is caused by a variety of antipsychotic drugs and also leads to sustained muscular contraction and hyperthermia.

Pathogenesis

MH results from a rapid, sustained increase in myoplasmic Ca²⁺ levels in response to halogenated anesthetics and depolarizing neuromuscular blocking agents. Susceptibility to MH results from mutations in calcium channel proteins that mediate excitation-contraction coupling, with the ryanodine receptor calcium release channel (RyR1) representing the major locus. The mode of inheritance appears to be autosomal dominant, with variable penetrance. The phenomenon occurs in persons who have a mutation in the ryanodine type 1 receptor, resulting in a defective protein in the skeletal muscle sarcoplasmic reticulum membrane.⁶³ The uncontrolled rise in the myoplasmic Ca²⁺ concentration disables the troponin inhibition of actin and myosin, resulting in uncontrolled muscle tetany. This surge in muscle metabolic activity causes thermogenesis to increase exponentially and is rapidly followed by total body rigidity and extreme hyperpyrexia.

Numerous familial myopathies (such as Evans myopathy, King-Denborough syndrome, and central core disease) have been associated with the reaction.64,65 Curiously, this genetic predisposition does not translate into the predictable development of MH. That is, an initial challenge with an anesthetic drug that leads to MH does not consistently predict whether or not MH will occur with future exposures to the same drug. Measured contraction in caffeine or halothane preparations of muscle biopsy specimens is the most reliable predictor of risk for MH.

Presentation

MH is characterized by the triad of (1) severe hyperthermia, (2) muscle rigidity, and (3) metabolic acidosis. MH usually is an acute and rapidly progressive process; however, many reports suggest that the syndrome may vary considerably in severity and rate of progression. In the anesthesia setting, capnography may provide the earliest clue of impending MH, as end-tidal CO₂ rises in response to the increased metabolic rate. Clinical harbingers of impending MH include masseter muscle rigidity or trismus and tachycardia, which is reported to occur in greater than 95% of patients.⁶⁴ Cyanosis, increased blood pressure, and increased respiratory rate all may be observed with the onset of the reaction as the hypermetabolic response is triggered.

Muscle rigidity may explosively progress from localized masseter contraction to diffuse rigidity of skeletal muscle groups. When uninterrupted, this process will lead to progressive, severe hyperthermia. Extreme hyperpyrexia is considered a late finding in MH. Mortality risk has been related to peak core body temperature, reflecting both MH severity and delayed recognition. With progressing rigidity, a mixed metabolic and respiratory acidosis may occur, along with a variety of other electrolyte abnormalities, including hyperkalemia, hypercalcemia, and hypermagnesemia. Severe chest wall rigidity may even prevent adequate mechanical ventilation, leading to life-threatening hypoxemia and hypoventilation. Rhabdomyolysis is reflected in elevated CK levels, usually greater than 1500 U/L and often greater than 10,000 U/L. Myoglobinuria may produce acute tubular necrosis with oliguric renal failure and severe DIC. High fever may result in myocardial dysfunction, pulmonary edema, and cerebral edema.

Diagnosis

Susceptibility to MH can be identified unequivocally only by an in vitro muscle test. Fascicles of muscle obtained from the thigh by biopsy are exposed to halothane and separately to increasing concentrations of caffeine in vitro. The muscle contractures are increased in persons who are susceptible to MH. This test is now widely used to identify susceptibility to MH in patients who have had a reaction to inhaled halogenated anesthetics or suxamethonium that is suggestive of MH. If the test results in the propositus are positive, testing can be offered to first-degree relatives for genetic counseling. Patients whose biopsied muscle demonstrates a contracture to 3% halothane of 0.5 g or more and a contracture to 2 mmol/L caffeine of 0.2 g or more are considered to be susceptible to MH.⁶⁶ An in vitro contracture test is the gold standard for diagnosing susceptibility to MH. Two different protocols are used. European laboratories use the protocol devised by Ellis in Leeds with incremental doses of halothane up to 2% and incremental doses of caffeine. In the United States, a single dose of 3% halothane and incremental doses of caffeine are used. The two protocols give essentially the same results.⁶⁷

Treatment

By far, the most important measure for MH is the immediate cessation of any suspected triggering agents. If anesthesia must be maintained, nontriggering agents should be used. Agents considered safe in MH include barbiturates, narcotics, benzodiazepines, and propofol, to name only a few. Nondepolarizing neuromuscular blockers such as vecuronium or atracurium, although also considered safe in these patients, will do nothing to abort the MH reaction because the primary disease resides within the skeletal muscle cell itself—beyond the neuromuscular junction.

In addition to discontinuing offending agents, sodium dantrolene should be administered. Sodium dantrolene initially was tested as an antimicrobial; however, dantrolene was found to produce muscle weakness by blocking the Ca²⁺ efflux from the sarcoplasmic reticulum. The agent is capable of reversing the MH reaction by lowering myoplasmic Ca²⁺ concentrations. The onset of action usually is within 2 to 3 minutes, with initial responses including muscle relaxation, decreasing heart rate, and decreasing core body temperature. Muscle weakness may follow drug administration, but this should never limit proper therapy. After the initial response, dantrolene may be dosed orally for 24 to 48 hours. Late recurrences of MH have been reported if inadequate dantrolene dosing occurs. Intravenous preparations of dantrolene contain significant amounts of mannitol, which may produce a subsequent osmotic diuresis. Although this reaction may be desirable in patients with rhabdomyolysis, volume and electrolyte management should take this effect into account.

Systemic cooling may be best achieved in these complex patients with evaporative techniques, cooling blankets, cold saline infusion, or ice packs. Because of its similar actions on myoplasmic Ca²⁺ concentration, procainamide was the drug of choice for this syndrome before the advent of dantrolene therapy. Cardiac dysrhythmias not responding to electrolyte correction may be safely treated with procainamide or lidocaine. Numerous reports suggest that intravenous calcium may be safely infused for toxic hyperkalemia. Diltiazem and verapamil may interact with dantrolene to produce hyperkalemia; therefore, these agents should be avoided. Although the effects of MH on cardiac muscle remain unclear, some authors advocate that cardiac glycosides also should be avoided because they increase intracellular Ca²⁺ concentration.

Pathophysiology

Some investigators suspect that the genetic predisposition to MH also defines patients at risk for NMS, but most work has failed to demonstrate a relationship between NMS and altered sarcolemmal membrane calcium permeability. Unlike in MH, patients with NMS appear to have both increased heat production and impaired central thermoregulation, compromising heat dissipation. In these patients, a decrease in central dopaminergic tone also results in extrapyramidal signs of skeletal muscle rigidity and tremor and may account for alterations in mental status due to effects in the mesolimbic system and mesocortical pathways.⁶⁸ Finally, even though altered central thermoregulation may contribute to hyperthermia in NMS, rapid resolution of fever after administration of neuromuscular relaxing agents or dantrolene suggests that hyperthermia is due primarily to increased heat generation by skeletal muscle rigidity.

Presentation

NMS should be considered when fever, muscular rigidity, catatonia, or dystonia occur in the setting of neuroleptic drug administration. Recent reviews have suggested the following criteria for the diagnosis of NMS: treatment with neuroleptics within 7 days; hyperthermia with core temperatures greater than 38° C; muscle rigidity; exclusion of other systemic or drug-related illness; and any five of the following: altered mental status, tachycardia, hypertension or hypotension, tachypnea or hypoxia, diaphoresis or sialorrhea, tremor, incontinence, CK elevation or myoglobinuria, leukocytosis, or metabolic acidosis.68,69

Altered mental status commonly precedes the onset of other symptoms and may manifest as confusion or agitation. More severe cases may progress to obtundation or coma, or may manifest as a mute catatonia that is difficult to differentiate from lethal catatonia. Muscle rigidity typically involves the neck, shoulders, and limbs but may compromise ventilation if chest wall involvement is severe. Other neuromuscular findings are diverse and may include dysarthria, dyskinesias, ataxia, or tremors.

Autonomic findings typically include diaphoresis, hypertension, and tachycardia. However, hypotension may develop in some patients. Fever is a late finding and usually occurs in the range of 38° to 42° C. When fever exceeds 42° C, it may cause end-organ damage like that seen in other hyperthermia syndromes.

Rhabdomyolysis occurs often, though it usually is of a milder caliber than that observed in MH or exertional heatstroke. Elevations in serum transaminases, BUN, and serum Cr often are seen, as well as a leukocytosis.

Treatment

When NMS is suspected, the offending drug should be discontinued immediately and supportive measures initiated. Volume resuscitation, physical measures for cooling, and monitoring of cardiopulmonary and renal parameters should be instituted immediately. Pharmacologic options for the treatment of NMS are more numerous than for other hyperthermia syndromes, because they may be directed toward restoring central dopaminergic tone or reducing peripheral rigidity until the neuroleptic effects subside.

Dopamine agonists such as bromocriptine, amantadine, and levodopa-carbidopa have been successfully employed in NMS.68,70 These agents act to directly increase central dopaminergic tone, thereby antagonizing the various effects of neuroleptic dopamine blockade. Regimens include bromocriptine or amantidine for up to 10 days before tapering, If a levodopa-carbidopa combination is used, it should be dosed four times a day owing to its shorter half-life. Some authors advocate avoiding central dopamine agonists if the diagnosis is unclear or if psychosis remains in the differential diagnosis, to avoid acutely exacerbating the psychotic state or contributing to a lethal catatonia.

Sodium dantrolene has been successfully used in numerous small series. The muscle relaxation that occurs helps to reduce temperature and decrease the sequelae of prolonged rigidity. Neuromuscular blockers also are effective at decreasing skeletal muscle tone, and in patients with high fever and autonomic instability, these agents offer a rapid means of establishing therapeutic effects. Combinations of central dopamine agonists and peripheral-acting agents have not as yet demonstrated a significant advantage over either treatment alone. Electroconvulsive therapy (ECT) has been used in a number of reports, but its advantages over supportive care alone have not been adequately assessed.⁷⁰ Furthermore, the need for anesthesia presents an additional hazard that may complicate management in these patients.

Airway-protective reflexes should be vigilantly assessed because dystonia and impaired bulbar functions increase the risk of gastric aspiration in patients with NMS. Morbidity and mortality risks in these cases often arise from pulmonary complications such as aspiration, pneumonia, ARDS, or pulmonary embolism. Cardiac complications such as arrhythmias or myocardial infarction in more fulminant cases also contribute to fatality in these patients. As in all of the hyperthermia syndromes, worsening rhabdomyolysis and acute renal failure have been identified as signs of poor prognosis.

Epidemiology

The incidence of rhabdomyolysis is dependent on the population undergoing analysis and the diagnostic criteria being used. It is recognized as a major cause of fatality following severe musculoskeletal injury from trauma.⁷² Following the 1999 Marmara earthquake in northwestern Turkey, 8.9% of hospitalized patients required renal replacement therapy for crush-related injuries.⁷³ Recently, a particular focus has been the ability of the HMG-CoA reductase (3-hydroxy-3-methyl-glutaryl-CoA reductase) inhibitor class of medications to cause rhabdomyolysis. Though likely a class phenomenon and rare overall, the incidence of rhabdomyolysis is not equivalent for all medications and is increased with the addition of other specific agents, in particular gemfibrozil, other fibrates, or cyclosporine.^74,75 Additional causes of rhabdomyolysis are listed in Box 69.4.^76–81 A recent review noted exogenous toxins, both prescribed and illicit, to be responsible for nearly 50% of cases.⁸²

Two additional scenarios that have received significant attention include “propofol infusion syndrome” and the potential for patients with sickle cell trait (SCT) to develop rhabdomyolysis. Both of these situations occur in younger patients. Propofol is rarely associated with a syndrome of metabolic acidosis and rhabdomyolysis. Risk factors include high-dose infusions over a prolonged period and a young age.83–86 SCT with subsequent rhabdomyolysis due to exertional sickling is now recognized as a cause for sudden deaths in young patients during strenuous workouts, in particular, football. ^87–93

The epidemiology of rhabdomyolysis is limited by a lack of uniformity regarding the critical value in CK elevation needed to make the diagnosis. Threshold values above which rhabdomyolysis may occur vary and have ranged from 1000 to 10,000 U/L, though 5000 to 10,000 U/L are most common.⁹⁴ From an intensivist’s perspective, CK elevations less than 5000 U/L should not be associated with myoglobin-induced renal failure unless clear additive causes such as volume depletion, sepsis, or radiocontrast are also present.

Pathophysiology

The primary event in rhabdomyolysis is muscle cell necrosis resulting in the accumulation of sodium and calcium intracellularly; disruption of the cell membrane and excessive requirements for adenosine triphosphate accelerate this insult.95,96 As muscle cells undergo necrosis, intracellular substances are released and include potassium, uric acid, phosphorus, lactic acid, and myoglobin. Under normal circumstances, haptoglobin binds any free myoglobin, thus prohibiting filtration across the glomerulus. As the haptoglobin binding is overwhelmed, free myoglobin is filtered and injures renal tubular cells. This process involves free radical toxicity. Additional causes include volume depletion, renal vasoconstriction, and tubular obstruction.^76,97 Myoglobin and urinary tubular-protein casts are more prone to precipitation at a lower pH in experimental models. As a result, inducing an alkaline diuresis has been a traditional part of therapy for cases of rhabdomyolysis.⁹⁸

Research has suggested that it is the reperfusion of ischemic muscle as much as the ischemia itself that produces a high burden of oxygen-derived free radicals with subsequent cellular lipid membrane injury.⁹⁹ As renal function worsens, particularly when accompanied by intravascular volume depletion and renal failure, patients cannot excrete the high load of metabolites associated with muscle death, especially potassium.

Myoglobin release occurs across a spectrum of physical injuries from moderate exercise to lethal crush injuries. Myoglobinemia was noted in 39% of a cohort of Marine recruits, illustrating the frequency of mild muscle cell necrosis with strenuous exercise.¹⁰⁰ Obviously, not all such injuries lead to AKI. Beyond the actual amount of muscle necrosis, the development of AKI is most dependent on the degree of volume depletion present during the initial insult and the rapidity with which it is restored. Many of the syndromes that lead to the development of rhabdomyolysis, such as very strenuous exercise, crush injuries, or intoxications, are accompanied by volume depletion.

Clinical Presentation

Patients with rhabdomyolysis present with a variety of symptoms. Often there is a history of injury, weakness, or muscle pain. Dark red or brown urine may or may not be present, depending on the amount of muscle necrosis and delay from injury. Frequently, the history is limited because of altered sensorium; clues include unexplained acidosis, hyperkalemia, hyperuricemia, hypocalcemia, elevations in CK not consistent with myocardial infarction, and unexplained renal failure. Recurrent presentations warrant an evaluation for a metabolic myopathy.¹⁰¹ Screening for rhabdomyolysis, through serial CK measurements, may be worthwhile in high-risk obese patients (body mass index over 56 kg/m²) undergoing gastric bypass surgery.¹⁰²

In most instances, serum CK will increase during the initial 48 hours of hospitalization. In a retrospective review of patients admitted to an ICU with rhabdomyolysis, defined as a CK greater than 10,000 U/L, significantly higher CK levels were associated with renal failure.¹⁰³ In the group with renal failure, the mean CK levels were 47,194 and 55,366 U/L at admission and peak, respectively; in the group without renal failure, the same levels were 17,531 and 28,643 U/L.

Although myoglobin is the most important protein in terms of nephrotoxicity, serum CK is routinely used in clinical practice as a marker of disease severity. This inconsistency is due to the widespread availability of the CK assay. Myoglobin clearance is not dependent on the kidneys and thus levels peak before CK levels.¹⁰⁴ Consequently, the CK levels being monitored for disease activity may not correlate with the timing of the renal injury. AKI due to peak CK levels less than 5000 U/L should not be attributed to rhabdomyolysis unless the diagnosis was made substantially after the peak period of muscle cell necrosis; in this scenario, the CK levels will have decreased from a previously undocumented level.

The change of serum Cr in nonrhabdomyolysis oliguric AKI is usually not more than 1 mg/dL/24 hours. In rhabdomyolysis, Cr enters the intravascular compartment at a higher rate due to cell lysis, yielding an unusually rapid rise in serum Cr. In an early report, Grossman and associates noted a rise in Cr frequently greater than 2.5 mg/dL/day.¹⁰⁵ Speculation exists that this change in Cr may, in part, be due to the larger than average size in patients affected with rhabdomyolysis.¹⁰⁶ These same authors noted the impressive rate of renal recovery from rhabdomyolysis-induced AKI seen in the majority of patients; this high rate of recovery is now well recognized.

Specific Treatment Requirements

The most important intervention to limit renal complications of crush-related injuries is early and aggressive volume resuscitation. Delays in initiation of intravenous fluid are associated with a higher frequency of patients requiring renal replacement therapy.¹⁰⁷ The damaged muscle cells provide a large reservoir for fluid sequestration; as a result large volumes of intravenous fluids have to be given and, ideally, should be instituted as early as possible, even on-site before victims of crush injuries are freed.^78,108 A debate exists in the medical literature regarding the ideal type of volume resuscitation. As previously mentioned, alkaline diuresis has been shown in animal models to decrease the formation of myoglobin casts and subsequent AKI.⁹⁸ Similarly, mannitol is an agent favored for its proposed ability to scavenge free radicals and to reduce tissue swelling due to osmotically induced fluid removal from damaged muscle.^109,110 These treatments have not been validated in well-designed, prospective trials. Retrospective studies suggest no benefit with the addition of mannitol or alkaline diuresis over normal saline alone.¹¹¹ In addition, there are potential risks to volume expansion with bicarbonate-based solutions or mannitol. They include the increased risk of calcium-phosphate complex formation and hypocalcemia from an increase in pH and the development of a hyperosmolar state when renal failure limits mannitol excretion. Finally, mannitol may increase the risk of renal failure in certain populations.¹¹² Risk factors for mannitol-induced AKI include kidney dysfunction, high-dose mannitol therapy, and use of cyclosporin A. In summary, volume expansion irrespective of the type of agent is the most important treatment modality. The focus on adequate diuresis is appropriate but presumes myoglobin-induced renal damage is ongoing. Intensivists often encounter patients whose myoglobin load is falling and whose renal insult has already occurred. Though the Cr may continue to rise, the onset of oliguria suggests limited benefit from further aggressive volume resuscitation, presuming adequate intravascular volume has been restored. In fact, given the good prognosis of AKI, overzealous volume resuscitation risks pulmonary compromise.

Historically, extremely aggressive volume resuscitation was pursued with an initial goal diuresis of up to 12 L/day, presuming intact renal function. Less aggressive volume resuscitation may be equally protective though data are lacking. The focus on diuresis downplays the importance of establishing and maintaining adequate intravascular volume. Central venous pressure or other means to monitor intravascular pressure may be more useful to determine adequate resuscitation. It is also likely that the rapidity with which volume status is restored, irrespective of the type or quantity of diuresis, is the key determininant. Unfortunately, these guidelines are poorly studied in a prospective format.

In the setting of AKI requiring renal replacement therapy, the ideal modality is the one most easily accessible, assuming hemodynamic stability. Options include hemodialysis, peritoneal dialysis, and continuous modalities. Though continuous renal replacement modalities provide the best theoretical protection from ongoing metabolic and volume complications, its superiority has not been verified in rigorous trials. In cases associated with large-scale injuries such as earthquakes, the remaining infrastructure often dictates which dialytic modality can and should be provided.72,113 Historically, peritoneal dialysis has not been considered adequate in its ability to remove the large solute load present with rhabdomyolysis.¹¹⁴ Nonetheless, if it is the only available modality its potential role in managing rhabdomyolysis may be improved with more frequent exchanges. It should be noted that no traditional renal replacement method has the capability of removing myoglobin because of its size. However, considering the rapid extrarenal clearance of myoglobin it is unclear if therapy focused on myoglobin clearance will provide any superiority over current care. A novel approach recently evaluated the use of super high-flux (SHF) membranes to clear myoglobin during continous venovenous hemofiltration.^115,116 The authors demonstrated a fivefold increase in myoglobin removal but did acknowledge the potential for the removal of albumin, clotting factors, and protein-bound medications.

Hypocalcemia is common in rhabdomyolysis and may provide challenging management choices. Calcium entry into necrotic muscle cells often causes profound hypocalcemia. Calcium supplementation should be reserved for those patients with symptomatic hypocalcemia as hypercalcemia is a frequent finding during disease recovery.¹¹⁷ In addition, rapid increases in serum pH through the administration of intravenous bicarbonate may worsen hypocalcemia. Rasburicase has been reported to reduce hyperuricemia in young patients with rhabdomyolysis.¹¹⁸

Additional issues include close monitoring for limb ischemia due to compartment syndromes induced by muscle damage and subsequent fluid sequestration. Intracompartmental pressure monitoring may predict the need for intervention though research has suggested additional factors, most importantly hypotension and the difference between mean arterial pressure and intracompartmental pressures, influence whether compartment syndrome develops.¹¹⁹ The history, logic, and disappointing results of early and aggressive fasciotomy have recently been described.¹²⁰ Mannitol is postulated to “decompress” intracompartmental edema in acute muscle compartment syndromes. Animal data support an acute reduction in intracompartmental pressures¹²¹; long-term tissue protection and human outcomes have not been validated. High-dose corticosteroids have been proposed as a treatment option for refractory cases of rhabdomyolysis but prospective studies are lacking.¹²²

In summary, rhabdomyolysis is a frequent, treatable disorder. Extensive metabolic research has yielded a number of clues about the cause of AKI during rhabdomyolysis. Therapy should emphasize aggressive and early volume resuscitation. Renal replacement therapy may be necessary to assist in managing the metabolic complications of patients; patients have a good prognosis for recovery of rhabdomyolysis-induced AKI.

1. Guly, H. History of accidental hypothermia. Resuscitation. 2011; 82:122–125.

2. Centers for Disease Control and Prevention. Hypothermia related deaths, United States 2003-2004. MMWR. 2005; 54(7):173–175.

3. Centers for Disease Control and Prevention. Hypothermia related deaths, Virginia, November 1996-April 1997. MMWR. 1997; 46:1157.

4. Koutsavlis, AT, Kostasky, T. Environmental-temperature injury in a Canadian metropolis. J Environ Health. 2003; 66:40.

5. Farnell, GS, Pierce, KE, Collinsworth, TA, et al. The influence of ethnicity on thermoregulation after acute cold exposure. Wilderness Environ Med. 2008; 19:238–244.

6. Ulrich, AS, Rathlev, NK. Hypothermia and localized cold injuries. Emerg Med Clin North Am. 2004; 22:281–298.

7. Vassal, T, Benoit-Gonnin, B, Carrat, F, et al. Severe accidental hypothermia treated in an ICU: Prognosis and outcome. Chest. 2001; 120:1998.

8. Danzl, D, Pozos, R, Auerback, P, et al. Multicenter hypothermia survey. Ann Emerg Med. 1987; 16:1042–1055.

9. Giesbrecht, GG. Cold stress, near drowning, and accidental hypothermia: A review. Aviat Space Environ Med. 2000; 71:733.

10. Jolly, BT, Ghezzi, KT. Accidental hypothermia. Emerg Med Clin North Am. 1992; 10:311.

11. Schneider, SM, Danzl, DR. Hypothermia from recognition to re-warming. Emerg Med Rep. 1992; 13:1.

12. McCulough, L, Arora, S. Diagnosis and treatment of hypothermia. Am Fam Physician. 2004; 70(12):2325–2332.

13. Tikuisis, P, Eyolfson, DA, Xu, X. Shivering endurance and fatigue during cold water immersion in humans. Eur J Appl Physiol. 2002; 87:50–58.

14. Guatam, P, Ghosh, S, Mandal, A, Vargas, E. Hypothermia: Sociomedical characteristics and the outcome in 86 patients. Public Health. 1989; 103:15.

15. Danzl, DF, Pozos, RS. Accidental hypothermia. N Engl J Med. 1994; 331:1756.

16. Jurkovich, GJ. Environmental cold induced injury. Surg Clin North Am. 2007; 87:247–267.

17. Ginsberg, MD, Globus, MY, Dietrich, WD, et al. Temperature modulation of ischemic brain injury: A synthesis of recent advances. Prog Brain Res. 1993; 96:13.

18. Silfvaot, T, Pettila, V. Outcome from severe accidental hypothermia in southern Finland—A 10 year review. Resuscitation. 2003; 59:285.

19. Ozaki, H, Nagai, Y, Tochihara, Y. Physiological responses and manual responses in humans following repeated exposures to cold at night. Eur J Appl Physiol. 2001; 84(4):343–349.

20. Gilbert, M, Busund, R, Skagseth, A, et al. Resuscitation from accidental hypothermia of 13. 7 degrees C with circulatory arrest. Lancet. 2000; 355(9201):375–376.

21. Aslam, AF, Aslam, AK, Vasarada, BC, Khan, IA. Hypothermia: Evaluation, electrocardiographic manifestations and management. Am J Med. 2006; 119(4):297–401.

22. Bartley, B, Crnkovich, DJ, Usman, AR, Carlson, RW. How to recognize hypothermia in critically ill patients. J Crit Care Illness. 1996; 11:118.

23. Cohen, D, Cline, J, Lepinski, S. Resuscitation of the hypothermic patient. Am J Emerg Med. 1998; 6:475–478.

24. Ledinham, I, Mone, J. Treatment of accidental hypothermia: A prospective clinical study. BMJ. 1980; 1:102–105.

25. Granberg, PO. Human physiology under cold exposure. Arctic Med Res. 1991; 50(Suppl 6):23–27.

26. Shapiro, BA. Temperature correction of blood gas values. Respir Care Clin North Am. 1995; 1:69.

27. Zander, R. Optimization of the acid-base status in hypothermia. Anaesthetist. 2007; 55(9):912–916.

28. Brieva, J, McFadyen, B, Rowley, M. Severe hypothermia. Anaesth Intensive Care. 2005; 33:662–664.

29. Levin, S, Brettman, LR, Holzman, RS. Infections in hypothermic patients. Arch Internal Med. 1981; 141:920–925.

30. Rohrer, MJ, Jatale, AM. Effect of hypothermia on the coagulation cascade. Crit Care Med. 1992; 20:1402.

31. Bokenes, L, Alexandersen, TE, Osterud, B, et al. Physiological and haematological responses to cold exposure in the elderly. Int J Circumpolar Health. 2000; 59:216–221.

32. Helman, A, Gilbert, M, Pfisler-Lemaire, N, et al. Glucagon and insulin secretion and their biological activities in hypothermic rats. Endocrinology. 1984; 115(5):1722–1728.

33. Weinberg, AD. Hypothermia. Ann Emerg Med. 1993; 22(Pt 2):370.

34. Braun, R, Krishel, S. Environmental emergencies. Emerg Med Clin North Am. 1997; 15:1451.

35. Lazar, HL. The treatment of hypothermia. N Engl J Med. 1997; 337:1545.

36. Sheaff, C, Fildes, J, Keogh, P, et al. Safety of 65 degrees intravenous fluid for the treatment of hypothermia. Am J Surg. 1996; 172:52–55.

37. American Heart Association. 2005 Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care: Hypothermia. Circulation. 2005; 112(24 Suppl):IV136.

38. Soar, J, Perkins, GD, Abbas, G, et al. European Resuscitation Council guidelines for resuscitation section 8—Cardiac arrest in special circumstances: Section 8d. Hypothermia. Resuscitation. 2010; 81:1408–1410.

39. Wira, CR, Becker, JV, Martin, G, Donnino, MW. Antiarrhythmic and vasopressor medications for the treatment of ventricular fibrillation in severe hypothermia: A systemic review of literature. Resuscitation. 2008; 78:21–29.

40. Vanderploeg, GJ, Goslings, JC, Walpoth, BH, Bierens, JJLM. Accidental hypothermia: Rewarming treatments, complications, and outcomes from university medical centre. Resuscitation. 2010; 81:1550–1555.

41. Keller, R, Schnider, TW, Nerdhart, P. Deep accidental hypothermia and cardiac arrest—Rewarming with forced air. Acta Anesthesiol Scand. 1997; 41:1359.

42. Steele, MT, Nelson, MJ, Sessler, DI, et al. Forced air speeds rewarming in accidental hypothermia. Ann Emerg Med. 1996; 27:479.

43. Lloyd, EL. Accidental hypothermia. Resuscitation. 1996; 32:111–124.

44. Slouis, CM, Bachvarov, HL. Heated inhalation treatment of hypothermia. Am J Emerg Med. 1984; 2:533.

45. Kjaerguard, B, Back, P. Warming of patients with accidental hypothermia using warm water lavage. Resuscitation. 2006; 68:203.

46. Sultan, N, Theakston, KD, Butler, R, Suri, RS. Treatment of severe accidental hypothermia with intermittent hemodialysis. Can J Emerg Med. 2009; 11(2):174–177.

47. Centers for Disease Control and Prevention. Monitoring environmental disease—United States, 1997. JAMA. 1998; 280:688–689.

48. Heat-related deaths—Philadelphia and the United States. MMWR Morb Mortal Wkly Rep. 1994; 43:453–455.

49. Kilbourne, EM, Choi, K, Jones, TS, et al. Risk factors for heat stroke. A case control study. JAMA. 1982; 247:3332.

50. Donoghue, ER, Graham, MA, Jentzen, JM, et al. Criteria for the diagnosis of heat-related deaths: National Association of Medical Examiners. Position paper. National Association of Medical Examiners Ad Hoc Committee on the Definition of Heat-Related Fatalities. Am J Forensic Med Pathol. 1997; 18:11–14.

51. Richards, D, Richards, R, Schofield, J. Management of heat exhaustion in Sydney’s the Sun City-to-Surf fun runners. Med J Aust. 1979; 2:457.

52. Nadel, ER. Temperature regulation and hyperthermia during exercise. Clin Chest Med. 1984; 5:13–20.

53. Schvartz, E, Shapiro, Y, Magazanik, A, et al. Heat acclimatization, physical fitness and response to exercise in temperate and hot environment. J Appl Physiol. 1977; 43:678.

54. Rousseau, JM, Villevieille, T, Schiano, P, et al. Reversible myocardial dysfunction after exertional heat stroke. Intensive Care Med. 2001; 27:328–329.

55. Tucker, LE, Stanford, J, Graves, B, et al. Classical heatstroke: Clinical and laboratory assessment. South Med J. 1985; 78:20.

56. Hashim, IA. Clinical biochemistry of hyperthermia. Ann Clin Biochem. 2010; 47:516–523.

57. Jacobsen, TD, Krenzelok, EP, Shicker, L, et al. Environmental injuries. Dis Mon. 1997; 43:809–907.

58. Bouchama, A, Devol, EB. Acid-base alterations in heatstroke. Intensive Care Med. 2001; 27:680–685.

59. Dematte, JE, O’Mara, K, Buescher, J, et al. Near-fatal heat stroke during the 1995 heat wave in Chicago. Ann Intern Med. 1998; 129:179–181.

60. White, DJ, Kamath, R, Nucci, R, et al. Evaporation versus iced peritoneal lavage treatment of heatstroke: Comparative efficacy in a canine model. Am J Emerg Med. 1993; 11:1–3.

61. Bouchama, A, Cafege, A, Devol, EB, et al. Ineffectiveness of dantrolene sodium in the treatment of heatstroke. Crit Care Med. 1991; 19:176–180.

62. Zucherman, GB, Singer, LP, Rubin, DH, et al. Effects of dantrolene on cooling times and cardiovascular parameters in an immature porcine model of heatstroke. Crit Care Med. 1997; 25:135–139.

63. Quane, KA, Healy, JM, Keating, KE, et al. Mutations in the ryanodine receptor gene in central core disease and malignant hyperthermia. Nat Genet. 1993; 5:51–55.

64. Brandon, BW. The genetics of malignant hyperthermia. Anesthesiol Clin North Am. 2005; 23:615–619.

65. Denborough, M. Malignant hyperthermia. Lancet. 1998; 352:1131–1136.

66. Moulds, RFW, Denborough, MA. Identification of susceptibility to malignant hyperthermia. BMJ. 1974; 2:245–247.

67. European Malignant Hyperpyrexia Group. A protocol for the investigation of malignant hyperpyrexia (MH) susceptibility. Br J Anaesth. 1984; 56:1267–1269.

68. Chan, TC, Evans, SD, Clark, RF. Drug-induced hyperthermia. Crit Care Clin. 1997; 13:785–808.

69. Caroff, SN, Mann, SC. Neuroleptic malignant syndrome. Med Clin North Am. 1993; 77:185.

70. Balzan, MV. The neuroleptic malignant syndrome: A logical approach to the patient with temperature and rigidity. Postgrad Med J. 1998; 74:72–76.

71. Bywaters, EG, Beall, D. Crush injuries with impairment of renal function. 1941. J Am Soc Nephrol. 1998; 9(2):322–332.

72. Sever, MS, Vanholder, R, Lameire, N. Management of crush-related injuries after disasters [see comment]. N Engl J Med. 2006; 354(10):1052–1063.

73. Sever, MS, Erek, E, Vanholder, R, et al. Renal replacement therapies in the aftermath of the catastrophic Marmara earthquake. Kidney Int. 2002; 62(6):2264–2271.

74. Ballantyne, CM, Corsini, A, Davidson, MH, et al. Risk for myopathy with statin therapy in high-risk patients [see comment]. Arch Internal Med. 2003; 163(5):553–564.

75. Amend, KL, Landon, J, Thyagarajan, V, et al. Incidence of hospitalized rhabdomyolysis with statin and fibrate use in an insured US population. Ann Pharmacother. 2011; 45(10):1230–1239.

76. Huerta-Alardin, AL, Varon, J, Marik, PE. Bench-to-bedside review: Rhabdomyolysis—An overview for clinicians. Crit Care. 2005; 9(2):158–169.

77. Bosch, X, Poch, E, Grau, JM. Rhabdomyolysis and acute kidney injury. N Engl J Med. 2009; 361(1):62–72.

78. Vanholder, R, Sever, MS, Erek, E, Lameire, N. Rhabdomyolysis. J Am Soc Nephrol. 2000; 11(8):1553–1561.

79. Berney-Meyer, L, Putt, T, Schollum, J, Walker, R. Nephrotoxicity of recreational party drugs. Nephrology (Carlton). 2012; 17(2):99–103.

80. Liang, WC, Nishino, I. State of the art in muscle lipid diseases. Acta Myol. 2010; 29(2):351–356.

81. Cervellin, G, Comelli, I, Lippi, G. Rhabdomyolysis: Historical background, clinical, diagnostic and therapeutic features. Clin Chem Lab Med. 2010; 48(6):749–756.

82. Melli, G, Chaudhry, V, Cornblath, DR. Rhabdomyolysis: An evaluation of 475 hospitalized patients. Medicine (Baltimore). 2005; 84(6):377–385.

83. Amrein, S, Amrein, K, Amegah-Sakotnik, A, et al. Propofol infusion syndrome—A critical incident report highlighting the danger of reexposure. J Neurosurg Anesthesiol. 2011; 23(3):265–266.

84. Wong, JM. Propofol infusion syndrome. Am J Ther. 2010; 17(5):487–491.

85. Roberts, RJ, Barletta, JF, Fong, JJ, et al. Incidence of propofol-related infusion syndrome in critically ill adults: A prospective, multicenter study. Crit Care. 2009; 13(5):R169.

86. Kam, PC, Cardone, D. Propofol infusion syndrome. Anaesthesia. 2007; 62(7):690–701.

87. Eichner, ER. Sickle cell considerations in athletes. Clin Sports Med. 2011; 30(3):537–549.

88. Eichner, ER. Sickle cell trait in sports. Curr Sports Med Rep. 2010; 9(6):347–351.

89. Eichner, ER. Pearls and pitfalls: Exertional sickling. Curr Sports Med Rep. 2010; 9(1):3–4.

90. Eichner, ER. Exertional rhabdomyolysis. Curr Sports Med Rep. 2008; 7(1):3–4.

91. Anzalone, ML, Green, VS, Buja, M, et al. Sickle cell trait and fatal rhabdomyolysis in football training: A case study. Med Sci Sports Exerc. 2010; 42(1):3–7.

92. Tsaras, G, Owusu-Ansah, A, Boateng, FO, Amoateng-Adjepong, Y. Complications associated with sickle cell trait: A brief narrative review. Am J Med. 2009; 122(6):507–512.

93. Makaryus, JN, Catanzaro, JN, Katona, KC. Exertional rhabdomyolysis and renal failure in patients with sickle cell trait: Is it time to change our approach? Hematology. 2007; 12(4):349–352.

94. Allison, RC, Bedsole, DL. The other medical causes of rhabdomyolysis. Am J Med Sci. 2003; 326(2):79–88.

95. Knochel, JP. Mechanisms of rhabdomyolysis. Curr Opin Rheumatol. 1993; 5(6):725–731.

96. Malinoski, DJ, Slater, MS, Mullins, RJ. Crush injury and rhabdomyolysis. Crit Care Clin. 2004; 20(1):171–192.

97. Boutaud, O, Roberts, LJ, 2nd. Mechanism-based therapeutic approaches to rhabdomyolysis-induced renal failure. Free Radic Biol Med. 2011; 51(5):1062–1067.

98. Zager, RA. Studies of mechanisms and protective maneuvers in myoglobinuric acute renal injury. Lab Invest. 1989; 60(5):619–629.

99. Harris, K, Walker, PM, Mickle, DA, et al. Metabolic response of skeletal muscle to ischemia. Am J Physiol. 1986; 250(2 Pt 2):H213–H220.

100. Olerud, JE, Homer, LD, Carroll, HW. Incidence of acute exertional rhabdomyolysis. Serum myoglobin and enzyme levels as indicators of muscle injury. Arch Internal Med. 1976; 136(6):692–697.

101. Lofberg, M, Jankala, H, Paetau, A, et al. Metabolic causes of recurrent rhabdomyolysis. Acta Neurol Scand. 1998; 98(4):268–275.

102. Youssef, T, Abd-Elaal, I, Zakaria, G, Hasheesh, M. Bariatric surgery: Rhabdomyolysis after open Roux-en-Y gastric bypass: A prospective study. Int J Surg. 2010; 8(6):484–488.

103. de Meijer, AR, Fikkers, BG, de Keijzer, MH, et al. Serum creatine kinase as predictor of clinical course in rhabdomyolysis: A 5-year intensive care survey. Intensive Care Med. 2003; 29(7):1121–1125.

104. Lappalainen, H, Tiula, E, Uotila, L, Manttari, M. Elimination kinetics of myoglobin and creatine kinase in rhabdomyolysis: Implications for follow-up. Crit Care Med. 2002; 30(10):2212–2215.

105. Grossman, RA, Hamilton, RW, Morse, BM, et al. Nontraumatic rhabdomyolysis and acute renal failure. N Engl J Med. 1974; 291(16):807–811.

106. Woodrow, G, Brownjohn, AM, Turney, JH. The clinical and biochemical features of acute renal failure due to rhabdomyolysis. Renal Fail. 1995; 17(4):467–474.

107. Gunal, AI, Celiker, H, Dogukan, A, et al. Early and vigorous fluid resuscitation prevents acute renal failure in the crush victims of catastrophic earthquakes. J Am Soc Nephrol. 2004; 15(7):1862–1867.

108. Better, OS, Stein, JH. Early management of shock and prophylaxis of acute renal failure in traumatic rhabdomyolysis [see comment]. N Engl J Med. 1990; 322(12):825–829.

109. Odeh, M. The role of reperfusion-induced injury in the pathogenesis of the crush syndrome [see comment]. N Engl J Med. 1991; 324(20):1417–1422.

110. Zager, RA. Rhabdomyolysis and myohemoglobinuric acute renal failure. Kidney Int. 1996; 49(2):314–326.

111. Brown, CV, Rhee, P, Chan, L, et al. Preventing renal failure in patients with rhabdomyolysis: Do bicarbonate and mannitol make a difference? J Trauma. 2004; 56(6):1191–1196.

112. Visweswaran, P, Massin, EK, Dubose, TD, Jr. Mannitol-induced acute renal failure. J Am Soc Nephrol. 1997; 8(6):1028–1033.

113. Sever, MS, Erek, E, Vanholder, R, et al. Marmara Earthquake Study G: Treatment modalities and outcome of the renal victims of the Marmara earthquake. Nephron. 2002; 92(1):64–71.

114. Nolph, KD, Whitcomb, ME, Schrier, RW. Mechanisms for inefficient peritoneal dialysis in acute renal failure associated with heat stress and exercise. Ann Internal Med. 1969; 71(2):317–336.

115. Naka, T, Jones, D, Baldwin, I, et al, Myoglobin clearance by super high-flux hemofiltration in a case of severe rhabdomyolysis: A case report. Crit Care. 2005(2):R90–R95.

116. Cruz, DN, Bagshaw, SM. Does continuous renal replacement therapy have a role in the treatment of rhabdomyolysis complicated by acute kidney injury? Semin Dial. 2011; 24(4):417–420.

117. Akmal, M, Goldstein, DA, Telfer, N, et al. Resolution of muscle calcification in rhabdomyolysis and acute renal failure. Ann Internal Med. 1978; 89(6):928–930.

118. Lin, PY, Lin, CC, Liu, HC, et al. Rasburicase improves hyperuricemia in patients with acute kidney injury secondary to rhabdomyolysis caused by ecstasy intoxication and exertional heat stroke. Pediatr Crit Care Med. 2011; 12(6):e424–e427.

119. Heppenstall, RB, Sapega, AA, Izant, T, et al. Compartment syndrome: A quantitative study of high-energy phosphorus compounds using 31P-magnetic resonance spectroscopy. J Trauma. 1989; 29(8):1113–1119.

120. Better, OS, Rubinstein, I, Reis, DN. Muscle crush compartment syndrome: Fulminant local edema with threatening systemic effects. Kidney Int. 2003; 63(3):1155–1157.

121. Better, OS, Zinman, C, Reis, DN, et al. Hypertonic mannitol ameliorates intracompartmental tamponade in model compartment syndrome in the dog. Nephron. 1991; 58(3):344–346.

122. Antoon, JW, Chakraborti, C. Corticosteroids in the treatment of alcohol-induced rhabdomyolysis. Mayo Clin Proc. 2011; 86(10):1005–1007.

123. Brumback, RA, Feeback, DL, Leech, RW. Rhabdomyolysis in childhood. A primer on normal muscle function and selected metabolic myopathies characterized by disordered energy production. Pediatr Clin North Am. 1992; 39(4):821–858.

124. Knochel, JP, Barcenas, C, Cotton, JR, et al. Hypophosphatemia and rhabdomyolysis. J Clin Invest. 1978; 62(6):1240–1246.

125. Knochel, JP, Carter, NW. The role of muscle cell injury in the pathogenesis of acute renal failure after exercise. Kidney Int Suppl. 1976; 6:S58–S64.

126. Knochel, JP, Schlein, EM. On the mechanism of rhabdomyolysis in potassium depletion. J Clin Invest. 1972; 51(7):1750–1758.

127. Trimarchi, H, Gonzalez, J, Olivero, J. Hyponatremia-associated rhabdomyolysis. Nephron. 1999; 82(3):274–277.

128. Mor, A, Wortmann, RL, Mitnick, HJ, Pillinger, MH. Drugs causing muscle disease. Rheum Dis Clin North Am. 2011; 37(2):219–231.