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General Medical Conditions: Section Articles

Sepsis, Septic Shock, and Fatal Exertional Heat Stroke

Epstein, Yoram PhD, FACSM; Roberts, William O. MD, MS, FACSM; Golan, Ron MD, PhD; Heled, Yuval PhD, FACSM; Sorkine, Patrick MD; Halpern, Pinchas MD

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Current Sports Medicine Reports: January 2015 - Volume 14 - Issue 1 - p 64-69
doi: 10.1249/JSR.0000000000000112
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Exertional heat illness (EHI) is a collective term referring to a spectrum of clinical conditions related to physical exertion. EHI is a continuum ranging from severe exhaustion, mild-to-moderate hyperthermia (rectal temperature (Tre), <40°C), and dehydration (known as heat exhaustion) to severe hyperthermia combined with encephalopathy and multiorgan dysfunction, known as exertional heat stroke (EHS) (15). In EHS, a cascade of pathophysiological responses to overheated cells results in tissue and organ failure that can be irreversible and ultimately fatal (14,19) if not promptly recognized and treated with total body cooling to prevent progression of the clinical syndrome (11,18,21,30).

In recent years, heat stroke was linked to an inflammatory response to strenuous exercise and heat stress, leading to a syndrome of multiorgan dysfunction (7,26,27,36). It is often difficult to dissociate the effects of exercise and hyperthermia on cell immune dynamics since these stressors stimulate common immune cellular disturbances. It is believed that a major contribution to the inflammatory response arises from subclinical hyperthermia associated with intense exercise rather than a direct result of exercise per se, as the response can be abolished completely with thermal clamping (controlling the body temperature to resting levels of approximately 37°C) (29). An inflammatory state affecting the whole body is called the “systemic inflammatory response syndrome” (SIRS). However during hospital clinical management of a patient with EHS, the inflammatory response related to EHS is akin to SIRS (Table) and may be overlooked easily because EHS is not a common problem in most hospitals’ intensive care units (ICU) and is not in the usual list of SIRS causes. Furthermore any delay in EHS recognition and total body cooling dramatically increases the SIRS response and its clinical consequences (2,7,22). Of note, Zeller et al. (40) followed the clinical course of 32 patients hospitalized for EHS and reported that 84% of all the patients presented with SIRS criteria and, when SIRS was associated with EHS, the hospital stay was prolonged.

The diagnostic criteria of SIRS (23).

This clinical case outlines the course of a runner with delayed recognition and slow cooling who apparently recovered from the acute phase of EHS but died 3 d later with a clinical picture of sepsis and septic shock. The connection of the EHS-induced systemic inflammatory response to the cause of death is discussed.

Case Report

A 42-year-old male Caucasian with no pertinent medical history or recent illness participated for the first time in a half-marathon (21 km) race associated with the “Tel Aviv Marathon.” He had completed a structured training regimen to prepare him for the run. The race took place in the early days of April under comfortable running climatic conditions (ambient temperature, 16°C to 20°C; relative humidity, 83% to 77%; the wet-bulb globe temperature at the 6:30 a.m. start was 15°C). During the first hour of the race, it drizzled, and the sky remained cloudy throughout the race. The athlete collapsed at the 18-km mark after about 2 h of running.

Approximately 40 min after the collapse, a race medic from the emergency medical services found him lying on the ground and confused but responsive to verbal stimuli. His physical examination at the site of collapse revealed the following: tachycardia (151 bpm), normal blood pressure (110/62 mm Hg), slight tachypnea (18 per minute), profuse sweating, responsive and equal pupils, and a soft abdomen. Body core temperature was not measured. Glucose testing showed hyperglycemia (180 mg·dL−1), and an electrocardiogram (ECG) recording revealed isolated ST elevation in lead V3. He was treated with 100% oxygen using a nonrebreathing mask and 300-mL intravenous (IV) isotonic saline and then evacuated to a nearby tertiary medical center. During evacuation, he became restless and aggressive, and midazolam 10 mg intramuscular (IM) was administered empirically.

Upon first examination at the hospital emergency department (ED), 75 min after collapse, the patient was confused and irritable. His first body core temperature by esophageal measurement was 39.9°C, his pulse rate was 115 bpm, his blood pressure was 100/56 mm Hg, and O2 saturation (by a finger probe) was 82%. His initial diagnostic studies revealed the following: severe hyperkalemia (9 mEq·L−1), normal sodium level (140.5 mEq·L−1), mild creatine phosphokinase (CPK) elevation (376 IU·L−1), mild acidosis (pH, 7.32), and mild hyperglycemia (glucose, 145 mg·dL−1). His ECG revealed nonspecific ST changes (Fig. 1).

Figure 1
Figure 1:
Nonspecific ST changes recorded by ECG in the ED 90 min after collapse.

The patient was given 2,000 mL of approximately 8°C isotonic (normal) saline IV in an attempt to reduce his core body temperature. He was ventilated manually with an Ambu bag and then anesthetized and intubated. A nasogastric tube was inserted. Hyperkalemia was treated with an IV infusion of 50% glucose in water (50 mL) and insulin (10 units), inhaled salbutamol, and 30 g polystyrene sulphate (KayexalateTM) was given through the nasogastric tube. Follow-up laboratory studies showed that the patient remained acidotic (pH, 7.25) but the potassium (K+) level had returned to normal (4.04 mEq·L−1). The patient then was transferred to the ICU with a diagnosis of EHS.

Upon arrival at the ICU (approximately 110 min after collapse and approximately 30 min after ED arrival), his Glasgow Coma Score (GCS) was 6, esophageal temperature was 38.4°C, pulse rate was 103 bpm, blood pressure was 100/51 mm Hg, and O2 saturation was 90%. Blood analysis showed that K+ had decreased to 4 mEq·L−1, lactate was 3 mmol·L−1, glucose was 50 mg·dL−1, creatinine was 1.65 mg·dL−1, blood urea nitrogen (BUN) was 18 mg·dL−1, and pH increased to 7.37. The CPK level has risen to 480 IU·L−1 with high CPK isoenzymes M & B (CK-MB) fraction (9.4%). Urine volume, obtained through a bladder catheter, was 1,500 mL, and its color was transparent. The ECG had returned to normal.

At noon, his vital signs stabilized, with the Tre around 37.5°C, heart rate at 80 to 95 bpm, and blood pressure at 106/81 mm Hg. By that evening, his cardiopulmonary and hemodynamic status was stable, and he was extubated. He still required 40% oxygen to maintain a normal O2 saturation, and Tre was 38.5°C. The laboratory monitoring showed a serum glucose level of 139 mg·dL−1, CPK level of 745 IU·L−1, and arterial pH of 7.32. Daily urine output was 2,240 mL.

On the morning of day 2, the patient’s Tre was 37.5°C to 38.0°C. The patient was oriented fully to the environment, awake and coherent (GCS, 15), with a stable hemodynamic and cardiorespiratory status, and all other clinical examinations and laboratory test results were normal. The urethral catheter was removed, and he was able to urinate spontaneously; however it was noted that his urine color was dark and urine output was 1,450 mL per 24 h. That evening, his arterial O2 saturation dropped to 84% and sublingual temperature measurement was 39.4°C. Oxygen by mask at 4 L·min−1 improved O2 saturation, but the IV infusion of dipyrone (an antipyretic) did not resolve the fever and his temperature elevation continued throughout the night. CPK activity level was now 1,000 IU·L−1 (CK-MB fraction, >4%), and ALT and AST levels were now 501 and 565 IU·L−1, respectively.

On the morning of day 3, the patient remained fully conscious, with no signs of encephalopathy and a GCS of 15. Tre was 37.2°C, but it then rose again to 39.4°C and was lowered by IV dipyrone. He was again hypoxemic on room air, and again, he responded to oxygen administration by mask with an O2 saturation of approximately 94%. He developed adventitious sounds over the central lobe of the right lung heard upon auscultation, and a chest radiograph showed bilateral perihilar infiltrates compatible with an acute injury to the lung in the form of acute respiratory distress syndrome (ARDS) or bronchopneumonia (Fig. 2). Urine output was 400 mL per 24 h, and fluid balance was +3.5 L, which was treated with furosemide (80 mg IV). Metabolic acidosis (pH, 7.30; HCO3, 12.1 mmol·L−1; anion gap, 15 mmol·L−1) was detected, and his CPK activity level was elevated to 1,390 IU·L−1 (CK-MB fraction, 3.7%). An echocardiogram in the late afternoon exhibited intact cardiac function.

Figure 2
Figure 2:
Chest radiograph (day 3). Bilateral perihilar infiltrates compatible with ARDS or bronchopneumonia.

Body temperature was elevated again to 39.6°C and was treated empirically by IV amoxicillin/clavulanic acid and steroids. The patient became increasingly restless and was treated with 2-mg morphine. ECG showed nonspecific lateral wall ST depression (CPK-MB, 3.7%), and an echocardiogram revealed a global reduction of heart muscle contractility. The clinical condition then deteriorated very rapidly, and the patient became hypoxemic and very hypotensive. An adrenaline infusion was started, and atropine was given by IV push for occasional bradycardia. Arterial pH declined from 7.3 to 7.02, and base access increased to 12. Progressive multiorgan failure developed, with serum creatinine increasing from 2.41 to 2.81 mg·dL−1, white cell count 18 × 103 cells per microliter with lymphopenia (4%), thrombocytopenia of 23 × 103 per microliter, and elevated prothrombin time (PT) and partial thromboplastin time (PTT). The patient died early the following morning, approximately 72 h after collapse, with a clinical picture of sepsis and septic shock after prolonged resuscitation attempts. Postmortem examination was not performed (for religious reasons), but Klebsiella pneumoniae grew later in a blood culture.


This case describes a healthy individual who was evacuated to a tertiary medical center after he collapsed during a half-marathon run in environmental conditions considered within safe limits and at low risk for heat stroke by current consensus guidelines (4,31). The initial diagnosis is unclear since body temperature was not measured at the time of collapse or at the initial intervention in the field. Thus differential diagnosis could be very broad (from extreme fatigue to hypoglycemia and a cardiac condition), but EHS seems most likely according to the constellation of history, physical examination, and diagnostic studies. Although it is possible for athletes to reach a Tre of 40°C during exercise, these athletes do not have signs or symptoms of central nervous system dysfunction that would lead to the presumed diagnosis of EHS. However the initial presenting neurological signs, stupor and delirium, combined with a rectal temperature of 39.9°C measured 80 min after collapse, are highly suggestive of the EHS diagnosis, even without a core body temperature measurement in the field (35). It is likely that once he collapsed and metabolic heat from running was no longer being produced, some body cooling was taking place but the overall cooling rate was not sufficient to preserve body tissue and organ functions. Although a normal body temperature was restored during the acute phase of hospitalization, the tissue cooling was too late and not adequate to stop the SIRS reaction. Thus the patient’s clinical condition deteriorated and he died on the third day after he collapsed.

This may be an example of prolonged hyperthermia resulting in a lethal exposure in degree-minutes under the cooling curve. The body temperature at the time of the collapse is unknown, but it could have been 1.5°C to 2.5°C higher at the time of collapse, assuming a spontaneous cooling rate of 0.02°C to 0.03°C per minute. In the ED, 80 min after collapse, his body temperature was still 39.9°C and was above 38.5°C for at least 110 min. It has been shown that the extent of organ failure and the mortality rate from heat stroke both are related directly to the temperature-time area (degrees (°C)-minutes) under the cooling curve (3,34). In this regard, the duration of temperature elevation above the critical heat stroke temperature threshold, rather than the peak body core temperature, determines the degree of morbidity and mortality (3). Therefore early recognition and rapid cooling of a heat stroke patient are critical to favorable prognosis and outcome (10,21,30,35).

Many cooling methods have been described in the literature, with the general consensus that a cooling rate >0.15°C per minute by any method is optimum to improve the prognosis (11,18,21). Furthermore reducing temperature to less than 40°C in less than 30 min from onset likely will reduce the fatality rate to zero (10). It is therefore likely that, in this case, the lag of >1 h in the application of effective cooling contributed to a fatal cascade of events that included SIRS progressing to respiratory failure, ARDS, nosocomial pneumonia, renal failure, electrolyte abnormalities, hyperglycemia, liver dysfunction, and disseminated intravascular coagulation (DIC).

Many stresses, including heat stress, elicit a noninfectious SIRS that initially promotes a homeostatic protective condition (5,7,39). As EHS evolves, SIRS will progress rapidly if a prompt and efficient cooling intervention is not initiated to eliminate further hyperthermic tissue stress and halt the catastrophic effects of SIRS. Delayed or inefficient body cooling allows the inflammatory response to transition to a noxious and often fatal condition. Therefore core body temperature reduction that is not applied rapidly and efficiently may not be sufficient to prevent excess morbidity and mortality. Recently it had been shown that SIRS may be present in about 85% of all EHS cases and in about 45% of those with moderate-to-severe EHS related SIRS persisted beyond the third day of hospitalization, with a mean duration of 7 d (40). In cases of delayed or inadequate cooling, the clinical team must anticipate the potential for a patient to develop an advanced inflammatory response although hyperthermia has been resolved (Table). This deserves further explanation, since the evolution to SIRS can be missed or ignored when it is not anticipated in the clinical care plan.

The initial cardiovascular response to heat exposure is an increase in skin blood flow to promote heat transfer to the skin from the body core (19,32). Increased skin blood flow is accompanied by a compensatory reduction in splanchnic blood flow to maintain systemic blood pressure. The reduction of intestinal blood flow results in gastrointestinal (GI) ischemia that adversely affects cell viability and cell wall permeability. The resulting oxidative and nitrosative stress can damage cell membranes and open tight cell-to-cell junctions, allowing endotoxins and possibly pathogens to leak from the gut into the systemic circulation (20,24).

With mild hyperthermia associated with exercise, minor damage to the gut wall leads to elevated leakage of lipopolysaccharide (LPS) into the portal vein with transport to the liver, where LPS is removed from the circulation and detoxified (23). Indeed after strenuous exercise with associated hyperthermia, high concentrations of endotoxin, inflammatory cytokines, and acute-phase proteins are found in the blood (6,9,25,28). When hyperthermia is prolonged, the inflammatory reaction progresses and becomes uncompensable. This results in a complex interplay among the associated acute physiological alterations (e.g., circulatory failure, hypoxia, increased metabolic demands) and the direct heat-related cytotoxicity resulting in the ensuing inflammatory responses that become noxious to the system (14,19,33). Noteworthy the increase in inflammatory cytokines also correlates with intracranial hypertension, low cerebral blood flow, and inflammatory changes to the nervous system (38).

At this stage of inflammation, major heat-induced damage to the gut wall leads to an excess of LPS leakage reaching the liver, which overwhelms the liver’s capacity to detoxify the offending agents. Consequently a spillover of LPS into the systemic blood circulation leads to a systemic inflammatory response that mimics septic shock and may be associated with gut microbiome-related bacterial sepsis that can deteriorate quickly to DIC, multiorgan failure, and death. The causes of death in heat stroke including respiratory failure, ARDS, nosocomial pneumonia, renal failure, GI bleeding, stress gastritis, anemia, deep venous thrombosis, electrolyte abnormalities, hyperglycemia, hepatic dysfunction, and DIC are nearly identical to the end-stage clinical picture for SIRS and sepsis (1).

On the second day of hospitalization, signs of liver dysfunction (high transaminase activity levels) and coagulopathy appeared in the patient. Additionally Klebsiella pneumoniae — a gram-negative bacterium that is found in the normal flora of the intestines — grew in the patient’s blood culture. This fits with the discussion by Garber et al. (17) that the compromised liver function in heat stroke worsens the endotoxemia and is a direct cause of death. The linkage between heat stroke and endotoxemia is not new, but many physicians tend to ignore or find alternate explanations for the evolving laboratory findings heralding its presence. Hales et al. (19) mentioned that patients with heat stroke exhibit endotoxemia and athletes under conditions of severe exercise in warm surroundings show rise in plasma LPS concentrations, impairing their performance. Brock-Utne et al. (8) showed that runners who collapsed during an ultramarathon run on a warm day could be clustered in two groups: fast and slow runners. The fast runners (those with higher physical fitness) exhibited mild clinical symptoms, recovered within 2 h, and had both high natural anti-LPS titer and low plasma LPS levels. In contrast, the slow runners (depicting potentially low physical fitness) had more severe clinical symptoms, longer recovery times, and lower natural anti-LPS titers, resulting in higher serum levels of LPS (8). Studies by Gathiram et al. (16) of anesthetized monkeys exposed to heat stress showed that elevated levels of LPS in the portal vein preceded LPS elevations in the systemic circulation. This suggests that spillover of LPS occurs when the endotoxin-heat compromised detoxifying capacity of the liver is exceeded (37). With this clinical mechanism in mind, Armstrong et al. (2) suggest that heat stroke treatment is a battle against endotoxemia that is won by rapid whole body cooling and likely lost if the cooling is delayed.

In some cases, even prompt recognition and cooling will not be enough for a favorable outcome and adjuvant treatments must be considered for patient survival. Thus, anticipating SIRS in heat stroke cases and immediate intervention with symptomatic support of organ functions with evolving SIRS should be the standard of care (e.g., fresh frozen plasma, cryoprecipitate, or platelet concentrates to treat DIC). In this regard, several new treatment modalities have been proposed and studied in animal models. For example, administration of a xanthine oxidase inhibitor (allopurinol) has been shown to reduce portal LPS concentration during heat stress by protecting the cell-to-cell tight junction integrity (20). Recombinant activated protein C has the potential capacity to attenuate both the coagulation cascade dysfunction and inflammation and has been suggested for patients with heat stroke to reduce mortality in sepsis therapy (7,12). Very recently, it has been reported that suppression of pancreatic enzyme activity in the lumen of the intestine by serine proteases substantially reduced systemic levels of inflammatory markers and enhanced survival in septic rats (13). It should be emphasized that, so far, these adjuvant therapies only have been shown to be beneficial in animal heat stroke models and have not been approved for use in human patients.


This case highlights the critical need for immediate field recognition and cooling in suspected cases of EHS and continued vigilance for SIRS in the patient with EHS. While the delay in aggressive cooling may have not prevented inflammation and its clinical consequences in this patient, earlier recognition along the race course and rapid cooling on site could have changed the outcome. Although the clinical indications during the first day of hospitalization suggested that the patient’s situation was improving, the cytotoxic effect of hyperthermia on the liver and gut wall cell junctions elicited a second phase of inflammatory reaction, which was associated with a massive leakage of endotoxins from the intestinal gram-negative microbiome to the blood stream that could not be detoxified by the heat-injured liver. This consequently led to the patient’s death.

The authors declare no conflicts of interest regarding the manuscript and the study did not receive any financial support.

The views and the conclusions in the present publication do not constitute endorsement by the American College of Sports Medicine.


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