EXERTIONAL HEAT STROKE & PATHOPHYSIOLOGY

1. EXERTIONAL HEAT STROKE & PATHOPHYSIOLOGY Michael N. Sawka, Ph.D. Thermal & Mountain Medicine Division US Army Research Institute of Environmental Medicine Natick, MA USA

2. Outline • Exertional Heat Stroke • Physiology & Pathophysiology • Emerging Concepts DISCLAIMER: The views expressed in this presentation (slides, etc.) are those of the author and do not reflect the official policy of the Department of the Army, Department of Defense, or the U.S. Government.

3. Exertional Heat Stroke

4. Exertional Heat Stroke (EHS) Heat Stroke:Characterized by central nervous dysfunction, organ (liver, renal) & tissue (muscle, gut) injury with high body temperature. Exertional:Physical activity & climatic heat stress inducing excessive heat strain. Commonly seen in athletes, military & workers. Classic: Exposed to overwhelming passive heat stress. Common seen in vulnerable populations (young children, elderly, sick). TBMED 507 – Heat Stress Control & Management, 2003

5. Exertional vs Classical Heat Stroke: Mortality in Rats 100 Run 80 Heated 60 % Mortality Within 24 Hours 40 20 0 0 20 40 60 80 100 120 140 o Total Area Above 40.4 (Degrees x Minutes) Hubbard et.al. JAP 1977

6. Exertional vs Classic Heat Stroke Winkenwerder & Sawka. Cecil’s Textbook of Medicine 2007

7. Physiology & Pathophysiology

8. Core Physiology of Severe Exercise-Heat Strain • High Metabolic Activity • High Body Temperatures • High Skin Blood Flow • Reduced Gut Blood Flow • Reduced Brain & Muscle Blood Flow • Dehydration & Energy Depletion • Elevated Brain Metabolism Sawka & Young ACSM Adv. Exerc. Physiol 2006

9. Heat Storage Cardiovascular Responses Cell Heat Shock & Ischemia Gut Constricts Skin Dilates Muscle Dilates Death Apoptosis Necrosis Injury Coagulopathy Inflammation Ischemia, ROS & RNS Cytokine Release (eg., IL-1,IL-6,IL-10, TNF) NO Increased Intestine Permeability Exertional Heat Injury / Stroke CNS & multi-organ damage via Fever, Shock, DIC, Hemorrhage, Stroke & Rhabdomyolysis Endotoxemia Heat Strain Progression to Exertional Heat Stroke Exercise & Climatic Heat Stress (Intestine, Hepatic, Renal, Endothelium, Brain, Muscle, Heart) Sawka & Young ACSM Adv. Exerc. Physiol 2006

10. Heating Increases Small Intestine Permeability (rats; passive heat; fluorescent dextran) 15.0 12.5 10.0 *Dehydration augments gut permeability during exercise Lambert et.al. IJSM, 2007 PLASMA FD -4 (mg·ml-1 ) 7.5 5.0 2.5 0.0 37ºC 41ºC 41.5ºC 42.5ºC Core Temperature (°C) Lambert et.al, JAP 2002

11. Heating Induces Intestinal Epithelial Damage (rats, Transmision Electron Micographs of Luminal Area Microvilli) Control Rat Hyperthermic Rat Lambert et.al, JAP 2002

12. Heat Stress & Cytokine Storm Ischemia to Gut • Endotoxin Release from Small Intestine • Pro-Inflammatory Cytokine Induction Muscle Hyperthermia & Ischemia • IL-6 & IL-1 Release Healthy Gut Endotoxin Leak http://www.feedindustrynetwork.com

13. Inflammatory & Coagulation Responses to Heat Stroke Systemic Inflammatory Response Syndrome (SIRS) “…form of hyperthermia associated with systemic inflammatory response leading to syndrome of multiorgan dysfunction…” Bouchama & Knochel. N. Eng. J. Med. 2002

14. Photomicrographs of Control & Heat Injured Organs Kidney Spleen Arrows mark tissue lesions heat injured (B,D) mouse tissues Leon, et.al. JAP 2005

15. Heat Injured Liver 3-days Post-Exposure Non-Heated Control Heated Survivor Leon, Progress Brain Research 2007

16. Hyperthermia Aggravates CNS Injury from Occlusion PMCAO is permanent cerebral artery occlusion; TMCAO is transient middle cerebral artery occlusion

17. Exertional Heat Stroke Mortality & CNS Pathophysiology Cerebral Cortex • Autopsy of ~40 Brains: • Slight Increase in Brain Weight • No massive hemorrhages • Cerebellum – “more striking than, more consistent than any other areas”; Purkinje layer severely degenerated • Hypothalmus – some edema, but little damage • Cerebral Cortex – edema & congestion Hypothalmus Cerebellum Malamud et.al. Military Surgeon, 1946

18. Heat Stroke & Brain Gray-White Matter Discrimination Loss Heat Stroke Headache Control A C • CT Axial cuts at lateral ventricles & centrum semiovale • N=6 • Severe GWMD Loss with no CNS bleed or anatomical displacements, perhaps edema D B White & Gray matter not discriminated White & Gray matter easily discriminated Szold et.al. EJ Radiol. 2002

19. Cerebellum Cerebral Cortex Control Heat Stroke Heat Stroke (42.7oC) & Mice Brain Tissue Stains: No Pathology but Altered Thermoregulatory Behavior (Mortality in matched animals) Leon et.al. Unpublished

20. Hyperthermia-Induced Brain Dysfunctions (other) • Blood Brain Barrier Breakdown • Blood-Cerebral Spinal Fluid Barrier Breakdown • Serum Protein Leakage Mediating Edema • Exacerbated Drug-Induced Toxicity • Exacerbated Nanoparticle (Quantum Dots)-Induced Toxicity Sharma Prog. Brain Res. 2007; Kiyatkin Prog. Brain Res. 2007

21. Emerging Concepts

22. EHS 50-60% occurred during early portions of march or run event Epstein et al. MSSE., 1999 EHS 75% in first 10 km of march or run Shibolet et al. Q.J.Med., 1967 EHS: Acutely Modified Thermoregulatory Control Core temperature response to exercise Epidemiology Findings: 110 Normal Heat Stroke 108 106 Degrees Fahrenheit 104 102 Fatal EHS 71% (125 cases) Acute without warning Malamud et.al. The Military Surgeon 1946 100 98 6:00 6:15 6:30 6:45 7:00 7:15 7:30 7:45 8:00 AM C.B. Wenger Unpublished

23. Neural Pathway for Rapid Fever POA PGE2 NE FEVER OVLT A1/2 NTS • LPS activates compliment cascade in Kupffer cells • Anaphylatoxin C5a produced which stimulates PGE2 • PGE2 peripheral trigger local vagal terminals • Peripheral febrile message conveyed by vagal afferents • NE secreted & activates adreno-receptors • Secondary Increase PGE2 Vagus Cytokines PGs Others Gastrointestinal Tract Liver Kupffer cells C3a/C5a LPS Blatteis, Progress Brain Research 2007

24. Cellulitis & Muscle Injury Can Modify Thermoregulatory Control during Exercise-Heat Stress (~45% VO2max; 40°C) (~50% VO2max ; 40oC) 40 C) Day 1 Day 3 Subject 7 Subject 9 ° 38.2 Day 2 Day 4 Cellulitis (heel ) 39 38.0 37.8 38 Controls 37.6 Rectal Temperature ( Esophageal Temperature, °C 37.4 37 37.2 Control Control 10 min rest 36 37.0 6 h after LBE 6 h after LBE 36.8 0 25 50 75 100 0 10 20 30 40 50 0 10 20 30 40 50 Time (min) Time, min Time, min Carter et.al. J. Sports Rehabil 2007 Montain et.al. JAP 2000

25. Cell Thermal Tolerance & Critical Thermal Maximum Cell Culture Studies (Thermal Tolerance) •  40°C (104°F) – adaptive response •  41°C (~106oF)- injury to cell •  42°C (~108oF) - apoptosis •  49°C (120°F) – rapid necrosis • Cell Type Dependent (Intestine, Hepatic, Renal, Endothelial, Brain, Muscle) Animal & Human Studies (Critical Thermal Maximum) •  40°C (104°F) - no mortality • > 41.5°C (~107°F) - humans • 41.7oC (107oF) dogs, 43.5oC (110oF) - cats • Population Dependent (Heat Acclimation, Training State, Age ) Adolph AJP 1947; Bynum et.al. AJP 1978; Gabai & Sherman JAP 2002; Massett et.al. AJP 1998

26. Cell Thermal Tolerance • Associated with induction of Heat Shock Proteins (HSPs) • Thermal Tolerance Occurs Without HSPs (Laszlo Int.J. Hyper 1988) • Heat Shock Induces Other Cell Defense Proteins(e.g., antioxidant enzymes) • Heat Shock Induces Extensive Gene Expression (Sonna et al. JAP 2002)

27. EHI Often Associated with Flu Like Symptoms: Might Interferons Degrade Cell Thermal Tolerance? • Sonna et.al. JAP 2004: For Marines with EHI, of 36 most highly upregulated non-HSP sequences (5-fold or more), at least ¼ are previously reported as interferon inducible. • Bouchama et al. Chest 1993: Half of patients presenting with non-exertional heat stroke had elevated levels of serum interferon gamma (IFN-g) • Abello and Buchman, Shock 1994: In transformed murine endothelial cells, IFN-g & TNFa altered cell fate after heat shock from survival to death by apoptosis (likely by NF-κB activation)

28. Effect of IFN-g on Cell Survival after Heat Shock MTS Assay (mitochondrial viability) Trypan Blue (cell membrane viability) 100 100 80 80 60 60 Surviving Cells (%) Surviving Cells (%) 40 40 20 20 0 0.1 1 10 100 1000 0 0 0 0.1 1 10 100 1000 g [IFN- ] (U/ml) g [IFN- ] (U/ml) Heat Shocked Cells Control Cells Heat Shocked Cells Control Cells • HepG2 in culture • IFN-g exposure for 18h • 43oC for 1 h • 24 h recovery • Survival Assay Sonna (Unpublished)

29. Exertional Heat Stroke (EHS): Conclusions • EHS Greater Morbidity & Mortality than “Classic” HS • High Metabolic Activity, Hyperthermia, Reduced Blood Flow, Ischemia • Systemic Inflammatory Response & Multi-Organ Dysfunction • (e.g., CNS, gut, liver, Kidney, muscle, spleen, cardiac; shock, DIC, hemorrhage) • Traditional: Lack of Acclimatization, Dehydration, Overweight, Low Fitness • Emerging: Acute Changes in Thermoregulation & Cell Thermal Tolerance • Emerging: Cumulative Effects of Prior Multiple Adverse Stimuli • (e.g., viral infection, muscle injury, toxic exposures) • Return to Duty? • (Organ Recovery & Long-Term Morbidity / Mortality; Adverse Stimuli Sensitivity; Biomarkers)

30. EXTRA SLIDES

31. Exertional Heat Stroke & Return to Duty: Other Slides • Heat Tolerance Test (HTT) • 120 min walk 5 km/h at 2% grade in 40oC, 40% RH • Steady-State Core Temperature <38.5oC • Assumes Heat Stroke recovery related to gross heat exchange • Modest Compensable Heat Stress • 70 kg, 1.92 m2 Soldier have Ereq/Emax = ~45% (223/485 w/m2) • Large Core-to-Skin Temperature Gradient (~4oC), so low skin blood flow & compensatory vasoregulatory requirement • No sophisticated thermoregulatory control evaluation & no pre-injury baseline • No profile of organ injury • Best criteria for return? • Issue is Multi-Organ Dysfunction, NOT gross heat exchange • Wallace et.al. (Science Direct 2007) – Soldiers hospitalized for heat stroke subsequently had increased mortality (30 years) from cardiovascular, liver, renal & GI diseases.

32. Exertional Heat Stroke & Return to Duty: Other Slides John Bowen – PA at TMC 14, Camp MacKall, MC Heat Stroke Return for Special Force Qualification Course “Best Guess from Experience” Clean Clinical Picture 30 days – P3(T) Profile (limit of 15 min vigorous exercise) 30 days – P3 Profile (limit maximal exercise & MOPP) 30 days – PT & Training (ramp & observation) “USARIEM Twist” (core temperature telemetry & blood analyses) Clean Clinical Picture 30 days – Observe & walk / jog to Tc to 38.5oC (PT Uniform) 30 days – Observe & ramp military activities to Tc to 38.5oC (ACU) 30 days – Observe & ramp military activities to Tc to 39.5oC (no restrictions)