ACUTE MOUNTAIN SICKNESS AT THE SOUTH POLE Tuesday June 25, 2013 UTMB-­‐NASA Aerospace Medicine Grand Rounds UniversiHes Space Research AssociaHon, Houston TX Michael F Harrison, MD PhD Mayo Clinic, Rochester MN Henry Ford Hospital, Detroit MI Disclosure InformaHon MICHAEL HARRISON I have no financial relaHonships to disclose. Dr Bruce Johnson’s Funding: NaHonal Science FoundaHon, B-­‐179-­‐M Mayo Clinic Center for TranslaHonal Science AcHvity (CTSA), Clinical Research Unit Grant Number 1 UL1 RR024150 from the NaHonal Center for Research Resources ObjecHves •  Discuss the current literature related to acute mountain sickness •  IdenHfy important variables idenHfied by research at the South Pole •  Illustrate the links between acute mountain sickness at the South Pole and future space operaHons –  Demonstrate the link between what we do and what you do… Overview •  What we know about AMS & alHtude illnesses •  What we don’t know about AMS •  What we did •  Why our AMS study is different •  What we found •  What it means •  Where do we go next ClassificaHons of AlHtude NO PERMANENT HUMAN HABITATION ABOVE THIS ALTITUDE Extreme High AlHtude (>5500m) E.g. Mt Everest, Mt Kilimanjaro Very High AlHtude (3500m to 5500m) E.g. Everest Base Camp, Pikes Peak High AlHtude (1500m to 3500m) E.g. Denver; South Pole AMS & other alHtude illnesses begin to appear >2500m1-­‐5 1Hackeg & Roach, 2001; 2Barry & Pollard, 2003; 3Basnyat & Murdoch, 2003; 4Schoene, 2008; 5Luks et al, 2010 “Room Air” at AlHtude •  PO2 with alHtude1 AlHtude (m) Sea Level PO2 (mmHg) 149.1 2743 106.0 3353 97.9 1Hackeg & Roach, 2001; 2Grocog et al, 2009 Changes in Arterial Mean Pressure of Oxygen, Oxygen Satura8on, and Oxygen Content in Climbers on Mount Everest2 2500m South Pole 1West, 1999 South Pole “AlHtude” •  AlHtude at South Pole: 2835m –  PO2 ~ 105mmHg1 •  Physiologic alHtude at South Pole: ~3200m2 –  PO2 ~ 98mmHg1 •  Pressure lower in winter than summer1 1Hackeg & Roach, 2001; 2Schoene, 2008; 3Linacre & Geerts, 1999 Hypoxic Hssue becomes inflamed Inflamed Hssue becomes hypoxic1 #
•  AlHtude decreases PO2 •  AMS sufferers may be more hypoxic aoer rapid transport than healthy travelers •  SaO2 81% vs 76% on 1st day at 4559m2 •  No AMS: N=10 •  AMS: N=14 •  SimilariHes to other pathologic condiHons1 •  E.g. sepsis, organ graos/rejecHon, inflammatory bowel disease, congesHve heart failure 1Eltzschig & Carmeliet, 2011; 2Bailey et al, 2004 ConHnuum of AlHtude Illnesses •  Acute Mountain Sickness (AMS) •  High AlHtude Cerebral Edema (HACE) •  High AlHtude Pulmonary Edema (HAPE) “…unpleasant but self-­‐
limiHng and benign syndrome…”1 Most common form of alHtude illness2,3,4 • 1850 – 2750m: 22% • >3000m: 42% • 4500-­‐5500m: 50-­‐85% 1Barry [text] & Pollard, 2003; 2Hultgren, 1979; 3Honigman et al., 1994; 4Bartsch & Swenson, 2013 Lake Louise Score “Headache is the major symptom of acute mountain sickness.”1 1Bartsch & Swenson, 2013 “…sleep is disturbed in 50% of subjects…because of periodic breathing, which may occur during 60% of sleep Hme…”1 “…have a mean [arterial oxygen] saturaHon of 64% during sleep. With irregular respiraHon during sleep, saturaHons below 40% have been observed.”2 [text] 1Bartsch & SalHn, 2008; 2Hultgren, 1979 Can We IdenHfy Who is at Risk for AMS Development? •  “Agempts to predict its development have so far been unsuccessful.”1
•  “…tests undertaken at sea level are disappoinHngly poor at predicHng alHtude illness.”2
•  “The physiological responses which determine an individual’s suscepHbility [to AMS], however, remain debateable.”3 •  “…a complete understanding of related mechanisms remains elusive…”4 1AusHn & Sleigh, 1995; 2Barry & Pollard, 2003; 3Hamlin & Ainslie, 2010; 4Bailey et al, 2004 Diagnosing AMS •  SUBJECTIVE diagnosis –  No physical SIGNS that are diagnosHc of AMS1,2,3
–  Presence of signs suggests progression to HACE • Ataxia • Aphasia • Abnormal pupillary response • Papilloedema • Altered level of consciousness • Seizures 1Barry & Pollard, 2003; 2Basnyat & Murdoch, 2003; 3Bartsch & Swenson, 2013 Previous AMS PublicaHons •
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•
Varying alHtudes Varying rates of ascent Varying methods of ascent Varying sample sizes & populaHons Varying diagnosHc tools1
–  LLSS: 25% at 1900-­‐3000m –  Hackeg’s AMS-­‐score: 3.1-­‐9% at 1900-­‐3000m •  Involves a physician examinaHon 1Roeggla et al, 1996 Factors to Predict AMS? •  Severe gag reflex1
•  Dizziness with hypervenHlaHon1 •   Arterial concentraHons of epinephrine & norepinephrine2 •   Mean arterial pressure at sea level3
•   Fluid retenHon & redistribuHon4,5
•  Obesity6
•  Inflammatory response to alHtude / hypoxia7,8
•  Exaggerated chemoreceptor vasoconstricHve response to hypoxia9
•  Respiratory rate > 20 aoer 1h at alHtude10
•  Previous hx of AMS9 1AusHn & Sleigh, 1995; 2Kamimori et al, 2009; 3Hamlin & Ainslie, 2010; 4Roach & Hackeg, 2001; 5Loeppky et al, 2005; 6Schoene, 2008; 7Bailey et al, 2004; 8Lipman et al, In Press; 9Lanfranchi et al, 2005; 10Jafarian et al, 2008 ProtecHve vs. Non-­‐Contributory / Non-­‐ProtecHve Factors •  ProtecHve
–  Age >50yrs / elderly1,2,3
–  Gradual ascent3,4 •  18% decrease for every extra day spent ascending from 2800m to 4000m5 •  300-­‐500m ascent per day aoer 3000m6 •  Descending to sleep7 “Diverse interacHons between geneHc factors and environment most likely explain individual suscepHbility…”2 •  Non-­‐contributory/Non-­‐
protecHve
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–
–
–
–
Youth8 Physical fitness8,9 Smoking4 Alcohol intake4 Male / Female10 Chronic CondiHons7 •  Diabetes •  Asthma/COPD •  HTN2 –  Pregnancy7 1Roach & Hackeg, 2001; 2Hackeg & Roach, 2001; 3Basnyat & Murdoch, 2003; 4Schneider et al, 2002; 5Basnyat et al, 1999; 6Bartsch & Swenson, 2013; 7Barry & Pollard 2003; 8Schoene, 2008; 9Hultgren, 1979; 10Basnyat & Murdoch, 2003 Consistent “Causes” of AMS •  Travel to elevaHons >2500m1-­‐5 •  Commonly idenHfied factors1,2,4,6,7: •  Rate of ascent •  AlHtude agained –  In parHcular, the sleeping alHtude •  Individual suscepHbility }
–  Physiology –  GeneHc & environmental interacHons? 1Barry & Pollard, 2003; 2Basnyat & Murdoch, 2003; 3Schoene, 2008; 4Luks et al, 2010; 5Bartsch & Swenson, 2013; 6Hackeg & Roach, 2001; 7Kamimori et al, 2009; HYPOXIA? PRESSURE? AntarcHc Study of AlHtude Physiology (ASAP) 1Adapted from Anderson et al, 2011 AntarcHc Study of AlHtude Physiology (ASAP) •  Goals: –  Frequency & severity of symptoms at the South Pole [COMPLETE] –  ContribuHng factors (e.g., age, gender, sleep habits, acHvity levels, cold exposure, geneHc markers) [IN PROGRESS] –  Algorithm for predicHng suscepHbility to symptoms [IN PROGRESS] AntarcHc Study of AlHtude Physiology (ASAP) •  2 Summer expediHons 2005-­‐2007 •  N=248 (169 M; 79 F) •  Acetazolamide for ANYONE who wanted it 2005-­‐2006 2006-­‐2007 Barometric Pressure (mmHg) 513 ± 1 513 ± 5 EsHmated PO2 (mmHg) 107 107 Physiologic AlHtude (m) 3197 ± 21 3184 ± 70 Temperature (oC) -­‐42 ± 2 -­‐ 43 ± 5 1Adapted from Anderson et al, 2011; Lalande et al, 2011 ASAP Travel •  AcclimaHzed ~14d at McMurdo StaHon •  Travelled by airplane to South Pole StaHon –  ~4h flight UNIQUE  LARGE populaHon got to same alHtude in the same way at the same rate ASAP Data •  Lake Louise QuesHonnaires (9x) •  Baseline / Sea Level •  Plane •  Days 1-­‐7 in AM •  Vital signs •  Anthropometrics •  Lifestyle quesHonnaires –  Residence alHtude –  Exercise –  Smoking / EtOH •  Health hx quesHonnaires •  Repeated blood samples –  Hematology •  CBC, Iron Studies –
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Serum electrolytes Catecholamine levels Liver FuncHon Tests Endocrinology •  Urinalysis •  Electrocardiogram (ECG) •  Repeated Pulmonary FuncHon Tests (PFT) Summary of CharacterisHcs of ASAP ParHcipants Age (years)
No
Whole group acetazolamide Acetazolamide P
36.8 ± 10.6
35.7 ± 9.7
39.1 ± 11.5
0.019
Gender, M (%)
168 (70)
94 (69)
63 (69)
0.92
BMI (kg/m2)
26.1 ± 4.2
25.6 ± 3.7
26.7 ± 4.7
0.07
Body fat (%)
Males
Females
16.5 ± 6.2
26.3 ± 7.1
15.5 ± 6.0
25.7 ± 7.3
17.9 ± 6.1
27.5 ± 6.8
0.015
0.32
Elevation of residence (last 3
months), no. (%)
<5,000 ft above sea level
5,000-7,500 ft above sea level
7,500-10,000 ft above sea level
>10,000 ft above sea level
1Anderson et al, 2011 0.13
152 (64)
74 (31)
11 (5)
1 (0)
78 (58)
49 (36)
7 (5)
1 (1)
66 (73)
21 (23)
4 (4)
0 (0)
1Anderson et al, 2011 1Anderson et al, 2011 1Anderson et al, 2011 [IN PRESS] ASAP without Acetazolamide •  N=248 (169 M; 79 F) –  No Acetazolamide with complete data, n=90 •  Complete quesHonnaires •  2 blood samples •  2 PFT (no significant results found) –  Two groups: •  No AMS (n=60) •  AMS (n=30) Table 1 – Subject CharacterisHcs Table 2 – Hematologic and Chemistry Results Table 3 – Endocrine Results LogisHc Regression Analysis •  No AMS vs AMS by LLSS –  Excluded objecHve data from South Pole •  Forward, stepwise binary logisHc regression –  P<0.25 for iniHal inclusion1 1Honigman et al, 1994 •  IniHal Variables –  Residence ElevaHon –  Cl-­‐ –  AST –  LDL –  Eosinophils (%) –  RDW –  LepHn –  Epi LogisHc Regression EquaHon Prob (AMS) = (e 1.593 + (-­‐0.037)(LDL) + (0.433)( eos)) x (1 + e 1.593 + (-­‐0.037)(LDL) + (0.433)( eos))-­‐1 • p<0.01 • -­‐2 log-­‐likelihood = 66.5 • Nagelkerke R2 = 0.278 • Sensi8vity = 26% • Specificity = 92% • PPV = 56% • NPV = 77% Prob (AMS) = (e 1.593 + (-­‐0.037)(LDL) + (0.433)( eos)) x (1 + e 1.593 + (-­‐0.037)(LDL) + (0.433)( eos))-­‐1 •  Eosinophils •  LDL •  Na+ •  Δ Plasma Volume •  Dopamine •  VEGF •  TNF-­‐α Prob (AMS) = (e 1.593 + (-­‐0.037)(LDL) + (0.433)( eos)) x (1 + e 1.593 + (-­‐0.037)(LDL) + (0.433)( eos))-­‐1 FLUID REGULATION •
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•
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LDL Na+ Δ Plasma Volume Dopamine INFLAMMATORY RESPONSE •
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Eosinophils LDL VEGF TNF-­‐α Hypothesized Pathophysiology of AMS 1Ward et al, 1995; Plasma Volume •  “…plasma volume is reduced over 24-­‐48h…”1 –  1500-­‐2000m •  200-­‐300mL reducHon in plasma volume –  3000-­‐4000m •  600-­‐900mL reducHon in plasma volume •  Body weight constant in ASAP ~10% plasma volume loss in AMS subjects ~2% in No AMS 1Bartsch & SalHn, 2008; FLUID REGULATION Variable Δ Plasma Volume LDL AMS vs No AMS AMS: -­‐9.4 ± 12.5% No AMS: -­‐2.9 ± 9.4% AMS: 97.7 ± 25.4 mg/dL No AMS: 105.9 ± 27.6 mg/dL Na+ AMS: 138.5 ± 1.8mEq/L No AMS: : 139.4 ± 1.6mEq/L Dopamine AMS: 16.2 ± 14.8 pg/mL No AMS: 24.4 ± 26.6 pg/mL Points of Interest No change in body weight at alHtude as compared to sea level baseline Contributes to oncoHc pressure  LDL but not HDL in response to nephroHc syndrome1,2 Largest component of serum osmolality 2[Na+] + [Gluc]/18 + [Urea]/2.8 Inhibits norepinephrine & acts as vasodilator; decreases lymphocyte acHvity; increases urine Na+ excreHon4 1Appel et al, 1985; 2Haymore et al, 2005; 3Barry & Pollard, 2003; 4Guyton & Hall, 2001 AMS & HACE on MRI 1Bailey et al, 2009; 2Schoonman et al, 2008 OncoHc Pressure •  ProporHonal to [proteins] in plasma –  Albumin; role of LDL? “Capillary permeability” AMS algorithm2 1Margarson & Soni, 2004; 2Ward et al, 1995 CorrelaHon between Plasma OncoHc Pressure and Total Plasma Cholesterol ConcentraHon (r = -­‐0.674, P<0.01) Appel et al, 1985 INFLAMMATORY RESPONSE Variable Eosinophils AMS vs No AMS AMS: 2.7 ± 2.0 x103/μL No AMS: : 1.9 ± 1.6 x103/μL Points of Interest Asthma and allergies  risk in asthma sufferers?1 Hypoxia modulates funcHon2  Cytokine producHon IL-­‐1, IL-­‐2, IL-­‐3, IL-­‐4, IL-­‐5, IL-­‐6, IL-­‐8, IL-­‐13, TNF-­‐α VEGF AMS: 76.4 ± 42.5 pg/mL No AMS: 57.0 ± 37.8 pg/mL TNF-­‐α AMS: 1.4 ± 0.7 pg/mL No AMS: 1.3 ± 0.6 pg/mL SHmulates angiogenesis; augments blood flow and oxygen supply to Hssues3  hypoxia-­‐induced vascular leakage in CNS4 Involved in inflammatory response in central nervous system aoer ischemic injury5,6 1Barry & Pollard, 2003; 2Nissim Ben Efraim et al, 2010; 3Schoene, 2008; 4Basnyat & Murdoch, 2003; 5Feuerstein & Barone, 1994; 6Barone et al, 1997 Cholesterol & Inflammatory Response •  Plasma cholesterol inversely related with: –  Sepsis & fever risk1 –  Sepsis severity2 •  Further decreases during treatment of sepsis associated with increased mortality3 –  LDL binds lipopolysaccharide •  Modulates inflammatory response –  IL-­‐1, IL-­‐6, TNF-­‐α •  Similar findings with HDL4 1Shor et al, 2007; 2Chiarla et al, 2004; 3Wilson et al, 2003; 4Chien et al, 2005 [IN PRESS] Physiologic Effects of Progesterone •  Respiratory sHmulant1,2,3 •  AnH-­‐inflammatory agent4 –  Powerful CNS acHon •  MineralocorHcoid antagonist5,6
–  Acts at aldosterone receptor •  CHOLESTEROL HORMONE2 1Bayliss & Milhorn, 1992; 2Guyton & Hall, 2001; 3Hannhart et al, 1990, 4Pan et al 2007; 5Popovic & White 1998; 6Quinkler et al, 2002 OCP Use & Reported Rates of AMS OCP Users Non-­‐OCP Users p-­‐value N 13 37 AMS 11 (85%) 19 (51%) 0.03 AMS in Acetazolamide Users 7/7 (100%) 8/16 (50%) <0.01 Age (yrs) 34.2±9.2 36.2±10.1 0.62 SL Progesterone (ng/mL) 0.7±0.5 3.2±4.6 0.02 ALTD Progesterone (ng/mL) 0.7±0.7 3.1±4.6 0.04 AMS Pharmacological OpHons •  DiureHcs •  Acetazolamide1,2,3,4,5 •  “facilitates acclima8za8on” •  Decreased periodic breathing during sleep? •  Decreased CSF produc8on?6 •  Loops/Thiazides not effec8ve5,6 •  Spironolactone7 •  Only other diure8c to be effec8ve •  Binds aldosterone receptor (same site as progesterone) 1Hultgren, 1979; 2Luks et al, 2010; 3Schoene, 2008; 4Barry & Pollard; 5Leaf & Goldfarb, 2007; 6Hackeg & Roach, 2001; 7Loeppky et al, 2005; 8Luks & Swenson, 2008; 9Bernhard et al, 1998; 10Lipman et al, 2012; 11Gertsch et al, 2010 AMS Pharmacological OpHons •  AnH-­‐Inflammatory MedicaHons •  Dexamethasone1,2,3,5 •  Can be started AFTER symptoms develop •  May be superior to acetazolamide in AMS treatment either alone4 or in combina8on6 •  NSAIDs7 –  As effec8ve as acetazolamide8 1Luks et al, 2010; 2Schoene, 2008; 3Barry & Pollard; 6Hackeg & Roach, 2001; 5Luks & Swenson, 2008; 6Bernhard et al, 1998; 7Lipman et al, 2012; 8Gertsch et al, 2010 Peripheral blood mononuclear cell (PBMC) gene expression in healthy adults rapidly transported to high alHtude •  Herman et al, submiged to BMJ –  “Increased metabolism in PBMCs suggests increased inflammatory acHvity.” –  “This would be consistent with proposed increases in PBMC acHvity and associated inflammaHon during exposure to high alHtude.” From Due South to Straight Up ApplicaHons to Space Flight? •  Rapid transport to “alHtude”? –  Decreased ambient pressures & PO2 •  Fluid shios1 •  Disturbed sleep •  Immune modulaHon –  ReacHvaHon of latent viruses2 –  Occurs at AntarcHca too2,3 •  PharmaceuHcal requirements in space?4 1Hargens & Richardson, 2009; 2Mehta et al, 2000; 3Tingate et al, 1997; 4Putcha et al, 1999 Fluid Shios1 1Hargens & Richardson, 2009 ApplicaHons to Space Flight? •  Disturbed sleep1 •  Frequent headaches •  PharmaceuHcal requirements in space2 1Putcha & Marshburn, 2008; 2Putcha et al, 1999 Pressures in Space Pressure (mmHg) O2 (%) PO2 (mmHg) South Pole 513 20.9 107 Space Shugle 527.5 26.5 127 InternaHonal Space StaHon (ISS) 760 21 150 Extravehicular Mobility Unit (EMU) 222.4 100 222.4 Future Vehicles? 365 32 117 457 34 128 Personal correspondence with Mr Jason Norcross, May-­‐June 2013 ASAP: In Summary Hypoxic Hssue becomes inflamed Inflamed Hssue becomes hypoxic1 #
•  Hypoxia & Hypoxemia •  Fluids & InflammaHon •  Specific to AMS1: Brain –   circulaHng levels of proinflammatory cytokines –   accumulaHon of inflammatory cells & mediators in mulHple organs in body –   vascular leakage 1Eltzschig & Carmeliet, 2011 ASAP: In Summary Hypoxic Hssue becomes inflamed Inflamed Hssue becomes hypoxic1 #
•  Unique variables to consider moving forward –  LDL Fluid? –  Progesterone InflammaHon? –  GeneHc markers of inflammaHon 1Eltzschig & Carmeliet, 2011 Conclusion •  In a populaHon of healthy adults who were rapidly transported to alHtude with minimal physical exerHon, a comprehensive analysis suggests importance of:
–  Tissue inflammaHon –  OncoHc pressures and fluid shios Acknowledgements •  The team would like to thank: –  US AntarcHc Program employees –  Cray Lab –  Jay O’Brien –  Kent Bailey –  Josh Mueller •  Dr Harrison would like to thank: –  Dr Lawrence Steinkraus (Mayo Clinic) –  Dr Bruce Johnson (Mayo Clinic) –  Ms Kathy O’Malley (Mayo Clinic) –  Mr Jason Norcross (Wyle) –  Dept of Emergency Medicine and Internal Medicine (Henry Ford Hospital) & Dr Kathrina Jaehne –  Ms Diane Ellison (UTMB) Funding was provided by NaHonal Science FoundaHon, B-­‐179-­‐M Mayo Clinic Center for TranslaHonal Science AcHvity (CTSA), Clinical Research Unit Grant Number 1 UL1 RR024150 from the NaHonal Center for Research Resources POINTS OF CONTACT: MICHAEL HARRISON, MD PHD MHARRI19@HFHS.ORG •
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