U-2 DCS Update. Background Information C-1. Original Review of Problem. Leonardo C. Profenna, MD, MPH, Col (ret)

Transcription

1 U-2 DCS Update Leonardo C. Profenna, MD, MPH, Col (ret) Medical Director, Wound Care Center Connally Memorial Medical Center Floresville, TX Thanks to: Steve McGuire, MD Lt Col Sean Jersey, MD Lt Col Alan Flower, DO $61 billion impact (2012), 116,000 jobs Production barrels/day 26 permits ,000 barrels/day 4,143 permits Projected to barrels/day Background Information Original Review of Problem U-2 Mission High altitude (+60,000 ft) reconnaissance High risk of DCS without prevention measures Standard DCS Prevention Measures Full pressure suit, 1-hour resting, 100% O2 Low Historical Incidence of U-2 DCS 90 incidents of joint pain reported in the literature as of 2000 Many unreported cases of joint/skin DCS No recorded cases of CNS DCS or permanent damage Number of U-2 DCS Incidents incidents of all types with 37 pilots Retrospective Review of U-2 DCS Incidents Before Dec 09 DGMC Travis AFB IRB Approval (FDG H) Series of CNS DCS Incidents Jan 02-Dec 09 Confirmed cases (16): documented in medical records Probable cases (4): reported but insufficient documentation Possible cases (0): retrospective reports (unofficial) by pilots Research Limited to Existing Sources: Medical & physiological support records Flight, maintenance, & safety records Many Severe Neurological Cases with Unusual Clinical Symptoms Jersey SL, Hundemer GL, Stuart RP, West KN, Michaelson RS, Pilmanis AA. Neurological decompression sickness among U-2 pilots: Aviat Space Environ Med 2011; 82: C-1

2 Patient Characteristics 20 Cases 16 Confirmed, 4 Probable Incidents 12 pilots with one incident each 4 pilots with two incidents each Pilot Ages: 30 to 48 yo Gender: 15 men, 1 woman BMI: 21 to 32 Prior Medical History: All non-smokers 2 pilots had prior history of rhino-septoplasty for sinus disease o/w negative No routine medical use prior to incidents No medications taken prior to flight 3 of 16 pilots used dexamphetamine during flight Initial Treatment Standard of Care Aircrew: descend & return ASAP after symptom onset Flight Docs: must TREAT if DCS is considered (diagnosis of exclusion) ABCs, O2, & transport to nearest hyperbaric chamber USN Treatment Table 6; keep treating until symptoms resolve/plateau Most Cases Received Appropriate Treatment 19 of 20 cases received prompt hyperbaric oxygen (HBO) treatment Responses varied by case (see following slides) Treatment delayed in some cases Some patients required multiple HBO treatments Treatment Delayed Inappropriately 1 Case Combination of factors contributed to delay Symptoms resolved after HBO treatment 11 days later 7 8 Expected Clinical Response Good Clinical Outcome Despite Treatment Delay Recurrent Symptoms After Treatment Persistent or Permanent Symptoms Despite Adequate Treatment Spectrum of Clinical Outcomes In 5/20 (25%) cases, pilots reported DCS symptoms immediately Prompt HBO treatment administered Full resolution of symptoms with no recurrence or persistence 4/20 (20%) cases: delayed symptom recognition, reporting, or treatment Treatment delayed by hours up to 11 days Symptoms resolved with no recurrence or persistence 19/20 (95%) cases received appropriate HBO treatment in theater 2/20 (10%) cases had recurrent symptoms during s Symptoms recurred in2 more (10%) after elevation changes while driving 10/16 (62.5%) pilots reported persistent symptoms for 3 months to 9 years+ Similar constellation of symptoms (headache, fatigue, irritability, etc.) Considered permanent in 2/16 (12.5%) pilots lasting > 6 & 9 years, respectively **NO FATALITIES** Clinical Course The Good 9/20 cases with no adverse clinical outcomes 5/20 (25%) reported promptly (in-flight) 4/20 (20%) delayed, but no problems after HBO Delays in treatment varied from a few hours up to 11 days: Situational: can t teleport to a chamber Pilots: hard to recognize vague symptoms in operational environment Docs: some didn t recognize or know how to treat DCS Both(): some pilots still didn t trust docs (fear of grounding) Symptoms resolved completely with HBO treatment No reported recurrent orpersistent symptoms Returned to after normal exam 6/9 (67%) of these pilots voluntarily left U-2 program after incidents Are historical outcomes as rosy as we think Reported permanent symptoms extremely rare No long-term follow-up in recorded DCS cases in literature 9 10 Most Common Symptoms Time Course of Presentation Presenting Symptoms Headache (10/20 cases) Fatigue (7/20) Confusion/memory lapses (7/20) Impaired mentation (5/20) Paresthesias (5/20) Vision problems (3/20) Nausea (3/20) Dizziness (2/20) Loss of consciousness (2/20) Disorientation (2/20) Weakness (2/20) CNS DCS symptomsareoftennon-specific Focal neurological symptomsare rare Requires highindex of suspicion If in doubt TREAT! MP16 MP14 MP15 MP14 MP13 MP12 MP11 MP10 MP6 MP8 MP9 MP8 MP7 MP7 MP6 MP5 MP4 MP3 MP2 MP1 Unreported time during flight Unreported time during flight Time of Recognized Symptom Onset (h) Unknown inflight 10% Onset postflight 40% Onset h inflight 15% 11 Onset 0-4 h inflight 35% Take-Home Points: DCSsymptoms vary markedly Delays in symptom recognitionare common Operational concerns also cause delays 12 C-2

3 Clinical Course The Bad Re-Injury After Treatment 1-hr resting Landing HBO treatment Pathophysiological Process Proposed by Goodman, et al. Based on animal (mice) model of traumatic brain injury Studies evaluating optimum time to fly following battlefield traumatic brain injury (TBI) Mild hypoxia of altitudes can exacerbate brain injury 4/20 (20%) cases had recurrent symptoms after HBO Rx 2 cases (2 pilots) occurred during s home Both pilots received repeat HBO treatment with resolution of symptoms Both pilots had persistent symptoms of fatigue, HA, & memory problems 2 cases (2 other pilots) occurred after elevation changes while driving home Both pilots experienced recurrent symptoms driving home after HBO Rx Both lived in same community, approximately 2,400 ft elevation Neither reported recurrence so did not receive repeat HBO treatment Both have symptoms persisting for years (likely permanent) & disqualified from flying So-Called Second Hit Phenomenon Initial CNS DCS injury damages neurons, initiates inflammatory cascade Symptoms resolve with treatment, but neurons incompletely recovered Subsequent hypoxia re-stresses damaged neurons & exacerbates inflammatory cascade recurrence of symptoms May Explain Unusual Symptoms in Some U-2 DCS Cases Recurrence of symptoms during s (2 cases) Recurrence of symptoms after elevation changes while driving (2 cases) Reported cases responded to repeat treatment with hyperbaric oxygen Clinical Course The Ugly 10/16 (62.5%) pilots with persistent symptoms Ranged from 3 months up to 9+ years Considered permanent in at least 2 cases 5 life-threatening cases* (4/5 cases at same location) 3 cases of severe neurological/pulmonary symptoms 2 cases of abrupt onset severe neurological symptoms in flight No fatalities all 5 pilots recovered & treated with HBO Good initial response to HBO treatment in all Appropriate HBO treatment in all cases (life saving in 5) Symptoms plateaued after repeat HBO treatments Common constellation of physical symptoms in 7/9 Symptoms similar to those seen after mild TBI *See published case reports fortwo life-threatening incidents: 1. Pickard BJ. Altitude decompression sickness in a pilot wearing a pressure suit above 70,000 ft. Aviat Space Environ Med 2003; 74: Jersey SL, Baril RT, McCarty RM, Millhouse CM. Severe neurological decompression sickness in a U-2 pilot. Aviat Space Environ Med 2010; 81:64-8. Persistent and/or Permanent Symptoms Landing Presenting Symptoms Headache (10/20 cases) Fatigue (7/20) Confusion/memory lapses (7/20) Impaired mentation (5/20) Paresthesias (5/20) Vision problems (3/20) Nausea (3/20) Dizziness (2/20) HBO treatment Loss of consciousness (2/20) Disorientation (2/20) Weakness (2/20) Persistent Symptoms Inappropriate fatigue (9/20) Headaches (7/20) Personality changes (5/20) Memory problems (5/20) Difficultyconcentrating (2/20) Difficultysleeping (2/20) 10 of 16 pilots (62.5%) Duration: 3 months to 9+ years Considered permanent in at least 2 cases 15 Foggy thinking 16 Clinical Course The Ugly Typical clinical course in each case: Good initial response to HBO treatment 2-4 days later: fatigue, headaches, etc. 3 of 4 treated with repeat HBO (partial relief) Medication for symptomatic relief problematic in one case Including: steroids, NSAIDs, ergot, sleep, anti-depressants Little relief with adverse clinical & occupational impacts Attempted repeat HBO months after incident no relief Pilot eventually permanently disqualified from all flying Minimized medication use in remaining pilots NSAIDs used as needed for headache Partial improvement with increased rest, duty restrictions Limited success only one pilot returned to unrestricted U-2 duties Heavy psychological sx (anxiety, depression, PTSD) in all Permanent flying restrictions (7) and/or DQ (2) Flying Status No Previous History of Long-Term Effects Fewcase reports oflasting effects after HBOtreatment Altitude DCSconsidered less severe than divingdcs Operational Incentives to Return Pilots to Flying EachnewU-2 pilot costs ~$2.5 million to train Limited poolofpilots to man deployment slots Limited housing& personnel slots at deployed locations Medical Consequences: Pilots flewhome from deployment ASAP (<72 h) after DCS Pilots attempted return to flyingstatus soon after DCS Waiver guide: returnafter resolutionofsymptoms,normal exam C-3

4 Persistent DCS Symptoms Aviation DCS is Rare, Particularly CNS Manifestations Overall incidence less than 1% (Butler et al. USAF, Bason et al. USN) Only 10-20% of these cases involved CNS symptoms Recurrent symptoms after treatment extremely rare (38 USAF, 6 USN cases) No reported incidents of CNS DCS in U-2 operations before 1991 Persistent CNS Symptoms Extremely Rare in Modern Aviation DCS Butler et al.: 95-98% treatment success with 1153 USAF cases ( ) Wirjosemito: 97.7% treatment success in 133 CNS DCS cases ( ) Fryer (1969): 6 CNS cases of persistent symptoms (all eventually cleared) No series we reviewed had any significant follow-up Persistent DCS Symptoms Permanent Neurological Sequelae Common with Diving-Related DCS 7/16 (44%) Pilots had Similar Constellation of Long-Term Symptoms Headaches, central fatigue, sleep disturbance, irritability, memory deficits Similar symptoms reported after TBI, concussions Is there a common final pathway for brain injury Have we overlooked significant long-term effects from altitude DCS Lessons Learned Lessons Learned Changes made as a result of these cases: Reinforced preexisting procedures (maintain hydration, descend, etc.) Encouraged pilots to report suspected symptoms Operational decision trial of exercise-enhanced Increased recovery time between flights Increased number of pilots in training (reduce operational burden) CNS DCS cases treated with USN TT6 with 2 extensions at baseline Results: Cultural resistance to some changes initially, eased with time Subjectively greater willingness to report symptoms Impact of changes positive 1-hr resting 4/20 (20%) cases had recurrent symptoms after indicated HBO treatment Possible explanations for recurrent symptoms: Mild hypoxia known to occur during s Damaged neurons susceptible to further injury during flight Changes made as a result of these cases: Pilots must wait at least 7 days before flying home after HBO treatment; pilots flying home must use supplemental oxygen Pilots at Travis AFB admitted or remain on base 72 hours after HBO No new cases of recurrent symptoms since changes implemented (Aug 09) Lessons Learned 10/16 (62.5%) pilots had persistent/permanent symptoms One pilot with medical course complicated by medication use At least 4/16 (25%) pilots reported clinically significant mental health problems Only 3/16 (19%) case pilots returned to unrestricted U-2 duty Lessons learned: Minimize use of medication (esp. narcotic/sedating meds) Provide proactive, persistent mental health support to pilots/family Flight surgeon & flying squadron manage work schedules Cooling off period of 6 months of no flying activities ACS Evaluation Six incident U-2 pilots underwent a directed evaluation 10/2010 1/2011 Comprehensive medical and neurological exam Cardiac exam to include ECHO (PFO in 1 of 6) Neurophysiological exam (EEG, VEP normal) Neurocognitive exam (no deficits) Comprehensive brain imaging MRI, MRS, DTI, PET C-4

5 MRI (pilot A ) 49 lesions (39 WMH/10 ependymal) cm 3 volume loss 158 clean controls age Population-based, Hispanic Avg 6.18 lesions cm 3 volume loss MRI (pilot B ) Necrotic appearing lesion at gray-white junction 1 WMH MRI Transformation Process Nonbrain removed from FLAIR image FLAIR registered to T1-weighted image Registered to Talairach-atlas-based stereotactic frame Lesions analyzed using Talairach-based boundaries Transformed MRI (pilot A ) Transformed FLAIR images Lesions better defined Normalized brain size Permits crosssubject comparison Lesion Number/Volume ACS Assessment Subject ID Subcortical Lesions Ependymal Lesions Lesions FLAIR Volume (cm 3 ) Subcortical Volume (cm 3 ) Ependymal Volume (cm 3 ) C C C1 * C2 * C C Mean Controls Subcortical injury occurring Unusual in pattern of distribution Single subject with an apparent embolic lesion U-2 population concerned Unknowns: Prevalence of injury in entire U-2 population Proximate precipitating factors for NDCS Possibly ops tempo related Neurocognitive impairment (now & long term) Mission impact * Does not include necrotic lesions C-5

6 Research Options 9/2011 Decision brief to AF/SG2 re: primate model Limited (nonsignificant p-value) data on 24 subjects Extremely high uncertainty re: primate protocol success Questions on validity of normative data and on new technology Research re-scoped to obtain true normative data Similar age range FC-II neurological standards Similar neurocognitive performance skills Normative Study Age active duty FC-II neurological standards Exclusionary criteria: Significant head trauma/surgery Significant headache/migraine history Significant psychiatric history Family history of degenerative neurological disease History of seizure after age 6 History of DCS Normative Study Doctorate limb (n=212) Flight Surgeon limb (n=82) 1 operational tour Altitude Exposure limb (n=82) > 50 exposures > 20,000 ft Calibration limb (n=20) Image at WHASC Cortical Thickness (n= 99 DCS; 75 DOC+FSG) Blue shaded regions represent areas of relative thinning of cortex compared to normative controls WMH Comparison U-2 Pilots 11/9/2012 Hypothesis Significant difference between control (DOC + FSG) and all U-2 (scaled and unscaled) irrespective of clinical NDCS symptoms Among only U-2 pilots significant difference between clinical NDCS vs. no clinical NDCS (p=0.026) whataboutthese folks DC S (n=105) U-2 pilots DOC+FSG (n=82) p-value (2-tailed Wilcoxon Rank) Subcortical WMH vol(scaled) 0.15±0.30 cm ±0.07 cm Subcortical WMH vol(unscaled) 0.13±0.27 cm ±0.07 cm Subcortical WMH count (scaled) 9.67± ±4.49 <0.001 Subcortical WMH count (unscaled) 7.57± ± If pilots exposedtohigh altitudes demonstrate changes onmri McGuire et al. Neurol 2013 (submitted) C-6

7 Typical Altitude Chamber Exposure MRI Abnormalities in Altitude Chamber Technicians 25K ft 18K ft 5K ftear/sinus check 30 min denitrogenation MRI Abnormalities in Altitude Chamber Technicians WMH Comparison Chamber 12/31/2012 PHY (n=57) DOC+FSG (n=102) p-value (2-tailed Mann-Whitney) Subcortical WMH vol Subcortical WMH count 0.157±0.481 cm ±0.076 cm 3 p= ± ±5.6 p=0.022 Significant difference between control (DOC+FSG) and PHY (hypobaric physiology personnel) WMH distribution similar in pattern to DCS (U-2 pilots) Unrelated to clinical episodes of NDCS Correlation with exposure hours not yet performed Difference noted for cortical thickness as well Cortical Thickness (n= 52 PHY; 75 DOC+FSG) Blue-shaded regions represent areas of relative thinning of cortex compared to normative controls WMH in Other Populations WMH nonspecific seen in a variety of neurological conditions as well as a consequence of aging WMH reported in high-altitude mountain climbers, even in the absence of clinical symptoms of mountain sickness attributed to a combination of hypoxia and hypobaria WMH change present in 23% (26/113) of Turkish military divers with no history of DCS compared with 11% (7/65) of controls WMH change was found in 43.7% of French military divers with no history of DCS compared with 21.8% of controls Fayed et al.amj Med 2006; 119(2):168.e1-6 Erdem et al. Aviat SpaceEnvironMed 2009;80:2-4 Gempp et al.aviatspaceenvironmed 2010; 81: C-7

8 Pathophysiology of NDCS (Classic View) Believed to be secondaryto nitrogen gas bubble formation Subsequent application of direct pressure on nerves and other tissues, blockage of small arteriolar vessels, and interaction with proteins in the blood Venous bubble formation occurs in 47%-66% of subjects exposed to chamber altitudes of 8992 m (29,500 ft) In lab clinical symptoms of DCS occur in 40%-42% CNS involvement (NDCS) is infrequent 49/1108 (4%) of lab DCS events Standard DCS therapy is U.S. Navy Treatment Table 6 (100% FIO 2; 2.8 atmospheres absolute) Based on empirical experience not laboratory studies Pilmanis et al. Aviat Space Environ Med 1999;70:22-9. Webb et al. Aviat SpaceEnviron Med 2002;73: Balldin et al. Aviat Space Environ Med 2004;75: Bennett et al. Cochrane Database of Systematic Reviews 2007 (2) DOI: / CD pub2 Pathophysiology (Alternative Mechanism) Lesion distribution pattern suggests simple compression of white matter by arteriolar gas bubble not complete explanation Microbubble (<30 μm) shower Accelerated coagulation of human whole blood and cell-free plasma with in vitro bubbles In rabbits, platelet thrombi found in pulm art In SCUBA platelet count decreased with venous bubbles In SCUBA microparticle production & neutrophil activation In cerebrovascular disease, early platelet adhesion and activation orchestrates a thrombo-inflammatory cascade not dependent upon platelet aggregation and thrombus formation Pontier et al. Aviat Space Environ Med 2008;79(12): Nieswandt et al. J Thromb Haemost 2011;9(suppl. 1): Thomet al. J Appl Physiol 2012;112: Pontier et al. J Appl Physiol 2011;110: Hallenbeck et al. Aerospace Med 1973;44: Tanoue et al. J Appl Physiolo 1987;62(5): Implications WMH associated with impairment of executive processing in other neurological diseases Statistical but not clinical deficits noted in U-2 pilots Is there a threshold effect Presumably a static process Standard treatment for NDCS is hyperbaria Should this be augmented by anti-thrombotic or anti-inflammatory treatment Is there a dose:effect relationship to exposure Questions C-8