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Hyperbaric Oxygen Therapy for Post-Concussion Syndrome: Contradictory Conclusions from a Study Mischaracterized as Sham-Controlled

2013; Mary Ann Liebert, Inc.; Volume: 30; Issue: 23 Linguagem: Inglês

10.1089/neu.2012.2799

1557-9042

Paul G. Harch,

Cardiac Arrest and Resuscitation

Journal of NeurotraumaVol. 30, No. 23 Letter to the EditorOpen AccessHyperbaric Oxygen Therapy for Post-Concussion Syndrome: Contradictory Conclusions from a Study Mischaracterized as Sham-ControlledPaul G. HarchPaul G. HarchPublished Online:19 Nov 2013https://doi.org/10.1089/neu.2012.2799AboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail Dear Editor,The recent study by Wolf and associates1 has affirmed the effectiveness of hyperbaric (oxygen) therapy in the treatment of patients with mild traumatic brain injury (mTBI)/post-concussion syndrome (PCS) and post-traumatic stress disorder (PTSD). This affirmation emerges from analysis of the study data, rather than from the study's stated conclusions. Mischaracterized as a sham-controlled (placebo implied) design, the study errs in concluding that "HBO2 at 2.4 ATA pressure had no effect on post-concussive symptoms after mild TBI." A reconsideration of the science of hyperbaric therapy reveals that the study by Wolf and colleagues1 is neither a sham nor placebo-controlled study. Rather, it is a Phase II study of two composite doses of hyperbaric therapy that demonstrated significant improvements in PCS and PTSD symptoms at the 2.4 atmospheres absolute (ATA) pure oxygen dose as well as the low-pressure 1.3 ATA air/oxygen dose.Hyperbaric (oxygen) therapy (HBOT) is a combination product of increased pressure and increased pressure of oxygen above ambient atmospheric pressure, according to scientific principles and current Food and Drug Administration understanding. Although traditionally misdefined as a treatment for diseases based on the increased oxygen component alone (>1.4 ATA oxygen),2 it is a treatment with hyperbaric pressure and hyperoxia for disease processes2,3 whose primary targets are oxygen and pressure sensitive genes.4–6Evidence for this dual component nature of hyperbaric therapy is found in the 351-year history of hyperbaric air therapy7 and the recent 60-year history of animal, human tissue, and human experiments that have documented biological effects of pressure, especially in the micropressure range8,9 of the Wolf and coworkers1 "sham" control group and the control groups of the Department of Defense (DoD) HBOT TBI studies.10 Examples of this literature are listed in Tables 1 and 2.11–28 Pressures from 1.21–1.26 ATA delivered to human29–31 and 1.0015–1.015 ATA to animal endothelial cells,32 and 1.10 and 1.20 ATA to human platelets33,34 for 15 min or longer have caused the elaboration or suppression of vasoactive substances,29–31 and the elaboration of growth factors,32 inflammatory mediators,33 oxidation products,34 and cell proliferation.32 This literature and biological effects from a 1-min exposure to 1.09 ATA or 3 min at 1.04 ATA17 inform the symptomatic improvements noted in the Wolf and associates1 "sham" group, as do benefits of hyperbaric air on spinal function and PTSD in spinal cord injured veterans during a SCUBA diving training course.28Table 1. In vitro and In vivo Studies on Hyperbaric (Pressure and Oxygen) EffectsStudyYearModel: In Vivo (IV), In Vitro (IVT)Animal/humanAmbient gas1. Cunningham, O.J.111900–1929Multiple medical disordersHumanAir2. Dowell, R.T.121978Aortic constriction (IV)Rat-neonate and adultAir3. Hishikawa, K.131994Vascular smooth muscle cells, IVTRatHelium4. Mattana, J.141995Mesangial (renal) cells (IVT)Rat95% air, 5% CO25. Teiger, E.151996Aortic constriction (IV)RatAir6. Kramer, M.R.161998COPD-pulmonary functionHumansAir7. Kawata, Y.171998Mesangial (renal) cells (IVT)RatAir8. Macdonald, A.G.-review91999Wide range of IV and IVTBacteria, insect, nematode, animal, human95% air, 100% air, helium9. Agar, A.182000Neuroblastoma (IVT), glaucoma modelRat95% air, 5% CO210. Dean, J.B.192000Brain stem neurons (IVT)RatAir, helium11. Heal, R.D.202001Dorsal root ganglion neurons (IVT)Rat95% air, 5% CO212. Collet, J.P.212001Cerebral palsy (IV)Human-childrenAir, 100% oxygen13. Yu, H.A.I.222002Subacute hypoxic-ischemia brain injury (IV)RatAir, 100% oxygen14. Heuser, G.232002Chronic toxic encephalopathy or autism (IV)Human-adults and children24% oxygen15. Kazantseva, N.V.242002Cerebrovascular injury, epilepsy, migraine (IV)Human adults30%, 40%, and 100% oxygen16. Rusyniak, D.E.252003Acute strokeHuman-adults100% oxygen17. Stanley, A.C.262005Fibroblast wound-healing (IVT)Human neonatal fibroblasts94% air, 6% CO218. Rossignol, D.A.272009AutismHuman-childrenAir, 24% oxygen19. Kaplin, A.282011Spinal cord injury and PTSDHuman-veteransAirCOPD, chronic obstructive pulmonary disease; PTSD, post-traumatic stress disorder.Table 2. Continuation ofTable 1In vitro and in Vivo Studies on Hyperbaric (Pressure and Oxygen) EffectsStudyOxygen pressure (ATA): Control:experimentalTotal pressure (ATA): Control:experimentalDuration/# RxsEffect1.No controls:0.281–0.496No controls: average1.34–2.36 ATA, max 3 ATA2–3 hours up to days. Multiple treatmentsGenerally, improvement in clinical and laboratory parameters2.0.129:0.129 (arterial oxygen partial pressure)1.103–1.163: 1.150–1.2172,3,4,5 weeksCardiac myocyte and non-myocyte proliferation3.0.205:0.2051.000:1.053, 1.105, 1.15824 and 48 hIncreased cell proliferation and DNA synthesis; process begins w/i 30s press.4.0.23:0.237, not measured for 2nd pressure1.000:1.053–1.066 and 1.066–1.0791 or 7 daysDecreased cell number and increased matrix collagen (MC) at 7d. Dose-response for MC.5.0.129:0.129 (arterial oxygen partial pressure)Approximately same as #1; same model1,2,4,7,15,30 daysIncreased apoptosis of cardiac myocytes by 1 day, peak at 4 days6.No controls (pre/post):0.221Pre: 0.912Post: 1.052621 daysImproved arterial oxygen and exercise capacity.7.0.270:0.2701.000:1.039, 1.066, 1.092, 1.1181–30 minutes, 12, 24, 48 hoursEnzyme activation w/i 1 min @ 1.092 ATA, gene expression/proliferation post 12 h and 24 h exposure8.0.199:0.2511.000:1.010–1.260Few sec-daysWide range of biological effects9.0.222:0.2221.000:1.1312 hIncreased apoptosis10.0.950:2.352–3.3321.000:1.000–4.0005–15 minDifferential effects of pressure and oxygen on firing rate11.0.199:0.5991.000:3.0008 min 20 secSuppression of firing rate12.0.273:1.7501.300:1.75060 minutes/d×40 dBoth groups: Significant improvements in motor and cognition13.0.250:0.625, 2.501.000:2.50060 minday×10 daysIncreased bFGF in hyperbaric air, increased bFGF and bFGF mRNA in HBO14.No control: 0.312No control: 1.301 h/day×10 daysImproved blood flow on SPECT brain imaging15.0.300:0.330, 0.480, 1.5001.000:1.100, 1.200, 1.50015–20m?×5: 15–20m×4–10, 20 m×1 or 4–5, 60 m×5Improvement symptoms, EEG, blood flow, vital signs, biochemical params. <1.5 ATA16.1.14:2.501.14:2.501 hBetter outcome in the low dose group17.0.194:0.205, 0.213, 0.2291.000:1.039, 1.079, 1.15812–18 hDelayed wound healing and less proliferating cell nuclear antigen18.0.216; 0.3121.03:1.301 h/day×40 daysClinical improvement19.SCUBA courseLikely <3 ATALikely <1 hImproved spinal cord function and PTSDATA, atmospheres absolute; bFGF, basic fibroblast growth factor; HBO, hyperbaric oxygen; EEG, electroencephalography; PTSD, post-traumatic stress disorder.To meet the definition of a true sham,35 any controlled experiment to test HBOT must omit in its control groups the active ingredients of increased pressure and hyperoxia. The Wolf and colleagues1 "sham" control group does neither; rather, it includes both. The "sham" control group is exposed to 1.3/1.2 ATA of air, which is a 20–30% increase in pressure and 28–43% increase in plasma oxygen36 over sea level plasma oxygen and a slightly greater increase over San Antonio (hyperbaric treatment site) atmospheric pressure.37 Because pressure and hyperoxia are non-inert—i.e., are biologically active—the Wolf and coworkers1 "sham" control group cannot test for placebo effects; placebo/placebo response is defined as "The effect that an inactive or inert substance has on a clinical condition."38 Wolf and associates1 allude to possible bioactivity of the control group, but the lack of discussion indicates a lack of appreciation that the presence of hyperoxia and pressure negate Wolf and colleagues1 characterization as a "sham" control group.Restating the design of the Wolf and coworkers1 study, it is a Phase II comparative dosing study of two composite doses of hyperbaric therapy (four actual doses), compressed air (low dose increased pressure and increased oxygen), and compressed oxygen (high dose pressure and high dose oxygen). Both doses were efficacious in the treatment of mTBI PCS and PTSD. The PTSD data demonstrated 18% and 22% reductions in the PCL-M (interpolated from the Figure 1 graph in Wolf and colleagues1) in the HBOT and "sham" groups, respectively, after 30 2 h treatments. These reductions compared favorably with five other therapies/six studies for PTSD39–44 that used the PCL-M (6–45% reductions).The PCS ImPACT data were similarly significantly improved in both groups, but it is the disparity in component and pattern change on the ImPACT results for the two groups that underscore the dual dose design of the study and efficacy of these two doses: 10 IMPACT scores significantly improved in the low dose group compared with 2 in the high dose group. For all 22 items of the ImPACT, 20 improved, 1 was unchanged, and 1 was worse in the low dose group, while 11 improved, 3 were unchanged, and 8 were worse in the high dose group (Table 1 in Wolf and associates1). The pattern of composite ImPACT scores over the course of the study is also different for the two groups (Figure 2 in Wolf and coworkers1). Subjects in the low dose group experienced initial deterioration then steady improvement until the end of the study while the high dose group showed improvement then a steady reversal of benefit to near baseline, followed by rebound improvement 6 weeks post-treatment.This sinusoidal trajectory in the high dose group suggests a differential dosing effect and possibly an overdose response with partial recovery after removal of the high dose, and is consistent with the worsening of eight scores in this group. It is also consistent with a phenomenon previously described and documented in multiple cases of HBOT treatment of chronic cerebral disorders.45Since the initial submission of this Letter to the Editor, Wolf and colleagues1 have now confirmed this overdosing effect on PCS symptoms in the 2.4 ATA group in a subset analysis presented on June 14, 2013.46 This demonstration of low dose effectiveness and progressive high dose overdosing is also evident in other animal and clinical studies.25,47,48Wolf and associates1 list multiple possibilities for the improvements in PCS and PTSD, including "placebo, Hawthorne effect, the natural resolution of symptoms over time,…exposure to sham-control partial pressures of oxygen and nitrogen,…and change in living environment…and daily routine." While 30 chamber experiences and change in living environment and daily routine are theoretical placebo contributions, the myriad standard clinical pressure/hyperoxia2 and micropressure-induced biological effects demonstrated in both animal and human studies8,9 and Tables 1 and 2 suggest that placebo is not the majority effect.At the same time, placebo effects were also present in all six of the aforementioned PTSD/PCL-M studies. Hawthorne effect is also theoretically possible, but the foundation/proofing of the Hawthorne effect has been undermined by re-evaluation of the initial data set.49 Symptoms in veterans with TBI and PTSD, in fact, do not resolve over time, as acknowledged by Wolf and coworkers1 in their conclusion "improved more than would be expected greater than 6 months after mTBI," and reports on persistent care and even worsening of condition over time in the Veterans Affairs system.50,51All of the explanations by Wolf and colleagues,1 however, do not explain the disparity in component and pattern change in the ImPACT data and transient overdose effect in the high dose oxygen group. If placebo, Hawthorne effect, and other non-biological etiologies are causally entertained, why wouldn't the component and pattern changes be identical in the two groups? The last choice, effects of increased partial pressures of oxygen and nitrogen, seems most plausible as the dominant etiology for the statistically significant improvements in both groups, but it is not necessarily nitrogen pressure, but pressure, per se, that is involved. Wolf and associates1 state, however, "…it seems very unlikely such a minimal dose of oxygen and nitrogen could influence brain function favorably." The preceding argument and studies in Table 1 and 2 suggest the opposite.In conclusion, the study by Wolf and colleagues1 is a non-sham/non-placebo/non-controlled Phase II two composite dose study of hyperbaric therapy (hyperbaric air and hyperbaric oxygen) in U.S. veterans with PCS from mTBI with or without PTSD. The study demonstrated significant net improvements in PCS and PTSD symptoms with both doses of hyperbaric therapy, improvements that are similar in magnitude to other therapies for PTSD and greater than would be expected for PTSD and PCS over time without treatment based on the natural history of the diseases and published persistence rates in veterans.50,51 Their results are thus comparatively effective to other existing therapies for PTSD and possibly PCS of mTBI.If further evidence for the efficacy of hyperbaric therapy in mTBI PCS and PTSD is deemed necessary, as alternatives to the "pivotal" trial,10 and in light of nearly $1 billion dollars of research and development money already spent by the Department of Defense (DoD) on research seeking effective treatments for TBI and PTSD, this author would suggest two options: (1) Abandoning the pursuit of a "sham" hyperbaric control group and prioritizing the data from the wait-list group in the DoD HOPP study10 (Wolf and coworkers1 mention a wait-list group in their recommendations for future studies). This option is based on the physical impossibility of controlling for a chamber experience because of the inability to control for pressure (no method to duplicate middle ear pressure changes without placement of pressure equalization tubes and no commercially available mechanisms to duplicate adiabatic heating and cooling on compression and decompression). Continued attempts at a "sham" pressure control group will only further confuse the scientific and lay community; and (2) an economical Civilian/DoD/Veterans Affairs (VA) off-label networked hyperbaric treatment program using a Medicare-like Coverage with Evidence Development52 pathway. The safety of HBOT 1.5 and even higher doses is not in issue; hyperbaric oxygen therapy in mTBI PCS/PTSD has satisfied one of the cardinal rules of medicine, "First, Do No Harm." The Coverage with Evidence pathway would allow the DoD and VA to immediately begin treating active military and veteran casualties with hyperbaric therapy in both military and civilian clinics/hospitals such that this health and quality of life improving therapy can be delivered without further delay to the hundreds of thousands of injured PCS/PTSD casualties and veterans now in need.Author Disclosure StatementDr. Harch owns a small consulting company, Harch Hyperbarics, Inc., and is president of a non-profit corporation, The International Hyperbaric Medical Foundation (IHMF). He derives no income, salary, or benefits from the IHMF.References1 Wolf G.Cifu D.Baugh L.Carne W.Profenna L.2012The effect of hyperbaric oxygen on symptoms after mild traumatic brain injuryJ. Neurotrauma2926062612.1. Wolf, G., Cifu, D., Baugh, L., Carne, W., and Profenna, L. (2012). The effect of hyperbaric oxygen on symptoms after mild traumatic brain injury. J. Neurotrauma 29, 2606–2612. Link, Google Scholar2 Gesell L.B.2009Hyperbaric Oxygen Therapy Indications12thThe Hyperbaric Oxygen Therapy Committee Committee ReportUndersea and Hyperbaric Medical SocietyDurham, NC45.2. Gesell, L.B., ed. (2009). Hyperbaric Oxygen Therapy Indications, 12th ed. The Hyperbaric Oxygen Therapy Committee Committee Report. Undersea and Hyperbaric Medical Society: Durham, NC, pps. 4–5. Google Scholar3 Harch P.G.Neubauer R.A.1999Hyperbaric oxygen therapy in global cerebral ischemia/anoxia and comaChapter 18Textbook of Hyperbaric Medicine3rdrevisedK.K.Jain Hogrefe and Huber PublishersSeattle319345.3. Harch, P.G., and Neubauer, R.A. (1999). Hyperbaric oxygen therapy in global cerebral ischemia/anoxia and coma, in: Chapter 18, Textbook of Hyperbaric Medicine, 3rd revised ed. K.K. Jain (ed.). Hogrefe and Huber Publishers: Seattle, pps. 319–345. Google Scholar4 Godman C.A.Chheda K.P.Hightower L.E.Perdrizet G.Shin D.G.Giardina C.2010Hyperbaric oxygen induces a cytoprotective and angiogenic response in human microvascular endothelial cellsCell Stress Chaperones15431442.4. Godman, C.A., Chheda, K.P., Hightower, L.E., Perdrizet, G., Shin, D.G., and Giardina, C. (2010). Hyperbaric oxygen induces a cytoprotective and angiogenic response in human microvascular endothelial cells. Cell Stress Chaperones 15, 431–442. Crossref, Medline, Google Scholar5 Chen Y.Nadi N.S.Chavko M.Auker C.R.McCarron R.M.2009Microarray analysis of gene expression in rat cortical neurons exposed to hyperbaric air and oxygenNeurochem. Res3410471056.5. Chen, Y., Nadi, N.S., Chavko, M., Auker, C.R., and McCarron, R.M. (2009). Microarray analysis of gene expression in rat cortical neurons exposed to hyperbaric air and oxygen. Neurochem. Res, 34, 1047–1056. Crossref, Medline, Google Scholar6 Kendall A.C.Whatmore J.L.Harries L.W.Winyard P.G.Eggleton P.Smerdon G.R.2013Different oxygen treatment pressures alter inflammatory gene expression in human endothelial cellsUndersea Hyper. Med.40115123.6. Kendall, A.C., Whatmore, J.L., Harries, L.W., Winyard, P.G., Eggleton, P., and Smerdon, G.R. (2013). Different oxygen treatment pressures alter inflammatory gene expression in human endothelial cells. Undersea Hyper. Med. 40:115–123. Medline, Google Scholar7 Jain K.K.2004The history of hyperbaric medicineTextbook of Hyperbaric Medicine4threvised and expanded editionK.K.Jain Hogrefe and Huber PublishersCambridge, MA38.7. Jain, K.K. (2004). The history of hyperbaric medicine, in: Textbook of Hyperbaric Medicine, 4th revised and expanded edition, K.K. Jain (ed). Hogrefe and Huber Publishers: Cambridge, MA, pps. 3–8. Google Scholar8 Dean J.B.Mulkey D.K.Garcia A.J.IIIPutnam R.W.Henderson R.A.III2003Neuronal sensitivity to hyperoxia, hypercapnia, and inert gases at hyperbaric pressuresJ. Appl. Physiol.95883909.8. Dean, J.B., Mulkey, D.K., Garcia, A.J., III, Putnam, R.W., and Henderson, R.A., III. (2003). Neuronal sensitivity to hyperoxia, hypercapnia, and inert gases at hyperbaric pressures. J. Appl. Physiol. 95, 883–909. Crossref, Medline, Google Scholar9 Macdonald A.G.Fraser P.J.1999The transduction of very small hydrostatic pressuresComp. Biochem. Physiol. A. Mol. Integr. Physiol.1221336.9. Macdonald, A.G., and Fraser, P.J. (1999). The transduction of very small hydrostatic pressures. Comp. Biochem. Physiol. A. Mol. Integr. Physiol. 122, 13–36. Crossref, Medline, Google Scholar10 Weaver L.K.Cifu D.Hart B.Wolf G.Miller S.2012Hyperbaric oxygen for post-concussion syndrome: design of Department of Defense clinical trialsUndersea Hyperb. Med.39807814.10. Weaver, L.K., Cifu, D., Hart, B., Wolf, G., and Miller, S. (2012). Hyperbaric oxygen for post-concussion syndrome: design of Department of Defense clinical trials. Undersea Hyperb. Med. 39, 807–814. Medline, Google Scholar11 Trimble V.H.1974The Uncertain Miracle: Hyperbaric OxygenationDoubleday & Company, Inc.Garden City, NY.11. Trimble, V.H. (1974). The Uncertain Miracle: Hyperbaric Oxygenation. Doubleday & Company, Inc.: Garden City, NY. Google Scholar12 Dowell R.T.McManus R.E.III1978Pressure-induced cardiac enlargement in neonatal and adult rats. Left ventricular functional characteristics and evidence of cardiac muscle cell proliferation in the neonateCirc. Res.42303310.12. Dowell, R.T., and McManus, R.E., III. (1978). Pressure-induced cardiac enlargement in neonatal and adult rats. Left ventricular functional characteristics and evidence of cardiac muscle cell proliferation in the neonate. Circ. Res. 42, 303–310. Crossref, Medline, Google Scholar13 Hishikawa K.Nakaki T.Marumo T.Hayashi M.Suzuki H.Kato R.Saruta T.1994Pressure promotes DNA synthesis in rat cultured vascular smooth muscle cellsJ. Clin. Invest.9319751980.13. Hishikawa, K., Nakaki, T., Marumo, T., Hayashi, M., Suzuki, H., Kato, R., and Saruta, T. (1994). Pressure promotes DNA synthesis in rat cultured vascular smooth muscle cells. J. Clin. Invest. 93, 1975–1980. Crossref, Medline, Google Scholar14 Mattana J.Singhal P.C.1995Applied pressure modulates mesangial cell proliferation and matrix synthesisAm. J. Hypertens.811121120.14. Mattana, J., and Singhal, P.C. (1995). Applied pressure modulates mesangial cell proliferation and matrix synthesis. Am. J. Hypertens. 8, 1112–1120. Crossref, Medline, Google Scholar15 Teiger E.Than V.D.Richard L.Wisnewsky C.Tea B.S.Gaboury L.Tremblay J.Schwartz K.Hamet P.1996Apoptosis in pressure overload-induced heart hypertrophy in the ratJ. Clin. Invest.9728912897.15. Teiger, E., Than, V.D., Richard, L., Wisnewsky, C., Tea, B.S., Gaboury, L., Tremblay, J., Schwartz, K., and Hamet, P. (1996). Apoptosis in pressure overload-induced heart hypertrophy in the rat. J. Clin. Invest. 97, 2891–2897. Crossref, Medline, Google Scholar16 Kramer M.R.Springer C.Berkman N.Glazer M.Bublil M.Bar-Yishay E.Godfrey S.1998Rehabilitation of hypoxemic patients with COPD at low altitude at the Dead Sea, the lowest place on earthChest113571575.16. Kramer, M.R., Springer, C., Berkman, N., Glazer, M., Bublil, M., Bar-Yishay, E., and Godfrey, S. (1998). Rehabilitation of hypoxemic patients with COPD at low altitude at the Dead Sea, the lowest place on earth. Chest 113, 571–575. Crossref, Medline, Google Scholar17 Kawata Y.Mizukami Y.Fujii Z.Sakumura T.Yoshida K.Matsuzaki M.1998Applied pressure enhances cell proliferation through mitogen-activated protein kinase activation in mesangial cellsJ. Biol. Chem.2731690516912.17. Kawata, Y., Mizukami, Y., Fujii, Z., Sakumura, T., Yoshida, K., and Matsuzaki, M. (1998). Applied pressure enhances cell proliferation through mitogen-activated protein kinase activation in mesangial cells. J. Biol. Chem. 273, 16905–16912. Crossref, Medline, Google Scholar18 Agar A.Yip S.S.Hill M.A.Coroneo M.T.2000Pressure related apoptosis in neuronal cell linesJ. Neurosci. Res.60495503.18. Agar, A., Yip, S.S., Hill, M.A., and Coroneo, M.T. (2000). Pressure related apoptosis in neuronal cell lines. J. Neurosci. Res. 60, 495–503. Crossref, Medline, Google Scholar19 Dean J.B.Mulkey D.K.2000Continuous intracellular recording from mammalian neurons exposed to hyperbaric helium, oxygen, or airJ. Appl. Physiol89807822.19. Dean, J.B., and Mulkey, D.K. (2000). Continuous intracellular recording from mammalian neurons exposed to hyperbaric helium, oxygen, or air. J. Appl. Physiol, 89, 807–822. Crossref, Medline, Google Scholar20 Heal R.D.Rogers A.T.Lunt G.G.Pointer S.A.Parsons A.T.2001Development of a neuronal pressure sensorBiosens. Bioelectron.16905909.20. Heal, R.D., Rogers, A.T., Lunt, G.G., Pointer, S.A., and Parsons, A.T. (2001). Development of a neuronal pressure sensor. Biosens. Bioelectron. 16, 905–909. Crossref, Medline, Google Scholar21 Collet J.P.Vanasse M.Marois P.Amar M.Goldberg J.Lambert J.Lassonde M.Hardy P.Fortin J.Tremblay S.D.Montgomery D.Lacroix J.Robinson A.Majnemer A.HBO-CP Research Group2001Hyperbaric oxygen for children with cerebral palsy: a randomized multicentre trialLancet357582586.21. Collet, J.P., Vanasse, M., Marois, P., Amar, M., Goldberg, J., Lambert, J., Lassonde, M., Hardy, P., Fortin, J., Tremblay, S.D., Montgomery, D., Lacroix, J., Robinson, A., and Majnemer, A., HBO-CP Research Group. (2001). Hyperbaric oxygen for children with cerebral palsy: a randomized multicentre trial. Lancet 357, 582–586. Crossref, Medline, Google Scholar22 Yu H.A.I.Tian R.L.Pan X.W.Luan Z.Song L.W.2002Effects of hyperbaric oxygen on brain bFGF and bFGF mRNA expression of neonatal rats after hypoxia-ischemia injuryThe Proceedings of the 2nd International Symposium on Hyperbaric Oxygenation for Cerebral Palsy and the Brain-Injured ChildJ.T.Joiner Best Publishing CoFlagstaff5766.22. Yu, H.A.I., Tian, R.L., Pan, X.W., Luan, Z., and Song, L.W. (2002). Effects of hyperbaric oxygen on brain bFGF and bFGF mRNA expression of neonatal rats after hypoxia-ischemia injury, in: The Proceedings of the 2nd International Symposium on Hyperbaric Oxygenation for Cerebral Palsy and the Brain-Injured Child. J.T. Joiner (ed). Best Publishing Co: Flagstaff, pps. 57–66. Google Scholar23 Heuser G.Heuser S.A.Rodelander D.Aguilera O.Uszler M.2002Treatment of neurologically impaired adults and children with "mild" hyperbaric oxygen (1.3ATA and 24% oxygen)The Proceedings of the 2nd International Symposium on Hyperbaric Oxygenation for Cerebral Palsy and the Brain-Injured ChildJ.T.Joiner Best Publishing CoFlagstaff109116.23. Heuser, G., Heuser, S.A., Rodelander, D., Aguilera, O., and Uszler, M. (2002). Treatment of neurologically impaired adults and children with "mild" hyperbaric oxygen (1.3ATA and 24% oxygen), in: The Proceedings of the 2nd International Symposium on Hyperbaric Oxygenation for Cerebral Palsy and the Brain-Injured Child. J.T. Joiner (ed). Best Publishing Co: Flagstaff, pps. 109–116. Google Scholar24 Kazantseva N.V.2002Mechanisms of curative effect of minimized hyperbaric treatment in cerebral ischemiaThe Proceedings of the 2nd International Symposium on Hyperbaric Oxygenation for Cerebral Palsy and the Brain-Injured ChildJ.T.Joiner Best Publishing CoFlagstaff199212.24. Kazantseva, N.V. (2002). Mechanisms of curative effect of minimized hyperbaric treatment in cerebral ischemia, in: The Proceedings of the 2nd International Symposium on Hyperbaric Oxygenation for Cerebral Palsy and the Brain-Injured Child. J.T. Joiner (ed). Best Publishing Co: Flagstaff, pps. 199–212. Google Scholar25 Rusyniak D.E.Kirk M.A.May J.D.Kao L.W.Brizendine E.J.Welch J.L.Cordell W.H.Alonso R.J.2003Hyperbaric oxygen therapy in acute ischemic stroke: results of the Hyperbaric Oxygen in Acute Ischemic Stroke Trial Pilot StudyStroke34571574.25. Rusyniak, D.E., Kirk, M.A., May, J.D., Kao, L.W., Brizendine, E.J., Welch, J.L., Cordell, W.H., and Alonso, R.J. (2003). Hyperbaric oxygen therapy in acute ischemic stroke: results of the Hyperbaric Oxygen in Acute Ischemic Stroke Trial Pilot Study. Stroke 34, 571–574. Crossref, Medline, Google Scholar26 Stanley A.C.Lounsbury K.M.Corrow K.Callas P.W.Zhar R.Howe A.K.Ricci M.A.2005Pressure elevation slows the fibroblast response to wound healingJ. Vasc. Surg.42546551.26. Stanley, A.C., Lounsbury, K.M., Corrow, K., Callas, P.W., Zhar, R., Howe, A.K. and Ricci, M.A. (2005). Pressure elevation slows the fibroblast response to wound healing. J. Vasc. Surg. 42, 546–551. Crossref, Medline, Google Scholar27 Rossignol D.A.Rossignol L.W.Smith S.Schneider C.Logerquist S.Usman A.Neubrander J.Madren E.M.Hintz G.Grushkin B.Mumper E.A.2009Hyperbaric treatment for children with autism: a multicenter, randomized, double-blind, controlled trialBMC Pediatr.13921.27. Rossignol, D.A., Rossignol, L.W., Smith, S., Schneider, C., Logerquist, S., Usman, A., Neubrander, J., Madren, E.M., Hintz, G., Grushkin, B., and Mumper, E.A. (2009). Hyperbaric treatment for children with autism: a multicenter, randomized, double-blind, controlled trial. BMC Pediatr. 13, 9–21. Google Scholar28 Kaplin A.Becker D.Scuba diving improves function of body, mind in vets with spinal cord injuryhttp://www.newswise.com/articles/view/580607September212013.28. Kaplin, A., and Becker, D. Scuba diving improves function of body, mind in vets with spinal cord injury. Available at: http://www.newswise.com/articles/view/580607. Accessed September 21, 2013. Google Scholar29 Tokunaga O.Watanabe T.1987Properties of endothelial cells and smooth muscle cell cultured in ambient pressureIn Vitro Cell Dev. Biol.23528534.29. Tokunaga, O., and Watanabe, T. (1987). Properties of endothelial cells and smooth muscle cell cultured in ambient pressure. In Vitro Cell Dev. Biol. 23, 528–534. Crossref, Medline, Google Scholar30 Tokunaga O.Fan J.L.Watanabe T.1989Atherosclerosis and endothelium. Part II. Properties of aortic endothelial and smooth muscle cells cultured at venous ambient pressuresActa Pathol Jpn39356362.30. Tokunaga, O., Fan, J.L., and Watanabe, T. (1989). Atherosclerosis and endothelium. Part II. Properties of aortic endothelial and smooth muscle cells cultured at venous ambient pressures. Acta Pathol Jpn, 39, 356–362. Medline, Google Scholar31 Hishikawa K.Nakaki T.Suzuki H.Saruta T.Kato R.1992New method of investigating functional roles of pressure sensitive mechanoreceptor in human endothelial cellsJ. Cardiovasc. Pharmacol.20Suppl. 12S66S67.31. Hishikawa, K., Nakaki, T., Suzuki, H., Saruta, T., and Kato, R. (1992). New method of investigating functional roles of pressure sensitive mechanoreceptor in human endothelial cells. J. Cardiovasc. Pharmacol. 20, Suppl. 12, S66–S67. Crossref, Medline, Google Scholar32 Acevedo A.D.Bowser S.S.Gerritsen M.E.Bizios R.1993Morphological and proliferative responses of endothelial cells to hydrostatic pressure: role of fibroblast growth factorJ. Cell Physiol.157603614.32. Acevedo, A.D., Bowser, S.S., Gerritsen, M.E., and Bizios, R. (1993). Morphological and proliferative responses of endothelial cells to hydrostatic pressure: role of fibroblast growth factor. J. Cell Physiol. 157, 603–614. Crossref, Medline, Google Scholar33 Torsellini A.Belvicci A.Citti S.Cozzolino F.Guidi G.Lombardi V.Vercilli D.Veloci M.1982Effects of pressure excursions on human platelets. In vitro studies on beta-thromboglobulin (β-TG) and platelet factor 4 (PF4)