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For short periods, even without the presence of red blood cells, hyperbaric oxygen can safely allow plasma to meet the oxygen delivery requirements of a human at rest. By this means, hyperbaric oxygen, in special instances, may be used as a bridge to lessen blood transfusion requirements. Hyperbaric oxygen, applied intermittently, can readily avert oxygen toxicity while meeting the body's oxygen requirements. In acute injury or illness, accumulated oxygen debt is shadowed by adenosine triphosphate debt. Hyperbaric oxygen efficiently provides superior diffusion distances of oxygen in tissue compared to those provided by breathing normobaric oxygen. Intermittent application of hyperbaric oxygen can resupply adenosine triphosphate for energy for gene expression and reparative and anti-inflammatory cellular function. This advantageous effect is termed the hyperbaric oxygen paradox. Similarly, the normobaric oxygen paradox has been used to elicit erythropoietin expression. Referfusion injury after an ischemic insult can be ameliorated by hyperbaric oxygen administration. Oxygen toxicity can be averted by short hyperbaric oxygen exposure times with air breaks during treatments and also by lengthening the time between hyperbaric oxygen sessions as the treatment advances. Hyperbaric chambers can be assembled to provide everything available to a patient in modern-day intensive care units. The complication rate of hyperbaric oxygen therapy is very low. Accordingly, hyperbaric oxygen, when safely available in hospital settings, should be considered as an adjunct for the management of critically injured or ill patients with disabling anemia

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TYPE ReviewPUBLISHED 08 October 2024DOI 10.3389/fmed.2024.1408816OPEN ACCESSEDITED BYCarmine Siniscalchi,University of Parma, ItalyREVIEWED BYLucia Prezioso,University Hospital of Parma, ItalyAlfredo Caturano,University of Campania Luigi Vanvitelli, ItalyCostantino Balestra,Haute École Bruxelles-Brabant(HE2B), Belgium*CORRESPONDENCEKeith W. Van Meterkvanme@lsuhsc.eduRECEIVED 28 March 2024ACCEPTED 19 August 2024PUBLISHED 08 October 2024CITATIONVan Meter KW (2024) Hyperbaric oxygentherapy in the ATLS/ACLS resuscitativemanagement of acutely ill or severely injuredpatients with severe anemia: a review.Front. Med. 11:1408816.doi: 10.3389/fmed.2024.1408816COPYRIGHT© 2024 Van Meter. This is an open-accessarticle distributed under the terms of theCreative Commons Attribution License (CCBY). The use, distribution or reproduction inother forums is permitted, provided theoriginal author(s) and the copyright owner(s)are credited and that the original publicationin this journal is cited, in accordance withaccepted academic practice. No use,distribution or reproduction is permittedwhich does not comply with these terms.Hyperbaric oxygen therapy in theATLS/ACLS resuscitativemanagement of acutely ill orseverely injured patients withsevere anemia: a reviewKeith W. Van Meter*Section of Emergency Medicine, Department of Medicine, LSU School of Medicine, New Orleans, LA,United StatesFor short periods, even without the presence of red blood cells, hyperbaricoxygen can safely allow plasma to meet the oxygen delivery requirementsof a human at rest. By this means, hyperbaric oxygen, in special instances,may be used as a bridge to lessen blood transfusion requirements. Hyperbaricoxygen, applied intermittently, can readily avert oxygen toxicity while meetingthe body’s oxygen requirements. In acute injury or illness, accumulated oxygendebt is shadowed by adenosine triphosphate debt. Hyperbaric oxygen ecientlyprovides superior di�usion distances of oxygen in tissue compared to thoseprovided by breathing normobaric oxygen. Intermittent application of hyperbaricoxygen can resupply adenosine triphosphate for energy for gene expressionand reparative and anti-inflammatory cellular function. This advantageous e�ectis termed the hyperbaric oxygen paradox. Similarly, the normobaric oxygenparadox has been used to elicit erythropoietin expression. Referfusion injuryafter an ischemic insult can be ameliorated by hyperbaric oxygen administration.Oxygen toxicity can be averted by short hyperbaric oxygen exposure timeswith air breaks during treatments and also by lengthening the time betweenhyperbaric oxygen sessions as the treatment advances. Hyperbaric chamberscan be assembled to provide everything available to a patient in modern-dayintensive care units. The complication rate of hyperbaric oxygen therapy is verylow. Accordingly, hyperbaric oxygen, when safely available in hospital settings,should be considered as an adjunct for the management of critically injured orill patients with disabling anemia.KEYWORDSanemia, normobaric oxygen, hyperbaric oxygen, adenosine triphosphate, advancedcardiac life support, advanced trauma life support, oxygen debt, normobaric oxygenparadoxFrontiers inMedicine 01 frontiersin.orgVan Meter 10.3389/fmed.2024.1408816Preclinical introductionThe clinical use of hyperbaric oxygen therapy (HBOT) toaddress the absence of sufficient hemoglobin levels began with thework of Dutch surgeon, I. Boerema, in the late 1950s. He rapidlyexsanguinated swine to hemoglobin levels as low as 1 g per deciliterand then resuscitated them by intravenous volume repletion with aRinger’s lactate–dextran 6%–dextrose water 5% solution. Next, hepressurized the unconscious, collapsed but still breathing, swineto three atmospheres of pressure in a hyperbaric chamber andmade them breathe 100% oxygen. At three atmospheres of pressure,inhaled oxygen of 100% provided a surface equivalent fraction ofinhaled oxygen of 300% (SEFIO2 300%). He kept the swine atthree atmospheres of pressure for 15min and then re-transfusedthem with their shed blood and depressurized the chamberto the surface, whereupon the swine walked off unimpaired.He published these results in an article entitled “Life WithoutBlood” (1).These results were replicated in a laboratory in theUnited Statesin 2010 at the LSU Health Sciences Center in New Orleans inan Institutional Animal Care Utilization Committee (IACUC)-approved pilot study. An acutely anesthetized, exsanguinatedswine was monitored by a polarographic oxygen tension probethrough a cranial burr hole (2). The swine, breathing normobaricroom air, had a baseline brain tissue pO2 level of 30 mmHg.After a rapid exsanguination involving the removal of 40%of the blood volume, the swine’s brain tissue pO2 droppedto 0 mmHg even while the swine was being ventilated withnormobaric 100% oxygen. For volume replacement, the swinereceived intravenous Ringers’ D5W solution. Next, the animalwas pressurized inside a hyperbaric chamber while being kepton 100% oxygen inhalation at three atmospheres of pressure.At this pressure, the oxygen inhalation provided SEFIO2 of300% oxygen. The brain tissue pO2 rose back to 30 mmHg,and the animal remained pressurized for 50min. Before ascentto the surface, the swine was transfused with its shed blood.Upon reaching the surface at ambient pressure, the animal wasrecovered from anesthesia, and monitoring access catheters wereremoved. The swine walked off unimpaired and was returnedto a rescue ranch for a long life (3). Table 1 shows a summaryof published animal experiments investigating the use of HBOTin severe anemia. The tabular summary includes a thumbnail ofevidence-based analysis using three different criteria (AHA/NCI-PDQ/BMJ) (4).The clinical use of hyperbaric oxygenHyperbaric oxygen (HBO) may be used as a bridgingtherapy in the Advanced Trauma Life Support (ATLS) andAdvanced Cardiac Life Support (ACLS) resuscitation of aprecariously anemic patient to prevent multiunit transfusionuntil damage control surgical efforts can be implemented.The initial damage control surgery aims at preventingcontinued blood loss to allow the patient to retain transfusedblood (35).Likewise, HBO may be used as a bridging therapy forpatients who refuse blood transfusions due to religious orphilosophical reasons. Tincture of time could then allow theprovision of hematinic nutrients and pharmaceuticals to supporthematopoiesis to endogenously provide red blood cell replacement(36). If hemoglobin’s ability to transport oxygen by carbonmonoxide, cyanide, or hydrogen sulfide is impaired, HBOcan be used acutely to treat these conditions to assist inpatient recovery from the chemical hypoxia imposed by thepoisoning (37–41).In yet another clinical instance, HBO may be used if ananticipated complication of a blood transfusion precludes furthertransfusion (42):1. Blood group incompatibility.2. Febrile non-hemolytic transfusion reaction (FNHTR).3. Both delayed amnestic and primary hemolytic anemia.4. Allergy from urticaria to anaphylaxis.5. Transfusion-associated graft-versus-host disease(TAGVHD).6. Acute radiation-induced anemia in disasters with a supplyshortage.7. Transfusion-transmitted infections (TTI).8. Both red blood cell and human leukocyte antigen (HLA)allosensitization.9. Confounding severe congestive heart failure with profoundanemia until stabilization, providing the safety oftransfusion.10. Stacking hemosiderosis from multiple transfusions bylessening the number of transfusions.11. The prevention of long-term transfusionimmunomodulation by lessening the number oftransfusions.12. The prevention of short-term induction of multiorganfailure by red blood cell-associated lipids and cytokines.13. Transfusion-related lung injury (TRALI).HBOT has been documented to ameliorate the adult respiratorysyndrome induced by trauma or infection in severely anemicpatients (43–46). This effect of HBOT may also be found to bean additional advantage of HBO as a bridging treatment untilsafe transfusions are possible in a patient with TRALI or acuterespiratory distress (ARDS) in SARS-CoV2 patients with severeanemia (47). Research into this area is necessary. A randomized,controlled study has been published evidencing the use of HBOTto perform this (44). Table 2 shows human case studies and seriesfor use in the treatment of severe anemia. The tabular summaryincludes a thumbnail, evidence-based analysis of the publishedpapers using three different criteria (AHA/NCI-PDQ/BMJ) (4).More recently, a randomized, controlled trial of HBOT used insevere anemia has been published (57).When considering the use of HBOT in cases of severe anemia,the clinician should consult a hyperbaric physician specialist todetermine whether HBOT would be helpful for the individualpatient. Figure 1 demonstrates the treatment course recommendedby the UHMS in their 2023 edition of the Hyperbaric MedicineFrontiers inMedicine 02 frontiersin.orgVanMeter10.3389/fmed.2024.1408816TABLE 1 Summary of published animal experiments investigating the use of hyperbaric oxygen therapy in severe anemia.Date References AnimalspeciesStudy groups Hemorrhagic insult Survival rates Thumbnail evidence-based analysis1. 1943 Frank et al. (5) Canine 1. Paper relied-on non-HBO2 controls fromresults of independent authors in the samemodel2. Controlled study of 3 HBO2 0.3 MPa150-180min treatment group (n= 18)Wiggers and Werle (6)“hypo-MAP” model forall animalsSurvival at 4½ h post-hem:1. non-HBO2 group (NBA or NBO2)=0%2. HBO2 groups= 20%AHA NCI-PDQ BMJ evidenceLevel Class NA NA6B Indeterminate2. 1959 Burnet et al. (7) Rat Controlled study:1. NBA/120min group (n= 25)2. HBO2 0.2 Mpa/120min group (n= 25)Intravascular hemolysisinduced by 1 ml/100 g IMglycerol for all animalsSurvival at 2 h. post insult, post-hem:1. non-HBO2 group (NBA)= 20%2. HBO2 group= 96%AHA NCI-PDQ BMJ evidenceLevel Class NA NA6A II.b.3. 1959 Boerema et al.(1, 8)Porcine Controlled study:1. HBO2 0.3 MPa/∴ι 75min group (n= 3)HBO2 0.3 MPa with 30◦C core temp/∴ι75min group (n= 20)NBA group (n= ?)All animals were subjected tovariable volume bleed whichproduced Hgb level of0.4-0.6 g/dLSurvival at 45min post-hem:HBO2 group= 100%HBO2+ hypothermic group= 50%NBA group= 0/2AHA NCI-PDQ BMJ evidenceLevel Class NA NA6B II.b.4. 1962 Attar et al. (9) Canine Controlled study:1. NBA group (n= 30) 2. HBO2 0.3 MPa/90minutes group (n= 25)Wiggers and Werle (6)“hypo-MAP” model forall animalsSurvival at 48 h post-hem:NBA group= 17%HBO2 group= 74%AHA NCI-PDQ BMJ evidenceLevel Class NA NA6B II.b.5. 1963 Cowley et al.(10)Canine Controlled study:1. NBA with hem group (n= 30)2. HBO2 with hem 0.3 MPa/150min group(n= 19)3. HBO2 without hem 0.3 MPa/150mingroup (n= 13)Wiggers and Werle (6)“hypo-MAP” model forall animalsSurvival at 48 h post-hem:1. NBA with hem group= 17%2. HBO2 with hem group= 74%3. HBO2 without hem group= 100%AHA NCI-PDQ BMJ evidenceLevel Class NA NA6A II.b.6. 1964 Blair et al. (11) Canine Controlled study:NBA group (n= 23)HBO2 0.3 MPa/120min group (n= 19)Wiggers and Werle (6)“hypo-MAP” model for allanimals“Long-term” survival post-hem:NBA group= 17%HBO2 group= 74%AHA NCI-PDQ BMJ evidenceLevel Class NA NA6A II.b.7. 1965 Clark andYoung (12)Canine Controlled study:NBA group (n= 8)HBO2 0.2 MPa/150min group (n= 5)NBA+ IV bicarb group (n= 6)Wiggers and Werle (6)“hypo-MAP” model for allanimalsSurvival at 18 h post-hem:NBA group= 75%HBO2 group= 100%AHA NCI-PDQ BMJ evidenceLevel Class NA NA6A II.b.8. 1965 Cowley et al.(13)Canine Controlled study:1. NBA group (n= 23) 2. HBO2 0.3MPa/120min group (n= 19)Wiggers and Werle (6)“hypo-MAP” model for allanimalsSurvival at 48 h post-hem:1. NBA group= 22% 2. HBO2 group= 74%AHA NCI-PDQ BMJ evidenceLevel Class NA NA6A II.b.(Continued)FrontiersinMedicine03frontiersin.orgVanMeter10.3389/fmed.2024.1408816TABLE 1 (Continued)Date References AnimalspeciesStudy groups Hemorrhagic insult Survival rates Thumbnail evidence-based analysis9. 1965 Elliot and Paton(14)Canine Controlled study:1. NBA group (n= 10)2. NBO2 group (n= 10)3. NBO2 with ventilator group (n= 10)4. HBO2 0.28 MPa/100min group (n= 11)Wiggers and Werle (6)“hypo-MAP” model for allanimalsSurvival at 72 h post-hem:1. NBA group= 10%2. NBO2 group= 50%3. NBO2 with ventilator group= 50%4. HBO2 group= 73%AHA NCI-PDQ BMJ evidenceLevel Class NA NA6A II.b.10. 1965 Attar et al. (15) Canine Controlled study: Group I:1. NBA/150min subgroup (n= 25)2. HBO2 0.3 Mpa/150min subgroup (n= 29)Group II: Subgroup A3. NBA/105min group (n= 30)4. HBO2 0.3 Mpa/105min group (n= 22)Subgroup B5. NBA/120min group (n= 17)6. NBO2/120min group (n= 25)7. HBO2/120min group (n= 23) Subgroup C8. NBA/150min group (n= 30)9. HBO2 0.3 MPa/ 0min group (n= 4)Subgroup D10. NBA/240min group (n= 20) (n= ?)11. HBO2 0.3 MPa/240min group (n= 24)Group III:12. HBO2 0.3 MPa/120min started 30minpost-hem group (n= ?)13. HBO2 0.3 MPa/120min started 150minpost-hem group (n= ?)Group IV:14. HBO2 0.2 MPa/120min group (n= 11)15. HBO2 0.2 MPa/150min group (n= ?)16. HBO2 0.3 MPa/120min (n= 23) seeabove17. HBO2 0.3 MPa/130min (n= 4)see aboveWiggers and Werle (6)“hypo-MAP” model for allanimalsSurvival at 72 h post-hem:1. NBA group= 20%2. HBO2 group= 41%3. NBA group= 66%4. HBO2 group= 47%5. NBA group= 29%6. NBO2 group= 20%7. HBO2 group= 72%8. NBA group= 17%9. HBO2 group= 50%10. NBA group= 50%11. HBO2 group= 48%12. HBO2 30min post- hem= 74%13. HBO2 150min post-hem 50%14. HBO2 0.2 MPa/120min= 82% (n=?)15. HBO2 0.2 MPa/150min= 30%16. HBO2 0.3 MPa/120min= 72%17. HBO2 0.3 MPa/150min= 50%AHA NCI-PDQ BMJ evidenceLevel Class NA NA6A II.b.11. 1965 Jacobsonet al.(16, 17)Rabbit Controlled study:1. NBA group (n= 10)2. NBO2 group (n= 10)3. HBO2 0.2 MPa/12 h (n= 10)Wiggers and Werle (6)“hypo-MAP” model for allanimalsSurvival at 48 h post-hem:1. NBA group= 0% 2. NBO2 group=10% 3. HBO2 group= 10%AHA NCI-PDQ BMJ evidenceLevel Class NA NA6A II.b.12. 1965 Whalen et al.(18)Canine Controlled study:1. NBA group (n= 5) 2. NBO2 group (n= 5)3. HBO2 0.35 MPa (n= 5)4. HBO2 0.35 MPaComplete replacement ofblood volume of group 4animals with dextran6%/dextrose, 5%/RL solutionto produce a Hct of 0.5%All groups 100% survival, but group 4had increased cardiac output anddecreased peripheral vascular resistanceAHA NCI-PDQ BMJ evidenceLevel Class NA NA6B Indeterminate(Continued)FrontiersinMedicine04frontiersin.orgVanMeter10.3389/fmed.2024.1408816TABLE 1 (Continued)Date References AnimalspeciesStudy groups Hemorrhagic insult Survival rates Thumbnail evidence-based analysis13. 1965 Navarro andFerguson (19)Canine Controlled study:1. NBA/120min dextran group (n= 15) 2.NBA/120min dextrose group (n= 15)3. HBO2 0.35 MPa/120min dextran group (n= 15) 4. HBO2 0.35MPa/120min dextrose groupWiggers and Werle (6)“hypo-MAP” model for allanimalsSurvival at 48 h post-hem afteradministration of exp:1. NBA dextran group= 26%2. NBA dextrose group= 6.6%HBO2 dextran group= 60%3. HBO2 dextrose group= 60%AHA NCI-PDQ BMJ evidenceLevel Class NA NA6A II.b.14. 1969 Necas andNeuwirt (20)Rat Controlled study:1a. NBA group (n= 5)2a. HBO2 0.3 MPa/360-420min group (n=3)3a. HBO2 0.2 MPa/360-420min group (n=2)1b. NBA group (n= 3)2b. HBO2 0.3 MPa/360-420min group (n=4)3b. NBA group (n= 13)4b. HBO2 0.3 MPa/360-420min group (n=9)Group a: Hemorrhage to Hctof 25%Group b: Hemorrhage to Hctof 10%Survival at h:1a. NBA with Hct 25% group= 60%2a. HBO2 with Hct 25% group= 100%3a. HBO2 with Hct 25% group= 100%1b. NBA with Hct 10%= 0%2b. HBO2 with Hct 10%= 100%3b. NBA with Hct 10% group= 0%4b. HBO2 with Hct 10%= 100%AHA NCI-PDQ BMJ evidenceLevel Class NA NA6A II.b.15. 1970 Doi and Onji(21)Canine Controlled study:1. NBA/90min (∴ι120min) group (n= 7)2. HBO2 0.2 MB/90min (∴ι 120min) group(n= 7)Wiggers and Werle (6)“hypo-MAP” model for allanimalsSurvival at 4½ hpost-hem:1. NBA group= 0% 2. HBO2 group= 100%AHA NCI-PDQ BMJ evidenceLevel Class NA NA6A II.b.16. 1970 Oda andTakeori (22)Canine Controlled study:1. NBA NS/5% dextran 40/80min (n= 5)2. HBO2 0.3 MPa/60min NS/3% dextran 40group (n= 5)3. NBA NS/5% dextran 200 group (n= 5)4. HBO2 0.3 MPa/60min NS/6% dextran 200group (n= 5)25 ml/kg shed blood withexchange of NS designatedexchange followed bycontinued bleed to produce aHct of 18%Survival rates:1. NBA dextran 40 group= 100%2. HBO2 dextran 40 group= 100%3. NBA dextran 200 group= 100%4. HBO2 dextran 200 group= 100%AHA NCI-PDQ BMJ evidenceLevel Class NA NA6A Indeterminate17. 1974 Trytyshnkov(23)Rat Controlled study:1. NBA no hem group2. NBA with hem group3. HBO2 0.2 MPa/60min no hem group4. immediate HBO2 0.2 MPa/60minpost-hem group5. delayed HBO2 0.2 MPa/60min post-hemgroup (total n= 179)3% body weight hemorrhageby jugular blood draw over30minSurvival rates:1. NBA group= 100%2. NBA with hem group= 0%3. HBO2 no hem group= 100%4. immediate HBO2 post-hem group=100%5. delayed HBO2 post- hem group= 0%AHA NCI-PDQ BMJ evidenceLevel Class NA NA6B II.b.(Continued)FrontiersinMedicine05frontiersin.orgVanMeter10.3389/fmed.2024.1408816TABLE 1 (Continued)Date References AnimalspeciesStudy groups Hemorrhagic insult Survival rates Thumbnail evidence-based analysis18. 1975 Norman (24) Controlled study: AHA NCI-PDQ BMJ evidenceLevel Class NA NA6A II.b.19. 1976 Barkova andPetrov (25)Rat Non-controlled study:1. NBA group (n= 60)2. HBO2 0.2 MPa/40min group (n= 60)2.8% of body weight bloodloss over 30minSurvival rate:1. NBA group= 0%2. HBO2 group= 100%AHA NCI-PDQ BMJ evidenceLevel Class NA NA6B II.b.20. 1977 Luonov andTakovlev (26)Cat Controlled study:1. NBA/60min group (n= ”?”) 2. HBO2 0.3MPa/60min group (n= ”?”)Wiggers and Werle (6)“hypo-MAP” model for allanimalsSurvival rate:1. NBA group= increase in brainammonia 2. HBO2 group= no increasein brain ammoniaAHA NCI-PDQ BMJ evidenceLevel Class NA NA6B Indeterminate21. 1983-84Gross et al.(27–29)Canine Controlled study:1. NBA 6% dextran 40 group (n= 6)2. NBA RL group (n= 6)3. NBA 10% dextrose group (n= 6)4. NBA 6% dextran 70 group (n= 6)5. HBO2 0.28 MPa/93-118min 6%dextran-40 group (n= 6)6. HBO2 0.28 MPa/93-118min RL group (n= 6)7. HBO2 0.28 MPa/93-118min 10% dextrose(n= 6)8. HBO2 9.28 MPa/93-118min 6%dextran-70 group (n= 6)9. HBA 0.6 MPa 6% dextran-40 (n= 6)10. HBA 0.6 RL group (n= 6)11. HBA 0.6 MPa 10% dextran group (n= 6)12. HBO2 0.6 MPa 6% dextran-70 group (n= 6)Wigger and Werle (6)“hypo-MAP” model for allanimalsSurvival post-hem:1. NBA 6% dextran-40 group= 100%2. NBA RL group= 100%3. NBA 10% dextrose group= 100%4. NBA 6% dextran 70 group= 100%5. HBO2 6% dextran- 40 group= 100%6. HBO2 RL group= 100%7. HBO2 10% dextrose group= 100%8. HBO2 6% dextran-70 group= 100%9. HBA 6% dextran-40 group= 100%10. HBA RL group= 100%11. HBA 10% dextrose group= 100%12. HBA 6% dextran-70 group= 100%AHA NCI-PDQ BMJ evidenceLevel Class NA NA6A Indeterminate(Continued)FrontiersinMedicine06frontiersin.orgVanMeter10.3389/fmed.2024.1408816TABLE 1 (Continued)Date References AnimalspeciesStudy groups Hemorrhagic insult Survival rates Thumbnail evidence-based analysis22. 1991 Bitterman et al.(30)Rat Controlled study:1. NBA sham group (n= 6)2. NBA+ hem group (n= 10)3. NBO2/90min+ hem group (n= 10)4. HB nitrox (7/93) 0.3 MPa/190min+ hemgroup (n= 8)5. HBO2 0.3 MPa/90min sham group (n= 6)6. HBO2 0.3 MPa/90min+ hem group (n= 10)Hemorrhage within 90min of3.2ml all animals sodesignatedSurvival post-hem: MAP > 40 mmHgfor 220 min:1. NBA sham group= 100%2. NBA+ hem group= 10%3. NBO2+ hem group= 50%4. HB nitrox+ hem group= 0%HBO2 sham group= 100%5.HBO2+ hem group= 100%AHA NCI-PDQ BMJ evidenceLevel Class NA NA6A II.b.23. 1992 Wen-Ren (31) Canine Controlled study:1. NBA/95min group (n= 6)2. HBO2 0.3 MPa/95min group (n= 6)Hemorrhage to 60 ml/kg Survival rate:1. NBA group= 0%2. HBO2 group= 100%AHA NCI-PDQ BMJ evidenceLevel Class NA NA6A II.b.24. 1992 Marzella et al.(32)Rat Controlled study:1. NBA hem with 90min monitoring group(n= ”?”)2. HBO2 hem 15min then 0.2 MPa/75minwith monitoring group (n= ”?”)Hemorrhage to 15 ml/kg Survival rates not provided for groups1. NBA group: BP decreased 25%, COdecreased 25%2. HBO2 group: BP increased 10%, COdecreased 25%AHA NCI-PDQ BMJ evidenceLevel Class NA NA6B Indeterminate25. 1995 Adir et al. (33) Rat Controlled study:1. NBA no hem group (n= 11)2. NBA+ hem group (n= 10)3. NBO2+ hem group (n= 10)4. HBO2 0.3 MPa/90min no hem group (n=7)5. HBO2 0.3 MPa/90min+ hem group ( n= 10)Hemorrhage 3.2 ml/100 gover 120min for all animalsso designatedSurvival at 24 hour/7 day post-hem:1. NBA no hem group= 100%/45%2. HBA hem group= 70%/10%3. NBO2 hem group= 90%/70%4.HBO2 no hem group= 100%/55%5. HBO2 hem group= 90%/10%AHA NCI-PDQ BMJ evidenceLevel Class NA NA6A Indeterminate26. 2000 Yamashita andYamashita (34)Rat Controlled study:1. NBA+ hem group (n= 15)2. HBO2 0.3 MPa/60min with 30mindecompression+ hem group (n= 10)3. HBO2 0.3 MPa/60min with 30mindecompression no hem group (n= 10)Hemorrhage of 40 ml/kg over1 hSurvival at 24 h post-hem:1. NBA+ hem group= 40%2. HBO2+ hem group= 83%3. HBO2 no hem group= 100%AHA NCI-PDQ BMJLevel Class NA NA6A IIbFrontiersinMedicine07frontiersin.orgVanMeter10.3389/fmed.2024.1408816TABLE 2 Human case reports and series for use of hyperbaric oxygen therapy in treatment of severe anemia.Date References Pt age/gender Quantification ofhemorrhagic insultAdjunctive transfusionAdjunctivehematinics andHBO2Survival Thumbnail evidence-based analysis1. 1969 Ledingham (48) 40 y/female Admission Hgb= 1.5 g/dLAdmission BP= 65/?Admission sensorium= AMSYes (patient wastransfused afterstabilization bycompleted HBO2)B12 folic acid, ascorbicacidHBO2 0.2 Mpa/5 hr+(at depth the pt wouldseize at first when oxygenmask was removed)Yes AHA NCI-PDQ BMJ evidenceLevel Class 3.iii. Likely to bebeneficial5 Indeterminate2. 1969 Amonic et al.(49)26 y/male (JW) S/P resuscitation ofleiomyoma to resolve GI bleedPost-op Hct= 10%3rd post-op day= CHFSerial HBO27th post-op day Hct= 12%7th post-op week Hct= 42%No Hematinics – yesSerial 17 cycles of HBO20.2 MPa/160min (atdepth the pt initiallyseized when oxygenmask was removed)Yes AHA NCI-PDQ BMJ evidenceLevel Class 3.iii. Likely to bebeneficial5 Indeterminate3. 1974 Hart (50) 27 y/female (JW) Perinatal pelvic hematomaand pulmonary embolismwith Hgb 3.8 g/dL, congestiveheart failure, AMS, and 88/40BPDiverticulosis with rectalbleeding with Hgb 2.6 g/dL,AMS, and 90/70 BPMVA with liver lacerationwith Hgb 6.9 g/dLNoYes (pt was transfused 2units PRBC’s on 4thhospital day afterContinued bleeding)NoIron dextran IMSerial HBO2 0.2 MPa/90Iron dextran IMSerial HBO2 0.2 MPa/90Iron dextran IMSerial HBO2 0.2 MPa/90YesYesYesAHA NCI-PDQ BMJ evidenceLevel Class 3.iii. Likely to bebeneficial5 Indeterminate67 y/female (JW)27 y/male (JW)4. 1974 Myking andSchreinen (51)55 y/femaleAIHA with HGB 4.6 g/dLFailed prednisone with Hgbfalling to 3 g/dL with AMSSerial HBO2 x 5 days withHgb 5 g/dLNo PrednisoneSerial HBO2 0.26MPa/240min QIDtapered to HBO2 0.26MPa/120min BID to day5 with D/CYes AHA NCI-PDQ BMJevidenceLevel Class 3.iii. Likely to bebeneficial5 IndeterminateLevel Class(Continued)FrontiersinMedicine08frontiersin.orgVanMeter10.3389/fmed.2024.1408816TABLE 2 (Continued)Date References Ptage/genderQuantification ofhemorrhagic insultAdjunctivetransfusionAdjunctivehematinics andHBO2Survival Thumbnail evidence-based analysis5. 1987 Hart et al. (52) 20 females (JW)6 males (JW)(subgroup analysisof those patientswithout AMS leaves19 pts)Mean Hct of all 26 patients= 13% (all with class IV hem)NoNoAll had hematinics,vitamin B12, vitamin c,ironAll patients averaged 9.6HBO2 sessions 0.2MPa/90min65%83%95%AHA NCI-PDQ BMJ evidenceLevel Class 3.iii. Beneficial5 II.b.6. 1989 Myerstein et al.(53)4 individual humanblood samples weretested for levels ofGSH, Hct/ free Hgb,MetHgb, and RBCvolumeStudy groups:Control RBCs, both fresh andstored samplesLow GSH RBCs induced bydiamide in both fresh andstored samplesRBCs exposed to HBO2 0.3MPa/120min in both freshand stored samples4. Low GSH RBCs induced bydiamide in both fresh andstored samples exposed toHBO2 0.3 MPa/120minNo damage orabnormalityinduced by HBO2over controlsAHA NCI- PDQ BMJ evidenceLevel Class NA NA6 II.b.7. 1992 Young andBurns (54)Yes AHA NCI- PDQ BMJ evidenceLevel Class 3.iii. Likely to bebeneficial5 II.b.8. 1999 McLoughlinet al. (55)38 y/female Antepartum hemorrhage withHgb 2 g/dL 39 day post-bleeddischarge Hgb 7.6 g/dLNo Vitamin B12, EPO, folicacid, ironHBO2 0.3 MPa/90minTID tapered to BID over16 days (total 22 HBO2sessions)Yes AHA NCI- PDQ BMJ evidenceLevel Class 3.iii. Likely to bebeneficial5 II.b.9. 2002 Hart (56) 20 y/female (JW) GSW to left chest with leftlung and hemidiaphragmpenetration with spleen, leftkidney and spinal cord injuryPost-op Hct 18 Post-opintestinal perforationPost-op day 28 Hct 22No EPOHBO2 0.2 MPa/90minTID tapering to BID fora total of 28 divesYes AHA NCI- PDQ BMJ evidenceLevel Class 3.iii. Likely to bebeneficial5 II.b.FrontiersinMedicine09frontiersin.orgVan Meter 10.3389/fmed.2024.1408816FIGURE 1Flowchart of Severe Anemia.Indications Manual. The patient would undergo HBOT at two–three ATA for 60–90min with one–two intermittent 5-min airbreaks (4).DiscussionThe operational practicality of using HBO as a bridging therapyin a remote non-medical setting was reported in a case of severeexsanguination of a commercial diver while in saturation offshorein the Gulf of Mexico. The patient bled out hemoglobin of 2 g perdeciliter acutely when his duodenal artery was eroded by a duodenalulcer. The requisite decompression to the surface required 3 days.During his recompression, he was kept alive without transfusionby Ringers’ D5 solution administered by hypodermoclysis andintermittent HBO breathing periods. At the surface, he was thentransfused with intravenous packed red blood cells (58).Many yearsbefore, three cases of patients with severe blood loss who eachrefused transfusion for religious belief were reported in the medicalliterature. The cases were successfully treated with intermittentlyadministered HBO in the same way at a naval dock in a hyperbaricchamber (50).High concentrations of continuously administered oxygen havebeen reported to be deleterious when used in patient’s resuscitativemanagement (59, 60). This observation has remained consistentregardless of whether the patients enrolled in clinical trials havehad high, normal, or low hemoglobin levels, whether acute orchronic (61). How could HBO provided by ventilation with SEFIO2of inhaled oxygen of 150%−300% not be deleterious? For one,the inhaled oxygen under these conditions is not continuousbut is intermittent, with administered air breaks incorporatedduring HBOT sessions (62). Additionally, as the series of HBOtreatment sessions progresses and the patient’s condition improves,the patient becomes increasingly tolerant of the off-oxygen periods.This allows the HBOT to be spread out with longer periods betweentreatments (49). During the HBO breathing periods, enoughoxygen is dissolved in plasma to allow plasma to deliver oxygento tissue mitochondria to reduce the previously accumulatingoxygen debt, which, in effect, is an adenosine triphosphate (ATP)debt (63–66).One might say that HBOT, as bridge therapy, servesto resuscitate patients much like the bridging function ofveno-venous extracorporeal membrane oxygenation (VV-ECMO)during resuscitative support of critically anemic patients withFrontiers inMedicine 10 frontiersin.orgVan Meter 10.3389/fmed.2024.1408816restrictions on red blood cell transfusion. In the instance ofintermittent non-invasive HBOT, the patient can similarly besuccessfully supported (67). By simile, one might compare VV-ECMO to a continuous weld and short-interval intermittent HBOTto a spot weld (in effect, intermittent HBOT is VV-ECMO-likeor “ECMoid” in function). Both therapeutic modalities attempt tohold the metabolic structure of the patient together. ECMO hasup to a 30% serious adverse side effect incidence (68). Hyperbaricoxygen has, on average, one in 10,000 incidences of serious sideeffects including pneumothorax, oxygen toxicity seizure, fire orexplosion, and arterial gas embolism (69–71). The ECMO hospitalfacility support fee is often US $50,000 per day (72) and a hospital-based HBOT series of 30 treatments includes a facility charge ofUS $7,500 (73, 74). In almost all instances, 30 HBOT treatmentswould be more than enough to bridge a patient through an anemiccrisis. In the United States, the cost of a unit of packed red bloodcells, along with its administration, is comparable to the cost of oneHBOT treatment (4).The tolerance to high-dose oxygen administration byintermittent application has been well-documented with oxygenadministered at one atmosphere pressure as well as at increasedatmospheric pressure (62, 75). There is more than just oxygentolerance provided by the intermittency of use; this is the effect ofintermittency itself. ATP resupply occurs when the mitochondrialintermembrane space minimally attains 1.5–2.0 mmHg of oxygen,which is a requisite for the unimpaired production of ATP by themitochondrial respiratory chain of enzymes (76). In a severelyanemic patient, equally important is the return of tissue hypoxiaafter the completion of an HBOT treatment. It is hypoxia thatincites ATP-dependent reparative cytokine tissue release andantioxidant production. For the reparative and anti-inflammatorycytokines to work at cellular receptor sites, ATP is needed. Theanteceding HBOT would have supplied the needed ATP for this tooccur. The ensuing tissue hypoxia between treatments induces thefollowing energy-dependent or ATP-dependent activity:1. Antioxidant productions and functions to include catalaseand peroxidase (77), glutathione (78), superoxide dismutase(79), and ATP itself as an antioxidant (80).2. Support of genomic activity (81).3. Support of epigenomic activity (82).4. Support of proteomic activity (83) and protein folding (84).5. Support of lipidomic activity (85).6. Support of anti-inflammatory and reparativecytokines/chemokines (86).7. Leukocyte function (87, 88).8. Adaptive function in hypoxia: (erythropoietin) (89, 90) (heatshock protein) (91) (nitric oxide) (92) (hypoxia-induciblefactor) (93).This oscillation between hyperoxia and hypoxia may begraphically depiected as a sinusoidal timeline by Figure 2 and is thecrux of the oxygen paradox.To provide ATP resupply in the instance of an acute hypoxicstate, pulsed high-dose HBO inhalation can be used to diffuseminimally 1.5–2.0 mmHg of oxygen into the mitochondrialFIGURE 2The sinusoidal horizontal timeline depicted by the thick wavy lines in the diagram represents an intermittent hyperbaric oxygen treatment course.The wave peaks represent a hyperbaric oxygen treatment producing ATP resupply (93). Post treatment when the tissue oxygen tension drops, energyrequiring cytokine and antioxidant release occurs (85).Frontiers inMedicine 11 frontiersin.orgVan Meter 10.3389/fmed.2024.1408816intermembrane space (94). At best, when a red blood cell gets to itsdestination in capillaries, it must offload a portion of its remainingoxygen content back into the plasma. As the patient inhales 100%oxygen at one atmosphere of pressure, the plasma can maximallycontain only 2.3 volumes% of dissolved oxygen. In contrast, thepatient in a hyperbaric chamber at three atmospheres of pressurewould inhale a SEFIO2 of 300%, thereby delivering to the capillaries6.6 volume% of dissolved oxygen with a five-fold diffusion distanceoutside of the capillary over that of a subject inhaling an FIO2 of100% oxygen at one atmosphere of pressure (95–97). This conceptwas reported over 60 years ago by W. Brummelkamp when hereported that during an HBOT treatment, “drenching of the tissuewith dissolved oxygen” occurred by way of immersing plasma withoxygen (98).HBOT inhalation can only be accomplished safely whenthe entire patient is pressurized above ambient pressure in anenclosure (i.e., a hyperbaric chamber). The spectrum of potentialtreatment doses of oxygen using HBO pressure incorporates thepharmacologic effect of the gases at increased pressure and thephysiologic effect of pressure itself (99).Ameasure of the safety of HBO can best be described by Pascal’sLaw, where in a confined space, any contained fluid will transmitthe pressure evenly throughout the fluid non-destructively. Thehuman skin envelope contains the fluid of all the body’s tissue(gas is not a problem in sinus spaces if vented by an openostia and in the middle ear if vented by a patient’s functioningEustachian tube) (100). By virtue of the principle of Pascal’s law,a patient may be ventilated without barotrauma by pressurized gasat the same pressure as that of hyperbaric chamber pressurization.Ventilators have been developed to do this safely, and chamberscan be fitted with all the functions of critical care hospitalunits (101, 102).Henry’s Gas Law states that the concentration of a solute gasin a solution is directly proportional to the partial pressure of thegas over the solution. Inhalation of HBO at three atmospheres ofpressure allows enough dissolved oxygen (6.6 volumes%) in plasmato supply the metabolic extraction rate of most of the tissue in ahuman body at rest (103).The operational safety of hyperbaric medicine units has evolvedthrough adherence to developing safety guidelines. This hasallowed a remarkable safety record for hospital-based units forequipment, patients, and healthcare providers for both multiplaceand monoplace chamber facilities (104, 105).At the 21% oxygen content of air in one atmosphere,hemoglobin makes up for plasma’s inability to deliver adequateoxygen to tissue. This is because a subject breathing air would have,at maximum, a 0.48 volume% of plasma dissolved oxygen, whichclearly would not be enough to support human life (0.003ml× 21%× 760 mmHg, where 0.003ml is the amount at one atmosphereof oxygen dissolved in plasma for each mmHg of pressure, 21%is the oxygen content of air, and 760 mmHg is the pressure foreach mmHg of pressure in the atmosphere at sea level) (106). Usingthe same equation for breathing 100% oxygen at one atmosphere,the maximum amount of dissolved oxygen in plasma would be2.3 volume%. As mentioned, this would be far below the averageoxygen extraction rate of most human tissue with the body at rest.To get around this problem, hemoglobin serves as a powerful gasclathrate, especially for oxygen. When a red blood cell picks upoxygen in the lung and discharges it in the periphery, the maximumoxygen conceivably dissolved in plasma would be 2.3 volume% atboth ends of the line.Plasma delivers the oxygen from the red blood cells to theendothelium, where it diffuses into the interstitial fluid, thendiffuses through cellular membranes into the cytosol, and finallypasses into the intermembrane space (IMS) of mitochondria. HBOadministered at three atmospheres of pressure (SEFIO2 300%)allows 6.6 volume% of oxygen to be dissolved in plasma. It isthis concentration that begins its journey by diffusion through thecapillary endothelium, ultimately filling the IMS of mitochondriaminimally with the 1.5–2.0 mmHg of dissolved oxygen requisite forthe electron transport chain along with ATP synthase to produceATP (107). Figures 3, 4 demonstrate this process.The increased diffusivity of oxygen in tissue afforded byhyperbaric pressure is important. Krogh has described the diffusiondistance of oxygen from plasma through the capillary endothelium(95, 97). This has been further expounded upon to includethe added effect of the diffusivity of oxygen in the hyperbaricenvironment (99) as demonstrated in Figure 5.Tissue oxygen capacitance increases during and after anHBOT treatment. The oxygen that is onloaded into the tissueduring HBOT is, in part, slowly off-gassed, much like aninert gas with tissue elimination half-lives supplemented by theadditional elimination of oxygen by metabolic consumption (109).Furthermore, some oxygen is retained in tissue by attaching tocellular gas clathrates [i.e., neuroglobin (110), cytoglobin (111),and myoglobin (112)]. With serial HBOT treatment, tissue oxygencapacitance increases (113).The red blood cell, as a biconcave disk, has a shape thatmaximizes its surface area. As a short-lived bag of hemoglobin,the mature red blood cell does not have mitochondria or anucleus. An important mission of the red blood cell is to overcomethe poor solubility of oxygen in plasma at one atmosphere inorder to adequately get a supply of oxygen to mitochondria. Theuse of HBOT, especially in remote settings, has compelled sometertiary urban trauma medical staff to consider the developmentof a hyperbaric ambulance to mimic the success of the deckdecompression chambers on operational sites to address injury ofcommercial divers (114). Figure 6 demonstrates this point.A consideration of the potential toxic properties of a prolongedadministration of O2 in almost all cases under normobaric,hyperbaric, or hypobaric exposures is a certainty (115–117).A judicious use of short-tie exposures of 60–90min withintermittency of 5min air breaks during administration andwith gradual spreading of time intervals between treatments hasthoroughly been documented to be safe, allowing the “hyperoxic–hypoxic paradox” prevail to the patient’s benefit (118–120).ConclusionRed blood cells play an important role in the chain of oxygendelivery to the mitochondrial IMS. Finally, in the IMS, oxygenattaches to cytochrome c oxidase in the electron transport chainof enzymes embedded in the inner IMS (121). Reacting with theoxygen and hydrogen ions, cytochrome c oxidase expels the by-product of water. The hydrogen ions in the IMS fall down theFrontiers inMedicine 12 frontiersin.orgVan Meter 10.3389/fmed.2024.1408816FIGURE 3The most oxygen that can conceivably be dissolved in plasma by a subject who breathes 100% oxygen is 2.3 volume%, and the plasma level entersthe red blood cells in the lung capillary, where the blood content can be boosted as high as 20 volume% by the presence of the gas-clathrate-likefunction of hemoglobin. When the red blood cell gets to its destination in a capillary of distant tissue, the highest possible concentration as theoxygen unloads from the red blood cell into the plasma possible at normobaric pressure is again at the very highest, 2.3 volume%. Under hyperbaricconditions at three atmospheres of pressure, the equivalent amount of oxygen possible in plasma during the circulatory route all the way to distalcapillaries at the very highest would be 6.6 volume% (108).FIGURE 4The increased ability of hyperbaric oxygen allows for an increased quantity of dissolved oxygen in body fluids. The facilitated delivery of oxygenthereby to the IMS of mitochondria throughout the body provides for necessary oxidative phosphorylation. Oxygen, by attaching to the cytochrome3 oxidase enzyme of the mitochondrial electron transport chain, produces the necessary supply of hydronium ions for ATP.Frontiers inMedicine 13 frontiersin.orgVan Meter 10.3389/fmed.2024.1408816FIGURE 5Krogh calculated the di�usion distance of oxygen outside of capillaries into tissue when a human breathed normobaric air. Extrapolationincorporating three atmospheres of pressure provided by hyperbaric treatment would provide a fivefold improvement in di�usion distance (94, 110).FIGURE 6Having a hyperbaric ambulance to bring immediate hyperbaric oxygen treatment to severely anemic, injured, or ill patients in transit to a hospitalemergency department increases the chance of having the same success rate as commercial diving operations, which require a hyperbaric chamberon site for accidents.molecular shoot of the ATP synthase nanomachine, and by rotarycatalysis, Pi ions join with ADP to form ATP. It is an evolutionarywonder that the red blood cell without mitochondria carts oxygento mitochondria in all the body’s cells to provide the energy for thehomeostasis of life.HBOT, if used promptly, can serve as a bridge therapy toalleviate illness and injury when transfusion of red blood cellsis necessary, otherwise requiring massive transfusion protocols.In other instances, HBOT could address severely anemic patientsburdened with complicating comorbidities that otherwise wouldpreclude the desirability of transfusion of red blood cells in anyamount or by transfusion altogether. Hypoxic stress simulatesrecovery, and recovery requires energy provided by ATP.Emerging ways that HBOT can safely and quickly beavailable are currently in existence (122). Hyperbaric unitscan be parts of emergency departments (123), intensivecare units (124), and ambulances (114). Figure 7 showsschematics for a designed hyperbaric ambulance. The costFrontiers inMedicine 14 frontiersin.orgVan Meter 10.3389/fmed.2024.1408816FIGURE 7The best of all possibilities would be to have a hyperbaric ambulance system that deploys to the street to transport a severely anemic, ill, or injuredpatient under pressure with oxygen administration. Upon arrival at the hospital, the pressurized patient compartment would hydraulically depart theambulance chaise and roll into the hospital emergency department to continue conventional normobaric resuscitation. The option could be for thedetached patient compartment of the ambulance to mate with a hyperbaric intensive care multiplace chamber for continued hyperbaricresuscitation (113).of an HBOT treatment is equal to the cost of a unit ofblood and its administration (4). HBOT does not needtype and crossing, or IV access, as the systemic doseof oxygen is administered via breathing or through apatient ventilator.Author contributionsKV: Writing – original draft, Writing – review & editing.FundingThe author(s) declare that no financial support was received forthe research, authorship, and/or publication of this article.Conflict of interestThe author declares that the research was conducted in theabsence of any commercial or financial relationships that could beconstrued as a potential conflict of interest.Publisher’s noteAll claims expressed in this article are solely those of theauthors and do not necessarily represent those of their affiliatedorganizations, or those of the publisher, the editors and thereviewers. Any product that may be evaluated in this article, orclaim that may be made by its manufacturer, is not guaranteed orendorsed by the publisher.References1. Boerema I, Meyne NG, Brummelkamp WK, Mensch MH, Kamermans F, SternHanf M, et al. 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