Oxygen Is A Drug!

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The Pre-brief

In the field of hyperbaric oxygen therapy (HBOT), oxygen is considered the drug, but how does it work?  The most readily apparent effect of HBOT is hyperoxia, but rather diverse studies have suggested detrimental outcomes from inappropriate oxygen administration in pathologies such as acute coronary syndrome and traumatic brain injury. Why then, is the extreme hyperoxia characteristic of HBOT therapeutic?  It is important to consider that the timing and dose of hyperoxia achieved in a hyperbaric chamber is quite different from that of unnecessary sea level administration of O2.  Carbon monoxide toxicity, necrotizing fasciitis, clostridial myonecrosis, crush injury, compromised tissue graft or flap, central retinal artery occlusion, and arterial gas embolism represent a diverse and non-exhaustive list of emergent indications for HBOT.  None of these are purely problems of hypoxia where hyperoxia might be assumed as the straightforward solution. HBOT therapeutic mechanisms then must go beyond an elevated partial pressure of O2.     

What is HBOT?

By definition, HBOT is the administration of 100% O2 at higher than atmospheric pressure.  The two most direct consequences of such therapy are elevated partial pressure of O2 and a decrease in volume of airspaces according to Boyle’s law.  

 

Reduction of airspace volume is effectively only relevant to diseases related to bubbles.  Outside of decompression sickness and arterial gas embolism, this has little to no therapeutic effect.  The elevated partial pressure of O2 on the other hand is the primary driver of the therapeutic mechanisms of HBOT.  Arterial O2 can reach 2,000 mmHg with tissue tensions reaching the 200-400 mmHg range.  Hyperoxia itself though is usually not the direct therapy but rather the catalyst to a myriad of downstream cellular and physiologic sequelae.

Controlled oxidative stress  

Oxidative stress does not imply oxidative injury.  The physiologic responses to controlled periods of oxidative stress during HBOT are the primary therapeutic mechanisms of HBOT.  Thinking of oxygen as a drug, keep in mind that it can be dosed.  For wound healing typical of non-emergent indications, the ‘dose’ is 1.5-2.5 hour treatments daily for 4-6 weeks at 2.0-2.4 atmospheres absolute (ATA).  For emergent indications, the ‘dose’ is typically 1.5-2.5 hour treatments daily, twice daily, or three times daily for 1-10 treatments at 2.8-3.0 ATA.  Note that these periods of oxidative stress are brief within the period of a day.   Studies demonstrate that the body’s antioxidant defenses are equipped to manage this oxidative stress, and furthermore, it is the very rise in reactive species that initiates many of the therapeutic mechanisms of HBOT.  

Reactive oxygen species        

It is generally accepted that HBOT leads to a brief increase in reactive oxygen species (ROS) and reactive nitrogen species (RNS).  ROS and RNS are generated as part of normal metabolism.  Both act as signaling molecules for diverse hormonal and cytokine-related cell signaling pathways.  Examples of reactive oxygen species include hydrogen peroxide and superoxide while RNS include nitric oxide and its derivatives.  While considered injurious in uncontrolled excess, they are involved in antioxidant defenses and are critical to normal metabolism, cell signaling, and redox systems.       

Wound healing

Briefly regarding the outpatient, non-emergent realm of hyperbaric medicine; diabetic foot ulcers and delayed radiation injuries predominate.  While different, these two types of wounds share characteristics in impaired repair mechanisms, chronic inflammation, and fibrosis.  Therapeutic mechanisms of HBOT here differ from those relevant to critical care indications but are not devoid of overlap.  In these patients, the downstream signaling from elevated ROS and RNS during HBOT leads to increased growth factor synthesis (i.e. VEGF) and stem cell mobilization from marrow.  The ultimate result is improved neovascularization with subsequent potential for wound healing.    

Ischemia, reperfusion and inflammation

Perhaps the most central therapeutic mechanism of HBOT in critical care indications is impaired β2 integrin function.  One of the first responses to an ischemic insult and reperfusion is local endovascular neutrophil adhesion.  This occurs via the β2 integrin of the neutrophil and effectively initiates an injurious positive feedback loop of local inflammation and further ischemia.  HBOT at 2.8-3.0 ATA increases reactive species which specifically lead to S-nitrosylation of cytoskeletal β actin.  This renders neutrophilic actin expression such that the β2 integrin function and adherence to vascular endothelium are impaired.  This mechanism has been shown to reduce ischemia reperfusion injury and improves outcomes in carbon monoxide poisoning and decompression sickness.  Importantly, anti-microbial and other functions of the neutrophil are preserved despite β2 integrin impairment.       

Also, macrophage cytokine production is reduced after HBOT.  Overall, this leads to a reduction in pro-inflammatory cytokine levels.  This is thought to be related to pathways involving heme oxygenase-1 (HO-1) and heat shock proteins (HSPs) activated by oxidative stress.   

Additionally, HBOT activation of antioxidant and anti-inflammatory pathways contributes to improved ischemic tolerance. This occurs due to the role oxidative stress plays in modifying hypoxia-inducible factor-1 (HIF-1) and its related downstream pathways.  Interestingly, this occurs in a time-dependent manner with paradoxical upregulation of HIF-1 occurring when using prophylactic pre-surgical HBOT for pre-ischemic conditioning.  Conversely, HIF-1 downregulation is demonstrated to be pivotal to mitigating post-ischemic injury with HBOT treatments employed in the post ischemic injury phase. 

Ischemic insult, reperfusion injury, and local inflammatory response are common, though not universal, themes amongst emergent HBOT indications.  Collectively, impaired neutrophil adherence, reduced chemokine synthesis, and overall reduced inflammatory response resulting from HBOT are felt to mitigate these injurious processes.  

The Debrief

  • Oxidative stress does not imply oxidative injury.  The physiologic responses to controlled periods of oxidative stress during HBOT are some of the primary therapeutic mechanisms of HBOT
  • ROS and RNS are increased during HBOT and are the upstream signaling molecules responsible for downstream therapeutic mechanisms
  • Augmented growth factor synthesis and stem cell mobilization lead to neovascularization after HBOT for wound healing
  • Impaired neutrophil adherence, reduced pro-inflammatory cytokine production, and ischemic conditioning are the HBOT mechanisms relevant to critical care indications (i.e. compromised tissue flaps)

References

  1. Dennog C, Hartmann A, Frey G, Speit G. Detection of DNA damage after hyperbaric oxygen (HBO) therapy. Mutagenesis. 1996 Nov;11(6):605-9. doi: 10.1093/mutage/11.6.605. PMID: 8962431.
  2. Martin JD, Thom SR. Vascular leukocyte sequestration in decompression sickness and prophylactic hyperbaric oxygen therapy in rats. Aviat Space Environ Med. 2002 Jun;73(6):565-9. PMID: 12056672.
  3. Thom SR. Oxidative stress is fundamental to hyperbaric oxygen therapy. J Appl Physiol (1985). 2009 Mar;106(3):988-95. doi:10.1152/japplphysiol.91004.2008. Epub 2008 Oct 9. PMID: 18845776; PMCID: PMC2660252.
  4. Thom SR. Hyperbaric oxygen: its mechanisms and efficacy. Plast Reconstr Surg. 2011 Jan;127 Suppl 1(Suppl 1):131S-141S. doi: 10.1097/PRS.0b013e3181fbe2bf. PMID: 21200283; PMCID: PMC3058327.
  5. Zamboni WA, Roth AC, Russell RC, Graham B, Suchy H, Kucan JO. Morphologic analysis of the microcirculation during reperfusion of ischemic skeletal muscle and the effect of hyperbaric oxygen. Plast Reconstr Surg. 1993 May;91(6):1110-23. doi: 10.1097/00006534-199305000-00022. PMID: 8479978.

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