Hyperbaric Treatment of Ischemia Reperfusion Injury

Function

Immediate reperfusion is often a necessary life-saving intervention for patients. Given that ischemia and hypoxic injury arise via insufficient oxygen delivery to tissue, one may think that restoration of adequate oxygen supply would remedy the problem. However, in IRI, reperfusion paradoxically leads to persistent and sometimes increasing tissue damage, as noted microscopically by preserved tissue architecture and relative cellularity in ischemic tissue, while tissue visualized following IRI reveals necrosis with neutrophil infiltration.[1] 

Tissue hypoxia causes mitochondrial dysfunction, oxidative damage, the activation of complement and inflammatory processes, and tissue death. Hyperbaric oxygen therapy aims to:

• restore oxygen levels
• maintain cellular metabolism
• restore ATP production
• mitigate mitochondrial dysfunction
• prevent oxidative stress
• inhibit apoptosis
• trigger the production of secondary antioxidants

All these effects aid in the recovery of damaged tissue, decrease cellular and tissue edema, stimulate growth factor production, and improve wound healing. 

Pathophysiology of Ischemia-Reperfusion Injury 

The mechanism of injury associated with IRI involves the production of reactive oxygen species (ROS), microvascular vasoconstriction, and endothelial cell-neutrophil adhesion, causing neutrophil infiltration of the involved tissue.[1][7] Reactive oxygen species are chemical entities with oxygen free radicals formed as a by-product of cellular metabolism involving oxygen. Reactive oxygen species likely play a significant role in IRI.[1][8] Following tissue ischemia, reperfusion increases the production of xanthine oxidase, subsequently elevating the production of various ROS, including superoxide and hydrogen peroxide.[1][9] The increased production of superoxide and hydrogen peroxide recruit neutrophils, which in turn, produce additional ROS.[1][10][11] Oxidative damage from the ROS causes tissue death.[1][12] Normally, glutathione, an endogenous antioxidant, neutralizes ROS. However, the capacity of these neutralizing agents is overwhelmed in IRI.[1][13]

The recruited neutrophils cause inflammatory tissue damage, representing another critical factor in IRI pathophysiology. Driven by interactions with beta-2-integrins, many neutrophils bind to the vascular endothelium, causing the expression of endothelial cell adhesion molecules. These adhesion molecules augment neutrophils' invasion of local tissues and subsequent inflammatory cascades via secretion of ROS and tumor necrosis factor-α.[1][2][14][15][16] CD4+ lymphocyte levels are also elevated in the affected tissue and further contribute to the inflammatory milieu by stimulating local macrophage activity and increasing cytokine production.[2][17] The net result of this inflammatory reaction serves to propagate IRI further.

Mechanisms of Action of Hyperbaric Oxygen Therapy

The primary mechanism of action of HBOT is hyperoxygenation and the restoration of oxygen to normal or above-normal levels in oxygen-deprived tissues. The secondary benefits of hyperoxygenation are vast and include:

• Vasoconstriction to reduce tissue edema and improve microcirculation
• Reduction of endothelial damage and restoration of cell-to-cell junctions
• Modulation of aquaporins that modulate water transport between cells and become dysfunctional during tissue ischemia
• Promotion of all active mechanisms that require ATP, like wound healing cascades, angiogenesis, and lymphogenesis
• Increased growth factor production
• Direct and indirect antimicrobial effects
• Mobilization of stem cells from bone marrow
• Enzymatic and non-enzymatic antioxidant protection
• Restoration of cellular ion homeostasis, reduction of acidosis, stabilization of cellular calcium, and restoration of mitochondrial oxidative phosphorylation
• Limiting the release of excitatory mediators, ROS toxicity, and apoptosis
• Increased levels of IL-10, an anti-inflammatory cytokine
• Limiting mitochondrial DNA damage
• Reducing the expression of adhesion molecules and endothelin-1

Evidence from rat skin flap models suggests that HBOT partly increases skin flap survival by decreasing ROS's destructive effect in IRI.[1][18] Hyperbaric oxygen therapy appears to produce this effect by modulating multiple pathways, including increasing both the function of free radical scavenging systems, such as superoxide dismutase, and antioxidant gene expression.[1][18][19]

Hyperbaric oxygen therapy additionally helps decrease neutrophil-mediated inflammation that contributes to IRI. A key step for neutrophil infiltration into tissue during IRI involves neutrophil interaction with cell adhesion molecules and beta-2-integrins on the vascular endothelium. Rat and in vitro models demonstrate that HBOT helps limit the neutrophil-endothelial interaction in IRI, in part, by decreasing endothelial cell adhesion molecule expression.[1][20][21] Limiting neutrophil interaction with the endothelium may help decrease neutrophil presence in the affected tissue and the inflammatory component of the IRI.

Hyperbaric oxygen therapy also appears to improve microcirculatory dysfunction that contributes to IRI. Rat models again show that HBOT, particularly when initiated during ischemia, helps decrease vasoconstriction associated with IRI.[1][20] Many mechanisms likely contribute to this phenomenon, though in vitro research suggests stimulation of nitric oxide synthase by HBOT may increase nitric oxide levels and, thus, local vasodilation.[1][21] Mitigating pathologic vasoconstriction during the IRI may help maintain nutrient delivery to tissues and help lessen tissue injury. In addition to acutely supporting microvascular function, rat models suggest HBOT may yield a longer-term benefit in the IRI setting by increasing vascular endothelial growth factor (VEGF) transcription and production, leading to angiogenesis and subsequently improved tissue perfusion.[1][22]

Issues of Concern

As discussed, multiple mechanisms contribute to producing the pattern of IRI. Given the high prevalence of clinical scenarios where IRI may contribute to morbidity and mortality, such as myocardial infarctions and strokes, investigations into therapies to mitigate its severity, such as HBOT, are of importance.

A limitation of HBOT for IRI is that for it to be effective, HBOT should begin within 6 hours of IRI. As of 2022, more than 1,000 hospitals in the United States offer hyperbaric oxygen therapy. Less than 100 offer 24-hour per day, 7-day-a-week availability for emergent and urgent programs. Only 60 can treat patients requiring critical care. 

Hyperbaric oxygen therapy is a relatively safe treatment, with the most common side effect being middle ear barotrauma. Estimates suggest this occurs to varying degrees during approximately 10% of HBOT treatments. Middle ear barotrauma initially manifests as ear pain during decompression due to the patient experiencing difficulty equalizing the pressure in the middle ear with that of the external environment. However, its most severe form can result in tympanic membrane rupture.[23] For patients with persistent difficulty equalizing their ears, myringotomy may be helpful for those for whom HBOT would be highly beneficial. Tympanostomy tubes may be especially important in pediatric patients who cannot pressurize their ears. Another serious risk is central nervous system oxygen toxicity, which could lead to seizures. Minor risks include clouding of vision leading to cataract formation, sinus pressure, hypoglycemia, or claustrophobia.

Contraindications for HBOT are untreated pneumothorax due to the risk of the pneumothorax worsening or acquiring tension physiology in the setting of increased barometric pressures.[24] Medications contraindicated with HBOT are:

• Bleomycin due to interstitial pneumonitis. Patients should be off bleomycin for an extended period before treatment.
• Cisplatin due to impaired wound healing. Patients should be off cisplatin for an extended period before treatment.
• Disulfiram blocks superoxide dismutase. Discontinue disulfiram.
• Doxorubicin due to cardiotoxicity. Discontinue doxorubicin.
• Sulfamylon due to impaired wound healing. Discontinue sulfamylon.

Relative Contraindications

• Asthma
• Claustrophobia
• High fever
• Upper respiratory infection
• Hereditary spherocytosis 
• Chronic obstructive pulmonary disease
• Pacemaker or implanted pain pump
• Pregnancy
• Seizures 
• Eustachian tube dysfunction 

A history of seizure disorder or a high fever may lower the patient's seizure threshold. Patients with implanted devices must ensure their device has been pressure tested. To date, the effects of HBOT in pregnancy are unknown. Hyperbaric oxygen therapy may be used in emergencies like carbon monoxide poisoning during pregnancy, as some studies show no adverse effects. 

Additional therapies under investigation to help mitigate IRI include using agents that decrease the level of ROS and free radicals, such as superoxide dismutase and antibodies that block the neutrophil-endothelial interaction to limit neutrophil tissue invasion and inflammation.[1][25][26] Future research may investigate synergistic applications of multiple strategies, including HBOT, to find an optimal regimen for treating IRI. 

Clinical Significance

Ischemia-reperfusion injury can occur following ischemia to many different tissues. Most nontraumatic ischemic events are related to vascular occlusion from atherosclerosis or other thromboembolic diseases. Given longer lifespans and an aging population, combined with high rates of metabolic disease, ischemic disease will likely increase in the future.[7][27] Some risk factors like genetics, advanced age, and gender are irreversible. Lifestyle modification, diet, physical activity, maintaining a healthy weight, moderation of alcohol intake, and medications when appropriate will help mitigate additional risks. 

Iatrogenic events like accidental extravasation of vasoactive substances, postoperative reactive inflammatory responses, or sudden hypotension in response to medical treatments can also cause IRI. Similarly, air-gas emboli can arise from insufflation during endoscopic procedures or delivery of anesthetic gases due to over-pressurization of poorly compliant lungs. 

Essential questions regarding HBOT for IRI are:

• When to initiate HBOT
• What treatment parameters to use, including treatment pressure and duration
• What number of HBOT treatments

Hyperbaric oxygen therapy is generally administered between 1.9 and 3.0 ATA in specialized chambers that accommodate 1 to multiple people. Along with IRI, HBOT treats decompression sickness, carbon monoxide poisoning, diabetic wounds, delayed radiation injury, necrotizing fasciitis, gas gangrene, and refractory osteomyelitis. These decisions can be supported by considering factors such as the specific tissue affected, the time since the ischemia started, the etiology of the ischemia, the patient’s overall clinical stability and status, and the patient’s response to preceding HBOT sessions. Currently, the Undersea and Hyperbaric Medical Society (UHMS) does not have an approved indication specifically for IRI. However, several clinical conditions that are UHMS-approved indications for HBOT feature pathophysiology where IRI contributes to tissue damage and where reduction of IRI plays a role in the benefit of HBOT. Such UHMS-approved indications include compromised grafts or flaps, arterial insufficiency, acute traumatic ischemia such as crush injuries, and necrotizing soft tissue infections.[28] 

Assessing the UHMS recommendation surrounding the management of compromised grafts or flaps provides an understanding of the treatment paradigm involving how HBOT contributes to reducing IRI. In this condition, UHMS suggests treating compromised grafts or flaps at a pressure of 2 to 2.5 ATA for 90 to 120 minutes immediately upon recognition of tissue compromise. The healthcare team, which generally includes a hyperbaric physician and a plastic surgeon in this case, should continually evaluate the tissue’s response to treatment to help determine how many hyperbaric treatments to pursue.

Generally, a hyperbaric clinician should refer to the most up-to-date recommendations from the UHMS regarding optimal treatment paradigms that apply to the particular condition they are treating or to the guidelines at the individual clinician’s specific practice location. Evidence suggests that HBOT is more effective when initiated earlier during the IRI, though specific treatment algorithms, such as those provided by UHMS, should be followed based on the specific clinical scenario.[1][20]

Other Issues

Pearls

• Ischemia-reperfusion injury can occur from any vascular interruption of blood flow, including trauma, thrombosis, embolism, and crush or pressure-related injuries.[1] 
• Multiple factors, including a combination of ROS and oxidative damage, inflammation, and microvascular dysfunction, interact and contribute to IRI.[1][7]
• Hyperbaric oxygen reduces IRI by limiting damage from ROS, improving microcirculatory function, suppressing excessive inflammation, and supporting angiogenesis.[1][3]
• Seek guidance regarding treatment algorithms for specific ischemic conditions by consulting a qualified hyperbaric healthcare professional and the most up-to-date recommendations from the UHMS or the practice guidelines at an individual clinician’s specific practice location.

Enhancing Healthcare Team Outcomes

Ischemia-reperfusion injury has the potential to occur in multiple clinical scenarios. Reperfusion after myocardial infarction, cerebrovascular accident, organ transplantation, and compartment syndrome are all common clinical scenarios encountered in modern medical practice. Reperfusion may result in tissue injury worse than the original ischemic insult. To improve patient care and reduce morbidity and mortality associated with IRI, healthcare professionals must understand the mechanisms underlying IRI and the benefits of HBOT. Clinicians across all specialties should know the clinical scenarios in which IRI occurs and the associated clinical findings. Hyperbaric oxygen treatment is not only an adjunctive treatment aimed at reducing ischemic tissue damage but, when used early enough post-injury, may help to mitigate the ischemia-reperfusion response.

Patients affected by IRI often have healthcare professionals from multiple specialties involved in their care. The complexity necessitates a collaborative approach among clinicians to ensure patient-centered care and improve overall outcomes. Clinicians must contribute individual expertise while providing effective interprofessional communication to provide the best patient care and reduce morbidity and mortality. Initiation of HBOT will reduce the amount of lost tissue while improving the patient's quality of life.

Nursing, Allied Health, and Interprofessional Team Interventions

Clinicians and members of interprofessional teams need to be fully aware of the specific indications for hyperbaric oxygen therapy (HBOT) and the practical aspects of its administration. To enhance the process of administering HBOT, treatment teams can take specific steps before sending patients to an HBOT facility. Early communication with a hyperbaric team is critical to facilitate these steps. For instance, for patients with an endotracheal tube (ET) in place, filling the cuff of an ET tube with fluid instead of air may be necessary to prevent pressure-related complications in the HBOT chamber. An air-filled cuff can lose volume during chamber compression, leading to air leaks, improper endotracheal tube positioning, and compromised ventilation. Moreover, when patients require intravenous infusions and HBOT simultaneously, special pressure-rated tubing and pumps capable of withstanding the higher pressures of HBOT are necessary. Regular and early communication between the primary and hyperbaric teams can streamline care coordination, address the logistical aspects of hyperbaric treatment, and improve patient outcomes.

Nursing, Allied Health, and Interprofessional Team Monitoring

The interprofessional team overseeing hyperbaric therapy must actively monitor potential risks associated with the treatment. These risks include central nervous system and pulmonary oxygen toxicity, barotrauma to the inner ear, sinuses, and lungs, and confinement anxiety or claustrophobia.

Vigilance regarding oxygen toxicity of the central nervous and pulmonary systems is essential, as the risk for these conditions increases with 100% oxygen pressurized above atmospheric pressure. Immediate symptom recognition is critical. The symptoms of central nervous system oxygen toxicity are:

• Headache
• Tinnitus
• Visual changes
• Paresthesias
• Seizures

Pulmonary oxygen toxicity symptoms are:

• Tickle or burning sensation with inhalation
• Hemoptysis
• Dyspnea

Early identification of these adverse effects by the interprofessional team facilitates timely interventions, improving patient outcomes.

Additionally, the team should be aware of the heightened risk of fire associated with hyperbaric oxygen due to the high oxygen concentrations used. A fire within a hyperbaric chamber can be catastrophic. Removing flammable materials from chambers and prohibiting electronics help mitigate these risks and can help prevent accidents. Enforcing the hyperbaric team's policies on fire reduction strategies and promptly recognizing fires, if they occur, are ways the interprofessional team can contribute to reducing the risk of fire incidents.