Continuing Education Activity

The ischemia-reperfusion inflammatory reaction can occur with any injury that involves the ischemic interruption of vascular flow. This includes many soft tissue injuries involving crushing force, myocardial ischemia, and stroke. Hyperbaric oxygen treatment is not only an adjunctive treatment aimed at reducing ischemic tissue damage but, when used early enough post-injury, may actually mitigate the ischemia-reperfusion response altogether. Due to a paucity of available hyperbaric chambers in many regions and lack of experience or knowledge regarding its indications, it is an often-missed therapeutic option. This activity educates the learner on the etiology and pathophysiology of ischemia-reperfusion injuries, reviews the treatment of these injuries with hyperbaric oxygen, and highlights the interprofessional team's role in managing patients with ischemia-reperfusion injuries.

Objectives:

• Describe the factors leading to reperfusion injury.
• Identify key treatment considerations related to the treatment of ischemia-reperfusion injury with hyperbaric oxygen.
• Review the potential adverse effects of treating ischemia-reperfusion injury with hyperbaric oxygen.
• Explain the importance of well-integrated interprofessional communication to advance the treatment of ischemia-reperfusion injury and improve patient outcomes.

Introduction

Ischemia-reperfusion (I/R) injury is a well-recognized phenomenon that may follow virtually any ischemic episode to tissues from interrupted blood flow, including direct traumatic tissue injuries, pressure-induced injuries, and cold injuries or burns, embolic, thrombotic, or localized inflammatory occlusion insults. It is also described following vascular or cardiovascular reperfusion procedures and post compartment syndrome fasciotomies. Tissue injury and/or death from this initial ischemic insult is determined by a combination of degree and duration of the occlusion and extent and type of tissue involved by the affected watershed area of capillary or arteriolar distribution. When circulation is restored, the occlusion is relieved, or the vessel is re-cannulated, a recurrent ischemic effect may occur within the following 4 to 8 hours, and cell death can continue for up to 3 days after the reperfusion. The release of endothelial chemotactic substances initiated by the original injury or insult creates an intravascular inflammatory response. This inflammatory response is at least partially responsible for further vascular occlusion of downstream tissues from edema. It is worsened by additional release from the second round of reactive oxygen species generated by the freshly oxygenated blood in an affected region depleted of protective free radical scavengers responding to the initial insult.[1][2]

If initiated early, hyperbaric oxygen therapy has been found to ameliorate the damaging effects of reperfusion by early modulation of inflammation, maintenance of metabolic function in downstream tissues, and reintroduction of oxidation scavengers.

Function

The initial microvascular injury may be caused indirectly by upstream vascular occlusion or directly from a traumatic crush injury. Either mechanism results in varying degrees of endothelial insult. The initial ischemia triggers hypoxia-inducible factors (HIF) that stimulate vascular endothelial growth factor (VEGF) release, associated with the enhanced permeability of capillaries and arterioles. Neutrophil aggregation and adhesion to sensitized endothelial cells result in further cellular permeability and the relaxation of the cell to cell junctions (diapedesis). The increased permeability leads to a greater diffusion of fluid across the tissues (edema) and extracellular extravasation of leukocytes. This leukocyte activation is part of the inflammatory response, concentrating and utilizing reactive oxygen species for the phagocytic process of killing bacteria. Ischemic hypoxia drives the affected tissue into anaerobic metabolism, resulting in adenosine 5´ triphosphate depletion and decreased intracellular pH with lactic acid accumulation.

Further ischemic injury may occur at the cellular level when calcium ion efflux occurs from inactivated adenosine triphosphatases, accompanied by the opening of the mitochondrial permeability transition pore, further impairing adenosine 5' triphosphate production. Other biochemical events occur that don’t directly relate to tissue injury, but when fueled by the reintroduction of oxygen when circulation is restored, trigger a cascade event of elements that exacerbates further injury and sometimes full end-organ failure in downstream flow.[1]

Following reperfusion, the endothelial cells in their activated state produce more reactive oxygen species but less nitric oxide, a highly effective regulator of vascular tone, leukocyte adhesion, and platelet aggregation. The mechanisms leading to reperfusion injury are complex and still not fully understood but are likely related to a combination of factors, including:

1. The rapid reintroduction of oxygen increases reactive oxygen species such as the potent superoxide anion and reactive nitrogen species (RNS), and reactive nitric oxide species (RNOS), overwhelming the already depleted source of antioxidant catalases.
2. Intracellular calcium overload with the opening of the mitochondrial permeability transition pore leads to mitochondrial swelling and apoptosis.
3. Endothelial dysfunction with a pronounced inflammatory reaction occurs.

Issues of Concern

Hyperbaric oxygen promotes the VEGF-induced enhancement of endothelial nitric oxide synthase (eNOS). In addition to the scavenger effect of this antioxidant, this catalase may affect the mitogenic and anti-apoptotic actions of VEGF in preserving the integrity of the endothelium, thereby improving blood supply to the ischemic tissues. Hyperbaric oxygen therapy reduced leukocyte adherence on the endothelium of venules and blocked the progressive arteriolar vasoconstriction associated with reperfusion injury.

Fragile tissues may have a greater risk of a total loss of function due to cellular apoptosis following the second hypoxic insult presented by the Ischemia-Reperfusion injury. These tissues include nervous tissue, lung parenchyma, or any other previously damaged connective tissue.

Clinical Significance

Most nontraumatic ischemic events are related to vascular occlusion from atherosclerosis or other thromboembolic diseases. This risk is usually from hereditary factors that, along with advanced age and gender, cannot be controlled by preventive measures. Many associated risk factors can be controlled, often with the management of a primary care provider. Diet, activity, alteration of nutritional balance for weight loss as needed, and moderation of alcohol intake may help mitigate some additional risk. Medication may be appropriate to help diabetic patients maintain good glycemic control. 

Iatrogenic causes can also contribute to ischemic tissue occlusive events, including postoperative reactive inflammatory responses or sudden hypotensive responses to medical management. Air-gas embolisms can arise from insufflation during endoscopic procedures or delivery of anesthetic gases due to over-pressurization of poorly compliant lungs. Any of these actions may be enough to cause a vaso-occlusive occurrence.

Additional endothelial damage may occur with the complete occlusion of flow, thereby inhibiting oxygen delivery in any concentration to the affected tissue. Early intervention with oxygenated hemoglobin may mitigate some of this risk by activation and increased production of protective antioxidants such as superoxide dismutase, catalase, heme oxygenase-1, nitric oxide synthase, and heat shock proteins.

Hyperbaric oxygen therapy is a relatively safe treatment with a primary risk (greater than 1%) of barotrauma to the middle ear and sinus cavities. The only direct contraindication for treatment is the presence of a pneumothorax. The risk for treatment-induced pneumothorax, however, is less than 0.01%. The potential benefits of hyperbaric oxygen therapy outweigh the risks.

Other Issues

Pearls

• Ischemia-reperfusion (I/R) injury can occur from any vascular interruption of blood flow, including results of trauma, either directly from a laceration or tearing forces or indirectly through crushing or pressure-related injury. It may also result from surgical procedures, cold or heat-related injuries, thrombotic, embolic, or inflammatory occlusions.

• The release of chemotactic factors from the injured vascular walls is responsible for the initial inflammatory response in an Ischemia-Reperfusion injury.

• Correction of blood flow may create an additional chemotactic response, with additive effects that may cause a second interruption of flow to already sensitized tissues as well as introducing a second inflammatory response to downrange organs, furthering injury.

• Hyperbaric oxygen reduces ischemia-reperfusion effects by interrupting leukocyte adhesion on the vascular walls, thereby diminishing inflammatory effects while inducing free radical scavengers to block further tissue damage. All the while, hyperbaric oxygen supports metabolic function through high concentration oxygen diffusion.

Enhancing Healthcare Team Outcomes

The ischemia-reperfusion inflammatory reaction occurs with any injury that involves ischemic interruption of vascular flow. This includes many injuries involving crushing force, myocardial ischemia, and stroke. Hyperbaric oxygen treatment is not only an adjunctive treatment aimed at reducing ischemic tissue damage but, when used early enough post-injury, may actually mitigate the ischemia-reperfusion response altogether. By initiating hyperbaric treatment early, outcomes may be improved. [Level 5]

Review Questions

• Access free multiple choice questions on this topic.
• Comment on this article.

References

1.

Chen Y, Fan Z, Liao L, Lin Y. Effect Analysis of Hyperbaric Oxygen Therapy with Methylprednisolone on Prevention of Spinal Cord Ischemia-Reperfusion Injury. J Coll Physicians Surg Pak. 2019 Oct;29(10):1016-1017. [PubMed: 31564284]

2.

Yilmaz Y, Tumkaya L. Effects of hyperbaric oxygen and iloprost on intestinal ischemia-reperfusion induced acute lung injury. Ann Surg Treat Res. 2019 Jan;96(1):34-40. [PMC free article: PMC6306501] [PubMed: 30603632]

Disclosure: Marc Robins declares no relevant financial relationships with ineligible companies.

Disclosure: H Alan Wyatt declares no relevant financial relationships with ineligible companies.