Reperfusion injury medical therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [4] Associate Editor(s)-in-Chief: Anjan K. Chakrabarti, M.D. [5] Shivam Singla, M.D.[6]

Overview

The most common myth about the ischemia-reperfusion injury is itself related to blood flow. One can easily think like if everything is happening due to ischemia and with the restoration of blood flow, the injury should heal. Here is the trick, reperfusion in turn further exacerbates the injury mainly due to the formation of free radicals. There are few approaches that are studied widely and do play a major role in controlling the injury related to ischemia-reperfusion injury

Hyperbaric oxygen therapy is also studied widely and best suited when used within 6 hrs of hypoxia as it helps in the reduction of local and systemic hypoxia and in turn, increases the survival of affected tissue.

Medical Therapy

Reperfusion injury treatment, shown at various steps the intermediates and the possible drugs and compounds that can help to inhibit those steps and in turn decresing the incidence of reperfusion injury at various steps. [1]

Various proposed medical managements studied are:

  • Hydrogen sulfide treatment
  • Ischemic Conditioning Flow chart- Ischemic Conditioning Mechanism- Role of ischemic conditioning in preventing and minimizing the damage associated with Reperfusion injury. [2]
    Stem cell therapy

Therapies Associated with Improved Clinical Outcomes

Pre-conditioning and Post-conditioning benefits in preventing severe damage to tissue during the ischemia-reperfusion injury. [3]

Therapies that have been associated with improved clinical outcomes include:

  1. "Preconditioning" - Preconditioning is basically an adaptive response in which ischemia is exposed for a brief period of time before the actual ischemia phase to the tissue. This phenomenon markedly increases the ability of the heart to withstand subsequent ischemic insults[15]. In addition to that, the application of brief episodes of ischemia at the onset of reperfusion is termed as "postconditioning" which reduces the extent of injury that is supposed to happen.
  2. "Postconditioning" (short repeated periods of vessel opening by repeatedly blowing the balloon up for short periods of time)[16].
  3. Inhibition of mitochondrial pore opening by cyclosporine.

Limitations to applying strategies that have demonstrated benefit in animal models are the fact that reperfusion therapy was administered prior to or at the time of reperfusion. In the management of STEMI patients, it is impossible to administer the agent before vessel occlusion (except during coronary artery bypass grafting). Given the time constraints and the goal of opening an occluded artery within 90 minutes, it is also difficult to administer experimental agents before reperfusion in STEMI.

Therapies Associated with Limited Success

Pharmacotherapies that have either failed or that have met with limited success in improving clinical outcomes include:

  1. Beta-blockade[18]
  2. GIK (glucose-insulin-potassium infusion) (Studied in the Glucose-Insulin-Potassium Infusion in Patients With Acute Myocardial Infarction Without Signs of Heart Failure: The Glucose-Insulin-Potassium Study (GIPS)-II and other older studies
  3. Sodium-hydrogen exchange inhibitors such as cariporide[19](Studied in the GUARDIAN and EXPEDITION trials)
  4. Adenosine (Studied in the AMISTAD I and AMISTAD II trials as well as ATTACC trial ). It should be noted that at high doses in anterior ST elevation myocardial infarction|ST elevation MI adenosine was effective in the AMISTAD trial. Likewise, intracoronary administration of adenosine prior to primary PCI has been associated with improved echocardiographic and clinical outcomes in one small study.
  5. Calcium-channel blockers[20]
  6. Potassium–adenosine triphosphate channel[21] openers
  7. Antibodies directed against leukocyte adhesion molecules such as CD 18 (Studied in the LIMIT AMI trial )
  8. Oxygen free radical scavengers/anti-oxidants, including Erythropoietin, estrogen, heme-oxygenase 1, and hypoxia induced factor-1 (HIF-1).
  9. Pexelizumab, a humanized monoclonal antibody that binds the C5 component of complement (Studied in the Pexelizumab for ST elevation myocardial infarction|Acute ST-Elevation Myocardial Infarction in Patients Undergoing Primary Percutaneous Coronary Intervention (APEX AMI) trial )
  10. KAI-9803, a delta-protein kinase C inhibitor(Studied in the Intracoronary KAI-9803 as an adjunct to primary percutaneous coronary intervention for acute ST-segment elevation myocardial infarction trial or DELTA AMI trial).
  11. Human atrial natriuretic peptide[22] (Studied in the Human atrial natriuretic peptide and nicorandil as adjuncts to reperfusion treatment for acute myocardial infarction (J-WIND): two randomized trials.)
  12. FX06, an anti-inflammatory fibrin derivative that competes with fibrin fragments for binding with the vascular endothelial molecule VE-cadherin which deters migration of leukocytes across the endothelial cell monolayer (studied in the F.I.R.E. trial (Efficacy of FX06 in the Prevention of Myocardial Reperfusion Injury)
  13. Magnesium[23], which was evaluated by the Fourth International Study of Infarct Survival (ISIS-4) and the MAGIC trial.
  14. Hyperoxemia, the delivery of supersaturated oxygen after PCI (Studied in the AMIHOT II trial).
  15. Bendavia studied in the EMBRACE STEMI trial

There are several explanations for why trials of experimental agents have failed in this area:

  1. The therapy was administered after reperfusion and after reperfusion injury had set in
  2. The greatest benefit is observed in anterior ST-elevation myocardial infarctions (as demonstrated in the AMISTAD study), and inclusion of non-anterior locations minimizes the potential benefit
  3. There are uninhibited redundant pathways mediating reperfusion injury
  4. Inadequate dosing of the agent

References

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