Clinical implications of ischaemia-reperfusion injury
Introduction
Perfusion of an organ with nutritious oxygenated blood is a necessity for cellular viability and end-organ function in addition to survival in life. For decades the largest contributors to morbidity and mortality data have been ischaemic cardiovascular and cerebro-vascular disease, and therefore, vascular insufficiency has long been a focus of scientific interest.
Ischaemia results in reversible cellular damage provided there is timely reperfusion. Restoration of blood flow, however, results in a phenomenon whereby reperfusion is attended by greater tissue injury than that which is produced by ischaemia per se. This is termed ischaemia-reperfusion injury (IRI), and may be associated with both local and remote organ dysfunction.
In 1986, one of the first documented accounts of I/R injury was observed in the histological changes of feline intestinal specimens. Observations in models exposed to 3 h of ischaemia followed by 1 h of reperfusion, when compared with 4 h of ischaemia alone resulted in more significant microscopic necrosis [1]. Many observations that specific tissues/organs are more susceptible to I/R injury exist, but it is still unclear as to the biological determinants of these differences. Experimentation has shown that neuronal and gastro-intestinal tissue can only withstand minutes of ischaemia, whilst skeletal myocytes may survive hours [2], [3], [4].
It should also be noted that the phenomenon of I/R injury is a spectrum of pathology, not only between tissues, but also between individuals: ranging from completely reversible cellular damage to multi-organ failure. In the intensive care setting, ‘systemic inflammatory response syndrome’ (SIRS) and ‘multiple organ dysfunction syndrome’ (MODS) are recognised as clinical entities with multiple common aetiological influences, resulting in similarly poor prognostic outcomes. In fact they are responsible for 30–40% of mortality in this clinical area [5].
Thrombolytic therapy, organ transplantation, aortic cross-clamping, balloon angioplasty and cardio-pulmonary bypass have all thrown I/R injury into the surgical limelight, and the evidence for, how; as well as the prevention and treatment of I/R injury are discussed below.
Section snippets
Pathophysiology
Shortly after the cessation of an organ's blood supply, intra-cellular ATP becomes depleted due to reduced oxidative phosphorylation. Organelle activity rapidly becomes reliant on anaerobic metabolism, and this initiates a cascade within energy-dependent pathways such that the overall extra-cellular cytokine milieu becomes pro-inflammatory. Numerous textbooks exist on this subject, and attempting to review these would be foolhardy. A brief summary regarding the concepts of the common mechanisms
Molecular mediators
By far the most important and well-researched sub-cellular effectors of I/R injury are reactive oxygen species. Free radical production involves catabolic activity within the cell producing an excess of hypoxanthine. This cannot be broken down due to the inactivity of oxygen-dependent xanthine oxidases. Accumulation has the potential for activation into reactive oxygen species (such as superoxide ions, hydroxyl radicals, hydrogen peroxide and hydrochlorous acid,) following reperfusion, and
The ‘No-Reflow’ hypothesis and leucocytes
The ‘No-Reflow’ hypothesis describes progressive tissue ischaemia following reperfusion. It has been elucidated from histopathological specimens of capillary beds that define activated leucocytes bound to platelet plugs within the narrowed lumen of swollen and partially detached endothelial cells [12]. One postulated mechanism proposes that as ionic pumps fail, a shift in the equilibrium across the cell membrane causes preferential influx of calcium, sodium and water and subsequent cellular
Microvascular dysfunction
Endothelial cells in particular are more susceptible to ischaemic damage and malfunction. They are not only the first cellular contact to reperfusate, but they play a key role in many homeostatic mechanisms, including the control of vascular tone. As previously discussed, nitric oxide plays a key role in local homeostasis, and the endothelium is its main source. Concomitantly, xanthine oxidase activity predominates in the endothelial component of many organs, and can be over 100 times more
Clinical manifestations
The repercussions of I/R injury can be subdivided into local, distant/remote and systemic. Local effects have been extensively investigated and although sharing in the common aetiology outlined previously, cellular changes are organ specific. Systemic sequelae and remote organ dysfunction are more difficult to explain, but SIRS and multi-organ failure are seen following varying insults such as single organ I/R injury, bilateral lower limb ischaemia and hypovolaemic shock.
Ruptured aortic
The heart
This is the most important organ relating to IRI due to its inherent physiological significance to the body, and the varying nature of the clinical scenarios in which it experiences temporary cessation of adequate blood supply. Angina, percutaneous trans-arterial coronary angioplasty, thrombolysis and external cardiac bypass (for transplantation or coronary artery bypass) subject myocytes to varying temporal changes in coronary artery, (and therefore, myocyte) oxygenation.
It has been
The lungs
We have had an ideal opportunity to study I/R injury in the lungs through the advent of cardio-pulmonary bypass in thoracic surgery. Damage may be manifested as conditions ranging from sub-clinical functional changes in most patients, to full-blown ‘adult respiratory distress syndrome’ in ∼2% of cases. Abnormal gas exchange and poor lung mechanics, characterised by increased pulmonary vascular resistance and alveolar-arterial oxygen pressure gradient mark the beginning of respiratory
The kidneys
Delayed graft function following cadaveric kidney transplantation is an independent risk factor (in addition to episodic acute rejection,) for subsequent graft failure secondary to chronic rejection. This phenomenon has been blamed on IRI of the kidney, [32] as an individual entity and as an enhancer of host alloresponsiveness [33]. The cells most affected by reperfusion are to be found in the S3 segment of the proximal convoluted tubule [34]. Loss of epithelial tubular polarity, and
Musculocutaneous tissue
Distal reperfusion following aortic or femoral bypass surgery runs the risk of ‘compartment syndrome’ of the lower limbs. Originally described by Volkmann in 1881, this refers to an elevation in extra-cellular pressure secondary to cellular swelling within an unyielding fascial envelope (or compartment). This hampers tissue perfusion as it rises to meet capillary pressure. The condition is significant as it is limb-threatening, and difficult to predict in the individual. For these reasons a
The central nervous system
The central nervous system is privileged in that it is separated from the general circulation by the blood–brain barrier (BBB). Unfortunately this is an endothelial structure and is, therefore, susceptible to the mechanisms of I/R injury previously delineated. Cerebrovascular ischaemia (embolic or thrombotic), traumatic head injury, carotid endarterectomy, aneurysm repair and circulatory arrest can cause disruption of the BBB, resulting in transmigration of leucocytes and cerebral oedema [40].
The gastrointestinal tract
Aortic surgery, strangulated bowel, hypovolaemic shock or ischaemic bowel secondary to arterial thrombosis/embolus is associated with I/R injury. Similar to the central nervous system, breakdown in the intestinal barrier allows permeation of molecules previously resisted [44]. In the case of the small bowel, absorption of bacterial endotoxins into the portal circulation, termed ‘translocation’ [45] are a potent stimulus to cytokine production, leucocyte activation and development of SIRS. The
The pancreas
I/R of the pancreas has been observed as a factor in the aetiology of acute pancreatitis, the progression of the condition to its severe narcotising form, and as a complication of pancreatic transplantation. Histological changes within the pancreas occur rapidly following reperfusion, and these are initially similar to the inflammatory response seen in other organs previously described. Further damage results in extensive necrosis that take weeks to regenerate [48].
Multi organ dysfunction syndrome
Clinically, MODS is usually heralded by the onset of acute respiratory insufficiency and renal failure. The common pathology involves increasingly leaky capillary beds causing fluid extravasation and tissue oedema. The lungs, kidneys and heart seem most susceptible to this injury, although this may be an artefact of their significance in intensive care management. During thoraco-abdominal aortic surgery, a recent review showed that of 28 patients in the series, ten experienced renal
Targets for prophylaxis and treatment
It is well known that hypothermia, extensively used in cardioplegic coronary artery bypass surgery, is efficacious in reducing myocardial injury by reducing oxygen demand through a reduction in metabolic activity, and increased tolerance to ischaemia. A decrease in metabolic activity also inhibits endothelial production of inflammatory mediators. This is especially evident in spinal cord protection during aortic surgery [54].
When contemplating therapeutic intervention against reperfusion
Controlled reperfusion and prophylactic fasciotomy
Evidence supports a gradual re-introduction of perfusate back into tissues. Additionally, effecting reperfusion by altering the perfusing solution through de-oxygenation, or through intermittent reperfusion has shown similar efficacy in targeting I/R injury [54]. These act to reduce the sudden exposure of the tissues to free radical damage. In skeletal muscle, reperfusion injury can be associated with compartment syndrome that acts to aggravate the ‘No-Reflow’ phenomenon in limb salvage by
Anti-oxidants
The majority of research into pharmacological intervention concerns this generic group (see Table 2). As previously described, the formation of highly reactive oxygen derived species is a primary sequela of ischaemic-reperfusion. Evidence abounds with regards clinical efficacy of these drugs. Unfortunately, clinical experience has been disappointing, and none have made it into regular practice.
Nitric oxide donation
The most physiological method of nitric oxide delivery is through inhalation, and it may prove to be of benefit in lung transplantation and ARDS for this reason. It has been shown to overcome ventilation perfusion-mismatch by vaso-dilating ventilated areas of lung tissue. It also antagonises vascular leakage through cyclic-GMP mediated mechanisms. This can also be used to ‘precondition’ transplanted lungs [56].
Anti-leucocyte therapy
Inhibition of inflammatory mediator release, chemokine-receptor engagement, adhesion molecule synthesis and expression, and antagonism of neutrophil adhesion and diapedesis all fall under this remit. Many drugs act in this manner, and have been shown to be very effective, but all still remain confined to experimental models. Cytokine receptor antagonists/antibodies attenuate I/R injury target the extracellular components of leucocyte-endothelial interaction, whilst anti-inflammatory drugs, (see
Ischaemic preconditioning
Ischaemic preconditioning describes the phenomenon of serial brief periods of ischaemia with intervening reperfusion that protects tissues from subsequent exposure to a prolonged ischaemic event. Preconditioning tissues has been shown to prevent the depletion of intracellular ‘high-energy’ phosphates and inhibit the accumulation of polymorphonuclear neutrophils, which are crucial to the ‘No-Reflow’ hypothesis. In fact, evidence of protection already exists within in vivo models, which show
Conclusions
IRI can affect any organ or several organs concomitantly. Its pathophysiology is complex, and putative targets for intervention, although well defined have not yet afforded us significant success in either treatment or prophylaxis, within the clinical arena. More research is needed into these predictable and devastating sequelae of IRI such that the transition between laboratory bench and the bed-side can be made.
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2019, Clinical Nutrition ExperimentalCitation Excerpt :To our best our knowledge, this is the first report clarifying that prehabilitation improves survival after severe gut I/R in mice. Because gut I/R is considered to be an important mechanism underlying organ dysfunction and death after severe surgical insults in clinical settings [2] appropriate prehabilitation with high tolerability might be a new strategy for preventing postoperative complications in addition to maintenance of muscle function. The present study also revealed that excessively demanding protocols may result in poorer outcomes.