The absence of oxygen and nutrients during ischaemia affects all tissues with aerobic metabolism. Ischaemia of these tissues creates a condition which upon the restoration of circulation results in further inflammation and oxidative damage (reperfusion injury). Restoration of blood flow to an ischaemic organ is essential to prevent irreversible tissue injury, however reperfusion of the organ or tissues may result in a local and systemic inflammatory response augmenting tissue injury in excess of that produced by ischaemia alone. This process of organ damage with ischaemia being exacerbated by reperfusion is called ischaemia-reperfusion (IR). Regardless of the disease process, severity of IR injury depends on the length of ischaemic time as well as size and pre-ischaemic condition of the affected tissue. The liver is the largest solid organ in the body, hence liver IR injury can have profound local and systemic consequences, particularly in those with pre-existing liver disease. Liver IR injury is common following liver surgery and transplantation and remains the main cause of morbidity and mortality.
The liver has a dual blood supply from the hepatic artery (20%) and the portal vein (80%). A temporary reduction in blood supply to the liver causes IR injury. This can be due to a systemic reduction or local cessation and restoration of blood flow. Liver resections are performed for primary or secondary tumours of the liver and carry a substantial risk of bleeding especially in patients with chronic liver disease. Significant blood loss is associated with increased transfusion requirements, tumour recurrence, complications and increased morbidity and mortality. Several methods of hepatic vascular control have been described in order to minimise blood loss during elective liver resection. The simplest and most common method is inflow occlusion by applying a tape or vascular clamp across the hepatoduodenal ligament (Pringle Manoeuvre). This occludes both the arterial and portal vein inflow to the liver and leads to a period of warm ischaemia (37 °C) to the liver parenchyma resulting in ‘warm’ IR injury when the temporary inflow occlusion is relieved. In major liver surgery, extensive mobilisation of the liver itself without inflow occlusion results in a significant reduction in hepatic oxygenation.
3. PATOPHYSIOLOGY and RISK FACTORS
A complex cellular and molecular network of hepatocytes, Kupffer cells, liver sinusoidal endothelial cells (LSEC), leukocytes and cytokines play a role in the pathogenesis of IR injury. In general, both warm and cold ischaemia share similar mechanisms of injury. Hepatocyte injury is a predominant feature of warm ischaemia, whilst endothelial cells are more susceptible to cold ischaemic injury. There are currently no proven treatments for liver IR injury. Understanding this complex network is essential in developing therapeutic strategies in prevention and treatment of IR injury. Identifying risk factors for IR injury are extremely important in patient selection for liver surgery and transplantation. The main factors are the donor or patient age, the duration of organ ischaemia, presence or absence of liver steatosis and in transplantation whether the donor organ has been retrieved from a brain dead or cardiac death donor.
4. PREVENTION and TREATMENT
There is currently no accepted treatment for liver IR injury. Several pharmacological agents and surgical techniques have been beneficial in reducing markers of hepatocyte injury in experimental liver IR, however, they are yet to show clinical benefit in human trials. The following is an outline of current and future strategies which may be effective in reducing the detrimental effects of liver IR injury in liver surgery and transplantation.
4.1 SURGICAL STRATEGIES
Inflow occlusion or portal triad clamping (PTC) can be continuous or intermittent; alternating between short periods of inflow occlusion and reperfusion. Intermittent clamping (IC) increases parenchymal tolerance to ischaemia. Hence, prolonged continuous inflow occlusion rather than short intermittent periods results in greater degree of post-operative liver dysfunction. IC permits longer total ischaemia times for more complex resections. Alternating between 15 min of inflow occlusion and 5 min reperfusion cycles can be performed safely for up to 120 min total ischaemia time. There is a potential risk of increased blood loss during the periods of no inflow occlusion. However, these intervals provide an opportunity for the surgeon to check for haemostasis and control small bleeding areas from the cut surface of the liver. The optimal IC cycle times are not clear, although intermittent cycles of up to 30 min inflow occlusion have also been reported with no increase in morbidity, blood loss or liver dysfunction compared to 15 min cycles. IC is particularly beneficial in reducing post-operative liver dysfunction in patients with liver cirrhosis or steatosis.
In liver surgery, IPC ( Ischaemic Preconditioning) involves a short period of ischaemia (10 min) and reperfusion (10 min) intraoperatively by portal triad clamping prior to parenchymal transection during which a longer continuous inflow occlusion is applied to minimise blood loss. It allows continuous ischaemia times of up to 40 min without significant liver dysfunction. However, the protective effect of IPC decreases with increasing age above 60 years old and compared to IC it is less effective in steatotic livers. Moreover, IPC may impair liver regeneration capacity and may not be tolerated by the small remnant liver in those with more complex and extensive liver resections increasing the risk of post-operative hepatic insufficiency.
In order to avoid direct ischaemic insult to the liver by inflow occlusion, remote ischaemic preconditioning (RIPC) has been used. RIPC involves preconditioning a remote organ prior to ischaemia of the target organ. It has been shown to be reduce warm IR injury to the liver in experimental studies. A recent pilot randomised trial of RIPC in patients undergoing major liver resection for colorectal liver metastasis used a tourniquet applied to the right thigh with 10 min cycles of inflation-deflation to induce IR injury to the leg for 60 min. This was performed after general anaesthesia prior to skin incision. A reduction in post-operative transaminases and improved liver function was shown without the use of liver inflow occlusion. These results are promising but require validation in a larger trial addressing clinical outcomes.
5. FUTURE PERSPECTIVES
Hepatic IR injury remains the main cause of morbidity and mortality in liver surgery and transplantation. Despite over two decades of research in this area, therapeutic options to treat or prevent liver IR are limited. This is primarily due to the difficulties in translation of promising agents into human clinical studies. Recent advances in our understanding of the immunological responses and endothelial dysfunction in the pathogenesis of liver IR injury may pave the way for the development of new and more effective and targeted pharmacological agents.