Anaesthesia, Pain, Intensive Care and Emergency - Part 4 pps

Pathophysiology The liver is a multifunctional organ that has an important role in metabolism, biosynthesis, excretion, secretion and detoxification. These processes require en- ergy, making the liver a highly aerobic oxygen-dependent tissue. It thus becomes clear that an impairment of its function will have significant haemodynamic, respiratory, metabolic and haemostatic consequences. The extent of liver cell damage depends on the nature, duration and severity of the initial trigger event. In addition, there is secondary damage caused by the release of cytokines and cytotoxic mediators from activated cells of the reticuloen- dothelial system (Kupfer cells). Further damage arises from the release of large amounts of free radicals and proteases as a result of interaction between neutrophil granulocytes and sinusoid endothelium. The activation of sinusoidal endothelial cells leads to lipid peroxida- tion of cell membranes, abnormalities in intrahepatic microcirculation with vaso- constriction and perfusion failure, tissue hypoxaemia and, ultimately, cell death. Haemodynamic changes and tissue oxygen debt In some ways, circulatory disturbances mimic septic shock, with a hyperdynamic pattern sustained by the release of toxic substances from injured hepatocytes. In the early stage of the syndrome, microcirculatory disturbances along with abnor- mal oxygen transport are responsible for the low peripheral oxygen utilisation despite the initial adequate blood pressure and arterial oxygen saturation. Circulatory abnormalities tend to worsen during the course of the illness: and the loss of autoregulation of vascular tone results in a generalised vasodilatation and reduction in systemic vascular resistance; hypotension is the rule; tachycardia and an increase in cardiac output are the most common compensatory conse- quences (Table 3). Table 3. Haemodynamic and oxyphoretic profile Acute liver failure Normal values CI nor¯¯ 2.5–4 l min –1 m –2 FC ¯¯ 60–80 bpm SVRI ¯¯¯ 1200–2400 dyn s –1 cm –5 m –2 DO2I ¯ or ¯ 400–600 ml min –1 m –2 VO2I ¯ 120–160 ml min –1 m –2 O2 Extraction ¯¯ 22–30% SvO2  60–80% Although delivery of oxygen to the tissues is often adequate, there is a decrease in its uptake, resulting in low arterio-venous oxygen content difference. Activation of platelets together with increased adhesion of leucocytes to endothe- Acute liver failure 131 lium predispose to microthrombi and circulatoryplugging, with shunting of blood (through low resistance vessels) away from active metabolic tissues.Consequently, the oxygen extraction ratio and oxygen consumption are decreased, anaerobic metabolism ensues and lactic acidosis develops (oxygen debt). Tissue hypoxia caused by severe peripheral hypoperfusion, and low blood pressure contribute to the development of multiorgan failure, which is associated with a very poor prognosis. Clinical features Early clinical presentation includes nonspecific symptoms such as sickness, ano- rexia, nausea and vomiting; more specific ones are jaundice and abdominal pain. Hepatic encephalopathy and coagulopathy typically define the syndrome. Other clinical manifestations are lacking as the liver is usually not palpable and there are no signs ofchronic liver diseasesuch as portalhypertension, spider naeviorascites. Careful history taking and accurate clinical examination of the patient make it possible todistinguish the altered mental status with thisfeature fromneurological impairment resulting from other causes; laboratory biochemistry and clotting pattern help in the diagnosis of acute liver failure. Progression of hepatic dysfunc- tion determines the involvement of the whole body with haemodynamic changes, metabolic disturbances and multiple organ failure. Encephalopathy Both vasogenic and cytotoxic mechanisms have been invoked in the pathogenesis of hepatic encephalopathy [6]. It has been demonstrated that many toxic sub- stances released from the damaged liver can alter the autoregulation of cerebral blood flow (CBF) and increase the permeability of the blood–brain barrier, thus leading to cerebral oedema. Failure of biotransformation and excretion of toxins normally processed by the liver is the main mechanism involved in cerebrovascular derangement. Ammonia is a nitrogenous molecule derived from the deamination of aminoacids; the two major sources are catabolism of endogenous proteins and gastrointestinal ab- sorption, since resident bacteria split urea to produce ammonia. In the brain, ammonia detoxification occurs inside the astrocytes, where it is converted into glutamine by the enzyme glutamine synthetase. The accumulation of glutamine in the astrocytes induced by hyperammonaemia produces osmotic stress and causes them to swell; other chemicals, such as mercaptans, fatty acids, aromatic chain aminoacids, benzodiazepine-like substances and g-aminobutyric acid, are also involved. The swelling of the astrocytes is an important mechanism in the increase of cerebral volume and ICP. While CBF is sometimes reduced in the first stage of ALF (local cerebral vasoconstriction in response to reduction of mean systemic arterial pressure), it tends to increase in the subsequent stage as hyperammonaemia decreases cerebral 132 P. Feltracco, M.L. Brezzi, C. Ori arteriolar tone. Despite vasodilatation in the systemic and splanchnic beds, cere- bral vessel resistance may increase, so that cerebral perfusion pressure may be preserved. When inthecourseofillnesscerebral vascular tone isnolongereffective, vasodilatation develops and rapidly becomes poorly responsive to carbon dioxide stimulation. The loss of autoregulatory tone is responsible for excessive CBF (vasogenic oedema). Prolonged hyperaemia may worsen brain swelling and cere- bral oedema. Brain oedema further aggravates the critically reduced cerebral perfusion, leading ultimately to marked cerebral ischaemia [7, 8]. Severity of hepatic encephalopathy is classified in four grades (I–IV; see Ta- ble 4), based on the progression from a normal mental status to deep hepatic coma. Brain oedema is a frequent and serious complication, occurring in up to 80% of patients with grade IV encephalopathy, and is a major cause of death. Table 4. Staging of hepatic encephalopathy Grade Intellectual function Neuromuscular function EEG Outcome (% survival) I Impaired attention, Incoordination, apraxia Usually 70% irritability, slowness normal of mentation, disturbed sleep II Drowsiness, inappropriate Tremors, slowed or slurred Generalised 60% behaviour (confusion, speech, ataxia slowing euphoria), sleep disorders III Marked confusion and Hypoactive reflexes, Severe slowing 40% disorientation, somnolence nystagmus, clonus and to semistupor but still muscular rigidity arousable, amnesia, can follow simple commands IV Stupor and coma Dilated pupils and decerebrate Severe slowing 20% posturing, absence to painful with frequencies stimuli in the theta and delta ranges One of the earliest signs of encephalopathy reflects the involvement of higher cortical functions: patients may be agitated and exhibit aggressive behaviour and changes in personality; they usually experience a change in sleep pattern (wakeful- ness at night and drowsiness during the day). The EEG is usually normal. Stage II is characterised by an exaggeration of these cortical manifestations, with more drowsiness and lethargy, and by the appearance of movement disorders that reflect increasing involvement of the descending reticular system or other neurological structures. These movement disturbances include tremors and inco- ordination. An EEG performed in stage II usually shows slower rhythms than normal. Spontaneous hyperventilation is common and can result in significant respiratory alkalosis. Progression to stage III is defined as increasing obtundation though the patient Acute liver failure 133 is still arousable: tremors may no longer be evident, leading to a generalised increase in muscle tone; hyperreflexia and muscle rigidity become evident, right up to the full decerebrate posture of stage IV. The EEG shows severe slowing in frequencies in the theta and delta ranges. These neurological manifestations are generally symmetrical, and the appea- rance of focal neurological motor or sensory abnormalities should always prompt investigation for other causes of neurological disease, such as intracerebral haem- orrhage. Even though the clinical features may be fully reversible, either spontaneously or by transplantation, grade IV encephalopathy is always a manifestation of ad- vanced liver disease and is associated with a poor long-term prognosis. Coagulopathy Coagulopathy is the second important hallmark of ALF. The liver has a central role in coagulation: it is responsible for the synthesis of the clotting factors and most of the inhibitorsof coagulation and fibrinolysis;it alsoclears activated clotting factors from the bloodstream. Coagulation disturbances include thrombocytopenia with abnormalities in aggregation and adhesion, and low circulating levels of fibrinogen and factors II, V, VII,IX andX. This causes prolongationof the prothrombintime, whichtogether with factor V level is widely used as an indicator of the severity of hepatic injury. In contrast, factor VIII, which is produced by endothelial cells and not by the liver, is usually increased. At the same time, coagulation inhibitors AT III, protein C and protein S are reduced, but this phenomenon fails to have a corrective effect on the coagulopathy [9, 10]. Fibrinolysis is enhanced, as manifested by an increase in fibrin degradation products, poor clot formation and a certain degree of dissemi- nated intravascular coagulation [11]. Bleeding occurs in as many as 75% of patients, usually from gastric mucosal erosions, butalso fromthe nasopharynx, lungs, retroperitoneum,kidneys and skin puncture sites. The prophylactic administration of fresh-frozen plasma in patients not suffer- ing from bleeding has not been shown to reduce morbidity or mortality [11], and management with blood products is indicated only in the presence of manifest bleeding or to promote coagulation during invasive procedures. Other laboratory data Other laboratory data include elevated serum aminotransferases, hyperbilirubin, hypoglycaemia, hyperammonaemia, elevated lactate and, often, electrolyte abnor- malities such as hyponatraemia, hypokalaemia and hypophosphataemia. Metabolic acidosis becomes evident late in the course of the illness even though it is an early sign of a poor prognosis in the case of acetaminophen overdose. 134 P. Feltracco, M.L. Brezzi, C. Ori Renal failure Renal impairment occurs in up to 60–70% of cases and indicates a poor prognosis [12]. The usual form is a functional failure, but acute necrosis is also found [13]. Renal blood flow isreducedbecause of intense renalarteriolarvasoconstriction; renin and aldosterone levels are, in fact, increased [14, 15]. No structural damage to the renal parenchyma occurs if hepatic cells recover or if liver transplantation is performed. Acute tubular necrosis can result either from systemic hypotension or from a direct toxic effect of acetaminophen [16], antibiotics and contrast agents. The urinary sodium excretion in acute tubular necrosis is usually >20 mmol/l, and the urinary sediment often shows cellular casts. Serum creatinine is a better index of renal function than blood urea, since urea synthesis is greatly decreased in these patients (with the risk of underestimation of the severity of renal dysfunction). Renal support is often required, preferably in the form of continuous techniques rather than intermittent haemodialysis. Continuous renal replacement methods are indicated particularly in the case of elevated ICP: they are, in fact, associated with greater cardiovascular stability and higher cerebral perfusion pressures than are standard intermittent techniques [17–20]. The rapid water shift provoked by inter- mittent haemodialysis is responsible for the poorer neurological outcome than is seen with the slow fluid exchange when the continuous technique is applied [21]. Other indications for continuous replacement methods include uncontrolled acidosis, hyperkalaemia, fluid overload and oliguria. Metabolic changes The main metabolic disorders are hypoglycaemia and hyperlactataemia. Low blood glucose levels result from impaired gluconeogenesis, inability to mobilise glycogen stores and inadequate hepatic uptake of insulin with augmenta- tion of circulating levels. Blood glucose should be monitored frequently, as clinical signs of hypoglycaemia can be masked in the presence of established encephalo- pathy. Hypoglycaemia may sometimes precede the onset of encephalopathy, with a precipitous deterioration of the mental status. Hyperlactataemia is common, with a reported incidence of approximately 80% [22]. Increased blood lactate is usually due to decreased hepatic clearance of syste- mically produced lactate by the Cori cycle and to increased lactate formation; increased production is sustained by microcirculatory shunting, which is respon- sible for generalised tissue hypoxia. Susceptibility to infections An increased susceptibility to infections in ALF relies on impaired phagocytic function and reduced complement levels. Sepsis enhances macrophage activation and cytokine release, which worsen circulation disturbances and tissue hypoxia, thus contributing to the development of multiorgan failure. Acute liver failure 135 Bacterial infections affect almost 80% of patients, whilst fungal diseases (pre- dominantly candidiasis) occur in 30%. Pneumonia accounts for 50% of infective episodes, and urinary infection for 20–25% [23]. Clinical signs of infection, such as fever and leucocytosis, are often absent. A high index of suspicion and close microbiological surveillance are always recom - mended to increase the likelihood of identifying subclinical infectious processes. Therapeutic suggestions While patients with minor hepatic injury can be well cared for on a medical ward, patients who rapidly deteriorate require close monitoringin an ICUsetting to allow careful observation and detection of any progression of the syndrome. Rapid deterioration is a particular feature of acute liver failure; patients with no neurolo- gical or circulatory disturbances may worsen rapidly, thus requiring inotropic support for hypotensi on and/or mechanical ventilation. As soon as the patient’s condition starts to worsen (if possible not in a higher stage of encephalopathy than II), early contact should be made with a transplant centre to acquire information both on appropriate treatment and on whether a transfer is indicated. Once the patient is in the ICU aggressive support of failing organs may improve his or her condition while winning time until the availability of an organ for transplantation, which is the only therapy of proven benefit at present. Intubation and mechanicalventilationareindicated when thepatientdrifts into grade III encephalopathy, when marked confusion, stupor and muscular rigidity arise and the pharyngeal reflexes are no longer capable of protecting the patient against aspiration and pulmonary damage. Sedation and assisted ventilation are useful for cerebral oedema, since they reduce cerebral irritation and rising ICP during nursing. Head elevation up to 20–30° and administration of mannitol should be considered, while thiopental, even if effective in protection of the CNS (by reducing the cerebral metabolism, decreasing cerebralbloodvolume andICP), may increasethe riskofcardiovascular instability and infection. Hyperventilation, whilst effective in reducingblood flowand oxygen consump- tion, can precipitate cerebral ischaemia. According to Nemoto et al., mild hypothermia could be adopted as a protective strategy, since it reduces the cerebral metabolic rate [24]. Indirect information about CBF can be obtained from transcranial Doppler of the middle cerebral artery [25] and/or with SjO 2 monitoring [26]. Continuous invasive ICP monitoring is possible with epidural, subdural or intraparenchymal transducers. While these may help in the identification of rapid intracranial pres- sure variations, their insertion has to be balanced against the risk of bleeding. Intravascular fluid assessment and optimal fluid balance are highly recom- mended, since relative hypovolaemia and splanchnic venous pooling are the rule. Volumetric monitoring with Pulsion PiCCO and a pulmonary artery catheter 136 P. Feltracco, M.L. Brezzi, C. Ori allow for better titration of volume replacement. Vasopressors or inotropes might be required to increase mean arterial pressure, thus preserving renal and cerebral perfusion. Use of blood products should be restricted to patients who are actively bleeding or are undergoing invasive procedures. Prostanoid derivatives, even though widely used in the past, are now no longer employed; in fact, any favourablemicrocirculatory influenceon tissue oxygenation have yet, to be confirmed. Broad-spectrum antibiotics and antifungal prophylaxis are recommended. Early antibiotic therapy reduces the incidence of infective episodes to 20% and the overall mortality to 44% [27]. Other recommendations include blood glucose level control and correction of electrolyte imbalances. Nephrotoxic medications, such as aminoglycoside antibi- otics and nonsteroidal anti-inflammatory drugs, should be avoided. As previously stated, continuous renal replacement therapy must be adopted in case of renal failure. Continuous replacement techniques are mandatory when fluid retention might exacerbate cerebral oedema. Specific medical therapy Specific treatments are currently recommended for ALF when its aetiology is definitely known. N-Acetylcysteine (NAC),for example, has beenintroducedasaspecific antidote for paracetamol overdose, since it may prevent progression to full-blown ALF. It has been shown to enhance tissueoxygenation and oxygen extraction while improv- ing haemodynamics. Since acetylcysteine increases the synthesis and availability of glutathione, it is particularly indicated in this setting, where oxidative stress is accentuated. The King’s College group [28] suggest its use in all cases of ALF syndrome regardless ofaetiology, eventhough other authors have notobserved [29] clinically relevant improvement after its administration. Fulminant hepatic failure resulting from herpesvirus benefits from aciclovir, while acute fatty liver of pregnancy requires rapid delivery of the fetus [30]. In acute decompensation ofWilson’s disease, largeamountso ffresh-frozenplasma have been sho wn to help in correcting the excessive retention of copper [31]. Liver-assisting devices Artificial hepatic support should provide metabolic, synthetic and detoxification functions, allowing time for recovery and regeneration of the host organ or for transplantation. Various liver-assisting therapies have been introduced since the early 1960s, but none has yet led to a significant clinical improvement, since it is still impossible to reproduce the unique and complex architecture of the liver. Basically, extracorporeal liver support systems are divided into biological, Acute liver failure 137 nonbiological (or artificial) and bioartificial (hybrid technique) devices. Biological methods: with these approaches liver support-detoxification was achieved by whole portal and artery perfusion through animal or human livers. They are no longer applied. Artificial devices: the main aim of these is to detoxify the patient by means of dialysis-derived techniques: plasma exchange, haemofiltration, haemodialysis (HD), albumin-dialysis, plasma adsorption, the Prometheus ® system. Two of the most widely applied are: MARS (molecular absorbent recirculating system), which is based on the prin- ciples of dialysis, filtration and adsorption. The patient’s blood is brought into contact with an albumin-coated membrane which is capable of removing some toxins such as ammonia,bilirubinandaromatic aminoacids. Themembraneadsorbs andholds thetoxinsfor atime,butthey are thenreleased(followingtheirconcentration gradient) and are carri ed to the o ther side of the membrane, where dialysi s against the albumin-rich dialysate removes the toxins from the membrane [32]. PAP (plasma adsorption perfusion) is another nonbiological device by which plasma is first separated from blood and then passed through a filter where toxins (especially bilirubin) are adsorbed. The artificial support systems are useful mainly for detoxification of some substances (ammonia, aromatic aminoacids, and bilirubin) and water-soluble toxins. Improvement of systemic haemodynamics and reduction of cerebral oe- dema and ICP have been demonstrated, but nothing has been reported relating to the promotionof liversynthetic function.Evidence ofany benefiton survivalis still lacking, since the removal of toxins, mediators, cytokines and other pro-inflam- matory factors can be associated with the simultaneous removal of regenerating growth factors. Bioartificial devices: with this approach biological tissues are combined with nonbiological materials; theaims of these devices areto provideboth excretory and biotransformational functions and to remove cytokines and other toxins. The patient’s blood passes through columns containing cultured hepatocytes (porcine cells for the BAL [bioartificial liver] and human hepatoblastoma cells for the ELAD [extracorporeal liver-Assisting device]). While the bioartificial systemshaveyieldedrealadvantagesintermsofneurological function and detoxification, serious drawbacks have nonetheless consistently limited their adoption, such as the risk of porcine retrovirus infections, graft-versus- host reactions, complement a ctivation, activation of the clotting cascade, thrombocytopoe- nia, drug-induced cytopoenia (DIC), haemodyna mic instability and higher costs. Auxiliary heterotopic live r transplantation is applied with satisfactory results in some centres [33]. Intraportal hepatocyte transplan tation has even been per- form ed, but for selective indications [34]; its benefit in AL F has yet to be con- firmed. Artificial and bioartificialextracorporealliver-supportsystems arestillfarfrom being incorporated into clinical routine; they should, however, be considered as a “bridge” while patients are waiting for transplants, which is the only definitive choice in most cases. 138 P. Feltracco, M.L. Brezzi, C. Ori References 1. 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