Anaesth Intens Care (1991), 19, 165-181

Review Liver Dysfunction in Critical Illness F. HAWKER* Intensive Care Unit, Royal Prince Alfred Hospital, Sydney, New South Wales SUMMARY Abnormal liver function commonly accompanies critical illness. Ischaemic hepatitis occurs with shock and is characterised by elevated plasma aminotransferase concentrations. 'ICV jaundice' occurs later in critical illness, especially after trauma and sepsis. The major biochemical abnormality is conjugated hyperbilirubinaemia. The clinical setting suggests that hepatic ischaemia and hepatotoxic actions ofinflammatory mediators are the major aetiological factors. Massive blood transfusion, effects of nutritional support and drug toxicity may contribute. Both the presence and degree of jaundice are associated with increased mortality in several nonhepatic diseases. It is proposed that Kupffer cell phagocytic depression associated with liver dysfunction permits systemic spread of endotoxin and inflammatory mediators and thus predisposes to multiple organ failure. Immunosuppression, metabolic abnormalities, impaired drug oxidation and myocardial depression may contribute to the poor prognosis. There is no specific treatment, but prompt resuscitation, definitive treatment of sepsis and meticulous supportive care will likely reduce the incidence and severity. Key Words: INTENSIVE CARE: liver dysfunction, critical illness, ICU jaundice

Abnormal liver function tests occur in up to 54% patients admitted to a general ICU.l Biochemical evidence of liver dysfunction has been associated with increased mortality in patients with Adult Respiratory Distress Syndrome CARDS), 2 after cardiopulmonary bypass surgery,3 with staphylococcal endocarditis,4 traumaS and intraabdominal sepsis. 5 ,6 Mortality rate has also been shown to increase progressively with increasing severity of liver dysfunction in multiple organ failure. 7 In trauma patients with hyperbilirubinaemia, plasma bilirubin concentrations have been shown to be higher in *F.F.A.R.C.S., F.F.A.R.A.C.S., Staff Specialist. Address for Reprints: Or. F. Hawker, Staff Specialist, Intensive Care Unit, Royal Prince Alfred Hospital, Missenden Road, Camperdown, N.S. W. 2050, Australia. Accepted for publication January 18, 1991 FOOTNOTE

This paper was the winning entry for the 1990 Bird ProductslTag Medical Prize for the best State of the Art review in the field of Intensive Care, held under the auspices of the Australian and New Zealand Intensive Care Society. Anaesthesia and Intensive Care. Vo!. 19, No. 2, May, /99/

patients who die than in those who ultimately survive. 8 Indeed even the initial description of postoperative jaundice as benign postoperative intrahepatic cholestasis 9 appears to be a misnomer, as survival of patients in this study was only 50%. In addition, prolonged intensive care support may be required. In a report of nine patients with jaundice associated with extrahepatic infection, median duration ofICU treatment was eight weeks. 10 Thus there is considerable evidence that both the occurrence and the degree of liver dysfunction in critical illness are associated with adverse consequences. The association of hyperbilirubinaemia with nonhepatic infection has been known since 1837 11 and characteristic hepatic histological changes in patients with major trauma were first described in 1946. 12 However many aspects ofliver dysfunction in primarily nonhepatic illness remain poorly understood. THE CLINICAL SYNDROME Two major syndromes of liver dysfunction in critical illness can be identified, ischaemic hepatitis and 'ICU jaundice'. The clinical features are summarised in Table 1.

166

F.

HAWKER TABLE

1

Clinical features of ischaemic hepatitis and 'lCU jaundice' Ischaemic hepatitis

'ICU jaundice'

Clinical setting

Shock

Pathogenesis

t Liver blood flow

Time of onset Liver function tests Bilirubin AST/ALT ALP/GGT Blood glucose Prothrombin time Bile salts Histology

within 24 hours

Sepsis Trauma Postoperative After severe shock Multiorgan failure t Liver blood flow Inflammatory mediators ? t Bilirubin load ? Nutritional factors ? Drugs Usually 1-2 weeks

Mortality Clinical course

> 50% Resolves if shock is reversed. Predisposes to 'ICU jaundice'

NormaUmoderate t > 1000 iu/l NormaUmoderate t Hypoglycaemia Prolonged Normal Centrilobular necrosis

150 -+ 800 I1moUl Normal/moderate t NormaUmoderate t Hyperglycaemia Normal Markedly elevated I1hepatic cholestasis Steatosis t Kupffer cells Hepatocyte necrosis + / >50% Associated with remote organ dysfunction, immunosuppression and abnormal intermediary and drug metabolism.

1. Ischaemic heptatitis

This syndrome occurs in association with severe marked metabolic acidosis and elevated plasma shock, and is due to a reduction in liver blood creatinine concentration flow. 13-1 5 Even though cardiac failure is commonly The diagnostic histological change is present,16-19 it remains widely held that hepatic centrilobular necrosis (Figure 2A). There is ischaemia, not congestion, is the major commonly marked congestion of the central vein mechanism. IS, 20 Further reductions in liver blood and distension of the sinusoids in the central area, flow due to the splanchnic vasoconstrictor actions neutrophil infiltration and nuclear changes. 17 of endogenous and therapeutically administered However, because this syndrome is readily catecholamines probably contribute. recognised clinically, liver biopsy is not necessary The hallmark of ischaemic hepatitis is elevation for diagnosis. of plasma aspartate aminotransferase (AST) and This condition is not a rarity. Twenty-nine cases alanine aminotransferase (ALT) concentrations. were identified in a six-month period at an These are commonly greater than 1000 IUn, but Australian teaching hospital 20 and ischaemic may rise to greater than 5000 and 3000 Iun hepatitis was found to be the commonest cause of respectively. Peak concentrations usually occur an AST activity greater than 1000 lUll in this within 24 hours of the ischaemic episode. 13 Plasma hospital population. Mortality approaches 60%20 bilirubin and alkaline phosphatase (ALP) and is due to shock or the underlying cause of the concentrations are normal or only moderately shock, not to hepatic failure. elevated. 13 Liver function tests in a typical patient In the quoted reports, it is implied that ischaemic are shown in Figure lA. Hepatomegaly occurs in hepatitis has no adverse consequences if the around 50% of cases. I4-16 Prolongation of the episode of shock can be reversed. However, as prothrombin time 1S and hypoglycaemia IS have discussed below, it is likely that hepatic ischaemia been documented. There are usually other predisposes to later development of 'Ieu manifestations of decompensated shock including jaundice'. Anaesthesia and Intensive Care, Vol. 19. No. 2. May. 1991

167

LIVER DYSFUNCTION IN CRITICAL ILLNESS

! ICU 50

Admission

50

~

45

!\

45

!\

40

!ICU Admission

40

/\

35

!:

35

30

30 : '

.

25

\-AST

, ',:

25

20

,.: ....

20

r···.

:

"

y'

:

'·.'.1 \~

.;\\

15

! AlT-\i

AST

\>:1

15

10

\!

\::;

!

10

5

....

.....

.....

,/~

.......

_----------'",1" "'-;;";;,.~,--:' ....... ::: .....•....• ,;; ........... -..

j/

Weeks

[/ o

Bilirubin

............l

................... 6

10

12

14

Days

FIGURE I.-A. Liver function tests in a patient with ischaemic hepatitis secondary to aortic stenosis. Plasma aminotransferase concentrations normalised with appropriate haemodynamic support in the ICU.

FIGURE I.-B. Liver function tests in a patient with 'ICU Jaundice' and multiple organ failure after trauma. Risk factors included profound shock, massive blood transfusion, bowel trauma, elevated intraabdominal pressure, recurrent sepsis and prolonged parenteral nutrition.

also develop with ongoing tissue damage in the absence of sepsis. In this context plasma bilirubin concentrations have been shown to be higher in 2. '/CU Jaundice' trauma patients receiving prolonged femoral Jaundice is a more common manifestation of traction than in those who had early fixation of liver dysfunction in critical illness than ischaemic femoral fractures. 31 An episode of shocks,27 and hepatitis, and has been documented in as many as massive blood transfusions also seem to be 44% patients admitted to the ICV because of severe predisposing factors. trauma or postoperative intra-abdominal sepsis. s 'ICV jaundice' represents the classic 'liver When compared with ischaemic hepatitis, 'ICV failure' of the multiple organ failure syndrome. On jaundice' develops later in the course of critical examination, the patient is jaundiced and illness, typically one to two weeks after the hepatomegaly is present in around 50% adults and initiating event. However it has been described as 60% children. 32 There are usually no signs of portal the presenting feature in both infants21 and adults 28 hypertension which are present in end stage liver with sepsis, and as early as one to two days disease, or itching which is prominent in chronic postoperatively.9,22 cholestatic syndromes. There may be evidence of Sepsis appears to be the most common sepsis and concurrent failure of other organ precipitant. 10,23·28 The reported incidence of systems. Signs and symptoms of liver dysfunction jaundice in patients with bacteraemia varies widely are often overshadowed by those of the underlying from 0.9 to 54%,28-30 and likely depends on severity disease. of illness rather than the site of infection or the The usual haemodynamic profile is that typically infecting organism. After trauma, sepsis is associated with both sepsis and liver disease; the diagnosed more commonly in jaundiced than cardiac output (CO) is high, the systemic vascular nonjaundiced patients,S and the bilirubin peak has resistance is low, oxygen consumption is increased, been observed to coincide with the diagnosis of but oxygen extraction in the peripheral tissues is infection.27 However, hyperbilirubinaemia may decreased. 33 Anaesthesia and Intensive Care, Vo!. 19, No. 1, May, 1991

168

F.

HAWKER

FIGURE2.-Hepatic histology in critical illness. A. Ischaemic hepatitis. There is hepatocellular necrosis surrounding the central vein (CV). Normal hepatocytes are present towards the periphery of the lobule. B. Steatosis. Arrows represent fatty infiltration. C. and D. Intrahepatic cholestasis. Arrows represent ductular and canalicular cholestasis C (low power) and intracellular cholestasis D (high power).

Biochemical tests show a progressive rise in plasma bilirubin concentration which usually peaks between 150-300 Ilmolll but may exceed 800 Ilmolll.lO,32 Most (70-80%) of the bilirubin is conjugated. 8,1O,23,26,32 If there has been a concurrent episode of hepatic ischaemia, plasma aminotransferase concentrations may be signifiqmtly increased. However, they typically are normal or only minimally elevated. 22 ,32 Plasma ALP concentrations usually range from normal to several times normal. 22,32 They are higher than in similar patients without jaundice5 but less than those usual with extrahepatic biliary obstruction. The peak in plasma ALP concentration usually follows the bilirubin peak. 8,1O There have been several reports of marked elevations in ALP activity with systemic infection with only minimal elevations in bilirubin. 34,35 Plasma concentrations of gamma glutamyl transpeptidase (GGT) usually rise at about the same time as the bilirubin peak to several times the normal value. 36 Liver function

tests in a patient with 'Ieu jaundice' are shown in Figure IB. Hyperglycaemia is usual. Subnormal plasma albumin concentrations are commonly reported, but levels are probably no lower than in nonjaundiced patients with similar underlying disease. 32 The prothrombin time may be marginally prolonged,22 but major coagulation abnormalities usually only occur if there is significant disseminated intravascular coagulation secondary to the underlying disease. There are increased plasma levels of bile saltS.I,1O Histological findings in 'Ieu jaundice' are shown in Figure 2 (BeD). The predominant finding is intrahepatic cholestatis, with dilated canaliculi containing bile casts, particles of bile pigment in the cytoplasm of the adjacent hepatocytes, and bile in Kupffer cells near the centres of the lobules. However intrahepatic cholestasis is not observed in all patients. 5,35 Diffuse steatosis and Kupffer cell hyperplasia may be prominent features. 35 The sinusoids are often narrowed due to swelling of Anaesthesia and Intensive Care. Vol. 19, No. 2, May, 1991

LIVER DYSFUNCTION IN CRITICAL ILLNESS Hormone Activation Haemodynamic Changes Lungs (ARDS) Kidneys (ARF) Brain (encephalopathy) Immune Suppression

FIGURE 3.-Schematic representation of Kupffer cell activation by gut-derived endotoxin. Endotoxin and inflammatory mediators may both influence the function of adjacent hepatocytes and 'spillover' into the systemic circulation resulting in remote organ failure.

hepatocytes in centrilobular zones. 26 Focal hepatocyte necrosis may be absent or prominent, but is reported more frequently after trauma8,36 and therefore may be an expression of preceding shock. The biochemical abnormalities responsible for the observed impairment of bilirubin metabolism are not known with certainty. Conjugated bilirubin is normally rapidly excreted from hepatocytes,37 and it is suggested that in this syndrome transport of conjugated bilirubin out of hepatocytes is inhibited. 38 These changes in bilirubin metabolism result in jaundice which is the most obvious clinical manifestation of this syndrome. However concurrent abnormalities in the function of remote organs, immune competence and intermediary and drug metabolism may be present. PATHOGENESIS OF 'ICU JAUNDICE' The clinical setting suggests that hepatic ischaemia and the hepatotoxic actions of mediators of sepsis and inflammation are together or independently the major factors in the pathogenesis of 'ICU jaundice'. Massive blood transfusion and effects of nutritional support and drugs may contribute. 1. Hepatic ischaemia Reduced liver blood flow is accepted to be the cause of ischaemic hepatitis. There is also evidence that hepatic ischaemia may be a major aetiologic Anaesthesia and Intensive Care, Vo!. 19, No. 2, May, 1991

169

factor for jaundice associated with trauma, sepsis and multiple organ failure. Animal studies show that decreases in hepatic blood flow occur in traumatised rats and are accompanied by parallel reductions in bile flow. 39 After trauma, Te Boekhorst and co-workers have reported that jaundice is more common when patients are shocked on presentationS and other reports have documented early shock in the majority of cases. 8,26,27 Moreover hepatic blood flow has been found to be reduced twelve hours after injury in patients with multiple trauma and, in this study, the degree of hepatic hypoperfusion correlated with the subsequent increase in serum bilirubin.40 In septic animal models, hepatic ischaemia has been shown to predate abnormalities of metabolism 41 and hepatic mitochondrial function. 42 Liver blood flow in critical illness Hepatic parenchymal cells are the most richly perfused of any organ. In health, total liver blood flow is 1500 ml/min. Approximately one quarter of this is supplied by the hepatic artery and the remainder by the portal vein. 43 The factors controlling hepatic blood flow in health and in chronic liver disease have been reviewed extensively.43-46 Accurate data on hepatic blood flow in patients with acute illness are lacking because the portal vein is relatively inaccessible for physiological measurements. In addition, many experimental studies have failed to control for differences in cardiac output and systemic blood pressure. However, some generalisations can be made. Severe haemorrhage results in a decrease in total hepatic blood flow 44 ,45,47 due to diminished mesenteric and portal venous flow. Hepatic arterial perfusion appears to be well maintained until the systemic arterial pressure drops below 50 mmHg.45 As already discussed, total hepatic blood flow is also reduced after trauma in animal studies 39 and in man, even with aggressive resuscitation. 4o Although it frequently coexists, shock does not seem to be necessary for this reduction in liver blood flow with trauma, as soft tissue injury has been observed to result in hepatic ischaemia in an animal model. 48 With sepsis, animal experiments suggest that liver blood flow is well maintained and even increased in hyperdynamic sepsis but decreased in late sepsis 49 and with septic shock. 50 Total liver blood flow is decreased with elevated intra-abdominal pressure. Animal studies show pressures of 25 to 40 cm H 20 result in 70-90% reductions in portal venous flow and are associated with total cessation of bile flow. 51 Effects of feu therapy on liver blood flow Total liver blood flow is decreased by

170

F.

HAWKER

intermittent positive pressure ventilation (IPPY) and positive end-expiratory pressure (PEEP). 52-54 This is largely due to a decrease in cardiac output (CO) due to raised intrathoracic pressure 52 and can be restored by volume expansion. 55 Bilirubin excretory capacity (assessed by bromosulphthalein (BSP) excretion) is also reduced with IPPY and PEEP. 56 The practical significance of this experimental observation is unclear. Although 10hnson and co-workers observed a 77% incidence of hyperbilirubinaemia in patients ventilated with IPPY and PEEP, 56 a retrospective analysis of trauma patients showed no relationship between the degree of jaundice and the use or duration of PEEP. 8 Reduced hepatic perfusion is also observed with hypocapnia.57 The effects of inotropic agents on hepatic blood flow are determined by the innervation and adrenoreceptor populations of the hepatic vasculature. The hepatic artery is supplied by sympathetic vasoconstrictor nerves, and has both a-adrenergic constrictor, ~2-dilator and dopaminergic (DA) dilator receptors. The portal vein has only a-adrenergic constrictor receptors, although portal blood flow may be increased by the dilator actions of DA agonists on the mesenteric vasculature. 58 Thus noradrenaline and high doses' of adrenaline (greater than 25 Ilg/kg/min) reduce total liver blood flow by up to 50% in animal models despite increases in systemic arterial pressure. 58 On the other hand, low dose dopamine infusion increases mesenteric blood flow in animal models (41lg/kg/min)59 and effective hepatic blood flow in patients recovering from open heart surgery (6 llg/kg/min).60 Changes in blood pressure and CO with vasoactive drugs will have effects on liver perfusion. For example, dobutamine increases liver blood flow as a passive effect of increasing CO.61 2. Actions of endotoxin and inflammatory mediators Microorganisms are normally present in large quantities in the human gut. 62 Bacterial counts in the stomach increase with gastric alkalinisation,63 and . paralytic ileus and broad spectrum antibiotics 64 predispose to bacterial overgrowth throughout the entire gastrointestinal tract. Bacteria and endotoxin derived from these microorganisms may translocate across the bowel wall in circumstances found in critical illness. Bacterial translocation has been documented in animal models of altered bowel flora,65 acute bowel ischaemia,66 bowel manipulation,66 haemorrhagic shock,67 bums,68 endotoxaemia,69 infusion of vasoactive substances,70 immunosuppression,71 total parenteral nutrition 72 and with some commercial enteral feeding solutions lacking fibre. 73 Although there is some evidence for

lymphatic uptake,62 it appears most translocated endotoxins and bacteria are transported in the portal vein to the liver. Liver disease itself also seems to predispose to bacterial translocation and portal endotoxaemia and bacteraemia. Deitch and co-workers observed bacterial translocation in an animal model of obstructive jaundice,74 and 50% patients with obstructive jaundice have been shown to have portal endotoxaemia.1 5-77 Endotoxin, bacteria and particulate matter in the portal circulation are phagocytosed by the fixed hepatic macrophages (Kupffer cells) which line the sinusoidal vascular network. The phagocytic capacity of Kupffer cells is depressed with hepatic ischaemia, hypoxaemia, large loads of phagocytosable material and with fibronectin deficiency.78 One or more of these factors are frequently present in critically ill patients. In addition liver disease may further impair Kupffer cell function. Depressed Kupffer cell phagocytosis has been observed in rats with biliary obstruction, 79 baboons with hepatic ischaemic injury80 and in patients with cholestasis,81 fulminant hepatic failure,82 acute alcoholic hepatitis and chronic liver disease. 83 In this setting, impairment of Kupffer cell phagocytic function may permit gut-derived endotoxin and bacteria to exert effects on adjacent hepatocytes (Figure 3). Furthermore, when exposed to endotoxin, Kupffer cells become activated and release a variety of mediators, including interleukin-l, 84 tumour necrosis factor (TNF),85 various metabolites of arachidonic acid,86 including the leukotrienes,87 and toxic oxygen radicals. Hepatocytes may thus become exposed to the toxic effects of endotoxin and these inflammatory mediators. The actions of these substances can explain many of the functional and histological changes of hepatocytes in 'ICU jaundice'. Endotoxin induces· cholestasis and its administration results in a dose related decrease in bile flow and BSP excretion in perfused rat liver88 and in human volunteers. 89 Reduced BSP excretion is also observed in patients with jaundice associated with sepsis. lO Endotoxin, interleukin-l and TNF have specific effects on hepatocyte metabolism which will be discussed later in this review. Cytochrome-P450 drug metabolism is depressed by endotoxin administration, although this effect is probably mediated by interleukin-1. 9o The leukotrienes contribute to cholestasis and potentiate the necrotic effects of hypoxia and endotoxin on hepatocytes. 87 It is likely that many other mediators are involved. Thus, many features of liver dysfunction in critical illness may be explained by the actions of endotoxin derived from the gut or a septic focus Anaesthesia and Intensive Care. Vol. 19. No. 2, May, 1991

171

LIVER DYSFUNCTION IN CRITICAL ILLNESS TABLE

2

Characteristics of liver injury due to therapeutic drugs

Drug and class Anaesthetic Halothane Psychotropic Chlorpromazine Haloperidol Diazepam Anticonvulsant Phenytoin Na valproate Carbemazepine Anti-inflammatory NSAIDs Salicylates Paracetamol (therapy) Allopurinol Sulphasalazine Antibiotic Tetracyclines Erythromycin estolate Synth penicillins (esp flucloxacillin) Cephalosporins Aminoglycosides Metronidazole Fusidic Acid Isoniazid and rifampicin Ketoconazole Flucytosine Antihypertensive Verapamil/nifedipine a-methyldopa Hydralazine Captopril Other Morphine Frusemide Theophylline Warfarin Heparin Streptokinase Cimetidine Ranitidine Amiodarone

Liver injury

Jaundice (% patients)

Raised AST/ALT (% patients)

Massive hepatic necrosis

HlC

0.0001

+++

1/10,000·

C mixed mixed

0.1-2

50

+ +

+ +

+

H/C H/C

+ ++ +

+++

•

+

+

+ + + + +

+ +++ ++ ++ +

+ +

mixed mixed

H/C H/C H/C H/C steatosis C mixed C mixed ? ? C

•

+

I

+

+

0-20

+

10-20 5-10 10

+ +

+

+

+ + +

30-50

+ + + +

>5

+ +

+

C enzyme effect

+

H/C

+ +

22-38

++

10-55

H/C H/C

Percentages from combined reports. 183,184 NSAIDs (nonsteroidal anti-inflammatory drugs, e.g. indomethacin). H/C (hepatocellular), C (cholestatic). - Not reported, + reported but rare, + + moderate propensity, ·Recognised cause of hepatic failure with high mortality. and the release of inflammatory mediators from endotoxin-triggered Kupffer cells. In particular, liver dysfunction itself may promote further hepatocyte injury because of the association with Anaesthesia and Intensive Care. Vol. 19, No. 2, May, 1991

• •

+ + + +

?

mixed

• •

++

H/C H/C

?

•

10-40

+

++ ++ +

H/C

•

1-2

H/C H/C H/C

mixed mixed

11-44

80

+ +

+++

+

•

common.

both increased bactenal translocation and Kupffer cell phagocytic depression. However, as jaundice occurs with gram positive as well as gram negative infections,4,23,25,28,32

F. HAWKER

172

3 Metabolic changes in sepsis and multiple organ failure TABLE

Metabolic rate Respiratory quotient Gluconeogenesis Lactate production Lipolysis Triglyceride clearance Nitrogen balance Hepatic protein synthesis Catabolism Jaundice AST/ALT

Early

Late

++

+ +t > 1.0 + +t ++ Ht t Ht +H +++ +++ +/-

0.8

+ + + + t ++ ++ +/-

bacterial products other than endotoxin have to be implicated in liver dysfunction if this hypothesis is true. The effects of gram positive organisms on aspects of liver function have not been widely studied, although Staphylococcus aureus bacteraemia and a product of S. aureus, lipoteichnoic acid, have been shown to inhibit BSP excretion in a manner similar to that of endotoxin. 4 3. Blood Transfusion Jaundice occurs after massive blood transfusion, especially when there is haemorrhage into body tissues. 91 Te Boekhorst and co-workers noted patients who developed jaundice after trauma had higher blood transfusion requirements than those without jaundice. 5 However, in other studies of patients with sepsis lO,25,28 and trauma,8 blood transfusion could not be implicated in the development of jaundice. Moreover, in 'ICV jaundice' plasma bilirubin is largely conjugated, whereas that derived from haemolytic transfusion reactions, free haemoglobin in old blood, destruction of nonviable transfused blood cells and resorption of haematomata, is initially unconjugated. It therefore appears that the capacity for clearing and conjugation of bilirubin is well maintained. As previously stated, transport of conjugated bilirubin out ofhepatocytes is impaired in 'ICV jaundice' although the mediators and biochemical pathways are unknown. Thus, massive blood transfusion will increase the load of bilirubin presented to this depressed transport mechanism and may be a promoting factor in the development of jaundice; but it is not, alone, the cause of the underlying hepatic abnormality. 4. Parenteral Nutrition Abnormal liver function tests have been observed in 68-93% of patients receiving total parenteral nutrition (TPN) for two weeks or

longer. 92 ,93 Because of the common requirement for TPN in patients at risk for 'ICV jaundice', it is difficult to distinguish TPN-induced changes from those of the underlying disease. Biochemically, there is an increase in ALT to around three times the initial levels, a twofold increase in ALP and variable changes in bilirubin in adult patients receiving TPN but with no other risk factors for liver dysfunction. 92 -96 Cholestatic jaundice occurs with TPN in infants97,98 and is related to the duration of therapy.98 Steatosis is the major histologic abnormality seen in animals 99,100 and patients92 fed parenterally, and occurs more commonly with hypercaloric, glucose-based TPN mixtures. Fatty infiltration of the liver is also a frequent finding in 'ICV jaundice'. Therefore the contribution of nutritional factors in general and TPN in particular cannot be ignored as promoting factors in the pathogenesis. No study of the incidence of jaundice in sepsis, trauma or multiple organ failure has reported the nutritional regimen used. 5. Drugs It is estimated that 2% of jaundiced patients admitted to hospitals have drug-induced liver disease. 101 Some drugs may cause a cholestatic jaundice similar biochemically to 'ICV jaundice', with elevations of plasma bilirubin, ALP and GGT concentrations. This group includes flucloxacillin,102 chlorpromazine l03 and erythromycin estolate (Table 2). Massive hepatic necrosis occurs occasionally as a result of drug administration (Table 2). Anticonvulsant drugs (including sodium valproate, phenytoin and carbemazepine) have been particularly implicated, although disturbances in hepatic oxygen delivery may contribute when hepatic necrosis follows status epilepticus. 104 Massive necrosis due to drugs is initially biochemically similar to ischaemic hepatitis but is usually readily distinguishable by the clinical setting. Both of these types of druginduced hepatic injury are predominantly idiosyncratic and therefore dose-independent. Many drugs used in the ICV have been reported to have hepatotoxic potential (Table 2). However, the evidence does not suggest that drug-induced cholestasis is a major aetiologic mechanism in 'ICV jaundice', although this possibility should be considered in each case. In reports of patients with jaundice associated with sepsis 5,28 and trauma 5,8,26 no clear relationship between anaesthetic agent or drug administration and the occurrence of jaundice has been elicited. ADVERSE EFFECTS OF 'ICV JAUNDICE' Many reports document a return to normal liver function in patients who survive 'ICV jaundice. IO,26,27,32 However, in patients who die, it Anaesthesia and Intensive Care, Vo!. 19, No. 2, May, 1991

LIVER DYSFUNCTION IN CRITICAL ILLNESS

remains unclear whether the fatal outcome is determined solely by the underlying disease, or whether liver dysfunction itself influences prognosis. In this section several adverse consequences of hepatic dysfunction will be described. However, because of the paucity of clinical studies in patients with 'ICV jaundice', many of the arguments are by necessity inferred from animal models and patients with primary liver disease and obstructive jaundice. I. The role of liver dysfunction in initiating or aggravating multiple organ failure There is strong circumstantial evidence that liver dysfunction predisposes to failure of other organ systems and ultimately to multiple organ failure. Indeed it is claimed that changes in hepatocyte metabolism are necessary for the definition of mUltiple organ failure. 105 Matuschak and Rinaldo have extensively reviewed the contribution ofliver dysfunction in promoting or exacerbating ARDS.l06 The same authors reported a 79% incidence of ARDS in patients with end-stage liver disease admitted to an ICV while awaiting liver transplantation. 107 Significant renal dysfunction occurs in up to 67% patients with jaundice associated with trauma and sepsis. 5,8,1O,23,26 Encephalopathy is a common accompaniment of both multiple organ failure l08 and endstage primary liver disease. Even the incidence of surgical wound breakdown is higher in jaundiced than in nonjaundiced patients. 109 The role of Kupffer cells in clearing portal venous blood of translocated microorganisms and endotoxin has been described in the previous section. Similarly, the factors depressing the phagocytic capacity of Kupffer cells, particularly liver disease, have been discussed. Thus in the setting of liver dysfunction in critical illness, gutderived bacteria and endotoxin and the inflammatory mediators generated during Kupffer cell activation, may 'spillover' into the systemic circulation in addition to affecting hepatocyte function. Endotoxin, TNF, the interleukins, metabolites of arachidonic acid and other inflammatory mediators have well documented systemic effects which may result in failure or dysfunction of other organ systems (Figure 3). Some support for a role of liver dysfunction in promoting multiple organ failure by this mechanism can be obtained from studies of patients with primary liver diseases. For example, in patients with fulminant hepatic failure, the degree of Kupffer cell phagocytic depression is related to the presence of encephalopathy and renal failure. 82 Endotoxaemia is common in patients with primary liver disease and is associated with remote organ dysfunction. Documentation of Anaesthesia and Intensive Care, Vo!. 19, No. 2, May, 1991

173

circulating endotoxin is associated with postoperative renal impairment 76 ,77 and coagulopathyllo in patients with obstructive jaundice, renal failure I I 1.112 and haemorrhagic gastritis l12 in cirrhosis, renal impairment and coagulopathy in fulminant hepatic failure l13 and encephalopathy in children with Reye's syndrome. 114 Endotoxaemia occurs during the anhepatic phase of liver transplantation, liS when Kupffer cells are obviously absent. In this setting plasma endotoxin levels have been shown to correlate with postoperative thrombocytopaenia, ventilator dependency and mortality. I 15 Thus, it appears the liver has a protective role to the whole organism. The failure of its phagocytic function in critical illness may potentiate the adverse effects of septic mediators on other organs. In this context, the gastrointestinal tract has been termed the motor of multiple organ failure. 116 2. Immunosuppression Acquired impairment of cell-mediated immunity is common in critically ill patients I 17 and is associated with an increased incidence of infection, septicaemia and death related to infection. I 18 There is evidence that hepatic dysfunction may contribute to this immunosuppression. Animal studies show that bile duct ligation results in suppression of cell-mediated immunity1l9,120 and cardiac allograft survival is prolonged in rats with bile duct ligation. 121 This immune dysfunction associated with obstructive jaundice can be partially reversed by biliary drainage. 122 Similar abnormalities in ceU-mediated immunity have been observed in children with intrahepatic cholestasis,123 More specifically, Iymphocytes from patients with various primary liver diseases react poorly when stimulated by mitogens l24-126 and sera from similar patients depress the function of lymphocytes from normal subjects. m ,128 This latter observation suggests a serum inhibitory factor is present in patients with liver disease. In this regard bile salts have been shown to inhibit the function of normal lymphocytes in a dose-related fashion l29 ,13o in concentrations as low as 75 Jlmolll. 129 Serum bile salt concentrations of this magnitude have been documented in patients with 'ICV jaundice' .1,10 However, other mechanisms for the observed immunosuppression have also been proposed. Border has hypothesised that the blunted immune response in sepsis may result from progressive activation of tissue macrophages, especially Kupffer cells. 131 Immunosuppression occurs in an animal model of Kupffer cell activation l32 and can be attentuated by Kupffer cell blockade. 133 However the improvement in systemic immunity

174

F.

HAWKER

with Kupffer cell blockade in this latter animal model did not result in improved survival. 133 This suggests that although activated Kupffer cells may exert immunosuppressive effects, their primary role as phagocytic cells is more important in critical illness.

3. The role of liver dysfunction in promoting changes in intermediary metabolism in critical illness Significant -changes in metabolism occur in critical illness. Cerra has divided these into early changes (occurring postoperatively, after trauma and with the onset of sepsis), and late changes representing the development of 'hepatic failure' in multiple organ failure. 134 These metabolic abnormalities have been reviewed extensively,l34136 and are outlined in Table 3. The early changes may normalise if the underlying sepsis, hypoperfusion or focus of necrotic tissue can be eliminated. However the acute malnutrition associated with multiple organ failure cannot be reversed by exogenous nutritional support 137 and is associated with poor wound healing,138,139 impaired resistance to infection 140 and respiratory dysfunction. 141 Cerra has termed this 'the hypermetabolism organ failure complex'135 and has attributed over 90% of surgical ICU deaths to this cause. 1"35 Although metabolic changes in critical illness are mediated in part by the central nervous and endocrine systems,142 the synthetic function of hepatocytes is directly influenced by ischaemia and actions of endotoxin and inflammatory mediators. Hepatic protein synthesis is impaired during and after hepatic ischaemic injury,143,144 but can be restored by increasing hepatic blood flow. In a rat model of liver ischaemia, low-dose dopamine administration (S l1g/kg/min) has been shown to increase liver blood flow and return protein synthetic rate towards normal values. 145 Kupffer cells appear to play a major role in modulating hepatocyte function, and both stimulate and inhibit hepatocyte protein synthesis depending on the presence of inflammatory stimuli. 146 Endotoxin, 147 interleukin-1 148 and TNF149 cause inhibition of albumin synthesis and increased synthesis of acute phase proteins by hepatocytes. Changes in plasma concentrations of these proteins are characteristic findings in acute illness. Apart from these effects on protein synthesis, endotoxin has been shown to increase metabolic rate in guinea pigs when injected into the portal vein, but not when injected intraperitoneally.150 This suggests that this common finding in acute illness is mediated at least in part by an effect of endotoxin on hepatocyte function.

4. Drug metabolism Most lipid-soluble drugs and steroids are metabolised in hepatic microsomes by the mixed function oxidase system, a chain of enzymes which includes cytochrome P-4S0. These enzymes are found chiefly in centrilobuar areas,45 and it is therefore likely their activity is reduced by hepatic hypoxia and ischaemia. Microsomal enzyme activity has been shown to be reduced in experimental models of trauma,151 endotoxin administration 152, 153 and severe burns. 154 ,155 Impaired drug handling has also been observed in patients with trauma 156 and burns,m although in the clinical setting, changes in hepatic blood flow, protein binding and drug excretion may occur in addition to alterations in drug metabolising capacity. Drug metabolism in 'ICU jaundice' has not been widely investigated. The only published study shows caffeine clearance to be reduced in a proportion of patients with jaundice associated with sepsis,1O although this measure may not accurately assess hepatic microsomal enzyme activity. However, cytochrome P-4S0 activity is depressed in liver biopsy specimens from patients with chronic cholestatic liver disease. 158 Piperacillin elimination rate has been observed to be reduced in proportion to the plasma bilirubin concentration in critically ill surgical patients. 159 Thus it appears likely that hepatic drug metabolism is impaired in patients with 'ICU jaundice'. This may have considerable practical importance as drugs metabolised by hepatic microsomal enzymes are commonly used in the ICU (barbiturates, benzodiazepines, narcotic analgesics, theophylline and others). However data are lacking and no recommendations regarding adjustment of drug dosage can be made at present. S. The jaundiced heart There is some evidence that jaundice may impair cardiac function. It has long been known that patients with obstructive jaundice may have bradycardia 160 and animal studies show that jaundice is associated with a blunted inotropic response to adrenergic stimulation. 161 Dogs made cholestatic by choledochocaval anastomosis have impairment of left ventricular function as measured by systolic time intervals and maximum dp/dt. 162 The authors termed this observation the 'jaundiced heart'. As cardiac function was not improved by oaubain in this study, they further suggested that the observed myocardial depression might be due to competitive antagonism at the digitalis membrane receptor, Na + K + ATPase, by some endogenous substance. In this regard both bile salts and a substance found in the plasma of Anaesthesia and Intensive Care, Vol. 19, No. 2, May, 1991

LIVER DYSFUNCTION IN CRITICAL ILLNESS

ICV patients with liver dysfunction l are structurally similar to digoxin. Both have been observed to inhibit Na+ K+ ATPase. 163 It is not clear whether these observations have significance for the patient with 'ICV jaundice'. IMPLICATIONS FOR TREATMENT OF THE PATIENT WITH 'ICV JAUNDICE' The principles of management of the patient with or at risk of 'ICV jaundice' are primarily those of prompt resuscitation, definitive treatment of sepsis and intensive support. There is no specific treatment at present. However, therapeutic advances are likely in the future if inflammatory mediators can be manipulated or controlled. Extrahepatic biliary obstruction should be excluded by ultrasonography or CT scan. Drug therapy should be rationalised, and consideration given to changing drugs with a high incidence of hepatic complications to those with less hepatotoxic potential (Table 2). Prompt resuscitation i. Blood volume replacement. As discussed, shock has the potential to adversely affect hepatic function by several mechanisms. Bowel ischaemia is associated with translocation of bacteria and endotoxin across the gut wall,66 and hypoxia and hepatic ischaemia both predispose to hepatocyte necrosisl 7 and impair Kupffer cell phagocytic function. 78 Thus prompt and complete replacement of circulating blood volume to restore splanchnic and hepatic perfusion may protect against development of liver dysfunction later in the illness. ii. Early surgery Definitive treatment of haemorrhage, for example, by early surgery or embolisation, will reduce blood transfusion requirements, facilitate blood volume replacement and in some circumstances reduce elevated intra-abdominal pressure. In patients with trauma, resuscitation should include stabilisation of skeletal injuries. Early fixation of fractures reduces the incidence and severity of jaundice occurring later in the illness. 31 iii. Choice of inotropes. After adequate blood volume replacement, reversal oflow cardiac output states with inotropic agents has been shown to reduce markers of ischaemic hepatitis. 61 Although vasoconstrictor inotropes (high dose adrenaline and noradrenaline) reduce liver blood flow, their use is indicated if cardiac output cannot be maintained by other means. Increased gut and liver blood flow occur with low dose dopamine infusions. In this regard, dopamine at 3-5 Ilglkglmin might be described as 'liver dose dopamine', rather than the more usual Anaesthesia and Intensive Care. Vol. 19, No. 2. May, 1991

175

'renal dose dopamine'. However, benefits to liver function tests, other markers of liver function or outcome have not been proven for low-dose dopamine therapy.

Definitive treatment of sepsis The close association of 'ICV jaundice' with uncontrolled infection has been described. Many reports document an improvement in liver function when sepsis is adequately treated. 4,10,27,29.30 Septic foci should be drained aggressively,164 and appropriate antibiotic therapy instituted. Measures which might reduce the incidence of ICV-acquired infection have obvious importance. Selective decontamination of the digestive tract (SDD). Because of the likely role of gut-deri ved bacteria and endotoxin in the pathogenesis of 'ICV jaundice', SDD has theoretical advantages in its prevention and treatment. Benefits to outcome have been shown for patients admitted to the ICV with trauma, but not for those admitted with other diagnoses. 165 The effects of this prophylactic regimen on aspects ofliver function have not been investigated. Fibronectin replacement Optimum Kupffer cell phagocytic function depends on adequate circulating levels of the opsonising glycoprotein, fibronectin. 166 Fibronectin levels are low in critical illness but can be replaced by infusions of fresh frozen plasma, cryoprecipitate or purified fibronectin. 166 However, fibronectin replacement does not improve survival in patients with trauma l67 or abdominal sepsis l68 and its role in supporting liver function in critically ill patients must therefore be questioned. Nutritional therapy The advantages of specific nutritional support in sepsis and multiple organ failure have been expounded by Cerra,137 although no particular nutritional regimen has been shown to improve survival in these situations. The arguments for nutritional regimens which avoid excess calories and provide increased amounts of amino acids appear to be relevant to patients with 'ICV jaundice'. In particular, the use offat as 25-40% of total nonprotein calories has been shown paradoxically to reduce the incidence of fatty liver, 169 and to preserve microsomal enzyme function in animals 170 and in patients, l7l when compared with regimens using glucose alone. Administration of 25% nonprotein calories as 'Intralipid' does not impair Kupffer cell phagocytic function in the rat. 172

F.

176

HAWKER

i. Branched chain amino acids The use of modified amino acid formulae which contain more branched chain amino acids and less gluconeogenic amino acids (alanine and glycine) remains controversial. These solutions decrease endogenous protein breakdown and seem to increase serum levels of albumin and other hepatically derived proteins in patients with posttraumatic sepsis 173 without improving survival. In cirrhotic patients, a recent meta-analysis has suggested they improve encephalopathy and probably reduce mortality. 174 Their use in patients with 'ICU jaundice' has not been investigated. ii. Glutamine Glutamine is a nonessential amino acid, which appears to be necessary for the integrity of the gut mucosal barrier. 175 Glutamine supplementation protects against bacterial translocation seen with standard TPN in an animal model. 176 Glutamine peptide supplements have been shown to improve nitrogen balance in elective surgical patients. 177 Benefits of glutamine supplementation to critically ill patients have not been tested. iii. Enteral feeding Enteral feeding has several potential advantages ov.er TPN in patients with 'ICU jaundice'. When compared with TPN, enteral feeding is associated with fewer septic complications in trauma patients, 178 and at least one study in a septic animal model has shown improved survival. 179 Small intestinal mucosal weight is better maintained in rats fed enterallyl80,181 and bacterial translocation rate is reduced.72 In infants, cholestasis resolves when enteral feeding is introduced96 ,98 and even healthy subjects show a fall in serum bilirubin levels with continuous enteral feeding. 182 CONCLUSION

Liver dysfunction in critical illness is more insidious in onset and less immediately lifethreatening than respiratory and renal failure in this setting. Whereas these latter organ failures have been studied extensively, many aspects of liver dysfunction in the ICU remain unexplored, despite the relatively common occurrence and poor prognosis. At the present time no specific therapy is available. However, the evidence presented suggests that meticulous intensive care treatment may reduce both the incidence and adverse effects. REFERENCES

I. Howarth DM, Sampson DC, Hawker FH, Young A. Digoxin-like immunoreactive substances in the plasma oflntensive Care Unit patients: relationship to organ dysfunction. Anaesth Intens Care 1990; 18:45-52. 2. Schwartz DB, Bone RC, Balk RA, Szidon JP. Hepatic dysfunction in the adult respiratory

distress syndrome. Chest 1989; 95:871-875. 3. Collins JD, Bassendine MF, Ferner R et al. Incidence and prognostic importance of jaundice after cardiopulmonary bypass surgery. Lancet 1983; i:1119-1123. 4. Quale JM, Mandel U, Bergasa NV, Straus EW. Clinical significance and pathogenesis of hyperbilirubinemia associated with staphylococcus aureus septicemia. Am J Med 1988; 85:615-618. 5. Te Boekhorst T, Urlus M, Doesburg W, Yap SH, Goris RJA. Etiologic factors of jaundice in severely ill patients. J Hepatol 1988; 7:111-117. 6. Pine RW, Wertz MJ, Lennard E, Dellinger EP, Carrico J, Minshew BH. Determinants of organ malfunction or death in patients with intraabdominal sepsis. Arch Surg 1983; 118:242-249. 7. Marshall JC, Christou NV, Horn R, Meakins JL. The microbiology of multiple organ failure. The proximal gastrointestinal tract as an occult reservoir of pathogens. Arch Surg 1988; 123:309-314. 8. Sarfeh IJ, Balint lA. The clinical significance of hyperbilirubinemia following trauma. J Trauma 1978; 18:58-62. 9. Schmid M, Hefti ML, Gattiker R, Kistler HJ, Senning, A. Benign postoperative intrahepatic cholestasis. N Engl Med J 1965; 272:545-550. 10. Pirovino M, Meister F, Rubli E, Karlaganis G. Preserved cytosolic and synthetic liver function in jaundice of severe extrahepatic infection. Gastroenterology 1989; 96: 1589-1595. 11. Garvin IP. Remarks on pneumonia biliosa. S Med and Surg 1837; 1:536:544. 12. Bywaters EGL. Anatomical changes in the liver after trauma. Clin Sci 1946; 6: 19-41. 13. Gibson PR, Dudley FJ. Ischemic hepatitis: clinical features, diagnosis and prognosis. Aust NZ J Med 1984; 14:822-825. 14. Bynum TE, Boitnott JK, Maddrey Wc. Ischaemic hepatitis. Dig Dis Sci 1979; 24:129-135. 15. Garland JS, Werlin SL, Rice TB. Ischemic hepatitis in children: diagnosis and clinical course. Crit Care Med 1988; 16:1209-1212. 16. Cohen JA, Kaplan MM. Left-sided heart failure presenting as hepatitis. Gastroenterology 1978; 74:583-587. 17. EllenbergM, OssermanKE. The role of shock in the production of central liver cell necrosis. Am J Med 1951; 2:170-178. 18. Logan RG, Mowry FM, Judge RD. Cardiac failure simulating viral hepatitis. Ann Int Med 1962; 56:784-788. 19. Clarke WTW. Centrilobular hepatic necrosis following cardiac infarction. Am J Pathol 1949; 26:249-253. 20. Anonymous (editorial). Ischaemic hepatitis. Lancet 1985; i:1019-1020. 21. Arthur AB, Wilson BDR. Urinary infection presenting with jaundice. Br Med J 1967; 1:539-540. 22. Miller DF, Irvine RW. Jaundice in acute appendicitis. Lancet 1969; i:321-323. 23. Miller DJ, Keeton GR, Webber BL, Saunders SJ. Jaundice in severe bacterial infection. Anaesthesia and Intensive Care, Vol. 19, No. 2, May, 1991

LIVER DYSFUNCTION IN CRITICAL ILLNESS Gastroenterology 1976; 71:94-97. 24. E1ey A, Hargreaves T, Lambert HP. Jaundice in severe infections. Br Med J 1965; 2:75-77. 25. Fahrlander H, Huber F, Gloor F. Intrahepatic retention of bile in severe bacterial infections. Gastroenterology 1964; 47:590-599. 26. Nunes G, Blaisdell FW, Margaretten W. Mechanism of hepatic dysfunction following shock and trauma. Arch Surg 1970; 100:546-556. 27. Champion HR, Jones RT, Trump BF et al. Posttraumatic hepatic dysfunction as a major etiology in post-traumatic jaundice. J Trauma 1976; 16:650-657. 28. Vermillion SE, Gregg JA, Baggenstoss AH, Bartholomew LG. Jaundice associated with bacteremia. Arch Intern Med 1969; 124:611-618. 29. Siku1er E, Guetta V, Keynan A, Neumann L, Schlaeffer F. Abnormalities in bilirubin and liver enzyme levels in adult patients with bacteremia. A prospective study. Arch Intern Med 1989; 149:2246-2248. 30. Franson TR, Hierholzer WJ, LaBrecque DR. Frequency and characteristics of hyperbilirubinemia associated with bacteremia. Rev Infect Dis 1985; 7: 1-9. 31. Seibel R, Laduca J, Hassett JM et al. Blunt mUltiple trauma (ISS 36), femur traction and the pulmonary failure-septic state. Ann Surg 1985; 202:283-295. 32. Zimmerman HJ, Fang M, Utili R, Seeff LB, Hoofnagle J. Jaundice due to bacterial infection. Gastroenterology 1979; 77:362-374. 33. Cerra FB, Siegel JH, Wiles J, McMenamy RR. The hepatic failure of sepsis: cellular versus substrate. Surgery 1979; 86:409-422. 34. Fang MH, Ginsberg AL, Dobbins WO. Marked elevation in serum alkaline phosphatase activity as a manifestation of systemic infection. Gastroenterology 1980; 78:592-597. 35. Neale G, Caughey DE, Mollin DL, Booth Cc. Effects of intrahepatic and extrahepatic infection on liver function. Br Med J 1966; 1:382-387. 36. Champion HR, Jones RT, Trump BF et al. A clinicopathologic study of hepatic dysfunction following shock. Surg Gynecol Obstet 1976; 142:657-663. 37. Bernstein LH, Ben Ezzer J, Gartner L, Arias IM. Hepatic intracellular distribution of tritiumlabelled unc{)njugated and conjugated bilirubin in normal and Gunn rats. J Clin Invest 1966; 45: 1194-1201. 38. Simon FR, Reichen 1. Bile secretory failure: recent concepts of the pathogenesis of intrahepatic cholestasis. In Popper H, Schnaffner F, eds. Progress in Liver Diseases VII. Grune and Stratton, New York 1982; 195-206. 39. Sarfeh IJ, Balint JA. Hepatic dysfunction following trauma; experimental studies. J Surg Res 1977; 22:370-375. 40. Gottlieb ME, Sarfeh I, Stratton H, Goldman ML, Newell JC, Shah DM. Hepatic perfusion and splanchnic oxygen consumption in patients post injury. J Trauma 1983; 23:836-843. 41. Machiedo GW, Hurd T, Rush BF, Dikdan G, McGee J, Lysz T. Temporal relationship of Anaesthesia and Intensive Care. Vol. 19. No. 2. May. 1991

177

hepatocellular dysfunction and ischemia in sepsis. Arch Surg 1988; 123:424-427. 42. Asher EF, Garrison R, Ratcliffe DJ, Fry DE. Endotoxin, cellular function and nutrient blood flow. Arch Surg 1983; 118:441-445. 43. Lautt WW, Greenway CV. Conceptual review of the hepatic vascular bed. Hepatology 1987; 7:952-963. 44. Greenway CV, Stark RD. Hepatic vascular bed. Physiol Rev 1971; 51:23-65. 45. Rappaport AM, Schneiderman JH. The function of the hepatic artery. Rev Physiol Biochem Pharmacol 1976; 76:129-175. 46. Richardson PDI, Withrington PG. Liver Blood Flow 1. Intrinsic and nervous control of liver blood flow. Gastroenterology 1981; 81:159-173. 47. Shoemaker WC, Walker WF, Newton Turk L. The role of the liver in the development ofhemorrhagic shock. Surg Gynecol Obstet 1961; 112:327-333. 48. Schirmer WJ, Schirmer JM, Townsend MC, Fry DE. Femur fracture with associated soft-tissue injury produces hepatic ischemia. Possible cause of hepatic dysfunction. Arch Surg 1988; 123:412-415. 49. Chaudry IH, Wichterman KA, Baue AE. Effect of sepsis on tissue adenine nucleotide levels. Surgery 1979; 85:205-211. 50. Imamura I, Clowes GHA. Hepatic blood flow and oxygen consumption in starvation, sepsis and septic shock. Surg Gynecol Obstet 1975; 141:27-34. 51. Olerud S. Experimental studies on portal circulation at increased intraabdominal pressure. Acta Physiol Scand Suppl 1954; 109: 1-84. 52. Bonnet F, Richard C, Glaser P et al. Changes in hepatic blood flow induced by continuous positive pressure ventilation in critically ill patients. Crit Care Med 1982; 10:703-705. 53. Johnson EE, Hedley-Whyte J. Continuous positive pressure ventilation and portal flow in dogs with pulmonary edema. J Appl Physiol 1972; 33:385-389. 54. Sha M, Saito Y, Yokoyama K, Sawa T, Amaha K. Effects of continuous positive-pressure ventilation on hepatic blood flow and intrahepatic oxygen delivery in dogs. Crit Care Med 1987; 15: 1040-1 043. 55. Matuschak GM, Pinsky MR, Rogers RM. Effects of positive end-expiratory pressure on hepatic blood flow and performance. J Appl Physiol 1987; 62:1377-1383. 56. Johnson EE, Hedley-Whyte J, Hall SV. Endexpiratory pressure ventilation and sulfobromophthalein sodium excretion in dogs. J Appl Physiol 1977; 43:714-720. 57. Fujita Y, Sakai T, Ohsumi A, Takaori M. Effects of hypocapnia and hypercapnia on splanchnic circulati{)n and hepatic function in the beagle. Anesth Analg 1989; 69:152-157. 58. Richardson PDI, Withrington PG. Liver blood flow 11. Effects of drugs and hormones on liver blood flow. Gastroenterology 1981; 81:356-375. 59. Higgins CB, Millard RW, Braunweld E, Vatner SF. Effects and mechanisms of action of dopamine on regional haemodynamics in the conscious dog. Am J Physiol 1973; 225:432-437. 60. Schmid E, Angehrn W, Althaus F, Gattiker R,

178

61. 62. 63. 64.

65.

66.

67. 68.

69.

F. HAWKER Rothlin M. The effect of dopamine on hepaticsplanchnic blood flow after open heart surgery. Intens Care Med 1979; 5:183-188. Kram HB, Evans T, Bundage B, Shoemaker Wc. Use of dobutamine for treatment of shock liver syndrome. Crit Care Med 1988; 16:644-645. Van Deventer SJH, Ten Cate JW, Tytgat GNJ. Intestinal endotoxemia. Clinical significance. Gastroenterology 1988; 94:825-831. Hillman KM, Riordan T, O'Farrell SM, Tabaqchali S. Colonization of the gastric contents in critically ill patients. Crit Care Med 1982; 10:444-447. Flynn DM, Weinstein RA, Nathan C, Gaston MA, Kabins SA. Patient's endogenous flora as the source of 'nosocomial' Enterobacter in cardiac surgery. J Infect Dis 1987; 156:363-368. Deitch EA, Maejima K, Berg R. Effect of oral antibiotics and bacterial overgrowth on the translocation of the GI microflora in burned rats. J Trauma 1985; 25:385-392. Redan JA, Rush BF, Lysz TW, Smith S, Machiedo GW. Organ distribution of gut-derived bacteria caused by bowel manipulation or ischemia. Am J Surg 1990; 159:85-90. Baker JW, Deitch EA, Berg RD, Specian RD. Hemorrhagic shock induces bacterial translocation from the gut. J Trauma 1988; 28:896-906. Maejima K, Deitch E, Berg R. Promotion by bum stress of the translocation of bacteria from the gastrointestinal tracts of mice. Arch Surg 1984; 11 9: 166-1 72. Deitch EA, Berg R, Specian R. Endotoxin promotes the translocation of bacteria from the gut. Arch Surg 1987; 122:185-190.

70. Cuervas P, Fine J. Production of fatal endotoxic shock by vasoactive substances. Gastroenterology 1973; 64:285-291. 71. Deitch EA, Winterton J, Berg R. Thermal injury promotes bacterial translocation from the gastrointestinal tract in mice with impaired T -cellmediated immunity. Arch Surg 1986; 121:97-101. 72. Alverdy JC, Aoys E, Moss GS. Total parenteral nutrition promotes bacterial translocation from the gut. Surgery 1988; 104:185-190. 73. Alverdy JC, Aoys E, Moss GS. Effect of commercially available chemically defined liquid diets on the intestinal microflora and bacterial translocation from the gut. J Parentr Entr Nutr 1990; 14: 1-6. 74. Deitch EA, Sittig K, Li M, Berg R, Specian RD. Obstructive jaundice promotes bacterial translocation from the gut. Am J Surg 1990; 159:79-84. 75. Pain JA, Bailey ME. Measurement of operative plasma endotoxin levels in jaundiced and nonjaundiced patients. Eur Surg Res 1987; 19:207-216. 76. Bailey ME. Endotoxin, bile salts and renal function in obstructive j aundice. Br J Surg 1976; 63:774-778. 77. Cahill CJ, Pain J A, Bailey ME. Bile salts, endotoxin and renal function in obstructive jaundice. Surg Gynecol Obstet 1987; 165:519-521. 78. Jones EA, Summerfield JA. Kupffer cells. In Arias IM, Jakoby WB, Popper H, eds. The Liver: biology

and pathobiology. Raven Press, New York, 1988; 683-704. 79. Holman JM, Rikkers LF. Biliary obstruction and host defence failure. J Surg Res 1982; 32:208-213. 80. Di Luzio NR, Olcay I, Holper K, Drapanas T, Trejo R. The relationship of reticuloendothelial dysfunction and endotoxemia to survival after hepatic ischemia injury in the baboon. Circ Shock 1975; 2:77-89. 81. Drivas G, James 0, Wardle N. Study of reticuloendothelial phagocytic capacity in patients with cholestasis. Br Med J 1976; 1: 1568-1569. 82. -Cannalese J, Gove CD,Gimson AES, Wilkinson SP, Wardle EN, Williams R. Reticuloendothelial system and hepatocyte function in fulminant hepatic failure. Gut 1982; 23:265-269. 83. Wardle EN, Anderson A, James 0. Kupffer cell phagocytosis in relation to BSP clearance in liver and inflammatory bowel diseases. Dig Dis Sci 1980; 25:414-419. 84. Dinarello CA. Interleukin-1. Rev Infect Dis 1984; 6:51-95. 85. Beutler B, Greenwald D, Hulmes JD et al. Identity of tumour necrosis factor and the macrophagesecreted factor cachectin. Nature 1985; 316:552-554. 86. Bowers GJ, MacVittie TJ, Hirsch EF et al. Prostanoid production by lipopolysaccharidestimulated Kupffer cells. JSurgRes 1985; 39:501-508. 87. Keppler D, Hagmann W, Rapp S, Denzlinger C, Koch HK. The relation of leukotrienes to liver injury. Hepatology 1985; 5:883-891. 88. Utili R, Abernathy CO, Zimmerman HJ. Cholestatic effects of escherichia coli endotoxin on the isolated perfused rat liver. Gastroenterology 1976; 70:248-253. 89. Blaschke TF, Elin RJ, Berk PD, Song CS, WolffSM. Effects of induced fever on sulfobromophthalein kinetics in man. Ann Int Med 1973; 78:221-226. 90. Ghezzi P, Saccardo B, Villa P, Rossi V, Bianchi M, Dinarello CA. Role of interleukin-l in the depression of liver drug metabolism by endotoxin. Infect Immun 1986; 54:837-840. 91. Kantrowitz PA, Jones WA, Greenberger NJ, Isselbacher KJ. Severe postoperative hyperbilirubinemia simulating obstructive jaundice. N Engl J Med 1967; 276:591:598. 92. Lindor KO, Fleming CR, Abrams A, Hirschkorn MA. Liver function variables in adults receiving total parenteral nutrition. JAMA 1979; 241 :2398-2400. 93. Grant JP, Cox CE, Kleinman LM et al. Serum hepatic enzyme and bilirubin elevations during parenteral nutrition. Surg Gynecol Obstet 1977; 145:573-580. 94. Host WR, Serlin 0, Rush BF. Hyperalimentation in cirrhotic patients. Am J Surg 1972; 123:57-61. 95. Sheldon GF, Peterson SR, Sanders R. Hepatic dysfunction during hyperalimentation. Arch Surg 1978; 113:504-508. 96. Allardyce DB, Salvian AJ, Quenville NF. Cholestatic jaundice during total parenteral nutrition. Can J Surg 1978; 21 :332-339. Anaesthesia and Intensive Care, Vo!. 19, No_ 2, May, 1991

LIVER DYSFUNCTION IN CRITICAL ILLNESS 97. Drongowski RA, Coran AG. An analysis of factors contributing to the development of total parenteral nutrition-induced cholestasis. J Parentr Entr Nutr 1989; 13:586-589. 98. Whitington PF. Cholestasis associated with total parenteral nutrition in infants. Hepatology 1985; 5:693-696. 99. Sax HC, Talamini MA, Brackett K, Fischer JE. Hepatic steatosis in total parenteral nutrition: failure of fatty infiltration to correlate with abnormal serum hepatic enzyme levels. Surgery 1986; 100:697:703. 100. Keim NL. Nutritional effectors of hepatic steatosis induced by parenteral nutrition in the rat. J Parentr Entr Nutr 1987; 11: 18-22. 101. Ockner RK. Drug induced liver disease. In: Zakim D, Boyer TD eds. Hepatology. A textbook of liver disease. WB Saunders Co, Philadelphia, 1982; 691-722. 102. Turner lA, Eckstein RP, Riley JW, Lunzer MR. Prolonged hepatic cholestasis after flucloxacillin therapy. Med J Aust 1989; 151:701-705. 103. Lee MG, Hanchard B, Williams NP. Drug-induced acute liver disease. Postgrad Med J 1989; 65:367-370. 104. Smith DW, Cullity GJ, Silberstein EP. Fatal hepatic necrosis associated with multiple anticonvulsant therapy. Aust NZ J Med 1988; 18:575-581. 105. Steinberg S, Flynn W, Kelley K et al. Development of a bacteria-independent model of the mutiple organ failure syndrome. Arch Surg 1989; 124:1390-1395. 106. Matuschak GM, Rinal