The optimal way to treat a patient with advanced acute liver failure, particularly in cases where the patient meets criteria for transplantation but a graft is not readily available, remains yet to be defined.
There are quite a few studies suggesting that vasoactive substances delivered into the circulation from the failing liver may perpetuate the circulatory abnormalities in this group of patients [1,2]. Therefore, the removal of the non-functioning liver in cases of fulminant hepatic failure or primary non-function of a liver graft while awaiting the availability of a donor organ has been advocated by some authors as a means of improving haemodynamic instability and acid-base disturbances associated with acute liver failure [3-5]. Others have argued that the anhepatic state is not always well tolerated and that there may be severe consequences of total removal of the liver .
The aim of the present experimental study was to investigate whether maintaining a necrotic liver in situ is preferable over removing it in terms of haemodynamic variables, after acute hepatic failure has been surgically induced.
Twenty young female Landrace pigs of mean body weight 22 ± 2 kg were used in this study conducted according to international experimental research standards and in compliance with international guidelines for humane care of experimental animals. Following a 12-h overnight deprivation of food, ketamine 10 mg kg−1, midazolam 0.4 mg kg−1 and atropine 0.02 mg kg−1 were administered intramuscularly. This preanaesthetic regimen allowed the subsequent establishment of intravenous (i.v.) access via a suitable ear vein (Vialon® 22G; Becton-Dickinson, Franklin Lakes, NJ, USA) General anaesthesia was then induced using thiopental sodium (5 mg kg−1) which allowed for subsequent endotracheal intubation with an endotracheal tube of internal diameter of 5.0-6.5 mm (Portex Tracheal Tube CE®; Portex, Hythe, UK) depending on animal weight and co-existing anatomical variability. A large-bore orogastric tube was inserted for stomach decompression. Analgesia was then provided with fentanyl 10 μg kg−1 h−1 and muscle relaxation with a loading dose of pancuronium bromide 0.1 mg kg−1 followed by a continuous infusion of 0.03 mg kg−1 h−1. The animals' lungs were ventilated by the use of oxygen in air mixtures from a volume-cycled ventilator (Sulla 808V®; Dräger, Lübeck, Germany) at an FiO2 of 0.6 with the addition of isoflurane 1.1-2%, as needed. Tidal volume and frequency of ventilation were properly adjusted in order to maintain end-tidal CO2 at about 3.5-4.0 kPa. Heart rate, arterial oxygen saturation, end-tidal CO2 and rectal temperature were monitored continuously (Cardiocap®; Datex, Helsinki, Finland). Body temperature was kept stable throughout the procedure by means of a heating pad.
The left carotid artery was cannulated (20G cannula; Arrow, Reading, PA, USA) for arterial pressure monitoring and serial blood sampling (blood gases and biochemical profile) after surgical exposure of the vessel. Subsequently, the left external jugular vein (which is larger than the internal jugular vein in pigs) was exposed and cannulated with a 6 Fr catheter sheath (Arrow-Flex®; Arrow, Reading, PA, USA), followed by the insertion of a thermodilution catheter (Swan-Ganz 5.5 Fr®; Abbott, North Chicago, IL, USA). Its position was confirmed by the characteristic changes in the transduced pressure waveform (Oximetrix 3®; Abbott; North Chicago USA). Mixed venous saturation (SvO2) was monitored continuously. Cardiac output was measured by the thermodilution method (Oximetrix 3®). Blood glucose concentrations were maintained at 3.5-5.0 mmol L−1 with dextrose infusion by guidance of serial blood glucose measurements.
After all the monitoring lines and devices had been inserted, the abdomen was entered via a midline incision under sterile conditions. A self-retaining urinary catheter was sutured into the bladder for continuous monitoring of urinary output. The liver was then mobilized by transection of all peritoneal adhesions and the infrahepatic inferior vena cava was isolated and cleared down to the region of the renal veins. The common bile duct was then ligated and transected. Next, the hepatic artery was tied and divided, while special care was taken to interrupt all accessory arterial supply to the liver. An end-to-side portocaval anastomosis was then performed using continuous 6-0 Prolene® (Ethicon, Somerville, NJ, USA), following division and transposition of the portal vein. The aim of the anastomosis was to maintain portal venous flow and to avoid splanchnic pooling. Thus, the liver was deprived of its afferent blood supply.
After hepatic devascularization, aspartate aminotransferase (AST) values (baseline values 50.4 ± 13.2 U L−1) showed a rapid increase, significant from 6 h onwards (485 ± 144, P < 0.05) and peaking at 18 h (1385 ± 503 U L−1). Similarly international normalized ratio (INR) levels (baseline values 1.04 ± 0.11) progressively increased after surgery. The rise was significant from 4 h onwards (2.99 ± 0.65, P < 0.05) and reached the value of 4.48 ± 1.47 at 18 h after hepatic devascularization. Guided by the severe impairment of biochemical and haematological indices, it was considered that the syndrome of acute liver failure, defined as a severe impairment of liver function, had been established. Subsequently the animals were randomly assigned to one of two groups. In 10 of them (Group A) no further surgical intervention was undertaken and the abdomen was closed. The other 10 (Group B) underwent total hepatectomy. Since the inferior vena cava (IVC) in the pig is tightly bound to the liver, the hepatectomy required the removal of the intrahepatic segment of the vein. The IVC was clamped closely above and below the liver and the liver was removed. The continuity of the IVC was ensured by means of a Dacron® prosthesis (Sulzer Vascutek, Renfrewshire, Scotland, UK) which was interposed between the cut ends of the IVC. During the hepatectomy procedure 100-150 mL of crystalloid had to be infused to replace blood loss. Thus, normovolaemia was maintained throughout the whole period of hepatectomy. After haemostasis was checked, the abdomen was closed as in Group A, leaving the urinary catheter draining externally. Haemodynamic monitoring was the same in both groups. No inotropes were administered throughout the whole period of observation. Fluid administration was guided by pulmonary capillary wedge pressure (PCWP) values with the aim of a PCWP 13-15 mmHg.
The haemodynamic variables evaluated included cardiac index (CI), mean arterial pressure (MAP), mean pulmonary arterial pressure (MPAP), pulmonary capillary wedge pressure (PCWP), systemic vascular resistance index (SVRI) and pulmonary vascular resistance index (PVRI).
Five different time-points were evaluated for each of the groups studied. The three initial time-points were common for both groups: baseline, after induction of anaesthesia (T1), 3 h after hepatic devascularization (T2) and 18 h after hepatic devascularization (T3). At this time-point the animals of Group B underwent total hepatectomy as mentioned above with a mean duration of operation 45 ± 10 min. Two further time-points were then considered for both groups: T4 and T5 which corresponded to 3 and 6 h respectively after the end of the hepatectomy procedure. The time-points were comparable in both groups in relation to the beginning of the experiment (T1).
The duration of the period of observation was pre-determined; at the end of the procedure all animals were subjected to euthanasia with a lethal dose of thiopental. No evidence of thrombosis of the Dacron® prosthesis was demonstrated in the post-mortem examination.
Time-based changes in haemodynamic variables were analyzed using analysis of variance for repeated measures (ANOVA). Haemodynamic variables at the same time-point between the two groups were compared using t-tests for unpaired data after confirmation of the normal distribution of the values; P < 0.05 was accepted as statistically significant. Results are reported as mean ± SD.
At 18 h after hepatic devascularization (T3), the haemodynamic state of the animals mimicked the hyperdynamic profile observed in patients with acute liver failure - high CI/low SVRI with values significantly different from baseline (Group A: CI 7.54 ± 1.13 L min−1 m−2 vs. 4.24 ± 0.66 L min−1 m−2, P < 0.05; SVRI 928 ± 251 dyn s cm−5 m−2 vs. 1748 ± 252 dyn s cm−5 m−2, P < 0.05). A similar picture was observed in Group B, which was expected since interventions in both groups had been the same until that particular point (Figs 1-4).
Deterioration in haemodynamic variables in comparison not only to time-point 3 (T3) but also to baseline was observed in Group B (hepatectomized pigs) after hepatectomy was performed, which persisted until the end of the experiment. The deterioration consisted of a statistically significant decrease in CI and MAP as well as an increase in SVRI and PVRI (Figs 1-4). In particular, at the end of the experiment CI values in Group B were lower than T3 values but also lower than baseline values and the difference was statistically significant: 2.92 ± 0.68 L min−1 m−2 vs. 4.58 ± 1.24 L min−1 m−2, P < 0.05). Additionally there was a two-fold increase in SVRI in comparison to baseline in Group B (2990 ± 210 dyn s cm−5 m−2 vs. 1595 ± 250 dyn s cm−5 m−2, P < 0.05) as well as a more spectacular three to fourfold increase in PVRI in comparison to baseline in the same group (532 ± 108 dyn s cm−5 m−2 vs. 162 ± 25 dyn s cm−5 m−2, P < 0.05). However, in Group A (ischaemic model of acute liver failure), haemodynamic stability with non-significant variations from time-point 3 was noted (Figs 1-4).
An additional observation was that lactate concentrations measured at the end of the experiment (time-point 5) were significantly different between the two groups (3.8 ± 0.65 mmol L−1 in Group A vs. 6.2 ± 1.1 mmol L−1 in Group B, P < 0.05).
In cases of fulminant hepatic failure or severe primary graft malfunction, some authors have advocated performing total hepatectomy in combination with a temporary portocaval shunt while awaiting the availability of a donor organ [3,7]. The rational for these suggestions was based on early clinical observations that mean arterial pressure appeared to improve following removal of the native liver in the transplant setting . Therefore, our hypothesis was that vasoactive metabolites and mediators partially derived by the failing liver are involved in the pathophysiology of the haemodynamic instability. It was thus assumed that it might be beneficial to excise the diseased liver as early as possible even before a suitable organ has been allocated and to postpone the implantation of the allograft to a second operation . Meanwhile, the patient is placed again in the intensive care unit and treated conservatively. Besides improved haemodynamic and pulmonary condition following this approach, beneficial effects on intracranial pressure have also been described, thus prolonging the time interval during which transplantation may be considered . Successful retransplantation has been reported after substantially prolonged anhepatic states [7,8].
Although the early results appeared encouraging, this approach has aroused much controversy in the medical community since it was first described. Many of these experiences were uncontrolled and anecdotal and probably do not support the routine use of this procedure [1,9]. It appears that there is more sound clinical backup to contemplate total hepatectomy in the patient with sustained massive unsalvageable liver trauma or rupture where exsanguinating haemorrhage is the overwhelming cause of death [10-13]. In cases of severe fulminant liver failure where it is deemed that there is no hope for recovery of the native liver function, the potential clinical role of such a procedure has yet to be medically and ethically defined since the consequences of a prolonged anhepatic state may be severe as it has been demonstrated in previous studies of anhepatic animals [14-16].
In our experimental model, we observed deterioration in haemodynamic variables in hepatectomized animals in contrast to the ones with the necrotic liver in situ. The latter demonstrated remarkable haemodynamic stability long after hepatic devascularization, although previous investigators have showed extensive extrahepatic multiple system organ damage results in rats subjected to hepatic inflow interruption for 120 min . It appears that in our experimental model hepatectomy per se was more harmful for the animals than maintenance of a necrotic liver in situ. Why this is happening is not clear. In a previous experimental animal study where total hepatectomy was performed, a sharp increase in pulmonary vascular resistance was observed after removal of the liver . The changes were shown to correlate with increased arterial plasma concentrations of catecholamines. If these studies are extrapolated to human beings, it would seem likely that an increase in circulating catecholamines may occur during prolonged anhepatic states partially as a result of their interrupted hepatic elimination or as a result of enhanced release due to the stress of the anhepatic state. It has also been shown that the removal of the liver may result in reduced renal output probably due to complex haemodynamic interactions . The fact that hepatectomy in Group B did not convey any haemodynamic stability to the animals, but on the contrary produced a marked hypodynamic profile (low CI and high SVRI and PVRI in comparison even to baseline) is further reinforced by the significant difference in lactate concentrations between Group A and Group B. A high lactate concentration, a potent index of tissue ischaemia and anaerobic metabolism , possibly indicates that in our experimental model hepatectomy is not as well tolerated by the animals as the maintenance of the ischaemic liver. Furthermore, the prolongation of a hyperdynamic state may be preferable to the initiation of a hypodynamic one. As mentioned above, no inotropic support was used in any of the groups. The reason was that our aim was to follow the natural history of the model without any exogenous haemodynamic interventions which could have been responsible for the haemodynamic picture of either group and mislead our conclusions. So the increase in SVRI after the hepatectomy occurred in the absence of vasopressor agents which could have modified the vascular tone. Moreover, normovolaemia was maintained by careful replacement of blood loss, which anyway did not exceed the amount of 100 mL in any of the animals. So there were no variations in cardiac filling pressures which might have induced a physiological response in the animals (low CI/high SVRI) and hypovolaemia was ruled out as the cause of haemodynamic deterioration. It appears therefore that the aggravation of the haemodynamic picture in our experimental model should be attributed solely to hepatectomy which per se may have severe haemodynamic consequences the reasons for which may still not be clearly understood possibly involving obscure hormonal and physiological changes. It has even been postulated that hepatectomy causes movement of water and electrolytes from the extracellular compartment resulting in circulatory collapse . The patency of the inferior vena cava graft was confirmed at postmortem so thrombosis leading to reduced venous return through the caval reconstruction was ruled out as the cause of instability. Moreover, other investigators have demonstrated that the anhepatic state is related to the development of cerebral oedema in experimental models and is not always well tolerated .
In fact in our experimental study, significant increases in intracranial pressure were demonstrated as early as 8 h after hepatic devascularization (28 ± 8 mmHg vs. baseline values 10 ± 3 mmHg, P < 0.05). Subsequently, intracranial pressure remained high without showing any significant difference between the hepatectomized group and the group with the ischaemic liver in situ (unpublished data). It appears that, by this time, irreversible damage to capillary endothelial cells has accrued due to the increased permeability of the blood/brain barrier. So it is possible that hepatectomy has no salutary effects on intracranial pressure if not adverse (via a decrease in cerebral perfusion pressure due to haemodynamic deterioration). Another point, which should be noted, is that our study design precluded assessment of glucose metabolism during the anhepatic phase since an exogenous dextrose solution was continuously administered. It has been shown that if exogenous glucose is withheld in the anhepatic context, progressive hypoglycaemia develops rapidly with blood glucose concentrations falling to dangerously low values after 2 h. This is thought to be directly related to the absence of the liver, which is known to be a potent source of endogenous glucose . So blood glucose concentrations were kept at acceptable values in our experiments so that hypoglycaemia could not be held responsible for the haemodynamic status or the overall survival of the animals.
In another experimental study, where total hepatectomy was undertaken in a porcine model, haemodynamic and biochemical stability was demonstrated , the animals subjected to hepatectomy were previously healthy. In contrast, in our experimental model acute hepatic failure had been surgically induced prior to hepatectomy with its presence clearly demonstrated (increased AST, decreased INR). So it could be considered that the animal population studied bore significant resemblance to the candidate in the human population for rescue hepatectomy. One could also argue that in the ischaemic model, release of hepatotoxins is limited. However, the devascularization model is well known in the literature as a satisfactory model of fulminant hepatic failure and its suitability for experimental studies of acute liver failure has been clearly demonstrated . The rationale is that soon after hepatic devascularization is initiated, changes develop that allow portal blood to bypass the liver and mix with the systemic circulation. This leads to accumulation of substances potentially toxic and eventually leading to hepatic coma. Moreover, inflammatory mediators derived by the liver itself are still dumped into the systemic circulation via collaterals, the hepatic attachments and lymphatic routes. Therefore, although there is no intrahepatic flow, there are still high circulating levels of hepatotoxic compounds . So our experimental model mimicked the clinical setting of acute liver failure, therefore hepatectomy had a more dismal outcome than in the aforementioned study . It appears that additional endotoxaemia during the hepatectomy itself may even be more deleterious than the pre-existing high circulating levels of compounds and, in combination with the complex haemodynamic interactions which are possibly initiated during the procedure, may account for the poor haemodynamic picture. Moreover, in the anhepatic period which follows total hepatectomy during clinical liver transplantation, the situation may be even more complex because pre-existing liver disease and portal hypertension as well as major blood loss often provide other reasons for metabolic and haemodynamic instability and coagulation disorders. Therefore, aiming at improving cardiovascular status by undertaking hepatectomy may have exactly the opposite results. Moreover, some of these patients treated with total hepatectomy might have survived with some less drastic manoeuvres such as good intensive care alone with attention to volume status and acid-base balance. In fact, recent experience with extracorporeal circulation and auxiliary transplantation suggests that the patient's metabolic disturbances may be corrected with aggressive intensive support and, if it eventually proves effective in more controlled trials, with supplementary support from extracorporeal liver-assist devices. Just as importantly, the native liver can recover following auxiliary transplantation, even in the face of massive collapse and necrosis on histological examination.
Moreover, as Lee points out , to subject a patient with severe coagulopathy and a dire prognosis to major heroic surgery with no hope of immediate rescue, by and large does not seem prudent. In fact, removal of the liver without the availability of a suitable organ seems futile, since the likelihood of finding a replacement in a short time interval is always uncertain. One might also argue that this approach represents an unwise use of the limited resource in the context of the well-known organ shortage. In most of the hepatectomy series the postoperative mortality was high and the risk of postoperative death was related to the length of waiting time for the liver graft while any remaining hope of spontaneous recovery is removed with the old liver. It is obvious that the risk of such a procedure is that the patient may still die on the waiting list before a graft is available while at the same time organ shortage is aggravated.
It is questionable whether there is any point in improving cardiovascular status with hepatectomy if there is no graft available. As Lee criticizes , if we begin to hepatectomize patients earlier, we are not helping the large number who eventually will not get grafts or those who might ultimately recover spontaneously, because in any case it is very difficult to decide when the prognosis is hopeless.
In conclusion, whether hepatectomy improves haemodynamic status still remains controversial and it has to be supported by more sound experimental back-up. In our experimental model, although we cannot maintain that our methodology was flawless, we demonstrated greater haemodynamic instability of the hepatectomized group. Since it is not yet clear that having no liver is better than having a failing one which might have some (admittedly small) hope of complete recovery, it is controversial whether hepatectomy alone consists rescue therapy if there is no graft available.
In any case, it is more likely that hepatectomy in combination with intensive plasmapheresis or extracorporeal liver assist devices to make up for the losses might be the answer in cases deemed hopeless and not hepatectomy alone, so further clinical and laboratory work should concentrate on supportive treatment [24-26]. With the possible exception of a liver with a lethal injury due to massive liver trauma or hepatic rupture, the concept of salvage hepatectomy for rapidly deteriorating patients should be reconsidered until clearer prognostic indicators are identified. Although our study is not a dogmatic argument against rescue hepatectomy, it appears that more appropriately controlled experimental and clinical studies are needed to determine the pathophysiological consequences of the anhepatic state on haemodynamic and biochemical status. Until then decision for or against hepatectomy will remain difficult since it seems that such therapeutic modalities lie still in the experimental arena and should only be conducted under the framework of a carefully controlled evaluation.
1. Husberg BS, Goldstein RM, Klintmalm GB, et al.
A totally failing liver may be more harmful than no liver at all: three cases of total hepatic devascularization in preparation for emergency liver transplantation. Transplant Proc
2. Bihari D, Gimson AE, Waterson M, Williams R. Tissue hypoxia during fulminant hepatic failure. Crit Care Med
3. Ringe B, Lubbe N, Kuse E, Frei U, Pichlmayr R. Total hepatectomy and liver transplantation as two-stage procedure. Ann Surg
4. Ringe B, Pichlmayr R, Lubbe N, Bornscheuer A, Kuse E. Total hepatectomy as temporary approach to acute hepatic or primary graft failure. Transplant Proc
5. Ringe B, Lubbe N, Kuse E, Frei U, Pichlmayr R. Management of emergencies before and after liver transplantation by early total hepatectomy. Transplant Proc
6. Lee WM. Total hepatectomy for acute liver failure: don't take out my liver! Gastroenterology
7. Oldhafer KJ, Bornscheuer A, Fruhauf NR, et al.
Rescue hepatectomy for initial graft non-function after liver transplantation. Transplantation
8. So SK, Barteau JA, Perdrizet GA, Marsh JW. Successful retransplantation after a 48-hour anhepatic state. Transplant Proc
9. Noun R, Zante E, Sauvanet A, Durand F, Bernuau J, Belghiti J. Liver devascularization improves the hyperkinetic syndrome in patients with fulminant and subfulminant hepatic failure. Transplant Proc
10. Ringe B, Pichlmayr R, Ziegler H, et al.
Management of severe hepatic trauma by two-stage total hepatectomy and subsequent liver transplantation. Surgery
11. Ringe B, Pichlmayr R. Total hepatectomy and liver transplantation: a life-saving procedure in patients with severe hepatic trauma. Br J Surg
12. Erhard J, Lange R, Niebel W, et al.
Acute liver necrosis in the HELLP syndrome: successful outcome after orthotopic liver transplantation. A case report. Transpl Int
13. Hunter SK, Martin M, Benda JA, Zlatnik FJ. Liver transplant after massive spontaneous hepatic rupture in pregnancy complicated by preeclampsia. Obstet Gynecol
14. Nilehn JE, Aronsen KF, Ericsson B. Changes in blood clotting factors after massive liver resection and total hepatectomy in dogs. Acta Chir Scand
15. Hickman R, Bracher M, Tyler M, Lotz Z, Fourie J. Effect of total hepatectomy on coagulation and glucose homeostasis in the pig. Dig Dis Sci
16. Tonnesen K. Experimental liver failure. A comparison between hepatectomy and hepatic devascularization in the pig. Acta Chir Scand
17. Liu D, Jeppsson B, Hakansson C, Odselius R. Multiple-system organ damage resulting from prolonged hepatic inflow interruption. Arch Surg
18. James MF, Hickman R, Janicki P, Mets B, Fourie J. Early effects of total hepatectomy on haemodynamic state and organ uptake of catecholamines in the pig. Br J Anaesth
19. Freeman JD, Shizgal HM, Slapack M, Gutelious JR. The effect of hepatectomy on body water distribution. J Surg Res
20. Hanid MA, Mackenzie RL, Jenner RE, et al.
Intracranial pressure in pigs with surgically induced acute liver failure. Gastroenterology
21. DeWolf AM, Kang YG, Todo S, et al.
Glucose metabolism during liver transplantation in dogs. Anesth Analg
22. Thompson JF, Bell R, Bookallil MJ, Sheil AG. Effects of total hepatectomy: studies in a porcine model. Aust NZ J Surg
23. Terblanche J, Hickman R. Animal models of fulminant hepatic failure. Dig Dis Sci
24. Hammer GB, So SK, Al-Uzri A, et al.
Continuous venovenous hemofiltration with dialysis in combination with total hepatectomy and portocaval shunting. Bridge to liver transplantation. Transplantation
25. Gerlach J, Ziemer R, Neuhaus P. Fulminant liver failure: relevance of extracorporeal hybrid liver support systems. Int J Artif Organs
26. Watanabe FD, Mullon CJ, Hewitt WR, et al.
Clinical experience with a bioartificial liver in the treatment of severe liver failure. A phase I clinical trial. Ann Surg