European Journal of Surgical Oncology 47 (2021) 216e224

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European Journal of Surgical Oncology

journal homepage: www.ejso.com

Review Article

Post hepatectomy liver failure (PHLF) e Recent advances in prevention

and clinical management
Jon Arne Søreide a, b, *, Rahul Deshpande c
a
Department of Gastrointestinal Surgery, Stavanger University Hospital, Stavanger, Norway
b
Department of Clinical Medicine, University of Bergen, Bergen, Norway
c
Department of HPB Surgery, Manchester Royal Infirmary, Manchester, UK

a r t i c l e i n f o a b s t r a c t

Article history: Background: Posthepatectomy liver failure (PHLF) is a relatively rare but feared complication following
Accepted 1 September 2020 liver surgery, and associated with high morbidity, mortality and cost implications. Significant advances
Available online 10 September 2020 have been made in detailed preoperative assessment, particularly of the liver function in an attempt to
predict and mitigate this complication.
Keywords: Methods: A detailed search of PubMed and Medline was performed using keywords “liver failure”, “liver
Post-hepatectomy
insufficiency”, “liver resection”, “postoperative”, and “post-hepatectomy”. Only full texts published in
Liver failure
English were considered. Particular emphasis was placed on literature published after 2015. A formal
Liver resection
Liver incsufficiency
systematic review was not found feasible hence a pragmatic review was performed.
Management Results: The reported incidence of PHLF varies widely in reported literature due to a historical absence of
Artificial liver support a universal definition. Incorporation of the now accepted definition and grading of PHLF would suggest
the incidence to be between 8 and 12%. Major risk factors include background liver disease, extent of
resection and intraoperative course. The vast majority of mortality associated with PHLF is related to
sepsis, organ failure and cerebral events. Despite multiple attempts, there has been little progress in the
definitive and specific management of liver failure. This review article discusses recent advances made in
detailed preoperative evaluation of liver function and evidence-based targeted approach to managing
PHLF.
Conclusion: PHLF remains a major cause of mortality following liver resection. In absence of a specific
remedy, the best approach is mitigating the risk of it happening by detailed assessment of liver function,
patient selection and general care of a critically ill patient.
© 2020 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical
Oncology. All rights reserved.

Introduction complications, including infections or sepsis, bleeding, leakage, or

cardiopulmonary events [4,5]. Post-hepatectomy liver failure
Liver resection has become a safe and a well-accepted treatment (PHLF) is a feared and severe complication after liver resection and
for a variety of primary and secondary tumors with excellent out- its incidence is higher after resection for hepatocellular carcino-
comes and acceptable morbidity [1]. Mortality after a liver resec- ma(HCC) and hilar cholangiocarcinoma compared to liver resection
tion varies from about 2% for colorectal metastases to about 10% for for colo-rectal liver metastases(CRLM) [6,7], resulting in increased
biliary tumors and hepatocellular carcinomas although some older morbidity and mortality [3,8e11]. In a large study, PHLF criteria
series have even reported much higher rates, up to 30% for major were satisfied in 70% of patients who died following a liver resec-
liver resections involving over 4 segments [2,3]. Non-lethal com- tion for all indications, with PHLF being the direct cause of death in
plications after liver resections are frequently encountered in up to over half of those [11]. Moreover, nearly half of in-hospital mor-
45%, and vary from less severe incidents to life-threatening tality due to PHLF occurs within 30 postoperative days [12].
Furthermore, significant costs are associated with management of
these complications, and more so when the attempts to salvage
* Corresponding author. Department of Gastrointestinal Surgery, Stavanger Uni- from complications fail [5,13].
versity Hospital, Stavanger, Norway. Although many treatment strategies have been entertained to
E-mail address: [email protected] (J.A. Søreide).

https://doi.org/10.1016/j.ejso.2020.09.001
0748-7983/© 2020 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.
 J.A. Søreide, R. Deshpande / European Journal of Surgical Oncology 47 (2021) 216e224 217

Table 1
Commonly used definitions for PHLF.

Definition Description

“50e50 criteria” or “Clichy criteria” Prothrombine time <50% of normal (INR>1.7)

(Balzan S et al., Ann Surg 2005) and serum bilirubin >50 mmol/l (>2.9 mg/dl) on
postoperative day 5
“Edinburgh criteria” The definition was based on serum
Schindl ML et al., Gut 2005 concentrations of total bilirubin and lactate,
prothrombin time, and signs of encephalopathy,
categorized into 3 levels each, and points were
given for each level, and summarized to provide
a score which indicated four grades of PHLF
(none/mild/moderate/severe)
Peak bilirubin criterion Postoperative peak serum bilirubin >120 mmol/
>120 mmol/ml ml (>7 mg/dl)
(Mullen JT et al., J Am Coll Surg 2007)
ISGLS “Postoperatively acquired deterioration in the
(Rahbari NN et al., Surgery 2011) ability of the liver to maintain its synthetic,
excretory, and detoxifying functions,
characterized by an increased INR and
hyperbilirubinemia on or after postoperative
day 500

rescue the patient with PHLF, the evidence for these managements coworkers [15] in 2005 and validated in 2009 as a useful predictor
is still limited, with only few of these routinely employed in a of death after liver resection [19]. A grading score of liver failure
clinical setting [8,9,14]. severity based on available blood tests and clinical observation was
The aim of this narrative review, based on a selection of relevant suggested in 2005 by Schindl et al. [16]. Currently, the International
and recent literature, is to discuss recent advances in work-up and Study Group of Liver Surgery (ISGLS) definition [3] of 2011 has now
risk assessment of patients undergoing major liver resections and been widely embraced as a standard to describe the PHLF. This
to explore the best current evidence in management of PHLF. entity involves the acquired deterioration of one or more synthetic,
excretory, or detoxifying functions of the liver, including hyper-
bilirubinemia, hypoalbuminemia, prolonged prothrombin time
Literature search
(PT) or an international normalized ratio (INR), elevated serum
lactate, and hepatic encephalopathy during the postoperative
An electronic literature search in the databases of PubMed and
period (Table 2).
Medline using keywords relating to “liver failure”, “liver insuffi-
ciency”, “liver resection”, “postoperative”, and “post-hepatectomy”
was done. Detailed search of published literature particularly over Epidemiology
the last 5e10 years revealed that whilst there were many articles
written about PHLF, none of these was a systematic review as such. The reported incidences of PHLF have varied tremendously,
The literature concentrated variously on etiology and pathogenesis between 0.7 and 34% [3,20], although a PHLF incidence of between
of PHLF whilst many others discussed preoperative and intra- 8 and 12% is more commonly described in recent reports [12,21,22].
operative strategies to minimize the occurrence of PHLF. Almost all This wide range in incidences may partly be explained by the use of
discussed in varying degrees of details, the basis of management of different definitions of PHLF, but likely also by variations in the
PHLF. At the outset, the aim of our manuscript was to focus on the extent of liver surgery and the case-mix of the patients included in
modern investigations employed towards work-up of patients with the studies reported.
liver disease and investigate new evidence-based protocols for
preoperative risk-assessment of patients undergoing liver re-
Work-up for a patient undergoing a major liver resection
sections for various indications. Hence, specific emphasis was
placed on such literature.
The aim of a detailed work-up for any patient undergoing major
Therefore, a formal systematic review was not found feasible
liver surgery, particularly for HCC, is manifold. Apart from accu-
based on the heterogeneous patterns of the identified articles, and
rately staging the disease and estimating prognosis, it involves
a pragmatic approach was chosen, with more attention paid to
evaluation of the patient’s general health, analysis of liver function,
pertinent literature published after 2015. Only published full-text
identification and modification, if possible, of pre-operative risk
papers written in the English language were considered.
factors and mitigating the effects of postoperative complications,
particularly PHLF.
Definition of PHLF A number of preoperative factors can potentially contribute
towards PHLF [6,8,23,24]. These have been extensively investigated
Hepatic insufficiency occurring after partial resection of the and discussed in other manuscripts and are listed in Table 3. These
liver, or more precisely described as post hepatectomy liver failure include patient factors, disease pathology, intraoperative features
(PHLF), has been described by the use of a variety of definitions in and postoperative course. Whilst many of these can be mitigated,
the literature [15e17] (Table 1). Several definitions have not probably the single most important factor that influences the
reached clinical use because the risk calculations were based on occurrence or otherwise of PHLF is the status of the liver. Hence it is
complicated formulae or more or less obscure laboratory tests(e.g., quite important to evaluate liver function in as much detail as
hapaplastin test by Eguchi et al. [18]). The “50e50 criteria” (PT<50% possible. The rest of the discussion in this section, therefore, con-
and bilirubin >50 mmol/l on POD 5) were introduced by Balzan and centrates on recent advances in preoperative assessment of liver
218 J.A. Søreide, R. Deshpande / European Journal of Surgical Oncology 47 (2021) 216e224

Table 2
The current International Study Group of Liver Surgery (ISGLS) definition of posthepatectomy liver failure (PHLF), based on the original description by Rahbari et al., Surgery
2011 [3].

A postoperatively acquired deterioration in the ability of the liver o maintain its synthetic, excretory, and detoxifying functions characterized, on postoperative
day 5, by:

If Pre-op LFTs Normal: If Pre-op LFTs abnormal:

- Increasing INR (or need - Increasing INR or prothrombin time (compared
of clotting factors to maintain to the day before)
INR) - Increasing bilirubin (compared to the day before)
- Hyperbilirubinaemia
Grade A Grade B Grade C
Abnormal laboratory parameters Deviation from the regular clinical Deviation from the regular clinical
but requiring no change in the management but manageable management and requiring invasive
clinical management of the patient without invasive treatment treatment.

LFTs, liver function tests; INR, international normalized ratio.

function. mortality [33]. If the liver is compromised, either by chemotherapy

treatment or pre-existing liver disease(e.g. cirrhosis), an increased
Biochemical evaluation of liver function %FLR of at least 30% and 40% respectively, is required [26,34].
For decades the Child-Pugh(CeP) score has served as an However, it is amply clear that liver volume, although important
essential tool for prognostication in patients with chronic liver per se, does not necessarily correlate with liver function which in
disease and is to some extent still a guiding factor in clinical turn are related to various factors such as liver pathology, steatosis,
decision-making [25,26]. The MELD score (‘Model for End-stage chemotherapy and parenchymal function, in general [28,35,36].
Liver Disease’) eventually turned out to be a better predictor of Traditional factors that have been proposed as relative contra-
prognosis in chronic liver disease. More importantly, the MELD indications for liver resection are small future liver remnant/FLR)
score was relevant in the early prediction of morbidity and mor- volumes, Child-Pugh scores B and C, hepatic portal pressure gra-
tality after liver resection [27]. dient(HVPG) of less than 10 mmHg, elevated serum bilirubin,
Although the Childs-Pugh score is still routinely used in many platelet count < 100 000 and indocyanine green retention test after
liver surgery protocols, it was somewhat subjective and not 15 min(ICG R15) < 15e20% [26,37,38]. However, many of these are
necessarily evidence-based. More recently, the Albumin-Bilirubin not absolute. There are inherent limitations with liver volumetry
(ALBI) score and its modifications have been proposed as an and Child-Pugh scores whilst estimation of HVPG entails an inva-
objective and evidence-based method of assessment of the clinical sive process, and cut-off values are considered to be too restrictive
liver function [28]. This has been validated as a reliable assessment [39]. Meta-analyses have shown these values to be more predictive
of liver dysfunction in the original and subsequent studies, both in of PHLF in the Eastern than the Western population [40,41]. How-
Eastern and Western populations [29,30] and has also been found ever, in recent years, there have been many advances in the func-
to be superior to the Childs-Pugh score in predicting outcomes after tional assessment of liver disease and liver volumes which are
liver resection for HCC [31]. Incidentally, ALBI score and its modi- likely to supersede these traditional investigations.
fications have also been found to correlate with ICG-clearance al-
gorithms with a somewhat better predictive value [28]. Assessment of functional liver remnant and functional liver volume
As mentioned earlier, Child-Pugh score was never meant to Assessment of functional liver remnant volume is superior,
prospectively prognosticate outcomes after liver resection for HCC compared to a simple calculation of future liver volume (%FLR)
but nevertheless, it has been used to stratify preoperative risk. The [42,43]. Amongst the myriad of tests used to assess functional liver
ALBI score and it’s modifications, however, have been examined not volume, the indocyanine green clearance (ICG R15) has been the
just to grade liver disease but also to specifically investigate prog- most commonly used test, at least in Eastern centers, resulting in a
nosis of HCC after curative management, both resection and useful algorithm devised to minimize PHLF and mortality following
transplantation. In two large retrospective studies [30,31], ALBI liver resection [44]. In a large single-centre study, the authors
grade predicted both short and long-term mortality after poten- strictly applied an algorithm based on bilirubin and then stratified
tially curative treatment of HCC. Moreover, it provided better cor- according to ICG clearance not only to decide what patients to
relation than traditional tests such as Childs-Pugh score and ICG subject to a resection but also what type of resection to perform.
clearance. However, to our knowledge, this has not been specif- Excellent results were achieved over a 10-year period with excep-
ically employed in a preoperative algorithm to select patients tionally low mortality of only 1 patient in over a thousand re-
suitable for undergoing liver resection for HCC. sections [44].
Moreover, Maruyama et al. [45] recently reported on the eval-
Volumetric assessment of liver function uation of the future liver remnant function after portal vein embo-
Assessment of the future liver remnant volume (%FLR) by lization(PVE) by use of the future liver remnant ICG clearance
computer tomography(CT) according to defined protocols is ach- rate(ICGK-F), and they found that ICGK-F was more useful for pre-
ieved by calculating the proportion of remaining liver tissue of the dicting PHLF than %FLV [45]. However, some limitations of the ICG
total liver volume and is explained in more detail elsewhere [32]. To clearance, particularly in perioperatively jaundiced patients [46]
possibly avoid PHLF, the %FLR was empirically suggested to be at and in those with hemodynamic compromise, are well known.
least 20% of the standardized total liver volume, given that the More recently, the Methacetin breath test, which evaluates
remaining parenchyma is normal [32,33]. Moreover, Truant et al. whole liver function by detecting the 13CO2/12CO2 ratio in expired
found that the remnant liver volume(RLV ¼ %FLR) related to the air, derived from the rate of metabolization of 13C-methacetin by
bodyweight provides added relevant information and showed that P450 1A2 (CYP1A2) in hepatocytes has been increasingly used,
patients with anticipated RLV <0.5% of their body weight were at particularly in the Western population [47]. A further algorithm,
considerable risk for postoperative hepatic dysfunction and similar to the one above for ICG clearance, has been proposed for
 J.A. Søreide, R. Deshpande / European Journal of Surgical Oncology 47 (2021) 216e224 219

Table 3
Risk factorsa for PHLF.

Patient factors Male sex

Advanced age (>65 years)

Obesity (BMI >30) and malnutrition

Diabetes and other comorbidity

Factors related to hepatic parenchyma Pre-existing liver disease

 cirrhosis
 fibrosis
 steatosis
Pre-operative chemotherapy effects
 sinusoidal congestion
 steatohepatitis
Cholestasisehyperbilirubinemia
Cholangitis
Surgery related Intraoperative blood loss (>1200 ml)
Intraoperative transfusion
Extended liver resection (>4 segments)
Prolonged inflow occlusion(“Pringle”)
Prolonged operating time (>240 min)
Need for associated resection (e.g. vascular, colon) or vascular reconstruction
Hypotension
Postoperative factors Postoperative hemorrhage
Intra-abdominal infections
Major postoperative complications
a
Summarized from [6,8,33].

clinical practice [48]. The Methacetin test algorithm was used in a scanner without the need for any specialist equipment. The EOB-
large series of patients undergoing liver resections for all in- MRI is reported to improve the prediction of PHLF in patients
dications. The authors reported a significant reduction in incidence suggested for liver resection, even in patients that have undergone
of PHLF (24.7%e9%) and liver-related postoperative mortality (4%e PVE, with an accuracy of 80.8% [57]. Moreover, it was found to
0.9%) with the application of the algorithm despite a corresponding correlate well with the methacetin clearance, a functional excretion
increase in the numbers, both of complex resections and patients test [56]. However, it is still in its infancy, and the conditional set-
with established cirrhosis [11]. However, both these tests provide a tings and the best imaging protocols are yet to be determined.
global evaluation of the liver, assuming that liver function is uni- Although some of these non-invasive radiological investigations
form throughout the parenchyma. It is, however, far more valuable do look promising, their use has yet to be translated into clinical
to assess regional liver function, particularly of the proposed FLR. algorithms either for ruling patients out of surgery or those spe-
Intraoperative ICG clearance test has been employed to assess cifically aimed at improving PHLF and perioperative mortality.
“real-time” functional liver volume [49,50]. More recently intra-
operative use of the Methacetin breath test was also evaluated in PHLF e diagnosis and differential diagnosis
pilot study, however, no definitive conclusion can be currently
drawn [51]. As discussed earlier, the diagnosis of PHLF is based on
derangement of liver function, coagulopathy, high lactate, and
Radiological assessment of fractional and regional liver function emerging encephalopathy. Although the early diagnosis of PHLF is
Various specialist radiological investigations have been more desirable, deranged liver function tests(LFTs) are in general
effective in quantifying the FLV better. One of the earlier tests more commonly encountered in critically ill patients. These can be
recently adopted into clinical practice is an excretion test based on further confounded in patients with sepsis. In an observational
99 m Technetium mebrofenin (99 m Tc-mebrofenin scintigraphy), study of patients without the hepatobiliary disease, abnormal liver
which uses a similar pharmacological pathway as ICG clearance. enzymes were found in up to 61% of patients admitted to a critical
Although it has some limitations, better correlation is achieved in care unit and were shown to correlate with in-hospital mortality
combination with conventional volumetry techniques. Complex [17]. However, in the majority of patients, the abnormalities were
equations are then better able to predict pre-operative regional less than twice the normal upper values. Elevation of bilirubin over
liver function and PHLF [52,53]. Another test that was developed to twice the upper limit of normal was also found to correlate with
precisely map regional liver function, particularly in diseased livers much higher mortality [58].
is the 99 mTc-GSA SPECT [54]. Since it utilizes a different metabolic Cholestasis is not uncommon in critically ill patients. A variety of
pathway, it can potentially be used in patients with jaundice and factors lead to cholestasis and elevated bilirubin in critically ill
obstructed biliary tree. In combination with spatial CT images, it patients, including drugs, parenteral nutrition, bacterial trans-
provides an estimation of functional rather than a plain volumetry. location, and biliary sludge. At a cellular level, there is significant up
Its best use, potentially, would be in surgery for hilar chol- or downregulation of bile salt transporters [59]. Hence, hyper-
angiocarcinoma and in ALPSS surgery [55]. However, it has pre- bilirubinemia in critically ill patients need not always be related to
dominantly been used in the far-east, mostly due to the complexity cholestasis alone.
and need for specialist equipment but has yet to be routinely uti- Hepatic hypoxia is frequently encountered in critically ill pa-
lized in the western population for further evaluation. tients with organ failure. Intraoperative factors such as significant
Finally, another image-based estimation of regional liver func- blood loss, prolonged episodes of hypotension, and long inflow
tion, which shows promise, is the Gd-EOB-DTPA enhanced mag- occlusion times contribute to significant hepatic ischemia. Hepatic
netic resonance imaging(EOB-MRI) [56]. It uses a standard MRI hypoxia is an independent risk factor for prolonged critical care
220 J.A. Søreide, R. Deshpande / European Journal of Surgical Oncology 47 (2021) 216e224

stay and higher mortality [60]. Moreover, liver congestion and patic ischemia as discussed earlier. Reduced systemic vascular in-
increased stiffness is common after major liver resection and is dex leads to peripheral pooling, fluid extravasation, and tissue
frequently seen in small for size syndrome. This can be further edema.
exaggerated postoperatively by fluid overload, mechanical venti- Acute kidney injury (AKI) is a common feature of PHLF whereas
lation, and cardiac dysfunction. Higher liver stiffness, even in non- excessive hydration can lead to pulmonary edema and acute res-
cirrhotic patients, correlates with higher in-hospital and long-term piratory distress syndrome. Impaired renal function is followed by
mortality [61]. an increase in total body water, which again cause derangements in
Liver stiffness measurement(LSM) has been accepted as a proxy electrolytes such as hyponatremia. Use of diuretics is frequently
for liver cirrhosis and has been evaluated by commercially available followed by hypokalemia. Other electrolyte disturbances can be
ultrasound types of equipment. Nishio et al. found that the LSM caused by hyperaldosteronism from failure of hormone breakdown,
provided independent predictive information for the risk of PHLF, uremia related to the renal impairment, and hypophosphatemia
but also added reliable and clinically useful information as to the associated with hepatic regeneration. A careful and timely adher-
functional remnant liver after resection in patients with HCC [62]. ence to readily available standard replacement scales is recom-
mended to maintain electrolyte homeostasis.
Management of PHLF e general principles Pulmonary complications such as acute lung injury(ALI) or acute
respiratory distress syndrome(ARDS) are detrimental to the prog-
Occurrence and resolution of PHLF is closely related to optimum nosis of patients with PHLF [14]. Early intubation and use of
liver regeneration [63,64], and all therapeutic measures should ventilator support is promoted by current ARDS guidelines. How-
essentially aim to satisfactorily promote it. However, specific eval- ever, prolonged use of increased positive end-expiratory pressure
uation of the extent and progress of postoperative liver regenera- may worsen hepatic congestion, leading to portal hypertension,
tion is quite difficult. Although in theory, serial evaluation of development of ascites and impaired liver regeneration.
growth factors markers and cytokines could predict the extent and
success of liver regeneration, there is a lack of firm clinical evidence
Renal and metabolic derangement
that they do [64].
Continuous hemofiltration or venovenous hemofil-
In the absence of any randomized data specifically related to the
tration(CVVHF) is frequently necessary for patients with ALF and
management of PHLF, general principles of management of acute
PHLF for the management of acute kidney injury and fluid over-
liver failure (ALF) and organ dysfunction apply. These have
loading. Given the multifactorial nature of acute kidney injury in
remained the same over the years and incorporate principles of
patients with PHLF, renal replacement therapy is challenging.
management of ALF from any cause, goal-directed therapy for or-
Hypoperfusion, diuretics and vasoactive drugs, and contrast im-
gan dysfunction, and identifying and treating reversible factors in
aging studies may all contribute to an ongoing renal insult in this
the postoperative period [14,65,66].
group of patients. When necessary, early commencement of renal
replacement therapy(RRT) is indicated. Continuous RRT is better
Identification and management of remediable causes
than intermittent application but there is no evidence that high
volume RRT is significantly better than standard rate [72].
Significantly higher bilirubin level is seen in PHLF as opposed to
Hypoglycemia is encountered in some patients with PHLF and is
other generic causes and it not only helps diagnose PHLF but is also
due to an impaired hepatic gluconeogenesis and hyperinsulinemia,
of prognostic relevance [67]. Obstructive causes of hyper-
combined with reduced glycogen stores in the remaining liver.
bilirubinemia must be looked for and reversed by a radiological or
Administration of glucose by enteral or parenteral route as toler-
operative intervention. Vascular inflow or outflow compromise of
ated, is necessary. Continuous monitoring of the glycemic status is
the liver remnant may rarely occur, particularly in the early post-
important. Of note, persistent hypoglycemia is regarded as a poor
operative period, and can lead to hepatic ischemia/congestion. The
prognostic factor [73].
risk of inflow thrombosis is higher if skeletonization of hep-
atoduodenal ligament or vascular reconstruction of inflow has been
performed [68]. Venous outflow can also be compromised by tor- Management of neurological complications
sion of the left liver remnant following a major right resection [69]. Cerebral edema and hepatic encephalopathy are common in ALF
Similarly, skeletonization of hepatic veins can lead to outflow as are levels of elevated serum ammonia. Raised intracranial
thrombosis [70]. Diagnosis can be achieved with a bedside Doppler pressure is the cause of death in nearly 15% of patients [74].
ultrasound or with cross-sectional imaging or definitive angiog- Elevated serum ammonia levels are associated with cerebral her-
raphy. Hepatic arterial thrombosis, as in the post-transplant setting, niation and are predictive of mortality [75]. CVVHF also has the
leads to irreversible hepatic ischemia. Portal and hepatic venous added benefit of achieving ammonia clearance. The rate of CVVHF
thrombosis can be managed expectantly with anticoagulation, also correlates with the amount of ammonia clearance although it
although thrombectomy or radiological thrombolysis has also been is unclear whether this specifically contributes towards improved
demonstrated to be effective [71]. Postoperative perihepatic col- survival [72]. Lactulose has been routinely used for the manage-
lections and abscesses contribute to and exacerbate SIRS and sepsis ment of hepatic encephalopathy (HE) although current literature
and need to be stringently looked for and drained with interven- would suggest little evidence that it improves outcomes [76]. It can
tional imaging. be poorly tolerated, can cause excessive GI disturbances and diar-
rhea which may potentially worsen the dehydration, AKI, and en-
Cardiovascular hemodynamic aspects cephalopathy. Albumin has also been used in the treatment of HE
Fluid resuscitation therapy is goal-directed to maintain alone or combination with lactulose with varying evidence of its
adequate tissue perfusion in the context of excessive capillary efficacy [77]. Rifaximin is a broad-spectrum, minimally absorbed
leakage. Excessive inotropic support can contribute towards he- oral antimicrobial agent that is concentrated in the gastrointestinal
tract is equally effective against both gram-positive and negative
 J.A. Søreide, R. Deshpande / European Journal of Surgical Oncology 47 (2021) 216e224 221

cocci as well as anaerobes and has been used for the management whilst in a human study, strict perioperative glycaemic control
of HE. A large randomized trial showed a clear benefit in main- resulted in improvement in liver dysfunction and postoperative
taining remission and preventing hospitalization from HE [78]. A complications [83]. However, none of these studies specifically
meta-analysis also confirms that antibiotics such as Rifaximin are dealt either with PHLF or mortality after liver resections.
better than disaccharides for the overall management of HE [76].
However, their role in specific management of HE related to PHLF Specific management of liver failure
hasn’t been investigated. As a rule, grade 1e2 HE which is usually
associated only with minimal cerebral edema can be managed The ultimate organ-specific management in PHLF and ALF in
expectantly. However, grade 3e4 HE is associated with significant general would be liver support systems. Ideally, any artificial liver
cerebral edema with potential for tentorial herniation and needs support should cover the whole range of liver function, including
the patient to be intubated and ventilated with specific measures detoxification, synthesis, excretion, metabolic and regulatory
such as hypothermia and administration of hypertonic saline. functions. However, in practice, it is only the detoxification and
Routine use of hyperventilation and steroids is not beneficial [65]. excretory functions that need to be artificially supported since
some of the synthetic and metabolic functions can potentially be
Coagulopathy and bleeding managed medically. Over the last few years, many artificial and bio-
Coagulopathy is invariably present in patients with PHLF and is artificial therapies have been attempted as discussed below.
indolent and frequently associated with thrombocytopenia, leaving
the patient at risk of hemorrhagic complications. It is well known Artificial liver support e extra-corporal liver support devices (ELSD)
that chronically low levels of platelets are well tolerated and there The main aim of any artificial device or treatment is to take over
is no role for routine platelet or fresh frozen plasma transfusion some of the vital liver functions until native liver has sufficiently
unless a therapeutic procedure is planned or the patient develops regenerated to hold its own, or, in case of irreversible failure, to act
active bleeding [79]. Apart from coagulopathy, other factors that as a bridge towards definitive treatment in form of liver trans-
contribute to higher incidence of GI bleeding include mechanical plantation [14,84,85].
ventilation, renal failure, sepsis, and shock. Several studies clearly Principally, the ELSD can be subclassified in two types: 1) Bio-
indicate benefit of stress ulcer prophylaxis with H2-receptor artificial type, which is based on the use of living cells (porcine or
antagonists(H2RA) or proton pump inhibitors(PPIs), however the human-derived) loaded in an extra-corporal bioreactor. Outside
mortality remains unaffected [80]. clinical trials, currently, no bioartificial system is available for
clinically use [86]. 2) Artificial liver support types, where blood
Infectious complications and sepsis purification of protein-bound substances is achieved by various
Postoperative perihepatic collections and abscesses contribute mechanical devices. Early ones included the molecular adsorbent
to and exacerbate systemic inflammatory response syndrome(SIRS) recirculation system (MARS®)(Gambro, Lund Sweden) [87] and the
and sepsis and need to be stringently looked for and drained with single-pass albumin dialysis(SPAD) [88]. Further improvements
interventional imaging. Repeat blood cultures should be obtained, included introduction of the fractionated plasma separation and
to enable goal-directed antimicrobial therapy. SIRS is encountered adsorption(FPSA) system by Falkenhagen et al., in 1999 [89]. Based
in over half the patients with ALF and is accompanied by both on the combination of the FPSA method and high-flux hemodialysis
gram-positive and gram-negative bacteremia [74]. Outcomes of the blood, the Prometheus® system (Fresenius Medical Care, Bad
worsen with the number of organ system failures, and septic shock Homburg, Germany) as an extracorporeal detoxification system
in patients with ALF is invariably fatal. Although there is no was introduced [90].
definitive role for postoperative antibiotic prophylaxis after liver A systematic review concluded that artificial and bioartificial
resection, it improves outcomes for established ALF and by exten- liver (BAL) support systems might reduce mortality in acute-on-
sion, likely for PHLF too. Broad-spectrum antibiotic therapy must be chronic liver failure (ACLF) compared with standard medical ther-
instituted as soon as possible. Fungal infections have worse out- apy, but not in patients with acute liver failure(ALF) [91]. Less than a
comes than bacterial ones and there may be a role for anti-fungal decade later, Strutchfield and coworkers came to the opposite
prophylaxis although there is no definite evidence of its thera- conclusion in their systematic review and meta-analysis that extra-
peutic role [74]. corporal liver support systems appeared to improve survival in ALF,
but not in those with ACLF [92].
Drugs used in the management of PHLF It is unknown whether these outcomes in patients with medical
N-acetylcysteine(NAC) has long been used in management of liver failure could be extrapolated to those who have sustained
ALF for its role as a cytoprotective agent. Although routinely used as PHLF. Moreover, patients with PHLF comprise a heterogeneous
a drug aiding recovery from paracetamol overdose and thereby group of patients, treated for a variety of malignant and benign
minimizing the need for liver transplantation, less is known about causes [93]. In a recent systematic review, Sparrelid et al. concluded
its role in minimizing PHLF in patients undergoing major liver that early MARS treatment is both safe and feasible in patients with
resection. Its potential benefit is based on the assumption that NAC PHLF [94]. However, before MARS can be recommended as stan-
has a protective effect on the remnant liver via its mechanism in dard therapy for this group of patients, further prospective studies
influencing the ischemia-reperfusion injury (IRI) pathway. are warranted [94].
Although many centers routinely use NAC postoperatively in pat- In a recent national population-based study, Wiesman and co-
ents deemed to be at high risk of developing PHLF, very little data workers [95] report on a stable use of extracorporeal liver support
are available to even draw any conclusive evidence for its benefit or between 2007 and 2015 in Germany. Interestingly since 2012, ECLS
otherwise [81]. therapy was used more often in cardiosurgical patients than in
In an experimental rat model of small-for-size transplant, those with liver dysfunction [95]. Unfortunately, no specific infor-
perioperative use of somatostatin improved graft survival [82] mation on ECLS related to PHLF was provided in this study.
222 J.A. Søreide, R. Deshpande / European Journal of Surgical Oncology 47 (2021) 216e224

Plasma exchange seems to be a valuable approach for patients Authors’ contributions

with ALF and ACLF [14,96]. The level of evidence is strong for the
use of high-volume plasma exchange in selected patients with ALF JAS proposed and designed the concept of this work. JAS and RD
[96]. However, there are only a few anecdotal case-reports of have both contributed to the literature search and reviewing of the
salvage plasmapheresis in patients with PHLF [97]. pertinent literature in detail, and both authors have also contrib-
In summary therefore, the use of ELSD in patients with liver uted in providing and comparing the data presented. JAS made a
failure is still not universally accepted and has been met with manuscript draft, which was further developed and revised by both
skeptical reluctance [98]. As an alternative form of therapy for acute authors, and the final submitted manuscript was approved by both
liver failure, including PHLF, both cell transplantation, bioartificial authors.
liver devices, or bioengineered whole organ liver transplantation
may add to the therapeutic repertoire. However, several concerns Declaration of competing interest
and obstacles need to be solved before widespread clinical imple-
mentation can take place [99,100]. In particular, safety concerns, The authors declare that they have no competing interests.
including zenozoonosis and tumorigenicity, have to be addressed
before cell transplantation, bioartificial liver devices, and bio- Funding
engineered livers may translate into clinical use for PHLF patients
[99]. No funding

Liver transplant Acknowledgments

Theoretically, the only definitive and potentially curative man-
agement of irreversible PHLF would be a salvage liver trans- None.
plantation. To be considered for LT, these patients would have to
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