Best Practice & Research Clinical Anaesthesiology 29 (2015) 151e161

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Best Practice & Research Clinical

Anaesthesiology
journal homepage: www.elsevier.com/locate/bean

Hepatic and renal effects of cardiopulmonary

bypass
Nora Di Tomasso, MD, Consultant a, 1,
Fabrizio Monaco, MD, Consultant a, 1,
Giovanni Landoni, MD, Consultant & Associate Professor a, b, *
a
IRCCS San Raffaele Scientific Institute, Milan, Italy
b
Vita-Salute San Raffaele University, Milan, Italy

Keywords:
Although associated with low morbidity and mortality, cardio-
cardiopulmonary bypass
pulmonary bypass remains a “non-physiologic” device that carries
hepatic dysfunction
shock liver a set of complications. Hepatic and renal impairment are associ-
renal injury ated with a poor outcome. The knowledge of pathophysiology, risk
anaesthesia factors and therapeutic interventions can help the anaesthesiolo-
cardiac anaesthesia gist in preventing these complications in daily practice. The pre-
intensive care sent narrative review provides an update of the literature on the
acute kidney injury effects of cardiopulmonary bypass on hepatic and renal functions,
focussing on markers of hepatic and renal injuries, perioperative
strategies in preserving organ function and replacement therapies.
© 2015 Elsevier Ltd. All rights reserved.

The haemodynamic, inflammatory and organic responses to cardiac surgery with cardiopulmonary
bypass (CPB) are well known, and they can lead to multiorgan dysfunction. Although multiorgan
dysfunction after CPB is generally subclinical in nature due to the physiologic reserve and resilience of
the liver and kidneys, cardiac surgery requiring CPB is being carried out for an extended patient
population who are older and undergoing complex surgical procedures [1], and thus it places them at
an increased risk of hepatic and renal impairment.

* Corresponding author. San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milano, Italy. Tel.: þ39 02 26436151; Fax:
þ39 02 26436152.
E-mail addresses: ditomasso.nora@hsr.it (N. Di Tomasso), monaco.fabrizio@hsr.it (F. Monaco), landoni.giovanni@hsr.it
(G. Landoni).
1
San Raffaele Scientific Institute, Via Olgettina 60, Milano 20132, Italy. Tel.: þ39 02 26436151; Fax: þ39 02 26436152.

URL: http://www.unisr.it/persona.asp?id=8713&linguacv=english

http://dx.doi.org/10.1016/j.bpa.2015.04.001
1521-6896/© 2015 Elsevier Ltd. All rights reserved.
152 N. Di Tomasso et al. / Best Practice & Research Clinical Anaesthesiology 29 (2015) 151e161

Hepatic effects of CPB

The hepatic integrity is affected during cardiac surgery in particular when CPB is adopted [2e4],
even in uncomplicated elective surgery [5].
Microembolism, free radicals generation, inadequate tissue perfusion [6], dilutional anaemia [7]
and haemodynamic changes play a major role in the development of hepatic dysfunction. Hyper-
bilirubinaemia and transient elevation of hepatic enzymes are commonly observed after cardiac sur-
gery with CPB, but in the vast majority of patients, the hepatocellular function recovers a few days after
surgery without developing perioperative clinically relevant hepatic failure.
In high-risk patients with a reduced physiological reserve, a severe liver dysfunction after CPB can
occur. Pre-operative risk factors are right-side heart failure, moderate-to-severe tricuspid regurgita-
tion, pulmonary hypertension (systolic pulmonary pressure above 45 mm Hg), high preload (central
venous pressure (CVP) above 8 mm Hg) chronic heart failure, New York Heart Association (NYHA) class
IIeIV and low ejection fraction [8] are at a higher risk to develop liver dysfunction after CPB [9].
Interestingly, as reported by Van Deursen et al. in 323 patients with heart failure, the haemodynamic
profile can affect the liver function tests (LFTs). In fact, elevated LFTs mainly indicate a higher CVP,
whereas only the presence of elevated aspartate aminotransferase (AST), alanine aminotransferase
(ALT) or direct bilirubinaemia may indicate a low cardiac index (CI) [10].
Once established, liver dysfunction is associated with high mortality, morbidity [11] and costs. An
early detection and a prompt treatment of the causative factors can significantly improve outcome.
However, there is no agreement on which strategy significantly improves the perioperative hepatic
dysfunction, reducing consequentially morbidity and mortality. In particular, the literature fails to
clarify the pathophysiology of liver dysfunction related to the extracorporeal circulation (CPB and
extracorporeal membrane oxygenator (ECMO)), and to suggest specific biochemical markers or im-
aging techniques to detect the occurrence of hepatic dysfunction.

Pathophysiology and markers of liver dysfunction

In the setting of cardiac surgery, organ hypoperfusion has been reported in a percentage ranging
between 1.2% and 2.3%, with an increased risk in on-pump cases [2,11]. The incidence of hepatic failure
after cardiac surgery is as low as 0.1%, but it is associated with high mortality (74%) [11].
CPB-related liver impairment can be attributed both to a pro-inflammatory syndrome, with the
release of hepatotoxic cytokines, and to the haemodynamic changes related to surgery and CPB (i.e.,
hypotension, low cardiac output syndrome (LCOS), hypoxia and right ventricular (RV) dysfunction).
These factors lead to two different clinical syndromes that can occur together or separately, named
ischaemic hepatitis (“shock liver”) [12,13] and passive liver congestion, respectively (Table 1) [14]. For
both, risk factors are prior history of congestive heart failure (CHF), inadequate hepatosplanchnic blood
flow and difficult weaning from CPB.
Ischaemic hepatitis can be found after a period of relatively profound hypotension and haemody-
namic instability, and it is often associated with left ventricular dysfunction. The reduction in the
hepatic blood flow leads to a consequent hypoxia/anoxia of hepatocytes histologically characterised by
the centrilobular necrosis of zone 3 hepatocytes [15]. Biochemical markers of ischaemic hepatitis are an
increase of serum AST and serum ALT 10e20 times the normal value, a rise of lactate dehydrogenase
(LDH), total bilirubin and a deficiency of hepatic coagulation factors with a consequent prolongation of
prothrombin time (PT), 1e3 days after the ischaemic injury. Usually, these biochemical indices return to
normal within 5e10 days. If the hepatic biomarkers remain persistently high and other organs are
affected from the perioperative systemic hypoperfusion, multiorgan failure (MOF) can occur. MOF leads
to death in the majority of cases [16,17].
Congestive hepatopathy, also known as “nutmeg liver” [17], is a liver dysfunction usually associated
to right heart failure [18]. Venous congestion couples with high CVP, fluid retention and blood stasis,
and it is related to the deoxygenation of hepatocytes surrounding the central venule of the liver.
Typically, the histological pattern shows hyperaemia and congestion of the hepatic lobule central zone.
As hepatocytes, biliary epithelium and bile ducts are the most sensitive to lobular congestion (Fig. 1),
cholestatic LFTs, such as total serum bilirubin, gamma-glutamyl transpeptidase (GGT), alkaline
 N. Di Tomasso et al. / Best Practice & Research Clinical Anaesthesiology 29 (2015) 151e161 153

Table 1
Clinical and biochemical markers of congestive hepatopathy versus ischaemic hepatitis.

Congestive hepatopathy Ischaemic hepatitis

Co-morbidity RH failure; high CVP LV dysfunction;

Hypoperfusion; ATN
Symptoms Usually none; if present: Usually none; if present:
jaundice, RUQ discomfort jaundice, RUQ discomfort
nausea, anorexia, vomiting
Hepatomegaly Yes No
Hepatojugular reflux Yes No
Bilirubinaemia >3 mg/dL (unconjugated) >3 mg/dL
ALP Raised twice UNL
GGT Raised Normal
Aminotransferase 2e3 times UNL 10e20 times UNL
Serum albumin 2.5 g/dL normal
PT Mildly raised Raised
Ammonia Usually normal Usually normal
LDH Usually normal Massively raised
ALT/LDH ratio e <1.5

RH ¼ right heart; CVP ¼ central venous pressure; LV ¼ left ventricular; ATN ¼ acute tubular necrosis; RUQ ¼ right upper
quadrant; ALP ¼ alkaline phosphatase; UNL ¼ upper normal limit; GGT ¼ gamma-glutamyl transpeptidase; PT ¼ prothrombin
time; LDH ¼ lactate dehydrogenase; ALT ¼ alanine transaminase.

Fig. 1. Hepatic lobule and mechanisms of liver injury. Centrilobular zone, sensitive to ischaemia; bile ducts, sensitive to lobular
congestion.

phosphatase (ALP) and albuminaemia, are severely abnormal. Conversely, AST and ALT are normal or
only moderately altered [19]. A mix of ischaemic and congestive hepatopathy pattern can be observed
when RV dysfunction is not promptly treated. A reduced left ventricle preload, related to RV failure,
results in an LCOS and impaired perfusion of hepatosplanchnic circulation [12].
CPB is probably one of the determinants of post-operative hepatic failure, but, as demonstrated by
Ascione et al. [2], patients undergoing off-pump cardiac surgery can develop this detrimental
complication as well. Probably, haemodynamic control, rather than CPB management, plays a pivotal
role in preventing hepatic failure in cardiac surgery.
However, predisposing factors can be identified: female gender, history of CHF, complex cardiac
surgery with prolonged CPB and aortic cross-clamp time, infective endocarditis and transfusions [11].
Post-operative liver dysfunction can be detected as an increase in both liver enzymes and bilir-
ubinaemia (>3 mg/dL or 51 mmol/L) [17]. The latter, which can be observed in a setting of normal LFTs,
154 N. Di Tomasso et al. / Best Practice & Research Clinical Anaesthesiology 29 (2015) 151e161

is an independent predictor of worse outcome after cardiac surgery accounting for 25% mortality
[20,21]. The risk factors for hyperbilirubinaemia are the same as the ones for hepatic failure [22].
Intrahepatic cholestasis rather than cell necrosis [23] seems related to post-CPB hyper-
bilirubinaemia and jaundice. Post-operative jaundice due to conjugated bilirubin has been associated
with a defect of the hepatic excretion of bilirubin [24]. This mainly occurs following gaseous micro-
emboli and debris during CPB.
On the contrary, post-operative jaundice due to unconjugated bilirubin is related to hepatocellular
damage, liver congestion, haemolysis or blood transfusion. Therefore, the increase of unconjugated
bilirubin is more frequently transient and less associated to mortality.
The biochemical markers routinely adopted in the post-operative period are tardive and affected by
low specificity. Thus, new markers have been proposed.
Sander et al. have observed that the plasma clearance of indocyanine green is an excellent method
for measuring the hepatic function and perfusion in 60 patients undergoing normothermic coronary
artery bypass grafting (CABG) [25,26]. Another precocious index of subclinical liver impairment is
monoethylglycinexylidide (MEGX)/lidocaine levels ratio [2]. MEGX is measured 15 and 30 min after
intravenous injection of 1 mg/kg bolus of lidocaine. Finally, Theodorakis et al. showed that the ultra-
sonographic evaluation of the portal vein and hepatic artery is a good predictor of post-operative
elevation of ALT [27]. However, further investigations on direct hepatic haemodynamic ultrasound
approach are needed.

Patient with pre-operative liver disease

Pre-operative liver dysfunction is a rare (0.5%) and detrimental condition in patients undergoing
cardiac surgery [28]. Two scores named ChildeTurcotteePugh (ChildePugh) [29] and model for end-
stage liver disease (MELD) have been proposed to stratify the risk of the patients with pre-operative
liver dysfunction undergoing cardiac surgery. Neither of the two has been prospectively validated in
this setting (Table 2).
The ChildePugh score considers two qualitative variables (ascites and encephalopathy), and three
laboratory tests, serum bilirubin, serum albumin and international normalised ratio (INR). The major
limitations are the subjective classification of the ascites and encephalopathy, and the “ceiling effect” of
the variables considered in the score [29].
The MELD score includes three standardised laboratory tests: INR, serum creatinine (sCrea) and
serum bilirubin, arranged in a mathematical formula. It has been validated to allocate organs for liver
transplantation. Although MELD score overcomes some Child score limitations, it fails to predict
perioperative mortality; thus, the American Society of Anaesthesiologists (ASA) physical status class,
the surgical severity score and cardiopulmonary co-morbidity have to be included [30].
Several studies have investigated perioperative mortality of patients who underwent cardiac sur-
gery with pre-operative liver disease [31,32]. Filsoufi et al. [28] reported, in a retrospective study, an
overall mortality of 26% after cardiac surgery in patients with cirrhosis, and an adjusted mortality of

Table 2
Model for end-stage liver disease (MELD) and ChildeTurcotteePugh (ChildePugh) scores to stratify the risk of patients with pre-
operative liver dysfunction undergoing cardiac surgery.

Objective variables Subjective variables Score Mortality

INR s-Bilirubin mg/dL s-Creatinine s-Alb Ascites Encephalopathy

mg/dL g/dL

MELD 11.2  3.78  9.57  loge(sCr) NO NO NO <9 2%

formula ¼ loge(INR)þ loge(sBil)þ þ6.4 >30 >50%

Child 1 <1.7 points <2 NO >3.5 Absent Absent 5e6 Child-A

points 2 1.7e2.3 2e3 2.8e3.5 Mild 1e2 Treatable 7e9 0%

3 >2.3 >3 <2.8 Mod-Severe 3e4 Refractory 10e15 Child-B
20%
Child-C
55%
 N. Di Tomasso et al. / Best Practice & Research Clinical Anaesthesiology 29 (2015) 151e161 155

11%, 18% and 67% in patients classified as ChildePugh A, B and C, respectively. Other authors reported a
mortality of 100% for patients with advanced liver disease (ChildePugh C) [33]. Morimoto et al. have
not confirmed these findings: they have observed, in a small retrospective study, that MELD rather than
Child predicts the operative mortality after cardiac surgery [34]. Similarly, Arif et al. in a population of
106 patients with cirrhosis undergoing cardiac surgery have reported a significantly higher area under
the curve for the MELD score and Euroscore than Child in predicting a 30-day mortality [35]. In a recent
retrospective paper led on a small cohort of 55 patients undergoing cardiac surgery with mild or severe
cirrhosis, neither MELD nor Child predicts early and late mortalities [36].
According to current data and our experience, it is important not to preclude patients with
advanced cirrhosis, on the basis of the MELD and Child classification, from cardiac surgery.
The use of CPB is related to a higher rate of complications. For instance, Hayashida et al. observed a
lower incidence of complications in patients undergoing off-pump coronary artery bypass surgery
compared to those undergoing on-pump surgery [37]. The major post-operative complications related
to pre-operative liver impairment are refractory coagulopathy, an increased susceptibility to infections,
a higher rate of RV failure, portopulmonary hypertension and hepatorenal syndrome (HRS). Therefore,
perioperative therapy optimisation is mandatory to minimise morbidity, mortality, hospital stay and
costs [38,39].
In conclusion, the surgical risk in hepatopathic patients undergoing cardiac surgery requiring CPB
remains high, and the standard surgical option has to be reserved to patients in whom other ap-
proaches (i.e., percutaneous cardiac surgery) are not feasible. Pre-operative therapy optimisation, strict
intraoperative monitoring of both haemodynamics (i.e., transoesophageal echocardiography and/or
continuous cardiac output monitoring) and coagulation (i.e., thromboelastography) [38] are manda-
tory to improve outcome.

Therapeutic intervention

Pre-operative
The first-line therapy of hepatic dysfunction is prevention. The identification of risk factors allows
prompt support of liver function, especially in patients with pre-operative liver dysfunction.
Usually, hepatic failure is related to LCOS and perioperative haemodynamic instability; thus, the
precocious use of inotropes/vasopressor or extracorporeal circulatory supports (intra-aortic balloon
pump (IABP), ECMO and ventricular assist device (VAD)) can reduce hepatic insults by optimising
organ perfusion. Pre-operative therapy and haemodynamic support of hepatopathic patients have to
be optimised before the surgery.

Intraoperative
The mean arterial pressure (MAP) is the circulatory system-driving pressure; thus, it should be
maintained above 60 mm Hg during surgery. However, the best MAP able to guarantee an adequate
liver perfusion remains unknown [40]. On the contrary, CVP should be as low as possible, compatibly
with a satisfactory stroke volume, in order to avoid liver congestion.
The use of fluids should be strictly monitored, and a dry approach preferred. In case of blood
transfusion, the benefits have to overcome the risks.
Metabolism and systemic effects of medications chronically administered have to be taken into
account during general anaesthesia (GA). The hypotensive effect of GA can reduce liver perfusion
pressure below a critical threshold. In case of acute liver dysfunction, the metabolism of anaesthetic
drugs is decreased, causing toxic effects and accumulation.
Although the haemodynamic stability rather than the anaesthesia “per se” is related to liver
dysfunction, the following considerations have to be taken into account. Most of the anaesthetic
medications undergo hepatic metabolism, which may be profoundly altered during liver disease. The
way hepatic metabolism acts on anaesthetic drugs is biphasic. The first step, usually altered in liver
disease, is cytochrome-p450-mediated, while the second step, often normal at the beginning of liver
dysfunction, is glucuronide conjugation. The distribution volume of drugs can significantly be affected
when hypoalbuminaemia coexists with liver dysfunction. These changes result in increased concen-
trations and reduced plasma clearance of drugs, which are often difficult to predict. For example,
156 N. Di Tomasso et al. / Best Practice & Research Clinical Anaesthesiology 29 (2015) 151e161

propofol may be more manageable than benzodiazepines because of its rapid redistribution in patients
with cirrhosis, also when administered in continuous perfusion [41]. In the same way, the metabolism
of opioids (morphine, fentatienil and fentanyl) is decreased during hepatic impairment, leading to a
slower elimination and a higher risk of toxicity [42]. Conversely, remifentanil, a newer opioid, is
metabolised by esterases that are widespread throughout the plasma, red blood cells and interstitial
tissues. For this favourable pharmacokinetic profile, we suggest administering continuous-perfusion
remifentanil rather than other opioids in patients with advanced liver dysfunction undergoing car-
diac surgery. Rocuronium and vecuronium are neuromuscular blocking agents (NBAs) metabolised by
the liver. Khalil et al. reported slower onset and longer duration of action when these agents were
administered in patients with liver disease [43,44]. On the contrary, atracurium and cisatracurium, as
their metabolism is not dependent on the hepatic function, have been suggested as the NBA of choice
during hepatic disease [45]. The use of halogenated anaesthetics in the context of liver dysfunction is
still debated because of their hepatotoxic effect. The metabolism of halothane, enflurane, isoflurane
and desflurane is dependent on cytochrome p450, and it may produce trifluoroacetylated components.
Besides, especially for halothane (no longer available in Western countries) and more rarely for the
newer halogenated agents, an autoimmune-mediated liver dysfunction can occur [46]. Among the
halogenated agents, sevoflurane, which is not metabolised to trifluoroacetyl compounds, has shown
less liver toxicity [45].

Post-operative
Once liver dysfunction has occurred, it is mandatory to precociously treat it by avoiding further
organ impairment. Kidney dysfunction, in particular, is commonly related to the end-stage liver disease
in the setting of HRS. As this fatal complication is associated with a very poor prognosis, during the last
decades therapeutic interventions aiming to reduce mortality have been investigated.
The optimisation of systemic haemodynamics and the improvement of renal perfusion are deter-
minant to reverse HRS, as confirmed by Solanki et al. [47], who demonstrated an improved survival at
15 days in patients treated with terlipressin.
Terlipressin, an analogue of arginine vasopressin, is a potent vasoconstrictor of splanchnic arterial
system. It increases MAP and urine output, and it decreases sCrea, plasma renin activity and plasma
aldosterone. A recent meta-analysis [48] of randomised trials confirmed that terlipressin improves HRS
reversal with no significant differences compared to noradrenaline. Moreover, Nguyen-Tat et al. re-
ported that terlipressin in combination with albumin improves survival in patients affected by HRS
[49]. Besides, albumin, compared to crystalloid and other colloids, has shown a nephroprotective effect
in patients with advanced liver disease who need volume expansion [50].
Liver replacement therapy, in which the detoxifying procedure is carried out with a molecular-
adsorbent recirculating system (MARS), has been extensively tested in patients with acute and
chronic liver diseases. Although MARS therapy is well tolerated and reduces hepatic toxins, it remains
unclear whether this “liver dialysis” improves the outcome, in the context of HRS [51].

Renal effects of CPB

Renal dysfunction after cardiac surgery remains a common complication and an independent pre-
dictor of post-operative morbidity and mortality [52]. The incidence is still unclear, and it ranges between
7% and 28% depending on the definitions of acute kidney injury (AKI). Post-operative renal replacement
therapy (RRT) is required in 1.4% of patients, and this percentage is higher in case of complex surgical
procedures (1% for isolated CABG; 5.1% for combined CABG and mitral valve surgery) [53].
The pathogenesis of AKI after cardiac surgery is multifactorial. As in the case of hepatic failure, the
release of pro-inflammatory agents, haemodynamic changes during CPB and patient-related predis-
posing factors may trigger AKI [54]. In particular, activated complement system, up-regulation of cy-
tokines, activation of platelets, oxygen-free radicals, among the others, are related to leucocyte
migration and fluid overload in the renal cellular interstitium [55]. The final result is a cytotoxic tubular
injury. Kidneys are sensitive to haemodynamic changes occurring in cardiac surgery. Renal medulla is
more prone to ischaemia than other organs, due to its peculiar blood circulation characterized by low
oxygen tension with limited reserve. Other intraoperative factors related to acute tubular necrosis
 N. Di Tomasso et al. / Best Practice & Research Clinical Anaesthesiology 29 (2015) 151e161 157

(ATN) are [1] perioperative ischaemic-reperfusion injury [2], low cardiac output syndrome (LCOS) [3],
vasoconstriction [4], hypovolmia [5] and haemodilution/anaemia [56].
The optimisation of intraoperative haemodynamic can prevent AKI. There is no target MAP or
haematocrit during CPB able to reduce the risk of AKI.
For example, Azau et al. [57] reported that a higher MAP does not reduce the incidence of AKI, length
of hospital stay and mortality rate compared to a lower MAP. Ranucci et al. [58] observed, in a pro-
spective observational study, that a high degree of haemodilution, with consequent low haematocrit, is
an independent risk factor for post-operative renal dysfunction, particularly when associated with a
low oxygen delivery (DO2). In fact, an adequate pump blood-flow rate could counteract the negative
effects of a low haematocrit, improving the DO2.
The loss of a pulsatile flow can add further insult to the kidney. On the contrary, a pulsatile flow,
during CPB, reduces vasoconstrictive reflexes, optimises oxygen consumption and decreases acidosis
[59]. Microemboli and hypothermia can be involved significantly in the genesis of AKI.
Because of the clinical impact of even mild pre-operative renal dysfunction on the post-operative
outcome, some authors have suggested to include mild renal dysfunction in the EuroSCORE system
[60,61].
In summary, the major risk factors for AKI during cardiac surgery are the duration of CPB and the
cross-clamp time [62,63]. Further studies are necessary to investigate a more reliable method for risk
stratification and perioperative haemodynamic optimisation.

Biomarkers of AKI

An early diagnosis of AKI is decisive to prevent any further progression of renal damage. The RIFLE
score is based on creatinine increase and reduction of urinary output [64] as markers of renal
impairment. Its major limitation is the use of sCrea as a surrogate for glomerular flow rate (GFR). The
sCrea is not a specific marker of renal impairment; in fact, it can be altered by age, trauma, fever and
immobilisation. Moreover, sCrea is a late marker of AKI, and the trend, rather than the single value, is
more reliable [65].
Several experimental biomarkers of AKI have been tested, but none of them has been adopted into
clinical practice [66].
Cystatin-C showed a higher sensitivity than creatinine in identifying precociously AKI in cardiac
surgery [67].
Neutrophil gelatinase-associated lipocalin (N-GAL) is another marker of renal proximal tubular
injury [68]. Several observational studies have reported that urinary N-GAL is specific and sensitive in
predicting AKI 1 h after CPB [69]. This biomarker has also been tested to discriminate prerenal from
intrinsic AKI [70].
The interleukin (IL)-6 [71] and IL-18 [70], expression of systemic inflammatory response, produced
by proximal renal tubules, have also been investigated. The TRIBE (Translational Research Involving
Biomarkers and Endpoints) study [72] recently validated the clinical predictivity of plasma N-GAL and
urine IL-18 in estimating postcardiac surgery AKI and relative outcomes, with an area under the curve
of 0.75 and 0.76, respectively.
Further studies are needed to determine which biochemical markers of AKI are able to guide
therapeutic interventions and to significantly change patients' outcome.

Therapeutic interventions

To date, no specific therapeutic strategies are recommended to prevent AKI in patients undergoing
cardiac surgery with or without CPB. Obviously, CPB adding cross-clamp, cardioplegia, haemodilution
and hypothermia are detrimental for the kidney. As observed by several authors, cardiac surgery
without CBP (off-pump CPB) carries less post-operative AKI compared to on-pump surgery [73,74].
However, neither a decrease of mortality [75] nor a better preservation of long-term kidney function
has been reported [76]. A recent systematic review and international survey identified several drugs,
techniques or strategies that could reduce mortality in patients with or at risk of AKI, as suggested by at
least one peer-reviewed manuscript showing statistically significant effect on survival [77].
158 N. Di Tomasso et al. / Best Practice & Research Clinical Anaesthesiology 29 (2015) 151e161

Perioperative haemodynamic optimisation, albumin administration in cirrhotic patients, peri-

angiography haemofiltration, plasma exchange in multiple-myeloma-associated AKI, increased in-
tensity and early use of renal replacement therapy, vasopressin in septic shock and furosemide by
continuous infusion, among others, have at least one manuscript supporting their beneficial effect on
survival in patients with, or at risk of, AKI.
In daily practice, the following approaches can be suggested:

1. The maintenance of MAP above 60 mm Hg during CPB. This target is not specific; in patients with
hypertension or diabetes, this threshold should probably be higher, to guarantee good renal
perfusion and consequent urinary output.
2. The maintenance of euvolaemia. In the setting of cardiac surgery with CPB, cardioplegia is a key
point. The risk of fluid overload is higher with crystalloid cardioplegia than with blood cardioplegia.
In the former, an adequate urinary output must be guaranteed.
3. The avoidance of low haematocrit. The kidney is sensitive to anaemia. Ranucci et al. have recom-
mended not tolerating haematocrit levels <25% during CPB.
4. Cardiac output support. The treatment of heart dysfunction is a cornerstone. A prompt use of
inotropes, vasopressors and paracorporeal devices provides sufficient renal perfusion pressure,
minimising renal damage.

Levosimendan, a calcium-sensitising agent increasing the contractility of cardiomyocytes without

increasing oxygen demand, is the most promising agent for AKI reduction, by acting on cardiac per-
formance [78]. Obviously, a pre-operative low ejection fraction is a risk factor for AKI.

5. The avoidance of nephrotoxic agents.

6. The administration of renoprotective drugs. A recent multicentre study has reported that fenol-
dopam does not reduce post-operative AKI and mortality in the setting of cardiac surgery [79].
Similarly, dopamine has shown no benefits in preventing renal dysfunction [80].
7. The type of administered fluid. A recent meta-analysis [81] of randomised trials supported the hy-
pothesis that albumin is nephroprotective, and hydroxyethyl starch is nephrotoxic. Albumin reduces
renal dysfunction and death, particularly in cirrhotic patients with spontaneous peritonitis [50].
8. The administration of terlipressin in extreme splanchnic vasodilatation syndrome.

HRS, indeed, as previously mentioned, is a common clinical state of renal impairment occurring in
cirrhotic patients, characterised by an intense renal vasoconstriction and reduced glomerular filtration.
This is probably due to the extreme splanchnic vasodilation and the relative reduced arterial volume.
Terlipressin, as a specific vasoconstrictor for splanchnic vessels, seems to improve circulatory function
and renal perfusion [47] in HRS.
Similarly, some studies showed that vasopressin [82,83] may reduce the progression of renal failure
and mortality in patients with septic shock, which is characterized by vasodilation and hyperdynamic
circulation. However, current clinical data are insufficient to conclude that one vasoactive agent is
better than another in preventing renal injury [84].

Conclusions

Post-operative hepatic and renal impairment are two of the most dreadful complications following
cardiac surgery requiring CPB. Nowadays, there are no conclusive studies on the prevention of hepatic
and renal perioperative failure. Further well-designed studies on the management of hepatic and renal
dysfunctions after cardiac surgery are necessary.

Conflict of interest statement

None.
 N. Di Tomasso et al. / Best Practice & Research Clinical Anaesthesiology 29 (2015) 151e161 159

Research agenda

 There is an urgent need to find more specific scores to classify patients at risk of renal and
hepatic dysfunction after CPB
 There is a need for stronger evidence about the negative effects of CPB on renal and hepatic
functions (e.g., comparison with off-pump surgery)
 Further works on novel hepatic and renal markers are warranted
 We need urgent well-designed randomised trials on the effectiveness of haemodynamic
optimisation in cardiac surgery for the prevention of organ failure and death

Practice points

 Every patient undergoing cardiac surgery should be clinically assessed and managed to
reduce the risk to develop renal or liver dysfunction
 In selected cases, multispecialty collaboration between cardiac surgeons, anaesthesiologists
and gastroenterologists or nephrologists is indispensable to correctly formulate the indica-
tion for surgery in patients with advanced liver (Child B or C) or kidney disease
 Perioperative haemodynamic optimisation is the most important factor to prevent both liver
and renal failure

Acknowledgements

The authors gratefully acknowledge the technical contribution of Alberto Castella and Valentina
Tarzia (San Raffaele Scientific Institute). None received compensation for their contributions.
This work was supported by departmental funds only. The department (sponsor) had no role in the
design of the study; the analysis and interpretation of the data; preparation, review or approval of the
manuscript; and decision to submit the manuscript for publication.

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