Best Practice & Research Clinical Anaesthesiology 29 (2015) 151e161
Contents lists available at ScienceDirect
Best Practice & Research Clinical Anaesthesiology journal homepage: www.elsevier.com/locate/bean
5
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 b
IRCCS San Raffaele Scientific Institute, Milan, Italy Vita-Salute San Raffaele University, Milan, Italy
Keywords: cardiopulmonary bypass hepatic dysfunction shock liver renal injury anaesthesia cardiac anaesthesia intensive care acute kidney injury
Although associated with low morbidity and mortality, cardiopulmonary bypass remains a “non-physiologic” device that carries a set of complications. Hepatic and renal impairment are associated with a poor outcome. The knowledge of pathophysiology, risk factors and therapeutic interventions can help the anaesthesiologist in preventing these complications in daily practice. The present narrative review provides an update of the literature on the 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: [email protected] (N. Di Tomasso), [email protected] (F. Monaco), [email protected] (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.
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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. Hyperbilirubinaemia and transient elevation of hepatic enzymes are commonly observed after cardiac surgery 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 regurgitation, 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 imaging 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 haemodynamic 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
Symptoms
Usually none; if present: jaundice, RUQ discomfort
Hepatomegaly Hepatojugular reflux Bilirubinaemia ALP GGT Aminotransferase Serum albumin PT Ammonia LDH ALT/LDH ratio
Yes Yes >3 mg/dL (unconjugated) Raised Raised 2e3 times UNL 2.5 g/dL Mildly raised Usually normal Usually normal e
LV dysfunction; Hypoperfusion; ATN Usually none; if present: jaundice, RUQ discomfort nausea, anorexia, vomiting No No >3 mg/dL twice UNL Normal 10e20 times UNL normal Raised Usually normal Massively raised 3 mg/dL or 51 mmol/L) [17]. The latter, which can be observed in a setting of normal LFTs,
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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 hyperbilirubinaemia 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 microemboli 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 ultrasonographic 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 endstage 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 surgery 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 preoperative liver dysfunction undergoing cardiac surgery. Objective variables INR MELD 11.2 formula ¼ loge(INR)þ Child 1 points 2 3
Subjective variables
s-Bilirubin mg/dL s-Creatinine mg/dL 3.78 loge(sBil)þ
2.3
s-Alb g/dL
9.57 loge(sCr) NO þ6.4 NO
Ascites
Encephalopathy
NO
NO
Score
Mortality
30
2% >50%
Absent Absent >3.5 Child-A 5e6 1e2 Treatable 7e9 2.8e3.5 Mild 0% Mod-Severe 3e4 Refractory 10e15 Child-B
Contents lists available at ScienceDirect
Best Practice & Research Clinical Anaesthesiology journal homepage: www.elsevier.com/locate/bean
5
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 b
IRCCS San Raffaele Scientific Institute, Milan, Italy Vita-Salute San Raffaele University, Milan, Italy
Keywords: cardiopulmonary bypass hepatic dysfunction shock liver renal injury anaesthesia cardiac anaesthesia intensive care acute kidney injury
Although associated with low morbidity and mortality, cardiopulmonary bypass remains a “non-physiologic” device that carries a set of complications. Hepatic and renal impairment are associated with a poor outcome. The knowledge of pathophysiology, risk factors and therapeutic interventions can help the anaesthesiologist in preventing these complications in daily practice. The present narrative review provides an update of the literature on the 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: [email protected] (N. Di Tomasso), [email protected] (F. Monaco), [email protected] (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. Hyperbilirubinaemia and transient elevation of hepatic enzymes are commonly observed after cardiac surgery 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 regurgitation, 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 imaging 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 haemodynamic 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
Symptoms
Usually none; if present: jaundice, RUQ discomfort
Hepatomegaly Hepatojugular reflux Bilirubinaemia ALP GGT Aminotransferase Serum albumin PT Ammonia LDH ALT/LDH ratio
Yes Yes >3 mg/dL (unconjugated) Raised Raised 2e3 times UNL 2.5 g/dL Mildly raised Usually normal Usually normal e
LV dysfunction; Hypoperfusion; ATN Usually none; if present: jaundice, RUQ discomfort nausea, anorexia, vomiting No No >3 mg/dL twice UNL Normal 10e20 times UNL normal Raised Usually normal Massively raised 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 hyperbilirubinaemia 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 microemboli 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 ultrasonographic 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 endstage 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 surgery 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 preoperative liver dysfunction undergoing cardiac surgery. Objective variables INR MELD 11.2 formula ¼ loge(INR)þ Child 1 points 2 3
Subjective variables
s-Bilirubin mg/dL s-Creatinine mg/dL 3.78 loge(sBil)þ
2.3
s-Alb g/dL
9.57 loge(sCr) NO þ6.4 NO
Ascites
Encephalopathy
NO
NO
Score
Mortality
30
2% >50%
Absent Absent >3.5 Child-A 5e6 1e2 Treatable 7e9 2.8e3.5 Mild 0% Mod-Severe 3e4 Refractory 10e15 Child-B
