Anaesthesia evaluation and perioperative strategies in liver disease patients with cardiohepatic syndrome

Abstract

Cardiohepatic syndrome (CHS) presents a significant challenge in perioperative management due to the complex interaction between liver and heart dysfunction. CHS, analogous to cardiorenal syndrome, encompasses various conditions where hepatic and cardiovascular pathologies exacerbate one another. Patients with chronic liver disease, cirrhosis, or heart failure often exhibit increased perioperative morbidity and mortality, necessitating tailored anesthetic strategies. A comprehensive understanding of CHS pathophysiology is crucial, as it informs risk assessment and guides perioperative management. Risk stratification tools such as the Child-Pugh and MELD scores are commonly used, but they have limitations in fully capturing perioperative risks. The updated STS 2024 model includes liver-specific parameters, improving risk prediction in cardiac surgeries. Additionally, the VOCAL-Penn score addresses gaps in traditional risk models, providing a more accurate assessment for patients with advanced liver disease.

Perioperative management focuses on minimizing hemodynamic stress and avoiding drugs metabolized by the liver. Agents like Remifentanil, Atracurium, and Esmolol are preferred for their minimal hepatic metabolism. Vasopressors such as terlipressin and vasopressin, which target the splanchnic circulation, improve hemodynamics in these patients. Within the Enhanced Recovery After Surgery (ERAS) framework, optimizing nutrition and fluid management is essential for reducing perioperative complications.

Effective management of patients with CHS requires a multidisciplinary approach that integrates comprehensive risk assessment and individualized anesthetic strategies. This approach improves outcomes by reducing perioperative complications and mortality in this high-risk population.

Resumen

El síndrome cardiohepático (SCH) representa un desafío importante para el manejo perioperatorio debido a la compleja interacción entre la función hepática y cardíaca. El SCH abarca diversas condiciones en las que las patologías hepáticas y cardiovasculares se exacerban mutuamente. Los pacientes con enfermedad hepática crónica, cirrosis o insuficiencia cardíaca suelen presentar una mayor morbilidad y mortalidad perioperatoria, lo que requiere estrategias anestésicas personalizadas. Una comprensión integral de la fisiopatología del SCH es valiosa para optimizar la evaluación de riesgos y guía el manejo perioperatorio. Las herramientas de estratificación de riesgo como las puntuaciones Child-Pugh y MELD se utilizan comúnmente, pero tienen limitaciones a la hora de calcular los riesgos perioperatorios. El modelo actualizado STS 2024 incluye parámetros específicos del hígado, mejorando la predicción de riesgos en cirugía cardíaca. La nueva puntuación VOCAL-Penn aborda las brechas en los modelos de riesgo tradicionales, proporcionando una evaluación más precisa para pacientes con enfermedad hepática avanzada.

El manejo perioperatorio se centra en minimizar el estrés hemodinámico y evitar fármacos de metabolismo hepático. Drogas como el Remifentanilo, el Atracurio y el Esmolol son preferidos por su mínimo metabolismo hepático. Vasopresores como la terlipresina y la vasopresina, que actúan sobre la circulación esplácnica, mejoran la hemodinámica en estos pacientes. Dentro del marco de Recuperación Intensificada post Cirugía (ERAS, por sus siglas en inglés), la optimización de la nutrición y el manejo de líquidos es esencial para reducir las complicaciones perioperatorias.

El manejo efectivo de los pacientes con SCH requiere un enfoque multidisciplinario que integre una evaluación de riesgos exhaustiva y estrategias anestésicas individualizadas. Este enfoque mejora los resultados al reducir las complicaciones perioperatorias y la mortalidad en esta población de alto riesgo.

Introduction

Patients with cardiohepatic syndrome (CHS) represent a unique challenge in perioperative care due to the interdependence between hepatic and cardiovascular dysfunction. CHS, which is analogous to cardiorenal syndrome, describes a range of conditions where dysfunction in the liver and heart are mutually exacerbated. CHS is increasingly recognized in clinical practice, particularly in patients with chronic liver disease, cirrhosis, and heart failure. These patients often present for surgery with higher rates of morbidity and mortality due to this complex interplay.

The global burden of liver disease continues to rise, with cirrhosis affecting over 2 million people worldwide annually, often coexisting with cardiac dysfunction. In perioperative settings, this dual organ failure complicates anaesthesia management and requires tailored strategies. For instance, patients with CHS face a unique set of risks, including hemodynamic instability, altered drug metabolism, and heightened susceptibility to complications such as coagulopathy and kidney failure. Understanding these risks and how they affect perioperative management is crucial for improving outcomes. To better understand the complications that arise during anaesthesia in patients with liver disease, it is essential to first review the anatomy and function of the liver. The liver, being the largest visceral organ in the human body, plays a central role in regulating the body's metabolic functions. It receives 25% of total cardiac output through a double circulatory system: 75% from the portal vein and 25% from the hepatic artery. This dual blood supply allows the liver to maintain significant functional reserve, even if blood flow is compromised. However, as liver function deteriorates, so too does its ability to maintain metabolic homeostasis and protein function, with clinical consequences becoming evident once its capacity drops below 30%. Understanding the underlying mechanisms of liver/heart interaction in cardiohepatic syndrome is key to developing effective management strategies.^1–3

Pathophysiology of perioperative liver failure

Cardiohepatic syndrome, drawing an analogy to cardiorenal syndrome, was first described by Poelzl & Auer as the bidirectional interaction between the liver and the heart, leading to a spectrum of interrelated disorders caused by neurohormonal and cytotoxic mechanisms. Five types of CHS have been defined, depending on whether the primary dysfunction originates in the heart or liver (Table 1). CHS type I is characterized by hypoperfusion and ischaemic liver injury despite the liver's ability to extract up to 95% of oxygen from the blood. When a critical decrease in blood flow occurs, hypoxaemia predominantly affects the centrilobular area, resulting in marked increases in transaminases, indicative of cytolysis induced by ischaemia. CHS type II presents a pattern of cholestasis caused by increased pressure in the right heart circuit. Elevated hydrostatic pressure leads to bile canaliculi compression, reversing bile flow and raising serum levels of alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT).^1–3 This pattern is typically associated with chronic right-sided heart failure. While CHS types I and II are primarily cardiac in origin, CHS type III occurs due to acute liver failure, often triggered by trauma, toxins (such as paracetamol poisoning), or infection. This leads to hyperdynamic circulation and systemic inflammatory response syndrome (SIRS). In 60% of cases, adrenal insufficiency exacerbates haemodynamic instability. Early identification and management of adrenal insufficiency, such as corticosteroid replacement therapy, can stabilize patients during the perioperative period.⁴ CHS type IV arises from chronic liver disease leading to progressive cardiac dysfunction, often asymptomatic until triggered by stressors such as surgery or infection. These patients are prone to cirrhotic cardiomyopathy, and exhibit features such as QT prolongation and diastolic dysfunction. Mechanistically, impaired β-adrenergic receptor signalling, nitric oxide overproduction, and increased endocannabinoid activity contribute to this form of cardiac failure. Lastly, CHS type V involves simultaneous dysfunction of both organs due to systemic conditions, such as sepsis, amyloidosis, or genetic disorders such as Wilson’s disease or haemochromatosis. For instance, infections such as HIV and hepatitis C can cause myocarditis, further complicating management in these patients.^1,5–8 See Fig. 1. Clinically, patients with CHS present high perioperative risk due to the combined impact of splanchnic vasodilation, hyperdynamic circulation, and impaired response to vasopressors such as norepinephrine.^9–11 These factors, along with elevated pulmonary capillary wedge pressure and central venous pressure (CVP), challenge fluid and haemodynamic management. Medications such as terlipressin, which selectively constricts splanchnic circulation, offer therapeutic benefits by redistributing blood flow to critical organs.^12,13

Table 1.

Comparison of cardiohepatic syndrome types and identification.

Type of CHS	Primary Cause	Clinical Features	Mechanism of Liver Damage	Diagnostic Clues / How to Identify	Management Focus
CHS Type I	Acute cardiac failure	- Marked hypotension - Shock liver - Increased AST/ALT	Hypoperfusion and ischemia; central lobular necrosis	- Sudden rise in liver enzymes (AST/ALT) - History of acute heart failure or cardiogenic shock	- Stabilize cardiac function - Monitor and support liver function - Manage shock and improve perfusion
CHS Type II	Chronic right-sided heart failure	- Ascites - Jaundice - Peripheral oedema	Passive congestion due to elevated right atrial pressure	- Hepatomegaly, ascites - Right-sided heart failure on imaging (echocardiogram, CXR)	- Reduce right-sided heart pressures - Diuretics, venodilators - Manage ascites and fluid overload
CHS Type III	Acute liver failure	- Hyperdynamic circulation - SIRS - Coagulopathy	Systemic inflammation and SIRS with hypotension	- Liver dysfunction (high bilirubin, INR) - Signs of sepsis or toxicity (e.g., acetaminophen, hepatitis)	- Supportive care - Manage SIRS, liver failure - Consider corticosteroid therapy for adrenal insufficiency
CHS Type IV	Chronic liver disease leading to cardiac dysfunction	- Fatigue - Dyspnoea - Cirrhosis-related findings (ascites, varices)	Cirrhotic cardiomyopathy (impaired diastolic function, QT prolongation)	- Cirrhosis on history/imaging - Echocardiogram: diastolic dysfunction, QT prolongation	- Manage both liver disease and cardiomyopathy - Beta-blockers for heart rate control
CHS Type V	Simultaneous cardiac and liver dysfunction due to systemic illness	- Fever - Fatigue - Multi-organ failure	Multiorgan dysfunction due to sepsis or systemic disease	- Signs of sepsis or systemic illness (e.g., amyloidosis, Wilson's disease, viral infections)	- Treat underlying cause (infection, amyloidosis) - Support both liver and cardiac functions

Figure 1.

Schematic representation of cardiohepatic syndrome in its different forms, causes and associated manifestations.

Pre-anaesthesia risk assessment

The first step in selecting an appropriate anaesthesia strategy is a comprehensive clinical evaluation to estimate the type and degree of liver involvement as accurately as possible. Several scoring systems have been developed to predict perioperative risk in patients with liver disease, with the Child-Pugh and MELD (Model for End-Stage Liver Disease) scores being the most widely used. However, each of these systems has limitations, especially when assessing dynamic factors that complicate perioperative risk. The Child-Pugh score, though extensively used, incorporates subjective elements such as encephalopathy and ascites, leading to variability in interpretation depending on the clinician's expertise. The MELD score, initially developed for liver transplant candidates undergoing TIPS, has been refined over time, with the latest version, MELD 3.0, incorporating factors such as sodium, albumin, and sex to improve its predictive power beyond transplant medicine. Because of these additions, MELD 3.0 provides a more comprehensive, accurate estimation of outcomes in a broader range of surgical contexts.^14–16 Despite these advances, traditional scoring systems often fail to capture the full scope of risk in patients undergoing cardiothoracic procedures. For example, cardiothoracic anaesthesia poses unique challenges in patients with liver involvement, and requires additional risk predictors. To meet this need, the STS 2024 scoring system has been updated to include more detailed calculations of morbidity and mortality in patients undergoing cardiac procedures. The new model adjusts for factors such as previous interventions, organ function (including liver parameters such as albumin and bilirubin), and complex surgeries, such as multi-valve repair. This represents a significant improvement in risk stratification, especially in patients with liver dysfunction, where accurate risk prediction is critical for guiding perioperative management.¹⁷ Despite these updates, not all liver-related factors are taken into consideration. The Euroscore does not yet include liver-specific parameters in its risk assessments, although the forthcoming Version 03 is expected to address this gap.¹⁸ Given the complexity of liver disease, combining multiple scoring systems may offer the most accurate pre-anaesthesia risk assessment. For example, combining Child-Pugh with MELD and integrating them with traditional cardiac risk models such as STS or Euroscore can provide a more comprehensive view of the patient's overall risk.

While the Child-Pugh and MELD scores are commonly used, they do not fully capture the complexity of perioperative risk in patients with advanced liver disease. This led to the development of the VOCAL-Penn score, designed to address this gap. This score is based on retrospective observational studies and has been validated in multiple centres across the United States. It includes parameters such as albumin, bilirubin, INR, creatinine, and platelet count, and offers a more accurate picture of the specific challenges faced by hepatopathic patients undergoing surgery. The inclusion of this score adds another dimension to risk prediction, particularly in abdominal and orthopaedic procedures, but its application is expanding to cardiac and vascular surgeries as well.¹⁹ The same applies to the Mayo Clinic Scoring.²⁰Table 2 summarizes the most widely used risk scores. Accurate risk assessment not only predicts morbidity and mortality, but it also directly informs perioperative decision-making. A comprehensive evaluation of risk using these tools helps guide key clinical decisions, such as the selection of anaesthetic agents, fluid management, and the need for closer intraoperative monitoring. For example, in patients with elevated MELD scores or advanced Child-Pugh stages, strategies that minimize haemodynamic stress and optimize fluid balance become critical to avoiding decompensation during and after surgery. Despite these advances, nutritional status is not fully captured by traditional risk models. Patients with chronic liver disease are often malnourished, and nutritional evaluation plays a pivotal role in risk assessment. Methods such as bioimpedance analysis and ultrasound can help identify sarcopenia, which is associated with worse surgical outcomes, prolonged hospital stays, and higher perioperative mortality. Early detection of sarcopenia and other nutritional deficiencies allows for targeted interventions, particularly within the enhanced recovery after surgery (ERAS) framework, aimed at optimizing nutritional status preoperatively.²¹

Table 2.

Risk scores for liver and cardiovascular disease in CHS patients.

Score	Clinical Research & Validation	Liver-Related Parameters	Risk Categories (Score Ranges)	Mortality per Risk Category	Clinical Notes	Limitations	Internet Resources
Child-Pugh	- Initial Study: Pugh et al., 1973 - Validation: Retrospective, single-center - Sample Size: 436 patients (Hammersmith Hospital)	- Bilirubin - Albumin - INR - Ascites - Encephalopathy	- Class A (5–6): Low - Class B (7–9): Moderate - Class C (10–15): High	- Class A: <10% - Class B: 10−30% - Class C: >30%	Used to assess severity of cirrhosis, guiding perioperative management in non-cardiac surgeries.	Encephalopathy and ascites scoring are subjective, leading to variability in clinical interpretation.	MDCalc: Child-Pugh
MELD 3.0	- Initial Study: Kamath et al., 2001 - Validation: Retrospective, multicentric - Sample Size: 2,319 patients (Mayo Clinic and other centers)	- Bilirubin - Creatinine - INR - Sodium - Albumin - Sex	- MELD <12: Low - MELD 13−20: Moderate - MELD > 20: High	- MELD <12: <5% - MELD 13−20: 15−20% - MELD > 20: 30−40%	Broadly used in liver transplant and non-cardiac surgeries; useful for predicting perioperative mortality.	Primarily designed for liver transplant patients, less accurate for cardiac surgeries.	UNOS MELD Calculator
VOCAL-Penn	- Initial Study: Malinchoc et al., 2000 - Validation: Retrospective, multicentric - Sample Size: 824 patients (Vanderbilt University and other centers)	- Albumin - Bilirubin - INR - Creatinine - Platelet Count	- Score <8: Low - Score 9−12: Moderate - Score >12: High	- Score <8: <10% - Score 9−12: 15−20% - Score >12: 30−50%	Useful for advanced liver disease and abdominal surgeries, expanding to cardiac cases.	Limited to hepatopathic patients and liver-related surgeries, not widely used in cardiac surgery.	VOCAL-Penn Calculator
Mayo Clinic Risk Score	- Initial Study: Hayashi et al., 2007 - Validation: Prospective, multicentric - Sample Size: 978 patients (Mayo Clinic and other centers)	- Albumin - Bilirubin - INR - Sodium	- Score <8: Low - Score 9−12: Moderate - Score >12: High	- Score <8: <10% - Score 9−12: 15−20% - Score >12: >30%	Primarily used in liver transplant settings, adapted for perioperative risk in major non-cardiac surgeries.	Limited utility in predicting outcomes for cardiac surgery due to exclusion of cardiovascular factors.	Mayo Clinic MELD
EuroSCORE	- Initial Study: Nashef et al., 1999 - Validation: Prospective, multicentric - Sample Size: 19,030 patients (128 centers in 8 European countries)	- Not specific to liver, includes liver disease as a comorbidity	- EuroSCORE <2: Low - EuroSCORE 3−5: Moderate - EuroSCORE >5: High	- EuroSCORE <2: <5% - EuroSCORE 3−5: 10−20% - EuroSCORE >5: >20%	Designed for cardiac surgery patients, incorporating comorbidities like liver disease into risk evaluation.	Limited assessment of liver-specific parameters; focuses on cardiac outcomes, missing nuanced liver data.	EuroSCORE Calculator
STS Score	- Initial Study: Shroyer et al., 1996 - Validation: Prospective, multicentric - Sample Size: 663,000 patients (STS Database, U.S.)	- Not specific to liver, includes liver disease as a comorbidity	- STS <2: Low - STS 3−5: Moderate - STS >5: High	- STS <2: <5% - STS 3−5: 10−20% - STS >5: >20%	Primary tool for cardiac surgeries, adapted to account for liver disease in perioperative risk.	Limited to cardiac surgeries, does not focus heavily on liver dysfunction outside of comorbidities.	STS Risk Calculator

Intraoperative and postoperative complications in patients with cardiohepatic syndrome

Patients with CHS are at significant risk for both intraoperative and postoperative complications due to the complex interplay between liver and cardiac dysfunction. Intraoperatively, refractory hypotension is a frequent, serious challenge, particularly in patients with CHS type IV, where reduced peripheral vascular resistance limits the effectiveness of standard vasopressors. Splanchnic hyperperfusion is also common, leading to difficulties in fluid management and potential organ hypoperfusion despite aggressive volume replacement. Cardiac arrhythmias are a frequent occurrence during surgery, particularly in patients with cirrhotic cardiomyopathy. These arrhythmias are often exacerbated by electrolyte imbalances, such as hyponatremia, which can increase the risk of ventricular arrhythmias and complicate anaesthesia management. Metabolic disturbances are another concern; hypoglycaemia can develop rapidly due to impaired hepatic gluconeogenesis, and metabolic acidosis may arise from tissue hypoperfusion, both of which require close intraoperative monitoring. Patients with CHS are also at increased risk of coagulopathy, which can manifest as excessive bleeding or, paradoxically, thrombosis, especially in the setting of portal hypertension. These coagulopathies present a challenge in balancing the risk of haemorrhage with the need to prevent thrombotic events.

In the postoperative period, acute hepatic decompensation is a significant concern. The physiological stress of surgery can exacerbate liver dysfunction, leading to worsening ascites, jaundice, or the onset of hepatic encephalopathy, which may be triggered by factors such as electrolyte disturbances, infections, or medications that impair hepatic clearance. Heart failure is another major postoperative risk, particularly in patients with cirrhotic cardiomyopathy and impaired left ventricular function. The combination of fluid management challenges and the potential for circulatory overload can precipitate acute decompensation.

Kidney complications are also common in these patients, who are at risk of developing acute kidney injury or hepatorenal syndrome, especially following periods of intraoperative hypotension or fluid imbalance. These kidney complications can significantly worsen postoperative outcomes. Infections also pose a serious risk for patients with CHS, who are often immunocompromised. Postoperative infections, such as spontaneous bacterial peritonitis, pneumonia, or sepsis, are frequent and can contribute to a rapid decline in clinical status. Respiratory complications, including acute respiratory distress syndrome, may also develop, particularly in cases of fluid overload or severe infections.

Management strategies

Given the high risk of complications, perioperative management in CHS patients must be carefully tailored to address both liver and cardiac dysfunction. General recommendations for management in both general and cardiac anaesthesia are shown in Table 3. As discussed in the pre-anaesthesia risk assessment, tools such as MELD and Child-Pugh scores provide a framework for identifying high-risk patients, which is critical for tailoring anaesthesia and perioperative strategies. Patients with higher scores, such as MELD > 16 or Child-Pugh B or C, face significantly increased risks and will need a more conservative approach and close intraoperative monitoring.^16,22

Table 3.

Checklist for general and cardiac procedures (Flashcard friendly).

Preoperative Phase:

☐ Risk Assessment: Use Child-Pugh or MELD 3.0 scores to assess liver function and determine perioperative risk. For advanced cases, consider using the VOCAL-Penn score.

☐ Vascular Access: Ensure adequate vascular access for fluid administration and transfusions. Assess the need for central venous access.

☐ Cardiac Output Monitoring: Plan for continuous cardiac output monitoring to optimize fluid therapy. ☐ Multidisciplinary Team: Conduct a thorough evaluation of comorbidities with a multidisciplinary team (gastroenterology/hepatology, cardiology, endocrinology, and hematology should be involved).

☐ Coagulation Profile: Evaluate coagulation status and optimize using point-of-care testing, including TEG/Rotem and Multiplate® for a detailed coagulation profile.

☐ Preoperative Coagulation Optimization: Administer vitamin K to optimize coagulation prior to surgery if needed. Check platelet function with aggregometry/platelet mapping if available

In Cardiac:

☐ Risk Assessment: Use EuroSCORE or STS Risk Score to evaluate perioperative risk, incorporating liver disease as a comorbidity. Consider combining with MELD for a more comprehensive risk evaluation.

☐ Multidisciplinary Strategy: Coordinate with the perfusionist and other specialists (cardiology, hepatology) to develop a comprehensive strategy for managing liver and cardiac dysfunction.

Intraoperative Phase:

Induction:

☐ Opioid: Use remifentanil.

☐ Benzodiazepine: for sedation consider remimazolam.

☐ Hypnotic: Choose etomidate, propofol, or ketamine, depending on the patient's condition.

☐ Muscle Relaxant: Prefer atracurium or cisatracurium. Use succinylcholine only if potassium levels and renal function are normal.

Note: rocuronium and vecuronium have prolonged effects; use them only if sugammadex is available for reversal.

Maintenance:

☐ Inhaled Agents: Prefer desflurane or isoflurane. Use sevoflurane cautiously. Consider nitrous oxide as a safe option.

☐ Neuromuscular Monitoring: Use train-of-four (TOF) monitoring throughout surgery, from induction to extubation. Ensure a TOF ratio >90% before extubation.

☐ Point Of Care (POC) Coagulation Management: Perform viscoelastic tests as available (TEG/ROTEM) and aggregometry measurements (Multiplate® or TEG6S platelet mapping) to tailor haemotherapy strategy.

In Cardiac:

☐ Cardiopulmonary Bypass (CPB): For patients undergoing CPB, use retrograde autologous priming to minimize hemodilution and fluid retention.

☐ Vasopressor Management: Start vasopressor therapy early to counteract splanchnic vasodilation. Preferred agents include: terlipressin: 0.5−2 mg IV every 6 h. Vasopressin: 0.01−0.03 U/min. Norepinephrine: 0.05−0.4 mcg/kg/min.

☐ Oncotic Pressure: Maintain adequate oncotic pressure. Aim to close the "albumin gap" by correcting low albumin levels.

☐ Blood Product Management: Ensure sufficient blood products are available, particularly for patients at high risk of bleeding

☐ Cell Salvage: Use cell saver technology to recover blood and reduce the need for allogeneic transfusions.

Postoperative Phase:

☐ Close Monitoring: Assess liver function regularly, especially in patients with high MELD or Child-Pugh scores. Adjust postoperative care based on fluid status, coagulation, and potential for liver decompensation.

☐ Nutritional Support: Follow enhanced recovery after surgery (ERAS) protocols to optimize postoperative nutrition and recovery, particularly in patients with preoperative malnutrition or sarcopenia.

In Cardiac:

☐ Continue Hemodynamic Monitoring: Continuously monitor for signs of liver or cardiac decompensation. In high-risk patients (e.g., MELD > 20 or Child-Pugh Class C), closely manage fluids and monitor for signs of hypotension or coagulopathy.

☐ Early Mobilization and Nutrition: Follow ERAS protocols to promote early mobilization and enhanced recovery. Ensure aggressive nutritional support for patients with liver disease to prevent postoperative complications.

In patients with elevated risk scores, it is crucial to adopt management strategies that minimize hemodynamic stress. These strategies often involve careful selection of drugs that bypass hepatic metabolism to reduce the burden on the liver while maintaining stable cardiovascular function. For example, vasopressors such as terlipressin, which selectively constricts splanchnic circulation, are preferred to improve systemic haemodynamics in CHS patients.

The choice of drugs must take into account altered liver metabolism and protein binding defects. Drugs that rely on cytochrome P450 (CYP450) enzymes may accumulate in patients with liver dysfunction, leading to prolonged effects and increased toxicity. Therefore, anaesthetic agents that are metabolized by plasma esterases, such as remifentanil and atracurium, are preferred due to their rapid clearance and minimal reliance on liver metabolism (Table 4). Atracurium, which undergoes Hofmann elimination and esterase metabolism, is particularly useful in patients with CHS type IV, who often present with both hepatic and cardiac dysfunction. Its predictable pharmacokinetic profile ensures effective neuromuscular blockade without the risk of prolonged action, even in severe liver disease. Rocuronium and vecuronium should be used cautiously in these patients, given that their metabolism is purely hepatic and neuromuscular blockade will be be prolonged. They are best avoided unless sugammadex is available for reversal. Sugammadex is not metabolized by the liver and is cleared almost exclusively by the kidneys. Studies have shown that there is no prolongation of recovery time and no recurrence of blockade in hepatopathologic patients.^23,24

Table 4.

Common anaesthesia drugs and their use in hepatic patients.

Drug	Clinical Use	Metabolism	Advantages in Hepatic Patients
Etomidate	Induction of anaesthesia	Metabolized by plasma and liver esterases	Minimal accumulation; provides hemodynamic stability, suitable for patients with liver dysfunction.
Propofol	Induction and maintenance of anaesthesia	Hepatic metabolism (CYP450); extrahepatic clearance	Rapid onset; short duration; safe in moderate liver dysfunction due to rapid redistribution.
Remifentanil	Intraoperative analgesia	Metabolized by non-specific esterases in plasma	Precise control of analgesia; rapid recovery, ideal for patients with impaired liver function.
Remimazolam	Conscious sedation and general anaesthesia	Metabolized by esterases in plasma	Quick onset and recovery; minimal accumulation, well-suited for patients with hepatic dysfunction.
Fentanyl	Intraoperative analgesia	Primarily hepatic (CYP3A4), but slow clearance	Potent analgesia with caution; longer duration in liver dysfunction, but manageable with careful dosing.
Atracurium	Non-depolarizing muscle relaxant	Degraded by Hofmann elimination and plasma esterases	Independent of hepatic metabolism; safe for use in hepatic and renal failure.
Cisatracurium	Non-depolarizing muscle relaxant	Mainly by Hofmann elimination and plasma esterases	Predictable profile; minimal histamine release, no reliance on liver or kidney function.
Mivacurium	Short-acting non-depolarizing muscle relaxant	Hydrolyzed by butyrylcholinesterase in plasma	Short duration of action; safe for patients with liver dysfunction due to non-hepatic metabolism.
Succinylcholine	Rapid intubation	Hydrolyzed by butyrylcholinesterase in plasma	Ultra-short onset and duration; can be used in hepatic patients if potassium and renal function are normal.
Rocuronium	Non-depolarizing muscle relaxant	Hepatic metabolism (minor renal excretion)	Prolonged effect in liver dysfunction, but reversible with sugammadex.
Vecuronium	Non-depolarizing muscle relaxant	Hepatic metabolism (CYP450)	Prolonged duration in liver dysfunction, but reversible with sugammadex; caution required.
Clevidipine	Acute blood pressure control	Metabolized by esterases in blood and tissues	Quick onset; short and controllable duration; independent of hepatic metabolism.
Esmolol	Acute control of heart rate and BP	Metabolized by esterases in erythrocytes	Ultrashort half-life; fast, reversible control of heart rate and blood pressure, liver-independent metabolism.
Ketamine	Induction and analgesia	Hepatic metabolism (CYP450)	Hemodynamically stable induction, but caution due to hepatic metabolism; use in mild liver dysfunction.
Dexmedetomidine	Sedation and analgesia	Hepatic metabolism (CYP2A6)	Provides sedation without significant respiratory depression, but can accumulate in severe liver dysfunction.
Midazolam	Sedation and induction	Hepatic metabolism (CYP450)	Prolonged sedation in liver failure; use cautiously or opt for alternatives like remimazolam in liver patients.
Nitrous Oxide	Anaesthetic adjunct	Exhaled unchanged	Safe for use in hepatic patients due to minimal metabolic burden.
Desflurane	Maintenance of anaesthesia	<0.02% hepatic metabolism	Minimal hepatic metabolism; rapid elimination via exhalation, making it ideal for liver-impaired patients.
Isoflurane	Maintenance of anaesthesia	<0.2% hepatic metabolism	Low hepatic metabolism; safe for use in patients with liver dysfunction, widely used and stable.
Sevoflurane	Maintenance of anaesthesia	∼5% hepatic metabolism	Limited hepatic metabolism; generally safe but used with caution in severe liver impairment due to potential accumulation.
Terlipressin	Vasopressor for haemodynamic control	Renal and hepatic elimination	Effective for counteracting splanchnic vasodilation in liver disease, improves systemic haemodynamics.
Vasopressin	Vasopressor for haemodynamic control	Hepatic metabolism	Useful in liver disease due to minimal direct hepatic metabolism, helps manage vasodilation.
Norepinephrine	Vasopressor for haemodynamic control	Hepatic and renal elimination	Effective for increasing vascular tone in liver patients, but requires close monitoring in severe dysfunction.
Phenylephrine	Vasopressor for blood pressure control	Hepatic metabolism (sulfation)	Increases vascular tone and blood pressure with limited cardiac effects; use cautiously in severe liver dysfunction.
Dobutamine	Inotropic support for heart failure	Hepatic metabolism (CYP450) and renal excretion	Improves cardiac output, but requires caution in liver disease due to potential accumulation and arrhythmias.
Lidocaine	Local anaesthesia, antiarrhythmic	Hepatic metabolism (CYP450)	Requires dose adjustment in liver disease; prolonged effect in hepatic impairment but safe with careful titration.
Bupivacaine	Local anaesthesia	Hepatic metabolism (CYP450)	Potent local anaesthetic; use with caution in liver disease due to potential accumulation and systemic toxicity.
Ropivacaine	Local anaesthesia	Hepatic metabolism (CYP450)	Less cardiotoxic than bupivacaine, but still requires caution and dose adjustment in patients with liver dysfunction.
Mepivacaine	Local anaesthesia	Hepatic metabolism	Similar to lidocaine, but longer duration; requires cautious dosing in liver dysfunction to avoid toxicity.

It is recommended to use TOF quantitative neuromuscular monitoring in the adductor pollicis brevis, provided NMB is used throughout surgery from induction to extubation. A normalized TOF ratio >90% is the criteria for extubation.

Ketamine, while commonly used in haemodynamically unstable patients, should be administered with caution in patients with liver dysfunction. Although it provides cardiovascular stimulation, which may be beneficial in some forms of CHS, its extensive liver metabolism raises concerns about prolonged recovery times and increased intracranial pressure in certain contexts. Ketamine, therefore, may be more suitable in patients with mild to moderate liver dysfunction and should be avoided in CHS type III, where liver failure and kidney failure are prevalent.

Etomidate is often the first-choice anaesthetic in patients with liver disease due to its minimal hepatic metabolism and rapid clearance. However, its potential to suppress adrenal function, particularly through inhibition of 11β-hydroxylase, necessitates careful consideration. This risk is particularly important in patients with CHS type III, who may already present adrenal insufficiency, but can be mitigated by administering perioperative corticosteroids. A suggested regimen could include 50–100 mg IV hydrocortisone at induction, followed by 50 mg every 6–8 h for 24–48 h. This approach supports adrenal function and minimizes the risk of haemodynamic instability.

Propofol, while metabolized in the liver, is usually safe in patients with moderate dysfunction due to its rapid redistribution, but should be used cautiously in cases of severe hepatic impairment.

Remimazolam offers significant advantages in liver-compromised patients due to its unique metabolism, which relies primarily on tissue esterases rather than hepatic pathways. This leads to predictable pharmacokinetics and minimizes the risk of drug accumulation in patients with impaired liver function. Its rapid onset, short duration of action, and predictable recovery make it suitable for procedural sedation and general anaesthesia in this population.

In liver disease patients, dosing adjustments are typically unnecessary for procedural sedation. For general anaesthesia, an initial bolus of 6–12 mg followed by a maintenance infusion at a reduced rate (e.g., 1–2 mg/kg/hour) can be considered to account for altered sensitivity. Always titrate to the patient’s response, and monitor carefully to avoid over-sedation.²⁵

In addition to drug choices, haemodynamic management is critical in these patients. Given the altered vascular tone and increased cardiac output often seen in CHS type IV, standard vasoconstrictors such as norepinephrine may be less effective. Alternatives such as terlipressin and vasopressin provide more selective vasoconstriction in the splanchnic circulation and redistribute blood flow to vital organs such as the kidneys and brain, which are often compromised due to the splanchnic steal phenomenon.^13,26,27

For haemodynamic management, esmolol and clevidipine, which bypass hepatic metabolism and offer short or ultra-short action, have proven beneficial, particularly in cardiothoracic and vascular anaesthesia.²⁸ These agents help maintain accurate control of blood pressure and heart rate while minimizing liver involvement, making them suitable for high-risk CHS patients.

In chronic liver impairment (CHS type IV), albumin should be replaced if levels fall below 3 g/dL, targeting 3.5 g/dL or higher, while considering left ventricular (LV) ejection fraction to prevent pulmonary oedema and adverse postoperative outcomes. The surgical episode can be considered a “predicted” decompensation of liver disease, so preoperative albumin can be considered preventive, and terlipressin and midodrine must be readily available.²⁹

Within the ERAS framework, preoperative optimization of patients with chronic liver disease undergoing non-hepatic surgery is pivotal for improving outcomes and reducing perioperative morbidity. Nutritional optimization is a cornerstone of ERAS; for hepatopathic patients, this involves addressing malnutrition with tailored dietary interventions rich in branched-chain amino acids to support hepatic function and enhance recovery. ERAS also promotes strategies such as minimizing preoperative fasting and implementing carbohydrate loading, which must be carefully adjusted in liver disease patients to prevent hypoglycaemia and encephalopathy. ERAS fluid management protocols aim to maintain euvolaemia and avoid fluid overload, thereby reducing the risk of exacerbating ascites or precipitating hepatic decompensation.

By integrating these liver-specific considerations into ERAS pathways, clinicians can effectively mitigate perioperative risks, shorten hospital stays, and improve overall patient outcomes.²¹

Conclusions

Managing patients with cardiohepatic syndrome requires careful risk assessment and tailored anaesthesia management. Using risk scores such as Child-Pugh and MELD, along with liver-safe drugs and ERAS protocols, helps reduce complications and improve outcomes. A multidisciplinary approach is crucial for ensuring patient safety in this high-risk group. Further research and clinical collaboration are essential to refine risk assessment tools and management protocols for this high-risk population and improve patient outcomes.

CRediT authorship contribution statement

AE, AM and JR conceived and prepared the initial version of the manuscript. YS and MJ contributed to the perioperative focus in cardiac surgery. AE, AM, RNP, AAG & MJ contributed to the preparation of tables and figures and the cardiac anaesthesia approach. AE, AM, RA and AAG contributed to the section focusing on physiopathology and the global gastroenterological considerations. All the authors have contributed to internal revision and general changes to the manuscript.