Impact of Liver Disease on Use of Muscle Relaxants in Anesthesia: A Comprehensive Review

Introduction

Neuromuscular blocking agents (NMBAs) are drugs commonly used in modern-day anesthesia in inducting muscle relaxation, enabling endotracheal intubation [1]. In the intensive care unit (ICU) NMBAs can be applied in the management of patients with acute respiratory distress syndrome (ARDS), increased intracranial pressure, and prevention of patient-ventilator asynchrony patients dependent on mechanical ventilation [2].

Neuromuscular blockers consist of depolarizing agents (among which succinylcholine is the only agent currently in clinical use) and non-depolarizing agents (including aminosteroids and benzylisoquinolones). Both groups act at the neuromuscular junction (NMJ), employing different mechanisms of action. Depolarizing agents cause depolarization of the motor plate, making it resistant to acetylcholine, thus preventing muscle contraction for a short period (approximately 5 minutes). The non-depolarizing drugs work by binding to acetylcholine receptors without depolarization. The block caused by non-depolarizing NMBAs can be reversed using neostigmine or sugammadex [3].

Many factors can influence the effectiveness of NMBAs and their reversals. These include kidney function disorders, acid-base balance disorders, age, body temperature, sex, and medications [4,5].

Hepatic function affects metabolism and elimination of many drugs, including neuromuscular blocking agents. Hepatic insufficiency has been found to cause an abundance of pharmacokinetic and pharmacodynamic changes. A decrease in liver protein synthesis can cause a lower level of protein binding, a decrease in volume of distribution, and an increase in free drug fraction, causing more intense therapeutic effects. Peripheral edema and ascites affect the volume of distribution, especially in hydrophilic compounds; as a result, its initial doses might have to be increased to achieve a comparable effect. Drug metabolism and clearance in hepatic dysfunction changes due to decreased enzyme activity and impaired oxygen and substance uptake. Liver metabolism can be separated into 2 phases: the first is facilitated by cytochrome P450 enzymes, requiring oxygen, increasing vulnerability to hepatic deficiencies and decreased perfusion; and the second is glucuronidation, which is less affected by organ insufficiency. Elimination of drugs can be altered, especially in primarily bile-excreted substances. Cholestasis complicating hepatic disorders causes accumulation of these compounds. Advanced liver dysfunction presenting with hepatorenal syndrome impairs kidney performance, requiring increased caution with use of drugs dependent on renal secretion [6].

Use of neuromuscular blocking agents (NMBA) is a noteworthy achievement in the progress of anesthesia, but a growing body of research shows the need for careful assessment of how hepatic function influences their action. Some NMBAs rely on hepatic metabolism and excretion. Moreover, the higher volume of distribution associated with liver disease impacts the pharmacokinetic and pharmacodynamic qualities of many drugs [7]. As the number of patients with chronic liver disease (CLD) increases, the need to thoroughly explore the relationship between drug management and hepatic function arises [8].

This article discusses tests used to assess liver function, the types of liver diseases that impair its function, including chronic liver disease (including steatotic liver disease), acute liver failure, acute-on-chronic liver failure, and liver cirrhosis, as well as reports on their impact on the use and effectiveness of neuromuscular blocking agents and reversals.

Anaesthesiologists should aim to understand the complicated relationship between muscle relaxants, reversal agents, and hepatic disease to provide patients with these disorders with the best quality and safety of care.

This article reviews the role of muscle relaxants in anesthesia for patents with liver disease.

Liver Function Tests and Assessment of Liver Function

Assessing liver damage and function can be a challenge. Assessment organ function and the location of liver and bile duct cell damage uses markers such as enzymes – alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transpeptidase (GGT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), the AST/ALT ratio known as the De Ritis ratio – plasma bilirubin levels (total bilirubin, conjugated (direct) bilirubin, unconjugated (indirect) bilirubin), as well as prothrombin time (PT), INR, total protein, globulin, and albumin levels. Performing these laboratory tests is helpful in determining the specific area affected by the damage. In the case of liver cell damage (hepatocellular pattern), there will be a disproportionately greater increase in AST and ALT relative to bilirubin and ALP. Conversely, an increase in bilirubin and ALP disproportionate to AST and ALT may suggest bile duct pathology (cholestatic pattern) [9].

Most of these tests are more useful for assessing the location of liver damage than for evaluating the organ’s function itself. Parameters most useful for assessing hepatic function include the ability to produce albumin, as well as vitamin K-dependent clotting factors and prothrombin time [9].

AST and ALT

In the evaluation of liver damage, the plasma concentrations of 2 aminotransferases are measured. Alanine aminotransferase is an enzyme primarily found in liver cells, but it is also present in other tissues such as kidney cells, the heart, skeletal muscles, brain, pancreas, spleen, and lungs. Its highest concentration is in the cytosol of hepatocytes, where its activity is many times greater than in the serum. Therefore, a significantly increased level of this enzyme in the serum is likely associated with acute or chronic hepatocyte damage [9,10].

AST is a less sensitive and less specific marker of liver damage. It is found in hepatocytes, heart muscle cells, kidneys, brain, lungs, pancreas, and blood system cells such as leukocytes and erythrocytes. There are 2 isoenzymes of AST – mitochondrial and cytosolic. The mitochondrial AST isoenzyme is responsible for most of the activity of AST assessed in tests [9,11].

The De Ritis Ratio

The De Ritis ratio is a useful tool for determining the pattern of liver damage. It is defined as the ratio of AST to ALT levels. In chronic liver inflammation not caused by alcohol, the AST/ALT ratio is typically <1, but progression to cirrhosis can lead to a reversal of this ratio [12]. A De Ritis ratio <1.0 is considered typical for chronic viral hepatitis. In acute viral hepatitis, ALT levels are usually higher than AST, and a De Ritis ratio >1.5 may suggest a severe course of the disease. In alcoholic hepatitis, AST values are typically higher than ALT; therefore, a De Ritis ratio >1.5 or >2.0 can suggest alcoholic hepatitis. In non-alcoholic steatohepatitis (NASH) in morbidly obese patients, the De Ritis ratio is <1 [11]. A De Ritis ratio >1.6 may serve as a tool for early prognosis of high-risk in-hospital mortality in adult trauma patients [11].

Chronic Liver Disease

Depending on the duration of liver function impairment, liver disease can be classified as chronic or acute, or acute liver damage superimposed on chronic liver disease.

Liver function impairment lasting more than 6 months is termed chronic liver disease (CLD). As mentioned earlier, liver dysfunction is associated with impaired synthesis of clotting factors, other proteins, detoxification of harmful metabolic by-products, and bile excretion. CLD has various etiologies, including alcoholic liver disease (ALD), steatotic liver disease (SLD), viral hepatitis, and autoimmune causes. The progression of CLD typically advances through several stages: hepatitis or steatosis or hepatosteatosis fibrosis, cirrhosis, and hepatocellular carcinoma (HCC), which is also a complication of liver cirrhosis [13].

Liver Cirrhosis

Liver cirrhosis is a late stage of fibrosis in which the liver is generally considered irreversibly damaged, with normal liver tissue replaced by scar tissue that impairs blood flow through the liver and hinders its proper functioning [12]. Liver cirrhosis can be divided into compensated (CLC), where the patient’s condition is relatively stable, and decompensated, where the patient’s condition rapidly deteriorates and clinical symptoms of systemic complications appear [14,15].

In liver cirrhosis, impaired liver function translates into systemic complications. These include respiratory system complications such as hepatopulmonary syndrome, porto-pulmonary hypertension, development of portal hypertension and hyperdynamic circulation (which are major causes of morbidity and mortality), reduced pulmonary diffusion capacity, gastrointestinal system complications (eg, ascites and its infections, hepatosplenomegaly, and esophageal varices and bleeding, which can be fatal), hematologic complications (eg, hypersplenism, folate deficiency anemia), renal complications (eg, hepatorenal syndrome), and endocrine complications (eg, hypogonadism and gynecomastia) [12,16]. Impaired kidney function is common in people with liver cirrhosis (present in up to 60% of those with cirrhosis in intensive care units) and is also a poor prognostic sign [15].

The occurrence of complications such as jaundice, hepatocellular carcinoma, esophageal variceal bleeding, or ascites indicates the transition from the compensated phase of liver cirrhosis to the decompensated phase, significantly worsening the prognosis by drastically reducing the median survival from 12 years to 1–2 years [14,16].

In the case of liver cirrhosis, AST and ALT levels are typically moderately elevated. Since albumin is produced exclusively in the liver, its serum level serves to support assessment of the severity of cirrhosis – its level decreases with the loss of liver synthetic function as the disease progresses [10]. Electrolyte imbalances such as hyponatremia, hypo/hyperkalemia, and hypomagnesemia are quite common and must be carefully monitored and corrected. Blood glucose levels should also be observed, as even a nighttime fasting period in preparation for a procedure can lead to hypoglycemia. In the case of liver cirrhosis, impaired liver function (causing alterations in the volume of distribution, plasma protein binding, metabolism, and clearance of drugs) and significant accompanying kidney dysfunction can change the strength and duration of action of neuromuscular blocking agents [15].

Steatotic Liver Disease

In recent years, there have been numerous reports on steatotic liver disease (SLD) (also known as fatty liver disease) and its impact on health. With new scientific findings, we are learning more about its etiology, pathophysiology, and complications. Over time, the nomenclature has been changed several times to better systematize the disease – from non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) to metabolic dysfunction-associated fatty liver disease (MAFLD), to metabolic dysfunction-associated steatohepatitis (MASH), and further to metabolic dysfunction-associated steatotic liver disease (MASDL), which now is the most common cause of chronic liver disease [17,18].

Non-alcoholic fatty liver disease (NAFLD) is a type of chronic liver disease, with fat accumulation in the liver without a clear cause. In some patients, this condition progresses to liver inflammation, known as non-alcoholic steatohepatitis (NASH), and subsequently to fibrosis and cirrhosis [17,19]. In 2020, an international team of scientists proposed changing the name to metabolic-associated fatty liver disease (MAFLD) due to the heterogeneous nature of the NAFLD patient population. An important societal aspect of this renaming was to exclude “alcoholic” from the new terminology to avoid stigmatizing patients and to emphasize the role of metabolic aspects in the disease’s pathophysiology [20].

MAFLD is more closely linked with the clinical variability and progression of liver fat accumulation under the influence of multiple factors such as sex, age, ethnic origin, diet, alcohol or tobacco use, genetic predispositions, and other metabolic conditions. Unlike NAFLD, diagnosing MAFLD does not require excluding other etiologies that can contribute to liver damage. Therefore, MAFLD criteria allow for diagnosis even in the presence of other potential causes of liver injury. The use of MAFLD criteria has been associated with increased detection of individuals at high risk of progressive liver disease compared to NAFLD. Additionally, some studies have shown that the diagnosis of MAFLD correlates better with higher degrees of liver fibrosis and non-invasive markers of steatosis [17]. However, there is a challenge in using MAFLD terminology, as there is a small group of patients who meet the criteria for NAFLD diagnosis but do not meet the criteria for MAFLD [21].

Shapses et al conducted a retrospective study in 2021 comparing recovery after anesthesia between subjects with fatty liver and those without. They found that fatty liver was associated with significantly delayed recovery from anesthesia [22].

In 2023, a proposed renaming to MASLD was suggested. This change was endorsed by the American Association for the Study of Liver Diseases (AASLD), the European Association for the Study of the Liver, and the Latin American Association for the Study of the Liver (ALEH). Updated diagnostic criteria were also introduced. The shift from NAFLD to MAFLD and MASLD aims to identify individuals at higher risk of developing liver and extrahepatic complications, emphasizing the link between metabolic disorders, metabolic risk factors, and SLD [17–19].

Despite significant differences in diagnostic criteria, particularly between NAFLD and MASLD, there are numerous reports suggesting a substantial overlap in the populations diagnosed with these conditions. Therefore, MASLD replaces the term NAFLD, with NAFL being replaced by MAFL, and MASH being substituted for NASH. Recommendations from the AASLD’s Practice Guidance on the clinical assessment and management of NAFLD can be applied to patients diagnosed with MASLD and MASH. Additionally, within the spectrum of SLD (steatotic liver disease), metabolic alcohol-associated liver disease (MetALD) can be distinguished, which represents overlapping MASLD with increased alcohol consumption in a patient, alongside alcohol-associated liver disease (ALD), specific etiology (SLD), and cryptogenic SLD [17,18,23].

To better understand the evolution and differences between disease entities associated with SLD, a comparison of diagnostic criteria is presented in Table 1 [17,19–21,24].

Acute Liver Failure

Acute liver failure (ALF) is defined as a condition where severe liver damage occurs with rapid deterioration of liver function within <26 weeks, leading to impaired liver function (INR ≥1.5) and the onset of any degree encephalopathy in individuals without pre-existing liver disease or cirrhosis. Common causes include hepatotoxic substance ingestion and viral infections.

During acute liver failure, several abnormalities can be encountered, including INR ≥1.5, elevated transaminase levels, ammonia, bilirubin, electrolyte disturbances such as hypokalemia and hypophosphatemia, hypoglycemia, anemia, and thrombocytopenia. Complications may include acute kidney injury with elevated creatinine due to hypovolemia, sepsis, encephalopathy, or brain edema, which is the most frequent cause of death in ALF [25].

Acute-On-Chronic Liver Failure

PROGNOSTIC SCALES IN LIVER DISEASES:

Due to the need for accurate assessment of clinical status and prognosis to determine the best course of action, scales such as the Child-Pugh score are used in CLD, ALD, and ACLD, especially in cases of existing liver cirrhosis. In Table 3 describes scales used to assess patients with liver diseases [13,26–34].

HEPATIC ENCEPHALOPATY AND THE WEST HAVEN CRITERIA:

Hepatic encephalopathy (HE) refers to brain dysfunction caused by liver insufficiency. It encompasses a wide range of neurological and psychiatric changes, clinically presenting as alterations in personality, consciousness, cognition, and motor function. Depending on the underlying disease, several types of HE are distinguished:

There is ongoing consideration regarding the classification of a fourth type (type D) in patients with HE occurring during acute-on-chronic liver failure (ACLF). This group differs clinically, pathophysiologically, and prognostically from individuals diagnosed with HE types A–C [35]. In 2014, guidelines were issued by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver regarding hepatic encephalopathy and its evaluation. The West Haven criteria have been recognized as the criterion standard for assessing the severity of hepatic encephalopathy. In individuals with significantly impaired consciousness, the Glasgow Coma Scale may be useful [34].

Characteristic of Succinylcholine

Succinylcholine is a depolarizing neuromuscular agent introduced in the 1950s. It is a quaternary ammonium ion and the bischoline ester of succinic acid, made up of 2 molecules of acetylcholine (an endogenous neurotransmitter of the neuromuscular plate) connected via their acetyl groups. The mechanism of action involves a prolonged period of membrane depolarization via binding to post-synaptic cholinergic receptors on neuromotor plates, first inducing fasciculations and then muscle paralysis [35]. The effects of the neuromuscular block caused by succinylcholine are influenced by acid-base disorders – metabolic and respiratory acidosis weakens the effect, whereas respiratory and metabolic alkalosis strengthen it [4].

It is commonly used because it has an onset much faster than that of many available depolarizing agents and has the shortest time of action. The dose of 0.1 mg.kg-1 enables muscle relaxation after approximately 45 second and a duration of 10–15 minutes. It primarily undergoes metabolism by plasma butyrylcholinesterase, an enzyme produced by the liver, with only 10% of administered succinylcholine being excreted unchanged in the urine [36,37]. Succinylcholine is considered safe for people with kidney failure, although repeated doses should be avoided [5].

While this elimination pathway enables administration by infusion, tachyphylaxis limits its practicality. Bolus delivery has been found to promote muscle fasciculations. Preventing tachyphylaxis require giving small doses (10% of intubating dose) of non-depolarizing muscle agents approximately 3–4 minutes before succinylcholine [36,37].

Succinylcholine has many adverse effects. Malignant hyperthermia syndrome caused by enormous muscle contraction contributes to hypermetabolism and hyperkalemia, and in some cases is fatal despite treatment. It can induce hyperkalemia, with potassium concentration typically increasing by 0.5–1.0 mEq/l (rarely, levels are higher). In some cases, electrolyte imbalance may lead to fatal cardiac arrest [36].

There is an effect on the cardiovascular system, and depending on the patients’ autonomic stimulation, drug administration has been found to affect the heart rate and blood pressure. Bradycardia has been reported with second doses (especially with a lack of atropine administration). Succinylcholine has been infrequently associated with asystole.

Succinylcholine can also contribute to masseter muscle spasms, although its rigidity does not prevent tracheal intubation. Muscle fasciculations complicating its administration cause myalgia. They also contribute to increased intraocular pressure; therefore, succinylcholine use is limited in cases of ocular trauma. Increased intragastric pressure after administration restricts its use in patients with gastric contents due to risk of regurgitation and possible aspiration. While the exact mechanism has not been explored, there is an association between succinylcholine use and increased intracranial pressure [36].

Impact of Hepatic Insufficiency on Succinylcholine Use

Hepatic insufficiency leading to pseudocholinesterase deficiency can extend the activity time of succinylcholine, as shown in a case study of a cirrhotic patient with reportedly prolonged muscle relaxation. Although an adjustment of the dose for those patients seems necessary, McClain et al (2015) dispute changing the dose of succinylcholine in facilitating tracheal intubation due to the length of liver transplant surgeries and the risk of aspiration during induction [37–39].

Characteristics of Benzylisoquinolones

Benzylisoquinolones are a group of drugs (eg, atracurium, cisatracurium, and mivacurium) from non-depolarizing neuromuscular blocking agents. Muscle relaxation occurs due to disruption in neuromuscular transmission. NMBAs attach to acetylcholine receptors without depolarizing the end plate [36].

Atracurium Characteristic and Its Use in Hepatic Insufficiency

Atracurium is a non-depolarizing neuromuscular blocking agent (NMBA) from the 1980s. This muscle relaxant from the benzylisoquinolones group is characterized by intermediate onset and duration [36]. It undergoes Hoffman elimination followed by ester hydrolysis via plasma esterases. Its clearance appears to be unaltered by hepatic insufficiency. However, the breakdown of its metabolite laudanosine depends on liver function. While an accumulation of laudanosine does not affect the neuromuscular block, studies have investigated the hypotensive and potential epileptogenic effects, but they have yet to provide evidence of such danger arising in humans [40]. Atracurium metabolites are excreted by the kidneys. In renal failure, laudanosine levels are significantly increased, bringing into question the application of the drug in those patients [36]. The duration of the neuromuscular blockade caused by atracurium is influenced by acid-base balance disorders – respiratory and metabolic acidosis enhance the drug’s effect, while metabolic and respiratory alkalosis weaken it [4].

Histamine release is an adverse effect of atracurium, although it does not usually result in hypotension and increased heart rate [36].

Protein binding of atracurium is about 82%. Hypoalbuminemia and ascites often complicate liver disease, thus increasing the volume of distribution [37].

Chow et al (2000) found that half-lives of atracurium are comparable among children undergoing orthotopic liver transplantation, children with stable impaired liver action, and healthy children [41].

In 2005, Weng et al established that to achieve adequate muscle relaxation during an orthotopic liver transplant throughout paleohepatic, anhepatic, and neohepatic phases, the dose of atracurium does not change, which demonstrates its independence of liver insufficiency [42]. Due to its lack of hepatic excretion, atracurium is considered safe for individuals with liver dysfunction [43].

Cisatracurium Characteristic and Its Use in Hepatic Insufficiency

Cisatracurium is a non-depolarizing neuromuscular agent from the 1990s with a slow onset and an intermediate duration. It is a stereoisomer of atracurium, with potency estimated to be 3 times that of the latter and slower onset at equipotent doses. It is important to note that in hepatic insufficiency, the volume of distribution increases and the onset of action is prolonged. Hypoalbuminemia, tissue edema, and ascites characterizing end-stage liver disease have been found to contribute to these processes [36,44,45].

Cisatracurium predominantly undergoes Hofmann elimination, a chemical process contingent on pH and temperature. It is an organ-independent chemical process occurring in plasma and tissues [44, 46].

Studies estimate that 77% of elimination is due to these chemical reactions, while 23% of clearance is due to organ elimination. The kidneys and the liver do not play major roles in elimination of cisatracurium, but are involved in elimination of its metabolites [44,45,47], which does not affect neuromuscular block, but in excess laudanosine may be harmful. Cisatracurium metabolites are further excreted into urine; hence, renal insufficiency contributes to elevation of laudanosine concentration, which is a 10% increase in post-atracurium administration, establishing cisatracurium as favorable in kidney disease [44,48]. In patients with hepatic disease, higher values of metabolites may be observed after long-term administration of cisatracurium due to a longer half-life [46].

Studies indicate that repeated administration does not produce an accumulation. Cisatracurium in a dose of 2 x ED95 ensures optimal muscle relaxation for living donor liver transplantation patients [44].

Ali et al (2014) found no clinically significant differences in the dose-response curve of cisatracurium between patients with chronic liver disease and healthy participants, so it appears to be a safe and effective muscle relaxant for use in patients with hepatic disorders [48].

Its safety is conditional on the lack of dose-dependent histamine release with doses varying from 0.1 to 0.4 mg/kg, 2–8 times the effective dose (ED95)]. Cisatracurium has fewer cardiovascular effects than other neuromuscular blocking agents [6,36,43].

In recent scientific reports, no clinically significant changes in recovery time were observed in individuals with liver or kidney dysfunction, making cisatracurium a good choice for these patients [43,46].

Mivacurium Characteristic and Its Use in Hepatic Insufficiency

Mivacurium is a non-depolarizing neuromuscular blocking agent from the 1990s, with an intermediate start and a short time of action. A dose of 0.2 mg·kg−1 provides muscle relaxation suitable for tracheal intubation, with an onset of 2–3 minutes and a duration of 25–45 minutes. Compared with other muscle relaxants, it has short activity (approximately twice that of succinylcholine) [36].

It undergoes hydrolysis by butyrylcholinesterase, similar to succinylcholine. Its clearance and infusion dose needed to maintain muscle relaxation depend on enzyme activity. Studies show that decreased plasma cholinesterase concentrations associated with hepatic disorders extend the action of mivacurium by up to 3 times depending on severity. As such, the mivacurium dosage should be lowered in this group [37,43]. Surprisingly, lower butyrylcholinesterase levels accompanying liver diseases in children do not yield prolonged mivacurium activity. Increased volume of distribution in patients with hepatic disease has been associated with a prolonged neuromuscular block [37,39]. Due to an increased volume of distribution, the duration of action of mivacurium appears to be longer in elderly individuals. [43]. In the case of end-stage renal failure, the block caused by mivacurium may be prolonged [5]. One of its adverse effects involves histamine release, rarely leading to decreased blood pressure, tachycardia, or bronchospasms [36].

Aminosteroids Charateristics

Amino steroids are a group of non-depolarizing NMBAs, including pipecuronium, pancuronium, vecuronium, and rocuronium. Similarly to benzylisoquinolones, they attach to acetylcholine receptors without depolarizing the end plate. They attach to the alpha subunit of the nicotinic receptors in the neuromuscular junction, preventing acetylcholine from doing so, thus simultaneously blocking muscle contraction [1].

Pipecuronium Characteristics and Uses in Liver Insufficiency

Pipecuronium is a long-acting non-depolarizing neuromuscular blocking agent that has been in use since the 1970s [49]. It is similar to pancuronium; however, it does not possess the cardiovascular risk associated with the latter (such as tachycardia and hypertension) [50,51]. Several studies confirmed that pipecuronium undergoes predominantly renal elimination, with a minor biliary pathway (2% in 24 hours). It is excreted unchanged (from 37% up to 56% in 24 hours) and as 3-disacetyl pipecuronium (from 1% to 15% in 24 hours) [52–55]. Some studies showed that liver dysfunction (eg, cirrhosis and cholestasis) does not alter the pharmacokinetics or pharmacodynamics of pipecuronium. However, D’Honneur et al reported that the onset of neuromuscular block can be longer in cirrhotic patients [56,57]. Most reports suggest that pipecuronium’s pharmacological properties can be impaired in patients with liver dysfunction.

Pancuronium Characteristics and Use in Patients with Hepatic Insufficiency

Pancuronium is an infrequently used, long-acting, non-depolarizing NMBA synthesized in 1964 [58]. The reason for its limited use is its cardiovascular risk, long onset time, and the introduction of shorter-acting neuromuscular blocking agents [59].

Pancuronium has a long elimination time and is excreted into urine and bile, with the kidneys constituting the primary pathway. Furthermore, some pancuronium undergoes biotransformation into 3-OH-, 17-OH-, and 3,17-OH-pancuronium, which are less potent than pancuronium. Additionally, pancuronium is not significantly bound to plasma proteins [51,60–62]. Kidney function disorders can prolong the neuromuscular block [5]. The duration of its effect is also influenced by acid-base disorders – metabolic and respiratory acidosis enhance the drug’s effect, while respiratory and metabolic alkalosis weaken it [4].

Several studies addressed the issue of pancuronium use in patients with hepatic insufficiency. It has been proven that larger doses of the drug are needed to achieve muscle relaxation. Moreover, longer elimination times have been observed. Both changes in pharmacokinetics probably occur due to the greater distribution volume and slower hepatic elimination in patients with liver dysfunction [63–66]. Additionally, in patients with biliary obstruction, the half-time is 2 times longer than in other patients [67].

In conclusion, hepatic disease severely impacts pancuronium properties, resulting in limited use of the drug.

Vecuronium Characteristic and Its Use in Hepatic Insufficiency

Vecuronium is another example of aminosteroidal NMBA introduced into clinical practice in the 1980s. Due to its intermediate duration of action, vecuronium is commonly used in anesthesia e.g., during intubation or to achieve muscle relaxation during surgical procedures [68].

Vecuronium is metabolized in the liver and eliminated mainly via the bile (60%), which suggests that hepatic dysfunction may impact its action. Additionally, vecuronium has 3 metabolites, of which 3-hydroxy vecuronium has 80% of the drug’s relaxing potency. Even though vecuronium itself depends predominantly on bile excretion, 3-hydroxy metabolite accumulates in renal failure and causes prolonged muscle relaxation [47,69–71]. For this reason, in patients with kidney failure, it is preferable to choose another skeletal muscle relaxant, and if vecuronium is administered, reduced doses should be used and repeating doses should be avoided [5]. Metabolic and respiratory acidosis enhance the block caused by vecuronium, while metabolic and respiratory alkalosis weaken it [4].

studies on vecuronium and liver dysfunction conclude that both the time of elimination and neuromuscular block are significantly prolonged in patients with cirrhosis, cholestasis, and liver failure after a bolus dose of 0.2 mg/kg and after prolonged administration in the intensive care unit. Additionally, plasma clearance decreases.

Interestingly, a study in 1988 conducted by Arden et al concluded that alcoholic liver disease does not affect vecuronium’s properties when administered in a bolus dose of 0.1 mg/kg. Moreover, some studies suggested that a bolus dose of 0.15 mg/kg in cirrhotic patients results in a recovery rate similar that in patients without liver disease, which Hunter et al (1985) attributed to the co-existing reduction of clearance (prolonging the action) and increased distribution volume (shortening the action) [64,72–75].

Summing up, caution is necessary when using vecuronium in patients with liver disease due to changes in its pharmacological properties, especially at higher doses.

Rocuronium Characteristic and Its Use in Hepatic Insufficiency

Rocuronium is an intermediate-acting NDMA characterized by short onset time and reversibility. It is currently one of the most used muscle relaxants in anesthesia [76].

Rocuronium depends mostly on liver uptake and biliary excretion, with a minor renal pathway (10–30%). It partially undergoes hepatic metabolism, producing a metabolite, which does not possess significant neuromuscular blocking activity [43,77]. In people with impaired kidney function, clearance is reduced, and the duration of the block is prolonged [5]. Respiratory and metabolic acidosis enhance the drug’s potency, while respiratory and metabolic alkalosis weaken it [4].

Weng et al (2005) demonstrated that during an orthotopic liver transplantation, the dose of rocuronium required to maintain optimal muscle relaxation changes depending on the phase of the procedure, with 0.468±0.167 mg/(kg·h) in a paleohepatic stage, 0.303±0.134 mg/(kg·h) in an anhepatic stage, and 0.429±0.130 mg/(kg·h) in a neohepatic stage. Therefore, this implies that the liver participates in the pharmacokinetics of rocuronium [8,42].

It has been observed that liver disease increases both its onset and duration of action, due to a larger volume of distribution and longer elimination half-life. Additionally, recovery time is also significantly prolonged in cirrhotic patients [78–80]. Therefore, rocuronium should be avoided in patients with liver dysfunction [43].

Although the liver plays a major role in rocuronium’s elimination, the kidneys’ role increases in patients with diminished bile excretion [81].

Patients with hepatic dysfunction also present high variability in response to rocuronium, but the wider use of rapidly acting muscle relaxants such as sugammadex might diminish that problem, allowing early extubation and rapid neuromuscular activity [82].

Neostigmine and Its Use in Hepatic Insufficiency

Neostigmine is an acetylcholinesterase inhibitor used to reverse the neuromuscular blockade caused by non-depolarizing blocking agents (eg, rocuronium). By binding with the acetylcholinesterase molecule, it ceases acetylcholine metabolism, consequently contributing to its increased concentration at the neuromuscular junction. A higher density of acetylcholine overcomes the inhibition of NMBA and allows muscle contraction. Since neostigmine impacts both nicotinic and muscarine receptors, several adverse effects have been observed, including bradyarrhythmias, bronchospasm, and increased secretions. Accordingly, its use should be complemented by administration of an anticholinergic drug such as atropine [83–85].

Neostigmine is metabolized by plasma acetylcholinesterase and hepatic microsomal enzymes. Approximately 50% of neostigmine is excreted unchanged in the urine. Additionally, around 20% of the drug is bound to plasma proteins [37,86].

Finally, even though the liver participates in neostigmine’s metabolism and excretion, dose adjustments are currently not recommended in patients with hepatic dysfunction. Sugammadex may be a better choice in reversal agents as it is less liver-dependent.

Sugammadex Characteristic and Its Use in Hepatic Insufficiency

Sugammadex is a novel antagonist to aminosteroidal non-depolarizing neuromuscular agents. With high affinity and selectivity, its binding contributes to formation of a stable chelate. It connects to rocuronium in a ratio of 1: 1 to form a complex further eliminated via renal secretion. Hence, sugammadex administration changes the elimination to a liver-independent renal pathway [78].

Sun et al (2023) investigated sugammadex-induced rocuronium-reversal in patients with different Child-Pugh liver function grades. Neuromuscular block was assessed via ultrasonography of the diaphragm at different points of time. At 10 minutes after administration of the same sugammadex dose, the incidence of residual muscle relaxation was 4%, 16%, and 40% in Child-Pugh class A, B, and C, respectively [87].

The sugammadex provided much faster reversal after rocuronium bolus and continuous infusion in patients undergoing liver transplantation in comparison to neostigmine – 9.4±4.6 min to 34.6±24.9 min, respectively [82].

Similar findings have been reported by Abdulatif et al (2018), with approximately 80% reduction in the time required to recover an adequate neuromuscular response with sugammadex antagonism as opposed to neostigmine. With rocuronium-sugammadex, the time to achieve a TOF ratio of 0.9 is 4.7 times faster than with cisatracurium-neostigmine. It provides anesthesiologists with the possibility of fast extubation, improving patient outcomes and lowering costs. Although cisatracurium may appear favorable in patients with hepatic dysfunction, in cases where rapid intubation and rapid neuromuscular recovery are required, rocuronium-sugammadex can be considered [78].

Sugammadex use in healthy subjects is associated with a transient prolongation of PT (prothrombin time) and aPTT (activated partial thromboplastin time). Caution is needed in patients with high bleeding risk, including patients with liver disease, as hepatic dysfunction causes decreased synthesis of several clotting factors [88].

Moon et al (2018) compared postoperative coagulation profiles in patients undergoing living-donor hepatectomy after sugammadex and pyridostigmine administration in the reversal of rocuronium-induced muscle relaxation. The average prolongation of PT (INR) was 0.21 in the sugammadex group, comparable to 0.20 prolongation of PT in the pyridostigmine group. A dose of 4 mg/kg did not affect the drain volume or the incidence of relaparotomy within 24 h after surgery for bleeding control. Despite the clinical implication, the bleeding risk after sugammadex administration is a subject of controversy, as several studies did not find a higher incidence of such complications, but its administration was associated with shorter anesthesia time and overall hospital stay [89].

Fujita et al (2014) demonstrated that recovery of the TOF ratio to 0.9 did not differ between groups with liver dysfunction and controls undergoing hepatic surgery. No prolongation of neuromuscular recovery and recurrence of the block indicates the safety of sugammadex [54].

Summary of Neuromuscular Blocking Agents Use in Hepatic Insufficiency and Actual Recommendations

Table 4 summarizes the literature on the impact of the drug’s elimination pathway on its use in cases of liver failure [36–44,48,51–56,60–66,59–71,77–80,86]. To ensure the best possible care for patients, recommendations and guidelines from scientific societies in the United States, New Zealand, and European countries are periodically updated every few years [90]. The latest recommendations and guidelines on use of skeletal muscle relaxants and neuromuscular blockade reversal agents are from 2023 and have been issued by both the European Society of Anaesthesiology and Intensive Care (ESAIC) and the American Society of Anesthesiologists (ASA). However, these guidelines do not address the use of these drugs in individuals with impaired hepatic function [91,92].

The most recent guidelines that include the use of these drugs in individuals with liver dysfunction are from 2020, when the French Society of Anesthesia & Intensive Care Medicine (SFAR) published “Guidelines on Muscle Relaxants and Reversal in Anesthesia”. According to these recommendations, it is probably best to use a benzylisoquinoline muscle relaxant (atracurium/cisatracurium) in patients with renal/hepatic failure, and it is recommended not to modify the initial dose in renal/hepatic failure patients, irrespective of the type of muscle relaxant used [93]. Table 5 summarizes the latest recommendations from ASA and ESAIC regarding the use of skeletal muscle relaxants and neuromuscular blockade reversal agents [91,92].

Future Directions

Thanks to advances in medicine, we know more than ever about liver disorders, their impact on health, complications, and therapeutic options. Recent reports on MASLD/MAFLD/NAFLD are particularly important. There is also growing knowledge of the relationship between neuromuscular blocking agents (NMBAs) and liver function, as well as their effects in individuals with liver dysfunction. Modern technologies allow for intraoperative monitoring of neuromuscular blockade, reducing the risk of residual blockade. Further research is needed to better understand the impact of muscle relaxants on liver function and to safely conduct anesthetic procedures in patients with liver dysfunction.

Conclusions

Liver dysfunction affects numerous processes in the body and can be associated with systemic complications such as decreased protein synthesis, resulting in reduced drug binding to serum proteins and increased free drug fraction in the bloodstream, prolonged INR with an increased risk of bleeding, thrombocytopenia, and accumulation of harmful metabolites in the body. Liver function disturbances also affect the duration of action of certain muscle relaxants by slowing their metabolism and prolonging their effects. It is important to use Train-of-Four (TOF) monitoring for neuromuscular blockade assessment in individuals with liver dysfunction.