Postoperative Cognitive Dysfunction Management in Cirrhotic Patients: Comparison
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Postoperative cognitive dysfunction (POCD) represents a decreased cognitive performance in patients undergoing general anesthesia for major surgery. Since liver cirrhosis is associated with high mortality and morbidity rates, cirrhotic patients also assemble many risk factors for POCD. Therefore, preserving cognition after major surgery is a priority, especially in this group of patients. POCD is roughly defined as decreased cognitive performance in patients undergoing anesthesia. Various risk factors, including increased age, baseline cognition level, depth of anesthesia, or postoperative pain level, were described to be involved in the development of POCD. In the cirrhotic patient, POCD is described as a “more than expected” decline in cognitive function. The judicious use of anesthetic agents and techniques, the monitoring of the depth of anesthesia, and the application of ERAS protocols may prove to be advantageous in this setting. However, specific and targeted therapies for POCD are lacking. 

  • postoperative cognitive dysfunction
  • cirrhosis
  • hepatic encephalopathy

1. Introduction

Nowadays, major abdominal surgery represents one of the most common occasions for exposure to general anesthesia. Bowel, liver, pancreatic surgery, or various oncologic surgical procedures for pelvic tumors exposes the patient usually hours to surgical stress and anesthesia. Due to the increased life expectancy, elderly patients with chronic medical conditions, such as liver cirrhosis, are prone to developing various postoperative complications, including postoperative cognitive dysfunction (POCD) [1,2,3][1][2][3].
POCD consists of decreased cognitive performance in patients undergoing general anesthesia during major surgery. Its pathophysiological mechanisms are not well known, but it is believed that approximately one-quarter of older individuals undergoing major surgery will suffer from cognitive decline, of which 50% will have permanent dysfunction [1].
The risk factors for POCD may be grouped into preoperative, intraoperative, and postoperative (Figure 1). Dementia, age, level of education, type of surgery, chronic obstructive pulmonary disease (COPD), psychiatric or degenerative disorders, alcohol, and illicit drug use are the most common preoperative risk factors [2,3][2][3] Intraoperative risk factors include bleeding (greater than 1000 mL), hypotension, hypocapnia, and depth of anesthesia [2,3][2][3]. The main postoperative risk factors are severe pain, benzodiazepines, and anticholinergic drugs, inadequate nutritional status, and low cardiac output [2,3][2][3].
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Figure 1. Risk factors and intervention strategies for POCD. POCD—postoperative cognitive dysfunction, COPD—chronic obstructive pulmonary disease.
POCD is usually transient and detectable with appropriate testing through comparison with preoperative cognition. It affects memory, learning abilities, perception, attention, executive functions, and verbal abilities and should be differentiated from postoperative delirium (POD) [4,5][4][5]. Usually, cirrhotic patients assemble many of the above-mentioned risk factors for developing POCD: preexisting hepatic encephalopathy (HE), alcohol and/or illicit drug use, poor nutritional status, cirrhotic coagulopathy, incomplete clearance of the endogenous benzodiazepines, hypotension, and modified drug pharmacokinetics. Thus, preserving cognition in cirrhotic patients after major surgery should be prioritized. Various pathophysiological pathways could lead to POCD-related impairments in cirrhotic patients: hyperammonemia, endotoxemia, chronic inflammation, and brain edema [6,7,8,9][6][7][8][9].
Hepatic encephalopathy (HE) is one of the various complications of end-stage liver disease and it represents a major clinical problem in assessing liver cirrhosis. Symptoms may vary from mild impairment in mental state, only diagnosed through psychometric tests, to coma [10,11][10][11]. Due to challenges in diagnosing minimal HE (mHE), its prevalence and incidence are hard to predict, but it is believed to affect approximately 40% of cirrhotic patients worldwide [12]. The first classification of HE was made in 1998 by the World Organization of Gastroenterology and modified by the European Association for the Study of the Liver-American Association for the Study of Liver Diseases (EASL-AASLD) consensus in 2014. It was categorized according to etiology, severity, time course, and occurrence (precipitated vs. spontaneous) [11]. For clinical purposes, West Haven criteria are used to classify HE into four stages, but they are often used subjectively and fail to accurately identify minimal hepatic encephalopathy (mHE). Thus, further efforts should be made to identify novel predictive biomarkers in various subclinical cirrhosis-associated conditions that could lead to cognitive impairment [8,9,10,11,12,13,14][8][9][10][11][12][13][14].
HE is proven to be the result of excessive amounts of ammonia produced by the liver [6,8,9,11][6][8][9][11]. Hyperammonemia leads to neurocognitive dysfunction consisting of memory loss, shortened attention span, confusion, agitation, changes in personality, seizures, and ultimately coma, regardless of anesthesia exposure [8,12][8][12]. Other neurological manifestations consist of neuromuscular changes (asterixis, paratonic rigidity, hyperreflexia, and tremor), believed to be the result of cerebral blood flow alterations, accumulation of brain metabolites, and release of inflammatory mediators [9]. Another consequence of liver failure is portosystemic shunting, leading to endotoxemia and consequently to reduced cognition [10,15][10][15]. Inflammation also plays a major role in the pathophysiology of HE [6,7,9,10,11][6][7][9][10][11]. In chronic liver dysfunction patients, urea synthesis is impaired, so astrocytes from the brain act as an alternate pathway for ammonia detoxification, resulting in the accumulation of glutamine within astrocytes, leading to swelling [9]. Mild diffuse brain edema was found in patients with the mHE using magnetic resonance imaging [16,17][16][17]. Diffuse white matter anomalies have been detected with magnetization transfer ratio measurements and fast-Flair sequences. Those abnormalities were found in the absence of clinical signs of HE and were reversible after liver transplantation surgery [16]. Animal and human models were used to prove that ammonia causes HE only in the presence of systemic inflammatory response syndrome (SIRS) [9]. Sepsis may trigger HE, due to altered nitrogen metabolism and the presence of an increased inflammatory response [7]. The possible mechanisms for HE are revealed in Figure 2.
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Figure 2.
The mechanisms of hepatic encephalopathy in cirrhotic patients.
Liver transplant is the only cure for liver cirrhosis, but preoperative HE may have negative effects on postoperative outcomes [18,19][18][19]. It was initially believed that HE symptoms are temporary, but new research shows that many neuropsychiatric and neuromuscular manifestations tend to have a long-term or permanent effect on the quality of life in these patients [18]. Neurological complications may affect approximately 75% of patients in the first month after transplantation, suggesting a link between preoperative status and the postoperative cognitive dysfunction seen in many older individuals after major surgery [19]. Neurologic symptoms were noticed even 1 year after the transplant, due to a variety of factors such as sepsis, the persistence of portosystemic shunts, and immunosuppressant-associated toxicity [18].
According to the EASL (European Association for the Study of the Liver) guideline, HE should be prevented with standard therapy first, by prescribing non-systemic antibiotics (e.g., rifaximin) and non-absorbable disaccharides (e.g., lactulose) [20]. Airway patency should also be preserved to prevent aspiration pneumonia. If possible, HE should be corrected prior to general anesthesia, as it may cause POCD. For better prophylaxis of POCD in cirrhotic patients, various risk factors for HE should also be considered and treated, as they may worsen the postoperative neurocognitive status of the patient and decrease survival [20].

2. Perioperative Cognitive Dysfunction Management in Cirrhotic Patients

With the increasing prevalence of chronic liver disease, up to 10% of cirrhotic patients may have non-transplant surgery within the last two years of their lives [21]. Depending on the degree of liver disease, perioperative mortality is generally 2–10 times higher in individuals with cirrhosis than in those without [22,23][22][23]. In cases of decompensated cirrhosis, general anesthesia and surgery might result in severe morbidity and significant perioperative mortality. The most significant clinical tools in identifying cirrhotic patients at risk for surgery and anesthesia, such as the MELD score, do not include, however, the presence of perioperative cognitive dysfunction, which can lead to prolonged ICU stay and, additionally, increase mortality [24,25][24][25]. Hemodynamic abnormalities, which are more obvious than all others, could occur as an inappropriate response to surgical stress due to the minimal hepatic reserve and the systemic disturbances brought on by liver dysfunction [24]. Furthermore, inappropriate blood flow to the brain along with disturbed liver metabolism could aggravate a subclinical cognitive dysfunction. Thus, supplementary perioperative complex cognitive assessments should be implemented, along with therapeutic strategies to mitigate this potentially dangerous complication. The clinician’s efforts should focus on the three main critical care stages: preoperative, intraoperative, and postoperative period, in order to develop new innovative strategies to reduce cognitive impairment in patients with end-stage liver disease. The most important perioperative strategies are summarized in Figure 43.
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Figure 43. The main perioperative strategies for reducing POCD in cirrhotic patients. Abbreviations: mHE—minimal hepatic encephalopathy, NIRS—near-infrared spectroscopy, AEP—auditory evoked potentials, rScO2—the regional cerebral oxygen saturation, ICU—Intensive care unit, AKI—acute kidney injury, ERAS—early recovery after surgery.

2.1. Preoperative Management of Cognitive Dysfunction in Cirrhotic Patients

According to the literature, age, ASA classification, and the degree of liver disease as mirrored by the MELD score are the three most significant predictors of mortality [25]. Nevertheless, emergency surgery has been linked to greater rates of morbidity and death rates than elective surgery in cirrhotic patients [24,26][24][26]. Even if no direct causality was observed between the degree of surgical emergency and cognitive decline, various perioperative complications such as hypotension, renal failure, and coagulation abnormalities could precipitate POCD in cirrhotic patients exposed to emergency surgery [27]. The most frequent indications for emergency surgery in cirrhotic patients are gallstones, abdominal wall hernia, small bowel, appendix, colorectal, or gastric surgery [24,28,29][24][28][29]. Thus, the clinician’s ability to predict and treat cirrhosis-associated comorbidities, regardless of the urgency grade, poses a central role in reducing the POCD rate.

Two of the most known scoring systems for predicting the outcome of cirrhotic patients undergoing surgery are the Model for End-Stage Liver Disease (MELD) and Child-Turcotte-Pugh (CTP) [27]. Both scores focus more on the general perioperative mortality in cirrhotic patients and to a lesser extent on the cognitive decline after surgery.
The CTP score lacks reproducibility because it relies on the observer’s perspective of the HE and ascites [27]. There are several studies that link the increasing mortality rate to Child classes A, B, and C. [27]. Telem et al. noticed that patients with cirrhosis undergoing abdominal surgery had lower mortality rates, 2% for CTP class A, and 12% for both CTP class B and C [48][30].
The MELD score takes into consideration the patient’s serum creatinine, bilirubin, and INR. These are objective laboratory parameters therefore the MELD score is more reproducible than the CTP score in terms of mortality but does not include any parameters for the evaluation of cognition [27]. Perkins et al. discovered that patients with a MELD score over eight have higher postoperative morbidity [49][31]. A study analyzing 140 surgical procedures in patients with cirrhosis showed that mortality is proportional with each point in the MELD score (1% increase until 20 points and 2% thereafter) [50][32].

2.2. Intraoperative Management of Cognitive Dysfunction in the Cirrhotic Patient

In addition to the significant risk of morbidity and mortality after anesthesia and surgery in cirrhosis, any preexistent cognitive deficit could influence postoperative care. The direct effect of anesthesia on the brain is still debatable [55,56][33][34]. Furthermore, specific novel biomarkers in cirrhosis could identify new predictive algorithms in patients at risk [14]. Elective interventions should be performed only in cases with compensated chronic liver disease [14,57][14][35]. Postponing elective surgery in patients with decompensated liver cirrhosis should be considered by weighting the risk-benefit ratio. Nevertheless, according to a study published by Friedman, there are several clinical conditions that contraindicate any elective surgery: fulminant hepatic failure, acute viral or alcoholic hepatitis, Child’s class C cirrhosis, severe coagulopathy, hypoxemia, cardiomyopathy, or acute renal failure [58][36]. Moreover, particular attention must be given to the neurological status of the patient and special measures taken in the perioperative period in order to minimize POCD, even if no consistent recommendation exists with regard to postponing an elective surgery based on the presence of HE or any other cognitive decline alone [59,60][37][38]. Intraoperative management poses a few challenges, such as optimization of the intravascular volume in the presence of ascites and peripheral edema. Goal-directed fluid therapy and avoiding overloading appear to be beneficial [1]. Blood products are routinely used in these cases and employment of point-of-care analysis of coagulopathy, such as ROTEM or TEG, proves to be an optimal approach [61][39].  Evaluating baseline cognitive function may prove useful in identifying patients at risk of developing POCD, as preoperative cognitive impairment is correlated with an increased probability of POCD [1]. Anesthesia and surgery-related risk factors for POCD refer to adequate analgesia or hypnosis, reduced blood flow to the brain, massive bleeding with an increased volume shift, and prolonged duration of the surgery [1]. Therefore, specific anesthetic strategies may be implemented in an attempt to minimize POCD. Intraoperative management becomes crucial in the health practitioners’ pursuit of maximizing postoperative brain health. Liver dysfunction associated with cirrhosis results in the alteration of all pharmacokinetic phases: absorption, distribution, and elimination [62][40]. Impaired liver function translates to increased portosystemic pressure, which increases the bioavailability of the drugs as a result of reduced first-pass metabolism. Diminished protein synthesis function, with lower serum albumin concentrations, as well as ascites formation and volume overload, explain the changes in the distribution phase in these patients [62][40]. Therefore, cirrhosis implies a higher volume of distribution for both highly protein-bound drugs and water-soluble drugs. The elimination phase is also subject to changes in liver disease, with different degrees of impairment of the various metabolizing enzymes, the cytochrome P450 system being more severely affected [62][40].

2.3. Postoperative Management of Cognitive Dysfunction in the Cirrhotic Patient

Postoperative care may prove to be challenging in cirrhotic patients; maintaining cognitive status should be prioritized, even if no sufficient objective assessment tools are available for diagnosing the postoperative neurocognitive decline. Surgery and anesthesia might induce cirrhosis decompensation [60][38]. In addition to encephalopathy, other major complications could impact the outcome: ileus, infection, allergies to antibiotics, bleeding, coagulopathy, renal or respiratory failure, and new onset or worsening ascites [44,61,94][39][41][42]. Thus, cirrhotic patients, especially those in CTP-B and C class, should be managed in the ICU in the early postoperative period [61][39]. Assessment of bleeding risk, close monitoring of coagulation, and cautious fluid management are of marked importance. Cirrhotic patients exhibit a hyperdynamic status, with hypotension being regarded as a normal occurrence in these cases. The general volume overload associated with reduced intravascular volume in cirrhotic patients may warrant the use of invasive monitoring [60,95][38][43]. Lactic acidosis may occur not only in the setting of inadequate perfusion but also as a sign of liver decompensation [95][43]. Moreover, renal dysfunction following surgery in liver disease patients may be a result of either acute tubular necrosis or hepatorenal syndrome. Thus, maintaining the intravascular circulating volume is crucial in these patients [61][39]. Salt restriction is required as a preventive measure for acute kidney injury (AKI), HE, or ascites occurrence. Regarding coagulation, INR has been suggested to be a sensitive test in assessing hepatic synthesis and a useful marker of hepatic decompensation. Targeting normal values and overcorrection of INR through the administration of FFP in an otherwise hemostatic patient is not required [60,95][38][43].

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