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Diario Oficial de la Sociedad Mexicana de Cirugía Cardiaca, A.C., y del Colegio Mexicano de Cirugía Cardiovascular y Torácica, A.C.

2025, Number 1

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Cir Card Mex 2025; 10 (1)

Hepatotoxic effects of lactated Ringer´s solution in patients undergoing cardiac surgery at a national referral center

Leyva-López, Yoana1; Rivera-Buendía, Frida2; Ortega-Zhindón, Diego B3

Language: English
References: 16
Page: 5-13
PDF size: 710.10 Kb.


ABSTRACT

Objective: we describe a case series of twelve patients who underwent cardiac surgery that developed acute hepatic failure (AHF) following the administration of Lactated Ringer's solution (LRS). Material and methods: an observational and retrospective study was carried out. Patients diagnosed with AHF undergoing cardiac surgery from January 1, 2018 and December 31, 2018, were included; perioperative characteristics and conditions were considered. Results: these patients received a mean of 100 ml/h of LRS for a hypovolemic replacement over about 3.8 ± 2.7 days. AHF and hepatocellular damage pattern, was confirmed in twelve patients and is potentially associated with drug-induced liver injury (DILI) due to LRS. At follow-up, four patients were discharged from the hospital, while eight died during hospital stay. Conclusions: carefully assessing lactic acid levels and liver enzymes in cardiac surgery patients during their intensive care unit stay before starting infusion with LRS is important. The prevention of hyperlactatemia complications requires an initial assessment of lactate metabolism.



ABBREVIATURES:

  • AHF = acute hepatic failure
  • AKI = acute kidney injury
  • ALP = alkaline phosphatase
  • ALT = alanine aminotransferase
  • AST = aspartate aminotransferase
  • AVR = aortic valve replacement
  • DILI = drug-induced liver injury
  • ICU = intensive care unit
  • LDH = lactate dehydrogenase
  • LRS = lactated Ringer's solution
  • MVR = mitral valve replacement
  • pCO2 = partial pressure of carbon dioxide
  • RUCAM = Roussel Uclaf causality assessment method
  • ULN = upper limit of normal

Patients who have undergone cardiac surgery, large volumes of crystalloid solutions, such as lactated Ringer's solution (LRS), are commonly administered to mitigate the effects of decreased tissue perfusion. The recommended dose of LRS ranged from 500 to 3,000 ml every 24 hours. Administration rates are adjusted based on the patient's clinical status, usually not exceeding 5 ml/kg/h.1 However, using LRS could exacerbate basal serum lactate levels in some patients, leading to micro vascular and macrovascular circulation changes, a systemic inflammatory response, and subsequent organ damage. Particularly, hyperlactatemia could result in diffuse liver damage, characterized by a rapid and marked elevation of serum aminotransferases.2 The prolonged exposure to hyperlactatemia may cause cellular and systemic dysfunction, resulting in severe metabolic acidosis, and in some cases, death. Although a relative increase in serum lactate levels is a common finding after cardiac surgery, the administration of LRS might drive the onset of severe hyperlactatemia and eventually, acute liver failure as a rare complication during the postoperative period.3,4

In this study, we describe a series of twelve cases who underwent cardiac surgery and further developed acute hepatic failure (AHF) during their intensive care unit (ICU) stay after receiving LRS as the initial replacement fluid therapy.



MATERIAL AND METHODS

We conducted a case series study of twelve patients undergoing cardiac surgery at the Instituto Nacional de Cardiología Ignacio Chávez from January 01, 2018 and December 31, 2018. We collected information on demographics, comorbidities, diagnoses, invasive procedures, biochemical parameters of liver function, and acid-base parameters of arterial gases (hydrogen potential (pH), partial pressure of carbon dioxide (pCO2), bicarbonate (HCO3−), and serum lactate) during the first seven days of ICU stay. We determined whether there was an acid-base disturbance (metabolic acidosis, respiratory alkalosis, or mixed alkalosis).5 AHF was defined according to the following: elevation of alanine aminotransferase (ALT) > 5 times the upper limit of normal (ULN) or alkaline phosphatase (ALP) > 2 times the ULN. Pattern of liver damage was defined as hepatocellular if the ULN of ALT or aspartate aminotransferase (AST) was greater than 5, cholestatic if there was a predominant elevation of ALP, and mixed if there was a combination of both.6 We used the Roussel Uclaf causality assessment method (RUCAM) to determine the presence of drug-induced liver injury (DILI). Clinical outcomes included mortality or hospital discharge; additionally, we analyzed the relationship between acid-base disturbance, altered lactate metabolism, LRS administration, and acute liver injury. The IRB approved the study (INCAR-DG-DI-DI-CI-053-2023), adhering to the Declaration of Helsinki and following the CARE guidelines.

Data was collected using the REDCap electronic software (Vanderbilt University, Nashville, Tenn).7 Continuous variables were presented as mean (± standard deviation) or median (interquartile range) according to the Anderson-Darling normality test. Categorical variables were presented as frequency and absolute proportion. Plots to visualize the changes in biochemical parameters and follow-up status were built with the ggplot2 R package.8 We conducted all statistical analyses using R Studio version 3.1.1 (R Foundation for Statistical Computing, Vienna, Austria).



RESULTS



SOCIODEMOGRAPHIC AND CLINICAL PROFILE

Table 1 displays the sociodemographic and clinical characteristics at admission. The age ranged between 19 and 76, with a mean of 44.9 ± 16.8 years. Women made up 58% (n = 7) of the sample. The most common comorbidities were systemic arterial hypertension (33.3%, n = 5), type 2 diabetes mellitus (16.6%, n = 2), and chronic kidney disease (16.6%, n = 2). The admission diagnoses included one patient with acute aortic dissection type Stanford A and two with mitral regurgitation. Other diagnoses are shown in Table 2.



CARDIAC SURGERY EVALUATION

Aortic valve replacement (AVR) and mitral valve replacement (MVR) were performed in six patients (50%), while Bentall-De Bono procedure was conducted in two patients (16.6%) (Table 1). The twelve underwent cardiac surgery using cardiopulmonary bypass (CPB). The mean CPB time was 194 ± 68 minutes, aortic cross-clamping was 129 ± 35 minutes, temperature was 28 ± 4 °C, and the operative bleeding was 718 ± 386 ml.



CLINICAL CONDITION

Table 2 shows patients' clinical findings during hospitalization. After the cardiac surgery, all patients were transferred to the ICU with normal hepatic function parameters. All patients received a mean dose of 100 ml per hour of LRS for hypovolemic replacement with a mean duration of 3.8 ± 2.7 days. During the first seven days of ICU stay, we observed clinical manifestations of increased lactate levels, lactic dehydrogenase, and clinical and laboratory evidence of hepatic damage (increase in the ALT/AST ratio) (Figure 1). Postoperative metabolic acidosis was observed in seven patients (58.3%) and metabolic acidosis/mixed in five (41.6%) patients, which confirmed the clinical pattern of lactate metabolism deterioration. We observed confirmed acute hepatic failure in twelve patients (91.6%) due to marked elevation of ALT/AST greater than 5 ULN.



EARLY OUTCOMES

The median length of hospital stay was 9 (IQR:2.5-22.5) days. Four patients were discharged by clinical improvement, while eight died during hospitalization. The main causes of death were AHF (25%, n = 2), cardiogenic shock (37.5%, n = 3), septic shock (25%, n = 2), and mixed shock (12.5%, n = 1) (Table 2 and Figure 1).



DISCUSSION

This case series evidenced that among 12 patients who were treated with LRS, 12 developed AHF and subsequently 8 died. Acute liver failure is feared complication in the ICU; DILI is diagnosed through the exclusion of other potential liver conditions and confirmed by relating potentially hepatotoxic substances to alterations in the liver's biochemical profile.9 The increase in liver enzymes and temporal relationship with drug intake are the hallmark indicators of DILI, as there is currently no secure and accurate method for diagnosing it.10 The most common type of DILI is hepatocellular, accounting for 52-75% of cases and characterized by a significant rise in ALT and/or AST concentrations due to drug administration.10

Exposure of hepatocytes to stress, most likely involving reactive metabolites, mitochondrial dysfunction, and oxidative stress, is believed to trigger DILI.11 Inhibition of cytoplasmic (glycolysis) or mitochondrial (Krebs's cycle, oxidative phosphorylation) pathways leads to inadequate ATP production despite adequate amounts of oxygen and glucose, resulting in pyruvate and lactate accumulation under aerobic conditions, a situation known as cytotoxic hypoxia.12 Histologic risk reduction and hypoxia impact the enzymatic pathways of pyruvate and lactate metabolism by stimulating anaerobic glycolysis and altering mitochondrial function, reducing lactate utilization and clearance. When the mitochondrial oxidative chain fails to generate NAD+, pyruvate is reduced to lactate to produce NAD+ and hypoxia affects both lactate utilization pathways.13 In this context, LRS contains 28 mEq of lactate per liter and is the only solution that undergoes normal cellular metabolism in the liver, responsible for 60% of lactate clearance. During its metabolism as part of the Cori cycle, lactate is transformed into pyruvate and then into HCO3−.2 A decrease in HCO3− and an increase in lactate indicate an alteration in lactate metabolism and excessive lactate administration beyond clearance can result in negative multiorgan effects. There is a theoretical possibility that administering large amounts of LRS could worsen existing lactic acidosis in septic shock and other states of peripheral hypoperfusion, which is further increased if there are bacterial infections and septic shock.14,15 The potential relationship between serum lactate concentration and the dose of LRS administered with liver function alteration is shown in Figure 2, but further clinical studies are needed to confirm this relationship in septic shock and other states of peripheral hypoperfusion. Zitek et al., conducted a randomized clinical trial that examined the relationship between LRS administration and an increase in serum lactate levels, comparing healthy volunteers receiving LRS to those receiving saline solution at a dose of 30 ml/kg, the results showed that the mean lactate level increased from 1.06 to 1.99 mmol/l, corresponding to an increase of 0.93 mmol/L after LRS administration, though these results were not statistically significant.14 Recently, another randomized clinical trial demonstrated that among patients undergoing cardiac surgery, the use of LRS did not reduce the risk of major adverse events over the following 90 days.16 Currently, there is diverse ongoing clinical research regarding the use of crystalloid solutions and their impact on acid-base status, intra- and extracellular water content, plasma electrolyte compositions, and organ function. This study had important limitations, such as the fact that biochemical parameters of ALT/AST or ALP were not taken in all patients before, during, and after the invasive procedure. Another limitation is that currently, only the RUCAM method is available to evaluate the causality of DILI.

Overall, in clinical practice, it is important to look for all possible triggers of acute hepatic failure, to perform an initial analysis of the adequate function in lactate metabolism, before starting the infusion of lactate-containing crystalloids to avoid adverse clinical outcomes. As a last resort, in patients with acute hepatic failure with no evident cause, all medications or solutions that could be associated with this condition should be evaluated and suspended until the liver function or clinical status is resolved or restored.



CONCLUSIONS

These cases highlight the importance of addressing lactic acid and liver enzymes during the ICU stay of patients who underwent cardiac surgery before starting lactate-containing crystalloid infusion. An initial analysis of patients' lactate metabolism function should be performed to prevent adverse clinical outcomes related to hyperlactatemia and its associated mechanisms. In cases where acute hepatic failure has been identified without an obvious cause, all medications or solutions that may be associated with this condition should be evaluated and suspended until liver function or clinical status is resolved or restored.



ACKNOWLEDGMENTS

We want to acknowledge the contribution of the Oficina de Apoyo Sistemático para la Investigación Superior (OASIS) of the Instituto Nacional de Cardiología Ignacio Chávez for the support for this manuscript.


REFERENCES

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AFFILIATIONS

1 Department of Clinical Research.

2 London School of Hygiene and Tropical Medicine. London, United Kingdom.

3 Department of Pediatric Cardiac Surgery and Congenital Heart Disease; Instituto Nacional de Cardiología Ignacio Chávez. Mexico City, México.



Funding: none.

Conflict of interest: the authors have no conflicts of interest to disclose.



CORRESPONDENCE

Dr. Diego B. Ortega-Zhindón, E-mail: diegob.ortegaz@gmail.com




Received: 10-20-2024. Accepted: 11-01-2024.

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