Significance of lactate clearance in septic shock patients with high bilirubin levels.

Abstract

Background

Although lactate clearance is affected by hepatic function, it is unclear whether the hepatic dysfunction is associated with lactate clearance as a prognostic marker of clinical outcomes in septic shock. We aimed to evaluate association between the lactate clearance and mortality divided by hepatic dysfunction based on total bilirubin level using two cohort of septic shock patients.

Methods

Lactate clearance, delta base excess and delta anion gap in 24 hours from septic shock onset were analyzed using two cohorts of septic shock patients (derivation cohort, n = 230; validation cohort, n = 396) categorized into two groups by total bilirubin levels (TBIL) < 2 mg/dL and ≥ 2 mg/dL on day 1. The primary analysis was association between lactate clearance and 28-day mortality by total bilirubin category.

Results

In derivation cohort, lactate clearance was lower in non-survivors compared to survivors in the patients with TBIL ≥ 2 mg/dL (P = 0.0035), while there was a no significant difference in those with TBIL < 2 mg/dL. There were no significant differences in delta base excess and delta anion gap between non-survivors and survivors both in the patients with TBIL ≥ 2 mg/dL and < 2 mg/dL. In the multivariate logistic regression analysis, increased lactate clearance was significantly associated with decreased 28-day mortality in TBIL ≥ 2 mg/d group (10% lactate clearance, adjusted odds ratio 0.88, 95%CI; 0.80–0.97, P = 0.0075), whereas there was no significant association in TBIL < 2 mg/d group. We next tested for lactate clearance in TBIL ≥ 2 mg/dL using the validation cohort; lactate clearance was lower in non-survivors compared to survivors in the TBIL ≥ 2 mg/dL group (P = 0.0006), while no significant difference was observed in TBIL < 2 mg/dL. Increased lactate clearance was significantly associated with decreased 28-day mortality in the TBIL ≥ 2 mg/dL group (10% lactate clearance, adjusted odds ratio 0.89, 95%CI; 0.83–0.96, P = 0.0038); while no significant difference was observed in TBIL < 2 mg/dL in the validation cohort.

Conclusions

Patients with increased lactate clearance had decreased 28-day mortality when patients had hepatic dysfunction (TBIL ≥ 2 mg/dL) in septic shock.

Background

Blood lactate levels potentially reflect the imbalance between oxygen delivery and consumption under the global tissue hypoxia, which reduces the availability of pyruvate into TCA cycle and accelerates an aerobic glycolysis caused by excess beta-adrenergic stimulation [1, 2]. Blood lactate level is a corner stone of diagnosis and management in patients with septic shock [3–6]. Patients with increased blood lactate levels have worse clinical outcome in septic shock; Persistent lactate elevation, in other words decreased lactate clearance may be a signal of danger in management of septic shock [7–10].

Lactate clearance consists of the balance of the generation and elimination [11, 12]. Hepatic function is key to eliminate lactate; hepatic dysfunction potentially decreases lactate clearance [13, 14]. Lactate clearance has been substantially investigated in septic shock [7–9, 15, 16]; However, it was rarely tested whether the association between lactate clearance and clinical outcomes is different among patients with and without hepatic dysfunction.

Thus, we hypothesized that hepatic function provides a difference in relationship between lactate clearance and mortality in septic shock. We tested for association between the lactate clearance and 28-day mortality in two groups divided by hepatic dysfunction based on total bilirubin value using two cohorts of septic shock patients. The change of anion gap and base excess were also examined, since these directly reflect the nonvolatile acid which is generated by tissue hypoxia and may be affected by hepatic function.

Materials And Methods

Study design, definition and patients

This observational study was retrospectively conducted. Septic shock was defined by the presence of systemic inflammatory response syndrome criteria caused by infection [17], at least one new organ dysfunction by the Brussels criteria, and hypotension despite adequate fluid resuscitation [18]. According to these criteria, hepatic dysfunction was defined by blood levels of total bilirubin (TBIL) ≥2 mg/dL [19].

Derivation cohort: CHIBA cohort

Patients admitted to the ICU at Chiba university hospital (CHIBA) in Chiba, Japan between October 2012 and September 2018 were screened (n=9290). Of these, 230 patients met the definition of septic shock on ICU admission and had blood lactate clearance, delta anion gap and delta base excess data available, who were included in the analyses. This study was approved by the Institutional Review Board of Chiba University Graduate School of Medicine.

Validation cohort: VASST cohort

VASST (Vasopressin and Septic Shock Trial) was a multicenter (ICUs, n=27, Canada, Australia, and the United States), randomized, double-blind trial conducted between July 2001 and April 2006 [18]. Of 6229 patients screened, 396 patients screened with septic shock were included in the analyses. The Institutional Review Board at St. Paul’s Hospital and the University of British Columbia (UBC) approved the study.

Measurements and clearance

Blood levels of lactate and base excess and anion gap were examined at the presentation of septic shock (day 1) and 24 hours later (day 2). Blood lactate clearance (percent) was defined as the following formula:

Lactate clearance (percent) = (Lactate^Day1 – Lactate^Day2) / Lactate^Day1 *100

(Lactate^Day1, Lactate level at recognition of septic shock; Lactate^Day2, Lactate level 24 hours after septic shock recognition)

Anion gap, which was calculated using sodium, chloride ion and bicarbonate, was only available in the derivation cohort. Delta base excess and anion gap were calculated by subtracting day 2 values from day 1 values.

Statistical analysis

The primary outcome variable was lactate clearance. Secondary outcome variables were delta base excess and delta anion gap. Patients were categorized into two groups by TBIL levels<2mg/dL and ≥2mg/dL on day 1.

The primary analysis used logistic regression to test association between lactate clearance and 28-day mortality by TBIL category (< and ≥2mg/dL). We chose this multivariate analysis approach to adjust for potential baseline imbalances (age, sex and APACHE II score). The correlation between lactate clearance and delta anion gap was analyzed using a Pearson correlation coefficient test.

Univariate analysis was performed using a Mann-Whitney U test. Differences were considered significant using a two-tailed value of P <0.05. Data were presented as means with standard deviations. Analyses were performed using R^® version 3.3.3 (R Foundation for Statistical Computing, Vienna, Austria, http://www.R-roject.org/) and PRISM^® version 8 (GraphPad Software, Inc. California, USA).

Results

Of 230 patients, 153 patients were TBIL < 2 mg/dL and 77 patients of TBIL ≥ 2 mg/dL in the derivation cohort (Table 1). In baseline characteristics, there was no significant difference in between patients with TBIL ≥ 2 mg/dL and < 2 mg/dL except for higher levels of lactate on day 1 in the patients with TBIL ≥ 2 mg/dL compared to TBIL < 2 mg/dL.

In the patients with TBIL ≥ 2 mg/dL, non-survivors had significantly lower lactate clearance compared to survivors (P = 0.0035), while in those with TBIL < 2 mg/dL, there was a no significant difference in lactate clearance between survivors and non-survivors (P = 0.88) (Fig. 1A). Lactate clearance was not significantly correlated to TBIL (TBIL ≥ 2 mg/dL group, P = 0.82; TBIL < 2 mg/dL group, P = 0.35, total, P = 0.80). There were no significant differences in delta base excess between non-survivors and survivors both in the patients with TBIL ≥ 2 mg/dL (P = 0.74) and < 2 mg/dL (P = 0.64). No significant differences in delta anion gaps were observed between non-survivors and survivors in the patients with TBIL < 2 mg/dL (P = 0.70), while there is a non-significant trend of decreased delta anion gap in survivors compared to non-survivors TBIL ≥ 2 mg/dL (P = 0.13) (Fig. 1B and 1C). Lactate clearance was significantly correlated to delta anion gap in the derivation cohort (all, R = 0.54, P < 0.0001; TBIL < 2 mg/dL, R = 0.56, P = 0.00017; TBIL ≥ 2 mg/dL, R = 0.57, P < 0.0001) (Fig. 2).

In the primary analysis using a multivariate logistic regression analysis with adjustments of baseline imbalances, patients with increased lactate clearance had significantly decreased 28-day mortality in TBIL ≥ 2 mg/d group (10% lactate clearance, adjusted odds ratio [OR] 0.88, 95%CI; 0.80–0.97, P = 0.0075); however, in TBIL < 2 mg/d group, lactate clearance was not significantly associated with altered 28-day mortality in the derivation cohort (10% lactate clearance, adjusted OR 0.99, 95%CI; 0.93–1.05, P = 0.69) (Table 3A). In accord with lactate clearance, patients with increased delta anion gap had significantly decreased 28-day mortality in TBIL ≥ 2 mg/d group (adjusted OR 1.09, 95%CI; 1.00-1.19, P = 0.045); however, in TBIL < 2 mg/d group, delta anion gap was not significantly associated with altered 28-day mortality (delta anion gap, adjusted OR 0.96, 95%CI; 0.83–1.11, P = 0.58) (Table 3B). Delta base excess was not significantly associated with altered 28-day mortality in the multivariate logistic regression analysis with the same adjustments of baseline imbalances (delta base excess, TBIL < 2 mg/dL, P = 0.65, TBIL ≥ 2 mg/dL, P = 0.74).

We next tested for the significant findings of lactate clearance in TBIL ≥ 2 mg/dL using the validation cohort (Table 2). In baseline characteristics, patients with TBIL ≥ 2 mg/dL were younger and had an increased probability of chronic hepatic failure compared to TBIL < 2 mg/dL. In accord with the derivation cohort, non-survivors had significantly lower lactate clearance compared to survivors in the TBIL ≥ 2 mg/dL group (P = 0.0006), while no significant difference in lactate clearance was observed in TBIL < 2 mg/dL (P = 0.46) (Fig. 3). Furthermore, patients with increased lactate clearance had significantly decreased 28-day mortality in the TBIL ≥ 2 mg/dL group (10% lactate clearance, adjusted odds ratio 0.89, 95%CI; 0.83–0.96, P = 0.0038); however, in the TBIL < 2 mg/dL group, lactate clearance was not significantly associated with altered 28-day mortality in the validation cohort (Table 3C).

Table 3. Multivariate logistic regression analysis for 28 days mortality

A. Derivation cohort, lactate clearance

B. Derivation cohort, delta anion gap 

C. Validation cohort

APACHE, acute physiology and chronic health evaluation

Discussion

In the present study of lactate clearance in septic shock patients, stratified by hepatic dysfunction, increased lactate clearance in the initial 24 hours was significantly associated with decreased mortality in patients with TBIL ≥ 2 mg/dL. In contrast, lactate clearance was not associated with altered mortality in patients with TBIL < 2 mg/dL

Lactate clearance has been substantially studied as a prognostic marker in sepsis/septic shock [7, 9, 15, 20]. However, increased lactate clearance has not always been observed to be associated with decreased mortality in sepsis/septic shock. In the present study of two septic shock cohorts, the association between increased lactate clearance and decreased 28-day mortality was significant only in TBIL ≥ 2 mg/dL group, but not in TBIL < 2 mg/dL, which may explain why the previous reports obtained inconsistent conclusions in mixed patient populations with hepatic dysfunction and no hepatic dysfunction. The present study may highlight the importance of the hepatic dysfunction when considering lactate clearance as a prognostic marker.

Lactate kinetics has been investigated [21–25]. An investigation using intravenous infusion of sodium lactate revealed that clearance of lactate from blood in normal postprandial subjects was 17.9 mL/kg/min [21]; it decreased 14.5 mL/kg/min in patients with hepatic dysfunction [22]. Additionally, a significant prolongation in lactate half-life was observed in the patients with liver cirrhosis due to impaired hepatic lactate uptake (18.8 min compared to 14.7 min) [23]. Similarly, in severe sepsis/septic shock, hepatic dysfunction was significantly associated with impaired lactate clearance and normalization during the early phase of quantitative resuscitations [13]. Thus, hepatic dysfunction decreased lactate elimination. In the condition of insufficient elimination, lactate generation has a large effect on lactate clearance, which is a potential explanation for the significance of lactate clearance in hepatic dysfunction.

In this study, delta base excess, which reflect the bicarbonate at the end of lactate metabolism, was not associated with 28-day mortality in both TBIL ≥ 2 mg/dL and TBIL < 2 mg/dL group. Base excess reflects increased non-volatile acid including lactate in sepsis [26], and low base excess predicted increased lactate levels [27, 28]. However, base excess is affected by other abnormalities such as a metabolic acidosis (ketoacidosis, renal tubular acidosis and uremia), acute respiratory acidosis or hemoglobin level change, which are sometimes observed in critically ill patients [29]. The change of base excess as a prognostic marker of septic shock may be affected by these complex acidosis mechanisms.

Conversely, delta anion gap was significantly associated with altered mortality and had a good correlation with lactate clearance. Anion gap directly reflect the nonvolatile acid compared to base excess calculated using pH and bicarbonate; anion gap simply shows the ion balance [30, 31]. In accord with this, lactate clearance was significantly correlated to delta anion gap. The significant association of delta anion gap with altered 28-day mortality is a supportive evidence on the significant finding in lactate clearance in the present study.

Our study has several limitations. First, it is a retrospective study, although we found the same effect of hepatic dysfunction in both cohorts of septic shock patients. Second, we defined hepatic dysfunction as TBIL ≥ 2 mg/dL based on Brussels criteria; however, there are different criteria or cut-off values of hepatic dysfunction.

Conclusions

In septic shock, patients with increased lactate clearance had decreased 28-day mortality when patients had hepatic dysfunction (TBIL ≥ 2 mg/dL). These highlighted the importance of hepatic dysfunction when considering the lactate clearance as a clinical parameter.

Abbreviations

TBIL, total bilirubin; CHIBA, Chiba university hospital; VASST, Vasopressin and Septic Shock Trial

Declarations

Ethics approval and consent to participate

This study was approved by the Institutional Review Board of Chiba University Graduate School of Medicine, the Institutional Review Board at St. Paul’s Hospital and the University of British Columbia. Written informed consent was waived because of the study design.

Consent for publication

Not applicable.

Availability of data and materials

The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests

The authors declare that they have no competing interests.

Funding

Not applicable.

Authors' contributions

N.T. and T.N. contributed to the study’s conceptualization and design, the acquisition of data, analysis, and interpretation of data, statistical analysis, and drafting and critical revision of the manuscript for intellectual content. K.W. and J.R. contributed to the acquisition of data, interpretation of data, and critical revision of the manuscript for intellectual content. All authors read and approved the manuscript.

Acknowledgements

Not applicable.

References

1. Garcia-Alvarez M, Marik P, Bellomo R. Sepsis-associated hyperlactatemia. Crit Care. 2014;18(5):503.
2. Levy B. Lactate and shock state: the metabolic view. Curr Opin Crit Care. 2006;12(4):315–21.
3. Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, Kumar A, Sevransky JE, Sprung CL, Nunnally ME, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Crit Care Med. 2017;45(3):486–552.
4. Casserly B, Phillips GS, Schorr C, Dellinger RP, Townsend SR, Osborn TM, Reinhart K, Selvakumar N, Levy MM. Lactate measurements in sepsis-induced tissue hypoperfusion: results from the Surviving Sepsis Campaign database. Crit Care Med. 2015;43(3):567–73.
5. Varpula M, Tallgren M, Saukkonen K, Voipio-Pulkki LM, Pettilä V. Hemodynamic variables related to outcome in septic shock. Intensive Care Med. 2005;31(8):1066–71.
6. Sterling SA, Puskarich MA, Shapiro NI, Trzeciak S, Kline JA, Summers RL, Jones AE. Characteristics and outcomes of patients with vasoplegic versus tissue dysoxic septic shock. Shock. 2013;40(1):11–4.
7. Marty P, Roquilly A, Vallée F, Luzi A, Ferré F, Fourcade O, Asehnoune K, Minville V. Lactate clearance for death prediction in severe sepsis or septic shock patients during the first 24 hours in Intensive Care Unit: an observational study. Ann Intensive Care. 2013;3(1):3.
8. Jones AE, Shapiro NI, Trzeciak S, Arnold RC, Claremont HA, Kline JA. Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial. JAMA. 2010;303(8):739–46.
9. Nguyen HB, Rivers EP, Knoblich BP, Jacobsen G, Muzzin A, Ressler JA, Tomlanovich MC. Early lactate clearance is associated with improved outcome in severe sepsis and septic shock. Crit Care Med. 2004;32(8):1637–42.
10. Wacharasint P, Nakada TA, Boyd JH, Russell JA, Walley KR. Normal-range blood lactate concentration in septic shock is prognostic and predictive. Shock. 2012;38(1):4–10.
11. Levraut J, Ciebiera JP, Chave S, Rabary O, Jambou P, Carles M, Grimaud D. Mild hyperlactatemia in stable septic patients is due to impaired lactate clearance rather than overproduction. Am J Respir Crit Care Med. 1998;157(4 Pt 1):1021–26.
12. Hernandez G, Bellomo R, Bakker J. The ten pitfalls of lactate clearance in sepsis. Intensive Care Med. 2019;45(1):82–5.
13. Sterling SA, Puskarich MA, Jones AE. The effect of liver disease on lactate normalization in severe sepsis and septic shock: a cohort study. Clin Exp Emerg Med. 2015;2(4):197–202.
14. Hernandez G, Regueira T, Bruhn A, Castro R, Rovegno M, Fuentealba A, Veas E, Berrutti D, Florez J, Kattan E, et al. Relationship of systemic, hepatosplanchnic, and microcirculatory perfusion parameters with 6-hour lactate clearance in hyperdynamic septic shock patients: an acute, clinical-physiological, pilot study. Ann Intensive Care. 2012;2(1):44.
15. Ryoo SM, Lee J, Lee YS, Lee JH, Lim KS, Huh JW, Hong SB, Lim CM, Koh Y, Kim WY. Lactate Level Versus Lactate Clearance for Predicting Mortality in Patients With Septic Shock Defined by Sepsis-3. Crit Care Med. 2018;46(6):e489-95.
16. Hernandez G, Castro R, Romero C, de la Hoz C, Angulo D, Aranguiz I, Larrondo J, Bujes A, Bruhn A. Persistent sepsis-induced hypotension without hyperlactatemia: is it really septic shock? J Crit Care. 2011;26(4):435.e9-14.
17. American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med. 1992;20(6):864 – 74.
18. Russell JA, Walley KR, Singer J, Gordon AC, Hébert PC, Cooper DJ, Holmes CL, Mehta S, Granton JT, Storms MM, et al. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med. 2008;358(9):877–87.
19. Vincent JL, de Mendonça A, Cantraine F, Moreno R, Takala J, Suter PM, Sprung CL, Colardyn F, Blecher S. Use of the SOFA score to assess the incidence of organ dysfunction/failure in intensive care units: results of a multicenter, prospective study. Working group on "sepsis-related problems" of the European Society of Intensive Care Medicine. Crit Care Med. 1998;26(11):1793–800.
20. Hayashi Y, Endoh H, Kamimura N, Tamakawa T, Nitta M. Lactate indices as predictors of in-hospital mortality or 90-day survival after admission to an intensive care unit in unselected critically ill patients. PLoS One. 2020;15(3):e0229135.
21. Connor H, Woods HF, Ledingham JG, Murray JD. A model of L(+)-lactate metabolism in normal man. Ann Nutr Metab. 1982;26(4):254–63.
22. Connor H, Woods HF, Murray JD, Ledingham JG. Utilization of L(+) lactate in patients with liver disease. Ann Nutr Metab. 1982;26(5):308–14.
23. Woll PJ, Record CO. Lactate elimination in man: effects of lactate concentration and hepatic dysfunction. Eur J Clin Invest. 1979;9(5):397–404.
24. Royle G, Kettlewell M. Liver function and lactate metabolism in the ill surgical patient. Br J Surg. 1978;65(9):661–2.
25. Druml W, Grimm G, Laggner AN, Lenz K, Schneeweiss B. Lactic acid kinetics in respiratory alkalosis. Crit Care Med. 1991;19(9):1120–4.
26. Montassier E, Batard E, Segard J, Hardouin JB, Martinage A, Le Conte P, Potel G. Base excess is an accurate predictor of elevated lactate in ED septic patients. Am J Emerg Med. 2012;30(1):184–7.
27. Smith I, Kumar P, Molloy S, Rhodes A, Newman PJ, Grounds RM, Bennett ED. Base excess and lactate as prognostic indicators for patients admitted to intensive care. Intensive Care Med. 2001;27(1):74–83.
28. Pongmanee W, Vattanavanit V. Can base excess and anion gap predict lactate level in diagnosis of septic shock? Open Access Emerg Med. 2018;10:1–7.
29. Noritomi DT, Soriano FG, Kellum JA, Cappi SB, Biselli PJ, Libório AB, Park M. Metabolic acidosis in patients with severe sepsis and septic shock: a longitudinal quantitative study. Crit Care Med. 2009;37(10):2733–9.
30. Mohr NM, Vakkalanka JP, Faine BA, Skow B, Harland KK, Dick-Perez R, Fuller BM, Ahmed A, Simson SQ. Serum anion gap predicts lactate poorly, but may be used to identify sepsis patients at risk for death: A cohort study. J Crit Care. 2018;44:223–8.
31. Iberti TJ, Leibowitz AB, Papadakos PJ, Fischer EP. Low sensitivity of the anion gap as a screen to detect hyperlactatemia in critically ill patients. Crit Care Med. 1990;18(3):275–7.