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 Table of Contents  
META-ANALYSIS
Year : 2019  |  Volume : 5  |  Issue : 1  |  Page : 1-9

The prognostic role of lactate in patients who achieved return of spontaneous circulation after cardiac arrest: A systematic review and meta-analysis


1 Department of Experimental Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, PR China
2 Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
3 Department of Experimental Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, PR China; Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA

Date of Submission05-Mar-2019
Date of Acceptance11-Mar-2019
Date of Web Publication28-Mar-2019

Correspondence Address:
Dr. Yanyang Tu
Department of Experimental Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710038, PR China

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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ctm.ctm_6_19

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  Abstract 


Aim: The aim of the study is to conduct a systematic review and meta-analysis of data showing the association of lactate levels with mortality and neurologic outcome in patients who achieved return of spontaneous circulation (ROSC) after cardiac arrest.
Methods: An electronic search of PubMed, Embase, Web of Science, and Cochrane Library databases was conducted. Lactate levels at 0, 6, 12, 24, and 48 h after ROSC in survivors versus nonsurvivors and in good versus poor neurologic outcome patients were extracted. Continuous variable and odds ratio were applied for data analysis. Inverse-variance fixed effects model with 95% confidence interval (CI) was used depending on interstudy heterogeneity.
Results: A total of 18 articles meeting the study criteria were included for systematic review and 15 for meta-analysis. The results showed that initial serum lactate levels in nonsurvivors were significantly higher than survivors (standardized mean difference [SMD] = −0.43; 95% CI = [−0.52, −0.33]; P < 0.00001), and a higher lactate level at admission was associated with increased hospital mortality. In addition, initial serum lactate levels were significantly higher in poor neurologic outcome patients than good neurologic outcome patients (SMD = −0.44; 95% CI = [−0.54, −0.34]; P < 0.00001), and initial higher lactate level was associated with poor neurologic outcome. There was a statistically significant difference in lactate levels at 6, 12, 24, and 48 h after ROSC, among survivors versus nonsurvivors and among patients presenting good neurologic outcome versus poor neurologic outcome. However, the included studies had small sample size and highly inconsistent data.
Conclusions: Higher lactate levels were associated with increased mortality and poor neurologic outcome. Lower lactate levels or faster lactate clearance was associated with higher survival and good neurologic outcome.

Keywords: Cardiac arrest, lactate, neurologic outcome, return of spontaneous circulation, survival


How to cite this article:
Ren D, Wang X, Tu Y. The prognostic role of lactate in patients who achieved return of spontaneous circulation after cardiac arrest: A systematic review and meta-analysis. Cancer Transl Med 2019;5:1-9

How to cite this URL:
Ren D, Wang X, Tu Y. The prognostic role of lactate in patients who achieved return of spontaneous circulation after cardiac arrest: A systematic review and meta-analysis. Cancer Transl Med [serial online] 2019 [cited 2019 Apr 22];5:1-9. Available from: http://www.cancertm.com/text.asp?2019/5/1/1/255124




  Introduction Top


Cardiac arrest (CA) is the major cause of sudden death in developed countries.[1] In 2011, ≈326,200 people experienced emergency medical services–assessed out-of-hospital CAs in the United States. Survival to hospital discharge after nontraumatic Emergency Medical Service-treated CA with any first recorded rhythm was 10.6% for patients of any age.[2] Patients suffering from sudden CA have a poor prognosis, prediction of survival, and neurologic outcome after CA remains difficult, especially within the first 48 h after the event.[3] The resuscitation of a CA victim does not end with return of spontaneous circulation (ROSC); post-ROSC care has a significant potential to improve early mortality caused by hemodynamic instability. During the early ROSC period, hemodynamic and metabolic prognostic factors are important to guide the resuscitation of arrest victims. Moon et al.[4] showed that MAP, serum lactate, P (a-et) CO2, and VdA/Vt were significantly different between survivors and nonsurvivors. Elevated serum lactate level is a traditional marker of tissue hypoxia and one of the therapeutic end points of shock resuscitation.[5],[6],[7] During cardiopulmonary resuscitation (CPR), lactate cannot be eliminated sufficiently because of low perfusion during cardiac massage.[8]

Lactate, a metabolite of easy and quick assessment, has been studied over time in critically ill patients to evaluate its prognostic ability.[9] Serum lactate which is the main cause of acidosis during CPR is a very simple and inexpensive procedure that can be measured out of hospital.[10],[11] Elevated lactate levels are always a signal of critical clinical situation and a marker of poor prognosis.[3],[12],[13],[14],[15],[16],[17],[18] Furthermore, the ability to clear lactate (described as “lactate clearance”') is believed to be associated with improved outcome.[13],[15] Early and effective serum lactate clearance or lower serum lactate measurements have been shown to be associated with decreased mortality in patients with a diverse set of critical illnesses, including sepsis and severe trauma.[19],[20],[21],[22]

There are several studies in the literature exploring the association between serum lactate or lactate clearance and clinical outcome in CA survivors. Despite differences in study design, timing of lactate measurements, and type of acute cardiac conditions (i.e., CA, cardiogenic shock, and refractory CA), available evidence strongly suggest that higher lactate levels were observed on admission in nonsurvivors, and higher lactate clearance was associated with better outcome. Predicting neurologic recovery and mortality in patients after CA is also challenging, especially in the early phase.


  Methods Top


Publication selection

This meta-analysis was performed using PubMed, Embase, Web of Science, MEDLINE, and Cochrane Library databases to identify all relative publications involving serum lactate levels after CA. The search keywords that were related to “lactate,” “lactate clearance,” and “cardiopulmonary resuscitation” were used to construct the search strategy [Supplementary]A and [Supplementary]B[Additional file 1]. All analyses were based on previously published studies; thus, no ethical approval and patient consent were required. In addition, we manually searched the reference list of previously published systematic reviews that investigated the same research question to obtain more eligible studies.

Study identification and selection

After deduplication, studies obtained from the search underwent title/abstract screening and full-text review. Studies meeting the criteria were as follows: (1) retrospective cohort studies; (2) adult patients (age ≥ 18 years) with ROSC after CA; (3) studies providing the mean and the standard deviation (mean ± SD) or mean and the standard error of serum lactate levels in CA patients; (4) lactate levels measured at 0, 12, and 24 h after ROSC; lactate clearance rate measured at 12 and 24 h with ROSC; and (5) 24-h survival rate. Details of study identification and selection are presented in [Figure 1] as per the requirement of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses.23
Figure 1: Flow chart of study identification and selection

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Data extraction and quality assessment

Important study characteristics were extracted by reviewers, independently. These characteristics included location of CA, inhospital CA/out-of-hospital CA (IHCA/OHCA), year of publication, study location, sample size, study year(s), study type, measurement approach, lactate sampling time, primary and secondary outcomes, and studies reporting hospital mortality.

Good neurological function was defined as a cerebral performance category (CPC) score of 1 or 2 and CPC scores of 3–5 for poor neurological outcome.

Data synthesis

We performed meta-analyses of the association between lactate levels and patient outcomes, including hospital survival, discharge from hospital among survivors, and CPC score of 1 or 2 at the end of each study's follow-up period. To evaluate the overall serum lactate levels, we calculated the standardized mean difference (SMD) for every study with 95% confidence intervals (CIs) due to the fact that the units of concentration of serum lactate were different. The mean ± SD was extracted and calculated in any included publications. While, if the original data were mean ± standard error of the mean or median (down limit to up limit), we converted them to mean ± SD. The results were summarized by forest plots using weighted inverse-variance fixed effects model with 95% CI (RevMan version 5.3, The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Kongeriget, Danmark). If patient data were not explicitly stated in the table or text, we extracted the outcome data (rounded to the nearest whole number) reported in the studies' figures. Meanwhile, we extracted the odds ratio (OR) with 95% CI for motility and poor neurologic outcome in multivariate logistic regression model, to research the association between lactate level and patient outcomes. The results were calculated by forest plots using weighted generic inverse-variance model with 95% CI.

The heterogeneity was detected with a Chi-square test and quantified using I2 statistic, and respective P values were also calculated.[24]I2 values of < 25%, 25%–50%, and > 50% were considered to have low, moderate, and high level of inconsistency between studies, respectively. We proposed to report a pooled estimate only when the I2 statistic was < 50%. If the I2 statistic was > 50%, forest plots would be used to display individual study results only. The funnel plot was applied to estimate the publication bias.


  Results Top


Study identification and selection

A total of 1077 records (PubMed: 504, Embase: 276, Web of Science: 202, and Cochrane Library: 95) were obtained by searching the electronic databases. Among these records, 693 were retained after deduplication. After title/abstract screening, 640 of these articles were excluded. Among the remaining 53 articles which were kept for full-text review process, 35 were excluded, and the reasons for exclusion were as follows: (1) 3 were not full text in English, (2) 2 review articles were excluded, (3) 14 articles did not use cohort study design, and (3) 16 articles had insufficient data for analysis. Finally, a total of 18 articles were included for this systematic review and 15 for meta-analysis [Figure 1].

Study characteristics and quality assessment

All 18 studies included were published in English between 2000 and 2018 from the United States of America, Korea, Australia, Taiwan, Belgium, France, and Germany and included 3861 patients (range per study: 34–518). Seven studies included OHCA patients (n = 1530), four studies included IHCA patients (n = 798), and four studies included both IHCA and OHCA patients (n = 663). Two studies used national multicenter databases and included only OHCA patients, and other 13 studies were single-center studies. Cohort design was used in all studies. Nine studies used CPC scores to evaluate the relationship between lactate levels and neurological outcomes after CA. Thirteen studies evaluate the prognosis using survival to hospital discharge or inhospital mortality. The serial lactate levels were obtained after ROSC, but existing difference in sampling time was not. While, there were several interventions affecting the prognostic markers level, including therapeutic hypothermia (TH), targeted temperature management, extracorporeal membrane oxygenation, and extracorporeal life support. Characteristics of the included studies are reported in [Table 1].
Table 1: The study characteristics

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  Results of Meta-Analysis Top


Fifteen studies reported quantitative data suitable for meta-analysis. Forest plots were constructed by combining additional patient data provided by the authors. In addition, data were extracted from the figure in the study by Luo D et al.[25] for meta-analysis.

Higher lactate levels were associated with increased mortality

We analyzed initial and 6-, 12-, 24-, and 48-h post-ROSC lactate levels in survivors and nonsurvivors to estimate the relationship between lactate level and hospital mortality.

For initial lactate level, the meta-analysis results showed that the heterogeneity was not statistically significant (P = 0.66; I2 = 0%). However, fixed effects model showed that initial serum lactate levels in survivors were statistically significant compared to nonsurvivors (SMD= −0.43; 95% CI = [−0.52, −0.33]; P < 0.00001) [Figure 2]. The shape of the funnel plot, which is recommended for estimating the bias, looks to be symmetrical, indicating that potential publication bias might slightly affeect the present meta-analysis [Figure 3]. On the other hand, the generic inverse-variance model analysis showed that initial higher lactate level was associated with hospital mortality (OR = 2.89; 95% CI = [0.928, 1.146]), but the heterogeneity was significant [Figure 4].
Figure 2: Forest plot of initial serum lactate levels for cardiac arrest survivors versus nonsurvivors. Each individual study was weighted by the mean and the standard deviation, the standardized mean difference for every study with 95% confidence intervals. I2 values of < 25%, 25%–50%, and > 50% were considered to have a low, moderate, and high level of inconsistency between studies, respectively

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Figure 3: The shape of funnel plot

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Figure 4: Forest plot of the association between initial lactate levels and hospital mortality. Each individual study was weighted by odds ratio with 95% confidence intervals

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For 6, 12, 24, and 48 h after ROSC, the forest plots show that lactate levels in survivors were significantly low compared to those in nonsurvivors (P < 0.05) and the heterogeneity was > 50%, which show inconsistency between these studies [Figure 5].
Figure 5: Forest plot for serum lactate levels 6, 12, 24, and 48 h after return of spontaneous circulation for cardiac arrest survivors versus nonsurvivors. Each individual study was weighted by the mean and the standard deviation, the standardized mean difference for every study with 95% confidence intervals

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Higher lactate levels were associated with poor neurologic outcome

We analyzed the association between serum lactate levels and neurologic outcome. For initial lactate levels, the heterogeneity was not statistically significant (P = 0.27; I2 = 20%); however, fixed effects model demonstrated a statistically significant difference between initial serum lactate levels of good neurologic outcome patients and poor neurologic outcome patients (SMD = −0.44; 95% CI = [−0.54, −0.34]; P < 0.00001) [Figure 6]. The shape of the funnel plot is shown in [Figure 7]. On the other hand, generic inverse-variance model analysis showed that initial higher lactate levels were associated with poor neurologic outcome (OR = 2.90; 95% CI= [2.78, 3.03]), and the heterogeneity was not statistically significant (P = 0.34; I2 = 11%) [Figure 8].
Figure 6: Forest plot of initial serum lactate levels for cardiac arrest patients with good neurological outcomes versus poor neurological outcomes. The standardized mean difference for every study was with 95% confidence intervals. I2 values of < 25% were considered to have a low level of inconsistency between studies

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Figure 7: The shape of funnel plot

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Figure 8: Forest plot of the association between initial lactate levels and neurologic outcome. Each individual study was weighted by odds ratio with 95% confidence intervals

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For 6-, 12-, 24-, and 48-h lactate levels after ROSC, the forest plots show that lactate level in good neurologic outcome group was significantly lower than poor neurologic outcome group (P < 0.05) and the heterogeneity was > 50%, displaying inconsistency between these studies [Figure 9].
Figure 9: Forest plot of serial serum lactate level 6, 12, 24, and 48 h after return of spontaneous circulation for good neurological outcomes versus poor neurological outcomes. Each individual study was weighted by the mean and the standard deviation, the standardized mean difference for every study with 95% confidence intervals

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  Discussion Top


Based on the results, we observed that there was a significant association between initial lactate levels and survival outcome; low lactate level presents higher survival rate. Furthermore, the lower initial lactate levels were strongly associated with good neurologic outcome. Fewer studies have examined the hospital mortality and neurologic outcome in CA patients.

The prognostic values of lactate levels and lactate clearance rate have been investigated in several studies, and there exist some controversies due to differences in study settings. Müller et al.[26] reported that initial lactate level is associated with duration of CA and weakly associated with neurological outcome. A retrospective study by Kliegel et al.3 found that lactate levels at 48 h were an independent predictor of mortality. Moreover, they showed that survivors had lower initial lactate levels. Donnino et al.[13] indicated that early lactate reduction is an independent predictor of mortality in postarrest patients. In addition, the initial lactate level was higher in nonsurvivors and those who had poor neurological outcome as compared to survivors and those with good neurological outcome. Survivors had lower lactate measurements at all time points (0, 12, and 24 h). Most recently, Lee et al.[27] found that higher serum lactate values were associated with poor neurologic outcome and increased inhospital mortality. However, Donnino et al.[18] and Starodub et al.[14] reported that initial serum lactate levels were not associated with survival outcomes in CA patients. Donnino et al.[18] reported that in 79 OHCA patients, the initial levels were not associated with patient outcome although effective lactate clearance was associated with improved outcome. However, the study had a small sample size, and TH was not considered. Thus, lack of significantly different initial lactate levels may reflect a clustering of patients with severe postarrest syndrome and not an inability of initial lactate levels to differentiate outcomes for the broader population. The pathophysiology of elevated lactate in post-CA is complex and likely multifactorial.

The study has several limitations. First, there are differences in patient characteristics among the included studies, including countries of origin of the study, the location of CA (IHCA versus OHCA versus IHCA/OHCA), the use of TH, and the timing as well as frequency of lactate measurements. Thus, there exists heterogeneity in outcomes in the review. All included studies were observational studies. These studies examined patients which suffered OHCA and IHCA. However, there are many differences between IHCA and OHCA which may affect outcome.[28] OHCA had a survival rate more than four times higher than IHCA. Success rates of CPR are variable, and especially, out-of-hospital CA is associated with an unfavorable prognosis.[29] Second, although measurement of serum lactate levels was of the protocol, some lactate values were missing. The relationship between the lactate levels 12 h and 24 h after ROSC with survival and neurologic outcomes was not evaluated due to incomplete data. We could not perform further analysis due to small number of studies.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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