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Abstract
Objectives To assess the associations of lactate level or lactate clearance at different time points with in-hospital mortality in critically ill patients with acute myocardial infarction (AMI).
Design A cohort study.
Setting The Medical Information Mart for Intensive Care III database.
Participant 490 AMI patients.
Intervention None.
Primary and secondary outcome measures In-hospital mortality of patients.
Results In total, 120 (24.49%) patients died at the end of follow-up. After adjusting for confounders, increased risk of in-hospital mortality in patients with AMI was observed in those with high lactate level (24 hours) (HR=1.156, 95%CI: 1.002 to 1.333). Increased lactate clearance (24 hours) was correlated with a decreased risk of in-hospital mortality in patients with AMI (HR=0.995, 95% CI: 0.994 to 0.997). The area under the curves (AUCs) of lactate level (24 hours) and lactate clearance (24 hours) were 0.689 (95% CI: 0.655 to 0.723) and 0.672 (95% CI: 0.637 to 0.706), respectively. The AUC of lactate level (24 hours) and lactate clearance (24 hours) was higher than lactate level (baseline).
Conclusions Increased lactate level (24 hours) was associated with an elevated risk of in-hospital mortality in patients with AMI and increased lactate clearance (24 hours) was correlated with a decreased risk of in-hospital mortality in patients with AMI despite the age and genders.
- Cardiac Epidemiology
- Myocardial infarction
- CARDIOLOGY
Data availability statement
Data are available upon reasonable request.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
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Strengths and limitations of this study
This study first evaluated the lactate clearance (6, 12 and 24 hours) with in-hospital mortality in critically ill patients with acute myocardial infarction.
This study analysed the data of critically ill patients with AMI who admitted to critical care units of the Beth Israel Deaconess Medical Center with lactate levels (baseline, 6, 12 and 24 hours), and those patients detected lactate level at four time points, which might suggest that these patients might be in critically ill state with severe diseases and the in-hospital mortality might be higher.
This was a retrospective study, and all data were collected from Medical Information Mart for Intensive Care III database, which might cause bias.
Introduction
Acute myocardial infarction (AMI) is a kind of heart disease in cardiology due to the blockage of the coronary arteries.1 AMI can cause a sudden decline in blood flow, myocardial hypoxia, necrosis, ischaemia and result in complications including chest pain and arrhythmia.2 The onset of AMI is fast and the disease progresses quickly, and if the treatments are not timely provided, AMI can be life-threatening.3 Although the introduction of potent platelet inhibitors,4 improvement in dosing and combinations of drugs5 and in stent technologies6 have greatly improved the clinical prognosis of patients with AMI, the disease is still the second leading cause of death in China.7 Early identification of factors associated with death of patients with AMI and providing timely interventions for these patients are of great value for improving the prognosis of them.
Lactate is reported to have a function of accelerated glycolysis, severity of anaerobic metabolism and hepatic clearance, which was identified as an essential predictor for the mortality of various diseases.8 9 Previously, blood lactate was found to be associated with short-term mortality in patients with myocardial infarction complicated by heart failure but without cardiogenic shock.10 Ceglarek et al constructed a mortality risk score in cardiogenic shock after AMI based on clinical biomarkers including lactate level.11 Lactate was associated with the prognosis of patients with suspected ST-elevation myocardial infarction.12 Lactate levels are not static over time, and the lactate trends may increase the precision of predicting the prognosis of patients.13 In recent years, the lactate clearance drew more attention in clinic, and Marbach et al found that lactate clearance might associate with the survival of patients with cardiogenic shock.14 Whether lactate clearance was correlated with the in-hospital mortality of patients with AMI was still unclear.
In our study, the purpose was to identify the associations between lactate levels (bassline, 6, 12 or 24 hours) as well as lactate clearance (6, 12 or 24 hours) with the in-hospital mortality of patients with AMI. We aimed to find which biomarker of lactate had higher predictive value for the in-hospital mortality of patients with AMI. Subgroup analysis was conducted in patients with different ages or genders.
Methods
Patient and public involvement statement
Not applicable.
Study design and population
This cohort study collected the data of 5032 patients with AMI aged ≥18 years with lactate data from Medical Information Mart for Intensive Care III (MIMIC-III) database. MIMIC-III is a large, freely available database, comprising deidentified health-related data of more than 40 000 patients who admitted to critical care units of the Beth Israel Deaconess Medical Center between 2001 and 2012. The database encompasses information including general information (demographics, insurance, ethnicity, etc), treatment process (charted clinical observations, laboratory tests, physiological scores, medications, surgery, etc) and survival data of patients.15 AMI was diagnosed on the basis of the International Classification of Diseases, Ninth Revision codes: 41000, 41001, 41002, 41010, 41011, 41012, 41020, 41021, 41022, 41030, 41031, 41032, 41040, 41041, 41042, 41050, 41051, 41052, 41060, 41061, 41062, 41070, 41071, 41072, 41080, 41081, 41082, 41090, 41091 and 41092.16 In our study, patients without data on lactate (baseline, 6 or 12 hours) (n=2439), lactate (24 hours), Glasgow Coma Scale (GCS), potassium, calcium, pH, fasting blood glucose, red blood cell distribution width (RDW) were excluded. Those with length of hospital or intensive care unit (ICU) stay <24 hours were not included. Finally, 490 patients were analysed.
Potential confounders
Demographic and clinical factors included gender, age (years), ethnicity, ventilation use (yes or no) and vasopressor use (yes or no). Vital signs included systolic blood pressure (mm Hg), diastolic blood pressure (mm Hg), respiratory rate (times/min), platelet (109 /L), haemoglobin (Hb, g/dL), RDW (%), total bilirubin (mg/dL), creatinine (mg/dL), albumin, blood urea nitrogen (BUN, mg/dL), sodium (mEq/L), potassium (mEq/L), pH, fasting blood glucose (mg/dL), bicarbonate (mEq/L), chloride (mEq/L), calcium (mg/dL), Elixhauser Comorbidity Index (ECI), the Simplified Acute Physiology Score II (SAPSII), Sequential Organ Failure Assessment (SOFA) and GCS.
Main variables and outcome variables
Lactate level (baseline, 6, 12 or 24 hours; mmol/L) and lactate clearance (6, 12 or 24 hours; %) were the main variables evaluated in our study. Lactate level (baseline) referred to baseline lactate level, which was measured at admission to the ICU. Lactate level (6 hours) referred to lactate level 6 hours after baseline, lactate level (12 hours) referred to lactate level 12 hours after baseline and lactate level (24 hours) referred to lactate level 24 hours after baseline. 6 hour lactate clearance=lactate level (baseline–6 hours)/lactate level (baseline)×100%, 12 hours lactate clearance=lactate level (baseline–12 hours)/lactate level (baseline)×100%, 24 hours lactate clearance=lactate level (baseline–24 hours)/lactate level (baseline)×100%.
The outcome in this study was the in-hospital mortality of patients. The follow-up started from the date of admission and ended at death. The median follow-up time was 13.7 (7.6–25.6) days.
Statistical analysis
Categorical variables were expressed as n (%), and χ2 test was used for comparisons between two groups. Continuous variables with non-normal distribution were represented by M (Q1, Q3) and Wilcoxon rank sum test was used for comparisons between two groups. Sensitivity analysis was performed to compare the equilibrium of data before and after deleting the missing values on the baseline lactate level, lactate clearance and outcome. Univariate and multivariable Cox regression analyses were applied for evaluating the associations between lactate level (baseline, 6, 12 or 24 hours) or lactate clearance (6, 12 and 24 hours) and in-hospital mortality of patients with AMI. Variables with p<0.05 in univariate Cox regression analysis were included in multivariable Cox regression analysis. Subgroup analysis was conducted in patients with different ages and genders. HR and CI were used for assessing the associations between lactate level (baseline, 6, 12 or 24 hours) or lactate clearance (6, 12 and 24 hours) and in-hospital mortality of patients with AMI. Receiver operator characteristic (ROC) curves were plotted to measure the predictive ability of lactate clearance for in-hospital mortality in patients with AMI. An α of 0.05 was set as confidence level. R V.4.1.2 (the R Foundation for Statistical Computing) was employed for data analysis.
Results
Characteristics of survivors and non-survivors in patients with AMI
In total, 5032 patients with AMI aged ≥18 years with lactate data from MIMIC-III database were collected. Participants without data on lactate (baseline, 6 or 12 hours) (n=2439) and those without data on lactate (24 hours) (n=1670) were excluded. Then, 923 patients were included, among them 9 patients stayed in ICU for <24 hours and 84 patients stayed in hospital for <24 hours were excluded. Patients without GCS data (n=306), potassium (n=2), calcium (n=26), pH (n=4), fasting blood glucose (n=1), RDW (n=1) were excluded. Finally, 409 patients were included with 370 patients survived and 120 died. The detailed screen process was shown in figure 1. Sensitivity analysis was performed to compare the equilibrium of data before deleting the missing values including GCS, potassium, calcium, pH, glucose and RDW with the final data. The results depicted that there was no significant difference in the baseline lactate level, lactate clearance and in-hospital mortality in patients with AMI before and after deleting the missing values (all p>0.05) except ECI (online supplemental table 1). The data before deleting participants without data on lactate (6 hours), lactate (12 hours) or lactate (24 hours) and RDW and data finally included were also compared (online supplemental table 2).
Supplemental material
The screen process of participants in our study. AMI, acute myocardial infarction; GCS, Glasgow Coma Scale; ICU, intensive care unit; MIMIC-III, Medical Information Mart for Intensive Care III; RDW, red blood cell distribution width.
As exhibited in table 1, the median age (76.0 years vs 72.8 years), respiratory rate (20.0 times/min vs 18.0 times/min) and BUN (29.0 mg/dL vs 24.0 mg/dL) in the non-survivors group was higher than the survivors group. The proportion of patients with vasopressor use in the non-survivors group was higher than the survivors group (73.3% vs 60.8%). The median lactate (baseline) (2.4 mmol/L vs 2.1 mmol/L), lactate (6 hours) (2.6 mmol/L vs 2.0 mmol/L), lactate (12 hours) (2.2 mmol/L vs 1.8 mmol/L) and lactate (24 hours) (2.1 mmol/L vs 1.5 mmol/L) in the non-survivors group were higher than the survivors group. The lactate clearance (24 hours) in the non-survivors group was lower than the survivors group (5.8% vs 17.9%).
The baseline characteristics of patients with AMI survived or dead
Associations between lactate level or lactate clearance and in-hospital mortality
According to the data in table 2, age (HR=1.018, 95% CI: 1.002 to 1.034), respiratory rate (HR=1.025, 95% CI: 1.002 to 1.049), pH (HR=0.117, 95% CI: 0.029 to 0.465), fasting blood glucose (HR=1.002, 95% CI: 1.000 to 1.003), SAPSII (HR=1.025, 95% CI: 1.012 to 1.039) and SOFA (HR=1.075, 95% CI: 1.021 to 1.132) might be the confounders affecting the associations between lactate level or lactate clearance and in-hospital mortality. In table 3, the associations between lactate level or lactate clearance and in-hospital mortality were evaluated. In the adjusted model 1, increased lactate level (24 hours) might associate with an increased risk of in-hospital mortality in patients with AMI (HR=1.154, 95% CI: 1.007 to 1.321). After adjusting for age, respiratory rate, pH, fasting blood glucose, SAPSII and SOFA, increased risk of in-hospital mortality in patients with AMI was observed in those with high lactate level (24 hours) (HR=1.156, 95% CI: 1.002 to 1.333). We further adjusted for lactate level (baseline) in model 3 and found that increased lactate clearance (24 hours) was correlated with a decreased risk of in-hospital mortality in patients with AMI (HR=0.995, 95% CI: 0.994 to 0.997). The area under the curve (AUC) of lactate level (baseline) for predicting in-hospital mortality was 0.631 (95% CI: 0.596 to 0.665) (figure 2). The AUCs of lactate level (24 hours) and lactate clearance (24 hours) were 0.689 (95% CI: 0.655 to 0.723) (figure 3) and 0.672 (95% CI: 0.637 to 0.706) (figure 4), respectively. The AUC of lactate level (24 hours) (p=0.004) and lactate clearance (24 hours) (p<0.001) were higher than lactate level (baseline).
Potential confounders associated with the in-hospital mortality of patients with AMI
Associations between lactate level or lactate clearance and in-hospital mortality of patients with AMI
The receiver operator characteristic (ROC) curve showing the predictive value of lactate level (baseline) for in-hospital mortality of patients with acute myocardial infarction. AUC, area under the curve.
The receiver operator characteristic (ROC) curve showing the predictive value of lactate level (24 hours) for in-hospital mortality of patients with acute myocardial infarction. AUC, area under the curve.
The receiver operator characteristic (ROC) curve showing the predictive value of lactate clearance (24 hours) for in-hospital mortality of patients with acute myocardial infarction. AUC, area under the curve.
Subgroup analysis on associations between lactate level or lactate clearance and in-hospital mortality in patients with different ages or genders
In patients with AMI aged <65 years, we observed that elevated lactate level (24 hours) was linked with an increased risk of in-hospital mortality (HR=1.158, 95% CI: 1.033 to 1.298). Increased lactate clearance (24 hours) associated with a decreased risk of in-hospital mortality (HR=0.994, 95% CI: 0.989 to 1.000). In patients with AMI ≥65 years, elevated lactate level (24 hours) was correlated with an increased risk of in-hospital mortality (HR=1.204, 95% CI: 1.135 to 1.277), while increased lactate clearance (6 hours) (HR=0.996, 95% CI: 0.993 to 0.999) or lactate clearance (24 hours) (HR=0.995, 95% CI: 0.994 to 0.997) was linked with a decreased risk of in-hospital mortality (table 4).
Subgroup analysis on associations between lactate level or lactate clearance and in-hospital mortality of patients with AMI with different age groups
As for different genders, increased lactate level (24 hours) was correlated with an increased risk of in-hospital mortality in both males (HR=1.13, 95% CI: 1.047 to 1.219) and females (HR=1.186, 95% CI: 1.111 to 1.266). Elevated lactate clearance (24 hours) was associated with a reduced risk of in-hospital mortality in both males (HR=0.997, 95% CI: 0.995 to 0.999) and females (HR=0.993, 95% CI: 0.991 to 0.996) (table 5).
Subgroup analysis on associations between lactate level or lactate clearance and in-hospital mortality of patients with AMI with different genders
Discussion
In the present study, the data of 490 patients with AMI were collected to assess the associations between lactate level or lactate clearance and in-hospital mortality in those patients. The data revealed that increased lactate level (24 hours) was associated with an elevated risk of in-hospital mortality, while increased lactate clearance (24 hours) was linked with a decreased risk of in-hospital mortality in patients with AMI. Both lactate level (24 hours) and lactate clearance (24 hours) showed better predictive value for in-hospital mortality in patients with AMI than lactate level (baseline). Subgroup analysis depicted that increased lactate level (24 hours) was associated with an elevated risk of in-hospital mortality and increased lactate clearance (24 hours) was linked with a reduced risk of in-hospital mortality in patients aged <65 years and ≥65 years as well men and women. Increased lactate clearance (6 hours) was associated with a decreased risk of in-hospital mortality in patients with AMI ≥65 years. The findings provided a reference for clinicians to attach importance to measure the lactate level (24 hours) and lactate clearance (24 hours) in patients with AMI and provide timely interventions for those with increased lactate level (24 hours).
In our study, increased lactate level (24 hours) was associated with higher in-hospital mortality in patients with AMI. Previously, the lactate level was regarded as a surrogate in assessing the severity of diseases in critically ill patients and as a prognostic marker in patients.17 Vermeulen et al demonstrated that higher arterial lactate levels in patients with ST-segment elevation myocardial infarction at admission were related with 30-day mortality and an overall worse response to percutaneous coronary intervention.18
In patients with AMI and signs of mild-to-moderate heart failure, lactate ≥2.5 mmol/L was associated with a higher risk of 30-day mortality.10 These studies provided evidence to the findings of this study. Relative to lactate level, lactate clearance shows the relative change in lactate levels over time, which can help the clinicians timely modify the treatments to patients.9 In previous studies, lactate clearance was reported to have prognostic value in heterogeneous populations such as patients with sepsis, trauma or respiratory failure, and increased lactate clearance was found to be correlated with lower risk of organ failure and mortality.19–21 Arnold et al depicted that lactate clearance of at least 10% at 6, 24 and 48 hours was independently associated with the mortality of patients with sepsis after adjusting for critically ill status or severity.22 Another study also identified the prognostic roles of lactate clearance at 6, 24 and 48 hours as well as the importance of delayed lactate clearance at 24 hours and 48 hours.23 Donnino et al identified that lower lactate levels at 0, 12 and 24 hours and greater per cent decrease in lactate over the first 12 hours post cardiac arrest were associated with survival and good neurologic outcome.24 In the present study, we found that the increased lactate clearance (24 hours) was associated with a decreased risk of in-hospital mortality. A subsequent lactate ≥4 mmol/L and lactate reduction<20% were associated with increased in-hospital mortality, whereas a lactate reduction <10% was not.25
Lactate level is extensively accepted as an index of altered tissue perfusion in critically ill patients26 and tissue hypoperfusion consequent to macrocirculatory or microcirculatory dysfunction.27 An elevated lactate level is associated with abnormal microcirculatory flow and increased mortality in patients.28 Lactate levels potentially represent the imbalance between oxygen delivery and consumption during global tissue hypoxia, which reduces the availability of pyruvate for the tricarboxylic acid cycle and accelerates aerobic glycolysis.29 Aerobic glycolysis was correlated with the activation of platelet, and further affected the arterial thrombosis and the risk of AMI.30 These might be the potential mechanisms explaining the association between lactate level or lactate clearance and mortality of patients with AMI. The findings in our study suggested that the initial lactate level is essential and follow-up on lactate levels is more important, especially lactate level at 24 hours. Clinicians should pay special attention to the dynamic changes of lactate level of patients with AMI and provide timely interventions in patients with low lactate clearance (24 hours). For patients aged ≥65 years, the lactate clearance (6 hours) should also be cautioned.
Several limitations existed in the current study. First, this study analysed the data of critically ill patients with AMI who admitted to critical care units of the Beth Israel Deaconess Medical Center with lactate levels (baseline, 6, 12 and 24 hours), and those patients detected lactate level at four time points, which might suggest that these patients might be in critically ill state with severe diseases and the in-hospital mortality might be higher. Second, this was a retrospective study, and all data were collected from MIMIC-III database, which might cause bias. Third, the time from myocardial infarction to the measurement of baseline lactate was no clear, which might affect the results in our study. In the future, more prospective studies were required to verify the results in our study.
Conclusions
This study assessed the associations between lactate levels (baseline, 6, 12 or 24 hours) as well as lactate clearance (6, 12 or 24 hours) with the in-hospital mortality of patients with AMI. The results delineated that increased lactate level (24 hours) was associated with an elevated risk of in-hospital mortality in patients with AMI and increased lactate clearance (24 hours) was correlated with a decreased risk of in-hospital mortality in patients with AMI despite the age and genders. The findings indicated the importance of detecting the dynamic changes of lactate levels especially at admission and 24 hours.
Data availability statement
Data are available upon reasonable request.
Ethics statements
Patient consent for publication
Ethics approval
This study involves human participants. The requirement of ethical approval for this was waived by the institutional review board of Shanghai municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, because the data was accessed from Medical Information Mart for Intensive Care III (a publicly available database). Participants gave informed consent to participate in the study before taking part.
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
Contributors HL and DL designed the study. HL wrote the manuscript. JC and XX collected, analysed and interpreted the data. DL critically reviewed, edited and approved the manuscript. All authors read and approved the final manuscript. DL is response for the overall content as the guarantor.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.