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Three Part Question

In [patients admitted to hospital with confirmed or suspected COVID-19] is [the level of serum lactate] able to [predict mortality]?

Clinical Scenario

A 40 year old male attends the emergency department with a persistent dry cough and fever. He tested positive for COVID-19 infection five days ago and has been isolating ever since. On examination his heart rate is 120 beats per minute, respiratory rate is 20 and his oxygen saturations are 94% on room air. Would measuring his serum lactate help you to risk stratify this patient and determine his requirement for medical intervention?

Search Strategy

PubMed search: 2019 – 09 October 2020 and 2019 – 25 November 2020
Scopus search: 2019 – 09 October 2020 and 2019 – 25 November 2020
Web of Science search: 2019 – 09 October 2020 and 2019 – 25 November 2020

((COVID-19 OR Coronavirus OR SARS-CoV-2) AND (Lactate OR Lactic Acid) AND NOT dehydrogenase)

Search Outcome

After the removal of duplicates from the primary search, 99 titles and abstracts were reviewed. 10 of these were deemed to be relevant to the clinical question. An additional 3 papers were identified during the second literature search. Of the 13 included studies, there were 12 cohort studies and 1 retrospective case series.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Ferrando-Vivas et al. 2020 United Kingdom	9,990 patients hospitalised with COVID-19. (Median age 60 years)	Cohort study (2b)	30-day ICU mortality	There were 3,933 ICU deaths. Highest serum lactate measurement in the first 24 hours of ICU admission was associated with 30-day ICU mortality (HR 1.499, 95% CI: 1.301 – 1.729; p<0.0001). Mortality increased steeply with increasing lactate up to approximately 2mmol/L, then increased more gradually in the Cox proportional-hazard regression model.	Missing data. Baseline medications not considered. Co-infections not considered. The method of confirming a COVID-19 case was not defined.
Goodall et al. 2020 England	981 patients hospitalised with COVID-19. A COVID-19 case was defined as a positive result on RT-PCR test for SARS-CoV-2. (Median age 69 years)	Retrospective cohort study (2b)	In-hospital mortality	There were 354 in-hospital deaths. Higher lactate levels were associated with an increased risk of death in the multivariable Cox proportional-hazard model analysis (adjusted HR 2.67, 95% CI: 1.65 – 4.33; p<0.001)	Single-centre study. Missing data. Co-infections not considered. Retrospective study design.
Vassiliou et al. 2020 Greece	45 patients hospitalised with COVID-19. A COVID-19 case was defined as a positive result on RT-PCR test for SARS-CoV-2. (Mean age 64 years)	Retrospective Cohort Study (2b)	28-day ICU mortality	There were 11 ICU deaths. Maximum lactate on admission was independently associated with 28-day ICU mortality (P = 0.008, multivariate Cox regression analysis). Mean daily lactate levels were higher in non-survivors (p<0.0001) on the mixed model analysis.	Single-centre study. Small sample size. Baseline medications not considered. Co-infections not considered. Retrospective study design.
Garcia et al. 2020 European	639 patients hospitalised with COVID-19. A COVID-19 case was defined as a positive result on RT-PCR test for SARS-CoV-2. (Median age 63 years)	Cohort study (2b)	ICU mortality	There were 97 ICU deaths. Lactate on admission was independently associated with ICU-mortality on multivariable Cox proportional-hazard regression model (p = 0.009).	Differences across centres. Missing data. Baseline medications not considered.
Alharthy et al. 2020 Saudi Arabia	352 patients hospitalised with COVID-19. A COVID-19 case was defined as a positive result on RT-PCR test for SARS-CoV-2. (Mean age 51 years)	Retrospective cohort study (2b)	28-day ICU mortality	There were 113 ICU deaths. An increased serum lactate level was a predictor for 28-day ICU mortality in the multivariate regression analysis (OR 3.9, 95% CI: 2.4 – 4.9; p = 0.035) Non-survivors had a significantly higher serum lactate level than survivors in the Student’s t-test (2.13 ±0.34 vs. 1.61 ±0.33, p = 0.0001).	Single-centre study. Missing data. Baseline medications not considered. Retrospective study design.
Kayina et al. 2020 India	235 patients hospitalised with COVID-19. A COVID-19 case was defined as a positive result on RT-PCR test for SARS-CoV-2. (Mean age 51 years)	Cohort study (2b)	24-hour ICU mortality	There were 20 ICU deaths. Non-survivors had a higher baseline serum lactate compared with survivors (p<0.01, n=122).	Single-centre study. Preliminary analysis. Missing data. Baseline medications not considered. Co-infections not considered.
Li et al. 2020 China	25 patients hospitalised with COVID-19. A COVID-19 case was defined as a positive result on RT-PCR test for SARS-CoV-2. (Median age 73 years)	Retrospective cohort study (2b)	In-hospital mortality	There were 25 in-hospital deaths. Lactate level increased in 100% (n=12) of patients with repeat measurements, from the first test (median = 1.35, IQR: 0.68 – 1.5) to the last test (median = 2.75, IQR: 1.83 – 3.55) taken before death.	Single-centre study. Small sample size. Missing data. No comparison with survivors. In-hospital treatment not considered. Descriptive analysis only - no analysis to determine statistical significance of findings. Retrospective study design
Zhang et al. 2020 China	20 patients hospitalised with COVID-19. A COVID-19 case was defined as positive on RT-PCR for SARS-CoV-2 AND positive chest CT findings AND clinical symptoms of COVID-19. (Median age 71 years)	Retrospective case series (4)	7-day mortality post tracheal intubation	There were 7 deaths post tracheal intubation. Non-survivors had a significantly higher lactate than survivors, both before and after tracheal intubation (Student’s t-test, p = 0.001).	Single-centre study. Small sample size. Baseline medications not considered. Co-infections not considered. Retrospective study design.
Chen et al. 2020 China	62 patients hospitalised with COVID-19. A COVID-19 case was defined as a positive result on RT-PCR test for SARS-CoV-2. (Median age 72 years)	Retrospective cohort study (2b)	In-hospital mortality	There were 62 in-hospital deaths. Lactic acid levels at the last follow-up before death were significantly worse than on admission (Student’s t-test, p = 0.013).	Single-centre study. Small sample size. Baseline medications not considered. No comparison with survivors. Retrospective study design.
Tan et al. 2020 China	142 patients hospitalised with COVID-19. A COVID-19 case was defined as a positive result on RT-PCR test for SARS-CoV-2. (Mean age 56 years)	Retrospective cohort study (2b)	In-hospital mortality	There were 15 in-hospital deaths. No significant difference was observed between lactic acid levels in non-survivors compared to survivors (p>0.05).	Single-centre study. Small sample size. Missing data. Lactate measurements available for only 15 non-survivors and 23 survivors. In-hospital treatment not considered. Baseline medications not considered. Retrospective study design.
Wang et al. 2020 China	843 patients hospitalised with COVID-19. A COVID-19 case was defined as a positive result on RT-PCR test for SARS-CoV-2. (Median age 60 years)	Retrospective cohort study (2b)	12-day in-hospital mortality	There were 77 deaths. Lactic acid level was lowest in the group with the best outcomes and lowest mortality rate (Kruskal-Wallis test, p<0.05).	Single-centre study. Missing data. Baseline medications not considered. Co-infections not considered. Retrospective study design. Only analysed admission laboratory results.
Zhao et al. 2020 China	539 patients hospitalised with COVID-19. A COVID-19 case was defined as a positive result on 2 or more RT-PCR test for SARS-CoV-2. (Median age 58 years)	Retrospective cohort study (2b)	In-hospital mortality	There were 125 in-hospital deaths. Lactic acid levels on admission were significantly higher in non-survivors than survivors (2.40 vs. 1.90 mmol/L, p<0.001).	Single-centre study. Missing data. Baseline medications not considered. Co-infections not considered. Retrospective study design.

Comment(s)

With the exception of one study (Tan et al.), there was an agreement within the reviewed literature that serum lactate levels correlate with disease progression and mortality in hospitalised COVID-19 patients. Twelve studies out of the thirteen studies found the serum lactate level to be significantly higher in non-survivors compared with survivors (n = 15,192 patients). Specifically, an actively increasing serum lactate was associated with mortality, supporting the use of serial lactate measurements in hospitalised COVID-19 patients in order to detect rising levels. Baseline serum lactate measurements were significantly greater in non-survivors than survivors (n = 12,909 patients), suggesting that a raised serum lactate level on admission is associated with mortality. This identifies serum lactate as not only a predictor of COVID-19 mortality, but an early predictor.

Clinical Bottom Line

A raised or increasing serum lactate level is an early predictor of mortality in patients hospitalised with COVID-19 and thus may be considered in the risk-stratification and management of these patients.

References

1. Ferrando-Vivas et al. Prognostic Factors for 30-Day Mortality in Critically Ill Patients With Coronavirus Disease 2019: An Observational Cohort Study Critical Care Medicine 2020; 102-111
2. Goodall et al. Risk factors for severe disease in patients admitted with COVID-19 to a hospital in London, England: a retrospective cohort study Epidemiology and Infection 2020; 148: e251
3. Bahl et al. Early predictors of in-hospital mortality in patients with COVID-19 in a large American cohort Internal and Emergency Medicine 2020; 1-15
4. Vassiliou et al. Lactate Kinetics Reflect Organ Dysfunction and Are Associated with Adverse Outcomes in Intensive Care Unit Patients with COVID-19 Pneumonia: Preliminary Results from a GREEK Single-Centre Study Metabolites 2020; 386
5. Garcia et al. Prognostic factors associated with mortality risk and disease progression in 639 critically ill patients with COVID-19 in Europe EClinicalMedicine 2020
6. Alharthy et al. Clinical Characteristics and Predictors of 28-Day Mortality in 352 Critically Ill Patients with COVID-19: A Retrospective Study Journal of Epidemiology and Global Health 2020; 98-104
7. Kayina et al. Epidemiological & clinical characteristic & early outcome of COVID-19 patients in a tertiary care teaching hospital in India: A preliminary analysis Indian Journal of Medical Research 2020; 100-104
8. Li et al. Clinical characteristics of 25 death cases with COVID-19: A retrospective review of medical records in a single medical center, Wuhan, China International Journal of Infectious Diseases 2020; 128-124
9. Zhang et al. Summary of 20 tracheal intubation by anesthesiologists for patients with severe COVID-19 pneumonia: retrospective case series Journal of Anesthesia 2020; 1-8
10. Chen et al. Changes in the Clinical Characteristics of 62 Patients Who Died from Coronavirus Disease 2019 BioMed Research International 2020
11. Tan et al. Validation of Predictors of Disease Severity and Outcomes in COVID-19 Patients: A Descriptive and Retrospective Study Med 2020; 128-138.e3
12. Wang et al. Time-dependent changes in the clinical characteristics and prognosis of hospitalized COVID-19 patients in Wuhan, China: A retrospective study Clinica Chimica Acta 2020; 220-227
13. Zhao et al. Abnormal immunity of non-survivors with COVID-19: predictors for mortality Infectious Diseases of Poverty 2020; 108