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| ORIGINAL ARTICLE |
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| Ahead of print publication |
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Early lactate clearance in predicting in-hospital mortality in patients with sepsis admitted in the paediatric intensive care unit
Janani Dinakaran, Shabd Singh Yadav, Saurabh Kumar Patel
Department of Pediatrics, Shyam Shah Medical College, Rewa, Madhya Pradesh, India
| Date of Submission | 26-Aug-2021 |
| Date of Acceptance | 03-May-2022 |
| Date of Web Publication | 18-Oct-2022 |
Correspondence Address:
Janani Dinakaran,
16/3 4th Street, Vellore Main Road, Arcot, Vellore, 632503 Tamilnadu
India
 Source of Support: None, Conflict of Interest: None DOI: 10.4103/aihb.aihb_127_21
Introduction: Mortality due to sepsis is increasing in the PICUs of India. This study was conducted with the aim to investigate the prognostic value of lactate level at the time of admission and lactate clearance for mortality in sepsis and estimate its cut-off value of predicting mortality. This study also aimed to estimate the correlation between lactate clearance with PRISM III score (Pediatric Risk of Mortality score) and duration of stay. Materials and Methods: This was a prospective study on 150 patients admitted with severe inflammatory response syndrome with a probable infection in the paediatric intensive care unit with an estimation of serial lactate levels in the blood at 0–3 h, 24 h and 48 h of admission. Lactate clearance was calculated, and patients were followed up till discharge/death. Results: Out of 150 patients, there were 94 survivors and 56 non-survivors; the mean lactate clearance at 24 h was 6.16% in non-survivors, which was lower than survivors at 28.41%. The cut-off value of lactate clearance for predicting mortality was estimated to be 17.6%. PRISM III score and lactate clearance were inversely related. The duration of intensive care unit stay was more in non-survivors with low lactate clearance. Conclusion: Lactate clearance can be used as a prognostic measure for mortality in patients with sepsis and can be used as a guide for treatment.
Keywords: Lactate clearance, mortality, paediatric intensive care unit, sepsis
How to cite this URL:
Dinakaran J, Yadav SS, Patel SK. Early lactate clearance in predicting in-hospital mortality in patients with sepsis admitted in the paediatric intensive care unit. Adv Hum Biol [Epub ahead of print] [cited 2023 Mar 30]. Available from: https://www.aihbonline.com/preprintarticle.asp?id=358845 |
| Introduction | |  |
The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) define sepsis as 'life-threatening organ dysfunction caused by a dysregulated host response to infection'.[1] Sepsis contributes to almost two-thirds of the admissions in the paediatric intensive care unit (PICU) in India.[2] Mortality due to sepsis was 14.2%, and mortality increased with the increasing severity of sepsis.[3] Internationally, severe paediatric sepsis cases are rising at a marked rate, with the maximum burden of sepsis incidence and mortality in Sub-Saharan Africa, Oceania, South Asia, East Asia and Southeast Asia, i.e., more in the developing countries than developed countries.[4],[5]
Sepsis is a multifaceted disruption of finely tuned immunological balance of inflammation and anti-inflammation producing a cascade of events, which includes endothelial injury and cytokine storm, progressing to septic shock and multi-organ damage.[6] In this process, various biomarkers are released into circulation, which have been used for both diagnostic and prognostic purposes. Examples of these biomarkers for sepsis include CRP andprocalcitonin, which were in use traditionally. The newer biomarkers includepresepsin, CD64, calprotectin and mir125a/mir125b, Lnc-NEAT1.[7] Because of the unaffordability, newer markers cannot be used in primary health centres in India. The quest for a simpler and easier option to guide therapy and assess mortality and morbidity in sepsis leads us to discern lactate levels and their clearance.
In recent years, lactate has been studied as a biomarker for sepsis and septic shock.[8],[9],[10] In addition, excretion of lactate which is normally done by the liver and kidney, when impaired, causes reduced lactate clearance. Hence, host equilibrium is mirrored biologically by lactate clearance. Comprehensive sufficiency of resuscitation is yielded by lactate clearance values.[11],[12],[13]
The present study aims to investigate the prognostic value of the lactate level at the time of admission and lactate clearance for mortality in sepsis and also to determine the optimal cut-off value of lactate clearance for predicting mortality in children with sepsis. The secondary objective of the study was to estimate the correlation between lactate clearance with Pediatric Risk of Mortality III score (PRISM III score)[14] and duration of stay.
| Materials and Methods | | |
The study was conducted at a tertiary care hospital in Central India from April 2019 to July 2020. It was a prospective study, in which 150 patients attending PICU fulfilling the Systemic Inflammatory Response Syndrome (SIRS) criteria[15] with suspicion of infection were included in the study. The institutional ethics committee (IEC/ETH/2019/239) approved the study during the IEC meeting held on February 20–21, 2019.
Inclusion criteria
The study included children of age 1 month to 15 years who were admitted with sepsis in PICU.
Exclusion criteria
The study excluded children admitted with other conditions which were known to cause elevated lactate levels such as chronic illnesses, malignancies, immunosuppressive treatment, inborn errors of metabolism and shock due to causes other than sepsis.
The study was explained to the patients' parents/legal guardians, and informed consent was obtained. Initial workup with complete history taking and examination was done with an active search for the underlying infection. Emergency resuscitation was done as per the clinical need of the patients. Routine haematological and biochemical profile was done. The severity of illness and organ dysfunction was assessed by the PRISM III score. Arterial blood gas analysis was performed at 0–3 h of PICU admission and then 24 h and 48 h, as and when required. Lactate levels were measured in arterial blood using a blood gas analyser (Siemens Rapid Point-500) with a standard setup for metabolite electrodes. The initial arterial blood lactate was done within 3 h of PICU admission and again at 24 h and 48 h, and then these serial lactate levels were labelled as lactate 1, lactate 2 and lactate 3, respectively. Lactate clearance-1 was defined as the percentage change in the lactate level from PICU admission (0–3 h) to 24 h of PICU admission, calculated as below.
Lactate clearance-2 was defined as the percentage change in the lactate level from 24 h of PICU admission to 48 h of admission, calculated as below.
Patients were given treatment as per hospital protocols, and they were followed up till discharge/death with a record of the requirement of ventilator support, fluid boluses, inotropes, duration of stay in intensive care unit (ICU) and total duration of stay in hospital. The outcome of the study is survival or non-survival at the end of the hospital stay.
Statistical analysis
Data was tabulated in Microsoft Excel sheet. Statistical Product and Service Solutions (SPSS) software acquired by International Business Machines Corporation (IBM), New York, U.S. was used for analysis of data. The comparison of mean lactate at the time of admission and lactate clearance at 24 h and 48 h amongst survivors and non-survivors was made by Student's t-test. The diagnostic ability of lactate at the time of admission and lactate clearance at 24 h and at 48 h for mortality was assessed by plotting the receiver operating characteristic (ROC) curve, and the optimal cut-off was chosen at the point where there is a maximum possible true positive value with a minimum true negative value (TNV) coinciding with the bend of ROC curve with a significant area under the curve (AUC). P < 0.05, odds ratio >1, AUC >0.5 and positive/negative r value were considered significant.
| Results | | |
[Table 1] shows the comparison of mean lactate clearance at the time of admission, mean lactate clearance at 24 h and 48 h with outcome. | Table 1: Comparison of lactate at the time of admission, lactate clearance at 24 h and lactate clearance at 48 h with outcome
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[Graph 1] shows the ROC curve of lactate on admission in predicting mortality with an AUC of 0.282 with a 95% confidence interval of 0.199–0.366 with P < 0.001, implying that lactate on admission was a bad predictor of mortality.
[Graph 2] shows the ROC curve of lactate clearance (%) at 24 h in predicting mortality with an AUC of 0.773 with a 95% confidence interval of 0.688–0.858 with P < 0.001, implying that lactate on admission was a good predictor of mortality with a cut-off point of 17.6% having a sensitivity of 84.0% and specificity of 69.1% with Youden Index of 0.53.
[Table 2] shows that, based on the cut-off estimated by ROC curve(17.6%) of lactate clearance at 24 h, the sample size was divided into 2 groups namely, group with lactate clearance <17.6% and group with lactate clearance ≥17.6% and compared. Non-survivors were estimated to be greater(67.9%) in the group with lactate clearance <17.6%. | Table 2: Comparison of lactate clearance groups with cut-off of 17.6% at 24 h with outcome
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[Graph 3] shows the ROC curve of lactate clearance (%) at 48 h in predicting mortality with an AUC of 0.515 with a 95% confidence interval of 0.420–0.610 with P = 0.767, implying that the test was insignificant and lactate clearance (%) at 48 h was a bad predictor of mortality.
[Table 3] shows that lactate clearance at 24 h and PRISM III scores were inversely correlated with a correlation value of 0.305, and the relationship was statistically significant with a P < 0.001, which indicated decreasing lactate clearance (%) at 24 h with increasing PRISM III score and vice versa. | Table 3: Correlation of Pediatric Risk of Mortality III score of patients with lactate clearance at 24 h
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[Table 4] shows the comparison of group with lactate clearance <17.6% at 24 h with duration of stay and outcome. | Table 4:Comparison of group with lactate clearance<17.6% at 24 h with duration of stay and outcome
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| Discussion | | |
Lactate on admission – prognostic value
The present study showed that the mean lactate levels on admission were 3.54 ± 2.38 mmol/l in non-survivors and 2.22 ± 1.32 mmol/l in survivors, and this difference was statistically significant, implying that the lactate level was significantly raised in non-survivors on admission. The Area Under the Curve (AUC) of lactate level on admission in ROC curve for diagnostic ability of lactate on admission for mortality in sepsis patients was 0.282 (±0.043) with a P – value of < 0.001, 95% confidence interval of 0.199-0.366 making lactate levels on admission, a poor prognostic test for mortality in patients of sepsis. The present study is supported by the study conducted by Choudhary et al., which showed a significant increase in lactate levels in non-survivors of 5.12 ± 3.51 mmol/l when compared to survivors of 3.13 ± 1.71 mmol/L with P < 0.01.[16]
Lactate clearance at 24 h – prognostic value
The present study showed that the mean lactate clearance at 24 h was 28.41% ± 15.89% in survivors and 6.16% ± 31.77% in non-survivors, with P < 0.001, implying a statistically significant reduction in lactate clearance amongst non-survivors. The greater standard deviation value in non-survivors (±31.77%) implies that there were patients with negative lactate clearance (or increasing lactate values) at 24 h in non-survivors. The AUC of lactate clearance at 24 h for in-hospital mortality was 0.773 (±0.043) with a 95% confidence interval of 0.688–0.858. These data were statistically significant, with P = 0.001. The cut-off of lactate clearance to predict mortality was estimated to be 17.6%, with a sensitivity of 84.0% and a specificity of 69.1% (TNV: 0.309). The study conducted by Herwanto et al. showed similar results, with a median lactate clearance at 24 h being −17.0% in non-survivors and 15.2% in survivors, with a significant P = 0.034.[17] The study conducted by Nazir et al. supported the present study with a mean lactate clearance at 24 h was - 3.2% in non-survivors and 53.4% in survivors, which was statistically significant, implying a significant decrease in lactate clearance in non-survivors. The study also showed that the AUC of lactate clearance at 24 h was 0.81 for predicting 60-day mortality by the ROC curve with a cut-off point of 20%.[18]
Lactate clearance at 48 h – prognostic value
In the present study, three patients died between 24 h and 48 h, so those three were excluded from assessing the prognostic value of lactate clearance at 48 h. The present study showed that the mean lactate clearance at 48 h was 8.55 ± 11.18% in survivors and -8.00±27.63% in non-survivors, showing a statistically significant reduction in lactate clearance at 48 h amongst non-survivors with P < 0.001. However, the AUC of lactate clearance at 48 h for in-hospital mortality was 0.515 (±0.049) with a 95% confidence interval of 0.420–0.610 with a P = 0.767. Thus, lactate clearance at 48 h was not a good measure of prognosis in patients with sepsis. There was no study estimating the prognostic value of lactate clearance at 48 h in sepsis patients in the paediatric population. The results of the present study were different from the adult studies, which might be attributed to the varying immunity and biokinetics of the paediatric and adult populations. In a study conducted on Surgical ICU(SICU) patients by Chertoff et al.(2016), lactate clearance at 48 hours was measured, and the median clearance value was estimated to be 31.6%. AUC for lactate clearance at 48 h was 0.7652 in non-survivors, which made lactate clearance measured at 48 h significant for predicting 30-day mortality in SICU patients.[19]
Comparison of lactate clearance groups with a cut-off of 17.6% at 24 h with the outcome
The present study showed that amongst non-survivors, there was a significantly increased proportion of patients (67.9%) below the cut-off value of lactate clearance (17.6%) at 24 h; amongst survivors, there was a significantly increased proportion of patients (84%) above the cut-off value of lactate clearance (17.6%) at 24 h, which was statistically significant by Chi-square test with P < 0.001. This result implied that non-survivors had lower lactate clearance at 24 h and survivors had better lactate clearance at 24 h, hence increased mortality with low lactate clearance at 24 h. The study conducted by Nazir et al. showed similar results with 85.7% of patients below cut-off value (20%) lactate clearance at 24 h amongst non-survivors implying increased mortality with low lactate clearance at 24 h.[18]
Association between Pediatric Risk of Mortality III score and lactate clearance and mortality
The present study showed that mortality with increasing PRISM III score had a significant decrease in lactate clearance (%) at 24 h and vice versa with P = 0.024 with a negative correlation (r = 0.305) between PRISM III score and lactate clearance. The study conducted by Munde et al. showed similar results with an inverse relationship between PRISM score and lactate clearance.[20]
Duration of stay
The present study showed significantly decreased duration of stay in non-survivors of the patient group with lactate clearance <17.6%. This significant decrease in duration of stay was probably because of early death. There was significantly increased duration of stay in non-survivors of the patient group with lactate clearance ≥17.6%, probably because of deterioration of clinical condition after 24 hours. This study is supported by the study conducted by Nazir et al. with less duration of hospital stay in patients with low lactate clearance and non-survivors explained due to early death of these patients.[18]
The limitation of the study is that the sample size is less as it was a single-centre study. Despite these limitations, the study showed a significant association between lactate clearance and mortality using simple equipment.
| Conclusion | | |
On the assessment of lactate clearance in patients admitted in PICU with features of SIRS and suspected sepsis, it was revealed that lactate on admission was higher and lactate clearance was lower in non-survivors; lactate clearance at 24 h was a good predictor of mortality with a cut-off at 17.6%; PRISM III score and lactate clearance were inversely related. Duration of ICU stay was more in non-survivors. Duration of total hospital stay was less in non-survivors.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
| References | | |
| 1. | Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al. The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA 2016;315:801-10.  |
| 2. | Kaur G, Vinayak N, Mittal K, Kaushik JS, Aamir M. Clinical outcome and predictors of mortality in children with sepsis, severe sepsis, and septic shock from Rohtak, Haryana: A prospective observational study. Indian J Crit Care Med 2014;18:437-41. [ PUBMED] [Full text] |
| 3. | de Souza DC, Shieh HH, Barreira ER, Ventura AM, Bousso A, Troster EJ, et al. Epidemiology of sepsis in children admitted to PICUs in South America. Pediatr Crit Care Med 2016;17:727-34. |
| 4. | Rudd KE, Johnson SC, Agesa KM, Shackelford KA, Tsoi D, Kievlan DR, et al. Global, regional, and national sepsis incidence and mortality, 1990-2017: Analysis for the Global Burden of Disease Study. Lancet 2020;395:200-11. |
| 5. | Tan B, Wong JJ, Sultana R, Koh JC, Jit M, Mok YH, et al. Global case-fatality rates in pediatric severe sepsis and septic shock: A systematic review and meta-analysis. JAMA Pediatr 2019;173:352-62. |
| 6. | Jarczak D, Kluge S, Nierhaus A. Sepsis-pathophysiology and therapeutic concepts. Front Med (Lausanne) 2021;8:628302. |
| 7. | Kim MH, Choi JH. An update on sepsis biomarkers. Infect Chemother 2020;52:1-18. |
| 8. | Chen H, Gong SR, Yu RG. Increased normalized lactate load is associated with higher mortality in both sepsis and non-sepsis patients: An analysis of the MIMIC-IV database. BMC Anesthesiol 2022;22:79. |
| 9. | Moran JL, Santamaria J. Reconsidering lactate as a sepsis risk biomarker. PLoS One 2017;12:e0185320. |
| 10. | Madabhushi S, Trikha A, Anand RK, Ramachandran R, Singh PM, Rewari V. Temporal evolution of the PcvCO 2-PaCO 2/CaO 2-CcvO 2 ratio vs. serum lactate during resuscitation in septic shock. Indian J Crit Care Med 2021;25:1370-6. |
| 11. | He Z, Yang X, Yang C, Wang R, He H. Efficacy analysis of inferior vena cava variability combined with difference of central venous-to-arterial partial pressure of carbon dioxide on guiding fluid resuscitation in patients with septic shock. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue 2022;34:18-22. |
| 12. | Yu C, Fan W, Shao M. Norepinephrine dosage is associated with lactate clearance after resuscitation in patients with septic shock. Front Med (Lausanne) 2021;8:761656. |
| 13. | Limapichat T, Pattanapong K. Normal saline solution or lactated ringer's solution to enhance lactate clearance in septic patients after initial resuscitation in the ED: A retrospective cohort trial. Open Access Emerg Med 2021;13:511-9. |
| 14. | Mirza S, Malik L, Ahmed J, Malik F, Sadiq H, Ali S, et al. Accuracy of pediatric risk of mortality (PRISM) III score in predicting mortality outcomes in a pediatric Intensive Care Unit in Karachi. Cureus 2020;12:e7489. |
| 15. | Marik PE, Taeb AM. SIRS, qSOFA and new sepsis definition. J Thorac Dis 2017;9:943-5. |
| 16. | Choudhary R, Sitaraman S, Choudhary A. Lactate clearance as the predictor of outcome in pediatric septic shock. J Emerg Trauma Shock 2017;10:55-9. [ PUBMED] [Full text] |
| 17. | Herwanto V, Lie K, Suwarto S, Rumende C. Role of 6-hour, 12-hour, and 24-hour lactate clearance in mortality of severe sepsis and septic shock patients. Crit Care 2014;18 Suppl 2:P2. |
| 18. | Nazir M, Wani W, Dar SA, Mir IH, Charoo BA, Ahmad QI, et al. Lactate clearance prognosticates outcome in pediatric septic shock during first 24h of Intensive Care Unit admission. J Intensive Care Soc 2019;20:290-8. |
| 19. | Chertoff J, Chisum M, Simmons L, King B, Walker M, Lascano J. Prognostic utility of plasma lactate measured between 24 and 48 h after initiation of early goal-directed therapy in the management of sepsis, severe sepsis, and septic shock. J Intensive Care 2016;4:13. |
| 20. | Munde A, Kumar N, Beri RS, Puliyel JM. Lactate clearance as a marker of mortality in pediatric Intensive Care Unit. Indian Pediatr 2014;51:565-7. |
[Table 1], [Table 2], [Table 3], [Table 4]
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