Prognostic Value of Lactate Clearance in Critically Ill Pediatric Patients Admitted to the Intensive Care Unit: A Single-Center Study from Southern Iran

Prognostic Value of Lactate Clearance in Critically Ill Pediatric Patients Admitted to the Intensive Care Unit: A Single-Center Study from Southern Iran | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Prognostic Value of Lactate Clearance in Critically Ill Pediatric Patients Admitted to the Intensive Care Unit: A Single-Center Study from Southern Iran Marjan Tariverdi, Narges Keshvar Parast, Hammed Sarbazi, Saeed Hosseini Teshnizi This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8775242/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 9 You are reading this latest preprint version Abstract Background: Lactate clearance is considered a reliable indicator of tissue perfusion and treatment response in critically ill patients. However, its prognostic significance in pediatric intensive care units has not been adequately defined. This study aims to investigate the prognostic value of lactate clearance in pediatric patients admitted to the intensive care unit of Bandar Abbas Children’s Hospital, Iran. Method: In this prospective cross-sectional study, critically ill children aged 1 month to 17 years admitted to the pediatric intensive care unit of Bandar Abbas Children’s Hospital, Iran, were consecutively enrolled. Arterial lactate levels were obtained at admission and at 6 and 24 hours, and lactate clearance was calculated. Clinical outcomes (survival or death) were recorded. Receiver operating characteristic curve analysis was performed to evaluate the prognostic performance of lactate clearance. The chi-square test and analysis of variance (ANOVA) were used, and a p-value < 0.05 was considered statistically significant. Result: A total of 169 children admitted to the pediatric intensive care unit were included, of whom 54 (31.9%) died; 59.3% were male, and the mean age was 7.56±1.03 years. Admission lactate clearance was not a reliable predictor of clinical outcome (P=0.064). In contrast, lactate clearance at 6 and 24 hours demonstrated high sensitivity for outcome prediction (97.39% and 94.78%, respectively). Comparative analysis showed that 24-hour lactate clearance, with a cut-off value of 48.7, exhibited superior prognostic performance. Conclusion: Twenty-four-hour lactate clearance appears to be a useful prognostic indicator in critically ill pediatric patients admitted to the PICU. Lactate monitoring allows for a more accurate assessment of treatment response and improved risk stratification. Lactate Clearance Resuscitation Mortality pediatric intensive care unit prognostic value Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Under normal physiological conditions, cellular energy is primarily generated through aerobic metabolism, with glucose serving as the principal substrate. In this pathway, glucose is metabolized to pyruvate via glycolysis, and pyruvate then enters the Krebs cycle, resulting in substantial production of adenosine triphosphate (ATP). However, in settings of inadequate oxygen delivery, such as shock, hypoxia, or other critical conditions, pyruvate is instead converted to lactate via anaerobic metabolism. This metabolic shift yields significantly less ATP and leads to elevated lactate levels in the bloodstream. In critically ill patients, increased serum lactate is often indicative of tissue hypoperfusion and cellular hypoxia, making it a valuable clinical biomarker for assessing the adequacy of oxygen delivery at the tissue level. Importantly, elevated lactate levels are not exclusively associated with hypoxia. Hyperlactatemia may also result from increased lactate production, such as in cases of drug toxicity or malignancy, or from impaired clearance due to hepatic or renal dysfunction. Therefore, both production and clearance mechanisms must be considered in the clinical interpretation of lactate levels(3). In intensive care settings, serum lactate is routinely measured at the time of admission to establish a baseline. Serial measurements are commonly performed at 6 and 24 hours post-intervention to assess the dynamics of lactate clearance. Beyond absolute lactate concentration, the rate of lactate clearance has gained recognition as a clinically relevant indicator of the effectiveness of resuscitation and prognosis in critically ill patients. It reflects the restoration of adequate tissue perfusion and cellular oxygenation (4, 5). This study aims to investigate the prognostic value of lactate clearance in pediatric patients admitted to the intensive care unit of Bandar Abbas Children’s Hospital, Iran. Methods Study Design and Setting This descriptive, prospective cross-sectional study was conducted over a six-month period in 2024. The study was performed in the Pediatric Intensive Care Unit (PICU) of Bandar Abbas Children’s Hospital, a tertiary referral center located in Hormozgan Province, southern Iran. Data were collected between March and August 2024. Participants A total of 169 pediatric patients, aged between 1 month and 17 years, who were admitted to the PICU during the study period, were enrolled. Inclusion criteria were all critically ill children admitted to the PICU within the specified age range. Exclusion criteria included patients with known metabolic disorders or malignancies. Sampling was performed consecutively based on eligibility at the time of admission. Variables The primary variable of interest was serum lactate clearance, while in-hospital mortality (survival vs. death) was considered the main outcome. Additional variables included demographic characteristics such as age and gender, and clinical parameters including length of stay in the PICU and arterial lactate levels measured at admission, 6 hours, and 24 hours post-admission. Data Sources and Measurements Arterial blood samples were collected at three time points: upon admission to the PICU, and subsequently at 6 and 24 hours post-admission. Lactate levels were measured using the GEM Premier 3000 Critical Care Analyzer (Instrumentation Laboratory, USA). Lactate clearance was calculated using the following formula(6): Sample Size A sample size of 160 patients was the minimum required to detect an area under the receiver operating characteristics (ROC) curve (AUC) of 0.65, relative to a null value of 0.5, as statistically significant with 80% power and at a significance of 0.05. The sample size was calculated using Medcalc Software version 14. Statistical Methods Data were entered, coded, and analyzed using IBM SPSS Statistics for Windows, version 20 (IBM Corp., Armonk, NY, USA). Categorical variables were compared using exact tests, while the Mann–Whitney U test and independent samples t-test were applied to compare medians and means, respectively. Receiver Operating Characteristic (ROC) curve analysis was conducted using MedCalc Software version 14 to determine the discriminative ability of lactate clearance, with the area under the curve (AUC) reported. The optimal cut-off point was determined using Youden's Index. Associations with mortality were assessed using the chi-square test for sex and analysis of variance (ANOVA) for continuous variables . Survival outcomes were analyzed using Kaplan–Meier curves, and a p-value < 0.05 was considered statistically significant. Result In this study, 169 patients admitted to the Pediatric Intensive Care Unit were evaluated, with a mean age of 7.56±1.03 years. Regarding clinical outcomes, 54 patients were deceased, of whom 59.3% were male. To assess the distribution of continuous variables, normality was evaluated separately within the survivor and non-survivor groups using the Shapiro–Wilk test. Because the normality assumption was not met for most variables, between-group comparisons of continuous variables were performed using the nonparametric Mann–Whitney U test. Continuous variables are presented as the median and interquartile range (IQR). Further details are provided in Table 1. In this study, blood lactate levels were assessed as a prognostic indicator for predicting patient outcomes at three different time intervals: upon admission to the PICU, 6 hours after PICU admission, and 24 hours after PICU admission. The highest sensitivity was observed at the 6-hour post-admission mark (97.39%), indicating that this time point demonstrated the best performance in identifying patients at high risk of mortality. Moreover, at this interval, the negative likelihood ratio (NLR = 0.074) reached its lowest value, highlighting the test’s strong ability to rule out mortality when lactate levels are low. In contrast, the specificity of the test remained low across all three time points (ranging from 14.81% to 35.19%), suggesting limited accuracy in identifying low-risk patients. Additional details are provided in Table 2 and Figure 1. As shown in Table 3 and Figure 2, baseline lactate demonstrated high sensitivity but poor specificity with a non-significant AUC (P = 0.750), limiting its value for mortality discrimination in hospitalized pediatric patients. In contrast, 6-hour and 24-hour lactate clearance maintained high sensitivity, with the 24-hour measure providing markedly better specificity, and both clearance indices showed statistically significant AUCs (P < 0.001) for identifying in-hospital mortality. Pairwise comparisons of the areas under the ROC curves were performed using the DeLong test for correlated ROC curves within the same cohort, and the AUC differences were reported together with the P values. The AUC for 6-hour and 24-hour lactate clearance was significantly higher than that of admission lactate (P < 0.0001 and P = 0.0005, respectively), whereas the AUC difference between 6-hour and 24-hour lactate clearance was not statistically significant . As shown in Table 5 , a 24-hour lactate clearance cut-off of 48.7 was applied to classify patients as survivors (<48.7) or non-survivors (≥48.7). This classification demonstrated significant agreement with the observed outcome, with an overall accuracy of 73.2% (Cohen’s kappa, P < 0.001) Using a cut-off value of 48.7, the 24-hour lactate clearance test correctly classified 109 of 140 survivors (77.8%), corresponding to a negative predictive value of 77.8%, while 41 of 54 non-survivors (91.11%) were correctly identified, yielding a positive predictive value of 91.11%. The overall accuracy of the test was high, calculated as Accuracy = (41 + 109) / 169 × 100 = 88.75%. In Figure 4, accuracy is plotted against sensitivity; at a sensitivity of 94.78% (24-hour lactate clearance sensitivity), the highest accuracy of 88.77% is observed.. Discussion Although numerous studies have evaluated lactate clearance over short time intervals, most commonly 2 or 6 hours after baseline measurement, evidence regarding lactate clearance monitoring over longer periods, particularly during the first 24 hours of admission to the PICU, remains limited(7–9). This gap is especially notable in critically ill pediatric populations, in whom physiological responses to shock, resuscitation, and lactate metabolism may differ from those observed in adults. While previous studies have shown that lactate-guided resuscitation strategies are associated with improved outcomes(10)The optimal timing and prognostic value of lactate clearance assessment during later phases of PICU hospitalization in children have not been clearly established. In the present study, admission lactate levels alone were not found to be strong predictors of mortality. In contrast, lactate clearance during the PICU stay, particularly within the first 24 hours after admission, demonstrated a stronger association with clinical outcomes. This observation is in line with prior reports, including the study by Chertoff et al., which showed higher mortality among patients with insufficient lactate reduction over time(9). Collectively, these findings suggest that changes in lactate levels may better reflect the adequacy of resuscitation and ongoing management than a single baseline measurement, even in patients presenting with initially elevated lactate concentrations. Our results further showed that both 6-hour and 24-hour lactate clearance after PICU admission were associated with mortality prediction, with sensitivities of 97.39% and 94.78%, respectively. However, comparative analysis indicated that 24-hour lactate clearance provided superior prognostic performance. Specifically, at a cut-off value of 48.7 for 24-hour lactate clearance, the overall predictive accuracy for mortality reached approximately 88.77%, suggesting improved discriminative ability compared with earlier measurements. For 6-hour lactate clearance, using a cut-off value of 14.8, sensitivity and specificity were 97.39% and 35.19%, respectively. Although the area under the ROC curve was significantly greater than the reference value (AUC = 0.75, P < 0.001), indicating acceptable discriminatory power, the relatively low specificity implies a higher rate of false-positive classifications. Therefore, 6-hour lactate clearance appears to be a sensitive early marker for identifying high-risk pediatric patients, but its limited specificity may reduce its reliability as a standalone prognostic indicator. In contrast, 24-hour lactate clearance demonstrated both high sensitivity (94.78%) and relatively high specificity (75.93%) at the identified cut-off point of 48.7. The area under the ROC curve (AUC = 0.80, P < 0.001) was significantly greater than the reference level, supporting the robustness of this parameter in predicting mortality among critically ill children admitted to the PICU. Additionally, the positive and negative predictive values for 24-hour lactate clearance were 91.11% and 77.8%, respectively, indicating a more balanced and reliable predictive performance compared with earlier measurements. The superior prognostic performance of 24-hour lactate clearance may be explained by the persistence of microcirculatory dysfunction and delayed recovery of cellular oxygen utilization beyond the initial resuscitation phase. Furthermore, ongoing impairment of hepatic and renal lactate clearance due to multiple organ dysfunction, commonly observed in critically ill pediatric patients, may contribute to sustained hyperlactatemia despite partial restoration of systemic hemodynamics(11). Accordingly, later lactate clearance measurements may more accurately reflect the true physiological response to treatment rather than transient early changes. Taken together, these findings suggest that serial lactate monitoring, with particular emphasis on 24-hour lactate clearance during PICU admission, may serve as a practical and readily available marker for assessing treatment response and estimating prognosis in critically ill pediatric patients. Importantly, our results highlight the potential value of 24-hour lactate clearance as a pediatric-specific prognostic indicator, which may help clinicians identify children who fail to demonstrate adequate physiological improvement despite early resuscitative efforts and prompt timely reassessment of therapeutic strategies. This study has several limitations that should be acknowledged. First, the relatively limited sample size may restrict the generalizability of the findings. Second, the study was conducted at a single center; therefore, variations in clinical practices and treatment protocols across institutions may lead to different associations between lactate dynamics and clinical outcomes. Third, the results are restricted to non-surgical patients, and extrapolation to surgical populations should be undertaken with caution. Finally, only patients admitted to the PICU were included, which may limit the applicability of the findings to less critically ill pediatric patients managed in non-ICU settings. Conclusion The present study aimed to evaluate the predictive value of lactate clearance in children admitted to the PICU. Our findings demonstrate that 24-hour lactate clearance serves as a strong prognostic marker for clinical outcomes in critically ill pediatric patients. Accordingly, serial lactate monitoring with particular emphasis on 24-hour clearance may facilitate early identification of high-risk patients. Further studies focusing on the implementation of novel therapeutic strategies and targeted interventions in patients with low lactate clearance are warranted to improve clinical outcomes and reduce mortality. Declarations Ethics approval and consent to participate: The study protocol was approved by the Research Ethics Committee of Hormozgan University of Medical Sciences (IR.HUMS.REC.1402.129). All study procedures were conducted in accordance with the ethical standards of the Declaration of Helsinki. As the study population consisted exclusively of children under 18 years of age, written informed consent for participation was obtained from the parents or legal guardians of all participants prior to enrollment. Consent for publication : Not applicable. Clinical trial number: 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 no competing interests. Funding : this research did not receive funding. Authors' contributions: M.T. conceived and designed the study and supervised the overall research process. N.K.P. contributed to data collection and participated in data interpretation. H.S., as a student researcher, assisted with data collection and contributed to drafting the initial version of the manuscript. S.H.T. performed the statistical analysis, contributed to data interpretation, and provided methodological support. All authors critically reviewed the manuscript, approved the final version, and agree to be accountable for all aspects of the work, ensuring that questions related to the accuracy or integrity of any part of the study are appropriately investigated and resolved. Acknowledgements: The authors sincerely thank Zahra Khoshouei for her valuable assistance and constructive input during this study. References Li X, Yang Y, Zhang B, Lin X, Fu X, An Y, et al. Lactate metabolism in human health and disease. Signal Transduct Target Ther. 2022;7(1):305. Kraut JA, Madias NE. Lactic acidosis. N Engl J Med. 2014;371(24):2309-19. Moustafa AA, Elhadidi AS, El-Nagar MA, Hassouna HM. Can Lactate Clearance Predict Mortality in Critically Ill Children? J Pediatr Intensive Care. 2023;12(2):112-7. Kushimoto S, Akaishi S, Sato T, Nomura R, Fujita M, Kudo D, et al. Lactate, a useful marker for disease mortality and severity but an unreliable marker of tissue hypoxia/hypoperfusion in critically ill patients. Acute Med Surg. 2016;3(4):293-7. Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Med. 2017;43(3):304-77. Munde A, Kumar N, Beri RS, Puliyel JM. Lactate clearance as a marker of mortality in pediatric intensive care unit. Indian Pediatr. 2014;51(7):565-7. Bakker J, Gris P, Coffernils M, Kahn RJ, Vincent JL. Serial blood lactate levels can predict the development of multiple organ failure following septic shock. Am J Surg. 1996;171(2):221-6. Krishna U, Joshi SP, Modh M. An evaluation of serial blood lactate measurement as an early predictor of shock and its outcome in patients of trauma or sepsis. Indian J Crit Care Med. 2009;13(2):66-73. 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. Marty P, Roquilly A, Vallée F, Luzi A, Ferré F, Fourcade O, et al. 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. van Genderen ME, Klijn E, Lima A, de Jonge J, Sleeswijk Visser S, Voorbeijtel J, et al. Microvascular perfusion as a target for fluid resuscitation in experimental circulatory shock. Crit Care Med. 2014;42(2):e96-e105. Tables Tables 1 to 5 are available in the supplementary files section Additional Declarations No competing interests reported. Supplementary Files Tables.docx Cite Share Download PDF Status: Under Review Version 1 posted Reviews received at journal 16 Mar, 2026 Reviews received at journal 11 Mar, 2026 Reviewers agreed at journal 06 Mar, 2026 Reviewers agreed at journal 06 Mar, 2026 Reviewers invited by journal 06 Mar, 2026 Editor assigned by journal 04 Mar, 2026 Editor invited by journal 09 Feb, 2026 Submission checks completed at journal 09 Feb, 2026 First submitted to journal 09 Feb, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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2","display":"","copyAsset":false,"role":"figure","size":299619,"visible":true,"origin":"","legend":"\u003cp\u003eArea under the curve for lactate on admission, lactate clearance at 6 hours and 24 hours from admission\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-8775242/v1/a836ea596e1d312a0a4f8d65.png"},{"id":104412388,"identity":"7d596e54-6e59-4940-a718-5240d6b34efc","added_by":"auto","created_at":"2026-03-11 12:59:25","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":68404,"visible":true,"origin":"","legend":"\u003cp\u003eComparison of ROC Curve AUCs for Lactate Clearance\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-8775242/v1/a1ad7437cfcea72f74a1fb72.png"},{"id":104414026,"identity":"794c2807-d22b-46b5-87fe-10f6d5fd483b","added_by":"auto","created_at":"2026-03-11 13:06:19","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":55339,"visible":true,"origin":"","legend":"\u003cp\u003eAccuracy Sensitivity Curve for 24-Hour Lactate Clearance (Cut-off = 48.7) in Predicting In-Hospital Mortality\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-8775242/v1/f2ec12f90e2dac3c5f13fcfe.png"},{"id":104416288,"identity":"7f1d69d0-3b86-44e3-b65f-e5473563181a","added_by":"auto","created_at":"2026-03-11 13:14:41","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":878939,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8775242/v1/88ace09f-7910-4968-8e1c-63737d02d23e.pdf"},{"id":104412105,"identity":"248a0f66-adbe-4fc2-b641-3fcb74a8ec12","added_by":"auto","created_at":"2026-03-11 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In this pathway, glucose is metabolized to pyruvate via glycolysis, and pyruvate then enters the Krebs cycle, resulting in substantial production of adenosine triphosphate (ATP). However, in settings of inadequate oxygen delivery, such as shock, hypoxia, or other critical conditions, pyruvate is instead converted to lactate via anaerobic metabolism. This metabolic shift yields significantly less ATP and leads to elevated lactate levels in the bloodstream. In critically ill patients, increased serum lactate is often indicative of tissue hypoperfusion and cellular hypoxia, making it a valuable clinical biomarker for assessing the adequacy of oxygen delivery at the tissue level.\u003c/p\u003e \u003cp\u003eImportantly, elevated lactate levels are not exclusively associated with hypoxia. Hyperlactatemia may also result from increased lactate production, such as in cases of drug toxicity or malignancy, or from impaired clearance due to hepatic or renal dysfunction. Therefore, both production and clearance mechanisms must be considered in the clinical interpretation of lactate levels(3).\u003c/p\u003e \u003cp\u003eIn intensive care settings, serum lactate is routinely measured at the time of admission to establish a baseline. Serial measurements are commonly performed at 6 and 24 hours post-intervention to assess the dynamics of lactate clearance. Beyond absolute lactate concentration, the rate of lactate clearance has gained recognition as a clinically relevant indicator of the effectiveness of resuscitation and prognosis in critically ill patients. It reflects the restoration of adequate tissue perfusion and cellular oxygenation (4, 5).\u003c/p\u003e \u003cp\u003eThis study aims to investigate the prognostic value of lactate clearance in pediatric patients admitted to the intensive care unit of Bandar Abbas Children\u0026rsquo;s Hospital, Iran.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eStudy Design\u003cspan dir=\"RTL\"\u003e\u0026nbsp;\u003c/span\u003eand Setting\u003c/p\u003e\n\u003cp\u003eThis descriptive, prospective cross-sectional study was conducted over a six-month period in 2024. The study was performed in the Pediatric Intensive Care Unit (PICU) of Bandar Abbas Children\u0026rsquo;s Hospital, a tertiary referral center located in Hormozgan Province, southern Iran. Data were collected between March and August 2024.\u003c/p\u003e\n\u003cp\u003eParticipants\u003c/p\u003e\n\u003cp\u003eA total of 169 pediatric patients, aged between 1 month and 17 years, who were admitted to the PICU during the study period, were enrolled. Inclusion criteria were all critically ill children admitted to the PICU within the specified age range. Exclusion criteria included patients with known metabolic disorders or malignancies. Sampling was performed consecutively based on eligibility at the time of admission.\u003c/p\u003e\n\u003cp\u003eVariables\u003c/p\u003e\n\u003cp\u003eThe primary variable of interest was serum lactate clearance, while in-hospital mortality (survival vs. death) was considered the main outcome. Additional variables included demographic characteristics such as age and gender, and clinical parameters including length of stay in the PICU and arterial lactate levels measured at admission, 6 hours, and 24 hours post-admission.\u003c/p\u003e\n\u003cp\u003eData Sources and Measurements\u003c/p\u003e\n\u003cp\u003eArterial blood samples were collected at three time points: upon admission to the PICU, and subsequently at 6 and 24 hours post-admission. Lactate levels were measured using the GEM Premier 3000 Critical Care Analyzer (Instrumentation Laboratory, USA). Lactate clearance was calculated using the following formula(6):\u003c/p\u003e\n\u003cp\u003e\u003cimg 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\"\u003e\u003c/p\u003e\n\u003cp\u003eSample Size\u003c/p\u003e\n\u003cp\u003eA sample size of 160 patients was the minimum required to detect an area under the receiver operating characteristics (ROC) curve (AUC) of 0.65, relative to a null value of 0.5, as statistically significant with 80% power and at a significance of 0.05. The sample size was calculated using Medcalc Software version 14.\u003c/p\u003e\n\u003cp\u003eStatistical Methods\u003c/p\u003e\n\u003cp\u003eData were entered, coded, and analyzed using IBM SPSS Statistics for Windows, version 20 (IBM Corp., Armonk, NY, USA). Categorical variables were compared using exact tests, while the Mann\u0026ndash;Whitney U test and independent samples t-test were applied to compare medians and means, respectively. Receiver Operating Characteristic (ROC) curve analysis was conducted using MedCalc Software version 14 to determine the discriminative ability of lactate clearance, with the area under the curve (AUC) reported. The optimal cut-off point was determined using Youden\u0026apos;s Index. Associations with mortality were assessed using the chi-square test for sex and analysis of\u003cspan dir=\"RTL\"\u003e\u0026nbsp;\u003c/span\u003evariance (ANOVA) for continuous variables\u003cspan dir=\"RTL\"\u003e.\u0026nbsp;\u003c/span\u003eSurvival outcomes were analyzed using Kaplan\u0026ndash;Meier curves, and a p-value \u0026lt; 0.05 was considered statistically significant.\u003c/p\u003e"},{"header":"Result","content":"\u003cp\u003eIn this study, 169 patients admitted to the Pediatric Intensive Care Unit were evaluated, with a mean age of 7.56\u0026plusmn;1.03 years. Regarding clinical outcomes, 54 patients were deceased, of whom 59.3% were male. To assess the distribution of continuous variables, normality was evaluated separately within the survivor and non-survivor groups using the Shapiro\u0026ndash;Wilk test. Because the normality assumption was not met for most variables, between-group comparisons of continuous variables were performed using the nonparametric Mann\u0026ndash;Whitney U test. Continuous variables are presented as the median and interquartile range (IQR). Further details are provided in Table 1.\u003c/p\u003e\n\u003cp\u003eIn this study, blood lactate levels were assessed as a prognostic indicator for predicting patient outcomes at three different time intervals: upon admission to the PICU, 6 hours after PICU admission, and 24 hours after PICU admission. The highest sensitivity was observed at the 6-hour post-admission mark (97.39%), indicating that this time point demonstrated the best performance in identifying patients at high risk of mortality. Moreover, at this interval, the negative likelihood ratio (NLR = 0.074) reached its lowest value, highlighting the test\u0026rsquo;s strong ability to rule out mortality when lactate levels are low. In contrast, the specificity of the test remained low across all three time points (ranging from 14.81% to 35.19%), suggesting limited accuracy in identifying low-risk patients. Additional details are provided in Table 2 and Figure 1.\u003c/p\u003e\n\u003cp\u003eAs shown in Table \u003cspan dir=\"RTL\"\u003e3\u003c/span\u003e and Figure 2, baseline lactate demonstrated high sensitivity but poor specificity with a non-significant AUC (P = 0.750), limiting its value for mortality discrimination in hospitalized pediatric patients. In contrast, 6-hour and 24-hour lactate clearance maintained high sensitivity, with the 24-hour measure providing markedly better specificity, and both clearance indices showed statistically significant AUCs (P \u0026lt; 0.001) for identifying in-hospital mortality.\u003c/p\u003e\n\u003cp\u003ePairwise comparisons of the areas under the ROC curves were performed using the DeLong test for correlated ROC curves within the same cohort, and the AUC differences were reported together with the P values. The AUC for 6-hour and 24-hour lactate clearance was significantly higher than that of admission lactate (P \u0026lt; 0.0001 and P = 0.0005, respectively), whereas the AUC difference between 6-hour and 24-hour lactate clearance was not statistically significant\u003cspan dir=\"RTL\"\u003e.\u003c/span\u003e\u003c/p\u003e\n\u003cp\u003e\u003cspan dir=\"RTL\"\u003eAs shown in Table \u003cspan dir=\"RTL\"\u003e5\u003c/span\u003e, a 24-hour lactate clearance cut-off of 48.7 was applied to classify patients as survivors (\u0026lt;48.7) or non-survivors (\u0026ge;48.7). This classification demonstrated significant agreement with the observed outcome, with an overall accuracy of 73.2% (Cohen\u0026rsquo;s kappa, P \u0026lt; 0.001)\u003c/span\u003e\u003c/p\u003e\n\u003cp\u003e\u003cspan dir=\"RTL\"\u003eUsing a cut-off value of 48.7, the 24-hour lactate clearance test correctly classified 109 of 140 survivors (77.8%), corresponding to a negative predictive value of 77.8%, while 41 of 54 non-survivors (91.11%) were correctly identified, yielding a positive predictive value of 91.11%. The overall accuracy of the test was high, calculated as Accuracy = (41 + 109) / 169 \u0026times; 100 = 88.75%. \u003cspan dir=\"RTL\"\u003e\u0026nbsp;\u003c/span\u003eIn Figure 4, accuracy is plotted against sensitivity; at a sensitivity of 94.78% (24-hour lactate clearance sensitivity), the highest accuracy of 88.77% is observed..\u003c/span\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eAlthough numerous studies have evaluated lactate clearance over short time intervals, most commonly 2 or 6 hours after baseline measurement, evidence regarding lactate clearance monitoring over longer periods, particularly during the first 24 hours of admission to the PICU, remains limited(7\u0026ndash;9). This gap is especially notable in critically ill pediatric populations, in whom physiological responses to shock, resuscitation, and lactate metabolism may differ from those observed in adults. While previous studies have shown that lactate-guided resuscitation strategies are associated with improved outcomes(10)The optimal timing and prognostic value of lactate clearance assessment during later phases of PICU hospitalization in children have not been clearly established.\u003c/p\u003e \u003cp\u003eIn the present study, admission lactate levels alone were not found to be strong predictors of mortality. In contrast, lactate clearance during the PICU stay, particularly within the first 24 hours after admission, demonstrated a stronger association with clinical outcomes. This observation is in line with prior reports, including the study by Chertoff et al., which showed higher mortality among patients with insufficient lactate reduction over time(9). Collectively, these findings suggest that changes in lactate levels may better reflect the adequacy of resuscitation and ongoing management than a single baseline measurement, even in patients presenting with initially elevated lactate concentrations.\u003c/p\u003e \u003cp\u003eOur results further showed that both 6-hour and 24-hour lactate clearance after PICU admission were associated with mortality prediction, with sensitivities of 97.39% and 94.78%, respectively. However, comparative analysis indicated that 24-hour lactate clearance provided superior prognostic performance. Specifically, at a cut-off value of 48.7 for 24-hour lactate clearance, the overall predictive accuracy for mortality reached approximately 88.77%, suggesting improved discriminative ability compared with earlier measurements.\u003c/p\u003e \u003cp\u003eFor 6-hour lactate clearance, using a cut-off value of 14.8, sensitivity and specificity were 97.39% and 35.19%, respectively. Although the area under the ROC curve was significantly greater than the reference value (AUC\u0026thinsp;=\u0026thinsp;0.75, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001), indicating acceptable discriminatory power, the relatively low specificity implies a higher rate of false-positive classifications. Therefore, 6-hour lactate clearance appears to be a sensitive early marker for identifying high-risk pediatric patients, but its limited specificity may reduce its reliability as a standalone prognostic indicator.\u003c/p\u003e \u003cp\u003eIn contrast, 24-hour lactate clearance demonstrated both high sensitivity (94.78%) and relatively high specificity (75.93%) at the identified cut-off point of 48.7. The area under the ROC curve (AUC\u0026thinsp;=\u0026thinsp;0.80, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) was significantly greater than the reference level, supporting the robustness of this parameter in predicting mortality among critically ill children admitted to the PICU. Additionally, the positive and negative predictive values for 24-hour lactate clearance were 91.11% and 77.8%, respectively, indicating a more balanced and reliable predictive performance compared with earlier measurements.\u003c/p\u003e \u003cp\u003eThe superior prognostic performance of 24-hour lactate clearance may be explained by the persistence of microcirculatory dysfunction and delayed recovery of cellular oxygen utilization beyond the initial resuscitation phase. Furthermore, ongoing impairment of hepatic and renal lactate clearance due to multiple organ dysfunction, commonly observed in critically ill pediatric patients, may contribute to sustained hyperlactatemia despite partial restoration of systemic hemodynamics(11). Accordingly, later lactate clearance measurements may more accurately reflect the true physiological response to treatment rather than transient early changes.\u003c/p\u003e \u003cp\u003eTaken together, these findings suggest that serial lactate monitoring, with particular emphasis on 24-hour lactate clearance during PICU admission, may serve as a practical and readily available marker for assessing treatment response and estimating prognosis in critically ill pediatric patients. Importantly, our results highlight the potential value of 24-hour lactate clearance as a pediatric-specific prognostic indicator, which may help clinicians identify children who fail to demonstrate adequate physiological improvement despite early resuscitative efforts and prompt timely reassessment of therapeutic strategies.\u003c/p\u003e \u003cp\u003eThis study has several limitations that should be acknowledged. First, the relatively limited sample size may restrict the generalizability of the findings. Second, the study was conducted at a single center; therefore, variations in clinical practices and treatment protocols across institutions may lead to different associations between lactate dynamics and clinical outcomes. Third, the results are restricted to non-surgical patients, and extrapolation to surgical populations should be undertaken with caution. Finally, only patients admitted to the PICU were included, which may limit the applicability of the findings to less critically ill pediatric patients managed in non-ICU settings.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThe present study aimed to evaluate the predictive value of lactate clearance in children admitted to the PICU. Our findings demonstrate that 24-hour lactate clearance serves as a strong prognostic marker for clinical outcomes in critically ill pediatric patients. Accordingly, serial lactate monitoring with particular emphasis on 24-hour clearance may facilitate early identification of high-risk patients. Further studies focusing on the implementation of novel therapeutic strategies and targeted interventions in patients with low lactate clearance are warranted to improve clinical outcomes and reduce mortality.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study protocol was approved by the Research Ethics Committee of Hormozgan University of Medical Sciences (IR.HUMS.REC.1402.129). All study procedures were conducted in accordance with the ethical standards of the Declaration of Helsinki. As the study population consisted exclusively of children under 18 years of age, written informed consent for participation was obtained from the parents or legal guardians of all participants prior to enrollment.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e: Not applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical trial number:\u003c/strong\u003e not applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials:\u003c/strong\u003e The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests:\u003c/strong\u003e The authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e: this research did not receive funding.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors' contributions:\u003c/strong\u003e M.T. conceived and designed the study and supervised the overall research process. N.K.P. contributed to data collection and participated in data interpretation. H.S., as a student researcher, assisted with data collection and contributed to drafting the initial version of the manuscript. S.H.T. performed the statistical analysis, contributed to data interpretation, and provided methodological support. All authors critically reviewed the manuscript, approved the final version, and agree to be accountable for all aspects of the work, ensuring that questions related to the accuracy or integrity of any part of the study are appropriately investigated and resolved.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements:\u003c/strong\u003e The authors sincerely thank Zahra Khoshouei for her valuable assistance and constructive input during this study.\u003c/p\u003e"},{"header":" References","content":"\u003col\u003e\n\u003cli\u003eLi X, Yang Y, Zhang B, Lin X, Fu X, An Y, et al. Lactate metabolism in human health and disease. Signal Transduct Target Ther. 2022;7(1):305.\u003c/li\u003e\n\u003cli\u003eKraut JA, Madias NE. Lactic acidosis. N Engl J Med. 2014;371(24):2309-19.\u003c/li\u003e\n\u003cli\u003eMoustafa AA, Elhadidi AS, El-Nagar MA, Hassouna HM. Can Lactate Clearance Predict Mortality in Critically Ill Children? J Pediatr Intensive Care. 2023;12(2):112-7.\u003c/li\u003e\n\u003cli\u003eKushimoto S, Akaishi S, Sato T, Nomura R, Fujita M, Kudo D, et al. Lactate, a useful marker for disease mortality and severity but an unreliable marker of tissue hypoxia/hypoperfusion in critically ill patients. Acute Med Surg. 2016;3(4):293-7.\u003c/li\u003e\n\u003cli\u003eRhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Med. 2017;43(3):304-77.\u003c/li\u003e\n\u003cli\u003eMunde A, Kumar N, Beri RS, Puliyel JM. Lactate clearance as a marker of mortality in pediatric intensive care unit. Indian Pediatr. 2014;51(7):565-7.\u003c/li\u003e\n\u003cli\u003eBakker J, Gris P, Coffernils M, Kahn RJ, Vincent JL. Serial blood lactate levels can predict the development of multiple organ failure following septic shock. Am J Surg. 1996;171(2):221-6.\u003c/li\u003e\n\u003cli\u003eKrishna U, Joshi SP, Modh M. An evaluation of serial blood lactate measurement as an early predictor of shock and its outcome in patients of trauma or sepsis. Indian J Crit Care Med. 2009;13(2):66-73.\u003c/li\u003e\n\u003cli\u003eChertoff 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.\u003c/li\u003e\n\u003cli\u003eMarty P, Roquilly A, Vall\u0026eacute;e F, Luzi A, Ferr\u0026eacute; F, Fourcade O, et al. 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.\u003c/li\u003e\n\u003cli\u003evan Genderen ME, Klijn E, Lima A, de Jonge J, Sleeswijk Visser S, Voorbeijtel J, et al. Microvascular perfusion as a target for fluid resuscitation in experimental circulatory shock. Crit Care Med. 2014;42(2):e96-e105.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 5 are available in the supplementary files section\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bped","sideBox":"Learn more about [BMC Pediatrics](http://bmcpediatr.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bped/default.aspx","title":"BMC Pediatrics","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Lactate, Clearance, Resuscitation, Mortality, pediatric intensive care unit, prognostic value","lastPublishedDoi":"10.21203/rs.3.rs-8775242/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8775242/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eLactate clearance is considered a reliable indicator of tissue perfusion and treatment response in critically ill patients. However, its prognostic significance in pediatric intensive care units has not been adequately defined. This study aims to investigate the prognostic value of lactate clearance in pediatric patients admitted to the intensive care unit of Bandar Abbas Children’s Hospital, Iran.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethod:\u003c/strong\u003e In this prospective cross-sectional study, critically ill children aged 1 month to 17 years admitted to the pediatric intensive care unit of Bandar Abbas Children’s Hospital, Iran, were consecutively enrolled. Arterial lactate levels were obtained at admission and at 6 and 24 hours, and lactate clearance was calculated. Clinical outcomes (survival or death) were recorded. Receiver operating characteristic curve analysis was performed to evaluate the prognostic performance of lactate clearance. The chi-square test and analysis of variance (ANOVA) were used, and a p-value \u0026lt; 0.05 was considered statistically significant.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResult:\u003c/strong\u003e \u0026nbsp;A total of 169 children admitted to the pediatric intensive care unit were included, of whom 54 (31.9%) died; 59.3% were male, and the mean age was 7.56±1.03 years. Admission lactate clearance was not a reliable predictor of clinical outcome (P=0.064). In contrast, lactate clearance at 6 and 24 hours demonstrated high sensitivity for outcome prediction (97.39% and 94.78%, respectively). Comparative analysis showed that 24-hour lactate clearance, with a cut-off value of 48.7, exhibited superior prognostic performance.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003eTwenty-four-hour lactate clearance appears to be a useful prognostic indicator in critically ill pediatric patients admitted to the PICU. Lactate monitoring allows for a more accurate assessment of treatment response and improved risk stratification.\u003c/p\u003e","manuscriptTitle":"Prognostic Value of Lactate Clearance in Critically Ill Pediatric Patients Admitted to the Intensive Care Unit: A Single-Center Study from Southern Iran","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-11 12:03:08","doi":"10.21203/rs.3.rs-8775242/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2026-03-16T09:22:05+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-11T12:34:38+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"196255862577785149901157364210356383213","date":"2026-03-06T20:29:59+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"332065590787146080519268338643180707618","date":"2026-03-06T08:49:16+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-03-06T05:34:26+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-03-04T09:05:27+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-02-10T04:38:10+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-02-09T11:15:32+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Pediatrics","date":"2026-02-09T11:02:22+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bped","sideBox":"Learn more about [BMC Pediatrics](http://bmcpediatr.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bped/default.aspx","title":"BMC Pediatrics","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"d43b9d3f-5abb-4c02-af8a-d7feaa2a17ca","owner":[],"postedDate":"March 11th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-03-11T12:03:08+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-11 12:03:08","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8775242","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8775242","identity":"rs-8775242","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}