Etiology and Therapeutic Approach to Elevated Lactate Levels

doi:10.1016/j.mayocp.2013.06.012

Mayo Clinic Proceedings

Volume 88, Issue 10, October 2013, Pages 1127-1140

https://doi.org/10.1016/j.mayocp.2013.06.012 Get rights and content

Abstract

Lactate levels are commonly evaluated in acutely ill patients. Although most often used in the context of evaluating shock, lactate levels can be elevated for many reasons. While tissue hypoperfusion may be the most common cause of elevation, many other etiologies or contributing factors exist. Clinicians need to be aware of the many potential causes of lactate level elevation as the clinical and prognostic importance of an elevated lactate level varies widely by disease state. Moreover, specific therapy may need to be tailored to the underlying cause of elevation. The present review is based on a comprehensive PubMed search between the dates of January 1, 1960, to April 30, 2013, using the search term lactate or lactic acidosis combined with known associations, such as shock, sepsis, cardiac arrest, trauma, seizure, ischemia, diabetic ketoacidosis, thiamine, malignancy, liver, toxins, overdose, and medication. We provide an overview of the pathogenesis of lactate level elevation followed by an in-depth look at the varied etiologies, including medication-related causes. The strengths and weaknesses of lactate as a diagnostic/prognostic tool and its potential use as a clinical end point of resuscitation are discussed. The review ends with some general recommendations on the management of patients with elevated lactate levels.

Section snippets

Physiology and Pathogenesis

Lactate is produced by most tissues in the human body, with the highest level of production found in muscle.3, 4 Under normal conditions, lactate is rapidly cleared by the liver, with a small amount of additional clearance by the kidneys.3, 5 In aerobic conditions, pyruvate is produced via glycolysis and then enters the Krebs cycle, largely bypassing the production of lactate. Under anaerobic conditions, lactate is an end product of glycolysis and feeds into the Cori cycle as a substrate for

Measurement

Lactate levels can be rapidly and easily measured in most clinical settings. A recent review by Kruse et al⁷ on the measurement of lactate levels concluded that peripheral venous lactate levels are highly correlated with arterial blood lactate levels, thus establishing that either method can be used. Tourniquet use during blood collection and the routine use of ice for transportation do not affect lactic acid levels provided the samples are measured within 15 minutes using a point-of-care

Etiologies of Elevated Lactate Levels

There are a multitude of causes for elevated lactate levels (Table 1). Recently, most of the medical literature on the importance of lactate levels has focused on septic shock, and this literature-based selection bias may lead clinicians to associate elevated lactate levels with sepsis alone. However, any form of shock or tissue hypoperfusion will result in elevated lactate levels, and a variety of causes of elevated lactate levels exist independent of shock states. The following subsections

Pharmacologic Agents and Toxins Associated With Elevated Lactate Levels

A variety of medications and toxins associated with elevated lactate levels are listed in Table 2.61, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131 Owing to the rarity of most of these clinical scenarios, there is a lack of research on treatment options, and some of the associations are highly suspected but not fully proved. Treatment choice should be based on the specific clinical scenario, and current

Approach to the Patient With an Elevated Lactate Level

In broad terms, elevated lactate levels can be divided into 2 categories: cases in which it is driven by hypoperfusion/hypoxemia and cases in which it is not. The hypoperfusion-driven cases include all forms of shock, the post–cardiac arrest state, and regional ischemia. In all of these clinical scenarios, lactate levels that remain elevated are often important prognostically, and treatment is aimed at improving perfusion to the affected tissues. In shock, treatment can involve volume

Lactate Clearance as an End Point of Resuscitation

As described previously, effective lactate clearance has been associated with decreased mortality in a variety of settings and conditions. Conversely, failure to clear lactate portends a worse outcome. In patients with presumed tissue hypoperfusion (eg, septic shock), failure to clear lactate should prompt reassessment of the resuscitation effort. As discussed throughout this article, lactate level elevation may derive from any of a variety of sources. Persistent lactate level elevation may

Limitations and Pitfalls of Interpreting Elevated Lactate Levels in Clinical Practice

As reviewed herein, the etiologies of lactate level elevation are varied (Table 1). The clinical importance of elevated lactate levels also varies widely (Figure 2). This difference highlights the importance of considering all potential etiologies in the initial evaluation and using the test result in context with the overall clinical picture. In addition, multiple reasons for lactate level elevation can be present in a given patient, making interpretation challenging. Given the variety of

Conclusion

Elevated lactate levels are encountered in a multitude of clinical presentations and disease states. Patients with elevated lactate levels may be at risk for considerable morbidity and mortality and require a prompt, thoughtful, and systematic approach to diagnosis and treatment. Despite the limitations and complexities discussed, a lactate level is an easily measured laboratory variable that can provide useful bedside information for the clinician when incorporated into the appropriate

Acknowledgments

We thank Francesca Montillo for her editorial assistance in preparing the submitted manuscript and Amy Uber and Michael Ganetsky, MD, for their contributions to the manuscript content.

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Cited by (463)

A Predictive Model for Thiamine Responsive Disorders Among Infants and Young Children: Results from a Prospective Cohort Study in Lao People's Democratic Republic
2024, Journal of Pediatrics
To develop a predictive model for thiamine responsive disorders (TRDs) among infants and young children hospitalized with signs or symptoms suggestive of thiamine deficiency disorders (TDDs) based on response to therapeutic thiamine in a high-risk setting.
Children aged 21 days to <18 months hospitalized with signs or symptoms suggestive of TDD in northern Lao People’s Democratic Republic were treated with parenteral thiamine (100 mg daily) for ≥3 days in addition to routine care. Physical examinations and recovery assessments were conducted frequently for 72 hours after thiamine was initiated. Individual case reports were independently reviewed by three pediatricians who assigned a TRD status (TRD or non-TRD), which served as the dependent variable in logistic regression models to identify predictors of TRD. Model performance was quantified by empirical area under the receiver operating characteristic curve.
A total of 449 children (median [Q1, Q3] 2.9 [1.7, 5.7] months old; 70.3% exclusively/predominantly breastfed) were enrolled; 60.8% had a TRD. Among 52 candidate variables, those most predictive of TRD were exclusive/predominant breastfeeding, hoarse voice/loss of voice, cyanosis, no eye contact, and no diarrhea in the previous 2 weeks. The area under the receiver operating characteristic curve (95% CI) was 0.82 (0.78, 0.86).
In this study, the majority of children with signs or symptoms of TDD responded favorably to thiamine. While five specific features were predictive of TRD, the high prevalence of TRD suggests that thiamine should be administered to all infants and children presenting with any signs or symptoms consistent with TDD in similar high-risk settings. The usefulness of the predictive model in other contexts warrants further exploration and refinement.
Clinicaltrials.gov NCT03626337.
Lactate combined with SOFA score for improving the predictive efficacy of SOFA score in patients with severe heatstroke
2024, American Journal of Emergency Medicine
The relationship between lactate levels and multiple organ dysfunction in patients with severe heatstroke remains unclear. In this study, we aimed to elucidate the clinical significance of lactate in severe heatstroke prognosis and assess whether incorporating lactate in the SOFA score improves its predictive efficacy.
This study was a multicenter retrospective cohort investigation included 275 patients. Logistic regression analysis was performed to examine the relationship between lactate levels and patient outcomes and complications, including acute kidney injury (AKI), disseminated intravascular coagulation (DIC), and myocardial injury. Further, receiver operating characteristic (ROC) curves and clinical decision curve analysis (DCA) were used to evaluate the predictive power of lactate and SOFA scores in severe heatstroke-associated death. Lastly, the Kaplan–Meier survival curve was employed to differentiate the survival rates among the various patient groups.
After adjusting for confounding factors, lactate was demonstrated as an independent risk factor for death (OR = 1.353, 95% CI [1.170, 1.569]), AKI (OR = 1.158, 95% CI [1.007, 1.332]), DIC (OR = 1.426, 95% CI [1.225, 1.659]), and myocardial injury (OR = 2.039, 95% CI [1.553, 2.679]). The area under the curve (AUC) of lactate for predicting death from severe heatstroke was 0.7540, with a cutoff of 3.35. The Kaplan–Meier survival curve analysis showed that patients with elevated lactate levels had higher mortality rates. Additionally, the ROC curves demonstrated that combining lactate with the SOFA score provided better predictive efficacy than the SOFA score alone in patients with severe heatstroke (AUC: 0.9025 vs. 0.8773, DeLong test, P < 0.001). Finally, the DCA curve revealed a higher net clinical benefit rate for lactate combined with the SOFA score.
Lactate is an independent risk factor for severe heatstroke-related death as well as a risk factor for AKI, DIC, and myocardial injury associated with severe heatstroke. Thus, combining lactate with the SOFA score can significantly improve its predictive efficacy in patients with severe heatstroke.
Development of a nomogram to predict 30-day mortality of sepsis patients with gastrointestinal bleeding: An analysis of the MIMIC-IV database
2024, Heliyon
We aimed to establish and validate a prognostic nomogram model for improving the prediction of 30-day mortality of gastrointestinal bleeding (GIB) in critically ill patients with severe sepsis.
In this retrospective study, the current retrospective cohort study extracted data from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database, then partitioned the cohort randomly into training and validation subsets. The cohort was partitioned into training and validation subsets randomly. Our primary endpoint was 30-day all-cause mortality. To reduce data dimensionality and identify predictive variables, the least absolute shrinkage and selection operator (LASSO) regression was employed. A prediction model was constructed by multivariate logistic regression. Model performance was evaluated using the concordance index (C-index), receiver operating characteristic (ROC) curve, and decision curve analysis (DCA).
The analysis included 1435 total patients, comprising 1005 in the training cohort and 430 in the validation cohort. We found that age, smoking status, glucose, (BUN), lactate, Sequential Organ Failure Assessment (SOFA) score, mechanical ventilation≥48h (MV), parenteral nutrition (PN), and chronic obstructive pulmonary disease (COPD) independently influenced mortality in sepsis patients with concomitant GIB. The C-indices were 0.746 (0.700–0.792) and 0.716 (0.663–0.769) in the training and validation sets, respectively. Based on the area under the curve (AUC) and DCA, the nomogram exhibited good discrimination for 30-day all-cause mortality in sepsis with GIB.
For sepsis patients complicated with GIB, we created a unique nomogram model to predict the 30-day all-cause mortality. This model could be a significant therapeutic tool for clinicians in terms of personalized treatment and prognosis prediction.
Fasting plasma lactate as a possible early clinical marker for metabolic disease risk
2024, Diabetes and Metabolic Syndrome: Clinical Research and Reviews
Elevated fasting plasma lactate concentrations are evident in individuals with metabolic diseases. However, it has yet to be determined if these associations exist in a young, healthy population as a possible early marker for metabolic disease risk. The purpose of this study was to determine if indices of the metabolic syndrome are related to plasma lactate concentrations in this population.
Fifty (29 ± 7 yr) men (n = 19) and women (n = 31) classified as overweight (26.4 ± 1.8 kg/m²) participated in this observational study. Blood pressure and blood metabolites were measured after an overnight fast. Lactate was also measured before and after a three-day eucaloric high-fat (70 %) diet. The homeostatic model assessment for insulin resistance (HOMA-IR) was calculated as a measure of insulin resistance. Visceral adipose tissue mass was determined via dual X-ray absorptiometry.
Triglycerides (r = 0.55, p=<0.0001), HOMA-IR (r = 0.53, p=<0.0001), and systolic and diastolic (both, r = 0.36, p = 0.01) blood pressures associated with fasting plasma lactate. No differences in visceral adipose tissue existed between the sexes (p = 0.41); however, the relationship between visceral adipose tissue and lactate existed only in females (r = 0.59, p = 0.02) but not in males (p = 0.53). Fasting lactate and HOMA-IR increased in males (p = 0.01 and p = 0.02, respectively), but not females, following a three-day high-fat diet.
Indices of the metabolic syndrome associated with fasting plasma lactates in young relatively healthy individuals. Fasting lactate also increased in a sex-specific manner after a three-day high fat diet. Thus, lactate could become a clinical marker for metabolic disease risk.
Heart failure related cardiogenic shock: An ISHLT consensus conference content summary
2024, Journal of Heart and Lung Transplantation
In recent years, there have been significant advancements in the understanding, risk-stratification, and treatment of cardiogenic shock (CS). Despite improved pharmacologic and device-based therapies for CS, short-term mortality remains as high as 50%. Most recent efforts in research have focused on CS related to acute myocardial infarction, even though heart failure related CS (HF-CS) accounts for >50% of CS cases. There is a paucity of high-quality evidence to support standardized clinical practices in approach to HF-CS. In addition, there is an unmet need to identify disease-specific diagnostic and risk-stratification strategies upon admission, which might ultimately guide the choice of therapies, and thereby improve outcomes and optimize resource allocation. The heterogeneity in defining CS, patient phenotypes, treatment goals and therapies has resulted in difficulty comparing published reports and standardized treatment algorithms. An International Society for Heart and Lung Transplantation (ISHLT) consensus conference was organized to better define, diagnose, and manage HF-CS. There were 54 participants (advanced heart failure and interventional cardiologists, cardiothoracic surgeons, critical care cardiologists, intensivists, pharmacists, and allied health professionals), with vast clinical and published experience in CS, representing 42 centers worldwide. State-of-the-art HF-CS presentations occurred with subsequent breakout sessions planned in an attempt to reach consensus on various issues, including but not limited to models of CS care delivery, patient presentations in HF-CS, and strategies in HF-CS management. This consensus report summarizes the contemporary literature review on HF-CS presented in the first half of the conference (part 1), while the accompanying document (part 2) covers the breakout sessions where the previously agreed upon clinical issues were discussed with an aim to get to a consensus.
Clinical significance of serum lactate and lactate dehydrogenase levels for disease severity and clinical outcomes in patients with colorectal cancer admitted to the intensive care unit
2024, Heliyon
Serum lactate (LA) and lactate dehydrogenase (LDH) levels have a major impact on the clinical treatment of malignant tumors and critically ill patients. Nevertheless, the assessment of disease severity in oncology patients admitted to the intensive care unit (ICU) remains incomplete when considering the serum LA and LDH levels. This study aimed to investigate the significance of serum LDH and LA levels in assessing disease severity and predicting clinical outcomes in patients with colorectal cancer (CRC) admitted to the ICU.
This retrospective study included patients with CRC who were admitted to the ICU between January 2017 and December 2022. The patients were divided into three groups based on the tumor treatment methods they had received within 3 months before ICU admission: post-chemotherapy group, post-surgery group, and palliative treatment group. The association between serum LA and LDH levels and disease severity and clinical outcomes was analyzed.
Of 137 patients with CRC admitted to the ICU were finally studied. Patients in the post-chemotherapy group exhibited higher serum LA and LDH levels compared to those in the other two groups. Additionally, they had higher Acute Physiology and Chronic Health Evaluation (APACHE) II scores, longer ICU length of stay, and a higher 30-day mortality. We found a significant positive correlation between serum LA levels and APACHE II scores as well as ICU length of stay and 30-day mortality. In contrast, we only observed a significant positive correlation between serum LDH levels and disease severity in the post-chemotherapy group, whereas no significant correlation between LDH levels and 30-day mortality in any of the three groups.
Our study concludes that elevated serum LA levels, rather than LDH levels, are more effective in assessing disease severity and could be used as predictors for clinical outcomes in patients with CRC admitted to the ICU.

View all citing articles on Scopus

: Grant Support: Dr Donnino is funded via the National Heart, Lung, and Blood Institute (grant 1K02HL107447-01A1) and the National Center for Complementary and Alternative Medicine (grant 1R21AT005119-01).

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ReviewEtiology and Therapeutic Approach to Elevated Lactate Levels

Abstract

Section snippets

Physiology and Pathogenesis

Measurement

Etiologies of Elevated Lactate Levels

Pharmacologic Agents and Toxins Associated With Elevated Lactate Levels

Approach to the Patient With an Elevated Lactate Level

Lactate Clearance as an End Point of Resuscitation

Limitations and Pitfalls of Interpreting Elevated Lactate Levels in Clinical Practice

Conclusion

Acknowledgments

J Crit Care

Ann Emerg Med

Lancet

Crit Care Clin

Resuscitation

J Crit Care

Chest

Am J Surg

Ann Emerg Med

Resuscitation

Resuscitation

Injury

J Am Coll Surg

Am J Emerg Med

Am J Med

Chest

J Emerg Med

J Pediatr Surg

Burns

Burns

J Emerg Med

Ann Emerg Med

Lancet

Ann Emerg Med

Metabolism

J Hepatol

J Crit Care

Excess lactate: an index of reversibility of shock in human patients

Science

Clinical and Biochemical Aspects of Lactic Acidosis

Contribution of liver and skeletal muscle to alanine and lactate metabolism in humans

Am J Physiol

Lactate kinetics in human tissues at rest and during exercise

Acta Physiol (Oxf)

A model of L(+)-lactate metabolism in normal man

Ann Nutr Metab

D-lactic acidosis

Nutr Clin Pract

Blood lactate as a predictor for in-hospital mortality in patients admitted acutely to hospital: a systematic review

Scand J Trauma Resusc Emerg Med

Occult hypoperfusion and mortality in patients with suspected infection

Intensive Care Med

Serum lactate and base deficit as predictors of mortality in normotensive elderly blunt trauma patients

J Trauma

Definition of clinically relevant lactic acidosis in patients with internal diseases

Am J Clin Pathol

Lactic acidosis during sepsis is related to increased pyruvate production, not deficits in tissue oxygen availability

Ann Surg

Early microcirculatory perfusion derangements in patients with severe sepsis and septic shock: relationship to hemodynamics, oxygen transport, and survival

Ann Emerg Med

Determination of the effect of in vitro time, temperature, and tourniquet use on whole blood venous point-of-care lactate concentrations

Acad Emerg Med

International Federation of Clinical Chemistry (IFCC): Scientific Division: Committee on pH, Blood Gases and Electrolytes: approved IFCC recommendations on whole blood sampling, transport and storage for simultaneous determination of pH, blood gases and electrolytes

Eur J Clin Chem Clin Biochem

Preanalytical handling of samples for measurement of plasma lactate in HIV patients

Scand J Clin Lab Invest

The anion gap does not accurately screen for lactic acidosis in emergency department patients

Emerg Med J

Anion gap, anion gap corrected for albumin, and base deficit fail to accurately diagnose clinically significant hyperlactatemia in critically ill patients

J Intensive Care Med

Prognostic value and agreement of achieving lactate clearance or central venous oxygen saturation goals during early sepsis resuscitation

Acad Emerg Med

Outcome effectiveness of the severe sepsis resuscitation bundle with addition of lactate clearance as a bundle item: a multi-national evaluation

Crit Care

The prognostic value of blood lactate levels relative to that of vital signs in the pre-hospital setting: a pilot study

Crit Care

Increased blood lacate levels: an important warning signal in surgical practice

Crit Care

Review
Etiology and Therapeutic Approach to Elevated Lactate Levels