Study of Early Lactate Clearance as an Independent Predictor of Survival in Patients with Presumed Sepsis

Aim: Measurement of serial serum lactate levels in patients presenting with sepsis and correlating with 1. early lactate clearance with mortality. 2. Early lactate clearance vs. first (baseline) lactate level in mortality prediction. 3. Early lactate clearance vs. ACUTE PHYSIOLOGY AND CHRONIC HEALTH EVALUATION II score in mortality prediction. 4. Early lactate clearance vs. non lactate clearance in mortality prediction. 50 patients male, females; Patient with sepsis were selected from Medicine ICU by using ACUTE PHYSIOLOGY AND CHRONIC HEALTH EVALUATION II score ≥ 12 points. Lactate levels at 0, 6, 12, 24 and 48 hours were measured by using ABG done by ABL 800 basic analyzer. ACUTE PHYSIOLOGY AND CHRONIC HEALTH EVALUATION II score was calculated on admission. Lactate clearance was calculated (<10% OR >10%) and was correlated with mortality (< 7 days or > 7 days). Results: Among 50 patients studied, 39 patients were in lactate clearance group and 11 patients were in lactate non-clearance group. In lactate clearance group 35 (89%) patients survived and 4 (11%) patients expired. In lactate non-clearance group 9 (81%) patients expired and 2 (19%) patients survived. On observing the lactate trend, Serial serum lactate levels were decreasing in survived patients while serial serum lactate levels were static or increasing in expired patients. There was no correlation between serum lactate at 0 hour and mortality in the study group (p value > 0.05). There was correlation between serum lactate at 6, 12, and 24 hours with mortality (p value <0.05). There was strong correlation between serum lactate clearance and mortality (p value < 0.01). Conclusion: Study confirmed the prognostic value of serial serum lactate monitoring and its clearance for prediction of mortality. We concluded that early lactate clearance could be used as an independent predictor of survival in patients with presumed sepsis.

(11%) patients expired. In lactate non-clearance group 9 (81%) patients expired and 2 (19%) patients survived. On observing the lactate trend, Serial serum lactate levels were decreasing in survived patients while serial serum lactate levels were static or increasing in expired patients. There was no correlation between serum lactate at 0 hour and mortality in the study group (p value > 0.05). There was correlation between serum lactate at 6, 12, and 24 hours with mortality (p value <0.05). There was strong correlation between serum lactate clearance and mortality (p value < 0.01). Conclusion: Study confirmed the prognostic value of serial serum lactate monitoring and its clearance for prediction of mortality. We concluded that early lactate clearance could be used as an independent predictor of survival in patients with presumed sepsis.

INTRODUCTION
Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection [1]. Clinical organ dysfunction [presumed sepsis] can be represented by an increase in the Sequential [Sepsis-related] Acute Physiology And Chronic Health Evaluation II score of 12 points or more, which is associated with in-hospital mortality greater than 10%. Sepsis is the most common cause of lactic acidosis, and septic patients with lactic acidosis show a higher mortality rate [2,3].
Lactic acidosis is a medical condition characterized by the buildup of lactate (especially L-lactate) in the body, with formation of an excessively low pH in the bloodstream. It is a form of metabolic acidosis, in which excessive acid accumulates due to a problem with the body's oxidative metabolism. Lactic acidosis is typically the result of an underlying acute or chronic medical condition, medication, or poisoning. The symptoms are generally attributable to these underlying causes, but may include nausea, vomiting, Kussmaul breathing (labored and deep), and generalized weakness. The etiology of lactic acidosis in sepsis is complex. It may result from either impaired lactate clearance or increased lactate production [4]. Therefore, increased or sustained lactate levels represent severe sepsis or septic shock. Lactate level has also been used as a prognostic indicator for mortality. In particular, the patients with an initial lactate level ≥ 3.0 mmol/L had higher mortality risks, and the probability of death was substantially increased with a high initial lactate level [5]. Some of the studies reported that lactate clearance, derived from calculating the change in lactate levels at different times, may have potential prognostic value [6,7,2].
These studies have proved that a decrease in these markers within the first several hours may be predictive of a favorable outcome. However, no study has yet examined which factor is the most important mortality risk factor among initial lactate, lactate clearance, or inflammatory markers in severe sepsis patients with lactic acidosis. Lactate elevation is an important marker of impaired tissue perfusion in patients with sepsis and is often elevated even in the absence of arterial hypotension [8]. Blood lactate concentrations ≥3 mmol/L are unusual in normal and non-critically ill hospitalized patients, regardless of their underlying comorbidities [9].

Inclusion and Exclusion Criteria
The inclusions criteria were Patients admitted in Medicine ICU. Patients had sepsis ≥ 12 ACUTE PHYSIOLOGY AND CHRONIC HEALTH EVALUATION II score and lactate level in ABG ≥3 mmol/L. Patients of sepsis had normal lactate level were excluded. Also, patients had hyperlactatemia due to any other causes apart from sepsis like Ethanol poisoning, Aluminum Phosphide, Cardiogenic shock, Hemorrhagic shock, Severe liver dysfunction, Diabetic ketoacidosis, Trauma, Burns, Seizures and Drugs were excluded.

Study Design
Patient with sepsis were selected from Medicine ICU by using ACUTE PHYSIOLOGY AND CHRONIC HEALTH EVALUATION II score ≥ 12 points. Lactate levels at 0, 6, 12, 24 and 48 hours were measured by using ABG done by ABL 800 basic analyzer. ACUTE PHYSIOLOGY AND CHRONIC HEALTH EVALUATION II score was calculated on admission. Lactate clearance was calculated (<10% OR >10%) and was correlated with mortality (< 7 days or > 7 days).

Statistical Analysis
Data was entered in MS EXCEL Spread sheet and analyzed with the help of Openepi & spss software version 2.0. The statistical analysis was done by appropriate Statistical method. Descriptive statistic was explained by frequency and percentage.
Chi-Square test was applied.
Out of 50 patients 37 (74%) patients survived and 13 (26%) patients did not survive more than 7 days. The data showed in Table 2 for survival  patients and Table 3 for expired patients.

Discussion
In this multicenter model of patients with severe sepsis. We found that early lactate clearance was a strong independent analyst of in-hospital death. The cause of raised serum lactate in patients with sepsis can be multifactorial. Lactate elevation may result from acute tissue hypoperfusion and anaerobic metabolism other possible causes may contain (a) sepsis encouraged impairment of pyruvatedehydrogenase enzyme activity, (b) increased lactate production through catechol amine-driven pathways, and (c) decreased lactate clearance due to hepatic disfunction [2,3,4].
Regardless of etiology of an elevated serum lactate, lactate elevation in sepsis has been dependably linked to increased mortality. Initial reports of lactate clearance in sepsis were published more than 16 years ago, evaluating lactate trends in dangerous patients are not yet part of the current consensus recommendations for sepsis management and is not routinely performed in practice. Our data show that assessment of lactate clearance is significant as a predictor of mortality. These data suggest that serial lactate measurement may provide unique and important information. Total 50 patients were registered in our study. The age range was from 18 years to 82 years. The mean age of the study population was 48 years. The maximum numbers of patients were found in the age group of 18-35 years and they constitute about 34% of the study population [4,6].
In our study the numbers of males were 36 (72 %) and females were 14 (28%). 13 (26%) patients had ARDS and 12 (24%) patients had community acquired pneumonia. So, 25 (50%) of patients had respiratory system involvement. Septicemia of unknown etiology was second most common diagnosis which included 13 (26%) patients. Rest of the patients had pyelonephritis 4 (8%), inflammatory bowel disease 2 (4%), spontaneous bacterial peritonitis 4 (8%), and meningitis 2 (4%). We had compared our study with a reference study of Arnold et al. which is multicenter prospective study of 166 patients which was published in SHOCK (Augusta Ga.) international journal in august 2009 [10]. In our study, 39 patients were in lactate clearance group out of which 35 (89%) survived and 4 (11%) expired. While Arnold et al. study had survival rate of 122(81%) in lactate clearance group of 151 patients. Both studies had p-value < 0.01, so there is significant correlation between serum lactate clearance and mortality. There were several shortcomings in this study including the small sample size, short follow up and single center study. All our patients were not culture proven sepsis. Larger multicentric studies with longer duration of patients' follow up will be useful.

CONCLUSION
Our study confirms the prognostic value of serial serum lactate monitoring and its clearance for prediction of mortality. Lactate values probably need to be followed for longer periods of time in critical patients even when they have tided over the present crisis. This study indicates that it is better to monitor serial lactate levels rather than going for single lactate value. If lactate levels are static or increasing than prognosis is grave and if its clearing than prognosis is good. The serial serum lactate levels between 6 hours to 36 hours are best predictor of mortality. We conclude that early lactate clearance can be used as an independent predictor of survival in patients with presumed sepsis.

ETHICAL APPROVAL AND CONSENT
The study was directed with the approval of the Institutional Ethical Committee. Volunteers eligible for the study were well-versed of the potential risks and benefits of the medication. Before the start of the study, volunteers signed consent forms. They were recruited in Department of General Medicine at SMIMER, Surat, Gujarat, India.