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Is vasoactive-inotropic score associated with early lactate clearance a predictive outcome of children with septic shock?

Background. The main goal of septic shock therapy is to keep hemodynamic parameters in the normal range for adequate tissue perfusion. Persistent lactic acidemia has increased mortality. We evaluate the association between vasoactive-inotropic score (VIS) and lactate clearance (LC) to predict mortality of septic shock in children. Methods. This is a retrospective study of consecutive septic shock in children admitted to the pediatric intensive care unit. Vital signs, laboratory values, and VIS were obtained at admission and the 6th hour of hospitalization. LC was calculated at the 6 th hour. The associations between LC and VIS were evaluated using univariate and multivariate analysis. Receiver operating characteristic analysis was used to describe the cutoff values of LC and VIS. Results. Eighty-two children, age 82.3 ± 59.8 months, were included, with an overall lactate clearance of 29 ± 26%, and a mortality rate of 25.6%. The optimal cutoff value of LC was 20%. Children with LC ≥ 20% compared with LC < 20% had a lower VIS [(21.41 ± 8.36) vs. (27.48 ± 10.11) (p: 0.009)]. In multivariate comparison, PELOD score and VIS were significantly associated with 6-hour lactate clearance < 20% but VIS at 6 hours had a significant inverse relationship with LC < 20%. The cutoff for VIS was ≥ 16.2 for prognosticating the 6-hour LC and the high VIS group had a significantly lower LC and higher mortality ratio than the low VIS group. Conclusions. High VIS was associated with lower lactate clearance and has been described as a predictor of greater mortality among septic shock in children.

Septic shock is characterized as a subset of sepsis in which especially severe cardiovascular collapse and abnormalities of cellular metabolism are related to increased mortality risk. 1 Early identification of septic shock and effective resuscitation within the first few hours may prevent the progression of shock and organ failure. 2 Elevated serum lactic acid level is an indicator of anaerobic metabolism and is accepted to be a useful biomarker of reduced tissue perfusion in septic shock patients. 3 Although serum lactate is commonly used to evaluate tissue perfusion in the intensive care unit, lactate clearance (LC) may be more beneficial than the baseline lactate level for assessing patient outcomes. 4,5 For adult patients with septic shock, maintaining mean arterial pressure (MAP) > 65mm Hg is recommended. 6 In the pediatric age group, a certain MAP value has not been determined, however, the goal of MAP is suggested between the 5th and 50th percentile or higher than the 50th percentile for age. 7 It was reported that hypoperfusion was associated with increased mortality risk regardless of the concomitant hypotension. 8 In pediatric septic shock, vasoactive-inotropic scores (VIS) are utilized to improve cardiovascular dysfunction and hypotension, however, increasing VIS is associated with the severity of cardiovascular dysfunction and mortality risk. 9,10 The mortality rate of hypotensive children requiring vasoactive agent with lactic acid greater than 2 mmol/L was higher than children with lactate less than 2 mmol/L. 11 Multiple variables such as high serum lactate, low LC, presence of multiorgan dysfunction syndrome, and high inotropic score have been determined as mortality prognosticator factors for septic shock. 4,10 According to our knowledge, the association between VIS and early LC in septic shock children has not been researched yet. This research was performed to evaluate whether VIS might be used to predict LC of patients after sufficient resuscitation therapy in septic shock children.

Patient population
This is a retrospective, observational singlecenter research that was performed to analyze the relationship between LC and VIS in septic shock patients who were admitted to the tertiary level pediatric intensive care unit (PICU) from March 2020 to January 2022. This study was approved by the Afyonkarahisar Health Science University Faculty Ethics Committee (date: 07.01.2022, no: 2022/1). Children aged 1 month to 18 years old who were diagnosed with septic shock enrollment. Septic shock was described based on International Consensus Conference on Pediatric Sepsis. 12 All children needed central venous catheterization for continuous inotropic infusion, medical therapy, and oxygenation monitoring. Hemodynamic support was managed according to the prescribed guidelines. 9 Restoration of tissue perfusion was defined by the following targeted resuscitation endpoints 9 : Broad-spectrum antibiotics were administered after blood cultures were taken. Children were supported by mechanical ventilation as needed.

Exclusion criteria
The study exclusion criteria were: 1) patients aged > 18 years or < 1 month 2) patients with serious hepatic disease 3) disease of inborn errors of metabolism 4) missing lactate data 5) staying for <24 hours in the Pediatric Intensive Care Unit 6) patients requiring renal replacement therapy within the first 6 hours of PICU admission.

Collection of blood samples
The baseline clinical and demographic information including age, sex, initial vital signs (heart rate, mean arterial pressure, and temperature), peripheral oxygen saturation, and the need for mechanical ventilation, the length of intensive care unit, outcome, and laboratory values at the time of admission were noted. The Pediatric Logistic Organ Dysfunction Score (PELOD) and Pediatric Risk of Mortality III score (PRISM III score) were calculated to determine the severity of the disease on admission. Lactate level in the blood was measured on admission to PICU and was accepted as the initial (0th) lactate level. More than two serum lactate values may be obtained within 6 hours, but only the initial and lactate at 6-hour values were analyzed. VIS contains dopamine, dobutamine, epinephrine, norepinephrine, vasopressin, and milrinone defines the amount of cardiovascular support required by patients (Fig. 1). 13 Data were acquired from patient files and an electronic hospital data management system.

Biochemical analysis
Lactate measurements were done by Radiometer Copenhagen ABL 555 blood gas analyzer. Lactate clearance (%) was calculated as follows: lactate at admission minus lactate at 6 hours, divided by lactate at admission, and then multiplied by 100. A positive result shows a reduction of LC, whereas a negative result shows an increase of LC after 6 hours.

Statistical analysis
In the univariable analysis, continuous parameters are described as mean ± standard deviation (SD) for normal distribution, median and interquartile range (IQR) for skewed distribution, and nonparametric data. Categorical parameters were evaluated by using the Chi-square test. Mann Whitney-U test was used for non-parametric parameters and the Student t-test was performed for normally distributed data. The significant parameters in the univariate comparison were then included in a multivariate logistic regression model. Cutoff levels of the VIS and LC were calculated by using the receiver operating characteristic curves (ROC curves). For all results, a p-value < 0.05 was regarded as the significance level. SPSS Statistics 22 software was used for the analysis of data.

Results
During the study period, a total of eightysix children with septic shock were recorded. According to the exclusion criteria, four patients were excluded. Baseline characteristics, vital signs of the patients, and initial laboratory data are demonstrated in Table I. Mean patient age was 82.3 ± 59.8 months, and 29 (35%) were   Fig. 3). Based on the VIS score cutoff value patients were divided into two groups: VIS ≥ 16.2 (high VIS group) and VIS < 16 (low VIS group). Although there was no significant differentiation between initial and 6 th -hour lactate values, the high VIS group had significantly lower LC than the low VIS group (p: 0.01). Thrombocyte count was higher in the low VIS group (p: 0.01). The base deficit at the 6 th hour was more negative in the high VIS group after resuscitation (p: 0.02). The high VIS score group had a significantly higher 28-day mortality rate (p: 0.02) (Table IV).

Discussion
The present research is a retrospective clinical research that analyzes the relationship between vasoactive-inotropic score and lactate clearance of septic shock children after resuscitation. The main results of this research are as follows. Firstly, some septic shock patients had high lactate levels and poor lactate clearances after resuscitation of intravenous fluid therapy and vasoactive medications. Mean arterial pressure, hemoglobin concentration, peripheral oxygen saturation, and temperature, which are essential for perceiving of production and consumption of lactate were not sufficient to accurately predict LC after resuscitation. Secondly, VIS was associated with LC closely and had high sensitivity and specificity for the prediction of 6 th hour LC after resuscitation in pediatric patients with septic shock. Finally, LC was found as inversely associated with hospital mortality in pediatric septic shock and patients with higher VIS had an increased mortality rate.
In critical illness, the benefit of evaluation of the lactate level has demonstrated that measurement of serum lactate values has an important role in the understanding of mortality risk. 14 During the early stage of resuscitation, values of lactate appear to be more nearly interested in mortality than hemodynamic variables. 15 Several types of research have emphasized that increased lactate values are a powerful sign to predict a high probability of mortality and morbidity ratio in critically ill patients, furthermore increasing LC decreases the odds of mortality at 24 hour. 16 Numerous septic shock patients who still have hyper lactic acidemia after completion of effective fluid resuscitation have a poor prognosis. 17 The significance of monitoring of lactate trend from high lactate value to normal lactate levels has been highlighted in Surviving Sepsis Campaign Guideline in 2016. 2 In this present study has a convenient outcome to previous research such as mortality was significantly higher among patients with lower LC.
Inotropic agents are routinely used to ensure cardiovascular support for adequate delivery of oxygen and tissue perfusion in septic shock children. 10 VIS is a clinical instrument that is used to understand the inotropic requirement of the cardiovascular system and can be utilized to predict morbidity and mortality. 18 VIS is independently associated with outcomes including ventilator days, length of hospital stay, and mortality in patients with sepsis. 19 Nguyen et al. 20 showed that hemodynamic parameters were similar between groups in patients with septic shock, while vasopressor dosage was significantly higher in the low LC group. Nazir et al. 16 presented that mean arterial pressure, central venous pressure, and VIS in the first 72 hours were not significantly different between high and low LC groups. Another previous study demonstrated that hemodynamic variables including mean arterial pressure, central venous pressure, central venous oxygen saturation, and central venous-to-arterial CO 2 difference were not useful to predict LC after resuscitation, but norepinephrine dose was better for prediction of LC. 21 We found that hemodynamic measurements were not useful to predict the early LC in this study, whereas VIS > 16.2 can predict early LC with high sensitivity and specificity after 6-hour resuscitation. Additionally, VIS was positively associated with increased mortality.
Walker et al. 19 reported that an optimal cutoff level of 6th hour LC was found at 36% which was independently associated with hospital mortality and also greater than the previously reported value. In another study, the Cutoff value of LC was calculated at 10% which predicted hospital mortality with maximum sensitivity and specificity. 5 In this research, we found an optimal cutoff of LC < 20% that is consistent with other research related to LC in septic shock patients, and also LC was inversely associated with risk of mortality.
Our research has some limitations. Firstly, this study was a retrospective clinical investigation and there was a risk of bias due to the limited number of cases. Secondly, it was a single-center study and institution-specific parameters may have affected the outcomes. Furthermore, one could discuss that all patients did not receive a similar antibiotic regimen that might affect lactate production.
As a conclusion, this is the first study to assess the association between LC and VIS to predict mortality among pediatric patients with septic shock. We perceived that some children with septic shock still had poor tissue oxygen metabolism after ensuring normal hemodynamic parameters. A high VIS may be associated with deterioration of tissue oxygen metabolism. After sufficient resuscitation, vasoactive inotropic drug doses should be withdrawn without causing permanent impairment in tissue oxygen metabolism in septic shock. Further prospective research is fundamental to better understand the relationship between lactate clearance and vasoactive-inotropic score in pediatric septic shock.