Predictive value of serum lactate dehydrogenase in diagnosis of septic shock in critical pediatric patients: A cross-sectional study

Hebat Allah Fadel Algebaly, Ahmed Abd-Elal, Rasha El Kaffas, Elshymaa Salah Ahmed?

1Pediatric Critical Care Department, Cairo University School of Medicine, Egypt

2Department of Clinical and Chemical Pathology, Cairo University School of Medicine, Egypt

ABSTRACT Objectives: To determine the predictive value of lactate dehydrogenase (LDH) in diagnosis of septic shock and its association with other prognostic scores in critical pediatric patients.Methods: A cross-sectional study was performed at Children’s Hospital of Cairo University between June 2019 and December 2019. A total of 200 pediatric patients were divided into the septic shock group [100 critically ill patients with septic shock from the pediatric intensive care unit (PICU)] and the control group (100 patients with only sepsis). LDH was determined in the first 24 hours of admission. The sensitivity and specificity of LDH in diagnosis of septic shock were assessed; the levels of related indicators of patients with different etiologies were compared; correlations between LDH, Paediatric Index of Mortality Ⅱ, and Pediatric Sequential Organ Failure Assessment (PSOFA) were analyzed.Results: LDH was 512 μL (406.50-663.00) in the septic shock group and was significantly higher than that (190 μL, range 160.00-264.50) in the control group (P＜0.001). Besides, median LDH in children with chest infecion was higher than that in children with other diagnoses (P=0.047). A good positive correlation was found between PSOFA and LDH (r=0.503, P＜0.001).Conclusions: LDH could be a potential inflammatory marker in diagnosis of septic shock and is valuable for PICU admission decisions.

KEYWORDS: Lactate dehydrogenase; Septic shock; Pediatrics version of the SOFA score

1. Introduction

Many cascade reactions involved in severe illness (e.g. sepsis)always begin with the pro-inflammatory process[1]. Lactate dehydrogenase (LDH) is one of the anaerobic metabolic pathway enzymes. Its serum level is elevated in multiple conditions resulting from tissue damage[2]. Several studies recorded a significant increase in LDH serum levels very early in sepsis[3]. Also, LDH levels have been proposed as a marker for sepsis prognosis[4]. They showed that LDH serum level was prognostically elevated in cases of severe sepsis and septic shock, and it is considered as an index to assess the extent to which the tissue was affected[5].

Besides, LDH was found associated with 28-day mortality in patients with severe sepsis[6]. Also, it has shown that pH, LDH and heart rate were the most important factors to assess the progress and outcome of a septic patient[7]. LDH level was found to be a prognostic marker for severe illness in neonates (e.g. early neonatal sepsis)[8]. Others said that if the LDH levels were not improved within 48 h in patients with severe sepsis, patients will be more likely to die[4].

Recently, LDH is considered a valuable biomarker in the diagnosis and follow-up of SARS-Cov-2 infection. One study concluded that LDH was a useful biomarker in the evaluation of case severity and for monitoring its response to treatment[9]. Another recommendation is successive measurements of LDH, C-reactive protein (CRP), and procalcitonin (PCT) in pediatric patients with COVID-19 infection as they may help follow the course of the illness[10]. Although there are a lot of studies on LDH, they have not explained the relation between LDH and severity in pediatric patients with sepsis.Moreover, several prognostic scores such as Sequential Organ Failure Assessment (SOFA) score and Paediatric Index of Mortality(PIM Ⅱ) score have been applied to assess the severity and predict the risk of death at PICU admission, which can be a guide for treatment and caring. PIM Ⅱ was first developed by Slateret al.in 1997, updated in 2003[11]. Also, the Sepsis-Related Organ Failure Assessment was developed initially to assess organ conditions in critically ill adults[12]. Recently, a pediatrics version of the SOFA score (PSOFA) was developed for critically ill children[13]. The score is composed of 6 variables for respiratory, cardiovascular, hepatic,coagulation, renal, and neurological systems, respectively[12]. This study aims to determine the predictive value of LDH in diagnosis of septic shock and its relationship with other proven prognostic scores.

2. Patients and methods

2.1. Study design

A cross-sectional, case-control study was performed at University Children Hospital from June 2019 till December 2019.

2.2. Ethical approval

The institutional review board at our institution approved our study with ethical approval No. I.101015.

2.3. Inclusion and exclusion criteria

We included patients with sepsis, severe sepsis, or septic shock who met the criteria of the American College of Critical Care Medicine[14]. The American College of Critical Care Medicine Clinical Practice Parameters for Hemodynamic Support of Pediatric and Neonatal Septic Shock 2012 defines septic shock by clinical signs, including hypothermia or hyperthermia, altered mental status,and peripheral vasodilatation (warm septic shock) or vasoconstriction with capillary refill time more than 2 seconds (cold septic shock)before hypotension occurs.

We excluded patients with lipid disorders, metabolic disorders,tumors, acute hemolytic anemia, chronic liver or kidney disease, and patients on steroid therapy.

2.4. Patients and grouping

Two hundred pediatric patients were grouped into the septic shock group (100 critically ill patients with septic shock from PICU) and the control group (100 patients with only sepsis).

2.5. Sample collection and assessments

The sample was taken for LDH assay as follows: 2 mL of whole blood were collected with plain tubes (BDO vacutainer). Samples were immediately centrifuged, and the serum was used for analysis through blood chemistry analyzer Dimension RXL M AX integrated chemistry system from Siemens Health care S.A.E, Germany I*.Principle of the enzymatic assay is that the reaction between pyruvate and Nicotinamide adenine dinucleotide dehydrogenase (NADH) is catalyzed by LDH to produce Nicotinamide adenine dinucleotide(NAD) andL-lactate: LDH+Pyruvate+NADH=L-lactate+NAD. The stronger the catalytic activity of LDH, the more NAD oxidation. It was estimated by measuring the decrease in absorbance at 340 nm.

Also, the PIMⅡscore at the time of admission was calculated. Ten items with yes or no answers for these variables scored as 1 or 0.These variables were entered into the system (www.sfar.org/scores2/pim22.html). The system calculates the mortality rate based on standard methods using logistic regression equations[11].

2.6. Statistical analysis

All data was analyzed using the Statistical Package Social Science(SPSS) version 16 and expressed as mean ± standard deviation (SD)or median and interquartile range (IQR). Differences in clinical and biochemical characteristics were analyzed by student’s paired and unpairedt-test and Mann-WhitneyUtest. Areas under curves was used to assess the specificity and sensitivity of LDH in diagnosis of spetic shock. Correlation analysis were conducted to determine the association between LDH and different parameters in the septic shock group. Kruskall WallisHtest was applied to assess the differences among diagnoses of septic shock regarding laboratory and clinical criteria. The significant level of this study was set at α=0.05.

3. Results

CRP in the septic shock group was 46.3 (23.35-80.80) mg/L,which was significantly higher than that in the control group of 11.00 (1.60-24.00) mg/L (P＜0.001). Serum glutamic-oxaloacetic transaminase (SGOT) in the septic shock group was 32.00 (22.00-56.50) μL, which was significantly higher than that in the control group of 23.00 (18.00-31.00) μL (P=0.001). Besides, LDH in the septic shock group was 512.00 (406.50-663.00) μL, which was significantly higher than that in the control group of (190.00(160.00-264.50) μL (P＜0.001) (Table 1). The cutoff point of 272 μL of LDH was a potential adjuvant for clinical evaluation and differentiation of septic shock from sepsis only with a sensitivity of 91% and specificity of 77% (Figure 1).

Also, our study revealed that there was a good positive correlation between LDH and liver enzyme (SGOT and SGPT) (r=0.581,P＜0.001;r=0.491,P＜0.001, respectively), and creatinine (r=0.202,P=0.043). Besides, the higher the PSOFA score, the higher the LDH(r=0.503,P＜0.001), unlikely with other score systems as PIM Ⅱ(r=0.034,P=0.738) (Figure 2) (Table 2) .

The results showed that the median of LDH in chest infection was higher than that in other diagnoses (P=0.047) (Table 3).

Table 1. Comparison of the clinical and laboratory criteria of the two groups.

Figure 1. Sensitivity and specificity curve for serum lactate dehydrogenase level.The area under curves is 0.9; Sensitivity: 91%; Sepecificity:77%; Green line:Reference line; Blue line: lactate dehydrogenase (μL).

Figure 2. Correlation between lactate dehydrogenase and Pediatrics version of the SOFA score. PSOFA: Pediatrics version of the SOFA score; LDH:Lactate dehydrogenase.

Table 2. Correlation between LDH and different parameters in the septic shock group (n=100).

4. Discussion

Last decade, a lot of biomarkers and scores have been developed for early diagnosis and assessment of severe illness in the Emergency Department[15]. LDH is the cornerstone in the diagnosis of different illnesses[16]. Erezet al.recorded a significant increase in serum level of LDH at the onset of sepsis[2].

Table 3. Differences among diagnoses of septic shock regarding laboratory and clinical criteria.

In our study, the median value of LDH in patients with severe sepsis/septic shock was 512 μL. A neonatal study by Ozkirazet al.described the usefulness of LDH and lactate in deciding to refer neonates who suffer from transient tachypnea of new born to highlevel neonatal care before the clinical situation deteriorates[17].

In our study, the cutoff value of 276 μL as a predictor for organ failure and the need for PICU admission with a sensitivity of 90%and specificity of 77% were able to distinguish septic shock and severe sepsis from sepsis only. Karlssonet al.concluded that LDH might be a significant value during the neonatal period, and its predictive value is more important than that of lactate. Preterm infants presented with a serum LDH level range of 500-700 μL with a cut-off of 600 μL were predicted to have a strong need for NICU admission[18].

Our study showed that LDH in chest infection was higher than that in other diagnoses (P=0.047). Another study shows LDH is a good biomarker for a limited list of diseases, mostly infections, particularly chest infection, tumor, liver metastases,and hematologic malignancies[19]. Hendyaet al.showed in a case presented with community-acquired pneumonia, LDH, albumin,CRP, and neutrophils should be determined to give an idea about the course, prognosis, and complication[20]. Pleural fluid LDH is useful for assessing the severity of pediatric community-acquired pneumonia patients with mycoplasma pneumonia and fever lasting for ＞3 d had a high level of LDH and total leucocytic count[21].LDH is usually used besides another marker and clinical criteria in the diagnosis of certain opportunistic infections, like pneumocystis crania pneumonia and toxoplasmosis[22], especially in patients suffering from AIDS[23]. Another report argued the specificity of LDH as it is highly increased within minutes of hypoxic-ischemic state occurring anywhere in the body[24]. However, we suggest its use in addition to other clinical signs of infection rather than to replace them to quantify sepsis severity.

Current study observed a good positive correlation between pSOFA and LDH, the higher the SOFA score, the higher the LDH(r=0.503,P＜0.001). Similarly, García-Gigorroet al.concluded that SOFA and changes in the SOFA score over time are good tools for assessing and follow up critically ill patients in ICUs[25].

The high LDH level was associated with a bad outcome in the form of more admission days, a higher risk factor for in-hospital mortality[26]. Its level was not considered as a dependent risk factor for mortality in patients with sepsis[6]. The patients with serum LDH more than 1 000 μL also had a long hospital stay and multiple organ affection as evident by SOFA score[27]. This is in agreement with Chkhaidzeet al., who found that SOFA scores are an excellent tool to assess the organ affection in critically ill patients while PIMⅡgives a good rank for diagnosis risk rather than specific organ involvement[28].

All in all, LDH could be a potential inflammatory marker in conjunction with the other clinical criteria to discriminate against critically ill children with severe sepsis. This can guide the decision of PICU admission.

Conflict of interest statement

The authors report no conflict of interest.

Authors’ contributions

H.A.F.A.: Creating idea of the work; A.A: Data collection; R.E.K.:Laboratory analysis; E.S.A.: Paper writing.