Discussion
The results suggest that VRI can be used to predict mortality in paediatric septic shock. The majority of subjects were in the 13–80 months age group. Most of the patients had come in critical condition, which caused the majority of PICU length of stay to be less than 7 days (54.4%) because some of them did not survive. This illustrates that Indonesia as a low and middle income country still has a high mortality rate due to septic shock in the paediatric group.
In septic shock, there are complex cardiovascular responses and changes in vascular tone that vary from individual. These conditions are critical for survival. The adult population usually manifests haemodynamic patterns of high cardiac index and low SVRI (hyperdynamic), while data are limited for children, but a greater proportion showed low cardiac index and high SVRI (hypodynamic). Adults can maintain high cardiac output through dilated ventricles and increased heart rate, while children have limited capability to improve these conditions.15 16 Furthermore, the baseline haemodynamic profile of patients was very diverse as shown in table 2. The highest number of subjects who died was in the high cardiac index and low SVRI group (17.6%). A study by Bierley et al15 in England also found more haemodynamic patterns of high cardiac index and low SVRI (94%) in septic shock children with the source of infection from a central venous catheter, while sepsis from community origin had a low cardiac index with varying SVRI (14%).15 Moreover, Lee et al17 analysed haemodynamic parameters to identify predictors of mortality in children with septic shock and cardiogenic shock.17 The study used a transpulmonary thermodilution technique through the pulse-induced cardiac output. The result showed that SVRI was significantly lower in children with septic shock who died compared with those who survived. The SVRI value for children who died was 901.08±305.69 compared with 1584.23±429.63 in survived children, with p<0.001. Meanwhile, the cardiac index was a predictor of mortality in the cardiogenic shock group.17
Another haemodynamic pattern was found as 16.1% of patients were in the normal cardiac index and SVRI group, indicating that compensated shock still occurred. A compensated shock phase was also observed in the low cardiac index and normal SVRI group of 16.1% in which normal vascular tone was maintained due to activation of the sympathetic system in the hypotensive state. Conversely, in the low cardiac index and SVRI groups of 8.8%, the patients were in a prolonged shock condition, hence, compensatory mechanisms failed to work which led to death.
The concept used in the VRI assessment was the occurrence of endothelial dysfunction in sepsis which causes the formation of reactive oxygen species, activation of complement systems, platelet aggregation and various cytokines. Multiple endothelial dysfunction reflects microvascular perfusion abnormalities and associated organ dysfunction. In septic shock, systemic vasodilation can occur which correlates with the severity and response to therapy.9 18
The VRI cut-off point of ≤32.1 correlated with higher mortality in children with septic shock. This supports a previous study by Lee et al9 that demonstrated the usefulness of VRI as a predictor of mortality in children with refractory septic shock. Lee et al9 assessed serial VRI at 6-hour intervals in the first 72 hours after PICU admission in a child with septic shock. The mean AUC within the first 72 hours was 0.8, and the serial values of VRI were significantly lower in the mortality group than in the survival group during the period from 0 to 48 hours. It was found that the VRI cut-off point <30 had good predictive power of mortality with an average AUC>80%, sensitivity 85%, specificity 77%, LR+3.7, LR− 0.2.9 Low VRI value suggests that systemic vascular reactivity had the worst response towards the vasoactive-inotropic agents and reflects the high mortality rate in children with septic shock. The differences in the cut-off point with the study of Lee et al9 are presumably due to the variation in the sample size.
The significance of predictive accuracy between VRI and PELOD-2 to mortality was analysed with Fisher’s exact test. It showed that both parameters were significant mortality predictors with p<0.001. The RR value for VRI ≤32.1 was higher 7.87 (95% CI 3.09 to 20.02) compared with PELOD-2 ≥11 which was 2.44 (95% CI 1.67 to 3.57). These data were considered because the component of PELOD-2 scoring is a biomarker of tissue dysfunction in microcirculation. Meanwhile, microcirculation biomarkers change more slowly due to hypoxia in shock, while the USCOM device is used to obtain VRI value and assesses macrocirculation in real-time. Disturbances in macrocirculation influence microvascular and related organ dysfunction. Thus, VRI can be used to detect organ dysfunction earlier than PELOD-2. The haemodynamic monitoring is also crucial in making appropriate decisions for the management and prognosis of paediatric septic shock. Therefore, USCOM is very useful because it is a non-invasive procedure in assessing haemodynamic components such as preload, contractility and afterload.19 20 Dhanani et al21 confirmed the reliability of intraobserver and interobserver about cardiac output measurement for the paediatric by using USCOM. Intraobserver reliability was considered by the coefficient of Lin concordance correlation of 0.92 and 0.85. The average differences±in SD by interobserver were 0.16±0.59 L/min/m2 and the coefficient of Lin’s concordance correlation was 0.87.21 22
This study has several limitations especially in relation to the retrospective method used which relies on medical records. However, all management algorithms were based on Indonesian Pediatric Society guidelines which referred to Surviving Sepsis Campaign international guidelines for the management of septic shock and sepsis-associated organ dysfunction in children, thereby minimising subjectivity in determining management. In addition, there are not a lot of studies on VRI in children with septic shock. The current meta-analysis study only conducted at adult populations, and there are insufficient data to quantitatively evaluate the relationship between vascular reactivity and multiple organ failure development.10