This study showed that the bedside and computed septic shock scores discriminated the most severe cases in a prospective cohort from India and confirmed the accuracy of these scores. Patients diagnosed in RSS had a very high mortality. While the presence of a severe myocardial dysfunction is not mandatory for the diagnosis of RSS, it was present in all patients in this study. This point reinforces the importance of septic cardiomyopathy in the pathophysiology of RSS. El Nawawy et al. demonstrated in a small monocentric cohort the added value of myocardial and hemodynamic evaluation with echocardiography and confirmed the high incidence of myocardial dysfunction in pediatric septic shock [12, 13]. The vasoactive-inotropic score used in the SSS is validated in pediatric sepsis as a marker of severity. Interestingly, MacIntosh et al. found a similar pattern of evolution of the VIS with a best correlation with morbidity after the 12th hour of care . Meanwhile, the addition of blood lactate and myocardial dysfunction in the SSS may explain the excellent discrimination power as early as within the first 6 h of management. Blood lactate with a cut-off value of 4 mmol/L was associated with mortality in a large cohort of pediatric sepsis patients . Despite having a higher lactate cut-off value of 8 mmol/L, the bSSS does not seem to have lower sensitivity than the cSSS. In this study, both bSSS and cSSS identified the same number of RSS patients with similar outcome. The high lactate cut-off value in the bSSS effectively selects patients at the highest risk of mortality and with catecholamine-refractory shock. Interestingly, bSSS ≥ 2 cut-off confirmed the one set in the original study . However, cSSS best cut-off is higher in this cohort than in the original. This is due to a strong impact of myocardial dysfunction (+ 18 points) and its elevated incidence in the present cohort where all patients in RSS had myocardial failure. The stronger association of myocardial dysfunction and mortality seen in this study emphasize the heterogeneity in the case mix and management, and further support the use of bSSS that shows to encompass accurately the whole spectrum of RSS.
Our previous study’s main limitation was the uncertainty about the simultaneity of the measure of lactate, VIS and/or the presence of cardiomyopathy. The present study focused on the first 24 h of management, all the measures were associated with discrimination for mortality. Nevertheless, the scores were best predictive of mortality after the first 12th hour of management. This may be explained by the need for the vasopressors to be progressively increased until the VIS cut-off is reached, or the patient deteriorates with the occurrence of septic cardiomyopathy. Timing is essential in RSS diagnosis. An early diagnosis of RSS in the first 24 h associated with a 60%  to 85.7% (present study) estimated mortality should be a strong indicator of need for adjunct therapies.
A recent study found that refractory shock is the first cause of mortality in pediatric septic shock patients . This fact emphasizes the need for a definition of RSS, thus, its validation in this study. Despite being a less frequent cause of death, multiple-organ dysfunction syndrome (MODS) can be diagnosed or assessed with several scores such as PELOD 2 and PIM 2. While PIM 2 may only be measured at admission, PELOD 2 can be measured sequentially . However, in our study PELOD was not calculated sequentially. The PRSIM III score, designed to estimate mortality, was found to be independently associated with mortality. Although formerly not evaluating organ failure, PRSIM III score is calculated using many clinical and biochemical criterion surrogated of organ failures. In the RSS definition process, individual organ failures were not retained by pediatric critical care experts preferring quantifiable cardio-circulatory criterion . Our study confirms the importance of cardio-circulatory failure in sepsis severity and prognostication and although not being specifically investigated, a potential hierarchical importance over individual organ failure may be suggested.
The first limitation of this study is that it was a post hoc analysis of a single-center randomized trial. The use of inotrope or vasopressor in the original study was protocolized, which may have affected the increase in the inotropes or vasopressors, hence the VIS and the predictive performances of the SSS in the first hour of management. Nevertheless, the randomization drug was not associated with increase mortality in the multivariable analysis. Secondly, all patients diagnosed with RSS had a severe cardiomyopathy diagnosed with cardiac ultrasound, which is a sufficient criterion for the diagnosis of RSS. Indeed, cardiac ultrasound is questionable due to the subjectivity of the exam and the risk of error for the diagnosis of cardiac failure due to the presence of hypovolemia. Yet, this risk for over-diagnosis of RSS appears unlikely when considering the good performance of the scores and the high mortality in the RSS group. Thirdly, most scores used or currently discussed in the question of sepsis and septic shock diagnosis were unavailable in our cohort, hence we could not compare their performance with the SSS.
This study’s strengths are the homogeneous and well-characterized cohort of patients with septic shock with timely measured SSS. It is to our knowledge the first prospective study to evaluate sequentially during the first 24 h the prognosis performances of these scores in pediatric septic shock patients. This study provides clear evidence that RSS is a specific entity responsible for most deaths in pediatric septic shock.