Validation of the pediatric refractory septic shock de nition: Posthoc analysis of a controlled trial

Luc MORIN Assistance Publique Hopitaux de Paris Karthik Natayanan RAMASWAMY Post Graduate Institute of Medical Education and Research Chandigarh Muralidharan JAYASHREE Post Graduate Institute of Medical Education and Research Arun Bansal Post Graduate Institute of Medical Education and Research Karthi NALLASAMY Post Graduate Institute of Medical Education and Research Pierre Tissieres (  pierre.tissieres@aphp.fr ) Assistance Publique Hopitaux de Paris https://orcid.org/0000-0001-5423-5532 Sunit SINGHI Post Graduate Institute of Medical Education and Research


Abstract Background
The European Society of Pediatric and Neonatal Intensive Care (ESPNIC) developed and validated a de nition of pediatric refractory septic shock (RSS), based on two septic shock scores (SSS). Both bSSS and cSSS were found to be strongly associated with mortality. We aimed at assessing the accuracy of the RSS de nition on a prospective cohort from India.

Methods
Post-hoc analysis of a cohort issued from a double-blind randomized trial that compared rst-line vasoactive drugs in children with septic shock. Sequential bSSS and cSSS from 60 children (single center study, 53% mortality) were analyzed. The prognostic value of the ESPNIC RSS de nition was tested for 28-day all-cause mortality.

Results
In this septic shock cohort, RSS was diagnosed in 35 patients (58.3%) during the rst 24 hours. Death occurred in 30 RSS patients (85.7% mortality) and in 2 non-RSS patients (8% mortality), OR=60.9 [95% CI: respectively. During the rst day of septic shock, the best interval for prognostication was after the 12 th hour following septic shock as compared to 0-6 hours or 6

Conclusions
The ESPNIC SSS accurately identi es children in refractory septic shock with a best interval between 12 and 24 hour of septic shock. Both bSSS and cSSS had high discrimination for 28-day mortality.

Background
Septic shock, de ned as uid refractory sepsis with organ dysfunction is encompassing various clinical and pathophysiological entities. The Surviving Sepsis Campaign (1) and the American College of Critical Care Medicine guidelines for Hemodynamic Support in Neonates and Children (2) issued guidelines for patient with sepsis including the subset of patients who are unresponsive to vasopressors and labelled as having refractory septic shock (RSS). RSS is described as a circulatory failure due to septic cardiomyopathy (3,4) with or without vasoplegia (5). Survival observed following short-term circulatory support with newer vasoactive agents or extra-corporeal life support (ECLS) (6) is an indicator that RSS is potentially reversible. To maximize the impact of these rescue therapies, a robust tool for early detection of RSS was required. The European Society of Pediatric and Neonatal Intensive Care (ESPNIC) de ned RSS as the association of high blood lactate with high vasopressor doses and/or myocardial dysfunction (7). This de nition based on two septic shock scores showed excellent discriminative power and suggest that both RSS scores are powerful and potentially useful tool to categorize severity at the bedside and compare patients in future interventional randomized multicenter studies on septic shock in children. Nevertheless, this RSS de nition was established on retrospective data. A prospective validation is mandatory as part of the validation of theses scores (8). Furthermore, it may not have been representative of the regional diversity of critically ill children etiology and management. In order to overcome these limitations, we evaluated the validity of the ESPNIC RSS de nition and SSS scores in a post-hoc analysis of a double blind randomized trial (9) aimed at comparing rst-line vasoactive drugs in children with septic shock in India.

Patients
All patients (n = 60) included in the double-blind randomized trial at the Advanced Paediatrics Center, Post Graduate Institute of Medical Education and Research, Chandigarh, India, were included in the post-hoc analysis. The study protocol has been previously described (9). In summary, this was a monocentric randomized controlled trial on septic shock children comparing dopamine to epinephrine as rst-line vasoactive agents. Patients aged between 3 months and 12 years were enrolled if they had uid refractory septic shock and admitted in pediatric intensive care unit between July 2013 and December 2014. The study was registered (CTRI/2014/02/004393) and a local IRB approved the use of the database for this study and waived the need for informed consent.

Data
Patients baseline characteristics including gender, age, PRISM III and PELOD scores, blood lactate, central venous oxygen saturation (ScvO 2 ), vasoactive-inotropic score (VIS) as well as the occurrence of severe Acute Respiratory Distress Syndrome (ARDS) de ned according to Berlin de nition (10) and use of renal replacement therapy were analyzed. There was no missing data, as analyzed items were part of the main outcome measurements from the original study (8). Both bedside septic shock score (bSSS) and computed septic shock score (cSSS) were calculated every 6 hours for the rst 24 hours. The bSSS is a 0 to 5 points score with 1 point for a lactate value above 8 mmol/L or increased > 1 mmol/L after 6 hour of management, 1 point for a VIS > 200 and 3 points for the presence of a severe cardiomyopathy de ned by a cardiac index < 2.2L/min.m 2 or a left ventricle ejection fraction < 25%. The cSSS is calculated with: cSSS = 1.1 blood lactate value + 1.001 VIS + 18 (in the presence of a severe cardiomyopathy). The impact of the interventional group (dopamine or epinephrine) was considered in the analysis. Primary outcome was 28 days all-cause mortality.
Statistical analysis Continuous variables were tested for normality with Kolmogorov-Smirnov test and compared with Student's t test or Mann-Whitney test, as appropriate. Non-continuous variables were tested with Chisquared test or Fisher's exact test, as appropriate. Data were described as frequencies and percentages, means and standard deviations or median and interquartile range, as appropriate. Multivariable Cox's regression with backward-stepwise method was performed having as outcome 28 days all-cause mortality. Covariates inserted in the models were PRISM III and computed SSS. We measured the discrimination of each score using the area under the receiver operating characteristic curve (AUROC). The best thresholds for these scores were obtained with the calculation of sensitivity, speci city, positive and negative predictive values and the Youden's index (Y = sensitivity + speci city -1). The DeLong test was used to compare the AUC of both scores. Survival of RSS patients according to both scores have been evaluated by Kaplan-Meier curves and these latter have been tested using Logrank test. A p value of less than 0.05 was considered statistically signi cant. Statistical analyses were performed with SPSS 19.0.0 (SPSS, Chicago, IL) software.

Results
Of the 210 patients diagnosed with sepsis and screened, 61 children were eligible for enrollment. One parent refused consent, 29 children were randomized to epinephrine group and 31 to dopamine group. All the enrolled subjects completed the study and were followed up to 28 days. Patients in the epinephrine group achieved earlier resolution of uid-refractory hypotensive shock in children as compared to dopamine. The baseline characteristics are presented in Table 1

Discussion
This study showed that the bedside and computed septic shock scores discriminated the most severe cases in a prospective cohort from India and con rmed the accuracy of these scores, particularly after the rst 12 hours of management. 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 vascular evaluation with echocardiography (11) and con rmed the high incidence of myocardial dysfunction in pediatric septic shock (12). The vasoactive-inotropic score (VIS), 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 (13). Meanwhile, the addition of blood lactate and myocardial dysfunction in the SSS may explain the excellent discrimination power as early as the diagnosis. Blood lactate with a cut-off value of 4 mmol/L was associated with mortality in a large cohort of pediatric sepsis patients (14). 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 identi ed 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.
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 rst 24 h of management, all the measures were associated with discrimination for mortality. Nevertheless, the scores were best predictive of mortality after the rst 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 rst 24 hours associated with a 60% (7) to 85% (present study) estimated mortality should be a strong indicator of need for adjunct therapies.
A recent study found that RSS is the rst cause of mortality in pediatric septic shock patients (15). This fact emphasizes the need for a de nition 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 (16), PELOD 2 can be measured sequentially. The assessment of a patient from sepsis diagnosis and throughout evolution is primordial in the dynamics of septic shock (17). The sepsis de nition for adult has changed and now encompasses lactate level and need for vasopressor or inotrope in a sepsis patient (18). Similarly, the pediatric sepsis de nition is deemed to change. Recent concept for a new de nition focus essentially on organ dysfunction considered as a uni ed concept rather than independent organ failure (19). Despite the focus of this RSS de nition on hemodynamics and circulatory failure, the performances are excellent with high prediction of mortality. Neither PELOD 2 nor pediatric adjusted SOFA were available in this study to evaluate their utility in actual questions for prognosis of septic shock. Meanwhile a MODS score, the PRISM III, was independently associated with mortality, hence supporting the fact that children die from RSS and/or MODS (15).
The rst limitation of this study is that it was a post hoc analysis on 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 rst 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 su cient 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 where 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 rst prospective study to evaluate the prognosis performances of these scores in pediatric septic shock patients. This study provides clear evidence that RSS is a speci c entity responsible for most death in pediatric septic shock. The use of septic shock scores (bedside and computed SSS) had excellent performance for the diagnosis of RSS particularly after the 12th hour of management.

Conclusion
This post-hoc prospective single centre study validates both septic shock scores used to diagnose refractory septic shock, showing excellent discriminatory power for mortality. Future studies should explore the application of this de nition in a multicentric prospective cohort of patients in high-resources units and investigate the bene ts obtained from adjunct therapies dedicated to the patients with the highest risk of death.  A. Survival curve of refractory septic shock patients diagnosed with a bedside septic shock score ≥ 2. B.
Survival curve of refractory septic shock patients diagnosed with a computed septic shock score ≥ 3.5 Figure 1