However, although focusing exclusively on adults, the main advance of the sepsis-3 definition is the stratification of patients into two categories: sepsis and septic shock. In adults, the SOFA score assesses organ failures after sepsis with good correlation to mortality [ 8 ]. This adult score is not adapted for paediatric patients. The paediatric index of mortality PIM2 [ 29 ] and the PELOD-2 [ 30 ] score are paediatric scores that can be used to compare population of patients but are not specific for sepsis.
In our study, the two scores were built with arterial lactate, vaso-inotrope score and septic cardiomyopathy and were associated with poor outcome. Each of those criteria was independently associated with mortality or the need for ECLS.
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Blood lactate is a widely used biomarker in septic shock patients. Dynamic values, such as lactime [ 32 ] or lactate clearance [ 33 ], are better predictors of mortality in adult patients, but they are not used routinely. Use of vasopressors or inotropes to treat fluid-unresponsive shock is still the first line of treatment [ 10 , 11 ].
In our study, norepinephrine was used in The cut-off chosen in the definition by the two-round survey is higher than the VIS scores found in the literature in patients under ECLS therapy for other indications [ 22 , 35 , 36 ] or alternative vasopressors [ 37 ], but similar to calculated inotrope scores in adult patients needing ECLS support for septic shock [ 21 ].
Septic cardiomyopathy is the component carrying the highest weight in the septic shock scores. Although the pathogenesis of septic cardiomyopathy is multifactorial, it is known to be reversible [ 36 , 37 , 38 ]. Diastolic dysfunction and right ventricle dysfunction in sepsis are less studied but their role in septic cardiomyopathy seems to precede systolic left ventricular dysfunction [ 39 ]. Cardiac arrest is the ultimate evolution of septic shock.
In our study, in both cohorts, Improved assessment of septic cardiomyopathy before cardiac arrest occurs is mandatory. Regular evaluation of cardiac output and function can be based on invasive and non-invasive criteria. Non-invasive quantification relies mostly on continuous oesophageal or supra-sternal Doppler or cardiac ultrasound. Importantly, it is well recognized that children with septic shock without apparent need for inotropes can subsequently develop septic cardiomyopathy and low cardiac output [ 19 ].
This haemodynamic pattern can be explained by the unmasking of septic cardiomyopathy by restoration of vasomotor tone in resuscitated shock after norepinephrine infusions, as well as over-enthusiastic fluid resuscitation [ 17 ]. This study has some limitations. First, the data collection was retrospective and thus is at risk of missing data and information bias. Second, data were collected during the whole septic shock care period with selection of a unique worst value for each item. Thus, the maximal values could be at varying time points in the clinical course.
Calculation of the score was based on worst values for each criterion that may not be synchronous. This could have increased the estimated risk of death for patients in the validation population as well as overestimating the AUCROC. Evaluating the kinetics of both scores as well as its composing criteria in the course of the disease is important and needs prospective evaluation. Third, there were significant baseline differences in the characteristics of the two populations development and validation and between centres included in the validation cohort.
The high mortality rate in the development cohort ensured the high power of this study to select the criteria associated with refractory septic shock. Meanwhile, the scores have an excellent discriminative value in the validation cohort. This reinforces the quality of the scores in various patients.
Finally, this definition is based on a draft definition that has been developed using fictitious clinical cases and an international PICU physician opinion survey. The risk of opinion bias has been adjusted with the modification of this definition and the constitution of the septic shock scores tailored to an actual patient population. This definition is very coherent in real life, shown by the excellent discriminative power of both scores in the validation cohort. In regard of these limitations, a prospective study is warranted for refinement and external validation of this definition.
In conclusion, we have defined refractory septic shock in children as the association of high blood lactate with high vaso-inotrope doses associated with myocardial dysfunction. This definition is based on two septic shock scores showing excellent discriminative power in a multicentre validation population. The RSS Computed Score is a powerful and potentially useful tool to compare patients in future interventional randomized multicenter studies on septic shock. The RSS Bedside Score is easy to calculate and may assist in determining patients who would be suitable for inclusion in clinical trials of rescue therapies.
Tissieres reports grants from Merieux Foundation, non-financial support from Chiesi Inc, outside the submitted work. All other authors declare that they have no conflict of interest. Skip to main content Skip to sections. Advertisement Hide. Download PDF. Open Access.
First Online: 05 October Purpose Although overall paediatric septic shock mortality is decreasing, refractory septic shock RSS is still associated with high mortality. Methods We conducted a two-round Delphi study followed by an observational multicentre retrospective study. Results From the Delphi process, the draft definition included evidence of myocardial dysfunction and high blood lactate levels despite high vasopressor treatment. Introduction Infection remains the leading cause of paediatric mortality worldwide [ 1 ]. Definition drafting The first part of the Delphi study was a clinical case-based questionnaire.
Development population application and definition adjustment The RSS draft definition was first tested in a development population. Inclusion and exclusion criteria were identical in the development and validation population. Data were collected retrospectively C. All six centres obtained local ethical approval for the retrospective analysis of the patient data and waiver of informed consent from legal representatives. Items graded A first quartile of association with diagnosis of RSS or B second quartile were selected for the second round.
They were condensed into a minimal definition lactic acidosis with vaso-inotrope dependency and myocardial dysfunction with additional organ failures graded A or B [hepatic insufficiency, severe acute respiratory distress syndrome ARDS with the Berlin definition [ 26 ] or failure to achieve effective continuous renal replacement therapy CRRT ].
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In the second round of the Delphi study, from September 23 to November 21 , 61 physicians answered the survey and 37 They validated six items determined in the first round as important with a grade A or B for the diagnosis of RSS. Data from the last step were selected and used to create septic shock scores. The validation population consisted of patients admitted for septic shock requiring inotropes or vasopressors, with a mortality rate of Thirty-two of these patients had limitations of life support on admission and were excluded from analysis.
The mortality for the remaining patients was The two studied populations differed significantly in terms of prognostic factors and outcomes. The paediatric index of mortality score PIM2 [17 11—21 vs. The origin of infection was nosocomial in A microbiological diagnosis was positive for patients The most prevalent pathogens were Neisseria meningitidis in 70 patients Open image in new window. Both scores were calculated for all patients and performance analysed with ROC curves Fig.
The bedside SSS with a cut-off at 2 was associated with a positive predictive value of The computed SSS with a cut-off at 3. Mortality rate were compared for RSS populations defined by the bedside and the computed scores, with, respectively, 41 deaths among 68 RSS patients mortality Survival curves for each score are presented in Fig.
The experts agreed with a conditional degree of consensus that vasopressors should be started before the completion of full fluid resuscitation. From the SSC guidelines, there is uncertainty about when vasopressors should be initiated in septic shock. This lack of clarity was criticized [ 44 ]. Although it is not mentioned which indicator can be used to select patients who require vasopressors, this recommendation clearly indicates that early administration before complete fluid resuscitation is an option.
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Some studies reported that delay in initiation of vasopressor therapy was associated with an increased mortality risk in patients with septic shock [ 46 , 47 ]. There are three potential reasons for this finding: early vasopressors could prevent the onset or progression of organ dysfunction by reaching the target MAP as the main component of organ perfusion pressure faster and by optimizing tissue perfusion [ 48 , 49 ]. Earlier vasopressor therapy may represent a marker of the intensity of delivered care which could result in improved outcome. Finally, earlier vasopressor use could lead to a decrease in the amount of fluids administered [ 50 ], e.
As these data reflect epidemiology rather than physiology, the optimal timing of vasopressor initiation needs to be studied in a personalized context. This might be related to the occurrence of catecholamine-associated complications although the mortality associated with high-dose norepinephrine varies considerably.
Research is needed to identify clinically relevant thresholds for the consistency of guidelines and for design of future clinical trials [ 54 ]. However, there is evidence that use of low-dose corticosteroids results in earlier shock reversal i. In our survey, we received contradictory responses to the question regarding the change in cardiac output when restoring MAP with norepinephrine. Studies have shown increases in cardiac output through an increase in cardiac preload and cardiac contractility in patients with septic shock treated with norepinephrine [ 48 , 59 , 60 , 61 , 62 ].
A recent systematic review has confirmed these findings [ 63 ]. It appears that the effect of norepinephrine was dependent on the basal microvascular state, being beneficial only when the microcirculation was compromised. Respondents had different opinions on how to measure blood pressure, MAP targets, dosing, timing, triggers for adding a second vasopressor, reasons for reducing the vasopressor dose, and stopping vasopressor treatment.
This variation may be interpreted in two ways.
Firstly, individual physicians may interpret the existing scientific evidence differently. For example, one physician may give more weight to a MAP target, while another may focus on signs of organ dysfunction. Secondly, the physicians may have interpreted the existing evidence in a similar manner, while the heterogeneity of septic shock drives the differences in treatment plans.
These treatments may be adapted to individual patients based on their history, underlying disease, comorbidities, and response to treatment [ 69 ].
If signs of hypoperfusion remain, the MAP target may need to be elevated. These nuances cannot be captured by a simple survey. Although surveys are not at the top of the evidence-based pyramid, the results of this survey present useful information on contemporary practice and preferences regarding vasopressor therapy, obtained from responders from many European and non-European countries Fig.
Non-European physicians more often used noninvasive techniques to measure ABP and less frequently considered other reasons than reaching the MAP target to increase the vasopressor dosage, such as persisting signs of organ dysfunction despite reaching MAP targets. These differences might reflect varying adoption rates of the Surviving Sepsis Campaign guidelines, or simply differences in available resources and local practices. Furthermore, this work identified areas for future research as reflected by heterogeneous opinions.
The results of our survey can be used as a benchmark for interpreting studies stating usual or standard care in control groups of intervention trials. However, if the control group is treated very differently from what was reported in our survey, then external validity of results is diminished. Physicians are less swayed by the impact of an intervention when compared against a control intervention that is currently not considered as standard for treating patients.