There is no consensus on the type of first-line fluid that should be used during resuscitation of septic shock. Evidence suggests that crystalloids whether balanced or not, are the most preferred. There are increasing reports of hyperchloremia and acute kidney injury when ‘chloride liberal’ normal saline is used [7,8]. In view of their restricted chloride content and lesser risk of acute kidney injury, currently balanced solutions are being promoted as a better alternative. Hypo-oncotic albumin solutions have also been suggested in patients requiring large volumes for fluid resuscitation. The hydroxyethyl starches have been demonstrated to increase mortality and hence should not be used in patients with septic shock [9]. While we await more answers on the use of albumin and balanced solutions, normal saline remains the standard of care [10].

The conventional teaching in septic shock emphasizes the need for aggressive fluid resuscitation to offset the massive capillary leak that is the major culprit for hypovolemia in these children. On the same lines, the current pediatric Surviving Sepsis Guidelines suggest that fluid resuscitation should be aggressive with repeated boluses of 20　mL/kg, so much so that some children may require as much as 200　mL/kg of fluid to achieve therapeutic endpoints [11]. The guidelines also recommend initiation of vasoactive therapy in patients with fluid-refractory shock defined as the presence of persistent signs of shock despite at least 60　mL/kg IV fluid boluses. Though evidence has shown reduced mortality and morbidity when the ACCM guidelines were followed, these recommendations for the volume of fluid resuscitation has emanated mainly from observational studies and expert opinions. Such an aggressive stand on fluid resuscitation in septic shock has recently been questioned by the Fluid Expansion as Supportive Therapy (FEAST) trial [12], which demonstrated increased mortality in children who received fluid boluses as compared to maintenance fluids, particularly in malnourished and anemic children. This study inferred that rapid fluid resuscitation may not be the best therapeutic strategy across the board for all children, especially in resource-limited settings where facilities to provide advanced ventilation and hemodynamic support are inadequate. This study threw open several questions regarding aggressive fluid resuscitation that until a few years back was considered the standard of care. Furthermore, subsequent studies [13-15] also suggested that excessive fluid resuscitation in patients with septic shock is associated with fluid overload, and increased morbidity and mortality.

The optimal volume of fluid resuscitation and the timing of initiation of vasoactive support in order to achieve therapeutic targets in children with septic shock are some other questions for which it is important to seek answers. Restricting maintenance fluids after initial fluid resuscitation and use of diuretics for fluid removal termed as ‘de-resuscitation’ is a useful strategy associated with increased number of ventilator-free days and shorter length of ICU stay [16]. The results of an ongoing trial [17] that plans to compare a goal-directed fluid-sparing strategy vs usual aggressive fluid strategy might provide more knowledge on this issue.

The classification of septic shock into ‘warm’ or ‘cold’ shock based on clinical assessment is often inaccurate given the complex derangements in myocardial function, vascular tone and distribution of blood flow. Bedside focused echocardiography is complementary to clinical examination as one can visualize the heart and great vessels directly. Ultrasound-guided fluid resuscitation is well established in adults but still in infancy stage in children due to lack of pediatric studies. In a cohort of 48 cases of fluid-refractory catecholamine-resistant septic shock (despite 60 mL/kg of fluid bolus and vasoactive drugs), uncorrected hypovolemia (33%) and decreased cardiac function (39.6%) were identified as causes of hypo-perfusion using focused ultrasound [22]. Also, shock being a dynamic state may swing from cold to warm or vice versa in the same child at different time points. A low systemic vascular resistance may masquerade clinically as a cold shock in presence of septic myocardial dysfunction and inadequate fluid resuscitation. Once the stroke volume improves following volume resuscitation and targeted inotrope therapy, the underlying warm vasodilatory state becomes clinically more apparent. This information is difficult to arrive at by physical examination even by experienced clinicians.

Only three to six hours of focused training has been found to be sufficient to infer useful data on volume responsiveness and cardiac contractility. However, the lack of formal training and certification process and limited availability of ultrasound devices restricts its widespread use in resource-limited settings.

There is a paucity of research regarding the choice of first-line vasoactive drug in children with fluid-refractory septic shock. Two recently published randomized trials report the superiority of epinephrine over dopamine with respect to resolution of shock within the first hour, lower Sequential Organ Function Assessment score on day 3 [23], more organ failure-free days (24 vs 20 d; P = 0.022), and lower mortality [24]. The recent ACCM/PALS guidelines support use of peripheral infusion of epinephrine 0.05– 0.3 mcg/kg/min as the first line inotrope in fluid refractory shock based on the recent evidence [3]. As regards the safety of peripheral administration of inotropes, the recent literature suggests that the short-term infusion of vasoactives through peripheral cannula is safe in a closely monitored setting and can act as a bridge before establishment of a central venous access [25]. However, dopamine being the time-tested inotrope can be administered safely through a peripheral line in a resource-limited setting, and given the limitations of these trials, it continues to be first line inotrope to be used in day to day clinical practice. More studies are needed to identify patients who may not respond to dopamine and further individualize the inotropic choice.

Early identification and treatment with appropriate antibiotics are considered the two most important cornerstones in management of children with sepsis. A delay in administration of appropriate antibiotic was shown to be associated with an increased mortality of 7.6% for each hour delay, 8.5　% for a 6-hour delay and 8% increase in progression to septic shock for every hour delay [26-28]. Two retrospective studies in children with sepsis reported an increased odds of ICU and 1-year mortality for a delay of >3 hours for first or appropriate antibiotic administration [29,30]. The emphasis of early and appropriate antibiotics in sepsis only got cemented further on. However, a recent meta-analysis of 8 studies including 11,017 patients, evaluating the timing of antibiotic administration after sepsis/septic shock recognition with mortality has brought out evidence to the contrary [31]. There was no significant increase in mortality with every hour delay from less than 1 hour to more than 5 hours from the time of identification of septic shock [31]. Despite this controversial evidence, early administration of antibiotics sounds more rational, and therefore continues to be recommended and followed.

The utility of steroids in sepsis lacks definitive evidence and consensus. Though the pathophysiological basis for starting steroids like sepsis-induced adrenal suppression, inotrope unresponsiveness, and the exaggerated inflammatory response is strong, it is not backed by strong evidence. Despite this, the surviving sepsis campaign guidelines state that hydrocortisone should be considered for a catecholamine-resistant septic shock with suspected or proven adrenal insufficiency. Adrenocorticotropic hormone stimulation test to prove adrenal insufficiency is however not routinely recommended. The adjunctive data from RESOLVE study [32] reported no obvious hemodynamic benefit or difference in outcomes with the administration of steroids in pediatric septic shock. Similarly, a systematic review [33] of 8 studies failed to prove an improvement in mortality or modification of shock duration, although the review was limited by small poorly performed trials. Furthermore, two recent retrospective cohorts in pediatric septic shock not only failed to demonstrate a benefit with steroids but showed an increase in new culture positivity rate, prolonged duration of antibiotic therapy and increased mortality [34,35]. A retrospective analysis of clinical practice revealed that the use of stress dose hydrocortisone correlated with severity of illness irrespective of the random serum total cortisol levels [36]. Notably, the outcomes like PICU and hospital length of stay and ventilation-free days were worse with the use of stress dose hydrocortisone irrespective of random cortisol levels. A randomized controlled trial for steroids in pediatric septic shock is much awaited to resolve this controversy. A feasibility study [37] of performing such a trial revealed that the major barrier was the high empiric usage of steroids by physicians.

Sepsis is defined as systemic inflammatory response syndrome (SIRS) with suspected or proven infection. However, it is difficult to differentiate it clinically from other causes of SIRS. Various biomarkers like C-reactive protein, procalcitonin, interleukin-6, human neutrophil gelatinase have been evaluated for their utility in diagnostic, prognostic and therapeutic monitoring. Procalcitonin is a specific marker for bacterial infection and helps in diagnosis and deciding duration of antibiotics. Serial trends rather than a single value helps in judging the clinical response to therapy. No single biomarker has the best diagnostic accuracy to differentiate sepsis from other inflammatory disorders.

Recently, in the Pediatric sepsis biomarker risk model (PERSEVERE), a combination of five biomarkers was found to reliably identify children at risk of death and those with higher illness severity from pediatric septic shock [41]. Such biomarker-based risk stratification could possibly pave way for assessing the efficacy of less proven therapies. Also, three gene expression diagnostics, based on genome-wide expression, that could help differentiate patients with sepsis from those with noninfectious inflammation have been developed and found to be useful [42]

Shock persisting despite optimization of preload, vasoactives, source control, appropriate antibiotics and correction of identifiable factors (intraabdominal hypertension, pneumothorax or pericardial tamponade, adrenal insufficiency) may require Extracorporeal membrane oxygenation (ECMO) therapy. A retrospective analysis of a database, revealed utilization of ECMO in 2.3%, renal replacement therapy in 6% and combination of both in 1% of children with septic shock [43]. The utilization of extracorporeal therapies was higher in those with multi organ dysfunction syndrome (MODS). Although mortality rates of about 48% have been reported for such children on ECMO [43], recent trends have been very encouraging; survival rates on ECMO of about 70-75% have been reported by experienced centers [44,45].

The concept of ‘de-resuscitation’ is gaining momentum, as evidence has clearly shown that fluid overload acts as a ‘third hit’ phenomenon resulting in increased mortality due to organ dysfunction. Therefore, after initial resuscitation and stabilisation, transition to a negative fluid balance needs to be aggressively achieved with restricted maintenance fluid, targeted diuresis or RRT. Use of continuous renal replacement therapy (CRRT) in severe sepsis not only helps in fluid removal but also in removal of toxic metabolites and inflammatory mediators. Early institution of CRRT in patients with MODS has been shown to reduce mortality [46,47] and hence the recent ACCM/PALS guidelines recommend use of either diuretics, peritoneal dialysis or CRRT in patients with fluid overload of more than 10% and impaired renal function [3].

Therapeutic plasma exchange (TPE) is indicated in thrombocytopenia associated multiorgan dysfunction (TAMOF) in which low ADAMTS-13 levels lead to widespread intravascular microthrombi and multiorgan dysfunction [48]. TPE in such patients may replenish ADAMTS-13 protease which helps cleave the ultra-large von Willebrand factor multimers and resolve organ dysfunction. A meta-analysis of adult trials reported a lower mortality with plasma exchange and hemoperfusion in patients with sepsis [49]. Similar beneficial effect has been demonstrated in a pediatric case series where TPE was shown to be an useful adjunct to reverse TAMOF [50]. Combining TPE with CRRT in an extracorporeal life support circuit in sepsis induced MODS was found to have high survival of about 71% [51]. TPE may therefore be tried as an adjunct to reverse MODS, after initial resuscitation.

Current evidence is moving away from protocolized early goal-directed therapy and entering a new age which emphasizes more on individualized approach to the treatment of septic shock. We are moving away from aggressive fluid resuscitation and liberal blood transfusion to a more restrictive regimen. Echocardio-graphic and Doppler based assessments of respirophasic variations in cardiac output for assessment of fluid responsiveness have replaced the static parameters like heart rate, blood pressure and central venous pressure. We are probably close to dismantling dopamine as the first choice inotrope in pediatric septic shock. We, however, await more answers on first hour antibiotics, type of fluids and steroids in septic shock. Extracorporeal therapies like ECMO, CRRT are being increasingly used for patients with refractory shock, resulting in an improved survival. Further research on biomarker-based risk stratification could possibly pave way for the assessing efficacy of less proven therapies.

Contributors: JI: literature search and drafted the manuscript; JM: guided the framework of the manuscript and critical review. Both authors approved the final version of manuscript.

Funding: None; Competing interest: None stated.

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