1302 SECTION XI Pediatric Critical Care Immunity and Infection (3) demonstrating the influence of developmental age on the transcriptomic response to pediatric septic shock172; (4) the obser vation th[.]
1302 S E C T I O N X I Pediatric Critical Care: Immunity and Infection (3) demonstrating the influence of developmental age on the transcriptomic response to pediatric septic shock172; (4) the observation that gene programs corresponding to mitochondrial function and biogenesis are repressed in certain subclasses of pediatric septic shock173; and (5) the observation that the prescription of adjunctive corticosteroids leads to further repression of adaptive immunity-related gene programs in children with septic shock.174 These transcriptomic studies have also enabled identification of new mechanistic pathways and candidate therapeutic targets for sepsis, which have been brought back to the basic science laboratory for formal hypothesis testing using rodent models of sepsis For example, following the observation that zinc homeostasis is altered in pediatric septic shock, it was demonstrated that zinc supplementation confers a survival advantage in rodent models of sepsis.82,175 As a direct consequence, a phase trial of intravenous zinc supplementation in critically ill children was recently completed and will inform the design of future trials of zinc supplementation in sepsis.176 In another example, it was reported that repression of the peroxisome proliferator activator receptor-a (PPARa) signaling pathway is associated with poor outcome in pediatric sepsis.177–179 This observation was subsequently corroborated in sepsis models involving PPARa null mice.180–182 Following the observation that matrix metalloproteinase-8 (MMP8) is consistently the highest expressed gene in children with septic shock, extensive studies were subsequently conducted to further delineate the role of MMP8 in sepsis Genetic ablation or pharmacologic inhibition of MMP8 confers a survival advantage in mice subjected to cecal ligation and puncture (CLP).183,184 These observations are associated with attenuated inflammation but without compromising bacterial clearance In addition, MMP8 can directly serve as a DAMP because primary macrophages stimulated ex vivo with recombinant MMP8 demonstrate increased NF-kB expression and increased expression of proinflammatory cytokines.183 Similarly, the observation that olfactomedin-4 (OLFM4) is the highest expressed gene among nonsurvivors of pediatric septic shock has led to translational studies focused on the role of OLFM4 in sepsis OLFM4 is a glycoprotein found in a subset of neutrophils Among children with septic shock, a higher percentage of OLFM41 neutrophils is independently associated with worse outcomes.185 Consistent with this clinical observation, genetic ablation of OLFM4 in mice has a protective effect against sepsis.186 Collectively, these data suggest that OLFM4 identified a pathogenic subset of neutrophils Studies are ongoing to further understand this pathogenic potential and the possibility of selectively inhibiting OLFM1 neutrophils in sepsis These transcriptomic studies have also enabled the discovery of sepsis biomarkers For example, IL-27 was identified as a candidate sepsis diagnostic biomarker via transcriptomics and follow-up studies demonstrated that serum IL-27 protein concentrations greater than ng/mL can distinguish critically ill children with bacterial infection from critically ill children with sterile inflammation with more than 90% specificity and positive predictive value.187 In another example, these transcriptomic studies enabled the discovery of biomarkers to predict the development of septic acute kidney injury.188,189 Finally, these transcriptomic studies enabled the discovery of stratification biomarkers to assign a baseline mortality probability for children and adults with septic shock.190–195 The concept of leveraging stratification biomarkers for the care of children with septic shock will be discussed in a subsequent section An endotype is a subclass of a condition defined by function or biology.196 Based on discovery-oriented computational approaches • Fig 110.3 Examples of individual pediatric patients allocated to septic shock endotypes A and B Each gene expression mosaic represents 100 endotype-defining genes, which correspond to adaptive immunity and glucocorticoid receptor signaling The color bar on the far right of the figure indicates color intensity relative to the level of gene expression, with the degree of blue intensity corresponding to decreased gene expression and the degree of red intensity corresponding to increased gene expression and hierarchical clustering of more than 8000 genes, these transcriptomic studies identified gene expression–based endotypes of pediatric septic shock.177 Post hoc analysis revealed that one of the endotypes had significantly greater illness severity, organ failure burden, and mortality; these observations were subsequently validated.178,179 With the goal of developing a clinically feasible test meeting the time-sensitive demands of critically ill patients,165 the endotyping method was refined by distilling the endotypedefining expression signature to the top 100 class predictor genes, expressing these genes using visually intuitive gene expression mosaics, and measuring mRNA expression using a digital mRNA quantification platform This approach validated that this endotyping method identifies patients with increased organ failure burden and mortality.197,198 Notably, the endotype-defining gene expression signature is enriched for genes corresponding to adaptive immune function and the glucocorticoid receptor signaling pathway; allocation to one of these endotypes is independently associated with increased mortality Thus, endotyping potentially has theranostic implications given the current interest surrounding therapies to augment the adaptive immune system in patients with sepsis199 and the ongoing controversies surrounding the role of adjunctive corticosteroids in septic shock.200 For example, the use of adjunctive corticosteroids is independently associated with four times the risk of mortality in one of the endotypes.197 Fig 110.3 shows examples of the recently identified pediatric septic shock endotypes Recently, analogous gene expression–based subgroups of sepsis were reported among adults with sepsis.201–203 Treatment Strategies As the biological response to sepsis becomes better understood and as we refine our ability to phenotype and stratify patients, the approach to treatment of sepsis will become more specific and more sophisticated At present, however, clinical treatment of sepsis entails four important goals, which, for the most part, rely on purely supportive measures founded on the fundamental CHAPTER 110 Pediatric Sepsis principles of critical care medicine: initial resuscitation, pathogen elimination, maintenance of oxygen delivery, and carefully directed regulation of the inflammatory response An update of pediatric- and neonatal-specific guidelines for sepsis management was recently published without any major changes in treatment per se The newest guidelines emphasize institutional recognition and treatment implementation, discussed in detail later, via the use of bundles.204 Initial Resuscitation As in any disease process, the first step in the treatment of sepsis is the initial stabilization of the patient In this regard, children present many of the same challenges as adult patients, including respiratory and cardiovascular stabilization The primary goals of therapy in the first hours are to maintain oxygenation and ventilation, achieve normal perfusion and blood pressure, and reestablish appropriate urine output and mental status Children with signs of sepsis may have significantly decreased mental status, raising concern about the ability to protect their airway Also, in septic shock, the work of breathing can represent a significant portion of oxygen consumption (as much as 15%– 30%) Because children with septic shock also receive large amounts of fluid to restore intravascular volume in the context of capillary leak, they are at increased risk for developing pulmonary edema Consequently, lung compliance decreases and work of breathing can increase substantially Together, these respiratory abnormalities often necessitate tracheal intubation and mechanical ventilation Arterial blood gas analysis often reveals, in early sepsis, respiratory alkalosis from centrally mediated hyperventilation As sepsis progresses, patients may have hypoxemia and respiratory acidosis secondary to parenchymal lung disease and/or hypoventilation due to altered mental status.205 However, the decision to initiate mechanical ventilation support should not necessarily be contingent on laboratory findings Rather, the decision should be primarily based on clinical findings of increased work of breathing, hypoventilation, and/or impaired mental status Mechanical ventilation provides the added benefit of reducing work of breathing—therefore, decreasing overall oxygen consumption—especially when combined with sedation and paralysis If early tracheal intubation is chosen, consideration of volume loading and inotropic/vasoactive support is recommended Sedative agents for induction should be selected to maintain hemodynamic stability The 2017 pediatric guidelines for septic shock continue to recommend ketamine for induction They also continue to recommend against the use of etomidate owing to its adrenosuppressive effects despite evidence that etomidate does not impact mortality in adults with septic shock intubated with etomidate.204 For a variety of reasons, patients with sepsis almost universally have decreased effective intravascular volume Many have poor oral intake of fluid for some time prior to developing sepsis With the development of increased vascular permeability, intravascular volume has been lost because of third spacing Finally, vasodilation partially related to excessive NO production (see earlier section) results in abnormally increased vascular capacitance, decreasing the effective intravascular volume When sepsis is suspected, vascular access should be obtained and 20 mL/kg of isotonic fluid administered as quickly as possible A second peripheral vascular access is recommended; difficulties in attaining venous access can be overcome with the use of an intraosseous catheter Intraosseous access can temporarily be the primary route 1303 for volume infusion, medications, and blood products when other intravascular access is not readily obtained While following clinical examination for signs of overly aggressive volume resuscitation (e.g., new onset of rales, increased work of breathing, development of a gallop, abdominal distension, or hepatomegaly), fluid should be administered quickly with the goal of improving blood pressure and tissue perfusion Administration of more than 60 mL/kg of isotonic fluid in the first hour of resuscitation is associated with improved survival.206–208 Aggressive fluid resuscitation for septic shock was recently criticized as being only weakly supported by evidence.209 Further, recent cohort studies have reported an association between positive fluid balance and increased mortality in adult and pediatric patients with sepsis, as well as other critical illnesses.210–220 The Fluid Expansion as Supportive Therapy (FEAST) study compared fluid boluses of 20 to 40 mL/kg to no bolus in over 3000 acutely ill African children, reporting significantly increased mortality in the group randomized to the fluid bolus arm.221 The FEAST study raises many questions regarding the efficacy of fluid resuscitation even though the relevance for resource-rich environments is unclear.222–224 At the time of this writing, there is an ongoing study testing the efficacy of a fluid-sparing protocol in children with septic shock (NCT1973907) It is hoped that this study will further inform the issue of appropriate fluid resuscitation in pediatric septic shock Fig 110.4 shows a pediatric algorithm for early goal-directed therapy This updated algorithm emphasizes the importance of guiding therapy based on clinical and objective evidence for ongoing shock Previous versions of this algorithm reflected studies in adults and children demonstrating reductions in sepsis-related mortality with goal-directed therapy guided by central venous oxygen saturation measurements.225,226 However, the generalizability of the single pediatric study that led to this algorithm is questionable because of the high mortality in the control group Similarly, a more recent study in children testing the efficacy of central venous oxygen saturation monitoring had an in-hospital mortality of 54% in the control group.227 More importantly, three large adult trials were completed showing no benefit of goal-directed therapy compared with standard care.228–230 An important caveat of these three trials is that standard care has evolved considerably over the last decade to emphasize early recognition and early aggressive resuscitation of sepsis A recent editorial opined that despite the results of the large adult studies, mixed venous saturation monitoring should remain a cornerstone target of guideline therapies for pediatric septic shock.231 An alternative opinion is that the cumulative data supports early recognition of sepsis and a highly attentive critical care team focused on early aggressive resuscitation of septic shock rather than supporting mixed venous oxygen saturations as a singular end point Accordingly, the updated pediatric septic shock algorithm now reflects deemphasizing the importance of central venous oxygen saturation and focuses more generically on early recognition, attentiveness, and early aggressive resuscitation Cardiovascular agents are indicated for fluid refractory septic shock; specific agent selection should ideally be predicated on the cardiovascular state of the patient Patients with septic shock can present with low cardiac output and elevated systemic vascular resistance, high cardiac output and low systemic vascular resistance, or low cardiac output and low systemic vascular resistance The incidence of sepsis-induced cardiac dysfunction in children is thought to be considerably higher than in adults, potentially representing up to 80% of fluid refractory patients.16 1304 S E C T I O N X I Pediatric Critical Care: Immunity and Infection • Recognize sepsis: altered perfusion, fever, tachycardia, changes in mental status, etc • Establish IV/IO access according to PALS; administer oxygen • • • • Begin antibiotics If no hepatomegaly or rales/crackles, rapidly administer 20 mL/kg isotonic crystalloid Reassess after bolus for improved perfusion Administer up to 60 mL/kg isotonic crystalloid if perfusion not improved, and no hepatomegaly or rales/crackles • Correct hypoglycemia and/or hypocalcemia 15 FLUID REFRACTORY SHOCK? • Begin peripheral IV/IO pharmacologic cardiovascular support ã Preferably epinephrine 0.05 to 0.3 àg/kg/min • Establish central venous access; tracheal intubation as needed; consider ketamine as anesthetic agent for needed procedures • Titrate epinephrine 0.05 to 0.3 µg/kg/min for cold shock (titrate central dopamine to àg/kg/min if epinephrine not available) ã Titrate norepinephrine 0.05 µg/kg/min and upward to reverse warm shock (titrate central dopamine >10 µg/kg/min if norepinephrine not available) 60 CATECHOLAMINE-RESISTANT SHOCK? • Consider adjunctive hydrocortisone if at risk for adrenal insufficiency • Consider advanced measurements of cardiovascular function to further direct fluid, inotropic, and vasopressor support • Suggested endpoints: normal MAP – CVP,ScvO2 >70%, and/or CI 3.3 to 6.0 L/min/m2 Normal blood pressure cold shock ScvO2 10 g/dL on epinephrine? Low blood pressure cold shock ScvO2 10 g/dL on epinephrine? Low blood pressure warm shock ScvO2