1307CHAPTER 110 Pediatric Sepsis several days after the initial resuscitation The choice of fluid to be used in this process is controversial, although there is general agreement that the fluid choice[.]
CHAPTER 110 Pediatric Sepsis several days after the initial resuscitation The choice of fluid to be used in this process is controversial, although there is general agreement that the fluid choice should be isotonic The three broad choices of fluids are crystalloid, nonblood colloid, and blood products As evident when calculating the arterial content of oxygen, maintaining an adequate hemoglobin level is an important factor in providing adequate oxygen delivery Although there is no clear recommended hemoglobin level for children with sepsis, one recent study showed that in patients with central venous oxygen saturation less than 70%, transfusion of packed red blood cells, in combination with other measures to increase oxygen delivery, is associated with improved outcomes.225 After initial resuscitation, ongoing myocardial dysfunction and altered vascular tone are likely to persist Therefore, ongoing titration of cardiovascular drugs will be required to maintain adequate oxygen delivery Many patients will require titration of inotropes and vasopressors simultaneously; it must be emphasized this will likely be a dynamic process requiring constant reassessment of the aforementioned indicators of adequate oxygen delivery It is important to recognize that blood pressure alone as a goal may not correlate with optimal tissue perfusion and oxygen delivery This concept is best illustrated by the subset of patients with septic shock who benefit from afterload reduction (i.e., vasodilation) Patients with high systemic vascular resistance and low cardiac output, who have adequate preload, can benefit tremendously from inodilators such as milrinone.251,252 Alternatively, this subset of patients can also benefit from pure vasodilators such as the NO donor, nitroprusside (in combination with a pure inotrope) After institution of afterload reduction, these types of patients may actually have lower blood pressures than one would typically target but will have enhanced tissue perfusion and oxygen delivery A subset of patients will have refractory shock despite optimization of these management strategies In this subset, the institution of extracorporeal membrane oxygenation (ECMO) is recommended as a consideration in the context of refractory shock.205 Our anecdotal and subjective experiences suggest that institution of ECMO support for refractory septic shock can be lifesaving in a subset of patients The challenges that come with institution of ECMO include the definition of refractory septic shock, timing of ECMO initiation before the onset of irreversible end-organ failure, and ensuring that ECMO support is not prematurely or unnecessarily instituted in patients who can be effectively managed with conventional support (i.e., not exposing patients to unnecessary risks) A summary of approaches to improving the relationship between oxygen delivery and oxygen consumption is provided in eBox 110.3 Additional Management Considerations Patients with sepsis may have poor nutrition prior to presentation and often are not fed during the first few days of illness Because of an increased metabolic rate and poor nutrition, patients with sepsis are frequently catabolic and at risk for development of protein calorie malnutrition.253 Intestinal ischemia in association with loss of the mucosal barrier from malnutrition is associated with translocation of bacteria and endotoxin from the intestine into the bloodstream Use of enteral feeding in critically ill patients has been shown to improve survival and decrease hospital stay.254 The benefit of enteral feeding should be balanced with the risk of stressing intestinal function in the face of poor splanchnic perfusion, especially in the presence of vasopressors such as 1307 epinephrine and norepinephrine.255 Regardless of the feeding mode, adequate nutrition and nitrogen balance are important for maintaining adequate host immune function and achieving homeostasis, as malnutrition adversely affects immune function Finally, in the absence of enteral feedings, pharmacologic prophylaxis against stress-related gastrointestinal bleeding is recommended by the most recent guidelines Other important management considerations—including fluid balance, renal replacement therapy, the type of fluids used for resuscitation, and management of hyperglycemia—are covered in other chapters Immunomodulation Since immune/inflammatory dysregulation is a well-accepted pathophysiologic concept in septic shock, there has been a great deal of effort in developing treatment strategies directly targeted at immune/inflammatory modulation Steroids have long been proposed as a general antiinflammatory strategy In many clinical settings, patients with septic shock demonstrate worsening of their shock temporally associated with antibiotic administration It is thought that this phenomenon results from a massive release of bacterial toxins after antibiotic-mediated bacterial killing and a subsequent inappropriately exuberant immune/inflammatory response However, the use of high-dose steroids to blunt this response is now universally accepted to be of no benefit and potentially harmful.256,257 A more recent approach to using corticosteroids in septic shock involves the concept of relative adrenal insufficiency and an association between relative adrenal insufficiency and catecholamine refractory shock.258,259 A landmark study by Annane and colleagues demonstrated a substantial benefit in adults with septic shock having “relative adrenal insufficiency” (based on cortisol levels and ACTH stimulation testing) and treated with replacement hydrocortisone.260 In a more recent study by Annane and colleagues, 90-day mortality was significantly lower among adults with septic shock who received hydrocortisone and fludrocortisone compared with those who received placebo Patients treated with hydrocortisone and fludrocortisone also had more vasopressor-free and organ failure–free days.261 While other large studies have found a decrease in time to reversal of shock with hydrocortisone, they have not found a mortality reduction.262–264 Further, Van den Berghe and colleagues reported a reduction in cortisol metabolism related to suppressed expression and activity of cortisol-metabolizing enzymes during adult critical illness, adding another confounding variable when considering administration of corticosteroids for septic shock.265 Conflicting data and controversy also exist in the pediatric septic shock population Existing data are currently limited to small randomized trials, meta-analyses, observational studies, and practitioner anecdotes and experience.266–270 Recently, a retrospective analysis of an existing transcriptomic database of pediatric septic shock demonstrated that the administration of corticosteroids in pediatric septic shock was associated with repression of genes corresponding to adaptive immunity, raising questions about potential harm associated with corticosteroid administration during septic shock.174 Jardine and colleagues examined genes involved in cortisol synthesis, metabolism, and activity in critically ill pediatric patients using tag SNP methodology.174,174a They identified an SNP in the MC2R gene (which codes for the ACTH receptor) and demonstrated that the AA genotype was associated with a low free cortisol response to critical illness A 1307.e1 • eBOX 110.3 Means of Altering the Relationship Between Oxygen Delivery and Oxygen Consumption Means of Improving Oxygen Delivery • Increase cardiac output • Increase stroke volume • Increase preload (volume resuscitation) • Increase contractility (administration of inotropes) • Decrease afterload (administration of vasodilators) • Increase heart rate (rarely a therapeutic goal in sepsis management) • Increase arterial oxygen content • Increase arterial oxygen tension (administer oxygen, apply positive pressure ventilation, etc.) • Increase arterial oxygen-carrying capacity (transfusion of packed red blood cells) • In select cases, cardiac output and arterial oxygen content can both be increased through the institution of venoarterial extracorporeal membrane oxygenation Means of Decreasing Oxygen Consumption • • • • Avoid/manage hyperthermia Remove work of breathing Administer sedation Administer paralytics 1308 S E C T I O N X I Pediatric Critical Care: Immunity and Infection recent report described the development and validation of a realtime subclassification method for septic shock using previously identified gene expression–based subclasses, which corresponded to genes for adaptive immunity and glucocorticoid receptor signaling.197 The study reported that allocation to the subclass with decreased expression of the glucocorticoid receptor signaling pathway genes was independently associated with increased mortality and that adjunctive corticosteroid administration to patients in that subclass was independently associated with almost four times the risk of mortality It is possible that patients with septic shock and high levels of illness severity stand to benefit the most from adjunctive corticosteroids Funk and colleagues recently stratified a large cohort of adults with septic shock into quartiles of illness severity using APACHE II scores Corticosteroid administration was associated with decreased mortality among patients in the highest quartile of illness severity.271 In contrast, when a large cohort of children with septic shock was stratified for baseline mortality risk using stratification biomarkers, corticosteroids were not associated with decreased mortality for patients in the intermediate or high baseline mortality risk groups.272 The role of hydrocortisone replacement in pediatric septic shock represents another major challenge in the field that must be directly addressed by a large, multicenter, randomized trial Current barriers to conducting this important trial include lack of equipoise in the pediatric critical care community, lack of consensus regarding the definition of relative adrenal insufficiency, and our inability to select which patients with septic shock are most likely to benefit from adjunctive corticosteroids.200,273 Thus, at present, treatment guidelines suggest hydrocortisone replacement therapy be considered for patients who appear refractory to resuscitative measures, have a known history of adrenal insufficiency, have already received exogenous steroids, or have an abnormal ACTH stimulation test result.205 Given the lack of objective evidence supporting the efficacy of adjunctive corticosteroids and accumulating evidence suggesting harm, the otherwise strong recommendation for corticosteroids in the current pediatric guidelines should be revised accordingly The role of adjunctive corticosteroids for pediatric septic shock might be definitively defined by way of the recently launched Stress Hydrocortisone for Pediatric Septic Shock (SHIPSS) trial, which involves a 10001 patient placebo controlled trial testing the efficacy of adjunctive hydrocortisone (NCT03401398) More recently, there is interest in using hydrocortisone in combination with ascorbic acid and thiamine.274,275 The pathophysiologic explanation for the use of hydrocortisone with ascorbic acid is a synergistic effect Glucocorticoids increase the expression of the sodium-vitamin C transporter (SVCT2), which is downregulated during inflammatory states Ascorbic acid, in turn, restores glucocorticoid receptor function Ascorbic acid also functions as an antioxidant, reducing endothelial permeability and improving vascular function, and plays a crucial role in the production of endogenous vasopressors Furthermore, it acts as an immunomodulator regulating macrophage function and reduction of inflammatory mediators Thiamine is a crucial cofactor for the Krebs cycle; thiamine deficiency can result in arrest of the Krebs cycle and shift from aerobic to anaerobic respiration, thereby increasing lactate levels Renewed interest in ascorbic acid has developed following several recent small studies Fowler and colleagues found that 24 septic adults had significant improvement in organ function scores (SOFA) over 96 hours after intravenous ascorbic acid administration and no adverse effects.276 More recently, Zabet and colleagues demonstrated a reduction in vasopressor requirement and mortality in septic patients receiving vasopressors.277 Following the vitamin C monotherapy trials, a study was published on the effects of combined hydrocortisone-ascorbic acid-thiamine in adults with septic shock Marik and colleagues found that the combined therapy decreased mortality and SOFA scores, and reduced vasopressor dependence in adult septic patients.274 At present, these small trials are not adequate to implement ascorbic acid routinely as a monotherapy or combined therapy in the management of septic patients However, at this time, there are multiple randomized control trials being conducted to address the role of ascorbic acid, thiamine, and hydrocortisone in sepsis Because the pathophysiology of septic shock is directly linked to circulating pathogen-derived toxins and circulating inflammatory mediators, removal of these molecules via hemofiltration or exchange transfusion (i.e., plasmapheresis) has been hypothesized to improve outcome Both hemofiltration and plasmapheresis were discussed in previous sections The fact remains that these approaches, while theoretically well founded, remain to be proven and cannot be recommended routinely in the absence of more objective data Both strategies carry significant risks that must be weighed against the potential theoretical benefits These include difficult vascular access in smaller children, fluid and electrolyte imbalance, hypothermia, anticoagulation requirements because of extracorporeal circuits, and acutely altered hemodynamics when instituting therapy In addition, beneficial proteins such as albumin, immunoglobulins, clotting factors, and counterregulatory cytokines may be removed to the detriment of the patient Part of the inflammatory response involves cytokines causing widespread activation of the coagulation cascade with suppression of fibrinolysis, as described in previous sections Disseminated intravascular coagulation has been implicated in the etiology of multiple-organ injury leading to MODS and is directly linked to alterations of endogenous anticoagulants such as antithrombin III and protein C While recombinant forms of these anticoagulants are available, they have not been demonstrated to be efficacious in the pediatric population and carry significant risks of serious adverse events due to bleeding As previously described, multiple antiinflammatory strategies have been attempted and some are now being reconsidered These include anti-TNF, anti-IL-1, antiendotoxin, TLR-4 antagonists, and anti-PAF (platelet-activating factor) strategies Thus far, none of these strategies has proven to be of sufficient clinical benefit in septic shock to warrant formal approval as standard of care It is hoped that better designed studies that carefully stratify patients, consider the presence or absence of an offending pathogen, and possibly identify genetic factors influencing outcome will provide insight into the appropriate immunomodulation agents clinically beneficial to pediatric patients with septic shock.278 An alternative approach to immunomodulation in septic shock focuses on immune “enhancement” rather than inhibition of inflammation As emphasized in previous sections, the paradigm of sepsis as an adaptive immune problem is increasingly gaining credence in the field Thus, there is now growing attention to the use of potentially immune-enhancing agents such as interferon-g, granulocyte-macrophage colony stimulating factor, zinc, selenium, prolactin, agonist antibody to CD40, PD-1 inhibitors, and IL-7.23,110,199,279–282 Thus, the next major advance in clinical septic shock management may involve one or more of these immune-enhancing approaches rather than an antiinflammatory approach CHAPTER 110 Pediatric Sepsis The Case for More Effective Stratification in Pediatric Septic Shock The vast majority of interventional clinical trials in septic shock have failed to demonstrate efficacy of the particular test agent A potential reason for failure in these trials is not because the biological/ physiological principle being tested was fundamentally flawed Rather, the primary reason for failure lies in the inability to effectively address the substantial heterogeneity characterizing the syndrome of septic shock As indicated throughout this chapter, septic shock is a heterogeneous syndrome with the potential to negatively and directly affect all organ systems This heterogeneity has consistently challenged multiple investigators attempting to evaluate the efficacy of various experimental interventions As astutely stated by Marshall, a key challenge in the field is to reduce and manage this heterogeneity by more effectively stratifying patients for the purposes of more rational and effective clinical research and clinical management.283 The concept of preintervention stratification in sepsis and its positive impact on the efficacy of an experimental therapy was corroborated in a murine model of polymicrobial sepsis.40 One potential strategy for stratifying children with septic shock involves early identification of septic shock endotypes based on genome-wide expression patterns As described earlier, endotypes of pediatric septic shock have been identified based exclusively on gene expression profiling conducted within 24 hours of admission; these expression-based subclasses have highly relevant differences in illness severity and mortality.177–179,197 A similar strategy was demonstrated in adult patients suffering from trauma and, recently, Knox and colleagues reported endotypes of adult sepsis based on organ failure patterns.283a As high-throughput technologies evolve and validation studies are rigorously performed, the ability to conduct expression-based endotyping of pediatric septic shock could very well become a clinical reality.278 Another potential strategy for stratifying children with septic shock is biomarker-based stratification Many biomarkers can be readily measured in the blood compartment, providing a clinically feasible strategy for early stratification of patients For example, IL-8 can be readily and rapidly measured in small-volume blood samples IL-8 was found to be a very robust outcome biomarker in children with septic shock.44 It has been proposed that these types of sepsis outcome biomarkers (i.e., biomarkers having high negative predictive values for mortality) could be used to stratify patients eligible for interventional septic shock trials.44,284 Patients having a high likelihood of survival with standard care, but otherwise meeting entry criteria for a given interventional trial, could be potentially excluded from the trial based on these biomarkers Such a stratification strategy would derive a study population with a more optimal risk-to-benefit ratio, improving the ability to demonstrate efficacy for a given test agent This type of strategy would be particularly useful for a test agent carrying more than minimal risk While single biomarker-based patient stratification is clinically appealing, it may not be sufficiently robust to meet all clinical and research needs Given the biological complexity of pediatric septic shock, a stratification strategy based on a panel of multiple biomarkers has more potential to meet the stratification needs for pediatric sepsis To this end, the Pediatric Sepsis Biomarker Risk Model (PERSEVERE) was derived and validated.190,191,194,285,286 PERSEVERE incorporates a panel of biomarkers into a decision tree derived using Classification and Regression Tree (CART) methodology The terminal nodes of the decision tree provide a range of reliable baseline mortality probabilities for children with septic shock eFig 110.5 shows the PERSEVERE II decision tree 1309 Several applications are possible for PERSEVERE These include stratification for clinical trial enrollment, serving as a benchmark for quality improvement efforts, and informing individual patient decision-making PERSEVERE has been used to conduct retrospective, stratified analyses of clinical data.223,272,285 In a recent study, combining PERSEVERE with endotyping identified a subgroup of children with septic shock more likely to benefit from corticosteroids.287 Conclusion Sepsis is and will continue to be an important challenge to the pediatric intensivist Indeed, sepsis is one of the few disease processes for which the pediatric intensivist can claim ownership Although much is known about the biological and molecular mechanisms involved in sepsis, much of this knowledge has not directly translated to improved bedside care At present, most of the therapeutic modalities for sepsis are fundamentally supportive and founded on the basic principles that define the discipline of critical care medicine Although this approach has directly improved the outcome of sepsis in children, the fact that more than 4000 children per year in the United States alone continue to die in association with severe sepsis warrants further advances Realization of this goal is feasible but requires further mechanistic insights at the physiologic, molecular, and genetic levels, as well as the design of large-scale, pediatric-specific interventional trials complemented by evolving stratification strategies As “owners” of pediatric septic shock, pediatric intensivists are well positioned to lead this effort on all fronts Key References Cuenca AG, Moldawer LL Myeloid-derived suppressor cells in sepsis: friend or foe? Intensive Care Med 2012:38(6):928-930 Goldstein B, Giroir B, Randolph A International pediatric sepsis consensus conference: definitions for sepsis and organ dysfunction in pediatrics Pediatr Crit Care Med 2005:6(1):2-8 Hotchkiss RS, Coopersmith CM, McDunn JE, Ferguson TA The sepsis seesaw: tilting toward immunosuppression Nat Med 2009:15(5): 496-497 Nadel S, Goldstein B, Williams MD, et al Drotrecogin alfa (activated) in children with severe sepsis: a multicentre phase III randomised controlled trial Lancet 2007:369(9564):836-843 Ranieri VM, Thompson BT, Barie PS, et al Drotrecogin alfa (activated) in adults with septic shock N Engl J Med 2012:366(22):20552064 Singer M, Deutschman CS, Seymour CW, et al The third international consensus definitions for sepsis and septic shock (Sepsis-3) JAMA 2016:315(8):801-810 Weiss SL, Fitzgerald JC, Pappachan J, et al Global epidemiology of pediatric severe sepsis: the sepsis prevalence, outcomes, and therapies study Am J Respir Crit Care Med 2015;191(10):1147–1157 Wong HR, Cvijanovich NZ, Allen GL, et al Corticosteroids are associated with repression of adaptive immunity gene programs in pediatric septic shock Am J Respir Crit Care Med 2014:189(8):940-946 Wong HR, Cvijanovich NZ, Anas N, et al Developing a clinically feasible personalized medicine approach to pediatric septic shock Am J Respir Crit Care Med 2015:191(3):309-315 Wong HR, Salisbury S, Xiao Q, et al The pediatric sepsis biomarker risk model Crit Care 2012:16(5):R174 Wong HR Genome-wide expression profiling in pediatric septic shock Pediatr Res 2013:73(4 Pt 2):564-569 The full reference list for this chapter is available at ExpertConsult.com 1309.e1 ROOT N = 424 Class # % Dead 49 11.6 Alive 375 88.4 CCL3 ≤ 150 % Class # Dead 20 7.0 Alive 266 93.0 TN1 HSPA1B ≤ 90,000 % Class # 0.0 Dead Alive 18 100.0 TN2 CCL3 > 150 % Class # Dead 109 32.0 Alive 232 68.0 TN7 Platelets ≤ 90 % Class # Dead 18 33.3 Alive 36 66.7 HSPA1B > 90,000 % Class # Dead 20 7.5 Alive 248 92.5 IL8 ≤ 200 % Class # 0.7 Dead Alive 142 99.3 TN8 GZMB ≤ 32 % Class # Dead 0.0 Alive 47 100.0 IL8 > 200 % Class # Dead 19 15.2 Alive 106 84.8 TN3 Platelets ≤ 38 % Class # Dead 44.4 Alive 10 55.6 TN9 GZMB > 32 % Class # Dead 11 29.7 Alive 26 70.3 Platelets > 38 % Class # Dead 11 10.3 Alive 96 89.7 IL8 ≤ 830 % Class # 5.7 Dead Alive 66 94.3 TN4 MMP8 ≤ 27,400 % Class # Dead 16.7 Alive 15 83.3 Platelets > 90 % Class # Dead 11 13.1 Alive 73 86.9 TN6 IL8 > 830 % Class # Dead 18.9 Alive 30 81.1 TN5 MMP8 > 27,400 % Class # 1.9 Dead Alive 51 98.1 • eFig 110.5 PERSEVERE II decision tree for assigning a baseline mortality probability for children with septic shock The decision tree entails six biomarker-based decision rules and two decision rules based on baseline platelet concentrations The biomarkers used for analysis are as follows: C-C chemokine ligand (CCL3), heat shock protein 70 kDa 1B (HSPA1B), interleukin-8 (IL8), granzyme B (GZMB), and matrix metalloproteinase-8 (MMP8) The top node of the decision tree, the root node, provides the total number of subjects as well as the number and proportion of survivors and nonsurvivors (28-day, all-cause mortality) Subjects in the root node are subsequently allocated to daughter nodes based on the results of binary recursive partitioning Each daughter node provides the criterion for deciding subsequent partitions, along with the number and proportion of survivors and nonsurvivors All biomarker concentrations are in pg/mL Terminal nodes (TN) reflect the final assignment of risk to an individual case TN1, TN2, TN5, and TN8 are low risk (mortality probability 0.000–0.019), TN4 and TN6 are intermediate risk (mortality probability 0.167–0.189), and TN3, TN7, and TN8 are high risk (mortality probability 0.297–0.444) ... regulating macrophage function and reduction of inflammatory mediators Thiamine is a crucial cofactor for the Krebs cycle; thiamine deficiency can result in arrest of the Krebs cycle and shift... management of septic patients However, at this time, there are multiple randomized control trials being conducted to address the role of ascorbic acid, thiamine, and hydrocortisone in sepsis Because... septic shock As indicated throughout this chapter, septic shock is a heterogeneous syndrome with the potential to negatively and directly affect all organ systems This heterogeneity has consistently