Pediatric sepsis









  • The typical patient with septic shock has simultaneous derangements of cardiovascular function, intravascular volume status, respiratory function, immune/inflammatory regulation, renal function, coagulation, hepatic function, and/or metabolic function.



  • The complexity and heterogeneity of septic shock warrants a systematic and multifaceted approach on the part of the pediatric intensivist.



  • Although some overlap exists among the terms spanning the sepsis spectrum ( systemic inflammatory response syndrome , sepsis , severe sepsis , and septic shock ), each term is intended to define a particular patient population.



  • Sepsis is now viewed as a dysregulation of the immunologic and inflammatory pathways normally directed toward pathogen eradication and restoration of homeostasis.



  • From a clinical standpoint, the treatment of sepsis entails four important goals: initial resuscitation, pathogen eradication, maintenance of oxygen delivery, and (in the future) carefully directed modulation of the inflammatory response.



  • Genomic medicine and systems biology represent novel approaches for studying complex processes such as septic shock.



  • The development of robust stratification and phenotyping strategies has the potential to more effectively manage the intrinsic heterogeneity of septic shock and, thus, improve the effectiveness of both clinical research and individual patient care.



Management of the patient with septic shock embodies the discipline of pediatric critical care medicine. The typical patient with septic shock has simultaneous derangements of cardiovascular function, intravascular volume status, respiratory function, immune regulation, renal function, coagulation, hepatic function, and/or metabolic function. The degree to which any one of these derangements manifests in a given patient is highly variable and influenced by multiple host and nonhost factors, including developmental stage, presence or absence of comorbidities, causative agent of septic shock, immune status, genetic background, and variations in therapy. These factors combine to profoundly influence the course and ultimate outcome of septic shock.


The complexity of septic shock warrants a systematic and multifaceted approach on the part of the pediatric intensivist. Optimal management requires a strong working knowledge not just of cardiovascular physiology and infectious diseases but also of multiple-organ function and interaction, inflammation-related biology, immunity, coagulation, pharmacology, and molecular biology. The pediatric intensivist also needs a working knowledge of genomic medicine for the future management of patients with septic shock. This chapter provides a comprehensive description of the many aspects influencing the development and outcome of septic shock, pathophysiology at the physiologic and molecular levels, contemporary management of septic shock, and what we believe to be the next important future directions in the field. Ultimately, this information must be integrated with bedside experience and clinical acumen, which cannot be supplanted by a book chapter.


Epidemiology


A true picture of the epidemiology of septic shock is clouded by the lack of a reliable case definition. This is true for both the adult and pediatric populations. A few pediatric-specific studies, however, illustrate the importance of sepsis in today’s modern intensive care unit (ICU). Proulx et al. analyzed the incidence and outcome of the systemic inflammatory response syndrome (SIRS), sepsis, severe sepsis, and septic shock (see next section for definitions) in a single institution. A total of 1058 admissions were analyzed over a 1-year period. SIRS was present in 82% of patients, 23% had sepsis, 4% had severe sepsis, and 2% had septic shock. The overall mortality rate for this patient population was 6%, with the majority of deaths occurring in patients with multiple-organ dysfunction syndrome (MODS). Among the patients with MODS, distinct mortality rates were associated with SIRS (40%), sepsis (22%), severe sepsis (25%) and septic shock (52%). Later studies by Watson et al. provided more comprehensive retrospective epidemiologic surveys of pediatric sepsis to date. By linking 1995 hospital records from seven large states (representing 24% of the US population) with census data, they estimated an incidence of 42,371 cases of severe sepsis in individuals younger than 20 years of age (0.6 cases/1000 population). The highest incidence was in neonates (5.2 cases/1000 population), compared with children ages 5 to 14 years, who had an incidence of 0.2 cases/1000 population. The overall mortality rate in this population was 10.3% (4364 deaths/year nationally). In addition, patients younger than 1 year of age and patients with comorbidities had higher mortality rates than patients between 5 and 14 years old and patients without comorbidities, respectively. Their study also estimated an annual national healthcare cost of $1.7 billion associated with severe sepsis.


In a follow-up study, these investigators used a similar approach to investigate severe sepsis trends in the United States from 1995 to 2005. They reported an overall decrease in the case-fatality rate over this period, from 10.3% to 8.9%, but an overall increase in the prevalence of severe sepsis. Most of this increase was accounted for by an increase in the prevalence of severe sepsis in newborns.


Czaja and colleagues used the discharge diagnosis of severe sepsis for Washington State to investigate the readmission rates and late mortality for children (1 month to 18 years old) following severe sepsis. From 1990 through 2004, 7183 children were diagnosed with severe sepsis and 6.8% of these patients died during the sentinel admission or within 28 days of discharge. Importantly, death certificates confirmed that an additional 434 (6.5%) of the initial survivors died during the follow-up period, with the highest late death rate occurring within 2 years of the initial hospitalization. Although most of the early and the late deaths occurred in children with comorbidities (8% early death, 10.4% late death), 8% of children with no comorbidities died during their initial hospitalization, with 2% of the 28-day survivors being classified as late deaths.


Schlapbach and colleagues recently reported on the epidemiology of invasive infections, sepsis, and septic shock in critically ill children in Australia and New Zealand. The age-standardized incidence increased every year, from 2002 to 2013, for all three study categories. Critically ill children with invasive infections, sepsis, or septic shock accounted for 26% of all pediatric deaths among all of the critically ill children in this cohort. Comparing 2008 to 2013 to 2002 to 2007, risk-adjusted mortality significantly decreased for invasive infections and sepsis but not for septic shock.


In 2015, Weiss and colleagues published the first international prospective epidemiologic study of pediatric severe sepsis. Almost 7000 patients younger than 18 years were screened on 5 days from 2013 to 2014 at 128 sites from 26 countries using a point prevalence study method. Severe sepsis was defined using the 2005 International Pediatric Sepsis Consensus Conference criteria. This large, comprehensive study demonstrated an 8.2% prevalence of pediatric severe sepsis in international pediatric ICUs (95% confidence interval [CI], 7.6%–8.9%), consistent with adult epidemiologic data. Hospital mortality was 25% regardless of age or country. Multiorgan dysfunction was demonstrated in 67% of patients at sepsis recognition, with 30% subsequently developing new or progressive multiorgan dysfunction. The higher mortality rate for severe sepsis reported in this study, relative to previous studies, might reflect the point prevalence methodology, given that the retrospective use of ICD9 codes is susceptible to underestimating disease severity. Thus, this most recent study suggests that mortality from pediatric sepsis can approach that of adults.


Collectively, these data illustrate that sepsis continues to present a major pediatric public health problem in terms of incidence, mortality, and healthcare costs. Nevertheless, there is an ongoing need for quality epidemiologic studies of sepsis in children. Quality epidemiologic studies are necessary for our understanding not only of incidence but also of the impact of new knowledge and therapies. One major issue that must be addressed is the development of more meaningful and consistent case definitions. Consistent case definitions will also facilitate and improve the design of more effective interventional trials specific to the pediatric population. Equally important is objectively measuring long-term outcomes in these patients (i.e., quality of life) beyond the dichotomy of “alive” or “dead.” Progress in this important area is steadily coming to fruition.


Definitions


Intuitively, experienced pediatric intensivists usually know when they encounter a patient with sepsis. Thus, strict definitions of sepsis and septic shock could be viewed as having relatively limited value in daily practice. Despite this common perception, there is a clear need for standard definitions of sepsis and septic shock for four primary reasons. First, with the development of standard definitions, we will be able to more accurately characterize the epidemiologic features of septic shock in the pediatric population. Second, as novel, expensive, and potentially higher-risk therapies are developed, it will be important to accurately identify and stratify patients early in the course of septic shock if we are to apply those therapies to the most appropriate groups and realize a more favorable benefit-to-risk ratio in a given patient population. Third, definitions allow for the development of sepsis recognition algorithms for frontline providers. Finally, standard definitions are crucial to the design of much needed pediatric-specific interventional trials.


The International Consensus Conference on Pediatric Sepsis and Organ Dysfunction was convened in 2002 to develop pediatric-specific definitions for SIRS, sepsis, severe sepsis, septic shock, and organ failure. The results of this conference were subsequently published in 2005. The standard terms to describe the sepsis spectrum are SIRS , sepsis , severe sepsis , and septic shock . Each term is intended to describe a clinical syndrome having increasing illness severity and relatively increasing specificity, which, in turn, drives important clinical decision and therapeutic processes.


SIRS is not a diagnosis. The term is intended to represent a state of relative inflammatory/immune activation in a given patient and is said to be present when a patient meets at least two of the four criteria listed in eBox 110.1 , one of which must be abnormal temperature or abnormal leukocyte count. Thus, patients with diverse clinical conditions—such as sepsis, pancreatitis, burns, or hypermetabolism following major trauma or surgery—can meet criteria for SIRS. Sepsis is defined as SIRS secondary to an infection, either documented by microbiology cultures or in the presence of other clinical evidence of infection. Severe sepsis is defined by sepsis criteria plus either cardiovascular dysfunction or acute respiratory distress syndrome (ARDS), or at least two other dysfunctional organ systems. Septic shock is defined by sepsis criteria, plus cardiovascular dysfunction. Importantly, each criterion takes into account the influence of developmental age on physiologic variables. The reader is referred to the original publication by Goldstein et al. for further details and definitions of organ dysfunction.



• eBOX 110.1

Criteria for Systemic Inflammatory Response Syndrome


The presence of at least two of the following four criteria, one of which must be abnormal temperature or leukocyte count:



  • 1.

    Core temperature (rectal, bladder, oral, or central catheter) >38.5°C or <36°C.


  • 2.

    Tachycardia, defined as a mean heart rate >2 standard deviations above normal for age in the absence of external stimulus, chronic drugs, or painful stimuli; or otherwise unexplained persistent elevation over a 0.5- to 4-hour time period; or for children <1 year: bradycardia, defined as a mean heart rate <10th percentile for age in the absence of external vagal stimulus, β-blocker drugs, or congenital heart disease; or otherwise unexplained persistent heart rate depression over a 0.5-hour time period.


  • 3.

    Tachypnea, defined as mean respiratory rate >90th percentile for age; or the need for mechanical ventilation for an acute process not related to underlying neuromuscular disease or the receipt of general anesthesia.


  • 4.

    Leukocyte count elevated or depressed for age (not secondary to chemotherapy-induced leukopenia) or >10% immature neutrophils.




Of note, in 2016, The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) put forth revised definitions of sepsis and septic shock for adult patients. They acknowledged that the criteria to meet SIRS is neither sensitive nor specific for sepsis. Accordingly, Sepsis-3 defined sepsis as life-threatening organ dysfunction caused by a dysregulated host response to infection. Septic shock is broadened to describe a subset of sepsis in which underlying circulatory and cellular metabolism abnormalities are profound enough to substantially increase mortality. Given that these definitions were developed relatively specific to the adult population, we will continue to use the pediatric-specific definitions described earlier until there is a consensus on the revised definitions for the pediatric population.


Clinical presentation


As a syndrome potentially affecting the entire body, the clinical presentation of sepsis is highly heterogeneous. The most common clinical manifestations of sepsis include fever or hypothermia, tachypnea, tachycardia, leukocytosis or leukopenia, thrombocytopenia, and change in mental status. It should be noted, however, that in the absence of meningitis changes in mental status are relatively late manifestations of septic shock and should not be relied on for early recognition of shock. One of the earliest signs alerting caregivers to the possibility of infection is fever. A number of the cytokines elicited in response to infection are pyrogens, particularly interleukin (IL)-1β and tumor necrosis factor (TNF)-α. Patients can also have hypothermia, which is generally more common in infants than older children. Finally, petechiae and/or purpura can be present and are potentially ominous signs of purpura fulminans.


Shock states can be grouped into four broad categories: hypovolemic, cardiogenic, obstructive, and distributive shock. Septic shock is unique because all four forms of shock may be involved simultaneously. The patient may have hypovolemic shock resulting from capillary leak, increased insensible water losses, poor intake, and/or decreased effective blood volume secondary to venodilation and arterial dilation (i.e., increased vascular capacitance). Cardiogenic shock manifests as depressed myocardial contractility and low cardiac output secondary to myocardial-depressant effects of bacterial toxins and inflammatory cytokines. Obstructive shock can result indirectly from diffuse microvascular thrombosis, or directly from abdominal compartment syndrome. Distributive shock can result directly from abnormally low systemic vascular resistance, leading to maldistribution of blood flow, or can result indirectly from the inability of tissues to adequately use oxygen at the mitochondrial level (i.e., cytopathic hypoxia).


The degree to which an individual patient manifests these physiologic perturbations is highly variable. In some cases, patients display increased cardiac output with diminished systemic vascular resistance. The presenting symptoms in this type of patient are tachycardia, a hyperdynamic precordium, bounding pulses, and warm, flushed skin characteristic of the distributive mode of shock or the so-called “warm” shock state. Despite this clinical appearance, the perfusion of major organs during warm shock may remain highly compromised secondary to maldistribution of blood flow. Alternatively, a patient with depressed cardiac output and elevated systemic vascular resistance has cool, mottled skin with diminished pulses and poor capillary refill characteristic of the “cold” shock state. Limited data and our collective anecdotal experience suggest that this latter presentation, cold shock, is more common in younger children compared with teenagers and adults. It has been suggested that patients who develop community-acquired septic shock more commonly present to the ICU with signs of “cold” shock, whereas patients who develop septic shock secondary to catheter-related infections more commonly present to the ICU with signs of “warm” shock. It is important to recognize that a given patient may transition from one shock state to another. Recognition and reassessment of these classes of shock are absolutely central to the choice of cardiovascular medications.


Patients with sepsis often have presenting symptoms of respiratory abnormalities, including tachypnea and hypoxia. Tachypnea alone can reflect a compensatory, respiratory alkalosis aimed at counteracting a metabolic acidosis secondary to shock. Chest roentgenogram in this setting often reveals a relatively small cardiac silhouette (potentially reflective of relative hypovolemia) with few vascular markings. However, in the face of capillary leak and decreased myocardial function, patients with septic shock often develop pulmonary edema and acute respiratory failure as fluid resuscitation proceeds. Alternatively, respiratory abnormalities can reflect pneumonia as the primary source of infection and/or the development of ARDS. In these situations, chest roentgenography will display patterns of pulmonary infiltrates characteristic of the respective scenarios.


All organ systems can be adversely affected by poor perfusion and decreased oxygen delivery. In addition, all organ systems can be directly or indirectly injured by bacterial toxins, circulating cytokines, and the products of activated white blood cells. The end result of these complex and interrelated pathologic mechanisms is MODS, which describes the serial and progressive failure of various organ systems and is associated with increased morbidity and mortality. Due to the increased mortality associated with MODS, there exist multiple screening tools to identify patients with multiorgan dysfunction who are therefore at increased risk for mortality from sepsis. Many of these screening tools have been in place; however, more recent tools, such as quick sequential organ failure assessment (qSOFA) discussed at Sepsis-3, are now being assessed for validity in the pediatric population. , ,


Pathogenesis


A large number of clinical and basic science studies have focused on the mechanisms underlying the development of sepsis. At least three major hypotheses have been proposed to explain the development of sepsis and its sequelae. The first hypothesis attributes the development of sepsis to an excessive or uncontrolled host inflammatory response. This “proinflammatory” hypothesis is broadly consistent with the concept of SIRS and is generally well supported by experimental and clinical data. However, a large number of clinical trials aimed directly at inhibition of various components of this putative excessive inflammatory response have failed, leading to the development of alternative hypotheses. One such alternative hypothesis states that sepsis is not directly the result of excessive inflammation but rather a more direct manifestation of failed antiinflammatory responses. Thus, in this alternative hypothesis, there is direct failure of the compensatory antiinflammatory response syndrome (CARS), which subsequently permits unchecked proinflammatory responses. Related to the CARS concept is the concept of immunoparalysis, which embodies the third overall hypothesis to account for the clinical manifestations of sepsis. The hypothesis of immunoparalysis postulates that sepsis is not a manifestation of too much or too little inflammation but rather a form of acquired immunodeficiency (both innate and adaptive immunity), leading to an inability to effectively clear pathogens and their products, causing direct tissue and organ injury. ,


A conceptual framework for integrating these 3 hypotheses/paradigms is provided in Fig. 110.1 . All three paradigms are biologically plausible and supported by the existing literature. While seemingly vastly different in concept, they are not mutually exclusive in the context of a highly heterogeneous syndrome such as human sepsis. It is plausible that all three paradigms are valid across a given cohort of heterogeneous patients with sepsis. In addition, each paradigm has the potential to influence all of the other paradigms, as indicated in Fig. 110.1 . The following sections review the existing literature supporting these three paradigms and will serve to frame the important concept of heterogeneity in sepsis. A major challenge in the field of sepsis is to more effectively understand how a given patient fits into one of these three paradigms (i.e., stratify or phenotype patients more effectively).




• Fig. 110.1


Three major paradigms for understanding the pathophysiology of sepsis and septic shock. Although the paradigms are mechanistically distinct, they are not mutually exclusive. Each paradigm has the potential to influence the others, and all are potentially operative in a heterogeneous patient cohort. Heterogeneity is a major component of septic shock, resulting from multiple host and environmental factors.


Persistent inflammation, immunosuppression, and catabolism syndrome (PICS) is a relatively new concept to describe patients with sepsis who do not seem to respond to therapy and require long-term hospital care. PICS is characterized by long-term, ongoing inflammation leading to long-term immunosuppression and organ injury and maladaptive metabolic derangements resulting in catabolism. As opposed to patients who respond rapidly to resuscitation and antimicrobial treatment, these patients are more likely to have prolonged stays in the ICU and suffer from subsequent sepsis episodes. Why some patients fall into this state and others respond rapidly to treatment is likely multifactorial and incompletely understood. , While PICS is best described among adult patients, studies documenting late mortality and frequent readmission among children who survive their initial episode of sepsis suggests that this phenotype might also exist in the pediatric population.


Pathogen recognition and signal transduction


The fundamental role of the immune system is to detect, contain, and eradicate invading pathogens. The first step in this process involves pathogen recognition, which is achieved by the activation of pattern recognition receptors (PRRs) on immune cells by pathogen-associated molecular patterns (PAMPs). Examples of PAMPs include lipopolysaccharide from the cell wall of gram-negative bacteria; lipoteichoic acid from the cell wall of gram-positive bacteria; mannans from the cell wall of yeast; double-stranded RNA of viruses; and unmethylated, CpG-rich deoxyribonucleic acid (DNA) unique to bacterial genomes. The most well-studied PRRs include the family of toll-like receptors (TLRs), which can have relatively specific recognition of PAMPs. For example, TLR-4 recognizes lipopolysaccharide, whereas TLR-2 recognizes lipoteichoic acid. Other examples of PRRs or PRR components include CD-14, scavenger receptors, nucleotide oligomerization domain (NOD) receptors, pentraxins, and collectins.


Engagement of PRRs on the cell surface of immune cells by PAMPs leads to activation of the immune system in the form of phagocytosis, proliferation, and production/secretion of cytokines. The latter process, cytokine expression, serves to orchestrate, direct, and amplify the innate and adaptive immune response toward pathogen eradication. However, if this process becomes dysregulated, this same production of cytokines, though required for pathogen eradication, can inadvertently lead to auto-injury of the host.


Much of the activation of the immune system upon PRR activation relies on signal transduction mechanisms, which serve to transfer the signal of pathogen recognition at the cell surface to the intracellular compartment in order to induce new gene expression or a change in cellular function. One of the major signal transduction mechanisms of the immune system is the nuclear factor-κB (NF-κB) pathway, which serves as a master “switch” for the expression of a wide variety of genes involved in inflammation and immunity. Indeed, activation of the NF-κB pathway is a major signaling pathway in the pathophysiology of sepsis and may represent a potential therapeutic target. , Another major signaling pathway for the regulation of genes involved in inflammation and immunity is the mitogen-activated protein kinase (MAPK) signaling pathway. The MAPKs consist of three major families: p38 MAP kinase, extracellular-regulated protein kinase (ERK), and c-Jun N-terminal kinases (JNK). These major kinase families are also referred to as stress-activated protein kinases (SAPKs). Similar to the NF-κB pathway, the MAPKs are also regarded as potential therapeutic targets in the context of sepsis. , , Finally, there is now increased attention on the phosphatase family of intracellular signaling molecules in the context of sepsis. Whereas kinases direct cellular signaling by adding phosphate groups to intracellular signaling proteins, phosphatases remove phosphate groups from these same intracellular signaling proteins. Thus, they can modulate proinflammatory cell signaling. ,


Cytokines as principal mediators of the sepsis response


Cytokines represent a broad family of proteins that have paracrine, autocrine, and endocrine properties; they have the ability to regulate and modulate virtually all aspects of immunity and inflammation. Common features of cytokines are provided in eBox 110.2 . This chapter reviews a selected group of cytokines thought to play an important role in the pathophysiology of sepsis.



• eBOX 110.2

mRNA, Messenger ribonucleic acid.

Common Features of Cytokines





  • Cytokine secretion is relatively brief and self-limited.



  • Secretion of many cytokines requires new mRNA transcription and new protein translation.



  • Expression and secretion is regulated by specific cellular signals.



  • A given cytokine can have multiple cellular sources.



  • A given cytokine can have multiple cellular targets.



  • A given cytokine can have multiple functions regarding cellular function or activation.



  • Cytokines can have redundant activities/functions with other cytokines.



  • Many cytokines regulate the activity and expression of other cytokines.




TNF-α is perhaps the most well-studied cytokine causally linked to sepsis. Evidence for TNF-α mediation of sepsis includes the observations that TNF is produced by hematopoietic cells, its expression is temporally related to the development of shock, it can by itself induce experimental septic shock in animals, and passive immunization against TNF blunts the endotoxin-induced sepsis response. The proinflammatory effects of TNF include leukocyte-endothelial cell adhesion, transformation to a procoagulant phenotype, induction of inducible nitric oxide (NO) synthase, and functioning as a principal “early” cytokine, inducing the subsequent cascade of mediators and cytokines promulgating the septic response. Despite a plethora of preclinical studies demonstrating the important proximal role of TNF-α in the pathophysiology of sepsis, multiple clinical trials targeted at neutralization of TNF-α activity have thus far failed to demonstrate efficacy.


IL-1β has many redundant biological properties to that of TNF-α and is also considered to be a major early cytokine in the sepsis response. IL-1β leads to inflammatory and immune cell activation via the NF-κB and MAPK pathways. Similar to TNF-α, clinical trials targeted at neutralization of IL-1β activity have thus far failed to demonstrate efficacy despite promising preclinical data.


IL-6 expression is highly dependent on TNF-α and IL-1β and is consistently found to be elevated during the course of sepsis. IL-6 is a pleiotropic cytokine possessing a number of functions, including driving the acute-phase response in hepatocytes, differentiating myeloid cells, stimulating immunoglobulin production, and activating T-cell proliferation. Because increased IL-6 admission levels have been correlated with death in the context of sepsis, there has been interest in using IL-6 as a stratification biomarker for interventional clinical trials in sepsis. While this stratification approach has been highly effective in animal models of sepsis, it has thus far failed when applied in the clinical setting.


IL-8 is a canonical member of the chemokine subclass of cytokines. The term chemokine refers to the ability of certain cytokines to serve as chemoattractants, which direct leukocyte movement to sites of infection and inflammation (chemotaxis). Both TNF-α and IL-1β can induce IL-8 production from a variety of cells, including endothelial cells, macrophages, neutrophils, and epithelial cells. IL-8 is the principal human chemoattractant for neutrophils; it appears to play a major role in the recruitment of neutrophils to the lungs in patients with sepsis-induced ARDS. Serum IL-8 measurements within 24 hours of presentation to the ICU can robustly predict good outcome in children with septic shock receiving standard care. Other chemokines relevant to the pathophysiology of septic shock include monocyte chemoattractant protein 1 (MCP-1) and macrophage inflammatory protein-1 (MIP-1).


Macrophage migration inhibitory factor (MIF) is another important cytokine in the pathophysiology of sepsis. High levels of MIF in patients with septic shock and ARDS correlate with poor outcome. , MIF possesses a number of biological activities generally directed toward a proinflammatory phenotype, including skewing of naïve T cells toward a Th1 phenotype. An unusual feature of MIF is that its secretion is enhanced by glucocorticoids, whereas the expression and activity of many cytokines are suppressed by glucocorticoids. In turn, MIF has the ability to antagonize the antiinflammatory effects of glucocorticoids.


IL-18 has also emerged as an important cytokine in the pathophysiology of sepsis. Depending on the local cytokine milieu, IL-18 has the ability to skew naïve T cells toward either a Th1 or Th2 phenotype. In addition, it appears that IL-18 may serve as an early biomarker to distinguish between gram-positive and gram-negative sepsis.


IL-10 is the best studied and most well-known antiinflammatory cytokine. , As an antiinflammatory cytokine, IL-10 antagonizes the proinflammatory effects of other cytokines and can thereby keep inflammation in check. IL-10 inhibits expression of cytokines such as TNF-α, IL-1β, and IL-8 and can inhibit expression of adhesion molecules. In addition, IL-10 can “deactivate” monocytes by downregulating the expression of major histocompatibility complex (MHC) surface molecules. Thus, IL-10 has a number of interesting properties that could potentially be leveraged therapeutically to limit excessive inflammation during sepsis. This theoretical consideration must be tempered by the ability of IL-10 to deactivate monocytes and thereby potentially impair the ability to adequately clear infection (i.e., the immunosuppression paradigm depicted in Fig. 110.1 ). Indeed, it has been reported that in children with MODS, higher plasma IL-10 levels correlate with higher mortality and that higher monocyte messenger ribonucleic acid (mRNA) levels of IL-10 correlate with increased length of stay in the ICU. Similar observations have been reported in adult patients with septic shock.


High-mobility group box 1 (HMGB-1) has long been known as a nonhistone DNA binding protein. More recently, it has been recognized that HMGB-1 also exists in the extracellular compartment, appears to have proinflammatory properties that may play a role in the pathophysiology of sepsis, and may represent a potential therapeutic target for sepsis. The attraction of HMGB-1 as a therapeutic target in sepsis stems from the observation that it may be a “late mediator” of sepsis in as much as it appears in the extracellular compartment within a time frame that is considerably later than that seen with the canonical sepsis cytokines such as TNF-α and IL-1β. Thus, the kinetics of HMGB-1 expression provide a potential therapeutic window that may be clinically feasible to exploit. This temporal observation is evident in both experimental models of sepsis and in humans with established septic shock. The biological properties of HMGB-1 appear to involve activation of TLRs and the receptor for advanced glycation end products (RAGE). More recently, it has been suggested that HMGB-1 intrinsically possesses very little proinflammatory biological activity but forms highly proinflammatory complexes with cytokines (e.g., IL-1β) and PAMPs (e.g., bacterial DNA and lipopolysaccharide).


HMGB-1 is also a prime example of a class of molecules known as alarmins or danger/damage-associated molecular patterns (DAMPs). Broadly speaking, DAMPs represent a class of molecules normally existing in the intracellular compartment at baseline but are released from damaged cells into the extracellular compartment during conditions such as trauma or sepsis. DAMPs appear to signal through many of the same PRRs recognizing pathogens; therefore, they have the ability to activate the immune/inflammatory system. Because DAMPs are released from damaged cells, they can serve to alert the inflammatory system of systemic damage or danger. Therefore, they can induce appropriate and adaptive activation of defense mechanisms. Alternatively, excessive DAMP-mediated activation of PRRs can lead to unnecessary and maladaptive amplification of inflammation damaging to host tissues. Other examples of DAMPs include calgranulins, hepatoma-derived growth factor, heat shock proteins, and uric acid. In this regard, heat shock proteins have been reported to be substantially elevated in the serum of children with septic shock. , More recently, formyl peptides released from mitochondria and mitochondrial DNA were reported as novel DAMPs.


Adhesion molecules


An important breakthrough in the molecular understanding of sepsis-induced organ dysfunction came with the identification of the processes responsible for the infiltration of leukocytes into tissues. The leukocyte-endothelial cell adhesion cascade ( Fig. 110.2 ) is characterized by early cytokine-mediated activation of the selectin family of endothelial cell adhesion molecules that can mediate a process of neutrophil “rolling” whereby sialylated moieties constitutively present on neutrophils interact with selectins on the endothelial cell membrane (e.g., E-selectin). In the second phase, activation of the rolling neutrophil causes increased expression and activation of the integrin family of adhesion molecules that interact with the similarly upregulated intercellular adhesion molecule (ICAM)-1 on the endothelial cell surface. This ligand interaction facilitates firm adhesion of the neutrophil to the endothelium. Subsequently, in response to a variety of chemotactic molecules, neutrophils transmigrate through the endothelial junctions to the site of inflammation. Release of a variety of radical species, both oxygen and nitrogen based, and proteases by the activated neutrophils can contribute to pathogen eradication but paradoxically can also cause endothelial and tissue injury.




• Fig. 110.2


Schematic and corresponding electron micrographs highlighting the process of leukocyte-endothelial cell adhesion and leukocyte transmigration from the intravascular compartment to the extravascular compartment. Cytokine-mediated activation of the selectin family of endothelial cell adhesion molecules mediate neutrophil “rolling” followed by ICAM-1–mediated adhesion. After adhesion, neutrophils transmigrate across “openings” between endothelial cell junctions to enter the extravascular space. The transmigration process is directed by chemokines serving as homing signals for neutrophils and other leukocytes. ICAM-1 , Intercellular adhesion molecule; IL-8 , interleukin-8; PMN , polymorphonuclear.

(Courtesy Thomas P. Shanley, MD, University of Michigan.)


Nitric oxide


NO was discovered in the 1980s as the molecule responsible for endothelial-derived relaxation of blood vessels. , Since then, NO has received tremendous attention as a potential mediator of septic shock. NO is produced by the enzyme nitric oxide synthase (NOS), which converts arginine and oxygen to NO and citrulline. Human NOS exists as three different isoforms (NOS1, NOS2, and NOS3). Each isoform has relatively unique tissue localizations, requirements for NO production, and kinetics of NO production. Several features of NO-related biology support an important role in the pathophysiology of sepsis. First, NOS2 (also known as inducible NOS ) is expressed in response to proinflammatory signals (e.g., lipopolysaccharide, TNF-α, and IL-1β) and produces large amounts of NO for prolonged periods of time. Second, NO can induce pathologic vasodilation and can function as a myocardial depressant. Third, NO can function as an oxidant either alone or by contributing to formation of other highly oxidizing, reactive molecules such as peroxynitrite. Fourth, NO has the potential to negatively affect mitochondrial function. Finally, elevated levels of NO metabolites have been well documented in children with septic shock and the levels correlate with the degree of cardiovascular dysfunction. , Despite these intriguing biological properties and a wealth of preclinical data testing the efficacy of NOS inhibition, clinical trials targeted at NOS inhibition have failed to demonstrate efficacy. Because NO has a myriad of biological properties important for homeostasis (particularly when NO is produced by the NOS1 and NOS3 isoforms), this lack of efficacy may represent the timing and specificity of NOS isoform inhibition.


Coagulation cascade


It is now well established that the inflammatory cascade is directly linked to the coagulation cascade, and the coagulation cascade can be pathologically activated in the context of sepsis. , This pathologic activation leads to disseminated intravascular coagulation, which subsequently leads to endothelial cell dysfunction and microvascular thrombosis. If endothelial dysfunction and microvascular thrombosis progress to a critical threshold, end organ failure ensues.


A complex network of multiple mediators takes part in this pathologic process, including proinflammatory cytokines, tissue factor, antithrombin III, protein C, protein S, tissue factor pathway inhibitor, and plasminogen activator inhibitor type 1 (PAI-1). Increased PAI-1 levels are a particularly strong feature of severe cases of meningococcemia and may be causally linked to a polymorphism in the promoter region of the PAI-1 gene. , Decreased levels of the endogenous anticoagulants antithrombin III, protein S, and protein C are consistently documented in the context of septic shock. These observations have led to multiple clinical trials in which recombinant forms of these endogenous anticoagulants have been administered to patients with septic shock. The majority of these trials have not demonstrated efficacy. Studies in the early 2000s suggested that recombinant activated protein C (APC) reduced mortality in adult patients with septic shock. This compound subsequently received approval by the US Food and Drug Administration (FDA). The beneficial effects of APC in septic shock are thought to be secondary to both prevention of microvascular thrombosis and an antiinflammatory effect. Unfortunately, a phase III trial of APC therapy in children with septic shock, the RESOLVE trial, failed to demonstrate efficacy. The RESOLVE trial was terminated after the second interim analysis owing to little chance of reaching the primary efficacy end point. In addition, there was an increased risk of serious bleeding in patients younger than 2 months of age. Consistent with this finding in children, a subsequent trial in adults with septic shock, PROWESS-SHOCK, also failed to confirm earlier findings of improved mortality, and APC was removed from the market in 2011. Nonetheless, the RESOLVE trial represents the largest and most well organized pediatric septic shock trial to date. It provides an important context and reference point for all future interventional trials in the field of pediatric critical care medicine.


Related to the paradigm of altered coagulation playing an important role in the pathophysiology of sepsis is the concept of thrombocytopenia-associated multiple-organ failure (TAMOF). New-onset thrombocytopenia in critically ill patients correlates with the evolution of persistent organ failure and poor outcome, including patients with sepsis. The mechanistic link between thrombocytopenia and organ failure is thought to involve a form of microangiopathy analogous to thrombotic thrombocytopenic purpura, including substantial decreases of ADAMTS-13 (a disintegrin and metalloprotease with thrombospondin type 13 motifs). ADAMTS-13 regulates microvascular thrombosis by cleaving the large thrombogenic von Willebrand factor multimers into smaller, less thrombogenic forms. Preliminary experience indicates that plasma exchange restores ADAMTS-13 levels and restores organ function in children with TAMOF. Fortenberry and colleagues conducted a longitudinal observational study of 81 pediatric patients with sepsis-induced TAMOF and found that therapeutic plasma exchange was associated with improved organ dysfunction and decreased 28-day mortality. Ultimately, the efficacy of plasma exchange for TAMOF will require more definitive evidence by way of a formal randomized trial.


Peroxisome proliferator-activated receptor-γ pathway


Peroxisome proliferator-activated receptor-γ (PPARγ) is a member of the PPAR nuclear receptor superfamily and is a ligand-activated transcription factor having well-known effects on lipid metabolism and cell proliferation. The thiazolidinedione class of insulin-sensitizing drugs are well-known PPARγ ligands (activators) that are currently widely used in the management of type II diabetes. Recently, it has become evident that pharmacologic activation of PPARγ has important antiinflammatory effects of significant benefit in experimental models of critical illness, including sepsis. The recent demonstration that PPARγ expression and activation is altered in children with septic shock, coupled with the availability of FDA-approved PPARγ ligands, provides an opportunity to test the efficacy of PPARγ ligands in sepsis. Kaplan et al. recently reported a phase I safety and pharmacokinetic study of pioglitazone, a PPARγ ligand, in critically ill children with sepsis.


Myeloid-derived suppressor cells


The neutrophil is often considered the first line in the innate immune response to infection. Patients with sepsis can present with elevated or extremely low neutrophil counts. In either case, the physiologic response to infectious stimuli is “emergency granulopoiesis” to generate a large number of myeloid cells to deal with the onslaught of infectious particles. This can lead to a much needed increase in cells to both contain and eliminate pathogens. However, in patients with sepsis, this can also give rise to a recently described myeloid-derived suppressor cell (MDSC) population. These cells produce antiinflammatory cytokines and suppress T-cell activation; thus, they may contribute in part to the failure of the adaptive immune system. These cells have been primarily characterized in the mouse model of sepsis, in which up to 30% of cells in the spleen 10 days after sepsis are MDSCs. Whether these cells are helpful to the immune response or lead to further immunosuppression is not entirely clear. , MDSCs can also be found in patients with other inflammatory conditions, such as cancer and autoimmunity. Further research is needed to determine if MDSCs represent a physiologically orchestrated part of the immune response or a pathologic arrest of developing myeloid cells leading to immunosuppression.


Paradigm of sepsis as an adaptive immune problem


Our conceptual framework of the pathophysiology of sepsis has evolved to include the concept of immune paralysis. Whereas sepsis has been traditionally viewed as being a reflection of uncontrolled hyperinflammation (i.e., an innate immunity problem), it is now thought that sepsis also has a strong, perhaps predominant, “antiinflammatory” component manifested as immunosuppression and the relative inability to effectively clear an infectious challenge (an adaptive immunity problem). , , , For example, monocyte deactivation related to decreased MHC gene mRNA expression and decreased surface expression of MHC molecules have been previously demonstrated in patients with septic shock, including children. , , , With regard to lymphocyte dysfunction, Heidecke and colleagues demonstrated that adult patients with intraabdominal infections and septic shock have defective T-cell proliferation and defective T cell-dependent cytokine secretion, all of which is consistent with anergy/immunosuppression. Felmet and colleagues identified prolonged lymphopenia and apoptosis-associated depletion of lymphoid organs as independent risk factors for the development of nosocomial infections and multiple organ failure in critically ill children. Muszynski and colleagues recently provided evidence for early adaptive immune dysfunction in children with septic shock, as measured by ex vivo production of interferon-γ by CD4 cells.


Animal studies have well documented the requirement of an intact T-cell system to adequately combat a septic challenge. , Interestingly, however, neonatal mice (4–6 days of age) do not appear to require an intact adaptive immune system to clear infection. More recently, animal-based experiments have demonstrated that experimental septic shock is characterized by widespread apoptosis of T cells and that preventing T-cell apoptosis positively impacts the outcome of experimental sepsis. Importantly, the concept of T-cell apoptosis in human sepsis has been indirectly corroborated by autopsy studies, including children, , and lymphocyte-based immunophenotyping was recently demonstrated to effectively stratify septic shock outcome in adults. Finally, it has been recently demonstrated in experimental models that alterations of the adaptive immune system in sepsis can persist well beyond the acute period (up to at least 6 weeks) via epigenetic mechanisms involving dendritic cells. , Despite these data, formal studies of T-cell function and adaptive immunity in pediatric septic shock have never been conducted in a systematic and comprehensive manner. Such studies hold the promise of radically changing our conceptual approach to the long sought, but not yet realized, goal of rational immunomodulation in septic shock. Recently, Hotchkiss et al. conducted a phase I trial of immune checkpoint inhibition in adults with sepsis using an antiprogrammed cell death–ligand 1 antibody.


Genomic medicine and sepsis


The initial completion and publication of the human genome, the development of molecular biology tools for efficient high-throughput data generation, and the evolution of the field of biomedical informatics have combined to generate a new field termed genomic medicine and the related field of systems biology . All aspects of medicine are potentially amenable to the concepts of genomic medicine and systems biology, including pediatric sepsis. One skeptical perspective of this concept is that clinical pediatric sepsis is too heterogeneous and multifactorial to be credibly interrogated by the current genomic and systems biology approaches. An alternative and more optimistic perspective is that the concepts of genomic medicine and systems biology are ideally suited to more effectively address the complex syndromes that we encounter in pediatric critical care medicine, such as septic shock. Herein, we will address the two areas of genomic medicine most well developed in the field of pediatric septic shock: candidate gene association studies and genome-wide expression profiling.


Genetic influence and septic shock


Susceptibility to sepsis and the clinical course of patients with sepsis are both highly heterogeneous, raising the strong possibility that the host response to infection is, at least in part, influenced by heritable factors (i.e., genetics). A landmark study by Sorensen et al., published more than 25 years ago, provides strong evidence linking genetics and susceptibility to infection. This study involved a longitudinal cohort of more than 900 adopted children born between 1924 and 1926. The adopted children and both their biological and adoptive parents were followed through 1982. If a biological parent died of infection before the age of 50 years, the relative risk of death from infectious causes in the child was 5.8 (95% CI, 2.5–13.7), which was higher than for all other causes studied, including cancer and cardiovascular/cerebrovascular disease. In contrast, the death of an adoptive parent from infectious causes did not confer a greater relative risk of death in the adopted child.


More recently, investigations attempting to link genetics with sepsis focused mainly on candidate gene association studies and gene polymorphisms. A gene polymorphism is defined as the regular occurrence (>1%) in a population of two or more alleles at a particular chromosome location. The most frequent type of polymorphism is called a single-nucleotide polymorphism (SNP): a substitution, deletion, or insertion of a single nucleotide occurring in approximately 1 per every 1000 base pairs of human DNA. SNPs can result in an absolute deficiency in protein, an altered protein, a change in the level of normal protein expression, or no discernible change in protein function or expression. There is a growing body of literature linking SNPs within several genes regulating inflammation, coagulation, and the immune response with critical illness and several excellent reviews exist on the topic.


The signaling mechanisms involved in pathogen recognition, immune response, and inflammation were described in previous sections. In this section, we will provide an overview of relevant SNPs described in many of the genes involved in these signaling mechanisms. TLR-4 (the primary receptor for recognition of lipopolysaccharide) mutations have been described in humans, all of which increase susceptibility to infections secondary to gram-negative organisms. While several SNPs in the TLR-4 receptor gene have been described, few have been found to be associated with an increased risk of septic shock or septic shock–related mortality in children. For example, an adenine for guanine substitution 896 base pairs downstream of the transcription start site for TLR-4 (+896) results in replacement of aspartic acid with glycine at amino acid 299 (Asp299Gly). The Asp299Gly polymorphism has been associated with reduced expression and function of the TLR-4 receptor in vitro. , Furthermore, adults who carry the Asp299Gly polymorphism appear to be at increased risk for septic shock and poor outcome in several cohort studies. While children who carry the Asp299Gly polymorphism appear to be at increased risk of urinary tract infection, this SNP does not appear to influence either the susceptibility or severity of meningococcal septic shock in children. , These results were further corroborated in a cohort study involving over 500 Gambian children.


SNPs related to other members of the LPS-receptor complex (e.g., CD14, MD-2, and MyD88) have been studied in adult populations, but no such studies have yet to be performed in children. , SNPs in other classes of TLRs have also been studied. For example, gene polymorphisms of TLR-1 and TLR-2, the primary PRRs for gram-positive bacteria, have been associated with increased length of hospitalization in pediatric sepsis and risk of infection in children and adults.


Several SNPs affecting cytokine expression have been described, but the corresponding gene association studies in critically ill adults with septic shock have been conflicting. , , For example, two allelic variants of the TNF-α gene have been described: the wild-type allele TNF1 (guanine at −308A), and TNF2 (adenosine at −308A). The TNF2 allele has been associated with higher expression of TNF-α and increased susceptibility to septic shock and mortality in at least one study involving critically ill adults. Nadel and colleagues found an increased risk of death in critically ill children with meningococcal septic shock who carried the TNF2 allelic variant. Several additional SNPs in TNF-β, IL-1, IL-6, IL-8, and IL-10 have also been shown to influence susceptibility to and severity of septic shock in children.


Because dysregulation of the coagulation cascade plays an important role in the pathophysiology of septic shock, several studies have examined polymorphisms of key genes involved in coagulation. For example, the 4G allele of a deletion/insertion ( 4G/5G ) SNP in the promoter region of the PAI-1 gene has been associated with higher plasma concentrations of PAI-1. The 4G allele increases susceptibility to and severity of septic shock as well as increasing the risk of mortality in children with meningococcal septic shock. , In addition, an SNP in the protein C promoter region has been associated with susceptibility to meningococcemia and illness severity in children.


SNPs in genes involved in phagocytosis and the complement cascade have also been studied in the context of septic shock. For example, SNPs affecting function have been described in virtually all family members of the Fcγ receptor (important for phagocytosis). Several of these SNPs have been associated with susceptibility to meningococcal sepsis, severity of meningococcemia, and poor outcome from meningococcal septic shock. In addition, an association between the FcγRIIa polymorphism and infection with other encapsulated bacteria has also been reported. , Several SNPs in the mannose binding lectin (MBL) gene have been associated with increased susceptibility to infection, as well as increased illness severity. Finally, an SNP of the bactericidal permeability increasing protein (BPI) gene has also been associated with increased mortality from septic shock in children. This polymorphism is particularly interesting because a well-conducted phase III trial of recombinant BPI in children with septic shock failed to demonstrate efficacy.


It is likely that many more studies are forthcoming that will attempt to link SNPs with the susceptibility and/or outcome of pediatric septic shock; all need to be carefully considered and evaluated. With respect to validity and wide clinical acceptance, the ideal candidate gene association study requires several important qualities, including biological plausibility; large sample sizes; a priori hypothesis statements and power calculations, accounting for confounding factors; and independent validation.


Genome-wide expression profiling in children with septic shock


The development of high-throughput technologies to measure gene expression has provided an unprecedented opportunity to efficiently measure genome-wide mRNA expression patterns in clinical samples. Over the last decade, this approach has been leveraged to enable more comprehensive understanding of the pathophysiology of pediatric septic shock and as a means of discovery and hypothesis generation. Comprehensive reviews of these studies were recently published.


The first studies to characterize the transcriptomic response of pediatric septic shock confirmed that septic shock is characterized by upregulation of gene programs corresponding to innate immunity and the inflammatory response. , These studies also noted concomitant downregulation of gene programs corresponding to adaptive immunity, which is consistent with the immune paralysis paradigm described earlier. These gene expression patterns are evident within 24 hours of admission to the ICU and persist at least through ICU day 3. Other notable data generated from these transcriptomic studies include (1) the observation that pediatric septic shock is characterized by repression of gene programs that either depend on zinc homeostasis or directly participate in zinc homeostasis ; (2) characterizing distinct gene programs across the spectrum of SIRS, sepsis, and septic shock ; (3) demonstrating the influence of developmental age on the transcriptomic response to pediatric septic shock ; (4) the observation that gene programs corresponding to mitochondrial function and biogenesis are repressed in certain subclasses of pediatric septic shock ; 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.


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. , As a direct consequence, a phase 1 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. In another example, it was reported that repression of the peroxisome proliferator activator receptor-α (PPARα) signaling pathway is associated with poor outcome in pediatric sepsis. This observation was subsequently corroborated in sepsis models involving PPARα null mice.


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). , 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-κB expression and increased expression of proinflammatory cytokines.


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 OLFM4+ neutrophils is independently associated with worse outcomes. Consistent with this clinical observation, genetic ablation of OLFM4 in mice has a protective effect against sepsis. 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 OLFM+ 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 5 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. In another example, these transcriptomic studies enabled the discovery of biomarkers to predict the development of septic acute kidney injury. , Finally, these transcriptomic studies enabled the discovery of stratification biomarkers to assign a baseline mortality probability for children and adults with septic shock. 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. Based on discovery-oriented computational approaches and hierarchical clustering of more than 8000 genes, these transcriptomic studies identified gene expression–based endotypes of pediatric septic shock. Post hoc analysis revealed that one of the endotypes had significantly greater illness severity, organ failure burden, and mortality; these observations were subsequently validated. , With the goal of developing a clinically feasible test meeting the time-sensitive demands of critically ill patients, the endotyping method was refined by distilling the endotype-defining 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. , 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 sepsis and the ongoing controversies surrounding the role of adjunctive corticosteroids in septic shock. For example, the use of adjunctive corticosteroids is independently associated with four times the risk of mortality in one of the endotypes. 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.




• 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.


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 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.


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. 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.


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 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.


Aggressive fluid resuscitation for septic shock was recently criticized as being only weakly supported by evidence. 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. 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. The FEAST study raises many questions regarding the efficacy of fluid resuscitation even though the relevance for resource-rich environments is unclear. 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. , 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. More importantly, three large adult trials were completed showing no benefit of goal-directed therapy compared with standard care. 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. 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.


May 20, 2021 | Posted by in RHEUMATOLOGY | Comments Off on Pediatric sepsis
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