One of the most serious and potentially life-threatening infectious diseases in childhood is a bacteremic illness. Bacteremia may be caused by a wide variety of gram-positive or gram-negative microorganisms, and it may or may not be associated with a specific focus of infection, such as pneumonia or meningitis. Some bacteremias are transient and self-limited; they are not discussed in this chapter.
The incidence of bacteremia in children has been studied in hospital and ambulatory settings. In otherwise normal children, beyond the newborn age group, Streptococcus pneumoniae, Escherichia coli, Staphylococcus aureus, group A streptococcus, Salmonella spp., and Neisseria meningitidis are the most common microorganisms causing bacteremia. The incidence of pneumococcal bacteremia has decreased substantially since the introduction of the conjugate pneumococcal vaccine. In contrast, methicillin-resistant S. aureus bacteremia has increased in children in the United States since 2000. Children with underlying illnesses that depress the host response to infection may develop bacteremia caused by these same microorganisms; however, in this population of children, especially when hospitalized, Enterobacteriaceae, S. aureus, coagulase-negative staphylococci, and fungi are the most important organisms commonly isolated from blood cultures. Indwelling vascular lines, urinary catheters, endotracheal tubes, and other foreign material further predispose already compromised children to nosocomial infections. The incidence of diagnosed septicemia has increased over the years, partly owing to improved medical technology and the greater numbers of individuals with immunocompromising conditions who previously would not have survived.
Gray and colleagues reported that the incidence of bloodstream infections in a pediatric intensive care unit (ICU) during a 3-year period was 39 cases per 1000 admissions. Of the episodes, 64% were acquired in the ICU and 20.6% were community-acquired infections. Gram-positive and gram-negative organisms accounted for 62% and 31% of the isolates. Yeasts were isolated in 5.6% of episodes. The frequency of catheter-related bloodstream infections has been decreasing in many PICUs as a result of implementing insertion and maintenance bundles. Children with acquired immunodeficiency syndrome or severe immunosuppression caused by human immunodeficiency virus infection also are at increased risk for developing bacteremias caused by gram-negative bacilli, especially Pseudomonas aeruginosa .
Using a seven-state hospital discharge database, Watson and associates estimated that the U.S. age-adjusted and sex-adjusted annual incidence of severe sepsis was 0.56 cases per 1000 children, or more than 42,000 cases per year. The highest age-specific incidence occurred in infants (5.16 cases per 1000), declining to 0.20 cases per 1000 for children 10 to 14 years old. Half of the children had underlying comorbidity, with neuromuscular, cardiovascular, and respiratory disorders being the most common.
One potential consequence of bacteremia is septic shock, a state characterized by inadequate tissue perfusion that is associated frequently with endotoxemia. Although most children with septic shock have infections caused by gram-negative enteric bacteria, P. aeruginosa, or N. meningitidis, organisms with endotoxin or lipopolysaccharide (LPS) within cell walls, septic shock also is associated with disease caused by gram-positive bacteria (especially S. aureus, Streptococcus pyogenes, and viridans streptococci), viruses, rickettsiae, and fungi. Community-acquired methicillin-resistant S. aureus (MRSA) in particular have been associated with severe sepsis and septic shock in young children and adolescents. In adults, the frequency of septic shock continues to increase as the population ages, new technology including more complicated surgery and immunosuppressive agents is developed, and antibiotic resistance grows.
In early studies of septic shock, Dupont and Spink reviewed the cases of 172 children, age 30 days to 16 years, who were hospitalized at the University of Minnesota Medical Center with gram-negative bacteremia. Shock occurred in 25% of the children, and 98% of children with shock died. In meningococcal infections, 11% to 40% of children develop hypotension. During a 10-month study period, Naqvi and colleagues reported that shock occurred in five of 39 (13%) episodes of gram-negative bacillary sepsis, with three deaths. Jacobs and associates reviewed the admissions of previously normal children to a pediatric ICU in a large children’s hospital for a 30-month period. Hypotension or evidence of peripheral hypoperfusion occurred in 143 children with confirmed bacterial sepsis, mostly Haemophilus influenzae type b (Hib), or apparent meningococcemia. Among 1058 consecutive admissions of 916 children to a pediatric ICU in Canada from July 1, 1991, to July 31, 1992, 25 episodes (2%) of septic shock occurred. During a 12-month period, 140 episodes of septicemia (135 bacterial and five fungal) were documented in 100 pediatric hematology-oncology patients. Septic shock occurred in 19%.
The organisms and case-fatality rates in the study by Watson and colleagues are outlined in Table 62.1 . N. meningitidis and fungi were associated with the highest mortality rates. Early-onset group B streptococcal infections in neonates and overwhelming S. pneumoniae infections in children with splenic dysfunction or asplenia are associated with shock in a high percentage of cases. S. aureus or group A streptococcus may cause hypotension in a child with or without other manifestations of toxic shock syndrome.
| Organism | <1 Y ( N = 4643) | 1–10 Y ( N = 2724) | 11–19 Y ( N = 2308) | |||
|---|---|---|---|---|---|---|
| Cases (%) | Case Fatality (%) | Cases (%) | Case Fatality (%) | Cases (%) | Case Fatality (%) | |
| Neisseria meningitidis | 0.3 | 20 | 8 | 10.4 | 2.3 | 15.1 |
| Haemophilus influenzae | 1.6 | 4.2 | 2.4 | 1.6 | 1.9 | 6.8 |
| Pseudomonas | 3.6 | 14.6 | 7.7 | 12.4 | 6.9 | 9.4 |
| Staphylococcus aureus | 2.3 | 5.7 | 2.9 | 0 | 3.5 | 3.8 |
| Group A streptococcus | 0.3 | 0 | 0.7 | 5 | 0.2 | 0 |
| Group B streptococcus | 3.1 | 7.6 | 0.1 | 50 | 0.8 | 5.6 |
| Fungus | 10 | 10.8 | 13.3 | 16.8 | 10.4 | 11.6 |
a Represents data from a seven-state hospital discharge database in 1995.
Using data from the Pediatric Health Information System database (2004–12; 43 hospitals), Ruth and associates estimated an overall prevalence of pediatric severe sepsis of 7.7% with an associated mortality of 14.4%. Mortality was highest in patients with malignancies (22.4%), hematologic or immunologic disorders (20.3%), and cardiovascular disease (20%). The most common sites of infection were bloodstream (67.8%), respiratory tract (57.2%), and genitourinary tract (21.6%). Staphylococcus spp. (9.9%) and Streptococcus spp. (5.4%) were the most common causative agents, with fungi accounting for less than 1% of isolates. In patients in whom a bacterial pathogen was identified, the reported mortality rate was 13.2%. Although fungal infections as a cause of pediatric severe sepsis was rare, mortality in this group was high (20.1%) when compared to the overall mortality rate (14.4%).
Weiss et al. described the global epidemiology of pediatric severe sepsis at 128 sites in 26 countries. The sites included 59 in North America, 39 in Europe, 10 in South America, 10 in Asia, 7 in Australia/New Zealand, and 3 in Africa. The overall point prevalence of pediatric severe sepsis was 8.2%. Point prevalence was highest in Asia (15.3%), South America (16.3%), and Africa (23.1%). The most common sites of infection were the respiratory tract (40%) and the bloodstream (19%). The proportion of infections caused by gram-positive and gram-negative organisms was similar (26.5% vs. 27.9%), with S. aureus accounting for most of the bacterial isolates (11.5%). Overall hospital mortality was 25% but varied across geographic regions (North America 21%, Europe 29%, Australia/New Zealand 32%, Asia 40%, and South America 11%).
Advances in understanding of the pathogenesis and pathophysiology of septic shock with respect to the host response to infection have required that more precise clinical definitions of sepsis and expanded syndromes be developed. Much of the impetus for this effort is related to the ability to more readily identify patients with infections who may benefit from administration of newer (expensive) adjunctive measures. An American College of Chest Physicians and Society of Critical Care Medicine Consensus Conference in 1991 developed new terminology to define sepsis and its sequelae. This terminology has been modified for use in children by an international consensus panel of 20 experts in sepsis and clinical research ( Box 62.1 ).
SIRS
The presence of two or more of the following four criteria, one of which must be abnormal temperature or white blood cell count:
- 1.
Core temperature (rectal, bladder, oral, or central catheter probe) >38.5°C (101.3°F) or <36°C (96.8°F)
- 2.
Tachycardia defined as more than two standard deviations above normal for age in the absence of external factors or drugs or otherwise unexplained persistent elevation of a 0.5- to 4-hour time period or for children younger than 1 year, bradycardia, defined as a mean heart rate of less than 10th percentile for age in the absence of external factors or drugs or otherwise unexplained persistent depression over a 0.5-hour period
- 3.
Mean respiratory rate more than two standard deviations for age or mechanical ventilation for an acute process not related to an underlying neuromuscular disease or to general anesthesia
- 4.
Peripheral white blood cell count elevated or depressed for age unrelated to medications or more than 10% immature neutrophils
Infection
A suspected or proven (by culture, tissue stain, polymerase chain reaction assay) infection caused by any pathogen or a clinical syndrome associated with a high probability of infection
Sepsis
SIRS in the presence of or caused by suspected or proven infection
Severe Sepsis
Sepsis plus one of the following: cardiovascular organ dysfunction, acute respiratory distress syndrome or two or more other instances of organ dysfunction as defined in the consensus statement
Septic Shock
Sepsis and cardiovascular organ dysfunction as defined in the consensus statement
In 2016, a 19-member joint task force of the Society of Critical Care Medicine and European Society of Intensive Care Medicine (ESICM) published new sepsis guidelines for adult patients. According to the new guidelines, sepsis is now defined as evidence of infection plus life-threatening organ dysfunction. Organ dysfunction will be characterized clinically by a change of 2 points or greater in the Sequential (sepsis-related) Organ Failure Assessment score (SOFA). Given that SOFA is based on laboratory tests, the new guidelines recommend that clinicians use a streamlined process called quick SOFA (qSOFA) to assess patients for sepsis outside the intensive care unit. The clinician will assess a patient for altered mental status, systolic blood pressure of 100 mm Hg or lower, and a respiratory rate of 22 breaths per minute or higher. Patients meeting two of the qSOFA criteria will require close monitoring.
The 2016 clinical criteria for septic shock in adults include sepsis with fluid-unresponsive hypotension, serum lactate level of greater than 2 mmol/L, and need for vasopressors to maintain a mean arterial pressure of 65 mm Hg or higher. The 2016 consensus definition eliminates the use of the term systemic inflammatory response syndrome (SIRS). It should be noted that the utility of these definitions among pediatric populations is still to be determined.
Pathophysiology
The pathophysiology of bacteremia is highly variable and depends on the specific microorganism isolated, the immune status of the host, and other factors such as the locations of indwelling catheters. Highly encapsulated organisms, such as S. pneumoniae, N. meningitidis, and Hib, normally may reside in the nasopharynx and, for reasons that are poorly understood, are capable of invading beyond mucosal barriers into the bloodstream. A preceding viral upper respiratory tract infection may play some role in alterations in local host defense mechanisms that result in bacteremia.
Using human columnar nasopharyngeal tissue in organ cultures, Stephens and colleagues showed that N. meningitidis organisms were ingested by the columnar cells, then found within phagocytic vacuoles, and later observed within subepithelial tissues, suggesting that the meningococci had penetrated the epithelial layer. In this same model, Hib organisms attach to nonciliated columnar epithelial cells and subsequently are found in the intercellular spaces in association with a preceding disruption of the tight junctions of epithelial cells. After passing the mucosal barriers, Hib may enter the bloodstream directly through pharyngeal blood vessels. Pneumococci adhere to specific ligands on respiratory cells. The inflammatory mediators generated during viral infections upregulate platelet-activating factor receptor on respiratory cells to which the pneumococci adhere more avidly and subsequently invade. Pili or adhesins of gram-negative enteric organisms seem to be important in attachment and adherence of these microorganisms to specific receptors expressed on epithelial surfaces. Pili also have been shown to be important in the pathogenesis of some gram-positive infections, such as S. pyogenes, group B streptococcus, and S. pneumoniae .
The placement of an endotracheal tube unmasks a greater number of these receptors, presumably through increased protease activity of secretions and decreased cell-bound fibronectin, and leads to colonization of the upper respiratory tract with gram-negative organisms, which are ubiquitous in the environment of an ICU. Biofilm formation on the endotracheal tube surface may contribute to colonization persisting. Altered host defense mechanisms allow these organisms to move beyond epithelial surfaces and cause bacteremia.
The gastrointestinal and genitourinary tracts are major sources of gram-negative organisms responsible for bacteremia. These organisms first may cause localized abscesses or peritonitis if intestinal perforation occurs, or they may translocate the intestinal mucosa, particularly when the mucosa is affected by antineoplastic agents. Viridans streptococci can cause bacteremia in a neutropenic patient with severe mucositis that develops after the patient undergoes chemotherapy. Microorganisms within the bladder may ascend the genitourinary tract and presumably enter the bloodstream through the kidneys. S. aureus and S. pyogenes are common inhabitants of the skin and skin structures. Any skin wound or foreign matter within the skin tissue renders the skin more susceptible to bacterial invasion. Staphylococci have a unique capability of adhering to solid surfaces, such as catheters, which may be an important prerequisite to colonization and subsequent catheter-related bacteremia.
The pathophysiology of septic shock is very complex. Septic shock associated with gram-negative organisms has been studied most extensively, especially with respect to endotoxin or bacterial LPS, which has multiple biologic effects. Bacterial LPS has three basic components, as follows:
- 1.
Terminal side chains consist of repeating oligosaccharides that differ from strain to strain and are responsible for the antigenic specificity of the O antigens.
- 2.
A core LPS also consists of oligosaccharides but has less diversity in structure among strains than do the terminal side chains.
- 3.
Lipid A is very similar among the different strains and is responsible for most of the biologic activity of endotoxin.
Endotoxin shock has been the subject of intensive animal research, and much of what is known about the pathogenesis of endotoxin shock has been derived from animal models. Although septic shock in humans is not simulated precisely in these animal models for a number of reasons, including that the animals do not have underlying host defense defects, much of what has been learned about endotoxin shock in animals has been corroborated in the human host.
Endotoxin Shock in Animals
Many animal models of endotoxin shock employ infusions of live gram-negative bacteria, usually Escherichia coli , or purified endotoxin, after which observations are made. The effects of purified endotoxin depend partly on the species of animal being studied. Models employing cecal ligation and puncture are thought to be more relevant to human disease than direct infusion of bacteria or endotoxin. The effects of endotoxin in animal models are summarized in Table 62.2 .
| Effects | Mediators |
|---|---|
| Cardiovascular Effects | |
| Decreased peripheral vascular resistance | Histamine, bradykinin, serotonin, complement activation, prostaglandins, anaphylatoxins |
| Decreased cardiac output | |
| Depressed myocardial function | |
| Decreased systemic blood pressure | |
| Metabolic Effects | |
| Hyperglycemia | Hypoinsulinemia |
| Hypoglycemia | |
| Increased adrenocorticotropic hormone, growth hormone, and antidiuretic hormone | |
| Decreased calcium | |
| Increased triglycerides | |
| Decreased iron, transferrin, and zinc | |
| Pulmonary Effects | |
| Congestive atelectasis | Polymorphonuclear leukocytes |
| Increased capillary permeability | Polymorphonuclear leukocytes |
| Vasoconstriction | Thromboxane, prostacyclin |
| Bronchoconstriction | Leukotrienes |
| Central Nervous System Effects | |
| Decreased regional and total cerebral blood flow | |
| Increased cerebral oxygen consumption | |
Numerous mediators induced by endotoxin play pivotal roles in the pathogenesis of endotoxin shock. Tumor necrosis factor (TNF), a polypeptide hormone, is a key cytokine mediating septic shock. The tissue injury induced by TNF largely is a result of other mediators that are induced by TNF, including interleukin-1β (IL-1β), IL-6, eicosanoids, and platelet-activating factor. TNF is synthesized by a wide variety of cells (including monocytes/macrophages, natural killer cells, microglial cells, hepatic Kupffer cells) after stimulation by LPS, C5a, viruses, and enterotoxins, among other agents. TNF initiates a cascade of events that leads to endothelial cell injury, an enhanced inflammatory response, and, ultimately, the characteristic findings of endotoxic shock.
Nitric oxide (i.e., endothelium-derived relaxing factor) is the final pathway by which endogenous vasodilators stimulated by endotoxin result in hypotension from altered control of microcirculation. LPS through the release of cytokines induces a form of the enzyme nitric oxide synthase II, which leads to increased production of nitric oxide. Inhibitors of nitric oxide synthase, such as N G -monomethyl- l -arginine, can reverse or prevent hypotension in animals challenged with LPS.
The pathophysiology of septic shock caused by gram-positive bacteria is similar to that described for gram-negative organisms. Cell wall components, such as peptidoglycan and teichoic acid, promote proinflammatory activity but are less potent than endotoxin.
Endotoxin Shock in Humans
The pathophysiology of septic shock is highly complex and is related predominantly to actions of endogenous mediators released as part of the systemic inflammatory response to an infection. The cascade of events is intertwining, with production of one cytokine stimulating the synthesis of others; synergistic, in that the activities of certain cytokines act in concert; and sometimes antagonistic, with the production of other molecules to inhibit or compete with various cytokines. This complicated response to an infectious stimulus has been studied best for LPS, but a similar series of events occurs in response to gram-positive infections. Although the best understood system is the one that recognizes bacterial LPS, others exist for sensing the presence of bacterial peptidoglycan, DNA, lipopeptides, flagella, viral double-stranded RNA, and other conserved microbial molecules.
The first host protein involved in the recognition of LPS is LPS-binding protein. LPS-binding protein is an acute-phase protein; its role is to bring LPS to the cell surface by binding to LPS and forming a ternary complex with the LPS receptor molecule, CD14. Formation of the complex between LPS and CD14 facilitates the transfer of LPS to the LPS receptor complex, which is composed of Toll-like receptor 4 (TLR4) and MD2. Studies over the course of several years led to the discovery of the TLR4/MD2 receptor complex as the signaling entity for LPS ( Fig. 62.1 ). MD2 is a secreted glycoprotein that functions as an indispensable extracellular adapter molecule for LPS-initiated signaling events, perhaps by aiding in ligand recognition. The resulting signal promotes mononuclear phagocytes to produce reactive oxygen molecules, cytokines, and arachidonic acid metabolites, including prostaglandin and leukotrienes. A counterregulatory protein is a bactericidal, permeability-increasing protein that is stored in the granules of polymorphonuclear leukocytes and inhibits the effects of LPS.
TNF is largely responsible for the biologic effects, including fever, shock, myocardial suppression, capillary leak (i.e., endothelial damage), coagulation alterations, and metabolic changes, of LPS in humans. In children, including neonates, the role of cytokines in sepsis caused by a variety of organisms, but especially N. meningitidis, is well documented. LPS and TNF each can induce the synthesis of other proinflammatory cytokines, such as IL-1β and IL-6. IL-6 levels in plasma correlate with mortality. IL-8 plasma concentrations also are increased after infusion of LPS or IL-1β. Serum IL-8 levels in children with septic shock were predictive of outcome in one study.
The antiinflammatory cytokine IL-10 is produced after LPS is injected and inhibits the production of TNF, IL-1β, and IL-6. Naturally occurring inhibitors of TNF or IL-1β are present in serum samples of patients with the sepsis syndrome. IL-1 receptor antagonist (IL-1a) binds competitively to the IL-1 receptor to block the action of IL-1. Soluble TNF receptors bind to circulating TNF, which prevents its proinflammatory actions (see Fig. 62.1 ).
In adults, gram-negative bacteremia is followed by a decrease in systemic vascular resistance and mean blood pressure and an increase in cardiac output. Decreased systemic vascular resistance may be accompanied by activation of the complement and kinin systems. After this early phase, the blood pressure decreases further without change in the central venous pressure. Certain patients, especially children, are able to maintain their cardiac output and cardiac index, and this ability may be associated with increased rates of survival. When peripheral resistance is measured within 12 to 24 hours of the onset of shock, its decrease is significant in patients who survive compared with patients who die. In contrast, cardiac output is reduced significantly in other patients; this decrease is associated with increased concentration of blood lactate, decreased arterial blood pH, and decreased rates of survival.
In one small study, two distinct patterns of septic shock in children admitted to the PICU of a tertiary children’s hospital were described. Fifteen of 16 children with bacteremia related to central venous lines had a high cardiac index and low systemic vascular resistance. This pattern was seen in only 2 of 14 children with community-onset infections in whom normal or low cardiac index with variable systemic vascular resistance was typically noted.
Depression of myocardial function has been shown in adult and pediatric patients in septic shock. These patients have a reduced ejection fraction, left ventricular dilation, and significantly altered ventricular performance in response to infusion of volume. This depression of myocardial function is transient in survivors, however, reverting to normal within 1 to 4 days. Parker and colleagues found that patients who did not survive septic shock did not have left ventricular dilation or reduction in the ejection fraction. When the systemic vascular resistance index was averaged over the course of time, nonsurvivors had a significantly lower ( P < .05) index than that of survivors of septic shock. This study included three children who were 9 to 17 years of age. Abraham and associates sequentially monitored hemodynamic and oxygen transport measurements in 33 patients with septic shock. In the 24-hour period before the onset of hypotension, the survivors showed significantly greater cardiac index, left cardiac work index, oxygen delivery, and oxygen consumption than the nonsurvivors.
A circulating myocardial depressant factor in patients with septic shock was proposed more than 50 years ago, but myocardial dysfunction was not quantitatively linked to a serum factor until the late 1980s. Kumar and colleagues later reported that the myocardial depressant activity of sera obtained from patients with septic shock could be eliminated by the immunoprecipitation of TNF and IL-1β. Several investigators also have shown that TNF and IL-1β synergistically depress myocardial function in vitro and that this effect can be abolished by an inhibitor of nitric oxide. Germane to this discussion is the observation that LPS-induced biosynthesis of TNF mRNA and protein is not strictly confined to peripheral mononuclear cells but also may occur within many different tissue compartments. Experimental studies have shown that the cardiac compartment can be a significant source of TNF during septic shock. Kapadia and colleagues showed that administration of LPS leads to intramyocardial production of TNF mRNA and protein in vivo. These observations raise the possibility that the myocardial depression occurring in sepsis may develop directly in response to the compartmentalized production of TNF and other cytokines within the heart, as opposed to systemic production of these mediators by circulating mononuclear cells. TLR4 is expressed in the heart, and investigators have suggested that it is involved in signaling the cytokine production induced by LPS within the heart. The complex interactions leading to myocardial dysfunction or “septic cardiomyopathy” are incompletely understood but remain an area of active investigation.
In children, the most comprehensive investigation of myocardial dysfunction has been in meningococcal septic shock. Thiru and coworkers measured serum concentrations of the cardiac muscle–specific protein cardiac troponin I, which is released from injured cardiac myocytes, in 101 children with meningococcal septicemia. Minimum left ventricular ejection fraction was inversely related to peak cardiac troponin I levels. The degree of myocardial dysfunction, as determined by inotrope measurement, was related directly to peak cardiac troponin I concentrations. Their results suggested that myocardial cell death might contribute, at least in part, to the cardiac dysfunction associated with meningococcal septic shock.
Hematologic changes, such as leukocytosis, leukopenia, and thrombocytopenia, have been observed in human volunteers after receiving an infusion of endotoxin. Thrombocytopenia commonly occurs in association with sepsis of any cause. Septic shock is one of the most common causes of disseminated intravascular coagulation in children. Hageman factor (i.e., factor XII), which initiates the coagulation cascade, can be activated directly by LPS or through endothelial damage induced by bacteria. In septic shock, concentrations of Hageman factor, prekallikrein, high-molecular-weight kininogen, and factor VII are decreased partly as a result of consumption. Similarly, levels of inactivators of clotting factors, such as C1 esterase inhibitor, α 2 -macroglobulin, and antithrombin III, also are diminished. Corrigan and Jordan diagnosed disseminated intravascular coagulation in 24 of 26 children with septic shock and found that improvement in coagulation parameters seemed to be related most to restoration of blood pressure. A disseminated intravascular coagulation score using four components (platelet count, fibrinogen concentration, fibrin degradation products, and prothrombin time) was found to correlate with mortality in children with sepsis or septic shock. Gram-negative bacteremia may be associated with a coagulopathy that is not disseminated intravascular coagulation but is characterized by prolongation of the prothrombin and partial thromboplastin times caused by a reduction in the vitamin K–dependent coagulation factors.
LPS or cell wall components of gram-positive organisms, through cytokine production, activate blood coagulation predominantly through the extrinsic pathway. The procoagulant state is enhanced further by decreased protein C activity, which is an important inhibitor of coagulation factors Va and VIIIa. The fibrinolytic system also is altered by endotoxemia and is mediated by plasminogen activator inhibitor 1–induced suppression. The coagulopathy associated with septic shock is characterized by a procoagulant state and inhibition of fibrinolysis. Protein C has antiinflammatory properties. The antithrombotic, profibrinolytic, and antiinflammatory actions of activated protein C counteract the effects of cytokine activation, but a deficiency of protein C may be acquired during severe sepsis. Low levels of protein C have been associated with increased morbidity and mortality rates in patients with severe sepsis and septic shock. For meningococcal disease in particular, dysfunction of the protein C activation pathway is a key factor in the development of the thrombosis associated with purpura fulminans. Downregulation of the endothelial thrombomodulin–endothelial protein C receptor pathway seems to be the mechanism for impaired activation of protein C during severe meningococcal sepsis. Cytokine increases also lead to elevated serum ferritin levels during severe sepsis and septic shock; in one pediatric study levels higher than 500 ng/mL were associated with greater mortality.
LPS can activate the complement cascade by the classic or the alternate pathway. Significantly depressed concentrations of C3 occur in patients with bacteremia and hypotension compared with normal individuals or with patients with uncomplicated bacteremia, and C3 is activated primarily by the alternate pathway. In patients with bacteremia and hypotension, C1, C4, and C2 levels were not depressed significantly from values found in normal controls or in normotensive patients with bacteremia. In contrast, C3, C5, C6, C9, properdin, and factor B levels were decreased significantly ( P < .05) in bacteremic patients with shock. In children with meningococcal disease, Tubbs found a mean C3 concentration (as a percentage of normal values) of 132% ± 21% for survivors versus 91% ± 21% for nonsurvivors. The C3 levels did not correlate with endotoxin levels in sera.
Many metabolic alterations have been documented in the human host during endotoxin shock. Hyperglycemia followed by hypoglycemia can complicate the shock state induced by sepsis. Whole-body use of glucose is increased during sepsis, which probably is cytokine mediated. Glycolysis and gluconeogenesis are increased, but insulin resistance occurs in skeletal muscle. Children with underlying liver disease or with reduced glycogen stores are most likely to develop hypoglycemia during septic shock. Lactic acidosis develops as a result of poor tissue perfusion and cellular hypoxia. Lactic acid concentrations are increased in nonsurvivors and patients with poor or low-flow cardiac output during sepsis.
In clinical studies, Clowes and associates identified a subgroup of patients with low-flow septic shock in whom concentrations of serum insulin were lower than concentrations in a control population. In children with meningococcal sepsis, van Waardenburg and colleagues found higher blood glucose concentrations and significantly lower insulin levels on day 2 or 3 of hospitalization in children with shock compared with children without shock. Levels of plasma insulin and soluble TNF receptor 75 were inversely correlated in these children. Their findings were consistent with the inflammatory response inhibiting insulin secretion. In another study of meningococcal sepsis, both insulin resistance and β-cell dysfunction contributed to the hyperglycemia that occurred in a third of the children.
Hypocalcemia and decreased serum ionized calcium concentrations occur frequently during bacterial sepsis. In one study, 12 (20%) of 60 critically ill adults with bacterial sepsis had hypocalcemia. The mortality rate in the hypocalcemic patients was 50% compared with 30% in the patients who were normocalcemic. Cardenas-Rivero and associates studied calcium homeostasis in 145 children admitted to an ICU. Of eight children with confirmed sepsis or meningitis (or both) not caused by Hib, seven had hypocalcemia, and six of seven had ionized hypocalcemia. Five of the six children with ionized hypocalcemia had inappropriately normal concentrations of parathyroid hormone, which suggests that transient hypoparathyroidism occurs in some children with sepsis. Hypocalcemia also occurs commonly in patients with toxic shock syndrome. In women with toxic shock syndrome and hypocalcemia, serum concentrations of calcitonin are elevated by unknown mechanisms. Hypocalcemia and elevated calcitonin concentrations also have been documented in children with fulminant meningococcemia.
Procalcitonin levels are elevated in several conditions associated with SIRS, including sepsis, and have been proposed as adjunctive laboratory tests for the early detection of, and indicators for prognosis of, meningococcal disease and many other infections. These changes in calcium levels are especially critical because the level of ionized calcium and cardiac output in septic shock can be correlated. Other metabolic changes may occur during septic shock in humans, as follows:
- 1.
Increased concentrations of cortisol and growth hormone (including in neonates)
- 2.
Relative adrenal insufficiency by adrenocorticotropin testing
- 3.
Depression of triiodothyronine and thyroxine levels related to poor nutrition
- 4.
Elevations in total concentrations of amino acid in plasma and the preferential use of branched-chain amino acids as an energy source for skeletal muscle
- 5.
Muscle proteolysis, possibly induced by one or more circulating agents in the plasma of patients with serious infections
- 6.
Elevations in concentrations of plasma thromboxane, which are observed in nonsurvivors of septic shock
- 7.
Elevations in concentrations of triglycerides and free fatty acid during gram-negative bacteremia
- 8.
Altered zinc homeostasis
Liver dysfunction is an important aspect of endotoxin shock in adults. Banks and colleagues found that clinical jaundice was apparent in 63% of their patients with septic shock, that it was found more commonly in nonsurvivors than in survivors, and that the degree of biochemical liver abnormalities was related to the duration of shock. Postmortem findings included focal liver necrosis, Kupffer cell hyperplasia, portal tract inflammation, venous congestion, and intrahepatic cholestasis.
Adult respiratory distress syndrome (ARDS), or shock lung, is a major complication of septic shock in children. The lungs of children with ARDS have characteristic changes consisting of increased lung weight reflecting congestion and atelectasis, alveoli lined with hyaline membranes, microthrombi, hemorrhage, and interstitial edema. Increased capillary permeability and intrapulmonary shunts have been documented in patients with ARDS. C5a, a potent chemotactic factor, causes aggregation of polymorphonuclear neutrophils, is elevated in the sera of patients who ultimately develop ARDS, and is found in increased concentrations in bronchoalveolar lavage fluid obtained from patients with ARDS. Leukocyte aggregates are thought to be trapped in lung tissue and may cause damage to the endothelium of the pulmonary microvasculature through the release of oxygen radicals, lysosomal enzymes, and products of arachidonic acid metabolism. Although neutrophils play a critical role in the pathogenesis of ARDS, other factors also are important, considering that ARDS can develop in patients who are neutropenic. Thromboxane, platelet-activating factor, fibrin, and other substances contribute to the lung injury in ARDS.
The effects of endotoxin shock on the central nervous system have not been studied carefully in humans. The encephalopathy associated with sepsis seems to be caused partly by altered phenylalanine metabolism; concentrations of phenylalanine and its metabolite, phenylacetic acid, are increased in the sera and cerebrospinal fluid of septic adults who are stuporous or comatose.
Endotoxin has been implicated in the pathogenesis of acute renal failure associated with sepsis. Wardle showed that 12 of 16 patients with acute tubular necrosis had endotoxemia. Renal arterial blood flow and renal vascular resistance are decreased significantly in baboons 2 to 4 hours after infusion of endotoxin. Inadequate perfusion pressure was associated with renal ischemia and negligible urine output in these animals shortly after administration of endotoxin. Pathologic examination of the kidneys revealed focal necrosis of the proximal tubular epithelium, eosinophilic casts within proximal and distal tubules, and microthrombi in the glomerular capillaries. Endothelin, a potent vasoconstrictor peptide produced by endothelial cells, is elevated in concentration in the plasma of patients with septic shock. Because endothelin contributes to the regulation of regional blood flow, elevated levels suggest that it may relate to renal vasoconstriction and dysfunction.
Endotoxin can be measured in the plasma of patients with gram-negative bacteremia as well as in patients with other infections, even upper respiratory tract infections. The presence of circulating endotoxin does not mean that bacteremia is present or ever has occurred because endotoxin presumably may be “absorbed or leak” into the circulation from the gastrointestinal tract. Endotoxemia may be a valid indicator, however, of impending gram-negative septicemia in febrile patients. Preformed antibody to LPS or lipid A is associated with protection against shock and death caused by gram-negative bacteremia in adults. McCartney and colleagues detected endotoxin in the blood (after chloroform extraction) of patients with gram-negative septic shock; all 18 patients with persistently positive endotoxin assays died. In contrast, nine patients who initially had endotoxemia but subsequently had negative assays survived. Other studies confirm the association between endotoxemia and outcome. Evidence exists that human endotoxin is cleared from the circulation by the liver and can be detoxified by neutrophil enzymes (i.e., acyloxacyl hydrolases).
The sequence of events in the evolution of endotoxin shock has been outlined by several investigators. Bacteria, endotoxin, or other bacterial products stimulate the production of TNF and other cytokines, which in concert with endotoxin set off a whole series of events. Potent mediators, including C3a, C5a, eicosanoids, platelet-activating factor, histamine, and myocardial depressant substance, are released. Potent vasodilators cause peripheral vasodilation, and decreased systemic peripheral resistance leads to pooling of blood and decreased venous return to the heart. Mean blood pressure may be low, or it may be normal if cardiac output increases sufficiently to compensate for these alterations despite depression of ventricular function. The central venous pressure, which partially depends on myocardial performance, may be low or in the normal range.
If intravascular volume is increased by the administration of sufficient fluids, shock may be prevented or corrected. Continued hypotension and diminished perfusion pressure may lead, however, to cellular hypoxia and increased production of lactic acid from pyruvate. The microcirculation is altered by local tissue acidosis. Capillary beds become congested, and intravascular fluid may leak into the interstitial spaces. Increased secretion of catecholamine leads to arteriolar and venular constriction and increased peripheral resistance. Pooling of blood is enhanced, which leads to a further diminution in venous return and a reduction of cardiac output. Oliguria, coagulation abnormalities, and additional metabolic alterations indicate multiple organ system failure and presage the death of the patient.
Wong et al. have studied the genome-level expression profiles of children with sepsis and septic shock. Multiple gene networks, primarily related to inflammation and immunity, were affected over time and were differentially regulated. These investigations have led to the identification of three subclasses of distinct gene expression profiles; higher mortality is associated with one of these subclasses. This type of classification scheme might be able to identify patients at the time of admission who are at greater risk for poor outcomes and who would be optimal candidates for studying newer interventions or strategies for treating children in septic shock.
Genetic polymorphisms in the immune response to infection have been shown to be associated with clinical outcomes. Functional and association studies involving genetic polymorphisms in essential genes, including Toll-like receptors, cytokines, and coagulation factors, have provided important insights into the mechanisms involved in the pathogenesis of sepsis-induced organ dysfunction. Precise categorization of patients based on genetic background may lead to individualized targeted treatment.
Clinical Presentation and Diagnosis
The signs and symptoms of bacteremia vary greatly depending on the age and underlying disease of the patient, the duration of illness, and the specific microorganisms. Young, otherwise healthy children aged 3 months to 3 years may present with fever and evidence of an upper or lower respiratory tract infection or no focus of infection and yet have unsuspected bacteremia. Most studies indicated that the risk of developing bacteremia increases as the body temperature increases, and, in the unimmunized child, almost 25% of these children may be bacteremic after the temperature exceeds 41°C. In a previously healthy child, the persistence of irritability and the inability to console the child despite optimal environmental conditions have been proposed as key points in the physical examination that should alert the clinician to the possibility of a serious infection such as bacteremia or meningitis.
Underlying illnesses with splenic dysfunction place a child at increased risk for serious infections caused by encapsulated organisms, whereas children with leukemia or other immunosuppressive diseases or children in the ICU are more likely to be infected with gram-negative bacilli or S. aureus. A history of diarrhea may suggest Salmonella spp. as a possible cause of illness. Preceding skin infections or wounds are important clues to infection caused by S. aureus or group A streptococcus. An indwelling vascular catheter may precipitate overlying erythema in a patient with evidence of phlebitis proximally. Gram-positive cocci, gram-negative bacilli, and yeast can be associated with catheter-related sepsis. Toxic shock syndrome should be considered in a hypotensive girl or woman with a recent menstrual period and history of tampon use, although toxic shock also is associated with S. aureus sepsis in males and nonmenstruating females. Evidence of osteomyelitis, with or without venous thrombosis, is a very common finding in staphylococcal sepsis. Intraabdominal sources of infection increase the likelihood of developing anaerobic bacteremia.
Petechiae may be associated with many microorganisms, especially invasive disease caused by N. meningitidis . Purpura is an ominous finding and frequently is associated with overwhelming infection caused by N. meningitidis, S. pneumoniae, and Hib. P. aeruginosa is associated specifically with erythema gangrenosum. Almost half of children presenting with erythroderma (diffuse erythema) either had shock at presentation or developed shock in one study. Other skin and soft tissue manifestations of gram-negative sepsis include bullous lesions, cellulitis, fasciitis, thrombophlebitis, and symmetrical peripheral gangrene with disseminated intravascular coagulation. Signs of meningeal irritation or increased intracranial pressure are important because they may modify the approach to management of fluids in a child in shock.
The onset of bacteremia may be heralded by chills, fever, nausea, vomiting, diarrhea, rashes, and petechiae. Initially, the skin feels warm and appears flushed. A change or impairment in mental status may be the first clue to the presence of shock. Hyperventilation also may develop before the onset of clinical shock occurs, which can alert the physician to impending circulatory insufficiency. In time, cold, clammy extremities; a weak pulse; tachycardia; tachypnea; hypotension; and oliguria may occur. The skin over the extremities, the tip of the nose, and the earlobes especially are prone to cyanosis. Auscultation of the lungs may reveal rales, indicating pneumonia or pulmonary edema. Abnormal distention or tenderness to palpation and guarding may be evidence of peritonitis. Costovertebral angle tenderness suggests acute pyelonephritis as a source of bacteremias.
The physician must distinguish among the following three main types of shock in children:
- 1.
Hypovolemic shock, such as occurs with blood loss, fluid and electrolyte loss, adrenal insufficiency, or other causes
- 2.
Cardiogenic shock, which is associated with drug intoxication, cardiac surgery, arrhythmias, and pericardial tamponade, among other causes
- 3.
Distributive shock, which indicates abnormal distribution of blood flow leading to inadequate tissue perfusion (e.g., septic shock, anaphylaxis)
The laboratory evaluation of a child with bacteremia, septic shock, or both conditions should provide information concerning the cause and the data required for optimal supportive management. Several studies showed that a total white blood cell (WBC) count exceeding 15,000 cells/mm 2 in a 3- to 36-month-old child who has not been immunized with conjugate vaccines and with a temperature greater than 39°C to 40°C and without a focus of infection is an indication that the child is at increased risk for having bacteremia, especially pneumococcal bacteremia. Since the introduction of the pneumococcal conjugate vaccine, pneumococcal bacteremia in this scenario has been greatly reduced. Elevated erythrocyte sedimentation rates and C-reactive protein levels also have been suggested as useful screening tools for detecting serious bacterial infections. A low peripheral WBC count also may suggest septicemia and commonly is observed during episodes of overwhelming bacteremic illnesses.
Procalcitonin levels are elevated in bacteremic children and are related to the severity of illness, such as organ failure and even death. Commercial kits for the rapid measurement of concentrations of procalcitonin are available. Hemoglobin and hematocrit results should help differentiate between septic and hemorrhagic shock. Examination of the peripheral smear may disclose evidence of splenic dysfunction (i.e., Howell-Jolly bodies) or fragmented red blood cells, as seen in disseminated intravascular coagulation. Thrombocytopenia, prolongation of prothrombin time and partial prothrombin time, and the presence of fibrin split products are consistent with disseminated intravascular coagulation.
Hyponatremia is a common finding. Concentrations of serum bicarbonate may be depressed, which may signify a state of metabolic acidosis. Elevated lactic acid concentrations result from inadequate tissue perfusion and, in some reports, have been significantly greater in nonsurvivors or patients with low-flow states than in survivors or patients with high-flow shock. In pediatric studies, serial lactate levels showing normalization are associated with recovery. Hyperglycemia or hypoglycemia may be encountered. In one study, serum glucose levels greater than 178 mg/dL were associated with a greater risk of death caused by septic shock. Transaminase levels may be elevated and presumably reflect cellular injury. Serum calcium concentrations (preferably ionized calcium levels) should be checked periodically because hypocalcemia may interfere with optimal myocardial function.
A chest radiograph may reveal a pulmonary source of infection or show a secondary pulmonary manifestation of an invasive infection such as pneumonia or septic emboli in children with staphylococcal sepsis. Arterial blood gases obtained early in endotoxin shock usually reveal hypocapnia and normal to elevated pH. At this point, the patient has a mixed metabolic acidosis and respiratory alkalosis. If the shock state progresses, the metabolic acidosis becomes so severe that respiratory compensation is ineffective, and the patient becomes acidotic. In some patients, respiratory acidosis accompanies metabolic acidosis. In either case, decompensated metabolic acidosis in a patient with septic shock is associated with a grave prognosis. A major consequence of ARDS is hypoxemia. For patients with ARDS, the chest radiograph characteristically shows bilateral and diffuse hazy infiltrates; opacification of all lung fields usually is seen during the late phases of ARDS. Positive fluid balance contributes to the pulmonary dysfunction in patients with acute lung injury, including those related to sepsis.
Concentrations of blood urea nitrogen and serum creatinine may be elevated. Jones and Weil found that the ratio of urine to plasma osmolality was the most valuable indicator of renal impairment in adult patients with shock. When this ratio was greater than 1.5, the likelihood of developing progressive renal failure was remote. A urine osmolality value greater than 400 mOsm/kg also indicated adequate renal function. Gene microarray studies may identify novel biomarkers that identify a patient in septic shock who is at greater risk for acute kidney injury. Many WBCs or WBC casts in the urine may suggest the genitourinary tract as the source of bacteremia. If one or more gram-negative rods are seen on the Gram stain of unspun urine, more than 10 5 colony-forming units/mL of bacteria are likely to be present.
Isolating the organism responsible for bacteremia or septic shock is important for documenting the infection and for providing optimal antimicrobial therapy. With instruments that continuously monitor growth in the blood culture bottles, growth can be detected sooner than if the bottles are inspected just once or twice daily. Before the use of the pneumococcal conjugate vaccine became routine, many authorities recommended that a blood culture be obtained in a 3- to 36-month-old child with temperature greater than 39°C to 40°C and a total WBC count greater than or equal to 15,000 cells/mm 2 and without a specific focus of infection. In this way, instances of “unsuspected” or “outpatient” bacteremia could be identified. In an outpatient setting, almost 90% of blood cultures growing true pathogens were positive within 24 hours of incubation using a continuously monitored system. This approach is now less useful in the era of administration of pneumococcal conjugate vaccine to young infants.
In an infant who has received three or more doses of the conjugate pneumococcal vaccine, the likelihood of developing invasive pneumococcal infection is reduced approximately 90%. The proportion of children with high fever without localizing findings and a WBC count of 15,000/mm 2 or greater who might have occult pneumococcal bacteremia may be less than 1%, a level that no longer justifies this approach. Most organisms isolated from blood cultures in these patients are now more likely to be a contaminant than a true pathogen. Currently, the approach to a febrile child without a source has changed in many emergency departments such that more selective criteria for obtaining blood cultures are being developed.
When appropriate, cerebrospinal fluid, urine, and other pertinent sites should be cultured before initiating antibiotic therapy, if possible. When an intraabdominal source of infection is likely, blood and other cultures should be processed anaerobically. Gram stain or acridine orange stain of a buffy coat smear of peripheral blood may reveal evidence of the causative microorganism, especially in an overwhelming infection. Gram stain of material obtained from petechial or purpuric lesions may show gram-negative diplococci suggestive of meningococcus. Polymerase chain reaction for detecting N. meningitidis is available in selected laboratories and may be the only method by which infection is documented when cultures are sterile. The development of newer molecular techniques hopefully will lead to a greater availability of tests to detect a wider range of pathogens rapidly.
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