Bacteremia, Sepsis, and Septic Shock

Stephanie H. Stovall and Richard F. Jacobs

Children presenting with pathogenic bacteria in a blood culture (bacteremia) manifest a wide spectrum of clinical signs and symptoms. The continuum from bacteremia to sepsis, severe sepsis, and septic shock depends on a complex series of interrelated factors that include the specific etiology, the inoculum of organisms, strain variations or virulence factors, extracellular components or toxin production, the site of infection, the immunologic competence of the host, and the host response to the infection. Bacteremia may be occult, a transient phenomenon not associated with a specific focus of infection, or it may result from the extension of an invasive bacterial infection originating in the genitourinary, gastrointestinal, upper or lower respiratory tracts, or skin and soft tissues. Specific secondary infection (meningitis, osteomyelitis, pyelonephritis, peritonitis, intra-abdominal abscess, or facial cellulitis) may also occur and affect management. Recurrent or persistent bacteremia may result from established infectious foci (endocarditis, abscess, foreign-body infection).

Systemic inflammatory response syndrome (SIRS) was defined by a consensus statement supported by the American College of Chest Physicians and Society of Critical Care Medicine in 1992.¹ Following that, definitions of sepsis, severe sepsis, and septic shock were developed for adult patients. In 2005, the International Consensus Conference on Pediatric Sepsis defined SIRS, sepsis, severe sepsis, and septic shock in pediatric patients.

The diagnosis of SIRS in a pediatric patient requires either abnormal temperature and abnormal leukocyte count, or one of the former and one of the following: tachypnea or tachycardia (or bradycardia if younger than 1 year) (Table 223-1). Sepsis is defined as SIRS plus proven or probable infection. The infectious etiology may be bacterial, viral, fungal, or rick-ettsial. Severe sepsis requires sepsis criteria plus acute respiratory distress syndrome, cardiovascular dysfunction, or multiorgan dysfunction. Septic shock is sepsis and cardiovascular dysfunction.²

EPIDEMIOLOGY

Epidemiologic factors that influence the incidence, etiology, morbidity, and mortality of bacteremia and sepsis in children include the site of acquisition, immunocompetence of the host, and the presence or absence of foreign material (central vascular, urinary, peritoneal, or intraventricular catheters or foreign material following complex congenital heart disease repair). As of the most recent available national vital statistics report in 2004, sepsis was the eighth leading cause of death in the first year of life.³

Neonatal bacteremia typically results from colonization and subsequent invasion of the neonate by organisms acquired from the maternal genital tract. In term newborns, early onset sepsis occurs in approximately 1 to 10 neonates per 1000 live births, with a mortality of approximately 20%. In premature infants, the attack rate for sepsis is 15 per 100, and mortality approaches 50%. The common bacterial agents of neonatal sepsis include Streptococcus agalactiae (group B streptococcus), Enterococcus species, Listeria monocytogenes, Escherichia coli, and other gram-negative enteric bacilli.

Once beyond the newborn period, Streptococcus pneumoniae, Neisseria meningitidis, Staphylococcus aureus, Streptococcus pyogenes (group A streptococcus),Salmonella species, and nontypeable Haemophilus influenzae are the most common bacteria causing community-acquired sepsis in the normal infant and child. Immunocompetent children with bacteremia must be evaluated for potential extension of local tissue infections.

Table 223-1. Criteria for Pediatric Systemic Inflammatory Response Syndrome*

*Must meet two criteria, and one must be either A or B.

In patients with underlying diseases causing an immunocompromised state, the presence or absence of foreign material affects the incidence and etiology of bacteremia. Indwelling vascular lines, urinary catheters, and endotracheal tubes, as well as other foreign material, predispose newborns and children to nosocomial infections due to coagulase-negative staphylococci (most commonly, Staphylococcus epidermidis), Enterobacteriaceae, enterococcus, fungi, and other less common opportunistic infections.⁴ In immunocompromised children without foreign bodies, endogenous sources, such as the gastrointestinal tract, become important causes of bloodstream infections commonly caused by Enterobacteriaceae, Enterococcus species, and Candida species. Certain described immunodeficiencies predispose patients to sepsis. Children with agammaglobulinemia are at high risk of pneumococcal and Hib sepsis. Likewise, children with terminal complement deficiency are prone to Neisseria infections. HIV-infected children and children without a functional spleen have higher rates of pneumococcal disease (see Chapter 229).

Sepsis and septic shock are relatively common occurrences among infants and children. The prevalence of sepsis in hospitalized patients increased significantly in the past decade; in some studies, the diagnosis of sepsis has accounted for more than 25% of admissions to high-acuity units, with an associated mortality approaching 10%. Advances in medical therapy and increased use of invasive medical procedures and devices are factors contributing to a growing population of immunocompromised and seriously ill patients at increased risk for sepsis. Septic shock occurred in 44% of immunocompromised patients admitted to our pediatric intensive care unit with an infectious disease diagnosis over a 3-year period.⁵

Although the organisms primarily responsible for sepsis and septic shock vary among different age groups, the clinical picture is the same. It has become clear over the past 10 years that the clinical syndrome of septic shock is the result of endogenous protein and phospholipid mediators secreted by the injured host. The failure of therapeutic interventions directed at single mediators of the sepsis cascade reiterates both the complex and multifactorial nature of the process and the need to classify patients unambiguously at the outset.

PATHOPHYSIOLOGY

Organ dysfunction as a result of sepsis begins with a focus of infection that triggers a cascade of events, such as injury with loss of vascular integrity, immunologic derangements including apoptosis of immune cells, hypovolemia, and hypoperfusion. Study of the pathophysiology of septic shock involves consideration of interactions between the host immune response, coagulation, and inflammation.

The innate immune response occurs when triggers (eg, microbial products) and receptors on immune cells (ie, monocytes or macrophages) called Toll-like receptors (TLRs) activate a signaling cascade that culminates in production of inflammatory mediators, such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and anti-inflammatory mediators like IL-10. TNF-α and IL-1β cause endothelial damage directly and also activate neutrophils and endothelial cells to enhance bacterial killing. However, these activated endothelial cells also upregulate receptors for neutrophils and other immune cells to allow for binding that then triggers release of prostaglandins, leukotrienes, and proteases that further cause endothelial damage and reduce vascular integrity. Stimulation of endothelial cells also alters coagulation in the host by reduced production of anticoagulant factors (protein C, protein S, and antithrombin III) and increased release of procoagulant factors (plasminogen activator inhibitor I), causing thrombus formation and subsequent tissue injury.^6,7

Lymphocytes are also activated by microbial products and cytokines. B lymphocytes are triggered to produce specific immunoglobulin to opsonize targets for natural killer cells and neutrophils. T lymphocytes of two types—T helper 1 (Th1) and 2 (Th2)—produce cytokines that either enhance inflammation (TNF-α and IL-1β) or suppress inflammation (IL-10), respectively (see Chapters 186 and 222).^6,7

CLINICAL FEATURES

Signs and symptoms of bacteremia are highly variable in children, depending on the age of the patient, comorbid conditions, duration of illness, specific microorganism, and host response to the infection. The spectrum of disease may range from fever alone to profound hypotension with acute respiratory distress syndrome.

Immunocompetent children between the ages of 3 months and 2 years may present with fever and no focus of infection; however, most children of all ages will have a systemic response to bacteremia. The primary systemic signs and symptoms of sepsis include fever or hypothermia, chills, hyperventilation, tachycardia, cutaneous lesions (petechiae, purpura, or both), and altered mental status involving confusion, agitation, lethargy, or coma. Important clinical parameters to assess in a child suspected of having sepsis include delayed capillary refill (>3–5 seconds), cyanosis, urinary output, and mental status. These, coupled with the laboratory findings of hypoxemia in the absence of pulmonary disease, acidosis, or oliguria, are definitive signs of hypoperfusion. Specific attention should be placed on accurate blood pressure measurement, as well as on adequacy of peripheral pulses.

Particular attention should be given to potential sites of infection that may not be evident at presentation. For instance, a swollen joint causing a patient to limp in the days preceding the clinical sepsis may not be particularly worrisome to a family of a patient in septic shock. If the limp is the result of an acute osteomyelitis, the patient may require debridement if it is the source of the sepsis episode, as has been seen with community-acquired methicillin-resistant Staphylococcus aureus (CAMRSA) infections.⁸

DIAGNOSIS

The laboratory evaluation of patients suspected of having bacteremia or sepsis includes blood culture, complete blood count with differential, a urinalysis and urine culture collected by sterile catheterization, and a chest roentgenogram. Depending on the individual patient, the completion of lumbar puncture, with cerebrospinal fluid analysis including Gram stain and culture, and specific laboratory tests, including electrolytes, renal function studies, aminotransferases, prothrombin and partial thromboplastin times, and serum fibrinogen levels, should be considered. In patients with petechial or purpuric cutaneous manifestations of sepsis, Gram stain of scrapings of the purpuric lesions may yield the etiologic organism, increasing the positive yield of rapid diagnostic tests and confirmatory culture by up to 10% in some studies. Close examination of the peripheral blood smear may disclose evidence of splenic dysfunction (Howell-Jolly bodies) or fragmented red blood cells, as seen in disseminated intravascular coagulation (DIC). In patients with respiratory distress, pulse oximetry is used to evaluate oxygenation. Arterial blood gases should be obtained early as a means of evaluating acid–base status, as well as ventilatory response in patients with severe sepsis or septic shock. Markers of inflammation such as C-reactive protein, erythrocyte sedimentation rate, and procalcitonin are nonspecific for infectious inflammation, since they will be elevated in cases of noninfectious systemic inflammatory response syndrome.

TREATMENT

Supportive management of sepsis, severe sepsis, and septic shock is directed toward restoration of adequate tissue perfusion and maintenance of efficient respiratory function (see Chapter 103). The ABCs (airway, breathing, and circulation) of emergency care are critical in the early stage of sepsis. This may require securing an alternate airway, providing mechanical ventilation and oxygenation and various agents to increase peripheral vascular resistance, increasing stroke volume, and maintaining cardiac output. Antimicrobial therapy should follow rapidly because delayed delivery of appropriate antimicrobial therapy has been associated with increased mortality. Sources of infection such as abscesses or indwelling devices should be debrided or removed if possible to decrease the microbial load.

The initial selection of presumptive antibiotics for a child with bacteremia, sepsis, severe sepsis, or septic shock is based on the clinical situation, including the age of the patient, the patient’s underlying immunologic status, the patient’s risk for nosocomial infection, secondary metastatic foci of infection, and local antibiotic resistance patterns. Presumptive antimicrobials are typically selected to cover the most serious organisms that cause bacteremia.

In the newborn, the combination of ampicillin plus gentamicin or ampicillin plus cefotaxime in standard dosages (or meningitic dosages if meningitis is not excluded) has been the mainstay of therapy. In the neonatal intensive care unit, the substitution of vancomycin for ampicillin in patients with central vascular catheters or foreign bodies (eg, ventricular shunts, cardiac patches) has been prompted by the increased incidence of coagulase-negative staphylococcal sepsis at this age. In the infant ages 1 to 3 months, the age-specific pathogens include those found in neonates, as well as bacterial isolates of older children. The combination of ampicillin plus cefotaxime is appropriate presumptive antibiotic coverage in these patients. In immunocompetent children older than 3 months, third-generation cephalosporins (cefotaxime or ceftriaxone) are the standard presumptive antibiotic regimens with significant clinical success in multiple studies. With drug resistance now identified as a common problem in many areas, the use of vancomycin plus cefotaxime or ceftriaxone is standard therapy for life-threatening sepsis, sepsis with meningitis, patients predisposed to invasive pneumococcal sepsis, and any patient with a concurrent or recent soft tissue or osteoarticular focus. Local susceptibility patterns should be considered in choosing a presumptive antimicrobial regimen.

In immunocompromised children, combination therapy using a broad-spectrum penicillin (eg, ticarcillin), monobactam, third- or fourth-generation cephalosporin (eg, ceftazidime), or carbapenem in combination with an aminoglycoside is appropriate for broad-spectrum gram-negative coverage, particularly if resistant gram-negative organisms are suspected. An intravascular catheter or other foreign material should prompt coverage for gram-positive organisms such as Staphylococcus epidermidis, Staphylococcus aureus, or enterococci, with the addition of a semisynthetic antistaphylococcal penicillin (eg, nafcillin or oxacillin), or vancomycin when methicillin-resistant gram-positive microorganisms are found to constitute a significant percentage of local confirmed infections. In immunocompromised patients not responding to broad-spectrum antibacterial therapy, presumptive antifungal therapy should be considered. All antibiotic or anti-infective regimens should be modified appropriately in culture-positive cases, depending on the specific organism and susceptibility testing. Indwelling devices (eg, intravascular catheters) should be removed if at all possible if they are the source of infection.

It is important to document therapeutic levels of specific antibiotics (aminoglycosides and vancomycin), especially in acutely ill patients with altered clearance and volumes of distribution that will affect antibiotic efficacy. Even before susceptibilities are known, isolation of the following bacteria in the blood culture should prompt consideration of the potential for antimicrobial resistance: Streptococcus pneumoniae (especially with concomitant meningitis), Enterococcus faecium, Neisseria meningitidis, Staphylococcus aureus, and selected gram-negative organisms such as Enterobacter, Serratia, and Acinetobacter.

Patients should be evaluated carefully for discrete sites of infection, particularly during episodes of community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) sepsis. In one study of 1451 pediatric patients admitted to a pediatric hospital for MRSA bacteremia, 58 required pediatric intensive care unit care. Of those 45 critically ill patients, 45 had pneumonia and/or pleural empyema and 46 had musculoskeletal symptoms, including 32 with osteomyelitis and 23 with septic arthritis. Twenty-nine patients required orthopedic drainage, and 18 of 21 patients required pleural drainage of empyema or cavitations.

The use of intravenous immunoglobulin (IVIG) for the prevention or treatment of sepsis has been somewhat controversial, with insufficient evidence to support routine administration in neonates with sepsis.⁹ However, a recent meta-analysis evaluating reported that studies of administration of polyclonal immunoglo-bins G, A, and M (IgGAM) to adults or neonates did show reduced mortality in both populations, with neonatal mortality reduction of 50% compared with adult mortality reduction of 34%.¹⁰

Adrenal insufficiency is common and variable in sepsis episodes. More recent meta-analyses have suggested that low dosages of hydrocortisone in patients with severe sepsis reduce duration of shock and 28-day mortality; however, a more recent randomized controlled trial failed to show an improvement in mortality or shortened duration of shock. It did show a more rapid reversal of shock in patients whose shock reversed.¹³

Drotrecogin alpha activated (DrotAA), which is a recombinant form of human activated protein C, was approved for use in adults with severe sepsis and no contraindication (recent neurosurgery, active internal bleeding, recent stroke, severe head trauma, indwelling epidural catheter, intracranial mass) after the PROWESS trial showed decreased 28-day mortality. However, the interpretation of these findings subsequent studies is controversial because in subgroup analysis it was noted that patients without severe sepsis actually had no improvement in outcomes, and some subgroups actually had poorer outcomes when treated with DrotAA. A subsequent well-controlled study in pediatric patients showed no efficacy of DrotAA in pediatric patients with severe sepsis. Therefore, DrotAA is not recommended for the treatment of pediatric patients with sepsis.^14-16 Bacteremia induces TNF and IL-1. A prospective, double-blind, randomized clinical trial with monoclonal antihuman TNF failed to reduce mortality in patients with sepsis. A more recent study using a TNF inhibitor, a dimer of an extracellular portion of the TNF receptor, and the Fc portion of IgG, showed that mortality was increased in the treated patients. Administration of IL-1 receptor antagonists has also failed to demonstrate any benefit for treatment of sepsis. Thus, anti-cytokine therapy for treatment of catastrophic illness has not been beneficial.

Other potential treatment agents include statins and Toll-like receptor 4 (TLR4) antagonists. Patients treated with statins have a lower incidence of sepsis, and a murine model demonstrates that treatment with statins prolongs survival in rats challenged with endotoxin-mediated shock. Statins may also have direct antimicrobial effects.^17,19 Toll-like receptor 4 binds LPS and initiates the inflammatory cascade producing NF-kB and other proinflammatory cytokines. At least two TLR4 antagonists have prevented shock in animal models and are in human trials.¹⁹

COMPLICATIONS

Complications of sepsis, severe sepsis, and septic shock are less frequent in the pediatric population than in adults. Patients who have inadequate or delayed resuscitation have poorer outcomes. Necrosis of digits and limbs requiring amputation may result from disseminated intravascular coagulation (DIC) such as is seen in meningococcemia. Patients with an osteoarticular focus of infection may have a permanently damaged joint or bone. Patients with significant hypoxia may suffer anoxic brain injury leading to seizures, arrest of development, or stroke.

PROGNOSIS

The mortality of sepsis, severe sepsis, and septic shock depends on the initial site of infection, the presence of multiple-organ dysfunction syndrome, and the bacterial pathogen. In studies of immunocompromised children with gram-negative sepsis, the mortality may range from 40% to 60%. Otherwise normal, healthy children with proven sepsis and shock had a mortality rate of 10% (7.8% in previously healthy children and 12.8% in children with underlying disease).²⁰ Poor prognostic signs in children include hypotension, coma, leukopenia (WBC <5000 cells/μL), thrombocytopenia (<100,000 platelets/μL), low fibrinogen level (<150 mg/dL), and evidence of multiple-organ dysfunction, including acute renal failure, adult respiratory distress syndrome, acute hepatic failure, CNS dysfunction, and myocardial depression. The morbidity for survivors of bacteremia, sepsis, severe sepsis, and septic shock is relatively low in children.

PREVENTION

Agents causing sepsis can be targeted individually to decrease the incidence of exposure. Such is true of microbes such as Haemophilus influenzae type b, which is quite rare in immunized populations in developed countries. Likewise, after the widespread use of the heptavalent conjugate pneumococcal vaccine, a decline in pneumococcal invasive disease (including sepsis) was noted. Certain patients known to be at risk for agents that cause invasive disease are targeted for vaccination. Asplenic patients and children younger than 5 years receive pneumococcal vaccine. Teenagers at increased risk due to their environment and patients with terminal complement deficiency receive meningococcal vaccine. Agammaglobulinemic patients received repeated infusions of high-dose IVIG.

REFERENCES

See references on DVD.

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