Pediatric septic shock.

Abstract

After completing this article, readers should be able to:Despite major advances in vaccines in the past two decades, septic shock continues to be an important pediatric problem. It is a frequent reason for admission to a pediatric intensive care unit, and this complex problem requires prompt recognition and intervention to improve the likelihood of a good outcome.Because the clinical picture of sepsis is not unique to infectious conditions, a number of definitions have been advocated. Investigators in the field have separated the clinical spectrum of sepsis into the categories of bacteremia, systemic inflammatory response syndrome, sepsis,severe sepsis, septic shock, and multiple organ dysfunction syndrome. Clinical observations over the past two decades have led to the description of the systemic inflammatory response syndrome (SIRS) and have identified the major role that endothelium plays in the pathogenesis of this disorder. Infection is one of the major causes of SIRS, but a number of other entities, including trauma,acute respiratory distress syndrome,neoplasms, burns, and pancreatitis,also have been recognized as triggers for this complex series of pathophysiologic events. Although initially written with adult vital sign parameters, the principles behind the definitions shown in Table 1 are valid, and modifications have been proposed for applying them to children.Sepsis is a recognized important cause of death, with the highest mortality rate occurring among infants. The most recent data report 5.9 deaths per 100,000 population in infants, with the fatality rate decreasing to 0.6/100,000 in the 1- to 4-year-old age group and 0.2/100,000 in the 5- to 14-year-old age group. As with most bacterial infections, the epidemiology of the causative organism varies considerably by age. In the neonatal period,group B streptococci and Gram-negative bacilli are the predominate pathogens; Streptococcus pneumoniae, Neisseria meningitidis,Staphylococcus aureus, and group A streptococci are major causes in older children. Children who have altered immune function, such as congenital immunodeficiencies or asplenia, or those undergoing chemotherapy are at risk for a wide spectrum of infections from bacteria,fungi, viruses, and parasites.Although the infection is an essential part of the development of septic shock, the host response plays a critical role in the clinical manifestations and pathophysiology of this disorder. Cellular and humoral immunity work along with the reticuloendothelial system to maintain homeostasis despite constant breaches of host defenses. These same defense mechanisms may produce a highly toxic and potentially lethal response to overwhelming challenges by infectious agents. This response is mediated by a vast array of hormones, cytokines, and enzymes.The inflammatory cascade is initiated by at least two groups of compounds following bacterial infection. Endotoxin, the lipopolysaccharide component of the Gram-negative organism’s cell wall, binds to receptors on macrophages and results in activation and expression of inflammatory genes. Superantigens (toxins associated with some Gram-positive organisms) and viruses result in nonspecific activation of a large number of circulating lymphocytes. These antigens bypass the normal process of antigen-presenting cells and T-cell receptors. The activated inflammatory cells further initiate the inflammatory mediator cascade with the release of cytokines, complement, and arachidonic acid metabolites.The clinical manifestations of sepsis are induced in part by tumor necrosis factor (TNF) alpha and interleukin-1 (IL-1) beta. Fever and vasodilatation occur and may progress to cardiovascular failure and lactic acidosis. These clinical signs result not only from the production of TNF alpha and IL-1 beta,but from their stimulation of the release of other interleukins that have both proinflammatory and anti-inflammatory properties. Nitric oxide, which is a major contributor to the hypotension of septic shock,may be released from either inflammatory cells or endothelium.Myocardial depression is caused at least in part by the presence of myocardial depressant factors. TNF and some of the interleukins may cause myocardial depression through the effects of myocardial nitric oxide, beta-endorphin,catecholamine depletion, and direct myocardial injury.Most patients who have sepsis exhibit alterations in temperature,with both hyperthermia and hypothermia being relatively common.Tachycardia and tachypnea are found almost uniformly. Cardiac output generally rises in early stages(the “hyperdynamic” phase) as homeostatic mechanisms attempt to maintain adequate oxygen delivery in the face of increasing metabolic demands. Later in the course of sepsis, cardiac output falls in response to the effects of numerous cytokines. Although hypotension may occur, it is a late finding among young children.Young children frequently exhibit other signs of diminished perfusion while maintaining a normal blood pressure, such as delayed capillary refill, weak peripheral pulses, and cool extremities. Capillary leak develops in response to cytokines causing the widening of endothelial junctions in the capillaries. Lactic acidosis is almost universally present, as a result of both increased tissue production and decreased hepatic clearance.Central nervous system symptoms include irritability, lethargy, or confusion, even when meningitis is not present. Very high fevers (>41.0°C[105.8°F]) are associated with a higher incidence of bacterial meningitis. Oliguria may be present. Skin findings may reveal hypoperfusion or show other diagnostic clues, such as the presence of petechaie or purpura.White blood cell counts frequently are elevated when bacteria cause septic shock, but they may be normal or even low. An increase in immature forms (bands, myelocytes,or promyelocytes) is common. Glucose concentrations may be elevated from a stress response or low if the child has exhausted glycogen reserves. Electrolyte levels frequently show evidence of a metabolic acidosis, with a low serum bicarbonate level. Calcium levels may be depressed from several different mechanisms. Frequently, the ionized calcium level must be evaluated to obtain a correct assessment because hypoalbuminemia may develop rapidly from the capillary leak, resulting in a depressed total calcium level. Renal function and coagulation studies should be performed.Cultures of the blood and other potential sites of infection are indicated in the evaluation of septic shock, including urine, cerebrospinal fluid (CSF), stool, or wound drainage if present. With the critically ill child, however, time must not be wasted on performing an extensive diagnostic evaluation. Obtaining only a blood culture before initiating antibiotic therapy may be prudent in the severely ill child. Care should be taken when performing a lumbar puncture in a critically ill child before adequate resuscitation has taken place because positioning for the lumbar puncture may impair an already compromised respiratory status, leading to subsequent respiratory arrest and even cardiopulmonary arrest. Airway management and fluid resuscitation must take first priority. It is legitimate to delay lumbar puncture because the likelihood of a positive CSF culture in children who have bacterial meningitis remains high for several hours after the first dose of antibiotics has been administered. Severe coagulopathy, as frequently seen in meningococcemia, may delay lumbar puncture because of the risk of spinal epidural hematoma.Priorities in resuscitation of the child who has septic shock mirror those with any other type of shock. Initial attention should focus on the presence of an adequate airway and breathing. All children should receive supplemental oxygen. The child in respiratory distress should be intubated,with particular care taken in choosing the sedating agent for this procedure. Drugs that cause vasodilatation or myocardial depression should be avoided. Volume resuscitation in addition to the use of an agent that maintains systemic vascular resistance such as ketamine (1 to 2 mg/kg) is useful in preventing hypotension that may result from positive pressure ventilation. When increased intracranial pressure is a concern, a benzodiazepine such as midazolam(0.1 to 0.2 mg/kg) may be used; ketamine causes an increase in intracranial pressure.Volume resuscitation is of paramount importance in supporting the child who has septic shock. Obtaining peripheral vascular access may be difficult, particularly in the later stages of the conditon. At least two separate intravenous (IV) lines are required to administer fluids and necessary medications. Intraosseous infusion may be used when peripheral vascular access cannot be obtained rapidly. An intraosseous needle or bone marrow aspiration needle is inserted into the lower extremity until a fall in resistance is felt (Figure). Frequently a small amount of bone marrow can be aspirated to confirm placement, and fluid should infuse easily without evidence of soft-tissue swelling. The technique is most successful in children younger than age 6,but it may be employed in older children. Central venous catheterization should be considered when experienced personnel are available.Aliquots of 20 mL/kg of isotonic crystalloid such as normal saline or lactated Ringer solution should be infused rapidly as needed to support the cardiovascular system. Children may require more than 60 to 100 mL/kg fluid in the first 1 to 2 hours of resuscitation to support their hemodynamic state. Few data are available regarding the use of colloid solutions in the treatment of pediatric septic shock, but many critical care practitioners prefer to use solutions such as albumin, fresh frozen plasma, or other blood products after a number of crystalloid fluid boluses have been administered.Fluid resuscitation alone is inadequate to support the cardiovascular system in many cases of septic shock. Initial therapy with dopamine at inotropic doses (5 to 10 mcg/kg per minute) may be adequate for cases of mild-to-moderate shock, but vasopressor doses (10 to 20 mcg/kg per minute) may be necessary for those who are more severely ill. The dose may need to be escalated rapidly. If the response is inadequate, an epinephrine infusion should be initiated. Some authorities recommend epinephrine as a first-line agent, with low (0.05 to 0.2 mcg/kg per minute) doses used to provide inotropic support and administration escalated to high doses if vasopressor doses are needed. For the very vasodilated patient,the addition of norepinephrine may be necessary to increase systemic vascular resistance and elevate diastolic pressure.Cardiovascular failure is a major contributor to refractory septic shock. Dobutamine has been used in septic shock,although its vasodilator effects may worsen hypotension in severe shock. Recent data have suggested that the newer phosphodiesterase inhibitor, milrinone, may be helpful in cases of refractory shock after adequate volume resuscitation and inotropic/vasopressor agents have been administered. Milrinone has vasodilator properties that may be beneficial when increased afterload is contributing to depressed cardiac output, but this drug is most appropriate for the pediatric critical care setting in which appropriate monitoring equipment is available. Doses for commonly used inotropes and vasopressors are shown in Table 2. The “rules of six” can be used to calculate and mix inotrope and vasopressor infusions rapidly (Table 3). With this tool, the patient’s weight(in kilograms) is multiplied by either 0.6 or 6, depending on the drug, and the calculated amount is placed in a total volume of 100 mL IV fluid. The IV rate then is adjusted to deliver the desired dose of the drug.Frequent hemodynamic monitoring is crucial in the management of the child who has septic shock, and most pediatric critical care practitioners employ both central venous pressure and invasive arterial pressure monitoring in severely ill children to obtain constant hemodynamic parameters. The use of pulmonary artery catheters for pressure measurement as well as for the thermodilution measurement of cardiac output varies substantially between pediatric centers. Some advocate using pulmonary artery catheters when the response to fluid resuscitation is inadequate, signs of pulmonary congestion occur with a normal central venous pressure, or there is evidence of myocardial dysfunction. Anemia should be treated in the setting of septic shock to improve delivery of oxygen to the tissues. Most experts recommend maintaining a hemoglobin level of 1.56 mmol/L (10 g/dL) (hematocrit of 0.30[30%]) in the setting of septic shock. If there is bleeding from disseminated intravascular coagulation, fresh frozen plasma or cryoprecipitate may be needed to replace coagulation factors, and platelet transfusion may be required. Routine transfusion of clotting substrates in the absence of clinical bleeding should be avoided. Antibiotics to cover appropriate age-specific pathogens should be administered IV early in the course of therapy. Antibiotic recommendations for empiric therapy are listed in Table 4. As drug resistance becomes increasingly prevalent, vancomycin is being added more frequently to empiric regimens to cover penicillin- and cephalosporin-resistant pneumococci. This is controversial in the absence of meningitis; some infectious disease experts believe that high doses of cephalosporins are sufficient in this situation. To minimize resistance to vancomycin, this drug should be discontinued when culture results indicate bacterial susceptibility to other agents.Hypoglycemia should be treated aggressively and monitored at the bedside. If it is present, 25% dextrose (0.5 to 1 g/kg) should be administered over 5 minutes. Ionized hypocalcemia may require IV calcium infusions. Steroids are not recommended routinely for the treatment of septic shock. Some practitioners continue to use corticosteroids such as hydrocortisone in cases of septic shock when the possibility of adrenal insufficiency exists,as with Waterhouse-Friderichsen syndrome in meningococcemia.Extracorporeal therapies may play an increasing role in the support of children who have refractory septic shock. Extracorporeal membrane oxygenation has been employed frequently in neonates who have sepsis with approximately 75% survival and has been used in older children,although the outcome has not been as favorable. Plasmapheresis was reported to be useful in a small series of children who had purpura fulminans.For facilities that do not have pediatric intensive care units, referral and transport should be part of the management plan after initial stabilization. Many referral centers provide telephone guidance to assist local practitioners while the team is en route. Outcome data have shown that survival is improved in centers that have pediatric critical care specialists.Because the host response to the invading organisms causes many of the adverse effects seen in the clinical picture of sepsis, the potential for therapeutic modification of the immune response has been attractive to many investigators in the field of sepsis research. A number of attempts have been made to modulate the cytokine cascade through the use of endogenous cytokine antagonists based on the finding that the immune system secretes cytokines with both proinflammatory and antiflammatory effects. Studies have evaluated a number of these agents, including soluble TNF receptors, IL-1 receptor antagonists, bactericidal permeability-increasing protein, and endogenous anti-endotoxin antibody.Modification of one specific cytokine has been largely unrewarding, most likely because of the complexity of the cascade. Another approach has been to modify the cellular effects of the cytokines, most notably through inhibition of nitric oxide. No large pediatric studies have been performed, but preliminary data are encouraging. Until more data become available, the cornerstone of management remains aggressive supportive care.The prognosis for patients who have septic shock varies widely in the literature. Reports from the mid-1980s reported overall survival at 32%, although a subset of patients who had normal-to-high cardiac indices had a survival of 67%. A number of scoring systems have been proposed to evaluate mortality risk. Most commonly they assess the degree of physiologic derangement from multiple parameters. Many studies have analyzed risk factors for death in various clinical syndromes associated with septic shock, most notably meningococcemia. A recent pediatric multicenter study reported improved survival(80%) when cardiovascular support was adjusted on the basis of pulmonary artery catheter measurements.Despite appropriate therapy in many circumstances, the multiple organ dysfunction syndrome develops in some cases. This may signal an unrecognized focus of infection, such as an abscess or bowel perforation. In this syndrome, there is variable involvement of many organs, such as ongoing shock from cardiovascular dysfunction, acute tubular necrosis,respiratory failure, hepatic dysfuction,encephalopathy, and coagulopathy. This syndrome is responsible for most of the delayed deaths in children who have septic shock. Treatment of this complex problem requires careful supportive care for each organ system, while ensuring that there is no ongoing site of infection or inflammation that can be treated.