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Pediatric Septic Shock


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  • 1. Pediatric Septic Shock Stephen M. Schexnayder, MD* OBJECTIVES After completing this article, readers should be able to: 1. Explain how the host’s immune response may cause toxic effects during sepsis. 2. Delineate the cornerstone of resuscitation in patients who have septic shock. 3. List the factors to be considered when prescribing empiric antimicro- bial therapy for septic shock. 4. Explain when referral and transport arrangements should be made for patients in septic shock. Introduction Despite major advances in vaccines in the past two decades, septic shock continues to be an important pediat- ric problem. It is a frequent reason for admission to a pediatric inten- sive care unit, and this complex problem requires prompt recognition and intervention to improve the like- lihood of a good outcome. Definitions Because the clinical picture of sepsis is not unique to infectious condi- tions, a number of definitions have been advocated. Investigators in the field have separated the clinical spectrum of sepsis into the catego- ries of bacteremia, systemic inflam- matory response syndrome, sepsis, severe sepsis, septic shock, and mul- tiple organ dysfunction syndrome. Clinical observations over the past two decades have led to the descrip- tion of the systemic inflammatory response syndrome (SIRS) and have identified the major role that endo- thelium 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 trig- gers 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. Epidemiology 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 consider- ably by age. In the neonatal period, group B streptococci and Gram- negative bacilli are the predominate pathogens; Streptococcus pneu- moniae, 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 che- motherapy are at risk for a wide spectrum of infections from bacteria, fungi, viruses, and parasites. Pathogenesis Although the infection is an essen- tial part of the development of sep- tic shock, the host response plays a critical role in the clinical manifesta- tions and pathophysiology of this disorder. Cellular and humoral immunity work along with the reticuloendothelial system to main- tain homeostasis despite constant breaches of host defenses. These same defense mechanisms may pro- duce 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 ini- tiated by at least two groups of compounds following bacterial infection. Endotoxin, the lipopoly- saccharide component of the Gram- negative organism’s cell wall, binds to receptors on macrophages and results in activation and expression of inflammatory genes. Superanti- gens (toxins associated with some Gram-positive organisms) and viruses result in nonspecific activa- tion 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 arachi- donic 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 pro- duction 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 inflam- matory 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, catechol- amine depletion, and direct myocar- dial injury. *Associate Professor of Pediatrics & Internal Medicine, University of Arkansas for Medical Sciences, Arkansas Children’s Hospital, Little Rock, AR. ARTICLE Pediatrics in Review Vol. 20 No. 9 September 1999 303
  • 2. Clinical Aspects SIGNS AND SYMPTOMS Most patients who have sepsis exhibit alterations in temperature, with both hyperthermia and hypo- thermia 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 sep- sis, cardiac output falls in response to the effects of numerous cytokines. Although hypotension may occur, it is a late finding among young chil- dren. Young children frequently exhibit other signs of diminished perfusion while maintaining a nor- mal blood pressure, such as delayed capillary refill, weak peripheral pulses, and cool extremities. Capil- lary leak develops in response to cytokines causing the widening of endothelial junctions in the capillar- ies. Lactic acidosis is almost univer- sally present, as a result of both increased tissue production and decreased hepatic clearance. Central nervous system symptoms include irritability, lethargy, or con- fusion, even when meningitis is not present. Very high fevers (Ͼ41.0°C [Ͼ105.8°F]) are associated with a higher incidence of bacterial menin- gitis. Oliguria may be present. Skin findings may reveal hypoperfusion or show other diagnostic clues, such as the presence of petechaie or purpura. LABORATORY ASSESSMENT White blood cell counts frequently are elevated when bacteria cause septic shock, but they may be nor- mal or even low. An increase in immature forms (bands, myelocytes, or promyelocytes) is common. Glu- cose concentrations may be elevated from a stress response or low if the child has exhausted glycogen re- serves. Electrolyte levels frequently show evidence of a metabolic acido- sis, 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 rap- idly from the capillary leak, result- ing in a depressed total calcium level. Renal function and coagula- tion studies should be performed. Cultures of the blood and other potential sites of infection are indi- cated in the evaluation of septic shock, including urine, cerebrospinal fluid (CSF), stool, or wound drain- age 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 respira- tory arrest and even cardiopulmo- nary arrest. Airway management and fluid resuscitation must take first priority. It is legitimate to delay TABLE 1. Definitions of the Systemic Inflammatory Response Syndrome Bacteremia: The presence of viable bacteria in the blood. The presence of other organisms (fungi, viruses) should be modified to reflect those conditions (ie, fungemia, viremia). Systemic inflammation response syndrome (SIRS): A clinical syndrome that represents the body’s response to a wide variety of severe insults. The condition is manifested by the presence of at least two of the following conditions: 1. Temperature Ͼ38°C or Ͻ36°C (Ͼ100.4°F or Ͻ96.8°F) 2. Tachycardia (heart rate Ͼ160 beats/min for infants, Ͼ150 beats/min for children) 3. Tachypnea (respiratory rate Ͼ60 breaths/min for infants, Ͼ50 breaths/min for children) or PaCO2 Ͻ32 torr 4. White blood cell count Ͼ12,000 cells/mm3 or Ͼ10% immature (band) forms Sepsis: The systemic response to infection manifested by two or more of the criteria for SIRS Severe sepsis: Sepsis associated with hypotension (systolic blood pressure Ͻ65 mm Hg in infants, Ͻ75 mm Hg in children or Ͻ5th percentile for age, Ͻ90 mm Hg in adolescents, or a reduction of Ͼ40 mm Hg from the baseline in the absence of other causes for hypotension), hypoperfusion, or organ dysfunction. Hypoperfusion and perfusion abnormalities may include, but are not limited to, lactic acidosis, oliguria, hypoxemia, or acute alteration in mental status (Glasgow Coma Scale score 3 below baseline). Septic shock: Sepsis with hypotension, despite adequate fluid resuscitation, with the presence of perfusion abnormalities that may include, but are not limited to, lactic acidosis, oliguria, or acute alteration in mental status. Note: Patients who are on inotropic or vasopressor agents may not be hypotensive at the time perfusion abnormalities are measured. Multiple organ dysfunction syndrome: Presence of altered organ function in an acutely ill patient such that homeostasis cannot be maintained without intervention. From American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference. Pediatric modification of vital signs are based on Jafari and McCracken. Pediatr Infect Dis J. 1992;11:739–749. INFECTIOUS DISEASES Septic Shock 304 Pediatrics in Review Vol. 20 No. 9 September 1999
  • 3. lumbar puncture because the likeli- hood of a positive CSF culture in children who have bacterial menin- gitis remains high for several hours after the first dose of antibiotics has been administered. Severe coagu- lopathy, as frequently seen in meningococcemia, may delay lum- bar puncture because of the risk of spinal epidural hematoma. Management AIRWAYS AND BREATHING 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 depres- sion 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 prevent- ing 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 Volume resuscitation is of para- mount importance in supporting the child who has septic shock. Obtain- ing 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 periph- eral 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 aspi- rated to confirm placement, and fluid should infuse easily without evidence of soft-tissue swelling. The technique is most successful in chil- dren younger than age 6, but it may be employed in older children. Cen- tral venous catheterization should be considered when experienced per- sonnel 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 prod- ucts after a number of crystalloid fluid boluses have been administered. CARDIOVASCULAR SUPPORT Fluid resuscitation alone is inade- quate 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 rap- idly. If the response is inadequate, an epinephrine infusion should be initiated. Some authorities recom- mend 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 vasopres- sor 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 sug- gested that the newer phosphodies- terase 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 after- load 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 vaso- pressor 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 monitor- ing is crucial in the management of the child who has septic shock, and most pediatric critical care practi- FIGURE. Correct site for intraosseous needle insertion into the tibia. Courtesy of Brahm Goldstein, MD, Editorial Board. INFECTIOUS DISEASES Septic Shock Pediatrics in Review Vol. 20 No. 9 September 1999 305
  • 4. tioners employ both central venous pressure and invasive arterial pres- sure monitoring in severely ill chil- dren to obtain constant hemody- namic parameters. The use of pulmonary artery catheters for pres- sure measurement as well as for the thermodilution measurement of car- diac 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 Anemia should be treated in the set- ting of septic shock to improve delivery of oxygen to the tissues. Most experts recommend maintain- ing a hemoglobin level of 1.56 mmol/L (10 g/dL) (hematocrit of 0.30 [30%]) in the setting of sep- tic shock. If there is bleeding from disseminated intravascular coagula- tion, fresh frozen plasma or cryopre- cipitate 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. ANTIBIOTIC THERAPY Antibiotics to cover appropriate age- specific pathogens should be admin- istered 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 pneumo- cocci. This is controversial in the absence of meningitis; some infec- tious disease experts believe that high doses of cephalosporins are sufficient in this situation. To mini- mize resistance to vancomycin, this drug should be discontinued when culture results indicate bacterial sus- ceptibility to other agents. HYPOGLYCEMIA Hypoglycemia should be treated aggressively and monitored at the bedside. If it is present, 25% dex- trose (0.5 to 1 g/kg) should be administered over 5 minutes. Ionized hypocalcemia may require IV cal- cium infusions. Steroids are not rec- ommended routinely for the treat- ment of septic shock. Some practitioners continue to use cortico- steroids such as hydrocortisone in cases of septic shock when the pos- sibility of adrenal insufficiency exists, as with Waterhouse- Friderichsen syndrome in menin- gococcemia. EXTRACORPOREAL THERAPY Extracorporeal therapies may play an increasing role in the support of children who have refractory septic shock. Extracorporeal membrane oxygenation has been employed fre- quently 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. REFERRAL For facilities that do not have pedi- atric intensive care units, referral and transport should be part of the management plan after initial stabili- zation. 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. TABLE 3. Rules of Six DRUG INFUSION PREPARATION INFUSION RATE Dopamine Dobutamine Body weight in kg ϫ 6 ϭ Amount of drug (mg) to be added to total volume of 100 mL IV fluid 1 mL/h ϭ 1 mcg/kg per minute (Example: to deliver 10 mcg/ kg per minute, run infusion at 10 mL/h) Epinephrine Norepinephrine Milrinone Body weight in kg ϫ 0.6 ϭ Amount of drug (mg) to be added to total volume of 100 mL IV fluid 1 mL/h ϭ 0.1 mcg/kg per minute (Example: to deliver 0.3 mcg/ kg per minute, run infusion at 3 mL/h) TABLE 2. Inotrope and Vasopressor Doses DRUG DOSE Dopamine 5 to 10 mcg/kg per minute (inotropic dose) 10 to 20 mcg/kg per minute (vasopressor dose) Epinephrine 0.1 to 0.3 mcg/kg per minute (inotropic dose) 0.3 to 2 mcg/kg per minute (vasopressor dose) Norepinephrine 0.05 to 1 mcg/kg per minute Dobutamine 2 to 20 mcg/kg per minute Milrinone 50 to 75 mcg/kg loading dose over 10 to 60 minutes, followed by infusion of 0.5 to 1 mcg/kg per minute INFECTIOUS DISEASES Septic Shock 306 Pediatrics in Review Vol. 20 No. 9 September 1999
  • 5. Immunomodulation Because the host response to the invading organisms causes many of the adverse effects seen in the clini- cal 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 modu- late the cytokine cascade through the use of endogenous cytokine antagonists based on the finding that the im- mune system secretes cyto- kines with both proinflammatory and antiflammatory effects. Studies have evaluated a number of these agents, including soluble TNF recep- tors, IL-1 receptor antagonists, bac- tericidal permeability-increasing pro- tein, and endogenous anti-endotoxin antibody. Modification of one specific cyto- kine has been largely unrewarding, most likely because of the complex- ity of the cascade. Another approach has been to modify the cellular effects of the cytokines, most nota- bly through inhibition of nitric oxide. No large pediatric studies have been performed, but prelimi- nary data are encouraging. Until more data become available, the cornerstone of management remains aggressive supportive care. Prognosis 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 syn- dromes 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 devel- ops in some cases. This may signal an unrecognized focus of infection, such as an abscess or bowel perfora- tion. In this syndrome, there is vari- able involvement of many organs, such as ongoing shock from cardio- vascular 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. SUGGESTED READING Barton P, Garcia J, Kouatli A, et al. Hemody- namic effects of IV milrinone lactate in pediatric patients with septic shock: a pro- spective, double blinded, randomized, pla- cebo controlled interventional study. Chest. 1996;109:1302–1312 Ceneviva G, Paschall A, Maffei F, Carcillo JA. Hemodynamic support in fluid- refractory pediatric septic shock. Pediat- rics. 1998;102:e19 http:www.pediatrics. org/cgi/content,full/102/2/e19 Committee on Infectious Disease, American Academy of Pediatrics. Severe invasive group A streptococcal infections: a subject review. Pediatrics. 1998;101:136–140 Goldstein B, Zimmerman JJ. Critical care of pediatric shock. New Horizons. 1998;6(2) Jafari RS, McCracken GH. Sepsis and septic shock: a review for clinicians. Pediatr Infect Dis J. 1992;1:739–749 TABLE 4. Antibiotic Choices for Empiric Therapy in Septic Shock Neonate Ampicillin plus aminoglycoside or cefotaxime; if nosocomial, add vancomycin Child Cefotaxime or ceftriaxone plus vancomycin;* if nosocomial, vancomycin plus an antibiotic against resistant Gram-negative bacteria specific to the institution such as: ● Antipseudomonal cephalosporin (ceftazidime or cefipime) ● Aminoglycoside (gentamicin, tobramycin) ● Extended-generation penicillin with beta-lactamase inhibitor (ticarcillin/clavulanic acid, pipracillin/sulbactam) ● Carbapenem (imipenem or meropenem) Invasive group A streptococci (consider following varicella infection) Penicillin AND clindamycin Herpes or varicella Acyclovir Tick endemic areas Add doxycycline to above regimens *In cases of suspected Gram-positive infection in an area that has increased staphylococcal or pneumococcal resistance or for patients who have been treated with antibiotics frequently (sickle cell anemia, frequent otitis media). INFECTIOUS DISEASES Septic Shock Pediatrics in Review Vol. 20 No. 9 September 1999 307
  • 6. PIR QUIZ Quiz also available online at 7. The systemic inflammation response syndrome includes which one of the following? A. Decreased level of conscious- ness. B. Decreased urine output. C. Evidence of bone marrow failure. D. Hypotension. E. Increased respiratory rate. 8. The pathogenesis of septic shock involves a number of different factors, including which one of the following? A. Endotoxin acts on the endothelial cells to increase the size of cell junctions, leading to fluid leak. B. Interleukin-1 beta stimulates the bone marrow to release leuko- cytes. C. Nitric oxide stimulates the myocardium, leading to tachycardia. D. Superantigens induce a very rapid humoral antibody response that, in turn, activates comple- ment. E. Tumor necrosis factor-alpha is released, the effects of which lead to fever and vasodilatation. 9. Early signs of sepsis and shock in young children may be different from those in adults. Which one of the following is least likely to be associated with sepsis in a young child? A. Delayed capillary refill. B. Lactic acidosis. C. Normal blood pressure. D. Normal temperature. E. Tachycardia. 10. Which one of the following is least likely to be helpful in the initial management of a child who presents with evidence of septic shock? A. Blood glucose. B. Cerebrospinal fluid culture. C. Renal function studies. D. Serum electrolytes. E. Serum ionized calcium level. 11. A number of different principles apply to the immediate management of a child in septic shock. In general, management should be prioritized in order of urgency. For the following priorities ranked 1 through 5, which one is most likely given an inappropriate priority? A. First, ensure that the child has adequate airway support. B. Second, correct anemia, if present, to ensure adequate oxygen delivery. C. Third, administer volume resusci- tation to maintain adequate perfusion. D. Fourth, support the cardiovas- cular system with inotropic drugs, vasopressors, and careful hemodynamic monitoring as appropriate. E. Fifth, initiate empiric antibiotics. INFECTIOUS DISEASES Septic Shock 308 Pediatrics in Review Vol. 20 No. 9 September 1999