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  • 1. ARTICLE Pediatric Septic Shock Stephen M. Schexnayder, MD* reticuloendothelial system to main- OBJECTIVES tain homeostasis despite constant After completing this article, readers should be able to: breaches of host defenses. These same defense mechanisms may pro- 1. Explain how the host’s immune response may cause toxic effects duce a highly toxic and potentially during sepsis. lethal response to overwhelming 2. Delineate the cornerstone of resuscitation in patients who have septic shock. challenges by infectious agents. This 3. List the factors to be considered when prescribing empiric antimicro- response is mediated by a vast array bial therapy for septic shock. of hormones, cytokines, and enzymes. 4. Explain when referral and transport arrangements should be made The inflammatory cascade is ini- for patients in septic shock. tiated by at least two groups of compounds following bacterial infection. Endotoxin, the lipopoly- Introduction definitions shown in Table 1 are saccharide component of the Gram- Despite major advances in vaccines valid, and modifications have been negative organism’s cell wall, binds in the past two decades, septic shock proposed for applying them to to receptors on macrophages and continues to be an important pediat- children. results in activation and expression ric problem. It is a frequent reason of inflammatory genes. Superanti- for admission to a pediatric inten- gens (toxins associated with some sive care unit, and this complex Epidemiology Gram-positive organisms) and problem requires prompt recognition Sepsis is a recognized important viruses result in nonspecific activa- and intervention to improve the like- cause of death, with the highest tion of a large number of circulating lihood of a good outcome. mortality rate occurring among lymphocytes. These antigens bypass infants. The most recent data report the normal process of antigen- 5.9 deaths per 100,000 population presenting cells and T-cell receptors. Definitions The activated inflammatory cells in infants, with the fatality rate Because the clinical picture of sepsis decreasing to 0.6/100,000 in the further initiate the inflammatory is not unique to infectious condi- 1- to 4-year-old age group and mediator cascade with the release of tions, a number of definitions have 0.2/100,000 in the 5- to 14-year-old cytokines, complement, and arachi- been advocated. Investigators in the age group. As with most bacterial donic acid metabolites. field have separated the clinical infections, the epidemiology of the The clinical manifestations of spectrum of sepsis into the catego- causative organism varies consider- sepsis are induced in part by tumor ries of bacteremia, systemic inflam- ably by age. In the neonatal period, necrosis factor (TNF) alpha and matory response syndrome, sepsis, group B streptococci and Gram- interleukin-1 (IL-1) beta. Fever and severe sepsis, septic shock, and mul- negative bacilli are the predominate vasodilatation occur and may tiple organ dysfunction syndrome. pathogens; Streptococcus pneu- progress to cardiovascular failure Clinical observations over the past moniae, Neisseria meningitidis, two decades have led to the descrip- and lactic acidosis. These clinical Staphylococcus aureus, and group signs result not only from the pro- tion of the systemic inflammatory A streptococci are major causes in response syndrome (SIRS) and have duction of TNF alpha and IL-1 beta, older children. Children who have but from their stimulation of the identified the major role that endo- altered immune function, such as thelium plays in the pathogenesis of release of other interleukins that congenital immunodeficiencies or have both proinflammatory and anti- this disorder. Infection is one of the asplenia, or those undergoing che- major causes of SIRS, but a number inflammatory properties. Nitric motherapy are at risk for a wide oxide, which is a major contributor of other entities, including trauma, spectrum of infections from bacteria, acute respiratory distress syndrome, to the hypotension of septic shock, fungi, viruses, and parasites. may be released from either inflam- neoplasms, burns, and pancreatitis, also have been recognized as trig- matory cells or endothelium. gers for this complex series of Myocardial depression is caused pathophysiologic events. Although Pathogenesis at least in part by the presence of initially written with adult vital sign Although the infection is an essen- myocardial depressant factors. TNF parameters, the principles behind the tial part of the development of sep- and some of the interleukins may tic shock, the host response plays a cause myocardial depression through critical role in the clinical manifesta- the effects of myocardial nitric *Associate Professor of Pediatrics & Internal Medicine, University of Arkansas tions and pathophysiology of this oxide, beta-endorphin, catechol- for Medical Sciences, Arkansas Children’s disorder. Cellular and humoral amine depletion, and direct myocar- Hospital, Little Rock, AR. immunity work along with the dial injury. Pediatrics in Review Vol. 20 No. 9 September 1999 303
  • 2. INFECTIOUS DISEASES Septic Shock 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 38°C or 36°C ( 100.4°F or 96.8°F) 2. Tachycardia (heart rate 160 beats/min for infants, 150 beats/min for children) 3. Tachypnea (respiratory rate 60 breaths/min for infants, 50 breaths/min for children) or PaCO2 32 torr 4. White blood cell count 12,000 cells/mm3 or 10% 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 65 mm Hg in infants, 75 mm Hg in children or 5th percentile for age, 90 mm Hg in adolescents, or a reduction of 40 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. Clinical Aspects increased tissue production and calcium level must be evaluated to decreased hepatic clearance. obtain a correct assessment because SIGNS AND SYMPTOMS Central nervous system symptoms hypoalbuminemia may develop rap- Most patients who have sepsis include irritability, lethargy, or con- idly from the capillary leak, result- exhibit alterations in temperature, fusion, even when meningitis is not ing in a depressed total calcium with both hyperthermia and hypo- present. Very high fevers ( 41.0°C level. Renal function and coagula- thermia being relatively common. [ 105.8°F]) are associated with a tion studies should be performed. Tachycardia and tachypnea are higher incidence of bacterial menin- Cultures of the blood and other found almost uniformly. Cardiac gitis. Oliguria may be present. Skin potential sites of infection are indi- output generally rises in early stages findings may reveal hypoperfusion cated in the evaluation of septic (the “hyperdynamic” phase) as or show other diagnostic clues, such shock, including urine, cerebrospinal homeostatic mechanisms attempt to as the presence of petechaie or fluid (CSF), stool, or wound drain- maintain adequate oxygen delivery purpura. age if present. With the critically ill in the face of increasing metabolic child, however, time must not be demands. Later in the course of sep- LABORATORY ASSESSMENT wasted on performing an extensive sis, cardiac output falls in response White blood cell counts frequently diagnostic evaluation. Obtaining to the effects of numerous cytokines. are elevated when bacteria cause only a blood culture before initiating Although hypotension may occur, it septic shock, but they may be nor- antibiotic therapy may be prudent in is a late finding among young chil- mal or even low. An increase in the severely ill child. Care should be dren. Young children frequently immature forms (bands, myelocytes, taken when performing a lumbar exhibit other signs of diminished or promyelocytes) is common. Glu- puncture in a critically ill child perfusion while maintaining a nor- cose concentrations may be elevated before adequate resuscitation has mal blood pressure, such as delayed from a stress response or low if the taken place because positioning for capillary refill, weak peripheral child has exhausted glycogen re- the lumbar puncture may impair an pulses, and cool extremities. Capil- serves. Electrolyte levels frequently already compromised respiratory lary leak develops in response to show evidence of a metabolic acido- status, leading to subsequent respira- cytokines causing the widening of sis, with a low serum bicarbonate tory arrest and even cardiopulmo- endothelial junctions in the capillar- level. Calcium levels may be nary arrest. Airway management and ies. Lactic acidosis is almost univer- depressed from several different fluid resuscitation must take first sally present, as a result of both mechanisms. Frequently, the ionized priority. It is legitimate to delay 304 Pediatrics in Review Vol. 20 No. 9 September 1999
  • 3. INFECTIOUS DISEASES Septic Shock lumbar puncture because the likeli- CARDIOVASCULAR SUPPORT hood of a positive CSF culture in Fluid resuscitation alone is inade- children who have bacterial menin- quate to support the cardiovascular gitis remains high for several hours system in many cases of septic after the first dose of antibiotics has shock. Initial therapy with dopamine been administered. Severe coagu- at inotropic doses (5 to 10 mcg/kg lopathy, as frequently seen in per minute) may be adequate for meningococcemia, may delay lum- cases of mild-to-moderate shock, but bar puncture because of the risk of vasopressor doses (10 to 20 mcg/kg spinal epidural hematoma. 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, Management an epinephrine infusion should be AIRWAYS AND BREATHING initiated. Some authorities recom- mend epinephrine as a first-line Priorities in resuscitation of the agent, with low (0.05 to 0.2 mcg/kg child who has septic shock mirror per minute) doses used to provide those with any other type of shock. inotropic support and administration Initial attention should focus on the escalated to high doses if vasopres- presence of an adequate airway and sor doses are needed. For the very breathing. All children should vasodilated patient, the addition of receive supplemental oxygen. The norepinephrine may be necessary to child in respiratory distress should increase systemic vascular resistance be intubated, with particular care and elevate diastolic pressure. taken in choosing the sedating agent Cardiovascular failure is a major for this procedure. Drugs that cause contributor to refractory septic vasodilatation or myocardial depres- shock. Dobutamine has been used in sion should be avoided. Volume septic shock, although its vasodilator FIGURE. Correct site for intraosseous resuscitation in addition to the use effects may worsen hypotension in needle insertion into the tibia. Courtesy of an agent that maintains systemic of Brahm Goldstein, MD, Editorial severe shock. Recent data have sug- vascular resistance such as ketamine Board. gested that the newer phosphodies- (1 to 2 mg/kg) is useful in prevent- terase inhibitor, milrinone, may be ing hypotension that may result helpful in cases of refractory shock from positive pressure ventilation. fluid should infuse easily without after adequate volume resuscitation When increased intracranial pressure evidence of soft-tissue swelling. The and inotropic/vasopressor agents is a concern, a benzodiazepine such technique is most successful in chil- have been administered. Milrinone as midazolam (0.1 to 0.2 mg/kg) dren younger than age 6, but it may has vasodilator properties that may may be used; ketamine causes an be employed in older children. Cen- be beneficial when increased after- increase in intracranial pressure. tral venous catheterization should be load is contributing to depressed considered when experienced per- cardiac output, but this drug is most sonnel are available. appropriate for the pediatric critical VOLUME RESUSCITATION care setting in which appropriate Aliquots of 20 mL/kg of isotonic Volume resuscitation is of para- crystalloid such as normal saline or monitoring equipment is available. mount importance in supporting the lactated Ringer solution should be Doses for commonly used inotropes child who has septic shock. Obtain- infused rapidly as needed to support and vasopressors are shown in Table ing peripheral vascular access may the cardiovascular system. Children 2. be difficult, particularly in the later may require more than 60 to The “rules of six” can be used to stages of the conditon. At least two 100 mL/kg fluid in the first 1 to calculate and mix inotrope and vaso- separate intravenous (IV) lines are pressor infusions rapidly (Table 3). 2 hours of resuscitation to support required to administer fluids and With this tool, the patient’s weight their hemodynamic state. Few data necessary medications. Intraosseous (in kilograms) is multiplied by either infusion may be used when periph- are available regarding the use of 0.6 or 6, depending on the drug, and eral vascular access cannot be colloid solutions in the treatment of the calculated amount is placed in a obtained rapidly. An intraosseous pediatric septic shock, but many total volume of 100 mL IV fluid. needle or bone marrow aspiration critical care practitioners prefer to The IV rate then is adjusted to needle is inserted into the lower use solutions such as albumin, fresh deliver the desired dose of the drug. extremity until a fall in resistance is frozen plasma, or other blood prod- Frequent hemodynamic monitor- felt (Figure). Frequently a small ucts after a number of crystalloid ing is crucial in the management of amount of bone marrow can be aspi- fluid boluses have been the child who has septic shock, and rated to confirm placement, and administered. most pediatric critical care practi- Pediatrics in Review Vol. 20 No. 9 September 1999 305
  • 4. INFECTIOUS DISEASES Septic Shock HYPOGLYCEMIA TABLE 2. Inotrope and Vasopressor Doses Hypoglycemia should be treated DRUG DOSE aggressively and monitored at the bedside. If it is present, 25% dex- Dopamine 5 to 10 mcg/kg per minute (inotropic dose) trose (0.5 to 1 g/kg) should be 10 to 20 mcg/kg per minute (vasopressor dose) administered over 5 minutes. Ionized Epinephrine 0.1 to 0.3 mcg/kg per minute (inotropic dose) hypocalcemia may require IV cal- 0.3 to 2 mcg/kg per minute (vasopressor dose) cium infusions. Steroids are not rec- ommended routinely for the treat- Norepinephrine 0.05 to 1 mcg/kg per minute ment of septic shock. Some practitioners continue to use cortico- Dobutamine 2 to 20 mcg/kg per minute steroids such as hydrocortisone in Milrinone 50 to 75 mcg/kg loading dose over 10 to cases of septic shock when the pos- 60 minutes, followed by infusion of 0.5 to sibility of adrenal insufficiency 1 mcg/kg per minute exists, as with Waterhouse- Friderichsen syndrome in menin- gococcemia. tioners employ both central venous cipitate may be needed to replace pressure and invasive arterial pres- coagulation factors, and platelet EXTRACORPOREAL THERAPY sure monitoring in severely ill chil- transfusion may be required. Routine Extracorporeal therapies may play dren to obtain constant hemody- transfusion of clotting substrates in an increasing role in the support of namic parameters. The use of the absence of clinical bleeding children who have refractory septic pulmonary artery catheters for pres- should be avoided. shock. Extracorporeal membrane sure measurement as well as for the oxygenation has been employed fre- thermodilution measurement of car- quently in neonates who have sepsis diac output varies substantially ANTIBIOTIC THERAPY with approximately 75% survival between pediatric centers. Some and has been used in older children, Antibiotics to cover appropriate age- advocate using pulmonary artery although the outcome has not been specific pathogens should be admin- catheters when the response to fluid as favorable. Plasmapheresis was resuscitation is inadequate, signs of istered IV early in the course of therapy. Antibiotic recommendations reported to be useful in a small pulmonary congestion occur with a series of children who had purpura normal central venous pressure, or for empiric therapy are listed in fulminans. there is evidence of myocardial Table 4. As drug resistance becomes dysfunction. increasingly prevalent, vancomycin is being added more frequently to REFERRAL ANEMIA empiric regimens to cover penicillin- For facilities that do not have pedi- Anemia should be treated in the set- and cephalosporin-resistant pneumo- atric intensive care units, referral ting of septic shock to improve cocci. This is controversial in the and transport should be part of the delivery of oxygen to the tissues. absence of meningitis; some infec- management plan after initial stabili- Most experts recommend maintain- tious disease experts believe that zation. Many referral centers provide ing a hemoglobin level of high doses of cephalosporins are telephone guidance to assist local 1.56 mmol/L (10 g/dL) (hematocrit sufficient in this situation. To mini- practitioners while the team is en of 0.30 [30%]) in the setting of sep- mize resistance to vancomycin, this route. Outcome data have shown tic shock. If there is bleeding from drug should be discontinued when that survival is improved in centers disseminated intravascular coagula- culture results indicate bacterial sus- that have pediatric critical care tion, fresh frozen plasma or cryopre- ceptibility to other agents. specialists. TABLE 3. Rules of Six DRUG INFUSION PREPARATION INFUSION RATE Dopamine Body weight in kg 6 Amount 1 mL/h 1 mcg/kg per minute Dobutamine of drug (mg) to be added to total (Example: to deliver 10 mcg/ volume of 100 mL IV fluid kg per minute, run infusion at 10 mL/h) Epinephrine Body weight in kg 0.6 Amount 1 mL/h 0.1 mcg/kg per minute Norepinephrine of drug (mg) to be added to total (Example: to deliver 0.3 mcg/ Milrinone volume of 100 mL IV fluid kg per minute, run infusion at 3 mL/h) 306 Pediatrics in Review Vol. 20 No. 9 September 1999
  • 5. INFECTIOUS DISEASES Septic Shock 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 Penicillin AND clindamycin following varicella infection) 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). Immunomodulation cornerstone of management remains able involvement of many organs, Because the host response to the aggressive supportive care. such as ongoing shock from cardio- invading organisms causes many of vascular dysfunction, acute tubular the adverse effects seen in the clini- necrosis, respiratory failure, hepatic cal picture of sepsis, the potential Prognosis dysfuction, encephalopathy, and for therapeutic modification of the The prognosis for patients who have coagulopathy. This syndrome is immune response has been attractive septic shock varies widely in the responsible for most of the delayed to many investigators in the field of literature. Reports from the mid- deaths in children who have septic sepsis research. A number of 1980s reported overall survival at shock. Treatment of this complex attempts have been made to modu- 32%, although a subset of patients problem requires careful supportive late the cytokine cascade through who had normal-to-high cardiac care for each organ system, while the use of endogenous cytokine indices had a survival of 67%. ensuring that there is no ongoing antagonists based on the finding that A number of scoring systems have site of infection or inflammation that the im- mune system secretes cyto- been proposed to evaluate mortality can be treated. kines with both proinflammatory risk. Most commonly they assess the and antiflammatory effects. Studies degree of physiologic derangement SUGGESTED READING have evaluated a number of these from multiple parameters. Many Barton P, Garcia J, Kouatli A, et al. Hemody- agents, including soluble TNF recep- studies have analyzed risk factors namic effects of IV milrinone lactate in tors, IL-1 receptor antagonists, bac- for death in various clinical syn- pediatric patients with septic shock: a pro- tericidal permeability-increasing pro- dromes associated with septic shock, spective, double blinded, randomized, pla- tein, and endogenous anti-endotoxin most notably meningococcemia. cebo controlled interventional study. Chest. 1996;109:1302–1312 antibody. A recent pediatric multicenter study Ceneviva G, Paschall A, Maffei F, Carcillo Modification of one specific cyto- reported improved survival (80%) JA. Hemodynamic support in fluid- kine has been largely unrewarding, when cardiovascular support was refractory pediatric septic shock. Pediat- most likely because of the complex- adjusted on the basis of pulmonary rics. 1998;102:e19 http:www.pediatrics. org/cgi/content,full/102/2/e19 ity of the cascade. Another approach artery catheter measurements. Committee on Infectious Disease, American has been to modify the cellular Despite appropriate therapy in Academy of Pediatrics. Severe invasive effects of the cytokines, most nota- many circumstances, the multiple group A streptococcal infections: a subject bly through inhibition of nitric organ dysfunction syndrome devel- review. Pediatrics. 1998;101:136 –140 oxide. No large pediatric studies ops in some cases. This may signal Goldstein B, Zimmerman JJ. Critical care of pediatric shock. New Horizons. 1998;6(2) have been performed, but prelimi- an unrecognized focus of infection, Jafari RS, McCracken GH. Sepsis and septic nary data are encouraging. Until such as an abscess or bowel perfora- shock: a review for clinicians. Pediatr more data become available, the tion. In this syndrome, there is vari- Infect Dis J. 1992;1:739 –749 Pediatrics in Review Vol. 20 No. 9 September 1999 307
  • 6. INFECTIOUS DISEASES Septic Shock PIR QUIZ Quiz also available online at 9. Early signs of sepsis and shock in 11. A number of different principles www.pedsinreview.org. young children may be different apply to the immediate management from those in adults. Which one of of a child in septic shock. In 7. The systemic inflammation response general, management should be the following is least likely to be syndrome includes which one of the prioritized in order of urgency. For associated with sepsis in a young following? the following priorities ranked 1 child? A. Decreased level of conscious- through 5, which one is most likely ness. A. Delayed capillary refill. given an inappropriate priority? B. Decreased urine output. B. Lactic acidosis. A. First, ensure that the child has C. Evidence of bone marrow failure. C. Normal blood pressure. D. Hypotension. adequate airway support. D. Normal temperature. E. Increased respiratory rate. B. Second, correct anemia, if E. Tachycardia. present, to ensure adequate 8. The pathogenesis of septic shock 10. Which one of the following is least oxygen delivery. involves a number of different C. Third, administer volume resusci- likely to be helpful in the initial factors, including which one of the tation to maintain adequate management of a child who presents following? perfusion. with evidence of septic shock? A. Endotoxin acts on the endothelial D. Fourth, support the cardiovas- cells to increase the size of cell A. Blood glucose. cular system with inotropic junctions, leading to fluid leak. B. Cerebrospinal fluid culture. drugs, vasopressors, and careful B. Interleukin-1 beta stimulates the C. Renal function studies. hemodynamic monitoring as bone marrow to release leuko- D. Serum electrolytes. appropriate. cytes. E. Serum ionized calcium level. E. Fifth, initiate empiric antibiotics. 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. 308 Pediatrics in Review Vol. 20 No. 9 September 1999