Objective. Experimental and clinical studies of septic shock support the concept that early resuscitation with fluid and inotropic therapies improves survival in a time-dependent manner. The new American College of Critical Care Medicine-Pediatric Advanced Life Support (ACCM-PALS) Guidelines for hemodynamic support of newborns and children in septic shock recommend this therapeutic approach. The objective of this study was to determine whether early septic shock reversal and use of resuscitation practice consistent with the new ACCM-PALS Guidelines by community physicians is associated with improved outcome.
Methods. A 9-year (January 1993–December 2001) retrospective cohort study was conducted of 91 infants and children who presented to local community hospitals with septic shock and required transport to Children’s Hospital of Pittsburgh. Shock reversal (defined by return of normal systolic blood pressure and capillary refill time), resuscitation practice concurrence with ACCM-PALS Guidelines, and hospital mortality were measured.
Results. Overall, 26 (29%) patients died. Community physicians successfully achieved shock reversal in 24 (26%) patients at a median time of 75 minutes (when the transport team arrived at the patient’s bedside), which was associated with 96% survival and >9-fold increased odds of survival (9.49 [1.07–83.89]). Each additional hour of persistent shock was associated with >2-fold increased odds of mortality (2.29 [1.19–4.44]). Nonsurvivors, compared with survivors, were treated with more inotropic therapies (dopamine/dobutamine [42% vs 20%] and epinephrine/norepinephrine [42% vs 6%]) but not increased fluid therapy (median volume; 32.9 mL/kg vs 20.0 mL/kg). Resuscitation practice was consistent with ACCM-PALS Guidelines in only 27 (30%) patients; however, when practice was in agreement with guideline recommendations, a lower mortality was observed (8% vs 38%).
Conclusions. Early recognition and aggressive resuscitation of pediatric-neonatal septic shock by community physicians can save lives. Educational programs that promote ACCM-PALS recommended rapid, stepwise escalations in fluid as well as inotropic therapies may have value in improving outcomes in these children.
Experimental and clinical studies of septic shock support the concept that persistent shock has an adverse impact on survival in a time-dependent manner.1–4 Recently, a randomized, controlled study of adult septic shock showed that early aggressive goal-directed resuscitation in the emergency department improves outcome.5 Although comparable randomized studies in children are lacking, the reported pediatric literature has been consistent with both experimental studies and the adult experience. We previously reported a role for early, aggressive fluid resuscitation in pediatric septic shock.6 Nadel et al7 (at St. Mary’s Hospital in London, England) attributed poor outcome from severe meningococcal disease to delayed recognition and treatment. Booy et al8 extended their findings at St. Mary’s Hospital by reporting decreased mortality from meningococcal disease over a 6-year period from 23% to 2% after they had implemented a community hospital-based education and resuscitation program with specialized, pediatric critical care transport.
In this regard, the American College of Critical Care Medicine (ACCM) recently published its Clinical Practice Parameters for Hemodynamic Support of Pediatric and Neonatal Patients in Septic Shock,9 which has been incorporated into the American Heart Association’s (AHA) Pediatric Advanced Life Support (PALS) Provider Manual.10 The ACCM-PALS Guidelines call for rapid, stepwise execution of therapeutic interventions with the goal to restore normal blood pressure and perfusion within 1 hour of patient presentation9 (Fig 1). Whether these new ACCM-PALS Guidelines will be effective in reversing shock and improving outcome in pediatric-neonatal septic shock remains to be determined. To begin to examine this question, we reviewed the interfacility transport database at Children’s Hospital of Pittsburgh (CHP) to determine whether early resuscitation and reversal of pediatric-neonatal septic shock by community hospital physicians is associated with improved outcome. We also examined the potential relevance of the new ACCM-PALS Guidelines to current resuscitation practice by community hospital physicians.
Patient Selection, Study Definitions, and Data Collected
The Human Rights Committee of CHP granted exemption of institutional review for this study. A 9-year (January 1, 1993–December 31, 2001), retrospective review of the CHP transport team’s interfacility transport database was performed. We identified infants and children with sepsis through a query of the database using the terms “sepsis,” “septic shock,” “meningococcemia,” and “bacteremia.” Transport records were then reviewed to determine which patients met clinical criteria for septic shock,9 which was defined by suspected infection as manifested by hyperthermia or hypothermia and signs of decreased perfusion, including decreased mental status, prolonged capillary refill time, diminished peripheral pulses, or mottled extremities. Although not necessary to meet criteria, the presence of hypotension and use of inotropic/vasopressor infusions to maintain normotension were considered confirmatory signs of decreased perfusion. All patients were transported to CHP by CHP’s pediatric critical care transport team. Premature infants <36 weeks’ corrected gestational age were excluded from the study.
Hypotension was defined as systolic blood pressure (SBP) less than the fifth percentile for age, using the formula taught in PALS.9 Prolonged capillary refill time was defined as >3 seconds. Shock reversal was defined by normalization of both SBP and capillary refill time. Appropriate fluid therapy was defined as the administration of any volume of fluid that resulted in successful shock reversal or ≥60 mL/kg when the patient remained in persistent shock. Resuscitation was considered to have been consistent with the new ACCM-PALS Guidelines when therapeutic interventions performed by community physicians had been similar to the stepwise algorithm covering the first hour of resuscitation (see Fig 1).
Demographic, epidemiologic, and outcome data were recorded for each patient. Clinical assessments were extracted from transport records at 3 time points: 1) transport team arrival at the patient’s bedside, 2) transport team departure from the community hospital, and 3) transport team return to our institution. These assessments were used to determine whether shock reversal had been achieved and whether resuscitation had been consistent with the new ACCM-PALS Guidelines for each transport time point. Using the time of initial call requesting transport as reference, “duration of persistent shock (beyond the time of call)” and “delay in resuscitation consistent with ACCM-PALS Guidelines” were determined and categorically scored into 1-hour increments. The frequencies that community hospital physicians executed specific therapeutic interventions were also recorded.
The Pediatric Risk for Mortality (PRISM) score11 is widely considered the “gold standard” tool to assess “severity of illness” in pediatric intensive care units (PICU) in the United States and many parts of the world. PRISM is scored from 14 routinely measured physiologic variables in a PICU setting and is calculated using the worst physiologic values observed during the first 24 hours after admission. PRISM scores were determined and recorded for our study patients as per scoring guidelines. Accordingly, patients who did not survive to 24 hours after admission to the PICU were not assigned a PRISM score. Mortality was defined as both transport and hospital mortality.
The computer statistical software program Jandel SigmaStat (version 2.0) was used for data analysis. Differences between groups were assessed by Mann-Whitney rank sum tests for continuous variables and by χ2 or Fisher exact tests for categorical data. Multiple logistic regression analyses, adjusting for severity of illness (PRISM scores), were performed to determine whether 1) shock reversal was associated with increased survival, 2) resuscitation consistent with the new ACCM-PALS Guidelines was associated with increased survival, 3) duration of persistent shock was associated with increased mortality, and 4) delay in resuscitation consistent with ACCM-PALS Guidelines was associated with increased hospital mortality. Severity-of-illness (PRISM) adjusted survival and mortality odds ratios with 95% confidence intervals were calculated using standard mathematical formulas.
During the 9-year study period, CHP’s pediatric critical care transport team performed 6196 transports; 186 (3%) transports involved infants and children with sepsis. Among these transports, 91 patients met criteria for septic shock, which accounted for 49% of the transported sepsis population and 1.5% of the total transport population. Fifty-three (58%) patients with septic shock presented with hypotension, 54 (59%) patients presented with prolonged capillary refill time, and 36 (40%) patients presented with both at the time of call. The characteristics of these patients with septic shock are presented in Table 1. A comorbid condition was present in 36 (40%) patients. The most common condition among these patients related to neurologic/musculoskeletal disease in 11 (31%) patients, followed by hematologic/oncologic disease in 8 (22%) patients, chromosomal/congenital disease in 7 (19%) patients, immunologic disease in 5 (14%) patients, and other disease in 5 (14%) patients. Identification of specific infectious cause was possible in 65 (71%) patients. Among these patients, the primary organism was isolated from blood in 42 (65%) patients, cerebrospinal fluid in 5 (8%) patients, trachea/lung in 8 (12%) patients, urine in 5 (8%) patients, peritoneum in 2 (3%) patients, and other sites in 3 (5%) patients.
A total of 26 patients died, accounting for an overall mortality rate of 29%. Among these 26 nonsurvivors, 2 (8%) patients died at the referring community hospital, 1 died before transport team arrival, 1 was receiving active cardiopulmonary resuscitation as the team arrived and subsequently died before team departure, and 1 died in the first 24 hours of the PICU stay. The PRISM scores (median [25th–75th percentile]) were significantly greater among nonsurvivors (26 [13–36]) versus survivors (11 [4–17]; P < .001). There were no differences in microbial cause for nonsurvivors (Staphylococcus aureus [n = 3], S epidermidis [n = 1], group B streptococcus [n = 4], S pneumoniae [n = 1], group A streptococcus [n = 1], Gram-positive cocci [n = 2], meningococcus [n = 1], Klebsiella [n = 1], Bacteroides fragilis [n = 1], Gram-negative bacilli [n = 2], Aspergillus [n = 2], Mucormycosis [n = 1], Enterovirus [n = 1], herpes simplex virus [n = 1]) compared with survivors (S epidermidis [n = 4], viridans streptococcus [n = 2], group B streptococcus [n = 6], Listeria [n = 1], group A streptococcus [n = 1], Gram-positive cocci [n = 1], Haemophilus influenza type B [n = 1], meningococcus [n = 7], Escherichia coli [n = 3], Klebsiella [n = 1], B fragilis [n = 1], Citrobacter [n = 2], Pseudomonas [n = 5], P mirabilis [n = 1], Candida albicans [n = 1], C parapsilosis [n = 1], Enterovirus [n = 2], herpes simplex virus [n = 1], respiratory syncytial virus [n = 2], H pylori [n = 1]). No significant differences were observed regarding other characteristics among nonsurvivors and survivors (Table 1).
Resuscitative efforts by community hospital physicians resulted in successful shock reversal in 24 (26%) patients by the time that the transport team arrived at the patient’s bedside (median time: 75 minutes). Successful shock reversal by community physicians was associated with 96% survival (Fig 2A) and >9-fold increased odds of survival (PRISM score-adjusted; Table 2). Community hospital physicians had implemented therapies consistent with the new ACCM-PALS Guidelines during the resuscitation of 27 (30%) patients. Resuscitation consistent with the new ACCM-PALS Guidelines was associated with 93% survival (Fig 2B) and >6-fold increased odds of survival (PRISM score-adjusted; Table 2). Each hour of persistent shock that passed was associated with >2-fold increased odds of mortality (PRISM score-adjusted), and each hour of delay in institution of resuscitation consistent with ACCM-PALS Guidelines was associated with a 50% increased odds of mortality (PRISM score-adjusted; Table 2).
Table 3 presents the frequencies that community hospital physicians executed specific therapeutic interventions for patients who presented in septic shock. Overall, community physicians had administered appropriate fluid therapy to fewer than half (45%) of these patients and had performed resuscitation consistent with the new ACCM-PALS Guidelines in fewer than one third (30%). Fluid and inotropic therapies administered by community physicians did not significantly differ between patients whose shock was successfully reversed when compared with those whose shock persisted. Consequently, community physicians had administered appropriate fluid therapy (25%) and had performed resuscitation consistent with the new ACCM-PALS Guidelines (4%) to even fewer patients with persistent shock. Community physicians infused hydrocortisone therapy to a minority of children (13%) during their resuscitation. However, hydrocortisone therapy trended toward successful shock reversal among these patients (50% with hydrocortisone vs 23% without hydrocortisone; P = .074 Fisher exact test).
Community physicians had implemented for nonsurvivors (when compared with survivors) significantly more mechanical ventilatory support (73% vs 38%), dopamine/dobutamine infusions (42% vs 20%), and epinephrine/norepinephrine infusions (42% vs 6%). However, community physicians had administered similar fluid therapy (both in volume administered and appropriateness) to both nonsurvivors and survivors and ultimately had performed resuscitation consistent with the new ACCM-PALS Guidelines-directed therapy to significantly fewer nonsurvivors when compared with survivors (8% vs 38%). Survival rate was similar among patients who did (67%) and did not (72%) receive hydrocortisone therapy in the community hospital emergency department setting.
Early Shock Reversal Is Associated With Improved Outcome
The results of our study support the hypotheses that early shock reversal and resuscitation consistent with the new ACCM-PALS Guidelines by community physicians can be associated with improved outcome. We report that when community physicians had implemented therapies that resulted in successful shock reversal (within a median time of 75 minutes), almost all of the infants and children who presented with septic shock survived. We also observed that the odds of mortality doubled with each hour of persistent shock that passed and that each hour of delay in resuscitation consistent with ACCM-PALS Guidelines was associated with a 50% increased odds of mortality for our study population regardless of underlying severity of illness measured by the PRISM score.
Our findings are consistent with the study by Rivers et al,5 who showed that when early goal-directed therapies were implemented in the emergency department, survival outcomes in adult septic shock significantly improved. Although the specific therapeutic targets of central venous pressure between 8 and 12 mm Hg, mean arterial pressure between 65 and 90 mm Hg, urine output ≥0.5 mL/kg/h, and central venous oxygen saturation ≥70% in the study by Rivers et al5 differed from our study (which targeted normal SBP for age and normal capillary refill time), the overall therapeutic goal of achieving rapid, hemodynamic optimization was conceptually similar. The present study builds on our group’s previous work, which reported that rapid, aggressive fluid resuscitation of pediatric septic shock within the first hour of presentation to the emergency department was associated with improved outcome.6 Our results also agree with the study by investigators at St. Mary’s Hospital in London, England, who found that avoidable delays and inappropriate treatments contributed to poor outcome among children with severe meningococcal disease.7 Shock had not been recognized or treated in 50% of these patients.7
Collectively, these findings have important implications for the pediatric population because many children live in communities without a pediatric-specialized center nearby, and subsequently they must access care through their local community hospital.12 It is likely that the initial resuscitation that community hospital physicians provide will have the greatest impact on determining the survival outcome for children who present with septic shock. For this reason, immediate, aggressive resuscitation of children with septic shock should be the community physician’s first priority rather than delaying resuscitation while awaiting transfer to a pediatric-referral center.
Fluid Resuscitation Practice May Not Be Adequate in the Community Hospital Setting
Our study suggests that fluid resuscitation practice in community hospitals remains conservative. We observed that community physicians administered similar median volumes of fluid therapy (20.0 mL/kg vs 23.9 mL/kg) to both patients in persistent shock and patients whose shock was reversed. This suggests that community physicians tend to administer a 20-mL/kg bolus of fluid during the initial resuscitation of pediatric-neonatal septic shock but then do not administer additional fluid boluses to patients who remain in persistent shock. When faced with particularly severe cases of septic shock (ie, nonsurvivors), community physicians seem to escalate preferentially to inotropic/vasopressor support rather than administer additional fluid therapy. Although most children in septic shock certainly require inotropic/vasopressor support, the hemodynamic impact of catecholamine infusions may be blunted by inadequate fluid resuscitation.6 The reason for this “limited fluid resuscitation” by community physicians remains to be determined. However, its practice partly explains the paradoxical finding that despite having received increased inotropic/vasopressor support, nonsurvivors in this study were less likely to have received resuscitation consistent with the new ACCM-PALS Guidelines. These guidelines speculate that stepwise escalation of therapies, starting with airway management and adequate fluid resuscitation, will improve survival outcomes in pediatric-neonatal septic shock.
Does Hydrocortisone Therapy Have a Role in Treating Septic Shock in the Community Hospital Setting?
We note that community physicians in our study administered hydrocortisone therapy to 13% of the patients in septic shock. Although it did not reach statistical significance, the use of hydrocortisone tended to be associated with greater shock reversal, lending support for a possible role for this therapy in the treatment of septic shock. This concept has been a topic of considerable interest and active investigation. It is widely recognized that certain patients are at risk for adrenal insufficiency secondary to an inadequate hypothalamic-pituitary-adrenal axis response from prolonged corticosteroid use or from an existing central nervous system abnormality. Adrenal insufficiency can also occur in the presence of purpura fulminans particularly during fatal meningococcal septic shock.13,14 One randomized controlled trial that examined the role of high-dose hydrocortisone (50 mg/kg intravenous bolus followed by a 50-mg/kg infusion over 24 hours) in Dengue shock syndrome found significant survival benefit.15,16 Hydrocortisone provides both glucocorticoid and mineralocorticoid effect. A randomized controlled trial of the pure glucocorticoid dexamethasone found no effect on the outcome in African children with sepsis.17 The ACCM-PALS Guidelines recommend empiric treatment with hydrocortisone infusion in children with catecholamine-resistant shock and purpura fulminans or other risk factors for adrenal insufficiency.
Can ACCM-PALS Guidelines Be Relevant to Community Practice?
Although prospective studies will need to be conducted to determine definitively whether the new ACCM-PALS Guidelines will be effective in improving outcome in pediatric-neonatal septic shock, our study lends support for its application to the community hospital setting. However, because these new ACCM-PALS Guidelines were developed in pediatric academic centers without specific regard for the community physician, barriers to its successful translation and implementation into the community hospital setting may exist. One barrier could be related to specialized technical skills needed to execute specific therapies. For example, not all health care providers who care for children possess sufficient pediatric airway management skills to perform oral endotracheal intubation. Also, some community physicians may not be comfortable placing central venous lines in critically ill children. However, these requisite technical skills did not seem to restrict the execution of these therapeutic interventions by community physicians in our study. Community physicians placed 73% of the nonsurvivors on mechanical ventilatory support and obtained central venous access in 38%. Rather, it seems that important, educational barriers might play a greater role in curtailing the implementation of the new ACCM-PALS Guidelines in the community setting. We observed that many community physicians provided limited fluid therapy to patients in persistent shock. Educational programs and future revisions of the ACCM-PALS Guidelines as well as the PALS curriculum will need to address these and other potential barriers to implementation in the community hospital setting.
It is likely that through ongoing, cooperative efforts between community hospitals and specialized, tertiary-care pediatric referral centers, these new ACCM-PALS Guidelines can be implemented successfully. Support for this view comes from Booy et al,8 who described an impressive reduction of mortality from meningococcal disease in southern England from 23% to 2% in a span of just 6 years. This improved case fatality rate occurred without any change in severity of illness defined by PRISM scores. This remarkable improvement in outcome can be attributed to improved health care delivery through a combination of dissemination of recommended guidelines for managing meningococcal disease (see Pollard et al18) to area community hospitals through educational outreach programs, facilitation of early communication and management recommendations between the local and referral hospital, and utilization of a mobile pediatric critical care transport team.8
Practical Measures That Community Physicians Can Use to Recognize and Treat Children With Septic Shock
It has been estimated in a recent epidemiologic study of severe sepsis in the United States that >42 000 annual cases, almost 4400 annual deaths, and annual costs on the order of $1.97 billion can be attributed to severe sepsis in children.19 The community physician can perform many important, life-saving interventions that are well within the scope of their community-based practice to help these children. Septic shock can be recognized in its earliest stages as tachycardia, bounding peripheral pulses, and altered mental alertness. In later stages, prolonged capillary refill time occurs, and still later, hypotension develops as these earlier compensatory mechanisms begin to fail. The community physician should strive to recognize and treat shock before hypotension occurs. If the child has no hepatomegaly or rales, then aggressive fluid resuscitation should be administered with rapid successions of 20-mL/kg boluses of isotonic crystalloid (eg, normal saline) or colloid (eg, 5% albumin) up to 60 mL/kg or until resolution of shock. Rapid blood glucose evaluation should be simultaneously performed and hypoglycemia corrected with glucose administration. Inotropic therapies can be administered through the peripheral vein, intraosseous route, or central venous access. Dobutamine (5 μg/kg/min) can be administered through the peripheral vein to improve capillary refill in normotensive patients8,18; however, in hypotensive patients, dopamine and, commonly, epinephrine infusion is required. Because infants and children have an age-specific insensitivity to dopamine, our transport team uses epinephrine only. The greatest efficacy is attained when epinephrine is infused through a central line (begin at 0.10 μg/kg/min); however, in children without central access, the intraosseous route can be used. Hydrocortisone should be given to children who are at risk for adrenal insufficiency, including children with purpura fulminans.
In the meantime, the regional pediatric center can be contacted for additional recommendations and arrangements can be made for possible transfer to a PICU, preferably using a pediatric-specialized transport team. In areas where telemedicine technology is available, pivotal decisions regarding the initial management of the child in shock can be facilitated through interactive conversations between the community physician and telemedicine “command” physician.
Our study has several limitations to consider. First, its retrospective nature brings inherent restrictions with regard to the strength of our conclusions. However, for at least 1 of our observations (persistent shock is associated with increased mortality), a retrospective study may be the only practical method to examine this relationship. Second, we have relied on clinical rather than laboratory or invasive hemodynamic parameters to define shock reversal. We chose this approach because we favored the idea of using simple, bedside assessments that could be adopted and practiced easily by community physicians. Third, to determine the duration of persistent shock, we made the assumption that patients presented to the community hospital at the onset of their symptoms. In fact, we are uncertain when each child became ill and how long he or she may have been in shock before being brought to medical attention. It is also uncertain when in relation to patient presentation the request for interfacility transport by the community hospital physician was actually made. Fourth, because the definitions of “ appropriate fluid therapy” and “delay in resuscitation consistent with ACCM-PALS Guidelines” were coupled to the condition of shock reversal, an inherent bias was introduced regarding the application of these definitions to outcome. However, not all patients need the full gamut of therapeutic interventions during resuscitation of septic shock. For some patients, fluid therapy may be the only therapy needed; for others, inotropic support with dopamine may be necessary; and in others, epinephrine may be required. In this regard, we contend that these definitions—although by no means ideal—serve their function in permitting a method to assess appropriateness of escalations in therapy. Fifth, it is possible that our study population was not truly representative of pediatric-neonatal septic shock in the community hospital. By virtue of needing transport to our tertiary-care pediatric referral center, only the most severe cases of septic shock may have been selected from each community hospital. Sixth, because previous clinical experience of the community physicians was not assessed, it is unknown whether physicians with more experience tended to resuscitate earlier with more success. Seventh, we do not have data on initial antibiotic choice and do not know the degree to which this influenced outcome.
Pediatric septic shock is a life-threatening illness that requires immediate recognition and aggressive treatment in the community hospital setting. The recently published ACCM Clinical Practice Parameters for Hemodynamic Support of Pediatric and Neonatal Patients in Septic Shock provides a stepwise algorithm that community physicians can incorporate into their practice of pediatric-neonatal septic shock resuscitation. Successful implementation of these guidelines will likely require educational efforts to increase physician comfort with early administration of aggressive fluid resuscitation. Future studies will be needed to address potential barriers to guideline implementation and to determine its efficacy in the community hospital setting.
Funding for this work was provided by Emergency Medical Services for Children, Maternal and Child Health Bureau Grant 1-MCH-4240030-01-0 (R.A.O.); a Laerdal Foundation for Acute Medicine grant (R.A.O.); and National Institutes of Health grants 3M01RR0056GCRC (J.A.C.) and T32-HD40686 (Y.Y.H.).
We thank Robert W. Hickey, MD, Patrick M. Kochanek, MD, Ann E. Thompson, MD, and Shekhar T. Venkataraman, MD, for constructive, critical reviews of the preliminary manuscript. We thank the members of Children’s Hospital of Pittsburgh’s Transport Team for dedication to the safe transport of critically ill infants and children and for meticulous maintenance of the transport database.
- Received November 18, 2002.
- Accepted April 2, 2003.
- Reprint requests to (J.A.C.) Department of Critical Care Medicine, Children’s Hospital of Pittsburgh, 3705 Fifth Ave, Pittsburgh, PA 15213. E-mail:
Preliminary work for this study was presented, in part, at the Society of Critical Care Medicine 29th Educational and Scientific Symposium; February 11–15, 2000; Orlando, FL; and at the Pediatric Academic Societies and American Academy of Pediatrics Joint Meeting; May 12–16, 2000; Boston, MA.
- Natanson C, Danner RL, Reilly JM, et al. Antibiotics versus cardiovascular support in a canine model of human septic shock. Am J Physiol.1990;259 :H1440– H1447
- ↵Nadel S, Britto J, Booy R, Maconochie I, Habibi P, Levin M. Avoidable deficiencies in the delivery of health care to children with meningococcal disease. J Accid Emerg Med.1998;15 :298– 303
- ↵Booy R, Habibi P, Nadel S, et al. Reduction in case fatality rate from meningococcal disease associated with improved healthcare delivery. Arch Dis Child.2001;85 :386– 390
- ↵Zaritsky AL, Nadkarni VM, Hickey RW, Schexnayder SM, Berg RA, eds. Pediatric Advanced Life Support Provider Manual. Dallas, TX: American Heart Association; 2002
- ↵van Woensel JP, Biezeveld MH, Aldes AM, et al. Adrenocorticotropin hormone and cortisol levels in relation to inflammatory response and disease severity in children with meningococcal disease. J Infect Dis.2001;184 :1532– 1537
- ↵McEvoy GK, ed. American Hospital Formulary Service Drug Information 2002. Bethesda, MD: American Society of Health System Pharmacists, Inc.; 2002:2931
- ↵Pollard AJ, Britto J, Nadel S, DeMunter C, Habibi P, Levin M. Emergency management of meningococcal disease. Arch Dis Child.1999;80 :290– 296
- Copyright © 2003 by the American Academy of Pediatrics