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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
World J Pediatr Congenit Heart Surg. Author manuscript; available in PMC 2012 July 1.
Published in final edited form as:
PMCID: PMC3277844

Sepsis in the Pediatric Cardiac Intensive Care Unit


The survival rate for children with congenital heart disease (CHD) has increased significantly coincident with improved techniques in cardiothoracic surgery, cardiopulmonary bypass, and myocardial protection, and post-operative care. Cardiopulmonary bypass, likely in combination with ischemia-reperfusion injury, hypothermia, and surgical trauma, elicits a complex, systemic inflammatory response that is characterized by activation of the complement cascade, release of endotoxin, activation of leukocytes and the vascular endothelium, and release of pro-inflammatory cytokines. This complex inflammatory state causes a transient immunosuppressed state, which may increase the risk of hospital-acquired infection in these children. Postoperative sepsis occurs in nearly 3% of children undergoing cardiac surgery and significantly increases length of stay in the pediatric cardiac intensive care unit as well as the risk for mortality. Herein, we review the epidemiology, pathobiology, and management of sepsis in the pediatric cardiac intensive care unit.

Keywords: systemic inflammatory response syndrome (SIRS), sepsis, severe sepsis, septic shock, congenital heart disease, pediatrics, pediatric cardiac surgery, immunoparalysis, PIRO


The survival rate for neonates, infants, and children with congenital heart disease (CHD) has increased significantly coincident with improved techniques in cardiothoracic surgery, cardiopulmonary bypass (CPB) and myocardial protection, and post-operative care. However, CPB, likely in combination with ischemia-reperfusion injury, hypothermia, and surgical trauma, elicits a complex, systemic inflammatory response that is characterized by activation of the complement cascade, release of endotoxin, activation of leukocytes and the vascular endothelium, and release of pro-inflammatory cytokines (1). This complex humoral and cellular-mediated immune response results in a transient and relative state of immune suppression, often referred to as “immunoparalysis” (13). Whole blood obtained from children following CPB stimulated ex vivo with lipopolysaccharide (LPS) results in markedly diminished pro-inflammatory cytokine production (2), consistent with the phenomenon known as “endotoxin tolerance” (4). This state of immunoparalysis may result in an increased risk of sepsis in children undergoing cardiac surgery for palliation or repair of CHD (57). In addition, chronic hypoxia and other co-morbid conditions associated with cyanotic CHD, as well as the need for invasive supportive devices may also increase the risk of sepsis in this population. Importantly, sepsis is a significant and independent risk factor for increased duration of mechanical ventilation, cardiac intensive care unit (CICU) length of stay (LOS), healthcare costs, and mortality in children with CHD (5, 710).

The Scope of the Problem

The diagnosis of sepsis is based upon the clinical recognition of a constellation of several, fairly consistent clinical signs and symptoms that occur in association with an infection or other inciting event, e.g. trauma, pancreatitis, cardiopulmonary bypass, or burns. Roger Bone first coined the term sepsis syndrome in 1989 (11), and shortly thereafter, an international panel of experts from the Society of Critical Care Medicine (SCCM) and the American College of Chest Physicians (ACCP) proposed the now familiar consensus definitions for the systemic inflammatory response syndrome (SIRS), sepsis, severe sepsis, and septic shock (Table 1) (12). These definitions have been subsequently modified for use in critically ill children (Table 2) (13) and are certainly applicable to children with CHD.

Table 1
American College of Physicians (ACCP)/Society of Critical Care Medicine (SCCM) Consensus Definitions for SIRS, Infection, Sepsis, Severe Sepsis, and Septic Shock
Table 2
Consensus Definitions for Pediatric SIRS, Infection, Sepsis, Severe Sepsis, and Septic Shock

According to the National Center for Health Statistics and the Centers for Disease Control and Prevention, sepsis was the 10th leading cause of death overall in 2007 (14). Recent estimates suggest that there are between 77 to 240 new cases of sepsis per 100,000 population each year (15, 16). The population is growing older, and patients are living longer, even in the face of diseases that were previously considered universally fatal. Hospitalized patients are becoming more dependent upon the use of invasive devices and technology, all of which are associated with increased risk of infection. As such, the incidence of sepsis is expected to increase by 1.5% every year, resulting in an additional 1 million cases per year by 2020 (15, 17, 18). The story in children is fairly similar. There are between 20,000 – 42,000 cases of severe sepsis every year in the United States alone, half of which occur in children with underlying diseases like cancer and congenital heart disease (19, 20). Again, as more children survive diseases that were previously fatal (21), the incidence of sepsis will likely increase further.

While the management of critically ill patients with sepsis is certainly better now compared to 20 years ago (2224), sepsis-associated mortality remains unacceptably high. Recent estimates suggest that there are approximately 4,500 children who die every year from sepsis in the United States alone (19, 25). The actual number of deaths associated with sepsis is likely to be much higher, as many patients usually die from sepsis during the course of an underlying disease, such as prematurity, congenital heart disease, or cancer. In many of these cases, deaths are frequently attributed to the underlying disease process, rather than to sepsis (17, 19, 26, 27). According to data from the World Health Organization (WHO), the United Nations Children’s Fund (UNICEF), and the Bill and Melinda Gates Foundation, nearly 70% of the 8 million deaths in children < 5 years of age were due to infectious disease (28). As sepsis is the final common pathway in many infectious diseases, such as malaria, dengue fever, pneumonia, influenza, and HIV, sepsis can and should be considered the #1 killer of children worldwide.

Unfortunately, there are relatively few studies that have determined the impact of sepsis on critically ill children with CHD (2931). Most of these studies are limited to critically ill children who develop sepsis secondary to hospital-acquired infections (HAIs), including (in decreasing order of frequency and importance in the CICU) catheter-associated bloodstream infections (CA-BSIs), ventilator-associated respiratory infections (VARIs), surgical site infections (SSIs), and catheter-associated urinary tract infections (CA-UTIs) (5, 6, 8, 9, 3236). Barker and colleagues (31) reviewed 30,078 cases from 48 centers in the Society of Thoracic Surgeons Congenital Heart Surgery Database from 2002–2006 and found that 2.8% of these cases had a major infectious complication, of which 2.6% were sepsis. Mortality and postoperative length of stay were significantly greater in these patients. More studies on the epidemiology of sepsis in children with CHD are therefore necessary and warranted.

The PIRO concept

The consensus definitions for sepsis provide a general framework for epidemiologic investigation, as well as providing consistent and relatively straightforward inclusion criteria for clinical trials, most experts recognize that these definitions are far from perfect (3739). As a result, several experts from SCCM and ACCP re-convened in December, 2001 and proposed a new staging system for sepsis (40). The “PIRO” staging system for sepsis is modeled after the TNM (Tumor, Nodes, Metastasis) system (41) for staging cancer and stratifies patients on the basis of their Predisposing conditions, the nature and extent of the insult (Infection), the nature and magnitude of the host Response, and the degree of concomitant Organ dysfunction. The PIRO staging system has many favorable attributes, but will require thorough validation and testing before it is widely adopted and applied in clinical practice (4246).


There are numerous factors that may increase the risk and severity of sepsis. Certainly, age (increased mortality at the extremes of age – both young and old) (17, 19, 47), gender (increased severity of illness and mortality in males compared to females) (48, 49), nutritional status (increased morbidity and mortality with malnutrition or obesity) (5052), and chronic diseases (17, 19, 24) are important. Genetic factors (see also below) likely play an important role as well, and there are several gene polymorphisms that have been linked with an increased susceptibility to sepsis (53). Aside from these factors, there are likely several reasons that children with CHD are at a particularly increased risk. First, there are several well-described malformation syndromes (e.g., 22q11 deletion or DiGeorge sequence) and chromosomal syndromes (trisomy 21) that are associated with congenital heart malformations and defects in immunity. Second, the chronic hypoxia associated with cyanotic CHD likely affects the host immune response. Third, children with CHD are exposed to invasive devices and technology, which carry an increased risk for HAI. Fourth, children who undergo heart or heart/lung transplantation require life-long immunosuppression to prevent graft rejection, which increases the risk of infection. Finally, ischemia-reperfusion injury following CPB frequently results in a state of functional immunoparalysis, which likely increases the risk of HAI as well.


There are likely important host-pathogen interactions that affect the response to therapy and outcome, which have been reviewed elsewhere (5456).


Individual differences in the host response to sepsis may also depend to a significant extent upon an individual’s particular genetic make-up. While no clear “sepsis gene” has been identified, genetic factors undoubtedly play an important role in the pathophysiology of sepsis (53, 5759). Sorensen and colleagues (60) conducted a longitudinal cohort study involving over 900 adopted children born between 1924 and 1926. The adopted children and both their biologic and adoptive parents were followed until1982. The death of a biologic parent before age 50 years resulted in a significantly increased risk of death in the adopted children (R.R. 1.71, 95% C.I. 1.14 to 2.57) for all causes. Of greater interest, if a biologic parent died of infection before the age of 50 years, the relative risk of death from infectious causes in the child was highly significant, with a relative risk of 5.81 (95% C.I. 2.47 to 13.7), which was higher than the increased risk of dying from cardiovascular disease or cancer, two conditions with well accepted genetic components. In contrast, the death of an adoptive parent from infectious causes did not confer a greater risk of death in the adopted child.

The prevailing evidence suggests that the individual response to sepsis is quite heterogeneous and that a “one-size fits all” approach to treatment is not likely to be successful. Sepsis results from a dysregulated host response, such that the balance between the pro-inflammatory mechanisms that are largely responsible for combating infection and the compensatory, anti-inflammatory mechanisms that counteract, “fine-tune”, and regulate these mechanisms largely determines the nature of the host response. For example, a shift in the homeostatic balance to a predominantly anti-inflammatory phenotype leads to a state of relative immune suppression or immunoparalysis, resulting in an inability to clear the pathogen and hence, an increased risk of HAI (61, 62). These patients would benefit from therapies that are designed to augment or stimulate the host immune response, e.g. interferon-γ (6365) and/or granulocyte-macrophage colony-stimulating factor (GM-CSF) (6670). Conversely, a shift in balance toward a predominantly pro-inflammatory phenotype results in further cellular injury, multiple organ failure, and death. These patients, on the other hand, would benefit from therapies that are designed to suppress or attenuate the host immune response. It is the nature of the host response, then, that largely determines the type of therapy required – either stimulation or attenuation of the host response to infection (59, 71). We believe that a strategy based upon “the right therapy, at the right time, in the right patient” will achieve the best possible outcome. The use of biomarkers (72) or gene expression profiling (73) will hopefully facilitate proper selection of the best therapy for critically ill children with sepsis.

Organ Dysfunction/Failure

Sepsis is characterized by a triad of inflammation, endothelial dysfunction, and alterations in the coagulation systems, which lead to perturbations in the delivery of oxygen and metabolic substrates to the tissues. These perturbations, in turn, lead to multiple organ dysfunction syndrome (MODS) (Table 4) and ultimately death. While relatively uncommon, MODS is associated with significant morbidity and mortality in critically ill children with CHD following cardiac surgery (7476). For example, Ben-Abraham and colleagues (76) showed that 80% all deaths occurring during the first post-operative week in their series were caused by MODS. Mortality is higher with increased numbers of organ systems failures. Acute kidney injury (AKI), in particular, appears to be an independent risk factor for mortality in this population (7780). Therefore, both the number and type of organ failures likely affects outcome in critically ill children with sepsis and CHD.

Table 4
Consensus Definitions for Pediatric Organ Dysfunction

Management of Sepsis in the Pediatric CICU

The American College of Critical Care Medicine Clinical Practice Parameters for Hemodynamic Support of Pediatric and Neonatal Septic Shock were published in 2002 as a set of “best clinical practices” for the management of critically ill neonates and children with septic shock (81). While these guidelines have not been rigorously tested in a randomized, controlled clinical trial, early resuscitation and reversal of shock has improved outcome in critically ill children with septic shock (82, 83). In addition, a randomized open-label clinical trial in Brazil showed that management targeted to superior vena cava oxygen saturation (ScvO2) using these guidelines resulted in a significant reduction in 28-day mortality (39.2% vs. 11.8%, p=0.002) (84). These guidelines were updated and revised in 2007 (85).

Unanswered Questions

Several unanswered questions for the management of critically ill neonates and children with sepsis and underlying CHD remain. First, as discussed above, there are few epidemiologic studies available to assess the impact of the presence of underlying heart disease and/or chronic hypoxemia on the outcome from sepsis. Second, there is an urgent need for better biomarkers for risk stratification and therapeutic monitoring in this population. Third, we need to understand the impact of CHD, and in particular, the effects of cardiopulmonary bypass, on the subsequent risk for hospital-acquired infections, such as VARI, CA-BSI, and CA-UTI. Finally, we need to better understand the nuances of managing critically ill children with cyanotic CHD and sepsis.

Table 3
The PIRO model of sepsis


Supported by the National Institutes of Health, 5KO8GM077432 (DSW)


1. Tarnok A, Schneider P. Pediatric cardiac surgery with cardiopulmonary bypass: pathways contributing to transient systemic immune suppression. Shock. 2001;16 (Suppl 1):24–32. [PubMed]
2. Allen ML, Hoschtitzky JA, Peters MJ, et al. Interleukin-10 and its role in clinical immunoparalysis following pediatric cardiac surgery. Crit Care Med. 2006;34:2658–2665. [PubMed]
3. Allen ML, Peters MJ, Goldman A, et al. Early postoperative monocyte deactivation predicts systemic inflammation and prolonged stay in pediatric cardiac intensive care. Crit Care Med. 2002;30:1140–1145. [PubMed]
4. Cavaillon J-M, Adrie C, Fitting C, et al. Endotoxin tolerance: is there a clinical relevance? J Endotoxin Res. 2003;9:101–107. [PubMed]
5. Levy I, Ovadia B, Erez E, et al. Nosocomial infections after cardiac surgery in infants and children: incidence and risk factors. J Hosp Infect. 2003;53:111–116. [PubMed]
6. Mehta PA, Cunningham CK, Colella CB, et al. Risk factors for sternal wound and other infections in pediatric cardiac surgery patients. Pediatr Infect Dis J. 2000;19:1000–1004. [PubMed]
7. Pollock EM, Ford-Jones EL, Rebeyka I, et al. Early noscomial infections in pediatric cardiovascular surgery patients. Crit Care Med. 1990;18:378–384. [PubMed]
8. Sarikivi E, Lyytikainen O, Nieminen H, et al. Nosocomial infections after pediatric cardiac surgery. Am J Infect Control. 2008;36:564–569. [PubMed]
9. Abou Elella R, Najm HK, Balkhy H, et al. Impact of bloodstream infection on the outcome of children undergoing cardiac surgery. Pediatr Cardiol. 2010;31:483–489. [PubMed]
10. Wheeler DS, Dent CL, Manning PB, et al. Factors prolonging length of stay in the cardiac intensive care unit following the arterial switch operation. Cardiol Young. 2008;18:41–50. [PMC free article] [PubMed]
11. Bone RC, Fisher CJ, Clemmer TP, et al. Sepsis syndrome: A valid clinical entity. Crit Care Med. 1989;17:389–393. [PubMed]
12. ACCP and SCCM. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med. 1992;20:864–874. [PubMed]
13. Goldstein B, Giroir B, Randolph A. International pediatric sepsis consensus conference: definitions for sepsis and organ dysfunction in pediatrics. Pediatr Crit Care Med. 2005;6:2–8. [PubMed]
14. Xu J, Kochanek KD, Murphy SL, et al. Deaths: Final data for 2007. Natl Vital Stat Rep. 2010;58:1–135. [PubMed]
15. Martin GS, Mannino DM, Eaton S, et al. The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med. 2003;348:1546–1554. [PubMed]
16. Finfer S, Bellomo R, Lipman J, et al. Adult population incidence of severe sepsis in Australian and New Zealand Intensive Care Units. Intensive Care Med. 2004;30:589–596. [PubMed]
17. Angus DC, Linde-Zwirble WT, Lidicker J, et al. Epidemiology of severe sepsis in the United States: Analysis of incidence, outcome, and associated costs of care. Crit Care Med. 2001;29:1303–1310. [PubMed]
18. Dombrovskiy VY, Martin AA, Sunderram J, et al. Rapid increase in hospitalization and mortality rates for severe sepsis in the United States: A trend analysis from 1993 to 2003. Crit Care Med. 2007;35:1244–1250. [PubMed]
19. Watson RS, Carcillo JA, Linde-Zwirble WT, et al. The epidemiology of severe sepsis in children in the United States. Am J Respir Crit Care Med. 2003;167:695–701. [PubMed]
20. Odetola FO, Gebremariam A, Freed GL. Patient and hospital correlates of clinical outcomes and resource utilization in severe pediatric sepsis. Pediatrics. 2007;119:487–494. [PubMed]
21. Simon TD, Berry J, Feudtner C, et al. Children with complex chronic conditions in inpatient hospital settings in the United States. Pediatrics. 2010;126:647–655. [PMC free article] [PubMed]
22. Friedman G, Silva E, Vincent JL. Has the mortality of septic shock changed with time. Crit Care Med. 1998;26:2078–2086. [PubMed]
23. Campaign SS. [Accessed November 9, 2010];Understanding progress in the management of sepsis: How the management of sepsis has improved and will improve further. Available online at: http://
24. Wheeler DS, Zingarelli B, Wheeler WJ, et al. Novel pharmacologic approaches to the management of sepsis: Targeting the host inflammatory response. Recent Pat Inflamm Allergy Drug Discov. 2009;3:96–112. [PMC free article] [PubMed]
25. Watson RS, Carcillo JA. Scope and epidemiology of pediatric sepsis. Pediatr Crit Care Med. 2005;2005:S3–S5. [PubMed]
26. Angus DC, Wax RS. Epidemiology of sepsis: An update. Crit Care Med. 2001;29:S109–116. [PubMed]
27. Balk RA. Severe sepsis and septic shock. Definitions, epidemiology, and clinical manifestations. Crit Care Clin. 2000;16:179–192. [PubMed]
28. Black RE, Cousens S, Johnson HL, et al. Global, regional, and national causes of child mortality in 2008: A systemic analysis. Lancet. 2010;375:1969–1987. [PubMed]
29. Hadzimuratovic E, Dinarevic SM, Hadzimuratovic A. Sepsis in premature newborns with congenital heart disease. Congenit Heart Dis. 2010;5:435–438. [PubMed]
30. Doell C, Bernet V, Molinari L, et al. Children with genetic disorders undergoing open-heart surgery: Are they at increased risk for postoperative complications? Pediatr Crit Care Med. 2010 [PubMed]
31. Barker GM, O’Brien SM, Welke KF, et al. Major infection after pediatric cardiac surgery: A risk estimation model. Ann Thorac Surg. 2010;89:843–850. [PMC free article] [PubMed]
32. Chakrabarti C, Sood SK, Parnell V, et al. Prolonged candidemia in infants following surgery for congenital heart disease. Infect Control Hosp Epidemiol. 2003;24:753–757. [PubMed]
33. San Miguel LG, Cobo J, Otheo E, et al. Candidemia in pediatric patients with congenital heart disease. Diagn Microbiol Infect Dis. 2006;55:203–207. [PubMed]
34. Grisaru-Soen G, Sweed Y, Lerner-Geva L, et al. Nosocomial bloodstream infections in a pediatric intensive care unit: 3-year survey. Med Sci Monit. 2007;13:251–257. [PubMed]
35. Lomtadze M, Chkhaidze M, Mgeladze E, et al. Incidence and risk factors of nosocomial infections after cardiac surgery in Georgian population with congenital heart diseases. Georgian Med News. 2010;178:7–11. [PubMed]
36. Tang CW, Liu PY, Huang YF, et al. Ventilator-associated pneumonia after pediatric cardiac surgery in southern Taiwan. J Microbiol Immunol Infect. 2009;42:413–419. [PubMed]
37. Marshall JC. SIRS and MODS: What is their relevance to the science and practice of intensive care? Shock. 2000;14:586–589. [PubMed]
38. Baue AE. A debate on the subject “Are SIRS and MODS important entities in the clinical evaluation of patients? ” The con position. Shock. 2000;14:590–593. [PubMed]
39. Vincent JL. Dear SIRS, I’m sorry to say that I don’t like you. Crit Care Med. 1997;25:372–374. [PubMed]
40. Levy MM, Fink MP, Marshall JC, et al. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med. 2003;31:1250–1256. [PubMed]
41. Denoix PX. Enquete permanent dans les centres anticancereaux. Bull Inst Natl Hyg. 1946;1:70–75.
42. Opal SM. Concept of PIRO as a new conceptual framework to understand sepsis. Pediatr Crit Care Med. 2005;6:S55–S60. [PubMed]
43. Howell MD, Talmor D, Schuetz P, et al. Proof of principle: The predisposition, infection, response, organ failure sepsis staging system. Crit Care Med. 2010 [PubMed]
44. Moreno RP, Metnitz B, Adler L, et al. Sepsis mortality prediction based on predisposition, infection, and response. Intensive Care Med. 2008;34:496–504. [PubMed]
45. Rubulotta F, Marshall J, Ramsay G, et al. Predisposition, insult/infection, response, and organ dysfunction: A new model for staging severe sepsis. Crit Care Med. 2009;37:1329–1335. [PubMed]
46. Rello J, Rodriguez A, Lisboa T, et al. PIRO score for community-acquired pneumonia: A new prediction rule for assessment of severity in intensive care unit patients with community-acquired pneumonia. Crit Care Med. 2009;37:456–462. [PubMed]
47. Wynn J, Cornell TT, Wong HR, et al. The host response to sepsis and developmental impact. Pediatrics. 2010;125:1031–1041. [PMC free article] [PubMed]
48. Marriott I, Huet-Hudson YM. Sexual dimorphism in innate immune responses to infectious organisms. Immunol Res. 2006;34:177–192. [PubMed]
49. Choudhry MA, Bland KI, Chaudry IH. Trauma and immune response - effect of gender differences. Injury. 2007;38:1382–1391. [PMC free article] [PubMed]
50. Carcillo JA. Reducing the global burden of sepsis in infants and children: A clinical practice research agenda. Pediatr Crit Care Med. 2005;6:S157–S164. [PubMed]
51. Nguyen TH, Nguyen TL, Lei HY, et al. Association between sex, nutritional status, severity of dengue hemorrhagic fever, and immune status in infants with dengue hemorrhagic fever. Am J Trop Med Hyg. 2005;72:370–374. [PubMed]
52. Sakr Y, Madl C, Filipescu D, et al. Obesity is associated with increased morbidity but not mortality in critically ill patients. Intensive Care Med. 2008;34:1999–2009. [PubMed]
53. Dahmer MK, Randolph A, Vitali S, et al. Genetic polymorphisms in sepsis. Pediatr Crit Care Med. 2005;6:S61–S73. [PubMed]
54. Opal SM, Cohen J. Clinical gram-positive sepsis: Does it fundamentally differ from gram-negative bacterial sepsis? Crit Care Med. 1999;27:1608–1616. [PubMed]
55. Moine P, Abraham E. Immunomodulation and sepsis: Impact of the pathogen. Shock. 2004;22:297–308. [PubMed]
56. van der Poll T, Opal SM. Host-pathogen interactions in sepsis. Lancet Infect Dis. 2008;8:32–43. [PubMed]
57. Cooke GS, Hill AV. Genetics of susceptibility to human infectious disease. Nat Rev Genet. 2001;2:967–977. [PubMed]
58. Cornell TT, Wynn J, Shanley TP, et al. Mechanisms and regulation of the gene-expression response to sepsis. Pediatrics. 2010;125:1248–1258. [PMC free article] [PubMed]
59. Wheeler DS, Wong HR. Genetic approach to pediatric septic shock. Personalized Med. 2008;5:249–263.
60. Sorensen TI, Nielsen GG, Andersen PK, et al. Genetic and environmental influences on premature death in adult adoptees. N Engl J Med. 1988;318:727–32. [PubMed]
61. Osuchowski MF, Welch K, Siddiqui J, et al. Circulating cytokine/inhibitor profiles reshape the understanding of the SIRS/CARS continuum in sepsis and predict mortality. J Immunol. 2006;177:1967–1974. [PubMed]
62. Ashare A, Powers LS, Butler NS, et al. Anti-inflammatory response is associated with mortality and severity of infection in sepsis. Am J Physiol Lung Cell Mol Physiol. 2005;288:L633–L640. [PubMed]
63. Docke WD, Randow F, Syrbe U, et al. Monocyte deactivation in septic patients: restoration by IFN-gamma treatment. Nat Med. 1997;3:678–81. [PubMed]
64. Volk HD, Reinke P, Krausch D, et al. Monocyte deactivation - rationale for a new therapeutic strategy in sepsis. Intensive Care Med. 1996;22 (Suppl 4):S474–S481. [PubMed]
65. Kox WJ, Bone RC, Krausch D, et al. Interferon gamma-1b in the treatment of compensatory anti-inflammatory response syndrome. A new approach: Proof of principle. Arch Intern Med. 1997;157:389–393. [PubMed]
66. Bundschuh DS, Barsig J, Hartung T, et al. Granulocyte-macrophage colony-stimulating factor and IFN-gamma restore the systemic TNF-alpha response to endotoxin in lipopolysaccharide-desensitized mice. J Immunol. 1997;158:2862–2871. [PubMed]
67. Pugin J. Immunostimulation is a rational therapeutic strategy in sepsis. Novartis Found Symp. 2007;280:21–36. 160–164. [PubMed]
68. Nelson LA. Use of granulocyte-macrophage colony-stimulating factor to reverse anergy in otherwise immunologically healthy children. Ann Allergy Asthma Immunol. 2007;98:373–382. [PubMed]
69. Spight D, Trapnell B, Zhao B, et al. Granulocyte-macrophage-colony-stimulating factor-dependent peritoneal macrophage responses determine survival in experimentally induced peritonitis and sepsis in mice. Shock. 2008;30:434–442. [PMC free article] [PubMed]
70. Flohe SB, Agrawal H, Flohe S, et al. Diversity of interferon gamma and granulocyte-macrophage colony-stimulating factor in restoring immune dysfunction of dendritic cells and macrophages during polymicrobial sepsis. Mol Med. 2008;14:247–256. [PubMed]
71. Monneret G, Venet F, Pachot A, et al. Monitoring immune dysfunctions in the septic patient: A new skin for the old ceremony. Mol Med. 2008;14:64–78. [PubMed]
72. Kaplan JM, Wong HR. Biomarker discovery and development in pediatric critical care medicine. Pediatr Crit Care Med. 2010
73. Wong HR, Wheeler DS, Tegtmeyer K, et al. Toward a clinically feasible gene expression-based subclassification strategy for septic shock: Proof of concept. Crit Care Med. 2010;38:1955–1961. [PMC free article] [PubMed]
74. Seghaye MC, Engelhardt W, Grabitz RG, et al. Multiple system organ failure after open heart surgery in infants and children. Thorac Cardiovasc Surg. 1993;41:49–53. [PubMed]
75. Shime N, Kageyama K, Ashida H, et al. Application of modified sequential organ failure assessment score in children after cardiac surgery. J Cardiothorac Vasc Anesth. 2001;15:463–468. [PubMed]
76. Ben-Abraham R, Efrati O, Mishali D, et al. Predictors for mortality after prolonged mechanical ventilation after cardiac surgery in children. J Crit Care. 2002;17:235–239. [PubMed]
77. Arora P, Kher V, Rai PK, et al. Prognosis of acute renal failure in children: A multivariate analysis. Pediatr Nephrol. 1997;11:153–155. [PubMed]
78. Bunchman TE, McBryde KD, Mottes TE, et al. Pediatric acute renal failure: Outcome by modality and disease. Pediatr Nephrol. 2001;16:1067–1071. [PubMed]
79. Otukesh H, Hoseini R, Hooman N, et al. Prognosis of acute renal failure in children. Pediatr Nephrol. 2006;21:1873–1878. [PubMed]
80. Zappitelli M, Bernier PL, Saczkowski RS, et al. A small post-operative rise in serum creatinine predicts acute kidney injury in children undergoing cardiac surgery. Kidney Int. 2009;76:885–892. [PubMed]
81. Carcillo JA, Fields AI. Clinical practice parameters for hemodynamic support of pediatric and neonatal patients in septic shock. Crit Care Med. 2002;30:1365–1378. [PubMed]
82. Han YY, Carcillo JA, Dragotta MA, et al. Early reversal of pediatric-neonatal septic shock by community physicians is associated with improved outcome. Pediatrics. 2003;112:793–799. [PubMed]
83. Oliveira CF, Nogueira de Sa FR, Oliveira DS, et al. Time- and fluid-sensitive resuscitation for hemodynamic support of children in septic shock: Barriers to the implementation of the American College of Critical Care Medicine/Pediatric Advanced Life Support Guidelines in a pediatric intensive care unit in a developing world. Pediatr Emerg Care. 2008;24:810–815. [PubMed]
84. de Oliveira CF, de Oliveira DS, Gottschald AF, et al. ACCM/PALS haemodynamic support guidelines for paediatric septic shock: An outcomes comparison with and without monitoring of central venous oxygen saturation. Intensive Care Med. 2008;34:1065–1075. [PubMed]
85. Brierley J, Carcillo JA, Choong K, et al. Clinical practice parameters for hemodynamic support of pediatric and neonatal septic shock: 2007 update from the American College of Critical Care Medicine. Crit Care Med. 2009;37:666–88. [PMC free article] [PubMed]