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Clinical course of sepsis in children with acute leukemia admitted to the pediatric intensive care unitClinical course of sepsis in children with acute leukemia admitted
to the pediatric intensive care unit*
Kanakadurga Singer, MD, MA; Perla Subbaiah, PhD; Raymond Hutchinson, MD;Folafoluwa Odetola, MD, MPH; Thomas P. Shanley, MD Objective: To describe the clinical course, resource use, and
inotropic and/or vasopressor drugs (p ؍ .01), and renal replace-
mortality of patients with leukemia admitted to the pediatric
ment therapy (p ؍ .028) than nonsepsis admission. There was
intensive care unit with sepsis and nonsepsis diagnoses over a
higher mortality among children with sepsis than other diagnoses
(52% vs. 17%, p ؍ .004). Also, mortality among children with
Design: Retrospective analysis.
sepsis was higher among those with acute lymphoblastic leuke-
Setting: Tertiary medical–surgical pediatric intensive care unit
mia (60% vs. 44%) compared with acute myelogenous leukemia.
at C.S. Mott Children’s Hospital, University of Michigan.
Administration of stress dose steroids was associated with higher
Patients: All patients with leukemia admitted to the pediatric
mortality (50% vs. 17%, p ؍ .005) and neutropenia. Patients with
intensive care unit from January 1, 1998, to December 31,
acute lymphoblastic leukemia and sepsis showed the greatest
mortality and resource use.
Interventions: None; chart review.
Conclusions: Patients with acute leukemia and sepsis had a
Measurements and Main Results: Clinical course was charac-
much higher mortality rate compared with previously described
terized by demographics, leukemia diagnosis, phase of therapy,
sepsis mortality rates for the general pediatric intensive care unit
leukocyte count on admission, presence of sepsis, steroid admin-
patient populations. Patients who received steroids had an in-
istration, intensity of care, and Pediatric Risk of Mortality score on
creased mortality rate, but given the retrospective nature of this
admission to the pediatric intensive care unit. The primary out-
study, we maintain a position of equipoise with regard to this
come was survival to pediatric intensive care unit discharge.
association. Variation in mortality and resource use by leukemia
Among 68 single admissions to the pediatric intensive care unit
type suggests further research is needed to develop targeted
with leukemia during the study period, 33 (48.5%) were admitted
intervention strategies to enhance patient outcomes. (Pediatr Crit
with sepsis. Admission to the pediatric intensive care unit for
Care Med 2011; 12:649 – 654)
sepsis was associated with greater compromise of hemodynamic
KEY WORDS: sepsis; leukemia; mortality; severity of illness;
and renal function and use of stress dose steroids (p ؍ .016),
length of stay; natural history
Sepsisisaleadingcauseofpe- velopmentofevidence-basedguidelines targetinterventionalrandomizedcon- limited by difﬁculty in performing ran- domized controlled trials in this patient pediatric deaths with associated signiﬁ- often unclear, there is current consensus pediatric sepsis also relates to the wide that aggressive treatment of pediatric pa- tients with leukemia is appropriate given current positive long-term outcomes (3).
*See also p. 680.
The last reported 5-yr mortality for acute From the Department of Pediatrics and Communi- cable Diseases (KS, RH, FO, TPS), University of Mich- igan Health System, Ann Arbor, MI; and the Depart- of pediatric sepsis is to study pediatric ment of Mathematics and Statistics (PS), OaklandUniversity, Rochester, MI.
Supplemental digital content is available for this ar- ticle. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article nesses, in part related to aggressive anti- on the journal’s Web site (www.pccmjournal.org).
The authors have not disclosed any potential con- For information regarding this article, E-mail: (5, 6). Other related risk factors for de- severely ill children. As such, high-risk Copyright 2011 by the Society of Critical Care Medicine and the World Federation of Pediatric Inten- kemia include the use of central vascular catheters, frequent hospitalizations, and DOI: 10.1097/PCC.0b013e31821927f1
Pediatr Crit Care Med 2011 Vol. 12, No. 6 Data Source and Subject Identiﬁcation. All Table 1. Relapse rates among patient groups
children 0 –20 yrs of age diagnosed with leu- kemia between January 1, 1998, and Decem- rence in patients with leukemia, even be- ber 31, 2008, were identiﬁed in the University fore the occurrence of sepsis (8). Current of Michigan Comprehensive Cancer CenterRegistry. Thereafter, their inpatient hospital- pediatric sepsis guidelines emphasize the ization records at the C.S. Mott Children’s Hospital were searched for with the EMERSE (12) search program to identify those patients do not address speciﬁc comorbid diagno- hospitalized in the PICU during the study pe- riod. Patients admitted to the neonatal inten- Study Variables. Patients with culture- positive sepsis were identiﬁed using the fol- lowing key terms: “sepsis,” “infection,” and all patients with leukemia admitted to the “culture.” To avoid potential bias toward over- diagnosing sepsis when these broader criteria administration of “stress” dose steroids in 75% were in initial treatment. As seen in are used, we decided a priori to report only on addition to the mainstay of broad-spectrum culture-positive sepsis to avoid potential cap- Table 1, most of the patients with relapse antibiotic therapy. For instance, during in- ture of patients exhibiting a systemic inﬂam- matory response as a result of nonspeciﬁc trig- there is often administration of high doses gers other than systemic infection (e.g., group. Of the 68 patients admitted to the of steroids with subsequent risk for adrenal adverse reaction to chemotherapy, viral upper insufﬁciency. On the other hand, patients respiratory illness, etc.) that is common in sepsis by clinical symptoms and a positive with AML do not typically receive steroids this cohort. Furthermore, given the retrospec- blood culture with bacteria (Enterobacter, during induction therapy and are expected tive nature of the study, it was not possible to Pseudomonas, Klebsiella, Enterococcus, ensure accurate identiﬁcation of “culture- to be at lower risk of adrenal suppression.
coagulase-positive Staphylococcus, Strep- negative” sepsis patients on the basis of clini- Knowledge of the outcomes of patients sub- tococcus), viruses (cytomegalovirus, para- cal judgment by the medical team. Data col- jected to steroid therapy is, however, very inﬂuenza), and fungi (Aspergillus, Can- demographic information (age, gender, length dida). Fifteen of the 33 patients with sepsis of PICU stay, source of admission), leukemia these patients has long been debated (10).
diagnosis (ALL or AML), phase of therapy, 35 patients without sepsis were diagnosed Speciﬁc studies have not been performed white blood cell count on admission, and in- tensity of PICU care. Indicators of the intensity admissions were for a variety of reasons, of care included use of mechanical ventilation, including 11% gastrointestinal, 11% post- mia impact outcomes from sepsis (11).
arterial catheterization, central venous cathe- therapy, use of inotropic and/or vasopressor in children with leukemia and the overall agents, and ﬂuid resuscitation. Severity of pa- high mortality in patients with leukemia, tient illness was further characterized by the No signiﬁcant differences were observed we conducted a retrospective study to in- Pediatric Risk of Mortality (PRISM) score on in age, gender distribution, or length of vestigate the clinical course among crit- admission to PICU when available (13). The stay among patients according to the diag- ically ill children with leukemia accord- primary outcome variable of the study was survival to PICU discharge or death.
Statistical Analysis. Continuous variables no sepsis. We present a large case series are presented as median values and categorical variables as frequencies. Comparisons among multiple groups of continuous variables were pediatric intensive care unit at C.S. Mott other intensive care units within the study made using the Kruskal-Wallis test. Compari- Children’s Hospital at the University of hospital, referring hospitals, emergency de- sons of proportions were made using Fisher’s exact test. A p value of .05 was taken as the threshold for statistical signiﬁcance. Calcula- tions were performed on the Minitab software formulate a description of clinical course platform (Minitab 15, Minitab Inc., State Col- PICU resource use to try to identify fac- tors that could be used for potential treat- individual inpatients carried the diagno- MATERIALS AND METHODS
sis of acute leukemia and 68 of these were Subjects. A retrospective analysis with medical chart review was performed. Approval for the study was obtained from the institu- tional review board of the University of Mich- Pediatr Crit Care Med 2011 Vol. 12, No. 6 Table 2. Patient characteristics
ED, emergency department; OSH, outside hospital.
Tables 3 and 4 [see Supplemental DigitalContent 1, http://links.lww.com/PCC/A33]).
There was a signiﬁcantly higher medianwhite blood cell count in patients with AMLwithout sepsis compared with all othergroups (p ϭ .009; Kruskal-Wallis test) asshown in Table 2.
Intensive Care Unit Course. To better characterize the intensity of illness andrequisite care in the PICU, use of PICUresources was compared among patientswith and without sepsis. There were nosigniﬁcant differences in the use of me-chanical ventilation, arterial catheteriza-tion, central venous catheterization, orﬂuid resuscitation among patients withand without sepsis (Table 4). However, agreater proportion of patients with sepsisreceived inotropic and/or vasopressoragents (p ϭ .001), stress dose steroids Figure 1. Median length of stay of patients admitted to the pediatric intensive care unit (PICU). ALL,
(p ϭ .016), and continuous renal replace- acute lymphocytic leukemia; AML, acute myelogenous leukemia.
ment therapy (p ϭ .028). This suggeststhat although there was signiﬁcant ill-ness in both groups, the sepsis group had penic patients in the sepsis group (19 of portions of neutropenic patients in the sub- with sepsis was signiﬁcantly higher than of 34 [41%]) is not statistically signiﬁcant (p ϭ .218, Fisher’s exact test). In assess- signiﬁcantly different (Supplemental Table 17%, p ϭ .0044). This increased mortal- ity and signiﬁcant differences in use of basis of receiving received steroids or not portions of neutropenic patients in the four dant with their increased severity of ill- ceived steroids and were septic (17 of 24 also signiﬁcantly associated with mortal- group eight of 15 [53%], sepsis death group ity (p ϭ .004). This relationship appeared with the other subclasses with neutropenia.
11 of 17 [65%]) are homogeneous (p ϭ The proportions of neutropenic patients in .226, chi-square test). Similarly, the pro- sepsis, although it was not statistically portions of neutropenic patients in the four signiﬁcant (Table 5). Similar associations sepsis (non sepsis nonsteroid group ten of 20 [50%], nonsepsis steroid group four of eight [25%], sepsis steroid group 17 of 24 [71%]) are signiﬁcantly different (p ϭ .033, (p ϭ .873, chi-square test) (Supplemental Pediatr Crit Care Med 2011 Vol. 12, No. 6 Table 3. Distribution of patients in subgroups of steroid use, neutropenia, and death
NN, not neutropenic; N, neutropenic; ND, not death; D, death.
aIn both the nonsepsis/steroid group and sepsis/no steroid group, a single patient had no absolute neutrophil count data recorded and thus was not Table 4. Comparison of intensive care unit course in patients with and without sepsis
comes of patients with acute leukemiaadmitted to the PICU at a single tertiary care center over a 10-yr period. Patients with leukemia who were admitted forsepsis had higher illness severity and pre- scoring and ultimately higher death rates than those admitted for other reasons.
The mortality rate in this speciﬁc cohort Median Pediatric Risk of Mortality severity of illness Median Pediatric Risk of Mortality-predicted mortality much broader, heterogeneous population(1, 8, 14). Studies of severe sepsis havereported higher mortality rates (17%), Table 5. Mortality rates among patients receiving
steroids during the intensive care unit course that rate (15, 16). This subgroup mortal- ity is also much higher then the reported and without sepsis. A signiﬁcantly larger sis received ﬂuid resuscitation, continu- in sepsis patients alone of 7.4% (18).
out sepsis (Table 6). Consequently, given without sepsis, who still required inten- sive care. Interestingly, similar differ- without sepsis (Table 6). Interestingly, no of illness measure was not available for all signiﬁcant differences in intensive care require further investigation, but one po- tential contributor this observed differ- sepsis group, n ϭ 31 in nonsepsis group), there was signiﬁcantly increased severity (Table 6). There were no signiﬁcant dif- of illness (p ϭ .036) and predicted mor- tality (p ϭ .013) among patients with mortality scores in the subgroup analysis.
pression proﬁles that may be activated in sepsis vs. those without sepsis. This dif- the setting of sepsis. A number of inves- DISCUSSION
expression proﬁles with notable differ- Pediatr Crit Care Med 2011 Vol. 12, No. 6 Table 6. Comparison of frequency of use of intensive care unit technology and outcomes among
no beneﬁt (34) from the use of cortico- patient subgroups with acute myelogenous leukemia and acute lymphocytic leukemia steroids in the treatment of septic shock.
It is unclear what protocol to follow in children, and this question is the subjectof ongoing debate, but our observations inquiry merits further investigation, par-ticularly in this high-risk cohort (35, 36).
help identify those with adrenal insufﬁ- we suggest a position of clinical equipoise with regard to the association of steroids ciency may serve as a stratiﬁcation tool.
Some studies have suggested the poten- tial association between levels of C-reac- associated molecular patterns (19 –22).
may be as long as 4 – 8 months (26 –28).
tive protein or interleukin-8 with patient outcomes and therefore serve as a strati- itary–adrenal axis with the low-dose ad- ﬁcation method for subsequent targeting renocorticotropin test (27, 29), baseline of therapies (39, 40). However, interleu- leukemia cohorts may differ to inﬂuence have focused only on adult populations.
lation were mostly in a relapse state and their applicability to the pediatric popu- tients with acute leukemia with sepsis for CONCLUSIONS
that this population used more resources, likely as a result of heightened severity of adrenal axis suppression, the use of cor- parison to other populations of critically ill children with sepsis. This study sug- ticosteroids is often prompted by a state gests the need for further investigation of of “relative adrenal insufﬁciency” in cohort, it is also likely that PRISM may be the differential mortality and signiﬁcant gree of physiological stress (31). Eighty- ological progression of organ failure oc- overall increased mortality in individuals receiving steroid treatment, but given the ing timeframe of the initial 24 hrs of care steroids during hospitalization died, al- though it is difﬁcult to ascertain in this maintain a position of equipoise with re- initiated and what doses of steroids were used. Overall, the group of patients with roids at induction, it is possible that ALL mortality. Formal testing for adrenal in- tions in sepsis may lead to better patient thalamic–pituitary–adrenal axis occurs REFERENCES
6 – 8 wks after induction with high dose adrenal axis, although the use of this test- 1. Watson RS, Carcillo JA: Scope and epidemi- ology of pediatric sepsis. Pediatr Crit Care 2. Marshall JC, Vincent JL, Guyatt G, et al: Outcome measures for clinical research in thalamic–pituitary–adrenal axis suppres- evidence of short-term beneﬁt (32, 33) or sepsis: A report of the 2nd Cambridge Collo- Pediatr Crit Care Med 2011 Vol. 12, No. 6 quium of the International Sepsis Forum.
17. Odetola FO, Clark SJ, Dechert RE, et al: coid therapy in children with acute lympho- Crit Care Med 2005; 33:1708 –1716 Going back for more: An evaluation of clini- blastic leukemia. Med Pediatr Oncol 2003; 3. Dalton HJ, Slonim AD, Pollack MM: Multi- cal outcomes and characteristics of readmis- sions to a pediatric intensive care unit. Pedi- 29. Rix M, Birkebaek NH, Rosthoj S, et al: Clin- tients requiring intensive care. In: 96th In- atr Crit Care Med 2007; 8:343–347; CEU quiz ical impact of corticosteroid-induced adrenal suppression during treatment for acute lym- Thoracic Society; May 3–10, 2000. Toronto, 18. Odetola FO, Clark SJ, Gurney JG, et al: Effect phoblastic leukemia in children: A prospec- Canada, Taylor & Francis Inc, 2000, pp of interhospital transfer on resource utiliza- tive observational study using the low-dose tion and outcomes at a tertiary pediatric in- adrenocorticotropin test. J Pediatr 2005; 4. Linet MS, Ries LA, Smith MA, et al: Cancer tensive care unit. J Crit Care 2009; 24: surveillance series: Recent trends in child- 30. Silva IN, Cunha CF, Finch FL, et al: Evalua- hood cancer incidence and mortality in the 19. Lyons PA, Koukoulaki M, Hatton A, et al: tion of hypothalamic–pituitary–adrenal axis United States. J Natl Cancer Inst 1999; 91: Microarray analysis of human leucocyte sub- recovery after corticotherapy by using basal sets: The advantages of positive selection and cortisol secretion [in Portuguese]. Arq Bras 5. Pancera CF, Costa CM, Hayashi M, et al: rapid puriﬁcation. BMC Genomics 2007; 8:64 Endocrinol Metabol 2006; 50:118 –124 Severe sepsis and septic shock in children 20. Feezor RJ, Baker HV, Mindrinos M, et al: 31. de Jong MF, Beishuizen A, Spijkstra JJ, et al: with cancer [in Portuguese]. Rev Assoc Med Whole blood and leukocyte RNA isolation for Relative adrenal insufﬁciency as a predictor gene expression analyses. Physiol Genomics of disease severity, mortality, and beneﬁcial 6. Hung IJ, Yang CP: Early-onset sepsis in chil- effects of corticosteroid treatment in septic dren with acute lymphoblastic leukemia.
21. De AK, Miller-Graziano CL, Calvano SE, et al: shock. Crit Care Med 2007; 35:1896 –1903 J Formos Med Assoc 1996; 95:746 –753 Selective activation of peripheral blood T cell 32. Sprung CL, Annane D, Singer M, et al: Ste- 7. Hakim H, Flynn PM, Srivastava DK, et al: subsets by endotoxin infusion in healthy hu- roids in patients with septic shock. Chest Risk prediction in pediatric cancer patients with fever and neutropenia. Pediatr Infect chemokine activation. J Immunol 2005; 175: 33. Annane D, Bellissant E, Bollaert PE, et al: Corticosteroids in the treatment of severe 8. Odetola FO, Gebremariam A, Freed GL: Pa- 22. Kloppenburg M, Brinkman BM, de Rooij-Dijk sepsis and septic shock in adults: A system- tient and hospital correlates of clinical out- HH, et al: The tetracycline derivative mino- atic review. JAMA 2009; 301:2362–2375 comes and resource utilization in severe pe- cycline differentially affects cytokine produc- 34. Markovitz BP, Goodman DM, Watson RS, et diatric sepsis. Pediatrics 2007; 119:487– 494 tion by monocytes and T lymphocytes. Anti- al: A retrospective cohort study of prognostic 9. Carcillo JA, Fields AI: Clinical practice pa- microb Agents Chemother 1996; 40:934 –940 factors associated with outcome in pediatric rameters for hemodynamic support of pedi- 23. Yeh TS, Pollack MM, Holbrook PR, et al: severe sepsis: What is the role of steroids? atric and neonatal patients in septic shock.
Assessment of pediatric intensive care— Pediatr Crit Care Med 2005; 6:270 –274 Crit Care Med 2002; 30:1365–1378 Application of the Therapeutic Intervention 35. Aneja R, Carcillo JA: What is the rationale for 10. Dobriner K, Kappas A, Gallagher TF: Studies Scoring System. Crit Care Med 1982; 10: hydrocortisone treatment in children with in steroid metabolism. XXVI. Steroid isola- infection-related adrenal insufﬁciency and tion studies in human leukemia. J Clin In- 24. Kuperman H, Damiani D, Chrousos GP, et al: septic shock? Arch Dis Child 2007; 92: Evaluation of the hypothalamic–pituitary– 11. Heying R, Schneider DT, Korholz D, et al: adrenal axis in children with leukemia before 36. Zimmerman JJ: Moving beyond Babel. Pedi- Efﬁcacy and outcome of intensive care in and after 6 weeks of high-dose glucocorticoid pediatric oncologic patients. Crit Care Med therapy. J Clin Endocrinol Metab 2001; 86: 37. Langer M, Modi BP, Agus M: Adrenal insuf- ﬁciency in the critically ill neonate and child.
12. Hanauer DA: EMERSE: The Electronic Med- 25. Felner EI, Thompson MT, Ratliff AF, et al: Curr Opin Pediatr 2006; 18:448 – 453 ical Record Search Engine. AMIA Annu Time course of recovery of adrenal function 38. Hildebrandt T, Mansour M, Al Samsam R: in children treated for leukemia. J Pediatr The use of steroids in children with septice- 13. Pollack MM, Ruttimann UE, Getson PR: Pe- mia: Review of the literature and assessment diatric Risk of Mortality (PRISM) score. Crit 26. Einaudi S, Bertorello N, Masera N, et al: of current practice in PICUs in the UK. Pae- Adrenal axis function after high-dose steroid 14. Watson RS, Carcillo JA, Linde-Zwirble WT, et therapy for childhood acute lymphoblastic 39. Hamalainen S, Kuittinen T, Matinlauri I, et al: The epidemiology of severe sepsis in chil- leukemia. Pediatr Blood Cancer 2008; 50: al: Neutropenic fever and severe sepsis in dren in the United States. Am J Respir Crit adult acute myeloid leukemia (AML) patients 27. Mahachoklertwattana P, Vilaiyuk S, Hongeng 15. Nadel S: RESOLVE-ing sepsis in children— S, et al: Suppression of adrenal function in and consequences. Leuk Lymphoma 2008; children with acute lymphoblastic leukemia 16. Nadel S, Goldstein B, Williams MD, et al: following induction therapy with corticoste- 40. Wong HR, Cvijanovich N, Wheeler DS, et al: Drotrecogin alfa (activated) in children with roid and other cytotoxic agents. J Pediatr Interleukin-8 as a stratiﬁcation tool for in- severe sepsis: A multicentre phase III ran- terventional trials involving pediatric septic domised controlled trial. Lancet 2007; 369: 28. Petersen KB, Muller J, Rasmussen M, et al: shock. Am J Respir Crit Care Med 2008; Impaired adrenal function after glucocorti- Pediatr Crit Care Med 2011 Vol. 12, No. 6
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