Outcome of Invasive Mechanical Ventilation After Pediatric Allogeneic Hematopoietic SCT: Results from a Prospective, Multicenter Registry

ORIGINAL ARTICLE Outcome of invasive mechanical ventilation after pediatric allogeneic hematopoietic SCT: results from a prospective, multicenter registry

JPJ van Gestel1, MB Bierings2, S Dauger3, J-H Dalle4, P Pavlíček5, P Sedláček6, LM Monteiro7, A Lankester8 and CW Bollen1

Exact data on prognosis of children receiving invasive mechanical ventilation (IMV) after allogeneic hematopoietic SCT (HSCT) is lacking. We therefore started a prospective registry in four European university HSCT centers (Leiden, Paris, Prague and Utrecht) and their pediatric intensive care units (PICUs). The registry started in January 2009. In January 2013, the four centers together had treated a total of 83 admissions with IMV. The case fatality rate in these patients was 52%. Mortality 6 months after PICU discharge was 45%. There were signiﬁcant differences between centers in the proportion of children who received IMV after HSCT (6–23%, Po0.01), in severity of disease on admission to PICU (predicted mortality 14–37%, Po0.01), in applying noninvasive ventilation before IMV (3–75% of admissions, Po0.01) and in the use of renal replacement therapy (RRT) (8–58% of admissions, Po0.01). Severe impairment in oxygenation, use of RRT and CMV viremia were independent predictors of mortality. Our study shows that mortality in children receiving IMV after HSCT remains high, but has clearly improved compared with older studies. Patient selection and treatment in PICU differed signiﬁcantly between centers, which underscores the need to standardize and optimize the PICU admission criteria, ventilatory strategies and therapies applied in PICU.

Bone Marrow Transplantation (2014) 49, 1287–1292; doi:10.1038/bmt.2014.147; published online 28 July 2014

INTRODUCTION associated with mortality in case of IMV and to describe PICU Pediatric hematopoietic SCT (HSCT) has become a widely treatments that were applied in these complex patients. established and potentially life-saving therapy for a range of diseases. Advancement over the years in the HSCT process has resulted in higher OS rates1 and in a growing number of indications for transplantation.2–4 However, HSCT still is a high- PATIENTS AND METHODS risk procedure, and a considerable proportion of children require Design and setting transfer to the pediatric intensive care unit (PICU) because of 5 The registry started in January 2009. We report the results after 4 years of complications associated with it. Acute respiratory failure is the inclusion (that is until January 2013). Four European HSCT centers and their 5,6 leading cause for PICU admission in children after HSCT. affiliated PICUs participate in the registry: Robert-Debré University Hospital Historically, children admitted to PICU for invasive mechanical from Paris (France), Charles University Hospital Motol from Prague (Czech ventilation (IMV) were thought to have a dismal prognosis.7 Republic), Leiden University Medical Centre from Leiden (The Netherlands) – Recent studies suggest improvement of survival.6,8 11 However, and Wilhelmina Children’s Hospital from Utrecht (The Netherlands). Leiden general applicability of previous studies is limited, as they are all joined the registry at a later stage and started with inclusion in June 2009. retrospective in design, and all but one6 are single center. All HSCTs in the Czech Republic are performed in Prague, and all pediatric Additionally, the inclusion period of most studies ended HSCTs in the Netherlands are performed either in Leiden or in Utrecht, and more than 6 years ago and, therefore, they do not reflect recent therefore, these centers encompass national pediatric cohorts. In France, improvements in HSCT and PICU management. Therefore, there among multiple centers that perform HSCTs in children, Robert-Debré University Hospital is highly specialized in transplantations for hematologic are limited data on current epidemiology of children receiving IMV disorders. after HSCT. All four hospitals have a PICU run by pediatric intensivists. The four To address this issue, we started a prospective, multicenter hospitals do not apply noninvasive ventilation (NIV) or inotropic therapy in registry with four European pediatric HSCT centers and their their HSCT units. In all four centers, a senior intensivist and a senior affiliated PICUs. The three main purposes were to describe member of the HSCT team are available around the clock and jointly mortality in children receiving IMV after HSCT, to assess factors decide on PICU admissions.

1Pediatric Intensive Care Unit, University Medical Center Utrecht, The Wilhelmina Children’s Hospital, Utrecht, The Netherlands; 2Department of Pediatric Hematology, Immunology and Bone Marrow Transplantation, University Medical Center Utrecht, The Wilhelmina Children’s Hospital, Utrecht, The Netherlands; 3Pediatric Intensive Care Unit, AP-HP, Robert-Debré Hospital and Paris Diderot University, Paris 7, Paris, France; 4Department of Pediatric Hematology, Immunology and Bone Marrow Transplantation, AP-HP, Robert-Debré Hospital and Paris Diderot University, Paris 7, Paris, France; 5Pediatric Intensive Care Unit, Charles University Hospital Motol, Prague, Czech Republic; 6Department of Pediatric Hematology and Oncology, Charles University Hospital Motol, Prague, Czech Republic; 7Pediatric Intensive Care Unit, Leiden University Medical Center, Leiden, The Netherlands and 8Department of Pediatric Hematology, Immunology and Bone Marrow Transplantation, Leiden University Medical Center, Leiden, The Netherlands. Correspondence: Dr JPJ van Gestel, Pediatric Intensive Care Unit, University Medical Center Utrecht, The Wilhelmina Children’s Hospital, PO Box 85090, Utrecht 3508 AB, The Netherlands. E-mail: [email protected] Received 27 January 2014; revised 2 June 2014; accepted 4 June 2014; published online 28 July 2014 Outcome of mechanical ventilation after pediatric allogeneic HSCT JPJ van Gestel et al 1288 Before the start of the HSCT process, all parents, and when appropriate signiﬁcance. Data were analyzed using SPSS version 20 (IBM SPSS Statistics, all patients, gave written informed consent to register and analyze Chicago, IL, USA). anonymous clinical data for study purposes.

Patients RESULTS All children younger than 19 years of age, who were admitted to PICU during the study period and who received IMV after allogeneic HSCT were Epidemiology and outcome of IMV in HSCT patients included. As applying NIV may decrease the need for IMV, children who Between January 2009 and January 2013, 601 children received an received NIV were followed during their PICU stay. Patients who only HSCT in the four centers together. Sixty-three of them (10%) received NIV and did not receive IMV were not included in statistical received IMV after transplantation. An additional seven patients analyses. had undergone HSCT between 2004 and 2009, but received IMV Patients admitted to PICU after HSCT older than 19 years of age, or those who did not receive NIV or IMV were excluded. after the registry started in 2009 and were also included. This brings the total number of patients who received IMV after HSCT to 70. These 70 patients had 83 admissions for IMV: 58 patients Data collection received IMV once, eight patients received IMV two times and At the time of admission to PICU, the following information was recorded: demographic information (sex, age), pre-existing diagnosis requiring HSCT three patients received IMV three times. Characteristics of these 83 (categorized as malignancy or non-malignant disorder), type of donor admissions are presented in Table 1. (matched related, unrelated or haploidentical), source of stem cells (BM, IMV was directly started in 67 admissions. In 16 other PBSCs or cord blood), presence of neutropenia (PMN count o500 cells per admissions, IMV was preceded by NIV. NIV was started in another mm3), grade of acute GvHD according to Glucksberg et al.12 (categorized 21 admissions, but not followed by IMV because respiratory failure as no/mild GvHD (grade 0, 1 or 2), severe GvHD (grade 3 or 4) or not improved (NIV successful, n = 19) or because it was decided not to applicable (for patients more than 100 days after their HSCT)), CMV status proceed to IMV (n = 2). A flow chart of patients who received NIV and adenovirus status (categorized as positive (based on plasma viral load identified by PCR, with or without clinical symptoms) or negative), and/or IMV is presented in Figure 1. Characteristics of patients presence of hepatic failure (total bilirubin 45 mg/dL and aspartate aminotransferase or lactate dehydrogenase more than two times the normal value without evidence of hemolysis),13 time interval between Table 1. Characteristics of the 83 admissions receiving IMV after HSCT HSCT and admission to PICU, reason for requirement of IMV (categorized as respiratory failure, airway protection including altered mental status, Variable Number of patients % sepsis, cardiopulmonary resuscitation or surgery/procedure)14 and severity of disease according to the Pediatric Index of Mortality 2 (PIM2) score.15 Sex, male 50 60 During the first 4 days of admission to PICU, the daily maximum Age on admission to PICU (years) (IQR) 5.4 (1.7–14.0) oxygenation index (OI, calculated as (100 × mean airway pressure × fraction Pre-existing diagnosis malignancy 32 39 of inspiratory oxygen)/partial pressure of arterial oxygen) was recorded. To TBI 11 13 evaluate changes over time in pulmonary condition, we calculated the sum of the daily maximum OI of the first 4 days of admission. When the OI was Source of stem cells unknown (for example because the patient had been extubated, or CB 37 45 because partial pressure of arterial oxygen was unknown in the absence of BM 29 35 an arterial line), the maximum OI on that day was estimated to be four PBSC 17 20 (that is a low OI). Patients who had died (n = 7) or were discharged (n =3) before day 4 were excluded from this calculation. NIV was defined as use Donor of continuous positive airway pressure or positive pressure ventilation Unrelated 67 81 through a mask, helmet or nasal prongs. Matched related 10 12 At discharge, the following information was recorded: outcome (survival Haploidentical 6 7 or death), length of stay in PICU, if IMV was preceded by NIV or not, – duration of IMV, use of high-frequency oscillatory ventilation (HFOV) and Risk of mortality based on PIM2 (IQR) 10% (4.4 24.1) use of renal replacement therapy (RRT) (including hemofiltration) during NIV before intubation 16 19 PICU stay. Six months survival was recorded for patients discharged alive Readmission with IMV 13 16 from PICU. HFOV 25 30 Reason for IMV Statistical analysis Respiratory failure 61 73 Results are reported as medians with interquartile ranges (IQR 1–3) or Airway protection 10 12 numbers and percentages. To evaluate patient characteristics, categorical Postprocedure 7 8 variables were compared using Pearson’s χ2 test. The relation between Sepsis 4 5 continuous variables and categorical variables were analyzed using the Cardiopulmonary resuscitation 1 1 nonparametric Mann–Whitney U-test or the Kruskal–Wallis test. The primary outcome of the study was status (survival or death) at GvHD on admission to PICU discharge from PICU in patients treated with IMV. To identify associations No/mild 42 51 between potential risk factors and PICU mortality, we first performed Severe 9 11 univariate logistic regression analyses to identify variables that significantly Not applicable 32 39 influenced likelihood of death in PICU, as measured by the estimated odds ratio and the 95% confidence interval levels. Variables yielding P-values CMV viremia on admission to PICU 39 47 o0.10 were selected for the multivariate logistic regression analysis to Adenovirus viremia on admission to PICU 23 28 assess their independent contribution to PICU mortality. As the number of Neutropenia on admission to PICU 27 33 non-survivors was limited, we had to restrict the number of equation terms Renal replacement therapy 20 24 Hepatic failure during PICU stay 22 27 in the multivariate model to those that were deemed clinically relevant and comprised more than 25% of patients. The Hosmer–Lemeshow test Abbreviations: HFOV = high-frequency oscillatory ventilation; HSCT = was used to check goodness of fit of the logistic regression analysis. hematopoietic SCT; IMV = invasive mechanical ventilation; NIV = noninva- Continuous variables that were not normally distributed were log- sive ventilation; PICU = pediatric intensive care unit; PIM2 = Paediatric transformed before entering the regression analyses. All tests were Index of Mortality 2 score.15 two-sided, and P-values o0.05 were considered to indicate statistical

Bone Marrow Transplantation (2014) 1287 – 1292 © 2014 Macmillan Publishers Limited Outcome of mechanical ventilation after pediatric allogeneic HSCT JPJ van Gestel et al 1289 who started with NIV did not differ significantly from patients who of 67: 49%) compared with patients who received IMV after failed immediately started with IMV (data not shown). NIV (10 out of 16: 63%) (P = 0.13). The most common indication to start IMV was respiratory failure In 39 of the 43 non-survivors (91%) maximal therapy was (73% of admissions, see Table 1). Median time between HSCT and applied. In the four remaining non-survivors, PICU treatment was IMV was 61 days (IQR 28–136 days). In eight admissions, IMV was withdrawn or limited because it was deemed to be futile. Mortality started more than 1 year after HSCT. IMV lasted for a median of 6 months after PICU discharge was 45%. 6 days (IQR 3–18 days). Table 2 displays HSCT and PICU outcome data for each center Forty-three of the admissions treated with IMV did not survive separately. The proportion of children who received IMV after to PICU discharge, giving a case fatality rate of 52%. Mortality rates HSCT and their severity of disease on admission to PICU based on were lower in patients who immediately started with IMV (33 out PIM2-scores15 differed significantly between centers (Po0.01 for both). Mortality rates in patients who received IMV were not significantly different between centers (P = 0.10).

NIV first: 37 Directly started IMV: 67 Risk factors for mortality in HSCT patients receiving IMV Results of univariate logistic regression analyses in children who NIV successful: 19 (51%) received IMV are shown in Table 3. Only variables with a P-value o0.20 are listed. Pre-existing diagnosis (malignancy versus NIV failure, nonmalignant disorder) and admission to PICU early or late decision of no (before or after 60 days) after HSCT did not inﬂuence mortality and intubation: 2 (5%) are therefore not listed in Table 3. NIV failure followed Variables that were identiﬁed by multivariate logistic regression by intubation: 16 (43%) analysis to be independently associated with PICU mortality are 83 admissions with ‘ ’ IMV listed in Table 4; Center was not independently associated with mortality. HFOV was not included in the multivariate analysis, as it Discharged alive Death in PICU: is mostly used in case of severe pulmonary problems. To prevent from PICU: 40 (48%) 43 (52%) colinearity, we preferred to include the cumulative maximum OI of Figure 1. Flow chart of children receiving NIV and/or IMV after HSCT days 1–4, which is more generally applicable. Status after TBI was in the four participating PICUs from January 2009 to 2013. not included, as it comprised too few patients (n = 11).

Table 2. HSCT and PICU outcome data per HSCT center

Number of patients receiving an TRM100—OS per HSCT % of HSCT patients Predicted mortality in patients Actual mortality in patients HSCT (2009–2013) center (%) receiving IMV (%) with IMV (PIM2) (%) with IMV (%)

A 104 11–75 7 25 83 B 117 7–65 23 14 42 C 149 7–70 9 21 50 D 231 8–78 6 37 53 Abbreviations: A, B, C, D = the four participating HSCT centers; HSCT = hematopoietic SCT; IMV = invasive mechanical ventilation; PICU = pediatric intensive care unit; PIM2 = Pediatric Index of Mortality 2 score;15 TRM100 = TRM on day 100.

Table 3. Results of the univariate logistic regression analyses: comparison between surviving and non-surviving pediatric HSCT patients receiving IMV

40 Survivors, n (%) 43 Non-survivors, n (%) Odds ratio 95% Conﬁdence interval P-value

Center Aa 2 (5) 10 (23) 7.0 1.34–36.69 0.02 Age (years) 2.9 8.1 1.35 0.93–1.96 0.11 TBI 2 (5) 9 (21) 5.03 1.01–24.92 0.05 Haploidentical donor 1 (3) 5 (12) 7.5 0.62–90.65 0.11 Risk of mortality (PIM2) 7.4% 13.4% 1.34 0.92–1.96 0.13 Readmission with intubation 9 (23) 4 (9) 0.35 0.1–1.26 0.11 Admission after surgery/procedure 5 (13) 2 (5) 0.32 0.06–1.77 0.19 CMV viremia 14 (35) 25 (58) 2.58 1.06–6.27 0.04 Cumulative maximum daily OI 24 40 1.86 1.07–3.24 0.03 Use of renal replacement therapy 5 (13) 15 (35) 3.75 1.21–11.58 0.02 HFOV 8 (20) 17 (40) 2.62 0.98–7.02 0.06 Hepatic failure 5 (13) 17 (40) 4.58 1.5–14.01 o0.01 Abbreviations: HFOV = high-frequency oscillatory ventilation; HSCT = hematopoietic SCT; OI = oxygenation index; PICU = pediatric intensive care unit; PIM2 = Pediatric Index of Mortality 2 score.15 aCenter B (having the lowest mortality rate) was used as reference. Data are shown as absolute numbers (%) or medians. Only variables with a P-value o0.20 are listed. Variables that are not shown (because P-value 40.20) include sex, indication for HSCT (malignant versus non-malignant), source of stem cells (BM, PBSC, CB), time between HSCT and admission to PICU, length of stay in PICU, severity of GvHD, adenoviremia and presence of neutropenia on admission to PICU.

© 2014 Macmillan Publishers Limited Bone Marrow Transplantation (2014) 1287 – 1292 Outcome of mechanical ventilation after pediatric allogeneic HSCT JPJ van Gestel et al 1290 PICU treatments per center required IMV during their PICU stay, whereas specifically IMV is Treatments applied in each PICU are listed in Table 5. Practices associated with the worst outcome. differed significantly between centers in using NIV (Po0.01). Hypoxic respiratory failure necessitating IMV in children after fi HSCT has been regularly reported as the most important predictor Variation in use of HFOV was not signi cant (P = 0.13). 5,17 The use of RRT differed significantly between centers (Po0.01). of poor prognosis. To include evolution of oxygenation It was used in 20 patients altogether: intermittent hemodialysis in problems over time, we calculated the sum of the daily maximum OI over the first 4 days of IMV. We believe this is more informative, one patient and continuous RRT in 19 patients (see Table 3). fl Mortality in patients receiving IMV and RRT was 75% (15 out of as it gives a better re ection of the clinical course over time. RRT has not been found before to be an independent predictor for 20 patients). During the first part of the study period, center C did mortality. This may be explained by a lack of power in previous not have the possibility for RRT in their PICU. Patients who studies, as several smaller studies found outcome to be dismal in required RRT in this center (n = 3) were transferred to another 14,16,18,19 children requiring IMV and RRT after HSCT. We found a PICU, but for the analyses these patients were regarded as if they mortality rate of 75% in these patients, identical to Flores et al.20 had been treated in center C. (71%), which may indicate improvements in outcome. There is ongoing discussion if early start of RRT at low degrees of fluid 20,21 DISCUSSION overload can prevent further deterioration. Neither the fi indication for RRT nor its timing were assessed in our study, and We report the rst prospective, multicenter data collection in need to be included in future versions of the database. children receiving IMV after allogeneic HSCT. The case fatality rate Interestingly, we found that CMV viremia was independently of 52% in these patients is high, but encouraging compared with associated with mortality. To our knowledge, this was not assessed older studies. Severity of disease at admission, intubation rates previously in this population. CMV viremia (identified by PCR) is a and treatments applied in the PICU differed between centers. known indicator of poor prognosis in HSCT patients in general. It These results underscore the limited general applicability of reflects an immunodeficient state, caused by either delayed previous single center studies, and stress the urgent need to immune reconstitution or intense immune suppression. Although establish best-practice guidelines in this fragile population. progression to CMV disease can be prevented by anti-viral The aforementioned limitations of previous studies hamper therapy, CMV viremia apparently persists as a poor prognostic direct comparison of outcomes with our study. However, one of sign.22,23 the main findings in our study, that mortality in children receiving We found clear differences between centers in severity of IMV has improved over time, is in line with the two other large and disease on admission to PICU, in the proportion of patients more recent studies.6,9 Long-term survival of children requiring receiving IMV and in therapies applied in PICU, although TRM100 PICU treatment after HSCT has not been assessed in many studies and OS were comparable between centers (Table 2). These before. Two studies report an overall 6 months survival in this differences may be explained by variations in case-mix between patient population of 19%16 and 25%,9 respectively, which is centers: as shown previously, patients with an immunodeficiency fi have a higher risk of requiring admission to PICU.6 Centers may comparable to our ndings (27%). A recent study found an overall 24 1 year survival of 40%,6 which is far better than we found. perform higher risk transplants, which could result in higher However, this study only included patients during their initial SCT odds of requiring admission to PICU. Second, selection of patients fi admission, included a considerable number of patients with admitted to PICU may vary between centers. The nding that autologous transplantation and not all patients in this study patients in center A had a higher risk for mortality compared with center B in the univariate analysis (Table 3), and no longer in the multivariate analysis (Table 4) fits this explanation. Third, PICU strategies may vary between centers, such as the policy of early Table 4. Multivariate logistic regression analysis: variables intubation, or use of NIV, HFOV or RRT. Variations in treatments independently associated with PICU mortality in children receiving among centers have been reported in a recent survey among IMV after HSCT North American HSCT centers.25 The consequences of these differences may be highly relevant: in several studies in adults, it Odds 95% Confidence P-value 26–28 ratio interval was shown that triage decisions or therapeutic strategies can influence survival. Further studies are warranted to explore the Renal replacement therapy 6.07 1.67–22 o0.01 observed variations. CMV viremia 3.09 1.07–8.92 0.04 As shown previously,16 PIM2 scores15 underestimated mortality Cumulative maximum daily 2.16 1.15–4.04 0.02 rates in our patients (Tables 1 and 2) and performed poorly in OI days 1–4 predicting mortality (Table 3). We had chosen PIM2 as it was fi Abbreviations: HSCT = hematopoietic SCT; OI = oxygenation index; PICU = already used in all four centers before the registry. Our ndings pediatric intensive care unit. Goodness-of-fit test (Homer–Lemeshow test), probably reflect the limited value of generic scoring systems in a P = 0.35. specific patient population. Moreover, PIM2 was developed on data collected between 1997 and 1999, which can explain the

Table 5. Overview of treatments applied in children admitted to PICU after HSCT

% of admissions treated with NIV % of HSCT patients treated with IMV % of IMV patients treated with RRT % of IMV patients treated with HFOV

A8 7 5833 B 3 23 8 42 C 42 9 17 22 D 75 6 41 12 Abbreviations: A, B, C, D = the four participating HSCT centers; HFOV = high-frequency oscillatory ventilation; HSCT = hematopoietic SCT; IMV = invasive mechanical ventilation; NIV = noninvasive ventilation; RRT = renal replacement therapy.

Bone Marrow Transplantation (2014) 1287 – 1292 © 2014 Macmillan Publishers Limited Outcome of mechanical ventilation after pediatric allogeneic HSCT JPJ van Gestel et al 1291 calibration drift over time. In the recently updated model of PIM2 4 Boelens JJ. Trends in haematopoietic cell transplantation for inborn errors of (i.e. PIM3), HSCT was added as a high-risk diagnosis to provide metabolism. J Inherit Metab Dis 2006; 29: 413–420. better estimates of mortality risk.29 O-PRISM score may be an 5 van Gestel JP, Bollen CW, van der Tweel I, Boelens JJ, van Vught AJ. Intensive care alternative in this patient population, but it was developed in a unit mortality trends in children after hematopoietic stem cell transplantation: a 36 – very small single center population, and has been used only in a meta-regression analysis. Crit Care Med 2008; :2898 2904. few small studies.18,30,31 6 Duncan CN, Lehmann LE, Cheifetz IM, Greathouse K, Haight AE, Hall MW et al. fi Clinical outcomes of children receiving intensive cardiopulmonary support NIV is often used as rst-line respiratory support in patients with during hematopoietic stem cell transplant. Pediatr Crit Care Med 2013; 14: acute respiratory failure, and may decrease mortality rates by 261–267. 32,33 avoiding intubation; conversely, NIV can have negative effects 7 Nichols DG, Walker LK, Wingard JR, Bender KS, Bezman M, Zahurak ML et al. on outcome by postponing intubation as has been shown in Predictors of acute respiratory failure after bone marrow transplantation in several studies in adult hematology patients.34,35 Restrictions on children. Crit Care Med 1994; 22: 1485–1491. use of curative NIV in adults were therefore recently proposed.36,37 8 van Gestel JP, Bollen CW, Bierings MB, Boelens JJ, Wulffraat NM, van Vught AJ. We found nonsignificant better survival in patients who immedi- Survival in a recent cohort of mechanically ventilated pediatric allogeneic ately started with IMV (49%) compared with patients who received hematopoietic stem cell transplantation recipients. Biol Blood Marrow Transplant 14 – IMV after failed NIV (63%, P = 0.13). This may well be biased by 2008; : 1385 1393. 9 Tamburro RF, Barfield RC, Shaffer ML, Rajasekaran S, Woodard P, Morrison RR et al. confounding by indication and selection bias. Further studies are – fi Changes in outcomes (1996 2004) for pediatric oncology and hematopoietic needed to identify bene ts of NIV in children after HSCT. stem cell transplant patients requiring invasive mechanical ventilation. Pediatr Crit By working with four dedicated centers, data for this study Care Med 2008; 9:270–277. could be collected accurately and completely. However, working 10 Cole TS, Johnstone IC, Pearce MS, Fulton B, Cant AJ, Gennery AR et al. Outcome of with a few centers is also a limitation of our study, as it slowed the children requiring intensive care following haematopoietic SCT for primary rate of inclusion. Moreover, it may have influenced our findings by immunodeficiency and other non-malignant disorders. Bone Marrow Transplant differences in intercenter case-mix and practices. A second 2012; 47:40–45. limitation of our registry is that it does not provide any 11 Aspesberro F, Guthrie KA, Woolfrey AE, Brogan TV, Roberts JS. Outcome of information on transplantation-related risk of mortality24 or on pediatric hematopoietic stem cell transplant recipients requiring mechanical 29 – patients who did not require admission to PICU, or in whom PICU ventilation. J Intens Care Med 2014; :31 37. 12 Glucksberg H, Storb R, Fefer A, Buckner CD, Neiman PE, Clift RA et al. Clinical admission was denied or not offered. Despite these limitations, fi manifestations of graft-versus-host disease in human recipients of marrow from our ndings indicate improvement in survival compared with HL-A-matched sibling donors. Transplantation 1974; 18: 295–304. older studies and raise the crucial questions: which children 13 Wilkinson JD, Pollack MM, Glass NL, Kanter RK, Katz RW, Steinhart CM. Mortality benefit from admission to PICU, what the optimal timing for PICU associated with multiple organ system failure and sepsis in pediatric intensive admission is and how PICU treatments can be optimized. For care unit. J Pediatr 1987; 111: 324–328. several reasons, it has been found to be difficult to obtain the 14 Keenan HT, Bratton SL, Martin LD, Crawford SW, Weiss NS. Outcome of children answers to these questions. Our study shows that a prospective, who require mechanical ventilatory support after bone marrow transplantation. observational registry can be a valuable tool for addressing these Crit Care Med 2000; 28:830–835. 15 Slater A, Shann F, Pearson G. PIM2: a revised version of the paediatric index of topics. Adding additional items to existing data reports in all HSCT 29 – centers, both in Europe as well as in the United States, could give mortality. Intens Care Med 2003; : 278 285. 16 Jacobe SJ, Hassan A, Veys P, Mok Q. Outcome of children requiring admission to information on a larger number of patients. an intensive care unit after bone marrow transplantation. Crit Care Med 2003; 31: 1299–1305. CONCLUSION 17 Demaret P, Pettersen G, Hubert P, Teira P, Emeriaud G. The critically-ill pediatric hemato-oncology patient: epidemiology, management, and strategy of transfer We present results of a prospective, multicenter registry on to the pediatric intensive care unit. 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Our ndings underscore the need to optimize and 20 Flores FX, Brophy PD, Symons JM, Fortenberry JD, Chua AN, Alexander SR et al. standardize PICU admission criteria, ventilatory strategies and Continous renal replacement therapy (CRRT) after stem cell transplantation. PICU treatments in this population. A report from the prospective pediatric CRRT Registry Group. Pediatr Nephrol 2008; 23:625–630. 21 Modem V, Thompson M, Gollhofer D, Dhar AV, Quigley R. Timing of continuous CONFLICT OF INTEREST renal replacement therapy and mortality in critically ill children. Crit Care Med The authors declare no conflict of interest. 2014; 42:943–953. 22 Broers AE, van der Holt R, van Esser JW, Gratama JW, Henzen-Logmans S, Kuenen-Boumeester V et al. Increased transplant-related morbidity and mortality AUTHOR CONTRIBUTIONS in CMV-seropositive patients despite highly effective prevention of CMV disease after allogeneic T-cell-depleted stem cell transplantation. 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