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%, P<0.01), in severity of disease on admission to PICU (predicted mortality 14–37%, P<0.01), in applying noninvasive ventilation before IMV (3–75% of admissions, P<0.01) and in the use of renal replacement therapy (RRT) (8–58% of admissions, P<0.01). 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.
Pediatric hematopoietic SCT (HSCT) has become a widely 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, 3, 4 However, HSCT still is a high-risk procedure, and a considerable proportion of children require transfer to the pediatric intensive care unit (PICU) because of complications associated with it.5 Acute respiratory failure is the leading cause for PICU admission in children after HSCT.5,6
Historically, children admitted to PICU for invasive mechanical ventilation (IMV) were thought to have a dismal prognosis.7 Recent studies suggest improvement of survival.6,8, 9, 10, 11 However, general applicability of previous studies is limited, as they are all retrospective in design, and all but one6 are single center. Additionally, the inclusion period of most studies ended more than 6 years ago and, therefore, they do not reflect recent improvements in HSCT and PICU management. Therefore, there are limited data on current epidemiology of children receiving IMV after HSCT.
To address this issue, we started a prospective, multicenter registry with four European pediatric HSCT centers and their affiliated PICUs. The three main purposes were to describe mortality in children receiving IMV after HSCT, to assess factors associated with mortality in case of IMV and to describe PICU treatments that were applied in these complex patients.
Patients and methods
Design and setting
The registry started in January 2009. We report the results after 4 years of inclusion (that is until January 2013). Four European HSCT centers and their affiliated PICUs participate in the registry: Robert-Debré University Hospital from Paris (France), Charles University Hospital Motol from Prague (Czech Republic), Leiden University Medical Centre from Leiden (The Netherlands) and Wilhelmina Children’s Hospital from Utrecht (The Netherlands). Leiden joined the registry at a later stage and started with inclusion in June 2009. All HSCTs in the Czech Republic are performed in Prague, and all pediatric HSCTs in the Netherlands are performed either in Leiden or in Utrecht, and therefore, these centers encompass national pediatric cohorts. In France, among multiple centers that perform HSCTs in children, Robert-Debré University Hospital is highly specialized in transplantations for hematologic disorders.
All four hospitals have a PICU run by pediatric intensivists. The four hospitals do not apply noninvasive ventilation (NIV) or inotropic therapy in their HSCT units. In all four centers, a senior intensivist and a senior member of the HSCT team are available around the clock and jointly decide on PICU admissions.
Before the start of the HSCT process, all parents, and when appropriate all patients, gave written informed consent to register and analyze anonymous clinical data for study purposes.
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 included. As applying NIV may decrease the need for IMV, children who received NIV were followed during their PICU stay. Patients who only received NIV and did not receive IMV were not included in statistical analyses.
Patients admitted to PICU after HSCT older than 19 years of age, or those who did not receive NIV or IMV were excluded.
At the time of admission to PICU, the following information was recorded: demographic information (sex, age), pre-existing diagnosis requiring HSCT (categorized as malignancy or non-malignant disorder), type of donor (matched related, unrelated or haploidentical), source of stem cells (BM, PBSCs or cord blood), presence of neutropenia (PMN count <500 cells per mm3), grade of acute GvHD according to Glucksberg et al.12 (categorized as no/mild GvHD (grade 0, 1 or 2), severe GvHD (grade 3 or 4) or not applicable (for patients more than 100 days after their HSCT)), CMV status and adenovirus status (categorized as positive (based on plasma viral load identified by PCR, with or without clinical symptoms) or negative), presence of hepatic failure (total bilirubin >5 mg/dL and aspartate aminotransferase or lactate dehydrogenase more than two times the normal value without evidence of hemolysis),13 time interval between HSCT and admission to PICU, reason for requirement of IMV (categorized as respiratory failure, airway protection including altered mental status, sepsis, cardiopulmonary resuscitation or surgery/procedure)14 and severity of disease according to the Pediatric Index of Mortality 2 (PIM2) score.15
During the first 4 days of admission to PICU, the daily maximum oxygenation index (OI, calculated as (100 × mean airway pressure × fraction of inspiratory oxygen)/partial pressure of arterial oxygen) was recorded. To 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 unknown (for example because the patient had been extubated, or because partial pressure of arterial oxygen was unknown in the absence of an arterial line), the maximum OI on that day was estimated to be four (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 of continuous positive airway pressure or positive pressure ventilation through a mask, helmet or nasal prongs.
At discharge, the following information was recorded: outcome (survival 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 use of renal replacement therapy (RRT) (including hemofiltration) during PICU stay. Six months survival was recorded for patients discharged alive from PICU.
Results are reported as medians with interquartile ranges (IQR 1–3) or numbers and percentages. To evaluate patient characteristics, categorical variables were compared using Pearson’s χ2 test. The relation between continuous variables and categorical variables were analyzed using the nonparametric Mann–Whitney U-test or the Kruskal–Wallis test.
The primary outcome of the study was status (survival or death) at discharge from PICU in patients treated with IMV. To identify associations between potential risk factors and PICU mortality, we first performed univariate logistic regression analyses to identify variables that significantly influenced likelihood of death in PICU, as measured by the estimated odds ratio and the 95% confidence interval levels. Variables yielding P-values <0.10 were selected for the multivariate logistic regression analysis to assess their independent contribution to PICU mortality. As the number of non-survivors was limited, we had to restrict the number of equation terms in the multivariate model to those that were deemed clinically relevant and comprised more than 25% of patients. The Hosmer–Lemeshow test was used to check goodness of fit of the logistic regression analysis. Continuous variables that were not normally distributed were log-transformed before entering the regression analyses. All tests were two-sided, and P-values <0.05 were considered to indicate statistical significance. Data were analyzed using SPSS version 20 (IBM SPSS Statistics, Chicago, IL, USA).
Epidemiology and outcome of IMV in HSCT patients
Between January 2009 and January 2013, 601 children received an HSCT in the four centers together. Sixty-three of them (10%) received IMV after transplantation. An additional seven patients had undergone HSCT between 2004 and 2009, but received IMV 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 received IMV once, eight patients received IMV two times and three patients received IMV three times. Characteristics of these 83 admissions are presented in Table 1.
IMV was directly started in 67 admissions. In 16 other admissions, IMV was preceded by NIV. NIV was started in another 21 admissions, but not followed by IMV because respiratory failure improved (NIV successful, n=19) or because it was decided not to proceed to IMV (n=2). A flow chart of patients who received NIV and/or IMV is presented in Figure 1. Characteristics of patients who started with NIV did not differ significantly from patients who immediately started with IMV (data not shown).
The most common indication to start IMV was respiratory failure (73% of admissions, see Table 1). Median time between HSCT and IMV was 61 days (IQR 28–136 days). In eight admissions, IMV was started more than 1 year after HSCT. IMV lasted for a median of 6 days (IQR 3–18 days).
Forty-three of the admissions treated with IMV did not survive to PICU discharge, giving a case fatality rate of 52%. Mortality rates were lower in patients who immediately started with IMV (33 out of 67: 49%) compared with patients who received IMV after failed NIV (10 out of 16: 63%) (P=0.13).
In 39 of the 43 non-survivors (91%) maximal therapy was applied. In the four remaining non-survivors, PICU treatment was withdrawn or limited because it was deemed to be futile. Mortality 6 months after PICU discharge was 45%.
Table 2 displays HSCT and PICU outcome data for each center separately. The proportion of children who received IMV after HSCT and their severity of disease on admission to PICU based on PIM2-scores15 differed significantly between centers (P<0.01 for both). Mortality rates in patients who received IMV were not significantly different between centers (P=0.10).
Risk factors for mortality in HSCT patients receiving IMV
Results of univariate logistic regression analyses in children who received IMV are shown in Table 3. Only variables with a P-value <0.20 are listed. Pre-existing diagnosis (malignancy versus nonmalignant disorder) and admission to PICU early or late (before or after 60 days) after HSCT did not influence mortality and are therefore not listed in Table 3.
Variables that were identified by multivariate logistic regression analysis to be independently associated with PICU mortality are listed in Table 4; ‘Center’ was not independently associated with mortality. HFOV was not included in the multivariate analysis, as it is mostly used in case of severe pulmonary problems. To prevent colinearity, we preferred to include the cumulative maximum OI of days 1–4, which is more generally applicable. Status after TBI was not included, as it comprised too few patients (n=11).
PICU treatments per center
Treatments applied in each PICU are listed in Table 5. Practices differed significantly between centers in using NIV (P<0.01). Variation in use of HFOV was not significant (P=0.13).
The use of RRT differed significantly between centers (P<0.01). It was used in 20 patients altogether: intermittent hemodialysis in one patient and continuous RRT in 19 patients (see Table 3). Mortality in patients receiving IMV and RRT was 75% (15 out of 20 patients). During the first part of the study period, center C did not have the possibility for RRT in their PICU. Patients who required RRT in this center (n=3) were transferred to another PICU, but for the analyses these patients were regarded as if they had been treated in center C.
We report the first prospective, multicenter data collection in children receiving IMV after allogeneic HSCT. The case fatality rate of 52% in these patients is high, but encouraging compared with older studies. Severity of disease at admission, intubation rates and treatments applied in the PICU differed between centers. These results underscore the limited general applicability of previous single center studies, and stress the urgent need to establish best-practice guidelines in this fragile population.
The aforementioned limitations of previous studies hamper direct comparison of outcomes with our study. However, one of the main findings in our study, that mortality in children receiving IMV has improved over time, is in line with the two other large and more recent studies.6,9 Long-term survival of children requiring PICU treatment after HSCT has not been assessed in many studies before. Two studies report an overall 6 months survival in this patient population of 19%16 and 25%,9 respectively, which is comparable to our findings (27%). A recent study found an overall 1 year survival of 40%,6 which is far better than we found. However, this study only included patients during their initial SCT admission, included a considerable number of patients with autologous transplantation and not all patients in this study required IMV during their PICU stay, whereas specifically IMV is associated with the worst outcome.
Hypoxic respiratory failure necessitating IMV in children after HSCT has been regularly reported as the most important predictor of poor prognosis.5,17 To include evolution of oxygenation 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, as it gives a better reflection of the clinical course over time. RRT has not been found before to be an independent predictor for mortality. This may be explained by a lack of power in previous studies, as several smaller studies found outcome to be dismal in children requiring IMV and RRT after HSCT.14,16,18,19 We found a mortality rate of 75% in these patients, identical to Flores et al.20 (71%), which may indicate improvements in outcome. There is ongoing discussion if early start of RRT at low degrees of fluid overload can prevent further deterioration.20,21 Neither the indication for RRT nor its timing were assessed in our study, and need to be included in future versions of the database. Interestingly, we found that CMV viremia was independently associated with mortality. To our knowledge, this was not assessed previously in this population. CMV viremia (identified by PCR) is a known indicator of poor prognosis in HSCT patients in general. It reflects an immunodeficient state, caused by either delayed immune reconstitution or intense immune suppression. Although progression to CMV disease can be prevented by anti-viral therapy, CMV viremia apparently persists as a poor prognostic sign.22,23
We found clear differences between centers in severity of disease on admission to PICU, in the proportion of patients receiving IMV and in therapies applied in PICU, although TRM100 and OS were comparable between centers (Table 2). These differences may be explained by variations in case-mix between centers: as shown previously, patients with an immunodeficiency have a higher risk of requiring admission to PICU.6 Centers may perform higher risk transplants,24 which could result in higher odds of requiring admission to PICU. Second, selection of patients admitted to PICU may vary between centers. The finding that 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 intubation, or use of NIV, HFOV or RRT. Variations in treatments among centers have been reported in a recent survey among North American HSCT centers.25 The consequences of these differences may be highly relevant: in several studies in adults, it was shown that triage decisions or therapeutic strategies26, 27, 28 can influence survival. Further studies are warranted to explore the observed variations.
As shown previously,16 PIM2 scores15 underestimated mortality rates in our patients (Tables 1 and 2) and performed poorly in predicting mortality (Table 3). We had chosen PIM2 as it was already used in all four centers before the registry. Our findings probably reflect the limited value of generic scoring systems in a specific patient population. Moreover, PIM2 was developed on data collected between 1997 and 1999, which can explain the calibration drift over time. In the recently updated model of PIM2 (i.e. PIM3), HSCT was added as a high-risk diagnosis to provide better estimates of mortality risk.29 O-PRISM score may be an alternative in this patient population, but it was developed in a very small single center population, and has been used only in a few small studies.18,30,31
NIV is often used as first-line respiratory support in patients with acute respiratory failure, and may decrease mortality rates by avoiding intubation;32,33 conversely, NIV can have negative effects on outcome by postponing intubation as has been shown in several studies in adult hematology patients.34,35 Restrictions on use of curative NIV in adults were therefore recently proposed.36,37 We found nonsignificant better survival in patients who immediately started with IMV (49%) compared with patients who received IMV after failed NIV (63%, P=0.13). This may well be biased by confounding by indication and selection bias. Further studies are needed to identify benefits of NIV in children after HSCT.
By working with four dedicated centers, data for this study could be collected accurately and completely. However, working with a few centers is also a limitation of our study, as it slowed the rate of inclusion. Moreover, it may have influenced our findings by differences in intercenter case-mix and practices. A second limitation of our registry is that it does not provide any information on transplantation-related risk of mortality24 or on patients who did not require admission to PICU, or in whom PICU admission was denied or not offered. Despite these limitations, our findings indicate improvement in survival compared with older studies and raise the crucial questions: which children benefit from admission to PICU, what the optimal timing for PICU admission is and how PICU treatments can be optimized. For several reasons, it has been found to be difficult to obtain the answers to these questions. Our study shows that a prospective, observational registry can be a valuable tool for addressing these topics. Adding additional items to existing data reports in all HSCT centers, both in Europe as well as in the United States, could give information on a larger number of patients.
We present results of a prospective, multicenter registry on children receiving IMV after HSCT. Overall mortality in these patients was high, but it has clearly improved compared with older studies. CMV viremia, RRT and severe impairment in oxygenation were independently associated with mortality. Patient selection and PICU treatments were not uniform between centers. Our findings underscore the need to optimize and standardize PICU admission criteria, ventilatory strategies and PICU treatments in this population.
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The authors declare no conflict of interest.
All authors have contributed substantially in the conception and design of the study. They all participated actively in the writing of the manuscript.
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van Gestel, J., Bierings, M., Dauger, S. et al. Outcome of invasive mechanical ventilation after pediatric allogeneic hematopoietic SCT: results from a prospective, multicenter registry. Bone Marrow Transplant 49, 1287–1292 (2014). https://doi.org/10.1038/bmt.2014.147
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