Outcome of Critically Ill Allogeneic Hematopoietic Stem-Cell Transplantation Recipients: A Reappraisal of Indications for Organ Fa
the Medical Intensive Care Unit, Cochin Hospital, AP-HP
Medical Intensive Care Unit and Bone Marrow Transplantation Unit, Saint-Louis Hospital, AP-HP
Hematology Department, Necker Hospital, AP-HP
Faculty of Medicine, Paris V-René Descartes University
Faculty of Medicine, Paris VII-Denis Diderot University, Paris
Intensive Care Unit and Bone Marrow Transplantation Unit, Institut Gustave Roussy, Villejuif, France
ABSTRACT
PURPOSE: Because the overall outcome of critically ill hematologic patients has improved, we evaluated the short-term and long-term outcomes of the poor risk subgroup of allogeneic hematopoietic stem-cell transplantation (HSCT) recipients requiring admission to the intensive care unit (ICU).
PATIENTS AND METHODS: This was a retrospective multicenter study of allogeneic HSCT recipients admitted to the ICU between 1997 and 2003.
RESULTS: Two hundred nine critically ill allogeneic HSCT recipients were included in the study. Admission in the ICU occurred during the engraftment period ( 30 days after transplantation) for 70 of the patients and after the engraftment period for 139 patients. The overall in-ICU, in-hospital, 6-month, and 1-year survival rates were 48.3%, 32.5%, 27.2%, and 21%, respectively. Mechanical ventilation was required in 122 patients and led to a dramatic decrease in survival rates, resulting in in-ICU, in-hospital, 6-month, and 1-year survival rates of 18%, 15.6%, 14%, and 10.6%, respectively. Mechanical ventilation, elevated bilirubin level, and corticosteroid treatment for the indication of active graft-versus-host disease (GVHD) were independent predictors of death in the whole cohort. In the subgroup of patients requiring mechanical ventilation, associated organ failures, such as shock and liver dysfunction, were independent predictors of death. ICU admission during engraftment period was associated with acceptable outcome in mechanically ventilated patients, whereas patients with late complications of HSCT in the setting of active GVHD had a poor outcome.
CONCLUSION: Extensive unlimited intensive care support is justified for allogeneic HSCT recipients with complications occurring during the engraftment period. Conversely, initiation or maintenance of mechanical ventilation is questionable in the setting of active GVHD.
INTRODUCTION
The overall prognosis of critically ill patients with malignancies has been improved over recent years.1-3 A more appropriate selection of patients probably accounted for the reduction of mortality.4,5 In addition, management of organ dysfunctions in these patients has moved towards early organ failure support in the intensive care unit (ICU) as a consequence of close cooperation between oncologists, hematologists, and intensive care physicians. For instance, early initiation of noninvasive ventilation resulted in a decrease of intubation rate and improved survival in critically ill cancer patients with acute respiratory failure.6,7
Hematopoietic stem-cell transplantation (HSCT) is associated with multiple infectious and noninfectious complications that often lead to organ failures requiring admission to the ICU. The course of both autologous and allogeneic HSCT is characterized by a common engraftment period during which the incidence of infection is similar and is essentially related to neutropenia.8 In addition, allogeneic HSCT is frequently complicated by graft-versus-host disease (GVHD) in more than half of the patients.9 GVHD requires reinforcement of immunosuppression with high-dose corticosteroids, resulting in a profound and sustained immunodeficiency, which accounts for the high procedure-related mortality.10,11 Pulmonary complications are particularly frequent, and 6% to 29% of HSCT recipients require endotracheal intubation and mechanical ventilation for acute respiratory failure.12-19 However, initiation of mechanical ventilation is a turning point in the course of transplantation with low survival rates.20 Moreover, association of acute respiratory failure requiring mechanical ventilation with other organ failures has been reported to be almost uniformly fatal.14 Recent studies reported a slight improvement in the outcome of mechanically ventilated autologous and allogeneic HSCT recipients, with 20% to 26% hospital survivors.18,19,21 However, few studies have emphasized the radically different outcomes between allogeneic and autologous HSCT recipients in the ICU, and the large proportion (47% to 100%) of autologous transplantation recipients in the recent cohorts was confounding and led to an underestimation of the mortality rate of allogeneic graft recipients.21-24 Therefore, allogeneic HSCT recipients remain considered as poor candidates for ICU admission.
Ethical and cost concerns may make the indications for aggressive life support in allogeneic HSCT recipients questionable or even futile, particularly concerning indications of mechanical ventilation. In this study, we analyzed the short- and long-term outcomes of a large cohort of allogeneic HSCT recipients admitted to the ICU within the recent years. We sought to identify whether improvements in outcomes of non-HSCT critically ill cancer patients are applicable to this population.
PATIENTS AND METHODS
Patients and Setting
All adult allogeneic HSCT recipients admitted to three medical ICUs of university hospitals between January 1997 and December 2003 were included in the study. Autologous HSCT recipients were excluded. Clinical charts were reviewed by two independent observers (F.P. and C.A.). All three units routinely admit critically ill immunocompromised patients with or without malignancies and are staffed by intensive care physicians who have been trained in hematology and oncology. In all centers, organ failure supports, such as noninvasive and invasive mechanical ventilation, vasoactive drugs, and renal replacement therapy, are restricted to ICU. The triage decisions were taken on by both the intensivist and the hematologist.
Data Collection
The following demographic variables and hematologic disease-related and transplantation-related characteristics were collected: age, sex, underlying hematologic disease and its status at transplantation, delay from diagnosis to transplantation, conditioning regimen, source of stem cells, type of transplantation, and corticosteroid treatment ( 0.5 mg/kg of prednisone per day) at ICU admission in the indication of GVHD. The underlying disease was considered as controlled for stable chronic diseases and for both complete remission and responding relapse in other malignancies. Time from HSCT to admission in the ICU was categorized into the following two periods: before 30 days, which corresponded to the neutropenic phase for engraftment; and after 30 days, which corresponded to the immune reconstitution period.
The following organ failure–related variables were collected: reasons for admission in the ICU, Simplified Acute Physiology Score II (SAPS II), Logistic Organ Dysfunction (LOD) score,25,26 serum creatinine and bilirubin levels, and organ support requirement (noninvasive ventilation, invasive mechanical ventilation, vasopressors, and renal replacement therapy). The SAPS II and LOD severity scores include physiologic and biologic variables at ICU admission and provide a probability of in-hospital mortality. Noninvasive ventilation was considered for patients with acute respiratory failure not requiring immediate intubation.6 Liver failure was defined as a total bilirubin level greater than 68 μmol/L.14,25 The diagnosis of hepatic veno-occlusive disease was mainly based on clinical and echographic findings.27 For patients who were admitted more than once to the ICU, only the first episode was analyzed.
End Points
The short-term outcome was assessed through in-ICU and in-hospital mortality rates. The long-term follow-up was assessed through the 6-month and 1-year survival rates. Prognostic factors related to in-hospital mortality were studied in the complete cohort and in the subgroup of patients undergoing invasive mechanical ventilation.
Statistical Analysis
Continuous variables were reported as medians and interquartile ranges (IQR), and categoric variables were reported as numbers and percentages. Continuous variables were compared using the Mann-Whitney U test, and categoric variables were compared using the 2 test. Survival curves were obtained using the Kaplan-Meier method and compared using the log-rank test. Correlations between patient characteristics and in-hospital mortality were assessed using univariate and multivariate Cox regression models. The variable of interest was in-hospital mortality, and results were expressed as hazard ratios and 95% CIs. For continuous variables, the hazard ratio was indexed to an increment of one unit. Categoric variables were expressed as absent or present. The proportional hazards assumption was checked for all Cox models constructed. Statistical analysis was performed with SPSS software version 10.0 (SPSS Inc, Chicago, IL).
RESULTS
Indications for ICU Admission and Organ Failures
During the study period, 1,025 patients underwent an allogeneic HSCT procedure, of whom 209 (20%) required 221 admissions in the ICU. The baseline characteristics of these patients are listed in Table 1. The main reason for admission to the ICU was acute respiratory failure in 141 patients (67%; Table 2). Infections were documented in 99 patients during the stay in the ICU, with the following distribution: bacteria (61 patients), fungi (39 patients, of whom 31 had invasive aspergillosis), virus (35 patients, of whom 28 had cytomegalovirus reactivation), and parasites (seven patients). The median LOD severity score was 6 (IQR, 4 to 9), with the following distribution: less than 6 in 85 patients (41%), between 6 and 10 in 89 patients (42%), and greater than 10 in 35 patients (17%). During their course in the ICU, 66 patients (32%) were primarily treated with noninvasive ventilation for a median of 2 days (IQR, 1 to 5 days; range, 1 to 13 days), of whom 44 (66%) required endotracheal intubation and mechanical ventilation after failure of the procedure. Overall, 122 patients (58%) required mechanical ventilation for a median duration of 5 days (IQR, 2 to 11 days; range, 1 to 56 days). Acute circulatory and renal failures were particularly frequent in mechanically ventilated patients, and 74% of these patients required vasoactive drugs, and 40% required renal replacement therapy. Liver failure, as assessed with a serum bilirubin level 68 μmol/L, was present in 56 patients (26%) and was mostly a result of transplantation-related complications (GVHD in 30 patients and veno-occlusive disease in 12 patients).
Short- and Long-Term Outcomes: Impact of Mechanical Ventilation
The overall in-ICU, in-hospital, 6-month, and 1-year survival rates were 48.3%, 32.5%, 27.2%, and 21%, respectively (Table 3). Survival depended on the extent of organ failures because in-hospital survival rates of patients with LOD scores of less than 6, between 6 and 10, and greater than 10 were 55%, 25%, and 0%, respectively (Fig 1). Transplantation-related mortality accounted for a large majority of deaths among ICU survivors who died within the first year and was mostly related to a disorder present in the ICU for 23 patients (Fig 2). Mechanical ventilation requirement was strongly associated with mortality (Fig 3). Only 22 (18%) of 122 mechanically ventilated patients were discharged from the ICU, and 19 (15.6%) were discharged from hospital, with 6-month and 1-year survival rates of 14% and 10.6%, respectively. The 87 nonventilated patients had a good in-ICU outcome, with a survival rate of 91%, but a large proportion of these patients secondarily died in the hospital. Thus, only 56.3% of this subgroup was discharged from the hospital, with 6-months and 1-year survival rates of 46% and 35.6%, respectively (Table 3). Among the patients who did not receive mechanical ventilation, 22 patients were successfully treated with noninvasive ventilation. The in-hospital survival rates of these 22 patients and the 65 other nonventilated patients were similar (45% and 60%, respectively; P = .21).
Prognostic Factors of In-Hospital Mortality
Among the HSCT-related variables, only corticosteroid treatment for GVHD was associated with poor in-hospital outcome in the univariate Cox regression analysis (Table 4). None of the other transplantation-related variables, including disease status at transplantation, were correlated with short-term outcome. In contrast, each organ failure indicator was strongly associated with a poor in-hospital outcome, including mechanical ventilation, acute circulatory failure as assessed through requirement of vasoactive drugs, renal replacement therapy, and serum bilirubin level reflecting liver dysfunction.
In the multivariate analysis, the following variables remained independently associated with a poor in-hospital outcome: corticosteroid treatment, mechanical ventilation, and serum bilirubin level. Although interval time between transplantation and ICU admission was not predictive of outcome in the univariate analysis, the engraftment period ( 30 days from transplantation) was found to be protective when forced into the multivariate model.
Prognostic Factors in Mechanically Ventilated Patients
Considering the poor survival rate associated with mechanical ventilation, we sought to identify early predictors of outcome in this subgroup of 122 patients. Interval time from HSCT to ICU admission substantially influenced the outcome. Indeed, patients in the engraftment period (n = 46) had higher short-term and long-term survival rates compared with patients admitted to the ICU 30 days or more after HSCT (n = 76; Fig 4). Thus, for patients admitted during the engraftment period compared with after the engraftment period, 26% and 13.1% were discharged from ICU, 21.7% and 11.8% were discharged from hospital, 21.7% and 9.2% remained alive at 6 months, and 17.3% and 6.5% were alive at 1 year, respectively. The multivariate analysis identified time from HSCT to ICU admission, liver dysfunction, and vasoactive drugs as independent predictors of in-hospital outcome in mechanically ventilated patients (Table 5).
DISCUSSION
Critically ill allogeneic transplantation recipients frequently require high use of ICU resources, with major investment from hematology and ICU teams. However, initiation of mechanical ventilation still raises ethical concerns because the procedure remains affected by a sustained considerable mortality rate. In this study, we report that interval time between transplantation and ICU admission, the presence of corticosteroid treatment for GVHD, and liver dysfunction are early important predictors of outcome that might be helpful to determine indications for ICU admission and initiation of mechanical ventilation.
The short-term outcome of critically ill patients with cancer or hematologic malignancies has been shown to be mainly determined by the number of organ failures and not by the characteristics of underlying malignancy.28,29 Accordingly, neither disease status at transplantation nor transplantation-related characteristics influenced the in-hospital outcome in allogeneic HSCT recipients. We did not observe any influence of source of stem cells on the outcome, whereas use of peripheral-blood stem cells has been shown to improve survival of mechanically ventilated patients.24 However, although nonmyeloablative conditioning regimens and peripheral-blood stem cells can reduce the duration of neutropenia, they remain associated with a high incidence of late infectious and noninfectious complications.9,30 Thus, the majority of prognostic factors were related to organ failures. The in-hospital mortality rate (67%) was largely underestimated by the SAPS II and LOD severity scores, which predicted mortality rates of 27% and 29%, respectively.25,26 Moreover, a LOD score of greater than 10 was associated with a 100% in-hospital mortality rate. These general severity scores, which have been validated in large but heterogeneous cohorts of critically ill patients, are clearly inadequate to predict the overall outcome in this subgroup of patients. In view of the limits of general scores in this setting, a prediction model developed by Groeger et al22 and specifically fitted for cancer patients admitted to the ICU certainly deserves high consideration and may help to refine our indications for organ failure supports in the specific subgroup of allogeneic HSCT recipients.
Mechanical ventilation, which is frequently associated with shock and acute renal failure, is the cornerstone of organ failure supports in allogeneic HSCT recipients and is recognized as the main determinant of short-term survival. Our results suggest that the outcome of mechanically ventilated allogeneic transplantation recipients has not improved for two decades, with consistent survival rates less than 20%.20 The in-ICU and in-hospital survival rates of 18% and 15.6% are far worse than the respective 69.7% and 61.8% survival rates reported in a large, worldwide, observational survey of unselected ICU patients requiring mechanical ventilation.31 For instance, a severe respiratory condition, such as acute respiratory distress syndrome, in non-HSCT patients is associated with in-hospital and 1-year survival rates of 69% and 50%, respectively.32,33 Beyond the poor short-term outcome, a number of mechanically ventilated survivors had a good long-term outcome, with 17 and 12 patients alive after 6 months and 1 year, respectively. Besides acute respiratory failure, we report the prognostic value of liver failure as an independent predictor of death, as previously described in HSCT recipients and cancer patients.1,14,16 Liver failure can be related to multiple etiologies in this setting, including veno-occlusive disease, GVHD, drug toxicity, and sepsis. Because liver biopsy carries a high risk of complications, the diagnosis remains presumptive in a large majority of patients. Although specific therapeutic interventions are limited, prevention of liver dysfunction or early treatment of veno-occlusive disease may help to improve the prognosis.27,34
We identified interval time between transplantation and ICU admission as a potent prognostic factor of outcome. Indeed, the survival rate of patients requiring mechanical ventilation within the engraftment period was acceptable and was similar to the rates reported in cohorts of mechanically ventilated cancer patients.23,35 In contrast, mechanically ventilated patients with late complications of HSCT had a poor survival rate, especially when associated with other organ failures such as shock or liver dysfunction. Corticosteroid treatment, which was present in the majority of patients after engraftment, was also identified as a poor prognostic factor. Indeed, GVHD through direct complications or by associated immunodeficiency that increases susceptibility to infections is known to account for the majority of late deaths not related to relapse.10 A prognostic role for the interval time between transplantation and mechanical ventilation has also been suggested by Huaringa et al.36 In their study, almost all survivors had required initiation of mechanical ventilation within 30 days after transplantation, and none of the patients with active GVHD survived. Similarly, a longer elapsed time since transplantation was found to be predictive of an increased risk of mortality in the study by Price et al.24 Therefore, the following two prognostic subgroups can be easily identified on the basis of the time interval between transplantation and ICU admission and corticosteroid treatment: patients with complications during the engraftment period for whom partial reversal of immunosuppression is expected in a few days with neutropenia recovery, and patients with late complications for whom organ failures are consequences of GVHD and severe long-term immunodeficiency.
This study has several limitations that have to be emphasized. First, we did not compare the outcome of allogeneic HSCT recipients to other cohorts of critically ill unselected or cancer patients hospitalized in the ICU during the same period. Interpretation of our results was largely based on historical comparison with previously published cohorts of patients. Second, on the basis of available data in the literature, triage decisions for ICU admission involving both hematologists and intensivists led to the consideration of ICU admission only for patients with a reasonable chance of recovery.5 The results were consistent between centers because we observed no differences in outcomes. Third, response of GVHD to corticosteroids was inaccurate to assess in a retrospective manner but should probably be considered in the decision-making process. In this setting, influence of GVHD grading and response to corticosteroids, if any, should be evaluated in a prospective study. Fourth, a large proportion of patients discharged from the ICU died in the hospital, thus leading to an in-hospital survival rate of 33%. Only a minority of patients were secondarily referred back to the ICU for aggressive treatment of complications. Thus, a large proportion of ICU survivors were probably subjected to therapeutic limitations and do not resuscitate orders, but a reliable collection of this important parameter was also limited by the retrospective design of the study. An assessment of the quality of life of hospital survivors, which is known to be lasting and profoundly affected by both HSCT and ICU admission, would contribute to the evaluation of the long-term outcome of these patients.37,38
In conclusion, the outcome of HSCT recipients requiring mechanical ventilation during the engraftment period is reasonable and justifies a policy of broad ICU admission with maximal organ supports, followed by frequent reappraisal of the benefits of intensive care. Conversely, HSCT recipients treated with corticosteroids for GVHD are unlikely to benefit from mechanical ventilation, especially when associated with shock or liver failure, and initiation or maintenance of mechanical ventilation is questionable in this setting. To avoid futile aggressive care, close interactions between hematologists and intensivists are necessary to identify patients who may potentially benefit from life-sustaining therapies with reasonable likelihood of survival.
Authors' Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
Author Contributions
Conception and design: Frédéric Pène, Cécile Aubron, Elie Azoulay, Gérard Socié, Jean-Paul Mira
Provision of study materials or patients: Frédéric Pène, Cécile Aubron, Elie Azoulay, Franois Blot, Guillaume Thiéry, Bruno Raynard, Benot Schlemmer, Gérard Nitenberg, Agnès Buzyn, Philippe Arnaud, Gérard Socié, Jean-Paul Mira
Collection and assembly of data: Frédéric Pène, Cécile Aubron
Data analysis and interpretation: Frédéric Pène, Cécile Aubron, Elie Azoulay, Franois Blot, Guillaume Thiéry, Bruno Raynard, Benot Schlemmer, Gérard Nitenberg, Agnès Buzyn, Philippe Arnaud, Gérard Socié, Jean-Paul Mira
Manuscript writing: Frédéric Pène, Cécile Aubron, Elie Azoulay, Gérard Socié, Jean-Paul Mira
Final approval of manuscript: Frédéric Pène, Cécile Aubron, Elie Azoulay, Franois Blot, Guillaume Thiéry, Bruno Raynard, Benot Schlemmer, Gérard Nitenberg, Agnès Buzyn, Philippe Arnaud, Gérard Socié, Jean-Paul Mira
Acknowledgment
We thank Catherine Chadelat, Armelle Morin, and Isabelle Hirsch for their help in the collection of data.
NOTES
F.P. and C.A. contributed equally to this work and should both be considered as first authors.
Presented in part at the 46th Annual Meeting of the American Society of Hematology, San Diego, CA, December 4-7, 2004.
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Faber-Langendoen K, Caplan AL, McGlave PB: Survival of adult bone marrow transplant patients receiving mechanical ventilation: A case for restricted use. Bone Marrow Transplant 12:501-507, 1993
Paz HL, Crilley P, Weinar M, et al: Outcome of patients requiring medical ICU admission following bone marrow transplantation. Chest 104:527-531, 1993
Rubenfeld GD, Crawford SW: Withdrawing life support from mechanically ventilated recipients of bone marrow transplants: A case for evidence-based guidelines. Ann Intern Med 125:625-633, 1996
Paz HL, Garland A, Weinar M, et al: Effect of clinical outcomes data on intensive care unit utilization by bone marrow transplant patients. Crit Care Med 26:66-70, 1998
Jackson SR, Tweeddale MG, Barnett MJ, et al: Admission of bone marrow transplant recipients to the intensive care unit: Outcome, survival and prognostic factors. Bone Marrow Transplant 21:697-704, 1998
Shorr AF, Moores LK, Edenfield WJ, et al: Mechanical ventilation in hematopoietic stem cell transplantation: Can we effectively predict outcomes Chest 116:1012-1018, 1999
Khassawneh BY, White P Jr, Anaissie EJ, et al: Outcome from mechanical ventilation after autologous peripheral blood stem cell transplantation. Chest 121:185-188, 2002
Soubani AO, Kseibi E, Bander JJ, et al: Outcome and prognostic factors of hematopoietic stem cell transplantation recipients admitted to a medical ICU. Chest 126:1604-1611, 2004
Bach PB, Schrag D, Nierman DM, et al: Identification of poor prognostic features among patients requiring mechanical ventilation after hematopoietic stem cell transplantation. Blood 98:3234-3240, 2001
Afessa B, Tefferi A, Dunn WF, et al: Intensive care unit support and Acute Physiology and Chronic Health Evaluation III performance in hematopoietic stem cell transplant recipients. Crit Care Med 31:1715-1721, 2003
Groeger JS, Lemeshow S, Price K, et al: Multicenter outcome study of cancer patients admitted to the intensive care unit: A probability of mortality model. J Clin Oncol 16:761-770, 1998
Groeger JS, White P Jr, Nierman DM, et al: Outcome for cancer patients requiring mechanical ventilation. J Clin Oncol 17:991-997, 1999
Price KJ, Thall PF, Kish SK, et al: Prognostic indicators for blood and marrow transplant patients admitted to an intensive care unit. Am J Respir Crit Care Med 158:876-884, 1998
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Medical Intensive Care Unit and Bone Marrow Transplantation Unit, Saint-Louis Hospital, AP-HP
Hematology Department, Necker Hospital, AP-HP
Faculty of Medicine, Paris V-René Descartes University
Faculty of Medicine, Paris VII-Denis Diderot University, Paris
Intensive Care Unit and Bone Marrow Transplantation Unit, Institut Gustave Roussy, Villejuif, France
ABSTRACT
PURPOSE: Because the overall outcome of critically ill hematologic patients has improved, we evaluated the short-term and long-term outcomes of the poor risk subgroup of allogeneic hematopoietic stem-cell transplantation (HSCT) recipients requiring admission to the intensive care unit (ICU).
PATIENTS AND METHODS: This was a retrospective multicenter study of allogeneic HSCT recipients admitted to the ICU between 1997 and 2003.
RESULTS: Two hundred nine critically ill allogeneic HSCT recipients were included in the study. Admission in the ICU occurred during the engraftment period ( 30 days after transplantation) for 70 of the patients and after the engraftment period for 139 patients. The overall in-ICU, in-hospital, 6-month, and 1-year survival rates were 48.3%, 32.5%, 27.2%, and 21%, respectively. Mechanical ventilation was required in 122 patients and led to a dramatic decrease in survival rates, resulting in in-ICU, in-hospital, 6-month, and 1-year survival rates of 18%, 15.6%, 14%, and 10.6%, respectively. Mechanical ventilation, elevated bilirubin level, and corticosteroid treatment for the indication of active graft-versus-host disease (GVHD) were independent predictors of death in the whole cohort. In the subgroup of patients requiring mechanical ventilation, associated organ failures, such as shock and liver dysfunction, were independent predictors of death. ICU admission during engraftment period was associated with acceptable outcome in mechanically ventilated patients, whereas patients with late complications of HSCT in the setting of active GVHD had a poor outcome.
CONCLUSION: Extensive unlimited intensive care support is justified for allogeneic HSCT recipients with complications occurring during the engraftment period. Conversely, initiation or maintenance of mechanical ventilation is questionable in the setting of active GVHD.
INTRODUCTION
The overall prognosis of critically ill patients with malignancies has been improved over recent years.1-3 A more appropriate selection of patients probably accounted for the reduction of mortality.4,5 In addition, management of organ dysfunctions in these patients has moved towards early organ failure support in the intensive care unit (ICU) as a consequence of close cooperation between oncologists, hematologists, and intensive care physicians. For instance, early initiation of noninvasive ventilation resulted in a decrease of intubation rate and improved survival in critically ill cancer patients with acute respiratory failure.6,7
Hematopoietic stem-cell transplantation (HSCT) is associated with multiple infectious and noninfectious complications that often lead to organ failures requiring admission to the ICU. The course of both autologous and allogeneic HSCT is characterized by a common engraftment period during which the incidence of infection is similar and is essentially related to neutropenia.8 In addition, allogeneic HSCT is frequently complicated by graft-versus-host disease (GVHD) in more than half of the patients.9 GVHD requires reinforcement of immunosuppression with high-dose corticosteroids, resulting in a profound and sustained immunodeficiency, which accounts for the high procedure-related mortality.10,11 Pulmonary complications are particularly frequent, and 6% to 29% of HSCT recipients require endotracheal intubation and mechanical ventilation for acute respiratory failure.12-19 However, initiation of mechanical ventilation is a turning point in the course of transplantation with low survival rates.20 Moreover, association of acute respiratory failure requiring mechanical ventilation with other organ failures has been reported to be almost uniformly fatal.14 Recent studies reported a slight improvement in the outcome of mechanically ventilated autologous and allogeneic HSCT recipients, with 20% to 26% hospital survivors.18,19,21 However, few studies have emphasized the radically different outcomes between allogeneic and autologous HSCT recipients in the ICU, and the large proportion (47% to 100%) of autologous transplantation recipients in the recent cohorts was confounding and led to an underestimation of the mortality rate of allogeneic graft recipients.21-24 Therefore, allogeneic HSCT recipients remain considered as poor candidates for ICU admission.
Ethical and cost concerns may make the indications for aggressive life support in allogeneic HSCT recipients questionable or even futile, particularly concerning indications of mechanical ventilation. In this study, we analyzed the short- and long-term outcomes of a large cohort of allogeneic HSCT recipients admitted to the ICU within the recent years. We sought to identify whether improvements in outcomes of non-HSCT critically ill cancer patients are applicable to this population.
PATIENTS AND METHODS
Patients and Setting
All adult allogeneic HSCT recipients admitted to three medical ICUs of university hospitals between January 1997 and December 2003 were included in the study. Autologous HSCT recipients were excluded. Clinical charts were reviewed by two independent observers (F.P. and C.A.). All three units routinely admit critically ill immunocompromised patients with or without malignancies and are staffed by intensive care physicians who have been trained in hematology and oncology. In all centers, organ failure supports, such as noninvasive and invasive mechanical ventilation, vasoactive drugs, and renal replacement therapy, are restricted to ICU. The triage decisions were taken on by both the intensivist and the hematologist.
Data Collection
The following demographic variables and hematologic disease-related and transplantation-related characteristics were collected: age, sex, underlying hematologic disease and its status at transplantation, delay from diagnosis to transplantation, conditioning regimen, source of stem cells, type of transplantation, and corticosteroid treatment ( 0.5 mg/kg of prednisone per day) at ICU admission in the indication of GVHD. The underlying disease was considered as controlled for stable chronic diseases and for both complete remission and responding relapse in other malignancies. Time from HSCT to admission in the ICU was categorized into the following two periods: before 30 days, which corresponded to the neutropenic phase for engraftment; and after 30 days, which corresponded to the immune reconstitution period.
The following organ failure–related variables were collected: reasons for admission in the ICU, Simplified Acute Physiology Score II (SAPS II), Logistic Organ Dysfunction (LOD) score,25,26 serum creatinine and bilirubin levels, and organ support requirement (noninvasive ventilation, invasive mechanical ventilation, vasopressors, and renal replacement therapy). The SAPS II and LOD severity scores include physiologic and biologic variables at ICU admission and provide a probability of in-hospital mortality. Noninvasive ventilation was considered for patients with acute respiratory failure not requiring immediate intubation.6 Liver failure was defined as a total bilirubin level greater than 68 μmol/L.14,25 The diagnosis of hepatic veno-occlusive disease was mainly based on clinical and echographic findings.27 For patients who were admitted more than once to the ICU, only the first episode was analyzed.
End Points
The short-term outcome was assessed through in-ICU and in-hospital mortality rates. The long-term follow-up was assessed through the 6-month and 1-year survival rates. Prognostic factors related to in-hospital mortality were studied in the complete cohort and in the subgroup of patients undergoing invasive mechanical ventilation.
Statistical Analysis
Continuous variables were reported as medians and interquartile ranges (IQR), and categoric variables were reported as numbers and percentages. Continuous variables were compared using the Mann-Whitney U test, and categoric variables were compared using the 2 test. Survival curves were obtained using the Kaplan-Meier method and compared using the log-rank test. Correlations between patient characteristics and in-hospital mortality were assessed using univariate and multivariate Cox regression models. The variable of interest was in-hospital mortality, and results were expressed as hazard ratios and 95% CIs. For continuous variables, the hazard ratio was indexed to an increment of one unit. Categoric variables were expressed as absent or present. The proportional hazards assumption was checked for all Cox models constructed. Statistical analysis was performed with SPSS software version 10.0 (SPSS Inc, Chicago, IL).
RESULTS
Indications for ICU Admission and Organ Failures
During the study period, 1,025 patients underwent an allogeneic HSCT procedure, of whom 209 (20%) required 221 admissions in the ICU. The baseline characteristics of these patients are listed in Table 1. The main reason for admission to the ICU was acute respiratory failure in 141 patients (67%; Table 2). Infections were documented in 99 patients during the stay in the ICU, with the following distribution: bacteria (61 patients), fungi (39 patients, of whom 31 had invasive aspergillosis), virus (35 patients, of whom 28 had cytomegalovirus reactivation), and parasites (seven patients). The median LOD severity score was 6 (IQR, 4 to 9), with the following distribution: less than 6 in 85 patients (41%), between 6 and 10 in 89 patients (42%), and greater than 10 in 35 patients (17%). During their course in the ICU, 66 patients (32%) were primarily treated with noninvasive ventilation for a median of 2 days (IQR, 1 to 5 days; range, 1 to 13 days), of whom 44 (66%) required endotracheal intubation and mechanical ventilation after failure of the procedure. Overall, 122 patients (58%) required mechanical ventilation for a median duration of 5 days (IQR, 2 to 11 days; range, 1 to 56 days). Acute circulatory and renal failures were particularly frequent in mechanically ventilated patients, and 74% of these patients required vasoactive drugs, and 40% required renal replacement therapy. Liver failure, as assessed with a serum bilirubin level 68 μmol/L, was present in 56 patients (26%) and was mostly a result of transplantation-related complications (GVHD in 30 patients and veno-occlusive disease in 12 patients).
Short- and Long-Term Outcomes: Impact of Mechanical Ventilation
The overall in-ICU, in-hospital, 6-month, and 1-year survival rates were 48.3%, 32.5%, 27.2%, and 21%, respectively (Table 3). Survival depended on the extent of organ failures because in-hospital survival rates of patients with LOD scores of less than 6, between 6 and 10, and greater than 10 were 55%, 25%, and 0%, respectively (Fig 1). Transplantation-related mortality accounted for a large majority of deaths among ICU survivors who died within the first year and was mostly related to a disorder present in the ICU for 23 patients (Fig 2). Mechanical ventilation requirement was strongly associated with mortality (Fig 3). Only 22 (18%) of 122 mechanically ventilated patients were discharged from the ICU, and 19 (15.6%) were discharged from hospital, with 6-month and 1-year survival rates of 14% and 10.6%, respectively. The 87 nonventilated patients had a good in-ICU outcome, with a survival rate of 91%, but a large proportion of these patients secondarily died in the hospital. Thus, only 56.3% of this subgroup was discharged from the hospital, with 6-months and 1-year survival rates of 46% and 35.6%, respectively (Table 3). Among the patients who did not receive mechanical ventilation, 22 patients were successfully treated with noninvasive ventilation. The in-hospital survival rates of these 22 patients and the 65 other nonventilated patients were similar (45% and 60%, respectively; P = .21).
Prognostic Factors of In-Hospital Mortality
Among the HSCT-related variables, only corticosteroid treatment for GVHD was associated with poor in-hospital outcome in the univariate Cox regression analysis (Table 4). None of the other transplantation-related variables, including disease status at transplantation, were correlated with short-term outcome. In contrast, each organ failure indicator was strongly associated with a poor in-hospital outcome, including mechanical ventilation, acute circulatory failure as assessed through requirement of vasoactive drugs, renal replacement therapy, and serum bilirubin level reflecting liver dysfunction.
In the multivariate analysis, the following variables remained independently associated with a poor in-hospital outcome: corticosteroid treatment, mechanical ventilation, and serum bilirubin level. Although interval time between transplantation and ICU admission was not predictive of outcome in the univariate analysis, the engraftment period ( 30 days from transplantation) was found to be protective when forced into the multivariate model.
Prognostic Factors in Mechanically Ventilated Patients
Considering the poor survival rate associated with mechanical ventilation, we sought to identify early predictors of outcome in this subgroup of 122 patients. Interval time from HSCT to ICU admission substantially influenced the outcome. Indeed, patients in the engraftment period (n = 46) had higher short-term and long-term survival rates compared with patients admitted to the ICU 30 days or more after HSCT (n = 76; Fig 4). Thus, for patients admitted during the engraftment period compared with after the engraftment period, 26% and 13.1% were discharged from ICU, 21.7% and 11.8% were discharged from hospital, 21.7% and 9.2% remained alive at 6 months, and 17.3% and 6.5% were alive at 1 year, respectively. The multivariate analysis identified time from HSCT to ICU admission, liver dysfunction, and vasoactive drugs as independent predictors of in-hospital outcome in mechanically ventilated patients (Table 5).
DISCUSSION
Critically ill allogeneic transplantation recipients frequently require high use of ICU resources, with major investment from hematology and ICU teams. However, initiation of mechanical ventilation still raises ethical concerns because the procedure remains affected by a sustained considerable mortality rate. In this study, we report that interval time between transplantation and ICU admission, the presence of corticosteroid treatment for GVHD, and liver dysfunction are early important predictors of outcome that might be helpful to determine indications for ICU admission and initiation of mechanical ventilation.
The short-term outcome of critically ill patients with cancer or hematologic malignancies has been shown to be mainly determined by the number of organ failures and not by the characteristics of underlying malignancy.28,29 Accordingly, neither disease status at transplantation nor transplantation-related characteristics influenced the in-hospital outcome in allogeneic HSCT recipients. We did not observe any influence of source of stem cells on the outcome, whereas use of peripheral-blood stem cells has been shown to improve survival of mechanically ventilated patients.24 However, although nonmyeloablative conditioning regimens and peripheral-blood stem cells can reduce the duration of neutropenia, they remain associated with a high incidence of late infectious and noninfectious complications.9,30 Thus, the majority of prognostic factors were related to organ failures. The in-hospital mortality rate (67%) was largely underestimated by the SAPS II and LOD severity scores, which predicted mortality rates of 27% and 29%, respectively.25,26 Moreover, a LOD score of greater than 10 was associated with a 100% in-hospital mortality rate. These general severity scores, which have been validated in large but heterogeneous cohorts of critically ill patients, are clearly inadequate to predict the overall outcome in this subgroup of patients. In view of the limits of general scores in this setting, a prediction model developed by Groeger et al22 and specifically fitted for cancer patients admitted to the ICU certainly deserves high consideration and may help to refine our indications for organ failure supports in the specific subgroup of allogeneic HSCT recipients.
Mechanical ventilation, which is frequently associated with shock and acute renal failure, is the cornerstone of organ failure supports in allogeneic HSCT recipients and is recognized as the main determinant of short-term survival. Our results suggest that the outcome of mechanically ventilated allogeneic transplantation recipients has not improved for two decades, with consistent survival rates less than 20%.20 The in-ICU and in-hospital survival rates of 18% and 15.6% are far worse than the respective 69.7% and 61.8% survival rates reported in a large, worldwide, observational survey of unselected ICU patients requiring mechanical ventilation.31 For instance, a severe respiratory condition, such as acute respiratory distress syndrome, in non-HSCT patients is associated with in-hospital and 1-year survival rates of 69% and 50%, respectively.32,33 Beyond the poor short-term outcome, a number of mechanically ventilated survivors had a good long-term outcome, with 17 and 12 patients alive after 6 months and 1 year, respectively. Besides acute respiratory failure, we report the prognostic value of liver failure as an independent predictor of death, as previously described in HSCT recipients and cancer patients.1,14,16 Liver failure can be related to multiple etiologies in this setting, including veno-occlusive disease, GVHD, drug toxicity, and sepsis. Because liver biopsy carries a high risk of complications, the diagnosis remains presumptive in a large majority of patients. Although specific therapeutic interventions are limited, prevention of liver dysfunction or early treatment of veno-occlusive disease may help to improve the prognosis.27,34
We identified interval time between transplantation and ICU admission as a potent prognostic factor of outcome. Indeed, the survival rate of patients requiring mechanical ventilation within the engraftment period was acceptable and was similar to the rates reported in cohorts of mechanically ventilated cancer patients.23,35 In contrast, mechanically ventilated patients with late complications of HSCT had a poor survival rate, especially when associated with other organ failures such as shock or liver dysfunction. Corticosteroid treatment, which was present in the majority of patients after engraftment, was also identified as a poor prognostic factor. Indeed, GVHD through direct complications or by associated immunodeficiency that increases susceptibility to infections is known to account for the majority of late deaths not related to relapse.10 A prognostic role for the interval time between transplantation and mechanical ventilation has also been suggested by Huaringa et al.36 In their study, almost all survivors had required initiation of mechanical ventilation within 30 days after transplantation, and none of the patients with active GVHD survived. Similarly, a longer elapsed time since transplantation was found to be predictive of an increased risk of mortality in the study by Price et al.24 Therefore, the following two prognostic subgroups can be easily identified on the basis of the time interval between transplantation and ICU admission and corticosteroid treatment: patients with complications during the engraftment period for whom partial reversal of immunosuppression is expected in a few days with neutropenia recovery, and patients with late complications for whom organ failures are consequences of GVHD and severe long-term immunodeficiency.
This study has several limitations that have to be emphasized. First, we did not compare the outcome of allogeneic HSCT recipients to other cohorts of critically ill unselected or cancer patients hospitalized in the ICU during the same period. Interpretation of our results was largely based on historical comparison with previously published cohorts of patients. Second, on the basis of available data in the literature, triage decisions for ICU admission involving both hematologists and intensivists led to the consideration of ICU admission only for patients with a reasonable chance of recovery.5 The results were consistent between centers because we observed no differences in outcomes. Third, response of GVHD to corticosteroids was inaccurate to assess in a retrospective manner but should probably be considered in the decision-making process. In this setting, influence of GVHD grading and response to corticosteroids, if any, should be evaluated in a prospective study. Fourth, a large proportion of patients discharged from the ICU died in the hospital, thus leading to an in-hospital survival rate of 33%. Only a minority of patients were secondarily referred back to the ICU for aggressive treatment of complications. Thus, a large proportion of ICU survivors were probably subjected to therapeutic limitations and do not resuscitate orders, but a reliable collection of this important parameter was also limited by the retrospective design of the study. An assessment of the quality of life of hospital survivors, which is known to be lasting and profoundly affected by both HSCT and ICU admission, would contribute to the evaluation of the long-term outcome of these patients.37,38
In conclusion, the outcome of HSCT recipients requiring mechanical ventilation during the engraftment period is reasonable and justifies a policy of broad ICU admission with maximal organ supports, followed by frequent reappraisal of the benefits of intensive care. Conversely, HSCT recipients treated with corticosteroids for GVHD are unlikely to benefit from mechanical ventilation, especially when associated with shock or liver failure, and initiation or maintenance of mechanical ventilation is questionable in this setting. To avoid futile aggressive care, close interactions between hematologists and intensivists are necessary to identify patients who may potentially benefit from life-sustaining therapies with reasonable likelihood of survival.
Authors' Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
Author Contributions
Conception and design: Frédéric Pène, Cécile Aubron, Elie Azoulay, Gérard Socié, Jean-Paul Mira
Provision of study materials or patients: Frédéric Pène, Cécile Aubron, Elie Azoulay, Franois Blot, Guillaume Thiéry, Bruno Raynard, Benot Schlemmer, Gérard Nitenberg, Agnès Buzyn, Philippe Arnaud, Gérard Socié, Jean-Paul Mira
Collection and assembly of data: Frédéric Pène, Cécile Aubron
Data analysis and interpretation: Frédéric Pène, Cécile Aubron, Elie Azoulay, Franois Blot, Guillaume Thiéry, Bruno Raynard, Benot Schlemmer, Gérard Nitenberg, Agnès Buzyn, Philippe Arnaud, Gérard Socié, Jean-Paul Mira
Manuscript writing: Frédéric Pène, Cécile Aubron, Elie Azoulay, Gérard Socié, Jean-Paul Mira
Final approval of manuscript: Frédéric Pène, Cécile Aubron, Elie Azoulay, Franois Blot, Guillaume Thiéry, Bruno Raynard, Benot Schlemmer, Gérard Nitenberg, Agnès Buzyn, Philippe Arnaud, Gérard Socié, Jean-Paul Mira
Acknowledgment
We thank Catherine Chadelat, Armelle Morin, and Isabelle Hirsch for their help in the collection of data.
NOTES
F.P. and C.A. contributed equally to this work and should both be considered as first authors.
Presented in part at the 46th Annual Meeting of the American Society of Hematology, San Diego, CA, December 4-7, 2004.
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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