Biol Blood Marrow Transplant xxx (2014) 1e4
Biology of Blood and Marrow Transplantation journal homepage: www.bbmt.org
Brief Article
Admission of Hematopoietic Cell Transplantation Patients to the Intensive Care Unit at the Pontificia Universidad Católica de Chile Hospital Karen Escobar, Patricio Rojas, Daniel Ernst, Pablo Bertin, Bruno Nervi, Veronica Jara, Maria Jose Garcia, Mauricio Ocqueteau, Mauricio Sarmiento, Pablo Ramirez* Department of Hematology Oncology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
Article history: Received 20 June 2014 Accepted 12 August 2014 Key Words: Hematopoietic cell transplantation Intensive care unit Outcomes
a b s t r a c t Patients undergoing hematopoietic cell transplantation (HCT) can have complications that require management in the intensive care unit (ICU). We conducted a retrospective study of patients undergoing HCT between 2007 and 2011 with admission to the ICU. We analyzed 97 patients, with an average age of 37 (range, 15 to 68). The main indications for HCT were hematologic malignancies (84%, n ¼ 82). Ninety percent (n ¼ 87) received myeloablative conditioning. Thirty-one percent were admitted (autologous transplant recipients 15%, allogeneic transplant recipients 34%, and umbilical cord blood [UCB] transplant recipients 48%) with an average length of stay of 19 days (range, 1 to 73 days). The average time between transplantation and transfer was 15 days. The main causes of admission were acute respiratory failure (63%) and septic shock (20%). ICU mortality was 20% for autologous transplantations and 64% for allogeneic transplantations (adult donor and UCB combined). On average, patients died 108 days after the transplantation (range, 4 to 320 days). One-year overall survival, comparing patients entering the ICU with those never admitted, was 16% versus 82% (P < .0001) for allogeneic transplantations (adult donor and UCB combined) and 80% versus 89% (P ¼ not significant) for autologous transplantations. Acute graft-versus-host disease was significantly associated with death in ICU after UCB HCT. ICU support is satisfactory in about one half of patients admitted, characterized by a short and medium term prognosis not as unfavorable as has been previously reported. Ó 2014 American Society for Blood and Marrow Transplantation.
INTRODUCTION Autologous and allogeneic hematopoietic cell transplantation (HCT) is a potentially curative treatment for many hematologic malignancies and hereditary disorders. However, this therapy is associated with significant morbidity and mortality for the recipient, and between 11% and 40% of patients require admission to the intensive care unit (ICU), according to various reports [1]. Initial series suggested an ominous prognosis over the short and medium term for transplantation patients after a stay in the ICU, especially in those who required ventilation support [2-6]. Overall survival rates at 6 months of less than 5% [7] were reported, giving rise to restrictions and limitations to ICU access or measures of support for these patients [8-12].
Financial disclosure: See Acknowledgments on page 4. * Correspondence and reprint requests: Pablo Ramirez, MD, Department of Hematology Oncology, Lira 85, Piso 4, Laboratorio de Hematologia, Santiago, Chile. E-mail address: [email protected] (P. Ramirez).
http://dx.doi.org/10.1016/j.bbmt.2014.08.009 1083-8791/Ó 2014 American Society for Blood and Marrow Transplantation.
Recently, several studies have been published that suggest that the prognosis of patients with hematological malignancies in the ICU has improved during the last decade [13,14], even in recipients of HCT [15-17]. There are no reports in Chile in this regard, and there is usually a reluctance to admit hematologic or HCT patients to local ICU units, considering older international reports showing poor survival of this population and limitations of resources, especially in public hospitals. In this study, we show for the first time in our country and institution that HCT patients who require ICU care during transplantation perform not as badly as previously reported. PATIENTS AND METHODS This analysis includes all adult HCT patients in the Health Network at the Universidad Católica de Santiago, between January 2007 and December 2011, who required admission to the ICU for any complication resulting from their transplantation during the first year of follow-up. The information was obtained from the database of the HCT unit at the Health Network of the Universidad Católica. Demographic data were extracted and related to the hematologic disease database. We also extracted the conditioning regime used, type of transplantation performed (autologous, allogeneic [related or unrelated], and umbilical cord blood
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K. Escobar et al. / Biol Blood Marrow Transplant xxx (2014) 1e4
Table 1 Patients Demographics Characteristic
All
No. of patients Age, mean (range), yr Diagnosis (n, %) ALL AML NHL HL MM Others Conditioning (n, %) MA RIC
97 33 37 (15-68) 48 (21-68)
Autologous Allogeneic UCB 41 23 33 (17-56) 27 (15-55)
28 20 13 5 13 18
17 13 1 1
(42%) (32%) (2%) (2%) 9 (22%)
11 (48%) 6 (26%) 2 (9%) 4 (17%)
34 (83%) 7 (17%)
23 (100%) -
(29%) (21%) (13%) (5%) (13%) (19%)
87 (90%) 10 (10%)
1 10 4 13 5
(3%) (30%) (12%) (39%) (16%)
30 (91%) 3 (9%)
ALL indicates acute lymphoblastic leukemia; AML, acute myeloid leukemia; NHL, non-Hodgkin lymphoma; HL, Hodgkin lymphoma; MM, multiple myeloma; MA, myeloablative conditioning; RIC, reduced-intensity conditioning.
[UCB]), admission to ICU, time from HCT to admission to the ICU and duration of stay, and mortality in the ICU and during the first year of follow-up. A descriptive analysis of the data obtained follows. Variables are reported as numbers and percentages. Survival curves were obtained using the Kaplan-Meier method and were compared with the log-rank test [18]. The statistical analysis was performed using SPSS software version 21 (IBM Corp., Armonk, NY).
RESULTS Patients Characteristics During the study period, 97 HCT were performed on patients with an average age of 36.9 years (range, 15 to 68). The main indications for HCT were hematologic malignancies (81%, n ¼ 79), with acute leukemias in 50% of cases (n ¼ 48). The main conditioning regimens were myeloablative, which included drugs such as cyclophosphamide, carmustine, melphalan, etoposide, busulfan, and total body irradiation. Demographic data are shown in Table 1. ICU Admission Thirty-one percent of patients (n ¼ 30) required admission to the ICU during the first year after transplantation; the average age was 37.4 years (range, 15 to 58). Specifically, those patients admitted were 15% (n ¼ 5) of patients who underwent autologous HCT, 34% (n ¼ 14) of patients who underwent allogeneic HCT, and 48% (n ¼ 11) of patients who underwent UCB HCT. The average length of stay in the ICU was 19 days (range, 1 to 73 days): 13 days for recipients of autologous HCT, 16 days for recipients of allogeneic HCT, and 22 days for recipients of UCB HCT. The main reasons for admission to the ICU were acute respiratory failure (63%; n ¼ 19), septic shock (20%; n ¼ 6), and neurological complications (13%; n ¼ 4), with a similar distribution between the various types of transplantations. One patient was admitted for acute myocardial infarction. It was not always possible to establish the exact cause of respiratory failure, as this group includes viral, bacterial, and fungal infections and pulmonary hemorrhage. The infections were documented in 24 patients, with the following distribution: bacterial etiology in 13 patients, viral in 4 patients (3 due to a reactivation of cytomegalovirus), and fungal infection in 7 patients (6 patients by invasive aspergillosis). ICU Mortality The proportion of patients admitted to the ICU and dying there was 20% (1 of 5) for autologous HCT patients, 64% (9 of
Figure 1. Number of patients admitted in the ICU versus patients who survive ICU. Overall and according to different transplantation types.
14) for allogeneic HCT patients, and 64% (7 of 11) of UCB HCT patients (Figure 1). On average, patients died 108 days (range, 4 to 320 days) after their transplantation (10, 131, and 119 days for autologous, allogeneic, and UCB HCT, respectively). ICU admissions due to respiratory failure were associated with higher mortality rates than nonrespiratory indications in allogeneic and UCB HCT. Globally, 63% (12 of 19) of patients died when respiratory failure was the reason for ICU admission versus 45% (5 of 11) of patients when nonrespiratory conditions were the indications for ICU admission. Overall, the ICU admission rate was similar between nonengrafted (47%) and engrafted patients (53%). The main causes of death within the ICU were respiratory complications (47%; 9 of 19) and refractory septic shock (21%; 4 of 19), whereas the remainder had various etiologies.
Survival after ICU Discharge Comparing patients who were admitted to the ICU (n ¼ 30) with those not requiring admission to the ICU (n ¼ 67), overall survival (OS) was 26% (8 of 30) and 85% (57 of 67), respectively (P ¼ .0001), 1 year after HCT (Figure 2A). Subgroup analysis showed no differences in OS in patients undergoing autologous HCT who required ICU versus those not requiring ICU, 80% (4 of 5) versus 89% (25 of 28) (P ¼ not significant). However, allogeneic (adult and UCB HCT patients) recipients had significant lower OS when requiring ICU versus those not requiring ICU, 16% (4 of 25) versus 82% (32 of 39) (P < .0001) (Figure 2B,C).
Graft-versus-Host Disease and Risk of Death in the ICU In the allogeneic adult graft group, 36% of patients developed acute graft-versus-host disease (GVHD) (5 of 14 patients at risk): 80% moderate (n ¼ 4; skin) and 20% severe (n ¼ 1; liver). On average, these patients died 174 days after transplantation (range, 50 to 280). Thirty percent of patients developed localized skin chronic GVHD (2 of 7 patients at risk). In the UCB group, 45% of patients developed acute GVHD (5 of 11 patients at risk): 80% moderate (n ¼ 4; liver, skin, and intestine) and 20% severe (n ¼ 1; skin and intestine in 1 patient). All these patients died, on average, 195 days after transplantation (range, 60 to 150). One of 5 patients at risk (20%) developed intestinal chronic GVHD. When comparing ICU deaths in UCB HCT in patients with or without acute GVHD, 50% (4 of 8) of the patients had acute GVHD versus only 13% (1 of 8) of patients without acute GVHD. In adult allogeneic grafts, 36% (5 of 14) of the patients who died had acute GVHD versus 43% (6 of 14) of the patients who did not have acute GVHD.
K. Escobar et al. / Biol Blood Marrow Transplant xxx (2014) 1e4
Figure 2. One-year OS from HCT, comparing ICU admitted patients versus patients not admitted in the ICU. (A) Shows all patients, (B) shows autologous recipients, and (C) shows allogeneic (adult donors and UCB) recipients.
DISCUSSION This study covers a 5-year period and is the first report from a Chilean university transplantation center on patients who underwent HCT and subsequently required admission to the ICU, evaluating the short- and medium-term results. Various studies between 1990 and 2000 described a poor prognosis for HCT patients in the ICU, particularly for those requiring invasive mechanical ventilation (IMV), even casting doubt on the actual benefit of intensive support for this subgroup of patients [8-12]. Currently, there is a large variation in the reported OS rates of patients with hematologic malignancies in the ICU,
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although the results of the studies of better quality and with a greater number of patients describe that approximately 40% of patients survive the hospital stay and that 20% of them are still alive at 6 months. For those patients who underwent some form of HCT, the data are less robust and reported OS in the medium- and long-term is 29% and 15%, respectively [19]. These differences in the results can be explained, at least in part, by the different types of HCT included in the studies, the variation in admission criteria to the ICU and for IMV, as well as in the resources available at each center and therapeutic decisions taken by medical teams. Despite these differences, recent studies suggest a better prognosis for these patients, attributed to various factors, including better support in intensive care units, integrated management by highly specialized multidisciplinary teams, development of new diagnostic and therapeutic strategies, improvements in the selection of patients for HCT, reduction in the intensity of regimen constraints, use of target drugs associated with lower organic toxicity, use of peripheral blood as a source of stem cells, antimicrobial prophylaxis in the period before and after HCT, evolution in the management of GVHD, and the use of colony-stimulating factors [20]. Our study describes an OS rate after 1 year in all patients receiving HCT of 68%. In patients requiring admission to the ICU, 57% died in the unit and 1 year later, 26.7% were still alive, similar to rates reported in contemporary international series [15,21-25]. As in most of the series, in our review the main cause of admission and death in the ICU was respiratory failure, which also was associated with a higher death risk when compared with nonrespiratory indications for ICU admission [15,22,25-27]. Although there is no specific factor to predict mortality in HCT patients, various reports have attempted to assess predictors. IMV and multiorgan failure have been classically described as relevant [15,21-23,25,28,29]. Although acute GVHD only affects a small number of patients, it is interesting to see that in UCB transplantations, there was almost 4 times the risk of death in the ICU when a patient had acute GVHD compared with not having acute GVHD (50% versus 13%, respectively). In contrast, that risk of death was similar in adult allogeneic grafts when comparing the patients who died in the ICU who did or did not present with acute GVHD (36% versus 43%, respectively). One explanation for this is that UCB HCT had more moderate and severe involvement of the intestine and liver compared with only 1 case of severe liver acute GVHD in an adult allogeneic graft recipient. The inherent limitations to our work are the retrospective nature of our study, the small number of patients included, and a single center analysis. However, this is the first study at a national level that evaluates this problem and raises the question, “For how long should a patient undergoing HCT, who requires ICU transfer for any reason, be treated?” Traditionally, in centers across our country, there has been a reluctance to offer these patients ICU care because of significant high mortality rates. Our results suggest that with proper treatment, a significant proportion of HCT patients can be offered adequate outcomes, considering the severity of their complications during their HCT and that in comparison, mortality of ICU nonimmunosuppressed patients with severe sepsis and septic shock has been shown to be between 20% and 40%, which is lower than the HCT population [30,31] but similar to non-HCT neutropenic patients with severe sepsis and septic shock [32]. Our study does not
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K. Escobar et al. / Biol Blood Marrow Transplant xxx (2014) 1e4
answer the question of which patients requiring ICU admission after allogeneic HCT should be denied that option. Although a significant proportion of those patients died in the ICU, roughly 1 of 4 of the other patients survive at least 1 year after the transplantation, and our data do not allow us to identify those patients. However, almost one half of the patients admitted because of respiratory failure died in the ICU compared with 1 of 3 from other causes of admission. In this regard, in cases of other severe complications, such as renal failure with hemodialysis requirement, which is associated with a significant death risk, this could induce limitations of care, as the mortality in this scenario is almost 100% [33,34]. On the other hand, ICU transfer after autologous HCT was not associated with an increased risk of death, so in these patients, care should not be limited upfront. In conclusion, mortality in HCT patients admitted to the ICU in our center is still high, especially after respiratory failure requiring IMV. However, intensive support may be satisfactory in about one half of patients admitted with a prognosis in the short and medium term that is not as unfavorable as has been previously reported, which leads us to offer ICU care to all HCT patients who require it during their transplantation period. ACKNOWLEDGMENT Financial disclosure: The authors have nothing to disclose. Conflict of interest statement: There are no conflicts of interest to report. Authorship Statement: K.E. and P. Rojas authors contributed equally to this work. REFERENCES 1. Pawson H, Jayaweera A, Wigmore T. Intensive care management of patients following haematopoietic stem cell transplantation. Curr Anaesth Crit Care. 2008;19:80-90. 2. Torrecilla C, Cortes JL, Chamorro C, et al. Prognostic assessment of the acute complications of bone marrow transplantation requiring intensive therapy. Intensive Care Med. 1988;14:393-398. 3. Afessa B, Tefferi A, Hoagland HC, et al. Outcome of recipients of bone marrow transplants who require intensive-care unit support. Mayo Clin Proc. 1992;67:117-122. 4. 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. 1998;21: 697-704. 5. 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. 1998;158:876-884. 6. Scott PH, Morgan TJ, Durrant S, Boots RJ. Survival following mechanical ventilation of recipients of bone marrow transplants and peripheral blood stem cell transplants. Anaesth Intensive Care. 2002;30:289-294. 7. Crawford SW, Petersen FB. Long-term survival from respiratory failure after marrow transplantation for malignancy. Am Rev Respir Dis. 1992; 145:510-514. 8. Martin PL. To stop or not to stop: how much support should be provided to mechanically ventilated pediatric bone marrow and stem cell transplant patients? Respir Care Clin N Am. 2006;12:403-419. 9. Lloyd-Thomas AR, Wright I, Lister TA, Hinds CJ. Prognosis of patients receiving intensive care for lifethreatening medical complications of haematological malignancy. Br Med J (Clin Res Ed). 1988;296: 1025-1029. 10. Brunet F, Lanore JJ, Dhainaut JF, et al. Is intensive care justified for patients with haematological malignancies? Intensive Care Med. 1990; 16:291-297.
11. Azoulay E, Recher C, Alberti C, et al. Changing use of intensive care for hematological patients: the example of multiple myeloma. Intensive Care Med. 1999;25:1395-1401. 12. Benoit DD, Vandewoude KH, Decruyenaere JM, et al. Outcome and early prognostic indicators in patients with a hematologic malignancy admitted to the intensive care unit for a life-threatening complication. Crit Care Med. 2003;31:104-112. 13. Peigne V, Rusinova K, Karlin L, et al. Continued survival gains in recent years among critically ill myeloma patients. Intensive Care Med. 2009; 35:512-518. 14. Hill QA. Intensify, resuscitate or palliate: decision making in the critically ill patient with haematological malignancy. Blood Rev. 2010;24: 17-25. 15. 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. 2003;31: 1715-1721. 16. Barnes RA, Stallard N. Severe infections after bone marrow transplantation. Curr Opin Crit Care. 2001;7:362-366. 17. Townsend WM, Holroyd A, Pearce R, et al. Improved intensive care unit survival for critically ill allogeneic haematopoietic stem cell transplant recipients following reduced intensity conditioning. Br J Haematol. 2013;161:578-586. 18. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assn. 1958;53:457-481. 19. McDowall K, Hart A, Cadamy A. The outcomes of adult patients with haematological malignancy requiring admission to the intensive care unit. J Intensive Care Soc. 2011;12:112-125. 20. McArdle JR. Critical care outcomes in the hematologic transplant recipient. Clin Chest Med. 2009;30:155-167. 21. Bach PB, Schrag D, Nierman DM, et al. Identification of poor prognostic features among patients requiring mechanical ventilation after hematopoietic stem cell transplantation. Blood. 2001;98:3234-3240. 22. Soubani AO, Kseibi E, Bander JJ, et al. Outcome and prognostic factors of hematopoietic stem cell transplantation recipients admitted to a medical ICU. Chest. 2004;126:1604-1611. 23. Trinkaus MA, Lapinsky SE, Crump M, et al. Predictors of mortality in patients undergoing autologous hematopoietic cell transplantation admitted to the intensive care unit. Bone Marrow Transplant. 2009;43: 411-415. 24. Hawari FI, Al Najjar TI, Zaru L, et al. The effect of implementing highintensity intensive care unit staffing model on outcome of critically ill oncology patients. Crit Care Med. 2009;37:1967-1971. 25. Pene F, Aubron C, Azoulay E, et al. Outcome of critically ill allogeneic hematopoietic stem-cell transplantation recipients: a reappraisal of indications for organ failure supports. J Clin Oncol. 2006;24:643-649. 26. Afessa B, Azoulay E. Critical care of the hematopoietic stem cell transplant recipient. Crit Care Clin. 2010;26:133-150. 27. Yang TM, Wang PN, Kao KC, et al. Outcome of hematopoietic stem cell recipients who were mechanically ventilated and admitted to intensive care units. J Formos Med Assoc. 2007;106:295-301. 28. Kim SW, Kami M, Urahama N, et al. Feasibility of acute physiology and chronic health evaluation (APACHE) II and III score-based screening in patients receiving allogeneic hematopoietic stem-cell transplantation. Transplantation. 2003;75:566-570. 29. Neumann F, Lobitz O, Fenk R, et al. The sepsis-related Organ Failure Assessment (SOFA) score is predictive for survival of patients admitted to the intensive care unit following allogeneic blood stem cell transplantation. Ann Hematol. 2008;87:299-304. 30. Kaukonen KM, Bailey M, Suzuki S, et al. Mortality related to severe sepsis and septic shock among critically ill patients in Australia and New Zealand, 2000-2012. JAMA. 2014;311:1308-1316. 31. Levy MM, Artigas A, Phillips GS, et al. Outcomes of the surviving sepsis campaign in intensive care units in the USA and Europe: a prospective cohort study. Lancet Infect Dis. 2012;12:919-924. 32. Legrand M, Max A, Peigne V, et al. Survival in neutropenic patients with severe sepsis or septic shock. Crit Care Med. 2012;40:43-49. 33. Kersting S, Koomans HA, Hené RJ, Verdnock LF. Acute renal failure after allogeneic myeloablative stem cell transplantation: retrospective analysis of incidence, risk factors and survival. Bone Marrow Transplant. 2007;39:359-365. 34. Parikh Ch, Schrier R, Storer B, et al. Comparison of ARF after myeloablative and nonmyeloablative hematopoietic cell transplantation. Am J Kidney Dis. 2005;45:502-509.
Biology of Blood and Marrow Transplantation journal homepage: www.bbmt.org
Brief Article
Admission of Hematopoietic Cell Transplantation Patients to the Intensive Care Unit at the Pontificia Universidad Católica de Chile Hospital Karen Escobar, Patricio Rojas, Daniel Ernst, Pablo Bertin, Bruno Nervi, Veronica Jara, Maria Jose Garcia, Mauricio Ocqueteau, Mauricio Sarmiento, Pablo Ramirez* Department of Hematology Oncology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
Article history: Received 20 June 2014 Accepted 12 August 2014 Key Words: Hematopoietic cell transplantation Intensive care unit Outcomes
a b s t r a c t Patients undergoing hematopoietic cell transplantation (HCT) can have complications that require management in the intensive care unit (ICU). We conducted a retrospective study of patients undergoing HCT between 2007 and 2011 with admission to the ICU. We analyzed 97 patients, with an average age of 37 (range, 15 to 68). The main indications for HCT were hematologic malignancies (84%, n ¼ 82). Ninety percent (n ¼ 87) received myeloablative conditioning. Thirty-one percent were admitted (autologous transplant recipients 15%, allogeneic transplant recipients 34%, and umbilical cord blood [UCB] transplant recipients 48%) with an average length of stay of 19 days (range, 1 to 73 days). The average time between transplantation and transfer was 15 days. The main causes of admission were acute respiratory failure (63%) and septic shock (20%). ICU mortality was 20% for autologous transplantations and 64% for allogeneic transplantations (adult donor and UCB combined). On average, patients died 108 days after the transplantation (range, 4 to 320 days). One-year overall survival, comparing patients entering the ICU with those never admitted, was 16% versus 82% (P < .0001) for allogeneic transplantations (adult donor and UCB combined) and 80% versus 89% (P ¼ not significant) for autologous transplantations. Acute graft-versus-host disease was significantly associated with death in ICU after UCB HCT. ICU support is satisfactory in about one half of patients admitted, characterized by a short and medium term prognosis not as unfavorable as has been previously reported. Ó 2014 American Society for Blood and Marrow Transplantation.
INTRODUCTION Autologous and allogeneic hematopoietic cell transplantation (HCT) is a potentially curative treatment for many hematologic malignancies and hereditary disorders. However, this therapy is associated with significant morbidity and mortality for the recipient, and between 11% and 40% of patients require admission to the intensive care unit (ICU), according to various reports [1]. Initial series suggested an ominous prognosis over the short and medium term for transplantation patients after a stay in the ICU, especially in those who required ventilation support [2-6]. Overall survival rates at 6 months of less than 5% [7] were reported, giving rise to restrictions and limitations to ICU access or measures of support for these patients [8-12].
Financial disclosure: See Acknowledgments on page 4. * Correspondence and reprint requests: Pablo Ramirez, MD, Department of Hematology Oncology, Lira 85, Piso 4, Laboratorio de Hematologia, Santiago, Chile. E-mail address: [email protected] (P. Ramirez).
http://dx.doi.org/10.1016/j.bbmt.2014.08.009 1083-8791/Ó 2014 American Society for Blood and Marrow Transplantation.
Recently, several studies have been published that suggest that the prognosis of patients with hematological malignancies in the ICU has improved during the last decade [13,14], even in recipients of HCT [15-17]. There are no reports in Chile in this regard, and there is usually a reluctance to admit hematologic or HCT patients to local ICU units, considering older international reports showing poor survival of this population and limitations of resources, especially in public hospitals. In this study, we show for the first time in our country and institution that HCT patients who require ICU care during transplantation perform not as badly as previously reported. PATIENTS AND METHODS This analysis includes all adult HCT patients in the Health Network at the Universidad Católica de Santiago, between January 2007 and December 2011, who required admission to the ICU for any complication resulting from their transplantation during the first year of follow-up. The information was obtained from the database of the HCT unit at the Health Network of the Universidad Católica. Demographic data were extracted and related to the hematologic disease database. We also extracted the conditioning regime used, type of transplantation performed (autologous, allogeneic [related or unrelated], and umbilical cord blood
2
K. Escobar et al. / Biol Blood Marrow Transplant xxx (2014) 1e4
Table 1 Patients Demographics Characteristic
All
No. of patients Age, mean (range), yr Diagnosis (n, %) ALL AML NHL HL MM Others Conditioning (n, %) MA RIC
97 33 37 (15-68) 48 (21-68)
Autologous Allogeneic UCB 41 23 33 (17-56) 27 (15-55)
28 20 13 5 13 18
17 13 1 1
(42%) (32%) (2%) (2%) 9 (22%)
11 (48%) 6 (26%) 2 (9%) 4 (17%)
34 (83%) 7 (17%)
23 (100%) -
(29%) (21%) (13%) (5%) (13%) (19%)
87 (90%) 10 (10%)
1 10 4 13 5
(3%) (30%) (12%) (39%) (16%)
30 (91%) 3 (9%)
ALL indicates acute lymphoblastic leukemia; AML, acute myeloid leukemia; NHL, non-Hodgkin lymphoma; HL, Hodgkin lymphoma; MM, multiple myeloma; MA, myeloablative conditioning; RIC, reduced-intensity conditioning.
[UCB]), admission to ICU, time from HCT to admission to the ICU and duration of stay, and mortality in the ICU and during the first year of follow-up. A descriptive analysis of the data obtained follows. Variables are reported as numbers and percentages. Survival curves were obtained using the Kaplan-Meier method and were compared with the log-rank test [18]. The statistical analysis was performed using SPSS software version 21 (IBM Corp., Armonk, NY).
RESULTS Patients Characteristics During the study period, 97 HCT were performed on patients with an average age of 36.9 years (range, 15 to 68). The main indications for HCT were hematologic malignancies (81%, n ¼ 79), with acute leukemias in 50% of cases (n ¼ 48). The main conditioning regimens were myeloablative, which included drugs such as cyclophosphamide, carmustine, melphalan, etoposide, busulfan, and total body irradiation. Demographic data are shown in Table 1. ICU Admission Thirty-one percent of patients (n ¼ 30) required admission to the ICU during the first year after transplantation; the average age was 37.4 years (range, 15 to 58). Specifically, those patients admitted were 15% (n ¼ 5) of patients who underwent autologous HCT, 34% (n ¼ 14) of patients who underwent allogeneic HCT, and 48% (n ¼ 11) of patients who underwent UCB HCT. The average length of stay in the ICU was 19 days (range, 1 to 73 days): 13 days for recipients of autologous HCT, 16 days for recipients of allogeneic HCT, and 22 days for recipients of UCB HCT. The main reasons for admission to the ICU were acute respiratory failure (63%; n ¼ 19), septic shock (20%; n ¼ 6), and neurological complications (13%; n ¼ 4), with a similar distribution between the various types of transplantations. One patient was admitted for acute myocardial infarction. It was not always possible to establish the exact cause of respiratory failure, as this group includes viral, bacterial, and fungal infections and pulmonary hemorrhage. The infections were documented in 24 patients, with the following distribution: bacterial etiology in 13 patients, viral in 4 patients (3 due to a reactivation of cytomegalovirus), and fungal infection in 7 patients (6 patients by invasive aspergillosis). ICU Mortality The proportion of patients admitted to the ICU and dying there was 20% (1 of 5) for autologous HCT patients, 64% (9 of
Figure 1. Number of patients admitted in the ICU versus patients who survive ICU. Overall and according to different transplantation types.
14) for allogeneic HCT patients, and 64% (7 of 11) of UCB HCT patients (Figure 1). On average, patients died 108 days (range, 4 to 320 days) after their transplantation (10, 131, and 119 days for autologous, allogeneic, and UCB HCT, respectively). ICU admissions due to respiratory failure were associated with higher mortality rates than nonrespiratory indications in allogeneic and UCB HCT. Globally, 63% (12 of 19) of patients died when respiratory failure was the reason for ICU admission versus 45% (5 of 11) of patients when nonrespiratory conditions were the indications for ICU admission. Overall, the ICU admission rate was similar between nonengrafted (47%) and engrafted patients (53%). The main causes of death within the ICU were respiratory complications (47%; 9 of 19) and refractory septic shock (21%; 4 of 19), whereas the remainder had various etiologies.
Survival after ICU Discharge Comparing patients who were admitted to the ICU (n ¼ 30) with those not requiring admission to the ICU (n ¼ 67), overall survival (OS) was 26% (8 of 30) and 85% (57 of 67), respectively (P ¼ .0001), 1 year after HCT (Figure 2A). Subgroup analysis showed no differences in OS in patients undergoing autologous HCT who required ICU versus those not requiring ICU, 80% (4 of 5) versus 89% (25 of 28) (P ¼ not significant). However, allogeneic (adult and UCB HCT patients) recipients had significant lower OS when requiring ICU versus those not requiring ICU, 16% (4 of 25) versus 82% (32 of 39) (P < .0001) (Figure 2B,C).
Graft-versus-Host Disease and Risk of Death in the ICU In the allogeneic adult graft group, 36% of patients developed acute graft-versus-host disease (GVHD) (5 of 14 patients at risk): 80% moderate (n ¼ 4; skin) and 20% severe (n ¼ 1; liver). On average, these patients died 174 days after transplantation (range, 50 to 280). Thirty percent of patients developed localized skin chronic GVHD (2 of 7 patients at risk). In the UCB group, 45% of patients developed acute GVHD (5 of 11 patients at risk): 80% moderate (n ¼ 4; liver, skin, and intestine) and 20% severe (n ¼ 1; skin and intestine in 1 patient). All these patients died, on average, 195 days after transplantation (range, 60 to 150). One of 5 patients at risk (20%) developed intestinal chronic GVHD. When comparing ICU deaths in UCB HCT in patients with or without acute GVHD, 50% (4 of 8) of the patients had acute GVHD versus only 13% (1 of 8) of patients without acute GVHD. In adult allogeneic grafts, 36% (5 of 14) of the patients who died had acute GVHD versus 43% (6 of 14) of the patients who did not have acute GVHD.
K. Escobar et al. / Biol Blood Marrow Transplant xxx (2014) 1e4
Figure 2. One-year OS from HCT, comparing ICU admitted patients versus patients not admitted in the ICU. (A) Shows all patients, (B) shows autologous recipients, and (C) shows allogeneic (adult donors and UCB) recipients.
DISCUSSION This study covers a 5-year period and is the first report from a Chilean university transplantation center on patients who underwent HCT and subsequently required admission to the ICU, evaluating the short- and medium-term results. Various studies between 1990 and 2000 described a poor prognosis for HCT patients in the ICU, particularly for those requiring invasive mechanical ventilation (IMV), even casting doubt on the actual benefit of intensive support for this subgroup of patients [8-12]. Currently, there is a large variation in the reported OS rates of patients with hematologic malignancies in the ICU,
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although the results of the studies of better quality and with a greater number of patients describe that approximately 40% of patients survive the hospital stay and that 20% of them are still alive at 6 months. For those patients who underwent some form of HCT, the data are less robust and reported OS in the medium- and long-term is 29% and 15%, respectively [19]. These differences in the results can be explained, at least in part, by the different types of HCT included in the studies, the variation in admission criteria to the ICU and for IMV, as well as in the resources available at each center and therapeutic decisions taken by medical teams. Despite these differences, recent studies suggest a better prognosis for these patients, attributed to various factors, including better support in intensive care units, integrated management by highly specialized multidisciplinary teams, development of new diagnostic and therapeutic strategies, improvements in the selection of patients for HCT, reduction in the intensity of regimen constraints, use of target drugs associated with lower organic toxicity, use of peripheral blood as a source of stem cells, antimicrobial prophylaxis in the period before and after HCT, evolution in the management of GVHD, and the use of colony-stimulating factors [20]. Our study describes an OS rate after 1 year in all patients receiving HCT of 68%. In patients requiring admission to the ICU, 57% died in the unit and 1 year later, 26.7% were still alive, similar to rates reported in contemporary international series [15,21-25]. As in most of the series, in our review the main cause of admission and death in the ICU was respiratory failure, which also was associated with a higher death risk when compared with nonrespiratory indications for ICU admission [15,22,25-27]. Although there is no specific factor to predict mortality in HCT patients, various reports have attempted to assess predictors. IMV and multiorgan failure have been classically described as relevant [15,21-23,25,28,29]. Although acute GVHD only affects a small number of patients, it is interesting to see that in UCB transplantations, there was almost 4 times the risk of death in the ICU when a patient had acute GVHD compared with not having acute GVHD (50% versus 13%, respectively). In contrast, that risk of death was similar in adult allogeneic grafts when comparing the patients who died in the ICU who did or did not present with acute GVHD (36% versus 43%, respectively). One explanation for this is that UCB HCT had more moderate and severe involvement of the intestine and liver compared with only 1 case of severe liver acute GVHD in an adult allogeneic graft recipient. The inherent limitations to our work are the retrospective nature of our study, the small number of patients included, and a single center analysis. However, this is the first study at a national level that evaluates this problem and raises the question, “For how long should a patient undergoing HCT, who requires ICU transfer for any reason, be treated?” Traditionally, in centers across our country, there has been a reluctance to offer these patients ICU care because of significant high mortality rates. Our results suggest that with proper treatment, a significant proportion of HCT patients can be offered adequate outcomes, considering the severity of their complications during their HCT and that in comparison, mortality of ICU nonimmunosuppressed patients with severe sepsis and septic shock has been shown to be between 20% and 40%, which is lower than the HCT population [30,31] but similar to non-HCT neutropenic patients with severe sepsis and septic shock [32]. Our study does not
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answer the question of which patients requiring ICU admission after allogeneic HCT should be denied that option. Although a significant proportion of those patients died in the ICU, roughly 1 of 4 of the other patients survive at least 1 year after the transplantation, and our data do not allow us to identify those patients. However, almost one half of the patients admitted because of respiratory failure died in the ICU compared with 1 of 3 from other causes of admission. In this regard, in cases of other severe complications, such as renal failure with hemodialysis requirement, which is associated with a significant death risk, this could induce limitations of care, as the mortality in this scenario is almost 100% [33,34]. On the other hand, ICU transfer after autologous HCT was not associated with an increased risk of death, so in these patients, care should not be limited upfront. In conclusion, mortality in HCT patients admitted to the ICU in our center is still high, especially after respiratory failure requiring IMV. However, intensive support may be satisfactory in about one half of patients admitted with a prognosis in the short and medium term that is not as unfavorable as has been previously reported, which leads us to offer ICU care to all HCT patients who require it during their transplantation period. ACKNOWLEDGMENT Financial disclosure: The authors have nothing to disclose. Conflict of interest statement: There are no conflicts of interest to report. Authorship Statement: K.E. and P. Rojas authors contributed equally to this work. REFERENCES 1. Pawson H, Jayaweera A, Wigmore T. Intensive care management of patients following haematopoietic stem cell transplantation. Curr Anaesth Crit Care. 2008;19:80-90. 2. Torrecilla C, Cortes JL, Chamorro C, et al. Prognostic assessment of the acute complications of bone marrow transplantation requiring intensive therapy. Intensive Care Med. 1988;14:393-398. 3. Afessa B, Tefferi A, Hoagland HC, et al. Outcome of recipients of bone marrow transplants who require intensive-care unit support. Mayo Clin Proc. 1992;67:117-122. 4. 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. 1998;21: 697-704. 5. 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. 1998;158:876-884. 6. Scott PH, Morgan TJ, Durrant S, Boots RJ. Survival following mechanical ventilation of recipients of bone marrow transplants and peripheral blood stem cell transplants. Anaesth Intensive Care. 2002;30:289-294. 7. Crawford SW, Petersen FB. Long-term survival from respiratory failure after marrow transplantation for malignancy. Am Rev Respir Dis. 1992; 145:510-514. 8. Martin PL. To stop or not to stop: how much support should be provided to mechanically ventilated pediatric bone marrow and stem cell transplant patients? Respir Care Clin N Am. 2006;12:403-419. 9. Lloyd-Thomas AR, Wright I, Lister TA, Hinds CJ. Prognosis of patients receiving intensive care for lifethreatening medical complications of haematological malignancy. Br Med J (Clin Res Ed). 1988;296: 1025-1029. 10. Brunet F, Lanore JJ, Dhainaut JF, et al. Is intensive care justified for patients with haematological malignancies? Intensive Care Med. 1990; 16:291-297.
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