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ORIGINAL ARTICLE Sequential Organ Failure Assessment predicts the outcome of SCT recipients admitted to

K Gilli1, M Remberger2, H Hjelmqvist1,3, O Ringden2,4 and J Mattsson2,4

1Department for Anaesthesiology and Intensive Care , Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden; 2Department of Clinical Immunology, Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden; 3Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden and 4Center for Allogeneic Stem Cell Transplantation, Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden

We analyzed all patients undergoing allogeneic stem cell Introduction transplantation (ASCT) and transferred to the intensive care unit (ICU) from January 1995 to December 2005. The question if and when patients undergoing allogeneic stem During this period, 661 patients underwent ASCT at our cell transplantation (ASCT) should be transferred to an center. A total of 91 patients were admitted to the ICU. intensive care unit (ICU) is controversial. Several variables Median time from ASCT to ICU admission was 69 days have been associated with mortality in ASCT patients (À24 to 1572) and median stay at the ICU was 4 transferred to the ICU. Most common are patients requiring (1–60) days. The survival after transfer to the ICU at day , multiorgan failure and .1 100 and at 1 year was 22 and 16%, respectively. Median Despite the poor prognosis, survival after ICU care has been Sequential Organ Failure Assessment (SOFA) score reported.2–4 Since 1998, the survival of ASCT patients treated was 10 (1–17). Patients with SOFA score o8(n ¼ 18) in the ICU has improved, probably attributed to improve- had a 44% survival compared with 17% with SOFA score ments in ASCT treatment, patient selection and ICU 8–11 (n ¼ 30) and no survival with SOFA score 411 management.1 At the ICU, more sophisticated ventilation (n ¼ 20) (P ¼ 0.0002). None of the 14 retransplanted strategies have been developed,5 such as invasive and patients survived compared with 31% among patients noninvasive ventilation (NIV), and early goal-directed after first ASCT (P ¼ 0.006). Patients receiving TBI had therapy (EGDT).6 The latter means that patients should be a lower survival compared with patients treated with stabilized to normal physiological level as soon as possible at chemotherapy only (14 vs 45%, P ¼ 0.02). Patients the ICU. Reduced-intensity conditioning (RIC) regimens needing vasopressor support had a worse survival, 15 vs before ASCT have resulted in less toxicity.7 Molecular 41%, compared with patients without vasopressor treat- , more effective prophylaxis and preemptive ment (P ¼ 0.01). In multivariate analysis of death, SOFA treatment strategies of various infections have been developed score was the only significant factor (Po0.001). In during the past decade, improving survival after ASCT.8,9 conclusion, SOFA score predicted prognosis in ASCT Traditional prognostic systems such as acute physiological patients treated at the ICU. and chronic health evaluation (APACHE) have shown limited Bone Marrow Transplantation (2010) 45, 682–688; value in ASCT patients.1 APACHE II underestimated survival doi:10.1038/bmt.2009.220; published online 31 August 2009 in patients with scores less than 35, and could only be used to Keywords: SOFA; intensive care unit; SCT; allogeneic; predict 100% mortality when it exceeded 45.10 Sequential APACHE; survival Organ Failure Assessment (SOFA) showed good correlation to prognosis in other patient groups.11–13 The primary aim of this study was to analyze the incidence and outcome of all ASCT patients transferred to the ICU at our center between 1995 and 2005. The secondary aim was to find a tool to monitor the prognosis of ASCT patients admitted to the ICU. A valid prognostic factor for these patients may be useful in deciding whether an ICU treatment should be started and also whether ICU therapy should be discontinued in deteriorating patients.

Correspondence: Dr J Mattsson, Department of Clinical Science, Center for Allogeneic Stem Cell Transplantation, Karolinska Institutet, Patients and methods Karolinska University Hospital, Huddinge, Stockholm SE-141 86, Sweden. E-mail: [email protected] Patients Received 5 February 2009; revised 8 July 2009; accepted 10 July 2009; A total of 661 patients received ASCT at Karolinska published online 31 August 2009 University Hospital, Huddinge between 1 January 1995 SOFA predicts outcome of ICU care after SCT K Gilli et al 683 Table 1 Characteristics of the 91 patients treated at ICU GVHD prophylaxis A total of 73 patients received a combination of CsA and All patients MTX as GVHD prophylaxis.16,17 In the absence of GVHD, Diagnoses CsA was discontinued after 6 months for patients who Non-malignant 9 received a matched unrelated donor or mismatched grafts, Acute leukemia 43 and after 3–4 months in the case of sibling transplant- Chronic leukemia 17 18 Other malignancy 15 ations. For patients with non-malignant disease, immu- Solid tumor 7 nosuppressive treatment was discontinued within 2 years.

Disease stage (early/late) 42/44 Previous SCT 14 (15%) Supportive care During the pancytopenic phase, all patients received Age 34 (1–67) prophylactic treatment with oral ciprofloxacin (500 mg Children o18 years 26 (29%) twice daily), fluconazole (100 mg daily) and nystatin 9 Sex (M/F) 51/40 (200 000 IU, 4 times daily) until ANC exceeded 0.5 Â 10 / liter. Details regarding supportive care were published Donor earlier.8 HLA-id related 31 MUD 46 Mismatched 14 Donor sex (M/F) 49/39 ICU scoring systems Donor age 37 (0–71) Patients younger than 15 years were not included in the analysis concerning ICU scoring systems. To monitor FD to MR 17 (19%) the patients at the ICU, the APACHE II and the SOFA SC source (BM/PBSC/CB) 44/42/5 scores were used. The SOFA score assesses the function of SC dose ( Â 108/kg) 4.8 (0.2–25.8) CD34+ ( Â 106/kg) 6.6 (0.2–32.8) six different organ systems: respiratory (partial arterial oxygen pressure (PaO2)/fraction of inspired oxygen (FiO2)), GVHD prophylaxis cardiovascular (, vasopressor use), renal No 1 (creatinine and diuresis), hepatic (bilirubin), neurological CsA+MTX 73 CsA+Pred 9 (Glasgow Score) and hematological (platelet count). TcD 4 Normally, it was calculated once daily using the most Other combinations 4 abnormal data from the preceding 24 h and given a score from 0 (normal) to 4 (most abnormal) in each organ Conditioning system.19 SOFA and APACHE II scores were calculated TBI based 44 Chemotherapy 28 retrospectively for the first day at the ICU using the initial RIC 19 blood samples and patient clinical status at ICU arrival. ATG 63 (69%)

Abbreviations: ATG ¼ antithymocyte globulin; CB ¼ cord blood; F ¼ female; ICU treatment FD to MR ¼ female donor to male recipient; HLA-id ¼ HLA-identical; The ventilation used at the ICU was distributed in three M ¼ male; MUD ¼ matched unrelated donor; Pred ¼ prednisolon; groups. All patients with spontaneous breathing, only RIC ¼ reduced-intensity conditioning; SC ¼ stem cell; TcD ¼ T-cell depletion. needing extra oxygen, were classified as spontaneous breathing. In the group with NIV, the most common and 31 December 2005. Of them, 91 patients (14%) were ventilation mode was continuous positive airway pressure admitted to the ICU during this period, and 4 patients were (CPAP) with assisted spontaneous breathing (CPAP-ASB). transferred to the ICU twice. The diagnoses for patients In the beginning of the studied period, pure CPAP without admitted to the ICU were hematological malignancies pressure assist was used. In the past years, CPAP was (n ¼ 65), solid tumors (n ¼ 7) and non-malignant diseases replaced by CPAP-ASB in our ICU. The third group, (n ¼ 9). Twenty-six patients (29%) were younger than 18 invasive ventilation, was defined by an intubation. In the years of age at the time of ASCT. Patient and donor beginning of the 11-year period studied, the dominating characteristics are shown in Table 1. ventilation mode was continuous positive pressure ventila- tion, which has been replaced by more lung-protective ventilation strategies such as BiPAB and CPAP-ASB. Conditioning The ventilation strategies with lower tidal volumes as A majority of patients received myeloablative conditioning recommended in the study from the ARDS network were (n ¼ 72). The myeloablative conditioning regimens con- implemented.5 A few patients received airway pressure sisted of CY (60 mg/kg daily) for 2 days in combination release ventilation (APRV). with either 10 Gy single-dose TBI or 12 Gy (4 Â 3 Gy) of As vasopressor/inotropy, was used alone fractionated TBI, or BU (4 mg/kg per day, divided in or in combination with epinephrine. Circulatory monitor- 4 doses). Nineteen patients received RIC.14 Sixty-three ing was performed with measurement of the arterial blood patients (69%) were treated with antithymocyte globulin pressure and central venous pressure. In the past years, (ATG) Thymoglobulin; Genzyme, Cambridge, MN, USA), transthoracic echocardiography was used to judge the for 3–5 days at a total dose of 4–8 mg/kg.15 cardiac output and volume status.

Bone Marrow Transplantation SOFA predicts outcome of ICU care after SCT K Gilli et al 684 Fluid and volume substitution was initially performed by patients received at admission or after admission albumin (4 and 20%); in the past years, albumin was to the ICU (Table 3). A majority of patients were also replaced by synthetic colloids such as hydroxyethylstarch. treated with antifungal and antiviral drugs. During ICU As crystalloid administration, Ringeracetat was used. treatment, the majority of patients were transfusion If needed, continuous venovenous hemodiafiltration dependent as shown in Table 3. (CVVHDF) was used as renal replacement therapy. All patients transferred to the ICU who needed respiratory support were classified as a , and patients ICU treatment with bacteremia and symptoms such as circulatory Patients were admitted to the ICU median 69 (À24 to 1572) instability, signs of systemic inflammation and dissemi- days after ASCT. One patient was at the ICU already nated intravasal coagulation were classified as . before ASCT. The median stay at the ICU was 4 (1–60) days. During the ICU treatment, five patients required renal replacement therapy with CVVHDF. Vasoactive and/ Statistics or inotropic agent support was used in 55 cases (58%) Analysis was performed in September 2006. Survival rates (Table 3). (death at ICU or within 30 days after discharge from ICU) were calculated using the method of Kaplan–Meier and compared with the log-rank method. In the four patients Respiration treatment treated twice at the ICU, only the last treatment period was Twenty-two patients (23%) were given inhalation of

counted. In the multivariate analysis of factors associated oxygen up to 15 liter/min (FiO2 1.0) presented by mask. with death at the ICU, the Cox regression method was In the beginning of the study period, NIV was not used. Death at the ICU or within 30 days after discharge developed. Therefore, intubation had to be performed if from the ICU was a censoring variable and time from treatment with inhalation of oxygen was not successful. admittance to the ICU until death or last follow-up was In the later years, respiratory support was in most cases calculated. A step-wise backward procedure was used to construct a set of independent predictors for death at the ICU. All predictors with a P-value below 0.10 were Table 3 Characteristics of patients at admission and treatment considered and sequentially removed if the P-value in the at ICU multiple models was above 0.05. All tests were two sided. No. of days at ICU 4 (1–60) The type I error rate was fixed at 0.05 for factors potentially Days SCT to ICU 69 (À24 to 1572) associated with time-to-event outcome. Analyses were Days ICU to death 14 (0–612) performed using the Statistica software (Tulsa, OK, USA). Death at ICU 53 (56%) Death o30 days after ICU 14 (15%) APACHE II 19 (6–30) Adj. pred. death 34.8 (2–100) Results SOFA 10 (1–17)

PO2 10.35 (3.9–44.0) P Reasons for ICU admission CO2 4.98 (2.7–4.02) pH 7.39 (6.98–7.59) A total of 39 patients (41%) were admitted because of BE À3.6 (À15.8 to 11.6) respiratory failure, and 29 patients (31%) because of septic Antibiotics 90 (95%) shock (Table 2). Eleven patients (12%) were transferred to Antifungal treatment 75 (79%) the ICU after neurological events such as seizures and Antiviral treatment 68 (72%) intracerebral bleeding. Immunosuppression 87 (92%) Respiratory Spontaneous 22 (23%) Transplant-related complications at transfer to ICU CPAP 27 (28) Acute GVHD grades II–IV were diagnosed in 44 patients Tube 46 (48%) (48%) before admission to the ICU. The majority (92%) of the transferred patients also received immunosuppressive Renal replacement therapy 5/5 treatment (Table 3). Ten patients had veno-occlusive Inotropic agents/vasoactive drugs 55 (58%) Albumin 42 (44%) disease (VOD) of the . Bacteremia was diagnosed in HAES 16 (17%) 54 patients (59%) before ICU treatment and 95% of the Dextran 6 (6%) Plasma transfusion 52 (56%) Erythrocyte transfusion 66 (69%) Platelet transfusion 56 (59%) Table 2 Reasons for transfer to the ICU

Respiratory failure 39 (41%) Abbreviations: Adj. pre. Death ¼ adjusted predicted death rate (predicted Septic shock 29 (31%) death in percent after APACHE score correlated to the ICU admission Neurological 11 (12%) reason); APACHE score ¼ acute physiological and chronic health evalua- Hemolysis 1 tion; BE ¼ base excess in arterial blood sample; CPAP ¼ continuous Liver failure 1 positive airway pressure; Dextran ¼ Dextran70 infusion as colloid; Hemorrhages 1 HAES ¼ hydroxyetylstarch (130/0.4); ICU ¼ intensive care unit; 1 PCO2 ¼ partial carbon dioxide pressure in arterial blood sample; pH ¼ pH Other 12 (13%) in arterial blood sample; PO2 ¼ partial oxygen pressure in arterial blood sample; SOFA ¼ Sequential Organ Failure Assessment.

Bone Marrow Transplantation SOFA predicts outcome of ICU care after SCT K Gilli et al 685 started with NIV. Twenty-seven patients (29%) remained allogeneic or autologous) showed a poor prognosis. None on NIV because of successful therapy or in some cases of the 14 retransplanted patients survived compared with because of the active decision not to perform an intubation 31% among patients after first SCT (P ¼ 0.006; Figure 4b). owing to the poor prognosis of the actual patient. Forty-six Patients receiving TBI-based pretreatment showed signifi- patients (48%) underwent intubation (Table 3). Patients cantly lower survival compared with patients receiving without respiratory support had a survival of 32%, chemotherapy, 14 vs 45% survival at 2 months after compared with 20% (P ¼ 0.28) in patients needing mechan- discharge from ICU (P ¼ 0.01; Figure 4c). Reasons for ICU ical ventilation. For patients with mechanical ventilation, admission did not show any impact on survival as shown in survival was 15% before and 24% (NS) after the year 2000. Figure 5. For patients without respiratory support, survival was 25 Thirty-five patients (38%) were admitted to the ICU and 41% (NS), respectively. more than 100 days after ASCT. Survival for these patients did not differ from patients admitted to the ICU within 100 days after ASCT (20 vs 30%, P ¼ 0.54). Prognostic scoring systems The median APACHE II score for the first 24 h at admission to the ICU was 19 (6–30). Patients with adjusted Multivariate analysis predicted death rate p20 showed significantly better In the multivariate analysis of factors associated with death survival compared with patients with APACHE score at the ICU or within 30 days after discharge from the ICU, 420 (53 vs 20%, P ¼ 0.004), illustrated in Figure 1. only the SOFA score remained significant (RH, 1.18; CI, The median SOFA score for the first 24 h after admission 1.10–1.27; Po0.001). to the ICU was 10 (1–17). Patients with SOFA o8 showed a cumulative survival of 44% compared with 17% in patients with SOFA 8–11. None of the 20 patients admitted 1.0 ≤ to the ICU with SOFA score 411 survived (P 0.0002; Adults 15y ¼ 0.9 Figure 2). 0.8 0.7 Survival 0.6 SOFA <8, n =18, 44% Fifty-three patients died during their ICU admission and an additional 14 patients (15%) within 1 month after 0.5 discharge from the ICU. Twenty-eight (30%) patients 0.4 survived more than 1 month after discharge from the ICU. 0.3 SOFA 8-11, n=30, 17% At 100 days and 1 year after admission to the ICU, 22 and 0.2 16%, respectively, were alive (Figure 3). 0.1 P =0.0002 There was a trend for better survival among children Cumulative proportion surviving SOFA >11, n=20, 0% (o18 years) compared with adults (46 vs 18%, P ¼ 0.07). 0.0 Patients needing vasoactive agents showed a lower 0 10 20 30 40 50 60 70 survival compared with patients without vasopressor Days after ICU admission support (18 vs 43%, P ¼ 0.01; Figure 4a). Patients who Figure 2 Survival of allogeneic stem cell transplantation (ASCT) needed ICU treatment after retransplantation (either recipients related to an SOFA score at admission to the intensive care unit (ICU). SOFA: Sequential Organ Failure Assessment. Only death at the ICU or within 30 days after discharge from the ICU was counted.

1.0 0.9

0.8 1.0 0.7 P=0.004 Adj Pred ≤ 20 n=17, 53% 0.9 0.6 0.8 0.5 0.7 100 days, 22% 1 year, 16% 0.4 0.6 Adj Pred >20 n=65, 20% 0.3 0.5 0.2 0.4 0.1 0.3 Cumulative proportion surviving 0.0 07010 20 30 40 50 60 0.2 Days after ICU admission 0.1 Cumulative proportion surviving 0.0 Figure 1 Survival of allogeneic stem cell transplantation (ASCT) patients 01825365 730 1095 1460 at the intensive care unit (ICU) related to the adjusted predicted death rate Days after ICU admission using APACHE II at admission to the ICU. APACHE, acute physiological and chronic health evaluation. Only death at the ICU or within 30 days Figure 3 Overall survival of allogeneic stem cell transplantation (ASCT) after discharge from the ICU was counted. recipients admitted to the intensive care unit (ICU).

Bone Marrow Transplantation SOFA predicts outcome of ICU care after SCT K Gilli et al 686 1.0 1.0 0.9 0.9 0.8 P=0.01 0.8 P =0.006 0.7 0.7 0.6 No vasopressor = 37, 41% 0.6 0.5 0.5 First SCT n =77, 31% 0.4 0.4

surviving Vasopressor = 53, 15% 0.3 surviving 0.3 0.2 0.2 Second SCT n =14, 0%

Cumulative proportion 0.1 0.1 Cumulative proportion 0.0 0.0 07010 20 30 40 50 60 07010 20 30 40 50 60 Days after ICU admission Days after ICU admission

1.0 0.9 0.8 P =0.02 0.7 0.6 0.5 No TBI n =40, 45% 0.4 surviving 0.3 TBI n =51, 14% 0.2 0.1 Cumulative proportion 0.0 07010 20 30 40 50 60 Days after ICU admission Figure 4 Survival after admission to the intensive care unit (ICU) depending on (a) vasopressor use or not, (b) TBI as part of the conditioning or chemotherapy alone and (c) first transplantation or retransplantation after earlier allogeneic or autologous transplantation. Only death at the ICU or within 30 days after discharge from the ICU was counted.

1.0 recipients has been shown.1,3,23,24 This is probably because of improved therapy.1,4,9,25 The development of new 0.8 respiratory strategies has improved the outcome of ICU patients with ARDS and respiratory failure.5 This may be one reason for the improved outcome of ASCT recipients 0.6 in the ICU. Other reasons for improved survival may involve less toxic conditioning regimens, better treatment of infectious complications and other transplant-related com- 0.4 Other n =16 plications such as VOD and improved supportive care for Septic shock n =29 visceral organ injury.1,9,17 0.2 Respiratory insuff. n =39 Patients admitted to the ICU who received TBI in the Neurological n =11 conditioning regimen did worse compared with patients

Cumulative proportion surviving receiving chemotherapy as conditioning. However, in an 0.0 earlier randomized study by the Nordic Bone Marrow 0 14 28 42 56 70 84 Transplantation group, a comparison of TBI/CY with Days after ICU admission BUCY showed that the latter was more toxic with more Figure 5 Survival after admission to the intensive care unit (ICU) VOD, chronic GVHD and obstructive bronchiolitis.26 depending on the reason for ICU transfer. Four patients were treated In several earlier studies, the incidence and fatalities of twice at the ICU. These patients were treated as alive until they were interstitial pneumonia after ASCT were similar between admitted to the ICU for the second time. The second ICU treatment period 27,28 was calculated from the second ICU admittance until death or the last TBI/CY and BUCY. The most plausible explanation follow-up. Only death at the ICU or within 30 days after discharge from may be that TBI is given above all to patients with acute the ICU was counted. lymphocytic leukemia, in most cases heavily treated before ASCT. In an earlier study by Kew et al.,23 the probability of survival for patients receiving vasopressor support was 5% Discussion at 30 days compared with 76.5% survival in patients not given vasopressor support. This was also recently shown by The indication for the use of ICU treatment and invasive Trinkaus et al.29 in patients after autologous SCT. The need ventilation for patients undergoing ASCT has been for vasopressors may therefore be a useful prognostic tool discussed since decades. Earlier studies have questioned in identifying ASCT patients with poor survival. Indeed, in whether patients after ASCT should even be transferred to this study, patients with vasopressor support showed a the ICU for mechanical respiratory support.2,10,20–22 How- worse survival (15%) compared with patients without ever, in more recent studies, a better prognosis for ASCT vasoactive agents (41%).

Bone Marrow Transplantation SOFA predicts outcome of ICU care after SCT K Gilli et al 687 No patient receiving a second ASCT and admitted to the Acknowledgements ICU survived. Second transplantation has earlier been associated with high transplant-related mortality, although We thank the staff at the Centre for Allogeneic Stem Cell patients of young age (o16 years), those with absence of Transplantation and at the Department for and GVHD and patients with late relapse (412 months) do for competent and compassionate care better.30 In this study, retransplantation indicates a poor of the patients. prognosis in patients transferred to the ICU and may be included in deciding whether ICU treatment should be applied. References We found a primary ICU survival of ASCT patients of 44% and a 30-day survival of 29%. The 1-year survival was 1 Naeem N, Reed MD, Creger RJ, Youngner SJ, Lazarus HM. still poor with 16% but comparable with other studies in Transfer of the hematopoietic stem cell transplant patient to ASCT recipients.1,3,23,24 However, the results of treating the intensive care unit: does it really matter? Bone Marrow ASCT patients in the ICU are poor in comparison with Transplant 2006; 37: 119–133. ICU treatment of non-transplanted patients, with a 1-year 2 Afessa B, Tefferi A, Hoagland HC, Letendre L, Peters SG. survival of 95% for patients with ICU treatment less than 5 Outcome of recipients of bone marrow transplants who require 31 10 intensive-care unit support. Mayo Clin Proc 1992; 67: 117–122. days. In accordance with Jackson et al., we found an 3 Diaz MA, Vicent MG, Prudencio M, Rodriguez F, Marin C, underestimation of the mortality in this patient group by Serrano A et al. Predicting factors for admission to an APACHE II. 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The Acute Respiratory ICU. With a SOFA score of 8–11, the mortality was 83% Distress Syndrome Network. N Engl J Med 2000; 342: compared with 56% in patients with SOFAo8. Therefore, 1301–1308. a consultation with ICU physicians may be considered 6 Otero RM, Nguyen HB, Huang DT, Gaieski DF, Goyal M, before patients reach a SOFA of 8. For patients with an Gunnerson KJ et al. Early goal-directed therapy in severe SOFA score above 11, ICU care may not be an option. and septic shock revisited: concepts, controversies, and There are several limitations in this study. This is a contemporary findings. Chest 2006; 130: 1579–1595. retrospective study without any stipulated criteria for ICU 7 Baron F, Storb R. Allogeneic hematopoietic cell transplant- admission. There may have been considerable variation ation following nonmyeloablative conditioning as treatment among ASCT and ICU physicians in considering and for hematologic malignancies and inherited blood disorders. 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