Copyright Blackwell Munksgaard 2005 Eur J Haematol 2005: 74: 511–516 All rights reserved EUROPEAN JOURNAL OF HAEMATOLOGY Sequential organ failure predicts mortality of patients with a haematological malignancy needing intensive care Cornet AD, Issa AI, van de Loosdrecht AA, Ossenkoppele GJ, Strack van Schijndel RJM, Groeneveld ABJ. Sequential organ failure predicts mortality of patients with a haematological malignancy needing intensive care. Eur J Haematol 2005: 74: 511–516. Blackwell Munksgaard 2005. Alexander D. Cornet1, Aart I. Issa1, Arjan A. van de Loosdrecht2, Gert J. Ossenkoppele2, Rob J. M. Strack van Schijndel1, A. B. Johan Groeneveld1 1 Abstract: Objectives: Poor survival of patients with a haematological malignancy admitted to the intensive care unit (ICU) prompts for proper admission triage and prediction of ICU treatment failure and long-term mortality. We therefore tried to ﬁnd predictors of the latter outcomes. Methods: A retrospective analysis of charts and a prospective follow-up study were done, of haemato-oncological patients, admitted to our ICU in a 7-year period with a follow-up until 2 yr thereafter. Clinical parameters during the ﬁrst four consecutive days were taken to calculate the simpliﬁed acute physiology (SAPS II) and the sequential organ failure assessment (SOFA) scores, of proven predictive value in general ICU populations. Results: From a total of 58 patients (n ¼ 47 with acute myelogenous leukaemia or non-Hodgkin lymphoma), admitted into ICU mostly because of respiratory insuﬃciency, sepsis, shock or combinations, 36 patients had died during their stay in the ICU. Of ICU survivors (n ¼ 22), 20 patients died during follow-up so that the 1-year survival rate was only 12%. The SAPS II and particularly the SOFA scores were of high predictive value for ICU and long-term mortality. Conclusions: Patients with life-threatening complications of haematological malignancy admitted to ICU ran a high risk for death in the ICU and on the long-term, and the risk can be well predicted by SOFA. The latter may help us to decide on intensive care in individual cases, in order to avoid potentially futile care for patients with a SOFA score of 15 or higher. Patients admitted into the intensive care unit (ICU) because of complications in the treatment of a haematological malignancy often have a poor prognosis, with an ICU or hospital mortality rate of 50–95%. The outcome varies widely among studies, however, partly due to diﬀerences in casemix, with extremely poor outcomes, for instance, reported for bone marrow/stem cell recipients (1–12). Moreover, the prognosis of haemato-oncological patients on the ICU might have improved over the past decades, at least on the short term (9, 11, 12). Data on long-term mortality (up to 1 yr) are scarce, however, so that it cannot be fully assessed if the eﬀorts in the ICU are still ÔworthwileÕ (3, 7, 8, 13). Indeed, long-term survival may depend Department of Intensive Care, Institute for Cardiovascular Research, Vrije Universiteit Medical Centre, Amsterdam, the Netherlands; 2Department of Haematology, Vrije Universiteit Medical Centre, Amsterdam, the Netherlands Key words: haematological malignancy; ICU (Intensive Care Unit); SOFA-score; SAPS II; long-term survival Correspondence: Prof. Dr Johan Groeneveld MD PhD FCCP FCCM, Intensive Care, Vumc, De Boelelaan 1117 1081 HV, Amsterdam, the Netherlands Tel.: +31-20-4444178 Fax: +31-20-4442392 e-mail: johan.groeneveld@vumc.nl Accepted for publication 19 December 2004 on the prognosis of the underlying disease rather than on superimposed vital organ dysfunction necessitating intensive care, while the latter may be of greater importance in predicting short-term mortality (6–8, 11, 13). Prediction of intensive care treatment failure or success and long-term outcome is important to help decision-making concerning ICU admission once a life-threatening complication of haematological malignancy has developed. In the past, several scoring methods have been developed to predict whether or not general ICU patients will survive. Even though some of these systems take the presence of haematological malignancy into account, it is unclear if the Acute Physiology and 511 Cornet et al. Chronic Health Evaluation (APACHE II/III) score (2, 5, 6, 8–10, 12), the Simpliﬁed Acute Physiology Score (SAPS II) (3, 7, 8, 10, 14) and the Sequential Organ Failure Assessment (SOFA) (11) are of major value in predicting ICU survival from such malignancies. Surprisingly, no or only minimal predictive values in haemato-oncologic patients have been reported (4–8, 10, 12, 14). The current study was undertaken to evaluate the ICU and long-term (i.e. 1 and 3 yr) outcome and its potential predictors SAPS II and SOFA, for critically ill patients with a haematological malignancy. Patients and methods A retrospective study was done on consecutive patients admitted with a known haematological malignancy from the haematological department into the 7-bed medical ICU of our 700-bed university hospital, from 1 November 1995 to 31 December 2002. Follow-up was completed on 1 January 2004, and for only one, ultimately dying patient the survival time remained unknown. Predeﬁned lists were completed of data collected, in a standardized manner, from patient charts. Demographics, underlying haematological malignancy, reason of admission to the ICU, and comorbidity were taken from the charts. Patients had been monitored by repeated laboratory determinations, at least once daily, and, when necessary, by invasive haemodynamic and ventilatory monitoring, and data had been recorded in an electronic patient data management system in use in our ICU. Data were extracted from the electronic and written patient charts in order to calculate, using the worst value in a 24 h time frame for each variable, and for the day of admission (Day 0) as well as the three following days (Days 1–3), the Simpliﬁed Acute Physiology Score (SAPS II, 0–160) (15), that takes the presence of a haematological malignancy into account, and the Sequental Organ Failure Assessment (SOFA, 0–24) score (Table 1, Ref. 16). The former score takes age, type of admission, presence of chronic disease and 12 organ-speciﬁc clinical and laboratory variables into account and the latter consists of a score of six organ-speciﬁc clinical and laboratory variables. The presedation score on the Glasgow coma scale was used. While SAPS II is typically an admission score, the daily SOFA has been developed to characterize disease course in time. Daily chest radiographs were scored from 1 to 4 for the number of quadrants with alveolar consolidations and together with ventilatory and gas exchange parameters, the Lung Injury Score (LIS, 17) was calculated. The score ranges between 0 and 4 and a value >2.5 have been regarded to indicate acute respiratory distress syndrome (ARDS). For scoring systems, missing values were classiﬁed as normal. Likely clinical infection sources were noted, as well as microbiological results, including those obtained from bronchoalveolar lavage (BAL) ﬂuid, within a window of 7 d around the day of admission. The use and duration of inotropic support, mechanical ventilation and continuous renal replacement techniques were recorded. Statistical analyses Outcome groups deﬁned on the basis of mortality/ survival in the ICU were compared with help of an unpaired Mann–Whitney U-test or, for categorical variables with the Fisher’s exact and v2-tests. The log rank test was used to compare long-term mortality in SOFA strata, after constructing Kaplan–Meier survival plots. Receiver operating characteristic (ROC) curves were constructed, plotting sensitivity vs. 1-speciﬁcity to evaluate the predictive value of variables for ICU outcome and the more an area under the curve (AUC with 95% conﬁdence intervals, CI) approaches 1, the Table 1. The sequential organ failure assessment (SOFA) score SOFA 0 1 £400 2 £300 3 £200 4 PaO2/FiO2 >400 Platelets (·109/L) Bilirubin (lM/L) No Hypotension Glasgow coma score Scale Creatinine (lMol/L) Urinary output (mL/d) >150 <20 £150 20–32 MAP <70 £100 33–101 Dop £5 or Dob (any dose) £50 102–204 Dop >5, Epi £0.1 or Nor £ 0.1 £100 With respiratory support £20 >204 Dob >15, Epi >0.1 or Nor >0.1 15 >170 13–14 110–170 10–12 171–299 6–9 300–440 <500 <6 >440 <200 PaO2: partial pressure of O2 in arterial blood; FiO2: inspiratory O2 fraction; MAP: mean arterial pressure, mmHg; Nor: norepinephrine; Dob: dobutamine; Dop: dopamine; Epi: epinephrine, adrenergic agents administered for at least 1 h (in lg/kg/min). 512 Sequential organ failure predicts mortality of patients greater the predictive value. Data were summarized by mean ± standard deviation (SD) or median (range), the latter for survival times. A P-value < 0.05 was considered statistically signiﬁcant. Results Patient characteristics In Table 2, the demographics are shown. The most frequent reason for admission was respiratory insuﬃciency, followed by pneumonia, renal insufﬁciency, shock and sepsis. Ninety percent (52/58) of the patients had undergone intubation and mechanical ventilation, shortly after admission, while one patient received non-invasive ventilation in the ICU. ICU outcome and its determinants Sixty-two percent (36/58) patients died during their stay in the ICU, and there was no change from 1995 to 2002. None of the reasons for admission was associated with an increased mortality on the ICU. The median length of stay of ICU nonsurvivors was 7.5 (0–48) d. Table 3 describes other Table 2. Patient characteristics Age (yr) Men/women In-hospital days before ICU Time from haematological diagnosis (wk) Acute myelogenous leukaemia Chronic myelogenous leukaemia Chronic lymphatic leukaemia Hodgkin's disease Non-Hodgkin lymphoma Multiple myeloma Allogeneic stem cell transplantation Autologous stem cell transplantation Prior radiotherapy Day 1 last chemotherapy, <4 wk No chemotherapy Complete remission Partial remission Reason for admission Infection/sepsis Shock PostCPR Respiratory insufficiency Renal insufficiency Myocardial infarction Liver insufficiency Postoperative Survival duration, days from admission Length of stay in the ICU, d Mortality during follow up ICU non-survivors (n ¼ 36) ICU survivors (n ¼ 22) 53.1 € 14.4 20/16 14 € 13 98 € 171 12 (33) 1 (28) 1 (28) 1 (28) 16 (44) 5 (14) 4 (11) 10 (28) 4 (11) 17 (47) 7 (19) 12 (33) 7 (19) 54.1 € 16.2 12/10 18 € 15 82 € 163 8 (36) 9 (25) 7 (19) 2 (5) 12 (33) 7 (19) 1 (3) 1 (3) 2 (5) 9 € 10 9 € 10 11 3 1 3 4 15 5 6 3 (50) (14) (4) (14) (18) (68) (23) (27) (14) 2 1 2 5 1 (9) (5) (9) (22) (4) 3 (14) 406 € 431 22 € 31 20 (91) Mean € SD or number (percentage), where appropriate. ICU: intensive care unit; CPR: cardiopulmonary resuscitation. Table 3. Variables on the day of admission ICU non-survivors (n ¼ 36) Hemodynamics Heart rate (min) Systolic blood pressure (mm Hg) Mean arterial blood pressure (mm Hg) Use of inotropic agents Respiration Duration (d) PaO2, (mm Hg) FiO2 PaO2/FiO2 PEEP (cm H2O) Total respiratory compliance (mL/cm H2O) Lung injury score Renal function Renal replacement therapy within 4 d Urinary output (mL/d) Serum creatinine (lmol/L) Serum urea (mmol/L) Hematology Haematocrit (%) White blood cell count (·109/L) Leucocytopenia <1 (·109/L) Prior duration leucocytopenia (d) Platelets (·109/L) Thrombocytopoenia <100 (·109/L) Prothrombin time, international ratio Activated partial thromboplastin time (s) Neurology Glasgow coma scale Infection Body temperature ( C) Documented respiratory infection Bacteremia (within 7 d window) Use of antibiotics (within 7 d window) Blood biochemistry Sodium (mmol/L) Potassium (mmol/L) Bicarbonate (mmol/L) Bilirubin (lmol/L) Albumin (g/L) Glucose (mmol/L) Lactate dehydrogenase (U/L) ICU survivors (n ¼ 22) 132 € 39 96 € 28 66 € 19 25 (69) 123 € 38 116 € 47 78 € 33 11 (50) 9 80 78 114 8 29 2.5 18 85 69 144 8 36 2.2 € € € € € € € 7 41 21 67 3 12 0.7 € € € € € € € 25 40 21 90 4 14 0.9 5 (13) 1555 € 1579 170 € 101 17 € 10 4 (18) 1766 € 1335 208 € 223 20 € 14 25 € 8 7.2 € 10.1 14 (39) 3€5 50 € 66 32 (89) 1.62 € 0.35 52 € 40 29 € 5 8.0 € 8.5 4 (18) 3€6 110 € 146* 14 (64)* 1.45 € 0.41* 46 € 22 13 € 2 12 € 3 37.9 € 1.8 6 (17) 21 (58) 26 (72) 38.0 € 1.7 144 4.2 19.5 65 20 9.5 1030 142 4.0 22.5 18 20 8.9 1081 € € € € € € € 8 1.0 5.7 70 7 4.5 1142 16 (73) 17 (77) € € € € € € € 7 1.1 4.6 16** 6 4.3 990 Mean € SD or number (percentage), where appropriate. PaO2: partial pressure of O2 in arterial blood; FiO2: inspiratory O2 fraction. *P < 0.05. **P < 0.01. characteristics of survivors and non-survivors and shows the prognostic signiﬁcance of thrombocytopenia, prolonged clotting times and hyperbilirubinaemia, rather than underlying disease. The frequency and severity of leucocytopenia on admission and its course over the subsequent 3 d did not have prognostic signiﬁcance. Nevertheless, the Day 0 SOFA scores diﬀered between leucocytopenic and non-leucocytopenic patients (P < 0.001), with values for the SOFA-score of 11.8 ± 3.1 (with leucocytopenia) and 8.4 ± 3.7 (without leucocytopenia). The Day 0 SOFA score also diﬀered between thrombocytopenic and non-thrombocytopenic patients (P < 0.001). Bronchoalveolar lavage 513 Cornet et al. Scoring systems The Day 0 SAPS II was higher (P < 0.01) in ICU non-survivors (58 ± 17) than in survivors (46 ± 14). Table 4 and Fig. 1 show the prognostic signiﬁcance of the SOFA score for ICU mortality. The AUC for the ROC curve for Day 0 SOFA was Table 4. SOFA-score and outcome SOFA on day 0 1 2 3 ICU n 58 55 47 43 ICU non-survivors 10.6 11.2 10.7 11.1 € € € € ICU Survivors 3.7 3.7 4.0 4.0 6.7 6.9 6.3 7.6 € € € € 3.4 3.4 3.6 3.9 P <0.001 <0.001 <0.001 <0.01 SOFA: sequential organ failure assessment. ICU: intensive care unit. 30 Died Number of patients Survived 20 10 0 0.8 0.6 SOFA 15–20 0.4 10–15 5–10 0.2 0–5 0.0 0 200 400 600 Days 800 1000 1200 1400 Fig. 2. Kaplan–Meier plot of long-term survival, in the strata (Fig. 1) of Day 0 SOFA (log rank test: P < 0.001). SOFA 0–5, n ¼ 10; SOFA 5–10, n ¼ 27; SOFA 1–15, n ¼ 16; SOFA 15–20, n ¼ 5. 0.77 (95% CI 0.65–0.90, P < 0.001) and for the SAPS II score 0.70 (95% CI 0.56–0.84, P < 0.01). The maximum (during the ﬁrst 4 d of ICU stay) SOFA was 12.8 ± 3.5 in non-survivors and 8.1 ± 3.8 in survivors (P < 0.001) and the AUC under the ROC curve was 0.80 (95% CI 0.69–0.91, P < 0.001). The mean SOFA score, over the ﬁrst 4 d of ICU, was 6.4 ± 3.3 in survivors and 11.2 ± 3.5 in non-survivors (P < 0.001), with an AUC under the ROC curve for mortality prediction of 0.84 (95% CI 0.74–0.94, P < 0.001). Long-term outcome The median survival time of ICU survivors was 307 (range 6–1417) days after admission or 254 (0– 1400) days after ICU discharge, because 20 patients had died after discharge from the ICU during time to follow-up (Fig. 2). The 22 ICU survivors had a length of stay in the ICU of median 7 (1–117) days. The two long-term survivors until follow-up ended had a non-Hodgkin lymphoma as underlying disease. The overall 1-yr survival rate was 12% and the 3-yr survival 5%. For ICU survivors, the 1-yr survival rate was 33%, with a median survival time for ultimate non-survivors of 258 (6–1417) days. The SOFA score was a determinant of survival time (Fig. 2). Discussion 0–5 5–10 10–15 15–20 SOFA Fig. 1. Sequential organ failure assessment (SOFA) scores and ICU survival (P < 0.01). ICU mortality increases from 20% at Day 0 SOFA 0–5, 63% at SOFA 5–10, 75% at SOFA 10–15 to 100% at SOFA 15–20 points. 514 1.0 Survival (BAL) was performed (within a 7 d window) in 17 patients and microorganisms were found in 8, but there was no diﬀerence among outcome groups. Aspergillus fumigatus was recovered in BAL from two patients ultimately dying in the ICU. Tracheal aspirate cultures were positive in 19 patients, without prognostic signiﬁcance. Another patient with A. fumigatus in tracheal aspirate survived the ICU stay. Thirteen patients had a prior autologous stem cell transplantation, they all died within the follow-up period, 6–2798 d after their transplantation. Five patients had undergone allogeneic stem cell transplantation and they had died also within the follow-up period, even though one patient lived for 790 d after ICU admission. In any case, 13/17 patients with stem cell transplants had died in the ICU. Our study shows that the prognosis for patients who are admitted to the ICU, having a haematological malignancy, is dismal, particularly on the long term, and that the ICU outcome and survival time can be well predicted by SOFA. Sequential organ failure predicts mortality of patients The overall ICU and hospital mortality of haemato-oncologic patients reported in the literature varies between 50% and 95% (1–12), so that our persistently high ICU mortality rate of about 60% may not indicate substantial improvement over time, while greatly exceeding the almost 27% mortality in our unit for general critically ill patients (18). Age was not a prognosticator, in contrast to other reports (5, 9, 12). Our results, as those collected by others (12), also do not conﬁrm that (prolonged) mechanical ventilation is associated with a very poor outcome (1, 4–6, 10), since respiratory insuﬃciency was a major reason for ICU admission in our patients and most of them had been intubated and mechanically ventilated from the day of admission on. In contrast, other investigators noted that the combination of mechanical ventilation and (need for) renal replacement therapy in haematological malignancy almost precluded survival (3, 6–8, 10), while this was not the case in our study. The same applies for the poor treatment status of the underlying malignancy (leukaemia), postbone marrow transplantation, leucocytopenia, septic shock and need for inotropes, carrying an adverse prognosis in some studies (2, 3, 5, 7, 9–11), while these factors, including the type of underlying malignancy, the type and intensity of prior treatment and (duration of) leucocytopenia were no major determinants of ICU outcome in our study, in accordance with recent literature (6, 19). Univariate predictors of mortality in our series included thrombocytopenia and elevated clotting times, as reported before (10). Leuco- and thrombocytopenia related to organ dysfunction (SOFA), possibly via toxicity of prior chemotherapy or superimposed infection/sepsis, suggesting a role of cytopenia in organ dysfunction. The prolonged clotting times may relate to disseminated intravascular coagulation, in the presence of similar albumin levels suggesting similar hepatic protein synthesis, even in the presence of hyperbilirubinaemia. The prognostic importance of liver abnormalities has been rarely reported before (6, 10). We can only speculate on the role of disseminated intravascular coagulation in a dismal outcome. Nevertheless, the outcome of our patients was relatively hard to predict by single variables, and the observation that SOFA was a better predictor than individual variables may conform with other studies (16). The high predictive value of the SOFA score underscores the use of organ-oriented scoring systems in haemato-oncological, critically ill patients to judge prognosis (3, 6, 8, 10), even though Blot et al. (14) reported lack of predictive value of organ dysfunction scoring on outcome of haematooncological disease in the ICU. The discrepancy with our study can be explained by the design of the Blot et al. (14) study, enrolling patients in the haematological wards only, while the scoring systems have been developed for ICU patients. Our data thus suggest that SOFA better predicts than admission disease severity scores such as the APACHE II/III or the SAPS II scores, that may not predict well in haemato-oncological patients (3, 5, 6, 8, 11, 12, 14). Indeed, the mean and maximum SOFA scores performed even better than the Day 0 SOFA score in our patients, as suggested before for a general ICU population (16). The ICU mortality for the latter populations approaches 20% at SOFA 6–7 until 80% at SOFA of 11 or higher (16). The data also suggest that mortality at low and intermediate SOFA scores is higher in haemato-oncological than in non-haemato-oncological, critically ill patients, but apparently this does not limit the predictive value of the SOFA score. In contrast, mortality has been reported to be higher for haemato-oncological than for non-haematooncological patients at low and intermediate disease severity scores, such as the SAPS II score, and this may have contributed to a relatively poor predictive value in the former patients (2, 4, 14). Inclusion of platelet counts, having predictive value, in the SOFA and not in the SAPS II score may have contributed to greater predictive value of the former. Our study conﬁrms the prognostic value of the SOFA score in critical haemato-oncologic disease, in a single prior publication on the subject, on 30 patients in a Scandinavian ICU (11) and extends these observations regarding its relation with longterm outcome. It suggests that a haemato-oncological patient, who is admitted with a SOFA score of 15 or higher will not survive an ICU stay. Obviously, we only studied a small population, so that treatment withdrawal in a patient with SOFA of 15 or higher cannot be defended on the basis of our study alone. Even though 38% of our patients left the ICU alive, the overall long-term prognosis is still grim, with a 1-yr survival of only 12%, again well predicted by the SOFA score on ICU admission and relatively independent of (the prognosis of) underlying haemato-oncological disease. The latter observation contrasts with studies by Yau et al. (13) and Massion et al. (8), in which the longterm prognosis was primarily determined by that of the haematological malignancy rather than by organ dysfunction, but agrees with observations by Kroschinsky et al. (7). The 1-yr survival was about 20% in the Kroschinsky et al. (7) and Silfvast et al. (11) studies, and 13% in the Yau et al. (13) studies, and the 1-yr survival of our ICU survivors of 33% also agrees with the literature (2, 3, 13). 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