Hematologic malignancies in the medical intensive care unit – Outcomes and prognostic factors

Abstract

Objectives

To analyze clinical characteristics, treatment, outcomes of critically ill patients with hematologic malignancies (HM) admitted to the medical intensive care unit (ICU) and to identify predictors of adverse outcome.

Methods

We analyzed prospectively 170 patients. Data included: demographic characteristics, hematologic diagnosis, reasons for ICU admission, transplant status, the presence of neutropenia, acute physiology and chronic health evaluation-II and sequential organ failure assessment scores, and level of organ support. Predictors of ICU mortality were evaluated using univariate and multivariate analysis.

Results

In total, 73% of patients had high-grade malignancy, 47.6% received intensive chemotherapy before admission, and 30% underwent hematologic stem cell transplantation procedure. In total, 116 (68.2%) of patients were mechanically ventilated; 88 (51.8%) required invasive mechanical ventilation (MV). Non-invasive ventilation started in 28 (16.5%) patients and was successful in 11 (6.5%). The ICU mortality rate was 53.5%, and the mortality of MV patients was 75.9%. Need for vasopressors at admission and MV were identified as independent predictors of fatal outcome.

Conclusion

The ICU mortality of critically ill patients with HM is high, particularly in the group of MV. Need for vasopressors at admission and MV were independent predictors of ICU mortality. Majority of patients required invasive MV due to severe respiratory failure and non-invasive MV was sufficient only in small number of cases with favorable outcome.

Keywords:

• Hematologic malignancies
• ICU
• Mechanical ventilation
• Mortality

Introduction

Hematologic malignancies (HM) and the complications related to their treatment cause substantial morbidity and mortality with poor prognosis.^1–3 In recent years, intensified chemotherapy, monoclonal antibodies, autologous and allogenic bone marrow transplantation (BMT) have improved the survival rate. However, application of aggressive therapeutic protocols, toxicity of chemotherapeutic agents, as well as profound or chronic immnosuppression, and graft-versus host disease (GVHD) can lead to serious complications requiring the treatment in the intensive care units (ICU).

The main reasons for ICU admission are: acute respiratory distress syndrome (ARDS), sepsis or septic shock, and postoperative care.⁴ Mechanical ventilation (MV) largely deteriorates outcome in HM patients,^4–6 particularly in those who received allogenic or autologous BMT, and in majority of cases it has a fatal effect.^7–12 Various factors have been associated with poor prognosis among critically ill patients with HM admitted to the ICU, including high acute physiology and chronic health evaluation-II (APACHE II) scores,^1,13–15 invasive MV,^13–16 neutropenia,² sepsis,¹ but the results of the published studies have been contradictory. The clear definition of parameters associated with fatal outcome would help hematologists and critical care specialists in recognizing the patients who could have benefited from ICU treatment and in decision making regarding treatment options.

The objective of this study was to evaluate the clinical characteristics, treatment modalities, and outcomes of critically ill patients with HM admitted to a medical ICU, and to identify potential predictors of adverse outcome.

Methods

This prospective, observational study included patients with HM treated in the medical ICU of the Department of Internal Medicine, University Hospital Centre Zagreb from January 2011 to December 2013. Our ICU is a ward with 12 beds that admits patients with acute medical conditions, and HM constitutes 9% of admittances. The study included patients >18 years admitted to the ICU, with HM as a primary diagnosis or a concurrent co-morbidity over a 5-year period. These patients were included regardless of the duration of the ICU treatment. The decision to admit the patient to the ICU was made by the intensivist, following the consultations with the attending hematologist. The patients with advanced disease or repeated relapses, who received intensive and potentially curable chemotherapeutic regime, as assessed by the attending hematologist, were also admitted. None of the patients had signed do not resuscitate or do not intubate consent. The institutional Committee of Clinical Research approved the collection of patients data for the purpose of this study.

Demographic, clinical, and laboratory data from the first day of ICU treatment were used for statistical analysis and included: HM type; disease status; reasons for admission; treatment modalities in the ICU (MV and type of ventilation, use of vasopressors, renal replacement therapy (RRT), and plasmapheresis); length of stay; ICU mortality; and mortality within 1 month following the discharge from the ICU. APACHE II score and sequential organ failure assessment (SOFA) score were calculated during the first 24 hours after admission to the ICU. Organ dysfunction was defined by a SOFA score ≥1 point for any organ system. Neutropenia was defined as absolute neutrophil count <1000/µl. In patients with multiple reasons for admissions (e.g. septic shock and acute respiratory or renal failure), only the most severe condition (e.g. septic shock) was considered as a primary reason for admission. The sepsis and septic shock were defined and treated according to the Surviving Sepsis Campaign.¹⁷

HM were grouped as acute leukemia (AML, ALL), chronic leukemia (CML, CLL/SCLL), high-grade lymphoma (NHL, HL, BL), indolent lymphoma (FL), multiple myeloma, and others. The phase of treatment was categorized as newly diagnosed, when the diagnosis was made during this hospitalization or within 30 days before admission and no specific chemotherapeutic regime has been started, first line of chemotherapy, treatment of advanced disease including transplantation procedure, repeated relapse/refractory disease, and complete remission. The treatment modalities in the ICU included invasive MV and non-invasive MV (NIV), RRT, plasmapheresis, and the use of vasopressors (noradrenaline, dopamine, and dobutamine).

Acute respiratory failure (ARF) was defined as respiratory rate >30 breaths per minute with respiratory distress symptoms, PaO₂ on room air <60 mmHg, or need for invasive MV or NIV. Furthermore, NIV was considered in patients who presented with ARF without severe hemodynamic instability (systolic blood pressure (SBP) >70 mmHg), who were awake and cooperative, able to clear their secretions adequately, and showed no signs of imminent respiratory arrest. It was delivered via face mask or Helmet system, and resumed when the arterial O₂ saturation was <85% during NIV or when dyspnea worsened, as evidenced by a respiratory rate of >35 breaths per minute and respiratory distress symptoms during NIV.

Criteria for orotracheal intubation were conditions necessitating endotracheal intubation to protect the airways (a seizure disorder or severe encephalopathy with a score on the Glasgow Coma Scale of ≤8); agitation requiring sedation; the development of copious tracheal secretions; an increase in the partial pressure of arterial CO₂ accompanied by a pH≤7.30; severe hemodynamic instability (SBP of <70 mmHg); ECG signs of ischemia or clinically significant ventricular arrhythmias; and inability of patient to tolerate the face mask or Helmet.

The use of vasopressors was defined as any vasopressor or inotropic drug that was started within 24 hours of admission. Vasopressors were started in patients with hypotension not responding to a fluid challenge or with proven cardiac failure on ECG and signs of organ failure (i.e. oliguria, renal failure, neurologic impairment, lactic acidosis). Oliguria was defined as a urinary output of <500 ml per 24 hours.

The RRT was initiated in patients with at least one of the following characteristics: metabolic acidosis; urea >35 mmol/l; K + >6.0 mEq/l; volume overload; severe hyperphosphatemia or dysnatremia; oligo/anuria; and uremia. Furthermore, RRT modes were daily conventional dialysis and continuous RRT. Patients receiving vasopressors with potential for hemodynamic instability were treated with continuous RRT.¹⁸

Decisions regarding initiation, termination, or selection of the mode of RRT were made by the intensivist. Plasmapheresis was used in patients with hyperleukocytary and hyperviscosity syndrome.

The primary outcome was ICU mortality and secondary outcome was mortality 1 month following the discharge from ICU.

Statistical analysis

All analyses were performed using the SPSS Statistics, V.17.0 (SPSS Inc., Chicago, USA). Categorical data were presented with absolute and relative frequencies, continuous data with mean and standard deviation or median with interquartile range as appropriate.

Chi-square test was used for group comparisons and analyses of categorical variables. Mann–Whitney test and t-test were used for comparisons of continuous variables as appropriate. The logistic regression of the variables that were in univariate analyses associated with an outcome was performed using stepwise approach. Statistical significance was set at P = 0.05.

Results

Overall, there were 1769 admissions to the medical ICU and 170 admissions (9.6%) of patients with HM. Their general characteristics are given in Table 1. There were 82 (48.2%) women and 88 (51.8%) men. In total, 73% had a high-grade malignancy, the most frequent diagnoses being the acute leukemia and high-grade lymphoma. Eighty-one patients (45.8%) were treated by intensive chemotherapy regimen in weeks prior to admission to the ICU, and 52 (30.6%) underwent allogenic or autologous BMT. Furthermore, 86 (50.6%) were neutropenic at admission. Shock and ARF were the most frequent indications for admission, in 80 (47.1%) and 63 (37.1%) patients, respectively (Table 2). Pulmonary infections were the most common underlying disease in patients with ARF, and septic shock was most common form of shock. Sixty-three patients (37.1%) admitted with shock and 46 (27.1%) admitted with ARF required some form of MV within the first 24 hours of ICU treatment. Moreover, MV was also started in seven patients (4.1%) admitted for other reasons (acute renal failure or disturbed consciousness) (Table 2). Totally, 116 patients (68.2%) required MV, NIV was started in 28 (26.6%) patients, and was successful in 11. Nine out of 11 patients treated only with NIV survived (9/11), and in the group of 17 patients who required orotracheal intubation and invasive MV following NIV, 6 patients (6/17) survived and were successfully weaned from the ventilator. Major treatment modalities and outcomes are given in Table 3.

Table 1. Characteristics of patients with hematological malignancies admitted to medical ICU

Table 2. The reasons for admission to the ICU, underlying pathology and proportion of mechanically ventilated patients in each group of patients with HM

Table 3. Major ICU treatment and outcomes of patients with hematological malignancies

Furthermore, RRT was required in 40 (23.5%) patients, and 65% died. Plasmapheresis was performed in 7 (4.2%). Ninety-seven (57.1%) patients required vasopressors at admission. The ICU mortality was 53.5%, and the mortality of MV patients was 75.9%. The 28-day survival rate was 31.3%.

In the univariate analysis, mortality was significantly associated with factors such as neutropenia at admission, need for vasopressors on the day of admission to the ICU, primary reason for ICU admission, MV within 24 hours of ICU treatment, and severity indices such as APACHE II and SOFA score values on the first day of ICU treatment (Table 4). Independent predictors of mortality in the multivariate analysis are reported in Table 5. Patients with fatal outcome in the ICU could have been identified by the need for vasopressors on the day of admission and the need for MV within 24 hours of ICU treatment (Table 5).

Table 4. Association of ICU mortality with hematological and intensive care factors

Table 5. Multivariate analysis of factors associated with mortal outcome

Discussion

Over the past decades, the survival of patients with HM has improved greatly, owing to the intensive chemotherapy and BMT procedures. However, these potentially life-saving treatments have been associated with some life-threatening complications, requiring the treatment in the ICU.^2,19–21 Critically ill patients with HM have a higher mortality than the general intensive care population,^1,22–24 particularly in case of ARF and need for MV. The poor short-term and long-term prognosis of critically ill hematologic patients, as well as the necessity of time and cost consuming treatments have caused some reluctance of intensivists to admit and treat patients with HM.¹ However, this approach has been disapproved in many studies, which have shown a great improvement of outcome of severely ill patients with HM and solid cancer admitted to ICU over the recent decades, and nowadays the mortality rates in these subgroups approach those observed in severely ill patients.^3,20,21,25 This can be attributed to better supportive care, but also to the better identification of the patients who can benefit from ICU treatment.^3,6,20,24 Therefore, the understanding of the predictors of the unfavorable outcome of critically ill patients with HM could help ICU professionals to make appropriate decisions regarding the admission and treatment.^3,13–16

Our study included 170 patients with HM admitted to the medical ICU over a 3 years period. The overall ICU mortality was 53%, and mortality 28 days from ICU admission was 68.8%, that is comparable to other studies.^7,14,16 While earlier studies report the ICU mortality rate of 65–67%^11,12 and in-hospital mortality 77–78%,^11,23 the recent single-center study by Bird et al.²⁵ reported the ICU mortality and in-hospital mortality of 37 and 45.7%, and a multi-center study from UK reported ICU and in-hospital mortalities of 43.1 and 59.2%, respectively, for patients with HM treated in the ICU, which is slightly lower than in our study.⁷ The median APACHE II score of the patients in the first study was 21 (IQR 16–25), and in the second one was 24.4 ± 7 (7, 25). The differences in reported mortalities could be partly explained by variations of admission and discharge criteria, implementation of end-of-life decisions and treatment modalities.²⁵ However, the severity of the disease, assessed by the average APACHE II score, of our patients was slightly higher in comparison with these studies. Although it is difficult to compare between series, average APACHE II score in our patients was 25 ± 9 which corresponds to the predicted mortality rate of 52.4% ± 25.17. The Department of Hematology in our institution is the only allogenic transplantation center in Croatia, and hematologic patients in our institution represent the selected population with a very high risk for complications. Furthermore, since this is the first study to analyze the outcome of critically ill hematologic patients in Croatia, we included all patients admitted to ICU, while most of the other studies do not include the patients who died within 6–24 hours from admission. In our study, 29 patients (17%) died within 24 hours from the admission to the ICU, which has a significant influence on the overall mortality. Expectedly, high APACHE II and SOFA scores on the day of admission were significantly associated with ICU mortality, but they were not found to be independent predictors of mortality in the multivariate analysis. The utility of scoring systems such as APACHE II and SOFA in predicting mortality is variable. Many studies have found their strong association with ICU or in-hospital mortality, and identified them as the independent predictors of mortality.^4,7,12 However, others have shown that APACHE II at admission underestimates mortality risk in hematologic patients.^10,23,27 Other scoring systems, such as SOFA and SAPS II, were also unspecific in predicting mortality.^7,12,14,28 Since both APACHE II and SOFA scores are composite variables, comprising respiration and circulation parameters, it is unsurprising that they are not the independent predictors when respiration and circulation parameters are used in multivariate model.

The most frequent indications for admission to ICU in our group were shock and ARF. ARF with the need for MV occurred in 63 patients initially admitted for shock. Infection was by far the most frequent cause of shock and pulmonary infection was most frequent cause of ARF (Table 2). The high incidence of serious infectious complications with hemodynamic instability, explains the strong association of vasopressors at admission with fatal outcome. As reported in other studies,^7,13,15 the use of vasopressors on the first day of ICU treatment was the strongest independent predictor of fatal outcome in our study.

ARF is frequent and severe in patients treated for HM and is the most frequent reason for admission of these patients in the ICU.²⁹ The overall mortality rate associated with ARF is 50%, but reaches as high as 90% in MV patients, particularly in recipients of allogenic BMT.^19,30 This can be explained by the severity of the patient's state, and the necessity of supporting vital functions, as well as by pulmonary involvement in the underlying disease (leukemic infiltration, leukostasis in pulmonary vessels in hyperleukocytary syndrome) and GVHD, or pulmonary toxicity of cytostatic drugs administered to patients with HM.^12,31 In our study, 116 patients (68.2%) required MV, and 88 (75.8%) patients immediately required orotracheal intubation and invasive MV. The ICU mortality of patients requiring MV was substantially higher than overall mortality (75 versus 53%), and MV was identified as the second independent predictor of fatal outcome in our setting.

Previously, NIV has been shown to be effective in immunocompromised patients with ARF.^32,33 It successfully increases oxygenation for bronchoscopy and bronchoalveolar lavage,³⁴ reduces rates of intubation, and improves survival in hematologic patients with hypoxemia and diffuse pulmonary infiltrates, as compared with the supportive oxygen treatment.^33–36 The early use of NIV can reduce the need for orotracheal intubation and ventilator associated lung injury.² However, failure of treatment with NIV and requirement of MV occurs in about 50% of patients.²⁹ The study of Adda et al.²⁸ has shown a significantly higher hospital mortality in hematologic patients who failed NIV and identified five independent predictors of NIV failure; respiratory rate under NIV; longer delay between admission and NIV; need for vasopressors or RRT and ARDS. Nevertheless, this study did not include the patients with allogenic stem transplantation.²⁹ In our study, only 28 patients with ARF could be treated by NIV (24.2%). Failure of treatment occurred in 17 patients (17/28) and 15 of those patients died. In the group of 11 patients (6.5%) treated only by NIV, only 2 (2/11) patients had a fatal outcome. The small proportion of patients eligible for NIV (24.2%) can be explained by a high proportion of patients with severe RF, septic shock, and hemodynamic instability at admission, in whom the severity of clinical condition did not allow the NIV trial. Although, the protective and beneficial role of NIV in hematologic patients with ARF has often been emphasized, according to our results, its role is very limited in severely ill hematological patients. The disease processes leading to RF have a major impact on mortality and influence the selection of ventilation mode, and some etiologies are inappropriate for NIV. The use of NIV did allow the avoidance of orotracheal intubation in a small number of patients with favorable outcome, but their better outcome could also be explained by the less severe underlying clinical condition. These results, although obtained from a very small number of patients, underline the importance of the careful selection of patients eligible for NIV trial, which has been emphasized by the recent studies. For instance, in a multi-center prospective study of Molina et al.,³⁶ NIV improved the outcome of some hematologic patients with RF, particularly those with rapidly reversible cause, but failure of NIV was associated with more severe respiratory impairment than elective intubation and invasive MV. In another study,³⁸ addressing the patients with RF following BMT procedure, early treatment with NIV was not associated with lower ICU admission rate, lower need for intubation, or better survival parameters.

We did not find any statistically significant association between ICU mortality and variables such as age, gender, type of malignancy, stage of disease or transplant status, which is in accordance with the recently published studies.²⁹ The lack of association of transplant status with mortality has been argumented by the advances in conditioning regimes, targeted therapies with less organ toxicity, routine use of anti-microbial prophylaxis, and the use of granulocyte colony-stimulating factor.²⁹ However, we found a significant association of neutropenia with fatal outcome, although it did not reach the strength of an independent predictor of mortality. Neutropenia was previously shown as an independent prognostic factor for ICU mortality,^3,36 although some studies did not support these results.^7,27 The intensive chemotherapy regimens and BMT procedures are associated with a serious immunological deficit and prolonged and severe neutropenia, often complicating with Gram negative and fungal infections, and limiting the utility of antibiotic treatment.³⁵ Nevertheless, some studies did not find the relation between the duration of neutropenia and mortality, although neutropenia was an independent predictor of adverse outcome. The high risk of death of neutropenic patients may be attributed not only to the susceptibility for infection but also to the concomitant chemotherapy-induced organ toxicity.^3,38

There are several limitations to this study. First, it is a single-center study. However, our Hematology department is the largest regional hematologic ward, referral center for stem cell treatment, and the only allogenic transplantation center in Croatia, which admits patients from the whole Croatia.³⁹ Second, at the time of initiation of the study, the experiences with NIV in hematologic patients were rather limited, which might have influenced the selection of ventilation modality.

Conclusion

The ICU mortality of critically ill patients with HM was 53.5% and the mortality of MV patients was 75.9%. Need for vasopressor therapy on the day of admission and MV were independent predictors of ICU mortality. In mechanically ventilated patients, the protective role of NIV was not demonstrated, since the clinical state was in most cases too severe for NIV trial. These results show that the outcome of hematologic patients in the ICU depends primarily on the severity of their clinical condition, development of organ failure, and the reversibility of the underlying disease.

Disclaimer statements

Contributors MGM contributed in manuscript writing, data collecting, and interpreting, IG contributed in statistical analysis, critical revision of the manuscript. VG contributed in critical revision and final approval of the version to be published.

Funding None.

Conflicts of interest None.

Ethics approval The institutional Committee of Clinical Research approved the collection of patients data for the purpose of this study.