PROFILE AND PREDICTORS OF OUTCOME IN PATIENTS WITH HEMATOLOGICAL MALIGNANCIES ADMITTED TO THE PEDIATRIC INTENSIVE CARE UNIT ATUL JINDAL, ARUN BANSAL From Department of Pediatrics, Advanced Pediatric Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India. Correspondence to: Dr. Arun Bansal, Assistant Professor, Department of Pediatrics, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh - 160012, India. E-mail: firstname.lastname@example.org. Background: Haematological malignancies requiring critical care support are associated with increased morbidity and mortality. Data is scarce from developing economies. We present the profile and predictors of outcome of children with hematological malignancies admitted to a PICU. Objectives: To study the profile of patients and predictors of outcome in children with hematological malignancies admitted in pediatric intensive care unit(PICU). Design: Retrospective cohort study in PICU of a tertiary referral center. Methods: Data of 72 critically ill, previously diagnosed children with hematological malignancies admitted to PICU of a tertiary centre from July 1999–August 2010 were retrieved retrospectively. Primary outcome was defined as survival or death. Survivors and non survivors were compared to determine predictors of outcome. Variables significant on univariate analysis were subjected to multivariate analysis to determine significant predictors of outcome. Results: Median (IQ range) age was 7years (4-10) and duration of PICU stay was 4 days (2- 10). Acute lymphoblastic leukemia was seen in 48 and 9 had acute myeloid leukemia. Respiratory failure was present in 22 children, septic shock and CNS complications in 11 each and both respiratory failure and shock in 21. Forty-nine children were ventilated and 39 required inotropes. There were 41(56.9%) deaths. Age >3 years (p=0.014), absolute neutrophil count < 1500 mm3 (p=0.019), thrombocytopenia<10,000/mm3 (p=0.007), prothrombin index <75% (p=0.0005), hypoalbuminemia < 2.5 gm/dL (p=0.0009), BUN >18 mg/dL (p=0.0008), creatinine > 0.7mg/dL (p=0.026), inotrope score > 20(p=0.0001), oxygenation ratio < 200 (p=0.004) , oxygenation index > 15(p=0.026) and acidosis (p=0.001) were associated with poor outcome. Presence of respiratory failure, ventilator associated pneumonia (VAP), ARDS, shock, increasing duration of mechanical ventilation, positive aerobic blood culture and fungal sepsis were significantly associated with death. In a multivariate logistic regression model, inotrope score >20 (p=0.000), albumin<2.5g/dl (p=0.001), age < 3 years (p=0.011), VAP (p=0.05), but not presence of shock, respiratory failure and increasing duration of ventilation, predicted outcome. Conclusion: Simple clinical and laboratory parameters can help in predicting outcome in critically ill children with haematological malignancies. Key Word: Hematological malignancy, PICU, Outcome Introduction Over the past 20 years, with the introduction of increasingly intensive protocols, the nature of paediatric oncology has changed significantly. This has been accompanied by improved survival figures for children with both haematological and solid malignancies. It has, however, resulted in children spending extended periods in hospital with severe and life threatening complications of their malignancy and/or the associated treatment. Close cooperation with an intensive care facility is therefore an essential part of any regional oncology centre. Admission to an intensive care unit has many costs that include emotional and social factors, as well as those that are medical and financial in nature. An understanding of the benefits of an intensive care unit is therefore important for decision making and for counselling of the families involved. It was for these reasons that we undertook the present study. Patients and Methods: This retrospective study was conducted in a 12 bedded PICU of Post Graduate Institute of Medical Education and Research, Chandigarh. Duration of study: This study was performed over a eleven years period, from July 1999 to August 2010. Data Collection: Retrospective record review of all patients with diagnosed haematological malignancies, who required admission to the pediatric intensive care unit. Charts were reviewed for disease, treatment and admission characteristics as shown in table 1. The following conditions were evaluated during the ICU stay: the need for mechanical ventilation, addition of inotrope therapy, neurological complications, appropriate antibiotics or steroids, the presence of microorganisms in the bloodstream or fungal infection, the duration of ventilation and the length of stay in the PICU and in the hospital. Fungal infection was defined as a growth of fungus from clinical specimen or any clinico-radiological finding suggestive of fungal infection and the initiation of treatment for that organism. Septic shock and respiratory failure were defined as per PALS guidelines 2006. Inotrope score is given by formula, inotrope score = dose of dopamine x 1 + dobutamine x 1+ adrenaline x 100 + noradrenaline x 100. All intubated and ventilated patients were looked for development of VAP and ARDS. Raised intracranial pressure (ICP) was labelled when children had any clinical signs like coma, hyperventilation, unequal pupils or fixed dilated pupils, posturing or ICP reading if on ICP monitor. If any measures for controlling raised ICP were done were recorded. Status epilepticus was defined according to International League Against Epilepsy definition.3 The data were analysed to identify factors related to PICU mortality. PICU outcome was recorded as survival and death. Statistical analysis Statistical analysis was performed using the unpaired Student’s t-test or the Mann– Whitney U test for continuous variables and the chi-squared or the Fisher’s exact test for categorical values, as appropriate. A logistic regression model with forward stepwise variable entry was fitted to analyse outcome adjusting for patient age, sex, disease and disease stage, treatment of underlying disease, main reason for PICU admission. Variables with a p value less than 0.05 in the univariate analysis were used for multivariate analysis. Values are expressed as median and interquartile range. The p values were two-sided, with p = 0.05 considered to be statistically significant. The analyses were performed using SPSS 17.0 (Chicago, IL, USA) and Epi info 6. Discussion Several studies have addressed outcome of patients with haematological disease admitted to the ICU.4-31 Very scant data is available for pediatric patients. The rationale for ICU admission is often discussed and strategies to maximise survival are weighed against limiting unnecessary suffering and costs.10 Surviving patients may return to a life of good quality.13 Many studies attempted to identify prognostic factors at the time of ICU admission, to guide clinicians and patients in decision making about intensity of treatment. Several patient- and disease-related factors have been shown to be associated with poor survival: age 7,14 although cut-off levels varied; type of disease;15 disease stage, remission status and response to chemotherapy6,14,17 stem cell transplantation including donor type 6,17,18 , time 7 interval between stem cell transplantation and ICU admission (> versus <90 days) , grade of acute GvHD19; and degree and duration of neutropenia6,16,19–21. Some of these factors were however not predictive of adverse outcome in other reports10,12, 21–25. We analysed a heterogeneous population of patients with hematological malignancies admitted to the PICU. The only similar paediatric report comes from a combined study of three hospitals in Australia and Canada.32 and one study from UK.33 Our study and studies published by Park et al40 and Thakker et al39 show that denying admission to a patient purely based on leukemia diagnosis is unreasonable. Forty three percent of patients in the present study and 40% and 32% of patients in the study by Park et al and Thakker et al. respectively survived ICU care. In our study age was an independent predictor of worse outcome with the mortality being higher for children who were more than 3 years of age. This finding is in contrast to earlier studies where age had no bearing on the mortality39 .Children who had low absolute neutrophil count, low platelet count, deranged coagulation profile, and hypoalbuminemia had more mortality. They were the ones who were probably more susceptible to nosocomial infections, fungal sepsis and pulmonary hemorrhage. High admission PRISM scores were also associated with poor outcome. The most difficult decision about ICU admission of patients with haematological malignancies is whether to intubate and mechanically ventilate a patient. As patients are suffering from a potentially terminal illness, end of life decisions become important. The mortality was higher for those children who required ventilation (71.4%). Six patients out of those who were not ventilated died subsequently. Thirty two patients developed ARDS and 10 patients developed VAP. Both ARDS and VAP were predictors of poor outcome. But in multivariate analysis presence of respiratory failure, duration of ventilation, low P/F ratios and high OI were not found as predictors of mortality except VAP which was an independent predictor of mortality which is in contrast to the studies done earlier which showed increased duration of ventilation to be an independent predictor of mortality. We reviewed in detail the case notes of the septicemic patients in an attempt to identify factors that may have contributed to mortality. Factors examined included the time from the onset of marked cardiovascular symptoms to the use of inotropes, the subsequent time to admission to the ICU and to intubation, the indications for intubation, and the time the patient died. There were no common patterns. In seven patients a possible factor for increased mortality may have been inadequate volume resuscitation and delayed use of inotropes which were given more than 24 hours after the onset of marked cardiovascular symptoms leading on to these patients having increased inotrope scores of > 20 during their hospital stay. If the prognosis is to be improved then rapid and adequate fluid resuscitation followed by early institution of inotropes is to be considered which is now the standard practice in our institute. Admission to the ICU is then considered if the patient's condition remains unstable or if increased inotropic doses or double inotropic agents are required. The mortality, for patients admitted with a systemic infection, was 73.9% (17/23) as compared to 84% in the study done by Heney D et al.41 Febrile neutropenia is a common indication for admission to our oncology ward. We have an aggressive management policy for these patients, and the overall survival is in the order of 98%.' Patients are treated early with broad spectrum antibiotics and receive haematological and cardiovascular support when necessary. The septicemic patients admitted to the ICU in our study therefore represent those patients where initial intensive therapy had failed and in whom cardiovascular and/or ventilatory support was required. The majority of febrile neutropenic patients in whom a bacteraemia is diagnosed have a Gram negative infection.10 All four patients who had three indications for the admission to the PICU i.e. shock, respiratory failure and raised ICP died. Type and phase of treatment of the underlying disease were not significantly associated with outcome. This wide range can be explained by different equipment for patient monitoring in oncology wards and most certainly by different criteria for PICU admission among centres. This study has several limitations: it is retrospective, with a small and heterogeneous patient population. The retrospective nature of this study might bias the estimates, as criteria for interventions might differ in different patient groups. Multiorgan failure remains the most difficult problem in these patients. Despite the generally poor prognosis for pediatric patients with hematological malignancies admitted to the PICU, intensive care continues to play an important role in the care of these patients. Although it is clear that patient who require mechanical ventilation and are having shock have a worse prognosis, we were unable to identify them as an independent predictor of mortality. We conclude, that in this study of 72 PICU admissions of patients with haematological malignancies, factors such as age, inotrope score, serum albumin levels, and absolute neutrophil count can independently predict the poor outcome. Simple clinical and laboratory parameters can help in predicting outcome in critically ill children with haematological malignancies. Results Patient profile The baseline clinical characteristics of children are listed in table 1. Out of 72 patients, 56 were males and 16 females. The median age was 7 years (4-10). The most common primary oncological diagnosis was acute lymphoblastic leukemia in 48 children followed by acute myeloid leukemia in nine. All of them received acute pre PICU care in the hemato-oncology ward of the hospital with a median duration of pre PICU stay of 48 hours (30 minutes – 24 days). This long delay in PICU shifting was due to non availability of beds in PICU. The median PRISM score was 12(0-39) and PRISM III score 32(20-57) were high. The median duration of PICU stay was 4 days (2-10). The median absolute neutrophil count was <367/mm3 (50-18900), the median platelet count was 28000/mm3 (1300-589000). The main cause of septic shock was pneumonia in 22 children. One third of children(24) had bacterial culture positive from blood or body fluids. The most common organism being acinetobacter followed by klebsiella and methicillin resistant staphylococcus aureus. Fungal infections were suspected in 40 children(55.5%). Two children also had CMV pneumonia proved by PCR for CMV, both these kids died. The various complications that were noticed during the PICU stay were barotrauma(3), BSI(15), VAP(10), lung collapse(3), fungemia (8) and pulmonary hemorrhage(5). The various other complications included pressure sores in 13 children, peritonitis in 2 children. The outcome and prognostic factors of PICU mortality Forty-one (56.9%) children died. Median duration of stay in the PICU was 4 days (2– 10 days). On univariate analysis, there was no significant difference in gender, subtype of acute leukemia, duration of PICU stay and duration of pre PICU care between survivors and nonsurvivors. At admission, the PRISM (p=0.004) and PRISM III (p= 0.029) scores were significantly high amongst nonsurvivors. Twenty-five (92.6%) out of 27 patients with acidosis died. Other factors associated with mortality were age < 3 years (OR 5.2, 95% CI- 1.3-21.2; p= 0.014); presence of shock (OR 6.7, 95% CI-2.3-19.8; p=0.0001); inotrope score>20 (OR 19.4; 95%CI-4.9-75.7; p=0.0001), respiratory failure (p=0.0001); oxygenation ratio<200 (p=0.004), oxygenation index>15(p=0.026); VAP (p=0.023); ARDS (p=0.000); BSI (p=0.046) and fungal sepsis(p=0.012). Among laboratory parameters at admission, absolute neutrophil count < 1500 mm3 (p=0.019), thrombocytopenia<10,000/mm3 (p=0.007), prothrombin index <75% (p=0.0005), hypoalbuminemia < 2.5 gm/dL (p=0.0009), BUN >18 mg/dL (p=0.0008), creatinine > 0.7mg/dL (p=0.026), showed significant differences between the survivors and non-survivors (Tables II). In a multivariate logistic regression model, inotrope score>20 (p=0.000), albumin <2.5 g/dL(p=0.001), Age > 3 years (p=0.011), VAP(p=0.05) were found to be independent predictors of death. Table 1 – Patient and Admission characteristics Patient characteristics (n%) 72 Male (n%) 56 77.8% Age (yrs, median, IQR) 7 4-10 Diagnosis Acute lymphoblastic leukemia (n%) 48 66.67% Acute Myeloid Leukemia (n%) 9 12.5% Non Hodgkin’s Lymphoma (n%) 7 9.72% Hodgkin’s Lymphoma (n%) 2 2.78% Others (n%) 6 8.3% Disease stage Newly diagnosed 8 11.11% Induction 25 34.72% Consolidation 10 13.89% Intensification 9 12.5% Maintenance 20 27.78% Main reason for ICU admission Septic shock 11 15.28% Respiratory failure 22 30.56% Shock and respiratory failure 21 29.16% Central nervous system complications 11 15.28% Miscellaneous 7 9.72% Duration of PICU admission (days, median, IQR) 4 2-10 PRISM (median, IQR) 12 0-39 PRISM 3 (median, IQR) 32 20-57 Mechanical ventilation (n%) 49 68.05% Vasopressor use (n%) 39 54.17% Figure 1: Mortality by number and type of organ failing after PICU admission, expressed as number of deaths per number of patients observed. Respiratory Shock failure 18/21 5/11 3/22 4/4 2/3 2/2 Neurological problem 2/11 Table II: Univariate outcomes N/N eval % P Age 0.014 <3years 3/12 25% >3years 38/60 63.33% Primary Oncological diagnosis 0.239 ALL 29/48 60.41% AML 6/9 66.66% NHL 3/7 42.86% ANC 0.019 <1500 35/54 64.81% >1500 6/18 33.33% PTI 0.005 <75% 28/53 52.83% >75% 3/19 15.79% Platelets 0.043 <10000 12/15 80% >10000 29/57 50.9% Albumin 0.001 <2.5 28/37 75.7% >2.5 13/35 37.1% BUN 0.001 >18 17/19 89.5% <18 24/53 45.3% Creatinine 0.026 >0.7 11/13 84.6% <0.7 30/59 50.85 Shock 0.000 Yes 30/39 76.9% No 11/33 33.3% Inotrope score 0.000 >20 28/31 90.3% <20 13/41 31.7% Respiratory failure 0.000 Yes 35/49 71.4% No 6/23 26.1% VAP 0.023 Yes 9/10 90% No 32/62 51.61% ARDS 0.000 Yes 26/32 81.25% No 15/40 37.5% Positive culture 0.046 Yes 17/23 73.9% No 24/49 48.97% Fungal sepsis 0.012 Yes 28/40 70% No 13/32 40.62% Acidosis 0.001 Yes 25/27 92.59% No 16/45 35.55% References 1. Ralston M, Hazinski M, Zaritsky A, et al. 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