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: drarunbansal@gmail.com.
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 (210). 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
interval between stem cell transplantation and ICU admission (> versus <90 days)7, 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% CI1.3-21.2; 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
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%
Newly diagnosed
8
11.11%
Induction
25
34.72%
Consolidation
10
13.89%
Intensification
9
12.5%
Maintenance
20
27.78%
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%
Diagnosis
Disease stage
Main reason for ICU admission
Figure 1: Mortality by number and type of organ failing after PICU admission,
expressed as number of deaths per number of patients observed.
Respiratory
failure
Shock
18/21
5/11
3/22
4/4
2/3
Neurological
problem
2/11
2/2
Table II: Univariate outcomes
Age
<3years
>3years
Primary Oncological diagnosis
ALL
AML
NHL
ANC
<1500
>1500
PTI
<75%
>75%
Platelets
<10000
>10000
Albumin
<2.5
>2.5
BUN
>18
<18
Creatinine
>0.7
<0.7
Shock
Yes
No
Inotrope score
>20
<20
Respiratory failure
Yes
No
VAP
Yes
No
ARDS
Yes
No
Positive culture
Yes
No
Fungal sepsis
Yes
No
Acidosis
Yes
No
N/N eval
%
3/12
38/60
25%
63.33%
P
0.014
0.239
29/48
6/9
3/7
60.41%
66.66%
42.86%
35/54
6/18
64.81%
33.33%
0.019
0.005
28/53
3/19
52.83%
15.79%
0.043
12/15
29/57
80%
50.9%
28/37
13/35
75.7%
37.1%
17/19
24/53
89.5%
45.3%
0.001
0.001
0.026
11/13
30/59
84.6%
50.85
0.000
30/39
11/33
76.9%
33.3%
28/31
13/41
90.3%
31.7%
0.000
0.000
35/49
6/23
71.4%
26.1%
0.023
9/10
32/62
90%
51.61%
26/32
15/40
81.25%
37.5%
17/23
24/49
73.9%
48.97%
0.000
0.046
0.012
28/40
13/32
70%
40.62%
0.001
25/27
16/45
92.59%
35.55%
References
1. Ralston M, Hazinski M, Zaritsky A, et al. Pediatric assessment. Pediatric advanced life
support, provider manual. Dallas (TX): American Heart Association; 2006. p. 1–32.
2. Valoor HT, Singhi S, Jayashree M. Low-dose hydrocortisone in pediatric septic shock: an
exploratory study in a third world setting. Pediatr Crit Care Med. 2009 Jan;10(1):121-5.
3. Newton C. Status epilepticus in resource poor countries. Epilepsia 2009.Dec;50(suppl 12):5455.
4. Perry AR, Rivlin MM, Goldstone AH. Bone marrow transplant patients with lifethreatening organ failure: when should treatment stop? J Clin Oncol 1999;17:298–
303.
5. Paz HL, Garland A, Weinar M, et al. Effect of clinical outcome data on intensive care
unit utilization by bone marrow transplant patients. Crit Care Med 1998;26:66–77.
6. Epner DE, White P, Krasnoff M, et al. Outcome of mechanical ventilation for adults
with haematologic malignancy. J Investig Med 1996;44:254–60.
7. Faber-Langendoen K, Caplan AL, McGlave PB. Survival of adult bone marrow
transplant receiving mechanical ventilation: a case for restricted use. Bone Marrow
Transpl 1993;12:501–7.
8. Bojko T, Nottermann DA, Greenwald BM, et al. Acute hypoxemic respiratory failure
in children following bone marrow transplantation: An outcome and pathologic study.
Crit Care Med 1995;23:755–9.
9. Denardo SJ, Oye RK, Bellamy PE. Efficacy of intensive care for bone marrow
transplant patients with respiratory failure. Crit Care Med 1989;17:4–6.
10. Brunet F, Lanore J, Dhainaut JF, et al. Is intensive care justified for patients with
haematological malignancies? Intensive Care Med 1990;16:291–7.
11. Rubenfeld GD, Crawford SW. Withdrawing life support from mechanically
ventilated recipients of bone marrow transplants:A case for evidence-based
guidelines. Ann Int Med 1996;125:625–33.
12. 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 Transpl 1998;21:697–704.
13. Yau E, Rohatiner AZS, Lister TA, Hinds CJ. Long term prognosis and quality of life
following intensive care for life-threatening complications of haematological
malignancy. Br J Cancer 1991;65:938–42.
14. Crawford SW, Petersen FB. Long term Survival from respiratory failure after bone
marrow transplantation. Am Rev Respir Dis 1992;145:510–4.
15. Tremblay LN, Hayland RH, Schouten BD, et al. Survival of acute myelogenous
leukaemia patients requiring intubation/ventilatory support. Clin Invest Med
1994;18:19–24.
16. Lloyd-Thomas AR, Wright I, Lister TA, et al. Prognosis of patients receiving
intensive care for lifethreatening medical complications of haematological
malignancy. Br Med J 1988;296:1025–9.
17. Groeger JS, White P Jr, Nierman DM, Glassman J, Shi W, Horak D, Price KJ.
Outcome for cancer patients requiring mechanical ventilation. J Clin Oncol
1999;17:991–7.
18. Price KJ, Thall PF, Kish SK, et al. Prognostic indicators for blood and bone marrow
transplant patients admitted to an intensive care unit. Am J Respir Crit Care Med
1998;158:876–84.
19. Torrecilla C, Cortés JL, Chamarro C, et al. Prognostic assessment of acute
complications of bone marrow transplantation requiring intensive therapy. Intensive
Care Med 1988;14:393–8.
20. Hinds CJ, Martin R, Quinton P. Intensive care for patients with medical
complications of haematological malignancy: is it worth it? Schweiz Med
Wochenschr 1998;128:1467–73.
21. Schuster DP, Marion JM. Precedents for meaningful recovery during treatment in
medical intensive care unit. Outcome in patients with haematologic malignancy. Am J
Med 1983;75:402–8.
22. Crawford SW, Schwartz DA, Petersen FB, et al. Mechanical ventilation after bone
marrow transplantation. Am Rev Respir Dis 1988;137:682–7.
23. Peters SG, Meadows AA, Gracey DR. Outcome of respiratory failure in
haematologic malignancy. Chest 1988;94:99–102.
24. Hayes C, Lush RJ, Cornish JM, et al. The outcome of children requiring admission to
an intensive care unit following bone marrow transplantation. Br J Haematol
1998;102:666–70.
25. Afessa B, Teferi A, Hoagland HC, et al. Outcome of recipients of bone marrow
transplants who require intensive care unit support. Mayo Clin Proc 1992;67:117–22.
26. Warwick AB, Mertens AC, ou Shu X, et al. Outcome following mechanical
ventilation in children undergoing bone marrow transplantation. Bone Marrow
Transpl 1998;22:787–94.
27. Wagner A, Staudinger T, Kofler J. Ergebnisse der intensivmedizinischen Betreuung
von
Patienten
nach
Knochenmarkstransplantation.Wien
Klin
Wochenschr
1996;108:667–82.
28. Paz HL, Crilley P, Weinar M, et al. Outcome of patients requiring medical ICU
admission following bone marrow transplantation. Chest 1993;102:527–31.
29. Estopa R, Torres-Marti A, Kastanos N, et al. Acute respiratory failure in severe
haematologic disorders. Crit Care Med 1984;12:26–8.
30. Todd K, Wiley F, Landaw E, et al. Survival outcome among 54 intubated pediatric
bone marrow transplant patients. Crit Care Med 1994;22:171–6.
31. Llyod-Thomas AR, Dhaliwal HS, Listal TA, Hinds CJ. Intensive therapy for lifethreatening medical complications of haematological malignancy. Intensive Care Med
1986;12:317–24.
32. Guiguet M, Blot F, Escudier B, Antoun S, Leclercq B, Nitenberg G. Severity-ofillness scores for neutropenic cancer patients in an intensive care unit: Which is the
best predictor? Do multiple assessment times improve the predictive value? Crit Care
Med 1998;26:488–93.
33. Blot F, Guiguet M, Nitenberg G, Leclercq B, Gachot B, Escudier B. Prognostic
factors for neutropenic patients in an intensive care unit: respective roles of
underlying malignancies and acute organ failures. Eur J Cancer 1997;33:1031–7.
34. Hebert PC, Drummond AJ, Singer J, Bernard GR, Russell JA. A simple multiple
system organ failure scoring system predicts mortality of patients who have sepsis
syndrome. Chest 1993;104:230–5.
35. Marshall JC, Cook DJ, Christou NV, Bernard GR, Sprung CL, Sibbald WJ. Multiple
organ dysfunction score: a reliable descriptor of a complex clinical outcome. Crit
Care Med 1995;23: 1638–52.
36. Watts CM, Knaus WA. The case for using objective scoring systems to predict
intensive care unit outcome. Crit Care Clin 1994;10:73–89.
37. Habicht JM, Reichenberger F, Gratwohl A, Zerkowski HR, Tamm M. Surgical
aspects of resection for suspected invasive pulmonary fungal infection in neutropenic
patients. Ann Thorac Surg 1999;68:321–5.
38. Butt W, Barker G, Walker C, et al. Outcome of children with hematologic malignancy
who are admitted to an intensive care unit. Crit Care Med 1988;16:761-4.
39. Thakkar SG, Fu AZ, Sweetenhem JW, et al. Survival and predictors of outcome of
patients with acute leukemia admitted to the intensive care unit. Cancer 2008;
112:2233-2240.
40. Park HY, Suh GY, Jeon K et al. Outcome and prognostic factors for patients with
acute leukemia admitted to the intensive care unit for septic shock. Leukemia and
Lymphoma, Oct. 2008;49(10):1929-1934.
41. Heney D, Lewis I J, Lockwood L, et al. The intensive care unit in paediatric
oncology. Archives of Disease in Childhood 1992; 67: 294-298.