Criteria abstracted from The Users' Guide to Medical Literature, from the Health Information Research Unit and Clinical Epidemiology and Biostatistics, McMaster University

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Article Reviewed:

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Prognosis of pediatric bone marrow transplant recipients requiring mechanical ventilation

Rossi R, Shemie SD, Calderwood S.

Crit Care Med 1999;27:1181-6. [abstract]

Reviewed by Judith Heggen DO, James Fortenberry MD, Children's Healthcare of Atlanta at Egleston, Emory University School of Medicine, Atlanta, GA

Review posted October 20, 2000

I. What is being studied?:

The study objective:

To assess the prognosis of pediatric bone marrow transplant recipients requiring mechanical ventilation and to identify risk factors for mortality.

The study design:

Retrospective chart review.

The outcomes assessed:

Extubation, PICU discharge, and 6 month survival.

II. Are the results in the study valid?

Primary questions:

1. Was there a representative and well-defined sample of patients at a similar point in the course of the disease?

Yes. 355 patients received bone marrow transplants (BMT) during the study period, 56% for primary malignant disease and 44% for nonmalignant conditions. 39 patients, between the ages of 11 months to 19 years (median age 6.5 yrs), were identified as having received a bone marrow transplant and subsequently admitted to the PICU and received mechanical ventilation from January 1986 through October 1995. Two patients were admitted to the PICU on two occasions for a total of 41 events. 33 patients underwent allogeneic BMT (18 from related donors and 15 from matched unrelated donors) and 6 received autologous transplants. There were 23 males and 16 females. Median time from BMT to PICU admission was 47 days (45 days for survivors and 61 for nonsurvivors). Lung failure was the most frequent diagnosis during PICU treatment (n = 37)) followed by multiple organ failure (two organ systems or more, n = 34; three organ systems or more, n = 28; four organ systems or more, n = 20). All consecutive PICU admissions and all consecutive BMT patients during that time period were reviewed to ensure that no patients were missed. Patients who required perioperative ventilation were excluded.

2. Was follow-up sufficiently long and complete?

Yes. All survivors were followed for 6 months after PICU discharge. No patients were lost to follow-up.

Secondary questions:

3. Were objective and unbiased outcome criteria used?

Yes. The outcomes were extubation, PICU discharge and survival at 6 months after PICU discharge. However, the mechanism of death, and in particular whether patients died from elective withdrawal of support, was not reported.

4. Was there adjustment for important prognostic factors?

Yes. The study was designed to identify easily measured and significant risk factors and clinical conditions associated with mortality. Risk factors analyzed included the primary diagnosis (malignant/nonmalignant), the transplant type (autograft or allograft), the presence of graft vs host disease, days after BMT, and leukocyte count ( 2 or > 2 x 10⁹/L). Indicators of clinical condition included PRISM score on admission, multiple organ system failure, pulmonary failure (PaO2/FiO2 ratio, oxygenation index, and alveolar-arterial oxygen difference), Glasgow Coma Scale score, renal failure, liver failure, and sepsis.

III. What are the results?

1. How large is the likelihood of the outcome event(s) in a specified period of time?

17 of 39 patients were extubated and discharged from the PICU for an acute survival rate of 44%. 14 of 17 patients were still alive 6 months after discharge for a medium term survival of 36%.

Primary disease, type of transplant, time after transplantation, leukocyte count, presence of graft vs. host disease and organ and lung dysfunction at admission were not significant risk factors associated with mortality. Median PRISM scores on admission were significantly different between survivors (7), vs nonsurvivors (14) (Wilcoxon test; p < .05). Only 4 of 20 patients with more than three failed organ systems survived (estimated probability of survival 8.4%), while 14 of 21 survived with up to 3 organ systems failing (estimated probability of survival 67%). This was significant by Fisher's exact and chi-squared tests (p < .001) and by multivariate analysis (p < .01). All patients who died had some degree of multiple organ failure (at least two systems), with lung failure in all cases (defined as PaO2/FiO2 ratio < 300). 16 of 36 patients survived with a PaO2/FiO2 ratio < 200, and 11 of 31 survived with a PaO2/FiO2 ratio of < 150. Pulmonary function deterioration and neurologic deterioration were the most important determinants of poor outcome (statistical analysis was not provided for neurologic deterioration). Severe liver failure and renal replacement therapy were also significant factors impacting survival.

2. How precise are the estimates of likelihood?

Confidence intervals (CI) were not reported for the main outcomes of extubation, survival to PICU discharge and 6 month survival. We were able to calculate the 95% CI from the standard error of a proportion (sep) using the formula:

Standard error of the proportion = square root of [p x (1-p)]/n
95% CI = 100 x [p - (1.96 x sep)], 100 x [p + (1.96 x sep)]

or can be performed online at: http://members.aol.com/johnp71/confint.html

17 of 39 (44%) patients survived to PICU discharge with a 95% CI around this estimate of 28.5% to 59.5%. 14 of 39 (36%) patients were alive at the 6 month follow-up with a 95% CI of 21% to 51.5%.

Confidence intervals for the risk factors for mortality were not reported. Using the standard error of a proportion we calculated the CI for survival if the PaO2/FiO2 was < 150. 11 of 31 (36%) survived with a 95% CI around this estimate of 19.1% to 52.9%.

We were also able to calculate the relative risk estimate for survival based on the number of organ systems failed.

Table 1. Number of organ systems failed and outcome

# of organs failed	N	Survived	Died	RR	95% CI
2 Yes       No	34	13	21	0.53	0.35, 1.4
	7	5	2	1
3 Yes       No	28	9	19	0.46	0.26, 1.03
	13	9	4	1
4 Yes       No	20	4	16	0.3	0.1, 0.77
	21	14	7	1

So we can conclude, with 95% certainty, that the true chance of survival in those with 4 organs failed to be between 10% and 77% of those with < 4 organs failed.

IV. Will the results help me in caring for my patients?

1. Were the study patients and their management similar to my own?

Yes. The patients in the study represented pediatric age patients who received bone marrow transplants for both malignant and nonmalignant diseases. They also represented patients who had received autologous and allogeneic transplants. The authors note that the need for PICU admission and mechanical ventilation in their total BMT population was 11% of the total BMT population compared to 19% in a previous study by Todd et al. (1) In a subsequent study published by Keenan et al (2) 12% of their total BMT population required mechanical ventilation for > 24 hrs. The authors also note relatively low PRISM scores on admission (mean 11.4) compared to the study by Bojko et al (3) with a mean PRISM score of 19.4 (calculated during the first 24 hrs of admission to the PICU). PRISM scores were not reported in the study by Keenan et al.(2) It is unclear whether this represents less severely ill patients in the current study. Of note, initial median oxygenation index scores were 10.22 and 15.4 in survivors and nonsurvivors respectively.

2. Will the results lead directly to selecting or avoiding therapy?

Possibly. The authors report improved survival rates compared to previous studies (1,3, 4), and to the subsequent study by Keenan et al. (2) Based on this current study alone, one would be encouraged to provide aggressive mechanical ventilation in the BMT patient with isolated respiratory failure in the absence of multiple organ failure. It is, however, unclear why the survival rate improved. The authors note that a high end-expiratory pressure and pressure limitation and permissive hypercapnia ventilatory strategy was used in approximately half the patients with severe respiratory failure. Data for survival was not analyzed comparing different strategies of mechanical ventilation. There were no preexisting conditions identified that support limiting the use of mechanical ventilation in this population. There were survivors even among patients with 4 organ systems failing.

3. Are the results useful for reassuring or counseling patients?

Possibly. While the results from the current study are encouraging, the subsequent study by Keenan et al (2) noted a survival rate of only 16%. Previous studies noted survival rates of 9% to 12%. (1,3,4) While the overall prognosis remains poor for this patient population, there are survivors. As the authors state, initiation of aggressive therapy appears to be warranted. The decision to continue therapy in light of worsening pulmonary status and multi-system organ failure will need to be made on an individual basis.

References

1. Todd K, Wiley F, Landaw E, Gajewski J, Bellamy PE, Harrison RE, Brill JE, Feig SA. Survival among 54 intubated pediatric bone marrow transplant patients. Crit Care Med 1994; 22:171-176. [abstract]
2. Keenan HT, Bratton SL, Martin LD, Crawford SW, Weiss NS. Outcome of children who require mechanical ventilatory support after bone marrow transplant. Crit Care Med 2000; 28:830-835. [abstract]
3. Bojko T, Notterman DA, Greenwald BM, Dr Bruin WJ, Magid MS, Godwin T. Acute hypoxemic respiratory failure in children following bone marrow transplantation: An outcome and pathologic study. Crit Care Med 1995; 23:755-759. [abstract]
4. Nichols DG, Walker LK, Wingard JR, Bender KS, Bezman M, Zahurak ML. Piantadosi S, Frey-Simon M, Rogers MC. Predictors of acute respiratory failure after bone marrow transplantation in children. Crit Care Med 1994; 22:1485-1491. [abstract]

 

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