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

Highlighted lines and questions below provide links to the pertinent description of criteria in The EBM User's Guide, now available at the Canadian Centres for Health Evidence

Article Reviewed:

Please visit the new Evidence Based Journal Club Reviews

Continuous veno-venous hemofiltration may improve survival from acute respiratory distress syndrome after bone marrow transplantation or chemotherapy.

DiCarlo JV, Alexander SR, Agarwal R, Schiffman JD.

J Pediatr Hematol Oncol. 2003 Oct;25(10):801-5. [abstract]

Reviewed by Edward J. Cullen Jr DO, Alfred I DuPont Hospital for Children, Wilmington, DE

Review posted December 15, 2003

---

I. What is being studied?:

The study objective:

Summarize one pediatric center's recent experience with continuous veno-venous hemodiafiltration with dialysis (CVVHDF) implemented within 24 hours of the institution of mechanical ventilation in the treatment of post bone marrow transplant or post chemotherapy patients who develop ARDS and propose possible hypothesis for the efficacy of the institution of such therapy.

The study design:

Case series

The patients included:

10 consecutive immuno-dysregulated children and young adults (ages 7 months to 17 years) with ARDS (initial Pa02/Fi02 ratio 94 ± 37 torr and diffuse, bilateral infiltrates). Immuno-dysregulation was due to aplastic anemia, myelodysplastic syndrome, AML, ALL, promyelocytic leukemia, T cell lymphoma or lymphoma.

The patients excluded:

None

The interventions compared:

None

The outcomes evaluated:

Successful extubation from mechanical ventilation, recovery of renal function, survival to intensive care and hospital discharge, follow up.

II. Are the results of the study valid?

Primary questions:

1. Was the assignment of patients to treatments randomized?

No

2. Were all patients who entered the trial properly accounted for and attributed at its conclusion?

Was followup complete?

Yes to 18 months

Were patients analyzed in the groups to which they were randomized?

No randomization

Secondary questions:

3. Were patients, health workers, and study personnel "blind" to treatment?

No

4. Were the groups similar at the start of the trial?

Not applicable since there were no control and experimental groups.

5. Aside from the experimental intervention, were the groups treated equally?

There was no comparison group. The time period it is not documented.

All patients in this case series were treated with oxygen and a non-protocol driven mechanical ventilation regimen that used small tidal volumes (6-8 ml/kg) and allowed permissive hypercapnea (PaC02 45-70 torr). All received hemofiltration plus countercurrent dialysis (CVVHDF) continuously while they were mechanically ventilated. Trisodium citrate was used as circuit anticoagulant. The dialytic component enhanced small molecule clearance and controlled sodium load. A targeted clearance rate fostered clearance of small and middle molecular weight molecules (e.g., proinflammatory mediators associated with ARDS). Intravenous replacement fluid was initially adjusted to allow a 10 to 100 ml/hr deficit if tolerated and eventually a "zero balance" strategy when premorbid weight was reached.

Temporary hemodialysis (13-30 days duration) was used for four patients after extubation and discontinuation of CVVHDF.

One patient received etanercept (a blocker of tumor necrosis factor, postulated to have immunomodulatory benefit in respiratory failure following BMT) on the 4th and 7th days of therapy.

III. What were the results?

1. How large was the treatment effect?

Nine of 10 patients successfully extubated after 14 ± 9 days mechanical ventilation. All survivors, including four who received temporary hemodialysis (13-30 days) after extubation and discontinuation of CVVFHF, recovered renal function. 8 survived to intensive care and hospital discharge (1 pending) and are alive and well at 18 months follow up. One non-survivor developed persistent, severe autonomic instability from a midbrain lesion and intensive care was withdrawn. One non-survivor with pre-existing chemotherapy related cardiomyopathy died of left ventricular failure within one day of therapy for septic shock.

Before instituting this single change in practice (early hemodiafiltration implemented within 24 hours of institution of mechanical ventilation required), the author's institution experienced an 85% mortality (34/40) in children with ARDS after BMT who needed mechanical ventilation for more than 48 hours. The similarity of these patients is not reported in the present article.

Although it is dangerous to compare the outcome of patients in a case series with the outcome of patients in the same institution treated differently during a different time period, we cautiously compare the two groups since the decrease in mortality from 85% to 33% seems dramatic.

Present Case Series

• BMT Patients
• Survival: 4 out of 6 survived (67%)
• Mortality: 2 out of 6 died (33%)

Chemotherapy only patients

• Survival: 4 out of 4 survived (100%)
• Mortality: 0%

Absolute Risk Reduction (ARR) in mortality for pediatric BMT patients with ARDS treated with early hemodiafiltration plus countercurrent dialysis implemented within 24 hours of institution of mechanical ventilation.

• ARR = 52% (85% -33%)
• Number needed to treat (NNT) = 1/ARR = 1.9

One would have to treat 1.9 pediatric bone marrow transplant ARDS patients with CVVHDF which is instituted at time of intubation and continued while they are mechanically ventilated in order to prevent 1 child from dying.

Relative Risk of death from ARDS in pediatric BMT patients if they also receive CVVHDF as outlined in the case series. (Ratio of the risk of an event among an exposed population to the risk among the unexposed)

• RR = .33/.85 = 39%

Relative Risk Reduction of death from ARDS in pediatric BMT patients if they also receive CVVHDF as outlined in the case series. (An estimate of the proportion of baseline risk that is removed by the therapy)

• RRR = 1-RR
• RRR = 1-.39
• RRR = 61%

More recent publications indicate a much better outcome for hematologic patients if intubation is instituted earlier (see references 15-18 in the article) with survival closer to 50%. If the historical experience of the studied institution was closer to 50% mortality then for the case series patients receiving the advocated therapy the ARR would be 17%, NNT 6, RR 58%, and RRR 42%.

Any of these comparisons between historical controls is highly speculative and should be regarded with great caution.

2. How precise was the estimate of the treatment effect?

Unable to calculate confidence intervals from the available data. Because of small numbers, expect large confidence intervals. With a case series like this with only 10 patients, there is no way to make any sort of conclusions about risk reduction or NNT. There can ONLY be speculation at best. It is intriguing, but we have to assume that if these 10 patients had been treated conventionally, there is a chance that the mortality rate would be the same.

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

1. Can the results be applied to my patient care?

We see similar post bone marrow transplant children with ARDS who are not in acute renal failure at time of presentation with their respiratory failure.

2. Were all clinically important outcomes considered?

Yes

• Successful extubation
• Ventilator days
• CVVHDF days
• Renal recovery
• Discharge alive from intensive care and hospital
• Follow up at 18 months

Considerations for future outcome measurements

• Barotrauma
• Reintubation rate until successful extubation
• PFTS post ARDS recovery
• Narcotic withdrawal issues
• Bleeding complications
• Electrolyte abnormalities
• Difficulties with citrate and calcium
• Mechanical problems encountered with CVVHFD
• Complications of venous catheters
• Number and timing of any organ systems failure
• Status of oncologic diagnosis at follow up

3. Are the likely treatment benefits worth the potential harms and costs?

Harms are not discussed. CVVHDF for renal failure is co- managed in our institution by Pediatric Critical Care attendings and Pediatric Nephrologists. Vascular access, coagulation issues, fluid and electrolyte problems are anticipated but can be managed. I would have to weigh the benefit of CVVHDF for non-renal failure indications against the known risks of CVVHDF in our population.

Cost was not discussed. There would be additional costs for vascular access, anticoagulation, dialysate, replacement fluid, additional monitoring labs and bedside nursing personnel. Shortened ventilator days, PICU and hospital days could reduce costs.

Clinical "bottom line"

Continuous veno-venous hemodiafiltration with dialysis at 50 ml/min/1.73 m², coincident with intubation and mechanical ventilation, may improve the survival of pediatric post bone marrow transplant ARDS patents.

For the next mechanically ventilated, pediatric, post bone marrow transplant ARDS patient who is not in renal failure, I would have to have a frank and informed discussion with family before routinely instituting CVVHDF at the same time that the child is intubated for ARDS (See references 1-6 below). After our discussion, if the family and the bone marrow transplant physician still desired this therapy, I would facilitate its implementation.

I look forward to a prospective, blinded, randomized, controlled, multicenter pediatric trial of early hemodiafiltration with dialysis in post bone marrow transplant ARDS patients as proposed by DiCarlo et al.

References

1. Anderson MR. Update on pediatric acute respiratory distress syndrome. Respir Care. 2003 Mar;48(3):261-76 [abstract]

   Prognosis for pediatric ARDS overall mortality rates: Timmons (1991) 75%, Davis, Furman, Costarino (1993) 62%, Paret et al (1999) 61%

2. Jacobe SJ, Hassan A, Veys P, Mok Q. Outcome of children requiring admission to an intensive care unit after bone marrow transplantation. Crit Care Med. 2003 May;31(5):1299-30 [abstract]

   Children who become ill after a BMT and require admission to the study ICU face a mortality rate of 72.5% at 6 months after ICU discharge even though 44% survived to discharge from the ICU. Children who required intubation had a mortality rate of 87%. Of ten patients with respiratory failure associated with pulmonary infection, there were no survivors among those (n=8) who remained ventilated at 48 hours. They were unable to identify factors clearly predictive of a poor outcome.

3. Keenan HT, Bratton SL, Martin LD, Crawford SW, Weiss NS. Outcome of children who require mechanical ventilatory support after bone marrow transplantation. Crit Care Med. 2000 Mar;28(3):830-5 [abstract]

   Cohort Study: 121 pediatric patients who received bone marrow transplant and subsequent mechanical ventilatory support. 19 (16%) survived to be extubated and survived ≥ 30 days postextubation Major risk for death: a) Respiratory failure as reason for endotracheal intubation (4% survival); b) Presence of pulmonary infection (6% survival); c) Impairment of more than one organ system (2% survival if more than one organ system was dysfunctional on day post intubation).

4. Lamas A, Otheo E, Ros P, Vazquez JL, Maldonado MS, Munoz A, Martos I. Prognosis of child recipients of hematopoietic stem cell transplantation requiring intensive care. Intensive Care Med. 2003 Jan;29(1):91-6 [abstract]

   Retrospective Study of cohort of patients: Overall mortality 70.4%. Mortality in patients requiring mechanical ventilation 76.5%. Mortality in patients not requiring mechanical ventilation 50%

5. Hagen SA, Craig DM, Martin PL, Plumer DD, Gentile MA, Schulman SR, Cheifetz IM. Mechanically ventilated pediatric stem cell transplant recipients: effect of cord blood transplant and organ dysfunction on outcome. Pediatr Crit Care Med. 2003 Apr;4(2):206-1 [abstract]

   Retrospective chart review: PICU, hospital and 2 year survival rates for mechanically ventilated umbilical cord blood transplant recipients were 37%, 25% and 19% respectively. PICU, hospital and 2 year survival rates for mechanically ventilated bone marrow recipients were 47%, 32% and 21% respectively. PICU, Hospital and 2 year survival rates for those requiring intubation for respiratory distress / failure were 25%, 16% and 10% respectively.

6. Smoyer WE, McAdams C, Kaplan BS, Sherbotie JR. Determinants of survival in pediatric continuous hemofiltration. J Am Soc Nephrol. 1995 Nov;6(5):1401-9. [abstract]

   Case reviews: 98 critically ill children (1988-1993). Ages 1 day to 23 year, 54% male. Primary diagnosis: sepsis and ARDS (11 each), liver transplantation and hypoplastic left heart (10 each), hemolytic uremic syndrome (9 patients). Overall survival rate 43%. Bone marrow transplant 0%, (0/6 patients). Survival to hospital discharge better in patients who did not receive pressors and in patients treated with combined ultrafiltration and dialysis.

Comments

Back to the EB Journal Club Index