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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Propofol infusion syndrome in children

Bray RJ

Paed Anaesth 1998; 8:491-499. [abstract]

 

Reviewed by Steven Cray Birmingham Children's Hospital, UK

Review posted March 2, 2000

I. What is being studied?:

The study objective:

To investigate the evidence for an association between the use of long term (> 48 hrs), high dose (> 4 mg/kg/hr) infusions of propofol for sedation of children receiving intensive care and the development of a syndrome including metabolic acidosis and bradycardia progressing to asystole. The author also collected information about similar cases from published literature, regulatory bodies and personal communications. (*)

The study design:

This is best described as a retrospective cohort study.

The patients investigated:

The author examined the admission records for one intensive care unit over a seven year period during which propofol had been used as a sedative in some children to identify all children who met the following criteria:

1. Age less than 12 years
2. Primary diagnosis of a respiratory tract infection
3. Minimum ICU stay of 48 hrs

130 children met the above criteria and the charts of 128 of them were reviewed. The records of two children, one of whom died, were incomplete. Of the 128 children reviewed, 44 were intubated for more than 48 hrs. Nine of these children received propofol for > 48 hrs at > 4 mg/kg/hr, 9 received propofol for < 48 hrs or at < 4 mg/kg/hr and 26 were sedated without propofol, mainly using combinations of benzodiazepines and opioids.

The author defined the "propofol infusion syndrome" as: 1) sudden onset of bradycardia resistant to treatment and progressing to asystole; 2) lipemia; 3) liver enlargement or fatty infiltration at autopsy; 4) metabolic acidosis (base excess > -10); 5) evidence of rhabdomyolysis or myoglobinuria. A positive diagnosis required 1) and at least one of 2), 3), 4) or 5).

II. Are the results of the study valid?

Primary questions:

1.Were there clearly identified comparison groups that were similar with respect to important determinants of outcome, other than the one of interest?

Unclear. All the children studied had diagnoses of respiratory infections, predominantly bronchiolitis or croup. However there is no information given about severity of illness or the presence of important co-morbidities such as congenital heart disease, malignancy or prematurity. The three children who died have previously been reported (1,2,3), without mention of co-morbidity.

2. Were the exposures and outcomes measured in the same way in the groups being compared?

Yes.

3. Was follow-up sufficiently long and complete?

Yes.

Secondary questions:

4. Is the temporal relationship correct?

Yes.

5. Is there a dose-response gradient?

Perhaps. All the children who developed the "syndrome" and died in this series and in most other reported cases had received infusions of propofol > 4 mg/kg/hr for > 48 hrs. No child who received propofol for either < 48 hrs or at < 4 mg/kg/hr developed the "syndrome" or died. However the child who received the largest dose of propofol did not develop the "syndrome".

III. What are the results?

1. How strong is the association between exposure and outcome?

Nine children were sedated with propofol at > 4 mg/kg/hr for > 48 hrs and 3 of them developed the "propofol infusion syndrome". In this series, all the children who developed the "propofol infusion syndrome" died. 26 children were sedated without propofol and none of them developed the "syndrome" or died. There was another child who died and another who survived whose records were incomplete. To give propofol the benefit of the doubt, I shall assume that the child who died did not receive propofol and that the survivor did (this also enables meaningful calculations to be made).

	Outcome
Exposure	Dead	Alive
Propofol	3	7
No propofol	1	26

In this study the relative risk of death after being sedated with propofol at > 4 mg/kg/hr for > 48 hrs was 8.1 times greater than after sedation with other agents.

2. How precise is the estimate of the risk?

This study involved a small number of patients and the 95% confidence intervals for the relative risk are wide (95% CI for RR are 0.9 to 69.1).

IV. What are the implications for my practice?

1. Are the results applicable to my practice?

Yes. The children described represent a group of typical pediatric intensive care patients.

2. What is the magnitude of the risk?

In this study the absolute increase in the risk of death after propofol at > 4 mg/kg/hr for > 48 hrs was 26.3%. Thus 1 additional death occurred for every 3.8 children sedated with propofol rather than with other agents.

3. Should I attempt to stop the exposure?

Probably. The design of this study is rather weak, in particular important information about co-morbidity is not included. However, there is little published evidence to support a conclusion that propofol is a safe agent for prolonged use in children receiving intensive care and there are other agents, such as benzodiazepines, which have an established role. In small studies that have zero in the numerator, the upper 95% CI is 3/n. So, in a study of 106 children who received propofol with a zero incidence of the "propofol infusion syndrome" (4), we can only state with 95% certainty that the occurrence rate is less than 3% - not very reassuring to us when using a drug that has alternatives. It would seem sensible, therefore, to avoid prolonged, high-dose infusions of propofol in children receiving intensive care until data is available from randomized controlled trials (5).

Footnote

A total of 20 cases are included in the review. The maximum age was 17 years. The lowest mean propofol infusion rate was 4.9 mg/kg/hr and the shortest duration of infusion was 29 hrs. Seventeen of 20 children developed myocardial failure bradyarrhythmias resistant to treatment and progressing to asystole were predominant. Lipemia occurred in 10 of 11 cases, hepatic enlargement in 9 of 11, metabolic acidosis in 15 of 17 and rhabdomyolysis in 7 of 11 (complete details were unavailable in all cases, hence the variation in denominator). Overall, 17 of 20 children died. (return to text)

References

1. Parke TJ, Stevens JE, Rice AS, et al. Metabolic acidosis and fatal myocardial failure after propofol infusion in children: five case reports. Br Med J 1992;305: 613-616. [abstract]
2. Bray RJ, Fatal myocardial failure associated with a propofol infusion in a child. Anaesthesia 1995; 50: 94. [citation]
3. Cook S. Propofol infusion in children. Br Med J 1992;305: 952. [citation]
4. Pepperman ML, MacRae D. A comparison of propofol and other sedative use in paediatric intensive care in the United Kingdom. Paed Anaesth 1997;7: 143-153. [abstract]
5. Hatch DJ. Propofol infusion syndrome in children. Lancet 1999; 353: 1117-1118. [abstract]

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