The FDA Warning Against Prolonged Sedation With Propofol in Children Remains Warranted
Kate Felmet, MDTrung Nguyen, MD
Robert S. Clark, MD
Dick Orr, MD
Joseph Carcillo, MD
Children’s Hospital of Pittsburgh, Department of Critical Care Medicine, Pittsburgh, PA 15213
To the Editor.—
We read with concern the article published by Cornfield et al1 describing the use of propofol for long-term sedation in critically ill children. The authors conclude that their study "provides justification for continued use of propofol in the pediatric intensive care unit (PICU) setting." The design of the study, without controls or investigation of markers defining propofol infusion syndrome, precludes any statement that the drug is safe for prolonged use in children.
An unpublished randomized, controlled trial of propofol in 327 pediatric patients reviewed by the Food and Drug Administration (FDA) described a concentration-dependent increase in 28-day mortality in propofol-treated patients with a trend toward significance. The group receiving standard sedatives had a 4% mortality, those treated with 1% propofol had an 8% mortality, and those treated with 2% propofol had an 11% mortality.2 Pediatric Risk of Mortality (PRISM) scores for the 3 groups were 7.5, 7.2, and 7.5, respectively. Although the concentration of propofol used is not given in the present study, the authors report a 7% mortality rate similar to the 1% treatment group in the FDA-reviewed study. In our own PICU, where propofol is not used for prolonged sedation, the mortality rate for similar patients is just under 4%. In general PICUs in the United States, cardiothoracic surgery patients with a mean PRISM score of 10 have a mortality rate of 3%.4
There is biological plausibility for increased sensitivity to propofol in children. Infants have altered propofol pharmacokinetics relative to adults.5 In states of stress, infants and young children are more dependent than adults on the use of fatty acids as fuel substrates. Propofol has been associated with failure of mitochondrial respiration and defects of fatty acid oxidation.6,7 Death from energy failure would be seen by the clinician as multiple organ failure or myocardial failure, similar to 4 of the 10 deaths occurring within 1 week of propofol infusion in this study.
The author’s retrospective investigations into drug safety were limited to its effects on blood pressure and the development of metabolic acidosis and hyperlactatemia. Propofol infusion syndrome has been defined as arrhythmia during propofol infusion plus 1 or more of the following: 1) lipemic plasma, 2) hepatomegaly or hepatic stenosis, 3) metabolic acidosis with or without increased serum lactate, or 4) rhabdomyolysis with myoglobinuria.2,8,9 The authors do not report the presence or absence of signs or symptoms of this syndrome in their population. It is our opinion that the FDA advisory against using propofol for prolonged sedation in the PICU remains warranted.
REFERENCES
- Cornfield DN, Tegtmeyer K, Nelson MD, Milla CE, Sweeney M. Continuous propofol infusion in 142 critically ill children.
Pediatrics.2002; 110
:1177
–1181
[Abstract/Free Full Text] - Dear health care provider letter. Newark, DE: AstraZeneca; March 26, 2001
- Bray RJ. Propofol infusion syndrome in children. Paediatr Anaesth.1998; 8 :491 –499[CrossRef][Web of Science][Medline]
- Care characteristics of the post-operative congenital hear disease patient. Crit Care Med.1997; 29 :A137
- Rigby-Jones AE, Nolan JA, Priston MJ, Wright PM, Sneyd JR, Wolf AR. Pharmacokinetics of propofol infusions in critically ill neonates, infants, and children in an intensive care unit. Anesthesiology.2002; 6 :1393 –400
- Wolf A, Weir P, Segar P, Stone J, Shield J. Impaired fatty acid oxidation in propofol infusion syndrome. Lancet.2001; 357 :606 –607[CrossRef][Web of Science][Medline]
- Branca D, Roberti MS, Lorensin P, Vincenti E, Scutari G. Influence of the anesthetic 2,6-diisopropylphenol on the oxidative phosphorylation of isolated rat liver mitochondria. Biochem Pharmacol.1991; 42 :87 –90[CrossRef][Web of Science][Medline]
- Crevner OL, et al. Long term propofol infusion and cardiac failure in adult head injured patients. Lancet.2001; 357 :117 –118[CrossRef][Web of Science][Medline]
- Kang TM. Propofol infusion syndrome in critically ill patients. Ann Pharmacother.2002; 36 :1453 –1456[Abstract]
David N. Cornfield, MD
Michael D. Nelson, MD
Carlos E. Milla, MD
Division of Pediatric Pulmonology and Critical Care Medicine, University of Minnesota, Minneapolis, MN
Michael Sweeney, MD
Division of Pediatric Pulmonology and Critical Care Medicine, Departments of Pediatrics and Anesthesia, University of Minnesota, Minneapolis, MN
Kenneth Tegtmeyer, MD
Department of Pediatrics, Oregon Health and Sciences University, Portland, OR
In Reply.—
The authors appreciate the careful and considered attention that Felmet et al provided to our article.1 Providing definitive evidence for safety is an imposing and, in most cases, impossible task. Thus, the present trial made no attempt to achieve such a lofty goal. Rather, the intent of the article was to provide a dosing algorithm that has been safely applied in our patient population to physicians choosing to use propofol to manage critically ill children in the pediatric intensive care unit (PICU). The article neither implicitly nor explicitly recommends propofol for use in the PICU. However, it remains our belief that propofol can be safely used in the PICU.
Nonetheless, the authors agree that any and all new data warrants vigorous scrutiny. While Felmet et al correctly calculated a 7% mortality rate, more detailed consideration of the patients in the trial who died is instructive. In 7 of the 10 deaths reported in the present trial, after both parents and providers determined that further care would be futile, life support was discontinued. In 3 patients with end-stage cystic fibrosis, mechanical ventilation was continued to allow extended family members an opportunity to visit with the children before death. Two children developed acute respiratory distress syndrome (ARDS), before the initiation of propofol, within 14 days after bone marrow transplantation. ARDS in children immediately after bone marrow transplantation has been previously reported as almost uniformly fatal.2,3 In 2 patients who died secondary to an underlying metabolic disorder, an inborn error of metabolism was identified. Both of these children presented to the PICU with a serum ammonia level in excess of 500 µg/dL and were treated emergently with hemodialysis. Support was withdrawn in these infants after diagnostic studies demonstrated profound neurologic injury. Overall, the average PRISM score upon admission to the PICU of all the patients who died in the present trial was 42, reflective of a mortality risk that approached 1.4 If patients in whom support was withdrawn because of poor prognosis were excluded, the mortality rate in the trial would be significantly below 3%.
With respect to signs and symptoms of propofol toxicity that were not addressed in the present trial, no patients enrolled in the trial had myoglobinuria. Although myocardial function was not directly measured, urine output did not decrease and metabolic acidosis did not develop after the initiation of propofol. In the absence of a change in urine output, blood pressure, heart rate, or acid-base status, the results of the present trial are not consistent with an effect of propofol on myocardial function in the dosing ranges outlined in our manuscript. No cardiac rhythm abnormalities were noted in any of the patients enrolled in the study.
The most salient difference between the present trial and those cited by Felmet et al is the dose of propofol used. In our trial the maximum dose was 67 µg/kg/min. Most patients in the trial were treated with a dose that was below the maximum. In contrast, in the trial that prompted the letter to health care providers, propofol was initiated at a dose of 85 µg/kg/min.5 Whether the deaths in the trial occurred in association with an even higher dose of propofol is unknown.
Despite the above comments, the authors agree wholeheartedly with Felmet et al that prudence and wariness are necessary whenever children are administered long-term sedation in the PICU. After all, a healthy dose of skepticism lies at the heart of all good medicine.
REFERENCES
- Cornfield DN, Tegtmeyer K, Nelson MD, Milla CE, Sweeney M. Continuous propofol infusion in 142 critically ill children. Pediatrics.2002; 110 :1177 –1181
- 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 –670[CrossRef][Web of Science][Medline]
- 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; 28 :830 –835[CrossRef][Web of Science][Medline]
- Pollack MM, Ruttimann UE, Getson PR. Pediatric risk of mortality (PRISM) score. Crit Care Med.1988; 16 :1110 –1116[Web of Science][Medline]
- Dear health care provider letter. Newark, DE: AstraZeneca; March 26, 2001
PEDIATRICS (ISSN 1098-4275). ©2003 by the American Academy of Pediatrics
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