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On-line version ISSN 1806-907X
Rev. Bras. Anestesiol. vol.57 no.5 Campinas Sept./Oct. 2007
FT síndrome de la infusión del propofol
Fabiano Timbó Barbosa, TSA
Anestesiologista da Unidade de Emergência Dr. Armando Lages e do Hospital Escola Doutor José Carneiro; Médico Intensivista da Clínica Santa Juliana; Tutor da Liga de Anestesia, Dor e Terapia Intensiva de Alagoas
BACKGROUND AND OBJECTIVES: Propofol infusion syndrome has been described
as a rare, and frequently fatal, syndrome that occurs after prolonged infusion
of this drug. It might result in severe metabolic acidosis, rhabdomyolysis,
cardiovascular failure, and death. The objective of this report was to review
the literature to present aspects related to the propofol infusion syndrome.
CONTENTS: The physiopathology, clinical characteristics, and treatment, of the propofol infusion syndrome as well as dose recommendations for severely ill patients are presented here.
CONCLUSIONS: Propofol should be used with caution when it is administered as continuous infusion for prolonged periods of time. The development of signs suggestive of the propofol infusion syndrome indicates the drug should be discontinued immediately and support measures instituted.
Key Words: ANESTHETICS, Intravenous, propofol; COMPLICATIONS: propofol infusion syndrome.
JUSIFICATIVA Y OBJETIVOS: El síndrome de la infusión
del propofol ha sido descrito como un síndrome raro y frecuentemente
fatal que ocurre después de la infusión prolongada de ese fármaco.
Puede resultar en acidez metabólica grave, rabdomiólisis, colapso
cardiovascular y deceso. El objetivo de este artículo fue mostrar aspectos
relacionados al síndrome de la infusión del propofol a través
de la revisión de la literatura.
CONTENIDO: Están definidas las características del síndrome de la infusión del propofol en cuanto a la fisiopatología, características clínicas, tratamiento y recomendaciones de dosis para pacientes gravemente enfermos.
CONCLUSIONES: El propofol debe ser usado con cautela cuando se planea su uso bajo el régimen de infusión continua por períodos prolongados. El aparecimiento de señales sugestivas del síndrome de la infusión del propofol indica la suspensión inmediata del fármaco y el inicio de medidas de soporte.
Propofol was introduced in clinical practice in 1977 exclusively as an intravenous drug to be used to induce anesthesia 1. Fast awakening of patients, even after prolonged infusion, called the attention of researchers for other uses 1. This drug has slowly replaced barbiturates to sedate patients on mechanical ventilation in intensive care units, with the advantage that it can protect the brain of patients hemodynamically unstable 2.
The first reports compatible with the propofol infusion syndrome (PRIS), with a high mortality rate, appeared when its use became more widespread 1.
PHARMACOKINETICS AND PHARMACODYNAMICS OF PROPOFOL
Propofol, or 2,6 diisopropylphenol, is relatively insoluble in water 3. It is commercialized as 1% or 2% milky, white solution containing 10% soy oil, 2.25% of glycerol, and 1.2% of purified egg phosphates 4. The presence of organic components makes it possible to be contaminated, but the addition of EDTA added more safety to its administration 4,5.
Some pharmacokinetic models suggested a distribution half-life between 2 and 4 minutes, and 1 to 3 hours of elimination half-life (T½b) 4,5. It has hepatic and extra-hepatic metabolism 3-5, probably in the lungs3, since its rate of degradation is higher than the hepatic blood flow 4,5. It forms inactive sulfates and glucuronides 4,5. Its T½b is slightly elevated in the presence of liver disease 4.
Propofol is eliminated in the urine, but there is little change in its pharmacokinetics in case of kidney disease 4-6.
Children need higher doses due to the larger volume of distribution in the central compartment and higher clearance; the opposite is true for the elderly 4,5.
More than one mechanism of action has been proposed for propofol. It potentiates the central inhibition of gamma-aminobutyric acid on its type A receptor, blocks the ion channel in the cerebral cortex and central nicotinic receptors, and inhibits the signaling of lysophosphatidate in receptors of lipid mediators 3.
This drug has a direct depressive action in the cardiovascular system, and it also decreases the tone of catecholamines, besides inhibiting the baroreceptor 3-5. It depresses the vascular smooth muscle and reduces pre- and post-load 4.
Propofol reduces intracranial pressure, brain blood flow, and brain oxygen consumption, protecting the central nervous system 3-5. However, it can also decrease cerebral perfusion pressure due to its hemodynamic effects 4. It preserves the reactivity of cerebral vessels to carbon dioxide (CO2) and cerebral self-regulation 3-5. Evidences have demonstrated that it has anticonvulsant properties, although this property is controversial 4.
Propofol causes central respiratory depression and reduces respiratory response to CO2 and hypoxemia 3-5. It causes bronchodilation in patients with chronic obstructive pulmonary disease, and it does not inhibit pulmonary vasoconstriction to hypoxemia 3.
Its actions in the immune system are controversial. Some authors suggested it has a beneficial action in patients with endotoxemia, but others demonstrated a reduction in interleukin-8 formation, with inhibition of the immune system 4,5.
PROPOFOL INFUSION SYNDROME
Propofol infusion syndrome is a set of adverse events, almost always fatal, that occur after continuous infusion of high doses of propofol. It affects adults and children, although it seems to be more frequent in children 1.
Clinical and laboratorial changes related to the syndrome include heart failure 1,6-8, arrhythmias1, metabolic acidosis 1,8, hypertriglyceridemia 1, rhabdomyolysis 6-8, and renal failure 6,8. Fatty infiltration of the liver 1,6, lungs, and other organs 6 is also present. Muscle biopsy might reveal necrotic areas along with regenerating areas, compatible with myonecrosis 1.
The physiopathology of the propofol infusion syndrome is not completely understood. Some theories proposed include: inhibition of mitochondrial activity by decreasing the activity of cytochrome C oxidase 1,10 and by failure in the oxidation of fatty acids 8-10, blockade of beta-adrenergic receptors 8-10, and the presence of a toxic metabolite in the tissues 1,10. The last hypothesis is not accepted by all authors as being possible because there is evidence that the known metabolites of propofol do not have clinically significant activity 1.
The doses mentioned in the literature as being capable of triggering the propofol infusion syndrome are greater than 5 mg.kg-1.h-1 for a period of more than 48 hours 2,6,10. Although this is the classic description, it has been described the development of the syndrome in an adult after 12 hours of infusion of high doses, in a child after 6 hours 8, and after 4 hours during anesthesia after the accidental use of 44.7 mg.kg-1.h-1 in a 6-month old child 7.
The main risk factors associated with this syndrome seem to be the dose and the duration of the infusion, and it is also possible that the concentration of the solution plays a role 1. Recently, the concomitant use of corticosteroids8 or vasoactive amines9 with propofol has also been implicated as a predisposing factor. Elevated levels of catecholamines have been related to the ventricular dysfunction that occurred in some cases 9.
Treatment of the propofol infusion syndrome includes the immediate discontinuation of the drug, support measures, and dialysis. When dialysis can not be used, mortality reaches 100% 1.
In a study by Sheridan et al. 11 with burned children, continuous infusion of propofol, with mean doses of 3.6 ± 2.9 mg.kg-1.h-1 for 8 hours, was successfully used to help weaning off mechanical ventilation, without signs of the propofol infusion syndrome. The authors suggested that infusion of moderate to low doses of propofol for a short period, hours instead of days, could be safely used in children. In this context of low to moderate doses, Sloan 12 reported that propofol is safer than halogenated agents, barbiturates, and nitrous oxide for short procedures in children with muscular mitochondrial disorders. In their pharmacokinetic studies in severely ill children, Rigby-Jones et al. 13 suggested that doses of up to 4 mg.kg-1.h-1. are safe; but one should remember that their patients were observed after cardiac surgeries 14.
Propofol should be used carefully when it is to be administered as a continuous infusion for long periods. The development of signs suggestive of the propofol infusion syndrome is an indication that the infusion should be discontinued immediately and the institution of support measures initiated.
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09. Cobett SM, Moore J, Rebuck JA et al. Survival of propofol infusion syndrome in a head-injured patient. Crit Care Med, 2006; 34:2479-2483. [ Links ]
10. Coetzee JF, Coetzer M Propofol in paediatric anaesthesia. Curr Opin Anesthesiol, 2003;16:285-290. [ Links ]
11. Sheridan RL, Keaney T, Stoddard F et al. Short-term propofol infusion as an adjunt to extubation in burned children. J Burn Care Rehabil, 2003;24:356-360. [ Links ]
12. Sloan IAJ Propofol syndrome in children. CMAJ, 2003; 168:669. [ Links ]
13. Rigby-Jones AE, Nolan JA, Priston MJ et al. Pharmacokinetcs of propofol infusion in critically ill neonates, infants, and children in an intensive care unit. Anesthesiology, 2002;97:1393-1400. [ Links ]
14. Baun VC Pharmacokinetcs of propofol infusion in critically ill neonates, infants, and children in an intensive care unit. Surv Anesthesiol, 2003;47:315-316. [ Links ]
Fabiano Timbó Barbosa
Rua Comendador Palmeira, 113/202
Edifício Erich Fromm Farol
57051-150 Maceió, AL
Submitted em 31 de agosto de 2006
Accepted para publicação em 25 de junho de 2007
Received from Hospital Escola Doutor José Carneiro