Journal: Curr Opin Anaesthesiol 21(5):544-551, 2008.
Reprint: Department of Intensive Care, University Medical Centre Utrecht, Utrecht, The Netherlands (LC Otterspoor, MD)
Faculty Disclosure: Abstracted by T. Tilton, who has nothing to disclose.
The use of propofol in patients with traumatic brain injury (TBI) reduces cerebral metabolic demand, facilitates control of intracranial hypertension, and possibly has added neuroprotective and anticonvulsive properties. Since 1992, reports have described the potentially fatal complications after prolonged infusions, which have been named the propofol infusion syndrome (PRIS). This review describes the clinical presentation of PRIS along with proposed cause, pathophysiology, and management.
Clinical features of PRIS are divided into early signs including lactic acidosis, lipemic serum (possibly related to impending failure of hepatic lipid regulation secondary to poor oxygenation and lack of glucose supply), and Brugada-like ECG abnormalities (coved-type ST-segment elevation in V1-V3), which can be an early warning sign of impending cardiac electrical instability, and late signs of cardiovascular collapse, rhabdomyolysis, hyperkalemia, arrhythmia/heart block, and renal failure. Death has been reported.
Risk factors include large cumulative doses of propofol, young age, acute neurological injury, low carbohydrate intake, high fat intake, catecholamine infusion, corticosteroid infusion, critical illness, and inborn errors of mitochondrial fatty acid oxidation. The authors found that in patients with TBI, PRIS did not occur with mean propofol doses < 5 mg/kg/hr but the incidence was 17% and 31% in patients receiving 5-6 and > 6 mg/kg/hr, respectively. Children may be more prone to PRIS due to lower glycogen stores.
The pathophysiology of PRIS is multifactorial and likely involves several parallel-acting mechanisms. A key pathogenic mechanism appears to be an imbalance between energy demand and utilization resulting in cardiac and peripheral muscle necrosis.
Propofol appears to decrease the ability of mitochondria to produce energy and probably should not be used in patients with an inborn error of mitochondrial fatty acid metabolism such as a very long chain acyl-coenzyme A dehydrogenase deficiency. This effect leads to the accumulation of free fatty acids, which appears to have pro-arrhythmogenic properties. Propofol increases serum triglycerides, leading to lipemia. Liver dysfunction secondary to circulatory failure or to direct hepatotoxic effects of propofol may adversely affect lipid kinetics. It is noted that lipemia alone can impair mitochondrial oxygen uptake, thereby contributing to the accelerated development and refractory nature of PRIS.
Propofol antagonizes β-adrenoreceptor binding, which explains why higher doses of catecholamines (CAT) may be needed in patients on propofol, although CAT administration decreases propofol plasma levels, likely due to increased propofol clearance with the rise in cardiac output and portal flow. The hyperdynamic state seen in patients with a systemic inflammatory response syndrome can increase propofol clearance and also dose requirements. A vicious cycle arises of progressively increasing the propofol infusion (resulting in hypotension) followed by increasing CAT infusions (resulting in a decreased level of sedation). High doses of CAT are associated with ECG signs of ischemia and histopathological findings such as myofibrillar degeneration or myocytolysis. Many critically ill patients with PRIS also received high-dose steroids, which can promote proteolysis of cardiac contractile myofilaments and may trigger acute muscle damage. Propofol can affect heart rhythm by reducing sympathetic tone more than parasympathetic tone causing bradycardia. High dose propofol may lead to Brugada ECG changes causing electrical instability and malignant arrhythmias.
Clinical management involves a high degree of suspicion of PRIS in the presence of lactic acidosis and when the need for inotropic support increases in patients on propofol in the absence of a well understood cause. Propofol should be immediately discontinued. Critically ill patients, especially those with TBI, should be monitored for other early signs such as lactate, creatine kinase and myoglobin levels and ECG monitoring for ST-segment elevations. Patients with severe bradyarrhythmia may require cardiac pacing. Hemodialysis and hemoperfusion eliminate propofol and its metabolites but remains unproven. Extracorporeal membrane oxygenation has been used for combined respiratory and circulatory support. An adequate carbohydrate intake (6-8 mg/kg/min) is recommended to provide ample substrate to the failing mitochondria and suppress lipid oxidation.
In conclusion, propofol infusion should not exceed 4 mg/kg in patients with severe TBI or others with high risk factors. Patients without risk factors may receive propofol up to 5 mg/kg/hr. If clinically acceptable sedation is not achieved with these rates, other sedatives should be added. Safe doses of propofol for anesthesia or short-term sedation are up to 15 mg/kg/hr for children and 12 mg/kg/hr for adults. |
