Propofol Infusion Syndrome or Not? A Case Report

DISCUSSION

Despite more than 20 years of intensive research, the complete pathophysiological mechanisms responsible for PRIS have not been identified. Potential risk factors for PRIS include high-dose infusions of propofol for lengthy periods. This risk factor was first described in a series of 5 cases reported in 1992 in relatively healthy children with acute epiglottitis or tracheobronchitis who died after being sedated with propofol in the ICU. In these cases, the pediatric patients developed metabolic acidosis, lipemic serum, and refractory bradycardia progressing to asystole.¹

The name PRIS was coined in 1998 when Bray summarized 13 additional propofol-related deaths of children, all of whom exhibited a similar constellation of symptoms, including metabolic acidosis, lipemic serum, and refractory bradycardia progressing to asystole.² In 1996, Marinella was the first author to suggest that a propofol reaction should be included in the differential diagnosis of metabolic acidosis developing in adult patients during long-term sedation with propofol.³ In 1998, the first case of PRIS in an adult was reported. In this case, nearly all of the earlier presenting signs of PRIS in pediatric patients were described, including hypoxia, metabolic acidosis, rhabdomyolysis, renal failure, and cardiac dysfunction.⁴

The true incidence of PRIS is unknown. In 2009, Roberts et al evaluated 1,017 critically ill patients receiving propofol infusions for longer than 24 hours and reported the incidence of PRIS to be 1.1%.⁵ Fong et al analyzed 1,139 suspected cases of PRIS from the United States Food and Drug Administration's MedWatch system and estimated an incidence of approximately 30%.⁶ In addition to the confusion regarding the true incidence of PRIS, no consensus exists on the management of PRIS other than early recognition and discontinuation of propofol.

The clinical manifestations that define PRIS include the development of metabolic acidosis, rhabdomyolysis (skeletal > cardiac), cardiac arrhythmias (including right bundle branch block, Brugada-like syndrome, atrial fibrillation, supraventricular tachycardia, ventricular tachycardia, ventricular fibrillation, and electromechanical dissociation), acute renal failure, lipemic serum, hepatomegaly, and fatal cardiac arrest.² The onset of PRIS might be related to inhibition of intracellular energy production by mitochondria, possibly by 2 mechanisms: (1) inhibition of transportation of long-chain fatty acids into cells during the nutritionally deficient states of critical illnesses and/or (2) inhibitory effects on the intracellular mitochondrial respiratory chain.⁷ The metabolic derangements in PRIS appear to be triggered by (1) metabolic stress and high energy demand during critical illness in susceptible patients; (2) low carbohydrate supplies, especially in children; and (3) high availability of fats, as in propofol's emulsion of soybean oil and egg whites.^8,9 However, anything that inhibits effective cellular aerobic respiration may result in lactic acidosis that, if left untreated, can result in rhabdomyolysis, hyperkalemia, and, ultimately, acute renal failure. Other risk factors for PRIS include respiratory infection, severe head injury, propofol sedation for more than 48 hours at doses >4 mg/kg/h, and increased catecholamine and glucocorticoid serum levels.⁸ The metaanalysis by Fong et al found that death from PRIS was more likely if the patient was younger than 18 years old, received a vasopressor, or developed any of the following symptoms: cardiac arrhythmias, rhabdomyolysis, impairment in renal function, metabolic acidosis, or dyslipidemia.⁶

In our case, the patient displayed many of the diagnostic criteria for PRIS, including the development of metabolic acidosis, rhabdomyolysis, acute renal failure requiring hemodialysis, and, later, unanticipated cardiac arrest. The most important preexisting risk factor for PRIS in our case was the patient's sedation with propofol for more than 48 hours. Although the autopsy showed no evidence of hepatomegaly and the serum was not lipemic, the chronic passive congestion of the liver could have resulted from congestive heart failure in an obese patient with cardiomegaly. The only gross anatomical findings at autopsy that may have supported a diagnosis of PRIS included extensive muscle damage in the pelvic musculature and 2 extremities, which were more likely caused by wound ballistics and independently associated with rhabdomyolysis.

A differential diagnosis of PRIS is presented in the Table. Congenital cardiac conduction disorders such as Brugada syndrome, an autosomal dominant disorder in right ventricular conduction, can result in sudden death. Genetic polymorphisms that affect lipid metabolism, such as medium-chain acyl-coenzyme A dehydrogenase deficiency, may also be risk factors for PRIS and should be included in the differential diagnosis. Medications can also be a cause of laboratory derangements resembling PRIS. The medications that should be considered when ruling out PRIS either have the capability to cause muscle injury or have been shown to cause renal damage. Finally, miscellaneous conditions that need to be considered in the differential diagnosis of PRIS include the use of typical antipsychotics in bipolar patients and the presence of ongoing seizures in epileptic patients, both of which can cause rhabdomyolysis.