JOURNAL OF THE LOUISIANA STATE MEDICAL SOCIETY
and the benzodiazepines, midazolam and diazepam, were the most commonly co-administered drugs in fatal propofol overdoses.
significant; and likely underreported. 14
Fatalities from propofol abuse must be differentiated from the very rare fatalities resulting from the propofol infusion syndrome (PRIS) which may occur at therapeutic and, more often, supra-therapeutic doses of propofol for prolonged periods. PRIS was first described in children in the 1990’s with several adult case reports following shortly afterwards. 15-19 The name “propofol infusion syndrome” was later coined in 1998 when Bray summarized thirteen more propofol-related deaths in children. 19 These children all exhibited a similar constellation of symptoms including metabolic acidosis, lipemic serum, and refractory bradycardia progressing to asystole. 19 In 1996, Marinella was among the first authors 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. 20 Subsequently, in 2000, the first fatal case of PRIS in an adult was reported. 18 Prior to the first adult 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. 21 In 2014, Diaz et al. reported the results of their retrospective review of PRIS cases at a Level 1 Trauma Center in New Orleans, Louisiana. 22 Inorder to identify risk factors for and any biomarkers of PRIS, the investigators conducted a chart review of all possible PRIS cases during a 1-year period in ICU patients over 18 years of age receiving continuous propofol infusions for three or more days. 22 Additional study inclusion criteria included vasopressor support and monitoring of serum triglycerides and creatinine. 21 The study results identified 72 patients, 61 males (84.7%) and 11 females (15.3%), who satisfied study inclusion criteria; and of these, threemalesmet the studydefinition for PRIS, withone case fatality. 22 The PRIS incidence was 4.1% with a case-fatality rate of 33%. The mean duration of propofol infusion was 6.96 days. 22 A positive linear correlation was observed between increasing triglyceride levels and infusion duration, but no correlation was observed between increasing creatinine levels and infusion duration. 22 The authors concluded that the most significant risk factor for PRIS were high dose intravenous infusions of propofol over prolonged periods, and that increasing triglyceride levels might serve as reliable biomarkers of impending PRIS. 22 The authors, however, recommended confirmation of their findings in future investigations with larger study subject sample sizes. 22 The history of propofol from its introduction as a sedative- hypnotic, intravenous anesthesia induction agent in Europe in 1977 to its worldwide predominance as an intravenous anesthesia induction agent today has been wrought with controversy, especially its use as a lethal intravenous injection agent in death-penalty-directed executions in the U.S. and elsewhere. Propofol (Diprivan®) was initially designed pharmacologically in 1977 as a sedative-hypnotic induction agent in the United Kingdom by Imperial Chemical Industries (ICI), now AstraZeneca. Due to its insolubility in sterile solutions for injections, propofol was solubilized in a cremaphor EL (polyethoxylated castor oil) emulsion, which precipitated anaphylaxis in several cases. As a result, the earliest preparations
DISCUSSION
Propofol is a popular sedative hypnotic agent which is commonly used for induction of general anesthesia in the operating room (OR) and sedation in the Intensive Care Unit (ICU). Propofol is a structurally distinct alkylphenol derivative anesthetic agent. At present, it is believed that the mechanism of action of propofol is through an interaction with gamma-aminobuytric acid type A (GABA), a principal inhibitory neurotransmitter within the central nervous system. 11 With activation of the GABA receptor, potentiation of the transmembrane chloride conduction hyperpolarizes the postsynaptic cell membrane resulting in functional inhibition of neurons. 11 It is commonly believed that increases in conduction of chloride channels results in hyperpolarization of cell membranes from decreases in the rate of dissociation after propofol interacts with GABA receptors. 11 Propofol is preferred over other currently available agents for its rapid onset of action, rapid emergence from sedation, and reduced likelihood of nausea and vomiting. Propofol also provides several key physiological benefits that make its use in neurosurgery and in the ICU very favorable, including reduced cerebral metabolic oxygen demand, decreased intracranial pressure, antiemetic effects, anticonvulsive properties, and neuroprotective effects. 12 The recreational use and abuse of propofol has been increasing among medical personnel and insomniacs primarily for the following reasons: (1) propofol is not scheduled as Class IV drug with abuse potential by the Drug Enforcement Administration (DEA) and is undetected by urine toxicology screens which target other more commonly abused drugs, such as amphetamines, cocaine, and opioids. (2) Propofol activates cannabinoid receptors and causes euphoric highs disinhibition, and hallucinations. 13 (3) Propofol induces short and deep and restful sleep in night shift workers and insomniacs. (4) The short- term use of propofol creates a physiological dependency and the long-term use of propofol is addictive. 13 Twenty-one deaths have now been reported frompropofol self-administration since 1992. Propofol abuse is most likely under-reported and over 50 propofol-related deaths are suspected today. 14 In the present investigation, fatalities from respiratory arrest occurred despite administration of therapeutic induction doses inaccidentaldeathcasesamongmedicalprofessionalscompared to overdoses in suicides and homicides. Healthcare workers have much easier access to propofol than the general public. 14 In a prevalence survey of one or more episodes of propofol abuse over a 10-year period in all 126 U.S. anesthesiology training programs, 29 cases with 6 deaths in 16 anesthesiology residents (38%) were reported. 14 Surviving abusers included attending anesthesiologists (n=6), nurse anesthetists (n=3), anesthesia technicians (n=2), and OR nurses (n=2). 14 The abuse of propofol by young healthcare professionals, particularly OR workers, was
J La State Med Soc VOL 169 MARCH/APRIL 2017 31
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