الفهرس 
Pharmacological background of propofolOnly 14 pages are availabe for public view
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Abstract
Critically ill patients in an intensive care unit (ICU) are subjected to a variety of noxious stimuli including pain after surgery, frequent venipuncture, invasive monitoring and
endotracheal intubation so analgesia is considered as an
essential component of care in these patients.
Ideal sedative should be effective, short-acting and
non-cumulative, free of adverse effects, having rapid onset and offset, with no effect on the metabolism of other drugs and lastly should have known pharmacokinetics and
pharmacodynamics in organ failure.
Propofol is the approved name of 2, 6 di-isopropyphenol, its empirical formula is C12 H18O; its molecular weight is 178.27 Dalton. It is a simple phenol substituted with 2
isopropyl groups in each of the position adjacent to the
hydroxyl group.
Propofol is available as a 1 percent solution in 20-mL clear glass ampoules, 50- and 100-mL vials. It is stable at room temperature and is not light sensitive. If a dilute solution of propofol is required, it is compatible with 5 percent dextrose in water.
Propofol infusion syndrome was first described among
pediatric population. The first case of death was in Denmark in 1990. She was a 2 years old girl with croup, who was sedated with propofol infusion (10 mg/ kg/hr) for 4 days. She developed metabolic acidosis, heart failure and hepatomegaly, but this case didn’t receive much attention as the syndrome had not been yet identified.
PRIS was initially considered a syndrome associated with pediatric patients; however it is now evident that it can occur in adults. Till 2007, 32 pediatric and 29 adult cases have been
recorded in the literature. Of these, 20 pediatric and 18 adult
patients died. Seven of the 12 pediatric patients and one of the 11 adult patients who survived had the hallmarks of PRIS. Seven of 61 cases reported occurred during general anesthesia using propofol infusions. Most of cases reported had either
respiratory or central nervous system illness.
Mechanism responsible for PRIS remains controversial and may be multifactorial. Many theories have been suggested, including impaired lactate metabolism due to intralipid
emulsion, inhibition of enzymes in mitochondrial respiratory chain, impaired fatty acid oxidation, diversion of carbohydrate metabolism to fat metabolism, and presence of unidentified
metabolites.
PRIS usually occurs with infusion of high doses of
propofol greater than 67µg/kg/min or > 4 mg/kg/hr for
prolonged period > 48 hours. It has also been associated with short term infusion of large doses during anesthesia, > 5 mg /kg/hr for about 3hours.
The main clinical features of PRIS are:
1. Acute refractory bradycardia leading to cardiovascular
collapse and asystole.
2. Metabolic acidosis (base deficit >10 mmol) in absence of shock.
3. Rhabdomyolysis in absence of other causes such as sei-zures and dopaminergic medication, depolarizing paralytic agent, hyperthermia or extensive trauma.
4. Acute renal failure and hyperkalemia.
5. Hyperlipidemia and enlarged fatty liver.
Once PRIS is suspected and/or diagnosed, management consists solely of supportive treatments addressing the clinical manifestations and the end organ damage associated with this syndrome. The propofol infusion should be discontinued
immediately, and an alternative sedative should be started.
They include intravenous crystalloids/colloids
replacement with escalating doses of vaso-pressors and
inotropes to treat hypotension and bradycardia. Unfortunately, these conventional methods have had limited success in
treatment of patients with PRIS because of the refractory nature of this condition. Cardiac pacing (either trans venous or
external) have also been considered in resistant bradycardia with limited success. Two case reports recorded the successful use of extracorporeal membrane oxygenation (ECMO) for
oxygenation and circulatory support. In one case, ECMO was successfully used in a child with arteriovenous malformation developing rhabdomyolysis and renal failure. In another case, patient had cardiogenic shock associated with propofol
infusion, after craniotomy, ECMO was started and dialysis was performed. After 48 hours cardiac output and rhythm
normalized and ECMO was discontinued, and patient recovered completely.
ECMO can be used in PRIS not as a treatment or cure, but as a substitute for the work of the heart and lungs, thus
allowing them to ”rest” until time or additional procedures
assist in reversing the syndrome.
Pressure and flow created by the mechanical pump help
circulate blood in the body, thus supporting cardiac function.