a) Apnea is common with administration of these agents as would be expected with this type of anesthetic agent (Prod Info LUSEDRA(R) IV injection, 2008; Prod Info DIPRIVAN(R) IV injectable emulsion, 2008; Goodman et al, 1987) .
b) Apnea of more than 30 seconds occurred in 24% and 44% of unpremedicated patients receiving propofol 2 and 2.5 mg/kg, respectively (McCollum & Dundee, 1986).
c) In one study induction of anesthesia with 2 mg/kg caused apnea in 48% of the patients with a mean duration of 51 seconds (Gepts et al, 1985).

a) Fever has been associated with prolonged propofol infusion (Prod Info DIPRIVAN(R) IV injectable emulsion, 2008; Plotz et al, 1997; Olmedo et al, 2000).

a) Intravenous propofol produces a dose-related degree of hypotension and decrease in systemic vascular resistance which is not associated with a significant increase in heart rate or decrease in cardiac output. This occurs in 3% to 10% of adult patients and 17% of pediatric patients (Prod Info DIPRIVAN(R) IV injectable emulsion, 2008). Hypotension has also been reported with therapeutic use of fospropofol (Prod Info LUSEDRA(R) IV injection, 2008).
b) In a phase 4 study, hypotension (systolic less than 90 mmHg) was reported in 15.7% of patients and bradycardia (HR less than 50 bpm) occurred in 4.8% of patients receiving propofol (Hug et al, 1993).
c) Systolic and diastolic arterial pressures decreased by a mean of 17 and 23 mmHg, respectively, within 5 minutes of administration of propofol 2 mg/kg (Gepts et al, 1985).
d) Venodilation may contribute to propofol mediated hypotension. Authors reported a mean decrease in systolic blood pressure of 30 mmHg and a mean decrease in diastolic blood pressure of 11 mmHg (Muzi et al, 1992).

a) Complex external ophthalmoplegia has been reported in patients recovering from propofol anesthesia (Marsch & Schaefer, 1994)

a) A patient undergoing propofol anesthesia developed a skin rash postoperatively. The patient complained of sore eyes, which was diagnosed as severe bilateral conjunctival chemosis; recovery did not occur until 3 months after surgery (Kumar & McNeela, 1989).

a) During anesthesia with propofol, a transient decrease in intraocular pressure has been reported (Guedes et al, 1988; Vanacker et al, 1987).

a) Two cases of life-threatening submandibular and laryngeal swelling with airway compromise have been reported (Couldwell et al, 1993).

a) Intravenous propofol produces a dose-related degree of hypotension and decrease in systemic vascular resistance which is not associated with a significant increase in heart rate or decrease in cardiac output. This occurs in 3% to 10% of adult patients, and 17% of pediatric patients (Prod Info DIPRIVAN(R) IV injectable emulsion, 2008). Hypotension has also been reported with therapeutic use of fospropofol (Prod Info LUSEDRA(R) IV injection, 2008).
b) In a phase 4 study, hypotension (systolic less than 90 mm Hg) was reported in 15.7% of patients and bradycardia (HR less than 50 bpm) occurred in 4.8% of patients. Only 1.3% patients had both symptoms concurrently (Hug et al, 1993).
c) Venodilation may contribute to propofol-mediated hypotension. Authors reported a mean decrease in systolic blood pressure of 30 mm Hg and a mean decrease in diastolic blood pressure of 11 mm Hg (Prod Info DIPRIVAN(R) IV injectable emulsion, 2008; Muzi et al, 1992).
d) PEDIATRIC: Several children have developed refractory hypotension associated with metabolic acidosis during prolonged propofol sedation (Parke et al, 1992; Strickland & Murray, 1995; Cray et al, 1998; Hanna & Ramundo, 1998).

a) In a phase 4 study, hypotension (systolic less than 90 mm Hg) was reported in 15.7% of patients and bradycardia (HR less than 50 bpm) occurred in 4.8% of patients. Only 1.3% patients had both symptoms concurrently (Hug et al, 1993).
b) Anesthesia was induced with propofol followed by suxamethonium in 6 healthy women. Severe sinus bradycardia was observed in 2 patients (Baraka, 1988).

a) Propofol infusion syndrome is a rare event that can be fatal in both adult and pediatric critically ill patients who have received long-term propofol infusions. Clinical features of propofol infusion have included: myocardial failure which is often accompanied by bradydysrhythmias, metabolic acidosis, hyperkalemia, lipemia, hepatomegaly, rhabdomyolysis, and renal failure (Prod Info DIPRIVAN(R) IV injectable emulsion, 2008). Biochemical findings are consistent with impaired fatty-acid oxidation; the resultant lack of substrates and the build-up of intermediaries in the metabolism of long-chain, medium-chain, and short-chain fatty acids could theoretically account for the clinical features present (Wolf et al, 2001).
b) Although children are more likely to develop this syndrome, cases of adults experiencing similar clinical effects, and even fatalities have been reported (Perrier et al, 2000; Cremer et al, 2001).
c) INCIDENCE: In a retrospective cohort analysis conducted over 4 years of 50 patients with severe traumatic brain injury administered a propofol infusion, 3 (6%) patients developed propofol infusion syndrome. Each patient developed symptoms at doses of less than or equal to 134 mcg/kg/minute for a time period ranging from 85 to 135 hours, which was adjusted upward to medically control intracranial pressure (ICP). These patients also received concomitant therapy with vasopressors (ie, phenylephrine, dopamine). Clinical signs and symptoms included: ECG changes (ST elevation, tachyarrhythmias, QTc interval prolongation, inverted T waves), creatine kinase elevation, and metabolic acidosis. Two patients recovered; one patient died following withdrawal of life support (Smith et al, 2008). In this study, the authors found that the concomitant use of propofol and vasopressors was associated with the development of propofol infusion syndrome (odds ratio 29, 95% CI 1.5-581). It was further suggested that propofol doses should not exceed 83 mcg/kg/min for more than a few days along with close monitoring.

a) ACUTE ON CHRONIC EXPOSURE: A 27-year-old man with a history of propofol abuse was found unconscious after self administration. Multiple needle marks were observed. At presentation, the ECG showed ST-elevation in V1-V3 with evidence of Brugada features. The patient also had severe hypotension (systolic BP 70 mmHg) and metabolic acidosis (pH 7.18, pCO2 27.5 mmHg, pO2 85 mmHg, bicarbonate level 16 mEq/L). Within 30 minutes of admission, prolonged QT interval, idioventricular rhythm and ventricular fibrillation occurred, that did not respond to resuscitation efforts (Riezzo et al, 2009). The authors suggest that although the mechanism remains unclear, the development of ST-segment elevation in the right precordial leads may be an initial warning to electrical instability and a predictor of imminent sudden death.

a) Bradydysrhythmias have been associated with progressive cardiac failure in several fatal cases of children receiving propofol for intensive care sedation (Parke et al, 1992; Strickland & Murray, 1995; Hanna & Ramundo, 1998).
b) CASE REPORT/PEDIATRIC: A 2-year-old developed propofol infusion syndrome after receiving an infusion at an average hourly rate of 5.2 mg/kg over a 72-hour period. A persistent nodal bradycardia (28 bpm) was observed along with oliguria and the development of metabolic acidosis. The infusion was stopped and the child was successfully treated with hemofiltration (Wolf et al, 2001).
c) CASE REPORT/PEDIATRIC: A 10-month old developed first degree AV-block with right bundle branch block following a prolonged propofol infusion (total dose 4370 milligrams over 50.5 hours) (Cray et al, 1998). Progressing metabolic acidosis and hypoxia clinically improved following continuous veno-venous hemofiltration.
d) CASE REPORT/PEDIATRIC: A 5-month old undergoing cleft lip repair required escalating doses of propofol and fentanyl for sedation postoperatively from a propofol dose of 11 mg/kg/hour to 13 mg/kg/hour to 15 mg/kg/hour by the second postoperative day for a total dose of 4339 mg over 6l.75 hours. The child became unstable hemodynamically, with hypotension and varying dysrhythmias including wide-complex tachycardia with right bundle branch block, second and third degree heart block and supraventricular tachycardia. Additionally, the child developed lactic acidosis, hepatic dysfunction, acute renal failure with hyperkalemia, rhabdomyolysis and a coagulopathy. Further investigation revealed an abnormality in acylcarnitine metabolism. He responded to two runs of charcoal hemoperfusion and hemodialysis, as well as fluid management and inotropic support and was discharged 3 weeks after the surgery (Withington et al, 2004).
e) CASE REPORT/ADULT: An 18-year-old unrestrained passenger with multiple injuries sustained during an auto accident received a continuous infusion of propofol (50 mg/hr) for agitation, which was increased to a rate of 55 mg/hr following surgery for sedation. On hospital day 5, the patient developed a new onset of left bundle branch block with bradycardia and progressive metabolic acidosis. The patient then developed pulseless electrical activity, asystole and death, despite aggressive supportive care. Propofol had been infused for 98 hours at a rate of 530 to 700 mg/hr (Perrier et al, 2000).
f) CASE SERIES/PEDIATRIC: Bradydysrhythmias along with metabolic acidosis were reported early in the clinical course of 5 children who developed fatal myocardial failure after receiving propofol for intensive care sedation (Parke et al, 1992).
g) An anxious patient had a 15 second period of asystole following induction of anesthesia with propofol (Guise, 1991).

a) CASE SERIES/PEDIATRIC: Five children with upper respiratory tract infections died following an extended period of sedation with propofol (Parke et al, 1992). The clinical course was similar in all cases, metabolic acidosis was associated with a bradydysrhythmia which progressed to myocardial failure unresponsive to resuscitation.
b) CASE SERIES/ADULT: Five adult patients with head injuries had fatal cardiac arrests after prolonged propofol infusions for sedation. The events appeared similar to that described in children (ie, progressive myocardial failure, various cardiac dysrhythmias, rhabdomyolysis, metabolic acidosis and hyperkalemia around the 4th or 5th day of sedation). All cases had received propofol at rates higher than 5 mg/kg/hour for more than 58 hours, and the authors found a dose-dependent association between long-term high-dose propofol infusion and cardiac failure. A causal relationship could not be determined (Cremer et al, 2001).
c) CASE SERIES/ADULT: In a review of 1465 propofol cases, 1 patient with a cardiac conduction defect suffered a cardiac arrest under anesthesia (Stark et al, 1985).

a) CASE REPORT/PEDIATRIC: A 3-year-old girl was intubated and ventilated after choking on a piece of bread was sedated with propofol, midazolam and fentanyl. Although 20 mg/hour of propofol was ordered, 20 mg/kg/hour was inadvertently given. The child developed bronchospasm and a combined respiratory/metabolic acidosis 15 hours later, the dosing error was discovered, and propofol was discontinued, with subsequent improvement in ventilatory status. However, a continued need for mechanical ventilation prompted re-institution of intravenous propofol at 1.25 mg/kg/hour. Eight hours later the child developed cardiac dysrhythmias, ectopy and incomplete right bundle branch block, with a severe drop in cardiac output. Despite successful pacemaker placement and improvements in the circulatory status with catecholamine supports, refractory metabolic acidosis persisted. The child suffered a cardiac arrest 7 hours later and died (Holzki et al, 2004).

a) CASE REPORTS: A patient underwent heterotopic cardiac transplant and developed ventricular tachycardia in the native heart. Propofol was used as sedation for cardioversion and was associated with an accelerated ventricular rate of 200 to 300 beats/minute (Jayamaha & Dowdle, 1993).
b) CASE REPORTS: A 28-month-old man received a 42-hour propofol infusion and developed metabolic acidosis, rhabdomyolysis and electrolyte dysfunction. Despite correction of the patient's electrolyte abnormalities, he died on postoperative day 3 after developing ventricular tachycardia which was unresponsive to therapy (Olmedo et al, 2000).

a) Apnea is common with administration of these agents, as would be expected with this type of anesthetic agent (Prod Info LUSEDRA(R) IV injection, 2008; Prod Info DIPRIVAN(R) IV injectable emulsion, 2008). Apnea of more than 30 seconds occurred in 24% and 44% of unmedicated patients receiving propofol 2 and 2.5 mg/kg, respectively (McCollum & Dundee, 1986).

a) Bronchospasm has been described in several reports; in patients with hyperreactive airway disease (Pedersen, 1992) and in patients with cough as a prelude to bronchospasm (Thompson & Davies, 1990).

a) Two cases of life-threatening submandibular and laryngeal swelling with airway compromise have been reported (Couldwell et al, 1993).

a) Acute pulmonary edema has been reported following propofol administration (Waheed & Oud, 2014).

a) In a review of 1465 patients, 14% had some manifestations of excitation. Symptoms included: twitching, tremor, hypertonus, masseter spasm, and hiccups (Stark et al, 1985).

a) BACKGROUND: It appears that propofol has both anticonvulsant and proconvulsant activity. There have been at least 50 reports of seizure activity following the use of propofol in the literature (Sutherland & Burt, 1994)
b) Seizures have been reported in patients with and without a prior history of seizure disorder (Hickey et al, 2005; Gildar, 1993; Hendley, 1990; DeFriez & Wong, 1992; Makela et al, 1993; Bendiksen & Larsen, 1998).
c) MECHANISM: Several possible mechanisms have been suggested: propofol has a primary action at or close to the GABA receptor with a much lower level of glycine antagonism responsible for the excitatory effects; antidopaminergic action; and lastly the authors suggested that an imbalance between cortical and subcortical effects with propofol is involved with the symptoms observed.
d) There are reports in the literature of convulsions occurring within 1 hour to several days after anesthesia (Russell & Kenny, 1993; Thomas & Boheimer, 1991). One woman developed a grand mal seizure during induction (50 mg IV) and had multiple episodes following surgery despite therapy. The patient made a complete recovery and no neurological deficit was reported (Sutherland & Burt, 1994).
e) A case of classical general depressant withdrawal syndrome (confusion, tremors, and hallucinations), that culminated in grand mal convulsions, was reported in a patient who received propofol for 5 days for sedation after cardiac surgery (Au et al, 1990).

a) Prolonged ataxia (for a period of 5 days with no signs of athetoid movements), seizures and episodes of hallucination were reported in a woman following an infusion of propofol (maintained for 6.5 hours for a total dose of 1600 mg). No permanent sequela was reported (Bendiksen & Larsen, 1998).

a) Paresthesia described as pain, burning or stinging sensation has been reported frequently in patients undergoing minor procedures who received a standard or modified dose of fospropofol. Up to 74% of patients reported some type of paresthesia. Hypotension has also been reported with therapeutic use of fospropofol (Prod Info LUSEDRA(R) IV injection, 2008).

a) Opisthotonus, hyperreflexia, and hypertonicity have been reported (DeFriez & Wong, 1992; Saunders & Harris, 1990).

a) SUMMARY: Central anticholinergic syndrome has been described as an impairment in central cholinergic transmission (i.e., a decreased number of impulses in the cholinergic synapses so that incomplete information reaches the cerebral cortex) that occurs after receiving drugs with direct or indirect cholinergic or anticholinergic action and includes drugs used during anesthesia including propofol.
b) CASE REPORT: Two patients (a 60-year-old man and a 25-year-old man) developed central anticholinergic syndrome after receiving anesthesia which included propofol. One patient remained somnolent for a long period after surgery and was given 2.5 mg IV physostigmine and was awake and calm within 10 minutes of administration. The younger patient was agitated and was also given physostigmine approximately 10 hours after symptoms developed (propofol infusion also stopped) with a resolution of symptoms within 30 minutes of administration (Katsanoulas et al, 1999).

a) Nausea and vomiting can occur with therapeutic use of these agents (Prod Info LUSEDRA(R) IV injection, 2008; Prod Info DIPRIVAN(R) IV injectable emulsion, 2008).
b) In a review of 1465 propofol cases, nausea and vomiting were reported in 2% and 2.5%, of patients, respectively (Stark et al, 1985).

a) CASE REPORT: A 28-year-old man developed elevated serum amylase levels (peak 734 Units/L and lipase 2542 Units/L) after receiving 9 days of propofol therapy (total dose 96 g) following a closed head injury that was sustained during a skiing accident. Abdominal ultrasound was normal; the patient made a gradual and slow recovery (Possidente et al, 1998).
b) Elevated serum amylase (peak 1309 Units/L) and AST (peak 4693 Units/L) levels were reported in a 10-month old receiving a propofol infusion for intensive care sedation (Cray et al, 1998).

a) CASE REPORT: A 21-year-old healthy, woman without hyperlipidemia developed pancreatitis after a single dose of propofol 150 mg was used along with lidocaine 200 mg and midazolam 2 mg were administered to induce anesthesia. Anesthesia was maintained with nitric oxide, oxygen, and isoflurane. After surgery, she developed abdominal pain and fullness, nausea and vomiting. A computed tomography scan revealed a diffusely enlarged and edematous pancreas with peripancreatic inflammatory changes and fluid collection. Although the woman had received propofol for 2 previous surgeries without untoward effect, the authors considered propofol to have been the most likely cause of this occurrence of pancreatitis (Jawaid et al, 2002).

a) CASE REPORT: A 27-year-old man who worked as a nurse anesthetist was found dead after self-administration of propofol. The exact amount of propofol was not known, however, three empty 20 mL ampules of propofol (10 mg/mL) were found beside him. There was evidence of chronic abuse. Propofol was detected in blood (0.026 mg/L), urine, and bile (0.25 mg/L) samples. The time line from death to the specimen collection was not described. Autopsy revealed signs of pulmonary edema and hemorrhagic pancreatitis (Roussin et al, 2006).

a) Elevated serum amylase (peak 1309 Units/L) and AST (peak 4693 Units/L) levels were reported in a 10-month old receiving a propofol infusion for intensive care sedation (Cray et al, 1998).

a) CASE REPORT - A 66-year-old man with a history of biliary pancreatitis with choledocholithiasis, underwent a therapeutic endoscopic retrograde cholangiopancreatography (ERCP) and received brief propofol sedation. Forty-eight hours after therapy, the patient developed acute gastrointestinal symptoms (ie, abdominal pian, nausea and vomiting). Serum laboratory findings included: an aspartate aminotransferase (AST) and alanine aminotransferase (ALT) at 50 times the reference range and slight increases in gamma-glutamyltransferase (GGT) and alkaline phosphatase, with a total bilirubin of 8.9 mg/dL (normal: 0.2 to 1 mg/dL). The patient refused a liver biopsy. The patient improved with symptomatic care. At 2 month follow-up liver enzymes were normal (Polo-Romero et al, 2008).

a) Hepatic steatosis has been reported in several children who developed metabolic acidosis, refractory hypotension and dysrhythmias while receiving prolonged propofol sedation (Parke et al, 1992).
b) Liver biopsy in one child showed 10% zone III necrosis with fatty changes (Cray et al, 1998).

a) SUMMARY: "Propofol infusion syndrome" is a rare event that can often be fatal in critically ill children and some adults who have received long-term propofol infusions. Clinical features of propofol infusion have included metabolic derangements: metabolic acidosis, metabolic myocardial failure, that is often accompanied by bradydysrhythmias, acidosis, and acute renal failure (Prod Info DIPRIVAN(R) IV injectable emulsion, 2008; Smith et al, 2008; Perrier et al, 2000; Cremer et al, 2001; Wolf et al, 2001).

a) Acute renal failure has developed rarely in both adults and children who developed refractory hypotension and metabolic acidosis associated with prolonged propofol infusions (Prod Info DIPRIVAN(R) IV injectable emulsion, 2008).
b) CASE REPORT/PEDIATRIC: Acute oliguric renal failure has developed in several children who developed refractory hypotension and metabolic acidosis associated with prolonged propofol infusions (Parke et al, 1992; Strickland & Murray, 1995).
c) CASE REPORT/PEDIATRIC: A 2-year-old man was treated with hemofiltration following the development of acute renal failure 4 days after a continuous infusion of propofol (average hourly rate of 5.2 mg/kg) for over 72 hours. Bradycardia and metabolic acidosis also improved (Wolf et al, 2001).

a) Discolored urine (olive green, rusty brown, tea-colored) has been reported in several pediatric exposures to prolonged propofol infusions used for intensive care sedation (Cray et al, 1998; Hanna & Ramundo, 1998).

a) CASE REPORT: Severe ketonuria (8+ by Ketostix(TM)) developed in a 12-year-old girl with a traumatic brain injury requiring prolonged propofol sedation (total 59 hours) to decrease agitation and unstable intracranial hypertension (Canivet et al, 1994). No evidence of metabolic acidosis was present. Symptoms improved within 8 hours after increasing glucose intake (to 50 Kcal/h) and decreasing the propofol infusion (to 11 Kcal/h), thereby, reducing lipid intake.

a) Myoglobinuria and an elevated creatine kinase were reported in a toddler requiring a prolonged propofol infusion for sedation (Cray et al, 1998). Symptomatically the child improved following continuous veno-venous hemofiltration; recovery was complete at 3 months.

a) Propofol infusion syndrome is a rare event that can often be fatal in critically ill children who have received long-term propofol infusions. Clinical features of propofol infusion have included: myocardial failure which are normally accompanied by bradydysrhythmias, acidosis, and renal failure (Wolf et al, 2001).
b) Although children are more likely to develop this syndrome, adults have experienced similar clinical effects, and even fatalities have been reported (Smith et al, 2008; Perrier et al, 2000; Cremer et al, 2001).

a) CASE SERIES: Metabolic acidosis with bradydysrhythmias appeared early in the clinical course in 5 children aged 4 weeks to 6 years who were hospitalized with upper respiratory infections (laryngotracheobronchitis (4) and bronchiolitis (1)) necessitating extended periods of propofol sedation (Parke et al, 1992). Despite aggressive treatment, each child developed fatal myocardial failure.
b) CASE SERIES/ADULT: Five adult patients with head injuries had fatal cardiac arrests after propofol infusions for sedation. The events appeared similar to those described in children (ie, progressive myocardial failure, various cardiac dysrhythmias, metabolic acidosis, rhabdomyolysis, and hyperkalemia around the 4th or 5th day of sedation) (Cremer et al, 2001). In another study, similar findings were observed in adults with severe head traumas that were treated with a propofol infusion and vasopressors (Smith et al, 2008).
c) CASE REPORT/ADULT: An 18-year-old unrestrained passenger with multiple injuries sustained during an auto accident received a continuous infusion of propofol (50 mg/hr) for agitation, which was increased to a rate of 55 mg/hr following surgery. On hospital day 5, the patient developed a new onset of left bundle branch block with bradycardia and progressive metabolic acidosis. The patient then developed pulseless electrical activity, asystole and death, despite aggressive supportive care. Propofol been infused for 98 hours at a rate of 530 to 700 mg/hr (Perrier et al, 2000).
d) CASE REPORT/ADULT: A 21-year-old woman developed metabolic acidosis after receiving a propofol infusion (Propofol, Baxter formulation with a pH 4.5 to 6.4). Hemodynamic instability was also reported, but renal function remained normal. The patient was treated with intravenous doses of sodium bicarbonate with no improvement. Despite clinical improvement after the discontinuation of the infusion, the patient's underlying neurologic function deteriorated and the patient died (Badr et al, 2001).
e) CASE REPORT/PEDIATRIC: A 5-month old undergoing cleft lip repair required escalating doses of propofol and fentanyl for sedation postoperatively from a propofol dose of 11 mg/kg/hour to 13 mg/kg/hour to 15 mg/kg/hour by the second postoperative day for a total dose of 4339 mg over 61.75 hours. The child became unstable hemodynamically, with hypotension and varying dysrhythmias including wide-complex tachycardia with right bundle branch block, second and third degree heart block and supraventricular tachycardia. Additionally, the child developed lactic acidosis, hepatic dysfunction, acute renal failure with hyperkalemia, rhabdomyolysis and a coagulopathy. Further investigation revealed an abnormality in acylcarnitine metabolism. He responded to two runs of charcoal hemoperfusion and hemodialysis, as well as fluid management and inotropic support, and was discharged 3 weeks after the surgery (Withington et al, 2004).
f) CASE REPORT/PEDIATRIC: A 10-month old requiring a propofol infusion for sedation at a mean rate of 10 mg/kg/hour for 50.5 hours in the intensive care developed severe symptoms of metabolic acidosis and bradydysrhythmias. Based on worsening symptoms resistant to treatment, plasmaphereses followed by continuous veno-venous hemofiltration (CVVH) was done. Acidosis improved over a 12-hour period using a bicarbonate predilution fluid. CVVH was discontinued after 2 days and the child made a complete recovery (Cray et al, 1998).
g) CASE REPORT/PEDIATRIC: A 2-year-old who developed propofol infusion syndrome after receiving a propofol for over 72 hours (an average hourly rate of 5.2 mg/kg) was successfully treated with hemofiltration with an in metabolic acidosis and cardiac function (Wolf et al, 2001).

a) CASE REPORT/PEDIATRIC: A 3-year-old girl was intubated and ventilated after choking on a piece of bread was sedated with propofol, midazolam and fentanyl. Although 20 mg/hour of propofol was ordered, 20 mg/kg/hour was inadvertently given. The child developed bronchospasm and a combined respiratory/metabolic acidosis. Fifteen hours later, the dosing error was discovered and propofol was discontinued, with subsequent improvement in ventilatory status. However, a continued need for mechanical ventilation prompted reinstitution of intravenous propofol at 1.25 mg/kg/hour. Eight hours later the child developed cardiac dysrhythmias, ectopy, and incomplete right bundle branch block, with a severe drop in cardiac output. Despite successful pacemaker placement and improvements in the circulatory status with catecholamine supports, refractory metabolic acidosis persisted. The child suffered a cardiac arrest 7 hours later and died (Holzki et al, 2004).

a) A patient with acute intermittent porphyria undergoing propofol anesthesia developed elevated porphyrins postoperatively (Elcock & Norris, 1994).

a) Hyperlipemia has occurred following prolonged, high dose infusions (greater than 5 mg/kg/hr for greater than 48 hours), but may also occur following a large dose or short-term therapy. It has been observed as part of the constellation of symptoms associated with propofol infusion syndrome (Prod Info DIPRIVAN(R) IV injectable emulsion, 2008). This effect has been observed in a pediatric case series of fatal exposures due to prolonged propofol use (Parke et al, 1992). The authors, however, concluded that the fat content of the propofol mixture was unlikely to be the sole cause of death in these children.

a) Pruritus has been reported frequently with therapeutic use of fospropofol. In clinical trials, pruritus was reported in 16 to 28% of patients receiving standard or modified doses of fospropofol (Prod Info LUSEDRA(R) IV injection, 2008).

a) Rhabdomyolysis has occurred following prolonged, high dose infusions (greater than 5 mg/kg/hr for greater than 48 hours), but may also occur following a large dose or short-term therapy. It has been observed as part of the constellation of symptoms associated with propofol infusion syndrome (Prod Info DIPRIVAN(R) IV injectable emulsion, 2008).
b) CASE REPORT: A maintenance infusion of propofol was used in the treatment of refractory status epilepticus in two children (Hanna & Ramundo, 1998). The first child, a 17-year-old with a history of mental retardation developed progressive metabolic acidosis, hypoxia, and an elevated creatine kinase (CK) (83,000 Units/L) following a 44-hour infusion of propofol (total dose 19,275 mg). Despite aggressive treatment the patient died 84 hours after anesthesia induction.
c) CASE REPORT: A 7-year-old developed similar clinical symptoms and had a CK of 49,992 Units/L after receiving a total dose of 35,330 milligrams (1,275 mg/kg). Death occurred 78 hours after therapy was begun.
d) CASE REPORT: A 10-month old receiving a propofol infusion developed progressive metabolic acidosis and bradydysrhythmias (Cray et al, 1998). A CPK of 9865 Units/L was reported on hospital day 7 and peaked at greater than 30,000 Units/L along with myoglobinuria. The child was successfully treated with continuous veno-venous hemofiltration for a 2 day period. At 3 months, recovery was complete.
e) CASE REPORT: A 28-month-old man received a 42-hour propofol infusion (total 372 mg/kg), and on hospital day 2 the patient developed hyperthermia, rhabdomyolysis (peak CPK 246,380 Units/L on postop day 3), hypocalcemia, and hyperphosphatemia. Despite correction of electrolyte abnormalities, the patient died of ventricular tachycardia unresponsive to therapy (Olmedo et al, 2000).

a) There have been rare reports of anaphylaxis with propofol use, with angioedema, bronchospasm, erythema, and hypotension observed during these events (Prod Info DIPRIVAN(R) IV injectable emulsion, 2008).
b) Several reports of anaphylactic shock have been reported in the literature (Laxenaire et al, 1988; McHale & Konieczko, 1992; De Leon-Casasola et al, 1992).

a) RATS AND RABBITS - There was no evidence of harm to the fetus due to propofol when rats and rabbits were treated with propofol IV doses of 15 mg/kg/day (equivalent to the recommended human induction dose on a mg/m(2) basis) (Prod Info DIPRIVAN(R) IV injectable emulsion, 2008).

a) RATS - In animal studies, pregnant rats treated with doses up to 0.6 times, respectively, the human dose on a mg/m(2) basis for a 16-minute procedure, did not result in impaired fertility, fetal harm, or adverse effects on embryo-fetal development (Prod Info LUSEDRA(R) IV injection, 2008).
b) RABBITS - In animal studies, pregnant rabbits treated with doses up to 1.7 times, respectively, the human dose on a mg/m(2) basis for a 16-minute procedure, did not result in impaired fertility, fetal harm, or adverse effects on embryo-fetal development (Prod Info LUSEDRA(R) IV injection, 2008).

a) Propofol rapidly crosses the placenta and distributes into the fetus (Prod Info DIPRIVAN(R) IV injectable emulsion, 2008; Gin et al, 1990). Levels in fetal blood are comparable to or slightly lower than maternal blood levels (Cicinelli et al, 1992; Gin et al, 1990; Schmitt, 1987).
b) Propofol concentrations in neonates born to women receiving propofol as a 2.5 mg/kg induction dose and 5 mg/kg/hr maintenance infusion ranged from 0.029 to 0.14 mcg/mL in a blood sample taken 2 hours after birth (Dailland et al, 1989).

a) Transient neurobehavioral effects have been reported in newborns exposed to propofol when used as an anesthetic in Caesarean sections, but long-term follow-up studies have not been done in these children (Dailland, 1989b; Valtonen, 1989; Moore, 1989; Bloor, 1987).
b) In another study, Apgar scores were lower with longer incision-to-delivery times, but did not correlate with cord blood propofol levels (Gin et al, 1990).
c) A comparative study evaluated induction with thiopental 5 mg/kg and propofol 2.8 mg/kg in 40 women undergoing cesarean section. The infants who received propofol had lower Apgar scores at 1 and 5 minutes; 25% had muscular hypotonus at 5 minutes. Depression in alert state, pinprick, and placing reflexes were noted 1 hr after birth in the newborns receiving propofol. Depression was not observed after 4 hours. These effects were not observed as frequently in those newborns who had received thiopental (Celleno et al, 1989). (Celleno et al, 1989a).

a) In several studies, no significant difference was observed in Apgar scores of newborns delivered from patients receiving either propofol or thiopental during cesarean sections (Valtonen et al, 1989; Moore et al, 1989).
b) CASE REPORT - In one case, no apparent ill effects were seen in a neonate born to a mother who had been sedated with propofol for 48 hours (Bacon & Razis, 1994).

a) RATS AND RABBITS - Propofol has been shown to result in maternal deaths in rats and rabbits and decreased pup survival during the lactating period in dams treated with 15 mg/kg/day (approximately equivalent to the recommended human induction dose) (Prod Info DIPRIVAN(R) IV injectable emulsion, 2008).
b) EWES - Propofol did not adversely affect uterine blood flow or other maternal-fetal parameters in pregnant ewes (Alon et al, 1993).

a) RATS - In pregnant rats treated with fospropofol disodium at IV doses of 5, 20, or 45 mg/kg/day from gestation day 7 through 17 (with the highest dose being 0.6 times the human dose on a mg/m(2) basis for a 16-minute procedure), the two highest doses resulted in maternal toxicity. In pregnant rats, there were no clear treatment-related effects on growth, development, behavior (passive avoidance and water maze) or fertility following treatment with fospropofol disodium doses of 0, 5, 10, or 20 mg/kg/day from gestation day 7 through lactation day 20 (with the highest dose being 0.2 times the human dose) (Prod Info LUSEDRA(R) IV injection, 2008).
b) RABBITS - In pregnant rabbits treated with fospropofol disodium at IV doses of 14, 28, 56, or 70 mg/kg/day from gestation day 6 through 18 (with the highest dose being 1.7 times the human dose on a mg/m(2) basis for a 16-minute procedure), significant maternal toxicity was noted at all doses (Prod Info LUSEDRA(R) IV injection, 2008).

a) At the time of this review, no data were available to assess the potential effects of exposure to this agent during lactation in humans (Prod Info LUSEDRA(R) IV injection, 2008).

a) Very low concentrations of propofol were found in breast milk of mothers receiving propofol anesthesia prior to cesarean section. Mothers who received an IV bolus of 2.5 mg/kg had propofol concentrations in their milk of 0.14 to 0.24 mcg/mL and 0.04 to 0.74 mcg/mL 4 and 8 hours post-administration, respectively. Mothers who also received a continuous infusion of propofol 5 mg/kg/hr for anesthesia maintenance achieved drug levels in their breast milk of 0.33 to 0.74 micrograms/mL 4 hours post-administration. The effects of oral absorption of small amounts of propofol are not known (Prod Info DIPRIVAN(R) IV injectable emulsion, 2008; Dailland et al, 1989a; Schmitt, 1987).

a) RATS - When female and male rats were given propofol IV doses up to 15 mg/kg/day from 2 weeks before pregnancy to day 7 of gestation and for 5 days, respectively, there was no evidence of impaired fertility (Prod Info DIPRIVAN(R) IV injectable emulsion, 2008).

a) RATS - When male and female rats were given fospropofol IV doses of 5, 10, or 20 mg/kg/day for 4 weeks and 2 weeks prior to mating, respectively, fertility was not affected at the highest dose (equivalent to 0.3-fold the total human dose for a 16-minute procedure based on a mg/m(2) basis) (Prod Info DIPRIVAN(R) IV injectable emulsion, 2008).

a) It may also be observed following a continuous infusion of propofol for sedation (ie, intensive care setting). The color change is thought to be due to the phenolic green metabolite produced in the liver and excreted in the urine. The effects are benign and reversible with drug discontinuation (Gupta & Gupta, 2011).

a) Monitor ECG and blood pressure in patients following overdose or prolonged exposure to these agents.
b) Continuous ECG monitoring should be required for all patients receiving monitored anesthesia care or intensive care unit (ICU) sedation. Bradydysrhythmias have been documented as early clinical features of toxicity in children receiving propofol for ICU sedation.
c) An echocardiogram may be useful to evaluate myocardial function.

1) Cray et al (1998) reported the successful use of continuous veno-venous hemofiltration (CVVH) in a previously healthy 10-month-old with an upper respiratory obstruction who developed metabolic acidosis and bradyarrhythmias following prolonged use of propofol for intensive care sedation. The mean rate of the propofol infusion was 10 mg/kg/hour for 50.5 hours.
2) CASE REPORTS: Goldfrank et al (1998) described two other successful cases of hemofiltration use in children who developed toxic effects from prolonged propofol infusions (56 hours and 72 hours, respectively) (Goldfrank et al, 1998a).
3) A 2-year-old developed oliguria with mildly elevated potassium, urea, and creatinine, and then developed a sudden onset of persistent nodal bradycardia and metabolic acidosis after receiving a 72 hour continuous infusion of propofol for sedation. The patient made a complete recovery following hemofiltration (Wolf et al, 2001).

a) INDUCTION (Healthy, less than 55 years): The dose should be titrated. Approximately 40 mg every 10 seconds until induction onset (2 to 2.5 mg/kg). Elderly, debilitated or adults classified as ASA III or IV may require a 50% decrease in dose (Prod Info DIPRIVAN(R) IV injectable emulsion, 2008).
b) MAINTENANCE INFUSION (Healthy, less than 55 years): Injectable emulsion at 100 to 200 mcg/kg/min (6 to 12 mg/kg/hour) administered in a variable rate of infusion. Elderly, debilitated or adults classified as ASA III or IV may require a 50% decrease in dose (Prod Info DIPRIVAN(R) IV injectable emulsion, 2008).

a) For intubated, mechanically ventilated adults, intensive care sedation should be initiated slowly with a continuous infusion. In most patients the initial infusion should be 5 mcg/kg/min (0.3 mg/kg/hour) for at least 5 minutes. Subsequent increments of 5 to 10 mcg/kg/min (0.3 to 0.6 mg/kg/hour) over 5 to 10 minutes may be used until desired level of sedation is achieved. Maintenance rates of 5 to 50 mcg/kg/min (0.3 to 3 mg/kg/hour) or higher may be required (Prod Info DIPRIVAN(R) IV injectable emulsion, 2008).

a) INDUCTION - Most healthy children 3 years of age or older require 2.5 to 3.5 mg/kg of propofol when unmedicated or lightly premedicated (Prod Info DIPRIVAN(R) IV injectable emulsion, 2008). A lower dosage is recommended for children classified ASA III/IV.
b) MAINTENANCE (Healthy, from 2 months to 16 years) - A dose of 125 to 300 mcg/kg/min (7.5 to 18 mg/kg/hour) should immediately follow the induction dose (Prod Info DIPRIVAN(R) IV injectable emulsion, 2008).

a) Propofol infusions for ICU sedation is NOT discussed by the manufacturer for pediatric use (Prod Info DIPRIVAN(R) IV injectable emulsion, 2008).
b) CAUTION - Long-term propofol infusions have resulted in fatalities in both children and adults. Propofol Infusion Syndrome is a rare event that results in the following clinical features: myocardial failure which is normally accompanied by bradydysrhythmias, metabolic acidosis, and renal failure (Perrier et al, 2000; Cremer et al, 2001; Wolf et al, 2001). A causal relationship has NOT been established (Parke et al, 1992; Strickland & Murray, 1995).

a) 1100 mg/kg (RTECS , 2001a)

a) 500 mg/kg (RTECS , 2001a)

a) SINGLE INTRAVENOUS BOLUS
b) REPEATED INTRAVENOUS BOLUSES
c) CONTINUOUS INTRAVENOUS INFUSION

a) SINGLE INTRAVENOUS BOLUS

a) PROPOFOL