Propofol

Observational studies

The incidence of adverse events related to the use of propofol has been examined in three prospective audits of nurse-administered endoscopy sedation regimens that primarily used propofol.

In the first study, adverse events were assessed in 300 patients over 3 months in a unit that already had experience with 8000 patients [ ]. The patients were carefully monitored with clinical observation, pulse oximetry, automated sphygmomanometry, and sidestream capnography via a nasal cannula sampling device. All received supplementary oxygen at 2 l/minute. There were no episodes of apnea, and assisted ventilation was not necessary. There were short periods of hypoxemia (defined as an oxygen saturation below 90%) in 11 patients. Three patients required an increase in supplementary oxygen to 4 l/minute. Hypotension (defined as a mean arterial pressure below 50 mmHg) occurred briefly in 22 patients. Two patients required a 500 ml infusion of isotonic saline. The authors concluded that propofol may be safely administered by non-anesthetists who are familiar with its pharmacological properties and use.

In the second study, nurses trained by an anesthesiologist gave propofol to 9152 patients in a private ambulatory setting [ ]. There were seven cases of airway or ventilation problems (three of prolonged apnea, three of laryngospasm, and one case of aspiration requiring hospitalization), all with upper endoscopy. Five patients required face-mask ventilation, but none required tracheal intubation. Monitoring did not include capnography.

The third study examined 1435 elderly patients aged 70–85 years and 351 aged over 85 years who received propofol sedation over 17 months [ ]. Four patients (0.3%) required airway manipulations and two required face-mask ventilation. There was bradycardia requiring atropine in four patients (0.3%), and a heart rate below 50/minute in 72 patients (5.7%). There was hypoxemia (SaO ₂ below 90%) in 52 patients (4.7%) and hypotension (systolic pressure below 90 mmHg) in 162 (11%). Capnography was not used routinely. The authors concluded that nurse-administered propofol in elderly patients is as safe as in younger ones.

The safety and efficacy of propofol sedation by an emergency physician (a non-anesthetist) for painful procedures (mostly fractures and joint dislocation reductions) in 393 children has been examined [ ]. The children also received morphine 0.1 mg/kg and/or fentanyl 1–2 micrograms/kg. There was hypoxemia in 19 (5%), 11 (3%) needed airway manipulation, and three (0.8%) required face-mask ventilation. Hypotension was very common (92%) but only required treatment with intravenous fluid boluses in two children (0.67%).

Comparative studies

Cardiovascular

Several aspects of the interactions of propofol with the cardiovascular system in patients with left ventricular dysfunction have been reviewed [ ]. Propofol reduces arterial blood pressure, mainly by reducing sympathetic tone, vascular resistance, and preload, and not by impairing myocardial contractility. Although it has negative inotropic effects, partly mediated by reduced uptake of calcium into the sarcoplasmic reticulum, they do not appear to be clinically important. It is not clear, however, how propofol affects cardiovascular function in patients with severe left ventricular dysfunction. Experiments in rodents have not shown any effects in compensated or congenital hypertrophic cardiomyopathy, and a study on left ventricular trabeculae from pigs with pacing-induced congestive heart failure suggested that the myocardial depressive effects of propofol might be more pronounced in the presence of left ventricular dysfunction than in healthy hearts [ ]. In dogs with dilated cardiomyopathy induced by continuous pacing at 240 Hz for up to 3 weeks, propofol reduced left ventricular preload, afterload, and regional chamber stiffness, caused a dose-related direct negative inotropic effect, and impaired early diastolic left ventricular filling [ ].

The protective effects of propofol in ischemia/reperfusion injury have been reviewed. Propofol inhibits specific subunits of K _ATP channels, but only in concentrations 5–15 times higher than those encountered during clinical anesthesia [ ]. Protection may also be provided by scavenging of free oxygen radicals, reduced disulfide bonding in proteins, and inhibition of lipid peroxidation. Additional protective effects may be related to inhibition of the mitochondrial permeability transition pore, which represents opening of non-specific pores in the inner mitochondrial membrane under conditions of increased oxidative stress. The authors concluded that propofol causes only minimal myocardial depression in the healthy heart at clinically relevant concentrations, but that the risk of cardiac depression may be increased in the failing heart. It should therefore be administered slowly, in order to allow the cardiovascular system to compensate for the associated hemodynamic changes. For intravenous anesthesia, propofol should be combined with opioids, which have relatively few cardiovascular adverse reactions and also protect against ischemia/reperfusion injury.

Respiratory

Respiratory depression due to propofol is well recognized; apnea can result, especially with rapid injection [ ].

Propofol is often the induction agent of choice in people with asthma, as it causes bronchodilatation. However, two cases of propofol-induced bronchoconstriction have been reported [ ]. Both patients had allergic rhinitis and had taken antihistamines during the hay fever season, but were otherwise healthy.

Sick building syndrome associated bronchial hyper-reactivity is thought to be due to volatile organic compounds such as formaldehyde, toluene and xylene. In one case it seems to have been exacerbated by propofol [ ].

• A 45-year-old woman with sick building syndrome developed bronchospasm after induction of anesthesia with propofol. She had taken oral aminophylline and inhaled fluticasone for 6 years and had a raised eosinophil count (17%). She received methylprednisolone 80 mg and aminophylline 125 mg preoperatively, but still went on to develop bronchospasm that eventually responded to sevoflurane. Four weeks later, she underwent intradermal skin tests that were negative for propofol, vecuronium, and other anesthetic drugs. Drug lymphocyte stimulation tests were weakly positive for propofol.

General anesthesia can cause airway compromise. In a prospective study in nine infants undergoing elective MRI scanning of the brain, spin echo magnetic resonance images of the airways were acquired during different stages of propofol anesthesia (80 and 240 micrograms/kg/minute) with and without 10 mmHg continuous positive airway pressure [ ]. At each anatomical level, airway caliber fell as the depth of propofol anesthesia increased, an effect that was completely reversed by continuous positive airway pressure. This study has highlighted the need for appropriate airway support as the depth of anesthesia increases, even if spontaneous ventilation is maintained.

In 82 patients who underwent sedation with propofol for mainly minor orthopedic procedures, the mean starvation time was 5.5 hours and the mean initial dose was 0.5 mg/kg in those with and without complications [ ]. There were 28 sedation events in 17 people. Hypoventilation was the commonest and nine developed brief hypoxemia (mean 1.2 minutes, SpO ₂ < 90%); none required assisted ventilation. All the episodes resolved with simple airway adjustments and supplementary oxygen.

There were similar results in a larger retrospective audit of children undergoing radiotherapy for 3833 oncology procedures [ ]. There were 49 complications (1.3%), of which one was hemodynamic instability; the others were airway complications, none of which required advanced airway intervention. There were no episodes of laryngospasm. Univariate analysis showed that the use of adjuncts (benzodiazepines, opioids, and ketamine) was significantly associated with an increased risk of complications.

This has been reinforced by a report of aspiration pneumonitis in a patient who had eaten before the operation and received a large dose of propofol and opiates [ ].

• A 65-year-old woman needed reduction of an ankle fracture 5 hours after a large meal taken with alcohol. She received fentanyl 100 micrograms followed by 20–40 mg boluses of propofol (total 120 mg). Reduction was unsuccessful and 20 minutes later she developed wheezing but had a normal chest X-ray. An hour later she was given further fentanyl 100 micrograms and propofol 60 mg and vomited and aspirated. She became hypoxic and hypotensive and required intubation. There were patchy areas bilaterally on the chest X-ray. Recovery was uneventful.

In a prospective case series of procedural sedations in 404 starved and non-starved patients in an emergency department, the attending physician gave opiates in 63% of cases [ ]. There were respiratory adverse effects in 22% after a mean bolus dose of propofol 0.82 mg/kg and a total dose of 1.78 mg/kg. All responded to basic airway maneuvers and there were no cases of aspiration, intubation, or unplanned admissions.

A smaller non-randomized study in 37 patients also showed no major adverse reactions (apnea, desaturation, airway compromise, or hypotension) after the use of propofol 0.5–1 mg/kg for sedation in the emergency department [ ]. Again, most patients received variable amounts of opiate analgesia.

In a crossover study of children who received sedation for lumbar puncture with propofol 2 mg/kg plus either alfentanil 20 micrograms/kg or ketamine 1 mg/kg, those who were given alfentanil had a statistically significant increase in respiratory depression, resulting in reduced oxygen saturation. However, advanced airway maneuvers were not required [ ]. There were no other differences between the groups.

Propofol can cause hiccups, which can be relieved by intravenous lidocaine [ ].

Pulmonary fat embolism after the use of propofol has been attributed to the milky emulsion in which the propofol was dissolved [ ].

Nervous system

Mutism has been attributed to propofol total intravenous anesthesia.

• A 56-year-old otherwise well woman underwent femoral fracture surgery, awoke, and was extubated after obeying commands and opening her eyes spontaneously, but was unable to speak [ ]. Clinical examination, blood tests, and a CT scan were otherwise unremarkable. There was no evidence of cerebral infarction on repeat imaging. She made a spontaneous recovery after 11 days.

A link between propofol and an antimuscarinic syndrome has been implied in a case report [ ].

• A 20-year-old healthy man became drunk, fell, and dislocated his elbow. He received therapeutic doses of pethidine and promethazine several hours before reduction of the dislocation and was given bolus injections of propofol (total 160 mg over 5 minutes); 5 minutes after the last dose of propofol he became agitated and confused and required midazolam. Mydriasis was absent but the antimuscarinic syndrome was diagnosed and he was given physostigmine 1 mg four times, with almost immediate effect. A drug screen was positive for caffeine, cannabinoids, nicotine, and the administered drugs and their metabolites.

This man received several drugs that have antimuscarinic activity (pethidine, promethazine, and propofol), and the addition of alcohol may have further impaired cholinergic transmission.

Psychological

In 19 patients who underwent colonoscopy or gastroscopy, took validated psychological tests, and answered driving licence questions to assess their ability to drive after anesthesia, propofol caused significantly impaired memory immediately after anesthesia [ ]. Four subjects had scores compatible with medium organic disorder and six had scores compatible with a slight disorder. After 1 hour, 91%, and after 2 hours 94% had either no or slight memory deficits, implying rapid recovery.

The pleasant psychoactive effects of subanesthetic doses of propofol can encourage abuse (see below) [ ].

Psychiatric

The association of propofol with a range of excitatory events is well recognized. Behavioral disturbances with repeated propofol sedation have been reported in a 30-month-old child [ ]. Propofol was well tolerated initially, but the child then became increasing irritable, aggressive, and uncooperative during awakening from subsequent sedations, including screaming, kicking, hitting, and biting. The next two sedations were performed using methohexital and were not followed by any behavioral disturbances.

Prolonged delirium after emergence from propofol anesthesia has also been reported [ ].

A psychotic reaction has been reported [ ].

• A 37-year-old man who had abused metamfetamine, paint thinner, psychotomimetic drugs, and alcohol for 20 years was given chlorpromazine, haloperidol, and flunitrazepam just before surgery. After spinal anesthesia he was given propofol 5 mg/kg/hour intravenously. However, euphoria and excitement occurred 10 minutes after the start of the infusion and he had excitement, hallucinations, and delirium. His symptoms were suppressed by intravenous haloperidol 5 mg.

The authors speculated that propofol may produce psychotic symptoms when it is used in patients with a history of drug abuse.

Hallucinations have been attributed to propofol in a 70-year-old man [ ].

Metabolism

Acid–base balance

See Propofol infusion syndrome under Multiorgan damage below.

Hematologic

In 10 patients, propofol, but not intralipos, its solvent, inhibited platelet aggregation both in vivo and in vitro [ , ]. This defect was not associated with a change in bleeding time, and it was assumed that the effect is not clinically significant. The cause was probably suppression of calcium influx and release from platelets.

Fat emulsions affect coagulation and fibrinolysis [ ]. In a study of 36 patients undergoing aortocoronary bypass operations with midazolam + fentanyl or propofol + alfentanil anesthesia, factor XIIa concentrations and kallikrein-like activity were about 30% higher in the propofol group. The authors suggested that there had been stronger activation of the contact phase at the start of recirculation and stronger fibrinolysis in the propofol group. They also found more hypotension in the propofol group, which they assumed to be due to release of kallikrein, resulting in release of bradykinin. Propofol has not been shown to cause increased perioperative bleeding.

Liver

Hepatocellular injury has been reported after the sole use of propofol for outpatient anesthesia [ ].

• A young woman with multiple allergies underwent femoral hernia repair and the next day developed acute hepatitis, with severe nausea and vomiting and diffuse abdominal tenderness. She had very high transaminase activities and the prothrombin time was slightly raised. No viral cause could be demonstrated. Antinuclear antibody and smooth muscle antibody titers were not raised and the ceruloplasmin concentration was normal. Abdominal ultrasound did not show gallstones or any other abnormality. The urine was normal and did not contain porphyrins or porphobilinogen. She recovered spontaneously and refused liver biopsy.

Postoperative serum aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase activities increased transiently after the use of propofol in 160 patients undergoing elective coronary artery surgery, more so than in 160 patients who were given sevoflurane [ ].

Pancreas

See also Hyperlipidemia under Metabolism above.

There have been several reports of postoperative pancreatitis in association with propofol-induced anesthesia [ ]. In view of the very widespread use of propofol for induction of anesthesia, the very rare reports, and the complexity of establishing the cause of acute pancreatitis, a causal relation between propofol and pancreatitis has not been clearly established.

• A healthy 35-year-old man developed acute pancreatitis a few hours after receiving a 15-minute propofol anesthetic for laser treatment of a urethral stricture [ ]. He spent 3 weeks in an intensive care unit, requiring both respiratory and renal support. There was no evidence of gallstones on abdominal imaging. There was no defect of lipid metabolism.

• A 51-year-old woman with a past medical history of a seizure disorder, schizophrenia, and asthma, who had been admitted with pneumonia, was sedated using a propofol infusion to assist mechanical ventilation [ ]. Over 7 days she received a total of 26.5 g of propofol at a maximum rate of 0.2 mg/kg/minute. When pancreatitis, which was associated with hypertriglyceridemia, was diagnosed, the propofol infusion was stopped. In addition to raised amylase activity, serum triglyceride concentrations peaked at 17 mmol/l and lipase activity at 564 U/l. She recovered over the next 7 days. On day 17 she underwent tracheostomy revision, during which she received propofol 200 mg. The subsequent postoperative period was complicated by another episode of pancreatitis, this time without associated hypertriglyceridemia. She recovered over the next several days. An ultrasound examination ruled out gallstone pancreatitis, despite the presence of cholelithiasis.

• A healthy 21-year-old woman developed acute pancreatitis a day after an anesthetic that lasted 138 minutes, with propofol for induction [ ]. She recovered after supportive therapy for 6 days. There was no evidence of gallstones on abdominal imaging and there was no defect in lipid metabolism.

• A 12-year-old girl developed acute pancreatitis within hours after exposure to a single dose of propofol [ ]. In the context of two cases of pancreatitis due to propofol in young patients with Cushing’s syndrome, it has been suggested that such patients may be at increased risk [ ]. Propofol is often the agent of choice in sedation of critically ill patients, particularly in neurological illnesses, as it allows rapid assessment on withdrawal.

• A 27-year-old woman with pneumococcal meningitis developed pancreatitis after sedation with propofol [ ]. This resolved slowly after withdrawal of propofol.

The association between propofol and pancreatitis has been listed as “probable” in 25 reports of pancreatitis associated with propofol to the FDA registry. However, the features of this case, which included resolution of pancreatitis on drug withdrawal and recurrence on rechallenge, suggested that the association should be upgraded to “definitely causal.”

Urinary tract

Changes in urine color can occur after propofol administration but are uncommon and self-limiting. Pink urine has been reported after propofol anesthesia in a 53-year-old woman with ovarian serous adenocarcinoma and a history of obesity, hypertension, and nephrolithiasis [ ]. The pink material contained dysmorphic erythrocytes and rhomboid crystals consistent with uric acid. Propofol increases the excretion of uric acid and precipitation is promoted if the urine is relatively acidic, which is promoted by obesity and the metabolic syndrome.

Skin

A fixed drug eruption has been attributed to propofol [ ].

Musculoskeletal

Rhabdomyolysis as part of the propofol infusion syndrome is discussed under Multiorgan damage below.

In an in vitro experiment using uterine muscle strips from 10 consenting parturients undergoing cesarean section, therapeutic concentrations of propofol had no effect on isometric tension developed during contraction of the muscle [ ]. However, higher than therapeutic concentrations did reduce the peak muscle tension that developed. These results confirm that propofol is free of this adverse reaction, which is a known cause of postpartum bleeding after the use of volatile anesthetic drugs.

Sexual function

Sexual illusions and disinhibition were a problem in two women (aged 20 and 47 years) after sedation with propofol [ ].

Immunologic

In an 11-year retrospective case series of allergic reactions to propofol in children with documented IgE-mediated egg and/or soy allergy who were subsequently given propofol, 1163 egg-allergic patients were identified, of whom 230 had received anesthesia [ ]. Propofol was used in 42, but 14 were excluded because of documented lack of reaction before propofol. The other 28 patients had 43 episodes of propofol administration. Atopic disease was common: eczema (n = 17), asthma (n = 9), peanut allergy (n = 12), and drug allergy (n = 3); 19 had a history of an allergic reaction to eggs and 9 had a strongly positive (≥ 7 mm) skin prick test reaction to egg white. All had a positive skin prick test (≥ 3 mm) with egg yolk. There was only one allergic reaction to propofol, which occurred in a patient with multiple food allergies who had had an allergic reaction after sucking confectionary containing egg albumin; a skin prick test with neat propofol was positive at 3 mm. Most egg-allergic patients tolerated propofol without adverse events.

True anaphylaxis to propofol has been observed [ ].

Infection risk

Propofol supports the growth of micro-organisms such as Staphylococcus aureus , Enterococcus faecalis , Escherichia coli , Pseudomonas aeruginosa , and Acinetobacter species [ ]. Soon after the introduction of propofol in 1989, clusters of infections related to its use were reported [ ], and there have since been several cases [ ], in some of which Klebsiella pneumoniae and Serratia marcescens were involved [ ]. The complications include hypotension, tachycardia, septic shock, convulsions, and death.

Various strategies have been studied in order to reduce the risk of infection. The combination of ketamine with propofol (ketofol) was associated with a reduced risk [ ], as was the addition of methohexital [ ], diphenhydramine [ ], and lidocaine in some studies [ ] but not in others [ , ].

Ethylenediaminetetra-acetic acid (EDTA; disodium edetate) can inhibit bacterial growth when it is added to propofol [ , ]. However, there have been concerns over the effects of this additive on trace element homeostasis, particularly when it is used in intensive care units for long-term sedation [ , ], although there is little evidence of adverse outcomes.

Multiorgan damage

Propofol infusion syndrome

A constellation of clinical symptoms including cardiac dysrhythmias, cardiovascular collapse, metabolic acidosis, rhabdomyolysis, and death associated with long-term administration of propofol has been termed the propofol infusion syndrome [ ]. Although it was initially recognized in children, the propofol infusion syndrome can occur in both children [ , ] and adults [ ]. It has been estimated to occur in about 1% of critically ill patients and occurs in those who are more severely ill, as judged by Apache II scores [ ]. It is associated with a high mortality [ ].

The EIDOS and DoTS classifications of the propofol infusion syndrome are shown in Figure 1 .