Propofol is currently the injectable anaesthetic agent which is most used in both human and veterinary medicine. In the early 1970s, studies were conducted on phenol derivatives that led to the development of a new molecule with hypnotic properties: 2,6 diisopropylphenol.
The first clinical trials, reported by Kay and Rolly in 1977, identified a new molecule for the intravenous induction of anaesthesia, known as ICI 35868, and confirmed the potential of this compound as an injectable anaesthetic agent. In recent years, there has been a considerable increase in the use of 2,6-di-isopropylphenol, commonly known as Diprivan (acronym derived from DiisoPRopyl Intra Venous ANaesthetic). Propofol is commonly used as an injectable anaesthetic, in combination with tranquilizers, sedatives and analgesics, for both the induction phase and for maintenance of the general anaesthesia.
Abbreviations
• t1/2: half-life of plasma concentration
• Vd: volume of distribution
• CNS: Central Nervous System
• NMDA: N-Methyl-D-Aspartate
• ANS: Autonomic Nervous System
• CBF: Cerebral Blood Flow
• s.c.: Subcutaneous
• i.m.: Intramuscular
• i.v.: Intravenous
PHYSICAL AND CHEMICAL CHARACTERISTICS
Propofol is an alkylphenol, which is oily at room temperature, insoluble in water but highly liposoluble.
It is available as an aqueous emulsion containing 1% propofol (equivalent to 10 mg/ml) and a nutrient compound ("Intralipid"), consisting of 10% soybean oil (100 mg/ml), 2.25% glycerol (2.5 mg/ml), 1.2% of purified egg lecithin (12 mg/kg) and sodium hydroxide (to adjust the pH). This emulsion is stable at room temperature and is not photosensitive; it has a pH of 7 and appears as a slightly viscous substance.
The formulation of propofol without the nutrient compound Intralipid has recently been introduced to the Italian veterinary market. In view of the absence of the phospholipid vehicle, allowed by the use of micro-emulsion technology, this propofol formulation is now immune from the previous problems associated with contamination of the product when not used immediately. However, apart from these considerations, the modality of use is totally comparable to the one of the formulation with Intralipid.
METABOLISM
Propofol is characterized by a rapid total body clearance. In fact, it is rapidly metabolized by the liver, via its conjugation with glucuronide and sulfate to produce water-soluble compounds that are excreted by the kidney. Less than 1% of propofol is excreted unchanged in the urine and only small amounts (2%) are found in the faeces. The site of extra-hepatic metabolism is not known, however in cats and sheep it has been shown that the lung tissue contributes to the metabolism of propofol, being responsible for 30% of the uptake in most species, including humans, and of up to 60% in cats. Cats have a reduced ability to metabolize phenolic compounds; indeed in this species, the gene designated to the production of the enzyme responsible for the glucuronidation of phenolic compounds (UGT1A6) has been identified as a pseudogene, and the enzyme produced is not fully functional.
PHARMACOKINETICS
When propofol is injected intravenously, its concentration at the effector site quickly reaches the maximum peak, which then decreases rapidly due to the redistribution of the drug to the various tissues and subsequently as a result of metabolism. This "rapid on, rapid off" feature of propofol has been a key factor in increasing the popularity of this anaesthetic in recent years. The amount of drug being distributed to the tissues depends on several factors, such as the difference in blood-tissue concentration, the solubility of the tissue and the blood flow per unit of volume in the tissue. In view of this, tissues and organs may be divided into 4 groups, based on the distribution speed of propofol:
• Group I: concentration reached very rapidly: brain, heart, liver, kidney and endocrine glands;
• Group II: concentration reached rapidly: skin and muscles;
• Group III: concentration reached slowly: adipose tissue;
• Group IV: concentration reached very slowly: bones, tendons and ligaments.
The pharmacokinetics of propofol can be altered by a variety of factors (gender, weight, breed, preexisting medical conditions, age and the concomitant administration of other drugs). In any case, in older animals, propofol is the drug of choice for induction of anaesthesia because of its limited effects on the kidneys and the lack of the so-called "hangover effect" upon awakening. Opinions are conflicting about the differences in dosage between the sexes. As no alterations in the pharmacokinetic parameters have been detected in patients with liver or kidney problems (except for a slight reduction in renal blood flow), propofol is probably the drug of choice in animals with compromised liver or renal function.
In the cat, the pharmacokinetics of propofol has not been exhaustively studied, however it seems that the response of cats to propofol is similar to the one in dogs, while a slightly higher dosage is required.
Propofol may alter its own clearance by reducing the cardiac output and consequently also the hepatic blood flow. Therefore, in the course of haemorrhagic shock, the concentration of propofol increases (the hepatic blood flow decreases), especially during phases of decompensation. In such cases, propofol should therefore be used with caution, reducing the dose and the rate of administration, in order to avoid myocardial depression and the sudden decrease in peripheral vascular resistance, which would lead to cardiovascular collapse.
MECHANISM OF ACTION
Propofol is primarily an hypnotic agent. The exact mechanism of action has not yet been fully clarified; however, it is assumed that its hypnotic action is linked to potentiation of the action of gamma aminobutyric acid (GABA), the most important inhibitory neurotransmitter in the CNS of mammals. Propofol binds in particular at the level of subunit b of the GABA A receptor. Via this action on the GABA A receptors in the hippocampus and the prefrontal cortex, propofol inhibits the release of acetylcholine from these sites.
EFFECTS ON THE CENTRAL NERVOUS SYSTEM
Propofol is an hypnotic agent, and like other hypnotic drugs it depresses CNS functions to the point of inducing loss of consciousness (Hypnos = sleep).
Propofol reduces intracranial pressure in both normal patients and in patients with increased intracranial pressure. In patients anaesthetized with propofol, the vascular reaction to changes in PaCO2 is maintained, consequently further reductions in intracranial pressure in patients with increased intracranial pressure may be induced by hyperventilation
By inhibiting lipid peroxidation, propofol also seems to have a protective and antioxidant effect on neurons.
In humans, considerable interest has been directed towards the use of propofol for maintenance of anaesthesia in neurosurgery, as the fast awakening can facilitate the rapid postoperative evaluation of the CNS function. Therefore, propofol is the best alternative to inhaled anaesthetics that cause cerebral vasodilation and, consequently, an increased intracranial pressure.
Propofol is shown to have a specific anti-emetic action, which is of particular importance in managing the perioperative phases. This action seems to be related to decreased levels of serotonin in the area postrema, probably achieved through its action on GABA receptors.
Finally, in humans, a sense of wellbeing and pleasure upon awaking from propofol anaesthesia has been reported, most likely due to an increased concentration of dopamine in the nucleus accumbens (a phenomenon also observed with other drugs used to obtain feelings of pleasure).
ANALGESIA
Propofol does not inhibit the autonomic responses to pain consequently procedures that cause pain cannot be performed with the use of propofol alone.
EFFECTS ON THE CARDIOVASCULAR SYSTEM
The most important cardiovascular effect of propofol is a decrease in systemic arterial pressure during its administration. In humans, this pressure decreases by as much as 25%-40%, regardless of the presence of cardiovascular diseases. In the dog, the pressure drop is of around 20-30% after a single dose of propofol. In dogs kept under propofol anaesthesia in which a rapid haemorrhage is induced (20 ml/kg of blood), there is a decrease in mean arterial pressure (of around 20-25%), a decreased heart rate (of around 20%) and maintenance of oxygen saturation and PaO2.
The cause of this systemic pressure drop is attributable to peripheral vasodilation and reduction (dose-dependent) of myocardial inotropism. In humans, it has been shown that hypotension is not accompanied by a significant compensatory increase in the heart rate. It has been suggested that propofol cancels or inhibits the baroreceptor reflex and consequently reduces the tachycardic response to hypotension. In the dog, this hypothesis is still debated.
Propofol should be injected slowly (> 30 sec) and, if used for maintenance of anaesthesia, requires constant monitoring, as it can cause myocardial depression; the monitoring should include: blood pressure, heart rate, ECG, pulse rate and quality, colour of the mucous membranes, capillary refill time, etc. In addition, in order to ensure a stable anaesthetic plan, it is recommended to evaluate: the tone of the masseter muscles, the position of the eye, eye reflexes, and any variation in the main clinical parameters.
EFFECTS ON THE RESPIRATORY SYSTEM
In the dog, cat, and in humans, the induction of anaesthesia with propofol causes respiratory depression, characterized by a decreased tidal volume and respiratory rate. Propofol influences the tidal volume and respiratory rate through depression of the respiratory centre and the reduced response of chemoreceptors, located in the centres of the aortic and carotid bodies, to changes in PaCO2. After the administration of propofol, apnoea may occur, and its incidence and duration may depend on: the administered dose, rate of administration, concomitant presence of other drugs and a state of hyperventilation and hyperexia. The latter situation occurs during preoxygenation of the patient with 100% oxygen prior to induction. Apnea is one of the most common adverse events after the administration of propofol in the dog and cat. Propofol causes a considerable depression of the pharyngolaryngeal reflex (more intense than the depression induced by thiopentone), and this generally allows a quick and easy intubation.Propofol seems to induce bronchodilation due to the direct anticholinergic action and the reduced release of intracellular calcium in the bronchial smooth muscles. At the same time, several studies have shown that an increase in the administered dose of propofol reduces the lumen of the upper airways. This could fovour their collapse, and consequently make obstruction of these structures more likely.
EFFECTS ON THE LIVER
The effects of propofol on the liver, and this is true also for other injectable anesthetics, have still not yet been clearly demonstrated. In general, however, any anaesthetic, such as propofol, which reduces cardiac output, also reduces hepatic perfusion. Propofol is now considered the drug of choice for induction of anaesthesia in patients with severe liver diseases.
EFFECTS ON THE DIGESTIVE SYSTEM
Propofol has only minor effects on gastrointestinal motility. Propofol has shown antiemetic properties at sub-hypnotic doses; in fact, it would appear that it is the only injectable anaesthetic that decreases the incidence of postoperative nausea and vomiting (18%), even in high-risk surgical operations. In humans, a sub-hypnotic dose of propofol administered at the end of surgery, prevents retching and emesis for 6 hours.
HAEMATOLOGICAL EFFECTS
In cats used in experimental trials, when propofol is administered by continuous infusion for about 30 minutes, with the same administration repeated for several days, propofol causes oxidative damage to the red blood cells (Heinz bodies) and clinical manifestations, such as: prolonged awakenings, anorexia, diarrhoea and generalized ailments. Propofol intoxication resolves spontaneously within 24-48 hours after cessation of dosing. Apart from the results of these experiments, which involved repeated administrations of high amounts of propofol, cats can safely undergo propofol anaesthesia, provided the dose and administration time of the drug are not exceeded.
Special attention must be given when administering this drug to dogs suffering from altered haemostasis and concomitant haemorrhages. Propofol, just like ketamine, significantly inhibits intra- and post-operative platelet aggregation.
METABOLIC AND ENDOCRINE EFFECTS
Given both in a single dose or in a prolonged infusion, propofol lowers the concentration of cortisol; however, it does not alter the adrenocortical secretion and synthesis of cortisol or aldosterone in response to surgical stress or to the adrenocorticotropic hormone stimulus.
PROPOFOL USE IN PREGNANCY AND DURING CAESAREAN SECTION
Anaesthesia for caesarean section requires a thorough understanding of anaesthetic drugs and of the methods necessary to reduce complications in the mother and offspring. Propofol, like other injectable anaesthetics, rapidly crosses the placenta and rapidly reaches the fetal circulation.
Normally, the concentration of propofol in newborns is not clinically significant, however high doses of an hypnotic drug by continuous infusion (>150 mg/kg/min i.v.) may cause respiratory depression in newborns.
In the dog, the survival rate of puppies after anaesthesia of the mother for a caesarean section using a protocol with propofol, followed by isoflurane, is similar to the survival rate in bithces undergoing epidural anaelgesia with local anaesthetics.
Propofol has no negative effects on uterine contractility and the awakening of the mother is not affected by the administration of the hypnotic agent.
In any case, after caesarean sections using propofol as an induction agent, no adverse effects directly related to the drug have been reported. Puppies are lively and responsive and the mother is vigilant enough to take care of them. To reduce the respiratory depression of the puppies, it is advisable to allow an interval of 18-20 minutes between induction with propofol and parturition, in order to allow the mother to metabolize most of the molecule.
In the cat, a slightly longer awakening time compared to dogs has been reported, therefore kittens born by caesarean section may be more depressed than puppies.
EFFECTS ON PAEDIATRIC AND ELDERLY ANIMALS
Propofol is the drug of choice in both paediatric patients and in elderly animals. In the first case, the immaturity of the hepatic microsomal enzyme systems must be considered, as they are not fully functional until 8 weeks of age. Propofol is therefore an ideal drug in paediatric patients, as it is metabolized in various organs and not solely by the microsomal system; the doses required in paediatric patients are however higher than in adult animals. The reason for this is probably a larger central volume and a more rapid hepatic clearance in paediatric patients. At the time of induction, propofol can cause respiratory depression and hypotension, so it is preferable to have the animal breathe oxygen through a mask for 5 minutes before induction of the anaesthesia; this reduces the risk of propofol-induced apnoea in both paediatric and elderly patients. Sedation of the animal, especially with sedative/analgesic drugs, reduces the dose of propofol required for induction. Special attention is necessary when dosing propofol and other anaesthetic agents in paediatric patients, in view of the limited weight that some of these patients may present at the time of surgery. An incorrect measurement by even just a few tens of grams could lead to incorrect doses of the drug and possible complications in the induction phase.
In geriatric patients, the dose of any intravenous agent should be reduced by 10-40%, to avoid overdose and also to allow a rapid awakening. The explanation for the decrease in the required dose lies in the reduced elimination clearance and in the drop in central volume. This may be due to a reduction of volume in highly perfused tissues, which is dependent on the body mass, or to a reduced perfusion of these tissues caused by a decreased cardiac output.
OPHTHALMOLOGICAL EFFECTS
Propofol reduces ocular pressure and is a suitable anaesthetic for induction in dogs with descemetocele, corneal lacerations or during cataract surgery. Propofol preserves the photoreceptor response and is considered a suitable anaesthetic to use for electroretinography (ERG).
EFFECTS ON THE MUSCULOSKELETAL SYSTEM
In humans and in the dog, phenomena of muscle twitching, tremors and involuntary muscle movements have been reported during induction and maintenance of anaesthesia with propofol (video 1).
In most cases, however, these signs cease following the administration of inhalation agents. In some cases, the administration of Diazepam (0.3 to 0.5 mg/kg) has reduced or totally eliminated these symptoms.
The cause of the excitatory phenomena remains unknown, although some assumptions have been made, including the idea of a primary action on the cortical structures, with a consequent decrease in the greater inhibitory stimulus. In any case, propofol should be used with particular caution in patients predisposed to seizures.
Malignant hyperthermia, a fatal disease caused by certain anaesthetic agents, is characterized by an uncontrolled increase in musculoskeletal metabolism, caused by a loss of control over intracellular calcium. Propofol does not trigger malignant hyperthermia, consequently it is a suitable anaesthetic for induction in dogs in which the disease has been diagnosed or suspected.
CLINICAL USE
Propofol is mainly an hypnotic agent, with no analgesic effect. It was initially used as a drug for the induction of anaesthesia, followed by maintenance with inhaled anaesthetics. Its use was subsequently extended to the maintenance of general anaesthesia and to sedation of patients in intensive care. In humans, propofol has also been approved in neurological and heart surgery.
INDUCTION OF GENERAL ANAESTHESIA
Induction with propofol is fast and gentle even if at times, especially in non-premedicated patients, a brief excitatory phase may be noticed. The induction dose depends on the presence or absence of premedication.
Unless analgesics such as opiates or α2-agonists are simultaneously used, an animal made unconscious with the administration of propofol may still respond to painful stimuli.
The dosage of propofol used for induction can be decreased if it is preceded by the administration of a pre-anaesthetic. For example, if the animal is premedicated with 0.02 to 0.04 mg/kg of acepromazine, the propofol dose required for induction decreases by 30/40%. The administration of xylazine (1mg/kg i.v.) or medetomidine (5-10 mg/kg i.v.) significantly reduces the propofol induction dose in the dog by up to 50-75%, and determines an increase in arterial pressure accompanied by bradycardia.
In premedicated dogs and cats, the dose required for endotracheal intubation is 2-4 mg/kg, while without premedication doses of 6-8 ml/kg i.v. are used. The bolus should be administered slowly (60-90 sec.), in order to reduce cardiovascular and respiratory adverse events. During drug infusion, the patient must be continuously controlled in order to evaluate the possibility of intubation at the lowest possible dose.
MAINTENANCE
The maintenance of anaesthesia with propofol may be performed with a constant rate infusion (CRI) or with intermittent boluses. The infusion rate depends on the co-administration of other drugs and the degree of surgical stimulation. In any event, it usually ranges between 0.1 and 0.4 mg/kg/min. Syringe infusion pumps are to be preferred as they ensure a high degree of precision.
Boluses are administered to effect (according to the anaesthetic requirement), with an interval between one administration and the next which can vary between 2 an 6 minutes.
In the cat, an infusion rate of 0.2-0.5 mg/kg/min is used.
Full awakening, after a continuous infusion in premedicated dogs, occurs in 8-10 min, while in dogs premedicated with sedatives and/or analgesics the complete awakening will depend on the effect of the premedication drug.
Suggested readings
- Fragen R, Diprivan (propofol): A historical perspective, Semin Anesth, 7: 1, 1988
- Kay B, Rolly G, I.C.I. 35868, a new intravenous induction agent, Acta Anaesthesiol Belg, 28: 303-316, 1977
- Morgan DWT, Legge K, Clinical evalutation of propofol as an intravenous anaesthetic agent inn cats and dogs, The Veterinary Record, 124: 31-33, 1989
- Weaver BMQ, Staddlon GE, Raptopoulos D, Mapleson WW, Measurement of propofol concentration in sheep blood and plasma: Effect of storage at different temperatures, Journal of Pharmacological and Toxicological Methods, 34: 199-202, 1995
- Branson, K.R. And Gross, M.E. 1994, Propofol in veterinary medicine, JAVMA 204: 1888-90
- Reves JG, Glass PS, Lubarsky DA, Nonbarbiturate intravenous anesthetics, In R.D. Miller, ed. Anesthesia, 4th ed., pp.247-90. New York: Churchill Livingstone
- Keith R Branson, Nicholas H Booth, Anestetici iniettabili. In: Adams H. Richard Farmacologia e terapeutica veterinaria EMSI-ROMA 1999:269
- Reid J, Nolan AM. Anestesia endovenosa, In: Anestesia e analgesia. SeymourC, Gleed R, UTET,1999:103
- Intravenous non opioid anesthetics. Chapter 10. In: Miller’s anesthesia. Miller RD Ed.6. New York: Churchill Livingstone, 2004
- Thomas DV, Propofol supports bacterial growth. Br J Anesth, 1991: 66:274
- SosisMB, Braverman B, Growth of Staphylococcus aureus in four intravenous anesthetics, Anesth Analg 1992:74:S302
- Simons P, Cockshott I, Douglas E, Blood concentrations, metabolism and elimination after a subanesthetic intravenous dose of (14)C-propofol (Diprivan) to male volunteers [abstract], Postgrad Med J, 61: 64,1985
- Veroli P, O’Kelly B, Bertrand F, et al, Extrahepatic metabolism of propofol in man during the anhepatic phase of orthotopic liver transplantation, Br J Anaesth 68: 183-186, 1992
- Gray PA, Park GR, Cockshott ID, et al, Propofol metabolism in man during the anhepatic and reperfusion phases of liver transplantation, Xenobiotica, 22: 105-114,1992
- Mather LE, Selby DG, Runciman W B, and McLean CF, Propofol: assay and regional mass balance in the sheep, Xenobiotica, 19: 1337-47.