- Email: [email protected]
Therapeutic Review: Propofol and Fospropofol
Author's Accepted Manuscript
Therapeutic Review: Propofol and Fospropofol Krista A. Keller DVM, Dipl ACZM
PII: DOI: Reference:
S1557-5063(15)00059-2 http://dx.doi.org/10.1053/j.jepm.2015.06.001 JEPM589
To appear in:
Journal of Exotic Pet Medicine
www.sasjournal.com
Cite this article as: Krista A. Keller DVM, Dipl ACZM, Therapeutic Review: Propofol and Fospropofol, Journal of Exotic Pet Medicine, http://dx.doi.org/10.1053/j. jepm.2015.06.001 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Therapeutic review: Propofol and Fospropofol Krista A Keller, DVM, Dipl ACZM From University Hills Animal Hospital, Denver, CO, USA 80222 Address correspondence: Krista A Keller, DVM, Dipl ACZM, University Hills Animal Hospital, 4175 East Warren Ave, Denver, CO 80222, [email protected]
Propofol is a non-barbiturate anesthetic that is widely used in both human and veterinary medicine. Chemically, it is an oily liquid known as 2,6-diisopropylphenol with a mechanism of action that is not well understood at this time.1,2 Administration produces a continuum of pharmacodynamic effects from hypnosis to general anesthesia; it also offers amnestic and muscle relaxant properties. 1,2 The most common use of propofol in veterinary medicine is for the induction and maintenance of general anesthesia and control of status epilepticus.1,2 Other potential pharmacodynamics properties include transient appetite stimulation properties in dogs (Canis lupus familiaris) when given at subhypnotic doses and antioxidant effects in humans (Homo sapiens).3,4 When given intravenously, propofol crosses the blood brain barrier with a rapid onset of action. It exhibits high protein binding capacity, crosses the placenta, and is highly lipophilic.1,2 Because of the highly protein bound nature of this drug, hypoproteinemic patients should be given this medication cautiously.1 Metabolism of propofol is mainly by the glucuronide and sulfate conjugation processes in the liver to form inactive metabolites which are then excreted by the kidneys. 1 In addition, extrahepatic metabolism also takes place by an unknown mechanism. 2,5,6
The most common veterinary preparation used is a white-opaque lipid emulsion, PropofloTM (Abbott Laboratories, North Chicago, IL USA), with propofol as the active ingredient (available at 10mg/mL) and soybean oil, glycerol, egg lecithin, oleic acid and sodium hydroxide as inactive ingredients. This commercial preparation of propofol is associated with rapid growth of bacteria due to a lack of preservatives and inactive ingredients that provide an appropriate substrate for the bacteria. Bacterial colonization, including Staphylococcus aureus and Escherichia coli, can occur within 6 hours of opening a vial. One study evaluated whether sterile handling conditions would reduce the colonization of bacteria and found that regardless of whether appropriate handling was adhered to, marked bacterial colonization occurs.7 Package recommendations for PropofloTM indicate that after opening the vial, the contents should be discarded after 6 hours.
A second veterinary lipid emulsion, PropofloTM28 (Abbott Laboratories), is also available; however, it has an additional inactive ingredient, benzyl alcohol. The addition of alcohol in this preparation acts as a preservative extends the shelf life of the drug to 28 days. This formulation is only approved for use in dogs, as the concentration of benzyl alcohol present may induce toxicity in cats (Felis catus) and other alcohol sensitive species. All propofol emulsion suspensions can become unstable when in contact with lidocaine and protamine sulfate; therefore, care should be taken that these medications are not mixed in the same intravenous lines.8
Fospropofol disodium, available as Aquavan® injection (MGI Pharma, Inc, Bloomington, MN USA), is a novel water soluble short acting prodrug of propofol that exhibits a slower onset, a longer half-life, and longer duration of action than propofol emulsion.9,10 Fospropofol is rapidly hydrolyzed by endothelial alkaline phosphatases after intravenous administration, thus releasing active propofol into circulation.9 As an anesthetic agent, fospropofol has been evaluated in rabbits (Oryctolagus cuniculus) and red-eared sliders (Trachemys scripta elegans). In rabbits, higher infusion rates of fospropofol are required to maintain an adequate depth of anesthesia, and rabbits anesthetized with fospropofol had longer recovery times in comparison to those administered propofol.10 In addition, the use of fospropofol was associated with the anesthetic death of a single rabbit during a prolonged recovery phase. 10 When giving intracoelomically in red-eared sliders, fospropofol was associated with unpredictable quality of anesthesia and prolonged recovery periods, with some turtles requiring resuscitation efforts.11 Based upon the limited research into this anesthetic agent, its use cannot be recommended for clinical patients at this time.
When considering the absorption of propofol, the intravenous route of administration is a requirement, unless propofol baths or intracoelomic injections are given to some aquatic species.12, 13 Propofol has been shown to have similar pharmacodynamic properties whether given intravenously or intraosseously in rabbits.14 Intraosseous and intracardiac routes of administration are reported to be safe and efficacious in green iguanas (Iguana iguana) and ball pythons (Python regius), respectively, while intracoelomic propofol in nestling iguanas resulted in only mild sedation with moderate variability in responses between animals. 15-17 Intracoelomic injection of propofol at 25 mg/kg to 35 mg/kg in tiger salamanders (Ambystoma tigrinum) resulted in sedation to surgical anesthesia (25 mg/kg, 40%; 35 mg/kg, 83%).13 Laboratory animals administered propofol exhibited limited or unpredictable efficacy in induction of sedation or anesthesia when administered intramuscularly in rats (Rattus norvegicus) or intraperitoneally in mice (Mus musculus); this was likely due to the hydrophobic nature of the drug leading to poor systemic uptake.18,19 In one study, attempts to increase intramuscular absorption of propofol with the addition of dimethyl sulfoxide (DMSO) had no effect on the sedative or anesthetic effects of propofol.18
Safe administration of propofol has been reported when administered into the subcarapacial sinus of chelonians.20, 21 However, due to the proximity of this vessel with the spinal canal, care must be taken to ensure that injections are within the vascular system as inadvertent administration into the cerebrospinal fluid (CSF) is associated with severe bradycardia, apnea, and death. A CSF tap yielding a milky white liquid may represent a rapid antemortem or post mortem confirmatory diagnostic that propofol has entered the CSF inadvertently.22
Although rarely encountered in clinical veterinary medicine, extravascular propofol has been shown to have marked tissue effects. In human medicine, small children are particularly prone to tissue necrosis after extravasation.23,24 In veterinary medicine, when given intramuscularly in rats, propofol induced moderate to severe inflammation and necrosis at the injection site.18 In contrast, in hatchling iguanas administered intracoelomic propofol, no lesions attributable to propofol administration were noted on post mortem evaluation 14 days after injection.17 Fospropofol has also been associated with adverse effects with extravascular injections, although only mild effects were noted. In rabbits administered fospropofol, a transient pruritis, manifested as scratching at the injection site, was noted for 3-5 minutes post injection.10 Up to 85% of humans administered fospropofol experience tingling, burning, or itching sensations.9
Respiratory depression, including apnea, is the most common adverse side effect noted after propofol administration. Apnea has been observed after administration of propofol in common buzzards (Buteo buteo), turkeys (Meleagris gallopavo), red-eared sliders, African clawed frogs (Xenopus laevis), loggerhead sea turtles (Caretta caretta), tiger salamanders, and green iguanas.12,13,15,20,25-27 Respiratory depression without apnea, including bradypnea and/or respiratory acidosis, has been observed in red-tailed hawks (Buteo jamaicensis), great horned owls (Bubo virginianus), koi (Cyprinus carpio), sturgeon (Acipenser oxyrinchus de soti), and rabbits.28-32 In a single study in mallard ducks (Anas platyrhynchos), an increase in respiratory rate was reported after propofol induction.33 Because these studies span a variety of species and include administration at a variety of dosages (Table 1), a dose dependent and species dependent nature of apnea or bradypnea is likely and clinicians should use caution and carefully monitor their patient while under propofol anesthesia.
The cardiovascular effects of propofol in veterinary species has been reported. The effect on heart rate appears to be species specific; bradycardia is reported in sturgeon, koi, tiger salamanders, and green iguanas, while cardiac arrest has been reported in rabbits during propofol induction.13,15,29,30,34 Conversely, no changes in heart rate are reported in red-eared sliders, common buzzards, spotted bamboo sharks (Chylloscyllium plagiosum), Japanese macaques (Macaca fsucata fsucata), loggerhead sea turtles, red-tailed hawks, or great horned owls.20,25,27,28,35,36 Electrocardiogram abnormalities have been noted in chickens (Gallus domesticus), canvasbacks (Aythya valisineria), and dogs; however, their cause is unknown.2,37-39 The effects of propofol on blood pressure also appear to be species specific; a continuous rate infusion of propofol in squirrel monkeys (Saimiri sciureus) has been associated with hypotension, while no changes in blood pressure were reported in red-tailed hawks or great horned owls.28,40 The effects of propofol on the cardiovascular system have been well documented in laboratory animals. In one study, intravenous propofol in rabbits induced a significant but transient reduction in ventricular performance and a decrease in peripheral vascular resistance.41 Other studies in rabbits have shown transient tachycardia that may be secondary to a concomitant hypovolemia.10,14,31 Although not proven, these vascular changes in rabbits may be induced secondary to propofol induced endothelial damage.42 In vitro studies in rats have shown that propofol induces vasodilation of the aorta.43
A severe cardiovascular disorder in humans has been described as propofol infusion syndrome. The classic clinical features includes bradycardia leading to asystole, metabolic acidosis, rhabdomyolysis, hyperlipidemia, and the development of fatty liver. Predisposing risk factors include high propofol infusion doses, pediatric status, severe nervous system or respiratory illness, exogenous catecholamine or glucocorticoid administration, and subclinical mitochondrial disease.44 This syndrome has yet to be described in veterinary patients.
The use of propofol for induction and/or maintenance of anesthesia in a variety of species of birds has been associated with excitation events. Excitatory movements have been noted during induction of canvasbacks, however, this was not reported in mute swans (Cygnus olor), redtailed hawks, great horned owls, or common buzzards.25,28,38,45 More commonly, excitatory central nervous system signs are seen during the recovery period from propofol anesthesia, and this has been reported in mute swans, red-tailed hawks, and great horned owls.28,45 Transient excitatory movements in other species have been reported in blue crabs (Callinectes sapidus) and rabbits (post-fospropofol administration).10,46
In most situations, propofol is not used solely as an anesthetic agent, but in conjunction with other agents in a balanced anesthetic protocol. Studies in rats and rabbits have shown that administration of an additional sedative, analgesic, and/or dissociative anesthetic will reduce propofol doses required to induce or maintain anesthesia.31,47 The practice of balanced anesthesia not only reduces the amount of propofol required to be given, which may in turn reduce potential adverse effects, but has the added benefit of applying analgesia, as propofol has no analgesic qualities. Despite the risks associated with propofol administration, a recent meta-analysis including 133 studies and over fourteen thousand human patients showed no difference in mortality between human patients receiving propofol vs any other injectable anesthetic.48 Although no such study has been performed in veterinary patients, the results are encouraging that with appropriate use and anesthetic monitoring, propofol can be an integral component of an anesthetic regime in the species in which it has been shown to be safe.
References 1. Plumb DV: Propofol, in Plumb DV (ed): Veterinary Drug Handbook (ed 6), Ames, IA, Blackwell Publishing, pp 778-779, 2008 2. Posner LP, Burns P: Injectable anesthetic agents, in Riviere JE, Papich MG (ed): Veterinary Pharmacology and Therapeutics (ed 9), Ames, IA, WileyBlackwell, pp 265-300, 2009 3. Long JP, Greco SC: The effect of propofol administered intravenously on appetite stimulation in dogs. Contemp Top Lab Anim Sci 39(6): 43-46, 2000 4. Khoshraftar E, Ranjbar A, Kharkhane B, et al: Antioxidant effects of propofol vs. ketamine in individuals undergoing surgery. Arch Iran Med 17(7): 486489, 2014 5. Langley MS, Heel RC: Propofol: a review of its pharmacodynamic and pharmacokinetic properties and use as an intravenous anaesthetic. Drugs 35(4): 334-372, 1988 6. Matot I, Neely CF, Katz RY, et al: Pulmonary uptake of propofol in cats (effect of fentanyl and halothane). Anesthesiology 78(6): 1157-1165, 1993 7. Strachan FA, Mansel JC, Clutton RE. A comparison of microbial growth in alfaxalone, propofol and thiopental. J Small Anim Pract 49(4): 186-190, 2008 8. Baker MT, Naguib M: Propofol the challenges of formulation. Anesthesiology 103(4): 860-876, 2005 9. Levitzky BE, Vargo JJ: Fospropofol disodium injection for the sedation of patients undergoing colonoscopy. Ther Clin Risk Manag 4(4): 733-738, 2008 10. Li R, Zhang WS, Liu J et al: Minimum infusion rates and recovery times from different durations of continuous infusion of fospropofol, a prodrug of propofol, in rabbits: a comparison with propofol emulsion. Vet Anaesth Analg 39(4): 373-384, 2012
11. Schroeder CA, Johnson RA: The efficacy of intracoelomic fospropofol in redeared sliders (Trachemys scripta elegans). J Zoo Wildl Med 44(4): 941-950, 2013 12. Guenettte SA, Beaudry F, Vachon P: Anesthetic properties of propofol in African clawed frog (Xenopus laevis). J Am Assoc Lab Anim Sci 47(5): 3538, 2008 13. Mitchell MA, Riggs SM, Singleton CB, et al: Evaluating the clinical and cardiopulmonary effects of clove oil and propofol in tiger salamanders (Ambystoma tigrinum). J Exotic Pet Med 18(1): 50-56, 2009 14. Mazaheri-Khameneh R, Sarrafzadeh-Rezaei F, Asri-Rezaei S, et al: Comparison of time to loss of consciousness and maintenance of anesthesia following intraosseous and intravenous administration of propofol in rabbits. J Am Vet Med Assoc 241(1):73-80, 2012 15. Bennett RA, Schumacher J, Hedjazi-Haring K, et al: Cardiopulmonary and anesthetic effects of propofol administered intraosseously to green iguanas. J Am Vet Med Assoc 212(1): 93-98, 1998 16. McFadden MS, Bennett A, Reavill DR, et al: Clinical and histologic effects of intracardiac administration of propofol for induction of anesthesia in ball pythons (Python regius). J Am Vet Med Assoc 239(6): 803-807, 2011 17. Milne VE, Hoover JP, Snider TA, et al: Intracoelomic administration of propofol in hatchling green iguanas, Iguana iguana. J Herp Med Surg 16(1): 20-26, 2006 18. McKune CM, Brosnan RJ, Dark MJ, et al: Safety and efficacy of intramuscular propofol administration in rats. Vet Anaesth Analg 35(6): 495500, 2008 19. Alves HC, Valentim AM, Olsson IA, et al: Intraperitoneal propofol and propofol fentanyl, sufentanil and remifentail combinations for mouse anaesthesia. Lab Anim 41(3): 329-36, 2007 20. Ziolo MS, Bertelsen MF: Effects of propofol administered via the supravertebral sinus in red-eared sliders. J Am Vet Med Assoc 234(3): 390393, 2009 21. Vigani A: Chelonia (Tortoises, Turtles, and Terrapins), In West G, Heard D, Caulkett N (ed): Zoo Animal and Wildlife Immobilization and Anesthesia (ed 2), Ames, IO, John Wiley & Sons, Inc 365-387, 2014 22. Quesada R, Aiken-Palmer C, Conley K, et al: Accidental submeningeal injection of propofol in gopher tortoises (Gopherus polyphemus). Vet Rec 167(13): 494-495, 2011 23. Roth W, Eschertzhuber S, Gardetto A, et al: Extravasation of propofol is associated with tissue necrosis in small children. Paediatr Anaesth 16(8): 887889, 2006 24. Tokumine J, Sugahara K, Tomori T, et al: Tissue necrosis caused by extravasated propofol. J Anesth 16(4): 358-359, 2002
25. Kilic N, Pasa S: Cardiopulmonary effects of propofol compared with those of a medetomidine-ketamine combination in the common buzzards (Buteo buteo). Revue Med Vet 160(3): 154-159, 2009 26. Schumacher J, Citino SB, Hernandez K: Cardiopulmonary and anesthetic effects of propofol in wild turkeys. Am J Vet Res 58(9): 1014-1017, 1997 27. MacLean RA, Harms CA, Braun-McNeill J: Propofol anesthesia in loggerhead (Caretta careetta) sea turtles. J Wildl Dis 44(1): 143-150, 2008 28. Hawkins MG, Wright BD, Pascoe PJ, et al: Pharmacokinetics and anesthetic and cardiopulmonary effects of propofol in red-tailed hawks (Buteo jamaicensis) and great horned owls (Bubo virginianus). Am J Vet Res 64(6): 677-683, 2003 29. Oda A, Bailey KM, Lewbart GA, et al: Physiologic and biochemical assessments of koi (Cyprinus carpio) following immersion in propofol. J Am Vet Assoc 245(11): 1286-1291, 2014 30. Fleming G, Heard DJ, Floyd RF, et al: Evaluation of propofol and medetomidine-ketamine for short-term immobilization of Gulf of Mexico sturgeon (Acipenser oxyrinchus de soti). J Zoo Wildl Med 34(2): 153-158, 2003 31. Cruz FS, Carregaro AB, Raiser AG: Total intravenous anesthesia with propofol and S(+)-ketamine in rabbits. Vet Anaesth Analg 37(2): 116-122, 2010 32. Martinez MA, Murison PJ, Love E: Induction of anaesthesia with either midazolam or propofol in rabbits premedicated with fentanyl/fluanisone. Vet Rec 164(26): 803-806, 2009 33. Machin KL, Caulkett NA: Cardiopulmonary effects of propofol and a medetomidine-midazolam-ketamine combination in mallard ducks. Am J Vet Res 59(5): 598-602, 1998 34. Yin H, Chen WM, Zhao P: Cerebral state index may reflect electrical brain activity during propofol or isoflurane anaesthesia in rabbits. Vet Rec 172(17): 184, 2011 35. Miller SM, Mitchell MA, Heatley JJ, et al: Clinical and cardiorespiratory effects of propofol in the spotted bamboo shark (Chylloscylluim plagiosum). J Zoo Wildl Med 36(4): 673-676, 2005 36. Miyabe-Nishiwaki T, Masui K, Kaneko A, et al: Hypnotic effects and pharmacokinetics of a single bolus dose of propofol in Japanese macaques (Macaca fsucata fsucata). Vet Anaesth Analg 37(6): 501-510, 2010 37. Lukasik VM, Gentz EJ, Erb HN, et al: Cardiopulmonary effects of propofol anesthesia in chickens (Gallus gallus domesticus). J Avian Med Surg 11: 9397, 1997 38. Machin KL, Caulkett NA: Cardiopulmonary effects of propofol infusion in canvasback ducks (Aythya valisineria). J Avian Med Surg 13: 167-172, 1999
39. Kamibayashi T, Hayashi Y, Sumikawa K, et al: Enhancement by propofol of epinephrine-induced arrhythmias in dogs. Anesthesiology 75(6): 1035-1040, 1991 40. Galante R, Muniz J, Castro PH, et al: Continuous infusion of propofol or intermittent bolus of tiletamine-zolazepam in squirrel monkeys (Saimiri sciureus). Vet Anaesth Analg 41(5): 506-515, 2014 41. Baumgartner C, Bollerhey M, Henke J, et al: Effects of propofol on ultrasonic indicators of haemodynamic functions in rabbits. Vet Anaesth Analg 35(2): 100-112, 2008 42. Paco CD, Vane MF, de Andrade RB, et al: Effects of propofol in lipid-based emulsion and in microemulsion on the incidence of endothelial lesions in rabbits. Acta Cir Bras 28(12): 833-841, 2012Sakai Y, Kawahito S, Takaishi K, et al: Propofol-induced relaxation of rat aorta is altered by aging. J Med Invest 61(3-4): 278-284, 2014 43. Kam PC, Cardone D: Propofol infusion syndrome. Anaesthesia 62(7): 690701, 2007 44. Muller K, Holzapfel J, Brunnberg L: Total intravenous anaesthesia by boluses or by continuous rate infusion of propofol in mute swans (Cygnus olor). Vet Anaesth Analg 38(4): 286-291, 2011 45. Quesada R, Smith CD, Heard DJ: Evaluation of parenteral drugs for anesthesia in the blue crab (Callinectes sapidus). J Zoo Wildl Med 42(2): 295299, 2011 46. Penderis J, Franklin RJ: Effects of pre- versus post-anaesthetic buprenorphine on propofol-anaesthetized rats. Vet Anaesth Analg 32(5):256-260, 2005 47. Passin L, Landoni G, Cabrini L, et al: Propofol and survival: a meta-analysis of randomized clinical trials. Acta Anaesthesiol Scand. 2014 Oct 14. doi: 10.1111/aas.12415
Table 1: Selected doses of propofol used in a variety of species in the literature. IV – intravenous, CRI – constant rate infusion, IC – intracardiac, IO – intraosseous, IP – intraperitoneal, CNS – central nervous system, ICe – intracoelomic. Species
Propofol dose
Comments
Common buzzard (Buteo buteo)
10mg/kg over 60 sec24
Transient apnea
Great horned owl (Bubo virginianus)
3.6mg/kg IV (1mg/kg/min) followed by 0.56mg/kg/min CRI27
Respiratory depression, excitatory CNS signs during recovery , light anesthesia
Mallard ducks (Anas platyrhynchos)
10mg/kg IV32
Transient increased respiratory rate
Mute swans (Cyngus olor)
2.9mg/kg IV by bolus44
Abrupt waking from anesthesia with excitement upon recovery
0.85mg/kg/min CRI44
Excitement upon recovery
4.5mg/kg IV (1mg/kg/min) followed by 0.5mg/kg/min CRI27
Respiratory depression, excitatory CNS signs during recovery, light anesthesia
Avian
Red-tailed hawk (Buteo jamaicensis)
Wild turkey 5mg/kg IV over 20 sec followed by (Meleagris gallopavo) 0.5mg/kg/min CRI25
Apnea
Japanese macaques (Macaca fsucata fsucata)
8mg/kg IV (6mg/kg/min)35
Hypnotic effect for 7 minutes,
Mouse (Mus musculus)
50-200mg/kg IP18
Not recommended
Rabbit (Oryctolagus cuniculi)
12.5mg/kg IV or IO followed by 1mg/kg/min CRI13
Both routes induced effective anesthesia; transient tachycardia
8mg/kg IV (8mg/kg/min) with fentanyl 5 mcg/kg followed by 0.7mg/kg/min33
Death of single animal during induction (cardiac arrest)
Mammals
2.2mg/kg (1mL/60 sec) after premedication with fentanyl/fluanisone 0.1mL/kg IM31 Rat (Rattus norvegicus)
0-490mg/kg IM17
Not recommended
Squirrel monkeys (Saimiri sciureus)
12mg/kg IV (4mg/kg/min) followed by 0.4mg/kg/min CRI39
Hypotension reported, faster induction and recovery compared to tiletamine-zolazepam anesthesia
Reptiles Aquatic Animals
Ball pythons (Python regius).
10mg/kg IC15
Shorter induction time but longer recovery time compared to isoflurane, no long term effects of IC injection
Green iguana (Iguana iguana)
5-10mg/kg IO followed by 0.5mg/kg/min14
Apnea, bradycardia
10mL/kg Ice16
Produces variable sedation – light anesthesia
Red-eared slider (Trachemys scripta elegans)
10-20mg/kg IV19
60-90 minutes of light – deep anesthesia
African clawed frog (Xenopus laevis)
88mg/L bath for 15 min12
Light anesthesia, apnea, narrow safety margin
Blue crab (Callinectes sapidus)
20mg/kg into hemolymph45
Short light anesthesia with limb autonomy and distress during recovery
Sturgeon (Acipenser oxyrinchus de soti)
6.5ng/kg IV29
Light anesthesia within 5 minutes
Spotted bamboo sharks (Chylloscylluim plagiosum)
2.5mg/kg IV over 30 sec34
Surgical plane of anesthesia within 5 minutes
Tiger salamander (Ambystoma tigrinum)
25-35 mg/kg13
Apnea and bradycardia; surgical anesthesia (40%, 25 mg/kg; 83%, 35 mg/kg)
Therapeutic Review: Propofol and Fospropofol Krista A. Keller DVM, Dipl ACZM
PII: DOI: Reference:
S1557-5063(15)00059-2 http://dx.doi.org/10.1053/j.jepm.2015.06.001 JEPM589
To appear in:
Journal of Exotic Pet Medicine
www.sasjournal.com
Cite this article as: Krista A. Keller DVM, Dipl ACZM, Therapeutic Review: Propofol and Fospropofol, Journal of Exotic Pet Medicine, http://dx.doi.org/10.1053/j. jepm.2015.06.001 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Therapeutic review: Propofol and Fospropofol Krista A Keller, DVM, Dipl ACZM From University Hills Animal Hospital, Denver, CO, USA 80222 Address correspondence: Krista A Keller, DVM, Dipl ACZM, University Hills Animal Hospital, 4175 East Warren Ave, Denver, CO 80222, [email protected]
Propofol is a non-barbiturate anesthetic that is widely used in both human and veterinary medicine. Chemically, it is an oily liquid known as 2,6-diisopropylphenol with a mechanism of action that is not well understood at this time.1,2 Administration produces a continuum of pharmacodynamic effects from hypnosis to general anesthesia; it also offers amnestic and muscle relaxant properties. 1,2 The most common use of propofol in veterinary medicine is for the induction and maintenance of general anesthesia and control of status epilepticus.1,2 Other potential pharmacodynamics properties include transient appetite stimulation properties in dogs (Canis lupus familiaris) when given at subhypnotic doses and antioxidant effects in humans (Homo sapiens).3,4 When given intravenously, propofol crosses the blood brain barrier with a rapid onset of action. It exhibits high protein binding capacity, crosses the placenta, and is highly lipophilic.1,2 Because of the highly protein bound nature of this drug, hypoproteinemic patients should be given this medication cautiously.1 Metabolism of propofol is mainly by the glucuronide and sulfate conjugation processes in the liver to form inactive metabolites which are then excreted by the kidneys. 1 In addition, extrahepatic metabolism also takes place by an unknown mechanism. 2,5,6
The most common veterinary preparation used is a white-opaque lipid emulsion, PropofloTM (Abbott Laboratories, North Chicago, IL USA), with propofol as the active ingredient (available at 10mg/mL) and soybean oil, glycerol, egg lecithin, oleic acid and sodium hydroxide as inactive ingredients. This commercial preparation of propofol is associated with rapid growth of bacteria due to a lack of preservatives and inactive ingredients that provide an appropriate substrate for the bacteria. Bacterial colonization, including Staphylococcus aureus and Escherichia coli, can occur within 6 hours of opening a vial. One study evaluated whether sterile handling conditions would reduce the colonization of bacteria and found that regardless of whether appropriate handling was adhered to, marked bacterial colonization occurs.7 Package recommendations for PropofloTM indicate that after opening the vial, the contents should be discarded after 6 hours.
A second veterinary lipid emulsion, PropofloTM28 (Abbott Laboratories), is also available; however, it has an additional inactive ingredient, benzyl alcohol. The addition of alcohol in this preparation acts as a preservative extends the shelf life of the drug to 28 days. This formulation is only approved for use in dogs, as the concentration of benzyl alcohol present may induce toxicity in cats (Felis catus) and other alcohol sensitive species. All propofol emulsion suspensions can become unstable when in contact with lidocaine and protamine sulfate; therefore, care should be taken that these medications are not mixed in the same intravenous lines.8
Fospropofol disodium, available as Aquavan® injection (MGI Pharma, Inc, Bloomington, MN USA), is a novel water soluble short acting prodrug of propofol that exhibits a slower onset, a longer half-life, and longer duration of action than propofol emulsion.9,10 Fospropofol is rapidly hydrolyzed by endothelial alkaline phosphatases after intravenous administration, thus releasing active propofol into circulation.9 As an anesthetic agent, fospropofol has been evaluated in rabbits (Oryctolagus cuniculus) and red-eared sliders (Trachemys scripta elegans). In rabbits, higher infusion rates of fospropofol are required to maintain an adequate depth of anesthesia, and rabbits anesthetized with fospropofol had longer recovery times in comparison to those administered propofol.10 In addition, the use of fospropofol was associated with the anesthetic death of a single rabbit during a prolonged recovery phase. 10 When giving intracoelomically in red-eared sliders, fospropofol was associated with unpredictable quality of anesthesia and prolonged recovery periods, with some turtles requiring resuscitation efforts.11 Based upon the limited research into this anesthetic agent, its use cannot be recommended for clinical patients at this time.
When considering the absorption of propofol, the intravenous route of administration is a requirement, unless propofol baths or intracoelomic injections are given to some aquatic species.12, 13 Propofol has been shown to have similar pharmacodynamic properties whether given intravenously or intraosseously in rabbits.14 Intraosseous and intracardiac routes of administration are reported to be safe and efficacious in green iguanas (Iguana iguana) and ball pythons (Python regius), respectively, while intracoelomic propofol in nestling iguanas resulted in only mild sedation with moderate variability in responses between animals. 15-17 Intracoelomic injection of propofol at 25 mg/kg to 35 mg/kg in tiger salamanders (Ambystoma tigrinum) resulted in sedation to surgical anesthesia (25 mg/kg, 40%; 35 mg/kg, 83%).13 Laboratory animals administered propofol exhibited limited or unpredictable efficacy in induction of sedation or anesthesia when administered intramuscularly in rats (Rattus norvegicus) or intraperitoneally in mice (Mus musculus); this was likely due to the hydrophobic nature of the drug leading to poor systemic uptake.18,19 In one study, attempts to increase intramuscular absorption of propofol with the addition of dimethyl sulfoxide (DMSO) had no effect on the sedative or anesthetic effects of propofol.18
Safe administration of propofol has been reported when administered into the subcarapacial sinus of chelonians.20, 21 However, due to the proximity of this vessel with the spinal canal, care must be taken to ensure that injections are within the vascular system as inadvertent administration into the cerebrospinal fluid (CSF) is associated with severe bradycardia, apnea, and death. A CSF tap yielding a milky white liquid may represent a rapid antemortem or post mortem confirmatory diagnostic that propofol has entered the CSF inadvertently.22
Although rarely encountered in clinical veterinary medicine, extravascular propofol has been shown to have marked tissue effects. In human medicine, small children are particularly prone to tissue necrosis after extravasation.23,24 In veterinary medicine, when given intramuscularly in rats, propofol induced moderate to severe inflammation and necrosis at the injection site.18 In contrast, in hatchling iguanas administered intracoelomic propofol, no lesions attributable to propofol administration were noted on post mortem evaluation 14 days after injection.17 Fospropofol has also been associated with adverse effects with extravascular injections, although only mild effects were noted. In rabbits administered fospropofol, a transient pruritis, manifested as scratching at the injection site, was noted for 3-5 minutes post injection.10 Up to 85% of humans administered fospropofol experience tingling, burning, or itching sensations.9
Respiratory depression, including apnea, is the most common adverse side effect noted after propofol administration. Apnea has been observed after administration of propofol in common buzzards (Buteo buteo), turkeys (Meleagris gallopavo), red-eared sliders, African clawed frogs (Xenopus laevis), loggerhead sea turtles (Caretta caretta), tiger salamanders, and green iguanas.12,13,15,20,25-27 Respiratory depression without apnea, including bradypnea and/or respiratory acidosis, has been observed in red-tailed hawks (Buteo jamaicensis), great horned owls (Bubo virginianus), koi (Cyprinus carpio), sturgeon (Acipenser oxyrinchus de soti), and rabbits.28-32 In a single study in mallard ducks (Anas platyrhynchos), an increase in respiratory rate was reported after propofol induction.33 Because these studies span a variety of species and include administration at a variety of dosages (Table 1), a dose dependent and species dependent nature of apnea or bradypnea is likely and clinicians should use caution and carefully monitor their patient while under propofol anesthesia.
The cardiovascular effects of propofol in veterinary species has been reported. The effect on heart rate appears to be species specific; bradycardia is reported in sturgeon, koi, tiger salamanders, and green iguanas, while cardiac arrest has been reported in rabbits during propofol induction.13,15,29,30,34 Conversely, no changes in heart rate are reported in red-eared sliders, common buzzards, spotted bamboo sharks (Chylloscyllium plagiosum), Japanese macaques (Macaca fsucata fsucata), loggerhead sea turtles, red-tailed hawks, or great horned owls.20,25,27,28,35,36 Electrocardiogram abnormalities have been noted in chickens (Gallus domesticus), canvasbacks (Aythya valisineria), and dogs; however, their cause is unknown.2,37-39 The effects of propofol on blood pressure also appear to be species specific; a continuous rate infusion of propofol in squirrel monkeys (Saimiri sciureus) has been associated with hypotension, while no changes in blood pressure were reported in red-tailed hawks or great horned owls.28,40 The effects of propofol on the cardiovascular system have been well documented in laboratory animals. In one study, intravenous propofol in rabbits induced a significant but transient reduction in ventricular performance and a decrease in peripheral vascular resistance.41 Other studies in rabbits have shown transient tachycardia that may be secondary to a concomitant hypovolemia.10,14,31 Although not proven, these vascular changes in rabbits may be induced secondary to propofol induced endothelial damage.42 In vitro studies in rats have shown that propofol induces vasodilation of the aorta.43
A severe cardiovascular disorder in humans has been described as propofol infusion syndrome. The classic clinical features includes bradycardia leading to asystole, metabolic acidosis, rhabdomyolysis, hyperlipidemia, and the development of fatty liver. Predisposing risk factors include high propofol infusion doses, pediatric status, severe nervous system or respiratory illness, exogenous catecholamine or glucocorticoid administration, and subclinical mitochondrial disease.44 This syndrome has yet to be described in veterinary patients.
The use of propofol for induction and/or maintenance of anesthesia in a variety of species of birds has been associated with excitation events. Excitatory movements have been noted during induction of canvasbacks, however, this was not reported in mute swans (Cygnus olor), redtailed hawks, great horned owls, or common buzzards.25,28,38,45 More commonly, excitatory central nervous system signs are seen during the recovery period from propofol anesthesia, and this has been reported in mute swans, red-tailed hawks, and great horned owls.28,45 Transient excitatory movements in other species have been reported in blue crabs (Callinectes sapidus) and rabbits (post-fospropofol administration).10,46
In most situations, propofol is not used solely as an anesthetic agent, but in conjunction with other agents in a balanced anesthetic protocol. Studies in rats and rabbits have shown that administration of an additional sedative, analgesic, and/or dissociative anesthetic will reduce propofol doses required to induce or maintain anesthesia.31,47 The practice of balanced anesthesia not only reduces the amount of propofol required to be given, which may in turn reduce potential adverse effects, but has the added benefit of applying analgesia, as propofol has no analgesic qualities. Despite the risks associated with propofol administration, a recent meta-analysis including 133 studies and over fourteen thousand human patients showed no difference in mortality between human patients receiving propofol vs any other injectable anesthetic.48 Although no such study has been performed in veterinary patients, the results are encouraging that with appropriate use and anesthetic monitoring, propofol can be an integral component of an anesthetic regime in the species in which it has been shown to be safe.
References 1. Plumb DV: Propofol, in Plumb DV (ed): Veterinary Drug Handbook (ed 6), Ames, IA, Blackwell Publishing, pp 778-779, 2008 2. Posner LP, Burns P: Injectable anesthetic agents, in Riviere JE, Papich MG (ed): Veterinary Pharmacology and Therapeutics (ed 9), Ames, IA, WileyBlackwell, pp 265-300, 2009 3. Long JP, Greco SC: The effect of propofol administered intravenously on appetite stimulation in dogs. Contemp Top Lab Anim Sci 39(6): 43-46, 2000 4. Khoshraftar E, Ranjbar A, Kharkhane B, et al: Antioxidant effects of propofol vs. ketamine in individuals undergoing surgery. Arch Iran Med 17(7): 486489, 2014 5. Langley MS, Heel RC: Propofol: a review of its pharmacodynamic and pharmacokinetic properties and use as an intravenous anaesthetic. Drugs 35(4): 334-372, 1988 6. Matot I, Neely CF, Katz RY, et al: Pulmonary uptake of propofol in cats (effect of fentanyl and halothane). Anesthesiology 78(6): 1157-1165, 1993 7. Strachan FA, Mansel JC, Clutton RE. A comparison of microbial growth in alfaxalone, propofol and thiopental. J Small Anim Pract 49(4): 186-190, 2008 8. Baker MT, Naguib M: Propofol the challenges of formulation. Anesthesiology 103(4): 860-876, 2005 9. Levitzky BE, Vargo JJ: Fospropofol disodium injection for the sedation of patients undergoing colonoscopy. Ther Clin Risk Manag 4(4): 733-738, 2008 10. Li R, Zhang WS, Liu J et al: Minimum infusion rates and recovery times from different durations of continuous infusion of fospropofol, a prodrug of propofol, in rabbits: a comparison with propofol emulsion. Vet Anaesth Analg 39(4): 373-384, 2012
11. Schroeder CA, Johnson RA: The efficacy of intracoelomic fospropofol in redeared sliders (Trachemys scripta elegans). J Zoo Wildl Med 44(4): 941-950, 2013 12. Guenettte SA, Beaudry F, Vachon P: Anesthetic properties of propofol in African clawed frog (Xenopus laevis). J Am Assoc Lab Anim Sci 47(5): 3538, 2008 13. Mitchell MA, Riggs SM, Singleton CB, et al: Evaluating the clinical and cardiopulmonary effects of clove oil and propofol in tiger salamanders (Ambystoma tigrinum). J Exotic Pet Med 18(1): 50-56, 2009 14. Mazaheri-Khameneh R, Sarrafzadeh-Rezaei F, Asri-Rezaei S, et al: Comparison of time to loss of consciousness and maintenance of anesthesia following intraosseous and intravenous administration of propofol in rabbits. J Am Vet Med Assoc 241(1):73-80, 2012 15. Bennett RA, Schumacher J, Hedjazi-Haring K, et al: Cardiopulmonary and anesthetic effects of propofol administered intraosseously to green iguanas. J Am Vet Med Assoc 212(1): 93-98, 1998 16. McFadden MS, Bennett A, Reavill DR, et al: Clinical and histologic effects of intracardiac administration of propofol for induction of anesthesia in ball pythons (Python regius). J Am Vet Med Assoc 239(6): 803-807, 2011 17. Milne VE, Hoover JP, Snider TA, et al: Intracoelomic administration of propofol in hatchling green iguanas, Iguana iguana. J Herp Med Surg 16(1): 20-26, 2006 18. McKune CM, Brosnan RJ, Dark MJ, et al: Safety and efficacy of intramuscular propofol administration in rats. Vet Anaesth Analg 35(6): 495500, 2008 19. Alves HC, Valentim AM, Olsson IA, et al: Intraperitoneal propofol and propofol fentanyl, sufentanil and remifentail combinations for mouse anaesthesia. Lab Anim 41(3): 329-36, 2007 20. Ziolo MS, Bertelsen MF: Effects of propofol administered via the supravertebral sinus in red-eared sliders. J Am Vet Med Assoc 234(3): 390393, 2009 21. Vigani A: Chelonia (Tortoises, Turtles, and Terrapins), In West G, Heard D, Caulkett N (ed): Zoo Animal and Wildlife Immobilization and Anesthesia (ed 2), Ames, IO, John Wiley & Sons, Inc 365-387, 2014 22. Quesada R, Aiken-Palmer C, Conley K, et al: Accidental submeningeal injection of propofol in gopher tortoises (Gopherus polyphemus). Vet Rec 167(13): 494-495, 2011 23. Roth W, Eschertzhuber S, Gardetto A, et al: Extravasation of propofol is associated with tissue necrosis in small children. Paediatr Anaesth 16(8): 887889, 2006 24. Tokumine J, Sugahara K, Tomori T, et al: Tissue necrosis caused by extravasated propofol. J Anesth 16(4): 358-359, 2002
25. Kilic N, Pasa S: Cardiopulmonary effects of propofol compared with those of a medetomidine-ketamine combination in the common buzzards (Buteo buteo). Revue Med Vet 160(3): 154-159, 2009 26. Schumacher J, Citino SB, Hernandez K: Cardiopulmonary and anesthetic effects of propofol in wild turkeys. Am J Vet Res 58(9): 1014-1017, 1997 27. MacLean RA, Harms CA, Braun-McNeill J: Propofol anesthesia in loggerhead (Caretta careetta) sea turtles. J Wildl Dis 44(1): 143-150, 2008 28. Hawkins MG, Wright BD, Pascoe PJ, et al: Pharmacokinetics and anesthetic and cardiopulmonary effects of propofol in red-tailed hawks (Buteo jamaicensis) and great horned owls (Bubo virginianus). Am J Vet Res 64(6): 677-683, 2003 29. Oda A, Bailey KM, Lewbart GA, et al: Physiologic and biochemical assessments of koi (Cyprinus carpio) following immersion in propofol. J Am Vet Assoc 245(11): 1286-1291, 2014 30. Fleming G, Heard DJ, Floyd RF, et al: Evaluation of propofol and medetomidine-ketamine for short-term immobilization of Gulf of Mexico sturgeon (Acipenser oxyrinchus de soti). J Zoo Wildl Med 34(2): 153-158, 2003 31. Cruz FS, Carregaro AB, Raiser AG: Total intravenous anesthesia with propofol and S(+)-ketamine in rabbits. Vet Anaesth Analg 37(2): 116-122, 2010 32. Martinez MA, Murison PJ, Love E: Induction of anaesthesia with either midazolam or propofol in rabbits premedicated with fentanyl/fluanisone. Vet Rec 164(26): 803-806, 2009 33. Machin KL, Caulkett NA: Cardiopulmonary effects of propofol and a medetomidine-midazolam-ketamine combination in mallard ducks. Am J Vet Res 59(5): 598-602, 1998 34. Yin H, Chen WM, Zhao P: Cerebral state index may reflect electrical brain activity during propofol or isoflurane anaesthesia in rabbits. Vet Rec 172(17): 184, 2011 35. Miller SM, Mitchell MA, Heatley JJ, et al: Clinical and cardiorespiratory effects of propofol in the spotted bamboo shark (Chylloscylluim plagiosum). J Zoo Wildl Med 36(4): 673-676, 2005 36. Miyabe-Nishiwaki T, Masui K, Kaneko A, et al: Hypnotic effects and pharmacokinetics of a single bolus dose of propofol in Japanese macaques (Macaca fsucata fsucata). Vet Anaesth Analg 37(6): 501-510, 2010 37. Lukasik VM, Gentz EJ, Erb HN, et al: Cardiopulmonary effects of propofol anesthesia in chickens (Gallus gallus domesticus). J Avian Med Surg 11: 9397, 1997 38. Machin KL, Caulkett NA: Cardiopulmonary effects of propofol infusion in canvasback ducks (Aythya valisineria). J Avian Med Surg 13: 167-172, 1999
39. Kamibayashi T, Hayashi Y, Sumikawa K, et al: Enhancement by propofol of epinephrine-induced arrhythmias in dogs. Anesthesiology 75(6): 1035-1040, 1991 40. Galante R, Muniz J, Castro PH, et al: Continuous infusion of propofol or intermittent bolus of tiletamine-zolazepam in squirrel monkeys (Saimiri sciureus). Vet Anaesth Analg 41(5): 506-515, 2014 41. Baumgartner C, Bollerhey M, Henke J, et al: Effects of propofol on ultrasonic indicators of haemodynamic functions in rabbits. Vet Anaesth Analg 35(2): 100-112, 2008 42. Paco CD, Vane MF, de Andrade RB, et al: Effects of propofol in lipid-based emulsion and in microemulsion on the incidence of endothelial lesions in rabbits. Acta Cir Bras 28(12): 833-841, 2012Sakai Y, Kawahito S, Takaishi K, et al: Propofol-induced relaxation of rat aorta is altered by aging. J Med Invest 61(3-4): 278-284, 2014 43. Kam PC, Cardone D: Propofol infusion syndrome. Anaesthesia 62(7): 690701, 2007 44. Muller K, Holzapfel J, Brunnberg L: Total intravenous anaesthesia by boluses or by continuous rate infusion of propofol in mute swans (Cygnus olor). Vet Anaesth Analg 38(4): 286-291, 2011 45. Quesada R, Smith CD, Heard DJ: Evaluation of parenteral drugs for anesthesia in the blue crab (Callinectes sapidus). J Zoo Wildl Med 42(2): 295299, 2011 46. Penderis J, Franklin RJ: Effects of pre- versus post-anaesthetic buprenorphine on propofol-anaesthetized rats. Vet Anaesth Analg 32(5):256-260, 2005 47. Passin L, Landoni G, Cabrini L, et al: Propofol and survival: a meta-analysis of randomized clinical trials. Acta Anaesthesiol Scand. 2014 Oct 14. doi: 10.1111/aas.12415
Table 1: Selected doses of propofol used in a variety of species in the literature. IV – intravenous, CRI – constant rate infusion, IC – intracardiac, IO – intraosseous, IP – intraperitoneal, CNS – central nervous system, ICe – intracoelomic. Species
Propofol dose
Comments
Common buzzard (Buteo buteo)
10mg/kg over 60 sec24
Transient apnea
Great horned owl (Bubo virginianus)
3.6mg/kg IV (1mg/kg/min) followed by 0.56mg/kg/min CRI27
Respiratory depression, excitatory CNS signs during recovery , light anesthesia
Mallard ducks (Anas platyrhynchos)
10mg/kg IV32
Transient increased respiratory rate
Mute swans (Cyngus olor)
2.9mg/kg IV by bolus44
Abrupt waking from anesthesia with excitement upon recovery
0.85mg/kg/min CRI44
Excitement upon recovery
4.5mg/kg IV (1mg/kg/min) followed by 0.5mg/kg/min CRI27
Respiratory depression, excitatory CNS signs during recovery, light anesthesia
Avian
Red-tailed hawk (Buteo jamaicensis)
Wild turkey 5mg/kg IV over 20 sec followed by (Meleagris gallopavo) 0.5mg/kg/min CRI25
Apnea
Japanese macaques (Macaca fsucata fsucata)
8mg/kg IV (6mg/kg/min)35
Hypnotic effect for 7 minutes,
Mouse (Mus musculus)
50-200mg/kg IP18
Not recommended
Rabbit (Oryctolagus cuniculi)
12.5mg/kg IV or IO followed by 1mg/kg/min CRI13
Both routes induced effective anesthesia; transient tachycardia
8mg/kg IV (8mg/kg/min) with fentanyl 5 mcg/kg followed by 0.7mg/kg/min33
Death of single animal during induction (cardiac arrest)
Mammals
2.2mg/kg (1mL/60 sec) after premedication with fentanyl/fluanisone 0.1mL/kg IM31 Rat (Rattus norvegicus)
0-490mg/kg IM17
Not recommended
Squirrel monkeys (Saimiri sciureus)
12mg/kg IV (4mg/kg/min) followed by 0.4mg/kg/min CRI39
Hypotension reported, faster induction and recovery compared to tiletamine-zolazepam anesthesia
Reptiles Aquatic Animals
Ball pythons (Python regius).
10mg/kg IC15
Shorter induction time but longer recovery time compared to isoflurane, no long term effects of IC injection
Green iguana (Iguana iguana)
5-10mg/kg IO followed by 0.5mg/kg/min14
Apnea, bradycardia
10mL/kg Ice16
Produces variable sedation – light anesthesia
Red-eared slider (Trachemys scripta elegans)
10-20mg/kg IV19
60-90 minutes of light – deep anesthesia
African clawed frog (Xenopus laevis)
88mg/L bath for 15 min12
Light anesthesia, apnea, narrow safety margin
Blue crab (Callinectes sapidus)
20mg/kg into hemolymph45
Short light anesthesia with limb autonomy and distress during recovery
Sturgeon (Acipenser oxyrinchus de soti)
6.5ng/kg IV29
Light anesthesia within 5 minutes
Spotted bamboo sharks (Chylloscylluim plagiosum)
2.5mg/kg IV over 30 sec34
Surgical plane of anesthesia within 5 minutes
Tiger salamander (Ambystoma tigrinum)
25-35 mg/kg13
Apnea and bradycardia; surgical anesthesia (40%, 25 mg/kg; 83%, 35 mg/kg)