Analgesia

014 Ketamine

Special K: Is Ketamine Really All That?

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Clinical use first reported in human medicine in 1965; approved for clinical use in 1970
First identified veterinary report: Glen JB. The use of ketamine (CI-581) in feline anaesthetic practice. Vet Rec 1973.

Unravelling story with respect to evidence-based medicine – in people and especially veterinary species. Less so regarding use in anaesthesia, more so regarding sedation and especially analgesia.

 “Ketamine may be the subject of misuse and, therefore, should be stored in the controlled drugs cabinet and its use recorded in an informal register.” (RCVS website, March 2015)

1. How does ketamine work? What does it do?

N-methyl-D-aspartate (NMDA) receptor antagonist:

  • Most widely reported and acknowledged mechanism; thought to be responsible for most clinical effects
  • But “nightmare of the pharmacologist” as myriad other proven/suggested mechanisms and receptors may be involved

2. Ketamine causes a continuum of central nervous system effects:

Dose-dependent CNS effects…with increasing doses: analgesia – sedation – partial dissociation – complete dissociation
Once complete dissociation reached, additional doses prolong duration of action without additional dissociation

Overlap between dose ranges for clinical effects; also depends on individual patient.

Analgesia:

Low/sub-dissociative dose use for analgesia has gained increasing recognition and popularity in last 10 years or so
Analgesic uses include acute emergency pain but also perioperative pain management
Typically as infusion after initial loading dose for analgesia but intermittent bolus therapy also feasible
Analgesic effects both supra-spinal (brain) and spinal
Likely to have both more classically reported anti-sensitisation (“wind up”) CNS effects and direct analgesia

3. Is ketamine contraindicated with raised intracranial pressure?

Long-standing contraindication in veterinary references – seems to have been extrapolated from human references.
Long-standing contraindication in human references – based on small number of poor quality studies from 1970s.

Active on-going clinical research in humans with raised ICP of different causes (e.g. trauma vs. mass lesion vs. hydrocephalus) to test traditional contraindication
Increasing consensus at this time refuting this contraindication and supporting positive risk-benefit profile for ketamine use in general population of acute emergency human patients with suspected/proven raised ICP

Original contraindication reported in veterinary resources extrapolated from human medicine with no species-specific evidence. At this time it seems reasonable and legitimate to discard this ‘myth’ while keeping future evidence under review.

4. Ketamine is sympathomimetic:

Stimulates sympathetic nervous system (by preventing catecholamine reuptake and/or increasing secretion – seems unclear)
May therefore help to support patients with cardiovascular instability and existing sympathetic nervous system-driven compensation
If sympathetic response is blunted/exhausted, ketamine may depress cardiovascular system

5. What about ketamine in cats with hypertrophic cardiomyopathy (HCM)?

Meant to be relatively contraindicated in cats with HCM; sympathomimetic effect may cause a cat with sub-clinical cardiomyopathy to decompensate – especially if obstructive component to HCM.
Relative not absolute contraindication – risk-benefit profile as always
Undoubtedly many cats with sub-clinical HCM will have received ketamine and true significance/risk remains unclear

6. ‘Ketamine head’:

Ketamine emergence, dysphoria, mania, hyperexcitability, spackiness - “ketamine head” (Aoife O’Sullivan); especially cats
Emergence can range from entirely unremarkable to really quite spectacular neurological/neuromuscular signs
Prevention is key. Ensure other agents (e.g. opioid, α2-agonist) on board and active during emergence
Quiet room, minimal stimulation etc.
May require pharmacological intervention

7. Can ketamine be used as a sole agent?

Is it okay for a patient not to have already received another agent (e.g. opioid) that is on board and working at the time of ketamine administration? Or indeed not to at least have one with a rapid onset co-administered alongside the ketamine?

Sole use of ketamine reported in children and seems more recognised
Evidence in adult humans does not seem to support sole use
Suggest (anecdotally) never using ketamine as sole agent in veterinary species – especially due to increased risk of potentially spectacular “ketamine head”

8. Is ketamine contraindicated with raised intraocular pressure?

Another long-standing listed contraindication in human and veterinary medicine; again substantive evidence woefully lacking
Increasingly rebutted as a ‘myth’ in human medicine based on emerging evidence
No good quality clinically relevant canine/feline evidence identified
Author is comfortable to recommend use of ketamine in patients with raised IOP where potential benefits supersede this theoretical and unproven risk

9. Ketamine in caesarean section:

Can and indeed should you be including ketamine as part of your c-section protocol?
Used in women relatively commonly for this purpose; no evidence identified that poses increased risk to mum or baby
Paucity of veterinary evidence and certainly identified demonstrating increased risk
“Absence of evidence is not evidence of absence” but overall happy to recommend pre-, intra- and post-operative ketamine use for c-section
Provides multimodal analgesia. Dose-sparing for potentially more harmful drugs, especially inhalant anaesthetics

10. Other bits ‘n’ pieces:

Other things to highlight about ketamine:
Protective airway reflexes preserved

  • Cats’ eyes remain open – must keep well lubricated
  • Cats reportedly may salivate excessively – reported more in humans
  • Hepatic metabolism in most species; minimal in cats
  • Parent compound and metabolites renally excreted. Available evidence in people at this time does not suggest the need for dose reduction with hepatic or renal impairment.

Use in treatment of refractory status epilepticus reported in people; one published canine case report but actual unpublished clinical experience likely to be greater than this.

Also sometimes used in children with refractory status asthmaticus due to potential bronchodilatory effect from β2-adrenergic receptor stimulation. Unclear if effective in asthmatic cats refractory to standard therapies – very rare patient anyway?

Some papers that informed this episode:

VETERINARY

Kovalcuka L, Birgele E, Bandere D, Williams DL. The effects of ketamine hydrochloride and diazepam on the intraocular pressure and pupil diameter of the dog’s eye. Vet Ophthal 2013. 16(1):29-34.

Pei-Yu Liao, Shi-Chieh Chang, Kuan-Sheng Chen, Hsien-Chi Wang. Decreased postoperative C-reactive protein production in dogs with pyometra through the use of low-dose ketamine. J Vet Emerg Crit Care 2014. 24(3):286-290.

Serrano S, Hughes D, Chandler K. Use of Ketamine for the Management of Refractory Status Epilepticus in a Dog. J Vet Int Med 2006. 20(1):194-197.

Wagner AE, Walton JA, Hellyer PW, et al. Use of low doses of ketamine administered by constant rate infusion as an adjunct for postoperative analgesia in dogs. J Am Vet Med Assoc 2002. 221(1):72-75.

HUMAN MEDICINE

Ahern TL, Herring AA, Stone MB, Frazee BW. Effective analgesia with low-dose ketamine and reduced dose hydromorphone in ED patients with severe pain. Am J Emerg Med 2013. 31(5):847-851.

Beaudoin FL, Lin C, Guan W, Merchant RC. Low-dose ketamine improves pain relief in patients receiving intravenous opioids for acute pain in the emergency department: results of a randomised, double-blinded, clinical trial. Acad Emerg Med 2014. 21(11):1193-1202.

Cohen L, Athaide V, Wickham ME, et al. The Effect of Ketamine on Intracranial and Cerebral Perfusion Pressure and Health Outcomes: A Systematic Review. Ann Emerg Med 2015. 65(1):43–51.

Drayna PC, Estrada C, Wang W, et al. Ketamine sedation is not associated with clinically meaningful elevation of intraocular pressure. Am J Em Med 2012. 30(7):1215-1218.

Green SM, Andolfatto G, Krauss BS. Ketamine and Intracranial Pressure: No Contraindication Except Hydrocephalus. Ann Emerg Med 2015. 65(1): 52-54.

Halstead SM, Deakyne Sj, Bajaj L, et al. The Effect of Ketamine on Intraocular Pressure in Pediatric Patients During Procedural Sedation. Acad Em Med 2012. 19(10):1145-1150.

Heesen M, Bohmer J, Brinck ECV, et al. Intravenous ketamine during spinal and general anaesthesia for caesarean section: systematic review and meta-analysis. Acta Anaes Scans 2015. 59(4):414-426.

Laskowski K, Stirling A, McKay WP, Lim HJ. A systematic review of intravenous ketamine for postoperative analgesia. Can J Anesth 2011. 58(10):911-923.

Anna Rosati, Manuela L’Erario, Lucrezia Ilvento. Rosati A, L’Erario M, Ilvento L. Efficacy and safety of ketamine in refractory status epilepticus in children. Neurol 2012. 79(24):2355-2358.

Terence L. Ahern, Andrew A. Herring, Erik S. Anderson, et al. The first 500: initial experience with widespread use of low-dose ketamine for acute pain management in the ED. Am J Emerg Med 2015. 33(2):197-201.

Tiwari A, Guglani V, Ram Jat K. Ketamine versus aminophylline for status asthmaticus in children: A randomized, controlled trial. Eur Resp J 2014. 44, Suppl 58 281.

Wadia S, Bhola R, Lorenz D, et al. Ketamine and Intraocular Pressure in Children. Ann Emerg Med 2014. 64(4):385-388.

Wang X, Ding X, Tong Y, et al. Ketamine does not increase intracranial pressure compared with opioids: meta-analysis of randomized controlled trials. J Anesth 2014. 28(6):821-827.

Zeiler FA, Teitelbaum J, West M, Gillman LM. The Ketamine Effect on ICP in Traumatic Brain Injury. Neurocrit Care 2014. 21(1):163-173.

Zeiler FA, Teitelbaum J, West M, Goillman LM. The ketamine effect on intracranial pressure in nontraumatic neurological illness. J Crit Care 2014. 29(6): 1096–1106.

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011 2015 AAHA/AAFP Pain Management Guidelines for Dogs and Cats

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Epstein M, Rodan I, Griffenhagen G. AAHA/AAFP Pain Management Guidelines for Dogs and Cats. J Fel Med Surg 2015. 17, 251–272.

Guidelines are more extensive but focusing here on ECC scenarios with acute/short-term pain.
Update to the last set of guidelines published in 2007
“The recommendations of the Guidelines Task Force are evidence based in so far as possible and otherwise represent a consensus of expert opinion.”

1. Pain management must be central to our clinical practice

Part of initial assessment of emergency patients; address during initial stabilisation

Pain management important as it improves patient welfare – ethical and professional obligation; also has implications for clinical morbidity, progression, recovery and potentially outcomes.

Uncontrolled pain has both adverse psychological and physiological consequences.

2. Pain physiology should be considered when implementing our pain management

Pain response is unique to each individual.

Try as much as possible to individualise pain management; adjust and amend protocol based on individual patient’s response.

Staff must communicate to one another information about each individual patient’s pain response and management needs; verbal communication and in medical record.

“Pain is the endpoint of nociceptive input and can only occur in a conscious animal. However, there is also involvement of autonomic pathways and deeper centers of the brain involved with emotion and memory. Hence, pain is a multidimensional experience; it is not just what you feel but also how it makes you feel.”

Underlying causes of pain can be classified as:

  • Nociceptive pain: occurs when peripheral neural receptors are activated by noxious stimuli (e.g. surgical incisions, trauma, heat or cold).
  • Inflammatory pain: results gradually from activation of the immune system in response to injury or infection.
  • Pathological pain, also called maladaptive pain: occurs when pain is amplified and sustained by molecular, cellular and microanatomic changes, collectively termed peripheral and central hypersensitisation or “wind up”.
    • Sensitisation is characterised by hyperalgesia, allodynia, expansion of the painful field beyond its original boundaries and protracted pain.
    • As far as wind up is concerned, anticipatory analgesia provided prior to pain onset is more effective than analgesia provided once pain has occurred. Get the pain of painful emergency patients under control as soon as possible and keep them as pain-free as possible.

Neuropathic pain can be considered a disease of the central nervous system. 

3. The patient’s behaviour is key to pain assessment

Approach to pain management based on anticipating when pain is likely to be present, regular assessment, and at times making assumptions.

“It is now accepted that the most accurate method for evaluating pain in animals is not by physiological parameters but by observations of behavior.”

Use behaviour essentially as a means of non-verbal communication, to try and learn to interpret behaviour as tell-tale signs of on-going pain.

“Because behavioral signs of pain are often overlooked or mistaken for other problems, the healthcare team must be vigilant in recognizing those anomalies in the total patient assessment.”

4. Pain scoring tools can be useful

Improve objectivity in pain assessment and consistency between individuals.

But also ensures that regular pain assessment actually occurs!

“Although there is currently no gold standard method for assessing pain in dogs and cats, the Guidelines Task Force strongly recommends utilizing pain scoring tools both for acute and chronic pain. It should be noted that those tools have varying degrees of validation, acute and chronic pain scales are not interchangeable, and canine and feline scales are not interchangeable.”

5. Multimodal (balanced) analgesia is another key strategy in pain management

Use analgesic agents from different classes with the intention of targeting multiple points in the pain pathways.

Combining agents hopefully allows lower doses of each individual drug and thereby minimises potential for side effects associated with any single drug.

Some analgesic agents may work synergistically.

6. Opioids are the best analgesics in many emergency patients

“Opioids are the most effective drug class for managing acute pain”. More specifically the authors say that “Full µ agonists [– so drugs such as methadone, morphine, hydromorphone etc.] – elicit greater and more predictable analgesia than partial µ agonists or κ agonists. In dogs, the µ antagonist/κ agonist butorphanol, in particular, appears to provide limited somatic analgesia and a very short duration of visceral analgesia.”

Likely consensus that buprenorphine is a useful analgesic in mild-to-moderate or even severe pain. BUT has a comparatively slower onset of peak effect (20-45 minutes) compared to pure opioids so not ideal as first line analgesic in patients with moderate-to-severe pain.

7. Non-steroidal anti-inflammatory drugs (NSAIDs) may be contraindicated in emergency patients

“The majority of conditions that cause pain have an inflammatory component….NSAIDs should be used for their central and peripheral effects in both dogs and cats after consideration of risk factors. There is no indication that any one of the veterinary-approved NSAIDs is associated with any greater or lesser incidence or prevalence of adverse events.”

NSAIDs can be very effective; possible synergism with opioids in particular.

But potential contraindications relatively common in emergency patients – hypovolaemia, dehydration, significant gastrointestinal disease etc.

Guidelines also mention local anaesthetics, ketamine, systemic lidocaine, tramadol and a variety of other agents.

8. Don’t overlook non-pharmacological measures

“Increasingly, evidence-based data and empirical experience justify a strong role for non-pharmacologic modalities for pain management. A number of those should be considered mainstream options and an integral part of a balanced, individualized treatment plan.

Examples of non-pharmacologic treatments supported by strong evidence include, but are not limited to, cold compression, weight optimization and therapeutic exercise. Treatment options gaining increasing acceptance include acupuncture, physical rehabilitation, myofascial trigger point therapy and therapeutic laser….”

9. DON’T OVERLOOK TLC!

“Non-pharmacologic adjunctive treatment includes an appreciation of improved nursing care, gentle handling, care-giver involvement….There is strong evidence that the stress of hospitalization inhibits normal behaviors in animals, including eating, grooming, sleeping and elimination….Fear, anxiety, stress and distress lead to hyperalgesia in both humans and animals…Strategies to mitigate hyperalgesia, therefore, include providing bedding, blankets or clothing from home with familiar scents; allowing visitation of hospitalized pets; separating the dogs from the cats; placing cages so that animals do not see each other; using species-specific synthetic pheromones; and proper handling, especially during procedures”.

10. Conflicts of interest

“These Guidelines were supported by an educational grant to AAHA from Abbott Animal Health, Elanco Companion Animal Health, Merial and Zoetis.”

“Mark Epstein has previously consulted for Abbott, Elanco and Merial. Sheilah Robertson is a key opinion leader for Novartis Animal Health.”

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