Ketamine: New Tricks for an Old Drug?

Philip R Judge BVSc MVS PG Cert Vet Stud MACVSc (Vet. Emergency and Critical Care; Medicine of Dogs)

Ketamine Tricks 2022

Introduction

Ketamine has been in clinical use for over half a century, mainly in the provision of anaesthesia. However, in recent year, a range of pharmacological properties of ketamine have been discovered, widening the potential use of the drug beyond its traditional anaesthetic role. The aim of this short review is to examine literature around the pharmacologic effects of ketamine, and to present evidence for potential additional use in dogs and cats1.

Pharmacology

Ketamine molecule (2-(O-chlorophenyl)-2-methylamino cyclohexanone) has a molecular weight of 238. Ketamine is prepared as a racemic mixture of the S and R stereoisomers, in a slightly acidic solution (pH 3.5-5.5), is freely water soluble, and has a pKa of 7.52

Ketamine also has the following pharmacokinetic properties2:

BioavailabilityIV: 100%
IM: 93%
Oral: 20-25%
Protein Binding20-50%
Elimination half-life2-3 hours
MetabolismHepatic – P450 cytochrome
MetabolitesNorketamine
Dehydronorketamine
ExcretionKidney

Mechanism of Action1-3

Ketamine acts on the central nervous system by the following mechanisms

  1. NMDA Receptor Antagonism in the CNS and spinal cord receptors
  2. Reduces pre-synaptic release of glutamate
  3. Mu receptor agonist modulation
  4. Kappa receptor agonist modulation
  5. Dopamine receptor stimulation
  6. AMPA receptor modulation
  7. Monoamine receptor antagonism
  8. Muscarinic receptor antagonism
  9. Nicotinic receptor antagonism 

Ketamine also has some local anaesthesia properties, likely mediated via inhibition of sodium channels.

Clinical Effects

Neurological Effects2-5:

Ketamine produces anaesthesia described as “dissociative” – characterised by functional and electrophysiological dissociation between the thalamo-neocortical, and limbic systems. Ketamine produces anaesthesia with the following characteristics:

  1. Catalepsy
  2. Catatonia 
  3. Open eyes +/- slow nystagmus
  4. Intact corneal and pupillary light reflexes
  5. Hypertonus with occasional muscle movements/spasms
  6. Increased salivation and lacrimation
  7. Amnesia 

Ketamine has anti-epileptic properties, despite increasing excitation in the thalamus and limbic neurons, owing to suppression of seizure propagation in cerebro-cortical neurons.

Ketamine has analgesic properties, mediated by NMDA receptor antagonism, that occur at sub-anaesthetic doses, and through direct inhibition of nitric oxide synthase3. Ketamine also prevents – and can even reverse opioid mu-receptor desensitization by affecting the degree of phosphorylation of down-stream receptors3. Additionally, ketamine activates serotonin and noradrenaline release, and inhibits re-uptake, further contributing to analgesic effect3.

Ketamine increases cerebral metabolic rate, as well as cerebral blood flow and intracranial pressure. Despite this, studies on the S isomer of ketamine show it does not affect cerebrovascular autoregulation.

Ketamine has neuro-protective effects, by NMDA-mediated reduction in abnormal intracellular calcium influx and glutamate accumulation, as well as immune-modulation following neural injury2,5.

Ketamine appears to have effects on chronic pain suppression that last well beyond the elimination of the drug. Ketamine administered at the time of surgery has been reported to limit development of chronic pain between 30-180 days post-operatively in humans. A single analgesic (low-dose) of ketamine can reduce ongoing pain of neuropathic origin, and hyperalgesia for up to 2-3 hours. Exact mechanisms of this prolonged analgesia are unclear at present, but are thought to include alterations in cell-cascades that interrupt propagation of changes associated with chronic pain development – including gene expression pathways linked to chronic pain, including NMDA receptor expression, astrocyte activation, and synaptic structure and function – resulting in analgesic effects that long outlast the detectable presence of the drug3

Cardiovascular Effects2:

Ketamine induction induces a sympathetic nervous system response, which increases heart rate, systolic arterial and mean arterial blood pressure, and cardiac output. Interestingly, when applied directly to heart muscle in experimental studies, ketamine has a direct myocardial depressant effect.

When administered by continuous infusion, the observed cardiovascular responses mentioned above are blunted, although blood pressure and cardiac output are maintained.

Respiratory Effects1,2:

Ketamine has the following effects on the respiratory system:

  1. Minimal effect on central respiratory drive – although transient decreases in ventilation rate can occur following bolus injection
  2. Bronchodilatation – via bronchial smooth muscle relaxation
  3. Improves pulmonary compliance
  4. Preserves diaphragmatic contractility, leading to maintenance of respiratory force

Immune Function2,5:

Ketamine produces significant reduction in leukocyte and platelet activation during hypoxaemia and sepsis, by reducing adhesion at sites of tissue injury. This suppresses pro-inflammatory cytokine production, producing an anti-inflammatory effect. 


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Clinical Uses of Ketamine: Present and Future

General Anaesthesia1,2,6

Ketamine induces general, dissociative anaesthesia in both animals and humans. As described above, dissociative anaesthesia is a form of anaesthesia that lacks complete unconsciousness, but is characterised by catatonia, catalepsy and amnesia. 

Ketamine may be administered intravenously, intramuscularly or via oral or nasal mucous membrane – although oral or intra-nasal administration typically results in sedation, rather than anaesthesia, owing to reduced drug bioavailability1,6.

Ketamine is frequently combined with skeletal muscle relaxants, such as benzodiazepines, to improve muscle relaxation in anaesthesia, thereby improving the quality of anaesthesia in patients requiring surgery or manipulation under anaesthesia1,2

Additionally, the use of ketamine continuous infusions in anaesthesia has a MAC-sparing effect, that can improve haemodynamic stability in compromised patients undergoing anaesthesia1,2.

Analgesia6-11

Aside from anaesthetic induction and maintenance, ketamine is considered useful as an opioid-sparing agent in the maintenance of analgesia in critically ill patients6,7. Human patients receiving ketamine infusions are more likely to achieve target pain scores than those treated with opioids and sedatives without ketamine8. Additionally, ketamine infusion reduces the requirement for concurrent sedative use in mechanically ventilated patients, whilst improving goal sedation criteria9. Similarly in dogs, a study showed that intravenous infusions of ketamine prior to, and for 18 hours following surgery provided improvement in pain scores for 3 days post-operatively when compared to control patients11.

Ketamine has also been used as an adjunctive local anaesthetic agent, alongside sodium channel blockers such as lidocaine or bupivacaine, both in peripheral nerves, and in epidural analgesia6,7.

Anti-Inflammatory2,5,6

Ketamine has been shown to inhibit the inflammatory reaction following traumatic injury and surgery. Ketamine reduces immune reaction-induced production of pro-inflammatory cytokines, including:

  • Interleukin-6
  • Tumour necrosis factor-alpha
  • C-reactive protein
  • Inducible nitric oxide synthase

Anti-inflammatory effects of ketamine are observed when administered both prior to, and following tissue injury and immune-stimulation, suggesting potential benefit in modulating the inflammatory response following tissue injury, as well as in the pre-operative period6.

Antidepressant6

Several studies have shown that ketamine infusions exert antidepressant activity within 2 hours and lasting an average of 7 days in patients’ refractory to standard antidepressant medications. Additionally, oral or intra-nasal ketamine administration appear to offer similar clinical benefits to intravenous infusions.

The mechanism of antidepressant effects of ketamine is not well understood, but appears to require endogenous opioid receptor stimulation12, in concert with at least some of ketamine’s mechanisms of action, including NMDA receptor antagonism, and dopaminergic effects, among others1-3.

Traumatic Brain Injury13-19

Maintaining an adequate level of sedation and analgesia plays a key role in the management of traumatic brain injury (TBI). To date, it is unclear which drug or combination of drugs is most effective in achieving these goals.

The use of ketamine as a sedative, analgesia and anaesthetic agent in patients with traumatic brain injury is of high interest, because ketamine may be of potential beneficial in patients with traumatic brain injury17, owing to the following properties:

  1. Maintenance of systolic arterial blood pressure following administration
  2. Maintenance of respiratory function following administration
  3. Anti-inflammatory effects, as previously outlined
  4. Inhibition of so-called “spreading depolarizations” – which occur due to loss of transmembrane ion gradients seen in the hours to several days following brain injury, that result from brain ischaemia and abnormal energy and oxygen delivery to the brain. Ketamine has an effect of increasing beta frequency neuronal discharge, which reduces propagation of spreading depolarizations

Despite theoretical advantages, there remains concern that ketamine may raise intracranial pressure in patients with traumatic brain injury, thereby reducing cerebral perfusion pressure. However, in reviews of populations with severe traumatic brain injury, ketamine was found not to increase intracranial pressure in sedated and normocapnic mechanically ventilated patients and was found to decrease intracranial pressure in selected cases17-19.

Conclusion

The use of ketamine for induction and maintenance of general anaesthesia is well-studied. When combined with muscle relaxants such as benzodiazepines, ketamine affords excellent analgesia and haemodynamic stability, which is of particular interest and use in compromised patients, including those with a wide range of tissue injury or illness, including traumatic brain injury.

The opioid-sparing analgesic effects of low-dose ketamine continuous infusions are well-known also. They produce minimal sedation, effective analgesia, and delay the development of opioid tolerance. The observation that the clinical effect of ketamine analgesia may persist well beyond drug excretion is of significant interest, and with more evidence, may serve as a potential therapy for management of long-term pain in some patients.

The anti-inflammatory effects of ketamine deserve further study also. At present, there may be theoretical benefits for the use of ketamine infusions in the management of traumatic brain injury, as well as in patients suffering acute traumatic or other inflammatory diseases, including SIRS and sepsis. Present studies show minimal deleterious haemodynamic effects of ketamine infusion in such patients, but evidence level for beneficial outcome is unclear at present in both humans and dogs and cats, despite promising studies. 

How ketamine produces these effects goes beyond simple NMDA receptor antagonism. In additional to NMDA receptor antagonism, ketamine affects a wide range of intracellular neuronal processes, through various mechanisms that affect cell signaling, receptor stimulation or antagonism, and cell signaling cascades. Further research into these mechanisms, and their effects on cell processes will enhance our understanding of potential value of ketamine beyond its traditional role in anaesthesia and acute analgesic therapy.


References

  1. Sleigh, Jamie, Martyn Harvey, Logan Voss, and Bill Denny. “Ketamine–More mechanisms of action than just NMDA blockade.” Trends in anaesthesia and critical care 4, no. 2-3 (2014): 76-81.
  2. Anirudda Pai, MD DNB FRCA, Mark Heining, MD FRCA, Ketamine, Continuing Education in Anaesthesia Critical Care & Pain, Volume 7, Issue 2, April 2007, Pages 59–63.
  3. Williams, Nolan R., Boris D. Heifets, Christine Blasey, Keith Sudheimer, Jaspreet Pannu, Heather Pankow, Jessica Hawkins et al. “Opioid receptor antagonism attenuates antidepressant effects of ketamine.” The American journal of psychiatry 175, no. 12 (2018): 1205.
  4. Engelhard, K., C. Werner, H. Lu, O. Möllenberg, and E. Kochs. “Effect of S-(+)-ketamine on autoregulation of cerebral blood flow.” Anasthesiologie, Intensivmedizin, Notfallmedizin, Schmerztherapie: AINS 32, no. 12 (1997): 721-725.
  5. Kawasaki, Takashi, Masanori Ogata, Chika Kawasaki, Jun-ichi Ogata, Yoshitaka Inoue, and Akio Shigematsu. “Ketamine suppresses proinflammatory cytokine production in human whole blood in vitro.” Anesthesia & Analgesia 89, no. 3 (1999): 665.
  6. Zanos, Panos, Ruin Moaddel, Patrick J. Morris, Lace M. Riggs, Jaclyn N. Highland, Polymnia Georgiou, Edna FR Pereira et al. “Ketamine and ketamine metabolite pharmacology: insights into therapeutic mechanisms.” Pharmacological reviews 70, no. 3 (2018): 621-660.
  7. Pruskowski, Kaitlin A., Kelly Harbourt, Mehrnaz Pajoumand, Sai‐Ho Jason Chui, and H. Neal Reynolds. “Impact of ketamine use on adjunctive analgesic and sedative medications in critically ill trauma patients.” Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy 37, no. 12 (2017): 1537-1544.
  8. Chan, Katalina, Lisa D. Burry, Christopher Tse, Hannah Wunsch, Charmaine De Castro, and David R. Williamson. “Impact of Ketamine on Analgosedative Consumption in Critically Ill Patients: A Systematic Review and Meta-Analysis.” Annals of Pharmacotherapy (2022): 10600280211069617.
  9. Garber, Paige M., Christopher A. Droege, Kristen E. Carter, Nicole J. Harger, and Eric W. Mueller. “Continuous infusion ketamine for adjunctive analgosedation in mechanically ventilated, critically ill patients.” Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy 39, no. 3 (2019): 288-296.
  10. Wagner, Ann E., Judy A. Walton, Peter W. Hellyer, James S. Gaynor, and Khursheed R. Mama. “Use of low doses of ketamine administered by constant rate infusion as an adjunct for postoperative analgesia in dogs.” Journal of the American Veterinary Medical Association 221, no. 1 (2002): 72-75.
  11. Groth, Christine M., Christopher A. Droege, Kathryn A. Connor, Kimberly Kaukeinen, Nicole M. Acquisto, Sai Ho J. Chui, Michaelia D. Cucci et al. “Multicenter Retrospective Review of Ketamine Use in the ICU.” Critical care explorations 4, no. 2 (2022).
  12. Williams, Nolan R., Boris D. Heifets, Christine Blasey, Keith Sudheimer, Jaspreet Pannu, Heather Pankow, Jessica Hawkins et al. “Opioid receptor antagonism attenuates antidepressant effects of ketamine.” The American journal of psychiatry 175, no. 12 (2018): 1205.
  13. Zanza, Christian, Fabio Piccolella, Fabrizio Racca, Tatsiana Romenskaya, Yaroslava Longhitano, Francesco Franceschi, Gabriele Savioli et al. “Ketamine in Acute Brain Injury: Current Opinion Following Cerebral Circulation and Electrical Activity.” In Healthcare, vol. 10, no. 3, p. 566. MDPI, 2022.
  14. Gregers, Mads Christian Tofte, Søren Mikkelsen, Katrine Prier Lindvig, and Anne Craveiro Brøchner. “Ketamine as an anesthetic for patients with acute brain injury: a systematic review.” Neurocritical care 33, no. 1 (2020): 273-282.
  15. Godoy, Daniel Agustin, Rafael Badenes, Paolo Pelosi, and Chiara Robba. “Ketamine in acute phase of severe traumatic brain injury “an old drug for new uses?”.” Critical Care 25, no. 1 (2021): 1-7.
  16. Carlson, Andrew P., Mohammad Abbas, Robert L. Alunday, Fares Qeadan, and C. William Shuttleworth. “Spreading depolarization in acute brain injury inhibited by ketamine: a prospective, randomized, multiple crossover trial.” Journal of neurosurgery 130, no. 5 (2018): 1513-1519.
  17. Godoy, D.A., Badenes, R., Pelosi, P. et al. Ketamine in acute phase of severe traumatic brain injury “an old drug for new uses?”. Crit Care 25, 19 (2021).
  18. Zeiler FA, Teitelbaum J, West M, Gillman LM. The ketamine effect on ICP in traumatic brain injury. Neurocrit Care. 2014;21:163–73.
  19. Gregers MCT, Mikkelsen S, Lindvig KP, Brøchner AC. Ketamine as an anesthetic for patients with acute brain injury: a systematic review [published online ahead of print, 2020 Apr 23]. Neurocrit Care. 2020.

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