Nuovi utilizzi clinici della ketamina a dosaggi subanestetici in medicina veterinaria

Abstract

Ketamine has been widely used in veterinary medicine since the seventies, and nowadays it is one of the most commonly used anesthetic drug. It is a noncompetitive antagonist of N-methyl-D-aspartate (NMDA) receptors. It provides dissociative anesthesia, characterized by altered consciousness or catalepsy. Ketamine also have analgesic and sedative properties. It causes a central adrenergic stimulation, resulting in an increased sympathetic tone combined with cardiovascular stimulatory effects and bronchodilator properties. It has mild respiratory effects. Ketamine provides poor muscle relaxation, sometimes even muscle rigidity or myoclonus, and it preserves pharyngeal and laryngeal reflexes. Ketamine is usually combined with sedatives or tranquilizers (i.e., benzodiazepine or alpha-2agonists) to prevent side effects, emergence delirium and psychomimetic signs. Ketamine is commonly used in veterinary medicine for premedication, induction and maintenance of anesthesia. Although its classical use for anesthetic properties, recent research has underscored multiple novel uses of this drug, especially concerning subanesthetic doses that has shown new promising prospects both in human and veterinary medicine. The crucial issue is that subanesthetic doses are sometimes combined with less psychomimetic and cardiovascular side effects which limit its clinical use. Subanesthetic doses have been recommended in humans for peri-operative pain management and to treat traumatic, neuropathic and chronic pain. Based on these encouraging results, low-dose ketamine is increasingly used in dogs for its analgesic properties as part of balanced anesthesia. The analgesic properties of subanesthetic doses of ketamine have been recently studied also in horses, in which subanesthetic dose of ketamine has shown its efficacy: Nevertheless its clinical applications have not been studied yet. Instead, recent studies in cats are not showing convincing results. Consequently, further studies are required. Different nociceptive testing methods and different therapeutic protocols could be tested in future in cats. Ketamine seems to have antinflammatory properties too, interacting with inflammatory cells recruitment, cytokines production, and inflammatory mediators regulation. Consequently, ketamine may have an anti-proinflammatory effect by limiting exacerbation of systemic inflammation without affecting local healing. Immunomodulating properties of subanesthetic doses of ketamine has been evaluated for several species, in vivo and in vitro. Ketamine provided immunomodulating effects in dogs suffering from pyometra undergoing ovariohysterectomy and in dogs with experimentally induced endotoxiemia, while in horses with experimentally induced endotoxiemia same effects have not yet been confirmed. Low doses of ketamine have been recently suggested to play a role in neuroprotection too. Through its NMDA receptors inhibition, ketamine reduces glutamate excitotoxicity by preventing excitatory aminoacid receptor stimulation, even in the setting of seizure. For this reason, ketamine appears extremely promising in treating long-lasting refractory status epilepticus (RSE) both in human beings and dogs, mostly because in prolonged seizures, the GABAergic drug efficacy decreases because of fewer synaptic targets. At the same time, NMDA receptors are upregulated and therefore represent an ideal pharmacologic target. Studies in dogs showed that ketamine seems primarily suitable and safe for the treatment of prolonged and uninterrupted seizure activity in cases of RSE that exhibit resistance to benzodiazepines. Another successful approach to RSE in dogs suffering from idiopathic epilepsy seems to be ketamine - dexmedetomidine infusion combined with mild hypothermia. Finally, in psychiatry too, subanesthetic ketamine doses have already proven to be a rapid and effective treatment for bipolar disorder, suicidal ideation and major depressive disorder in humans. It has also been demonstrated that ketamine is efficacy for Post-Traumatic Stress Disorder. Subanesthetic ketamine dose may increase neuronal perfusion and therefore alters neuronal function in brain regions involved in depression and anxiety disorders. Same changes were reported both in dogs and in humans suffering from behavioral disorders such as anxiety, impulsive aggression, and compulsive disorders. Studies in dogs demonstrates a dose-related increased regional cerebral blood flow in the left frontal cortex and thalamus after administration of subanesthetic ketamine administration in healthy dogs. These increases in perfusion may probably contribute to ketamine’s beneficial effects in psychiatric disorders. Low dose of ketamine seems a promising application not only in human psychiatry, but also in behavioral disordered dogs with an incomplete response to standard behavioral pharmacotherapy. Furthermore, all these new aspects and effects of subanesthetic ketamine dose are combined with few adverse effects.