Some of the Ketamine effects discussed here. Ketamine does not increase the intraocular pressure (lOP) in routine analgesic doses. Even after the IM injection of 8 mg/kg, ketamine doses not raise lOP.
However, in an: other study, in children anaesthetized with halothane, ketamine demonstrated a dose-dependent effect on lOP. A dose of 6 mg/kg IM caused a small increase in lOP.
In analgesic doses (0.3 mg/kg) with other sedatives ketamine does not produce any rise of IOP.
The following is an extract from Miller’s Anesthesia 7th edition on ketamine effects –
Ketamine effects on the Central Nervous System
Ketamine produces dose-related unconsciousness and analgesia. The anesthetized state has been termed dissociative anesthesia because patients who receive ketamine alone appear to be in a cataleptic state, in contrast with other states of anesthesia that resemble normal sleep. Patients anesthetized with ketamine have profound analgesia, but keep their eyes open and maintain many reflexes. Corneal, cough, and swallow reflexes all may be present, but should not be assumed to be protective. There is no recall of surgery or anesthesia, but amnesia is not as prominent with ketamine as with the benzodiazepines. Because ketamine has a low molecular weight, a pKa near the physiologic pH, and relatively high lipid solubility, it crosses the blood-brain barrier rapidly and has an onset of action within 30 to 60 seconds of administration. The maximal effect occurs in about 1 minute.
After ketamine administration, pupils dilate moderately, and nystagmus occurs. Lacrimation and salivation are common, as is increased skeletal muscle tone, often with coordinated but seemingly purposeless movements of the arms, legs, trunk, and head. Although there is great interindividual variability, plasma levels of 0.6 to 2 µg/mL are considered the minimum concentrations for general anesthesia; children may require slightly higher plasma levels (0.8 to 4 µg/mL). The duration of ketamine anesthesia after a single IV administration of a general anesthetic dose (2 mg/kg) is 10 to 15 minutes , and full orientation to person, place, and time occurs within 15 to 30 minutes.
The S(+) enantiomer enables quicker recovery (by a couple of minutes) than the racemic mixture. This is thought to be due to the lower dose necessary to produce an equianesthetic effect and to the 10% faster hepatic biotransformation.
The duration of ketamine anesthesia is determined by the dose; larger doses produce more prolonged anesthesia, and the concurrent use of other anesthetics prolongs the time of emergence. Because there is a good correlation between blood level of ketamine and CNS effect, it seems that the relatively short duration of action of ketamine is due to its redistribution from the brain and blood to the other tissues in the body. The termination of effect after a single bolus administration of ketamine is caused by drug redistribution from the well-perfused to the less well-perfused tissues. Concomitant administration of benzodiazepines, a common practice, may prolong the ketamine effects. When used in combination with a benzodiazepine, the S(+) enantiomer was no different in terms of awareness at 30 minutes, but it was significantly better at 120 minutes than the racemic mixture. Analgesia occurs at considerably lower blood levels than loss of consciousness.
Ketamine provides important postoperative analgesia. The plasma level at which pain thresholds are elevated is 0.1 µg/mL or greater. This means there is a considerable period of postoperative analgesia after ketamine general anesthesia, and subanesthetic doses can be used to produce analgesia. Ketamine has been shown to inhibit nociceptive central hypersensitization. Ketamine also attenuates acute tolerance after opiate administration.
The primary site of CNS action of ketamine seems to be the thalamoneocortical projection system. The drug selectively depresses neuronal function in parts of the cortex (especially association areas) and thalamus, while stimulating parts of the limbic system, including the hippocampus. This process creates what is termed a functional disorganization of nonspecific pathways in midbrain and thalamic areas. There also is evidence that ketamine depresses transmission of impulses in the medial medullary reticular formation, which is important for transmission of the affective-emotional components of nociception from the spinal cord to higher brain centers. In volunteers experiencing heat pain, functional magnetic resonance imaging (MRI) studies showed ketamine produced a dose-dependent effect on pain processing by decreasing activation of the secondary somatosensory cortex (S2), insula, and anterior cingulate cortex. Blockade of CNS sodium channels has been shown not to be the mechanism of action by which ketamine produces anesthesia. There is some evidence that ketamine occupies opiate receptors in the brain and spinal cord, and this property could account for some of the analgesic effects. The S(+) enantiomer has been shown to have some opioid µ-receptor activity, accounting for part of its analgesic effect. NMDA receptor interaction may mediate the general anesthetic effects and some analgesic actions of ketamine. The spinal cord analgesic effect of ketamine is postulated to be due to inhibition of dorsal horn wide dynamic range neuronal activity. Although some drugs have been used to antagonize ketamine, no specific receptor antagonist is yet known that reverses all the CNS ketamine effects.
Ketamine increases cerebral metabolism, CBF, and ICP . Because of its excitatory CNS ketamine effects, which can be detected by generalized EEG development of theta wave activity and by petit mal seizure–like activity in the hippocampus, ketamine increases CMRO2. Although theta wave activity signals the analgesic activity of ketamine, alpha waves indicate its absence. There is an increase in CBF, which appears higher than the increase in CMRO2 would mandate. With the increase in CBF and the generalized increase in sympathetic nervous system response, there is an increase in ICP after ketamine. The increase in CMRO2 and CBF can be blocked by the use of thiopental or diazepam. Cerebrovascular responsiveness to carbon dioxide seems to be preserved with ketamine; reducing Paco2 attenuates the increase in ICP after ketamine.
In animal models of incomplete cerebral ischemia and reperfusion, ketamine reduces necrosis and improves neurologic outcome. Decreased sympathetic tone and inhibition of NMDA receptor–mediated ion currents were believed to mediate the reduction of necrotic cell death. More recently, S (+) ketamine was found to influence the expression of apoptosis-regulating proteins in rat brains 4 hours after cerebral ischemia/reperfusion. The neuroprotection observed with ketamine may involve antiapoptotic mechanisms in addition to reducing necrotic cell death.
In contrast, ketamine or other NMDA receptor antagonists accentuate apoptosis in the newborn brain of animals. This has been shown with other anesthetics either at high relative doses or with prolonged exposure. This finding has sparked controversy over the use of ketamine in neonates. An editorial in the journal Anesthesiology and the Anesthetic and Life Support Drugs Advisory Committee of the U.S. FDA cautioned changing clinical practice based on present available data.
Ketamine, similar to other phencyclidines, produces undesirable psychological reactions, which occur during awakening from ketamine anesthesia and are termed emergence reactions. The common manifestations of these reactions, which vary in severity and classification, are vivid dreaming, extracorporeal experiences (sense of floating out of body), and illusions (misinterpretation of a real, external sensory experience). These incidents of dreaming and illusion are often associated with excitement, confusion, euphoria, and fear. They occur in the first hour of emergence and usually abate within 1 to several hours. It has been postulated that the psychic emergence reactions occur secondary to ketamine-induced depression of auditory and visual relay nuclei, leading to misperception or misinterpretation of auditory and visual stimuli. The incidence ranges from 3% to 100%. A clinically relevant range is probably 10% to 30% of adult patients who receive ketamine as a sole or major part of the anesthetic technique.
Factors that affect the incidence of emergence reactions are age, dose, gender, psychological susceptibility, and concurrent drugs. Pediatric patients do not report as high an incidence of unpleasant emergence reactions as do adult patients; men also report a lower incidence compared with women. Larger doses and rapid administration of large doses seem to predispose patients to a higher incidence of adverse effects. Finally, certain personality types seem prone to the development of emergence reactions. Patients who score high in psychotism on the Eysenck Personality Inventory are prone to develop emergence reactions, and individuals who commonly dream at home are more likely to have postoperative dreams in the hospital after ketamine. Numerous drugs have been used to reduce the incidence and severity of postoperative reactions to ketamine ; the benzodiazepines seem to be the most effective group of drugs to attenuate or to treat ketamine emergence reactions. Midazolam, lorazepam, and diazepam are useful in reducing reactions to ketamine. Midazolam reduces the psychotomimetic effect of the S (+) enantiomer.
Ketamine effects on the Respiratory System
Ketamine has minimal effects on the central respiratory drive as reflected by an unaltered response to carbon dioxide. There can be a transient (1 to 3 minutes) decrease in minute ventilation after the bolus administration of an induction dose of ketamine (2 mg/kg intravenously). Unusually large doses can produce apnea, but this is seldom seen. Arterial blood gases generally are preserved when ketamine is used alone for anesthesia or analgesia. With the use of adjuvant sedatives or anesthetic drugs, however, respiratory depression can occur. Ketamine has been shown to affect ventilatory control in children and should be considered a possible respiratory depressant when the drug is given to them in bolus doses.
Ketamine is a bronchial smooth muscle relaxant. When it is given to patients with reactive airway disease and bronchospasm, pulmonary compliance is improved. Ketamine is as effective as halothane or enflurane in preventing experimentally induced bronchospasm. The mechanism for this effect is probably a result of the sympathomimetic response to ketamine, but there are isolated bronchial smooth muscle studies showing that ketamine can directly antagonize the spasmogenic effects of carbachol and histamine. Owing to its bronchodilating effect, ketamine has been used to treat status asthmaticus unresponsive to conventional therapy.
A potential respiratory problem, especially in children, is the increased salivation that follows ketamine administration. This increased salivation can produce upper airway obstruction, which can be complicated further by laryngospasm. The increased secretions also may contribute to or may complicate further laryngospasm. In addition, although swallow, cough, sneeze, and gag reflexes are relatively intact after ketamine administration, there is evidence that silent aspiration can occur during ketamine anesthesia.
Ketamine effects on the Cardiovascular System
Ketamine also has unique cardiovascular effects; it stimulates the cardiovascular system and is usually associated with increases in blood pressure, heart rate, and cardiac output . Other anesthetic induction drugs either cause no change in hemodynamic variables or produce vasodilation with cardiac depression. The S(+) enantiomer, despite hope that reducing the dose by half (equianesthetic potency) would attenuate side effects, is equivalent to the racemic mixture regarding hemodynamic response. The increase in hemodynamic variables is associated with increased work and myocardial oxygen consumption. The healthy heart is able to increase oxygen supply by increased cardiac output and decreased coronary vascular resistance, so that coronary blood flow is appropriate for the increased oxygen consumption. The hemodynamic changes are not related to the dose of ketamine (e.g., there is no hemodynamic difference between IV administration of 0.5 mg/kg and 1.5 mg/kg). A second dose of ketamine produces hemodynamic effects less than or even opposite to the ketamine effects the first dose.
The hemodynamic changes after anesthesia induction with ketamine tend to be the same in healthy patients and in patients with various acquired or congenital heart diseases. In patients with congenital heart disease, there are no significant changes in shunt directions or fraction or systemic oxygenation after ketamine induction of anesthesia. In patients who have elevated pulmonary artery pressure (as with mitral valvular and some congenital lesions), ketamine seems to cause a more pronounced increase in pulmonary than systemic vascular resistance.
The mechanism by which ketamine stimulates the circulatory system remains enigmatic. It seems not to be a peripheral mechanism such as baroreflex inhibition, but rather to be central. There is some evidence that ketamine attenuates baroreceptor function via an effect on NMDA receptors in the nucleus tractus solitarius. Ketamine injected directly into the CNS produces an immediate sympathetic nervous system hemodynamic response. Ketamine also causes the sympathoneuronal release of norepinephrine, which can be detected in venous blood. Blockade of this effect is possible with barbiturates, benzodiazepines, and droperidol. Ketamine in vitro probably has negative inotropic effects. Myocardial depression has been shown in chronically instrumented dogs, and isolated canine heart preparations. In isolated guinea pig hearts, ketamine was the least depressant of all the major induction drugs, however. The finding that ketamine may exert its myocardial effects by acting on myocardial ionic currents (which may exert different effects from species to species or among tissue types) may explain the tissue and animal model variances in direct myocardial action.
The centrally mediated sympathetic responses to ketamine usually override the direct depressant ketamine effects. Some peripheral nervous system actions of ketamine play an undetermined role in the hemodynamic ketamine effects. Ketamine inhibits intraneuronal uptake of catecholamines in a cocaine-like effect, and inhibits extraneuronal norepinephrine uptake.
Stimulation of the cardiovascular system is not always desirable, and certain pharmacologic methods have been used to block the ketamine-induced tachycardia and systemic hypertension. Successful methods include use of adrenergic antagonists (α and β), various vasodilators, and clonidine. Probably the most fruitful approach has been prior administration of benzodiazepines. Modest doses of diazepam, flunitrazepam, and midazolam all attenuate the hemodynamic ketamine effects. It also is possible to decrease the tachycardia and hypertension caused by ketamine by using a continuous infusion technique with or without a benzodiazepine. Inhalation anesthetics and propofol blunt the hemodynamic effect of ketamine. Ketamine can produce hemodynamic depression in the setting of deep anesthesia, when sympathetic responses do not accompany its administration.