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 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Initial resistance of bacterial infection is mediated primarily by polymorphonuclear leucocytes (PMN). Anaesthetic agents have been reported to impair various aspects of PMN function. It is possible that the use of these agents to sedate critically ill patients may further compromise an already depressed host defence mechanism. A flow cytometric technique with fresh whole blood from 10 healthy volunteers was used. Phagocytic and respiratory burst activity of PMN incubated for 1 h with either propofol, thiopentone, midazolam or ketamine at both clinical plasma concentrations and 100 times this concentration were determined. Thiopentone at the higher concentration reduced both respiratory burst activity (mean peak channel 50.7 compared with control value of 77.6 (P < 0.0001)) and phagocytosis (mean peak channel 47.5 compared with 79.9 (P < 0.0001)). Ketamine at 100 times the clinical plasma concentration also reduced respiratory burst and phagocytosis, but this failed to reach statistical significance (P = 0.10 and P = 0.053, respectively). No significant depression occurred in the other groups. The results suggest that these i.v. anaesthetic agents, at clinically relevant concentrations, have minimal effects on PMN phagocytosis and oxygen free radical production. At higher concentrations thiopentone and ketamine may affect phagocytic function and thiopentone may impair intracellular cytolysis.
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PMID:Comparison of the effects of four i.v. anaesthetic agents on polymorphonuclear leucocyte function. 771 79

The epidural and intrathecal administration of opioids has gained wide acceptance among anaesthesiologists during recent years. Ketamine, an anaesthetic agent with an unusual pharmacological profile, has also attracted some interest in this context, as in subanaesthetic doses it provides marked analgesia without inducing respiratory depression. Since the first publication on the epidural administration of ketamine in humans in 1982, various studies on the pharmacology, toxicology and clinical use of ketamine by the epidural and intrathecal routes have been published. PHARMACOLOGY. There is a large body of evidence to show that systemically administered ketamine interacts with different neurotransmitter systems and may even produce local anaesthetic effects when used for intravenous regional anaesthesia. The results of animal studies suggest that ketamine may cause complete sensory and motor blockade after intrathecal administration, which leads to high concentrations in the cerebrospinal fluid. One study investigating the effects after epidural administration showed motor blockade only after high doses of ketamine. Binding to local opiate receptors seems to play only a minor role, whereas significant analgesia after even low doses of ketamine is the result of antagonism to NMDA receptors. In vitro and animal data also suggest an involvement of the descending inhibitory pathways, mainly through inhibition of re-uptake of neurotransmitters. NEUROTOXICITY. Data relating to the neurotoxicity of ketamine after intrathecal administration are confusing. While no neurotoxic effects have been observed in studies in primates and rabbits, experimental rats and monkeys have sustained lesions: they may have been caused by a faulty puncture technique or by inherent neurotoxicity of the drug. CLINICAL RESULTS. The only study of intrathecal administration of ketamine in humans revealed local anaesthetic effects after doses of 50 mg. For epidural use, doses up to 30 mg did not give adequate pain relief after surgery in controlled studies, but had some analgesic effect in patients with chronic pain syndromes. When doses of 30 mg and over were used, postoperative analgesia was generally assessed as good. CONCLUSIONS. When administered intrathecally, ketamine shows local anaesthetic effects in both animals and humans. Unfortunately, all commercially available ketamine preparations contain disinfectant agents whose intrathecal administration is prohibited. Epidurally administered ketamine doses of 30 mg and more seem to provide adequate postoperative analgesia, while smaller doses might be effective in chronic pain syndromes. More studies investigating the neurotoxicity and clinical effects of ketamine on the spinal cord are needed before wider use of the substance by this route of administration can be recommended.
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PMID:[Pharmacology and clinical results with peridural and intrathecal administration of ketamine]. 784 Apr 12

To check for suspected opioid-receptor mediated hypnotic and antinociceptive effects of S(+)-ketamine, highly selective antagonists were used after the anaesthetic. METHODS. To determine the hypnotic effects of increasing doses of S(+)-ketamine (2-5-10-20 mg/kg given at 10-min intervals), EEG power spectra (delta, theta, alpha, beta) were derived (Lifescan), and antinociceptive potency was evaluated using the somatosensory evoked potential (SEP, Lifescan) in awake, trained dogs (n = 10). To check for an opioid-receptor-related interaction, an antagonist of the methoxymorphinane series (HS-275, 80 micrograms/kg i.v.) with higher selectivity than naloxone for the mu-receptor was given at the end. After washout the same animals were exposed to S(+)-ketamine. This time, however, the highly selective delta-antagonist naltrindole (160 micrograms/kg i.v.) was given. To show up any respiratory depression arterial blood gases were taken after each dose. RESULTS. S(+)-Ketamine induced a dose-related increase in power in the theta band (3-8 Hz), with a ceiling effect at 10 mg/kg. The changes were reversed by both antagonists. In the beta band (13-30 Hz) and in the delta domain, power decreased or increased, respectively, in a highly significant manner (P < 0.005) at 20 mg/kg. Both effects reversed after the antagonists with an overshoot in beta (+12% and +14%, respectively) and a decrease in delta (-45% and -62%, respectively) compared with control. S(+)-Ketamine induced a dose-dependent increase in peak latency and depression of the SEP amplitude by a maximum of over 50%. Latency changes were completely reversed only by HS-275. Amplitude height was only partly restored by both antagonists. A clinical relevant decrease in PaO2 and increase in PaCO2 increase were seen at 20 mg/kg. Hypoxia was reversed by both antagonists; hypercapnia was only partially reversed. CONCLUSION. The results confirm the suspicion that S(+)-ketamine induces an opioid theta- and delta-receptor-mediated deep hypnotic effect. Blockade of nociceptive impulses in afferent sensory nervous pathways suggests an efficient analgesic effect mediated partly by the opioid mu-receptor. Other mechanisms, such as an interaction with the NMDA receptor, have to be taken into consideration to account for the full antinociceptive effect. Respiratory depression may be of clinical importance when high dosages of S(+)-ketamine are given.
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PMID:[Interaction of S-(+)-ketamine with opiate receptors. Effects on EEG, evoked potentials and respiration in awake dogs]. 784 Apr 15

Myogenic motor-evoked responses to transcranial magnetic stimulation of the motor cortex (tcmag-MERs) may become clinically useful for the noninvasive assessment of motor pathway conduction during surgery. However, application is hindered because most anesthetic regimens result in severe depression of tcmag-MER amplitudes. As part of our systematic attempts to identify anesthetic agents and supplements suitable for use during tcmag-MER recording, we studied the effect of bolus doses of pentobarbital (1.5 mg/kg), droperidol (0.07 mg/kg), or ketamine (1 mg/kg), administered intravenously, on compound muscle action potentials to transcranial magnetic stimulation in five healthy volunteers. The doses were chosen to be comparable with doses that might be suitable for supplementation of a nitrous oxide/opioid anesthetic technique. Droperidol administration resulted in sustained amplitude depression of both tibialis and adductor pollicis tc-MERs to 30 +/- 9% and 39 +/- 14% of baseline (P < 0.01). Tcmag-MER amplitude changes after pentobarbital were variable, ranging from no change to substantial amplitude depression (to 20% of baseline) in two subjects. In contrast, ketamine administration did not result in significant amplitude depression. In three subjects, tibialis anterior amplitude increased to 150 to 220% of control values in the first 10 minutes after ketamine. Onset latency was unchanged after any drug. These data indicate that tcmag-MERs are moderately depressed after droperidol and pentobarbital but well preserved after ketamine. Ketamine may be a more suitable supplement to opioid/nitrous oxide anesthesia than droperidol or pentobarbital.
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PMID:Effects of droperidol, pentobarbital, and ketamine on myogenic transcranial magnetic motor-evoked responses in humans. 788 50

1. The purpose of this study was to investigate further the role of the excitatory amino acid (EAA) system of neurotransmission, particularly of the NMDA receptor, in the central regulation of cardiac function. 2. Electrical stimulation of the paraventricular nucleus of the hypothalamus (PVN) in pentobarbitone anaesthetized rabbits induced a cardiovascular response mainly characterized by a positive inotropic effect, hypertension and a marked increase in the myocardial oxygen demand index. 3. The intracerebroventricular (i.c.v.) or intravenous (i.v.) injection of different EAA antagonists acting on different sites of the NMDA receptor/channel complex dose-dependently blunted the excitatory cardiovascular effects of PVN stimulation. 4. 5,7 Dichlorokynurenic acid was used as a specific glycine site antagonist and 2-amino-5-phosphonovaleric acid was used to block the agonist recognition site; ketamine was used as a channel blocker site antagonist and ifenprodil as a blocker of the polyamine binding site. 5. 5,7 Dichlorokynurenic acid (125 and 250 micrograms kg-1, i.c.v.) virtually abolished the cardiovascular responses, inducing only haemodynamic depression at the highest dose used. 2-Amino-5-phosphonovaleric acid (0.1 to 1.0 mg kg-1, i.c.v.) elicited a reduction of the peak values observed during PVN stimulation which was accompanied by a decrease of the basal cardiovascular parameters. Ketamine (2.5 and 10 mg kg-1) and ifenprodil (1 mg kg-1), injected intravenously, blocked the haemodynamic response induced by PVN stimulation without marked reduction of the basal haemodynamics. 6. It is concluded that glutamate neurotransmission is not only involved in vasomotor tone control but also in the central control of cardiac function and can therefore modulate the myocardial oxygen demand.
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PMID:Prevention by NMDA receptor antagonists of the centrally-evoked increases of cardiac inotropic responses in rabbits. 791 76

Several situations arise in the PICU patient that require the administration of drugs for sedation and analgesia. A "cookbook" approach is impossible because of the diversity of patient and clinical scenarios. When amnesia is required, these authors prefer a continuous infusion of a benzodiazepine such as midazolam or lorazepam. Although the majority of clinical experience has been with midazolam, lorazepam either by bolus dose or continuous infusion offers a cost-effective alternative. When analgesia is required, the addition of a continuous infusion of narcotic or the use of a PCA device in the older patient should prove effective. Although fentanyl is frequently chosen, morphine is an effective and cost-effective alternative for patients with stable cardiovascular function. The synthetic narcotics are recommended for neonates, especially following cardiac surgical procedures and those at risk for pulmonary vasospasm. Narcotics may also be used for the treatment of agitation in those situations that do not necessarily require analgesia. Our clinical experience suggests that narcotics may be more effective for sedation than benzodiazepines in children less than 1 year of age. When the above agents fail to be effective or are associated with cardiovascular depression, alternatives may include ketamine or pentobarbital. Ketamine may be useful for the unstable patient or those with a bronchospastic component to their disease process. We have found pentobarbital to be effective when the combination of benzodiazepines and narcotics fails to provide the desired level of sedation. Aside from these techniques, regional anesthesia may offer a more effective means of controlling pain in the PICU patient. These techniques may be effective when parenteral narcotics are inadequate or lead to undesired effects. Although most commonly used for postoperative analgesia, their use in patients with pain from other causes (e.g., multiple trauma) may be indicated, especially when parenteral narcotics may interfere with respiratory function or the ongoing assessment of the patient's mental status.
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PMID:Pain management and sedation in the pediatric intensive care unit. 798 86

Twelve healthy dogs were used to determine the cardiorespiratory effects of i.v. administered ketamine (10 mg/kg of body weight) and midazolam (0.5 mg/kg). Half the dogs received a ketamine-midazolam combination (K-M) as a bolus over 30 seconds and the other half received the K-M as an infusion over 15 minutes. Induction of anesthesia by use of K-M was good in all dogs. Ketamine-midazolam combination as a bolus or infusion induced minimal cardiorespiratory effects, except for significant (P < 0.05) increases in mean heart rate and rate-pressure product. The increase in heart rate was greater in dogs of the infusion group. Mild and transient respiratory depression was observed in dogs of both groups immediately after administration of K-M, but was greater in dogs of the bolus group than in dogs of the infusion group. Duration of action of K-M for chemical restraint was short. Salivation and defecation were observed in a few dogs. Extreme muscular tone developed in 1 dog after K-M bolus administration.
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PMID:Cardiorespiratory effects of intravenous bolus administration and infusion of ketamine-midazolam in dogs. 825 Mar 97

The mechanism(s) of action of anesthetics on cell membrane ionic currents are not known. To investigate this further the effects of clinically relevant concentrations of ketamine, methohexital, and propofol on the delayed rectifier (IK) and the inward rectifier (IK1) currents of single dispersed guinea pig ventricular myocytes were studied. These voltage-gated currents are major components of cardiac cell electrophysiologic function regulating resting potential and repolarization. Each of the three anesthetics had a distinct spectrum of activity. Ketamine (10(-4) M) decreased IK1 (P < 0.05) but had no effect on IK. Methohexital (10(-4) M) had no significant effect on either current. Propofol (2.8 x 10(-5) M) resulted in significant depression of IK (P < 0.001) but had no effect on IK1. These results suggest that these intravenous anesthetics may have more specific effects on sarcolemma than volatile anesthetics, whose effects may be more generalized membrane effects.
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PMID:Distinctive effects of three intravenous anesthetics on the inward rectifier (IK1) and the delayed rectifier (IK) potassium currents in myocardium: implications for the mechanism of action. 841 22

The goal of therapy in patients with severe head injury is to avoid secondary brain damage. Analgesia and sedation are an essential part of the therapy, and several drugs are in current use. However, few controlled clinical trials have been performed so far, and none of these drugs has proved to be superior. Although in the past the therapy has been focused on controlling elevated intracranial pressure (ICP), many authors emphasize the role of cerebral ischaemia in the prognosis of patients. Therefore, cerebral perfusion pressure (CPP) i.e. the difference between ICP and mean arterial pressure (CPP = MAP-ICP), seems to be more important than ICP alone. Analgesics and sedatives reduce the cerebral metabolic rate (CMR), and the consequent decrease in cerebral oxygen uptake might prevent ischaemic damage in regions with low perfusion. Moreover, a decrease in CMR is often associated with a decrease of cerebral blood flow (CBF) in regions with normal perfusion and, as a result, ICP is also reduced. Basically, the cerebral effects (on ICP, CMR, and CBF) and the haemodynamic effects with respect to maintenance of a sufficient CPP are most important in the selection of drugs for analgosedation. In addition, the effects on general intensive care management must be considered (pulmonary function, immunreactivity bowel motility). The purpose of this paper is to describe drugs commonly used for analgosedation in severe head injury. Barbiturates bring about the most pronounced decrease of CMR and ICP. In the past these drugs were used routinely in high doses ("barbiturate coma"). However, no improvement in outcome was demonstrable, and vitally dangerous side effects, such as infection, pulmonary dysfunction, arterial hypotension, and renal failure often occurred. High-dose barbiturate therapy is therefore only indicated in exceptional cases, such as refractory increase in ICP with preserved CO2 response of cerebral vessels. The effect is dependent on CMR at the start of this therapy. Benzodiazepines are frequently used in patients with head injury. They cause only a moderate decrease of CMR and ICP. In general, side effects are negligible. However, a possible decrease of MAP by reduced central sympathetic drive has to be taken into account. Opioids are also frequently used in patients with head trauma. The observed cerebral effects are inconsistent. Some authors have described increases in ICP, CBF, and CMR, but in most studies no influence on these values, or a decrease, has been observed. In any case, cautious titration of these drugs and cerebral monitoring are therefore desirable. As with benzodiazepines, a decrease in MAP due to central effects is possible. In addition, opioids inhibit bowel motility. Ketamine is generally used because of its favourable circulatory effects, bronchodilatation and absence of inhibition of bowel motility. In patients with increased ICP, however, it is often considered contraindicated, since it can be associated with cerebral vasodilation and ICP increase. Other studies did not confirm an increase of ICP when controlled ventilation and additional sedation were applied. More recent studies have demonstrated the role of neuroexcitatory NMDA-receptors in ischaemic and traumatic brain damage. Since ketamine exerts an antagonistic effect on N-methyl-D-aspartate receptors (NMDA) and studies in animals have demonstrated a protective effect of ketamine against ischaemic and traumatic brain damage, controlled clinical studies in patients with head injury are desirable. Propofol results in a profound decrease of CMR and a significant decrease of ICP, but often also in haemodynamic depression. Few results obtained during long-term administration are available, but it seems to be beneficial. More clinical studies are warranted. Gamma-hydroxybutyrate (GHB) is a physiological substance, which has only sporadically been investigated for sedation in patients with head trauma. The few available studies show beneficial res
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PMID:[Analgesia and sedation in patients with head-brain trauma]. 859 67

Pharmacological praemedication. In patients receiving regional anaesthetics induction of deep sedation prior to the performance of the block should be avoided because during the installation of the nerve block it is an advantage to have a cooperative patient. Adequate anxiolytic effects are achieved by oral administration of chloracepate (0.3-0.5 mg/kg body weight). Intraoperative sedation. Once regional anaesthesia is established deep sedation or even a light sleep might be appropriate to improve the patient's comfort. Short acting i.v. substances are the agents of choice. Propofol (1.5-5 mg/kg per h) and midazolam (0.03-0.09 mg/kg per h) are recommended. Both substances should be titrated as needed. Since respiratory depression or loss of airway patency may occur, close observation and pulse oxymetric monitoring are mandatory. Intraoperative analgesia. Restlessness due to pain is not an indication for sedatives and/or hypnotics. Pain can be caused not only by incomplete regional anaesthesia, but also by a tourniquet or uncomfortable body positions, for example, and it should be treated in different ways according to its cause. In the case of an incomplete block, a catheter technique makes a top-up dose for augmentation possible; additional peripheral nerve blocks can also be used to complete the analgesia. If these attempts are unsuccessful, systemic analgesics (preferable narcotics) or even anaesthetics must be given. Opioids are recommended only in mild to moderate pain or discomfort. The risk of respiratory depression should be considered. The administration of oxygen by mask and pulse oxymetric monitoring are useful. Ketamine is a common drug with a potent analgesic effect, which possesses the advantages of good support for the cardiovascular system, because of its sympathomimetic action, and minimal depression of the ventilatory drive. However, with the exception of a few specific indications, Ketamine is not a drug that is initially an integral part of planned regional anaesthetic procedures. In case of incomplete regional blocks administration of ketamine is more frequently the "ultima ratio" following a number of previous, unsuccessful attempts-primarily with sedatives and/or opioids-to achieve a condition that will permit surgical procedures; as a result, the hypnotic and respiratory depressant effects of subsequently administered drugs are enhanced and potentiated. An important consequence of this complex pharmacodynamic interaction scenario is a potential loss of the advantages that would otherwise be gained by using "subanaesthetic" ketamine doses (< 0.5 mg/kg), namely: a cooperative patient who is breathing spontaneously and has an intact laryngopharyngeal reflex response and, therefore, an uncompromised airway competence. Pulse oxymetric monitoring of the potentially endangered respiratory function is obligatory. The individual transition to general anaesthesia is not easy to determine. Therefore, it is essential that, whenever the need arises, intubation and mechanical ventilation intervention procedures be carried out immediately.
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PMID:[Analgesia and sedation to supplement incomplete regional anesthesia]. 859 70


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