General intravenous anesthetics - pharmacodynamics, pharmacokinetics and chiral properties.

In continuation of our published review on general inhalational anesthetics, the current article presents a survey of intravenous agents for general anaesthesia. From chemical point of view these compounds belong to structurally diverse categories, such as barbiturates - thiopental (Sodium pentothal®, Trapanal®, Pentothal®), methohexital (Brevital®), and hexobarbital (Evipan®, Hexenal®, Citopan®, Tobinal®); non-barbiturate derivatives - ketamine (Ketalar® Ketaset®), esketamine (Ketanest®), and etomidate (Amidate®, Hypnomidate®), phenolic derivatives - propofol (Diprivan®); steroid derivatives - mixture of alfadolone and alfaxalone (Althesin® in human and Saffan® in veterinary anesthesia); and derivatives of phenylacetic acid - propanidid (Epontol®, Sombrevin®). Most of these compounds are chiral, with the exception of propofol and propanidid. Apart from etomidate and esketamine, they are used in the form of their racemates. Besides their characteristics and mechanism of action, attention is centred also on their chiral properties.

Absence of coronary artery calcification and all-cause mortality.

OBJECTIVES: We sought to quantify the mortality rates associated with absent and low positive (CAC 1 to 10) coronary artery calcium (CAC). BACKGROUND: There is increasing interest in the absence of CAC as a "negative" cardiovascular risk factor. However, published event rates for individuals with no CAC vary, likely owing to differences in baseline risk, follow-up period, and outcome ascertainment. The prognostic significance of low CAC (CAC 1 to 10) is not well described. METHODS: Annualized all-cause mortality rates were assessed in 44,052 consecutive asymptomatic patients referred for CAC testing. Mean follow-up of the cohort was 5.6 +/- 2.6 years (range 1 to 13 years). RESULTS: A total of 19,898 patients (45%) had no CAC on screening electron beam tomography, whereas 5,388 (12%) had low levels of CAC (CAC 1 to 10), and 18,766 (43%) had CAC >10. There were 104 deaths in those with no CAC (0.52%), 58 deaths in those with CAC 1 to 10 (1.06%), and 739 deaths in those with CAC >10 (3.96%). Annualized all-cause mortality rates for CAC = 0, CAC 1 to 10, and CAC >10 were 0.87, 1.92, and 7.48 deaths/1,000 person-years, respectively. The hazard ratio (HR) for all-cause mortality among CAC 1 to 10 versus CAC = 0 after adjustment for traditional risk factors was 1.99 (95% confidence interval [CI]: 1.44 to 2.75). Smoking (HR: 3.97, 95% CI: 2.75 to 5.41) and diabetes mellitus (HR: 3.36, 95% CI: 2.09 to 5.41) were associated with few events observed in CAC = 0 group. CONCLUSIONS: In appropriately selected asymptomatic patients, the absence of CAC predicts excellent survival with 10-year event rates of approximately 1%. A finding of 0 CAC might be used as a rationale to emphasize lifestyle therapies rather than pharmacotherapy and to forgo repeated imaging studies. Individuals with low CAC score (CAC 1 to 10) are at increased risk above individuals with a 0 score and could be considered a distinct risk group by physicians and investigators.

The effect of ketamine and saffan on the beta-endorphin and ACTH response to hemorrhage in the minipig.

The endocrine response is an important component of the physiological response to blood loss. There is some variability in reported levels of certain hormones during hemorrhage such as the stress hormone adrenocorticotrophic hormone (ACTH). Therefore, the effect of two anesthetic agents, ketamine and saffan, on ACTH and beta-endorphin levels during hemorrhage was assessed in 12 minipigs. The animals were divided into two groups, group I saffan and group II ketamine (n=6). Pigs were subjected to a continuous fixed volume hemorrhage under one of the above anesthetics while spontaneously breathing. Blood pressure and heart rate responses were recorded together with beta-endorphin and ACTH levels both before and at 10, 20, 30, 40 min after the onset of bleeding. ACTH levels were higher in the ketamine-anesthetized pigs and rose significantly faster with falling blood pressure than ACTH measured in pigs under saffan anesthesia. In contrast, the hemorrhage induced beta-endorphin increase was not significantly different between the two anesthetic groups. These results indicate that choice of anesthetic agent is important when investigating the hormone response to hemorrhage and may account for the variable hormone levels in the published literature to date.

Comparison of the depressive effects of four anesthetic regimens on ventilatory and cardiovascular variables in the guinea pig.

BACKGROUND AND PURPOSE: Guinea pigs are one of the most difficult rodents to anesthetize safely, and as a consequence, there is a paucity of reports regarding the effects of anesthesia on their cardiorespiratory variables. We used long-term indwelling cannulas for studying the guinea pig in the conscious state, and subsequently investigated the effects of four types of injectable anesthetic regimens on cardiorespiratory variables. METHODS: Using barometric plethysmography (conscious: long-term cannulated, n = 11; no cannulation, n = 28) or trachea-out plethysmography (anesthetized: n = 7 for each of the four groups), we recorded ventilatory, cardiovascular, metabolic, and arterial gas variables during air breathing and in response to 10 min of hypoxia (8% O2) and 10 min of hypercapnia (8% CO2). The four anesthetic regimens tested were: Saffan (infused at 9.75 mg/kg of body weight/h, i.v.); ketamine/xylazine (14.6/3.7 mg/kg/h, i.v.); pentobarbitone (8.3 mg/kg/h, i.v.) plus Innovar Vet (0.15 mg/kg every 1 to 1.5 h, s.c.); or pentobarbitone alone (22 mg/kg/h, i.v.). RESULTS: The least depressive anesthetic with regard to ventilation (VE) was ketamine/xylazine. Air breathing was depressed by only 17% (cf approx 50 to 60% for all other regimes), and the VE responses to hypoxia and hypercapnia were attenuated the least. All anesthetics equally depressed mean arterial blood pressure (from 70 mmHg to 56 mmHg) and ketamine/xylazine was the only anesthetic to reduce heart rate (from 260 beats/min to 198 beats/min). CONCLUSION: Although all anesthetics induce cardiorespiratory depression to some extent, the use of ketamine/ xylazine is recommended for future use in respiratory studies of the guinea pig where anesthesia cannot be avoided.

A magnetic resonance spectroscopic imaging study of adult nonhuman primates exposed to early-life stressors.

BACKGROUND: Long-term behavioral, immunologic, and neurochemical alterations have been found in primates exposed to adverse early rearing. METHODS: Bonnet macaque (Macaca radiata) mother-infant dyads were exposed to uncertain requirements for food procurement (variable foraging demand, VFD) for a few months. Ten years later, these offspring and age- and gender-matched control subjects were studied using proton magnetic resonance spectroscopic imaging (MRSI). RESULTS: In anterior cingulate, VFD-reared subjects displayed significantly decreased N-acetylaspartate (NAA) resonance and significantly increased glutamate-glutamine-gamma-aminobutyric acid (Glx) resonance relative to the stable neurometabolite creatine (Cr). Across all subjects, NAA/Cr and Glx/Cr ratios in the anterior cingulate were negatively correlated (r = -.638, p =.014). In the medial temporal lobe, the ratio of choline-containing compounds to Cr was significantly increased in VFD subjects. CONCLUSIONS: These findings indicate that adverse early rearing in primates has an enduring impact on adult MRSI measures considered reflective of neuronal integrity and metabolism, membrane structure and glial function, and cerebral glutamate content, and that these alterations occur in the same brain regions implicated in trauma-related psychiatric disorders.

Evidence that central 5-HT2A and 5-HT2B/C receptors regulate 5-HT cell firing in the dorsal raphe nucleus of the anaesthetised rat.

1. Systemic administration of phenethylamine-derived, 5-hydroxytryptamine(2) (5-HT(2)) receptor agonists inhibits the firing of midbrain 5-HT neurones, but the 5-HT receptors involved are poorly defined, and the contribution of peripheral mechanisms is uncertain. This study addresses these issues using extracellular recordings of 5-HT neurones in the dorsal raphe nucleus of anaesthetised rats. 2. The 5-HT(2) receptor agonists DOI ((+/-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride) and DOB ((+/-)-2,5-dimethoxy-4-bromoamphetamine hydrobromide), caused a dose-related (10-100 micro g kg(-1) i.v.) inhibition of 5-HT neuronal activity, with the highest dose reducing firing rates by >80%. 3. Pretreatment with the 5-HT(2) receptor antagonist ritanserin (1 mg kg(-1) i.v.) completely blocked the action of DOI. The 5-HT(2A) receptor antagonist MDL 100,907 (0.2 mg kg(-1) i.v.) blocked the action of both DOI and DOB. In comparison, the 5-HT(2B/C) receptor antagonist SB 206553 (0.5 mg kg(-1) i.v.) caused a small, but statistically significant, shift to the right in the dose response to DOI and DOB. 4. Pretreatment with the peripherally acting 5-HT(2) receptor antagonist BW 501C67 (0.1 mg kg(-1) i.v.) had no effect on the DOI-induced inhibition of 5-HT cell firing, but completely blocked the DOI-induced rise in mean arterial blood pressure. 5. These data indicate that the inhibition of 5-HT cell firing induced by systemic administration of DOI and DOB is mediated predominantly by the 5-HT(2A) receptor-subtype, but that 5-HT(2B/C) receptors also play a minor role. Moreover, central and not peripheral mechanisms are involved. Given evidence that 5-HT(2) receptors are not located on 5-HT neurones, postsynaptic 5-HT feedback mechanisms are implicated.

Effects of different anesthetics on the paired-pulse depression of the h reflex in adult rat.

Hyperreflexia is a common feature of spinal cord injury (SCI), and changes in reflex excitability have been reported to be useful in assessing treatments in animal models of cord damage. However, spinal reflexes are known to be dependent on anesthetic level. As a preliminary to its use in SCI, the excitability of the Hoffman reflex (H reflex) has been assessed under several commonly used anesthetics. The H reflex was recorded in the distal foot muscles (dorsal interossei) of adult rats, while the lateral plantar nerve was stimulated. Five different anesthetics were used: ketamine, halothane, Nembutal, Etomidate, and Saffan. Recording and stimulating electrodes were inserted directly through the skin to minimize the surgical procedure for each experiment, allowing repeated recording to be made in the same animal on a weekly basis. Suppression of the H reflex was tested using twin-pulse stimulation. Halothane and ketamine produced suppression of the H response when interpulse intervals were shortened to less than 1 s. The H-reflex suppression profiles recorded under Etomidate, Saffan, and Nembutal anesthesia were less sensitive to the stimulation rate, with little reduction until intervals were 200 ms or less. The suppression profiles of halothane and ketamine resemble that seen in unanesthetized humans, whereas that under the other anesthetics tried here resembles that observed in spinal-cord-injured animals. The results suggest a preferential action of some anesthetics on descending pathways involved in reflex modulation and the importance of assessing reflex excitability under anesthetics such as ketamine or halothane.

Antinociceptive properties of neurosteroids II. Experiments with Saffan and its components alphaxalone and alphadolone to reveal separation of anaesthetic and antinociceptive effects and the involvement of spinal cord GABA(A) receptors.

Studies have shown that the steroid anaesthetic alphaxalone positively modulates gamma-aminobutyric acid (GABA) receptors in vitro. It has also been reported that positive modulation of GABA(A) receptors in the rat spinal cord can produce antinociception in vivo. This present study looks at the interaction of an intraperitoneal injection (i.p.) of the steroid anaesthetic combination Saffan (alphaxalone 9 mg/ml, alphadolone acetate 3 mg/ml) with GABA(A) receptors in the spinal cord. Full recovery from anaesthesia induced by Saffan 2 ml/kg i.p., as assessed by the rotarod test, occurred after 28.78 +/- 0.86 min. Residual antinociceptive effects were assessed by application of electrical current at two skin sites (neck and tail) and also tail withdrawal from noxious heat. Residual antinociception was observed at both skin sites assessed by the electrical test but not when assessed by noxious heat. The antinociceptive effects in the tail but not the neck were suppressed by intrathecal administration of GABA(A) antagonists (bicuculline and SR-95531). In a separate group of experiments alphaxalone and alphadolone were given i.p. individually at the same doses that were given when formulated in Saffan. Alphaxalone produced sedative and anaesthetic effects with no antinociception. Alphadolone caused no sedation but it did cause antinociceptive effects equal in magnitude to those produced by Saffan. We conclude that Saffan produces antinociception in rats when given i.p. by an interaction with spinal GABA(A) receptors. Furthermore, this antinociception is due to the alphadolone content of the neurosteroid anaesthetic and not the alphaxalone.

The role of the pedunculopontine region in basal-ganglia mechanisms of akinesia.

The akinesia of Parkinsonism is relieved by pallidotomy and subthalamic nucleotomy, but not by thalamotomy. Therefore, this disabling symptom probably depends upon connections other than the pallidalthalamocortical tracts, possibly efferents of the medial pallidum descending to the upper brainstem. We have previously demonstrated akinesia in the normal monkey following radiofrequency lesioning in the region of the pedunculopontine nucleus (PPN), one of the primary targets for descending pallidal outflow. Here, we confirm that selectively destroying neurones in the PPN area, whilst sparing fibres of passage, results in an akinetic state in normal macaques.

Anaesthesia of the common marmoset (Callithrix jacchus) using continuous intravenous infusion of alphaxalone/alphadalone.

A safe means of anaesthetizing common marmosets (Callithrix jacchus) for a study using magnetic resonance imaging (MRI) to investigate cerebral ischaemia was required. Continuous infusion of alphaxalone/alphadalone was used to anaesthetize 37 marmosets for non-recovery and recovery experiments. This was found to give safe, reliable anaesthesia when coupled with pulse oximetry and electrocardiographic (ECG) monitoring.

Actions of the anaesthetic Saffan on rat sympathetic preganglionic neurones in vitro.

1. Whole-cell patch-clamp recordings were used to investigate the effects of the anaesthetic Saffan on the electrophysiological properties of sympathetic preganglionic neurones (SPNs) in rat spinal cord slices. 2. Saffan (1-54 microM) abolished or reduced the frequency of spontaneous action potential firing and abolished spontaneous, sub-threshold membrane potential oscillations. Saffan caused dose-dependent decreases in input resistance and depending upon the initial resting membrane potential, either a depolarization, a hyperpolarization or no change in membrane potential. 3. Responses to Saffan were blocked by the GABAA receptor antagonists bicuculline (5-20 microM) and picrotoxin (20 microM), but not by the glycine receptor antagonist strychnine (20 microM) indicating that they were mediated by GABAA receptors. 4. Changes in the properties of SPN action potentials were also observed. In the presence of Saffan the amplitude and duration of the action potential after-hyperpolarization were reduced and larger depolarizations were required in order to evoke trains of action potentials. 5. To examine the effects of Saffan on electrotonic coupling between SPNs, experiments were performed with the Na+ channel blocker QX-314 in the intracellular solution and antidromic oscillations were evoked by ventral root stimulation. Saffan failed to abolish antidromic oscillations, but reduced their amplitude and duration. This indicates that the abolition of spontaneous membrane potential oscillations was not a direct effect on the coupling between SPNs, but was a result of the abolition of spontaneous activity by Saffan. 6. The responses to Saffan occurred within the plasma concentration range of Saffan during anaesthesia, suggesting that the electrophysiological properties of SPNs may be altered during anaesthesia with Saffan. This would be expected to lead to changes in sympathetic tone and in the integration of sympathetic output.

Myocardial mechanics and energetics during continuous positive airway pressure in sedated pigs.

OBJECTIVE: To test the hypothesis that increased cardiac output with continuous positive airway pressure (CPAP) leads to increased myocardial metabolic cost. DESIGN: Prospective, repeated-measures, laboratory studies. SETTING: University-affiliated hospital animal research laboratory. SUBJECTS: Eight sedated pigs that had been previously instrumented for collection of hemodynamic data. INTERVENTIONS: Application of CPAP at 0, 5, 10, and 15 cm H2O and recovery under conditions of normal blood volume (normovolemia) and after administration of hetastarch 35 mL/kg (hypervolemia). MEASUREMENTS AND MAIN RESULTS: We measured mean arterial pressure, cardiac output, systemic vascular resistance index, the first derivative of the left ventricular pressure at a left ventricular pressure of 50 mm Hg, rate-pressure product, left ventricular tension-time index, stroke work index, myocardial pressure-myocardial segment length area, coronary artery blood flow and coronary vascular resistance, and myocardial oxygen consumption (four pigs). With normovolemia, cardiac output decreased with CPAP (4.9 +/- 1.2 L/min at CPAP of 0 cm H2O to 4.5 +/- 1.3 L/min at CPAP of 15 cm H2O, p < .005) and systemic vascular resistance index increased (2509 +/- 702 to 3095 +/- 1080 dyne.sec/cm5.m2, p < .01). With hypervolemia, cardiac output increased at low-level CPAP (5.7 +/- 1.4 L/min at CPAP of 0 cm H2O to 6.4 +/- 1.6 L/min at CPAP of 5 cm H2O, p < .05) and systemic vascular resistance index decreased (2412 +/- 552 to 2033 +/- 436 dyne.sec/cm5.m2, p < .01). There were no associated significant changes in myocardial oxygen consumption, or its major correlates when cardiac output increased with CPAP (hypervolemic conditions). CONCLUSIONS: In normal pigs, there is no change in myocardial oxygen demand with CPAP, whatever the change in cardiac output. Thus, increased cardiac output with CPAP carries little extra metabolic cost. Increased cardiac output with low-level CPAP in hypervolemia is associated with systemic vasodilation.

[Total intravenous anesthesia (TIVA) with alphaxolon/alphadolon (Saffan) for permanent restraint of two cats with severe dyspnea]. / Die total intravenöse Anästhesie (TIVA) mit Alphaxolon/Alphadolon (Saffan) zur dauerhaften Ruhigstellung bei zwei Katzen mit schwerer Dyspnoe.

Total intravenous anaesthesia is a form of anaesthesia which is more often used in human medicine for high risk patients. The case reports of two cats with a severe dyspnoe are presented. Both patients received anaesthesia with the steroid anaesthetic agent Saffan for 19 and 25 hours, respectively. Saffan is a well-tolerated agent with little side effects. Dosage and monitoring results are presented.

Effect of thiopental, saffan, and propofol anesthesia on cardiovascular parameters and bronchial smooth muscle in the rhesus monkey.

The application of human pediatric equipment for measuring respiratory function in nonhuman primates is rapidly gaining popularity in the evaluation of anti-asthma drugs. An important difference between primate procedures and the human clinical situation is the requirement for anesthesia for some techniques because of poor animal compliance. We studied the actions of three potential maintenance anesthetic agents-thiopental, saffan, and propofol-and their effects on a range of cardiovascular parameters under conditions of a broncho-provocation test in rhesus monkeys. The spasmolytic effect of saffan on bronchial smooth muscle was investigated in smooth muscle preparations in vitro and in the rhesus monkey in vivo. Thiopental proved to be a useful sedating agent for this application. Saffan proved to be a bronchodilator in vitro, but the sedative dose was lower than that required to induce appreciable bronchodilator activity in vivo. In comparison, propofol was not appropriate for this application because of the poor sedative effect at nonbronchodilator doses.

Inhibition of erythrocyte membrane ATPases with antisickling and anaesthetic substances and ionophoric antibiotics.

A study has been carried out into the effects of clinically important antisickling and anaesthetic substances and ionophoric antibiotics on the activities of (Na+, K+)- and (Ca+2, Mg2+)-ATPases of the human erythrocyte membrane. In general, these drugs, with the exception of nystatin, inhibit both types of enzymic activities but with varying degrees of efficacy. (Ca2+, Mg2+)-ATPases was more sensitive to the lipophilic anaesthetics and (Na+,K+)-ATPase to the ionophoric antibiotic, amphotericin B. These results are explained in the light of the partition coefficients of these drugs in erythrocyte membranes, their effects on the fluidity of the erythrocytes membranes, the changes they induce in the permeability properties of erythrocytes and the subsequent effect of procaine on sickling of erythrocytes, and their potential interaction with specific membrane components.

Development of a swine animal model for the study of sudden infant death syndrome.

An animal model with selective cardiac autonomic denervation was developed in neonatal swine for the purpose of future studies concerning the possible role of abnormal cardiac innervation in the etiology of sudden infant death syndrome. Twenty-six 4- to 8-day old piglets were randomly assigned to one of the following treatment groups: right stellate ganglionectomy (RSG), left stellate ganglionectomy (LSG), right cardiac vagotomy (RCV), and sham-operated control group. Piglets were anesthetized with Saffan and mechanically ventilated on room air. The thoracic wall was opened, and the sternum was divided, permitting exposure of pleura, heart, and lungs. After completion of one of these operative procedures, the thoracic wall was closed in layers. On successful recovery from anesthesia and extubation, piglets were returned to their sows. Postoperative administration of antibiotics was performed during the first week. Electrocardiograms were recorded once a week over an 8-week period. The sham-operated control group had a postnatal increase in QTc and decrease in heart rate. The RSG group had significantly longer QTc than the sham-operated control group QTc, whereas the RCV group had significantly shorter QTc interval than sham-operated controls. Surgical complications caused the death of two piglets (hemorrhage in one and aspiration in the other), infection caused the death of one piglet 2 weeks after surgery, and three died of unknown causes (one from the RSG group and two from the RCV group). The cause of death for these three animals could not be determined (necropsy was not revealing) because they were not monitored at the time of their demise.(ABSTRACT TRUNCATED AT 250 WORDS)