Selective tolerance of group III and IV somatosympathetic reflexes to the effects of alfentanil.

The effect of alfentanil on responses in renal sympathetic nerves evoked by supramaximal electrical stimulation of the radial nerve, has been observed in 6 dogs anaesthesized with alpha-chloralose, paralysed with suxamethonium and ventilated artificially. During an initial infusion of alfentanil the responses of the late group IV (C fibre) and early group III (A delta) were abolished by mean doses of 68 micrograms kg-1 (SEM 3.2 micrograms kg-1) and 797 micrograms kg-1 (SEM 120 micrograms kg-1), respectively. Recovery was allowed to occur to approximately 50% of control values (mean time 76 +/- 14.3 min). The preparations were then conditioned with 7 incremental doses from 7.5 to 120 micrograms kg-1 (i.v.) (total dose 308.5 micrograms kg-1), administered at intervals of 10 min, and subsequently tested with large bolus doses (up to 2000 micrograms kg-1) of alfentanil. In two preparations, the responses of both group IV and group III became completely tolerant to the effects of alfentanil while in the other four the response of the group IV was still eliminated by the drug and the response of group III showed selective tolerance. The heart rate and arterial pressure were reduced by 45 and 29%, respectively during the initial infusion of alfentanil. Thereafter there were no further significant changes in the circulation until the administration of naloxone (2 mg i.v.), which restored the sympathetic responses, heart rate and arterial pressure to control values.

Selective effect of fentanyl on group III and IV somatosympathetic reflexes.

The effect of fentanyl on sympathetic reflexes evoked by supramaximal electrical stimulation of the radial nerve, and the subsequent reversal of its effects by naloxone, have been observed in 10 dogs anaesthetized with alpha-chloralose, paralysed with suxamethonium and artificially ventilated. During infusions of 5 micrograms kg-1 min-1 the late, long-latency, sympathetic response evoked by unmyelinated fibres was abolished at a mean dose of 27 micrograms kg-1 (SD 12.6 micrograms kg-1) after which the early, short-latency response evoked by small myelinated fibres was eliminated at a mean dose of 90.3 micrograms kg-1 (SD 54.6 micrograms kg-1) so that there was no longer any response to stimulation of the radial nerve. During a subsequent infusion of naloxone (200 micrograms min-1) the late response returned to control values at a mean dose of 0.5 mg and subsequently the early response reappeared to return to control values at a total dose of 1.6 mg. In 2 preparations phrenic nerve activity was abolished after 6.1 and 17.4 micrograms kg-1 of fentanyl and returned immediately before the late response, during the infusion of naloxone. In 2 preparations, induced tolerance occurred so that the early response could not be eliminated.

Synergism between the antinociceptive effects of intrathecal midazolam and fentanyl on both A delta and C somatosympathetic reflexes.

The interaction between the antinociceptive effects of fentanyl and midazolam, administered intrathecally (i.t.), was examined in dogs. Midazolam 1 mg (i.t) depressed the A delta and C fibre mediated somatosympathetic reflexes to 68.3 and 85.2% of control values and then reduced the subsequent doses of fentanyl (i.t.) required to abolish these reflexes by 50%. After midazolam (1 mg, i.t.) the ED values for fentanyl were markedly less than the theoretical predicted additive values. This indicates synergism between the effects of fentanyl and midazolam.

Relative effects of intrathecal administration of fentanyl and midazolam on A delta and C fibre reflexes.

The effects of fentanyl and midazolam, administered intrathecally, on somatosympathetic reflexes evoked by tibial nerve stimulation were investigated in 12 anaesthetized and paralysed dogs. Fentanyl depressed both the C and A delta fibre evoked reflexes in a dose ratio of approx 1:2. In contrast, midazolam had a greater effect on A delta compared with C fibre reflexes; while A delta reflexes were abolished by a total dose of 3 mg midazolam, C fibre reflexes were depressed by only 50%. The effect of fentanyl was reversed by naloxone (2 mg, i.v.) and that of midazolam by flumazenil (1 mg, i.v.). The results suggest that fentanyl and midazolam have different relative effects on A delta and C fibre pathways.

Responses in sympathetic nerves of the dog evoked by stimulation of somatic nerves.

Responses in thoracic and renal sympathetic nerves evoked by electrical stimulation of cutaneous and muscle nerves in anaesthetized mongrel dogs were observed. Supramaximal stimulation of cutaneous nerves evoked two responses in both thoracic and renal nerves with latencies in the ranges 58--184 msec and 349--733 msec which are referred to as the early and late responses. It was shown that the early and late responses were evoked by group III and group IV afferent fibres respectively. Stimulation of muscle nerves of the forelimb and the hypoglossal nerve evoked smaller early responses which were considered to be due to activation of group III fibres and which had latencies in the range 92--157 msec. Supramaximal stimulation of muscle nerves in the hind limb failed to evoke any responses in approximately two-thirds of preparations and in the remainder only low level inconsistent early responses were observed. No matter how intense the stimuli applied to muscle nerves there were never any responses which could be related to the activation of group IV fibres.

Effect of ICI197067, a kappa-opioid receptor agonist, spinally on A delta and C reflexes and intracerebrally on respiration.

Intrathecal (i.t.) injection of a kappa-opioid receptor agonist, ICI197067, caused a similar dose dependent depression of A delta and C fibre mediated nociceptive reflexes in renal sympathetic nerves due to supramaximal electrical stimulation of tibial nerves in anaesthetized dogs. A total dose of 8 mg i.t. abolished these reflexes. When administered into the 4th ventricle (i.c.v.) in a total dose range from 0.1-2.5 mg ICI197067 caused no respiratory depression; a total dose of 10 mg i.c.v. abolished both phrenic nerve activity and spontaneous respiration. The ED50 ratio of ICI197067 for depression of respiration (i.c.v.) and somatosympathetic reflexes (i.t.) is approximately 1.5:1 compared with 0.3:1 for fentanyl. ICI197067 i.c.v. caused a similar reduction in arterial pressure compare to fentanyl without comparable changes in heart rate. Thus in terms of cardiorespiratory depression and blockade of A delta and C fibre pathways kappa-opioid receptor agonists may be safer and more effective for producing spinal analgesia than mu-opioid receptor agonists.

Cardiorespiratory effects of conventional and high frequency ventilation in rabbits with bilateral pneumothoraces and surfactant depleted lungs.

We compared high frequency ventilation (HFV) to conventional mechanical ventilation (CMV) under normoxic and normocapnic condition in surfactant depleted rabbits with bilateral pneumothoraces. We hypothesized that lower airway pressures would be required with HFV under these conditions. We applied CMV and HFV in 8 anaesthetized rabbits with a prototype ventilator at frequencies of 30, 100, 200, and 300 cycles/min. A positive end-expiratory pressure (PEEP) just below the pressure sufficient to open the air leak from the pneumothoraces was applied at all frequencies. Airway pressures, gas exchange, heart rate, and mean arterial pressure were recorded. Peak airway pressure decreased significantly from 2.50 to 2.10 kPa when the frequency of ventilation was increased from 30 to 300 cycles/min. There were no significant changes in mean airway pressure, PaO2, arterial pH, heart rate, and mean arterial pressure when HFV was compared to CMV. In conclusion, during HFV peak airway pressures measured at the mouth were decreased. Our ability to maintain adequate gas exchange in the face of ongoing pulmonary air leaks may reflect lower alveolar pressures.

Ventilation techniques to minimize circulatory depression in rabbits with surfactant deficient lungs.

Changes in aortic blood flow were measured in rabbits with both normal and surfactant depleted lungs in order to elucidate the effect of different modes of ventilation on the circulation while optimizing arterial oxygenation (PaO2). Conventional mechanical ventilation (CMV), reversed inspiratory to expiratory ratio of CMV (IRV), high frequency positive pressure ventilation (HFV), and high frequency oscillation (HFO) were used. Normocapnia was maintained throughout during different modes of ventilation. In normal lungs the aortic blood flow during IRV was significantly lower with similar levels of PaCO2 compared with CMV, HFV, and HFO. In lavaged lungs, without positive end-expiratory pressure (PEEP), the aortic blood flow during CMV was significantly higher than with other modes of ventilation. When 10 cm H2O of PEEP was applied, the PaO2 increased maximally to normal values at all modes of ventilation, but the aortic blood flow was significantly reduced (P < 0.05) during CMV and IRV compared to HFV and HFO. The aortic blood flows at 5 cm H2O of PEEP were very similar during CMV, HFV, and HFO but significantly reduced during IRV. This study showed that at an optimal arterial oxygenation with higher PEEP levels, maintenance of aortic blood flow was maximal during HFV and HFO.

Flumazenil and midazolam in anaesthesia.

Flumazenil, the first benzodiazepine antagonist, is currently used widely as an emergency drug, and has also been utilized in planned procedures, to time arousal intra- or post-operatively. It is known that flumazenil, used at the end of a procedure, causes instant recovery by reversing the residual effects of, for example, midazolam. An agonist-antagonist concept, midazolam-flumazenil, where benzodiazepine sedation or anaesthesia is terminated at will, is, therefore, finding increasing application. In neuroanaesthesia, for example, it facilitates immediate recovery, cardiovascular stabilization and the use of midazolam as an alternative to thiopentone and inhalational agents, and in ear, nose and throat endoscopies, it permits more rapid turnover of patients and is a good choice for haemodynamic stability in patients with a high cardiovascular risk factor. There continues to be debate over the term used to describe the level of sedation remaining after the effects of the antagonist have worn off. 'Resedation' is often used incorrectly to describe what is in reality residual sedation. Given the correct use of midazolam or the exploitation of synergism using opioids, flumazenil will cause arousal, while maintaining the benefit of opioid analgesia. Such a technique may eliminate the need for formal recovery facilities in many ambulatory patients, thereby reducing dependence on trolleys, beds and nurses. This has major implications for health economics, particularly in relation to endoscopy clinics and when co-induction of anaesthesia is employed.

Co-induction of anaesthesia: day-case surgery.

The term co-induction of anaesthesia has been applied to the use of two or more drugs to induce anaesthesia. The term was introduced in 1986 to describe the unplanned induction of anaesthesia by non-anaesthetically trained personnel practising sedation. A new benzodiazepine was combined with opioids, with synergistic effects, causing unplanned anaesthesia in an unsuitable environment leading to several fatalities. Currently, planned co-induction of anaesthesia is practised by anaesthetists exploiting drug interactions, particularly synergism, principally between midazolam, fentanyl, sufentanil and alfentanil, and propofol. It can produce an improvement in all phases of anaesthesia, including induction, maintenance and recovery. There are advantages in combining midazolam with propofol, thereby reducing the risk of awareness and also the dose of propofol and hence its side-effects and cost. Propofol is the principal intravenous induction agent for day-case anaesthesia. The pre-administration of 0.03 mg kg-1 of midazolam (approximately 2 mg in normal healthy adults) is now being practised widely. Current papers suggest that 2 mg of midazolam administered to an average, otherwise healthy, adult does not compromise recovery, whereas an increase to 5 mg may be expected to delay the possibility of final discharge of such patients by about 20 min. The use of midazolam and propofol with or without either fentanyl or alfentanil is probably the principal technique for the induction of day-case anaesthesia at the present time. A major advantage is that by reducing the dose of propofol there is less chance of the severe bradycardia that is sometimes associated with the combined use of propofol and opioids, although this can be prevented by vagolytic agents. However, the use of opioids increases the incidence of post-operative nausea and vomiting. Another important drug is ketamine, the effects of which are often additive with other drugs. The combination of ketamine and midazolam is an important technique, particularly in the management of critically ill patients. The alpha 2-agonists, e.g. clonidine and dexmedetomidine, may also have a role in this context in the future. This paper presents the current approach to the co-induction of anaesthesia, particularly in relation to the reduced risk of awareness when using midazolam, and the health economics in relation to the potential reduction in the dose and hence cost of propofol.

Classification of peripheral nerve fibres. An historical perspective.

The historical development of the nomenclature used to describe peripheral nerve fibres is described. Some of the properties of nerve fibres and their maturation are discusses. It is suggested that when grouping fibres by their conduction velocities the original terminology introduced by Erlanger and Gasser41 (i.e. A-alpha, beta, gamma, delta, B and C) should be used for efferent nerve fibres, while the nomenclature introduced by Lloyd44 (i.e. groups I,II, III and IV) should be applied to afferent fibres. The terms B, 'gamma efferent', Ia and Ib have specific implications with regard to their source or distribution irrespective of the conduction velocities of the fibres contributing to these groups.

APUD cells and the apudomas. A concept relevant to anaesthesia and endocrinology.

A variety of cells found in the pituitary and pineal glands, sympathetic nervous system and adrenal glands, the gut, pancreas, thyroid (C-cells), chemoreceptors (type I-Cells), lungs (P-cells), skin (melanocytes) and the urogenital tract have a common origin from the neural crest. These cells are programmed for neuro-endocrine function and, as a group, can be regarded as one of the physiological control systems. They secrete a variety of amine and peptide hormones and have common cytochemical characteristics from which the term APUD cell is derived. Tumours of these cells are referred to as 'apudomas' and may synthesise not only their own hormones but also those which are normally produced by other APUD cells. The relevant physiological properties of some of the peptides which have been described relatively recently are discussed and the principal clinical syndromes produced by the APUDomas are described.

The use of midazolam and flumazenil in diagnostic and short surgical procedures.

Benzodiazepines, used correctly, provide a relatively safe means of providing sedation in a variety of clinical situations and midazolam, which is shorter acting than other benzodiazepines (BZ), is the drug of choice in ambulatory patients. Flumazenil is a highly effective specific competitive BZ antagonist which provides a safe means of rapidly attenuating or terminating BZ sedation. Its mean half-life is 54 min, and in this contact the optimal dosage is 0.2 to 0.5 mg. Although it reverses sedation and amnesia, there is still a question about whether its efficacy in reversing the respiratory depressant effects of benzodiazepines is adequate. This remains an area of critical debate, as does resedation and also its administration to chronic benzodiazepine users. The use of flumazenil to reverse midazolam-induced sedation introduces, for the first time, the possibility of terminating sedation at a predetermined time. Were it to be adopted routinely, it has major implications for the improvement of patient management affecting all aspects of post-operative care.

The current status of pulse oximetry. Clinical value of continuous noninvasive oxygen saturation monitoring.

The history of the development of pulse oximetry is outlined and the principle of how the apparatus works is described. The instrument detects hypoxic hypoxia and the shape of the oxygen dissociation curve means that the minimum saturation alarm should be set at 94% in anaesthetic usage. It is accurate to within 2% and is usually unaffected by racial pigmentation, but accuracy can be affected in low perfusion states, hypothermia and in the presence of abnormal forms of haemoglobin and pigments in the blood. Its clinical evaluation in the operating theatre and intensive care unit is reported. It was found to be useful and reliable and would appear to have logistical and other advantages over current methods of detecting hypoxia. Pulse oximetry may make a significant contribution to the safety of anaesthetic practice.