Frank W. Cervenko

Haemodynamic responses to laryngoscopy and tracheal intubation in geriatric patients: effects of fentanyl, lidocaine and thiopentone

The haemodynamic responses to laryngoscopy and intubation after induction of anaesthesia with thiopentone alone or in combination with 1.5 mg · kg−1 lidocaine and/or 1.5 or 3.0 μg · kg−1 fentanyl were measured in 150 patients over 64 years of age to determine whether lidocaine, fentanyl or both lidocaine and fentanyl attenuated the pressor response. Fentanyl reduced the rises in systolic, diastolic and mean arterial pressures, heart rate, and rate pressure product and lidocaine decreased the rises in arterial blood pressure and rate pressure product (P < 0.05). Fentanyl decreased the incidence of marked fluctuations in haemodynamic variables, often seen in geriatric patients (P < 0.05). The haemodynamic effects of lidocaine and fentanyl were independent of each other. Complications occurred in all groups. Lidocainetreated patients had fewer cardiac dysrhythmias (P < 0.05) and 34 per cent of them had tinnitus. Fentanyltreated patients had a higher incidence of hypotension (P < 0.05). Respiratory depression developed in only one per cent of the fentanyltreated patients. Both lidocaine and fentanyl are recommended adjuncts to induction of anaesthesia with thiopentone in geriatric patients.RésuméNous avons mesuré les conséquences hémodynamiques de la laryngoscopie et de l’ intubation chez 150 patients de plus de 64 ans qui avaient eu une induction de leur anesthésie avec du thiopental seul ou en combinaison avec 1.5 mg · kg−1 de lidocaine etlou 1.5 ou 3.0 μg-kg−1 de fentanyl. Le fentanyl atténua l’augmentation des pressions artêrielles systolique, diastolique et moyenne, du pouls et du produit pouls-pression alors que la lidocaïne fït de même avec la pression artérielle et le produit pouls-pression (P < 0.05). En plus, les fluctuations himodynamiques fréquentes chez les patients agés, furent moins marquées avec le fentanyl (P < 0.05). Par ailleurs la lidocaine et le fentanyl agissaient indépendamment l’un de l’autre. Il y eu des complications dans tous les groupes: entre autres, 34 pour cent de tinnitus mais moins de dysrythmies pour la lidocaine (P < 0.05) et plus d’hypotension pour le fentanyl (P < 0.05) qui ne deprima la respiration que dans un seul cas. La lidocaïne et le fentanyl peuvent done être recommandés à titre de complément à l’induction de l’anesthésie au thiopental chez les patients agés.

Intrathecal Clonidine: Analgesia and Effect on Opiate Withdrawal in the Rat

Clonidine, an α2, adrenergic agonist, has analgesic properties and recently has been used to suppress opiate withdrawal. These two properties theoretically make it a suitable analgesic substitute in patients tolerant to opioids. The objectives of this study were to see if intrathecal clonidine is analgesic and whether it can modify morphine withdrawal at the spinal level. Rats chronically implanted with catheters in the lumbar subarachnoid space were utilized. In analgesia experiments, intrathecal clonidine produced analgesia with the peak effect in the paw-lick test occurring at 200 nM, and in the tail-flick test analgesia was apparent at 100 nM and peaked at 400 nM (in 10 μL Ringers lactate). In dependency experiments, animals dependent on morphine (300 mg · kg−1) received intrathecal clonidine 25, 50, 200 nM in 10 μ1 Ringers lactate 72 h after morphine. Following this, a naloxone challenge, 3 mg · kg−1 was administered and withdrawal assessed. Clonidine-treated animals showed significant weight loss and decrease in temperature, and those treated with high doses showed marked hypothermia and hind-limb flaccidity. Intrathecal clonidine prevented the hyperalgesia associated with opiate withdrawal but did not affect the occurrence of the majority of behavioral signs (e.g., piloerection, irritability) associated with morphine withdrawal. Intrathecal clonidine prevented the naloxone-induced increase in blood pressure during withdrawal and in animals not treated with morphine-produced hypotension. Thus, intrathecal clonidine is analgesic, and part of the antiwithdrawal action of clonidine may be exerted at the spinal level.

Monoamine and opioid interactions in spinal analgesia and tolerance

Noradrenergic and serotonergic neurons, originating in the brainstem and terminating in the dorsal horn, modulate the spinal processing of nociception. The inhibitory effects of norepinephrine (NE) and serotonin (5-HT) on elements of nociceptive transmission may be direct, or secondary to the release of neuromodulators such as opioid peptides. Two major criteria have been used in pharmacological studies of spinal opioid and monoamine interactions: the ability of opioid antagonists to attenuate the antinociceptive effects evoked by stimulating the release of endogenous NE and 5-HT in the lumbar spinal cord, or by the intrathecal injection of exogenous NE and 5-HT; and the development of cross tolerance between opioids and each of NE and 5-HT. Evidence regarding the spinal interaction between opioids and monoamines in mediating behavioural analgesia is reviewed. Recent results from this laboratory indicate that IT (-)naloxone but not (+)naloxone produces dose-dependent antagonism of IT NE-induced antinociception in the rat. This effect was not due to hyperalgesia. In rats made tolerant to spinal morphine using continuous IT infusion, the antinociceptive effect of continuous IT NE was significantly attenuated. However, no cross tolerance was observed between morphine and 5-HT. Observations from a variety of studies support the hypothesis of a spinal opioid link which contributes, in part, to NE-induced antinociception. However, this interaction remains to be conclusively established.

Determination of cross tolerance in rat spinal cord using intrathecal infusion via sequential mini-osmotic pumps

Continuous intrathecal (IT) infusion via ALZET mini-osmotic pumps was used to induced spinal tolerance to morphine in the rat. Naloxone (1 mg/kg IP), injected on day 3 of continuous IT morphine (10 micrograms/hr), produced mild withdrawal symptoms in all morphine-treated animals. In rats pretreated with continuous IT morphine (10 micrograms/hr) or saline, systemic morphine (2, 4, 8, 10 and 15 mg/kg IP) produced equivalent, dose-dependent antinociception using the tail-flick and paw pressure tests. The rostral and caudal distribution of methylene blue dye in rat spinal cord was determined on days 1-7 of continuous IT infusion. The dye remained localized near the catheter tip throughout infusion; maximum distribution was 1.5 cm rostrally and 1.0 cm caudally. The data indicate that morphine, infused at the rate of 10 micrograms/hr, does not undergo extensive redistribution in the spinal cord. A sequential, double mini-osmotic pump technique for cross tolerance studies in rat spinal cord is described. In rats pretreated with continuous IT norepinephrine for 4 days, the antinociceptive actions of continuous IT morphine were reduced but not significantly different from saline-pretreated animals. These data suggest that morphine, injected into the spinal cord, does not produce behavioural analgesia by activation of local adrenergic systems.

Analgesia and tolerance to intrathecal morphine and norepinephrine infusion via implanted mini-osmotic pumps in the rat☆

&NA; The objectives of this study were to investigate the duration of analgesia and the development of tolerance following continuous intrathecal administration of morphine and norepinephrine alone, and morphine followed by norepinephrine via mini‐osmotic pumps in the rat. Analgesia was assessed by the tail‐flick test. In single pump experiments morphine 1 &mgr;l (10 &mgr;g)/h (7 days) and 0.5 &mgr;l (10 &mgr;g)/h (14 days) produced analgesia with tolerance by days 5–7. Norepinephrine 1 &mgr;l (15 &mgr;g)/h (7 days) produced analgesia equivalent to that of morphine with tolerance developing by day 3. Following continuous intrathecal morphine 1 &mgr;l (10 &mgr;g)/h for 5 days, norepinephrine 1 &mgr;l (15 &mgr;g)/h for 7 days failed to produce a significant increase in analgesia. This was in contrast to the increase in analgesia seen when the norepinephrine infusion followed a saline infusion. Determination of the norepinephrine concentration in the solution from the osmotic pumps verified that the norepinephrine is stable for the treatment period.

The haemodynamic effects of intraaortic versus intravenous administration of protamine for reversal of heparin in man

A recent report suggests that there may be advantages of intraaortic (IA) versus intravenous (IV) administration of protamine for reversal of heparin at the end of cardiopulmonary bypass. Because complete haemodynamic measurements were not performed in that study, we prospectively and randomly assessed the effects of protamine sulphate administered via either route. Patients were studied in the period immediately following cardiopulmonary bypass. Heparin, 300 units.Kg-1, plus 150 units.Kg-1 when required, was administered to keep the activated clotting time > 400 sec. Protamine 3 mg.Kg-1 was injected over 30 sec. intravenously in the IV group (n = 5) and into the ascending aorta in the IA group (n = 5). There was a significant decrease in arterial blood pressure (28.6 per cent) from 109.2 ±5.6 mmHg (S.E.) systolic to 78.0 ± 9.0 mmHg observed in the IA group one minute post protamine, which returned to baseline by 2.5 min (analysis of variance p < 0.05). No significant hypotension was observed in the IV group. There was no significant change in heart rate, left alrial pressure, central venous pressure, systemic vascular resistance or cardiac index with either IA or IV protamie. In contrast to our recent study in pigs there was no significant change in pulmonary artery pressure, pulmonary vascular resistance or cardiac output with protamine. Results indicate that there are no haemodynamic benefits of IA vs IV injection of protamine.RésuméUne élude récente a suggéré qu’il pourrait être avantageux d’administrer la protamine par voie intra-aortique à la fin de la circulation extra-corporelle. Cependant, celte étude ne comporte pas de mesures précises des conséquences hémodynamiques d’un tel procédé. Nous avons donc décidé d’étudier les effets cardiovasculaires du sulfate de protamine selon qu’il est administré par voie intra-veineuse (IV) ou intra-aortique (1A) et ceci de façon prospective et aléatoire. Dix patients ont été étudiés immédiatement après le sevrage de la circulation extra-corporelle. Les patients avaient reçu de l’héparine 300 unités.Kg-1 plus 150 unités.Kg-1 au besoin pour maintenir un temps de coagulation activé (ACT) plus grand que 400 sec. La protamine, 3 mg.Kg-1, a été injectée en 30 sec. par voie intra-veineuse (N = 5) ou intra-aortique (N = 5). On a noté une minute après l’injection intra-aortique, une diminution significative de la pression artérielle (28.6 pour cent), la syndique passant de 109.2 ±5.6 mmHg (ET) à. 78 ± 9 mmHg et un retour aux valeurs de contrôle à2.5 min. (analyse de variancep < 0.05). Par contre, il n’y a pas eu d’hypotension significative dans le groupe IV. Dans les deux groupes, il n’y a pas eu de changement significatif de la fréquence cardiaque, des pressions auriculaire gauche et veineuse centrale, de la résistance périphérique ou de l’index cardiaque. Contrairement à notre élude récente chez leporc, il n’y a pas eu, associé à la protamine, de changement significatif dans la pression artérielle, la résistance vasculaire pulmonaire ou le débit cardiaque. Les résultats obtenus indiquent qu’il n’est pas avantageux d’administrer la protamine par voie intra-aortique plutôt que par voie intra-veineuse.

A study of the interaction between clonidine and morphine on analgesia and blood pressure during continuous intrathecal infusion in the rat

In the rat, the continuous intrathecal (i.t.) infusion of clonidine (0.4 microgram/hr) significantly increased the tail-flick latency (TF) and the threshold for paw pressure (PP) withdrawal for 5 days and decreased the systolic blood pressure (up to 24 mm Hg) for 7 days. The antinociceptive effect of continuous intrathecal infusion of clonidine (0.4 microgram/hr) in the tail flick and paw pressure tests was not attenuated in rats that were tolerant to morphine. The acute intrathecal administration of clonidine (2.7 micrograms) and morphine (1.0 microgram) resulted in a synergistic interaction in the tail-flick and paw pressure tests. A synergistic interaction was also observed during the continuous intrathecal infusion of morphine (1.25 micrograms/hr) and clonidine (0.2 microgram/hr) in the tail-flick and paw pressure tests. Individually, these doses of morphine and clonidine had no antinociceptive effect. However, intrathecal infusion together yielded peak tail-flick and paw pressure responses comparable to that of 0.4 microgram/hr clonidine alone, without affecting systolic blood pressure. No delay in the onset of tolerance to the analgesic effect was observed with the combination as compared with clonidine (0.4 microgram/hr) alone. The data indicate that clonidine-induced spinal analgesia is independent of endogenous opioid systems linked to mu-receptors in the spinal cord, and that optimization of spinal analgesia (e.g. synergism) can be achieved during continuous intrathecal infusion without affecting cardiovascular activity.

Intrathecal oxymetazoline produces analgesia via spinal α-adrenoceptors and potentiates spinal morphine

The intrathecal (i.t.) injection of 100 nmol of oxymetazoline to male, Sprague-Dawley rats significantly increased tail flick latency and paw pressure threshold for 10 h as compared to i.t. saline-treated rats. Oxymetazoline-induced antinociception was accompanied by a 2 degree C decrease in rectal temperature and a delayed but mild sedative effect. Intrathecal phentolamine (50 micrograms), injected 8 h after i.t. oxymetazoline, completely reversed the analgesic and hypothermic effects but did not affect sedation. The intravenous injection of oxymetazoline (100 nmol) had no effect in the paw pressure test and virtually no effect in the tail flick test. Co-injection of i.t. morphine and i.t. oxymetazoline in a molar ratio of 1:28 resulted in significant potentiation of their antinociceptive effects as determined by isobolographic analysis. For i.t. morphine alone, the ED50 and 95% confidence interval (95% CI) was 3.8 nmol (2.8-5.6) in the tail flick test and 7.7 nmol (5.4-12.8) in the paw pressure test. In the combination, the ED50 (95% CI) of i.t. morphine was 0.7 nmol (0.6-0.8) in the tail flick test and 1.2 nmol (1.1-1.4) in the paw pressure test, corresponding to an approximate 6-fold increase in potency. The data indicate that: (1) the antinociceptive and hypothermic effects of i.t. oxymetazoline at 8 h are mediated by spinal alpha-adrenoceptors; (2) peripheral sites, and probably supraspinal sites, do not contribute to i.t. oxymetazoline-induced antinociception [corrected]; and (3) oxymetazoline potentiates the analgesic effects of morphine in the spinal cord of the naive rat.

Arterial isoflurane concentration and EEG burst suppression during cardiopulmonary bypass

Isoflurane (1.5 to 3.0 vol% in oxygen) was used to control intraoperative hypertension in 10 patients undergoing hypothermic cardiopulmonary bypass surgery. Isoflurane was administered through the membrane oxygenator of the bypass pump and yielded plateau concentrations in arterial blood ranging from 36.6 to 84.4 μg/ml (0.5 and 1.16 vol%, respectively). Isoflurane dosing resulted in prolonged periods (21 to 63 minutes) of EEG burst suppression and isoelectric activity in nine patients. Burst suppression was not a result of hypothermia. There was a close temporal relationship between isoflurane concentration and the onset of burst suppression (mean onset time: 27.3 ± 4.56 minutes after isoflurane was begun). The mean arterial isoflurane concentration at the onset of burst suppression was 46.5 ± 10.7 μg/ml; the nasopharyngeal temperature was 26.0° ± 0.61° C Isoflurane was eliminated rapidly from blood with a mean apparent t1/2 of 18.8 ± 5.46 minutes.

Prolonged spinal analgesia in the rat with the α-adrenoceptor agonist oxymetazoline

Abstract The acute intrathecal (i.t.) injection of 50, 100, 200, 250 and 300 nmol of oxymetazoline produced dose-dependent antinociception in rats as assessed by tail flick and paw pressure tests. Significant antinociception was observed with all doses of oxymetazoline except 50 nmol in the paw pressure test. The ED50 values for i.t. oxymetazoline in the tail flick and paw pressure testswere 120 nmol (95% CI: 76–178 nmol) and 148 nmol (95% CI: 120–186 nmol), respectively. Oxymetazoline had a long duration of action; a single i.t. dose of 100 nmol significantly elevated tail flick latency and paw pressure threshold for 8 h. The α-adrenoceptor antagonist phentolamine, given i.t. 1 h after oxymetazoline, attenuated the antinociceptive effect in a dose-dependent manner. Phentolamine (50 μg i.t.) produced almost complete antagonism in the tail flick and paw pressure tests. These data indicate that oxymetazoline produces long lasting antinociception in the rat following i.t. injection, and that the effect is mediated by α-adrenoceptors in the spinal cord.