Thomas J. Luger

The spinal potentiating effect and the supraspinal inhibitory effect of midazolam on opioid-induced analgesia in rats

The authors investigated the effects of spinal and supraspinal administration of the benzodiazepine receptor agonist midazolam alone and with opioids on tests of nociception (tail-flick and hot-plate tests) and motor function (catalepsy) in rats. At the spinal level, the dose-response curves for peak effect and area under the curve for morphine were shifted to the left (indicating potentiation) by a submaximal dose of intrathecal (i.t.) midazolam (20 micrograms) in both nociceptive tests. Additionally, 2.5 micrograms of i.t. midazolam, a dose having no effect when given alone, increased antinociception in both tests when given with i.t. morphine. Isobolographic analysis confirmed that i.t. injection of midazolam potentiated antinociception induced by i.t. morphine. At the supraspinal level, intracerebroventricular (i.c.v.) injection of 4 micrograms of midazolam inhibited morphine antinociception, i.e., the dose-response curve for morphine in the hot-plate test shifted to the right. Midazolam did not affect morphine antinociception in the tail-flick test. Catalepsy occurred only when the highest doses of i.t. or i.c.v. morphine or midazolam were injected alone. The differing effect of midazolam on morphine-induced antinociception suggests that different mechanisms are involved in the spinal cord and brain.

LONG-TERM ADMINISTRATION OF PANCURONIUM AND PIPECURONIUM IN THE INTENSIVE-CARE UNIT

This study was performed to determine the optimum dose of pancuronium (n = 30) and pipecuronium (n = 30) under continuous sedation and analgesia in the intensive care unit (ICU). This was an open clinical investigation in 60 critically ill patients with head injury, multiple trauma (in some complicated with sepsis and multi-organ failure), requiring neuromuscular block for ventilation for at least 48 h. Emphasis was placed on the neuromuscular monitoring with a peripheral nerve stimulator and adequate sedation and analgesia. Satisfactory block was achieved in all cases with an average dose of 3 mg/h with either compound. None of the patients experienced prolonged paralysis, muscle weakness, or other neuromuscular dysfunctions in the postventilatory period. We suggest that adequate use of sedative hypnotics and opioids plus neuromuscular monitoring allowed us to optimize the dose of muscle relaxants according to the need of individual patients.

Enhancement of morphine analgesia by fenfluramine in subjects receiving tailored opioid infusions

&NA; We evaluated the ability of fenfluramine, a serotonin releaser, to increase the analgesic potency of morphine administered by tailored i.v. infusion. Ten normal volunteers participated in 4 test sessions, involving different treatments on different days: (1) oral placebo/saline infusion, (2) oral placebo/morphine infusion, (3) oral fenfluramine (60 mg)/saline infusion, and (4) oral fenfluramine/morphine infusion. Subjects experienced repetitive painful dental electrical stimuli at strong but tolerable intensities during testing. On the 2 test days involving morphine, the opioid was administered by a computer‐pump system that used individual pharmacokinetic parameters to achieve consecutive, steady plasma concentrations near target values of 16, 32 and 64 ng morphine/ml; each morphine concentration plateau was maintained for 45 min. On the saline infusion days, our procedures were identical to morphine test days except that the infused fluid contained no drug. For all sessions outcome measures included subject ratings of pain intensity, dental evoked potential (EP) amplitude, and visual analog scale (VAS) ratings of subjective side‐effect intensities (nausea, alertness, dizziness, itching, mood). We obtained these measures during baseline and at each morphine concentration plateau or at corresponding times during saline infusions. Fenfluramine significantly increased the analgesic potency of morphine during the opioid infusion, while fenfluramine alone produced borderline analgesic effects. Fenfluramine alone decreased alertness slightly, but did not significantly increase morphine side effects. Thus, we conclude that fenfluramine enhances the analgesic potency of morphine without a parallel increase in opioid side‐effect potency.

Mechanisms of the influence of midazolam on morphine antinociception at spinal and supraspinal levels in rats

The mechanisms for the combined antinociceptive effect of midazolam and morphine administered at spinal (intrathecal, i.t.) and supraspinal (intracerebroventricular, i.c.v.) levels were investigated in rats. Nociceptive test results showed that co-administration of midazolam and morphine at the spinal level potentiated morphine-induced antinociception, and that this interaction was blocked by intraperitoneal (i.p.) naloxone and reversed by i.t. bicuculline and i.p. flumazenil. Also, bicuculline and flumazenil blocked midazolam-induced antinociception at the spinal level, and naloxone completely reversed morphine antinociception. In contrast, when drugs were injected intracerebroventricularly, midazolam inhibited the antinociceptive effect of morphine (as determined by the hot-plate test). The inhibitory effects of i.c.v. midazolam upon i.c.v. morphine antinociception were partly blocked by flumazenil and bicuculline. Midazolam-induced antinociception was increased by bicuculline and decreased by flumazenil; naloxone i.p. blocked both i.c.v. morphine antinociception and i.c.v. morphine-midazolam antinociception. Results after i.t. injection may be due to an interaction between morphine and midazolam/GABAA receptor-activated systems. At the supraspinal level, this interaction may also activate other systems that are distinct from those governing the individual action of each agonist.

Systolic anterior motion of the mitral valve with left ventricular outflow tract obstruction: three cases of acute perioperative hypotension in noncardiac surgery.

In this report we describe three cases of severe perioperative hypotension in noncardiac surgery patients. As systolic anterior motion of the mitral valve in combination with subaortic left ventricular outflow tract obstruction is an unrecognized cause for hypotension in noncardiac surgery patients, delayed diagnosis can result in erroneous treatment regimen. The aim of the present report is to provide an informative and brief synopsis of the pathophysiological consequences and diagnostic/therapeutic strategies for the perioperative management of systolic anterior motion.

Liposome encapsulation prolongs alfentanil spinal analgesia and alters systemic redistribution in the rat

The effect of liposome encapsulation on the analgesia produced by intrathecally administered alfentanil was examined in the rat. In rats prepared with chronic intrathecal catheters, alfentanil in doses of 1-50 micrograms was administered intrathecally in either saline or in multilamellar liposomes (dipalmitoylphosphatidylcholine and cholesterol). Animals were then tested for analgesia by hot-plate and paw-pressure tests. A second group of animals received intrathecal injections of 30 micrograms alfentanil in saline or liposomes, and blood samples were obtained at 5, 15, 45, and 135 min thereafter for measurement of alfentanil plasma concentrations. The liposome preparation markedly prolonged spinal analgesia in the paw-pressure test and to a lesser extent in the hot-plate test. Neither the time to peak analgesia nor the intensity of analgesia differed between the saline and liposome groups. Liposome encapsulation significantly reduced the peak alfentanil plasma concentration at 5 min and prolonged the period in which low but measurable levels of alfentanil could be measured in plasma. These pharmacokinetic data demonstrate that liposome encapsulation resulted in a slow but prolonged appearance of free alfentanil into a diffusible pool available for uptake into the spinal cord. Consistent with the lower peak plasma concentration of alfentanil, the liposome group demonstrated a significantly lower incidence of catalepsy, indicating less systemic redistribution of alfentanil to supraspinal sites. Liposome encapsulation thus appears to produce a significant reduction in peak plasma concentration with a concomitant reduction in systemic side effects and an increase in the duration of action for a given intrathecal dose of the otherwise rapidly cleared alfentanil.

Unilateral Anesthesia Does Not Affect the Incidence of Urinary Retention After Low-Dose Spinal Anesthesia for Knee Surgery

We evaluated whether unilateral low-dose spinal anesthesia may reduce the likelihood of postoperative urinary retention. Forty patients scheduled for knee arthroscopy randomly received bilateral (n = 20) or unilateral (n = 20) spinal anesthesia with 6-mg hyperbaric bupivacaine 0.5%. The incidence of urinary retention (>500 mL) assessed with an ultrasound device (Bladderscan) and subsequent temporary catherization was 7/20 patients in the bilateral versus 6/20 in the unilateral group (not significant). We concluded that unilateral low-dose spinal anesthesia does not further decrease the likelihood of urinary retention. Our results demonstrate the value and necessity of monitoring bladder volume postoperatively.

Can midazolam diminish sufentanil analgesia in patients with major trauma? A retrospective study with 43 patients.

Benzodiazepine agonists in combination with opioid analgesics are commonly used for combined analgesia and sedation in intensive care patients as well as for anesthesia. In animals, studies indicate either agonistic or antagonistic interactions of benzodiazepine agonists and opioids. This retrospective study of 43 patients evaluated the possible clinical relevance of benzodiazepine-opioid interactions related to pain management. We observed an increase of greater than 50% of the maximal sufentanil infusion rate in significantly more patients in group 2 (13 patients vs 6 patients; chi 2: p = 0.04) and a decrease of the sufentanil infusion rate in eight group 1 patients, but only in one patient in group 2 (chi 2: p = 0.03). We believe that an interaction between midazolam and sufentanil on nociceptive transmission and/or a rapid development of tolerance to sufentanil may be responsible for the observed difference. Contrary to the common clinical impression that midazolam potentiates opioid analgesia, these results indicate that systemic co-administration of midazolam over a period of more than three days can diminish sufentanil efficacy.

Oxygen application by a nasal probe prevents hypoxia but not rebreathing of carbon dioxide in patients undergoing eye surgery under local anaesthesia

BACKGROUND/AIM Hypoxia and carbon dioxide rebreathing are potential problems during eye surgery in spontaneously breathing patients. The aim of the present study was to determine effectiveness of nasal application of oxygen to prevent hypoxia and carbon dioxide accumulation in spontaneously breathing patients undergoing cataract surgery. METHODS Oxygenation and carbon dioxide rebreathing were examined in 40 elderly patients using two different methods of oxygen supply—nasalv ambient air—with a constant flow of 2 l/min. Partial pressure of carbon dioxide under ophthalmic drapes, transcutaneous pressure of carbon dioxide, and the respiratory rate were measured during 25 minutes while oxygen was supplied via a nasal cannula or into the ambient air under the drapes. RESULTS In both groups carbon dioxide accumulation under the drapes, carbon dioxide rebreathing, tachypnoea, and an increase in peripheral oxygen saturation occurred. No significant differences were found between the two methods. CONCLUSION Nasal application of oxygen prevented hypoxia but did not prevent carbon dioxide accumulation in patients undergoing eye surgery under retrobulbar anaesthesia. Additionally, as a side effect when using nasal probes, irritation of the nose was described in half of the patients investigated.