John S. McDonald

Role of spinal opioid receptors in the antinociceptive interactions between intrathecal morphine and bupivacaine.

In studies on the clinical management of pain, a combination of morphine and bupivacaine is more effective than either of them alone in producing analgesia. The present study was designed to examine the effect of bupivacaine on morphine-induced antinociception as measured by the tail-flick test in the rat. To understand the basis of this interaction, the effect of bupivacaine on the binding of opioid ligands to their spinal opioid receptors in the rat also was investigated. Intrathecal administration of 5, 20, or 50 micrograms bupivacaine significantly potentiated the antinociception produced by intrathecal administration of 10 micrograms morphine. There was more than a 10-fold increase in the area under the curve (AUC0-60 min) for morphine-induced antinociception in the presence of bupivacaine. At higher doses of morphine (20 micrograms), bupivacaine was not very effective, increased AUC0-60 min for antinociception by only about 25%, and in fact significantly decreased the total duration of morphine-induced antinociception. Radioreceptor assays done with rat spinal cord membrane preparations revealed that bupivacaine (0.1-10 nM) inhibited the binding of specific ligands to mu-receptors but increased the binding to delta- and kappa-receptors. The authors conclude that the facilitation of morphine-induced antinociception by bupivacaine may be associated with a conformational change in the spinal opioid receptors induced by bupivacaine. Although increasing the binding of morphine to kappa-opioid receptors is the most prominent effect, the binding of opioid ligands to all spinal receptors is inhibited at high doses of bupivacaine.

Differences between handwritten and automatic blood pressure records.

Comparison of 46 handwritten and electromechanically generated blood pressure records revealed substantial differences between the recordings. The highest automated record pressures exceeded the highest pressures found in corresponding handwritten records. Similarly, the lowest pressures from automated records were lower than those from handwritten records. Seventeen records (37%) had at least three automatic blood pressure determinations with values substantially in excess of the most extreme values recorded by hand. No handwritten record contained a diastolic pressure above 110 mmHg. Discrepancies between handwritten and automatic records may arise from one or more causes. Among these are readings captured automatically but not observed by the anesthesiologist, faulty reconstruction of handwritten records from memory, and bias in favor of less controversial values.

Inhibition of Morphine-induced Tolerance and Dependence by a Benzodiazepine Receptor Agonist Midazolam in the Rat

We investigated whether midazolam administration influenced morphine-induced antinociception and tolerance and dependence in the rat. Antinociception was assessed by the tail-flick (TF) and the hot-plate test (HP 52°C). Morphine tolerance developed after daily single injections of morphine for 11 days. The effect of midazolam on morphine-induced antinociception and tolerance was assessed by giving daily injections of various doses of midazolam for 11 days. The first injection of saline or midazolam was given intraperitoneally and 30 min later morphine (10 mg/kg body weight) was administered subcutaneously. Antinociception was monitored by measuring TF and HP latencies 60 min after the second injection. Midazolam was injected at four different concentrations: 0.03, 0.1, 0.3, and 3 mg/kg body weight. Chronic administration of morphine resulted in the development of tolerance to antinociception in both TF and HP tests, with rats exhibiting baseline antinociception on Day 9. Animals treated with midazolam alone showed little antinociception on Days 3–9. However, midazolam administration in morphine-treated animals attenuated morphine-induced tolerance to antinociception on Days 1–11 as measured by the tail-flick test. Midazolam also decreased the jumping behavior following naloxone injections in morphine-dependent rats. These results suggest that midazolam may prolong the effects of morphine by delaying morphine-induced development of tolerance to antinociception. Midazolam also attenuated a decrease in weight gain induced by chronic injections of morphine.

IS LYSERGIC-ACID DIETHYLAMIDE A TERATOGEN ?

Abstract A girl with a malformed right leg was born to a 19-year-old woman who had taken lysergic-acid diethylamide (L.S.D.) on the 25th day after her last menstrual period and three times between the 45th and 98th days. Her husband had also taken the drug. The child presented with the typical picture of the unilateral fibular aplastic syndrome. Since the mother took the second dose of L.S.D. in the period critical for the production of leg deformities, it is not unreasonable to suspect a causal relationship. Chromatid breaks were found in peripheral white blood-cells of the father (2 breaks), mother (5), and child (3).

Cell Swelling, Blebbing, and Death Are Dependent on ATP Depletion and Independent of Calcium During Chemical Hypoxia in a Glial Cell Line (ROC-1)

The morphological and biochemical changes that occur during chemical hypoxic injury in a neural cell line were studied in the presence and absence of calcium. Oligo‐dendroglial‐glioma hybrid cells (ROC‐1) were subjected to inhibitors of glycolytic and oxidative ATP synthesis (chemical hypoxia). Complete respiratory inhibition depleted [ATP] to <5% of control by 4 min. Blebs appeared on the cell surfaces and cells began to swell within a few minutes of ATP depletion. A 200% increase in cell volume and bleb coalescence preceded irreversible cell injury (lactate dehy‐drogenase release) which began at ∼20 min with 50% cell death by 40 min. In energized cells an equivalent degree of osmotic swelling induced by ouabain inhibition of the Na+, K+‐ATPase pump did not produce blebbing or cell death. Partial inhibition of respiration decreased [ATP] to ∼10% of control by 40 min. Blebbing and swelling began at 40 min and bleb coalescence preceded plasma membrane disruption which began at ∼55 min. ATP depletion, blebbing, swelling, and death followed similar time courses in the presence or absence of extracellular calcium ([Ca2+]e). Intracel‐lular calcium ([Ca2+]i) was measured using fura‐2. In calcium‐containing medium metabolic inhibition caused a transient increase in resting [Ca2+]i (100 ± 17 nM) followed by a low steady‐state level preceding plasma membrane disruption. Following deenergization in calcium‐free medium, [Ca2+]i remained below 60 nM throughout injury and death. These data suggest that decreased ATP initiates a sequence of events including bleb formation and cell swelling that lead to irreversible cell injury in the absence of large increases in [Ca2+]i.

Evaluating the human engineering of microprocessor-controlled operating room devices

Although human engineering features are widely appreciated as a potential cause of operating room incidents, evaluating the human engineering features of devices is not widely understood. Standards, guidelines, laboratory and field testing, and engineering discipline are all proposed methods for improving the human engineering of devices. New microprocessor technology offers designers great flexibility in the design of devices, but this flexibility is often coupled with complexity and more elaborate user interaction. Guidelines and standards usually do not capture these features of new equipment, in part because technology improvements occur faster than meaningful guidelines can be developed. Professional human engineering of new devices relies on a broad, user-centered approach to design and evaluation. Used in the framework of current knowledge about human operator performance, these techniques offer guidance to new equipment designers and to purchasers and users of these devices.

Computed tomography-guided pudendal block for treatment of pelvic pain due to pudendal neuropathy.

Background Severe pelvic pain secondary to pudendal neuropathy can be treated with repeated local anesthetic nerve blocks or with surgical decompression of the nerve. Computed tomographic (CT) needle guidance to identified reliable anatomic points might be useful for improved success rates. Technique A CT scan is used to determine baseline anatomy and identify the sacrospinous process. A metallic marker is used to create a perpendicular pathway from the sacrospinous process upward to the skin surface, where a local anesthetic is injected. A 22-gauge, 5-inch needle is inserted downward in a perpendicular direction to the target. Deep penetration and direction are confirmed by serial CT scans. Medication is injected and the needle is removed. Experience Twenty-six women with diagnoses of pudendal neuropathy were treated with injection therapy once per month, for five total treatments each. About three-quarters experienced improvement. There were no complications in this series. Outcomes were gratifying considering the complex patient population, all having failed multiple therapeutic trials. Conclusion We believe this technique warrants further evaluation and application in instances where noninvasive therapy of pudendal neuropathy is indicated.

DIFFERENTIAL EFFECTS OF INTRATHECAL MIDAZOLAM ON MORPHINE-INDUCED ANTINOCICEPTION IN THE RAT : ROLE OF SPINAL OPIOID RECEPTORS

The antinociceptive effects of an intrathecally administered benzodiazepine agonist midazolam, alone and in combination with morphine, were examined in the rat by using the tail-flick test. The duration of antinociceptive effect produced by midazolam was significantly less (P less than 0.05) than that produced by morphine. Low doses of midazolam (10 micrograms) and morphine (10 micrograms) produced a synergistic effect in prolonging antinociceptive effect. However, at higher doses (20 or 30 micrograms), these drugs reduced the extent of antinociception produced by each other. Naloxone administration prevented antinociception produced by these drugs, indicating interactions between midazolam and opioid receptors. Midazolam had dual effects on the binding of opioid ligands to the spinal opioid receptors. At low dose, it potentiated the displacement of [3H]naloxone by morphine. At higher doses, midazolam inhibited the binding of opioid ligands to their spinal receptors in the following order: kappa greater than delta greater than mu. These results indicate that differential antinociceptive effects of midazolam on morphine-induced antinociception involve interaction of this benzodiazepine with spinal opioid receptors.

A Comparison of Arterial Gas Tensions, Radiographs and Physical Examination

A study was made on 27 patients undergoing elective surgery. Preoperative and postoperative chest roentgenograms and arterial blood-gas studies were compared. Temperature, pulse rate, respiratory frequency, and clinical observations were noted. A high incidence (19 of 27) of low oxygen tensions occurring with normal or increased ventilation was observed. No correlation could be established between roentgen-ray or clinical finding on the one hand and laboratory findings on the other. The concept is presented that the findings represent “miliary” atelectasis occurring so diffusely as to escape detection by physical or radiographic examination. More severe reductions in ventilation-perfusion ratios and complete atelectasis are best considered as a continuum since they produce the same effects and may not be distinguishable. Postoperative patients present a pattern of near constant tidal volume without sighing, known to produce these changes. That these changes occur without airway obstruction is suggested by improvement with deep breathing. Although appearing benign, decreases in oxygen tension may be of serious magnitude.

Performance of residents in anesthesiology as related to measures of personality and interests

79 male and 16 female residents in anesthesiology at six training centers took the California Psychological Inventory (CPI) and Strong Interest Inventory (Sil) in Year 1 and were rated for performance two years later. Descriptively, the total sample scored highest on CPI scales for Dominance, Social Presence, and Achievement via Independence, and on Sil scales for investigative, mathematical, and medical science interests. Scores from a four-scale CPI cluster of Empathy, Socialization, Achievement via Conformance, and Achievement via Independence correlated 39 with ratings for men and 31 with ratings for women. In another sample of 20 residents, the cluster score correlated 30 with ratings gathered three years after testing. These findings, consonant with prior research, suggest that attributes such as empathy, strong internalization of pronormative values, and the ability to work well within either structured or open settings are conducive to superior performance in the specialty.