Thomas J. Gal

Analgesic and respiratory depressant activity of nalbuphine: a comparison with morphine.

To compare the respiratory depressant and analgesic effects of nalbuphine and morphine, six healthy male subjects were given the drugs as single 0.15-mg/kg doses, and as four successive doses of 0.15 mg/kg. Respiratory depression was monitored by ventilatory and mouth occlusion pressure responses during CO2 rebreathing, while analgesia to experimental pain was tested with the submaximal effort tourniquet ischemia test. When given as single 0.15-mg/kg doses, both drugs significantly increased the threshold and tolerance for experimental pain. The analgesic effect was similar for both drugs at this dosage, as was depression of the ventilatory and occlusion pressure responses to CO2. Morphine administered in multiple doses progressively increased pain tolerance from 30 ± 13% above control with the first dose of 0.15 mg/kg to 107 ± 13% above control after the fourth dose (cumulative total 0.60 mg/kg). Nalbuphine produced a 40 ± 12% increase in pain tolerance with an initial dose of 0.15 mg/kg, but additional increments of nalbuphine did not result in significantly greater analgesia. The increasing morphine dosage was associated with progressive rightward displacement and ultimately decreases in the slope of the CO2 response curves. Nalbuphine produced an initial rightward displacement of the CO2 response curves similar to morphine, but continued administration of the drug did not result in further displacement or changes in slope. These findings demonstrate that nalbuphine, in contrast to morphine, exhibits a ceiling effect for respiratory depression which is paralleled by its limited analgesic effect on experimental pain.

Prolonged Antagonism of Opioid Action with Intravenous Nalmefene in Man

To identify the opioid antagonist activity of nalmefene and to determine its duration in man, six healthy male subjects were pretreated on separate days with a saline placebo, 0.5 mg, 1 mg, or 2 mg nalmefene intravenously in a randomized double-blind fashion. Opioid challenges with fentanyl, 2 μg/kg, then were administered 1,2,4,6, and 8 h afterward. Respiratory depression was monitored by ventilatory and occlusion pressure responses during CO2 re-breathing, while analgesia to experimental pain was identified with the submaximal effort tourniquet ischemia test. One hour following placebo pretreatment, the initial fentanyl dose produced marked respiratory depression. Minute ventilation and occlusion pressure at a PCO2 60 mmHg during rebreathing (VE60 and P0.160) were reduced to 29 and 41% of control, respectively. The slopes of the ventilatory and occlusion pressure responses also decreased significantly to 51 and 55% of control. Respiratory effects were similar with all subsequent fentanyl doses. Pretreatment with 2 mg nalmefene completely prevented the subjective and respiratory effects of fentanyl for the entire 8 h of the experiment. Nalmefene, 1 mg, significantly blunted the fentanyl effects for the same period, but VE60 values at 6 and 8 h were depressed significantly (P < 0.05) to 66 and 61% of control. The antagonist effects of the lowest nalmefene dose, 0.5 mg, persisted for about 4 h, at which time V E60 was 64% of control. Fentanyl administration produced consistent increases in pain tolerance (44–55% above control) throughout the experiment. Nalmefene pretreatment abolished this analgesic response in a dose-related time course that mirrored the respiratory effects almost exactly. These findings demonstrate that nalmefene is an effective opioid antagonist with a duration of action far in excess of naloxone and more clearly related to dose.

Bronchial hyperresponsiveness and anesthesia : physiologic and therapeutic perspectives

ntermittent airflow obstruction manifested by episodes of bronchospasm is an important feature of I clinical asthma but may also be found in other disease states, such as chronic bronchitis, emphysema, and allergic rhinitis. All of these disorders are characterized by an exaggerated sensitivity to a variety of physical, chemical, and pharmacologic stimuli which is termed ”bronchial hyperresponsiveness.” The term refers both to the ease with which airway narrowing is elicited, and the degree to which it occurs (1). Essentially, the bronchoconstrictive response occurs with a lower level of stimulus and is increased in magnitude compared to normals. This discussion will outline some of the factors responsible for this hyperresponsiveness, as well as those that modify it. The goal is to provide the practicing anesthesiologist with a background for dealing more effectively with the potential problem of bronchospasm in the perioperative period.

Prolonged blockade of opioid effect with oral nalmefene

In a placebo‐controlled, double‐blind study we evaluated the ability of a single 50 mg oral dose of nalmefene to block the effects of intravenous opioid challenge (2 µg/kg fentanyl). Fentanyl‐induced respiratory depression (CO2 responsiveness), analgesia (tourniquet ischemia), and subjective effects were totally blocked for 48 hours and showed only minimal breakthrough 72 hours after nalmefene. Plasma concentration‐time data for nalmefene indicate good oral bioavailability and a prolonged terminal elimination phase (mean t1/2 11.1 hours). These findings suggest that nalmefene could provide prolonged effectiveness in limiting emergence of opioid effects during addiction therapy.

Resistance to breathing in healthy subjects following endotracheal intubation under topical anesthesia.

To identify possible airway constriction following endotracheal intubation under topical anesthesia, airway resistance (Raw) and specific conductance (sGaw) were measured with a body plethysmograph in six awake, healthy, nonsmoking men aged 23 to 29. Subjects were studied while breathing under four conditions: (1) through a large bore mouthpiece (control); (2) through an 8.0-mm internal diameter 25-cm long endotracheal tube held externally (external resistance); (3) while intubated with an identical endotracheal tube; and (4) following extubation as they again breathed through the mouthpiece. To determine the effect of the lidocaine aerosol used for topical anesthesia prior to intubation, Raw was measured in six additional subjects before and after the upper airway had been topically anesthetized. Topical anesthesia produced no significant change in Raw or sGaw in these subjects. In subjects whose tracheas were intubated the mean values of Raw (in cm H2O/L/sec) and sGaw (in L/sec/cm H2O/L) in each of the four above conditions were: control, 0.99, 0.30; external resistance, 2.34, 0.13; intubation, 2.75, 0.11; and following extubation, 1.00 and 0.30. The increase in Raw and decrease in sGaw during tracheal intubation were significantly greater than the changes noted with subjects breathing through the tube as an external resistance (p < 0.01). Tracheal intubation increased residual volume and decreased vital capacity but did not alter functional residual capacity or total lung capacity. We conclude that tracheal intubation under topical anesthesia increases airway resistance more than the resistance produced by the addition of the tube to the control airway. This additional resistance reflects reflex narrowing of airways distal to the tube, which may be more severe in patients whose airways are not anesthetized.

Nunn’s Applied Respiratory Physiology. 5th ed.

As one whose career in anesthesiology has spanned three decades, this reviewer was fortunate to own a copy of the first edition of this classic monograph while a resident. Although the title continues to emphasize the adjective “Applied,” the material has always been an easily digestible compendium of basic physiological principles, many of which are relevant if not directly applicable to the clinical practice of anesthesiology. The new edition represents an attempt to depart from the emphasis on basic physiology by dividing the text into three separate topic areas: basic, applied, and clinical (i.e., a discussion of pulmonary disease). Despite this attempt to expand the breadth and depth of clinical topics, essentially half of the 638 actual text pages remain devoted to basic respiratory physiology. One particularly noteworthy improvement in the present edition is the change to sequential numbering of references and their inclusion with each chapter. This provides improved reader access and a better sense of relevance to the topics discussed. Among the chapters devoted to basic physiology, Chapters 6, 7, and 8 are without question the strongest. They provide superb discussions of pulmonary ventilation, the pulmonary circulation, and their interrelationships. In the applied physiology section, the 40-page Chapter 21, titled “Anesthesia,” is perhaps the best of the entire book. It provides a concise but comprehensive consideration of the control of breathing, respiratory mechanics, and gas exchange in the anesthetized state. The material could easily stand alone as a quality review article. In contrast, Chapter 27, “Airways Disease,” proved to be much of a disappointment largely because of the short and rather superficial discussion of chronic obstructive pulmonary disease. Perhaps at the risk of accusations of nitpicking, one additional item deserves comment. In the chapter devoted to the functional anatomy of the respiratory tract, Figure 2.2 seems to provide somewhat misleading information. The suggested cross-sectional area of the glottis estimated from acoustic reflection is nearly twice that estimated more directly from photographic measurements of glottic width and anterior-posterior diameter. More disturbing, however, is the suggestion that the glottis is nearly 30 cm from the incisors. If this were so, laryngoscopy with presently available laryngoscopes would be highly impractical. Whatever minor shortcomings the monograph may have, this “born again” classic deserves a place on the bookshelves of anesthesiologists. It possesses many of the attributes of desirable texts, beginning with practical size, attractive cover, and easy readability. Had it also a price tag below

Atropine and glycopyrrolate effects on lung mechanics in normal man.

100, it would be irresistible.

Ventilatory and Analgesic Effects of Dezocine in Humans

To assess the comparative bronchomotor effects of large systemic doses of glycopyrrolate and atropine intravenous glycopyrrolate (10 μg/kg), atropine (20 μg/kg), or a placebo was administered to six healthy male volunteers in double-blind fashion. Both drugs produced bronchodilation reflected by significant decreases in airway resistance and increases in specific airway conductance (SGAW) compared to placebo. Glycopyrrolate increased SGAW to a maximal level of 100% ± 7% above control; bronchodilation persisted at this level for more than 4 hours after drug administration. Atropine increased SGAW to a maximum of 88% ± 5% above control 30 minutes after administration, but SGAW returned to control levels between 3 and 4 hours after the drug was given. Both drugs increased maximum expiratory flow rates over the same time course as SGAW, but the percent increases in flow were significantly less than changes in SGAW. Lung elastic recoil was decreased by both drugs over the full range of lung volume. The 32% maximum increase in heart rate after glycopyrrolate was significantly less (p < 0.01) than the 60% increase after atropine. It was concluded that vagal blockade with glycopyrrolate dilates large and small airways to the same extent as atropine, but that the effect is more sustained and associated with less cardiac vagal blockade. Lower doses of glycopyrrolate were also studied and the findings showed that maximal bronchodilation is achieved with lower doses (3.2 μg/kg), which are commonly used in routine premedication.

Decreasing Airflow Resistance during Infant and Pediatric Bronchoscopy

The respiratory depressant and analgesic effects of intravenous dezocine were evaluated in six healthy volunteers. Single 0.15 mg/kg doses were compared with identical amounts of morphine, and the two drugs were given in combination. Five successive 0.15 mg/kg doses of dezocine also were given to identify dose-effect relationships. Respiratory center sensitivity was monitored by carbon dioxide (CO2) rebreathing and mouth occlusion pressure (P0.1) measurements, while analgesia to experimental pain was tested with submaximal tourniquet ischemia. Single 0.15 mg/kg doses of dezocine produced significantly more tolerance to experimental pain and greater respiratory depression than a comparable dose of morphine in the first hour, but effects of both drugs were similar thereafter. Multiple doses of dezocine progressively increased pain tolerance from 46 ± 14% above control with the first dose to 70 ± 18% above control with the second dose (cumulative total 0.30 mg/kg). Additional dezocine doses did not result in significantly more analgesia. Depression of CO2 sensitivity followed a similar pattern. Morphine 0.15 mg/kg, when given to subjects who had received a prior dose of dezocine, produced no additional effect beyond that observed with dezocine. With the reverse sequence, dezocine increased the respiratory depression of morphine but also produced a dramatic increment in analgesia, which suggested an additive action. Dezocine is therefore an effective analgesic with morphine-like effects. In human subjects it appears to be a slightly more potent analgesic than morphine in identical clinical doses (0.15 mg/kg). Dezocine is similar to other agonist-antagonist analgesics in that it exhibits a ceiling effect for respiratory depression that parallels its analgesic activity.

Airway responses in normal subjects following topical anesthesia with ultrasonic aerosols of 4% lidocaine.

Rigid bronchoscopy in infants and small children is fraught with problems of inadequate ventilation and gas exchange, due in part to compromise of the lumen of a small-caliber bronchoscope by insertion of a telescope (1). The standard Storz-Hopkins pediatric telescope has an outer diameter of 4.0 mm whereas the smallest Storz 30-cm-bronchoscope has an inner diameter of 4.9 mm. The size of this bronchoscope, designated by the manufacturer (nominal size), is actually 3.5 (Table 1). Thus the 4.0-mm telescope occupies about two-thirds of the cross-sectional area of the 3.5 bronchoscope lumen and impedes airflow (2). This bronchoscope is the size usually required for children under 3 yr of age, the group in which the largest proportion of anesthetics is administered for pediatric bronchoscopies (3) . A smaller telescope (Hopkins 27020 A) that is currently available, although marketed for use with the Storz optical forceps, fits all Storz 30-cm-long bronchoscopes. The diameter of this telescope (2.8 mm) would present much less resistance to airflow, but there are no actual measurements to prove this or to indicate how much the resistance is decreased. This study was performed to compare this smaller diameter telescope with the standard 4.0-mm telescope principally in terms of airflow resistance, but brightness and image resolution were compared as well.