Paul A. Leonard

Wide variation in responses to neuromuscular blocking agents is well described but typically underappreciated in clinical practice. We present 2 patients with unexpected responses to rocuronium, despite being otherwise unremarkable. Quantitative neuromuscular monitoring provided clear documentation of the events, providing illustrations of these atypical responses.

We recommend that those who train tomorrow’s providers increase their modeling of many of the attitudes displayed by the authors of The Initiation of Simulation Training at a Large Community Hospital (Article #9 of this issue of Proc Obstet Gynecol). Challenging low-volume, high-risk clinical situations are identified, experienced senior providers are coached using scientifically-informed educational methods with support and resources from leaders in the organization, and an attempt is made to measure progress.

Bradykinin, an endogenous nonapeptide and an important mediator of inflammation, is also implicated in the initiation and maintenance of pain. Both des-Arg⁸, Leu⁸-bradykinin (dALBK) and HOE-140, the prototypic bradykinin B1 and B2 receptor antagonists, respectively, have been shown to reduce pain behaviors and inflammation in animal models of persistent nociception. We studied them for activity against incision-induced pain behaviors in a rat model for postoperative pain. A 1-cm plantar incision was made in the hind paw of halothane-anesthetized rats and closed with 5–0 nylon. Withdrawal responses to punctate and nonpunctate mechanical stimuli were tested with von Frey filaments and a plastic disk attached to a von Frey filament, respectively. Withdrawal latency to radiant heat was also tested. Rats were tested 1 day before the incision, 1 h after the incision, and 0.5, 1, 1.5, and 2.5 h after the injection of the drug. They were then retested at the same times before and after the injection of the drug on each of the first 2 postoperative days. The rats received the saline vehicle dALBK (0.1, 0.3, 1.0, or 3.0 mg/kg) or HOE-140 (0.1, 0.3, 1.0, or 3.0 mg/kg) IV. Another group of rats had the drug injected 1 h before incision and tested as above. Statistical significance (P < 0.05) was determined with Kruskal-Wallis test and a two-way analysis of variance. None of the doses of either dALBK or HOE-140 affected the responses to punctate or blunt mechanical stimulation or heat, either as a pretreatment or as a posttreatment. These data support the unique mechanisms for incision-induced pain relative to inflammation-related pain. Although inflammation may represent a component of incisional pain, the etiology of inflammation and its role seem different than in other models.

Background: Children who are unwell often display signs of circulatory compromise. It has been observed that pronounced changes occur in the appearance of the photoplethysmogram (pulse oximeter tracing) in these children. The aim of the study was to discover if wavelet transforms can identify more subtle changes in the photoplethysmogram of children who are unwell. Methods: Photoplethysmograms were obtained from children attending a paediatric accident and emergency department with clinical features suggestive of significant bacterial illness or circulatory compromise. Photoplethysmograms were also obtained from a control group of well children. Wavelet transforms were applied to the traces in an attempt to separate the two groups. Results: 20 traces were obtained from unwell children and 12 from controls. Analysis of the entropy of the wavelet transform of the photoplethysmogram allows the differentiation of unwell children from controls (p = 0.00002). Conclusions: Wavelet transform of the photoplethysmogram offers the possibility of a rapid non-invasive method of screening children for significant illness.

Although volatile anesthetics result in cerebral arterial dilation, the precise mechanisms underlying this effect are not known. In vitro tension recordings were used to study the vasodilating potencies of halothane and isoflurane in isolated cerebral vessels and to examine the possible role of the endothelium in modulating any effects observed. Cylindrical segments of the rabbit basilar artery and midline ear artery from the same animal were placed in a flow-through bath of 37 degrees C oxygenated (95% O2/5% CO2) physiologic salt solution and stretched to a resting tension of approximately 2,000 dynes. They were then constricted with 3.0 x 10(-2) M K+, 1.0 x 10(-3) M norepinephrine, or 5.0 x 10(-6) M serotonin and exposed to either halothane or isoflurane at concentrations of approximately 0.5, 1.0, 1.5, and 2.0 MAC in varied order for 15 min at each concentration. A 30-min period of perfusion with anesthetic-free, vasoconstrictor-containing perfusate separated successive exposures to an anesthetic. Vessels prepared in this fashion retained their responsiveness to both vasoconstrictors and volatile anesthetics for as long as 4 h. They also relaxed appropriately to acetylcholine, indicating that the endothelium was intact. Concentrations of volatile anesthetic in the tissue perfusate were directly measured using gas chromatography, and the relationship between bath concentrations (expressed as MAC fractions) and the degree of relaxation were determined. The data were analyzed by parallel line regression. Halothane was found to be a significantly more potent vasodilator of the isolated basilar artery than was isoflurane. For example, in K(+)-constricted vessels, the concentration of halothane needed to produce a 50% reduction in tension was 1.32 MAC, compared with 1.66 MAC for isoflurane. Comparable differences were found in the basilar artery in the presence of other constrictors. However, there was no significant difference between the two agents in their effects upon the ear artery. In a separate series of experiments, the endothelium of basilar artery segments was removed by drying. Removal was confirmed by observing a diminished dilator response to acetylcholine. These vessels were subsequently constricted with K+, and relaxation dose-response curves were obtained for both halothane and isoflurane. There were no differences in the dose-response curves for deendothelialized versus intact vessels, with halothane still the more potent relaxant after endothelial removal. These data demonstrate that halothane and isoflurane cause a dose-dependent relaxation of rabbit cerebral vessels, regardless of the vasoconstrictor used. Halothane was a more potent relaxant of the basilar artery when expressed on a MAC-fraction basis.(ABSTRACT TRUNCATED AT 400 WORDS)

On the basis of the premise that the dopaminergic agonist profile of 2-(di-n-propylamino)-5-hydroxy-6-methyltetralin (1a) is due to in vivo oxidation of the 6-methyl moiety and that 1a may represent a novel prodrug strategy, the vicinal methyl-hydroxyl substitution pattern was incorporated into the 6- and 7-positions of 2-(di-n-propylamino)tetralin ti give the 6-methyl-7-hydroxy and 6-hydroxy-7-methyl isomers 8 and 9, respectively. A multistep synthetic approach was devised which permitted preparation of target molecules 8 and 9. Pharmacological data revealed that both target compounds exhibit model dopamine-like effects in the cardioaccelerator nerve assay in the cat, but neither appeared to be metabolically activated as was in the case with 1a. The effects of 9 (but not of 8) were antagonized by pretreatment with haloperidol. Thus, the 5-hydroxy-6-methyl substitution pattern in the 2-aminotetralins remains unique as a dopaminergic agonist prodrug structure.

Prompted by previous findings that a p-dimethoxy substitution pattern on an aromatic ring permits retention of dopaminergic agonist effects in certain ring systems, catechol derivatives of which are potent dopaminergic agonists, an 8,11-dimethoxy substitution pattern was introduced into the aporphine ring in place of the 10,11-dihydroxy moiety in apomorphine. Acid-catalzyed rearrangement of an appropriate morphine derivative provided the aporphine ring system with retention of the stereochemical integrity of the 6a asymmetric center. The hydroxyl group at position 10 was removed by catalytic hydrogenolysis of its phenyltetrazolyl ether. The methyl ether of the resulting 11-hydroxyaporphine was iodinated in high yield at position 8 with trifluoroacetyl hypoiodite. This is the first account of sythesis of an iodinated aporphine derivative. The 8-iodo substituent was replaced with methoxyl by reaction with sodium methoxide and cuprous iodide. Neither the N-methyl target compound 7 nor the N-n-propyl derivative 8 demonstrated dopaminergic nor serotonergic agonism. However, 7 exhibited receptor-binding characteristics and other pharmacological properties suggesting that it may be a 5-HT1A receptor antagonist.