Direct effects of propofol on myocardial and vascular tissue from mature and immature rats.

OBJECTIVE: To determine the effect of age on the direct myocardial and vascular effects of propofol in rats. DESIGN: Randomized, prospective with repeated measures. SETTING: University research laboratory. PARTICIPANTS: Myocardial and aortic tissue from 12 immature (4-week-old) and 12 mature (16-week-old) male Sprague-Dawley rats. INTERVENTIONS: Change in force of contraction was measured in isolated myocardial strips or in isolated descending thoracic aorta rings during exposure to propofol or intralipid. MEASUREMENTS AND MAIN RESULTS: Propofol produced a dose-dependent decrease in vascular tone (p < 0.05). This effect was similar for intralipid. Propofol was more potent in the younger animals (EC(50), 5.3 microg/mL [confidence interval, 2.5 to 11.1] for 4-week-old and 26.6 microg/mL [confidence interval, 6.8 to 103.7] for 16-week-old rats; p < 0.05). In contrast, propofol produced a dose-dependent decrease in contractility (p = 0.001), whereas intralipid produced no decrease in contractility. CONCLUSIONS: Although propofol does produce a dose-dependent decrease in contractility, this effect is similar at different ages. Propofol produces more direct vascular relaxation in the immature tissue. Propofol's direct cardiovascular effect and its indirect cardiovascular effects should be considered in the young and old, especially when cardiovascular reserve is limited.

Effect of alkalinization of lidocaine on median nerve block.

Median nerve blocks were performed in 10 volunteers in a randomized, double-blind, crossover study to compare the effects of 1% plain lidocaine with 1% lidocaine in sodium bicarbonate 0.1 mmol litre-1. Sensations of hot, cold, pinprick and light touch, compound motor and sensory nerve action potentials, and skin temperature were assessed at 2-min intervals. pH was 6.4 +/- 0.1 for plain lidocaine and 7.7 +/- 0.2 for alkalinized lidocaine (P < 0.001). Alkalinized lidocaine produced more rapid inhibition of compound motor action potentials than plain lidocaine (median 4 (range 2-6) vs 9 (2-14) min) (P = 0.039). Alkalinized lidocaine also produced more rapid onset of inhibition of compound motor than sensory nerve action potentials (4 (2-6) vs 8 (4-12) min) (P = 0.0039). There was no significant difference in any other sensory modality between alkalinized and plain lidocaine. These data suggest that addition of bicarbonate to lidocaine for median nerve block significantly increased the rate of motor block without changing the onset or extent of sensory block.

Vasodilatory actions of the dietary peptide carnosine.

The objective of this study was to test the hypothesis that the dietary dipeptide carnosine (beta-alanine-L-histidine) causes direct decreases in arterial tone. Isolated descending thoracic aortic rings from male Sprague-Dawley rats were used for all studies. Preconstriction of vessels was accomplished with phenylephrine. Carnosine (0.625-20 mM) produced dose-dependent vascular relaxation (P < 0.05) that was independent of endothelium. The constituent amino acid L-histidine did not produce any significant relaxation over the same dose range, whereas beta-alanine actually produced dose-dependent vasoconstriction (P < 0.05). The soluble guanylate cyclase inhibitor methylene blue (10(-5) M) significantly decreased the relaxation produced by carnosine (P < 0.05). Measurement of cyclic GMP in the presence and absence of methylene blue after carnosine and phenylephrine exposure was also done. Methylene blue 10(-5) M resulted in a decrease in cyclic GMP levels from 65.3 +/- 15.6 fmol/mg protein to 8.6 +/- 0.9 fmol/mg of protein (P = 0.001). We conclude that carnosine produces relaxation of isolated rat aorta independent of endothelium. The effect of carnosine is at least in part mediated via cyclic GMP production and is not reproduced by its constituent amino acids, L-histidine and beta-alanine.

Hemifacial microsomia: anatomical prediction of difficult intubation.

Hemifacial microsomia (HFM) is associated with a difficult airway. We hypothesized that a difficult intubation would be predicted by radiographic evaluation of the severity of mandibular hypoplasia. A retrospective review of anaesthetic and surgical records of 102 children with HFM from 1986 to 1996 was conducted for radiographic classification of mandibular hypoplasia and degree of difficulty with intubation. Intubation was classified as Grade A-easy, Grade B-difficult, or Grade C-very difficult. The mandibular anatomy was categorized as Type I-'mini-mandible', Type II-abnormal condylar size and shape, or Type III-absent ramus, condyle, and temporomandibular joint. In the 82 patients with HFM, 70% were classified as Grade A, 21% had Grade B and 9% had Grade C airways. No patients with Type I mandible had Grade C airway, while 25% of the patients with Type III mandible had Grade C airway. The correlation of the degree of airway difficulty with mandibular type was significant (P=0.001). In 20 patients with bilateral mandibular hypoplasia, 30% had Grade A, 35% had Grade B, and 35% had Grade C airways. We conclude that radiographic classification of mandibular deformity is a useful adjunct for preoperative prediction of airway difficulty in the management of children with unilateral HFM.

Effects of cardiopulmonary bypass and deep hypothermic circulatory arrest on the thyroid axis during and after repair of congenital heart defects: preservation by deep hypothermia?

UNLABELLED: Thyroid function is altered by cardiopulmonary bypass (CPB) in children. To better understand the cause of altered thyroid hormone levels, we compared the effects on the pituitary-thyroid axis of CPB in 23 children undergoing elective repair of congenital heart defects. Twelve patients underwent CPB with moderate hypothermia without a period of deep hypothermic circulatory arrest (DHCA), and eleven underwent CPB with DHCA. Nine blood samples were collected from each patient before, during, and after CPB. Free T3 (FT3), free T4 (FT4), total T3 (TT3), total T4 (TT4), thyrotropin (TSH), and albumin were measured; concentrations of each decreased significantly with the onset of CPB (P < 0.05). There was a greater decline in hormone than in albumin concentrations, which suggests that factors in addition to hemodilution were present (P < 0.05). TSH concentrations in the DHCA group began to increase during cooling, exceeding baseline values after rewarming and after separation from CPB. Patients undergoing CPB without DHCA had persistently low TSH concentrations (P < 0.05). By Postoperative Days 1 and 2, TSH concentrations in both groups were similar and significantly lower than baseline values (P < 0.001). FT3, FT4, TT3, TT4, and albumin all increased during CPB after an initial decrease. Of these, only albumin and FT4 recovered to their baseline values after the initial decrease. Nevertheless, by Postoperative Day 1, both groups demonstrated the "sick" euthyroid syndrome and could not be distinguished from one another. This study demonstrates greater pituitary release of TSH in children undergoing repair of congenital heart defects with DHCA compared with CPB alone, the cause of which could not be determined in this study. However, despite the increase in TSH in the DHCA group, the thyroid hormone concentrations failed to increase appropriately. IMPLICATIONS: Early after deep hypothermia circulatory arrest, thyrotopin concentrations increase appropriately, responding to decreased concentrations of T3; however, all children undergoing cardiopulmonary bypass eventually develop a "sick" euthyroid syndrome by Postoperative Day 1. Whether this difference represents better protection of neuroendocrine function by deep hypothermic circulatory arrest (relative to cardiopulmonary bypass alone) remains speculative.

The response of patients with Duchenne's muscular dystrophy to neuromuscular blockade with vecuronium.

BACKGROUND: The authors hypothesized that patients with Duchenne's muscular dystrophy (DMD) are more sensitive to nondepolarizing muscle relaxants. METHODS: Eight children with DMD and eight healthy children having orthopedic procedures were studied. Anesthesia consisted of thiopental, 60% nitrous oxide in 40% oxygen, and intravenous fentanyl and midazolam. Using electromyography, the ulnar nerve was stimulated and the electromyographic train-of-four ratio (TOFr) of the first dorsal interosseous muscle was recorded every 60 s. After baseline TOFr recording, all patients received 50 microg/kg vecuronium and the TOFr at 3 min was compared. Vecuronium (10 microg/kg) was then administered every minute until TOFr was < or =0.1. The TOFr was followed until TOFr was > or =0.01. Then 10 microg/kg of vecuronium were administered to maintain TOFr < or = 0.1. At the conclusion of the procedure, TOFr was allowed to recover to 0.25, and then neostigmine and glycopyrrolate were administered. Data are presented as medians and ranges. RESULTS: The initial dose of vecuronium resulted in greater TOFr depression in patients with DMD than in controls (0.14 vs. 0.86). Less vecuronium was needed to produce TOFr < or = 0.1 in the patients with DMD than in the control patients (55 microg/kg vs. 95 microg/kg). Recovery time for the TOFr to > or =0.1 after the initial dose was longer in the patients with DMD than in the controls (28 vs. 20 min; P = 0.03), and the maintenance dose of vecuronium was less in patients with DMD (0.6 vs. 1.3 microg x kg[-1] min[-1]; P < 0.01). The time for TOFr recovery from 0.1 to 0.25 was 36 min in the patients with DMD and 6 min in the controls (P < 0.01). After neostigmine, the TOFr was 1.0 in the controls and 0.91 (P = 0.03) in the patients with DMD. CONCLUSION: There is increased sensitivity to vecuronium from neuromuscular blockade in patients with DMD.

Differential onset of median nerve block: randomized, double-blind comparison of mepivacaine and bupivacaine in healthy volunteers.

We have compared the delay in onset of 1% mepivacaine and 0.33% bupivacaine in different nerve fibre types in 10 volunteers undergoing median nerve blocks, in a randomized, double-blind, crossover study. Hot, cold, pinprick and light touch sensations, compound motor action potentials (CMAP), sensory nerve action potentials (SNAP) and skin temperature were recorded at 2-min intervals. Hot, cold, pinprick, light touch sensations, SNAP and CMAP were significantly inhibited, and skin temperature was significantly increased after administration of both agents. The first noticeable reduction in cold sensation was detected later after bupivacaine compared with mepivacaine, but after a delay similar to that of other nerve functions. Bupivacaine and mepivacaine inhibited SNAP and CMAP with a similar time delay to steady-state. Bupivacaine produced steady-state inhibition of hot and cold sensations significantly later than mepivacaine; nevertheless, the sequence that sensory modalities failed, with few exceptions, and the extent of anaesthesia at 40 min were similar for both agents. Our technique provides a novel, multi-modal method of comparing local anaesthetics and related agents over time.

Unexpected interaction of methylphenidate (Ritalin) with anaesthetic agents.

We report difficulty with conscious sedation of a child taking methylphenidate for attention deficit disorder and possible delayed adverse interaction of ketamine and methylphenidate resulting in severe nausea, vomiting and dehydration. The effects of methylphenidate and its potential interactions with anaesthetic agents is discussed. We suggest that anaesthesiologists who provide sedation or anaesthesia to patients receiving methylphenidate be aware of the potential need for high sedative doses and the possibility of undesirable interactions.

Triiodothyronine increases contractility independent of beta-adrenergic receptors or stimulation of cyclic-3',5'-adenosine monophosphate.

BACKGROUND: Triiodothyronine regulates cardiac contractility; however, the mechanisms by which it produces its acute contractile effects remains unknown. We compared the acute effects of thyroid hormones (triiodothyronine [T3] and thyroxine [T4]) and of isoproterenol on the contractility of isolated rat hearts. In addition, we sought to determine whether the acute inotropic effects of thyroid hormones were mediated by beta-adrenergic receptors or by increased production of cyclic-3',5'-adenosine monophosphate (cAMP). METHODS: A Langendorff heart preparation harvested from euthyroid male Sprague-Dawley rats was used. Drugs were administered through an aortic perfusion catheter. A pressure-transduced left-ventricular balloon catheter measured pressure and heart rate changes. Changes in the maximum positive rate of change in pressure (dP/dT) and maximum negative dP/dT were determined. Responses to varying doses of T3, T4, and isoproterenol were assessed in the presence and absence of beta-adrenergic receptor blockade with propranolol. cAMP production, measured by radioimmunoassay, was determined in myocardial cell suspensions after incubation with T3 or isoproterenol. RESULTS: T3 0.74 nmol rapidly and significantly increased maximum dP/dT by 335 +/- 38 mmHg/s within 30 s after bolus injection; however, contractility was unchanged after as much as 12.9 nmol T4. The maximal increase in dP/dT after 0.8 nmol isoproterenol was comparable to that produced by T3. However, the cardiotonic actions of isoproterenol were significantly slower to develop (peaking at 60 vs. 15 s) and lasted longer than those of T3. Pretreatment with propranolol 1 mumol diminished the contractile effects of isoproterenol but had no effect on those of T3. Concentrations of isoproterenol that increase contractility also significantly increased cAMP production in isolated rat myocardial cells. However, T3 failed to increase cAMP production. CONCLUSIONS: These results demonstrate that the acute inotropic effects of T3 are not shared by T4 and appear unrelated to beta-adrenergic receptor mechanisms or to generation of cAMP. Thus, T3 acutely stimulates cardiac contraction by mechanisms that differ from those of the more commonly used beta-adrenergic receptor agonists and phosphodiesterase inhibitors. Further studies are needed to identify the mechanisms underlying the acute contractile effects of T3 and to determine whether T3 will prove useful for increasing ventricular function in patients.

Phenobarbital-dependent proliferation of putative initiated rat hepatocytes.

The mitogenic effects of phenobarbital (PB) were examined using cultures of putative initiated hepatocytes that proliferate and form colonies under conditions in which normal hepatocytes senesce and die. The frequencies of colony-forming hepatocytes in primary cultures isolated 2 weeks after initiation with methyl(acetoxymethyl)nitrosamine or benzo[a]pyrene-7,8-diol-9,10-epoxide(anti) were in the range of 2-38 per million in the presence of PB. Colony-formation frequencies were 0.1 per million in the absence of PB. Proliferative hepatocyte colonies were not observed in cultures grown in serum-free medium containing PB, epidermal growth factor, nor-epinephrine and insulin. The requirement for PB was characterized further using secondary cultures of hepatocytes that had been isolated from a liver 5 weeks after initiation. The colony-forming efficiency of these hepatocytes was about 10% in the presence of 2 mM PB and less than 0.2% in its absence. Colony formation displayed a linear response to concentrations of PB in the range of 0.5-2 mM and a decline above the optimal 2 mM concentration. Autoradiography was used to determine the percentages of hepatocytes in secondary cultures that synthesized DNA in the presence or absence of PB. By the third day after seeding as single cells, hepatocytes exhibited a labeling index of about 50% and this level of labeling was preserved for up to 2 weeks after seeding. Very few hepatocytes were found to synthesize DNA in the absence of PB and most senesced. A small fraction of the colony-forming hepatocytes continued to proliferate in the absence of PB and formed colonies with a high labeling index. These results suggest that the proliferation of initiated hepatocytes in vivo may be conditional upon the presence of the hepatic tumor promoter, PB.

Mechanisms of cytotoxicity of asbestos fibres in rat tracheal epithelial cells in culture.

Little is known about the mechanism(s) of asbestos toxicity, especially in respiratory epithelium. Studies were carried out to elucidate some important aspects of the cytotoxic effects of asbestos, using a tracheal epithelial cell line in culture. Chrysotile and crocidolite asbestos with similar aspect ratios were used. Both induced in 2C5 cells a concentration-dependent inhibition of colony-forming ability, a measure of proliferative capacity. In this respect, chrysotile (LC(50), 0.95 mug/cm(2)) was about six times more toxic than crocidolite (LC(50), 5.8 mug/cm(2)). Both types of asbestos caused only minor changes in membrane permeability, measured by trypan blue exclusion and by [(75)Se]selenomethionine release, even at concentrations of asbestos that caused > 90% inhibition in colony formation. Thus membrane damage was only a minor component of the toxicity produced by the fibres. Chrysotile was phagocytized much more readily than crocidolite and produced an approximately threefold greater increase in binucleated cells and micronuclei than crocidolite, suggesting that phagocytosis was the rate-limiting step in fibre toxicity. Our studies suggest a potentially important pathway of fibre toxicity involving binding, phagocytosis, nuclear damage, disruption of mitosis, inhibition of proliferation and/or cell death. In this process, the fibre aspect ratio is not the only determinant of fibre toxicity, since chrysotile and crocidolite fibres of similar length and diameter exhibit very different degrees of toxicity. It appears that other fibre characteristics, such as fibre surface charge, are of equal importance.

[Changes in the retina accompanying the Osler syndrome (author's transl)]. / Netzhautveränderungen beim Osler Syndrom.

A histological examination was carried out on the eye of an eleven-year-old patient who, like his brother, was suffering from the lung variety of the Osler syndrome. The examination showed rubeosis of the iris accompanied by secondary glaucoma. One striking feature was extensive proliferous retinopathy presumably caused by chronic lack of oxygen in the arterial blood.

Central retinal vein occlusion in a patient with familial antithrombin III deficiency: case report.

A 60-year old man with familial antithrombin III deficiency, a primary cause of hypercoagulation, developed central retinal vein occlusion. Familial antithrombin III deficiency is inherited as an autosomal dominant condition. It is characterized by recurrent episodes of thromboembolism. The occurrence of central retinal vein occlusion in a person with familial deficiency of antithrombin III suggests the possibility of a casual relationship.