George B. Bikhazi

A comparison of three doses of a commercially prepared oral midazolam syrup in children.

Midazolam is widely used as a preanesthetic medication for children. Prior studies have used extemporaneous formulations to disguise the bitter taste of IV midazolam and to improve patient acceptance, but with unknown bioavailability. In this prospective, randomized, double-blinded study we examined the efficacy, safety, and taste acceptability of three doses (0.25, 0.5, and 1.0 mg/kg, up to a maximum of 20 mg) of commercially prepared Versed® syrup (midazolam HCl) in children stratified by age (6 mo to <2 yr, 2 to <6 yr, and 6 to <16 yr). All children were ASA class I–III scheduled for elective surgery. Subjects were continuously observed and monitored with pulse oximetry. Ninety-five percent of patients accepted the syrup, and 97% demonstrated satisfactory sedation before induction. There was an apparent relationship between dose and onset of sedation and anxiolysis (P < 0.01). Eight-eight percent had satisfactory anxiety ratings at the time of attempted separation from parents, and 86% had satisfactory anxiety ratings at face mask application. The youngest age group recovered earlier than the two older age groups (P < 0.001). There was no relationship between midazolam dose and duration of postanesthesia care unit stay. Before induction, there were no episodes of desaturation, but there were two episodes of nausea and three episodes of emesis. At the time of induction, during anesthesia, and in the postanesthesia care unit, there were several adverse respiratory events. Oral midazolam syrup is effective for producing sedation and anxiolysis at a dose of 0.25 mg/kg, with minimal effects on respiration and oxygen saturation even when administered at doses as large as 1.0 mg/kg (maximum, 20 mg) as the sole sedating medication to healthy children in a supervised clinical setting.

Dose-ranging study in younger adult and elderly patients of ORG 9487, a new, rapid-onset, short-duration muscle relaxant

The purpose of this multicenter, randomized, assessor-blind placebo-controlled study was to determine which of five doses of the new, rapid-onset neuromuscular relaxant, ORG 9487, provided both good to excellent tracheal intubating conditions 60 s after administration and a clinical duration of action <20 min in 120 younger (aged 18-64 yr) and 61 elderly (aged 65-85 yr) adult patients. Anesthesia was induced with fentanyl (2-5 micro g/kg) and thiopental (3-6 mg/kg) and maintained with N2 O/O2 and a propofol infusion (50-300 micro g [centered dot] kg-1 [centered dot] min-1). Neuromuscular train-of-four (TOF) monitoring by electromyography (Datex Relaxograph) commenced immediately after anesthetic induction and was followed, within 30 s, by one of five doses of ORG 9487 (0.5, 1.0, 1.5, 2.0, 2.5 mg/kg) or a placebo. Tracheal intubation was attempted at 60 s and again, in the case of failure, at 90 s. Conditions were assessed with a 4-point scale. Maximum block, clinical duration (time to 25% T1 recovery), and recovery (TOF >or=to 0.7) were measured. Dose-dependent changes were observed in tracheal intubating conditions and neuromuscular block. Good to excellent intubating conditions at 60 s were present in most younger adult (52 of 60) and elderly (26 of 31) patients administered doses >or=to1.5 mg/kg. Mean clinical durations <20 min were observed in adult patients at doses up to 2.0 mg/kg and in geriatric patients up to 1.5 mg/kg. Thus, doses of 1.5-2.0 mg/kg ORG 9487 enabled both rapid tracheal intubation and a short clinical duration of action in adult and elderly patients. (Anesth Analg 1997;84:1011-8)

Mutual potentiation of the neuromuscular effects of antibiotics and relaxants.

The interaction of d-tubocurarine, pancuronium, or succinylcholine with neomycin, streptomycin, or polymyxin B was investigated using a rat phrenic nerve-hemidiaphragm preparation. All neuromuscular blocking agents (relaxants) mutually potentiated the neuromuscular blocking action of one another; combinations of ineffective concentrations of relaxants and antibiotics caused an 82 to 98% neuromuscular block. This extensive potentiation of the neuromuscular effects of relaxants by antibiotics can be attributed to the fact that antibiotics not only have a curare-like stabilizing effect on the post junctional membrane, but also decrease presynaptic acetylcholine release. Neostigmine (0.25 μg/ml) only partially antagonized the neuromuscular block caused by the various drug combinations. In contrast, 4 7mu;g/ml of 4-aminopyridine returned the twitch tension, depressed by combined administration of relaxants and antibiotics, to or above control values except in the case of neuromuscular block caused by the combinations of succinylcholine and polymyxin B.

Potentiation of neuromuscular blocking agents by calcium channel blockers in rats.

The effect of calcium channel blockers (Ca-antagonists) on the potency and reversibility of muscle relaxants (MR) was investigated in the in vitro phrenic nerve-hemidiaphragm and in vivo sciatic nerve-tibialis anterior preparation of rats. To increase the relevance of the experimental findings to the clinical situation, the [Ca++] and [Mg++] in vitro were the same as in the plasma of rats and humans and the stimulation parameters used in vitro and in vivo were similar to those that elicit voluntary movements of the muscles used. Both verapamil and nifedipine significantly decreased the I50 and I90 of d-tubocurarine (d-Tc), pancuronium, vecuronium, and atracurium in vitro and those of the first three MR in vivo (P > 0.001). In vitro, the depression of the force of contraction of the diaphragm (P) caused by all the Ca-antagonist-MR combinations could be reversed only partially by washout, neostigmine, or 4-aminopyridine. In vivo, because of limitations imposed by their cardiovascular depressant effect, the muscles were exposed to lower concentrations of Ca-antagonists for shorter periods. Under these circumstances the decrease of P caused by all Ca-antagonist-MR combinations recovered spontaneously close to control levels. This study indicates that acute administration of verapamil during anesthesia may increase MR potency, but it is unlikely that spontaneous recovery or reversibility of the residual neuromuscular (NM) block at the end of anesthesia will be significantly affected. However, long-term administration of Ca-antagonists may make difficult the reversal of the residual NM block.

Phantom limb pain in young cancer-related amputees: recent experience at St Jude children's research hospital.

Objectives:This study in children and young adults having cancer-related amputation aimed to examine the incidence of phantom limb pain (PLP) in the first year after amputation and also the proportion of patients who had preamputation pain. Methods:A retrospective review of medical records was undertaken. The proportion of patients with PLP was reported. Fisher exact test was used to examine the association between PLP and the presence of preamputation pain and between PLP and age (⩽18 y vs. >18 y). Results:Twenty-six amputations were performed on 25 patients. During the year after amputation, 76% of patients had experienced PLP at some time. After 1 year, though, only 10% still had PLP. Preamputation pain was present in 64% of patients. Although both of our patients with PLP at 1 year were young adults (older than or equal to 18 y) and both had preamputation pain, we found no statistically significant associations between age or the presence of preamputation pain with PLP. Discussion:PLP after cancer-related amputation in children and young adults seems to be common but generally short lived in most patients.

Neuromuscular Drug Interactions of Clinical Importance

The addition of marginally effective concentrations of d-tubocurarine (d-Tc), neomycin, or polymyxin B to the organ bath of rat phrenic nerve-hemidiaphragm preparations significantly (p < 0.05 to 0.001) increased the neuromuscular (NM) blocking effect of lidocaine. When both d-Tc and neomycin or polymyxin B were added the increase of the NM effect of lidocaine was even greater (p < 0.001). Washout re-established NM transmission. The NM block produced by combinations of d-Tc, neomycin, or polymyxin and lidocaine could be reversed partially by Ca2+ or neostigmine, and completely by 4-aminopyridine. The block caused by d-Tc and lidocaine was partially antagonized by neostigmine or 4-aminopyridine. The neomycin-lidocaine or the polymyxin B-lidocaine block, however, was not antagonized by these compounds. The concentrations of d-Tc, antibiotics, and lidocaine that caused significant block in this in vitro preparation may be present at the NM junction of patients, who in the perioperative period had received combinations of therapeutic doses of d-Tc, neomycin, other aminoglycosides, or polymyxin B and lidocaine. This may cause impairment of spontaneous respiration requiring assisted ventilation.

Factors affecting the pharmacokinetic characteristics of rapacuronium.

BACKGROUND Rapacuronium is a new nondepolarizing muscle relaxant with rapid onset and offset. As part of a study to determine its neuromuscular effects, the authors sampled plasma sparsely to determine the influence of age, gender, and other covariates on its pharmacokinetic characteristics. METHODS Of 181 patients receiving a single bolus dose of 0.5-2.5 mg/kg rapacuronium, 43 (aged 24-83 yr) had plasma sampled 3 or 4 times to determine plasma concentrations of rapacuronium and its metabolite, ORG9488. Pharmacokinetic analysis was performed using a population approach (mixed-effects modeling) to determine the influence of demographic characteristics and preoperative laboratory values on the pharmacokinetic parameters. RESULTS Rapacuroniums weight-normalized plasma clearance was 7.03 x (1 - 0.0507 x (HgB - 13)) ml x kg(-1) x min(-1), where HgB is the patients preoperative value for hemoglobin (g/100 ml); however, rapacuroniums blood clearance (11.4+/-1.4 ml x kg(-1) x min(-1), mean +/- SD) did not vary with hemoglobin. Rapacuroniums weight-normalized pharmacokinetic parameters were not influenced by age, gender, or other covariates examined. Plasma concentrations of ORG9488 were typically less than 14% those of rapacuronium during the initial 30 min after rapacuronium administration. CONCLUSIONS In this patient population, neither age nor gender influence elimination of rapacuronium. This finding contrasts to an age-related decrease in plasma clearance observed in a study of 10 healthy volunteers and in a pooled analysis of the pharmacokinetic data from 206 adults in multiple clinical studies. Even if ORG9488 has a potency similar to that of rapacuronium, its plasma concentrations after a single bolus dose of rapacuronium are sufficiently small to contribute minimally to neuromuscular blockade.

The effect of verapamil and EGTA on the rat phrenic nerve-hemidiaphragm preparation.

Relatively high concentrations of verapamil or EGTA [ethylene glycol-bis (β-aminoethyl ether) N, N, N′, N′-tetra acetic acid] inhibit contraction (P) of the rat phrenic nerve--hemidiaphragm preparation elicited by direct or indirect stimulation. The inhibitory effect of verapamil is greater (P < 0.002) with direct (I50 = 26.3 ± 1.7 μM) than indirect (I50 = 37.6 ± 2.9 μM) stimulation. For EGTA the reverse is true: I50 is 1320 ± 80 μM with direct and 1100 ± 60 μM with indirect stimulation. The greater than 90% verapamil-induced depression of P can only be partially reversed by washout. Increasing the [Ca2+] or the addition of 4-aminopyridine (4AP) has insignificant antagonist effect. Except for the antagonism by 4AP during direct stimulation, the EGTA-induced depression of P is better antagonized by washout, increase of the [Ca2+], or the addition of 4AP than that caused by verapamil. Neostigimine did not antagonize the depression of P caused by either verapamil or EGTA. The findings presented indicate that the primary site of action of verapamil is postjunctional and that of EGTA is prejunctional.

Isosulfan blue causes factitious methemoglobinemia in an infant

A 9 month‐old girl was given subcutaneous isosulfan blue to outline lymphatic channels during surgery for thoracic duct ligation. Her pulse oximetry values rapidly declined to a nadir of 85%, 35 min after dye injection. Arterial blood gases revealed methemoglobinemia ([MetHb] = 6.5%). Although abnormal pulse oximetry has already been reported in association with isosulfan blue, methemoglobinemia has not previously been reported. The absorption spectrum for isosulfan blue was determined and when superimposed on that of methemoglobin it was found to have an overlying peak. Interference by the dye was postulated to have caused the abnormal methemoglobin result. The phenomenon was simulated in vitro by adding isosulfan blue to whole blood, and analysing it in the same blood gas analyser as was used for the case, as well as another for comparison. One blood gas analyser reported elevated methemoglobin concentration and the other did not. The samples were sent to a reference laboratory using a chemical method to detect methemoglobin to confirm that the elevated methemoglobin level was spurious.

Near‐fatal acute bronchovenous fistula in a child undergoing radiofrequency ablation of a metastatic lung tumor

SIR—Radiofrequency ablation (RFA) of solid tumors was pioneered in the early 1990s for the treatment of malignant lesions of the lung and liver (1). Serious acute complications have been described as rare (2) and include pneumothorax, bleeding, and air embolism, and are mostly reported in adults (2,3). We wish to report a near-fatal episode of massive hemoptysis and air embolism in a child undergoing RFA of lung metastases. The patient was a 4-year-old male child who had been diagnosed with stage IV metastatic hepatoblastoma 3 years previously. Despite multiple prior surgeries (resection of the left lobe of the liver and three thoracotomies with wedge resections), extensive treatment with chemotherapy and an unrelated donor stem cell transplantation, progression of disease occurred, with new lung metastases noted in the left lung on computed tomography (CT) of the chest (Figure 1a). The patient had an episode of respiratory failure requiring 30 days of mechanical ventilation 3 months previously, and together with a history of extensive previous chest surgery, no further surgery was deemed appropriate to treat the newly discovered metastases in the lungs. The patient’s family remained committed to pursuing curative treatment, so RFA of the lung tumors was offered. Immediately before the RFA procedure, his vital signs were: weight 12.8 kg, BP 91 ⁄ 66 mmHg, HR 80 bÆmin, RR 32, SpO2 99% on room air, and temperature 36.3 C. Physical examination was otherwise normal. His hemoglobin was 9.6 gÆdl, platelets 116 · 10 l, INR 1.0, and electrolytes, BUN, and creatinine were normal. Anesthetic induction consisted of propofol 30 mg, fentanyl 20 lg, and rocuronium 10 mg via a central line. He was intubated with a size 5 uncuffed oral endotracheal tube, and an air leak at 12 cm H2O was noted. Anesthesia was maintained with 2–3% sevoflurane in an oxygen ⁄ air mixture to provide a FiO2 of 30–50% within a circle breathing circuit. After approximately 90 min, RFA of the larger lung nodule had already been completed and the smaller