Is distal chronic thromboembolic pulmonary hypertension treatable with PAH targeted drugs?

Chronic thromboembolic pulmonary hypertension (CTEPH) is a life-threatening condition that historically has a poor outcome with supportive medical treatment. Pulmonary endarterectomy (PEA) is the treatment of choice and offers the only chance of cure. A significant proportion of patients is either not suitable due to the distal distribution of the disease or has persistent pulmonary hypertension (PH) after PEA. Despite the lack of licensed therapies for CTEPH, the similarities in pathobiology of pulmonary arterial hypertension (PAH) and CTEPH has led to the compassionate use of PAH therapies in CTEPH patients. This article reviews the pathobiology of CTEPH and summaries the available evidence for the use of PAH-targeted drugs in CTEPH.

Global analysis of the haematopoietic and endothelial transcriptome during zebrafish development.

In this paper, we use zebrafish embryos to characterise the transcriptome of the developing blood and endothelium, two cell types that are closely associated during development. High-throughput sequencing identified 754 genes whose transcripts are enriched threefold or more in blood and/or vascular endothelial cells compared with the rest of the embryo at 26-28 h post fertilisation. Of these genes, 388 were classified as novel to these cell types after cross-reference with PubMed and the zebrafish information network (ZFIN). Analysis by quantitative PCR and in situ hybridisation showed that 83% (n=41) of these novel genes are expressed in blood or vascular endothelium. Of 10 novel genes selected for knockdown by antisense morpholino oligonucleotides, we confirmed that two, tmem88a and trim2a, are required for primitive erythropoiesis and myelopoiesis. Our results provide a catalogue of genes whose expression is enriched in the developing blood and endothelium in zebrafish, many of which will be required for the development of those cell types, both in fish and in mammals.

Varying the temperature of the liquid used for high-pressure processing of prerigor pork: effects on fresh pork quality, myofibrillar protein solubility, and frankfurter textural properties.

UNLABELLED: The objective was to evaluate high-pressure processing (HPP) with varying liquid (water) temperatures on pork quality and textural properties of frankfurters. HPP pressurization liquid temperatures were 15.5 °C (HPP Low) and 29.4 °C (HPP Med). Analyses were conducted using paired boneless loins and paired boneless hams. Loins were evaluated for pH, purge loss, objective color, subjective color, firmness; and changes in color after a bloom period. Eight independent batches (2 batches each of HPP Low, paired untreated, HPP Med, and paired untreated) of frankfurters were manufactured from the outside portion of the ham and the knuckle. Both HPP treatments resulted in higher (P < 0.05) ultimate pH and less (P < 0.05) purge loss of the loin. Loin tenderness was not different among either HPP treatment temperature groups when compared to untreated controls except HPP Med chops were more tender (P = 0.02) than untreated controls. Salt-soluble protein extractability of inside ham muscles was lower (P < 0.05) for both HPP treatment levels when compared to untreated controls, but was not different between the 2 HPP treatment levels. Textural properties of frankfurters were not different for either HPP treatment group when compared to its respective untreated control for any parameter except springiness. HPP Low frankfurters had lower (P = 0.10) springiness values than untreated controls. Fracturability of HPP Med samples was lower (P = 0.12) than untreated controls. Overall, HPP caused higher ultimate pH and increased water-holding capacity, but did not affect tenderness of fresh meat or textural properties of frankfurters. PRACTICAL APPLICATION: HPP can be used on prerigor pork as means to improve fresh pork quality. Loins from HPP-treated pork sides had higher ultimate pH values and less package purge loss. Tenderness values were not affected positively or negatively by HPP treatment. The high pH and water-holding capabilities of treated samples have positive implications for further processing applications. Frankfurter textural properties suggest emulsified products can be made with pressurized pork without sacrifice to the textural profile.

The effects of high pressure processing on pork quality, palatability, and further processed products.

The objective was to evaluate high pressure processing (HPP) on postmortem metabolism and pork quality. Six pigs were randomly selected immediately after slaughter. After splitting, one side was randomly designated for HPP of 215 MPa for 15 s with water temperature at 33 °C and the other side (non-pressure treated) served as the control. Chilled sides were fabricated into loins, boneless picnic, boneless Boston butt, and ham. Samples were cut from the loin, inside portion of the ham and cushion (M. triceps brachii). Pork quality, lipid oxidation, connective tissue solubility, protein functionality, sensory analysis, and processed characteristics of restructured hams were evaluated. HPP partially inhibits postmortem metabolism, indicated by lower muscle lactate levels and higher ultimate pH values. Cook and drip loss were both reduced in HPP treated muscles compared to controls. HPP treated sides were more tender than controls. Collagen content was not different between HPP and control groups.

Intersegmental vessel formation in zebrafish: requirement for VEGF but not BMP signalling revealed by selective and non-selective BMP antagonists.

BACKGROUND AND PURPOSE: Bone morphogenetic proteins (BMPs) were first identified through their role in inducing bone and cartilage formation, but many other important functions have since been ascribed to BMPs, including dorsoventral patterning, angiogenesis and tissue homeostasis. Using dorsomorphin and LDN193189, selective small molecule inhibitors of BMP signalling, we investigated the role of BMP signalling in early vascular patterning in zebrafish. EXPERIMENTAL APPROACH: The effects of dorsomorphin and LDN193189 on vascular endothelial growth factor-a (VEGF) and BMP signalling in developing zebrafish and in human pulmonary artery endothelial cells were determined using confocal microscopy, Western blotting and quantitative PCR. KEY RESULTS: We showed that dorsomorphin, similar to the VEGF inhibitor SU5416, strongly inhibits intersegmental vessel formation in zebrafish and that this is due to inhibition of VEGF activation of VEGF receptor 2 (VEGFR2), leading to reduced VEGF-induced phospho-ERK (extracellular regulated kinase) 1/2 and VEGF target gene transcription. These effects occurred at concentrations of dorsomorphin that block BMP signalling. We also showed that LDN193189, an analogue of dorsomorphin, more potently blocks BMP signalling but has no effect on VEGF signalling in zebrafish and does not disrupt early vascular patterning. CONCLUSIONS AND IMPLICATIONS: Dorsomorphin inhibits both BMP and VEGF signalling, whereas LDN193189 is a more selective BMP antagonist. Results obtained in cardiovascular studies using dorsomorphin need to be interpreted with caution, and use of LDN193189 would be preferable due to its selectivity. Our data also suggest that BMP signalling is dispensable for early patterning of intersegmental vessels in zebrafish.

The effects of feeding diets containing corn distillers dried grains with solubles, and withdrawal period of distillers dried grains with solubles, on growth performance and pork quality in grower-finisher pigs.

A study was conducted to determine the quantitative effects of feeding amount and withdrawal period of corn distillers dried grains with solubles (DDGS) from the diet on growth performance, carcass quality, and pork fat fatty acid profile. A total of 432 pigs (29.8 +/- 0.2 kg of BW) were randomly allotted to 1 of 9 dietary treatments in a completely randomized arrangement. The 9 treatments were the control (D0), D15-0 wk, D15-3 wk, D15-6 wk, D15-9 wk, D30-0 wk, D30-3 wk, D30-6 wk, and D30-9 wk, where D0, D15, and D30 indicate the dietary content of DDGS (0, 15, and 30%, respectively) and 0 wk, 3 wk, 6 wk, and 9 wk indicate the withdrawal period of DDGS from the diets before slaughter (0, 3, 6, and 9 wk, respectively). A dietary DDGS inclusion rate of 15 or 30%, without or with a withdrawal period, had no effect (P = 0.76) on ADG, ADFI, and G:F, except for a slight reduction (0.87 vs. 0.92 kg/d; P < 0.05) in ADG when pigs received the D30-0 wk treatment compared with the D0 treatment. Carcass quality, LM quality, and Japanese fat color scores for backfat and belly fat were not affected by dietary DDGS content (backfat, P = 0.47; belly fat, P = 0.17) or withdrawal period (backfat, P = 0.33; belly fat, P = 0.95). Compared with pigs fed the D0 diet, a smaller belly firmness score was observed (P = 0.04) in pigs that received the D30-0 wk treatment, but belly firmness in pigs fed the other treatments was not different (P = 0.26) from that of pigs fed the D0 diet. Linoleic acid content (C18:2; P < 0.001) and iodine value (IV; P < 0.001) of belly fat increased with increasing dietary DDGS content. Withdrawal of DDGS from the diet for 0 to 9 wk before slaughter resulted in a linear reduction in C18:2 content and the IV of belly fat in pigs fed the D15 diets (C18:2 content: 14.6, 13.3, 12.6, and 10.9%; P = 0.001; IV: 67.3, 64.4, 64.1, and 62.7; P = 0.02; for 0-, 3-, 6-, and 9-wk withdrawal, respectively) and the D30 diets (C18:2 content: 17.3, 16.1, 14.2, and 12.4%; P < 0.001; IV: 71.2, 68.2, 64.5, and 62.7; P < 0.001; for 0-, 3-, 6-, and 9-wk withdrawal, respectively). These results indicate that an inclusion rate of DDGS up to 30% in grower-finisher diets has minor effects on growth performance and that the desired effect of reducing the C18:2 content and IV of pork fat could be elicited in as little as 3 wk after withdrawing DDGS from the diet before slaughter.

Effects of feeding diets containing increasing content of corn distillers dried grains with solubles to grower-finisher pigs on growth performance, carcass composition, and pork fat quality.

Crossbred pigs (n = 512) with an average initial BW of 22.1 +/- 0.54 kg were used to evaluate growth performance, carcass characteristics, and pork fat quality of grower-finisher pigs fed corn-soybean meal diets containing increasing content of distillers dried grains with solubles (DDGS). One of 4 dietary treatments was randomly assigned to each pen within sex. Dietary treatment and sex were the main factors in a 3-phase feeding program (BW = 22 to 53 kg, 53 to 85 kg, and 85 to 115 kg). Dietary treatments consisted of a corn-soybean meal control, or a corn-soybean meal diet containing 10, 20, or 30% DDGS. Overall, increasing the dietary DDGS content had no effect on ADG (P = 0.74), but ADFI was linearly reduced and G:F was linearly increased (P < 0.01). Dressing percentage, LM marbling and firmness, and belly firmness were linearly reduced (P < 0.01), but percentage of fat-free lean was linearly increased (P < 0.05) with increasing dietary DDGS. Subjective LM color score (P = 0.65), drip loss (P = 0.37), and ultimate pH of LM (P = 0.21) were not influenced by dietary DDGS. Japanese color scores for backfat (P = 0.41) and belly fat (P = 0.85) were similar among dietary treatments (P = 0.41). Feeding an increasing content of DDGS linearly increased (P < 0.05) PUFA concentration, particularly linoleic acid (C18:2), in belly fat, backfat, and LM intramuscular fat, but the increase in LM intramuscular fat was smaller in magnitude (P < 0.05) than in backfat and belly fat. Pigs fed an increasing content of DDGS had a linear increase (P < 0.05) in the iodine value of backfat, belly fat, and LM intramuscular fat of 58.4 to 72.4, 61.5 to 72.3, and 54.8 to 57.7, respectively. Oxidation of LM intramuscular fat measured on d 0, 14, 21, and 28 of storage was not affected by dietary treatment. Taste tests for LM showed no effects of diet on flavor, off-flavor (P = 0.36), tenderness (P = 0.66), juiciness (P = 0.58), and overall acceptability (P = 0.52) scores. Similarly, bacon flavor (P = 0.88), off-flavor, crispiness, and overall liking scores were not affected by increasing dietary DDGS, but bacon fattiness (P < 0.01) and tenderness (P < 0.05) scores were linearly reduced. These results showed no negative effects on growth performance or dressing percentage when growing-finishing pigs were fed diets containing up to 30% DDGS, but fat quality may not meet the standards of all pork processors when feeding diets containing more than 20% DDGS.

Vitamin-mineral supplementation and accelerated chilling effects on quality of pork from pigs that are monomutant or noncarriers of the halothane gene.

We examined the effects of vitamin and mineral supplementation of the finishing diet on growth and accelerated chilling of carcasses on carcass and muscle traits of halothane gene carrier and noncarrier pigs. Barrows and gilts that were either monomutants (MON, n = 49) or noncarriers (NON, n = 28) of the halothane gene were fed a standard finishing diet until they reached 86 kg. They then were randomly assigned to one of four finishing diets formulated to contain 11 IU/kg vitamin E (0), 311 IU/kg vitamin E plus additional vitamins and minerals (300), 611 IU/kg vitamin E plus additional vitamins and minerals (600), or 911 IU/kg vitamin E plus additional vitamins and minerals (900) until they were slaughtered (118 kg). Alternating carcass sides were assigned either a normal chilling procedure (NC, 4 degrees C for 24 h) or an accelerated chilling procedure (AC, -20 degrees C for 1.5 h and then 4 degrees C for 22.5 h). Supplementing vitamin E in the finishing diet increased (P < 0.05) the concentration of vitamin E in the longissimus muscle. Supplementing vitamin E in the diets of MON pigs did not affect color, firmness, or cooking losses of loins or color and firmness of hams. For the NON genotype, increasing the level of vitamin E in the diet decreased (P < 0.05) the percentage of PSE loins and hams. Color and firmness scores of the gluteus medius and longissimus muscles were improved 0.4 unit (P < 0.005) by AC compared with NC of carcasses. Loin chop juiciness and flavor were improved (P < 0.05) in the MON genotype for AC compared to NC. Accelerated chilling reduced (P < 0.05) the percentage of PSE loins from 38 to 17% and PSE hams from 32 to 10% for the MON genotype, but percentage of PSE was not affected (P > 0.05) by chilling treatment for the NON genotype. No interaction between diet and chill treatments existed for muscle quality traits (P > 0.05). Supplementing finishing diets of NON pigs with at least 600 IU/kg vitamin E, in addition to other vitamins and minerals, or accelerated chilling of MON carcasses can reduce the incidence of PSE pork.

A two-center study evaluating the hemodynamic and pharmacodynamic effects of cisatracurium and vecuronium in patients undergoing coronary artery bypass surgery.

OBJECTIVE: To determine the hemodynamic and pharmacodynamic effects of rapid bolus administration of cisatracurium compared with vecuronium. DESIGN: A randomized, prospective, double-blind study. SETTING: Tertiary-care university hospitals. PARTICIPANTS: Seventy-nine adult patients with diagnosed coronary artery disease (CAD). INTERVENTION: Elective coronary artery bypass graft surgery (CABG). MEASUREMENTS AND MAIN RESULTS: Patients were randomly divided into four groups. Patients received a rapid bolus of two or four times the 95% peak depression of twitch (ED95) of either cisatracurium (groups 1 and 2) or vecuronium (groups 3 and 4). Three minutes after a midazolam induction, all patients received a rapid bolus administration of either study drug. Maintenance of anesthesia was with a standardized propofol-sufentanil-oxygen anesthetic. Patients were monitored with radial and pulmonary artery catheters and electromyography. End points of the study were hemodynamic stability at induction, after bolus administration of study drugs, and after intubation; the quality of intubating conditions; drug interventions to correct hemodynamic instability; the onset, duration, and recovery of neuromuscular function; and drug cost. Mean arterial pressure (MAP) and heart rate (HR) decreased in a similar proportion in all four groups after induction while, following study drug administration, MAP and HR did not change significantly. Both cisatracurium groups required more boluses to maintain neuromuscular block, but spontaneous recovery rates were faster. Both agents, but cisatracurium to a lesser degree, showed increased duration with repeated maintenance doses. Both agents afforded good to excellent intubating conditions, but the cost of cisatracurium was significantly less. CONCLUSION: The authors conclude there is no evidence of a hemodynamic difference between the two neuromuscular blocking drugs (NMBDs). There are some clinical and cost advantages in favor of cisatracurium.

Effect of ractopamine on growth performance, carcass composition, and cutting yields of pigs slaughtered at 107 and 125 kilograms.

At approximately 68 kg live weight, crossbred barrows and gilts (n = 144) were allocated to be fed to one of two weight end points (107 kg and 125 kg). Pigs from each weight group were treated with Ractopamine (RAC) (0, 10, or 20 ppm; n = 24/ treatment for the last 40 kg of gain. Feed consumption and weight gain were measured. Pigs were slaughtered and carcass measurements made at 24 h postmortem. Carcasses were fabricated into wholesale, trimmed wholesale, and boneless wholesale cuts for cutting yields. Hams were separated into muscle, fat, and bone. The RAC improved growth characteristics and carcass characteristics. Pigs fed RAC had increased (P < .01) average daily gain and improved (P < .01) feed:gain ratio over controls in each weight group. Carcasses from pigs treated with RAC had larger (P < .01) longissimus muscle area and reduced (P < .01) fat at the 10th rib. Cuts from 125-kg pigs were generally heavier than those from 107-kg pigs. The RAC increased (P < .05) the boneless cut weights of both weight groups. Percentage of dissected lean from the hams of RAC-treated pigs was (P < .05) higher than that of controls. Few consistent differences were observed between the 10 and 20 ppm of RAC treatments. Results from this study indicate that RAC had positive effects on the growth characteristics, carcass characteristics, and carcass cutting yields of pigs representative of the broad spectrum of market weights.

Growth and fresh meat quality characteristics of pigs supplemented with vitamin E.

Crossbred pigs (n = 30) were fed to determine the influence of supplementation with vitamin E on growth and slaughter characteristics of swine and on the quality characteristics of fresh pork. Pigs received either a control diet containing no vitamin E (CON) or a diet formulated to contain 100 mg of vitamin E/kg feed (VITE). During 84 d of feeding, feed intake and weight gain were measured every 2 wk. After the feeding period, pigs were slaughtered and the loin from the left side of each carcass was removed 4 d after death. Alpha-Tocopherol concentration and proximate composition of the longissimus muscle were determined. Loins were sliced into 10-cm sections and stored under vacuum (2 degrees C) for 0, 14, 28, and 56 d. After storage, loins were sliced into 2.54-cm chops, wrapped in polyvinyl chloride film and stored in a retail case (2 to 4 degrees C) for 5 d. Thiobarbituric acid (TBA) values, Hunter L, a, and b values, total plate counts, pH, purge loss, drip loss, cook loss, taste panel characteristics, and visual panel characteristics were evaluated. Growth traits, slaughter characteristics, and proximate composition did not differ (P > .05) between dietary treatment groups. Alpha-Tocopherol concentrations were greater (P < .05) and TBA values during extended retail display were less (P < .05) for VITE chops than for CON chops. Overall palatability ratings were more desirable (P < .05, at 14 d of vacuum storage) for VITE chops than for CON chops. Color measurements, sensory characteristics, total plate counts, pH, purge loss, drip loss, and cook loss were not influenced (P > .05) by vitamin E supplementation. These results indicated that at the tissue alpha-tocopherol concentrations of the present study, vitamin E supplementation of the growing-finishing diet of hogs reduced lipid oxidation in fresh pork but did not influence pork color or tissue drip loss.

Effects of diet containing extruded full-fat soybeans or butter on the growth, composition, and sensory characteristics of pork.

Ninety-six crossbred barrows were randomly allotted to five replications of four treatments to determine the effects of diets containing 20% extruded full-fat soybeans (FFS) or 4% butter (B) on the growth, composition, and sensory characteristics of finishing pigs. Pigs were housed five per pen, except for one replication that had four pigs per pen, in environmentally regulated barns. Pigs were given ad libitum access to a corn-soybean meal diet for 11 wk (control); a corn-extruded soybeans and soft wheat midds diet for 11 wk (FFS-11); a corn-soybean meal diet for 6 wk, changed to a corn-extruded soybeans and soft wheat midds diet for 5 wk (FFS-5); or a corn-soybean meal diet for 6 wk, changed to a corn-soybean meal, soft wheat midds, and 4% butter diet for 5 wk (B). Feed intake and weight gain were measured once every 2 wk. Pigs were slaughtered and carcass data were collected. Sensory characteristics (tenderness, juiciness, pork flavor intensity, off-flavor intensity, and overall acceptability), shear force, moisture, and fat content were determined for the longissimus muscle. Sensory characteristics (pork flavor, off-flavor, rubbery, cohesiveness, and juiciness) and 2- thiobarbituric acid values were determined for ground pork (30% fat) after 1, 4, and 7 d for control, FFS-11, and B treatments. No differences (P > .05) in ADG were observed between diets. Feed efficiency of the FFS-11 group was better (P < .05) than that of the control or B groups. No consistent differences were observed for carcass, sensory, or shear-force characteristics of the longissimus muscle or ground pork.(ABSTRACT TRUNCATED AT 250 WORDS)

Pneumocephalus following attempted epidural anaesthesia.

This report describes iatrogenic pneumocephalus in an obstetrical patient following attempted epidural anaesthesia using the loss of resistance technique. On the fourth attempt at epidural injection, an apparent loss of resistance was identified and 5 ml air was injected. The patient complained immediately of severe bifrontal headache followed by emesis. The baby was eventually delivered by Caesarean section, with general anaesthesia and avoiding nitrous oxide. The patient's headache resolved within 24 hr without further sequelae.

Atracurium, vecuronium, and pancuronium do not alter the minimum alveolar concentration of halothane in humans.

The authors studied 64 unpremedicated, healthy surgical patients, aged 42 +/- 14 yr, to determine the effects of atracurium, vecuronium, and pancuronium on the minimum alveolar concentration (MAC) of halothane. Anesthesia was induced using halothane/nitrous oxide/oxygen via a mask without the administration of other drugs. Nitrous oxide was discontinued, the trachea was intubated without prior administration of neuromuscular blocking drugs, and anesthesia was maintained with halothane in oxygen. Participating patients were assigned to one of five groups: 1) no neuromuscular blocking drug (control group, n = 9); 2) atracurium 0.5 mg/kg (n = 10); 3) atracurium 1.0 mg/kg (n = 15); 4) vecuronium 0.1 mg/kg (n = 20); or, 5) pancuronium 0.1 mg/kg (n = 10). Tourniquets, inflated to 300 mmHg immediately before iv administration of neuromuscular blocking drug and 15-30 min prior to skin incision, were used to isolate extremities from circulating neuromuscular blocking drug in all patients. A positive response to stimulation was defined as movement of at least one extremity occurring distal to the tourniquet within 1 min following skin incision. The first patients in the control and atracurium groups were studied at an end-tidal halothane concentration of 0.95%. The first patient in the pancuronium group was studied at a halothane concentration of 0.75%, and the first patient in the vecuronium group at 0.70%. Subsequent patients were studied at end-tidal halothane concentrations 0.10% above or below that of the preceding patient, depending on the presence or absence of movement with skin incision. Control MAC for halothane was 0.74% +/- 0.09% (mean +/- SEM).(ABSTRACT TRUNCATED AT 250 WORDS)

Large doses of vecuronium and plasma histamine concentrations.

The authors studied 20 surgical patients to determine the effect of large doses of vecuronium on plasma histamine concentrations. Patients were unpremedicated and anaesthetized with nitrous oxide and halothane via a mask. Tracheal intubation was performed without the use of muscle relaxants. Fifteen min later and before surgery had begun, vecuronium, in doses of 0.1 and 0.2 mg.kg-1 (n = 10 for each dose), was administered as an IV bolus. Arterial blood samples were obtained prior to and 2, 5, and 10 min after vecuronium administration and analyzed for plasma histamine by a radioenzymatic method. Arterial blood pressure and heart rate were measured continuously. In one patient who received 0.1 mg.kg-1 of vecuronium, plasma histamine concentrations at 2 min were 275 per cent of the control histamine value but fell below control at 10 min. This increase in plasma histamine was not associated with clinically important changes in blood pressure or heart rate. As a group, study patients had no significant changes in plasma histamine concentrations with either dose of vecuronium. In addition, mean plasma histamine values for each sampling interval did not differ between the two patient groups. Mean arterial blood pressure (MAP) decreased significantly at 10 min in patients receiving vecuronium 0.1 mg.kg-1, and at 2 and 10 min in patients receiving 0.2 mg.kg-1 of vecuronium. However, these decreases in MAP were not clinically important. Changes in plasma histamine concentrations did not correlate with corresponding changes in MAP. Heart rate did not change significantly in any patient during the study.(ABSTRACT TRUNCATED AT 250 WORDS)

Vecuronium inhibits histamine N-methyltransferase.

Although there have been clinical reports of significant hypotension and flushing associated with the use of vecuronium, it produces minimal cardiovascular effects in the vast majority of patients. In addition, there is no evidence that vecuronium stimulates the release of histamine. The authors performed in vitro kinetic studies to determine the effect of vecuronium on histamine N-methyltransferase (HNMT), the primary catabolic enzyme for histamine in humans. They also examined plasma from patients who had received vecuronium (0.1 or 0.2 mg/kg) to determine whether clinically used concentrations of the drug could inhibit HNMT. It was determined that vecuronium is a strong inhibitor of HNMT; apparent Ki = 1 microM. The inhibition is competitive with respect to methyl-donor and noncompetitive with respect to histamine. Vecuronium, in doses greater than or equal to 0.1 mg/kg, may delay the metabolism of histamine by HNMT in vitro.

Continuous infusion of vecuronium: the effect of anesthetic agents.

The authors studied the effects of enflurane, isoflurane, and fentanyl, each in combination with 60% nitrous oxide, on the vecuronium infusion rate necessary to maintain constant 90% depression of control muscle twitch tension. Thirty healthy surgical patients were given an initial 0.1 mg/kg bolus of vecuronium, followed by an infusion of vecuronium at an initial rate of 1.0 microgram . kg-1 . min-1. After 1 h of steady-state 90% twitch depression, plasma vecuronium concentrations (Css90) were measured by capillary column gas chromatography. Total plasma clearance of vecuronium was estimated using Css90 values. Vecuronium infusion rates (mean +/- SD) were similar for patients given enflurane (0.28 +/- 0.13 microgram . kg-1 . min-1) and isoflurane (0.30 +/- 0.13 microgram . kg-1 . min-1), but significantly higher in patients given fentanyl (0.92 +/- 0.37 microgram . kg-1 . min-1). Values for Css90 in the patients receiving enflurane and isoflurane were similar (71 +/- 34 and 72 +/- 44 ng/ml, respectively), but significantly higher in those receiving fentanyl (165 +/- 48 ng/ml). Total plasma clearance was similar during enflurane, isoflurane, and fentanyl anesthesia (4.4 +/- 2.6, 4.6 +/- 1.2, and 5.6 +/- 1.9 ml X kg-1 min-1, respectively). The authors conclude that patients receiving isoflurane and enflurane require markedly lower vecuronium infusion rates to achieve 90% neuromuscular blockade than those receiving fentanyl. The enhancement of neuromuscular blockade by isoflurane and enflurane represents a change in the pharmacodynamics of vecuronium-induced neuromuscular blockade, rather than a change in pharmacokinetics.