A comparison of cisatracurium (51W89) and atracurium by infusion in critically ill patients.

OBJECTIVE: To evaluate and compare the safety and efficacy of cisatracurium (51W89) and atracurium administered by continuous infusion to critically ill patients requiring neuromuscular blocking agents to facilitate mechanical ventilation. DESIGN: Open, randomized, multicenter study of patients receiving cisatracurium or atracurium infusion to facilitate mechanical ventilation. SETTING: Five university teaching hospital intensive care units in the United Kingdom. PATIENTS: Sixty-one adult patients requiring neuromuscular blocking agents to facilitate mechanical ventilation. INTERVENTIONS: Bolus doses followed by continuous infusions of cisatracurium or atracurium were administered. Onset, maintenance, and recovery of neuromuscular blockade were measured, using transcutaneous ulnar nerve stimulation and an accelerometer. MEASUREMENTS AND MAIN RESULTS: Forty patients received cisatracurium (mean duration 48.1 +/- 4.2 [SEM] hrs), and 21 patients received atracurium (mean duration 46.1 +/- 5.8 hrs). The infusion rate for patients receiving cisatracurium was 3.1 +/- 0.2 microg/kg/min, and for patients receiving atracurium 10.4 +/- 0.9 microg/kg/min. There were no significant differences in mean times to 70% recovery of Train-of-Four ratio (cisatracurium 60 mins, atracurium 57 mins), although there was considerable interpatient variation (20 to 175 mins with cisatracurium vs. 35 to 85 mins with atracurium). One patient who received cisatracurium exhibited intermittent bronchospasm during and after the study period. CONCLUSIONS: Cisatracurium, an isomer of atracurium, appears to be a suitable agent for providing muscle relaxation in critically ill patients.

The use of neuromuscular blocking drugs in intensive care practice.

Critically ill patients represent a very different population from that of the operating theatre, but much of our knowledge of many of the neuromuscular blocking drugs is derived from intraoperative use. The diversity of clinical-practice and case-mix differences in intensive care are probably responsible for the absence of a formal consensus about the use of neuromuscular blocking drugs in the intensive care unit (ICU). Various surveys suggest that these drugs are used comparatively infrequently, but we do not know whether current usage is either safe or appropriate. In addition to the adverse effects which inevitably accompany prolonged paralysis and immobility, the steroidal relaxants, pancuronium and vecuronium, have also been associated with myopathy. This seems to be aggravated by concurrent use of pharmacologic doses of corticosteroids or the aminoglycoside antibiotics. Neither the mechanism nor the validity of the association with steroidal relaxants is known at present. Muscle dysfunction is a common feature of critical illness, and it is possible that neuromuscular blocking drugs interfere with muscle repair and regrowth. Patients with multiple organ failure present a particular challenge both because of the extent of tissue injury and because drug clearance via the liver or kidneys is generally impaired.

Glucose absorption and hepatic gluconeogenesis in dairy cows fed diets varying in forage content.

One dry and four lactating Holstein cows were prepared with chronic catheters in the mesenteric, hepatic and portal veins and used to study glucose absorption and hepatic gluconeogenesis. The dry cow was used in a preliminary assessment of the methods. In the main experiment high concentrate and high forage diets, providing equal energy intake, were delivered in hourly portions from an automatic feeder as total mixed rations. A few data were collected with the high concentrate ration fed ad libitum in early lactation. A few additional observations were made with limited feed intake by using the same cows subsequent to the main experiment. Portal and hepatic vein blood flow rates were determined by using para-aminohippuric acid. Glucose entry rates were significantly higher during ad libitum feeding of the high concentrate diet than during feeding of the two diets with restricted intake. There was no difference between high concentrate and high forage diets when fed at equal energy intakes. Net glucose appearance in portal blood was demonstrated. Data from this study and from the literature were used to develop general relationships between digestible energy intake and 1) portal vein blood flow, 2) rate of portal appearance of glucose and 3) total splanchnic glucose entry rate.

Effect on feed intake of infusing sodium propionate or sodium acetate into a mesenteric vein of cattle.

Solutions containing sodium propionate or sodium acetate were infused into a mesenteric vein of eight steers in order to examine the effect of increasing the entry rate of these metabolites on feed intake. Infusion of propionate inhibited feed intake to varying degrees, but acetate infused at equivalent rates had no effect. Rate of entry of propionate into the visceral circulation may be a physiological mechanism for controlling feed intake in cattle, but it is mainly effective when the animal has eaten close to its voluntary maximum intake.

Endocrine changes with infusion of propionate in the dairy cow.

Sodium propionate (2.5 mmol/kg) was infused rapidly via a jugular vein into each of 13 multiparous Holstein cows at 7 wk postpartum for observation of clearance of propionate. Associated concentration changes of acetate and glucose in blood plasma and glucagon and insulin in blood serum were quantified. This dose elevated concentrations of propionate, which declined subsequently at an exponential rate (.108 min-1). Concentrations of glucagon and insulin were increased in the sampling immediately following infusion, yet subsequent decline of insulin concentrations acted to decrease the molar ratio of insulin:glucagon as propionate returned to preinfusion concentrations. Analysis of sample means disclosed a negative correlation -.82 between glucose and molar ratio of insulin:glucagon. These experimental observations suggest that a supraphysiological dose of propionate has an immediate effect on the pancreas to alter endocrine secretion in the lactating cow.

Effects of cobalt or hydroxycobalamin supplementation on vitamin B-12 content and (S)-methylmalonyl-CoA mutase activity of tissue from cobalt-depleted sheep.

Lambs (3 months of age) and ewes were fed ad libitum a depletion diet low in cobalt (0.06 ppm) for 7 months. Five sheep were then assigned to each of the following treatments: 330 micrograms hydroxocobalamin (OH-B-12) intramuscularly, 2.7 mg cobalt (Co) orally, and no supplementation (no suppl). Treatments were given on alternate days for 9 weeks. Both forms of resupplementation increased the animal's body weight at slaughter compared to nonsupplementation, while absolute weights and protein concentrations of brain, liver, heart, rumen and kidney were not affected. Supplementation increased concentrations of vitamin B-12 in all tissues; Co and OH-B-12 being equally effective in brain and ruminal mucosa, whereas OH-B-12 had a greater effect in heart, liver and kidney. The greatest concentrations of vitamin B-12 were observed in liver (2630 +/- 160, 1500 +/- 230 and 60 +/- 20 ng/g wet liver for OH-B-12, Co and no suppl groups, respectively) and kidney, although liver contained the greatest absolute amount of vitamin B-12. Activity of (S)-methylmalonyl-CoA mutase, assayed in the presence of added coenzyme B-12, was not increased with resupplementation except in kidney. The activity of mutase without coenzyme added in vitro was correlated with tissue content of vitamin B-12. Through this study we demonstrate that in sheep tissue the activity of (S)-methylmalonyl-CoA mutase is limited by coenzyme rather than enzyme per se. Liver possesses the greatest quantitative activity of mutase and is most responsive to alterations of vitamin B-12 status.

Urinary excretion of acetate and propionate by the Holstein cow as affected by physiological state and propionate infusion.

Daily urinary excretion of acetate and propionate was determined for 13 Holstein cows fed for ad libitum consumption a 40% soy-corn concentrate: 60% corn silage diet prepartum and 60% concentrate: 40% silage diet postpartum. Daily excretion of acetate did not differ between periods corresponding to -3, 7, and 11 wk postpartum. Cows excreted more propionic acid at 7 and 11 wk postpartum than at 3 wk prepartum. However, propionic acid excretion did not differ between the two postpartum periods. Propionic acid excretion was not associated with intake of feed during lactation. Rapid intrajugular infusion of propionate (2.5 mmol/kg) increased propionate excretion at -3 and 7 wk postpartum and acetate excretion at 7 wk postpartum. Under physiological conditions urinary excretion of acetate and propionate does not represent a meaningful energy loss.

Characterisation of [3H]lysergic acid diethylamide binding to a 5-hydroxytryptamine receptor on human platelet membranes.

Specific binding of [3H]lysergic acid diethylamide (LSD) to human platelet membranes, as defined by 300 nM spiperone, was saturable over the concentration range of 0.25-2.5 nM [3H]LSD. At 0.5 nM [3H]LSD the half-time for association at 37 degrees C was 56 min, half-time for dissociation was 173 min, and the kinetically derived affinity was 0.24 nM. In 19 control subjects equilibrium binding studies gave an affinity of 0.53 +/- 0.02 nM (mean +/- S.E.M.) and capacity of 57.1 +/- 5.6 fmol/mg protein (mean +/- S.E.M.). The inhibition profile was consistent with that of a 5-hydroxytryptamine (5-HT) receptor. There was a significant correlation between the inhibition of [3H]LSD binding and the inhibition of 5-HT-induced shape change, but not inhibition of active platelet uptake of 5-HT. There was also a significant correlation between the inhibition of [3H]LSD binding to human platelet membranes and human frontal cortex. Platelet [3H]LSD binding may therefore be a useful model for study of peripheral and central 5-HT receptors in man.

Inhibition in vitro of lipogenic enzymes from bovine (Bos taurus) mammary tissue by methylmalonyl-coenzyme A and coenzyme A.

Bovine mammary fatty acid synthetase was inhibited by approximately 50% by 40 microM methylmalonyl-CoA; this inhibition was competitive with respect to malonyl-CoA (apparent Ki = 11 microM). Similarly, 6.25 microM coenzyme A inhibited the synthetase by 35% and this inhibition was again competitive (apparent Ki = 1.7 microM). Apparent Km for malonyl-CoA was 29 microM. The short-chain dicarboxylic acids malonic, methylmalonic and ethylmalonic at high concentrations (160-320 microM) and ATP (5 mM) enhanced the synthetase activity by about 50% respectively; the activating effects of methylmalonic acid and ATP on the synthetase were additive. Methylmalonyl-CoA at 50 microM concentration inhibited the partially purified acetyl-CoA carboxylase uncompetitively by 10% and the propionyl-CoA carboxylase activity of the enzyme preparation competitively (apparent Ki = 21 microM) by 40%. Malonyl-CoA also inhibited the acetyl-CoA carboxylase activity competitively (apparent Ki = 7 microM) by 35% and the propionyl-CoA carboxylating activity of the preparation competitively (apparent Ki = 4 microM) by 82%. The possibility that methylmalonyl-CoA may be a causal factor in the aetiology of the low milk-fat syndrome in high yielding dairy cows is discussed.

Effect of vitamin B12 status on performance of the lactating ewe and gluconeogenesis from propionate.

Ewes fed a diet containing .06 ppm cobalt prior to and after parturition were used to examine effects of hydroxycobalamin supplementation upon production of milk. Four ewes were assigned to each of three treatments after hand milking at 3 wk postpartum. At 7 wk postpartum, B12 concentrations in liver were enhanced in the group receiving intramuscular injections of 200 micrograms on alternate days (750 ng/g wet liver) relative to low groups that received 20 and 0 micrograms on alternate days (190 and 200 ng/g wet liver). Following 1 wk of treatment, B12-enhanced ewes had greater daily intake of feed and increased live weight. Vitamin B12 status was without significant effect on production of milk, total solids, fat, and solids-not-fat at 4, 5, and 6-wk milkings; however, production of milk protein was increased for B12-enhanced ewes. After lactations were terminated and feed intakes standardized, slices of liver obtained from B12-enhanced ewes incorporated 2-carbon 14-labeled propionate into glucose at rates greater than did slices from low B12 ewes. Subclinical changes affecting production may occur in lactating sheep when B12 status is at the lower end of what usually is considered the normal range.

Changes of glucose, insulin and glucagon associated with propionate infusion and vitamin B-12 status in sheep.

The effect of propionate on hormonal and metabolic events was studied in ewes that were vitamin B-12 depleted (de-B12) and repleted (re-B12). Experiments were conducted before and after hydroxocobalamin resupplementation. De-B12 sheep had greater blood concentrations and total hepatic influx and efflux of glucose. However, rates of net hepatic release of glucose were similar. Comparable glucagon concentrations and fluxes were reduced in de-B12, but insulin values were unaffected by vitamin B-12 status. Intramesenteric infusion of propionate elevated concentrations of glucose, insulin and glucagon at nearly all samplings. Secretion of insulin was elevated at the first sampling only (15 minutes), while glucagon appeared elevated until 30 minutes. Rates of hepatic removal of hormones were not altered during infusion. Net hepatic release of glucose was increased at nearly all samplings, but de-B12 ewes had a greater increment of total hepatic influx and efflux. De-B12 ewes exhibited a diminished glucagon response to propionate infusion, whereas insulin concentrations and hepatic uptakes tended to be greater. Vitamin B-12 status, within the range usually considered normal, thus influences metabolic and hormonal responses to increased rates of propionate entry in the sheep, independent of feed intake.

Influence of vitamin B-12 status on hepatic propionic acid uptake in sheep.

Pregnant ewes were fed a depletion diet low in cobalt (0.06 ppm) for 3 1/2 months. Chronic catheters were implanted 8 weeks postpartum and 7 experiments were performed on these nonlactating vitamin B-12-depleted sheep (de-B12: 340 +/- 30 ng vitamin B-12 per gram wet liver) prior to repletion by intramuscular injection of hydroxocobalamin. Six experiments were then repeated after vitamin B-12 repletion (re-B12: 2220 +/- 50 ng vitamin B-12 per gram wet liver). The hepatic extraction ratios (HER) in continuously fed sheep were 0.81 and 0.77 for de-B12 and re-B12 corresponding to net hepatic uptakes of 460 +/- 50 and 440 +/- 40 mumol propionate per minute, respectively. Continuous infusion of unlabeled propionate into a mesenteric vein at 1 mmol/minute reduced the HER, yet this depression was greatest for re-B12 (0.74 vs. 0.63 for de-B12 and re-B12, respectively). Net hepatic uptake of propionate was increased (1145 +/- 100 vs. 985 +/- 95 mumol/minute, respectively), although vitamin B-12 status was without effect. It is concluded that the ability of liver to extract propionate is not affected at vitamin B-12 concentrations greater than 250 ng/g wet liver. However, when propionate entry rate was enhanced by intramesenteric infusion, the livers of de-B12 sheep had a greater capacity to remove propionate suggesting that alternate routes of metabolism may occur.

Effect of factor B on vitamin B12 status and propionate metabolism in sheep.

Growing lambs fed diets containing two concentrations of Co (basal and basal plus 1 ppm) were injected with Factor B (cobinamide) or saline during an 8-wk trial conducted to determine the effects of Factor B on liver B12 levels and on propionate metabolism. At the end of the trial, lambs given Factor B had lower (P less than .05) liver vitamin B12 concentrations and higher (P less than .05) Factor B concentrations than controls fed the high Co diet. The high Co diet did not enhance liver B12 levels in the lambs treated with Factor B. Feed intake and body weight gain were not significantly affected by treatment. Plasma propionate increased (P less than .05) with time on experiment, and concentrations during the final period were negatively correlated (r = -.45; P less than .05) with liver B12 levels. When the lambs were loaded with propionate, a similar correlation (r = -.59; P less than .05) was observed between log plasma level at t = 20 and liver B12 levels. Liver B12 levels (.2 to 1.1 micrograms/g) were all within what is usually considered a normal range. . No significant relationship between plasma propionate and liver Factor B levels were observed.

Vitamin B12 administration for milk fat synthesis in lactating dairy cows fed a low fiber diet.

Thirty lactating Holstein cows were in two groups in a study of effects of vitamin B12 injections on milk fat synthesis. All cows were fed a normal fiber diet for the first 28 days after calving and then adjusted gradually to a low fiber diet over the next 28 days. After adjustment to the low fiber diet, in a single reversal trail, cows received either 150 mg of vitamin B12 in the form of hydroxocobalamin intramuscularly every 7 days for 21 days or no treatment for 21 days. Daily milk yield (kg), percent milk fat, and milk fat yield (g) for the normal fiber, low fiber adjustment, low fiber control, and low fiber plus vitamin B12 treatments were 29.6, 3.59, 1192; 31.5, 2.85, 840; 28.0, 2.58, 715; and 28.8, 2.65, 760. Injections of vitamin B12 did not correct the milk fat depression associated with the low fiber diets. In addition, there was no consistent relationship between blood B12 and milk fat production. Milk fat production was highly correlated with molar percent acetate in the rumen .63 and with blood acetate concentration .74.

Mammary extraction of propionate in lactating cows.

Four cows with exteriorized carotid arteries were in an intensive study of concentrations in plasma and mammary extraction of propionate. A restricted-roughage, high-grain diet produced higher arterial propionate concentrations and larger carotid-subcutaneous abdominal vein (arteriovenous) differences that the control diet. Concomitant changes in acetate, beta-hydroxybutyrate, and glucose in plasma and in fat and protein in milk were measured. Mammary arteriovenous difference in propionate was correlated negatively with milk fat percentage. However, since arterial propionate and beta-hydroxybutyrate also were correlated negatively, evidence of a direct inhibitory effect of propionate in mammary gland is equivocal.

Vitamin B12 binding proteins in bovine serum.

Examination of bovine serum by the diethylaminoethyl cellulose small column method revealed three proteins binding vitamin B12. The elution pattern suggested that they are similar to the three transcobalamins recognized in human serum. Distribution of unbound binding capacity among serum binders was assessed in serum from normal, ketotic, and B12- and Factor B-supplemented cows in early lactation. No major differences were observed among groups; however, cow serum displayed a pattern different from human serum. Mean total binding capacity of bovine serum for B12 as well as mean unbound binding capacity were lower than the corresponding means for human serum.

Milk fat as related to vitamin B12 status.

Two experiments examined whether vitamin B12 status of liver affects milk fat percentage or yield. In Experiment 1 B12 concentration in liver, measured at approximately 8 and 15 wk postpartum in 35 cows, was not correlated significantly with milk fat percentage or yield. In Experiment 2 twenty-two cows were fed a ratio similar to one used to depress milk fat percentage. The B12 status of 12 of these cows was enhanced by intramuscular injection of vitamin B12 while the other 10 served as controls. During wk 2 to 8 of lactation, milk fat percentages were almost identical for the two groups. A difference in milk fat yield in favor of the B12-treated group resulted from a difference in milk yield. The data do not support a recent hypothesis of the metabolic cause of milk fat depression.