Neuromuscular interactions between suxamethonium and magnesium sulphate in the cat

In order to study the neuromuscular interactions between suxamethoniumand magnesium sulphate (MgSO₄), we have determined the dose-responserelationship of suxamethonium and the neuromuscular actionsof 1.25xED₅₀ dose of suxamethonium, both before and after pretreatmentwith MgSO₄. We have also compared the effect of 1.25xED₅₀ doseof suxamethonium in the absence and in the presence of 50%neuromuscularblock, established previously by infusion of MgSO₄. Twenty-onecats were anaesthetized with urethane. Train-of-four stimulationwas applied every 12s to the sciatic nerve and the force ofcontraction of the tibialis anterior muscle was measured. Thepotency of suxamethonium decreased in each instance with pretreatmentwith MgSO₄. The ED₅₀ of suxamethonium increased significantlyfrom mean 21.0 (SEM 1.9) µg kg^–1 before MgSO₄ to25.6 (2.3) µg kg^–1 after MgSO₄ 60 mg kg^–1and to 26.6 (2.2) µg kg^–1 after MgSO₄ 90 mg kg^–1(P<0.05). Twitch depression produced by 1.25xED₅₀ dose ofsuxamethonium decreased significantly with MgSO₄ pretreatment,from 76.7 (2.6)% before MgSO₄ to 61.7 (6.4)% after MgSO₄ 60mg kg^–1 and 48.7 (7.5)% after MgSO₄ 90 mg kg^–1 (P<0.05).With stable 50% neuromuscular block, established previouslyby infusion of MgSO₄ the 1.25xED₅₀ dose of suxamethonium producedmore twitch augmentation (133 (6.3)%vs 108.3 (1.3)%; P<0.05)and less twitch depression (31.6 (9.6)% vs 74.1 (0.6)%, P<0.05)than in the absence of MgSO₄. The results of all three methodsdemonstrated that the pharmacological interaction between suxamethoniumand magnesium was antagonistic.     

ACTIONS OF THE HYPNOTIC ANAESTHETIC, DEXMEDETOMIDINE, ON NORADRENALINE RELEASE AND CELL FIRING IN RAT LOCUS COERULEUS SLICES

We have examined the effects of the highly selective alpha₂adrenoceptor agonist, dexmedetomidine, on noradrenaline releaseand cell firing in isolated, superf used slices of rat locuscoeruleus. Dexmedetomidine decreased both noradrenaline releaseand cell firing rate in a concentration-dependent fashion, withan EC₅₀ of 3.97 (SEM 0.97) x 10^–9morl litre^–1 fornoradrenaline release and 0.92 (0.53) x 10^–9 mol litre^–1for unit activity. Both effects were reversed completely bythe selective alpha₂ antagonist, atipamezole 10^–6 mollitre^–1 These results suggest that cell firing and noradrenalinerelease are under alpha receptor control and that dexmedetomidinepotently stimulates these receptors. We conclude that theseeffects are consistent with the locus coeruleus being a majorsite of action of the hypnotic anaesthetic alpha₂ agonists.     

CARDIOVASCULAR AND RENAL HEMODYNAMIC EFFECTS OF DOPEXAMINE: COMPARISON WITH DOPAMINE

We have studied the effects of dopexamine and dopamine on systemicand renal haemodynamics in 20 male patients undergoing electivecoronary artery bypass surgery. Patients were allocated randomlyto two groups (n = 10) who were treated with incremental dosesof either dopexamine 1, 2 and 4 µg kg^–1 min^–1,or dopamine 2.5 and 5 µg kg^–1 min^–1, eachdose being maintained for 15 min. Measurements were performedbefore administration of the drug and at the end of the infusionperiod at each dose. Fentanyl and midazolam were used as anaestheticagents. Renal blood flow was measured with the argon washintechnique. Dopexamine 4 µg kg^–1 min^–1 producedan increase in cardiac index of 117% caused by a 65% reductionin afterload and an increase in heart rate by 61%. Dopamine5 µg kg^–1 min^–1 caused a 40% increase in cardiacindex as a result of an increase in stroke volume. Renal vascularresistance decreased more than systemic vascular resistancewith dopamine. With dopexamine, the increase in renal bloodflow (66%) was less than the increase in cardiac index, whilerenal vascular resistance and systemic vascular resistance declinedto almost the same extent. The results show that dopexamineexerts systemic and renal effects mainly via stimulation ofß₂-receptors. An action of dopexamine at renal DA₁-receptorscould not be demonstrated in this study.     

Differential effects of propofol and ketamine on cytosolic calcium concentrations of astrocytes in primary culture

Propofol has been shown recently to alter cellular communicationmediated by gap junctions between astrocytes (a glial cell subpopulationinvolved in major brain functions). As marked increases in concentrationsof cytosolic calcium ([Ca²⁺]_i) produce closure of the gap junction,we have investigated the effects of both propofol and ketamineon resting [Ca²⁺]_i concentrations in mouse cultured astrocytesusing microfluorimetry with the indo-1 fluorescent probe. Propofol10^–5and 10^–4mol litre^–1 induced a monophasictransitory Ca²⁺ peak in a large subpopulation of the cells tested.This response exhibited characteristics close to those of thepeak elicited by [L-Pro⁹] substance P (10^{– 7} mol litre^–1),an activator of phospholipase C in astrocytes. In both cases,it possibly corresponded to mobilization of Ca²⁺ from endogenousstores. In a few cases, however, administration of propofolinduced a moderate, but sustained increase in [Ca²⁺+]_j, correspondingto the entry of external Ca²+ into the cells. In contrast ketamine10^–5 and 10^–4mol litre^–1 failed to affect[Ca²⁺+]_i resting concentrations. These findings indicate thatclinically relevant concentrations of propofol, but not ketamine,increased [Ca²⁺_j concentration in astrocytes. (Br. J. Anaesth.1994: 72: 351–353) ^*Present address for correspondence: Department of Anaesthesiology,Hospital Bichat, 46 rue Henri Huchard, 75018 Paris, France.     

DIRECT VASOCONSTRICTOR AND VASODILATOR EFFECTS OF PROPOFOL IN ISOLATED DOG ARTERIES

We have measured the direct effects of propofol 10^–7-10^–4mol litre^–1 on isolated canine cerebral, coronary, mesenteric,femoral and renal arteries. In arterial strips precontractedsubmaximally with potassium chloride or prostaglandin F₂     

DOSE REQUIREMENTS OF PROPOFOL BY INFUSION DURING NITROUS OXIDE ANAESTHESIA IN MAN: I: Patients Premedicated with Morphine Sulphate

The study was performed to determine the ED₅₀ and ED₉₅ of acontinuous infusion of the emulsion formulation of propofolduring 67% nitrous oxide anaestheisa in 57 patients premed-icatedwith morphine sulphate 0.15 mg kg^–1. Anaesthesia was inducedwith propofol 2 mg kg^–1, and maintained before incisionwith a fixed-rate infusion of propofol to supplement nitrousoxide. The response to the first surgical incision, made atleast 30 min after induction of anaesthesia, was observed. TheED₅₀; was 53.5 µg kg^–1 min^–1 and the ED₉₅was 112.2 µg kg^–1 min^–1. At the time of thefirst surgical incision, the venous whole blood concentrationsof propofol at the ED₅₀ and ED₉₅ infusion rates (EC₅₀and EC₉₅were 1.66 µg ml^–1 and 3.39 fig ml^–1 respectively.The satisfactory maintenance of anaesthesia provided by nitrousoxide supplemented with propofol was associated with stabilityand rapid, uncomplicated recovery.     

EFFECT OF DOBUTAMINE ON OXYGEN SUPPLY AND UPTAKE IN HEALTHY VOLUNTEERS

We have measured the changes in Vo₂ and the Vo₂; D_o2 relationshipduringinfusion of dobutamine in healthy volunteers. Nine healthy,adult, non-obese, male physicians were infused with an incrementalinfusion of dobutamine starting at 2.5 µg kg^–1 min^–1increasing to 5.0 and then 7.5 y.g kg^–1 min^–1 for15 min each. Vo ₂ and cardiac index were measured every fiveminutes. Vo₂/(VO₂ m^–2) increased from a baseline of 128(SEM 6.1) ml min^–1 m^–2 to 159 (8.0)ml min¹ m^–2(P< 0.05) at 7.5 fig kg^–1 min^–1. The correspondingchanges for Do₂l (Do₂m^–2) were from 643 (35) ml min^–1m^–2 to 1240 (142) ml min^–1 m^–2 (P<0.05).The coefficient of correlation for pairs of Vo₂ and DO₂ values,at baseline and each dobutamine infusion in individual subjects,range from 0.89 to 0.99 (mean 0.95, SD 0.03). Dobutamine haspotent calorigenic effects; demonstration of a positive correlationbetween Vo₂ and Do₂ after infusion of dobutamine does not necessarilyimply an underlying tissue oxygen debt.     

HAEMODYNAMIC EFFECTS OF THE PHOSPHODIESTERASE INHIBITOR ENOXIMONE IN COMPARISON WITH DOBUTAMINE IN ESMOLOL-TREATED CARDIAC SURGERY PATIENTS

In a randomized study, the haemodynamic effects of the new phosphodiesterase-III-inhibitor,enoximone, were compared with dobutamine in acutely ß-adrenoceptorblocked patients. Twenty patients scheduled for aorto-coronarybypass grafting suffering from tachycardia (heart rate (HR)> 100 beat min^–1) were treated by infusion of esmolol,an ultra-short acting, selective ß₁-blocker. Twentyminutes after the start of esmolo, either enoximone 0.5 mg kg^–1as a bolus (n = 10) or dobutamine 5 µg kg^–1 min^–1was administered. Haemodynamic effects were monitored for 40min, including measurement of left ventricular haemodynamics.Esmolol reduced HR (–27%) and dP/dt_max (–38%) significantlyin both groups. Cardiac index (Cl) was decreased also. Enoximoneincreased Cl (+35%) and dP/dt_max (+39%) significantly, whileno change in dobutamine-treated patients was observed. Systemicvascular resistance increased only in the dobutamine group (+44%).     

Interaction of magnesium sulphate with vecuronium-induced neuromuscular blockt

We have investigated the interaction between magnesium sulphate40 mg kg^–1 i.v. and vecuronium. First, we determined theeffect of pretreatment with magnesium on the potency of vecuroniumusing a single bolus dose-response technique. In addition, wecompared the time course of vecuronium-induced neuromuscularblock (vecuronium 100 µg kg^–1) with and withoutmagnesium pretreatment. For both parts, neuromuscular blockwas assessed by electromyography. In addition, the effect ofmagnesium pretreatment on vecuronium-induced neuromuscular blockwas investigated in the context of rapid sequence inductionof anaesthesia. We found that the neuromuscular potency of vecuroniumwas increased by pretreatment with magnesium sul phate. TheED₅₀ and ED₉₀ of vecuronium with MgSO₄ were 25% lower than withoutMgSO₄ (ED₅₀ 21.3 vs 26.9 µg kg^–1 ED₉₀ 34.2 vs 45.7µg kg^–1 P < 0.05 for both). Mean onset time was147.3 (SD 22.2) s in the MgSO₄ group vs 297.3 (122) s for controls(P < 0.05). Clinical duration was prolonged (MgSO₄-vecuronium43.3 (9) min vs 25.2 (5.1) min for controls; P < 0.05). Thiswas also true for the recovery index (20.1 (6.6) mm vs 10.6(3.4) min; P < 0.05) and duration to 75% recovery (63.4 (9.9)min vs 35.8 (6.9) min; < 0.05). In the context of rapid sequenceinduction, pretreatment with MgSO₄ improved the intubating scoreof vecuronium compared with vecuronium without MgSO₄ reach ingthe same quality as that with suxamethonium 1 mg kg^–1.We conclude that magnesium pretreat ment increased the neuromuscularpotency of vecuronium, in addition to modifying the time courseof its neuromuscular block.      

GENERAL ANAESTHETICS INDUCE ONLY HISTAMINE RELEASE SELECTIVELY FROM HUMAN MAST CELLS

We have examined the in vitro effects of increasing concentrationsof propofol (5–70 µg ml^–1), ketamine (10^–6–10^–1mol litre^–1) and thiopentone (10^–5–8 –10^–4 mol litre^–1) on the release of preformed histamineand de novo synthesized mediators (peptide leukotriene C₄ (LTC₄) or prostaglandin D₂ (PGD₂) from human basophils and mastcells isolated from lung parenchyma and skin tissue and fromheart fragments. Propofol, ketamine and thiopentone failed toinduce the release of histamine and de novo synthesis of LTC4from basophils. Propofol induced histamine release from lung(mean 8.6 (SEM 1.6)%) and skin mast cells (3.8 (1.5)%), butnot from heart mast cells. Ketamine caused release of histaminefrom lung (6.2 (0.9) %) and skin mast cells (2.5 (1.5) %). Thiopentonecaused a small amount of histamine release from lung mast cells(3.1 (1.2)%). Propofol, ketamine and thiopentone did not inducede novo synthesis of PGD₂ and L TC₄ from lung and skin mastcells. These results demonstrate that general anaestheticsinduce only histamine release selectively from human mast cells.     

Effects of endogenous and synthetic opioid peptides on neutrophil function in vitro

Background. Opioid peptides released from immunocytes duringinflammation and stress in critically ill patients are associatedwith an altered immune response. Moreover, concentrations ofopioid peptides are increased in peripheral blood and at thesites of inflammatory reactions. Methods. Using flow cytometric assay of whole human blood, weinvestigated direct effects of endogenous and synthetic opioidpeptides on surface expression of complement receptors CD35and CD11b/CD18 and Fcã receptor III CD16, and superoxideanion generation of neutrophils. Results. The endogenous opioid peptides ß-endorphin_1–31and met-enkephalin, representing the N-terminal fragment ofß-endorphin_1–31, and the synthetic opioid receptoragonists D-Ala₂-D-Leu₅-enkephalin and D-Pen₂-enkephalin producedconcentration-dependent stimulation of neutrophil activity.Incubation with met-enkephalin 10^–7 M or ß-endorphin_1–3110^–7 M led to an increase in receptor expression of upto 10% (met-enkephalin) and 15% (ß-endorphin_1–31).After incubation with D-Ala₂-D-Leu₅-enkephalin or D-Pen_2/5-enkephalin,receptor expression was increased by up to 30%. This correlatedwith concentration-dependent stimulation of the production ofreactive oxygen intermediates, as shown by an increase of upto 40% in oxidative burst activity. All effects were abolishedafter preincubation with naloxone or with the selective opioidantagonist naltrindole, whereas the selective µ receptorantagonist d-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH₂ showed onlypartial inhibitory effects. Conclusions. Our data suggest a opioid receptor-mediated stimulatoryeffect on neutrophil function. ß-Endorphin_27–31,the C-terminal fragment of ß-endorphin_1–31,did not alter neutrophil function, indicating that ß-endorphin_1–31mediates its effect on neutrophils via the N-terminal fragment.This study may contribute to a better understanding of neuroimmuneinteraction. Br J Anaesth 2003; 91: 546–50     

Effects of halothane and diltiazem on L-type calcium currents in single smooth muscle cells from rabbit portal veins

We have studied the effects of halothane and diltiazem on L-typevoltage-dependent calcium currents (I_Ca) in single smooth musclecells from rabbit portal veins using a whole cell voltage clamptechnique. The threshold of I_Ca was –30 mV and the peakcurrent was reached at 0 mV. Halothane (0.25, 0.5, 1.0, 1.5and 2.07%) decreased I_Ca in a concentration-dependent mannerand shifted the I_Ca activation threshold to the depolarizingside. Halothane 2.0% abolished Diltiazem 10^–8–10^–6mol litre^–1, a calcium channel antagonist, also depressedI_Ca in a concentration-dependent manner. Administration of both0.5% halothane and diltiazem 10 mol litre^–1 (concentrationslower than the clinical therapeutic range) abolished I_Ca however,halothane did not exhibit use-dependent inhibition of I_Ca whereasdiltiazem showed partial use-dependency. We conclude that thedecrease in I_Ca produced by halothane is associated with a directvasodilator effect of this anaesthetic, but is not explainedby block of Ca²⁺ channels similar to the action of diltiazem.Furthermore, administration of low concentrations of both halothaneand diltiazem decreased I_Ca and may reduce the contractilityof the vascular smooth muscle cells.     

Angiotensin II stimulates cellular hypertrophy of LLC-PK1 cells through the AT1 receptor

We have investigated possible growth-promoting effects of angiotensinII (ANG II) in the pig tubular epithelial cell line LLC-PK₁.1O^–6–10^–10 M ANG II inhibited proliferationas measured by [³H]thymidine incorporation. However, the sameconcentration of peptide induced tubular hypertrophy as assessedby increases in de novo protein synthesis, total protein, andRNA content. These effects were mediated through AT₁ receptors.Furthermore, LLC-PK₁. cells exhibited specific binding sitesfor ANG II and expressed mature mRNA for the vascular smoothmuscle AT₁ receptor. ANG II incubation of cells significantlylowered intracellular cAMP, and the hypertrophogenic actionof ANG II was abolished by co-incubation with the relative stableanalogue dibutyryl-cAMP, suggesting the involvement of intracellularnucleotides in the signal-transduction processes leading tohypertrophy. Our results collectively suggest that ANG II isa hypertrophogenic growth factor for LLC-PK₁ cells. Consideringthe importance of tubular hypertrophy in the progression ofrenal failure in many models, strategies to block the actionof ANG II on tubular cells may offer an attractive alternativeway to control deterioration of renal function besides modulationof haemodynamics.     

ATRACURIUM AND VECURONIUM: EFFECT OF DOSE ON THE TIME OF ONSET

The time intervals measured from the administrations of eitheratracurium or vecuronium to maximum or 95% neuromuscular blockade(T_max) were compared in 70 patients using the evoked compoundaction potential of the adductor pollicis muscle. Equipotentdoses, calculated from the relationship between dose and responsefor both drugs obtained in an earlier study, were compared.The doses of atracurium and vecuronium ranged from 0.135 to0.5 mg kg^–1 and from 0.02 to 0.1 mg kg^–1, respectively.The dose range for both drugs included the ED₅₀, ED₉₅ and thedose required to produce 100% blockade (ED_"100"). No significantchanges in mean T_max occurred for doses of atracurium in therange 0.135–0.2 mg kg^–1 and in the range 0.24–0.5mg kg^–1. Similarly, no change in T_max occurred at dosesof vecuronium in the range 0.02–0.05 mg kg^–1 and0.06–0.1 mg kg^–1. T_max, changed significantly inthe dose ranges atracurium 0.2–0.24 mg kg^–1 andVecuronium 0.05–0.06 mg kg^–1. There was no significantdifference in T_max when equipotent doses of atracurium and vecuroniumwere compared.     

EFFECTS OF THIOPENTONE OR CHLORMETHAZOLE ON HUMAN PLACENTAL STEM VILLOUS ARTERIES

Small placenta/ stem villous arteries were micro dissected fromspecimens obtained at normal term vaginal delivery (n= 25).Ring preparations of the vessels were mounted in organ bathsand isometric tension was measured. Prostaglandin F_2a(PGF_2a)10^{– 7} mol litre^–1 produced concentration-dependentcontractile responses that were inhibited by thiopentone 10^–410^–3/>‘mollitre^–1 and by ch/ormethiazole 3x10^–4-3x 10* mollitre^–1. Thiopentone 10^–410^–3mol litre^–1and chlormethiazole 3x x 10^–4/>-3x x 10^–3 mollitre^–1 decreased the tension in vessels previously treatedwith PGF_2a10^{– 5} mol litre^–1. Chlormethiazole 3x10^–3 mol litre’^–1 inhibited, and thiopenone10^–4-10‘^–3 mol litre abolished contractileresponses to 5-hydroxytryptamine. Contractions induced by angiotensinII were inhibited by thiopentone 1O^–3 mol litre^–1and chlormethiazole 3x 10^{– 3} mol litre^–1. The concentrationsof the two drugs needed to affect contractile activation ofisolated human stem villous arteries exceeded the free plasmaconcentrations reached during anaesthesia induced by the agentsduring Caesarean section, and the present results do not suggestany major effects of thiopentone or chlormethiazole on fetalplacenta/ vascular resistance during the clinical use of thesedrugs.     

Post-conditioning by a short administration of desflurane reduced renal reperfusion injury after differing of ischaemia times in rats

Background. ‘Anaesthetic post-conditioning’, thatis administration of anaesthetics during early reperfusion,is known to have positive effects on several organs. For thekidney, however, the effects of post-conditioning by volatileanaesthetics are not well researched. We examined renal functionand morphology after post-conditioning by desflurane. Methods. Anaesthetized rats were subjected to 30 or 45 min ofrenal ischaemia 14 days after contralateral nephrectomy. Post-conditioningwas achieved by administration of 1 MAC desflurane (6.7 vol%)for 15 min during early reperfusion (all groups n=8). CystatinC (CyC), creatinine clearance (Cl_Cr) and fractional sodium excretion(FE_Na) were measured in the awake rats over 3 days. Cell damagewas graded from 1 to 4 in histological sections. Functionalvariables [mean (SD)] were compared statistically by a one-wayANOVA followed by Bonferroni's multiple comparison test andhistological scores (median and range) by Kruskal–Wallistest followed by Dunn's multiple comparison test. Results. Pre-ischaemia function did not differ between the groups,but was markedly reduced after ischaemia. After 30 min ischaemia,the area under the curve (AUC) for Cl_Cr was smaller in the desfluranethan in the control group [21.5 (5.0) vs 31.6 (5.1) ml min^–1h, P<0.05]. After 45 min desflurane reduced the AUC comparedwith the control group for both CyC [15 (4) vs 21 (3) mg litre^–1h] and FE_Na [1054 (221) vs 1570 (572)% h, both P<0.05). Morphologicaldifferences were greater between the 30 min groups [control:2.75 (2.0–3.5) vs desflurane: 1.5 (1.0–2.5); P<0.05]than between the 45 min groups [control: 3.5 (3.0–4.0)vs desflurane: 3.0 (1.5–4.0)]. Conclusion. Desflurane post-conditioning protects renal functionand tissue. This protection was greater after the short episodethan after the long episode of ischaemia.     

Relative potency of vecuronium in male and female patients in Britain and Australia

We compared the potency of vecuronium when given to similarpatients in Brisbane, Australia, and Cardiff, United Kingdom.Forty patients in each centre were anaesthetized using the sametechnique with propofol, fentanyl, nitrous oxide and vecuroniumeither 20 or 30 µg kg^–1 by random allocation. Neuromuscularblock was measured with similar Datex Relaxographs. There wasno significant difference in potency between British and Australianpatients. The ED₅₀, and ED₉₅ for a British male of average weightwere 29.5 µg kg^–1 (95% confidence limits 27.3–32.3µg kg^–1) and 51.3 µg kg^–1 (44.3–63.9µg kg^–1), respectively. ED₅₀ and ED₉₅ for Australianswere 5.5% greater, with confidence limits from 4% less to 17%greater. Females were significantly more sensitive to vecuroniumthan males, requiring 22% less drug to achieve the same degreeof neuromuscular block (confidence limits 12–32%). Theresults are consistent with the ED₅₀ being independent of bodyweight when the dose is expressed as µg kg^–2/3,but not as µg or µg kg^–     

Actions of morphine on noradrenaline efflux in the rat locus coeruleus are mediated via both opioid and {alpha}2 adrenoceptor mechanisms

A recent report showed that morphine inhibited [³H]clonidinebinding to human platelet ₂ receptors. As the analgesic effectsof morphine and clonidine are clinically additive, we investigatedthe possibility that morphine might stimulate ₂ receptors or₂ mechanisms in rat locus coeruleus (LC) slices. StimulatedLC noradrenaline efflux was measured by fast cyclic voltammetry.Cumulatively applied morphine 10^–8–10^–4mollitre^–1 had no effect on noradrenaline efflux evoked bypseudo-single-pulse stimulations (20 pulses at 100 Hz) whilethe ₂ agonist dexmedetomidine 2 x 10^–10–10^–7mol litre^–1 decreased efflux of noradrenaline in a concentration-dependentmanner. Administration of single concentrations of morphine10^–6–10^–4 mol litre^–1 significantlydecreased efflux of noradrenaline (by 22% and 17%, respectively)and attenuated the effect of dexmedetomidine in a concentration-dependentfashion. Morphine 10^–6–10^–4mol litre^–1also decreased efflux of noradrenaline on long stimulus trains(50 pulses at 50 Hz). These data suggest that the analgesicpotentiation of ₂ and opioid agonists is not mediated via LC₂ receptors.     

Pharmacokinetics and dynamics of atracurium infusions after paediatric orthotopic liver transplantation{dagger}

We examined the pharmacokinetics and pharmacodynamics of atracuriumbesylate and its metabolites in children after orthotopic livertransplantation (OLT), as a suitable model for critically illchildren. Ten children were studied after OLT on return to theintensive care unit (ICU). The mean (range) age was 36 (7–78)months, and weight 6–24.2 kg. Atracurium was startedat induction of anaesthesia and adjusted in the ICU accordingto clinical need. Neuromuscular block was measured using accelerometry(TOFguard) and the train-of-four (TOF) ratio or count. Arterialplasma samples for atracurium and metabolites taken before,12-hourly during, and at frequent intervals after the infusionwere analysed by HPLC. The mean (range) maximum infusion rateduring steady-state conditions was 1.44 (0.48–3.13) mg kg^–1 h^–1and the duration of infusion 36.9 (22.5–98.4) h. Tachyphylaxiswas not observed. The mean terminal half-life (t_1/2) for atracuriumwas 18.8 (12–32.3) min. The steady-state plasma clearance(CL_ss) was 13.9 (7.9–20.3) ml min^–1 kg^–1and the terminal volume of distribution (V_Z) 390 (124–551)ml kg^–1; both were higher than in adults after successfulOLT. The maximum concentration (C_max) of laudanosine was 1190(400–1890) ng ml^–1 and t_1/2 was 3.9 (1.1–6.7)h. The renal clearance of laudanosine was 0.9 (0.1–2.5) ml min^–1 kg^–1and increased with urine flow, but there was no significantrelationship with serum creatinine. EEG spikes were confirmedin one child only; the corresponding laudanosine C_max was 720 ng ml^–1.Monoquaternary alcohol C_max was 986 (330–1770) ng ml^–1and t_1/2 42.9 (30–57.7) min. Mean recovery time on stoppingthe atracurium infusion to a TOF ratio >0.75 was 23.6 (12–27)min. Atracurium is an effective and safe neuromuscular blockingagent in this population. Laudanosine concentrations are notexcessive if graft function is satisfactory. Br J Anaesth 2000; 85: 850–5     

ATRACURIUM, VECURONIUM AND PANCURONIUM IN END-STAGE RENAL FAILURE: Dose-Response Properties and Interactions with Azathioprine

Dose-response relations for atracurium, vecuronium and pancuroniumwere determined in patients in end-stage renal failure for theinitial neuromuscuiar blockade (using three cumulative doses)and for the maintenance of stable 90% response (during continousinfusion). All measurements were during renal transplant surgery,and the interaction of azathioprine on neuromuscuiar blockadewas estimated. Mean ED₉₅ doses were (µg kg^–1): atracurim375.6, vecuronium 67.2, pancuronium 86.6; the intial blockaderequired significantly larger doses than in normal patients(37%, 20% and 45%, respectively, using ED₅₀ values). Mean infusionrates for 90% sustained blockade in renal failure were (µgkg^–1h^{– 1}): atracurium 409.4, vecuronium 78.3, pancuronium14.2. The atracurium dose was not influenced by renal function,wheread vecuronium and pancuronium requirements were significantlyreduced by 23.2 % and 61.5%, respectively, compared with normalpatients (Previous study). Azathioprine was injected at therate of 1 mg kg–¹ min–¹ for 3 min at stable 90%neuromuscuiar blockade with constant-rate infusion of the neuromuscuiarblocking drug. This produced a relatively small and transientantagonism of blockadelprobably of negligible clinical significance.