ERRATA

Delete: "During infusions of alfentanil... can be derived". Insert: "During infusions of fentanyl at 3 µg kg^–1h^–1,the plasma concentration was 3.28±0.54 ng ml^–1,from which a clearance of 15.2 litre kg^–1 min^–1can be derived." Page 123. Formula for A (ml min^–1) should be: A (ml min^–1) = Page 258, line 13. The dose of pancuronium should have been0.1 ng kg^–1 and not 0.001 ng kg^–1 as printed.      

Light-chain-induced renal tubular acidosis: effect of sodium bicarbonate on sodium-proton exchange

We measured sodium-proton (Na⁺/H⁺) exchange in lymphocytes andplatelets of a 46-year-old woman with the adult Fanconi syndromebefore, during, and after treatment with NaHCO₃. Kappa lightchains in her urine and unique but rarely observed crystallinestructures confirmed the presence of light-chain nephropathy.Her glomerular filtration rate was only moderately impairedat 72 ml/min. NaHCO₃ at 1, 3, and 5 mmol/kg/day for 5 days increasedher serum HCO₃ and pH from 17 to 21 mmol/l and 7.28 to 7.39respectively. Plasma renin and aldosterone values were decreasedby NaHCO₃. Na⁺/H⁺ exchange (H_i/min) was measured with the fluorescentmarker BCECF after acidification of lymphocytes and plateletswith sodium propionate at five (10–50mM) doses. Na⁺/H⁺exchange was accelerated in this patient compared to normalcontrols. NaHCO₃ treatment significantly decreased Na⁺/H⁺ exchangein lymphocytes, but not in platelets. These findings suggestthat Na⁺/H⁺ exchange can be influenced by NaHCO₃ ingestion atdoses that only modestly affect systemic pH. Since Na⁺/H⁺ exchangeis involved in stimulus response coupling, cell growth regulation,cell differentiation, and perhaps the progression of nephrosclerosis,these observations may have clinical relevance.     

PHARMACOKINETICS OF ATRACURIUM IN ANAESTHETIZED INFANTS AND CHILDREN

The pharmacokinetics of atracurium were studied in infants andchildren anaesthetized with isoflurane and nitrous oxide inoxygen. There were no significant differences in volume of distribution(area) (139 v. 152 ml kg^–1), clearance (5.1 v. 5.3 mlkg^–1 min^–1), T (2.1 v. 2.0 mim), or T^ß(19.1 v. 20.3 min) between children with normal hepatic andrenal function and those with moderately impaired hepatic functionpresenting for hepatic transplantation. There were significantdifferences in volume of distribution (area) (176 v. 139 mlkg^–1) and in clearance of atracurium (9.1 v.5.1 ml kg^–1min^–1) between infants and children with normal excretoryfunction. In infants the clearance of atracurium in ml m^–1min^–1 (153 v. 133) tended to be greater and the T andT^ß tended to be shorter (1.0 v. 2.0 and 13.6 v. 19.1)than in children with normal excretory function; however, thesetrends did not reach statistical significance. Plasma laudanosineconcentration was around 100 ng ml^–1 greater in patientswith liver disease than in normal children from 15–45min following a bolus of atracurium 0.5 mg kg^–1.     

FENTANYL PHARMACOKINETICS IN ANAESTHETIZED PATIENTS WITH CIRRHOSIS

Fentanyl kinetics were studied in patients with cirrhosis andin patients with normal hepatic and renal function undergoingsurgery under general anaesthesia, the latter group served asthe controls. Plasma fentanyl concentrations declined bi-exponentiallyin the controls with an average elimination half-life (T^ß)of 263 mm; total plasma clearance (C7) was 10.8mlmin^–1kg^–1,and total apparent volume of distribution (V^ß) 3 81litre kg^–1. No significant change was observed in patientswith cirrhosis: T( T^ß) was 304mm, Cl 11.3 ml min^–1kg^–1 and V^ß 4.41 litre kg^–1. These datasuggest that the elimination half-life of fentanyl is not primarilyinfluenced by the rate at which it is metabolized in the liver.     

Mg2+ dependence of Ca2+ release from the sarcoplasmic reticulum induced by sevoflurane or halothane in skeletal muscle from humans susceptible to malignant hyperthermia

Background. In normal resting muscle, cytosolic Mg²⁺ exertsa potent inhibitory influence on the sarcoplasmic reticulum(SR) Ca²⁺ release channel (ryanodine receptor, RyR1). ImpairedMg²⁺-regulation of RyR1 has been proposed as a causal factorin malignant hyperthermia (MH). The aim of this study was tocompare the effects of cytosolic Mg²⁺ on SR Ca²⁺ release inducedby halothane or sevoflurane in normal (MHN) and MH susceptible(MHS) human skeletal muscle fibres. Methods. Samples of vastus medialis muscle were obtained frompatients under investigation for MH susceptibility. Single fibreswere mechanically skinned and perfused with solutions mimickingthe intracellular milieu. Changes in [Ca²⁺]_i were detected usingfura-2 fluorescence after application of equimolar halothaneor sevoflurane. Results. In MHN fibres, concentrations of sevoflurane or halothaneas high as 10 mM typically failed to induce SR Ca²⁺ releaseat physiological free [Mg²⁺] (1 mM). However, when [Mg²⁺] wasdecreased to 0.4 mM, SR Ca²⁺ release occurred in 51% (16/33)and 6% (2/33) of MHN fibres after the addition of 1 mM halothaneor 1 mM sevoflurane, respectively. Further decreases in [Mg²⁺]increased the proportion of responsive fibres. In the presenceof 0.1 mM [Mg²⁺], Ca²⁺ release occurred in all fibres (33/33)after the introduction of 1 mM halothane or 1 mM sevoflurane.In MHS fibres, 1 mM halothane or 1 mM sevoflurane-induced Ca²⁺release in 54% (7/13) or 15% (2/13) of fibres, respectively,at 1 mM Mg²⁺. A decrease in [Mg²⁺] to 0.2 mM Mg²⁺ was sufficientto render 100% of MHS fibres (13/13) responsive to 1 mM halothaneor 1 mM sevoflurane. Conclusions. In both MHS and MHN fibres (i) halothane is a morepotent activator of SR Ca²⁺ release than sevoflurane and (ii)as with halothane, the efficacy of sevoflurane-induced SR Ca²⁺release exhibits a marked dependence on cytosolic [Mg²⁺]. Themarked potentiation of SR Ca²⁺ release after a moderate reductionin cytosolic [Mg²⁺] suggests that conditions which cause hypomagnesaemiawill increase the probability and possibly severity of an MHevent. Conversely, maintenance of a normal or slightly increasedcytosolic [Mg²⁺] may reduce the probability of MH.     

PHARMACOKINETICS OF GALANTHAMINE (A LONG-ACTING ANTICHOLINESTERASE DRUG) IN ANAESTHETIZED PATIENTS

The pharmacokinetics of the long-acting anti-cholinesterasedrug, galanthamine, were investi-gated in eight patients. Afteri.v. injection of 0.3 mg kg^–1, the decrease in the serumconcen-tration of galanthamine followed a biexponential curve.The serum concentration decreased rapidly from 543±47ng ml^–1 to 128±14 ng ml^–1 be-tween 2 and30 min with a T of 6.42 ± 2.15 min, and then declinedmore slowly with a T^ß of 264±28min. Total serumclearance of galanthamine amounted to 5.37±0.87ml min^–1kg^–1, and the renal clearance was 1.36±0.10 mlmin^–1 kg^–1. The cumulative urinary excretion ofgalanthamine between 0 and 48 h after injection amounted to28.0±5.4% of the administered dose. The biliary excretionof galanthamine during 24 h amounted to 0.2 ±0.1% ofthe dose. There was no evidence of glucuronide or sulphate conjugationof galanthampine.     

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.     

EFFECTS OF URAPIDIL, KETANSERIN AND SODIUM NITROPRUSSIDE ON VENOUS ADMIXTURE AND ARTERIAL OXYGENATION FOLLOWING CORONARY ARTERY BYPASS GRAFTING

Thirty patients who developed arterial hypertension followingcoronary artery bypass grafting, despite sedation, were treatedrandomly with sodium nitroprusside (SNP), ketanserin or urapidil.All drugs significantly decreased arterial pressure. Two patientswere withdrawn because hypertension failed to respond to ketanserin.Significant tachycardia was noted only in the SNP group. Anincrease in and significant decreases in systemic and pulmonaryvascular resistances were seen in all groups. Following administrationof SNP, (PA^o2–Pa^o2) and s/t increased significantly, whereasPa^o2 decreased significantly. Three patients were withdrawnfrom the SNP group because s/t was > 30%. (PA^o2—Pa^o2)and s/t showed no significant changes following the administrationof ketanserin or urapidil. These drugs may have advantages overSNP in the management of hypertension following coronary arterybypass surgery.     

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.     

Quantitative versus Semiquantitative Procalcitonin Measurement

Background: Procalcitonin, an excellent marker of sepsis, is measured in trauma intensive care units by a standard quantitative test. Recently, a quicker semiquantitative test has become available. The aim of this study was to compare both tests to determine whether the quicker new test is as reliable as the standard test for trauma patients. Patients and Methods: This prospective 4-month study included all severely traumatized patients admitted to our intensive care unit. Parallel procalcitonin measurements were performed daily, comparing the standard LUMItestPCT^® to the categorization (normal < 0.5 ng/ml, moderately increased 0.5-2 ng/ml, or highly increased > 2 ng/ml) by the quicker PCT-Q^® test (both B.R.A.H.M.S.-Diagnostica GmbH, Henningsdorf, Germany). Results: Procalcitonin was measured in 167 samples from 15 patients (Injury Severity Score 29 - 13). Among the increased procalcitonin levels (increased LUMItest-PCT^®), the PCT-Q^® test picked up only 14 of 38 samples (36.8%). Among the normal procalcitonin levels (normal LUMItestPCT^®) the PCT-Q^® test classified 127 of 129 samples (98.4%) the same, i.e. correctly, and two samples (1.6%) moderately increased, i.e. too high. Compared to the LUMItestPCT^®, the PCT-Q^® test has a low sensitivity of 44% and a high specificity of 97%. Conclusions: The semiquantitative PCT-Q^® test is highly specific but far less sensitive than the LUMItestPCT^®. Normal procalcitonin readings by the PCT-Q^® test are often incorrectly low, while moderately (0.5-2 ng/ml) and highly increased (> 2 ng/ml) readings are usually correct. Because of the rate of incorrectly low readings, the PCT-Q^® test is unreliable for trauma patients.     

PHARMACOKINETICS OF PHENOPERIDINE IN ANAESTHETIZED PATIENTS UNDERGOING GENERAL SURGERY

The pharmacokinetics of phenoperidine have been studied in fiveanaesthetized patients receiving a 2-mg bolus dose i.v. Plasmaconcentrations were measured using a sensitive radioimmunoassaymethod. The distribution of phenoperidine was described accordingto a two-compartment open model. The mean distribution half-life(T) for the five patients was short (2.2 min); the mean eliminationhalf-life (T^ß) was 193 min. The mean whole body clearancewas 22 ml min^-1 kg^-1 and the apparent steady state distributionvolume (V^SS) was 5.7 litre kg^-1. Secondary concentration peaksoccurred in all patients; in two patients these were substantialand occurred 80 min after injection.     

THE ROLE OF {alpha}1-ADRENOCEPTORS IN ADRENALINE INDUCED HYPERKALAEMIA

The hyperkalaemic action of adrenaline was investigated in 44anaesthetized domestic pigs. Plasma and epicardial concentrationsof K⁺ were measured, in the latter case with an ion-selectiveelectrode. Adrenaline 10 µg kg^–1 caused a rapidincrease in the plasma concentration of K⁺ from 4.2 to 5.9 mmollitre^–1. The magnitude and the time course of epicardialconcentration of K⁺ were similar. Alpha-adrenoceptor block witheither phentolamine 5 mg kg^–1 (non-selective block) orprazosin 0.1 mg kg^–1 (selective 1-adrenoceptor block)abolished the hyperkalaemic effect of adrenaline in the plasmaand on the epicardium. The 1-adrenoceptor agonist phenylephrineincreased the K⁺ concentration, but the 2-adrenoceptor agonistUK 14.304 did not cause any change in concentration. These resultssuggest that the hyperkalaemia induced by adrenaline occursin the interstitial fluid of the myocardium and is mediatedby 1-adrenoceptors. These findings may be important in patientsat risk of hyperkalaemia, with implications, for example, inthe use of suxamethonium during induction of anaesthesia.     

OESOPHAGEAL CONTRACTILITY DURING TOTAL I.V. ANAESTHESIA WITH AND WITHOUT GLYCOPYRRONIUM

Somatic movement and spontaneous and provoked oesophageal contractionswere noted at time of incision in 51 patients receiving totali.v. anaesthesia with alfentanil and propofol. Probit analysisof the dose of propofol required to prevent spontaneous movementrevealed an ED₅₀ (95% confidence limits) of 2.5 (1.8-2.9) mgkg^–1 h^–1 and ED₉₅ of 4.7 (4.0-7.5) mg kg^–1h^–1. Corresponding venous blood concentrations gave anEC₅₀ of 1.2 (0.4-1.6) µg ml^–1 and an EC₉₅ of 4.0(2.8-18.5) µg ml^minus;1. ED₅₀ of propofol for preventingspontaneous oesophageal contraction was 3.0 (1.9-3.6) mg kg^–1h^–1. ED₉₅ was 6.9 (5.0-27.3) mg kg^–1 h^–1;EC₅₀ for oesophageal contractions was 1.7 (0.7-2.3) µgml^–1 and EC₉₅ was 5.9 (3.7-70.6) µg ml^–1.Another group of 10 patients were given glycopyrronium 5 µgkg^–1 at induction; oesophageal contractility was significantlyreduced in this group. Preliminary results of this research were presented to the AnaestheticResearch Society, Nottingham, July 1990. ^*Department of Anaesthesia, Derriford Hospital, Plymouth, DevonPL6 8DH. Department of Anaesthesia, Darlington Memorial Hospital, Darlington,Durham DL3 6HX.     

PHARAMACOKINETICS OF PROPOFOL IN YOUNG CHILDREN AFTER A SINGLE DOSE

The pharmacokinetics of propofol were studied following a singlebolus injection (2.5 mg kg^–1) in 10 healthy children (4–7yr). Propofol was distributed rapidly and extensively (Vss 10.9(1.2) litre kg^–1) and cleared rapidly from the body (Cl30.6 (2.9) ml min^–1 kg^–1). With the exception ofa larger central compartment volume (V 722 (113) ml kg^–1).these data are similar to those reported for young adults whoreceived an identical dose and who underwent sampling over thesame period. The larger value of V is consistent with the higherinduction dose requirement reported for children.     

THE CONCEPT OF DEADSPACE WITH SPECIAL REFERENCE TO THE SINGLE BREATH TEST FOR CARBON DIOXIDE

We present a review and a theoretical analysis of factors determiningairway deadspace (VD^aw) and alveolar deadspace (VD^alv), thetwo constituents of physiological deadspace (VD^phys). VD^aw isthe volume of gas between the lips and the alveolar/fresh gasinterface, the location of which is determined by inspiratoryflow pattern and airway geometry. VD^alv can be caused by incompletealveolar gas mixing and associated / mismatching within the terminal respiratoryunits, temporal / mismatching within units, spatial / mismatching between units, and venous admixture. Most causes of VD^phys are influencedby inspiratory flow pattern and the time available for gas diffusionand distribution. Analysis can be made from the single breathtest for carbon dioxide (SBT–CO₂) which is the plot offraction of carbon dioxide in expired gas against expired volume.The common causes of VD^alv are associated with a sloping SBT-CO₂phase III. Combination of SBT-CO₂ with PaCO₂ yields VD^phys andVD^alv. A sloping phase III with a negative arterial-end-tidalPco₂ gradient implies compensation by perfusion for early emptying,overventilated alveoli.     

LIGNOCAINE KINETICS DURING CARDIOPULMONARY BYPASS: Optimum Dosage and the Effects of Haemodilution

Lignocaine was administered to patients undergoing cardiopulmonarybypass at 28–29°C in bolus doses of 1.5, 2.5 and 3.5mg kg^–1. Plasma concentrations greater than 1.5 µgml^–1 were found briefly and inconsistently in patientsreceiving the usually recommended dose (1.5 mg kg^–1),but reliably for 14min in those receiving 2.5 mg kg^–1.The 3.5 mg kg^–1 dose produced statistically and clinicallysignificant decreases in mean arterial pressure. Examinationof calculated kinetic parameters showed a two-fold decreasein T, two-fold increases in Tß and V^es and unalteredCl_p and V_p when compared with those of unanaesthetized, normothermicpatients. The alteration in pharmacokinetics may be attributedlargely to decreased binding to albumin following haemodilution.     

PHARMACOKINETICS OF ORG NC45 (NORCURON) IN PATIENTS WITH AND WITHOUT RENAL FAILURE

To determine the influence of renal failure on the pharmacokineticsand neuromuscular blockade of Org NC 45 (Norcuron), a new monoquaternaryhomologue of pancuronium, 13 patients under halothane and nitrousoxide anaesthesia were studied. Org NC45 was administered by2-min infusion in doses of 0.28mgkg^–1 (normal renal functiongroup, n = 4) and 0.14mgkg^–1 (renal failure group, n =5). Four additional patients with normal renal function weregiven Org NC45 0.14mg kg^–1 to determine the onset, durationand recovery rate of neuromuscular blockade. The serum concentrationof Org NC 45 was determined by normal-phase high performanceliquid chromatography (sensitivity 50ng ml^–1), and a two-compartmentopen pharmacokinefic model was fitted to resulting data. Estimatesof distribution half-life , elimination half-life , volume of distribution at steady state (V^ss) and clearance ofOrg NC 45 did not differ significantly between patients withnormal renal function and those with renal failure. The onset,duration and recovery rate times of the neuromuscular blockadeby Org NC 450.14mg kg^–1 in patients with normal renalfunction and those with renal failure also did not differ significantly.     

Effect of extracellular fluid volume on single-sample measurement of glomerular filtration rate

Objective. The objective of our study was to evaluate the effectof extracellular fluid volume (ECV) on the accuracy of measurementof glomerular filtration rate from a single sample (GFR1). Methods. Multi-sample GFR (GFR6) and ECV (per 1.73 m²) weremeasured with both Cr-51-EDTA and iohexol, injected into oppositearms (110 studies in 80 subjects). Six plasma samples were obtainedbilaterally 20– 240 min post-injection to measure GFR6/1.73m². GFR1/1.73 m² was calculated from 2-, 3- and 4-h samplesusing Jacobsson's formula for iohexol and the Christensen andGroth formula for Cr-51-EDTA. The quotient, GFR1/GFR6, was takento indicate the accuracy of GFR1. Results. When GFR6 was <60 ml/min/1.73 m², GFR1/ GFR6 correlatedpositively with ECV at all single-sample times. When GFR6 was60–90 ml/min/1.73 m² or >90 ml/min/1.73m², GFR1/GFR6 correlated positively with ECV at 2 h, but negativelyat 4 h, indicating that at some time between 2 and 4 h, GFR1/GFR6was transiently independent of ECV. A plot of the regressiongradient of GFR1/GFR6 on ECV against sample time indicated thatthe time of transient independence, at which time GFR1 dependsexclusively on GFR6, was 3.2–3.9 h (depending on indicatorcombination used) when GFR6 was 60–90 ml/min/1.73 m² and2.4–2.9 h when GFR was >90 ml/min/1.73 m². Transientindependence when GFR6 was <60 ml/min/1.73 m² was not reachedby 4 h and estimated to be 5–7 h. Conclusion. The accuracy of GFR1 depends on ECV, overestimationor underestimation respectively depending on sample time andGFR. The time at which GFR1 is independent of ECV increaseswith decreasing GFR. If sampling time is too early, GFR1 overestimatesGFR, but the reverse occurs when sampling is too late, evenif GFR is abnormally low.     

CALCIUM AND MAGNESIUM CONTENT OF SKELETAL MUSCLE: Studies in Subjects Undergoing Diagnostic Testing for Malignant Hyperthermia

Ca²⁺ and Mg²⁺ contents were measured and compared among threedifferent malignant hyperthermia susceptible (MHS) diagnosticgroups. No difference was found among mean values for Ca²⁺ content,whereas Mg²⁺ content was greater in MHS muscle. Variance ofmeasured values was unequal and greatest among MHS muscles,suggesting a possible abnormal distribution associated withMHS. Although more muscle fibres with Ca²⁺ 12 µmol g^–1were observed in MHS muscle, this difference was not statisticallysignificant. In contrast, non-parametric analysis showed thatthe population of Mg²⁺ values was significantly greater in theMHS muscle. This study suggests that the distribution of Ca²⁺and Mg²⁺ values is different in MHS muscle as a result of unknowngenetic factors associated with the disease.     

INCREASED VENTILATION REQUIREMENTS DURING OBSTETRIC GENERAL ANAESTHESIA

The inspiratory fresh gas flow rate (FGF) required to producean end-tidal carbon dioxide tension (PE' _CO2)of 4kPa duringgeneral anaesthesia, neuromuscular blockade and artificial ventilation,was compared in a group of 46 obstetric patients and a matchedgroup of 50 non-pregnant female patients. The non-pregnant patientsrequired a mean (SD) inspiratory FGF of 77 (10.6) ml kg^–1min^–1, whereas the pregnant patients required a mean FGFof 121 (24.6) ml kg^–1 min^–1 before delivery (inthose who reached a stable state), and 109 (19.3) ml kg^–1min^–1 after delivery. These represent significant (P <0.0001) increases of 57% and 42%, respectively, over the non-pregnantstate. ^*Anaesthetics Unit, The London Hospital, Whitechapel, LondonEl IBB. 335, Southampton Road, Titchfield, Hants PO14 4AX. Northampton General Hospital, Whitechapel, London E1 1BB.