Low-dose calcitriol prevents the rise in 1,84 iPTH without affecting serum calcium and phosphate in patients with moderate renal failure (prospective placebo-controlled multicentre trial)

BACKGROUND: Higher doses of calcitriol are effective in lowering markedlyelevated 1,84 PTH levels of patients with renal secondary hyperparathyroidism.It has not been established, however, whether prophylactic administrationof low doses of calcitriol prevents an increase of 1,84 PTHwithout causing side-effects, i.e. hypercalcaemia, hypercalciuria,or hyper-phosphataemia. STUDY DESIGN: We carried out a placebo-controlled, double-blind prospectivemulticentre trial over 12 months in 45 patients with mild tomoderate renal failure. Criteria for inclusion were S-creatinine1.4mg/dl and 1,84 PTH>6pmol/l (normal 6). Calcitriol 0.125ug/day per os was compared with placebo. The patients receivedcalcium carbonate per os if serum P exceeded 1.7 mmol/1. RESULTS: Baseline 1,84 iPTH concentrations were not significantly different,i.e. 14.0 pmol/1 (6.7–63.3) on placebo vs 16.2 (6.85–82.0)on calcitriol. Intention to treat analysis revealed a significantdifference of final 1,84 iPTH, i.e. 27.8 (4.2–68.5) onplacebo vs 18.2 (4.45–75.5) on calcitriol. On post-hocanalysis the difference was even more pronounced at S-creatinineconcentrations above 3 mg/dl. S-calcium, S-phosphate, and urinaryexcretion of calcium did not change significantly on eitherplacebo or on calcitriol. There were no episodes of hypercalcaemiaor hyperphosphataemia. There was no significant difference offinal S-creatinine or change in S-creatinine between placeboand calcitriol. One patient on calcitriol and two on placeboprogressed to terminal renal failure. Bone alkaline phosphataseas a non-invasive index of bone metabolism was not decreasedto subnormal levels. CONCLUSIONS: The results document that a therapeutic window exists in patientswith moderate renal failure and elevated of 1,84 iPTH, wherelow-dose calcitriol (0.125 ug/day) prevents the increase in1,84 iPTH without causing side-effects. This observation suggeststhat the parathyroid is more sensitive to calcitriol than intestineand bone.     

PTH/PTHrP receptor mRNA is down-regulated in epiphyseal cartilage growth plate of uraemic rats

PTH/PTHrP receptor mRNA is down-regulated in epiphyseal cartilagegrowth plate of uraemic rats. Growth retardation, hypocalcaemia,hyperphosphataemia, and skeletal resistance to the action ofPTH are well known features of advanced chronic renal failure(CRF). It has been suggested that the downregulation of renaland skeletal PTH receptors (PTH/PTHrP-R) could play an importantrole in the occurrence of these abnormalities. In the presentstudy, four uraemic (4 weeks after 5/6 nephrectomy) and fourcontrol (sham-operated) rats were analysed for PTH/PTHrP-R mRNAexpression at the proximal femoral and tibial growth platesby in situ hybridization. Uraemic rats had plasma biochemicalabnormalities of advanced CRF including high creatinine, phosphate,and PTH, and low calcium and calcitriol levels. The femoraland tibial bones of uraemic animals were shorter in length thanthose of control rats, and had reduced width and cellularityof the epiphyseal cartilage growth plate. Mean (±SD)tibia growth plate width was 152±30 µm in uraemicrats, compared with 170±35 µm in control rats.The difference was mostly due to a marked reduction of the zoneexpressing PTH/PTHrP-R (mature chondrocytes) which was 30±5µm in tibias from uraemic versus 44±10 µmin tibias from control rats. The hybridization signals of PTH/PTHrP-Rper individual cell were quantified on dark field images usinga computer-assisted image analysis system. The number of grainsin PTH/PTHrP-R positive cells was also decreased in uraemicrats, 103±13 compared with 123±14 arbitrary units(dark pixel density)/cell in control rats (P 0.005). In conclusion,these data indicate that rats with severe CRF and secondaryhyperparathyroidism have reduced epiphyseal cartil age PTH/PTHrP-RmRNA expression. This alteration may be relevant in the pathogenesisof growth retardation in uraemia.     

Comparison of chronic renal failure rats and modification of the preparation protocol as a hyperphosphataemia model

Background: Several animal models with chronic renal failure have been established and used for demonstrating complications including hyperphosphataemia. Although long‐time feeding is required to cause hyperphosphataemia in animals, a few modifications have been reported to provide more useful models for research. Methods: Three separate experiments were carried out in the present study. First, characteristics of commonly used subnephrectomized (5/6Nx) rats and rats fed an adenine diet (0.75% adenine in normal diet) were compared as hyperphosphataemia models. Next, using adenine‐diet rats, the inhibitory effect of sevelamer hydrochloride (Sev) on serum phosphorus elevation was examined. Third, oral adenine dosing for induction of hyperphosphataemia and validation as a model using Sev were examined. Results: Serum phosphorus in 5/6Nx rats became elevated in 8–17 weeks, but the levels and time points of elevation differed among animals. In adenine‐fed rats, the elevation was more clearly demonstrated with less diversity at 4 weeks. The data revealed a potential shorter model preparation period and the importance of controlling feeding amounts. Oral adenine dosing induced hyperphosphataemia by 12 days, and Sev treatment was inhibitory. After a maintenance period of over a month (no treatments), Sev‐treated rats showed hyperphosphataemia as did oral adenine‐dosed control rats. The serum phosphorus levels significantly decreased on further Sev treatment. Conclusion: Oral dosing with adenine made the model preparation period definitely shorter, and its usefulness as a hyperphosphataemia model was revealed using Sev.     

Calcinosis universalis with hyperphosphataemia--successful treatment with phosphorus deprivation

Seven year old boy with calcinosis universalis associated with high serum phosphorus was reported. Over one year's treatment with aluminum hydroxide up to 18 grams per day have reduced calcified mass remarkably, while serum phosphorus levels were remaining still above the normal range. Concomitant use of probenecid seemed to be effective in reducing serum phosphorus levels as well as decreasing the calcified mass. Pathogenetic mechanisms of soft tissue calcification in calcinosis universalis is not clear, but in this case hyperphosphataemia is considered to be one important factor accelerating soft tissue calcification. Although hyperphosphataemia associated with tumoral calcinosis has been frequently observed, no report is yet available on calcinosis universalis associated with hyperphosphataemia. This case might represent one unique type of calcinosis.     

Management of hyperphosphataemia of chronic kidney disease: lessons from the past and future directions.

A historical look at research in hyperphosphataemia of chronic kidney disease over the last 40 years shows remarkable advances in our understanding of this abnormality and in the technology used to manage it. Phosphate binders, which have become a mainstay in the management of hyperphosphataemia, have evolved from the early use of aluminium gels to calcium salts, to novel, non-absorbed, aluminium-free, calcium-free agents such as sevelamer hydrochloride, and to magnesium-, iron-, and lanthanum-based compounds. With recent advances, clinical management of this complication of chronic renal disease is evolving from adequate care to optimal care, such that new standards in phosphorous management are being set, and various parameters of patient care are being integrated to optimize outcomes and minimize side effects. This paper provides a historical view of the clinical management of hyperphosphataemia, and looks to advances in treatment that are changing the course of renal bone disease management.     

High-normal calcium (1.35 mmol/I) dialysate in patients on CAPD: efficient and safe long-term control of plasma calcium, phosphate, and parathyroid hormone

AIM.: The aim of the present study was to examine the long-term efficacyand safety of treatment with a high-normal calcium dialysatewith a calcium concentration of 1.35 mmol/l in patients on CAPD.This dialysate calcium concentration is close to the high-normalplasma ionized calcium level aimed at in dialysis patients inorder to suppress the parathyroid hormone secretion. The end-pointsof the study were (1) plasma ionized calcium (iCa) and phosphate(P) levels, (2) plasma intact parathyroid hormone (PTH) levels,(3) doses of calcium carbonate and alfacalcidol, (4) requirementsof Al-containing phosphate binders, and (5) bone mineral density(BMD). RESULTS.: Thirty-seven non-selected patients on CAPD treatment were followedfor an average of 10 months after switching from a dialysateCa of 1.75 to 1.35 mmol/l. After 1 week, a significant decreaseof mean iCa from 1.26±0.01 to 1.23±0.01 mmol/l(P<0.05) and an increase of median PTH from 80 to 135 pg/ml(P<0.01) were seen. From the 2nd week and onwards, however,basal levels of iCa and PTH were restored and remained stable.Mean plasma iCa was kept within 1.23–1.31 mmol/l; meanplasma P below 1.65 mmol/l and median PTH within 52–135pg/ml. Episodes of hypercalcaemia were few (1.2 cases of plasmaiCa>1.45 mmol/l per 100 treatment weeks), and the need forAl-containing P binders low with only five patients requringthis treatment for isolated and four patients for repeated episodesof hyperphosphataemia or hypercalcaemia. After switching froma dialysate Ca of 1.75 to 1.35 mmol/l, the doses of calciumcarbonate and alfacalcidol could be significantly increased.Furthermore, using the dialysate Ca of 1.35 mmol/l made it possibleto induce a controlled increase of PTH levels to 80–100pg/ml by a temporarily discontinuation of alfacalcidol and/ora reduction of calcium carbonate dosage in the patients wherePTH had become suppressed to levels below the upper normal limit.The intention of the treatment was to maintain PTH levels within1.5–2.5 times the upper normal limit for non-uraemic patients.Pre-study BMD of the vertebral bodies L2–L4 and of thefemoral neck were normal and not significantly different frompost-study measurements. CONCLUSIONS.: The present study demonstrated that when using a high-normaldialysate Ca concentration of 1.35 mmol/l in non-selected patientson CAPD treatment, high-normal plasma iCa and near-normal plasmaP levels could be readily achieved with a minimal risk of incidentalhypercalcaemia despite use of calcium carbonate as the mainP binder. As a consequnce of the tight Ca and P regulation,minimal doses of alfacalcidol were required to keep PTH withinacceptable limits. We recommend this dialysate Ca concentrationas a first-choice therapy for the majority of patients startingon CAPD treatment.     

Economic evaluations of interventions to manage hyperphosphataemia in adult haemodialysis patients: A systematic review

Managing hyperphosphataemia in haemodialysis patients is resource‐intensive. A search for cost‐effective interventions in this field is needed to inform decisions on the allocation of healthcare resources. NHSEED, MEDLINE, EMBASE and CINAHL were searched for full economic evaluations of hyperphosphataemia‐managing interventions in adult haemodialysis patients, published between 2004 and 2014, in English, French, Dutch or German. Incremental cost‐effectiveness ratios of the interventions were up‐rated to 2013US$ using Purchasing Power Parity conversion rates and Consumer Price Indices. The quality of included studies was assessed using the Extended Consensus on Health Economic Criteria List. Twelve out of the 1681 retrieved records fulfilled the inclusion criteria. They reported only on one aspect of hyperphosphataemia management, which is the use of phosphate binders (calcium‐based and calcium‐free, in first‐line and sequential use). No economic evaluations of other phosphorus‐lowering interventions were found. The included articles derived from five countries and most of them were funded by pharmaceutical companies. The incremental cost‐effectiveness ratios of phosphate binders ranged between US$11 461 and US$157 760 per quality‐adjusted life‐year gained. Calcium‐based binders (especially calcium acetate) appear to be the optimal cost‐effective first‐ and second‐line therapy in prevalent patients, while the calcium‐free binder, lanthanum carbonate, might provide good value for money, as second‐line therapy, in incident patients. The studies' overall quality was suboptimal. Drawing firm conclusions was not possible due to the quality heterogeneity and inconsistent results. Future high‐quality economic evaluations are needed to confirm the findings of this review and to address other interventions to manage hyperphosphataemia in this population.     

Stereoselective in vitro degradation pattern of mivacurium in human plasma

Background. Mivacurium is a mixture of three isomers, two ofwhich are rapidly broken down in vivo by plasma cholinesterases.This study investigates the stereospecificity of mivacuriumin vitro degradation to determine if it accounts for its invivo behaviour. Methods. The in vitro rate of degradation of each isomer ofmivacurium and the in vitro rate of formation of their primary(monoesters and alcohols) and secondary (alcohols) metaboliteswere examined using human plasma from six healthy volunteers.The in vitro rate of degradation of the monoester metaboliteswas also assessed. All these determinations were made usinga stereospecific high-performance liquid chromatography assay. Results. The in vitro rate of disappearance of the two activeisomers of mivacurium was very rapid, with mean values for thetrans trans and cis trans isomers of 0.803 and 0.921 min^–1respectively. These values are twofold faster than publishedin vivo data. The in vitro rate of disappearance was much slowerfor the cis cis isomer, with a mean value of 0.0106 min^–1.The cis trans isomer was converted exclusively to cis monoesterand trans alcohol, while only metabolites in the trans and cisconfiguration were found for the trans trans and cis cis isomersrespectively. Mean in vitro rates of disappearance for the transand cis monoester were 0.00750 and 0.000633 min^–1respectively. Conclusions. The in vitro rates of hydrolysis of the activeisomers of mivacurium confirm that plasma cholinesterases playa major role in their in vivo degradation, but that in vivoelimination is slowed by extravascular distribution. Mivacuriumhydrolysis is stereoselective, the ester group in the transconfiguration being more accessible to enzymatic attack. Thisstereoselective pattern, along with the relatively slow breakdownof the cis cis isomer, sheds light on the in vivo dispositionof the cis alcohol metabolite. Br J Anaesth 2002; 89: 832–8     

Gabapentin attenuates the pressor response to direct laryngoscopy and tracheal intubation

Background. Laryngoscopy and tracheal intubation increase bloodpressure and heart rate (HR). The aim of the present study wasto investigate the effect of gabapentin when given before operationon the haemodynamic responses to laryngoscopy and intubation. Methods. Forty-six patients undergoing abdominal hysterectomyfor benign disease were randomly allocated to receive gabapentin1600 mg or placebo capsules at 6 hourly intervals starting theday (noon) before surgery. Anaesthesia was induced with propofoland cis-atracurium. Systolic, diastolic arterial blood pressures(SAP, DAP) and heart rate (HR) were recorded before and afterthe anaesthetic and 0, 1, 3, 5 and 10 min after tracheal intubation. Results. SAP was significantly lower in the gabapentin vs thecontrol group 0, 1, 3, 5 and 10 min after intubation [128 (27)vs 165 (41), P=0.001, 121 (14) vs 148 (29), P=0.0001, 115 (13)vs 134 (24), P=0.002, 111 (12) vs 126 (19), P=0.004 and 108(12) vs 124 (17), P=0.001 respectively]. DAP also was lowerin the gabapentin group 0, 1, 3, and 10 min after intubation[81 (18) vs 104 (19), P=0.0001, 77 (9) vs 91 (16), P=0.001,71 (10) vs 84 (13), P=0.001 and 67 (10) vs 79 (12), P=0.004].HR did not differ between the two groups at any time [82 (11)vs 83 (15), 79 (10) vs 80 (12), 86 (17) vs 92 (10), 82 (11)vs 88 (10), 81 (12) vs 81 (11), 77 (13) vs 79 (13), and 75 (15)vs 78 (12)]. Conclusion. Gabapentin, under the present study design attenuatesthe pressor response but not the tachycardia associated withlaryngoscopy and tracheal intubation.     

Influence of dialyser clearance measurement accuracy on haemodialysis prescription based onKt/V

Kt/V urea (u) has been used as a measure of adequacy of haemodialysis(HD). However, the accurate assessment of its components isdifficult and subject to error in a clinical setting. This studywas designed to evaluate different forms of dialyser clearance(K) measurements and their influence on Kt/V. Sixteen patientson high-flux HD were studied at blood flow (Q_b) rates of 250and 350 ml/min and at constant dialysate flow rates. K of ureawas measured by the arteriovenous blood sampling technique (K_bu),corrected for access recirculation (K_bru) and compared withK as determined by dialysate collection (K_du) using a new samplingdevice. At Q_b 250 and 350 ml/min, K_bu as based on dialysatecollection was significantly lower than K_bru and K_bu as basedon arteriovenous blood sampling: at Q_b 250, K_du 169.0±13.3, K_bru 191.2±11.5, and K_bu 203.0±9.3 ml/min(P<0.0005); at Q_b 350, K_du 196.5±17.3, K_bru 227.7±15.5,and K_bu 243.6±12.7 ml/min (P<0.0005). At Q_b 250 ml/minK_bu t/V (1.33±0.17) overestimated K_du t/V (1.11±0.13)by 16.8%, at Q_b 350 ml/min by 19.3% (1.58 ± 0.19 versus1.27±0.15). Dialyser clearances based on arteriovenousdifferences in blood overestimate true clearances (and thereforeKt/V) as measured by dialysate collection. This overestimationis more marked with higher blood flow rates.     

IS THE END-TIDAL PARTIAL PRESSURE OF ISOFLURANE A GOOD PREDICTOR OF ITS ARTERIAL PARTIAL PRESSURE?

End-tidal partial pressure of isoflurane (PE'_iso) may be usedas a measure of anaesthetic depth. During uptake, an arterialpartial pressure (Pa_iso) which is considerably less than PE'_iso(Pa_iso/PE'_iso«1)leads to underestimation of depth of anaesthesia and, duringelimination, PE'_iso/Pa_iso«1 will lead to an overestimationof anaesthetic depth. We measured Pa_iso/PE'_iso during a 60-minuptake period of 1% isoflurane and PE'_iso/Pa_iso during the subsequent60-min elimination period in 26 patients (age 13–88 yr,ASA I–III) undergoing various surgical procedures. After15 min of isoflurane uptake, Pa_iso/PE'_iso of 26 patients wasmean 0.78 (SD 0.10) and this increased only marginally at 60min (0.79 (0.09)), whereas during elimination, PE'_iso/Pa_isowas in the range 0.79 (0.14)–0.83 (0.11). Predictabilityof Pa_iso in a given patient is hindered by the high SD of Pa_iso/PE'_isoand PE'_iso/Pa_iso, but it may be improved by taking into accountage, ASA physical status category, vital capacity, inspiredminus end-tidal isoflurane partial pressure and arterial minusend-tidal carbon dioxide partial pressure during uptake; andobesity, end-tidal isoflurane partial pressure and arterialminus end-tidal carbon dioxide partial pressure during elimination.However, even with multiple regression analysis (to accountfor the various possible variables), clinically useful predictionof Pa_iso/PE'_iso and PE'_iso/Pa_iso in a particular patient isnot possible (residual SD 0.084 and 0.113, respectively).     

Gastric mucosal end-tidal PCO2 difference as a continuous indicator of splanchnic perfusion

Gastric mucosal and arterial blood PCO₂ must be known to assessmucosal perfusion by means of gastric tonometry. As end-tidalPCO₂ (PE'_CO2) is a function of arterial PCO₂, the gradient betweenPE'_CO2 and gastric mucosal PCO₂ may reflect mucosal perfusion.We studied the agreement between two methods to monitor gutperfusion. We measured the difference between gastric mucosalPCO₂ (air tonometry) and PE'_CO2 (=DPCO_2gas) and the differencebetween gastric mucosal PCO₂ (saline tonometry) and arterialblood PCO₂ (=DPCO_2sal) in 20 patients with or without lung injury.DPCO_2gas was greater than DPCO_2sal but changes in DPCO_2gas reflectedchanges in DPCO_2sal. The bias between DPCO_2gas and DPCO_2salwas 0.85 kPa and precision 1.25 kPa. The disagreement betweenDPCO_2gas and DPCO_2sal increased with increasing dead space.We propose that the disagreement between the two methods studiedmay not be clinically important and that DPCO_2gas may be a methodfor continuous estimation of splanchnic perfusion. Br J Anaesth 2000; 85: 563–9 ^* Corresponding author: Department of Anesthesiology and IntensiveCare, Division of Critical Care, Kuopio University Hospital,PO Box 1777, FIN-70211 Kuopio, Finland     

In vitro oxyhaemoglobin saturation measurements in haemoglobin solutions using fibreoptic pulmonary artery catheters

We compared in vitro oxyhaemoglobin saturations using two pulmonaryartery catheters (catheter So₂) with oxyhaemoglobin saturations(So₂) measured by the IL282 co-oximeter and derived partialoxyhaemoglobin saturations (partial So₂) at different oxygentensions (Po₂) in six solutions: whole blood, 50:50 mixtureof whole blood and Plasmalyte A (haemodiluted blood), 50:50mixture of whole blood and 8% pyridoxylated haemoglobin-polyoxyethylene(PHP) conjugate (WB-PHP), 75:25 mixture of 8% PHP and PlasmalyteA solution (PHP66), 50:50 mixture of 8% PHP and Plasmalyte Asolution (PHP44) and stroma-free haemoglobin solution (SFH).Calculated P₅₀ values (Po₂, vs So₂) were 3.79, 3.58, 3.49, 3.15,3.04 and 2.07 kPa, respectively. However, if partial So₂ wasused the curves were shifted to the left, reducing P₅₀. CatheterSo₂ correlated well with So in whole blood (r² > 0.99 forboth catheters), haemodiluted blood (r² > 0.98 for both catheters)and WB-PHP solution (r² = 0.94 for both catheters). In PH P44(r² = 0.64 and r² = 0.57), PHP P66 (r² = 0.40 for the Oximetrixand r² = 0.25 for the Edwards catheter) and SFH solutions (r²= 0.33 for the Oximetrix and r² = 0.22 for the Edwards catheter)both catheters performed poorly. We conclude that mixed venousoxyhaemoglobin saturations measured by oximetric pulmonary arterycatheters are inaccurate in the presence of haemoglobin solutions.For accuracy a multi-wavelength co-oximeter should be used ifblood containing PHP or SFH is to be analysed. Present address: Department of Anaesthetics, Bristol Royal Infirmary,Bristol, UK     

Cerebral hypoperfusion in immediate postoperative period following coronary artery bypass grafting, heart valve, and abdominal aortic surgery

Perioperative levels of jugular bulb oxyhaemoglobin saturation(Sj_O2) and lactate concentration (Lj), and postoperative durationof Sj_O2<50% were compared between patients undergoing coronaryartery bypass grafting (CABG) (n=86), heart valve (n=14) andabdominal aortic (n=16) surgery. Radial artery and jugular bulbblood samples were aspirated after induction of anaesthesia,during re-warming on cardiopulmonary bypass (CPB) (36°C),on arrival in the intensive care unit (ICU) and, subsequently,at 1, 2 and 6 h after ICU admission. Most patients having heartsurgery were hypocapnic at 36°C on CPB. Following CABG andheart valve surgery, many patients were hypocapnic whereas afterabdominal aortic surgery, most were hypercapnic. During CPBand postoperatively, Sj_O2 and Lj were significantly correlatedto Pa_CO2 and the arterial concentration of lactate (La) respectively(P<0.05). After correction for arterial carbon dioxide tension(Pa_CO2) and La, there were no significant changes in Sj_O2 orLj on CPB. Postoperatively, having corrected for Pa_CO2, therewere significant effects on Sj_O2 over all groups as a resultof time from surgery (P<0.001) and its interaction with operationtype (P<0.001). Following correction for La, there were nopostoperative effects on Lj. No significant differences (P=0.2)in duration of Sj_O2<50% existed between patients undergoingCABG (1054 (82) min), abdominal aortic (893 (113) min) and heartvalve (1073 (91) min) surgery. The lack of significant reciprocaleffects on Lj combined with the frequency of hypocapnia andstrong influence of Pa_CO2on Sj_O2, suggest that Sj_O2<50% duringCPB and after cardiac surgery represents hypoperfusion as aconsequence of hypocapnia rather than cerebral ischaemia. Br J Anaesth 2001; 87: 229–36     

Mutations in PLCE1 are a major cause of isolated diffuse mesangial sclerosis (IDMS)

Background and objectives. Diffuse mesangial sclerosis (DMS)is a histologically distinct variant of nephrotic syndrome (NS)that is characterized by early onset and by progression to end-stagekidney disease (ESKD). Besides syndromic DMS, isolated (non-syndromic)DMS (IDMS) has been described. The etiology and pathogenesisof DMS is not understood. We recently identified by positionalcloning recessive mutations in the gene PLCE1/NPHS3 as a novelcause of IDMS. We demonstrated a role of PLCE1 in glomerulogenesis.Mutations in two other genes WT1 and LAMB2 may also cause IDMS.We therefore determine in this study the relative frequencyof mutations in PLCE1, WT1 or LAMB2 as the cause of IDMS ina worldwide cohort. Methods. We identified 40 children from 35 families with IDMSfrom a worldwide cohort of 1368 children with NS. All the subjectswere analyzed for mutations in all exons of PLCE1 by multiplexcapillary heteroduplex analysis and direct sequencing, by directsequencing of exons 8 and 9 of WT1, and all the exons of LAMB2. Results. The median (range) age at onset of NS was 11 (1–72)months. We detected truncating mutations in PLCE1 in 10/35 (28.6%)families and WT1 mutations in 3/35 (8.5%) families. We foundno mutations in LAMB2. Conclusions. PLCE1 mutation is the most common cause of IDMSin this cohort. We previously reported that one child with truncatingmutation in PLCE1 responded to cyclosporine therapy. If thisobservation is confirmed in a larger study, mutations in PLCE1may serve as a biomarker for selecting patients with IDMS whomay benefit from treatment.     

ARTERIAL WASHIN OF HALOTHANE AND ISOFLURANE IN YOUNG AND ELDERLY ADULT PATIENTS

We have studied the effect of age on washin of isoflurane andhalothane by comparing end - tidal (PE') and arterial (Pa) partialpressures of the agents in young (18–32 yr) and elderly(63–82 yr) healthy patients for 20 min after introductionof the agents, before surgery. PE' was measured by infra - redanalysis and Pa by gas chromatography. Washin of isofluraneoccurred at the same rate in the young and elderly, with nosignificant difference between young and elderly in PE' or Paas proportions of the inspired partial pressure (PI). After20 min of isoflurane administration, mean Pa/Pl in the youngwas 0.57 (95% confidence limit (CL) 0.53–0.62) and 0.55in the elderly (95% CL 0.51–0.59). Washin of halothanewas slower in the elderly than in the young, with Pa/Pl significantlyless in the elderly from 10 min after introduction of halothane.The difference between age groups, however, was small: meanPa/Pl after 20 min of halothane administration 0.45 (95% CL0.41–0.49) in the young and 0.38 (95% CL 0.35–0.41)in the elderly. Washin of isoflurane was significantly fasterthan that of halothane in both young and elderly subjects. Forisoflurane, the PE'-Pa gradient was small relative to Pa anddid not differ significantly between young and elderly. Forhalothane, PE'-Pa in the young did not differ significantlyfrom that for isoflurane. In the elderly, PE'-Pa for halothanewas significantly greater than in the young and than PE'-Pafor isoflurane.     

DEPRESSION OF RESPIRATORY DRIVE BY DIAZEPAM AS PREMEDICATION

The respiratory effects of premedication with i.v. injectionof diazepam have been assessed in 10 healthy patients awaitingminor operative procedures. Measurements were recorded beforeand 60min after administration of diazepam 0.14mg kg^–1.Mouth occlusion pressure (P_0.1) was used as an index of neuromuscularinspiratory drive. Minute-ventilation (V_E), respratory frequency(f) and mean inspiratory flow rate (V_T/T_I) were significantlyreduced after diazepam. During carbon dioxide rebreathing theslopes of V_E, f, V_T/T_I and P_0.1 with PA_CO, were significantlyreduced. These results confirm that i.v. diazepam produces significantrespiratory depression in healthy subjects. We conclude thatdiazepam used under clinical conditions depresses the respiratorycentre.     

ON-LINE Po2 AND PN2o ANALYSIS WITH AN IN VIVO CATHETER ELECTRODE

A technique was developed for the in vivo determination of Po₂and PN₂o with a catheter electrode using double-pulse polarography.The method was evaluated in dog studies comparing readings fromthe electrode with those from a mass spectrometer employingan in vivo probe. The oxygen readings obtained from the catheterelectrode were also compared with values obtained by conventionalblood-gas analysis. Good agreement was observed between theelectrode and the mass spectrometer for both Po₂ and PN₂o. Similaragreement was found between the electrode readings and blood-gasanalysis for Po₂. In the presence of halothane, the electrodeover-read for both Po₂ and PN₂O; a remedy is suggested. Thein vivo electrode provides an effective, less expensive, alternativeto the mass spectrometer for the on-line measurement of Po₂,and PN₂o in vivo. ^*Also Physical Chemistry Laboratory, University of Oxford.     

Comparative efficacy and safety of remifentanil and fentanyl in 'fast track' coronary artery bypass graft surgery: a randomized, double-blind study

This multi-centre, parallel group, randomized, double-blindstudy compared the efficacy and safety of high-dose remifentaniladministered by continuous infusion with an intermittent bolusfentanyl regimen, when given in combination with propofol forgeneral anaesthesia in 321 patients undergoing elective coronaryartery bypass graft surgery. A significantly lower proportionof the patients who received remifentanil had responses to maximalsternal spread (the primary efficacy endpoint) compared withthose who received fentanyl (11% vs 52%; P<0.001). More patientswho received remifentanil responded to tracheal intubation comparedwith those who received fentanyl (24% vs 9%; P<0.001). However,fewer patients who received remifentanil responded to sternalskin incision (11% vs 36%; P<0.001) and sternotomy (14% vs60%; P <0.001). Median time to extubation was longer in thesubjects who received remifentanil than for those who receivedfentanyl (5.1 vs 4.2 h; P=0.006). There were no statisticallysignificant differences between the two groups in the timesfor transfer from intensive care unit or hospital dischargebut time to extubation was significantly longer in the remifentanilgroup. Overall, the incidence of adverse events was similarbut greater in the remifentanil group with respect to shivering(P<0.049) and hypertension (P<0.001). Significantly moredrug-related adverse events were reported in the remifentanilgroup (P=0.016) There were no drug-related adverse cardiac outcomesand no deaths from cardiac causes before hospital dischargein either treatment group. Br J Anaesth 2001; 87: 718–26