D-dimer levels for Risk Stratification in Patients with Suspected COVID-19 - A Prospective Observational Study.

BACKGROUND: Elevated D-dimer levels have been observed in COVID-19 and are of prognostic value, but have not been compared to an appropriate control group. METHODS: Observational cohort study including emergency patients with suspected or confirmed COVID-19. Logistic regression defined the association of D-dimer levels, COVID-19 positivity, age, and gender with 30-day-mortality. RESULTS: 953 consecutive patients (median age 58, 43% women) presented with suspected COVID-19: 12 (7.4%) patients with confirmed SARS-CoV-2-infection died, compared with 28 (3.5%) patients without SARS-CoV-2-infection. Overall, most (56%) patients had elevated D-dimer levels (≥0.5mg/l). Age (OR 1.07, CI 1.05-1.10), D-dimer levels ≥0.5mg/l (OR 2.44, CI 0.98-7.39), and COVID-19 (OR 2.79, CI 1.28-5.80) were associated with 30-day-mortality. CONCLUSION: D-dimer levels are effective prognosticators in both patient groups.

Circadian rhythm of cardiac troponin I and its clinical impact on the diagnostic accuracy for acute myocardial infarction.

BACKGROUND: High-sensitivity cardiac troponin T (hs-cTnT) blood concentrations were shown to exhibit a diurnal rhythm, characterized by gradually decreasing concentrations throughout daytime, rising concentrations during nighttime and peak concentrations in the morning. We aimed to investigate whether this also applies to (h)s-cTnI assays and whether it would affect diagnostic accuracy for acute myocardial infarction (AMI). METHODS: Blood concentrations of cTnI were measured at presentation and after 1 h using four different cTnI assays: three commonly used sensitive (s-cTnI Architect, Ultra and Accu) and one experimental high-sensitivity assay (hs-cTnI Accu) in a prospective multicenter diagnostic study of patients presenting to the emergency department with suspected AMI. These concentrations and their diagnostic accuracy for AMI (quantified by the area under the curve (AUC)) were compared between morning (11 p.m. to 2 p.m.) and evening (2 p.m. to 11 p.m.) presenters. RESULTS: Among 2601 patients, AMI was the final diagnosis in 17.6% of patients. Concentrations of (h)s-cTnI as measured using all four assays were comparable in patients presenting in the morning versus patients presenting in the evening. Diagnostic accuracy for AMI of all four (h)s-cTnI assays were high and comparable between patients presenting in the morning versus presenting in the evening (AUC at presentation: 0.90 vs 0.93 for s-cTnI Architect; 0.91 vs 0.94 for s-cTnI Ultra; 0.89 vs 0.94 for s-cTnI Accu; 0.91 vs 0.94 for hs-cTnI Accu). CONCLUSIONS: Cardiac TnI does not seem to express a diurnal rhythm. Diagnostic accuracy for AMI is very high and does not differ with time of presentation. CLINICAL TRIAL REGISTRATION: NCT00470587, http://clinicaltrials.gov/show/NCT00470587.

Acute Effects of Lysergic Acid Diethylamide on Circulating Steroid Levels in Healthy Subjects.

Lysergic acid diethylamide (LSD) is a serotonin 5-hydroxytryptamine-2A (5-HT2A ) receptor agonist that is used recreationally worldwide. Interest in LSD research in humans waned after the 1970s, although the use of LSD in psychiatric research and practice has recently gained increasing attention. LSD produces pronounced acute psychedelic effects, although its influence on plasma steroid levels over time has not yet been characterised in humans. The effects of LSD (200 µg) or placebo on plasma steroid levels were investigated in 16 healthy subjects using a randomised, double-blind, placebo-controlled, cross-over study design. Plasma concentration-time profiles were determined for 15 steroids using liquid-chromatography tandem mass-spectrometry. LSD increased plasma concentrations of the glucocorticoids cortisol, cortisone, corticosterone and 11-dehydrocorticosterone compared to placebo. The mean maximum concentration of LSD was reached at 1.7 h. Mean peak psychedelic effects were reached at 2.4 h, with significant alterations in mental state from 0.5 h to > 10 h. Mean maximal concentrations of cortisol and corticosterone were reached at 2.5 h and 1.9 h, and significant elevations were observed 1.5-6 h and 1-3 h after drug administration, respectively. LSD also significantly increased plasma concentrations of the androgen dehydroepiandrosterone but not other androgens, progestogens or mineralocorticoids compared to placebo. A close relationship was found between plasma LSD concentrations and changes in plasma cortisol and corticosterone and the psychotropic response to LSD, and no clockwise hysteresis was observed. In conclusion, LSD produces significant acute effects on circulating steroids, especially glucocorticoids. LSD-induced changes in circulating glucocorticoids were associated with plasma LSD concentrations over time and showed no acute pharmacological tolerance.

Urinary and plasma catecholamines and metanephrines in dogs with pheochromocytoma, hypercortisolism, nonadrenal disease and in healthy dogs.

BACKGROUND: Diagnosis of pheochromocytoma (PC) is based on a combination of clinical suspicion, finding an adrenal mass, increased plasma, and urine concentrations of catecholamine metabolites and is finally confirmed with histopathology. In human medicine, it is controversial whether biochemically testing plasma is superior to testing urine. OBJECTIVES: To measure urinary and plasma catecholamines and metanephrines in healthy dogs, dogs with PC, hypercortisolism (HC), and nonadrenal diseases (NAD) and to determine the test with the best diagnostic performance for dogs with PC. ANIMALS: Seven PC dogs, 10 dogs with HC, 14 dogs with NAD, 10 healthy dogs. METHODS: Prospective diagnostic clinical study. Urine and heparin plasma samples were collected and stored at -80°C before analysis using high-pressure liquid chromatography (HPLC) coupled to electrochemical detection or tandem mass spectrometry were performed. Urinary variables were expressed as ratios to urinary creatinine concentration. RESULTS: Dogs with PC had significantly higher urinary normetanephrine and metanephrine:creatinine ratios and significantly higher plasma-total and free normetanephrine and plasma-free metanephrine concentrations compared to the 3 other groups. There were no overlapping results of urinary normetanephrine concentrations between PC and all other groups, and only one PC dog with a plasma normetanephrine concentration in the range of the dogs with HC and NAD disease. Performances of total and free plasma variables were similar. Overlap of epinephrine and norepinephrine results between the groups was large with both urine and plasma. CONCLUSION AND CLINICAL IMPORTANCE: Measurement of normetanephrine is the preferred biochemical test for PC and urine was superior to plasma.

Population pharmacokinetic modelling and evaluation of different dosage regimens for darunavir and ritonavir in HIV-infected individuals.

OBJECTIVES: Darunavir is a protease inhibitor that is administered with low-dose ritonavir to enhance its bioavailability. It is prescribed at standard dosage regimens of 600/100 mg twice daily in treatment-experienced patients and 800/100 mg once daily in naive patients. A population pharmacokinetic approach was used to characterize the pharmacokinetics of both drugs and their interaction in a cohort of unselected patients and to compare darunavir exposure expected under alternative dosage regimens. METHODS: The study population included 105 HIV-infected individuals who provided darunavir and ritonavir plasma concentrations. Firstly, a population pharmacokinetic analysis for darunavir and ritonavir was conducted, with inclusion of patients' demographic, clinical and genetic characteristics as potential covariates (NONMEM(®)). Then, the interaction between darunavir and ritonavir was studied while incorporating levels of both drugs into different inhibitory models. Finally, model-based simulations were performed to compare trough concentrations (Cmin) between the recommended dosage regimen and alternative combinations of darunavir and ritonavir. RESULTS: A one-compartment model with first-order absorption adequately characterized darunavir and ritonavir pharmacokinetics. The between-subject variability in both compounds was important [coefficient of variation (CV%) 34% and 47% for darunavir and ritonavir clearance, respectively]. Lopinavir and ritonavir exposure (AUC) affected darunavir clearance, while body weight and darunavir AUC influenced ritonavir elimination. None of the tested genetic variants showed any influence on darunavir or ritonavir pharmacokinetics. The simulations predicted darunavir Cmin much higher than the IC50 thresholds for wild-type and protease inhibitor-resistant HIV-1 strains (55 and 550 ng/mL, respectively) under standard dosing in >98% of experienced and naive patients. Alternative regimens of darunavir/ritonavir 1200/100 or 1200/200 mg once daily also had predicted adequate Cmin (>550 ng/mL) in 84% and 93% of patients, respectively. Reduction of darunavir/ritonavir dosage to 600/50 mg twice daily led to a 23% reduction in average Cmin, still with only 3.8% of patients having concentrations below the IC50 for resistant strains. CONCLUSIONS: The important variability in darunavir and ritonavir pharmacokinetics is poorly explained by clinical covariates and genetic influences. In experienced patients, treatment simplification strategies guided by drug level measurements and adherence monitoring could be proposed.

Effects of iatrogenic hypercortisolism on gallbladder sludge formation and biochemical bile constituents in dogs.

An association between gallbladder mucoceles and hypercortisolism (HC) was recently described in dogs. Because the formation of a mucocele from clear bile without the transitional formation of microprecipitates appears unlikely, the aim of this study was to investigate the effects of iatrogenic HC on sludge formation and changes in the biochemical composition of bile. Bile samples from 6 dogs obtained by percutaneous ultrasound-guided cholecystocentesis before (day 0), during (days 28, 56, and 84), and after (days 28p, 56p, and 84p) oral administration of hydrocortisone (8 mg/kg every 12 h) were analysed for calcium, cholesterol and bilirubin concentrations and pH. In addition the gallbladder was examined ultrasonographically for sludge. Six dogs receiving a placebo served as controls. Although gallbladder sludge was observed in all treated dogs at day 56, it was also noted in 50% of control dogs, and no significant differences were seen between groups at any sampling time. Bilirubin and cholesterol concentrations decreased significantly and reversibly during treatment, and calcium concentration showed a similar trend. Bile pH was consistently slightly alkaline during iatrogenic HC, whereas it was slightly acidic in control animals. A 3-month period of iatrogenic HC does not lead to ultrasonographically detectable gallbladder sludge or to an increase in bile constituents that are commonly implicated in sludge formation in humans.

The macrolide clarithromycin inhibits experimental post-transplant bronchiolitis obliterans.

Chronic allograft dysfunction in form of bronchiolitis obliterans is the most important hurdle to improved longterm survival after clinical lung transplantation to date. Recently, it was observed that the progression of bronchiolitis obliterans in lung transplant recipients might be inhibited by macrolide antibiotics. The authors therefore tested whether macrolide therapy can attenuate fibrous obliteration of airways in an animal model of bronchiolitis obliterans. Rats with heterotopic tracheal allografts were treated intraperitoneally with clarithromycin and compared to untreated transplanted animals with respect to allograft histology and expression of selected cytokines. At day 21 after transplantation, the tracheal allografts of treated animals were free of fibrous material or partially occluded dependent of clarithromycin dosage. Untreated animals had completely obliterated allografts. In treated animals, tumor necrosis factor alpha (TNF-alpha) was down-regulated early (5 days) and late (21 days) post transplant, whereas interferon gamma (IFN-gamma) expression was decreased only early after transplantation. Transforming growth factor beta (TGF-beta) expression was not affected. Therapy with low-dose macrolides in post-transplant obliterative bronchiolitis is based on their immunomodulatory rather than antimicrobial properties. In the setting of lung transplantation, macrolides primarily act as modulators of the early inflammatory response to stressed, damaged, or infected cells.

Phosphate concentration in ophthalmic corticoid preparations.

BACKGROUND: Topical preparations, high in phosphate, may cause calcification when used on a damaged corneal surface. The knowledge of the phosphate concentration in medications helps to prevent corneal calcifications. Our study gives an overview of the amount of phosphate contained in ophthalmic corticoid preparations. METHODS: Samples of 38 commercially available corticoid preparations were tested. The quantification of phosphate was performed using the molybdate method on a Modular P autoanalyzer. RESULTS: 18 of 38 preparations (47%) had a phosphate concentration above physiological levels (>1.45 mmol/l). It varied greatly, and ranged from less than 0.1 mmol/l (18 preparations) to 62.6 mmol/l. The corticoids that were tested included betamethasone sodium phosphate (18.3-35.5 mmol/l), dexamethasone (0.1-17.6 mmol/l), dexamethasone sodium phosphate (<0.1-62.6 mmol/l), fluorometholone (<0.1-22.5 mmol/l), and prednisolone acetate (<0.1-0.5 mmol/l). CONCLUSIONS: The phosphate concentration in corticoid-phosphate formulations varies greatly, and is mainly determined by the chosen buffer. The prednisolone acetate preparations showed physiological phosphate concentrations. For a treatment on a damaged corneal surface, preparations with physiological phosphate concentrations should be used.

Phosphate concentrations in antiglaucoma medication.

BACKGROUND: Eye drops may contain phosphates as part of their buffer system. In the presence of epithelial keratopathy a high concentration of phosphate favours corneal calcification. To date European legislation does not require a quantitative declaration of the phosphates since buffers are regarded as additives. The knowledge of the phosphate concentration in medications helps to prevent corneal calcifications. Our study gives an overview on the amount of phosphate contained in antiglaucoma drops. METHODS: 21 samples of commercially available antiglaucoma drops were tested. The quantification of phosphate was performed using the molybdate method on a Modular P autoanalyzer. RESULTS: 10 of 21 (47 %) glaucoma drops had a phosphate concentration above physiological levels (> 1.45 mmol/L). A concentration higher than 100 mmol/L was found in four preparations that contained timolol. CONCLUSIONS: Many antiglaucoma drops contain unphysiological levels of phosphate, very high concentrations are found in some beta-blockers. These preparations have the potential to favour the formation of insoluble crystalline calcium phosphate deposits when used on a damaged corneal surface, and should therefore be avoided.

["Ghost peak" in gas chromatography in a delirious woman with severe metabolic acidosis. Intoxication with an unknown substance?]. / "Geisterpeak" in der Gas-Chromatografie bei schwerer metabolischer Azidose. Intoxikation mit unbekannter Substanz?

HISTORY AND CLINICAL FINDINGS: A 31-year-old female with known type 1 diabetes mellitus was referred because of symptomatic hyperglycemia. On admission she was delirious and impressed with marked Kussmaul breathing. All other vital signs were normal. INVESTIGATIONS: Blood serum glucose concentration was 26.4 mmol/l. Arterial blood gas analysis revealed massive metabolic acidosis (pH 6.80) with an elevated anion gap (21 mmol/l) and a marginally increased osmolar gap (21,5 mOsm/l). TREATMENT AND COURSE: Despite normalization of the serum glucose and acidemia after administration of normal saline, insulin and bicarbonate, the delirium persisted, and the possibility of an additional intoxication had to be considered. Serum headspace analysis for intoxication with solvents (gas chromatography) finally detected a "ghost peak", which could not be assigned to any established substance. The same peak was, however, found in a healthy subject's serum and was found to be a "toluene peak". Toluene is contained as "contaminator" in gels in blood collection tubes. The patient gradually regained consciousness and "merely" suffered from diabetic ketoacidosis associated with cocaine use. CONCLUSION: The differential diagnosis of high anion gap metabolic acidosis includes among other reasons intoxications with different kinds of solvents. When looking for solvents in the serum when poisoning is suspected (headspace analysis), only blood collection tubes without gel (EDTA plasma) should be used, because all gels contain solvents (in this case toluene).

Intrapleural topical application of cisplatin with the surgical carrier Vivostat increases the local drug concentration in an immune-competent rat model with malignant pleuromesothelioma.

OBJECTIVE: We sought to investigate whether intrapleural topical application of cisplatin with a surgical carrier has a prolonged local tissue level in comparison with cisplatin solution while reducing systemic toxicity. METHODS: Forty immune-competent Fischer rats were inoculated with 10(6) mesothelioma cells. Ten days later, left pneumonectomy with tumor debulking was performed. Twenty animals underwent local application of cisplatin solution (100 mg/m2), whereas the same quantity of cisplatin was topically applied as a gel with the Vivostat (Vivolution) system in 20 other animals. In each group 5 subgroups of 4 animals were defined according to the harvesting time of blood and tissue samples (2, 4, 24, and 72 hours and 1 week) after local therapy. Platinum concentrations in serum and tissue and systemic toxicity were analyzed. RESULTS: Platinum concentrations in tissue were significantly higher in the gel group (group 1) than in the solution group (group 2) at 1, 3, and 7 days after therapy (1510, 1224, and 1069 pg/mg for group 1 vs 598, 382, and 287 pg/mg for group 2; P = .007, P = .005, and P = .0002, respectively). Laboratory findings showed renal insufficiency in the animals of the solution group at 1 week, with values of 98 mmol/L versus 7.7 mmol/L for urea and 410 mumol/L versus 43 mumol/L for creatinine (P = .02 and P = .01, respectively), which was confirmed by means of pathologic analysis. CONCLUSIONS: Intrapleural administration of cisplatin with the carrier Vivostat significantly provides sustained higher platinum concentrations up to 1 week in tissue in comparison with application of cisplatin solution without conferring systemic toxicity in this model.

Corneal calcification following intensified treatment with sodium hyaluronate artificial tears.

AIM: To report a potential adverse effect of intensified treatment with sodium hyaluronate artificial tears. METHODS: Five cases of deep calcium deposition in the cornea associated with ocular surface disease and frequent use of hyaluronic acid artificial tears are described. All patients used one formulation of phosphate buffered hyaluronate eye drops when rapid calcification developed. All eyes required corneal graft surgery for visual rehabilitation. Specimens at keratoplasty were available for light microscopy and investigation by dispersive x ray analysis. The phosphate concentration in the medication used for topical treatment was measured and compared to alternative hyaluronate preparations. RESULTS: Light microscopy showed dense mineralisation of the entire stroma. The crystalline deposits consisted of hydroxyapatite, Ca5(PO4)3OH. A 50-fold higher concentration of phosphate was measured in the sodium hyaluronate eye drops used for treatment (50.9 mmol/l) when compared with normal serum. The other hyaluronate formulations showed phosphate concentrations from <0.1 mmol/l to 10.9 mmol/l. CONCLUSIONS: The hyaluronate artificial tear formulation "Hylo-Comod" favours the formation of insoluble crystalline calcium phosphate deposits in presence of epithelial keratopathy. This is because of its high phosphate concentration and typically frequent instillation. Manufacturers and prescribers should be aware that topical preparations may contain considerable amounts of phosphate which may lead to sight threatening corneal complications.

Phosphate concentration in artificial tears.

BACKGROUND: Irrigating solutions and eye drops may contain phosphates as part of their buffer system. In the presence of epithelial keratopathy, a high concentration of phosphate favours corneal calcification. Knowledge of the phosphate concentration in artificial tear products helps to prevent this sight-threatening complication. This study gives an overview on the amount of phosphate contained in artificial tears. METHODS: Fifty-nine samples of commercially available artificial tear preparations were tested. The quantification of phosphate was performed using the molybdate method on a Modular P autoanalyzer. RESULTS: Twenty-six of 59 (44%) artificial tear products had a phosphate concentration above physiological levels (>1.45 mmol/l). A phosphate concentration above 25 mmol/l was found in nine products (15%), a concentration higher than 50 mmol/l in three (5%). CONCLUSIONS: Many artificial tear formulations contain unphysiological levels of phosphate, but very high concentrations are found only in a few products. These preparations have the potential to favour the formation of insoluble crystalline calcium phosphate deposits when used on a damaged corneal surface, and should therefore be used cautiously.

Thiopurine S-methyltransferase polymorphisms: efficient screening method for patients considering taking thiopurine drugs.

OBJECTIVE: More than 11% of the Caucasian population are heterozygous or homozygous carriers of thiopurine S-methyltransferase (TPMT) mutants and are at risk for toxic side effects when treated with thiopurine drugs. Therefore, screening for TPMT polymorphisms in a patient prior to prescribing these agents is recommended. The goal of this study was to determine a cut-off concentration of the TPMT activity assay beyond which genotyping of the TPMT gene should be performed. METHODS: The TPMT activity of 240 unrelated Caucasian subjects was measured using high-performance liquid chromatography. Genotyping for the most frequent allelic variants, TPMT*2, *3A, *3B, *3C and *7 was performed by LightCycler technology and sequencing. RESULTS: The inter-individual TPMT activity showed a range from 23 nmol MTG/g*Hb*h(-1) to 97 nmol MTG/g*Hb*h(-1) with a median of 56 nmol MTG/g*Hb*h(-1). Using a cut-off concentration of 45.5 nmol MTG/g*Hb*h(-1), a test sensitivity of 100% and a specificity of 89% were reached for heterozygous carriers of a TPMT mutation. We identified 1 carrier of TPMT*2, 14 carriers of TPMT*3A and 3 carriers of TPMT*3C, resulting in a TPMT heterozygosity prevalence of 7.5%. CONCLUSIONS: This study defines the cut-off value for the TPMT phenotyping assay at 45.5 nmol/g*Hb*h(-1), beyond which additional genotyping elucidates the individual risk for drug therapy. Using this cut-off concentration, the number of genotyping assays could be reduced by about 60%.

Concentration of rocuronium in cerebrospinal fluid of patients undergoing cerebral aneurysm clipping.

BACKGROUND: This study assessed the concentration of rocuronium in the cerebrospinal fluid (CSF) of patients undergoing cerebral aneurysm clipping, and investigated whether the mode of administration (single bolus vs continuous infusion) influenced the CSF concentration. METHODS: Twenty patients with subarachnoid haemorrhage were randomly allocated to receive a bolus dose (bolus group), or a bolus followed by a continuous infusion of rocuronium (infusion group) (n=10 for each group). Arterial blood and ventricular CSF were sampled 2 h after the rocuronium bolus. Samples were analysed by liquid chromatography electrospray ionization-tandem mass spectrometry. RESULTS: Rocuronium could be detected in all the CSF samples. The mean (range) CSF concentration was 2.2 (0.9-4.6) ng x ml(-1) in the bolus group and 12.4 (2.4-34.6) ng x ml(-1) in the infusion group; P<0.01. CONCLUSIONS: This study demonstrated that rocuronium, normally not considered to cross the blood-brain barrier, is regularly found in the CSF of patients undergoing cerebral clipping; continuous infusion of the drug led to higher plasma and CSF concentrations than after a single bolus dose.

Risk of recurarization during retransfusion of autologous blood withdrawn after injection of muscle relaxants: a comparison of rocuronium and mivacurium.

STUDY OBJECTIVES: In the context of acute normovolemic hemodilution (ANH) recurarization, defined as significant decrease of train-of-four ratio (TOFR) during retransfusion of autologous blood withdrawn after induction of anesthesia, has been described for vecuronium and atracurium. The present study for the first time examined this risk for rocuronium and mivacurium. DESIGN: Prospective, randomized, unblinded clinical study. SETTING: University Hospital in Zurich/Switzerland. PATIENTS: 20 ASA physical status I and II patients undergoing general anesthesia for major maxillofacial surgery. INTERVENTIONS: Anesthesia was induced and maintained with propofol and remifentanil, and rocuronium (0.9 mg kg(-1)) or mivacurium (0.25 mg kg(-1)) was given to facilitate intubation. Thereafter, ANH was started with the removal of 500 mL autologous blood and the subsequent replacement by the same amount of 6% hydroxyethyl starch. The withdrawn blood was stored at 4 degrees C until retransfusion at the end of surgery. MEASUREMENTS: To estimate the risk of recurarization during retransfusion, the degree of recurarization during retransfusion of the autologous blood was assessed mechanomyographically. Plasma levels of rocuronium and mivacurium in the patients' plasma and the autologous blood were determined after its removal and before retransfusion. MAIN RESULTS: The TOFR before retransfusion was 0.97 (range: 0.96 to 0.98) for rocuronium (n = 10) and 0.98 (range: 0.96 to 1.0) for mivacurium (n = 8); n.s. During retransfusion, a slight, but statistically significant reduction of TOFR occurred in one patient in each group. In the mivacurium group, this recurarization occurred 10 minutes after the start of retransfusion; in the rocuronium group, it occurred 20 minutes after retransfusion. The plasma levels of rocuronium and mivacurium in the autologous blood did not change during storage. The plasma concentration of mivacurium in the autologous blood after its removal was 420 +/- 142 microg/L; before retransfusion, it was 384 +/- 147 microg/L. The respective concentrations for rocuronium were 2930 +/- 516 microg/L and 2660 +/- 464 microg/L. CONCLUSIONS: Recurarization during retransfusion may occur with both neuromuscular blocking drugs, mivacurium and rocuronium, when these drugs were injected before the removal of the autologous blood.

Clonidine decreases propofol requirements during anaesthesia: effect on bispectral index.

Assessment of the effect of clonidine on depth of anaesthesia is difficult because clonidine combines analgesic, sedative and direct haemodynamic effects. We thus evaluated the influence of clonidine on the bispectral index (BIS) and its potential dose-sparing effect on propofol. After induction of anaesthesia with target-controlled infusion of propofol and obtaining an unchanged bispectral index (pre-BIS), clonidine 4 microg kg(-1) or placebo was administered randomly to 50 patients in a double-blind manner. Subsequently, if there was a decrease in BIS we reduced the target concentration of propofol until pre-BIS was reached. The pre-BIS was maintained and a remifentanil infusion was added during surgery. The courses of the BIS, heart rate and blood pressure were recorded and the total amounts of intra-operative propofol and remifentanil were determined. Assessment of implicit memory during anaesthesia was performed with an auditory implicit memory test consisting of item sequences. Administration of clonidine resulted in a decrease in the BIS from 45 (SD 4) to 40 (6) (P<0.001), which allowed a reduction of propofol target concentration from 3.3 (0.6) to 2.7 (0.7) microg ml(-1) (P<0.001) and measured propofol concentration from 2.9 (0.6) to 2.5 (0.7) kg ml(-1) (P=0.009) in order to maintain the pre-BIS value. During subsequent surgery, propofol requirements were reduced by 20% (P=0.002) in the clonidine group and a similar amount of remifentanil was used in each group. The increase in anaesthetic depth given by clonidine can therefore be measured with bispectral EEG analysis and allows reduction of the propofol dose to achieve a specific depth of anaesthesia.