Biomedical subjects
Publications and source records attributed to L B Nilsson.
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BACKGROUND: The precision of bolus thermodilution cardiac output measurements in patients with atrial fibrillation (AF) has not previously been determined. A priori we suspected that the precision would be lower in patients with AF than in patients with sinus rhythm (SR). Consequently, we also determined if the precision could be improved by injecting the thermal indicator into the right ventricle instead of the right atrium. METHODS: Cardiac output was determined as the average result of four injections of 10 ml of iced saline. Replicate measurements were performed with thermal indicator injections into the right atrium and ventricle. The coefficients of variation and the precisions were calculated. RESULTS: In the 25 patients with AF, mean cardiac output was 3.96 l min(-1) (range 2.4-7.4), the coefficient of variation 0.073 (95% CI +/- 0.011), and the precision 0.38 l min(-1) (95% CI +/- 0.14) with injection into the right atrium. In the 25 patients with SR, mean cardiac output was 4.73 l min(-1) (range 2.4-7.3), the coefficient of variation 0.047(95% CI +/- 0.006), and the precision 0.38 l min(-1) (95% CI +/- 0.14). In both groups, an agreement analysis demonstrated that the injection of indicator into the right ventricle resulted in a significantly higher cardiac output [AF+0.25 (95% CI +/- 0.15) l min(-1), SR+0.29 ( +/- 0.20) l min(-1)]. CONCLUSION: The coefficient of variation for cardiac output determinations is 55% higher in patients with AF. Two measurements, separated by time or intervention, must differ by 15% in AF patients and 9% in SR patients before one can be 95% confident that a real change has taken place.
BACKGROUND: Bolus thermodilution cardiac output measurements have been a mainstay in clinical monitoring of critically ill patients for more than 30 years. Usually the results of an arbitrarily chosen number (1-6) of thermal indicator injections are averaged to increase the reliability of the measurement. The number of injections needed to achieve a given level of precision has, however, not previously been systematically investigated. METHODS AND RESULTS: In 80 hemodynamically stable patients cardiac output was determined as the average of eight injections of 10 ml of iced saline. From the 638 measurements we examined the relationship between the number of thermal indicator injections and the precision of the resulting cardiac output estimate. Furthermore, the association between the number of injections and the least detectable difference among two sets of measurements was established. CONCLUSION: The current study shows that one needs to average the results of four injections to be 95% confident that the result is within 5% of the 'true' cardiac output and that two series of four measurements have to differ by at least 7% before one can be sure (95%) that a change in cardiac function has taken place.
BACKGROUND: The feasibility of thermodilution cardiac output measurements with the more convenient room temperature thermal indicator instead of cold injectates has been repeatedly investigated. However, the issue has not been addressed with the appropriate statistical approach advocated by Altman and Bland. Furthermore, we wished to determine if the incorporation of a second thermistor in the thermodilution catheter, to measure the temperature of the thermal indicator where it is delivered into the right atrium/superior caval vein, would result in more precise cardiac output measurements. METHODS: Fifty patients were randomized to receive a single or dual thermistor pulmonary artery thermodilution catheter. Cardiac output was calculated as the average of four injections of 10 ml of isotonic saline. Precision (2 x SD of differences in replicate measurements) for the two catheters and injectate temperatures, and bias and limits of agreement between measurements, with cold and room temperature injectates, were determined. RESULTS: Precision was (0 degrees C) 0.42 l/min and (20 degrees C) 0.90 l/min, and bias and limits of agreement -0.83 l/min and -1.93-0.27 l/min for the single thermistor catheter. For the dual thermistor system precision was (0 degrees C) 0.34 l/min and (20 degrees C) 0.58 l/min. Bias and limits of agreement were -0.03 l/min and -0.61-0.55 l/min. CONCLUSION: The second thermistor is redundant if cold injectates are used. If one wishes to use room temperature injectates the single thermistor system is inadequate. A dual thermistor catheter is, on the other hand, acceptable.
The ideal anaesthesia for direct laryngoscopy is profound and yet brief. The present study sought to determine whether a new anaesthetic technique based on infusion of the ultra short-acting opioid remifentanil was superior to our routine alfentanil multiple-dose technique in terms of haemodynamic stability, stress responses and recovery. A total of 58 patients were randomized to receive propofol and either remifentanil or alfentanil as part of a total intravenous anaesthesia. In the remifentanil group, systolic blood pressure during anaesthesia remained significantly lower than baseline values, while it increased significantly in the alfentanil group. None of the patients receiving remifentanil showed stress responses (hypertension, tachycardia, somatic or autonomic responses), compared to 22 patients (79%) in the alfentanil group (P < 0.0001). In the remifentanil group, hypotension or bradycardia requiring intervention arose in 5 (18%) and 3 patients (11%); neither response was seen in the alfentanil group. The period from the end of propofol infusion until extubation was 5 min longer in the remifentanil group (P < 0.0001), whereas the time from extubation until discharge was similar in the two groups. Thus, neither technique showed sufficient haemodynamic stability, and further studies are needed to determine optimal dosages of propofol and opioid.
INTRODUCTION: This investigation was based on the surmise that the scientific activity in the specialty of anaesthesiology and intensive care medicine in Denmark is declining. MATERIAL AND METHODS: A quantitative and qualitative analysis of the development in Danish anaesthesiological research during the seven-year period of 1992-1998 was performed with bibliometrical methods and a count of the PhD and doctoral theses produced by Danish anaesthesiologists during that period. RESULTS: In the period investigated, a total of 906 scientific articles were published, of which 749 (83%) originated from university hospitals. Total production decreased by 15% between the two-year periods of 1992-1993 and 1997-1998, whereas the output from university hospitals alone decreased by 10%. The number of scientific publications per anaesthesiologist decreased by 34%, corresponding to 6.7% per year. The quality of the research published, as examined by the cumulative and average impact, showed a slight increase. The number of PhD and doctoral theses per year showed no change. DISCUSSION: Research activity in Danish anaesthesiology is declining, and the specialty seems to be losing scientific ground, both nationally and internationally.
Batch-wise pH-adjustment of plasma samples for free concentration determinations can be performed directly in the ultrafiltration devices using a CO(2) incubator. The pH of the samples could be adjusted to within a sufficiently narrow interval though the initial differences in pH were large. The possibilities for simultaneous determination of free and total concentrations were studied using NAD-299 as a model compound. By adding a known concentration of a (13)C-labelled isotope of the studied drug to the sample prior to ultrafiltration it was possible to calculate the total concentration from the ratio of the drug peak area to the isotope peak area while the free concentration was calculated from the drug peak area. Initial experiments showed good precision and accuracy as well as a good correlation with concentration data acquired in the conventional way.
BACKGROUND: A continuous, accurate, non-invasive monitor of cardiac output would represent a major step forward in patient management. A cardiac output computer, NICO2, based on the Fick principle and an automatic partial carbon dioxide (CO2)-rebreathing technique has just become available. We compared the performance of this monitor with the standard thermodilution method. METHODS: Thirty patients were investigated after cardiac surgery. Replicate measurements were performed simultaneously with the thermodilution and NICO2 techniques. An Altman-Bland analysis was used to assess repeatability of each of the two methods and to determine the agreement between the two techniques. RESULTS: The repeatabilities of thermodilution and CO2-rebreathing cardiac output were excellent, with coefficients of repeatability of 0.35 l/min and 0.60 l/min. Mean thermodilution and NICO2 cardiac output were 4.4 l/min (SD 0.9, range 2.7-6.1) and 4.6 l/min (SD 1.3, range 1.6-6.9). A comparison of the methods, however, revealed excessive limits of agreement (+/-1.80 l/min). CONCLUSION: The agreement between the NICO2 derived cardiac output and the de facto standard - thermodilution cardiac output - is poor. The methods are not interchangeable with the present version of the NICO2. The repeatability of the partial CO2-rebreathing technique holds promise that a sufficient accuracy may be obtained by suitable modifications of the monitor's algorithms.
The in vivo effects of remoxipride, in relation to some of its identified metabolites, were investigated in adult male Sprague-Dawley rats. The methods used included: (1) estimation of the in vivo rate of brain monoamine synthesis by measuring the accumulation of dihydroxyphenylalanine and 5-hydroxytryptophan after decarboxylase inhibition; (2) observations of spontaneous locomotor activity in a photocell-equipped open-field arena ( approximately 0. 5 m2); (3) treadmill locomotion ( approximately 4 m min-1); (4) inclined grid (60 degrees ) catalepsy test; (5) d-amphetamine-induced (1.0 mg kg-1) hyperlocomotion;(6) quinpirole-induced (0.4 mg kg-1) hypothermia. By use of one or more of these tests, the findings with remoxipride were as follows: First, remoxipride had a late onset of action (up to 3 h). Second, potency and efficacy depended on exposure to hepatic metabolism. Thus, intraperitoneal administration was more effective than the subcutaneous route, whereas virtually all biological effects were lost on intracerebroventricular administration. The ED50 values (micromol kg-1, neostriatal dihydroxyphenylalanine accumulation) for remoxipride and a range of its phenolic aromatic ring metabolites were: remoxipride (approximately 20), NCQ-344 (approximately 0.01), FLA-797 (approximately 0.1), FLA-908 (approximately 2.2), NCQ-436 (approximately 25) and NCQ-469 (approximately 30). Considering remoxipride as a nonclozapine atypical antipsychotic drug, together with the fact that remoxipride behaves as a prodrug in the laboratory studies above, further characterization of the pharmacodynamic profile of its metabolites remains a challenge.
Remoxipride and its active metabolites, the phenolic compounds FLA797(-) and FLA908(-) and the catecholic NCQ436(-) and haloperidol, were examined for their ability to block hypothermia in the rat induced by dopamine (DA) D2 receptor stimulation. In addition, plasma levels of remoxipride and its active metabolites were measured using HPLC methods. Remoxipride (1 mumol/kg), given 30 or 15 min prior to, or 5 and 15 min after, the DA agonists, blocked the hypothermia induced by the DA D2 receptor agonists quinpirole (0.25 mg/kg s.c.) and pergolide (0.1 mg/kg s.c.). Administration of remoxipride by the i.v. or s.c. routes was more effective than by the i.p. route. FLA797(-), FLA908(-), and haloperidol were more effective than remoxipride in preventing the hypothermia caused by quinpirole, while NCQ436(-) was less effective than remoxipride. The variation in time of remoxipride's action and effectiveness in blocking the induced hypothermia followed the variations in plasma concentrations. The plasma concentrations of the active metabolites were below the limit of determination (< 2 nmol/l). Based on estimation of free brain concentrations at effective dose levels together with in vitro affinities for the DA D2 receptor it was concluded that the metabolites FLA797(-), FLA908(-), and NCQ436(-) do not appear to contribute to the antagonism of DA D2 mediated neurotransmission following a low remoxipride dose (1 mumol/kg).
The cataleptic effect of remoxipride was examined in the horizontal bar test after i.v.,i.p. and s.c. administration to male rats. Remoxipride induced immediate catalepsy after high i.v. doses (ED50 = 49 mumol/kg) while peak effects were seen 60-90 min after i.p. administration (ED50 = 38 mumol/kg). Following s.c. administration remoxipride failed to produce a statistically significant catalepsy in the 20-100 mumol/kg dose range (ED50 > 100 mumol/kg). In contrast, haloperidol was found to be more effective in inducing catalepsy after i.v. (ED50 = 0.4 mumol/kg) than after i.p. or s.c. administration (ED50 = 0.9 mumol/kg). The atypical antipsychotic profile of remoxipride was more pronounced when the compound was given i.v. or s.c. as compared with the i.p. route. Plasma and brain (striatum and nucleus accumbens) concentrations of remoxipride and its active phenolic metabolites FLA 797(-) and FLA 908(-) were measured by high performance liquid chromatography. The 40 mumol/kg dose of remoxipride resulted in plasma and brain concentrations of remoxipride which were 300-1000-fold higher (depending on the route of administration) than the most potent of the phenolic metabolites, e.g., FLA 797(-). The plasma and brain concentrations of remoxipride and its phenolic metabolites were related to DA D2 receptor blocking potency and to the temporal course and effectiveness to induce catalepsy. This analysis suggested that the unbound concentrations of the phenolic metabolites were too low to play a major role in the DA blocking action of remoxipride. However, FLA 797(-) may contribute marginally to the cataleptic effects following high (i.p.) doses of remoxipride.
Twelve healthy male volunteers took part in a double-blind randomised cross-over study composed of three treatment sessions: remoxipride 100 mg; remoxipride 100 mg plus biperiden 4 mg; and biperiden 4 mg. Plasma and urine concentrations of remoxipride and biperiden, plasma prolactin levels, salivary flow and adverse events were recorded to assess pharmacodynamic interactions. Remoxipride and biperiden had no effect on each other's plasma concentrations. Biperiden did not affect the urinary recovery or renal clearance of remoxipride. Prolactin levels were unaffected by biperiden but increased following remoxipride administration. Differences in prolactin Cmax and tmax following remoxipride versus concomitant (remoxipride + biperiden) treatment were not statistically significant. However, a slight but statistically significant (P = 0.04) increase in prolactin AUC was observed after concomitant treatment. No significant differences could be observed between the recorded salivary flow in all the treatment sessions. Single doses of remoxipride and biperiden showed no pharmacokinetic or pharmacodynamic interaction.
1. The pharmacokinetics of remoxipride, a new neuroleptic, were investigated in an open study with three parallel groups. Twenty-one patients with severely impaired (ClCr < 25 ml min-1), moderately impaired (ClCr 25-50 ml min-1) and normal (ClCr > 65 ml min-1) renal function were evaluated. A single oral dose of remoxipride hydrochloride 100 mg was administered, and blood and urine were collected over 48 h. Concentrations of remoxipride and metabolites were measured by h.p.l.c. 2. In patients with severely decreased renal function, the AUC and Cmax of remoxipride were increased significantly, and t1/2 was prolonged, as compared with the control patients. The renal clearance and urinary recovery of the unchanged drug were significantly diminished. 3. The unbound fraction of remoxipride in plasma was decreased in patients with renal failure, in association with a disease-related increase in alpha 1-acid glycoprotein. In spite of a 25% recovery of unchanged drug in the urine in patients with normal renal function, the AUC of unbound drug was twice as high in patients with severely impaired renal function. 4. A strong correlation between creatinine clearance and renal drug clearance was observed indicating a direct relationship between kidney function and the renal clearance of remoxipride. 5. Remoxipride was the predominant compound in plasma as well as in urine in patients with severely decreased as well as normal renal function. In patients with severely decrease renal function, remoxipride and all five pharmacologically inactive metabolites showed increased peak plasma concentrations, delayed tmax, increased AUC, prolonged half-lives and decreased renal clearance.
The pharmacokinetics and metabolism of the new antipsychotic agent remoxipride ((S)-(-)-3-bromo-N(-)[(1-ethyl-2-pyrrolidinyl)methyl]-2, 6-dimethoxybenzamide, FLA731(-), Roxiam, CAS 80125-14-0) was studied in rodents (mice, rats, hamsters), dogs and human subjects using the unlabelled or the labelled (3H or 14C) drug. Oral administration of 20-40 mumol/kg to animals and approximately 3 mumol/kg to human volunteers showed that the absorption of remoxipride through the intestinal wall was rapid and almost complete in all species. However, the bioavailability was low in the rodents (< 10% in mice and hamsters and < 1% in rats) due to an extensive first-pass elimination in the hepato-portal system. Blood clearance estimated after the same intravenous doses was high in rodents and similar to or exceeding normal liver blood flow. In dogs and humans, clearance values were low and the bioavailability high (> 90%). In mice and rats the contribution of renal clearance to the total clearance was approximately 10%, while it was higher in dogs (approximately 15%) and humans (approximately 30%). Species differences were also observed in the degree of protein binding which was low in rodent plasma (20-30%) but fairly high in canine and human plasma (approximately 80%). In dogs and humans, remoxipride was shown to bind primarily to the plasma alpha 1-acid glycoprotein fraction. In accordance with the binding data, the volume of distribution (Vss) was higher in rodents (3-6 l/kg) than in dogs (1.6 l/kg) and man (0.7 l/kg). Studies in dogs with 14C-remoxipride showed that the compound was rapidly distributed to tissues and eliminated at rates similar to that in plasma (t1/2 3-4 h). Retention of radioactivity was only observed in melanin-rich tissues. However, studies in pigmented mice showed that the affinity of remoxipride to melanin was lower than that of the other neuroleptics haloperidol and chlorpromazine. The excretion of radioactivity following oral administration of the labelled drug mainly occurred in the urine in all species. However, species differences were observed in the identification and analysis of the various metabolites present in plasma and excreted in urine. In rodents, metabolic reactions occurred mainly at the aromatic moiety, i.e. O-demethylation and aromatic hydroxylation. The resulting phenols were excreted mainly in conjugated forms. In dogs and humans, the predominant metabolic reactions were oxidations at the alpha-carbons of the pyrrolidine moiety leading to N-demethylated and/or pyrrolidone and hydroxypyrrolidone products.(ABSTRACT TRUNCATED AT 400 WORDS)
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A simple and sensitive procedure for the routine assay of the analgesic drug dextropropoxyphene and its main metabolite, norpropoxyphene, in plasma is described. After liquid-liquid extraction from alkalinized plasma and back-extraction into a small volume of an acidic aqueous phase, the aqueous phase was injected into a column packed with 3-microns octadecylsilica particles. Ultraviolet absorbance detection at 210 nm was used. Concentrations down to 2 nM could be determined for both compounds; at this level, the intra-assay coefficient of variation was 5%.
A peak compression system is optimized for FLA797 (I), a phenolic tertiary amine and a metabolite to the antipsychotic drug remoxipride. An application is described where this effect is used to give a 6-7-fold improvement of the quantification limit in an assay of I in plasma. The liquid chromatographic system is constructed so that the injection of I dissolved in a solution of a competing amine gives a very high and narrow analyte peak with an apparent efficiency of 1.5 x 10(6) plates/m. When the levels of I in plasma are determined, an internal standard, giving a normal isocratic peak, is added to the plasma sample before the extraction. Concentrations of I down to 0.5-1.0 nM can be determined with reasonable precision. FLA908, another phenolic remoxipride metabolite and a regioisomer to I, eluting as a normal isocratic peak, can be determined simultaneously although only at concentrations higher than 10-15 nM.
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