DFTB+, a software package for efficient approximate density functional theory based atomistic simulations.

DFTB+ is a versatile community developed open source software package offering fast and efficient methods for carrying out atomistic quantum mechanical simulations. By implementing various methods approximating density functional theory (DFT), such as the density functional based tight binding (DFTB) and the extended tight binding method, it enables simulations of large systems and long timescales with reasonable accuracy while being considerably faster for typical simulations than the respective ab initio methods. Based on the DFTB framework, it additionally offers approximated versions of various DFT extensions including hybrid functionals, time dependent formalism for treating excited systems, electron transport using non-equilibrium Green's functions, and many more. DFTB+ can be used as a user-friendly standalone application in addition to being embedded into other software packages as a library or acting as a calculation-server accessed by socket communication. We give an overview of the recently developed capabilities of the DFTB+ code, demonstrating with a few use case examples, discuss the strengths and weaknesses of the various features, and also discuss on-going developments and possible future perspectives.

Relation of sedation and amnesia to plasma concentrations of midazolam in surgical patients.

The kinetics and dynamics of midazolam were investigated in 20 female patients undergoing lower abdominal surgery. The relation between the plasma concentrations of midazolam and pharmacokinetic end points was evaluated after an intravenous infusion regimen in 10 patients given an epidural anesthetic. The remaining 10 patients were anesthetized with a totally intravenous anesthetic technique with midazolam and alfentanil. The effect was assessed by means of a rating scale divided into degree of sedation and amnesia. A good correlation was found between plasma level of midazolam and pharmacodynamic response. The relation between the quantal response data and the plasma concentration was represented by an s-shaped concentration-effect curve. Despite similar kinetics of midazolam in the two groups, the postoperative drowsiness was more pronounced in the group receiving total intravenous anesthesia. The concomitant administration of alfentanil shifted the concentration-effect curve regarding sedation to the left.

Anesthesia and monitoring during whole body radiation in children.

During whole body radiation therapy of children, treatment may be done in places not equipped with acceptable scavenging systems for anesthetic gases and where clinical observation of the patient may be impossible. In order to solve this problem, the authors have used a total intravenous (IV) anesthetic technique using midazolam, pancuronium, and fentanyl. With midazolam as the only hypnotic agent, the problem with scavenging is solved, and a computer simulation of the plasma concentration of midazolam is presented. A modified stethoscope for monitoring during radiation also has been developed. This anesthetic technique and the stethoscope have been used in seven children. The total IV anesthesia proved to be a useful method for children during whole body radiation. The modified stethoscope functioned very well and was a useful complement to the monitoring equipment.

[Sonographic scanning of the non-descended testes]. / Ultralydskanning ved non-descensus testis.

More active treatment of boys with non-descended testes increases the demand for methods to identify and localize the retained testes. Sonography is non-invasive and is now in common use, but experience with the method is still limited. A retrospective series of 112 examinations, performed in 88 boys, aged 2-16 years, is presented. The indications were uncertainly palpable or non-palpable testes. The results of sonography could be compared with the findings at surgery in 62 instances, 17 testes subsequently descended or were controlled, while 33 examinations were without further verification. Fiftythree testicles were identified at operation, and 50 demonstrated by sonography with a good correlation according to anatomic localization. The suprafascial, everted position was not specified. Abdominal retention was, contrary to previous reports, diagnosed in 86%, when present. Surgery revealed aplasia in nine instances, corresponding to the results of sonography in eight. At a pre-operative control-sonography one false positive examination was corrected, and false sonographic diagnoses of aplasia at the first examination in eight instances were reduced to three at preoperative sonographic control. In the group of subsequently descended testicles the result of sonography was considered to be consistent with this cause. It is concluded, that sonography, performed on the indications of uncertainly palpable or non-palpable testes, is of value, since demonstration of a testicle is an accurate diagnosis, and furthermore a correct anatomical localization including abdominal lodging will most often be possible. A single negative ultrasound examination, especially in small boys, should be controlled.

Pharmacokinetics of alfentanil in total i.v. anaesthesia.

Alfentanil was administered, together with midazolam, as part of a total i.v. anaesthetic technique. The pharmacokinetics of alfentanil were determined in 10 female patients undergoing lower abdominal surgery. The dose regimen of alfentanil, based on simulation studies, consisted of a two-stage infusion following an initial bolus dose. The kinetics of alfentanil were described by a linear two-compartment open model. The total plasma clearance ranged between 93 and 431 ml min-1 (mean 249 ml min-1). The apparent volume of distribution at steady-state ranged between 0.27 and 0.64 litre kg-1 (mean 0.44 litre kg-1). The apparent volume of distribution (Vd beta) was 0.58 litre kg-1, resulting in a terminal half-life of 112 min. Alfentanil concentrations at the time of extubation and postoperative analgesic requirements were also monitored. Good correlation between respiratory depression and plasma alfentanil concentration was found. Neither lower abdominal surgery nor the simultaneous administration of midazolam seemed to affect the kinetics of alfentanil as compared with results from studies in healthy volunteers. The short half-life of alfentanil, resulting from a small volume of distribution, makes it suitable as part of a total i.v. technique. Consideration must be paid, however, to interindividual differences in the pharmacodynamic response and in plasma clearance.

Effect of total intravenous anaesthesia with midazolam/alfentanil on the adrenocortical and hyperglycaemic response to abdominal surgery.

The effect of anaesthesia on the hyperglycaemic and adrenocortical response induced by surgery was studied in patients undergoing abdominal hysterectomy. The study group was anaesthetized with midazolam and alfentanil using a totally intravenous anaesthetic technique. A reference group received anaesthesia with thiopentone, alfentanil and nitrous oxide. Midazolam 0.42 mg.kg-1 was given as a loading infusion followed by a maintenance infusion of 0.125 mg.kg-1.h-1. Alfentanil was given as a bolus dose of 0.075 mg.kg-1 in both groups, followed by a loading infusion of 0.3 mg.kg-1.h-1 for 15 min and a maintenance infusion of 0.065 mg.kg-1.h-1. Increments of alfentanil were given whenever heart rate or systolic blood pressure exceeded pre-induction values by more than 10%. During anaesthesia mean arterial pressure and heart rate were similar in both groups and there was no difference in alfentanil requirement. An immediate increase in blood glucose concentrations was seen following incision, but maximum concentrations were measured in the early postoperative period. Serum cortisol concentrations decreased after induction of anaesthesia. During surgery they returned to pre-induction values, and in the postoperative period they increased to about twice the pre-induction values. It is concluded that midazolam/alfentanil anaesthesia is as effective as anaesthesia induced by thiopentone, alfentanil and nitrous oxide in suppressing the stress-response to surgery until the postoperative period. No signs of prolonged adrenocortical depression were observed.

Effects of flumazenil on post-operative recovery after total intravenous anesthesia with midazolam and alfentanil.

Midazolam and alfentanil were infused in a totally i.v. anesthetic technique (TIVA) to patients undergoing hysterectomy. Correlations of midazolam plasma concentrations and effects were made during recovery. Due to the high doses of midazolam administered during TIVA, metabolism and not redistribution mainly governed the duration of effects post-infusion. The concomitant administration of alfentanil contributed to the sedative effect, as illustrated by a shift of the concentration-response curve to the left. As a result of these effects, recovery was prolonged and extended over 2-6 h. The effect of the benzodiazepine antagonist flumazenil on post-operative performance after total i.v. anaesthesia with midazolam and alfentanil was studied. A bolus dose of flumazenil, 1.0 mg i.v., significantly improved recovery during the first post-operative hour but was followed later by resedation. The reduction in sedation followed by improvement in ventilation, without reduction of analgesia, demonstrated that antagonism of hypnosis is the primary factor in enhancing recovery from total i.v. anaesthesia.

Pulmonary disposition of pethidine in postoperative patients.

1. Two methods of pethidine administration, namely constant-rate infusion and single i.v. injection, were used to assess the pulmonary disposition of the drug in 10 postoperative patients. Using two sites of blood sampling, the pulmonary extraction ratio was determined. 2. Pronounced pulmonary uptake of pethidine was found in all patients (n = 10). On the other hand, there was no significant evidence of pulmonary clearance. 3. The mean total plasma clearance was 810 ml min-1 and the volume of distribution was 3.11 kg-1. 4. A flow model was used to describe the disposition of pethidine in man. The concentration-time profiles calculated by the model were in accordance with observed data. The data showed that both pulmonary uptake and pulmonary release of pethidine were rapid. 5. Constant-rate infusion was found advantageous in the determination of pulmonary extraction, with respect to the accuracy and precision of the results. The extraction obtained after a single injection may be overestimated on account of uptake of the drug by the lungs.

Effects of the benzodiazepine antagonist flumazenil on postoperative performance following total intravenous anaesthesia with midazolam and alfentanil.

Postoperative performance following total intravenous anaesthesia (TIVA) using midazolam and alfentanil was studied with and without the administration of a single dose of a benzodiazepine antagonist, flumazenil (Ro 15-1788). Performance was compared with a reference group anaesthetized with thiopentone, alfentanil and nitrous oxide. All patients were assessed by use of a rating scale which took into account the degree of sedation, amnesia, comprehension and cooperation as well as temporal and spatial orientation. There was a slow recovery following TIVA with somnolence and amnesia lasting several hours. Administration of flumazenil 1.0 mg i.v. at extubation caused a significant reduction of sedation (P less than 0.001) during the first postoperative hour, with patients fully awake or only lightly sedated, but was later followed by resedation. The patients of the reference group were moderately sedated during the observation period. Five and six hours postoperatively there was no difference between the groups. Amnesia was more profound in the groups that received midazolam; the effect of the antagonist could only be seen for 15 min after its administration. Comprehension and cooperation, as well as orientation, were equally good in the antagonist and in the reference group during the immediate postoperative period, whereas in the TIVA group a gradual improvement over the first hours was seen. In the antagonist group there was no increase in the number of analgesic requirements, no anxiety attacks or other adverse effects. It is concluded that flumazenil offers an improvement in postoperative performance following TIVA induced by midazolam and alfentanil, but the effects are of short duration.

Potential pulmonary uptake and clearance of morphine in postoperative patients.

The influence of lung uptake and lung clearance on the disposition of morphine was studied in surgical patients. In the postoperative period morphine was given intravenously by a two-rate infusion regimen. Under steady-state conditions samples of mixed central venous blood (pulmonary artery) and peripheral arterial blood (radial artery) were taken simultaneously and at the same time cardiac output was measured. The concentration differences between venous and arterial blood were used to calculate the extraction ratio of morphine across the lung. In all patients there was marked pulmonary uptake, but the concentration differences in most of them were small under steady-state conditions. The extraction ratio (mean +/- SD) across the lung was 0.06 +/- 0.10, implying insignificant lung clearance. However, in two patients, both with diabetes mellitus, there was a significant concentration gradient, indicating that the lung could contribute to the total body elimination of morphine. On the other hand, the total clearance was similar in diabetic and nondiabetic patients (1190 and 1150 ml/min, respectively), implying that pulmonary clearance would have no significant influence on the kinetics of morphine. A physiologically based pharmacokinetic model was used to describe the disposition of morphine in post-operative patients. The model allowed simulation of pulmonary diffusion, uptake and elimination and supported conclusions based on model-independent experimental data.

Atracurium infusion in total intravenous anesthesia.

The neuromuscular blocking effect of atracurium given as a bolus dose (0.5 mg X kg-1) followed by a maintenance infusion was studied during two different anesthetic techniques. It has been reported that benzodiazepines interact with non-depolarising neuromuscular blockers. In this study no difference was found in the effect of atracurium given with conventional fentanyl/nitrous oxide anesthesia when compared to total intravenous anesthesia using midazolam/alfentanil. More than 90% twitch depression was achieved after 123 and 137 s, respectively. Recovery time to 10% twitch height following the bolus dose was around 32 min. The dosage range for atracurium given by infusion (0.29-0.44 mg X kg-1 X h-1) was confirmed.

Pharmacokinetics of epidural morphine and meperidine in humans.

Five groups of surgical patients, each comprising six individuals, received epidural doses of morphine or meperidine, and the plasma and CSF kinetics were studied. Three groups received epidural doses of morphine 3 mg in 1 or 10 ml or meperidine 30 mg in 1 ml. Cerebrospinal fluid (CSF) and central venous blood opioid concentrations were measured intermittently for 6 h after injection. Two groups received epidural doses of morphine 3 mg in 1 ml or meperidine 30 mg in 1 ml, and opioid CSF concentrations were determined over a 24-h period. Morphine appeared rapidly in plasma, and maximum plasma concentrations were usually detected 5 min after injection and averaged 33 ng.ml-1 in the 1-ml volume group and 40 ng.ml-1 in the 10-ml volume group. The terminal plasma half-life averaged 91 +/- 34 min and 87 +/- 27 min, respectively (mean +/- SEM). Maximal plasma concentrations of meperidine were usually detected 10 or 15 min post-injection and averaged 196 +/- 29 ng.ml-1. The terminal plasma half-life averaged 124 +/- 26 min. Morphine crossed the dura relatively slowly, and the absorption half-life across the dura averaged 22 min. Maximal CSF concentrations were usually seen 60-90 min post-injection. In contrast, meperidine crossed the dura quickly, with an absorption half-life averaging 7.6 +/- 2.0 min. Maximal CSF concentrations were seen 15 or 30 min post-injection. Morphine and meperidine concentrations remained several times higher in the CSF than in the plasma. The fraction of the opioid dose crossing the dura was calculated to be 3.6% for morphine and 3.7% for meperidine. There were no significant differences in the kinetics of morphine administered in 1 or in 10 ml when CSF was sampled close to the site of lumbar epidural injection. The CSF concentration-time curves of both drugs decreased biexponentially after the initial rise due to diffusion across the dura. The early half-life in CSF averaged 73.3 +/- 11.5 min for morphine and 71.3 +/- 3.1 min for meperidine, and the late half-life averaged 369 +/- 113 min for morphine and 982 +/- 449 min for meperidine. Dose-normalized morphine and meperidine CSF concentrations after epidural administration showed that meperidine concentrations were down to one-fourth the corresponding morphine concentrations from the 2nd to the 15th h after administration, which may partly explain the longer duration of analgesia from morphine.(ABSTRACT TRUNCATED AT 400 WORDS)

Pharmacokinetics of intrathecal morphine and meperidine in humans.

Two groups of surgical patients each comprising six individuals received an intrathecal injection of morphine 0.3 mg or meperidine 10 mg. Cerebrospinal fluid (CSF) and plasma were sampled frequently during a 6-h period and analyzed for morphine or meperidine. Maximum plasma morphine concentrations were found 5-10 min after injection, and averaged 4.5 +/- 1.1 ng.ml-1 (mean +/- SEM). Maximum CSF morphine concentrations were considerably higher than maximum plasma concentrations, 6410 +/- 1290 ng.ml-1. Maximum plasma concentrations of meperidine were also measured 5 or 10 min after injection and were low (36 +/- 9 ng.ml-1) compared with the maximum CSF concentrations (364 +/- 105 micrograms.ml-1). After a rapid initial decline for about 15 min after injection, the CSF concentrations decreased with a half-life of 89.8 +/- 16.1 min for morphine and 68.0 +/- 5.1 min for meperidine during the rest of the study period. The initial volume of distribution in CSF was similar for both drugs, or 22 +/- 8 ml for morphine and 18 +/- 5 ml for meperidine. After 6 h, 1.6 +/- 0.9% of the injected morphine dose and 0.41 +/- 0.09% of the meperidine dose remained in the initial volume of distribution. Large inter-individual differences in morphine and meperidine CSF kinetics existed, which may explain some of the reported individual differences in duration of effects. The disappearance of meperidine from CSF tended to be faster than that of morphine, which may be explained, in part, by the differences in lipid solubilities of the drugs.