The effect of non-adherence to antipsychotic treatment on rehospitalization in patients with psychotic disorders.

BACKGROUND AND AIMS: Many patients with psychotic disorders are non-adherent to antipsychotic (AP) medication(s), potentially contributing to rehospitalization. It is unknown whether non-adherence in different phases of AP use is associated with rehospitalization. The aim of this study was to assess the association between non-adherence to APs and rehospitalization in patients with psychotic disorders. Non-adherence was assessed specifically for the initiation, continued drug use and early discontinuation of AP use. METHODS: A retrospective follow-up study was performed. Adult patients were included at discharge if they suffered from schizophrenia, psychotic, or bipolar I disorder; had been hospitalized in a psychiatric hospital for ⩾7 days; and were treated with oral APs. Patients discharged between January 2006 and December 2009 from Altrecht Mental Health Care were included. Non-adherence was studied in the three phases of medication use: initiation, continued drug use (implementation) and (early) discontinuation after discharge until the end of follow up or until patients were rehospitalized. Cox regression analysis was used to assess the strength of the association between non-adherence for the different phases of AP use and rehospitalization during follow up and expressed as relative risk (RR) with 95% confidence intervals (CI). RESULTS: A total of 417 patients were included. Patients who did not initiate their APs compared with those who did in the first month (RR = 1.62, 95% CI: 1.19-2.19) and between the first and third month after discharge (RR = 1.70, 95% CI: 1.04-2.79) had the highest risk for rehospitalization during follow up. Overall, patients who did not initiate their AP medication within the first year after discharge had a RR of 2.70 (95% CI: 1.97-3.68) for rehospitalization during follow up compared with those that initiated their AP. CONCLUSION: Not initiating APs right after discharge was associated with an increased risk of rehospitalization. Interventions should aim to promote the initiation of APs soon after discharge to minimize the risk of rehospitalization.

Non-invasive continuous arterial pressure and pulse pressure variation measured with Nexfin(®) in patients following major upper abdominal surgery: a comparative study.

We compared the accuracy and precision of the non-invasive Nexfin(®) device for determining systolic, diastolic, mean arterial pressure and pulse pressure variation, with arterial blood pressure values measured from a radial artery catheter in 19 patients following upper abdominal surgery. Measurements were taken at baseline and following fluid loading. Pooled data results of the arterial blood pressures showed no difference between the two measurement modalities. Bland-Altman analysis of pulse pressure variation showed significant differences between values obtained from the radial artery catheter and Nexfin finger cuff technology (mean (SD) 1.49 (2.09)%, p < 0.001, coefficient of variation 24%, limits of agreement -2.71% to 5.69%). The effect of volume expansion on pulse pressure variation was identical between methods (concordance correlation coefficient 0.848). We consider the Nexfin monitor system to be acceptable for use in patients after major upper abdominal surgery without major cardiovascular compromise or haemodynamic support.

The effect of propofol on haemodynamics: cardiac output, venous return, mean systemic filling pressure, and vascular resistances.

BACKGROUND: Although arterial hypotension occurs frequently with propofol use in humans, its effects on intravascular volume and vascular capacitance are uncertain. We hypothesized that propofol decreases vascular capacitance and therefore decreases stressed volume. METHODS: Cardiac output (CO) was measured using Modelflow(®) in 17 adult subjects after upper abdominal surgery. Mean systemic filling pressure (MSFP) and vascular resistances were calculated using venous return curves constructed by measuring steady-state arterial and venous pressures and CO during inspiratory hold manoeuvres at increasing plateau pressures. Measurements were performed at three incremental levels of targeted blood propofol concentrations. RESULTS: Mean blood propofol concentrations for the three targeted levels were 3.0, 4.5, and 6.5 µg ml(-1). Mean arterial pressure, central venous pressure, MSFP, venous return pressure, Rv, systemic arterial resistance, and resistance of the systemic circulation decreased, stroke volume variation increased, and CO was not significantly different as propofol concentration increased. CONCLUSIONS: An increase in propofol concentration within the therapeutic range causes a decrease in vascular stressed volume without a change in CO. The absence of an effect of propofol on CO can be explained by the balance between the decrease in effective, or stressed, volume (as determined by MSFP), the decrease in resistance for venous return, and slightly improved heart function. CLINICAL TRIAL REGISTRATION: Netherlands Trial Register: NTR2486.

Prevalence of medication use for somatic disease in institutionalized psychiatric patients.

INTRODUCTION: Psychiatric patients may use medications for their psychiatric condition as well as for treating concurrent somatic diseases or somatic side effects of psychiatric medicines. The objective of this study was to estimate the prevalence of use of medication for somatic disease in institutionalized psychiatric patients and changes therein during 2006-2010. METHOD: A cross-sectional study in institutionalized psychiatric patients was performed. Medication use for somatic disease on 10 time points between 2006 and 2010 was investigated and stratified by gender, age, psychiatric medication class and the number of different psychiatric medication classes used. RESULTS: The prevalence of use of medication for somatic disease increased from 67.5% in 2006 to 76.9% in 2010. The median number of medications used for somatic disease per patient was 3 between 2006 and 2010. Approximately one-third (34.1%) of the patients received ≥ 3 medications intended for treating somatic disease in 2006 which increased to 46.3% in 2010. In 2010, the prevalence of medication use for somatic disease was highest for analgesics and antirheumatics (34.0%), acid and bowel related medication (25.6%) and anticholinergic medication (24.2%). Medication use for somatic disease was highest in patients ≥ 60 years (95.3%), patients treated with more than one psychiatric medication class (87.5%) and patients treated with mood stabilizers (90.6%). DISCUSSION: Somatic medication use is high in institutionalized psychiatric patients. More attention is needed for co-use of psychiatric and somatic medications to prevent side effects, drug-disease or drug-drug interactions. More research is needed to investigate if somatic care is optimal in institutionalized psychiatric patients.

[Routine outcome monitoring and benchmarking: how can treatment results be compared in a responsible manner?]. / Routine outcome monitoring en benchmarking: hoe kunnen we behandelresultaten op een zorgvuldige manier vergelijken?

BACKGROUND: The structural measurement of the results of treatment under the Dutch mental health services and a comparison of these results between mental health centres help to provide insight into the effectiveness of treatment in general practice. AIM: To provide an overview of the issues that require attention when the results of mental health centres are being compared. METHOD: Documentation, policy information and practical experience with routine outcome monitoring were analysed. RESULTS: We describe the problems that can arise when results obtained by mental health centres are compared and we suggest some solutions for these problems. Important factors that have emerged from our study are as follows: working with routine outcome monitoring is a process of natural growth and involves experiences with several solutions and the making of definitive choices on the basis of experience. CONCLUSION: It is instructive to compare mental health centres with each other and with regards to so-called 'best practices' (benchmarking). However, mental health centres draw on a differing wide mix of patients and use different measurement procedures and instruments. In this article we express the view that in the near future it should be possible to draw meaningful comparisons.

Pheochromocytomas detected by biochemical screening in predisposed subjects are associated with lower prevalence of clinical and biochemical manifestations and smaller tumors than pheochromocytomas detected by signs and symptoms.

CONTEXT: Sporadic pheochromocytomas are detected by clinical signs and symptoms, whereas pheochromocytomas in patients with a known hereditary predisposition for these tumors are detected by repetitive screening for catecholamine excess. OBJECTIVE: To document the clinical, biochemical, and pathological differences between patients with sporadic pheochromocytomas, detected by signs and symptoms and patients with pheochromocytomas, detected by biochemical screening in established hereditary syndromes. DESIGN: Retrospective follow-up study. PATIENTS AND METHODS: We included 60 consecutive patients diagnosed with pheochromocytoma (pheochromocytomas detected by signs and symptoms: n=28 and pheochromocytomas detected by screening: n=32) in our center. RESULTS: Patients with pheochromocytomas detected by screening presented with less complaints of diaphoresis (P<0.01), palpitations (P=0.01), paleness (P=0.01), nausea (P<0.01), and vomiting (P=0.01) compared with patients with symptomatic pheochromocytomas. Patients with pheochromocytomas detected by screening tended to be younger at the time of diagnosis (41+/-2 vs 47+/-3 years, P=0.07). In addition, patients with pheochromocytomas detected by screening had significantly lower rates of 24-h urinary catecholamine excretion, and considerably smaller tumors (3.7+/-0.5 vs 7.3+/-0.7 cm, P<0.01). CONCLUSIONS: Pheochromocytomas detected by screening of patients with a hereditary predisposition have a much lower prevalence of signs and symptoms, lower catecholamine excess, and smaller tumors, compared with sporadic pheochromocytomas, detected by signs and symptoms. These data support the benefits of screening for pheochromocytomas in patients with hereditary syndromes predisposing for these tumors.

[Bispectral analysis of the electroencephalogram: a new method for recording the level of consciousness during anaesthesia]. / Bispectraalanalyse van het elektro-encefalogram: een nieuwe methode van bewustzijnsregistratie tijdens anesthesie.

Until recently, no measure was available that provided objective and reproducible information on the level of consciousness in patients under general anaesthesia. Several decades of research to find a reliable measure for determining the depth of anaesthesia has now led to the clinical introduction of the bispectral index scale (BIS), a parameter derived from the electroencephalogram. Implementation of the BIS-monitor in anaesthetic practice leads to a reduced use of hypnotic agents, a more rapid recovery phase and possibly a reduced incidence of awareness.

Predictive performance of computer-controlled infusion of remifentanil during propofol/remifentanil anaesthesia.

BACKGROUND: The predictive performance of the available pharmacokinetic parameter sets for remifentanil, when used for target-controlled infusion (TCI) during total i.v. anaesthesia, has not been determined in a clinical setting. We studied the predictive performance of five parameter sets of remifentanil when used for TCI of remifentanil during propofol anaesthesia in surgical patients. METHODS: Remifentanil concentration-time data that had been collected during a previous pharmacodynamic interaction study in 30 female patients (ASA physical status I, aged 20-65 yr) who received a TCI of remifentanil and propofol during lower abdominal surgery were used in this evaluation. The remifentanil concentrations predicted by the five parameter sets were calculated on the basis of the TCI device record of the infusion rate-time profile that had actually been administered to each individual. The individual and pooled bias [median performance error (MDPE)], inaccuracy [median absolute performance error (MDAPE)], divergence and wobble of the remifentanil TCI device were determined from the pooled and intrasubject performance errors. RESULTS: A total of 444 remifentanil blood samples were analysed. Blood propofol and remifentanil concentrations ranged from 0.5 to 11 micro g ml(-1) and 0.1 to 19.6 ng ml(-1) respectively. Pooled MDPE and MDAPE of the remifentanil TCI device were -15 and 20% for the parameter set of Minto and colleagues (Anesthesiology 1997; 86: 10-23), 1 and 21%, -6 and 21%, and -6 and 19% for the three parameter sets described by Egan and colleagues (Anesthesiology 1996; 84: 821-33, Anesthesiology 1993; 79: 881-92, Anesthesiology 1998; 89: 562-73), and -24 and 30% for the parameter set described by Drover and Lemmens (Anesthesiology 1998; 89: 869-77). CONCLUSIONS: Remifentanil can be administered by TCI with acceptable bias and inaccuracy. The three pharmacokinetic parameter sets described by Egan and colleagues resulted in the least bias and best accuracy.

[The effect of anesthetics on control of respiration]. / Einfluss von Anästhetika auf die Atemkontrolle.

Ventilatory control in humans depends on complex mechanisms which aim to maintain a cellular CO2-, O2- and H(+)-homeostasis under physiological conditions. This regulation is based on chemical control which predominantly acts via peripheral chemoreceptors in the carotid bodies and central chemoreceptors in the ventral medulla of the brainstem on the one hand, and behavioural control on the other, by which it is possible to adapt respiration to conditions of daily living. The influence of anaesthesia and related conditions may depress respiration and have a sustained effect on ventilatory control. Perioperative respiratory depression remains a serious clinical problem in perioperative medicine. This review will give an overview of ventilatory control and discuss the most relevant responses, describe the effects of pain, anaesthetics and opioids on ventilatory control and their interaction. The current body of knowledge is put into perspective to identify patients at risk for perioperative respiratory depression.

Gender differences in the pharmacokinetics of propofol in elderly patients during and after continuous infusion.

Differences in the pharmacokinetics of propofol between male and female patients during and after continuous infusion have not been described in detail in patients aged 65 yr and older. To increase our insight into the pharmacokinetics of propofol in this patient population and to obtain pharmacokinetic parameters applicable in target controlled infusion (TCI), the pharmacokinetics of propofol during and after continuous infusion were studied in 31 ASA class 1 and 2 patients, aged 65-91 yr, scheduled for general surgery. Patients received propofol 1.5 mg kg(-1) i.v. in 1 min followed by 7 mg kg(-1) h(-1) until skin closure in the presence of a variable rate infusion of alfentanil during oxygen-air ventilation. On the basis of arterial blood samples that were taken up to 24 h post-infusion, the pharmacokinetics of propofol were evaluated in a two-stage manner. Multiple linear regression analysis was used to explore the effect of age, weight, gender and lean body mass as covariates. Gender significantly affected the pharmacokinetics of propofol. V3, Cl1 and Cl2 were significantly different between male and female patients, weight only affected Cl1. The pharmacokinetic parameters were: V1=4.88 litre, V2=24.50 litre, V3 (litre)=115+147 x gender (gender: male=1, female=2), Cl1 (litre min(-1))=-0.29+0.022 x weight+0.22 x gender, Cl2 (litre min(-1))=2.84-0.65 x gender (male=1, female=2), and Cl3=0.788 litre min(-1).

Propofol alters the pharmacokinetics of alfentanil in healthy male volunteers.

BACKGROUND: The influence of propofol on the pharmacokinetics of alfentanil is poorly understood. The authors therefore studied the effect of a pseudo-steady state concentration of propofol on the pharmacokinetics of alfentanil. METHODS: The pharmacokinetics of alfentanil was studied on two occasions in eight male volunteers in a randomized crossover manner with a 3-week interval. While breathing 30% O2 in air, 12.5 microg/kg intravenous alfentanil was given in 2 min, followed by 25 microg.kg(-1).h(-1) for 58 min (sessions A and B). During session B, a target controlled infusion of propofol (target concentration, 1.5 microg/ml) was given from 10 min before the start until 6 h after termination of the alfentanil infusion. Blood pressure, cardiac output, electrocardiogram, respiratory rate, oxygen saturation, and end-tidal carbon dioxide were monitored. Venous blood samples for determination of the plasma alfentanil concentration were collected until 6 h after termination of the alfentanil infusion. Nonlinear mixed-effects population pharmacokinetic models examining the influence of propofol and mean arterial pressure were constructed. RESULTS: A three-compartment model, including a lag time accounting for the venous blood sampling, adequately described the concentration-time curves of alfentanil Propofol decreased the elimination clearance of alfentanil by 15%, rapid distribution clearance by 68%, slow distribution clearance by 51%, and lag time by 62%. Mean arterial pressure and systemic vascular resistance were significantly lower in the presence of propofol. Scaling the pharmacokinetic parameters to the mean arterial pressure instead of propofol improved the model. CONCLUSIONS: Propofol alters the pharmacokinetics of alfentanil. Hemodynamic changes induced by propofol may have an important influence on the pharmacokinetics of alfentanil.

Clinical interpretation of pharmacokinetic and pharmacodynamic propofol-opioid interactions.

This manuscript describes the pharmacokinetic and pharmacodynamic interactions between propofol and the opioids. PHARMACOKINETIC INTERACTIONS: In vitro studies describe the reduced clearance of opioids in the presence of propofol, midazolam and etomidate due to interaction at the cytochrome P450 enzyme system. In vivo, however, pharmacokinetic interaction studies by mixed effects modelling predominantly focus on haemodynamic factors affecting distribution and elimination of concomitantly administered agents. In the presence of propofol the elimination clearance and rapid and slow distribution clearance of alfentanil is decreased. Consequently, plasma alfentanil concentrations are increased in the presence of propofol. Vice versa alfentanil reduces propofol elimination clearance and increases the deep volume of distribution. PHARMACODYNAMIC INTERACTIONS: Propofol and the opioids interact in a synergistic manner for various clinical end points. The magnitude of interaction is similar between the various opioids and hypnotic agents, taken into consideration the differences in potency between the opioids. CLINICAL INTERPRETATION OF PK/PD INTERACTIONS: A. Speed of induction. Using PK/PD interaction data speed of induction can be optimised. Of importance are the magnitude of PD interaction between propofol and the various opioids, the rate of administration and the time to peak effect of the agents involved. B. Haemodynamic stability. In ASA 1-2 patients the opioid induced hypnotic dose reduction is not associated with an increased haemodynamic stability of induction of loss of consciousness. In elderly patients or patients known with cardiovascular instability high opioid-low propofol anaesthesia may be associated with improved haemodynamic stability during induction of anaesthesia, however, no data are available regarding this yet. C. Speed of recovery. Time to return of consciousness after termination of propofol-opioid infusions of various duration can be reduced using optimal propofol-opioid concentrations. In general, optimal propofol target concentrations to assure this are 5 micrograms/ml in the presence of fentanyl, 3.5 micrograms/ml in the presence of alfentanil and sufentanil and 2.5 micrograms/ml in the presence of remifentanil. D. Spontaneous respiration. For single agents some data allow proper targeting of a drug concentration that is associated with adequate intraoperative respiration. However, no data exist on drug interactions regarding the respiratory depressant effects of hypnotic-opioid combinations. CONCLUSION: The proper exploration and use of published pharmacokinetic and pharmacodynamic interaction data allows the clinical anaesthesiologist to optimise the clinical administration of propofol and the various opioids when given alone or in combination.

Target-controlled infusion systems: role in anaesthesia and analgesia.

Drug delivery by target-controlled infusion (TCI) allows automatic adjustments of the infusion rate of a drug to maintain a desired target concentration. Since drug effect is more closely related to blood concentration than to infusion rate, drug delivery via TCI is capable of creating stable blood concentrations of intravenous anaesthetics and analgesics. In this article the concept and history of TCI are described. The rational administration of TCI requires an appropriate pharmacokinetic data set and knowledge of the concentration-effect relationship; therefore, general pharmacokinetic and pharmacodynamic aspects of intravenous anaesthetics and analgesics are also addressed. Intraoperative investigations have demonstrated that TCI drug delivery allows rapid titration to a desired effect. The use of TCI for postoperative analgesia is still experimental, but TCI can, in part, overcome the disadvantages associated with continuous infusions and patient-controlled analgesia regimens in the postoperative period. Although TCI is capable of creating stable blood concentrations, when the target concentration is changed the resulting effect correlates better with a theoretical effect site concentration. The efficacy of TCI systems that can perform effect-site steering are still to be explored.

Drug interactions in anaesthesia.

Anaesthesia is nowadays seldom accomplished by a single agent because no single agent is able to provide all components of anaesthesia without seriously compromising haemodynamic and/or respiratory function, reducing operating conditions, or postponing postoperative recovery. Because of the small therapeutic window a detailed characterisation of the concentration-effect relationships of anaesthetic agents is required to allow a proper selection of the various intravenous agents and the combinations thereof to an optimal therapeutic pharmacological effect in the absence of significant side effects. During the past decade, for propofol and the various opioids fentanyl, alfentanil, sufentanil, and remifentanil considerable progress has been made in the characterisation of the pharmacokinetics and pharmacodynamics of these agents and of the combinations thereof. This manuscript describes the pharmacokinetic and dynamic interactions between these agents and the determination of optimal concentrations that assure adequate anaesthesia and a rapid return of recovery.

Pharmacodynamic interaction of eltanolone and alfentanil during lower abdominal surgery in female patients.

We have studied the influence of eltanolone on intraoperative alfentanil requirements in 18 female patients undergoing lower abdominal surgery receiving target-controlled infusions of eltanolone and alfentanil. While target concentrations of eltanolone were maintained constant, target concentrations of alfentanil changed in response to the presence or absence of responses. With serum eltanolone concentrations increasing from 500 to 2000 ng ml-1, the EC50 of alfentanil for suppression of responses to surgical stimulation decreased from 233 to 9 ng ml-1. The findings suggest that the interaction between eltanolone and alfentanil is synergistic.

TCI: supplementation and drug interactions.

The pharmacokinetic and pharmacodynamic interactions between propofol and adjuvant agents have increasingly been recognised as clinically important and the improved knowledge of these interactions is being used to optimise the quality of intravenous anaesthesia. It is now known that propofol interferes with opioid metabolism, thereby increasing the plasma concentrations of the opioids, while opioids such as alfentanil increase propofol concentrations by reducing both the distribution and clearance of propofol. The pharmacokinetic interactions, however, are of relatively minor clinical importance compared with pharmacodynamic interactions. The pharmacodynamic interaction between propofol and other sedative agents, or one of the synthetic opioids, is synergistic. From the pharmacodynamic interaction data, optimal target propofol-opioid concentrations and optimal infusion regimens have been developed that ensure adequate anaesthesia in 50% and 95% of patients with the most rapid recovery possible. These optimal target propofol concentrations and infusion regimens are affected by the opioid with which propofol is combined, as well as the duration of infusion.

Pharmacokinetic and pharmacodynamic interactions between opioids and propofol.

The pharmacokinetic and pharmacodynamic interactions between opioids and propofol increasingly have been described and used in clinical practice. It is now known that propofol inhibits both alfentanil and sufentanil metabolism, thereby increasing the plasma concentrations of these opioids, while alfentanil also elevates propofol concentrations. Pharmacodynamically the interaction between propofol and the opioids is generally found to be synergistic. From the interaction data, the optimal propofol concentrations have been extracted that assure adequate anesthesia and the most rapid recovery possible. In the presence of fentanyl, sufentanil, and alfentanil, the optimal propofol concentration is approximately 3.5 microgram/ml, whereas in the presence of remifentanil, lower propofol concentrations of 2.5 to 3 microgram/ml are required.

Pharmacodynamic interaction between propofol and alfentanil when given for induction of anesthesia.

BACKGROUND: Propofol and alfentanil often are combined during induction of anesthesia. However, the interaction between these agents during induction has not been studied in detail. The influence of alfentanil on the propofol concentration-effect relationships was studied for loss of eyelash reflex, loss of consciousness, and hemodynamic function in 20 unpremedicated ASA physical status 1 patients aged 20-55 yr. METHODS: Patients were randomly divided into four groups to receive a computer- controlled infusion of alfentanil with target concentrations of 0, 50, 200, or 400 ng/ml (groups A, B, C, and D, respectively). While the target concentration of alfentanil was maintained constant, patients received a computer- controlled infusion of propofol, with an initial target concentration of 0.5-1 microgram/ml, that was increased every 12 min by 0.5-1 microgram/ml. Every 3 min, the eyelash reflex and state of consciousness were tested an an arterial blood sample was taken for blood propofol and plasma alfentanil determination. The propofol-alfentanil concentration-response relationships for loss of eyelash reflex and loss of consciousness were determined by nonlinear regression, and for the percentage of change in systolic blood pressure and heart rate by logistic regression. RESULTS: The patient characteristics did not differ significantly among the four groups. The patients in groups A and B continued to breathe adequately, whereas all patients in groups C and D required assisted ventilation. End-tidal carbon dioxide partial pressure remained less than 46 mmHg in all patients. With plasma alfentanil concentrations increasing from 0 to 500 ng/ml, the EC(50) of propofol decreased from 2.07 to 0.83 microgram/ml for loss of eyelash reflex and from 3.62 to 1.55 microgram/ml for loss of consciousness. With plasma alfentanil concentrations increasing from 0 to 500 ng/ml, the blood propofol concentrations associated with a 10% decrease in systolic blood pressure and heart rate decreased from 1.68 to 0.17 microgram/ml and from 2.36 to 0.04 microgram/ml, respectively. CONCLUSIONS: Alfentanil significantly reduces blood propofol concentrations required for loss of eyelash reflex and loss of consciousness. In addition, alfentanil enhances the depressant effects of propofol on systolic blood pressure and heart rate. Hemodynamic stability, therefore, does not increase in patients receiving propofol in combination with alfentanil compared to those receiving propofol as the sole agent for induction of anesthesia.