Sigridur Kalman

Cost-effectiveness Analysis of Goal-directed Hemodynamic Treatment of Elderly Hip Fracture Patients: Before Clinical Research Starts.

Background: Health economic evaluations are increasingly used to make the decision to adopt new medical interventions. Before such decisions, various stakeholders have invested in clinical research. But health economic factors are seldom considered in research funding decisions. Cost-effectiveness analyses could be informative before the launch of clinical research projects, particularly when a targeted intervention is resource-intensive, total cost for the trial is very high, and expected gain of health benefits is uncertain. This study analyzed cost-effectiveness using a decision analytic model before initiating a large clinical research project on goal-directed hemodynamic treatment of elderly patients with hip fracture. Methods: A probabilistic decision analytic cost-effectiveness model was developed; the model contains a decision tree for the postoperative short-term outcome and a Markov structure for long-term outcome. Clinical effect estimates, costs, health-related quality-of-life measures, and long-term survival constituted model input that was extracted from clinical trials, national databases, and surveys. Model output consisted of estimated medical care costs related to quality-adjusted life-years. Results: In the base case analysis, goal-directed hemodynamic treatment reduced average medical care costs by &OV0556;1,882 and gained 0.344 quality-adjusted life-years. In 96.5% of the simulations, goal-directed hemodynamic treatment is less costly and provides more quality-adjusted life-years. The results are sensitive to clinical effect size variations, although goal-directed hemodynamic treatment seems to be cost-effective even with moderate clinical effect. Conclusion: This study demonstrates that cost-effectiveness analysis is feasible, meaningful, and recommendable before launch of costly clinical research projects.

Combined photoplethysmographic monitoring of respiration rate and pulse : A comparison between different measurement sites in spontaneously breathing subjects

Background:  The non‐invasive photoplethysmographic (PPG) signal reflects blood flow and volume in a tissue. The PPG signal shows variation synchronous with heartbeat (PPGc), as used in pulse oximetry, and variations synchronous with breathing (PPGr). PPGr has been used for non‐invasive monitoring of respiration with promising results. Our aim was to investigate PPG signals recorded from different skin sites in order to find suitable locations for parallel monitoring of variations synchronous with heartbeat and breathing.

The effect of perioperative glucose control on postoperative insulin resistance

BACKGROUND & AIMS Postoperative insulin resistance and the consequent hyperglycemia affects clinical outcome. Insulin sensitivity may be modulated by preoperative nutrition, adequate pain management and minimal invasive surgery. This study aims to disclose the impact of perioperative glucose control on postoperative insulin resistance. METHODS Twenty patients scheduled for elective open hepatectomy were enrolled in this prospective, randomized study. In the treatment group (n = 9) insulin was administered intravenously to keep blood glucose between 6 and 8 mmol/l during surgery. The control group (n = 8) received insulin if blood glucose >14 mmol/l. Insulin sensitivity was measured by a hyperinsulinemic normoglycemic clamp (0.8 mU/kg/min), performed on all patients both on the day before surgery and immediately postoperatively. Plasma cortisol, insulin and C-peptide were measured. RESULTS There was a significant difference in mean glucose value during surgery. In the control group 8.8 mmol/l (SD 1.5) vs. 6.9 mmol/l (SD 0.4) in the treated group, p = 0.003. In the control group insulin sensitivity decreased to 21.9% ± 16.2% of the preoperative value and in the insulin treated group to 46.8 ± 15.5%, p < 0.005. Insulin levels were significantly higher in the treatment group as well as consequently lower C-peptide levels. CONCLUSIONS This trial revealed a significant difference in postoperative insulin resistance in the group treated with insulin during surgery.

Shaping the future of Scandinavian anaesthesiology: a position paper by the SSAI

Traditionally, Scandinavian anaesthesiologists have had a very broad scope of practice, involving intensive care, pain and emergency medicine. European changes in the different medical fields and the constant reorganising of health care may alter this. Therefore, the Board of the Scandinavian Society of Anaesthesiology and Intensive Care Medicine (SSAI) decided to produce a Position Paper on the future of the speciality in Scandinavia. The training in the various Scandinavian countries is very similar and provides a stable foundation for the speciality. The Scandinavian practice in anaesthesia and intensive care is based on a team model where the anaesthesiologists work together with highly educated nurses and should remain like this. However, SSAI thinks that the role of the anaesthesiologists as perioperative physicians is not fully developed. There is an obvious need and desire for further training of specialists. The SSAI advanced educational programmes for specialists should be expanded and include formal assessment leading to a particular medical competency as defined by the European Union of Medical Specialists (UEMS). In this way, Scandinavian anaesthesiologists will remain leaders in perioperative, intensive care, pain and critical emergency medicine.

First Human Study of the Investigational Sedative and Anesthetic Drug AZD3043: A Dose-Escalation Trial to Assess the Safety, Pharmacokinetics, and Efficacy of a 30-Minute Infusion in Healthy Male Volunteers.

BACKGROUND: AZD3043 is a positive allosteric modulator of the &ggr;-aminobutyric acid type A receptor that is rapidly metabolized to an inactive metabolite by esterases present in blood and liver. Preclinical results suggest that AZD3043 has the potential as a short-acting IV sedative/anesthetic drug with rapid and predictable recovery characteristics and a favorable safety and tolerability profile. METHODS: Our primary objective in this phase 1, single-center, open-label study was to evaluate the safety and tolerability of AZD3043 after IV infusion and to estimate the maximal tolerated dose. Secondary objectives included the evaluation of AZD3043 pharmacokinetics, pharmacodynamics, and efficacy. Sequential ascending-dose cohorts of 5 or 6 healthy male volunteers aged 18 to 45 years received a single 30-minute IV infusion of AZD3043. Assessments included adverse events, vital signs, blood gases, laboratory values, clinical signs of sedation/anesthesia, and bispectral index. RESULTS: Fifty-three subjects received AZD3043 in infusion rate cohorts of 1, 3, 6, 12, 18, 27, 36, 54, and 81 mg/kg/h. There were no discontinuations, and dose escalation was stopped on reaching the predefined exposure limit. Adverse events occurring in >1 subject were headache (n = 4), erythema (n = 3), chest discomfort (n = 2), nausea (n = 2), and dyspnea (n = 2). The frequency and character of adverse events appeared unrelated to dose. There were no spontaneous reports of pain on injection and no clinically relevant changes in respiratory rate or arterial blood pressure. However, heart rate increased dose-dependently at infusion rates >18 mg/kg/h. Occurrence of sedation/anesthesia corresponded with dose; the lowest applied infusion rate to induce anesthesia according to clinical signs of sedation/anesthesia at predefined time points was 12 mg/kg/h (1 of 6 subjects anesthetized), and all subjects in the 3 highest dose groups were anesthetized. The onset of anesthesia ranged from 4 minutes in the highest infusion rate group to 29 minutes in the 12-mg/kg/h infusion rate group. Return of response to oral command occurred at 3 minutes after the end of infusion in the single subject who was anesthetized in the 12-mg/kg/h group and median 25 minutes in the 81-mg/kg/h group. Involuntary movements ranging from minor twitches to extensive movements were accompanied by increased muscle tone. CONCLUSIONS: AZD3043 was well tolerated in this first human study and seems to exhibit rapid onset and recovery, indicating potential use as a short-acting drug for anesthesia and sedation.

A Bolus and Bolus Followed by Infusion Study of AZD3043, an Investigational Intravenous Drug for Sedation and Anesthesia: Safety and Pharmacodynamics in Healthy Male and Female Volunteers.

BACKGROUND: AZD3043 (THRX-918661) is an investigational phenylpropanoid sedative/anesthetic that is rapidly metabolized by esterases in blood and liver. In the first-in-man study, a 30-minute constant IV infusion of AZD3043 induced anesthesia without major safety or tolerability concerns and with rapid recovery characteristics. METHODS: The primary objective of this phase 1, single-center, open-label study (clinicaltrials.gov NCT00984880) was to evaluate the safety and tolerability of AZD3043 administered as a single IV bolus and as a bolus followed by infusion. Secondary objectives included evaluation of AZD3043 pharmacodynamics and efficacy. Sequential ascending dose cohorts of 8 healthy volunteers aged 18 to 65 years received either a single 1-minute bolus IV infusion (part A) or a 1-minute bolus followed by a 30-minute infusion (part B). Assessments included adverse events, vital signs, blood gases, laboratory values, clinical signs of sedation/anesthesia, and bispectral index score. RESULTS: Seventy-two subjects (8 females, 64 males) received AZD3043 doses of 1, 1.5, 2, 4, and 6 mg/kg bolus over 1 minute (part A) or 0.8 + 10, 1 + 15, 3 + 30, and 4 + 40 mg/kg bolus + mg/kg/h infusion for 30 minutes (part B). There were no discontinuations. Adverse events occurring in >1 subject were headache (n = 15; 21%), nausea (n = 7; 10%), vomiting (n = 3; 4%), and fatigue (n = 2; 3%). Twenty-one subjects experienced at least 1 adverse event. There seemed to be no dose relationship associated with any adverse event. Ventilation was maintained, but there was a dose-dependent increase in heart rate. There were no spontaneous reports of pain on injection. Thirty-two subjects were anesthetized, including all subjects in the highest dose group in part A and all subjects in the 2 highest dose groups in part B. Recovery from anesthesia was rapid, with swift return of orientation and proprioception. All subjects were able to walk 10 m without support at their first assessment, 30 minutes after end of dosing, except for 1 subject in each of the 2 mg/kg bolus (part A) and 4 mg/kg bolus + 40 mg/kg/h 30-minute infusion (part B) dose groups, who passed this test at the subsequent assessment, 45 minutes after the end of dosing. Involuntary movements were observed at higher doses, accompanied by increased muscle tone. CONCLUSIONS: AZD3043 provided rapid recovery from anesthesia with maintained ventilation. Further studies are warranted in a clinical setting.

Creating an environment for patient safety and teamwork training in the operating theatre: A quasi-experimental study

Abstract Introduction: Positive safety and a teamwork climate in the training environment may be a precursor for successful teamwork training. This pilot project aimed to implement and test whether a new interdisciplinary and team-based approach would result in a positive training climate in the operating theatre. Method: A 3-day educational module for training the complete surgical team of specialist nursing students and residents in safe teamwork skills in an authentic operative theatre, named Co-Op, was implemented in a university hospital. Participants’ (n = 22) perceptions of the ‘safety climate’ and the ‘teamwork climate’, together with their ‘readiness for inter-professional learning’, were measured to examine if the Co-Op module produced a positive training environment compared with the perceptions of a control group (n = 11) attending the conventional curriculum. Results: The participants’ perceptions of ‘safety climate’ and ‘teamwork climate’ and their ‘readiness for inter-professional learning’ scores were significantly higher following the Co-Op module compared with their perceptions following the conventional curriculum, and compared with the control group’s perceptions following the conventional curriculum. Conclusion: The Co-Op module improved ‘safety climate’ and ‘teamwork climate’ in the operating theatre, which suggests that a deliberate and designed educational intervention can shape a learning environment as a model for the establishment of a safety culture.

A Recirculatory Model for Pharmacokinetics and the Effects on Bispectral Index After Intravenous Infusion of the Sedative and Anesthetic AZD3043 in Healthy Volunteers

BACKGROUND: AZD3043 is a positive allosteric modulator of the &ggr;-aminobutyric acid type A receptor, with sedative and anesthetic properties. We describe a population pharmacokinetic (PK) model of arterial and venous concentrations of AZD3043 and the pharmacodynamic effects on bispectral index (BIS) in healthy volunteers. METHODS: Arterial and venous plasma concentrations of AZD3043 and BIS were measured in 2 clinical studies in 125 healthy volunteers, where AZD3043 was given as a 1-minute bolus (1–6 mg/kg), a 30-minute infusion (1–81 mg/kg/h), or 0.8 + 10, 1 + 15, 3 + 30, and 4 + 40 (mg/kg bolus + mg/kg/h infusion for 30 minutes). Population PK/pharmacodynamic analysis was performed with NONMEM. RESULTS: A recirculatory model, comprising a series of 5 compartments for the transit of drug between venous and arterial plasma, 2 peripheral distribution compartments, and 1 compartment for the nondistributive transit of drug from arterial to venous plasma, described the PK of AZD3043. Systemic clearance was high (2.2 L/min; 95% confidence interval, 2.12–2.25), and apparent volumes of distribution were low, leading to a short elimination half-life. The apparent volumes of distribution of the arterial and peripheral compartments increased with increasing administered dose, giving a total apparent volume of distribution of 15 L after the lowest dose and 37 L after the greatest dose. A sigmoid maximum effect (E max) model with an EC 50 of 15.6 µg/mL and a &ggr; of 1.7 described the relationship between AZD3043 effect-site concentrations and BIS. The between-subject variability in EC 50 was 37%. An effect compartment model, with a half-life of the equilibration rate constant ke0 of 1.1 min, described the delay in effect in relation to the arterial plasma concentrations. CONCLUSIONS: AZD3043 had a high clearance and a low apparent volume of distribution, leading to a short half-life. However, the apparent volume of distribution was dose dependent (P < 0.001), leading to an increased half-life with increasing dose. The distribution to the effect site was fast and together with the short plasma half-life led to a fast onset and offset of effects.

Value of information: interim analysis of a randomized, controlled trial of goal-directed hemodynamic treatment for aged patients

BackgroundA randomized, controlled trial, intended to include 460 patients, is currently studying peroperative goal-directed hemodynamic treatment (GDHT) of aged hip-fracture patients. Interim efficacy analysis performed on the first 100 patients was statistically uncertain; thus, the trial is continuing in accordance with the trial protocol. This raised the present investigation’s main question: Is it reasonable to continue to fund the trial to decrease uncertainty? To answer this question, a previously developed probabilistic cost-effectiveness model was used. That model depicts (1) a choice between routine fluid treatment and GDHT, given uncertainty of current evidence and (2) the monetary value of further data collection to decrease uncertainty. This monetary value, that is, the expected value of perfect information (EVPI), could be used to compare future research costs. Thus, the primary aim of the present investigation was to analyze EVPI of an ongoing trial with interim efficacy observed.MethodsA previously developed probabilistic decision analytic cost-effectiveness model was employed to compare the routine fluid treatment to GDHT. Results from the interim analysis, published trials, the meta-analysis, and the registry data were used as model inputs. EVPI was predicted using (1) combined uncertainty of model inputs; (2) threshold value of society’s willingness to pay for one, quality-adjusted life-year; and (3) estimated number of future patients exposed to choice between GDHT and routine fluid treatment during the expected lifetime of GDHT.ResultsIf a decision to use GDHT were based on cost-effectiveness, then the decision would have a substantial degree of uncertainty. Assuming a 5-year lifetime of GDHT in clinical practice, the number of patients who would be subject to future decisions was 30,400. EVPI per patient would be €204 at a €20,000 threshold value of society’s willingness to pay for one quality-adjusted life-year. Given a future population of 30,400 individuals, total EVPI would be €6.19 million.ConclusionsIf future trial costs are below EVPI, further data collection is potentially cost-effective. When applying a cost-effectiveness model, statements such as ‘further research is needed’ are replaced with ‘further research is cost-effective and ‘further funding of a trial is justified’.Trial registrationClinicalTrials.gov NCT01141894

Evaluation of central venous catheters coated with a noble metal alloy—A randomized clinical pilot study of coating durability, performance and tolerability

Abstract The use of Central Venous Catheters (CVCs) commonly results in complications. Coatings with silver or metal alloys can reduce the risk associated with the use of CVC. We have evaluated the durability of a noble metal coated CVC (the Bactiguard Infectious Protection, BIP CVC) and compared with an uncoated CVC for clinical tolerability (Adverse Events, AEs) and performance, in order to create a baseline for a large future study. Patients undergoing major surgery, randomised at a 2:1 ratio to BIP CVC (n = 22) or standard CVC (n = 12), were catheterized 9 ‐ 12 days, respectively. Adverse events, microbial colonization and metal release were measured. Findings: There were no AEs in the BIP CVC‐group, but 5 AEs occurred in 4 patients (1 patient had 2 AEs) in the standard CVC‐group, p = 0.011 (whereof 3 were catheter related). The BIP CVC showed an initial release of coating metals in blood (gold, silver and palladium), which rapidly decreased and were far below Permitted Paily Exposure (PDE) for chronical use. The levels of silver concentration were far below those needed to develop microbial resistance. The performance was equal, and there was no difference concerning microbial colonization, for the two CVCs. Conclusion: In this pilot study the BIP CVC had significantly lower AEs and showed a comparable performance to the standard CVC. The coating was durable throughout the study length (up to 16 days) and toxicological evaluation showed good safety margins. Larger studies are needed.