Surgical Outcome Risk Tool (SORT) to predict 30-day postoperative mortality in a mixed surgical population in Swedish tertiary hospitals.

BACKGROUND: The Surgical Outcome Risk Tool (SORT) was derived and validated in the UK to improve preoperative prediction of postoperative risk. The aim of this study was to validate the SORT in a European mixed-case surgical population outside of the UK. METHODS: The study included patients aged at least 18 years with ASA Physical Status (ASA-PS) grades I-V who underwent non-cardiac surgery at four tertiary hospitals in Sweden between November 2015 and February 2016. Exclusion criteria were surgery under local anaesthesia and missing data on the SORT predictors (ASA-PS, surgical urgency, high-risk surgery, surgical severity, malignancy, age over 65 years). The outcome was 30-day mortality. Discrimination and calibration of the SORT were assessed using area under the receiver operating curve (AUROC) statistics and calibration plots. A sensitivity analysis was done in a high-risk subgroup (ASA-PS III or higher; surgical complexity major to Xmajor according to the SORT; gastrointestinal, orthopaedic, urogenital/obstetric surgery; and age at least 18 years). RESULTS: The validation cohort included 17 965 patients; median age was 58 (i.q.r. 40-70) years, 43.2 per cent were men, and the mortality rate at 30 days was 1.6 per cent. The SORT had excellent discrimination, with an AUROC of 0.91 (95 per cent c.i. 0.89 to 0.92), and good calibration. The high-risk subgroup (1807 patients) had a 30-day mortality rate of 5.6 per cent; in the sensitivity analysis, the SORT had good discrimination, with an AUROC of 0.79 (0.74 to 0.83), and calibration remained good. CONCLUSION: The estimates of the original the SORT for prediction of 30-day mortality were valid and reliable in a mixed-case surgical population in a non-UK European setting.

ASA classification and surgical severity grading used to identify a high-risk population, a multicenter prospective cohort study in Swedish tertiary hospitals.

BACKGROUND: Identification of surgical populations at high risk for negative outcomes is needed for clinical and research purposes. We hypothesized that combining two classification systems, ASA (American Society of Anesthesiology physical status) and surgical severity, we could identify a high-risk population before surgery. We aimed to describe postoperative outcomes in a population selected by these two classifications system. METHODS: Data were collected in a Swedish multicentre, time-interrupted prospective, consecutive cohort study. Eligibility criteria were age ≥18 years, ASA ≥3, elective or emergent, major to Xmajor/complex (Specialist Procedure Codes used in United Kingdom), gastrointestinal, urogenital or orthopaedic procedures. Postoperative morbidity was identified by the Postoperative Morbidity Survey on postoperative days 3 ± 1, 7 ± 1, 10 + 5 and graded for severity by the Clavien-Dindo system. Mortality was assessed at 30, 180 and 360 days. RESULTS: Postoperative morbidity was 78/48/47 per cent on postoperative days 3/7/10. Majority of morbidities (67.5 per cent) were graded as >1 by Clavien-Dindo. Any type of postoperative morbidity graded >1 was associated with increased risk for death up to one year. The mortality was 5.7 per cent (61/1063) at 30 days, 13.3 per cent (142/1063) at 6 months and 19.1 per cent (160/1063) at 12 months. CONCLUSION: Severity classification as major to Xmajor/complex and ASA ≥3 could be used to identify a high-risk surgical population concerning postoperative morbidity and mortality before surgery. Combining the two systems future electronic data extraction is possible of a high-risk population in tertiary hospitals.

Peri-operative oxygen consumption revisited: An observational study in elderly patients undergoing major abdominal surgery.

BACKGROUND: Monitoring oxygen consumption (VO2) is neither recommended nor included in peri-operative haemodynamic algorithms aiming at optimising oxygen delivery (DO2) in major abdominal surgery. Estimates of peri-operative VO2 changes are uncertain in earlier publications and have limited generalisability in the current high-risk surgical population. In a prospective non-interventional observational study in elderly patients undergoing major abdominal procedures, we investigated the change of VO2 after induction of anaesthesia and secondarily, the further changes during and after surgery in relation to DO2 and estimated oxygen extraction ratio (O2ER) by routine monitoring. METHODS: VO2 was determined by indirect calorimetry (QuarkRMR) in 20 patients more than 65 years (ASA II to IV), scheduled for elective open upper abdominal surgery with combined epidural and general anaesthesia. Data were collected during 20-minute periods pre-operatively and after anaesthesia induction, with subsequent measurements during surgery and postoperatively. Simultaneously, DO2 was monitored using LiDCOplus. The O2ER was estimated from arterial-central venous oxygen content calculation. Mixed models were used to analyse the peri-operative changes. RESULTS: VO2 decreased after induction of anaesthesia by a mean of 34% (95% CI, 28 to 39). After 2 h of surgery, VO2 was reduced by 24% (95% CI, 20 to 27) compared with the awake baseline measurements. Pre-operative mean DO2 was 440 (95% CI, 396 to 483) ml min m and decreased by a mean of 37% (95% CI, 30 to 43) during anaesthesia. The estimated O2ER did not change intra-operatively 0.24 (95% CI, 0.21 to 0.26) but increased postoperatively to 0.31 (95% CI, 0.27 to 0.36). The changes of VO2 were parallel with changes of DO2 and O2ER in the intra-operative period. CONCLUSION: General anaesthesia reduced VO2 by approximately a third in elderly patients undergoing major abdominal surgery. Parallel changes of intra-operative VO2 and delivery were demonstrated while oxygen extraction was low. The relevance of these changes needs further assessment in relation to outcomes and haemodynamic interventions. TRIAL REGISTRATION: Clinicaltrials.gov NCT03355118.

Congruency Between Planned and Performed Procedures and Adherence to Recommended Perioperative Practices: A Chart Audit of High-Risk Surgical Patients.

Documentation in an electronic health record system helps ensure that perioperative personnel provide appropriate treatment and care to surgical patients. A retrospective chart review performed with an audit instrument sought to describe the extent to which the documented preoperative plan for a surgery corresponded to the procedure performed. The secondary aim was to describe to what extent perioperative nurses' and physicians' documented care was in accordance with national and international guidelines. Extracted data consisted of physicians' and nurses' documentation of 24 high-risk surgical patients who died within 30 days after a procedure at two hospitals within a single health system. Surgeons documented a planned surgical method for 23 of the 24 patients and the surgical team performed 20 surgeries as planned. Perioperative nurses' and anesthesia professionals' documentation showed a lack of adherence to recommended practices: compliance with guidelines concerning antibiotic prophylaxis and preoperative hygiene preparation were low.

Prerequisites for safe intraoperative nursing care and teamwork-Operating theatre nurses' perspectives: A qualitative interview study.

AIM: To describe operating theatre nurses' experience of preconditions for safe intraoperative nursing care and teamwork. BACKGROUND: Surgical interventions are often needed for patients' well-being and survival from health problems. Adequate information to professionals responsible within the surgical organisation is of importance for patient safety in connection to the surgery. The members in the surgical team need correct information about the patients' health and planned care. The information is mainly transferred by computerised systems that do not necessarily provide all information needed. METHOD: A qualitative descriptive design was chosen. Narrative interviews were carried out with 16 experienced operating theatre nurses in four different hospitals in rural and urban areas in Sweden. The data were analysed using qualitative content analysis. The study complied with criteria to Consolidated Criteria for Reporting Qualitative Research (COREQ). RESULT: Operating theatre nurses strived to get adequate information about the patients' care, the surgical intervention and the equipment to be well prepared for intraoperative nursing care. The information from the computerised systems was described as fragmented and obliged the operating theatre nurses to demand a preoperative dialogue between the members of the surgical team. Professional collegial teamwork and committed leadership were considered to enhance patient safety. CONCLUSION: From the operating theatre nurses' perspective, prerequisites for intraoperative safe nursing care and teamwork depend upon a preoperative dialogue between the members in the surgical team for collegial teamwork, obtaining a reliable preoperative overall picture based on adequate information transfer, and the support of a committed first-line manager. RELEVANCE TO CLINICAL PRACTICE: The operating theatre nurses need a reliable preoperative overall picture in advance, to be able to be well prepared for the patients' surgery. The overall picture should be based on adequate data about the patients' health status and needs, details about the surgical intervention and prescriptions.

A 1-year perspective on goal-directed therapy in elderly with hip fracture: Secondary outcomes.

BACKGROUND: We have previously reported inconclusive results from a randomized controlled trial in elderly with hip-fracture comparing intra-operative goal-directed therapy with routine fluid treatment. Now we aimed to describe and compare secondary outcomes at 4 months and 1 year follow-up and to analyze the cost-effectiveness. METHODS: Patients with hip fracture (age ≥70) were randomized for GDT or routine fluid treatment (RFT). The secondary outcomes were long-term survival, complications, number of hospital readmissions, and quality of life (EQ-5D) changes. Additionally, cost effectiveness was analyzed by an analytic tool which combines the clinical effectiveness, quality of life changes and costs. RESULTS: Patient data (GDT n = 74; RFT n = 75) were analyzed on an intention to treat basis. Statistically significant differences (GDT vs RFT) were not found considering survival (RR 0.76, 95%CI 0.45-1.28) and complications (RR 0.68, 95% CI 0.4-1.10) at 12 months. No statistically significant difference was found between hospital readmissions and quality of life changes. CONCLUSION: The statistical uncertainty of risk reduction of negative outcomes and the large variability of the collected data indicate the need of further research in large sample sizes. To enable future health economic evaluation for decision support surrounding implementation of GDT, we suggest adding patient-oriented outcomes in future trials.

The effects of general anaesthesia on oxygen consumption: A meta-analysis guiding future studies on perioperative oxygen transport.

BACKGROUND: Increased oxygen extraction, the ratio of consumption to delivery, has been associated with poor outcome after surgery. Oxygen consumption (VO2) can change in several ways in the perioperative period, but is seldom monitored directly in routine care. This study investigates the effects of general anaesthesia on VO2. METHODS: We searched PubMed, EMBASE, and Cochrane Library 1946-2018 for studies including VO2 measurements before and after anaesthesia induction. Quality was assessed by Cochrane risk of bias tool and NIH Quality Assessment tool for before-and-after studies. Changes in VO2 after anaesthesia induction were pooled in a random effects model meta-analysis with standardized mean differences transformed to absolute changes of VO2. Changes in VO2 after surgical incision and after recovery from anaesthesia were analysed as secondary outcomes in the included studies. RESULTS: Twenty-four studies including 453 patients were analysed for VO2 changes induced by anaesthesia. Studies were published during 1969-2000 and mean age of patients ranged 28-70 years. VO2 decreased after anaesthesia induction by -65 (-75; -55, 95% CI) mL min-1 and indexed VO2 (VO2I) by -33 (-38; -28, 95% CI) mL min-1  m-2 . After surgical incision and in the post-operative period VO2 increased again. Heterogeneity was considerable among the studies and the overall quality of evidence was very low. CONCLUSIONS: General anaesthesia probably reduces oxygen consumption but the effect estimate is uncertain. Given the limited generalizability and low quality of the available evidence, new studies in modern perioperative settings and in today's older high-risk surgical patient populations are needed.

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

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. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 2337-2344, 2018.

Effects of neoadjuvant chemo or chemoradiotherapy for oesophageal cancer on perioperative haemodynamics: A prospective cohort study within a randomised clinical trial.

BACKGROUND: Neoadjuvant chemoradiotherapy might improve oncological outcome compared with chemotherapy after surgery for oesophagus or gastrooesophageal junction cancer. However, radiotherapy may induce cardiovascular side-effects that could increase the risk of perioperative adverse effects and postoperative morbidity. OBJECTIVES: The aim of this study was to compare the perioperative haemodynamics in patients undergoing oesophagectomy following neoadjuvant chemotherapy or chemoradiotherapy for cancer. DESIGN: A prospective single-centre cohort study within a randomised multi-centre trial. SETTING: A Swedish University Hospital from January 2009 to March 2013. PATIENTS: A total of 31 patients (chemotherapy 17, chemoradiotherapy 14) included in a multi-centre trial randomising chemotherapy vs. chemoradiotherapy and operated at Karolinska University Hospital, Huddinge. INTERVENTIONS: Cisplatin and 5-fluorouracil, either with or without concurrent radiotherapy (40 Gy), were given prior to surgery. Cardiac function was assessed with LiDCOplus (LiDCO Ltd, London, United Kingdom), echocardiography, troponin T and N-terminal pro-B-type natriuretic peptide, before, during and after surgery. MAIN OUTCOME MEASURES: The primary outcome was the interaction effect of the neoadjuvant treatment on stroke volume index during the perioperative period. Secondary outcomes were the interaction effects of oxygen delivery index, cardiac index, echocardiography and biochemical markers. RESULTS: The groups were matched regarding comorbidities, but patients in the chemoradiotherapy group were older (66 vs. 60 years P = 0.03). Haemodynamic values changed in a similar way in both groups during the study period. The chemoradiotherapy group had a lower cardiac index before surgery (2.9 vs. 3.4 l min m, P = 0.03). On the third postoperative day, both groups displayed a hyperdynamic state compared with baseline, with no increase in troponin T, and a similar increase in N-terminal pro-B-type natriuretic peptide. CONCLUSION: Neoadjuvant chemoradiotherapy for oesophageal or gastrooesophageal junction cancer seems to induce only a marginal negative effect on cardiac function compared with neoadjuvant chemotherapy. This difference did not remain when patients' haemodynamics were challenged by surgery. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01362127.

Tolerability and performance of BIP endotracheal tubes with noble metal alloy coating--a randomized clinical evaluation study.

BACKGROUND: Hospital acquired infections worsen the outcome of patients treated in intensive care units and are costly. Coatings with silver or metal alloys may reduce or alter the formation of biofilm on invasive medical devices. An endotracheal tube (ETT) is used to connect the patient to a ventilator and coated tubes have been tested in relation to bacterial colonization and respiratory infection. In the present study, we aimed to evaluate and compare a coated and uncoated ETT for patient symptoms and local tracheal tolerability during short term clinical use. Degree of bacterial colonization was also described. METHODS: A silver-palladium-gold alloy coating ('Bactiguard®'Infection Protection, BIP) has been extensively used on urinary tract catheters and lately also on central venous catheters. We performed a randomised, single-blinded, controlled, first in man, post Conformité Européenne (EC) certification and CE marking study, focused on Bactiguard® coated ETTs (BIP ETT). Thirty patients at a tertiary university hospital scheduled for upper abdominal elective surgery with an expected duration of anaesthesia of at least 3 h were randomised; BIP ETT (n = 20) or standard ETT (n = 10). The tolerability was assessed with a modified version of Quality of Life Head and Neck Module, QLQ-H&N35 and by inspection of the tracheal mucosa with a fibre-optic bronchoscope before intubation and at extubation. Adverse Events (AE) and bacterial adherence were also studied. Statistical evaluations were carried out with the Fisher's Exact Test, the Clopper-Pearson method, as well as a Proportional Odds Model. RESULTS: Differences between groups were identified in 2 of 8 patient related symptoms with regard to tolerability by QLQ-H&N35 (cough, p = 0.022 and dry mouth, p = 0.014 in the treatment group.). No mucosal damage was identified with bronchoscopy. A low level of bacterial colonization with normal flora, equal between groups, was seen after short-term of intubation (median 5 h). No serious Adverse Events related to the use of an ETT were observed. The results should be treated with caution due to statistical confounders, a small study size and large inter-individual variability in bacterial adhesion. CONCLUSIONS: The new device BIP ETT is well tolerated and has good clinical performance during short-term intubation. Studies with larger sample sizes and longer intubation periods (>24 h) in the ICU-setting are needed and can now be planned in order to identify possible differences in clinical outcomes. TRIAL REGISTRATION: Registered in ClinicalTrials.gov, REGISTRATION NUMBER: NCT01682486 , Date of Registration: August, 30, 2012.

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 γ-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 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 γ-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 (Emax) model with an EC50 of 15.6 µg/mL and a γ of 1.7 described the relationship between AZD3043 effect-site concentrations and BIS. The between-subject variability in EC50 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.

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.

Effects on heart function of neoadjuvant chemotherapy and chemoradiotherapy in patients with cancer in the esophagus or gastroesophageal junction - a prospective cohort pilot study within a randomized clinical trial.

BACKGROUND: Neoadjuvant therapy for cancer of the esophagus or gastroesophageal (GE)-junction is well established. The pros and cons of chemoradiotherapy and chemotherapy are debated. Chemoradiotherapy might impair cardiac function eliciting postoperative morbidity. The aim of this pilot study was to describe acute changes in left ventricular function following chemoradiotherapy or chemotherapy. METHODS: Patients with esophageal and (GE)-junction cancer enrolled at our center into a multicenter trial comparing neoadjuvant chemoradiotherapy and chemotherapy were eligible. Patients were randomized to receive cisplatin and 5-fluorouracil with or without the addition of 40 Gy radiotherapy prior to surgery. Left ventricular function was evaluated using echocardiography and plasma N-Terminal Pro-B-Type Natriuretic Peptide (NT-proBNP) before and after neoadjuvant treatment. The primary outcome measure was left ventricular global strain (GS). Clinical effects were assessed using repeated exercise tests. Linear mixed models were used to analyze the effects of treatment group, and the interaction between groups. RESULTS: 40 patients participated (chemoradiotherapy, n=17; chemotherapy, n=23). In the chemoradiotherapy group there was no change in left ventricular global strain but mitral annular plane systolic excursion (MAPSE) of the ventricular septum, early diastolic filling velocity (E-velocity), and the ratio of early to late ventricular filling velocities (E/A ratio) decreased significantly (p=0.02, p=0.01, and p=0.03, respectively). No changes were observed in the chemotherapy group. There was a trend towards an interaction effect for MAPSE sept and E (p=0.09 and p=0.09). NT-proBNP increased following chemoradiotherapy (p=0.05) but not after chemotherapy (p>0.99), and there was a trend towards an interaction effect (p=0.07). Working capacity decreased following neoadjuvant treatment (chemoradiotherapy p = 0.001, chemotherapy p=0.03) and was more pronounced after chemoradiotherapy with a trend towards an interaction effect (p=0.10). CONCLUSIONS: Neoadjuvant chemoradiotherapy but not chemotherapy before surgery for cancer of the esophagus or GE-junction seems to induce an acute negative effect on both systolic and diastolic left ventricular function. Future studies on neoadjuvant treatment for esophageal cancer are suggested to add measurements of cardiac function. TRIAL REGISTRATION: Clinical Trials.gov NCT01362127 .

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

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.

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

BACKGROUND: A 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. METHODS: A 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. RESULTS: If 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. CONCLUSIONS: If 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 REGISTRATION: ClinicalTrials.gov NCT01141894.

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 €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.

Effects of midazolam and nitrous oxide on endocrine and metabolic measurements in children.

OBJECTIVE: Pain, stress as well as drugs may affect metabolic and endocrine measurements, especially in stressed children. The aim was to study how release of glucose and stress hormones are affected when procedural sedation with nitrous oxide or midazolam are used for establishing intravenous access in obese and lean children. METHODS: In a prospective, double-blind, randomized study 90 children, 60 obese and 30 growth-retarded (GR), aged 5-18 years, with reported anxiety or difficulties connected with i.v. access, were randomized to 1 of 3 groups: oral midazolam (0.3 mg/kg, max. 15 mg), 50% nitrous oxide (N(2)O), and 10% N(2)O. In addition, all children received anesthesia cream (EMLA®) locally 1 h before i.v. access. Blood samples were drawn at 4 time points during 30 min after establishing venous access and, when feasible, after 24 h. The 24-hour sample was regarded as obtained during unstressed condition. The effect of procedural sedation was analyzed. Children's evaluations of pain (Numeric Rating Scale) and procedure (Likert Scale) were correlated with mean values of cortisol and glucose after i.v. access. For the metabolic and hormone control measurements, 60 children aged 4-18 years (40 obese and 20 GR) served as controls. These children underwent a 24-hour blood sampling and did not receive sedation. The control samples were drawn 10-12 h after i.v. access. RESULTS: After midazolam, significantly lower cortisol levels were found compared to both 50% N(2)O and 10% N(2)O and to unstressed controls. The growth hormone levels decreased with time in the midazolam group compared to 50 and 10% N(2)O, where the effect of time was reversed. Glucose levels among GR children increased from 0 to 30 min, whereas the opposite was found in obese children regardless of treatment. A post hoc analysis demonstrated significant correlations between children's evaluations of the procedure and mean values of cortisol (r = -0.53), growth hormone (r = -0.52), and norepinephrine (r = -0.5) in children treated with a very low dose of N(2)O (10%). CONCLUSIONS: When sedation is insufficient during i.v. access, and blood sampling pain and stress affect hormone values, treatment with N(2)O or midazolam influence the glucose and stress hormone levels differently. These differences need to be accounted for when results are used for diagnosis and clinical decisions.