Influence of clinical and genetic factors on propofol dose requirements: A genome-wide association study.

BACKGROUND: Propofol is a widely used intravenous hypnotic. Dosing is mostly based on weight with great interindividual variation in consumption. Suggested factors affecting propofol requirements include age, gender, ethnicity, anxiety, alcohol consumption, smoking, and concomitant valproate use. Genetic factors have not been widely explored. METHODS: We studied 1000 women undergoing breast cancer surgery under propofol and remifentanil anesthesia. Depth of anesthesia was monitored with State Entropy TM. Propofol requirements during surgery were recorded. DNA from blood was genotyped with a genome-wide array. A multivariable linear regression model was used to assess the relevance of clinical variables and select those to be used as covariates in a genome-wide association study (GWAS). Imputed genotype data were used to explore selected loci further. In silico functional annotation was used to explore possible consequences of the discovered genetic variants. Additionally, previously reported genetic associations from candidate gene studies were tested. RESULTS: BMI, smoking status, alcohol use, remifentanil dose (ln(mgkg -1min -1)), and average state entropy during surgery remained statistically significant in the multivariable model. Two loci reached genome-wide significance (P < 5×10 -8). The most significant associations were for SNPs rs997989 (30 kb from ROBO3), likely affecting expression of another nearby gene FEZ1, and rs9518419, close to NALCN (sodium leak channel); rs10512538 near KCNJ2 encoding Kir2.1 potassium channel showed suggestive association (P = 4.7×10 -7). None of these SNPs are coding variants but possibly affect the regulation of nearby genes. None of the SNPs previously reported as affecting propofol pharmacokinetics or pharmacodynamics showed association in our data. CONCLUSION: In this first GWAS exploring propofol requirements, we discovered novel genetic associations suggesting new biologically relevant pathways for propofol and general anesthesia. The roles of the gene products of ROBO3/FEZ1, NALCN and KCNJ2 in propofol anesthesia warrant further studies.

Clinical and genetic factors associated with post-operative nausea and vomiting after propofol anaesthesia.

BACKGROUND: The incidence of post-operative nausea and vomiting (PONV) remains at about 30% despite all therapeutic efforts to reduce it. The clinical risk factors guiding the prophylactic treatment are well established, but genetic factors associated with PONV remain poorly known. The aim of this study was to explore clinical and genetic factors impacting PONV by performing a genome-wide association study (GWAS) together with relevant clinical factors as covariates, and systematically attempt to replicate previously reported PONV associations. Relevant clinical factors are explored with logistic regression model. METHODS: This was an observational case control study in Helsinki University Hospital between 1 August 2006 and 31 December 2010. One thousand consenting women with elevated risk for PONV, undergoing breast cancer surgery with standardised propofol anaesthesia and antiemetics. After exclusions for clinical reasons and failed genotyping, 815 patients were included with 187 PONV cases and 628 controls. Emergence of PONV up to 7th post-operative day was recorded. PONV at 2-24 h after surgery was selected to be the primary outcome. The GWAS explored associations between PONV and 653 034 genetic variants. Replication attempts included 31 variants in 16 genes. RESULTS: The overall incidence of PONV up to 7th post-operative day was 35%, where 3% had PONV at 0-2 h and 23% at 2-24 h after surgery. Age, American Society of Anaesthesiologists status, the amount of oxycodone used in the post-anaesthesia care unit, smoking status, previous PONV, and history of motion sickness were statistically significant predictive factors in the logistic model. The receiver operating characteristic-area under the curve of 0.75 (95% CI 0.71-0.79) was calculated for the model. The GWAS identified six variants with suggestive association to PONV (p < 1 × 10-5 ). Of the previously reported variants, association with the DRD2 variant rs18004972 (TaqIA) was replicated (p = .028). CONCLUSIONS: Our GWAS approach did not identify any high-impact PONV susceptibility variants. The results provide some support for a role of dopamine D2 receptors in PONV.

Expert-Identified Practices for Achieving Measurable Performance Improvements With Lean Implementation.

BACKGROUND AND OBJECTIVES: Despite the rapid spread of Lean management in health care, few organizations have achieved measurable overall performance improvements with Lean. What differentiates these organizations from those that struggle with realizing the potential benefits of Lean management is unclear. In this qualitative study we explore measuring the impact of Lean and the recommended practices for achieving measurable performance improvements with Lean in health care organizations. METHODS: Informed by preliminary quantitative results from analyses of high- and low-performing Lean hospitals, we conducted 17 semi-structured interviews with Lean health care experts on the Lean principles and practices associated with better performance. We conducted qualitative content analyses of the interview transcripts based on grounded theory and linking to core principles and practices of the Lean management system. RESULTS: The qualitative data revealed 3 categories of metrics for measuring the impact of Lean: currently used institutional measures, measures tailored to Lean initiatives, and population-level measures. Leadership engagement/commitment and clear organizational focus/prioritization/alignment had the highest weighted averages of success factors. The lack of these 2 factors had the highest weighted averages of biggest barriers for achieving measurable performance improvements with Lean implementation. CONCLUSIONS: Leadership engagement and organizational focus can facilitate achieving the organization's performance improvement goals, whereas their absence can considerably hinder performance improvement efforts. Many different approaches have been used to quantify the impact of Lean, but currently used institutional performance measures are preferred by the majority of Lean experts.

Validation of the Lean Healthcare Implementation Self-Assessment Instrument (LHISI) in the finnish healthcare context.

BACKGROUND: Lean management is growing in popularity in the healthcare sector worldwide, yet healthcare organizations are struggling with assessing the maturity of their Lean implementation and monitoring its change over time. Most existing methods for such assessments are time consuming, require site visits by external consultants, and lack frontline involvement. The original Lean Healthcare Implementation Self-Assessment Instrument (LHISI) was developed by the Center for Lean Engagement and Research (CLEAR), University of California, Berkeley as a Lean principles-based survey instrument that avoids the above problems. We validated the original LHISI in the context of Finnish healthcare. METHODS: The original HISI survey was sent over a secure organizational email system to the over 26,000 employees of the Hospital District of Helsinki and Uusimaa in March 2020. The data were randomly split with one part used to carry out an exploratory factor analysis (EFA), and the other for testing the resulting model using confirmatory factor analysis (CFA). RESULTS: A total of 6073 employees responded to the LHISI survey, for an overall response rate of 23%. The results indicated that the 43 items used in the original LHISI can be reduced to 25 items, and these items measure a five-dimensional model of the progress of Lean implementation: leadership, commitment, standard work, communication, and daily management system. In comparison with a single-factor model, the fit measures for the 5-factor model were better: smaller X2, larger comparative fit index (CFI), smaller root mean square error of approximation (RMSEA), and smaller standardized root mean square residual (SRMR). CONCLUSIONS: The 25 item LHISI is valid and feasible to use in the context of Finnish healthcare. The LHISI allows the organization to self-monitor the progress of its Lean implementation and provides the leadership with actionable knowledge to guide the path towards Lean maturity across the organization. Our findings encourage further studies on the adoption and validation of the LHISI in healthcare organizations worldwide.

The cross-national applicability of lean implementation measures and hospital performance measures: a case study of Finland and the USA.

BACKGROUND: Health-care organizations around the world are striving to achieve transformational performance improvement, often through adopting process improvement methodologies such as lean management. Indeed, lean management has been implemented in hospitals in many countries. But despite a shared methodology and the potential benefit of benchmarking lean implementation and its effects on hospital performance, cross-national lean benchmarking is rare. Health-care organizations in different countries operate in very different contexts, including different health-care system models, and these differences may be perceived as limiting the ability of improvers to benchmark lean implementation and related organizational performance. However, no empirical research is available on the international relevance and applicability of lean implementation and hospital performance measures. To begin understanding the opportunities and limitations related to cross-national benchmarking of lean in hospitals, we conducted a cross-national case study of the relevance and applicability of measures of lean implementation in hospitals and hospital performance. METHODS: We report an exploratory case study of the relevance of lean implementation measures and the applicability of hospital performance measures using quantitative comparisons of data from Hospital District of Helsinki and Uusimaa (HUS) Helsinki University Hospital in Finland and a sample of 75 large academic hospitals in the USA. RESULTS: The relevance of lean-related measures was high across the two countries: almost 90% of the items developed for a US survey were relevant and available from HUS. A majority of the US-based measures for financial performance (66.7%), service provision/utilization (100.0%) and service provision/care processes (60.0%) were available from HUS. Differences in patient satisfaction measures prevented comparisons between HUS and the USA. Of 18 clinical outcome measures, only four (22%) were not comparable. Clinical outcome measures were less affected by the differences in health-care system models than measures related to service provision and financial performance. CONCLUSIONS: Lean implementation measures are highly relevant in health-care organizations operating in the USA and Finland, as is the applicability of a variety of performance improvement measures. Cross-national benchmarking in lean healthcare is feasible, but a careful assessment of contextual factors, including the health-care system model, and their impact on the applicability and relevance of chosen benchmarking measures is necessary. The differences between the US and Finnish health-care system models is most clearly reflected in financial performance measures and care process measures.

First genome-wide association study on rocuronium dose requirements shows association with SLCO1A2.

BACKGROUND: Rocuronium, a common neuromuscular blocking agent, is mainly excreted unchanged in urine (10-25%) and bile (>70%). Age, sex, liver blood flow, smoking, medical conditions, and ethnic background can affect its pharmacological actions. However, reasons for the wide variation in rocuronium requirements are mostly unknown. We hypothesised that pharmacogenetic factors might explain part of the variation. METHODS: One thousand women undergoing surgery for breast cancer were studied. Anaesthesia was maintained with propofol (50-100 µg kg-1 min-1) and remifentanil (0.05-0.25 µg kg-1 min-1). Neuromuscular block was maintained with rocuronium to keep the train-of-four ratio at 0-10%. DNA was extracted from peripheral blood and genotyped with a next-generation genotyping array. The genome-wide association study (GWAS) was conducted using an additive linear regression model with PLINK software. The FINEMAP tool and data from the Genotype-Tissue Expression project v8 were utilised to study the locus further. RESULTS: The final patient population comprised 918 individuals. Of the clinical variables tested, age, BMI, ASA physical status, and total dose of propofol correlated significantly (all P<0.001) with the rocuronium dose in a linear regression model. The GWAS highlighted one genome-wide significant locus in chromosome 12. The single-nucleotide polymorphisms (SNPs) with the most significant evidence of association were located in or near SLCO1A2. The two top SNPs, rs7967354 (P=5.3e-11) and rs11045995 (P=1.4e-10), and the clinical variables accounted for 41% of the variability in rocuronium dosage. CONCLUSIONS: Genetic variation in the gene SLCO1A2, encoding OATP1A2, an uptake transporter, accounted for 4% of the variability in rocuronium consumption. The underlying mechanism remains unknown.

Benchmarking outcomes on multiple contextual levels in lean healthcare: a systematic review, development of a conceptual framework, and a research agenda.

BACKGROUND: Reliable benchmarking in Lean healthcare requires widely relevant and applicable domains for outcome metrics and careful attention to contextual levels. These levels have been poorly defined and no framework to facilitate performance benchmarking exists. METHODS: We systematically searched the Pubmed, Scopus, and Web of Science databases to identify original articles reporting benchmarking on different contextual levels in Lean healthcare and critically appraised the articles. Scarcity and heterogeneity of articles prevented quantitative meta-analyses. We developed a new, widely applicable conceptual framework for benchmarking drawing on the principles of ten commonly used healthcare quality frameworks and four value statements, and suggest an agenda for future research on benchmarking in Lean healthcare. RESULTS: We identified 22 articles on benchmarking in Lean healthcare on 4 contextual levels: intra-organizational (6 articles), regional (4), national (10), and international (2). We further categorized the articles by the domains in the proposed conceptual framework: patients (6), employed and affiliated staff (2), costs (2), and service provision (16). After critical appraisal, only one fifth of the articles were categorized as high quality. CONCLUSIONS: When making evidence-informed decisions based on current scarce literature on benchmarking in healthcare, leaders and managers should carefully consider the influence of context. The proposed conceptual framework may facilitate performance benchmarking and spreading best practices in Lean healthcare. Future research on benchmarking in Lean healthcare should include international benchmarking, defining essential factors influencing Lean initiatives on different levels of context; patient-centered benchmarking; and system-level benchmarking with a balanced set of outcomes and quality measures.

Transumbilical versus lateral transabdominal removal of benign adnexal masses in laparoscopic surgery-A randomized trial.

OBJECTIVE: In laparoscopic adnexal surgery the conventional method of removing a mass from the abdominal cavity in Finland is through a 10-mm-wide lateral abdominal port. The larger the lateral trocar, the greater the risk of pain, complications and delayed recovery. Here, we assumed that adnexal mass removal through a 10-mm umbilical port together with 5-mm side trocars would decrease the postoperative need of analgesics when compared with removal through a 10-mm lateral abdominal port. STUDY DESIGN: Women scheduled for laparoscopic surgery of a benign adnexal mass were invited to participate. The participants were randomized into two groups: removal via the transumbilical (TU) (n=21) or lateral transabdominal (TA) (n=21) route. General anesthesia and use of local anesthetics were standardized. The amount of postoperative opioid (oxycodone) and visual analog scale (VAS) scores for pain were the primary outcome measures. Secondary outcome measures were nausea/vomiting (VAS evaluation), time to discharge, peri- and postoperative complications, surgeons' opinions of the alternative methods and patients' satisfaction, evaluated via a questionnaire sent six months postoperatively. RESULTS: There were no significant differences in the use of opioids or median pain-VAS scores between the groups during the first 24h postoperatively. However, in the TU group the amount of women with very low pain-VAS scores (0-1) during the whole 12-h follow-up time was significantly greater than in the TA group (4 vs. 0 women p=0.04). The amounts of nausea and vomiting, and median times to discharge were similar in both groups. There were no major complications. CONCLUSIONS: Both transumbilical and transabdominal routes of abdominal mass removal during laparoscopy were feasible and safe. However, the transumbilical route resulted in more women with very low pain-VAS scores.

How much oxycodone is needed for adequate analgesia after breast cancer surgery: effect of the OPRM1 118A>G polymorphism.

UNLABELLED: Most clinically used opioids are mu-opioid receptor agonists. Therefore, genetic variation of the OPRM1 gene that encodes the mu-opioid receptor is of great interest for understanding pain management. A polymorphism 118A>G (rs1799971) within the OPRM1 gene results in a missense mutation and affects the function of the receptor. We studied the association between the 118A>G polymorphism and oxycodone analgesia and pain sensitivity in 1,000 women undergoing breast cancer surgery. Preoperatively, experimental cold and heat pain sensitivities were tested. Postoperative pain was assessed at rest and during motion. Intravenous oxycodone analgesia was titrated first by a research nurse and on the ward using a patient-controlled analgesia device. The primary endpoint was the amount of oxycodone needed for the first state of adequate analgesia. For each patient, the 118A>G polymorphism was genotyped using the Sequenom MassARRAY (Sequenom, San Diego, CA). The association between this variant and the pain phenotypes was tested using linear regression. The 118A>G variant was associated significantly with the amount of oxycodone requested for adequate analgesia (P = .003, ß = .016). Collectively, oxycodone consumption was highest in individuals having the GG genotype (.16 mg/kg), lowest for those with the AA genotype (.12 mg/kg), and moderate for those having the AG genotype (.13 mg/kg). Furthermore, the G allele was associated with higher postoperative baseline pain ratings (P = .001, ß = .44). No evidence of association with other pain phenotypes examined was observed. PERSPECTIVE: This study demonstrates that the OPRM1 118A>G polymorphism was associated with the amount of oxycodone required in the immediate postoperative period. Although a significant factor for determining oxycodone requirement, the 118A>G polymorphism alone explained less than 1% of the variance. No association was found between 118A>G and experimental pain

Pain in 1,000 women treated for breast cancer: a prospective study of pain sensitivity and postoperative pain.

BACKGROUND: This article describes the methods and results of the early part (experimental pain tests and postoperative analgesia) of a study that assesses genetic and other factors related to acute pain and persistent pain after treatment of breast cancer in a prospective cohort of 1,000 women. METHODS: One thousand consenting patients were recruited to the study. Before surgery (breast resection or mastectomy with axillary surgery), the patients filled in questionnaires about health, life style, depression (Beck Depression Inventory), and anxiety (State-Trait Anxiety Inventory). They were also exposed to experimental tests measuring heat (43° and 48°C, 5 s) and cold (2-4°C) pain intensity and tolerance. Anesthesia was standardized with propofol and remifentanil, and postoperative analgesia was optimized with i.v. oxycodone. RESULTS: The patients showed significant interindividual variation in heat and cold pain sensitivity and cold pain tolerance. There was a strong correlation between the experimental pain measures across the tests. Presence of chronic pain, the number of previous operations, and particularly state anxiety were related to increased pain sensitivity. Previous smoking correlated with decreased heat pain sensitivity. These factors explained 4-5% of the total variance in pain sensitivity in these tests. Oxycodone consumption during 20 h was significantly higher in patients who had axillary clearance. Oxycodone consumption had only a weak correlation with the experimental pain measures. CONCLUSIONS: Contact heat and cold pressure tests identify variability in pain sensitivity which is modified by factors such as anxiety, chronic pain, previous surgery, and smoking. High levels of anxiety are connected to increased pain sensitivity in experimental and acute postoperative pain.

The effective analgesic dose of dexamethasone after laparoscopic hysterectomy.

BACKGROUND: Apart from being antiemetic, glucocorticoids have an analgesic property. The optimal dose of dexamethasone in the management of pain after surgery has not been established. In this placebo-controlled, dose-finding study, we evaluated the analgesic effect of three doses of dexamethasone after laparoscopic hysterectomy. METHODS: We randomized 129 women scheduled for laparoscopic hysterectomy to receive placebo, dexamethasone 5 mg (D5), 10 mg (D10), or 15 mg (D15) IV before the induction of anesthesia. The patients were anesthetized with propofol and remifentanil in a standardized manner. Until the first postoperative morning, postoperative pain was managed with IV oxycodone using patient-controlled analgesia. The visual analog scale scores for pain and side effects, and the amounts of the analgesics were recorded for 3 days after surgery. RESULTS: The total dose of oxycodone (0-24 h after surgery) was smaller in the D15 (0.34 mg/kg [0.11-0.87]) group than in the placebo group (0.55 mg/kg [0.19-1.13]) (P = 0.003). The doses of oxycodone during Hours 0-2 after surgery were smaller in the D10 (0.17 mg/kg [0.03-0.36]) and D15 (0.17 mg/kg [0.03-0.35]) groups than in the placebo (0.26 mg/kg [0.10-0.48]) (P = 0.001, D10 versus placebo; P < 0.001, D15 versus placebo) group. During Hours 2-24 after surgery, however, the doses of oxycodone were equal in the placebo, D5, D10, and D15 groups (0.31 mg/kg [0.03-0.78], 0.22 mg/kg [0.03-0.92], 0.24 mg/kg [0.05-0.87], and 0.20 mg/kg [0-0.65], respectively). The visual analog scale scores for pain at rest, in motion, or at cough did not differ in the study groups. The incidence of dizziness was lower in the D15 group than in the placebo group (P = 0.001), the D5 group (P = 0.006), and the D10 group (P = 0.030) during the first 24 h after surgery. During the later course of recovery, the incidence of dizziness did not differ among the four study groups. CONCLUSIONS: IV dexamethasone 15 mg before induction of anesthesia decreases the oxycodone consumption during the first 24 h after laparoscopic hysterectomy. During first 2 h after surgery, dexamethasone 10 mg reduces the oxycodone consumption as effectively as the 15 mg dose.

A randomized controlled trial of perioperative administration of pregabalin for pain after laparoscopic hysterectomy.

Pregabalin has anticonvulsant, antihyperalgesic, and anxiolytic properties. In this study we evaluated the control of pain after perioperative administration of pregabalin 300 or 600 mg, compared with diazepam 10mg. Altogether 91 women scheduled for laparoscopic hysterectomy were randomized to receive diazepam 10mg (D10), pregabalin 150 mg (P300) or 300 mg (P600) for premedication, and the dose was repeated after 12h, except for the D10 group, in which the patients received placebo. Up until the 1st postoperative morning, analgesia was provided by oxycodone using patient controlled analgesia. The visual analogue scale scores for pain and side effects, and the amounts of the analgesics were recorded for three days after surgery. The doses of oxycodone during hours 0-12 after surgery were similar in the three groups, whereas the dose of oxycodone during hours 12-24 after surgery was smaller in the P600 group than in the P300 group (0.09 vs. 0.16 mg kg(-1); P=0.025). The total dose of oxycodone (0-24h after surgery) was smaller in the P600 group than in the D10 group (0.34 vs. 0.45 mg kg(-1); P=0.046). The incidence of dizziness (70% vs. 35%; P=0.012), blurred vision (63% vs. 14%; P=0.002) and headache (31% vs. 7%; P=0.041) were higher in the P600 group than in the D10 group. In conclusion, perioperative administration of pregabalin 600 mg decreases oxycodone consumption compared with diazepam 10mg, but is associated with an increased incidence of adverse effects.

A comparison of selective spinal anesthesia with hyperbaric bupivacaine and general anesthesia with desflurane for outpatient knee arthroscopy.

In this randomized and controlled trial, 64 adult ambulatory knee arthroscopy patients received either selective spinal anesthesia (SSA) with 4 mg of hyperbaric bupivacaine or general anesthesia (GA) with desflurane. We conducted the study to determine whether SSA with small-dose bupivacaine provides equal fast-tracking possibilities, a shorter stay in the postanesthesia care unit, and earlier discharge home compared with GA with desflurane. Patients with a high risk for postoperative nausea and vomiting received prophylaxis in the GA group. No difference was seen in the fast-tracking possibilities or time in the postanesthesia care unit between the groups. Home readiness was achieved after 114 (31-174) and 129 (28-245) min (NS) in the SSA and GA groups, respectively. In the hospital, the pain scores were significantly (P < 0.001) lower in the SSA group compared with the GA group and the need for postoperative opioids was significantly (P = 0.008) larger after GA. The incidence of postoperative nausea and vomiting was 0% versus 19% in the SSA and GA groups (P = 0.024), respectively. We conclude that for outpatients undergoing knee arthroscopy, SSA with hyperbaric bupivacaine provides equal recovery times with less frequent side effects compared with GA with desflurane.

A factorial trial of six interventions for the prevention of postoperative nausea and vomiting.

BACKGROUND: Untreated, one third of patients who undergo surgery will have postoperative nausea and vomiting. Although many trials have been conducted, the relative benefits of prophylactic antiemetic interventions given alone or in combination remain unknown. METHODS: We enrolled 5199 patients at high risk for postoperative nausea and vomiting in a randomized, controlled trial of factorial design that was powered to evaluate interactions among as many as three antiemetic interventions. Of these patients, 4123 were randomly assigned to 1 of 64 possible combinations of six prophylactic interventions: 4 mg of ondansetron or no ondansetron; 4 mg of dexamethasone or no dexamethasone; 1.25 mg of droperidol or no droperidol; propofol or a volatile anesthetic; nitrogen or nitrous oxide; and remifentanil or fentanyl. The remaining patients were randomly assigned with respect to the first four interventions. The primary outcome was nausea and vomiting within 24 hours after surgery, which was evaluated blindly. RESULTS: Ondansetron, dexamethasone, and droperidol each reduced the risk of postoperative nausea and vomiting by about 26 percent. Propofol reduced the risk by 19 percent, and nitrogen by 12 percent; the risk reduction with both of these agents (i.e., total intravenous anesthesia) was thus similar to that observed with each of the antiemetics. All the interventions acted independently of one another and independently of the patients' baseline risk. Consequently, the relative risks associated with the combined interventions could be estimated by multiplying the relative risks associated with each intervention. Absolute risk reduction, though, was a critical function of patients' baseline risk. CONCLUSIONS: Because antiemetic interventions are similarly effective and act independently, the safest or least expensive should be used first. Prophylaxis is rarely warranted in low-risk patients, moderate-risk patients may benefit from a single intervention, and multiple interventions should be reserved for high-risk patients.