Glucagon-like peptide-1 receptor agonists: a narrative review of clinical pharmacology and implications for peri-operative practice.

BACKGROUND: Glucagon-like peptide-1 receptor agonists are used increasingly in the management of patients living with type 2 diabetes mellitus and obesity. In patients using glucagon-like peptide-1 receptor agonists, a key concern in the peri-operative period is the increased risk of pulmonary aspiration due to delayed gastric emptying. This review provides an overview of the pharmacodynamic and pharmacokinetic properties of glucagon-like peptide-1 receptor agonists and the risk of delayed gastric emptying and aspiration. METHODS: We conducted searches of MEDLINE and EMBASE databases of articles published before January 2024 using the keywords and medical subject headings: incretins; glucagon-like peptide-1; GLP-1; glucagon-like peptide-1 receptor agonists; GLP-1 RA; peri-operative period; perioperative; peri-operative; stomach emptying; gastric emptying; pulmonary aspiration; aspiration; food regurgitation; and regurgitation. The evidence was analysed, synthesised and reported narratively. RESULTS: A total of 1213 articles were located after duplicates were removed. Two authors screened the titles and abstracts to identify those studies which assessed specifically the risk of delayed gastric emptying and pulmonary aspiration or regurgitation in the peri-operative period. We searched manually the reference lists of relevant studies to identify any additional case reports. Ten studies were identified. Available evidence was limited to case reports, case series and observational work. CONCLUSIONS: There is insufficient evidence to put forward definitive guidance regarding the ideal cessation period for glucagon-like peptide-1 receptor agonists before elective surgery. Precautionary practice is required until more evidence becomes available. We suggest an individualised, evidence-based approach. In patients living with type 2 diabetes mellitus, there is concern that prolonged cessation before surgery will have a detrimental effect on peri-operative glycaemic control and discussion with an endocrinologist is advised. For patients taking glucagon-like peptide-1 receptor agonists for weight management, these drugs should be withheld for at least three half-lives before an elective surgical procedure.

Association between intraoperative oliguria and postoperative acute kidney injury in non-cardiac surgical patients: a systematic review and meta-analysis.

PURPOSE: This systematic review and meta-analysis aimed to evaluate the association between intraoperative oliguria and the risk of postoperative acute kidney injury (AKI) in patients undergoing non-cardiac surgery. METHODS: The MEDLINE and EMBASE databases were searched up to August 2022 for studies in adult patients undergoing non-cardiac surgery, where the association between intraoperative urine output and the risk of postoperative AKI was assessed. Both randomised and non-randomised studies were eligible for inclusion. Study selection and risk of bias assessment were independently performed by two investigators. The risk of bias was evaluated using the Newcastle-Ottawa scale. We performed meta-analysis of the reported multivariate adjusted odds ratios for the association between intraoperative oliguria (defined as urine output < 0.5 mL/kg/hr) and the risk of postoperative AKI using the inverse-variance method with random effects models. We conducted sensitivity analyses using varying definitions of oliguria as well as by pooling unadjusted odds ratios to establish the robustness of the primary meta-analysis. We also conducted subgroup analyses according to surgery type and definition of AKI to explore potential sources of clinical or methodological heterogeneity. RESULTS: Eleven studies (total 49,252 patients from 11 observational studies including a post hoc analysis of a randomised controlled trial) met the selection criteria. Seven of these studies contributed data from a total 17,148 patients to the primary meta-analysis. Intraoperative oliguria was associated with a significantly elevated risk of postoperative AKI (pooled adjusted odds ratio [OR] 1.74; 95% confidence interval [CI] 1.36-2.23, p < 0.0001, 8 studies). Sensitivity analyses supported the robustness of the primary meta-analysis. There was no evidence of any significant subgroup differences according to surgery type or definition of AKI. CONCLUSIONS: This study demonstrated a significant association between intraoperative oliguria and the risk of postoperative AKI, regardless of the definitions of oliguria or AKI used. Further prospective and multi-centre studies using standardised definitions of intraoperative oliguria are required to define the thresholds of oliguria and establish strategies to minimise the risk of AKI.

Treatment of in-transit Merkel cell carcinoma by isolated limb infusion with cytotoxic drugs.

Merkel cell carcinoma of the skin is a rare but aggressive malignancy, which predominantly affects older adults with fair skin. Isolated limb infusion (ILI) using melphalan and actinomycin D was first developed as a minimally invasive treatment option to treat unresectable metastatic melanoma confined to the limb. We report on a 62-year-old male with in-transit metastases (ITMs) treated with ILI to highlight the ongoing role this treatment has when all other therapies have been exhausted. At presentation, the patient had widespread ITMs in the right leg. Positron emission tomography scan demonstrated recurrent disease in the thigh and pelvis, and it was decided to treat the patient with ILI. The patient progressed well in the immediate post-operative period. The patient was able to mobilize from Day 6 post-ILI and was discharged on Day 10. There was an immediate clinical response seen in the lesions, with necrosis developing in the larger lesions.

Burnout in anaesthesiology residents: A systematic review of its prevalence and stressors.

BACKGROUND: Burnout is an occupational hazard precipitated by chronic exposure to excessive work-related stress. It can have negative impacts on the health and safety of patients and clinicians. Anaesthesiologists are at a high risk of burnout; anaesthetic residents especially may experience higher levels of stress as a result of training requirements and postgraduate examinations. However, the scale of burnout among anaesthesiology residents is not well evaluated. OBJECTIVES: To determine the prevalence of burnout and identify risk factors contributing to it among anaesthesiology residents worldwide and evaluate preventive strategies at institutional and departmental levels. DESIGN: A systematic review without meta-analysis. DATA SOURCES: We searched PubMed, Embase, Scopus and PsycInfo for English language articles published up to 24 May 2021. ELIGIBILITY CRITERIA: The inclusion criteria for qualitative analysis were a reported burnout prevalence in anaesthesiology residents and the use of an assessment tool. Exclusion criteria were reviews/meta-analyses/correspondence, non-English articles, articles without anaesthesiology residents and lacking information on burnout prevalence and metrics for assessment. RESULTS: Twelve studies met the inclusion criteria; seven studies utilised the 22-item Maslach Burnout Inventory Human Services Survey (MBI-HSS) and five utilised the abbreviated Maslach Burnout Inventory (aMBI). The reported burnout prevalence among anaesthesiology residents varied between 2.7 and 67.0% (median = 24.7%). Differences in burnout criteria contributed significantly to methodological heterogeneity. Factors predisposing to burnout included long working hours, poor workplace relationships, professional examinations and adverse clinical events. Protected rest time and restricted work hours were identified as effective strategies to prevent burnout. Other preventive strategies include mindfulness and resilience courses, as well as departmental initiatives such as exercise. CONCLUSION: Burnout is common amongst anaesthesiology residents. Standardised tools and diagnostic criteria are needed to distinguish methodological heterogeneity from true heterogeneity in study populations. Interventions have been proposed to improve management strategies to minimise burnout anaesthesiology residents. PROSPERO REFERENCE: CRD42019140472.

The role of prehabilitation in frail surgical patients: A systematic review.

INTRODUCTION: Increasing emphasis is being placed on the detection of frailty in the pre-operative setting given its association with surgical morbidity and mortality. Prehabilitation seeks to increase the physiological reserve of frail patients, attenuating the risk of irreversible functional decline following surgery. AIM/HYPOTHESIS: This systematic review appraises the evidence available for prehabilitation in frail surgical patients. We proposed that exercise prehabilitation would especially benefit frail patients, with improvements in pre-operative functional capacity, and reductions in complications and length of hospital stay. METHODS: A literature search was conducted in MEDLINE, PubMed and CINAHL databases. Studies were included if they consisted of a prehabilitation intervention in frail patients undergoing surgery and specified a frailty model/index. Eight studies were included for analysis, 2 of which are ongoing studies. RESULTS: In 3 studies, prehabilitation consisted of an exercise intervention alone. There was a high feasibility of prehabilitation and a trend to improved pre-operative function, however, no evidence of improved post-operative functional recovery was there. In 2 studies, prehabilitation consisted of both exercise and nutritional interventions. Reductions in mortality and duration of hospital stay were reported, but the quality of evidence was judged to be very low. There was a lack of evidence of improved outcomes following pre-operative inspiratory muscle training in frail patients. DISCUSSION: This systematic review focuses on prehabilitation in frail surgical patients and reports that evidence supporting any outcome is limited, despite high feasibility and acceptability. There is a need for large randomised controlled trials to better establish the effects of prehabilitation in frail patients.

Inferior vena cava and intra-cardiac invasion of hepatocellular carcinoma: a rare but catastrophic complication.

Intra-cardiac extension of hepatocellular carcinoma (HCC) is an uncommon but serious condition related to poor prognosis. We report a 57-year-old male diagnosed with HCC with intra-cardiac extension into the right atrium at presentation. There were no symptoms related to cardiac involvement and intra-cardiac extension was incidentally noted on radiological imaging. He was offered palliative treatment and succumbed to his disease within 50 days of first diagnosis.

Age and sex based reference values for incidental coronary artery and thoracic aorta calcifications on routine clinical chest CT: a powerful tool to appreciate available imaging findings.

OBJECTIVE: To establish age and gender specific reference values for incidental coronary artery and thoracic aorta calcification scores on routine diagnostic CT scans. These reference values can aid in structured reporting and interpretation of readily available imaging data by chest CT readers in routine practice. METHODS: A random sample of 1572 (57% male, median age 61 years) was taken from a study population of 12,063 subjects who underwent diagnostic chest CT for non-cardiovascular indications between January 2002 and December 2005. Coronary artery and thoracic aorta calcifications were graded using a validated ordinal score. The 25th, 50th and 75th percentile cut points were calculated for the coronary artery and thoracic aorta calcification scores within each age/gender stratum. RESULTS: The 75th percentile cut points for coronary artery calcification scores were higher for men than for women across all age groups, with the exception of the lowest age group. The 75th percentile cut points for thoracic aorta calcifications scores were comparable for both genders across all age groups. Based on the obtained age and gender reference values a calculation tool is provided, that allows one to enter an individual's age, gender and calcification scores to obtain the corresponding estimated percentiles. CONCLUSIONS: The calculation tool as provided in this study can be used in daily practice by CT readers to examine whether a subject has high calcifications scores relative to others with the same age and gender.

Incidental imaging findings from routine chest CT used to identify subjects at high risk of future cardiovascular events.

PURPOSE: To investigate the contribution of incidental findings at chest computed tomography (CT) in the detection of subjects at high risk for cardiovascular disease (CVD) by deriving and validating a CT-based prediction rule. MATERIALS AND METHODS: This retrospective study was approved by the ethical review board of the primary participating facility, and informed consent was waived. The derivation cohort comprised 10 410 patients who underwent diagnostic chest CT for noncardiovascular indications. During a mean follow-up of 3.7 years (maximum, 7.0 years), 1148 CVD events (cases) were identified. By using a case-cohort approach, CT scans from the cases and from an approximately 10% random sample of the baseline cohort (n = 1366) were graded visually for several cardiovascular findings. Multivariable Cox proportional hazards analysis with backward elimination technique was used to derive the best-fitting parsimonious prediction model. External validation (discrimination, calibration, and risk stratification) was performed in a separate validation cohort (n = 1653). RESULTS: The final model included patient age and sex, CT indication, left anterior descending coronary artery calcifications, mitral valve calcifications, descending aorta calcifications, and cardiac diameter. The model demonstrated good discriminative value, with a C statistic of 0.71 (95% confidence interval: 0.68, 0.74) and a good overall calibration, as assessed in the validation cohort. This imaging-based model allows accurate stratification of individuals into clinically relevant risk categories. CONCLUSION: Structured reporting of incidental CT findings can mediate accurate stratification of individuals into clinically relevant risk categories and subsequently allow those at higher risk of future CVD events to be distinguished.

Isolated limb infusion with melphalan and actinomycin D for melanoma: a systematic review.

Isolated limb infusion (ILI) was developed as a simplified and minimally invasive alternative to isolated limb perfusion (ILP) to treat unresectable limb melanoma. A number of centers around the world have reported their results using this procedure. In this study a systematic review of reported ILI experiences was undertaken. A literature search was conducted according to the guidelines for systematic reviews in order to select eligible papers reporting limb toxicity and response rates following ILI using melphalan and actinomycin D to treat limb melanoma. A total of 576 patients from seven publications were included. Regional toxicity following ILI was low: no visible effect of the treatment or slight erythema or edema was observed in 79% of the patients, while considerable erythema and/or edema with blistering was experienced by 19%. In 2% there was a threatened or actual compartment syndrome. No procedure-related amputation was reported. Complete response occurred in 33% of the patients and partial response in 40%, an overall response rate of 73%. Stable disease and progressive disease were achieved in 14% and 13% of the patients, respectively. This first systematic review of ILI procedures using melphalan and actinomycin D indicates that regional toxicity was generally low, with satisfactory response rates. When comparing ILI and ILP, it must be borne in mind that ILI is often performed in significantly older patients and in patients with higher stages of disease, which decreases the likelihood of a favorable response.

Isolated limb infusion: technical aspects.

OBJECTIVE: To describe the technique of isolated limb infusion (ILI) for regional high dose chemotherapy in patients with advanced malignancies confined to a limb, as currently practiced at Melanoma Institute Australia (MIA). BACKGROUND: ILI is progressively being used around the world but to date the reported response rates are generally lower than those reported by MIA. DISCUSSION: This description of the ILI protocol at MIA provides details that may allow other surgeons to improve results.

Preoperative cardiac evaluation and management of patients undergoing elective non-cardiac surgery.

Perioperative cardiac complications are a common cause of death and major morbidity in patients undergoing non-cardiac surgery. Preoperative evaluation and medical optimisation can improve outcomes, although the evidence base is limited. Evidence of effectiveness is strongest for prophylactic use of ß-blockers in high-risk patients and aspirin in patients with coronary artery disease. Particular challenges arise among patients with heart failure or valvular heart disease or those receiving antithrombotic therapy for coronary artery stents or atrial fibrillation. Close liaison between general practitioners, surgeons, anaesthetists and cardiologists is needed for optimising preoperative management and subsequent clinical outcomes in high-risk patients.

Is melphalan dose adjustment according to ideal body weight useful in isolated limb infusion for melanoma?

BACKGROUND: Isolated limb infusion (ILI), introduced in 1992, is a technique used to deliver regional chemotherapy to treat advanced melanoma confined to a limb. Adjusting melphalan dose according to ideal body weight (IBW) has been proposed as a method of decreasing limb toxicity without compromising outcome. The current study analyzed this proposed dose adjustment. METHODS: We reviewed 99 consecutive patients with lower extremity melanomas treated by ILI at our institution between May 1998 and February 2009. Toxicity and outcomes were tested for correlation with differences between administered dose and calculated adjusted dose, both in mg and mg/L, and with differences between actual limb volume and calculated adjusted limb volume. RESULTS: The median actual body weight was 71 kg, whereas the calculated median IBW was 57 kg (p < .001). Median administered melphalan dose was 7.7 mg/L. The median calculated adjusted dose was 6.5 mg/L (range 3.2-9.3 mg/L, p < .001). None of the three aforementioned parameters correlated with either Wieberdink toxicity grade or outcome. BMI did not correlate with toxicity either. Interestingly, a higher total melphalan dose did not only correlate with higher toxicity, but also with a lower response rate. CONCLUSIONS: Adjusting the melphalan dose for IBW does not appear to reduce toxicity following ILI for melanoma. The effect on outcome remains uncertain. More research is needed to optimize melphalan concentrations in individual patients during ILI to limit toxicity without compromising the response.

Does increased experience with isolated limb infusion for advanced limb melanoma influence outcome? A comparison of two treatment periods at a single institution.

BACKGROUND: Isolated limb infusion (ILI) with cytotoxic drugs has been used since 1992 to treat advanced melanoma confined to a limb. Over this time the technique has undergone progressive modification. In this study we evaluated our experience with ILI by analyzing outcome and toxicity from an "early" and a "late" treatment period. METHODS: We compared the results from our institution for 94 patients treated by ILI in the early period (1992-1999) with the results for 91 patients treated in the late period (2000-2007). All patients had advanced limb melanoma and received a combination of melphalan and actinomycin D. RESULTS: The patient characteristics of the early and late groups were similar, but there was greater tumor load in the late group, who had a significantly greater number of lesions (median 4 vs. 5; p = 0.02) and deeper tumor infiltration (p = 0.03). Drug circulation times were longer in the late group: 22 vs. 31 min (p < 0.0001). In the late group, higher initial and final limb temperatures were achieved. Overall response rates were 85% in both groups. The late treatment group showed a trend towards less toxicity (p = 0.06). CONCLUSIONS: Response rates and survival following ILI for advanced melanoma in our late treatment period were similar to those of our early treatment period, despite the significantly greater tumor load of the patients treated in the late period. This could be attributed to increased experience and protocol modifications, which allowed longer drug exposure times and higher limb temperatures to be achieved without increased toxicity.

Isolated limb infusion with melphalan and actinomycin D in melanoma patients: factors predictive of acute regional toxicity.

IMPORTANCE OF THE FIELD: Isolated limb infusion (ILI) is a simple, minimally invasive technique of delivering high concentrations of cytotoxic drugs to a diseased limb for achieving disease control in that limb. Recent studies have suggested that mild hyperthermic (38 degrees C) ILI might be the best initial treatment for extensively recurrent limb melanoma given its simplicity, low morbidity and a complete response rate of 30 - 40%. AREAS COVERED IN THIS REVIEW: Since 1994 when ILI was first described by Thompson et al., the procedure has been adopted by several centres around the world; research and improvements in the technique have resulted in reduction in limb toxicity without reducing its clinical efficacy. The pharmacokinetics of melphalan and the clinical efficacy and adverse effects of ILI from various centres are summarised. Minor but possibly important differences in the ILI techniques used in different institutions may be important in improving its efficacy and reducing the toxic effects. WHAT THE READER WILL GAIN: An understanding of the efficacy and toxicity associated with ILI with cytotoxic drugs in melanoma patients and of methods to optimise regional therapy for malignant disease in a limb. TAKE HOME MESSAGE: ILI with mild hyperthermia (38 degrees C) is well tolerated with tumour remission rates in melanoma patients similar to those achieved by isolated limb perfusion. Mild (grade I - II) and moderate/severe (grade > or = III) limb toxicities occur in 58 - 68% and 32 - 41% of patients, respectively, but long-term morbidity is rare. A high peak and high final melphalan concentration in the infusate, the AUC of melphalan concentration in the infusate and an increased postoperative serum creatine phosphokinase concentration are factors predictive of acute regional toxicity. Drug dose adjusted for ideal body weight and gender may reduce acute toxicity following ILI. It has been suggested that the use of papaverine prior to the infusion of melphalan might increase its efficacy, but it may also increase toxicity. Large prospective studies are needed to more accurately define the perioperative factors that influence acute regional toxicity after ILI and to establish strategies to optimise clinical outcome.

Coronary artery calcification scoring in low-dose ungated CT screening for lung cancer: interscan agreement.

OBJECTIVE: In previous studies detection of coronary artery calcification (CAC) with low-dose ungated MDCT performed for lung cancer screening has been compared with detection with cardiac CT. We evaluated the interscan agreement of CAC scores from two consecutive low-dose ungated MDCT examinations. SUBJECTS AND METHODS: The subjects were 584 participants in the screening segment of a lung cancer screening trial who underwent two low-dose ungated MDCT examinations within 4 months (mean, 3.1 +/- 0.6 months) of a baseline CT examination. Agatston score, volume score, and calcium mass score were measured by two observers. Interscan agreement of stratification of participants into four Agatston score risk categories (0, 1-100, 101-400, > 400) was assessed with kappa values. Interscan variability and 95% repeatability limits were calculated for all three calcium measures and compared by repeated measures analysis of variance. RESULTS: An Agatston score > 0 was detected in 443 baseline CT examinations (75.8%). Interscan agreement of the four risk categories was good (kappa = 0.67). The Agatston scores were in the same risk category in both examinations in 440 cases (75.3%); 578 participants (99.0%) had scores differing a maximum of one category. Furthermore, mean interscan variability ranged from 61% for calcium volume score to 71% for Agatston score (p < 0.01). A limitation of this study was that no comparison of CAC scores between low-dose ungated CT and the reference standard ECG-gated CT was performed. CONCLUSION: Cardiovascular disease risk stratification with low-dose ungated MDCT is feasible and has good interscan agreement of stratification of participants into Agatston score risk categories. High mean interscan variability precludes the use of this technique for monitoring CAC scores for individual patients.

Semiquantitative assessment of cardiovascular disease markers in multislice computed tomography of the chest: interobserver and intraobserver agreements.

OBJECTIVE: To investigate the interobserver and intraobserver agreements for the semiquantitative assessment of markers of subclinical cardiovascular disease as identified by routine care, diagnostic computed tomography (CT) of the chest, to improve the quality of reporting of these incidental findings. METHODS: Two observers independently evaluated 109 consecutive chest CT scans in routine care, clinical patients from one tertiary referral center. All nongated, contrast-enhanced scans were acquired on a 16-slice CT scanner. Images were scored for the presence of aortic wall abnormalities and calcifications of the coronary artery, the heart valves, the thoracic aorta, and the proximal supraaortic arteries. Furthermore, the presence of left ventricular scarring and elongation of the aorta were recorded. All markers were scored on a semiquantitative scale. Interobserver and intraobserver agreements are presented as weighted kappa and intraclass correlation coefficients. RESULTS: Interobserver and intraobserver agreements for individual markers were good to excellent, with weighted kappa coefficients of 0.54 to 0.89 for interobserver agreement and 0.55 to 0.96 for intraobserver agreement. CONCLUSIONS: Semiquantitative assessment of subclinical cardiovascular disease markers in routine care, diagnostic chest CT scans is possible with good to excellent interobserver and intraobserver agreements. Use of these definitions in clinical practice will enable a more standardized assessment and reporting of incidental findings in diagnostic chest CT.

Improved enzymatic activity of Thermomyces lanuginosus lipase immobilized in a hydrophobic particulate mesoporous carrier.

Lipase from Thermomyces lanuginosus has been immobilized within particulate mesoporous silica carriers, with either hydrophilic or hydrophobic supporting surfaces, produced by the newly developed emulsion and solvent evaporation (ESE) method. The Michaelis-Menten model was used to calculate the parameters related to the enzymatic activity of lipase i.e. the turnover number, k(cat), and the specific activity. The specific activity was improved by immobilization of lipase onto the hydrophobic support, compared to lipase immobilized onto the hydrophilic support and lipase free in solution. The enhanced enzymatic activity of lipase onto a hydrophobic support was attributed to interfacial activation of the Thermomyces lanuginosus lipase when it is attached to a hydrophobic surface and a reduced denaturation. Confocal scanning laser microscopy (CLSM) studies, of fluorescently tagged lipase, showed that leakage of the lipase from the mesoporous particles was limited to an initial period of only a few hours. Both the rate and the amount of lipase leached were reduced when the lipase was immobilized onto the hydrophobic support.

Safety and efficacy of isolated limb infusion with cytotoxic drugs in elderly patients with advanced locoregional melanoma.

INTRODUCTION: The treatment of elderly patients with advanced metastatic melanoma confined to a limb remains controversial. Isolated limb infusion (ILI) is an effective minimally invasive alternative to isolated limb perfusion (ILP) and is therefore a potentially valuable therapeutic option for this group. METHODS: From our prospective database 185 patients with advanced metastatic melanoma of the limb treated with a single ILI between 1992 and 2007 were identified. In all patients a cytotoxic combination of melphalan and actinomycin-D was used. RESULTS: Eighty-six patients (46%) were >or=75 years of age (range: 75-93). The patient characteristics in both groups were comparable except that the older group comprised more women (71% vs. 54%; P = 0.02) and had a lower body mass index (median: 24.4 vs. 26.4; P = 0.008). Complete response rates were 34% for those >or=75 years and 41% in the younger group (P = 0.28). There was no difference in limb recurrence free interval after a complete response (median: 24 months for both groups; P = 0.51) or in survival (median: 36 months for <75, 39 months for >or=75; P = 0.36) between both groups. Older patients experienced less limb toxicity after the procedure (Wieberdink grade III/IV toxicity in 36%) compared with younger patients (51%; P = 0.009) while systemic toxicity, complications, and long-term morbidity were similar. CONCLUSIONS: Elderly patients with advanced metastatic melanoma of the limb experience the same or lower toxicity after ILI compared with younger patients while response rates, limb recurrence free interval, survival, and morbidity are similar. ILI is an attractive alternative to the more laborious ILP, especially for older patients.