Preventing pain on injection of propofol: A comparison between lignocaine pre-treatment and lignocaine added to propofol

Publisher's copy made available with the permission of the publisherA randomized double-blind study compared two methods of preventing the pain from injection of propofol, lignocaine pre-treatment followed by propofol and lignocaine added to propofol. One hundred patients received a 4 ml solution intravenously with a venous tourniquet for 1 minute, followed by propofol mixed with 2 ml of solution. Patients were divided into two treatment groups of 50 patients each: 4 ml 1% lignocaine pre-treatment followed by propofol and 2 ml saline, or 4 ml saline followed by propofol and 2 ml 2% lignocaine. Pain was assessed with a 100 mm visual analogue scale after induction and in recovery. The incidence of injection pain was 8% in the propofol mixed with lignocaine group, and 28% in the lignocaine pre-treatment group. This difference is statistically significant (P=0.017). For those patients who had pain, the mean pain score was 26.5 on induction for the propofol with lignocaine group (n=4), while the mean score was 44.4 for the pre-treatment group (n=13). The difference was not statistically significant (P=0.25). None of the propofol mixed with lignocaine group recalled pain, while 13 of the pre-treatment group did so. Lignocaine pre-treatment does not improve the immediate or the recalled comfort of patients during propofol induction when compared to lignocaine added to propofol. It is recommended that lignocaine should be added to propofol for induction rather than given before induction.P. Lee, W. J. Russellhttp://www.aaic.net.au/Article.asp?D=200339

The Effect of Isovolemic Hemodilution with Oxycyte®, a Perfluorocarbon Emulsion, on Cerebral Blood Flow in Rats

BACKGROUND: Cerebral blood flow (CBF) is auto-regulated to meet the brain's metabolic requirements. Oxycyte is a perfluorocarbon emulsion that acts as a highly effective oxygen carrier compared to blood. The aim of this study is to determine the effects of Oxycyte on regional CBF (rCBF), by evaluating the effects of stepwise isovolemic hemodilution with Oxycyte on CBF. METHODOLOGY: Male rats were intubated and ventilated with 100% O(2) under isoflurane anesthesia. The regional (striatum) CBF (rCBF) was measured with a laser doppler flowmeter (LDF). Stepwise isovolemic hemodilution was performed by withdrawing 4ml of blood and substituting the same volume of 5% albumin or 2 ml Oxycyte plus 2 ml albumin at 20-minute intervals until the hematocrit (Hct) values reached 5%. PRINCIPAL FINDINGS: In the albumin-treated group, rCBF progressively increased to approximately twice its baseline level (208+/-30%) when Hct levels were less than 10%. In the Oxycyte-treated group on the other hand, rCBF increased by significantly smaller increments, and this group's mean rCBF was only slightly higher than baseline (118+/-18%) when Hct levels were less than 10%. Similarly, in the albumin-treated group, rCBF started to increase when hemodilution with albumin caused the CaO(2) to decrease below 17.5 ml/dl. Thereafter, the increase in rCBF was accompanied by a nearly proportional decrease in the CaO(2) level. In the Oxycyte-treated group, the increase in rCBF was significantly smaller than in the albumin-treated group when the CaO(2) level dropped below 10 ml/dl (142+/-20% vs. 186+/-26%), and rCBF returned to almost baseline levels (106+/-15) when the CaO(2) level was below 7 ml/dl. CONCLUSIONS/SIGNIFICANCE: Hemodilution with Oxycyte was accompanied with higher CaO(2) and PO(2) than control group treated with albumin alone. This effect may be partially responsible for maintaining relatively constant CBF and not allowing the elevated blood flow that was observed with albumin

Telehealth delivery of adapted CBT-I for insomnia in chronic pain patients: a single arm feasibility study

Objectives: A large proportion of individuals with chronic pain experience insomnia-related symptoms which can be persistent in nature, and negatively impact one’s quality of life. This single arm trial aimed to investigate the feasibility and preliminary efficacy of CBT-I, adapted for people with chronic musculoskeletal pain, delivered via telehealth. Methods: We conducted a single arm feasibility trial in which 10 adult women (M age = 50.76 years, SD = 8.03 years) with self-reported insomnia and a diagnosed chronic musculoskeletal chronic pain received six CBT-I individual treatment sessions over 6–10 weeks. Treatment was delivered via telehealth. Participants completed weekly sleep diaries, and self-reported measures of insomnia, pain, anxiety and depression pre-treatment, post-treatment, and one-month follow-up. Results: The trial yielded, high levels of compliance with intervention protocols, and affirmative feedback on satisfaction which demonstrated feasibility. The enrolment rate into the study was 37% (27 participants screened, 10 participants enrolled). The intervention was associated with statistically and clinically meaningful improvements in self-reported insomnia severity. There were statistically significant improvements in sleep efficiency, wake after sleep onset, sleep onset latency, anxiety and depression. Conclusion: Adapted CBT-I delivered via telehealth may be a feasible, acceptable, and efficacious therapeutic approach for individuals with co-existent sleep and chronic pain. Future trials should adopt a randomized design against usual care

Bench to Bedside Development of [18F]Fluoromethyl-(1,2-2H4)choline ([18F]D4-FCH)

malignant transformation is characterised by aberrant phospholipid metabolism of cancers, associated with the upregulation of choline kinase alpha (CHK alpha). due to the metabolic instability of choline radiotracers and the increasing use of late-imaging protocols, we developed a more stable choline radiotracer, [F-18]fluoromethyl-[1,2-H-2(4)]choline ([F-18]D4-FCH). [F-18]D4-FCH has improved protection against choline oxidase, the key choline catabolic enzyme, via a H-1/D-2 isotope effect, together with fluorine substitution. Due to the promising mechanistic and safety profiles of [F-18]D4-FCH in vitro and preclinically, the radiotracer has transitioned to clinical development. [F-18]D4-FCH is a safe positron emission tomography (PET) tracer, with a favourable radiation dosimetry profile for clinical imaging. [F-18]D4-FCH PET/CT in lung and prostate cancers has shown highly heterogeneous intratumoral distribution and large lesion variability. treatment with abiraterone or enzalutamide in metastatic castrate-resistant prostate cancer patients elicited mixed responses on PET at 12-16 weeks despite predominantly stable radiological appearances. the sum of the weighted tumour-to-background ratios (TBRs-wsum) was associated with the duration of survival

Bench to Bedside Development of [18F]Fluoromethyl-(1,2-2H4)choline ([18F]D4-FCH)

Malignant transformation is characterised by aberrant phospholipid metabolism of cancers, associated with the upregulation of choline kinase alpha (CHKα). Due to the metabolic instability of choline radiotracers and the increasing use of late-imaging protocols, we developed a more stable choline radiotracer, [18F]fluoromethyl-[1,2-2H4]choline ([18F]D4-FCH). [18F]D4-FCH has improved protection against choline oxidase, the key choline catabolic enzyme, via a 1H/2D isotope effect, together with fluorine substitution. Due to the promising mechanistic and safety profiles of [18F]D4-FCH in vitro and preclinically, the radiotracer has transitioned to clinical development. [18F]D4-FCH is a safe positron emission tomography (PET) tracer, with a favourable radiation dosimetry profile for clinical imaging. [18F]D4-FCH PET/CT in lung and prostate cancers has shown highly heterogeneous intratumoral distribution and large lesion variability. Treatment with abiraterone or enzalutamide in metastatic castrate-resistant prostate cancer patients elicited mixed responses on PET at 12–16 weeks despite predominantly stable radiological appearances. The sum of the weighted tumour-to-background ratios (TBRs-wsum) was associated with the duration of survival

Healthcare systems data in the context of clinical trials - A comparison of cardiovascular data from a clinical trial dataset with routinely collected data

BACKGROUND: Routinely-collected healthcare systems data (HSD) are proposed to improve the efficiency of clinical trials. A comparison was undertaken between cardiovascular (CVS) data from a clinical trial database with two HSD resources. METHODS: Protocol-defined and clinically reviewed CVS events (heart failure (HF), acute coronary syndrome (ACS), thromboembolic stroke, venous and arterial thromboembolism) were identified within the trial data. Data (using pre-specified codes) was obtained from NHS Hospital Episode Statistics (HES) and National Institute for Cardiovascular Outcomes Research (NICOR) HF and myocardial ischaemia audits for trial participants recruited in England between 2010 and 2018 who had provided consent. The primary comparison was trial data versus HES inpatient (APC) main diagnosis (Box-1). Correlations are presented with descriptive statistics and Venn diagrams. Reasons for non-correlation were explored. RESULTS: From 1200 eligible participants, 71 protocol-defined clinically reviewed CVS events were recorded in the trial database. 45 resulted in a hospital admission and therefore could have been recorded by either HES APC/ NICOR. Of these, 27/45 (60%) were recorded by HES inpatient (Box-1) with an additional 30 potential events also identified. HF and ACS were potentially recorded in all 3 datasets; trial data recorded 18, HES APC 29 and NICOR 24 events respectively. 12/18 (67%) of the HF/ACS events in the trial dataset were recorded by NICOR. CONCLUSION: Concordance between datasets was lower than anticipated and the HSD used could not straightforwardly replace current trial practices, nor directly identify protocol-defined CVS events. Further work is required to improve the quality of HSD and consider event definitions when designing clinical trials incorporating HSD

Conventional radical versus focal treatment for localised prostate cancer: a propensity score weighted comparison of 6-year tumour control

Background: For localised prostate cancer, focal therapy offers an organ-sparing alternative to radical treatments (radiotherapy or prostatectomy). Currently, there is no randomised comparative effectiveness data evaluating cancer control of both strategies. Methods: Following the eligibility criteria PSA < 20 ng/mL, Gleason score ≤ 7 and T-stage ≤ T2c, we included 830 radical (440 radiotherapy, 390 prostatectomy) and 530 focal therapy (cryotherapy, high-intensity focused ultrasound or high-dose-rate brachytherapy) patients treated between 2005 and 2018 from multicentre registries in the Netherlands and the UK. A propensity score weighted (PSW) analysis was performed to compare failure-free survival (FFS), with failure defined as salvage treatment, metastatic disease, systemic treatment (androgen deprivation therapy or chemotherapy), or progression to watchful waiting. The secondary outcome was overall survival (OS). Median (IQR) follow-up in each cohort was 55 (28–83) and 62 (42–83) months, respectively. Results: At baseline, radical patients had higher PSA (10.3 versus 7.9) and higher-grade disease (31% ISUP 3 versus 11%) compared to focal patients. After PSW, all covariates were balanced (SMD < 0.1). 6-year weighted FFS was higher after radical therapy (80.3%, 95% CI 73.9–87.3) than after focal therapy (72.8%, 95% CI 66.8–79.8) although not statistically significant (p = 0.1). 6-year weighted OS was significantly lower after radical therapy (93.4%, 95% CI 90.1–95.2 versus 97.5%, 95% CI 94–99.9; p = 0.02). When compared in a three-way analysis, focal and LRP patients had a higher risk of treatment failure than EBRT patients (p < 0.001), but EBRT patients had a higher risk of mortality than focal patients (p = 0.008). Conclusions: Within the limitations of a cohort-based analysis in which residual confounders are likely to exist, we found no clinically relevant difference in cancer control conferred by focal therapy compared to radical therapy at 6 years

Preconditioning with hyperbaric oxygen in pancreaticoduodenectomy: a randomized double-blind pilot study.

In a prospective randomized double-blind study, we evaluated the post-operative biological and clinical effects of a single preoperative hyperbaric-treatment the day before surgery for pancreatic ductal adenocarcinoma. Patients and Methods: Twenty one patients were randomized and divided into two groups: group-A (10 patients, 48%) were exposed to a HyperBaric Oxygen (HBO) session the day before intervention [Pre-Intervention Day (PID)], group-B (11 patients, 52%) breathed air for 40 min in a hyperbaric chamber pressurized to 1.15 ATA (placebo group). For all patients blood samples were obtained before HBO treatment or the placebo procedure (T0); at the end of HBO session or placebo procedure (T1); on the first post-operative day (POD)(T2) and on seventh POD(T3) day, measuring interleukin (IL)-1, IL-6, IL-8, IL-10, IL-12 and TNF-\u3b1, recording postoperative pancreatic fistula (POPF), biliaryfistula, fever, intra-abdominal abscess, bleeding, pulmonary complications, delayed gastric emptying and requirement for post-operative antibiotics. The results of the present pilot study suggest that a single preoperative hyperbaric oxygen treatment on the day before surgery may reduce the complication rate in pancreatic resection

Effect of hyperbaric oxygenation and gemcitabine on apoptosis of pancreatic ductal tumor cells in vitro.

Gemcitabine is first-line therapy for advanced pancreatic ductal adenocarcinoma (PDAC) with a poor survival and response rate. Hyperbaric oxygenation (HBO) enhances delivery of oxygen to hypoxic tumor cells and increases their susceptibility to cytotoxic effects of chemotherapy. We hypothesized that the anticancer activity of gemcitabine (GEM) may be enhanced if tumor cells are placed in an oxygen-rich environment. The present study evaluated the effects of gemcitabine, HBO and their combination on apoptosis of tumor cells. Materials and Methods: PANC-1 and AsPc-1 PDAC tumor cell lines wereused. Cultured tumor cells were treated with GEM at its growth-inhibitory concentration (IC50) and HBO at 2.5 ATA for 90 min or a combination of both (HBO then GEM and GEM then HBO). Twenty-four hours later, apoptotic cells ineach group were analyzed and the apoptotic index (AI) wascalculated. Results: PANC-1 cell line: HBO alone had noeffect on AI: 6.5\ub10.1 vs. 5.9\ub10.1. HBO before and aftergemcitabine did not further increase AI: 8.2\ub10.1 (HBOGEM),8.5\ub10.1 (GEM-HBO) vs. 8.1\ub10.1 (GEM). The combination of HBO and gemcitabine significantly increased AI: 10.7\ub10.02 (p&lt;0.001 vs. all groups). AsPc-1 cell line: HBO-alone had no effect on AI: 5.9\ub10.1 vs. 5.9\ub10.1. HBO before and after gemcitabine did not further increase AI:8.2\ub10.1 (HBO-GEM), 8.4\ub10.1 (GEM-HBO) vs. 8.0\ub10.1 (GEM). The combination of HBO and gemcitabine significantly increased AI: 9.7\ub10.1 (p&lt;0.001 vs. all groups). Conclusion: HBO-alone, whether administered before and after gemcitabine has no effect on apoptosis of PDAC cellsin vitro. HBO significantly enhanced gemcitabine-induced apoptosis when administered during gemcitabine. Our findings suggest that the time window would be critical for using HBO as adjuvant to chemotherapy

Transdermal oestradiol for androgen suppression in prostate cancer: long-term cardiovascular outcomes from the randomised Prostate Adenocarcinoma Transcutaneous Hormone (PATCH) trial programme

Background Androgen suppression is a central component of prostate cancer management but causes substantial long-term toxicity. Transdermal administration of oestradiol (tE2) circumvents first-pass hepatic metabolism and, therefore, should avoid the cardiovascular toxicity seen with oral oestrogen and the oestrogen-depletion effects seen with luteinising hormone releasing hormone agonists (LHRHa). We present long-term cardiovascular follow-up data from the Prostate Adenocarcinoma Transcutaneous Hormone (PATCH) trial programme. Methods PATCH is a seamless phase 2/3, randomised, multicentre trial programme at 52 study sites in the UK. Men with locally advanced or metastatic prostate cancer were randomly allocated (1:2 from August, 2007 then 1:1 from February, 2011) to either LHRHa according to local practice or tE2 patches (four 100 μg patches per 24 h, changed twice weekly, reducing to three patches twice weekly if castrate at 4 weeks [defined as testosterone ≤1·7 nmol/L]). Randomisation was done using a computer-based minimisation algorithm and was stratified by several factors, including disease stage, age, smoking status, and family history of cardiac disease. The primary outcome of this analysis was cardiovascular morbidity and mortality. Cardiovascular events, including heart failure, acute coronary syndrome, thromboembolic stroke, and other thromboembolic events, were confirmed using predefined criteria and source data. Sudden or unexpected deaths were attributed to a cardiovascular category if a confirmatory post-mortem report was available and as other relevant events if no post-mortem report was available. PATCH is registered with the ISRCTN registry, ISRCTN70406718; the study is ongoing and adaptive. Findings Between Aug 14, 2007, and July 30, 2019, 1694 men were randomly allocated either LHRHa (n=790) or tE2 patches (n=904). Overall, median follow-up was 3·9 (IQR 2·4–7·0) years. Respective castration rates at 1 month and 3 months were 65% and 93% among patients assigned LHRHa and 83% and 93% among those allocated tE2. 157 events from 145 men met predefined cardiovascular criteria, with a further ten sudden deaths with no post-mortem report (total 167 events in 153 men). 26 (2%) of 1694 patients had fatal cardiovascular events, 15 (2%) of 790 assigned LHRHa and 11 (1%) of 904 allocated tE2. The time to first cardiovascular event did not differ between treatments (hazard ratio 1·11, 95% CI 0·80–1·53; p=0·54 [including sudden deaths without post-mortem report]; 1·20, 0·86–1·68; p=0·29 [confirmed group only]). 30 (34%) of 89 cardiovascular events in patients assigned tE2 occurred more than 3 months after tE2 was stopped or changed to LHRHa. The most frequent adverse events were gynaecomastia (all grades), with 279 (38%) events in 730 patients who received LHRHa versus 690 (86%) in 807 patients who received tE2 (p<0·0001) and hot flushes (all grades) in 628 (86%) of those who received LHRHa versus 280 (35%) who received tE2 (p<0·0001). Interpretation Long-term data comparing tE2 patches with LHRHa show no evidence of a difference between treatments in cardiovascular mortality or morbidity. Oestrogens administered transdermally should be reconsidered for androgen suppression in the management of prostate cancer. Funding Cancer Research UK, and Medical Research Council Clinical Trials Unit at University College London