Prospective observational cohort study of the association between antiplatelet therapy, bleeding and thrombosis in patients with coronary stents undergoing noncardiac surgery.

BACKGROUND: The perioperative management of antiplatelet therapy in noncardiac surgery patients who have undergone previous percutaneous coronary intervention (PCI) remains a dilemma. Continuing dual antiplatelet therapy (DAPT) may carry a risk of bleeding, while stopping antiplatelet therapy may increase the risk of perioperative major adverse cardiovascular events (MACE). METHODS: Occurrence of Bleeding and Thrombosis during Antiplatelet Therapy In Non-Cardiac Surgery (OBTAIN) was an international prospective multicentre cohort study of perioperative antiplatelet treatment, MACE, and serious bleeding in noncardiac surgery. The incidences of MACE and bleeding were compared in patients receiving DAPT, monotherapy, and no antiplatelet therapy before surgery. Unadjusted risk ratios were calculated taking monotherapy as the baseline. The adjusted risks of bleeding and MACE were compared in patients receiving monotherapy and DAPT using propensity score matching. RESULTS: A total of 917 patients were recruited and 847 were eligible for inclusion. Ninety-six patients received no antiplatelet therapy, 526 received monotherapy with aspirin, and 225 received DAPT. Thirty-two patients suffered MACE and 22 had bleeding. The unadjusted risk ratio for MACE in patients receiving DAPT compared with monotherapy was 1.9 (0.93-3.88), P=0.08. There was no difference in MACE between no antiplatelet treatment and monotherapy 1.03 (0.31-3.46), P=0.96. Bleeding was more frequent with DAPT 6.55 (2.3-17.96) P=0.0002. In a propensity matched analysis of 177 patients who received DAPT and 177 monotherapy patients, the risk ratio for MACE with DAPT was 1.83 (0.69-4.85), P=0.32. The risk of bleeding was significantly greater in the DAPT group 4.00 (1.15-13.93), P=0.031. CONCLUSIONS: OBTAIN showed an increased risk of bleeding with DAPT and found no evidence for protective effects of DAPT from perioperative MACE in patients who have undergone previous PCI.

Abdominal aortic aneurysm repair in the United Kingdom: an exemplar for the role of anaesthetists in perioperative medicine.

The past two decades have seen an increasing recognition that the delivery of safe surgery with low complication rates and good long-term outcomes is a team endeavour embracing the whole patient care pathway. The key role of the anaesthetist in managing the patient through the surgical process is widely understood and has driven the emergence of perioperative medicine. In parallel with these developments there has been a sea change in the organisation of the care of patients presenting for elective abdominal aortic aneurysm (AAA) repair. Data from the 2008 report of the VASCUNET vascular registry suggested that the UK had the highest mortality for elective open AAA repair in Europe (7.9%). In response, a national quality improvement programme (AAAQIP) spanning the disciplines of surgery, anaesthesia, radiology and nursing was put in place. This led to significant changes in all aspects of AAA repair including the role of the anaesthetist. Preoperative assessment by an anaesthetist with a vascular practice was mandated and the role of the anaesthetist in the vascular multidisciplinary team meeting (MDT) established. Anaesthetic data were included in the national data collection system for vascular surgery, the National Vascular Registry. These changes paralleled and in some cases led the wider evolution of the role of the anaesthetist in perioperative medicine. The mortality from infrarenal AAA repair in the UK decreased to 2.4% by 2012. This improvement reflects changes in perioperative care supported and in some cases led by anaesthetists.

Effect of supervised aerobic exercise rehabilitation on physical fitness and quality-of-life in survivors of critical illness: an exploratory minimized controlled trial (PIX study).

BACKGROUND: Evidence is limited for the effectiveness of interventions for survivors of critical illness after hospital discharge. We explored the effect of an 8-week hospital-based exercise-training programme on physical fitness and quality-of-life. METHODS: In a parallel-group minimized controlled trial, patients were recruited before hospital discharge or in the intensive care follow-up clinic and enrolled 8-16 weeks after discharge. Each week, the intervention comprised two sessions of physiotherapist-led cycle ergometer exercise (30 min, moderate intensity) plus one equivalent unsupervised exercise session. The control group received usual care. The primary outcomes were the anaerobic threshold (in ml O2 kg(-1) min(-1)) and physical function and mental health (SF-36 questionnaire v.2), measured at Weeks 9 (primary time point) and 26. Outcome assessors were blinded to group assignment. RESULTS: Thirty patients were allocated to the control and 29 to the intervention. For the anaerobic threshold outcome at Week 9, data were available for 17 control vs 13 intervention participants. There was a small benefit (vs control) for the anaerobic threshold of 1.8 (95% confidence interval, 0.4-3.2) ml O2 kg(-1) min(-1). This advantage was not sustained at Week 26. There was evidence for a possible beneficial effect of the intervention on self-reported physical function at Week 9 (3.4; -1.4 to 8.2 units) and on mental health at Week 26 (4.4; -2.4 to 11.2 units). These potential benefits should be examined robustly in any subsequent definitive trial. CONCLUSIONS: The intervention appeared to accelerate the natural recovery process and seems feasible, but the fitness benefit was only short term. CLINICAL TRIAL REGISTRATION: Current Controlled Trials ISRCTN65176374 (http://www.controlled-trials.com/ISRCTN65176374).

Capivasertib and fulvestrant for patients with hormone receptor-positive advanced breast cancer: characterization, time course, and management of frequent adverse events from the phase III CAPItello-291 study.

BACKGROUND: Capivasertib is a potent, selective pan-AKT inhibitor. In CAPItello-291, the addition of capivasertib to fulvestrant resulted in a statistically significant (P < 0.001) improvement in progression-free survival over fulvestrant monotherapy in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer and disease progression on or after aromatase inhibitor-based therapy. Characterization of the capivasertib-fulvestrant adverse event (AE) profile as managed in CAPItello-291 can inform future management guidance and optimize clinical benefit. PATIENTS AND METHODS: Seven hundred and eight patients were randomized 1 : 1 to capivasertib (400 mg twice daily; 4 days on, 3 days off) or placebo, plus fulvestrant, on a 4-week cycle. Dose reductions/interruptions for capivasertib/placebo were permitted (up to two dose reductions). Safety analyses included exposure, AE, and clinical laboratory data and were conducted in patients who received at least one dose of capivasertib, fulvestrant, or placebo. Frequent AEs associated with phosphoinositide 3-kinase (PI3K)/protein kinase (AKT) pathway inhibition (diarrhea, rash, hyperglycemia) were characterized using group terms. AEs were summarized using descriptive statistics; time-to-event analyses were conducted. RESULTS: Safety analyses included 705 patients: capivasertib-fulvestrant (n = 355) and placebo-fulvestrant (n = 350). Frequent any-grade AEs with capivasertib-fulvestrant were diarrhea (72.4%), rash (38.0%), and nausea (34.6%); frequent grade ≥3 AEs were rash (12.1%), diarrhea (9.3%), and hyperglycemia (2.3%). Diarrhea, rash, and hyperglycemia occurred shortly after starting capivasertib-fulvestrant [median days to onset (interquartile range) of any grade: 8 (2-22), 12 (10-15), and 15 (1-51), respectively], and were managed with supportive medications, dose reductions, interruptions, and/or discontinuation. Discontinuation rates were 2.0%, 4.5%, and 0.3%, respectively. Overall, 13.0% discontinued capivasertib due to AEs. CONCLUSIONS: Frequent AEs associated with PI3K/AKT pathway inhibition occurred early and were manageable. The low rate of treatment discontinuations suggests that, when appropriately managed, these AEs do not pose a challenge to clinical benefit.

Meta-analysis of prospective trials determining the short- and mid-term effect of elective open and endovascular repair of abdominal aortic aneurysms on quality of life.

BACKGROUND: Repair of an abdominal aortic aneurysm (AAA) is undertaken to prevent rupture. Intervention is by either open repair (OR) or a more minimally invasive endovascular repair (EVAR). Quality-of-life (QoL) analysis is an important health outcome and a number of single studies have assessed QoL following OR and EVAR. This was a meta-analysis of published studies to assess the effect of an intervention on QoL in patients with an AAA. METHODS: A systematic literature search was undertaken for studies prospectively reporting QoL analysis in patients with an AAA undergoing elective intervention. A multivariable meta-analysis model was developed in which the outcomes were mean changes in QoL scores over time, both for all AAA repairs (OR and EVAR) and comparing OR with EVAR. RESULTS: Data were collated from 16 studies (14 OR, 12 EVAR). The results suggested that treating an AAA had an effect on patient-reported QoL, evident from the statistically significant changes predominantly in domains assessing physical ability and pain. QoL was affected most within the first 3 months after any form of intervention, and was more pronounced following OR. Furthermore, a deterioration in the Physical Component Summary score following an AAA repair (either OR or EVAR) was evident at 12 months after intervention. CONCLUSION: Treating an AAA deleteriously affects patient-reported QoL over the first year following intervention.

Process, structural, and outcome quality indicators to support perioperative opioid stewardship: a rapid review.

Opioids are effective analgesics but can cause harm. Opioid stewardship is key to ensuring that opioids are used effectively and safely. There is no agreed set of quality indicators relating to the use of opioids perioperatively. This work is part of the Yorkshire Cancer Research Bowel Cancer Quality Improvement programme and aims to develop useful quality indicators for the improvement of care and patient outcomes at all stages of the perioperative journey.A rapid review was performed to identify original research and reviews in which quality indicators for perioperative opioid use are described. A data tool was developed to enable reliable and reproducible extraction of opioid quality indicators.A review of 628 abstracts and 118 full-text publications was undertaken. Opioid quality indicators were identified from 47 full-text publications. In total, 128 structure, process and outcome quality indicators were extracted. Duplicates were merged, with the final extraction of 24 discrete indicators. These indicators are based on five topics: patient education, clinician education, pre-operative optimization, procedure, and patient-specific prescribing and de-prescribing and opioid-related adverse drug events.The quality indicators are presented as a toolkit to contribute to practical opioid stewardship. Process indicators were most commonly identified and contribute most to quality improvement. Fewer quality indicators relating to intraoperative and immediate recovery stages of the patient journey were identified. An expert clinician panel will be convened to agree which of the quality indicators identified will be most valuable in our region for the management of patients undergoing surgery for bowel cancer.

Diagnosing postoperative neuropathic pain: a Delphi survey.

BACKGROUND: Although postoperative pain is traditionally considered to be nociceptive in origin, a proportion of patients experience a significant neuropathic component to their pain experience. Diagnosing neuropathic pain in this setting is challenging, and there are no published guidelines or screening tools designed for use in the immediate postoperative setting. We hypothesized that acute pain specialists were diagnosing a neuropathic component to acute pain, and this study aimed to obtain an expert agreed list of pain characteristics that could be used to aid diagnosis. METHODS: A three-round Internet-based Delphi survey of acute pain specialists was used to generate a list of acute neuropathic pain characteristics, and achieve consensus on the importance of each item. Items were ranked on a 1-10 scale of importance, with a median score of ≥ 7 considered important and an inter-quartile range of ≤ 3 indicative of consensus. Cronbach's α was used to investigate internal consistency. RESULTS: Twenty-four items were generated by round 1 of the Delphi survey. Fourteen panellists participated in round 2, and 10 in round 3. After round 3, consensus of opinion was achieved for 13 items, with nine rated as important in the diagnosis of acute neuropathic pain. CONCLUSIONS: The Delphi survey suggests that neuropathic pain in the immediate postoperative period is diagnosed in a different way to chronic neuropathic pain, with items such as response to medications considered more useful than signs such as those representing autonomic changes.

National Institute of Academic Anaesthesia research priority setting exercise.

BACKGROUND: Formal research priority setting is a recognized way of identifying important clinical research questions and promoting these as topics for commissioned research. This paper describes a research priority setting exercise conducted by the National Institute of Academic Anaesthesia (NIAA). METHODS: Possible research questions were identified from a questionnaire sent to holders of the Final Fellowship in Anaesthesia in Great Britain and Ireland and to lay representatives. The responses to the first questionnaire were collated to produce a list of potential research questions which were then sent to the same constituency for scoring. The results of this scoring process were considered by an expert panel and statements of research need generated for selected questions. The questions from the first round were also reviewed with the help of representatives of NIHR Evaluation, Trials and Studies Coordinating Centre (NETSCC). RESULTS: For the first questionnaire, 308 responses with 447 suggestions for research were received. A total of 15 questions were included in the second questionnaire, for which 2226 responses were received. The expert panel identified five questions for prioritization. A further nine were identified from discussions with representatives of NETSCC. CONCLUSIONS: A total of 14 research priorities were identified by the exercise, two of which have been submitted to the NIHR Health Technology Assessment (HTA) programme as statements of research need. Potential funding streams for the remaining questions are being sought. We discuss some implications of this exercise for research strategy in the speciality.

The UK national breast cancer screening programme for survivors of Hodgkin lymphoma detects breast cancer at an early stage.

BACKGROUND: Supradiaphragmatic radiotherapy (SRT) to treat Hodgkin's lymphoma (HL) at a young age increases the risk of breast cancer (BC). A national notification risk assessment and screening programme (NRASP) for women who were treated with SRT before the age of 36 years was instituted in the United Kingdom in 2003. In this study, we report the implementation and screening results from the largest English Cancer Network. METHODS: A total of 417 eligible women were identified through cancer registry/hospital databases and from follow-up (FU) clinics. Screening results were collated retrospectively, and registry searches were used to capture BC cases. RESULTS: Of the 417 women invited for clinical review, 243 (58%) attended. Of these 417 women, 23 (5.5%) have been diagnosed with BC, a standardised incidence ratio of 2.9 compared with the age-matched general population. Of five invasive BCs diagnosed within the NRASP, none involved axillary lymph nodes compared with 7 of 13 (54%) diagnosed outside the programme (P<0.10). The mean latency for BC cases was 19.5+/-8.35 years and the mean FU duration for those unaffected by BC was 14.6+/-9.11 years (P<0.01), suggesting that those unaffected by BC remain at high risk. Recall and negative biopsy rates were acceptable (10.5 and 0.8%, respectively). CONCLUSIONS: The NRASP appears to detect BC at an early stage with acceptable biopsy rates, although numbers are small. Determination of NRASP results on a national basis is required for the accurate evaluation of screening efficacy in women previously treated with SRT.

The Immediate Management of the Patient with Rupture: Open Versus Endovascular repair (IMPROVE) aneurysm trial--ISRCTN 48334791 IMPROVE trialists.

BACKGROUND: Systematic reviews have suggested a survival advantage for patients with ruptured abdominal aortic aneurysm (AAA), who are managed by endovascular repair. These reviews are based on single centre experiences of selected patients. OBJECTIVE: To determine whether a policy of endovascular repair improves the survival of all patients with ruptured AAA. METHODS: A randomized controlled trial, IMPROVE (ISRCTN 48334791) will randomize patients with a clinical diagnosis of rAAA, made in hospital, either to immediate CT scan and endovascular repair whenever anatomically suitable (endovascular first), or to open repair, with CT scan being optional (normal care), The trial is set on a background of guidelines for emergency care, CT scanning and anaesthesia, which incorporate the protocol of permissive hypotension. Recruitment started in October 2009 and 600 patients are required to show a 14% survival benefit at 30 days (primary outcome) for the endovascular first policy. Recruitment will be from the UK and Europe. Secondary outcomes include 24h, in-hospital and 1 year survival, complications, major morbidities, costs and quality of life. DISCUSSION: This is a "real life" trial that will answer the fundamental relevant clinical dilemma, namely, do patients who present with ruptured AAA derive benefit from treatment in a system, which offers a preferential strategy of endovascular repair? The trial addresses whether the anticipated reduced mortality and morbidity associated with endovascular repair is offset by the relatively greater ease of access and speed to conventional surgery. This issue is pivotal to future patient care and provision of services.

Optimizing gh therapy in adults and children.

Until the advent of modern neuroradiological imaging techniques in 1989, a diagnosis of GH deficiency in adults carried little significance other than as a marker of hypothalamo-pituitary disease. The relatively recent recognition of a characteristic clinical syndrome associated with failure of spontaneous GH secretion and the potential reversal of many of its features with recombinant human GH has prompted a closer examination of the physiological role of GH after linear growth is complete. The safe clinical practice of GH replacement demands a method of judging overall GH status, but there is no biological marker in adults that is the equivalent of linear growth in a child by which to judge the efficacy of GH replacement. Assessment of optimal GH replacement is made difficult by the apparent diverse actions of GH in health, concern about the avoidance of iatrogenic acromegaly, and the growing realization that an individual's risk of developing certain cancers may, at least in part, be influenced by cumulative exposure to the chief mediator of GH action, IGF-I. As in all areas of clinical practice, strategies and protocols vary between centers, but most physicians experienced in the management of pituitary disease agree that GH is most appropriately begun at low doses, building up slowly to the final maintenance dose. This, in turn, is best determined by a combination of clinical response and measurement of serum IGF-I, avoiding supraphysiological levels of this GH-dependent peptide. Numerous studies have helped define the optimum management of GH replacement during childhood. The recent requirement to measure and monitor GH status in adult life has called into question the appropriateness of simplistic weight- and surface area-based dosing regimens for the management of GH deficiency in childhood, with reliance on linear growth as the sole marker of GH action. It is clear that the monitoring of parameters other than linear growth to help refine GH therapy should now be incorporated into childhood GH treatment protocols. Further research will be required to define the optimal management of the transition from pediatric to adult GH replacement; this transition will only be possible once the benefits of GH in mature adults are defined and accepted by pediatric and adult endocrinologists alike.

Randomized clinical trial of the effects of methylprednisolone on renal function after major vascular surgery.

BACKGROUND: Perioperative renal dysfunction following abdominal aortic aneurysm (AAA) repair is multifactorial and may involve hypotension, hypoxia and ischaemia-reperfusion injury. Studies of cardiac and hepatic transplant surgery have demonstrated beneficial effects on renal function of high-dose methylprednisolone administered before surgery. METHODS: Twenty patients undergoing elective open AAA repair were randomized to receive either methylprednisolone 10 mg/kg or dextrose (control) before induction of anaesthesia. Blood was analysed for a panel of cytokines representative of T helper cell type 1 and 2 subsets. Urine was analysed for subclinical markers of renal dysfunction (albumin, alpha(1)-microglobulin and N-acetyl-beta-D-glucosaminidase). RESULTS: Data from 18 patients were analysed. Both groups demonstrated glomerular and proximal convoluted tubular dysfunction that was unaffected by steroid treatment. Steroid administration increased serum levels of urea and creatinine (both P < 0.001). The steroid group had increased interleukin 10 levels (P = 0.005 compared to controls). There were no differences between groups in overall surgical complications, length of intensive care unit (P = 0.821) and hospital (P = 0.719) stay, or 30-day mortality. CONCLUSION: Methylprednisolone administration altered the cytokine profile favourably but adversely affected postoperative renal function.

Perioperative management of patients undergoing non-cardiac vascular surgery.

Patients undergoing non-cardiac vascular surgery have arterial disease affecting more than one vascular bed and commonly have multiple significant co-morbidities. The surgical and anaesthetic teams are asked to address pre-, peri- and postoperative management issues relating not only to the surgery but arising from these co-morbidities. Here we review the strategies and rationale for the optimisation of these high risk patients.