Volatile vs Total intravenous Anaesthesia for major non-cardiac surgery: a pragmatic randomised triaL (VITAL).

BACKGROUND: Improving outcomes after surgery is a major public health research priority for patients, clinicians and the NHS. The greatest burden of perioperative complications, mortality and healthcare costs lies amongst the population of patients aged over 50 years who undergo major non-cardiac surgery. The Volatile vs Total Intravenous Anaesthesia for major non-cardiac surgery (VITAL) trial specifically examines the effect of anaesthetic technique on key patient outcomes: quality of recovery after surgery (quality of recovery after anaesthesia, patient satisfaction and major post-operative complications), survival and patient safety. METHODS: A multi-centre pragmatic efficient randomised trial with health economic evaluation comparing total intravenous anaesthesia with volatile-based anaesthesia in adults (aged 50 and over) undergoing elective major non-cardiac surgery under general anaesthesia. DISCUSSION: Given the very large number of patients exposed to general anaesthesia every year, even small differences in outcome between the two techniques could result in substantial excess harm. Results from the VITAL trial will ensure patients can benefit from the very safest anaesthesia care, promoting an early return home, reducing healthcare costs and maximising the health benefits of surgical treatments. TRIAL REGISTRATION: ISRCTN62903453. September 09, 2021.

Ward monitoring 4.0: real-time metabolic insights from continuous glucose monitoring into perioperative organ dysfunction.

The now-routine clinical deployment of continuous glucose monitoring has demonstrated benefit in real-world settings. We make the case that continuous glucose monitoring can help re-examine, at scale, the role that (stress) hyperglycaemia plays in fuelling organ dysfunction after tissue trauma. Provided robust perioperative data do emerge, well-established continuous glucose monitoring technology could soon help transform the perioperative landscape.

Body Mindsets are Associated With Pain and Threat-Related Risk Factors for Pain in Survivors of Childhood Cancer.

Pain is a common consequence of childhood cancer. While most research has examined biomedical predictors of post-cancer pain, biopsychosocial conceptualisations such as the cancer threat interpretation (CTI) model hold promise for guiding comprehensive pain management strategies. Guided by the CTI model, this cross-sectional study evaluated correlates of post-cancer pain in childhood cancer survivors including threat-related risk factors (bodily threat monitoring, fear of cancer recurrence, help-seeking) and mindsets about the body. In the preceding three months, 21.8% of the survivors reported chronic pain (>3 months), and 14.3% experienced pain most days. Greater bodily threat monitoring, more fear of cancer recurrence, and more help-seeking were associated with more pain. There was heterogeneity in the mindsets that survivors of childhood cancer hold about their bodies. Holding the mindset that the 'body is an adversary' was associated with more pain, greater bodily threat monitoring, and more fear of cancer recurrence. Holding the mindset that the 'body is responsive' was associated with less bodily threat monitoring, while the mindset that the 'body is capable' was associated with greater help-seeking. A path model demonstrated a significant combined indirect effect of the 'body is an adversary' mindset on pain through bodily threat monitoring and fear of cancer recurrence. Overall, this study supported that a sub-group of childhood cancer survivors experience persistent and interfering pain and provided cross-sectional support for threat-related correlates for pain aligning with the CTI model. Body mindsets were associated with pain and threat-related correlates and may represent a novel target to support survivors with pain. PERSPECTIVE: This article presents associations of body mindsets, threat-related risk factors, and pain in survivors of childhood cancer (aged 11-25), guided by the Cancer Threat Interpretation model. The study indicates that body mindsets may be novel targets to embed in comprehensive post-cancer pain management approaches to support young survivors with pain.

Patients with cancer and sepsis trials: an unfair representation?

Approximately 20% of sepsis cases are thought to occur in patients with cancer. Thus, such patients are an important cohort to be represented and characterised among sepsis trials. However, patients with cancer are commonly excluded from sepsis trials, although the extent to which is unknown. In this opinion article, we discuss our findings that suggest that patients with cancer are being under-represented in sepsis trials, often with an unclear rationale. We question the validity of generalising results from sepsis trials to heterogenous cancer populations and call for wider inclusion of patients with cancer to bridge this knowledge gap in sepsis management.

Heart rate recovery after orthostatic challenge and cardiopulmonary exercise testing in older individuals: prospective multicentre observational cohort study.

Background: Impaired vagal function in older individuals, quantified by the 'gold standard' delayed heart rate recovery after maximal exercise (HRRexercise), is an independent predictor of cardiorespiratory capacity and mortality (particularly when HRR ≤12 beats min-1). Heart rate also often declines after orthostatic challenge (HRRorthostatic), but the mechanism remains unclear. We tested whether HRRorthostatic reflects similar vagal autonomic characteristics as HRRexercise. Methods: Prospective multicentre cohort study of subjects scheduled for cardiopulmonary exercise testing (CPET) as part of routine care. Before undergoing CPET, heart rate was measured with participants seated for 3 min, before standing for 3 min (HRRorthostatic). HRRexercise 1 min after the end of CPET was recorded. The primary outcome was the correlation between mean heart rate change every 10 s for 1 min after peak heart rate was attained on standing and after exercise for each participant. Secondary outcomes were HRRorthostatic and peak VO2 compared between individuals with HRRexercise <12 beats min-1. Results: A total of 87 participants (mean age: 64 yr [95%CI: 61-66]; 48 (55%) females) completed both tests. Mean heart rate change every 10 s for 1 min after peak heart rate after standing and exercise was significantly correlated (R2=0.81; P<0.0001). HRRorthostatic was unchanged in individuals with HRRexercise ≤12 beats min-1 (n=27), but was lower when HRRexercise >12 beats min-1 (n=60; mean difference: 3 beats min-1 [95% confidence interval 1-5 beats min-1]; P<0.0001). Slower HRRorthostatic was associated with lower peak VO2 (mean difference: 3.7 ml kg-1 min-1 [95% confidence interval 0.7-6.8 ml kg-1 min-1]; P=0.039). Conclusion: Prognostically significant heart rate recovery after exhaustive exercise is characterised by quantitative differences in heart rate recovery after orthostatic challenge. These data suggest that orthostatic challenge is a valid, simple test indicating vagal impairment. Clinical trial registration: researchregistry6550.

Sotrovimab restores neutralization against current Omicron subvariants in patients with blood cancer.

Wu et al. report that patients with hematologic malignancies have reduced immunity against SARS-CoV-2 Omicron subvariants and Sotrovimab retains neutralizing capacity against all tested Omicron subvariants.

Functional immune responses against SARS-CoV-2 variants of concern after fourth COVID-19 vaccine dose or infection in patients with blood cancer.

Patients with blood cancer continue to have a greater risk of inadequate immune responses following three COVID-19 vaccine doses and risk of severe COVID-19 disease. In the context of the CAPTURE study (NCT03226886), we report immune responses in 80 patients with blood cancer who received a fourth dose of BNT162b2. We measured neutralizing antibody titers (NAbTs) using a live virus microneutralization assay against wild-type (WT), Delta, and Omicron BA.1 and BA.2 and T cell responses against WT and Omicron BA.1 using an activation-induced marker (AIM) assay. The proportion of patients with detectable NAb titers and T cell responses after the fourth vaccine dose increased compared with that after the third vaccine dose. Patients who received B cell-depleting therapies within the 12 months before vaccination have the greatest risk of not having detectable NAbT. In addition, we report immune responses in 57 patients with breakthrough infections after vaccination.

On the horns of a dilemma: choosing total intravenous anaesthesia or volatile anaesthesia.

There are two established techniques of delivering general anaesthesia: propofol-based total intravenous anaesthesia (TIVA) and volatile agent-based inhaled anaesthesia. Both techniques are offered as standard of care and have an established safety track record lasting more than 30 years. However, it is not currently known whether the choice of anaesthetic technique results in a fundamentally different patient experience or affects early, intermediate-term, and longer-term postoperative outcomes. This editorial comments on a recently published study that suggests that inhaled volatile anaesthesia might be associated with fewer postoperative surgical complications than propofol-based TIVA for patients undergoing colorectal cancer surgery. We consider the strengths and limitations of the study, place these findings in the context of the broader evidence, and discuss how the current controversies regarding anaesthetic technique can be resolved, thereby helping to bring precision medicine into the modern practice of perioperative care.

Peak power output testing: novel method for preoperative assessment of exercise capacity.

BACKGROUND: Assessment of exercise capacity is an important component of risk assessment before major surgery. Cardiopulmonary exercise testing (CPET) provides comprehensive assessment but is resource-intensive, limiting widespread adoption. Measurement of a patient's peak power output (PPO) using a simplified test on a cycle ergometer has the potential to identify patients likely to have abnormal CPET findings and to be at increased perioperative risk. The aim of this study was to investigate the potential for PPO to identify those with abnormal CPET and to determine whether PPO predicted the risk of adverse postoperative outcomes. METHODS: In a retrospective analysis of a single-centre cohort, the ability of PPO to predict a high-risk CPET result in patients undergoing major cancer surgery was analysed. The assessment was validated in patients undergoing major abdominal surgery from a UK national multicentre cohort. The association between PPO and adverse postoperative outcomes to traditional CPET-derived variables were compared. RESULTS: In 2262 patients from a single centre, PPO was an excellent discriminator of high-risk CPET, with an area under the receiver operating characteristic curve (AUROC) of 0.901 (95 per cent c.i. 0.888 to 0.913). In the national cohort of 2742 patients, there was excellent discrimination, with an AUROC of 0.856 (0.842 to 0.871). A PPO cut-off of 1.5 W/kg may be appropriate for use in screening, with a sensitivity of 90 per cent in both cohorts. PPO and traditional CPET-derived predictors demonstrated similar discrimination of major postoperative complications and death. The association between PPO and major postoperative complications persisted on multivariable analysis. CONCLUSION: These results suggest a role for the PPO test in preoperative screening and risk stratification for major surgery. Prospective evaluation is recommended.

Integrated palliative care: triggers for referral to palliative care in ICU patients.

INTRODUCTION: Palliative care within intensive care units (ICU) benefits decision-making, symptom control, and end-of-life care. It has been shown to reduce the length of ICU stay and the use of non-beneficial and unwanted life-sustaining therapies. However, it is often initiated late or not at all. There is increasing evidence to support screening ICU patients using palliative care referral criteria or "triggers". The aim of the project was to assess the need for palliative care referral during ICU admission using "trigger" tools. METHODS: Electronic record review of cancer patients who died in or within 30 days of discharge from oncology ICU, between 2016 and 2018. Patients referred to palliative care before or during ICU admission were identified. Three sets of palliative care referral "triggers" were applied: one that is being tested locally and two internationally derived tools. The proportion of patients who met any of these triggers during their final ICU admission was calculated. RESULTS: Records of 149 patients were reviewed: median age 65 (range 20-83). Most admissions (89%) were unplanned, with the most common diagnoses being haemato-oncology (31%) and gastrointestinal (16%) cancers. Most (73%) were unknown to palliative care pre-ICU admission; 44% were referred between admission and death. The median time from referral to death was 0 day (range 0-19). On ICU admission, 97-99% warranted referral to palliative care using locally and internationally derived triggers. CONCLUSION: All "trigger" tools identified a high proportion of patients who may have warranted a palliative care referral either before or during admission to ICU. The routine use of trigger tools could help streamline referral pathways and underpin the development of an effective consultative model of palliative care within the ICU setting to enhance decision-making about appropriate treatment and patient-centred care.

The 'hub and spoke model' for the management of surgical patients during the COVID-19 pandemic.

During the on-going COVID-19 pandemic a number of key public health services have been severely impacted. These include elective surgical services due to the synergetic resources required to provide both perioperative surgical care whilst also treating acute COVID-19 patients and also the poor outcomes associated with surgical patients who develop COVID-19 in the perioperative period. This article discusses the important principles and concepts for providing important surgical services during the COVID-19 pandemic based on the model of the RMCancerSurgHub which is providing surgical cancer services for a population of approximately 2 million people across London during the pandemic. The model focusses on creating local and regional hub centres which provide urgent treatment for surgical patients in an environment that is relatively protected from the burden of COVID-19 illness. The model extensively utilises the extended multidisciplinary team to allow for a flexible approach with core services delivered in 'clean' sites which can adapt to viral surges. A key requirement is that of a clinical prioritisation process which allows for equity in access within and between specialties ensuring that patients are treated on the basis of greatest need, while at the same time protecting those whose conditions can safely wait from exposure to the virus. Importantly, this model has the ability to scale-up activity and lead units and networks into the recovery phase. The model discussed is also broadly applicable to providing surgical services during any viral pandemic.

A Wolf in Sheep's Clothing: Systemic Immune Activation Post Immunotherapy.

Introduction: Immune checkpoint inhibitors (ICIs) are increasingly a standard of care for many cancers; these agents can result in immune-related adverse events (irAEs) including fever, which is common but can rarely be associated with systemic immune activation (SIA or acquired HLH). Methods: All consecutive patients receiving ICIs in the Drug Development Unit of the Royal Marsden Hospital between May 2014 and November 2019 were retrospectively reviewed. Patients with fever ≥ 38°C or chills/rigors (without fever) ≤ 6 weeks of commencing ICIs were identified for clinical data collection. Results: Three patients met diagnostic criteria for SIA/HLH with median time to onset of symptoms of 10 days. We describe the clinical evolution, treatment used, and outcomes for these patients. High-dose steroids are used first-line with other treatments, such as tocilizumab, immunoglobulin and therapeutic plasmapheresis can be considered for steroid-refractory SIA/HLH. Conclusion: SIA/HLH post ICI is a rare but a potentially fatal irAE that presents with fever and a constellation of nonspecific symptoms. Early recognition and timely treatment are key to improving outcomes.

Prioritisation by FIT to mitigate the impact of delays in the 2-week wait colorectal cancer referral pathway during the COVID-19 pandemic: a UK modelling study.

OBJECTIVE: To evaluate the impact of faecal immunochemical testing (FIT) prioritisation to mitigate the impact of delays in the colorectal cancer (CRC) urgent diagnostic (2-week-wait (2WW)) pathway consequent from the COVID-19 pandemic. DESIGN: We modelled the reduction in CRC survival and life years lost resultant from per-patient delays of 2-6 months in the 2WW pathway. We stratified by age group, individual-level benefit in CRC survival versus age-specific nosocomial COVID-19-related fatality per referred patient undergoing colonoscopy. We modelled mitigation strategies using thresholds of FIT triage of 2, 10 and 150 µg Hb/g to prioritise 2WW referrals for colonoscopy. To construct the underlying models, we employed 10-year net CRC survival for England 2008-2017, 2WW pathway CRC case and referral volumes and per-day-delay HRs generated from observational studies of diagnosis-to-treatment interval. RESULTS: Delay of 2/4/6 months across all 11 266 patients with CRC diagnosed per typical year via the 2WW pathway were estimated to result in 653/1419/2250 attributable deaths and loss of 9214/20 315/32 799 life years. Risk-benefit from urgent investigatory referral is particularly sensitive to nosocomial COVID-19 rates for patients aged >60. Prioritisation out of delay for the 18% of symptomatic referrals with FIT >10 µg Hb/g would avoid 89% of these deaths attributable to presentational/diagnostic delay while reducing immediate requirement for colonoscopy by >80%. CONCLUSIONS: Delays in the pathway to CRC diagnosis and treatment have potential to cause significant mortality and loss of life years. FIT triage of symptomatic patients in primary care could streamline access to colonoscopy, reduce delays for true-positive CRC cases and reduce nosocomial COVID-19 mortality in older true-negative 2WW referrals. However, this strategy offers benefit only in short-term rationalisation of limited endoscopy services: the appreciable false-negative rate of FIT in symptomatic patients means most colonoscopies will still be required.

The role of CT chest in screening for asymptomatic COVID-19 infection in self-isolating patients prior to elective oncological surgery: findings from a UK Cancer Hub.

OBJECTIVES: In accordance with initial guidance from the Royal College of Surgeons and Royal College of Radiologists, we evaluated the utility of CT of the chest in the exclusion of asymptomatic COVID-19 infection prior to elective cancer surgery on self-isolating patients during the pandemic. METHODS: All surgical referrals without symptoms of COVID-19 infection in April and May 2020 were included. Patient records were retrospectively reviewed. Screening included CT chest for major thoracic and abdominal surgery. CTs were reported according to British Society of Thoracic Imaging guidelines and correlated with reverse transcriptase polymerase chain reaction (RT-PCR) and surgical outcomes. RESULTS: The prevalence of RT-PCR confirmed COVID-19 infection in our screened population was 0.7% (5/681). 240 pre-operative CTs were performed. 3.8% (9/240) of CTs were reported as abnormal, only one of which was RT-PCR positive. 2% (5/240) of cases had surgery postponed based on CT results. All nine patients with CTs reported as abnormal have had surgery, all without complication. CONCLUSION: The prevalence of asymptomatic COVID-19 infection in our screened population was low. The pre-test probability of CT chest in asymptomatic, self-isolating patients is consequently low. CT can produce false positives in this setting, introducing unnecessary delay in surgery for a small proportion of cases. ADVANCES IN KNOWLEDGE: Self-isolation, clinical assessment and RT-PCR are effective at minimising COVID-19 related surgical risk. The addition of CT chest is unhelpful. Our data have particular relevance during the second wave of infection and in the recovery phase.

Effect of delays in the 2-week-wait cancer referral pathway during the COVID-19 pandemic on cancer survival in the UK: a modelling study.

BACKGROUND: During the COVID-19 lockdown, referrals via the 2-week-wait urgent pathway for suspected cancer in England, UK, are reported to have decreased by up to 84%. We aimed to examine the impact of different scenarios of lockdown-accumulated backlog in cancer referrals on cancer survival, and the impact on survival per referred patient due to delayed referral versus risk of death from nosocomial infection with severe acute respiratory syndrome coronavirus 2. METHODS: In this modelling study, we used age-stratified and stage-stratified 10-year cancer survival estimates for patients in England, UK, for 20 common tumour types diagnosed in 2008-17 at age 30 years and older from Public Health England. We also used data for cancer diagnoses made via the 2-week-wait referral pathway in 2013-16 from the Cancer Waiting Times system from NHS Digital. We applied per-day hazard ratios (HRs) for cancer progression that we generated from observational studies of delay to treatment. We quantified the annual numbers of cancers at stage I-III diagnosed via the 2-week-wait pathway using 2-week-wait age-specific and stage-specific breakdowns. From these numbers, we estimated the aggregate number of lives and life-years lost in England for per-patient delays of 1-6 months in presentation, diagnosis, or cancer treatment, or a combination of these. We assessed three scenarios of a 3-month period of lockdown during which 25%, 50%, and 75% of the normal monthly volumes of symptomatic patients delayed their presentation until after lockdown. Using referral-to-diagnosis conversion rates and COVID-19 case-fatality rates, we also estimated the survival increment per patient referred. FINDINGS: Across England in 2013-16, an average of 6281 patients with stage I-III cancer were diagnosed via the 2-week-wait pathway per month, of whom 1691 (27%) would be predicted to die within 10 years from their disease. Delays in presentation via the 2-week-wait pathway over a 3-month lockdown period (with an average presentational delay of 2 months per patient) would result in 181 additional lives and 3316 life-years lost as a result of a backlog of referrals of 25%, 361 additional lives and 6632 life-years lost for a 50% backlog of referrals, and 542 additional lives and 9948 life-years lost for a 75% backlog in referrals. Compared with all diagnostics for the backlog being done in month 1 after lockdown, additional capacity across months 1-3 would result in 90 additional lives and 1662 live-years lost due to diagnostic delays for the 25% backlog scenario, 183 additional lives and 3362 life-years lost under the 50% backlog scenario, and 276 additional lives and 5075 life-years lost under the 75% backlog scenario. However, a delay in additional diagnostic capacity with provision spread across months 3-8 after lockdown would result in 401 additional lives and 7332 life-years lost due to diagnostic delays under the 25% backlog scenario, 811 additional lives and 14 873 life-years lost under the 50% backlog scenario, and 1231 additional lives and 22 635 life-years lost under the 75% backlog scenario. A 2-month delay in 2-week-wait investigatory referrals results in an estimated loss of between 0·0 and 0·7 life-years per referred patient, depending on age and tumour type. INTERPRETATION: Prompt provision of additional capacity to address the backlog of diagnostics will minimise deaths as a result of diagnostic delays that could add to those predicted due to expected presentational delays. Prioritisation of patient groups for whom delay would result in most life-years lost warrants consideration as an option for mitigating the aggregate burden of mortality in patients with cancer. FUNDING: None.

Mildly elevated lactate levels are associated with microcirculatory flow abnormalities and increased mortality: a microSOAP post hoc analysis.

BACKGROUND: Mildly elevated lactate levels (i.e., 1-2 mmol/L) are increasingly recognized as a prognostic finding in critically ill patients. One of several possible underlying mechanisms, microcirculatory dysfunction, can be assessed at the bedside using sublingual direct in vivo microscopy. We aimed to evaluate the association between relative hyperlactatemia, microcirculatory flow, and outcome. METHODS: This study was a predefined subanalysis of a multicenter international point prevalence study on microcirculatory flow abnormalities, the Microcirculatory Shock Occurrence in Acutely ill Patients (microSOAP). Microcirculatory flow abnormalities were assessed with sidestream dark-field imaging. Abnormal microcirculatory flow was defined as a microvascular flow index (MFI) < 2.6. MFI is a semiquantitative score ranging from 0 (no flow) to 3 (continuous flow). Associations between microcirculatory flow abnormalities, single-spot lactate measurements, and outcome were analyzed. RESULTS: In 338 of 501 patients, lactate levels were available. For this substudy, all 257 patients with lactate levels ≤ 2 mmol/L (median [IQR] 1.04 [0.80-1.40] mmol/L) were included. Crude ICU mortality increased with each lactate quartile. In a multivariable analysis, a lactate level > 1.5 mmol/L was independently associated with a MFI < 2.6 (OR 2.5, 95% CI 1.1-5.7, P = 0.027). CONCLUSIONS: In a heterogeneous ICU population, a single-spot mildly elevated lactate level (even within the reference range) was independently associated with increased mortality and microvascular flow abnormalities. In vivo microscopy of the microcirculation may be helpful in discriminating between flow- and non-flow-related causes of mildly elevated lactate levels. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01179243 . Registered on August 3, 2010.