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Purpose of review Addressing the reduced quality of life that affects ICU survivors is the most pressing challenge in critical care medicine. In order to meet this challenge, we must translate lessons learnt from assessing and training athletes to the clinical population, utilizing measurable and targeted parameters obtained during cardiopulmonary exercise testing (CPET). Recent findings Critical illness survivors demonstrate a persistent reduction in their physical and metabolic function. This manifests in reduced aerobic exercise capacity and metabolic inflexibility. CPET-guided targeted metabolic conditioning has proved beneficial in several clinical populations, including those undergoing high-risk surgery, and could be successfully applied to the rehabilitation of ICU survivors. Summary CPET shows great promise in the guidance of rehabilitation in functionally limited ICU survivors. Parallels in the physiological response to exercise in athletes and clinical populations with the stress and consequences of critical illness must be investigated and ultimately applied to the burgeoning population of ICU survivors in order to treat the consequences of survival from critical illness.

Background and Aims The incidence of frailty is increasing as the population ages, which has important clinical implications given the associations between frailty and poor outcomes in the bladder cancer population. Due to a multi-organ system decline and decreased physiologic reserve, frail patients are vulnerable to stressors of disease and have poorer mortality and morbidity rates than their nonfrail peers. The association between frailty and poor outcomes has been documented across multiple populations, including radical cystectomy, creating a need for frailty assessments to be used preoperatively for risk stratification. We aim to provide a review of the common frailty assessments and their relevance to radical cystectomy patients. Findings A variety of assessments for frailty exist, from short screening items to comprehensive geriatric assessments. The syndrome spans multiple organ systems, as do the potential diagnostic instruments. Some instruments are less practical for use in clinical practice by urologists, such as the Canadian Study of Health and Aging Frailty Index and Comprehensive Geriatric Assessment. The tool most studied in radical cystectomy is the modified Frailty Index, associated with high grade complications and 30-days mortality. Frailty often coexists with malnutrition and sarcopenia, stressing the importance of screening for and addressing these syndromes to improve patient's perioperative outcomes. Conclusions There is no universally agreed upon frailty assessment, but the most studied in radical cystectomy is the modified Frailty Index, providing valuable data with which to counsel patients preoperatively. Alterations in immune phenotypes provide potential future diagnostic biomarkers for frailty.

PURPOSE OF REVIEW: Survivorship or addressing impaired quality of life (QoL) in ICU survivors has been named 'the defining challenge of critical care' for this century to address this challenge; in addition to optimal nutrition, we must learn to employ targeted metabolic/muscle assessment techniques and utilize structured, progressive ICU rehabilitative strategies. RECENT FINDINGS: Objective measurement tools such as ccardiopulmonary exercise testing (CPET) and muscle-specific ultrasound show great promise to assess/treat post-ICU physical dysfunction. CPET is showing that systemic mitochondrial dysfunction may underlie development and persistence of poor post-ICU functional recovery. Finally, recent data indicate that we are poor at delivering effective, early ICU rehabilitation and that there is limited benefit of currently employed later ICU rehabilitation on ICU-acquired weakness and QoL outcomes. SUMMARY: The combination of nutrition with effective, early rehabilitation is highly likely to be essential to optimize muscle mass/strength and physical function in ICU survivors. Currently, technologies such as muscle-specific ultrasound and CPET testing show great promise to guide ICU muscle/functional recovery. Further, we must evolve improved ICU-rehabilitation strategies, as current methods are not consistently improving outcomes. In conclusion, we must continue to look to other areas of medicine and to athletes if we hope to ultimately improve 'ICU Survivorship'.

Complications after major surgery account for a disproportionate amount of in-hospital morbidity and mortality. Recent efforts have focused on preoperative optimization in an attempt to modify the risk associated with major surgery. Underaddressed, but important, modifiable risk factors are physical fitness and nutritional status. Surgical patients are particularly at risk of 3 related, but distinct, conditions: frailty, sarcopenia, and reduced physical fitness. Exercise-based prehabilitation strategies have shown promise in terms of improving aerobic fitness, although their impact on key clinical perioperative outcome measures have not been fully determined. Preoperative nutritional status also has a strong bearing on perioperative outcome.

BACKGROUND There is a need for standardized and cost-effective identification of frailty risk. The objective was to validate the Hospital Frailty Risk Score which utilizes International Classification Diagnoses in a cohort of older surgical patients, assess the score as an independent risk factor for adverse outcomes and compare discrimination properties of the frailty risk score with other risk stratification scores. METHODS Data were analysed from all patients ≥65 years undergoing primary surgical procedures from 2006-2018. Patients were categorized based on the frailty risk score. The primary outcomes were 30-day mortality and 180-day risk of readmission. RESULTS Of 16 793 patients evaluated, 7480 (45%), 7605 (45%) and 1708 (10%) had a low, intermediate and high risk of frailty. There was a higher incidence of 30-day mortality for individuals with intermediate (2.9%) and high (8.3%) compared with low (1.4%) risk of frailty (P

Quality Improvement Success Stories are published by the American Diabetes Association in collaboration with the American College of Physicians and the National Diabetes Education Program. This series is intended to highlight best practices and strategies from programs and clinics that have successfully improved the quality of care for people with diabetes or related conditions. Each article in the series is reviewed and follows a standard format developed by the editors of Clinical Diabetes. The following article describes a project at an academic tertiary-care medical center aimed at identifying surgical patients with uncontrolled diabetes early in the preoperative process to improve their perioperative glycemic control and surgical outcomes.

BACKGROUND: Perioperative neurocognitive disorders (PND) are common complications in older adults associated with increased 1-year mortality and long-term cognitive decline. One risk factor for worsened long-term postoperative cognitive trajectory is the Alzheimer’s Disease (AD) genetic risk factor APOE4. APOE4 is thought to elevate AD risk partly by increasing neuroinflammation, which is also a theorized mechanism for PND. Yet, it is unclear whether modulating apoE4 protein signaling in older surgical patients would reduce PND risk or severity. OBJECTIVES: MARBLE is a randomized, blinded, placebo-controlled phase II sequential dose escalation trial designed to evaluate perioperative administration of an apoE mimetic peptide drug, CN-105, in older adults (age ≥60 years). The primary aim is evaluating the safety of CN-105 administration, as measured by adverse event (AE) rates in CN-105 versus placebo-treated patients. Secondary aims include assessing perioperative CN-105 administration feasibility and its efficacy for reducing postoperative neuroinflammation and PND severity. METHODS: 201 patients undergoing non-cardiac, non-neurological surgery will be randomized to control or CN-105 treatment groups and receive drug or placebo before and every six hours after surgery, for up to three days after surgery. Chart reviews, pre- and postoperative cognitive testing, delirium screening, and blood and CSF analyses will be performed to examine effects of CN-105 on perioperative adverse event rates, cognition, and neuro-inflammation. Trial results will be disseminated by presentations at conferences and peer-reviewed publications. CONCLUSION: MARBLE is a transdisciplinary study designed to measure CN-105 safety and efficacy for preventing PND in older adults and to provide insight into the pathogenesis of these geriatric syndromes.

Background Optimal fluid therapy in the perioperative and critical care settings depends on understanding the underlying cardiovascular physiology and individualizing assessment of the dynamic patient state. Methods The Perioperative Quality Initiative (POQI-5) consensus conference brought together an international team of multidisciplinary experts to survey and evaluate the literature on the physiology of volume responsiveness and perioperative fluid management. The group used a modified Delphi method to develop consensus statements applicable to the physiologically based management of intravenous fluid therapy in the perioperative setting. Discussion We discussed the clinical and physiological evidence underlying fluid responsiveness and venous capacitance as relevant factors in fluid management and developed consensus statements with clinical implications for a broad group of clinicians involved in intravenous fluid therapy. Two key concepts emerged as follows: (1) The ultimate goal of fluid therapy and hemodynamic management is to support the conditions that enable normal cellular metabolic function in order to produce optimal patient outcomes, and (2) optimal fluid and hemodynamic management is dependent on an understanding of the relationship between pressure, volume, and flow in a dynamic system which is distensible with variable elastance and capacitance properties.

BACKGROUND: Elevated high-sensitivity troponin (hsTnT) after noncardiac surgery is associated with higher mortality, but the temporal relationship between early elevated troponin and the later development of noncardiac morbidity remains unclear. METHODS: Prospective observational study of patients aged ≥45 yr undergoing major noncardiac surgery at four UK hospitals (two masked to hsTnT). The exposure of interest was early elevated troponin, as defined by hsTnT >99th centile (≥15 ng L(−1)) within 24 h after surgery. The primary outcome was morbidity 72 h after surgery, defined by the Postoperative Morbidity Survey (POMS). Secondary outcomes were time to become morbidity-free and Clavien–Dindo ≥grade 3 complications. RESULTS: Early elevated troponin (median 21 ng L(−1) [16–32]) occurred in 992 of 4335 (22.9%) patients undergoing elective noncardiac surgery (mean [standard deviation, sd] age, 65 [11] yr; 2385 [54.9%] male). Noncardiac morbidity was more frequent in 494/992 (49.8%) patients with early elevated troponin compared with 1127/3343 (33.7%) patients with hsTnT

Objective Experimental animal models demonstrate that autonomic activity regulates systemic inflammation. By contrast, human studies are limited in number and exclusively use heart rate variability (HRV) as an index of cardiac autonomic regulation. HRV measures are primarily dependent on, and need to be corrected for, heart rate. Thus, independent autonomic measures are required to confirm HRV-based findings. Here, the authors sought to replicate the findings of preceding HRV-based studies by using HRV-independent, exercise-evoked sympathetic and parasympathetic measures of cardiac autonomic regulation to examine the relationship between autonomic function and systemic inflammation. Methods Sympathetic function was assessed by measuring heart rate changes during unloaded pedaling prior to onset of exercise, divided into quartiles; an anticipatory heart rate (AHRR) rise during this period is evoked by mental stress in many individuals. Parasympathetic function was assessed by heart rate recovery (HRR) 60 s after finishing cardiopulmonary exercise testing, divided into quartiles. Parasympathetic dysfunction was defined by delayed heart rate recovery (HRR) ≤12.beats.min −1 , a threshold value associated with higher cardiovascular morbidity/mortality in the general population. Systemic inflammation was primarily assessed by neutrophil-lymphocyte ratio (NLR), where a ratio >4 is prognostic across several inflammatory diseases and correlates strongly with elevated plasma levels of pro-inflammatory cytokines. High-sensitivity C-reactive protein (hsCRP) was also measured. Results In 1624 subjects (65 ± 14 y; 67.9% male), lower HRR (impaired vagal activity) was associated with progressively higher NLR (p = 0.004 for trend across quartiles). Delayed HRR, recorded in 646/1624 (39.6%) subjects, was associated with neutrophil-lymphocyte ratio >4 (relative risk: 1.43 (95%CI: 1.18–1.74); P = 0.0003). Similar results were found for hsCRP (p = 0.045). By contrast, AHRR was not associated with NLR (relative risk: 1.24 (95%CI: 0.94–1.65); P = 0.14). Conclusions Delayed HRR, a robust measure of parasympathetic dysfunction, is independently associated with leukocyte ratios indicative of systemic inflammation. These results further support a role for parasympathetic modulation of systemic inflammation in humans.

Systemic arterial pulse pressure (systolic minus diastolic pressure) ≤53 mm Hg in patients with cardiac failure is correlated with reduced stroke volume and is independently associated with accelerated morbidity and mortality. Given that deconditioned surgical and heart failure patients share similar cardiopulmonary physiology, we examined whether lower pulse pressure is associated with excess morbidity after major surgery.This was a prospective observational cohort study of patients deemed by their preoperative assessors to be at higher risk of postoperative morbidity. Preoperative pulse pressure was calculated before cardiopulmonary exercise testing. The primary outcome was any morbidity (PostOperative Morbidity Survey) occurring within 5 days of surgery, stratified by pulse pressure threshold ≤53 mm Hg. The relationship between pulse pressure, postoperative morbidity, and oxygen pulse (a robust surrogate for left ventricular stroke volume) was examined using logistic regression analysis (accounting for age, sex, BMI, cardiometabolic co-morbidity, and operation type).The primary outcome occurred in 578/660 (87.6%) patients, but postoperative morbidity was more common in 243/ 660 patients with preoperative pulse pressure ≤53 mm Hg{odds ratio (OR): 2.24 [95% confidence interval (CI): 1.29-3.38]; P0.001). Pulse pressure ≤53 mm Hg [OR:1.23 (95% CI: 1.03-1.46); P=0.02] and type of surgery were independently associated with all-cause postoperative morbidity (multivariate analysis). Oxygen pulse90% of population-predicted normal values was associated with pulse pressure ≤ 53 mm Hg [OR: 1.93 (95% CI: 1.32-2.84); P=0.007].In deconditioned surgical patients, lower preoperative systemic arterial pulse pressure is associated with excess morbidity. These data are strikingly similar to meta-analyses identifying low pulse pressure as an independent risk factor for adverse outcomes in cardiac failure. Low preoperative pulse pressure is a readily available measure, indicating that detailed physiological assessment may be warranted.ISRCT registry, ISRCTN88456378.

Focused cardiac ultrasound (FoCUS)—a simplified, qualitative version of echocardiography—is a well-established tool in the armamentarium of critical care and emergency medicine. This review explores the extent to which FoCUS could also be used to enhance the preoperative physical examination to better utilise resources and identify those who would benefit most from detailed echocardiography prior to surgery. Among the range of pathologies that FoCUS can screen for, the conditions it provides the most utility in the preoperative setting are left ventricular systolic dysfunction (LVSD) and, in certain circumstances, significant aortic stenosis (AS). Thus, FoCUS could help answer two common preoperative diagnostic questions. First, in a patient with high cardiovascular risk who subjectively reports a good functional status, is there evidence of LVSD? Second, does an asymptomatic patient with a systolic murmur have significant aortic stenosis? Importantly, many cardiac pathologies of relevance to perioperative care fall outside the scope of FoCUS, including regional wall motion abnormalities, diastolic dysfunction, left ventricular outflow obstruction, and pulmonary hypertension. Current evidence suggests that after structured training in FoCUS and performance of 20–30 supervised examinations, clinicians can achieve competence in basic cardiac ultrasound image acquisition. However, it is not known precisely how many training exams are necessary to achieve competence in FoCUS image interpretation. Given the short history of FoCUS use in preoperative evaluation, further research is needed to determine what additional questions FoCUS is suited to answer in the pre-operative setting.

Background Enhanced recovery after surgery (ERAS) pathways aim to standardize and integrate perioperative care, incorporating the best available evidence-based practice throughout the perioperative period targeted at attenuating the surgical stress response while optimizing physiologic function, with the goal of facilitating recovery. Radical cystectomy is associated with significant postoperative morbidity, but comprehensive ERAS pathways have not been well studied in this population. Methods This is a before and after cohort study of an ERAS pathway for radical cystectomy at a large academic medical center. Following introduction of the ERAS pathway and a wash in period, we prospectively collected data from the next 100 consecutive subjects undergoing radical cystectomy with the ERAS pathway. This cohort was compared to a retrospective cohort of 100 consecutive patients undergoing radical cystectomy with traditional care. The primary outcome was hospital length of stay. Secondary outcomes included perioperative management, time to recovery milestones, complications, and costs. Results Implementation of an ERAS pathway for radical cystectomy was associated with reduced hospital length of stay (median LOS 10 days (IQR = 8–18) vs 7 days (IQR = 6–11); p

IntroductionIntubation-related complications are less frequent when intubation is successful on the first attempt. The rate of first attempt success in the emergency department (ED) and intensive care unit (ICU) is typically less than 90%. The bougie, a semirigid introducer that can be placed into the trachea to facilitate a Seldinger-like technique of tracheal intubation and is typically reserved for difficult or failed intubations, might improve first attempt success. Evidence supporting its use, however, is from a single academic ED with frequent bougie use. Validation of these findings is needed before widespread implementation.Methods and analysisThe BOugie or stylet in patients Undergoing Intubation Emergently trial is a prospective, multicentre, non-blinded randomised trial being conducted in six EDs and six ICUs in the USA. The trial plans to enrol 1106 critically ill adults undergoing orotracheal intubation. Eligible patients are randomised 1:1 for the use of a bougie or use of an endotracheal tube with stylet for the first intubation attempt. The primary outcome is successful intubation on the first attempt. The secondary outcome is severe hypoxaemia, defined as an oxygen saturation less than 80% between induction until 2 min after completion of intubation. Enrolment began on 29 April 2019 and is expected to be completed in 2021.Ethics and disseminationThe trial protocol was approved with waiver of informed consent by the Central Institutional Review Board at Vanderbilt University Medical Center or the local institutional review board at an enrolling site. The results will be submitted for publication in a peer-reviewed journal and presented at scientific conferences.Trial registration numberClinicalTrials.gov Registry (NCT03928925).

Molecular mechanisms linking autonomic dysfunction with poorer clinical outcomes in critical illness remain unclear. We hypothesized that baroreflex dysfunction alone is sufficient to cause cardiac impairment through neurohormonal activation of (nicotinamide adenine dinucleotide phosphate oxidase dependent) oxidative stress resulting in increased expression of G-protein-coupled receptor kinase 2, a key negative regulator of cardiac function.Laboratory/clinical investigations.University laboratory/medical centers.Adult rats; wild-type/nicotinamide adenine dinucleotide phosphate oxidase subunit-2-deficient mice; elective surgical patients.Cardiac performance was assessed by transthoracic echocardiography following experimental baroreflex dysfunction (sino-aortic denervation) in rats and mice. Immunoblots assessed G-protein-coupled receptor recycling proteins expression in rodent cardiomyocytes and patient mononuclear leukocytes. In surgical patients, heart rate recovery after cardiopulmonary exercise testing, time/frequency measures of parasympathetic variables were related to the presence/absence of baroreflex dysfunction (defined by spontaneous baroreflex sensitivity of6 ms mm Hg). The associations of baroreflex dysfunction with intraoperative cardiac function and outcomes were assessed.Experimental baroreflex dysfunction in rats and mice resulted in impaired cardiac contractility and upregulation of G-protein-coupled receptor kinase 2 expression. In mice, genetic deficiency of gp91 nicotinamide adenine dinucleotide phosphate oxidase subunit-2 prevented upregulation of G-protein-coupled receptor kinase 2 expression in conditions of baroreflex dysfunction and preserved cardiac function. Baroreflex dysfunction was present in 81 of 249 patients (32.5%) and was characterized by lower parasympathetic tone and increased G-protein-coupled receptor kinase 2 expression in mononuclear leukocytes. Baroreflex dysfunction in patients was also associated with impaired intraoperative cardiac contractility. Critical illness and mortality were more frequent in surgical patients with baroreflex dysfunction (relative risk, 1.66 [95% CI, 1.16-2.39]; p = 0.006).Reduced baroreflex sensitivity is associated with nicotinamide adenine dinucleotide phosphate oxidase subunit-2-mediated upregulation of G-protein-coupled receptor kinase 2 expression in cardiomyocytes and impaired cardiac contractility. Autonomic dysfunction predisposes patients to the development of critical illness and increases mortality.

Background: Delirium is a common post-operative complication, particularly in older adults undergoing major or emergency procedures. It is associated with increased length of intensive care and hospital stay, post-operative mortality and subsequent dementia risk. Current methods of predicting delirium incidence, duration and severity have limitations. Investigation of blood and cerebrospinal fluid (CSF) biomarkers linked to delirium may improve understanding of the underlying pathophysiology, particularly with regard to the extent this is shared or distinct with underlying dementia. Together, these have the potential for development of better risk stratification tools and perioperative interventions. Methods: 200 patients over the age of 70 scheduled for surgery with routine spinal anaesthetic will be recruited from UK hospitals. Their cognitive and functional baseline status will be assessed pre-operatively by telephone. Time-matched CSF and blood samples will be taken at the time of surgery and analysed for known biomarkers of neurodegeneration and neuroinflammation. Patients will be assessed daily for delirium until hospital discharge and will have regular cognitive follow-up for two years. Primary outcomes will be change in modified Telephone Interview for Cognitive Status (TICS-m) score at 12 months and rate of change of TICS-m score. Delirium severity, duration and biomarker levels will be treated as exposures in a random effects linear regression models. PRIMED Risk has received regulatory approvals from Health Research Authority and London – South East Research Ethics Committee. Discussion: The main anticipated output from this study will be the quantification of biomarkers of acute and chronic contributors to cognitive impairment after surgery. In addition, we aim to develop better risk prediction models for adverse cognitive outcomes.

Background Systemic inflammation is pivotal in the pathogenesis of cardiovascular disease. As inflammation can directly cause cardiomyocyte injury, we hypothesised that established systemic inflammation, as reflected by elevated preoperative neutrophil-lymphocyte ratio (NLR) >4, predisposes patients to perioperative myocardial injury. Methods We prospectively recruited 1652 patients aged ≥45 yr who underwent non-cardiac surgery in two UK centres. Serum high sensitivity troponin T (hsTnT) concentrations were measured on the first three postoperative days. Clinicians and investigators were blinded to the troponin results. The primary outcome was perioperative myocardial injury, defined as hsTnT≥14 ng L−1 within 3 days after surgery. We assessed whether myocardial injury was associated with preoperative NLR>4, activated reactive oxygen species (ROS) generation in circulating monocytes, or both. Multivariable logistic regression analysis explored associations between age, sex, NLR, Revised Cardiac Risk Index, individual leukocyte subsets, and myocardial injury. Flow cytometric quantification of ROS was done in 21 patients. Data are presented as n (%) or odds ratio (OR) with 95% confidence intervals. Results Preoperative NLR>4 was present in 239/1652 (14.5%) patients. Myocardial injury occurred in 405/1652 (24.5%) patients and was more common in patients with preoperative NLR>4 [OR: 2.56 (1.92–3.41); P Conclusions Preoperative NLR>4 is associated with perioperative myocardial injury, independent of conventional risk factors. Systemic inflammation may contribute to the development of perioperative myocardial injury. Clinical trial registration NCT01842568.

Background: Myocardial injury after noncardiac surgery (MINS) was defined as prognostically relevant myocardial injury due to ischemia that occurs during or within 30 days after noncardiac surgery. The study’s four objectives were to determine the diagnostic criteria, characteristics, predictors, and 30-day outcomes of MINS. Methods: In this international, prospective cohort study of 15,065 patients aged 45 yr or older who underwent in-patient noncardiac surgery, troponin T was measured during the first 3 postoperative days. Patients with a troponin T level of 0.04 ng/ml or greater (elevated “abnormal” laboratory threshold) were assessed for ischemic features (i.e., ischemic symptoms and electrocardiography findings). Patients adjudicated as having a nonischemic troponin elevation (e.g., sepsis) were excluded. To establish diagnostic criteria for MINS, the authors used Cox regression analyses in which the dependent variable was 30-day mortality (260 deaths) and independent variables included preoperative variables, perioperative complications, and potential MINS diagnostic criteria. Results: An elevated troponin after noncardiac surgery, irrespective of the presence of an ischemic feature, independently predicted 30-day mortality. Therefore, the authors’ diagnostic criterion for MINS was a peak troponin T level of 0.03 ng/ml or greater judged due to myocardial ischemia. MINS was an independent predictor of 30-day mortality (adjusted hazard ratio, 3.87; 95% CI, 2.96–5.08) and had the highest population-attributable risk (34.0%, 95% CI, 26.6–41.5) of the perioperative complications. Twelve hundred patients (8.0%) suffered MINS, and 58.2% of these patients would not have fulfilled the universal definition of myocardial infarction. Only 15.8% of patients with MINS experienced an ischemic symptom. Conclusion: Among adults undergoing noncardiac surgery, MINS is common and associated with substantial mortality.

Baroreflex dysfunction is a common feature of established cardiometabolic diseases that are most frequently associated with the development of critical illness. Laboratory models show that baroreflex dysfunction impairs cardiac contractility and cardiovascular performance, thereby increasing the risk of morbidity after trauma and sepsis. We hypothesized that baroreflex dysfunction contributes to excess postoperative morbidity after major surgery as a consequence of the inability to achieve adequate perioperative tissue oxygen delivery.In a randomized controlled trial of goal-directed haemodynamic therapy (GDT) in higher-risk surgical patients, baroreflex function was assessed using the spontaneous baroreflex sensitivity (BRS) method via an arterial line placed before surgery, using a validated sequence method technique (one beat lag). The BRS was calculated during the 6 h postoperative GDT intervention. Analyses of BRS were done by investigators blinded to clinical outcomes. The primary outcome was the association between postoperative baroreflex dysfunction (BRS6 mm Hg s(-1), a negative prognostic threshold in cardiovascular pathology) and early postoperative morbidity. The relationship between baroreflex dysfunction and postoperative attainment of preoperative indexed oxygen delivery was also assessed.Patients with postoperative baroreflex dysfunction were more likely to sustain infectious {relative risk (RR) 1.75 [95% confidence interval (CI): 1.07-2.85], P=0.02} and cardiovascular morbidity [RR 2.39 (95% CI: 1.22-4.71), P=0.008]. Prolonged hospital stay was more likely in patients with baroreflex dysfunction [unadjusted hazard ratio 1.62 (95% CI: 1.14-2.32), log-rank P=0.004]. Postoperative O2 delivery was 36% (95% CI: 7-65) lower in patients with baroreflex dysfunction in those not randomly assigned to GDT (P=0.02).Baroreflex dysfunction is associated with excess morbidity, impaired cardiovascular performance, and delayed hospital discharge, suggesting a mechanistic role for autonomic dysfunction in determining perioperative outcome.ISCRTN76894700.

In February the international consensus definitions for sepsis and septic shock were updated to reflect current understanding of the syndrome. A new scoring system was also released (qSOFA) to aid early identification of organ dysfunction in sepsis.

Objective Reduced exercise capacity is well documented in end-stage chronic kidney disease (CKD), preceded by changes in cardiac morphology in CKD stage 3. However, it is unknown whether subclinical cardiopulmonary dysfunction occurs in CKD stage 3 independently of heart failure. Methods Prospective observational cross-sectional study of exercise capacity assessed by cardiopulmonary exercise testing in 993 preoperative patients. Primary outcome was peak oxygen consumption (VO2peak). Anaerobic threshold (AT), oxygen pulse and exercise-evoked measures of autonomic function were analysed, controlling for CKD stage 3, age, gender, diabetes mellitus and hypertension. Results CKD stage 3 was present in 93/993 (9.97%) patients. Diabetes mellitus (RR 2.49 (95% CI 1.59 to 3.89); p

Summary Background Morbidity after major surgery is associated with low oxygen delivery. Haemodynamic therapy aimed at increasing oxygen delivery in an effort to reduce oxygen debt, tissue injury, and morbidity, is controversial. The most appropriate target for this strategy is unclear and might have several off-target effects, including loss of neural (parasympathetic)-mediated cellular protection. We hypothesised that individualised oxygen delivery targeted haemodynamic therapy (goal-directed therapy) in high-risk surgical patients would reduce postoperative morbidity, while secondarily addressing whether goal-directed therapy affected parasympathetic function. Methods In this multicentre, randomised, double-blind, controlled trial, adult patients undergoing major elective surgery were allocated by computer-generated randomisation to a postoperative protocol (fluid, with and without dobutamine) targeted to achieve their individual preoperative oxygen delivery value (goal-directed therapy) or standardised care (control). Patients and staff were masked to the intervention. The primary outcome was absolute risk reduction (ARR) in morbidity (defined by Clavien–Dindo grade II or more) on postoperative day 2. We also assessed a secondary outcome focused on parasympathetic function, using time-domain heart rate variability measures. Analyses were done on an intention-to-treat basis. The trial was registered with Controlled Clinical Trials (number ISRCTN76894700). Findings We enrolled 204 patients between May 20, 2010, and Feb 12, 2014. Intention-to-treat analysis of the 187 (92%) patients who completed the trial intervention period showed that early morbidity was similar between goal-directed therapy (44 [46%] of 95 patients) and control groups (49 [53%] of 92 patients) (ARR −7%, 95% CI −22 to 7; p=0·30). Prespecified secondary analysis showed that 123 (66%) of 187 patients achieved preoperative oxygen delivery (irrespective of intervention). These patients sustained less morbidity (ARR 19%, 95% CI 3–34; p=0·016), including less infectious complications. Goal-directed therapy reduced parasympathetic activity postoperatively (relative risk 1·33, 95% CI 1·01–1·74). Interpretation Achievement of preoperative oxygen delivery values in the postoperative phase was associated with less morbidity, but this was not affected by the use of an oxygen delivery targeted strategy. Reduced parasympathetic activity after goal-directed therapy was associated with the failure of this intervention to reduce postoperative morbidity. Funding Academy of Medical Sciences and Health Foundation Clinician Scientist Award.

Many of the insults that lead to critical illness, such as sepsis, trauma and major surgery, either cause, or are perhaps the consequence of, profound alterations in autonomic nervous system control. Several cardinal features of chronic critical illness – regardless of the etiology – support the assertion that autonomic dysfunction is a core mechanism underlying the development and perpetuation of multiorgan failure. By reconsidering the spectrum that autonomic dysfunction encompasses, we explore the pivotal and multi-faceted impact exerted by aberrant autonomic control in chronic critical illness.

Stratifying preoperative risk and guiding perioperative therapy objectively has acquired critical importance, given robust data demonstrating that morbidity following non-cardiac surgery confers substantially increased risk of death, even beyond hospital discharge. The development of useful perioperative biomarkers depends fundamentally on both prospective morbidity data that enable the identification of higher risk patients as well as the translational understanding of pathophysiological mechanisms underlying postoperative organ dysfunction, the development of which may be specific to the perioperative environment. The emergence of cardiac insufficiency, rather than cardiac ischaemia, as the dominant factor associated with excess risk of prolonged postoperative morbidity has promoted the application of biomarkers used commonly in cardiovascular medicine. Several novel, organ specific biomarkers offer potential perioperative application. Nevertheless, common tests/biomarkers that are widely available do provide valuable, objective information that is perhaps under-utilised perioperatively. Despite significant challenges, perioperative medicine presents exciting—arguably unique—opportunities for novel biomarker development.

Objective Recent perioperative trials have highlighted the urgent need for a better understanding of why sympatholytic drugs intended to reduce myocardial injury are paradoxically associated with harm (stroke, myocardial infarction). We hypothesised that following a standardised autonomic challenge, a subset of patients may demonstrate excessive sympathetic activation which is associated with exercise-induced ischaemia and impaired cardiac output. Methods Heart rate rise during unloaded pedalling (zero workload) prior to the onset of cardiopulmonary exercise testing (CPET) was measured in 2 observation cohorts of elective surgical patients. The primary outcome was exercise-evoked, ECG-defined ischaemia (>1 mm depression; lead II) associated with an exaggerated increase in heart rate (EHRR ≥12 bpm based on prognostic data for all-cause cardiac death in preceding epidemiological studies). Secondary outcomes included cardiopulmonary performance (oxygen pulse (surrogate for left ventricular stroke volume), peak oxygen consumption (VO2peak), anaerobic threshold (AT)) and perioperative heart rate. Results EHRR was present in 40.4–42.7% in both centres (n=232, n=586 patients). Patients with EHRR had higher heart rates perioperatively (p

Null zones and head postures were studied in two patients with idiopathic congenital nystagmus who had been carefully selected from a larger group of patients who had nystagmus with compensatory head postures. Oculomotor and sensory features of the two patients indicated that they would have a reasonable chance of profiting from surgery. Neither patient had a periodic alternating or manifest latent nystagmus or any ocular disease of the fixating eye. Postoperative evaluation of the head posture and the nystagmus behavior of both patients was carried out over a period in excess of 6 years. Neither of the patients readopted a head turn, and visual acuity was found to be equivalent to that prior to surgery when using the null zone. In one of the patients the postoperative null zone was located in the primary position, while in the other the null zone was decreased from an eccentricity of 30 degrees to 15 degrees. These results suggest that the position of the postoperative null zone is not always an accurate predictor of head turn.

We investigated the factors that determine the nature and extent of abnormal head postures in patients with congenital nystagmus. The head positions and eye movements of 16 patients were monitored while they adopted a variety of gaze positions. Five patients displayed a single head posture and four displayed multiple head postures. Six of the nine head postures matched the minimum intensity zone. The extent of the head posture was also found to be dictated by the velocity distribution of the slow phase, the nystagmus beat direction, and the neutral zone. Our results suggest that the surgical management of a head posture should not always be based only on the relocation of the minimum intensity zone to the primary gaze position.