Preoperative aerobic fitness and perioperative outcomes in patients undergoing cystectomy before and after implementation of a national lockdown.

Background: Lower fitness is a predictor of adverse outcomes after radical cystectomy. Lockdown measures during the COVID-19 pandemic affected daily physical activity. We hypothesised that lockdown during the pandemic was associated with a reduction in preoperative aerobic fitness and an increase in postoperative complications in patients undergoing radical cystectomy. Methods: We reviewed routine preoperative cardiopulmonary exercise testing (CPET) data collected prior to the pandemic (September 2018 to March 2020) and after lockdown (March 2020 to July 2021) in patients undergoing radical cystectomy. Differences in CPET variables, Postoperative Morbidity Survey (POMS) data, and length of hospital stay were compared. Results: We identified 267 patients (85 pre-lockdown and 83 during lockdown) who underwent CPET and radical cystectomy. Patients undergoing radical cystectomy throughout lockdown had lower ventilatory anaerobic threshold (9.0 [7.9-10.9] vs 10.3 [9.1-12.3] ml kg-1 min-1; P=0.0002), peak oxygen uptake (15.5 [12.9-19.1] vs 17.5 [14.4-21.0] ml kg-1 min-1; P=0.015), and higher ventilatory equivalents for carbon dioxide (34.7 [31.4-38.5] vs 33.4 [30.5-36.5]; P=0.030) compared with pre-lockdown. Changes were more pronounced in males and those aged >65 yr. Patients undergoing radical cystectomy throughout lockdown had a higher proportion of day 5 POMS-defined morbidity (89% vs 75%, odds ratio [OR] 2.698, 95% confidence interval [CI] 1.143-6.653; P=0.019), specifically related to pulmonary complications (30% vs 13%, OR 2.900, 95% CI 1.368-6.194; P=0.007) and pain (27% vs 9%, OR 3.471, 95% CI 1.427-7.960; P=0.004), compared with pre-lockdown on univariate analysis. Conclusions: Lockdown measures in response to the COVID-19 pandemic were associated with a reduction in fitness and an increase in postoperative morbidity among patients undergoing radical cystectomy.

Heart Rate Recovery Assessed by Cardiopulmonary Exercise Testing in Patients with Cardiovascular Disease: Relationship with Prognosis.

BACKGROUND: The use of exercise testing has expanded in recent decades and there is a wealth of information examining the prognostic significance of exercise variables, such as peak oxygen consumption or ventilatory measures whilst exercising. However, a paucity of research has investigated the use of recovery-derived parameters after exercise cessation. Heart rate recovery (HRR) has been considered a measure of the function of the autonomic nervous system and its dysfunction is associated with cardiovascular risk. OBJECTIVES: We aim to provide an overview of the literature surrounding HRR and its prognostic significance in patients with cardiovascular disease undertaking an exercise test. DATA SOURCES: In December 2020, searches of PubMed, Scopus, and ScienceDirect were performed using key search terms and Boolean operators. STUDY SELECTION: Articles were manually screened and selected as per the inclusion criteria. RESULTS: Nineteen articles met inclusion criteria and were reviewed. Disagreement exists in methodologies used for measuring and assessing HRR. However, HRR provides prognostic mortality information for use in clinical practice. CONCLUSIONS: HRR is a simple, non-invasive measure which independently predicts mortality in patients with heart failure and coronary artery disease; HRR should be routinely incorporated into clinical exercise testing.

MicroRNA signatures of perioperative myocardial injury after elective noncardiac surgery: a prospective observational mechanistic cohort study.

BACKGROUND: Elevated plasma or serum troponin, indicating perioperative myocardial injury (PMI), is common after noncardiac surgery. However, underlying mechanisms remain unclear. Acute coronary syndrome (ACS) is associated with the early appearance of circulating microRNAs, which regulate post-translational gene expression. We hypothesised that if PMI and ACS share pathophysiological mechanisms, common microRNA signatures should be evident. METHODS: We performed a nested case control study of samples obtained before and after noncardiac surgery from patients enrolled in two prospective observational studies of PMI (postoperative troponin I/T>99th centile). In cohort one, serum microRNAs were compared between patients with or without PMI, matched for age, gender, and comorbidity. Real-time polymerase chain reaction quantified (qRT-PCR) relative microRNA expression (cycle quantification [Cq] threshold <37) before and after surgery for microRNA signatures associated with ACS, blinded to PMI. In cohort two, we analysed (EdgeR) microRNA from plasma extracellular vesicles using next-generation sequencing (Illumina HiSeq 500). microRNA-messenger RNA-function pathway analysis was performed (DIANA miRPath v3.0/TopGO). RESULTS: MicroRNAs were detectable in all 59 patients (median age 67 yr [61-75]; 42% male), who had similar clinical characteristics independent of developing PMI. In cohort one, serum microRNA expression increased after surgery (mean fold-change) hsa-miR-1-3p: 3.99 (95% confidence interval [CI: 1.95-8.19]; hsa-miR-133-3p: 5.67 [95% CI: 2.94-10.91]; P<0.001). These changes were not associated with PMI. Bioinformatic analysis of differentially expressed microRNAs from cohorts one (n=48) and two (n=11) identified pathways associated with adrenergic stress and calcium dysregulation, rather than ischaemia. CONCLUSIONS: Circulating microRNAs associated with cardiac ischaemia were universally elevated in patients after surgery, independent of development of myocardial injury.

Acquired loss of cardiac vagal activity is associated with myocardial injury in patients undergoing noncardiac surgery: prospective observational mechanistic cohort study.

BACKGROUND: Myocardial injury is more frequent after noncardiac surgery in patients with preoperative cardiac vagal dysfunction, as quantified by delayed heart rate (HR) recovery after cessation of cardiopulmonary exercise testing. We hypothesised that serial and dynamic measures of cardiac vagal activity are also associated with myocardial injury after noncardiac surgery. METHODS: Serial autonomic measurements were made before and after surgery in patients undergoing elective noncardiac surgery. Cardiac vagal activity was quantified by HR variability and HR recovery after orthostatic challenge (supine to sitting). Revised cardiac risk index (RCRI) was calculated for each patient. The primary outcome was myocardial injury (high-sensitivity troponin ≥15 ng L-1) within 48 h of surgery, masked to investigators. The exposure of interest was cardiac vagal activity (high-frequency power spectral analysis [HFLn]) and HR recovery 90 s from peak HR after the orthostatic challenge. RESULTS: Myocardial injury occurred in 48/189 (25%) patients, in whom 41/48 (85%) RCRI was <2. In patients with myocardial injury, vagal activity (HFLn) declined from 5.15 (95% confidence interval [CI]: 4.58-5.72) before surgery to 4.33 (95% CI: 3.76-4.90; P<0.001) 24 h after surgery. In patients who remained free of myocardial injury, HFLn did not change (4.95 [95% CI: 4.64-5.26] before surgery vs 4.76 [95% CI: 4.44-5.08] after surgery). Before and after surgery, the orthostatic HR recovery was slower in patients with myocardial injury (5 beats min-1 [95% CI: 3-7]), compared with HR recovery in patients who remained free of myocardial injury (10 beats min-1 [95% CI: 7-12]; P=0.02). CONCLUSIONS: Serial HR measures indicating loss of cardiac vagal activity are associated with perioperative myocardial injury in lower-risk patients undergoing noncardiac surgery.

Autonomic regulation of systemic inflammation in humans: A multi-center, blinded observational cohort study.

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) 60s 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±14y; 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.

Vagal determinants of exercise capacity.

Indirect measures of cardiac vagal activity are strongly associated with exercise capacity, yet a causal relationship has not been established. Here we show that in rats, genetic silencing of the largest population of brainstem vagal preganglionic neurons residing in the brainstem's dorsal vagal motor nucleus dramatically impairs exercise capacity, while optogenetic recruitment of the same neuronal population enhances cardiac contractility and prolongs exercise endurance. These data provide direct experimental evidence that parasympathetic vagal drive generated by a defined CNS circuit determines the ability to exercise. Decreased activity and/or gradual loss of the identified neuronal cell group provides a neurophysiological basis for the progressive decline of exercise capacity with aging and in diverse disease states.

Subclinical cardiopulmonary dysfunction in stage 3 chronic kidney disease.

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<0.001), and hypertension (RR 3.20 (95% CI 2.04 to 5.03); p<0.001)) were more common in CKD stage 3. Cardiac failure (RR 0.83 (95% CI 0.30 to 2.24); p=0.70) and ischaemic heart disease (RR 1.40 (95% CI 0.97 to 2.02); p=0.09) were not more common in CKD stage 3. Patients with CKD stage 3 had lower predicted VO2peak (mean difference: 6% (95% CI 1% to 11%); p=0.02), lower peak heart rate (mean difference:9 bpm (95% CI 3 to 14); p=0.03)), lower AT (mean difference: 1.1 mL/min/kg (95% CI 0.4 to 1.7); p<0.001) and impaired heart rate recovery (mean difference: 4 bpm (95% CI 1 to 7); p<0.001)). CONCLUSIONS: Subclinical cardiopulmonary dysfunction in CKD stage 3 is common. This study suggests that maladaptive cardiovascular/autonomic dysfunction may be established in CKD stage 3, preceding pathophysiology reported in end-stage CKD.

Sympathetic autonomic dysfunction and impaired cardiovascular performance in higher risk surgical patients: implications for perioperative sympatholysis.

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<0.05). Significant ST segment depression during CPET was more common in EHRR patients (relative risk 1.7 (95% CI 1.3 to 2.1); p<0.001). EHRR was associated with 11% (95%CI 7% to 15%) lower predicted oxygen pulse (p<0.0001), consistent with impaired left ventricular function. CONCLUSIONS: EHRR is common and associated with ECG-defined ischaemia and impaired cardiac performance. Perioperative sympatholysis may further detrimentally affect cardiac output in patients with this phenotype.

The effect of total hip/knee replacement surgery and prophylactic dabigatran on thrombin generation and coagulation parameters.

INTRODUCTION: Total hip/knee replacement surgery (THR/TKR respectively) is associated with an increased risk of venous thromboembolism. Dabigatran is recommended as a thromboprophylactic agent post orthopaedic surgery. The aim of this study was to assess the post-operative (Day-1 and Day-2) effect of prophylactic Dabigatran on: the thrombin generation (TG) assay; prothrombin fragment 1.2 (F1.2); thrombin-antithrombin complexes (TAT); D-dimer (D-D); and other coagulation parameters. METHODS AND SAMPLES: Nineteen patients (12 THR, 7 TKR) who received 110 mg dabigatran 4 hours post-operatively, then 220 mg the following day, were recruited. Blood was collected: pre-operatively (Pre-); peri-operatively (Peri-); 19 hours after 110 mg dabigatran (Day-1); and 17 hours after 220 mg dabigatran (Day-2). The TG assay was measured using the Calibrated Automated Thrombogram and a low concentration of tissue factor. Other coagulation parameters measured included activated partial thromboplastin time (APTT), thrombin-time (TT), ecarin-clotting time (ECT) and Hemoclot tests. RESULTS: From Pre- to Peri-, ETP/peak-thrombin, F1.2, TAT and D-D increased significantly. From Peri- to Day-1 and Day-2: TAT reduced progressively; D-D increased; F1.2 did not change significantly; lag-time and time-to-peak prolonged; ETP/Peak-thrombin increased spuriously, due to Dabigatran interfering with the α-2 macroglobulin:thrombin complex in the TG assay. APTT, TT, ECT and Hemoclot increased progressively post-operatively; good correlations were seen between these tests. CONCLUSION: The effect of dabigatran on the TG assay, showed a spurious increase in ETP and Peak-thrombin due to its interference with the TG assay. Dabigatran reduced TAT, but not F1.2, suggesting that thrombin was still being generated after surgery, but was blocked by Dabigatran.

The emergency airway.

The 'can't intubate, can't ventilate' scenario is a nightmare for all clinicians who manage airways. Cricothyroidotomy is one of several emergency airway management techniques. Cricothyroidotomy is a short-term solution which provides oxygenation, not ventilation, and is not a definitive airway. Although there are tests which can help predict whether an intubation will be difficult, they are not always good predictors. As the can't intubate, can't ventilate scenario is rare, cricothyroidotomy is an unfamiliar procedure to many. In this situation, expert help must be called for early on. In the meantime, it is vital that all other simple airway manoeuvres have been attempted, such as good positioning of the patient with head tilt and chin lift, and use of airway adjuncts like the oral (Guedel) airway or nasopharyngeal airway, and the laryngeal mask airway. However, if attempts to secure the airway are unsuccessful, there may be no other option than to perform a cricothyroidotomy. It is a difficult decision to make, but with increasing hypoxia, it is essential that one oxygenates the patient. Cricothyroidotomy provides an opening in the pace between the anterior inferior border of the thyroid cartilage and the anterior superior border of the cricoid cartilage, allowing access to the airway below the glottis. The anatomical considerations are important when performing this procedure (Ellis, 2009), and there are other scenarios when it is used. It is not without consequence, as with any procedure.

Role of bacterial endotoxin in chronic heart failure: the gut of the matter.

Proinflammatory cytokines are now thought to play a key role in the pathophysiology of chronic heart failure, driving both symptomatic presentation and disease progression. We propose that this proinflammatory state, in turn, may be sustained through a chronic release of enterically derived bacterial endotoxin. Human trials have indicated that bacterial decontamination of the gut with concomitant decrease in lipopolysaccharide (LPS) has a positive outcome on heart disease patients. Antiendotoxin antibodies may thus represent therapeutic agents in this setting. Previously, antiendotoxin antibodies were targeted to the inner hydrophobic lipid A moiety of endotoxin in an attempt to neutralize its toxicity. These antibodies failed because they lacked specificity and bound to LPS weakly. In contrast, our studies on antiendotoxin antibodies have revealed that antibodies targeted to the hydrophilic oligosaccharides of the endotoxin have the potential to bind specifically with high affinity. Development of immunotherapeutics that can reduce systemic LPS or other agents, such as bactericidal/permeability-increasing protein that can neutralize LPS and limit inflammation safely, will enable the role of LPS in chronic heart failure to be elucidated and may pave the way to develop a new generation of effective therapeutic agents that may be directed to the treatment of chronic heart failure.

Low-dose endotoxin elicits variability in the inflammatory response in healthy volunteers.

Endotoxin has been implicated as a cause of sepsis, inflammation and organ dysfunction after surgery. Patients differ in their response to endotoxin, and this may account for differences in outcome. The traditional human model of endotoxin challenge (2-4 ng/kg) is not associated with significant inter-individual variability in systemic inflammation and may not be suitable for studying variability in the inflammatory response. We examined whether low-dose regimens of endotoxin cause significant variability in inflammation. Volunteers (n = 30) were randomised in a double-blinded ('double-dummy') study to one of 6 dosing regimens: saline (placebo) or Escherichia coli O:113 endotoxin as a 4 ng/kg bolus (positive control), 0.25 ng/kg (bolus), 0.25 ng/kg (30 min infusion), 0.75 ng/kg (bolus) or 0.75 ng/kg (30 min infusion). Temperature, white cell count, platelet count, C-reactive protein and cytokine changes from baseline were measured. In contrast to subjects receiving placebo, those randomised to 4 ng/kg endotoxin exhibited significant systemic inflammation during the 10-h observation period. The four low-dose regimens elicited variability in most markers of inflammation. We conclude that low-dose endotoxin elicits inter-individual variability in inflammation and could be used to test factors that may affect the human response to endotoxin.