Predictors of UK healthcare worker burnout during the COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic is putting health professionals under increasing pressure. This population is already acknowledged to be at risk of burnout. AIM: We aim to provide a 'snapshot' of the levels of burnout, anxiety, depression and distress among healthcare workers during the COVID-19 pandemic. METHODS: We distributed an online survey via social media in June 2020 open to any UK healthcare worker. The primary outcome measure was symptoms of burnout measured using the Copenhagen Burnout Inventory. Secondary outcomes of depression, anxiety, distress and subjective measures of stress were also recorded. Multivariate logistic regression analysis was performed to identify factors associated with burnout, depression, anxiety and distress. RESULTS: A total of 539 persons responded to the survey; 90% female and 53% nurses. Participants with moderate-to-severe burnout were younger (49% vs. 33% under 40 years, P = 0.004), more likely to have pre-existing comorbidities (21% vs. 12%, P = 0.031), twice as likely to have been redeployed from their usual role (22% vs. 11%; P = 0.042), or to work in an area dedicated to COVID-19 patients (50% vs. 32%, P < 0.001) and were almost 4 times more likely to have previous depression (24% vs. 7%; P = 0.012). CONCLUSION: Independent predictors of burnout were being younger, redeployment, exposure to patients with COVID-19, being female and a history of depression. Evaluation of existing psychological support interventions is required with targeted approaches to ensure support is available to those most at risk.

Direct comparison of selective endothelin A and non-selective endothelin A/B receptor blockade in chronic heart failure.

OBJECTIVE: To investigate the potential differential effects of selective endothelin (ET) A and dual ET-A/B receptor blockade in patients with chronic heart failure. METHODS: Nine patients with chronic heart failure (New York Heart Association class II-III) each received intravenous infusions of BQ-123 alone (selective ET-A blockade) and combined BQ-123 and BQ-788 (dual ET-A/B blockade) in a randomised, placebo controlled, three way crossover study. RESULTS: Selective ET-A blockade increased cardiac output (maximum mean (SEM) 33 (12)%, p < 0.001) and reduced mean arterial pressure (maximum -13 (4)%, p < 0.001) and systemic vascular resistance (maximum -26 (8)%, p < 0.001), without changing heart rate (p = 0.38). Dual ET-A/B blockade significantly reduced the changes in all these haemodynamic variables compared with selective ET-A blockade (p < 0.05). Selective ET-A blockade reduced pulmonary artery pressure (maximum 25 (7)%, p = 0.01) and pulmonary vascular resistance (maximum 72 (39)%, p < 0.001). However, there was no difference between these effects and those seen with dual ET-A/B blockade. Unlike selective ET-A blockade, dual ET-A/B blockade increased plasma ET-1 concentrations (by 47 (4)% with low dose and 61 (8)% with high dose, both p < 0.05). CONCLUSIONS: While there appeared to be similar reductions in pulmonary pressures with selective ET-A and dual ET-A/B blockade, selective ET-A blockade caused greater systemic vasodilatation and did not affect ET-1 clearance. In conclusion, there are significant haemodynamic differences between selective ET-A and dual ET-A/B blockade, which may determine responses in individual patients.

Comparative toxicity of citalopram and the newer antidepressants after overdose.

OBJECTIVE: To compare the toxicity of citalopram, venlafaxine, mirtazapine, and nefazadone after overdose. METHODS: Two-year retrospective review of consecutive patients admitted to the toxicology unit of Edinburgh Royal Infirmary. Outcome measure included physiological variables, ECG recordings, peak creatine kinase, development of arrhythmias, seizure, tremor or agitation, and the need for admission to a critical care facility. RESULTS: A total of 225 patients were studied. Venlafaxine was associated with a significantly higher pulse rate (p < 0.0001) and tremor (p = 0.007) than other antidepressants. Citalopram was associated with a significantly longer QT interval on ECG recording (p < 0.0001) but mean QTc durations were not significantly different between all drugs studied. No arrhythmias were recorded. Only venlafaxine and citalopram caused seizures and were associated with the need for admission to Intensive Care, but there was no significant difference between them. CONCLUSIONS: Mirtazapine and nefazadone appear safe in overdose and were associated with minimal features of neurological or cardiovascular toxicity. Citalopram is more likely to cause QT prolongation but other features of cardiovascular toxicity were uncommon. Both citalopram and venlafaxine are proconvulsants. Venlafaxine also causes more frequent features of the serotonin syndrome.

Abnormal endothelin B receptor vasomotor responses in patients with Hirschsprung's disease.

BACKGROUND: Hirschsprung's disease is associated with defects in the endothelin-3 and endothelin B receptor genes. AIM: To assess the in vivo vasomotor responses to endothelin B receptor stimulation in patients with Hirschsprung's disease. METHODS: Forearm blood flow was measured using venous occlusion plethysmography in 10 patients with Hirschsprung's disease and 10 matched healthy controls during intra-brachial infusion of the highly selective endothelin B receptor agonist, sarafotoxin S6c. To simulate endothelin B receptor dysfunction, sarafotoxin S6c was co-infused with the highly selective endothelin B receptor antagonist, BQ-788, in six of the healthy controls. RESULTS: Sarafotoxin S6c caused a brief initial vasodilatation followed by a slow-onset, sustained vasoconstriction (p<0.001). Compared to control subjects, patients with Hirschsprung's disease had a substantial impairment of the initial vasodilatation whilst producing a more pronounced subsequent vasoconstriction (p<0.001). In healthy controls, co-infusion of BQ-788 and sarafotoxin S6c caused a similar pattern of responses to those obtained in patients with Hirschsprung's disease: abolition of the initial vasodilatation and augmentation of subsequent vasoconstriction (p<0.001). DISCUSSION: In the majority of patients with Hirschsprung's disease, there is a functional defect of the vascular endothelin B receptor.

Systemic ETA receptor antagonism with BQ-123 blocks ET-1 induced forearm vasoconstriction and decreases peripheral vascular resistance in healthy men.

1. The effect on systemic haemodynamics of BQ-123, a selective endothelin A (ETA) receptor antagonist, was investigated in healthy men by giving, on separate occasions, ascending intravenous doses of 100, 300, 1000 and 3000 nmol min(-1) BQ-123, each for 15 min, in a randomized, placebo-controlled, double-blind study. The response of forearm blood flow to brachial artery infusion of endothelin-1 (ET-1; 5 pmol min(-1) for 90 min) was also studied using bilateral forearm plethysmography, after systemic pre-treatment, on separate occasions, with one of two doses of BQ-123 (300 and 1000 nmol min(-1) for 15 min) or placebo. 2. Systemic BQ-123 dose-dependently decreased systemic vascular resistance (P<0.01 for all doses vs placebo) and mean arterial pressure (P<0.05 for 300 nmol min(-1) and P<0.01 for 1000 and 3000 nmol min(-1)) during the 60 min following infusion. There were concurrent increases in heart rate and cardiac index. BQ-123, when infused systemically for 15 min, appeared to reach a maximum effect at 1000 nmol min(-1). 3. Intra-brachial ET-1 infusion, after pre-treatment with placebo, caused a slow onset progressive forearm vasoconstriction without systemic effects. This vasoconstriction was attenuated by pre-treatment with BQ-123 at 300 nmol min(-1) and abolished by BQ-123 at 1000 nmol min(-1) (P<0.01 vs placebo). 4. These effects occurred at concentrations of BQ-123 in the plasma (510+/-64 nmol l(-1)) that were ETA receptor selective, and were not accompanied by an increase in plasma ET-1 that would have indicated ETB receptor blockade. 5. We conclude that ETA-mediated vascular tone contributes to the maintenance of basal systemic vascular resistance and blood pressure in healthy men.

Big endothelin-3 constricts forearm resistance vessels but not hand veins in humans.

BACKGROUND: Endothelin-3 (ET-3) and its inactive precursor, big endothelin-3 (big ET-3), are both found in human plasma. We investigated whether big ET-3 is converted to ET-3 in the human forearm resistance vessels and dorsal hand veins in vivo. METHODS: In a 4-phase study, 6 subjects received 90 minute intrabrachial artery infusions of big ET-3 (50 and 100 pmol x min(-1)) and ET-3 (5 and 10 pmol x min(-1)) in random order. Forearm blood flow was measured by venous occlusion plethysmography. In a second 3-phase study, 6 subjects received 90-minute dorsal hand vein infusions of saline solution, big ET-3 (50 pmol x min(-1)) and ET-3 (5 pmol x min(-1)) in random order. In a third 2-phase study, 6 subjects received 90-minute dorsal hand vein infusions of big ET-3 (100 pmol x min(-1)) and ET-3 (10 pmol x min(-1)). In the dorsal hand vein studies, vessel diameter was measured by the Aellig technique. RESULTS: Intra-arterial ET-3 caused local forearm vasoconstriction of 20%+/-9% (P = .009) at 5 pmol x min(-1) and 20%+/-10% (P = .001) at 10 pmol x min(-1) after 90 minutes, with no difference between doses (P = .69). Intra-arterial big ET-3 also caused local forearm vasoconstriction of 22%+/-6% at 50 pmol x min(-1) (P = .004) and 18%+/-3% at 100 pmol x min(-1) (P<.0001) after 90 minutes, with no difference between doses (P = .44). There were no significant differences between the responses to intra-arterial big ET-3 and ET-3 at these doses. Local intravenous ET-3 caused a constriction of 9%+/-2% at 5 pmol x min(-1) (P = .04) and 22%+/-8% at 10 pmol x min(-1) (P = .002) after 90 minutes. Big ET-3 at 50 pmol x min(-1) and 100 pmol x min(-1) did not affect hand vein tone. All responses were slowly progressive. CONCLUSIONS: Based on vasoconstriction, measurable conversion of big ET-3 to ET-3 occurs in forearm resistance vessels but not in dorsal hand veins in vivo. An endothelin-converting enzyme, capable of converting exogenously administered big ET-3 to ET-3, appears to be present in upper limb resistance arteries but not in capacitance vessels in humans.

A novel S-nitrosothiol (RIG200) causes prolonged relaxation in dorsal hand veins with damaged endothelium.

BACKGROUND: Reduced nitric oxide bioavailability caused by endothelial dysfunction or damage is a contributory factor in the initiation and progression of a number of cardiovascular diseases. Delivery of exogenous nitric oxide is an attractive therapeutic option, but current agents lack selectivity for areas of endothelial damage. We tested the hypothesis that a novel nitric oxide donor drug, N-(S-nitroso-N-acetylpenicillamine)-2-amino-2-deoxy-1,3,4,6-tetra-O-acet yl-P-glucopyranose [RIG200], which has selective effects in endothelium-denuded isolated arteries in vitro, would exert similar effects in dorsal hand veins with experimentally damaged endothelium in vivo. METHODS: Venodilator responses to sodium nitroprusside and RIG200 were compared in two groups of healthy volunteers (age range, 18 to 63 years; n = 7 for each group) in norepinephrine 70% maximum effective concentration (EC70) preconstricted hand veins with use of the Aellig technique. In this doubleblind study, subjects were randomly assigned to receive either sodium nitroprusside or RIG200 (infusions of 0.06 and 6 nmol/min into the hand vein) before and 2 days after 15 minutes of local venous irription with distilled water. Endothelial function was assessed in all subjects on both visits with use of the endothelium-dependent vasodilator acetylcholine (1 nmol/min). RESULTS: Irrigation of hand veins with distilled water abolished endothelium-dependent dilatation in response to acetylcholine in both study groups (n = 14) but did not affect the amplitude or duration of responses to the conventional nitric oxide donor sodium nitroprusside (P = .87; n = 7). However, responses to RIG200 were significantly prolonged during the washout phase (30 minutes) in veins after water irrigation (P = .02; n = 7). CONCLUSION: These studies confirm that RIG200 has prolonged effects in veins with damaged endothelium, a characteristic that might be exploited therapeutically to target nitric oxide delivery to damaged blood vessels.

Constriction to ETB receptor agonists, BQ-3020 and sarafotoxin s6c, in human resistance and capacitance vessels in vivo.

AIMS: The aim of the study was to examine the effects of the ETB receptor selective agonists sarafotoxin S6c (SFTX6c) and BQ-3020 on the forearm resistance and capacitance vessels in healthy subjects in vivo. METHODS: The local response to intra-arterial or intravenous infusion of SFTX6c (5 pmol min-1) or BQ-3020 (50 pmol min-1) was assessed, on separate occasions, in eight healthy men (aged 20-28 years). Data (mean +/- s.e.mean) were examined by ANOVA. Results are expressed as percentage change from baseline at 90 min. RESULTS: SFTX6c and BQ-3020 reduced forearm blood flow, following local intra-arterial infusion (-25 +/- 7% and -27 +/- 7%, respectively; P < 0.001) and reduced hand vein diameter, following local intravenous infusion (-30 +/- 8% and -16 +/- 7%, respectively; P < 0.001). CONCLUSIONS: We have shown that locally active infusions of the selective ETB receptor agonists SFTX6c and BQ-3020 cause arterial constriction and venoconstriction in healthy human blood vessels in vivo. These results indicate that ETB receptor stimulation may mediate vasoconstriction in humans.

Systemic blockade of the endothelin-B receptor increases peripheral vascular resistance in healthy men.

Endothelin-1 (ET-1) is an important mediator of vascular tone in humans, and a number of endothelin receptor antagonists are currently in clinical development as vasodilator agents. While the vasoconstrictor role of the ETA receptor is undisputed, the role of the ETB receptor remains unclear. Hemodynamic effects of systemic doses of the ETB-selective antagonist BQ-788 were investigated in 5 healthy male volunteers (age range, 33 to 48 years) in a placebo-controlled, four-way crossover study. After a 15-minute infusion of BQ-788 (3, 30, or 300 nmol/min) or placebo, plasma ET-1 and big ET-1, blood pressure, heart rate, cardiac index, and stroke index were measured. Total peripheral vascular resistance was calculated from cardiac index and mean arterial pressure. Hemodynamic data are expressed as maximum, placebo-corrected, percentage change from baseline following BQ-788 (300 nmol/min) and were examined by ANOVA. Plasma ET-1 increased by 3.7+/-1.2 pg/mL (maximum at 15 minutes, P=0.02), whereas there was no significant change in plasma big ET-1. Although BQ-788 had no effect on mean arterial pressure, there was a reduction in heart rate (13+/-7% at 50 minutes; P=0.002), cardiac index (17+/-5% at 40 minutes; P<0. 0001), and stroke index (8+/-4% at 40 minutes; P=0.002) and an increase in total peripheral vascular resistance (24+/-5% at 40 minutes; P<0.0001). The selective ETB receptor antagonist BQ-788 causes peripheral vasoconstriction in healthy volunteers, suggesting that the overall balance of effects of endogenous ET-1 at the vascular ETB receptor favors vasodilatation. Further investigation is now clearly required to address whether selective ETA or combined ETA/ETB receptor blockade will be more effective in the clinical setting.

Clinical experience with endothelin antagonists.

Endothelin-1, discovered in 1988, is a 21-amino-acid peptide and currently the most potent vasoconstrictor and pressor substance known. Generated by vascular endothelial cells in response to a variety of chemical and mechanical signals, endothelin-1 is known to potentiate the actions of other vasoconstrictor substances and act as a comitogen in addition to directly causing vasoconstriction. There is evidence that endothelin-1 may contribute to the pathophysiology of conditions associated with sustained vasoconstriction, such as hypertension and heart failure, vasospastic conditions, such as subarachnoid hemorrhage, and atherogenesis. Studies using endothelin receptor antagonists show that endothelin-1 plays an important role in the maintenance of vascular tone and blood pressure in healthy humans, predominantly via an effect on the vascular smooth muscle ETA receptors. The endothelin receptor antagonist bosentan also effectively lowers blood pressure in hypertensive subjects and produces sustained and favorable effects on systemic and pulmonary hemodynamics in patients with chronic heart failure. A good side-effect profile, together with a potential for inhibition of atherogenesis, makes the endothelin receptor antagonists a potentially interesting class of novel agents for the treatment of cardiovascular disease.

Endothelin-A receptor antagonist-mediated vasodilatation is attenuated by inhibition of nitric oxide synthesis and by endothelin-B receptor blockade.

BACKGROUND: The role of endothelin (ET)-1 in maintenance of basal vascular tone has been demonstrated by local and systemic vasodilatation to endothelin receptor antagonists in humans. Although the constrictor effects mediated by the vascular smooth muscle ET(A) receptors are clear, the contribution from endothelial and vascular smooth muscle ET(B) receptors remains to be defined. The present study, in human forearm resistance vessels in vivo, was designed to further investigate the physiological function of ET(A) and ET(B) receptor subtypes in human blood vessels and determine the mechanism underlying the vasodilatation to the ET(A)-selective receptor antagonist BQ-123. METHODS AND RESULTS: Two studies were performed, each in groups of eight healthy subjects. Brachial artery infusion of BQ-123 caused significant forearm vasodilatation in both studies. This vasodilatation was reduced by 95% (P=.006) with inhibition of the endogenous generation of nitric oxide and by 38% (P<.001) with coinfusion of the ET(B) receptor antagonist BQ-788. In contrast, inhibition of prostanoid generation did not affect the response to BQ-123. Infusion of BQ-788 alone produced a 20% reduction in forearm blood flow (P<.001). CONCLUSIONS: Selective ET(A) receptor antagonism causes vasodilatation of human forearm resistance vessels in vivo. This response appears to result in major part from an increase in nitric oxide generation. ET(B) receptor antagonism either alone or on a background of ET(A) antagonism causes local vasoconstriction, indicating that ET(B) receptors in blood vessels respond to ET-1 predominantly by causing vasodilatation.

Endogenous angiotensin II does not contribute to sympathetic venoconstriction in dorsal hand veins of healthy humans.

BACKGROUND: Sympathetically mediated venoconstriction is augmented by exogenously administered angiotensin II. This study was designed to assess whether endogenous angiotensin II influences sympathetically mediated venous tone. METHODS: Responses of dorsal hand veins to local intravenous administration of subsystemic doses of losartan, an angiotensin II type-1 receptor antagonist, were assessed with use of a well-validated displacement technique in eight healthy male volunteers. In a four-phase study, responses to local infusions of angiotensin II (4 to 64 ng/min) and norepinephrine (1 to 128 ng/min) or to sympathetic venoconstriction produced by a single deep breath were compared in the presence of either saline placebo or 30 microg/min losartan. Each phase of the study was conducted on a separate day, in random order, and each phase was separated by at least 1 week. RESULTS: Angiotensin II (p = 0.03) and norepinephrine (p < 0.001) caused dose-dependent venoconstriction. Losartan attenuated the venoconstriction induced by angiotensin II (p = 0.048) but had no effect on the responses to norepinephrine or the venoconstriction induced by a single deep breath. CONCLUSIONS: In contrast to exogenously administered angiotensin II, basal endogenous angiotensin II does not influence sympathetically mediated venoconstriction in healthy humans. However, endogenous angiotensin II may have a role in circumstances of renin-angiotensin system activation, such as salt depletion.

Endothelin ETA and ETB receptors cause vasoconstriction of human resistance and capacitance vessels in vivo.

BACKGROUND: The role of endothelin ETB receptors in mediating vasoconstriction in humans is unclear. As yet, there have been no in vivo studies in resistance vessels, and in vitro data have been contradictory. We therefore investigated the function of ETB receptors in vivo in human forearm resistance and hand capacitance vessels using endothelin-1 as a nonselective agonist at ETA and ETB receptors and endothelin-3 and sarafotoxin S6c as selective agonists at the ETB receptor. METHODS AND RESULTS: A series of single-blind studies were performed, each in six healthy men. Brachial artery infusion of endothelin-1 and endothelin-3 caused slow-onset dose-dependent forearm vasoconstriction. Although endothelin-3 caused significantly less forearm vasoconstriction than endothelin-1 at low doses, vasoconstriction was similar to the two isopeptides at the highest dose (60 pmol/min). Endothelin-3 caused transient forearm vasodilatation at this dose, whereas endothelin-1 showed only a nonsignificant trend toward causing early vasodilatation. Intra-arterial sarafotoxin S6c caused a progressive reduction in forearm blood flow, although less than that to endothelin-1 (P = .04). Dorsal hand vein infusion of sarafotoxin S6c caused local venoconstriction that was also less than that to endothelin-1 (P = .002). CONCLUSIONS: Selective ETB receptor agonists cause constriction of forearm resistance and hand capacitance vessels in vivo in humans, suggesting that both ETA and ETB receptors mediate vasoconstriction. Hence, antagonists at both ETA and ETB receptors, or inhibitors of the generation of endothelin-1, may be necessary to completely prevent vasoconstriction to endogenously generated endothelin-1.

Endothelium-dependent modulation of venoconstriction to sarafotoxin S6c in human veins in vivo.

We investigated the vascular effects mediated by ETA and ETB receptors in human dorsal hand veins in vivo, using sarafotoxin S6c (SFTX6c) as a selective agonist of ETB receptors and endothelin-1 (ET-1) as a nonselective agonist of ETA and ETB receptors. The cyclo-oxygenase inhibitor aspirin and the nitric oxide synthase inhibitor L-NMMA were used to examine the modulating role of endothelial vasodilators on the response to SFTX6c. Drugs were all infused into the hand veins, at locally but not systemically active doses, via a 23 SWG butterfly cannula, with the exception of aspirin, which was administered orally. Hand vein size was measured by the Aellig technique. The study was performed in six healthy male subjects. Data (mean +/- SEM) were examined by ANOVA. Results are expressed as percent change from baseline at 60 min. ET-1 (5 pmol/min for 60 min) caused venoconstriction of 68 +/- 6% (p = 0.0001). SFTX6c at the same dose caused venoconstriction of 19 +/- 4% (p = 0.003). The response to SFTX6c was significantly less than to ET-1 (p = 0.002). Constriction to SFTX6c tended to increase when this agent was co-administered with aspirin (25 +/- 7%) or L-NMMA (24 +/- 10%) and was significantly potentiated when these agents were co-administered (45 +/- 4%; p = 0.01 vs. SFTX6c alone). We have demonstrated that the selective ETB agonist SFTX6c produces venoconstriction in human hand veins in vivo and that this venoconstriction is modulated by the generation of endothelium-derived vasodilators. In this vascular bed, venoconstriction rather than venodilatation appears to be the predominant effect of stimulation of ETB receptors with SFTX6c.

Forearm vasoconstriction to endothelin-1 is mediated by ETA and ETB receptors in vivo in humans.

The role of endothelin (ET)-B (ETB) receptors in mediating vasoconstriction in humans is unclear. As yet, in vitro data have been contradictory, and there have been no in vivo studies in resistance vessels. We investigated the function of ETB receptors in vivo in human forearm resistance vessels using ET-1 as a nonselective agonist at ETA and ETB receptors and ET-3 and sarafotoxin S6c as ETB receptor agonists. Brachial artery infusion of ET-1 and ET-3 caused slow-onset, dose-dependent forearm vasoconstriction. Although ET-3 caused significantly less forearm vasoconstriction than ET-1 at low doses, vasoconstriction to the two isopeptides was similar at the highest dose (60 pmol/min). ET-3 caused initial transient forearm vasodilatation at this dose, whereas ET-1 showed only a nonsignificant trend toward causing early vasodilatation. Intra-arterial sarafotoxin S6c caused a progressive reduction in forearm blood flow, although less than that to ET-1. Therefore, ETB receptor agonists contract human resistance vessels in vivo. The effects of ET-3 and sarafotoxin S6c, compared with ET-1, suggest that both ETA and ETB receptors mediate vasoconstriction. Antagonists at both ETA and ETB receptors, or inhibitors of the generation of ET-1, may be necessary to completely prevent vasoconstriction to endogenously generated ET-1.