Niels Henry Secher

Cerebral autoregulation is impaired in the postcardiac arrest period, potentially altering cerebral blood flow and exacerbating neurological injury after resuscitation. To our knowledge, the current study is the first to demonstrate that cerebral arteries exhibit reduced myogenic response, tone, and contractility in an animal model following resuscitation from cardiac arrest. These alterations in vasoreactivity appear to result, at least in part, from decreased calcium sensitivity in cerebral vascular smooth muscle cells.

Hyperoxia provokes hyperventilation, reducing arterial carbon dioxide pressure (PaCO₂), which in turn decreases cerebral blood flow (CBF) and oxygen delivery (DO₂). While hyperoxia-induced hypocapnia reduces CBF, its influence on brain oxygen extraction fraction (OEF) and metabolic rate for oxygen (CMRO₂) remains unclear, particularly given that reduced CDO₂ could modulate these parameters. We investigated how hyperoxia-induced hypocapnia affects CDO₂, OEF, and CMRO₂ in humans. Nine young men underwent two randomized sessions, each consisting of a 5-minute normoxic baseline, followed by either a 10-minute trial of isocapnic hyperoxia (IH; 100%O₂ with PaCO₂ clamp) or poikilocapnic hyperoxia (PKH; 100%O₂). Heart rate, beat-by-beat blood pressure (photoplethysmography), and ventilation were continuously monitored. CBF was measured via Doppler ultrasonography, and CDO₂, OEF, and CMRO₂ were calculated from arterial and right internal jugular venous blood samples. PaCO₂ and systemic hemodynamics remained stable during IH. In contrast, PKH provoked hyperventilation (+3.1 ± 2.9 L/min, P = 0.013) and hypocapnia (−3.0 ± 2.2 mmHg, P = 0.012). Both IH and PKH reduced CBF (ΔPKH: −257.9 ± 127.1 vs. ΔIH: −146.2 ± 105.0 mL/min, P = 0.006) and CDO₂ (ΔPKH: −37.0 ± 24.7 vs. ΔIH: −14.1 ± 21.8 mL/min, P = 0.012), with greater reductions during PKH. OEF remained unchanged during IH but increased significantly during PKH (+7.4 ± 9.3%, P = 0.016). CMRO₂ decreased during IH (−7.8 ± 11.9 mL/min, P = 0.048) but remained stable during PKH. These findings suggest that the reduction in PaCO₂ contributes to the modulation of cerebral hemodynamics and oxidative metabolism during hyperoxia.

Purpose: During abdominal surgery, manipulation of internal organs may induce a “mesenteric traction syndrome” (MTS) including a triad of flushing, hypotension, and tachycardia that lasts for approximately 30 min. We evaluated whether MTS affects internal carotid artery blood flow.Methods: This prospective cohort study included 27 patients aged 65 ± 11 years (mean ± SD) undergoing stomach resection (n = 12), esophageal resection (n = 14), or gastro-entero anastomosis (n = 1) during propofol-remifentanil and thoracic epidural anesthesia. Duplex ultrasound determined internal carotid artery blood flow, laser Doppler flowmetry assessed forehead skin blood flow, and near-infrared spectroscopy determined cerebral oxygenation. Development of MTS was defined by flushing within 60 min after incision.Results: Seven patients developed MTS 22 [20–26; median (IQR)] min after incision and at that time the change in heart rate (to 87 ± 13 vs. 70 ± 11 bpm; P = 0.0007) and skin blood flow (to 214 (134–269) vs. 84 (59-112 PU; P = 0.0044) was higher in the patients who developed MTS as compared to those who did not, while mean arterial pressure (63 ± 13 vs. 64 ± 14 mmHg; P = 0.1433), cerebral oxygenation (69 ± 9% vs. 63 ± 10%; P = 0.2485), and internal carotid artery flow (225 ± 53 vs. 203 ± 69 ml/min; P = 0.9529) were similar.Conclusion: Hemodynamic perturbations are observed in some patients in response to manipulation of the viscera, but the development of MTS appears not to influence internal carotid artery flow.Clinical trial registration: https://clinicaltrials.gov/ct2/show/NCT02951273?term=NCT02951273&rank=1, identifier: NCT02951273.

Exercise facilitates cerebral lactate uptake, likely by increasing arterial lactate concentration and hence the diffusion gradient across the blood brain barrier. However, non-specific β-adrenergic blockade by propranolol has previously reduced the arterio-jugular venous lactate difference (AV_Lac) during exercise, suggesting β-adrenergic control of cerebral lactate uptake. Alternatively, we hypothesize that propranolol reduces cerebral lactate uptake by decreasing arterial lactate concentration. To test that hypothesis, we evaluated cerebral lactate uptake taking changes in arterial concentration into account. Nine healthy males performed incremental cycling exercise to exhaustion with and without intravenous propranolol (18.7 ± 1.9 mg). Lactate concentration was determined in arterial and internal jugular venous blood at the end of each workload. To take changes in arterial lactate into account we calculated the fractional extraction (FE_Lac) defined as AV_Lac divided by the arterial lactate concentration. Arterial lactate concentration was reduced by propranolol at any workload (p-1 during maximal exercise without and with propranolol, respectively. While AV_Lac and FE_Lac increased during exercise (both p<0.05), they were both unaffected by propranolol at any workload (p=0.68 and p=0.26) or for any given arterial lactate concentration (p=0.78 and p=0.22). These findings support that, while propranolol may reduce cerebral lactate uptake, this effect reflects the propranolol-induced reduction in arterial lactate concentration and not inhibition of a β-adrenergic mechanism within the brain. We hence conclude that cerebral lactate uptake during exercise is directly driven by the increasing arterial concentration with work rate.

Hypoxia increases heart rate (HR) in humans by sympathetic activation and vagal withdrawal. However, in anaesthetized dogs hypoxia increases vagal activity and reduces HR if pulmonary ventilation does not increase and we evaluated whether that observation applies to awake humans. Ten healthy males were exposed to 15 min of normoxia and hypoxia (10.5% O ₂ ), while respiratory rate and tidal volume were volitionally controlled at values identified during spontaneous breathing in hypoxia. End-tidal CO ₂ tension was clamped at 40 mmHg by CO ₂ supplementation. β-Adrenergic blockade by intravenous propranolol isolated vagal regulation of HR. During spontaneous breathing, hypoxia increased ventilation by 3.2 ± 2.1 l/min ( P = 0.0033) and HR by 8.9 ± 5.5 beats/min ( P < 0.001). During controlled breathing, respiratory rate (16.3 ± 3.2 vs. 16.4 ± 3.3 breaths/min) and tidal volume (1.05 ± 0.27 vs. 1.06 ± 0.24 l) were similar for normoxia and hypoxia, whereas the HR increase in hypoxia persisted without (8.6 ± 10.2 beats/min) and with (6.6 ± 5.6 beats/min) propranolol. Neither controlled breathing ( P = 0.80), propranolol ( P = 0.64), nor their combination ( P = 0.89) affected the HR increase in hypoxia. Arterial pressure was unaffected ( P = 0.48) by hypoxia across conditions. The hypoxia-induced increase in HR during controlled breathing and β-adrenergic blockade indicates that hypoxia reduces vagal activity in humans even when ventilation does not increase. Vagal withdrawal in hypoxia seems to be governed by the arterial chemoreflex rather than a pulmonary inflation reflex in humans. NEW & NOTEWORTHY Hypoxia accelerates the heart rate of humans by increasing sympathetic activity and reducing vagal activity. Animal studies have indicated that hypoxia-induced vagal withdrawal is governed by a pulmonary inflation reflex that is activated by the increased pulmonary ventilation in hypoxia. The present findings, however, indicate that humans experience vagal withdrawal in hypoxia even if ventilation does not increase, indicating that vagal withdrawal is governed by the arterial chemoreflex rather than a pulmonary inflation reflex.

Endothelial dysfunction is observed in the peripheral vasculature of hypertensive patients, but it is unclear how the cerebral circulation is affected. More specifically, little is known about the impact of human hypertension on vertebral artery (VA) endothelial function. This study evaluated whether the endothelial function of the VA is impaired in hypertensive men. For 13 male hypertensive subjects (46 ± 3 yr) and eight age-matched male controls (46 ± 4 yr), blood pressure (BP; photoplethysmography), VA, and common carotid (CC) blood flow (duplex ultrasound) were determined at rest and during 30 min of intravenous l-arginine (30 g; a precursor of nitric oxide) or isotonic saline infusion. Controls and hypertensive subjects demonstrated a similar resting CC (601 ± 30 vs. controls 570 ± 43 ml/min; P = 0.529) and VA blood flow (119 ± 11 vs. controls 112 ± 9 ml/min; P = 0.878). During administration of l-arginine, CC blood flow increased similarly between groups (hypertensive 12 ± 3%, controls 13 ± 2%; P = 0.920). In contrast, the increase in VA blood flow was nonexistent in the hypertensive subjects (0.8 ± 3% vs. controls: 16 ± 4%; P = 0.015) with no significant change in BP. Both CC and VA flow returned to near-resting values within 30 min after the infusion, and for four hypertensive subjects and three controls, time-control experiments using 0.9% saline did not affect VA or CC blood flow significantly. The results demonstrate endothelial dysfunction in the posterior cerebral circulation of middle-aged hypertensive men.

Cardiac arrest carries a poor prognosis. The typical cardiac arrest patient is comorbid, and studies have shown that diabetes mellitus is an independent risk factor for increased mortality after cardiac arrest. Despite this, animal studies lack to investigate cardiac arrest in the setting of diabetes mellitus. We hypothesize that type 2 diabetes mellitus in a rat model of cardiac arrest is associated with increased organ dysfunction when compared with non-diabetic rats. Zucker diabetic fatty (ZDF) rats (n = 13), non-diabetic Zucker lean control (ZLC) rats (n = 15), and non-diabetic Sprague Dawley (SprD) rats (n = 8), underwent asphyxia-induced cardiac arrest. Animals were resuscitated and monitored for 180 min after return of spontaneous circulation (ROSC). Blood levels of neuron-specific enolase were measured to assess neurological injury. Cardiac function was evaluated by echocardiography. No differences in cardiac output or neuron-specific enolase existed between the groups at baseline. Median levels of neuron-specific enolase 180 min after ROSC was 10.8 μg/L (Q25;Q75—7.6;11.3) in the ZDF group, which was significantly higher compared to the ZLC group at 2.0 μg/L (Q25;Q75—1.7;2.3, p < 0.05) and the SprD group at 2.8 μg/L (Q25;Q75—2.3;3.4, p < 0.05). At 180 min after ROSC, cardiac output was 129 mL/min/kg (SD 45) in the ZDF group, which was not different from 106 mL/min/kg (SD 31) in the ZLC group or 123 mL/min/kg (SD 26, p = 0.72) in the SprD group. In a cardiac arrest model, neuronal injury is increased in type 2 diabetes mellitus animals compared with non-diabetic controls. Although this study lacks to uncover the specific mechanisms causing increased neuronal injury, the establishment of a cardiac arrest model of type 2 diabetes mellitus lays the important foundation for further experimental investigations within this field.

Sympathetic vasoconstriction is blunted in exercising muscle (functional sympatholysis) but becomes attenuated with age. We tested the hypothesis that functional sympatholysis is further impaired in chronic obstructive pulmonary disease (COPD) patients. We determined leg blood flow and calculated leg vascular conductance (LVC) during 1) femoral-arterial Tyramine infusion (evokes endogenous norepinephrine release, 1 µmol·min⁻¹·kg leg mass⁻¹), 2) one-legged knee extensor exercise with and without Tyramine infusion [10 W and 20% of maximal workload (WL_max)], 3) ATP (0.05 µmol·min⁻¹·kg leg mass⁻¹) and Tyramine infusion, and 4) incremental ATP infusions (0.05, 0.3, and 3.0 µmol·min⁻¹·kg leg mass⁻¹). We included 10 patients with moderate to severe COPD and 8 age-matched healthy control subjects. Overall, leg blood flow and LVC were lower in COPD patients during exercise ( P < 0.05). Tyramine reduced LVC in both groups at 10-W exercise (COPD: −3 ± 1 ml·min⁻¹·mmHg⁻¹and controls: −3 ± 1 ml·min⁻¹·mmHg⁻¹, P < 0.05) and 20% WL_max(COPD: −4 ± 1 ml·min⁻¹·mmHg⁻¹and controls: −3 ± 1 ml·min⁻¹·mmHg⁻¹, P < 0.05) with no difference between groups. Incremental ATP infusions induced dose-dependent vasodilation with no difference between groups, and, in addition, the vasoconstrictor response to Tyramine infused together with ATP was not different between groups (COPD: −0.03 ± 0.01 l·min⁻¹·kg leg mass⁻¹vs. controls: −0.04 ± 0.01 l·min⁻¹·kg leg mass⁻¹, P > 0.05). Compared with age-matched healthy control subjects, the vasodilatory response to ATP is intact in COPD patients and their ability to blunt sympathetic vasoconstriction (functional sympatholysis) as evaluated by intra-arterial Tyramine during exercise or ATP infusion is maintained.NEW & NOTEWORTHY The ability to blunt sympathetic vasoconstriction in exercising muscle and ATP-induced dilation in chronic obstructive pulmonary disease patients remains unexplored. Chronic obstructive pulmonary disease patients demonstrated similar sympathetic vasoconstriction in response to intra-arterial Tyramine during exercise and ATP-induced vasodilation compared with age-matched healthy control subjects.