Conduit artery structure and function in lowlanders and native highlanders: relationships with oxidative stress and role of sympathoexcitation

Research detailing the normal vascular adaptions to high altitude is minimal and often confounded by pathology (e.g. chronic mountain sickness) and methodological issues. We examined vascular function and structure in: (1) healthy lowlanders during acute hypoxia and prolonged ( 2 weeks) exposure to high altitude, and (2) high-altitude natives at 5050 m (highlanders). In 12 healthy lowlanders (aged 32 ± 7 years) and 12 highlanders(Sherpa; 33 ± 14 years) we assessed brachial endothelium-dependent flow-mediated dilatation(FMD), endothelium-independent dilatation (via glyceryl trinitrate; GTN), common carotid intima–media thickness (CIMT) and diameter (ultrasound), and arterial stiffness via pulse wave velocity (PWV; applanation tonometry). Cephalic venous biomarkers of free radical-mediated lipid peroxidation (lipid hydroperoxides, LOOH), nitrite (NO2 –) and lipid soluble antioxidants were also obtained at rest. In lowlanders, measurements were performed at sea level (334 m) and between days 3–4 (acute high altitude) and 12–14 (chronic high altitude) following arrival to 5050 m. Highlanders were assessed once at 5050 m. Compared with sea level, acute high altitude reduced lowlanders’ FMD (7.9 ± 0.4 vs. 6.8 ± 0.4%; P = 0.004) and GTN-induced dilatation (16.6 ± 0.9 vs. 14.5 ± 0.8%; P = 0.006), and raised central PWV (6.0 ± 0.2 vs. 6.6 ± 0.3 m s−1; P = 0.001). These changes persisted at days 12–14, and after allometricallyscaling FMD to adjust for altered baseline diameter. Compared to lowlanders at sea level and high altitude, highlanders had a lower carotid wall:lumen ratio ( 19%, P 0.04), attributable to a narrower CIMT and wider lumen. Although both LOOH and NO2 – increased with high altitude in lowlanders, only LOOH correlated with the reduction in GTN-induced dilatation evident during acute (n = 11, r=−0.53) and chronic (n = 7, r=−0.69; P 0.01) exposure to 5050 m. In a follow-up, placebo-controlled experiment (n=11 healthy lowlanders) conducted in a normobaric hypoxic chamber (inspiredO2 fraction (FIO2 )=0.11; 6 h), a sustained reduction in FMD was evident within 1 h of hypoxic exposure when compared to normoxic baseline (5.7±1.6 vs. 8.0 ±1.3%; P < 0.01); this decline in FMD was largely reversed following α1-adrenoreceptor blockade. In conclusion, high-altitude exposure in lowlanders caused persistent impairment in vascular function, which was mediated partially via oxidative stress and sympathoexcitation. Although a lifetime of high-altitude exposure neither intensifies nor attenuates the impairments seen with short-term exposure, chronic high-altitude exposure appears to be associated with arterial remodelling

Loop gain response to increased cerebral blood flow at high altitude

PURPOSE: To compare loop gain (LG) before and during pharmacological increases in cerebral blood flow (CBF) at high altitude (HA). Loop gain (LG) describes stability of a negative-feedback control system; defining the magnitude of response to a disturbance, such as hyperpnea to an apnea in periodic breathing (PB). "Controller-gain" sensitivity from afferent peripheral (PCR) and central-chemoreceptors (CCR) plays a key role in perpetuating PB. Changes in CBF may have a critical role via effects on central chemo-sensitivity during sleep.METHODS: Polysomnography (PSG) was performed on volunteers after administration of I.V. Acetazolamide (ACZ-10mg/kg) + Dobutamine (DOB-2-5 μg/kg/min) to increase CBF (via Duplex-ultrasound). Central sleep apnea (CSA) was measured from NREM sleep. The duty ratio (DR) was calculated as ventilatory duration (s) divided by cycle duration (s) (hyperpnea/hyperpnea + apnea), LG = 2π/(2πDR-sin2πDR).RESULTS: A total of 11 volunteers were studied. Compared to placebo-control, ACZ/DOB showed a significant increase in the DR (0.79 ± 0.21 vs 0.52 ± 0.03, P = 0.002) and reduction in LG (1.90 ± 0.23 vs 1.29 ± 0.35, P = 0.0004). ACZ/DOB increased cardiac output (CO) (8.19 ± 2.06 vs 6.58 ± 1.56L/min, P = 0.02) and CBF (718 ± 120 vs 526 ± 110ml/min, P &lt; 0.001). There was no significant change in arterial blood gases, minute ventilation (VE), or hypoxic ventilatory response (HVR). However, there was a reduction of hypercapnic ventilatory response (HCVR) by 29% (5.9 ± 2.7 vs 4.2 ± 2.8 L/min, P = 0.1).CONCLUSION: Pharmacological elevation in CBF significantly reduced LG and severity of CSA. We speculate the effect was on HCVR "controller gain," rather than "plant gain," because PaCO 2 and VE were unchanged. An effect via reduced circulation time is unlikely, as the respiratory-cycle length did not change. </p

Loop gain response to increased cerebral blood flow at high altitude

PURPOSE: To compare loop gain (LG) before and during pharmacological increases in cerebral blood flow (CBF) at high altitude (HA). Loop gain (LG) describes stability of a negative-feedback control system; defining the magnitude of response to a disturbance, such as hyperpnea to an apnea in periodic breathing (PB). "Controller-gain" sensitivity from afferent peripheral (PCR) and central-chemoreceptors (CCR) plays a key role in perpetuating PB. Changes in CBF may have a critical role via effects on central chemo-sensitivity during sleep.METHODS: Polysomnography (PSG) was performed on volunteers after administration of I.V. Acetazolamide (ACZ-10mg/kg) + Dobutamine (DOB-2-5 μg/kg/min) to increase CBF (via Duplex-ultrasound). Central sleep apnea (CSA) was measured from NREM sleep. The duty ratio (DR) was calculated as ventilatory duration (s) divided by cycle duration (s) (hyperpnea/hyperpnea + apnea), LG = 2π/(2πDR-sin2πDR).RESULTS: A total of 11 volunteers were studied. Compared to placebo-control, ACZ/DOB showed a significant increase in the DR (0.79 ± 0.21 vs 0.52 ± 0.03, P = 0.002) and reduction in LG (1.90 ± 0.23 vs 1.29 ± 0.35, P = 0.0004). ACZ/DOB increased cardiac output (CO) (8.19 ± 2.06 vs 6.58 ± 1.56L/min, P = 0.02) and CBF (718 ± 120 vs 526 ± 110ml/min, P &lt; 0.001). There was no significant change in arterial blood gases, minute ventilation (VE), or hypoxic ventilatory response (HVR). However, there was a reduction of hypercapnic ventilatory response (HCVR) by 29% (5.9 ± 2.7 vs 4.2 ± 2.8 L/min, P = 0.1).CONCLUSION: Pharmacological elevation in CBF significantly reduced LG and severity of CSA. We speculate the effect was on HCVR "controller gain," rather than "plant gain," because PaCO 2 and VE were unchanged. An effect via reduced circulation time is unlikely, as the respiratory-cycle length did not change. </p

Increasing cerebral blood flow reduces the severity of central sleep apnea at high altitude

Earlier studies have indicated an important role for cerebral blood flow in the pathophysiology of central sleep apnea (CSA) at high altitude, but were not decisive. To test the hypothesis that pharmacologically altering cerebral blood flow (CBF) without altering arterial blood gas (ABGs) values would alter the severity of CSA at high altitude, we studied 11 healthy volunteers. (8M, 3F; 31{plus minus}7 years) in a randomized placebo-controlled single-blind study at 5,050 metres in Nepal. CBF was increased by intravenous (iv) acetazolamide (Az; 10mg/kg) plus iv dobutamine (Dob) infusion (2-5 ug/kg/min) and reduced by oral indomethacin (Indo; 100mg). ABG samples were collected and ventilatory responses to hypercapnia (HCVR) and hypoxia (HVR) were measured by rebreathing and steady-state techniques before and after drug/placebo. Duplex ultrasound of blood flow in the internal carotid and vertebral arteries was used to measure global CBF. The initial 3-4 hours of sleep were recorded by full polysomnography. Iv Az+Dob increased global CBF by 37{plus minus}15% compared to placebo (P&lt;0.001), whereas it was reduced by 21{plus minus}8% by oral Indo (P&lt;0.001). ABGs and HVR were unchanged in both interventions. HCVR was reduced by 28%{plus minus}43% (P=0.1) during iv Az{plus minus}Dob administration and was elevated by 23%{plus minus}30% (P=0.05) by Indomethacin. During iv Az+Dob, the CSA index fell from 140{plus minus}45 (control night) to 48{plus minus}37 events/hour of sleep (P&lt;0.001). Oral Indo had no significant effect on CSA. We conclude that increasing cerebral blood flow reduced the severity of CSA at high altitude; the likely mechanism is via a reduction in the background stimulation of central chemoreceptors.</p

Transition to active learning in rural Nepal: an adaptable and scalable curriculum development model

International audienceBackgroundTraditional medical education in much of the world has historically relied on passive learning. Although active learning has been in the medical education literature for decades, its incorporation into practice has been inconsistent. We describe and analyze the implementation of a multidisciplinary continuing medical education curriculum in a rural Nepali district hospital, for which a core objective was an organizational shift towards active learning.MethodsThe intervention occurred in a district hospital in remote Nepal, staffed primarily by mid-level providers. Before the intervention, education sessions included traditional didactics. We conducted a mixed-methods needs assessment to determine the content and educational strategies for a revised curriculum. Our goal was to develop an effective, relevant, and acceptable curriculum, which could facilitate active learning. As part of the intervention, physicians acted as both learners and teachers by creating and delivering lectures. Presenters used lecture templates to prioritize clarity, relevance, and audience engagement, including discussion questions and clinical cases. Two 6-month curricular cycles were completed during the study period. Daily lecture evaluations assessed ease of understanding, relevance, clinical practice change, and participation. Periodic lecture audits recorded learner talk-time, the proportion of lecture time during which learners were talking, as a surrogate for active learning. Feedback from evaluation and audit results was provided to presenters, and pre- and post-curriculum knowledge assessment exams were conducted.ResultsLecture audits showed a significant increase in learner talk-time, from 14% at baseline to 30% between months 3–6, maintained at 31% through months 6–12. Lecture evaluations demonstrated satisfaction with the curriculum. Pre- and post-curriculum knowledge assessment scores improved from 50 to 64% (difference 13.3% ± 4.5%, p = 0.006). As an outcome for the measure of organizational change, the curriculum was replicated at an additional clinical site.ConclusionWe demonstrate that active learning can be facilitated by implementing a new educational strategy. Lecture audits proved useful for internal program improvement. The components of the intervention which are transferable to other rural settings include the use of learners as teachers, lecture templates, and provision of immediate feedback. This curricular model could be adapted to similar settings in Nepal, and globally