James D. Anholm

DYNAMICS OF PERIODIC BREATHING AND AROUSAL DURING SLEEP AT EXTREME ALTITUDE

To determine whether nocturnal periodic breathing (PB) at altitude is due primarily to unstable control of ventilation or the inability to maintain stable sleep states, we performed visual and computer analyses of the electroencephalographic and respiratory records of healthy volunteers at simulated altitudes of 4572, 6100 and 7620 m. Transient arousals were associated with < 52% of the apneas identified; thus, the PB cycle was not always associated with transient arousal. Following the termination of oxygen breathing, the reinitiation of PB was not dependent on the occurrence of arousal as the primary event. The transition from apnea to breathing preceded the appearance of arousal by approximately 1 to 4 sec. Ventilatory drive in the breaths immediately following arousal was significantly larger than corresponding control breaths, matched for SaO2. Our findings suggest that altitude-induced PB is unlikely to result from primary fluctuations in state. Arousals promote the development of PB with apnea and help to sustain these episodes, but are not necessary for their initiation.

Sleep and Breathing at High Altitude.

Sleep at high altitude is characterized by poor subjective quality, increased awakenings, frequent brief arousals, marked nocturnal hypoxemia, and periodic breathing. A change in sleep architecture with an increase in light sleep and decreasing slow-wave and REM sleep have been demonstrated. Periodic breathing with central apnea is almost universally seen amongst sojourners to high altitude, although it is far less common in long-standing high altitude dwellers. Hypobaric hypoxia in concert with periodic breathing appears to be the principal cause of sleep disruption at altitude. Increased sleep fragmentation accounts for the poor sleep quality and may account for some of the worsened daytime performance at high altitude. Hypoxic sleep disruption contributes to the symptoms of acute mountain sickness. Hypoxemia at high altitude is most severe during sleep. Acetazolamide improves sleep, AMS symptoms, and hypoxemia at high altitude. Low doses of a short acting benzodiazepine (temazepam) may also be useful in improving sleep in high altitude.

Ischemic preconditioning of the lower extremity attenuates the normal hypoxic increase in pulmonary artery systolic pressure.

Ischemic pre-condition of an extremity (IPC) induces effects on local and remote tissues that are protective against ischemic injury. To test the effects of IPC on the normal hypoxic increase in pulmonary pressures and exercise performance, 8 amateur cyclists were evaluated under normoxia and hypoxia (13% F(I)O(2)) in a randomized cross-over trial. IPC was induced using an arterial occlusive cuff to one thigh for 5 min followed by deflation for 5 min for 4 cycles. In the control condition, the resting pulmonary artery systolic pressure (PASP) increased from a normoxic value of 25.6±2.3 mmHg to 41.8±7.2 mmHg following 90 min of hypoxia. In the IPC condition, the PASP increased to only 32.4±3.1 mmHg following hypoxia, representing a 72.8% attenuation (p=0.003). No significant difference was detected in cycle ergometer time trial duration between control and IPC conditions with either normoxia or hypoxia. IPC administered prior to hypoxic exposure was associated with profound attenuation of the normal hypoxic increase of pulmonary artery systolic pressure.

Prophylactic bosentan does not improve exercise capacity or lower pulmonary artery systolic pressure at high altitude

Hypoxic pulmonary vasoconstriction in response to high altitude ascent may contribute to decreased exercise capacity. Endothelin receptor antagonists reduce pulmonary artery pressure and improve exercise capacity in patients with pulmonary arterial hypertension, but their effects on exercise capacity at altitude are unknown. We studied the efficacy of bosentan started 5 days prior to ascent on exercise capacity and pulmonary artery systolic pressure (PASP) at 3800 m altitude. Eight healthy subjects completed a double-blinded, randomized, placebo-controlled, crossover study. The end-points were time to complete a cycle ergometer time trial, PASP, and hemoglobin oxygen saturation (SpO2). The time to complete the time trial at altitude in subjects on placebo and bosentan was 527+/-159 and 525+/-156 s respectively (P=0.90). PASP was not different on bosentan compared with placebo. Mean SpO2 during the altitude time trial was lower in subjects taking bosentan compared to placebo (78+/-6 vs. 85+/-8% respectively, P=0.03). Bosentan initiated 5 days prior to ascent to high altitude did not improve exercise capacity or reduce PASP, and worsened SpO2 during high intensity exercise at altitude.

Con: Hypoxic pulmonary vasoconstriction is not a limiting factor of exercise at high altitude.

Ascent to altitude uniformly reduces exercise capacity. Even following acclimatization, maximal oxygen consumption (VO2max) remains well below sea level values (Calbet et al, 2003b; Fulco et al, 1998). The factors responsible for limiting exercise capacity and performance have spawned considerable research and debate over the last 30–40 years (Calbet et al, 2003a; 2003b; Calbet et al, 2009; Cerretelli 1976; Dill and Adams 1971; Dill et al, 1967; Lundby and Damsgaard 2006; Lundby et al, 2006; Naeije 2010; Wagner 1996; 2000a; 2000b; 2010). With acute exposure to altitudes below *4000 m, the reduction in VO2max is largely due to decreased arterial oxygen content (CaO2) related to hemoglobin oxygen desaturation (Calbet et al, 2003a). Above *4000m VO2max is reduced more than can be explained by changes in CaO2. Calbet et al. attribute this additional reduction to a combination of impaired gas exchange in the lungs, reduced maximal cardiac output, and a reduction in maximal leg blood flow (Calbet et al, 2003a; Calbet et al, 2009). At sea level, improving oxygen delivery to working muscles results in a higher VO2max (Audran et al, 1999; Birkeland et al, 2000; Ekblom and Berglund 1991; Robach et al, 2008; Russell et al, 2002). At altitude, the factors limiting exercise performance appear to be different from those at lower elevations, leading several authors to suggest that reducing hypoxic pulmonary vasoconstriction (HPV) improves exercise performance (Faoro et al, 2009; Ghofrani et al, 2004; Naeije et al, 2010). The argument follows the intuitive premise that lowering pulmonary artery pressure (PAP) by decreasing pulmonary vascular resistance (PVR) will reduce RV afterload, allowing higher maximal cardiac output. Since output from the left and right ventricles is coupled, it is postulated that elevated RV afterload will significantly limit left ventricular cardiac output. The focus of this debate is two-fold: 1) do changes in right ventricular (RV) afterload have a significant influence on maximal cardiac output? and 2) are the observed improvements in exercise performance at altitude after pulmonary vasodilators due to an increased cardiac output? For the current debate, we will limit our discussion to normal, healthy individuals either acutely or chronically hypoxic. These subjects would have a normal HPV response to altitude. Subjects with exaggerated HPV, as seen in individuals susceptible to high altitude pulmonary edema (HAPE), will only be briefly mentioned. We propose that reduction of PAP in healthy subjects at high altitude (above*4000 m) does not impact exercise performance or improve VO2max. Four lines of evidence for this argument are evaluated, namely: 1) altitude modeling studies indicate that substantial changes in cardiac output produce minimal effects on VO2max, 2) breathing supplemental oxygen at altitude restores working capacity to normal sea level values without normalizing PVR, 3) individuals with elevated PAP at altitude have similar VO2max values as compared to those with lower PVR, and 4) improved oxygen saturation and other mechanisms, not lower PAP, are primarily responsible for improved exercise performance following pulmonary vasodilator treatments. Each line of evidence is expanded upon below.

The effect of α1 -adrenergic blockade on post-exercise brachial artery flow-mediated dilatation at sea level and high altitude.

Our objective was to quantify endothelial function (via brachial artery flow‐mediated dilatation) at sea level (344 m) and high altitude (3800 m) at rest and following both maximal exercise and 30 min of moderate‐intensity cycling exercise with and without administration of an α1‐adrenergic blockade. Brachial endothelial function did not differ between sea level and high altitude at rest, nor following maximal exercise. At sea level, endothelial function decreased following 30 min of moderate‐intensity exercise, and this decrease was abolished with α1‐adrenergic blockade. At high altitude, endothelial function did not decrease immediately after 30 min of moderate‐intensity exercise, and administration of α1‐adrenergic blockade resulted in an increase in flow‐mediated dilatation. Our data indicate that post‐exercise endothelial function is modified at high altitude (i.e. prolonged hypoxaemia). The current study helps to elucidate the physiological mechanisms associated with high‐altitude acclimatization, and provides insight into the relationship between sympathetic nervous activity and vascular endothelial function.

Adenosine receptor-dependent signaling is not obligatory for normobaric and hypobaric hypoxia-induced cerebral vasodilation in humans

Hypoxia increases cerebral blood flow (CBF) with the underlying signaling processes potentially including adenosine. A randomized, double-blinded, and placebo-controlled design, was implemented to determine if adenosine receptor antagonism (theophylline, 3.75 mg/Kg) would reduce the CBF response to normobaric and hypobaric hypoxia. In 12 participants the partial pressures of end-tidal oxygen ([Formula: see text]) and carbon dioxide ([Formula: see text]), ventilation (pneumotachography), blood pressure (finger photoplethysmography), heart rate (electrocardiogram), CBF (duplex ultrasound), and intracranial blood velocities (transcranial Doppler ultrasound) were measured during 5-min stages of isocapnic hypoxia at sea level (98, 90, 80, and 70% [Formula: see text]). Ventilation, [Formula: see text] and [Formula: see text], blood pressure, heart rate, and CBF were also measured upon exposure (128 ± 31 min following arrival) to high altitude (3,800 m) and 6 h following theophylline administration. At sea level, although the CBF response to hypoxia was unaltered pre- and postplacebo, it was reduced following theophylline (P < 0.01), a finding explained by a lower [Formula: see text] (P < 0.01). Upon mathematical correction for [Formula: see text], the CBF response to hypoxia was unaltered following theophylline. Cerebrovascular reactivity to hypoxia (i.e., response slope) was not different between trials, irrespective of [Formula: see text] At high altitude, theophylline (n = 6) had no effect on CBF compared with placebo (n = 6) when end-tidal gases were comparable (P > 0.05). We conclude that adenosine receptor-dependent signaling is not obligatory for cerebral hypoxic vasodilation in humans.NEW & NOTEWORTHY The signaling pathways that regulate human cerebral blood flow in hypoxia remain poorly understood. Using a randomized, double-blinded, and placebo-controlled study design, we determined that adenosine receptor-dependent signaling is not obligatory for the regulation of human cerebral blood flow at sea level; these findings also extend to high altitude.

One session of remote ischemic preconditioning does not improve vascular function in acute normobaric and chronic hypobaric hypoxia

What is the central question of this study? It is suggested that remote ischemic preconditioning (RIPC) might offer protection against ischaemia–reperfusion injuries, but the utility of RIPC in high‐altitude settings remains unclear. What is the main finding and its importance? We found that RIPC offers no vascular protection relative to pulmonary artery pressure or peripheral endothelial function during acute, normobaric hypoxia and at high altitude in young, healthy adults. However, peripheral chemosensitivity was heightened 24 h after RIPC at high altitude.

The independent effects of hypovolaemia and pulmonary vasoconstriction on ventricular function and exercise capacity during acclimatisation to 3800 m

We sought to determine the isolated and combined influence of hypovolaemia and hypoxic pulmonary vasoconstriction on the decrease in left ventricular (LV) function and maximal exercise capacity observed under hypobaric hypoxia. We performed echocardiography and maximal exercise tests at sea level (344 m), and following 5–10 days at the Barcroft Laboratory (3800 m; White Mountain, California) with and without (i) plasma volume expansion to sea level values and (ii) administration of the pulmonary vasodilatator sildenafil in a double‐blinded and placebo‐controlled trial. The high altitude‐induced reduction in LV filling and ejection was abolished by plasma volume expansion but to a lesser extent by sildenafil administration; however, neither intervention had a positive effect on maximal exercise capacity. Both hypovolaemia and hypoxic pulmonary vasoconstriction play a role in the reduction of LV filling at 3800 m, but the increase in LV filling does not influence exercise capacity at this moderate altitude.

A multi-center evaluation of a disposable catheter to aid in correct positioning of the endotracheal tube after intubation in critically ill patients

Purpose: To demonstrate that use of a minimally invasive catheter reduces endotracheal tube (ETT) malposition rate after intubation. Materials and methods: This study is a multi‐center, prospective observational cohort of intubated patients in the medical intensive care unit. The catheter was inserted into the ETT immediately after intubation. The ETT was adjusted accordingly based on qualitative color markers on the catheter. A confirmatory chest radiograph was obtained to determine the ETT position. Malposition of the ETT was defined by the distal ETT not being within 2–5 cm above the carina. Results: Sixty‐nine patients were enrolled, age 56.2 ± 19.5 years, body mass index 31.0 ± 13.8 kg/m2. The catheter prompted repositioning of the ETT in 39 (56.5%) patients. Using the catheter, the rate of malposition decreased to 7.2%, with the distal ETT position at 3.7 ± 1.2 cm above the carina. Without the catheter, the ETT malposition rate would have been 39.1%. The time for catheter use and chest radiograph completion at our institutions was 1.7 ± 1.5 and 44.4 ± 36.4 min, respectively. Conclusions: With use of an ETT positioning catheter after intubation, the ETT malposition rate was reduced by 82%. This catheter‐based system was safe, and its use may perhaps decrease the need for the post‐intubation chest radiograph.