Normoxic Baseline Research Articles

Influence of tramadol on the ventilatory response to hypoxia in humans

We studied the effect of tramadol on the ventilatory response to 7 min acute isocapnic hypoxia (SpO2 85.1 (SD 0.4)%) during steady mild hypercapnia (PE'CO2 0.7 kPa above normoxic baseline) in 14 healthy volunteers (seven male). The acute hypoxic response was measured before and 1 h after oral placebo or tramadol (100 mg). After tramadol, ventilation during mild hypercapnia (mean 11.28 litres min-1) was significantly less (P < 0.05) than during placebo baseline (13.93 litres min-1), tramadol baseline (14.63 litres min-1), or after placebo (14.95 litres min-1), confirming that tramadol has a small depressive effect on the hypercapnic ventilatory response. There was no significant difference in the hypoxic ventilation/SpO2 response (1 min-1 %-1) measured during the placebo baseline (0.99), placebo (1.18), tramadol baseline (0.78) or tramadol (0.68) runs. These data suggest that tramadol does not depress the hypoxic ventilatory response.

Pulmonary expression of early growth response-1: biphasic time course and effect of oxygen concentration.

Hypoxia induces complex adaptive responses. In this report, induction of early growth response-1 (Egr-1) transcripts in lungs of mice subjected to hypoxia is shown to be dose and time dependent. Within 30 min of hypoxia, Egr-1 transcripts were approximately 20-fold elevated in 6% oxygen, approximately 5.2-fold increased by 10% oxygen, and returned to the normoxic baseline by 12% oxygen. Time course studies up to 48 h showed a biphasic profile with an initial steep rise in Egr-1 transcripts after 0.5 h of hypoxia and a second elevation beginning after 20-24 h. Hypoxic induction of Egr-1 was paralleled by enhanced expression of the downstream target gene tissue factor. Egr-1 and tissue factor antigen were visualized in bronchial and vascular smooth muscle and in alveolar macrophages. Egr-1 has the capacity to modulate expression of genes involved in the remodeling of the extracellular matrix and properties of smooth muscle, thus possibly contributing to the pulmonary response to chronic hypoxia.

Changes in pulmonary vascular resistance in response to partial liquid ventilation

Background/Purpose: Partial liquid ventilation (PLV) with perfluorocarbons decreases pulmonary vascular resistance (PVR) in injured piglet lungs without supplemental oxygen. These PVR changes may result either from direct mechanical effects or improved arterial oxygenation. In an uninjured hypoxic model of elevated PVR the authors asked the following questions: (1) Does prophylactic or therapeutic PLV ameliorate the PVR response to hypoxia? (2) Do prophylactic and therapeutic PLV have different PVR effects? (3) Does supplemental oxygen modify PVR response to PLV? Methods: Piglet (3 to 4 kg) lungs were isolated in situ without ischemia, hypoxia, or reperfusion injury. Pulmonary artery (PA) and left atrial (LA) cannulae were attached to a bloodprimed extracorporeal membrane oxygenation (ECMO) perfusion circuit with a flow (Q PA) of 80 mL/kg/min. Pressure-limited, volume-cycled ventilation (PIP < 25 mm Hg, T v = 15 mL/kg) was initiated. PLV with perfluorodecalin (15 mL/kg) was administered endotracheally. Continuously monitored blood gas parameters allowed airway and extracorporeal adjustment of Fio 2 to produce a Po 2 appropriate to the experimental phase. PVR was calculated as ( P PA−P LA Q PA ). After a stable 30-minute normoxic baseline, animals were assigned randomly to three groups. In group I, control (n = 7), PVR was measured for 150 minutes in hypoxic lungs ( Fio 2 = 0.07, P PAo 2 = 40 mm Hg, S PAo 2 = 70%). In group II, prophylactic (n = 8), PLV was administered, followed by 90 minutes of hypoxia, and 60 minutes of oxygen recovery ( Fio 2 = 0.21 – 0.30, P PAo 2 > 100 mm Hg, S PAo 2 = 100%). In group III, therapeutic (n = 8), after 30 hypoxic minutes, PLV was administered and maintained for 90 minutes, followed by a 60-minute oxygen recovery phase. Results were expressed as mean ± SEM. Statistical analysis of groups was performed by repeated measures of analysis of variance (ANOVA) and Tukey correction. Results: In group I normoxic gas-ventilated PVR was 174 ± 12 mm Hg/L/kg/min. After 90 hypoxic minutes PVR was 318 ± 37 ( P < .01 v baseline). In group II baseline PVR was 183 ± 14. PVR after 30 normoxic minutes of PLV was 199 ± 14 ( P = ns v baseline). After 90 hypoxic minutes, PVR was 350 ± 31 ( P < .01 v baseline, and PLV alone) followed by a decrease to 192 ± 19 after 60 minutes of oxygen recovery ( P = ns v baseline or PLV alone). In group III baseline PVR was 160 ± 17 and 325 ± 29 after 30 hypoxic minutes. After 90 hypoxic minutes of PLV, PVR was 366 ± 22 ( P = ns v hypoxia control, P < .01 v normoxic baseline). PVR recovered to 189 ± 19 after 60 minutes of oxygen recovery ( P = ns v baseline). Conclusions: Prophylactic/therapeutic PLV had no effect on hypoxia-induced increases in PVR and did not differ from each other. Although PLV alone decreases PVR in the injured lung without supplemental oxygen, elevated PVR associated with hypoxia was ameliorated only by supplemental oxygen in the liquid ventilated lung.

Influence of age on the sympathetic neural adjustments to alterations in systemic oxygen levels in humans.

We tested the hypothesis that aging influences the regulation of sympathetic nervous system activity (SNA) and arterial blood pressure during alterations in systemic O2 levels in humans. To accomplish this, we performed direct (intraneural) measurements of SNA to skeletal muscle (MSNA) in 10 young and 7 older healthy normotensive men during room air breathing (normoxic-control), moderate isocapnic hypoxemia [15 min of 10% fractional inspired O2 (FIO2)], and hyperoxemia (10 min of 50% FIO2). After hypoxemia, arterial O2 saturation (SaO2) declined similarly in the young and older men. MSNA (burst frequency and total minute activity) increased significantly (P < 0.05) in both groups. The magnitudes of the absolute increases in MSNA and the delta MSNA/delta SaO2 were not significantly different in the young and older men; however, because of higher normoxic baseline levels, the percentage increases in burst frequency were smaller (P = 0.02) and those for total minute activity tended to be smaller (P = 0.11) in the older men. Arterial blood pressure increased modestly (P < 0.05) and similarly in both groups, although the older men demonstrated a smaller increase in heart rate. After hyperoxemia [corrected], SaO2 increased and MSNA decreased (both P < 0.05) similarly in the young and older men. Arterial blood pressure did not change significantly from normoxic control levels in either group; however, a small (P < 0.05) reduction in heart rate was observed in both groups. In conclusion, aging does not obviously influence the regulation of absolute levels of MSNA or arterial blood pressure during alterations in systemic O2 levels in healthy men, although older men demonstrate a smaller percentage increase in MSNA from their elevated baseline levels, as well as an attenuated tachycardia in response to acute hypoxemia. As such, the present results are consistent with our previous findings on aging and sympathocirculatory control during other types of acute stress in humans.

Slow ventilatory dynamics after isocapnic hypoxia and voluntary hyperventilation in humans: effects of isoflurane

Short-term potentiation (STP) of breathing refers to respiratory activity that persists at termination of a primary stimulus and is not related just to the dynamics of chemoreceptors. In humans, STP is activated by brief episodes of hypoxia and voluntary hyperventilation (VHV). STP exerts a stabilizing influence on breathing pattern. To investigate the effects of a subanaesthetic concentration of isoflurane on STP, we studied recovery from mild and moderate hypoxic hyperpnoea and VHV. Experiments were performed in eight healthy volunteers. If necessary, subjects were aroused to maintain a state of wakefulness. In the hypoxic studies, a control study involved 1 min of isocapnic hypoxia (end-tidal PO2 (PE'O2 6.1) kPa) followed by sudden transition to normoxia. In the isoflurane studies, 1 min of mild hypoxia (Iso-1 study: PE'O2 6.2 kPa) and 1 min of moderate hypoxia (Iso-2 study: PE'O2 5.7 kPa) were followed by sudden transition to normoxia during inhalation of 0.1 minimum alveolar concentration (MAC) of isoflurane. PE'CO2 was maintained at 5.9 kPa. In the VHV study, ventilatory recovery from 1 min of normoxic VHV was monitored before and during inhalation of 0.1 MAC of isoflurane. Subjects performed multiple transitions in each study. In the hypoxic studies, peak ventilation after 1 min of hypoxic stimulation did not differ between treatments. The averaged responses reached normoxic baseline after 56.3 (SEM 10.7) s in the control study (n = 47 transitions), 18.0 (3.3) s in the Iso-1 study (n = 41; P < 0.05 vs control) and 15.3 (2.4) s in the Iso-2 study (n = 23; P < 0.05 vs control). In the VHV studies, VE at termination of VHV was not different from baseline after 36 s in the control study. An immediate reduction to less than baseline ventilation, lasting 24 s, was present in the isoflurane study. We believe that shortening of the time required to reach baseline in the hypoxic studies, and hypoventilation at cessation of VHV in the isoflurane studies, are related to the inability to activate STP of breathing via an effect of isoflurane on respiratory neurones in the brain stem. Increasing the stimulus intensity during isoflurane inhalation (Iso-2 study) did not (re)-activate STP.

Endogenous nitric oxide and pulmonary vascular tone in the neonate

Purpose: In newborns, inhaled nitric oxide (NO) has been shown to ameliorate increased pulmonary vascular resistance (PVR) precipitated by hypoxia. The role of endogenous NO production in this response is not clear. The contribution of endogenous NO to resting PVR in normoxic newborns also has not been well studied. The authors used an isolated, in situ, neonatal piglet lung-perfusion model, devoid of systemic detractors in which endogenous NO could be selectively inhibited, to determine whether (1) endogenous NO plays a role in the maintenance of PVR with normoxia, (2) endogenous NO plays a role in the response to hypoxia, and (c) inhaled NO can reverse changes induced by inhibition of endogenous NO. Methods: Sixteen neonatal piglets underwent occlusive tracheostomy and pressure-cycled ventilation. After heparinization and ligation of the ductus arteriosus, left atrial and pulmonary arterial cannulation were performed, without ischemia, via a median sternotomy. The aorta was ligated, and lung perfusion was set at 80 mL/kg/min via an extracorporeal membrane oxygenation circuit. Hematocrit (40% to 45%), pH (7.37 to 7.44), P co 2 (35 to 40 mm Hg), and peak inspiratory pressures (20 mm Hg) were constant. Pulmonary artery pressure (P PA), left atrial pressure (P LA), and circuit flow (Q PA) were recorded continuously. PVR calculated as follows: PVR[(dynes × seconds × cm −5) × 1,000] = [ (P PA − P LA) (Q PA × 1,000 60 ) ] × 1,332 . The experimental animals were ventilated with normoxic gas (F IO 2, 0.21), followed by hypoxic gas (F IO 2, 0.07), returned to normoxia, and then divided into two groups of eight animals each. One group remained normoxemic (F IO 2, 0.21; S PA o 2, 100%) while the other group was made hypoxemic by ventilation with hypoxic gas (F IO 2, 0.07; S PA o 2, 50%). Endogenous NO was suppressed with l-arginine- N-omega methyl ester ( l-NAME) at 40 mg/kg in both groups. Inhaled NO was given at 40 ppm in both groups. Analysis of variance for repeated measures was used to test for statistical significance. Results: Baseline normoxic PVR (3,403 ± 1,169) was increased significantly by hypoxia (6,524 ± 1,018, P < .01) and was fully restored to baseline by normoxia (3,497 ± 1,079; P = NS). In normoxic animals, inhibition of endogenous NO production by l-NAME increased PVR to levels similar to those seen during hypoxic stress (6,345 ± 1,441, P < .01). Replacement of endogenous NO by inhaled NO reversed PVR to normoxic baseline values (3,986 ± 1,363, P = NS). In hypoxic animals, inhibition of endogenous NO production by l-NAME also increased PVR from hypoxic baseline (9,655 ± 1,642, P < .01). Replacement of endogenous NO by inhaled NO reversed PVR to hypoxic baseline (6,450 ± 1,796, P = NS). Conclusion: In this piglet model, endogenous NO is important in the regulation of pulmonary vascular tone during both normoxia and hypoxia. Inhaled NO completely reversed the elevations in PVR caused by inhibition of endogenous NO and may normalize PVR in diseases in which the production of endogenous NO is compromised.

Influence of hypoxic duration and posthypoxic inspired O2 concentration on short term potentiation of breathing in humans.

1. Short term potentiation (STP) of breathing refers to respiratory activity at a higher level than expected just from the dynamics of the peripheral and central chemoreceptors. In humans STP is activated by hypoxic stimulation. 2. To investigate the effects of the duration of hypoxia and the posthypoxic inspired O2 concentration on STP, the ventilatory responses to 30 s and 1, 3 and 5 min of hypoxia (end-tidal PO2, P(ET.O2) approximately 6.5 kPa) followed by normoxia (P(ET.O2) approximately 14.5 kPa) and hyperoxia (P(ET.O2) approximately 70 kPa) were studied in ten healthy subjects. End-tidal PCO2 (P(ET.CO2)) was clamped during hypoxic and recovery periods at 5.7 kPa. 3. Steady-state ventilation (VE) was 13.7 +/- 0.6 l min-1 during normoxia and increased to 15.5 +/- 0.3 l min-1 during hyperoxia (P < 0.05) due to the reduced Haldane effect and some decrease in cerebral blood flow (CBF). 4. The mean responses following hypoxia reached normoxic baseline after 69, 54, 12 and 12 s when 30 s and 1, 3 and 5 min of hypoxia, respectively, were followed by normoxia. An undershoot of 10 and 20% below hyperoxic baseline was observed when 3 and 5 min of hypoxia, respectively, were followed by hyperoxia. Hyperoxic VE reached hyperoxic baseline after 9, 15, 12 and 9 s at the termination of 30 s and 1, 3 and 5 min of hypoxia, respectively. 5. Normoxic recovery from 30 s and 1 min of hypoxia displayed a fast and subsequent slow decrease towards normoxic baseline. The fast component was attributed to the loss of the hypoxic drive at the site of the peripheral chemoreceptors, and the slow component to the decay of the STP that had been activated centrally by the stimulus. A slow decrease at the termination of 30 s and 1 min of hypoxia by hyperoxia was not observed since this component was cancelled by the increase in ventilatory output due to the reduced Haldane effect and some decrease of CBF. 6. Decay of the STP was not apparent in the normoxic recovery from 3 and 5 min of hypoxia as a slow component since it cancelled against the slow ventilatory increase related to the increase of brain tissue PCO2 due to the reduction of CBF at the relief of hypoxia. The undershoot observed when hyperoxia followed 3 and 5 min of hypoxia reflects the stimulatory effects of hyperoxia on VE. 7. The manifestation of the STP as a slow ventilatory decrease depends on the duration of hypoxia and the subsequent inspired oxygen concentration. We argue that STP is not abolished by the central depressive effects of hypoxia, although the manifestation of the STP may be overridden or counteracted by other mechanisms.

Effect of hypoxia and norepinephrine on cytoplasmic free Ca2+ in pulmonary and cerebral arterial myocytes

The fluorescent calcium indicator, fura 2, was used to test whether contraction of primary cultured smooth muscle cells (SMC) from small pulmonary arteries in response to hypoxia and the relaxation by large pulmonary and cerebral artery SMC were mediated by changes in cytoplasmic free Ca2+ (Ca2+c). Because SMC from large pulmonary and cerebral arteries contract to norepinephrine (NE), Ca2+c levels during NE exposure were measured to determine if they differed from those seen with hypoxia. Under hypoxic conditions, Ca2+c increased 64.1 +/- 11.1% above the normoxic baseline in small pulmonary artery SMC. In SMC from large pulmonary and cerebral arteries, Ca2+c decreased 25.2 +/- 9.20 and 28.1 +/- 5.80%. Ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA) and ryanodine attenuated the Ca2+c increase in the small pulmonary artery SMC. On exposure to NE, Ca2+c increased markedly in all three SMC types. EGTA and ryanodine treatment also attenuated NE-induced Ca2+c increases in all three SMC types. These results show that the three SMC types mobilize their available Ca2+ stores differently when exposed to hypoxia but similarly when exposed to NE. The data also suggest that a change in the Ca2+c concentration, rather than a change in the Ca2+ sensitivity of the contractile apparatus, is involved in the response to hypoxia.

Nitric oxide synthesis and regional cerebral blood flow responses to hypercapnia and hypoxia in the rat.

The role of nitric oxide (NO) synthesis in the cerebral hyperemic responses to hypercapnia and hypoxia was investigated in anesthetized rats. Regional CBF (rCBF) measurements were obtained in the cortex (CX), subcortex (SC), brainstem (BS), and cerebellum (CE) using radiolabeled microspheres. The rCBF responses to either hypercapnia (PaCO2 = 70-80 mm Hg) or hypoxia (PaO2 = 40-45 mm Hg) were compared in rat groups studied in the presence and absence of NO synthase inhibition induced via the intravenous infusion of nitro-L-arginine methyl ester (L-NAME, 3 mg kg-1 min-1). Administration of L-NAME under normocapnic/normoxic conditions produced a 40-60% reduction in baseline rCBF values, indicating the presence of a NO "tone" in the cerebral vasculature. Infusion of L-NAME resulted in a substantial attenuation, in all regions measured, of the rCBF increases that normally accompany hypercapnia. In comparing saline-infused to L-NAME-infused rats, the percentage increases in rCBF (from normocapnic baseline values) were 351% versus 166% (CX), 446% versus 199% (SC), 443% versus 206% (BS), and 483% versus 174% (CE), respectively. The rCBF changes from baseline (delta rCBF in ml 100 g-1 min-1) were 488 versus 57 (CX), 570 versus 60 (SC), 434 versus 72 (BS), and 393 versus 45 (CE), respectively. These differences were all statistically significant (p < 0.05). During hypoxia, when compared to rats not given L-NAME, inhibition of NO synthase activity resulted in significantly greater (p < 0.05) percentage increases in rCBF (from normoxic baseline values) in most regions.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of H2-receptor blockers on response of cerebral blood flow to normocapnic hypoxia.

Cimetidine blunts the increase in cerebral blood flow (CBF) normally observed during hypoxia. It is important, therefore, to know whether other H2-blockers also affect the cerebral circulation adaptation to hypoxia. Cerebral blood flow was measured in 24 awake dogs after an intravenous injection of either saline (control) or one of three H2-blockers: 1 mg/kg ranitidine, 0.4 mg/kg famotidine, or 1 mg/kg roxatidine. These doses are equipotent blockers of H2-gastric receptors. Each dog was studied during normoxia and after 2 and 4 h of normocapnic hypoxia (FIO2, 0.10; FICO2, 0.035). During each set of experimental conditions, a bolus of either saline or one of the anti-H2 drugs was administered, and, 15 min later, radiolabeled microspheres (ruthenium 103, scandium 46, and cerium 141) were injected into the left atrium for measurement of regional CBF. After death by an overdose of thiopental, each dog's brain was excised and fixed in 10% formaldehyde; it was then weighed and dissected by region, with the radioactivity measured in each region using a gamma counter. During hypoxia, PaO2 ranged from 45 to 50 mm Hg, and pH, PaCO2, and hematocrit were within the normal limits. In the control group CBF increased 34% above normoxic baseline levels after 2 h and 31% after 4 h of hypoxia. Ranitidine (1 mg/kg) did not prevent the increase in CBF during hypoxia, but famotidine and roxatidine prevented it. When the dose of ranitidine was doubled (2 mg/kg), it too abolished the increase of CBF induced by hypoxia. In conclusion, H2-receptor blockers could interfere with the adaptation of CBF during hypoxia.

Hypoxic exposure and activation of the afterdischarge mechanism in conscious humans

After voluntary hyperventilation, normal humans do not develop a significant ventilatory depression despite low arterial CO2 tension, a phenomenon attributed to activation of a brain stem mechanism referred to as the "afterdischarge." Afterdischarge is one of the factors that promote ventilatory stability. It is not known whether physiological stimuli, such as hypoxia, are able to activate the afterdischarge in humans. To test this, breath-by-breath ventilation (VI) was measured in nine young adults during and immediately after a brief period (35-51 s) of acute hypoxia (end-tidal O2 tension 55 Torr). Hypoxia was terminated by switching to 100% O2 (end-tidal O2 tension of first posthypoxic breath greater than 100 Torr). Brief hypoxia increased VI and decreased end-tidal CO2 tension. In all subjects, termination of hypoxia was followed by a gradual ventilatory decay; hyperoxic VI remained higher than the normoxic baseline for several breaths and, despite the negative chemical stimulus of hyperoxia and hypocapnia, reached a new steady state without an apparent undershoot. We conclude that brief hypoxia is able to activate the afterdischarge mechanism in conscious humans. This contrasts sharply with the ventilatory undershoot that follows relief of sustained hypoxia, thereby suggesting that sustained hypoxia inactivates the afterdischarge mechanism. The present findings are of relevance to the pathogenesis of periodic breathing in a hypoxic environment. Furthermore, brief exposure to hypoxia might be useful for evaluation of the role of afterdischarge in other disorders associated with unstable breathing.