Effects of L-glutamine supplementation on maternal and fetal hemodynamics in gestating ewes exposed to alcohol.

Not much is known about effects of gestational alcohol exposure on maternal and fetal cardiovascular adaptations. This study determined whether maternal binge alcohol exposure and L-glutamine supplementation could affect maternal-fetal hemodynamics and fetal regional brain blood flow during the brain growth spurt period. Pregnant sheep were randomly assigned to one of four groups: saline control, alcohol (1.75-2.5 g/kg body weight), glutamine (100 mg/kg body weight) or alcohol + glutamine. A chronic weekend binge drinking paradigm between gestational days (GD) 99 and 115 was utilized. Fetuses were surgically instrumented on GD 117 ± 1 and studied on GD 120 ± 1. Binge alcohol exposure caused maternal acidemia, hypercapnea, and hypoxemia. Fetuses were acidemic and hypercapnic, but not hypoxemic. Alcohol exposure increased fetal mean arterial pressure, whereas fetal heart rate was unaltered. Alcohol exposure resulted in ~40 % reduction in maternal uterine artery blood flow. Labeled microsphere analyses showed that alcohol induced >2-fold increases in fetal whole brain blood flow. The elevation in fetal brain blood flow was region-specific, particularly affecting the developing cerebellum, brain stem, and olfactory bulb. Maternal L-glutamine supplementation attenuated alcohol-induced maternal hypercapnea, fetal acidemia and increases in fetal brain blood flow. L-Glutamine supplementation did not affect uterine blood flow. Collectively, alcohol exposure alters maternal and fetal acid-base balance, decreases uterine blood flow, and alters fetal regional brain blood flow. Importantly, L-glutamine supplementation mitigates alcohol-induced acid-base imbalances and alterations in fetal regional brain blood flow. Further studies are warranted to elucidate mechanisms responsible for alcohol-induced programming of maternal uterine artery and fetal circulation adaptations in pregnancy.

Transcranial Doppler ultrasonography CO2 reactivity does not predict recurrent ischaemic stroke in patients with symptomatic carotid artery occlusion.

BACKGROUND: Patients with transient ischaemic attacks (TIAs) or minor disabling ischaemic stroke associated with an internal carotid artery (ICA) occlusion have a high risk of recurrent stroke in case of compromised cerebral blood flow. Recent studies showed that increased oxygen extraction fraction measured by positron emission tomography (PET) is still an independent predictor of subsequent stroke under current medical treatment, but PET facilities are not widely available. Transcranial Doppler (TCD) ultrasonography CO2 reactivity is a cheap and non-invasive alternative to measure haemodynamic compromise. The aim of our study was to investigate whether TCD CO2 reactivity is an independent predictor of recurrent ischaemic stroke in a large cohort of patients with symptomatic ICA occlusion in a time where rigorous control of vascular risk factors has been widely implemented in clinical practice. METHODS: Between July 1995 and December 2009, we included consecutive patients with TIAs or minor disabling ischaemic stroke (modified Rankin Scale ≤3) associated with ICA occlusion who were referred to the University Medical Centre Utrecht, The Netherlands. All patients were treated with antiplatelet therapy and received rigorous control of vascular risk factors, including statins, treatment for diabetes and hypertension and lifestyle advices. CO2 reactivity was measured with TCD within 3 months after presentation. We determined the predictive value of TCD CO2 reactivity for recurrent ischaemic stroke using Cox proportional hazard analysis. RESULTS: We included 201 patients with a median follow-up time of 7.1 years. Mean CO2 reactivity was 15% (±20 standard deviation). The annual rate for ipsilateral ischaemic stroke was 2.2% [95% confidence interval (CI) 1.4-3.2] and for any recurrent stroke 3.2% (95% CI 2.3-4.4). We did not find a significant relationship between CO2 reactivity and the risk of ipsilateral [hazard ratio (HR) for every increase in percentage point 1.01, 95% CI 0.99-1.02] or any recurrent ischaemic stroke (HR 1.01, 95% CI 0.998-1.02). Multivariable analysis showed a significant relationship with history of stroke (HR 4.0, 95% CI 1.8-9.0) for ipsilateral recurrent stroke, and age (HR for increase per year 1.05, 95% CI 1.01-1.09) and a history of stroke (HR 3.4, 95% CI 1.7-6.6) for any recurrent stroke. CONCLUSIONS: In patients with TIAs or non-disabling stroke associated with occlusion of the carotid artery, the long-term annual risk of stroke is generally low with careful control of vascular risk factors. Impaired CO2 reactivity measured within 3 months after presentation does not identify the subgroup of patients at high risk of recurrent ischaemic stroke.

The effects of inspiratory muscle training on plasma interleukin-6 concentration during cycling exercise and a volitional mimic of the exercise hyperpnea.

It is unknown whether the respiratory muscles contribute to exercise-induced increases in plasma interleukin-6 (IL-6) concentration, if this is related to diaphragm fatigue, and whether inspiratory muscle training (IMT) attenuates the plasma IL-6 response to whole body exercise and/or a volitional mimic of the exercise hyperpnea. Twelve healthy males were divided equally into an IMT or placebo (PLA) group, and before and after a 6-wk intervention they undertook, on separate days, 1 h of 1) passive rest, 2) cycling exercise at estimated maximal lactate steady state power (EX), and 3) volitional hyperpnea at rest, which mimicked the breathing and respiratory muscle recruitment patterns achieved during EX (HYPEX). Plasma IL-6 concentration remained unchanged during passive rest. The plasma IL-6 response to EX was reduced following IMT (main effect of intervention, P = 0.039) but not PLA (P = 0.272). Plasma IL-6 concentration increased during HYPEX (main effect of time, P < 0.01) and was unchanged postintervention. There was no evidence of diaphragm fatigue (measured by phrenic nerve stimulation) following each trial. In conclusion, plasma IL-6 concentration is increased during EX and HYPEX and this occurred in the absence of diaphragm fatigue. Furthermore, IMT reduced the plasma IL-6 response to EX but not HYPEX. These findings suggest that the respiratory muscles contribute to exercise-induced increases in plasma IL-6 concentration in the absence of diaphragm fatigue and that IMT can reduce the magnitude of the response to exercise but not a volitional mimic of the exercise hyperpnea.

[The changes of physiological reactivity of cardiorespiratory system to respiratory homeostasis with the use of complex stimulation of special work capacity].

We present the influence of the program of special additional stimulation of work capacity of high-performance athletes on the sensitivity of cardiorespiratory system to hypercapnic and hypoxic shifts in respiratory homeostasis. We found that under the influence of the pre-start complex a decrease in the sensitivity of ventilator responses to CO2-H+ stimuli in combination with a reduction in the thresholds of the reaction take place. This creates conditions for increased mobilization properties of the cardiorespiratory system and economization of its reaction under conditions of changes of respiratory homeostasis characteristic of intense training and competitive loads in the sport.

Effects of tryptophan depletion and tryptophan loading on the affective response to high-dose CO2 challenge in healthy volunteers.

RATIONALE: It has been reported that in panic disorder (PD), tryptophan depletion enhances the vulnerability to experimentally induced panic, while the administration of serotonin precursors blunts the response to challenges. OBJECTIVES: Using a high-dose carbon dioxide (CO(2)) challenge, we aimed to investigate the effects of acute tryptophan depletion (ATD) and acute tryptophan loading (ATL) on CO(2)-induced panic response in healthy volunteers. METHODS: Eighteen healthy volunteers participated in a randomized, double-blind placebo-controlled study. Each subject received ATD, ATL, and a balanced condition (BAL) in separate days, and a double-breath 35% CO(2) inhalation 4.5 h after treatment. Tryptophan (Trp) manipulations were obtained adding 0 g (ATD), 1.21 g (BAL), and 5.15 g (ATL) of l-tryptophan to a protein mixture lacking Trp. Assessments consisted of a visual analogue scale for affect (VAAS) and panic symptom list. A separate analysis on a sample of 55 subjects with a separate-group design has also been performed to study the relationship between plasma amino acid levels and subjective response to CO(2). RESULTS: CO(2)-induced subjective distress and breathlessness were significantly lower after ATD compared to BAL and ATL (p < 0.05). In the separate-group analysis, ΔVAAS scores were positively correlated to the ratio Trp:ΣLNAA after treatment (r = 0.39; p < 0.05). CONCLUSIONS: The present results are in line with preclinical data indicating a role for the serotonergic system in promoting the aversive respiratory sensations to hypercapnic stimuli (Richerson, Nat Rev Neurosci 5(6):449-461, 2004). The differences observed in our study, compared to previous findings in PD patients, might depend on an altered serotonergic modulatory function in patients compared to healthy subjects.

[Salbutamol improves diaphragmatic contractility in chronic airway obstruction]. / El salbutamol mejora la contractilidad diafragmática en la obstrucción crónica de la vía aérea.

INTRODUCTION: Chronic airflow obstruction in conditions such as chronic obstructive pulmonary disease is associated with respiratory muscle dysfunction. Our aim was to study the effects of salbutamol-a beta-adrenergic agonist known to improve muscle strength in physiologic and pathologic conditions-on diaphragm contractility in an animal model of chronic airway obstruction achieved by tracheal banding. MATERIALS AND METHODS: Twenty-four Sprague-Dawley rats were randomized into a control group and 3 tracheal banding groups, 1 that received acute salbutamol treatment, 1 that received chronic salbutamol treatment, and 1 that received nothing. Arterial blood gases, acid-base balance, and in vitro diaphragmatic contractility were evaluated by measuring peak twitch tension, contraction time, contraction velocity, half-relaxation time, relaxation velocity, and force-frequency curves. RESULTS: The 3 study groups had significantly reduced arterial pH and increased PaCO2 and bicarbonate levels compared to the control group (P<.05). The untreated tracheal banding group had significantly reduced peak twitch tension and contraction velocity, and a significantly lower force-frequency curve in comparison with the other groups (P<.05). The chronic treatment group had a higher relaxation velocity than the untreated study group (P<.05). The mean (SE) peak twitch tension values were 6.46 (0.90)N/cm(2) for the control group, 3.28 (0.55)N/cm(2) for the untreated tracheal banding group, 6.18 (0.71)N/cm(2) for the acute treatment group, and 7.09 (0.59)N/cm(2) for the chronic treatment group. CONCLUSIONS: Diaphragmatic dysfunction associated with chronic airflow obstruction improves with both the acute and chronic administration of salbutamol. The mechanisms involved in respiratory muscle dysfunction warrant further study.

Active cycle of breathing techniques in non-invasive ventilation for acute hypercapnic respiratory failure.

We hypothesised that applying the active cycle of breathing techniques (ACBT) in patients with acute hypercapnic respiratory failure undergoing non-invasive ventilation would improve patient outcome. Thirty-four patients were randomised so that 17 patients with acute hypercapnic respiratory failure received the ACBT and non-invasive ventilation (ACBT group), and 17 patients received non-invasive ventilation alone (control group). The primary outcome measure was length of time requiring non-invasive ventilation, and secondary outcome measures were change in acute physiology score, change in arterial blood gas values, total duration of non-invasive ventilation, and length of stay in the intensive care unit. Although not significant, there was a greater decrease in arterial carbon dioxide pressure in the ACBT group compared to the control group (-21.41 mmHg vs -17.45 mmHg, p = 0.27). Total duration of ventilation tended to be shorter in the ACBT group than in the control group (64.9 hours vs 84.1 hours, p = 0.15). Length of time in need of non-invasive ventilation was significantly lower in the ACBT group than in the control group (5.0 days vs 6.7 days, p = 0.03). There was no significant difference in length of stay in the intensive care unit between the two groups (8.0 vs 9.4 days, p = 0.31). The use of ACBT may have positive effects in the treatment of patients with acute hypercapnic respiratory failure, resulting in a shorter length of time requiring non-invasive ventilation.

Acute effects of deep diaphragmatic breathing in COPD patients with chronic respiratory insufficiency.

This study investigated the impact of deep diaphragmatic breathing (DB) on blood gases, breathing pattern, pulmonary mechanics and dyspnoea in severe hypercapnic chronic obstructive pulmonary disease (COPD) patients recovering from an acute exacerbation. Transcutaneous partial pressure of carbon dioxide (Ptc,CO2) and oxygen (Ptc,O2) and arterial oxygen saturation (Sa,O2), were continuously monitored in 25 COPD patients with chronic hypercapnia, during natural breathing and DB. In eight of these patients, breathing pattern and minute ventilation (V'E) were also assessed by means of a respiratory inductance plethysmography. In five tracheostomized patients, breathing pattern and mechanics were assessed by means of a pneumotachograph/pressure transducer connected to an oesophageal balloon. Subjective rating of dyspnoea was performed by means of a visual analogue scale. In comparison to natural breathing deep DB was associated with a significant increase in Ptc,O2 and a significant decrease in Ptc,CO2, with a significant increase in tidal volume and a significant reduction in respiratory rate resulting in increased V'E. During DB, dyspnoea worsened significantly and inspiratory muscle effort increased, as demonstrated by an increase in oesophageal pressure swings, pressure-time product and work of breathing. We conclude that in severe chronic obstructive pulmonary disease patients with chronic hypercapnia, deep diaphragmatic breathing is associated with improvement of blood gases at the expense of a greater inspiratory muscle loading.

Correction of blood pH attenuates changes in hemodynamics and organ blood flow during permissive hypercapnia.

OBJECTIVES: To determine whether changes in cardiac output, regional blood flow, and intracranial pressure during permissive hypercapnia are blood pH-dependent and can be attenuated by correction of intravascular acidemia. DESIGN: Prospective, controlled study. SETTING: Research laboratory. SUBJECTS: Female Marino ewes. INTERVENTIONS: Animals were instrumented with a pulmonary artery catheter, femoral arterial and venous catheters, a catheter in the third cerebral ventricle, and ultrasonic flow probes on the left carotid, superior mesenteric, and left renal arteries 1 wk before experimentation. At initiation of the protocol, ewes underwent endotracheal intubation and mechanical ventilation under general anesthesia. Minute ventilation was reduced to induce hypercapnia with a target PaCO2 of 80 torr (10.7 kPa). In the pH-uncorrected group (n = 6), arterial blood pH was allowed to decreased without treatment. In the pH-corrected group (n = 5), 14.4 mEq/kg of sodium bicarbonate was given intravenously as a bolus to correct arterial blood pH toward a target arterial pH of 7.40 (dose calculated by the Henderson-Hasselbalch equation). MEASUREMENTS AND MAIN RESULTS: Arterial blood pH, PCO2, cardiac output, intracranial pressure, and carotid, superior mesenteric, and renal artery blood flow rates were measured at normocapnic baseline and at every hour during hypercapnia for 6 hrs. In the pH-uncorrected group, arterial blood pH decreased from 7.41 +/- 0.03 at normocapnia to 7.14 +/- 0.01 (p < .01 vs. normocapnia) as blood PCO2 increased to 81.2 +/- 1.8 torr (10.8 +/- 0.2 kPa). In the pH-corrected group, arterial blood pH was 7.42 +/- 0.02 at normocapnia and was maintained at 7.37 +/- 0.01 while PaCO2 was increased to 80.3 +/- 0.9 torr (10.7 +/- 0.1 kPa). Significant increases in cardiac output occurred with the initiation of hypercapnia for both groups (pH-uncorrected group: 4.3 +/- 0.6 L/min at normocapnia vs. 6.8 +/- 1.0 L/min at 1 hr [p < .05]; pH-corrected group: 4.1 +/- 0.4 at normocapnia vs. 5.7 +/- 0.4 L/min at 1 hr [p < .05]). However, this increase was sustained only in the uncorrected group. Changes in carotid and mesenteric artery blood flow rates, as a percent of baseline values, showed sustained significant increases in the pH-uncorrected groups (p < .05) and only transient (carotid at 1 hr) or no (superior mesenteric) significant change in the pH-corrected groups. Conversely, significant increases in renal artery blood flow were seen only in the pH-uncorrected group during the last 2 hrs of the experiment (p < .05). Organ blood flow, as a percent of cardiac output, did not change significantly in either group. Intracranial pressure increased significantly in the pH-uncorrected group (9.0 +/- 1.5 mm Hg at normocapnia vs. 26.8 +/- 5.1 at 1 hr, p < .05), and remained increased, while showing no significant change in the pH-corrected group (8.5 +/- 1.6 mm Hg at normocapnia to 7.7 +/- 4.2 at 1 hr). CONCLUSIONS: Acute hypercapnia, induced within 1 hr, is associated with significant increases in cardiac output, organ blood flow, and intracranial pressure. These changes can be significantly attenuated by correction of blood pH with the administration of sodium bicarbonate, without adverse effects on hemodynamics.

Modification of oxygen tolerance in rats by adaptation to combined hypoxia and hypercapnia.

Tolerance to 100% O2 or to O2 with 60 torr PICO2 (O2-CO2) was determined at pressures of 1.0-4.0 atm abs in normal rats and in rats adapted to combined hypoxia and hypercapnia (HHA) before O2 or O2-CO2 exposure. Results were compared with previous studies of tolerance to O2 or O2-CO2 after adaptation to hypoxia or hypercapnia alone. Both the positive effect on pulmonary O2 tolerance and the negative effect on CNS O2 tolerance found in hypoxia-adapted rats were reduced or eliminated in HHA rats. The increased CNS tolerance to O2-CO2 found in hypercapnia-adapted rats was also reduced in HHA rats. The observation that some of the O2 tolerance modifications associated with adaptation to hypoxia or hypercapnia were reduced or eliminated by adaptation to both stresses concurrently may be because physiologic responses to chronic hypoxia and chronic hypercapnia are opposite in some ways. Results of the present and previous related studies indicate that physiologic adaptations to chronic alterations in the oxygen and acid-base environments have prominent influences on O2 tolerance over a range of useful pressures.

Effects of different techniques of endotracheal epinephrine administration in pediatric porcine hypoxic-hypercarbic cardiopulmonary arrest.

OBJECTIVE: To compare three endotracheal epinephrine instillation techniques in a pediatric porcine hypoxic-hypercarbic cardiopulmonary arrest model. DESIGN: Prospective, randomized, laboratory comparison of three instillation techniques. SETTING: Large animal research facility at a children's hospital. SUBJECTS: Thirty-six preadolescent anesthetized and paralyzed Yucatan swine (mean weight 10.0 +/- 1.9 kg) with apnea-induced hypoxic and hypercarbic cardiopulmonary arrest. INTERVENTIONS: After 8 mins of cardiopulmonary arrest and 1 min of cardiopulmonary resuscitation (CPR), 500 micrograms (51 +/- 9 micrograms/kg) of radiolabeled endotracheal epinephrine was administered by direct injection (n = 17), injection via feeding catheter (n = 10), or via monitoring lumen built into the sidewall of the endotracheal tube (n = 9). CPR was resumed and continued for 5 mins. If resuscitation occurred, monitoring was continued for 1 hr. Outcome variables included successful resuscitation, pulmonary distribution, heart rate, mean arterial pressure, plasma radiolabeled epinephrine counts, and total plasma epinephrine concentrations. Analysis by Fisher's exact test, one-way analysis of variance and Pearson's phi coefficient was performed. MEASUREMENTS AND MAIN RESULTS: Successful resuscitation occurred in 31% of all pigs with no difference between groups (p = .69). Bilateral distribution occurred in 39% with no difference between groups (p = .25). No correlation was noted between successful resuscitation and distribution (p = .65). HR, mean arterial pressure, plasma radiolabeled epinephrine counts, and total plasma epinephrine concentrations showed significant changes over time within groups, but no difference between groups at any time point. Adherence of the epinephrine dose to the endotracheal tube was < or = 1.5% in all cases. CONCLUSIONS: Instillation of 50 micrograms/kg of endotracheal epinephrine by three different techniques during pediatric porcine asphyxial arrest does not affect resuscitation rate, pulmonary distribution, hemodynamic response, or plasma exogenous and total epinephrine concentrations. No correlation was found between successful resuscitation and bilateral distribution. Therefore, currently recommended cumbersome endotracheal epinephrine instillation techniques may offer no resuscitation advantage over commonly used direct injection in this setting.

Action of carbon dioxide on hypoxic pulmonary vasoconstriction in the rat lung: evidence against specific endothelium-derived relaxing factor-mediated vasodilation.

OBJECTIVES: The effect of hypercapnia on pulmonary vascular tone is controversial with evidence for both a vasoconstrictor and vasodilator action. The objective of this study was to investigate the possibility that this dual response to CO2 could be explained by a direct constrictor action on smooth muscle and an indirect dilator action via the release of endothelium-derived relaxing factor. The effect of ventilation with hypercapnia (FICO2 0.15) on pulmonary pressor response to hypoxia (FIO2 0.3) was investigated. DESIGN: Prospective, randomized study. SETTING: The National Heart and Lung Institute, UK. SUBJECTS: The isolated, blood-perfused rat lung. INTERVENTIONS: Angiotensin-II and a blocker of endothelium-derived relaxing factor synthesis, NG-monomethyl-L-arginine (L-NMMA). MEASUREMENTS AND MAIN RESULTS: The vasomotor effect of hypercapnia depended on pulmonary arterial pressure. Under resting tone, CO2 acted as a mild constrictor (change in mean pulmonary arterial pressure from 14 +/- 2 to 15 +/- 2 mm Hg, n = 4; p < .05. At increased tone, induced either by hypoxia or Angiotensin-II, CO2 was a vasodilator. Thus, hypoxia increased mean pulmonary arterial pressure from 17 +/- 2 to 32 +/- 2 mm Hg (n = 8; p < .01), but simultaneous ventilation with hypoxia and hypercapnia reduced this by 16 +/- 1% (p < .01). Angiotensin-II (1 microgram) increased pulmonary arterial pressure from 14 +/- 2 to 39 +/- 5 mm Hg (n = 8; p < .01), but with hypercapnia, this angiotensin-induced pulmonary vasoconstriction was reduced by 18 +/- 6% (p < .001). The reduction in hypoxic pulmonary vasoconstriction induced by hypercapnia was not significantly different from that seen with Angiotensin-II hypercapnia. Blocking endothelium-derived relaxing factor synthesis using 30 microM NG-monomethyl-L-arginine did not significantly change either basal pulmonary arterial pressure or the response to hypercapnia, but increased hypoxic pulmonary vasoconstrictor by 24 +/- 4% (n = 4; p < .01). There was no significant difference between the change in hypoxic pulmonary vasoconstriction induced by hypercapnia after saline control (21 +/- 8% decrease) and the change in hypoxic pulmonary vasoconstriction caused by CO2 after 30 microM L-NMMA (25 +/- 10% decrease, p < .05, n = 8). CONCLUSION: Endothelium-derived relaxing factor seems unlikely to specifically modulate CO2-induced vasodilation in the rat pulmonary circulation.

Cerebrovascular and metabolic changes during the delayed vasospasm following experimental subarachnoid hemorrhage in baboons, and treatment with a calcium antagonist.

A model has been designed in baboons for simulating the clinical situation during the late phase of vasospasm in patients with subarachnoid hemorrhage (SAH). A total amount of 14-33 ml autologous blood was injected into the cisternal system on 3 occasions in the course of 4 days. Neurological symptoms were seen, and the mortality rate was 29%. Angiography 3 days after the last injection showed arterial vasoconstriction amounting to 23% in the vertebro-basilar system, and 11% (right) and 18% (left) in the carotid system. Cerebral blood flow (CBF) measured by the intra-arterial 133Xe technique and the cerebral metabolic rate of oxygen (CMRO2) were reduced by 18% and 11%, respectively. The hypercapnic CBF response was significantly impaired, from a mean of 3.90 ml/100 g/min to 1.72 ml/100 g/min of flow increase for each mm Hg elevation of paCO2. Autoregulation, tested by administration of angiotensin II, was also significantly affected as evidenced by a pressure-dependent increment of CBF during hypertension in 5 out of 7 animals tested. The impaired autoregulation was reflected in the autoregulatory index, which in the whole group increased from 0.06 ml/100 g/min for each mm Hg increase in MABP in the pre-SAH animals to 0.29 ml/100 g/min per mm Hg post-SAH. Treatment with the calcium antagonist, nimodipine (0.5 microgram/kg/min i.v. during 45 min), enhanced CBF significantly by 17% before experimental SAH, whereas after SAH the effect was slight and did not reach statistical significance; CMRO2 was not significantly affected in either group. Intravenous nimodipine combined with hypertension resulted in a marked increase in the autoregulatory index to 1.58 ml/100 g/min per mm Hg in pre-SAH animals and a less pronounced increment to 0.58 ml/100 g/min per mm Hg following experimental SAH. The beneficial effect of nimodipine reported in SAH patients is therefore, in view of our findings, more likely due primarily to a protective mechanism at the cellular level than to an influence on the vascular bed.

Effects of acute and chronic hypercapnia on oxygen tolerance in rats.

Groups of 16-52 normal or CO2-adapted rats were exposed top 100% O2 or to O2 with 60 Torr PICO2 (O2-CO2) at pressures of 1.0, 1.5, 2.0, 3.0, and 4.0 ATA. Exposure durations for 50% mortality (LD50) in normal rats at 4.0, 3.0, 2.0, 1.5, and 1.0 ATA O2 were 6.3, 9.3, 17.2, 27.4, and 76.1 h, respectively. Corresponding LD50 values for normal rats exposed to O2-CO2 were 2.0, 2.9, 16.3, 24.8, and 74.8 h. Survival times of CO2-adapted rats exposed to O2 were nearly identical to those of normal rats. LD50 values for CO2-adapted rat exposed to O2-CO2 were 4.1, 7.5, 17.9, 23.6, and 65.4 h, respectively. These data confirm acceleration of O2 intoxication by acute hypercapnia at 4.0 and 3.0 ATA, but they show less prominent effects at 2.0, 1.5, and 1.0 ATA. Hypercapnia adaptation clearly has a protective effect in rats exposed to O2-CO2 at 4.0 and 3.0 ATA. At 2.0, 1.5, and 1.0 ATA, where acute hypercapnia has less effect, the effects of CO2 adaptation are also less prominent. The observed changes in oxygen tolerance can be explained by cerebral vasodilation with increased brain oxygenation in acute hypercapnia and by significant amelioration of this response during chronic hypercapnia.