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Asphyxiated newborns are usually resuscitated with high concentrations of O2 (1). The guidelines of the American Heart Association for resuscitation of newborn infants recommend ventilation by bags that can give as close to 100% O2 as possible (2).

The possible toxic effects of hyperoxia have been known for many years (3). The sudden reintroduction of high concentrations of O2 to hypoxic tissues may result in a burst of oxygen free radical formation (4,5), which may increase the hypoxic tissue damage. A recently published clinical study indicates that there are no major differences in outcome when resuscitation is performed with room air compared with 100% oxygen (6). However, time to first breath and time to first cry was significantly shorter in the room air group than the in the oxygen group.

The dramatic circulatory changes during transition from intra- to extrauterine life are controlled by a number of factors, many of which are poorly understood. Persistent hypoxemia after birth inhibits this transition (7). Pulmonary vascular resistance is also augmented by acidosis and hypercapnia (8). The O2-mediated pulmonary vasodilatation is regulated, at least in part, by the release of endothelium-derived nitric oxide (NO) (9). O2 is considered a pulmonary vascular dilator (10). Studies on newborn piglets have shown previously that room air is as effective as 100% O2 in normalizing both regional and cerebral blood flow and evoked potentials after hypoxemia (11,12). However, it is not known whether reoxygenation with room air is equally efficient in normalizing pulmonary vasoconstriction after hypoxemia.

We hypothesized that the increased PVRI and the increased mean PAP during hypoxemia are normalized more rapidly during resuscitation with 100% O2 than with room air in a newborn animal model with normal lungs. Despite an observation time of 2 h, we were specifically interested in the changes during the first 10 min of reoxygenation. To our knowledge this is the first study with induced hypoxic hypoxemia that compared pulmonary hemodynamics during early reoxygenation with room air and 100% oxygen in newborn animals.

ET-1 is a potent vasoactive peptide first described in 1988 (13). There is substantial evidence that ET-1 plays a role in the regulation of the pulmonary vascular tone, partly by regulation of the tone of the smooth muscle in the wall of the pulmonary arteries and partly by regulation of production of NO from the endothelium (14,15). To better understand the regulatory mechanisms of the pulmonary circulation during hypoxemia and reoxygenation, we also determined the plasma concentration of ET-1.

METHODS

Surgical preparation. Thirty-nine 1- to 3-d-old piglets were delivered from a local farmer on the day of the experiment. Anesthesia was induced with halothane (Fluothan) 3% in 100% oxygen until surgical anesthesia was achieved. Halothane was then reduced to 1-1.5% in 30% oxygen. A tracheostomy was established and a 3.5-mm ID uncuffed Sheridan endotracheal tube was inserted. The endotracheal tube was connected to a volume-controlled ventilator (Servo 900 B, Elema-Schønander, Stockholm, Sweden), and the animals were ventilated at a rate of 30 breaths per min. End-tidal O2 and CO2 were continuously monitored by a capnograph (Datex Multicap, Datex, Helsinki, Finland). Inspired oxygen concentration was monitored by an O2 monitor (OT-101 O2 monitor, Datex, Helsinki, Finland). PaCO2 was kept in normal range (4.5-6 kPa) throughout the experiment by adjusting the minute volume of the ventilator.

Pentobarbital sodium (20 mg/kg) and pethidine (10 mg/kg) was then administered i.v. through a cannulated ear vein, and halothane was discontinued. A continuous pentobarbital infusion of 6 mg kg-1 h-1 was given during surgery and stabilization, 3 mg kg-1 h-1 was given during hypoxemia, and reoxygenation was given throughout the experiment. The control piglets were given pentobarbital 6 mg kg-1 h-1 through the whole study period. Additional pentobarbital was given if necessary. Lidocaine 1% was used s.c. for incisions.

Both femoral arteries, the right femoral vein, and the right external jugular vein were cannulated with polyethylene catheters (Portex PE-50; ID: 0.58 mm), and the arterial catheters were advanced to the abdominal aorta. The catheters were regularly flushed with heparinized saline (4 U/mL). A small left-sided thoracotomy was performed by an incision between the fourth and fifth costal rib. The pericardium was opened at the base of the common pulmonary artery without affecting the heart, and the vessel was dissected free from the underlying aorta. An 8-mm ultrasonic transit-time flowprobe (CardioMed, Medi-Stim, Oslo, Norway) was fitted around the common pulmonary artery proximal to the ductus arteriosus for measurement of CO. Ultrasound conductive gel was applied between the probe and the artery to maximize signal transduction. A central venous catheter with 0.8-mm outside diameter and 100-mm length (Vygon, Écouen, France), was then inserted into the common pulmonary artery proximal to the flow probe by introducing a 20-guage needle with 0.5-mm outside diameter guidewire, withdrawing the needle, introducing the catheter by the guidewire, and finally withdrawing the guidewire. The catheter was advanced 2-3 cm. The correct position was verified by the typical pressure curve of the pulmonary artery. The left atrium was identified and a 5F catheter with an inflatable balloon (Baxter Healthcare Corp., Irvine, CA) was advanced into the atrium through a small incision, the balloon was inflated with 0.25 mL of air, and a suture was performed around the incision. After proper placement of the flow probe and catheters, the thoracic wall was closed in two layers.

One of the arterial catheters and the catheters in the external jugular vein, in the pulmonary artery, and in the left atrium were connected to strain gauge transducers. MABP, central venous pressure, PAP, and left atrial pressure were continuously recorded by a Gould recorder TA 5000 (Gould Inc. Recording Systems, Cleveland, OH). The other arterial catheter was used for blood samples. The femoral vein catheter was used for the pentobarbital infusion and for an infusion containing 0.7% NaCl and 1.25% glucose at a rate of 10 mL kg-1 h-1. Blood glucose was monitored regularly throughout the experiment (Haemo-Glucotest 1-44R, Boehringer Mannheim GmbH, Mannheim, Germany); extra glucose was given if blood glucose was less than 4 mmol/L, and pure saline was given if blood glucose was above 10 mmol/L. HR was monitored by skin electrodes. Rectal temperature was kept between 38.0 and 39.5°C with a heating blanket or a radiant heating lamp.

Experimental protocol. After a 60-min recovery period, the piglets were randomly assigned to control or hypoxemia. Animals allocated to hypoxemia were ventilated with 8% O2-balanced N2 until MABP was <20 mm Hg or BE was < -20 mmol/L. At the end of hypoxemia the piglets were randomized into two reoxygenation groups: 21% O2 (n = 9) and 100% O2 (n = 9). The decision when to start reoxygenation was always taken without knowing to which group the piglet was allocated. Reoxygenation continued for 2 h. Control animals (n = 5) were ventilated with 21% O2 for 2 h and 45 min, and identical blood samples were taken.

Eight piglets were excluded during the study. Four were excluded during surgical procedures due to anemia (Hb < 50 g/L) (n = 2), bleeding during surgery (n = 1), or errors in the administration of anesthesia (n = 1). Four were excluded because of sudden death during hypoxemia before randomization to reoxygenation groups. Results concerning these piglets are not included in the study.

Blood samples. Blood samples for blood gas analysis were drawn from the abdominal aorta 30 min before the start of hypoxemia, at the beginning of hypoxemia, every 15 min during hypoxemia, at end of hypoxemia, and at 15, 30, 60, 90, and 120 min of reoxygenation. Additional samples were drawn during hypoxemia if considered necessary. Temperature-corrected acid/base status were measured with a Bloodgas Analyzer 845 (Ciba Corning Diagnostics Corp., Medfield, MA). Hb was measured 30 min before hypoxemia and at the end of reoxygenation with a CO-Oximeter 482 (Instrumentation Laboratory, Lexington, MA).

Samples for measuring plasma ET-1 were drawn from aorta at baseline, at 15 and 30 min of hypoxemia (results not shown), at the end of hypoxemia, and at 30 and 120 min of reoxygenation. In addition, one sample was also drawn from the pulmonary artery at the end of hypoxemia. All samples were immediately put in prechilled EDTA tubes on ice, and centrifuged at 3°C for 6 min at 1600 × g. One milliliter of plasma was transferred to prechilled polypropylene tubes and stored immediately at -70°C, until analysis within 14 d.

The analysis was performed by an enzyme-linked immuno-adsorbent assay (Parameter, R&D Systems, Abington, UK). One milliliter of plasma was extracted with 1.5 mL of extraction solvent (acetone 1 M CHl/water = 40:1:5), vortexed, and centrifuged at 2000 × g for 20 min at 4°C. The supernatant was decanted and dried in a centrifugal evaporator (Savant AES 1010) for 4 h using an external light source for 50 min. The sample was reconstituted in 0.25 mL of sample diluent and vortexed, giving an up-concentration of 4. Each sample was analyzed in duplicate directly after reconstitution. Two antibodies, directed at different epitopes of the ET-1 molecule, were used, and the colored product from a horseradish peroxidase reaction was measured at 620 and 450 nm in a spectrophotometer. The intraassay coefficient of variation for the kit is 4.2%, and plasma samples are relatively stable between 1 wk and 2 mo in storage at -70°C (data not shown). All withdrawn blood samples were replaced with a double volume of 0.9% saline.

Data collection and analysis. MABP, PAP, CVP, LAP, CO, and HR were logged into a computer using a software system developed for the logging of data (Work Bench PC for Windows, Sunnyvale, CA). Using a logging frequency of 0.5 Hz, CI, SVRI and PVRI were continuously calculated in the computer system during the experiment. SVI and SVRI/PVRI ratio were calculated at the end of the experiment. The formulas for calculations of the measured variables are as follows: CI = CO/body weight; SVRI = (MABP - CVP)/CI; PVRI = (PAP - left arterial pressure/CI; SVI = CI/HR.

The exact time point for start and end of hypoxemia was registered in the data file so that comparison of the time course between the groups could be performed accurately. Before statistical evaluation, mean values for the logged and calculated variables for each animal were calculated in blocs of 1 min (mean of 30 samples) at baseline and during hypoxemia, in blocks of 12 s (mean of 6 samples) during the first 10 min of reoxygenation, in blocks of 30 s (mean of 15 samples) from 10 to 25 min of reoxygenation, and in blocks of 1 min through the rest of the reoxygenation period.

Statistics. All values are given as mean ± SEM. The control group was performed to investigate the stability of the preparation and was included in the statistical analysis only at baseline. At baseline, the analyses have been performed by using a Kruskal-Wallis test for the three groups. During hypoxemia, all variables were compared with baseline; both groups were combined because the treatment was identical and the randomization took place at the end of hypoxemia. During reoxygenation, each group was compared with baseline values for the same group. For statistical analysis, we have looked at the changes of the recorded and calculated hemodynamic variables at 1, 2, 5, and 10 min of reoxygenation for an investigation of the hemodynamic changes during early reoxygenation. Evaluation during hypoxemia and comparison of each group to baseline during early reoxygenation was performed by using a Wilcoxon signed rank test. Comparison of the two groups during early reoxygenation was performed by using a Mann-Whitney U test. When repeated analyses (n) during a time course were done (hypoxemia or early reoxygenation), a Bonferroni correction was performed before presenting the results [p = p* × (n - 1)]. All analyses were done with a statistical computer program (StatView 4.5.1, Abacus Concepts, Inc., Berkeley, CA).

Approval. The experimental protocol was approved by the Norwegian Animal Experimental Board.

RESULTS

There were no differences in age: 61 ± 5, 45 ± 5, and 63 ± 6 h; or body weight: 1.809 ± 132, 1.712 ± 90, and 2.078 ± 225 g in the room air, oxygen, and control groups, respectively; and no difference in hypoxemia time: 45 ± 4 and 53 ± 5 min in the room air and oxygen groups, respectively. The two hypoxemia groups were also comparable with regard to MABP, PAP, CI, SVRI, PVRI, HR, SVI, and blood gases (Table 1) at baseline (5 min before start of hypoxemia). There were no significant differences between the two groups during hypoxemia or at the start of reoxygenation with regard to the same variables. During the study period Hb was reduced from 78 ± 3 to 74 ± 3 g/L (p = 0.018) in all three groups combined.

Table 1 Changes in blood gases and acid/base status
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Pulmonary hemodynamics. PAP increased significantly from 21 ± 1 mm Hg at baseline to 33 ± 2 mm Hg at midhypoxemia (both groups combined) and decreased to 24 ± 2 and 27 ± 3 mm Hg at the end of hypoxemia in the room air and oxygen groups, respectively (Fig. 1). During early reoxygenation there was a rapid increase in PAP to values significantly above baseline: 28 ± 3 and 28 ± 2 mm Hg at 1 min and 35 ± 3 and 30 ± 2 mm Hg at 5 min of reoxygenation in the room air and oxygen groups, respectively. PAP returned to values comparable to baseline within 90 min of reoxygenation in both groups. There were no differences between the two groups during early reoxygenation as well as the rest of the observation period.

Figure 1
figure 1

PAP during hypoxemia and reoxygenation. H5, 5 min of hypoxemia; Mid, mid time hypoxemia for each animal; R5, 5 min before end of hypoxemia; R0, end of hypoxemia. The points of 1- and 2-min reoxygenation are not shown on the x axis. Mean ± SEM. §p < 0.003 both groups combined vs baseline; *p = 0.036 both groups combined vs baseline; #p = 0.023 vs baseline each group; ¥p = 0.033 vs baseline each group.

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PVRI increased from 0.08 ± 0.01 mm Hg mL kg-1 min-1 at baseline to 0.22 ± 0.04 mm Hg mL-1 kg-1 min-1 (p < 0.003) at the end of hypoxemia (Fig. 2). During early reoxygenation PVRI decreased rapidly in both groups. At 1 min of reoxygenation PVRI was barely different from baseline in any of the groups. At 5 min of reoxygenation PVRI was comparable to baseline in both groups. There were no differences between the two groups during early reoxygenation, as well as the rest of the observation period.

Figure 2
figure 2

PVRI during hypoxemia and reoxygenation. §p < 0.003 both groups combined vs baseline; #p < 0.04 oxygen group vs baseline; ¥p = 0.05 room air group vs baseline.

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Systemic hemodynamics. SVRI was reduced from 0.29 ± 0.03 mm Hg mL-1 kg-1 min-1 at baseline to 0.18 ± 0.03 mm Hg mL-1 kg-1 min-1 (p = 0.12) at the end of hypoxemia and increased to 0.21 ± 0.04 (NS) and 0.22 ± 0.03 mm Hg mL-1 kg-1 min-1 (NS) at 10 min of reoxygenation in the room air and oxygen groups, respectively.

The SVRI/PVRI ratio decreased from 3.9 ± 0.3 at baseline to 0.9 ± 0.1 at end of hypoxemia, increased to 1.2 ± 0.2 and 1.7 ± 0.3 at 1 min, and to 2.6 ± 0.3 and 2.4 ± 0.2 at 10 min of reoxygenation in the room air and oxygen groups, respectively (Fig. 3). There were no differences between the two groups during reoxygenation.

Figure 3
figure 3

SVRI/PVRI ratio during hypoxemia and reoxygenation. *p = 0.012 both groups combined vs baseline; #p < 0.05 each group vs baseline.

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MABP decreased during hypoxemia to values significantly below baseline at midhypoxemia and end hypoxemia (Table 2). During early reoxygenation there was a rapid increase in MABP. At 5 min of reoxygenation, MABP was not different from baseline in the two groups. There were no differences between the two groups during reoxygenation.

Table 2 Mean arterial blood pressure (mmHg) during hypoxemia and reoxygenation
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CI increased during early hypoxemia and was reduced during late hypoxemia to values almost 50% of baseline (Fig. 4). During early reoxygenation there was a rapid increased of CI in both groups to values comparable to baseline and for the room air group significantly above baseline at 5 min of reoxygenation. There were no differences between the two groups during reoxygenation.

Figure 4
figure 4

CI during hypoxemia and reoxygenation. §p < 0.003 both groups combined vs baseline; *p = 0.021 both groups combined vs baseline; ¥p < 0.05 vs baseline.

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SVI decreased to 50% of baseline during hypoxemia (Fig. 5). During early reoxygenation there were rapid increases in SVI toward baseline values in both groups. There were no differences between the two groups during reoxygenation.

Figure 5
figure 5

SVI during hypoxemia and reoxygenation. §p < 0.004 both groups combined vs baseline. NS in any group vs baseline during early reoxygenation.

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HR increased during hypoxia but was not different from baseline at the end of hypoxemia (Table 3). During reoxygenation there was an increase in HR in both groups, reaching significance only at 5 min in the oxygen group. There were no differences between the groups during reoxygenation.

Table 3 Heart rate (beats/min) during hypoxemia and reoxygenation
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Blood gases and acid base status. There were no differences in pH or BE between the two groups during hypoxemia or reoxygenation (Table 1). There were no differences in PaCO2 during hypoxemia. During reoxygenation there was a significant difference only at 30 min of reoxygenation. There were no differences between the two groups in PaO2 at baseline or during hypoxemia. During reoxygenation PaO2 in the room air group was not significantly different from baseline; Pao2 in the oxygen group was significantly higher than baseline and the room air group. At the end of reoxygenation both pH (p < 0.012 in each group) and BE (p < 0.008 in each group) were significantly lower than baseline.

Plasma ET-1. There was a highly significant reduction in aortic plasma ET-1 at the end of hypoxemia (p = 0.0028) (Table 4). During reoxygenation there was a highly significant increase in aortic plasma ET-1 at 30 min of reoxygenation (p = 0.0077 and p = 0.0015 in the room air and oxygen groups, respectively), reaching levels comparable to baseline. Furthermore, there were no differences between the two groups at 30 min and 2 h of reoxygenation. Aorta and pulmonary artery samples did not show any difference in plasma ET-1 concentration at the end of hypoxemia (p = 0.78, both groups combined).

Table 4 Plasma Endothelin-1 (ng/L) during hypoxemia and reoxygenation
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During the study period, the control group was stable (Table 5). At baseline the control group was comparable to the two hypoxemia groups for all recorded or calculated variables. There were no significant differences for any of the variables during the study period.

Table 5 Control group; values at baseline and end of experiment
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DISCUSSION

In this study we demonstrated that the hypoxemia-induced increase in PVRI was normalized as efficiently during early reoxygenation when reoxygenation was performed with room air as with 100% oxygen and that the hypoxemia-induced increase in PAP during early reoxygenation is similar when performed with either room air or with 100% oxygen. Furthermore, we have shown that the reduced SVI during hypoxemia was normalized as quickly with room air as with 100% oxygen. The combination of a moderate increase in HR and an almost doubling of SVI led to an increase of CI by approximately 150% within 5 min of reoxygenation in the two groups. Furthermore, we have demonstrated that aortic plasma ET-1 concentrations were significantly reduced during hypoxemia and returned to baseline levels within 30 min of reoxygenation. We have therefore not been able to confirm the assumption that supranormal arterial concentrations of oxygen leads to a more rapid dilatation of the pulmonary vascular bed during reoxygenation following hypoxemia.

The increase in CI is measured as an increase in flow in the pulmonary artery proximal to the ductus arteriosus. The ductus arteriosus is anatomically open in piglets at birth but is reported to be functionally closed within 4 h (16). During the study we did an echocardiographic examination in four piglets during late hypoxemia and early reoxygenation. We did not find any flow in the ductus arteriosus in any of the piglets. This result is supported by other studies (17,18). It is therefore not likely that a shunt through the ductus arteriosus should interfere with our results.

The foramen ovale is functionally closed at birth because of a higher pressure in the left side of the heart after birth. During hypoxemia and reoxygenation MABP was higher than PAP. At the end of hypoxemia, MABP and PAP were comparable (24 ± 4 and 25 ± 2 mm Hg, respectively). Within 1 min of reoxygenation, MABP exceeded PAP (35 ± 3 and 28 ± 2 mm Hg, respectively). It is not likely that a flow-through foramen ovale would interfere with our results.

Under normal conditions, PaO2 levels achieved with room air will almost fully saturate Hb. However, because acidosis markedly reduces the affinity of Hb for oxygen, this was not the case in this study. Calculated oxygen saturation (based on a standard human oxygen dissociation curve) in the 21% O2 group was about 75% after 15 min of reoxygenation. Despite this, the normalization of the measured and calculated hemodynamic variables were comparable in the two groups.

The response to hypoxemia was different in the pulmonary and systemic resistance vessels. In the pulmonary vascular bed there was a vasoconstriction, leading to a 3-fold increase in vascular resistance. In the systemic vascular bed there was a decrease in resistance by more than 50%. At the end of hypoxemia, the mean pressure in the pulmonary vascular bed was 1 mm Hg above mean systemic pressure, leading to a highly significant reduction of the SVRI/PVRI ratio. This strongly indicates that there are different mechanisms regulating the pulmonary vascular resistance vessels and systemic resistance vessels during hypoxemia.

In the mature fetal lamb the pulmonary circulation is sensitive to oxygen; this is not the case with immature lambs (19,20). When the mature lamb fetus was exposed to hyperoxia with a 6.5-fold increase of PaO2, the pulmonary blood-flow increased 9- to 10-fold; in the immature lamb fetus the response to hyperoxia was almost absent (20% increase). Ventilation of the term fetus with a hypoxic gas mixture, which did not change the fetal blood gases, increased the pulmonary blood flow 4-fold and decreased the PVR to one third of baseline (21). In that study, pulmonary blood flow increased to values 6 times baseline and PVR decreased further to 10% of baseline by ventilation with 100% O2.

In newborn lambs, there were no changes in the pulmonary circulation when excess of O2 was introduced at baseline levels (10). After hypoxia, there was a rapid reduction in PAP and PVR when 100% oxygen was introduced, which may be interpreted as a beneficial effect of hyperoxia. However, in this study there were no comparisons with alternative O2 concentrations or with room air.

Hypoxia without generation of acidosis led to pulmonary vasoconstriction in newborn piglets (18), and it was attenuated by hypocarbia in 0- to 3-d-old lambs (22). When normocarbia was reestablished the response returned to baseline hypoxia levels. The mechanical influence from the increased ventilation rate, keeping PaCO2 unchanged by adding CO2 to the inhalation gas, did not interfere with the pulmonary vasoconstriction in lambs 1 to 3 d of age (8). Alkalosis achieved by hyperventilation was responsible for the attenuated vasoconstriction during hypoxia, rather than reduction of PCO2 in lambs less than 1 wk of age (23). In a model of pulmonary hypertension induced by U46619 (a thromboxane A2 analog) or by Nω-nitro-L-arginine, an inhibitor of NO synthesis, there was a significant reduction of PAP and PVR when the ventilation was performed either with excess of oxygen or with hyperventilation with room air, leading to alkalosis in lambs less than 1 wk of age (24).

There is strong evidence that ET-1 is involved in the regulation of pulmonary circulation (14). Infusion of ET-1 during hypoxia in pigs led to attenuated pulmonary hypertension (25). In piglets normoventilated with 100% oxygen, an infusion of a high dose of ET-1 led to a biphasic response: an early reduction of PAP and PVR and a later increase in PAP with PVR back to baseline (26). The action of ET-1 may be dose-dependent: in low concentrations ET-1 acted as a vasodilator and in higher concentrations as a vasoconstrictor of the pulmonary vascular bed both during the baseline situation and during pulmonary hypertension induced by U-46619 (27) or by hypoxia (28). Blocking of the ETA-receptor during hypoxia with BQ-123 (a selective ETA-receptor antagonist) did not change the pulmonary vascular response to hypoxia (28). ETB-receptor agonists mediated pulmonary vasodilatation in a lamb model with induced pulmonary hypertension by U-46619 (29) and in a near-term fetal lamb model (30).

In isolated piglet lungs, both perfusion with a selective ETB-receptor agonist and infusion of ET-1 led to vasodilatation (31). In another study, in isolated piglet lungs, blocking of the ETA receptor with BQ-123 resulted in incomplete blocking of the constrictor response of ET-1 (32). These findings indicate that ET-1 acts both via the ETA and the ETB receptors, and that the ETA receptor acts as a vasoconstrictor and the ETB receptor acts as a vasodilator of the pulmonary vascular bed. This may indicate that the pulmonary hypertension caused by hypoxemia is partly mediated by reduced plasma ET-1, leading to reduced vasodilator response from the ETB-receptor on the smooth muscular cells. The results from the present study with a reduction of ET-1 during hypoxic pulmonary vasoconstriction support these indications. However, further investigations are needed to learn more about the influence of ET-1 on the regulation of the pulmonary vascular tone.

The present study confirms previous findings from our group that room air and 100% oxygen is just as effective in normalizing MABP, HR (33), pH, and BE (33,34). Because PaO2 in the room air group during reoxygenation is comparable to baseline values, this indicates that the gas exchange ability in the lung tissue was not damaged by hypoxemia in this experimental model.

In conclusion, this study suggests that the normalization of pulmonary hemodynamics is just as efficient when reoxygenation is performed with room air compared with the recommended use of 100% oxygen. Furthermore, the study suggests that CI is normalized just as quickly with room air as with 100% O2. Therefore, reoxygenation with room air seems adequate for pulmonary hemodynamics. Furthermore, ET-1 decreases during hypoxemia; this may indicate a vasodilatory effect on the pulmonary vascular bed.