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From the École d’Optométrie, Université de Montréal, Montréal, Québec, Canada.
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Abstract |
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METHODS. In this experiment, 16 and 22 healthy volunteers breathed 100% O2 and carbogen, respectively. POBF and intraocular pressure (IOP) were measured twice with a UK OBF tonograph for each of the following conditions: in ambient room air breathing, after breathing pure O2 or carbogen through a face mask, and in ambient room air 10 minutes after mask removal. Heart rate (HR), hemoglobin oxygen saturation level (SaO2), and systemic arterial blood pressure (BP) were monitored throughout testing. The end-tidal CO2 (EtCO2) level and respiratory rate (RR) were also recorded during carbogen breathing.
RESULTS. Results revealed that HR was reduced (P < 0.004) and SaO2 was increased (P = 0.0001) by both oxygen and carbogen breathing. Systemic arterial BP remained stable throughout the experiment. EtCO2 was increased during carbogen breathing (P = 0.0001), whereas RR was reduced (P = 0.0175). IOP was significantly decreased during both phases of the experiment (P = 0.0001). Finally, POBF was not altered by pure O2 breathing, but it increased on average by 7.7% during carbogen breathing (P = 0.0222).
CONCLUSIONS. The data obtained with POBF tonography indicate that the choroid reacts to increased blood CO2 concentration, but not to systemic hyperoxia, in a manner similar to that in retinal and brain vessels.
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Introduction |
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The response of the retinal circulation to variations in inspired O2 and CO2 concentrations has been widely studied in the past decades in both animals and humans. Hyperoxia is known to constrict retinal vessels1 2 3 4 and to reduce blood flow,2 3 4 5 whereas hypoxia2 and hypercapnia5 6 7 8 dilate retinal vessels and increase blood flow. Carbogen, a gas mixture usually containing 4% to 7% CO2 and 93% to 96% O2, has frequently been used in humans for the treatment of central retinal artery occlusion. The assumption is that CO2 will prevent oxygen-induced vasoconstriction and, therefore, maintain or even increase blood flow while providing the retina with increased oxygenation.1 3 5 In fact, recent studies have shown that carbogen breathing oxygenates the retina better than O2 alone.9 10 However, retinal hemodynamic results obtained with carbogen are still controversial. Specifically, in some studies carbogen did not reduce the vasoconstrictive effect of pure O2 breathing,1 3 11 whereas results from other investigations indicate that carbogen decreases retinal blood flow to a lesser extent than 100% O23 and increases perimacular leukocyte velocity5 and retinal blood velocity.11
The control of the choroidal circulation is quite different from that of the retinal vasculature. Choroidal blood flow (ChBF) is very high compared with other vascular beds in the body6 and has long been considered to exceed local metabolic requirements. This high flowrate has, therefore, been attributed a major role in stabilizing the temperature of the eye according to changes in the environment, such as is the case during intense light stimulation.12 13 The work of Linsenmeier14 demonstrates, however, that the choroid also plays a vital role in ensuring the proper oxygenation of the distal retina. Linsenmeier14 has shown that the choroid must have a very high flow rate to maintain the high venous partial pressure of oxygen that is required to properly nourish the photoreceptors. Several researchers have suggested that variations in choroidal circulation are primarily due to autonomic innervation, as opposed to vascular myogenic factors or metabolism within the outer retina.12 13 15 However, more recent investigations in rabbits demonstrate that myogenic factors may regulate the choroid to minimize arterial pressure changes in choroidal blood volume.16 17 18
Studies evaluating the effects of inspired O2 and CO2 concentrations on choroidal circulation are limited, especially in humans. Some authors have reported that systemic hyperoxia decreases ChBF in albino rabbits19 and cats,20 and hypercapnia increases ChBF and choroidal blood volume.6 19 20 Carbogen breathing also increases choroidal blood volume and ChBF and reduces choroidal peripheral resistance in albino rabbits.19 In the monkey, hyperoxia slightly decreases blood circulation within the choriocapillaris at the level of the posterior pole, whereas CO2 breathing increases blood flow throughout the choriocapillaris.21 These modifications are likely due to altered vessel resistance within the choroidal arteries during blood gas perturbation.22
In humans, laser Doppler flowmetry measurements indicate that hyperoxia does not affect the foveolar ChBF23 but that hypercapnia increases ChBF in the fovea. Other studies measuring fundus pulsations in the macula by laser interferometry have shown that hyperoxia slightly reduces ChBF24 25 but that CO2, combined with either air24 or oxygen,25 increases ChBF in the macula.
Few studies have investigated more global variations in ChBF in response to changes in the environment. The purpose of this study was to evaluate the global response of the choroidal vasculature to 100% O2 and carbogen breathing in humans with noninvasive recordings of pulsatile ocular blood flow (POBF).
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Materials and Methods |
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Pulsatile Ocular Blood Flow and Intraocular Pressure
The POBF was measured with a handheld ocular blood flow pneumatic
tonometer (OBF laboratories UK Ltd., Malmesbury, Wiltshire, UK). This
instrument allows repeated tonometry recordings at a rate of 200/sec,
and it measures dynamic changes in intraocular pressure (IOP) over
time. The computerized tonometer system analyzes the various
characteristics of each IOP pulse wave and compares them to one another
as they are recorded. The pulses are compared for shape, amplitude,
systolic and diastolic times, and the base level of IOP. The five most
representative pulses are selected and processed to mathematically
derive POBF values from the IOP readings. This method provides a
high-fidelity measure of the IOP and its time variation.26
Before the measurements, each subject was asked to sit on a comfortable chair and rest for 10 to 15 minutes to stabilize the various pressures within the body. The cornea of the right eye was anesthetized with one or two drops of proparacaine HCl 0.5%. Care was taken to ensure that the head was resting straight up against the chair, without any bending of the neck, to avoid any perturbations of blood flow in the vessels of the neck. The head was kept in the same position throughout testing. Subjects were asked to fixate either the red light-emitting diode housed within the tonometer probe or a fixation target on the wall. Two POBF measurements were taken for each of 3 conditions: while subjects were breathing ambient room air (baseline), at the end of a 5-minute period of pure O2 breathing (O2 experiment) or at the end of a 10-minute period of carbogen breathing (carbogen experiment) through a face mask, and while the subject was breathing room air, 10 minutes after removing the mask. One or two drops of artificial tears were administered on the surface of the eye before the second measurement for each test condition. This precaution was found to optimize the quality of the results by improving the contact between the probe and the cornea as well as by better preserving the integrity of the corneal epithelium. All manipulations were performed by the same experienced person.
Phase 1: Oxygen Breathing
Pure O2 from a cylinder tank was
administered through a disposable high-concentration
O2 mask with a one-way valve and a 1-liter
reservoir bag (Inspiron, Intertech Resources, Bannockburn, IL). The
mask was adjusted as tight and comfortable as possible, and the subject
was asked to breathe normally inside the mask. The flow rate of
O2 was adjusted to 5 l/min, a level found to
provide adequate ventilation for all subjects.
Phase 2: Carbogen Breathing
The carbogen used contained a mixture of 5%
CO2 and 95% O2.
High-concentration disposable O2 masks with a
one-way valve and a 1-liter reservoir bag (Inspiron; Intertech
Resources) were modified slightly for the carbogen study to further
increase their airtightness. The flow rate of carbogen was started at
8.5 l/min and adjusted for each subject according to the speed at which
the reservoir bag deflated and inflated during the respiratory cycle.
End-Tidal CO2 and Respiratory Rate Monitoring
End-tidal CO2 (EtCO2)
and respiratory rate (RR) were monitored during the carbogen
experiment. A disposable nasal cannula (model No. 1606; Salter
Laboratories, Arvin, CA) was connected to a capnograph
(EtCO2/SaO2 monitor, model
7100, CO2SMO; Novametrix, Medical Systems,
Trudell Medical, London, Ontario, Canada) that monitored and recorded
the EtCO2 levels and RR every 8 seconds. Subjects
were asked to breathe as normally as possible by the nose only, to
enable a portion of the expired gas to be evacuated by the cannula and
then collected and analyzed by the capnograph. The excess in expired
gas was evacuated through the one-way valve on the side of the face
mask.
Arterial Blood Pressure, Oxygen Saturation and Heart Rate
Monitoring
The systemic arterial blood pressure (BP) was monitored with a
90601 SpaceLabs monitor (Redmond, WA). Two consecutive measurements of
systolic, diastolic, and mean arterial BPs were taken 2 to 3 minutes
before the POBF measurement within each phase of the experiment. The
heart rate (HR) and oxygen saturation level
(SaO2) level were continuously monitored by
finger pulse oximetry.
Time Control Study
To ensure that any changes in the variables measured in the two
phases of the experiment were directly related to either
O2 or carbogen breathing, we conducted a time
control study on 10 subjects (mean age, 23.1 years; SD, 4.1 years).
Each participant underwent the same experimental protocol described
above, where POBF (and therefore IOP) was measured (1) while breathing
ambient room air, (2) immediately after 10 minutes of wearing the mask,
and (3) while breathing ambient air after 10 minutes of mask removal.
For this control study, however, no gas was delivered into the face
mask, which was slightly modified with an opening in the front to allow
subjects to breathe ambient room air. For each of the three phases of
this control study, the systemic BP was measured using automated
sphygmomanometry just before the POBF/IOP recordings. Two measurements
of both the systemic BP and the POBF/IOP were averaged to derive each
data point. Throughout the time control evaluation,
EtCO2, RR, SaO2, and HR
were monitored by capnography involving a nasal cannula (for
EtCO2 and RR values) and a finger probe (for
SaO2 and HR recordings). For all four variables
measured, an average of the recordings obtained within the last 5
minutes of the evaluation (in all three phases of this control study)
was considered representative of the individual variables. By closely
monitoring the digital readings on the capnograph, we ensured that the
subjects did not breathe their expired air; a digital indicator on the
capnograph warned the experimenter each time this happened. For a few
subjects, the mask had to be slightly repositioned on a few occasions
during the 10-minute breathing period because the indicator signaled
that CO2 was being inspired. The repositioning of
the mask cleared that signal, which was on for a few seconds only.
Data Analyses
The mean of two consecutive measurements of POBF, IOP, and BP was
calculated for each subject, and repeated-measures ANOVA was performed
across the mean values taken before, during, and after gas inhalation.
For the carbogen experiment, data acquired within the last 5 minutes of
each condition were averaged and taken as representative values for
EtCO2, RR, SaO2, and HR.
This corresponded to the phase within each test condition in which the
EtCO2 levels were most stable. The mean values
were calculated, and repeated-measures ANOVA was performed to compare
the results between test conditions. For all variables, the level of
significance was set to P < 0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The RR was reduced from 15.7 to 14.2 breaths/min (-9.6%) with carbogen and recovered to 15.5 breaths/min after 10 minutes in ambient air (P = 0.0175). The mean HR was reduced from 75.4 to 72.8 bpm (-3.5%) during carbogen inhalation and returned to its baseline value 10 minutes after mask removal (P = 0.0005). All subjects had normal baseline systolic (average, 120.66 mm Hg), diastolic (average, 71.8 mHg), and mean (average, 86.84 mm Hg) arterial BP levels that remained stable throughout the experiment.
The mean IOP was reduced from 15.2 mm Hg in ambient air to 14.0 mm Hg during carbogen inhalation, and it was still low (13.3 mm Hg) 10 minutes after the end of carbogen breathing (P = 0.0001; Fig. 1 ). The mean POBF at baseline was 822 µl/min. The POBF increased on average by 7.7% with carbogen breathing (P = 0.0222; Fig. 2 ). The POBF values at the end of the experiment were not different from those recorded during baseline and carbogen breathing conditions.
Time Control Study
The averaged data (n = 10) for POBF;
EtCO2; RR; systemic, diastolic, and mean BP;
SaO2; and HR monitored throughout the time control study
did not vary (P 
0.08). The systemic systolic BP
decreased (P = 0.0174) from 119.0 to 116.15 mm Hg
during the period when the face mask was worn, and it returned to
baseline (119.4 mm Hg) 10 minutes after mask removal. The IOP changed
(P = 0.0001) from 14.8 mm Hg (at baseline) to 13.1 mm
Hg (with face mask), and it was 12.4 mm Hg at the end of 10 minutes of
ambient room air breathing after the mask was removed.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The RR was not monitored in the first experiment involving pure O2 breathing, but it was found to be reduced during the carbogen breathing condition. This finding is probably related to a high O2 content in the inspired gas. Hyperoxia is known to reduce the RR and tidal volume, whereas CO2 normally increases these two variables to increase the minute ventilation and better eliminate the excess of CO2.28 In the present study, although carbogen produced a significant decrease in RR, eight subjects reported that their breaths seemed to be amplified during carbogen inhalation. The minute ventilation was not monitored, but it may be that the decrease in RR was compensated for by an increase in tidal volume during carbogen breathing.
Consistent with our findings, a decrease in HR during O2 breathing has been reported by investigators previously,25 but it is not a universal finding.29 30 Some studies have also indicated that an increase in CO2 concentration in inspired air is accompanied by an increase in HR,7 30 31 although other reports have shown that changes in CO2 levels do not affect HR.8 These previous experiments were not conducted with carbogen, however, which means that there was a failure to induce hyperoxia and may thus explain the discrepant findings. Moreover, in the present study, the stimulating effect of CO2 on HR may likely have been inhibited by the carbogen-induced increase in SaO2 concentration.
In agreement with previous findings, our data show that arterial BP did not vary with O2 breathing.29 30 Several investigations in which BP levels have been monitored during hypercapnia not accompanied by hyperoxia have revealed that BP remains unchanged,8 30 or increases slightly,7 24 during this manipulation. Data on BP variations with carbogen breathing are limited, however. Schmetterer et al.25 found an increase in the mean arterial BP, and in a parallel experiment,32 we found that 10 minutes of carbogen breathing increased diastolic, but not systolic, BP.
The presently observed decrease in IOP is probably due to both O2 breathing and repeated tonometry measurements. A reduction in IOP with O2 breathing has been demonstrated in humans33 34 and rabbits.34 However, similar results have not been reported by other investigators.24 29 In a control study (n = 20) using a single Perkins measurement and, therefore, minimizing the ocular massaging effect of repeated tonometry, we also found a 1–mm Hg reduction in IOP after a 5-minute period of 100% O2 breathing (P = 0.007), suggesting that at least a small portion of the IOP changes are related to O2 levels. Furthermore, the results obtained in our time control study in which only ambient air was used reveal a decrease in IOP after repeated tonometry. This clearly demonstrates the importance of the massaging effect of repeated tonometry on the reduction of baseline IOP.
The mean POBF values for our baseline conditions (experiment 1: 821 µl/min; experiment 2: 822 µl/min) were in agreement with published normative data obtained with the same system.35 Our data indicate that systemic hyperoxia does not alter POBF. This parallels previous results in cats36 but is in disaccord with other data showing that hyperoxia decreases ChBF.19 20 Studies in humans that investigated the effect of systemic hyperoxia on a more focal aspect of choroidal circulation have demonstrated either no change23 or a slight reduction24 25 in ChBF within the macular area. In the monkey, hyperoxygenation has been found to alter choriocapillary blood circulation at the posterior pole only.21 The POBF technique used in the current investigation evaluates the global response of ocular blood flow and would likely not detect any perturbations restricted to a small area of the fundus.
The response of POBF to increased CO2 concentrations in inspired air that we have demonstrated in this experiment parallels the findings of previous studies investigating ChBF levels within the macula in humans23 24 25 as well as most studies evaluating choroidal circulation in animals,6 19 20 21 22 with the exception of an investigation by Goldstick and Ernest36 showing that CO2 has little effect on choroidal circulation. Importantly, the systemic systolic and diastolic BPs did not vary throughout the experimental protocol, indicating that the changes in blood flow can be safely attributed to alterations taking place in the ocular circulation.
The POBF used in this study is believed to reflect the pulsatile component of the total ChBF. The proportion of pulsatile to nonpulsatile flow has not been clearly identified, but the pulsatile component is believed to approximate 50% to 80% of the total flow.37 38 39 Although POBF tonography is a technology that remains controversial for some,40 it provides valid measurements of the pulsatile component of ocular blood flow26 and can be safely and noninvasively applied in human research. POBF is dependent on arterial pulse pressure amplitude and pulse rate.41 In this study, the various systemic physiological variables measured did not change throughout the experimental protocol. Any alterations in POBF that are associated with O2 or carbogen breathing may, therefore, be attributed to changes in the ocular, rather than the systemic, circulation.
Within the limitations of the instrumentation and experimental protocol used to measure ocular blood flow, our results pertaining to POBF levels represent new data that confirm that the choroid reacts like the retinal,5 6 7 8 11 optic nerve head,30 and cerebral blood42 43 vessels, as well as the vasculature of other organs,6 to an increase in blood CO2 content. The exact mechanism underlying this vasodilation, and consequent increase in blood flow, remains unknown but may likely involve a reduction in arterial pH.6 25 44 45
Carbogen-induced vasodilation and increased blood flow in the choroidal vascular bed may increase O2 diffusion from the choroid through the outer retina. This would provide a better oxygenation to inner retinal layers compared with pure O2,9 10 which is not efficient in supplying adequate oxygenation to the whole retina when retinal circulation is absent or compromised.10 46 47
Animal models investigating retinal PO2, arterial and local pH, electrical activity of the retina, and ocular circulation during the inhalation of different CO2/O2 concentrations may help to determine the relationships between these factors and improve our knowledge of the influence of O2 and carbogen on both ocular circulation and oxygenation of the retina. This may lead to improved therapeutic modalities for various vascular/ischemic ocular disorders. One should be careful, however, when comparing results obtained from animal versus human studies. Typically, animal studies are performed under systemic anesthesia, which may introduce a bias in experimental designs, especially when the vascular system is being examined. It has been shown that some anesthetic agents impair blood flow48 49 and O2 delivery to tissues,49 even when mechanical ventilation is provided. Lee et al.50 have demonstrated that anesthesia also alters the cerebrovascular response to CO2 inhalation. Therefore, the constant evolution of noninvasive techniques, such as POBF tonography, laser interferometry, and laser Doppler flowmetry, are instrumental in investigating ChBF in humans. Parallel objective and noninvasive evaluations of visual function and ocular structure, such as those provided by electrophysiological recordings or scanning laser tomography, are also important to correlate visual function and ocular structure with altered ocular hemodynamics.
In summary, our results obtained with POBF tonography indicate that the choroid reacts in a fashion similar to that of retinal and brain vessels to increased blood CO2 concentration, but not to systemic hyperoxia.
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Acknowledgements |
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Footnotes |
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Submitted for publication November 11, 1998; revised April 19, 1999; accepted May 27, 1999.
Commercial relationships policy: N.
Corresponding author: Hélène Kergoat, École d’Optométrie, Université de Montréal C.P. 6128, Succursale Centre–Ville, Montréal (Québec) Canada H3C 3J7. E-mail: kergoath{at}ere.umontreal.ca
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