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University Laboratory of Physiology, University of Oxford, Oxford OX1 3PT, United Kingdom
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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In humans, 8 h of isocapnic hypoxia causes a progressive rise in ventilation associated with increases in the acute ventilatory responses to hypoxia (AHVR) and hypercapnia (AHCVR). To determine whether 8 h of hyperoxia causes the converse of these effects, three 8-h protocols were compared in 14 subjects: 1) poikilocapnic hyperoxia, with end-tidal PO2 (PETO2) = 300 Torr and end-tidal PCO2 (PETCO2) uncontrolled; 2) isocapnic hyperoxia, with PETO2 = 300 Torr and PETCO2 maintained at the subject's normal air-breathing level; and 3) control. Ventilation was measured hourly. AHVR and AHCVR were determined before and 0.5 h after each exposure. During isocapnic hyperoxia, after an initial increase, ventilation progressively declined (P < 0.01, ANOVA). After exposure to hyperoxia, 1) AHVR declined (P < 0.05); 2) ventilation at fixed PETCO2 decreased (P < 0.05); and 3) air-breathing PETCO2 increased (P < 0.05); but 4) no significant changes in AHCVR or intercept were demonstrated. In conclusion, 8 h of hyperoxia have some effects opposite to those found with 8 h of hypoxia, indicating that there may be some "acclimatization to hypoxia" at normal sea-level values of PO2.
ventilation; acute ventilatory response to hypoxia; acute ventilatory response to hypercapnia
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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IN HUMANS, ON
EXPOSURE to hypoxia there is an abrupt increase in ventilation
(
E) and an associated decrease in end-tidal PCO2 (PETCO2). If
hypoxia is sustained over a period of hours to days,
E rises further in a process known as ventilatory
acclimatization to hypoxia. This rise in E is
associated with increases in the acute ventilatory response both to
hypoxia (AHVR) (15, 30, 34) and
hypercapnia (AHCVR) (5, 26, 34).
A question that arises naturally from the above observations is whether our sea-level values for AHVR and AHCVR represent basal levels for these sensitivities or whether they can be further suppressed by a period of hyperoxia. In experimental animals, both prolonged hyperbaric hyperoxia (3, 25) and prolonged normobaric hyperoxia (19) blunted the hypoxic ventilatory drive. The hypercapnic ventilatory drive has been reported as either reduced (19) or unchanged (32), although the carotid body's sensitivity to hypercapnia may be augmented (20).
In humans, data on the effects of sustained hyperoxia on the chemoreflexes are scarce. Gelfand et al. (12) studied hyperbaric hyperoxia of 1.5, 2.0, and 2.5 ATA in humans for periods of 17.7, 9.0, and 5.7 h, respectively. They concluded that the ventilatory response to hypoxia was unchanged, whereas the response to CO2 was augmented. However, in their study there was a significant degree of pulmonary oxygen toxicity as demonstrated by an increase in breathing frequency, a reduction in pulmonary diffusing capacity, and a reduction in lung compliance.
The aim of this study was to examine the effects of a sustained period of hyperoxia on respiratory chemoreflex sensitivities in humans but under conditions that would avoid pulmonary oxygen toxicity (6). The particular level and duration of hyperoxia was chosen as 8 h at an end-tidal PO2 (PETO2) of 300 Torr. Because previous studies have shown that hyperoxia causes mild hyperventilation (23) and a decrease in PETCO2 (22), we decided to study both poikilocapnic and isocapnic exposures to hyperoxia.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Subjects
Fourteen healthy subjects (9 men, 5 women) took part in the study. Their average age was 25 ± 9 (SD) yr with a range of 18-55 yr. All were healthy, and none had a history of respiratory disease. The basic experimental procedure was explained to them, but they were naive as to the exact purpose of the experiment and the specific exposure employed on any given day. Each subject visited the laboratory once or twice before the main experimental protocols to be familiarized with the apparatus. Subjects were requested to refrain from alcohol and caffeine-containing drinks on each experimental day. Female subjects participated in the experiments only during the first 14 days of their menstrual cycles. All subjects gave informed consent before participating in the study. The study was approved by the Central Oxford Research Ethics Committee.Protocols
Each subject underwent three different 8-h exposures: 1) poikilocapnic hyperoxia (protocol PH), with PETO2 held at 300 Torr and PETCO2 left uncontrolled; 2) isocapnic hyperoxia (protocol IH), with PETO2 held at 300 Torr and PETCO2 held at each subject's preexposure value; and 3) control (protocol C), in which the subjects breathed air throughout. All exposures were separated from one another by at least 1 wk for any given subject. The order in which the protocols were undertaken differed between subjects. During each exposure,E was measured at hourly intervals.
The sustained effects of the exposure were determined by making a
set of measurements before and 0.5 h after each exposure. First,
air-breathing PETCO2 and
PETO2 were determined. Then, AHVR and
AHCVR were assessed using a set of variations in
PETO2 and PETCO2. The profiles for the variations in
PETO2 and
PETCO2 are shown in Fig.
1, which illustrates an actual set of
measurements on one of the subjects. To determine AHVR,
PETO2 was held at 100 Torr for the first 5 min, and this was followed by six square waves of
PETO2 stepping between 50 and 100 Torr,
with each level of PETO2 lasting for
60 s. PETCO2 was held at 1-2
Torr above the subject's control value. Immediately after this, AHCVR
was assessed under hyperoxic conditions
(PETO2 = 200 Torr) by holding
PETCO2 first at 1-2 Torr above the
control value for 5 min and then at 10 Torr above the control value for
a further 5 min. E was averaged over the last 2 min
of these 5 min periods. The slope of the relation between
E and PETCO2 for these
two points provided an estimate for AHCVR, and the intercept of this
relation with the PETCO2 axis was also
determined.
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Experimental Techniques
A specially built chamber was used to conduct the three 8-h exposures. Subjects were seated comfortably inside the chamber, wearing fine catheters at the opening of each nostril, through which respired gas was sampled and analyzed by mass spectrometry for PO2 and PCO2. The data were logged by computer and analyzed to identify inspiratory and end-tidal values of PO2 and PCO2 on a breath-by-breath basis. At the start of each experiment involving hyperoxia, the composition of the inspired gas required to produce the desired end-tidal gas tensions was estimated and set manually before the subject entered the chamber. Once the subject had entered the chamber, the composition of the inspired gas was adjusted automatically every 5 min, or at manually overridden intervals, to minimize the error between the actual and the desired end-tidal gases. The process has been described in detail elsewhere (14).Measurements of E inside the chamber were made with
the subject breathing through a mouthpiece fixed in series with a
turbine volume-measuring device (18) with his or her nose
occluded. Respiratory flows and timing information were obtained from a pneumotachograph. The total dead space associated with the apparatus was 100 ml. Gas was sampled continuously from this dead space from a
point close to the mouth at a rate of 80 ml/min and was analyzed by
mass spectrometry for PO2 and
PCO2. The data were recorded on a computer
that was also used to determine inspiratory and expiratory
durations and volumes, together with
PETO2 and PETCO2. Each determination of
E involved the subject breathing from the
mouthpiece for 5 min, and in each case the last 2 min of data were
averaged to obtain the value for E for that time point.
Determinations of AHVR and AHCVR were undertaken outside the chamber by using a dynamic end-tidal forcing system. The subject was seated in an upright position and breathed through a mouthpiece with his or her nose occluded with a clip. Respiratory volumes were measured by a turbine volume-measuring device (18) fixed in series with the mouthpiece. A pulse oximeter was attached to the forefinger to monitor the oxygen saturation of the blood. Before the procedure began, a "forcing function" was calculated, which consisted of the predicted inspired gas compositions on a second-by-second basis that would be required to produce the desired levels of PETO2 and PETCO2 in the subject. This forcing function was entered into a computer that controlled a gas-mixing system (17) and was used to generate the initial inspiratory gas mixture. During the course of the experiment, actual values for PETO2 and PETCO2 were passed to the controlling computer from a data-acquisition computer. Deviations of these actual values from the desired values were used to modify the inspired gas mixtures by use of an integral-proportional feedback control scheme. The control scheme has been described in more detail elsewhere (29).
Model Fitting
To quantify AHVR from the data, the responses to the six square waves of hypoxia were fitted by a single compartment model (model 3) as described by Clement and Robbins (7). In this model, totalE is divided
into hypoxia-independent (central) (c) and
hypoxia-dependent (peripheral) (p) components. As isocapnia was maintained in our assessments of AHVR,
c can be assumed constant. The model is given by
![&tgr; <FR><NU>d<A><AC>V</AC><AC>˙</AC></A><SUB>p</SUB></NU><DE>d<IT>t</IT></DE></FR><IT>+</IT><A><AC>V</AC><AC>˙</AC></A><SUB>p</SUB><IT>=</IT>G<SUB>p</SUB>[<IT>100−</IT>S(<IT>t−T</IT><SUB>d</SUB>)]](/content/vol89/issue2/fulltext/655/img001.gif)
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(1) |
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is the time constant for the peripheral chemoreflex,
Td is the time delay for the peripheral
chemoreflex, and S is the saturation (%) of arterial blood, calculated
from PETO2 as described by Severinghaus (31).
In addition to modeling the deterministic effects of hypoxia on the
respiratory system, we also used a model in parallel to describe the
correlation that exists between successive breaths. The particular
model employed was one in state-space form described by Liang et al.
(24)
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(2) |
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(3) |
To fit these models to the data, difference equations were obtained from the models to describe the model output for the current breath in terms of the model output for the previous breath, the input function, and the parameters of the model. These calculations are described in detail for the deterministic component of the model by Clement and Robbins (7) and for the stochastic component of the model by Liang et al. (24).
The parameters of the model (Gp, c, ,
Td, f, and
Rv/Rw) were
then estimated by nonlinear regression. This was undertaken by using
the Numerical Algorithms Group (Oxford, UK) FORTRAN library routine
E04FDF to minimize the sum of squares of the residuals. All of the
parameters were constrained to be >0, and the dynamic parameters were
constrained to be <30 s. Initially, the model was fitted separately to
each determination of AHVR. However, after checking that the values for
and Td did not differ significantly before
and after exposures, the model was refitted to the combined pre- and
postexposure determinations of AHVR with the constraint that and
Td have a common value between the two data
sets. This helped reduce the variance associated with the other
parameter estimates.
Statistical Analysis
ANOVA was used to test the null hypotheses, first, that there was no effect of a prior period of hyperoxia on the variable in question and, second, that the presence or absence of hypocapnia during the hyperoxic exposure had no effect on the variable in question. Subjects were treated as a random factor. Time of measurement (pre- or postexposure) was treated as a fixed factor. Direct tests of the null hypotheses were obtained by introducing further factors for the presence or absence of hyperoxic exposure (i.e., protocols PH and IH vs. protocol C) and for the presence or absence of hypocapnia. The reductions in the squared errors were calculated sequentially. The analysis was performed using the SPSS software package.| |
RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Subjects
All of the 14 subjects completed the study, and none reported discomfort from the chamber exposures.Changes Occurring During the Exposures in the Chamber
End-tidal gases.
Figure 2 illustrates the end-tidal gases,
averaged every 5 min, recorded for each subject while in the chamber.
These plots illustrate the quality of control achieved over the
PETO2 in hyperoxic protocols and
PETCO2 in protocol IH. Average
values for PETCO2 at hourly intervals for
all subjects in each protocol are shown in Fig.
3. During protocol PH,
PETCO2 fell from a preexposure value of
38.9 ± 0.9 to 36.7 ± 0.7 (SE) Torr within the first hour and then remained low for the rest of the exposure.
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Ventilatory responses.
Figure 3 shows the mean ventilatory responses for all subjects for each
exposure measured at hourly intervals over the course of the 8-h
experiments. In isocapnic hyperoxia, E rose
considerably from 9.5 ± 0.5 to 17.3 ± 2.6 l/min in the
first hour, declined progressively after this, but still remained
higher than the preexposure value for the entire 8-h period. Both the
increase in E and the subsequent decline in
E differed significantly (P < 0.01 and P < 0.01) from the responses observed with the
other two protocols. The changes in E appear to be
related mainly to changes in tidal volume (Fig. 3). No significant
changes in respiratory frequency were detected (Fig. 3).
Changes Persisting After the Chamber Exposures
Air-breathing end-tidal gases.
Air-breathing values for PETCO2 and
PETO2, measured before and 0.5 h after the
cessation of each chamber exposure, are listed in Table
1. There was a significant increase in
PETCO2 after the hyperoxic exposures compared with control
(F1,13 = 4.74, P < 0.05).
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AHVR.
An example experimental record (subject 1091, protocol
C) for the measurement of AHVR (and AHCVR) is shown in Fig. 1. It
demonstrates the quality of control over the end-tidal gases attained
during the measurements. The average ventilatory responses and
end-tidal gas tensions for the hypoxic square waves imposed before and
after each protocol are illustrated in Fig.
4. To generate this figure, the six
hypoxic square waves for each assessment of AHVR for a given protocol
were averaged for each subject, and these responses were then averaged
across all the subjects. From Fig. 4, it appears that, after both types
of hyperoxic exposure, the ventilatory response to hypoxia was
decreased.
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c, ,
and Td, as described in METHODS.
Individual subject and mean values for the parameters are given in
Tables 2 and
3. There was a significant
decrease in both Gp
(F1,13 = 8.72, P < 0.05)
and c (F1,13 = 4.76, P < 0.05) after the hyperoxia exposures when compared
with air control. This is consistent with the impressions obtained from
Fig. 4.
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AHCVR.
The slope and intercept (E = 0) for each
determination of the
E-PETCO2
responses are listed in Table 4. There were no significant effects
detected after any of the exposures.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The main findings of this study were as follows.
1) After the initial rise in E on
induction of isocapnic hyperoxia, E fell
significantly over the subsequent 8-h exposure. 2)
Gp was significantly reduced after an 8-h exposure to
isocapnic or poikilocapnic hyperoxia. 3) The component of
E that was insensitive to hypoxia (c) was significantly reduced after an 8-h exposure
to isocapnic or poikilocapnic hyperoxia, and this was associated with a
significant increase in air-breathing
PETCO2 after the exposures. The findings are all the inverse of those experienced with 8-h exposures to isocapnic and poikilocapnic hypoxia (15, 16),
suggesting that there may be a degree of "acclimatization" to
hypoxia at normal sea-level values for PO2.
Poikilocapnic vs. Isocapnic Hyperoxia
The initial responses to the induction of both poikilocapnic and isocapnic hyperoxia were similar to those that have been reported previously in the literature and are considered to arise from stimulatory effects of hyperoxia that have a central origin. In the case of poikilocapnic hyperoxia, a modest reduction in PETCO2 occurs (21) together with a small increase inE (23). In the
case of isocapnic hyperoxia, when the fall in
PETCO2 that normally accompanies a rise in
E is prevented, the rise in E is
more substantial (4). In the present experiments, after the first hour, the increase in PETO2 to
300 Torr under poikilocapnic conditions caused a fall in
PETCO2 of
only 2.2 Torr with a change in E that did not reach
significance, whereas, under isocapnic conditions, this increase in
PETO2 caused an approximate doubling in
E. Essentially, the effects on the respiratory
system are more obvious under isocapnic conditions, when the negative
feedback loop between E and
PETCO2 has been opened, a situation that has analogies with studies of the respiratory response to hypoxia.
A new finding of this study was the progressive decline in
E that was observed over the 8-h exposure to
isocapnic hyperoxia. We are unaware of any other such data for
isocapnic hyperoxia, although Arieli (2) reported a modest
progressive increase in E in rats exposed to 60 h of pure oxygen under poikilocapnic conditions. The progressive
decline in E with 8 h of isocapnic hyperoxia is
the opposite of the progressive increase in E that has been observed over an 8-h exposure to isocapnic hypoxia
(16). By way of contrast, no progressive changes in either
E or PETCO2 were
observed with poikilocapnic hyperoxia. However, this absence of effect
under poikilocapnic conditions may well be a type II statistical error
that arises from the generally less obvious nature of the responses
that occur under conditions when the feedback loop between
E and PETCO2 remains
intact. Consistent with this proposition, the reduction in
c and elevation in air-breathing PETCO2 that occurred after hyperoxic
exposure did not differ between the poikilocapnic and isocapnic exposures.
Possible Mechanisms Underlying the Changes in Respiratory Control After Hyperoxic Exposures
The general pattern of response observed with the 8-h exposures to hyperoxia appears very much to be the converse of the pattern of response to 8-h exposures to hypoxia (15, 16). The decline over 8 h inE
with isocapnic hyperoxia mirrors the rise in E with
8 h of isocapnic hypoxia. The relative absence of effect during
poikilocapnic conditions when the PETCO2
is low is similar for both hyperoxic and hypoxic exposures. On
postexposure testing under isocapnic conditions, the effects of the
hyperoxic exposures were similar whether the exposures were
poikilocapnic or isocapnic, just as was the case for hypoxic exposures.
After hyperoxic exposure, both Gp and c
were decreased as opposed to the increase in Gp and
c after hypoxic exposure. Thus one possible
explanation of the progressive fall in E with 8 h of isocapnic hyperoxia is that it is simply the converse effect of
that observed with an 8-h exposure to hypoxia. If so, it implies that
individuals at sea level possess a degree of acclimatization to the
PO2 of sea level. The increase in air-breathing
PETCO2 seems to support this.
Despite the above comments, it is clearly also possible that the
effects of sustained hyperoxia arise from mechanisms that are different
from those associated with the responses to sustained hypoxia. In
relation to the progressive fall in E associated with the sustained isocapnic exposure to hyperoxia, one possibility is
that whatever causes the initial hyperventilation of hyperoxia is
itself not sustained. Potential causes of the hyperventilation with
hyperoxia include a rise in tissue PCO2 and
H+ concentration centrally, either via a decrease in
cerebral blood flow or via a reduction in the efficiency of
CO2 carriage by the blood (21), and a direct
effect of hyperoxia on central respiratory neurons (13,
27). It does, however, seem less likely that such
mechanisms could also explain the reduction in Gp that is observed after hyperoxic exposure.
Clearly another potential cause of the changes observed with 8 h of isocapnic hyperoxia is that they result from a progressively increasing degree of oxygen toxicity. Pulmonary oxygen toxicity is a well-recognized phenomenon, and the oxygen level and exposure time were carefully chosen in the present study so as to avoid any possibility of this occurring (6). Furthermore, such toxicity is clearly associated with significant increases in respiratory frequency in humans, and these were not present in our data. However, apart from oxygen toxicity within the lungs, oxygen toxicity may also occur at the carotid body. In cats, it has been shown that exposure to pure oxygen at 1 atmosphere for 60-65 h results in ultrastructural changes (28) and a decrease in the chemosensory response to hypoxia in the carotid body (20). Similar structural and functional changes were observed in rats exposed to ~60 h of pure oxygen at 1 atmosphere (2, 9) and in cats exposed to short periods (90-135 min) of 5 atmospheres of pure oxygen (33). In the present study, both the dose and duration of the hyperoxic exposure tended to be much lower than in these animal studies. Thus, in terms of a common mechanism, it is not entirely clear how closely the results from these animal studies should be related to those from the present study.
Oxygen toxicity appears to arise from certain metabolic products of oxygen in the form of reactive oxygen species (11). However, studies in recent years have suggested that reactive oxygen species also play an important role as signal transduction molecules within certain oxygen-sensing pathways (1, 8, 35). In the case of exposure to hyperoxia, an uncertainty therefore arises as to whether any effects that are observed result from indiscriminate damage from free radicals or whether they result from changes in intracellular signaling. Of course, with longer exposures and higher doses of oxygen, the toxic effects are more likely to be dominant.
After the hyperoxic exposures, we did not find any significant change
in either AHCVR or in the intercept of the
E-PETCO2 response
relation with the PCO2 axis. In this sense, our
results are not the complete converse of the effects of an 8-h exposure of hypoxia, in which both AHVR and AHCVR increase (10,
15). One possibility is that the absence of any effect of
hyperoxia on the slope or intercept of the
E-PETCO2 response
relation is a type II statistical error. The significant fall in
c after hyperoxia tends to suggest this notion,
because c may be viewed simply as a point on the
E-PETCO2 response
relation. It could be that some rather longer exposures to hyperoxia
would result in larger responses that would help to clarify this issue.
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ACKNOWLEDGEMENTS |
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We thank D. O'Connor for skilled technical assistance.
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FOOTNOTES |
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This study was supported by the Wellcome Trust. X. Ren holds an Overseas Research Students Award and is supported by a K. C. Wong Scholarship.
Address for reprint requests and other correspondence: P. A. Robbins, Univ. Laboratory of Physiology, Parks Rd., Oxford OX1 3PT, United Kingdom (E-mail: peter.robbins{at}physiol.ox.ac.uk).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Received 30 August 1999; accepted in final form 31 March 2000.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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PETCO2) from control were averaged
every 5 min from the data collected breath by breath over 8 h for
all 14 subjects in all 3 protocols. Protocol PH,
poikilocapnic hyperoxia; protocol IH, isocapnic hyperoxia;
protocol C, control.
, Protocol PH; 
,
protocol IH; 
, protocol C.
