Repeated Pre-Syncope from Increased Inspired CO 2 in a Background of Severe Hypoxia

Abstract

Fan, Jui-Lin, and Bengt Kayser. Repeated pre-syncope from increased inspired CO₂ in a background of severe hypoxia. High Alt Med Biol. 15:70—77, 2014.—We describe a case of experimentally induced pre-syncope in a healthy young man when exposed to increased inspired CO₂ in a background of hypoxia. Acute severe hypoxia (FIO₂=0.10) was tolerated, but adding CO₂ to the inspirate caused pre-syncope symptoms accompanied by hypotension and large reductions in both mean and diastolic middle cerebral artery velocity, while systolic flow velocity was maintained. The mismatch of cerebral perfusion pressure and vascular tone caused unique retrograde cerebral blood flow at the end of systole and a reduction in cerebral tissue oxygenation. We speculate that this occurrence of pre-syncope was due to hypoxia-induced inhibition of brain regions responsible for compensatory sympathetic activity to relative hypercapnia.

Introduction

Syncope is defined as a transient loss of consciousness followed by rapid recovery, and it accounts for a significant portion of emergency department visits and hospital admissions (Kapoor, 1990; Kapoor and Brant, 1992; Van Lieshout et al., 2003). Vasovagal or reflex syncope is the most common type of syncope in both young and elderly subjects (Ganzeboom et al., 2003; Serletis et al., 2006; Tan and Parry, 2008; Van Lieshout et al., 2003) and is preceded by pre-syncope signs (epigastric discomfort, nausea, sweating, desire to change position), with a gradual decline in vascular tone, bradycardia, and hypotension (Kapoor, 2002; Van Lieshout et al., 2003). The pathophysiology of the hypotension/bradycardia reflex in vasovagal syncope is not completely understood, but changes in sympathetic tone are believed to be critical in the peripheral vasodilation preceding syncope (Kapoor, 1990; Kapoor and Brant, 1992; Van Lieshout et al., 2003; Wang et al., 1996). While the hypotension underscores the role of cardiovascular regulation in the development of vasovagal syncope, the subsequent loss of consciousness is ultimately the result of cerebral hypo-perfusion (Ganzeboom et al., 2003; Serletis et al., 2006; Tan and Parry, 2008; Van Lieshout et al., 2003). As such, it is of interest to monitor the response of cerebral blood flow (CBF) while observing such events.

Syncope is well documented during acute exposure to hypoxia (Nicholas et al., 1992; Sagawa et al., 1997; Westendorp et al., 1997; Kapoor, 2002; Roche et al., 2002; Van Lieshout et al., 2003; Halliwill and Minson, 2004), while high altitude acclimatization appears to be rather protective against syncope at high altitude (Thomas et al., 2010). In this case report, we present novel data from two trials of acute exposure to severe hypoxia in combination with relative hypercapnia. We observed pre-syncope symptoms accompanied by hypotension, cerebral hypo-perfusion, and cerebral tissue desaturation in a 21-year old male, when inspired CO₂ tension was increased in a background of hypoxia equivalent to an altitude of 5000 m.

Methods

Subject details

The subject was one of a group of volunteers participating in a study designed to examine the effect of inspired CO₂ on exercise capacity in hypoxia. He was a 21-year-old healthy nonsmoking physically active male (BMI=23.2, Vo₂max=45 mL/kg/min), with no known medical conditions, not taking any regular medication, and no history of syncope. He abstained from caffeine for 12 h and from heavy exercise and alcohol for 24 h prior to the experiments. The experiments were carried out under consistent laboratory conditions (temperature 22.3±0.5°C, humidity 27±7%, barometric pressure 725±4 mmHg). Two medical practitioners were present during the experimental sessions. The study was approved by the Research Ethical Committee of the University Hospitals of Geneva and conformed to the standards set by the Declaration of Helsinki.

Consent

Written informed consent was obtained from the subject for publication of this case report.

Measurements

The following variables were recorded continuously: bilateral systolic, diastolic and mean middle cerebral artery velocity (MCAv, transcranial Doppler ultrasound, ST3, Spencer Technology, Seattle, USA; monitoring probe (2 MHz) power: 50%, depth: 57 mm); heart rate (HR), cardiac output (Q’), stroke volume (SV), total peripheral resistance (TPR), beat-to-beat systolic, diastolic and mean arterial blood pressure (ABP, finger plethysmography, Finometer-MIDI, Finapress Medical Systems, Amsterdam, Netherlands); peripheral O₂ saturation (Spo₂; Rad-7, Masimo, Irvine, USA); breath-by-breath ventilation (V'E), partial pressure of end-tidal O₂ (Peto₂) and CO₂ (Petco₂) (Medgraphics CPX, Loma Linda, USA). Cerebrovascular resistance (CVR) was estimated by dividing mean MCAv by mean ABP. Beat-to-beat heart rate variability was analyzed with dedicated software (Kubios, version 2.1, freely available at http://kubios.uef.fi). We analyzed the HR data separately during the normoxia, hypoxia, and CO₂+hypoxia epochs, and when symptoms were maximal, just after coming off the mouthpiece. Because of the nonstationary characteristics of the data, we removed trend components prior to analysis using the smoothing priors algorithm with a lambda of 500, as recommended by the software manufacturer. The data were analyzed in the frequency domain using a fast Fourier transformation and a Welch window of 256 with a 50% window overlap. We report, as a rough index of sympathetic versus parasympathetic activity, the LF/HF (ratio between low frequency (0.04–0.15 Hz) and high frequency (0.15–0.4 Hz) power, unit less).

Experimental protocol

The original protocol foresaw, with the subject seated on a cycle-ergometer, 4 min of normoxia baseline measurements, 2–3 min of hypoxia, followed by 4 min of increased inspired CO₂, to bring Petco₂ back to normoxic resting levels, before starting an incremental exercise protocol.

Throughout the experimental sessions, the subject wore a nose-clip and breathed through a mouthpiece attached to a low resistance one-way non-rebreathing valve (Hans-Rudolph 2700, Kansas City, USA). The hypoxia and added CO₂ to the inspirate were achieved using a modified gas mixing system (Altitrainer, SMTec, Nyon, Switzerland), described in detail by Fan et al., (2013). For this experiment Fio₂ was set at either 0.21 or 0.10 (in Geneva the equivalent of an altitude of about 5000 m) during normoxia and hypoxia conditions, respectively. Under feedback of on-screen Petco₂ (Datex infrared CO₂ analyzer, Helsinki, Finland), Fico₂ was continuously adapted as to bring Petco₂ to its target value of 40–45 mmHg. The subject was unaware of the rationale of the study and was not informed to what gas mixture he was breathing.

Results

The subject attended the laboratory on four occasions. On the first two visits, he successfully completed incremental maximal cycling tests (30 w/min ramp) in conditions of normoxia and normoxia+CO₂ without any adverse events. On the third occasion, the subject was seated on the cycle ergometer in preparation of the next test, breathing room-air for 4 min. He was then switched to hypoxia for 3 min, followed by increased inspired CO₂ in hypoxia. After 134 sec, pre-syncope symptoms prompted the subject to come off the mouthpiece and request the session to be aborted. The subject reported symptoms of dizziness, blurry vision, and nausea. We invited the subject to come back to the laboratory on another occasion, this time adding the measurement of oxy- (O₂Hb) and deoxygenated hemoglobin (HHb) over the left frontal cortex with near-infrared spectroscopy (index of brain tissue oxygenation; NIRS, Oxymon Mk-II, Artinis, Zetten, Netherlands), expressed as absolute changes from baseline room-air breathing. The experiments were performed at the same time of the day. On the second occasion, the subject was left on hypoxia for more than 4 min before switching to increased inspired CO₂ to exclude that he was not simply developing a vasovagal reaction to hypoxia. The subject indicated that he was fine, after which he was switched to added CO₂. Following 55 sec of breathing CO₂-enriched hypoxic gas, the subject indicated that pre-syncope symptoms were developing again and came off the mouthpiece, requesting the experiment to be aborted. We then excluded the subject from further participation.

Table 1 shows the values for the measured and derived variables during the different epochs of the two episodes of hypoxic+CO₂, as well as the data from the normoxic+CO₂ visit for reference (means over 20 sec at the end of each epoch). Hypoxia alone lowered Peto₂, Petco₂, and Spo₂ during the two episodes by 51–58 mmHg, 3–4 mmHg, and 18%–19 %, respectively (Fig. 1 and 2). At the same time, hypoxia lowered mean ABP, systolic ABP, diastolic ABP, TPR, and HR by 12–20 mmHg, 15–35 mmHg, 11–17 mmHg, 23%–18%, and 12–9 b/min, while V'E, mean, systolic and diastolic MCAv (mean of left and right MCAv), Q’, and SV remained relatively unchanged with hypoxia (Fig. 1 and 2). At the end of the period of added CO₂ in hypoxia, when pre-syncope developed, mean, systolic and diastolic ABP were further lowered by 9–18 mmHg, 14–30 mmHg, and 3–15 mmHg, respectively (Fig. 2). SV dropped by 27–26 mL with inspired CO₂ in hypoxia compared to normoxia, while HR remained relatively unchanged compared to hypoxia only (Figs. 1 and 2). Mean and diastolic MCAv had now dropped by 15%–20% and 51%–55%, respectively, compared to normoxia, while both systolic MCAv and CVR remained relatively unchanged (Figs. 1 and 2). During breathing CO₂ enriched gas in hypoxia, we observed a reduced cardiac cycle time, which was predominantly mediated by a reduced time in diastole (Fig. 3). Inspired CO₂ elevated V'E and Spo₂ by 8.1 L/min and 4%, respectively (Table 1). When pre-syncope symptoms were strongest (when the subject came off the mouthpiece), there was bradycardia and hypotension (Figs. 1 and 2). We observed a distinct triphasic pattern in the MCAv traces, which resulted in slight retrograde blood flow at the end of systole (Fig. 3). During the first visit, the HRV index LF/HF was 4.6 during normoxia, 4.7 during hypoxia, 0.9 during hypoxia+CO₂, and 1.2 after the subject came off the mouthpiece. During the second visit, LF/HF was 6.3 during normoxia, 2.2 during hypoxia, 2.7 during hypoxia+CO₂, and 1.3 after the subject came off the mouthpiece.

FIG. 1.

Cerebrovacsular and cardiovascular variables during visit one. Middle cerebral artery velocity (MCAv), cerebral vascular resistance (CVR), arterial blood pressure (ABP), total peripheral resistance (TPR), cardiac output (Q’), stroke volume (SV), heart rate (HR), and peripheral O₂ saturation (Spo₂). During exposure to hypoxia+CO₂ despite increases in HR, mean, systolic and diastolic ABP progressively decrease due to decreases in Q’ and SV. This reduction in ABP causes declines in mean and diastolic MCAv, while systolic MCAv is maintained. The mean, systolic, and diastolic ABP continued to decline following the hypoxia+CO₂ exposure, despite the subject coming off the mouthpiece.

FIG. 2.

Cerebrovascular and cardiovascular variables during visit two. Middle cerebral artery velocity (MCAv), cerebral hemoglobin concentration (Hb), cerebral vascular resistance (CVR), arterial blood pressure (ABP), total peripheral resistance (TPR), cardiac output (Q’), stroke volume (SV), heart rate (HR), and peripheral O₂ saturation (SpO₂).

FIG. 3.

Middle cerebral artery velocity traces during hypoxia (A) and immediately following hypoxia+CO₂ exposure (B). The velocity trace immediately following hypoxia+CO₂ exhibits a distinct triphasic flow pattern, characterized by large flow during systole, followed by retrograde flow at the end of systole and small flow during diastole. The white horizontal line denotes zero flow.

Table 1.

Means (over 20 sec) Over Measured and Derived Variables at the End of Each Epoch During the Two Hypoxic+CO₂ Episodes and a Reference Episode (normoxia+CO₂)

	Reference		Visit 1				Visit 2
	Normoxia	Normoxia+CO₂	Normoxia	Hypoxia	Hypoxia+CO₂	Post	Normoxia	Hypoxia	Hypoxia+CO₂	Post
Ventilatory
Peto₂ (mm Hg)	98	115	92	41	46	o.m.	101	43	45	o.m.
Petco₂ (mm Hg)	37	43	39	36	42	o.m.	41	37	38	o.m.
V'E (L/min)	14	25	15	15	23	o.m.	15	17	24	o.m.
Spo₂ (%)	98	98	97	80	84	85	96	78	80	96
Cerebrovascular
Mean MCAv (cm/s)	57	65	61	61	52	46	62	53	49	55
Systolic MCAv (cm/s)	91	101	99	108	102	108	103	97	117	88
Diastolic MCAv (cm/s)	40	47	45	40	22	15	43	29	19	35
CVR (mmHg/cm/s)	0.65	0.74	0.72	0.83	0.81	1.21	0.69	0.75	0.83	0.81
Cerebral O₂Hb (μmol)	n.m.	n.m.	n.m.	n.m.	n.m.	n.m.	0.24	−2.10	−4.07	.066
Cerebral HHb (μmol)	n.m.	n.m.	n.m.	n.m.	n.m.	n.m.	−0.88	2.92	2.30	2.40
Cardiovascular
Mean ABP (mm Hg)	88	87	85	73	64	41	88	69	51	66
Systolic ABP (mm Hg)	121	123	114	99	85	55	144	110	80	106
Diastolic ABP (mm Hg)	70	70	67	56	53	34	69	53	38	51
TRP (mm Hg/L/min)	0.68	0.63	0.65	0.50	0.51	0.67	0.56	0.46	0.45	0.52
Q’ (L/min)	7.8	8.6	7.6	9.1	6.7	3.7	10.5	10.5	9.2	8.6
SV (mL)	106	108	101	97	74	51	110	99	84	90
HR (beat/min)	74	80	81	93	91	72	95	104	113	94
HRV index LF/HF			4.6	4.7	0.9	1.2	6.3	2.2	2.7	1.3

n.m.: not measured; o.m.: off mouth piece.

Discussion

We report the sudden development of pre-syncope symptoms in a healthy 21-year old male during acute exposure to inspired CO₂ in a background of severe hypoxia. The pre-syncope symptoms were accompanied by bradycardia, hypotension, cerebral hypo-perfusion, and cerebral tissue deoxygenation. The observed changes in vital signs, HRV index LF/HF, and development of symptoms seems coherent with a vasovagal reaction.

The mechanisms involved in acute hypoxia syncope are complex. The increased susceptibility to syncope in hypoxia has been attributed to a reduced baroreflex sensitivity (Nicholas, 1992; Sagawa et al., 1997; Roche et al., 2002; Klemenc and Golja, 2011), which is further compounded by greater cardiac output decline and withdrawal of sympathetic vasoconstrictive tone during orthostatic stress in hypoxia, resulting in greater hypotension (Wang et al., 1996; Van Lieshout et al., 2003). Westendorp et al., (1997) proposed that an enhanced vasodilatory response to epinephrine during hypoxia (Blauw et al., 1995) would lead to greater sympathetic withdrawal as well as elevated parasympathetic activity. They further proposed that an increase in atrial natriuretic peptide during hypoxemia might attenuate the carotid baroreflex-mediated cardiac acceleration and inhibit sympathetic nervous activity, thus further increasing the risk of syncope in hypoxia.

To the best of our knowledge, this is the first report documenting reduced CBF during a pre-syncope response triggered by CO₂-enriched inspired gas in a background of hypoxia. The observation during the second episode of a drop in frontal cortex oxygenation suggests that the pre-syncope syndrome was accompanied by reduced cerebral oxygen availability (Fig. 2). We found dramatic reductions in mean and diastolic MCAv during and immediately following hypoxia+CO₂ exposure (Fig. 1). Meanwhile, the reduction in cerebral O₂Hb followed closely to the changes in diastolic MCAv (Fig. 2), suggesting that diastolic perfusion pressure is the main determinant of cerebral O₂ delivery. Vasovagal syncope typically involves both central and peripheral mechanisms. However, since severe and uncompensated hypotension, below the threshold of cerebral autoregulation, leads to cerebral hypo-perfusion ( Skinhoj and Strandgaard, 1973; Chillon and Baumbach, 1997), while hypotension per se blunts the CBF responsiveness to CO₂ during both normoxic and hypoxic conditions ( Harper and Glass, 1965; Ainslie et al., 2012), we attribute the observed reduction in CBF and subsequent cerebral tissue deoxygenation to the direct effect of severe hypotension per se.

According to Van Lieshout et al., (2003), when a pre-syncope progresses, it is the fall in mean ABP below the lower limit of cerebral autoregulation that reduces cerebral perfusion and oxygenation, leading to unconsciousness. In the present case, we observed dramatic reductions in mean ABP with increased inspired CO₂ in background hypoxia, which persisted for some time following the exposure (Fig. 1). In addition to this drop in ABP, we observed a distinct triphasic flow pattern in the CBF velocity waveform, characterized by large flow during systole, followed by a distinct retrograde flow at the end of systole, and very little flow during diastole (Fig. 3). Since CO₂ is a potent vasodilator of the cerebral vasculature, we reasoned that the reduction in mean ABP associated with increased inspired CO₂ would lead to a greater mismatch of cerebral perfusion pressure and vascular tone (i.e., impairment of cerebral autoregulation). This mismatch of cerebral perfusion pressure and vascular tone could potentially account for the retrograde flow observed in our subject.

What are potential mechanisms for such an effect of increased inspired CO₂ in a background of hypoxia? In normoxic conditions, hypercapnia has been shown to elicit a vasodilatory effect on the peripheral vasculature in humans (Lennox and Gibbs, 1932; Kontos, 1971; Kontos et al., 1972; Gastaldo et al., 1974; Ainslie et al., 2005). Hypercapnia (10% CO₂) causes an immediate, but transient hypotension, which is corrected within 30–40 sec from increased sympathetic activity, in anesthetized, sino-aortic denervated and vagotomized rats (Takakura et al., 2011). Since inhibition of the retro-trapezoid nucleus (RTN) lowers sympathetic nerve activity and attenuates mean ABP recovery at the end of the hypercapnic exposure (Takakura et al., 2011), those authors concluded that the compensatory increase in sympathetic nerve activity is partly dependent on RTN activation during hypercapnic exposure. Similarly, pontine noradrenergic neurons, astrocytes, neurons of the nucleus solitary tract, and wake-ON orexinergic neurons, have all been shown to be hypercapnia/pH-sensitive and linked to sympathetic tone, contributing to peripheral vascular tone during hypercapnic exposure (Dean et al., 1989; Dun et al., 2000; Johnson et al., 2008; Allen and Barres, 2009). In humans, profound sympatho-inhibition has been reported during exposure to combined hypoxia and hypercapnia, resulting in vasovagal syncope (Halliwill, 2003). Our data of reduced LF/HF (Table 1) are in agreement with that finding. Furthermore, since our subject's ABP was well maintained during hypercapnic exposure in normoxia (Table 1), we speculate that the output of the brain regions responsible for compensatory sympathetic response to hypercapnia might be attenuated during exposure to hypoxia.

An alternative explanation is a blunted peripheral chemoreflex response to severe hypoxia, which might increase an individual's susceptibility to hypoxia-induced syncope due to greater central hypoxic depression associated with greater arterial desaturation. We observed Spo₂ of 78–80% at the end of a 3–4 min exposure to hypoxia (Table 1), at the lower end of the 77%–91% range typically observed in our laboratory using this setup (Fan et al., 2013; Fan and Kayser, 2013). Since cerebral O₂Hb was relatively well maintained during hypoxia and decreased only at the onset of hypotension during hypoxia+CO₂ (Fig. 2), it seems unlikely that a blunted hypoxic ventilatory response and associated arterial (and presumably cerebral) desaturation was responsible of the pre-syncope observed in our case report. Nevertheless, due to a lack of a more prolonged hypoxic control trial, we cannot fully exclude the possibility that hypoxia alone was responsible for the development of pre-syncope observed in this report.

Implications

The present case report, together with previous findings, highlights the increased risk of syncope for climbers and trekkers upon rapid ascent to high altitude. Accordingly, particular care should be taken during postural changes, whereby impaired compensatory mechanisms, coupled with reduced arterial and cerebral tissue oxygenation associated with hypoxic exposure, would lead to greater risk of hypotension and subsequently greater cerebral hypo-perfusion/tissue deoxygenation during orthostatic challenges.

Conclusions

We present a case of repeated pre-syncope during exposure to relative hypercapnia in a background of severe hypoxia. The development of hypotension suggests an impaired compensatory sympathetic response to an increase in Paco₂, leading to reduced venous return, decreased stroke volume, and a drop in cardiac output. The resultant mismatch of perfusion pressure and cerebrovascular tone caused a distinctive triphasic flow pattern in the brain, characterized by a unique retrograde flow at the end of systole. Since the subject exhibited no adverse response to CO₂ during normoxic conditions, we speculate that sympatho-inhibition and subsequent loss of systemic vascular tone was responsible for the development of pre-syncope.

Footnotes

Acknowledgments

B.K. contributed to the conception and design of the experiment, the interpretation of the data, and the writing of the manuscript. J-L.F. carried out data collection, and led the analysis, interpretation, and writing of the manuscript. Both authors approved the final version of this manuscript.

Author Disclosure Statement

The authors do not declare any competing financial interests.

The Swiss National Science Foundation and the Fondation de Reuter supported this study.

References

Ainslie

, Ashmead

, Ide

, Morgan

, and Poulin

. (2005). Differential responses to CO₂ and sympathetic stimulation in the cerebral and femoral circulations in humans. J Physiol, 566, 613–624.

Ainslie

, Lucas

SJE

, Fan

, et al. (2012). Influence of sympathoexcitation at high altitude on cerebrovascular function and ventilatory control in humans. J Appl Physiol, 113:1058–1067.

Allen

, and Barres

. (2009). Neuroscience: Glia—more than just brain glue. Nature, 457:675–677.

Blauw

, Westendorp

, Simons

, Chang

, Frolich

, and Meinders

. (1995). beta-Adrenergic receptors contribute to hypoxaemia induced vasodilation in man. Br J Clin Pharmacol, 40:453–458.

Chillon

, and Baumbach

. (1997). Autoregulation of cerebral blood flow. In: Welch

KMA

, Caplan

, Reis

, Siesjo

, Weir

. (Eds.), Cerebrovascular Diseases. Academic Press, San Diego, CA.

Dean

, Lawing

, Millhorn

. (1989). CO₂ decreases membrane conductance and depolarizes neurons in the nucleus tractus solitarii. Exp Brain Res, 76:656–661.

Dun

, Le Dun

, Che

, Hwang

, Kwok

, and Chang

. (2000). Orexins: A role in medullary sympathetic outflow. Regul Pept, 96:65–70.

Fan

, Bourdillon

, and Kayser

. (2013). Effect of end-tidal CO₂ clamping on cerebrovascular function, oxygenation and performance during 15 km time trial cycling in severe normobaric hypoxia: The role of cerebral O₂ delivery. Physiol Reports. 1:1–15.

Fan

, and Kayser

. (2013). The effect of hypoxia and CO₂ on cerebral blood velocity and breathing during exercise. PloS One. 8:e81130.

10.

Ganzeboom

, Colman

, Reitsma

, Shen

, and Wieling

. (2003). Prevalence and triggers of syncope in medical students. Am J Cardiol, 91:1006–8– A8.

11.

Gastaldo

, Rosenbaum

, Hayes

MFJ

, and Matsumoto

. (1974). Relationship between peripheral blood flow and tissue gases. Int Surg, 59:521–523.

12.

Halliwill

. (2003). Hypoxic regulation of blood flow in humans—Skeletal muscle circulation and the role of epinephrine. Adv Exp Med Biol, 543:223–236.

13.

Halliwill

, and Minson

. (2004). Cardiovagal regulation during combined hypoxic and orthostatic stress: Fainters vs. nonfainters. J Appl Physiol, 98:1050–1056.

14.

Harper

, and Glass

. (1965). Effect of alterations in the arterial carbon dioxide tension on the blood flow through the cerebral cortex at normal and low arterial blood pressures. J Neurol Neurosurg Psychiatry, 28:449–452.

15.

Johnson

, Haxhiu

, and Richerson

. (2008). GFP-expressing locus ceruleus neurons from Prp57 transgenic mice exhibit CO₂/H₊ responses in primary cell culture. J Appl Physiol, 105:1301–1311.

16.

Kapoor

. (1990). Evaluation and outcome of patients with syncope. Medicine (Baltimore), 69:160–175.

17.

Kapoor

. (2002). Current evaluation and management of syncope. Circulation, 106:1606–1609.

18.

Kapoor

, and Brant

. (1992). Evaluation of syncope by upright tilt testing with isoproterenol. A nonspecific test. Ann Intern Med, 116:358–363.

19.

Klemenc

, and Golja

. (2011). Baroreflex sensitivity in acute hypoxia and carbohydrate loading. Eur J Appl Physiol, 111:2509–2515.

20.

Kontos

. (1971). Role of hypercapnic acidosis in the local regulation of blood flow in skeletal muscle. Circ Res, 28, Suppl 1:98

21.

Kontos

, Richardson

, Raper

, Zubair ul

, and Patterson

JLJ

. (1972). Mechanisms of action of hypocapnic alkalosis on limb blood vessels in man and dog. Am J Physiol, 223:1296–1307.

22.

Lennox

, and Gibbs

. (1932). The blood flow in the brain and the leg of man, and the changes induced by alteration of blood gases. J Clin Investig, 11:1155–1177.

23.

Nicholas

. (1992). Is syncope related to moderate altitude exposure?. JAMA, 268:904.

24.

Nicholas

, O'Meara

, and Calonge

. (1992). Is syncope related to moderate altitude exposure?. JAMA, 268:904–906.

25.

Roche

, Reynaud

, Garet

, Pichot

, Costes

, and Barthelemy

. (2002). Cardiac baroreflex control in humans during and immediately after brief exposure to simulated high altitude. Clin Physiol Funct Imaging, 22:301–306.

26.

Sagawa

, Torii

, Nagaya

, Wada

, Endo

, and Shiraki

. (1997). Carotid baroreflex control of heart rate during acute exposure to simulated altitudes of 3,800 m and 4,300 m. Am J Physiol, 273:R1219–1223.

27.

Serletis

, Rose

, Sheldon

, and Sheldon

. (2006). Vasovagal syncope in medical students and their first-degree relatives. Eur Heart J, 27:1965–1970.

28.

Skinhoj

, and Strandgaard

. (1973). Pathogenesis of hypertensive encephalopathy. Lancet, 1:461–462.

29.

Takakura

, Colombari

, Menani

, and Moreira

. (2011). Ventrolateral medulla mechanisms involved in cardiorespiratory responses to central chemoreceptor activation in rats. Am J Physiol Regul Integr Compar Physiol, 300:R501–R510.

30.

Tan

, and Parry

. (2008). Vasovagal syncope in the older patient. J Am Coll Cardiol, 51:599–606.

31.

Thomas

, Burgess

, Basnyat

, et al. (2010). Initial orthostatic hypotension at high altitude. High Alt Med Biol, 11:163–167.

32.

Van Lieshout

, Wieling

, Karemaker

, and Secher

. (2003). Syncope, cerebral perfusion, and oxygenation. J Appl Physiol, 94:833–848.

33.

Wang

, Chan

, Kong

, Lee

, Wang

, and Chang

. (1996). Hemodynamic mechanism of vasovagal syncope. Jpn Heart J, 37:361–371.

34.

Westendorp

, Blauw

, Frolich

, and Simons

. (1997). Hypoxic syncope. Aviation Space Environ Med, 68:410–414.