- Email: [email protected]
Profound hyperventilation and development of periodic breathing during exceptional orthostatic stress in a 21-year-old man
Respiratory Physiology & Neurobiology 177 (2011) 66–70
Contents lists available at ScienceDirect
Respiratory Physiology & Neurobiology journal homepage: www.elsevier.com/locate/resphysiol
Short communication
Profound hyperventilation and development of periodic breathing during exceptional orthostatic stress in a 21-year-old man Joseph Donnelly a,∗ , Samuel J.E. Lucas a,b , Kate N. Thomas a , Sean D. Galvin c , Philip N. Ainslie d a
Department of Physiology, University of Otago, Dunedin, New Zealand School of Physical Education, University of Otago, Dunedin, New Zealand c Department of Medical and Surgical Sciences, University of Otago, Dunedin, New Zealand d Department of Health and Human Kinetics, Faculty of Health and Social Development, University of British Columbia Okanagan, Kelowna, British Columbia, Canada b
a r t i c l e
i n f o
Article history: Accepted 23 February 2011 Keywords: CBF Hypotension Vasovagal syncope
a b s t r a c t In this case report we describe a trial of experimentally induced syncope in a healthy young volunteer that produced abnormal periods of hyperventilation (V˙ A = 57 L/min) and periodic breathing; the latter persisting for approximately 60 min following termination of the trial. In this example, independent of systemic hypotension, the severe hyperventilation and related hypocapnia (end-tidal PETCO2 ∼5 mm Hg) induced by orthostatic stress (lower body negative pressure) resulted in a ∼65% reduction in cerebral blood flow velocity. Potential mechanisms underlying these striking cardiorespiratory patterns are discussed. © 2011 Elsevier B.V. All rights reserved.
1. Introduction
2. Methods
Vasovagal syncope is the most common form of syncope encountered in medical practice. Hypotension during presyncope is probably precipitated by vasodilatation in the skeletal muscle and/or a fall in cardiac output, but loss of consciousness during syncope is caused by cerebral hypoperfusion (Van Lieshout et al., 2003), underscoring the critical importance of cerebral blood flow (CBF) regulation in the pathophysiology of vasovagal syncope. CBF velocity (CBFv) has been shown to fall significantly at syncope, even in healthy subjects (Van Lieshout et al., 2003), and a relationship between the declines in CBFv and hyperventilatory-induced hypocapnia after head-up tilt has been well established (Thomas et al., 2009). Hence, the occurrence of hyperventilation, in addition to the systemic hypotension, ultimately exacerbates cerebral hypoperfusion resulting in syncope. In this case report, we present novel data from a trial of experimentally induced syncope where progressive orthostatic stress elicited periods of abnormally high ventilation followed by periods of apnea; a pattern that continued for 60 min following the trial. The periods of hyperventilation markedly decreased pressure of end-tidal CO2 and resulted in a ∼65% reduction in cerebral blood flow velocity – independent of changes in blood pressure. Potential mechanisms responsible for these unexpected responses are highlighted.
The subject was one of a group of ‘control’ volunteers in a study designed to examine the changes in cerebral perfusion at syncope. He was a 21-year-old healthy man, with no known medical conditions and took no regular medication. Transthoracic echocardiogram and 12-lead ECG were normal. He abstained from caffeine and alcohol for 24 h before the experiments and attended the laboratory on 2 occasions, separated by 7 days. Following full familiarization, the subject completed an experimental testing session conducted at room temperature (22–24 ◦ C).
∗ Corresponding author. Tel.: +64 3 4794209. E-mail address: [email protected] (J. Donnelly). 1569-9048/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.resp.2011.02.012
2.1. Measurements of CBFv, arterial blood pressure, end-tidal gases and ventilation The following dependent measures were recorded continuously: Blood flow velocity in the right middle cerebral artery (MCAv, transcranial Doppler, DWL Doppler, Sterling, VA); beat-to-beat blood pressure (finger photoplethysmography, Finapres, Biomedical Instruments, Netherlands); end-tidal carbon dioxide partial pressure using a rapid response (25 ms) gas analyser (PETCO2 , AEI Technologies, Pittsburgh, PA); and 3-lead electrocardiography (ECG). The subject breathed through a respiratory mask (Hans-Rudolph 8980, Kansas City, MO) attached to a one-way nonrebreathing valve (Hans-Rudolph 2700). All data were sampled continuously at 200 Hz using an analog-digital converter (Powerlab/16SP ML795, ADInstruments, USA) interfaced with a computer and were later analyzed using commercially available software (Chart v5.5, ADInstruments). V˙ E and its components (tidal volume
J. Donnelly et al. / Respiratory Physiology & Neurobiology 177 (2011) 66–70
and breathing frequency) were measured using a heated pneumotachograph. In addition, V˙ A was estimated, assuming a dead space for this 70 kg male of 150 mL: V˙ A = (VT − dead space) f 2.2. Head-up tilt and lower body negative pressure (LBNP) The subject was placed on a combined tilt-LBNP table and rested supine for 20 min. He was then tilted to 60◦ (head up tilt) and, after 5 min, progressive lower-body suction was applied in −10 mm Hg incremental steps for 5 min each (Thomas et al., 2009). Testing was terminated on subject’s request or when a continuous drop in systolic BP to below 70 mm Hg for more than 10 s was observed. 2.3. Ethics The study was approved by the Lower South Regional Ethics Committee and conformed to the standards set by the Declaration of Helsinki. 3. Results To the best of our knowledge, this is the first report documenting a severely abnormal hyperventilatory response during and following a trial of experimentally induced syncope. During the testing session, marked hyperventilation (V˙ E = 80 L/min, f = 170 breaths per minute, and calculated V˙ A ∼57 L/min) occurred to an extent that severely decreased end-tidal CO2 (from ∼46 mm Hg to 5 mm Hg). Despite a ∼65% reduction in MCAv and related symptoms of dizziness, dimming of vision and nausea, blood pressure was well maintained (mean arterial blood pressure 90 mm Hg at supine rest and 87 mm Hg at −70 mm Hg LBNP during head up tilt) throughout the exceptional orthostatic stress (Fig. 1). Indeed, the orthostatic stress induced was outside the 95% confidence interval for that normally required to induce syncope (Thomas et al., 2009). This marked hyperventilatory-induced hypocapnia and cerebral vasoconstriction reduced CBF (∼65%) to a level associated with cerebral ischemia (Van Lieshout et al., 2003), yet the normal hypotension and bradycardia associated with syncope never occurred. During and following the experimentally induced syncope, marked oscillations in ventilation occurred (Fig. 2). This periodictype breathing was reflected in a classical ‘waxing and waning’ pattern of tidal volume and periods of apnea which lasted ∼15 s. The periodic breathing continued for approximately 60 min after completion of the testing session. 4. Discussion The marked hyperventilation, preserved blood pressure, and development of a periodic breathing pattern were unexpected and novel findings. Potential mechanisms responsible for these cardiorespiratory patterns are discussed. 4.1. Abnormal hyperventilation during orthostatic stress Although hyperventilation is well known to be associated with orthostatic stress, the hyperventilation in this case report was far greater than was expected, and furthermore, the mechanism underlying the response is unknown. One potential mechanism for the hyperventilatory response to LBNP is an activation of group 3 and 4 muscle afferents by lower limb venous distension. Support for such a mechanism comes from both animal and human studies where: (1) activation of these fibres
67
has been shown to stimulate ventilation; (2) the presence of these nerve fibres has been confirmed in the adventitia of muscle venules; (3) the fibres have been shown to be sensitive to mechanical stimuli; and (4) a population of these fibres are stimulated by venous occlusion (Haouzi et al., 2004). In the current trial, however, venous distension was not assessed and therefore invoking such a mechanism is purely speculative. Indeed, it could be argued that significant venous distension is unlikely to have occurred on account of the preserved blood pressure (MAP was 90 mm Hg vs 87 mm Hg at the start and end of the trial respectively; Fig. 1). However, estimated stroke volume did decrease progressively over the course of the trial (87 mL at supine rest vs 43 mL at −70 mm Hg during head up tilt), leaving open the possibility of a sizeable translocation of blood volume from central to peripheral (lower limb) areas and an associated venous distension. Another potential mechanism contributing to the large increase in ventilation during this orthostatic challenge is a baroreceptormediated sympathetic activation and subsequent modulation of the carotid chemoreceptor output. Support for such a mechanism comes from studies that have shown a progressive increase in sympathetic nerve activity with LBNP (Cooke et al., 2009) and the excitatory effect of sympathetic nervous activity on ventilation thorough the carotid body (Biscoe and Purves, 1967). 4.2. Preserved blood pressure during orthostatic stress Despite the aforementioned progressive decrease in stroke volume during the orthostatic challenge, cardiac output and mean arterial pressure remained stable (cardiac output 6.0 L at baseline and end of test; MAP 90 mm Hg vs 87 mm Hg at baseline and end of test). These too, were unexpected findings, especially given the exceptional orthostatic stress induced. It has previously been reported that an unloading of cardiopulmonary baroreceptors, at least during mild orthostatic stress, potentiates the gain of the high pressure arterial baroreceptors (Ichinose et al., 2004). Such an increase in the sensitivity of the arterial baroreflex could conceivably act to maintain MAP within tight limits as demonstrated in the current case report. Whatever the mechanism, this case report serves as an impressive example of the potential effectiveness of the baroreflex control of blood pressure. In addition, the cerebral ischemia induced by the orthostatic stress could elicit a pressor response (i.e., the ‘Cushing’ response), thus acting to maintain blood pressure and cerebral perfusion, independent of the baroreflex. Support for such a mechanism comes from animal studies where induced cerebral ischemia causes an increase in systemic arterial blood pressure (McGillicuddy et al., 1978). 4.3. Prolonged periodic breathing during and following relief of orthostatic stress A similar periodic breathing pattern with a waxing–waning pattern of tidal volume has been associated with several diverse conditions including severe decompensated heart failure, ascent to high altitude, and opioid administration (Dempsey et al., 2010). Despite the wide range of conditions being associated with such a ventilatory pattern, a leading hypothesis implicates a common factor; that is a sleep-related apnea threshold triggered the resultant hypocapnia (i.e., a decrease in the partial pressure of arterial CO2 ). Indeed in this case, on account of the marked hyperventilatory response, end-tidal (∼arterial) PCO2 was markedly reduced; therefore, the severe hypocapnia may be one important mechanism acting via disfacilitation of the peripheral and central respiratory chemoreceptors to cause apnea and the related periodic breathing pattern.
68
J. Donnelly et al. / Respiratory Physiology & Neurobiology 177 (2011) 66–70
Fig. 1. Original trace of the progressive changes in respiratory flow, inspired and expired CO2 (PCO2 ), middle cerebral artery blood flow velocity (MCAv), heart rate (HR) and arterial blood pressure (BP) with progressive lower body negative pressure (LBNP) during 60◦ head-up tilt. The arrow on the time axis denotes the point at which the test was terminated due to cerebral ischemia and related marked subjective symptoms of dizziness, dimming of vision and nausea. Note: (1) marked hyperventilation and related hypocapnia with increasing orthostatic stress (∼30 min); (2) major reduction in MCAv that tracks the declines in PCO2 ; and (3) despite significant orthostatic stress and major reductions in CBFv, arterial blood pressure and heart rate were well maintained.
Another factor potentially contributing to the development of the periodic breathing pattern was the profound cerebral ischemia. For example, early studies have investigated the ventilatory responses to acute reductions of CBF by clamping the vertebral and/or the common carotid arteries. Following a reduction in CBF, ventilation was usually increased and, if the CBF reduction was great enough, apnea developed (Chapman et al., 1979). Whether cerebral ischemia is relevant in this case study, and may somehow produce periodic breathing, is unclear. However, since CBF was returned to near normal levels following the orthostatic challenge and the brain has an excellent capacity to extract O2 to maintain neuronal O2 delivery, such an influence seems unlikely.
The occurrence of periodic type breathing during the orthostatic stress was an unexpected finding, but the continuation of this breathing pattern for 60 min after the trial was exceptionally intriguing. It seems that an inherent instability in the breathing pattern was induced, which from a systems control perspective (Dempsey et al., 2010) might be speculated to have arisen from an increase in the controller gain (the ventilatory sensitivity to CO2 ) following the orthostatic stress. Indeed, a recent report describes a blunted cerebrovascular CO2 reactivity during mild LBNP (15 mm Hg) (Zhang et al., 2011), which, if extrapolated, could indicate a significant rise in controller gain during the orthostatic stress induced in the current case. Whether such a mechanism
J. Donnelly et al. / Respiratory Physiology & Neurobiology 177 (2011) 66–70
69
Fig. 2. Original trace of the progressive changes in respiratory flow, inspired and. expired CO2 (PCO2 ), cerebral blood flow velocity (MCAv), heart rate (HR) and arterial blood pressure (BP) during the last 5 min of maximal orthostatic stress (LBNP, −70 mm Hg) and during the following 4 min of supine recovery with no orthostatic stress. The arrow on the time axis denotes the point at which the test was terminated due to cerebral ischemia and related marked subjective symptoms of dizziness, dimming of vision and nausea. Note: (1) The air flow trace exhibits a waxing and waning pattern with periods of apnea lasting ∼15 s; (2) despite the absence of any orthostatic stress and restoration of MCAv, the periodic breathing continued (for a further 60 min).
could account for the persistence of periodic breathing 60 min after the orthostatic stress is unclear. It is of interest to note, that although end-tidal CO2 pressures were markedly decreased immediately following termination of the experiment (∼20 mm Hg; Fig. 2), the CBF was at a similar level to the supine rest prior to experimentation (where end-tidal CO2 was ∼46 mm Hg; Fig. 1). In addition, contrary to the PETCO2 and ventilation responses, CBF did not show marked oscillations during LBNP and following subsequent return to supine rest. Given the usual tight coupling between PETCO2 and CBF, these two observations
were unexpected and the mechanisms underlying this apparent dissociation are unclear but could potentially involve the transient opening of right to left cardiopulmonary shunts (Eldridge et al., 2004). 5. Conclusion This is the first report that documents a severely abnormal hyperventilatory response during orthostatic stress. The resultant hypocapnia may have caused cerebral ischemia in spite of
70
J. Donnelly et al. / Respiratory Physiology & Neurobiology 177 (2011) 66–70
the maintained blood pressure, and contributed to the development of periodic breathing. The mechanisms underpinning this cardiorespiratory response are likely complex and multifactorial, however we speculate that a potential chain of events could be a LBNP induced venous distension and sympathetic activation, leading to a hyperventilation and enhanced controller gain, ultimately contributing to the development of periodic breathing. Elucidation upon important issues raised in this case report will require research that carefully disentangles complex cardiorespiratory and cerebrovascular interactions. Acknowledgements This work was supported by The Marsden Fund, The Royal Society of New Zealand. We would like to thank Jerome Dempsey, Barbara Morgan, and James Cotter for informal discussion and feedback on this case report. References Biscoe, T.J., Purves, M.J., 1967. Factors affecting the cat carotid chemoreceptor and cervical sympathetic activity with special reference to passive hind-limb movements. J. Physiol. 190, 425–441.
Chapman, R.W., Santiago, T.V., Edelman, N.H., 1979. Effects of graded reduction of brain blood flow on chemical control of breathing. J. Appl. Physiol. 47, 1289–1294. Cooke, W.H., Rickards, C.A., Ryan, K.L., Kuusela, T.A., Convertino, V.A., 2009. Muscle sympathetic nerve activity during intense lower body negative pressure to presyncope in humans. J. Physiol. 587, 4987–4999. Dempsey, J.A., Veasey, S.C., Morgan, B.J., O’Donnell, C.P., 2010. Pathophysiology of sleep apnea. Physiol. Rev. 90, 47–112. Eldridge, M.W., Dempsey, J.A., Haverkamp, H.C., Lovering, A.T., Hokanson, J.S., 2004. Exercise-induced intrapulmonary arteriovenous shunting in healthy humans. J. Appl. Physiol. 97, 797–805. Haouzi, P., Chenuel, B., Huszczuk, A., 2004. Sensing vascular distension in skeletal muscle by slow conducting afferent fibers: neurophysiological basis and implication for respiratory control. J. Appl. Physiol. 96, 407–418. Ichinose, M., Saito, M., Kitano, A., Hayashi, K., Kondo, N., Nishiyasu, T., 2004. Modulation of arterial baroreflex dynamic response during mild orthostatic stress in humans. J. Physiol. 557, 321–330. McGillicuddy, J.E., Kindt, G.W., Raisis, J.E., Miller, C.A., 1978. The relation of cerebral ischemia, hypoxia, and hypercarbia to the Cushing response. J. Neurosurg. 48, 730–740. Thomas, K.N., Cotter, J.D., Galvin, S.D., Williams, M.J., Willie, C.K., Ainslie, P.N., 2009. Initial orthostatic hypotension is unrelated to orthostatic tolerance in healthy young subjects. J. Appl. Physiol. 107, 506–517. Van Lieshout, J.J., Wieling, W., Karemaker, J.M., Secher, N.H., 2003. Syncope, cerebral perfusion, and oxygenation. J. Appl. Physiol. 94, 833–848. Zhang, P., Huang, G., Shi, X., 2011. Cerebral vasoreactivity during hypercapnia is reset by augmented sympathetic influence. J. Appl. Physiol. 110, 352–358.
Contents lists available at ScienceDirect
Respiratory Physiology & Neurobiology journal homepage: www.elsevier.com/locate/resphysiol
Short communication
Profound hyperventilation and development of periodic breathing during exceptional orthostatic stress in a 21-year-old man Joseph Donnelly a,∗ , Samuel J.E. Lucas a,b , Kate N. Thomas a , Sean D. Galvin c , Philip N. Ainslie d a
Department of Physiology, University of Otago, Dunedin, New Zealand School of Physical Education, University of Otago, Dunedin, New Zealand c Department of Medical and Surgical Sciences, University of Otago, Dunedin, New Zealand d Department of Health and Human Kinetics, Faculty of Health and Social Development, University of British Columbia Okanagan, Kelowna, British Columbia, Canada b
a r t i c l e
i n f o
Article history: Accepted 23 February 2011 Keywords: CBF Hypotension Vasovagal syncope
a b s t r a c t In this case report we describe a trial of experimentally induced syncope in a healthy young volunteer that produced abnormal periods of hyperventilation (V˙ A = 57 L/min) and periodic breathing; the latter persisting for approximately 60 min following termination of the trial. In this example, independent of systemic hypotension, the severe hyperventilation and related hypocapnia (end-tidal PETCO2 ∼5 mm Hg) induced by orthostatic stress (lower body negative pressure) resulted in a ∼65% reduction in cerebral blood flow velocity. Potential mechanisms underlying these striking cardiorespiratory patterns are discussed. © 2011 Elsevier B.V. All rights reserved.
1. Introduction
2. Methods
Vasovagal syncope is the most common form of syncope encountered in medical practice. Hypotension during presyncope is probably precipitated by vasodilatation in the skeletal muscle and/or a fall in cardiac output, but loss of consciousness during syncope is caused by cerebral hypoperfusion (Van Lieshout et al., 2003), underscoring the critical importance of cerebral blood flow (CBF) regulation in the pathophysiology of vasovagal syncope. CBF velocity (CBFv) has been shown to fall significantly at syncope, even in healthy subjects (Van Lieshout et al., 2003), and a relationship between the declines in CBFv and hyperventilatory-induced hypocapnia after head-up tilt has been well established (Thomas et al., 2009). Hence, the occurrence of hyperventilation, in addition to the systemic hypotension, ultimately exacerbates cerebral hypoperfusion resulting in syncope. In this case report, we present novel data from a trial of experimentally induced syncope where progressive orthostatic stress elicited periods of abnormally high ventilation followed by periods of apnea; a pattern that continued for 60 min following the trial. The periods of hyperventilation markedly decreased pressure of end-tidal CO2 and resulted in a ∼65% reduction in cerebral blood flow velocity – independent of changes in blood pressure. Potential mechanisms responsible for these unexpected responses are highlighted.
The subject was one of a group of ‘control’ volunteers in a study designed to examine the changes in cerebral perfusion at syncope. He was a 21-year-old healthy man, with no known medical conditions and took no regular medication. Transthoracic echocardiogram and 12-lead ECG were normal. He abstained from caffeine and alcohol for 24 h before the experiments and attended the laboratory on 2 occasions, separated by 7 days. Following full familiarization, the subject completed an experimental testing session conducted at room temperature (22–24 ◦ C).
∗ Corresponding author. Tel.: +64 3 4794209. E-mail address: [email protected] (J. Donnelly). 1569-9048/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.resp.2011.02.012
2.1. Measurements of CBFv, arterial blood pressure, end-tidal gases and ventilation The following dependent measures were recorded continuously: Blood flow velocity in the right middle cerebral artery (MCAv, transcranial Doppler, DWL Doppler, Sterling, VA); beat-to-beat blood pressure (finger photoplethysmography, Finapres, Biomedical Instruments, Netherlands); end-tidal carbon dioxide partial pressure using a rapid response (25 ms) gas analyser (PETCO2 , AEI Technologies, Pittsburgh, PA); and 3-lead electrocardiography (ECG). The subject breathed through a respiratory mask (Hans-Rudolph 8980, Kansas City, MO) attached to a one-way nonrebreathing valve (Hans-Rudolph 2700). All data were sampled continuously at 200 Hz using an analog-digital converter (Powerlab/16SP ML795, ADInstruments, USA) interfaced with a computer and were later analyzed using commercially available software (Chart v5.5, ADInstruments). V˙ E and its components (tidal volume
J. Donnelly et al. / Respiratory Physiology & Neurobiology 177 (2011) 66–70
and breathing frequency) were measured using a heated pneumotachograph. In addition, V˙ A was estimated, assuming a dead space for this 70 kg male of 150 mL: V˙ A = (VT − dead space) f 2.2. Head-up tilt and lower body negative pressure (LBNP) The subject was placed on a combined tilt-LBNP table and rested supine for 20 min. He was then tilted to 60◦ (head up tilt) and, after 5 min, progressive lower-body suction was applied in −10 mm Hg incremental steps for 5 min each (Thomas et al., 2009). Testing was terminated on subject’s request or when a continuous drop in systolic BP to below 70 mm Hg for more than 10 s was observed. 2.3. Ethics The study was approved by the Lower South Regional Ethics Committee and conformed to the standards set by the Declaration of Helsinki. 3. Results To the best of our knowledge, this is the first report documenting a severely abnormal hyperventilatory response during and following a trial of experimentally induced syncope. During the testing session, marked hyperventilation (V˙ E = 80 L/min, f = 170 breaths per minute, and calculated V˙ A ∼57 L/min) occurred to an extent that severely decreased end-tidal CO2 (from ∼46 mm Hg to 5 mm Hg). Despite a ∼65% reduction in MCAv and related symptoms of dizziness, dimming of vision and nausea, blood pressure was well maintained (mean arterial blood pressure 90 mm Hg at supine rest and 87 mm Hg at −70 mm Hg LBNP during head up tilt) throughout the exceptional orthostatic stress (Fig. 1). Indeed, the orthostatic stress induced was outside the 95% confidence interval for that normally required to induce syncope (Thomas et al., 2009). This marked hyperventilatory-induced hypocapnia and cerebral vasoconstriction reduced CBF (∼65%) to a level associated with cerebral ischemia (Van Lieshout et al., 2003), yet the normal hypotension and bradycardia associated with syncope never occurred. During and following the experimentally induced syncope, marked oscillations in ventilation occurred (Fig. 2). This periodictype breathing was reflected in a classical ‘waxing and waning’ pattern of tidal volume and periods of apnea which lasted ∼15 s. The periodic breathing continued for approximately 60 min after completion of the testing session. 4. Discussion The marked hyperventilation, preserved blood pressure, and development of a periodic breathing pattern were unexpected and novel findings. Potential mechanisms responsible for these cardiorespiratory patterns are discussed. 4.1. Abnormal hyperventilation during orthostatic stress Although hyperventilation is well known to be associated with orthostatic stress, the hyperventilation in this case report was far greater than was expected, and furthermore, the mechanism underlying the response is unknown. One potential mechanism for the hyperventilatory response to LBNP is an activation of group 3 and 4 muscle afferents by lower limb venous distension. Support for such a mechanism comes from both animal and human studies where: (1) activation of these fibres
67
has been shown to stimulate ventilation; (2) the presence of these nerve fibres has been confirmed in the adventitia of muscle venules; (3) the fibres have been shown to be sensitive to mechanical stimuli; and (4) a population of these fibres are stimulated by venous occlusion (Haouzi et al., 2004). In the current trial, however, venous distension was not assessed and therefore invoking such a mechanism is purely speculative. Indeed, it could be argued that significant venous distension is unlikely to have occurred on account of the preserved blood pressure (MAP was 90 mm Hg vs 87 mm Hg at the start and end of the trial respectively; Fig. 1). However, estimated stroke volume did decrease progressively over the course of the trial (87 mL at supine rest vs 43 mL at −70 mm Hg during head up tilt), leaving open the possibility of a sizeable translocation of blood volume from central to peripheral (lower limb) areas and an associated venous distension. Another potential mechanism contributing to the large increase in ventilation during this orthostatic challenge is a baroreceptormediated sympathetic activation and subsequent modulation of the carotid chemoreceptor output. Support for such a mechanism comes from studies that have shown a progressive increase in sympathetic nerve activity with LBNP (Cooke et al., 2009) and the excitatory effect of sympathetic nervous activity on ventilation thorough the carotid body (Biscoe and Purves, 1967). 4.2. Preserved blood pressure during orthostatic stress Despite the aforementioned progressive decrease in stroke volume during the orthostatic challenge, cardiac output and mean arterial pressure remained stable (cardiac output 6.0 L at baseline and end of test; MAP 90 mm Hg vs 87 mm Hg at baseline and end of test). These too, were unexpected findings, especially given the exceptional orthostatic stress induced. It has previously been reported that an unloading of cardiopulmonary baroreceptors, at least during mild orthostatic stress, potentiates the gain of the high pressure arterial baroreceptors (Ichinose et al., 2004). Such an increase in the sensitivity of the arterial baroreflex could conceivably act to maintain MAP within tight limits as demonstrated in the current case report. Whatever the mechanism, this case report serves as an impressive example of the potential effectiveness of the baroreflex control of blood pressure. In addition, the cerebral ischemia induced by the orthostatic stress could elicit a pressor response (i.e., the ‘Cushing’ response), thus acting to maintain blood pressure and cerebral perfusion, independent of the baroreflex. Support for such a mechanism comes from animal studies where induced cerebral ischemia causes an increase in systemic arterial blood pressure (McGillicuddy et al., 1978). 4.3. Prolonged periodic breathing during and following relief of orthostatic stress A similar periodic breathing pattern with a waxing–waning pattern of tidal volume has been associated with several diverse conditions including severe decompensated heart failure, ascent to high altitude, and opioid administration (Dempsey et al., 2010). Despite the wide range of conditions being associated with such a ventilatory pattern, a leading hypothesis implicates a common factor; that is a sleep-related apnea threshold triggered the resultant hypocapnia (i.e., a decrease in the partial pressure of arterial CO2 ). Indeed in this case, on account of the marked hyperventilatory response, end-tidal (∼arterial) PCO2 was markedly reduced; therefore, the severe hypocapnia may be one important mechanism acting via disfacilitation of the peripheral and central respiratory chemoreceptors to cause apnea and the related periodic breathing pattern.
68
J. Donnelly et al. / Respiratory Physiology & Neurobiology 177 (2011) 66–70
Fig. 1. Original trace of the progressive changes in respiratory flow, inspired and expired CO2 (PCO2 ), middle cerebral artery blood flow velocity (MCAv), heart rate (HR) and arterial blood pressure (BP) with progressive lower body negative pressure (LBNP) during 60◦ head-up tilt. The arrow on the time axis denotes the point at which the test was terminated due to cerebral ischemia and related marked subjective symptoms of dizziness, dimming of vision and nausea. Note: (1) marked hyperventilation and related hypocapnia with increasing orthostatic stress (∼30 min); (2) major reduction in MCAv that tracks the declines in PCO2 ; and (3) despite significant orthostatic stress and major reductions in CBFv, arterial blood pressure and heart rate were well maintained.
Another factor potentially contributing to the development of the periodic breathing pattern was the profound cerebral ischemia. For example, early studies have investigated the ventilatory responses to acute reductions of CBF by clamping the vertebral and/or the common carotid arteries. Following a reduction in CBF, ventilation was usually increased and, if the CBF reduction was great enough, apnea developed (Chapman et al., 1979). Whether cerebral ischemia is relevant in this case study, and may somehow produce periodic breathing, is unclear. However, since CBF was returned to near normal levels following the orthostatic challenge and the brain has an excellent capacity to extract O2 to maintain neuronal O2 delivery, such an influence seems unlikely.
The occurrence of periodic type breathing during the orthostatic stress was an unexpected finding, but the continuation of this breathing pattern for 60 min after the trial was exceptionally intriguing. It seems that an inherent instability in the breathing pattern was induced, which from a systems control perspective (Dempsey et al., 2010) might be speculated to have arisen from an increase in the controller gain (the ventilatory sensitivity to CO2 ) following the orthostatic stress. Indeed, a recent report describes a blunted cerebrovascular CO2 reactivity during mild LBNP (15 mm Hg) (Zhang et al., 2011), which, if extrapolated, could indicate a significant rise in controller gain during the orthostatic stress induced in the current case. Whether such a mechanism
J. Donnelly et al. / Respiratory Physiology & Neurobiology 177 (2011) 66–70
69
Fig. 2. Original trace of the progressive changes in respiratory flow, inspired and. expired CO2 (PCO2 ), cerebral blood flow velocity (MCAv), heart rate (HR) and arterial blood pressure (BP) during the last 5 min of maximal orthostatic stress (LBNP, −70 mm Hg) and during the following 4 min of supine recovery with no orthostatic stress. The arrow on the time axis denotes the point at which the test was terminated due to cerebral ischemia and related marked subjective symptoms of dizziness, dimming of vision and nausea. Note: (1) The air flow trace exhibits a waxing and waning pattern with periods of apnea lasting ∼15 s; (2) despite the absence of any orthostatic stress and restoration of MCAv, the periodic breathing continued (for a further 60 min).
could account for the persistence of periodic breathing 60 min after the orthostatic stress is unclear. It is of interest to note, that although end-tidal CO2 pressures were markedly decreased immediately following termination of the experiment (∼20 mm Hg; Fig. 2), the CBF was at a similar level to the supine rest prior to experimentation (where end-tidal CO2 was ∼46 mm Hg; Fig. 1). In addition, contrary to the PETCO2 and ventilation responses, CBF did not show marked oscillations during LBNP and following subsequent return to supine rest. Given the usual tight coupling between PETCO2 and CBF, these two observations
were unexpected and the mechanisms underlying this apparent dissociation are unclear but could potentially involve the transient opening of right to left cardiopulmonary shunts (Eldridge et al., 2004). 5. Conclusion This is the first report that documents a severely abnormal hyperventilatory response during orthostatic stress. The resultant hypocapnia may have caused cerebral ischemia in spite of
70
J. Donnelly et al. / Respiratory Physiology & Neurobiology 177 (2011) 66–70
the maintained blood pressure, and contributed to the development of periodic breathing. The mechanisms underpinning this cardiorespiratory response are likely complex and multifactorial, however we speculate that a potential chain of events could be a LBNP induced venous distension and sympathetic activation, leading to a hyperventilation and enhanced controller gain, ultimately contributing to the development of periodic breathing. Elucidation upon important issues raised in this case report will require research that carefully disentangles complex cardiorespiratory and cerebrovascular interactions. Acknowledgements This work was supported by The Marsden Fund, The Royal Society of New Zealand. We would like to thank Jerome Dempsey, Barbara Morgan, and James Cotter for informal discussion and feedback on this case report. References Biscoe, T.J., Purves, M.J., 1967. Factors affecting the cat carotid chemoreceptor and cervical sympathetic activity with special reference to passive hind-limb movements. J. Physiol. 190, 425–441.
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