Hyperventilation-induced Hypocapnia Research Articles

Exercise-induced potentiation of the acute hypoxic ventilatory response: Neural mechanisms and implications for cerebral blood flow.

A given dose of hypoxia causes a greater increase in pulmonary ventilation during physical exercise than during rest, representing an exercise-induced potentiation of the acute hypoxic ventilatory response (HVR). This phenomenon occurs independently from hypoxic blood entering the contracting skeletal muscle circulation or metabolic byproducts leaving skeletal muscles, supporting the contention that neural mechanisms per se can mediate the HVR when humoral mechanisms are not at play. However, multiple neural mechanisms might be interacting intricately. First, we discuss the neural mechanisms involved in the ventilatory response to hypoxic exercise and their potential interactions. Current evidence does not support an interaction between the carotid chemoreflex and central command. In contrast, findings from some studies support synergistic interactions between the carotid chemoreflex and the muscle mechano- and metaboreflexes. Second, we propose hypotheses about potential mechanisms underlying neural interactions, including spatial and temporal summation of afferent signals into the medulla, short-term potentiation and sympathetically induced activation of the carotid chemoreceptors. Lastly, we ponder how exercise-induced potentiation of the HVR results in hyperventilation-induced hypocapnia, which influences cerebral blood flow regulation, with multifaceted potential consequences, including deleterious (increased central fatigue and impaired cognitive performance), inert (unchanged exercise) and beneficial effects (protection against excessive cerebral perfusion).

Impaired cerebrovascular CO2 reactivity at high altitude in prematurely born adults.

Premature birth impairs cardiac and ventilatory responses to both hypoxia and hypercapnia, but little is known about cerebrovascular responses. Both at sea level and after 2days at high altitude (3375m), 16 young preterm-born (gestational age, 29 ± 1weeks) and 15 age-matched term-born (40 ± 0weeks) adults were exposed to two consecutive 4min bouts of hyperoxic hypercapnic conditions (3% CO2 -97% O2 ; 6% CO2 -94% O2 ), followed by two periods of voluntary hyperventilation-induced hypocapnia. We measured middle cerebral artery blood velocity, end-tidal CO2 , pulmonary ventilation, beat-by-beat mean arterial pressure and arterialized capillary blood gases. Baseline middle cerebral artery blood velocity increased at high altitude compared with sea level in term-born (+24 ± 39%, P=0.036), but not in preterm-born (-4 ± 27%, P=0.278) adults. The end-tidal CO2 , pulmonary ventilation and mean arterial pressure were similar between groups at sea level and high altitude. Hypocapnic cerebrovascular reactivity was higher at high altitude compared with sea level in term-born adults (+173 ± 326%, P=0.026) but not in preterm-born adults (-21 ± 107%, P=0.572). Hypercapnic reactivity was altered at altitude only in preterm-born adults (+125 ± 144%, P<0.001). Collectively, at high altitude, term-born participants showed higher hypocapnic (P=0.012) and lower hypercapnic (P=0.020) CO2 reactivity compared with their preterm-born peers. In conclusion, exposure to high altitude revealed different cerebrovascular responses in preterm- compared with term-born adults, despite similar ventilatory responses. These findings suggest a blunted cerebrovascular response at high altitude in preterm-born adults, which might predispose these individuals to an increased risk of high-altitude illnesses. KEY POINTS: Cerebral haemodynamics and cerebrovascular reactivity in normoxia are known to be similar between term-born and prematurely born adults. In contrast, acute exposure to high altitude unveiled different cerebrovascular responses to hypoxia, hypercapnia and hypocapnia. In particular, cerebral vasodilatation was impaired in prematurely born adults, leading to an exaggerated cerebral vasoconstriction. Cardiovascular and ventilatory responses to both hypo- and hypercapnia at sea level and at high altitude were similar between control subjects and prematurely born adults. Other mechanisms might therefore underlie the observed blunted cerebral vasodilatory responses in preterm-born adults at high altitude.

Hypocapnia attenuates local skin thermal perception to innocuous warm and cool stimuli in normothermic resting humans.

When one is exposed to a stressful situation in their daily life, a common response is hyperventilation. Although the physiological significance of stress-induced hyperventilation remains uncertain, this response may blunt perception of the stress-inducing stimulus. This study examined the effects of voluntary hyperventilation and resultant hypocapnia on the local skin thermal detection threshold in normothermic resting humans. Local skin thermal detection thresholds were measured in 15 young adults (three females) under three breathing conditions: 1) spontaneous breathing (Control trial), 2) voluntary hypocapnic hyperventilation (HH trial), and 3) voluntary normocapnic hyperventilation (NH trial). Local skin thermal detection thresholds were measured using thermostimulators containing a Peltier element that were attached to the forearm and forehead. The temperature of the probe was initially equilibrated to the skin temperature, then gradually increased or decreased at a constant rate (±0.1 °C/s) until the participants felt warmth or coolness. The difference between the initial skin temperature and the local skin temperature at which the participant noticed warmth/coolness was assessed as an index of the local skin warm/cool detection threshold. Local detection of warm and cool stimuli did not differ between the Control and NH trials, but it was blunted in the HH trial as compared with the Control and NH trials, except for detection of warm stimuli on the forearm. These findings suggest that hyperventilation-induced hypocapnia, not hyperventilation per se, attenuates local skin thermal perception, though changes in responses to warm stimuli may not be clearly perceived at some skin areas (e.g., forearm).

AMPK facilitates the hypoxic ventilatory response through non-adrenergic mechanisms at the brainstem

We recently demonstrated that the hypoxic ventilatory response (HVR) is facilitated by the AMP-activated protein kinase (AMPK) in catecholaminergic neural networks that likely lie downstream of the carotid bodies within the caudal brainstem. Here, we further subcategorise the neurons involved, by cross-comparison of mice in which the genes encoding the AMPK-α1 (Prkaa1) and AMPK-α2 (Prkaa2) catalytic subunits were deleted in catecholaminergic (TH-Cre) or adrenergic (PNMT-Cre) neurons. As expected, the HVR was markedly attenuated in mice with AMPK-α1/α2 deletion in catecholaminergic neurons, but surprisingly was modestly augmented in mice with AMPK-α1/α2 deletion in adrenergic neurons when compared against a variety of controls (TH-Cre, PNMT-Cre, AMPK-α1/α2 floxed). Moreover, AMPK-α1/α2 deletion in catecholaminergic neurons precipitated marked hypoventilation and apnoea during poikilocapnic hypoxia, relative to controls, while mice with AMPK-α1/α2 deletion in adrenergic neurons entered relative hyperventilation with reduced apnoea frequency and duration. We conclude, therefore, that AMPK-dependent modulation of non-adrenergic networks may facilitate increases in ventilatory drive that shape the classical HVR, whereas AMPK-dependent modulation of adrenergic networks may provide some form of negative feedback or inhibitory input to moderate HVR, which could, for example, protect against hyperventilation-induced hypocapnia and respiratory alkalosis.

Cerebrovascular Carbon Dioxide Reactivity with Hyperoxia and Hypoxia in Humans with Treated Hypertension

Hypertension increases the risk of cerebrovascular diseases such as stroke and dementia, but the underlying mechanisms are currently unclear. While chronic hypertension can lead to anatomical and functional adaptations within the cerebral circulation, its effect on cerebral blood flow (CBF) control remains poorly understood. We tested the hypothesis that the CBF responses to CO2 with either high or low oxygen levels are impaired in treated hypertensive patients compared to normotensive aged‐matched controls.In 14 treated hypertensive patients (age: 68±5 years, mean±SD) and 8 normotensive age‐matched controls (age: 66±6 years), we assessed cardiorespiratory and cerebrovascular variables at rest, during voluntary hyperventilation (partial pressure of end‐tidal CO2 [PETCO2] ~25 mmHg), and hyperoxic and hypoxic rebreathing. Using transcranial Doppler ultrasound and finger photoplethysmography, we measured beat‐to‐beat middle cerebral artery blood velocity (MCAv: index of CBF) and BP, respectively, while PETCO2 was assessed using a gas analyzer. Linear regression was used to determine the MCAv‐CO2 slope (i.e., cerebrovascular CO2 reactivity).At rest, mean BP was higher in the hypertensive patients (108±9 mmHg) compared to normotensive controls (93±10 mmHg, p=0.001), while MCAv (46.8±11.4 vs. 53.3±10.4 cm/s) and PETCO2 (41±4 vs. 42±3 mmHg) were not different between groups (p&lt;0.05). Hyperventilation‐induced hypocapnia elicited similar reductions in MCAv in the hypertensive and normotensive groups (Δ14.8±4.7 vs. Δ16.5±5.7 cm/s, p=0.484). Similarly, the MCAv‐CO2slope was not different between the hypertensive and normotensive groups during either hyperoxic rebreathing (1.53±1.05 vs. 1.98±0.56 cm/s/mmHg, p=0.320) or hypoxic rebreathing (1.94±1.04 vs. 2.21±1.13 cm/s/mmHg, p=0.815).These preliminary findings indicate that in treated hypertensive patients, the MCAv responses to hypocapnia, and hypercapnia administrated with either high or low oxygen levels, do not differ from that observed in age‐matched normotensive controls.

Effects of LI11 Acupuncture on CO2 reactivity in the anterior and middle cerebral arteries during hyperventilation-induced hypocapnia in normal subjects: A before and after study

Objectives: The LI11 (Quchi) acupuncture point has always been included in the Seven acupoints for stroke; however, additional LI11 acupuncture research is needed. In this study, the effect of LI11 acupuncture on cerebral blood flow of the anterior cerebral arteries (ACA) and middle cerebral arteries (MCA) was investigated.Method: This study included 10 healthy young male subjects. Cerebral blood flow velocity and cerebrovascular reactivity were measured using transcranial Doppler sonography. Changes in hyperventilation-induced carbon dioxide (CO2) reactivity and modified ACA and MCA blood flow velocity at 40 mmHg (CV40), blood pressure, and heart rate were observed before and after LI11 acupuncture treatment.Results: A statistically significant increase in contralateral anterior cerebral artery CO2 reactivity (p=0.036) and decrease in contralateral middle cerebral artery CV40 (p=0.047) were observed. No significant difference in mean blood pressure was shown. A statistically significant increase in heart rate occurred after LI11 acupuncture; however, it was not clinically significant as there were negligible changes in the heart rhythm.Conclusions: LI11 acupuncture treatment could improve cerebral blood flow velocity. These results might be explained by regulating endothelium-dependent vessel dilation in the anterior cerebral artery region.Trial registration: This trial has been registered with Clinical Research Information Service, a service of the Korea Centers for Disease Control and Prevention: KCT0004494 (retrospectively registered). https://cris.nih.go.kr/cris/search/search_result_st01.jsp?seq=15359

Hyperventilation: A Possible Explanation for Long-Lasting Exercise Intolerance in Mild COVID-19 Survivors?

Since the outbreak of the coronavirus (COVID-19) pandemic, most attention has focused on containing transmission and addressing the surge of critically ill patients in acute care settings. As we enter the second phase of the pandemic, emphasis must evolve to post-acute care of COVID-19 survivors. Persisting cardiorespiratory symptoms have been reported at several months after the onset of the infection. Information is lacking on the pathophysiology of exercise intolerance after COVID-19. Previous outbreaks of coronaviruses have been associated with persistent dyspnea, muscle weakness, fatigue and reduced quality of life. The extent of Covid-19 sequelae remains to be evaluated, but persisting cardiorespiratory symptoms in COVID-19 survivors can be described as two distinct entities. The first type of post-Covid symptoms are directly related to organ injury in the acute phase, or the complications of treatment. The second type of persisting symptoms can affect patients even with mild initial disease presentation without evidence of organ damage. The mechanisms are still poorly qualified to date. There is a lack of correlation between initial symptom severity and residual symptoms at exertion. We report exercise hyperventilation as a major limiting factor in COVID-19 survivors. The origin of this hyperventilation may be related to an abnormality of ventilatory control, by either hyperactivity of activator systems (automatic and cortical ventilatory control, peripheral afferents, and sensory cortex) or failure of inhibitory systems (endorphins) in the aftermath of pulmonary infection. Hyperventilation-induced hypocapnia can cause a multitude of extremely disabling symptoms such as dyspnea, tachycardia, chest pain, fatigue, dizziness and syncope at exertion.

Early hours in the development of high-altitude pulmonary edema: time course and mechanisms.

Clinically evident high-altitude pulmonary edema (HAPE) is characterized by severe cyanosis, dyspnea, cough, and difficulty with physical exertion. This usually occurs within 1-2 days of ascent often with the additional stresses of any exercise and hypoventilation of sleep. The earliest events in evolving HAPE progress through clinically silent and then minimally recognized problems. The most important of these events involves an exaggerated elevation of pulmonary artery (PA) pressure in response to the ambient hypoxia. Hypoxic pulmonary vasoconstriction (HPV) is a rapid response with several phases. The first phase in both resistance arterioles and venules occurs within 5-10 min. This is followed by a second phase that further raises PA pressure by another 100% over the next 2-8 h. Combined with vasoconstriction and likely an unevenness in the regional strength of HPV, pressures in some microvascular regions with lesser arterial constriction rise to a level that initiates greater filtration of fluid into the interstitium. As pressures continue to rise local lymphatic clearance rates are exceeded and interstitial fluid begins to accumulate. Beyond elevation of transmural pressure gradients there is a dynamic noninjurious relaxation of microvascular and epithelial cell-cell contacts and an increase in transcellular vesicular transport which accelerate leakage. At some point with further pressure elevation, damage occurs with breaks of the barrier and bleeding into the alveolar space, a late-stage situation termed capillary stress failure. Earlier before there is fluid accumulation, alveolar hypoxia and hyperventilation-induced hypocapnia reduce the capacity of the alveolar epithelium to reabsorb sodium and water back into the interstitial space. More modest ascent which slows the rate of rise in PA pressure and allows for adaptive remodeling of the microvasculature, drugs which lower PA pressure, and those that can enhance fluid reabsorption will all forestall the deleterious early rise of microvascular pressures and diminished active alveolar fluid reabsorption that precede and underlie the development of HAPE.

Isolating the independent effects of hypoxia and hyperventilation-induced hypocapnia on cerebral haemodynamics and cognitive function.

What is the central question of this study? What are the independent effects of hypoxia and hypocapnia on cerebral haemodynamics and cognitive function? What is the main finding and its importance? Exposure to hyperventilation-induced hypocapnia causes cognitive impairment in both normoxia and hypoxia. In addition, supplementation of carbon dioxide during hypoxia alleviates the cognitive impairment and reverses hypocapnia-induced vasoconstriction of the cerebrovasculature. These data provide new evidence for the independent effect of hypocapnia on the cognitive impairment associated with hypoxia. Hypoxia, which is accompanied by hypocapnia at altitude, is associated with cognitive impairment. This study examined the independent effects of hypoxia and hypocapnia on cognitive function and assessed how changes in cerebral haemodynamics may underpin cognitive performance outcomes. Single reaction time (SRT), five-choice reaction time (CRT) and spatial working memory (SWM) tasks were completed in 20 participants at rest and after 1h of isocapnic hypoxia (IH, end-tidal oxygen partial pressure ( )=45mmHg, end-tidal carbon dioxide partial pressure ( ) clamped at normal) and poikilocapnic hypoxia (PH, =45mmHg, not clamped). A subgroup of 10 participants were also exposed to euoxic hypocapnia (EH, =100mmHg, clamped 8mmHg below normal). Middle cerebral artery velocity (MCAv) and prefrontal cerebral haemodynamics were measured with transcranial Doppler and near infrared spectroscopy, respectively. IH did not affect SRT and CRT performance from rest (566±50 and 594±70ms), whereas PH (721±51 and 765±48ms) and EH (718±55 and 755±34ms) slowed response times (P<0.001vs. IH). Performance on the SWM task was not altered by condition. MCAv increased during IH compared to PH (P<0.05), which was unchanged from rest. EH caused a significant fall in MCAv and prefrontal cerebral oxygenation (P<0.05vs. baseline). MCAv was moderately correlated to cognitive performance (R2 =0.266-0.289), whereas prefrontal cerebral tissue perfusion and saturation were not (P>0.05). These findings reveal a role of hyperventilation-induced hypocapnia per se on the development of cognitive impairment during normoxic and hypoxic exposures.

Determining differences between critical closing pressure and resistance-area product: responses of the healthy young and old to hypocapnia.

Healthy ageing has been associated with lower cerebral blood flow velocities (CBFVs); however, the behaviour of hemodynamic parameters associated with cerebrovascular tone (critical closing pressure, CrCP) and cerebrovascular resistance (resistance-area product, RAP) remains unclear. Specifically, evidence supports ageing being associated with greater cerebrovascular tone and resistance during exercise with elevated CrCP and RAP in older individuals at rest and during exercise. Comprehensive hemodynamic assessment of CrCP and RAP during hyperventilation-induced hypocapnia in two distinct age groups (young ≤ 49 and old > 50) has not been described. CBFV in the middle cerebral artery (CBFV, transcranial Doppler), blood pressure (BP, Finometer) and end-tidal CO2 (EtCO2, capnography) were recorded in 104 healthy individuals (43 young [age 33.8 (9.3) years], 61 old [age 64.1 (8.5) years]) during a minimum of 60s of metronome-driven hyperventilation-induced hypocapnia. Autoregulation index was calculated as a function of time, using a moving window autoregressive-moving average model. CBFV was reduced in response to age (p < 0.0001) and hypocapnia (p = 0.023) (young 57.3 (14.4) vs. 44.9cms-1 (11.1), old 51.7 (12.9) vs. 37.8cms-1 (9.6)). Critical closing pressure (CrCP) increased significantly in response to hypocapnia (young 37.6 (18.5) vs. 39.7mmHg (16.0), old 33.9 (13.5) vs. 39.3mmHg (11.4); p < 0.0001). Resistance-area product was increased in response to age (p = 0.001) and hypocapnia (p = 0.004) (young 1.02 (0.40) vs. 1.09mmHgcms-1 (11.07), old 1.16 (0.34) vs. 1.34mmHgcms-1 (0.39)). RAP and not CrCP mediates differences in cerebrovascular resistance responses to hypocapnia between the healthy young and old individuals.

Different strategies to initiate and maintain hyperventilation: their effect on continuous estimates of dynamic cerebral autoregulation

Objective: Capnography is a key monitoring intervention in several neurologically vulnerable clinical states. Cerebral autoregulation (CA) describes the ability of the cerebrovascular system to maintain a near constant cerebral blood flow throughout fluctuations in systemic arterial blood pressure, with the partial pressure of arterial carbon dioxide known to directly influence CA. Previous work has demonstrated dysautoregulation lasting around 30 s prior to the anticipated augmentation of hyperventilation-associated hypocapnia. In order assess to potential benefit of hypocapnic interventions in an acute stroke setting, minimisation of dysregulation is paramount. Approach: Hyperventilation strategies to induce and maintain hypocapnia were performed in 61 healthy participants, effects on temporal estimates of dynamic cerebral autoregulation (autoregulation index, ARI) were assessed to validate the most effective strategy for inducing and maintaining hypocapnia. Main results: The extent of initial decrease was significantly smaller in the continuous metronome strategy compared to the delayed metronome and voluntary strategies (▵ARI 0.33 ± 1.18, 2.80 ± 3.33 and 3.69 ± 2.79 respectively, p < 0.017). Significance: The use of a continuous metronome to induce hypocapnia rather than the sudden inception of an auditory stimulus appears to reduce the initial decrease in autoregulatory capacity seen in previous studies. Dysautoregulation can be minimised by continuous metronome use during hyperventilation-induced hypocapnia. This advancement in understanding of the behaviour of CA during hypocapnia permits safer delivery of CA targeted interventions, particularly in neurologically vulnerable patient populations.

Slow [formula omitted] kinetics in acute hypoxia are not related to a hyperventilation-induced hypocapnia

We examined whether slower pulmonary O2 uptake (V˙O2p) kinetics in hypoxia is a consequence of: a) hypoxia alone (lowered arterial O2 pressure), b) hyperventilation-induced hypocapnia (lowered arterial CO2 pressure), or c) a combination of both. Eleven participants performed 3–5 repetitions of step-changes in cycle ergometer power output from 20W to 80% lactate threshold in the following conditions: i) normoxia (CON; room air); ii) hypoxia (HX, inspired O2 = 12%; lowered end-tidal O2 pressure [PETO2] and end-tidal CO2 pressure [PETCO2]); iii) hyperventilation (HV; increased PETO2 and lowered PETCO2); and iv) normocapnic hypoxia (NC-HX; lowered PETO2 and PETCO2 matched to CON). Ventilation was increased (relative to CON) and matched between HX, HV, and NC-HX conditions. During each condition VO2p˙ was measured and phase II V˙O2p kinetics were modeled with a mono-exponential function. The V˙O2p time constant was different (p < 0.05) amongst all conditions: CON, 26 ± 11s; HV, 36 ± 14s; HX, 46 ± 14s; and NC-HX, 52 ± 13s. Hypocapnia may prevent further slowing of V˙O2p kinetics in hypoxic exercise.

Effect of hypocapnia on the sensitivity of hyperthermic hyperventilation and the cerebrovascular response in resting heated humans.

Elevating core temperature at rest causes increases in minute ventilation (V̇e), which lead to reductions in both arterial CO2 partial pressure (hypocapnia) and cerebral blood flow. We tested the hypothesis that in resting heated humans this hypocapnia diminishes the ventilatory sensitivity to rising core temperature but does not explain a large portion of the decrease in cerebral blood flow. Fourteen healthy men were passively heated using hot-water immersion (41°C) combined with a water-perfused suit, which caused esophageal temperature (Tes) to reach 39°C. During heating in two separate trials, end-tidal CO2 partial pressure decreased from the level before heating (39.4 ± 2.0 mmHg) to the end of heating (30.5 ± 6.3 mmHg) ( P = 0.005) in the Control trial. This decrease was prevented by breathing CO2-enriched air throughout the heating such that end-tidal CO2 partial pressure did not differ between the beginning (39.8 ± 1.5 mmHg) and end (40.9 ± 2.7 mmHg) of heating ( P = 1.00). The sensitivity to rising Tes (i.e., slope of the Tes - V̇E relation) did not differ between the Control and CO2-breathing trials (37.1 ± 43.1 vs. 16.5 ± 11.1 l·min-1·°C-1, P = 0.31). In both trials, middle cerebral artery blood velocity (MCAV) decreased early during heating (all P < 0.01), despite the absence of hyperventilation-induced hypocapnia. CO2 breathing increased MCAV relative to Control at the end of heating ( P = 0.005) and explained 36.6% of the heat-induced reduction in MCAV. These results indicate that during passive heating at rest ventilatory sensitivity to rising core temperature is not suppressed by hypocapnia and that most of the decrease in cerebral blood flow occurs independently of hypocapnia. NEW & NOTEWORTHY Hyperthermia causes hyperventilation and concomitant hypocapnia and cerebral hypoperfusion. The last may underlie central fatigue. We are the first to demonstrate that hyperthermia-induced hyperventilation is not suppressed by the resultant hypocapnia and that hypocapnia explains only 36% of cerebral hypoperfusion elicited by hyperthermia. These new findings advance our understanding of the mechanisms controlling ventilation and cerebral blood flow during heat stress, which may be useful for developing interventions aimed at preventing central fatigue during hyperthermia.

Respiratory and hemodynamic contributions to emotion-related pre-syncopal vasovagal symptoms

Vasovagal reactions are conventionally understood as resulting from systemic changes in cardiovascular activity; however, there exists a complementary perspective focused on specific changes in cerebral vasoconstriction associated with hyperventilation-induced hypocapnia. The present study investigated the role of cardiovascular and respiratory activity in self-reported pre-syncopal vasovagal reactions to a surgery video in a sample of 49 healthy women. Participants who indicated more previous real-life episodes of dizziness reported experiencing significantly more symptoms in the laboratory consistent with a vasovagal response. They also showed lower total peripheral resistance and higher pre-ejection period in general, suggesting lower sympathetic nervous system activity. Significant decreases in end-tidal carbon dioxide (PETCO2) occurred during the surgery video among susceptible participants, without significant increases in respiration rate. Further, participants who experienced reductions from the neutral video in PETCO2, systolic blood pressure, or both, reported vasovagal symptoms during the surgery video. The results suggest that patterns of respiration associated with decreases in PETCO2 may contribute to vasovagal symptoms reported in non-clinical groups as well as those with blood-injection-injury phobia and are associated with susceptibility to dizziness.

Sleep apnoea in heart failure: To treat or not to treat?

Heart failure (HF) and sleep apnoea are common disorders which frequently coexist. Two main types of apnoea occur: one is obstructive which, through recurring episodes of snoring, hypoxaemia, large negative intra-thoracic pressures and arousals from sleep leading to downstream inflammatory and autonomic nervous system changes, is thought to be a causative factor to the development of systemic hypertension and HF. The other type of apnoea, Cheyne-Stokes respiration with central sleep apnoea (CSR-CSA), is characterized by an oscillatory pattern of ventilation with a prevailing hyperventilation-induced hypocapnia, often in the absence of significant hypoxaemia and snoring, and is thought to be a consequence of advanced HF-related low cardiac output, high sympathetic nervous system activation and pulmonary congestion. CSR-CSA may be a compensatory response to advanced HF. Rostral fluid shift during sleep may play an important role in the pathogenesis of both obstructive sleep apnoea (OSA) and CSA. Studies of positive airway pressure (PAP) treatment of OSA and CSA in HF have shown short-term improvements in cardiac and autonomic function; however, there is no evidence of improved survival. Loop gain may provide useful marker of continuous PAP (CPAP) responsiveness in patients with central apnoea. A greater understanding of the pathophysiology of the interaction between obstructive and central apnoea and the various types of HF, and the mechanisms of therapies, such as PAP, is required to develop new strategies to overcome the disabling symptoms, and perhaps improve the mortality, that accompany HF with sleep apnoea.

Tetany During Intravenous Conscious Sedation in Dentistry Resulting From Hyperventilation-Induced Hypocapnia

Hyperventilation can be a manifestation of anxiety that involves abnormally fast breathing (tachypnea) and an elevated minute ventilation that exceeds metabolic demand. This report describes a case of hyperventilation-induced hypocapnia resulting in tetany in a 16-year-old girl undergoing orthodontic extractions under intravenous conscious sedation. Pulse oximetry is the gold standard respiratory-related index in conscious sedation. Although the parameter has great utility in determining oxygen desaturation, it provides no additional information on respiratory function, including, for example, respiratory rate. In this case, we found capnography to be a very useful aid to monitor respiration in this patient and also to treat the hypocapnia.

Corticospinal excitability is associated with hypocapnia but not changes in cerebral blood flow.

Reductions in cerebral blood flow (CBF) may be implicated in the development of neuromuscular fatigue; however, the contribution from hypocapnic-induced reductions (i.e. P ETC O2) in CBF versus reductions in CBF per se has yet to be isolated. We assessed neuromuscular function while using indomethacin to selectively reduce CBF without changes in P ETC O2 and controlled hyperventilation-induced hypocapnia to reduce both CBF and P ETC O2. Increased corticospinal excitability appears to be exclusive to reductions in P ETC O2 but not reductions in CBF, whereas sub-optimal voluntary output from the motor cortex is moderately associated with decreased CBF independent of changes in P ETC O2. These findings suggest that changes in CBF and P ETC O2 have distinct roles in modulating neuromuscular function. Although reductions in cerebral blood flow (CBF) may be involved in central fatigue, the contribution from hypocapnia-induced reductions in CBF versus reductions in CBF per se has not been isolated. This study examined whether reduced arterial PCO2 (P aC O2), independent of concomitant reductions in CBF, impairs neuromuscular function. Neuromuscular function, as indicated by motor-evoked potentials (MEPs), maximal M-wave (Mmax ) and cortical voluntary activation (cVA) of the flexor carpi radialis muscle during isometric wrist flexion, was assessed in ten males (29±10years) during three separate conditions: (1) cyclooxygenase inhibition using indomethacin (Indomethacin, 1.2mgkg(-1) ) to selectively reduce CBF by 28.8±10.3% (estimated using transcranial Doppler ultrasound) without changes in end-tidal PCO2 (P ETC O2); (2) controlled iso-oxic hyperventilation-induced reductions in P aC O2 (Hypocapnia), P ETC O2 =30.1±4.5mmHg with related reductions in CBF (21.7±6.3%); and (3) isocapnic hyperventilation (Isocapnia) to examine the potential direct influence of hyperventilation-mediated activation of respiratory control centres on CBF and changes in neuromuscular function. Change in MEP amplitude (%Mmax ) from baseline was greater in Hypocapnia tha in Isocapnia (11.7±9.8%, 95% confidence interval (CI) [2.6, 20.7], P=0.01) and Indomethacin (13.3±11.3%, 95% CI [2.8, 23.7], P=0.01) with a large Cohen's effect size (d ≥ 1.17). Although not statistically significant, cVA was reduced with a moderate effect size in Indomethacin (d=0.7) and Hypocapnia (d=0.9) compared to Isocapnia. In summary, increased corticospinal excitability - as reflected by larger MEP amplitude - appears to be exclusive to reduced P aC O2, but not reductions in CBF per se. Sub-optimal voluntary output from the motor cortex is moderately associated with decreased CBF, independent of reduced P aC O2.

Delineating the Role of Cerebral Blood Flow and Hypocapnia on Neuromuscular Function

Neuromuscular fatigue, defined as the inability of a muscle to maintain a given level of force regardless of whether or not a task can be sustained, has been attributed, in part, to central mechanisms. Although reductions in cerebral blood flow (CBF) may be implicated in the development of central fatigue, the contribution from hypocapnic-reductions (i.e., PETCO2) in CBF versus reductions in CBF per se has yet to be isolated. PURPOSE: To examine the hypothesis that hypocapnia, independent of concomitant reductions in CBF, cause impairments in neuromuscular function. METHODS: Neuromuscular function, as indicated by motor evoked potentials (MEP), M-waves and cortical voluntary activation (cVA) of the flexor carpal radialis muscle during isometric wrist flexion, was assessed in 8 males (31±12 y) during 3 separate conditions: 1) cyclooxygenase inhibition using Indomethacin (Indo) to selectively reduce CBF; 2) controlled hyperventilation-induced hypocapnia (Hypocapnia); and 3) isocapnic hyperventilation (Isocapnia). CBF was estimated using transcranial Doppler ultrasound velocity measurements of the middle cerebral artery. Change from baseline and comparison of the 3 conditions was assessed using two-way repeated measures ANOVA. Relationships between variables were assessed using Pearson‘s correlations. RESULTS: The experimental conditions successfully isolated CBF and PETCO2. MEP amplitude (% M-wave amplitude) increased in hypocapnia (14.6±9.5%, p < 0.01) in comparison to Indo (-2.0±2.8%) and Isocapnia (0.6±1.8%); however, no significant changes were observed in M wave (p = 0.666) or cVA (p = 0.117). Correlation analysis revealed that MEP amplitude was inversely associated with PETCO2 (r = -0.54, p < 0.01) and cVA was weakly associated with CBF (r = 0.30, p < 0.05). CONCLUSIONS: Increased motor cortex excitability appears to be exclusive to hypocapnia but not reductions in CBF per se. However, a weak relationship between reductions in CBF and cVA exists, such that further research is required to confirm this finding and explore the potential implications. Supported by NSERC Discovery 227912-2012.

Studying cerebral hemodynamics and metabolism using simultaneous near-infrared spectroscopy and transcranial Doppler ultrasound: a hyperventilation and caffeine study.

Caffeine is one of the most widely consumed psycho-stimulants in the world, yet little is known about its effects on brain oxygenation and metabolism. Using a double-blind, placebo-controlled, randomized cross-over study design, we combined transcranial Doppler ultrasound (TCD) and near-infrared spectroscopy (NIRS) to study caffeine's effect on middle cerebral artery peak blood flow velocity (Vp), brain tissue oxygenation (StO2), total hemoglobin (tHb), and cerebral oxygen metabolism (CMRO2) in five subjects. Hyperventilation-induced hypocapnia served as a control to verify the sensitivity of our measurements. During hypocapnia (∼16 mmHg below resting values), Vp decreased by 40.0 ± 2.4% (95% CI, P < 0.001), while StO2 and tHb decreased by 2.9 ± 0.3% and 2.6 ± 0.4%, respectively (P = 0.003 and P = 0.002, respectively). CMRO2, calculated using the Fick equation, was reduced by 29.3 ± 9% compared to the isocapnic-euoxia baseline (P < 0.001). In the pharmacological experiments, there was a significant decrease in Vp, StO2, and tHb after ingestion of 200 mg of caffeine compared with placebo. There was no significant difference in CMRO2 between caffeine and placebo. Both showed a CMRO2 decline compared to baseline showing the importance of a placebo control. In conclusion, this study showed that profound hypocapnia impairs cerebral oxidative metabolism. We provide new insight into the effects of caffeine on cerebral hemodynamics. Moreover, this study showed that multimodal NIRS/TCD is an excellent tool for studying brain hemodynamic responses to pharmacological interventions and physiological challenges.

Cerebral vasomotor reactivity: steady-state versus transient changes in carbon dioxide tension.

New FindingsWhat is the central question of this study?The relationship between changes in cerebral blood flow and arterial carbon dioxide tension is used to assess cerebrovascular function. Hypercapnia is generally evoked by two methods, i.e. steady-state and transient increases in carbon dioxide tension. In some cases, the hypercapnia is immediately preceded by a period of hypocapnia. It is unknown whether the cerebrovascular response differs between these methods and whether a period of hypocapnia blunts the subsequent response to hypercapnia.What is the main finding and its importance?The cerebrovascular response is similar between steady-state and transient hypercapnia. However, hyperventilation-induced hypocapnia attenuates the cerebral vasodilatory responses during a subsequent period of rebreathing-induced hypercapnia.Cerebral vasomotor reactivity (CVMR) to changes in arterial carbon dioxide tension () is assessed during steady-state or transient changes in . This study tested the following two hypotheses: (i) that CVMR during steady-state changes differs from that during transient changes in ; and (ii) that CVMR during rebreathing-induced hypercapnia would be blunted when preceded by a period of hyperventilation. For each hypothesis, end-tidal carbon dioxide tension () middle cerebral artery blood velocity (CBFV), cerebrovascular conductance index (CVCI; CBFV/mean arterial pressure) and CVMR (slope of the linear regression between changes in CBFV and CVCI versus ) were assessed in eight individuals. To address the first hypothesis, measurements were made during the following two conditions (randomized): (i) steady-state increases in of 5 and 10 Torr above baseline; and (ii) rebreathing-induced transient breath-by-breath increases in . The linear regression for CBFV versus (P = 0.65) and CVCI versus (P = 0.44) was similar between methods; however, individual variability in CBFV or CVCI responses existed among subjects. To address the second hypothesis, the same measurements were made during the following two conditions (randomized): (i) immediately following a brief period of hypocapnia induced by hyperventilation for 1 min followed by rebreathing; and (ii) during rebreathing only. The slope of the linear regression for CBFV versus (P < 0.01) and CVCI versus (P < 0.01) was reduced during hyperventilation plus rebreathing relative to rebreathing only. These results indicate that cerebral vasomotor reactivity to changes in is similar regardless of the employed methodology to induce changes in and that hyperventilation-induced hypocapnia attenuates the cerebral vasodilatory responses during a subsequent period of rebreathing-induced hypercapnia.