Control of breathing


The increase in ventilation (E) that takes place in the first few days at altitude is one of the most important aspects of the acclimatization process. Increases in V˙E result in higher alveolar and arterial PO2 (PAO2 and PaO2, respectively) and lower alveolar and arterial PCO2 (PACO2 and PaCO2, respectively) than would have been obtained if the V˙E were unchanged. The higher PaO2 also facilitates improvements in arterial oxygen content (CaO2) and, as such, convective oxygen delivery to tissue. Interest in the mechanisms underlying these changes goes back to the early years of the 20th century, when Haldane, who showed that the level of carbon dioxide (CO2) in the body was stable at sea level, soon realized that altitude resulted in reduction in PACO2 due to increased V˙E. While Haldane and his companions were on the Pikes Peak Expedition of 1911, he suggested that his colleague Mabel FitzGerald measure the PACO2 in residents at mining camps at various altitudes in Colorado. She found that the PACO2 fell linearly with altitude (FitzGerald 1913). The mechanism for sensing arterial hypoxemia and altering V˙E remained unknown until Heymans and Heymans (1927) subsequently discovered that the carotid body detected hypoxemia in 1927.

Despite a considerable amount of research in this area since that time, the complex and multifaceted mechanisms mediating this ventilatory acclimatization (and deacclimatization) remain poorly understood. In addition to the well-established independent roles of the peripheral and central chemoreceptors, more current hypotheses incorporate newer and controversial concepts such as cardioventilatory control based on plasticity of chemosensitivity, multiple sites of hypoxic sensing, interdependence of central and peripheral chemoreceptors, and upregulation of CNS neurons comprising respiratory and sympathetic regulatory pathways. Such factors are likely regulated in a manner that explains the temporal changes in V˙E over time at high altitude, including the reported ventilatory depression in some populations native to high altitude. This chapter outlines these integrative mechanisms involved in control of breathing in hypoxia and high altitude.

Hypoxic Ventilatory Response

The hypoxic ventilatory response (HVR) is the increase in V˙E brought about by acute hypoxia. If the inspired PO2 (PIO2) is reduced acutely (i.e., over a period of a few minutes), either by breathing a low oxygen mixture or by decompression in a hypobaric chamber, V˙E immediately increases. However, this increase in V˙E varies greatly from individual to individual and does not usually begin until the PIO2 is reduced to approximately 100 mmHg (equivalent to about 3000 m altitude) (Rahn and Otis 1949). This corresponds to PAO2 of about 50 mmHg. Thereafter, as PIO2 is further reduced, V˙E increases more rapidly. The HVR is not a simple linear response and is complicated by the effect of V˙E on pH and PaCO2. As V˙E rises in response to hypoxia, PaCO2 falls and pH rises (i.e., respiratory alkalosis). Thus, the HVR is reduced via the dependent interactions with pH unless measures are taken to prevent this fall in PaCO2 (Nielsen and Smith 1952).

The relationship of V˙E to PO2 is hyperbolic, as shown in Figure 9.1. However, if arterial saturation is measured by a peripheral pulse oximeter, the relationship with ventilation is found to be approximately linear (Figure 9.1). The PaO2 at which V˙E starts to increase corresponds to the PO2 at which the hemoglobin-oxygen dissociation curve begins to steepen. Thus, the HVR protects CaO2, increasing V˙E as saturation begins to fall.

Figure 9.1

Figure 9.1Hypoxic ventilatory response to decreasing alveolar PO2 (PAO2) and to decreasing arterial oxygen saturation (SaO2).

As noted above, the actual effect of acute hypoxia on V˙E depends on whether PaCO2 is allowed to fall or not. Unless the experimental arrangement allows control of PACO2, a rise in ventilation will result in a concomitant fall of PaCO2. This is the normal situation as a person ascends to altitude, and if the HVR is measured in this way it is termed poikilocapnic. As PaCO2 is reduced, some drive to breathe will be lost, so that the full intrinsic acute hypoxic ventilatory response is not observed. In order to quantify the full acute HVR, PACO2 is usually held constant, and the response measured is termed the isocapnic HVR.

Time course of ventilatory response to hypoxia: Acute and prolonged exposure

There are four general phases to the HVR response, as illustrated in Figure 9.2:

  • In the first few seconds to about 10 minutes there is an increase in V˙E (and fall in PaCO2) if the hypoxia is sufficiently severe.

  • From about 5 to 20 minutes there is a reduction of V˙E back toward the control value; this can occur even in the absence of reductions in PaCO2 and is called the hypoxic ventilatory decline (HVD) or “roll off.” The exact mechanisms causing HVD are uncertain; however, its occurrence could result from a decreased chemoreceptor sensitivity (Duffin and Mahamed 2003), elevations in cerebral blood flow (CBF) (Hoiland et al. 2014), and/or neural stimulus (reviewed in Pamenter and Powell 2016).

  • There is further increase in V˙E and reduction in PaCO2 from about 30 minutes to few days, which continues up to about two weeks at a given altitude. This is termed ventilatory acclimatization and is due to an increase in HVR, changes in CO2 chemosensitivity, and, perhaps, some direct effects of hypoxia on the central nervous system (CNS) as discussed in further sections of this chapter.

  • With prolonged exposure to high altitude over many years, some indigenous populations to high altitude or lowlanders who relocate to high altitude manifest evidence of HVD (Weil et al. 1971).

Figure 9.2

Figure 9.2Temporal changes in ventilation upon acute and prolonged exposure to hypoxia. Acute ventilatory response to hypoxia (AHVR) is followed within minutes by hypoxic ventilatory decline (HVD) before ventilatory acclimatization to hypoxia occurs. Hypoxic ventilatory depression may occur in some natives after many years at high altitude. (Source: Ainslie et al. 2013, with permission.)

Peripheral Chemoreceptors


The stimulating effect of hypoxemia on respiration had been known for many years before it became apparent at the turn of the 20th century that, under normal sea-level conditions, CO2 was the main chemical stimulus to V˙E. In the late 1920s, the father and son team of Heymans and Heymans, using complex cross-circulation experiments in dogs, localized the main sensing organ for hypoxia to the carotid body (Heymans and Heymans 1927). Not long afterward, Comroe (1939) showed that the aortic bodies have a similar function. These organs are known collectively as the peripheral chemoreceptors. However, in most animals, including humans (Timmers et al. 2003), the main organ for transduction of the hypoxic signal are the carotid bodies and if these are removed or denervated, acute hypoxia actually results in depression of ventilation. However, upon removal or denervation of the carotid bodies, over time, chemoreceptors in the aortic bodies begin to compensate (Forster and Bisgard 1976).

Anatomy and physiology of the carotid body

The human carotid body weighs about 10 mg and is situated just above the bifurcation of the common carotid artery. Per unit of mass, the carotid bodies have the highest blood flow of any other organ in the human body. Because of this extremely rich blood flow for its mass and oxygen consumption, it extracts only a very small percentage of the oxygen in the blood presented to it. This explains how it is able to respond to PaO2 and not to oxygen content. In other words, it responds to hypoxemia but not anemia or reduced flow. This is appropriate since an increase in ventilation would not help the organism overcome the tissue hypoxia caused by anemia or low cardiac output, but does help in a hypoxic environment.

Mechanisms of the Ventilatory Response to Acute Hypoxia

Based on an enormous amount of research work carried out on the carotid body, it is now generally accepted that the glomus cell (type I), the characteristic sensing cell of the carotid body, is the site of chemoreception, and that modulation of neurotransmitter release from the glomus cells by physiological and chemical stimuli affects the discharge rate of the carotid body afferent fibers. Undoubtedly the signal is modified, enhanced, or suppressed by parts of the system not involved with the primary sensing process. As a chemical signal is transduced into an electrical signal, information on the PaO2 travels via the carotid sinus nerve and cranial nerve IX to the respiratory centers in the brainstem, which then affect their output to motor neurons, thereby leading to changes in breathing rate, tidal volume, and hence minute ventilation.

The mechanisms by which hypoxemia is sensed by the carotid body and transmitted as increased neural discharge have been reviewed extensively elsewhere (Holmes et al. 2018; Lahiri and Cherniack 2001; Prabhakar and Jacono 2005; Wilson et al. 2005; Wilson and Teppema 2016). There is now a general consensus that a series of key processes contribute to the carotid body hypoxic chemotransduction cascade that are critically initiated via hypoxia-induced mitochondrial inhibition. These include attenuation of outward K+ current, type I cell depolarization, Ca2+ influx through L-type Ca2+ channels, neurosecretion (i.e., release of neurotransmitters), and chemoafferent excitation (Holmes et al. 2018). Although it seems clear that the mitochondria can adequately function as acute oxygen sensors in the carotid body, what remains highly controversial is the molecular identity of the specific oxygen sensor within the type I cell. The key processes contributing to the carotid body hypoxic chemotransduction are illustrated in Figure 9.3.

Figure 9.3

Figure 9.3Carotid body mitochondrial signaling mechanisms activated during hypoxia. Hypoxia-induced mitochondrial inhibition is proposed to increase lactate generation (Chang et al. 2015), augment mitochondrial complex I reactive oxygen species (ROS) production (Fernández-Agüera et al. 2018), or reduce mitochondrial ATP synthesis (Buckler and Turner 2013). These changes are proposed to directly or indirectly (e.g., via Olf78 receptor activation, reduced MgATP concentration or stimulation of AMP-activated protein kinase; AMPK) modify ion channel function leading to resting membrane potential (RMP) depolarization. This causes opening of L-type Ca2+ channels, neurosecretion, and an increase in discharge frequency of the adjacent chemoafferent fibers. TRP, transient receptor potential channel; NSC, nonselective cation channel; BKCa, large conductance Ca2+-activated K+ channel; TASK, TWIK-related acid-sensitive K+ channel; TREK, TWIK-related K+ channel; AP, action potential. (Modified from: Holmes et al. 2018, with permission.)

Dopamine is the most abundant transmitter found in the carotid body. Hypoxia increases the rate of release of dopamine from glomus cells. Norepinephrine (noradrenalin) and 5-hydroxytryptamine (i.e., serotonin) are next in abundance. There are also small quantities of acetylcholine, ATP, and enkephalin-like peptides in some glomus cells (Leonard et al. 2018). Substance P, endothelin-1, adenosine, angiotensin erythropoietin, and purinergic receptors are also present and may be involved in modulating the hypoxic response (Leonard et al. 2018; Wilson et al. 2005). It should be noted that, although in the context of high altitude, the most important function of the peripheral chemoreceptors (carotid and, to a lesser extent, aortic bodies) is to respond to hypoxia, they also respond to changes in pH and PaCO2 in dependent fashion through stimulus interaction; there is also growing consensus that the peripheral chemoreceptors also act as general metabolic sensors and, for example, are stimulated by changes in glucose and/or insulin (Conde et al. 2018). The greatest systemic response to PaCO2 is via the central chemoreceptors in the brainstem. As an example of the relative contribution of the chemoreceptors, a study by Fatemian et al. (2003) revealed that subjects who had had both carotid bodies removed had about 36% lower hypercapnic ventilatory response (HCVR) than normal subjects.

Chronic Hypoxia

Anatomically, chronic hypoxia results in hypertrophy of the carotid body in animals and humans, probably due to upregulation of growth factors (e.g., vascular endothelial growth factor; VEGF) (Prabhakar and Jacono 2005). Physiologically there is an increase in sensitivity over a period of about 30 minutes to some weeks (see Figure 9.4). The mechanism of this involves a number of systems including those mentioned above and no doubt others. It is likely that during this period gene induction is involved.

Figure 9.4

Figure 9.4Changes in HVR over time at high altitude and during laboratory hypoxia. Studies at altitude (filled symbols; solid lines) and in controlled laboratory settings (open symbols; dashed lines) demonstrate a progressive increase in HVR over time. Further it can be seen that the increase in HVR is related to the prevailing level of end-tidal partial pressure of oxygen (PETO2) during hypoxia, as previously noted by Donoghue and colleagues (Donoghue et al. 2005). Note that, although using different approaches to assess the HVR, comparable changes have been reported in other studies at high altitude following measured HVR serially in seven lowland subjects after arrival at Lhasa (3658 m) as they acclimatized over 27 days (Masuda et al. 1992; Yamaguchi et al. 1991); and in three out of four subjects after one to three months at 5800 m as part of the Silver Hut expedition (Michel and Milledge 1963).

HVR at Sea Level

Methods for measuring HVR

A number of different methods have been used to measure HVR, including rebreathing (e.g., (Rebuck and Campbell 1974), steady-state (e.g., Severinghaus et al. 1966) and single breath methods (e.g., Dejours et al. 1959), each of which has its advantages and disadvantages. Typically performed using an oximeter to measure oxygen saturation continuously while PaCO2 is held constant, both the rebreathing method (i.e., consuming O2 from a closed circuit to induce progressive hypoxemia) and steady-state methods (i.e., breathing a hypoxic mixture) are used to quantify the HVR as a change in ventilation for a given change in oxygen saturation. The general assumption has been than the HVR reflects the activity of the peripheral chemoreceptors; however, the extent and nature of the interactions (i.e., additive [no interaction], hypoadditive, or hyperadditive) between the peripheral and central chemoreflexes remain debatable (Wilson and Teppema 2016).

Single- or multiple-breath methods (typically one to eight breaths) have also been used (Dejours et al. 1959; Pfoh et al. 2016) in which breaths of altered oxygen or CO2 are given and the change in ventilation in the following few breaths is measured. Typical examples in order to target the peripheral and central chemoreflex include one to eight breaths of 100% N2 or a single-breath of 13% CO2, in air (Pfoh et al. 2016). These types of single breath methods were thought to reflect the activity of peripheral and not central chemoreceptors, would not be influenced by HVD and have minimal cardiovascular and cerebrovascular confounders. There would also be no time for a significant change in PCO2. The steady-state methods would reflect the activity of both central and peripheral chemoreceptors and the effect of HVD, depending upon how long the “steady state” was held. In addition to unknown interactions between the chemoreflexes (Wilson and Teppema 2016), the steady-state methods are also influenced by changes in CBF, which alter the arteriovenous blood-gas difference such that the central chemoreceptors may be exposed to a change in PCO2 even if end-tidal PCO2 is held constant (Ainslie and Duffin 2009). Therefore, simple and popular progressive hypoxia tests are likely to be influenced by both sets of chemoreceptors, HVD, CBF, and sympathetic nervous system activation. In the end, no method is free of criticism on one count or another and there is no consensus as to the preferred method. Fundamentally, the utility of the various tests depends on the specific question, equipment, and location (laboratory versus field) at hand.

It should also be considered that posture influences HVR, but not HCVR (Rigg et al. 1974; Weissman et al. 1982). For example, the supine position results in a 52% reduction in HVR and microgravity a reduction of 46% (Prisk et al. 2000). Presumably these reductions in HVR occur via the same mechanism—that of an increase in the blood pressure in the carotid baroreceptors—since it is known that there is interaction of baroreceptor and chemoreceptor reflexes (Somers et al. 1991; Timmers et al. 2003)

Variability of HVR: Effect of age, specific groups, and drugs

The range of HVR found in healthy sea level residents is wide. The coefficient of variation varies between 23 and 72% in different studies (Cunningham et al. 1964; Weil et al. 1970; Rebuck and Campbell 1974). Interestingly, on the basis of studies in pairs of monozygotic and dizygotic twins, HVR has been repeatedly shown to be heritable in a number of age groups spanning infancy to adulthood (MacLeod et al. 2013). Various groups of subjects at sea level have been shown to have lower HVRs than age-matched controls, for instance endurance athletes (Byrne-Quinn et al. 1971) and elite synchronized swimmers (Bjurstrom and Schoene 1987). With increasing age HVR becomes lower (Kronenberg and Drage 1973; Poulin et al. 1993). Alcohol (Sahn et al. 1974) and respiratory depressant drugs and anesthetics also inhibit HVR (Davis et al. 1982).

HVR under Different Conditions

HVR and acclimatization

Ventilatory acclimatization takes place during the first few days at high altitude, as demonstrated by an increase in ventilation and a decrease in PACO2. PAO2 falls immediately on exposure to acute altitude and then rises (as PACO2 falls) over the next few days. The rise in V˙E on acute exposure to hypoxia is mediated by the HVR (by definition) but further increases in V˙E are due to changes in HCVR and HVR with more time at altitude (see below).

The peripheral chemoreceptors are essential for normal ventilatory acclimatization, and animals which have had their carotid bodies denervated fail to acclimatize normally (Forster et al. 1981; Lahiri et al. 1981; Smith et al. 1986). After denervation these animals have raised PaCO2 at rest, which rises further with acute hypoxia, likely due to hypoventilation. In these denervation studies, with chronic hypoxia, there is a small fall in PaCO2, which has been taken by some investigators as evidence of acclimatization (Sorensen and Mines 1970). This and other evidence suggests that chronic hypoxia produces some effect on ventilation via mechanisms other than the carotid body, possibly via upregulation of the aortic bodies (Forster et al. 1976) and/or the direct influence of hypoxia on the CNS (Gourine and Funk 2017). All agree, however, that denervated animals appeared ill at altitude and a proportion die.

Under normal conditions, HVR occurs when PaO2 falls below ∼50 mmHg and the resulting hypoxemia is detected by the carotid bodies to stimulate hyperventilation, thereby slightly increasing PaO2. The primary mechanism underlying ventilatory acclimatization to hypoxia (VAH) in response to chronic hypoxic exposure is a greater sensitivity of the HVR (in addition to changes in the HCVR). Well-controlled laboratory data indicate that as little as eight hours (awake) (Fatemian et al. 2001) to 24 hours (one day/night) (Donoghue et al. 2005; Fatemian et al. 2001) of mild hypoxia (e.g., PIO2 = 127 mmHg) is adequate to increase isocapnic HVR (Donoghue et al. 2005; Fatemian et al. 2001). However, upon arrival to high altitude, HVR appears initially unaltered compared to sea level (Sato et al. 1992; White et al. 1987). However, it is well established that the slope of the V˙E-SaO2 response steepens following several days of acclimatization (Bhaumik and Banerjee 2003; Donoghue et al. 2005; Rupp et al. 2014; Sato et al. 1992; White et al. 1987), with this response progressing in a graded manner over time (Figure 9.4). Potentiation of the HVR can occur with very minor, but sustained, changes in PaO2 (∼10 mmHg PaO2) highlighting that the physiological mechanisms underlying this response are also important at sea level (Donoghue et al. 2005). The HVR response, at high altitude, is apparently similar between men and women (Bhaumik and Banerjee 2003; Muza et al. 2001; Pfoh et al. 2016).

Laboratory studies have demonstrated that several hours following an eight-hour period of isocapnic or poikilocapnic hypoxia, V˙E remains elevated during acute hyperoxic breathing, indicating that factors other than acid-base changes (i.e., increased carotid body activity) are responsible for the progressive rise in V˙E (Tansley et al. 1997). In support of these findings, Barnard et al. observed that two to three hours of hypoxia was insufficient to increase the carotid body activity of anaesthetized cats, but that it had increased following chronic exposure (Barnard et al. 1987). It is also noteworthy that, in line with acute laboratory studies (Tansley et al. 1997), a potentiated HVR remains present five days after return to sea level from altitude (Sato et al. 1992) and that this aspect of acclimatization is partially retained on re-exposure to high altitude (Subudhi et al. 2014). Hence, it appears that continuous exposure of the carotid bodies to hypoxemia might be required to elicit adjustments of HVR.

This increase in HVR over the period of a few days to a few weeks can, at least in part, explain the further increase in ventilation over this period of altitude exposure. The mechanism for this increase in HVR is not clear. A study in awake goats using selective inhibitors indicates that 5-HT is not essential for this aspect of ventilatory acclimatization (Herman et al. 2001).

Extensive evidence indicates that hypoxia-inducible factors mediate adaptive responses to hypoxemia and are sensed by the carotid body (see Figure 9.3: reviewed in: Semenza and Prabhakar 2018). Kline et al. (2002) studied the importance of the hypoxia-inducible factor-1α (HIF-1α) in the changes in HVR with acclimatization. In this study, heterozygous transgenic mice, with one chromosome for HIF-1α knocked out (homozygous knock-out mice die in utero), were compared with wild-type mice. Whereas there was no difference in response to acute hypoxia, the effect of chronic hypoxia (three days at 0.4 atm) was different. The wild-type mice showed the expected increase in HVR, while the knock-out mice showed reduced HVR. They showed this result both in terms of V˙E, especially respiratory rate, and in carotid sinus nerve activity, indicating it was an effect in the carotid body as opposed to a purely central effect.

As a master regulator of oxygen homeostasis (Semenza and Prabhakar 2018), HIF-1α induces transcription of many genes that are influenced by hypoxia, including those mentioned above. It may also be the mechanism by which hypoxia affects potassium channel activity in glomus cells leading to depolarization and increases in calcium concentration and neurotransmitter release (Prabhakar 2000). Gassmann et al. (2009) showed, in mice, that enhanced erythropoietin (EPO) in the brainstem increased the HVR. This effect was abolished by an EPO antagonist (soluble EPO receptor). The effect was more pronounced in female than male mice. Another study from the same group (Soliz et al. 2009) using transgenic mice, overexpressing the EPO gene, found the same effect. They then went on to conduct a small “proof of concept” study in humans. Subjects were given intravenous EPO before being exposed to an FIO2 of 0.1. Although HVR was increased in both male and female subjects, the effect was greater in women than men, although this sex difference was not confirmed in a more recent study where the HVR was unchanged following a clinically relevant dose of EPO (Berendsen et al. 2016). Similar studies have not been completed at high altitude, and perhaps more chronic changes in EPO and expression are required to influence chemoreflex control. Malik et al. (2005) found that, in knock-out mice, the transcription factor gene active in the brain (e.g., fos B) plays a critical role in eliciting changes in HVR with acclimatization.

In considering this body of work, it should be noted that no single mechanism explains progressive changes in HVR or ventilatory acclimatization. Beyond the role played by the peripheral and central chemoreceptors, cardioventilatory control based on plasticity of chemosensitivity, multiple sites of hypoxic sensing, and an upregulation of CNS neurons comprising respiratory and sympathetic regulatory pathways all are likely implicated in the control of breathing at altitude.

HVR and intermittent hypoxia

With the increase in the use of intermittent hypoxia (IH) in athletic training and preacclimatization prior to high altitude travel, as well as interest in clinical conditions such as obstructive sleep apnea, there have been a number of studies examining the effect of IH on HVR.

Serebrovskaya et al. (1999) exposed subjects to three, five-to-six-minute hypoxic rebreathing sessions per day, separated by two five-minute breaks, for 14 days. During the procedure the end-tidal PO2 progressively decreased from 105–100 mmHg to 50–40 mmHg during the first week and to 40–35 mmHg during the second week as subjects tolerance to hypoxia increased. With end-tidal PCO2 (PETCO2) held constant, they found that the HVR increased significantly by 43% after the training compared with pretraining control values.

Using two hours a day of hypoxia equivalent to 3800 m for 12 days, Garcia et al. (2000) found HVR increased to 193% above control by day 5 but then declined to 70% above control by day 12. Katayama et al. (2001) showed that as little as one hour of hypoxia equivalent to 4500 m equivalent per day for seven days significantly increased HVR, while Townsend et al. (2002) in their study of trained athletes “living high–training low” also found a dose-dependent increase in HVR. That is, the groups having the greatest magnitude of hypoxia had the greatest increase in HVR, which continued to increase with the number of nights spent in hypoxia. They were also able to show a decrease in PETCO2 of about 3 mmHg in normoxia, although they found no change in ventilation. Foster et al. (2005) and Katayama et al. (2007) confirmed that IH increased HVR, but interestingly this did not result in an increase in exercise V˙E.

The changes in HVR following IH are likely mediated in part by an upregulation of the carotid body mitochondrial signaling mechanisms and/or neurotransmitters activated during hypoxia (Figure 9.3). Studies involving IH exposures in humans, for example, have reported relationships between elevations in HVR and concurrent elevations in markers of oxidative stress (Pialoux 2009) and EPO (Brugniaux et al. 2011). In support of the former, antioxidants have been reported to reverse the depression of HVR by acetazolamide in humans (Teppema et al. 2006). Using HIF-1α knock-out mice, Peng et al. (2006) have shown that the increase in HVR induced by IH is HIF-1 dependent. More recent studies show that IH induces formation of reactive oxygen species (ROS) and increases intracellular Ca2+ levels (at the level of the carotid body), which drive increased expression of HIF-1α and a decrease in the levels of HIF-2α (Semenza and Prabhakar 2018). The ROS generated by dysregulated HIF activity in the carotid body results in oxidation and inhibition of heme oxygenase-2, and the resulting reduction in the levels of carbon monoxide leads to increased hydrogen sulfide production, triggering glomus cell depolarization (Semenza and Prabhakar 2018). The effects of IH on other aspects of the physiology of hypoxia are addressed in other chapters. Likewise, although high altitude and IH are often viewed in separate contexts, it is relevant to note that IH in the form of periodic breathing during sleep also occurs at high altitude (see Chapter 17).

HVR and high altitude residents

Chiodi (1957) reported that high altitude residents in the Andes had higher PACO2 than acclimatized lowlanders. Severinghaus et al. (1966) showed that Andean natives born and living at altitude had a blunted HVR, while similar findings were reported in Sherpa natives born and living at high altitude in the Himalayas (Lahiri and Milledge 1967; Milledge and Lahiri 1967). More recently, however, a recent review of 21 related papers (Gilbert-Kawai et al. 2014) concluded that the HVR of Tibetans/Sherpa was not different from lowlanders. Inevitably, methodological differences between studies, the acclimatization process, and differences in altitude at which Sherpa and lowlanders were assessed have all been considered contributing factors to these inconsistent findings. Further, measurements of HVR lack consistency between studies, and pulmonary V˙E may not be purely representative of differences in alveolar ventilation (A) between groups, especially considering the noted differences in lung volumes (Droma et al. 1991) and diffusion capacity (Zhuang et al. 1996). However, as mentioned elsewhere, PaCO2 provides an effective means to index V˙A that accounts for potential differences in volumes and diffusion capacities (Chapter 8). Thus, in a recent study (Willie et al. 2018), Rahn and Otis (1949) curves were plotted for the purposes of comparing effective V˙A between the Sherpa and lowlander groups upon progressive ascent to high altitude (Figure 9.5). As depicted in the figure, it can be seen that below a PaO2 of ∼50 mmHg, lowlanders have a downward shift in the curve, indicating that V˙A is greater in lowlanders under the assumption that CO2 production (V˙CO2) is not different. Given the lower oxygen consumption (V˙O2) of Sherpa (Flück et al. 2017; Gilbert-Kawai et al. 2014), and therefore, V˙CO2, differences in V˙A are underrepresented by the plotted lines.

Figure 9.5

Figure 9.5Rahn and Otis curves for Sherpa and lowlanders upon ascent to altitude. Lowlanders are denoted by the open circle symbol (◦), and Sherpa by the open square symbol (◻). Moving right to left, data are plotted from Kathmandu (1400 m), Namche Bazaar (3400 m), Pheriche (4371 m), and the Pyramid Laboratory (5050 m). * Denotes a significant difference between Sherpa and lowlanders for PaCO2 at a given altitude (P < 0.05). (Reproduced from Willie et al. 2018.)

Overall, these arterial blood gas data, in line with previous smaller studies (Lahiri and Milledge 1967), indicate that subsequent to a short de-acclimatization period, Sherpa possess a lower V˙A and are, therefore, less alkalotic than lowlanders during the same ascent profile. The lower V˙A cannot be attributed to central chemoreceptor drive to breathe, as arterial pH was lower, which should lead to a greater V˙E, under the assumption of comparable changes in brain tissue pH at the level of the brainstem. Consistent with this point, Zhuang et al. (1993) found HVR in Tibetan subjects at 3658 m to be less than in acclimatized Han Chinese (native lowlanders) at the same altitude. One large study compared Tibetan with Andean high altitude residents directly. Beall et al. (1997) studied 320 Tibetans and 552 Andean subjects and found resting V˙E to be higher in Tibetans by a factor of about 1.5, and their HVR to be roughly double that of the Andean subjects. Comparison of these two populations is discussed further in Chapter 4.

One important question raised by the research on long-term residents at high altitude is the time course over which these changes in HVR develop. Lahiri et al. (1976) found evidence in Andean natives that HVR was normal in children and became blunted only as they grew into adulthood at high altitude and that the rate of blunting was more rapid the higher the place of residence. Weil et al. (1971) showed that in North American subjects in Leadville, Colorado, blunted HVR was a function of time at altitude, such that after 25 years, values resemble those of high altitude natives. The precise time necessary for such changes in humans has not been elucidated but Tatsumi et al. (1991) have shown that blunting is seen in cats after three to five weeks of exposure to a simulated altitude of 5500 m. They also found that neural HVR, measured by recording from the carotid sinus nerve, was also blunted and argued that both central and peripheral components of the respiratory control system contributed to the reduction in overall HVR.

HVR in lowlanders residing at high altitude

Early studies of lowlanders who had lived for a few years at high altitude suggested that HVR was almost abolished (Lahiri et al. 1969; Sorensen and Severinghaus 1968); however, later studies refined this concept. Whereas HVR is acutely increased in lowlanders after ascending to high altitude, it is approximately halved in long-term (nonnative) high altitude residents and almost completely abolished in lifelong highlanders, suggesting chronic attenuation of the carotid body (Weil et al. 1971). The subjects in the aforementioned study lived at high altitude in Colorado, USA (Rocky Mountains); therefore, “native” highlanders may have only populated this region for a couple of generations, indicating that chronic attenuation of HVR can occur independent of genetic adaptation (Weil et al. 1971), which would require a much longer duration of time to occur. The potential influences of genetic adaptation on ventilatory control at altitude are outlined elsewhere (Moore 2017) and detailed in Chapter 6.

HVR in highlanders residing at sea level

The HVR was unchanged in Andean high altitude natives who came down to live at low altitude for 10 months (Lahiri et al. 1969). Similarly, Vargas et al. (1998) found no difference in HVR between high and low altitude South American natives measured at low altitude. Gamboa et al. (2003) reported that the persistent blunting of HVR of high altitude Andean natives resident at sea level is substantially less to acute than to sustained hypoxia, when hypoxic ventilatory depression can develop. In contrast, both Tibetans and Han Chinese who resided at sea level for >4 years in the UK showed similar increases in HVR both before and following eight hours of exposure to normobaric isocapnic hypoxia (Petousi et al. 2013). It seems therefore that the extent of chemoreflex changes in highlanders residing at sea level depend on the nature and extent of prior adaptation and, in particular, whether the individual is of Andean or Tibetan heritage.

Acute Altitude Illness and HVR

Individuals who rapidly ascend to altitudes above 2440 m are at risk for one of three forms of acute altitude illness, including acute mountain sickness (AMS), high altitude cerebral edema (HACE), and high altitude pulmonary edema (HAPE), which are described in Chapters 20, 21, and 22, respectively. On the surface, it would seem that impaired HVR would predispose to these diseases as individuals with blunted HVR would have lower PaO2 at any given altitude, which would set in motion maladaptive responses and the associated adverse consequences. Strong support for such a link, however, has been lacking.

Acute mountain sickness

While some studies have suggested a possible link between HVR and AMS susceptibility (Hu et al. 1982; Richalet et al. 1988), a number of other field and chamber studies have failed to find such a relationship (Milledge et al. 1988, 1991; Richard et al. 2014; Savourey et al. 1995). Hohenhaus et al. (1995), for example, found that compared with healthy individuals, HVR was significantly lower in subjects who developed HAPE but not in subjects with AMS, while Bärtsch et al. found no relationship between HVR, measured at sea level with both isocapnic and poikilocapnic hypoxia, and subsequent AMS upon ascent to 4559 m (Bärtsch et al. 2002). In the latter study, however, they did document that failure to raise the HVR on the first day at altitude was associated with a higher incidence of AMS and more hypoxemia (Figure 9.6).

Figure 9.6

Figure 9.6Changes in isocapnic hypoxic ventilatory response (HVR) between baseline and day 1 at altitude (4559 m) versus Lake Louise acute mountain sickness (AMS) scores on day 2. (Source: Bärtsch et al. 2002, with permission.)

In most of these studies, HVR was measured with only a few minutes of hypoxia, and thus assessed the initial phase of the ventilatory response, whereas any correlation with AMS might be more expected only with the third phase of the response, the HVD. Burtscher et al. (2004) argued this point and studied 63 AMS-susceptible and 87 nonsusceptible subjects. They found that the SaO2 of the AMS-susceptible group averaged 4.9% lower than the nonsusceptible group after 20–30 minutes of poikilocapnic hypoxia. Another feature of many of these studies is that they generally measured the ventilatory response to hypoxia at rest. In a very large prospective cohort study, Richalet et al. (2012) demonstrated that blunted ventilatory responses to exercise in hypoxia were one of several factors associated with increased risk of developing severe AMS.

High altitude pulmonary edema

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Jul 25, 2021 | Posted by in RESPIRATORY | Comments Off on Control of breathing
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