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Hypoxia

Hypoxia refers to the decreased availability of oxygen at the cellular level which impairs normal aerobic metabolism.  The aerobic metabolism depends on continuous supply of oxygen and lack of oxygen diverts the metabolism to inefficient anaerobic pathways in addition to producing harmful reactive oxygen species.

Ventilation

Ventilation refers to the movement of air in and out of the lungs and depends on the rhythmic inflation and deflation of the lungs.

Hypoxic Ventilatory Response

Human body has several coping mechanisms in acute hypoxia, one of which is reflexively increasing the ventilation in response to hypoxia. This is known as hypoxic ventilatory response (HVR). HVR is triphasic with three components, the occurrence of which depend on the duration of hypoxia; initial acute and rapid increase in ventilation in the first 30 minutes (acute hypoxic response), followed by ventilatory decline (hypoxic ventilatory decline) and if the hypoxia is sustained there is progressive increase in ventilation which may reach a plateau by 24 hours (Ventilatory response to sustained hypoxia).  If the hypoxia is chronic as it occurs in the high altitudes, then the several physiological changes happen to acclimatize with the new environment (Ventilatory acclimatization to chronic hypoxia). The HVR depends on the pattern, intensity and duration of hypoxia. 

The above mentioned response happens in isocapnic hypoxia, where the CO2 level is kept constant. But in real life clinical situations CO2 level is variable and hence the hypoxic ventilatory response (HVR) may be affected by pCO2 levels (1). Hypercapnia enhances the HVR and hypocapnia depresses the HVR.

In the fetus, paradoxically drop in maternal pO2 or umbilical cord occlusion results in decrease in respiratory movements. The mechanisms mediating this decrease in fetal breathing movements to hypoxia are complex and unclear. One of the postulated hypotheses is that fetal respiratory movements account for the significant percentage of oxygen consumption in the fetus and as one of the adaptations to decreased oxygen availability the overall metabolism drops including that of fetal breathing movement(2). Animal studies show that the carotid body mediated hypoxic ventilatory response matures during the immediate post natal life, while the central hypoxic response in fetus continues into the postnatal life (3). Some postulate that the hypoxic ventilatory decline present in adults is a remnant of the fetal response to hypoxia. The hypoxic chemosensitivity of the carodid bodies develop in the post natal period.

Causes of hypoxia

Broadly hypoxia can occur due to decreased availability of oxygen in the alveoli, defective diffusion across the alveolar capillary membranes, transport of oxygen in the blood into the tissues and impaired transport into the cells. At the level of the lungs hypoxia occurs by either one or combination of the following mechanisms; hypoventilation, shunt, V/Q mismatch and diffusion limitation. In addition if the transport of oxygen in the blood is compromised by severe anemia, carbon monoxide poisoning, methemoglobinemia or if there is impaired extraction of oxygen at the cellular level, it can lead to tissue hypoxia.

Central Chemoreceptor

The central chemoreceptor is located in the ventrolateral surface of the medulla. The central chemoreceptors are more sensitive hypercapnia rather than hypoxia, though it has contributory action in hypoxic ventilatory response.

Peripheral Chemoreceptor

The carotid bodies and the aortic bodies are the peripheral chemoreceptors. While carotid body has predominant response in the respiratory system, the aortic body affects the circulation. The aortic bodies play a major role when the carotid bodies are removed as in carotid endarterectomy.  The carotid bodies are located close to the bifurcation of the common carotid artery and contain chemosensitive glomus cells (4). They have the highest blood flow-to-metabolism ratio in the human body. The carotid bodies have afferents to the nucleus tractus solitarius(NTS). NTS is connected to the brain stem respiratory network and phrenic nerve nucleus and thereby control the movements of diaphragm, the major inspiratory muscle. The peripheral chemoreceptor monitors the arterial blood and responds to fall in pO2, a rise in pCO2 and H+ concentration. In contrast to this in situations of hyperoxia, there is a sudden and brief withdrawal of chemosensory discharges. In clinical context; the respiratory stimulant doxapram acts on the peripheral chemoreceptors to increase the minute ventilation. The carotid bodies may undergo hyperplasia or hypertrophy in response to chronic hypoxia

Mechanism

The exact mechanism is likely to be complex and there are several peripheral and central mechanisms that mediate hypoxic ventilatory response. Some of the pathways are as below

Hypoxia induces discharges from the carotid receptor which transmits inputs to nucleus  tractus solitarius (NTS), which in turn has afferents to phrenic motor nucleus. The phrenic nerve innervates the diaphragm, a major inspiratory muscle. The activity of diaphragm can increase ventilation movements (5). The central mediation is presumed to be done by glutamate neurotransmitter (6).

Hypoxia induces the hemoglobin to release molecules of nitric oxide metabolism (S-nitrosothiols) that directly act on the nucleus tractus solitaries to increase the ventilation(7).

Changes in the brain stem neurotransmitters glutamate, GABA and taurine during hypoxia correlates with the phrenic nerve activity. This may possibly contribute to HVR (8)

Acute Hypoxic Ventilatory Response

When a subject is exposed to isocapnic hypoxia, there is a rapid increase in ventilation within a short time. The increase in ventilation is primarily due to increase in the tidal volume and the mean inspiratory flow with little change in the respiratory rate (9).  The peripheral carotid chemoreceptor plays a major role in the acute response. The carotid body senses the drop in pO2 and in turn sends impulses to the NTS, which relays the impulse to phrenic nerve nucleus to increase the ventilation. The duration of the acute hypoxic response varies from 5 to 10 minutes and can have significant inter individual variations.  After the acute response reaches the peak it is followed by a phase of slowly decreasing ventilation despite the hypoxia known as the ‘hypoxic ventilatory decline’ (HVD).

Variations in the acute hypoxic response among different individuals can be due to varied reasons. In general the acute hypoxic response is less in people residing in high altitudes. Possibly exposure to chronic hypoxia in the high altitudes over a long period of time would have blunted their acute hypoxic response (10). The acute hypoxic response is obliterated in bilateral carotid body removal emphasizing the primary role of the carotid bodies in this response (11).

Some normal individuals may have decreased the acute hypoxic response and these individuals are prone to high altitude sickness (12)while those with high HVR are better climbers and have increased exercise tolerance at high altitude (13).

Hypoxic Ventilatory Decline (HVD)

Hypoxic ventilatory decline is a response that occurs after the acute hypoxic response reaches the peak. It occurs in moderate isocapnic hypoxia if it is sustained over 3 to 5 minutes. The decline in ventilation is slow and reaches a new level of steady state in 15 to 20 minutes.  It is a counteracting mechanism that results in decline in the minute ventilation.  Greater the initial acute hypoxic ventilatory response greater is the magnitude of the HVD (9). It is mediated by peripheral chemoreceptor in the awake state with neuronal inputs from the NTS and through unknown central mechanisms during anesthesia (14)and is absent in bilateral carotid body resection. The mediator of the HVD is presumed to be GABA which is an inhibitory neurotransmitter (15).

Ventilatory response to sustained hypoxia

If the hypoxia is sustained, the initial acute hypoxic response and the ventilatory decline are followed by gradual increase in minute ventilation. This increase in ventilation reaches a steady state after nearly 24 hours. Other mechanisms can counteract the increase in ventilation. Notably the increase in ventilation causes hypocapnia. Hypocapnia acts through central mechanisms to decrease the ventilation. One of the hypothesis is that drop in arterial pCO2 results in lowering of CSF pCO2. This drop in pCO2 in CSF affects the central chemoreceptor and hypoventilation results.

Recovery of the HVR after sustained hypoxia has been studied. HVR declines during sustained hypoxia and may require upto one hour of breathing in normoxic conditions to recover to its initial sensitivity and ventilatory response (16).

Sustained Hypoxia Vs Intermittent Hypoxia

Animal studies suggest that there are variations in physiological response to intermittent hypoxia when compared to that of sustained hypoxia (17)(18).

Ventilatory acclimatization to chronic hypoxia (VAH)

As we ascent up a mountain from the sea level, the barometric pressure of the inspired air decreases progressively though the fraction of the oxygen in the air remains the same. The p02 of the inspired gas is related to FiO2 and barometric pressure by the following formula; p02 of the inspired gas = FiO2 (Barometric pressure – water vapor pressure),Hence a drop in barometric pressure will result in decrease in the pO2 of the inspired oxygen. As the pO2 of the inspired air drops, the arterial pO2 also drops leading the peripheral chemoreceptor to increase the minute ventilation. The increased minute ventilation lowers the pCO2 (hypocapnia). The respiratory alkalosis is compensated by the renal excretion of bicarbonate.

Adaptation to Chronic Hypoxia in High Altitudes

In contrast to the acclimatization that happens in lowlanders moving to high altitudes, natural high altitude dwellers have certain fundamental physiological changes called as adaptation. For example; genetic changes in the Himalayan sherpas make them ventilate less than acclimatized low landers.

Other responses in hypoxia–

Hypoxic pulmonary vasoconstriction The pulmonary distribution of blood flow is improved by hypoxia as a result of hypoxic pulmonary vasoconstriction. The perfusion is more in the well ventilated regions of the lungs.

Polycythemia Long standing hypoxia results in increase in the hemoglobin content of blood.

Behavioral arousal can occur in acute hypoxia.

Increased vascularization of the cardiac myocardium

Clinical Diseases with HVR malfunction

1. SIDS – Sudden Infant Death Syndrome. Immature development of the chemosensitive sensory function of carotid body to hypoxia is one of the causes attributed to the development of SIDS (19)(20).
2. Obesity Hypoventilation Syndrome – The HVR is decreased in obesity hypoventilation syndrome and may be one of the causes of alveolar hypoventilation seen in such patients.
3. Acute Mountain Sickness – The acute mountain sickness is more common in people with diminished HVR compared to controls.

Clinical Measurement of Response to Hypoxia

The ventilatory response to hypoxia can be measured though rarely of any use in clinical practice except in situations like primary alveolar hypoventilation. Some of the methods of measuring HVR are as follows (21).

1)      Steady state method

2)      Rebreathing method

3)      Intermittent inhalation of high oxygen concentration.

Factors affecting hypoxic ventilatory response.

Inter-individual variations– Large inter individual variations in HVR has been noted and these may be related to variations in the peripheral chemoreceptor sensitivity (22). A very small percentage of the normal population lack the hypoxic ventilatory response. While they are asymptomatic at sea level, they can go it for dangerous hypoxia while ascending up a mountain at high altitudes in view of the absence of the increase in ventilation.

Genetic– There is a familial clustering of magnitude of the HVR suggesting a genetic role (23). Factors like transcriptional activator hypoxia-inducible factor 1 play a role in HVR (24)

Age– HVR is slightly affected in old age in humans (25). Neonates when exposed to sustained hypoxia, there is a rapid transient increase in ventilation followed by decrease in oxygen requirement by reduction in metabolism (hypoxic hypometabolism). In adults, the oxygen conserving reduction in metabolism doesn’t happen but the response is one of sustained increase in ventilation (hyperpnea). Thus in neonates the predominant adaptation to hypoxia is hypometabolism while it is hyperpnea in adults.  Neonatal environmental hypoxia or hyperoxia can influence the development and response of HVR

Removal of Carotid Bodies- The peripheral chemoreceptor – carotid bodies can be removed surgically for select patients with severe incapacitating chronic dyspnea due to severe asthma or COPD- though the procedure is controversial, in carotid body tumours, surgical procedure in the neck such as carotid endarteriectomy and tumour excision from the neck also results in the loss of carotid bodies.  The normal hypoxic ventilatory response is lost. But a partial restoration of HVR can occur due a complex mechanism. The pattern of response may vary between the unilateral resection and that of bilateral resection. In unilateral resection the HVR is present but the magnitude of response is decreased. In bilateral carotid body removal the hypoxic ventilatory decline was lost (26). 

CO2 levels- Hypercapnia enhances HVR and Hypocapnia depresses HVR

Race

Gender– No difference in HVR occurs between the males and females (27)(28)

Pregnancy– HVR increases with pregnancy. The increase in HVR correlated with infant birth weight in high altitude pregnancies (29)

Menstrual cycle– HVR can be affected by the menstrual cycle.

Inter day and intra day variabilityhas be known

Body temperature– Increase in body temperature increases the HVR (30)

Hormonal status

Anxiety

Adenosine– Endogenous adenosine plays a modulatory role in hypoxic ventilatory response (31).

Medications(32)

Congenital Cyanotic Heart diseasedepresses the HVR (33)

Sleep – HVR decreases during sleep esp. during the REM sleep (34)(35). This reduced response may be secondary to changes in the lung mechanics during sleep including increased upper airway resistance and supine position decreasing the lung  compliance

Starvation and decreased metabolic rate– HVR decreases during starvation and possibly contribute to hypoxemia and this emphasizes the need for adequate caloric supplementation in case of respiratory failure (36).

Exercise – enhances HVR

Anesthesia and Neuromuscular blockade– HVR is depressed (37)(38)(39)(40)

Activity – Mountaineers have high HVR while endurance athletes have HVR even lower than sedentary people (41)

Hypothyroidism and Myxedema– The HVR is depressed and improve with hormone replacement (42)

Reference

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