Altitude adaptation through hematocrit changes.

Adaptation takes place not only when going to high altitude, as generally accepted, but also when going down to sea level. Immediately upon ascent to high altitude, the carotid body senses the lowering of the arterial oxygen partial pressure due to a diminished barometric pressure. High altitude adaptation is defined as having three stages: 1) acute, first 72 hours, where acute mountain sickness (CMS or polyerythrocythemia) can occur; 2) subacute, from 72 hours until the slope of the hematocrit increase with time is zero; here high altitude subacute heart disease can occur; and 3) chronic, where the hematocrit level is constant and the healthy high altitude residents achieve their optimal hematocrit. In the chronic stage, patients with CMS increase their hematocrit values to levels above that of normal individuals at the same altitude. CMS is due to a spectrum of medical disorders focused on cardiopulmonary deficiencies, often overlooked at sea level. In this study we measured hematocrit changes in one high altitude resident traveling several times between La Paz (3510 m) and Copenhagen (35 m above sea level) for the past 3 years. We have also studied the fall in hematocrit values in 2 low-landers traveling once from La Paz to Copenhagen. High altitude adaptation is altitude and time dependent, following the simplified equation: Adaptation=Time/Altitude where High altitude adaptation factor=Time at altitude (days)/Altitude in kilometers (km). A complete and optimal hematocrit adaptation is only achieved at around 40 days for a subject going from sea level to 3510 m in La Paz. The time in days required to achieve full adaptation to any altitude, ascending from sea level, can be calculated by multiplying the adaptation factor of 11.4 times the altitude in km. Descending from high altitude in La Paz to sea level in Copenhagen, the hematocrit response is a linear fall over 18 to 23 days.

Hypoventilation in chronic mountain sickness: a mechanism to preserve energy.

Chronic Mountain Sickness (CMS) patients have repeatedly been found to hypoventilate. Low saturation in CMS is attributed to hypoventilation. Although this observation seems logical, a further understanding of the exact mechanism of hypoxia is mandatory. An exercise study using the Bruce Protocol in CMS (n = 13) compared to normals N (n = 17), measuring ventilation (VE), pulse (P), and saturation by pulse oximetry (SaO(2)) was performed. Ventilation at rest while standing, prior to exercise in a treadmill was indeed lower in CMS (8.37 l/min compared with 9.54 l/min in N). However, during exercise, stage one through four, ventilation and cardiac frequency both remained higher than in N. In spite of this, SaO(2) gradually decreased. Although CMS subjects increased ventilation and heart rate more than N, saturation was not sustained, suggesting respiratory insufficiency. The degree of veno-arterial shunting of blood is obviously higher in the CMS patients both at rest and during exercise as judged from the SaO(2) values. The higher shunt fraction is due probably to a larger degree of trapped air in the lungs with uneven ventilation of the CMS patients. One can infer that hypoventilation at rest is an energy saving mechanism of the pneumo-dynamic and hemo-dynamic pumps. Increased ventilation would achieve an unnecessary high SaO(2) at rest (low metabolism). This is particularly true during sleep.

Essentials in the diagnosis of acid-base disorders and their high altitude application.

This report describes the historical development in the clinical application of chemical variables for the interpretation of acid-base disturbances. The pH concept was already introduced in 1909. Following World War II, disagreements concerning the definition of acids and bases occurred, and since then two strategies have been competing. Danish scientists in 1923 defined an acid as a substance able to give off a proton at a given pH, and a base as a substance that could bind a proton, whereas the North American Singer-Hasting school in 1948 defined acids as strong non-buffer anions and bases as non-buffer cations. As a consequence of this last definition, electrolyte disturbances were mixed up with real acid-base disorders and the variable, strong ion difference (SID), was introduced as a measure of non-respiratory acid-base disturbances. However, the SID concept is only an empirical approximation. In contrast, the Astrup/Siggaard-Andersen school of scientists, using computer strategies and the Acid-base Chart, has made diagnosis of acid-base disorders possible at a glance on the Chart, when the data are considered in context with the clinical development. Siggaard-Andersen introduced Base Excess (BE) or Standard Base Excess (SBE) in the extracellular fluid volume (ECF), extended to include the red cell volume (eECF), as a measure of metabolic acid-base disturbances and recently replaced it by the term Concentration of Titratable Hydrogen Ion (ctH). These two concepts (SBE and ctH) represent the same concentration difference, but with opposite signs. Three charts modified from the Siggaard-Andersen Acid-Base Chart are presented for use at low, medium and high altitudes of 2500 m, 3500 m, and 4000 m, respectively. In this context, the authors suggest the use of Titratable Hydrogen Ion concentration Difference (THID) in the extended extracellular fluid volume, finding it efficient and better than any other determination of the metabolic component in acid-base disturbances. The essential variable is the hydrogen ion.

Non-invasive measurement of circulation time using pulse oximetry during breath holding in chronic hypoxia.

Pulse oximetry during breath-holding (BH) in normal residents at high altitude (3510 m) shows a typical graph pattern. Following a deep inspiration to total lung capacity (TLC) and subsequent breath-holding, a fall in oxyhemoglobin saturation (SaO(2) is observed after 16 s. The down-pointed peak in SaO(2) corresponds to the blood circulation time from the alveoli to the finger where the pulse oximeter probe is placed. This simple maneuver corroborates the measurement of circulation time by other methods. This phenomenon is even observed when the subject breathes 88% oxygen (PIO(2) = 403 mmHg for a barometric pressure of 495 mmHg). BH time is, as expected, prolonged under these circumstances. Thus the time delay of blood circulation from pulmonary alveoli to a finger is measured non-invasively. In the present study we used this method to compare the circulation time in 20 healthy male high altitude residents (Group N with a mean hematocrit of 50%) and 17 chronic mountain sickness patients (Group CMS with a mean hematocrit of 69%). In the two study groups, the mean circulation time amounted to 15.94 +/-2.57 s (SD) and to 15.66 +/-2.74 s, respectively. The minimal difference was not significant. We conclude that the CMS patients adapted their oxygen transport rate to the rise in hematocrit and blood viscosity.

Clinical application of the pO(2)-pCO(2) diagram.

Based on the classic, linear blood gas diagram a logarithmic blood gas map was constructed. The scales were extended by the use of logarithmic axes in order to allow for high patient values. Patients with lung disorders often have high arterial carbon dioxide tensions, and patients on supplementary oxygen typically respond with high oxygen tensions off the scale of the classic diagram. Two case histories illustrate the clinical application of the logarithmic blood gas map. Variables from the two patients were measured by the use of blood gas analysis equipment. Measured and calculated values are tabulated. The calculations were performed using the oxygen status algorithm. When interpreting the graph for a given patient it is recommended first to observe the location of the marker for the partial pressure of oxygen in inspired, humidified air (I) to see whether the patient is breathing atmospheric air or air with supplementary oxygen. Then observe the location of the arterial point (a) to see whether hypoxemia or hypercapnia appears to be the primary disturbance. Finally observe the alveolo-arterial oxygen tension difference to estimate the degree of veno-arterial shunting. If the mixed venous point (v) is available, then observe the value of the mixed venous oxygen tension. This is the most important indicator of global tissue hypoxia.

Endogenous benzodiazepine system and regulation of respiration in the cat.

Benzodiazepines, a class of drugs widely used as anxiolytics, can induce a depression of respiration. This study was designed to determine if endogenous benzodiazepine ligands could act in a similar fashion and exert a tonic inhibitory influence on respiration. Administration of a benzodiazepine antagonist should then facilitate respiration. This might be especially visible in hypoxia, the condition characterized by both central respiratory depression and potentially enhanced benzodiazepine expression. We addressed this issue by comparing the effects on the phrenic neurogram of the specific benzodiazepine antagonist flumazenil (200 micrograms i.v. boluses) in the contrasting conditions of hypoxia and hyperoxia in anesthetized, both spontaneously breathing and paralyzed ventilated cats. Contrary to our hypothesis, flumazenil showed a modest but definite inhibitory effect on respiration. Flumazenil also lengthened the duration of the Hering-Breuer inspiratory inhibition. The respiratory depression was neither related to chemical drive nor to the GABA receptor complex, for it was sustained after antagonism of GABA with picrotoxin and bicuculline. We conclude that the endogenous benzodiazepine system is unlikely to play an inhibitory role in the regulation of respiration. The physiologic role of this system remains to be established.

Cardiorespiratory reactions to static, isometric exercise in man.

Cardiac output (Q), stroke volume (SV), heart rate (HR), and respiratory variables were measured in ten healthy men performing static, isometric muscular contraction (handgrip) during air breathing. We found an instantaneous rise in ventilation (VI) and in HR, accompanied by a minimal rise in cardiac output. The rise in VI was due to a rise in tidal volume (VT) and a reduction in expiratory duration (TE). These effects of isometric exercise are explainable as due to a muscle reflex instantly inhibiting the cardiac, vagal motoneurons and, at the same time, stimulating neurons in the respiratory area of the medulla. These medullary neurons seem capable of independent operation. The rise in mean arterial pressure (MAP) during isometric exercise is 27% just as the rise in total peripheral vascular resistance (TPVR). The MAP rise is too high to be caused by vascular occlusion due to the high tension of contracted muscles in only one upper extremity. Thus, redistribution of Q in the system of many parallel vascular resistances is a likely possibility--with possible cutaneous vasodilation and dominating vasoconstriction of other vascular regions.

Ventilatory and cardiovascular responses to hypoxic and hyperoxic static handgrip exercise in man.

The purpose of this study was to evaluate the ventilatory and cardiovascular responses to static handgrip exercise at different levels of arterial chemoreceptor activation. The study was done on 10 healthy subjects. They performed handgrip of 50% of maximal voluntary contraction on a background of either hypoxia (PE'O2 approximately 47 mm Hg) or hyperoxia (PE'O2 approximately 216 mm Hg), i.e., enhanced or suppressed chemoreceptor activity. The subjects were able to sustain the handgrip for 50-60 sec, during which time no steady-state responses were attainable. Minute ventilation (VI), cardiac output (Q), heart rate (HR), and a number of other variables were recorded. Handgrip exercise resulted in a rapid initial VI rise followed by a subsequent slow increase. Hyperoxia diminished the VI response over the exercise range. The ventilatory response was associated with an HR acceleration, increased arterial pressure and peripheral vascular resistance. No appreciable changes in Q were noted, nor was there any particular relationship between ventilatory and circulatory changes. These results provide no support for the Q mediated ventilatory stimulus during static handgrip exercise in man. It is concluded that the ventilatory and cardiovascular responses are of independent nature.

Cardiac responses to hypoxia and hypercapnia in spinal man.

The purpose of this study was to evaluate the effect of interruption of the descending supraspinal sympathetic outflow on heart rate control during exposures to chemical stimuli. We investigated the heart rate responses to progressive isocapnic hypoxia and hyperoxic hypercapnia using the rebreathing technique and quantified the relationship between heart rate (HR), oxygen saturation (SaO2), alveolar PCO2 (PACO2), and minute ventilation (VE) in 16 chronic tetraplegic subjects with low cervical spinal cord transection. The HR responses were determined from the linear slopes of HR on SaO2 and HR on PACO2. We found that mean resting heart rate was within normal range; 66 +/- 3 (SEM) beats min-1. HR increased as oxygenation fell or CO2 tension rose. The mean tetraplegic delta HR/delta SaO2 was 0.83 +/- 0.14 beats min-1 per 1% fall in SaO2 and that of delta HR/delta PACO2 was 0.30 +/- 0.13 beats min-1 per mmHG rise in PACO2. The HR and VE responses to either hypoxia or hypercapnia were related in the tetraplegic subjects. We conclude that the stimulatory HR responses to chemical stimuli are not suppressed by cervical spinal cord transection. Thus, the descending sympathetic activity does not underlie the HR acceleration by chemical stimuli.

Cardiac output and heart rate in man during simulated swimming while breath-holding.

We measured stroke volume (SV), heart rate (HR), cardiac output (Q), arterial pressure and intrapulmonic (mouth) pressure in four healthy, male subjects during simulated swimming (i.e., performing crawl movements with the legs continuously at a constant rhythm) with and without apnea (water temperature: 31 degrees C). We wanted to see whether the exercise tachycardia response persisted, or whether the HR decreased during apnea, just as in the "diving response" of diving animals. The SV and the Q fell to half its value in the control phase (i.e., swimming with normal breathing), when the 15-s apnea was performed at a high mouth-pressure; at low mouth-pressure, SV and Q hardly changed. These results are replicates of our previous findings in man during rest in air. Due to the light work, HR increased slightly from rest, but the exercise HR did not change much during apnea with or without high mouth-pressure. The results show that man tends to preserve his exercise HR response, and does not react as an oxygen-conserving animal, whether he is in air or in water under these conditions. However, man, as well as diving animals, may well have a "diving response" as an emergency reaction, which may not be restricted to only the water environment.

A constant flux of carbon dioxide injected into the airways mimics metabolic carbon dioxide in exercise.

This paper reports the expired minute-ventilation (VE) responses of 5 subjects to three step levels in a) work rate on a bicycle ergometer (30, 50, and 70 W), b) inhaled constant fraction (CF) of CO2 (3, 5, and 7%), and c) inhaled constant flux (CFlux) of CO2 (0.3, 0.4, and 0.5 l/min (STPD) injected in the inspired air-stream). Both exercise (isocapnic with regulated PETCO2) and CFlux provoke larger and similar steady-state responses in VE, than CF. Both the CF and CFlux responses are hypercapnic, but the CFlux responses show evidence of "hypercapnic regulation." VE and total CO2 input into the alveoli (i.e., VCO2 plus inhaled CO2) are excellently correlated in both the CF and the CFlux cases. However, the CFlux delivery provokes a far greater VE for a given total input of CO2 than CF, and the CFlux response resembles the VE/VCO2 plot of exercise. We conclude that CFlux inhalation of CO2 simulates the metabolic CO2 production rate of exercise, and thus the humoral aspects of exercise hyperpnea in the steady state.

Modeling of alveolar carbon dioxide oscillations with or without exercise.

In five persons the transient ventilatory response was measured to three step levels of exercise, inhaled constant fraction of CO2, and inhaled constant flux of CO2. With constant CO2 fraction inhalation (3, 5, and 7%), the transient response of the minute-ventilation (VE) is associated with on- and off-time delays (Td). Our Td periods include equipment delay, and our bolus inhalations by constant flux provoke on- and off-Td's of 6-8 s, which approximate to the transport delay of blood passing from the alveoli to the peripheral chemosensitive areas. With exercise (30, 50, and 70 W) we found a fast rise in VE (i.e., mainly in respiratory frequency) within the first breath, but no detectable on- and off-Td. The ventilatory responses to exercise are equal to those of constant CO2 flux inhalation. We modeled PACO2 oscillations, which occur through a respiratory cycle, and show that the oscillations provoked by constant CO2 flux have modified timing, amplitude, and slope compared with those of constant CO2 fraction. The increase in ventilation is the same when the CO2 is achieved by constant flux inhalation at rest or by exercise.

Facial cold receptors and the survival reflex "diving bradycardia" in man.

We measured heart rate (HR), stroke volume (SV), systemic arterial blood pressure (BP), and mean arterial pressure (MAP) in 7 healthy volunteers in response to face immersion in water with concomitant breath-holding at different lung volumes. The subjects were at rest in the prone position. During breath-holding at total lung capacity (TLC), baseline HR (70 to 75 beats/min) fell by 10% within fractions of a second, both in the control preimmersion state when the head was surrounded by room air, and when it was immersed in water of 33 degrees C. This response was associated with rises in MAP and in SV. Immersion of the face in 10 degrees C water while breath-holding, was associated with a strong, negative chronotropic effect (22% fall in HR), which developed within 10 s. Breath-holding at functional residual capacity (FRC) reduced HR substantially only in 10 degrees C water, and in contrast to that at TLC, the response was slowly developing with a latency of 10-15 s. All these reductions in HR were significant and accompanied by increases in BP and MAP. The strong, negative chronotropic effect of cold water was typically linked to a rise in SV. The study identified two temporal components of HR reduction to face immersion: a fast parasympathetic response dependent on the input from the high pressure baroreceptors, and a late response mediated, in all likelihood, by sympathetic efferent activity. Facial receptors sensitive to cold seem to be vital in the largest responses observed. The fast response to breath-holding with the face in water of neutral temperature was equal to that in air. Thus "diving bradycardia" is in fact a basic survival response independent of water.

Are central respiratory chemoreceptors confined to ventrolateral medulla?

There is ample evidence that the ventrolateral medulla (VLM) is involved in regulation of respiration. The VLM is considered to be the site of location of the central respiratory chemoreceptors. Neither neuroanatomical nor neurophysiological coordinates of the chemoreceptor have ever been indisputably identified or verified, despite decades of research. This commentary addresses new hypotheses concerning the process of central chemoreception and recent findings calling into question the exclusivity of VLM for the chemoreceptor location and function. These findings rekindle the possibility of medullary respiratory neurons being chemosensors. Crucial issues concerning the central chemoreception remain unsettled and are open to further research.

Heart rate response to breath-holding during supramaximal exercise.

The cardiovascular responses to breath-holding (BH) during short-lasting supramaximal exercise (415 W) on a cycle ergometer were investigated in 15 healthy male subjects. The arterial oxygen saturation, heart rate (HR), endtidal PO2 and PCO2 were continuously monitored. Firstly, 15 subjects performed exercise during BH, preceded by air breathing (air-BH test), and secondly, exercise without BH. Then 9 of the subjects performed the same procedure as in the air-BH test, except that all subjects breathed 100% O2 for 1 min before apnoea (O2-BH test). In 2 of these subjects, the systemic arterial blood pressure was continuously measured via a catheter in the radial artery and plasma catecholamine concentration [CA] was also measured both during the air-BH and the O2-BH tests. In the later period of the air-BH test, the high HR level became progressively depressed. This response, however, was absent in the O2-BH test. There was a late increase in the arterial blood pressure in both tests, and both tests produced hypercapnia. Only the air-BH test resulted in hypoxia, substantial hypertension and HR-depression. The increase in plasma CA was similar in both tests. The marked HR-depression demonstrated here is ascribed mainly to activation of the peripheral arterial chemoreceptors by asphyxia, and partially to baroreceptor activity due to elevated blood pressure.

Opioid involvement in the perception of pain due to endurance exercise in trained man.

The purpose of this study was to evaluate the role of endogenous opiates in modulating physical performance during dynamic exercise in conscious man. The plasma concentration of beta-endorphin (BEP) and of adrenocorticotropic hormone (ACTH) along with muscle pain (McGuill Pain Questionnaire) were assessed in 17 trained, male runners before and after running the longest possible distance within 12 min (i.e., the Cooper test). Each runner participated twice in the test (double-blind cross-over design), with a 1-week interval--with or without an injection of the opiate antagonist naloxone (0.8 mg i.v.). The average (SEM) distance reached was 3,198 (45) m in the naloxone test and 3,240 (38) m in the placebo test. The BEP increased significantly during the tests by a factor of 4.1 on naloxone and by 2.8 on placebo (from the normal resting averages of 1.7 and 2.1 pmol/l, respectively). The ACTH also increased significantly by a factor of 2.0 on naloxone and 2.5 on placebo (from the normal resting averages of 19.3 and 16.8 pmol/l, respectively). There were no significant differences between the naloxone and the placebo test with respect to the increments of BEP or ACTH by exercise. However, the perception of muscle pain was enhanced with naloxone. The increased perception of pain did not decrease the athletes ability to perform in terms of the distance run. We conclude that endogenous opiates are involved in the perception of pain associated with exhaustive exercise and may subserve psychological rather than physiological functions during exercise.

Circulatory and respiratory responses to lower body negative pressure in man.

Circulatory and ventilatory responses to lower body negative pressure (LBNP) were simultaneously investigated in 8 healthy men before, during, and after the application of -20, -40, and -60 mmHg pressure. Minute ventilation (VE) decreased during LBNP due to a fall in respiratory frequency with sustained tidal volume. The cardiac output (Q) was reduced in proportion to the applied LBNP exposure, while VE decreased to almost the same level at all LBNP applications. In spite of decreased VE, end-tidal PO2 and PCO2 were increased and decreased, respectively, indicating a relative alveolar hyperventilation. The ventilation equivalent for O2 (VE/VO2) increased, while the cardiac output equivalent for O2 (Q/VO2) decreased. The relation between VE/VO2 and Q/VO2 showed a significant negative correlation (r = -0.93, p less than 0.01). The veno-arterial CO2 concentration difference (CvCO2--CaCO2) increased with LBNP, due to a fall in CaCO2 with constant CvCO2. The constant CvCO2 indicated a constant tissue acid-base balance. These observations suggest the existence of a ventilatory mechanism improving the efficiency of respiration in order to compensate for the sustained LBNP depression of Q at a given gas exchange.

Estimation of peripheral chemoreceptor contribution to exercise hyperpnea in man.

Nine normal male subjects were studied at three levels of exercise (0, 40, and 80 W). Single vital capacity breath test was applied at rest and during exercise (phases 2 and 3). Minimum minute ventilation found within 4 breaths following the test was compared to the control value. Significant depression in minute ventilation was invariably observed. The minute ventilation was depressed more and more with increasing intensity of exercise. A significant difference was found between exercise and rest. However, the relative contribution of chemoreceptor activity remained the same 10-20% at all exercise levels. The magnitude of ventilatory depression (delta V resp) in phase 2 was larger than that in phase 3, when work rate increased to 80 W, both relative and absolute. A significant part of the exercise hyperpnea is due to peripheral chemoreceptor activity. The peripheral chemoreceptor activity is greater in phase 2 than in phase 3 at work rates of light to moderate intensity.

Brady- and tachycardia in light of the Valsalva and the Mueller maneuver (apnea).

With a computerized impedance cardiograph we measured stroke volume (sv), cardiac output and heart rate (HR) in four men, during apnea with positive or negative intrapulmonic pressure (i.e., Valsalva and Mueller maneuver) in air. During Valsalva maneuvers the sv was reduced, and the compensatory rise in HR failed to keep the cardiac output at the control level before apnea. During both types of apnea, the diastolic pressure was increased as was the total peripheral resistance (TPR). The vasoconstriction and tachycardia during Valsalva maneuvers can be explained as a sino-aortic baroreceptor phenomenon in man. The smaller changes occurring during Mueller maneuvers result in no change in the transmural arterial pressure in the thorax, compared to the control level. Thus, without a stimulus there is no change in heart rate. The alveolar oxygen uptake and carbon dioxide elimination during apnea at total lung capacity was much larger than in the control phase before both types of apnea. The arteriolar vasoconstriction with increased TPR during the Valsalva apnea, was accompanied by a reduction in the stroke work of the left ventricle to approximately 50% of the work in the control phase.

Ductus arteriosus in pilot whales.

The ductus arteriosus (DA), connecting the aorta with the pulmonary artery in the fetus, which normally closes up just after birth in terrestrial mammals, has been claimed not to close, but to remain open in normal, adult cetaceans, just as in the adult lungfish. We have examined the hearts from two Pilot Whales. In those we found no persisting DA, but an almost totally obliterated lumen. Blood flow through the ductus of these two whales could be excluded. Instead of an anatomical shunt mammals may use a functional pulmonary shunt. To the extent diving mammals can empty their alveoli for air at depth through reinforced bronchioli, and their very compliant thorax, they block alveolar gas exchange, and thus avoid decompression sickness, nitrogen narcosis and pulmonary squeeze.