Pathophysiology hipoxia

8/6/2019 Pathophysiology hipoxia

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Pathophysiology and Clinical Effects of Chronic Hypoxia

David J Pierson MD FAARC

Introduction

Mechanisms of Tissue Hypoxia

Physiologic Responses to Hypoxia

Respiratory System

Cardiovascular System

Central Nervous System

Adaptation to Altitude

Symptoms and Signs of Hypoxia

Chronic Mountain Sickness

Hypoxia during Sleep

Chronic Hypoxia in Chronic Obstructive Pulmonary Disease

Pathogenesis of Cor Puhnonale in Chronic Obstructive Pulmonary Disease

Clinical Manifestations of Hypoxia and Cor Pulmonale in Chronic

Obstructive Pulmonary Disease

Effects of Hypoxemia on Mortality in Chronic Obstructive Pulmonary

Disease

Summary

[Respir Care 2000;45(1):39-511Key words: hypoxia, hypoxemia, desaturation,respiratory system, clinical effects, altitude, chronic obstructive pulmonary

disease, car pulmonale, oxygen therapy, mortality.

Introduction

No aspects of respiratory care receive more attention in

both education and clinical practice than assessing whether

the body is getting enough oxygen and providing more

oxygen when it is not. Several years ago a R ESPIRATORY

CARE Journal conference focused on problems with oxy-

genation in the critically ill patient. For that conference I

reviewed the pathophysiology and clinical effects of an

acute deficiency ofoxygen2 To lay the physiologic ground-work for this conference on long-term oxygen therapy

(LTOT), this article addresses the pathophysiologic and

David J Pierson MD FAARC is affiliated with the Division of Pulmonaryand Critical Care Medicine, Department of Medicine, University of Wash-

ington, and the Respiratory Care Department, Harborview Medical Cen-ter, Seattle, Washington.

Correspondence: David J Pierson MD FAARC, Division of Pulmonaryand Critical Care Medicine, Box 359762, Harborview Medical Center,

325 Ninth Avenue, Seattle WA 98104. E-mail: [email protected].

RESPIRATORY CARE l JANUARY 2000 VOL 45 No 1 39

clinical effects of chronic oxygen deficiency in patients

with pulmonary disease. After clarifying the terminology

used to describe impaired oxygenation in the clinical set-

ting, it discusses the basic physiologic mechanisms of tis-

sue hypoxia, the effects of oxygen deficiency on the var-

ious organ systems of the body, and the clinical

manifestations of chronic hypoxia in different contexts.

Pertinent to the context of this conference, the last section

focuses in some detail on the effects of chronic hypoxia in

patients with chronic obstructive pulmonary disease

(COPD).

Although clinicians use the terms hypoxia and hypox-emia every day, the majority of textbooks of physiology,

respiratory care, and pulmonary medicine do not give ex-

plicit definitions for them. Dictionaries define them, but

they vary somewhat in how they do this (Table 1).3-5Although the wording is a bit different, all three of the

commonly used dictionaries in the table state that hypoxia

is a decrease in tissue oxygen supply below normal levels.

Stedman s Medical Dictionary5 also lists several subtypesof hypoxia, which include the following terms relevant to

this article:


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P AT HOPHYSI OL OGY A ND C LINICAL EFFECTS OF C H RONIC H Y P O X I A

Table 1. Definitions of Hypoxia-Related Terms from Three Dictionaries

Dorlands4 Sredman 9Hypoxia

Anoxia

Hypoxemia

A deficiency in the amount

of oxygen that reaches the

tissues of the body

An abnormally low amountof oxygen in the body

tissuesInadequate oxygenation of

the blood

Reduction of oxygen supply to tissue below

physiological levels despite adequateperfusion of tissue by blood

A total lack of oxygen; often used

interchangeably with hypoxia to mean a

reduced supply of oxygen to the tissuesDeficient oxygenation of the blood; hypoxia

Decrease below normal levels of oxygen in

inspired gases, arterial blood, or tissue, shortof anoxia

Absence or almost complete absence of oxygen

from inspired gases, arterial blood, or tissues;

to be differentiated from hypoxiaSubnormal oxygen of arterial blood, short of

anoxia

l Anemic hypoxia: hypoxia due to a decreased concen-

tration of functional hemoglobin or a reduced number of

red blood cells, as seen in anemia and hemorrhage;

l Hypoxic hypoxia: hypoxia resulting from a defectivemechanism of oxygenation in the lungs, as caused by a

low tension of oxygen, abnormal pulmonary function, air-

way obstruction, or a right-to-left shunt in the heart;

l Ischemic hypoxia: tissue hypoxia characterized by tis-

sue oligemia and caused by arteriolar obstruction or vaso-constriction;

l Oxygen affinity hypoxia: hypoxia due to reduced abil-

ity of hemoglobin to release oxygen;

l Stagnant hypoxia: tissue hypoxia characterized by in-

travascular stasis due to impairment of venous outflow or

decreased arterial inflow.

The definition of anoxia varies somewhat more than

that of hypoxia in the sources commonly available to cli-

nicians. The former term generally refers to a more severe

state of oxygen deficiency and generally carries an impli-

cation of irreversible damage, as in anoxic encephalopathy

following cardiac arrest. As shown in Table 1, the greatest

variation of all in the context of this article is encounteredin definitions for the term hypoxemia. In Dorlands Illus-

trated Medical Dictionary4hypoxemia is a synonym for

hypoxia. However, all three sources say that hypoxemia

refers to deficient oxygen in the blood. Stedrnan~,~ but notthe others, indicates that hypoxemia refers specifically to

arterial blood.

None of the dictionaries cited, nor any of the textbooks

I could find in preparing this article, define hypoxemia in

the setting of the abnormal oxygenation we encounter clin-

ically. That is, none of them say that it means less oxygen

than would be present in a normal persons blood under

the same circumstances. For clinical purposes I will there-

fore use hypoxemia to mean a decreased oxygen tension

(Paz) in the blood below the normal range. Thus, the termshould not be used when P, is in the normal range, evenif pulmonary gas exchange k markedly deranged or thereis one of the other subtypes of hypoxia defined above.

Using this definition, a patient with an arterial Po,(P&of 100 mm Hg is not hypoxemic. This would be true even

if to achieve that Pao 2 the patient had to breathe a high

40

fraction of inspired oxygen (F,& or if the hemoglobinconcentration (and thus the bloods total oxygen content)

were greatly reduced. Finally, in the absence of consis-

tency in the cited references, since a reduced Po2 may beas important clinically in mixed venous blood as it IS in the

arterial blood, whether the blood in question is venous or

arterial should be specified when referring to hypoxemia.

This article is ultimately about hypoxia at the tissue

level. Directly measuring tissue oxygenation is not feasi-ble in most clinical circumstances, however, and either

Pao, or arterial oxyhemoglobin saturation (S,,J is usuallymeasured. Nonetheless, it is important to remember that it

is the adequacy of tissue oxygen supply, not necessarily

the values of Pao, or Sao,, that determines whether thepatients life or organ function is threatened.

Mechanisms of Tissue Hypoxia

Figure l6 emphasizes the interconnectedness of the com-ponents of tissue oxygenation. Oxygen enters the body via

the lungs, is transported to the tissues via the blood, and is

consumed by the intracellular respiratory engine to pro-vide the energy for metabolism. A defect at any point in

the system-lungs, heart, blood, or tissues-can disrupt

normal oxygenation and cause tissue damage or death of

the organism.

In clinical practice a deficiency of oxygen in the arterial

blood is commonly defined in relation to the oxyhemo-

globin dissociation curve (Fig. 2).7 Because of the sigmoidshape of the relationship between Pao, and So?, concernabout arterial hypoxemia increases when PaoZ is m the areaof the elbow of the curve (at approximately 60-70 mm

Hg), below which Sao, decreases more rapidly with furtherdecrements in PaoZ. Clinical concern intensifies as Pao,falls below 50-60 mm Hg and S,, diminishes even morerapidly, and hypoxemic acute respiratory failure is gener-

ally considered to be present when Paoz is below 50 mmHg.7 However, although hypoxemia is probably the mostcommon cause of life-threatening tissue hypoxia, this def-

inition is too narrow.2Table 2 lists the physiologic mechanisms of tissue hyp-

oxia as encountered clinically. The table emphasizes the

R ESPIRATORY C AR E l JANUARY 2000 VOL 45 No 1


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P ATHOPHYSIOLOGY AND C LINICAL E FFECTS OF C HRONIC H YPOXIA

PA PI

-Alveolar - capillary interface

\

i

f

Circulation-,

Tissues-

!

Pulmonary vessels

c-Systemic vessels- C a p i l l a r y - tissue interface

Intracellular respiratory engine

Fig. 1. Pathway for oxygen from outside air to ultimate consumption within the mitochondria of cells.Tissue hypoxia may result from an abnormality anywhere in the system, and its prevention or cor-rection is the ultimate goal of supplemental oxygen therapy. Oxygen tensions in the diagram are

inspired (P,), alveolar (PA), arterial (Pa), and venous (Pv). ADP = adenosine diphosphate. ATP =adenosine triphosphate. (Adapted from Reference 6, with permission,)

16

t8 h-5

D i s s o l v e d .:*0 ./A 0

0 20 40 60 80 100 800Pa02 (mm Hg)Fig. 2. Relationship of arterial oxygen tension (P,,,, horizontal axis)to oxyhemoglobin saturation (S,,,, left vertical axis) and arterialoxygen content (C,,,, right vertical axis) in the clinically relevantP,,, range (O-l 00 mm Hg) as well as at a P,,, of 600 mm Hg. Theamount of oxygen dissolved in plasma is unimportant in mostclinical settings, virtually all of it being bound to hemoglobin. The

values for Cao2 assume a normal blood hemoglobin concentrationof 1.5 g/dL. (From Reference 7, with permission.)

potential role of mechanisms other than hypoxemia (that

is, a low Paoz). For example, life-threatening anemic hyp-oxia may be present in the face of a normal P,,. In Figure2 the right vertical axis shows the arterial oxygen content

(C,oz) corresponding to the Sao, associated with a givenPaoz in a person with a normal blood hemoglobin concen-tration of 15 g/dL. Clinicians may assume that a normalPao, means that tissue oxygenation is normal, but such isnot necessarily the case. This is because, except under

hyperbaric conditions, for clinical purposes CaO, is as highas it can get once the hemoglobin is fully saturated. With

hemoglobin concentrations less than normal, CaO, mustalso be proportionally reduced. Figure 3 shows what the

Cao, curve looks like when the hemoglobin concentrationvaries. Even in the absence of hypoxemia, with Sao,lOO%,Cao, can be only about two thirds of normal with a hemo-globin concentration of 10 g/dL, and much less than thatwith more severe anemia.

Systemic oxygen delivery is the product of Cao, andcardiac output. Even when CaO, is normal, tissue oxygen-ation may be inadequate if cardiac function is impaired.

The latter is commonly encountered both in the intensive

care unit (as with cardiac failure or the application of

excessive positive end-expiratory pressure*) and in the am-

bulatory care setting (as with chronic congestive heart fail-

ure). Reference to Figure 1 and Table 2 shows that im-

paired tissue oxygen utilization can also be a cause of

oxygenation failure, even when systemic oxygen delivery

is adequate. However, this mechanism is seldom encoun-

tered in the setting of chronic lung disease.

While it is important to remember the additional mech-

anisms for tissue hypoxia discussed above, arterial hypox-

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P A TH OP HY SI OL OG Y A ND CLINICAL E FFECTS OF C H R ONIC H Y P O X I A

Table 5. Physiologic Responses to Hypoxia Normalventilation

Hypoventilation

Obstructed airwayRespiratory Increased ventilation

Respiratory alkalosis

Cardiovascular Pulmonary vasoconstriction

Pulmonary hypertension

Decreased maximum oxygen consumption

Decreased myocardial contractility

Pa02 (mm Hg)

Fig. 5. General relationship between arterial oxygen tension (P,,,)and hypoxic ventilatory drive. As P,,, falls below about 65 mm Hgin most normal individuals, hypoxic drive progressively increases

its stimulus to breathe. The vertical axis depicts the intensity of the

hypoxic stimulus, whether the individual is capable of increasing

minute ventilation or prevented from doing so by airway obstruc-

tion or other disease process. (From Reference 12, with permis-

sion.)

ygen supply set in motion adaptive mechanisms designed

to maintain cellular activity at a minimum acceptable lev-

el; the failure of these mechanisms during hypoxia resultsin cellular dysfunction and can lead to irreversible cell

damage.rO Discussion of hypoxia at the tissue and intra-cellular levels, the focus of much ongoing research,ir isbeyond the scope of this review.

Table 5 summarizes the normal responses of the respi-

ratory and cardiovascular systems to hypoxia. In most in-

stances these responses are compensatory and serve to

prevent organ dysfunction or tissue damage that would

otherwise occur. Differences among normal individuals in

the presence and vigor of these responses probably ac-

count for much of the variation in clinical presentation

observed in patients with chronic hypoxia caused by pul-

monary disease.

Respiratory System

The main respiratory response to hypoxia is an increase

in hypoxic ventilatory drive, which in normal individuals

results in increased ventilation (Fig. 5).i2-I4 This responseis to Pao2, not to S,, or Cao,, and is mediated by theperipheral arterial chemoreceptors, located in the carotid

44

Pulmonary artery

Fig. 6. In comparison to the situation in a normally oxygenated

lung unit (left), hypoxic vasoconstriction (right) reduces blood flow

to poorly ventilated regions, thus improving ventilation-perfusion

matching. However, widespread hypoxic vasoconstriction in-

creases overall pulmonary vascular resistance and thus the pres-

sure required to maintain perfusion. (From Reference 18, with per-

mission.)

bodies.13 At sea level, ventilation is driven primarily byCO2 and by input from stretch receptors in the chest wall,so that only about 10% of the minute ventilation can be

accounted for by hypoxic ventilatory drive. Regardless of

whether ventilation or central drive is measured, the hy-poxic response is curvilinear, unlike the linear response tohypercapnia. The vigor of the response, and thus the po-

sition and slope of the curve in Figure 5, is affected by

PaCo,. Hypercapnia displaces the curve upward and to theright, whereas hypocapnia has the opposite effect.

Hypoxic ventilatory drive is diminished in a small pro-portion (less than 5%) of the normal population, and also

in many highly successful athletes and after prolonged

residence at high altitude. It declines with normal aging. Itis also blunted in congenital cyanotic heart disease, in

myxedema and severe hypothyroidism, in certain types of

autonomic nervous system dysfunction, and with the

chronic use of narcotics. Patients who have undergone

carotid body resection, a now-abandoned procedure once

performed as treatment for dyspnea in emphysema, also

have blunted hypoxic ventilatory drive.

The increased ventilation associated with hypoxia is per-

ceived as dyspnea by many individuals. Available evi-

dence suggests that dyspnea in this context may also result

in part from a direct stimulus ofbreathlessness,i5 althoughthis appears highly variable among individuals. As with

chronic hyperventilation in other settings, the normal re-sponse to prolonged hypoxia leads to compensatory met-

abolic acidosis produced by increased renal bicarbonate

loss.

Cardiovascular System

The most characteristic and important cardiovascular

response to hypoxia is pulmonary vasoconstriction, which

R ESPIRATORY C AR E l JANUARY 2000 VOL 45 No 1


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PATHOPHYSIOLOGY AND CLINICAL EFFECTS OF CHRONIC HYPOXIA

reduces the caliber of pulmonary vessels and raises vas-cular resistance in a region of low alveolar Po,.16-18 Hy-poxic pulmonary vasoconstriction (HPV), first described ahalf century ago by Euler and Liljestrand,lg serves to main-tain v/Q matching in a localized area of airway obstruc-tion or infiltration (Fig. 6),l* but has a deleterious overalleffect when alveolar hypoxia is widespread throughout the

lung, as in chronic mountain sickness or COPD. Occurringprimarily at the precapillary level and involving small mus-cular arteries and arterioles, and augmented by acidosis,HPV causes pulmonary hypertension and is a primary fac-tor in the pathogenesis of car pulmonale, as will be dis-cussed later. The pulmonary vascular response to hypoxiaoccurs in two phases.*O The first is the acute hypoxic va-soconstrictor response described above. When the hypoxiais prolonged for at least several weeks, a second phaseconsisting of vascular remodeling begins.

A variety of substances counteract HPV. In addition toinhalational anesthetics, these substances include prosta-cyclin and inhaled nitric oxide. Both of the latter agentshave been used, at least experimentally, to treat chronicpulmonary hypertension.21

Severe hypoxia has a direct deleterious effect on cardiacfunction.g922 Myocardial contractility and maximum out-put are diminished during conditions of reduced oxygensupply.23 While maximum oxygen consumption is reducedin chronic hypoxia, cardiac output remains normal at rest,owing primarily to an increased red blood cell mass.22Central Nervous System

Representing only 2-3% of an adults body mass, the

brain receives 20% of the cardiac output and accounts forabout one fourth of overall resting oxygen consumption.The brain is one of the most oxygen-sensitive organs ofthe body, and it is not surprising that neurologic dysfunc-tion is a prominent manifestation of hypoxia.*Q5 As dis-cussed by Wedzicha elsewhere in this issue,z6neuropsy-chiatric manifestations of chronic hypoxia can be a majorsource of morbidity in patients with COPD.

Cerebral vascular resistance is prominently affected byacute hypoxia, and increases when Paoz falls below 50-60mm Hg.*5 However, with continued hypoxia, adaptationoccurs, and overall cerebral blood flow in hypoxemic pa-tients with COPD is normal. The brain is very sensitive to

changes in perfusion, and effects of hypoxia on the brainare more likely to be due to decreased perfusion than tohypoxemia.25Adaptation to Altitude.

At high altitude FIo, remains the same, but Pro2 de-creases as barometric pressure falls. In comparison with its

value of about 150 mm Hg at sea level, PIo, is approxi-

RESPIRATORY CARE l JANUARY 2000 VOL 45 No 1

mately 130 mm Hg at Denvers altitude of 5,280 feet and80 mm Hg at 14,000 feet. 27 With acute ascent, as inspiredoxygen tension falls, the body responds with a variety ofphysiologic adaptations to maintain adequate tissue oxy-genation (Table 6). Stimulation of the peripheral arterialchemoreceptors results in increased ventilation, which oc-curs immediately.28 Hypoxic pulmonary vasoconstrictionalso occurs concomitantly with the decrease in PIoZ, in-creasing pulmonary vascular resistance and mean pulmo-nary arterial pressure. Acute hypoxia increases renal se-cretion of erythropoietin, which serves to augmentperipheral oxygen delivery by increasing red blood cell

mass, although this takes at least a week to become evi-dent. Increased blood hemoglobin concentration occurs inthe initial hours at altitude, however, due to hemoconcen-tration as a result of water diuresis.

Many otherwise healthy individuals experience acutemountain sickness within a day or two after ascent to

altitudes above 8,000 feet, particularly if they arrived by

air from sea leve1.*7~*9 Symptoms include headache, leth-argy, insomnia, anorexia, and in some cases nausea andvomiting. Believed to be due to mild cerebral edema, acute

mountain sickness typically resolves over several days even

if the individual remains at altitude. High altitude cerebraledema and high altitude pulmonary edema are more seri-

ous, sometimes fatal maladaptations of previously healthyindividuals who ascend rapidly above lO,OOO-12,000 feet,

which typically occur several days after arriva1.27*30*31Chronic mountain sickness, described below, occurs insome individuals after months or years of residence at high

altitude.

The maladaptations shown in Table 6 occur in individ-

uals for whom the chronic hypoxia of residence at highaltitude is something for which they are evolutionarilyunprepared. There is evidence that evolution may be atwork among peoples who have resided at altitude for thou-

sands of generations to make them better adapted and lesslikely to suffer altitude-related illness.32.33 Altitude illnessis much more common among residents of the ColoradoRockies, where people of European ancestry have lived for

less than 150 years, and also more common among thehigh altitude residents of the Andes, who have been therefor up to several thousand years, than on the Tibetan Pla-

teau, where the Tibetan peoples may have resided for a

much longer period.32333 Compared with the two formergroups, Tibetans have higher resting ventilation, stronger

hypoxic ventilatory responses, lower hemoglobin concen-trations, and increased cerebral blood flow with exercise.32Their resting pulmonary artery pressures are normal by sea

level standards, and they exhibit only minimal HPV both

at rest and during exercise. 34 In addition, Tibetans haveless intrauterine growth retardation than high altitude res-idents of the Rocky Mountains and the Andes.32

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PATHOPHYSIOLOGY AND CLINICAL E FFECTS OF C HRONIC H YPOXIA

Fig. 8. Two patients with severe chronic obstructive pulmonary

disease and comparable degrees of airflow obstruction, who illus-

trate two clinical extremes of the syndrome believed to be deter-

mined at least in part by how they respond to hypoxia. The blue

bloater on the left has longstanding severe chronic hypoxemiaand car pulmonale but little dyspnea, whereas the pink puffer onthe right maintains relatively normal oxygenation in the face of

severe dyspnea. (From Reference 60, with permission,)

Effects of Hypoxemia on Mortality in Chronic

Obstructive Pulmonary Disease

Evidence for the effects of chronic hypoxia on mortality

and morbidity in COPD is largely indirect. Early studies of

the natural history of severe COPD61-63 did not examinethe separate influences of hypoxia, the severity of airflow

obstruction, and other factors. However, by examining thefindings of several large-scale studies some useful conclu-

sions may be drawn about the impact of chronic hypoxia

as a factor separate from other prognosticators.

Among patients with COPD, the more severe the pul-

monary hypertension the worse the prognosis.aJjs Figure9 shows that 5-year survival among COPD patients withmean pulmonary artery pressures less than 25 mm Hg

when initially examined is not very different from that

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60vPAP(mmHg


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PATHOPHYSIOLOGY AND CLINICAL EFFECTS OF C H R O N I C H Y P O X I A

% Survival

t I I 10 5 10 15

Years of follow-up

Fig. 10. Relationship of severity of airflow obstruction, as mea-

sured by forced expiratory volume in the first second (FEV,), tosurvival in 200 patients with chronic obstructive pulmonary dis-ease followed prospectively for 15 years. Group A (n = 58) hadinitial FEV, values of < 750 mL; Group B (n = 90) 750-l ,250 mL;and Group C (n = 52) > 1,250 mL. (From Reference 60. withpermission.)

years of the study than patients assigned to continuous

oxygen use.O Using data from the NOTT study and alsothe results of the Intermittent Positive Pressure Breathing

Trial (IPPB),* Anthonisen et al were able to demonstratethe downward shift of the survival curve due to chronic

hypoxia for a given degree of airflow obstruction.68p69 Pa-tients included in the IPPB study had COPD but had to benormoxemic as a criterion for inclusion. Anthonisen et al

matched patients in the IPPB study, the nocturnal-only

oxygen arm of the NOTT, and the continuous oxygen armof the NOTI for degree of airflow obstruction as measuredby FEW,. They found that survival was the same for the IPPB

patients and the continuous-oxygen NOTT patients, and bet-ter than for the nocturnal-oxygen NOTI patients (Fig. 1 1).68Thus, COPD patients with the same severity of disease as

measured by FFV, had worse survival if they were hypox-emit and the hypoxemia was relieved only about half thetime, whereas chronic hypoxemia did not worsen survival if

oxygen was used most of the time.

The MRC and NOTT studies show that, with respect tosurvival, for COPD patients with stable chronic hypox-

emia, some oxygen every day is better than none, but moreoxygen is better yet. Survival in the MRC oxygen group

and in the NOTT nocturnal-only group was approximately

the same (and better than in the MRC no-oxygen group),

but survival in the NOTT continuous-oxygen group was

substantially better than in either of them. The NOTT

included measurements of actual oxygen use by the pa-

v NOTT~ ~ h r s20

0 1 2 3

Time (years)

Fig. 11. Effect of hypoxemia on survival in patients under 65 years

of age with chronic obstructive pulmonary disease and compara-

ble severity of airflow obstruction, as determined from results of

the Nocturnal Oxygen Therapy Trial (NOT-T) and the IntermittentPositive Pressure Breathing Trial (IPPB). Hypoxemic patientstreated with oxygen only at night (triangles, solid line) had worse

survival than either nonhypoxemic patients (triangles, dashed line)or hypoxemic patients treated with continuous oxygen (circles,

solid line). (Adapted from Reference 64, with permission.)

(24 h) (Hypothetical)

MRC Male (15 h]

OJ0 1 2

Time FYears) i 5 6Fig. 12. Dose-response relationship between daily hours of use

and survival in chronically hypoxemic patients with chronic ob-

structive pulmonary disease treated with long-term oxygen ther-

apy, as extrapolated from the Nocturnal Oxygen Therapy Trial(NOTI) and the British Medical Research Council Study (MRC).Patients in the NOTT continuous oxygen therapy group (actual useaveraging 18 h/d) had better survival than those in the MRC oxy-

gen group (15 h/d) and those in the NOlT nocturnal group (aver-age use 12 h/d), and all oxygen-treated patients fared better than

the MRC nonoxygen group. Although it has not been shown ex-

perimentally, it may reasonably be hypothesized that true 24 h/duse would increase survival even more.

tients, and showed that the continuous-oxygen patients

actually used their oxygen on average only about 18 h/d.

Based on the dose-response relationship inferred from com-

bining the results of the two studies, it may be hypothesized

that true 24 hour-per-day oxygen use would have improved

survival to an even greater extent (Fig. 12). There is no direct

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PATHOPHYSIOLOGY A N D C LINICAL E FFECTS OF C H RONIC H Y P O X I A

The Second Breath of Life. The first

breath of life, of course, is the babys

breath that allows the child to live in

the first place, and the second breath

of life is your spirogram during adult-

hood that tells how long youre proba-

bly going. to live.

ODonohue: Dave, in your defini-

tion of hypoxemia as decreased oxygen

in the blood, would you consider some-

one who is anemic to be hypoxemic

since they have decreased oxygen in the

blood, or is it strictly the Po2?Pierson: Dorhnds, from which Itook that (and I surveyed a number of

other dictionaries as well), gives us a

number of different kinds of hypoxia.

Theres anemic hypoxia, stagnant hyp-oxia, hypoxic hypoxia, histotoxic hyp-oxia, and one or two others, and they

would describe anemic hypoxia as that

due to insufficient delivery of oxygen

by virtue of not enough. ..

ODonohue: Hypoxemia is the term

to which I am referring, not hypoxia.

Pierson: Hypoxemia. Here Ive not

been able to find unanimous agree-

ment. For example, Stedmans Medi-cal Dictionary says hypoxemia is de-ficient oxygen in the arterial blood,

whereasDorlands doesnt specify the

condition of the blood. I have always

used the definition that hypoxemia

means that your Paz is abnormally low.So, if Im breathing 100% oxygen, and

I have acute respiratory distress syn-

drome (ARDS) and am on a ventila-

tor, and my Po, is 80, I am not hy-poxemic. Likewise, if my hemoglobinis only 5, I may have an oxygen con-

tent thats only a third of normal, but

Im not hypoxemic by that conven-tion. But I think that its difficult to

find a universally-agreed-upon identi-

fication. Does that agree with your

concept, Walter?

ODonohue: Yes, absolutely. I have

always personally used the term to

mean a decreased Po2. Patients withsevere anemia have decreased oxygen

52

content, but I have never referred to

them as being hypoxemic.

Pierson: It would be a shame if we

couldnt at least agree on the ABCs

for our discussion for these next two

and a half days.

ODonohue: But in both cases they

have decreased oxygen in the blood.

Stoller: David, I thought it was a

wonderful talk. At the risk of being a

splitter, I just want to comment on

your use of the hepatopulmonary syn-

drome as an example of right-to-left

shunt, and lumping it with arterio-venous malformation. Regarding your

self-acknowledged 20-year-old slide

about the 5 mechanisms of hypoxemia

(eg, V/Q mismatch and so on), someauthors have suggested that the hepa-topulmonary syndrome represents an

unusual admixture of diffusion impair-

ment and right-to-left shunt, such that

some authors have actually added a

sixth cause of hypoxemia called dif-

fusion-perfusion impairment. In the

hepatopulmonary syndrome, there is

dilatation of the capillaries causing the

unusual circumstances in which blood

is passing very quickly through dilated

capillaries. This creates an impedimentto diffusion of oxygen to the very cen-

ter of the stream, which partially cor-

rects with supplemental oxygen, al-

beit incompletely. 1*2 So, at the risk ofbeing a nitpicker about that issue, we

should mention diffusion-perfusion

impairment as another physiologic

cause of hypoxemia, to make the list

complete.

REFERENCES

1. Castro M, Krowka MJ. Hepatopulmonarysyndrome: a pulmonary vascular complica-tion of liver disease (review). Clin Chest Med

1996;17(1):35-48.2. Lange PA, Stoller JK. The hepatopulmonary

syndrome: effect of liver transplantation (re-

view). Clin Chest Med 1996;17(1):115-123.Pierson: Im glad you brought that

up, Jamie, because Im ready for you!

In ARDS, the studies back in the 1970s

by Dantzker and, subsequently, by

the group in Seattle,* using the mul-

tiple inert gas elimination technique,

showed that, in fact the shunt in

ARDS was predominantly very low

V/Q areas. And that has been demon-strated in a lot of other situations where

there isnt purely an anatomical con-nection such as in arteriovenous mal-

formation. The reason I left those

things off is that I think it helps the

clinicians understanding to have the

concept that hypoxemia in certain clin-

ical settings behaves as if it were shunt,

which in other clinical settings behaves

as if it were V/Q mismatching. Thephysiologist may be able to demon-

strate to us that theres a little bit more

to it than that;but I dont believe thatsof much help to the clinician at the bed-

side who is faced with relieving the hy-poxemia, who doesnt really care

whether ARDS is very low V/Q areasor shunt, because it gets better when

you use positive end-expiratory pres-

sure, and it wont get better unless you

do something physical like that. So, with

apologies for the specifics of accuracy,

that is the reason I left that out.

!_ Dantzker DR, Brook CJ,Dehart P, Lynch JP,Weg JG. Ventilation-perfusion distributions in

the adult respiratory distress syndrome. AmRev Respir Dis 1979;120(5):1039-1052.Ralph DD, Robertson HT. Weaver LJ,Hlastala MP, Carrico CJ, Hudson LD. Dis-

tribution of ventilation and perfusion during

positive end-expiratory pressure in the adult

respiratory distress syndrome. Am Rev Re-spir Dis 1985;131(1):54-60.

McCoy: Ive got a practical sort of

question for you, about the fact that

long-term oxygen therapy is mostly

delivered in the home setting. The peo-

ple who manage the reimbursement

for home oxygen therapy seem to notunderstand the question of the effects

of hypoxemia, and come back with a

So what? It seems that most of the

research shows that survival is the So

what? answer. To a payer, as bad as

it sounds, So what? with someone

not surviving costs less. One of the

things they need to understand is what

the cost and consequences are of some-

REFERENCES

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PATHOPHYSIOLOGY AND CLINICAL EFFECTS OF CHRONIC HYPOXIA

one who is not treated correctly for

their disease with regard to hospital-

ization, doctors visits, medication,

other modalities, and just exactly what

is involved in that process so that they

can better understand the So what?

Pierson: I think thats an excellent

observation, and in my discussion of

the clinical effects, if you will, of

chronic hypoxia, I should include the

effects on the person, the effects on

the family, and the effects on the health

care system, because, in fact, chronic

hypoxia extracts an enormous cost.

This gets back to something Tom was

saying about plopping those medical

records down on the desk of the state

health administrator. I think thats a

very well-made point.

Zielinski: David, you mentioned

that you had no time to develop in

detail as many items as you talked

about. May I add some data on adap-

tation of Tibetans, who are the only

population, I think, who adapted very

well to the conditions of living at high

altitude. It was found that Tibetans do

not react to hypoxia with pulmonary

vasoconstriction. Of course, it is very

difficult to perform pulmonary cathe-

terization in those people. Five youngTibetans-l ifelong residents of

Lhasa-agreed to have pulmonary ar-

tery catheterization with hemody-namic measurements taken at rest,

breathing hypoxic mixture, and on ex-

ercise. At rest, pulmonary arterial pres-

sure was perfectly normal (15 * 1mm Hg). Pulmonary vascular resis-

tance was also normal. Breathing hy-poxic mixture lowering their PaoZ 36 ?2 mm Hg only slightly increased pul-

monary vascular resistance. These data

suggest that Tibetans lost hypoxic pul-

monary vasoconstriction and remod-

eling common to lowlanders and res-

idents of the Andes in South America.

Also in China there is the High Alti-

tude Medical Research Institute. Pro-

fessor Tianyi Wu, director of the in-

s ti tu te , had an opportuni ty to

catheterize 3 or 4 healthy Tibetans.

They also had normal pulmonary ar-

terial pressure despite living at alti-

tude of some 4,000 meters (personal

communication). In a study compar-

ing working capacity at high altitude

of trained lowlanders and Sherpas, the

latter showed superior work capacity.This was attributable to (1) economy

of ventilation with preservation of nor-

mal blood pH, (2) a very high lungdiffusing capacity for oxygen, and (3)

a high cardiac output relative to work

intensity.* Lifelong Tibetan residents

of Lhasa (3,658 m) had higher hy-poxic ventilatory response and minute

ventilation than acclimatized Han Chi-

nese coming from lowlands.3REFERENCES

Groves BM, Droma T, Sutton JR, McCul-lough RG, McCullough RE, Zhuang J, et al.

Minimal hypoxic pulmonary hypertension in

normal Tibetans at 3,658 m. J Appl Physiol

1993;74(1):312-318.2. Pugh LGCE, Gill B, Labiri S, Milledge JS,

Ward PM, West JB. Muscular exercise at great

altitudes. J Appl Physiol 1964;19(3):431-440.3. Sun SF, Huang SY, Zhang JG, Droma TS,

Banden G, McCullough RE, et al. Decreasedventilation and hypoxic ventilatory responsive-

ness are not reversed by naloxone in Lhasaresidents with chronic mountain sickness. Am

Rev Respir Dis 1990;142(6 Pt 1):1294-1300.

Pierson: I go into considerably moredetail about these things in my paper.

A natural experiment has been done

since Tibet was absorbed into China

politically about 50 years ago, in that

there is now a large population of Han

Chinese living with the Tibetans in

Tibet. The Han have now been there

for up to 50 years, whereas the Tibet-

ans have been there perhaps as much

as a million years. Comparative stud-

ies of those two populations-4 showa number of striking differences. For

example, failure to carry pregnancies

to term is much more prevalent in the

Han Chinese (as are low birth weight,

pulmonary hypertension, and a num-

ber of the clinical maladies associated

with living at high altitude) than in

the Tibetans. This may be an example

of evolution at work even within a

single species.

REFERENCES

1. Moore LG. Niermeyer S, Zamudio S. Hu-man adaptation to high altitude: regional and

life-cycle perspectives. Yearbook Phys An-thropol 1998;41:25-64.

2. Moore LG. Curran-Everett L, DramaTS ,Groves BM, McCullough RE, McCullough

RG, et al. Are Tibetans better adapted? Int

J Sports Med 1992;13(Suppl l):S86-S88.3. Neirmeyer S, Yang P, Shanmina, Drolkar,

Zuang J, Moore LG. Arterial oxygen satura-

tion in Tibetan and Han infants born in Lhasa,

Tibet. NEnglJMed 1995;333(19):1248-1252.4. Halperin BD, Sun S, Zhuang J, Droma T,

Moore LG. ECG observations in Tibetan and

Han residents of Lhasa. J Electrocardiol

1998;31(3):237-243.Spratt:* A question on the treatmentof nocturnal hypoxemia. I believe right

now the American Thoracic Society

standards for chronic obstructive pul-

monary disease suggest treatment only

if you have signs and symptoms ofcarpulmonale. From Fletchers work2 andfrom what we know from obstructive

sleep apnea patients developing pulmo-

nary hypertension, a part of the pulmo-

nary hypertension is going to be nonre-

versible. Are we waiting too late to treat

those people if were waiting for signs

and symptoms ofcar pulmonale, and isthere a way we can predict those pa-

tients who are more likely to develop

those long-term problems so we can treatthem earlier?

REFERENCES

1. American Thoracic Society. Standard for the

diagnosis and care of patients with chronic

obstructive pulmonary disease. Am J Respir

Crit Care lMed1995;152(5 Pt 2):S77-S121.2. Fletcher EC, Luckett RA, MillerT, Costaran-

gos C, Kutka N, Fletcher JG. Pulmonary vas-

cular hemodynamics in chronic lung disease

patients with and without oxyhemoglobin de-saturation during sleep. Chest 1989;95(4):757-766.

Pierson: We thought that was such

an important question that we devoted

an entire presentation to it. Walters

going to give that presentation, and I

look forward to the answers to those

questions.

*Greg Spratt, Rotech Medical Corporation,

Kirksville, Missouri.

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