pathophysiology and clinical effects of chronic...

Pathophysiology and Clinical Effects of Chronic Hypoxia

David J Pierson MD FAARC

IntroductionMechanisms of Tissue HypoxiaPhysiologic Responses to Hypoxia

Respiratory SystemCardiovascular SystemCentral Nervous SystemAdaptation to Altitude

Symptoms and Signs of HypoxiaChronic Mountain SicknessHypoxia during SleepChronic Hypoxia in Chronic Obstructive Pulmonary Disease

Pathogenesis of Cor Puhnonale in Chronic Obstructive Pulmonary DiseaseClinical Manifestations of Hypoxia and Cor Pulmonale in Chronic

Obstructive Pulmonary DiseaseEffects of Hypoxemia on Mortality in Chronic Obstructive Pulmonary

DiseaseSummary

.

[Respir Care 2000;45(1):39-511 Key words: hypoxia, hypoxemia, desaturation,respiratory system, clinical effects, altitude, chronic obstructive pulmonarydisease, car pulmonale, oxygen therapy, mortality.

Introduction

No aspects of respiratory care receive more attention inboth education and clinical practice than assessing whetherthe body is getting enough oxygen and providing moreoxygen when it is not. Several years ago a RESPIRATORYCARE Journal conference focused on problems with oxy-genation in the critically ill patient. For that conference Ireviewed the pathophysiology and clinical effects of anacute deficiency of oxygen2 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 patientswith pulmonary disease. After clarifying the terminologyused 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 clinicalmanifestations of chronic hypoxia in different contexts.Pertinent to the context of this conference, the last sectionfocuses in some detail on the effects of chronic hypoxia inpatients 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, butthey vary somewhat in how they do this (Table 1).3-5Although the wording is a bit different, all three of thecommonly used dictionaries in the table state that hypoxiais a decrease in tissue oxygen supply below normal levels.Stedman s Medical Dictionary5 also lists several subtypesof hypoxia, which include the following terms relevant tothis article:

P A T H O P H Y S I O L O G Y 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 9

Hypoxia

Anoxia

Hypoxemia

A deficiency in the amountof oxygen that reaches thetissues of the body

An abnormally low amountof oxygen in the bodytissues

Inadequate oxygenation ofthe blood

Reduction of oxygen supply to tissue belowphysiological levels despite adequateperfusion of tissue by blood

A total lack of oxygen; often usedinterchangeably with hypoxia to mean areduced supply of oxygen to the tissues

Deficient oxygenation of the blood; hypoxia

Decrease below normal levels of oxygen ininspired gases, arterial blood, or tissue, shortof anoxia

Absence or almost complete absence of oxygenfrom inspired gases, arterial blood, or tissues;to be differentiated from hypoxia

Subnormal oxygen of arterial blood, short ofanoxia

l Anemic hypoxia: hypoxia due to a decreased concen-tration of functional hemoglobin or a reduced number ofred blood cells, as seen in anemia and hemorrhage;

l Hypoxic hypoxia: hypoxia resulting from a defectivemechanism of oxygenation in the lungs, as caused by alow 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 ordecreased arterial inflow.

The definition of anoxia varies somewhat more thanthat of hypoxia in the sources commonly available to cli-nicians. The former term generally refers to a more severestate of oxygen deficiency and generally carries an impli-cation of irreversible damage, as in anoxic encephalopathyfollowing cardiac arrest. As shown in Table 1, the greatestvariation of all in the context of this article is encounteredin definitions for the term hypoxemia. In Dorlands Illus-trated Medical Dictionary4 hypoxemia is a synonym forhypoxia. However, all three sources say that hypoxemiarefers to deficient oxygen in the blood. Stedrnan~,~ but notthe others, indicates that hypoxemia refers specifically toarterial blood.

None of the dictionaries cited, nor any of the textbooksI could find in preparing this article, define hypoxemia inthe setting of the abnormal oxygenation we encounter clin-ically. That is, none of them say that it means less oxygenthan would be present in a normal persons blood underthe 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 evenif 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 thearterial blood, whether the blood in question is venous orarterial should be specified when referring to hypoxemia.

This article is ultimately about hypoxia at the tissuelevel. Directly measuring tissue oxygenation is not feasi-ble in most clinical circumstances, however, and eitherPao, or arterial oxyhemoglobin saturation (S,,J is usuallymeasured. Nonetheless, it is important to remember that itis the adequacy of tissue oxygen supply, not necessarilythe 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 viathe lungs, is transported to the tissues via the blood, and isconsumed by the intracellular respiratory engine to pro-vide the energy for metabolism. A defect at any point inthe system-lungs, heart, blood, or tissues-can disruptnormal oxygenation and cause tissue damage or death ofthe organism.

In clinical practice a deficiency of oxygen in the arterialblood 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 mmHg), 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.2

Table 2 lists the physiologic mechanisms of tissue hyp-oxia as encountered clinically. The table emphasizes the

R ESPIRATORY C ARE l JANUARY 2000 VOL 45 No 1

PATHOPHYSIOLOGY AND CLINICAL EFFECTS OF CHRONIC HYPOXIA

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

16

t

8h-5

D i s s o l v e d .:*0 ./A0

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

potential role of mechanisms other than hypoxemia (thatis, 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 underhyperbaric conditions, for clinical purposes CaO, is as highas it can get once the hemoglobin is fully saturated. Withhemoglobin concentrations less than normal, CaO, mustalso be proportionally reduced. Figure 3 shows what theCao, 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 intensivecare unit (as with cardiac failure or the application ofexcessive 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 ofoxygenation failure, even when systemic oxygen deliveryis 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-



Table 2. Mechanisms of Tissue Hypoxia

Category

Inadequate oxygenation of arterial bloodHypoxemiaInadequate arterial oxygen content

Inadequate systemic oxygen delivery

Inadequate peripheral oxygen utilization

Pq = oxygen tension. S.q = arterial oxyhemoglobin saturation. C.q = arterial oxygen content.

Determinants

Decreased arterial P,,Decreased S,, and/or hemoglobin concentration

Decreased C,,, and/or cardiac output

Impaired intracellular use and/or peripheral left-to-right shunting

emia is the most common cause encountered in the long-term setting. Table 3 lists the four physiologic mechanismsof chronic arterial hypoxemia and provides clinical exam-ples of each mechanism. Diffusion impairment is a fifthpossible mechanism, although it occurs mainly during ex-ercise at very high altitude and is not a significant con-tributor to hypoxemia as seen in patients with COPD. Areduction in the inspired Po? (P,oz), as encountered at highaltitude produces hypoxemia despite the normal functionof all the components of respiration. In primary lung dis-ease, hypoxemia is the result of one or more of the threeremaining processes in the table-alveolar hypoventila-tion, ventilation-perfusion ratio (v/Q) mismatching, andright-to-left shunting.

The most common mechanism for hypoxemia in pa-tients with chronic pulmonary disease is mismatching ofventilation and perfusion, or, more accurately, an increasein low-?@ regions in the lung. Patients with COPD alsooften have a component of alveolar hypoventilation result-ing from reduced carbon dioxide elimination in relation to

Hb 15 gmldl

Hb 0 gmldl

80 100 120 140

Pa02 (mm Hg)Fig. 3. Relationship of arterial oxygen content (C,,,) to arterialoxygen tension (P,,,) in the presence of different hemoglobin con-centrations. Blood with 15 g/dL of hemoglobin contains 20 mLoxygen per 100 mL when fully saturated. Despite normal or evenelevated P,,,, the blood of an anemic patient contains a markedlyreduced amount of oxygen. (From Reference 7, with permission.)

its production by the body, and determined by the presenceof hypercapnia. Chronic hypoxemia due to right-to-leftintrapulmonary shunting is rarely encountered, and thismechanism is generally not a significant contributor tohypoxemia in patients with COPD. That the latter is so isfortunate for both patient and clinician with respect toLTOT, because it means that hypoxemia in COPD is rel-atively easy to correct, as discussed below.

Knowing the mechanism or mechanisms of hypoxemiain a given patient is important in diagnosis, because dif-ferent diseases produce hypoxemia in different ways andalso in therapy, as hypoxemia caused by the different mech-anisms responds differently to administration of supple-mental oxygen and to other measures. To determine themechanism or mechanisms of hypoxemia in a given pa-tient, it is first necessary to estimate the alveolar-to-arterialPo, difference [P(,_,,o,l, commonly called the A-a gradi-ent. Alveolar Paz (PAo,) must first be determined using thealveolar gas equation:

P*oz = PIO* - PDCO,~

wherein PacO is the arterial carbon dioxide tension and Ris the respimtory quotient. In this equation, the Pie, iscalculated from barometric pressure (Pn), the partial pres-sure of water vapor (P,,,) at body temperature, and theF10,:

PI O, = FB - 5-1~01 X 50,

When breathing air at sea level, PIoz is: (760 - 47 mmHg) X 0.21, or approximately 150 mm Hg. The respiratoryquotient (R), the overall ratio of CO, produced to O2 con-sumed by the body, is about 0.8 for persons eating a usualNorth American mixed diet, and this assumed value isused in calculating PAO,. Thus, if the patients P,ooz is 40mm Hg:

P*oz = 15OmmHg - 4OmmHg/O.8 = IOOmmHg

42 R ESPIRATORY C ARE l JANUARY 2000 VOL 45 No 1

P A T H O P H Y S I O L O G Y A N D C L I N I CAL EFFECTS OF C HRONIC H Y P O X I A

Table 3. Mechanisms of Chronic Arterial Hypoxemia

Physiologic Mechanism Clinical Examples

Low inspired Po, Chronic mountain sickness

Alveolar hypoventilation COPD with hypercapniaObesity hypoventilation syndrome

Ventilation-perfusion COPDmismatching Pulmonary fibrosis

Most other chronic pulmonary diseases

Right-to-left shunting Arteriovenous malformationHepatopulmonary syndrome

Pe = oxygen tension. COPD = chronic obstructive pulmonary disease.

Table 4. Practical Distinction Among the Main Mechanisms ofHypoxemia

Physiologic Mechanism

Alveolar hypoventilation

Ventilation-perfusionmismatching

Right-to-left shunting

Clinical Findings

Hypercapnia

Normal PcA+.)02Increased PA_,+Good response to supplemental 0,High Fro2 not requiredIncreased PcA_sjo2Poor response to supplemental 0,High F,, or PEEP may be required to

correct hypoxemia

PcA_a,02 = alveolar-atterial oxygen gradient. F,q = fraction of inspired oxygen. PEEP =

positive end-expiratoty pressure.

If this patients Pao, were 85 mm Hg, PcA_a)o, wouldthus be 100 - 85 or 15 mm Hg. A PcA_a)O, value of lessthan about 20 mm Hg can be considered normal for clin-ical purposes, and a value greater than about 30 mm Hg isdistinctly abnormal.The different physiologic mechanisms of hypoxemia canbe distinguished clinically using the patients initial arte-rial blood gas results and the response to administration ofsupplemental oxygen (Table 4). If the patient is hypercap-nit, alveolar ventilation is present by definition. In thepresence of a normal PcA+02, alveolar hypoventilation pro-duces a fall in Pao, that is roughly equivalent to the in-crease in P,, . Pao, falls a bit more than the increase inPaCo, because me body consumes a greater quantity of 0,than the CO, it produces, by the relationship R. This isillustrated in Figure 4, which shows that P, and Pacechange in opposite directions, assuming an inchangingPcA_a)oz and R = 0.8. An increase in P,co2 of 20 mm Hgwill be associated with a fall in Pao, of about 25 mm Hgin an otherwise normal individual. Equivalent changes inthe opposite direction occur with hyperventilation.

As shown in Table 4, alveolar hypoventilation (alongwith a low inspired Paz, not shown) causes hypoxemia

R ESPIR ATORY CARE l J ANUARY 2000 VOL 45 No 1

Fig. 4. Schematic depiction of how arterial oxygen and carbondioxide tensions (Pac2 and PBco2, respectively) change in oppositedirections, assuming an unchanging alveolar-to-arterial oxygen-tension difference (P,_,,oJ and a normal respiratory exchange ra-tio of 0.8. Alveolar hypoventilation raises the Pacot above the nor-mal value of 40 mm Hg and decreases Pao2 proportionally. (FromReference 7, with permission.)

without increasing PcA_a)02. Both \;r/Q mismatching andright-to-left shunting increase PcA_a)02, but they can bedistinguished for practical purposes by the response ofPao, to the administration of low-flow supplemental oxy-gen. If supplemental oxygen restores the P,oz to the nor-mal range or substantially increases it, v/Q can be as-sumed to be the cause, while persistent hypoxemia impliesthe presence of very low VilQ areas, if not actual shunt.The clinical importance of this distinction is that high Fro*,positive end-expiratory pressure, or other measures maybe required if the hypoxemia is caused by shunt, whileu/Q mismatch causes hypoxemia that can easily be cor-rected. If both hypercapnia and an increased PcA_a)o, arepresent, then both alveolar ventilation and v/Q mismatch-ing are contributing to the hypoxemia.

,

Physiologic Responses to Hypoxia

JBS Haldane is said to have remarked that a lack ofoxygen not only stops the machine but also wrecks themachinery. The correctness of this observation is mani-festly apparent with acute, severe hypoxia as encounteredin cardiopulmonary arrest or severe hypoxemic acute re-spiratory failure. However, in the context of this reviewthe destructive effect of hypoxia on the machinery of thebody is less dramatic and most often encountered in theform of altered function rather than structural damage.

In the 1960s it was shown that a Paz of at least 18 mmHg is necessary to sustain mitochondrial function, and togenerate adenosine triphosphate, which is essential for allmajor cellular biochemical functions8 Cellular hypoxiamay be defined as a state in which convective or diffusiveoxygen transport fails to meet the tissue demand for oxy-gen and when the rate of adenosine triphosphate synthesisbecomes limited by the oxygen s~pply.~ Decreases in ox-

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P A T H O P H Y S I O L O G 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 ventilationRespiratory alkalosis

Cardiovascular Pulmonary vasoconstrictionPulmonary hypertensionDecreased maximum oxygen consumptionDecreased 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 increasesits stimulus to breathe. The vertical axis depicts the intensity of thehypoxic stimulus, whether the individual is capable of increasingminute 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 designedto maintain cellular activity at a minimum acceptable lev-el; the failure of these mechanisms during hypoxia resultsin cellular dysfunction and can lead to irreversible celldamage.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 toprevent organ dysfunction or tissue damage that wouldotherwise occur. Differences among normal individuals inthe presence and vigor of these responses probably ac-count for much of the variation in clinical presentationobserved in patients with chronic hypoxia caused by pul-monary disease.

Respiratory System

The main respiratory response to hypoxia is an increasein hypoxic ventilatory drive, which in normal individualsresults 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 oxygenatedlung unit (left), hypoxic vasoconstriction (right) reduces blood flowto poorly ventilated regions, thus improving ventilation-perfusionmatching. 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 beaccounted for by hypoxic ventilatory drive. Regardless ofwhether 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 byPaCo,. 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 alsoin many highly successful athletes and after prolongedresidence at high altitude. It declines with normal aging. Itis also blunted in congenital cyanotic heart disease, inmyxedema and severe hypothyroidism, in certain types ofautonomic nervous system dysfunction, and with thechronic use of narcotics. Patients who have undergonecarotid body resection, a now-abandoned procedure onceperformed as treatment for dyspnea in emphysema, alsohave 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 resultin part from a direct stimulus of breathlessness,i5 althoughthis appears highly variable among individuals. As withchronic hyperventilation in other settings, the normal re-sponse to prolonged hypoxia leads to compensatory met-abolic acidosis produced by increased renal bicarbonateloss.

Cardiovascular System

The most characteristic and important cardiovascularresponse to hypoxia is pulmonary vasoconstriction, which

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


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 thelung, 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.22

Central Nervous System

Representing only 2-3% of an adults body mass, thebrain 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,z6 neuropsy-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 tochanges in perfusion, and effects of hypoxia on the brainare more likely to be due to decreased perfusion than tohypoxemia.25

Adaptation to Altitude.

At high altitude FIo, remains the same, but Pro2 de-creases as barometric pressure falls. In comparison with itsvalue 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 cellmass, 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 toaltitudes above 8,000 feet, particularly if they arrived byair 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, acutemountain sickness typically resolves over several days evenif 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 highaltitude.

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 forless 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 amuch longer period.32333 Compared with the two formergroups, Tibetans have higher resting ventilation, strongerhypoxic ventilatory responses, lower hemoglobin concen-trations, and increased cerebral blood flow with exercise.32Their resting pulmonary artery pressures are normal by sealevel standards, and they exhibit only minimal HPV bothat 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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P A T H O P H Y S I O L O G Y AND C LINICAL E FFECTS OF C H R O NIC H YPOXIA

Table 6. Adaptation and Maladaptation to High Altitude

Minutes, Hours Days, Weeks Months, Years

Increased ventilation Increased RBC mass (Cor pulmonale)Increased PA pressures (Acute mountain sickness) (Chronic mountain sickness)Diuresis (High-altitude pulmonary edema)Hemoconcentration (High-altitude cerebral edema)

Maladaptations (altitude-related illness) are shown in parentheses. RBC = red blood cell. HVR = hypoxic pulmonary vasoconsuiction. PA = pulmonary artery.

Generations

Increased HVRIncreased lung volumesIncreased cardiac outputOther adaptations

A natural experiment has been carried out in Tibet sincethat country was assimilated politically into China 50 yearsago. A number of physiologic studies have been carriedout in Lhasa (altitude 3,658 m) comparing the native Ti-betans with Han (Chinese) residents, the latter having livedat altitude for only a few years.35-41 These studies showthat, compared with healthy Han residents of Lhasa, nativeTibetans have increased resting ventilation,35 increased hy-poxic ventilatory response,35 larger vital capacity,41 andlower resting P,co2 and PcA_a)o,.41 Tibetans also have lesselectrocardiographic evidence of right ventricular hyper-trophy than do their Han counterparts.37 From the resultsof these studies it can be concluded that the Tibetans arebetter adapted to life at altitude than are the Han, perhapsindicating evolutionary adaptation to chronic hypoxia overmany generations.

clinical value in detecting hypoxemia. These observationsemphasize the importance of the objective measurement ofoxygenation in both diagnosis and treatment of hypoxia.

Chronic Mountain Sickness

Symptoms and Signs of Hypoxia

The symptoms and signs of hypoxia (Table 7) are non-specific and similar to those of heart failure and severalother conditions.42 Although many patients with hypoxiaare dyspneic, this is highly variable, and the clinical man-ifestations tend to be neurological and cardiovascular ratherthan respiratory. Similarly, although cyanosis is supposedto be present whenever there is more than 5 g/dL of de-oxygenated hemoglobin, this sign varies enough from pa-tient to patient and among different observers to be of little

Table I. Symptoms and Signs of Hypoxia

Symptoms Signs

(Dyspnea) (Respiratory distress)Restlessness (Cyanosis)Palpitations TachypneaConfusion TachycardiaAgitation Cardiac dysrhythmiasHeadache HypertensionTremor HypotensionAsterixis LethargyDiaphoresis Coma

Symptoms and signs in parentheses are highly variable among individuals.

Chronic mountain sickness is a disorder affecting manylong-term residents of altitudes above 9,000 feet.*7.43,44It is similar in some ways to what is seen in COPD patientswith chronic hypoxemia, although it does not involveairflow obstruction and has several features not generallyobserved in COPD.45 As mentioned above, it occurs com-monly in the Rockies and the Andes, but is uncommonamong natives of the Himalayas and the Tibetan Plateau.Symptoms of chronic mountain sickness include lethargy,mental slowness, and decreased exercise capacity. Affectedindividuals are plethoric and usually have conjunctival in-jection and peripheral edema. Laboratory evaluation showsmore severe hypoxemia and higher P,co2 than observed inothers at the same altitude, along with erythrocytosis thatmay be profound, with hematocrit values of 75% or more.

The disorder is believed to result from maladaptation tohigh altitude, with relative hypoventilation, pulmonary hy-pertension, and car pulmonale.43s44 It becomes more com-mon with increasing age,46 and is more commonly seen inmen than in women before menopause.47 Treatment aimsto relieve hypoxemia and blood hyperviscosity. Ideally,affected individuals should move permanently to a loweraltitude, but this may not be an option for socioeconomicreasons. Similarly, LTOT is seldom available in the re-mote regions where chronic mountain sickness is preva-lent. Staged phlebotomy is performed to maintain the he-matocrit closer to the level expected for the altitude atwhich the patient lives.

Hypoxia during Sleep

Although the subject of hypoxia during sleep is beyondthe scope of this review, this phenomenon affects millionsof people and has assumed increasing importance in recentyears.48 There is considerable overlap between COPD andsleep-disordered breathing .4g-51 The separate problem ofnocturnal oxygen desaturation in patients who are not hy-

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


.Capillary

Vascular Resistance Destruction(emphysema)

Polycythemia

1 Riaht Ventricular 1 >kypertrophy 1 I

Fig. 7. Pathogenesis of car pulmonale in chronic obstructive pul-monary disease. Long-term oxygen therapy attempts to reversethis process by eliminating alveolar hypoxia, the primary stimulusto increased pulmonary vascular resistance (PVR). However, asindicated in the diagram, the increased PVR is multifactorial, andonly a partial reduction in pulmonary arterial pressures is achieved.

poxemic during the daytime52*53 is discussed by ODonohuein another paper from this conference.S4

Chronic Hypoxia in Chronic ObstructivePulmonary Disease

Pathogenesis of Cor Pulmonale in ChronicObstructive Pulmonary Disease

The term car pulmonale refers to alterations in the struc-ture and function of the right ventricle due to disease of thelungs rather than of the heart per se. More specifically, asdefined by an expert committee of the World Health Or-ganization, car pulmonale is hypertrophy of the right ven-tricle resulting from diseases affecting the function and/orstructure of the lungs, except when these pulmonary alter-ations are the result of diseases that primarily affect theleft side of the heart, as in congenital heart disease.55 Theterm car pulmonale applies to patients who show evidenceof structural change in the right ventricle, whether or notthey have overt right-sided heart failure. However, it shouldnot be used as a synonym for right heart failure, nor inpatients with pulmonary hypertension who show no evi-dence of right ventricular hypertrophy.56

The pathophysiology of car pulmonale in COPD, re-viewed in a classic paper by Fishman5 has been revisited

more recently in a comprehensive review by MacNee.56x58The factors involved in its pathogenesis are depicted inFigure 7.5g Alveolar hypoxia triggers HPV and its atten-dant increase in pulmonary vascular resistance. If the hyp-oxia is prolonged, the increased right ventricular afterloadproduced by the chronically elevated pulmonary arterypressure results in hypertrophy of the right ventricle. Even-tually, if the process continues, overt right-sided heart fail-ure ensues, with peripheral edema, hepatic congestion, andother signs of increased blood volume and elevated centralvenous pressure.

As suggested in the figure, the pathogenesis is not sostraightforward as implied by the preceding description.Hypoxemia exerts an effect on the pulmonary vasculatureseparate from alveolar hypoxia, as does acidosis. Reduc-tion in pulmonary capillary surface area caused by em-physema also contributes to the increased pulmonary vas-cular resistance. In addition, when present, erythrocytosismay further augment the pulmonary hypertension.

Clinical Manifestations of Hypoxia and CorPulmonale in Chronic ObstructivePulmonary Disease .

Just as the symptoms and signs of hypoxia are variableamong individuals, the clinical manifestations of chronichypoxia and car pulmonale in patients with COPD showconsiderable variation. How dyspneic COPD patients withchronic hypoxemia are depends a lot on the severity oftheir airflow obstruction, but may also be a function oftheir underlying hypoxic ventilatory drive. The relation-ship between P,02 and the urge to breathe, as depicted inFigure 5, varies among normal individuals, as mentionedpreviously, with some small fraction of the populationhaving markedly blunted hypoxic chemosensitivity. Forindividuals with COPD and normal or heightened under-lying hypoxic drive, the development of hypoxemia wouldbe expected to increase the severity of their dyspnea. Suchindividuals might seek to avoid hypoxemia by increasingventilation insofar as they were capable of doing so. Thesepatients would remain normoxic until very late in the courseof their disease, but would be very dyspneic. On the otherhand, it may be surmised that, for those individuals withnaturally blunted hypoxic drives who develop COPD, hy-poxemia might not stimulate additional breathlessness. Notbeing distressed by the development of chronic hypoxemia(with its attendant cyanosis), such individuals might developcar pulmonale earlier than their normoxic, more dyspneiccounterparts. These two extremes in clinical presentation-the pink puffer (also known as Type A COPD) and theblue bloater (Type B) (Fig. 8)60-are atypical, but areconsistent with present understanding of pathophysiology andillustrate the spectrum of clinical presentation in patients withchronic hypoxemia complicating COPD.



Fig. 8. Two patients with severe chronic obstructive pulmonarydisease 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 bluebloater 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 ofsevere dyspnea. (From Reference 60, with permission,)

Effects of Hypoxemia on Mortality in ChronicObstructive Pulmonary Disease

Evidence for the effects of chronic hypoxia on mortalityand morbidity in COPD is largely indirect. Early studies ofthe natural history of severe COPD61-63 did not examinethe separate influences of hypoxia, the severity of airflowobstruction, and other factors. However, by examining thefindings of several large-scale studies some useful conclu-sions may be drawn about the impact of chronic hypoxiaas 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 Hgwhen initially examined is not very different from that

80

60vPAP(mm Hg< 2525-330.4L245

1 2 3 4 5

Time (years)

Fig. 9. Relationship between mean pulmonary arterial pressure(PAP) and survival in patients with chronic obstructive pulmonarydisease. (From Reference 64, with permission,)

expected for persons of the same age. However, the prog-nosis worsens progressively with increasing mean pulmo-nary arterial pressure, and few patients with initial valuesexceeding 45 mm Hg survive 5 years. The data in Figure964 do not take the severity of airflow obstruction intoaccount, and no doubt those individuals who fared bestalso tended to have less severe disease. As previouslydiscussed, hypoxia is also not the only factor contributingto pulmonary hypertension in these patients, and LTOTdoes not restore pulmonary arterial pressures to nor-ma1.64-66 However, the data in the figure provide strongevidence for an important impact of the magnitude of pul-monary hypertension on survival in patients with COPD.

Studies have attempted to correlate numerous anatomic,spirometric, imaging, and functional measurements withsurvival in COPD patients. Of these, the forced expiratoryvolume in the first second (FEV,) remains the best singleassessment of functional impairment and predictor of sur-viva1.61.67 Burrows6r performed a long-term follow-upstudy on 200 patients with COPD and showed a clearseparation into survival groups according to initial FEV,(Fig. 10). Half of all patients with initial FEV, valuesexceeding 1.25 L were alive 10 years after starting thestudy, while 75% of those with initial FEV, values lessthan 750 mL were dead within 5 years61

Chronic hypoxia increases mortality regardless of theseverity of airflow obstruction.68@ Thus, each of the curvesin Figure 10 is shifted downward by the presence of chronicstable hypoxemia. The Nocturnal Oxygen Therapy Trial(NOTT)O and British Medical Research Council (MRC)multicenter study of LTOT demonstrated that LTOT im-proved survival in patients with COPD and chronic stablehypoxemia. In the NOTT, patients who used oxygen onlyat night had a significantly poorer survival over the three

48 RESPIRATORY CARE l JANUARY 2000 VOL 45 No 1


% 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 continuousoxygen use.O Using data from the NOTT study and alsothe results of the Intermittent Positive Pressure BreathingTrial (IPPB),* Anthonisen et al were able to demonstratethe downward shift of the survival curve due to chronichypoxia 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 almatched patients in the IPPB study, the nocturnal-onlyoxygen 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 IPPBpatients 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 asmeasured 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 ifoxygen 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 groupand in the NOTT nocturnal-only group was approximatelythe same (and better than in the MRC no-oxygen group),but survival in the NOTT continuous-oxygen group wassubstantially better than in either of them. The NOTTincluded measurements of actual oxygen use by the pa-

v NOTT~~ hrs

200 1 2 3

Time (years)

Fig. 11. Effect of hypoxemia on survival in patients under 65 yearsof age with chronic obstructive pulmonary disease and compara-ble severity of airflow obstruction, as determined from results ofthe Nocturnal Oxygen Therapy Trial (NOT-T) and the IntermittentPositive Pressure Breathing Trial (IPPB). Hypoxemic patientstreated with oxygen only at night (triangles, solid line) had worsesurvival 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 6

Fig. 12. Dose-response relationship between daily hours of useand 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 thanthe 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 patientsactually 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 hypothesizedthat true 24 hour-per-day oxygen use would have improvedsurvival to an even greater extent (Fig. 12). There is no direct


PATHOPHYSIOLOGY AND CLINICAL EFFECTS OF CHRONIC HY P O X I A

evidence in support of this hypothesis, but it provides a ra-tionale for encouraging patients who qualify for LTOT to usetheir oxygen as much of the time as possible.

Summary

Hypoxia exists when there is a reduced amount of ox-ygen in the tissues of the body. Hypoxemia refers to areduction in PO, below the normal range, regardless ofwhether gas exchange is impaired in the lung, Cao, isadequate, or tissue hypoxia exists. There are several po-tential physiologic mechanisms for hypoxemia, but in pa-tients with COPD the predominant one is V/Q mismatch-ing, with or without alveolar hypoventilation, as indicatedby P,co,. Hypoxemia caused by V/o mismatching as seenin COPD is relatively easy to correct, so that only com-paratively small amounts of supplemental oxygen (lessthan 3 L/min for the majority of patients) are required forLTOT. Although hypoxemia normally stimulates ventila-tion and produces dyspnea, these phenomena and the othersymptoms and signs of hypoxia are sufficiently variable inpatients with COPD as to be of limited value in patientassessment.

Chronic alveolar hypoxia is the main factor leading todevelopment of car pulmonale-right ventricular hyper-trophy with or without overt right ventricular failure-inpatients with COPD. Pulmonary hypertension adverselyaffects survival in COPD, to an extent that parallels thedegree to which resting mean pulmonary artery pressure iselevated. Although the severity of airflow obstruction asmeasured by FEV, is the best correlate with overall prog-nosis in patients with COPD, chronic hypoxemia increasesmortality and morbidity for any severity of disease. Large-scale studies of LTOT in patients with COPD have dem-onstrated a dose-response relationship between daily hoursof oxygen use and survival. There is reason to believe thatcontinuous, 24-hours-per-day oxygen use in appropriatelyselected patients would produce a survival benefit evengreater than that shown in the NOTT and MRC studies.

Special issues. Oxygenation in the critically ill patient. Parts I & II.Respir Care 1993;38(6):587-704 and 1993;38(7):739-846.Pierson DJ. Normal and abnormal oxygenation: physiology and clinicalsyndromes. Respir Care 1993;38(6):587-599; discussion 599-602.Websters unabridged dictionary of the English language. New York:Portland House; 1989; pp 61:702Dorlands illustrated medical dictionary. Philadelphia: WB Saun-ders, 28th edition; 1994; pp 89:812.Stedmans medical dictionary. Baltimore: Williams & Wilkins, 26thedition, 1995; pp 95:841.Taylor CR, Weibel ER. Design of the mammalian respiratory sys-tem. I. Problem and strategy. Respir Physiol 1981;44(1):1-10.Pierson DJ. Respiratory failure: introduction and overview. In: Pier-son DJ, Kacmarek RM, eds. Foundations of respiratory care. NewYork: Churchill Livingstone; 1992:295-302.

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Banchero N. Cardiovascular responses to chronic hypoxia (review).Ann Rev Physiol 1987;49:465476.Walley KR, Becker CJ, Hogan RA, Teplinsky K, Wood LDH. Pro-gressive hypoxemia limits left ventricular oxygen consumption andcontractility. Circ Res 1988;63(5):849-859.Gibson GE, Pulsinelli W, Blass JP, Duffy TE. Brain dysfunction innild to moderate hypoxia. Am J Med 1981;70(6):1247-1254.3ombein TF. Hypoxia and the brain. In Crystal RG, West JB. The lung:scientific foundations. New York Raven Press; 1991:1535-1541.Wedzicha JA. Effects of long-term oxygen therapy on neuropsychi-mic function and quality of life. Respir Care 2000;45(1): 119-124.jchoene RB. Adaptation and maladaptation to high altitude. In: Pier-;on DJ, Kacmarek RM, eds. Foundations of respiratory care. NewYork: Churchill Livingstone; 1992: 141-145.

!jchoene RB. Control of breathing at high altitude (review). Respi-ation 1997;64(6):407-415.

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32. Moore LG, Niermeyer S, Zamudio S. Human adaptation to highaltitude: regional and life-cycle perspectives. Am J Phys Anthropol1998;Suppl 27125-64.

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Discussion

Petty: David, its a fact that FEV,is a good prognostic indicator, and itsthe better prognostic indicator if made

age-specific. That is, at what age your such a passion today for the NationalFEV, is abnormal, and is it revers- Lung Health Education program, be-ible? And that becomes the indicator cause our real challenge now is tofor early identification and interven- deal with early stages of disease, andtion. Thats the reason why we have I have a pin for most of you called

R ES P IR ATORY C A RE l J A NUARY 2000 VOL 45 No I 51

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

The Second Breath of Life. The firstbreath of life, of course, is the babysbreath that allows the child to live inthe first place, and the second breathof 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 oxygenin the blood, would you consider some-one who is anemic to be hypoxemicsince they have decreased oxygen in theblood, or is it strictly the Po2?

Pierson: Dorhnds, from which Itook that (and I surveyed a number ofother dictionaries as well), gives us anumber of different kinds of hypoxia.Theres anemic hypoxia, stagnant hyp-oxia, hypoxic hypoxia, histotoxic hyp-oxia, and one or two others, and theywould describe anemic hypoxia as thatdue to insufficient delivery of oxygenby virtue of not enough. . .

ODonohue: Hypoxemia is the termto which I am referring, not hypoxia.

Pierson: Hypoxemia. Here Ive notbeen able to find unanimous agree-ment. For example, Stedmans Medi-cal Dictionary says hypoxemia is de-ficient oxygen in the arterial blood,whereas Dorlands doesnt specify thecondition of the blood. I have alwaysused the definition that hypoxemiameans that your Paz is abnormally low.So, if Im breathing 100% oxygen, andI 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, butIm not hypoxemic by that conven-tion. But I think that its difficult tofind a universally-agreed-upon identi-fication. Does that agree with yourconcept, Walter?

ODonohue: Yes, absolutely. I havealways personally used the term tomean a decreased Po2. Patients withsevere anemia have decreased oxygen

52

content, but I have never referred tothem as being hypoxemic.

Pierson: It would be a shame if wecouldnt at least agree on the ABCsfor our discussion for these next twoand a half days.

ODonohue: But in both cases theyhave decreased oxygen in the blood.

Stoller: David, I thought it was awonderful talk. At the risk of being asplitter, I just want to comment onyour use of the hepatopulmonary syn-drome as an example of right-to-leftshunt, and lumping it with arterio-venous malformation. Regarding yourself-acknowledged 20-year-old slideabout the 5 mechanisms of hypoxemia(eg, V/Q mismatch and so on), someauthors have suggested that the hepa-topulmonary syndrome represents anunusual admixture of diffusion impair-ment and right-to-left shunt, such thatsome authors have actually added asixth cause of hypoxemia called dif-fusion-perfusion impairment. In thehepatopulmonary syndrome, there isdilatation of the capillaries causing theunusual circumstances in which bloodis passing very quickly through dilatedcapillaries. 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, weshould mention diffusion-perfusionimpairment as another physiologiccause of hypoxemia, to make the listcomplete.

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2. Lange PA, Stoller JK. The hepatopulmonarysyndrome: effect of liver transplantation (re-view). Clin Chest Med 1996;17(1):115-123.

Pierson: Im glad you brought thatup, Jamie, because Im ready for you!In ARDS, the studies back in the 1970sby Dantzker and, subsequently, by

the group in Seattle,* using the mul-tiple inert gas elimination technique,showed that, in fact the shunt inARDS was predominantly very lowV/Q areas. And that has been demon-strated in a lot of other situations wherethere isnt purely an anatomical con-nection such as in arteriovenous mal-formation. The reason I left thosethings off is that I think it helps theclinicians understanding to have theconcept that hypoxemia in certain clin-ical settings behaves as if it were shunt,which in other clinical settings behavesas if it were V/Q mismatching. Thephysiologist may be able to demon-strate to us that theres a little bit moreto 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 carewhether ARDS is very low V/Q areasor shunt, because it gets better whenyou use positive end-expiratory pres-sure, and it wont get better unless youdo something physical like that. So, withapologies 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 inthe 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 duringpositive end-expiratory pressure in the adultrespiratory distress syndrome. Am Rev Re-spir Dis 1985;131(1):54-60.

McCoy: Ive got a practical sort ofquestion for you, about the fact thatlong-term oxygen therapy is mostlydelivered in the home setting. The peo-ple who manage the reimbursementfor home oxygen therapy seem to notunderstand the question of the effectsof hypoxemia, and come back with aSo what? It seems that most of theresearch shows that survival is the Sowhat? answer. To a payer, as bad asit sounds, So what? with someonenot surviving costs less. One of thethings they need to understand is whatthe cost and consequences are of some-

REFERENCES

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one who is not treated correctly fortheir disease with regard to hospital-ization, doctors visits, medication,other modalities, and just exactly whatis involved in that process so that theycan better understand the So what?

Pierson: I think thats an excellentobservation, and in my discussion ofthe clinical effects, if you will, ofchronic hypoxia, I should include theeffects on the person, the effects onthe family, and the effects on the healthcare system, because, in fact, chronichypoxia extracts an enormous cost.This gets back to something Tom wassaying about plopping those medicalrecords down on the desk of the statehealth administrator. I think thats avery well-made point.

Zielinski: David, you mentionedthat you had no time to develop indetail as many items as you talkedabout. May I add some data on adap-tation of Tibetans, who are the onlypopulation, I think, who adapted verywell to the conditions of living at highaltitude. It was found that Tibetans donot react to hypoxia with pulmonaryvasoconstriction. Of course, it is verydifficult to perform pulmonary cathe-terization in those people. Five youngTibetans-lifelong residents ofLhasa-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 datasuggest 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-stitute, had an opportunity tocatheterize 3 or 4 healthy Tibetans.

They also had normal pulmonary ar-terial pressure despite living at alti-tude of some 4,000 meters (personalcommunication). In a study compar-ing working capacity at high altitudeof trained lowlanders and Sherpas, thelatter showed superior work capacity.This was attributable to (1) economyof ventilation with preservation of nor-mal blood pH, (2) a very high lungdiffusing capacity for oxygen, and (3)a high cardiac output relative to workintensity.* Lifelong Tibetan residentsof Lhasa (3,658 m) had higher hy-poxic ventilatory response and minuteventilation than acclimatized Han Chi-nese coming from lowlands.3

REFERENCES

Groves BM, Droma T, Sutton JR, McCul-lough RG, McCullough RE, Zhuang J, et al.Minimal hypoxic pulmonary hypertension innormal Tibetans at 3,658 m. J Appl Physiol1993;74(1):312-318.

2. Pugh LGCE, Gill B, Labiri S, Milledge JS,Ward PM, West JB. Muscular exercise at greataltitudes. 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. AmRev 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 donesince Tibet was absorbed into Chinapolitically about 50 years ago, in thatthere is now a large population of HanChinese living with the Tibetans inTibet. The Han have now been therefor up to 50 years, whereas the Tibet-ans have been there perhaps as muchas a million years. Comparative stud-ies of those two populations-4 showa number of striking differences. Forexample, failure to carry pregnanciesto term is much more prevalent in theHan Chinese (as are low birth weight,pulmonary hypertension, and a num-ber of the clinical maladies associatedwith living at high altitude) than inthe Tibetans. This may be an exampleof evolution at work even within asingle species.

REFERENCES

1. Moore LG. Niermeyer S, Zamudio S. Hu-man adaptation to high altitude: regional andlife-cycle perspectives. Yearbook Phys An-thropol 1998;41:25-64.

2. Moore LG. Curran-Everett L, Drama TS,Groves BM, McCullough RE, McCulloughRG, et al. Are Tibetans better adapted? IntJ 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 andHan residents of Lhasa. J Electrocardiol1998;31(3):237-243.

Spratt:* A question on the treatmentof nocturnal hypoxemia. I believe rightnow the American Thoracic Societystandards for chronic obstructive pul-monary disease suggest treatment onlyif you have signs and symptoms of carpulmonale. From Fletchers work2 andfrom what we know from obstructivesleep 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 treatthose people if were waiting for signsand symptoms of car pulmonale, and isthere a way we can predict those pa-tients who are more likely to developthose long-term problems so we can treatthem earlier?

.

REFERENCES

1. American Thoracic Society. Standard for thediagnosis and care of patients with chronicobstructive pulmonary disease. Am J RespirCrit Care lMed 1995;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 diseasepatients with and without oxyhemoglobin de-saturation during sleep. Chest 1989;95(4):757-766.

Pierson: We thought that was suchan important question that we devotedan entire presentation to it. Waltersgoing to give that presentation, and Ilook forward to the answers to thosequestions.

*Greg Spratt, Rotech Medical Corporation,Kirksville, Missouri.

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