710 THE NEW ENGLAND JOURNAL OF MEDICINE Sept.

14, 1995

REVIEW ARTICLE

contribute to chronic malnutrition in patients with se-

vere obstructive pulmonary disease.10
CURRENT CONCEPTS
EFFECTS OF LONG-TERM OXYGEN THERAPY
In patients with hypoxemia, oxygen supplementation
LONG-TERM OXYGEN THERAPY improves survival, pulmonary hemodynamics, exercise
capacity, and neuropsychological performance. It may
STEPHEN P. TARPY, M.D., also decrease the oxygen cost of breathing and improve
the quality of sleep.
AND BARTOLOME R. CELLI, M.D.
Survival

T HE concept of oxygen as a therapeutic agent was

introduced in the 1920s by Alvin Barach.1 Since
then, a better understanding of the effects of hypox-
Long-term oxygen therapy improves survival. In a
study by the British Medical Research Council, pa-
tients with hypoxemia were randomly assigned to re-
emia, and of their reversal with oxygen supplementa- ceive 15 hours of continuous oxygen or no oxygen. Dur-
tion, has enhanced the treatment of patients with pul- ing five years of follow-up, 19 of 42 patients treated
monary diseases. There are close to 800,000 patients with oxygen died, as compared with 30 of 45 controls.9
receiving long-term oxygen therapy in the United States, In the Nocturnal Oxygen Therapy Trial (NOTT), pa-
at a yearly cost of $1.8 billion.2,3 We need to understand tients were randomly assigned to either 12 or 24 hours
the effects of oxygen therapy, the indications for it, and of daily oxygen therapy. After 26 months, mortality in
its modes of delivery in order to make the most appro- the continuous-treatment group was half that in the 12-
priate use of this effective therapeutic resource. In this hour group.8 Because the improvement in survival with
article, we discuss long-term oxygen therapy, empha- long-term oxygen therapy seems to be proportional to
sizing its use in the care of patients with chronic ob- the number of hours of therapy, the current recommen-
structive pulmonary disease, the application that has dation for patients with hypoxemia (defined as a PaO2
been most carefully studied.4-9 Some of the same prin- of 55 mm Hg or an oxygen saturation of 88 per-
ciples may apply to the treatment of patients with inter- cent) is continuous 24-hour-a-day oxygen (Table 1). Pa-
stitial and neuromuscular diseases. tients with a PaO2 of 56 to 59 mm Hg or an oxygen sat-
uration of 89 percent, cor pulmonale, or polycythemia
PHYSIOLOGIC RESPONSES TO HYPOXEMIA should also receive long-term oxygen therapy.
Hypoxemia induces several physiologic responses Patients receiving long-term oxygen therapy should
designed to maintain adequate oxygen delivery to the be reevaluated within two months to assess whether hy-
tissues. At a partial pressure of arterial oxygen (PaO2) poxemia persists. Up to 40 percent of treated patients
below 55 mm Hg, ventilatory drive increases, leading have sufficient improvement after one month to make
to a higher PaO2 and a lower partial pressure of car- continued supplemental oxygen unnecessary.8,11
bon dioxide (PaCO2). The vascular beds supplying hy-
poxic tissue dilate, inducing a compensatory tachycar- Pulmonary Hemodynamics
dia that increases cardiac output and improves oxygen Supplemental oxygen can improve pulmonary hemo-
delivery. The pulmonary vasculature constricts in re- dynamics and reduce cardiac work. Right heart cathe-
sponse to alveolar hypoxia, thereby improving the terization was performed in 16 patients who had hy-
match between ventilation and perfusion in the affect- poxemia with chronic obstructive pulmonary disease
ed lung. Subsequently, the secretion of erythropoietin 41 months before, just before, and 31 months after ox-
by the kidney causes erythrocytosis, thus increasing ygen therapy.7 Before therapy, there was a mean (SD)
the oxygen-carrying capacity of the blood and oxygen yearly increase in the pulmonary-artery pressure of
delivery. These early benefits may have detrimental 1.472.3 mm Hg. After supplemental oxygen therapy,
long-term effects, however (Fig. 1). Prolonged vaso- the pressure improved in 12 of the patients, with a mean
constriction, erythrocytosis, and increased cardiac out- annual decrease of 2.154.4 mm Hg. In the NOTT
put cause pulmonary hypertension, right ventricular study, six months of oxygen significantly improved pul-
failure, and often death.4-9 The cost of breathing in monary-artery pressure, peripheral vascular resistance,
terms of increased ventilation and oxygen demand may and stroke volume at rest and during exercise.6
The condition of many patients worsens despite sup-
From the Pulmonary Center, Boston University School of Medicine (S.P.T.), plemental oxygen. Early identification of these patients
and St. Elizabeth’s Medical Center and Tufts University School of Medicine would allow them to avoid the cost and inconvenience
(B.R.C.) — all in Boston. Address reprint requests to Dr. Celli at the Department
of Pulmonary and Critical Care, St. Elizabeth’s Medical Center, 736 Cambridge of therapy. Unfortunately, attempts to correlate short-
St., Boston, MA 02135. term hemodynamic responses to oxygen with long-term

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Vol. 333 No. 11 CURRENT CONCEPTS 711

Effect Possible Benefit Negative Consequences

Respiratory
Increases Increases Increases work
ventilation PaO2 of breathing

Cardiovascular
Increases heart rate and Improves ventilation –
stroke volume perfusion matching
Increases
Hypoxemia Induces Increases pulmonary-artery
pulmonary PaO2 and pressure
vasoconstriction oxygen delivery

Hematologic
Increases
Increases
erythropoietin Increases oxygen-
myocardial
and hemoglobin carrying capacity
work
concentrations

Figure 1. Short-Term and Long-Term Effects of Hypoxemia on the Respiratory, Cardiovascular, and Hematologic Systems.

survival have not succeeded.6,12,13 The use of noninva- nisms by which it does so are not clear.25,26 The benefi-
sive methods to predict the response to oxygen, such as cial effect of oxygen on ventilation and the work of
oxygen uptake during maximal exercise12 or the change breathing may help explain the decreased sensation of
in the right ventricular ejection fraction after oxygen dyspnea that patients with mild hypoxemia experience
therapy,14 have been disappointing. Therefore, long- when given oxygen. Currently, a desire to decrease the
term oxygen therapy is indicated for all patients who work of breathing is not an accepted indication for the
have hypoxemia as defined above, since some benefit is long-term administration of oxygen.
possible and other options are limited.
Neuropsychological Effects
Exercise Capacity Hypoxemia (PaO2, 45 to 60 mm Hg) impairs judg-
Ventilatory rather than circulatory factors limit exer- ment, learning, and short-term memory in young men.27
cise in many patients with airflow obstruction.15 Supple- It also decreases neuropsychological performance in pa-
mental oxygen increases the distance patients can walk tients with chronic obstructive pulmonary disease.28,29
and their endurance in tests on a treadmill or a bicy- The NOTT investigators studied neuropsychological
cle.16-18 In patients with hypoxemia and those who have performance in 203 patients with a mean PaO2 of 51
oxygen desaturation with exercise, supplemental oxygen mm Hg,30 whereas the Canadian Intermittent Positive
increases oxygen delivery and its utilization by muscles Pressure Breathing Trial included 100 patients with
during exercise.19,20 However, increased oxygen satura- less severe hypoxemia (mean PaO2, 66 mm Hg).31 Both
tion does not predict improved exercise performance.16 these studies demonstrated an increase in the frequency
Supplemental oxygen also reduces minute ventilation of neuropsychological deficits as the PaO2 decreased.
and the respiratory rate for a given workload.17 In addi-
tion, it improves ventilatory-muscle function during ex- Table 1. Indications for Long-Term Oxygen Therapy.
ercise by postponing the onset of respiratory-muscle fa- Continuous oxygen
tigue and improving the capacity of the diaphragm to Resting PaO2 55 mm Hg or oxygen saturation 88 percent
sustain work.21 Supplemental oxygen may also decrease Resting PaO2 of 56–59 mm Hg or oxygen saturation of 89 percent in the presence
dyspnea and improve endurance by directly reducing of any of the following:
Dependent edema suggesting congestive heart failure
chemoreceptor activity.18 Currently, supplemental oxy- P pulmonale on the electrocardiogram (P wave greater than 3 mm in standard
gen during exercise should be prescribed for patients leads II, III, or aVF)
Erythrocythemia (hematocrit 56 percent)
with a documented PaO2 of 55 mm Hg or less or oxygen Resting PaO2 59 mm Hg or oxygen saturation 89 percent
saturation of 88 percent or less during exercise. In the Reimbursable only with additional documentation justifying the oxygen pre-
future, measures of exercise endurance, dyspnea, and scription and a summary of more conservative therapy that has failed
ventilatory-muscle fatigue may serve as criteria for pre- Noncontinuous oxygen
scribing supplemental oxygen. Oxygen flow rate and number of hours per day must be specified
During exercise: PaO2 55 mm Hg or oxygen saturation 88 percent with a
low level of exertion
The Work of Breathing
During sleep: PaO2 55 mm Hg or oxygen saturation 88 percent with asso-
Supplemental oxygen decreases minute ventilation ciated complications, such as pulmonary hypertension, daytime somnolence,
and cardiac arrhythmias
and the oxygen cost of breathing,22-25 but the mecha-

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712 THE NEW ENGLAND JOURNAL OF MEDICINE Sept. 14, 1995

The incidence ranged from 27 percent in patients with In the United States, a certificate of medical necessity
mild hypoxemia (PaO2, 60 mm Hg) to 61 percent in for home oxygen therapy must be completed.
those with severe hypoxemia (PaO2, 50 mm Hg).32 Airline travel is safe for most patients with chronic
In the NOTT study, six months of supplemental ox- obstructive pulmonary disease. Patients with hypoxe-
ygen improved the participants’ general alertness, mo- mia should be evaluated clinically, and their oxygen re-
tor speed, and hand grip, but not their emotional state quirements assessed; regression formulas may be help-
or the quality of their lives.33 Supplemental oxygen ful in that assessment. In general, patients receiving
should not currently be prescribed for the sole purpose oxygen should be instructed to increase the flow by 1 to
of trying to improve a patient’s mental function. 2 liters per minute during the flight.43 At present, the
airlines have different policies regarding patients trav-
Sleep eling with oxygen, but a single policy that will make
During rapid-eye-movement sleep, breathing be- traveling easier is being studied.
comes more variable, and oxygen saturation falls.34 In
chronic obstructive pulmonary disease, sleep is associ- SYSTEMS OF OXYGEN DELIVERY
ated with hypoxemia and retention of carbon dioxide, Long-term oxygen therapy can be administered from
phenomena best explained by rapid, shallow breathing, an oxygen concentrator or in the form of compressed
hypoventilation, episodes of hypopnea, reductions in gas or liquid oxygen (Table 2). Because home oxygen
functional residual capacity, and alterations in ventila- therapy is supplied under a fixed-reimbursement policy
tion–perfusion matching.35,36 During rapid-eye-move- regardless of the system used,44 vendors in the United
ment sleep, the contribution of the rib cage to ventila- States provide the least expensive system unless the
tion decreases, as a consequence of hypotonia.37 This physician requests otherwise. It is therefore important
factor may be particularly important in patients with that the prescription clearly specify the desired oxygen-
severe obstruction, who greatly depend on the acces- delivery system.
sory muscles of respiration for breathing.38 There may Most patients require a stationary source of supple-
be an association between nocturnal oxygen desatura- mental oxygen, usually an oxygen concentrator. Concen-
tion and pulmonary hypertension in patients with trators are relatively inexpensive ($1,500) and require
chronic obstructive pulmonary disease and a daytime little maintenance. Oxygen concentrators are electrical
PaO2 above 60 mm Hg.39,40 devices that use a molecular sieve to separate oxygen
Patients with chronic obstructive pulmonary disease from air, thereby delivering supplemental oxygen to the
have poor-quality sleep41 and frequent arousals during patient while returning nitrogen to the atmosphere. Be-
periods of desaturation.42 It is unclear whether supple- cause the concentrators weigh about 35 lb (16 kg) and
mental oxygen improves the quality of sleep.41,42 Pa- require wall current to operate, they are used as a fixed
tients who have hypoxemia while awake should receive source of oxygen.
supplemental oxygen during sleep. In addition, patients Unless they are immobile or confined to bed, pa-
with nocturnal desaturation (oxygen saturation, 88 tients should have both stationary and mobile systems
percent) should receive supplemental oxygen if they of oxygen delivery. Compressed gas or liquid oxygen
have complications attributable to hypoxemia during can be portable sources of oxygen. Compressed oxygen
sleep, such as pulmonary hypertension, daytime somno- is provided in high-pressure cylinders. In the United
lence, or cardiac arrhythmias.2 States, standard sizes are 200, 16, 9, and 3 lb (91, 7, 4,
and 1.4 kg). These cylinders provide oxygen at a flow
DETERMINING THE NEED FOR OXYGEN rate of 2 liters per minute for 2.4 days, 5.2 hours,
The need for supplemental oxygen should be deter- 2 hours, and 1.2 hours, respectively. Cylinders are
mined by obtaining arterial-blood gas values.2,22 Oxy- bulky and require frequent refills. The smaller units,
gen saturation, measured by finger or ear oximetry, cor- however, are quite portable and, coupled with electron-
relates with PaO2, but this measurement is less precise. ic oxygen-conserving devices, may deliver oxygen for as
For patients who do not have hypercapnia, measure- long as eight hours.
ment of oxygen saturation is adequate to adjust treat- Oxygen stored at temperatures below 183°C be-
ment. To avoid excessive retention of carbon dioxide, comes a liquid. The volume of liquid oxygen is less than
blood gases should be monitored whenever oxygen 1 percent of the volume of a comparable amount of at-
therapy is adjusted in patients with hypercapnia. Sup- mospheric oxygen. Stationary units of liquid oxygen
plemental oxygen should be administered to increase typically weigh 240 lb (109 kg) and provide seven days
the PaO2 to no less than 60 mm Hg or the oxygen sat- of continuous oxygen at a flow rate of 2 liters per
uration to 90 percent or more. minute. The portable 9.5-lb (4.3-kg) and 6.5-lb (3-kg)
containers provide oxygen for eight and four hours, re-
PRESCRIBING OXYGEN spectively, at the same flow rate. As compared with ox-
Guidelines for prescribing oxygen are listed in Ta- ygen in the form of a compressed gas, a container of liq-
ble 1. The prescription should include the source of uid oxygen of equivalent weight will last four times
supplemental oxygen, the type of delivery system, and longer at a given flow rate. Although liquid oxygen is
the flow rate at rest, during exercise, and during sleep. more portable and containers are easier to refill than

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Vol. 333 No. 11 CURRENT CONCEPTS 713

Table 2. Modes of Oxygen Delivery. eyes. In some patients higher oxygen flows may induce
some retention of carbon dioxide. This hazard is best
SYSTEM ADVANTAGES DISADVANTAGES
avoided by careful adjustment of the flow rate of supple-
Gas Moderate cost Heavy weight mental oxygen to maintain the PaO2 between 60 and
Wide availability Difficulty of refilling 65 mm Hg.
Fair portability Need for frequent refills
Little need for
maintenance
OXYGEN-ADMINISTRATION DEVICES
Liquid Light weight High cost Patients usually receive oxygen through a nasal can-
Excellent porta- Incompatibility of parts
bility among vendors nula. Oxygen at a flow rate of 2 liters per minute in-
Ease of refilling Pressure venting creases the fraction of inspired oxygen from 21 percent
Need for moderate mainte-
nance
to approximately 27 percent.2 Although effective, this
Oxygen con- Low cost Heavy weight method is inefficient. During the respiratory cycle, the
centrator Good availability Relatively poor porta- movement of oxygen to the lungs occurs only during
Ease of use bility
Need for regular mainte- early inhalation — one sixth of the cycle. Alveolar ven-
nance tilation does not occur during late inspiration and ex-
halation.2,22 Only oxygen flowing during early inspira-
tion gets to the alveoli; the remainder is wasted.
high-pressure cylinders, there are several disadvantag- To improve the efficiency of oxygen delivery, several
es. Liquid oxygen has a higher cost ($3,500 for a station- devices have been designed (Table 3). They include
ary system, as compared with $350 for a compressed- reservoir nasal cannulas, transtracheal catheters, and
oxygen tank), and coupling devices for stationary and electronic demand devices. As compared with conven-
portable systems made by different manufacturers may tional nasal cannulas, these devices decrease oxygen
not be compatible. The liquid-oxygen tanks also need waste by a factor of two to four. The reservoir nasal
pressure-relief venting as the tanks warm up and the cannula has a pouch that stores 20 ml of oxygen during
gas expands; this process wastes unused oxygen. expiration and delivers this oxygen as a bolus at the on-
Liquid oxygen is particularly desirable for active pa- set of inspiration.2,22 Electronic demand devices sense
tients. A study comparing two types of portable oxygen the beginning of inspiration and deliver a pulse of oxy-
systems, gaseous and liquid, found that patients used gen during early inhalation.2,22
liquid oxygen more hours per day (23.5 vs. 10) and left Transtracheal catheters improve oxygen delivery by
their houses for more hours per week (19.5 vs. 15.5).45 bypassing anatomical dead space and using the upper
airways as a reservoir for oxygen during end-expira-
MISCONCEPTIONS AND HAZARDS tion.22,46 Transtracheal oxygen is delivered directly into
There is no place in medical care for the adminis- the trachea. The hollow catheter is surgically implanted
tration of “short” courses of oxygen. Temporary oxy- under local anesthesia between the second and third
gen is indicated during sleep and exercise when hypox- tracheal rings. Both the catheter and the procedure are
emia is present only during those activities. Patients covered by Medicare. Reimbursement to suppliers of
may want to avoid continuous oxygen therapy, fearing the oxygen-delivery equipment is tied to the flow rate
that it may cause “addiction.” Education about the dif- of oxygen. Therefore, oxygen flow at rates below 1 liter
ference between an addictive substance and a neces- per minute, which are frequent with the transtracheal
sary one frequently resolves the problem. In some pa- catheter, discourages the provision of these devices by
tients, arterial oxygen pressure may return to levels the suppliers of medical equipment. Other advantages
higher than 60 mm Hg after prolonged therapy. In of transtracheal oxygen include its inconspicuousness;
such cases, physicians (sometimes pressed by the pa- the lack of nasal, auricular, or facial irritation; and the
tients) are tempted to discontinue the oxygen. If this is infrequency of displacement of the catheter during ex-
done, the patients should be closely followed, because ercise or sleep.47 Rates of acceptance by patients range
their condition frequently deteriorates to a point at from 80 to 96 percent.47-49 The implantation procedure
which supplemental oxygen is again needed. is usually performed by a pulmonologist or otolaryngol-
Supplemental oxygen is a fire hazard. Patients must ogist, and procedure-related complications, which oc-
abstain from smoking — something
that will also help their lung disease. Table 3. Oxygen-Conserving Devices.
Tanks should be safely secured to a
wall, to prevent both disconnection TYPE MECHANISM COST ADVANTAGES DISADVANTAGES

of the regulator and explosion if the Reservoir Stores oxygen Low Reliable, easy to initiate Poor appearance
tank falls. Tanks should be stored in exhalation use
away from heaters and furnaces. Demand Delivers at be- Substantial Saves the most oxygen Mechanical failure possi-
ginning of ble, complicated
Low-flow supplemental oxygen has inhalation
been remarkably free of important Transtracheal Bypasses dead High, including Good appearance, excellent Important complications
space cost of pro- compliance, decreases (e.g., mucous plugs),
side effects, but occasional patients cedure work of breathing requires special care
report local irritation in the nose and

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714 THE NEW ENGLAND JOURNAL OF MEDICINE Sept. 14, 1995

cur in 3 to 5 percent of cases, include subcutaneous em- 22. Barker AF, Burgher LW, Plummer AL. Oxygen conserving methods for
adults. Chest 1994;105:248-52.
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the oxygen cost of breathing. Am Rev Respir Dis 1993;147:1207-10.
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FUTURE DIRECTIONS nasal cannula on the oxygen cost of breathing in chronic airflow obstruction
(CAO). Am Rev Respir Dis 1992;145:A646. abstract.
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