The British MRC trial

and
The NOTT (Nocturnal Oxygen Therapy Trial)

-Dr. Samyek Napit

Resident-Ist Year
Internal Medicine

08-Aug-23 1
 The British MRC trial (1981)

The NOTT trial (1980)

NOT trial (Nocturnal Oxygen Therapy) (1999)

Long Term Oxygen therapy Trial (LOTT) (2016)

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COPD and LTOT
• 1970s

• The prognosis for patients in whom chronic bronchitis and emphysema is

complicated by hypoxic cor-pulmonale and carbon dioxide retention is grave

• the three year mortality rate varying from 32 to 100%.

• Correction of hypoxemia reduces pulmonary HTN and reduces secondary

polycythemia BUT the value of this treatment had not been assessed till this
point
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• In 1973 the Medical Research Council set up in the U.K.,a multicentre
controlled trial of long term oxygen therapy in COPD patients in
Birmingham, Edinburgh, and Sheffield.

• The British MRC trial was planned to determine if oxygen, given for 15
hours in a day, over a three year period, could reduce mortality and
improve exercise tolerance and working capacity.
• Changes in the physiological variables were also to be studied.

• Published in 1981
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Design
• Multicenter, double blind, parallel group, randomized placebo
controlled trial
• N = 87
• Setting: Birmingham, Edinburgh, Sheffield
• Enrollment: not specified but in early 1970s
• Follow up: 5 years
• Primary end point: reduction in mortality
• Secondary end point : improve exercise tolerance and ability to work

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Inclusion criteria
• Age < 70 years
• FEV1 < 1.2
• PaO2 40-60 mm of Hg
• One or more recorded episodes of heart failure with ankle edema
• Stable ABG, FEV1 and Body weight measurements at least 3 weeks
apart

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Exclusion criteria
• Fibrotic or infiltrative lung disease
• pneumoconiosis (category 2 or more)
• severe kyphoscoliosis
• overt episodes of pulmonary embolism
• systemic hypertension (diastolic pressure >100 mm Hg under 60 years
of age or > 110 mm Hg over 65 years of age)
• proven coronary arterial disease, or other life threatening diseases

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Interventions
• Patients who agreed to participate in the trial after careful explanation

• allocated to the treatment or control group by means of a table of random numbers, so that within each
centre successive groups of 8 patients contained 4 treated patients and 4 controls

• treatment other than oxygen was given according to the discretion of the clinician in charge of the
patient, and included diuretics, digoxin, and antibiotics.

• All patients were urged to give up smoking.

• All patients were seen at a clinic every 2 months throughout the trial, being admitted to hospital for other
treatment as necessary, at the discretion of their clinician.

• The patients were otherwise at home, but visited from time to time by research registrars or technicians
attached
08-Aug-23 to the trial to check oxygen usage and, occasionally, to sample arterial blood at home 9
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Oxygen therapy
• oxygen supplemented for at least 15 h a day (including the sleeping
hours), given by nasal prongs, at a flow rate of 2 l/min, or at a higher
flow rate if this was necessary to achieve a Pa02 >60 mm Hg.

• Source of oxygen : concentrator, liquid oxygen delivered to home,

oxygen cylinder

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Physiological measurements

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• Red cell mass was measured by 5lCr-tagged red cells.

• Cardiac catheterisation was carried out with the patient semi-

recumbent, the zero reference point for pressure measurements being
5 cm below the sternal angle. Recordings were made over three of four
respiratory cycles, mean pressure being measured electronically or by
planimetry.

• Cardiac output was measured by either the direct Fick or indicator

dilution method, with dye injected into the right atrium.
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Results
• 33 men and 9 women received oxygen, 33 men and 12 women
forming the control group

• The four groups (men and women both treated and control), were
well matched clinically and physiologically, apart from the mean
weight in the women being less than that in the men

• 1 patient was withdrawn from the treatment group due to failure to

comply.

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 Mortality
• 19 of the 42 patients who received oxygen died,
compared with 30 of the 45 controls.

• In the men, mortality in both treated and control

groups was very similar for the first 500 days after
entry to the trial. It was initially low and then
increased in both groups.

• After about 500 days mortality in the treated men

was lower than that in the control men, and the
risk of death then appeared to be constant, at 12%
per annum in the treated and 29% per annum in
the08-Aug-23
controls (p=0.04). 16
• The mortality of the control women was significantly more than that
of the treated women from the start of the study (log rank test, p <
0 .05)

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Cause of Mortality
• Most patients who died did so at home in respiratory failure, often
suddenly, and at night.

• 5 died from lung cancer-

• 1 man and 1 woman in the treated group and
• 2 women and 1 man in the control group.

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 Predictors of Mortality
• red cell mass (RCM) in ml/kg and PaC02 (mm Hg), when
breathing air, provided the best discriminant between
those men who survived for 500 days (both treated and
control) and those who died within this period

• RCM + PaCO2 in room air > 98

• 61% mortality in 500 days
• RCM + PaCO2 in room air < 98
• 17% mortality in 500 days

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Hospital stay and work record
• no significant difference in the number of days spent in hospital due
to exacerbations of respiratory failure between the treated and
control groups,

• or in the number of days spent in work after the start of the trial

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Rates of Change in Physiological Variables
• in both treated and control groups those who died early (180-500
days), tended to show a fall in Pa02 and rise in PaC02 when they were
breathing air

• RCM fell slightly in oxygen group, in contrast to a slight rise in red cell
mass in the control men who survived over 500 days.

• The mean pulmonary arterial pressure showed little change in the men
who survived longer, whereas it tended to rise in the 21 control men
who survived over 500 days
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Conclusion
• long term oxygen therapy, given for 15 h in the 24 h day at a flow rate
of 2 litres/minute by nasal prongs can reduce mortality over three
years in both men and women with severe hypoxic cor pulmonale
complicating chronic bronchitis and emphysema

• but that this effect only became evident in men after some 500 days
from starting the treatment.

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• the long term oxygen therapy can reduce red cell mass, and prevent a
further rise in the pulmonary vascular resistance, as well as
prolonging life, but only after the interval of 500 days

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Introduction
• Patients with COPD had poor prognosis despite treatment regimens
aimed at improving the mechanical function of the lungs.

• such patients were often treated with supplementary oxygen on an

outpatient basis.

• early studies of this treatment, which compared patients before and

after oxygen therapy, indicated that chronic 02 therapy resulted in
improved exercise tolerance, decreased pulmonary hypertension and
erythrocytosis, and improved neuropsychological function
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• Trial where oxygen was provided to one group and withheld from another
group was being conducted in the UK and the preliminary reports had showed
that it was associated with reduced mortality

• As long-term oxygen administration was an expensive and It was not clear

whether continuous oxygen therapy was necessary;

• patients suffer their most severe hypoxemia while sleeping , and it is

possible that hypoxemic sequelae such as erythrocytosis and pulmonary
hypertension could be prevented by exclusively nocturnal oxygen
administration.
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• The division of National Heart, Lung, and Blood Institute initiated a
multicenter clinical trial comparing continuous 0xygen therapy with
nocturnal oxygen therapy in patients with hypoxemic chronic
obstructive lung disease

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Design
• Multicenter, double blind, parallel group, randomized placebo
controlled trial
• N = 203
• Setting: 6 centers
• Enrollment over 27 months 1977-1979
• Follow up: at least 1 year
• Primary end point: death in the two treatment groups and times of
follow-up

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 Inclusion criteria Exclusion criteria
• clinical diagnosis of chronic obstructive lung
disease
• Previous 02 therapy: 12 h/d for 30
• Hypoxemia Pa02 <=55 mm Hg
days during previous 2 months
• Pao2 <= 59 plus one of the following:
• Edema
• Hematocrit > 55% • Other disease that might be
• P pulmonale on ECG: 3 mm in leads II, III, aVf expected to influence mortality,
• Lung function morbidity, compliance with
• FEV,/FVC < 70% after inhaled bronchodilator
• TLC > 80% predicted
therapy, or ability to give informed
• The •protocol
Age > 35 consent
required that this criterion be fulfilled on at least two occasions more than 1 week
apart during a 3-week observation period while the subject was free of exacerbations and was
managed
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• informed consent was obtained and the patient was
hospitalized for a week of baseline studies

• Randomly allocated to one of the groups by the data center

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• after 6 months of nocturnal or continuous 0 2 therapy, all were
repeated except sleep studies, right heart catheterization, and
neuropsychological testing

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• Each patient received the lowest flow in whole litres per minute
that demonstrably increased resting, semirecumbent arterial Po2
at least 60 mm Hg and maintained a resting arterial Po2 of 60 to
80 mm Hg

• This dose was increased by 1 L/min for periods of exercise and

sleep

• Compliance with therapy was checked in two ways

• Oxygen source fitted with timers
• Family members required to keep record

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• oral theophylline and inhaled • steroids, cardiac glycosides,
beta-2 agonists. sedatives, tranquilizers,
• Diuretics and antibiotics were antidepressants and oral beta
used as clinically indicated agonists, was discouraged.

• Therapeutic phlebotomies were

not done.

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• For the first six months, patients were visited weekly

• After six months, visited monthly

• At 1-month intervals during the first 6 months and at 3-month

intervals thereafter, samples of arterial blood were obtained
while the patient breathed his prescribed dose of oxygen and
the dose adjusted if arterial P02 was not 60 to 80 mm Hg

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 Hatched =
nocturnal oxygen
group

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Results

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 Circle = continuous oxygen therapy group

Square = nocturnal oxygen therapy

group

P 0.01

The 12-month mortality was 20.6% (SE = 4.0%)

in the nocturnal 02 therapy group and 11.9%
(SE = 3.2%) in the continuous 02
therapy group, whereas the 24-month
mortality was 40.8% (SE = 5.5%) and 22.4%
(SE = 4.6%)

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• relative risk of death for the nocturnal 0xygen therapy group
compared with the continuous 0 2 therapy group was 1.94 with 95%
confidence limits ranging from 1.17 to 3.24

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 Circle = oxygen
group

survival was better in the

continuous oxygen therapy
group, and this difference
was highly significant (P <
0.002).

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 Mortality
according to
baseline
characters

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In conclusion
• mortality was lower in continuous 02 therapy patients than in
nocturnal 02 therapy patients, particularly in those with more severe
derangements of lung and brain function and high levels of mood
disturbance

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• prospective, multicentric study
• Objective: The effectiveness of NOT in patients with mild-to-moderate daytime hypoxemia and exhibiting sleep-
related oxygen desaturation

N= 118, 76 randomized, 46 NOT vs 35 without NOT

Inclusion criteria::
(FEV1)/ vital capacity ratio <60%
TLC> 80% of the predicted value (rule out restrictive disease
The presence of mildto-moderate daytime hypoxaemia, with a daytime PaO2 in the range 56±69 mmHg on two
measurements separated by 4 weeks

nocturnal desaturation, which was defined, as spending 30% of the recording time (time in bed) with a
transcutaneous arterial oxygen saturation (Sa,O2) of <90%
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 RESULTS - - - - - control

Solid = NOT
• The risk of death was not significantly different (p=0.84 group
using the log rank test) in the 41 patients randomized to
nocturnal oxygen therapy (NOT) compared with the 35
patients without NOT

• risk of worsening of respiratory failure was not significantly

different (p=0.98 using the log rank test) in the two groups.

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• This study has shown that NOT given to COPD patients not justifying
conventional LTOT, but exhibiting sleep related oxygen desaturation,
did not alter the evolution of pulmonary haemodynamics

• NOT did not allow delay in the initiation of conventional LTOT

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GOLD 2023

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 Thank You

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