ISO/TS 16976-3:2011

TECHNICAL ISO/TS
SPECIFICATION 16976-3
First edition
2011-08-15
Respiratory protective devices — Human
factors —
Part 3:
Physiological responses and limitations
of oxygen and limitations of carbon
dioxide in the breathing environment
Appareils de protection respiratoire — Facteurs humains —
Partie 3: Réponses physiologiques et limitations en oxygène et en gaz
carbonique dans l'environnement respiratoire

Reference number
©
ISO 2011
©  ISO 2011
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ii © ISO 2011 – All rights reserved

Contents Page
Foreword . iv
Introduction . v
1 Scope . 1
2 Terms and definitions, symbols and abbreviated terms . 1
2.1 Terms and definitions . 1
2.2 Symbols and abbreviated terms . 4
3 Oxygen and carbon dioxide in the breathing environment: physiological responses and
limitations . 5
3.1 General . 5
3.2 Oxygen and carbon dioxide gas exchange in the human lung . 5
3.3 Oxygen and carbon dioxide transport in the blood . 6
3.4 Oxygen and carbon dioxide and the control of respiration . 8
3.5 Hyperoxia: physiological effects . 9
3.6 Hypoxia: physiological effects . 10
3.7 Hypercarbia: physiological effects . 13
3.8 Relevance to the use of respiratory protective devices (RPD) . 16
3.9 Interpretation of results . 19
3.10 Significance of results . 20
Bibliography . 21

Foreword
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In other circumstances, particularly when there is an urgent market requirement for such documents, a
technical committee may decide to publish other types of document:
— an ISO Publicly Available Specification (ISO/PAS) represents an agreement between technical experts in
an ISO working group and is accepted for publication if it is approved by more than 50 % of the members
of the parent committee casting a vote;
— an ISO Technical Specification (ISO/TS) represents an agreement between the members of a technical
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vote.
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International Standard or be withdrawn.
Attention is drawn to the possibility that some of the elements of this document may be the subject of patent
rights. ISO shall not be held responsible for identifying any or all such patent rights.
ISO/TS 16976-3 was prepared by Technical Committee ISO/TC 94, Personal safety — Protective clothing and
equipment, Subcommittee SC 15, Respiratory protective devices.
ISO/TS 16976 consists of the following parts, under the general title Respiratory protective devices — Human
factors:
 Part 1: Metabolic rates and respiratory flow rates
 Part 2: Anthropometrics
 Part 3: Physiological responses and limitations of oxygen and limitations of carbon dioxide in the
breathing environment
iv © ISO 2011 – All rights reserved

Introduction
Due to the nature of their occupations, millions of workers worldwide are required to wear respiratory
protective devices (RPD). RPD vary considerably, from filtering devices, supplied breathable gas devices, and
underwater breathing apparatus (UBA), to escape respirators used in emergency situations (self-contained
self-rescuer or SCSR). Many of these devices protect against airborne contaminants without supplying air or
other breathing gas mixtures to the user. Therefore, the user might be protected from particulates or other
airborne toxins but still be exposed to an ambient gas mixture that differs significantly from that which is
normally found at sea level. RPD that supply breathing air to the user, such as an SCBA or UBA, can
malfunction or not adequately remove carbon dioxide from the breathing space, thus exposing the user to an
altered breathing gas environment. In special cases, RPD intentionally expose the wearer to breathing gas
mixtures that significantly differ from the normal atmospheric gas mixture of approximately 79 % nitrogen and
21 % oxygen with additional trace gases. These special circumstances occur in aviation, commercial and
military diving, and in clinical settings.
Breathing gas mixtures that differ from normal atmospheric can have significant effects on most physiological
systems. Many of the physiological responses to exposure to high or low levels of either oxygen or carbon
dioxide can have a profound effect on the ability to work safely, to escape from a dangerous situation, and to
make clear judgements about the environmental dangers. In addition, alteration of the breathing gas
environment can, if severe enough, be dangerous or even fatal. Therefore, monitoring and controlling the
breathing gas, and limiting user exposure to variations in the concentration or partial pressure of oxygen and
carbon dioxide, is crucial to the safety and health of the worker.
This Technical Specification discusses the gas composition of the Earth's atmosphere; the basic physiology of
metabolism as the origin of carbon dioxide in the body, respiratory physiology and the transport of oxygen to
the cells and tissues of the body; and the subsequent transport of carbon dioxide from the tissues to the lungs
for removal from the body. Following the basic physiology of respiration, this Technical Specification
addresses the physiological responses to altered breathing environments (hyperoxia, hypoxia) and to the
effects of excess carbon dioxide in the blood (hypercarbia). Examples are given from the relevant biomedical
literature.
Finally, it deals with the impact of altered partial pressures/concentrations of oxygen and carbon dioxide on
respirator use. The content of this Technical Specification is intended to serve as the basis for advancing
research and development of RPD with the aim of minimizing the changes in the breathing environment, thus
minimizing the physiological impact of RPD use on the wearer. If this can be accomplished, the health and
safety of all workers required by their occupation to wear RPD will be enhanced.

TECHNICAL SPECIFICATION ISO/TS 16976-3:2011(E)

Respiratory protective devices — Human factors —
Part 3:
Physiological responses and limitations of oxygen and
limitations of carbon dioxide in the breathing environment
1 Scope
This Technical Specification gives:
 a description of the composition of the Earth's atmosphere;
 a description of the physiology of human respiration;
 a survey of the current biomedical literature on the effects of carbon dioxide and oxygen on human
physiology;
 examples of environmental circumstances where the partial pressure of oxygen or carbon dioxide can
vary from that found at sea level.
This Technical Specification identifies oxygen and carbon dioxide concentration limit values and the length of
time within which they would not be expected to impose physiological distress. To adequately illustrate the
effects on human physiology, this Technical Specification addresses both high altitude exposures where low
partial pressures are encountered and underwater diving, which involves conditions with high partial
pressures. The use of respirators and various work rates during which RPD can be worn are also included.
2 Terms and definitions, symbols and abbreviated terms
2.1 Terms and definitions
For the purposes of this document, the following terms and definitions apply.
2.1.1
alveoli
s. alveolus
terminal air sacs of the lungs in which respiratory gas exchange occurs between the alveolar air and the
pulmonary capillary
NOTE The alveoli are the anatomical and functional unit of the lungs.
2.1.2
ambient temperature pressure saturated
ATPS
standard condition for the expression of ventilation parameters related to expired air
NOTE Actual ambient temperature and atmospheric pressure; saturated water pressure.
2.1.3
body temperature pressure saturated
BTPS
standard condition for the expression of ventilation parameters
NOTE Body temperature (37°C), atmospheric pressure 101,3 kPa (760 mmHg) and water vapour pressure (6,27
kPa) in saturated air.
2.1.4
carbaminohaemoglobin
HbCO
haemoglobin that has bound carbon dioxide at the tissue site for transport to the lungs
2.1.5
dead space
‹anatomical› conducting regions of the pulmonary airways that do not contain alveoli and, therefore, where no
gas exchange occurs
NOTE These areas include the nose, mouth, trachea, large bronchia, and the lower branching airways. This volume
is typically 150 ml in a male of average size.
2.1.6
dead space
‹physiological› sum of all anatomical dead space as well as under-perfused (reduced blood flow) alveoli which
are not participating in gas exchange
NOTE The volume of the physiological dead space can vary with the degree of ventilation. Thus, the physiological
dead space is the fraction of the tidal volume that does not participate in gas exchange in the lungs.
2.1.7
dyspnoea
sense of air hunger, difficult or laboured breathing, or a sense of breathlessness
2.1.8
end-tidal carbon dioxide
ET CO
volume fraction of carbon dioxide in the breath at the mouth at the end of exhalation
NOTE End-tidal carbon dioxide corresponds closely to alveolar carbon dioxide.
2.1.9
haemoglobin
Hb
specific molecules contained within all red blood cells that bind oxygen or carbon dioxide under normal
physiological states and transport either oxygen or carbon dioxide to or from the tissues of the body
2.1.10
hypercarbia
hypercapnia
excess amount of carbon dioxide in the blood
2.1.11
hyperoxia
volume fraction or partial pressure of oxygen in the breathing environment greater than that which is found in
the Earth's atmosphere at sea level, which contributes to an excess of oxygen in the body
NOTE This can occur when a person is under hyperbaric conditions (i.e. diving), subjected to breathing gas mixtures
with an elevated oxygen fraction, or during certain medical procedures
2 © ISO 2011 – All rights reserved

2.1.12
hypoxia
volume fraction or partial pressure of oxygen in the breathing environment below that which is found in the
Earth's atmosphere at sea level
NOTE Anaemic hypoxia is due to a reduction of the oxygen carrying capacity of the blood as a result of a decrease in
the total haemoglobin or an alteration in the haemoglobin constituents.
2.1.13
hypocapnia
volume fraction or partial pressure of carbon dioxide in the breathing environment or in the body that is lower
than that which is found in the Earth's atmosphere at sea level
NOTE This usually occurs under hyperventilation conditions (i.e. diving) or in medical settings that contribute to a
reduction of carbon dioxide in the body
2.1.14
inotropic
affecting the force of muscle contraction
NOTE A negative inotropic effect reduces and a positive inotropic effect increases the force of muscular contraction
(e.g. both skeletal and heart muscle).
2.1.15
medulla oblongata, pons
areas of the brain where the respiratory control centre is located
2.1.16
oxyhaemoglobin
HbO
haemoglobin that has bound oxygen from the lungs for transport to the body tissues
2.1.17
partial pressure
pressure exerted by each of the components of a gas mixture to form a total pressure
EXAMPLE Air is a mixture of oxygen, nitrogen, carbon dioxide, inert gases (argon, neon), and water vapour. The
volume fraction of oxygen in air is about 20,9 %. At sea level, total atmospheric pressure is 101,3 kPa (760 mmHg). Water
vapour pressure is 6,26 kPa (47 mmHg) (fully saturated in the lungs at a body temperature of approximately 37 °C). To
find partial pressure of oxygen, subtract vapour pressure from total atmospheric pressure and then multiply the oxygen
volume fraction by the dry atmospheric pressure. Thus, 101,3  6,3 = 95,1 kPa (760 mmHg  47 mmHg = 713 mmHg);
0,21  95,1 kPa = 19,9 kPa (= 149 mmHg). If the ambient pressure increases (as in diving), the partial pressure of each
component gas increases. Thus, at 2 atm absolute, the partial pressure of oxygen in dry gas is 101,3  2 = 202,6 kPa
(760 mmHg  2 = 1 520 mmHg); 0,21  202,6 = 42,6 kPa (0,21  1520 mmHg = 319 mmHg) oxygen.
NOTE 1 Partial pressure is dependent on the volume fraction of the component gas.
NOTE 2 The partial pressure of a gas can increase or decrease while its relative volume fraction remains the same.
Partial pressure drives the diffusion of gas across cell membranes and is, therefore, more important than relative volume
fraction of the gas.
2.1.18
respiratory quotient
R
Q
ratio of volume of carbon dioxide exhaled to the volume of oxygen consumed as follows
R VVCO O
Q
where
VCO is the volume of carbon dioxide exhaled;
VO is the volume of oxygen consumed
NOTE R gives an estimate of the content of substrate utilization during steady-state respiration and metabolism. At
Q
rest, R = 0,82 reflecting a substrate utilization of a combination of carbohydrates and fats as the primary energy source.
Q
2.1.19
respiratory system
tubular and cavernous organs (mouth, trachea, bronchi, lungs, alveoli, etc.) and structures which bring about
pulmonary ventilation and gas exchange between ambient air and blood
2.1.20
standard temperature pressure dry
STPD
standard conditions for expression of oxygen consumption
NOTE Standard temperature (0 °C) and pressure (101,3 kPa, 760 mmHg), dry air (0 % relative humidity).
2.1.21
ventilation (general)
process of exchange of air between the lungs and the ambient environment
2.2 Symbols and abbreviated terms
APR air purifying respirator
BSA body surface area, expressed in m
PAPR powered air purifying respirator
SAR supplied air respirator
SCBA self-contained breathing apparatus
UBA underwater breathing apparatus
PCO partial pressure of carbon dioxide
P CO alveolar partial pressure of carbon dioxide
A 2
P CO arterial partial pressure of carbon dioxide
a 2
P CO venous partial pressure of carbon dioxide
v 2
PO partial pressure of oxygen
P O alveolar partial pressure of oxygen
A 2
P O arterial partial pressure of oxygen
a 2
O partial pressure of inspired oxygen
P
i 2
P O venous partial pressure of oxygen
v 2
4 © ISO 2011 – All rights reserved

V minute ventilation (expired)
E
total volume expired from the lungs in 1 min, in l/min (BTPS)
V minute ventilation (inspired)
I
total volume of air inspired into the lungs in 1 min, in l/min (BTPS)
VO oxygen consumption
volume of oxygen consumed by the human tissues, in l/min, derived from the difference
between the minute volume of inhaled oxygen and the minute volume of exhaled oxygen.
VCO carbon dioxide elimination rate
volume of carbon dioxide produced per minute, derived from the product of minute
ventilation and the difference between the fractional concentrations of exhaled and
inhaled carbon dioxide
3 Oxygen and carbon dioxide in the breathing environment: physiological
responses and limitations
3.1 General
The Earth's atmosphere is composed primarily of nitrogen and oxygen along with some trace gases.
Atmospheric carbon dioxide occurs in very low concentrations (approximately 0,03 %). Humans require
oxygen as a primary element in the production of energy during aerobic cellular metabolism. Low atmospheric
oxygen concentrations or partial pressures (such as occur at high altitude) can limit production of metabolic
energy, leading to a compromise in physiological function. On the other hand, low concentrations of carbon
dioxide in the breathing atmosphere do not appear to have any physiological consequence. Carbon dioxide is
produced as a by-product of cellular metabolism and it is this source of carbon dioxide, not the normal
atmospheric concentration, which carries a physiological consequence. However, increased environmental
levels of carbon dioxide, as in the breathing space of respirators or in confined areas, can also have a
profound effect on the respiratory system.
High concentrations of either oxygen or carbon dioxide can have dramatic physiological consequences.
Hyperoxia, especially under ambient pressures greater than one atmosphere (atm), such as occur in diving,
can be toxic and even fatal to humans. High concentrations of carbon dioxide can also have a profound effect
on respiration and metabolism. This overview will address several issues:
 Oxygen and carbon dioxide in normal human physiology;
 Effects of hypoxia and hyperoxia on physiology;
 Effects of hypercarbia on physiology;
 Relevance to respiratory protective devices.
3.2 Oxygen and carbon dioxide gas exchange in the human lung
Normal minute ventilation takes place as a result of neural activity in the respiratory centres in areas of the
brainstem known as the medulla oblongata and the pons. The movement of air in and out of the lungs
facilitates the gas exchange necessary for normal metabolic function.
Gas exchange does not occur in all regions of the pulmonary system. Anatomical dead space (regions where
gas diffusion to the blood does not occur) comprises about 150 ml volume within the pulmonary system.
However, the physiological dead space can add a much larger volume depending on activity level. Inhaled
gas passes through the regions of dead space to the pulmonary alveoli. Gas exchange occurs in the alveoli,
which are in contact with blood capillaries.
The exchange of oxygen into the blood stream and carbon dioxide out of the blood stream into the alveoli is
driven by simple diffusion down a partial pressure gradient. The partial pressure of oxygen in the alveoli
(P O ) is approximately 13,3 kPa (100 mmHg) whereas the partial pressure of oxygen in the venous blood
A 2
(P O is approximately 5,3 kPa (40 mmHg). Therefore, oxygen will move from the area of higher
v 2)
concentration of oxygen in the alveoli to the area of lower concentration of oxygen in the venous blood.
Oxygen will also be transported into the red blood cells along a similar partial pressure gradient to be bound to
haemoglobin. Conversely, the partial pressure of carbon dioxide in the venous blood (P CO ) is roughly
v 2
6,1 kPa (46 mmHg) and is only 5,3 kPa (40 mmHg) in the alveoli. Therefore, carbon dioxide will move from
the venous blood to the alveoli to be exhaled to the atmosphere.
After this gas exchange has taken place, arterial blood contains a P O of 13,3 kPa (100 mmHg) and a P CO
a 2 a 2
of 5,3 kPa (40 mmHg). The arterial blood arriving at the cells will release oxygen and take up carbon dioxide
based on a similar process of moving along a partial pressure gradient. After oxygen delivery to the cells has
taken place, the red blood cells have a PO of 5,3 kPa (40 mmHg) and a PCO of 6,1 kPa (46 mmHg). Upon
2 2
return to the lungs for another round of gas exchange, each gas again moves along its partial pressure
gradient to repeat the process. Proper oxygen delivery to the cells and carbon dioxide removal from the body
will occur as long as a match exists between ventilation of the lungs and blood perfusion driven by a healthy
circulatory system.
3.3 Oxygen and carbon dioxide transport in the blood
Oxygen has a very low solubility in the blood. Therefore, oxygen is transported to the vital organs, working
muscles, and brain by a special transport mechanism in the blood. When oxygen from the atmosphere
diffuses from the alveoli to the circulation, about 25 % of the oxygen present in the alveoli is rapidly
transported into the red blood cells and binds to haemoglobin to form oxyhaemoglobin. Oxyhaemoglobin in
the red blood cells is carried through the arterial circulation to the capillaries where the oxygen diffuses from
the red blood cells to the cells of the target tissues. The oxygen is then utilized in the aerobic metabolic
processes in the cell mitochondria.
Several factors affect the affinity of oxygen for haemoglobin. For any given ambient PO , an increase in body
temperature, blood lactic acid (↓ pH), increased P CO , or an increase in 2,3-diphosphoglycerate (DPG, a
a 2
[4]
product of anaerobic metabolism in red blood cells), can decrease the affinity of oxygen for haemoglobin ).
This phenomenon is known as the Bohr Shift, which makes oxygen delivery easier under acidotic conditions.
6 © ISO 2011 – All rights reserved

Key
X oxygen partial pressure (torr)
Y haemoglobin saturation (%)
1 decreased P50 (P50 = one half saturation pressure)(increased affinity)
2 increased P50 (decreased affinity)
T temperature
PCO partial pressure of carbon dioxide
2,3-DPG 2,3-diphosphoglycerate
pH measure of the acidity or basicity of a solution
NOTE 1 1 torr = 133 Pa.
NOTE 2 See Reference [4].
Figure 1 — Shift of the oxyhaemoglobin dissociation curve by pH, carbon dioxide temperature, and
2,3-diphosphoglycerate (2,3-DPG)
By contrast, carbon dioxide is about 20 to 25 times more soluble in blood than oxygen. Carbon dioxide
produced as a by-product of metabolically active tissues diffuses from the cells of the tissue to the red blood
cells in the circulation along a concentration gradient. Some of the carbon dioxide (approximately 5 to 10 %) is
carried to the lungs in solution in the blood plasma. A portion of the carbon dioxide combines with water to
form carbonic acid according to the equation:
CO + H O  H CO (1)
2 2 2 3
This reaction occurs slowly in the plasma and most of the carbon dioxide remains in solution in the plasma.
However, a small amount of carbonic acid in the plasma dissociates to bicarbonate following the equation:
+
H CO  H + HCO (2)
2 3 3
Whereas the reaction in Equation (2) occurs in very small amounts in the plasma, it occurs to a very large
extent in red blood cells. Red blood cells contain the enzyme carbonic anhydrase (CA), which catalyzes the
reversible reaction between carbon dioxide and H O extremely rapidly (approximately 10 reactions per
[3]
second) in the following manner:
+
CO + H O H CO  H + HCO (3)
2 2 2 3 3
Approximately 70 % of the carbon dioxide is transported to the lungs in the form of bicarbonate. In addition,
carbon dioxide combines with haemoglobin to form carbaminohaemoglobin. The affinity of haemoglobin for
carbon dioxide increases as oxygen dissociates from haemoglobin during delivery of oxygen to the tissues
[5]
(see also the Haldane effect ). Approximately 15 % of the carbon dioxide in the blood is transported to the
lungs in the form of carbaminohaemoglobin.
3.4 Oxygen and carbon dioxide and the control of respiration
Human life is strongly dependent on an adequate supply of oxygen to support the metabolic processes that
produce energy. As a result, the ability to sense changes in ambient PO has evolved. In addition, although
atmospheric carbon dioxide concentrations are almost negligible, carbon dioxide is produced as a product of
metabolism and has a profound effect on the respiratory system. Thus, mechanisms for sensing PCO in the
blood have also evolved. Indeed, changes in PCO are more powerful stimulators of respiration than changes
in ambient PO . A detailed discussion of the physiological mechanisms involved in sensing changes in oxygen
and carbon dioxide in the atmosphere or the blood is beyond the scope of this Technical Specification.
However, a brief overview of the process is given below.
Chemical sensors (chemoreceptors) are present in both the central nervous system (medulla oblongata in the
brain stem) and the peripheral nervous system integrated with the vascular system (i.e. carotid bodies in the
carotid artery in the neck and chemoreceptors in the aorta) that are capable of sensing changes in P O
2,
a
P CO and pH in the arterial blood. When these areas sense changes in P O and P CO , neural signals are
2 2 2
a a a
integrated into a respiratory response that usually results in a normalization of the P O and/or P CO . Under
2 2
a a
conditions of hypoxia, the decreased P O is sensed primarily by peripheral chemoreceptors in the carotid
a
bodies and the aortic bodies. The respiratory response is an increase in ventilation in order to increase the
oxygen uptake to maintain metabolic energy production. However, if the carotid and aortic bodies are
removed or damaged, a decrease in P O can result in a decrease in ventilation because a reduction in brain
a
P O can act directly to depress respiratory cells in the brain. Low P O also increases brain blood flow,
2 2
a a
+
thereby lowering P CO and [H ] and decreasing ventilation. Figures 2 and 3 illustrate the basic relationships
a
involved in the control of respiration.

Figure 2 — Basic relationships between sensor inputs, processing and outputs from the respiratory
control mechanisms in the central nervous system, and the effectors (respiratory muscles) that
actuate the respiratory process
8 © ISO 2011 – All rights reserved

a) carbon dioxide response
b) pH response
Key
Key
X1 arterial PCO [mm Hg]
2 X2 arterial pH
Y total ventilation, in l/min
Y total ventilation, in l/min
Figure 3 — Ventilatory responses to changes in arterial carbon dioxide partial pressure
and arterial pH for a person at rest
Inhalation of supra-atmospheric concentrations of carbon dioxide also increases pulmonary ventilation.
However, the increased P CO stimulates ventilation largely in central chemoreceptors located in the medulla
a
oblongata and pons area of the brainstem and, to a much lesser extent, in the peripheral carotid bodies. The
increase in ventilation with increased P CO is exaggerated in the presence of hypoxia. From a functional
a
standpoint, ventilation is stimulated either in the presence of a decreased P O (hypoxia) or an increased
a
P CO (hypercapnia). This results in a ventilatory response that ensures appropriate oxygenation of the blood
a
and excretion of carbon dioxide as a product of metabolism.
3.5 Hyperoxia: physiological effects
One does not normally encounter an elevated oxygen level (hyperoxia) in the atmosphere. Hyperoxia is
normally encountered in a hospital setting (e.g. when breathing 70 % oxygen) or during the use of special gas
mixtures for underwater diving. Hyperoxia is defined as an excess of oxygen in the body due to exposure to
an oxygen concentration above 20,9 % in the breathing environment or to a normoxic gas concentration under
hyperbaric conditions. Breathing mild hyperoxic gas mixtures (i.e. with ambient PO of approximately 1,3 kPa
or 10 to 300 mmHg higher than normal) for a limited period of time (e.g. a working shift) is usually not harmful
However, breathing hyperoxic gas mixtures under hyperbaric conditions above 1 atm can be harmful.
Oxygen toxicity can occur when the partial pressure of inspired oxygen reaches a level where neurological or
pulmonary changes become pathological. At sea level, breathing a hyperoxic gas mixture over many hours
can result in pulmonary changes through a direct effect of oxidative stress on alveolar cells. Under greater
pressure than 1 atm (101,3 kPa or 760 mmHg), such as occurs during diving and caisson work, hyperoxic
exposure can have effects on the nervous system as manifested by seizures. Seizures will not occur while
breathing 100 % oxygen at sea level (1 atm). However, seizures are a potential risk while breathing 100 %
oxygen at 2 atm or more (≥ 202,6 kPa or 1520 mmHg). Much of the research on hyperoxia has been
performed on the professional underwater diving community (commercial and military). Professional divers are
often required to breathe gas mixtures other than air during the dive. Greater than normal oxygen can be
administered to effect “nitrogen washout”, thereby limiting the potential for decompression sickness and inert
gas narcosis. However, breathing hyperoxic gas mixtures carries the risk of oxygen toxicity since the partial
pressure of oxygen increases with depth. The potentially heavy exercise performed by commercial and
[11].
military divers and an increase in hypercarbia can accelerate the effects of oxygen toxicity
3.6 Hypoxia: physiological effects
Much of the physiological research on hypoxia has been performed during high altitude studies (mountain
climbing or aviation). In extreme hypoxia, there is not enough oxygen to maintain basal metabolism and the
person dies.
Before the first successful ascent to the summit of Mt. Everest without supplemental oxygen in 1978, research
suggested that the ambient PO at that altitude (8 848 m or 29 028 ft) was lower than that needed to sustain
basal metabolic needs. Therefore, ascent to the summit could not be performed without supplemental
[36]
oxygen . Calculations indicated that the maximal oxygen uptake was equal to that required for basal
metabolism. Therefore, there was not enough “extra” oxygen available to perform physical work. However, the
air density (and therefore the atmospheric PO ) at the summit of Mt. Everest varies seasonally. Refined
calculations based on data collected indicated that, during the months of May to October, the atmospheric
PO was enough to perform the physical work required to reach the summit, whereas during the winter
months the ambient PO was not enough. The atmospheric PO at the summit of Mt. Everest is 6,6 kPa
2 2
(49,3 mmHg) and is approximately the same as breathing a gas mixture containing only 5 to 6 % (ambient
PO of 5,1 to 6,0 kPa or 38 to 45 mmHg) oxygen at sea level.
NOTE Atmospheric PO at sea level is 21,2 kPa or 159 mmHg.
Exposure to hypoxia results in several significant physiological adjustments. The most noticeable change
[9]
occurs with pulmonary ventilation. Acute hypoxia results in an increased ventilatory response and if the
hypoxia is sustained, the peripheral chemoreceptors become hypersensitized and the ventilatory response to
hypoxia and hypercapnia increases. The increased ventilatory response serves to increase the oxygen
[4]
content of the blood and eliminate the increased PCO in the lungs and is accompanied by a concomitant
[11]
increase in cardiac output as a result of central nervous system stimulation . At the summit of Mt. Everest,
alveolar PO is 4,7 kPa (35 mmHg) despite the low atmospheric PO (see Figure 4). This level of alveolar PO
2 2 2
is maintained primarily by extreme hyperventilation, which results in a decrease in PCO leading to
[35]
respiratory alkalosis . However, the ventilatory suppression normally associated with respiratory alkalosis is
overcome by the hypoxic stimulation of ventilation. Whereas measurable adaptive changes in the
[40]
cerebrovascular response to mild hypoxia occur over days to weeks , when the ambient PO falls below a
critical value, there is not enough oxygen being transported to the vital organs and the central nervous system
to sustain life and health. With atmospheric oxygen concentrations below about 4 to 5 % (ambient PO is
3,9 to 5,3 kPa or 30 to 40 mmHg), a loss of consciousness and death will ensue within minutes. The victim is
[11]
often unaware of the progression to loss of consciousness .
Much of our knowledge of the consequences of quick and complete removal of oxygen comes from research
on rapid decompression of pilot cabins and the re-supply of emergency gas. Of particular relevance is
effective performance time (EPT), the duration of time that one is able to conduct useful flying duties, e.g.
taking appropriate corrective action, in this situation. At 10 000 m where P O is approximately 40 mmHg, i.e.
i
lower than normal P O , EPT will be less than 1 min. This is relevant to users of RPD who become
v 2
[10]
disconnected from their breathable gas supply .
NOTE EPT is also known as “time of useful consciousness”.
10 © ISO 2011 – All rights reserved

Key
X barometric pressure (mmHg)
Y maximum oxygen uptake [(ml/min)/kg]
1 summit of Mt. Everest
2 basal oxygen uptake
NOTE 1 The maximal oxygen uptake at the summit was predicted to be the same as the basal oxygen uptake,
indicating that no work would be possible. Also note that VO near the summit is exquisitely sensitive to barometric
2 max
pressure.
NOTE 2 See Reference [36].
Figure 4 — Maximal oxygen uptake in acclimatized subjects plotted against barometric pressure
using the data from the Silver Hut expedition
Humans can adapt to chronic hypoxia. Some 40 million people live and work at altitudes between 3 048 m
and 5 486 m (10 000 to 18 000 ft). There are some immediate adaptive responses to exposure to hypoxia,
e.g. an increase in ventilation. Nevertheless, full adaptation to chronic hypoxia can take months, or even
years. Native populations in the Peruvian Andes and the Himalayas reside at altitudes as high as 5 486 m
[22]
(18 000 ft) . The barometric pressure at this altitude is approximately 50,6 kPa (380 mmHg), about half of
that measured at sea level. At this altitude, atmospheric PO is roughly 10,5 kPa (79 mmHg). The
physiological adaptations to this low atmospheric PO from living at high altitude include increases in the
number of pulmonary alveoli, increased blood concentration of haemoglobin and myoglobin (Mb) in the
[11]
muscle, increased pulmonary ventilation, and a decreased ventilatory response to hypoxia . In spite of an
atmospheric PO of 10,5 kPa (79 mmHg), and an arterial PO of 5,1 kPa (38 mmHg), the blood haemoglobin
2 2
is still 73 % saturated. Because the oxyhaemoglobin dissociation curve is sigmoidal, even a small decrease in
atmospheric PO at this altitude can result in a rapid oxygen desaturation of haemoglobin, down to about
50 %.
Although the vast majority of high altitude acclimatized individuals show little or no adverse effects under
these circumstances, a small minority of those acclimatized individuals develop Monge's disease (chronic
mountain sickness) over time, characterized by a poor ventilatory response to hypoxia, low P O and high
a 2
[20]
P CO, high hematocrit, pulmonary hypertension, right heart failure, dyspnoea, and lethargy .
a 2
Unacclimatized individuals rapidly exposed to high altitude would eventually be incapacitated from the
potentially life-threatening health effects of hypoxia.
There is also evidence that hypoxia can affect the thermoregulatory response to cold stressors. Exposure to
intermittent hypobaric hypoxia sufficient to cause acclimation resulted in a blunted thermoregulatory response
to a standard cold air exposure test at sea level. Much of the response was through peripheral
vasoconstriction that might have been driven by hypocapnia due to the increase in the ventilatory response to
[18]
hypoxia .
[1]
In studies conducted by Angerer and Norwak , designed to determine if human subjects could tolerate short-
term intermittent exposure to hypoxia, it was found that humans could tolerate daily occupational exposure to
an atmosphere composed of 13 to 15 % (atmospheric PO of 13,2 to 15,2 kPa or 99 to 114 mmHg) oxygen
(balance nitrogen) for periods of approximately 8 h without significant physiological or health consequences.
However, drops in P O to values of less than 50 mmHg have been recorded at an oxygen concentration of
a
14,8 % (approximately equal to PO at an altitude of 3 400 m). The results of this study have been used to
support the suggestion that healthy workers could function in a hypoxic atmosphere designed for fire
suppression with no significant ill-effects. However, the authors cautioned that workers with cardiovascular or
pulmonary disease might not tolerate a hypoxic work environment. A summary of the effects of hypoxia and
hyperoxia appear in Table 1 below.
Table 1 — Potential effects and limitations on human tolerance imposed by exposure to decreasing
concentrations of oxygen in the inspired air while at rest and at an extremely high workrate (see
References [1] and [14])
At rest Extremely high workrate
Average
Average
ambient PO
level Exposure Exposure
*(i.e. altitude) in
Potential effects and/or Potential effects and/or
of oxygen limit limit
the breathing
limitations limitations
in the air
space
(time) (time)
(%)
(mmHg)
Mild respiratory Slight increase in
depression, followed by Many
exercise performance,
100 760 hours
stimulation, pulmonary hours pulmonary injury due to
injury
toxic effects of oxygen
1520 Seizure, loss of Seizure, loss of
(2 atm) consciousness, consciousness,
100 30 min 30 min
e.g. underwater depression of the cardiopulmonary
diving cardiopulmonary system depression, death
No restrictions within the No restrictions within the
70 exposure limit, well days exposure limit, well days
(1 atm)
tolerated tolerated
(1 atm)
Normal – no symptoms in Normal – no symptoms
20,9 e.g. normal indefinite indefinite
a healthy person in a healthy person
atmospheric
pressure
Large increase in
79 Collapse,
20,9 ventilation, severe
30 min 30 min
(5 486 m) unconsciousness
limitations on activity
2 min,
Large increase in
49 Collapse / unable to
20,9 ventilation, severe 30 min
(8 848 m) unconsciousness
perform
limitations on activity
work
148 Easily tolerated, no Easily tolerated,
19,5 indefinite indefinite
(1 atm) symptoms no symptoms
Decrease in exercise
Tolerated in a healthy
tolerance,
99 to 114 individual,
13 to 15
hours cardiopulmonary 5 min
(1 atm) cardiopulmonary patients
patients might show
might show symptoms
symptoms
12 © ISO 2011 – All rights reserved

3.7 Hypercarbia: physiological effects
The physiological effect of increasing the PCO in the breathing atmosphere has been studied extensively for
decades. Hypercarbia actually serves a protective purpose due to its stimulatory effect on ventilation. As
previously noted, alveolar and arterial PO can be maintained by hyperventilation by direct stimulation of the
chemoreceptors in the carotid bodies as well as stimulation of the respiratory centres in the brain and
[4]
brainstem .
Endogenously produced carbon dioxide is known to induce pronounced vasodilation in heavy working
muscles. Systemic hypercarbia is also a potent stimulus of peripheral vasculature. In cerebral blood vessels
hypercarbia also induces vasodilation due to the critical importance of maintaining full oxygenation to the
[38]
brain . This effect of carbon dioxide seems, therefore, to increase both the oxygen uptake by stimulating
ventilation, but also oxygen delivery through increased cerebral blood flow (probably due to vasodilation of
cerebral blood vessels). In fact, when atmospheric carbon dioxide was chemically scrubbed while human
subjects were exposed to simulated high altitude in a hypobaric chamber, both regional cerebral oxygen and
[16]
peripheral oxygen levels decreased . Indeed, breathing gas mixtures containing 3 % carbon dioxide and
35 % oxygen have been used at altitude to increase both pulmonary ventilation and cerebral oxygen delivery

by increasing cerebral vasodilation and peripheral oxygen delivery to skeletal muscle, thereby increasing
[17]
human performance .
In spite of the use of supplemental carbon dioxide in both clinical and high altitude settings, there are some
drawbacks to breathing elevated concentrations of carbon dioxide. Stereoacuity and perception of coherent
[31], [37]
motion are reduced at atmospheric concentrations of only 2,5 % carbon dioxide . Breathing carbon
dioxide concentrations ranging from 2,5 to 8 % (balance oxygen) has been shown to reduce retinal blood
[21] [14]
flow , and increase the rate of body core temperature heat loss during snow burial . Nevertheless, there
appear to be no pronounced dis
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