-Falla respiratoria -Hipoxemia -Hipercapnia -Falla de bomba -Falla mecánica ventilatoria

1. REVIEW
Pathophysiology of respiratory failure
F.J. Belda*, M. Soro, C. Ferrando
Anesthesia and Critical Care Department, Hospital Clinico Universitario, University of Valencia, 46010 Valencia, Spain
Keywords:
Respiratory failure
Hypoxaemia
Hypercapnia
Respiratory pump dysfunction
Respiratory mechanical failure
s u m m a r y
Respiratory failure (RF) is defined as a disturbance in gas exchange in the respiratory system which
produces in arterial BGA a PaO2 < 60 mmHg (hypoxaemia) and/or a PaCO2 > 50 mmHg (hypercapnia).
However hypoxaemic normocapnic (or hypocapnic) RF due to the failure in gas exchange is very common
and should be separated from mechanical RF. Respiratory failure (hypercapnic) with or without hypo-
xaemia related to a failure in the respiratory pump. This review is focused on the pathophysiology of the
mechanical RF less well known amongst anaesthesiologists.
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
Respiratory failure (RF) is defined as an inadequate oxygen de-
livery and carbon dioxide elimination at tissue level.1
At pulmonary
level this represents the inability of the respiratory system to cope
with the metabolic needs of the organism, oxygenate venous blood
and remove CO2. However, due to the lack of direct measurements
for these functions, clinicians use the values of arterial pressure for
oxygen (PaO2) and carbon dioxide (PaCO2) obtained from arterial
blood gas analysis (BGA) which evaluate the ability of gas exchange
at the pulmonary level. This way, respiratory failure is defined as a
disturbance in gas exchange in the respiratory system which pro-
duces in arterial BGA a PaO2 < 60 mmHg (hypoxaemia) and/or a
PaCO2 > 50 mmHg (hypercapnoea).2e5
Not every RF presents hypoxaemia in the beginning. The res-
piratory system can be divided in two parts: the organ producing
gas exchange (lung) and the respiratory pump (thoracic cage, res-
piratory muscles and the system for respiratory control).7
This di-
vision was used by Rochester to differentiate the hypoxaemic
normocapnoeic (or hypocapnoeic) respiratory failure due to the
failure in gas exchange and the mechanical respiratory failure
(hypercapnoeic) with or without hypoxaemia related to a failure in
the respiratory pump. On the other hand, RF can be acute or chronic
which have different pathophysiological features. In this paper only
acute RF will be addressed which centres on mechanical RF and is
less well known amongst anaesthetists.
2. Hypoxaemic respiratory failure
Hypoxaemic respiratory failure is an inadequate pulmonary gas
exchange due to the inability to oxygenate venous blood. The main
feature is hypoxaemia with PaO2 values below 60 mmHg breathing
room air which corresponds to an SpO2 below 90%.3e5,7,8
Table 1
shows the more important and frequent pathophysiological
mechanisms producing this type of RF which are summarized
below.9
2.1. Ventilation/perfusion mismatch
This is the most common cause of hypoxaemia. It is due to the
blood circulating through non-ventilated alveoli or through alveoli
having a reduced volume; this blood is either not or only partially
oxygenated. It is called alveolar shunt (V/Q ¼ 0 or <1). This type of
RF is refractory to oxygen because it does not reach the alveoli or its
concentration is reduced there.10,11
Clinical causes of shunt effect are diverse, mainly those in which
alveoli are flooded by oedema fluid (lung oedema) which can be
due to cardiac origin (increase in hydrostatic pulmonary blood
pressure) or due to an increase in pulmonary capillary permeability
like in pneumonia or ARDS. Other common causes of shunt effect
are atelectasis, emphysema and partially in pulmonary embolism in
which blood is diverted from the occluded vessels to the rest of the
lung which will become this way hyperperfused (V/Q < 1).13e15
2.2. Severe haemodynamic dysfunction
Several causes are responsible for hypoxaemia of haemody-
namic origin with cardiac failure seen as the most important.
Even though the final consequence is hypoxaemia we should
* Corresponding author.
E-mail address: fjbelda@uv.es (F.J. Belda).
Contents lists available at SciVerse ScienceDirect
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Trends in Anaesthesia and Critical Care 3 (2013) 265e269

2. differentiate between right or left ventricular failure because the
pathophysiological mechanisms for hypoxaemia are different. In
right ventricular failure the cause is due to pulmonary hyperten-
sion whilst in the left ventricular failure hypoxaemia can be related
to a desaturation of mixed venous blood or to the shunt effect due
to pulmonary oedema.5,14,15
Other common causes of hypoxaemia
of haemodynamic origin are hypovolaemia and anaemia.14,15
2.3. Alveolar hypoventilation
Minute volume (VE) is the amount of exhaled gas per minute
and is responsible for maintaining PaCO2 in the normal range (35e
45 mmHg). It has two components: respiratory frequency (RF) and
tidal volume (VT) and in turn, VT has another two components:
dead space volume (VD) and the alveolar volume (VA) being the
last the efficient component for CO2 elimination.9
Remember that:
PaCO2 ¼ V0
CO2=V0
A
Being V0CO2 the CO2 production by the organism and V0A the
alveolar ventilation. In this sense all causes producing alveolar
hypoventilation carried CO2 retention (and hypercapnoea). The
most frequent are VT and/or RF reduction. Nevertheless, as can be
seen in Table 2, hypercapnoea is also related to an increase in CO2
production (without a compensatory increase of V0A) and in cases of
increase in VD/VT (see Table 3).
Hypercapnoea inevitably produces a drop in the alveolar oxygen
pressure (PaO2). Indeed, following the alveolar gas equation4,5,9
:
PaO2¼ PiO2 À ½PaCO2=RŠ
Being PiO2 oxygen inspired pressure (P barometric times FiO2;
150 at FiO2 0.21) and R respiratory quotient (relationship between
CO2 production and O2 consumption: 250/300 ¼ 0.8).
This way, following the equation we can see that an increase in
PaCO2 will reduce PaO2, although the resulting hypoxaemia is not
relevant. For example, hypoventilation with a PaCO2 of 65 mmHg
will produce:
PaO2 ¼ 150 À ½65=0:8Š ¼ 150 À 80 ¼ 70 mmHgðSpO2 > 90%Þ
If 30% oxygen is administered PaO2 will turn in 130 mmHg and
PaO2 will be above 100 mmHg. Even in cases of severe hyper-
capnoea, let’s say a PCO2 of 80 mmHg with 30% oxygen, the PaO2
will be 110 mmHg and undetectable by pulse oximetry
(SpO2 > 98%).
Following all the above we could say that hypercapnoea does
not produce significant hypoxaemia and that it can be reversed by
increasing FiO2 to 30%.
2.4. Hypoxaemia due to low FIO2
This hypoxaemia is not very important due to its infrequency.
This may only happen at high altitude, when smoke is inhaled or
during fire where combustion produces oxygen consumption in
breathing air. Obviously, looking at the alveolar gas equation, a drop
in PiO2 will produce a parallel drop in PaO2.9
2.5. Diffusion disorders
Another infrequent cause of hypoxaemia is the disorder of the
ability of the lung to transport oxygen into and out of the blood. It is
produced at the alveolar-capillary membrane level. Gas diffuses
through this membrane due to a pressure gradient between the
venous blood and alveolar gas and a thickening of the membrane
could slow down oxygen uptake and CO2 elimination. However, red
blood cells are fully oxygenated after one third of its course in the
alveolar capillary bed; this way despite a slow uptake, there is a
high reserve in the transit time to reach the equilibrium. CO2
elimination is even less affected because its diffusion capacity is 20
times higher than the O2.5,12
Membrane thickening and diffusion disorders are produced in
pulmonary fibrosis, asbestosis, pneumoconiosis, diffuse lung lymph
granulomatosis and other more uncommon diseases.9,12
These
diseases do not produce hypoxaemia in resting conditions but
during exercise because tachycardia produces a reduction in the
transit time of the venous blood through the alveolar-capillary
membrane. However there are many other causes more frequent
in anaesthesia that may produce hypoxaemia, for example the loss
of alveolar-capillary surface due to pulmonary resections. Hypo-
xaemia in pneumonectomized patients may appear after subse-
quent interventions if patients become tachycardic.
3. Mechanical respiratory failure
Mechanical respiratory failure is characterized by a disorder of
effective alveolar ventilation producing hypercapnoea with or
without concomitant hypoxaemia. Causes of this disorder are many
but of particular importance are pathophysiological mechanisms
which cause alteration of the respiratory pump. The causes of the
pump failure are organized below following the several compo-
nents of the respiratory pump.4,7,9,17
3.1. Depression of the respiratory centre
Depression of the respiratory centre located in the medulla
oblongata is a frequent cause of mechanical RF in anaesthesia
because most hypnotic and analgesic drugs produce depression of
the respiratory centre. In these cases respiratory dive is abolished
Table 1
Causes of hypoxaemic respiratory failure.
1. Ventilation/perfusion mismatch: shunt effect
2. Severe haemodynamic dysfunction
3. Alveolar hypoventilation
4. Low FiO2
5. Diffusion impairment
Table 2
Causes of increase in CO2 production.4,5
1. Burns
2. Sepsis
3. Agitation
4. Exercise
5. Hyperthermia
6. Malignant hyperthermia
7. Hypercaloric intake or carbohydrate rich diet
8. Shivering, seizures, tremor
Table 3
Causes of increase in VD/VT.16
1. Obstructive pulmonary diseases (emphysema.)
2. Interstitial pulmonary diseases
3. Acute reduction in cardiac output
4. Pulmonary embolism
5. Acute pulmonary hypertension
6. Positive pressure ventilation, especially with PEEP
F.J. Belda et al. / Trends in Anaesthesia and Critical Care 3 (2013) 265e269266

3. or obtunded producing a reduction in RF, VT or both generating
hypoventilation and hypercapnoea. Other causes that may produce
hypoventilation due to respiratory centre depression appear in
Table 4.
3.2. Muscle pump dysfunction
Muscle pump dysfunction may be due to an increase in the
respiratory muscle workload or because of a reduction of contrac-
tile ability in these muscles. Increase in workload can be due to an
increase in minute ventilation or an increase in the resistive or
elastic load. The following will deal with the diverse pathophysi-
ological mechanisms which result in failure of the muscular pump.
3.2.1. Increase in workload
As we have mentioned above, an increase in the workload may
arise from an increase in minute ventilation or an increase in the
resistive or elastic load.
1. Increase in minute ventilation (VE)
An increase in minute ventilation is considered to produce
mechanical respiratory failure followed by muscle fatigue and
consequently hypoventilation and hypercapnoea.
An increase in minute ventilation is frequently due to increased
CO2 production mostly in cases of hyperthermia (infectious fever,
subarachnoid haemorrhage.). Another cause of increased VE is the
increase in dead space (VD) which is accompanied with a drop in
alveolar ventilation. This way, in order to maintain the same CO2
elimination, the patient must increase VE (in general, increasing
RF). Other clinical situations producing a rise in VD are shown in
Table 5.
Finally, there are some situations like fear, anxiety or pain that
without lung origin may produce tachypnoea and an increase in
ventilatory demands with an increase in minute ventilation and
work of breathing although these normally entail hypocapnoea
instead of hypercapnoea.
2. Increase of the elastic resistance
The respiratory system is formed by an elastic component (lung
and chest wall) and a resistive component (airway), both of them
with a resistance to ventilation.19
The elastic resistance is referred
to as the resistance that the respiratory system opposes to an in-
crease in volume over the functional residual capacity (FRC). This
elastic resistance is represented by the elastance (Esr) or by the
compliance (Csr), the inverse of the Esr. Csr ¼ dV/dP.20
So, it can be said that the elastic resistance for the muscle pump
is increased when Csr is decreased. This means more pressure
(increased DP) to maintain the same VT when compliance is
reduced (Csr). The increase in pressure is traduced to an increase in
the work of breathing (WOB ¼ DP Â VT). The causes that produce an
increase in the elastic resistance, that is to say, a reduction of the Csr
are many and frequent as shown in Table 6.
3. Increases of the resistive resistance
The resistive component is the frictional resistance to gas flow
(R) produced by the airway in the respiratory system, quantified as
the pressure required to generate a determined gas flow (V0)
throughout the airway: R ¼ DP/V0.23
According to the equation, to generate a constant inspiratory gas
flow (to maintain the VT and the VE) when resistance is increased,
pressure must increase (pleural or airway). The increase in pressure
is turned to an increase in the work of breathing (WOB ¼ DP Â VT).
The increase of the resistive component can also affect the
expiratory part of the respiratory cycle producing an obstruction to
the expiratory gas flow that generates hyperinflation (auto-PEEP).
At the same time auto-PEEP increases the elastic resistance. The
different causes of increase in the resistive resistance are shown in
Table 7.
3.2.2. Reduction of the contractile capacity
The respiration is divided into two clearly distinct phases, the
inspiration that is active and requires the inspiratory muscle ac-
tivity and the expiration that is passive and does not require
muscular activity. Therefore, all the causes that produce a reduction
of the respiratory muscles contraction (muscle weakness), either
muscular or neurological causes (or both), will produce a decrease
in the inspiratory strength, a secondary reduction of the VT,
hypoventilation and hypercapnoea, thereby a mechanical respira-
tory failure.
1. Neurological and neuromuscular disorders
The most common disorder is the diaphragmatic dysfunction.
60% of VT is produced by the diaphragmatic contraction, thereby a
diaphragmatic dysfunction reduces VT, and the reduction is pro-
portional to the magnitude of the disorder. If the reduction of the
VT is not compensated for with an increase in RF, hypoventilation
and hypercapnoea are generated.
Diaphragmatic dysfunction appears in 100% of postoperative
thoracic surgery patients and in 36e50% of postoperative cardiac
surgical patients, especially after coronary artery bypass when the
Table 4
Other causes of respiratory centre depression.4,18
1. Brain injuries: Subarachnoid haemorrhage, brain trauma, ictus.
2. Toxic encephalopathy
3. Infections of CNS
4. Myxoedema
5. Sleep apnoea-hypopnoea syndrome
6. Non-convulsive status epilepticus
Table 5
Causes of increase in dead space.
1. Increase in anatomical dead space: Mechanical ventilation (compressibility),
PEEP, interface for NIV
2. Increase in alveolar dead space: Hypotension, ventilation/perfusion
mismatch (shunt effect), pulmonary embolism
Table 6
Causes of increase in the elastic resistance.21,22
1. Low chest wall compliance:
- Obesity and causes that produces intra-abdominal hypertension.
- Kyphoscoliosis, ankylosing spondylitis.
2. Low lung compliance (most frequent cause of reduction of the Csr):
- ARDS, pneumonia, fibrosis, oedema, lung resection, atelectasis, pleural
effusion
3. Hyperinflation:
- Auto-PEEP (tachypnoea, asthma, emphysema, chronic obstructive pul-
monary disease (COPD) exacerbation.
- Very high levels of PEEP
F.J. Belda et al. / Trends in Anaesthesia and Critical Care 3 (2013) 265e269 267

4. mammary artery is used; the incidence increases from 4 to 8 times
with local hypothermia and to 10 times in diabetic patients. The
reasons are inhibition of nerve activation of the diaphragm and a
direct injury of the phrenic nerve by cold or ischaemia. Without
nerve injury, a reduction of the diaphragmatic contractility can also
appear produced by direct contusion or by pain. It also appears
after a chest trauma (10%) and oesophageal surgery (2%) especially
in radical oesophagectomy (16%). In these cases the dysfunction is
produced by direct injury of the phrenic nerve, trauma or
retraction.24
Usually this diaphragmatic dysfunction is reversible in up to 80%
of cases at 6 months and up to 90% at 1 year. The clinical diagnosis is
simple because it produces a paradoxical inspiratory movement:
during inspiration the chest wall expansion movement is normal
due to the intercostal and the sternocleidomastoid muscles, whilst
there is no abdominal movement (because there is no diaphrag-
matic activity) or even retraction (due to the passive movement of
the diaphragm to the thorax produced by the negative pleural
pressure generated by the intercostal muscles). In the chest radi-
ography, initially we can observe a blunting of the costophrenic
angles and finally a diaphragmatic elevation.
The diaphragm produces 60% of VT. This is why a bilateral pa-
ralysis of the diaphragm causes a marked reduction of VT with
hypoventilation and hypercapnoea. On the other hand, unilateral
diaphragmatic paralysis or dysfunction may have no clinical effect.
So, diaphragmatic dysfunction could occur asymptomatically
resulting in the requirement for mechanical ventilation with a
mortality rate as high as 25%.24
Another pathology in our patients that produces muscle weak-
ness of the respiratory system is the critical illness poly-
neuropathy.25
It is a neuromuscular dysfunction caused by
disturbances in the microcirculation of the peripheral nerves
(neuropathy) and muscle (myopathy) in the context of prolonged
critical illness and frequently associated with SIRS and prolonged
used of sedatives and mechanical ventilation. Bedsides, electro-
myography shows a marked decrease in the muscle action potential
amplitude.
Today three entities are recognized: 1. polyneuropathy; 2.
myopathy and 3. polyneuromyopathy. All of these cause muscle
weakness in the respiratory system, ventilator weaning failure,
prolongation of ICU stay and increased mortality. Until now, there
has been no specific treatment for this neuromuscular dysfunc-
tion.26e29
Finally, injuries to the upper cervical medulla are frequent in
polytrauma. Injuries over C-5 produce diaphragm and intercostal
muscle paralysis. These patients have a possibility of recovering
when the spinal section is incomplete and maintains some phrenic
nerve conduction. In these patients VT is generated by the dia-
phragmatic contraction (60% of VT) because the contraction of the
intercostal inspiratory muscles (T-1 to T-6) are responsible for 40%
of the lost VT. In these cases a paradoxical respiratory movement
appears: during inspiration, the abdominal movement is normal
(expansion) due to the diaphragmatic contraction while there is no
chest wall movement or even retraction because of the negative
pleural pressure generated by the diaphragmatic contraction.30,31
Contrary to the bilateral phrenic nerve paralysis (produced by
spinal injury) that almost always requires mechanical ventilation,
in the intercostal muscle paralysis it is normal to maintain
spontaneous breathing some days after the injury. Therefore
weaning from mechanical ventilation is not too prolonged.
Other neuromuscular disorders that infrequently cause me-
chanical failure in the critical care setting are shown in Table 8.
2. Muscular dysfunction
In this section, unlike the previous, we expose the muscular
disorders to a reduction in respiratory muscle contractility but with
normal neurological activity.
Muscular dysfunction can originate outside the diaphragm, and
is likely to occur during acute hyperinflation in bronchospam,
asthma or chronic obstructive pulmonary disease (COPD). The in-
crease of the FRC together with airway obstruction (intra-
pulmonary gas trapping) and auto-PEEP produces numerous
adverse respiratory effects32,33
and specifically produces a situation
that reduces the respiratory system’s muscular contraction, known
as “mechanical disadvantage”.32
Pulmonary hyperinflation pro-
duces a flattening of the diaphragm which reduces the length of the
muscular fibres and therefore the diaphragm strength. The reduc-
tion of the diaphragm strength can be up to 15%.6
Also the ratio of
curvature of the diaphragm is reduced therefore decreasing the
efficacy to generate an inspiratory pressure. The costal horizonta-
lization reduces chest wall expansion and increases its elastic
resistance. The reduction in the efficacy to generate an inspiratory
pressure, the increase in the elastic resistance and the reduction in
the diaphragm strength increase the risks of mechanical failure.
On the other side, we have some causes originating in the dia-
phragm that produce muscle weakness and therefore a reduction in
the muscular contraction. More frequently are the ones that pro-
duce muscular atrophy like malnutrition, hypercatabolism (burn,
severe SIRS and post-traumatic stress) or muscular inactivity longer
than two days like in prolonged mechanical ventilation. Other
causes of muscle weakness are metabolic disorders like metabolic
alkalosis, hypokalaemia, hypophosphataemia, hypocalcaemia and
hypomagnesaemia. Muscular contraction can be reduced by drugs
frequently used in critical care like corticosteroids, neuromuscular
blockers, aminoglycosides, etc.4,18
Most of the pathophysiological mechanisms of respiratory fail-
ure are compensated for with an increase in the work of breathing.
This increase in weak muscles may end up producing muscular
fatigue, and finally a mechanical respiratory failure due to muscle
dysfunction.
4. Conclusions
Clinically, it is important to consider the relationship between
hypoxaemia and mechanical failure in the respiratory system:
hypoxaemia is produced by shunt effect with a loss of pulmonary
volume and therefore a reduction in the Csr. This increases the
elastic resistance and the need to increase pressure to maintain the
same VT, increasing the work of breathing and the risks of me-
chanical failure. On the other side, muscle pump failure will pro-
duce in many cases reductions in the pulmonary volume with more
Table 8
Neuromuscular disorders.4,18
Transverse myelitis
Amyotrophic lateral sclerosis
Guillain-Barré syndrome
Duchenne disease
Eaton-Lambert syndrome
Muscular dystrophies
Myotonic dystrophies
Multiple sclerosis
Table 7
Causes of increase in the resistive resistance.
1. External resistances: Naso-orotracheal tube, breathing circuit, ventilator
2. Internal resistances: Secretions, asthma, bronchoconstriction, chronic
obstructive pulmonary disease
F.J. Belda et al. / Trends in Anaesthesia and Critical Care 3 (2013) 265e269268

5. or less alveolar collapse and hypoxaemia. Even if hypoxaemia is an
emergency and can initially be treated by increasing the FiO2, if we
do not treat the cause of hypoxaemia, we will have to deal with a
mechanical failure soon. More importantly, with the clinical signs
of mechanical failure, if the cause is not treated, hypoxaemia will
soon appear. Finally, it is important to remember that hypoxaemia
and mechanical failure often appear together but whilst hypo-
xaemia is easy to diagnose, mechanical failure requires a more
detailed exploration of the patient.
Conflict of interest statement
The authors declare that they have no conflicts of interest.
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