The document discusses refractory hypoxemia, defining hypoxia and arterial hypoxemia along with their causes such as hypoventilation, low inspired oxygen, shunting, ventilation-perfusion inequality, and diffusion impairment. It outlines various steps for diagnosing and managing refractory hypoxemia in patients, highlighting both low-resource and high-tech treatment options, as well as the goals of mechanical ventilation and specific therapies like prone positioning and neuromuscular blockade. Ultimately, it emphasizes the importance of identifying reversible causes and potential advanced treatments like extracorporeal membrane oxygenation (ECMO) for severe cases.

1. APPROACH TO
REFRACTORY HYPOXEMIA
- DR ISHA CHHEDA

2. DEFINITION
• HYPOXIA : is defined as deficiency in either the delivery or the utilization of oxygen
at the tissue level, which can lead to changes in function, metabolism and even
structure of the body.
• ARTERIAL HYPOXEMIA : is defined as partial pressure of oxygen in arterial blood
(PaO2) less than 80 mmHg while breathing in room air.

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5. CAUSES OF HYPOXEMIA
• The mechanisms that can cause hypoxemia can be divided into those that increase
P(A-a)O2 and those where P(A-a)O2 is preserved.
1) HYPOVENTILATION
2) LOW INSPIRED OXYGEN
3) RIGHT TO LEFT SHUNT
4) VENTILATION PERFUSION INEQUALITY
5) DIFFUSION IMPAIRMENT
A – stands for
ALVEOLAR
a – stands for
arterial blood

6. HYPOVENTILATION
• Hypoventilation refers to condition in which alveolar ventilation is abnormally low in
relation to oxygen uptake or carbon dioxide output.
• Alveolar ventilation is the volume of fresh inspired gas going to the alveoli (i.e. non dead
space ventilation).
• Hypoventilation occurs when the alveolar ventilation in reduced and the alveolar PO2
therefore settles out at a lower level than normal. For the same reason, the alveolar PCO2
and thus arterial PCO2 are raised.
• P(A-a)O2 is normal.
• PaCO2 is elevated (hypercapnia)
• Increasing the fraction of oxygen (FiO2) can alleviate the hypoxemia and the hypercapnia
can be corrected by mechanically ventilating the patient to eliminate CO2.

7. CAUSES OF HYPOVENTILATION
• 1. Depression of the respiratory center by drugs, such as morphine derivatives and barbiturates.
• 2. Diseases of the brain stem, such as encephalitis.
• 3. Abnormalities of the spinal cord conducting pathways, such as high cervical dislocation; anterior
horn cell diseases, including poliomyelitis.
• 4. Affecting the phrenic nerves or supplying the intercostal muscles.
• 5. Diseases of the myoneural junction, such as myasthenia gravis.
• 6. Diseases of the respiratory muscles themselves, such as progressive muscular dystrophy; thoracic
cage abnormalities (e.g., crushed chest).
• 7. Diseases of nerves to respiratory muscles (e.g., Guillain Barre syndrome).
• 8. Upper airway obstruction (e.g. thymoma).
• 9. Hypoventilation associated with extreme obesity (pickwickian syndrome)
• 10. Miscellaneous causes, such as metabolic alkalosis and idiopathic states.

8. LOW INSPIRED OXYGEN [ PI O2 ]
• Examples-
1) A decrease in barometric pressure [e.g. breathing at high altitude].
2) A decrease in FIO2 – accidental [e.g. anesthetist does not supply enough oxygen or
improper installation of oxygen supply lines or a leak in the breathing circuit].
• Here P(A-a)O2 normal
• PaCO2 is decreased.This reduction in PaCO2 (hypocapnia) is due to
hyperventilation in response to hypoxemia.
• Peripheral chemoreceptors sense the low arterial PO2 and initiate an increase in
ventilation through their input to the medullary respiratory centre

9. RIGHT TO LEFT SHUNT
• Shunt refers to the entry of blood into the systemic arterial system without going through ventilated areas of lung.
• Shunt may be anatomical or physiological.
• P(A-a)O2 is elevated.
• PaCO2 is normal.
Anatomic shunt: when a portion of blood bypasses the lungs through an anatomic channel.
• In healthy individuals :
i) A portion of the bronchial circulation’s (blood supply to the conducting zone of the airways) venous blood drains into the
pulmonary vein.
ii) A portion of the coronary circulation’s venous blood drains through the thebesian veins into the left ventricle.
Note: i & ii represent about 2% of the cardiac output and account for 1/3 of the normal P(A-a)O2 observed in health.
• Congenital abnormalities :
• i) intra-cardiac shunt [e.g.Tetralogy of Fallot: ventricular septal defect + pulmonary artery stenosis] •
• ii) intra-pulmonary fistulas [direct communication between a branch of the pulmonary artery and a pulmonary vein].

10. Physiologic shunt:
In disease states, a portion of the cardiac
output goes through the regular pulmonary
vasculature but does not come into contact
with alveolar air due to filling of the alveolar
spaces with fluid [e.g. pneumonia, drowning,
pulmonary edema]
An important diagnostic feature of a shunt is
that the arterial PO2 does not rise to the
normal level when the patient is given 100%
oxygen to breathe.
Examples of intrapulmonary shunt-
(a) Collapsed and fluid filled alveoli are
examples of intrapulmonary shunt.
(b) Anomalous blood return of mixed venous
blood bypasses the alveolus and thereby
contributes to the development of
intrapulmonary shunt.

11. VENTILATION PERFUSION INEQUALITY
• PaCO2 is normal
• P(A-a)O2 is elevated
• VA/Q inequality is the most common cause of hypoxemia in disease states
• In patients with obstructive or restrictive ventilatory diseases, decreased ventilation
may result from structural or functional abnormalities of the airway and can lead to
decreased VA/Q units
• On the other hand, lung units with increased VA/Q ratios can develop disorders that
lead to over ventilation of lung units, conditions such as emphysema, for example, in
which patients have airspace enlargement as a result of the destruction of the
alveolar sac distal to the terminal bronchiole.
• Moreover, the development of impaired perfusion through the pulmonary
vasculature, as observed in cases of pulmonary embolism or pulmonary
vasospasm, may cause high VA/Q ratios

13. VENTILATION PERFUSION INEQUALITY
• Reflex mechanisms are present in the lung to minimize the effect of VA/Q inequality, thus avoiding or
minimizing the detrimental effects of impaired gas exchange
• One mechanism is hypoxic pulmonary vasoconstriction (HPV), whereby a fall in VA/Q leads to the
development of alveolar hypoxia which in turn causes vasoconstriction of the perfusing arteriole.
• This effect is beneficial for pulmonary gas exchange because it decreases the denominator of the
VA/Q relationship, thereby partially correcting regional VA/Q imbalance and improving arterial
hypoxemia
• HPV appears to operate over a range of alveolar PO2 values between 30 and 150 mmHg.
• The mechanism by which alveolar hypoxia sends the message to trigger regional vasoconstriction
is unclear, but may involve the release of humoral messengers.
• Many factors, however, can significantly interfere with HPV
1. certain drugs such as calcium channel blockers, beta-agonists, and inhalational anesthetic agents.
2. Lower respiratory tract infections or disease processes that cause elevations in left atrial pressure
can also interfere with HPV.
• In addition, although HPV may be helpful in improving arterial hypoxemia, a progression in
vasoconstrictor effect can lead to the development of secondary pulmonary hypertension and,
eventually, right heart failure

14. DIFFUSION LIMITATION
• It is now generally believed that oxygen, carbon dioxide, and indeed all gases cross the blood-gas barrier by simple
passive diffusion
• Fick's law of diffusion states that the rate of transfer of a gas through a sheet of tissue is proportional to the tissue area (A)
and the difference in partial pressure (P1-P2) between the two sides, and is inversely proportional to the thickness (T)
• The rate of diffusion is also proportional to a constant, D, which depends on the properties of the tissue and the particular
gas.
• The constant is proportional to the solubility (Sol) of the gas, and inversely proportional to the square root of the
molecular weight (MW)

15. DIFFUSION LIMITATION CONT..
• PaCO2 is normal.
• P(A-a)O2 is normal at rest but may be elevated during exercise.
• Diffusing capacity is reduced by diseases in which the thickness is increased,
including diffuse interstitial pulmonary fibrosis, asbestosis, and sarcoidosis.
• It is also reduced when the area is decreased, for example, by pneumonectomy.
• The fall in diffusing capacity that occurs in emphysema may be caused by the loss of
alveolar walls and capillaries

16. No

17. DIAGNOSIS OF RESPIRATORY FAILURE
• History
• Physical examination
• Laboratory investigations

18. SYMPTOMS
Neurologic symptoms:
• Headache
• Visual disturbances
• Anxiety
• Confusion
• Memory loss
• Hallucinations
• Loss of consciousness
• Asterixis (hypercapnia)
• Weakness
• Decreased functional performance

19. SPECIFIC ORGAN SYMPTOMS:
Pulmonary
• Cough
• Chest pains
• Sputum production
• Stridor
• Dyspnea (resting vs.
exertional)
Cardiac
• Orthopnea
• Peripheral edema
• Chest pain
Other
• Fever
• Abdominal pain
• Anemia
• Bleeding

20. PHYSICAL EXAMINATION
Physical examination of patients with hypoxemia begins with a quick, but thorough, general
assessment.
The initial priority is to triage patients who present with severe forms of respiratory failure from those
with less severe form
1)General findings:
• Mental alertness
• Ability to speak in complete
sentences
• Respiratory rate > 35
breaths/min
• Heart rate > or < 20 beats
from normal
• Pulsus paradoxus present?
• Elevated work of breathing?
• Using accessory muscles
• Rib cage or abdominal
paradox
2) Specific organ
dysfunction:
Pulmonary:
• Stridor
• Wheezes
• Rhonchi
• Crackles.
Cardiac:
• Tachycardia, bradycardia
• Hypertension, hypotension •
Crackles
• New murmur
Renal
• Anuria
Gastrointestinal
• Distended
• Pain to palpation
• Decreased bowel sounds

23. REFRACTORY HYPOXEMIA
There is no standard definition of refractory hypoxemia so far. However in patients on
lung protective ventilation, majority of clinicians define refractory hypoxemia as:
P/F < 100 or SaO2 < 88% or PaO2 < 60 mm Hg with FiO2 > 0.8 and Pplat > 30 cm H2O

24. Step 1: Initiate Resuscitation and Identify the Reason for Deterioration
Perform quick physical examination and initiate basic investigations such as
arterial blood gas and the chest X-ray to arrive at probable cause for deterioration
in respiratory status.
• Prior to labelling patients as refractory hypoxemia, it is important to rule out
reversible causes of hypoxemia

25. • Step 2: Identifying the Therapies for Refractory Hypoxemia in a Given Setting
• Once reversible causes of refractory hypoxemia are ruled out, identify the availability of
rescue therapies in the given resource setting and patient needs
• Broadly therapies for refractory hypoxemia (based on resource availability) can be
classified into two categories:
1. Therapies requiring minimal resources:
• Recruitment manoeuvres
• Prone ventilation
• Neuro-muscular blockade
2. Therapies requiring high end gadgets:
• Inhaled pulmonary vasodilators
• HFOV
• Extracorporeal membrane based techniques

26. • Step 3: Understanding the Goals of Mechanical Ventilation in ARDS
• One has to be understand that irrespective of modalities used to improve
oxygenation in refractory hypoxemia the goals of mechanical ventilation in ARDS
stays the same.
• Oxygenation goal: PaO2 55–80 mm Hg or SaO2 88–95%.
• Plateau pressure (Pplat): <30 cm H2O.
• Driving Pressure < 14 cm H2O.
• pH goal: 7.20–7.45 (Permissive Hypercapnoea).

27. • Step 4: Consider Recruitment Manoeuvres
• Recruitment manoeuvre is application of a high level of sustained airway pressure to open up the
collapsed alveoli and then apply appropriate PEEP to prevent the collapse of the recruited alveoli.
There is still insufficient evidence to use recruitment manoeuvres routinely and electively in all
patients of severe ARDS.
• Indications
1. As a temporary rescue therapy to improve oxygenation.
• Pre-requisites
• Patient should be well sedated/paralysed.
• Patient should be hemodynamically stable.
• Patient should be well hydrated and not hypovolemic.
• Avoid in patients with chronic obstructive airway disease, intracranial hypertension and pregnancy.
Patient with early diffuse ARDS are generally good recruiters, but patients with late ARDS (>1 week)
and patients with focal ARDS generally do not respond well.

28. Step 5: Consider ProneVentilation
Physiology
• Prone ventilation reduces ventral-dorsal transpulmonary pressure difference.
• Reduces lung compression (gravitational readjustment of edema fluid).
• Improves ventilation perfusion mismatch.
• Improves bronchial drainage.
• Reversal of acute cor pulmonale
• Indications
P/F < 150 with PEEP > 10 cm H2O.
Within 36 h of onset of ARDS.

29. • Step 6: Consider Adjunctive Neuromuscular Blockade
Neuromuscular blockade has been postulated to facilitate lung protective
low volume ventilation by improving patient ventilator synchrony. It limits the
risk of asynchrony related alveolar collapse and regional alveolar pressure
increase with overdistension of alveoli.
It is also postulated to cause decrease in lung
inflammation.
Benefit with neuromuscular blockade have been documented in early ARDS
with P/F < 150 (infusion for 48 h).
This benefit has been shown with cisatracurium.
It may also be used as an adjunct in patient having severe patient ventilator
asynchrony despite heavy sedation.
Neuromuscular blockade should be used judiciously
considering that, its use is associated with critical illness neuromyopathy and
is a confounder to neurological assessment.

30. STEP 7: Consider Extracorporeal Membrane Oxygenation (ECMO)
• ECMO is a technique where blood is removed from patient and passed through
artificial biomembrane which functions to oxygenate blood and remove CO2 from
blood and then return it back to patient.Thus essentially it is decoupling of
mechanical ventilation and gas exchange. ECMO can be considered in severe ARDS
especially in cases of refractory hypoxemia and in cases where adherence to lung
protective ventilation leads to severe hypercapnic respiratory acidosis.
• ECMO thus provides an way to manage gas exchange well while managing
mechanical ventilation with acceptable tidal volumes and plateau pressures.This
decreases chances of VALI.

31. • Other Rescue Therapies
• HFOV -HFOV is a type of ventilation which combines high respiratory rate (>180 breaths/min) with
tidal volumes as low as anatomical dead space.The oscillator delivers very low tidal volume.
• This prevents alveolar collapse and at the same time avoids high airway pressures. Risks with HOFV
include hypotension and barotraumas.
Inhaled PulmonaryVasodilators – NITRIC OXIDE AND EPOPROSTENOL
• They promote pulmonary vasodilatation and improved blood flow to ventilated areas of lungs and
divert blood away from poorly ventilated areas of lung.This improves ventilation perfusion mismatch
and thus improves oxygenation.

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