oxygen therapy

Oxygen Therapy

Introduction & history

Oxygen is an essential molecule for life. However oxygen is a commonly and wrongly prescribed drug. Oxygen was isolated by Joseph Priestley in 1772. Thomas Beddoes used oxygen for the first time in early 1800s for medical disorders. Oxygen was commercially produced first time by Carl Von Linde in 1895 by fractional distillation of liquid air.  However in last few decade only oxygen use have gained momentum. Response to hypoxia is variable among individual organs and cells. Neurons, cardiomyocytes, and renal tubular cells are highly sensitive to a sudden reduction in oxygen supply and are unable to survive long periods of hypoxia. After complete cessation of cerebral perfusion, nuclear magnetic resonance (NMR) measurements show a 50% decrease in cellular adenosine triphosphate (ATP) within 30 seconds and irreversible damage occurs within 3 minutes. Kidneys and liver can tolerate 15–20 minutes of total hypoxia, skeletal muscle 60–90 minutes, and vascular smooth muscle 24–72 hours. The most extreme example of hypoxic tolerance is that of hair and nails which can grow for several days after death. Goal of oxygen therapy is to-

•         Treat hypoxaemia

•         Decrease work of breathing

•         Decreased myocardial work

Oxygen transport

Knowledge of oxygen transport mechanism is an important to understand oxygen therapy. Only the salient points of oxygen transport mechanism are given. Key steps in oxygen transport are uptake in the lungs, carrying capacity of blood, global delivery from lungs to tissue, regional distribution of oxygen delivery, diffusion from capillary to cell and cellular use of oxygen. The delivery of oxygen from capillary blood to the cell depends on:

• Factors that influence diffusion

• Rate of oxygen delivery to the capillary (DO2);

• Position of the oxygen-haemoglobin dissociation relationship

• Rate of cellular oxygen utilisation and uptake (VO2).

Figure1 : Oxygen transport from atmosphere to mitochondria. Values in parentheses for a normal 75 kg individual (BSA 1.7 m2) breathing air (FIO2 0.21) at standard atmospheric pressure (PB 101 kPa). Partial pressures of O2 and CO2 (PO2, PCO2) in kPa; saturation in %; contents (CaO2, CvO2) in ml/l; Hb in g/l; blood/gas flows (Qt, Vi/e) in l/min. P50 = position of oxygen haemoglobin dissociation curve; it is PO2 at which 50% of haemoglobin is saturated (normally 3.5 kPa). DO2 = oxygen delivery; VO2 = oxygen consumption, VCO2 = carbon dioxide production; PIO2, PEO2 = inspired and mixed expired PO2; PECO2 = mixed expired PCO2; PAO2 = alveolar PO2.

Clinical feature

Early detection of tissue hypoxia is essential for successful treatment. But it is not always easy as the clinical features are often non­specific. Clinical manifestations of hypoxia are highly variable and nonspecific and depend on both duration of the hypoxia (acute or chronic) and the individual response to it. Symptoms and signs associated with acute hypoxia include changes in mental status, dyspnea, tachypnea, respiratory distress, and cardiac arrhythmias. Alterations in mental status due to hypoxia range from impaired judgment to confusion or coma. Cyanosis which is considered a hallmark of hypoxia, occurs only when the concentration of reduced hemoglobin in the blood is 1.5 g/dl or greater. But this is not a reliable sign, as it may be absent in anemia and during periods of poor peripheral perfusion.

Organ specific sign and symptoms of hypoxia
System	Sign and symptoms
Respiratory	Tachypnea, breathlessness, dyspnea, cyanosis
cardiovascular	Increased cardiac output, palpitations, tachycardia, arrhythmias, hypotension, angina, vasodilatation, diaphoresis, and shock
CNS	Headache, impaired judgment, inappropriate behavior, confusion, euphoria, delierium, restlessness, papilledema, seizures, obtundation, coma
neuromuscular	Weakness, tremor, asterixis, hyper-reflexia, incoordination
metabolic	Sodium and water retention, lactic acidosis

Mechanism of hypoxia

Hypoxia is deficiency of oxygen in tissue and hypoxemia is deficiency of oxygen in blood. Hypoxia may occur even in absence of hypoxemia. There are several mechanisms of hypoxia. Understanding of these mechanisms will help to treat the patient adequately. The various mechanisms is being summarised in table 1.

Table1 : Mechanism of hypoxemia

Mechanism	Clinical conditions	Diagnostic criteria	General treatment	Response to oxygen therapy
Low FiO2	High altitude, fire, smoke	History, low atmospheric pressure of oxygen	Supportive care	Rapid
Hypoventilation	Neuromuscular disease, CNS depression, narcotics	Increase in PaCO2 similar to decrease in PaO2	ventilator care (invasive/non invasive)	Good initial response
V/Q mismatch	COPD	Increase PAO2-PaO2, corrected by 100% O2	Bronchodilator, bronchial hygine	Moderately rapid
Right to left shunt	Pneumonia, collapse, pulmonary edema	Not corrected by 100% O2	Antibiotics, diuretics, PEEP	variable
Diffusion defect	Interstitial lung diseases	Low vital capacity, low diffusion capacity	Corticosteroids, immunosupresant etc	Moderately rapid

Indications of oxygen therapy

In acute care/ emergency setting

Role of oxygen therapy in acute care setting is very essential. Restoration of global oxygen delivery is an important goal in early resuscitation but thereafter circulatory manipulation to sustain “supranormal” oxygen delivery does not improve survival and may be harmful. There are conditions where oxygen is life saving particularly in acute conditions. Timely administration of oxygen and in adequate dose is very important. There are diseases where oxygen need to be give in higher dose and in some conditions it need to be give in controlled amount.

Table 2: indications of oxygen in emergency care setting

	Clinical conditions (grade of recommendations)	Comment
Critical illnesses requiring high levels of supplemental oxygen	Cardiac arrest or resuscitation(Grade D) Shock, sepsis, major trauma, near-drowning, anaphylaxis, major pulmonary haemorrhage(Grade D) Major head injury(Grade D) Carbon monoxide poisoning(Grade C)	The initial oxygen therapy is a reservoir mask at 15 l/min. Once stable, reduce the oxygen dose and aim for target saturation range of 94–98% If oximetry is unavailable, continue to use a reservoir mask until definitive treatment is available. Patients with COPD and other risk factors for hypercapnia who develop critical illness should have the same initial target saturations as other critically ill patients pending the results of blood gas measurements, after which these patients may need controlled oxygen therapy or supported ventilation if there is severe hypoxaemia and/or hypercapnia with respiratory acidosis
Serious illnesses requiring moderate levels of supplemental oxygen if the patient is hypoxaemic	Acute hypoxaemia (cause not yet diagnosed) (Grade D) Acute asthma (Grade C) Pneumonia ( Grade C) Lung cancer (Grade C) Postoperative breathlessness (Grade D) Acute heart failure (Grade D) Pulmonary embolism (Grade D) Pleural effusions (Grade D) Pneumothorax (Grade C & D) Deterioration of lung fibrosis or other interstitial lung disease (Grade D) Severe anaemia Grade B & D) Sickle cell crisis (Grade B)	The initial oxygen therapy is nasal cannulae at 2–6 l/min (preferably) or simple face mask at 5–10 l/min unless stated otherwise.
conditions requiring controlled or low-dose oxygen therapy	COPD(Grade C) Exacerbation of CF(Grade D) Chronic neuromuscular Disorders(Grade D) Chest wall disorders(Grade D) Morbid obesity (Grade D)	Prior to availability of blood gases, use a 28% Venturi mask at 4 l/min and aim for an oxygen saturation of 88–92% for patients with risk factors for hypercapnia but no prior history of respiratory acidosis. [Grade D] Adjust target range to 94–98% if the PaCO2 is normal (unless there is a history of previous NIV or IPPV) and recheck blood gases after 30–             60 min [Grade D]
Conditions for which patients should be monitored closely but oxygen therapy is not required unless the patient is hypoxaemic	Myocardial infarction and acute coronary syndromes(Grade D) Stroke (Grade B) Pregnancy and obstetric Emergencies (Grade A- D) Hyperventilation or dysfunctional Breathing (Grade C) Most poisonings and drug Overdoses (Grade D) Poisoning with paraquat or Bleomycin (Grade C) Metabolic and renal disorders (Grade D) Acute and subacute neurological and muscular conditions producing muscle weakness (Grade C)	If hypoxaemic, the initial oxygen therapy is nasal cannulae at 2–6 l/min or simple face mask at 5–10 l/min unless saturation is ,85% (use reservoir mask) or if at risk from hypercapnia The recommended initial target saturation range, unless stated otherwise, is 94–98% If oximetry is not available, give oxygen as above until oximetry or blood gas results are available

Long term oxygen therapy

Long term oxygen therapy (LTOT) is a mode of delivery oxygen particular for chronic respiratory diseases with hypoxia. Initially it was established in patient of chronic obstructive pulmonary  disease (COPD) and later on extrapolated in various other diseases like interstitial lung disease, bronchiectasis, cystic fibrosis, khyphoscoliosis, sleep apnea, severe cardiac failure etc. Nocturnal oxygen therapy trial (NOTT) and medical research council oxygen therapy trial long back has established the role of LTOT in COPD patient.

General selection criteria for LTOT-

1. A definitive documented diagnosis of chronic hypoxemia (3 week apart)
2. Patient is on optical medical management and stable
3. Oxygen administration should have been shown to improve hypoxemia and provide clinical benefit

Specific criteria for LTOT-

1. At rest, in non recumbent position, the PaO2 of 55 mm Hg or less
2. Patient with  PaO2 between 55 to 60 mm Hg is considered for LTOT if-
1. Patient on optimal medical treatment with demonstrable hypoxic organ dysfunction like secondary pulmonary arterial hypertension, cor pulmonale, polycythemia or CNS dysfunction
2. When there is demonstrable fall in PaO2 < 55 mm Hg during sleep, associated with disturbed sleep pattern, cardiac arrhythmias or pulmonary hypertension. These patient may be benefited from nocturnal oxygen therapy.
3. When there is demonstrable fall in PaO2 during exercise and oxygen administration is shown to improve exercise performance, duration or capacity. These patient may be benefited from oxygen therapy during exercise.

For LTOT oxygen supply source can be compressed gas cylinder, liquid oxygen system and oxygen concentrator. Delivery devices includes nasal cannulae, prongs and masks. There are some oxygen conserving devices which reduce wastage and cost. These devices includes reservoir oxygen delivery, electromechanical pulsing device, transtracheal catheter etc.

Oxygen delivery devices

Method of oxygen delivery is determined by degree of hypoxaemia, required precision,                                                                                                 comfort of the patient, cost and availability. Oxygen delivery systems are basically two types-

1. Rebreathing systems
1. Have a CO₂ absorber
2. Used in anaesthesia
2. Non-rebreathing systems

a)      Low flow (variable performance)

b)      High flow (fixed performance)

Table3: low flow and high flow system

Low flow system	High flow system
Nasal cannula and catheters Facemasks -Simple facemask -Reservoir masks -Partial rebreather -Non rebreathers Endotracheal and tracheostomy tubes with T Piece	Venturi masks Non rebreathing reservoir mask with blending device and high flow meters Endotracheal and tracheostomy tubes with mechanical ventilation
FiO2 depends upon: •         Size of available oxygen reservoir •         Flow rate •         Breathing pattern (VT and RR)	FiO2 depends on: •         velocity of the jet (the size of orifice and oxygen flow rate) •         size of the valve ports High flow systems deliver about 40 l/min of gas through the mask, which is usually sufficient to meet the total respiratory demand This ensures that the breathing pattern will not affect the FiO2

Table4 :Following is an example how FiO2 depends on ventilatory minute volume and flow rate of oxygen.

	Patient in respiratory distress	Stable patient
Ventilatory minute volume (Respiratory rate x tidal volume)	30 l/min (40 breaths/min x 750 ml/breath)	5 l/min (10 breaths/min x 500 ml/breath)
Oxygen flow rate	2L/min	2L/min
Calculation of inspired oxygen concentration (FiO2)	2 l/min of 100% oxygen + 28 l/min of air drawn into the mask (21% oxygen) = 30 l/min minute volume Thus FiO2 = (1.0x2) + (0.21x28) /30 = 0.26 (26%)	2 l/min of 100% oxygen + 3 l/min of air drawn into the mask (21% oxygen) = 5 l/min minute volume Thus FiO2 = (1.0x2) + (0.21x3)/ 5= 0.53 (53%)

Table5 : delivery devices and FiO2

Delivery devices	Oxygen flow(lit/min)	FiO2
Nasal cannula	1 2 3 4 5 6	24% 28% 32% 36% 40% 44%
Simple face mask	6-10	40-60%
Reservoir mask	6-10	40-60%
Partial rebreathing	8-10	35-80%
Non rebreahting	8-10	40-100%

Unconventional oxygen delivery

In critically ill patient conventional oxygen delivery system may not work all the time. Therefore alternate modalities of oxygen carriers have developed and are being used in certain clinical situation. They have shown some early promising result and may play a bigger role in days to come. Theses alternate systems includes-

1. Blood substitutes-

Due to complication related to blood transfusion and need for safer alternative to blood that can carry oxygen scientist has developed several blood substitute. These artificial oxygen carriers are of two types-

1. Hemoglobin based oxygen carriers (HBOC)-

In HBOC hemoglobin is modified to improve oxygen off loading by decreasing oxygen affinity. This at present in investigational stage. Other red cell substitutes under trial are polymerized, pyridoxylated, stroma free human hemoglobin and oligomeric hemoglobin solution.

2. Perfluorocarbon based oxygen carriers-

Chemically inert synthetic molecules and can augent oxygen delivery to tissue.

2. Extracorporeal membrane oxygenation (ECMO)-

It is a artificial technique to provide life support when lung is unable to maintain sufficient oxygenation of the body’s organ system. It is a modified cardiopulmonary bypass technique where patient’s circulation is connected to a external blood pump and membrane oxygenator.

3. Heliox therapy-

It is a mixture of helim and oxygen with reduced density and viscosity of oxygen in a concentration depended manner. Clinical utility of heliox has been observer in decompression illness, severe asthma, COPD, upper airway obstruction, broncholitis, croup, post extubation stridor etc.

How to calculate required FiO2 ?

The amount of required FiO2 can be calculated from alveolar gas equation-

PAO2=FIO2(PB-PH2O)-PACO2[FIO2 + (1-FIO2) / R]

Where PAO2 is partial pressure of alveolar oxygen, FiO2 is fraction of inspired oxygen, PB barometric pressure, PH2O water vapor pressure (usually 47mmHg), PACO2 is partial pressure of alveolar carbon dioxide (which is usually similar to PaCO2 that is partial pressure of carbon dioxide in arterial blood) and R is the respiratory quotient (0.8)

In abbreviated from the alveolar gas equation is PAO2=FIO2(PB-47)-1.2(PaCO2)

FiO2 is calculated for the equation bellow after calculation PAO2 from alveolar gas equation

FiO2 = (PAO2 + PaCO2 / R )/ PB-PH2O

For example a patient has a PaO2 of 41mmHg on FiO2 of 40% (0.4) and PaCO2 is 25 mmHg, his arterial (A - aO2) oxygen gradient calculated as follows

PAO2=FIO2 (PB-47)-1.2(PaCO2)

PAO2=0.4(760-47)-1.2(25)=285.2-30=255.2

Therefore arterial (A - aO2) oxygen gradient is 255.2- 41= 214.2

To increase PaO2 to 60 mmHg the inspired oxygen tension should be 214.2+60= 274.2

Therefore required FiO2 is

(PAO2 + PaCO2 / R)/ PB-PH2O= (274.2+ 30)/713= 0.42

Oxygen in flight

Some patient required oxygen during flight. The following table shows the British Thoracic Society recommendations. Since hypoxic challenge test is not available widely in India we have to recommend according to SpO2 level.

Table 6:

Pulse oxymetry	recommendation
SpO2 >95%	Oxygen not required
SpO2 92-95% without risk factors	Oxygen not required
SpO2 92-95% with risk factors (eg COPD, asthma, previous venous thromboembolism etc)	Hypoxic challenge test
SpO2 <92%	In flight oxygen
After Hypoxic challenge test
Blood gas report	recommendation
PaO2 >55 mmHg	Oxygen not required
PaO2 50-55 mmHg	borderline
PaO2 <50 mmHg	In flight oxyen

How to write an oxygen prescription?

In study it has been found that 21% of prescriptions inappropriate and 85%patients inadequately supervised. Oxygen should always be prescribed or ordered on a designated Document. The use of oxygen by paramedics, nurses, doctors, physiotherapists and others in emergency situations is similar to the use of all other medicinal products by these people. Clinical governance requires that the intentions of the clinician who initiates oxygen therapy should be communicated clearly to the person who actually administers oxygen to the patient and an accurate record must be kept of exactly what has been given to the patient Safe and effective treatment prescriptions should contain-

Ø  The indication

Ø  flow rate

Ø  delivery system

Ø  duration

Ø  how to monitoring of treatment

Ø  specific instruction during exercise and sleep if indicated

Side effect

Inappropriate dose and failure to monitor treatment can have serious consequences. Vigilant monitoring to detect and correct adverse effects swiftly is essential. The toxic effects of oxygen on the lung occur due to physiological disturbances caused by excess oxygen administration or free radical production during hyperoxic exposure that override the intrinsic antioxidant defence mechanism. Physiological complications includes-

1. Suppression of hypoxic ventilator drive seen patient with chronic hypoxemia and hypercapnea whose ventilator drive is primarily driven by hypoxia (eg COPD). This can be prevented by controlled oxygen delivery.
2. Absorption atelectasis seen in patient receiving very high FiO2.
3. FiO2 >80% cause mild increase in peripheral vascular resistance and mild decrease in cardiac output.
4. Inhalation of 100% FiO2 causes about 10% decrease in minute ventilation and decrease in diffusion capacity.

Excess free radicals interact with cellular components, resulting in cytotoxic events which produce a characteristic cascade of biochemical, cellular, morphologic, and physiological changes. The biochemical reactions, in turn, result in a sequence of characteristic cellular and morphologic changes. Four basic phases constitute the development of oxygen toxicity in lung tissue. The first three phases—initiation, inflammation, and destruction—occur during exposure to both lethal and sublethal doses of hyperoxia. The fourth phase—proliferation and fibrosis—occurs if there is re-exposure to sublethal oxygen levels. Therefore it is essential to administer oxygen in adequate dose and stop oxygen therapy when it is no longer indicated.

Pulmonary Changes during Hyperoxic Exposure in Humans
O2 at 1 atm	Duration of exposure	Pathophysiological changes
100%	>12 h	Decreased tracheobronchial clearance; decreased forced vital capacity; cough; chestpain
	>24hr	Altered endothelial function
	>36hr	Increased alveolar-arterial oxygen gradient; decreased carbon monoxide diffusing capacity
	>48hr	Increasing alveolar permeability; pulmonary edema; surfactant inactivation
	>60hr	Acute respiratory distress syndrome
60%	7 days	Mild chest discomfort without changes in lung mechanics; possible changes in morphometry
24-28%	months	Subclinical pathological changes; no clinical toxicity documented

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