Pulmonary function tests (PFTs) are noninvasive tests that show how well the lungs are working. The tests measure lung volume, capacity, rates of flow, and gas exchange. This information can help your healthcare provider diagnose and decide the treatment of certain lung disorders.

Pulmonary function tests (PFTs) allow physicians to evaluate the respiratory function of their patients. They are reproducible and accurate. Ultimately, the results of the PFTs are affected by the effort of the patient. PFTs do not provide a specific diagnosis, but together with the history, physical exam, and laboratory data help clinicians reach a diagnosis. PFTs also allow physicians to quantify the severity of the pulmonary disease, follow it up over time, and assess its response to treatment.[rx]

There are 2 types of disorders that cause problems with air moving in and out of the lungs:

• Obstructive. This is when air has trouble flowing out of the lungs due to airway resistance. This causes a decreased flow of air.
• Restrictive. This is when the lung tissue and/or chest muscles can’t expand enough. This creates problems with airflow, mostly due to lower lung volumes.

PFT can be done with 2 methods. These 2 methods may be used together and perform different tests, depending on the information that your healthcare provider is looking for:

• Spirometry. A spirometer is a device with a mouthpiece hooked up to a small electronic machine.
• Plethysmography. You sit or stand inside an air-tight box that looks like a short, square telephone booth to do the tests.

PFT measures

• Tidal volume (VT). This is the amount of air inhaled or exhaled during normal breathing.
• Minute volume (MV). This is the total amount of air exhaled per minute.
• Vital capacity (VC). This is the total volume of air that can be exhaled after inhaling as much as you can.
• Functional residual capacity (FRC). This is the amount of air left in the lungs after exhaling normally.
• Residual volume. This is the amount of air left in the lungs after exhaling as much as you can.
• Total lung capacity. This is the total volume of the lungs when filled with as much air as possible.
• Forced vital capacity (FVC). This is the amount of air exhaled forcefully and quickly after inhaling as much as you can.
• Forced expiratory volume (FEV). This is the amount of air that expired during the first, second, and third seconds of the FVC test.
• Forced expiratory flow (FEF). This is the average rate of flow during the middle half of the FVC test.
• Peak expiratory flow rate (PEFR). This is the fastest rate that you can force air out of your lungs.
• Spirometry measures the rate of airflow and estimates lung size. For this test, you will breathe multiple times, with regular and maximal effort, through a tube that is connected to a computer. Some people feel lightheaded or tired from the required breathing effort.
• Lung volume tests are the most accurate way to measure how much air your lungs can hold. The procedure is similar to spirometry, except that you will be in a small room with clear walls. Some people feel lightheaded or tired from the required breathing effort.
• Lung diffusion capacity assesses how well oxygen gets into the blood from the air you breathe. For this test, you will breathe in and out through a tube for several minutes without having to breathe intensely. You also may need to have blood drawn to measure the level of hemoglobin in your blood.
• Pulse oximetry estimates oxygen levels in your blood. For this test, a probe will be placed on your finger or another skin surface such as your ear. It causes no pain and has few or no risks.
• Arterial blood gas tests directly measure the levels of gases, such as oxygen and carbon dioxide, in your blood. Arterial blood gas tests are usually performed in a hospital, but may be done in a doctor’s office. For this test, blood will be taken from an artery, usually in the wrist where your pulse is measured. You may feel brief pain when the needle is inserted or when a tube attached to the needle fills with blood. It is possible to have bleeding or infection where the needle was inserted.
• Fractional exhaled nitric oxide tests measure how much nitric oxide is in the air that you exhale. For this test, you will breathe out into a tube that is connected to the portable device. It requires steady but not intense breathing. It has few or no risks.

Normal values for PFTs vary from person to person. The amount of air inhaled and exhaled in your test results are compared to the average for someone of the same age, height, sex, and race. Results are also compared to any of your previous test results. If you have abnormal PFT measurements or if your results have changed, you may need other tests.

Why might I need pulmonary function tests?

There are many different reasons why pulmonary function tests (PFTs) may be done. They are sometimes done in healthy people as part of a routine physical. They are also routinely done in certain types of work environments to ensure employee health (such as graphite factories and coal mines). Or you may have PFTs if your healthcare provider needs help to diagnose you with a health problem such as:

• Allergies
• Respiratory infections
• Trouble breathing from injury to the chest or a recent surgery
• Chronic lung conditions, such as asthma, bronchiectasis, emphysema, or chronic bronchitis
• Asbestosis, a lung disease caused by inhaling asbestos fibers
• Restrictive airway problems from scoliosis, tumors, or inflammation or scarring of the lungs
• Sarcoidosis, a disease that causes lumps of inflammatory cells around organs, such as the liver, lungs, and spleen
• Scleroderma, a disease that causes thickening and hardening of connective tissue

PFTs may be used to check lung function before surgery or other procedures in patients who have lung or heart problems, who are smokers, or who have other health conditions. Another use of PFTs is to assess treatment for asthma, emphysema, and other chronic lung problems. Your healthcare provider may also have other reasons to advise PFTs.

Procedures

Spirometry

Spirometry is a physiological test that measures the ability to inhale and exhale air in relation to time. Spirometry is a screening test of general respiratory health. The main results of spirometry are forced vital capacity (FVC) and forced expiratory volume (FEV). The procedure of spirometry has 3 phases: 1) maximal inspiration; 2) a “blast” of exhalation; 3) continued complete exhalation to the end of the test. There are within-maneuver acceptability and between-maneuver reproducibility criteria for spirometry (Table 2).

Vital capacity (VC) is the volume of gas expelled from full inspiration to residual volume. The FVC is similar, but the patient is exhaling at maximal speed and effort.

The FEV is the forced expiratory volume in t seconds from a position of full inspiration. Forced expiratory volume in the first second (FEV)) is used to classify the severity of obstructive lung diseases. The reversibility testing is administered using a bronchodilator (short-acting beta 2-agonist or anticholinergic agent). An increase in either FEV or FVC of 3^12% and 3^200 mL is considered a positive bronchodilator response. A lack of a response does not predict lack of response to bronchodilators. The patient should hold their bronchodilators before the reversibility testing.

The maximal flow-volume curves are a great asset to detect mild airflow obstruction. There is an inspiratory and expiratory loop. [rx]

Lung Volume

The key measurement of lung volumes is functional reserve capacity (FRC). Once FRC has been measured, all other volumes can be calculated. FRC is the volume of the amount of gas in the lungs at the end of expiration during tidal breathing. FRC is the sum of expiratory reserve volume (ERV) and residual volume (RV). ERV is the volume of gas maximally exhaled after end-inspiratory tidal breathing. RV is the volume of gas in the airways after a maximal exhalation.

In addition to RV and ERV, there is tidal volume (TV) and inspiratory reserve volume (IRV). IRV is the volume of gas that can be maximally inhaled from the end-inspiratory tidal breathing. TV is the volume of gas inhaled or exhaled with each breath at rest.

There are 2 methods to measure lung volumes: body plethysmography and gas dilution methods (nitrogen washout and inert gas dilution). Gas dilution method uses an inert gas (poorly soluble in alveolar blood and lung tissues), either nitrogen or helium. The subject breathes a gas mixture until equilibrium is achieved. The volume and mixture of gas exhaled after the equilibrium have been achieved permit the calculation of FRC. In body plethysmography, the subject sits inside a body box and breathes against a shutter valve. FRC is calculated using Boyle Law (at a given temperature, the product of gas volume and pressure is constant). FRC calculated by body plethysmography is usually larger in subjects with obstructive lung disease and air trapping than FRC calculated using gas dilution methods. Body plethysmography is considered the gold standard for lung volumes measurement.

Capacities are the sum of 2 or more volumes (Figure 1). TLC is the gold standard for diagnosis of restrictive lung disease. TLC less than 5 percentile of predicted or less than 80% predicted are diagnostic of a restrictive ventilatory defect.[rx][rx]

Diffusion Capacity

Diffusion studies the diffusion of gases across the alveolar-capillary membranes. Its measurement uses carbon monoxide (CO) to calculate the pulmonary diffusion capacity. The most common method is the standard single-breath D. It is measured in milliliters per minute per mm Hg.

The factors affecting the D are volume and distribution of ventilation, mixing and diffusion, the composition of the gas, characteristics of the alveolar membrane and lung parenchyma, the volume of alveolar-capillary plasma, concentration, and binding properties of hemoglobin, and gas tensions in blood entering the alveolar capillaries. A detailed list of factors affecting DLCO is listed in Table 3.

The diffusion capacity depends on multiple factors, and its value should be adjusted. Specific adjustments should be made for hemoglobin, carboxyhemoglobin, and FiO for a correct interpretation. Adjustment for lung volumes is controversial, and further studies are needed.

The DLCO is interpreted in conjunction with spirometry and lung volumes. Table 3 shows the severity classification for DLCO. For example, high DLCO is associated with asthma, obesity, and intrapulmonary hemorrhage. Normal spirometry and lung volumes with low DLCO can be present in pulmonary vascular diseases, early ILD, or emphysema. An obstructive ventilatory defect with low DLCO suggests emphysema or lymphangiomyomatosis.[rx][rx]

Respiratory Muscle Pressures

The respiratory muscle strength is assessed with the maximal inspiratory pressure (MIP); also called negative inspiratory force (NIF) and maximal expiratory pressure (MEP). The MIP reveals the strength of the diaphragm and other inspiratory muscles; whereas, the MEP indicates the strength of the abdominal and other expiratory muscles.

MIP and MEP are measured three times, maximal value is reported. For adults 18 to 65 years old, MIP should be lower than -90 cmHO in men and -70 cmHO in women. In adults older than 65 years old, MIP should be less than -65 cmH2O in men and -45 cmH2O in women. MEP should be higher than 140 cmH2O in men and 90 cmH2O in women. MEP less than 60 cmH2O predicts a weak cough and difficulty clearing secretions.

Central and Upper Airway Obstruction

Central or upper airway obstruction (UAO) could occur in the extrathoracic (pharynx, larynx, and the extrathoracic part of the trachea) and intrathoracic airways (intrathoracic trachea and main bronchi). The FEV and/or FVC are not affected by this type of obstruction, but the peak expiratory flow (PEF) can be severely decreased. An FEV/PEF ratio of greater than 8 suggests central or UAO.

Three maximal and repeatable forced inspiratory and expiratory flow-volume curves are necessary. It is key that efforts, both inspiratory and expiratory are maximal.

The maximal inspiratory flow is largely decreased with an extrathoracic airway obstruction because there is a negative pressure inside the airways during inspiration. Inspiratory flows are not affected by intrathoracic lesions; the negative pleural pressure maintains the intrathoracic airways open. The maximal expiratory flow (peak flow) is decreased with intrathoracic and extrathoracic lesions.

The obstructions can be intrathoracic or extrathoracic and variable or fixed. In summary, fixed obstructions will have decreased inspiratory and expiratory flows; variable obstruction will depend on the location (intrathoracic or extrathoracic). The flow curve is not a sensitive test; the absence of the classic pattern does not rule out a central or UAO.[rx][rx][rx][rx]

Indications

There are multiple indications to obtain PFTs. Table 1 summarizes the most commons indications.

• PFTs can be physically demanding for patients, and it is recommended to wait one month after an acute coronary syndrome or myocardial infarction.
• Other relative contraindications are thoracic/abdominal surgery, brain/eye/ear/otolaryngological surgery, pneumothorax, ascending aortic aneurysm, hemoptysis, pulmonary embolism, severe hypertension (SBP greater than 200 mm Hg, DBP greater than 120 mm Hg).[rx]
• asthma
• allergies
• chronic bronchitis
• respiratory infections
• lung fibrosis
• bronchiectasis, a condition in which the airways in the lungs stretch and widen
• COPD, which used to be called emphysema
• asbestosis, a condition caused by exposure to asbestos
• sarcoidosis, an inflammation of your lungs, liver, lymph nodes, eyes, skin, or other tissues
• scleroderma, a disease that affects your connective tissue
• pulmonary tumor
• lung cancer
• weaknesses of the chest wall muscles

What are the risks of pulmonary function tests?

Because pulmonary function testing is not an invasive procedure, it is safe and quick for most people. But the person must be able to follow clear, simple directions.

All procedures have some risks. The risks of this procedure may include:

• Dizziness during the tests
• Feeling short of breath
• Coughing
• Asthma attack brought on by deep inhalation
• Recent eye surgery, because of increased pressure inside the eyes during the procedure
• Recent belly or chest surgery
• Chest pain, recent heart attack, or an unstable heart condition
• A bulging blood vessel (aneurysm) in the chest, belly, or brain
• Active tuberculosis (TB) or respiratory infection, such as a cold or the flu

Your risks may vary depending on your general health and other factors. Ask your healthcare provider which risks apply most to you. Talk with him or her about any concerns you have.

Certain things can make PFTs less accurate. These include:

• The degree of patient cooperation and effort
• Use of medicines that open the airways (bronchodilators)
• Use of pain medicines
• Pregnancy
• Stomach bloating that affects the ability to take deep breaths
• Extreme tiredness or other conditions that affect a person’s ability to do the tests (such as a head cold)

How do I get ready for pulmonary function tests?

Your healthcare provider will explain the procedure to you. Ask him or her any questions you have. You may be asked to sign a consent form that gives permission to do the procedure. Read the form carefully. Ask questions if anything is not clear.

Tell your healthcare provider if you take any medicines. This includes prescriptions, over-the-counter medicines, vitamins, and herbal supplements.

Make sure to:

• Stop taking certain medicines before the procedure, if instructed by your healthcare provider
• Stop smoking before the test, if instructed by your healthcare provider. Ask your provider how many hours before the test you should stop smoking.
• Not eat a heavy meal before the test, if instructed by your healthcare provider
• Follow any other instructions your healthcare provider gives you

Your height and weight will be recorded before the test. This is done so that your results can be accurately calculated.

What happens during pulmonary function tests?

You may have your procedure as an outpatient. This means you go home the same day. Or it may be done as part of a longer stay in the hospital. The way the procedure is done may vary. It depends on your condition and your healthcare provider’s methods. In most cases, the procedure will follow this process:

• You’ll be asked to loosen tight clothing, jewelry, or other things that may cause a problem with the procedure.
• If you wear dentures, you will need to wear them during the procedure.
• You’ll need to empty your bladder before the procedure.
• You’ll sit in a chair. A soft clip will be put on your nose. This is so all of your breathing is done through your mouth, not your nose.
• You’ll be given a sterile mouthpiece that is attached to a spirometer.
• You’ll form a tight seal over the mouthpiece with your mouth. You’ll be instructed to inhale and exhale in different ways.
• You will be watched carefully during the procedure for dizziness, trouble breathing, or other problems.
• You may be given a bronchodilator after certain tests. The tests will then be repeated several minutes later after the bronchodilator has taken effect.

Below are the steps for the most common types of lung function tests.

For a spirometry test

• You’ll sit in a chair and a soft clip will be put on your nose. This is done so you’ll breathe through your mouth, rather than your nose.
• You’ll be given a mouthpiece that is attached to a machine called a spirometer.
• You’ll place your lips tightly around the mouthpiece, and breathe in and out as instructed by your provider.
• The spirometer will measure the amount and rate of airflow over a period of time.

For a lung volume (body plethysmography) test

• You’ll sit in a clear, airtight room that looks like a telephone booth.
• As with a spirometry test, you’ll wear a nose clip and place your lips around a mouthpiece connected to a machine.
• You’ll breathe in and breathe out as instructed by your provider.
• The pressure changes inside the room help measure lung volume.

For a gas diffusion test

• You’ll wear a mouthpiece connected to a machine.
• You will be asked to inhale (breathe in) a very small, non-dangerous amount of carbon monoxide or other types of gas.
• Measurements will either be taken as you breathe in or as you breathe out.
• The test can show how effective your lungs are in moving gases to your bloodstream.

For an exercise test, you will

• Ride a stationary bike or walk on a treadmill.
• You’ll be attached to monitors and machines that will measure blood oxygen, blood pressure, and heartbeat.
• This helps show how well your lungs perform during exercise.

Complications

PFTs are safe in general, and there are no complications. There is some potential harm from 4 key factors:

• Maximal pressures generated in the thorax and their impact on abdominal and thoracic organs/tissues
• Large swings in blood pressure causing stresses on tissues in the body
• Expansion of the chest wall and lungs
• Spread of infections (e.g., tuberculosis, hepatitis B, HIV)

Contraindications of PFTs are related to those 4 factors to prevent potential complications like acute coronary syndrome, rupture of aneurysms, and dehiscence of the surgical wound.[rx]

• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5297948/
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4562454/
• https://www.ncbi.nlm.nih.gov/books/NBK538183/
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• https://www.ncbi.nlm.nih.gov/books/NBK448186/
• https://www.ncbi.nlm.nih.gov/books/NBK539742/
• https://www.ncbi.nlm.nih.gov/books/NBK538314/
• https://www.ncbi.nlm.nih.gov/books/NBK538324/
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• https://www.ncbi.nlm.nih.gov/books/NBK441904/
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6212352/
• https://www.sciencedirect.com/topics/medicine-and-dentistry/mechanics-of-breathing
• https://training.seer.cancer.gov/anatomy/respiratory/capacity.html
• https://www.atsjournals.org/doi/10.1164/ajrccm.157.4.nhlbi-5
• https://www.nhlbi.nih.gov/health-topics/pulmonary-function-tests
• https://www.hopkinsmedicine.org/health/treatment-tests-and-therapies/pulmonary-function-tests
• https://medlineplus.gov/lab-tests/lung-function-tests/

• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5297948/
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4562454/
• https://www.ncbi.nlm.nih.gov/books/NBK538183/
• https://www.ncbi.nlm.nih.gov/books/NBK539907/
• https://www.ncbi.nlm.nih.gov/books/NBK448186/
• https://www.ncbi.nlm.nih.gov/books/NBK539742/
• https://www.ncbi.nlm.nih.gov/books/NBK538314/
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• https://www.ncbi.nlm.nih.gov/books/NBK563244/
• https://www.ncbi.nlm.nih.gov/books/NBK482316/
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• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6212352/
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Positive end-expiratory pressure (PEEP) is a value that can be set up in patients receiving invasive or non-invasive mechanical ventilation. This activity reviews the indications, contraindications, complications, and other key elements of the use of PEEP in the clinical setting as relates to the essential points needed by members of an interprofessional team managing the care of patients requiring assisted ventilation.

Positive end-expiratory pressure (PEEP) is the positive pressure that will remain in the airways at the end of the respiratory cycle (end of exhalation) that is greater than the atmospheric pressure in mechanically ventilated patients.[rx]

An analogous term used for non-invasive ventilation is end positive airway pressure (EPAP) for patients receiving bi-level positive airway pressure (BPAP).

Continuous positive airway pressure therapy (CPAP), although not an interchangeable term, works by delivering a constant pressure, which at the time of exhalation works in the same way as PEEP.

PEEP can be a therapeutic parameter set in the ventilator (extrinsic PEEP), or a complication of mechanical ventilation with air trapping (auto-PEEP).

Function

Extrinsic PEEP can be used to increase oxygenation. By Henry’s law, the solubility of a gas in a liquid is directly proportional to the pressure of that gas above the surface of the solution. This applies to mechanical or noninvasive ventilation in that increasing PEEP will increase the pressure in the system. This, in turn, increases the solubility of oxygen and its ability to cross the alveolocapillary membrane and increase the oxygen content in the blood.

Extrinsic PEEP also can be used to improve ventilation-perfusion (VQ) mismatches. The application of positive pressure inside the airways can open or “splint” airways that may otherwise be collapsed, decreasing atelectasis, improving alveolar ventilation, and, in turn, decreasing VQ mismatch.[rx]

The application of extrinsic PEEP will, therefore, have a direct impact on oxygenation and an indirect impact on ventilation. By opening up airways, the alveolar surface increases, creating more areas for gas exchange and somewhat improving ventilation. Nevertheless, extrinsic PEEP should never be used for the sole purpose of increasing ventilation. If a patient needs to clear CO2 by improving ventilation, he should receive some level of pressure support for his ventilation, either via BPAP or invasive ventilation.

Extrinsic PEEP also significantly decreases the work of breathing.[rx][rx] This is especially important for stiff lungs with low compliance. In intubated patients with low compliance, work of breathing can represent an important part of their total energy expenditure (up to 30%). This increases CO2 and lactate production, both of which may be problems of their own. By decreasing work of breathing, CO2 and lactate production decreases, decreasing the need for high minute ventilation (to correct the hypercapnia and acidosis) and thereby decreasing respiratory drive and further decreasing the work of breathing needed by the patient in a positive-effect loop.

Issues of Concern

The use of Extrinsic PEEP also can cause some complications. Normal respiratory physiology works as a negative pressure system. When the diaphragm pushes down during inspiration, negative pressure in the pleural cavity is generated, creating negative pressure in the airways that suck air into the lungs. This same negative intrathoracic pressure decreases the right atrial (RA) pressure and generates a sucking effect on the IVC increasing venous return. The application of extrinsic PEEP changes this physiology. The positive pressure generated by the ventilator or BPAP transmits to the upper airways and finally to the alveoli which are transmitted to the alveolar space and thoracic cavity, creating positive pressure (or at least less negative pressure). This increases RA pressure and decreases venous return, generating a decrease in preload. This has a double effect in decreasing cardiac output: less blood in RV means less blood reaching LV and less blood that can be pumped out decreasing cardiac output, at the same time, the decreased preload means that the heart works at a less efficient point in the frank-startling curve, generating less effective work and further decreasing cardiac output and resulting in a drop in mean arterial pressure (MAP) if there is not a compensatory response by increasing systemic vascular resistance (SVR). This is a very important point to have in mind, especially with patients who may not be able to increase their SVR, such as those with distributive shock (e.g., septic, neurogenic, or anaphylactic).

This effect on RA pressure and venous return (VR) may be beneficial when used in patients with cardiogenic pulmonary edema. In patients with volume overload, decreasing VR will have a dual beneficial effect: the LV may be over distended, also be working at a less-than-optimal point of the frank starling curve. Decreasing VR will again decrease preload, but in this particular case, it has been proposed that the decrease in preload will place the LV at a more efficient workload, possibly increasing cardiac output and improving pulmonary edema, although it has never been shown that higher PEEP directly improves LV function.[rx] At the same time, decreased VR means less blood pumped by RV and less pulmonary edema being generated.

Another special circumstance in which extrinsic PEEP’s effect on CO and MAP is important to consider is in patients in whom a cerebral perfusion pressure (CCP) has to be maintained after a stroke or subarachnoid hemorrhage. In this case, although PEEP does not directly affect CCP, and cerebral autoregulation will normally compensate for changes in MAP, special attention has to be given in cases of disturbed cerebrovascular autoregulation, as the decrease in MAP can directly affect CCP causing adverse effects.[rx]

Other adverse effects of extrinsic PEEP include its capacity for generating barotrauma, especially in non-compliant lungs by increasing plateau pressures, and its interference with hemodynamic measurements in patients with right-heart catheters.

Clinical Significance

Using extrinsic PEEP clinically requires an understanding of all the principles discussed and will depend on many factors including the type of ventilation the patient is receiving (nasal intermittent positive pressure ventilation versus invasive mechanical ventilation) and the mode of ventilation (assist control, synchronized intermittent mandatory ventilation, airway pressure release ventilation). All of these different setups have a way to set extrinsic PEEP or an equivalent measure of positive pressure, and their specific set up in each case escapes the scope of this review. Nonetheless, there are some basic principles that apply to all modes of ventilation for PEEP:

• Start low and increase as tolerated and dial to patient comfort and desired oxygenation.
• Constantly check your plateau pressures to prevent barotrauma. As a general rule of thumb, you should aim the keep a plateau pressure below 30 cm H2O.
• Follow the MAP as you are dialing up or down the PEEP.
• When extubating a patient with cardiogenic pulmonary edema who are receiving extrinsic PEEP, consider its effects on VR as removing PEEP may precipitate new pulmonary edema and re-intubation.
• When managing patients with acute respiratory distress syndrome, the ARDSnet protocol provides clear guidance on how to titrate extrinsic PEEP and FiO2%.[rx]

Other Issues

Auto-PEEP or intrinsic PEEP

Intrinsic or auto-PEEP is a complication of mechanically ventilated patients.[rx] Usually, passive exhalation will permit complete emptying of the air in the lungs until lung pressure equalized with atmospheric pressure, but in some cases the lungs may not completely deflate, leaving air trapped inside the lung at the end of exhalation which generates a positive pressure that remains in the lungs. This pressure is called auto or intrinsic PEEP. When this process repeatedly happens with each respiratory cycle, the amount of air trapping increases with each breath and consequently the intrathoracic pressure increases pathologically, compressing the RA and decreasing VR causing hypotension, as well as increasing plateau pressure (intra-alveolar pressure) and causing barotrauma. The increased air trapping also will make it harder for the patient to bring new air in, increasing the work of breathing, which increases oxygen consumption and CO2 production, thereby increasing the need for ventilation, increasing respiratory rate, and worsening auto-PEEP in a vicious cycle.

Factors leading to auto-PEEP 

• Airway inflammation and mucus plugs generate dynamic airflow obstruction as a forced expiratory effort will increase the pressure around the airway leading to closure around the plugs or inflamed area and trapping air in the alveoli that are dependent on that airway.
• High lung compliance as in chronic obstructive pulmonary disease (COPD) works similarly, as the airways lack scaffolding to stay open during forced exhalation, leading to dynamic airway collapse and air trapping.
• High tidal volume ventilation, where the tidal volume may be too high to be exhaled in a set amount of time, so air is retained by the time the next breath is delivered.
• The high respiratory rate is generating a short exhalation time.
• Slow inspiratory flow generating a higher inspiratory to expiratory time ratio (too much time taken during inhalation does not leave enough time for a full exhalation).

Two types of auto-PEEP

• Dynamic hyperinflation with intrinsic expiratory flow obstruction is the most common cause of auto-PEEP in COPD patients in whom alveolar collapse during expiration leads to air trapping. It has been stipulated that low-level extrinsic PEEP can help decrease auto-PEEP in these patients by splinting airways open, leading to the easier release of air from the alveoli. Airway inflammation and mucus plugs also cause dynamic hyperinflation in a similar fashion, although the use of extrinsic PEEP in these patients has not been shown to be beneficial as in COPD.
• Dynamic hyperinflation without airflow obstruction occurs when not enough time is given for the patient to exhale, for example in high respiratory rate, low inspiratory flow, or high tidal volume in which there may not be enough time for the air to leave the lungs before the next respiratory cycle leading to air trapping. In cases like this application of extrinsic PEEP would be detrimental as it would generate backpressure preventing air to flow freely out of the lungs.

When to suspect auto-PEEP

• Exhalation is still ongoing when the next respiratory cycle starts. This can be easily checked by looking at the volume curve in the ventilator display. If this curve fails to go back to zero, then it is a sign that air is being trapped.[rx]
• Increasing plateau pressures on the ventilator.
• Active exhalation by the patient as seen by the use of accessory muscles of respiration during exhalation.
• Drop-in blood pressure.
• Long expiratory times.
• Respiratory distress.

Although there is a big differential for an intubated patient, who develops respiratory distress, the presence of a volume curve that does not go back to zero before the next breath is delivered is very highly suggestive of auto-PEEP.

Treating auto-PEEP

It is important to minimize or prevent the development of auto-PEEP in the ventilated population as its consequences may be dire.

In the most extreme case in which patients are in respiratory distress and shock, disconnecting the patient from the ventilator and allowing enough time for exhalation before manually bagging the patient is a quick life-saving measure.

For less dramatic cases, several measures can be taken to reduce the amount and prevent the development of auto-PEEP.

Assuring enough time for exhalation so that all the air in the lungs can get out is the most important principle governing the prevention of auto-PEEP. This may be achieved by multiple methods:[rx]

• Decreasing respiratory rate will increase the time between breaths and decrease the inspiratory to expiratory (I:E) ratio to 1:3 to 1:5.
• Increasing the inspiratory rate to 60 to 100 L/min will assure fast delivery of air during inspiration, lending more time for exhalation.
• Utilize a square waveform for ventilation delivery. This is uncomfortable for the patient but speeds the inspiration process.
• Decrease tidal volume. When there is less air being pushed into the lungs, there is less air needed to be pushed out and less time is required to finish a full exhalation.
• Decrease respiratory demand by decreasing CO2 and lactate production (minimize work of breathing, control fever and pain, ensure adequate sedation, control anxiety, treat sepsis)

If there is also flow obstruction, minimize it by treating bronchoconstriction with bronchodilators and suctioning mucus plugs. Treat airway inflammation with steroids when indicated.

The use of extrinsic PEEP is tricky, and although it may be beneficial, it has to be guided by good clinical sense. In cases of dynamic flow obstruction, especially in COPD where there is alveolar collapse, (Note: This does not include asthma where there is inflammation of the airway but not necessarily airway collapse.) the application of extrinsic PEEP will splint the airways open, permitting this way for air to be flushed from alveolar pouches and decreasing auto-PEEP. Extrinsic PEEP will also decrease the work of breathing in the appropriate setting. Nevertheless, when applied in the wrong setting, like in patients without dynamic airflow obstruction, the application of extrinsic PEEP will generate back pressure that will prevent air from getting out of the lungs, worsening air trapping. It is also important to understand that the extrinsic PEEP initially will add to the auto-PEEP, increasing the intrathoracic pressure. When used, it is recommended to maintain extrinsic PEEP below 75% to 85% of the auto-PEEP. Again, the use of extrinsic PEEP to treat auto-PEEP has to be driven by strong clinical sense as not all patients will benefit from it and others will be harmed. A practical way to assess the effects of extrinsic PEEP in auto-PEEP is to apply small increments of extrinsic PEEP and check the static pressures in the lungs. If the static pressures do not increase, then applying extrinsic PEEP may benefit the patient, but if the pressures increase, then it is time to back down on this strategy.

• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5297948/
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4562454/
• https://www.ncbi.nlm.nih.gov/books/NBK538183/
• https://www.ncbi.nlm.nih.gov/books/NBK539907/
• https://www.ncbi.nlm.nih.gov/books/NBK448186/
• https://www.ncbi.nlm.nih.gov/books/NBK539742/
• https://www.ncbi.nlm.nih.gov/books/NBK538314/
• https://www.ncbi.nlm.nih.gov/books/NBK538324/
• https://www.ncbi.nlm.nih.gov/books/NBK545226/
• https://www.ncbi.nlm.nih.gov/books/NBK560535/
• https://www.ncbi.nlm.nih.gov/books/NBK563244/
• https://www.ncbi.nlm.nih.gov/books/NBK482316/
• https://www.ncbi.nlm.nih.gov/books/NBK441904/
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6212352/
• https://www.sciencedirect.com/topics/medicine-and-dentistry/mechanics-of-breathing
• https://training.seer.cancer.gov/anatomy/respiratory/capacity.html
• https://www.atsjournals.org/doi/10.1164/ajrccm.157.4.nhlbi-5

Hypoxia is a state in which oxygen is not available in sufficient amounts at the tissue level to maintain adequate homeostasis; this can result from inadequate oxygen delivery to the tissues either due to low blood supply or low oxygen content in the blood (hypoxemia). Hypoxia can vary in intensity from mild to severe and can present in acute, chronic, or acute and chronic forms. This activity reviews the etiology, pathophysiology, and presentation of hypoxia and highlights the role of the interprofessional team in the management of affected patients.

Hypoxia is a state in which oxygen is not available in sufficient amounts at the tissue level to maintain adequate homeostasis; this can result from inadequate oxygen delivery to the tissues either due to low blood supply or low oxygen content in the blood (hypoxemia).

Hypoxia can vary in intensity from mild to severe and can present in acute, chronic, or acute and chronic forms. The response to hypoxia is variable; while some tissues can tolerate some forms of hypoxia/ischemia for a longer duration, other tissues are severely damaged by low oxygen levels.[rx][rx][rx]

Hypoxia is a condition in which tissues of the body do not receive sufficient oxygen (O₂) supply. The imbalance between tissue O₂ supply and consumption results in an insufficient O₂ supply to maintain cellular function. Hypoxia is defined as an O₂ saturation (SpO₂) < 90%. Hypoxemia is a decrease in oxygen tension in the arterial blood (PaO₂) and is defined as a PaO₂ < 60 mmHg. A SpO₂ < 90% or a PaO₂ < 60 mmHg places a patient on the “steep” area of the oxygen–hemoglobin dissociation curve, where small changes in PaO₂ cause large changes in SpO₂ and rapid clinical deterioration

Types of Hypoxia

• Asphyxia – condition of severely deficient supply of oxygen to the body caused by abnormal breathing
• Cerebral hypoxia – Oxygen shortage of the brain or cerebral anoxia, a reduced supply of oxygen to the brain
• Erotic asphyxiation – Intentional restriction of oxygen to the brain for sexual arousal or autoerotic hypoxia, intentional restriction of oxygen to the brain for sexual arousal
• Fink effect – Changes of oxygen partial pressure in the pulmonary alveoli caused by a soluble anesthetic gas, or diffusion hypoxia, a factor that influences the partial pressure of oxygen within the pulmonary alveolus
• G-LOC cerebral hypoxia induced by excessive g-forces
• histotoxic hypoxia, the inability of cells to take up or utilize oxygen from the bloodstream
• Hyperoxia – exposure of tissues to abnormally high concentrations of oxygen.
• Hypoventilation training – Physical training method in which reduced breathing frequency are interspersed with periods with normal breathing
• Hypoxemia – Abnormally low level of oxygen in the blood or hypoxemic hypoxia, a deficiency of oxygen in arterial blood
• Hypoxia in fish – Response of fish to environmental hypoxia, responses of fish to hypoxia
• Hypoxia-inducible factors
• Hypoxic hypoxia, a result of insufficient oxygen available to the lungs
• Hypoxic ventilatory response
• Hypoxicator a device intended for hypoxia acclimatisation in a controlled manner
• Intermittent hypoxic training
• Intrauterine hypoxia, when a fetus is deprived of an adequate supply of oxygen
• Latent hypoxia – Tissue oxygen concentration which is sufficient to support consciousness at depth, but not at surface pressure or deep water blackout, loss of consciousness on ascending from a deep freedive
• Pseudohypoxia, increased cytosolic ratio of free NADH to NAD⁺ in cells
• Rhinomanometry
• Sleep apnea – Disorder involving pauses in breathing during sleep
• Time of useful consciousness
• Tumor hypoxia, the situation where tumor cells have been deprived of oxygen

Causes of Hypoxia

There are two major causes of hypoxia at the tissue level, low blood flow to the tissue, or low oxygen content in the blood (hypoxemia).[rx][rx][rx]

In order to understand the mechanism of hypoxia, we have to know that in order to have the oxygen carried by hemoglobin, direct interaction between red blood cells in pulmonary capillaries and the air in the alveoli is needed. This process can be compromised at any one of the following three points: blood flow to the lung (perfusion), airflow to the alveoli (ventilation), and the gas exchange through the interstitial tissue (diffusion).

The brain depends on the blood to provide it with a constant supply of oxygen. Thus disruptions to any part of the body that plays a role in blood or oxygen supply can lead to hypoxia. The four primary causes of hypoxia are:

• No blood supply to the brain – This occurs when the blood vessels that supply the brain with blood are completely obstructed. This is extremely rare and usually fatal.
• Low blood supply to the brain – Low blood supply can occur when even a single blood vessel is blocked or partially obstructed, as often happens with a stroke. This form of hypoxia frequently affects a specific region of the brain, interfering with functions governed by that region.
• No blood oxygen – When the body can’t take in oxygen, or the heart or lungs can’t properly provide the blood with oxygen, the brain — and all other organs — suffer from hypoxia. This is quickly fatal.
• Low blood oxygen – When the body can’t properly oxygenate the blood, often due to illnesses such as emphysema or a crisis such as a heart attack, the brain gets less oxygen than it needs to properly function.

Reduced Oxygen Tension

As in cases of high altitude.

Hypoventilation

• Airway obstruction can be proximal as in laryngeal edema or foreign body inhalation, or distal as in bronchial asthma or chronic obstructive pulmonary disease (COPD).
• Impaired respiratory drive as in cases of deep sedation or coma.
• Restricted movement of the chest wall as in obesity hypoventilation syndrome, circumferential burns, massive ascites, or ankylosing spondylitis.
• Neuromuscular diseases, such as myasthenia gravis, muscular dystrophy, amyotrophic lateral sclerosis, or phrenic nerve injuries.

Ventilation-Perfusion Mismatch (V/Q Mismatch)

• Decreased V/Q Ratio (impaired ventilation or high perfusion) such as chronic bronchitis, obstructive airway disease, mucus plugs, pulmonary edema impair the ventilation and therefore decrease the ratio of ventilation to perfusion.
• Increased V/Q Ratio (impaired perfusion): such as in cases of pulmonary embolism or increased ventilation as in emphysema (large bullae in the lungs) the surface area available for gas exchange is decreased, which causes higher ventilation in comparison to perfusion leading to a high V/Q ratio.

Others

• Hypoxemic Hypoxia – Low oxygen tension in the arterial blood (PaO2) is due to the inability of the lungs to properly oxygenate the blood. Causes include hypoventilation, impaired alveolar diffusion, and pulmonary shunting.
• Circulatory Hypoxia – It is due to pump failure (heart is unable to pump enough blood, and therefore oxygen delivery is impaired).
• Anemic Hypoxia – It is because of a decrease in oxygen-carrying capacity due to low hemoglobin leading to inadequate oxygen delivery.
• Histotoxic Hypoxia (Dysoxia) – Cells are unable to utilize oxygen effectively, the best example of this is Cyanide poisoning which inhibits the enzyme cytochrome C oxidase in the mitochondria, blocking the use of oxygen to make ATP.
• Traveling to high altitudes, especially for people in poor health and for those who quickly rise to high altitudes.
• Carbon monoxide poisoning.
• Strangulation or smothering. For example, the choke holds that some law enforcement officers use can cause hypoxia if held too long.
• Very low blood pressure, which is usually caused by something else, such as a hemorrhage.
• Smoke inhalation.
• Choking.
• Heart attack or stroke.
• Medical conditions such as a heart attack or stroke.
• Allergic reactions that lead to anaphylactic shock.
• Severe cases of asthma.
• Allergies
• In infants, improper sleep positions or unsafe sleep environments. For example, young babies can be smothered in crib bumpers, or get inadequate oxygen while sleeping on their stomachs.
• Hyperventilation.

Right to Left Shunt

The blood crosses from the right to the left side of the heart without being oxygenated. Causes include:

• Anatomic Shunts: Blood bypasses the alveoli, e.g., intracardiac shunts (ASD, VSD, PDA), pulmonary arteriovenous malformations, fistulas, and hepato-pulmonary syndrome.
• Physiologic Shunting: Blood passes through non-ventilated alveoli, for example, pneumonia, atelectasis, and ARDS.

Impaired Diffusion of Oxygen

Oxygen diffusion is impaired between the alveolus and the pulmonary capillaries. Causes are usually interstitial edema, interstitial inflammation, or fibrosis. Clinical examples include pulmonary edema and interstitial lung disease.

Hypoventilation

This includes the factors that decrease the percentage of oxygen in the alveoli, either due to obstruction of the airways or an increase in partial pressure of alveolar gases other than oxygen. Carbon dioxide is one example. Hypoventilation can also occur due to impaired respiratory drive as in cases of deep sedation or because of restricted movement of the chest wall as in obesity hypoventilation syndrome or ankylosing spondylitis. In this setting, the A-a gradient will be normal as the oxygen is deficient in both alveoli and the bloodstream.

In alveoli, an increase in partial pressure of one gas will be on the cost of the other gases composing the air, e.g., an increase in carbon dioxide partial pressure results in a decrease of partial pressure of oxygen, both at alveolar as well as the arterial level. This type of hypoxemia is easily corrected with supplemental oxygen.

Ventilation-Perfusion Mismatch (V/Q Mismatch)

This occurs when there is an imbalance between lung ventilation and blood flow. Even in the normal lung, there is a V/Q mismatch. In an upright individual, the V/Q ratio is higher in the apices than at the lung base. This difference is responsible for the normal A-a gradient. V/Q mismatch increases in pulmonary vascular disease, thromboembolic disease, or atelectasis to name a few. Such a process ultimately results in hypoxemia which is more difficult to correct with supplemental oxygen.

Right to Left Shunt

Occurs when blood passes from the right to the left side of the heart without being oxygenated. Anatomic abnormalities, such as atrial or ventricular septal defects as well as pulmonary arteriovenous malformations can cause hypoxemia that is notoriously difficult to correct with supplemental oxygen. Similar physiology is observed in hepato-pulmonary syndrome. Physiologic right-to-left shunt exists when the blood passes through non-ventilated alveoli in cases of atelectasis, pneumonia, and acute respiratory distress syndrome (ARDS).

Impaired Diffusion of Oxygen Across the Alveoli into Blood

The usual causes are interstitial edema, lung tissue inflammation, or fibrosis. Depending on the disease’s extent, a moderate to a large amount of supplemental oxygen may be required to correct this type of hypoxemia. Exercise can worsen hypoxemia resulting from impaired diffusion. An increase in cardiac output with exercise results in accelerated blood flow through alveoli, reducing the time available for gas exchange. In the case of the abnormal pulmonary interstitium, gas exchange time becomes insufficient, and hypoxemia ensues.

Symptoms of Hypoxia

Oxygen plays an important part in your body’s cells and tissues. The only way for your body to get oxygen is through your lungs.

COPD results in inflammation and swelling of your airways. It also causes the destruction of the lung tissue called alveoli. COPD causes a restricted flow of oxygen in your body as well.

Symptoms of hypoxia often include:

• shortness of breath while resting
• severe shortness of breath after physical activity
• decreased tolerance to physical activity
• waking up out of breath
• feelings of choking
• wheezing
• frequent cough
• bluish discoloration of the skin
• Changes in the color of your skin, ranging from blue to cherry red
• Confusion
• Cough
• Fast heart rate
• Rapid breathing
• Shortness of breath
• Slow heart rate
• Sweating
• Wheezing

Symptoms of oxygen deprivation include

• Something obstructing the face, mouth, or nose; increased carbon monoxide exposure can be a problem in enclosed areas, so a person in a very small space or whose face is covered may suffer from oxygen deprivation even if they can breathe.
• Changes in mood or personality; the victim may seem confused.
• Loss of consciousness, including fainting or seizures.
• Blue or white lips, tongue, or face.
• Tingling in the extremities.
• Pupils that don’t respond normally to light.
• Not breathing, or not expelling air when exhaling.
• Hyperventilating or gasping for air.
• Unable to speak; a person who is truly choking may not cough.

COPD is a chronic condition, so you may experience any of these symptoms on an ongoing basis. If you experience any of these symptoms, it’s considered a medical emergency.

You should call your local emergency services, or go to an emergency room, if you experience a change from your baseline or if your symptoms worsen. This is especially important if the symptoms are associated with chest pain, fever, fatigue, or confusion.

Diagnosis of Hypoxia

The presentation of hypoxia can be acute or chronic; acutely the hypoxia may present with dyspnea and tachypnea. Symptom severity usually depends on the severity of hypoxia. Sufficiently severe hypoxia can result in tachycardia to provide sufficient oxygen to the tissues. Some of the signs are very evident on physical exam; stridor can be heard once the patient arrives in cases of upper airway obstruction. Skin can be cyanotic, which might indicate severe hypoxia.

When oxygen delivery is severely compromised, organ function will start to deteriorate. Neurologic manifestations include restlessness, headache, and confusion with moderate hypoxia. In severe cases, altered mentation and coma can occur, and if not corrected quickly may lead to death.

The chronic presentation is usually less dramatic, with dyspnea on exertion as the most common complaint. Symptoms of the underlying condition that induced the hypoxia can help in narrowing the differential diagnosis. For instance, productive cough and fever will be seen in cases of lung infection, leg edema, and orthopnea in cases of heart failure, and chest pain and unilateral leg swelling may point to pulmonary embolism as a cause of hypoxia.

The physical exam may show tachycardia, tachypnea, and low oxygen saturation. Fever may point to infection as the cause of hypoxia.

Lung auscultation can yield a lot of useful information. Bilateral basilar crackles may indicate pulmonary edema or volume overload, other signs of that includes jugular venous distention and lower limb edema. Wheezing and rhonchi can be found in obstructive lung disease. Absent unilateral air entry can be caused by either massive pleural effusion or pneumothorax. Chest percussion can help differentiate the two and will reveal dullness in cases of pleural effusion and hyper-resonance in cases of pneumothorax. Clear lung fields in a setting of hypoxia should raise suspicion of pulmonary embolism, especially if the patient is tachycardic and has evidence of deep vein thrombosis (DVT).

Lab Test And Imaging

Evaluation of Acute Hypoxia

Pulse Oximetry to Evaluate Arterial Oxygen Saturation (SaO2)

The arterial oxygen saturation (SaO2) refers to the amount of oxygen bound to hemoglobin in arterial blood. The measurement is given as a percentage. Resting SaO2 less than or equal to 95% or exercise desaturation greater than or equal to 5% is considered abnormal. However, clinical correlation is always necessary as the exact cutoff below which tissue hypoxia ensues has not been defined.[rx][rx][rx]

Arterial Blood Gas

It is a useful tool to evaluate hypoxemia. Aside from the diagnosis of hypoxemia, additional information obtained, such as PCO2, can shed light on the etiology of the process.

• Arterial oxygen tension (PaO2): Partial pressure of oxygen is the amount of oxygen dissolved in the plasma. A PaO2 less than 80 mmHg is considered abnormal. However, this should be in line with the clinical situation.
• The partial pressure of CO2: It is an indirect measure of exchange of CO2 with the air via the alveoli, its level is related to minute ventilation. PCO2 is elevated in hypoventilation like in obesity hypoventilation, deep sedation, or maybe in the setting of acute hypoxia secondary to tachypnea and washout of CO2.

PaO2:FiO2 ratio (Normal ratio is 300 to 500), if this ratio drops this may indicate a deterioration in gas exchange, this is particularly important in defining ARDS.

Imaging

Imaging studies of the chest, such as chest x-rays or CT help in identifying the cause of the hypoxia, e.g., pneumonia, pulmonary edema, hyperinflated lungs in COPD, and other conditions. CT chest can give more detailed images that outline the exact pathology, CT angiogram of the chest is of particular importance in detecting the pulmonary embolism. Another modality is the VQ scan which can detect the ventilation-perfusion mismatch, which is helpful in diagnostics of acute or chronic pulmonary embolism. VQ scan can be particularly useful when renal failure or allergy to iodinated contrast increases the risks of CT angiography.

The first step in evaluating the hypoxia is to calculate the A-a gradient of oxygen. This is the difference in the amount of oxygen between the Alveoli “A” and the amount of oxygen in the blood “a.” In other terms, the A-a oxygen gradient = PAO2 – PaO2.

PaO2 can be obtained from the arterial blood gas; however, PAO2 is calculated using the alveolar gas equation:

• PAO2 = (FiO2 x [760-47]) – PaCO2/0.8)

760 is the atmospheric pressure at the sea level in mmHg, 47 is the partial pressure of water at a temperature of 37 C, and 0.8 is the steady-state respiratory quotient.

The A-a gradient changes with age, and thus it is corrected for age using this equation; A-a gradient = (age/4+4).

If the A-a gradient is normal, then the cause of hypoxia is low oxygen content in the alveoli, either due to low O2 content in the air (low FiO2, as in the high altitude) or more commonly due to hypoventilation like the central nervous system (CNS) depression, OHS, or obstructed airways as in COPD exacerbation.

If the gradient is height then the cause of hypoxia is either due to a diffusion defect or perfusion defect (VQ mismatch), an alternative explanation is shunting of blood flow around the alveolar circulation, administering 1.0 FiO2 may help differentiate the two, as the oxygenation will improve in VQ mismatch in contrast to cases where shunt physiology is present.

PaO2:FiO2 Ratio

This ratio is another way to measure the degree of hypoxia. A normal PaO2/FiO2 ratio is about 300 to 500 mmHg. The ratio of less than 300 indicates abnormal gas exchange, and values less than 200 mmHg indicate severe hypoxemia. The PaO2/FiO2 ratio is used mostly as a definition of acute respiratory distress syndrome severity.

Evaluation of Chronic Hypoxia

Pulmonary Function Test (PFT)

PFT provides a direct measure of the lung volumes, bronchodilator response, and diffusion capacity, which can help in establishing the diagnosis and guiding the treatment of lung disorders. Aiding the history and physical exam, PFTs can be used to differentiate between the obstructive (bronchial asthma, COPD, upper airway obstruction) versus restrictive lung diseases (interstitial lung diseases, chest wall abnormalities). PFTs play a role in the assessment of airway obstruction severity as well as a response to therapy. One has to keep in mind that PFTs are effort-dependent and require the patient’s ability to cooperate and understand instructions.

Nocturnal (overnight) Trend Oximetry

It provides information about oxyhemoglobin saturation over a period (usually overnight). This test is primarily used to assess adequacy or need for oxygen supplementation at night. Use of overnight trend oximetry as a surrogate for a diagnostic sleep study is possible, however, is discouraged. A formal sleep study should be used whenever possible.

Six-Minute Walk Test

This test provides information on oxyhemoglobin saturation response to exercise as well as the total distance a patient can walk in 6 minutes on a ground level. This information can be used to titrate oxygen supplementation as well as evaluate the response to therapy. The 6-minutes walk test is frequently used in the preoperative pulmonary evaluation, pulmonary hypertension treatment and assessment of supplemental oxygen need with exercise.

Hemoglobin

Secondary polycythemia can be an indicator of chronic hypoxia.

Treatment of Hypoxia

Management of hypoxia falls under 3 categories: maintaining patent airways, increasing the oxygen content of the inspired air, and improving the diffusion capacity.[rx][rx][rx]

Maintaining Patent Airways

Ensure patency of the upper airways with good suctioning, maneuvers that prevent occlusion of the throat (head tilt and jaw thrust if necessary), sometimes the placement of an endotracheal tube or tracheostomy is necessary.

In chronic conditions like obesity hyperventilation syndrome, maintaining patent airways can be achieved with positive pressure ventilation like CPAP or BiPAP.

Bronchodilators and aggressive pulmonary hygiene, such as chest physiotherapy, the flutter valve, and incentive spirometry can be used to maintain the patency of the lower airways.

Increase Fraction of the Inspired O2 (FiO2)

This is indicated for low PaO2 less than 60 or SaO2 less than 90, and this can be achieved by increasing the percentage of oxygen in the inspired air that reaches the alveoli.

Low-Flow Devices

• Use: mild hypoxia (with FiO2 approximately 92%)
• Flow rate: up to 6 L per minute
• FiO2 delivered: up to 45% (0.45)
• Advantage: Easy to use and more convenient to the patient (can be used during eating, drinking, talking)
• Disadvantage: Dry nasal mucosa (humidify if the flow is greater than or equal to 4 L per minute), FiO2 being delivered varies greatly. Mouth breathers derive less benefit from using a nasal cannula.
• The following formula can be used to approximate the percentage of FiO2; FiO2 = 20% + (4 times oxygen flow liters) For example, oxygen flow 2L/min would deliver approximately FiO2 of 0.3, 6 L per minute would deliver approximately FiO2 of 0.45 (more commonly known as 45%).

• Use: Moderate to severe hypoxia, initial treatment
• Flow rate: up to 10 L per minute
• FiO2 delivered: 35% to 50%
• Advantage: provides higher FiO2, no pressures involved, well tolerated by patients
• Disadvantage: Dry oral mucosa (needs humidification), the flow must be at least 5 L per minute to flush CO2, not high flow. Also, the mask itself can interfere with activities of daily living.

• The device uses a reservoir space, which stores O2 during expiration, making it available as a bolus during the next inspiration. This way the patient gets a higher oxygen delivery without increasing flow.
• Flow rate: up to 16 L per minute.
• FiO2 = up to 90% (0.9)
• Reservoir cannulas are available as mustache configuration (Oxymizer), where the  reservoir is located directly beneath the nose, pendant configuration (Oxymizer Pendant) which is connected to a plastic reservoir on the anterior chest

• Has a 300 to 500 mL reservoir bag and 2 one-way valves to prevent exhaling into the reservoir
• Use: Moderate to severe hypoxia, initial treatment
• Flow rate: 6 to 10 L per minute (flow must be sufficient to keep reservoir bag from collapse during inspiration)
• FiO2 delivered: 50% to 70%
• Advantage: Higher FiO2 can be delivered
• Disadvantage: Interferes with activities of daily living

• Has a 300 to 500 mL reservoir bag and 2 one-way valves
• Use: Moderate to severe acute hypoxia, initial treatment
• Flow rate: 10 to 15 (at least 10 L per minute to avoid bag collapse during inspiration)
• FiO2 delivered: 85% to 90%
• Advantage: even higher FiO2 can be achieved
• Disadvantage: Interferes with activities of daily living

High-Flow Devices 

Usually, this requires an oxygen blender, humidifier, and heated tubing.

• Mask attached an air entrainment valve
• Use: Moderate to severe hypoxia, initial treatment
• The flow rate and FiO2: (depends on the color). (Blue = 2 to 4 L per minute = 24% O2, White = 4 to 6 L per minute = 28% O2, Yellow = 8 to 10 L per minute = 35% O2, Red = 10 to 12 L per minute = 40% O2, Green = 12 to 15 L per minute = 60% O2)
• Advantage: provides the most accurate O2 delivery, high flow
• Disadvantage: need to be removed for eating. Less accurate at high flow rates
• Does not guarantee the total flow with O2 percentages above 35% in patients with high inspiratory flow demands; the problem with air entrainment systems is that as this is increased, the air to oxygen ratio decreases

• High-flow oxygen (HFO) consists of a heated, humidified O2
• Flow rate: 10 to 60 L per minute
• FiO2 delivered: Up to 100%
• Advantages: More convenient, Can deliver up to 100% heated and humidified oxygen at a maximum flow of 60 L
• Disadvantages: Fairly large cannula, can be a source of (although usually rather minimal) discomfort

• Provides accurate oxygen delivery independent of the patient’s inspiratory flow demands
• Positive end-expiratory pressure may be generated
• For approximately every 10 liters of flow delivered, about 1 cm/HO of positive pressure is obtained

Positive Pressure Ventilation

It allows for accurate delivery of any necessary FiO2 and includes the following:

Non-Invasive Ventilation

It is usually used as the last resort to avoid the intubation

• Mainly used in patients with obstructive sleep apnea or in acute pulmonary edema.
• Delivers oxygen (or air) under pre-determined high pressure via a tightly fitting face mask.
• Positive pressure is continuous, to ensure that the airways are open (split them)

• Mainly used in patients with acute Hypercarbia as in patients with COPD exacerbation and ARDS patients.
• High positive pressure on inspiration and lower positive pressure on expiration.
• Pressure delivery is variable throughout the respiratory cycle, with high positive pressure on inspiration and lower positive pressure on expiration.

Invasive Ventilation

• Positive pressure ventilator attached to (usually) endotracheal tube.
• Allows for accurate delivery of predetermined minute ventilation as well as accurate FiO2 and positive end-expiratory pressure.
• Can be used electively during surgery.

Improve the Diffusion of Oxygen through the Alveolar Interstitial Tissue

The overall idea s to treat the underlying cause of respiratory failure:

• Diuretics can be used in cases of pulmonary edema.
• Steroids in certain cases of interstitial lung disease.
• Extracorporeal membrane oxygenation (ECMO) can be used as an ultimate method of increasing oxygenation.

Other Issues

• Hypoventilation presents with an elevated PaCO2 with a normal A-a gradient.
• Low-inspired oxygen presents with a normal PaC02 plus normal A-a gradient.
• Shunting presents with a normal PaC02 and elevated A-a gradient that does not correct with the administration of 100% oxygen.
• V/Q mismatch presents with a normal PaC02 and elevated A-a gradient that does correctly with 100% oxygen.
• Oxygen supplementation varies between FiO2 of 0.21 and 1.00. A variety of low and high flow devices exist to facilitate this process, each with unique advantages and disadvantages.
• The delivery of oxygen depends on two variables:

1. • FiO2
   • Flow rate

• There are several devices designed to deliver oxygen at different rates and concentrations as described above.
• Oxygen toxicity may result if oxygen is delivered at a higher concentration for a long duration of time.
• Decreased body temperature decreases metabolic rate, which lowers oxygen consumption and minimizes the adverse effects of tissue hypoxia (especially brain) Therapeutic hypothermia is based on this principle.
• Long-term oxygen therapy can reduce mortality, and it is indicated in these patient populations:

1. • Group 1 (Absolute): PaO2 55 mm Hg or SaO2  88%
   • Group 2 (In the presence of cor pulmonale): PaO2 55 to 59 mm Hg or SaO2 89%, ECG evidence of right atrial enlargement, hematocrit greater than  55%, congestive heart failure

• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5297948/
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4562454/
• https://www.ncbi.nlm.nih.gov/books/NBK538183/
• https://www.ncbi.nlm.nih.gov/books/NBK539907/
• https://www.ncbi.nlm.nih.gov/books/NBK448186/
• https://www.ncbi.nlm.nih.gov/books/NBK539742/
• https://www.ncbi.nlm.nih.gov/books/NBK538314/
• https://www.ncbi.nlm.nih.gov/books/NBK538324/
• https://www.ncbi.nlm.nih.gov/books/NBK545226/
• https://www.ncbi.nlm.nih.gov/books/NBK560535/
• https://www.ncbi.nlm.nih.gov/books/NBK563244/
• https://www.ncbi.nlm.nih.gov/books/NBK482316/
• https://www.ncbi.nlm.nih.gov/books/NBK441904/
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6212352/
• https://www.sciencedirect.com/topics/medicine-and-dentistry/mechanics-of-breathing
• https://training.seer.cancer.gov/anatomy/respiratory/capacity.html
• https://www.atsjournals.org/doi/10.1164/ajrccm.157.4.nhlbi-5

Ventilator-induced lung injury is the acute lung injury inflicted or aggravated by mechanical ventilation during treatment and has the potential to cause significant morbidity and mortality. The potential morbidity and the mortality impact of ventilator-induced lung injury are increasingly recognized across the world. However, accurate data on the incidence and prevalence of this condition is still scanty. This activity covers the etiology, clinical evaluation, and measures to attenuate or prevent this dreaded condition highlighting the importance of an interprofessional team in the diagnosis and management.

Ventilator-induced lung injury (VILI) is the acute lung injury inflicted or aggravated by mechanical ventilation during treatment. Ventilator-induced lung injury could occur during invasive as well as non-invasive ventilation and might contribute significantly to the morbidity and mortality of critically ill patients. Though mechanical ventilation potentially injures both normal and diseased lungs, the injury will be much more severe in the latter due to higher microscale stresses. Ventilator-induced lung injury (VILI) has been used synonymously with ventilator-associated lung injury (VALI). However, the latter terminology is more appropriate when the lung injury is strongly presumed to be due to ventilation but lacking any strong evidence to confirm the same.

The concept of injury by mechanical ventilation dates back to 1744 when John Fothergill, after successful resuscitation of a patient by mouth to mouth respiration, expressed the view that mouth to mouth ventilation might be a better option than machine bellows in resuscitation since the latter could potentially harm the lungs with the uncontrolled push of air. Investigators during the 1952 polio epidemic had documented structural lung damages caused by mechanical ventilation.[rx]

In 1967, the term “respirator lung” was coined to describe the post mortem lung pathology of patients who had undergone mechanical ventilation and whose lungs showed extensive alveolar infiltrates and hyaline membrane formation.[rx] Further confirmatory evidence for ventilator-induced lung injury comes from the landmark ARDS Nett trial, where low tidal volume ventilation was proved to be superior to high tidal volume ventilation in ARDS patients.[3]

Causes of Ventilator-Induced Lung Injury

The predominant mechanisms by which the ventilator-induced lung injury occurs include alveolar overdistention (volutrauma), barotrauma, atelectotrauma, and inflammation (biotrauma). Other mechanisms that are attributed include adverse heart-lung interactions, deflation-related, and effort-induced injuries.[rx] Related factors being studied in this context also include heterogeneous local lung mechanics, alveolar stress frequency, and stress failure of pulmonary capillaries. Variation in the expression of genetically determined inflammatory mediators has been known to affect VILI susceptibility.[rx]

In a study on  332 mechanically ventilated patients who were not having ARDS at the initiation of ventilation, the risk factors found for ventilator-induced lung injury were larger tidal volume, blood product transfusion, acidemia, and history of restrictive lung disease.[rx] Though factors such as respiratory acidosis, respiratory rate, pulmonary vascular pressures, and body temperature are found to be associated with ventilator-induced lung injury, many experts consider them only as second-order effects at this stage.

The excessive stretch from high tidal volumes results in volutrauma. Faridy et al., in their study on dogs, found that increasing the tidal volume and decreasing the PEEP resulted in lower lung volumes for similar transpulmonary pressures.[rx] They concluded that high tidal volume and lower PEEP resulted in high surface-activ forces, which could cause collapse and inflammation of the lungs. Dreyfuss et al., in a 1988 paper, described the development of pulmonary edema in animals undergoing ventilation at high tidal volumes. It was also noticed that such edema did not develop in animals with similar airway pressures when the lower tidal volume is ensured with straps around the chest and abdomen.[rx] A randomized controlled trial by Amato et al., and subsequently, the landmark ARDS Nett study, have indisputably proved that low tidal volume ventilation improves the morality in ARDS patients.[rx][rx] Even a higher tidal volume due to high patient efforts on non-invasive ventilation could result in self-inflicted lung injury.[rx]

Barotrauma is a pressure-related lung injury. Limiting the inflation pressure to prevent overdistension has conventionally been used as a part of the lung-protective strategy(i.e., plateau pressure < 28 to 30 cms H2O) for ARDS patients. Air leaks, pneumothoraces, and pneumomediastinum could result from overdistention. One also needs to understand that regional lung overdistention is a key factor for such ventilator-induced lung injuries. However, the evaluation of local lung mechanics is experimental at this stage. Transpulmonary pressure, which is the difference between alveolar pressure and pleural pressure, is the pressure that keeps the lung inflated when the airflow is zero at end inspiration. Hence there is a strong relation between transpulmonary pressure and tidal volume. Plateau pressure has been used as a surrogate of transpulmonary pressure at the bedside despite certain inherent limitations.

Animal experiments have shown that cyclical opening and closing of the atelectatic alveoli during the respiratory cycle could damage the adjacent non- atelectatic alveoli and airways by shear stress forces.[rx][rx][rx] This mechanism is called atelectotrauma. The application of optimal PEEP is important in the prevention of atelectrauma. Higher PEEP can cause alveolar overdistension, and lower PEEP may be inadequate to stabilize the alveoli and keep them open. The first in vivo study on VILI was published in 1974 by Webb and Tierney who found that rats ventilated at high airway pressures without PEEP died shortly with florid hemorrhagic pulmonary edema, and this could be mitigated by the application of PEEP  while maintaining the same airway pressure.[rx]

Biotrauma is the release of inflammatory mediators from the cells in the injured lungs in response to volutrauma and atelectotrauma. In ventilator-induced lung injury, the neutrophils, macrophages, and probably alveolar epithelial cells secrete various inflammatory mediators, including TNF-alpha, interleukins 6 & 8, transcription factor nuclear factor(NF)-kB, and matrix metalloproteinase-9. These cytokines could trigger detrimental effects locally and systemically, resulting in multiorgan failure.

Adverse heart-lung interaction could result in ventilator-associated lung injury, especially in the setting of high tidal volume and low PEEP, as observed in animal studies.[rx][rx] During inspiration, the pulmonary blood flow is significantly decreased due to compression of the right ventricular cavity by the expanding lung, and the blood flow is exaggerated during expiration. This results in a  cyclic occurrence of high flow- no flow-high flow state, which damages pulmonary capillaries’ endothelium, termed capillary stress failure. An endothelial injury could result in increased permeability of capillaries, promoting leakage of protein and water, resulting in pulmonary edema. Within a period of about 20 minutes, left ventricular failure with pulmonary edema ensues as a result of right ventricular failure and RV dilatation, pushing the interventricular septum towards the left ventricle, thereby increasing the left ventricular end-diastolic pressure.

In a 2018 publication, Katira et al. showed that abrupt deflation after sustained inflation could cause ventilator-induced lung injury in rat models.[rx] Extrapolating these findings into human scenarios, any abrupt disconnection from the mechanical ventilator could potentially cause lung injury by loss of PEEP with resultant alveolar collapse. The authors have termed this phenomenon as lung deflation injury. The authors attribute this phenomenon to decreased cardiac output during sustained inflation, which is usually compensated by increased systemic vascular resistance to maintain blood pressure. When there is sudden deflation, the cardiac output becomes normalized but faces significant afterload due to the increased systemic vascular resistance, which results in back pressure causing increased left ventricular end-diastolic pressure and pulmonary edema. Another contributory factor is the high pulmonary forward blood flow after sudden deflation causing sudden high pressure in capillaries, causing capillary injury. The authors suggest avoiding open suctioning and slow lowering of PEEP in ventilated ARDS patients. Abrupt disconnection from NIV could also cause potential harm, as per the authors.

The following points need to be noted to understand the concept of effort-induced lung injury(self-inflicted lung injury). Early paralysis has been known to improve lung function and mortality.[rx][rx][rx]. A post hoc analysis of the LUNG SAFE study showed that patients with severe ARDS fared worse on NIV than mechanical ventilators.[rx][rx] Airway pressure release ventilation(APRV) in a single centered randomized trial showed high mortality in the interventional group, promoting spontaneous breathing.[rx]

Patients with already injured lung are much more susceptible to effort-induced lung injury. The proposed mechanisms of lung injury during spontaneous efforts at breathing include increased pleural negative pressure during spontaneous efforts causing increased transpulmonary pressure resulting in higher tidal volumes causing volutrauma, pendelluft phenomenon resulting in tidal recruitment of injured alveoli, increased transvascular pressure predisposing to pulmonary edema in volume cycled mode, and patient-ventilator asynchrony.[rx]

Driving pressure is the difference between the plateau pressure and PEEP, and is also derived by dividing Vt by static compliance of the respiratory system (Crs). In 2002, Estenssoro et al. first described the consistent ability of driving pressure values in the first week to identify survivors versus non-survivors in ARDS patients (along with other variables, including P/F ratio and SOFA).[rx] Amato et al., in a 2015 meta-analysis on more than 3500 patients, showed that driving pressure is the physical variable that has correlated best with mortality.[rx] A driving pressure-based ventilatory strategy to prevent lung injury in ARDS patients on a ventilator has been proposed and debated actively.[rx][rx]

Ventilator-induced lung injury mostly occurs in patients with underlying physiological insults such as sepsis, trauma, and major surgery, where the immune system is already primed for a cascading response to mechanical lung injury. Volutrauma, atelectrauma, and biotrauma are the key mechanisms of ventilator-induced lung injury, although each component’s relative contribution is unclear at this stage. Alveolar distention and injury cause increased alveolar permeability, alveolar and interstitial edema, alveolar hemorrhage, and formation of hyaline membranes, resulting in diminished functional surfactant with resultant alveolar collapse.[rx][rx][rx]

Diagnosis of Ventilator-Induced Lung Injury

Clinical diagnosis of ventilator-induced lung injury is made at the bedside with a high degree of suspicion and ruling out of other causes that could closely mimic the picture. The patient on a mechanical ventilator typically develops worsening hypoxemia with low PaO2 and a fall in saturation. X-ray chest will show bilateral diffuse alveolar/interstitial infiltrates without cardiac enlargement. A CT scan thorax may show heterogeneous consolidation and atelectasis with focal areas of hyperlucencies suggestive of alveolar overdistension.

New-onset pulmonary infections and pulmonary edema are the commonest differential diagnosis to be ruled out initially. A thorough bedside clinical evaluation needs to be performed to exclude new-onset bronchospasm or crackles. Evidence for pneumothorax, pleural effusion, limb edema, ascites, and intra-abdominal hypertension has to be evaluated. The history of drug allergy or blood product transfusion needs to be clarified. Ventilatory settings need to be cross-checked to look for any contributing factors for acute lung injury.

Lab Test and Imaging

Evaluation should be targeted at ruling out other associated etiologies causing hypoxemia in ventilated patients. Aspiration, infective pneumonia, auto PEEPing, acute coronary syndromes, venous, fat, air or amniotic fluid embolism, pneumothoraces, pleural effusion, and intra-abdominal distension are to be ruled out. A thorough clinical evaluation bedside chest X-ray, ultrasound of the chest and abdomen along with a 12 lead ECG with a bedside ECHO can throw light to rule out most of the above etiologies. Auto PEEPing could be detected by analyzing the flow-time curve.

Chest X-ray in ventilator-induced lung injury could be almost similar to ARDS patients. It will show bilateral diffuse alveolar interstitial shadows without cardiomegaly. A CT scan thorax can show bilateral heterogeneous consolidation and atelectasis with focal areas of hyperlucency consistent with alveolar distension.

Laboratory investigations include lipase levels, cardiac enzymes & blood culture, and other body secretions. A lower limb Doppler and CT pulmonary angiogram may be necessary in certain cases. Fiber-optic bronchoscopy and biopsy are rarely indicated.

Gattinoni et al., in a 2016 paper, hypothesized that ventilator-related etiology of lung injury could be converted into a single variable called mechanical power. Mechanical power can be computed from tidal volume/driving pressure, flow, PEEP, and respiratory rate. They have proposed a simple ventilator software where the mechanical power equation (hence identifying the contribution of each component causing ventilator-induced lung injury) could be easily computed and analyzed at the bedside.[rx]

A 2019 review mentions that quantitative bedside measurement of dynamic elastance (E) and the interpretation of the way it varies as a function of time and PEEP could be utilized to evaluate not only the degree and nature of lung injury but also the degree of contributions each from volutrauma, and atelectrauma.[rx]

Treatment of Ventilator-Induced Lung Injury

The most important measure to prevent ventilator-induced lung injury is to select appropriate ventilatory settings that prevent overdistension of alveoli, causing volutrauma and biotrauma and atelectrauma.

The concept of “baby lung’ in ARDS represents the relatively small areas of aerated normal lung (which is just the size of a baby’s lung), which needs to be protected from injury during mechanical ventilation. Since most of the remaining alveoli are non-aerated and collapsed, delivery of a large tidal volume could overinflate the baby lung areas inciting lung injury. The baby lung is not a fixed anatomic structure since redistribution of dependent atelectasis occurs in prone positioning. The ideal tidal volume might have been the tidal volume required to ventilate the baby’s lung, which has been evaluated only in physiologic studies at this stage.

In ARDS patients, a low tidal volume strategy of 6 ml /Kg of predicted body weight(PBW) has been shown to prevent overdistension of the alveoli and improved mortality when compared with a higher tidal volume (i.e., 12 ml/Kg of predicted body weight) as shown in the ARDS Nett trial.[rx] In non-ARDS patients, a meta-analysis of 15 small randomized control trials and 5 large observational studies concluded that a tidal volume of 6-8 ml/Kg of predicted body weight is associated with improved survival.[rx] Patients with mild to moderate ARDS who are on a trial of non-invasive ventilation could generate high efforts with large tidal volumes, which have the potential to harm the lung. It is better to abort NIV in such settings and consider early intubation.[rx]

PEEP is an important aspect of the ARDS ventilatory strategy, offering protection from atelectrauma apart from improving alveolar recruitment & oxygenation. PEEP needs to be carefully titrated since an inappropriately high PEEP can cause overdistension injury, and a lower PEEP could be insufficient to stabilize and keep the alveoli open. The PEEP is most commonly selected at the bedside for a given FiO2 based on the PEEP selection criteria adopted at the landmark ARDS Nett trial. Optimal PEEP titration based on pressure-volume curve analysis, transpulmonary pressure measurements, CT, and ultrasound pictures have been tried in various studies though proved clinical benefits with such strategies are lacking. Closed suction catheters should be preferred in mechanically ventilated ARDS patients to avoid abrupt disconnection and PEEP derecruitment, which could cause hypoxemia as well as lung deflation injury.

Recruitment maneuvers should reduce ventilator-associated injury in theory.[rx] However, due to concerns regarding complications (e.g., hemodynamic compromise, pneumothorax) and uncertainty regarding clinical benefits, they are not applied widely. High-frequency oscillatory ventilation(HFOV) is theoretically promising in providing a low tidal volume(even lower than dead space and high frequency). However, the landmark OSCILLATE and OSCAR trials failed to provide any clinical superiority in ARDS patients.[rx][rx]

The use of neuromuscular agents has been known to reduce cytokine levels in previous studies.[rx] The ACURASYS study on 340 patients published in 2010 showed approximately 10% morality benefit at 28 days and 90 days in ARDS patients who received a neuromuscular agent for 48 hours.[rx] The morality benefit attributed in the cisatracurium arm is likely due to decreased multiorgan dysfunction due to decreased biotrauma resulting from decreased effort-induced lung injury.

Prone position ventilation has been known to increase the homogeneity of ventilation in animal studies, thus protecting from lung injury.[rx][rx] A 2010 metanalysis of seven trials involving 1724 patients showed a reduction in absolute mortality by 10 % in severely hypoxemic patients with ARDS with a PaO2: FiO2 ratio < 100. The landmark PROSEVA trial on 466 patients with severe ARDS with a PaO2: FiO2 ratio < 150 also showed a significant 28-day mortality difference of 16.8 % compared to patients who were not prone.[rx]

Partial or total extracorporeal support (ECMO/ECCO2-R) have been conceptually promising in the prevention of ventilator-related lung injury. However, data supporting clinical benefits prompting the routine initiation of extracorporeal support are scanty at this stage.

Anti-inflammatory strategies and the use of mesenchymal stem cells have been employed in animal studies to prevent the consequences of ventilator-induced lung injury.[rx][rx] However, their clinical utility in humans is yet to be proven. A 2017 Chinese study found that both ketamine and propofol could increase the pulmonary function index in patients with a ventilatory-induced injury. Ketamine was found to be superior to propofol as an anti-inflammatory agent in reducing IL-1β, Caspase-1, and NF-κB.[rx]

• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5297948/
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4562454/
• https://www.ncbi.nlm.nih.gov/books/NBK538183/
• https://www.ncbi.nlm.nih.gov/books/NBK539907/
• https://www.ncbi.nlm.nih.gov/books/NBK448186/
• https://www.ncbi.nlm.nih.gov/books/NBK539742/
• https://www.ncbi.nlm.nih.gov/books/NBK538314/
• https://www.ncbi.nlm.nih.gov/books/NBK538324/
• https://www.ncbi.nlm.nih.gov/books/NBK545226/
• https://www.ncbi.nlm.nih.gov/books/NBK560535/
• https://www.ncbi.nlm.nih.gov/books/NBK563244/
• https://www.ncbi.nlm.nih.gov/books/NBK482316/
• https://www.ncbi.nlm.nih.gov/books/NBK441904/
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6212352/
• https://www.sciencedirect.com/topics/medicine-and-dentistry/mechanics-of-breathing
• https://training.seer.cancer.gov/anatomy/respiratory/capacity.html
• https://www.atsjournals.org/doi/10.1164/ajrccm.157.4.nhlbi-5

• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5297948/
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4562454/
• https://www.ncbi.nlm.nih.gov/books/NBK538183/
• https://www.ncbi.nlm.nih.gov/books/NBK539907/
• https://www.ncbi.nlm.nih.gov/books/NBK448186/
• https://www.ncbi.nlm.nih.gov/books/NBK539742/
• https://www.ncbi.nlm.nih.gov/books/NBK538314/
• https://www.ncbi.nlm.nih.gov/books/NBK538324/
• https://www.ncbi.nlm.nih.gov/books/NBK545226/
• https://www.ncbi.nlm.nih.gov/books/NBK560535/
• https://www.ncbi.nlm.nih.gov/books/NBK563244/
• https://www.ncbi.nlm.nih.gov/books/NBK482316/
• https://www.ncbi.nlm.nih.gov/books/NBK441904/
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6212352/
• https://www.sciencedirect.com/topics/medicine-and-dentistry/mechanics-of-breathing
• https://training.seer.cancer.gov/anatomy/respiratory/capacity.html
• https://www.atsjournals.org/doi/10.1164/ajrccm.157.4.nhlbi-5

Pulmonary barotrauma is a damage to the lung from rapid or excessive pressure changes, as may occur when a patient is on a ventilator and is subjected to high airway pressure. Pulmonary barotrauma can also occur in scuba and other forms of diving.

Barotrauma is damage to body tissue secondary to pressure difference in enclosed cavities within the body. Barotrauma is commonly observed in scuba divers, free-divers, or even in airplane passengers during ascent and descent. The most common organs affected by barotrauma are the middle ear (otic barotrauma), sinuses (sinus barotrauma), and the lungs (pulmonary barotrauma). This article will focus on pulmonary barotrauma.[rx]

Barotrauma is tissue injury caused by a pressure-related change in body compartment gas volume. Factors increasing risk of pulmonary barotrauma include certain behaviors (eg, rapid ascent, breath-holding, breathing compressed air) and lung disorders (eg, COPD [chronic obstructive pulmonary disease]). Pneumothorax and pneumomediastinum are common manifestations. Patients require neurologic examination and chest imaging. Pneumothorax is treated. Prevention involves decreasing risky behaviors and counseling high-risk divers.

Causes of Pulmonary Barotrauma

Pulmonary barotrauma results from positive pressure mechanical ventilation. Positive pressure ventilation may lead to elevation of the trans-alveolar pressure or the difference in pressure between the alveolar pressure and the pressure in the interstitial space. Elevation in the trans-alveolar pressure may lead to alveolar rupture, which results in leakage of air into the extra-alveolar tissue.

Every patient on positive pressure ventilation is at risk of developing pulmonary barotrauma. However, certain ventilator settings, as well as specific disease processes, may increase the risk of barotrauma significantly. When managing a ventilator, physicians and other health care professionals must be aware of these risks to avoid barotrauma.

Specific disease processes, including chronic obstructive pulmonary disease (COPD), asthma, interstitial lung disease (ILD), pneumocystis jiroveci pneumonia, and acute respiratory distress syndrome (ARDS), may predispose individuals to pulmonary barotrauma. These diseases are associated with either dynamic hyperinflation or poor lung compliance, both of which predispose patients to increased alveolar pressure and ultimately barotrauma.[rx]

Patients with obstructive lung disease, COPD, and asthma are at risk of dynamic hyperinflation. These patients have a prolonged expiratory phase, and therefore have difficulty exhaling the full volume before the ventilator delivers the next breath. As a result, there is an increase in the intrinsic positive end-expiratory pressure (PEEP), also known as auto-PEEP. The hyperinflation is progressive and worsens with each tidal volume delivered. It leads to overdistention of the alveoli and increases the risk for barotrauma. Dynamic hyperinflation can be managed by decreasing the respiratory rate, decreasing the tidal volume, prolonging the expiratory time, and in some cases by increasing the external PEEP on the ventilator.[rx] The static auto-peep is easily measurable on a ventilator by performing an expiratory pause; by using this method you would obtain the total PEEP, the external PEEP subtracted from the total PEEP will equal the intrinsic PEEP or auto-PEEP. In many cases, auto-PEEP results in ventilator asynchrony, which may result in an increased risk of barotrauma. For a patient to be able to trigger a breath on the ventilator and for the flow to begin, the inspiratory muscles must overcome the recoil pressure. When intrinsic PEEP is present, it imposes an additional force that the inspiratory muscles have to overcome to trigger a breath. In many instances, auto-PEEP may lead to ventilator asynchrony, increased alveoli distention, and ultimately barotrauma.[rx]

Elevated plateau pressure is perhaps one of the most critical measurements of which to be aware. Plateau pressure is the pressure applied to the alveoli and other small airways during ventilation. Elevated plateau pressures, particularly pressures higher than 35 cmH2O, have been associated with an elevated risk for barotrauma.[rx] Plateau pressures are easily measurable on a ventilator by performing an inspiratory hold. Based on current data, as well as the increased mortality associated with barotrauma, the ARDSnet protocol suggests keeping plateau pressures below 30 cmH2O in patients on mechanical ventilation for ARDS management.[rx]

Peak pressure is the plateau pressure in addition to the pressure needed to overcome flow resistance and the elastic recoil of the lungs and chest wall. The risk for barotrauma increases whenever the peak pressures and plateau pressures become elevated to the same degree.[rx]

Elevated positive end-expiratory pressure (PEEP) may theoretically lead to overdistention of healthy alveoli in regions not affected by disease and ultimately barotrauma. However, clinical data has not associated increased PEEP with increased risk of barotrauma when used in conjunction with lung protective strategies, such as low tidal volume and target plateau pressure under 30 cmH2O. If higher PEEP is necessary for oxygenation, it should be titrated up slowly with close monitoring of the peak inspiratory and plateau pressures.[rx]

The exact pathophysiology for lung injury and barotrauma due to mechanical ventilation remains unclear; however, evidence suggests that overdistention and increased pressures in the alveoli units lead to inflammatory changes and possibly rupture and leakage of air into the extra alveolar tissue.

Researchers have described several mechanisms in the literature for the rupture of alveoli. Most of the mechanisms have their basis in overdistention and increased pressures in the alveoli. Historically, large tidal volumes were the approach in patients requiring mechanical ventilation to minimize atelectasis and improve oxygenation and ventilation. Such ventilatory settings usually lead to high inspiratory pressures and overdistention of the alveolar unit. Overdistention is more pronounced in patients with ARDS and other non-uniform lung diseases. In non-uniform lung disease, not every alveoli unit is affected equally; normal alveoli receive a greater percentage of the tidal volume, which leads to preferential ventilation and ultimately overdistention to accommodate the larger tidal volume.[rx]

Some animal studies have looked at the association between alveolar overdistention and lung injury. Tsuno et al. looked at histopathologic changes in the lungs of baby pigs. The settings on the ventilator produced a peak inspiratory pressure (PIP) of 40 cmH2O for up to 32 hours as well as the tidal volume of 15 mL/kg. Pathological findings on the subject’s studies included interstitial lymphocyte proliferation, alveolar hemorrhage, and hyaline membrane formation; all of which are similar to the histopathology observed in patients with ARDS.[rx] Other studies in human subjects have also demonstrated an association between high volume ventilation and increased levels of TNF-alpha and MIP-2; both are inflammatory cytokines researchers believe are implicated in the multi-organ dysfunction associated with ARDS.[rx]

Associate causes

• Acute respiratory distress syndrome (ARDS)
• Bacterial/viral pneumonia
• Aspiration pneumonitis
• Shock (distributive, cardiogenic, hemorrhagic)
• Flail chest, chest trauma
• Secondary pneumothorax
• Pulmonary emboli
• Asthma exacerbation
• COPD exacerbation
• Acute coronary syndrome

Symptoms of Pulmonary Barotrauma

Examples of organs or tissues easily damaged by barotrauma are:

• Middle ear (barotitis or aerotitis)
• Paranasal sinuses^[rx][rx][rx] (causing aerosinusitis)
• Lungs
• Eyes (the under-pressure air space is inside the diving mask^[rx])
• Skin (when wearing a diving suit which creates an air space)
• Brain and cranium (temporal lobe injury secondary to temporal bone rupture)^[rx]
• Teeth (causing barodontalgia, i.e., barometric pressure related dental pain, or dental fractures
• Genital (squeeze and associated complications of P-valve use)^[rx]

or

• Head and neck
  • Hypopharyngeal Petechiae
• Lung findings
  • Dyspnea
  • Cough
  • Wheezing
  • Hemoptysis
  • Chest Pain
  • Hypoxia
  • Apnea
  • Decreased breath sounds
• Cardiovascular findings
  • Bradycardia
  • Hypotension
  • Cyanosis
• Skin findings
  • Subcutaneous Emphysema

Diagnosis of Pulmonary Barotrauma

The history and physical exam in patients with barotrauma secondary to mechanical ventilation are usually limited since those patients are sick and under sedation while on mechanical ventilation. In cases of clinically significant pneumothorax, patients will present with acute changes in vital signs, including tachypnea, hypoxia, and tachycardia. Patients may also present with obstructive shock if a tension pneumothorax occurs. Physical examination may be significant for absent breath sounds if a pneumothorax exists. Subcutaneous emphysema may also present in some cases. In some, less severe cases, no systemic or hemodynamic changes may be present.[rx]

The patient’s past medical history is also essential when it comes to the diagnosis and management of pulmonary barotrauma. As mentioned previously, patients with a known history of chronic obstructive pulmonary disease (COPD), asthma, interstitial lung disease (ILD), pneumocystis jiroveci pneumonia, or ARDS, are at increased risk of developing pulmonary barotrauma. Underlying pulmonary pathology will also be important to be aware of when it comes to selecting the ventilator mode as well as the settings as we will discuss later.

Lab Test and Imaging

Ventilator data may be useful in the evaluation of pulmonary barotrauma. Ventilator asynchrony, acute elevation of the plateau and peak pressures above 30 cmH2O, or sudden decrease of delivered tidal volume may suggest respiratory distress secondary to pneumothorax or other complications from barotrauma. Ventilator data can give a clue to physicians regarding which patients are at higher risk for barotrauma.

Once pulmonary barotrauma secondary to the mechanical ventilator is suspected, action must take place immediately. Pneumothorax is an acute complication from pulmonary barotrauma, which is an emergency. The physical exam will be remarkable for absent breath sounds, and in most cases, patients who can communicate will complain of shortness of breath and chest pain. Vital signs usually demonstrate hypoxia as well as hypotension secondary to obstructive shock in the case of a tension pneumothorax. In patients who develop a tension pneumothorax, action is necessary before obtaining a chest radiograph. Tension pneumothorax requires urgent needle decompression to evacuate the pneumothorax, followed by thoracotomy tube placement. In patients presenting with a less acute complication, such as a simple pneumothorax with stable vital signs, pneumomediastinum, or subcutaneous emphysema, the clinician should obtain a chest radiograph immediately. The chest radiograph is able to identify the presence of pneumothorax, pneumomediastinum, subcutaneous emphysema, and other less common manifestations of pulmonary barotrauma, such as pneumatoceles, sub-pleural air collections, and pulmonary interstitial emphysema (PIE). If a chest x-ray is obtained but inadequate for evaluation, a CT of the chest can be done. It is important to remember that barotrauma is a clinical diagnosis and should always be high in the differential diagnosis for patients on invasive and non-invasive mechanical ventilation presenting with acute decompensation.[rx]

Treatment of Pulmonary Barotrauma

First aid

Pre-hospital care for lung barotrauma includes basic life support of maintaining adequate oxygenation and perfusion, assessment of airway, breathing and circulation, neurological assessment, and managing any immediate life-threatening conditions. High-flow oxygen up to 100% is considered appropriate for diving accidents. Large-bore venous access with isotonic fluid infusion is recommended to maintain blood pressure and pulse.^[rx]

Emergency treatment

Pulmonary barotrauma:^[rx]

• Endotracheal intubation may be required if the airway is unstable or hypoxia persists when breathing 100% oxygen.
• Needle decompression or tube thoracostomy may be necessary to drain a pneumothorax or haemothorax
• Foley catheterization may be necessary for spinal cord AGE if the person is unable to urinate.
• Intravenous hydration may be required to maintain adequate blood pressure.
• Therapeutic recompression is indicated for severe AGE. The diving medical practitioner will need to know the vital signs and relevant symptoms, along with the recent pressure exposure and breathing gas history of the patient. Air transport should be below 1,000 feet (300 m) if possible, or in a pressurized aircraft which should be pressurized to as low an altitude as reasonably possible.

Sinus squeeze and middle ear squeeze are generally treated with decongestants to reduce the pressure differential, with anti-inflammatory medications to treat the pain. For severe pain, narcotic analgesics may be appropriate.^[49]

Suit, helmet and mask squeeze are treated as trauma according to symptoms and severity.

There is no single strategy to prevent pulmonary barotrauma on patients on mechanical ventilation. The most efficient mechanism that has been described to prevent the risk of developing barotrauma on mechanical ventilation involves maintaining the plateau and peak inspiratory pressures low. The goal plateau pressure should be below 35 cmH2O, and ideally below 30 cmH2O, on most patients on mechanical ventilation as recommended by the ARDS Network group. Various techniques may be employed to aid in maintaining the plateau pressure at goal. Various ventilator modes are available. The two modes most commonly used in intensive care units are volume assist control (volume AC), a volume cycled mode, and pressure assist control (pressure AC), a pressure cycled mode. Lung protective ventilator strategies should be used in every ARDS and most other patients, regardless of the mode of mechanical ventilation. Lung protective ventilator strategies derive for the most part from a study published in the year 2000 by the ARDS Network group. The study involved ARDS patients and compared outcomes in ARDS patients using higher tidal volume ventilation (about 12 mL/kg of IBW) and patients using lower tidal volume ventilation (about 6 mL/kg OF IBW). Although tidal volume was the variable in this study, the goal with the low volume ventilation group was to keep the plateau pressure below 30 cmH2O. The low tidal volume ventilatory strategy correlated with a lower mortality rate (31% vs. 40%).[rx] The incidence of barotrauma in this study was not lower when using lung-protective ventilator strategies; however, other studies have demonstrated a higher incidence of barotrauma when the plateau pressure rises above 35 cmH2O.[rx] Low tidal volume ventilation is especially important in patients at higher risk for barotrauma, such as patients with ARDS, COPD, asthma, Pneumocystis jiroveci pneumonia (PJP), and chronic interstitial lung disease (ILD).[rx]

The driving pressure is another concept with which physicians managing patients at risk of barotrauma must be familiar. The driving pressure is measurable in patients not making an inspiratory effort; one can obtain the calculated pressure by subtracting the PEEP from the plateau pressure. Driving pressure became a hot topic of discussion after the ARDS trial proposed that high plateau pressures increase mortality in patients with ARDS but that high PEEP pressure is associated with improved outcomes. Amato et al., in 2015, proposed that the driving pressure was a better ventilation variable to stratify risk. In the trial, published in the NEJM in 2015, they concluded that an increment of 1 standard deviation in driving pressure was associated with increased mortality even in patients receiving protective plateau pressure and tidal volumes. Individual changes in tidal volume and PEEP were only associated with improved survival if these changes led to a reduction in driving pressure.[rx] Based on the data available, clinicians should maintain the optimal driving pressure between 13 and 15 cm H2O.[rx]

As mentioned previously, patients with obstructive lung disease are at risk of dynamic hyperinflation due to a prolonged expiratory phase, and difficulty exhaling the full volume before the ventilator delivers the next breath. Physicians must be aware of intrinsic PEEP or auto-PEEP, particularly in patients at high risk, such as those with obstructive lung disease. An expiratory pause maneuver on the ventilator will provide static intrinsic pressure. If intrinsic PEEP is present, then the physician may increase the external PEEP to help with ventilator synchronization by allowing the patient to trigger the ventilator and initiate a breath more effectively. The goal is to increase the external PEEP by 75 to 85% of the intrinsic PEEP [rx]. Other methods that the physician may employ to decrease the intrinsic PEEP include decreasing the respiratory rate, decreasing the tidal volume, and prolonging the expiratory time.[rx]

High positive end-expiratory pressure (PEEP) may theoretically lead to overdistention of healthy alveoli in regions not affected by disease and ultimately lead to barotrauma. Many conditions, such as moderate to severe ARDS, require the use of high PEEP pressures to improved oxygenation by recruiting as many alveoli units as possible. When used in conjunction with lung protective strategies, as described above, the risk of barotrauma due to high PEEP is minimal.[rx] Several methods exist to aid physicians in determining the adequate level of PEEP to treat individual patients based on lung compliance. A system pressure-volume curve may be used to determine the lower inflection point and the higher inflection point. The lower inflection point in the curve determines the minimal level of PEEP required to start alveolar recruitment. The upper inflection point in the curve determines the pressure level at which the risk of barotrauma and lung injury occurs.[rx]

The stress index is another method that may be used by physicians to determine the adequate amount of PEEP for individual patients. For the stress index to be an accurate measurement, the patient must be well sedated, and the flow must be constant. The physician may look at the pressure waveform on the ventilator to determine the stress index. A pressure wave that is concave down indicates a stress index less than 1. A stress index of less than 1 indicates that the patient may benefit from increased PEEP to help with alveoli recruitment. A pressure wave that is concave up indicates a stress index higher than 1. A stress index higher than one should alert the physician that the patient’s alveoli unit is at risk of distention and barotrauma. A straight diagonal line in the pressure wave is ideal because it correlates with a stress index between 0.9 and 1.1, which is the ideal range for proper alveoli recruitment with a low risk of distention and rupture.[rx]

Different ventilator modes also exist, which may be better tolerated by some patients and decrease the risk of barotrauma. There is no evidence to suggest that one ventilator mode is better than the other. However, in patients who are difficult to manage, physicians may try different modes to synchronize the patient with the ventilator better.

Volume AC mode is a volume cycled mode. It will deliver a set volume on every ventilator-assisted breath, which will lead to significant variations in peak inspiratory pressures as well as plateau pressures depending on the compliance of the lung parenchyma. The peak inspiratory and plateau pressures may be kept at goal using this mode of ventilation by using low tidal volume ventilation (between 6 to 8 mL/kg based on the ideal body weight). The respiratory rate and inspiratory time may be adjusted as well to prevent intrinsic PEEP. In some cases, sedation, and even neuromuscular blocking agents may be to be used to improve ventilator synchrony and maintain inspiratory peak and plateau pressures at goal.[rx]

Pressure AC mode is a pressure cycled mode. It allows medical personnel to set an inspiratory pressure level as well as the applied PEEP. The advantage of using a pressure cycled mode is that the peak inspiratory pressure will remain constant and will be equal to the inspiratory pressure in addition to the PEEP. The plateau pressure will also be lower or equal to the peak inspiratory pressure; therefore, this mode of ventilation correlates with a lower rate of barotrauma. The disadvantage, however, is that the tidal volume delivered will vary depending on lung compliance. Patients with poor lung compliance may not receive an adequate tidal volume using this ventilator mode.[rx]

Effect Management

The management of complications due to barotrauma depends on the specific complication. Pneumothorax, or tension pneumothorax, is a medical emergency. A tension pneumothorax must be treated immediately with needle decompression. The diagnosis of tension pneumothorax is made clinically and must be acted upon quickly without waiting for chest radiography. Signs and symptoms of tension pneumothorax include the absence of breath sounds, hemodynamic instability, as well as symptoms of chest pain and shortness of breath. The clinician must perform an urgent needle decompression followed by the placement of a thoracotomy tube.[rx]

The management of most non-tension pneumothorax in patients on mechanical ventilation involves the placement of a thoracostomy tube to evacuate the air due to the high incidence of progression to tension pneumothorax while on mechanical ventilation.[rx] Once the thoracotomy tube is in place, additional changes in the ventilator may be made to help with the resolution of the pneumothorax. Tidal volume may be decreased to decrease the plateau and peak inspiratory pressures. FiO2 in the ventilator may be increased temporarily to help decrease the partial pressure of nitrogen and aid with the absorption of air from the pleural cavity and hasten lung re-expansion.[rx] PEEP should also be lowered to decrease overdistention of the alveoli units, and patients should be well sedated to prevent ventilator asynchrony and further trauma.

Other complications, such as subcutaneous emphysema, pneumomediastinum, and pneumoperitoneum, are usually self-resolving and management is conservative. Conservative management involves reducing the plateau pressures below 30 cmH2O as well as continuous monitoring. Other strategies to minimize complications include reducing the PEEP on the ventilator, using sedation and neuromuscular blockade in patients who are difficult to synchronize with the ventilator, and decreasing the ventilatory pressures. Ultimately, the best way to prevent barotrauma and complications is liberating the patient from mechanical ventilation.[rx]

Tension pneumomediastinum is an exception. Intension pneumomediastinum, the pressure in the mediastinum increases significantly and ultimately may lead to physiological effects similar to pericardial tamponade. It may cause compression of the great vessels and compromise the right heart filling leading to shock and eventually, cardiac arrest. Chest radiography will show a heart silhouette resembling a sphere. The initial management involves ventilator changes to decrease the airway pressures and increase the FiO2 in the ventilator to 100%. Ultimately surgical mediastinal decompression is required.[rx]

Subcutaneous emphysema rarely may lead to compartment syndrome. Compartment syndrome should be suspected in patients with hemodynamic instability and elevated bladder pressures. Management involves decreasing the airway pressures, but ultimately, surgical evaluation is warranted. Surgical decompression must be performed in all patients with hemodynamic instability as this condition is associated with a high mortality rate.[rx]

Patients presenting with pneumoperitoneum may also progress to compartment syndrome. An immediate surgical evaluation must take place due to the high mortality associated with this condition. Pneumoperitoneum due to barotrauma is rare, and other causes for pneumoperitoneum should be ruled out, such as ruptured viscus and abdominal trauma.[rx]

Hypercapnia is among the most common side effects that present when managing a patient with lung-protective ventilatory strategies. The lower tidal volume may lead to decreased minute ventilation, and in some cases, hypercapnia. Guidelines for ARDS recommend allowing for permissive hypercapnia up to a pH of 7.2. If the pH drops below 7.2, the initiation of a bicarbonate infusion should be a therapeutic consideration to correct the pH to 7.2.[rx]

• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5297948/
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4562454/
• https://www.ncbi.nlm.nih.gov/books/NBK538183/
• https://www.ncbi.nlm.nih.gov/books/NBK539907/
• https://www.ncbi.nlm.nih.gov/books/NBK448186/
• https://www.ncbi.nlm.nih.gov/books/NBK539742/
• https://www.ncbi.nlm.nih.gov/books/NBK538314/
• https://www.ncbi.nlm.nih.gov/books/NBK538324/
• https://www.ncbi.nlm.nih.gov/books/NBK545226/
• https://www.ncbi.nlm.nih.gov/books/NBK560535/
• https://www.ncbi.nlm.nih.gov/books/NBK563244/
• https://www.ncbi.nlm.nih.gov/books/NBK482316/
• https://www.ncbi.nlm.nih.gov/books/NBK441904/
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6212352/
• https://www.sciencedirect.com/topics/medicine-and-dentistry/mechanics-of-breathing
• https://training.seer.cancer.gov/anatomy/respiratory/capacity.html
• https://www.atsjournals.org/doi/10.1164/ajrccm.157.4.nhlbi-5

Pulmonary barotrauma is a potentially life-threatening complication in patients on mechanical ventilation. It is important to recognize and quickly act to prevent barotrauma for prolonged periods as this may lead to significant morbidity and mortality in patients intubated in the intensive care unit. This activity will highlight how to recognize, diagnose, prevent, and manage barotrauma in patients on mechanical ventilation.

Pulmonary barotrauma is a damage to the lung from rapid or excessive pressure changes, as may occur when a patient is on a ventilator and is subjected to high airway pressure. Pulmonary barotrauma can also occur in scuba and other forms of diving.

Barotrauma is damage to body tissue secondary to pressure difference in enclosed cavities within the body. Barotrauma is commonly observed in scuba divers, free-divers, or even in airplane passengers during ascent and descent. The most common organs affected by barotrauma are the middle ear (otic barotrauma), sinuses (sinus barotrauma), and the lungs (pulmonary barotrauma). This article will focus on pulmonary barotrauma.[rx]

Barotrauma is tissue injury caused by a pressure-related change in body compartment gas volume. Factors increasing risk of pulmonary barotrauma include certain behaviors (eg, rapid ascent, breath-holding, breathing compressed air) and lung disorders (eg, COPD [chronic obstructive pulmonary disease]). Pneumothorax and pneumomediastinum are common manifestations. Patients require neurologic examination and chest imaging. Pneumothorax is treated. Prevention involves decreasing risky behaviors and counseling high-risk divers.

Causes of Pulmonary Barotrauma

Pulmonary barotrauma results from positive pressure mechanical ventilation. Positive pressure ventilation may lead to elevation of the trans-alveolar pressure or the difference in pressure between the alveolar pressure and the pressure in the interstitial space. Elevation in the trans-alveolar pressure may lead to alveolar rupture, which results in leakage of air into the extra-alveolar tissue.

Every patient on positive pressure ventilation is at risk of developing pulmonary barotrauma. However, certain ventilator settings, as well as specific disease processes, may increase the risk of barotrauma significantly. When managing a ventilator, physicians and other health care professionals must be aware of these risks to avoid barotrauma.

Specific disease processes, including chronic obstructive pulmonary disease (COPD), asthma, interstitial lung disease (ILD), pneumocystis jiroveci pneumonia, and acute respiratory distress syndrome (ARDS), may predispose individuals to pulmonary barotrauma. These diseases are associated with either dynamic hyperinflation or poor lung compliance, both of which predispose patients to increased alveolar pressure and ultimately barotrauma.[rx]

Patients with obstructive lung disease, COPD, and asthma are at risk of dynamic hyperinflation. These patients have a prolonged expiratory phase, and therefore have difficulty exhaling the full volume before the ventilator delivers the next breath. As a result, there is an increase in the intrinsic positive end-expiratory pressure (PEEP), also known as auto-PEEP. The hyperinflation is progressive and worsens with each tidal volume delivered. It leads to overdistention of the alveoli and increases the risk for barotrauma. Dynamic hyperinflation can be managed by decreasing the respiratory rate, decreasing the tidal volume, prolonging the expiratory time, and in some cases by increasing the external PEEP on the ventilator.[rx] The static auto-peep is easily measurable on a ventilator by performing an expiratory pause; by using this method you would obtain the total PEEP, the external PEEP subtracted from the total PEEP will equal the intrinsic PEEP or auto-PEEP. In many cases, auto-PEEP results in ventilator asynchrony, which may result in an increased risk of barotrauma. For a patient to be able to trigger a breath on the ventilator and for the flow to begin, the inspiratory muscles must overcome the recoil pressure. When intrinsic PEEP is present, it imposes an additional force that the inspiratory muscles have to overcome to trigger a breath. In many instances, auto-PEEP may lead to ventilator asynchrony, increased alveoli distention, and ultimately barotrauma.[rx]

Elevated plateau pressure is perhaps one of the most critical measurements of which to be aware. Plateau pressure is the pressure applied to the alveoli and other small airways during ventilation. Elevated plateau pressures, particularly pressures higher than 35 cmH2O, have been associated with an elevated risk for barotrauma.[rx] Plateau pressures are easily measurable on a ventilator by performing an inspiratory hold. Based on current data, as well as the increased mortality associated with barotrauma, the ARDSnet protocol suggests keeping plateau pressures below 30 cmH2O in patients on mechanical ventilation for ARDS management.[rx]

Peak pressure is the plateau pressure in addition to the pressure needed to overcome flow resistance and the elastic recoil of the lungs and chest wall. The risk for barotrauma increases whenever the peak pressures and plateau pressures become elevated to the same degree.[rx]

Elevated positive end-expiratory pressure (PEEP) may theoretically lead to overdistention of healthy alveoli in regions not affected by disease and ultimately barotrauma. However, clinical data has not associated increased PEEP with increased risk of barotrauma when used in conjunction with lung protective strategies, such as low tidal volume and target plateau pressure under 30 cmH2O. If higher PEEP is necessary for oxygenation, it should be titrated up slowly with close monitoring of the peak inspiratory and plateau pressures.[rx]

The exact pathophysiology for lung injury and barotrauma due to mechanical ventilation remains unclear; however, evidence suggests that overdistention and increased pressures in the alveoli units lead to inflammatory changes and possibly rupture and leakage of air into the extra alveolar tissue.

Researchers have described several mechanisms in the literature for the rupture of alveoli. Most of the mechanisms have their basis in overdistention and increased pressures in the alveoli. Historically, large tidal volumes were the approach in patients requiring mechanical ventilation to minimize atelectasis and improve oxygenation and ventilation. Such ventilatory settings usually lead to high inspiratory pressures and overdistention of the alveolar unit. Overdistention is more pronounced in patients with ARDS and other non-uniform lung diseases. In non-uniform lung disease, not every alveoli unit is affected equally; normal alveoli receive a greater percentage of the tidal volume, which leads to preferential ventilation and ultimately overdistention to accommodate the larger tidal volume.[rx]

Some animal studies have looked at the association between alveolar overdistention and lung injury. Tsuno et al. looked at histopathologic changes in the lungs of baby pigs. The settings on the ventilator produced a peak inspiratory pressure (PIP) of 40 cmH2O for up to 32 hours as well as the tidal volume of 15 mL/kg. Pathological findings on the subject’s studies included interstitial lymphocyte proliferation, alveolar hemorrhage, and hyaline membrane formation; all of which are similar to the histopathology observed in patients with ARDS.[rx] Other studies in human subjects have also demonstrated an association between high volume ventilation and increased levels of TNF-alpha and MIP-2; both are inflammatory cytokines researchers believe are implicated in the multi-organ dysfunction associated with ARDS.[rx]

Associate causes

• Acute respiratory distress syndrome (ARDS)
• Bacterial/viral pneumonia
• Aspiration pneumonitis
• Shock (distributive, cardiogenic, hemorrhagic)
• Flail chest, chest trauma
• Secondary pneumothorax
• Pulmonary emboli
• Asthma exacerbation
• COPD exacerbation
• Acute coronary syndrome

Symptoms of Pulmonary Barotrauma

Examples of organs or tissues easily damaged by barotrauma are:

• Middle ear (barotitis or aerotitis)
• Paranasal sinuses^[rx][rx][rx] (causing aerosinusitis)
• Lungs
• Eyes (the under-pressure air space is inside the diving mask^[rx])
• Skin (when wearing a diving suit which creates an air space)
• Brain and cranium (temporal lobe injury secondary to temporal bone rupture)^[rx]
• Teeth (causing barodontalgia, i.e., barometric pressure related dental pain, or dental fractures
• Genital (squeeze and associated complications of P-valve use)^[rx]

or

• Head and neck
  • Hypopharyngeal Petechiae
• Lung findings
  • Dyspnea
  • Cough
  • Wheezing
  • Hemoptysis
  • Chest Pain
  • Hypoxia
  • Apnea
  • Decreased breath sounds
• Cardiovascular findings
  • Bradycardia
  • Hypotension
  • Cyanosis
• Skin findings
  • Subcutaneous Emphysema

Diagnosis of Pulmonary Barotrauma

The history and physical exam in patients with barotrauma secondary to mechanical ventilation are usually limited since those patients are sick and under sedation while on mechanical ventilation. In cases of clinically significant pneumothorax, patients will present with acute changes in vital signs, including tachypnea, hypoxia, and tachycardia. Patients may also present with obstructive shock if a tension pneumothorax occurs. Physical examination may be significant for absent breath sounds if a pneumothorax exists. Subcutaneous emphysema may also present in some cases. In some, less severe cases, no systemic or hemodynamic changes may be present.[rx]

The patient’s past medical history is also essential when it comes to the diagnosis and management of pulmonary barotrauma. As mentioned previously, patients with a known history of chronic obstructive pulmonary disease (COPD), asthma, interstitial lung disease (ILD), pneumocystis jiroveci pneumonia, or ARDS, are at increased risk of developing pulmonary barotrauma. Underlying pulmonary pathology will also be important to be aware of when it comes to selecting the ventilator mode as well as the settings as we will discuss later.

Lab Test and Imaging

Ventilator data may be useful in the evaluation of pulmonary barotrauma. Ventilator asynchrony, acute elevation of the plateau and peak pressures above 30 cmH2O, or sudden decrease of delivered tidal volume may suggest respiratory distress secondary to pneumothorax or other complications from barotrauma. Ventilator data can give a clue to physicians regarding which patients are at higher risk for barotrauma.

Once pulmonary barotrauma secondary to the mechanical ventilator is suspected, action must take place immediately. Pneumothorax is an acute complication from pulmonary barotrauma, which is an emergency. The physical exam will be remarkable for absent breath sounds, and in most cases, patients who can communicate will complain of shortness of breath and chest pain. Vital signs usually demonstrate hypoxia as well as hypotension secondary to obstructive shock in the case of a tension pneumothorax. In patients who develop a tension pneumothorax, action is necessary before obtaining a chest radiograph. Tension pneumothorax requires urgent needle decompression to evacuate the pneumothorax, followed by thoracotomy tube placement. In patients presenting with a less acute complication, such as a simple pneumothorax with stable vital signs, pneumomediastinum, or subcutaneous emphysema, the clinician should obtain a chest radiograph immediately. The chest radiograph is able to identify the presence of pneumothorax, pneumomediastinum, subcutaneous emphysema, and other less common manifestations of pulmonary barotrauma, such as pneumatoceles, sub-pleural air collections, and pulmonary interstitial emphysema (PIE). If a chest x-ray is obtained but inadequate for evaluation, a CT of the chest can be done. It is important to remember that barotrauma is a clinical diagnosis and should always be high in the differential diagnosis for patients on invasive and non-invasive mechanical ventilation presenting with acute decompensation.[rx]

Treatment of Pulmonary Barotrauma

First aid

Pre-hospital care for lung barotrauma includes basic life support of maintaining adequate oxygenation and perfusion, assessment of airway, breathing and circulation, neurological assessment, and managing any immediate life-threatening conditions. High-flow oxygen up to 100% is considered appropriate for diving accidents. Large-bore venous access with isotonic fluid infusion is recommended to maintain blood pressure and pulse.^[rx]

Emergency treatment

Pulmonary barotrauma:^[rx]

• Endotracheal intubation may be required if the airway is unstable or hypoxia persists when breathing 100% oxygen.
• Needle decompression or tube thoracostomy may be necessary to drain a pneumothorax or haemothorax
• Foley catheterization may be necessary for spinal cord AGE if the person is unable to urinate.
• Intravenous hydration may be required to maintain adequate blood pressure.
• Therapeutic recompression is indicated for severe AGE. The diving medical practitioner will need to know the vital signs and relevant symptoms, along with the recent pressure exposure and breathing gas history of the patient. Air transport should be below 1,000 feet (300 m) if possible, or in a pressurized aircraft which should be pressurized to as low an altitude as reasonably possible.

Sinus squeeze and middle ear squeeze are generally treated with decongestants to reduce the pressure differential, with anti-inflammatory medications to treat the pain. For severe pain, narcotic analgesics may be appropriate.^[49]

Suit, helmet and mask squeeze are treated as trauma according to symptoms and severity.

There is no single strategy to prevent pulmonary barotrauma on patients on mechanical ventilation. The most efficient mechanism that has been described to prevent the risk of developing barotrauma on mechanical ventilation involves maintaining the plateau and peak inspiratory pressures low. The goal plateau pressure should be below 35 cmH2O, and ideally below 30 cmH2O, on most patients on mechanical ventilation as recommended by the ARDS Network group. Various techniques may be employed to aid in maintaining the plateau pressure at goal. Various ventilator modes are available. The two modes most commonly used in intensive care units are volume assist control (volume AC), a volume cycled mode, and pressure assist control (pressure AC), a pressure cycled mode. Lung protective ventilator strategies should be used in every ARDS and most other patients, regardless of the mode of mechanical ventilation. Lung protective ventilator strategies derive for the most part from a study published in the year 2000 by the ARDS Network group. The study involved ARDS patients and compared outcomes in ARDS patients using higher tidal volume ventilation (about 12 mL/kg of IBW) and patients using lower tidal volume ventilation (about 6 mL/kg OF IBW). Although tidal volume was the variable in this study, the goal with the low volume ventilation group was to keep the plateau pressure below 30 cmH2O. The low tidal volume ventilatory strategy correlated with a lower mortality rate (31% vs. 40%).[rx] The incidence of barotrauma in this study was not lower when using lung-protective ventilator strategies; however, other studies have demonstrated a higher incidence of barotrauma when the plateau pressure rises above 35 cmH2O.[rx] Low tidal volume ventilation is especially important in patients at higher risk for barotrauma, such as patients with ARDS, COPD, asthma, Pneumocystis jiroveci pneumonia (PJP), and chronic interstitial lung disease (ILD).[rx]

The driving pressure is another concept with which physicians managing patients at risk of barotrauma must be familiar. The driving pressure is measurable in patients not making an inspiratory effort; one can obtain the calculated pressure by subtracting the PEEP from the plateau pressure. Driving pressure became a hot topic of discussion after the ARDS trial proposed that high plateau pressures increase mortality in patients with ARDS but that high PEEP pressure is associated with improved outcomes. Amato et al., in 2015, proposed that the driving pressure was a better ventilation variable to stratify risk. In the trial, published in the NEJM in 2015, they concluded that an increment of 1 standard deviation in driving pressure was associated with increased mortality even in patients receiving protective plateau pressure and tidal volumes. Individual changes in tidal volume and PEEP were only associated with improved survival if these changes led to a reduction in driving pressure.[rx] Based on the data available, clinicians should maintain the optimal driving pressure between 13 and 15 cm H2O.[rx]

As mentioned previously, patients with obstructive lung disease are at risk of dynamic hyperinflation due to a prolonged expiratory phase, and difficulty exhaling the full volume before the ventilator delivers the next breath. Physicians must be aware of intrinsic PEEP or auto-PEEP, particularly in patients at high risk, such as those with obstructive lung disease. An expiratory pause maneuver on the ventilator will provide static intrinsic pressure. If intrinsic PEEP is present, then the physician may increase the external PEEP to help with ventilator synchronization by allowing the patient to trigger the ventilator and initiate a breath more effectively. The goal is to increase the external PEEP by 75 to 85% of the intrinsic PEEP [rx]. Other methods that the physician may employ to decrease the intrinsic PEEP include decreasing the respiratory rate, decreasing the tidal volume, and prolonging the expiratory time.[rx]

High positive end-expiratory pressure (PEEP) may theoretically lead to overdistention of healthy alveoli in regions not affected by disease and ultimately lead to barotrauma. Many conditions, such as moderate to severe ARDS, require the use of high PEEP pressures to improved oxygenation by recruiting as many alveoli units as possible. When used in conjunction with lung protective strategies, as described above, the risk of barotrauma due to high PEEP is minimal.[rx] Several methods exist to aid physicians in determining the adequate level of PEEP to treat individual patients based on lung compliance. A system pressure-volume curve may be used to determine the lower inflection point and the higher inflection point. The lower inflection point in the curve determines the minimal level of PEEP required to start alveolar recruitment. The upper inflection point in the curve determines the pressure level at which the risk of barotrauma and lung injury occurs.[rx]

The stress index is another method that may be used by physicians to determine the adequate amount of PEEP for individual patients. For the stress index to be an accurate measurement, the patient must be well sedated, and the flow must be constant. The physician may look at the pressure waveform on the ventilator to determine the stress index. A pressure wave that is concave down indicates a stress index less than 1. A stress index of less than 1 indicates that the patient may benefit from increased PEEP to help with alveoli recruitment. A pressure wave that is concave up indicates a stress index higher than 1. A stress index higher than one should alert the physician that the patient’s alveoli unit is at risk of distention and barotrauma. A straight diagonal line in the pressure wave is ideal because it correlates with a stress index between 0.9 and 1.1, which is the ideal range for proper alveoli recruitment with a low risk of distention and rupture.[rx]

Different ventilator modes also exist, which may be better tolerated by some patients and decrease the risk of barotrauma. There is no evidence to suggest that one ventilator mode is better than the other. However, in patients who are difficult to manage, physicians may try different modes to synchronize the patient with the ventilator better.

Volume AC mode is a volume cycled mode. It will deliver a set volume on every ventilator-assisted breath, which will lead to significant variations in peak inspiratory pressures as well as plateau pressures depending on the compliance of the lung parenchyma. The peak inspiratory and plateau pressures may be kept at goal using this mode of ventilation by using low tidal volume ventilation (between 6 to 8 mL/kg based on the ideal body weight). The respiratory rate and inspiratory time may be adjusted as well to prevent intrinsic PEEP. In some cases, sedation, and even neuromuscular blocking agents may be to be used to improve ventilator synchrony and maintain inspiratory peak and plateau pressures at goal.[rx]

Pressure AC mode is a pressure cycled mode. It allows medical personnel to set an inspiratory pressure level as well as the applied PEEP. The advantage of using a pressure cycled mode is that the peak inspiratory pressure will remain constant and will be equal to the inspiratory pressure in addition to the PEEP. The plateau pressure will also be lower or equal to the peak inspiratory pressure; therefore, this mode of ventilation correlates with a lower rate of barotrauma. The disadvantage, however, is that the tidal volume delivered will vary depending on lung compliance. Patients with poor lung compliance may not receive an adequate tidal volume using this ventilator mode.[rx]

Effect Management

The management of complications due to barotrauma depends on the specific complication. Pneumothorax, or tension pneumothorax, is a medical emergency. A tension pneumothorax must be treated immediately with needle decompression. The diagnosis of tension pneumothorax is made clinically and must be acted upon quickly without waiting for chest radiography. Signs and symptoms of tension pneumothorax include the absence of breath sounds, hemodynamic instability, as well as symptoms of chest pain and shortness of breath. The clinician must perform an urgent needle decompression followed by the placement of a thoracotomy tube.[rx]

The management of most non-tension pneumothorax in patients on mechanical ventilation involves the placement of a thoracostomy tube to evacuate the air due to the high incidence of progression to tension pneumothorax while on mechanical ventilation.[rx] Once the thoracotomy tube is in place, additional changes in the ventilator may be made to help with the resolution of the pneumothorax. Tidal volume may be decreased to decrease the plateau and peak inspiratory pressures. FiO2 in the ventilator may be increased temporarily to help decrease the partial pressure of nitrogen and aid with the absorption of air from the pleural cavity and hasten lung re-expansion.[rx] PEEP should also be lowered to decrease overdistention of the alveoli units, and patients should be well sedated to prevent ventilator asynchrony and further trauma.

Other complications, such as subcutaneous emphysema, pneumomediastinum, and pneumoperitoneum, are usually self-resolving and management is conservative. Conservative management involves reducing the plateau pressures below 30 cmH2O as well as continuous monitoring. Other strategies to minimize complications include reducing the PEEP on the ventilator, using sedation and neuromuscular blockade in patients who are difficult to synchronize with the ventilator, and decreasing the ventilatory pressures. Ultimately, the best way to prevent barotrauma and complications is liberating the patient from mechanical ventilation.[rx]

Tension pneumomediastinum is an exception. Intension pneumomediastinum, the pressure in the mediastinum increases significantly and ultimately may lead to physiological effects similar to pericardial tamponade. It may cause compression of the great vessels and compromise the right heart filling leading to shock and eventually, cardiac arrest. Chest radiography will show a heart silhouette resembling a sphere. The initial management involves ventilator changes to decrease the airway pressures and increase the FiO2 in the ventilator to 100%. Ultimately surgical mediastinal decompression is required.[rx]

Subcutaneous emphysema rarely may lead to compartment syndrome. Compartment syndrome should be suspected in patients with hemodynamic instability and elevated bladder pressures. Management involves decreasing the airway pressures, but ultimately, surgical evaluation is warranted. Surgical decompression must be performed in all patients with hemodynamic instability as this condition is associated with a high mortality rate.[rx]

Patients presenting with pneumoperitoneum may also progress to compartment syndrome. An immediate surgical evaluation must take place due to the high mortality associated with this condition. Pneumoperitoneum due to barotrauma is rare, and other causes for pneumoperitoneum should be ruled out, such as ruptured viscus and abdominal trauma.[rx]

Hypercapnia is among the most common side effects that present when managing a patient with lung-protective ventilatory strategies. The lower tidal volume may lead to decreased minute ventilation, and in some cases, hypercapnia. Guidelines for ARDS recommend allowing for permissive hypercapnia up to a pH of 7.2. If the pH drops below 7.2, the initiation of a bicarbonate infusion should be a therapeutic consideration to correct the pH to 7.2.[rx]

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• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6212352/
• https://www.sciencedirect.com/topics/medicine-and-dentistry/mechanics-of-breathing
• https://training.seer.cancer.gov/anatomy/respiratory/capacity.html
• https://www.atsjournals.org/doi/10.1164/ajrccm.157.4.nhlbi-5

High blood pressure affects 75 million adults in the United States[rx] and accounts for 8.6% of all primary care visits.[rx] Renovascular hypertension is one of the most common causes of secondary hypertension and often leads to resistant hypertension. It is defined as systemic hypertension that manifests secondary to the compromised blood supply to the kidneys, usually due to an occlusive lesion in the main renal artery.

Causes of Renal Hypertension

The cause of renovascular hypertension is consistent with any narrowing/blockage of blood supply to the renal organ (renal artery stenosis). As a consequence of this action the renal organs release hormones that indicate to the body to maintain a higher amount of sodium and water, which in turn causes blood pressure to rise. Factors that may contribute are: diabetes, high cholesterol and advanced age,^[rx] also of importance is that a unilateral condition is sufficient to cause renovascular hypertension.^[rx]

It is important to realize that any condition that compromises blood flow to the kidneys can contribute to renovascular hypertension.[rx] The most common causes of renovascular hypertension include:

• Renal artery stenosis (RAS), mostly secondary to atherosclerosis
• Fibromuscular dysplasia (FMD)
• Arteritides such as Takayasu’s, Antiphospholipid Antibody (APLA) or Mid aortic syndrome[rx][rx]
• Extrinsic compression of a renal artery
• Renal artery dissection or infarction[rx]
• Radiation fibrosis
• Obstruction from aortic endovascular grafts[rx]

The underlying mechanism in renovascular hypertension involves decreased perfusion to the kidney and activation of the Renin-Angiotensin-Aldosterone (RAAS) pathway. This was first explained by Goldblatt et al. in the 1930s. His model studied the effect of decreased blood supply to the kidneys in dogs and found that ischemic kidneys contribute to persistent hypertension. He also proposed the presence of a substance that “may affect a pressor action like that of a hormone.” This hormone he was referring to was ‘renin,’ which is secreted by juxtaglomerular cells of the kidney. Renin secretion by the kidneys is stimulated by three main pathways,

• 1) renal baroreceptors that sense decrease perfusion to the kidney,
• 2) low sodium chloride levels detected by the macula densa and
• 3) beta-adrenergic stimulation. Prolonged ischemia also increases the number of renin expressing cells in the kidney in a process called ‘JG recruitment.’[rx] When renin is secreted into the blood, it acts on angiotensinogen (produced by the liver). Renin cleaves angiotensinogen to angiotensin I, which is then converted to angiotensin II by angiotensin-converting enzyme (ACE) that is primarily found in the vascular endothelium of lungs and kidney. Angiotensin II raises blood pressure by multiple mechanisms, which include:
• Vasoconstriction, mostly in the heart, kidney, and vascular smooth muscle[rx]
• Sympathetic nervous stimulation causing a presynaptic release of norepinephrine
• Stimulates secretion of aldosterone by the adrenal cortex, which in turn causes sodium and water retention, thereby raising blood pressure.
• It also causes the increased synthesis of collagen type I and III in fibroblasts, leading to thickening of the vascular wall and myocardium, and fibrosis
• It has been shown to have a growth effect on renal cells, which has been implicated in the development of glomerulosclerosis and tubulointerstitial fibrosis

Though atherosclerotic renal artery stenosis (ARAS) and FMD are the two most common conditions causing this cascade, any pathology leading to decreased blood flow to the kidneys can essentially trigger this and lead to high blood pressure.

Symptoms Of Renal Hypertension 

The main symptoms of renovascular hypertension are rapidly increasing blood pressure of 180/120 or higher and signs of organ damage. Usually, the damage happens to the kidneys or the eyes.

Other symptoms depend on how the rise in blood pressure affects your organs. A common symptom is bleeding and swelling in the tiny blood vessels in the retina. The retina is the layer of nerves that line the back of the eye. It senses light and sends signals to the brain through the optic nerve, which can also be affected by renovascular hypertension. When the eye is involved, can renovascular hypertension cause changes in vision.

Other symptoms of malignant hypertension include

• Pheochromocytoma – Sweating, increased frequency or force of heartbeats, headache, anxiety
• Cushing’s syndrome – Weight gain, weakness, abnormal growth of body hair or loss of menstrual periods (in women), purple striations (lines) on the skin of the abdomen
• Thyroid problems – Fatigue (tiredness), weight gain or weight loss, intolerance to heat or cold
• Conn’s syndrome or primary aldosteronism – Weakness due to low levels of potassium in the body
• Obstructive sleep apnea – excessive fatigue or sleepiness during daytime, snoring, pauses in breathing during sleep
• High blood pressure at a young age
• High blood pressure that suddenly gets worse or is hard to control
• Kidneys that are not working well (this can start suddenly)
• Narrowing of other arteries in the body, such as to the legs, the brain, the eyes and elsewhere
• Sudden buildup of fluid in the air sacs of the lungs (pulmonary edema)
• High blood pressure (early age)
• Kidney dysfunction
• Narrowing of arteries elsewhere in the body
• Pulmonary edema
• Change in mental status, such as anxiety, confusion, decreased alertness, decreased ability to concentrate, fatigue, restlessness, sleepiness, or stupor
• Chest pain (feeling of crushing or pressure)
• Cough
• Headache
• Nausea or vomiting
• Numbness of the arms, legs, face, or other areas
• Reduced urine output
• Seizure
• Shortness of breath
• Weakness of the arms, legs, face, or other areas
• Blurred vision
• Chest pain (angina)
• Difficulty breathing
• Dizziness
• Numbness in the arms, legs, and face
• Severe headache
• Shortness of breath

In rare cases, renovascular hypertension can cause brain swelling, which leads to a dangerous condition called hypertensive encephalopathy. Symptoms include:

• Changes in mental status
• Coma
• Confusion
• Drowsiness
• Headache that continues to get worse
• Nausea and vomiting
• Seizures

Diagnosis of Renal Hypertension

History and Physical

Salient points in history that suggest the presence of renovascular hypertension include:

• Resistant hypertension –  Uncontrolled blood pressure necessitating the use of 2 or 3 antihypertensive agents of different classes, one of which is a diuretic
• Trial of multiple medications to control blood pressure
• History of multiple hospital admissions for hypertensive crisis
• Elevation in creatinine of more than 30% after starting an angiotensin-converting enzyme (ACE) inhibitor (ACEI)
• Patients with renal artery stenosis secondary to atherosclerosis are usually older and might have the presence of other atherosclerotic diseases such as carotid artery stenosis, peripheral artery stenosis or coronary artery disease
• A premenopausal female (15-50 years) with hypertension is most likely to have FMD[rx]
• Long term history of smoking
• Patients with systemic vasculitis can develop vasculitis of renal arteries and present with renovascular hypertension
• Recurrent episodes of flash pulmonary edema and/or unexplained congestive heart failure
• Unexplained Azotemia
• Elevation in serum creatinine on starting ACE-I, which occurs due to interference with autoregulation and post glomerular arterial tone
• Unexplained hypokalemia and metabolic alkalosis
• Unilateral small or atrophic kidney.

Physical examination may reveal an abdominal bruit, indicating the presence of renal artery stenosis.

Lab Test

Patients with renovascular hypertension often undergo an extensive evaluation to find a cause for uncontrolled hypertension.

Laboratory tests

• Urine analysis – to check for proteinuria, hematuria, and casts. The presence of proteinuria indicates the presence of renal parenchymal disorder, whereas the presence of hematuria or RBC casts indicates the presence of glomerulonephritis.
• Blood urea nitrogen and serum creatinine – to assess baseline kidney function.
• Basal metabolic profile: to assess for electrolyte disturbances and acid-base balance.
• Complement levels and autoimmune profile – in suspected cases of autoimmune diseases affecting the renal vasculature.
• Plasma free metanephrines or 24-hour urinary fractionated metanephrines and normetanephrine to rule out pheochromocytoma
• Plasma renin-aldosterone ratio to rule out hyperaldosteronism
• 24 hr urinary free cortisol or low dose dexamethasone suppression test to rule out Cushing’s syndrome

Imaging

• Catheter angiography  – There are multiple imaging modalities available to evaluate renovascular hypertension. Since the most common cause of renovascular hypertension is renal artery stenosis, renal arteriography remains the gold standard diagnostic test.[rx] However, catheter angiography is invasive, costly, time-consuming, and can lead to complications such as renal artery dissection or cholesterol embolization. Other imaging tests that can be done to evaluate the renal vessels include duplex ultrasonography, computed tomography with angiography (CTA), and magnetic resonance angiography (MRA). The type of imaging test used often depends on the suspicion for high-grade lesions, and the need for intervention.[rx]
• Duplex ultrasonography – is the initial imaging test of choice to evaluate the renal arteries. It is relatively cheap, non-invasive, and does not involve the administration of contrast or exposure to radiation. A duplex scan has been shown to have an excellent correlation with contrast-enhanced angiography.[rx] Though there are several criteria to assess the presence of renal artery stenosis, the most important sign is peak systolic velocity (PSV). A PSV higher than 180 cm/s suggests the presence of stenosis of greater than 60%.[rx]
• Ultrasonography – can also measure the resistive index (RI), which is calculated as ((PSV-End diastolic velocity)/PSV)). A value of more than 0.7 indicates the presence of pathological resistance to flow, and studies have shown that a value >0.8 predicts poor response to revascularization treatments.[rx] The most significant setbacks for duplex ultrasonography are its reduced sensitivity in obese patients, hindrance by overlying bowel gas and operator dependence.
• CT angiography – involves the administration of intravenous contrast and acquiring detailed images of blood vessels or tissues by moving the beam in a helical manner across the area being studied. In a study by Wittenberg et al, the sensitivity and specificity for hemodynamically significant RAS (>50%) by CTA was found to be 96% and 99%. CTA also has a comparable negative predictive value to MRA in ruling out renal artery stenosis.[rx] It can also diagnose extrinsic compression of renal arteries, FMD, arterial dissection, and help in evaluating surrounding structures. However, CTA can only provide an anatomical assessment of the lesion and is not able to evaluate the degree of obstruction to renal blood flow. Exposure to radiation, allergy to contrast, and acute kidney injury are other downfalls of CTA.
• MRA  – uses a powerful magnetic field, pulses of radio waves, and intravenous gadolinium to evaluate the renal blood vessels and surrounding structures. Several studies have shown the sensitivity and specificity of MRA to be around 97% and 92%[rx] in diagnosing renal artery. MRA does not involve radiation, and gadolinium contrast is less likely to cause an allergic reaction as compared to the iodine contrast used in CTA. However, MRA has been shown to overestimate the grade of stenosis and is often affected by motion artifacts or opacification of renal veins, leading to difficulty visualizing the renal arteries.[15] Also, gadolinium has been shown to induce a rare, progressively fatal disease called nephrogenic systemic fibrosis (NSF).  NSF can affect the skin, joints, and multiple organs leading to progressive, irreversible fibrosis and eventual death. This occurs due to a transmetalation reaction that displaces gadolinium ion from its chelate, resulting in the deposition of gadolinium in the skin and soft tissues. The 1-year incidence of NSF has been reported to be around 4.6%[rx] and almost all cases occurred in patients with a glomerular filtration rate < 30 mL/min/1.73 m.
• Nuclear medicine ACE-Inhibitor (ACE-I) renography – is another non-invasive, relatively safe imaging method that uses radioactive material, a special camera, and a computer to evaluate for renovascular hypertension. It involves the administration of an ACE-I to determine if the cause of hypertension is due to the narrowing of the renal arteries. The sensitivity and specificity of this test have shown to be variable, with values between 74% – 94% for sensitivity and 59% – 95% for specificity.[rx] It is a time-consuming procedure, and there is a risk of radiation exposure and irritation or pain from the injection of the radiotracer. The sensitivity of ultrasound has shown to be higher than captopril renography[rx] which makes it a better choice for an initial diagnostic test.
• Magnetic resonance angiogram, or MRA – Images from this test show blood flow and organ function without using x-rays. Contrast medium may be injected into a vein in your arm to better see the structure of your arteries. You remain awake, although a muscle relaxer may be used, if necessary. You lie still on a table that slides into a tunnel-shaped device. There is no radiation exposure with this study. Claustrophobia can be an issue with MRAs as the tube is quite narrow.
• Catheter angiogram – A special kind of x-ray in which a catheter, or a thin, flexible tube, is threaded through your large arteries into your renal artery. This often is from a small slit in the groin. The patient is usually awake, although a muscle relaxer may be given to lessen anxiety during the procedure. A contrast medium, or a colored dye, is injected through the catheter, so the renal artery shows up more clearly on the x-ray. The benefits of this study are that it is more accurate than the other tests and if a significant narrowing is seen, it can be dilated with a balloon (angioplasty) or stented (a tube-like cage that keeps the vessels open) at the same time. A catheter angiogram is an invasive procedure so this is usually reserved for patients who have a positive result of one of the other tests and plans are made to dilate the blood vessel.

Catheter arteriography – is the gold standard test to evaluate for renovascular hypertension and provides the best temporal and spatial resolution. Catheter angiography has the added advantage of measuring translesional pressure gradients to assess the hemodynamic significance of anatomically severe lesions.[rx] It is most useful in:

• Patients with a disparity between imaging modalities
• Patients with a high index of suspicion and negative imaging findings
• Patients anticipated having an intervention

It can also evaluate anatomical abnormalities of the kidney, renal arteries, aorta, and can be followed by endovascular intervention for the treatment of significant lesions. Also, the surrounding tissues and bones can be removed or subtracted from the final image revealing only the arterial framework. This method is known as digital subtraction angiography (DSA). However, the radiation doses are higher than CTA, and because it is an invasive procedure, there are risks of complications such as arterial dissection, tear, rupture, or thromboembolic phenomenon.[rx]

Treatment of Renal Hypertension

The management of renovascular hypertension aims to treat the underlying cause. Several options are available, which include pharmacological and invasive therapy.

Pharmacological therapy entails the use of antihypertensive medications to control blood pressure. The American College of Cardiology and the American Heart Association (ACC/AHA) advocates pharmacological therapy as the first-line treatment for renal artery stenosis.[rx] Since RAAS is the most prominent pathway contributing to hypertension in these disorders,

• ACEI and angiotensin receptor blockers (ARBs) form the cornerstone of managing renovascular hypertension (Class 1a indication). Often more than one medication will be needed to control the blood pressure.
• Calcium channel blockers, thiazides, beta-blockers, and hydralazine have been shown to be effective to control blood pressure in patients with RAS.[rx] Direct renin inhibitors such as aliskiren have been studied as monotherapy or in combination with ACEIs/ARBs to treat hypertension. Though it has been shown to be effective for the treatment of hypertension[rx][rx][rx][rx][rx] there is not enough data to prove its efficacy in treating renovascular hypertension.
• ACEIs and ARBs inhibit the action of angiotensin II, thereby causing vasodilation and promote sodium and water excretion. However, these medications are contraindicated in patients with a single functioning kidney or bilateral lesions as they can cause efferent arteriolar vasodilatation leading to interruption in autoregulation and thereby decreasing glomerular filtration. While these medications are effective in controlling blood pressure, they can also lead to worsening renal function.
• Percutaneous angioplasty is the treatment of choice for renovascular hypertension due to FMD and for patients with atherosclerotic renal artery stenosis that is not controlled with medications.[rx] The ACC/AHA guidelines recommend revascularization for renal artery disease in the following scenarios:[rx]
• Patients with hemodynamically significant RAS and recurrent, unexplained congestive heart failure or sudden, unexplained pulmonary edema (class Ia)
• Hemodynamically significant RAS and accelerated hypertension, resistant hypertension, malignant hypertension or hypertension with an unexplained unilateral small kidney, and hypertension with intolerance to medication (Class IIa)
• Patients with bilateral RAS and progressive chronic kidney disease or a RAS to a solitary functioning kidney (Class IIa)
• Patients with hemodynamically significant RAS and unstable angina (class IIa)
• Asymptomatic bilateral or solitary viable kidney with hemodynamically significant RAS (Class IIb)
• Patients with RAS and chronic renal insufficiency with unilateral RAS (class IIb)
• In addition to angioplasty, renal stent placement is indicated for patients with ostial atherosclerotic lesions (Class I).
• Patients with FMD and renovascular hypertension are also treated with percutaneous intervention with or without a stent.[rx] Multiple studies have shown a decrease in baseline blood pressure after intervention for FMD.[rx][rx] However, there remains an ongoing debate about the benefit of revascularization when compared to medical management in patients with atherosclerotic renal artery stenosis (ARAS). Several studies have failed to show a significant decrease in blood pressure or the number of antihypertensive agents between angioplasty and medical treatment groups.

A meta-analysis of 7 trials by Zhu et al. revealed that medical management is as effective as percutaneous revascularization in the treatment of RAS.[rx] Three recent trials ASTRAL, CORAL, and STAR found no difference between stenting and medical therapy in patients with atherosclerotic renal artery stenosis.[rx] [rx][rx] Thus it can be established that revascularization does not reverse renal damage or decrease blood pressure in patients with atherosclerotic renal artery stenosis.

In the case of recurrent renal artery stenosis or blood pressure not controlled with medication and or/angioplasty, renal bypass surgery may be an option. In this procedure, the surgeon uses a vein or synthetic tube to connect the kidney to the aorta, to create an alternate route for blood to flow around the blocked artery into the kidney. This is a complex procedure and rarely used. The ACC/AHA guidelines recommend surgery for RAS in[rx]

• Patients with RAS secondary to FMD, especially those with complex disease and/or those having microaneurysms
• Patients with atherosclerotic RAS involving multiple vessels or involvement of early primary branch of the main renal artery
• Patients with atherosclerotic RAS who require pararenal aortic reconstructions (such as with aortic aneurysms or severe aortoiliac obstruction).

Several studies have also evaluated the role of unilateral nephrectomy in patients with renovascular hypertension and have shown improvement in blood pressure control, renal function, and decrease in the use of anti-hypertensives.[rx][rx] However, this is an invasive procedure with inherent risks and long term consequences of such a procedure are unclear.

Surgery

• In terms of treatment for renovascular hypertension surgical revascularization versus medical therapy for atherosclerosis, it is not clear if one option is better than the other according to a 2014 Cochrane review; balloon angioplasty did show a small improvement in blood pressure .^[rx]
• Surgery can include percutaneous surgical revascularization, and also nephrectomy or autotransplantation, and the individual may be given beta-adrenergic blockers.^[rx] Early therapeutic intervention is important if ischemic nephropathy is to be prevented. Inpatient care is necessary for the management of hypertensive urgencies, quick intervention is required to prevent further damage to the kidneys.^[rx]

References