and alveolar distending pressure to no more than 30 cm H2O. As noted above, the use of a low tidal volume ventilatory strategy in patients with ARDS has been demonstrated to decrease mortality, whereas the use of higher levels of PEEP has not resulted in decreased mortality versus using lower levels of PEEP.

Use of a low tidal volume ventilatory strategy in patients with ARDS has been demonstrated to decrease mortality.

Another major adverse effect of positive-pressure ventilation is potential impairment of cardiovascular function. At least two mechanisms are thought to play a role. The first involves a decrease in venous return to the heart. Whereas the normally negative intrathoracic pressure during inspiration promotes venous return from the periphery, positive inspiratory pressure from a ventilator impedes venous return. The hemodynamic consequences of low cardiac output and blood pressure are even more likely when the patient is also receiving PEEP and is somewhat volume depleted. In many cases, judicious administration of fluids can restore the effective intravascular volume and reverse the adverse hemodynamic consequences of positive-pressure ventilation.

The second mechanism involves an increase in pulmonary vascular resistance. When alveolar volume is increased with positive-pressure mechanical ventilation, alveolar vessels are compressed, compromising the overall cross-sectional area of the pulmonary vascular bed. As a result, pulmonary vascular resistance and the workload placed on the right ventricle increase. Right ventricular output is potentially compromised, and the right ventricle may dilate. This shifts the interventricular septum toward the left ventricular cavity, also impairing left ventricular filling and stroke volume.

Management of patients receiving positive-pressure ventilation, particularly those with hypoxemic respiratory failure who require PEEP, is complicated. Many factors interact in a complex way, specifically oxygenation, cardiac output, and fluid status. Optimal care requires both sophisticated patient monitoring and substantial expertise from the team responsible for patient care. Such care is necessary for proper support of vital functions and to minimize the complications of therapy.

Selected aspects of therapy for chronic respiratory failure

Chronic ventilatory support

Working with patients who have chronic irreversible respiratory or neuromuscular disease and require continuous long-term ventilatory support involves difficult clinical decisions. The first question is whether the patient wishes “to be on a machine” for the rest of his or her life. Some patients clearly wish to prolong life even if it means permanent ventilatory support; others choose not to be dependent on a ventilator for the remainder of their lives. When the patient chooses to be maintained on a ventilator, support usually is given by positive-pressure ventilation administered through a tracheostomy tube. The care of some patients can be handled at home with the proper support of family and visiting healthcare personnel. Management of other cases continues in chronic care hospitals or other facilities equipped to care for such patients.

A subgroup of patients with chronic respiratory insufficiency does not require continuous ventilatory support but benefits from nocturnal assistance with ventilation. These patients often have chronic neuromuscular or chest wall disease accompanied by chronic hypercapnia. More recent data suggest that some patients with COPD and hypercapnia may also benefit from chronic nocturnal ventilation. Although the degree to which respiratory muscle fatigue contributes to the hypercapnia experienced by these

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usually manifested as bronchiolitis obliterans, which is characterized by progressive inflammation, fibrosis, and obstruction of small airways. The physiologic consequence of this process is progressive airflow obstruction, which typically is unresponsive to augmentation of immunosuppressive therapy. As a result, bronchiolitis obliterans is the major cause of graft failure and death occurring later in the course after lung transplantation. Pharmacologic treatment of severe bronchiolitis obliterans has been disappointing, and the main treatment option for posttransplant patients with this syndrome is repeat transplantation.

The major complications occurring after lung transplantation are rejection and infection.

Progressive airflow obstruction from bronchiolitis obliterans is thought to represent chronic transplant rejection.

Another major complication of lung transplantation is infection, the risk of which is greatly increased by the need for immunosuppressive therapy. In some cases, organisms (e.g., bacteria, cytomegalovirus) accompanied the donor organ, and development of a complicating infection was precipitated by immunosuppression and impairment of the recipient’s defense mechanisms. Patients are also subject to the variety of opportunistic infections common to patients with impaired cell-mediated immunity, including other viruses, fungi, and Pneumocystis. Finally, there is also an increased risk of malignancy in lung transplant recipients, notably with what has been called posttransplant lymphoproliferative disease, a type of malignant expansion of lymphocytes that is usually related to Epstein-Barr virus infection and frequently can be controlled by reducing the intensity of immunosuppression.

Accompanying the growing experience with lung transplantation over the past decade has been a modest improvement in survival. Survival is approximately 75% to 80% at 1 year after transplantation; however, median survival is only approximately 5 to 7 years. Lung transplantation is an accepted but expensive therapeutic option for a highly selected group of patients, and future improvements in donor organ preservation and immunosuppression may lead to improved outcomes and broader application of the procedure.

Suggested readings

Mechanical ventilation

Abrams D, Schmidt M, Pham T, Beitler J.R, Fan E, Goligher E.C., et al. Mechanical ventilation for acute respiratory distress syndrome during extracorporeal life support. Research and practice American Journal of Respiratory and Critical Care Medicine 2020;201: 514-525.

Azoulay E, Lemiale V, Mokart D, Nseir S, Argaud L, Pène F., et al. Effect of high-flow nasal oxygen vs standard oxygen on 28-day mortality in immunocompromised patients with acute respiratory failure: The HIGH randomized clinical trial JAMA 2018;320: 20992107.

Baldomero A.K, Melzer A.C, Greer N, Majeski B.N, MacDonald R, Linskens E.J., et al.

Effectiveness and harms of high-flow nasal oxygen for acute respiratory failure: An evidence report for a clinical guideline from the American College of Physicians Annals of Internal Medicine 2021;174: 952-966.

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Patel B.K. & Kress J.P. The changing landscape of noninvasive ventilation in the intensive care unit JAMA 2015;314: 1697-1699.

Putensen C, Theuerkauf N, Zinserling J, Wrigge H. & Pelosi P. Meta-analysis: Ventilation strategies and outcomes of the acute respiratory distress syndrome and acute lung injury

Annals of Internal Medicine 2009;151: 566-576.

Qaseem A, Etxeandia-Ikobaltzeta I, Fitterman N, Williams J.W,Jr, Kansagara D., et al: Clinical Guidelines Committee of the American College of Physicians. Appropriate use of high-flow nasal oxygen in hospitalized patients for initial or postextubation management of acute respiratory failure: A clinical guideline from the American College of Physicians Annals of Internal Medicine 2021;174: 977-984.

Rello J, Lisboa T. & Koulenti D. Respiratory infections in patients undergoing mechanical ventilation Lancet Respiratory Medicine 2014;2: 764-774.

Rochwerg B, Brochard L, Elliott M.W, Hess D, Hill N.S, Nava S., et al. Official ERS/ATS clinical practice guidelines: Noninvasive ventilation for acute respiratory failure

European Respiratory Journal 2017;50: 1602426.

Sahetya S.K, Goligher E.C. & Brower R.G. Setting positive end-expiratory pressure in acute respiratory distress syndrome American Journal of Respiratory and Critical Care Medicine 2017;195: 1429-1438.

Scala R. & Pisani L. Noninvasive ventilation in acute respiratory failure: Which recipe for success? European Respiratory Review 2018;27: 180029.

Schjørring O.L, Klitgaard T.L, Perner A, Wetterslev J, Lange T, Siegemund M., et al. Lower or higher oxygenation targets for acute hypoxemic respiratory failure New England Journal of Medicine 2021;384: 1301-1311.

Slutsky A.S. History of mechanical ventilation. From Vesalius to ventilator-induced lung injury American Journal of Respiratory and Critical Care Medicine 2015;191: 1106-1115.

Subirà C, Hernández G, Vázquez A, Rodríguez-García R, González-Castro A, García C., et al.

Effect of pressure support vs T-piece ventilation strategies during spontaneous breathing trials on successful extubation among patients receiving mechanical ventilation: A randomized clinical trial JAMA 2019;321: 2175-2182.

Thille A.W, Muller G, Gacouin A, Coudroy R, Decavèle M, Sonneville R., et al. Effect of postextubation high-flow nasal oxygen with noninvasive ventilation vs high-flow nasal oxygen alone on reintubation among patients at high risk of extubation failure: A randomized clinical trial JAMA 2019;322: 1465-1475.

Tobin M.J, Laghi F. & Jubran A. Narrative review: Ventilator-induced respiratory muscle weakness Annals of Internal Medicine 2010;153: 240-245.

Support of chronic respiratory failure

Ergan B, Oczkowski S, Rochwerg B, Carlucci A, Chatwin M, Clini E., et al. European Respiratory Society guidelines on long-term home non-invasive ventilation for management of COPD European Respiratory Journal 2019;54: 1901003.

Hannan L.M, Dominelli G.S, Chen Y.W, Darlene Reid W. & Road J. Systematic review of non-invasive positive pressure ventilation for chronic respiratory failure Respiratory Medicine 2014;108: 229-243.

Hind M, Polkey M.I. & Simonds A.K. Homeward bound: A centenary of home mechanical ventilation American Journal of Respiratory and Critical Care Medicine 2017;195: 1140-

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of North America 2010;57: 375-391.

van der Mark S.C, Hoek R.A.S. & Hellemons M.E. Developments in lung transplantation over the past decade European Respiratory Review 2020;29: 190132.

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pH = 7.55 What is AaDO2?

Answers

1. = 1000 mL/breath × 10 breaths/min = 10, 000 mL/min = 10 L/min VD/VT = (40 mm Hg − 30 mm Hg)/40 mm Hg = 0.25

VA = VT − VD = 1000 mL − (0.25 × VT) = 1000 mL − 250 mL = 750 mL = VA × f = 750 mL/breath × 10 breaths/min = 7.5 L/min

2.New VD = 250 mL + 250 mL = 500 mL New VD/VT = 500 mL/1000 mL = 0.5

3.Because PaCO2 is inversely proportional to , the new PaCO2 can be calculated from the old

and the new (assuming remains constant).

As per Problem 1, old = 7.5 L/min

New VA = 1000 mL − new VD = 1000 mL − 500 mL = 500 mL

New PaCO2 = 3/2 × old PaCO2 = 3/2 × 40 mm Hg = 60 mm Hg 4. On the basis of the new settings:

a. = 500 mL/breath × 20 breaths/min = 10 L/min VA = 500 mL − 250 mL = 250 mL

= 250 mL/breath × 20 breaths/min = 5 L/min

New PaCO2 = 3/2 × old PaCO2 = 3/2 × 40 mm Hg = 60 mm Hg

c.Because VD/VT = (PaCO2 − PECO2)/PaCO2, substitute the known values and solve the equation for PECO2.

0.5= (60 mm Hg − PECO2)/60 mm Hg

PECO2 = 30 mm Hg

5.PAO2 = (0.4 × 713 mm Hg) − (40 mm Hg/0.8) = 285 mm Hg − 50 mm Hg = 235 mm Hg AaDO2 = PAO2 − PaO2 = 235 mm Hg − 95 mm Hg = 140 mm Hg

6.PAO2 = 150 mm Hg − (40 mm Hg/0.8) = 100 mm Hg

AaDO2 = 100 mm Hg − 75 mm Hg = 25 mm Hg = 150 mm Hg − (20 mm Hg/0.8) = 125 mm Hg

AaDO2 = 125 mm Hg − 80 mm Hg = 45 mm Hg

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indicating coexisting airflow obstruction. Therefore, in the presence of decreased lung volumes, a low FEF25%–75% indicates obstruction, primarily if the decrease in FEF25%– 75% is out of proportion to the decrease in lung volumes.

(3) Taking into account the aforementioned qualifications, FEF25%–75% may be a relatively sensitive measurement for airway obstruction. An isolated abnormality in FEF25%–75%

has sometimes been considered a marker for early or very mild airflow obstruction, theoretically reflecting “small airway disease.”

c.The criteria for a significant response to a bronchodilator, indicating at least partial reversibility of airflow obstruction, are an improvement over baseline of either the FEV1 or FVC by 10% of the predicted value. Patients with asthma characteristically fulfill at least one of these criteria, as do some patients with chronic obstructive pulmonary disease (COPD) who have a reversible component to their disease.

3.Interpretation of the flow-volume curve:

a.An obstructive pattern is reflected by decreased flow relative to lung volume, generally accompanied by a “scooped out” or “coved” appearance to the descending part of the expiratory curve (see Fig. 3.21).

b.A restrictive pattern is characterized by decreased volumes (i.e., narrowing of the curve along the volume or X-axis) and relatively preserved flow rates. The flow rates often appear increased relative to the small lung volumes, producing a tall, narrow curve.

4.Interpretation of diffusing capacity of the lung for carbon monoxide (DLCO):

a.Ensure that the value has been corrected for the patient’s hemoglobin level. If not, the value will be falsely low if the patient is anemic.

b.A decrease in the diffusing capacity reflects disease affecting the alveolar-capillary membrane (decreased surface area for gas exchange and/or abnormal thickness of the membrane) or a decrease in pulmonary capillary blood volume.

c.An increase in the diffusing capacity can reflect increased pulmonary capillary blood volume or erythrocytes within alveolar spaces (pulmonary hemorrhage).

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Answers

1. All measurements of lung volume (TLC, VC, FRC, RV) are significantly decreased, indicative of

restrictive disease. FEV1 and FVC are decreased because of low lung volumes, but FEV1/FVC is

preserved. This finding, along with the fact that FEF25%–75% is not decreased out of proportion to the decrease in lung volumes, indicates there is no obstruction. Diffusing capacity is decreased, suggesting that the restrictive disease is secondary to an abnormality of the pulmonary parenchyma rather than a result of chest wall or neuromuscular disease. The flow-volume curve is tall and narrow, consistent with a restrictive pattern. Diagnosis: Diffuse parenchymal lung disease secondary to pulmonary sarcoidosis.

2. FEV1 and FVC are both decreased. Because FEV1 is decreased more than FVC, FEV1/FVC is

decreased. FEF25%–75% is also decreased. These values are indicative of obstructive lung disease. TLC is normal, and RV and FRC are increased. RV/TLC ratio is also increased. Therefore, there is no restriction, but the high RV/TLC ratio indicates there is “air trapping, ” as is often expected with airflow obstruction. The diffusing capacity is decreased, reflecting loss of alveolar-capillary bed. The flow-volume curve shows an obstructive pattern characterized by a striking decrease in flow rates, well seen throughout most of the expiratory curve after the initial peak flow rate. This combination of significant airflow obstruction with normal or increased volumes and a low diffusing capacity suggests emphysema.

3.TLC and FRC are reduced, indicating restrictive disease. RV is relatively preserved. FEV1 and FVC both are decreased, but FEV1/FVC ratio is preserved. There is no evidence for coexisting

obstructive disease. Diffusing capacity is normal, suggesting the alveolar-capillary bed is preserved. The flow-volume curve is relatively tall and narrow, without any evidence of obstructive disease. Diagnosis: Restrictive pattern secondary to chest wall disease (kyphoscoliosis).

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Table C.1

Expected Compensation for Primary Acid-Base Disorders

Modified from Narins, R. G., & Emmett, M. (1980). Simple and mixed acid-base disorders: A practical approach. Medicine (Baltimore), 59, 161–187. © by Williams & Wilkins, 1980.

Alternatively, one can use other guidelines relating PCO2 and pH values. Because these latter guidelines are based on direct measurements obtained with arterial blood gases—and because they are relatively easy to remember—they are used in the method outlined here. It is worth noting that formulas relating PCO2 and pH become less accurate at the extremes of PCO2 and pH values and provide only rough guidelines. The human body does not respond to physiologic disturbances with mathematical precision.

Analysis of acid-base status

1.Look at the pH value to determine the net disturbance in acid-base balance. An alkalotic pH (>7.44) indicates the presence of a primary respiratory alkalosis, a metabolic alkalosis, or both. An acidotic pH (<7.36) indicates the presence of a primary respiratory acidosis, a metabolic acidosis, or both. A normal pH (approximately 7.36-7.44) indicates normal acid-base status or a mixed disturbance (of two balancing problems).

2.Look at PCO2. A high PCO2 (>44) indicates that a respiratory acidosis is present. A low PCO2

(<36) indicates that a respiratory alkalosis is present. If the pH value moves in the appropriate direction for the PCO2 change (i.e., ↓ pH with ↑ PCO2; ↑ pH with ↓ PCO2), the respiratory disorder is the primary disturbance. If the pH value does not move in the appropriate direction for the PCO2 change, a metabolic disorder is the primary disorder.

3.When a primary respiratory disorder is present, the pH value should change approximately 0.08 units for each 10 mm Hg change in PCO2 if the process is acute. If the process is chronic, the

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kidneys compensate (by retaining or losing HCO3−) and blunt the pH change in response to any change in PCO2. The resulting change in pH when the respiratory disorder is chronic is slightly different for acidosis versus alkalosis. With a chronic respiratory acidosis, the expected pH decrease is approximately 0.03 for each 10 mm Hg increase in PCO2. With a chronic respiratory alkalosis, the expected pH increase is approximately 0.02 for each 10 mm Hg decrease in PCO2.

4.If a pH change cannot be explained by an alteration in PCO2, a primary metabolic disturbance is present. A low pH value with a low PCO2 indicates a primary metabolic acidosis with respiratory compensation. A high pH value with a high PCO2 can indicate a primary metabolic

alkalosis with secondary suppression of respiratory drive. However, in many patients the latter pattern of a high pH value with a high PCO2 often represents a complex acid-base disturbance, such as a chronic compensated respiratory acidosis with a superimposed primary metabolic alkalosis (e.g., as a result of diuretics, vomiting, or nasogastric suction).

5.To determine whether there has been appropriate respiratory compensation for a primary metabolic disorder, a rough guideline is that PCO2 should approximate the last two digits of the

pH value. For example, a PCO2 of 25 mm Hg accompanying a pH value of 7.25 indicates appropriate respiratory compensation for a primary metabolic acidosis. However, the degree of compensatory hyperventilation (i.e., lowering of PCO2) for a metabolic acidosis tends to be more predictable than the degree of compensatory hypoventilation (i.e., CO2 retention) accompanying a metabolic alkalosis.

Analysis of oxygenation

1. When analyzing arterial PO2, first calculate alveolar PO2 according to the following equation:

For ambient air (FiO2 = 0.21), the equation can be simplified as follows: PAO2 = 150 − (1.25 × PCO2). Then calculate the alveolar-arterial O2 gradient (AaDO2), which is the difference between the calculated PAO2 and the measured PAO2: AaDO2 = PAO2 − PaO2.

2.If the patient is hypoxemic, PCO2 is elevated, and AaDO2 is normal (<15 mm Hg on ambient air in a young person, although it increases with age), hypoventilation is the cause of the hypoxemia.

3.If the patient is hypoxemic, PCO2 is normal or low, and AaDO2 is increased, either

mismatch or shunting is present. With mismatch, the patient’s PaO2 has a good response to administration of supplemental O2. With a true shunt, PaO2 does not rise appropriately with supplemental O2 (even 100% O2).

4.If the patient is hypoxemic, PCO2 is high, and AaDO2 is increased, the patient has both hypoventilation and either mismatch or shunt as the cause of the low PaO2.

Sample problems

Determine the acid-base status and calculate the alveolar-arterial oxygen difference (AaDO2) for each numbered problem. All blood gases are drawn with the patient breathing room air (FiO2 = 0.21), except

as otherwise noted.

Answers

1.Acute respiratory alkalosis. On room air, the patient’s AaDO2 = 67.5 mm Hg, which is elevated. The minimal elevation in PO2 with 100% O2 indicates that a shunt is the major cause of the

hypoxemia.

2. Identical to Problem 1, except that the dramatic increase in PO2 with 100% O2 indicates that ventilation-perfusion mismatch is the major cause of the hypoxemia.

3. Acute respiratory alkalosis. Even though PO2 appears normal, AaDO2 is elevated to 37 mm Hg, indicating the presence of a disorder impairing normal oxygenation of blood.

4. Chronic respiratory acidosis. AaDO2 = 10 mm Hg, indicating that hypoxemia is due to hypoventilation.

5. Chronic respiratory acidosis, as in Problem 4. However, in contrast to Problem 4, AaDO2 is elevated (to 45 mm Hg), indicating that both hypoventilation and either ventilation-perfusion mismatch or shunting (most likely the former) are responsible for the hypoxemia.

6.Mixed acid-base disorder with a primary metabolic acidosis complicated by a primary respiratory alkalosis. PCO2 is too low to represent only compensation for the metabolic acidosis,

indicating the presence of a respiratory alkalosis as well. AaDO2 = 15 mm Hg, the upper limit of normal for a young adult.

7.The simplest explanation of the acid-base status is a compensated metabolic alkalosis. However, this pattern is probably seen more commonly with a mixed acid-base disorder consisting of a compensated respiratory acidosis complicated by a superimposed primary metabolic alkalosis. AaDO2 = 35 mm Hg. Therefore, hypoxemia is partly due to hypoventilation but mostly due to

ventilation-perfusion mismatch or shunt, probably the former.

8. Something is wrong because AaDO2 is negative (−15 mm Hg). Several possible explanations are

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