The respiratory muscles share with other major muscle groups of the body the characteristic that excessive work leads to fatigue.21,40,41 This concept seems to explain why patients with severe airflow obstruction or airspace flooding ultimately stop breathing, and why patients requiring mechanical ventilation for these and other causes of respiratory failure are unable to breathe independent from the ventilator until the load on their respiratory muscles is reduced, the respiratory muscles become stronger, or both. Note, however, that while this is a useful paradigm with which to manage patients with RF, it is exceedingly difficult to identify fatigue under clinical conditions. Nonetheless, as a rough guide, spontaneous ventilation can be sustained indefinitely when the effort of each spontaneous breath is less than one third the maximal respiratory effort achievable.40,41 In normal patients, the maximum negative inspiratory pressure (MIP) measured at FRC exceeds 100 cm H2O, whereas the work of spontaneous breathing is less than 10 cm H2O, providing considerable respiratory muscle reserve before the conditions of fatigue are approached. In contrast, patients with acute respiratory failure frequently have values of MIP <30 cm H2O, while the load on the respiratory muscles, as measured by the pressure generated by the ventilator during each breath, exceeds 30 cm H2O.22–24 Such values predict that the patient's respiratory muscles will fatigue quickly if spontaneous ventilation were required, a hypothesis easily confirmed in such patients who breathe rapidly and insufficiently when taken off the ventilator.42 Another measure of maximum respiratory effort in the conscious patient is vital capacity (VC). As a rough guideline, when VC is three times the tidal volume (Vt) required to maintain eucapnia and normal pH, respiratory muscle fatigue is unlikely. A corresponding alternate measure of respiratory load is the minute ventilation required to maintain normal PaCO2 and pH. Factors that increase CO2 production, dead space, or metabolic acidosis necessarily increase this ventilation and so promote respiratory muscle fatigue. Such fatigue is often signaled by increased respiratory rate (RR >35 breaths per minute), by paradoxical respiratory motion (the abdomen moves in with inspiration as the fatigued diaphragm is pulled craniad by the negative pleural pressure), and by the patient's unexplained somnolence or decreased responsiveness.21,41 Accordingly, evaluation of the patient's ability to resume spontaneous ventilation includes measurements of MIP, VC, Vt, RR, and V̇e, as well as direct observation of the respiratory motions during a period of spontaneous breathing43,44 (see Chap. 44).