The use of controlled mechanical ventilation (CMV) in patients who experience weaning failure after a spontaneous breathing trial or after extubation is a strategy based on the premise that respiratory muscle fatigue (requiring rest to recover) is the cause of weaning failure. Recent evidence, however, does not support the existence of low frequency fatigue (the type of fatigue that is long-lasting) in patients who fail to wean despite the excessive respiratory muscle load. This is because physicians have adopted criteria for the definition of spontaneous breathing trial failure and thus termination of unassisted breathing, which lead them to put patients back on the ventilator before the development of low frequency respiratory muscle fatigue. Thus, no reason exists to completely unload the respiratory muscles with CMV for low frequency fatigue reversal if weaning is terminated based on widely accepted predefined criteria. This is important, since experimental evidence suggests that CMV can induce dysfunction of the diaphragm, resulting in decreased diaphragmatic force generating capacity, which has been called ventilator-induced diaphragmatic dysfunction (VIDD). The mechanisms of VIDD are not fully elucidated, but include muscle atrophy, oxidative stress and structural injury. Partial modes of ventilatory support should be used whenever possible, since these modes attenuate the deleterious effects of mechanical ventilation on respiratory muscles. When CMV is used, concurrent administration of antioxidants (which decrease oxidative stress and thus attenuate VIDD) seems justified, since antioxidants may be beneficial (and are certainly not harmful) in critical care patients.