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can impair the ventilator withdrawal process by leading to excess carbon dioxide production, which can further increase the ventilation loads on ventilatory muscles. Studies77,78 have suggested that proper nutritional support can increase the likelihood of success of ventilator withdrawal. A number of electrolyte imbalances also can impair ventilatory muscle function.5,9,79–81 Phosphate deficiency has been associated with respiratory muscle weakness and ventilator withdrawal failure. A study demonstrating improved transdiaphragmatic pressure values with the repletion of serum phosphorus levels in patients receiving mechanical ventilation, however, did not specifically address the issue of ventilator withdrawal.79 Magnesium deficiency also has been reported to be associated with muscle weakness,82 although the relationship to ventilator dependence has not been specifically addressed. Finally, bicarbonate excretion from inappropriate overventilation (often occurring in patients with chronic obstructive pulmonary disease (COPD) with chronic baseline hypercapnia) can impair ventilator withdrawal efforts as the patient has a diminished capacity to compensate for hypercapnia. Severe hypothyroidism and myxedema directly impair diaphragmatic function and blunt ventilatory responses to hypercapnia and hypoxia.83,84 Other hormonal factors that are important for optimal muscle function include insulin/glucagon and adrenal corticosteroids. As in other organs, adequate oxygen delivery and oxygen uptake by the ventilatory muscles is necessary for proper muscle function.85,86 Impaired oxygen delivery can be a consequence either of inadequate oxygen content or of inadequate cardiac output.87 Impaired oxygen uptake occurs most commonly during systemic inflammatory syndromes such as sepsis.88 Gas Exchange Factors: Gas exchange abnormalities can develop during ventilatory support reductions for several reasons. Various lung diseases produce ventilation-perfusion imbalances and shunts. Ventilator dependence thus may be a consequence of a need for high levels of expiratory pressure and/or the fraction of inspired oxygen (FIO2 ) to maintain an adequate oxygen content.5,9 A patient with hypoxemia also can develop a fall in mixed venous PO2 levels from the cardiovascular factors described below. Cardiovascular Factors: Several groups of investigators have drawn attention to cardiovascular responses in ventilator-dependent patients and have emphasized the potential for ventilatory support reductions to induce ischemia or heart failure in susceptible patients with limited cardiac reserve.9,89–93 Putative mechanisms include the following: (1) increased metabolic demand and hence circulatory demands that are associated with the transition from mechanical ventilation to spontaneous breathing in patients with limited cardiac reserve; (2) increases in venous return as the contracting diaphragm displaces blood from the abdomen to the thorax; and (3) the increased left ventricular afterload that is imposed by negative pleural pressure swings. Lemaire and colleagues demonstrated left ventricular dysfunction (ie, the pulmonary capillary wedge pressure increased from 8 to 25 mm Hg) during failed ventilator withdrawal attempts in 15 patients with COPD. Following diuresis, 9 of these 15 patients were successfully withdrawn from the ventilator.90 Psychological Factors: Psychological factors may be among the most important nonrespiratory factors leading to ventilator dependence. Fear of the loss of an apparent life support system as well as social/familial/economic issues all may play a role. Stress can be minimized by frequent communication among the staff, the patient, and the patient’s family.94 Environmental stimulation using television, radio, or books also appears to improve psychological functioning.2 Ambulation using a portable ventilator (or bagging) has been shown to benefit attitudes and outlooks in long-term ventilator-dependent patients. Sleep deprivation may cause impairment of the respiratory control system,95 although this may be related to accompanying factors rather than to sleep deprivation per se.96 Finally,