Abstract-␤-Adrenergic receptors (␤AR) regulate active Na ϩ transport in the alveolar epithelium and accelerate clearance of excess airspace fluid. Accumulating data indicates that the cystic fibrosis transmembrane conductance regulator (CFTR) is important for upregulation of the active ion transport that is needed to maintain alveolar fluid homeostasis during pulmonary edema. We hypothesized that ␤AR regulation of alveolar active transport may be mediated via a CFTR dependent pathway. To test this hypothesis we used a recombinant adenovirus that expresses a human CFTR cDNA (adCFTR) to increase CFTR function in the alveolar epithelium of normal rats and mice. Alveolar fluid clearance (AFC), an index of alveolar active Na ϩ transport, was 92% greater in CFTR overexpressing lungs than controls. Addition of the Cl Ϫ channel blockers NPPB, glibenclamide, or bumetanide and experiments using Cl Ϫ free alveolar instillate solutions indicate that the accelerated AFC in this model is due to increased Cl Ϫ channel function. Conversely, CFTR overexpression in mice with no ␤ 1 -or ␤ 2 -adrenergic receptors had no effect on AFC. Overexpression of a human ␤ 2 AR in the alveolar epithelium significantly increased AFC in normal mice but had no effect in mice with a non-functional human CFTR gene (⌬508 mutation). These studies indicate that upregulation of alveolar CFTR function speeds clearance of excess fluid from the airspace and that CFTRs effect on active Na ϩ transport requires the ␤AR. These studies reveal a previously undetected interdependency between CFTR and ␤AR that is essential for upregulation of active Na

The development and subsequent clinical application of the beta-adrenergic receptor blocking drugs over the past 50 years represent one of the major advances in human pharmacotherapy. No other class of synthetic drugs has demonstrated such widespread therapeutic utility for the treatment of so many cardiovascular and noncardiovascular diseases. In addition, these drugs have proven to be molecular probes that have contributed to our understanding of disease, and on the molecular level, both the structure and the function of the 7 transmembrane G protein receptors, which mediate the actions of many different hormones, neurotransmitters, and drugs. The evolution of beta-blocker drug development has led to refinements in their pharmacodynamic actions that include agents with relative beta1-selectivity, partial agonist activity, concomitant alpha-adrenergic blockers activity, and direct vasodilator activity. In addition, long-acting and ultra-short-acting formulations of beta-blockers have also demonstrated a remarkable record of clinical safety in patients of all ages. Indeed, the beta-adrenergic blockers have provided us with a great clinical legacy for now and in years to come.

BackgroundProlonged sedation is common in mechanically ventilated patients and is associated with increased morbidity and mortality. We sought to determine the diagnostic value of head computed tomography (CT) in mechanically ventilated patients who remain unresponsive after discontinuation of sedation.MethodsA retrospective review of adult (age >18 years of age) patients consecutively admitted to the medical intensive care unit of a tertiary care medical center. Patients requiring mechanical ventilation for management of respiratory failure for longer than 72 hours were included in the study group. A group that did not have difficulty with awakening was included as a control.ResultsThe median time after sedation was discontinued until a head CT was performed was 2 days (interquartile range 1.375–2 days). Majority (80%) of patients underwent head CT evaluation within the first 48 hours after discontinuation of sedation. Head CT was non-diagnostic in all but one patient who had a small subarachnoid hemorrhage. Twenty-five patients (60%) had a normal head CT. Head CT findings did not alter the management of any of the patients. The control group was similar to the experimental group with respect to demographics, etiology of respiratory failure and type of sedation used. However, while 37% of subjects in the control group had daily interruption of sedation, only 19% in the patient group had daily interruption of sedation (p < 0.05).ConclusionIn patients on mechanical ventilation for at least 72 hours and who remain unresponsive after sedative discontinuation and with a non-focal neurologic examination, head CT is performed early and is of very limited diagnostic utility. Routine use of daily interruption of sedation is used in a minority of patients outside of a clinical trial setting though it may decrease the frequency of unresponsiveness from prolonged sedation and the need for head CT in patients mechanically ventilated for a prolonged period.

Medical intensivists make heterogenous decisions using pulmonary artery catheter (PAC) data in medical intensive care unit patients. The object was to determine if cardiologists given PAC data from critically ill cardiology patients make uniform management choices. A survey questionnaire containing 3 coronary care unit (CCU) clinical vignettes was designed and mailed to board-certified cardiologists who are members of the American College of Cardiology. Twenty board-certified medical intensivists were also asked to complete the vignettes. Each vignette contained PAC data and one-half of the surveys contained echocardiographic (ECHO) information. Every respondent was asked to select 1 of 6 interventions for each vignette. In 2 of 3 vignettes 1 intervention was selected by more than 70% of cardiologists. In the third vignette, 1 intervention was selected by more than 50% of cardiologists. For each vignette, 1 intervention was selected by at least 75% of medical intensivists. There was no significant difference in the distribution of management choices between the ECHO and the non-ECHO subgroups. There is relative homogeneity in selecting an intervention based on PAC data among cardiologists and medical intensivists in CCU patients and is probably due to patient-related factors. The presence of ECHO information did not change the intervention selected. Cardiology patients may represent an ideal group in which to evaluate PAC efficacy.