Extrathoracic expiratory flow limitation in obesity and obstructive and restrictive disorders: effects of increasing negative expiratory pressure.

BACKGROUND: The negative expiratory pressure (NEP) technique is used to detect intrathoracic expiratory flow limitation (EFL) in patients with respiratory disorders. Application of NEP may result in a sustained decrease of flow below control as a result of upper airway collapse, which may invalidate interpretation of the test. This response to NEP is common in patients with obstructive sleep apnea syndrome (OSAS). The prevalence of this phenomenon, however, has not been studied in healthy subjects and patients with obstructive and restrictive disorders without OSAS. PURPOSE: The purpose of this study was as follows: (1) to assess the effects of increasing NEP levels on upper airway patency, and (2) to determine the factors that predispose to intrathoracic flow limitation or upper airway collapse during NEP application in different postures in healthy nonobese and obese subjects, and in patients with obstructive and restrictive respiratory disorders. SUBJECTS: Fifty-six patients with obstructive airway disease (21 patients with COPD, 16 patients with simple chronic bronchitis, and 19 patients with asthma) were compared with 47 patients with restrictive respiratory disorders, 20 nonobese and healthy subjects, and 9 obese subjects (body mass index > 30) without a history of snoring or OSAS. METHODS: NEP at levels of 5 cm H(2)O, 10 cm H(2)O, and 15 cm H(2)O were applied at the mouth immediately after the onset of tidal expiration while seated and supine. Intrathoracic EFL was defined as no change in expiratory flow over any portion of the immediately preceding control breath. Upper airway collapse or narrowing was detected when flows decreased below those of the control breath. RESULTS: Ten patients (18%) with obstructive airway disease (7 patients with COPD) exhibited EFL at NEP of 5 cm H(2)O (4 patients were supine only, and 6 patients were both supine and sitting). No patient with restrictive disorders or healthy obese and nonobese subjects presented EFL at NEP of 5 cm H(2)O. In almost all subgroups, both seated and supine, subjects exhibited a transient decrease of flow below control immediately after the application of NEP in occasional breaths. As NEP increased, the number of subjects who exhibited this response in occasional breaths declined, while the number of subjects who displayed this pattern in all breaths increased. Conversely, there were very few subjects in each subgroup who exhibited a sustained decrease in flow below control in occasional breaths at NEP at 5 cm H(2)O, and only one healthy obese subject who displayed this response in all breaths in supine position only. CONCLUSIONS: In general, an increase in NEP resulted in only rare instances of sustained decrease in flow below control in all breaths. While transient decreases in flow exhibited immediately after the onset of NEP in all breaths are common and become more prevalent as NEP is increased beyond 5 cm H(2)O, there are only rare instances of sustained decrease in flow below control throughout expiration at all levels of NEP tested, indicating an appropriate upper airway dilator response that maintains patency. Thus, in subjects without OSAS, assessment of intrathoracic EFL with NEP is valid in almost all instances.

Effect of once-daily dosing vs. multiple daily dosing of tobramycin on enzyme markers of nephrotoxicity.

OBJECTIVE: To determine the incidence of nephrotoxicity of once-daily dosing (ODD) and multiple daily dosing (MDD) regimens of tobramycin in critically ill patients. DESIGN: Randomized, prospective clinical trial. SETTING: : Adult intensive care units at two university hospitals. PATIENTS: Fifty-eight critically ill patients with a suspected or documented aerobic Gram-negative infection. INTERVENTIONS: Patients were randomized to receive tobramycin by ODD (7 mg/kg) or MDD. Baseline urine aliquots and 24-hr urine collections were collected on days 3, 7, and 11 during therapy and on days 3, 7, and 11 following discontinuation of therapy for measurement of alanine aminopeptidase (AAP), N-acetyl-beta-d-glucosaminidase (NAG), and creatinine. MEASUREMENTS AND MAIN RESULTS: Fifty-four patients were evaluable (ODD n = 25; MDD n = 29). The groups were similar with regard to demographic and clinical variables. The tobramycin dose was higher in the ODD group compared with the MDD group (425 +/- 122.5 mg vs. 312.8 +/- 116.6 mg, p <.001). Patients in the MDD group received a mean of 3.89 +/- 1.14 mg.kg(-1)day(-1) at intervals of 11.92 +/- 3.12 hrs. In the ODD group, patients had a higher measured creatinine clearance at the end of therapy compared with MDD group (70 +/- 18.6 vs. 64.8 +/- 17.5 mL/min, p =.047). Fewer patients in the ODD group developed nephrotoxicity than the MDD group (5 vs. 12, p =.142). Although there were increases in urinary enzymes in both treatment groups (AAP, 8.7 +/- 2.9 vs. 5.2 +/- 2.1 units/24 hrs, p <.01 MDD vs. ODD; NAG, 14.7 +/- 4.9 vs. 6.8 +/- 3.1, p <.01 MDD vs. ODD), the increases in the ODD group were significantly lower than in the MDD group. CONCLUSIONS: : The ODD tobramycin regimen appeared to be less nephrotoxic than the MDD regimen despite significantly higher doses. Tobramycin administered by ODD may be the preferred dosing method in selected critically ill medical patients to reduce the incidence and extent of renal damage.