Effects of Estazolam and Flurazepam on Cardiopulmonary Function in Patients with Chronic Obstructive Pulmonary Disease

Abstract

Benzodiazepine drugs have been shown to suppress respiratory function in patients with chronic obstructive pulmonary disease (COPD). We designed a placebo-controlled crossover study to compare the effects of a new benzodiazepine, estazolam ('ProSom'), with those of flurazepam ('Dalmane') on cardiopulmonary function in COPD patients. 29 patients completed all treatment phases (estazolam 2 mg, flurazepam 30 mg or placebo). Respiratory and cardiovascular function were assessed in awake patients on days 1 and 5 (acute and cumulative effects). Eight patients were also assessed during sleep in each period. The effects of estazolam and flurazepam on ventilatory response to CO2 and mouth occlusion pressure were no different from those of placebo. However, acute administration of flurazepam lowered tidal volume and increased inspiratory flow. Although no clinical signs of respiratory depression were observed with any long term treatment, flurazepam decreased oxygen saturation and inspiratory time and increased respiratory frequency. Neither drug altered breathing control during sleep. Our results indicate that estazolam 2 mg is equally as safe a hypnotic agent as flurazepam for patients with mild COPD.

Benzodiazepine drug use and adverse respiratory outcomes among older adults with COPD

“…Our results are consistent with previous studies that have reported links with benzodiazepines and a variety of adverse respiratory physiology outcomes in COPD [6][7][8][9][10][11][12]. Benzodiazepines are also reported to decrease arousability in healthy individuals during sleep [29], which may prolong the duration of respiratory physiological abnormalities or contribute to aspiration.…”

“…In addition, a true relationship between benzodiazepine use and adverse respiratory outcomes in the older COPD population is supported by biological plausibility (benzodiazepine use is associated with negative respiratory physiology markers) [6][7][8][9][10][11][12].…”

“…Benzodiazepines have been linked with a variety of adverse respiratory physiology outcomes in COPD, including decreased minute ventilation [6][7][8], hypoxaemia and/or hypercapnea [6][7][8][9][10][11], dulling of central respiratory drive and chemoreceptor responsiveness to hypercapnea [8,11,12], decreased respiratory muscle strength [7], and ventilation-perfusion mismatch [6]. Based on this evidence, joint American Thoracic Society/European Respiratory Society guidelines recommend that hypnotics, such as benzodiazepines, be avoided in patients with severe COPD [13].…”

Sleep disorders and their management in patients with COPD

“…A single sublingual dose of lorazepam decreased minute ventilation 20% and reduced 1015% respiratory muscle strength and endurance in patients with COPD [Jolly et al 1996]. Cohn and colleagues report flurazepam (30 mg) acutely lowered tidal volume, decreased oxygen saturation and increased respiratory frequency [Cohn et al 1992]. In a double-blind, randomized, placebo-controlled study, a single dose of triazolam, a very short-acting BZD and zolpidem, a very short-acting BZRA, had no obvious effect on oxygen saturation in patients with mild to moderate COPD (awake PaO 2 55 mmHg and no carbon dioxide retention [PaCO 2 48]).…”

Role of α1‐ and α2‐GABAA receptors in mediating the respiratory changes associated with benzodiazepine sedation

“…Human and animal studies have shown little to moderate alterations in the resting breathing pattern in either of the two directions, depression or stimulation, upon benzodiazepine treatment during wakefulness and sleep (Dalen et al ., 1969; Utting and Pleuvry, 1975; Prato and Knill, 1983; Longbottom and Pleuvry, 1984; Morel et al ., 1984; Schneider et al ., 1996; Carley et al ., 1998; Tulen and Man in't Veld, 1998; Bonnet et al ., 1990; Wettstein et al ., 1990; Pirnay et al ., 2008; Carraro et al ., 2009; Abdala et al ., 2010). Even ventilatory depression, defined as a reduction in tidal volume and/or an increase in partial pressure in carbon dioxide (CO 2 ), and tachypnoea have been reported in the same benzodiazepine‐treated individuals during rest (Berggren et al ., 1987; Mora et al ., 1995; Cohn et al ., 1992). Occurrence of a change in the respiratory frequency or depth depends on the benzodiazepine used, its dosage and route of administration, and is often attributed to its other actions.…”