Original Papers Respiration 1990:57:65-69
Is There Central Respiratory Depression after Intravenous Administration of Propranolol?1* Peter L. Bailey\ Man-Cheong Fung3, Ronald L. Price'', Katherine A. East3, Nathan L. Pace '. Michael D. Goldman b Department of “ Anesthesiology and h Interna! Medicine, Division of Respiratory, Critical Care and Occupational Medicine, University of Utah School of Medicine, Salt Lake City, Utah, USA
Key Words. Beta-adrenergic blockade • Propranolol • Respiratory depression • Ventilatory response to CO;
Introduction Beta-adrenergic blockers are administered perioperatively in order to continue chronic therapy and avoid exacerbating cardiac ischemia [I, 2], to acutely manage untreated hypertensive patients [3], and to control the hemodynamic response to major stimuli such as laryngoscopy and sternotomy [4], It is now rec ognized that continued beta-adrenergic blockade, up to the day of surgery, does not place the surgical can didate at increased risk and that general anesthesia does not potentiate the hemodynamic manifestations of beta-adrenergic blockade [5]. Increasingly beta blocking drugs are being used as part of every anesthesiologist’s drug armamentarium. Beta-adrenergic blockade can, however, produce or predispose patients to adverse respiratory effects. Although normal subjects are not likely to demon1 This study was supported in part by the Stanley Research Foun dation, Salt Lake City.
strate increased airway resistance from therapeutic beta-adrenergic blockade, smokers and patients with asthma or chronic bronchitis are distinctly susceptible to bronchospasm. A less well appreciated problem with medications such as propranolol is their poten tial to depress central respiratory drive. Knowledge of the significance of such an effect would be important to anesthesiologists who administer beta-adrenergic blockers perioperatively. Unfortunately, the current literature yields conflicting results with regard to this phenomenon; while several investigators report that beta-adrenergic blockade does depress the ventilatory response to CO; by a central mechanism [6-8], these findings are not consistently reported [9-11], Drawing conclusions from many of these studies is also limited by methodological Haws. We, therefore, thought it worthwhile to examine 12 volunteers in a double blind, placebo-controlled study to determine if any significant central respiratory depression occurs after intravenous administration of a beta-adrenergic blocking dose of propranolol.
Downloaded by: Karolinska Institutet, University Library 130.237.122.245 - 1/18/2019 12:59:05 AM
Abstract. Beta-adrenergic blockers have been reported to depress central ventilatory drive. The authors in vestigated this possibility in a double-blind, randomized fashion in 12 healthy volunteers who received 0.1 mg • kg"1of propranolol and normal saline intravenously at two separate study sessions. A modified Read rebreathing technique was used. Both ventilatory and occlusion pressure responses to CO; were measured to help separate peripheral (airway) from central mechanisms. Significant beta blockade was demonstrated by statistically lower heart rate responses to CO; rebreathing after propranolol, but not normal saline. Neverthe less, propranolol exerted no significant effect on resting end-tidal CO; or the ventilatory and occlusion pres sure responses to C 0 2. Although healthy subjects appear to have minimal alterations in their ventilatory re sponse to CO; after beta-adrenergic blockade, patients with airway disease may still experience significant changes in ventilation. In addition, drug interaction studies may give further insight into the presence or ab sence of any respiratory effects of propranolol.
Bailey/Fung/Price/East/Pace/Goldman
66
Permission to perform the study was obtained from the Institu tional Review Board at the University of Utah Medical Center Hospital. Study subjects were healthy, nonsmoking adult males with no history of asthma. Informed consent was obtained, and the subjects refrained from alcohol, caffeine, and aspirin consumption for 24 h prior to their participation in the study. No subject ate for 8 h prior to study, and all studies started between 07.00 and 08.00 h. Twelve subjects were studied for approxiamtely 30 min before and 1 h after the administration of propranolol at one session and placebo (normal saline) at another session in a double-blind fash ion. The order of allocation was randomized, so that 6 subjects re ceived propranolol and then saline, and the other 6 received saline and then propranolol. Upon arrival in the morning, the subjects reclined in a dimly lit area. After local infiltration with 0.5 cm' of 1% lidocaine, an intravenous cannula was inserted into a pe ripheral arm vein and. Ringer’s lactate infused at 100 ml • h '1. After blood pressure (Datascope® automatic blood pressure cuff) and heart rate (Nelcor® pulse oximeter) were recorded, an initial C 0 2 rebreathing challenge (for details see below) was performed by sub jects at the first session to familiarize them with the test, during each CO, challenge, the subjects wore comfortable headphones emitting white noise to standardize the auditory stimulus and soft occlusive nose clips to prevent nasal breathing during the test. The subjects were instructed to keep their eyes closed during each CO, challenge. After a 10-min rest interval, a baseline response to progressive hyperoxic hypercapnia was obtained. Maximal heart rate (by pulse oximetry) also was recorded during this and every CO, challenge to ascertain if beta-adrenergic blockade from propranolol had been obtained. After this, and following another 10-min rest interval, ei ther propranolol (0.1 mg - kg'1) or normal saline (both in 100 ml) was infused at a constant rate over 10 min, and the heart rate was recorded every minute during the infusion. 5, 30, and 60 min after finishing the infusion additional CO, challenges were performed. The subjects returned no sooner than 48 h later to receive proprano lol or normal saline, whichever had not been received during the first trial, and be evaluated in the same fashion. C 0 2 Rebreathing Circuit and Response Measurement We used a modified Read rebreathing circuit. The rebreathing apparatus had a 7.5-liter neoprene rebreathing bag enclosed in a lucite box. A Validyne® differential pressure transducer measured the pressure drop across a Fleisch® pneumotachograph at the outlet of the box to assess ventilatory flow. Flow was directed either into the bag or through the pneumotachograph by a three-way valve located at the mouth of the box, permitting the subject to breathe directly into the room when not rebreathing C 0 2. inspiratory and expira tory limbs of the circuit were separated by a Collins® J valve. A solenoid-operated occlusion valve was located at the proximal end of the inspiratory airway. The CO, concentration was measured by a Beckman® LB-2 infrared CO, Analyzer which sampled gas at the mouthpiece at a rate of 200 ml • m in '1and returned it to the central chamber of the Collins valve. The airway occlusion pressure was measured by a Microswitch® pressure transducer in the central chamber of the Collins valve. The pressure signal was low-pass fil tered at 30 Hz. The total circuit volume was 9 liters. The inspiratory circuit resistance was 1.9 cm H ,0 • l '1• s '1. The expiratory circuit re sistance was 1.7 cm H ,0 • l '1• s"1and constant between flow rates of 15 and 135 liters • min"'.
Flow, CO,, and pressure signals were sampled by a microcom puter (Motorola® Exociser II) 12-bit analog-to-digital converter (Burr-Brown® MP7208 Data Acquisition System) with a resolution of 4.8 mV per analog-to-digital unit and a range of ± 10 V. Occlu sion pressure (P0,) measurements were made at the start of every in spiration. The inspiratory occlusion valve was closed 300 ms after the start of expiration. If the shape of the occluded pressure wave form was satisfactory, the inspiration pressure was sampled and stored. A signal to reopen the valve was sent 120 ms after the onset of inspiration. After allowing the subject to breathe quietly through the mouth piece with the nose clip in place, the resting (PCT) C 0 2concentration was recorded, and the three-way valve was switched to the re breathing bag previously filled with 7.8% CO, and 92.2% 0 2. For each breath, the following data were displayed on the video termi nal and stored in memory: inspiratory time (T,), breath duration (T tot), fractional inspired concentration (% IN C02) and end-tidal CO, concentration (%ETCO,), tidal volume (VT). minute ventila tion (VK ), inspiratory mouth occlusion pressure at 100 ms (P„,), and elapsed time since start of C 0 2 rebreathing. All gas volumes were corrected to BTPS. Subjects were encouraged to rebreathe as long as possible, but could stop at any time: the desired goal was to reach a Pet CO, of 60 mm Hg. The change in Pgr CO, during rebreathing challenges was always an increase of at least 15 mm Hg. After completion of each C 0 2 challenge, plots of Vt. versus PhT CO, and P0, versus P ^ CO, were displayed on the video display terminal. To ensure that the regression line reflected only data from the linear portion of ventilatory response, data from the first 10 breaths were not used for least-squares linear regression. The rest ing PCT C 0 2 (to quantify ‘set point' shift) [12] and both the slope of VKversus Pp,- CO, and the slope of P0, versus P ^ CO, (to quantify changes in respiratory drive ‘gain’) were saved for later analysis. Statistical analysis included use of the Hotelling t square test, the paired Student t test, and univariate repeated-measures analysis of variance. Statistical software was from the BMDP package (mod ules P3D and P2V). Statistical significance was set for p < 0.05.
Results Subjects were all Caucasian males with an age range of 24-35 years and a weight and height range of 66-93 kg and 175-188 cm, respectively. Heart rates from beginning to end of the 10 min of infusion changed from a mean (± SD) of 60.4 ± 8.5 to 58.7 ± 8.4 beats/min with normal saline and from 65.0 ±7.7 to 56.2 ±7.8 beats/min with propranolol (F999 = 8.85; p
Is There Central Respiratory Depression after Intravenous Administration of Propranolol?1* Peter L. Bailey\ Man-Cheong Fung3, Ronald L. Price'', Katherine A. East3, Nathan L. Pace '. Michael D. Goldman b Department of “ Anesthesiology and h Interna! Medicine, Division of Respiratory, Critical Care and Occupational Medicine, University of Utah School of Medicine, Salt Lake City, Utah, USA
Key Words. Beta-adrenergic blockade • Propranolol • Respiratory depression • Ventilatory response to CO;
Introduction Beta-adrenergic blockers are administered perioperatively in order to continue chronic therapy and avoid exacerbating cardiac ischemia [I, 2], to acutely manage untreated hypertensive patients [3], and to control the hemodynamic response to major stimuli such as laryngoscopy and sternotomy [4], It is now rec ognized that continued beta-adrenergic blockade, up to the day of surgery, does not place the surgical can didate at increased risk and that general anesthesia does not potentiate the hemodynamic manifestations of beta-adrenergic blockade [5]. Increasingly beta blocking drugs are being used as part of every anesthesiologist’s drug armamentarium. Beta-adrenergic blockade can, however, produce or predispose patients to adverse respiratory effects. Although normal subjects are not likely to demon1 This study was supported in part by the Stanley Research Foun dation, Salt Lake City.
strate increased airway resistance from therapeutic beta-adrenergic blockade, smokers and patients with asthma or chronic bronchitis are distinctly susceptible to bronchospasm. A less well appreciated problem with medications such as propranolol is their poten tial to depress central respiratory drive. Knowledge of the significance of such an effect would be important to anesthesiologists who administer beta-adrenergic blockers perioperatively. Unfortunately, the current literature yields conflicting results with regard to this phenomenon; while several investigators report that beta-adrenergic blockade does depress the ventilatory response to CO; by a central mechanism [6-8], these findings are not consistently reported [9-11], Drawing conclusions from many of these studies is also limited by methodological Haws. We, therefore, thought it worthwhile to examine 12 volunteers in a double blind, placebo-controlled study to determine if any significant central respiratory depression occurs after intravenous administration of a beta-adrenergic blocking dose of propranolol.
Downloaded by: Karolinska Institutet, University Library 130.237.122.245 - 1/18/2019 12:59:05 AM
Abstract. Beta-adrenergic blockers have been reported to depress central ventilatory drive. The authors in vestigated this possibility in a double-blind, randomized fashion in 12 healthy volunteers who received 0.1 mg • kg"1of propranolol and normal saline intravenously at two separate study sessions. A modified Read rebreathing technique was used. Both ventilatory and occlusion pressure responses to CO; were measured to help separate peripheral (airway) from central mechanisms. Significant beta blockade was demonstrated by statistically lower heart rate responses to CO; rebreathing after propranolol, but not normal saline. Neverthe less, propranolol exerted no significant effect on resting end-tidal CO; or the ventilatory and occlusion pres sure responses to C 0 2. Although healthy subjects appear to have minimal alterations in their ventilatory re sponse to CO; after beta-adrenergic blockade, patients with airway disease may still experience significant changes in ventilation. In addition, drug interaction studies may give further insight into the presence or ab sence of any respiratory effects of propranolol.
Bailey/Fung/Price/East/Pace/Goldman
66
Permission to perform the study was obtained from the Institu tional Review Board at the University of Utah Medical Center Hospital. Study subjects were healthy, nonsmoking adult males with no history of asthma. Informed consent was obtained, and the subjects refrained from alcohol, caffeine, and aspirin consumption for 24 h prior to their participation in the study. No subject ate for 8 h prior to study, and all studies started between 07.00 and 08.00 h. Twelve subjects were studied for approxiamtely 30 min before and 1 h after the administration of propranolol at one session and placebo (normal saline) at another session in a double-blind fash ion. The order of allocation was randomized, so that 6 subjects re ceived propranolol and then saline, and the other 6 received saline and then propranolol. Upon arrival in the morning, the subjects reclined in a dimly lit area. After local infiltration with 0.5 cm' of 1% lidocaine, an intravenous cannula was inserted into a pe ripheral arm vein and. Ringer’s lactate infused at 100 ml • h '1. After blood pressure (Datascope® automatic blood pressure cuff) and heart rate (Nelcor® pulse oximeter) were recorded, an initial C 0 2 rebreathing challenge (for details see below) was performed by sub jects at the first session to familiarize them with the test, during each CO, challenge, the subjects wore comfortable headphones emitting white noise to standardize the auditory stimulus and soft occlusive nose clips to prevent nasal breathing during the test. The subjects were instructed to keep their eyes closed during each CO, challenge. After a 10-min rest interval, a baseline response to progressive hyperoxic hypercapnia was obtained. Maximal heart rate (by pulse oximetry) also was recorded during this and every CO, challenge to ascertain if beta-adrenergic blockade from propranolol had been obtained. After this, and following another 10-min rest interval, ei ther propranolol (0.1 mg - kg'1) or normal saline (both in 100 ml) was infused at a constant rate over 10 min, and the heart rate was recorded every minute during the infusion. 5, 30, and 60 min after finishing the infusion additional CO, challenges were performed. The subjects returned no sooner than 48 h later to receive proprano lol or normal saline, whichever had not been received during the first trial, and be evaluated in the same fashion. C 0 2 Rebreathing Circuit and Response Measurement We used a modified Read rebreathing circuit. The rebreathing apparatus had a 7.5-liter neoprene rebreathing bag enclosed in a lucite box. A Validyne® differential pressure transducer measured the pressure drop across a Fleisch® pneumotachograph at the outlet of the box to assess ventilatory flow. Flow was directed either into the bag or through the pneumotachograph by a three-way valve located at the mouth of the box, permitting the subject to breathe directly into the room when not rebreathing C 0 2. inspiratory and expira tory limbs of the circuit were separated by a Collins® J valve. A solenoid-operated occlusion valve was located at the proximal end of the inspiratory airway. The CO, concentration was measured by a Beckman® LB-2 infrared CO, Analyzer which sampled gas at the mouthpiece at a rate of 200 ml • m in '1and returned it to the central chamber of the Collins valve. The airway occlusion pressure was measured by a Microswitch® pressure transducer in the central chamber of the Collins valve. The pressure signal was low-pass fil tered at 30 Hz. The total circuit volume was 9 liters. The inspiratory circuit resistance was 1.9 cm H ,0 • l '1• s '1. The expiratory circuit re sistance was 1.7 cm H ,0 • l '1• s"1and constant between flow rates of 15 and 135 liters • min"'.
Flow, CO,, and pressure signals were sampled by a microcom puter (Motorola® Exociser II) 12-bit analog-to-digital converter (Burr-Brown® MP7208 Data Acquisition System) with a resolution of 4.8 mV per analog-to-digital unit and a range of ± 10 V. Occlu sion pressure (P0,) measurements were made at the start of every in spiration. The inspiratory occlusion valve was closed 300 ms after the start of expiration. If the shape of the occluded pressure wave form was satisfactory, the inspiration pressure was sampled and stored. A signal to reopen the valve was sent 120 ms after the onset of inspiration. After allowing the subject to breathe quietly through the mouth piece with the nose clip in place, the resting (PCT) C 0 2concentration was recorded, and the three-way valve was switched to the re breathing bag previously filled with 7.8% CO, and 92.2% 0 2. For each breath, the following data were displayed on the video termi nal and stored in memory: inspiratory time (T,), breath duration (T tot), fractional inspired concentration (% IN C02) and end-tidal CO, concentration (%ETCO,), tidal volume (VT). minute ventila tion (VK ), inspiratory mouth occlusion pressure at 100 ms (P„,), and elapsed time since start of C 0 2 rebreathing. All gas volumes were corrected to BTPS. Subjects were encouraged to rebreathe as long as possible, but could stop at any time: the desired goal was to reach a Pet CO, of 60 mm Hg. The change in Pgr CO, during rebreathing challenges was always an increase of at least 15 mm Hg. After completion of each C 0 2 challenge, plots of Vt. versus PhT CO, and P0, versus P ^ CO, were displayed on the video display terminal. To ensure that the regression line reflected only data from the linear portion of ventilatory response, data from the first 10 breaths were not used for least-squares linear regression. The rest ing PCT C 0 2 (to quantify ‘set point' shift) [12] and both the slope of VKversus Pp,- CO, and the slope of P0, versus P ^ CO, (to quantify changes in respiratory drive ‘gain’) were saved for later analysis. Statistical analysis included use of the Hotelling t square test, the paired Student t test, and univariate repeated-measures analysis of variance. Statistical software was from the BMDP package (mod ules P3D and P2V). Statistical significance was set for p < 0.05.
Results Subjects were all Caucasian males with an age range of 24-35 years and a weight and height range of 66-93 kg and 175-188 cm, respectively. Heart rates from beginning to end of the 10 min of infusion changed from a mean (± SD) of 60.4 ± 8.5 to 58.7 ± 8.4 beats/min with normal saline and from 65.0 ±7.7 to 56.2 ±7.8 beats/min with propranolol (F999 = 8.85; p
