Anatomical Dead Space and Airway Resistance After Glycopyrrolate Or Atropine Premedication

ANATOMICAL DEAD SPACE AND AIRWAY RESISTANCE AFTER GLYCOPYRROLATE OR ATROPINE PREMEDICATION

ALEXANDER W, GOTTA, COLE RAY, COLLEEN A. SULLIVAN AND PAUL L. GOLDINER

ABSTRACT The effects of atropine and glycopyrrolate on anatomical dead space, one and three second forced expiratory volume, maximal expiratory flow rate, and total forced expiratory volume were determined in ten healthy volunteers. Using Fowler's single breath nitrogen analyzing technique, atropine was found to increase dead space by 19.2 per cent at one hour, declining to 11.02 per cent at four hours. Glycopyrrolate increased dead space by 21.57 per cent at one hour, 29.28 per cent at two hours, and 26.65 per cent at four hours. When compared to the effects of saline control injection, the dead space increases are significant. The difference between glycopyrrolate and atropine is significant only at four hours. Increases in maximal expiratory flow rate induced by atropine and glycopyrrolate were significant at one-half hour, while atropine alone induced a significant increase in one second forced expiratory volume. Three second forced expiratory volume and total forced expiratory volume were not significantly altered.

KEY WORDS: PREMEDICATION, atropine, glycopyrrolate; LUNG, deadspace; AIR- WAY, resistance.

THE ABILITY OF ATROPINE to increase anatomi- METHOD cal dead space and to reduce intrapulmonary re- sistance to air flow has been well documented, t-4 The protocol for this study was approved by The synthetic anticholinergic drug glycopyrro- the Clinical Investigations Committee of the late shares the ability of atropine to decrease Memorial Sloan-Kettering Cancer Center. airway secretions and to prevent vagal reflexes Ten non-smoking, healthy volunteers (seven and, additionally, decreases the volume of gastric males, three females, aged 23-32 years), reported secretions and increases intragastric pH. s The to the laboratory early in the morning, after an antimuscarinic action of glycopyrrolate appears overnight fast. The nature of the experiment, side to last longer than that of atropine. 6"7 It was the effects and hazards of the drugs involved were purpose of this study to determine the effect of explained in detail, and informed consent was glycopyrrolate on pulmonary dynamics and to obtained. After familiarization with the Hewlett compare it to atropine with respect to magnitude Packard 47402A Pulmonary Function Analyzer, and duration of effect. base line determinations were made of anatomi- cal dead space (VD anat), using Fowler's single Alexander W. Gotta, M.D., Associate Attending breath nitrogen analyzing technique, s One and Anesthesiologist; Director, Research and Education. three second forced expiratory volume (FEV~, Cole Ray, RPT, Chief of Respiratory Therapy; Colleen FEV~), total forced expiratory volume (FEV) and A. Sullivan, M.B., Ch.B., Associate Attending Anes- thesiologist; Paul L. Goldiner, M.D., Chairman, De- maximal expiratory flow rate (MEFR) were also partment of Anesthesiology: Memorial Sloan-Kettering measured. The maximal expiratory flow rate is Cancer Center, 1275 York Avenue, New York, NY the forced expiratory flow rate between 200 and 10021, U.S.A. 1200 ml expired gas. All tests were done with the Address Correspondence to: Alexander W. Gotta, M.D., Associate Professor of Clinical Anaesthesia, subjects seated comfortably and they were al- State University of New York, Downstate Medical lowed to rest or walk at will between studies, but Center, 450 Clarkson Avenue, Box 6, Brooklyn, New were not to exert themselves. In a randomized York 11203. double-blind manner each subject then received Supported by a grant from the A.H. Robins Co., Richmond, Virginia. Presented in part at the Annual atropine sulphate 0.0085 rag-kg -~ body weight, Meeting, Canadian Anesthetists' Society, June 23, glycopyrrolate 0.005 rag. kg -1 body weight, and 1980. sterile saline solution one ml intramuscularly,

51 Canad. Anaesth. Soc. J., vol. 28, no. l, January 1981 52 CANADIAN ANAESTHETISTS' SOCIETY JOURNAL one drug on each of three consecutive days. The significant (P < 0.01, with atropine significant at injections were made into the deltoid muscle of two hours, P< 0.05). The mean increase in dead alternate arms. Repeat determinations of all space caused by glycopyrrolate was 21.57 per studies were done for the next four hours, with cent at one hour and increasing further to 26.65 the timed forced expiratory volume and MEFR per cent at four hours (Table I). These increases beginning at one-half hour and repeated at hourly are significant at all times (P< 0.01). Although all intervals. The first repeat dead space determina- subjects had an increase of dead space in re- tion was made at one hour, and repeated at hourly sponse to atropine and glycopyrrolate, there was intervals. Dead space and forced expiratory great individual variation, maximal increases curves were recorded graphically, and volumes ranging from 10.3 per cent to 50 per cent for measured at BTPS. Dead space determinations atropine, and 6.7 to 60.7 per cent for glycopyrro- were measured by Fowler's "estimation" tech- late. The difference between atropine and nique of equal areas. S Alterations in the deter- glycopyrrolate is not significant except at four mined parameters were expressed as percentage hours, when the glycopyrrolate-induced increase increase or decrease from pre-drug measure- in dead space is significantly greater than that for ments, and the mean changes tested for atropine (P < 0.05). The increase in dead space significance against values for the saline controls, caused by glycopyrrolate at one hour did not vary using Student's t test. Findings were considered significantly from the glycopyrrolate increases at significant at a P< 0.05 level. either two, three, or four hours. Thus, the in- crease of dead space caused by glycopyrrolate RESULTS was maximal within two hours, and lasted at least four hours without declining, while the increase The pre-drug anatomical dead space averaged produced by atropine was maximal within one 155ml in the seven males (l.98ml/kg body hour, but was definitely declining by four hours. weight), and 132ml in the three females Both atropine and glycopyrrolate increased the (2.42 ml/kg body weight). Both atropine and gly- one second forced expiratory volume (Table I1). copyrrolate increased dead space in all subjects, The atroplne-induced increases are significant the mean increase for atropine being 19.2 per cent (P < 0.05) except at 3 hours. The glycopyrro- at one hour and declining to ! 1.02 per cent at 4 late changes are not significant. hours. The dead space increases were at all times Although the maximal expiratory flow rate was

TABLE I PER CENT INCREASE(DECREASE) or ANATOMICALDEAD SPACE (_ SEM) n= 10

Time after injection (hours) 1 2 3 4 Atropine 19.2 (3.89) 16.7 (5.74) 19.1 (5.01) 11.02 (2.89) Glycopyrrolate 21.57 (3.99) 29.28 (6.03) 23.74 (5.51) 26.65 (6.33) Saline 3.3 (2.05) 1.3 (1.72) 0.8 (2.42) (1.4) (1.92) Alterations in anatomical dead space after atropine sulphate 0.008.$ mg.kg -x body weight, glycopyrrolate 0.005 mg-kg -1, or normal saline 1 ml intramuscularly. Dead space was increased significantly by both atropine and glycopyrrolate at all times, when compared to saline control. The glycopyrrolate-induced increase is significantly greater than that of atropine only at four hours.

TABLE I[ PER CENT INCREASE(DECREASE) OF FEVI (_+ SEM) n=10

Time after injection (hours) ~- 1 2 3~ Atropine 8.15 (3.06) 9.87 (2.66) 7.71 (3.05) 5.97 (2.91) Glyeopyrrolate 3.73 (2.04) 5.32 (2.11) 4.98 (3.06) 6.63 (3.01) Saline (0.82) (1.65) 2.68 0.41) 0.83 (1.0) 2.06 (1.47) Alterations in one second forced expiratory volume after atropine, glycopyrrolate or saline intramuscularly. The atropine changes are significant, except at 3~- hours. The glycopyrrolate changes are not significant. GOTTA, et al.: DEAD SPACE AFTER GLYCOPYRROLATE OR ATROPINE 53 TABLE III PER CENTINCREASE (DECREASE) OF MEFR (• n=10

Time after injection (hours) 1 2 3

Atropine 12.18 (5.69) 12.44 (6.16) 10.9 (5.22) 6.99 (5.69) Glycopyrrolate 11.71 (5.69) 12.84 (6.93) 10.86 (6.31) 6.07 (9.46) Saline (2.38) (3.44) 7.01 (3.07) 0.23 (2.58) 4.85 (2.51) Alteration in maximal expiratory flow rate after atropine, glycopyrrolate and saline intramuscularly. The changes for both atropine and glycopyrrolate are significant only at { hour. increased by both atropine and glycopyrrolate resistance resides in the larger conducting bron- (see Table III), the changes were significant only chi, an increase in diameter predominantly in the at one-half hour (P < 0.05). Total forced expira- smaller tubules would produce a marked increase tory volume and three second forced expiratory in dead space, while at the same time having a volume were not changed. significantly lesser effect on airway resistance. Smaller tubules may be considered as those DISCUSSION two mm or less in diameter and are the fifth to eighteenth generation of air tubule.' t In 1915 Higgins and Means demonstrated the The bronchodilating effect of atropine is evi- ability of atropine to increase anatomical dead dent within 15 minutes of injection. Earlier space by 6.73 per cent in one subject, and by studies have been single tests at one time period, 15.48 per cent in another, determinations being and have not demonstrated the duration of the made two hours after the subcutaneous adminis- bronchodilating effect. The effect of atropine on tration of atropine 1 mg.1 Fowler's development heart rate is maximal at 30 minutes after in- of the single breath nitrogen analyzing technique tramuscular injection, with a return to near pre- gave a reliable method of determining anatomical drug levels at 3 hours, and exact pre-drug levels at dead space, s His base line dead space averaged 5 hours.': The duration of the bronchodilating 156 ml in males (2.13 ml/kg) and 120 ml in females effect of atropine is thus similar to its effect on (l.91 ml/kg). Using Fowler's technique, Severing- heart rate. Blood levels of atropine are maximal haus demonstrated an increase of 29 per cent in 15-50 minutes after intramuscular injection. '2 anatomical dead space 40 minutes after atropine Earlier studies of glycopyrrolate indicate that its 0.5 mg subcutaneously, and 47 per cent when the course of action is longer than that of atropine drug was administered intravenously.2 He also while its anticholinergic intensity is similar. Our showed that any atropine-induced increase in study indicates that the bronchodilating effect of dead space was maximal, in that it was not in- glycopyrrolate is similar in magnitude to that of creased by epinephrine after atropine. 9 Nunn atropine, but longer in duration. Although both found an increase of 12.7 per cent in dead space drugs produced a significant drying effect, there 15 minutes after atropine sulphate 0.6mg in- was no difference between the subjective feelings travenously. 3 Both Higgins and Nunn attributed of discomfort produced by either drug. Nausea increases in respiratory minute volume after at- and vomiting did not occur. ,3 ropine to attempts to maintain normocapnia by hyperventilation. The broncho-dilating ability of SUMMARY atropine has also been demonstrated radio- graphically in dogs, increasing the diameter of Both atropine and glycopyrrolate in usual trachea and primary bronchi by 20 per cent and pre-medicant doses increase anatomic dead lobar bronchi by 9.7 per cent.'~ space while, at the same time, they cause minor The marked increase in anatomical dead space, alterations in pulmonary air flow. These changes with smaller decreases in resistance to air flow is are attributable to dilation of smaller bronchioles. probably attributable to the ability of atropine to dilate smaller conducting airways more than REFERENCES larger airways. TM Glycopyrrolate emulates the ability of atropine to increase dead space I. HIOGINS,H.L. & MEANS, J.H. The effect of cer- tain drugs on the respiration and gaseous metabo- significantlywith only minor alterations in airway lism in normal human subjects. J. Pharm. Exp. resistance. Since 80 per cent of tracheobronchial Therap. 7:1 (1915). 54 CANADIAN ANAESTHETISTS' SOCIETY JOURNAL

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RI~SUMI~ Le retentissement de I'administration d'atropine et de glycopyrrolate sur I'espace mort anatomique, le volume expiratoire maximal apr/~s une et trois secondes, le dGbit expiratoire maximal et le volume total maximal expire a ~t~ ~tudi~ sur dix volontalres en bonne sant& En utilisant la technique d'analyse h I'azote de Fowler, la mesure de I'espace mort apr~s atropine moutrait une augmentation de 19.2 pour cent apr~,s une heure et de 1 t .02 apr~s quatre heures. Avec la glycopyrrolate, I'espace mort a augment6 de 21.57 pour cent/~ la premibre heure, 29.28 pour cent ~t la deuxi/~me heure et de 26.65 pour cent h la quatri~me heure. Lorsque comparde au contr61e obtenu par l'injection de solut6 p hysiologique, I'augmentation de I'espace mort 6tait signifieative. La diffdrenee entre le glycopyrrolate et I'atropine n'a ~t~ significative qu'a la quatrieme heure. L'augmentation du dGbit expiratoire maximal produite par I'atropine et le glyeopyrrolate a 6t6 signifieative aprGs trente minutes, alors que I'atropine seule a provoqu~ une augmentation du volume expiratoire maximal une seconde. Le volume expiratoire maximal trois secondes et le volume total maximal expird n'ont pas dtd altdrGs de fad:on significative.