Eur Respir J 1989, 2, 758-763

Effect of protriptyline on ventilatory responses to hypercapnia and asphyxia in normal subjects

A.K. Simonds*, N. Carrell*, M.A. Branthwaite*, N.A. Saunders**

Effect of protripty/ine on venJilatory responses to hypercapnia and asphyxia in •Dcpt of Thoracic Medicine, Brompton Hospital, normal subjects. A. K . Simonds, N. Carroll, M. A. BranJhwaite, N. A. Saunders. London, SW3 6HP. ABSTRACT: A double-blind crossover study was undertaken to assess the effect of protrlptyline on ventilatory responses in normal subjects. Seven '"'"The Royal Newcastle Hospital, Newcastle, NSW, Australia, 2300. subjects received in random order placebo, 10 mg and 20 mg protrlptyUne dally for 2 weeks. Measurements of hypercapnic ventilatory response Correspondence: Dr A.K. Simonds, Dept of Thoracic (HCVR) and asphyxial hypoxic ventUatory response (HVR) were made Medicine, Royal Free Hospital, Pond Street, London, before treatment, 6-8 h after the first dose, and after 2 weeks treatment. NW3 2QG. Mean HCVR and HVR following 10 mg and 20 mg protrlptyline did not differ significantly from measurements on placebo, neither for the single Keywords: Asphyxia; hypercapnia; protriptyline; res­ dose study or after 2 weeks. piratory drive. Eur Respir J., 1989, 2, 758-763. Accepted for publication: May 23, 1989.

The stimulant tricyclic agent protriptyline decreases hospital Ethics Committee and informed consent was episodic nocturnal desaturation in patients with obstruc­ obtained from participants. tive sleep apnoea [1, 2] and more recently, has been The double-blind, placebo-controlled, crossover trial shown to improve nocturnal gas exchange and diurnal consisted of 3 phases each lasting 2 weeks, with a 2 arterial oxygen saturation in patients with sleep related week washout period between each phase. In random disturbances of breathing secondary to restrictive chest order subjects received placebo, 10 mg protriptyline or wall disease [3) and chronic airflow limitation [4). The 20 mg protriptyline daily for the duration of the phase. mechanism of action of protriptyline in sleep disordered Measurements of HCVR and HVR were made the day breathing has been attributed to a reduction in rapid eye before starting each phase, on the first day of each phase movement (REM) sleep associated episodes of apnoea 6-8 h after ingestion of the tablet (acute study), and after and hypopnoea, with an additional action on upper airway 2 weeks treatment (long term study). After the first day muscle tone [5]. However, an independent respiratory of each phase subjects were requested to take the trial stimulant effect has not been excluded. tablet on retiring. The timing of the studies of both acute This trial was carried out to assess the effect of and long term effects was selected because peak levels protriptyline on hypercapnic and hypoxic ventilatory drive following a single oral dose of protriptyline arc reached in normal subjects. The response to a hypercapnic hy­ after 6-12 hand stable plasma levels are demonstrable in poxic (asphyxial) stimulus rather than to a conventional the majority of subjects after 2 weeks [7, 8). Half-life eucapnic hypoxic challenge was chosen for two reasons. varies between subjects with a mean value estimated at Firstly, hypercapnia potentiates the effect of hypoxia on 78.4 h [9). peripheral chemoreceptors [6] and secondly, as the drug The order of HCVR and HVR was randomised and is being used increasingly in patients with nocturnal measurements were made at the same time of day. The hypoventilalion, hypercapnic hypoxia would seem a more 4 week period between assessments meant the measure­ relevant stimulus. ments were probably made at the same stage of the menstrual cycle in each female subject. Venous samples for de_termination of protriptyline lev­ Subjects and methods els were collected at each measurement session with the exception of the first. Samples were analysed by gas The effect of protriptyline on hypercapnic ventilatory liquid chromatography (10). response (HCVR) and asphyxial hypoxic ventilatory response (HVR) was assessed in seven normal subjects (3 male; 4 female) aged 27-53 yrs (mean age 36.1 yrs). Assessment of ventilatory response Subjects were hospital staff members with no previous experience of the measurement techniques. All were Measurements were made after subjects breathed at nonsmokers with no history of cardiovascular disorders the mouthpiece for 5-10 min until end-tidal carbon and normal spirometry. The study was approved by the dioxide tension (Pco2) was stable. Ventilatory response VENTILATORY RESPONSE TO PROTRIPTYLINE 759

to hyperoxic hypercapnia was determined using a ments of HVR was used for analysis. Ventilatory rebreathing technique [11). Subjects rebreathed for 4 min response to asphyxia was calculated by plotting breath from a 6 I reservoir bag containing 7% carbon dioxide in by breath minute ventilation against arterial oxygen satu­ 93% oxygen. Expiratory flow was intergrated to give a ration at the start of each breath. No attempt was made volume trace using a Fleisch pneumotachograph (size 3) to correct the arterial oxygen saturation reading for the

and end-tidal Pco2 was sampled using a Hewleu Packard instrument response time. The position of the HVR line capnometer (model 47201A). The pneumotachograph was determined. by calculating ventilation at a saturation and capnograph were calibrated before each experimen­ level of 95% (V9 ~. tal session with room air and 7% carbon dioxide in 93% Regression lines were only accepted if the correlation oxygen. Calibrations were checked at the end of each coefficient exceeded 0.8. HCVR and HVR before and session. Two sets of measurements of HCVR were made after placebo, 10 mg and 20 mg were compared by 2- at each assessment and the mean of these values was way analysis of variance. Differences between male and used for analysis. To calculate HCVR, measurements female subjects were analysed using the Mann-Whitney 1 during the first 45 s of rebreathing were discarded and test. The correlation between dose (mg·kg· ) and plasma 1 ventilation over subsequent 30 s periods was plolled levels, and dose (mg·kg- ) and side effects was calculated using the Spearman rank correlation test. against the end-tidal Pco2 value at the mid-point of each period. The ventilatory response to hypercapnia, expressed by the slope of this relationship, was calculated by linear regression analysis. The position of the response line was Results

established by estimating ventilation ~t an end-tidal Pco2 • HCVR, HVR, V and Y on entry to the trial were of 55 mmHg (7.3 kPa) and termed V55 55 95 The ventilatory response to hypercapnic hypoxia was greater in male subjects than females, although these measured using the method of fuNSLEY and READ [12]. A differences were not significant (p>0.05). controlled decrease in arterial oxygen saturation to ap­ Values before and after placebo, 10 mg and 20 mg proximately 70%, in the presence of a stable elevation of protriptyline are shown in figures 1-4. No placebo effect , Pco2 was obtained by breathing from two reservoir bags was evident and 10 mg and 20 mg protriptyline did not in sequence. From breathing room air, the subject was alter the slope or position of the response curve in both switched into a one-way circuit and rebreathed for 4-5 the acute and long term studies. No trend between breaths from a bag containing 7% carbon dioxide in air. response to 10 mg and 20 mg was observed. Without the subject's awareness he was then switched to Inter-subject variation in pre-treatment data is clearly a second bag containing 7.5% carbon dioxide in nitro­ shown, but no overall difference was seen comparing gen. The expiratory tap was open to air at this stage so initial values for each phase. The coefficient of variation that rebreathing did not occur. When arterial oxygen for control tests was 0.24 for HCVR and 0.37 for HVR. saturation began to fall the subject was switched back to The lower limit of accurate measurement of protrip­ the bag containing carbon dioxide in air and rebreathed tyline using the gas liquid chromatographic method is 1 1 this mixture until the ramp of desaturation was complete. 5 J.Lg·/· • Levels below 5 J.l.&·l· are therefore denoted as Arterial oxygen saturation (Saoz) was monitored continu­ undetectable and assumed to be zero. Plasma protrip­ ously using a Hewlett Packard oximeter model 47201A tyline levels are shown in table 1. 1 whose response to a step change in input from 100-80% No correlation was found between dose (mg·kg' ) is 90% complete in 1.3 s. The mean of three measure- and plasma levels. All subjects noted a dry mouth

HYPERCAPNIC VENTILATORY RESPONSE (HCVR)

20 mg Placebo 10 mg fmln''·mmHg·• • 4 ..c: ~ ~ 3 ~ 0 !i 'E 2 ..> c" D. ! Before Altllf Before Alter Beforo After

Fig. 1. - Hypercapnic ventilatory response (HCVR) before and after 2 weeks trealment with placebo, 10 mg and 20 mg protriptyline·day·1• Mean values and 95% confidence intervals (Cl) of change in HCVR are shown. 760 A.K. SIMONDS ET AL.

HYPOXIC (ASPHYXIAL) VENTILATORY RESPONSE (HVR)

fmtn·'·%Sao1·' 4 =c 0 & 10 mg ;r .. PlacebO 2 .. ! 0 0 3 ::r ;r l:' 2 .. '2 .. :::0 :> i C l r+I! "'• "';;• < E.. 2 ;; :IJ .. :I: .. Cl .. < ;u~ :Jl 3 ~ Cl 0 5' .. .!. ~ 3 0. 3 0 .. 0 :> - ~ ~ ~ - ~ - tar z:::: • I H~'* _, _, ...!: ~0t ~i t,.. ...!: :z:: ...!: Before After Before After Before Alter

Fig. 2. - Hypoxic (asphyxial) venti.latory response (HVR) before and after 2 weeks treatment with placebo, 10 mg and 20 mg

protriptyline·day'. Mean values and 95% confidence intervals (Cl} of change in HVR are shown. Sao1 : arterial oxygen saturation.

HYPERCAPNIC VENTILATORY RESPONSE

PlacebO 10 mg 20 mg

40 0 ;r '10 ~ "'• 0 ;; < · 20 :: <;: •10 3 3

Before After Before Alter Before After

Fig. 3. - Minute ventilation at end-tidal Pco1 level of 55 mmHg {V,) before and after 2 weeks treatment with placebo, 10 mg and 20 mg protriptyline·day·•. Mean values and 95% confidence intervals (Cl) for change in V, are shown.

HYPOXIC (ASPHYXIAL) VENTILATORY RESPONSE

PlacebO 10 mg 20 mg

40

>t OO ~ c 1-+10 Q & :::0 OD Cl .. 0 ;; 20 < · 11 -~ - 1 <;: 3 - ~ - r H · 10 3 - 10 5-

Before After Before After Before Alter

) Fig. 4. - Minute ventilation at arterial oxygen saturation level of 95% {V,1 before and after 2 weeks treatment with placebo, 10 mg and 20 mg protriptyline·day·•. Mean values and 95% confidence intervals (Cl) for change in V91 are shown. VENTILATORY RESPONSE TO PROTRIPTYLINE 761

Table 1. - Plasma protriptyline levels (J.Lg·/ ·1) in seven normal subjects 10 mg 20 mg Placebo Subject BL Ac Chr BL Ac Chr BL Ac Chr

1 NT ND 10 ND ND 18 ND ND ND 2 ND 5 15 ND 7 30 NT ND ND 3 ND 8 10 NT 6 5 ND ND ND 4 NT 9 25 ND 7 53 NO ND NO 5 ND ND ND NO 8 16 NT NO NO 6 NT 7 24 NO 8 43 ND ND ND 7 ND 13 29 ND 7 * NT NO ND *: tube broken; NT: not measured (assessment pre phase I); ND: not detected (lower limit of accurate measurement is 5 jlg·t 1); BL: initial measurement before start of phase; Ac: measurement 6-8 h post dose; Chr: measurement at end of 2 wk phase. on active drug and in this respect it was difficult to than this and, therefore, we consider it unlikely that an blind the trial. Five subjects noted other anticholinergic effect has been missed that would be clinically meaning­ side effects including constipation and mild visual ful in the context of nocturnal hypoxaemia. Sleep is disturbance. associated with an approximate halving of HCVR and to Discussion a lesser extent HVR [17- 21]. If the effect of protrip­ tyline on nocturnal hypoxaemia in obstructive sleep Protriptyline had no effect on the slope or position of apnoea [1, 2], restrictive chest wall disease [3) and chronic hypercapnic and hypoxic ventilatory response in normal airflow limitation [4] was due primarily to augmentation subjects. Several points are worth consideration. First, of ventilatory responsiveness the drug should restore the pneumotachograph and capnometcr were not cali­ sleeping responsiveness towards daytime values and thus brated with all the gas mixtures used to test HCVR and it might be expected to double awake ventilatory response. HVR. This will introduce small errors into the measure­ We therefore chose conservatively Lo accept a 50% ments of tidal volume and carbon dioxide. Since the increase in awake HCVR and HVR as being clinically experimental procedure was standardized, it is unlikely meaningful. The power of the study to detect such an that these measurement errors will have biased the study increase in HCVR and HVR at the 0.05 level was 99% against finding any change in ventilatory responsiveness and 92% respectively. due to prot.riptyline adminisl!ati on. A third consideration is that HCVR and HVR were not Second, inter-subject variat ion and variation within measured during sleep. It is unlikely that protriptyline subjects over time [13] limits interpretation of ventila­ has substantial effects on ventilatory control during sleep lOry response data. Within subject coefficient of vari ­ without clearly measurable effects awake but the point ation for con11ol tests was 0.2A for HCVR and 0.37 for remains to be tested. It is relevant to note that prochlop­ HVR, values similar to those reported previously using erazine doubles HVR awake [15] and asleep [21) yet the same methods to induce hypercapnia and hypoxia does not have any clinically significant effect on apnoea [12-151. It is possible that a slow ramp of isocapnie index or oxygenation in patients with obstructive sleep hypoxia such as that used in the method of REBUCK and apnoea [21). CAMPBELL [16] may have reduced variability of HVR. Plasma levels after 2 weeks treatment with 10 and Our interest in the effects of protriptyline in obstructive 20 mg protriptyline were lower than those obtained after sleep apnoea led us to choose a brief ramp of moderate 6 weeks treatment with a similar dose in patients with asphyxia as Lhe relevant stimulus. The baseline variabil­ restrictive chest wall disease [3]. despite a greater ity of HCVR and HVR may have hidden an effect of mg·kg-1 dosage in normal s ubjects receiving 20 mg. As protriptyline that would be of pharmacological interest many of the patients with restrictive chest wall disease and that might have thrown new Ught on mechanisms were in cardiorespiratory failure and their mean age was controlling breathing. This was not the purpose of the greater, altered hcpat.ic metabolism and plasma prOLein study, however, which was directed at examining an effect binding were likely to have contributed to differences in of protriptylinc on venti latory control of sufficient plasma concentration of protriptyHne. Also, it should be magnitude to explain improvement of nocturnal oxygena­ noted that plasma levels were measured in the normal tion in a number of clinical settings. Given the 95% subjects after 2 weeks treatment, but at 4-6 wks in the confidence intervals of the mean differences between restricti ve chest wall disease group. One possible con· control and drug studies, it is possible that mean HCVR sequence of the low plasma concentrations is that a signfi­ increased from 1.73-2.28/·min·1-mmHg·1 after two weeks cant effect on HCVR and HVR was missed. However, if adm inistration of protriptyline 10 mg and from this was so a trend in response between 10 and 20 mg 1.75- 2.47 /-min·1-mmHg·1 after 2 weeks of protriptyline might be expected and this was not seen. The difficulty 20 mg. Similarly, HVR may have increased from of est.ab)jshing the presence of concentrations of less 1 than J..Lg·/'1 is a source of concern, but in the absence 0.83-0.96 /-min· ·% Sao1 after protriptyline 10 mg and 5 1 of a more discri minant assay, is an unavoidable source from 1.39-2.10 /·min· ·% Sao2 after protriptyli ne 20 mg. The data are not consistent with a drug effect greater of error. 762 A.K. SIMONDS ET AL.

The conclusion that protriptyline has no effect on Pharmacokinetic aspects of protriptyline plasma levels. Eur J HCVR and HVR supports the work of others. BROWNELL Clin Pharm, 1977, 11, 51-56. et al. (1] found that protriptyline did not alter HCVR in 10. Dawling S, Braithwaite RA. - Simplified method for nonnocapnic patients with obstructive sleep apnoea, and monitoring tricyclic antidepressant therapy using gas liquid CoNw AY et al. [22] were unable to demonstrate a change chromatography with nitrogen detection. J Chromatography, in eucapnic HVR in a similar group with sleep apnoea. 1978, 146, 449-456. 11. Read DJC. - A clinical method for assessing the ventila­ The data are also consistent with that obtained from a tory response to carbon dioxide. Aust Ann Med, 1967, 16, 20-32. trial of protriptyline in patients with restrictive chest wall 12. Hensley MJ, Read DJC. - A test of the ventilatory re­ disease [3]. In the latter study, no change in diurnal arterial sponse to hypoxia and hypercapnia for clinical use. Aust NZ J Pco2 or base excess was seen; an unlikely finding if the Med, 1977, 7, 362-367. drug stimulates HCVR. Also drugs such as almitrine 13. Sahn SA, Zwillich CW, Dick N, McCulbough RE, which enhance peripheral chemoreceptor drive tend to Lakshminarayan S, Weil N. - Variability of ventilatory re­ sponses to hypoxia and hypercapnia. J Appl Physio/, 1977, 43, lower Pco2 by increasing total ventilation [23]. Finally, if HVR is a mechanism for limiting nocturnal 1019-1025. episodes of desaturation, a drug which stimulates HVR 14. Saunders NA, Hei!pem S, Rebuck AS.- Relation between personality and ventilatory response to carbon dioxide in nor­ would be expected to promote earlier tennination of mal subjects: A role in asthma. Brit Med J, 1972, l, 719-721. apnoeic/hypopnoeic episodes, thereby reducing the dura­ 15. Olson LG, Hensley MJ, Saunders NA. - Augmentation of tion of such events and minimum arterial oxygen ventilatory response to asphyxia by prochlorperazine in humans. saturation. Almitrine has been shown to reduce mini­ J Appl Physiol, 1982, 53, 637-643. mum arterial oxygen saturation and time spent at a level 16. Rebuck AS, Campbell ElM. - A clinical method for of oxygen saturation of less than 80% in patients with assessing the ventilatory response to hypoxia. Am Rev Respir chronic bronchitis and emphysema [24]. In contrast, Dis, 1974, 109, 345-350. protriptyline had no effect on minimal arterial oxygen 17. Berthon-Jones M, Sullivan CE.- Ventilatory and arousal saturation in patients with restrictive chest wall disease. responses to hypoxia in sleeping humans. Am Rev Respir Dis, In these individuals the improvement in nocturnal oxy­ 1982, 125, 623-639. 18. Berthon-Jones M, Sullivan CE. - Ventilation and arousal genation is closely correlated with a reduction in REM responses to hypercapnia in normal sleeping adults. J Appl P hys­ sleep related hypopnoeic episodes. We conclude that iol, 1984, 57, 59-67. stimulation of HCVR and HVR is unlikely to be an 19. Douglas NJ, White DP, Weil Net al. -Hypoxic venti­ additional clinically significant mechanism of action of latory response decreases during sleep in normal men. Am Rev protriptyline. Respir Dis, 1982, 125, 286-289. 20. Douglas NJ, White DP, Weil N et al. - Hypercapnic Acknowledgements: A.K. Simonds was supported ventilatory response in sleeping adults. Am Rev Respir Dis, by the Doverdalc Fellowship of the National Heart and 1982, 126, 758-762. Chest Hospitals. We are grateful to Guy's Hospital 21. Olson LG, Hensley MJ, Saunders NA. -Breathing during Poisons Unit for measuring plasma protriptyline con­ sleep: the responses to asphyxia and prochlorperazine in nor­ centrations. mal subjects and patients with obstructive sleep apnoea. Aust NZ J Med, 1983, 13, 613-620. References 22. Conway W, Roth T, Zorick F.- Protriptyline therapy in upper airway sleep apnoea. Am Rev Respir Dis, 1982, 125, 102. 1. Brownell LG, West P, Sweatman P, Acres JC, Kryger 23. Stradling JR, Bames P, Pride NB. -The effects of alrni­ MH. - Protriptyline in obstructive sleep apnoea - a double­ trine on the ventilatory response to hypoxia and hypercapnia in blind trial. N Engl J Med, 1982, 307, 1037-1042. normal subjects. Clin Sci, 1982, 63, 401-404. 2. Smith PL, Haponik EF, Alien RP, Bleeker ER. - The 24. Connaughton JJ, Douglas NJ, Morgan AD, Shapiro CM, effects of protriptyline in sleep disordered breathing. Am Rev Critchley JAJH, Pauly N, Flenley DC. - Almitrine improves Respir Dis, 1983, 127, 8-13. nocturnal oxygenation in patients with chronic bronchitis and 3. Sirnonds AK, Parker RA, Branthwaite MA. - Effects of emphysema. Am Rev Respir Dis, 1985, 132, 206-210. protriptyline on sleep related disturbances of breathing in re­ strictive chest wall disease. Thorax, 1986, 41, 586-590. Absence d'effet de la protriptyline sur les reponses ventila­ 4. Carroll NA, Parker RA, Branthwaite MA - Use of toires a l'hypercapnie et a l'asphyxie chez les sujets normaux. protriptyline in chronic airflow limitation. Thorax, 1988, 43, A.K. Simonds, N. Carroil, MA. Branlhwaite, NA. Sounders. 253p. RESUME: Une etude en double anonymat avec permutation 5. Bonora M, St John WM. Bledsoe TA. - Differential ele­ croisee a ete entreprise pour determiner l'effet de la protrip­ vation by protriptyline and depression by diazepam of upper tyline sur les responses ventilatoires des sujets normaux. Pen­ airway respiratory motor activity. Am Rev Respir Dis, 1985, dant 2 semaincs, du placebo et des doses de 10 et 20 mg de 131, 41-45. protriptyline Ont etc administres quotidiennement chez 7 sujets 6. Hombein TF, Griffo ZJ, Roos A. - Quantitation of de maniere randomisee. Des mesures de la reponse ventilatoire chemoreceptor activity: interrelation of hypoxia and hypercapnia. a !'hypercapnic et de la reponse ventilatoire a l'asphyxie hy­ J Neurophysiol, 1961, 24, 561-568. poxique ont ete realisees avant traitement et 6 a 8 h apres la 7. Ziegler YE, Biggs IT, Wylie LT, Coryell WH, Hanifi KM, premiere dose ainsi qu'apres 2 semaines de traitement Les Hawf DJ, Rosen SH.- Protriptyline kinetics. Clin Pharm Thera­ valeurs moyennes de la reponse ventilatoire hypercapnique et peutics, 1978, 23, 580-584. de la reponse ventilatoire a l'hypoxie asphyxique apres lO et 20 8. Charalampous KD, Johnson PC. - Studies of C14-Protrip­ mg de protriptyline ne different pas significativement des tyline in man: plasma levels and excretion. J Clin Pharm, 1967, mesures apres placebo, que ce soit apres une dose unique ou 7, 93-96. apres 2 semaines. 9. Moody JP, Whyte SF, MacDonald AJ, Naylor GJ. - Eur Respir J., 1989, 2, 758-762