A STUDY OF THE BIPHASIC VENTILATORY EFFECTS OF PROPANIDID

Brit. J. Anaesth. (1964), 36, 655 A STUDY OF THE BIPHASIC VENTILATORY EFFECTS OF PROPANIDID BY EVA HARNIK Department Anaesthesia, Royal Free Hospital, London SUMMARY The respiratory effects propanidid (FBA.1420) were observed when used to induce anaesthesia in 100 patients after sedative or atropine premedication. Premedication had no significant relation to the length hyperpnoea or apnoea. Hyperpnoea itself was associated with apnoea variable duration but there was a tendency for the duration apnoea to be shorter the longer the preceding hyperpnoea. The findings suggest that this drug is not only a respiratory stimulant but also a depressant. Induction side effects included hiccough, involuntary movements, and urinary incontinence. The new intravenous narcotic propanidid (FBA.1420), among other characteristics described recently (Dundee and Clarke, 1964; Howells et al., 1964), displays a biphasic action on ventilation consisting stimulation followed by depression. The purpose this study was to investigate the relationship between the extent hyperventilation and apnoea and to decide whether or not either these features was influenced by different types premedication. Observations were also made on the side effects occurring during induction. METHOD A hundred patients were selected at random with regard to sex, age and type operation. Severely ill patients were not included in the experiment. The patients were divided into four groups according to the pre-operative medication given, as displayed in table I. As the period hyperpnoea and apnoea is definitive and not influenced by previous information a "blind" trial with regard to the premedicant groups was not considered necessary. The 5 per cent preparation FBA.1420 was used in the dosage 10 mg/kg and the speed injection was arranged at 1 ml/sec. A Mitchell needle was employed in veins on the dorsum the hand. The period hyperventilation was timed in seconds with the aid a stopwatch from the first deep breath to the last. The length apnoea was TABLE I Showing the four types premedication and the number and age range patients. Premedication Atropine 0.6 mg Chlorpromazine mg Promethazine mg Papaveretum 10-20 mg Hyoscine 0.4 mg Pethidine 50-100 mg Atropine 0.6 mg No. patients Age range 16-83 12-67 12-53 19-72 timed similarly, until the patient resumed respiration. Hypoventilation occasionally preceding and following apnoea was not timed. The endpoint between the phase stimulation and depression was always obvious to within a few seconds. To illustrate this, three spirometric tracings are presented (figs. 1-3). Hiccough appeared in twenty-nine cases either immediately after hyperpnoea or during apnoea. As there was no evidence effective respiration, hiccough was included in the length duration taken for apnoea. During the experiment no other anaesthetic was given 3 but the anaesthetist took meticulous care to maintain a free airway. After both the periods hyperpnoea and apnoea were timed the anaesthetic proceeded according to the nature the operation to follow. All patients were lying in the supine position during the observation. 655

656 BRITISH JOURNAL OF ANAESTHESIA FIG. 1 Hyperpnoea (as indicated by arrows) was followed by apnoea lasting more than 60 seconds and then by a period hypoventilation. FIG. 2 The period apnoea was brief and marked hypoventilation did not occur. FIGS. 1-3 Spirometric tracings taken during induction anaesthesia with propanidid. The arrows point to the onset hyperpnoea and apnoea. The vertical divisions represent 60 seconds and the horizontal divisions 100 ml tidal volume. All three readings were taken after premedication with pethidinc 100 mg and atropine 0.5 mg. A Benedict-Roth spirometer was used.

A STUDY OF THE BIPHASIC VENTILATORY EFFECTS OF PROPANIDID 657 TABLE II This shows the average duration hyperpnoea and apnoea and the standard deviation each in the premedicant groups. Duration hyperpnoea Duration apnoea Premedication group Atropine Phenothiazine Papaveretum Pethidine All No. patients 100 40.6 44.6 34.0 31.6 37.8 SD average 4.5 4.3 2.4 2.2 23.4.6 31.2 29.2 27.3 SD average 3.9 4.5 4.6 3.6 RESULTS The results are graphically represented in figures 4 7. The data were submitted to statistical analysis and the results are set out in tables II and m. The purpose statistical analysis the data was to ascertain whether the type premedica- i U ft r u I I III BOO 1 fil&jooo n Ul iiflhi 1 IVVRNI i lull OMIT 1 Illlll ^ Mi Mlfldl sooo..111 II.1 Ii MII ii luuuyini 11 ' 1 ^MJlllJlW" vyv FIG. 3 In this tracing it is seen that apnoea did not occur at all and hyperpnoea was followed by hyperventilation moderate degree. tion had any effect on either hyperventilation or apnoea. Duration hyperpnoea and apnoea. At the 5 per cent level significance the difference between the averages the four groups is not significant for either hyperpnoea or apnoea (table II). Relation between duration hyperpnoea and duration apnoea. As the type premedication did not appear to affect the duration hyperpnoea or apnoea, the data from the four premedicant groups were pooled, and for each recorded duration hyperpnoea the average duration the succeeding apnoea was calculated (table HI). There is evidence a tendency for the duration apnoea to be shorter, the longer the preceding hyperpnoea. This tendency is also apparent in figures 4 7. In three the four groups it was found that when hyperpnoea lasted more than 60 seconds apnoea lasted no longer than 10 seconds, if it occurred at all. Apart from this observation no other definite relationship is obvious. That is to say, any length hyperventilation may be associated with any length apnoea (within the limits described) and the outstanding feature this drug was its unpredictability in its effect on ventilation. The type premedication did, however, affect the incidence side effects. Atropine premedication alone was associated with the highest incidence hiccough (60 per cent) and involuntary movements. Three the 100 cases voided urine during induction. These findings are summarized in table IV.

CASE NQ 12 345 Premed: ATROPINE 0.6 mg Fio. 4 ^oo- Premed: CHLORPROMAZINE mg PROMETHAZINE mg Fio. 5 CASE No -OO- Premed: PAPAVERETUM 10-20 mg HYOSCINE 0.4 mg Premed: PETHIDINE 50-100 mg ATROPINE 0.6 mg Fio. 6 FIG. 7 The figures illustrate the relationship between hyperpnoea and apnoea in each patient in the four premedicant groups. This is displayed by showing the time duration hyperpnoea in seconds in the order increasing lengths above the zero line and showing below the line the corresponding length apnoea (in seconds) for each case.

A STUDY OF THE BIPHASIC VENTILATORY EFFECTS OF PROPANIDID 659 TABLE III The average duration apnoea for given durations hyperpnoea is shown. The figures in parenthesis are the number patients on which each average is based. Duration hyperpnoea 5 15 20 30 35 40 45 50 duration apnoea (1) 10 (2) 35 (10) 37 (14) 35 (19) 29 (12) (13) 21 (11) 37 (6) 27 Duration hyperpnoea 55 60 65 70 75 90 120 130 duration apnoea (4) 26 (2) 13 (1) 5 0) 0 The influence gas tensions on the length apnoea remains open to question especially when it is noted that the longest periods hyperpnoea were associated with brief periods apnoea or with no apnoea. Conversely, some periods hyperpnoea lasting only 20 seconds or less were associated with apnoea lasting 50-90 seconds. The role arterial carbon dioxide tension in the production apnoea could only be established with continuous blood gas analysis. Intermittent sampling would be inadequate taking into consideration the rapidity respiratory changes. ACK NOWLEDOMENTS I am grateful to the photographic department this hospital for supplying the plates, to Miss M. Smith for the figures and to Mrs. C. Roudette for her kind assistance in the preparation the manuscript. TABLE IV Showing the incidence side effects during induction in each premedicant group. Premedication Atropine Chloropromazine Promethazine Morphine and derivatives No. patients 50 Hiccough 15 8 6 Involuntary movements 13 13 8 Incontinence urine 2 1 0 DISCUSSION During early work with this drug there was a suggestion (mainly from workers abroad) that it did not possess the marked respiratory depressant effects commonly associated with barbiturate narcosis. When using the drug in a dose 5 mg/kg respiratory stimulation is not marked and depression is moderate with only occasional apnoea. When doses 10 mg/kg are employed the ventilatory effects, both stimulatory and depressive, are marked, but in no case was any tendency towards cyanosis during apnoea observed. Due to the rapid recovery with this agent it was considered that the dose 10 mg/kg would be more use in clinical practice, particularly if the drug is used as the sole anaesthetic agent in the out-patient department. It would seem, however, that when this larger dose is employed, as with so many other intravenous narcotic agents, this drug also has respiratory depressant effects. REFERENCES Dundee, J. W., and Clarke, R. S. J. (1964). Clinical studies induction agents. IX: A comparative study a new eugenol derivative FBA.1420, with G.29505 and standard barbiturates. Brit. J. Anaesth., 36, 100. Howells, T. G., Odell, J. R., Hawkins, T. J., and Steane, P. M. (1964). An introduction to FBA.1420. Brit. J. Anaesth., 36, 295. ETUDE DES EFFETS VENTILATOIRES DIPHASIQUES DU PROPANIDIDE SOMMAIRE On a observe des effets secondaires du Propanidide (FBA.1420) quand on 1'a utilise' pour induire l'anesthesie chez 100 malades aprfes une pre'rne'dication par des s&latifs ou par l'atropine. La pre'm&iication n'a pas eu de rapport net avec la longueur de 1'hyperpnee ou de l'apnie. L'hyperpnee elk-mfime e'tait associe'e a une apnee de durec variable, mais il y avait tendance a ce que la duree de 1'apnie soit plus courte plus e'tait longue l'hyperpne'e qui la precede. Les resultats suggerent que cette drogue n'est pas seulement un analeptique respiratoire mais aussi un dspresseur. Les effets secondaires de l'induction consistaient en hoquet, mouvements involontaires et incontinence d'urine.

660 BRITISH JOURNAL OF ANAESTHESIA EINE UNTERSUCHUNG OBER DIE BIPHASISCHE WIRKUNG DES PROPANIDID AUF DIE ATMUNG ZUSAMMENFASSUNO Bei 100 Patienten wurde nach Sedierung oder Atropin- Pramedikation die Wirkung des zur Anfisthesieeinleitung verwendeten Propanidid (FBA.1420) auf die Atmung beobachtet. Die Pra'medikation war ohne signifikanten EinfluB auf die Dauer der Hyperpnoe oder Apnoe. Auf die Hyperpnoe kam es nachfolgend zu einer Apnoe von unterschiedlicher Dauer, aber die Dauer der Apnde war gewohnlich umso kurzer, je langer die vorausgehende Hyperpnoe angehalten hatte. Diese Befunde sprechen dafur, dafi diese Droge nicht nur ein Stimulanz fur die Atmung sondern auch ein Depressivum ist Alst Nebenwirkungen bei der Einleitung traten Singultus, unwillkurliche Bewegungen und Urininkontinenz auf. BOOK REVIEW L'Inlubation Intra-trachiale. By Jean Thuri^s. Published by Librairie Arnette, Paris. Pp 119; 63 illustrations. I have read the preface by Pressor Ren6 Fontaine and the book by Le M6decin-Commandant Jean Thuries; the former is charming and a perusal the book shows that truth is a major factor in that charm. It is obvious that the author is versed not only in the practice intratracheal anaesthesia but also in its history, "Circled through all experiences" but we hope not all personal ones. The author states on page 1 under the heading Apercu Historique, "En 1900 Kuhn precise la technique", and on the last page under the heading Conclusion, "Intratracheal intubation was born in the service surgery the maxilla and face in the course the first world war". It is perhaps hypercritical to suggest that these two statements seem contradictory. We were using the Kuhn's tube for such operations as the Caldwell Luc, for example, and also for operations on the abdomen when an open airway was particularly useful in obtaining relaxation the abdominal muscles, in 1911. Of course the introduction rubber tubes and the nasal route greatly extended the use intratracheal intubation. The manual is all that Pressor Fontaine says about it. Unlike much medical literature it is "Depourvu de toute floriture inutile". It is prusely illustrated, plainly written, nice large print easy to read. It will teach the student and be a constant and valued companion for the practising anaesthetist The author, enthusiast as he obviously is, tempers enthusiasm with judgment as is shown by his summing up in the last paragraph his book. "It is a manoeuvre which should be carried out with gentleness, precision and rapidity. If not it is 'nuisible', hurtful, injurious. With these reservations it nearly always assures the safety the patient, the comfort the surgeon and the serenity the anaesthetist" E. Falkner Hill