- Email: [email protected]
RESPIRATORY STIMULANTS IN THE NEWBORN
742
effects were encountered. Colistin seems to be a very useful addition to the list of existing antibiotics. A supply of ’Colomycin’ was made available by Dr. M. F. Cuthbert, of Messrs. Pharmax Ltd. REFERENCES
Carroll, G., Malette, W. F. (1961) J. Urol. 85, 86. Forni, P. V., Guidetti, E. M. (1956) Minerva med. 2, suppl. 77, p. 823. Gomirato Sandrucci, M. (1956) ibid. p. 839. Koyama, Y. (1950) J. Antibiot. 3, 457. Ross, S., Puig, J. R., Zaremba, E. A. (1959-60) Antibiot. Annu. p. 89. Yow, E. M., Tan, E., Shane, L., Schonfeld, S., Abu-Nassar, H. (1961) Arch. intern. Med. 108, 664.
RESPIRATORY STIMULANTS IN THE NEWBORN HERBERT BARRIE M.D. Lond., M.R.C.P. SENIOR REGISTRAR
DENNIS COTTOM M.C., B.M. Oxon., M.R.C.P. PHYSICIAN
CHILDREN’S DEPARTMENT,
irritation, depression,
Method monitored Respiration by a method similar to that described by Holland et al. (1960). A continuous record of oesophageal pressure and chest movement was obtained on a two-channel Evershed recorder. (Esophageal pressures were measured with a water-filled polyethylene catheter, 0-5 mm. in internal diameter, passed via the nose to midsternal level and attached to a Statham strain-gauge manometer. The rate and amplitude of the chest movements were registered by means of a mercury strain-gauge pneumograph applied around the chest and upper abdomen (fig. 1). This instrument cannot be calibrated and records non-respiratory as well as respiratory movements. Rhythmic deflections are probably proportional to tidal ventilation, and those obtained during crying (" vital capacity ") are usually eight to ten times greater than those obtained during quiet breathing. However, overall shifts from the baseline may be due to trunk movement and do not necessarily indicate changes in lung volume. was
B. D. R. WILSON Lond., F.R.C.P.
M.B.
PHYSICIAN
ST.
studied on the 18th day. Babies with cerebral difficult births were not tested.
or
THOMAS’S HOSPITAL, LONDON, S.E.1
THE value of respiratory stimulants in neonatal resusciThe current view is, rightly, to tation is uncertain. condemn their use until the air-passages have been cleared and unless adequate ventilation with oxygen can be performed. Nevertheless, these drugs are used widely. Ampoules of nikethamide, lobeline, and various other drugs are to be found in most labour wards, whereas few are adequately equipped for the giving of intermittent positive pressure oxygen. In addition to this conflict between current opinion and actual practice, there is TABLE I-OBSERVATIONS ON TWO SERIES
Series I A sterile catheter was inserted into the umbilical vein as far the inferior vena cava, and 5 % dextrose solution was infused slowly to prevent clotting. Injections were given rapidly in volumes of 2 ml. through a two-way tap between the catheter and the infusion set, and flushed through with a few millilitres of dextrose solution. The test substances were given in random order except that small doses and inert agents were used first in order to avoid undue restlessness. Sufficient time was allowed between injections for the respiratory pattern to return to normal. Nikethamide, caffeine sodium benzoate, lobeline, amiphenazole, vanillic acid diethylamide (’Vandid), and spiractin (’ Karion’) were studied in this way. Intramuscular injections were given into the outer side of the thigh, and the period of observation was extended to thirty minutes. Only nikethamide, vanillic acid diethylamide, and spiractin were studied in this way. as
much confusion on the relative merits of the various drugs, the correct dosage, and the best route of administration. Evidence based on clinical observation may be grossly misleading, as past experience with intragastric oxygen has shown, and even a careful experimental evaluation, such as that on newborn rabbits by Lim and Snyder (1945), may not be strictly applicable to the human infant. The present investigation was undertaken in babies with normal respiration in the hope that the data might provide a rational basis for the use of respiratory stimulants in neonatal asphyxia. Material The data comprise a total of 120 observations on 25 infants and include 25 control observations. The infants belong to two series (table i): Series 1.-5 babies with congenital lumbar meningomyeloceles in whom the responses to intravenous and intramuscular injections were measured. These babies had extensive cord damage with anxsthesia of the lower limbs, into which injections could be given without disturbing the baby. The tests were performed as soon as possible after birth, but some were repeated later. Clinical examination of the heart and lungs was normal and the neurological status relevant to respiration was considered intact at the time of measurement. The prognosis and the nature of the investigation was explained to the parents, from whom permission was obtained. Series 11.-20 normal babies in whom the response to lingual administration was studied. All were term babies less than 24 hours old, except for 1 premature baby who was
Fig. 2- Normal variations of the respiratory pattern.
743
Series II These babies
ing after birth, and the most effective stimulants
studied a few hours after birth and before feeds were demanded. 1 % lignocaine was applied to the tongue to block any reflex stimulation resulting from the bitter taste of some of the test substances; control tests using water, infusion of gentian, which is bitter, brandy, and a drug solvent were also made. The test solutions were dropped on to the tongue in volumes of 1/4 1/2 ml. from a small catheter attached to a 1 ml. syringe. The respiratory pattern was allowed to return to normal between the test doses. The drugs investigated in this way included nikethamide, lobeline, spiractin, vanillic acid diethylamide, and prethcamide (’ Micoren ’). Results During quiet respiration the rate varied from 22 to 60 breaths per minute; the oesophageal swings were negative and ranged from 2 to 4 cm. of water. No attempt was made to attain a physiologically basal state; and sponwere
deviations from normal, such as swallowing, sneezing, hiccoughing, and sighing, were often seen. Swallow waves (fig. 2), shown as large positive cesophageal deflections with normal chest movements, were readily provoked when solutions were dropped on to the tongue. The normal crying pattern (fig. 3) is also particularly relevant since crying is the physiological onset of breath-
simulate this pattern. The results tables II and III. to
are
are
likely
summarised in
Amiphenazole.-Intravenous injections of 1 to 3 mg. had effect on respiration; 6 mg. did not influence the respiratory pattern but caused vomiting. no
TABLE III-RESULTS
taneous
sodium benzoate.-6 out of 8 measurements effect from intravenous doses of up to 30 mg. (fig. 4). Only the smallest infant, weighing 2 kg. (4 lb. 7 oz.), was mildly stimulated. A 3-5 kg. infant showed increased oesophageal pressure swings after an intravenous dose of 45 mg., but with remarkably little change in chest movement (fig. 5). This pattern is suggestive of
Caffeine
showed
no
bronchospasm. Lingual administration of caffeine sodium benzoate had no measurable effect on
respiration. Spiractin.-The
recommended intravenous dose of 7’5 to 15 mg. produced slight to
pronounced respira-
tory stimulation but also caused vomiting in 2 cases. There was much individual variation in the response, but doses under 10 mg. had no measurable effect on
B
respiration.
Likewise,-
intramuscular dose of 25 mg. and lingual administration proved ineffective. Lobeline.-Intraan
venous
3 mg.
doses of 1-5 to and lingual
administration of. up to 6 mg. did not alter the respiratory pattern Fig. 4-Ineffectiveness of commonly recommended dose of caffeine sodium benzoate
on
respiration.
significantly.
744
doses used. 250 mg. resulted in brief flushing, hiccoughing, retching, and undue restlessness. Half this amount is the probable dose of choice by this route. Vanillic acid diethylamide.-The effect of this substance resembled that of nikethamide except in its slightly later onset and its shorter but more powerful stimulant action. The characteristic response began to thirty seconds fifteen of a dose of sodium caffeine (12mg. per kg.) large Fig. 5-Effect benzoate, which persisted for five minutes. after intravenous or Appearances suggest bronchospasm. lingual administration of The oesophageal this were not available with head extension and breath-holding. drug Prethcamide.-Samples fifteen seconds’ then rose ten to when the intravenous studies were made. Lingual adminipressure during apnosa, stration of 15 to 75 mg. showed this drug to be somewhat which ended abruptly with forceful hyperventilation, unpredictable in action. Pronounced respiratory stimula- crying, expulsion of mucus from the mouth, and a characteristic generalised flush. These manifestations tion of up to six minutes’ duration occurred in 3 instances, no effect in 5, and a slight effect in the remainder. resemble the onset of respiration of the normal baby after Nikethamide.-The effect of this drug was dramatic birth. The drug appeared to be metabolised quickly, the compared to the agents listed so far. Intense respiratory respirations returning to normal after five minutes in most stimulation, beginning fifteen seconds after injection and cases. The longest effect recorded was eighteen minutes persisting for five to fifteen minutes, followed intravenous and followed an intravenous dose of 25 mg. In general, injections of 60 and 125 mg. The babies hyperventilated neither tolerance nor intolerance to repeated administraforcefully, and the larger dose produced restlessness and tion was seen, but one infant who was given 32-5 mg. crying. (Esophageal pressure swings of up to 40 cm. of intravenously in divided doses in thirty minutes showed water and chest movement deflections of ten times the brief toxic effects after the last injection; these consisted basal were recorded. At the height of stimulation the rate in excessive flushing, restlessness, and myoclonic twitches became slow and irregular, but it subsequently accelerated of the eyelids, and lasted less than a minute. As with to slightly greater than normal. In contrast, an intramuscular injection of 125 mg. proved ineffective during thirty minutes’ observation. Lingual administration proved as effective as intravenous injection in its effect on respiration (fig. 6). Forceful efforts began within thirty seconds of placing as little as 30 mg. (0-125 ml. of the standard 25 % Fig. 6-Effect of nikethamide dropped on to the tongue on respiration, which is immediately stimulated, solution) on the tongue;
oesophageal pressure swings of 40 cm. of water ment
and chest movedeflections of six
times the normal were observed. The duration of the effect was related to the dose. 125 mg. resulted in stimulation for about ten minutes, whereas the effect of 30 mg. lasted only three minutes. No serious side-effects or vomiting were encountered in the
7-Effect of vanillic acid stimulated.
Fig.
diethylamide dropped
on to
the tongue
on
respiration, which is immediately
745
i ’
nikethamide, the drug was remarkably effective by the lingual route. With regard to the time of onset and the degree of action, lingual administration proved equally effective to intravenous injection (fig. 7). The duration depended on the dose given; and the smallest effective lingual dose was 1-5 mg., which acted for one minute. The optimum lingual dose would appear to be between t2’5 and 25 mg. or 5 mg. per kg. body-weight. Intramuscular injection of 25 mg. resulted in slight respiratory stimulation fifteen minutes later in 1 of 2 infants; the breathing pattern of the other remained unchanged during thirty minutes’ observation. NorNKe.—This drug, which is not a stimulant but a specific antagonist of morphine and related narcotics, was tested in view of its reputation of causing respiratory depression in its own right if given in excess or for depression following other anaesthetics. However, 0-5 mg. intravenously in an unanassthetised infant produced no change in respiration.
probably ineffective in abnormal states. Amiphenazole is another central stimulant with an undeserved reputation. Spiractin, a synthetic aminoketone related chemically and pharmacologically to lobeline, is too unpredictable in its action and apt to excite vomiting. Lobeline itself was not fully investigated since its unsuitability in neonatal resuscitation (on account of its vagal excitation of vomiting, hypertension, and bradycardia) has been recognised for many years. Prethcamide, a compound dimethylamide chemically related to nikethamide but with mainly a central action, also proved too unpredictable. Nikethamide and vanillic acid diethylamide are two agents with a distinct and specific respiratory stimulant action. They are chemically related and their main site of action is thought to be on the carotid chemoreceptors, although some central stimulation also occurs. Therapeutic doses appear to be metabolised quickly since respiratory stimulation rarely persisted more than ten minutes. Vanillic acid diethylamide may be superior
Electrocardiography A continuous electrocardiograph record (lead I) was obtained in 2 babies, when no significant changes following lingual administration of nikethamide, vanillic acid diethylamide, or prethcamide could be shown.
in this respect because animals which survive ten to fifteen minutes after a toxic dose recover rapidly, whereas nikethamide toxicity usually persists for several hours (Ginzel 1952). Of particular interest is their rapid absorption from the mucous membrane of the tongue and mouth, the effect on respiration being comparable to that of an Since both intravenous injection of the same dose.
Discussion
Our knowledge of the effectiveness of respiratory stimulants in neonatal resuscitation is far from complete. The pharmacological basis of these drugs, derived mainly from animal experiments, is not always applicable to the human infant, least of all to the asphyxiated baby at birth. There is conflicting evidence as to the state of the chemoreceptor mechanism in newborn animals and there may well be species differences in the development and function of the carotid bodies at birth. This may account for the discrepancy, for instance, between the negative findings of Lim and Snyder (1945) of nikethamide in newborn rabbits and the distinct respiratory stimulant effect in newborn infants of this investigation. Moreover, care must be exercised in translating such data to the asphyxiated baby. The various causes of neonatal asphyxia (e.g., prematurity, cerebral injury, cedema, and analgesia) and the extent of any particular disorder profoundly influences the degree of respiratory depression and consequently the response to resuscitation. The limitations of clinical diagnosis are obstacles to any objective assessment in neonatal asphyxia. Our data on the responses in normal babies can therefore only be a tentative guide to the use of drugs in pathological states. -
I.. -
’
i
In the report resuscitation of the Newborn Infant (1956) the special Committee on Infant Mortality of the Medical Society of New York commented: " The properties of drugs used in respiratory depression of newborn infants indicate that most of them are of dubious value and may be dangerous. The least toxic of the respiratory stimulants, and therefore the safest to use, is caffeine."
A dose of 16 to 32 mg. of caffeine sodium benzoate intramuscularly or intravenously was recommended.
I
I
B i
Few would dispute the limitations of chemical respiraton stimulants; but, on our evidence, intramuscular stunulants have no place in neonatal resuscitation at any time, and the use of caffeine sodium benzoate by any route seems unjustified. It is reasonable to suppose that a stimulant which fails to excite the normal respiratory
centre
is
adequate circulation, no advantage gained by giving the drugs intravenously. The lingual route, on the other hand, has much to commend it, especially in small infants. It has been suggested that chemoreceptor stimulants may not be effective in the presence of asphyxia since the reflex is already under maximum stress in response to oxygen lack. This argument probably does not hold true for newborn and premature infants, who may respond to hypoxia with respiratory depression instead of increased ventilation (Miller and Behrle 1954). Also, the fact that hypoxic babies can be induced to gasp by such means as lung inflation and peripheral or chemical stimulants suggests that the respiratory centre is responsive to impulses in addition to those produced by the chemoroutes
depend
would
seem to
receptors
as a
that
some
on an
be
result of oxygen lack.
drugs
Whilst it may be
powerfully on a depressed than on a normal centre, even a powerful stimulant, such as vanillic acid diethylamide, can hardly be expected to reverse any more than mild to moderate respiratory depression. Fortunately the rapid buccal absorption of nikethamide or vanillic acid diethylamide makes this distinction academic. In favourable cases, the baby will respond by gasping respiration within one minute, followed by crying and the expulsion of upper-respiratorytract secretions. Failure to respond to a lingual dose within one minute implies a degree of respiratory centre depression irreversible by any known safe chemical stimulant, and such infants should be intubated and artificially ventilated without delay. Our experience so far suggests that the need for intubation is reduced by 25% by the prior use of these drugs. The dose of vanillic acid diethylamide recommended is 5 mg. per kg. body-weight or, as a simple practical rule, 25 mg. (0-5 ml. of 5% solution) to full-term and 12-5 mg. to premature infants; the equivalent doses of nikethamide are 30 mg. per kg. body-weight or, in practice, 60 to 125 mg. (0-25 to 0-5 ml. of 25% solution). Our present rule is to give the former, dropped on the tongue from a syringe or capsule, to babies true
act more
746
who are not breathing three minutes after birth and who have failed to respond to clearing of the pharynx and the giving of nasal oxygen. If breathing does not begin within one minute, endotracheal intermittent positive-pressure oxygen is given. The importance of early and adequate oxygenation, by assisted ventilation when necessary, cannot be overemphasised, and, in the case of premature infants and those in poor condition at birth, we do not allow three minutes’ delay. However, it must be pointed out that the majority of deliveries in this country are attended by midwives who are still neither instructed nor encouraged in the use of intermittent positive-pressure respiration. Faced with the desperate emergency of the baby who fails to breathe, their choice rests between giving a drug which occasionally helps and doing nothing. For this reason, stimulant drugs will continue to be widely used, and one would not be justified in depriving the obstetric staff of a measure of uncertain but possible benefit without offering a better alternative.
Summary The action of various respiratory stimulants was investigated in 25 newborn infants. The drugs were given by injection to 5 babies with congenital meningomyeloceles and by oral drops to 20 normal babies. The effect on respiration was measured by changes in oesophageal pressure and chest expansion. Only nikethamide and vanillic acid diethylamide Vandid ’) showed a consistent and predictable stimulant action on respiration. The effect of lingual administration was equal in time of onset and degree of action to that of
THYROID FUNCTION IN CHRONIC ALCOHOLISM MARSHALL GOLDBERG M.D. Wisconsin ASSOCIATE, ALCOHOLISM CLINIC, ST. VINCENT’S HOSPITAL, WORCESTER, MASSACHUSETTS, AND CONSULTANT TO THE MASSACHUSETTS COMMISSIONER ON ALCOHOLISM* FORMER
RESEARCH
Richter’s work (1956, 1957) suggested the existence of inverse relationship between the level of circulating thyroid hormones and voluntary alcoholic intake in rats. Applying his observations to man, he reasoned that an increased appetite for alcohol might indicate a hypothyroid condition. A preliminary study of thyroid function in a group of chronic alcoholics among military personnel in 1958 seemed to support Richter’s contention : 33 patients tested, 21 (64%) were found thyroid deficient in varying degrees (Goldberg 1960a). The present investigation was undertaken to confirm and extend these findings; in particular, to test thyroid function in a larger group of alcoholics, and to explore the possibility that chronic, excessive intake of alcohol may exert a damaging or toxic effect on the thyroid gland. an
Methods and Materials
From January, 1960, extensive thyroid-function studies carried out on 100 chronic alcoholics selected at random from the registry of the St. Vincent’s Hospital Alcoholism Clinic. were
The group was in age from 23 TABLE
composed of 74 males and 18 females, ranging to
65 years.
All
were
I-AGE, SEX, WEIGHT, AND ALCOHOLIC AND EUTHYROID
confirmed chronic
HISTORY IN HYPOTHYROID
ALCOHOLICSt
intravenous injection. The recommended doses are 25 mg. (0-5 ml. of 5% solution) of vanillic acid diethylamide or 125 mg. (0-5 ml. of 25% solution) of nikethamide for full-term infants, and half these amounts for prematures. Failure to respond within one minute to lingual administration of these agents implies severe respiratory depression irreversible by any known safe stimulant. Their prior use in less severe degrees of asphyxia may avoid the need for intubation and assisted ventilation in small proportion of cases.
a
We thank Dr. J. E. Cullis for his part in originating this investigaMiss J. Dewe, medical artist, and the photographic department for the illustrations.
tion ; and
Vanillic acid diethylamide (’Vandid’) and its solvent were supplied by Riker Laboratories; prethcamide (’ Micoren ’) by Geigy Pharmaceutical Co., Ltd.; and spiractin (’Karion’) by Medimpex and G. Richter Chemical Works. REFERENCES
Ginzel, K. H. (1952) Wien. Z. inn. Med. 1, 16. Holland, W. W., Colley, J. R. T., Barraclough, M.
A.
(1960) Lancet, ii,
1166.
Lim, K. T., Snyder, F. F. (1945) Amer. J. Obstet. Gynec. 50, 146. Miller, H. C., Behrle, F. C. (1954) Pediatrics, 14, 93. Resuscitation of Newborn Infants (1956). A Report by the Special Committee on Infant Mortality of the Medical Society of the County of New York. Obstet. Gynec. 8, 336.
"... I have
a
strong repugnance
to
falling asleep without
my mind from the business of the day with at least a few pages of detached reading. To seek unconsciousness direct from papers or engagements seems as insalubrious as to go to bed unwashed."-Mr. ENOCH PowELL, Times, Sept. 27, 1962.
first, however briefly, disinfecting
alcoholics. The details of their alcoholic history and previous anti-alcoholic treatment are shown in table i. About twothirds of the patients had previously attended the clinic and were in remission at the time of thyroid testing. The remaining third were drawn from hospital patients convalescing from acute alcoholism. During the first appointment a detailed history was taken and the patient was examined with special emphasis on the detection of the stigmata of hepatic or endocrine disorders. Patients were also carefully screened for potential coronaryartery disease and adrenal insufficiency-both relative contraindications to liberal thyroid-hormone therapy. Insofar as possible, those with detectable hepatomegaly, spider angio*
Present address: Department of Medicine, University of Wisconsin Medial School, Madison 6, Wisconsin.
effects were encountered. Colistin seems to be a very useful addition to the list of existing antibiotics. A supply of ’Colomycin’ was made available by Dr. M. F. Cuthbert, of Messrs. Pharmax Ltd. REFERENCES
Carroll, G., Malette, W. F. (1961) J. Urol. 85, 86. Forni, P. V., Guidetti, E. M. (1956) Minerva med. 2, suppl. 77, p. 823. Gomirato Sandrucci, M. (1956) ibid. p. 839. Koyama, Y. (1950) J. Antibiot. 3, 457. Ross, S., Puig, J. R., Zaremba, E. A. (1959-60) Antibiot. Annu. p. 89. Yow, E. M., Tan, E., Shane, L., Schonfeld, S., Abu-Nassar, H. (1961) Arch. intern. Med. 108, 664.
RESPIRATORY STIMULANTS IN THE NEWBORN HERBERT BARRIE M.D. Lond., M.R.C.P. SENIOR REGISTRAR
DENNIS COTTOM M.C., B.M. Oxon., M.R.C.P. PHYSICIAN
CHILDREN’S DEPARTMENT,
irritation, depression,
Method monitored Respiration by a method similar to that described by Holland et al. (1960). A continuous record of oesophageal pressure and chest movement was obtained on a two-channel Evershed recorder. (Esophageal pressures were measured with a water-filled polyethylene catheter, 0-5 mm. in internal diameter, passed via the nose to midsternal level and attached to a Statham strain-gauge manometer. The rate and amplitude of the chest movements were registered by means of a mercury strain-gauge pneumograph applied around the chest and upper abdomen (fig. 1). This instrument cannot be calibrated and records non-respiratory as well as respiratory movements. Rhythmic deflections are probably proportional to tidal ventilation, and those obtained during crying (" vital capacity ") are usually eight to ten times greater than those obtained during quiet breathing. However, overall shifts from the baseline may be due to trunk movement and do not necessarily indicate changes in lung volume. was
B. D. R. WILSON Lond., F.R.C.P.
M.B.
PHYSICIAN
ST.
studied on the 18th day. Babies with cerebral difficult births were not tested.
or
THOMAS’S HOSPITAL, LONDON, S.E.1
THE value of respiratory stimulants in neonatal resusciThe current view is, rightly, to tation is uncertain. condemn their use until the air-passages have been cleared and unless adequate ventilation with oxygen can be performed. Nevertheless, these drugs are used widely. Ampoules of nikethamide, lobeline, and various other drugs are to be found in most labour wards, whereas few are adequately equipped for the giving of intermittent positive pressure oxygen. In addition to this conflict between current opinion and actual practice, there is TABLE I-OBSERVATIONS ON TWO SERIES
Series I A sterile catheter was inserted into the umbilical vein as far the inferior vena cava, and 5 % dextrose solution was infused slowly to prevent clotting. Injections were given rapidly in volumes of 2 ml. through a two-way tap between the catheter and the infusion set, and flushed through with a few millilitres of dextrose solution. The test substances were given in random order except that small doses and inert agents were used first in order to avoid undue restlessness. Sufficient time was allowed between injections for the respiratory pattern to return to normal. Nikethamide, caffeine sodium benzoate, lobeline, amiphenazole, vanillic acid diethylamide (’Vandid), and spiractin (’ Karion’) were studied in this way. Intramuscular injections were given into the outer side of the thigh, and the period of observation was extended to thirty minutes. Only nikethamide, vanillic acid diethylamide, and spiractin were studied in this way. as
much confusion on the relative merits of the various drugs, the correct dosage, and the best route of administration. Evidence based on clinical observation may be grossly misleading, as past experience with intragastric oxygen has shown, and even a careful experimental evaluation, such as that on newborn rabbits by Lim and Snyder (1945), may not be strictly applicable to the human infant. The present investigation was undertaken in babies with normal respiration in the hope that the data might provide a rational basis for the use of respiratory stimulants in neonatal asphyxia. Material The data comprise a total of 120 observations on 25 infants and include 25 control observations. The infants belong to two series (table i): Series 1.-5 babies with congenital lumbar meningomyeloceles in whom the responses to intravenous and intramuscular injections were measured. These babies had extensive cord damage with anxsthesia of the lower limbs, into which injections could be given without disturbing the baby. The tests were performed as soon as possible after birth, but some were repeated later. Clinical examination of the heart and lungs was normal and the neurological status relevant to respiration was considered intact at the time of measurement. The prognosis and the nature of the investigation was explained to the parents, from whom permission was obtained. Series 11.-20 normal babies in whom the response to lingual administration was studied. All were term babies less than 24 hours old, except for 1 premature baby who was
Fig. 2- Normal variations of the respiratory pattern.
743
Series II These babies
ing after birth, and the most effective stimulants
studied a few hours after birth and before feeds were demanded. 1 % lignocaine was applied to the tongue to block any reflex stimulation resulting from the bitter taste of some of the test substances; control tests using water, infusion of gentian, which is bitter, brandy, and a drug solvent were also made. The test solutions were dropped on to the tongue in volumes of 1/4 1/2 ml. from a small catheter attached to a 1 ml. syringe. The respiratory pattern was allowed to return to normal between the test doses. The drugs investigated in this way included nikethamide, lobeline, spiractin, vanillic acid diethylamide, and prethcamide (’ Micoren ’). Results During quiet respiration the rate varied from 22 to 60 breaths per minute; the oesophageal swings were negative and ranged from 2 to 4 cm. of water. No attempt was made to attain a physiologically basal state; and sponwere
deviations from normal, such as swallowing, sneezing, hiccoughing, and sighing, were often seen. Swallow waves (fig. 2), shown as large positive cesophageal deflections with normal chest movements, were readily provoked when solutions were dropped on to the tongue. The normal crying pattern (fig. 3) is also particularly relevant since crying is the physiological onset of breath-
simulate this pattern. The results tables II and III. to
are
are
likely
summarised in
Amiphenazole.-Intravenous injections of 1 to 3 mg. had effect on respiration; 6 mg. did not influence the respiratory pattern but caused vomiting. no
TABLE III-RESULTS
taneous
sodium benzoate.-6 out of 8 measurements effect from intravenous doses of up to 30 mg. (fig. 4). Only the smallest infant, weighing 2 kg. (4 lb. 7 oz.), was mildly stimulated. A 3-5 kg. infant showed increased oesophageal pressure swings after an intravenous dose of 45 mg., but with remarkably little change in chest movement (fig. 5). This pattern is suggestive of
Caffeine
showed
no
bronchospasm. Lingual administration of caffeine sodium benzoate had no measurable effect on
respiration. Spiractin.-The
recommended intravenous dose of 7’5 to 15 mg. produced slight to
pronounced respira-
tory stimulation but also caused vomiting in 2 cases. There was much individual variation in the response, but doses under 10 mg. had no measurable effect on
B
respiration.
Likewise,-
intramuscular dose of 25 mg. and lingual administration proved ineffective. Lobeline.-Intraan
venous
3 mg.
doses of 1-5 to and lingual
administration of. up to 6 mg. did not alter the respiratory pattern Fig. 4-Ineffectiveness of commonly recommended dose of caffeine sodium benzoate
on
respiration.
significantly.
744
doses used. 250 mg. resulted in brief flushing, hiccoughing, retching, and undue restlessness. Half this amount is the probable dose of choice by this route. Vanillic acid diethylamide.-The effect of this substance resembled that of nikethamide except in its slightly later onset and its shorter but more powerful stimulant action. The characteristic response began to thirty seconds fifteen of a dose of sodium caffeine (12mg. per kg.) large Fig. 5-Effect benzoate, which persisted for five minutes. after intravenous or Appearances suggest bronchospasm. lingual administration of The oesophageal this were not available with head extension and breath-holding. drug Prethcamide.-Samples fifteen seconds’ then rose ten to when the intravenous studies were made. Lingual adminipressure during apnosa, stration of 15 to 75 mg. showed this drug to be somewhat which ended abruptly with forceful hyperventilation, unpredictable in action. Pronounced respiratory stimula- crying, expulsion of mucus from the mouth, and a characteristic generalised flush. These manifestations tion of up to six minutes’ duration occurred in 3 instances, no effect in 5, and a slight effect in the remainder. resemble the onset of respiration of the normal baby after Nikethamide.-The effect of this drug was dramatic birth. The drug appeared to be metabolised quickly, the compared to the agents listed so far. Intense respiratory respirations returning to normal after five minutes in most stimulation, beginning fifteen seconds after injection and cases. The longest effect recorded was eighteen minutes persisting for five to fifteen minutes, followed intravenous and followed an intravenous dose of 25 mg. In general, injections of 60 and 125 mg. The babies hyperventilated neither tolerance nor intolerance to repeated administraforcefully, and the larger dose produced restlessness and tion was seen, but one infant who was given 32-5 mg. crying. (Esophageal pressure swings of up to 40 cm. of intravenously in divided doses in thirty minutes showed water and chest movement deflections of ten times the brief toxic effects after the last injection; these consisted basal were recorded. At the height of stimulation the rate in excessive flushing, restlessness, and myoclonic twitches became slow and irregular, but it subsequently accelerated of the eyelids, and lasted less than a minute. As with to slightly greater than normal. In contrast, an intramuscular injection of 125 mg. proved ineffective during thirty minutes’ observation. Lingual administration proved as effective as intravenous injection in its effect on respiration (fig. 6). Forceful efforts began within thirty seconds of placing as little as 30 mg. (0-125 ml. of the standard 25 % Fig. 6-Effect of nikethamide dropped on to the tongue on respiration, which is immediately stimulated, solution) on the tongue;
oesophageal pressure swings of 40 cm. of water ment
and chest movedeflections of six
times the normal were observed. The duration of the effect was related to the dose. 125 mg. resulted in stimulation for about ten minutes, whereas the effect of 30 mg. lasted only three minutes. No serious side-effects or vomiting were encountered in the
7-Effect of vanillic acid stimulated.
Fig.
diethylamide dropped
on to
the tongue
on
respiration, which is immediately
745
i ’
nikethamide, the drug was remarkably effective by the lingual route. With regard to the time of onset and the degree of action, lingual administration proved equally effective to intravenous injection (fig. 7). The duration depended on the dose given; and the smallest effective lingual dose was 1-5 mg., which acted for one minute. The optimum lingual dose would appear to be between t2’5 and 25 mg. or 5 mg. per kg. body-weight. Intramuscular injection of 25 mg. resulted in slight respiratory stimulation fifteen minutes later in 1 of 2 infants; the breathing pattern of the other remained unchanged during thirty minutes’ observation. NorNKe.—This drug, which is not a stimulant but a specific antagonist of morphine and related narcotics, was tested in view of its reputation of causing respiratory depression in its own right if given in excess or for depression following other anaesthetics. However, 0-5 mg. intravenously in an unanassthetised infant produced no change in respiration.
probably ineffective in abnormal states. Amiphenazole is another central stimulant with an undeserved reputation. Spiractin, a synthetic aminoketone related chemically and pharmacologically to lobeline, is too unpredictable in its action and apt to excite vomiting. Lobeline itself was not fully investigated since its unsuitability in neonatal resuscitation (on account of its vagal excitation of vomiting, hypertension, and bradycardia) has been recognised for many years. Prethcamide, a compound dimethylamide chemically related to nikethamide but with mainly a central action, also proved too unpredictable. Nikethamide and vanillic acid diethylamide are two agents with a distinct and specific respiratory stimulant action. They are chemically related and their main site of action is thought to be on the carotid chemoreceptors, although some central stimulation also occurs. Therapeutic doses appear to be metabolised quickly since respiratory stimulation rarely persisted more than ten minutes. Vanillic acid diethylamide may be superior
Electrocardiography A continuous electrocardiograph record (lead I) was obtained in 2 babies, when no significant changes following lingual administration of nikethamide, vanillic acid diethylamide, or prethcamide could be shown.
in this respect because animals which survive ten to fifteen minutes after a toxic dose recover rapidly, whereas nikethamide toxicity usually persists for several hours (Ginzel 1952). Of particular interest is their rapid absorption from the mucous membrane of the tongue and mouth, the effect on respiration being comparable to that of an Since both intravenous injection of the same dose.
Discussion
Our knowledge of the effectiveness of respiratory stimulants in neonatal resuscitation is far from complete. The pharmacological basis of these drugs, derived mainly from animal experiments, is not always applicable to the human infant, least of all to the asphyxiated baby at birth. There is conflicting evidence as to the state of the chemoreceptor mechanism in newborn animals and there may well be species differences in the development and function of the carotid bodies at birth. This may account for the discrepancy, for instance, between the negative findings of Lim and Snyder (1945) of nikethamide in newborn rabbits and the distinct respiratory stimulant effect in newborn infants of this investigation. Moreover, care must be exercised in translating such data to the asphyxiated baby. The various causes of neonatal asphyxia (e.g., prematurity, cerebral injury, cedema, and analgesia) and the extent of any particular disorder profoundly influences the degree of respiratory depression and consequently the response to resuscitation. The limitations of clinical diagnosis are obstacles to any objective assessment in neonatal asphyxia. Our data on the responses in normal babies can therefore only be a tentative guide to the use of drugs in pathological states. -
I.. -
’
i
In the report resuscitation of the Newborn Infant (1956) the special Committee on Infant Mortality of the Medical Society of New York commented: " The properties of drugs used in respiratory depression of newborn infants indicate that most of them are of dubious value and may be dangerous. The least toxic of the respiratory stimulants, and therefore the safest to use, is caffeine."
A dose of 16 to 32 mg. of caffeine sodium benzoate intramuscularly or intravenously was recommended.
I
I
B i
Few would dispute the limitations of chemical respiraton stimulants; but, on our evidence, intramuscular stunulants have no place in neonatal resuscitation at any time, and the use of caffeine sodium benzoate by any route seems unjustified. It is reasonable to suppose that a stimulant which fails to excite the normal respiratory
centre
is
adequate circulation, no advantage gained by giving the drugs intravenously. The lingual route, on the other hand, has much to commend it, especially in small infants. It has been suggested that chemoreceptor stimulants may not be effective in the presence of asphyxia since the reflex is already under maximum stress in response to oxygen lack. This argument probably does not hold true for newborn and premature infants, who may respond to hypoxia with respiratory depression instead of increased ventilation (Miller and Behrle 1954). Also, the fact that hypoxic babies can be induced to gasp by such means as lung inflation and peripheral or chemical stimulants suggests that the respiratory centre is responsive to impulses in addition to those produced by the chemoroutes
depend
would
seem to
receptors
as a
that
some
on an
be
result of oxygen lack.
drugs
Whilst it may be
powerfully on a depressed than on a normal centre, even a powerful stimulant, such as vanillic acid diethylamide, can hardly be expected to reverse any more than mild to moderate respiratory depression. Fortunately the rapid buccal absorption of nikethamide or vanillic acid diethylamide makes this distinction academic. In favourable cases, the baby will respond by gasping respiration within one minute, followed by crying and the expulsion of upper-respiratorytract secretions. Failure to respond to a lingual dose within one minute implies a degree of respiratory centre depression irreversible by any known safe chemical stimulant, and such infants should be intubated and artificially ventilated without delay. Our experience so far suggests that the need for intubation is reduced by 25% by the prior use of these drugs. The dose of vanillic acid diethylamide recommended is 5 mg. per kg. body-weight or, as a simple practical rule, 25 mg. (0-5 ml. of 5% solution) to full-term and 12-5 mg. to premature infants; the equivalent doses of nikethamide are 30 mg. per kg. body-weight or, in practice, 60 to 125 mg. (0-25 to 0-5 ml. of 25% solution). Our present rule is to give the former, dropped on the tongue from a syringe or capsule, to babies true
act more
746
who are not breathing three minutes after birth and who have failed to respond to clearing of the pharynx and the giving of nasal oxygen. If breathing does not begin within one minute, endotracheal intermittent positive-pressure oxygen is given. The importance of early and adequate oxygenation, by assisted ventilation when necessary, cannot be overemphasised, and, in the case of premature infants and those in poor condition at birth, we do not allow three minutes’ delay. However, it must be pointed out that the majority of deliveries in this country are attended by midwives who are still neither instructed nor encouraged in the use of intermittent positive-pressure respiration. Faced with the desperate emergency of the baby who fails to breathe, their choice rests between giving a drug which occasionally helps and doing nothing. For this reason, stimulant drugs will continue to be widely used, and one would not be justified in depriving the obstetric staff of a measure of uncertain but possible benefit without offering a better alternative.
Summary The action of various respiratory stimulants was investigated in 25 newborn infants. The drugs were given by injection to 5 babies with congenital meningomyeloceles and by oral drops to 20 normal babies. The effect on respiration was measured by changes in oesophageal pressure and chest expansion. Only nikethamide and vanillic acid diethylamide Vandid ’) showed a consistent and predictable stimulant action on respiration. The effect of lingual administration was equal in time of onset and degree of action to that of
THYROID FUNCTION IN CHRONIC ALCOHOLISM MARSHALL GOLDBERG M.D. Wisconsin ASSOCIATE, ALCOHOLISM CLINIC, ST. VINCENT’S HOSPITAL, WORCESTER, MASSACHUSETTS, AND CONSULTANT TO THE MASSACHUSETTS COMMISSIONER ON ALCOHOLISM* FORMER
RESEARCH
Richter’s work (1956, 1957) suggested the existence of inverse relationship between the level of circulating thyroid hormones and voluntary alcoholic intake in rats. Applying his observations to man, he reasoned that an increased appetite for alcohol might indicate a hypothyroid condition. A preliminary study of thyroid function in a group of chronic alcoholics among military personnel in 1958 seemed to support Richter’s contention : 33 patients tested, 21 (64%) were found thyroid deficient in varying degrees (Goldberg 1960a). The present investigation was undertaken to confirm and extend these findings; in particular, to test thyroid function in a larger group of alcoholics, and to explore the possibility that chronic, excessive intake of alcohol may exert a damaging or toxic effect on the thyroid gland. an
Methods and Materials
From January, 1960, extensive thyroid-function studies carried out on 100 chronic alcoholics selected at random from the registry of the St. Vincent’s Hospital Alcoholism Clinic. were
The group was in age from 23 TABLE
composed of 74 males and 18 females, ranging to
65 years.
All
were
I-AGE, SEX, WEIGHT, AND ALCOHOLIC AND EUTHYROID
confirmed chronic
HISTORY IN HYPOTHYROID
ALCOHOLICSt
intravenous injection. The recommended doses are 25 mg. (0-5 ml. of 5% solution) of vanillic acid diethylamide or 125 mg. (0-5 ml. of 25% solution) of nikethamide for full-term infants, and half these amounts for prematures. Failure to respond within one minute to lingual administration of these agents implies severe respiratory depression irreversible by any known safe stimulant. Their prior use in less severe degrees of asphyxia may avoid the need for intubation and assisted ventilation in small proportion of cases.
a
We thank Dr. J. E. Cullis for his part in originating this investigaMiss J. Dewe, medical artist, and the photographic department for the illustrations.
tion ; and
Vanillic acid diethylamide (’Vandid’) and its solvent were supplied by Riker Laboratories; prethcamide (’ Micoren ’) by Geigy Pharmaceutical Co., Ltd.; and spiractin (’Karion’) by Medimpex and G. Richter Chemical Works. REFERENCES
Ginzel, K. H. (1952) Wien. Z. inn. Med. 1, 16. Holland, W. W., Colley, J. R. T., Barraclough, M.
A.
(1960) Lancet, ii,
1166.
Lim, K. T., Snyder, F. F. (1945) Amer. J. Obstet. Gynec. 50, 146. Miller, H. C., Behrle, F. C. (1954) Pediatrics, 14, 93. Resuscitation of Newborn Infants (1956). A Report by the Special Committee on Infant Mortality of the Medical Society of the County of New York. Obstet. Gynec. 8, 336.
"... I have
a
strong repugnance
to
falling asleep without
my mind from the business of the day with at least a few pages of detached reading. To seek unconsciousness direct from papers or engagements seems as insalubrious as to go to bed unwashed."-Mr. ENOCH PowELL, Times, Sept. 27, 1962.
first, however briefly, disinfecting
alcoholics. The details of their alcoholic history and previous anti-alcoholic treatment are shown in table i. About twothirds of the patients had previously attended the clinic and were in remission at the time of thyroid testing. The remaining third were drawn from hospital patients convalescing from acute alcoholism. During the first appointment a detailed history was taken and the patient was examined with special emphasis on the detection of the stigmata of hepatic or endocrine disorders. Patients were also carefully screened for potential coronaryartery disease and adrenal insufficiency-both relative contraindications to liberal thyroid-hormone therapy. Insofar as possible, those with detectable hepatomegaly, spider angio*
Present address: Department of Medicine, University of Wisconsin Medial School, Madison 6, Wisconsin.