742

effects were encountered. Colistin seems to be a veryuseful 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 BARRIEM.D. Lond., M.R.C.P.

SENIOR REGISTRAR

DENNIS COTTOMM.C., B.M. Oxon., M.R.C.P.

PHYSICIAN

B. D. R. WILSONM.B. Lond., F.R.C.P.

PHYSICIAN

CHILDREN’S DEPARTMENT, ST. THOMAS’S HOSPITAL, LONDON, S.E.1

THE value of respiratory stimulants in neonatal resusci-tation is uncertain. The current view is, rightly, to

condemn their use until the air-passages have been clearedand unless adequate ventilation with oxygen can be

performed. Nevertheless, these drugs are used widely.Ampoules of nikethamide, lobeline, and various otherdrugs are to be found in most labour wards, whereas feware adequately equipped for the giving of intermittentpositive pressure oxygen. In addition to this conflictbetween current opinion and actual practice, there is

TABLE I-OBSERVATIONS ON TWO SERIES

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 grosslymisleading, as past experience with intragastric oxygen hasshown, and even a careful experimental evaluation, suchas that on newborn rabbits by Lim and Snyder (1945),may not be strictly applicable to the human infant.The present investigation was undertaken in babieswith normal respiration in the hope that the datamight provide a rational basis for the use of

respiratory stimulants in neonatal asphyxia.Material

The data comprise a total of 120 observations on25 infants and include 25 control observations. Theinfants belong to two series (table i):

Series 1.-5 babies with congenital lumbar meningomyelo-celes in whom the responses to intravenous and intramuscularinjections were measured. These babies had extensive corddamage with anxsthesia of the lower limbs, into which injec-tions could be given without disturbing the baby. The testswere performed as soon as possible after birth, but some wererepeated later. Clinical examination of the heart and lungswas normal and the neurological status relevant to respirationwas considered intact at the time of measurement. The

prognosis and the nature of the investigation was explained tothe parents, from whom permission was obtained.

Series 11.-20 normal babies in whom the response to

lingual administration was studied. All were term babies lessthan 24 hours old, except for 1 premature baby who was

studied on the 18th day. Babies with cerebral irritation, depression,or difficult births were not tested.

Method

Respiration was monitored by a method similar to thatdescribed by Holland et al. (1960). A continuous record ofoesophageal pressure and chest movement was obtained on atwo-channel Evershed recorder. (Esophageal pressures weremeasured with a water-filled polyethylene catheter, 0-5 mm. ininternal diameter, passed via the nose to midsternal level andattached to a Statham strain-gauge manometer. The rate and

amplitude of the chest movements were registered by means ofa mercury strain-gauge pneumograph applied around the chestand upper abdomen (fig. 1). This instrument cannot becalibrated and records non-respiratory as well as respiratorymovements. Rhythmic deflections are probably proportionalto tidal ventilation, and those obtained during crying (" vitalcapacity ") are usually eight to ten times greater than thoseobtained during quiet breathing. However, overall shifts fromthe baseline may be due to trunk movement and do not

necessarily indicate changes in lung volume.

Series IA sterile catheter was inserted into the umbilical vein as far

as the inferior vena cava, and 5 % dextrose solution was infusedslowly to prevent clotting. Injections were given rapidly involumes of 2 ml. through a two-way tap between the catheterand the infusion set, and flushed through with a few milli-litres of dextrose solution. The test substances were given inrandom order except that small doses and inert agents wereused first in order to avoid undue restlessness. Sufficient timewas allowed between injections for the respiratory pattern toreturn 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 ofthe thigh, and the period of observation was extended to thirtyminutes. Only nikethamide, vanillic acid diethylamide, andspiractin were studied in this way.

Fig. 2- Normal variations of the respiratory pattern.

743

Series II

These babies were studied a few hours after birth and beforefeeds were demanded. 1 % lignocaine was applied to the tongueto block any reflex stimulation resulting from the bitter taste ofsome of the test substances; control tests using water, infusionof gentian, which is bitter, brandy, and a drug solvent were alsomade. The test solutions were dropped on to the tongue involumes of 1/4 1/2 ml. from a small catheter attached to a 1 ml.syringe. The respiratory pattern was allowed to return tonormal between the test doses. The drugs investigated in thisway included nikethamide, lobeline, spiractin, vanillic acid

diethylamide, and prethcamide (’ Micoren ’).Results

During quiet respiration the rate varied from 22 to 60breaths per minute; the oesophageal swings were negativeand ranged from 2 to 4 cm. of water. No attempt wasmade to attain a physiologically basal state; and spon-taneous deviations from normal, such as swallowing,sneezing, hiccoughing, and sighing, were often seen.

Swallow waves (fig. 2), shown as large positive cesophagealdeflections with normal chest movements, were readilyprovoked when solutions were dropped on to the tongue.The normal crying pattern (fig. 3) is also particularlyrelevant since crying is the physiological onset of breath-

ing after birth, and the most effective stimulants are likelyto simulate this pattern. The results are summarised intables II and III.

Amiphenazole.-Intravenous injections of 1 to 3 mg. hadno effect on respiration; 6 mg. did not influence therespiratory pattern but caused vomiting.

TABLE III-RESULTS

Caffeine sodium benzoate.-6 out of 8 measurementsshowed no 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. infantshowed increased oesophageal pressure swings after anintravenous dose of 45 mg., but with remarkably little

change in chest move-ment (fig. 5). This

pattern is suggestive ofbronchospasm. Lingualadministration of caf-feine sodium benzoatehad no measurable effecton respiration.Spiractin.-The

recommended intra-venous dose of 7’5 to

15 mg. produced slightto pronounced respira-tory stimulation but alsocaused vomiting in 2cases. There was much Bindividual variation inthe response, but dosesunder 10 mg. had nomeasurable effect on

respiration. Likewise,-an intramuscular doseof 25 mg. and lingualadministration provedineffective.

Lobeline.-Intra-venous doses of 1-5 to3 mg. and lingualadministration of. up to6 mg. did not alter therespiratory patternsignificantly.Fig. 4-Ineffectiveness of commonly recommended dose of caffeine sodium benzoate on respiration.

744

Fig. 5-Effect of a large dose (12 mg. per kg.) of caffeine sodium benzoate, which persisted for five minutes.Appearances suggest bronchospasm.

Prethcamide.-Samples of this drug were not availablewhen the intravenous studies were made. Lingual admini-stration of 15 to 75 mg. showed this drug to be somewhatunpredictable in action. Pronounced respiratory stimula-tion of up to six minutes’ duration occurred in 3 instances,no effect in 5, and a slight effect in the remainder.Nikethamide.-The effect of this drug was dramatic

compared to the agents listed so far. Intense respiratorystimulation, beginning fifteen seconds after injection andpersisting for five to fifteen minutes, followed intravenousinjections of 60 and 125 mg. The babies hyperventilatedforcefully, and the larger dose produced restlessness andcrying. (Esophageal pressure swings of up to 40 cm. ofwater and chest movement deflections of ten times thebasal were recorded. At the height of stimulation the ratebecame slow and irregular, but it subsequently acceleratedto slightly greater thannormal. In contrast, anintramuscular injectionof 125 mg. proved in-effective during thirtyminutes’ observation.

Lingual administrationproved as effective as

intravenous injection inits effect on respiration(fig. 6). Forceful efforts

began within thirtyseconds of placing as

little as 30 mg. (0-125ml. of the standard 25 %solution) on the tongue;oesophageal pressureswings of 40 cm. ofwater and chest move-ment deflections of sixtimes the normal wereobserved. The durationof the effect was relatedto the dose. 125 mg.resulted in stimulationfor about ten minutes,whereas the effect of 30

mg. lasted only threeminutes. No seriousside-effects or vomitingwere encountered in the

doses used. 250 mg.resulted in brief flush-

ing, hiccoughing, retch-ing, and undue restless-ness. Half this amountis the probable dose ofchoice by this route.

Vanillic acid diethyl-amide.-The effect ofthis substance re-sembled that of nik-ethamide except in itsslightly later onset andits shorter but more

powerful stimulantaction. The character-istic response beganfifteen to thirty secondsafter intravenous orlingual administration

with head extension and breath-holding. The oesophagealpressure then rose during ten to fifteen seconds’ apnosa,which ended abruptly with forceful hyperventilation,crying, expulsion of mucus from the mouth, and a

characteristic generalised flush. These manifestationsresemble the onset of respiration of the normal baby afterbirth. The drug appeared to be metabolised quickly, therespirations returning to normal after five minutes in mostcases. The longest effect recorded was eighteen minutesand followed an intravenous dose of 25 mg. In general,neither tolerance nor intolerance to repeated administra-tion was seen, but one infant who was given 32-5 mg.intravenously in divided doses in thirty minutes showedbrief toxic effects after the last injection; these consistedin excessive flushing, restlessness, and myoclonic twitchesof the eyelids, and lasted less than a minute. As with

Fig. 6-Effect of nikethamide dropped on to the tongue on respiration, which is immediately stimulated,

Fig. 7-Effect of vanillic acid diethylamide dropped on to the tongue on respiration, which is immediatelystimulated.

745

i nikethamide, the drug was remarkably effective by the’

lingual route. With regard to the time of onset and thedegree of action, lingual administration proved equallyeffective to intravenous injection (fig. 7). The duration

depended on the dose given; and the smallest effectivelingual dose was 1-5 mg., which acted for one minute.The optimum lingual dose would appear to be betweent2’5 and 25 mg. or 5 mg. per kg. body-weight. Intra-muscular injection of 25 mg. resulted in slight respiratorystimulation fifteen minutes later in 1 of 2 infants; thebreathing pattern of the other remained unchanged duringthirty minutes’ observation.

NorNKe.—This drug, which is not a stimulant but aspecific antagonist of morphine and related narcotics, wastested in view of its reputation of causing respiratorydepression in its own right if given in excess or for

depression following other anaesthetics. However, 0-5 mg.intravenously in an unanassthetised infant produced nochange in respiration.

ElectrocardiographyA continuous electrocardiograph record (lead I) was

obtained in 2 babies, when no significant changes follow-ing lingual administration of nikethamide, vanillic acid

diethylamide, or prethcamide could be shown.

Discussion

Our knowledge of the effectiveness of respiratorystimulants in neonatal resuscitation is far from complete.The pharmacological basis of these drugs, derived mainlyfrom animal experiments, is not always applicable to thehuman infant, least of all to the asphyxiated baby at birth.There is conflicting evidence as to the state of the chemo-receptor mechanism in newborn animals and there maywell be species differences in the development and functionof the carotid bodies at birth. This may account for the

discrepancy, for instance, between the negative findings ofLim and Snyder (1945) of nikethamide in newbornrabbits and the distinct respiratory stimulant effect innewborn infants of this investigation. Moreover, caremust be exercised in translating such data to the asphyxi-ated baby. The various causes of neonatal asphyxia (e.g.,prematurity, cerebral injury, cedema, and analgesia) and theextent of any particular disorder profoundly influencesthe degree of respiratory depression and consequentlythe response to resuscitation. The limitations of clinical

diagnosis are obstacles to any objective assessment inneonatal asphyxia. Our data on the responses in normalbabies can therefore only be a tentative guide to the useof drugs in pathological states.

-

In the report resuscitation of the Newborn Infant (1956)the special Committee on Infant Mortality of the Medical

I. 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 respiratoryi stimulants, and therefore the safest to use, is caffeine."

A dose of 16 to 32 mg. of caffeine sodium benzoate intra-muscularly or intravenously was recommended.

I Few would dispute the limitations of chemical respira-I ton stimulants; but, on our evidence, intramuscular

B stunulants have no place in neonatal resuscitation at anytime, and the use of caffeine sodium benzoate by anyroute seems unjustified. It is reasonable to suppose that astimulant which fails to excite the normal respiratory

i

centre is probably ineffective in abnormal states. Ami-

phenazole is another central stimulant with an undeservedreputation. Spiractin, a synthetic aminoketone relatedchemically and pharmacologically to lobeline, is too

unpredictable in its action and apt to excite vomiting.Lobeline itself was not fully investigated since its unsuit-ability in neonatal resuscitation (on account of its vagalexcitation of vomiting, hypertension, and bradycardia)has been recognised for many years. Prethcamide, acompound dimethylamide chemically related to nike-thamide but with mainly a central action, also proved toounpredictable.

Nikethamide and vanillic acid diethylamide are twoagents with a distinct and specific respiratory stimulantaction. They are chemically related and their main site ofaction is thought to be on the carotid chemoreceptors,although some central stimulation also occurs. Thera-

peutic doses appear to be metabolised quickly since

respiratory stimulation rarely persisted more than tenminutes. Vanillic acid diethylamide may be superiorin this respect because animals which survive ten to

fifteen minutes after a toxic dose recover rapidly, whereasnikethamide toxicity usually persists for several hours

(Ginzel 1952). Of particular interest is their rapid absorp-tion from the mucous membrane of the tongue and mouth,the effect on respiration being comparable to that of anintravenous injection of the same dose. Since bothroutes depend on an adequate circulation, no advantagewould seem to be gained by giving the drugs intra-

venously. The lingual route, on the other hand, has muchto commend it, especially in small infants.

It has been suggested that chemoreceptor stimulantsmay not be effective in the presence of asphyxia since thereflex is already under maximum stress in response tooxygen lack. This argument probably does not hold truefor newborn and premature infants, who may respond tohypoxia with respiratory depression instead of increasedventilation (Miller and Behrle 1954). Also, the fact thathypoxic babies can be induced to gasp by such means aslung inflation and peripheral or chemical stimulants

suggests that the respiratory centre is responsive to

impulses in addition to those produced by the chemo-receptors as a result of oxygen lack. Whilst it may betrue that some drugs act more powerfully on a depressedthan on a normal centre, even a powerful stimulant, suchas vanillic acid diethylamide, can hardly be expected toreverse any more than mild to moderate respiratorydepression. Fortunately the rapid buccal absorption ofnikethamide or vanillic acid diethylamide makes thisdistinction academic. In favourable cases, the baby willrespond by gasping respiration within one minute, fol-lowed by crying and the expulsion of upper-respiratory-tract secretions. Failure to respond to a lingual dose withinone minute implies a degree of respiratory centre depress-ion irreversible by any known safe chemical stimulant,and such infants should be intubated and artificiallyventilated without delay. Our experience so far suggeststhat the need for intubation is reduced by 25% by theprior use of these drugs. The dose of vanillic acid

diethylamide recommended is 5 mg. per kg. body-weightor, 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

746

who are not breathing three minutes after birth and whohave failed to respond to clearing of the pharynx and thegiving of nasal oxygen. If breathing does not begin withinone minute, endotracheal intermittent positive-pressureoxygen is given.The importance of early and adequate oxygenation, by

assisted ventilation when necessary, cannot be over-

emphasised, and, in the case of premature infants andthose in poor condition at birth, we do not allow threeminutes’ delay. However, it must be pointed out that themajority of deliveries in this country are attended bymidwives who are still neither instructed nor encouraged inthe use of intermittent positive-pressure respiration.Faced with the desperate emergency of the baby whofails to breathe, their choice rests between giving a drugwhich 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 obstetricstaff of a measure of uncertain but possible benefitwithout offering a better alternative.

SummaryThe action of various respiratory stimulants was

investigated in 25 newborn infants. The drugs weregiven by injection to 5 babies with congenital meningo-myeloceles 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 stimulantaction on respiration. The effect of lingual administrationwas equal in time of onset and degree of action to that ofintravenous 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-terminfants, and half these amounts for prematures.

Failure to respond within one minute to lingualadministration of these agents implies severe respiratorydepression irreversible by any known safe stimulant.Their prior use in less severe degrees of asphyxia mayavoid the need for intubation and assisted ventilation in asmall proportion of cases.We thank Dr. J. E. Cullis for his part in originating this investiga-

tion ; and Miss J. Dewe, medical artist, and the photographic depart-ment for the illustrations.

Vanillic acid diethylamide (’Vandid’) and its solvent were

supplied by Riker Laboratories; prethcamide (’ Micoren ’) by GeigyPharmaceutical Co., Ltd.; and spiractin (’Karion’) by Medimpexand G. Richter Chemical Works.

"... I have a strong repugnance to falling asleep withoutfirst, however briefly, disinfecting my mind from the businessof the day with at least a few pages of detached reading. Toseek unconsciousness direct from papers or engagementsseems as insalubrious as to go to bed unwashed."-Mr.ENOCH PowELL, Times, Sept. 27, 1962.

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 Com-

mittee on Infant Mortality of the Medical Society of the County of NewYork. Obstet. Gynec. 8, 336.

THYROID FUNCTION

IN CHRONIC ALCOHOLISM

MARSHALL GOLDBERGM.D. Wisconsin

FORMER RESEARCH ASSOCIATE, ALCOHOLISM CLINIC, ST. VINCENT’S

HOSPITAL, WORCESTER, MASSACHUSETTS, AND CONSULTANT TO THEMASSACHUSETTS COMMISSIONER ON ALCOHOLISM*

* Present address: Department of Medicine, University of Wisconsin MedialSchool, Madison 6, Wisconsin.

Richter’s work (1956, 1957) suggested the existence ofan inverse relationship between the level of circulatingthyroid hormones and voluntary alcoholic intake in rats.Applying his observations to man, he reasoned that anincreased appetite for alcohol might indicate a hypo-thyroid condition. A preliminary study of thyroidfunction in a group of chronic alcoholics among militarypersonnel in 1958 seemed to support Richter’s conten-tion : 33 patients tested, 21 (64%) were found thyroiddeficient in varying degrees (Goldberg 1960a).The present investigation was undertaken to confirm

and extend these findings; in particular, to test thyroidfunction in a larger group of alcoholics, and to explorethe possibility that chronic, excessive intake of alcoholmay exert a damaging or toxic effect on the thyroid gland.

Methods and Materials

From January, 1960, extensive thyroid-function studieswere carried out on 100 chronic alcoholics selected atrandom from the registry of the St. Vincent’s HospitalAlcoholism Clinic.The group was composed of 74 males and 18 females, ranging

in age from 23 to 65 years. All were confirmed chronic

TABLE I-AGE, SEX, WEIGHT, AND ALCOHOLIC HISTORY IN HYPOTHYROIDAND EUTHYROID ALCOHOLICS t

alcoholics. The details of their alcoholic history and previousanti-alcoholic treatment are shown in table i. About two-thirds of the patients had previously attended the clinic andwere in remission at the time of thyroid testing. The remainingthird were drawn from hospital patients convalescing fromacute alcoholism.

During the first appointment a detailed history was takenand the patient was examined with special emphasis on thedetection of the stigmata of hepatic or endocrine disorders.Patients were also carefully screened for potential coronary-artery disease and adrenal insufficiency-both relative contra-indications to liberal thyroid-hormone therapy. Insofar as

possible, those with detectable hepatomegaly, spider angio-