' 11: N 0 m 1

Roberta M. McKay, MD

Vesiculo-Bullous Disorders of the NeonateSUMMMARYThis is the first of three artides which outlinethe diagnoses to be considered whenvesiculo-bullous lesions are identfified in theneonate, children, and adults. This paperpresents a brief sketch of blistering disorderswhich may occur during the first few weeksof life. Vesiculo-bullous lesions in the neonatemay represent benign, infectious, genetic, orlife-threatening disorders. Early recognition,appropriate diagnostic procedures, andspecific therapeutic interventions can be vitalin reducing potential morbidity and mortality.General guidelines for diagnostic proceduresand therapeutic interventions are discussed,along with some of the newer etiologic andepidemiologic concepts. (Can Fam Physician1987; 33:2297-2301.)

RESUMEII s'agit du premier d'une serie de trois articles ayantpour but de decrire le diagnostic a considerer enpresence de lesions vesiculo-bulleuses identifieeschez les nouveau-nes, les enfants et les adultes. Cetarticle presente un bref apercu des affectionsvesiculaires qui peuvent se manifester au cours despremieres annees de vie. Chez le nouveau-ne, leslesions vesiculo-bulleuses peuvent s'averer desaffections benignes, infectieuses, genetiques oumenaqantes sur le plan du pronostic vital.L'identification precoce, les proceduresdiagnostiques appropriees et des interventionstherapeutiques specifiques peuvent jouer un rolecritique dans la reduction de la morbidit6 et de lamortalit6 potentielles. L'auteur discute les lignes deconduite generales permettant de choisir desprocedures diagnostiques et des interventionstherapeutiques, de meme que certains nouveauxconcepts etiologiques et epidemiologiques.

Key words: vesiculo-bullous disorders., neonatal blisters, neonatal dermnatology-__~~~~~~~~~~~~~~~~~~~~~m --- ---m

Dr. McKay, a dermatologist, isan assistant clinical professor in theDepartment of Medicine, Universityof Saskatchewan, and Coordinatorof the Undergraduate StudentIntern and Resident Trainingprograms in Internal Medicine,Plains Health Centre, Regina.Reprint requests to: Dr. RobertaM. McKay, Regina InternalMedicine Specialists, 1821 RoseStreet, Regina, Sask. S4P 1Z7

G ENETIC ABERRATIONS, in-J trauterine events, and the fact

that the neonatal immunologic systemis anatomically intact but antigeni-cally inexperienced and functionallydeficient, may result in a variety ofvesiculo-bullous disorders in the new-born. This paper will review a spec-trum of infectious and non-infectiousdiseases in the neonate which rangefrom the banal to life-threatening.

Infectious Neonatal BlistersHerpes simplex

Neonatal herpes simplex viral (HSV)infection constitutes a medical emer-

CAN. FAM. PHYSICIAN Vol. 33: OCTOBER 1987

gency. First reported in the mid-1930s, it is estimated to occur in one in3,000 to one in 15,000 live births peryear. Without therapy, widely dissem-inated disease occurs in more than80% of cases. Of these severely af-fected infants, 50%-80% die, andthose who survive rarely escape sig-nificant neurologic impairment. Evenlocalized involvement of skin, eyesand/or mucosae can lead to neuro-logic impairment in as many as 30%of the affected babies.'

Cutaneous signs of HSV infectionmay be evident at birth or may de-

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velop as late as 28 days post partum;the average interval before the signsdevelop is seven to 11 days. The vesi-cles, as small as 1mm in diameter,appear in clusters and evolve throughpustular and crusted stages. Conjunc-tivitis and keratoconjunctivitis mayalso be present. Only 70%-80% ofneonates develop cutaneous lesions;the remaining 20%- 30% shed thevirus from the oropharynx or showevidence of neural involvement.

Early diagnosis of HSV infection isessential. Isolation of the HSV fromvesicular fluid is the hallmark of in-fection. A Tzanck smear from thebase of the vesicle, electron micro-scopy of vesicular fluid, and a skinbiopsy suggest the possibility of aviral etiology. Babies without skin le-sions who display neurologic signs re-quire cultures of cerebrospinal fluidand possibly a brain biopsy to estab-lish a definitive diagnosis. A historyof genital herpes in the mother or hersexual partners, a characteristicallyabnormal EEG or CT scan in the infant,or an increasing cerebrospinal fluid(CSF) protein parallelling clinical de-terioration provide other diagnosticclues. The infant's eyes should alsobe evaluated for corneal involvement.

Treatment of all HSV-infected neo-nates, even those with the most lim-ited forms of the disease, is essential.Both adenosine arabinoside (ARA-A,VIRA-A) and acyclovir (Zovirax) havedemonstrated efficacy when adminis-tered intravenously.

Staphylococcal infectionsBacterial colonization studies of

neonatal skin and mucous membranesshow the absence of staphylococci atbirth. Only 30% of infants had evi-dence of colonization at six days ofage. Resident staphylococci are moreoften acquired from nursery staff thanfrom the mother. Infants with nasalcolonization at the time of hospitaldischarge are more likely to have con-

tinued nasal carriage and to developclinical infection during the first sixmonths of life. However, the inci-dence of colonization does not alwayscorrelate with the incidence of clinicalinfection because certain strains of thebacteria are more virulent thanothers.2

The clinical manifestations of Sta-phylococcus aureus infection are mul-tiple. The staphylococcal toxin syn-

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dromes are notable for their bullouslesions. Epidermolysin or exfoliatin,an exotoxin elaborated most com-monly by S. aureus, group II, phagetype 70/71, causes cleavage of theepidermis in the granular layer. Thelocalized form (bullous impetigo) andthe generalized exfoliative state (sta-phylococcal scalded skin syndrome)occur more frequently in neonates be-cause their relatively immature kid-neys are unable to excrete the exo-toxin efficiently.

Localized bullous impetigo is char-acterized by discrete flaccid bullaecontaining clear or cloudy yellowfluid and surrounded by normal-ap-pearing skin. Ruptured bullae show aglistening red base which re-epi-thelializes in five to seven days. Thelesions are often localized to the um-bilical, axillary, or diaper areas. Theinfant has no other signs of disease.

Staphylococcal scalded skin syn-drome (ssss) begins with diffuseblanchable erythema which, within 24hours, acquires a scalded appearance.Large, ill-defined, flaccid, wrinkledbullae may cover the entire skin sur-face. Exquisite tenderness of the in-volved areas results in irritability,lethargy, and poor feeding, whiletemperature regulation is abnormalbecause of the extensive areas ofdamaged and denuded skin. Lightstroking of the skin will cause separa-tion of the upper epidermal layers(positive Nikolsky's sign). Healingoccurs in five to seven days.A diagnosis of bullous impetigo

may be established by preparingGram stain smears and culturing vesi-cular fluid. However, Gram stainsmears and cultures of material fromskin lesions in ssss will be negative,as the primary site of infection isusually an extracutaneous site such asthe nasopharynx, conjunctiva, or mid-dle ear.

Systemic therapy with penicillin-ase-resistant penicillins appropriate toculture and sensitivity profiles is re-quired. Mortality is low (2%- 3%)and morbidity uncommon if treatmentis given.

Congenital cutaneous candidiasis

As a result of improved nutritionand medical care, oral candidiasis inneonates is less commonly encoun-

tered today,3 and congenital cuta-neous candidiasis (ccc) is distinctly

rare. When it does occur, ccc isusually present at birth, though it oc-casionally appears a few days later,with intense diffuse erythema andvesiculopustular lesions on the trunkand limbs. Palmar and plantar lesionsare the hallmark of the disease, whilethe face and oral mucosa are rela-tively free of lesions. Nail involve-ment with nail dystrophy sometimesoccur. The infant is clinically well.The duration of the eruption varieswith the intensity of the reaction.A Gram stain of the pus or a potas-

sium hydroxide preparation of des-quamating skin will demonstrate bud-ding yeasts and pseudomycelia.Routine cultures will confirm theseobservations. Neonates of low birthweight or with respiratory distressshould be observed for signs of disse-minated disease, and if such signs areobserved cultures of urine, stool, andgastric aspirates are required.

Topical therapy using standard anti-candidal preparations (clotrimazole,econazole, miconazole, nystatin),usually effect resolution of the cuta-neous infection within days. Oralnystatin may be given to eradicatepossible gastrointestinal seeding. Dis-seminated disease requires much moreaggressive therapy with parenteral an-tifungal agents.

Congenital varicellaIf maternal infection with varicella

occurs within 17 days of delivery,about 24% of infants will develop thedisease. In infants with this disease,teardrop or "dewdrop on a rosepetal" vesicles appear during the first10 days of life and gradually evolveinto crusted lesions. These infants candevelop severe illness in which therisk of mortality is 20%.A Tzanck smear may demonstrate

the presence of multinucleated giantcells and balloon cells, electron mi-croscopy may show the viral parti-cles, and a culture may provide evi-dence for a positive identification ofthe virus.

In the absence of clinically appar-ent disease, immediate administrationof zoster-immune globulin to the in-fant is recommended if maternal in-fection was present for five days be-fore, to two days after, delivery.

As in herpes simplex viral infec-tions, efficacy of acyclovir and vi-darabine have been demonstrated, butthe lower toxicity and ease of admin-

CAN. FAM. PHYSICIAN Vol. 33: OCTOBER 1987

istration of acyclovir make it the drugof choice. The recommended dose is500mg./m2 each eight hours for sevendays.4 To be effective, therapy mustbe instituted early.

Congenital syphillisFortunately, congenital syphillis is

now rare in North America. A com-plete discussion of this is not possiblehere, other than to indicate that bul-lous lesions may occur especially onthe palms and soles. Their occurrenceis infrequent, but if present, they areconsidered diagnostic. Other featuresof the disease, such as "'snuffles",mucous patches, maculopapular erup-tions, as well as visceral and osseoussigns, are more likely to occur and toalert one to the diagnosis than are thebullous lesions.

ScabiesSarcoptes scabiei infestations in in-

fants have an altered distribution com-pared with that in older children andadults. This distribution includes theneck, face, head, palms, and soles.Bullous lesions are uncommon, butvesicles are frequently present, owingto the predisposition for blister forma-tion found in this age group. Secon-dary complications are common as aresult of scratching and rubbing, over-zealous attempts at hygiene, and ap-plication of numerous topical thera-peutic agents. In infants, especiallythose predisposed to atopic disease,the complications may be widespreadand severe.

Secondary pustulation, bullous im-petigo, and severe crusting may bepresent. Cultures should be obtained,as scabetic lesions seem to be particu-larly favourable to the growth of viru-lent M-strains of nephretogenic strep-tococci.

Corticosteroid administration, topi-cal or systemic, can mask the diag-nosis of scabies by causing a diminu-tion of the signs and symptoms. Thisoften results in unusual clinical pre-sentations and atypical distributionswhich in some cases closely simulatea variety of other conditions. Referredto as "'scabies incognito", this situa-tion is notable because the transmissi-bility of the infestation persists. Inany pruritic patient, the diagnosis ofscabies should always be considered.Recommended treatment in neo-

nates consists of 10% crotamiton(Eurax), 6%- 10% sulfur in petrol-

atum, or a suspension of benzyl ben-zoate in a 12.5%-25% concentration.Since Eurax has no reported systemiceffects, it is safe for infants. How-ever, it has the disadvantage of beingirritating on raw or denuded skin.Thus it should be used with cautionon acutely inflamed skin. It is prefera-ble to delay treatment of the scabiesuntil the eczematous reaction isbrought under control with topicalsteroids and, if necessary, antibiotics.Two applications of Eurax in 48 hoursis recommended, and bathing shouldbe delayed for three days post ther-apy.Gamma benzene hexachloride

(Kwellada) is recommended therapyfor all household occupants and closecontacts of a patient with scabies. Itshould be applied to all these personson the same night. A second applica-tion may be done one week later, butrepeated treatments must be dis-couraged, as this will lead to irritantand hypersensitivity reactions. Theprimary reason for overuse is that pa-tients are not informed that the pruritusmay continue until all remnants of themite are eliminated from the stratumcorneum. The hypersensitivity con-tinues, but the infectivity is eliminatedwithin 24 hours after proper treatment.Reported instances of toxicity and con-vulsions in infants are most probably aresult of such over-treatment. If thetreatment modalities mentioned abovedo not result in a cure, the infant mayrequire one 12-hour application ofKwellada.

Non-InfectiousNeonatal BlistersErythema toxicum neonatorum

Erythema toxicum neonatorum is acharacteristic, asymptomatic, benign,self-limiting, cutaneous eruption thatoccurs in approximately 50% of neo-nates. The eruption, which is of un-known etiology, seems to have a lowerrate of incidence in premature infantsthan in full-term infants. It appearsmost frequently in the first three tofour days of life, but does occur frombirth to the tenth day of life.

Blotchy erythema, extending from afew millimeters to several centimeters,heralds the onset of this disease; then1mm- 3mm papulo-vesicular or pa-pulo-pustular lesions develop withinthese areas. Exacerbation and remis-sions may occur during the first two

CAN. FAM. PHYSICIAN Vol. 33: OCTOBER 1987

weeks of life, and individual lesionsmay last a few hours to 16 days. Palmsand soles are spared.

Diagnostic procedures include aWright's or Giemsa's stain of lesionalcontents and histologic examination ofa biopsy specimen. In both cases, ifthe disease is present, eosinophils areseen in abundant numbers. Micro-scopic examination of the biopsy willshow clustering of eosinophils aroundthe pilosebaceous unit. Peripheralblood shows eosinophilia in 7%-15%of cases.5 Eosinophilia in adults is as-sociated with hypersensitivity reac-tions, but in neonates it appears to ac-company a variety of inflammatoryresponses. Perhaps this disorder repre-sents a transient and normal responseto mechanical and thermal stimuli.

Treatment is not required, but thephysician should always rule out theother disorders listed in this article,especially if they represent a threat ofcontagion, systemic dissemination, ormortality.

Transient neonatal pustular melanosisAlthough the name of this disorder

appears restrictive because it includesthe word 'pustular', it must be recog-nized that skin lesions can change veryrapidly. Vesicles become pustules tothe naked eye when enough acute in-flammatory cells accumulate at a su-perficial epidermal level. If the degreeof edema is great in contrast to the vol-ume of cells, a lesion is more likely tobe perceived as a vesicle. Thus pap-ules may become vesicles which, inturn, may become pustules. The nearerthe damage is to the surface, the morelikely the lesion is to appear vesicularor pustular.

This disorder, which is more com-mon in Blacks (4.4%) than Caucasians(0.2%), is characterized by vesiculo-pustules which rupture easily and thenresolve leaving hyperpigmented ma-cules, often with a collarette of finewhite scales. Most commonly, lesionsare found under the chin, on the fore-head, nape of neck, lower back andshins, but other areas may be in-volved.The lesions are sterile; with

Wright's stain, they demonstrate vari-able neutrophils and cellular debris butfew or no eosinophils, in contrast toerythema toxicum neonatorum. Abiopsy is useful to obtain additionalsupportive data.

This benign disorder has no syste-2299

mic manifestations and requires notreatment, but it is always importantto rule out the infectious and life-threatening disorders before decidingthat therapy need not be instituted.

MiliariaThere are two commonly recog-

nized forms of this sweat-retention dis-order: miliaria crystallina and miliariarubra. The pathogenetic pathway in-volves the maceration and occlusion ofeccrine sweat ducts, arising from heat,occlusion, perspiration, and possiblybacterial toxins. In neonates, imma-turity of sweat ducts may also be a fac-tor.6 The blocked ducts rupture, andsweat escapes into the tissues belowthe level of obstruction. If the obstruc-tion is within the superficial layers ofskin, the sweat accumulates and formsa blister, the response typical of mi-liaria crystallina. A deeper level of ob-struction results in the inflammatoryresponse seen in miliaria rubra.

Infants suffering from miliaria crys-tallina present with crops of 1mm-2mm vesicles on otherwise normal-appearing skin. These asymptomaticlesions occur most frequently in inter-triginous areas.

Miliaria rubra or "prickly heat"occurs in areas where friction fromclothing is an additional etiologic fac-tor. The papules, vesicles, or papulo-vesicles are surrounded by erythemaand are pruritic. Magnified examina-tion will show that none of the lesionsare associated with hair follicles, a fea-ture which differentiates this conditionfrom folliculitis.

Management requires avoidance ofexcessive heat and humidity.

Sucking blistersSucking blisters are said to occur in

one of every 240 deliveries. A bulla orerosion varying from 0.5cm to 2cm indiameter may be present on the dor-sum of digits, hands, wrists orforearms. No management is requiredbeyond observing that there are noprogression of the lesion and no newareas of involvement, which mightsuggest the more serious diagnosis ofEpidermolysis Bullosa.

Bullous congenital ichthyosiformerythroderma

This disorder, which is also termed'epidermolytic hyperkeratosis', was

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the first inherited skin disorder to bediagnosed by fetoscopy.7 It is an auto-somal dominant disorder, but it has ahigh rate of spontaneous mutation. Ifneither parent of an affected infant hasthe disorder, the subsequent offspringare not at increased risk for the dis-order. As this form of ichthyosis is oneof the most disfiguring of the hyper-keratotic disorders, it is important forthe physician to recognize the signsand to give the infant's parents appro-priate counselling.

At birth, the appearance of the dis-order may be striking, with largeerythematous denuded areas not unlikethose seen with epidermolysis bullosa.With time, the hyperkeratosis devel-ops on planes transverse to the longitu-dinal axes of the extremities. The thickridges of grayish-brown scales aremore pronounced in the anticubital andpopliteal fossa. Bulla which are easilydenuded are common in childhood andcontinue to appear in 20% of adults.One of the socially handicapping

aspects of this disorder is the distinc-tive and unpleasant odour related tobacterial decomposition within thethick, compact, keratinaceous scales.Characteristically, these scales aretightly adherent, and removal createslarge eroded areas. In addition, hyper-keratosis of the palms and soles maybe present, but the central face isusually spared.

Since the introduction of the syste-mic retinoids, particularly etretinate(Tegison), treatment has been benefi-cial in some cases. The drug, how-ever, is not without side-effects, andlong-term therapeutic complicationsmay develop. Antibiotics may be re-quired to control or diminish theodour.

Incontinentia pigmentiAs 97% of the 600 reported cases of

incontinentia pigmenti occur in fe-males, incontinentia pigmenti is as-sumed to be an X-linked disorder. Af-fected mothers also have an increasedspontaneous abortion rate, which is as-sumed to mean lethality in hemizygousmales. The pattern of the skin lesionsis also thought to lend support to theX-linked theory, as random lyoniza-tion of X chromosomes in neural crestcells would produce the characteristicswirled lesions.

This neurocutaneous disease hasthree phases: vesicular, verrucous, andpigmentary. The latter two phases do

not occur in the newborn period. Onsetof the vesiculo-bullous stage is at birthor within six weeks, and the disordermay be intermittent or persistent formonths. Erythema with vesicles in lin-ear or swirling arrangements occursmainly on extremities but occasionallyon the trunk and head. Leucocytosis to50,000 per mm2 and blood eosinophil-ia of 50% may be present, but in spiteof this, the infant appears well.7 Asmear of vesicular fluid will also showmany eosinophils.The verrucous phase occurs in two-

thirds of affected infants, and may re-semble a linear epidermal nevus. Thefinal pigmentary stage occurs in over98% of affected infants; it begins asthe first two stages are resolving. Itmay even be present at birth if the pre-vious stages occur in utero.

Extracutaneous involvement mayresult in hair, nail, tooth and ocular ab-normalities in 50% of affected per-sons. One-third have central nervoussystem signs and symptoms such asconvulsive disorders, mental retarda-tion, and motor deficits.8

Curious cutaneous pigmentation orvesicular lesions in a "marble cake"pattern provide visible clues to thisdisorder. It is believed that the numberof cases is under-reported as a result ofpoor recognition or misdiagnosis.

Unfortunately, there is no cure forthis disorder, but systemic retinoids(Tegison, Accutane) may be useful inreducing the verrucous lesions. Paren-tal counselling about potential extracu-taneous manifestations in the affectedinfant is essential. Most important,however, is the fact that early recogni-tion will allow for genetic counsellingso that future pregnancies may beavoided if the parents so desire. At thepresent time prenatal diagnosis by fe-toscopy or amniocentesis is not pos-sible.

Epidermolysis bullosaAlthough this disorder may appear

and be diagnosed in the neonatalperiod, it will be discussed in the sec-ond article of this series, Vesiculo-bullous Disorders of Childhood.

ConclusionsWhen vesiculo-bullous lesions are

present in the neonate, the essentialdiagnostic protocol should include: adetailed maternal and family history, aTzanck smear, a Wright's or Giemsa

CAN. FAM. PHYSICIAN Vol. 33: OCTOBER 1987

stain, viral and bacterial cultures, anda biopsy. The discussions and descrip-tions in this article are far from ex-haustive, but I hope that some of thedetails covered will help the readers todetermine quickly the nature of blistersin neonates.

References1. Whitby RJ, Barnes DW. Herpes simplexvirus infection. In: Kass EH, Platt R, eds.Current therapy in infectious diseases.Toronto: B.C. Decker Company, 1986;pp. 376-81.2. Herbert AA, Esterley NB. Bacterial andcandidal infections in the neonate. In: Hur-witz S, ed. Dermatology clinics. Philadel-phia: W.B. Saunders Company. Vol. 4,No. 1, January, 1986; pp. 3-21.3. Allen HB, Rippon JW. Superficial anddeep mycoses. In: Moschella SL, HurleyHJ, eds. Dermatology. 2nd ed. Philadel-phia: W.B. Saunders Company, 1985;p. 230.4. Savoia M, Oxman MN. Guidelines forantiviral therapy. In: Kass EH, Platt R,eds. Current therapy in infectious diseases.Toronto: B.C. Decker Co., 1986;p. 2330.5. Hurwitz S. Clinical pediatric dermatol-ogy. Philadelphia: W.B. Saunders Com-pany, 1987; pp. 11-2.6. Fitzpatrick TB, et al. eds. Dermatologyin general medicine. 3rd ed. New York:McGraw-Hill Book Co., 1987; p. 2625.

7. Golbus MS. Prenatal diagnosis of bul-lous congenital ichthyosiform erythro-derma by fetal skin biopsy. New Engl JMed 1980; 302:93- 5.

8. Kegel MF. Dominant disorders withmultiple organ involvement. In: Hurwitz S,ed. Dermatology clinics. Philadelphia:W.B. Saunders Co., Vol 5, No. 1, 1987;pp. 205-219.

CAN. FAM. PHYSICIAN Vol. 33: OCTOBER 1987

SAl UpentsIlLBRONCHODILAMRTHERAPYSyrup THArS EASY

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PRESCRIBING INFORMATIONIndicationsAlupent has been found useful in thefollowing conditions Bronchial asthma,Chronic bronchitis, pulmonary emphysemaAlupent is also useful in sarcoidosis, silicosis,carcinoma of the lung and tuberculosis whenbronchospasm contributes to the disability.When used regularly, Alupent offers effectivemanagement of chronic bronchospasm withreduction in frequency and severity of acuteattacks.

As ith all drugs, the ideal dosage of Alupentvaries from patient to patient The followingrecommended dosages represent generalguidelines which will be found suitable for themajority of patients.Tablets 20 mgAges 4-12, 10 mg (1/2 tablet) ti.d.above 12, 20 mg (1 tablet) ti.d. - qi.dSyrup 10 mg/5 mlAges 4-12, 10 mg (one teaspoonful) ti.dabove 12, 20 mg (two teaspoonsfu) ti.d. -qi.d.Metered AerosolOne to two inhalations will usually providecontrol of an acute attack of bronchospasmfor periods of 5 hours or longer. As a generalrule, patients should not exceed a total of 12inhalations per day.Solution 5%Hand nebulizer. 5 to 15 inhalations of 5%solution by hand nebulizer DeVilbiss No. 40or 42 administered up to three times daily.Intermittent positive pressure breathing: 1/2-1 ml of 5% solution diluted if desired andadministered over a period of about 20minutes.Side EffectsIn the recommended dosage, adversereactions to Alupent are infrequent Mildtachycardia, nausea, vomiting, palpitafions,minimal hypertension, nervousness, badtaste and tremor have been reportedPrecautionsIn acute tests, Alupent has shown minimaleffect on blood pressure and pulse. The drugshould be used with care, however, inasthmatic or emphysematous patients whoalso have systemic hypertension, coronaryartery disease, acute and recurringcongestive heart failure, diabetes mellitus,glaucoma or hyperthyroidism. Extreme caremust also be exercised in the concomitantuse of Alupent with epinephrine or MAOinhibitorsWamingsAlupent should not be administered topregnant women or to women of childbearingpotential unless, in the opinion of thephysician, the expected benefits outweighthe possible risk to the foetus. Occasionalpatients have been reported to havedeveloped severe paradoxical airwaysresistance with repeated excessive use ofsympathomimetic inhalation preparationsThe cause of this refractory state is unknown.It is advisable that in such instances the useof the preparation be discontinuedimmediately and altemative therapyinstituted, since in the reported cases thepatients did not respond to other forms oftherapy until the drug was withdrawn.Fatalities have been reported followingexcessive use of isoproterenol inhalationpreparations and the exact cause isunknown. Cardiac arrest was noted in severalinstances.Patients should be advised to seek medicalaid in the event that they do not respond totheir usual dose of a sympathomimetic amineaerosol. The failure to respond may be due toretention of viscid bronchial secretions,associated with an allergic or infectiveexacerbation of the patient's condition.

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