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Aminophylline (theophylline ethylenediamine) poisoning in children
AMINOPHYLLINE ( T t I E O P H Y L L I N E E T H Y L E N E D I A M I N E ) POISONING IN CHILDREN BEN H. WHITE,
M.D.,
AND C . W M .
D A E S C H N E R , ~r
I~OUSTON, T E X A S
due to the oral or recp talOISONING administration of theophyllinc in ethylenediamine (aminophylline) has been infrequently reported since the drug first came into general use about 1936. Death associated with the enteral use of aminophylline was first reported by Gardner and associates 1 in 1950. They described the ease of a 2-year-old female who ingested no more than 1.0 Gin. of theophylline, 0.2 Gin. of ephedrine, and 0.065 Gin. of phenobarbital. Within one hour the child was noted to be restless and hyperactive. In spite of cathartics, lavage, and general supportive therapy, the patient subsequently developed convulsions, eyanosis, and severe hematemesis. She died thirteen hours later in severe shock. Death was attributed to the toxic effects of theophylline potentiated by ephedrine. Three years later, Pioppi, 2 unaware of Gardner's report, described the death of a 2-year-old child with asthma and bronchitis, following the rectal administration of aminophylline. The author felt that aminophylline had contributed to the patient's death in spite of an autopsy report showing " a fulminating virus infection of the lungs." Pioppi also described one case of sublethal toxicity in a 31~-year-old asthmatic boy F r o m t h e D e p a r t m e n t of Pediatrics, Baylor U n i v e r s i t y College of Medicine, the T e x a s Children's Hospital, a n d the Pediatric Service of the Jefferson D a v i s Hospital. 262
who received one aminophylline suppository (Aminet). Frazier 3 w a s stimulated by Pioppi's reports to describe a third fatal case. A baby of unstated age was given aminophylline rectal suppositories at intervals of several hours. The author emphasized that hematemesis might result from aminophylline intoxication, and attributed the patient's death to this cause. Two recent articles describe sublethal aminophylline toxicity in children. Rounds 4 in 195.4 reported his experience with six cases of aminophylline toxicity in children. Two of his patients received the drug intravenously, one of these with a fatal outcome, the other developed severe toxicity but survived. Four others developed severe sublethal toxicity following enterally administered aminophylline. In 1955 Love and Corrado ~ reported five instances of nonfatal aminophylline toxicity in four children. In these authors' experience the toxic dose was usually in excess of the recommended therapeutic dose. The present report describes four additional patients, showing varying' degrees of intoxication associated with oral or rectal aminophylline therapy, and summarizes the published eases of aminophylline intoxication in childhood.
WHITE AND DAESCHNER: CASE REPORTS CASE ] . ~ A 23-month-old N e g r o male was admitted to the hospital twenty-four hours following the accidental ingestion of an unknown number of aminophylline tablets (300 n ag . tablets). Twelve hours prior to admission the patient developed repeated projectile vomiting. He was awake most of the night with intermittent vomiting of clear gastric contents. I n between episodes of vomiting he was described as being weak and extremely restless. The patient was hospitalized when physical examination revealed an apprehensive and hyperactive child. The vital signs were: temperature 99.2 ~ F. (rectal), pulse 120, respirations 48, and shallow, and blood pressure 114/80. The reflexes were somewhat hyperactive, but equal bilaterally. The rest of the physical examination was within normal limits. Laboratory studies revealed hemoglobin 7.5 grams per cent, red blood cells 2.92 million, white blood cells 31,700 with 93 per cent segmentals, 6 per cent lymphocytes, and 1 per cent monocytes. CO2 content was 12.5 meq. per liter, C1 90 meq. per liter, BUN 16 rag. per cent. Urinalysis revealed a specific gravity of 1.020, 3 plus acetone, and 2 grams per liter of chloride (Fantus test). Chest roentgenograms were negative. In the hospital the patient continued to vomit all oral fluids for the first five to six hours. He was given 15 mg. of phenobarbital and 4 c.c. of aluminum hydroxide gel every six hours. The hyperactivity present on admission gradually disappeared over a twelve-hour period, and by the end of the first hospital day he was able to tolerate a soft diet. His subsequent course was uneventful.
CASE 2 . ~ A n 18-month-old white male with asthmatic bronchitis and otitis media was seen by a private physician seven and one-half hours prior to admission to the hospital. The patient had been given parenteral penicillin in oil and started on aminophylline by r e c t a 1 suppository.
AiVII,NOPHYLLINE POISONING
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Shortly after the first suppository the patient became restless and extremely excited. A sedative failed to bring about evidence of improvement and the child was admitted to the hospital. Physical examination revealed an extremely active and restless child, weighing 6.8 kilograms. The pupils were widely dilated and there was minimal injection of the right tympanic membrane. The chest was clear. There were areas of atopic eczema over the legs. The patient responded to intermittent sedation and was asymptomatic within twelve hours. CASE 3.---A 6-year-old Negro female was brought to the emergency room by her mother with the chief complaints of: (1) hallucinations and (2) the sudden onset Of "spasms in her hands." The mother described the patient as talking " o u t of her head, " in a repetitious manner, of babies and waterfalls, speaking to persons not present, and being oblivious of the presence of her family. The disturbed sensorium appeared three hours prior to hospital admission and was associated with marked physical hyperactivity, including involuntary extension of fingers and toes. F u r t h e r history revealed t hat the child had developed an acute upper respiratory infection with bronchitis three days prior to admission. One day prior to admission she received penicillin by injection and the mother was given a prescription for aminophy]line suppositories. (Later it was learned that by mistake the patient had been given a total of eight 500 mg. aminophylline rectal suppositories, or a total of 4.0 Gin. of aminophylline in a twenty-four-hour period). On this treatment the respiratory symptoms improved rapidly, but shortly after administration of the first aminophylline suppository, the patient developed anorexia, nausea, and vomiting. This vomitus was scanty, dark, unrelated to feedings, and recurred at about thirty-minute intervals until the time of admission. The patient was admitted with a tentative diag-
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T H E J O U R N A L OF PEDIATRICS
nosis of " t o x i c e n c e p h a l o p a t h y . " Physical examination on admission revealed a completely uncooperative, acutely ill, wide-eyed, grimacing, hyperactive, irrational child. She babbled c o n s t a n t l y in an incoherent manher and was continuously in physical motion to the extent t h a t restraints were necessary for the patient's proteetion. The skin was w a r m and dry. The initial signs were : blood pressure 100/60, t e m p e r a t u r e 106 ~ F. (R), pulse 22, respiration 28. E x t r a o c u l a r movements were normal (fundus examination was unsatisfactory). The n a s o p h a r y n g e a l mueosa was injected. There were scattered rhonchi and rgles over both lung fields, with prolonged expiration. The abdomen was negative. The fingers of both hands were i n t e r m i t t e n t l y extended and flexed in a somewhat athetoid manner. P a t e l l a r reflexes were absent bilaterally, other deep tendon reflexes were within physiological limits, and no pathological reflexes were elicited. Response to painful stimuli was depressed. L a b o r a t o r y studies revealed: hemoglobin 14.5 grams per cent, red blood cells 6.73 million, white blood cells 20,550 with 75 per cent polymorphonuclears, 22 per cent lymphoeytes, 1 per cent eosinophils, and 2 per cent monocytes. Urinalysis was negative. Cerebrospinal fluid examination revealed an initial pressure of 130 ram. of water, 2 cells per cubic millimeter, protein 37.0 mg. per cent, chlorides 120 meq. per liter. I n the hospital, phenobarbital sedation was a t t e m p t e d but was only partially effective. I n t r a m u s c u l a r penicillin and i n t r a v e n o u s l y administered fluids were begun shortly a f t e r admission. Six and one-half hours later the patient h a d a few w a t e r y stools. Shortly t h e r e a f t e r exacerbation of her hallucinations and shouting occurred, and she experienced a generalized convulsion lasting about five minutes. This was controlled b y increased b a r b i t u r a t e sedation. No other seizures occurred. The initially elevated t e m p e r a t u r e fell to normal
in f o u r t e e n hours. H e r sensorimn g r a d u a l l y cleared over the next thirty-six to forty-eight hours. She t o l e r a t e d a soft diet on the second hospital day. A second lmnbar puneture done on the f o u r t h hospital day was normal. She was discharged a s y m p t o m a t i e on the fifth hospital day. CASE 4.--This was a 7-month-old white male who was admitted to the hospital a f t e r three days of illness consisting of dyspnea, audible wheezing, and low-grade fever. These progressed ig the face of penicillin injections and the administration of cough mixture. Aminophylline suppositories of u n k n o w n size were begun on an e v e r y four-hour schedule, t w e n t y - f o u r hours p r i o r to admission. The patient began vomiting almost immediately a f t e r the first aminophylline suppository, and twelve hours before admission t h e vomitus contained b r o w n flecks. I n the hospital, examination revealed the i n f a n t to be acutely ill, mildly dehydrated, hyperactive, and restless. Vital signs were: temperature 106 ~ F.; pulse 180; and respiration. 60. Evidences of an u p p e r respiratory infection were present. The chest findings were compatible with an obstructive emphysema. Seatt e r e d r~les and musical wheezes were present throughout, as well as a markedly prolonged expiratory phase. Neur01ogieal examination was negative. L a b o r a t o r y studies of peripheral blood and urine were normal. A l u m b a r p u n c t u r e was negative except for an initial pressure of 300 ram. of water. Bleeding and clotting times and platelet counts were normal. Chest roentgenograms revealed moderate generalized emphysema. A diagnosis of asthmatic bronchitis was made and at this point the possibility of aminophylline intoxication was not entertained. The patient was put in humidified oxygen, and penicillin injections were continued. Aminophylline 60 rag. was administered reetally and an intravenous
WHITE
AND DAESCttNER:
infusion of aminophylline in 5 per cent glucose was begun. Watery greenish-black streaked stools which were 2 plus positive by benzidine test were noted shortly a f t e r admission. The t e m p e r a t u r e remained eIevated at 103 ~ to 104 ~ F. in spite of cool sponging. E i g h t e e n hours a f t e r admission the patient was " j u m p y " and restless and bilateral ankle elonus was present. I n t r a v e n o u s sodium Luminal 15 mg. was given with little benefit. I n t e r m i t t e n t vomitus of "coffeeg r o u n d " material continued. A t this point .the possibility of amiuophyIline intoxication in this patient was considered and the d r u g was discontinued. I n spite of this the patient did n o t . improve immediately and six hours later he experienced a generalized tonic-clonie convulsion w i t h cyanosis. This seizure continued until intravenous sodium Luminal 15 rag. was given. A t this time 50 e.e. of w a t e r y " c o f f e e - g r o u n d " material was aspirated from the stomach in an effort to relieve m o d e r a t e abdominal distention and to aid respiration, His general condition i m p r o v e d steadily, but he continued to have minimal vomiting and passed t a r r y stools for three days. The hemoglobin level, however, remained normal. CLINICAL FINDINGS AND COMMENT
Table I summarizes the cases of aminophylline intoxication from the literature plus the four cases herein reported. The ages of the patients included r a n g e f r o m 7 months to 6 years, with a mean age of 23 months. In the nineteen eases where sex is recorded, fifteen were males and four females. Ingestion was accidental in two instances, and its administration was directed by a physician in eighteen instances. Of the twenty instances of aminophylline poisoning in eighteen patients, four were fatal, seven were classified as severe, three were m o d e r a t e l y severe, three were
AMINOPHYLLINE
POISONING
265
moderate, and three mild. The dose in two fatal cases is unknown. Certainly m a n y factors influenced the final effects: individual susceptibility to the drug, v a r i a t i o n in absorption, route of administration, and the degree of incapacity caused by the original illness u n d e r treatment. The latter f a c t o r is k n o w n to be significant in infantile salicylate intoxication since it occurs almost invariably in the sick child. I n the fatal cases, one child ingested the material orally, one received the d r u g by vein, and two b y rectal suppositories. In the cases classed as severe, four patients received the d r u g b y rectum, one intramuscularly, and two both int,avenously and rectally. The presence of an u n d e r l y i n g disease, generally a r e s p i r a t o r y infection, makes it difficult to appraise the over-all effects of the drug, particularly as it effects rate and character of respirations. These were described as difficult or labored in ten instances, rapid in four, slow and deep in one, deep and pauseless in one, and shallow in one. Pulse was recorded in too few cases to make any evaluation w o r t h while. T e m p e r a t u r e s above normal were r e c o r d e d in only six cases. It is notable t h a t of the patients with severe h y p e r t h e r m i a , all three were critical and showed evidence of m a r k e d dehydration. A common f e a t u r e in all cases was some sign of central nervous system irritability. The xanthines are k n o w n to be directly stimulating to the brain cells, p a r t i c u l a r l y those of the cereb r u m and the m e d u l l a r y centers2 Some degree of cerebral anoxia was u n d o u b t e d l y present in m a n y of the children in acute attacks of asthma. It has been shown t h a t theophylline
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THE
T A B L E I. S U M M A R Y
JOURNAL
OF P E D I A T R I C S
OF T H E CLINICAL I~INDINGS IN T W E N T Y AIv[INOPIIYLLINE INTOXICATION
CASES OF
AlVflNOPHYLLINE
(~G./KG.) * AGE SCHEDULE ENCE W E I G H T I~0UTE OTHERDRUGS Gardner1 2 yr. 83 Ephedrine l2 kg. Stat Phenobarbital Oral REFER-
GLINICAL COURSES One hour after accidental ingestion, patient became emotionally upset. Heart rate normal. Dilated pupils; in 8 hr. muscular twitchlngs, hematemesis, seizures, cyanosis, shock, and death.
Pioppi2 Case 1
31/2 yr. 15 kg.
(17) Rectal Star
Nembutal Benzocaine
Within 30 mln. developed pallor, limpness, and tachycardia; responded in 3 hr. to oxygen and supportive therapy. Had appeared terminal. Dx: Asthma and bronchitis.
Pioppie Case 2
2 yr. 12 kg.
(21) Stat Rectal
Nembutal Benzocaine
Within 3 hr.: pallor, limpness, and vomiting. Wheezing cleared but patient died in spite of supportive therapy. Author felt aminophylline intoxication contributed to death. Autopsy: Fulminating pneumonitis.
Fraziera
Baby ?
? ? Rectal
None
Developed acute vomiting progressing to hematemesis and death. Suggested a f t e r autopsy that death due to aminophylline intoxication.
Rounds~ Case1
18mo. (11kg.)
None
Bronchiolitis one day. Treatment given and patient immediately apneic and cyanotic. On admission critical, cyanotic, restless, albuminurla. Died 8 hr. after admission.
Rounds4 Case2
16 mo. 10kg.
25 q 24 h • 3 Rectal
None
Dyspnea 5 days. Aminophylline administratiou 48 hr. prior to admission--irritable with rapid respiration, vomiting. Physical revealed dehydration, restlessness, and excitement. Recovered rapidly a f t e r sedation and supportive therapy.
Rounds4 Case 3
18 mo. 11 kg.
? Star and q 2h x 2 I.V.
0.1 mg. epinephrine
Wheezing all day; after therapy developed vomiting, hematemesis. Severe dehydration on admission. No respiratory distress. 14 hr. later received an aminophylline suppository followed by generalized convulsion and eyanosis, responded to sedation. EEG: Slow waves consistent with cerebral edema. Recovery slow.
Rouuds4 Case4
3 yr. 14kg.
18 q 8 h x 4 Rectal
None
Wheezing 3 days. A f t e r aminophylline, vomiting became projectile and b]oody. On admission: critical, restless, dehydrated, staring, no response to painful stimuli, respirations slow and deep, few rhonchi, albuminuria. Improved in 5 hr. with supportive therapy, recovered in 29 hr.
7 Star I.V. Rectal
None
Stat I.V.
Asthma not relieved by Adrenalin so aminophylline given, became restless and vomited. On admission: acutely ill, dehydrated, respirations labored, expiratory wheeze~ albuminuria, hyperthermia, and hematamesis, but recovered in 24 hr. EEG: Slow waves consistent with cerebral edema, negative 3 days later. *Values in parenthesis are data estimated from authors' summary.
Rounds4 Case5
3 yr. 14kg.
WHITE AND DAESCHNER:
AMINOPHYLLINE POISONING
267
TABLE I--CONT 'D
AMINOREFERENCE Rounds4 Case 6
PIIYLLINE (~ G./~. ) SCHEDULE
AGE WEIGHT ROUTE 11 too. (~8) 9 kg. Star
OTHER DBUOS None
CLINICAL COURSES TWO days bronchitis, t r e a t e d w i t h aminophylline. Immediately restless, shrill cry, muscle twitching, facial weakness. On admission: rest]es% nausea, cyanotic periods, facial paralysis, afebrile, albuminuria. Generalized convulsions at 12 and 16 hr. a f t e r medication. E E G : Slow waves consistent with cerebral edema. Recovery complete.
I.M.
Case I
15 too. 10 kg.
5O Phenobarbital q4h• None 25-I.V. Star
Severe asthma, given oxygen, phenobarbital, and aminophylline. Restless immediately. Vomiting second day; third day hematemesis, apathy, marked restlessness, muscle twitehings, dehydration. Improved 3 hr. a f t e r aminophylline stopped, f u l l y recovered 3 days later.
Love5 Case 1
]6 mo. 10 kg.
25 q4h• Rectal
Epinephrine 1:100 Phenobarbital
One month later: recurrence of asth~na. Treatment with rectal aminophylline follov~ed by restlessness, repeated vomiting, lethargy and muscular twitcbing. Improved 5 hr. a f t e r stopping aminophylline.
Love 5
21~ yr. 13 kg.
19
Phenobarbital
Asthma. Admitted with vomiting, dyspnea, and dehydration following aminophylline. Frequent vomiting and restlessness altern a t i n g with stupor. P~espiratlons deep and pauseless. Aminophylliae discontinued, fluids given, patient greatly improved in 4 hr.
Love 5
Case 2
q6h•
Rectal
Love 5
Case 3
Love 5
Case 4
19 mo. 11 kg.
22 q8hx2 Rectal
Phenobarbital Benzocaine
Asthma 14 hr. Alert, apprehensive, wheezing, before medication with rectal aminophylline. On admission: vomiting and melena, wakeful but not restless, albuminuria. Symptoms subsided spontaneously.
2 yr, 12 kg.
2.6 Oral
Epinephrine Phenobarbital Benzocaine
Wheezing s 3 days. IIydryllin and eplnephrine given at home. Admission status: Asthmatic breathing, well hydrated. Rectal aminophylline given. Vomiting, restlessness, hematemesis. Subsided with hydration and sedation.
2.7
NH4C1
Received H y d r y l l i n for asthma. Albuminuria and vomiting appeared. Admission status: Abdominal distention and pedal edema. B P 90/60. Received aminophylline suppository and fluids. Restlessnes% emesis continued 24 hr.
q4hx18 21 Rectal q4h•
Love 5
Case 5
White Case I
23 me. 10.6 kg.
(90) Star Oral
None
I n 12 hr. projectile vomiting, weak, restless ; apprehensive; rapid and shallow respirations, hyperactive reflexes, cleared in 36 hr.
White Case 2
18 mo. 6.8 kg.
36 Stat Rectal
Phenobarbital
Asthmatic bronchitis, restless, excited. Not responsive to sodium Luminal I.M. Adm~ssmn status: hyperactive, pupils dilated. Given more sedation and cleared within 10 hr.
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THE JOURNAL OF PEDIATRICS TABLE I--CoNT 'D AlbINO= PHYLLINE
(~e./~e.) * REFER= ENCE White Case 3
AGE SCtIEDULE WEI~tIT ROUTE OTHERDRUGS 6 yr. 23 None 21.5 kg. q 3 h x 8 Rectal
White Case
7too. 8 kg.
? q 4 h x 6 Rectal
CLINICAL COURSES Bronchitis treated with aminophyllinc. Admission status: acutely ill, hyperactive, grimacing, irrational, involuntary spasm of hands, vomiting, febrile; later hallucinations, generalized convulsions, diarrhea. Lumbar puncture normal.
Epinephrine
Dyspnea, wheezing, fever, vomiting, and hematemesis before admission. Admission status: acutely ill, dehydrated, hyperactivity, restlessness. More aminophylline given. Ankle e]onus generalized tonie-clonie convulsions, hematemesis, melena, al] cleared in 5 days.
decreases cerebral blood flow, and hence causes cerebral a n o x i a J Petechial h e m o r r h a g e s in the brain and other o r g a n s f o u n d at a u t o p s y in G a r d n e r ' s ease m a y be explained on the basis of anoxia. Thirteen instances of " r e s t l e s s n e s s " were recorded in these t w e n t y children with aminophylline intoxication. Nou r were described as excited, one other as irritable, one as emotionally upset, and two as " a p p r e h e n s i v e . " One developed m u s c u l a r twitehings but no convulsions, a n d five experienced generalized convulsions. There was one instance of fatal d i a p h r a g m a t i c paralysis, a n d one ease w i t h facial paralysis. Our Case 3 showed e x t r e m e disorientation and grossly a b n o r m a l behavior, to the extent t h a t the admission diagnosis was toxic psychosis. Three of R o u n d ' s p a t i e n t s had E E G t r a c i n g s ; all these showed " s l o w waves consistent w i t h cerebral edema. ' ' V o m i t i n g o c c u r r e d in fifteen of the t w e n t y instances of aminophylline int o x i c a t i o n described. Of these, eight developed hematemesis. M a s s i v e h e m o r r h a g e o c c u r r e d t e r m i n a l l y in
two of the above. Age incidence prevents a n y estimate of nausea, w i t h o u t vomiting. The presence of a s t h m a m a k e s the incidence of v o m i t i n g difficult to evaluate in these patients, since viscid mucus is f r e q u e n t l y present in a s t h m a t i c patients. The mechanism of p r o d u c t i o n of v o m i t i n g b y theophylline is not clear, although m o s t observers feel t h a t it is directly i r r i t a t i n g to the gastric mucosa. H o w e v e r , v o m i t i n g m a y be seen in association with rectal or i n t r a v e n o u s as well as oral aminophylline t h e r a p y . Careful studies have shown t h a t there is no associated h y p e r a c i d i t y following its administration. T h e f r e q u e n t association of nausea and v o m i t i n g in adults with a sudden d r o p in a r t e r i a l blood pressure d u r i n g i n t r a v e n o u s aminophylline t h e r a p y suggests either t h a t a m e d u l l a r y stimulation is responsible for both phen o m e n a or t h a t nausea and v o m i t i n g m a y be the result of a mild state of shock. The m e c h a n i s m of the hematemesis is not clear; some h e m o r r h a g e is k n o w n to occur on the basis of direct g a s t r i c i r r i t a t i o n and anoxia. P e r h a p s these factors can also ex-
WHITE
AND DAESCHNER:
AMINOPHYLLINE
in the d e v e l o p m e n t aminophylline.
plain the more extensive h e m o r r h a g e s in the severe cases. Differing opinions are f o u n d r e g a r d i n g the effect of m e t h y l a t e d x a n t h i n e s on the clotting mechanism. 1 Venous thrombosis due to h y p e r p r o t h r o m b i n e m i a h a s been a t t r i b u t e d to a m i n o p h y l l i n e ; coagulation time has been f o u n d in other cases to be i n c r e a s e d as long as five minutes. 1 (Gardner, quoting Scherf and S e h l a c h m a n e ' s article).
Toxicology.--Except
i n o n e instance, those p a t i e n t s classed as "sev e r e " or " m o d e r a t e l y s e v e r e " and who survived received aminophylline at f r e q u e n t i n t e r v a l s rectally or in a single large i n t r a m u s c u l a r or intravenous dose. i n G a r d n e r ' s f a t a l case, the aminophylline ingested was app r o x i m a t e l y 83 rag. per k i l o g r a m
2 5 0 Mg. AMINOPHYLLINE INTRAVENOUSLY
M--M
250Mg.
AMINOPHYLLINE INTRAMUSCULAR
R " 5 0 0 Mg. AMINOPHYLL1NE RECTALLY
C---C
2 0 0 Mg. AMINOPHYLLINE ORALLY (ENTERIC COATED)
0.--'0
200Mg.
500 V'"
500
269
of t o x i c i t y to
V....... V R 600
POISONING
AMINOPHYLLINE ORALLY(UNCOATED)
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Fig'. 1 . - - T h e o p i l y l l i n e blood l e v e l s in a d u l t s u b j e c t s following" t h e a d m i n i s t r a t i o n of a m i n o p h y l line b y v a r i o u s r o u t e s . ( P r e p a r e d f r o m d a t a of W a x i e r a n d SchaekS.)
Bleeding a n d d o t t i n g times were perf o r m e d in our Case 4 a n d were norreal. Seven p a t i e n t s in the r e p o r t e d group (Table I) showed albuminuria, but this was transient, a n d unassoeiated with other evidence of renal damage. P e d a l edema w a s noted in one p a t i e n t associated w i t h albuminuria. This cleared spontaneously. Several p a t i e n t s h a d a urine of high specific g r a v i t y s u g g e s t i n g hydropenia. This m a y h a v e been a f a c t o r
along w i t h ephedrine 17 rag. per kilogram. A n o t h e r f a t a l case received a single rectal dose of 21 rag. p e r kilogram. N e i t h e r the dosage, the number of doses, n o r the route of administration can be c o r r e l a t e d with severity. Careful studies of the absorption and excretion of aminophylline have been carried out b y W a x l e r and Sehack. 8 T h e y studied individually the theophylline blood levels obtained
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THE JOUI~NAL OF PEDIATRICS
iu adults following the administration of single doses of aminophylline (Fig. 1). Oral, rectal, intravenous, and intramuscular routes were used. AIthough the weight of the subjects is not given by the authors, they do state that all were adults. If we assume an average subject weight of 70 kilograms then the dose used in their studies ranged from 3 to 7 rag. per kilogram of body weight. This dosage level produced a significant blood level (more than 100 t~g per cent) in all subjects studied. In patients receiving the intramuscular or intravenous route of medication peak levels occurred almost immediately and persisted for seven to eight hours, while oral medication showed an absorption peak at one hour for uncoated tablets and five hours for the coated tablets with significant levels persisting for eight to ten hours. Rectal administration was variable and usually delayed one to two hours with a peak at three to five hours and significant levels still present nine hours later. F o r details of the range of values obtained, the reader is referred to Waxler and Schack's original publication. 8 Study of the data in Fig. 1 reveals that no matter which route of medication was chosen, significant blood theophylline levels were still present seven to eight hours later. This implies that blood levels of theophylline are accumulative when the dosage is high or the interval of administration is frequent. The standard pediatric texts list no oral or rectal aminophylline dosage. One suggests an intravenous dose for a 10- to 12-year-old boy of 0.25 Gm. every eight to twelve hours. This is approximately 7 rag. per kilogram of
body weight. The usual adult dose is 0.5 Gin. or 7 rag. per kilogram. The frequeney of dosage is not suggested in either of two medical texts consulted. Chronie toxicity studies 9 in rabbits using 7 rag. per kilogram of body weight intravenously daily for thirty consecutive days showed no demonstrable pathology in the organs of the sacrificed animals. However, when fourteen times this dose daily (]00 rag. per kilogram of body weight, or two-thirds of the LDso for rabbits) was given for t hi rt y consecutive days to rabbits, and the animals then sacririced, there was microscopic evidence of low-grade renal and meningeal irritation. (The drug was not found to be concentrated in any particular organ of sacrificed animals one hour following its intravenous administration. It was not demonstrated in the erythroeytes, and its concentration ia the plasma was of the same order as that of the parenehymal organs.) Since ephedrine is so frequently used in eonjunetion with aminophylline, it is felt that the potentiation of aminophylline toxicity by ephedrine should be re-emphasized. Gardner and associates 1 showed that in white rats there is a fourfold increase in the toxicity of ephedrine by the inclusion of a small dose of aminophylline, and a doubling of the toxicity of aminophylline by the administration of a relatively small dose of ephedrine. Phenobarbital decreases the excitatory effects of both ephedrine and aminophy]line. Although there are reports suggesting death from an anaphylactoid type of reaction from aminophylline, 1~ details available on these cases are scanty. In all the cases ade-
WHITE AND DAESCHNER:
quately described the toxic symptoms seem clearly related to an excessive dose of aminophylline. SU1VIMAI~Y
Aminophylline (theophylline i n ethylenediamine) poisoning in children was first reported in 1950. Subsequent authors have reported sixteen other instances of acute aminophylline intoxication and the present authors describe four additional cases. In this group of twenty reported cases of aminophylline intoxication there are four deaths, while ten additional children who recovered were described initially as severely ill. The widespread use of aminophylline in the management of respiratory disease in infants and children suggests that the over-all incidence of acute intoxication is not great. Nevertheless, our experience and the experience of others lead us to believe that the possibility of intoxication should be considered whenever the instituted treatment is followed by excitation, irritability, vomiting, muscle twitching, and pallor. If these early signs remain unrecognized, the patient may go on to hematemesis, convulsions, cyanosis, shock, and death. A suggested dosage that appears to be both effective and safe is 3.5 rag. per kilogram for intramuscular or intravenous therapy, 5.0 rag. per kilogram for oral therapy, and 7.0 rag. per kilogram when given a rectal suppository. Studies of blood theophylline levels following single oral doses
A]~[INOPHYLLINE POISONING
271
indicate that to prevent an accumulative effect, the frequency of dosage should not exceed every six hours and preferably be given only at seven- to elght-hour intervals. Treatment consists principally of sedation and hydration, with other supportive symptomatic therapy given as indicated by the patient's condition. REFEREN CES 1. Gardne 5 R. A , tIansen, A. E., Ewing, P. L., and Emerson, G . A . : Unexpected F a t a l i t y in a Child From Accidental Consumption of A n t i a s t h m a t l c Preparat i o n C o n t a i n i n g Ephedrine, Theophylline, a n d P h e n o b a r b i t a l , Texas IV[. J. 46: 516, 1950. 2. Pioppi, N . W . : A L e t t e r to the Editor, 5. A. 1~[. A. 154: 543, 1954. 3. Frazler, C . A . : A L e t t e r to the Editor, J. A. M. A. 155: 222, 1954. 4. Rounds, V. J . : Aminophylline Poisoning, P e d i a t r i c s 14: 528, 1954. 5. Love, F. M., and Corrado, A. G.: Aminophylline Overdosage in Children-Report of F o u r Cases W i t h Toxic Symptoms, Am. J. Dis. Child. 89: 468, ]955. 6. Goodman, L., and Gilman, A.: The Pharmacological Basis of Therapeutics, New York, 1955, The ~ [ a e m i l l a n Co., p. 340. 7. Wechsler, R. L., Klein, L. M., and Kety, S.S.: The Effects of I n t r a v e n o u s l y A d m i n i s t e r e d Aminophylline on Cereb r a l Circulation a n d l~[etabolism in 1Y[an, J-. Clin. Invest. 29: 28, ]950. 8. Waxler, S. H., and Schaek, J . A . : Adm i n i s t r a t i o n of Aminophylline, 5. A. M. A. 143: 736, 1950. 9. Luduena, F. P.: Bronchial Antispasmodic Actions of Theophylline Derivatives, I n c l u d i n g Effects of Continued A d m i n i s t r a t i o n , J. Pharmacol. & Exper. Therap. 75: 316, 1942. 10. Merrill, G. A.: Aminophylline Deaths, J. A. ~r A. 123: 1115, 1943. 11. Bresnick, E., Woodward, W. K., and Sageman, C . B . : F a t a l Reactions to the I n t r a v e n o u s A d m i n i s t r a t i o n of Aminophylline, J. A. M. A. 136: 397, 1948. 12. Lueas, G. It.: The Symptoms and T r e a t m e n t of Acute Poisoning, New York, 1953, The Macmillan Co., p. 256.
M.D.,
AND C . W M .
D A E S C H N E R , ~r
I~OUSTON, T E X A S
due to the oral or recp talOISONING administration of theophyllinc in ethylenediamine (aminophylline) has been infrequently reported since the drug first came into general use about 1936. Death associated with the enteral use of aminophylline was first reported by Gardner and associates 1 in 1950. They described the ease of a 2-year-old female who ingested no more than 1.0 Gin. of theophylline, 0.2 Gin. of ephedrine, and 0.065 Gin. of phenobarbital. Within one hour the child was noted to be restless and hyperactive. In spite of cathartics, lavage, and general supportive therapy, the patient subsequently developed convulsions, eyanosis, and severe hematemesis. She died thirteen hours later in severe shock. Death was attributed to the toxic effects of theophylline potentiated by ephedrine. Three years later, Pioppi, 2 unaware of Gardner's report, described the death of a 2-year-old child with asthma and bronchitis, following the rectal administration of aminophylline. The author felt that aminophylline had contributed to the patient's death in spite of an autopsy report showing " a fulminating virus infection of the lungs." Pioppi also described one case of sublethal toxicity in a 31~-year-old asthmatic boy F r o m t h e D e p a r t m e n t of Pediatrics, Baylor U n i v e r s i t y College of Medicine, the T e x a s Children's Hospital, a n d the Pediatric Service of the Jefferson D a v i s Hospital. 262
who received one aminophylline suppository (Aminet). Frazier 3 w a s stimulated by Pioppi's reports to describe a third fatal case. A baby of unstated age was given aminophylline rectal suppositories at intervals of several hours. The author emphasized that hematemesis might result from aminophylline intoxication, and attributed the patient's death to this cause. Two recent articles describe sublethal aminophylline toxicity in children. Rounds 4 in 195.4 reported his experience with six cases of aminophylline toxicity in children. Two of his patients received the drug intravenously, one of these with a fatal outcome, the other developed severe toxicity but survived. Four others developed severe sublethal toxicity following enterally administered aminophylline. In 1955 Love and Corrado ~ reported five instances of nonfatal aminophylline toxicity in four children. In these authors' experience the toxic dose was usually in excess of the recommended therapeutic dose. The present report describes four additional patients, showing varying' degrees of intoxication associated with oral or rectal aminophylline therapy, and summarizes the published eases of aminophylline intoxication in childhood.
WHITE AND DAESCHNER: CASE REPORTS CASE ] . ~ A 23-month-old N e g r o male was admitted to the hospital twenty-four hours following the accidental ingestion of an unknown number of aminophylline tablets (300 n ag . tablets). Twelve hours prior to admission the patient developed repeated projectile vomiting. He was awake most of the night with intermittent vomiting of clear gastric contents. I n between episodes of vomiting he was described as being weak and extremely restless. The patient was hospitalized when physical examination revealed an apprehensive and hyperactive child. The vital signs were: temperature 99.2 ~ F. (rectal), pulse 120, respirations 48, and shallow, and blood pressure 114/80. The reflexes were somewhat hyperactive, but equal bilaterally. The rest of the physical examination was within normal limits. Laboratory studies revealed hemoglobin 7.5 grams per cent, red blood cells 2.92 million, white blood cells 31,700 with 93 per cent segmentals, 6 per cent lymphocytes, and 1 per cent monocytes. CO2 content was 12.5 meq. per liter, C1 90 meq. per liter, BUN 16 rag. per cent. Urinalysis revealed a specific gravity of 1.020, 3 plus acetone, and 2 grams per liter of chloride (Fantus test). Chest roentgenograms were negative. In the hospital the patient continued to vomit all oral fluids for the first five to six hours. He was given 15 mg. of phenobarbital and 4 c.c. of aluminum hydroxide gel every six hours. The hyperactivity present on admission gradually disappeared over a twelve-hour period, and by the end of the first hospital day he was able to tolerate a soft diet. His subsequent course was uneventful.
CASE 2 . ~ A n 18-month-old white male with asthmatic bronchitis and otitis media was seen by a private physician seven and one-half hours prior to admission to the hospital. The patient had been given parenteral penicillin in oil and started on aminophylline by r e c t a 1 suppository.
AiVII,NOPHYLLINE POISONING
263
Shortly after the first suppository the patient became restless and extremely excited. A sedative failed to bring about evidence of improvement and the child was admitted to the hospital. Physical examination revealed an extremely active and restless child, weighing 6.8 kilograms. The pupils were widely dilated and there was minimal injection of the right tympanic membrane. The chest was clear. There were areas of atopic eczema over the legs. The patient responded to intermittent sedation and was asymptomatic within twelve hours. CASE 3.---A 6-year-old Negro female was brought to the emergency room by her mother with the chief complaints of: (1) hallucinations and (2) the sudden onset Of "spasms in her hands." The mother described the patient as talking " o u t of her head, " in a repetitious manner, of babies and waterfalls, speaking to persons not present, and being oblivious of the presence of her family. The disturbed sensorium appeared three hours prior to hospital admission and was associated with marked physical hyperactivity, including involuntary extension of fingers and toes. F u r t h e r history revealed t hat the child had developed an acute upper respiratory infection with bronchitis three days prior to admission. One day prior to admission she received penicillin by injection and the mother was given a prescription for aminophy]line suppositories. (Later it was learned that by mistake the patient had been given a total of eight 500 mg. aminophylline rectal suppositories, or a total of 4.0 Gin. of aminophylline in a twenty-four-hour period). On this treatment the respiratory symptoms improved rapidly, but shortly after administration of the first aminophylline suppository, the patient developed anorexia, nausea, and vomiting. This vomitus was scanty, dark, unrelated to feedings, and recurred at about thirty-minute intervals until the time of admission. The patient was admitted with a tentative diag-
264
T H E J O U R N A L OF PEDIATRICS
nosis of " t o x i c e n c e p h a l o p a t h y . " Physical examination on admission revealed a completely uncooperative, acutely ill, wide-eyed, grimacing, hyperactive, irrational child. She babbled c o n s t a n t l y in an incoherent manher and was continuously in physical motion to the extent t h a t restraints were necessary for the patient's proteetion. The skin was w a r m and dry. The initial signs were : blood pressure 100/60, t e m p e r a t u r e 106 ~ F. (R), pulse 22, respiration 28. E x t r a o c u l a r movements were normal (fundus examination was unsatisfactory). The n a s o p h a r y n g e a l mueosa was injected. There were scattered rhonchi and rgles over both lung fields, with prolonged expiration. The abdomen was negative. The fingers of both hands were i n t e r m i t t e n t l y extended and flexed in a somewhat athetoid manner. P a t e l l a r reflexes were absent bilaterally, other deep tendon reflexes were within physiological limits, and no pathological reflexes were elicited. Response to painful stimuli was depressed. L a b o r a t o r y studies revealed: hemoglobin 14.5 grams per cent, red blood cells 6.73 million, white blood cells 20,550 with 75 per cent polymorphonuclears, 22 per cent lymphoeytes, 1 per cent eosinophils, and 2 per cent monocytes. Urinalysis was negative. Cerebrospinal fluid examination revealed an initial pressure of 130 ram. of water, 2 cells per cubic millimeter, protein 37.0 mg. per cent, chlorides 120 meq. per liter. I n the hospital, phenobarbital sedation was a t t e m p t e d but was only partially effective. I n t r a m u s c u l a r penicillin and i n t r a v e n o u s l y administered fluids were begun shortly a f t e r admission. Six and one-half hours later the patient h a d a few w a t e r y stools. Shortly t h e r e a f t e r exacerbation of her hallucinations and shouting occurred, and she experienced a generalized convulsion lasting about five minutes. This was controlled b y increased b a r b i t u r a t e sedation. No other seizures occurred. The initially elevated t e m p e r a t u r e fell to normal
in f o u r t e e n hours. H e r sensorimn g r a d u a l l y cleared over the next thirty-six to forty-eight hours. She t o l e r a t e d a soft diet on the second hospital day. A second lmnbar puneture done on the f o u r t h hospital day was normal. She was discharged a s y m p t o m a t i e on the fifth hospital day. CASE 4.--This was a 7-month-old white male who was admitted to the hospital a f t e r three days of illness consisting of dyspnea, audible wheezing, and low-grade fever. These progressed ig the face of penicillin injections and the administration of cough mixture. Aminophylline suppositories of u n k n o w n size were begun on an e v e r y four-hour schedule, t w e n t y - f o u r hours p r i o r to admission. The patient began vomiting almost immediately a f t e r the first aminophylline suppository, and twelve hours before admission t h e vomitus contained b r o w n flecks. I n the hospital, examination revealed the i n f a n t to be acutely ill, mildly dehydrated, hyperactive, and restless. Vital signs were: temperature 106 ~ F.; pulse 180; and respiration. 60. Evidences of an u p p e r respiratory infection were present. The chest findings were compatible with an obstructive emphysema. Seatt e r e d r~les and musical wheezes were present throughout, as well as a markedly prolonged expiratory phase. Neur01ogieal examination was negative. L a b o r a t o r y studies of peripheral blood and urine were normal. A l u m b a r p u n c t u r e was negative except for an initial pressure of 300 ram. of water. Bleeding and clotting times and platelet counts were normal. Chest roentgenograms revealed moderate generalized emphysema. A diagnosis of asthmatic bronchitis was made and at this point the possibility of aminophylline intoxication was not entertained. The patient was put in humidified oxygen, and penicillin injections were continued. Aminophylline 60 rag. was administered reetally and an intravenous
WHITE
AND DAESCttNER:
infusion of aminophylline in 5 per cent glucose was begun. Watery greenish-black streaked stools which were 2 plus positive by benzidine test were noted shortly a f t e r admission. The t e m p e r a t u r e remained eIevated at 103 ~ to 104 ~ F. in spite of cool sponging. E i g h t e e n hours a f t e r admission the patient was " j u m p y " and restless and bilateral ankle elonus was present. I n t r a v e n o u s sodium Luminal 15 mg. was given with little benefit. I n t e r m i t t e n t vomitus of "coffeeg r o u n d " material continued. A t this point .the possibility of amiuophyIline intoxication in this patient was considered and the d r u g was discontinued. I n spite of this the patient did n o t . improve immediately and six hours later he experienced a generalized tonic-clonie convulsion w i t h cyanosis. This seizure continued until intravenous sodium Luminal 15 rag. was given. A t this time 50 e.e. of w a t e r y " c o f f e e - g r o u n d " material was aspirated from the stomach in an effort to relieve m o d e r a t e abdominal distention and to aid respiration, His general condition i m p r o v e d steadily, but he continued to have minimal vomiting and passed t a r r y stools for three days. The hemoglobin level, however, remained normal. CLINICAL FINDINGS AND COMMENT
Table I summarizes the cases of aminophylline intoxication from the literature plus the four cases herein reported. The ages of the patients included r a n g e f r o m 7 months to 6 years, with a mean age of 23 months. In the nineteen eases where sex is recorded, fifteen were males and four females. Ingestion was accidental in two instances, and its administration was directed by a physician in eighteen instances. Of the twenty instances of aminophylline poisoning in eighteen patients, four were fatal, seven were classified as severe, three were m o d e r a t e l y severe, three were
AMINOPHYLLINE
POISONING
265
moderate, and three mild. The dose in two fatal cases is unknown. Certainly m a n y factors influenced the final effects: individual susceptibility to the drug, v a r i a t i o n in absorption, route of administration, and the degree of incapacity caused by the original illness u n d e r treatment. The latter f a c t o r is k n o w n to be significant in infantile salicylate intoxication since it occurs almost invariably in the sick child. I n the fatal cases, one child ingested the material orally, one received the d r u g by vein, and two b y rectal suppositories. In the cases classed as severe, four patients received the d r u g b y rectum, one intramuscularly, and two both int,avenously and rectally. The presence of an u n d e r l y i n g disease, generally a r e s p i r a t o r y infection, makes it difficult to appraise the over-all effects of the drug, particularly as it effects rate and character of respirations. These were described as difficult or labored in ten instances, rapid in four, slow and deep in one, deep and pauseless in one, and shallow in one. Pulse was recorded in too few cases to make any evaluation w o r t h while. T e m p e r a t u r e s above normal were r e c o r d e d in only six cases. It is notable t h a t of the patients with severe h y p e r t h e r m i a , all three were critical and showed evidence of m a r k e d dehydration. A common f e a t u r e in all cases was some sign of central nervous system irritability. The xanthines are k n o w n to be directly stimulating to the brain cells, p a r t i c u l a r l y those of the cereb r u m and the m e d u l l a r y centers2 Some degree of cerebral anoxia was u n d o u b t e d l y present in m a n y of the children in acute attacks of asthma. It has been shown t h a t theophylline
266
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OF T H E CLINICAL I~INDINGS IN T W E N T Y AIv[INOPIIYLLINE INTOXICATION
CASES OF
AlVflNOPHYLLINE
(~G./KG.) * AGE SCHEDULE ENCE W E I G H T I~0UTE OTHERDRUGS Gardner1 2 yr. 83 Ephedrine l2 kg. Stat Phenobarbital Oral REFER-
GLINICAL COURSES One hour after accidental ingestion, patient became emotionally upset. Heart rate normal. Dilated pupils; in 8 hr. muscular twitchlngs, hematemesis, seizures, cyanosis, shock, and death.
Pioppi2 Case 1
31/2 yr. 15 kg.
(17) Rectal Star
Nembutal Benzocaine
Within 30 mln. developed pallor, limpness, and tachycardia; responded in 3 hr. to oxygen and supportive therapy. Had appeared terminal. Dx: Asthma and bronchitis.
Pioppie Case 2
2 yr. 12 kg.
(21) Stat Rectal
Nembutal Benzocaine
Within 3 hr.: pallor, limpness, and vomiting. Wheezing cleared but patient died in spite of supportive therapy. Author felt aminophylline intoxication contributed to death. Autopsy: Fulminating pneumonitis.
Fraziera
Baby ?
? ? Rectal
None
Developed acute vomiting progressing to hematemesis and death. Suggested a f t e r autopsy that death due to aminophylline intoxication.
Rounds~ Case1
18mo. (11kg.)
None
Bronchiolitis one day. Treatment given and patient immediately apneic and cyanotic. On admission critical, cyanotic, restless, albuminurla. Died 8 hr. after admission.
Rounds4 Case2
16 mo. 10kg.
25 q 24 h • 3 Rectal
None
Dyspnea 5 days. Aminophylline administratiou 48 hr. prior to admission--irritable with rapid respiration, vomiting. Physical revealed dehydration, restlessness, and excitement. Recovered rapidly a f t e r sedation and supportive therapy.
Rounds4 Case 3
18 mo. 11 kg.
? Star and q 2h x 2 I.V.
0.1 mg. epinephrine
Wheezing all day; after therapy developed vomiting, hematemesis. Severe dehydration on admission. No respiratory distress. 14 hr. later received an aminophylline suppository followed by generalized convulsion and eyanosis, responded to sedation. EEG: Slow waves consistent with cerebral edema. Recovery slow.
Rouuds4 Case4
3 yr. 14kg.
18 q 8 h x 4 Rectal
None
Wheezing 3 days. A f t e r aminophylline, vomiting became projectile and b]oody. On admission: critical, restless, dehydrated, staring, no response to painful stimuli, respirations slow and deep, few rhonchi, albuminuria. Improved in 5 hr. with supportive therapy, recovered in 29 hr.
7 Star I.V. Rectal
None
Stat I.V.
Asthma not relieved by Adrenalin so aminophylline given, became restless and vomited. On admission: acutely ill, dehydrated, respirations labored, expiratory wheeze~ albuminuria, hyperthermia, and hematamesis, but recovered in 24 hr. EEG: Slow waves consistent with cerebral edema, negative 3 days later. *Values in parenthesis are data estimated from authors' summary.
Rounds4 Case5
3 yr. 14kg.
WHITE AND DAESCHNER:
AMINOPHYLLINE POISONING
267
TABLE I--CONT 'D
AMINOREFERENCE Rounds4 Case 6
PIIYLLINE (~ G./~. ) SCHEDULE
AGE WEIGHT ROUTE 11 too. (~8) 9 kg. Star
OTHER DBUOS None
CLINICAL COURSES TWO days bronchitis, t r e a t e d w i t h aminophylline. Immediately restless, shrill cry, muscle twitching, facial weakness. On admission: rest]es% nausea, cyanotic periods, facial paralysis, afebrile, albuminuria. Generalized convulsions at 12 and 16 hr. a f t e r medication. E E G : Slow waves consistent with cerebral edema. Recovery complete.
I.M.
Case I
15 too. 10 kg.
5O Phenobarbital q4h• None 25-I.V. Star
Severe asthma, given oxygen, phenobarbital, and aminophylline. Restless immediately. Vomiting second day; third day hematemesis, apathy, marked restlessness, muscle twitehings, dehydration. Improved 3 hr. a f t e r aminophylline stopped, f u l l y recovered 3 days later.
Love5 Case 1
]6 mo. 10 kg.
25 q4h• Rectal
Epinephrine 1:100 Phenobarbital
One month later: recurrence of asth~na. Treatment with rectal aminophylline follov~ed by restlessness, repeated vomiting, lethargy and muscular twitcbing. Improved 5 hr. a f t e r stopping aminophylline.
Love 5
21~ yr. 13 kg.
19
Phenobarbital
Asthma. Admitted with vomiting, dyspnea, and dehydration following aminophylline. Frequent vomiting and restlessness altern a t i n g with stupor. P~espiratlons deep and pauseless. Aminophylliae discontinued, fluids given, patient greatly improved in 4 hr.
Love 5
Case 2
q6h•
Rectal
Love 5
Case 3
Love 5
Case 4
19 mo. 11 kg.
22 q8hx2 Rectal
Phenobarbital Benzocaine
Asthma 14 hr. Alert, apprehensive, wheezing, before medication with rectal aminophylline. On admission: vomiting and melena, wakeful but not restless, albuminuria. Symptoms subsided spontaneously.
2 yr, 12 kg.
2.6 Oral
Epinephrine Phenobarbital Benzocaine
Wheezing s 3 days. IIydryllin and eplnephrine given at home. Admission status: Asthmatic breathing, well hydrated. Rectal aminophylline given. Vomiting, restlessness, hematemesis. Subsided with hydration and sedation.
2.7
NH4C1
Received H y d r y l l i n for asthma. Albuminuria and vomiting appeared. Admission status: Abdominal distention and pedal edema. B P 90/60. Received aminophylline suppository and fluids. Restlessnes% emesis continued 24 hr.
q4hx18 21 Rectal q4h•
Love 5
Case 5
White Case I
23 me. 10.6 kg.
(90) Star Oral
None
I n 12 hr. projectile vomiting, weak, restless ; apprehensive; rapid and shallow respirations, hyperactive reflexes, cleared in 36 hr.
White Case 2
18 mo. 6.8 kg.
36 Stat Rectal
Phenobarbital
Asthmatic bronchitis, restless, excited. Not responsive to sodium Luminal I.M. Adm~ssmn status: hyperactive, pupils dilated. Given more sedation and cleared within 10 hr.
268
THE JOURNAL OF PEDIATRICS TABLE I--CoNT 'D AlbINO= PHYLLINE
(~e./~e.) * REFER= ENCE White Case 3
AGE SCtIEDULE WEI~tIT ROUTE OTHERDRUGS 6 yr. 23 None 21.5 kg. q 3 h x 8 Rectal
White Case
7too. 8 kg.
? q 4 h x 6 Rectal
CLINICAL COURSES Bronchitis treated with aminophyllinc. Admission status: acutely ill, hyperactive, grimacing, irrational, involuntary spasm of hands, vomiting, febrile; later hallucinations, generalized convulsions, diarrhea. Lumbar puncture normal.
Epinephrine
Dyspnea, wheezing, fever, vomiting, and hematemesis before admission. Admission status: acutely ill, dehydrated, hyperactivity, restlessness. More aminophylline given. Ankle e]onus generalized tonie-clonie convulsions, hematemesis, melena, al] cleared in 5 days.
decreases cerebral blood flow, and hence causes cerebral a n o x i a J Petechial h e m o r r h a g e s in the brain and other o r g a n s f o u n d at a u t o p s y in G a r d n e r ' s ease m a y be explained on the basis of anoxia. Thirteen instances of " r e s t l e s s n e s s " were recorded in these t w e n t y children with aminophylline intoxication. Nou r were described as excited, one other as irritable, one as emotionally upset, and two as " a p p r e h e n s i v e . " One developed m u s c u l a r twitehings but no convulsions, a n d five experienced generalized convulsions. There was one instance of fatal d i a p h r a g m a t i c paralysis, a n d one ease w i t h facial paralysis. Our Case 3 showed e x t r e m e disorientation and grossly a b n o r m a l behavior, to the extent t h a t the admission diagnosis was toxic psychosis. Three of R o u n d ' s p a t i e n t s had E E G t r a c i n g s ; all these showed " s l o w waves consistent w i t h cerebral edema. ' ' V o m i t i n g o c c u r r e d in fifteen of the t w e n t y instances of aminophylline int o x i c a t i o n described. Of these, eight developed hematemesis. M a s s i v e h e m o r r h a g e o c c u r r e d t e r m i n a l l y in
two of the above. Age incidence prevents a n y estimate of nausea, w i t h o u t vomiting. The presence of a s t h m a m a k e s the incidence of v o m i t i n g difficult to evaluate in these patients, since viscid mucus is f r e q u e n t l y present in a s t h m a t i c patients. The mechanism of p r o d u c t i o n of v o m i t i n g b y theophylline is not clear, although m o s t observers feel t h a t it is directly i r r i t a t i n g to the gastric mucosa. H o w e v e r , v o m i t i n g m a y be seen in association with rectal or i n t r a v e n o u s as well as oral aminophylline t h e r a p y . Careful studies have shown t h a t there is no associated h y p e r a c i d i t y following its administration. T h e f r e q u e n t association of nausea and v o m i t i n g in adults with a sudden d r o p in a r t e r i a l blood pressure d u r i n g i n t r a v e n o u s aminophylline t h e r a p y suggests either t h a t a m e d u l l a r y stimulation is responsible for both phen o m e n a or t h a t nausea and v o m i t i n g m a y be the result of a mild state of shock. The m e c h a n i s m of the hematemesis is not clear; some h e m o r r h a g e is k n o w n to occur on the basis of direct g a s t r i c i r r i t a t i o n and anoxia. P e r h a p s these factors can also ex-
WHITE
AND DAESCHNER:
AMINOPHYLLINE
in the d e v e l o p m e n t aminophylline.
plain the more extensive h e m o r r h a g e s in the severe cases. Differing opinions are f o u n d r e g a r d i n g the effect of m e t h y l a t e d x a n t h i n e s on the clotting mechanism. 1 Venous thrombosis due to h y p e r p r o t h r o m b i n e m i a h a s been a t t r i b u t e d to a m i n o p h y l l i n e ; coagulation time has been f o u n d in other cases to be i n c r e a s e d as long as five minutes. 1 (Gardner, quoting Scherf and S e h l a c h m a n e ' s article).
Toxicology.--Except
i n o n e instance, those p a t i e n t s classed as "sev e r e " or " m o d e r a t e l y s e v e r e " and who survived received aminophylline at f r e q u e n t i n t e r v a l s rectally or in a single large i n t r a m u s c u l a r or intravenous dose. i n G a r d n e r ' s f a t a l case, the aminophylline ingested was app r o x i m a t e l y 83 rag. per k i l o g r a m
2 5 0 Mg. AMINOPHYLLINE INTRAVENOUSLY
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250Mg.
AMINOPHYLLINE INTRAMUSCULAR
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200Mg.
500 V'"
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269
of t o x i c i t y to
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POISONING
AMINOPHYLLINE ORALLY(UNCOATED)
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Fig'. 1 . - - T h e o p i l y l l i n e blood l e v e l s in a d u l t s u b j e c t s following" t h e a d m i n i s t r a t i o n of a m i n o p h y l line b y v a r i o u s r o u t e s . ( P r e p a r e d f r o m d a t a of W a x i e r a n d SchaekS.)
Bleeding a n d d o t t i n g times were perf o r m e d in our Case 4 a n d were norreal. Seven p a t i e n t s in the r e p o r t e d group (Table I) showed albuminuria, but this was transient, a n d unassoeiated with other evidence of renal damage. P e d a l edema w a s noted in one p a t i e n t associated w i t h albuminuria. This cleared spontaneously. Several p a t i e n t s h a d a urine of high specific g r a v i t y s u g g e s t i n g hydropenia. This m a y h a v e been a f a c t o r
along w i t h ephedrine 17 rag. per kilogram. A n o t h e r f a t a l case received a single rectal dose of 21 rag. p e r kilogram. N e i t h e r the dosage, the number of doses, n o r the route of administration can be c o r r e l a t e d with severity. Careful studies of the absorption and excretion of aminophylline have been carried out b y W a x l e r and Sehack. 8 T h e y studied individually the theophylline blood levels obtained
270
THE JOUI~NAL OF PEDIATRICS
iu adults following the administration of single doses of aminophylline (Fig. 1). Oral, rectal, intravenous, and intramuscular routes were used. AIthough the weight of the subjects is not given by the authors, they do state that all were adults. If we assume an average subject weight of 70 kilograms then the dose used in their studies ranged from 3 to 7 rag. per kilogram of body weight. This dosage level produced a significant blood level (more than 100 t~g per cent) in all subjects studied. In patients receiving the intramuscular or intravenous route of medication peak levels occurred almost immediately and persisted for seven to eight hours, while oral medication showed an absorption peak at one hour for uncoated tablets and five hours for the coated tablets with significant levels persisting for eight to ten hours. Rectal administration was variable and usually delayed one to two hours with a peak at three to five hours and significant levels still present nine hours later. F o r details of the range of values obtained, the reader is referred to Waxler and Schack's original publication. 8 Study of the data in Fig. 1 reveals that no matter which route of medication was chosen, significant blood theophylline levels were still present seven to eight hours later. This implies that blood levels of theophylline are accumulative when the dosage is high or the interval of administration is frequent. The standard pediatric texts list no oral or rectal aminophylline dosage. One suggests an intravenous dose for a 10- to 12-year-old boy of 0.25 Gm. every eight to twelve hours. This is approximately 7 rag. per kilogram of
body weight. The usual adult dose is 0.5 Gin. or 7 rag. per kilogram. The frequeney of dosage is not suggested in either of two medical texts consulted. Chronie toxicity studies 9 in rabbits using 7 rag. per kilogram of body weight intravenously daily for thirty consecutive days showed no demonstrable pathology in the organs of the sacrificed animals. However, when fourteen times this dose daily (]00 rag. per kilogram of body weight, or two-thirds of the LDso for rabbits) was given for t hi rt y consecutive days to rabbits, and the animals then sacririced, there was microscopic evidence of low-grade renal and meningeal irritation. (The drug was not found to be concentrated in any particular organ of sacrificed animals one hour following its intravenous administration. It was not demonstrated in the erythroeytes, and its concentration ia the plasma was of the same order as that of the parenehymal organs.) Since ephedrine is so frequently used in eonjunetion with aminophylline, it is felt that the potentiation of aminophylline toxicity by ephedrine should be re-emphasized. Gardner and associates 1 showed that in white rats there is a fourfold increase in the toxicity of ephedrine by the inclusion of a small dose of aminophylline, and a doubling of the toxicity of aminophylline by the administration of a relatively small dose of ephedrine. Phenobarbital decreases the excitatory effects of both ephedrine and aminophy]line. Although there are reports suggesting death from an anaphylactoid type of reaction from aminophylline, 1~ details available on these cases are scanty. In all the cases ade-
WHITE AND DAESCHNER:
quately described the toxic symptoms seem clearly related to an excessive dose of aminophylline. SU1VIMAI~Y
Aminophylline (theophylline i n ethylenediamine) poisoning in children was first reported in 1950. Subsequent authors have reported sixteen other instances of acute aminophylline intoxication and the present authors describe four additional cases. In this group of twenty reported cases of aminophylline intoxication there are four deaths, while ten additional children who recovered were described initially as severely ill. The widespread use of aminophylline in the management of respiratory disease in infants and children suggests that the over-all incidence of acute intoxication is not great. Nevertheless, our experience and the experience of others lead us to believe that the possibility of intoxication should be considered whenever the instituted treatment is followed by excitation, irritability, vomiting, muscle twitching, and pallor. If these early signs remain unrecognized, the patient may go on to hematemesis, convulsions, cyanosis, shock, and death. A suggested dosage that appears to be both effective and safe is 3.5 rag. per kilogram for intramuscular or intravenous therapy, 5.0 rag. per kilogram for oral therapy, and 7.0 rag. per kilogram when given a rectal suppository. Studies of blood theophylline levels following single oral doses
A]~[INOPHYLLINE POISONING
271
indicate that to prevent an accumulative effect, the frequency of dosage should not exceed every six hours and preferably be given only at seven- to elght-hour intervals. Treatment consists principally of sedation and hydration, with other supportive symptomatic therapy given as indicated by the patient's condition. REFEREN CES 1. Gardne 5 R. A , tIansen, A. E., Ewing, P. L., and Emerson, G . A . : Unexpected F a t a l i t y in a Child From Accidental Consumption of A n t i a s t h m a t l c Preparat i o n C o n t a i n i n g Ephedrine, Theophylline, a n d P h e n o b a r b i t a l , Texas IV[. J. 46: 516, 1950. 2. Pioppi, N . W . : A L e t t e r to the Editor, 5. A. 1~[. A. 154: 543, 1954. 3. Frazler, C . A . : A L e t t e r to the Editor, J. A. M. A. 155: 222, 1954. 4. Rounds, V. J . : Aminophylline Poisoning, P e d i a t r i c s 14: 528, 1954. 5. Love, F. M., and Corrado, A. G.: Aminophylline Overdosage in Children-Report of F o u r Cases W i t h Toxic Symptoms, Am. J. Dis. Child. 89: 468, ]955. 6. Goodman, L., and Gilman, A.: The Pharmacological Basis of Therapeutics, New York, 1955, The ~ [ a e m i l l a n Co., p. 340. 7. Wechsler, R. L., Klein, L. M., and Kety, S.S.: The Effects of I n t r a v e n o u s l y A d m i n i s t e r e d Aminophylline on Cereb r a l Circulation a n d l~[etabolism in 1Y[an, J-. Clin. Invest. 29: 28, ]950. 8. Waxler, S. H., and Schaek, J . A . : Adm i n i s t r a t i o n of Aminophylline, 5. A. M. A. 143: 736, 1950. 9. Luduena, F. P.: Bronchial Antispasmodic Actions of Theophylline Derivatives, I n c l u d i n g Effects of Continued A d m i n i s t r a t i o n , J. Pharmacol. & Exper. Therap. 75: 316, 1942. 10. Merrill, G. A.: Aminophylline Deaths, J. A. ~r A. 123: 1115, 1943. 11. Bresnick, E., Woodward, W. K., and Sageman, C . B . : F a t a l Reactions to the I n t r a v e n o u s A d m i n i s t r a t i o n of Aminophylline, J. A. M. A. 136: 397, 1948. 12. Lueas, G. It.: The Symptoms and T r e a t m e n t of Acute Poisoning, New York, 1953, The Macmillan Co., p. 256.