Respiratory Arrest in Infants Secondary to Gastroesophageal Reflux

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segment of the liver can be treated by partial hepatectomy.9 The central location of the AVF and the small size of our patient precluded resection or direct repair.

Unresectable arteriovenous malformations of the CNS, pelvis, and extremities have been successfully treated by intraarterial embolization to occlude the multiple vascular channels charac-teristic of this lesion.’#{176}Attempts at embolization in our patient were unsuccessful, probably because of the aneurysmal dilatation of the

AVF.

Corticosteroids have been reported to be effec-tive in the management of hepatic hemangioen-dotheliomas in infants.” The mechanism of action is not known, but probably involves a hastening of the natural process of involution of hemangiomas. Whether steroids would have any effect on large vascular channels, as in the present case, is

unknown. In any event, the response of heman-gioendotheliomas to steroid administration, while prompt, is not immediate. A trial of steroid therapy might be considered in a child with hepatoportal AVF if symptoms were less acute.

Ligation of the arterial side of hepatoportal AVFs has been effective in several patients and appeared to be the safest approach in our

patient.’’2” Detailed arteriograms were helpful in delineating the arteries to be ligated. Since the venous side remains patent, recurrence of the fistula is a theoretical possibility.

M.

A. HELIKSON,

M.D.

D. L.

SHAPIRO,

M.D.

J.

H.

SEASHORE,

M.D.

Departments of Surgery and Pediatrics,

Yale University, School of Medicine

New Haven, Connecticut

ADDRESS FOR REPRINTS: (J.H.S.) Department of

Surgery, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06510.

REFERENCES

1. Martin LW, Benzing G, Kaplan, S: Congenital intrahep-atic arteriovenous fistula: Report of a successfully treated case. Ann Surg 161:209, 1965.

2. Sachs R: About cases ofblood vessel diseases. Dtsch Med

Wochenschr 18:443, 1892.

3. Kaude

J,

Dudgeon DL, Talbert JL: The role of selective angiography in the diagnosis and treatment of hepatoportal arteriovenous fistula. Radiology 92:1271, 1969.

4. Gryboski JD, Clemett A: Congenital hepatic artery aneurysm with superior mesenteric artery insuffi-ciency: A steal syndrome. Pediatrics 39:344, 1967.

5. VanWay CW, Crane JM, Riddell DH, Foster JH: Arteriovenous fistula in the portal circulation.

Surgery 70:876, 1971.

6. Stone HH, Jordan WD, Acker JJ, Martin JD: Portal

arteriovenous fistulas. Am

J

Surg 109:191, 1965.

7. Foley WJ, Turcotte JG, Hoskins PA, et al: Intrahepatic

arteriovenous fistulas between the hepatic artery

and portal vein. Ann Surg 174:849, 1971.

8. Fulton RL, Wolfel DA: Hepatic artery-portal vein

arteriovenous fistula: Report of a case with notes on the pathophysiology of this condition. Arch Surg

100:307, 1970.

9. Shumacher HB, Waldhausen JA: Intrahepatic arteriove-nous fistula of hepatic artery and portal vein. Surg

Gynecol Obstet 112:497, 1961.

10. Olcott C, Newton TH, Stoney RJ, Ehrenfeld WK: Intra-arterial embolization in the management of arteriovenous malformations. Surgery 79:3, 1976.

11. Rocchini AP, Rosenthal A, Issenberg HJ, Nadas AS: Hepatic hemangioendothelioma: Hemodynamic

observations and treatment. Pediatrics 57:131, 1976.

12. Madding GF, Smith WL, Hershberger LR: Hepato-portal arteriovenous fistula. JAMA 156:593, 1954.

13. Foster JH, Sandblom P: Portal hypertension secondary to an hepato-portal arteriovenous fistula. Ann Surg

14:300, 1961.

Respiratory

Arrest

in Infants

Secondary

to Gastroesophageal

Reflux

Gastroesophageal reflux is being recognized with increasing frequency in infancy and child-hood. Once thought to be rare, or of no signifi-cance, it is now commonly recognized when sought for by proper radiologic techniques in suspected individuals. Its manifestations are protean. Although in most instances it is rela-tively harmless, gastroesophageal reflux in

infan-cy may be responsible for failure to thrive, blood loss anemia resulting from peptic esophagitis, and

recurrent aspiration pneumonia, The importance of the last has been well described by several authors.

‘-In recent years, we have treated ten children less than 6 months old for episodes of respiratory

arrest which appeared to be due to gastroesopha-geal reflux (Table I). Each had repeated episodes of apnea. Clearly, recognition of gastroesophageal reflux as a possible causal mechanism is essential

if

these patients are to be properly treated and possibly fatal recurrent episodes prevented.

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TABLE I

EXPERIENCE AND REASON 925

RESPIRATOEY ARREST AND GASTROESOPHAGEAL REFLUX

Patient Age No. of 1st Previous Pneumonia Treatment Additional Comment

at Spells UGIS#{176} History at Spells

Onset Positive of

Vomiting

1st

Spell

1 4 mo 5 + No No No Gastrostomy

Fundoplication

Yes

No

Symptoms recurred 5 mo

after gastrostomy

2 1 mo 2 Yes Yes No Medical No . . .

3 1 mo 6 No Yes Yes Fundoplication No ...

4 2 wk 4 Yes No Yes Gastrostomy No ...

5 2 mo 3 Yes Yes No Fundoplication No Pierre-Robin syndrome

6 2 wk 3 Yes Yes Yes Medical Yes Subglottic stenosis

-

Fundoplication No

7

8

5 mo

2 wk

2 +

5 + Yes

Yes

No

-No

Fundoplication

.

Fundoplication

No

Esophageal atresia &

tra-cheoesophageal fistula as

newborn

. . .

9 2 mo 2 Yes No No Medical Yes On apnea monitor 10 mo

10 2 mo

-2 Yes Yes No Medical No Discovered in retrospective

review

#{176}Uppergas tromtest mal series.

CASE REPORTS

Case 1

A 6-month-old girl was first admitted for treatment of cyanotic spells and failure to thrive. At the age of 4 months, she began having episodes during which she choked, gasped, and became cyanotic and limp. Her condition improved when she was vigorously shaken and struck on the back. Roentgenographic abnormalities of the cervical spine were consistent with Klippel-Feil syndrome.

In the hospital she had several episodes of respiratory arrest that required emergency endotracheal intubation.

Prolonged intubation prevented further episodes. These

episodes were therefore thought to be due to recurrent

aspiration even though pneumonia had not developed.

Roentgenographic studies of the esophagus done on two occasions failed to reveal gastroesophageal reflux, Because her presumed “aspiration” was thought to be due to an

abnormality in swallowing, a gastrostomy was performed.

Her symptoms disappeared while the gastrostomy tube was open, and she was discharged.

Six months later, she again began to have apneic spells after feedings. Upper gastrointestinal roentgenograms at that time revealed free gastroesophageal reflux. A fundoplication was performed. She had no more symptoms during the next six years.

Case 3

A 4-week-old boy was admitted after two episodes of respiratory arrest and successful mouth-to-mouth resuscita-tion. Tachypnea and vomiting had been observed two days

before admission. The patient was cyanotic and had inter-costal retractions and bilateral rales. A chest roentgenogram revealed patchy infiltrates in all five lobes.

Numerous diagnoses were considered: congenital heart disease, cor pulmonale, viral pneumonitis, cystic fibrosis,

immunologic deficiency, chronic pulmonary disease, CNS

disorder, and aspiration pneumonia secondary to gastro-esophageal reflux.

He had four more episodes of respiratory arrest in the next five days. Each occurred after a feeding and required endotracheal intubation. The initial upper gastrointestinal roentgenogram was interpreted as normal. A repeated study, with attention specifically directed to the presence of reflux, showed active reflux into a patulous distal esophagus.

Fundoplication was performed. Pneumonia cleared, and he had no more episodes of respiratory arrest or pneumonia during the next three years.

Case 9

A male infant was admitted at the age of 8 weeks because of an episode of cardiorespiratory arrest. One week earlier, a cold had developed for which he was treated with Novahis-tine. On the day of the episode, he had been fed and placed in his bed on his abdomen. Five minutes later, his mother returned to find the baby had vomited, and he was apneic and “black.” She gave him mouth-to-mouth resuscitation and cardiac massage, and he began breathing in about one to

two minutes. He was brought to the hospital.

Barium swallow indicated gastroesophageal reflux. He was treated with 24-hour positioning in a chalasia chair and given thickened feedings. He was discharged with orders to be on a

continuous apnea monitor. Three days later he was

read-mitted because of two more episodes of respiratory arrest, the last requiring extensive stimulation to reestablish normal breathing. A chest roentgenogram taken at this time showed a right upper lobe infiltrate. Antibiotic therapy was

insti-tuted, and the infiltrate cleared during the next four days. He was then discharged and positional therapy was continued together with continuous apnea monitoring for ten months. He had no more spells, and use of both the monitor and chalasia chair was discontinued when he was 1 year old.

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TABLE II

RESPIRATORY ARREST AND GASTROESOPHAGEAL REFLUX

TREATMENT

No. Patie

of

nts

No Additional

Spells

%

Medical 4 2 50

Gastrostomy 2 1 50

Fundoplication 6 6 100

DISCUSSION

Table

I

summarizes the important clinical

features in these patients. All of the infants were less than 6 months old, seven less than 3 months

old. The

youngest was 2 weeks old at the onset of

symptoms. None was premature. All of the infants

had had

at least two episodes of respiratory arrest

before the diagnosis of gastroesophageal reflux was confirmed. In two patients the initial barium study failed to reveal reflux. Both were early in our experience and undoubtedly reflect the lack of roentgenographic sophistication. Three infants had pneumonia at the time of the first episode of

respiratory arrest. Five patients had no history of vomiting or regurgitation before the first apneic spell. Reflux was occult and not recognized until a barium study was obtained.

Two infants had other anatomic abnormalities that could have accounted for the apneic spells

(

Pierre-Robin syndrome and subglottic stricture). However, correction of the reflux led to disap-pearance of the spells despite the continued presence of the other anatomic abnormality. The importance of considering gastroesophageal re-flux as a possible cause of respiratory arrest even in the presence of an obvious abnormality is apparent.

Table

II

summarizes the treatment of these

patients. Four were treated medically with 24-hour positioning in a chalasia chair at an angle of

600 and with thickened feedings. Two of these patients had repeated spells, and one eventually required fundoplication. Two were treated initially with gastrostomy, because the primary disorder was thought to be a swallowing problem. In one patietit, this form of treatment was success-ful; the other subsequently underwent fundopli-cation. Including the aforementioned treatment failures, six patients were treated by fundoplica-tion. None has had any more spells.

Gastroesophageal reflux in infants is frequently not diagnosed, either clinically or radiologically.

If the

patient’s symptom is vomiting, a feeding

problem or hypertrophic pyloric stenosis is often

considered. If he has respiratory complications, then pneumonia, cystic fibrosis, Pneumocystis caririii infection, tracheoesophageal fistula, or congenital heart disease may be suspected. If apneic spells intervene, sepsis, aspiration, or neurologic disorders may be suspected. Frequent-ly the simple diagnosis of gastroesophageal reflux

is nt considered or, if it is, demonstrated reflux is thought to be unrelated. Although some of the patients in this series had significant pulmonary symptoms as well, most did not, and the episodes of respiratory arrest were the sole problem.

The

diagnosis

of

gastroesophageal

reflux

is

confirmed by roentgenographic examination. Lilly and Randolph4 noted that an experienced pediatric radiologist is essential for making the

diagnosis. Darling6 emphasized the importance of adequate filling, but not overfilling, of the stomach, having the patient relaxed, and exami-nation performed with the patient in the supine position as well as repeated roentgenograms of the distal part of the esophagus after 30 minutes.

The

clinician

must

tell

the

radiologist

that

he

suspects gastroesophageal reflux. Even with these precautions, the study may have to be repeated before the reflux is demonstrated radiographi-cally. This was true in two patients in this

series.

Respiratory arrest or death resulting from gastroesophageal reflux has rarely been reported. Lilly and Randolph4 described a 9-month-old boy with hiatal hernia who abruptly began to have

periods of apnea and bradycardia and who died. Postmortem examination disclosed extensive aspi-rated material in the tracheobronchial tree. In 1954, Forshall7 reported on two infants with gastroesophageal reflu.x who died from aspiration of vomitus. Aspiration of gastric contents may result in respiratory arrest if it is massive and

obstructs the air passages, or in lesser amounts if it

is superimposed on preexisting respiratory insuffi-ciency. None of our patients

had

this

kind

of

aspiration.

Experimentally, respiratory arrest may be produced in iiglets if distilled water or cow’s milk is introduced into the trachea. In a majority of

these subjects, the apnea is sustained and is fatal.

This response may be abolished by section of the superior laryngeal nerve, or reproduced by sUm-ulation of the nerve.8

The

absence

of evidence

of gross

aspiration

in

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EXPERIENCE AND REASON 927

aspirated, thereby producing apnea, laryngo-spasm, or both. Unrelieved, this respiratory arrest will lead to cardiac arrest. Several patients had preexisting pneumonia and might well have had some degree of hypoxia that accelerated the progress to cardiac arrest.9’#{176}

GASTROESOPHAGEAL REFLUX AND

THE SUDDEN INFANT DEATH SYNDROME

Do some of these patients represent victims of

aborted crib deaths? The recognition that gastroe-sophageal reflux may cause respiratory arrest in nonpremature infants after the neonatal period raises the question of whether occult gastroesoph-ageal reflux might be one cause of the sudden

infant death syndrome (SIDS).

Certain epidemiologic aspects of SIDS are consistent with gastroesophageal reflux as a causal mechanism. The peak age incidence is the

same as in the infants in our series: 1 to 6 months.”’2 Most occur during sleep when the patient is in a horizontal position.1’ (The distal esophageal sphincter relaxes during sleep, and the horizontal position favors reflux.) Not infre-quently the infant has recently been fed. There were respiratory symptoms in 25% to 45% of babies with SIDS in the 48 hours preceding death; these symptoms might have been secondary to unrecognized minor episodes of aspiration.’3”4

Recent pathologic evidence strongly suggests that crib deaths are respiratory in origin. Beck-with” has found petechiae in the lungs or thymus of 87% of SIDS infants on whom autopsy has been performed. He believes these are evidence of

vigorous respiratory effort against an airway obstruction, and he suggests that laryngospasm may be the final common event in SIDS. In primates, he was able to produce similar pete-chiae when the airway was occluded during vigorous respiratory effort.’3

It has been noted that the left ventricular Po2 is lower in autopsied infants with SIDS than in those who die of other causes, thereby suggesting that hypoxia precedes cardiac arrest.’6 Furthermore, blood in the autopsied patients is more fluid, indicating increased circulating fibrinolysins, which is further evidence of perfusion of hypoxic tissues before the cardiac arrest.”

Changes have been observed in the larynx at autopsy which support the hypothesis that laryn-gospasm is the final fatal event in SIDS. Valdes-Dapena’7 reported that the larynx in 65% of SIDS victims showed fibrinoid necrosis compared with none in controls. In a more exhaustive study, Pinkham and Beckwith’8 demonstrated

signifi-cant pathologic abnormalities in the larynges of 100% of SIDS victims autopsied, but they also noted the prevalence of these changes in many

infants coming to autopsy for other causes.’8 Whether these changes might result from prolonged laryngospasm or repeated injury from refluxed gastric juice is unknown. The evidence regarding milk aspiration and apnea from experi-ments in piglets has already been mentioned.

Hypothesis

Gastroesophageal reflux in some infants causes respiratory arrest which, if unrecognized, may progress to cardiac arrest. The reflux may be

occult and not associated with any recognizable regnrgitation or vomiting. We propose that this may be the mechanism of death in some patients with SIDS. We are not suggesting that all patients

with SIDS have reflux, but that some do, and that the known facts about SIDS are consistent with gastroesophageal reflux as the initiating mecha-nism.

TREATMENT

Surgical repair is recommended for all patients who have respiratory arrests secondary to gastroe-sophageal reflu.x. Although the condition of some infants will improve if they are propped up and fed a thickened formula, we do not feel the 10% to 20% risk of failure of medical therapy is justified in this life-threatening situation. Surgical treat-ment has been shown to have a significantly higher success rate. Fundoplication is a simple, low-risk operation and has few complica-tions.’’5’920 In this group, there were no deaths or surgical complications. Apneic spells are clearly the most serious possible complication of gastroesophageal reflux and require the most sure form of treatment. Gastrostomy and gastropexy are not recommended since they do not correct the basic pathologic condition and frequently fail. Fundoplication is the preferred procedure.

LUCIAN L. LEAPE, M.D.

THOMAS M. HOLDER, M.D. JOHN D. FRANKLIN, M.D. RAYMOND A. AMOURY, M.D.

KEITH W. ASHCRAFr, M.D. Division of Pediatric Surgery, Tufts University School of Medicine

Boston, Massachusetts

Children’s Mercy Hospital

Kansas City, Missouri

ADDRESS FOR REPRINTS: (L.L.L.) Boston Floating

Hospital, 20 Ash Street, Boston, MA 02111.

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REFERENCES

1. Cahill JL, Aberdeen E, Waterston DJ: Results of surgical treatment of esophageal hiatal hernia in infancy and childhood. Surgery 66:597, 1969.

2. Carre IJ: Pulmonary infections in children with a partial thoracic stomach (“hiatus hernia”). Arch Dis Child

35:481, 1960.

3. Davis MV, Fiuzat J: Application of the Belsey hiatal hernia repair to infants and children with recurrent bronchitis, bronchiolitis and pneumonitis due to

regurgitation and aspiration. Ann Thorac Surg 3:99,

1967.

4. Lilly JR. Randolph JG: Hiatal hernia and gastroesopha-geal reflux in infants and children. JThorac Cardio-vasc Surg 55:42, 1968.

5. McNamara JJ, Paulson DL, Urschel HC: Hiatal hernia and gastroesophageal reflux in children. Pediatrics

43:527, 1969.

6. Darling DB: Hiatal hernia and gastroesophageal reflux

in infancy and childhood: Analysis of the radiologic

findings. Am J Rontgenol Radium Ther Nucl Med 123:724, 1975.

7. Forshall I: The cardio-oesophageal syndrome in

child-hood. Arch Dis Child 30:46, 1955.

8. Downing SE, Lee JC: Laryngeal chemosensitivity: A

possible mechanism for sudden infant death.

Pediat-rics55:640, 1975.

9. Chernick V Avery ME: The functional basis of respira-tory pathology, in Kendig EL (ed): Disorders of the Respiratory Tract in Children. Philadelphia, WB

Saunders Co. 1967, pp 3-56.

10. Miller HC, Behrle FC: The effects of hypoxia on the respiration of newborn infants. Pediatrics 14:93, 1954.

11. Beckwith JB: The sudden infant death syndrome. Curr

Probl Pediatr 3:1, 1973.

12. Froggatt F: Sudden death in babies: Epidemiology. Am J

Cardiol 22:457, 1968.

13. Houstek J: Sudden infant death syndrome in

Czechoslo-vakia, in Bergman AB, Beckwith JB, Ray CG, (eds): Sudden Infant Death Syndrome. Seattle, University of Washington Press, 1970, pp 55-63.

14. Adelson L: Specific studies of infant victims of sudden death, in Wedgwood RJ, Benditt EP (eds): Sudden

Death in Infants. US Dept of Health, Education, and Welfare, 1965, pp 11-40.

15. Beckwith JB: Pathology discussion, in Bergman AB,

Beckwith JB, Ray CG (eds): Sudden Infant Death Syndrome. Seattle, University of Washington Press, 1970, p 122.

16. Patrick JR: Cardiac or respiratory death, in Bergman AB, Beckwith JB, Ray CG (eds): Sudden Infant

Death Syndrome. Seattle, University of Washington

Press, 1970, p 131.

17. Valdes-Dapena M: Sudden infant death syndrome and necrosis of larynx. I Forensic Sci Soc 3:503, 1958. 18. Pinkham JR. Beckwith JB: Vocal cord lesions in the

sudden infant death syndrome, in Bergman AB,

Beckwith JB, Ray CG (eds): Sudden Infant Death

Syndrome. Seattle, University of Washington Press, 1970, pp 104-107.

19. Randolph JG, Lilly JR. Anderson KD: Surgical treat-ment of gastroesophageal reflux in infants. Ann Surg 180:479, 1974.

20. Bettex M, Kuffer F: Long-term results of fundoplication

in hiatus hernia and cardio-esophageal chalasia in

infants and children. J Pediatr Surg 4:526, 1969.

Cat-Scratch Skin Test Antigen:

Purification

by Heating

Since the first use of a skin test for cat-scratch

disease by Harry Rose, M.D., on Frankline Hanger, M.D., in 1946,’ there have been no reports of transmission of hepatitis or other

disease through the use of hundreds of tests with the antigen on thousands of people. Use of the

antigen has prevented countless surgical pro-cedures, especially biopsy or removal of lymph nodes, and it has also helped relieve the anxiety of patients and parents of- patients faced with an unexplained lymphadenopathy. Nevertheless, po-tential danger from the test has prevented its use in some locations, including important medical centers, and has caused some physicians to worry about safety.

The cat-scratch skin test antigen is a crude substance prepared by dilution of

bacteriologi-cally sterile pus obtained from a suppurant lymph node in a patient who has cat-scratch disease.

After dilution, this material is subjected, tradi-tionally, to a water bath of 60 C for one hour on two successive 2 The model for preparation

is the Frei test antigen. Many minor variations, such as the one described by Cramblett,3 have

been used.

It has been known for decades that hepatitis viruses A and B are not destroyed by heat of 60 C for four hours, and that they are made nonviable when subjected to the same temperature for ten hours.

We subjected an aliquot of a high-potency cat-scratch antigen, which had been used on more than 20 patients with cat-scratch disease or control subjects, to a water bath held at 56 C for 12 hours. We used this antigen along with the standard antigen from which it was prepared in random sequence on seven patients with sits-pected cat-scratch disease and control subjects. Reactions were read approximately 48 hours later by me and independently by a physician who was experienced in reading such tests and who did not

know the code.

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1977;60;924

Pediatrics

Ashcraft

Lucian L. Leape, Thomas M. Holder, John D. Franklin, Raymond A. Amoury and Keith W.