Unsuspected Hyperosmolality of Oral Solutions Contributing to Necrotizing Enterocolitis in Very-Low-Birth-Weight Infants

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85 incidents. Thirty-seven were found and reviewed. This review did not identify any frac-tures other than the one noted above.

DISCUSSION

In most cases, when a child falls out of bed or from a sofa, a trivial injury occurs. This study documents the absence of significant cerebral injury. At a cost of $33 per examination, the cost of 246 skull radiographs would be $8,018 with a yield of three in 246, or 1.2%. Even in those cases where a fracture occurred, treatment was not necessary. It is to be noted that in the fractures seen, none were bilateral and none were diastatic. None were greater than 1 mm in width. Bilater-ality, diastasis, or signs of increased intracranial pressure were not foundinthese 85 children who fell "out of bed." In this study, the relationship between the three skull fractures and the fall cannot be stated for certain. In the fracture that was found in the hospital incident, there was no soft tissue swelling to indicate a recent injury to the head.

Thenecessity forobtaining skull radiographsin every case of trauma to the head has been scrutinized with the conclusion that the physi-cian'sclinical evaluation of signs and symptomsis themostimportant factor inthedetermination of a skull fracture or other cerebral injury.' 2 "Twenty per cent of skull radiographs are

performed for trivial injury and 34% for medical

legal reasons."' By adhering to more stringent criteria forordering skullradiographs, Children's Hospital of Michigan has decreased these exami-nations by 16%.3

In the Hardwood-Nash study when significant cerebral injuries such as epidural hematoma and subdural hematoma didoccur, at least 50% of the children had no skull fractures.2 The results of

physical examination provide the most important

indicationforcontinuing the workup (skull radio-graphs, computerized axial tomography, arteriog-raphy, etc.). The physician should be.extremely suspicious of child abuse if he/she examines a child with serious head injury, with or without skull fracture, when the cause of the injury is reported to be a fall from a bed, sofa, or crib.

CONCLUSIONS

The review of results of 246

children,

aged

5 years or less, falling out of bed (219 athome and 95 in the hospital) revealed no occurrence of serious injury. Three children had identifiable skull fracture on x-ray films; none had resultant CNS damage from reports of the

physician's

records. Emphasis should be giventothefact that

the follow-up of the incidentsin the hospital was generally24hours, whereasinthe homeit was, of course, considerably longer. From this study we must conclude that severe head injury and CNS damage or injury of any type are extremely rare when children, aged 5 years or less, fall out of bed.

RAY E. HELFER, M.D. THOMAS L. SLOVIS, M.D. MARY BLACK, B.S.

Department of Human Development,

College ofHuman Medicine,

Michigan State University EastLansing, Michigan 48824

Department ofRadiology and Pediatrics,

Children's Hospital, Wayne State University Detroit, Michigan

REFERENCES

1. Bell RE, Loop JW: The utility and futility of radio-graphicskullexaminationfor trauma.NEngl J Med 284:236, 1971.

2. Hardwood-Nash DC, Hendrick EB, Hudson AR: The significance of skull fractures in children. Radiology 101:151, 1971.

3. Ad Hoc Committee Report Children's Hospital of

MichiganConcerning RadiographicExaminationof Skullfor Trauma, December 1975.

ACKNOWLEDGMENT

Wewish tothankMaryAbramson, R.N.,for her assistance with the chart reviews.

Unsuspected

Hyperosmolality

of Oral Solutions

Contributing

to

Necrotizing

Enterocolitis in

Very-Low-Birth-Weight

Infants

In recentyearsnecrotizing enterocolitis (NEC) hasbecomeamajorprobleminneonatalintensive

care units. Recent incidences ashigh as8% in all infants with a birth weight less than 2.5 kg and

14% inthose with abirth weightless than 1.5 kg have been reported from one center.' Despite intensive searches for possible causative factors, nodefinite entity has been identified, but

asphyx-ia,2 circulatory changes associated with exchange transfusion,3 umbilical vessel catheterization,4 immatureimmunestatus,5 infection,68and hyper-tonic feedings9 have all been implicated.

In the course of a series of nutritional studies involving thriving very-low-birth-weight infants

PEDIATRICS Vol. 60 No. 4 October 1977 535

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we encountered a period of unusually frequent, severe gastrointestinal disturbances. A hyperos-molal vehicle used for the administration of a medication wasfound to be a contributing patho-genetic factor.

We wish to report this experience to draw attention to thepotential dangers of oral prepara-tions given in small volumes to susceptible neonates.

PATIENTS AND METHODS

Seventy-four patients with a birth weight < 1.3 kg who were involved in a study of their mineralrequirementsduring1974to 1976arethe subjects of this report. All infants were fed by nasogastric tube, either SMA-S26 (Wyeth Ltd., Downsview, Ontario, Canada) or a special formula identical to SMA-S26 except for differ-ences in sodium and phosphorus concentrations. Allinfants received a daily caloricintakeof 150 to 160calories/kg ineither 150- or 200-ml/kg quan-tities divided into 12 or 8 feedings. The caloric content of the formula was 80 or 100calories/dI.

Some infants also received a 67-calories/dl

formula at 200 ml/kg/24 hr for brief periods.

Patients wereselected for the study if they had no major congenital abnormality or respiratory distress in the first two weeks of life and if they

were able to tolerate at least 80% of the desired

caloricintakeby indwellingnasogastrictube (No.

5French), whichwaschangedweekly. The babies entered the study at age 2 to 3 weeks and left it when weighing 1.8 kg at an average age of 45 days. The management of all infants was as outlined in a previous publication.10

All infants were given calcium lactate supple-ment (600 mg/kg/24 hr; 100 mg/ml) in 0.5- to 1.0-mlquantities. In group 1 theinfants received thesupplementmixed with eachfeeding.Because

of reports in the literature"'2 that calcium salts (lactate orgluconate) are better absorbed if given not mixed with milk or formula, we gave the

calcium lactate to the 13 infants of group 2 20 minutesbefore eachfeeding. AfterOctober 1974, the calcium lactate was dispersed in water and given at the end of each feeding to the infants of group 3.

Gastrointestinal (GI) symptoms that occurred

during the course of this study were categorized according to severity. "No GI signs" included infants in whom feeding was not increased

according to schedule due to incidentalproblems

(e.g., recurrent apnea, suspected sepsis). Patients who had only occasional watery stools were also included in this category since none of the patients who developed NEC presented with this

sign. "Mild GI signs" included mild to moderate abdominal distension or some diarrhea, but blood was absent in the stools and thebabies had normal GI radiographs and did not require continuous suction. Patients with suspected NEC included those with severe abdominal distension requiring decompression, and bile-stained gastric aspirate and/or blood in stools. However, although some of these patients showed evidence of edema of the bowel wall, they did not have the characteristic radiographic sign of intramural air. Patients with

"confirmed NEC" were those who had moderate to severe abdominal distension, blood in the stools, and radiographic evidence of intramural air with or without perforation.

RESULTS

As shown in the Table only one of the 26 infants

of group 1 developed NEC, whereas of the 13 infants in group 2 six developed suspected or

confirmed NEC

(X2

= 10.54; P< .005). One death following perforation and

overwhelming.

sepsis occurredin this group. Hemoglobin, BUN, and plasma electrolyte concentrations did not

changewith the onset of symptoms inthe infants

with suspected or confirmed NEC.

Comparing the incidence of suspected or

confirmed NECwith respectto caloricdensityof theformulaininfants of groups 1 and 2,oneof the 13 infants fed the 100-calories/dl formula in group 1 developed NEC compared to six of the remaining 13 of group 1 and the 13 infants of group 2, all fed the 67- or 80-calories/dl formula. This difference, however, was not statistically significant (P> .1).

The osmolality of the formula was found to be 275 mOsm/kg H20 (67 calories/dl), 343 mOsm/

kg

H2O

(80 calories/dl), and 428 mOsm/kg H20

(100 calories/dl). The osmolality of the calcium

lactate preparation inusefor groups 1 and2 was found to be > 1,700 mOsm/kg H20. Calcium lactate solution inwaterhasan osmolalityof 405

mOsm/kg

H20.

The difference was tracedto the vehicle used in the pharmacy in the preparation of the calcium lactate. Thiswas a20%solutionof sucrose.

After the change of the calcium lactate to the preparation in water, the incidence of suspected orconfirmed NEC decreased comparedto thatin group 2 (P< .05). Although five instances of NEC occurred in this group of 35 patients, the difference between groups 2 and 3 remained

significant

(X2

= 5.43; P < .05). None was seen

during July to October 1975.

Comparing the incidence of suspected or confirmed NEC of group 2 with that of groups 1

536 HYPEROSMOLALITY OF ORAL SOLUTIONS

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INCIDENCEAND SEVERITYOFGASTROINTESTINAL SIGNS INVERY-LOW-BIRTH-WEIGHTINFANTS ACCORDING TOMODE OF CALCIUM LACTATE ADMINISTRATION AND TIMEOF YEAR

"No GI "Mild GI "Severe GI NEC Total Signs and Signs" Signs"

Symptoms"

Group 1

January-June 1974 13 6 0 1

July-October1974 4 1 0 0 26

November 1974-June 1975 1 0 0 0

Group 2, July-October 1974 4 3 2 4 13

Group3

November 1974-June 1975 8 3 0 3

July-October 1975 7 2 0 0 [ 35

November 1975-January 1976 9 1 0 2 J

'Definitions intext.

and 3 during the months July to

October,

the difference was statistically significant

(X2

= 8.31;

P< .005). When the frequency of suspected and

confirmed NEC wascombinedfor groups 1 and3 andcompared with that in group 2, the difference also was statistically significant (x2 = 10.4;

P< .005)..

The age at onset of suspected or confirmed NEC variedbetween 16 and 33days, but didnot differ among groups. The time interval between the start of calcium supplementation and the onset of GI symptoms also did not differ

signifi-cantly between groups 2 and 1 andgroups 2and 3: it wasthreedaysinthe former andeightinthe latter (P< .1).

Oneinfant in group2 and one ingroup 3died from NEC and two patients in group 3 had successful resection of the involved part of the smallbowel. The gross and microscopic examina-tions disclosed the typical picture of NEC.

DISCUSSION

The highest incidence ofNEC has been noted in this unit during the winter months, notably Januaryto March.Cases areinfrequently encoun-tered in the months July through October.13 We were alerted to the possibility of a novel patho-genetic mechanism by the occurrence of severe GI symptoms at an unusual timeof the year in a group of infants selected for their healthy status.

Only small amounts, ranging from 0.5to 1.0ml,

of the calcium lactate preparation were used. It appears that these small quantities given to the babies of group 2undiluted with formulainduced

effects onthe upper bowel that resultedinsevere GI disturbances and in some instances led to

classicalNEC with distalbowel involvement. The mechanism is unclear. The fact that no changes

occurred in hemoglobin, BUN, or plasma elec-trolyte levels suggests that major fluid shifts between body compartments did not occur. The

frequency of umbilical vesselcatheterization and of infections and the osmolality of the feedings

were similar in these groups. Infants with severe asphyxia at birth were not included in the study and none ofthe infants had required respiratory assistance before the development of NEC.

Calcium lactate solution in water (100mg/ml) has an osmolality of 405 mOsm/kg H,O. When formulated in a vehicle of highosmolality such as the 20% sucrose used here in groups 1 and 2, the

osmolalityof theresultant solution becomes much greater than the 280 mOsm/kg H2O of the duodenal contents."4 It appears that this hyperos-molal solution ifnotdiluted with thefeedingmay result in local trauma to the upper gut wall, which could initiate the pathological process resulting in NEC. Among alternative pathoge-netic mechanisms, redistribution of blood supply and/or alteration of bowel flora resulting from the sucrose bolus should be considered.

Whereas the extreme hyperosmolality of concentrated solutions such asthat reported here may be a factor in NEC, we were unable to implicate themoreconcentrated (100 calories/dl)

formula,which was receivedby 13 ofthe infants in group 1. It isimportant to note, however, that unlike other reports of adverse effects of hyper-tonic feedings,15 none of the infants included in the present report received this concentrated formula during their first two weeks of life.

Although sodium bicarbonate administered

orally in the treatment of "late metabolic acido-sis" to very-low-birth-weight infants has an

os-molality similar to that of calcium lactatein 20% sucrose solution (1,800 vs. > 1,700 mOsm/kg

H2O), this medication is always given to our

EXPERIENCE AND REASON 537

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patients mixed withthefeeding and the measured osmolality of this mixture never exceeds 500 mOsm/kg H20.

The criteria of "health" necessary for entry of patients to our nutritional study presumably explain the differences in age at onset of NEC in the patients reported here and that of the infants studied bySantulli et al.16 In that report the onset of the disease was during the first five days of age in 75%of the 64 affected infants; in only 6% did it

develop after age 14 days.

DIANA M. WILLIS, M.D. JOANN CHABOT, R.N. INGEBORG C. RADDE, M.D. GRAHAM W. CHANCE, M.B. Division ofPerinatology, Research Institute,

The Hospital for Sick Children; and the Department of

Pediatrics,

University of Toronto Toronto, Ontario, Canada

10. Roy RN, Chance GW, Radde IC, et al: Late

hypona-tremia invery lowbirthweight infants (< 1.3kg).

Pediatr Res 10:526, 1976.

11. Dormandy TL, Begum R: The plasma calcium and magnesium response tostandard metabolic loads in

infants, in Baltrop D, Burland WL (eds): Mineral Metabolism in Paediatrics (Glaxo Symposium). Oxford, England,Blackwell ScientificPublications, 1969, p31.

12. Barr DGD, Forfar JO: Oral calcium loading test in

infancy with particular reference to idiopathic hypercalcemia. Br MedJ 1:477, 1969.

13. Pape K, Fitzhardinge P: Necrotizing enterocolitis: Is infection an important etiology? Read before the

annualmeetingof the Canadian Paediatric Society,

Toronto, 1975.

14. Fordtran JS, Locklear TW: Ionic constituents and

os-molality ofgastric and small intestinal fluids after eating. AmJDig Dis 11:503, 1966.

15. HerbstJJ: Dietand necrotizingenterocolitis, in Necro-tizing Enterocolitis in the Newborn Infant. Ross Conference Reports 68:71, 1975.

16. Santulli TV, Schullinger JN, Heird WC, et al: Acute

necrotizing enterocolitis ininfancy: Areviewof64 casesPediatrics55:376, 1975.

ADDRESS FOR REPRINTS: (G.W.C.) The Hospital for

Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8,Canada.

REFERENCES

1. YuVYH,TudehopeDI, GillGJ, SinclairJC: Increasing incidence of necrotizing enterocolitis (NEC):

Failure to identify perinatal risk factors. Read

before the annual meeting of the Canadian

Paediatric Society, Vancouver, June 1976. 2. TouloukianRJ, PoschJW, Spencer RP: The

pathogen-esisof ischemicgastroenterocolitis of theneonate.J

Pediatr Surg 2:194, 1972.

3. Touloukian RJ, Kadar A, Spencer RP: The gastrointes-tinal complications of neonatal umbilical venous

exchange transfusion: A clinical and experimental study. Pediatrics 51:36, 1973.

4. LivaditisA,WallgrenG,Faxelius G: Necrotizing

enter-ocolitis after catheterization of the umbilical vessels. Acta Paediatr Scand 63:277, 1974. 5. Barlow B, Santulli TV, Heird WC, et al: An

experi-mental study ofacute neonatal enterocolitis: The importance of breast milk. J Pediatr Surg 9:587,

1974.

6. SternH, Beck J, Solomon A,SchmamanA:

Gastroenter-itis with necrotizing enterocolitis in premature

babies. BrMedJ2:616, 1972.

7. Hill MR, Hunt CE, Matsen JM: Nosocomial

coloniza-tionwithKlebsiellatype26,inaneonatalintensive care unit associated with an outbreak of sepsis, meningitis andnecrotizing enterocolitis. J Pediatr

85:415, 1974.

8. Frantz ID, L'Heureux P, Engel RR, Hunt CE: Necro-tizingenterocolitis. JPediatr 86:259, 1975. 9. BookLS,HerbstJJ, Atherton SO,JungAL: Necrotizing

enterocolitis in low birthweight infants fed an

elementalformula. JPediatr87:602, 1975.

Transient

Neonatal

Hypothyroidism Detected by Newborn

Screening Program

A screening program for the detection of

neonatal hypothyroidism has been in effect in

Oregon since May 1975. Blood samples are obtained from all newborn infants to test for phenylketonuria and other metabolic diseases. A secondspecimen isobtained from morethan 90% ofthese infantswhoareretestedat4to6weeksof age. These Guthrie filterpaperbloodsamplesare analyzedforthyroxine

(T,),

and allsampleswitha low

T,

value areanalyzed for thyroid stimulating hormone (TSH). At the outset of the program, it

was speculated that the screening might detect infants who had reducedT4 concentrations inthe newborn periodbutwholaterhadnoevidenceof thyroiddisease,and thiswaspart of thereasonfor obtaining samples at two time periods.1 We would like to report an infant who, in fact, had unequivocal biochemical hypothyroidism de-tected by the newborn screening program. On further study, however, this infant became biochemically euthyroidandhas remained euthy-roid at age 8 months.

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1977;60;535

Pediatrics

CHANCE

DIANA M. WILLIS, JOANN CHABOT, INGEBORG C. RADDE and GRAHAM W. Enterocolitis in Very-Low-Birth-Weight Infants

Unsuspected Hyperosmolality of Oral Solutions Contributing to Necrotizing

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1977;60;535

Pediatrics

CHANCE

DIANA M. WILLIS, JOANN CHABOT, INGEBORG C. RADDE and GRAHAM W. Enterocolitis in Very-Low-Birth-Weight Infants

Unsuspected Hyperosmolality of Oral Solutions Contributing to Necrotizing

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