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CLINICAL NOTES

NEONATAL

HYPOGLYCEMIA

Report

of

a Case

of

Unusual

Duration

By Oscar Schwartz, M.D.,* Martin G. Goidner, M.D.,

Jacob Rosenblum, M.D., and Joseph Avin, M.D

N

EONATAL hypoglycemia is a frequent

physiologic occurrence.’3 Usually it

is mild, asymptomatic, requires no therapy and disappears during the first week of life. Whenever hypoglycemia is prolonged and attended by clinical manifestations, it

mdi-cates pathologic derangement of carbohy-drate metabolism. Often the etiology

re-mains unknown. In 1954 McQuarrie

pre-sented a series of 25 cases of “spontaneous

infantile idiopathic hypoglycemia.” Only 2 of his cases showed symptoms from birth and most of the remainder were recognized

within the first 2 years of life.

In the case reported here, the

hypogly-cemia was diagnosed at 35 hours after birth

and has not abated after 23% months. This

case is of special interest because it afforded

the opportunity for 17% months of continu-ous hospital observation, and for the evalua-tion of various therapeutic procedures in-cluding the administration of glucagon, a hyperglycemic-glycogenolytic factor of the pancreas.5

Clinical Findings

CASE REPORT

S.S. (M.H. #14033, 14169, 16821; J.C.D.H.

#K1075), a white female was delivered spon-taneously at the Maimonides Hospital following a full-term uneventful pregnancy. There was no

From the Departments of Pediatrics and Medi-cine, Jewish Chronic Disease Hospital and the De-partment of Pediatrics, Maimonides Hospital, Brooklyn, New York.

Read before the Pediatric Section of the Kings

County Medical Society, Brooklyn, on April 26, 1954.

This study was aided by support from the Jewish Philanthropic League, Belle Harbor, New York.

* ADDRESS: 5019 20th Avenue, Brooklyn 4, New

York.

familial history of metabolic disturbances and particularly no history of hypoglycemia. The baby breathed spontaneously and cried im-mediately at birth. The weight was 3.5 kg. and

length was 50 cm. Head and chest

circumfer-ences were considered average. The physical examination revealed no apparent congenital deformities, no enlarged liver or other viscera

and the reflexes were normal. A mild alternating strabismus was observed.

At 35 hours of age the infant had a general-ized convulsion lasting about 30 minutes.

Fre-quent, often daily, seizures followed. The serum concentration of glucose was initially 18 mg./

100 ml. and has been fluctuatiimg ever since between levels as low as 4 mg./iOO ml. and as high as 60 mg./100 ml. except in periods when specific therapy has been given. The child

ap-peared normal between her repeated general-ized convulsions which readily responded to

in-jections of epinephrine and/or glucose. On

many occasions the blood sugar value was cx-tremely low without any clinical signs. The low-est value, 4 mg./iOO ml., was obtained during a quiescent period.

Laboratory Studies

Several studies were made during the first few

weeks of life in attempt to establish an etiology

for the prolonged neonatal hypoglycemia. The glycogenolytic response to injection of epi-nephrine hydrochloride (0.5 minim kg. of 1:

1000 solution) was demonstrated by a rise of

serum glucose from a fasting level of 56 mg. to 105 mg./i00 ml. 30 minutes after injection.

The radioactive iodine uptake was 33 per cent.

Roentgenographic examination showed 2 epi-physeal centers in the knee and 2 minute carpal bones in the wrist. The glucose tolerance test (3 gm. glucose/kg. body weight orally)

showed a prolonged hypoglycemic phase at the end of 4% hours observation (Table I). Injection of epinephrine was followed by a decline in

(2)

of Glucose

(hr.) (mg./100 ml.)

0

4

1 1 2 24 3 3 4 14 40 82 75 71 -40 -22 -18

(ACTH) gave eosinopenic responses of near

zero levels. The serum content of carbon

di-oxide was 25.4, Cl 103.9, Na 133, and K 4.5

mEq./l. Values for calcium varied between

7.0 and 11.8 and for phosphorus between 11.0

and 7.3 mg./l00 ml. The alkaline phosphatase

on one occasion was 20.8 Bodansky units. The calcium, phosphorus, and alkaline phosphatase

values subsequently were always normal. Total

protein was 5.3 gm./100 ml. and the albumin/ globulin ratio was 3.6/1.7. Other blood

chemi-cal findings were urea nitrogen 17 mg./iOO

ml.; cholesterol 217 mg./l00 ml.; cholesterol esters 173 mg./iOO ml., and cephalin floccula-tion 2 plus. The hemograms showed a mild hypochromic anemia and the bone marrow was

not significant. Routine urinalysis was normal.

Excretion of 17-ketosteroids in the urine was 1.10 mg. in 24 hours. Roentgenographic

exami-nations of the skull, chest and long bones were

normal, as were repeated electrocardiographic and electroencephalographic studies.

Treatment and Course

An attempt to control the hypoglycemia witim

diets high in protein and low in carbohydrate67

was unsatisfactory and, at the age of 4 weeks,

ACTH and cortisone therapy were instituted. On either regimen the serum glucose values rose to levels between 41 and 96 mg./100 ml.

Convulsions did not recur unless the dose of hormone was decreased below 20 mg. of ACTH or 30 mg. of cortisone daily. Because continu-ous hormone therapy was still necessary when

tolerated well and no diabetic symptoms fol-lowed. According to routine histological

exami-nation, the resected tissue was normal. Re-ex-amination with a silver impregnation technique was done later and showed a normal ratio of

alpha to beta cells.*

Soon after the operation hypoglycemic

con-vulsions recurred. Since prolonged hospitaliza-tion seemed necessary, the patient was trans-ferred at 6 months of age to the Jewish Chronic Disease Hospital for further observation and

study.

During the early observation period at this hospital the clinical status was re-evaluated and prior data confirmed. In addition, at this time we were fortunate to receive a giucagon prepa-ration for therapeutic evaluation. f When single

doses of 5 mg. of this preparation were ad-ministered to the patient and a normal control,

hyperglycemic responses occurred in both (Fig. 1). In the normal child the increased serum glucose value of 190 mg. dropped to a fasting level of 92 mg./100 ml. in less than 2 hours. However, the serum glucose concentration of the patient was 135 mg./100 ml. at the

end of 3 hours. In the next test, with 2.5 mg. glucagon, the induced hyperglycemia in the

patient was sustained for 6 hours (Fig. 2,

upper half) before returning to near fasting levels of 39 mg./100 ml. Two injections of

glu-cagon were then given at 6-hour intervals (Fig.

2, lower half) combined with feedings (F) of

milk and cereal. Two such tests were performed

and gave similar responses. From a level of 40 mg./iOO ml. during fasting, the concentration of blood sugar rose to 168 mg./100 ml. 1 hour

after the first injection and to 160 mg./iOO ml. in 2 hours. Values declined to fasting levels in

6 hours. When a second dose was administered

at that time there was a milder hyperglycemic

response, and again a return to fasting levels

in the same period.

aWe are indebted to Dr. Bruno W. Volk, Direc

tor of Laboratories of the Jewish Chronic Disease Hospital for this examination.

I Eli Lilly and Company, lot No. 183-47-52. The

(3)

160

140

0 2 120

100

-J CD

a,

2

BABY

60

40

I I

GLUCAGON

80

O 15’ 30 60 90

TIME IN MINUTES

120 150 ieo

Ftc. 1. Effect of a single dose of glucagon on the fasting blood sugar levels of the 6-month-old hypoglycemic baby and the control, a normal bcby, of the same age.

B

0

0

‘U In

0 U

-I C,

a

2

5 6 7 8

TIME IN HOURS

(4)

--...--- 3-4-54 DURING CORTISONE

THERAPY

I

I

I t

I #{149},

I I

- I l\

/

II

//SULIN REGULAR ‘‘‘#{149}t

I.v. (O.I UnIt I Kg.)

GLUCOSE SOmg.% (0.66 ccI Kg) I.V.

I . I I

E

0 75 0

Lu 60 U

-J 045

30

15

-0 30 60 90

TIME IN MINUTES

120 150 180

Ftc. 3. Modified intravenous glucose-insulin tolerance test (Lazarus and Volk). The insulin sensitivity noted before and during cortisone therapy are similar.

Following the glucagon studies, observations

on insulin sensitivity were made. These were

done before and during periods of cortisone therapy (Fig. 3). The modified intravenous glu-cose-insulin tolerance test of Lazarus and Volk8

was used. A 50 per cent solution of glucose was administered intravenously to the fasting

pa-tient in amounts of 0.66 ml./kg. body weight.

Thirty minutes later, regular insulin 0.1 unit/kg. was administered intravenously. The

insulin sensitivity is expressed as the rate of

decline of blood sugar in mg./100 ml./min.

during the 30-minute period following the in-jection of insulin. (Normal is 3.8 ±0.7 mg./100

ml./min.) The insulin sensitivity of the patient

before cortisone was 2.2 and during cortisone

therapy was 2.9 mg./100 ml./min.

The clinical course of the patient at the

Jew-ish Chronic Disease Hospital between

admis-sion at 6 months of age and discharge at 17%

months of age can be divided into an early phase of dietary management and a later phase of hormone therapy. While receiving dietary management consisting of feedings high in protein and low in carbohydrate, the metabolic

status appeared to be relatively stable for 2% months. Mild and short seizures were easily stopped. At 8% months of age a sudden, severe,

generalized convulsion occurred with a blood

sugar of 9.3 mg./100 ml. A return to

continu-ous hormone therapy with cortisone or ACTH permitted satisfactory control of the patient.

At 15 months of age an acute intestinal ob-struction developed caused by many fibrous

bands between segments of the small bowel.

In the postoperative period, a disturbance of

electrolytes was manifested by inverted pre-cordial T waves in the electrocardiogram and low serum values of sodium (130 mEq./l.),

potassium (3.9 mEq./l.), and carbon dioxide (18.6 mEq./l.). These were quickly restored to normal and convalescence was uneventful.

The clinical course between the ages of 6 and

17 months is illustrated in Figure 4. Twelve

minor and one major seizure were noted during

2% months of dietary management as contrasted

to 2 minor and 1 major convulsion within the

(5)

I,” TINE IN WEEKS 454

Ftc. 4. Fluctuations of fasting blood sugar levels during varied managements, ages 6 to 17 months. Broken line = Dietary Period; Solid line = Cortisone and ACTH Period; C = Severe convulsive seizure; c = Mild convulsive seizure.

in dosage of 150 mg. on the day of operation

and that the patient was controlled with 8 units

of ACTH-gel at the end of this period. Three

weeks later, at 17% months of age, the patient was discharged from the hospital.

At home, under the observation of one of us

(

O.S.), no convulsions were observed for the next 5 months while the dosage of ACTH-gel

was further gradually decreased. When it

ap-peared that as little as 2 units of ACTH-gel

every third day was satisfactory to control the

patient, ACTH was discontinued for 2 weeks.

Convulsions recurred and hormone therapy was

reinstituted. At the present writing, at 23%

months of age, she is maintained on 5 units of

ACTH-gel daily.

Her general development has been some-what retarded. On admission to the Jewish Chronic Disease Hospital at 6 months of age, her weight was 5.0 kg., height 62.5 cm. and

motor coordination below average. On dis-charge 11% months later, her weight was 10.0 kg., height 78.0 cm. and motor development more satisfactory. Socially, on the Gesell and

Vineland maturity scales, at 1 year she operated only at an 8 months level, and when discharged at 17% months she was still considered socially

retarded. During the subsequent 6 months at

home she has shown an accelerated rate of motor, adaptive and language development.

DISCUSSION

Hypoglycemia may be caused by abso-lute or relative hyperinsulinism. The former denotes an excessive insulin secretion where-as the latter a deficiency of hyperglycemic factors.

The failure to demonstrate pathologic changes of the islets of Langerhans did not

rule out the possibility of absolute

hyper-insulinism. Howard et a!.9 in a review of recorded pancreatic tumors at all ages em-phasized that even in the best surgical hands many insulinomas were overlooked. These were subsequently found at later

op-eration, or at post-mortem examination.

However, insulinomas as well as hyper-plasia or hypertrophy of the islets are ex-tremely rare in infants. In Howard’s series

of 98 tumors recorded prior to 1950, a

diagnosis of organic hyperinsulinism in

(6)

longs in the group of familial

hypoglyce-mosis described by McQuarrie.1#{176} In these

cases hypoglycemia is associated with an

absence of pancreatic alpha cells, a finding

frequently interpreted as evidence that the alpha cells secrete the hyperglycemic fac-tor, glucagon. This has been disputed in a recent study.’1 The presence of adequate numbers of alpha cells in the pancreas of our patient, therefore does not necessarily exclude an insufficiency of glucagon.

It is of interest that when glucagon was administered, the glycemic response was

sustained longer than in the normal infant.

Unfortunately this response could not be maintained beyond 6 hours even when

re-peated injections combined with frequent

feedings were given.

Other clinical entities known to cause

hypoglycemia in infancy were considered

in the differential diagnosis. The normal size

of the liver and the glycemic response to injection of epinephrine ruled out hepatic

glycogen storage disease. The absence of

cataracts and dwarfism removed congenital galactosemia from consideration. Failure to find glucose in the urine excluded renal

glycosuria. The normal iodine uptake, bone

maturation, and lack of clinical cretinism eliminated severe hypothyroidism as a pos-sible factor. Adrenal cortical insufficiency

was ruled out by the absence of clinical features, the normal electrolyte pattern, and the adequate glycemic and eosinopenic re-sponses to ACTH. The glucose and insulin tolerance tests furnished additional support for this viewpoint. In the glucose tolerance

test the initial phase was not the “flat”

type seen in adrenal insufficiency. The

pro-longed hypoglycemic phase which followed

was considered non-specific. The insulin sensitivity was not increased in the modified glucose-insulin tolerance tests and no sig-nificant differences were noted before and

the production of insulin or insulin antago-nists. Further knowledge is needed on the role of the hypothalamus and its

neuro-endocrine connections.

In the final analysis, it appeared that our case best fits into the group of spontaneous idiopathic hypoglycemia in infants.4 Many of the criteria are met. These include onset

during infancy, lack of ascertainable meta-bolic, endocrine, or nutritional etiologic fac-tors and excellent clinical response to corti-sone and corticotropin. “No genuine case

. . .has failed to respond favorably to

treat-ment with corticotropin.” Our patient, too, demonstrated strabismus as did 4 children in McQuarrie’s series. However, our infant showed no familial or hereditary trait and, unlike the majority of reported cases, it

oc-curred in a female. McQuarrie believes that this syndrome occurs more frequently than has hitherto been suspected and is the most common cause for spontaneous hypogly-cemia in infancy. It is often unrecognized, especially when mild symptoms of hypo-glycemia prevail. After prolonged treat-ment, as observed in this case, very small amounts or even no hormone therapy is necessary to maintain a fasting normogly-cemic state. Whether the beneficial action of these hormones results from an increased gluconeogenesis and/or from a direct effect on the beta cells of the 213 has

not been decided.

It must be kept in mind that infantile

hypoglycemia is never harmless, even when

(7)

Early recognition and hormone treatment probably prevented serious brain damage. Therapy was started as soon as dietary management proved unsatisfactory. No at-tempt was made to use alloxan;’4 its de-sirable diabetogenic action is seriously offset

by its hepatotoxic and nephrotoxic effects. Administration of epinephrine was helpful in establishing diagnosis but was felt to be impractical therapeutically because of its transient action. In patients without pan-creatic tumors partial pancreatectomy has been reported to be 915 16 J our

patient no benefit was observed after ex-cision of a portion of the pancreas. The ex-perimental use of glucagon was encourag-ing but its real value must await future clinical trials. At the present time, adreno-corticotropin and cortisone appeared to be the best therapeutic agents.

SUMMARY

A case of neonatal hypoglycemia of 23% months’ duration associated with recurrent convulsions has been presented.

The case best fits the classification of “idiopathic spontaneous hypoglycemia in in-fants.”

Dietary management was partially suc-cessful for a period of 2% months.

The therapeutic effects of administration of glucagon, cortisone and ACTH were stud-ied. Only the administration of cortisone and ACTH permitted control of the hypo-glycemic state.

REFERENCES

1. Talbot, N. B., Sobel, E. H., McArthur,

J.

W., and Crawford,

J.

D.: Functional

Endocrinology From Birth Through

Adolescence. Cambridge, Harvard, 1952, p. 578.

2. Norval, M. A., Kennedy, R. L.

J.,

and Berk-sen,

J.:

Blood Sugar in newborn infants.

J.

Pediat., 34:342, 1949.

3. Desmond, M. M.: Observations related to neonatal hypoglycemia.

J.

Pediat., 43:

253, 1953.

4. McQuarrie, I. : Idiopathic spontaneously occurring hypoglycemia in infants; clini-cal significance of problem and treat-ment. Am.

J.

Dis. Child., 87:399, 1954. 5. Staub, A., Sinn, L., and Behrens, 0. K.:

Purification and crystallization of

hyper-glycemic-glycogenolytic factor. Science,

117:628, 1953.

6. Conn,

J.

W. : Diagnosis and Management of spontaneous hypoglycemia. J.A.M.A.,

134:130, 1947.

7. John, H.

J.

: Medical treatment of

hyper-insulinism: with report of a case. Ohio

State M.

J.,

46:446, 1950.

8. Lazarus, S. S., and Volk, B. W. : The

esti-mation of insulin sensitivity by the

modi-fled glucose insulin tolerance test.

J.

Lab.

& Clin. Med., 39:404, 1952.

9. Howard,

J.

M., Moss, N. H., and Rhoads,

J.

E. : Hyperinsulinism and islet cell

tumors of the pancreas with 398 re-corded tumors. Internat. Abstr. Surg.,

90:417, 1950.

10. McQuarrie, I., Bell, E. T., Zimmerman, B., and Wright, W. S. : Deficiency of alpha cells of pancreas as possible etiological

factor in familial Imypoglycemosis.

Feder-ation Proc., 9:337, 1950.

11. Volk, B. W., Lazarus, S. S., and Goidner, M. C. : Alpha cells of pancreas -

morpho-logic and physiologic considerations. Arch. Int. Med., 93:87, 1954.

12. Baker, B. L. : A comparison of the histo-logical changes induced by experimental, hyperadreno-corticalism and inanition. Recent Prog. Hormone Res., 7:331, 1952.

13. Kobernick, S. D., and \Iore, R. H. :

Dia-betic state with lipaemia and hydropic

changes in the pancreas produced in

rabbits by cortisone. Proc. Soc. Exper. Biol. & Med., 74:602, 1950.

14. Talbot, N. B., Crawford,

J.

D., and Bailey, C. C.: Use of mesoxalyl urea (Alloxan) in treatment of infant with convulsions

due to idiopathic hypoglycemia.

PEDI-ATRICS, 1:337, 1948.

15. Cralmam, E. A., and Hartmann, A. F.: Sub-total resection of pancreas for hypo-glycemia. Surg., Cynec. & Obst., 59:474,

1934.

16. Callaway, E.: Subtotal resection of the pan-creas of an eight year old child for hy-perinsulinism.

J.

M. A. Georgia, 35:164,

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1955;16;658

Pediatrics

Oscar Schwartz, Martin G. Goldner, Jacob Rosenblum and Joseph Avin

NEONATAL HYPOGLYCEMIA: Report of a Case of Unusual Duration

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