Recurrent Hyperosmolar Nonketotic Episodes in a Young Diabetic Fredda
Ginsberg-Fellner, MD,
William A.
A 15-month-old girl was successfully treated for substantial hyperosmolarity in the absence of ketosis at the onset of permanent insulin-requiring diabetes mellitus. Hypotonic solutions containing small amounts of glucose and subcutaneous administration of low doses of insulin were employed. Potassium was added to the hydrating solutions during the second hour of treatment. In the next three months, two recurrences of this syndrome were verified and successfully treated in a similar manner.
syndrome of hyperosmolar Theverified diabetes adults
non¬
ketotic
mellitus has been in since 1957.1-4 In 1965 ten young children who died due to this illness were briefly de¬ scribed,0 and a year later, the first case in a surviving child was re¬ ported." Since that time, only three other children have been described who survived with permanent insu¬ lin-requiring diabetes mellitus. Re¬ cently, we treated a 15-month-old girl who had this syndrome. In the three months following the initial diag¬ nosis, she had two additional hyper¬ osmolar nonketotic episodes and an episode of classical diabetic ketoaci¬ dosis. She has continued to require daily insulin injections and has grown and developed at a normal rate over the 2Vè years of subsequent follow-up. REPORT OF A CASE The
patient
was
born
spontaneously
six
Received for publication March 15, 1973; accepted June 12, 1974. From the Department of Pediatrics, Mount Sinai School of Medicine of the City University of New York.
Reprint requests to Department of Pediatrics, Mount Sinai School of Medicine of the City University of New York, 11 E 100th St, New York, NY 10029 (Dr. Ginsberg-Fellner).
Primack,
MD
weeks before term after an uncomplicated gestation. The mother was 21 years old and Rh-positive, and she had a negative se¬ rologie test for syphilis. The vertex deliv¬ ery was accomplished under epidural anes¬ thesia after a labor of 4Vè hours. The baby's Apgar score was 8 at one minute and 10 at five minutes. Nasotracheal suc¬ tion and oxygen were used during the first five minutes of life only. The baby's birth weight was 1.93 kg (4.3 lb), length was 43 cm (17.0 in), and head circumference was 29 cm (11.4 in). The neonatal course was uneventful and the baby was discharged from the hospital at 20 days of age, weigh¬ ing 2.28 kg (5.0 lb). For the first year of life, the patient did well except for a viral exanthem at age 10 months. At age 15 months, she weighed 10 kg (22.0 lb), walked well with support, and spoke sev¬ eral words. Three days prior to her first hospital ad¬ mission, she began to vomit and was found to have a temperature of 38.4 C (101.1 F). A diagnosis of gastroenteritis was made in the emergency room and she was treated at home with clear fluids and four doses of aspirin given at least eight hours apart. Two days later, after repeated episodes of vomiting, severe dehydration was noted. Her weight had fallen to 8.6 kg (19.0 lb). She was given intravenously 750 ml of a solution of 0.3% sodium chloride in 5% dex¬ trose in the emergency room. Her weight increased by 0.32 kg (0.7 lb) and she was sent home. A blood sample taken prior to therapy showed a glucose level of 1,160 mg/100 ml; sodium level, 144 mEq/liter; potassium level, 4.8 mEq/liter; blood urea nitrogen (BUN) level, 11 mg/ml; and a calculated serum osmolarity of 349 mOsm/liter. (The serum osmolarity is cal¬ culated as follows: mOsm/liter 2 (sodium level, mEq/liter) =
mEq/liter glucose level, mg/100
ml
~^18
Values greater than 310 mOsm/liter de-
hyperosmolarity.) The pa¬ recalled and admitted to the hos¬ pital after an 18-hour delay. At this time, a five-day history of polyuria was obtained and it was learned that the patient had taken only about 240 ml of liquid orally during the 24 hours preceding her admis¬ sion to the hospital. On admission, the child was lethargic and had a high-pitched cry. Bilateral otitis media was present. Her weight was 8.69 kg (19.2 lb); length, 78.3 cm (30.8 in); and tem¬ perature, 39.4 C (103 F). The serum sodium level was 159 mEq/liter; potassium level, 4.3 mEq/liter; chloride level, 125 mEq/ liter; carbon dioxide level, 17.5 mEq/liter; BUN level, 44 mg/100 ml; glucose level, 1,350 mg/100 ml; and calculated serum osmo¬ larity, 393 mOsm/liter. Arterial pH was 7.37; plasma insulin level, 25/iU/ml; plas¬ ma free fatty acid level, 920 mEq/liter; and plasma growth hormone level, greater than 50 ng/ml. The laboratory data and treatment dur¬ ing the first 16 hours of hospitalization are shown in the Figure. Ketonuria was absent or present in only small amounts during this entire period. A solution of glucose, 2.5 gm/100 ml, in water was given intrave¬ nously for only two hours (between the fourth and sixth hours of therapy). Five units of insulin was given subcutaneously at the third hour of therapy and again at the 14th hour. During the next ten hours, no additional insulin was given. Thus, the patient received approximately 1 unit of insulin injection per kilogram during the first 24 hours of therapy. Potassium chlo¬ ride, 40 mEq/liter, was added to the intra¬ venous solutions beginning with the second hour of therapy and was given until a fourhour period of oliguria developed at the tenth hour of therapy. The oliguria dis¬ appeared when the rate of fluid adminis¬ tration was increased. A total of 1,030 ml of intravenous solu¬ tions was given from the 16th to the 24th hour. These contained sodium, 51 mEq/ note substantial
tient
was
Downloaded From: http://archpedi.jamanetwork.com/ by a University of Pennsylvania User on 06/19/2015
Intravenous Fluid, ml
Sodium Chloride,
mEq/Liter
Potassium Chloride,
Glucose, gm/100 ml Insulin, Units
mEq/Liter
|95)~ 235 *|* 170 —f*70*j\V\* 26 -f- 39 -»-4-26-4— |0k
(
40
0
*f*
2.5
"4*
*j 51 H -j* ' *|*25*) 0 -*\ 500
Serum Osmolarity, mOsm/Liter
Blood Glucose, mg/100 ml
Time, hr Blood glucose level, calculated serum osmolarity, and treatment during hospitalization in 15-month-old diabetic weighing 8.69 kg (19.2 lb).
liter; potassium, 25 mEq/liter; chloride, 51 mEq/liter; lactate, 25 mEq/liter; and glu¬ cose, 2.5 gm/100 ml. Total fluid adminis¬ tered over the first 24 hours of hospitaliza¬ tion was 2,100 ml or 220 ml/kg of body weight. Thus the patient received in 24 hours a total of the following: sodium, 12 mEq/kg; potassium, 6 mEq/kg; chloride, 14.5 mEq/kg; lactate, 3.5 mEq/kg; and glu¬ cose, 3.4 gm/kg. However, less than 0.5 gm of glucose per kilogram was given during
the first 16 hours of therapy. The course was complicated by a gener¬ alized seizure that lasted five minutes at the 23rd hour of therapy. Blood drawn dur¬ ing the seizure showed the following val¬ ues: glucose level, 340 mg/100 ml; sodium level, 146 mEq/liter; chloride level, 110 mEq/liter; calcium level, 8.0 mg/100 ml; magnesium level, 2.0 mg/100 ml; and calcu¬ lated serum osmolarity, 317 mOsm/liter. A lumbar puncture was performed immedi¬ ately after the seizure had subsided. Cere¬ brospinal fluid (CSF) was clear and had a protein concentration of 29 mg/100 ml, a chloride concentration of 172 mEq/liter, and a glucose concentration of 700 mg/100 ml. Thus, the CSF glucose level was still much higher than the blood glucose level. There were four lymphocytes per cubic milliliter and no bacteria on culture. Phénobarbital was given in a dose of 45 mg daily. This was later increased to 60
initial 16 hours of
mg/day
and has been continued at that level to the present time. During the second 24 hours of hospitali¬ zation, the patient was given subcutaneously a total of 8 units of insulin in four doses of 2 units each. During the same in¬ terval, she received intravenously 3,300 ml of fluids that contained glucose, 2.5 gm/100
ml; potassium, 25 mEq/liter; sodium, 39 mEq/liter; chloride, 39 mEq/liter; and lac¬ tate, 25 mEq/liter.
On the morning of the third day of hos¬ pitalization, 5 units of isophane insulin suspension was given subcutaneously. This same dose administered daily provided ad¬ equate control during the remaining three weeks of hospitalization. After the patient was discharged from the hospital, she was treated during a two-month period in the outpatient diabetic clinic. The long-acting isophane insulin suspension dose was grad¬ ually increased to 9 units given once a day. Her weight rose to 9.86 kg (21.7 lb) and urine acetonuria was consistently absent. In the following month, however, she was readmitted to the hospital on three oc¬ casions. On two of these readmissions she had severe hyperosmolarity without ke¬ tosis, and on the third she was in diabetic ketoacidosis. At the time of the first readmission, serum sodium level was 139 mEq/ liter; potassium level, 5.9 mEq/liter; chlo¬ ride level, 110 mEq/liter; carbon dioxide
level, 19.0 mEq/liter; glucose level, 1,500 mg/100 ml; BUN level, 25 mg/100 ml; arte¬ rial pH, 7.37; and calculated serum os¬ molarity, 361 mOsm/liter. This episode was apparently precipitated by failure to drink a sufficient quantity of liquids and by repeated episodes of vomiting. The pa¬ tient again responded rapidly to intra¬ treatment with a solution of 0.3% sodium chloride that did not contain glu¬ cose for the first eight hours of therapy. Potassium chloride, 40 mEq/liter, was also administered intravenously starting at the second hour of therapy. The dose of potas¬ sium chloride was decreased to 25 mEq/ liter beginning with the ninth hour of ther¬ apy. For the first 48 hours of therapy, insu¬ lin was given in four doses of 2 units each injected subcutaneously every six hours. On the third hospital day, the patient was venous
again given isophane insulin suspension. Satisfactory control was achieved with 10 units of isophane insulin suspension per •day. The patient was discharged in good condition on the sixth hospital day. However, she was again admitted to the hospital ten days later because of repeated episodes of vomiting and insufficient oral liquid intake. At this time, serum sodium level was 145 mEq/liter; potassium level, 116 chloride level, 6.2 mEq/liter; mEq/liter; carbon dioxide level, 17.0 mEq/liter; glucose level, 1,440 mg/100 ml; BUN level, 28 mg/100 ml; arterial pH, 7.33; and calculated serum osmolarity, 370 mOsm/liter. A therapeutic regimen identi¬ cal to that described during her second hospitalization was employed, except that the concentration of the solution of potas¬ sium chloride that was given intravenously was kept constant at 25 mEq/liter. During this admission, which lasted six days, the dose of isophane insulin suspension was in¬ creased to 11 units/day. Thirteen days after her third discharge from the hospital, she was again admitted to the hospital with classical diabetic ketoacidosis. At this time, serum sodium level was 130 mEq/liter; potassium level, 6.5 mEq/liter; chloride level, 118 mEq/ liter; carbon dioxide level, 5.0 mEq/ liter; glucose level, 720 mg/100 ml; ar¬ terial pH, 7.14; and calculated serum os¬ molarity, 300 mOsm/liter. The ketoacidosis cleared after 12 hours of intravenous ther¬ apy with 1,500 ml of fluid containing so¬ dium, 77 mEq/liter, and glucose, 2.5 gm/100 ml. Sodium bicarbonate, 40 mEq/ liter, was administered in the first three hours of therapy. Potassium chloride, 40 mEq/liter, was added at the beginning of the third hour of therapy. Twelve units of insulin was given subcutaneously in three divided doses over the 12-hour period dur¬ ing which intravenous therapy was used.
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During this hospitalization the patient's condition was finally controlled with a dose of 12 units of isophane insulin suspension once a day. Recurrent bilateral otitis media was present during these repeated hospitalizations, but this infection was eventually cured by prolonged antibiotic treatment.
During the 18 months following her hospitalization, the patient gained 3.83 kg (8.4 lb). During this time her condi¬ fourth
tion was maintained on an insulin dose of 12 units of isophane insulin suspension given once a day. It is interesting to note that electroencephalograms taken 36 hours, six months, and one year after the patient experienced a convulsion during her first hospitalization were all entirely normal. Developmental screening tests at ages 25 and 36 months, using the Knobloch et al7 modification of the Gesell infant test¬ ing scale, indicated that the patient func¬ tioned appropriately for her age.
COMMENT There are complete reports of only ten children with hyperosmolar non¬ ketotic diabetes mellitus in the litera¬ ture.6-811 Six of these children died during the initial therapy, and severe
pancreatic /3-cell degeneration
was
found at postmortem examination.911 Five of these patients were born pre¬ maturely or had a history of neuro¬ logical impairment. Only four of the reported patients survived after treatment. Two of these have mon¬ golism and a third is an infant born prematurely.88 The latter infant and one other surviving infant9 developed in a normal manner. To our knowl¬ edge, no recurrences of hyperosmolar nonketotic diabetes in childhood have previously been described. A comparison of the 11 well-docu¬ mented cases shows many similar¬ ities. None of the patients had diabe¬ tes prior to the appearance of the hy¬ perosmolarity. Eight were less than 2 years of age. All had a history of ex¬ cess fluid loss, secondary to fever, vomiting, or polyuria, and all suffered severe dehydration. An extremely high initial blood glucose level (aver¬ aging 1,048 mg/100 ml) was noted in all patients. The five young survivors received between 1 and 6 units of in¬ sulin injection per kilogram during the first 24 hours of treatment. Of these patients, only one received sub¬ stantial amounts of glucose during
the first 12 hours of intravenous ther¬ apy, and he had the lowest blood glu¬ cose level (770 mg/100 ml) of any of the reported survivors." Five of the six patients who died received sub¬ stantial amounts of glucose in their initial hydrating solutions and 2 to 72 units of insulin injection per kilogram in the first 24 hours of treatment.
However, one patient with mongol¬ ism died, although he received only
small amounts of glucose intrave¬ nously and VA units of insulin injec¬ tion per kilogram during the first day of therapy.1" It thus appears that administration of smaller doses of insulin and initial intravenous use of solutions with little or no glucose are associated with the most favorable outcome. Early addition of potassium to hy¬ drating solutions may also be impor¬ tant, as severe hypokalemia has been described, particularly in adults.4 The pathogenesis of severe hyper¬ glycemia without ketosis is still not well understood. By far the largest percentage of cases have occurred in adults in whom the case fatality rate approaches 50%.' The most obvious clinical feature in all cases is severe dehydration. In children, the pre¬ dominance of patients under 2 years of age or with neurological damage strongly suggests that inappropriate responses to thirst or inability to take sufficient liquids orally in the pres¬ ence of vomiting, fever, or diarrhea may be the primary factor in the pathogenesis of the syndrome. The course of nonketotic hyperosmolar di¬ abetes then parallels that observed in the experimental model in rats pretreated with hydrocortisone acetate and rendered moderately diabetic with streptozotocin or alloxan.42 In such animals, water deprivation is the primary requirement for the develop¬ ment of the hyperosmolarity, which, in turn, is known to inhibit free fatty acid release from adipose tissue. Any insulin that is present then further depresses this lipolysis. The fact that all juvenile patients showed symp¬ toms at the onset of their diabetes mellitus when some endogenous insu¬ lin is still being produced lends sup¬ port to the hypothesis that this small amount of insulin may be sufficient to
adipose tissue lipolysis in this insulin-sensitive tissue. Re¬ ported insulin levels in adult patients with this syndrome have usually been low.4 In one child with mongolism, pancreatic insulin content was dimin¬ ished at postmortem examination.11 In our patient, a single determination of serum immunoreactive insulin con¬ centration, which was obtained prior to therapy, was inappropriately low for the elevated blood glucose concen¬ tration present. However, the free fatty acid level was not substantially higher than that recorded in our labo¬ ratory for nondiabetic children of similar ages. The elevated growth hormone level in our patient con¬ trasts with the low levels reported in adults.4 This finding may reflect the enormous stress of the patient's ill¬ ness or confirm previously reported elevated levels of growth hormone in "juvenile" diabetics."-14 The syndrome of hyperosmolar nonketotic diabetes mellitus should be considered whenever a young child has substantial glucosuria and severe hyperglycemia without ketosis. Other causes of this syndrome, as previous¬ ly reported in adults (including di¬ azoxide [Hyperstat],15 diphenylhydantoin,111 and corticosteroid17 therapy), should also be considered, although they have not yet been reported in children. In addition, in all young children with similar laboratory find¬ ings, the possibility of inappropri¬ ately diluted formulas18 and severe gastroenteritis must always be enter¬ tained.19 A detailed history and, if possible, laboratory data should be obtained prior to institution of ther¬ apy. However, it may be wise in all cases to start with low doses of insu¬ lin, since such doses are also now rec¬ ommended for the treatment of clas¬ sical ketoacidosis.20 This procedure was used successfully in the treat¬ ment of one episode of ketoacidosis in inhibit most
our
patient.
References 1. Sament S, Schwartz MB: Severe diabetic stupor without ketosis. S Afr Med J
1957. 2. Jackson WPU: A critical appraisal of mechanisms concerned in non-ketotic hy-
31:893-896,
Downloaded From: http://archpedi.jamanetwork.com/ by a University of Pennsylvania User on 06/19/2015
perosmolar diabetic coma. Postgrad Med J 47(suppl):399-402, 1971. 3. McCurdy DK: Hyperosmolar hyperglycemic nonketotic diabetic coma. Med Clin North Am 54:683-699, 1970. 4. Gerich JE, Martin MM, Recant L: Clinical and metabolic characteristics of hyperosmolar nonketotic coma. Diabetes 20:228-238, 1971. 5. Nabarro JDN: Diabetic acidosis: Clinical aspects, in Leibel BS, Wrenshall GA (eds): On the Nature and Treatment of Diabetes. Amsterdam, Excerpta Medica Foundation, 1965, p 560. 6. Vaan GA de: Hyperosmolair diabetisch coma zonder ketoacidose. Maandschr Kindergeneesk 34:279-283, 1966. 7. Knobloch H, Pasamanick B, Sherard ES Jr: A developmental screening inventory for infants. Pediatrics 38:1095-1104, 1966. 8. Ehrlich
RM, Bain HW: Hyperglycemia and hyperosmolarity in an 18-month\x=req-\ old child. N Engl J Med 276:683-684, 1967.
Ago
60 Years
9. Rubin HM, Kramer R, Drash A: Hyperosmolarity complicating diabetes mellitus in childhood. J Pediatr 74:177-186, 1969. 10. Belmonte MM, Colle E, Murphy DA, et al: Nonketotic hyperosmolar diabetic coma in Down's syndrome. J Pediatr
77:879-881,
1970.
Kogut MD, Landing BH: Coma and hyperglycemia in the absence of ketonemia: Present in a 12-year-old boy. Am J Dis Child 114:676-683, 1967. 12. Bavli S, Gordon EE: Experimental diabetic hyperosmolar syndrome in rats. Diabetes 20:92-98, 1971. 13. Johansen K, Hansen AP: High 24\x=req-\ hour level of serum growth hormone in juvenile diabetes. Br Med J 2:356-357,1969. 14. Drash A, Field JB, Garces LY, et al: Endogenous insulin and growth hormone response in children with newly diagnosed 11.
diabetes mellitus. Pediatr Res 2:94-102, 1968. 15. Charles MA, Danforth E Jr: Non-
ketoacidotic hyperglycemia and coma during intravenous therapy in uremia. Diabe-
20:501-503, 1971. 16. Limas CJ, Samad A, Seff D: Hyperglycemic nonketotic coma as complication of steroid therapy. NY State J Med 71:1542-1543, 1971. 17. Goldberg EM, Sanbar S: Hypernonketotic coma following adglycemic ministration of Dilantin (diphenyl hydantoin). Diabetes 18:101-106, 1969. 18. Jung AL, DoneAK: Extreme hyperosmolality and "transient diabetes": Due to inappropriately diluted infant formula. Am J DiCh118:859-863, sild 1969. 19. Stevenson RE, Bowyer FP: Hyperglycemia with hyperosmolal dehydration in nondiabetic infants. J Pediatr 77:818\x=req-\ 823, 1970. 20. Alberti KFMM, Hockaday JDR, Turner RC: Small doses of intramuscular insulin in the treatment of diabetic coma. Lancet 2:515-522, 1973. tes
in AJDC Congenital Syphilis
The patient, a female child, 2 months old, of Panamanian parentage, was admitted to Ancon Hospital, Dec. 20, 1913. The father . had a chancre in June, 1910. The Wassermann test was again positive in December, 1913. .
.
.
.
.
The mother
.
was
admitted to the
ma-
ternity wards of Ancon Hospital, Oct. 23, 1913. . Her delivery was accomplished by a cesarean section. The baby was read.
.
.
.
. .
mitted at the age of 2 months. The temperature ran an average course of about 100 degrees, the pulse averaging 132, and respirations 36. The child died twelve hours after its admission to the hospital. The clinical factors present and the father's known condition led to the diagnosis of congenital syphilis. Anatomical Report.\p=m-\Autopsy3763. Performed three hours and twenty minutes after the death of the child. Smears from blood of jugular vein were stained with a polychrome stain (Hastings).... At¬ tention was arrested by the presence in al¬ most every field of from one to three or more treponemas with the characteristic morphology of T. pallidum. Similarly stained smears from the liver near the gummatous-like region revealed .
.
.
.
.
.
the
organisms in fair numbers. A protracted search in smears from
same
more
spleen and bone-marrow and lymph-nodes resulted in sparse findings of the same na¬ ture. A Wassermann test
on
the cadaver
obtained and found
positive. Microscopical Report.—Skin: This speci¬
was
.
.
.
taken from the anterior surface of the right thigh and although no vari¬ ation in its histology was noted in the sec¬ tions stained with hematoxylin and eosin, yet in Levaditi preparations T. pallidum, in fair numbers, were found in focal man¬ ner in the superficial layers of the corium. Brain: No lesion was found in any of the preparations. After a tedious search over many specimens of Levaditi preparations a few forms were found which faithfully represented T. pallidum. Noguchi's identification of this organism in the brain in cases of general paralysis made it seem quite likely that this case of congenital syphilis would easily reveal the presence of T. pallidum in fair numbers. Heart: It was disappointing to find these preparations of the heart among the most difficult in the body in our case in which to locate the organism. There was no men was
.
.
.
...
relation between those found and a focal lesion or perivascular space. Liver: Sections from the dome of the right lobe were not far from normal. Sections from the gummatous-like margin showed almost complete destruction of the liver tissue. This case presents one instance in which, at present, all the conditions conform to Colles' law. The mother at the time of the death of the child and again six months later reacted in a negative manner to the Wassermann test performed by Dr. L. B. Bates according to Noguchi's modification of the test. Pearce claims that it has al¬ ways been a question whether immunity is real or whether the mother is so lightly in¬ fected as to present none of the actual manifestations of the disease. At present, the mother has failed to present any symp¬ toms of the disease while the father con¬ tinues to respond in a positive manner to the test.—"Treponema Pallidum Found at Autopsy, in the Blood-Stream and Else¬ where, in a Case of Congenital Syphilis," H. C. Clark, MD, and I. N. Gates, MD, Ancon, CZ.
Downloaded From: http://archpedi.jamanetwork.com/ by a University of Pennsylvania User on 06/19/2015
.
.
.
.
.
.
.
.
.
Ginsberg-Fellner, MD,
William A.
A 15-month-old girl was successfully treated for substantial hyperosmolarity in the absence of ketosis at the onset of permanent insulin-requiring diabetes mellitus. Hypotonic solutions containing small amounts of glucose and subcutaneous administration of low doses of insulin were employed. Potassium was added to the hydrating solutions during the second hour of treatment. In the next three months, two recurrences of this syndrome were verified and successfully treated in a similar manner.
syndrome of hyperosmolar Theverified diabetes adults
non¬
ketotic
mellitus has been in since 1957.1-4 In 1965 ten young children who died due to this illness were briefly de¬ scribed,0 and a year later, the first case in a surviving child was re¬ ported." Since that time, only three other children have been described who survived with permanent insu¬ lin-requiring diabetes mellitus. Re¬ cently, we treated a 15-month-old girl who had this syndrome. In the three months following the initial diag¬ nosis, she had two additional hyper¬ osmolar nonketotic episodes and an episode of classical diabetic ketoaci¬ dosis. She has continued to require daily insulin injections and has grown and developed at a normal rate over the 2Vè years of subsequent follow-up. REPORT OF A CASE The
patient
was
born
spontaneously
six
Received for publication March 15, 1973; accepted June 12, 1974. From the Department of Pediatrics, Mount Sinai School of Medicine of the City University of New York.
Reprint requests to Department of Pediatrics, Mount Sinai School of Medicine of the City University of New York, 11 E 100th St, New York, NY 10029 (Dr. Ginsberg-Fellner).
Primack,
MD
weeks before term after an uncomplicated gestation. The mother was 21 years old and Rh-positive, and she had a negative se¬ rologie test for syphilis. The vertex deliv¬ ery was accomplished under epidural anes¬ thesia after a labor of 4Vè hours. The baby's Apgar score was 8 at one minute and 10 at five minutes. Nasotracheal suc¬ tion and oxygen were used during the first five minutes of life only. The baby's birth weight was 1.93 kg (4.3 lb), length was 43 cm (17.0 in), and head circumference was 29 cm (11.4 in). The neonatal course was uneventful and the baby was discharged from the hospital at 20 days of age, weigh¬ ing 2.28 kg (5.0 lb). For the first year of life, the patient did well except for a viral exanthem at age 10 months. At age 15 months, she weighed 10 kg (22.0 lb), walked well with support, and spoke sev¬ eral words. Three days prior to her first hospital ad¬ mission, she began to vomit and was found to have a temperature of 38.4 C (101.1 F). A diagnosis of gastroenteritis was made in the emergency room and she was treated at home with clear fluids and four doses of aspirin given at least eight hours apart. Two days later, after repeated episodes of vomiting, severe dehydration was noted. Her weight had fallen to 8.6 kg (19.0 lb). She was given intravenously 750 ml of a solution of 0.3% sodium chloride in 5% dex¬ trose in the emergency room. Her weight increased by 0.32 kg (0.7 lb) and she was sent home. A blood sample taken prior to therapy showed a glucose level of 1,160 mg/100 ml; sodium level, 144 mEq/liter; potassium level, 4.8 mEq/liter; blood urea nitrogen (BUN) level, 11 mg/ml; and a calculated serum osmolarity of 349 mOsm/liter. (The serum osmolarity is cal¬ culated as follows: mOsm/liter 2 (sodium level, mEq/liter) =
mEq/liter glucose level, mg/100
ml
~^18
Values greater than 310 mOsm/liter de-
hyperosmolarity.) The pa¬ recalled and admitted to the hos¬ pital after an 18-hour delay. At this time, a five-day history of polyuria was obtained and it was learned that the patient had taken only about 240 ml of liquid orally during the 24 hours preceding her admis¬ sion to the hospital. On admission, the child was lethargic and had a high-pitched cry. Bilateral otitis media was present. Her weight was 8.69 kg (19.2 lb); length, 78.3 cm (30.8 in); and tem¬ perature, 39.4 C (103 F). The serum sodium level was 159 mEq/liter; potassium level, 4.3 mEq/liter; chloride level, 125 mEq/ liter; carbon dioxide level, 17.5 mEq/liter; BUN level, 44 mg/100 ml; glucose level, 1,350 mg/100 ml; and calculated serum osmo¬ larity, 393 mOsm/liter. Arterial pH was 7.37; plasma insulin level, 25/iU/ml; plas¬ ma free fatty acid level, 920 mEq/liter; and plasma growth hormone level, greater than 50 ng/ml. The laboratory data and treatment dur¬ ing the first 16 hours of hospitalization are shown in the Figure. Ketonuria was absent or present in only small amounts during this entire period. A solution of glucose, 2.5 gm/100 ml, in water was given intrave¬ nously for only two hours (between the fourth and sixth hours of therapy). Five units of insulin was given subcutaneously at the third hour of therapy and again at the 14th hour. During the next ten hours, no additional insulin was given. Thus, the patient received approximately 1 unit of insulin injection per kilogram during the first 24 hours of therapy. Potassium chlo¬ ride, 40 mEq/liter, was added to the intra¬ venous solutions beginning with the second hour of therapy and was given until a fourhour period of oliguria developed at the tenth hour of therapy. The oliguria dis¬ appeared when the rate of fluid adminis¬ tration was increased. A total of 1,030 ml of intravenous solu¬ tions was given from the 16th to the 24th hour. These contained sodium, 51 mEq/ note substantial
tient
was
Downloaded From: http://archpedi.jamanetwork.com/ by a University of Pennsylvania User on 06/19/2015
Intravenous Fluid, ml
Sodium Chloride,
mEq/Liter
Potassium Chloride,
Glucose, gm/100 ml Insulin, Units
mEq/Liter
|95)~ 235 *|* 170 —f*70*j\V\* 26 -f- 39 -»-4-26-4— |0k
(
40
0
*f*
2.5
"4*
*j 51 H -j* ' *|*25*) 0 -*\ 500
Serum Osmolarity, mOsm/Liter
Blood Glucose, mg/100 ml
Time, hr Blood glucose level, calculated serum osmolarity, and treatment during hospitalization in 15-month-old diabetic weighing 8.69 kg (19.2 lb).
liter; potassium, 25 mEq/liter; chloride, 51 mEq/liter; lactate, 25 mEq/liter; and glu¬ cose, 2.5 gm/100 ml. Total fluid adminis¬ tered over the first 24 hours of hospitaliza¬ tion was 2,100 ml or 220 ml/kg of body weight. Thus the patient received in 24 hours a total of the following: sodium, 12 mEq/kg; potassium, 6 mEq/kg; chloride, 14.5 mEq/kg; lactate, 3.5 mEq/kg; and glu¬ cose, 3.4 gm/kg. However, less than 0.5 gm of glucose per kilogram was given during
the first 16 hours of therapy. The course was complicated by a gener¬ alized seizure that lasted five minutes at the 23rd hour of therapy. Blood drawn dur¬ ing the seizure showed the following val¬ ues: glucose level, 340 mg/100 ml; sodium level, 146 mEq/liter; chloride level, 110 mEq/liter; calcium level, 8.0 mg/100 ml; magnesium level, 2.0 mg/100 ml; and calcu¬ lated serum osmolarity, 317 mOsm/liter. A lumbar puncture was performed immedi¬ ately after the seizure had subsided. Cere¬ brospinal fluid (CSF) was clear and had a protein concentration of 29 mg/100 ml, a chloride concentration of 172 mEq/liter, and a glucose concentration of 700 mg/100 ml. Thus, the CSF glucose level was still much higher than the blood glucose level. There were four lymphocytes per cubic milliliter and no bacteria on culture. Phénobarbital was given in a dose of 45 mg daily. This was later increased to 60
initial 16 hours of
mg/day
and has been continued at that level to the present time. During the second 24 hours of hospitali¬ zation, the patient was given subcutaneously a total of 8 units of insulin in four doses of 2 units each. During the same in¬ terval, she received intravenously 3,300 ml of fluids that contained glucose, 2.5 gm/100
ml; potassium, 25 mEq/liter; sodium, 39 mEq/liter; chloride, 39 mEq/liter; and lac¬ tate, 25 mEq/liter.
On the morning of the third day of hos¬ pitalization, 5 units of isophane insulin suspension was given subcutaneously. This same dose administered daily provided ad¬ equate control during the remaining three weeks of hospitalization. After the patient was discharged from the hospital, she was treated during a two-month period in the outpatient diabetic clinic. The long-acting isophane insulin suspension dose was grad¬ ually increased to 9 units given once a day. Her weight rose to 9.86 kg (21.7 lb) and urine acetonuria was consistently absent. In the following month, however, she was readmitted to the hospital on three oc¬ casions. On two of these readmissions she had severe hyperosmolarity without ke¬ tosis, and on the third she was in diabetic ketoacidosis. At the time of the first readmission, serum sodium level was 139 mEq/ liter; potassium level, 5.9 mEq/liter; chlo¬ ride level, 110 mEq/liter; carbon dioxide
level, 19.0 mEq/liter; glucose level, 1,500 mg/100 ml; BUN level, 25 mg/100 ml; arte¬ rial pH, 7.37; and calculated serum os¬ molarity, 361 mOsm/liter. This episode was apparently precipitated by failure to drink a sufficient quantity of liquids and by repeated episodes of vomiting. The pa¬ tient again responded rapidly to intra¬ treatment with a solution of 0.3% sodium chloride that did not contain glu¬ cose for the first eight hours of therapy. Potassium chloride, 40 mEq/liter, was also administered intravenously starting at the second hour of therapy. The dose of potas¬ sium chloride was decreased to 25 mEq/ liter beginning with the ninth hour of ther¬ apy. For the first 48 hours of therapy, insu¬ lin was given in four doses of 2 units each injected subcutaneously every six hours. On the third hospital day, the patient was venous
again given isophane insulin suspension. Satisfactory control was achieved with 10 units of isophane insulin suspension per •day. The patient was discharged in good condition on the sixth hospital day. However, she was again admitted to the hospital ten days later because of repeated episodes of vomiting and insufficient oral liquid intake. At this time, serum sodium level was 145 mEq/liter; potassium level, 116 chloride level, 6.2 mEq/liter; mEq/liter; carbon dioxide level, 17.0 mEq/liter; glucose level, 1,440 mg/100 ml; BUN level, 28 mg/100 ml; arterial pH, 7.33; and calculated serum osmolarity, 370 mOsm/liter. A therapeutic regimen identi¬ cal to that described during her second hospitalization was employed, except that the concentration of the solution of potas¬ sium chloride that was given intravenously was kept constant at 25 mEq/liter. During this admission, which lasted six days, the dose of isophane insulin suspension was in¬ creased to 11 units/day. Thirteen days after her third discharge from the hospital, she was again admitted to the hospital with classical diabetic ketoacidosis. At this time, serum sodium level was 130 mEq/liter; potassium level, 6.5 mEq/liter; chloride level, 118 mEq/ liter; carbon dioxide level, 5.0 mEq/ liter; glucose level, 720 mg/100 ml; ar¬ terial pH, 7.14; and calculated serum os¬ molarity, 300 mOsm/liter. The ketoacidosis cleared after 12 hours of intravenous ther¬ apy with 1,500 ml of fluid containing so¬ dium, 77 mEq/liter, and glucose, 2.5 gm/100 ml. Sodium bicarbonate, 40 mEq/ liter, was administered in the first three hours of therapy. Potassium chloride, 40 mEq/liter, was added at the beginning of the third hour of therapy. Twelve units of insulin was given subcutaneously in three divided doses over the 12-hour period dur¬ ing which intravenous therapy was used.
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During this hospitalization the patient's condition was finally controlled with a dose of 12 units of isophane insulin suspension once a day. Recurrent bilateral otitis media was present during these repeated hospitalizations, but this infection was eventually cured by prolonged antibiotic treatment.
During the 18 months following her hospitalization, the patient gained 3.83 kg (8.4 lb). During this time her condi¬ fourth
tion was maintained on an insulin dose of 12 units of isophane insulin suspension given once a day. It is interesting to note that electroencephalograms taken 36 hours, six months, and one year after the patient experienced a convulsion during her first hospitalization were all entirely normal. Developmental screening tests at ages 25 and 36 months, using the Knobloch et al7 modification of the Gesell infant test¬ ing scale, indicated that the patient func¬ tioned appropriately for her age.
COMMENT There are complete reports of only ten children with hyperosmolar non¬ ketotic diabetes mellitus in the litera¬ ture.6-811 Six of these children died during the initial therapy, and severe
pancreatic /3-cell degeneration
was
found at postmortem examination.911 Five of these patients were born pre¬ maturely or had a history of neuro¬ logical impairment. Only four of the reported patients survived after treatment. Two of these have mon¬ golism and a third is an infant born prematurely.88 The latter infant and one other surviving infant9 developed in a normal manner. To our knowl¬ edge, no recurrences of hyperosmolar nonketotic diabetes in childhood have previously been described. A comparison of the 11 well-docu¬ mented cases shows many similar¬ ities. None of the patients had diabe¬ tes prior to the appearance of the hy¬ perosmolarity. Eight were less than 2 years of age. All had a history of ex¬ cess fluid loss, secondary to fever, vomiting, or polyuria, and all suffered severe dehydration. An extremely high initial blood glucose level (aver¬ aging 1,048 mg/100 ml) was noted in all patients. The five young survivors received between 1 and 6 units of in¬ sulin injection per kilogram during the first 24 hours of treatment. Of these patients, only one received sub¬ stantial amounts of glucose during
the first 12 hours of intravenous ther¬ apy, and he had the lowest blood glu¬ cose level (770 mg/100 ml) of any of the reported survivors." Five of the six patients who died received sub¬ stantial amounts of glucose in their initial hydrating solutions and 2 to 72 units of insulin injection per kilogram in the first 24 hours of treatment.
However, one patient with mongol¬ ism died, although he received only
small amounts of glucose intrave¬ nously and VA units of insulin injec¬ tion per kilogram during the first day of therapy.1" It thus appears that administration of smaller doses of insulin and initial intravenous use of solutions with little or no glucose are associated with the most favorable outcome. Early addition of potassium to hy¬ drating solutions may also be impor¬ tant, as severe hypokalemia has been described, particularly in adults.4 The pathogenesis of severe hyper¬ glycemia without ketosis is still not well understood. By far the largest percentage of cases have occurred in adults in whom the case fatality rate approaches 50%.' The most obvious clinical feature in all cases is severe dehydration. In children, the pre¬ dominance of patients under 2 years of age or with neurological damage strongly suggests that inappropriate responses to thirst or inability to take sufficient liquids orally in the pres¬ ence of vomiting, fever, or diarrhea may be the primary factor in the pathogenesis of the syndrome. The course of nonketotic hyperosmolar di¬ abetes then parallels that observed in the experimental model in rats pretreated with hydrocortisone acetate and rendered moderately diabetic with streptozotocin or alloxan.42 In such animals, water deprivation is the primary requirement for the develop¬ ment of the hyperosmolarity, which, in turn, is known to inhibit free fatty acid release from adipose tissue. Any insulin that is present then further depresses this lipolysis. The fact that all juvenile patients showed symp¬ toms at the onset of their diabetes mellitus when some endogenous insu¬ lin is still being produced lends sup¬ port to the hypothesis that this small amount of insulin may be sufficient to
adipose tissue lipolysis in this insulin-sensitive tissue. Re¬ ported insulin levels in adult patients with this syndrome have usually been low.4 In one child with mongolism, pancreatic insulin content was dimin¬ ished at postmortem examination.11 In our patient, a single determination of serum immunoreactive insulin con¬ centration, which was obtained prior to therapy, was inappropriately low for the elevated blood glucose concen¬ tration present. However, the free fatty acid level was not substantially higher than that recorded in our labo¬ ratory for nondiabetic children of similar ages. The elevated growth hormone level in our patient con¬ trasts with the low levels reported in adults.4 This finding may reflect the enormous stress of the patient's ill¬ ness or confirm previously reported elevated levels of growth hormone in "juvenile" diabetics."-14 The syndrome of hyperosmolar nonketotic diabetes mellitus should be considered whenever a young child has substantial glucosuria and severe hyperglycemia without ketosis. Other causes of this syndrome, as previous¬ ly reported in adults (including di¬ azoxide [Hyperstat],15 diphenylhydantoin,111 and corticosteroid17 therapy), should also be considered, although they have not yet been reported in children. In addition, in all young children with similar laboratory find¬ ings, the possibility of inappropri¬ ately diluted formulas18 and severe gastroenteritis must always be enter¬ tained.19 A detailed history and, if possible, laboratory data should be obtained prior to institution of ther¬ apy. However, it may be wise in all cases to start with low doses of insu¬ lin, since such doses are also now rec¬ ommended for the treatment of clas¬ sical ketoacidosis.20 This procedure was used successfully in the treat¬ ment of one episode of ketoacidosis in inhibit most
our
patient.
References 1. Sament S, Schwartz MB: Severe diabetic stupor without ketosis. S Afr Med J
1957. 2. Jackson WPU: A critical appraisal of mechanisms concerned in non-ketotic hy-
31:893-896,
Downloaded From: http://archpedi.jamanetwork.com/ by a University of Pennsylvania User on 06/19/2015
perosmolar diabetic coma. Postgrad Med J 47(suppl):399-402, 1971. 3. McCurdy DK: Hyperosmolar hyperglycemic nonketotic diabetic coma. Med Clin North Am 54:683-699, 1970. 4. Gerich JE, Martin MM, Recant L: Clinical and metabolic characteristics of hyperosmolar nonketotic coma. Diabetes 20:228-238, 1971. 5. Nabarro JDN: Diabetic acidosis: Clinical aspects, in Leibel BS, Wrenshall GA (eds): On the Nature and Treatment of Diabetes. Amsterdam, Excerpta Medica Foundation, 1965, p 560. 6. Vaan GA de: Hyperosmolair diabetisch coma zonder ketoacidose. Maandschr Kindergeneesk 34:279-283, 1966. 7. Knobloch H, Pasamanick B, Sherard ES Jr: A developmental screening inventory for infants. Pediatrics 38:1095-1104, 1966. 8. Ehrlich
RM, Bain HW: Hyperglycemia and hyperosmolarity in an 18-month\x=req-\ old child. N Engl J Med 276:683-684, 1967.
Ago
60 Years
9. Rubin HM, Kramer R, Drash A: Hyperosmolarity complicating diabetes mellitus in childhood. J Pediatr 74:177-186, 1969. 10. Belmonte MM, Colle E, Murphy DA, et al: Nonketotic hyperosmolar diabetic coma in Down's syndrome. J Pediatr
77:879-881,
1970.
Kogut MD, Landing BH: Coma and hyperglycemia in the absence of ketonemia: Present in a 12-year-old boy. Am J Dis Child 114:676-683, 1967. 12. Bavli S, Gordon EE: Experimental diabetic hyperosmolar syndrome in rats. Diabetes 20:92-98, 1971. 13. Johansen K, Hansen AP: High 24\x=req-\ hour level of serum growth hormone in juvenile diabetes. Br Med J 2:356-357,1969. 14. Drash A, Field JB, Garces LY, et al: Endogenous insulin and growth hormone response in children with newly diagnosed 11.
diabetes mellitus. Pediatr Res 2:94-102, 1968. 15. Charles MA, Danforth E Jr: Non-
ketoacidotic hyperglycemia and coma during intravenous therapy in uremia. Diabe-
20:501-503, 1971. 16. Limas CJ, Samad A, Seff D: Hyperglycemic nonketotic coma as complication of steroid therapy. NY State J Med 71:1542-1543, 1971. 17. Goldberg EM, Sanbar S: Hypernonketotic coma following adglycemic ministration of Dilantin (diphenyl hydantoin). Diabetes 18:101-106, 1969. 18. Jung AL, DoneAK: Extreme hyperosmolality and "transient diabetes": Due to inappropriately diluted infant formula. Am J DiCh118:859-863, sild 1969. 19. Stevenson RE, Bowyer FP: Hyperglycemia with hyperosmolal dehydration in nondiabetic infants. J Pediatr 77:818\x=req-\ 823, 1970. 20. Alberti KFMM, Hockaday JDR, Turner RC: Small doses of intramuscular insulin in the treatment of diabetic coma. Lancet 2:515-522, 1973. tes
in AJDC Congenital Syphilis
The patient, a female child, 2 months old, of Panamanian parentage, was admitted to Ancon Hospital, Dec. 20, 1913. The father . had a chancre in June, 1910. The Wassermann test was again positive in December, 1913. .
.
.
.
.
The mother
.
was
admitted to the
ma-
ternity wards of Ancon Hospital, Oct. 23, 1913. . Her delivery was accomplished by a cesarean section. The baby was read.
.
.
.
. .
mitted at the age of 2 months. The temperature ran an average course of about 100 degrees, the pulse averaging 132, and respirations 36. The child died twelve hours after its admission to the hospital. The clinical factors present and the father's known condition led to the diagnosis of congenital syphilis. Anatomical Report.\p=m-\Autopsy3763. Performed three hours and twenty minutes after the death of the child. Smears from blood of jugular vein were stained with a polychrome stain (Hastings).... At¬ tention was arrested by the presence in al¬ most every field of from one to three or more treponemas with the characteristic morphology of T. pallidum. Similarly stained smears from the liver near the gummatous-like region revealed .
.
.
.
.
.
the
organisms in fair numbers. A protracted search in smears from
same
more
spleen and bone-marrow and lymph-nodes resulted in sparse findings of the same na¬ ture. A Wassermann test
on
the cadaver
obtained and found
positive. Microscopical Report.—Skin: This speci¬
was
.
.
.
taken from the anterior surface of the right thigh and although no vari¬ ation in its histology was noted in the sec¬ tions stained with hematoxylin and eosin, yet in Levaditi preparations T. pallidum, in fair numbers, were found in focal man¬ ner in the superficial layers of the corium. Brain: No lesion was found in any of the preparations. After a tedious search over many specimens of Levaditi preparations a few forms were found which faithfully represented T. pallidum. Noguchi's identification of this organism in the brain in cases of general paralysis made it seem quite likely that this case of congenital syphilis would easily reveal the presence of T. pallidum in fair numbers. Heart: It was disappointing to find these preparations of the heart among the most difficult in the body in our case in which to locate the organism. There was no men was
.
.
.
...
relation between those found and a focal lesion or perivascular space. Liver: Sections from the dome of the right lobe were not far from normal. Sections from the gummatous-like margin showed almost complete destruction of the liver tissue. This case presents one instance in which, at present, all the conditions conform to Colles' law. The mother at the time of the death of the child and again six months later reacted in a negative manner to the Wassermann test performed by Dr. L. B. Bates according to Noguchi's modification of the test. Pearce claims that it has al¬ ways been a question whether immunity is real or whether the mother is so lightly in¬ fected as to present none of the actual manifestations of the disease. At present, the mother has failed to present any symp¬ toms of the disease while the father con¬ tinues to respond in a positive manner to the test.—"Treponema Pallidum Found at Autopsy, in the Blood-Stream and Else¬ where, in a Case of Congenital Syphilis," H. C. Clark, MD, and I. N. Gates, MD, Ancon, CZ.
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