Case Report Dengue Hemorrhagic Fever Grade III with Diabetic Ketoacidosis: A Case Report

Pra-on Supradish M D * , N u a n p h o n g R i e n m a n e e M D * * , A d i d s u d a F u e n g f o o M D * , Siripen K a l a y a n a r o o j M D * * Department of Pediatrics, Queen Sirikit National Institute of Child Health, College of Medicine, Rangsit University, Bangkok, Thailand ** Phyathai 2 Hospital, Bangkok, Thailand

A 16-year-old, previously healthy Thai girl presented with DHF grade III. Fifteen hours after the first episode of shock, she had received an excessive amount of crystalloid isotonic solution and 20 ml per kilograms of Dextran-40 however she still had persistently rapid pulse rate and high hematocrit but also had polyuria with more than 4 mllkglhr of urine output. She was re-evaluated. Clinical signs showed severe dehydration with some ascites without signs of pleural effusion. Blood gas revealed increased anion gap metabolic acidosis. The cause of polyuria and metabolic acidosis was identified with hyperglycemia, ketouria and glucosuria. Afterwards she was diagnosed and treated as DHF grade III andDKA. Besides insulin administration, fluid resuscitation was very crucial. Intravenous fluid rehydration was needed while the unnecessary extra-volume could cause massive plasma leakage and later on fluid overload. Volume replacement was adjusted to degree of dehydration when signs of volume overload were monitored closely. She was out ofDKA at 14 hours after the start of insulin and the intravenous fluid was stopped at 27 hours (36 hours after the first episode of shock). The final diagnosis was DHF grade III, diabetes mellitus with DKA and hepatitis. Keywords: Dengue Hemorrhagic Fever, Diabetic ketoacidosis

JMedAssocThai2011;94(Suppl.3):S233-S240 Full text. e-Journal: http://www.mat.or.th/journal

D e n g u e virus infection is o n e of the m o s t important m o s q u i t o - b o r n e viral diseases in h u m a n s . About 50 million dengue virus infections and 25,000 deaths occur yearly''' worldwide. Clinical manifestations include undifferentiated fever. D e n g u e Fever ( D F ) and D e n g u e H e m o r r h a g i c F e v e r ( D H F ) . T h e r e are 4 grades of D H F severity: grade I and II without shock; grade III shock and g r a d e I V profound s h o c k ' - ' . D H F g r a d e III a n d I V a r e a l s o c a l l e d D e n g u e S h o c k S y n d r o m e (DSS)'^'. T h e p r e s e n t e d patient presented with shock caused not only by plasma leakage found in D H F but also o s m o t i c diuresis found in diabetic ketoacidosis ( D K A ) . Case Report A previously healthy, 16-year-old T h a i girl from Samut Prakarn p r o v i n c e presented with a 5-day history of fever without other s y m p t o m s and a 2-day
Correspondence to: Supradish P, Department of Pediatrics, Queen Sirikit National Institute of Child Health, Bangkok 10400, Thailand. Phone: 0-2345-8333 ext. 3333 E-mail: praonsu@yahoo.com

history of bleeding per g u m , vomiting and poor appetite. S h e h a d b e e n t a k i n g o n l y a c e t a m i n o p h e n a n d oral electrolyte solution ( O R S ) . O n the day of a d m i s s i o n , she had n o fever but she felt very w e a k and had coffee ground vomiting once. Her body weight was 40 k i l o g r a m s (kg) and height w a s 154 c m . Initial physical examination at a c o m m u n i t y hospital showed an afebrile g i r l w i t h o u t s i g n s of p l e u r a l e f f u s i o n , a s c i t e s o r h e p a t o m e g a l y . H e r hematocrit ( H c t ) w a s 5 4 % ; w h i t e b l o o d cell c o u n t ( W B C ) w a s 8 , 0 0 0 / m c L w i t h 4 9 % neutrophils (N), 4 0 % lymphocytes (L), 1 0 % m o n o c y t e s ( M ) and 1 % e o s i n o p h i l (E); platelet c o u n t w a s 1 0 , 0 0 0 / m c L . Liver function test results i n c l u d e d an a l b u m i n c o n c e n t r a t i o n of 3.4 g / d L , aspartate a m i n o t r a n s f e r a s e ( A S T ) of 1,090 U / L a n d alanine aminotransferase (ALT) of 8 0 0 U / L . O n e hour after a d m i s s i o n , she d e v e l o p e d s h o c k w i t h a b l o o d pressure ( B P ) of 1 3 0 / 1 1 0 m m H g , pulse rate ( P R ) of 190 b e a t s / m i n and Hct of 5 6 % . S h e w a s initially d i a g n o s e d as D H F g r a d e III and received 10 milliliters per k i l o g r a m s ( m l / k g ) of 5 % D e x t r o s e in N o r m a l Saline intravenously. After the l o a d i n g d o s e ; B P w a s 130/100 m m H g ; P R w a s 136 beats/min; and Hct was 54%.

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S h e w a s transferred to the d e n g u e w a r d at the Q u e e n S i r i k i t N a t i o n a l I n s t i t u t e of C h i l d H e a l t h ( Q S N I C H ) b e c a u s e she had a persistently rapid pulse rate ( 1 3 0 - 1 4 2 b e a t s / m i n ) and high Hct ( 5 4 - 5 6 % ) even t h o u g h there w a s n o fever and the B P w a s about 120/ 8 0 - 1 3 0 / 8 0 m m H g . Five h u n d r e d ml of D e x t r a n - 4 0 w a s g i v e n in one h o u r before referral in conjunction with 1 0 % Calcium Gluconate, Vitamin K l and 20 ml of diluted 7 . 5 % S o d i u m Bicarbonate because carbon dioxide (from electrolyte results) w a s 10 m m o l / L . S e v e n h o u r s after s h o c k , her total i n t r a v e n o u s intake w a s 2,900 ml with 5 % Dextrose in N o r m a l Saline, Acetar and Dextran. T h e calculated amount of her maintenance fluid requirement p l u s 5 % deficit w a s 3,900 m l for 2 4 h o u r s after s h o c k and the urine output, r e c o r d e d from urinary catheter, w a s 1,200 ml (4.3 ml/kg/hr). T h e Hct after Dextran w a s 44%. O n admission at Q S N I C H , 9 hours after shock, she w a s afebrile and had g o o d c o n s c i o u s n e s s . P R w a s 140 b e a t s / m i n , B P w a s 1 4 0 / 9 0 m m H g and respiratory rate ( R R ) w a s 38 breaths/min. L u n g signs s h o w e d equal b r e a t h s o u n d s , n o c r e p i t a t i o n s or w h e e z i n g . H e r a b d o m e n w a s t e n d e r at the epigastric area, w i t h the liver e n l a r g e d 1 c m b e l o w the right costal m a r g i n , with no splenomegaly. Meningeal signs were absent. Petechial rash w a s present at b o t h a r m s and legs with a positive t o u r n i q u e t test. O t h e r p h y s i c a l findings w e r e unremarkable. Laboratory results s h o w e d Hct of 4 9 % , W B C 1 1 , 2 5 0 / m c L with 5 7 % N, 2 9 % L, 6 % M and 8 % atypical l y m p h o c y t e s (ATL); platelet c o u n t w a s 10,000 / m c L . Liver function tests included an a l b u m i n concentration of 2.54 g/dL, cholesterol of 133 m g / d L , A S T of 941 U/L, A L T of 5 1 2 U/L, total bilirubin of 0.61 m g / d L and direct bilirubin of 0.22 m g / d L . Venous blood gas revealed p H 7.22, p C 0 2 15.5 m m H g , H C O , - 6.1 m m o l / L and b a s e e x c e s s ( B E ) - 1 8 m m o l / L . B l o o d c h e m i s t r i e s disclosed ionized c a l c i u m 1.33 m m o l / L , B U N 13.17 m g / d L and creatinine 0.45 m g / d L . Blood sugar from glucose meter w a s 2 8 7 m g / d L . Pleural effusion and infiltration could not b e n o t i c e d from a portable chest x-ray in supine position. After six h o u r s in the d e n g u e w a r d (15 h o u r s after shock), she vomited about 3 0 ml once. N o diarrhea,

fever or active b l e e d i n g w a s observed. For 6 hours her intake w a s 7 9 0 ml and urine w a s 1,410 m l , with total intake of 3,690 ml. Despite c o n t i n u o u s administration of s o d i u m b i c a r b o n a t e and 5 % D e x t r o s e in Ringer Acetate ( 5 % D A R ) , she still had a very rapid pulse rate ( m o r e than 150 b e a t s / m i n ) , rising Hct up to 5 5 % and persistent m e t a b o l i c acidosis (pH 7.23, p C 0 2 13.7 m m H g , H C O , 5.6 m m o l / L and B E -19 m m o l / L ) even t h o u g h she passed adequate urine (about 5.9 ml/kg/ hr). T h e s e c o n d dose of D e x t r a n - 4 0 w a s given at the s a m e time as the patient w a s re-evaluated. T h e patient had a past history of polyuria i n c l u d i n g n o c t u r i a , p o l y d i p s i a and p o l y p h a g i a for s e v e r a l m o n t h s . H e r g r a n d m o t h e r and her m o t h e r d e v e l o p e d d i a b e t e s m e l l i t u s ( D M ) w h i c h had been controlled with oral diabetic drugs at age of 5 0 and 3 0 years respectively. T h e patient did not take any t o x i c s u b s t a n c e s , a l c o h o l or m e d i c a t i o n . P h y s i c a l e x a m i n a t i o n revealed signs of severe dehydration with dry lips, s u n k e n eyeballs, and tachycardia (PR of 140 b e a t s / m i n ) with a B P of 130/90 m m H g . T h e patient's b o d y m a s s index ( B M I ) w a s 17. A c a n t h o s i s nigricans w a s not present. T h e patient had tachypnea without s i g n s of p l e u r a l e f f u s i o n or p u l m o n a r y e d e m a . A b d o m i n a l e x a m i n a t i o n s h o w e d the liver enlarged 2 c m below the right costal margin and ascites. Additional investigations revealed blood sugar 390 mg/dL, sodium 127 with corrected sodium'^'** 132.8, potassium 5 . 5 1 , chloride 103 and carbondioxide 3.8 m m o l / L with anion gap'^"*' of 26 m m o l / L (formulations to calculate corrected sodium in h y p e r g l y c e m i a condition and anion gap are shown in Table 1). Urine analysis demonstrated positive urine sugar (3+) and positive urine ketone (4+) without any cells. C o a g u l o g r a m results contained prothrombin time (PT) of 14.6 s e c o n d s (10.0-13.4) with INR of 1.3, partial thromboplastin time of 50.1 seconds (24.7-37.2), and thrombin time of 6.3 s e c o n d s (4.5-6.0). Only sinus t a c h y c a r d i a w a s p r e s e n t in t h e e l e c t r o c a r d i o g r a m . E r y t h r o c y t e sedimentation rate ( E S R ) w a s 3 m m / m i n . Serum ketone, C-peptide and autoimmune markers: antig l u t a m i c acid d e c a r b o x y l a s e ( a n t i - G A D ) , islet cell antigen 5 1 2 antibody (anti A I - 2 ) , anti-islet and antii n s u l i n a u t o a n t i b o d i e s w e r e not sent d u e to s o m e limitations.

Table 1. Formulations to calculate corrected sodium in hyperglycemia and anion gap''' Formulation Corrected sodium (Na)(mmoI/L) Anion gap (mmol/L) . Na + 2 [(glucose mg/dl - 100) x 100] Na - (CI + HC03)

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At this point, the patient w a s d i a g n o s e d as D H F grade III with diabetic ketoacidosis. Intravenous fluid w a s changed to Acetar solution without dextrose. After a consultation with a pediatric endocrinologist, c o n t i n u o u s i n t r a v e n o u s a d m i n i s t r a t i o n of r e g u l a r i n s u l i n w a s s t a r t e d at 0.1 u n i t / k g / h r a n d f l u i d resuscitation w a s adjusted due to degree of dehydration and severity of D K A with close m o n i t o r i n g of signs of excessive plasma leakage. Acetar w a s given at 10 m l / kg/hr in 2 hours because of clinical severe dehydration, then BP w a s 120/90 m m H g and PR w a s 110 beats/min and the rate of fluid w a s gradually titrated d o w n . Blood sugar by glucose meter, urine sugar, and ketone w e r e m o n i t o r e d e v e r y h o u r w h i l e Hct, e l e c t r o l y t e s and venous blood gas w e r e monitored every 4 hours; vital signs and urine output were m o n i t o r e d hourly until stable then every 4 hours according to DKA'"^^' and DHF'-**' m a n a g e m e n t guidelines. Potassium chloride w a s added in i n t r a v e n o u s fluid a c c o r d i n g to b l o o d potassium level and only O R S with s o d i u m 75 m E g / L w a s allowed orally. T h e r e w a s an attempt to limit total fluid intake at a v o l u m e of maintenance plus 5 % deficit (3,900 ml) per day. Eight hours after c o n t i n u o u s regular insulin drip with m a x i m a l dose at 0.14 unit/kg/hr, the patient's blood sugar w a s 218 m g / d L . Intake w a s 2,100 ml and urine was 2,200 ml. The patient looked mildly dehydrated with slightly increased ascites. T h e n Acetar w a s switched to 5 % D A R at m a i n t e n a n c e rate and the rate of regular insulin w a s gradually decreased. At 14 hours after the beginning of regular insulin and 29 hours after shock, the patient w a s out of D K A with a blood sugar of 199 m g / d L , negative urine sugar and k e t o n e , blood pH 7.43 and H C O , of 18.8 m m o l / L . Intravenous fluid w a s stopped at 20 hours after the b e g i n n i n g of regular insulin (36 h o u r s after s h o c k ) . In total, the patient received 5,800 ml of intravenous fluid including 2 0 ml/kg of Dcxtran-40 within 3 6 hours. Laboratory results revealed B U N of 8.35 m g / d L , creatinine 0.28 mg/dL, A S T and ALT of 5 0 3 and 398 U/L, respectively. Coagulogram w a s normal with an INR of 1.0. Repeated portable chest x-ray s h o w e d no effusion or infiltration. Twenty-seven h o u r s into the treatment, the c o n t i n u o u s r e g u l a r i n s u l i n w a s c h a n g e d to intermittently s u b c u t a n e o u s regular insulin. T w o days after that, insulin could be adjusted to s u b c u t a n e o u s intermediate insulin. N e u t r a l P r o t a m i n e H a g e d o r n ( N P H ) twice a day, and regular insulin w h e n needed. Finally the patient received 24 units of N P H and 12 units of regular insulin in the m o r n i n g before meals, 10 units of regular insulin in the evening before m e a l s and

10 units of N P H at bed t i m e . T h e patient w a s in the hospital for 9 d a y s with diagnosis of D H F grade III, diabetes mellitus with D K A and hepatitis. T h e patient w a s in the convalescent p h a s e with stable vital signs and g o o d appetite on the third day of a d m i s s i o n . T h e later d a y s of her hospital stay were for insulin adjustment, self-injection training and learning about diet control. Additional investigations before discharge s h o w e d h e m o g l o b i n (Hb) A l e of 11.2% and serum insulin of 2 m c U / L , while blood sugar w a s 3 9 0 m g / d L , with n o bacterial g r o w t h in the blood and urine cultures, Hct of 3 8 % and platelet c o u n t of 1 0 0 , 0 0 0 / m c L . P C R for d e n g u e v i r u s w a s negative but dengue antibodies (using e n z y m e i m m u n o a s s a y , E I A ) , taken on the 6th day of illness, w e r e positive with D e n g u e I g M of 4 8 and I g G of 184. O n e w e e k later, the patient c a m e for a f o l l o w - u p with excellent clinical w e l l - b e i n g . Her Hct w a s 3 9 % and platelet count had increased to 4 3 3 , 0 0 0 / m c L . Liver e n z y m e s d e c r e a s e d to n o r m a l as A S T and A L T of 2 7 and 3 4 U / L and albumin w a s 4.32 g/dL. Discussion The patient presented with clinical s y m p t o m s and signs of D H F , a c c o r d i n g to the World H e a l t h O r g a n i z a t i o n c a s e d e f i n i t i o n for D H F ' - ' as s h o w n in T a b l e 2. T h e s e w e r e a h i s t o r y of fever, b l e e d i n g t e n d e n c i e s ; b l e e d i n g per g u m , h e m a t e m e s i s and p e t e c h i a e with positive t o u r n i q u e t test, t h r o m b o c y t o p e n i a (platelet c o u n t of 1 0 , 0 0 0 / m c L ) and e v i d e n c e of p l a s m a l e a k a g e ; h e m o c o n c e n t r a t i o n (Hct of 5 4 % ) a n d h y p o a l b u m i n e m i a ( 3 . 4 g / d L w h i c h decreased to 2.54 g/dL). T h e patient d e v e l o p e d s h o c k with n a r r o w pulse pressure ( B P of 1 3 0 / 1 1 0 m m H g ) , a very rapid pulse rate ( 1 9 0 b e a t s / m i n ) and higher Hct ( 5 6 % ) . T h e initial d i a g n o s i s w a s D H F g r a d e III. After an excessive a m o u n t of crystalloid i n t r a v e n o u s fluid (2,400 ml in 6 hours), w h i c h w a s m o r e than half of the v o l u m e of m a i n t e n a n c e plus 5 % deficit, w a s given, she still had a rapid pulse rate even t h o u g h urine output w a s still more than 4 ml/kg/hr. T h e r e c o m m e n d e d a m o u n t of fluid i n t a k e during the critical (leakage when platelet count < 100,000 / m c L ) p h a s e is m a i n t e n a n c e plus 5 % deficit'^ **''' w h i c h should be divided in 2 4 h o u r s in D S S . F o r e x a m p l e , in this 4()-kg patient, m a i n t e n a n c e p l u s 5 % deficit e q u a l s 3,900 ml. Within 6 hours, the v o l u m e of fluid intake should not exceed 1,000 m l . T h e patient's Hct w a s 5 4 % so the first dose of D e x t r a n - 4 0 w a s g i v e n , then Hct d r o p p e d to 4 4 % . But later on at 15 h o u r s after shock the patient had received

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Table 2. World Health Organization Case Definitions for DF/DHF/DSSP'

Manifestations DF

Case Definitions Probable DF: - Fever of 2 to 7days' duration, with two or more of the following: Headache, retro-orbital pain, myalgia, arthralgia, rash, hemorrhagic manifestations. WBC < 5,000/mcL - and supportive serology or occurrence at the same location and time as other confirmed cases of DF Confirmed cases: by isolation of the dengue virus, demonstration of the dengue virus antigen including by PCR or fourfold change in reciprocal IgM or IgG All of the following must be present: 1. Fever or history of acute fever, lasting 2 to 7 days 2. Hemorrhagic manifestations in the form of at least one of the following: - A positive tourniquet test - Petechiae, ecchymosis, or purpura - Mucosal or gastrointestinal bleeding - Bleeding from injection site or other locations 3. Thrombocytopenia (< 100,000/mcL) 4. Evidence of plasma leakage as evidenced by one or more of the following: - A rise in the Hct (> 20% over baseline or average Hct for age, sex and population) - A drop in Hct following volume replacement treatment > 20% of baseline - Signs of plasma leakage such as pleural effusion, ascites and hypoalbuminemia DHF plus evidence of circulatory failure manifested by: - Rapid and weak pulse - Narrow pulse pressure(<20 mm Hg) or hypotension for age - Cold, clammy skin and altered mental status

DHF "

DSS

3,990 ml of total fluid, equally to amount of maintenance p l u s 5% deficit, s h e still h a d r a p i d p u l s e rate a n d m e t a b o l i c acidosis. W h e n D H F p a t i e n t s s t i l l h a v e s i g n s of i m p e n d i n g s h o c k , for e x a m p l e ; rapid pulse rate (not related to d e g r e e of t e m p e r a t u r e ) or s h o c k and h a v e already r e c e i v e d an e x c e s s i v e a m o u n t of i n t r a v e n o u s fluid, especially m o r e than the a m o u n t of m a i n t e n a n c e p l u s 5 % d e f i c i t a c c o r d i n g t o t i m e , at l e a s t f o u r p a r a m e t e r s should be considered***. T h e first p a r a m e t e r is u s i n g Hct to d e t e r m i n e the m a s s i v e l e a k a g e w i t h high Hct level or bleeding, especially concealed bleeding w h e n the Hct d r o p s or is not as high as the level of h e m o c o n c e n t r a t i o n ( 2 0 % rising Hct from b a s e l i n e ) . S e c o n d , b l o o d gas should be sent to detect m e t a b o l i c acidosis found in p r o l o n g e d shock, b l e e d i n g and other c a u s e s . T h i r d , h y p o g l y c e m i a c a n b e d e t e c t e d in u n r e s p o n s i v e s h o c k . T h e last p a r a m e t e r is b l o o d chemistry including ionized calcium. T h e initial m a n a g e m e n t in this case w a s 10 m l / k g in 1 h o u r of D e x t r a n - 4 0 b e c a u s e of the high Hct w h e n the results of other investigations w e r e p e n d i n g .

T h e p r e s e n t e d patient w a s re-evaluated by h i s t o r y - t a k i n g , p h y s i c a l e x a m i n a t i o n a n d further investigations. T h e striking history w a s that the patient h a d a s e v e r a l - m o n t h s history of p o l y u r i a including nocturia, polydipsia and polyphagia. T h e patient had a good urine output of m o r e than 4 ml/kg/hr even though t h e p a t i e n t w a s in u n r e s p o n s i v e s h o c k . P h y s i c a l e x a m i n a t i o n s h o w e d s i g n s of s e v e r e d e h y d r a t i o n w i t h o u t history of m a s s i v e c o n c u r r e n t loss such as s e v e r e v o m i t i n g a n d d i a r r h e a . S i g n s of s e v e r e dehydration should not be observed in D S S with plasma l e a k a g e w i t h o u t fluid loss outside the body and other distributive s h o c k i n c l u d i n g septic shock. Polyuria w i t h o u t a d e q u a t e fluid replacement can cause severe d e h y d r a t i o n ; so the cause of polyuria in the presented case should be evaluated. T h e patient presented with polyuria and signs of severe dehydration together with hyperglycemia (390 m g / d L ) and increased anion gap m e t a b o l i c acidosis (pH 7.23, p C 0 2 1 3 . 7 m m H g , H C O , 5.6 mmol/L and anion g a p of 2 6 m m o l / L ) . U r i n e e x a m i n a t i o n found positive u r i n e k e t o n e a n d s u g a r . A l l of t h e s e r e s u l t s w e r e

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Table 3. Definition of DKA'"" Criteria 1. Hyperglycemia 2. Acidosis 3. Ketosis ISPAD 2009'") Blood glucose > 11 mmol/L (approximately 200 mg/dL) venous pH < 7.3 or bicarbonate < 15 mmol/L Ketonemia and ketonuria

ADA 2006'3>

Blood glucose > 11 mmol/L (approximately 200 mg/dL) venous pH < 7.25 or arterial/ capillary pH < 7.3 and/or bicarbonate < 15 mmol/L Ketonemia andketonuria

ADA = American Diabetes Association, ISPAD = International Society for Pediatric and Adolescent Diabetes compatible with diabetic ketoacidosis''"*'' as s h o w n in Table 3 . Other causes of increased anion gap m e t a b o l i c a c i d o s i s s h o u l d be e x c l u d e d e s p e c i a l l y p r o l o n g e d shock in D S S ' " " " due to inadequate or delayed fluid r e s u s c i t a t i o n of p l a s m a l e a k a g e or d e l a y e d b l o o d transfusion in case of b l e e d i n g ; acute renal failure as D S S c o m p l i c a t i o n ' " * " ' ; sepsis and toxic s u b s t a n c e s for e x a m p l e : s a l i c y l a t e s , N S A I D , m e t f o r m i n a n d a l c o h o l ' ' ^ ' ' ' . A few can cause ketosis as in D K A for example, alcohol intoxication''^'"* and prolonged starvation'"' which can be ruled out in the presented patient by her history of illness. Sepsis or septic s h o c k w a s unlikely in the present case because her clinical manifestation w a s worse after defervescence; there w e r e n o s y m p t o m s and signs of localized infection and chest x-ray and urinalysis provided no evidence of infection. W B C count and differential count favored viral infection with lymphocytosis and p r e s e n c e of atypical l y m p h o c y t e s without immature neutrophils. E S R w a s low (3 m m / h r ) , which is more c o m m o n in dengue infection than in other viral or bacterial i n f e c t i o n s ' " ' . T h e p a t i e n t ' s s h o c k presented with high diastolic p r e s s u r e , not the l o w diastolic B P seen in septic shock. Stable vital signs responded to fluid resuscitation and declining b l o o d sugar level despite no antibiotics b e i n g g i v e n . Afterwards, b l o o d a n d u r i n e c u l t u r e s d i s c l o s e d n o bacterial growth. A c u t e renal failure w a s e x c l u d e d by n o r m a l and no escalating tendency of B U N and creatinine o n the same day of s h o c k and later d a y s after shock. Prolonged shock caused from massive leakage was unlikely even though her initial shock could have been a result of p l a s m a leakage. T h e patient had evidence of p l a s m a leakage such as ascites w h i c h w a s later detected; h e m o c o n c e n t r a t i o n d e m o n s t r a t e d by 4 7 % rising Hct (with maximal Hct of 5 6 % and m i n i m u m of 3 8 % ) ; h y p o a l b u m i n e m i a at the b e g i n n i n g a n d dropping from 3.4 to 2.54 g/dL within hours. Concealed b l e e d i n g w a s also less possible b e c a u s e of persistently high Hct ( 5 4 - 5 6 % ) and i m p r o v e m e n t of liver e n z y m e s and B U N / creatinine level w h i c h could w o r s e n if the issue of inadequate tissue o x y g e n a t i o n , such as lack of red b l o o d cells to carry o x y g e n , w a s left u n s o l v e d . Later on, especially m a n y h o u r s after s h o c k , unstable vital signs w i t h a rapid p u l s e rate in the c a s e could not be explained solely by a continuingly increasing a m o u n t of plasma leakage. First presentation of s h o c k in D H F is the peak rate of the p l a s m a leakage, after w h i c h the rate of l e a k a g e gradually d e c r e a s e s and usually stops at 2 4 h o u r s after first e p i s o d e of shock'"'^'. T h e p r e s e n t patient still had a rapid pulse rate at 15 h o u r s after s h o c k e v e n t h o u g h e x c e s s i v e amounts of crystalloid and 2 0 ml/kg of Dextran-40 w e r e given and there w a s n o further sign of m a s s i v e l e a k a g e e n o u g h to c a u s e s h o c k s h o w n on the p h y s i c a l examination or chest films. Pleural effusion w a s not s h o w n in the present case from physical e x a m i n a t i o n or portable chest films b u t the s u p i n e position w a s less sensitive to detect right pleural effusion than right lateral d e c u b i t u s . T h e patient m i g h t h a v e presented with m o r e l e a k a g e into a b d o m i n a l space than pleural space. Pleural effusion is m o r e c o m m o n than ascites in D H F ; however, detection of pleural effusion, w h e n there is not a lot of effusion, m a y need a p r o p e r x-ray t e c h n i q u e , or an ultrasound, or a follow-up film during early c o n v a l e s c e n t phase'""'. In a d d i t i o n t o u n s t a b l e v i t a l s i g n s w i t h excessive crystalloid and colloid fluid a d m i n i s t r a t i o n , the i m p o r t a n t clues w e r e p o l y u r i a and increased a n i o n g a p m e t a b o l i c a c i d o s i s w h i c h w a s u n r e s p o n s i v e to fluid and s o d i u m b i c a r b o n a t e r e p l a c e m e n t . D e c r e a s e of intravascular v o l u m e in this case occurred from t w o m a i n c a u s e s : p l a s m a l e a k a g e in D H F and o s m o t i c diuresis from h y p e r g l y c e m i a . After fluid resuscitation to replace fluid loss in urine and insulin to decrease b l o o d sugar and prevent further g l u c o n e o g e n e s i s from lipolysis and proteolysis.

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the patient had more stable vital signs and improvement of m e t a b o l i c acidosis. A c e t a r and 5 % D A R w e r e used b e c a u s e of t h e i r a d v a n t a g e s a b o v e o t h e r i s o t o n i c crystalloid solution in D H F with its additional content especially potassium 4 m E q / L and acetate 2S m E q / L that can be c h a n g e d to b i c a r b o n a t e . A n o t h e r benefit of A c e t a r a b o v e R i n g e r ' s lactate in the p a t i e n t s w i t h elevated liver e n z y m e s w a s that acetate can be changed to b i c a r b o n a t e b u t lactate n e e d s to b e c h a n g e d to a c e t a t e first in t h e l i v e r . H e r b l o o d s u g a r l e v e l progressively d e c r e a s e d along with a decline in urine sugar and urine output, so the a m o u n t of intravenous fluid could be reduced and stopped at 2 0 hours since the start of insulin (36 hours after the first episode of shock). T h e fluid r e p l a c e m e n t in the presented case w a s v e r y c r u c i a l b e c a u s e t h e p a t i e n t had s i g n s of severe dehydration due to o s m o t i c diuresis that need 10-20 m l / k g of fluid resuscitation, but at the s a m e time she w a s in an active p l a s m a leakage p h a s e of DHF. W h e n t h e l o a d i n g d o s e of A c e t a r w a s s t a r t e d , t h e capillary p e r m e a b i l i t y still increased but the rate of leakage d e c r e a s e d b e c a u s e it w a s already 15-16 h o u r s after the first e p i s o d e of shock. T h e u n n e c e s s a r y extra a m o u n t of fluid resuscitation could a g g r a v a t e massive pleural effusion and ascites; later on fluid o v e r l o a d could c o m p r o m i s e respiration and v e n o u s return and acute p u l m o n a r y e d e m a w h e n the patient w a s in the c o n v a l e s c e n t p h a s e w i t h fluid r e - a b s o r p t i o n . T h e a m o u n t of fluid resuscitation should be c o m p o s e d of t h e c o r r e c t i o n of d e h y d r a t i o n and r e p l a c e m e n t of p l a s m a l e a k a g e . In the presented case, the v o l u m e of fluid s u b s t i t u t i o n s h o u l d be able to m a i n l y correct severe d e h y d r a t i o n at the very first h o u r s of the start of D K A m a n a g e m e n t b e c a u s e the rate of leakage at this point w a s very m i n i m a l . After the severe and later m o d e r a t e dehydration w e r e i m p r o v e d , the v o l u m e of the fluid r e p l a c e m e n t should be equal to m a i n t e n a n c e a m o u n t . W h e n the patient w a s able to eat and drink well, the a m o u n t of oral intake should be subtracted from the planned total v o l u m e . D u r i n g the time of fluid r e p l a c e m e n t , the s i g n s of fluid o v e r l o a d had to be m o n i t o r e d i n c l u d i n g the s i g n s of a c u t e p u l m o n a r y e d e m a w h i c h c o u l d o c c u r d u r i n g the c o n v a l e s c e n t phase of D H F (usually h a p p e n e d 3 6 - 4 8 hours after the first e p i s o d e of shock)''''. Finally the p a t i e n t w a s d i a g n o s e d as D M w h i c h might h a v e been h a p p e n i n g for several m o n t h s because Hb A l e w a s more than 6.5%"^' and this episode of D K A w a s precipitated by D H F g r a d e HI. It w a s difficult to classify the type of D M in the presented

patient from the available data. Type I D M is more c o m m o n l y p r e s e n t e d w i t h D K A b e c a u s e of l o w o r a b s e n c e of e n d o g e n o u s i n s u l i n . B u t D K A is not u n c o m m o n in type 2 D M with insulin resistance a n d r e l a t i v e i n s u l i n d e f i c i e n c y , e s p e c i a l l y in a d o l e s c e n t s ' " " " ' . T h e patient presented with insidious onset of disease at puberty and history of D M in her family members which were compatible with type 2 DM. H o w e v e r , the patient w a s not obese and did not have a c a n t h o s i s n i g r i c a n s , w h i c h w a s a sign of insulin resistance"^'"'. L o w levels of insulin and C-peptide can be found in both types. A u t o a n t i b o d y markers for e x a m p l e ; a n t i - G A D , anti-AI2 can be found in 9 0 % of type 1 D M patients even though one third of type 2 D M patients can have one of these markers. Therefore, close f o l l o w - u p and additional investigations w e r e required in this patient. T h e presented patient w a s a good e x a m p l e of D H F occurring with other severe diseases. The patient's presentation w a s not usual D H F grade 111 because the patient also had signs of severe dehydration, polyuria despite sustainably rapid pulse rate and increased anion gap metabolic acidosis. Parameters, which can be found in u n r e s p o n s i v e shock in d e n g u e , should be evaluated in the s a m e time of r e a s s e s s m e n t of other possible causes of individual unusual manifestation. Acknowledgement T h e authors wish to thank the department of virology of the A r m e d Forces Research Institute of M e d i c a l S c i e n c e s for d e n g u e d i a g n o s t i c t e s t i n g ; p e d i a t r i c i a n s , p e d i a t r i c r e s i d e n t s and nurses of the dengue ward at Queen Sirikit National Institute of Child Health for patient care. Potential conflicts of interest None. References 1. World Health Organization. D e n g u e and dengue h e m o r r h a g i c fever. Publication No. 117. Geneva: W H O ; 2008. 2. World Health Organization. D e n g u e hemorrhagic fever: diagnosis, treatment, prevention and control. 2"" ed. Geneva: W H O ; 1997. 3. Wolfsdorf J, Glaser N, Sperling M A . Diabetic ketoacidosis in infants, children, and adolescents: A c o n s e n s u s statement from the A m e r i c a n Diabetes Association. Diabetes Care 2006; 29: 1150-9. 4. Wolfsdorf J, Craig M E , D a n e m a n D, Dunger D, E d g e J, Lee W, et al. Diabetic ketoacidosis in chil-

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dren and adolescents with diabetes. Pediatr Diabetes 2009; 10 (Suppl 12): 118-33. 5. T h a i Society of pediatric E n d o c r i n o l o g y , T h e Royal College of Pediatricians of T h a i l a n d and Pediatric Society of Thailand. M a n a g e m e n t guideline for diabetic ketoacidosis of childhood and adolescence [database on the Internet]. c 2 0 0 8 - 2 0 0 9 [updated 2 0 1 0 S e p 3 0 ; cited 2 0 1 0 D e c 2 9 ] . Available from: http://www.thaipediatrics.org/ demo/download/Diabetic_Ketoacidosis_28_09_ 20101.pdf 6. Klein M, Sathasivam A, N o v o a Y, Rapaport R. R e cent c o n s e n s u s ' s t a t e m e n t s in pediatric e n d o c r i nology: a selective review. Endocrinol M e t a b Clin North A m 2009; 3 8 : 8 1 1 - 2 5 . 7. Kwon KT, Tsai VW. Metabolic emergencies. Emerg Med Clin North A m 2007; 2 5 : 1 0 4 1 - 6 0 . 8. Kalayanarooj S, Nimmannitya S. Guidelines for deng u e / d e n g u e h e m o r r h a g i c fever diagnosis and case m a n a g e m e n t . 2"'' Thai ed. B a n g k o k : Ministry of Public Health, Thailand; 2 0 0 7 . 9. Kalayanarooj S, Nimmannitya S. Guidelines for dengue hemorrhagic fever case m a n a g e m e n t . Bangkok: B a n g k o k Medical Publisher; 2 0 0 4 . 10. Nimmannitya S, Thisyakom U, Hemsrichart V. Dengue h a e m o r r h a g i c fever with unusual manifestations. Southeast A s i a n J T r o p M e d Public H e a l t h 1987; 18:398-406. 11. L a o p r a s o p w a t t a n a K, Pruekprasert P, D i s s a n e e w a t e P, Geater A , V a c h v a n i c h s a n o n g P. O u t c o m e of d e n g u e h e m o r r h a g i c f e v e r - c a u s e d

acute kidney injury in Thai children. J Pediatr 2010; 157:303-9. 12. Ballal S A , M c i n t o s h P. E n d o c r i n o l o g y . In: Custer JW, R A u R E , editors. T h e Harriet Lane h a n d b o o k . 18"'ed. Philadelphia: Elsevier M o s b y ; 2 0 0 9 2 6 9 - 7 3 . 13. S h a n n o n M W , B o r r o n SW, B u r n s M . H a d d a d and W i n c h e s t e r ' s clinical m a n a g e m e n t of p o i s o n i n g and drug o v e r d o s e . 4"' ed. Philadelphia: S a u n d e r s ; 2007. 14. M c G u i r e L C , C r u i c k s h a n k A M , M u n r o PT. A l c o holic ketoacidosis. E m e r g M e d J 2 0 0 6 ; 2 3 : 4 1 7 - 2 0 . 15. Kalayanarooj S, N i m m a n n i t y a S. A study of erythrocyte s e d i m e n t a t i o n rate in d e n g u e h e m o r r h a g i c fever. Southeast A s i a n J T r o p M e d Public Health 1989;20:325-30. 16. Srikiatkhachorn A , K r a u t r a c h u e A , R a t a n a p r a k a r n W, W o n g t a p r a d i t L, N i t h i p a n y a N , K a l a y a n a r o o j S, et al. Natural history of p l a s m a l e a k a g e in d e n g u e h e m o r r h a g i c fever: a serial u l t r a s o n o g r a p h i c study. Pediatr Infect Dis J 2 0 0 7 ; 2 6 : 2 8 3 - 9 2 . 17. A m e r i c a n C o l l e g e of E n d o c r i n o l o g y c o n s e n s u s s t a t e m e n t o n g u i d e l i n e s for g l y c e m i c c o n t r o l . Endocr Pract 2002; 8(Suppl 1): 5 - 1 1 . 18. A l e m z a d e h R, Wyatt DT. Diabetes mellitus in children. In: K l i e g m a n R M , B e h r m a n R E , Jenson H B , Stanton BE, editors. N e l s o n t e x t b o o k of pediatrics. 18"' ed. Philadelphia: Saunders Elsevier; 2 0 0 7 : 2404-27. 19. F o w l e r M J . Classification of d i a b e t e s : not all h y p e r g l y c e m i c is the s a m e ? Clinical D i a b e t e s 2 0 0 7 ; 25:274-6.

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