J Pediatr Endocr Met 2014; 27(11-12): 12271231

Patient report
Wenjing Li, Chunxiu Gong*, Di Wu and Min Liu

Two case reports of severe pediatric hyperosmolar

hyperglycemia and diabetic ketoacidosis
accompanied with rhabdomyolysis and acute
renal failure
Introduction

Abstract
Objective: This report describes two adolescent males in
China who suffered from type 2 diabetes mellitus (T2DM)
and hyperglycemic hyperosmolar syndrome (HHS) complicated by rhabdomyolysis (RM). After sufficient fluid
administration, both patients recovered.
Design: Case report.
Results: These two obese patients suffered from T2DM,
DKA and HHS. Because of insufficient fluid administration, these patients became aggravated and suffered from
RM. After aggressive fluid resuscitation and insulin injection, the conditions of the two patients improved. Insulin
administration was ceased after approximately 1 month of
subcutaneous injections. The two patients attained good
glucose control with diet management.
Conclusions: HHS is one of the most severe complications
of T2DM. RM is a sign that the condition of a patient with
HHS may worsen. Although management strategies are
undefined, effective fluid infusion was shown to be helpful. Thus, the early signs of HHS and RM should be recognized so as to avoid severe complications.
Keywords: diabetic ketoacidosis (DKA); hyperglycemic
hyperosmolar state (HHS); obese adolescent; rhabdomyolysis (RM); type 2 diabetes.
DOI 10.1515/jpem-2014-0131
Received March 23, 2014; accepted June 10, 2014; previously published online July 18, 2014
*Corresponding author: Chunxiu Gong, MD, PhD, Endocrinology
and Genetics Metabolism Department, Beijing Childrens Hospital,
Capital Medical University, No. 56, South Lishi Road, Xicheng
District, Beijing, P. R. China, Phone: +86 13370115001,
Fax: +86 01059618682, E-mail: chunxiugong@163.com
Wenjing Li, Di Wu and Min Liu: Endocrinology and Genetics
Metabolism Department, Beijing Childrens Hospital, Capital
Medical University, Beijing, China

Recent trends indicate a rising incidence of type 2 diabetes mellitus (T2DM) in children younger than 18 years, with
increases in morbidity due to obesity year after year (15).
The prevalence of T2DM in patients under the age of 20 in
2050 may be up to four times that in 2010 (6). There are
some severe complications of T2DM occurring in adolescents that were previously seen only in adults (7). In addition, the incidence of severe complications has increased
in recent years. Hyperglycemic hyperosmolar syndrome
(HHS) has been a rare pediatric complication of diabetes
mellitus (DM) in the past. HHS is characterized by hyperglycemia and hyperosmolality with or without metabolic
acidosis (8, 9). HHS is typically associated with T2DM,
while diabetic ketoacidosis (DKA) is usually caused by type
1 DM (10). The prognosis of HHS is worse than that of DKA.
HHS might cause thrombosis, rhabdomyolysis (RM), renal
failure, and irreversible cardiac arrhythmias (1113). The
medical literature contains a few reports of RM caused by
HHS occurring in adolescents with T2DM (7, 1421). Herein,
we report on two adolescent patients newly diagnosed with
T2DM complicated with DKA and HHS, and presenting with
RM during treatment on the first day after admission. The
relevant literature is reviewed, and the experiences of identifying and treating such patients are summarized so as to
aid in finding a useful therapeutic regimen.

Case reports
The two patients were obese adolescent males, both
healthy previously. They were presented at the emergency
room and admitted immediately.
Case 1 was 11.5years old and had complained of chest
distress for 6 days. He went to another hospital 6 days
before admission, where myocarditis was suspected; he

Brought to you by | University of California - San Francisco

Authenticated
Download Date | 2/17/15 10:16 AM

1228Li etal.: HHS and DKA with rhabdomyolysis

was given glucose solution or nutrients intravenously
daily, and he gradually became remarkably lethargic. He
had generalized weakness for 2 days, presented polyuria
and polydipsia for 10 h, and then was presented to the
emergency room. The blood glucose level was high, and
urine glucose and ketones were both positive.
The patient presented with chest distress and lethargy after being treated with a large infusion of glucose
solution. He was diagnosed with T2DM complicated with
severe dehydration and DKA based on signs of polydipsia,
polyuria, obesity, acanthosis nigricans, and dehydration.
The serum glucose level was >33.3 mmol/L, and the osmolality was >320 mOsm/L. Urine ketones were positive, and
the venous pH was <6.8. Early stage shock was diagnosed
because of symptoms of unconsciousness, tachycardia,
and the presence of striae on the flanks. Resuscitation and
acidosis correction treatment were given immediately. The
fluid infusion speed for the first step was 13.9 mL/(kg h),
and the subsequent fluid infusion speed was reduced to
1.7 mL/(kg h). However, after fluid infusion for 5 h, the
patient deteriorated to an unconscious state accompanied with a decrease in blood pressure, and urine output
decreased sharply. The urine color changed to dark red,
while laboratory evaluation revealed elevated levels of
creatinine, creatine kinase-MB (CK-MB), and myoglobin.
These results led to the diagnosis of RM and acute renal
failure. The patient was diagnosed with T2DM accompanied with DKA-HHS and severe dehydration. The main
manifestations and laboratory examination results are
detailed in Tables 1 and 2. The patients parents were generally healthy.
The patients urine output and blood pressure
decreased, which indicated that the shock worsened.
The fluid infusion speed was increased to 200 mL/h
[2.7 mL/(kg h)], and hemofiltration was performed; the
boy gradually recovered. Myalgia with weakness of limbs
occurred after the patient recovered consciousness.

Table 1Main manifestations of the two patients.

Item

Age, years

Polyuria, days

Consciousness

Weight loss

Dehydration

Deep breathing

Capillary refill time, s

Blood pressure, mm Hg
Body mass index, kg/m2
Acanthosis nigricans

Case 1

11.5

0.5

Lethargic
+

Severe
+

>3

125/50
25.4

Case 2
14.5
1
Lethargic
+
Severe
+
>3
135/80
26
+

Table 2Physical examination and laboratory test data of the two

patients.
Item

Case 1

Case 2

Blood glucose, mmol/L

pH

d-3-Hydroxybutyric acid, mmol/L

HbA1c,%

Sodium, mmol/L

Corrected serum sodium, mmol/L

Effective serum osmolality, mOsm/L
Creatine kinase, IU/L

Myoglobin, ng/L

Blood urea nitrogen, mmol/L

47.25
6.8
9.47
11.2
134.3
149.2
327.6
20,784
>1000
17.31

68.11
7.05
11.61
13.0
127
149.3
334.4
12,362
>1000
12.73

Electromyography was performed; neither myogenic nor

neurogenic impairments were found. RM may have been
the cause of the myalgia. The patient took regular subcutaneous insulin injections for 33 days. He was discharged
and given dietary treatment.
Case 2 complained of fatigue for 3days and polyuria
for 1 day. He imbibed a large amount of sugary beverages
and milk due to extreme thirst the night before admission,
and then he experienced lethargy and stupor. He was
sent to our hospital, and it was found that his peripheral
blood glucose level was higher than the limit that could be
tested; urine ketones and electrolytes were abnormal, etc.
He became extremely lethargic after drinking large
quantities of cola, fruit juice, and milk. He was diagnosed with T2DM complicated with severe dehydration,
DKA, and HHS based on clinical manifestations. Early
stage shock was diagnosed due to symptoms of unconsciousness, tachycardia, and the presence of striae on the
flanks. Fluid resuscitation was administered immediately.
However, after fluid infusion for 13 h, the patient deteriorated to a coma accompanied with a decreased blood
pressure and anuria. The urine color after fluid infusion
was dark red, and laboratory evaluation revealed elevated
creatinine, CK-MB, and myoglobin levels. The diagnosis of
RM and acute renal failure was made based on these laboratory tests (Table 1).
The fluid infusion speed at the beginning was
11.7mL/(kg h), and then it was reduced to 2.0 mL/(kgh).
As a consequence of an apparently insufficient fluid
supplementation, the patients urine output and blood
pressure decreased, which indicated that the shock
was worsening. To increase the fluid supplementation,
the speed of the fluid infusion was quickly increased
to 5.8 mL/(kg h) combined with the administration of
vasoactive agents, which increased the urine output
and stabilized the blood pressure. Ten hours later, the
infusion speed was decreased to 2.3 mL/(kg h) and the

Brought to you by | University of California - San Francisco

Authenticated
Download Date | 2/17/15 10:16 AM

Li etal.: HHS and DKA with rhabdomyolysis1229

administration of vasoactive agents was maintained. The

boy recovered consciousness 2days later. He was treated
with regular insulin injections for 1 month. The patient
was discharged and kept on dietary treatment.

Discussion
The two patients were diagnosed with T2DM combined
with severe dehydration, DKA-HHS, and early stages of
shock. These are the first two cases of HHS complicated
by RM, hypovolemic shock, and acute renal failure out
of more than 1700 diabetic patients hospitalized in our
hospital in the last 40 years whom we have treated and
managed. No RM has been reported to have occurred in
diabetic children or adolescents previously.
RM is a syndrome characterized by breakdown of
muscle tissue, followed by dispersion of its intracellular
components into the circulatory system (22). The released
intracellular components include electrolytes, purines,
enzymes (e.g., creatine kinase), and myoglobin, which
cause impairment of body homeostasis and organ function. In diabetic patients with HHS, energy supplementation is insufficient and metabolic disturbances destroy
the structure of the muscle cells (23). Hyponatremia,
hypernatremia, hypokalemia, and hypophosphatemia
may disrupt the cell membrane homeostasis, mainly by
disturbing the Na/K ATPase pump, and result in RM (22).
Normally, the muscle function in RM patients recovers
with no sequelae in most patients. However, life-long
weakness and atrophy may persist (24) if large amounts
of myocytes become necrotic or the pathogenic factors
are not eliminated. Singhal et al. (25) concluded that
serum sodium, serum osmolality, and blood glucose are
the major determinants for the occurrence of RM in the
diabetic state.
Both of the patients imbibed sweet drinks or were
administered a solution containing glucose, which led to
the aggravation of the hyperglycemia. Increasing levels of
osmolality and blood glucose might trigger HHS (25). The
low level of insulin also results in lipolysis, thus causing
ketosis. In T2DM patients, hyperglycemia increases
plasma osmolarity and polyuria, resulting in dehydration.
After the first step of intravenous fluid compensation,
we reduced the speed of fluid infusion according to DKA
guidelines, which aggravated the hypovolemic shock.
Consequently, ATP production was reduced, causing the
ATP-dependent sodium-potassium pump to not function
properly, resulting in RM (26).
Four cases of T2DM combined with DKA and HHS,
with the development of RM, have been reported in the

literature (20). Successful treatment depended on a

large fluid infusion given at an early stage, at a speed of
715 mL/(kg h) over 10 h. All patients experienced successful fluid resuscitation at the early stages, but regardless of the intensive treatment, all suffered from RM. One
patient was newly diagnosed with T2DM combined with
DKA and HHS (7). An insufficient fluid supply caused the
RM. Another patient (14) was complicated with slight RM
during fluid therapy at an early stage of severe shock. The
Pediatric Association of the Netherlands (NVK) guideline
distinguishes the treatment of DKA from HHS. Correction
of intravascular hypovolemia with fluid replacement is
the most important initial treatment in children with HHS.
If adequate fluid replacement does not decrease serum
glucose levels satisfactorily, administration of insulin
should be considered (12).
Massive osmotic diuresis in HHS patients can result
in severe dehydration, with fluid losses estimated to be
twice as those of DKA patients (27). The hypertonicity
of the hyperosmolar state maintains the intravascular
volume, which can mask the clinical signs of dehydration.
Low osmolality in plasma can result in water movement
from the intravascular to the intracellular space (11). For
both patients described here, the severity of dehydration
may have been underestimated due to patient obesity,
which caused the inadequate fluid resuscitation. Singhal
etal. (25) reported that serum osmolality levels and blood
glucose are the major determinants of the occurrence of
rhabdomyolysis in the diabetic state. Insufficient fluid
infusion might be the main cause of RM. When patients are
treated for severe HHS and acidosis, the severe damage due
to dehydration must be adequately considered and appropriate management should be carried out under intensive
supervision (28). In the cases reported here, the low speed
of fluid infusion aggravated the condition of dehydration,
which was reversed by increasing the fluid infusion speed.
Although the combination of HHS and DKA with T2DM
in children has been reported, there is no standard protocol available for management (29, 30). We recommend
treating RM caused by HHS with the following methods.
To treat dehydration due to HHS, fluid infusion equal
to 1215% of the body weight should be administered
(7). Patients with HHS should undergo more rapid fluid
replacement than that recommended for DKA patients
(31). A minimum initial bolus of 20 mL/kg of isotonic
saline (0.9% NaCl) with repeated boluses should be given
until peripheral perfusion is restored. After the initial
boluses, the fluid deficit should be replaced over 12days
(7). Colloid fluid may be administered intravenously if
necessary. After volume expansion, vasoactive agents
can be administered once needed. For adult patients, it

Brought to you by | University of California - San Francisco

Authenticated
Download Date | 2/17/15 10:16 AM

1230Li etal.: HHS and DKA with rhabdomyolysis

is recommended (26) that 0.9% saline is initially administered at 1500 mL/h, followed by 300500 mL/h when the
circulatory volume is stable. In addition, the urine output
should be >200 mL/h. The choice of the fluid should be
individualized based on serum electrolytes (7).
Sever etal. (32) reported that mannitol administration
can remove liquids from the damaged muscular interstitium and increase urine output, which might prevent acute
kidney failure. However, Cervellin etal. (26) proposed that
there is little clinical support for the use of bicarbonate,
mannitol, or furosemide. In addition, hemodialysis may
be initiated when water and electrolyte disturbances or
acute renal failure exists (33). Furthermore, appropriate adequate fluid administration can lower the serum
glucose level. Low-dose and late insulin administration is
recommended (7, 28).
Here, we reported two cases of patients diagnosed
with RM caused by DKA-HHS in adolescents with T2DM
in China. These cases highlight that severe complications
may occur in pediatric diabetic patients. RM has also been
reported in a patient suffering from fulminant type 1 DM
(34); therefore, early and aggressive fluid resuscitation
and intensive monitoring may prevent severe complications such as acute renal failure and reduce the mortality.
Funding: The Capital Development Fund 2009-1046.

References
1. Liu LL, Lawrence JM, Davis C, Liese AD, Pettitt DJ, etal. Prevalence of overweight and obesity in youth with diabetes in USA:
the SEARCH for Diabetes in Youth study. Pediatr Diabetes
2010;11:411.
2. Mayer-Davis EJ, Beyer J, Bell RA, Dabelea D, DAgostino RJ, etal.
Diabetes in African American youth: prevalence, incidence, and
clinical characteristics: the SEARCH for Diabetes in Youth Study.
Diabetes Care 2009;32:S11222.
3. Liu LL, Yi JP, Beyer J, Mayer-Davis EJ, Dolan LM, etal. Type 1
and Type 2 diabetes in Asian and Pacific Islander U.S. youth:
the SEARCH for Diabetes in Youth Study. Diabetes Care
2009;32:S13340.
4. Bell RA, Mayer-Davis EJ, Beyer JW, DAgostino RJ, Lawrence JM,
etal. Diabetes in non-Hispanic white youth: prevalence, incidence, and clinical characteristics: the SEARCH for Diabetes in
Youth Study. Diabetes Care 2009;32:S10211.
5. Haines L, Wan KC, Lynn R, Barrett TG, Shield JP. Rising incidence of type 2 diabetes in children in the U.K. Diabetes Care
2007;30:1097101.
6. Imperatore G, Boyle JP, Thompson TJ, Case D, Dabelea D, etal.
Projections of type 1 and type 2 diabetes burden in the U.S.
population aged <20years through 2050: dynamic modeling
of incidence, mortality, and population growth. Diabetes Care
2012;35:251520.

7. Tsai SL, Hadjiyannakis S, Nakhla M. Hyperglycemic hyperosmolar syndrome at the onset of type 2 diabetes mellitus in an
adolescent male. Paediatr Child Health 2012;17:246.
8. Nyenwe EA, Kitabchi AE. Evidence-based management of hyperglycemic emergencies in diabetes mellitus. Diabetes Res Clin
Pract 2011;94:34051.
9. Canarie MF, Bogue CW, Banasiak KJ, Weinzimer SA,
TamborlaneWV. Decompensated hyperglycemic hyperosmolarity without significant ketoacidosis in the adolescent
and young adult population. J Pediatr Endocrinol Metab
2007;20:111524.
10. Cochran JB, Walters S, Losek JD. Pediatric hyperglycemic hyperosmolar syndrome: diagnostic difficulties and high mortality
rate. Am J Emerg Med 2006;24:297301.
11. Rosenbloom AL. Hyperglycemic hyperosmolar state: an emerging pediatric problem. J Pediatr 2010;156:1804.
12. Mul D, Meijer CR. Hyperglycaemic crises in children and adolescents. Ned Tijdschr Geneeskd 2013;157:A5185.
13. Stoner GD. Hyperosmolar hyperglycemic state. Am Fam Phys
2005;71:172330.
14. Bassham B, Estrada C, Abramo T. Hyperglycemic hyperosmolar
syndrome in the pediatric patient: a case report and review of
the literature. Pediatr Emerg Care 2012;28:699702.
15. Cao B, Gong C, Wu D, Gu Y, Meng X, etal. Clinical features of
new-onset diabetes complicated by a combination of diabetic
ketoacidosis and hyperglycemia hyperosmolar syndrome in
children. J Clin Pediatr 2012;30:11059.
16. Murthy S, Sharara-Chami R. Aggressive fluid resuscitation in
severe pediatric hyperglycemic hyperosmolar syndrome: a case
report. Int J Pediatr Endocrinol 2010;2010:379063 (Epub 2010
Mar 18).
17. Kim MS, Muratore C, Snelling L, Mandelbaum DE, McEachern R,
etal. Ischemic stroke and rhabdomyolysis in a 15-year-old girl
with paraganglioma due to an SDHB exon 6 (Q214X) mutation.
J Pediatr Endocrinol Metab 2009;22:56571.
18. Al-Matrafi J, Vethamuthu J, Feber J. Severe acute renal failure in
a patient with diabetic ketoacidosis. Saudi J Kidney Dis Transpl
2009;20:8314.
19. Hoorn EJ, de Vogel S, Zietse R. Insulin resistance in an 18-yearold patient with Down syndrome presenting with hyperglycaemic coma, hypernatraemia and rhabdomyolysis. J Int Med
2005;258:2858.
20. Carchman RM, Dechert-Zeger M, Calikoglu AS, Harris BD. A new
challenge in pediatric obesity: pediatric hyperglycemic hyperosmolar syndrome. Pediatr Crit Care Med 2005;6:204.
21. Hollander AS, Olney RC, Blackett PR, Marshall BA. Fatal malignant hyperthermia-like syndrome with rhabdomyolysis complicating the presentation of diabetes mellitus in adolescent
males. Pediatr 2003;111(6 Pt 1):144752.
22. Keltz E, Khan FY, Mann G. Rhabdomyolysis. The role of diagnostic and prognostic factors. Muscles Ligaments Tendons J
2013;3:30312.
23. Izumi T, Shimizu E, Imakiire T, Kikuchi Y, Oshima S, etal. A
successfully treated case of hyperosmolar hyperglycemic state
complicated with rhabdomyolysis, acute kidney injury, and
ischemic colitis. Intern Med 2010;49:23216.
24. Pistor K, Graben N, Heber F, Kreuzfelder E, Bartholome K. Nontraumatic rhabdomyolysis with reversible acute kidney failure
following hyperosmolar diabetic coma in a child. Monatsschr
Kinderheilkd 1984;132:514.

Brought to you by | University of California - San Francisco

Authenticated
Download Date | 2/17/15 10:16 AM

Li etal.: HHS and DKA with rhabdomyolysis1231

25. Singhal PC, Schlondorff D. Hyperosmolal state associated with
rhabdomyolysis. Nephron 1987;47:2024.
26. Cervellin G, Comelli I, Lippi G. Rhabdomyolysis: historical background, clinical, diagnostic and therapeutic features. Clin Chem
Lab Med 2010;48:74956.
27. Kitabchi AE, Umpierrez GE, Miles JM, Fisher JN. Hyperglycemic crises in adult patients with diabetes. Diabetes Care
2009;32:133543.
28. Wetter J, Gohlke BC, Stutte S, Woelfle JF. Pediatric hyperglycemic hyperosmolar coma diabeticum: diagnostic evaluation and
therapeutic concept. Klin Padiatr 2012;224:2631.
29. Nwosu BU, Adhami S, Rogol AD. Stroke in a child with AdamsOliver syndrome and mixed diabetic ketoacidosis and hyperglycemic hyperosmolar syndrome. J Pediatr Endocrinol Metab
2012;25:35761.

30. Zeitler P, Haqq A, Rosenbloom A, Glaser N. Hyperglycemic

hyperosmolar syndrome in children: pathophysiological considerations and suggested guidelines for treatment. J Pediatr
2011;158:914.
31. Petzold S, Kapellen T, Siekmeyer M, Hirsch W, Bartelt H, etal.
Acute cerebral infarction and extra pontine myelinolysis in children with new onset type 1 diabetes mellitus. Pediatr Diabetes
2011;12:5137.
32. Sever MS, Vanholder R, Lameire N. Management of crushrelated injuries after disasters. N Engl J Med 2006;354:105263.
33. Rosenbloom AL. Hyperglycemic crises and their complications
in children. J Pediatr Endocrinol Metab 2007;20:518.
34. Huang Z, Xu L, Li F, Deng W, Li Y. Fulminant type 1 diabetes mellitus with rhabdomyolysis: have we overlooked the situation?
Diabetes Res Clin Pract 2010;90:e479.

Brought to you by | University of California - San Francisco

Authenticated
Download Date | 2/17/15 10:16 AM