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Hyperosmolar Hyperglycemic State: A Historic Review of The Clinical Presentation, Diagnosis, and Treatment
Hyperosmolar Hyperglycemic State: A Historic Review of The Clinical Presentation, Diagnosis, and Treatment
adult patient with severe polydipsia, of patients with diabetic coma, noting (glycogenolysis) and by inadequate use
polyuria, and a large amount of glucose that not all cases presented with the char- of glucose by peripheral tissues, pri-
in the urine followed by progressive acteristic Kussmaul respiration or positive marily muscle. From the quantitative
decline in mental status and death (8). urine acetone or diacetic acid (22–26). standpoint, increased hepatic glucose
Several case reports followed this publi- These reports created confusion and production represents the major patho-
cation, describing patients with newly di- were taken with skepticism, as the genic disturbance responsible for hyper-
agnosed or previously known diabetes source of ketone bodies and the role of glycemia in DKA (34). As the glucose
presenting with drowsiness or coma, acetoacetic acid in the pathogenesis of concentration and osmolality of extra-
most of them with a peculiar breath diabetic coma were not known at the cellular fluid increase, an osmolar gra-
odor resembling acetone (9). In 1857, time. Many physicians were against ac- dient is created that draws water out of
Petters (10) detected a substance in cepting that adult patients could prog- the cells. Glomerular filtration is ini-
the urine of a fatal case of diabetic ress to diabetic coma in the absence of tially increased, which leads to glucosu-
coma that resembled acetone in its reac- ketonuria. For example, in the 1930s, ria and osmotic diuresis. The initial
tion with sulfuric acid and caustic alkalis Elliot P. Joslin (17) and others (27) glucosuria prevents the development
and was later recognized as acetoacetic stated that the presence of acetone or of severe hyperglycemia as long as the
in response to insulin therapy and nor- cause of HHS in essentially all series and and trauma, that provokes the release
malization of blood glucose concentra- occurs in 40–60% of patients, with the of counterregulatory hormones and/or
tion (39). most common precipitating infections compromises the access to water can re-
being pneumonia (40–60%) and urinary sult in severe dehydration and HHS. In
Precipitating Factors tract infection (5–16%) (40–42). Up to most patients, restricted water intake is
HHS occurs most commonly in elderly pa- 20% do not have a previous diagnosis of due to the patient being bedridden or re-
tients with type 2 diabetes. Infection rep- diabetes (7). Underlying medical illness, strained and is exacerbated by the altered
resents the commonest precipitating such as stroke, myocardial infarction, thirst response of the elderly. Certain
medications associated with metabolic plasma bicarbonate level of 17.0 6 6 osmolality are .340 and 320 mOsm/kg,
decompensation and HHS include gluco- mEq/L, a mean arterial pH of 7.31, and respectively (32,63).
corticoid, thiazide diuretics, phenytoin, an average plasma glucose level of
b-blockers, and more recently atypical 1,076 6 350 mg/dL (range 650–1,780 Evolution of HHS treatment
antipsychotics (43–49). mg/100 mL). Current diagnostic criteria In the 19th century and preinsulin
Recent case reports and series sug- of HHS recommended by the American era, a large number of treatment mo-
gest an increasing incidence of this dis- dalities were recommended to treat di-
Diabetes Association (ADA) and interna-
order in children and adolescents abetic coma. Kussmaul tried blood
tional guidelines include a plasma
(50,51). In children, most common pre- transfusions with only temporary results.
glucose level .600 mg/dL, plasma ef-
cipitating causes are diseases of the cir- Reynolds (64) published two cases of re-
fective osmolarity .320 mOsm/L, and covery with castor oil followed by 63
culatory, nervous, and genitourinary
an absence of significant ketoacidosis grains of citrate of potassium. In the
systems (52). In addition, some children
(Table 2) (4,58,59). The term HHNK late 1900s, the most common therapeu-
with T1DM may present with features
was replaced with “hyperglycemic hy- tic regimen was the administration of
of HHS (severe hyperglycemia) if high-
carbohydrate–containing beverages have perosmolar state” to reflect the fact subcutaneous and intravenous saline so-
Table 2—Diagnostic criteria of HHS first reported by Arieff and Carroll and current ADA criteria
Arieff and Carroll (56) ADA (4)
Plasma glucose, mg/dL .600 .600
Arterial pH N/A .7.30
Serum bicarbonate, mEq/L N/A .18
Urine or serum ketones by nitroprussiate test
(acetoacetate) 0 to 2 pluses Negative or small
Serum b-hydroxybutyrate, mmol/L N/A ,3 mmol/L
Total serum osmolality, mOsm/kg* .350 N/A
Effective serum osmolality, mOsm/L** N/A .320
Anion gap, mEq/L N/A Variable
Mental status N/A Variable; most patients present with stupor, coma
*Total serum osmolality formula = 2(Na) + 18/glucose + BUN/2. **Effective serum osmolality formula = 2(Na) + 18/glucose.
3128 Hyperosmolar Hyperglycemic State Diabetes Care Volume 37, November 2014
of 200–400 units i.v. soluble insulin de- In 1973, Alberti et al. (69) were the studies have been conducted in patients
pending on the severity of the mental first to report the successful treatment with HHS, and those patients are treated
status. Three arbitrary stages were of patients with diabetic coma using following the protocols designed to treat
used to guide initial bolus doses: stage small intramuscular doses of regular in- DKA. Low-dose insulin infusion protocols
1, drowsy but easily rousable; stage 2, sulin. They treated 14 patients with have been shown to be effective, with res-
rousable with difficulty; and stage 3, un- ketoacidosis, one patient with hyperosmo- olution of hyperglycemia in ;9 6 2 h and
conscious on admission. These re- lar nonketotic coma, and two cases of hy- resolution of HHS in 11 6 1 h (7).
searchers suggested giving an initial perglycemic nonketotic state with an initial The importance of hydration and
injection of 200 units to patients in stage mean dose of 16 6 2 units followed by electrolyte replacement has been recog-
1, 300 units to patients in stage 2, and 5 or 10 units i.v. or i.m. every hour. The nized in the management of patients
400 units to patients in stage 3, followed patients’ plasma glucose rates fell at a with HHS (32,72). Isotonic saline (0.9%
by boluses of 50 units i.v. injected into regular rate of 90 mg/h (69). The authors NaCl) is recommended at 15–20 mL/kg
drip tubing every 30 min until the urine reported a cumulative insulin dose of during the first 1–2 h, followed by 250–
became free of acetone bodies (67). ,100 units per day, which was a significant 500 mL/h until resolution of the hyper-
From 1950 to the 1970s, most experts reduction from previous reports that used glycemic crisis. Fluid replacement alone
Table 3—Evolution of treatment regimens for patients with diabetic coma and HHS
Years (reference nos.) Insulin therapy Fluids Other
Preinsulin era (13,14) d NS/3% NS (s.c.) Alcohol, laxatives, alkalies,
salicylate, oxygen inhalations,
castor oil and citrate of
potassium, camphor and ether,
caffeine, circulatory stimulants
1930–1950 (17,27) 20–100 units i.v. or s.c. bolus NS (s.c. or i.v.) at variable rates Routine gastric lavage, cleansing
followed by 20 units s.c. every enema, blood transfusion
30–60 min depending on
glucosuria
1950–1970s (29,88,89) 2 units/kg bolus of crystalline NS followed by hypotonic Gastric aspiration
insulin; up to 920 units in the solution ;30 mL/kg or 600–800
first 7 h cc 3 m2
Early 1970s (54,68,90) 50 units i.v. bolus followed by NS at 1–1.5 L over the first 2 h, Add 20 mEq potassium to the
50–80 units/h i.v. or s.c. followed by hypotonic solution at second or third liter of fluid when
;100 mL/h potassium level is ,6.0 mEq/L
Late 1970s (60,71) Low-dose insulin regimens. NS at 1–2 L over the first 2 h, Risk of hypokalemia during
Regular insulin 0.1 units/kg i.v. followed by NS or half NS. Add insulin treatment identified. Early
followed by 0.1–0.3 units/h i.v., dextrose-containing solutions potassium replacement when
s.c., or i.m. when glucose ;250 mg/dL serum potassium ,5.5 mEq/L
1990s (7) 0.1 units/kg i.v. bolus, then 0.1 0.9% saline, 500–1,000 mL/h for No gastric lavage or gastric
units/kg/h as continuous infusion 2 h, then switch to 0.45% saline at suction recommended
until glucose level ,13.8 mmol/L 250–500 mL/h. Add dextrose-
(250 mg/dL) containing solutions when
glucose ;250 mg/dL
2004–2009 (4,87): ADA Initial bolus (0.1 units/kg i.v.), NS at 500–1,000 mL/h
consensus for treatment of followed by 0.1 units/kg/h until for 2–4 h, then 0.45% saline at
DKA and HHS in adult patients glucose ,250 mg/dL, then 250–500 mL/h
reduce insulin by 50%
2011 (59): Pediatric Endocrine In HHS: no intravenous insulin 20 mL/kg NS bolus until adequate Dantrolene*
Society guidelines for bolus, start at 0.025–0.05 tissue perfusion
treatment of HHS in children units/kg/h when no decline
in glucose with fluids alone; in
hyperosmolar DKA: start
0.05–0.1 units/kg/h
NS, normal saline (0.9% NaCl). *If a malignant hyperthermia-like syndrome is suspected.
care.diabetesjournals.org Pasquel and Umpierrez 3129
which cause a shift of potassium from of free fatty acids and counterregulatory patients than in DKA patients (5,7).
the intracellular compartment into hormones are comparable between pa- Thus, prospective studies are needed
plasma (74,75). During insulin treat- tients with DKA and HHS. Additional to determine effective and safe insulin
ment and hydration, serum potassium studies are also needed to determine and hydration strategies, as well as to
levels rapidly fall; therefore, it is recom- the role of inflammatory and oxidative determine glucose targets during intra-
mended that potassium replacement stress markers and clinical outcomes in venous insulin infusion and during the
should be initiated when serum levels fall patients with hyperglycemic crises. Elu- transition to subcutaneous insulin ther-
,5.5 mEq/L, with the goal to maintain a cidating the roles of these pathways apy in patients with HHS.
serum potassium concentration in the might provide valuable information for
range of 4–5 mEq/L. reducing the high cardiovascular and
Arieff and colleagues (56,76,77) first thrombotic morbidity rates associated Duality of Interest. No potential conflicts of
reported the development of brain with hyperglycemic emergencies. interest relevant to this article were reported.
Author Contributions. F.J.P. reviewed the
edema, a feared complication of treat- Hospitalizations for HHS in children literature and drafted the manuscript. G.E.U.
ment after rapid correction of hyper- and adolescents have increased signifi- critically reviewed and revised the manuscript.
glycemia and hyperosmolality. They cantly in recent reports. Population
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