Expert Review of Endocrinology & Metabolism

ISSN: 1744-6651 (Print) 1744-8417 (Online) Journal homepage: http://www.tandfonline.com/loi/iere20

Management of diabetic ketoacidosis and

hyperglycemic hyperosmolar state in adults

Isabel Anzola M.D, Patricia C. Gomez M.D & Guillermo E. Umpierrez M.D

To cite this article: Isabel Anzola M.D, Patricia C. Gomez M.D & Guillermo E. Umpierrez M.D
(2016): Management of diabetic ketoacidosis and hyperglycemic hyperosmolar state in adults,
Expert Review of Endocrinology & Metabolism, DOI: 10.1586/17446651.2016.1145049

To link to this article: http://dx.doi.org/10.1586/17446651.2016.1145049

Accepted author version posted online: 21

Jan 2016.

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 Publisher: Taylor & Francis

Journal: Expert Review of Endocrinology & Metabolism

DOI: 10.1586/17446651.2016.1145049
Management of diabetic ketoacidosis and hyperglycemic hyperosmolar state in adults

Authors:

Isabel Anzola, M.D.

Downloaded by [Umeå University Library] at 19:08 05 February 2016

Patricia C. Gomez, M.D.

Guillermo E. Umpierrez, M.D.

Institution:

1
Department of Medicine, Division of Endocrinology and Metabolism at Emory University,
Atlanta, GA

Correspondence:

Guillermo Umpierrez, M.D.

Professor of Medicine
Emory University School of Medicine
49 Jesse Hill Jr. Drive
Atlanta, Georgia 30303
Tel: 404- 778 1665
E-mail: geumpie@emory.edu

1
 Abstract:

Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic syndrome (HHS) are two acute
complications of diabetes associated with high mortality rate if not efficiently and effectively
treated. Both entities are characterized by insulinopenia, hyperglycemia and dehydration. DKA
and HHS are two serious complications of diabetes associated with significant mortality and a high
healthcare costs. The overall DKA mortality in the US is less than 1%, but a rate higher than 5% is
reported in the elderly and in patients with concomitant life-threatening illnesses. Mortality in
patients with HHS is reported between 5% and 16%, which is about 10 times higher than the
mortality in patients with DKA. Objectives of management include restoration circulatory volume
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and tissue perfusion, resolution of hyperglycemia, correction of electrolyte imbalance and

increased ketogenesis.

Key Words: ketoacidosis, hyperglycemia hyperosmolar state, diabetic ketoacidosis, hospital, inpatient
care

2
 Diabetic ketoacidosis (DKA) and hyperglycemic hyperosmolar state (HHS) are two serious

complications of diabetes that require prompt recognition, diagnosis and treatment. DKA is common

with approximately 145,000 cases per year in the United States.1 The rate of hospital admissions

for HHS is lower, accounting for less than 1% of all diabetes-related admissions. DKA occurs most

commonly in children and young adults with type 1 diabetes (T1D) and HHS occurs in older

patients with type 2 diabetes (T2D). Although most patients with DKA have autoimmune T1D;

patients with T2D are also at risk during the catabolic stress of acute illness such as trauma,
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surgery or infections.2 Both entities are characterized by insulinopenia, hyperglycemia and

dehydration 3. Clinically, they differ by the presence of increased ketones bodies and severity of

metabolic acidosis (Table 1) 4.

DKA and HHS are two serious complications of diabetes associated with significant

mortality and a high healthcare costs. DKA is the leading cause of mortality in children and young

adults with T1D, accounting for approximately 50% of deaths in children and young adults with

diabetes 5. The overall DKA mortality in the US is less than 1%, but a rate higher than 5% is

reported in the elderly and in patients with concomitant life-threatening illnesses (2-4). Similar

mortality rates have been reported in European countries, but the reported mortality continues to be
6,7
higher than 10% in Indonesia and sub-Saharan African countries . HHS occurs most commonly

in older patients with T2D with an intercurrent illness such as infection, surgery or ischemic

events, and is associated with higher mortality rate than DKA. Mortality in patients with HHS is

reported between 5 and 16% (2; 5-7), which is about 10 times higher than the mortality in patients

with DKA (2; 5-7). The prognosis and outcome of patients with HHS is determined by the severity

of dehydration, presence of co-morbidities and advanced age 8-10.

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 Treatment of DKA utilizes a large number of resources and represents a substantial

economic burden. In the US, it is estimated that DKA episodes represent more than $1 of every $4

spent on direct medical care for adult patients with type 1 diabetes and $1 of every $2 in those

patients experiencing multiple episodes 11. Based on an annual average of 135,000 hospitalizations

for DKA in the U.S., with an average cost of $17,500 per patient, the annual hospital cost for

patients with DKA may exceed $2.4 billion per year 9.

Pathogenesis of DKA and HHS

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The pathogenesis of DKA and HHS is multifactorial and includes a combination of

absolute or relative insulin deficiency, impaired insulin action, and increased concentration of

counterregulatory hormones (glucagon, catecholamines, cortisol, and growth hormone) 3,4 (Figure

1). Hyperglycemia results from increased hepatic glucose production and reduced glucose uptake

in peripheral tissues 12. Increased hepatic glucose production results from increased generation of

gluconeogenic substrates (alanine, lactate and glycerol) 3 and increased activition of gluconeogenic

enzymes (phosphoenol pyruvate carboxykinase, fructose-1,6-bisphosphatase and pyruvate

carboxylase) 12,13. In addition, hyperglycemia above the renal threshold of ~ 10 mmol/L or 180

mg/dL causes osmotic diuresis, dehydration, and decreased glomerular filtration rate; the latter

further aggravates hyperglycemia 3,14.

Severe insulin deficiency is associated with increased activity of the hormone sensitive

lipase in adipose tissue, which results in breakdown of triglyceride into glycerol and high

circulating levels of free fatty acids 12. In the liver, free fatty acids are oxidized to ketone bodies, a

process predominantly stimulated by glucagon. Increased concentration of glucagon lowers the

hepatic levels of malonyl coenzyme A (CoA), the first rate-limiting enzyme in the novo fatty acid

synthesis. Malonyl CoA, inhibits the enzyme carnitine palmitoyl-transferase I (CPT I), modulates

4
 movement of free fatty acid into the hepatic mitochondria where fatty acid oxidation takes place 15.

The increased fatty acyl CoA and CPT-I activity in DKA lead to increased production of ketone

bodies (acetoacetate [AcAc], and β- hydroxybutyrate [BOHB]). High ketone levels are strong acids

that lead to metabolic acidosis.

HHS, formerly referred as hyperosmolar hyperglycemic nonketotic coma, is characterized

by reduced insulin concentration to maintain normoglycemia, but sufficient insulin levels to

prevent lipolysis and ketogenesis. Patients with HHS have been shown to have higher insulin
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concentration, reduced concentration of FFA, cortisol, growth hormone and glucagon than patients

with DKA 4,16.

Precipitating Cause of DKA AND HHS

Table 2 depicts the most common precipitating cause of DKA reported in different

epidemiological studies worldwide (Table 2). In the United States and Western countries, the most

common precipitating cause were poor adherence to therapy (insulin omission), infection and

newly diagnosed diabetes. In contrast, in third-world countries, infections and access of care were

the most prevalent precipitating causes.

DKA is the initial presentation of diabetes in ~20% of adult patients and in ~30 to 40% of

children with T1D.10,17 In patients with a known history of diabetes, precipitating factors for DKA

include infections, intercurrent illnesses, psychological stress and poor compliance with therapy.

Poor adherence to insulin treatment is the most common precipitating cause of DKA in young
10,18
patients with T1D and in inner city populations in the United States . In other countries,

infections are the most common precipitating factor, occurring in 30-50% of cases (Table 2). Risk

factors for DKA are previous episodes of ketoacidosis, poor metabolic control, limited access to

medical services and socioeconomic factors. Psychological factors, including depression and

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 eating disorders are reported in up to 20% of recurrent episodes of ketoacidosis in young patients
18-20
.

Drugs that affect carbohydrate metabolism such as corticosteroid, sympathomimetic agents

and atypical antipsychotic agents may also precipitate the development of DKA 3,18. Recently, the

sodium glucose co-transporter 2 (SGLT2) inhibitors, a new class of oral antidiabetic agents that

decrease concentrations of plasma glucose by inhibiting proximal tubular reabsorption of glucose

in the kidney have been reported to be associated with the development of DKA in patients with
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21,22
T1D and T2D . The underlying mechanisms are not known, but most patients receiving

SGLT2-inhibitors require reduction in insulin dose to avoid hypoglycemia, and the lower insulin

dose may be insufficient to suppress lipolysis and ketogenesis. In addition, SGLT2 inhibitors are
23
expressed in pancreatic alpha-cells and may promote glucagon secretion . Furthermore,

SGLT transporters have been shown to reduce urinary excretion of ketone bodies, which might

increase plasma ketone levels 22,24.

HHS is the initial manifestation of diabetes in 7-17% of patients 3,4. Infection is the major

precipitating factor occurring in 30-60% of HHS patients, with urinary tract infections and

pneumonia being the most common infections. Similar than DKA, intercurrent illnesses such as

cerebrovascular events, myocardial infarction, trauma, surgery and drugs (glucocorticoids, diazoxide,

antipsychotics) may result in HHS 3,4.

Diagnosis of DKA and HHS

The diagnosis of DKA or HHS should be suspected in every ill patient with significant

hyperglycemia. Patients with DKA usually presents with a few days of polyuria, polydipsia, and

weight loss. Nausea, vomiting and abdominal pain are present in 40 – 75% of cases of DKA 25.

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 Physical examination reveals signs of dehydration, changes in mental status, hypothermia acetone-

odoured breath and labored Kussmaul respiration, particularly in patients with severe metabolic

acidosis. As outlined in Table 1, DKA consists of the triad of hyperglycemia, hyperketonemia and

metabolic acidosis. It is classified as mild, moderate, or severe, depending on the extent of

metabolic acidosis and level of sensorium. The key diagnostic criterion is the elevation of serum

ketone bodies concentration. Although the majority of patients with DKA present with a blood

glucose level greater than 300 mg/dL, some patients can present with mild elevations in glucose
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levels after receiving insulin injections, reduction of food intake, pregnancy, and patients with

impaired gluconeogenesis such as in patients with alcohol abuse or liver failure. Normoglycemia

DKA has also been reported in patients treated with SGLT2-inhibitors. Therefore, the level of

blood glucose should not be viewed as a primary factor in determining the diagnosis or severity of

DKA.

The diagnostic criteria for HHS include a plasma glucose greater than 600 mg/dL, a

effective serum osmolality greater than 320 mOsm/kg, and the absence of significant metabolic

acidosis and ketonemia 9. Although by definition, patients with HHS have a serum pH greater than

7.3, a serum bicarbonate greater than 18 mEq/L, and negative ketone bodies in urine and plasma,

between 30% to 50% of patients with HHS have an increased anion gap metabolic acidosis as the

result of concomitant ketoacidosis and/or to an increase in serum lactate levels.

Confirmation of increased ketone bodies production, the key diagnostic feature of DKA is

performed by the nitroprusside reaction or by direct measurement of -hydroxybutyrate. The

nitroprusside reaction provides a semiquantitative estimation of acetoacetate and acetone levels in

plasma or urine, but does not recognize the presence of -hydroxybutyrate, which is the main

ketoacid in DKA 26. Therefore, the nitroprusside reaction may underestimate the level of ketosis.

7
 Direct measurement of -hydroxybutyrate by the laboratory or by point-of-care meter is preferred

to diagnose ketoacidosis (≥ 3 mmol/L), as well as to follow the response to medical treatment.

Management

There is considerable individual variability in the presentation of patients with DKA and HHS.

The clinical presentation may range from mild hyperglycemia and acidosis to severe

hyperglycemia, dehydration and coma; therefore, treatment individualization based on a careful

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clinical and laboratory assessment is needed to determine optimal treatment of an individual

patient. Figure 2 shows the recommended algorithm suggested by the recent position statement

from the American Diabetes Association for treatment of DKA and HHS 9. Objectives of

management include restoration circulatory volume and tissue perfusion, resolution of

hyperglycemia, correction of electrolyte imbalance and increased ketogenesis. Most patients with

DKA can be safely managed in observational and step-down units, without requiring admission in

an intensive care unit (ICU). The mortality rate, length of hospital stay, or time to resolve

ketoacidosis are similar between patients treated in ICU and non-ICU setting 27,28. Thus, only

patients with severe DKA, severe alteration of mental status, or those with a critical illness as

precipitating cause (i.e., myocardial infarction, gastrointestinal bleeding, sepsis) require treatment

in the ICU. In contrast, due to the higher mortality, the presence of comorbid conditions and

altered mental status, most patients with HHS are treated in the ICU.

Fluid Therapy

The estimated water deficit in DKA is ~ 100 ml/kg of body weight 3 and between 100 and 200

ml/kg in HHS 4,20. The water deficit can be estimated using the following equation: water deficit =

(0.6)(body weight in kilograms) x [corrected sodium/140] -1 3. Fluid therapy is the mainstay of

8
 therapy restoring intravascular volume and renal perfusion and reducing the level of counter-

regulatory hormones and hyperglycemia. Isotonic saline (0.9% NaCl) infused at a rate of 500-1000

mL/h is recommended during the first 2-4 hours in order to restore normal blood pressure and

tissue perfusion. This is followed by the infusion of normal saline at 250 -500 mL/h or 0.45%

saline depending upon the serum sodium concentration and state of hydration 3. Subsequent choice

and rate of fluid replacement depends on hemodynamics, the state of hydration, serum electrolyte

levels, and urinary output 3. In general, 0.45% NaCl infused at 250-500ml/hr is appropriate if the
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corrected serum sodium is normal or elevated; 0.9% NaCl at a similar rate is appropriate if

corrected serum sodium is low 3. Corrected sodium is calculated with the formula: measured

sodium + (((Serum glucose - 100)/100) x 1.6). Once the plasma glucose is ~250 mg/dL, 5–10%

dextrose should be added to replacement fluids to allow continued insulin administration until

ketonemia is controlled, while at the same time avoiding hypoglycemia 9.

The administration of large amounts of chloride-rich intravenous solutions (such as normal saline)

may be associated with the development of hyperchloremia (defined as a ratio of chloride:sodium

>0.79) 29 and normal anion gap metabolic acidosis 30.

During treatment of DKA, hyperglycemia is usually corrected faster than ketoacidosis.

Therefore, when plasma glucose is ~250 mg/dL, 5–10% dextrose is added to intravenous fluids in

order to reduce the risk of hypoglycemia during insulin infusion until ketoacidosis resolves 9.

Insulin Therapy

Insulin administration is essential to restore normal cellular metabolism and to normalize

glucose concentration and suppress lipolysis and ketogenesis 31. There is evidence that low-dose

insulin infusion, given by intravenous (IV), intramuscular (IM) or subcutaneous (SC) routes, is

safe and effective in correcting DKA. In critically ill and mentally obtunded patients, continuous

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 intravenously infusion is the treatment of choice. Most treatment algorithms recommend the

infusion of an IV bolus dose of 0.1 unit/kg followed by continuous IV infusion of 0.1 unit/kg per

hour (5-10 unit/h) 9. The initial bolus of insulin is not necessary if the hourly insulin infusion rate is

given at 0.14 U/kg body weight (e.g., 10 U/h in a 70-kg patient). When plasma glucose reaches

~200 mg/dL, the insulin rate should be decreased to 0.05 unit/kg per hour and the intravenous fluids

changed to dextrose containing solutions. In DKA, the rate of insulin should be adjusted to maintain

blood glucose between 150 and 200 mg/dL until DKA is resolved. Similarly, in patients with
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HHS, treatment should be adjusted to maintain a plasma glucose concentration ~ 200 mg/dL until

mental obtundation and hyperosmolar state are corrected.

Several studies have shown that patient with uncomplicated mild to moderate DKA, the use

of subcutaneous lispro 32-34 or insulin aspart 35 given every 1 to 2 hours is as effective as the use of

IV regular insulin in the ICU (Table 3). After an initial bolus SC dose of 0.2 to 0.3 U/kg, the

administration of lispro or aspart, given in doses of 0.1 unit/kg every hour or 0.2 unit/kg every two

hours results in a similar decline in glucose concentration as the IV route. When, glucose levels

reach ~250 mg/dl, SC insulin dose is reduced by half and continue at the same interval until

resolution of DKA. This is done with the caveat that adequate personnel are available for frequent

measuring of blood glucose by finger-stick testing every 1 - 2 hours and frequent monitoring of

electrolytes and venous pH (every 4-6 hours) with adequate administration of hydrating fluid. In

the above-mentioned studies, the incidence of hypoglycemia was the same as with the intravenous

insulin protocol in the ICU. The use of rapid-acting insulin analogs is not recommended for

patients with complicated and severe DKA or with HHS.

Potassium

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 Patients with DKA and HHS have total-body potassium deficit of ~ 3-5 mmol/kg. Despite

the total body deficit, the admission serum potassium is frequently normal or high due to the shift

from the intracellular to the extracellular space due to hypertonicity, insulin deficiency and

acidosis. During treatment, insulin therapy result in lower serum potassium levels due to increased

cellular potassium uptake in peripheral tissues. Therefore, it is important that potassium be

carefully monitored during the therapy. In patients with normal or high serum concentration, the

administration of potassium should be initiated when the serum concentration is below 5.0 mEq/L
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to maintain a serum potassium levels within the normal range of 4 to 5 mEq/L 9. The

administration of 20 – 40 mmol of potassium per litter is usually necessary for most patients.

Exception to this recommendation includes patients with acute renal failure and low urine output

or with end-stage renal disease; in this case, potassium should be repleted only if low and

monitored carefully. In addition, patients with an initial serum potassium lower than 3.3 mmol/l,

potassium replacement should begin at a rate of 10 - 20 mmol per hour, and insulin therapy should

be delayed until serum potassium is > 3.3 mmol/l. In such patients, insulin administration may

precipitate profound hypokalemia, which can induce life-threatening arrhythmias and respiratory

muscle weakness 9.

Bicarbonate

Severe metabolic acidosis may lead to impaired myocardial contractility, cerebral

vasodilatation and coma. The results of 9 studies evaluating the effect of alkalinization on a total

of 434 patients with DKA reported that bicarbonate therapy offers no advantage in improving

cardiac and neurologic functions or in the rate of recovery of hyperglycemia and ketoacidosis.

Moreover, bicarbonate therapy may increase the risk of hypokalemia, tissue oxygen uptake, and

cerebral edema 9. Despite that lack of evidence in support of the use of bicarbonate in DKA,

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 clinical guidelines recommend the administration of 50–100 mmol of sodium bicarbonate given as

isotonic solution (in 200 ml of water) in patients with venous pH <6.9. Patients with DKA with

pH >7.0 or with HHS, should not receive bicarbonate therapy.

Phosphate

Depletion of total body intracellular phosphate is universally present in patients with DKA. Severe

hypophosphatemia may lead to rhabdomyolysis, hemolytic uremia, muscle weakness, and

paralysis; however, several studies have failed to show any beneficial effect of phosphate
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replacement on clinical outcome. Furthermore, aggressive phosphate administration my induce

hypocalcemia 36,37. Theoretic advantages of phosphate therapy include prevention of respiratory

depression and generation of erythrocyte 2,3-diphosphoglycerate, thus in patients with serum

phosphate concentration lower than 1.0-1.5 mg/dL, careful phosphate replacement may be

indicated in patients with cardiac dysfunction, anemia, respiratory depression, and in those with

serum phosphate concentration lower than 1.0-1.5 mg/dL 9.

The majority of reviews and position statements on the management of hyperglycemic

crises in adult patients proposed a single treatment algorithm for treating DKA and HHS. Low-

dose insulin infusion protocols for treating DKA appear to be effective; however, the mortality rate

is about ten times higher in HHS patients than in DKA patients 10,38. Despite the poor outcome, no

prospective, randomized studies have determined best treatment strategies in patients with HHS.

Thus, prospective studies are needed to determine effective and safe insulin and hydration

strategies, as well as to determine glucose targets during IV insulin infusion and during the

transition to SC insulin therapy in patients with HHS.

Management after Resolution of DKA and HHS

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 Criteria for resolution of DKA include the following a blood glucose lower than 250 mg/dL; a

serum bicarbonate level equal to or greater than 18 mmol/l, and a venous or arterial pH greater

than 7.3 3,9. The resolution of HHS is indicated when effective serum osmolality is lower than 310

mOsm/kg, blood glucose is ≤ 250 mg/dL and a gradual recovery to mental alertness 3,9.

It is important to recognize that the half-life of intravenous regular insulin is very short (less

than 10 minutes); therefore, if low-dose insulin infusion is interrupted suddenly, patients may be at

risk of ketoacidosis relapse and/or rebound hyperglycemia. Therefore, we recommend that

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intravenous infusion of insulin be continued for 2 to 4 hours after subcutaneous insulin is started. It

has been suggested that the administration of SC insulin early in the course of treatment (4 to 6 hours after

initiation of insulin infusion) facilitates treatment and prevent rebound hyperglycemia after discontinuation

of IV insulin infusion 39.

Clinical guidelines recommend transition from IV to SC insulin therapy once the patient is

alert and able to take food by mouth. Patients with previously known diabetes who were treated

with SC insulin previous to admission can resume their previous insulin regimen. Newly diagnosed

patients or insulin-naïve adult patients can be started at a daily total dose of 0.5 to 0.7 U/kg/d 9. The

American Diabetes Association (ADA) position statement recommends a transition to a split-

mixed insulin regimen with neutral protamine Hagedorn (NPH) and regular insulin twice daily or

to a multi-dose regimen of short- or rapid-acting and intermediate- or long-acting insulin 9.

However, recent randomized studies have reported that the use of human insulin (NPH/regular

insulin) is associated with two-to three-fold increase in the frequency of hypoglycemic events

compared to the use of basal bolus regimen with insulin analogs 40. The short duration of action

and the undesirable peak activity at 4–6 h after injection of NPH insulin explain the higher rate of

hypoglycemic events. A recent randomized study reported that during the transition to SC insulin,

13
 there were no differences in mean daily glucose levels, but 41% patients treated with NPH and

regular insulin had higher rate of hypoglycemia compared to 15% of patients treated with glargine

once daily and glulisine before meals 40.

Prevention of Hyperglycemia Crises

With improved outpatient treatment and follow-up programs and better adherence to self-

care, about 50 to 75% of DKA admissions could be avoided. The frequency of hospitalizations for

DKA has been reduced following diabetes education programs, improved follow-up care, and
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access to medical advice. Many patients with recurrent DKA are unaware of sick-day management

or the consequences of skipping or discontinuing insulin therapy 41. It has been shown that frequent

visits to diabetes centers can improve glycemic control and reduce the frequency of emergency

admissions for DKA 42,43. Sick day rule education is of great importance in the management of

patients with diabetes, in particular in patients with history of DKA. Patients should be instructed

on how to adjust insulin dosage during illness emphasizing that insulin should never be

discontinued, how to contact with healthcare providers, as well as adequate fluid intake 3. In

addition, diabetes education and sick-day management should be reviewed periodically in patients

with T1D. Recent studies have reported that multidisciplinary diabetes teams addressing barriers to

communication, access to care, and medical adherence on the family, school, and health-care

levels could reduce the number of admission with DKA. Despite the expense of providing such an

intensive intervention, the multidisciplinary intervention incurred less cost to the health-care

system because of the decreased number of DKA admissions. In addition, patients with T1D

should be instructed on the use of home blood ketone monitoring during illness and persistent

hyperglycemia, which may allow for early recognition of impending ketoacidosis.

Expert Commentary

14
 The prevalence of diabetic ketoacidosis and hyperosmolar hyperglycemic state continue increase
and are associated with significant morbidity and mortality. Programs to enhance treatment
adherence are needed to prevent these important acute complications of diabetes.

Five Year View

Poor adherence to insulin administration is the most common precipitating cause, thus programs to
enhance compliance are needed to prevent these important acute complications of diabetes. Such
programs will include behavioral and social support and improved diabetes education programs.
Randomized controlled clinical trials are needed in patients with HHS.
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Key Issues

1. Diabetic ketoacidosis (DKA) and hyperglycemic hyperosmolar state (HHS) are

characterized by insulinopenia, hyperglycemia and dehydration. Clinically, they differ by the
presence of increased ketones bodies and severity of metabolic acidosis.
2. The overall DKA mortality in the US is less than 1%, but a rate higher than 5% is reported
in the elderly and in patients with concomitant life-threatening illnesses.
3. Mortality in patients with HHS is reported between 5 and 16%, which is about 10 times
higher than the mortality in patients with DKA.
4. Treatment of DKA represents a substantial economic burden. The estimated hospital cost
for patients with hyperglycemic crises exceeds $2 billion per year.
5. In the United States, the most common precipitating cause are poor adherence to therapy
(insulin omission), infection and newly diagnosed diabetes. In contrast, in third-world countries,
infections and access of care are the most prevalent precipitating causes.
6. Objectives of management include restoration circulatory volume and tissue perfusion,
resolution of hyperglycemia, correction of electrolyte imbalance and increased ketogenesis.
7. Most patients with DKA can be safely managed in observational and step-down units,
without requiring admission in an intensive care unit (ICU).
8. With improved outpatient treatment and follow-up programs and better adherence to self-
care, about 50 to 75% of DKA admissions could be avoided

15
 Financial and competing interests disclosure

G.E. Umpierrez is supported in part by research grants from the American Diabetes Association
(1-14-LLY-36), PHS grant UL1 RR025008 from the Clinical Translational Science Award
Program (M01 RR-00039), National Institute of Health, National Center for Research Resources
and has received unrestricted research support for inpatient studies (to Emory University) from
Novo Nordisk, Boehringer Ingelheim and Merck and has received consulting fees and/or honoraria
for membership in advisory boards from Novo Nordisk, Glytec, Sanofi, Merck, and Boehringer
Ingelheim. The authors have no other relevant affiliations or financial involvement with any
organization or entity with a financial interest in or financial conflict with the subject matter or
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materials discussed in the manuscript apart from those disclosed.

16
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 Table 1. Diagnostic Criteria for Diabetic Ketoacidosis (DKA) and Hyperglycemic Hyperosmolar State (HHS). Data taken from [9].

DKA HHS
_____________________________________
Mild Moderate Severe
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__________________________________________________________________________________________
Plasma glucose, mg/dL* > 250 > 250 > 250 > 600

pH£ 7.25-7.30 7.00- < 7.24 < 7.00 > 7.30

Bicarbonate, mmol/L 15 - 18 10 - < 15 < 10 > 15

Urine/blood ketones, mmol/L† Positive Positive Positive Small

Serum Osmolality, mOsm/kg§ Variable Variable Variable > 320

Anion Gap >10 >12 >12 <12

Alteration in sensorium Alert Alert/Drowsy Stupor/Coma Stupor/Coma

___________________________________________________________________________________________
Plasma glucose, mg/dL*: Euglycemic DKA, defined as plasma glucose < 250 mg/dl is reported in ~10% of cases of DKA.

pH£: Arterial or venous.

Urine/blood ketones, mmol/L†: Measurement of aceto-acetate (nitroprusside reaction) and β-Hydroxybutyrate by laboratory or point
of care meters. Coexistence of DKA and HHS is reported in up to 30% of cases

Serum Osmolality, mOsm/kg§: Formula: 2 measured Na (mmol/L) + glucose (mg/dl)/18

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 Table 2 Precipitating causes in patients with DKA

Australia Brazil China Indonesia Israel Korea Nigeria Spain Syria Taiwan USA

44 45 46 47 48 49 50 51 52 53 18
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New diagnosis 6 20 NR 3.3 7.8 NR NR 12.8 NR 18.2 17-23

of diabetes, %

Infection, % 29 25 39 58 31 23.6 32.5 33.2 48 31.7 14

Poor treatment 40 39 26 13.3 44.8 32.5 27.5 30.7 24 27.7 49-59

adherence, %

Other, % 25 15 9.5 17 6 13.8 4.8 23 8 6.3 12-18

Unknown, % 8.8 26 8.3 19 30 34.6 21 16.2 4

NR: Not reported

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 Table 3. Treatment of Diabetic Ketoacidosis with Subcutaneous Rapid-Acting Insulin Analogs

Umpierrez, et al 32 Ersoz, et al 33 Karoli, et al 34 Umpierrez, et al 35 Della Manna, et al 54

Insulin formulation Lispro Regular Lispro Regular Lispro Regular Aspart Regular Lispro Regular
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Number of patients 20 20 10 10 25 25 15 15 30 30

Medicine Medicine ICU or ICU or

floor or Emergency floor or emergency emergency

Hospital setting ICU NR NR ICU ICU
step- department step- department department

down down

Age, years 37 39 39 49 34 35 37 40 11.3 12

BMI 26 27 NR NR 25 24 28 27 NR NR

DM duration, years 7 7 5 7 7 6 NR NR NR NR

Admission pH 7.17 7.19 7.18 7.16 7.16 7.18 7.15 7.11 7.17 7.18

Admission BG,
674 611 556 650 650 679 774 720 443 443
mg/dL

Time to resolution,
10 11 13.2 12 12 11 10.4 11 <12 h <6 h
hrs

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 Hosp. length of stay,
4 ±2 4 ±1 NR NR 6.0 ±1.2 6.6 ±1.5 3.7±4 4.5±3 3.7±4 4.5±3
days

Hypoglycemia
1 1 0 1 1 2 1 1 4 6
events, n
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Total daily insulin

0.37
dose until resolution, 84 98 65.2 100 100 104 89.5 82 0.28 U/Kg
IU/Kg
Units

BMI: body mass index; DM: diabetes mellitus; Hrs: hours, NR: not reported; ICU: intensive care unit

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 Downloaded by [Umeå University Library] at 19:08 05 February 2016

Figure 1. Pathogenesis of DKA and HHS

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 PROTOCOL FOR MANAGEMENT OF ADULT PATIENTS WITH DKA and HHS

IV Fluids Insulin Potassium

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Administer 0.9% If serum K+ is <3.3

IV SC
NaCl at 500 -1000 mmol/L, hold insulin and
Route* Route**
ml/hr during the first give 10-20 mmol per
1-2 hrs hours hour of KCl until serum
0.1 U/kg IV 0.2 U/kg
K+  3.3 mEq/L
Evaluate Corrected Serum bolus SC bolus
Na+
If serum K+ > 5.0 mmol/L,
High Normal Low 0.1 U/kg/hr 0.2 U/kg do not give K+ but check
IV insulin SC every 2 serum K+ q 2 hr
infusion hrs
0.45% NaCl at 250- 0.9% NaCl at 250-500
500 mL/hr depending mL/hr depending on Check serum or capillary glucose If serum K+ < 5.0 mmol/L,
on state of hydration state of hydration every 1-2 hrs. When glucose add 20-40 mEq of KCl in
reaches ~ 200 - 250 mg/dl each liter of IV fluid to
keep serum K+ between
When plasma or capillary glucose 4-5 mmol/L
Reduce insulin to 0.1 U/kg SC
reaches ~ 200 - 250 mg/dl
every 2 hrs to maintain glucose
between 150-200 mg/dl until
resolution of ketoacidosis***
Change to 5% dextrose with 0.45% NaCl
until resolution of ketoacidosis*
Transition to SC insulin when the patient is alert and can eat. Identify
and treat precipitating cause.

* Regular insulin is the preferred insulin formulation for continuous intravenous insulin infusion (IV). 26
** Rapid-acting insulin analogs (lispro, aspart) are the preferred insulin formulation during subcutaneous (SC)
insulin therapy