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Diabetic Emergencies, Diagnosis and Clinical Management: Hyperosmolar Non-ketotic Hyperglycemia, Part 4

Konstantinos Makrilakis, MD, PhD
Nikolaos Katsilambros, MD, PhD.


Avoidance of complications

Hypoglycemia and hypokalemia are the two most common complications of treatment of hyperglycemic crises with insulin. They have both been reduced significantly, however, with the administration of low-dose insulin and careful monitoring and replacement of serum potassium. 27,28 Frequent blood glucose monitoring (every 1-2 hours) is mandatory to recognize hypoglycemia because many patients with long-standing hyperglycemia who develop hypoglycemia during treatment do not experience adrenergic manifestations of sweating, nervousness, fatigue, hunger, and tachycardia….

Another complication is hyperglycemia, which may result from abrupt interruption of intravenous insulin without prior coverage with subcutaneous insulin. This too has been decreased with careful adherence to treatment protocols.3

Two of the most serious complications of hyperglycemic crises are the development of cerebral edema and thromboembolic complications. Cerebral edema most commonly develops in young children with DKA 29 and has very rarely been reported in adult patients with HHS. It is associated, however, with a high mortality rate (20-40%). Symptoms and signs are variable and include onset of headache, gradual deterioration in the level of consciousness, seizures, sphincter incontinence, papillary changes, papilledema, bradycardia, elevation in blood pressure, and respiratory arrest. Proposed mechanisms include the role of cerebral ischemia/hypoxia, the generation of various inflammatory mediators, increased cerebral blood flow, disruption of cell membrane ion transport, and a rapid shift in extracellular and intracellular fluids, resulting in changes in osmolality. Prevention might include avoidance of excessive hydration and rapid reduction of plasma osmolality, a gradual decrease in serum glucose, and maintenance of serum glucose between 250 and 300 mg/dl (13.9-16.7 mmol/L) until the patient’ s serum osmolality is normalized and mental status is improved. Data evaluating the outcome and treatment of cerebral edema in adults are not available. Recommendations for treatment are based upon clinical judgment in the absence of scientific evidence. Mannitol infusion (0.25-1.0 g/kg), hypertonic saline infusion (3% normal saline at a rate of 5-10 ml/kg over 30 min), and mechanical ventilation are suggested for treatment of cerebral edema.29 These approaches raise the plasma osmolality, resulting in osmotic movement of water out of the brain and a reduction in cerebral edema.30

Summary box
  • Gradual deterioration in the level of consciousness in a patient being treated for a hyperglycemic crisis should alert the physician to the possibility of cerebral edema
  • Avoidance of excessive hydration and rapid reduction of plasma osmolality, a gradual decrease in serum glucose, and maintenance of serum glucose between 250 and 300 mg/dl (13.9 – 16.7 mmol/L) until the patient’s serum osmolality is normalized and mental status is improved are recommended preventive measures for cerebral edema.


HHS patients are also predisposed to thromboembolic complications due to their extreme dehydration status, diminished cardiac output, and increased blood viscosity owing to hyperosmolality. Increased platelet activation, plasminogen activator inhibitor (PAI)-1 activation, and endothelial dysfunction also contribute. The administration of prophylactic low-molecular-weight heparin subcutaneously is recommended by some, while others only treat clinically overt thromboembolic events as they occur.18

Rhabdomyolysis is another potential complication of HHS, possibly attributable to severe hyperosmolality.18 The diagnosis is suggested by a greatly elevated serum creatinine kinase (CK) concentration (usually > 1000 IU/L) in the absence of alternative causes such as myocardial infarction, stroke, end-stage renal failure, or hypothyroidism. Aggressive hydration is needed to prevent renal damage from circulating myoglobin, but dialysis is sometimes required.

Follow-up management/care

Patients with HHS should be aggressively treated with intravenous fluids/electrolytes and insulin administration until the hyperglycemic crisis is resolved. Criteria for resolution of HHS include return of serum osmolality to levels < 315 mOsm/kg, a normal mental status, and ability of the patient to eat.

Summary box

Criteria for resolution of HHS include:

  • return of serum osmolality to levels < 315 mOsm/kg
  • a normal mental status
  • ability of the patient to eat

When this occurs, subcutaneous insulin therapy can be started. Insulin has a half-life of only 8-9 minutes. Thus, to prevent recurrence of hyperglycemia during the transition period to subcutaneous insulin, it is important to allow an overlap of 1-2 hours between discontinuation of intravenous insulin and the administration of subcutaneous insulin.3 If the patient is unable to take oral nutrition, it is preferable to continue the intravenous insulin infusion. Patients with known diabetes may be given insulin at the dosage they were receiving before, as long as it was controlling glucose properly and provided other acute stressful conditions (e.g., acute myocardial infarction, stroke) are not present. In insulin-naïve patients, a multi-dose insulin regimen should be started at a dose of 0.5-0.8 IU/kg per day, including bolus and basal insulin, until an optimal dose is established. Good clinical judgment and frequent glucose assessment are vital in initiating a new insulin regimen in insulin-naïve patients.

Following discharge from the hospital, insulin treatment is often recommended for the first 2-3 months.18 Many patients with HHS secrete sufficient endogenous insulin to be successfully treated in the long term with oral antidiabetic medicines. Pointers to insulin independence include excellent glycemic control (or recurrent hypoglycemia) with relatively small doses of insulin. Nevertheless, these features are not always reliable and the overall clinical and biochemical profi le of the patient should be carefully evaluated before deciding not to use insulin.

Summary box

To prevent recurrence of hyperglycemia during the transition period to subcutaneous insulin, it is important to allow an overlap of 1-2 hours between discontinuation of intravenous insulin and the administration of subcutaneous insulin



Patient advice 

HHS is a serious medical condition with a high mortality rate. The majority of affected patients are elderly, with impaired access to medical care, a diminished social network, and other intercurrent illnesses. Many cases can be prevented by proper patient education, better access to medical care, and effective communication of the patient with a health care provider during periods of intercurrent illness.

Proper advice to patients should include the following (see also Chapter 8):

  • Never discontinue insulin during an acute illness and communicate with the health care provider as quickly as possible.
  • Intensify home self-monitoring of blood glucose and initiate early treatment with short-acting insulin if needed.
  • In cases of nausea/vomiting/diarrhea, drink plenty of fluids and avoid dehydration.
  • Education on sick-day rules is required for family members or caregivers for elderly or hospitalized patients in long-term facilities.
Case studies
Case study 3.1

An 82-year-old man with a 17-year history of Type 2 diabetes was brought by family members to the Emergency Room (ER) with fever, confusion, and an infected ulcer on the right little toe that had developed over the previous few days. He had been treated with metformin and glimepiride for the last 15 years, with inadequate diabetic control. He did not frequently check his blood sugar levels at home and his last HbA1c was 10.2% around 1.5 years earlier. He had been advised to start insulin then, but had refused. Family members said he had been urinating a lot lately and was gradually getting fatigued and sleepy. 

On physical examination in the ER, his blood pressure was 84/52 mmHg, pulse rate 112/min, and temperature 38.4° C (101.1° F). He was drowsy and disoriented to place and time. His oral mucosa was dry and skin turgor diminished. Laboratory evaluation revealed a serum glucose level of 1120 mg/dl (62.3 mmol/L), sodium 152 mEq/L, potassium 5.4 mEq/L, bicarbonate 20 mmol/L, urea 84 mg/dl (13.9 mmol/L), creatinine 1.9 mg/dl (168 μ mol/L), normal arterial blood gases, and 1(+) ketones in the urine. His WBC count was 18,000/ μ l (80% polymorphonuclears), hematocrit and platelet counts were normal, the C-reactive protein was 122 mg/L (normal < 5), and erythrocyte sedimentation rate (ESR) 85 mm/h (normal 0-20).

What is your diagnosis and what should immediate care be?

The patient obviously has a hyperglycemic crisis with extremely high blood glucose levels and evidence of dehydration. He has no acidosis and minimal, if any, ketosis. His effective serum osmolality is calculated to be very high, at 366.3 Osm/kg [2(Na) + glucose (mg/dl)/18]. Thus, he fulfills all the criteria for HHS, with dehydration and obtundation. His infected toe ulcer, on top of his chronically uncontrolled diabetes, is most likely the precipitating factor that led to this crisis. He should immediately be aggressively hydrated, started on insulin, and treated for his toe infection.

An ECG showed sinus tachycardia and no evidence of ischemia. A chest X-ray was normal and a right foot X-ray showed no evidence of osteomyelitis. Blood cultures and cultures from the foot ulcer area were obtained and IV antibiotics were started.

The patient was also started on IV fluids (he received 0.9% normal saline 1 L within 1 hour in the ER) and another 1 L was continued for the next 2 hours. At the same time he was started on IV regular insulin: he received an 8 IU IV bolus (his weight was estimated to be 80 kg) and a continuous IV infusion of 8 IU/h was initiated.

The patient was admitted to the hospital. His blood sugar levels were monitored by finger-stick every hour and by laboratory evaluation (together with the electrolytes) every 2 hours. One hour later, his finger-stick blood sugar level using a portable bedside glucose meter showed "HI." The treating physician got worried that his condition was not improving appropriately and consulted a diabetes specialist. Was his worry justified?

The answer is that a bedside portable glucose meter is usually able to measure blood glucose levels up to 600 mg/dl (33.3 mmol/L). As this patient’s initial blood glucose level was 1120 mg/dl (62.3 mmol/L) and as an appropriate blood glucose decline should be 50-70 mg/dl (2.8-3.9 mmol/L) per hour, it is appropriate one hour after the initiation of treatment for the blood sugar still to be > 600 mg/dl (33.3 mmol/L); thus it is not necessarily true that the condition is not improving appropriately. The physician should send a serum glucose level to the laboratory and judge the progress of the patient’s condition by an exact plasma measurement.

Laboratory evaluation one hour later showed a plasma glucose level of 970 mg/dl (53.9 mmol/L), serum K+ 4.1 mEq/L, serum Na+ 148 mEq/L, phosphate 2.3 mg/dl (0.74 mmol/L), urea 48 mg/dl (8.0 mmol/L), and creatinine 1.3 mg/dl (114.9 μ mol/L).

The blood glucose level is decreasing appropriately with treatment (by 150 mg/dl [8.3 mmol/L] in 2 hours). His IV fluids were continued at a rate of 500 ml/h 0.9% normal saline, and 20 mEq of potassium chloride were added to each L of fluids. Insulin infusion was continued at the same rate. Laboratory monitoring continued every 2 hours. His mental status and hemodynamics improved (blood pressure was raised to 112/74 mmHg). Two hours later his blood glucose was 800 mg/dl (44.4 mmol/L), serum K+ 4.5 mEq/L, serum Na+ 145 mEq/L.

Since his hyperosmolality has improved (estimated now at 334.4 mOsm/kg) but has not completely resolved (the goal was to gradually drop to < 315 mOsm/kg), his IV fluids were changed to 0.45% normal saline with continued K+ supplementation, at an infusion rate of 250 ml/h, and insulin administration was continued.

Six hours later his blood sugar was 290 mg/dl (16.1 mmol/L), serum K+ 4.9 mEq/L, serum Na+ 138 mEq/L. His insulin infusion rate was decreased to 4 IU/h and his IV fluids changed to 5% dextrose in water with 0.45% normal saline, infused at a rate of 250 ml/h, with the goal of keeping the glucose level around 250-300 mg/dl (13.9-16.7 mmol/L). Next morning the patient was alert and oriented. Blood pressure was normal, his blood sugar level was 240 mg/dl (13.3 mmol/L), and electrolytes were within normal limits. He was able to eat without nausea or vomiting.

He was given a subcutaneous injection of 10 IU regular insulin and 10 IU glargine insulin and the IV insulin infusion was stopped 1 hour later, to continue with blood glucose monitoring every 6 hours and glargine and regular insulin subcutaneously. His family members were educated regarding insulin administration techniques and doses. The patient was discharged from the hospital after 4 days, in stable condition, to continue with p.o. antibiotics and insulin at home. He was to follow up in the outpatient clinic in one week’s time.

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Nikolaos Katsilambros, MD, PhD, FACP

SCOPE Founding Fellow
Professor of Internal Medicine
Athens University Medical School
Evgenideion Hospital and Research Laboratory ‘Christeas Hall’
Athens, Greece
Christina Kanaka-Gantenbein, MD, PhD
Associate Professor of Pediatric Endocrinology and Diabetology
First Department of Pediatrics, University of Athens
Agia Sofia Children’s Hospital
Athens, Greece
Stavros Liatis, MD
Consultant in Internal Medicine and Diabetology
Laiko General Hospital
Konstantinos Makrilakis, MD, MPH, PhD
Assistant Professor of Internal Medicine and Diabetology
Athens University Medical School
Laiko General Hospital
Athens, Greece
Nikolaos Tentolouris, MD, PhD
Assistant Professor of Internal Medicine and Diabetology
University of Athens
Laiko General Hospital
Athens, Greece
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Diabetic Emergencies: Diagnosis and Clinical Management provides emergency room staff, diabetes specialists and endocrinologists with highly practical, clear-cut clinical guidance on both the presentation of serious diabetic emergencies like ketoacidosis, hyperosmolar coma and severe hyper- and hypoglycemia, and the best methods of both managing the emergencies and administering appropriate follow-up care.
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