Acute Hyperglycemic Complications

Acute Hyperglycemic Complications

Dr. S.M.Sadikot
Hon. Endocrinologist,
Jaslok Hospital and Research Centre,
Mumbai 400026

Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS) or, as this is more popularly known, Hyperglycemic Hyperosmolar Non Ketotic state (HHNK), are the two most serious acute hyperglycemic complications of diabetes.

They continue to be important causes of morbidity and mortality among patients with diabetes in spite of major advances in the understanding of their pathogenesis and more uniform agreement about their diagnosis and treatment.

Although DKA is usually associated with people with Type 1 DM, it is also often seen in people with Type 2 DM. HHS is more typically seen in the older Type 2 patient.

The outcomes are especially poor in the absence of immediate and optimal management. The mortality associated with these disorders is still untenably high, and with DKA can reach almost 10% even in the best of hands. HHS has a mortality which approaches almost 50%.

Although for the purpose of discussion, these are considered separately as two entities, DKA and NKH should be thought of as a continuum of disease. At one extreme is pure DKA without hyperosmolarity of significant amount. As noted above these patients may present with more modest degrees of glucose elevation. At the other extreme is NKH with extreme elevations of glucose, and hyperosmolarity, but without significant ketosis (see table below). Finally, there are a range of patients who will have features of both.

It is due to this continuum, that a significant discussion about aspects of HHS has been dealt with in conjunction with the discussion on DKA. In fact. many leading authorities, feel that DKA and HHS presenting with a comatose state should be considered the opposite boundaries of a spectrum of presentations, rather than thinking of them as different disease states.

DKA is a metabolic disorder consisting of three major abnormalities: elevated blood glucose level, high ketone bodies, and a metabolic acidosis with an elevated anion gap. Dehydration and hyperosmolarity may be present as well. There is no "typical" presentation and individual patients may present with a range of clinical findings not clearly meeting the above criteria.

Diabetic Ketoacidosis
Figure 1. The triad of DKA (hyperglycemia, acidemia, and ketonemia) and other conditions with which the individual components are associated.

To understand what happens in DKA, it is helpful to understand the normal process of glucose metabolism.

Although the pathogenesis of DKA is better understood than that of HHS, the basic underlying mechanism for both disorders is a reduction in the net effective concentration of circulating insulin, coupled with a concomitant elevation of counterregulatory stress hormones (glucagon, catecholamines, cortisol, and growth hormone). Thus, DKA and HHS are extreme manifestations of impaired carbohydrate regulation that can occur in diabetes. Although many patients manifest overlapping metabolic clinical pictures, each condition can also occur in relatively pure form.

In patients with DKA, the deficiency in insulin can be absolute, or it can be insufficient relative to an excess of counterregulatory hormones. In HHS, there is a residual amount of insulin secretion that minimizes ketosis but does not control hyperglycemia. This leads to severe dehydration and impaired renal function, leading to decreased excretion of glucose. These factors coupled with the presence of a stressful condition result in more severe hyperglycemia than that seen in DKA. In addition, inadequate fluid intake contributes to hyperosmolarity without ketosis, the hallmark of HHS.

These hormonal alterations in DKA and HHS lead to increased hepatic glucose production and impaired glucose utilization in peripheral tissues, which result in hyperglycemia and parallel changes in osmolality of the extracellular space. The combination of insulin deficiency and increased counterregulatory hormones in DKA also leads to release of free fatty acids into the circulation from adipose tissue (lipolysis) and to unrestrained hepatic fatty acid oxidation to ketone bodies (ß-hydroxybutyrate [ß-OHB] and acetoacetate), with resulting ketonemia and metabolic acidosis. HHS on the other hand may be due to plasma insulin concentration inadequate to facilitate glucose utilization by insulin-sensitive tissues but adequate (as determined by residual C-peptide) to prevent lipolysis and subsequent ketogenesis, although the evidence for this is weak.

Under normal circumstances the body is able to maintain blood glucose within a narrow range during both these feeding and fasting states due to a complex interplay between insulin and certain counter regulatory hormones.

Normal Glucose Metabolism: Post - absorptive
Figure 2 Normal Glucose Metabolism: Post - absorptive state.

In the fed state, there is an abundance of glucose and insulin available. The glucose that is not immediately used is preserved in short and long term storage forms. The liver transforms glucose to glycogen through the actions of insulin. Insulin also promotes the formation of fat and protein - it is an anabolic protein. Insulin also prevents lipolysis (an opposite process), protein degradation, glycogenolysis (breakdown of glycogen into glucose), and gluconeogenesis (production of glucose from other sources in the liver).

After a meal has been absorbed, both glucose and insulin levels begin to fall. At this time events begin to occur to maintain a constant glucose level (and thus a constant supply of fuel for the brain and the rest of the body). The most important mechanism is hepatic glucose production - as glucose levels begin to fall, glycogen is broken down into glucose and released into the blood stream. Later, the liver may use other substances such as protein, amino acids, and ketone bodies to manufacture glucose and to release it into the circulation.

In the period between meals there is a relative insulin lack, which allows a mobilization of free fatty acids from adipose tissue. When this occurs, metabolism shifts slightly so that the lipids are used by peripheral tissues for energy rather than glucose. This allows the remaining glucose to be available to tissues such as the brain. It is important to be aware that brain cells are both insulin insensitive (they do not require insulin for transport of glucose into the cells) and primarily use glucose for energy. This means that the brain continues to use glucose as its fuel, even during fuel deprivation, starvation, and DKA.

Some of the fatty acids released are taken up by the liver and converted to ketones which can be oxidized in the brain to provide backup fuel should hepatic glucose production fail. These changes are typical of the post-prandial phase and would usually end at the next meal. If the fasting period is extended the ketone levels will begin to rise, but usually are limited by the fact that ketones stimulate insulin release which prevents further breakdown of adipose tissue. Obviously, in severe starvation conditions this mechanism can be overridden so that adipose stores can be used.

Normal Glucose Metabolism: Fasting State
Figure 3 Normal Glucose Metabolism: Fasting State

The counter-regulatory hormones (glucagon, cortisol, growth hormone, and epinephrine) promote this process and work in opposition to insulin. They promote catabolism - the breakdown of stored fuel. They promote lipolysis, gluconeogenesis, and glycogenolysis and increase the serum glucose level to prevent hypoglycemia.

Glucagon: Promotes hepatic production of glucose and ketones,

Catecholamines: promotes hepatic glucose output (glycogenolysis), inhibits muscle glucose uptake, enhances fatty acid mobilization (lipolysis),

Cortisol and Growth Hormone: Promotes hepatic glucose production and antagonizes the peripheral effects of insulin on glucose disposal, primarily in the muscle.

Normally, there is a precise balance between insulin and the counter-regulatory hormones that allows for fairly constant glucose levels at all times.

DKA can be viewed as a state of absolute or relative insulin deficit and increased levels of counter-regulatory hormones (glucagon, catecholamines, cortisol, growth hormone). As discussed above, under normal conditions these hormones balance out their actions on the fat cells and the liver allowing for well regulated management of glucose and lipids within the liver and adipose tissues. In cases where the counter-regulatory hormones outweigh the effects of insulin, for whatever reason, DKA supervenes.

In some ways, DKA can be seen as starvation in the midst of plenty. Clearly, there is an excess of glucose, the normal substrate used for energy production. Unfortunately, without the presence of insulin, the glucose goes largely unused since most cells are unable to transport glucose into the cell without the presence of insulin. Many of the cells in the body feel as though they are starving and they innocently activate homeostatic mechanisms to provide even greater quantities of glucose, thus resulting in greater hyperglycemia. In response to the sense of starvation, other alternative fuels, such as ketoacids and fatty acids, are produced.

Despite these fuels, the majority of cells remain "hungry" and continue to order more food production.

In the setting of insulin deprivation three organs are primarily affected, the liver, the fat cell, and the muscle. When insulin levels decrease in DKA, large quantities of fatty acids are released from the fat cell, into the blood. These free fatty acids are taken up by the liver where, in the setting of decreased insulin and increased glucagon, become the precursors for ketoacid production. In addition, the elevated free fatty acid levels increase gluconeogenesis within the liver, increasing the glucose levels even more. If there were no free fatty acids there would be no DKA.

In Type 1 DM, there is insulin deficiency, and the precise balance is altered. Glucose is no longer able to pass from the serum to the cells, and the cells perceive a fuel shortage, therefore stimulating intact mechanisms to increase the supply of fuel. As a result, counterregulatory hormones increase, the liver releases more glucose, and blood glucose values rise.

Major components of the pathogenesis of diabetic ketoacidosis are reductions in effective concentrations of circulating insulin and concomitant elevations of counterregulatory hormones (catecholamines, glucagon, growth hormone and cortisol). These hormonal alterations bring about three major metabolic events:

  • (1) Hyperglycemia resulting from accelerated gluconeogenesis and decreased glucose utilization,
  • (2) Increased proteolysis and decreased protein synthesis; and increased lipolysis and ketone production.

This will lead to an increase in the blood glucose levels, but the glucose cannot pass into cells without insulin. Hyperglycemia initially causes the movement of water out of cells, with subsequent intracellular dehydration, extracellular fluid expansion and hyponatremia.

When the blood glucose levels rise over a certain threshold, excess glucose spills over into the urine. Glucose in the urine pulls extra water with it and creates an "osmotic diuresis", and the symptoms of polyuria and polydipsia ensue.

In this diuresis, the water losses exceed sodium chloride losses. Urinary losses then lead to progressive dehydration and volume depletion, which causes diminished urine flow and greater retention of glucose in plasma. The net result of all these alterations is hyperglycemia with metabolic acidosis and an increased plasma anion gap (see figure 4).

Effect of altered carbohydrate, Lipid, and protein metabolism in DKA
Figure 4 The effect of altered carbohydrate, Lipid, and protein metabolism in DKA with resultant fluid and electrolyte deficiencies,impaired renal function and metabolic acidosis

Carbohydrate Metabolism

When insulin is deficient (absolute or relative), hyperglycemia develops as a result of three processes: increased gluconeogenesis, accelerated glycogenolysis, and impaired glucose utilization by peripheral tissues. Increased hepatic glucose production results from the high availability of gluconeogenic precursors, such as amino acids (alanine and glutamine; as a result of accelerated proteolysis and decreased protein synthesis), lactate (as a result of increased muscle glycogenolysis), and glycerol (as a result of increased lipolysis), and from the increased activity of gluconeogenic enzymes. These include PEPCK, fructose-1,6-biphosphatase, pyruvate carboxylase, and glucose-6-phosphatase, which are further stimulated by increased levels of stress hormones in DKA and HHS. From a quantitative standpoint, increased glucose production by the liver represents the major pathogenic disturbance responsible for hyperglycemia in these patients, and gluconeogenesis plays a greater metabolic role than glycogenolysis.

Although the detailed biochemical mechanisms for gluconeogenesis are well established, the molecular basis and the role of counterregulatory hormones in DKA are the subject of debate; very few studies have attempted to establish a temporal relationship between the increase in the level of counterregulatory hormones and the metabolic alterations in DKA. However, studies of insulin withdrawal in previously controlled patients with type 1 diabetes indicate that a combination of increased catecholamines and glucagon (and a decreased level of free insulin) in a well-hydrated individual may be the initial event. Furthermore, in the absence of dehydration, vomiting, or other stress situations, ketosis is usually mild, while glucose levels increase with simultaneous increases in serum potassium.

Animal studies have shown that catecholamines stimulate glycogen phosphorylase via -receptor stimulation and subsequent production of cAMP-dependent protein kinase. Decreased insulin in the presence of an ambient level of glucagon, which is usually higher in diabetic than in nondiabetic individuals, leads to a high glucagon-to-insulin ratio, which inhibits production of an important metabolic regulator: fructose-2,6-biphosphate. Reduction of this intermediate stimulates the activity of fructose-1,6-biphosphatase (an enzyme that converts fructose-1,6-biphosphate to fructose-6-phosphate) and inhibits phosphofructokinase, the rate-limiting enzyme in the glycolytic pathway. Gluconeogenesis is further enhanced through stimulation of PEPCK by the increased ratio of glucagon to insulin in the presence of increased cortisol in DKA. In addition, the rapid decrease in the level of available insulin also leads to decreased glycogen synthase. These interactions can be summarized as follows:

Biochemical Basis of changes seen in DKA and HHS

The final step of glucose production occurs by conversion of glucose-6-phosphate to glucose, which is catalyzed by another rate-limiting enzyme of gluconeogenesis, hepatic glucose-6-phosphatase, which is stimulated by increased catabolic hormones and decreased insulin levels. Major substrates for gluconeogenesis are lactate, glycerol, alanine (in the liver), and glutamine (in the kidney). Alanine and glutamine are provided by the process of excess proteolysis and decreased protein synthesis, which occurs as a result of increased catabolic hormones and decreased insulin.

In DKA and HHS, hyperglycemia causes an osmotic diuresis due to glycosuria, resulting in loss of water and electrolytes, hypovolemia, dehydration, and decreased glomerular filtration rate, which further increase the severity of hyperglycemia. Although increased hepatic gluconeogenesis is the main mechanism of hyperglycemia in severe ketoacidosis, recent studies have shown a significant portion of gluconeogenesis may be accomplished via the kidney.

Decreased insulin availability and partial insulin resistance, which exist in DKA and HHS by different mechanisms, also contribute to decreased peripheral glucose utilization and add to the overall hyperglycemic state in both conditions.

Biochemical basis of changes seen in DKA and HHS

Proposed biochemical changes that occur during DKA leading to increased gluconeogenesis and lipolysis and decreased glycolysis. Note that lipolysis occurs mainly in adipose tissue. Other events occur primarily in the liver (except some gluconeogenesis in the kidney). Lighter arrows indicate inhibited pathways in DKA. F-6-P, fructose-6-phosphate; G-(X)-P, glucose-(X)-phosphate; HK, hexokinase; HMP, hexose monophosphate; PC, pyruvate carboxylase; PFK, phosphofructokinase; PEP, phosphoenolpyruvate; PK, pyruvate kinase; TCA, tricarboxylic acid; TG, triglycerides.

The increased production of ketones in DKA is the result of a combination of insulin deficiency and increased concentrations of counterregulatory hormones, particularly epinephrine, which lead to the activation of hormone-sensitive lipase in adipose tissue.

The increased activity of tissue lipase causes a breakdown of triglyceride into glycerol and free fatty acids (FFAs). Although glycerol is used as a substrate for gluconeogenesis in the liver and the kidney, the massive release of FFAs assumes pathophysiological predominance in the liver, the FFAs serving as precursors of the ketoacids in DKA.

In the liver, FFAs are oxidized to ketone bodies, a process predominantly stimulated by glucagon. Increased concentration of glucagon in DKA reduces the hepatic levels of malonyl-CoA by blocking the conversion of pyruvate to acetyl-CoA through inhibition of acetyl-CoA carboxylase, the first rate-limiting enzyme in de novo fatty acid synthesis. Malonyl-CoA inhibits carnitine palmitoyl-transferase (CPT)-I, the rate-limiting enzyme for transesterification of fatty acyl-CoA to fatty acyl-carnitine, allowing oxidation of fatty acids to ketone bodies. CPT-I is required for movement of FFA into the mitochondria, where fatty acid oxidation takes place. The increased fatty acyl- CoA and CPT-I activity in DKA leads to increased ketogenesis in DKA.

In addition to increased production of ketone bodies, there is evidence that clearance of ketones is decreased in patients with DKA. This decrease may be due to low insulin concentration, increased glucocorticoid level, and decreased glucose utilization by peripheral tissues.

The development of dehydration and sodium depletion in DKA and HHS is the result of increased urinary output and electrolyte losses. Hyperglycemia leads to osmotic diuresis in both DKA and HHS. In DKA, urinary ketoanion excretion on a molar basis is generally less than half that of glucose. Ketoanion excretion, which obligates urinary cation excretion as sodium, potassium, and ammonium salts, also contributes to a solute diuresis.

The extent of dehydration, however, is typically greater in HHS than in DKA. At first, this seems paradoxical because patients with DKA experience the dual osmotic load of ketones and glucose. The more severe dehydration in HHS, despite the lack of severe ketonuria, may be attributable to the more gradual onset and longer duration of metabolic decompensation and partially to the fact that patients presenting with HHS typically have an impaired fluid intake.

Other factors that may contribute to excessive volume losses include diuretic use, fever, diarrhea, and nausea and vomiting. The more severe dehydration, together with the older average age of patients with HHS and the presence of other comorbidities, almost certainly accounts for the higher mortality of HHS. In addition, osmotic diuresis promotes the net loss of multiple minerals and electrolytes (Na, K, Ca, Mg, Cl, and PO4). Although some of these can be replaced rapidly during treatment (Na, K, and Cl), others require days or weeks to restore losses and achieve balance.

The severe derangement of water and electrolytes in DKA and HHS is the result of insulin deficiency, hyperglycemia, and hyperketonemia (in DKA). In DKA and HHS, insulin deficiency per se may also contribute to renal losses of water and electrolytes because insulin stimulates salt and water reabsorption in the proximal and distal nephron and phosphate reabsorption in the proximal tubule.

During severe hyperglycemia, the renal threshold of glucose and ketones is exceeded. Thereby, urinary excretion of glucose in DKA and HHS may be as much as 200 g/day, and urinary excretion of ketones in DKA may be ~20-30 g/day, with total osmolar load of ~2,000 mOsm. The osmotic effects of glucosuria result in impairment of NaCl and H2O reabsorption in the proximal tubule and loop of Henle.

Moreover, the ketoacids formed during DKA ( -hydroxybutyric and acetoacetic) are strong acids that fully dissociate at physiological pH. Thus, ketonuria obligates excretion of positively charged cations (Na, K, NH4+). The hydrogen ions are titrated by plasma bicarbonate, resulting in metabolic acidosis. The retention of ketoanions leads to an increase in the plasma anion gap.

The average losses of electrolytes and water in DKA and HHS are summarized below.

Typical Total Body Deficits of Water and Electrolytes in DKA and HHS

Total water (liters) 6 9
Water (ml/kg) 100 100-200
Na+ (mEq/kg) 7-10 5-13
Cl- (mEq/kg) 3-5 5-15
K+ (mEq/kg) 3-5 4-6
PO4 (mmol/kg) 5-7 3-7
Mg2+ (mEq/kg) 1-2 1-2
Ca2+ (mEq/kg) 1-2 1-2

During HHS and DKA, intracellular dehydration occurs as hyperglycemia and water loss lead to increased plasma tonicity, leading to a shift of water out of cells.

Thus, patients with a better history of food, salt, and fluid intake prior to and during DKA have better preservation of kidney function, greater ketonuria, lower ketonemia, and lower anion gap and are less hyperosmolar. These patients may, therefore, present with greater degrees of hyperchloremic metabolic acidosis.

On the other hand, patients with a history of diminished fluid and solute intake during the development of acute metabolic decompensation, plus loss of fluid through nausea and vomiting, typically present with greater degrees of volume depletion, increased hyperosmolarity, and impaired renal function and greater retention of glucose and ketoanions in plasma. The greater retention of plasma ketoanions is reflected in a greater increment in the plasma anion gap. Such patients may present with greater alteration of sensoria, which is more commonly found in HHS than DKA. However, in HHS, as mentioned above, the inability to take fluid (often in elderly patients) plus other pathogenic mechanisms leads to greater hyperosmolarity.

Potassium deserves special attention in the patient with DKA. As a rule, the total body potassium levels in the patient with DKA are decreased. However, the patient may be hyperkalemic or have a normal serum potassium level at presentation. This falsely normal or elevated plasma potassium level is multifactorial. First, the osmotic pull of the extracellular fluid shifts water and potassium out of the intracellular fluid of the muscle cells. The shift is then further increased by the breakdown of intracellular protein which liberates more potassium. Additionally, potassium moves out of cells in exchange for hydrogen ions which are present in excess during DKA. Finally, in the absence of insulin potassium is unable to move back into cells once it has been pulled out. All of this potassium that is pulled from the intracellular arena is initially brought to the kidneys, where it is lost in the osmotic pull present due to the extreme glycosuria. When the patient finally becomes so dehydrated that they cannot maintain adequate glomerular filtration, the potassium present in the extracellular fluid appears as a normal or increased amount, despite severe total body depletion.

Pathogenesis of DKA and HHS

When considering the precipitating factors for the development of DKA it is important to remember that DKA develops due to either an absolute or a relative absence of insulin. An absolute insulin deficiency is the major precipitant for those patients presenting in DKA who have new onset type I diabetes. It is estimated that 10-20% of patients with new onset diabetes will present in DKA as their initial presentation. Another major cause of absolute insulin deficiency is omission of normal insulin in a patient with know type I diabetes.

In those patients with known diabetes the precipitating factor for DKA can be identified in greater than 80% of the cases. Except in the case where the patient stops taking their insulin, the usual cause of the DKA is a relative lack of insulin. Relative insulin deficiency occurs when there is an increased requirement for insulin due to an increased physiologic stress such as seen with an infection, trauma, or other process. Infection is the most frequent identifiable cause of DKA with pneumonia and urinary tract infections being two of the most common causes. Myocardial infarction should always be considered in the list of precipitating factors of DKA, particularly in older patients, as the condition is associated with elevations of epinephrine which may stimulate a pathologic process that results in DKA.

Other precipitating causes are noted in the table below.

Absolute lack of insulin

Relative lack of Insulin
    Acute Illness
  • Infection or other inflammatory process
  • Myocardial Infarction
  • Stroke
  • Trauma
Endocrine Disorders
  • Steroids * Calcium channel blockers
  • Pentamidine * Beta-blocking agents
  • Dilantin * Alcohol
  • HCTZ

The diagnostic criteria for DKA include a glucose greater than 250 mg/dl, a pH lower than 7.30-7.35, a low HCO3, an elevated anion gap, and positive serum ketones greater than 1:2 dilution with the nitroprusside reaction. When considering a patient presenting with an anion gap metabolic acidosis it is essential to consider the entire differential diagnosis before deciding the patient has DKA.

Causes of Metabolic Acidosis (Classified by Anion Gap)

A: High Anion-Gap Acidosis
  • Diabetic Ketoacidosis
  • Alcoholic Ketoacidosis
  • Starvation Ketoacidosis
Lactic Acidosis
  • Type A Lactic acidosis (Impaired perfusion)
  • Type B Lactic acidosis (Impaired carbohydrate metabolism)
Renal Failure
  • Uraemic Acidosis
  • Acidosis with acute renal failure
  • Ethylene glycol
  • Methanol
  • Salicylates
B: Normal Anion-Gap Acidosis (or Hyperchloraemic acidosis)
Renal Causes
  • Renal tubular acidosis
  • Carbonic anhydrase inhibitors
GIT Causes
  • Severe diarrhoea
  • Uretero-enterostomy or Obstructed ileal conduit
  • Drainage of pancreatic or biliary secretions
  • Small bowel fistula
Other Causes
  • Recovery from ketoacidosis
  • Addition of HCl, NH4Cl

The causes of a high anion gap can be easily remembered by remembering the word.

CATMUDPILES ( C= CO, CN; A= Alcoholic ketoacidosis; T= toluene; M= Methanol; U= Uremia D= DKA; P= Paraldehyde; I= Iron, INH; L= Lactic acidosis; E= Ethylene glycol; S= Salicylates and strychnine).

Usually the diagnosis can be assumed by the combination of history and laboratory tests. Briefly, some of the other diagnosis to consider are as follows. Carbon monoxide and cyanide often have a traceable source of exposure as well as multiple victims. Drugs such as iron give very pronounced gastrointestinal symptoms and pill fragments which are visible on abdominal radiograph. Isoniazid is associated with intractable seizures, and it is these seizures that result in the acidosis. Paraldehyde has an odor of vinyl which may help make this diagnosis. The acidosis is not usually too severe and ketones may be present in the urine. Toluene is an aromatic petroleum distillate that is commonly used as a solvent in paint, pharmaceutical, and chemical companies. This agent may have associated pulmonary complaints if any of it was aspirated, however, the most common route of exposure seen in drug abusers. These people inhale toluene and may present with GI disturbances, weakness, and neuropyschiatric problems. These patients may have paint on their hands, or smell of paint products when they present. Methanol and ethylene glycol can cause mild abdominal discomfort as well as apparent intoxication. Methanol may also present with visual complaints and specific findings on physical exam.

Initial tests to consider are those that are likely already available since electrolytes, BUN, creatinine, and glucose are often ordered early in the evaluation of ill patients. If the BUN, creatinine, and glucose are normal then uremia and DKA (unless the patient has euglycemic DKA) have been removed from the differential. Alcoholic ketoacidosis usually causes a mild to moderate acidemia and moderate elevation of the anion gap. Commonly, the patient has a negative ethanol level and has complaints of abdominal pain. They classically have a long history of significant drinking. Also, they are unlikely to have rapid hemodynamic compromise. Clearly, this patient has an elevated glucose, ketones, and an acidosis.

At this point, a urinalysis will likely be helpful. The urine dipstick can evaluate for glucose and ketones. This will help further evaluate for DKA as well as be a marker for the other sources of ketonuria (ketones may be present in exposure to salycilates, alcoholic ketoacidosis, and in toluene overdoses). If there is any suspicion of ethylene glycol exposure then the urine should be exposed to a Wood's lamp. If the patient ingested fluorescien-containing antifreeze (ethylene glycol) then their urine will fluoresce under the lamp. Also, ethylene glycol is metabolized in such a way that calcium oxalate crystals may be present in the urine (the absence of these findings does not rule out ethylene glycol exposure). Another useful bedside test or urine is the ferric chloride test. This is a qualitative test to measure whether the patient has had exposure to salycilates. If the test is positive, a serum salycilate level must be sent.

If the patient presents comatose, then the causes of acidosis and coma should be considered. These include starvation, DKA, lactic acidosis, uremic acidosis, alcoholic ketosis, salicylate intoxication, toxic alcohol ingestion, NKH, and hypoglycemic coma. Again, with careful history, physical, and directed laboratory testing the diagnosis can usually be made.

In addition to the above differential diagnosis, it is important to understand special instances when the patient has DKA, but does not meet the usual diagnostic criteria.

There are three cases that should be considered:

Euglycemic DKA: In cases where a patient maintains good hydration, or has an increased glomerular filtration rate (as seen in a pregnant patient), ketoacidosis may occur with minimal hyperglycemia. It may also be seen in patients who are taking insulin, but the amount of insulin is not adequate for a ketogenic process, such as acute illness. A careful history, can usually explain the minimal elevation of glucose and lead to appropriate treatment.

Alkalemic DKA: This is a condition of the expected primary metabolic acidosis, being mixed with a primary metabolic alkalosis. A markedly elevated anion gap is generally present. This condition most commonly occurs in a patient with DKA who develops severe, protracted vomiting. It may also be seen in those on diuretics, or those with Cushing's syndrome. The laboratory results come from DKA, which lowers the bicarbonate, and vomiting which lowers the chloride. Taken together there is a marked elevation of the anion gap, but the pH is not as low as predicted by the PCO2.

Nonketotic DKA: In normal conditions there is approximately a 1:5 ratio of acetoacetate to beta-hydroxybutyrate. In conditions that cause tissue hypoxemia (such as sepsis, shock, severe hypotension) this reaction gets driven toward beta-hydroxybutyrate and the ratio may reach 1:20 (acetoacetate to beta-hydroxybutyrate). This situation leaves little acetoacetate to be measured by the nitroprusside reaction and can make the diagnosis of DKA less clear. These patients still have an elevated anion gap and, usually, and elevated glucose.

History And Physical Examination

The evolution of the acute DKA episode in type 1 Diabetes or even in type 2 diabetes tends to have a much shorter time span as compared to HHS. Although the symptoms of poorly controlled diabetes may be present for several days, the metabolic alterations typical of ketoacidosis usually evolve within a short time frame (typically <24 h). Occasionally, the entire symptomatic presentation may evolve or develop more acutely, and the patient may present in DKA with no prior clues or symptoms.

The classical clinical picture includes a history of polyuria, polydipsia, polyphagia, weight loss, vomiting, abdominal pain, dehydration, weakness, clouding of sensorium, and finally coma. Patients with DKA usually present with complaint of fatigue, malaise, thirst, and polyuria. Depending on the length of symptoms the patient may be able to report weight loss. As the patient becomes increasingly ill they may begin to vomit and complain of abdominal pain.

Physical findings may include poor skin turgor, Kussmaul respirations , tachycardia, hypotension, alteration in mental status, shock, and ultimately coma. Up to 25% of DKA patients have emesis, which may be coffee-ground in appearance and guaiac positive. Endoscopy has related this finding to the presence of hemorrhagic gastritis. Mental status can vary from full alertness to profound lethargy or coma, with the latter more frequent in HHS. Although infection is a common precipitating factor for both DKA and HHS, patients can be normothermic or even hypothermic primarily because of peripheral vasodilation. Hypothermia, if present, is a poor prognostic sign.

The physical signs of DKA can be variable. Most patients will have some degree of tachycardia, but the blood pressure is often normal.

Evidence of dehydration, such as loss of skin turgor, and dry mucus membranes may be present. The patient may be febrile, and extreme elevations of temperature should not be assumed to be the result of dehydration. Hypothermia may also be seen. The respiratory rate may be normal or somewhat rapid, but if the patient is examined closely the deep breathing typical of "Kussmaul" respirations may be noted.

Caution needs to be taken with patients who complain of abdominal pain on presentation. The exact cause of abdominal pain that is associated with DKA is not known. The abdominal pain is disturbing since it may be secondary to the DKA, or be from the pathologic process that initiated the crisis, such as pyelonephritis, pancreatitis, etc. Usually, abdominal pain secondary to DKA will begin to resolve with treatment. Further evaluation is necessary if this complaint does not resolve with resolution of dehydration and metabolic acidosis.

Physical examination reveals other findings, such as a fruity breath odor (similar to the odor of nail polish remover) as the result of volatile acetone and signs of dehydration, including loss of skin turgor, dry mucous membranes, tachycardia, and hypotension.

Mental status can vary from full alertness to profound lethargy; however, <20% of patients with DKA or HHS are hospitalized with loss of consciousness. In HHS, mental obtundation and coma are more frequent because the majority of patients, by definition, are hyperosmolar. In some patients with HHS, focal neurological signs (hemiparesis or hemianopsia) and seizures may be the dominant clinical features. Although the most common precipitating event is infection, most patients are normothermic or even hypothermic at presentation, because of either skin vasodilation or low fuel-substrate availability.

Although usually straightforward, the diagnosis of diabetic ketoacidosis is occasionally missed in unusual situations, such as when it is the initial presentation of diabetes in infants or elderly patients or when patients present with sepsis or infarction of the brain, bowel or myocardium. These presentations can distract the physician from the underlying diagnosis of diabetic ketoacidosis.

In general, the laboratory diagnosis of DKA is based on an elevated blood glucose (usually above 250mg/dl), a low serum bicarbonate level (usually below 15 mEq/L), and elevated anion gap, and demonstrable ketonemia. Individually, all of these values may vary considerably, but taken together they help make the diagnosis of DKA. In addition to the above there are several calculations that are important in the evaluation and therapy of the patient with DKA.

Mental status changes can occur in DKA and may be the result of DKA, or some underlying process that may have caused the patient to develop DKA. Obviously, it is critical to determine the cause of the patient's altered mental status. It has been well documented that mental status changes in DKA correlate with the effective serum osmolality. Thus, a patient with mental status changes can only have this decompensation explained by the elevated glucose level if the serum osmolality is significantly elevated.

The effective serum osmolality is calculated as follows:

Serum Osmolality = 2(Na+K) + glu/18 + BUN/2.8

Calculated total osmolalities of greater than 340 mOsm/kg H2O are associated with stupor and coma. Calculated values below this level would not explain a patient with coma and an additional cause such as meningitis, or stroke should be considered.

Despite volume depletion, serum sodium may be low, normal, or elevated. This variation has several causes. First, dehydration from an osmotic diuresis may result in excess loss of water compared to sodium, this may give increased values of serum sodium despite total body sodium depletion. On the other hand, serum sodium level frequently "appears" low. Insulin deficiency results in reduced clearance of triglycerides. The presence of triglycerides displaces plasma water and cause a low reading for the sodium concentration (this is pseudohyponatremia). It is possible to recognize this clinically by noting that the plasma is milky or cloudy appearing. Finally, Sodium levels often appear artificially low due to the osmotic pull of the elevated serum glucose levels. The presence of the increased glucose causes water to shift into the extracellular space resulting in a dilutional reduction on the serum sodium. When trying to determine the degree of dehydration in a patient it is best to use corrected serum sodium level.

To assess the severity of sodium and water deficits, serum sodium may be corrected by adding 1.6 mEq to the measured serum sodium for each 100 mg/dl of glucose above 100 mg/dl

This can be calculated using the following formula:

Corrected Na = [Na+] + 1.6 x [glu in mg/dl] - 100

Often, the initial serum sodium appears low, but when the above calculation in performed, the final value is elevated. This indicates a marked intracellular dehydration.

The ketoacids produced during DKA are buffered by the serum bicarbonate and then excreted in the urine. This causes a loss of bicarbonate which is a measured anion. As the bicarbonate is lost the anion gap increases.

The three ketone bodies are beta- hydroxybutyrate, acetoacetate, and acetone. Only acetoacetate and acetone are measured in the nitroprusside reaction, but the formation of these ketone bodies favors the development of beta-hydroxybutyrate. Thus, the test for ketone bodies may be only weakly positive even when large amounts of total ketones are present. Acetone does not contribute to the anion gap, but it is measured in the nitroprusside reaction and is a precursor for the regeneration of bicarbonate. It is not uncommon for the patient to be improving clinically, but to have the nitroprusside test become more strongly positive since acetone is being produced. At this point, the anion gap should be narrowing, even as the nitroprusside test is getting stronger.

Other tests should be varied out initially. Many of these common tests will give the data needed to do the above important calculations. A tube should be sent for exact glucose determination, but a bedside test can me used to determine gross blood sugar levels. To determine the degree of acidosis and bicarbonate loss, an ABG should be sent early in the evaluation of a patient considered to have DKA.

The complete blood count often shows an elevation of the white blood cells. This may be, in part, due to hemoconcentration secondary to dehydration. Thus, WBC's of 20,000 occur commonly. Those patients with WBC's greater than 30,000 who have a bandemia on peripheral smear should be assumed to have an infectious process.

Additional evaluation should take into consideration the best tests to help determine the potential cause of the patient's decompensation into DKA. Urinalysis, chest radiograph, and electrocardiogram should be done on most patients.

In assessment of blood glucose and electrolytes in DKA, certain precautions need to be taken in interpreting results. Severe hyperlipidemia, which is occasionally seen in DKA, could reduce serum glucose and sodium levels, factitiously leading to pseudohypo- or normoglycemia and pseudohyponatremia, respectively, in laboratories still using volumetric testing or dilution of samples with ion-specific electrodes. This should be rectified by clearing lipemic blood before measuring glucose or sodium or by using undiluted samples with ion-specific electrodes. Creatinine, which is measured by a colormetric method, may be falsely elevated as a result of acetoacetate interference with the method. Hyperamylasemia, which is frequently seen in DKA, may be the result of extrapancreatic secretion and should be interpreted cautiously as a sign of pancreatitis. The usefulness of urinalysis is only in the initial diagnosis for glycosuria and ketonuria and detection of urinary tract infection. For quantitative assessment of glucose or ketones, the urine test is unreliable, because urine glucose concentration has poor correlation with blood glucose levels and the major urine ketone, -hydroxybutyrate, cannot be measured by the standard nitroprusside method.

Therapeutic Goals

The therapeutic goals for treatment of hyperglycemic crises in diabetes consist of 1) improving circulatory volume and tissue perfusion, 2) decreasing serum glucose and plasma osmolality toward normal levels, 3) clearing the serum and urine of ketones at a steady rate, 4) correcting electrolyte imbalances, and 5) identifying and treating precipitating events.


The severity of fluid and sodium deficits is determined primarily by the duration of hyperglycemia, the level of renal function and the patient's fluid intake. Dehydration can be estimated by clinical examination and by calculating total serum osmolality and the corrected serum sodium concentration.

The severity of dehydration and volume depletion can be estimated by clinical examination using the following guidelines, with the caveat that these criteria are less reliable in patients with neuropathy and impaired cardiovascular reflexes:

  1. An orthostatic increase in pulse without change in blood pressure indicates ~10% decrease in extracellular volume (i.e., ~2 liters isotonic saline).
  2. An orthostatic drop in blood pressure (>15/10 mmHg) indicates a 15-20% decrease in extracellular volume (i.e., 3-4 liters).
  3. Supine hypotension indicates a decrease of >20% in extracellular fluid volume (i.e., >4 liters).

The measured serum sodium concentration must be corrected for the changes related to hyperglycemia. Corrected serum sodium concentrations of greater than 140 mEq per L (140 mmol per L) and calculated total osmolalities of greater than 330 mOsm per kg of water are associated with large fluid deficits. Calculated total osmolalities are correlated with mental status, in that stupor and coma typically occur with an osmolality of greater than 330 mOsm per kg of water.

The initial priority in the treatment of diabetic ketoacidosis is the restoration of extracellular fluid volume through the intravenous administration of a normal saline (0.9 percent sodium chloride) solution. This step will restore intravascular volume, decrease counterregulatory hormones and lower the blood glucose level. As a result, insulin sensitivity may be augmented.

The initial treatment is typically with a 0.9 percent saline solution administered at a rate of 7 to 14 mL per kg per hour. In patients with mild to moderate volume depletion, infusion rates of 7 mL per kg per hour have been as efficacious as infusion rates of 14 mL per kg per hour. The subsequent administration of a hypotonic saline (0.45 percent sodium chloride) solution, which is similar in composition to the fluid lost during osmotic diuresis, leads to gradual replacement of deficits in both intracellular and extracellular compartments.

When the blood glucose concentration is approximately 250 mg%, glucose should be added to the hydration fluid (i.e., 5 percent dextrose in hypotonic saline solution). This allows continued insulin administration until ketonemia is controlled and also helps to avoid iatrogenic hypoglycemia.

Another important aspect of rehydration therapy in patients with diabetic ketoacidosis is the replacement of ongoing urinary losses.

The use of isotonic versus hypotonic saline in treatment of DKA and HHS is still controversial, but there is uniform agreement that in both DKA and HHS, the first liter of hydrating solution should be normal saline (0.9% NaCl), given as quickly as possible within the 1st hour and followed by 500-1,000 ml/h of 0.45 or 0.9% NaCl (depending on the state of hydration and serum sodium) during the next 2 h. State of hydration can also be estimated by calculating total and effective plasma osmolality and by calculating corrected serum sodium concentration.

Dextrose should be added to replacement fluids when blood glucose concentrations are <250 mg/dl in DKA or <300 mg/dl in HHS. This can usually be accomplished with the administration of 5% dextrose; however, in rare cases, a 10% dextrose solution may be needed to maintain plasma glucose levels and clear ketonemia. This allows continued insulin administration until ketogenesis is controlled in DKA and avoids too rapid correction of hyperglycemia, which may be associated with development of cerebral edema (especially in children).

An additional important aspect of fluid replacement therapy in both DKA and HHS is the replacement of ongoing urinary losses. Failure to adjust fluid replacement for urinary losses leads to a delay in repair of sodium, potassium, and water deficits. Overhydration is a concern when treating children with DKA, adults with compromised renal or cardiac function, and elderly patients with incipient congestive heart failure. Once blood pressure stability is achieved with the use of 10-20 ml · kg-1 · h-1 0.9% NaCl for 1-2 h, one should become more conservative with hydrating fluid.

Reduction in glucose and ketone concentrations should result in concomitant resolution in osmotic diuresis of DKA. The resulting decrease in urine volume should lead to a reduction in the rate of intravenous fluid replacement. This reduces the risk of retention of excess free water, which contributes to brain swelling and cerebral edema, particularly in children. The duration of intravenous fluid replacement in adults and children is ~48 h depending on the clinical response to therapy. However, in a child, once cardiovascular stability is achieved and vomiting has stopped, it is safer and as effective to pursue oral rehydration.

Modern management of diabetic ketoacidosis has emphasized the use of lower doses of insulin. This has been shown to be the most efficacious treatment in both children and adults with diabetic ketoacidosis. The current recommendation is to give low-dose (short-acting regular) insulin after the diagnosis of diabetic ketoacidosis has been confirmed by laboratory tests and fluid replacement has been initiated.

It is prudent to withhold insulin therapy until the serum potassium concentration has been determined. In the rare patient who presents with hypokalemia, insulin therapy may worsen the hypokalemia and precipitate life-threatening cardiac arrhythmias.

Standard low-dose insulin therapy consists of an initial intravenous bolus of 0.15 unit of regular insulin per kg followed by the continuous intravenous infusion of regular insulin prepared in normal saline or hypotonic saline solution at a rate of 0.1 unit per kg per hour.

In clinical situations in which continuous intravenous insulin cannot be administered, the recommended initial insulin dose is 0.3 unit per kg, with one half of the dose given as an intravenous bolus and the remainder given subcutaneously or intramuscularly. Subsequently, regular insulin should be given in a dosage of 0.1 unit per kg per hour until the blood glucose level is approximately 250 mg per dL.

If the blood glucose concentration does not fall by 50 to 70 mg per dL (2.8 to 3.9 mmol per L) in the first hour, the intravenous infusion rate should be doubled or additional intravenous 10-unit boluses of insulin should be given every hour. Either of these treatments should be continued until the blood glucose level falls by 50 to 70 mg per dL. Low-dose insulin therapy typically produces a linear fall in the glucose concentration of 50 to 70 mg per dL per hour.

More rapid correction of hyperglycemia should be avoided because it may increase the risk of cerebral edema. This dreaded treatment complication occurs in approximately 1 percent of children with diabetic ketoacidosis. The typical presentation is onset of headache and decreased mental status occurring several hours after the start of treatment. Cerebral edema is associated with a mortality rate of up to 70 percent.

When a blood glucose concentration of 250 mg per dL has been achieved, the continuous or hourly insulin dosage can be reduced to 0.05 unit per kg per hour. The insulin and fluid regimens are continued until ketoacidosis is controlled. This requires the achievement of at least two of these acid-base parameters: a serum bicarbonate concentration of greater than 18 mEq per L, a venous pH of 7.3 or greater and an anion gap of less than 14 mEq per L. The ketosis and acidemia in DKA take longer to resolve than the elevation of glucose. For this reason, the insulin therapy must be continued even when the blood glucose levels have improved to near normal levels. When the glucose levels begin to approach 250 mg/dl, insulin infusions are continued, but the fluid composition is changed to include 5-10% dextrose in water to avoid hypoglycemia.

Regardless of the serum potassium level at the initiation of therapy, during treatment of DKA there is usually a rapid decline in the potassium concentration in the patient with normal kidney function. Patients who have life-threatening elevation of potassium should be treated in the same manner as any other patient with severe hyperkalemia. The drop in potassium is a result of hydration and resolution of acidemia, but in particular is due to insulin administration. As insulin is given potassium is driven into the intracellular compartment. Additionally, early in the course of therapy potassium is usually still being lost in the urine due to ongoing osmotic diuresis and ketonuria. Since potassium is normally an intracellular ion, it is not well conserved as these mechanisms begin to take effect.

While it is not uncommon to have hyperkalemia, the development of severe hypokalemia is usually a greater threat. Total body deficits are estimated at 3-5 mEq/kg. When treating the patient with DKA the clinician should be able to anticipate all of these shifts and maintain potassium levels at near normal throughout therapy.

General recommendations for potassium replacement are as follows. If the patient does not have marked elevation of potassium, is not in renal failure, the ECG does not show evidence of hyperkalemia beyond peaked T-waves, potassium therapy is initiated once good urine output has been established. Potassium is usually added to the intravenous fluids and should not exceed 40 mEq per liter of intravenous fluids. Some authors recommend spitting the potassium replacement as KCL and KPO4. The potassium level should be checked every one to two hours initially since this is when the greatest shift occurs. After the patient has stabilized the potassium can be checked every 6 to 8 hours.

To prevent hypokalemia, potassium replacement is initiated after serum levels fall below 5.5 mEq/l, assuming the presence of adequate urine output. Generally, 20-30 mEq potassium (2/3 KCl and 1/3 KPO4) in each liter of infusion fluid is sufficient to maintain a serum potassium concentration within the normal range of 4-5 mEq/l. Rarely, DKA patients may present with significant hypokalemia. In such cases, potassium replacement should begin with fluid therapy, and insulin treatment should be delayed until potassium concentration is restored to >3.3 mEq/l to avoid arrhythmias or cardiac arrest and respiratory muscle weakness. During treatment of diabetic ketoacidosis, a rapid decline in the serum potassium level is typical. When the serum potassium concentration is less than 5.5 mEq per L, 20 to 30 mEq per L of potassium chloride is added to the intravenous fluids.

During treatment of DKA and HHS with hydration and insulin, there is typically a rapid decline in plasma potassium concentration as potassium reenters the intracellular compartment. However, potassium replacement should not be initiated until the serum potassium concentration is <5.5 mEq/l.

The use of bicarbonate in the treatment of DKA is highly controversial. The advocates of bicarbonate suggest that acidosis is detrimental to cardiac function, while opponents of this therapy point out several problems. These include: (1) paradoxical lowering of intracellular pH from diffusion into cells of CO2 which is produced from the bicarbonate, (2) a decrease in tissue oxygenation from a shift in the oxygen dissociation curve, (3) sodium overload, (4) increased chance of acute hypokalemia. There are a limited number of studies evaluating the use of bicarbonate but those that are present have found that bicarbonate therapy does not significantly alter the recovery or outcome in DKA. To date there are not studies looking at the use of bicarbonate in severely acidotic patients (those with pH less than 6.9) and it is generally felt that this group should probably receive bicarbonate therapy.

Current recommendations for bicarbonate therapy are as follows. Use of bicarbonate is considered unnecessary when the blood pH is greater than 7.1. For those patients with pH between 6.9 and 7.1 there are no clear guidelines. If the patient is elderly or very debilitated there may be some benefit to the bicarbonate in this range. If it is given it should be given with the intravenous fluids and not as IV push. For those patients with pH below 6.9 bicarbonate should be added to the intravenous fluids. One ampule of bicarbonate has 44 mEq of sodium bicarbonate. Attempts should be made to create an isotonic fluid with the bicarbonate being added to either one-half normal saline or D5W.

In general, supplemental bicarbonate therapy is no longer recommended for patients with diabetic ketoacidosis, because the plasma bicarbonate concentration increases with insulin therapy. Insulin administration inhibits ongoing lipolysis and ketone production and also promotes the regeneration of bicarbonate.

Insulin, as well as bicarbonate therapy, lowers serum potassium; therefore, potassium supplementation should be maintained in intravenous fluid as described above and carefully monitored. Thereafter, venous pH should be assessed every 2 h until the pH rises to 7.0, and treatment should be repeated every 2 h if necessary.

Phosphate is normally an intracellular substance that is dragged out of the cell during DKA. Similarly to potassium, at presentation the serum level may be normal, high, or low while the total body supply is depleted. Despite this depletion, replacement of phosphate has not been shown to affect patient outcome and routine replacement is not recommended.

Phosphate, along with potassium, shifts from the intracellular to the extracellular compartment in response to hyperglycemia and hyperosmolarity. Osmotic diuresis subsequently leads to enhanced urinary phosphate losses. Because of the shift of phosphate from the intracellular to the extracellular compartment, serum levels of phosphate at presentation with DKA or HHS are typically normal or increased. During insulin therapy, phosphate reenters the intracellular compartment, leading to mild to moderate reductions in serum phosphate concentrations. Adverse complications of hypophosphatemia are uncommon, occurring primarily in the setting of severe hypophosphatemia (phosphate <1 mg/dl).

Potential complications of severe hypophosphatemia include respiratory and skeletal muscle weakness, hemolytic anemia, and worsened cardiac systolic performance. Phosphate depletion may also contribute to decreased concentrations of 2,3-diphosphoglycerate, thus shifting the oxygen dissociation curve to the left and limiting tissue oxygen delivery. Controlled and randomized studies have not demonstrated clinical benefits from the routine use of phosphate replacement in DKA. Five days of PO4 therapy increased 2,3-diphosphoglycerate without a significant change in the oxygen dissociation curve and resulted in a significant decrease in serum ionized calcium. Similar studies have not been performed in patients with HHS.

Although routine phosphate replacement is unnecessary in DKA, replacement should be given to patients with serum phosphate concentrations <1.0 mg/dl and to patients with moderate hypophosphatemia and concomitant hypoxia, anemia, or cardiorespiratory compromise. Excessive administration of phosphate can lead to hypocalcemia with tetany and metastatic soft tissue calcifications. In HHS, because the duration of symptoms may be prolonged and because of comorbid conditions, the phosphate level may be lower than in DKA; therefore, it is prudent to monitor phosphate levels in these patients.

If phosphate replacement is needed, 20-30 mEq/l potassium phosphate can be added to replacement fluids and given over several hours. In such patients, because of the risk of hypocalcemia, serum calcium and phosphate levels must be monitored during phosphate infusion. Despite whole-body phosphate deficits in DKA that average 1.0 mmol/kg body wt, serum phosphate is often normal or increased at presentation. Phosphate concentration decreases with insulin therapy. Prospective randomized studies have failed to show any beneficial effect of phosphate replacement on the clinical outcome in DKA, and overzealous phosphate therapy can cause severe hypocalcemia with no evidence of tetany. However, to avoid cardiac and skeletal muscle weakness and respiratory depression due to hypophosphatemia, careful phosphate replacement may sometimes be indicated in patients with cardiac dysfunction, anemia, or respiratory depression and in those with serum phosphate concentration <1.0 mg/dl. When needed, 20-30 mEq/l potassium phosphate can be added to replacement fluids.

In most instances, it may be necessary to start treatment with a broad spectrum antibiotic without waiting for specific proof of the presence of an infection and a culture and sensitivity test.

  • In severely ill patients, electrolytes including potassium, pH and serum creatinine should be monitored hourly for the first 4 hours then at 4 hourly intervals, over the next 12 hours.
  • Vital signs (eg; pulse, temperature, respiration, blood pressure and mental status) should be monitored with similar frequency.
  • Once the glucose is < 15 mmol/L, the pH is near normal and the patient is eating and drinking well, the frequency of laboratory blood tests can be reduced further. At this stage, start checking the urine for ketones to ascertain whether these are clearing.

Brain Edema: Clinical brain edema occurs in less than one percent of the pediatric population and even less frequently in adults. When it does occur the mortality rate is high. It is probably prudent to prevent overvigorous correction of severe hyperosmolarity and hypernatremia.

When this complication does develop it typically has a rapid onset of severe headache and depression of the mental status. CT scan will show characteristic changes. Treatment must be started rapidly with intravenous mannitol and intubation as indicated.

Adult Respiratory Distress Syndrome: This complication usually occurs during therapy with fluids, insulin, and electrolyte replacement. Fluid therapy causes an increase in the right atrial pressure and additionally, decreases colloid oncotic pressure.

These conditions could favor the development of pulmonary edema in a normal patient, but those with DKA may also have an increased pulmonary capillary permeability for unclear reasons.

Patients who have a widened A-a gradient or who have rales on lung exam at the time that they present with DKA seem to be at an increased risk for developing ARDS. In patients with these risk factors it is probably wise to use lower rates of fluid replacement.

Hyperchloremic Acidosis: This complication can be recognized by a low bicarbonate level, low to normal pH, normal anion gap, and an increased serum chloride level. The cause of this condition is multifactorial: (1) ketoacid anions are metabolized by the regeneration of bicarbonate. Therefore, the prior loss of the ketoacids in the urine prevents regeneration of bicarbonate, This causes a hyperchloremic acidosis, (2) During the development of ketoacidosis, sodium is lost preferentially to chloride leaving more of this anion in the body.

Generally, this condition causes no adverse outcome and will usually resolve on its own with ongoing therapy. It may be minimized by switching to hypotonic fluids during therapy and by using smaller amounts of chloride during therapy (KPhos rather than KCl).

Hypokalemia: As the patient is being treated for DKA, the volume expansion, and insulin therapy can rapidly lower potassium. As long as these therapies are ongoing, the potassium level will continue to decline unless it is being aggressively replaced. To avoid sudden decompensation due to severe hypokalemia, it is prudent to recheck a serum potassium, following each liter of fluid. If large doses of insulin are required to control the patient's blood glucose, the potassium level will need to be checked more frequently.

Hypoglycemia: As discussed previously, during DKA therapy, the serum glucose typically normalizes before the ketotic state has been corrected. To reverse this state it is necessary to continue insulin therapy after the glucose levels have improved. Without close monitoring, this can result in life-threatening hypoglycemia. To help avoid this, glucose measurements should be done frequently, and as the glucose level nears 250 mg/dl, the insulin infusion rate should be slowed, and glucose infusion with D5W should be started.

The two major precipitating factors in the development of DKA are inadequate insulin treatment (including noncompliance) and infection. In many cases, these events may be prevented by better access to medical care, including intensive patient education and effective communication with a health care provider during acute illnesses.

Goals in the prevention of hyperglycemic crises precipitated by either acute illness or stress have been outlined. These goals included controlling insulin deficiency, decreasing excess stress hormone secretion, avoiding prolonged fasting state, and preventing severe dehydration. Therefore, an educational program should review sick-day management with specific information on administration of short-acting insulin, including frequency of insulin administration, blood glucose goals during illness, means to suppress fever and treat infection, and initiation of an easily digestible liquid diet containing carbohydrates and salt.

Sick-day management should be reviewed periodically with all patients. It should include specific information on 1) when to contact the health care provider, 2) blood glucose goals and use of supplemental short-acting insulin during illness, 3) means to suppress fever and treat infection, and 4) initiation of an easily digestible liquid diet containing carbohydrates and salt. Most importantly, the patient should be advised never to discontinue insulin and to seek professional advice early in the course of the illness. Successful sick-day management depends on involvement by the patient and/or a family member. The patient/family member must be able to accurately measure and record blood glucose, urine ketone determination when blood glucose is >300 mg/dl, insulin administered, temperature, respiratory and pulse rate, and body weight and must be able to communicate this to a health care professional. Adequate supervision and help from staff or family may prevent many of the admissions for HHS due to dehydration among elderly individuals who are unable to recognize or treat this evolving condition. Better education of care givers as well as patients regarding signs and symptoms of new-onset diabetes; conditions, procedures, and medications that worsen diabetes control; and the treatment regimen.

The second major hyperglycemic emergency is the Hyperosmolar Hyperglycemic State (HHS) and is one that is most commonly seen in an older population with type 2 diabetes. This complication is perhaps best known as hyperglycemic hyperosmolar nonketotic (HHNK) coma. However, since patients rarely present in coma (less than 10% of patients) other names have been suggested that might truly represent the condition in which the patient presents. Thus, this discussion will use the term HHS.

When considering the patient with HHS there are patients who present purely with this disorder while others seem to have a combination of both. Thus, DKA and NKH should be thought of as a continuum of disease. At one extreme is pure DKA without hyperosmolarity of significant amount. As noted above these patients may present with more modest degrees of glucose elevation. At the other extreme is NKH with extreme elevations of glucose, and hyperosmolarity, but without significant ketosis (see table below). Finally, there are a range of patients who will have features of both.

It is due to this continuum, that a significant discussion about aspects of HHS has been dealt with above in conjunction with the discussion on DKA. Some leading authorities, feel that DKA and HHS presenting with a comatose state should be considered the opposite boundaries of a spectrum of presentations, rather than thinking of them as different disease states.

It has been shown that HHS may be due to plasma insulin concentration inadequate to facilitate glucose utilization by insulin-sensitive tissues but adequate (as determined by residual C-peptide) to prevent lipolysis and subsequent ketogenesis. In addition, inadequate fluid intake contributes to hyperosmolarity without ketosis, the hallmark of HHS.

This happens when the body is stressed and needs greater insulin secretion but is unable to meet these increasing demands due to deficient reserves.

  • Acute illness
  • Acute infection (32- 60%)
  • Pneumonia
  • Urinary tract infection
  • Sepsis
  • Cerebral vascular accident
  • Myocardial infarction
  • Acute pancreatitis
  • Acute Pulmonary embolus
  • Intestinal obstruction
  • Dialysis, peritoneal
  • Mesenteric thrombosis
  • Renal failure
  • Heat stroke
  • Hypothermia
  • Subdural hematoma
  • Severe burns
  • Endocrine
  • Acromegaly
  • Thyrotoxicosis
  • Cushing's syndrome
  • Drugs/therapy
  • Beta Adrenergic Blockers
  • Calcium - Channel blockers
  • Chlorpromazine
  • Chlorthalidone
  • Cimetidine
  • Diazoxide
  • Diuretics
  • Encainide
  • Ethacrynic
  • Ethacrynic acid
  • Immunosuppressive agents
  • L-asparaginase
  • Loxapine
  • Phenytoin
  • Propranolol
  • Steroids
  • Total parenteral nutrition
  • Previously undiagnosed diabetes

The initial steps in the development of NKH are similar to those seen in DKA. Insulin is present in these patients, however the organs are insulin resistant and in the relative absence of insulin hepatic glucose production is markedly increased. The excess glucose is deposited in the extracellular space where it cannot be appropriately utilized because of the insulin resistance. However, while there is insulin present in patients with NKH, this alone does not explain all the differences seen between DKA and NKH and there are several theories as to the cause of these differences.

One theory is that the counter-regulatory hormones are not as elevated in NKH as in DKA. Thus, there is not as great a driving force for the break down of fats and ketone formation. Additionally, in NKH the extreme hyperosmolarity that develops actually suppresses lipolysis, so the patient with NKH does not have the substrate needed to form ketones. Finally, it is thought that since pancreatic insulin secretion is present in NKH, there is enough circulating insulin to prevent lipolysis but not enough to prevent hepatic glucose overproduction. Whatever the exact cause, the net result in the patient with NKH is the development of severe dehydration, electrolyte imbalance, and hyperosmolarity, with far less ketone production.

The precipitating factors that lead to development of NKH in a patient with type II diabetes are similar to those noted to cause DKA. Illness, particularly pneumonia, is the most common reason for a patient with type II diabetes to decompensate. As was the case with DKA, many medications can precipitate NKH and this should be considered before starting a diabetic on a new medication.

History and Physical

HHS is a slowly progressive disease and it is not uncommon to have 3-10 day history of increasing thirst, polyuria, and malaise. Patients usually have evidence of dehydration such as dry mucus membranes, tachycardia, poor skin turgor, and sometimes a low grade fever. The blood pressure is usually well preserved unless there is severe dehydration or infection. Respiratory symptoms are usually absent unless the patient has pneumonia. Central nervous system dysfunction is relatively common in patients with HHS. Lethargy and disorientation are common, but frank coma is rare. It is critical to remember that these CNS symptoms rarely present unless the effective osmolarity is greater than 340-350 mOsm/L. Patients with altered sensorium and osmolarity less than this should have a different etiology searched for. Any area within the brain can be affected, and while focal neurologic findings are uncommon in DKA, they are fairly common in patients with HHS. Seizures may be present in up to one-fourth of patients and can be focal or generalized. Cerebral edema is very rare in patients with HHS.

Comparison of Laboratory Findings in DKA and HHNC

Table2 Laboratory Characteristics in Patient Presenting with DKA VERSUS HHNC
Parameter DKA HHNC
Plasma glucose (mg/d) >250 >600
pH <7.3 >7.3
Serum HCO3 (mEq/l) <15 >20
Urine ketones positive negative
Serum Ketones positive negative
Serum osmolality > 300 mOsm/kg >330 mOsm/kg
Serum Na +(mEq/l) 130-140 145-155
Serum K +(mEq/l) 5-6 4-5
BUN (mg/dl) 18-25 20-40

In general, HHS is defined as those individuals with: serum glucose levels in excess of 600 mg/dl, serum osmolality greater than 330 mOsm/kg, absent or minimal serum ketones, arterial pH above 7.3, and a serum bicarbonate above 20 mEq/L. HHS is characterized by severe fluid and electrolyte depletion due to the osmotic diuresis produced by the extreme levels of glucose in the serum. Serum potassium levels can be normal, high, or low, but as was true in DKA the total body amount of potassium is significantly depleted.

Elevations in white blood cell count are not uncommon in patients with HHS. Leukocytosis can result simply from the stress of HHS and not necessarily from infection. However, extreme elevations in WBC should probably be considered evidence for infection. It is wise to have a low threshold for doing complete septic workups and for obtaining a head CT to avoid missing the pathologic process that precipitated the patients.

(NOTE: Many aspects of diagnosis, differential diagnosis and management have been discussed in the section dealing with DKA.)

Table3 Treatment goals in HHNC

Intial therapy (hours 0-12)
Volume resoration
Second Stage (hours 12-48)
Treatment of underlying causes HHNC
Restoration of tonicity to normal
Correction fo acid-based imbalance
Third stage (days 2-14)
Replenishment of electrolytes

The immediate aim of treatment is to rapidly expand the contracted intravascular volume to stabilize BP and to improve circulation and urine flow.

Treatment is started by infusing 2 to 3 L of 0.9% sodium chloride solution over 1 to 2 h. If this stabilizes BP and circulation and restores good urine flow, then the IV infusion can be changed to 0.45% sodium chloride solution to provide additional water. The rate of the 0.45% sodium chloride solution infusion must be adjusted in accordance with frequent assessments of BP, cardiovascular status, and the balance between fluid input and output.

K replacement is usually started by adding 20 mmol/L potassium as a phosphate salt to the initial liter of the IV-infused 0.45% sodium chloride solution, provided urine flow is adequate and the resulting initial rate of K infusion does not exceed 20 to 40 mmol/h.

Insulin treatment should not be aggressive and may be unnecessary because adequate hydration will usually decrease plasma glucose levels. Patients with NKHHC are often very sensitive to insulin, and large doses can precipitously decrease plasma glucose. A too-quick reduction in osmolality can lead to cerebral edema.

However, many obese type II DM patients with HONK require larger insulin doses to reduce their marked hyperglycemia. If insulin is administered, 5% glucose should be added to the IV fluids when the plasma glucose reaches approximately 250 mg/dL (13.88 mmol/L) to avoid hypoglycemia. After recovery from the acute episode, patients are usually switched to adjusted doses of subcutaneous regular insulin at 4- to 6-h intervals.

The complications of HONK are essentially the same as those seen in DKA. The exception to this is the development of cerebral edema. This complication is quite rare in HHS.