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Complications

Hyperglycemia and ketoacidemia are due to insulin lack, hyperglucagonemia, and elevated levels of the stress hormones catecholamines, cortisol, and growth hormone.

A. HYPERGLYCEMIA
Hyperglycemia results from increased hepatic production of glucose as well as diminished glucose uptake by peripheral tissues. Hepatic glucose output is a consequence of increased gluconeogenesis resulting from insulinopenia as well as from an associated hyperglucagonemia.

B. KETOACIDEMIA
Ketoacidemia represents the effect of insulin lack at multiple enzyme loci. Insulin lack associated with elevated levels of growth hormone, catecholamines, and glucagon contributes to an increase in lipolysis from adipose tissue and in hepatic ketogenesis. In addition, there is evidence that reduced ketolysis by insulin-deficient peripheral tissues contributes to the ketoacidemia. The only true "keto" acid present is acetoacetic acid, which, along with its by-product acetone, is measured by nitroprusside reagents (Acetest and Ketostix). The sensitivity for acetone, however, is poor, requiring over 10 mmol, which is seldom reached in the plasma of ketoacidotic subjects - although this detectable concentration is readily achieved in urine. Thus, in the plasma of ketotic patients, only acetoacetate is measured by these reagents. The more prevalent β-hydroxybutyric acid has no ketone group and is therefore not detected by conventional nitroprusside tests. This takes on special importance in the presence of circulatory collapse during diabetic ketoacidosis, wherein an increase in lactic acid can shift the redox state to increase β-hydroxybutyric acid at the expense of the readily detectable acetoacetic acid. Bedside diagnostic reagents would then be unreliable, suggesting no ketonemia in cases where β-hydroxybutyric acid is a major factor in producing the acidosis. A combined glucose and ketone meter (Precision, Medisense) that is able to measure blood β-hydroxyubtyrate concentration on capillary blood is available.

C. FLUID AND ELECTROLYTE DEPLETION
Hyperglycemia results in an osmotic diuresis and dehydration and secondary loss of electrolytes. Ketonuria similarly causes loss of water and electrolytes. Balance studies during withdrawal of insulin and treatment in patients with type 1 diabetes show that on average the water depletion is about 5 L; sodium, 300-500 mmol; potassium, 270-400 mmol; chloride, 100-400 mmol.

Drowsiness is fairly common but frank coma only occurs in about 10% of patients. There is a correlation between the degree of depression of the sensorium and extracellular osmolarity. When serum hyperosmolality exceeds 320-330 mosm/L, central nervous system depression or coma may ensue. Coma in a diabetic patient with a lower osmolality should prompt a search for cause of coma other than hyperosmolality.

Treatment

A. PREVENTION
Education of diabetic patients to recognize the early symptoms and signs of ketoacidosis has done a great deal to prevent severe acidosis. Urine ketones should be measured in patients with signs of infection or in insulin pump-treated patients when capillary blood glucose is unexpectedly and persistently high. When heavy ketonuria and glycosuria persist on several successive examinations, supplemental regular insulin should be administered and liquid foods such as lightly salted tomato juice and broth should be ingested to replenish fluids and electrolytes. The patient should be instructed to contact the physician if ketonuria persists, and especially if vomiting develops or if appropriate adjustment of the infusion rate on an insulin pump does not correct the hyperglycemia and ketonuria. In juvenile-onset diabetics, particularly in the teen years, recurrent episodes of severe ketoacidosis often indicate poor compliance with the insulin regimen, and these patients will require intensive family counseling.

B. EMERGENCY MEASURES
If ketosis is severe, the patient should be placed in the hospital for correction of the hyperosmolality as well as the ketoacidemia. An ICU or, at the least, a step-down unit is preferable for more severe cases.

1. Therapeutic flow sheet - One of the most important steps in initiating therapy is to start a flow sheet listing vital signs and the time sequence of diagnostic laboratory values in relation to therapeutic maneuvers. Indices of the metabolic defects include urine glucose and ketones as well as arterial pH, plasma glucose, acetone, bicarbonate, serum urea nitrogen, and electrolytes. Serum osmolality should be measured or estimated and tabulated during the course of therapy.

A convenient method of estimating effective serum osmolality is as follows (normal values in humans are 280-300 mosm/kg):

These calculated estimates are usually 10-20 mosm/kg lower than values measured by standard cryoscopic techniques in patients with diabetic coma. Urea is freely permeable across cell membranes and therefore not included in calculations of effective serum osmolality. One physician should be responsible for maintaining this therapeutic flow sheet and prescribing therapy. An indwelling urinary catheter is required in all comatose patients but should be avoided if possible in a fully cooperative diabetic because of the risk of introducing bladder infection. Fluid intake and output should be recorded. Gastric intubation is recommended in the comatose patient to correct the commonly associated gastric dilatation that may lead to vomiting and aspiration. The patient should not receive sedatives or narcotics.

2. Insulin replacement - Only regular insulin should be used initially in all cases of severe ketoacidosis, and it should be given immediately after the diagnosis is established. Regular insulin can be given in a loading dose of 0.15 unit/kg as an intravenous bolus to prime the tissue insulin receptors. Following the initial bolus, doses of insulin as low as 0.1 unit/kg/h are continuously infused or given hourly as an intramuscular injection; this is sufficient to replace the insulin deficit in most patients. Replacement of insulin deficiency helps correct the acidosis by reducing the flux of fatty acids to the liver, reducing ketone production by the liver, and also improving removal of ketones from the blood. Insulin treatment reduces the hyperosmolality by reducing the hyperglycemia. It accomplishes this by increasing removal of glucose through peripheral utilization as well as by decreasing production of glucose by the liver. This latter effect is accomplished by direct inhibition of gluconeogenesis and glycogenolysis, as well as by lowered amino acid flux from muscle to liver and reduced hyperglucagonemia.

The insulin dose should be "piggy-backed" into the fluid line so the rate of fluid replacement can be changed without altering the insulin delivery rate. If the plasma glucose level fails to fall at least 10% in the first hour, a repeat loading dose is recommended. The availability of bedside glucometers and of laboratory instruments for rapid and accurate glucose analysis (Beckman or Yellow Springs glucose analyzer) has contributed much to achieving optimal insulin replacement. Rarely, a patient with immune insulin resistance is encountered, and this requires doubling the insulin dose every 2-4 hours if hyperglycemia does not improve after the first two doses of insulin.

3. Fluid replacement - In most patients, the fluid deficit is 4-5 L. Initially, 0.9% saline solution is the solution of choice to help reexpand the contracted vascular volume and should be started in the emergency department as soon as the diagnosis is established. The saline should be infused rapidly to provide 1 L/h over the first 1-2 hours. After the first 2 L of fluid have been given, the intravenous infusion should be at the rate of 300-400 mL/h. Use 0.9 % ("normal") saline unless the serum sodium is greater than 150 mEq/L, when 0.45% ("half normal") saline solution should be used. The volume status should be very carefully monitored. Failure to give enough volume replacement (at least 3-4 L in 8 hours) to restore normal perfusion is one of the most serious therapeutic shortcomings adversely influencing satisfactory recovery. Excessive fluid replacement (more than 5 L in 8 hours) may contribute to acute respiratory distress syndrome or cerebral edema. When blood glucose falls to approximately 250 mg/dL, the fluids should be changed to a 5% glucose solution to maintain serum glucose in the range of 250-300 mg/dL. This will prevent the development of hypoglycemia and will also reduce the likelihood of cerebral edema, which could result from too rapid decline of blood glucose. Intensive insulin therapy should be continued until the ketoacidosis is corrected.

4. Sodium bicarbonate - The use of sodium bicarbonate in management of diabetic ketoacidosis has been questioned since clinical benefit was not demonstrated in one prospective randomized trial and because of the following potentially harmful consequences: (1) development of hypokalemia from rapid shift of potassium into cells if the acidosis is overcorrected, (2) tissue anoxia from reduced dissociation of oxygen from hemoglobin when acidosis is rapidly reversed (leftward shift of the oxygen dissociation curve), and (3) cerebral acidosis resulting from lowering of cerebrospinal fluid pH. It must be emphasized, however, that these considerations are less important when severe acidosis exists. It is therefore recommended that bicarbonate be administered to diabetic patients in ketoacidosis if the arterial blood pH is 7.0 or less, with careful monitoring to prevent overcorrection. One or two ampules of sodium bicarbonate (one ampule contains 44 mEq/50 mL) should be added to 1 L of 0.45% saline. (Note: Addition of sodium bicarbonate to 0.9% saline would produce a markedly hypertonic solution that could aggravate the hyperosmolar state already present.) This should be administered rapidly (over the first hour). It can be repeated until the arterial pH reaches 7.1, but it should not be given if the pH is 7.1 or greater since additional bicarbonate would increase the risk of rebound metabolic alkalosis as ketones are metabolized. Alkalosis shifts potassium from serum into cells, which could precipitate a fatal cardiac arrhythmia.

5. Potassium - Total body potassium loss from polyuria and vomiting may be as high as 200 mEq. However, because of shifts of potassium from cells into the extracellular space as a consequence of acidosis, serum potassium is usually normal to slightly elevated prior to institution of treatment. As the acidosis is corrected, potassium flows back into the cells, and hypokalemia can develop if potassium replacement is not instituted. If the patient is not uremic and has an adequate urinary output, potassium chloride in doses of 10-30 mEq/h should be infused during the second and third hours after beginning therapy as soon as the acidosis starts to resolve. Replacement should be started sooner if the initial serum potassium is inappropriately normal or low and should be delayed if serum potassium fails to respond to initial therapy and remains above 5 mEq/L, as in cases of renal insufficiency. An ECG can be of help in monitoring the patient's potassium status: High peaked T waves are a sign of hyperkalemia, and flattened T waves with U waves are a sign of hypokalemia. Foods high in potassium content should be prescribed when the patient has recovered sufficiently to take food orally. Tomato juice has 14 mEq of potassium per 240 mL, and a medium-sized banana provides about 10 mEq.

6. Phosphate - Phosphate replacement is seldom required in treating diabetic ketoacidosis. However, if severe hypophosphatemia of less than 1 mg/dL (< 0.32 mmol/L) develops during insulin therapy, a small amount of phosphate can be replaced per hour as the potassium salt. Correction of hypophosphatemia helps restore the buffering capacity of the plasma, thereby facilitating renal excretion of hydrogen. It also corrects the impaired oxygen dissociation from hemoglobin by regenerating 2,3-diphosphoglycerate. However, three randomized studies in which phosphate was replaced in only half of a group of patients with diabetic ketoacidosis did not show any apparent clinical benefit from phosphate administration. Moreover, attempts to use the phosphate salt of potassium as the sole means of replacing potassium have led to a number of reported cases of severe hypocalcemia with tetany. To minimize the risk of inducing tetany from too-rapid replacement of phosphate, the average deficit of 40-50 mmol of phosphate should be replaced intravenously at a rate no greater than 3-4 mmol/h in a 60-70-kg person. A stock solution (Abbott) provides a mixture of 1.12 g KH₂PO₄ and 1.18 g K₂HPO₄ in a 5-mL single-dose vial (this equals 22 mmol of potassium and 15 mmol of phosphate). One-half of this vial (2.5 mL) should be added to 1 L of either 0.45% saline or 5% dextrose in water. Two liters of this solution, infused at a rate of 400 mL/h, will correct the phosphate deficit at the optimal rate of 3 mmol/h while providing 4.4 mEq of potassium per hour. (Additional potassium should be administered as potassium chloride to provide a total of 10-30 mEq of potassium per hour, as noted above.) If the serum phosphate remains below 2.5 mg/dL after this infusion, a repeat 5-hour infusion can be given.

7. Hyperchloremic acidosis during therapy - Because of the considerable loss of keto acids in the urine during the initial phase of therapy, substrate for subsequent regeneration of bicarbonate is lost and correction of the total bicarbonate deficit is hampered. A portion of the bicarbonate deficit is replaced with chloride ions infused in large amounts as saline to correct the dehydration. In most patients, as the ketoacidosis clears during insulin replacement, a hyperchloremic, low-bicarbonate pattern emerges with a normal anion gap. This is a relatively benign condition that reverses itself over the subsequent 12-24 hours once intravenous saline is no longer being administered.

8. Treatment of associated infection - Antibiotics are prescribed as indicated. Cholecystitis and pyelonephritis may be particularly severe in these patients.

Prognosis

The frequency of deaths due to diabetic ketoacidosis has been dramatically reduced by improved therapy of young diabetics, but this complication remains a significant risk in the aged and in patients in profound coma in whom treatment has been delayed. Acute myocardial infarction and infarction of the bowel following prolonged hypotension worsen the outlook. A serious prognostic sign is renal failure, and prior kidney dysfunction worsens the prognosis considerably because the kidney plays a key role in compensating for massive pH and electrolyte abnormalities. Cerebral edema has been reported to occur rarely as metabolic deficits return to normal. This is best prevented by avoiding sudden reversal of marked hyperglycemia. Maintaining glycemic levels of 200-300 mg/dL for the initial 24 hours after correction of severe hyperglycemia reduces this risk.

Bibliography

Kitabchi AE et al: Management of hyperglycemic crises in patients with diabetes. Diabetes Care 2001;24:131. [PMID: 11194218]