Diabetic Ketoacidosis

Diabetic Ketoacidosis

Diabetic ketoacidosis (DKA) is the classical acute metabolic complication of type 1 diabetes, although it may also occur much less commonly in type 2 diabetes, being primarily due to severe insulin deficiency.

The hormonal pattern favoring DKA is represented by severe insulin defi- ciency and/or excess of counterregulatory hormones (or stress hormones) which include glucagon, catecholamines, cortisol and GH. Among counterregulatory hormones, however, glucagon plays the major role, so that the key hormonal condition favoring DKA is depression of the insulin/glucagon ratio. Insulin de- ficiency may occur because of interruption or inadequacy of insulin administra- tion or in the setting of the first manifestation of type 1 diabetes. Counter- regulatory hormones may increase following physical (infections, surgery, trauma) or emotional stresses, and oppose insulin action. In addition, epineph- rine may also stimulate glucagon release, which is also favored by lack of insulin.

The deficiency of insulin reduces peripheral glucose utilization, while the low insulin/glucagon ratio stimulates hepatic gluconeogenesis (and therefore hepatic glucose production) by inducing a decrease of the key regulatory compound fructose-2,6-P (which stimulates glycolysis and depresses glucone- ogenesis). Gluconeogenesis utilizes the gluconeogenic precursors which come from muscle (pyruvate and lactate derived from glucose, alanine derived from proteolysis as well as from amination of pyruvate, and other amino acids derived from proteolysis) and to a minor extent from adipose tissue (glycerol, released together with FFA during lipolysis). These changes result in marked The deficiency of insulin reduces peripheral glucose utilization, while the low insulin/glucagon ratio stimulates hepatic gluconeogenesis (and therefore hepatic glucose production) by inducing a decrease of the key regulatory compound fructose-2,6-P (which stimulates glycolysis and depresses glucone- ogenesis). Gluconeogenesis utilizes the gluconeogenic precursors which come from muscle (pyruvate and lactate derived from glucose, alanine derived from proteolysis as well as from amination of pyruvate, and other amino acids derived from proteolysis) and to a minor extent from adipose tissue (glycerol, released together with FFA during lipolysis). These changes result in marked

the enzyme acetyl-CoA carboxylase that catalyzes the latter step (conversion of acetyl-CoA to malonyl-CoA). The resulting activation of b-oxidation of FFA leads to formation of excessive amounts of acetyl-CoA which is then condensed to form b-hydroxybutyrate (two molecules of acetyl-CoA are con- verted into acetoacetate, which can then be converted to b-hydroxybutyrate).

Thus, in DKA the liver exerts two main functions: (a) as concerns carbohy- drate metabolism, it takes up gluconeogenic precursors and releases glucose (producing hyperglycemia, osmotic diuresis and dehydratation, with osmolality in the 310–330 mosm/l range) and (b) concerning lipid metabolism, it takes up FFA and releases VLDL and ketone bodies (which results in hypertriglyceri- demia and acidosis).

Clinical Picture Preceded by polyuria (due to osmotic diuresis), the clinical picture begins

with anorexia, nausea, vomiting (which precludes oral fluid intake) and, often, abdominal pain (periumbilical and constant) which can mimic a surgical emer- gency. If treatment is not started, alterations in consciousness ensue, which may evolve to frank coma. Physical signs are due to dehydration and acidosis and include: sweet, sickly smell of the patient’s breath, deep and rapid respira- tion (Kussmaul respiration), low jugular venous pressure and tachycardia. In most severe cases, vascular collapse and acute renal failure may develop. White blood cell count may be markedly elevated, even in the absence of infection. Body temperature is normal or tendencially low, unless infections develop.

Laboratory Data Laboratory data show increase of the anion gap, and abnormalities in

potassium, sodium, triglycerides, azotemia and amylase. The anion gap is the difference between the routinely measured cations and anions. Normally, to

maintain a pH close to neutrality (7.35–7.45), the sum of cations, including sodium, potassium, calcium and magnesium, should be approximately equal to the sum of anions, such as chloride, bicarbonate, and other routinely not measured anions comprising some organic acids (lactic acid, pyruvic acid, FFA, etc.) and inorganic acids (phosphates, sulfates) as well as anionic proteins (albumin and others). When, in pathologic conditions, an acidic compound enters or increases in the blood (ketone bodies in the case of DKA), it is neutralized with the sodium (and potassium) subtracted from bicarbonates. The latter in this way become carbonic acid which rapidly dissociates into

CO 2 (which will be lost with the breath) and H 2 O (which will be eliminated by the kidneys). As result of this process, the concentration of blood bicarbo- nates falls to an extent proportional to the amount of the acidic compounds which originate from the perturbation. In the clinical setting, the cations and

anions measured as routine are Na + ,K + , Cl Ö and HCO Ö 3 whereas other cations and anions remain unmeasured. Therefore, considering only the rou- tinely measured cations and anions there is, already in the normal state, an anion gap which can be calculated as follows: Serum anion gap>

([Na + ]+[K + ])Ö([Cl Ö ]+[HCO Ö 3 ]), with normal values of about 14–16 mmol/ l or, in a simpler way: Serum anion gap>[Na + ]Ö([Cl Ö ]+[HCO Ö 3 ]), with nor- mal values of about 10–12 mmol/l. About half of the normal anion gap is accounted for by albumin and the other by anionic proteins. With the technical procedures in use in recent years, which yield higher values for Cl Ö , the normal anion gap may be remarkably lower. It is therefore useful to refer to the normal values of the local laboratory. In DKA, the increased anion gap is due to the fall in bicarbonate (6–10 mmol/l) caused by the accumulation in the blood of the ketone bodies (acetoacetate and b-hydroxybutyrate), with minimal contri- bution of lactate and FFA.

Potassium content of total body decreases markely, although serum K + levels may be initially normal due to the cell buffering mechanism (exchange

of intracellular K + for extracellular H + ), before diminishing as a consequence of the osmotic diuresis (together with other electrolytes such as magnesium and phosphates). Sodium concentration tends to be moderately lowered (in the 130–132 range) due to the osmotic shift of water into the plasma space, and may become severe if prolonged vomiting plus water drinking occur.

Triglycerides are elevated, sometimes to very high values, due to both enhanced hepatic prodution of VLDL (stimulated by the hyperafflux of FFA to

the liver) and diminished VLDL disposal due to reduced activity of lipoprotein the liver) and diminished VLDL disposal due to reduced activity of lipoprotein

Azotemia may develop as result of dehydration and volume depletion (prerenal azotemia). Elevation of serum amylase (of nonpancreatic origin) often occurs which, when associated to severe abdominal pain, may simulate pancreatitis.

Complications and Mortality While the frequency and mortality rate have markedly diminished with the

improvement of diabetes knowledge and patient care, in some settings mortality may still be as high as 10%, and it is due mainly to superimposed complications. The latter include: gastric dilation (vomiting of bloody or dark material), infec- tions (especially pneumonia), mucormycosis (epistaxis, unilateral headache, al- teration in mental status, eye symptoms), respiratory distress syndrome, myocardial infarction and vascular thrombosis (signs and symptoms of ischemia in the cerebral or other vascular regions). In addition, cerebral edema is a serious complication, more often seen in children than in adults. It may be due to the low osmolality of plasma compared to brain after therapeutically induced glu- cose fall and rehydration. Once diagnosed (on the basis of CT findings), it should

be treated with mannitol (1 g/kg as 20% solution) and dexamethasone (whose efficacy is not certain); if improvement is not observed, hyperventilation (to lower PaCO 2 to about 28 mm Hg) may be helpful.

Diagnosis Diagnosis should be made by excluding lactic acidosis, alcoholic ketoaci-

dosis, pancreatitis, uremia, and poisonings. The exact diagnosis is suggested by elevated plasma glucose and ketone bodies. Concerning the latter, measure- ment in plasma should be performed, since positivity in the urine may also occur with starvation ketosis. A semiquantitative assay can be performed using ketone reagent strips (Ketostix) or tablets (Acetest) on diluted plasma: a positivity with dilution higher than 1:1 suggests DKA (it may also be seen in patients with alcoholic ketoacidosis in whom, however, blood glucose rarely exceeds 160 mg/dl or 8.4 mmol/l). It should be pointed out that ketogenesis produces acetoacetate, which (in addition to undergoing spontaneous decar- boxylation to acetone) may be converted into b-hydroxybutyrate through an oxido-reductive reaction, with simultaneous conversion of NADH to NAD. Normally, the ratio b-hydroxybutyrate/acetoacetate is around 3:1, but in se- verely ill patients with dehydration and vascular collapse, there is some degree dosis, pancreatitis, uremia, and poisonings. The exact diagnosis is suggested by elevated plasma glucose and ketone bodies. Concerning the latter, measure- ment in plasma should be performed, since positivity in the urine may also occur with starvation ketosis. A semiquantitative assay can be performed using ketone reagent strips (Ketostix) or tablets (Acetest) on diluted plasma: a positivity with dilution higher than 1:1 suggests DKA (it may also be seen in patients with alcoholic ketoacidosis in whom, however, blood glucose rarely exceeds 160 mg/dl or 8.4 mmol/l). It should be pointed out that ketogenesis produces acetoacetate, which (in addition to undergoing spontaneous decar- boxylation to acetone) may be converted into b-hydroxybutyrate through an oxido-reductive reaction, with simultaneous conversion of NADH to NAD. Normally, the ratio b-hydroxybutyrate/acetoacetate is around 3:1, but in se- verely ill patients with dehydration and vascular collapse, there is some degree

Treatment Therapy of DKA relies upon rehydration and insulin administration. It

is useful to prepare a local care protocol and to distribute it to relevant professionals. Saline solution should be given intravenously at the rate of 2 liters in 2 h, followed by infusion of 0.4 liter/h of saline or half-normal saline (0.45%) for about 6 h, based on the clinical response. The total fluid deficit is of about 3–5 liters. Hypotonic saline should be given with caution (if plasma Na + ? 155 mmol/l: 1 liter over 8 h). Colloid solutions should be used in presence of hypotension (systolic blood pressure=100 mm Hg after 2 h). When glucose level decreases to =250–300 mg/dl, infusion of 5% glucose should be added, to prevent excessively rapid glucose fall that may contribute to the severe complication of cerebral edema as well as to allow continuing insulin infusion until ketosis disappears (often plasma glucose falls more rapidly than plasma ketone bodies). Insulin (rapid-acting or regular) should

be administered in low doses, by infusing a bolus of about 10 U followed by 8–10 U/h (in contrast to the higher doses previously used), until disappearance of ketone bodies and normalization of glycemia is obtained. This regimen often ensures a progressive decrease in blood glucose, avoiding a precipitous fall which may favor cerebral edema. These doses, however, should not be regarded as ‘low’ when compared to the amount of insulin produced in 24 h in the normal man (25–28 U). However, it should be considered that in DKA,

a variable degree of insulin resistance is present, as result of several factors (see chapter III, paragraph on Insulin Resistance in Type I Diabetes). For this reason, in some patients, higher doses of insulin may be required, i.e. a bolus of 20 U or higher followed by infusion of 15 U/h or more. These excessive amounts of insulin are justified in view of the possibility that, after saturation of insulin receptors, the surplus of available insulin may act through activation of the IGF-1 receptors. It is noteworthy that up to 20% of insulin binds to the flask and tubing (much higher percentage with lower doses) and that, when we use the same set for a second infusion, the binding sites are saturated and therefore the amount of free insulin actually infused will be higher.

Potassium administration is often required. This cation may be normal in serum even if the total body content is decreased. When the plasma level is low, 30–40 mmol/h of potassium should be infused, and a lower dose (20 mmol/h) should also be given when serum potassium is normal, because with the beginning of therapy a further fall in serum potassium occurs as a result of the effect of insulin (which causes a shift of potassium into the cells) and fluid replacement (that dilutes serum potassium). ECG represents a useful tool to assess intracellular potassium concentration, showing flat or inverted T waves when intracellular potassium is low and peaked T waves when in- tracellular potassium is high.

Bicarbonate administration is only required in patients with severe acidosis (pH=7). Bicarbonate should be given at a slow rate (about 44 mEq during 1 or 2 h) and discontinued when the pH rises to 7.1. In DKA, 2,3-diphospho- glycerate (2,3-DPG) is low in red cells, which decreases oxygen delivery. This is counterbalanced by acidosis, which favors oxygen delivery. A rapid correc- tion of acidosis with bicarbonate may leave the effect of the 2,3-DPG unop- posed, causing impaired oxygen release which, in presence of volume depletion and reduced tissue perfusion may favor the development of tissue hypoxia and lactic acidosis.

In presence of infections, antibiotic therapy should be employed. When the patient is comatose, insert a nasogastric tube, use a urinary catheter (if no urine passes within 3 h) and heparinize in case of hyperosmolar coma development or in presence of thrombosis risk factors.

After the recovery from a diabetic ketoacidotic episode, it is useful to accurately review the causes to reduce the risk of recurrence.