**6. Treatment**

Successful treatment of DKA requires correction of dehydration, hyperglycemia and elec‐ trolyte imbalances, identification of comorbid precipitating events and above all, frequent patient monitoring. Protocols for the management of patients with DKA is summarized in Fig. 2 [10].

### **6.1. Fluid therapy**

The most important initial therapeutic intervention is fluid replacement followed by in‐ sulin administration. DKA is a volume depletion state with water deficit, varying widely but averaging 6 L [51]. Initial fluid therapy is directed toward expansion of the intravas‐ cular, interstitial and intracellular volume (all of which are reduced in hyperglycemic cri‐ ses), to establish tissue perfusion for insulin to reach cells [148] and restoration of renal perfusion. The goal of fluid resuscitation is to replace half of the estimated water deficit over the first 12-24 hours and adding for the ongoing losses (eg: vomiting) [51]. Replace‐ ment fluids may decrease the blood glucose by up to 23% because of increased renal perfusion and loss of glucose in urine [149] Hyperglycemia can reduce serum sodium by causing an osmotically driven shift of water from intracellular to extracellular compart‐ ments. In the previous estimated models; each 5.5 mmol/L (100 mg/dL) increase in glu‐ cose above normal resulted in a decrease of 1.6 mmol/L (1.6 mEq/L) in measured serum sodium [150], Hillier et al. suggested that 2.4 mmol/L (2.4 mEq/L) per 5.5 mmol/L (100 mg/dL) glucose increase is more accurate [151].

The initial fluid of choice is isotonic saline, generally given for the first 4 hours of therapy (Table 4). Subsequent choice for fluid replacement depends on hemodynamics, the state of hydration, serum electrolyte levels and urinary output. Fluid resuscitation should be individualized according to the patient's degree of dehydration, mental sta‐ tus and underlying diseases such as congestive heart failure or renal failure [51]. Glu‐ cose, an osmotic diuretic, may produce a high urine output even in severely dehydrated patients. The threshold for glycosuria in healthy adults occurs at plasma glucose concentration of approximately 180 mg/dL (9.99 mmol/L), though adults with long-standing diabetic nephropathy may have considerably higher thresholds. As a re‐ sult, urine output should not be considered a reliable predictor of volume status in hyperglycemic states [152].

**Figure 2.** Protocols for the management of patients with DKA (Data adapted from reference 10)

be easily differentiated from this condition by the presence of an increased anion gap and hyperglycemia. In complicated diabetics, especially in diabetic nephropathy, if there is hypoalbunemia, it can affect the apparent anion gap, since albumin is negatively charged protein contibuting 50-60% to the normal anion gap. If albumin is below the normal value of 4 g/dL (40 g/L), the calculated anion gap should be corrected by adding 2.5 for every 10 g/L (1 g/dL) to determine whether excessive abnormal anions are

Successful treatment of DKA requires correction of dehydration, hyperglycemia and elec‐ trolyte imbalances, identification of comorbid precipitating events and above all, frequent patient monitoring. Protocols for the management of patients with DKA is summarized

The most important initial therapeutic intervention is fluid replacement followed by in‐ sulin administration. DKA is a volume depletion state with water deficit, varying widely but averaging 6 L [51]. Initial fluid therapy is directed toward expansion of the intravas‐ cular, interstitial and intracellular volume (all of which are reduced in hyperglycemic cri‐ ses), to establish tissue perfusion for insulin to reach cells [148] and restoration of renal perfusion. The goal of fluid resuscitation is to replace half of the estimated water deficit over the first 12-24 hours and adding for the ongoing losses (eg: vomiting) [51]. Replace‐ ment fluids may decrease the blood glucose by up to 23% because of increased renal perfusion and loss of glucose in urine [149] Hyperglycemia can reduce serum sodium by causing an osmotically driven shift of water from intracellular to extracellular compart‐ ments. In the previous estimated models; each 5.5 mmol/L (100 mg/dL) increase in glu‐ cose above normal resulted in a decrease of 1.6 mmol/L (1.6 mEq/L) in measured serum sodium [150], Hillier et al. suggested that 2.4 mmol/L (2.4 mEq/L) per 5.5 mmol/L (100

The initial fluid of choice is isotonic saline, generally given for the first 4 hours of therapy (Table 4). Subsequent choice for fluid replacement depends on hemodynamics, the state of hydration, serum electrolyte levels and urinary output. Fluid resuscitation should be individualized according to the patient's degree of dehydration, mental sta‐ tus and underlying diseases such as congestive heart failure or renal failure [51]. Glu‐ cose, an osmotic diuretic, may produce a high urine output even in severely dehydrated patients. The threshold for glycosuria in healthy adults occurs at plasma glucose concentration of approximately 180 mg/dL (9.99 mmol/L), though adults with long-standing diabetic nephropathy may have considerably higher thresholds. As a re‐ sult, urine output should not be considered a reliable predictor of volume status in

present [145-147].

262 Type 1 Diabetes

**6. Treatment**

in Fig. 2 [10].

**6.1. Fluid therapy**

mg/dL) glucose increase is more accurate [151].

hyperglycemic states [152].


**Table 5.** Suggested average initial replacement rate of fluid in DKA (after hemodynamic resuscitation with normal saline when indicated)

Many guidelines recommend initial fluid resuscitation with colloid in hypotensive patients. However, the hypotension results from a loss of electrolyte solution and it is more physio‐ logical to replace with crystalloid. A recent Cochrane review did not support the use of col‐ loid in preference to crystalloid fluid [153]. In the absence of cardiac compromise, isotonic saline (0.9% NaCl) is infused at a rate of 15–20 ml kg/body wt/h or 1–1.5 L during the first hour. In general, 0.45% NaCl infused at 250–500 ml/hour is appropriate if the corrected se‐ rum sodium is normal or elevated; 0.9% NaCl at a similar rate is appropriate if corrected se‐ rum sodium is low (Fig. 2). That total fluid administered should not exceed 4 L/m²/24 hour for fear of causing cerebral edema is most often the mainstay of therapy in many pediatric critical care unit protocols [154,155]. Successful treatment with fluid replacement can be evaluate by hemodynamic monitoring (improvement in blood pressure), measurement of fluid input/output, laboratory values and clinical improvement. In patients with renal or cardiac failure, monitoring of serum osmolality and frequent assessment of cardiac, renal and mental status must be performed during fluid resuscitation to avoid iatrogenic fluid overload [10,37,148]. During treatment of DKA, hyperglycemia is corrected faster than ke‐ toacidosis. The mean duration of treatment until blood glucose is <250 mg/dl and ketoacido‐ sis (pH>7.30; bicarbonate >18 mmol/l) is corrected is 6 and 12 hours [36,156]. Once the plasma glucose falls to <200-250 mg/dL (11.1-13.88 mmol/L), 5% dextrose should be added to replacement fluids to allow continued insulin administration until ketonemia is control‐ led while at the same time avoiding hypoglycemia [93,135]. In hypotensive patients, aggres‐ sive fluid resuscitation with isotonic saline should be continued until blood pressure normalized [51].

Umpierrez et al. used subcutaneous rapid-acting insulin (insulin lispro or aspart) 0.2 units/kg initially followed by 0.1 unit/kg every hour or an initial dose of 0.3 units/kg fol‐ lowed by 0.2 units/kg every 2 hours, until blood glucose is ≤ 250 mg/dL; the insulin dose is then decreased by half (to 0.05 or 0.1 unit/kg, respectively) every 1-2 hours until resolution [162,163]. There were no differences in length of hospital stay, total amount of insulin need‐ ed for resolution of hyperglycemia or ketoacidosis. Patients treated with insulin analogs were managed in the open medical wards which reduced cost of hospitalization by 30% [162-164]. This approach is not widely used for many reasons, including titration difficulties with longer half-life preparations, requirement for hourly nursing interventions and lack of staff experience compared to that with standard insulin infusions. However, until these studies are confirmed outside the research arena, patients with severe DKA, hypotension, anasarca or associated severe critical illness should be managed with intravenous regular in‐

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In patients younger than 4 years of age there is a prolonged time lag for plasma glucose lev‐ els to reach 12 to 14 mmol/L, because young children and adolescents who have high growth velocity and higher levels of the human growth hormone, a diabetogenic hormone. In addition to this, patients with fever or infections and higher metabolic requirements may

In rare cases of patients with allergy to human insulin presenting with hyperglycemic crisis, desensitization to human insulin may be performed before treatment with human insulin. A recent case report documented the successful treatment of a woman with allergy to human insulin and its analogs with continuous subcutaneous infusion of human insulin [166].

Despite a total body potassium deficit resulting from the glycosuric osmotic diuresis, mild-to-moderate hyperkalemia is common in patients with hyperglycemic crises upon initial presentation because of proteolysis, acidosis, and insulin deficiency [10,167]. In‐ sulin therapy, correction of acidosis and volume expansion decrease serum potassium

Occasionally patients with DKA may present with significant hypokalemia, in which case insulin therapy should be delayed until potassium concentration is corrected to >3.5 me‐ quiv./l to avoid arrhythmias and respiratory muscle weakness [168,169]. To prevent hypoka‐ lemia, potassium replacement is initiated after serum levels fall below the upper level of normal for the particular laboratory (5.0-5.2 mEq/l) in patients without renal impairment. The treatment goal is to maintain serum potassium levels within the normal range of 4–5 mEq/l. Generally, 20–30 mEq potassium in each liter of infusion fluid is sufficient to main‐ tain serum potassium concentration within the normal range but additional doses may be

The rare patient with severe hyperkalemia (>6.0 mEq/l) on admission with concomitant elec‐

trocardiographic changes may benefit from bicarbonate therapy [170].

sulin in the intensive care unit [93].

**6.3. Potassium**

concentration [10].

necessary [10,30].

need 15% to 20% more insulin than the usual dose [165].

#### **6.2. Insulin therapy**

Insulin lowers the serum glucose concentration (by decreasing gluconeogenesis and glyco‐ genolysis, increasing tissue glucose uptake) and arrests ketone production (by reducing lip‐ olysis and glucagon secretion). The most important point in the treatment of DKA involves insulin administration. There was major concern about; physiologic or low dose insulin therapy was superior to pharmacologic dose regimen and the administration of regular in‐ sulin via continuous intravenous infusion or by frequent subcutaneous or intramuscular in‐ jections [10,157-160]. Several randomized controlled studies have shown that physiologic or low dose insulin therapy was superior to pharmacologic dose regimen and low-dose insulin therapy is effective regardless of the route of administration in DKA [118,159,160]. In clinical practice most patients are treated with low dose, intravenous regular insulin until resolution of DKA [30]. The administration of continuous intravenous infusion of regular insulin is preferred because of its short half-life and easy titration and the delayed onset of action and prolonged half-life [107,127,160].

Previous treatment algorithms have recommended the administration of an initial intrave‐ nous bolus of regular insulin (0.1 unit/kg) followed by the infusion of 0.1 unit/kg/h [10,17], but a recent prospective randomized study showed that a bolus dose is not required if pa‐ tients are given hourly insulin infusion at 0.14 unit/kg body weight [161]. Low-dose insulin infusion protocols decrease plasma glucose concentration at a rate of 50–75 mg/d/ h. If plas‐ ma glucose does not decrease by 50–75 mg in the first hour, the insulin infusion should be increased every hour until a steady glucose decline is achieved. When the plasma glucose reaches 200 mg/dl in DKA, the insulin infusion rate may decrease to 0.02–0.05 units/kg/h, at the same time dextrose should be added to the intravenous fluids for avoiding hypoglyce‐ mia. The rate of insulin administration or the concentration of dextrose may need to be ad‐ justed to maintain glucose values between 150 and 200 mg/dl until DKA resolved [90]. Resolution of ketoacidosis includes these criteria; a blood glucose <200 mg/dl and two of the following criteria: a serum bicarbonate level >15 mEq/l, a venous pH >7.3, and a calculated anion gap in normal range. Once hyperglycemia is corrected, 12-24 hours of intravenous in‐ sulin treatment is sufficient to clear ketones from the circulation [51].

Subcutaneous rapid-acting insulin analogs (lispro and aspart) offer an efficacious and costeffective alternative to continuous intravenous infusions in the treatment of DKA [162-164]. Umpierrez et al. used subcutaneous rapid-acting insulin (insulin lispro or aspart) 0.2 units/kg initially followed by 0.1 unit/kg every hour or an initial dose of 0.3 units/kg fol‐ lowed by 0.2 units/kg every 2 hours, until blood glucose is ≤ 250 mg/dL; the insulin dose is then decreased by half (to 0.05 or 0.1 unit/kg, respectively) every 1-2 hours until resolution [162,163]. There were no differences in length of hospital stay, total amount of insulin need‐ ed for resolution of hyperglycemia or ketoacidosis. Patients treated with insulin analogs were managed in the open medical wards which reduced cost of hospitalization by 30% [162-164]. This approach is not widely used for many reasons, including titration difficulties with longer half-life preparations, requirement for hourly nursing interventions and lack of staff experience compared to that with standard insulin infusions. However, until these studies are confirmed outside the research arena, patients with severe DKA, hypotension, anasarca or associated severe critical illness should be managed with intravenous regular in‐ sulin in the intensive care unit [93].

In patients younger than 4 years of age there is a prolonged time lag for plasma glucose lev‐ els to reach 12 to 14 mmol/L, because young children and adolescents who have high growth velocity and higher levels of the human growth hormone, a diabetogenic hormone. In addition to this, patients with fever or infections and higher metabolic requirements may need 15% to 20% more insulin than the usual dose [165].

In rare cases of patients with allergy to human insulin presenting with hyperglycemic crisis, desensitization to human insulin may be performed before treatment with human insulin. A recent case report documented the successful treatment of a woman with allergy to human insulin and its analogs with continuous subcutaneous infusion of human insulin [166].

### **6.3. Potassium**

cardiac failure, monitoring of serum osmolality and frequent assessment of cardiac, renal and mental status must be performed during fluid resuscitation to avoid iatrogenic fluid overload [10,37,148]. During treatment of DKA, hyperglycemia is corrected faster than ke‐ toacidosis. The mean duration of treatment until blood glucose is <250 mg/dl and ketoacido‐ sis (pH>7.30; bicarbonate >18 mmol/l) is corrected is 6 and 12 hours [36,156]. Once the plasma glucose falls to <200-250 mg/dL (11.1-13.88 mmol/L), 5% dextrose should be added to replacement fluids to allow continued insulin administration until ketonemia is control‐ led while at the same time avoiding hypoglycemia [93,135]. In hypotensive patients, aggres‐ sive fluid resuscitation with isotonic saline should be continued until blood pressure

Insulin lowers the serum glucose concentration (by decreasing gluconeogenesis and glyco‐ genolysis, increasing tissue glucose uptake) and arrests ketone production (by reducing lip‐ olysis and glucagon secretion). The most important point in the treatment of DKA involves insulin administration. There was major concern about; physiologic or low dose insulin therapy was superior to pharmacologic dose regimen and the administration of regular in‐ sulin via continuous intravenous infusion or by frequent subcutaneous or intramuscular in‐ jections [10,157-160]. Several randomized controlled studies have shown that physiologic or low dose insulin therapy was superior to pharmacologic dose regimen and low-dose insulin therapy is effective regardless of the route of administration in DKA [118,159,160]. In clinical practice most patients are treated with low dose, intravenous regular insulin until resolution of DKA [30]. The administration of continuous intravenous infusion of regular insulin is preferred because of its short half-life and easy titration and the delayed onset of action and

Previous treatment algorithms have recommended the administration of an initial intrave‐ nous bolus of regular insulin (0.1 unit/kg) followed by the infusion of 0.1 unit/kg/h [10,17], but a recent prospective randomized study showed that a bolus dose is not required if pa‐ tients are given hourly insulin infusion at 0.14 unit/kg body weight [161]. Low-dose insulin infusion protocols decrease plasma glucose concentration at a rate of 50–75 mg/d/ h. If plas‐ ma glucose does not decrease by 50–75 mg in the first hour, the insulin infusion should be increased every hour until a steady glucose decline is achieved. When the plasma glucose reaches 200 mg/dl in DKA, the insulin infusion rate may decrease to 0.02–0.05 units/kg/h, at the same time dextrose should be added to the intravenous fluids for avoiding hypoglyce‐ mia. The rate of insulin administration or the concentration of dextrose may need to be ad‐ justed to maintain glucose values between 150 and 200 mg/dl until DKA resolved [90]. Resolution of ketoacidosis includes these criteria; a blood glucose <200 mg/dl and two of the following criteria: a serum bicarbonate level >15 mEq/l, a venous pH >7.3, and a calculated anion gap in normal range. Once hyperglycemia is corrected, 12-24 hours of intravenous in‐

Subcutaneous rapid-acting insulin analogs (lispro and aspart) offer an efficacious and costeffective alternative to continuous intravenous infusions in the treatment of DKA [162-164].

sulin treatment is sufficient to clear ketones from the circulation [51].

normalized [51].

264 Type 1 Diabetes

**6.2. Insulin therapy**

prolonged half-life [107,127,160].

Despite a total body potassium deficit resulting from the glycosuric osmotic diuresis, mild-to-moderate hyperkalemia is common in patients with hyperglycemic crises upon initial presentation because of proteolysis, acidosis, and insulin deficiency [10,167]. In‐ sulin therapy, correction of acidosis and volume expansion decrease serum potassium concentration [10].

Occasionally patients with DKA may present with significant hypokalemia, in which case insulin therapy should be delayed until potassium concentration is corrected to >3.5 me‐ quiv./l to avoid arrhythmias and respiratory muscle weakness [168,169]. To prevent hypoka‐ lemia, potassium replacement is initiated after serum levels fall below the upper level of normal for the particular laboratory (5.0-5.2 mEq/l) in patients without renal impairment. The treatment goal is to maintain serum potassium levels within the normal range of 4–5 mEq/l. Generally, 20–30 mEq potassium in each liter of infusion fluid is sufficient to main‐ tain serum potassium concentration within the normal range but additional doses may be necessary [10,30].

The rare patient with severe hyperkalemia (>6.0 mEq/l) on admission with concomitant elec‐ trocardiographic changes may benefit from bicarbonate therapy [170].

### **6.4. Bicarbonate therapy**

The hepatic metabolism of free fatty acids generates ketoanions, such as beta-hydroxybuty‐ rate and acetoacetate [171,172]. Impaired tissue perfusion due to volume contraction and the adrenergic response to the often severe underlying precipitating illness result in lactate pro‐ duction [173]. Acute kidney injury leads to accumulation of other unmeasured anions, such as sulphate, urate and phosphate [174]. All these, together with hyperchloremia which pre‐ dominates during the recovery phase of DKA [175], contribute to the development of acide‐ mia, which often is severe [176,177].

**6.6. Transition to subcutaneous insulin**

they are receiving [160].

of somatostatin in treatment of DKA.

When DKA has resolved, patients who are appropriate for oral intake can be started on a multiple dose insulin regimen with a long acting insulin (e.g. glargine or detemir) to cover basal insulin requirements and short/rapid acting insulin (lispro, aspart or glulisine) given before meals to control plasma glucose. To ensure adequate plasma insulin levels and to avoid hyperglycemia and ketonemia intravenous insulin infusion should be continued for 1–2 hours after the subcutaneous insulin is given. Patients who are inappropriate for oral in‐ take the treatment should be continued with an infusion of intravenous fluids and insulin [10,17,49,93,187]. A multiple-dose subcutaneous combination regimen is preferred, as it is related with less hypoglycemia and provides a better physiologic pattern of control than other regimens. In insulin-naїve patients, a multidose insulin regimen should be started at a dose of 0.5-0.8 units/kg body weight per day. Patients with known diabetes, whose blood glucose monitoring are in the normal ranges before DKA, may start with dose of insulin

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In the past human insulin (NPH and regular) were usually given in two or three doses per day. With the development of new analogue insulins, basal-bolus regimens with basal (glar‐ gine and detemir) and rapid-acting (lispro, aspart, or glulisine) insulin treatments became a major concern in the treatment of DKA. A prospective randomized trial compared with a split mixed regimen of NPH plus regular insulin twice daily treatment and a basal-bolus regimen, including glargine once daily and glulisine before meals following the resolution of DKA. Glycemic control were similar between the two groups but the study showed that treatment with basal-bolus insulin regimen was associated with a lower rate of hypoglyce‐ mic events (15%) than the rate in those treated with NPH and regular insulin (41%). This

trial showed that analogue insulins may offer a more physiologic effect [156].

**6.7. Somatostatin therapy in the management of resistant diabetic ketoacidosis**

As a inhibiting hormone for counterregulatory hormones, somatostatin may be used in the treatment of DKA. Somatostatin analogues have been successfully used in the treat‐ ment of diabetes associated autonomic neuropathy and they have also been shown to de‐ crease the requirements for insulin [188,189]. Continuous subcutaneous octreotide infusion suppresses counterregulatory hormones, increases insulin-mediated glucose me‐ tabolism by enhancing glucose storage and reduces energy expenditure [189]. There are limiting data in the literature about somatostatin use in DKA. Diem et al. were assessed preventive effects of octreotide on diabetic ketogenesis during insulin withdrawal. Oc‐ treotide led to a marked suppression of beta-hydroxybutyrate, acetoacetate and glucagon levels and an associated diminution of bicarbonate consumption and the fall in pH [190]. Anthony et al. reported a case of DKA with glucagonoma who was unresponsive to con‐ ventional therapy and treated with octreotide [191]. In conclusion, for patients who do not respond to conventional DKA treatment, somatostatin could be added to therapy. More data and further randomized controlled clinical trials should be made with the use

Metabolic acidemia can impair myocardial contractility, reduce cardiac output, affect oxyhe‐ moglobin dissociation and tissue oxygen delivery, inhibit intracellular enzymes, such as phosphofructokinase, alter cellular metabolism, and result in vital organ dysfunction [178-181]. In the past, therapy in DKA has placed importance on the rapid reversal of acide‐ mia. But based on currently available evidence, several deleterious effects of bicarbonate therapy have been reported, such as increased risk of hypokalemia, decreased tissue oxygen uptake, cerebral edema and development of paradoxical central nervous system acidosis [182]. The use of bicarbonate in DKA remains a controversial subject.

Since severe acidosis may be associated with adverse effects, patients with pH <6.9 or when pH is <7.1 and hemodynamic instability or hyperkalemic electrocardiographic changes are present [93,135], bicarbonate should be given. A choice is to give 100 mmol sodium bicar‐ bonate (two ampules) in 400 ml sterile water with 20 mEq KCI at a rate of 200 ml/h for 2 hours. If the pH is stil <7.0 after infusion, we recommend repeating infusion every 2 hours until pH reaches >7.0 [17,93]. Potassium replacement should be considered before adminis‐ tering bicarbonate or KCL should be added in the bicarbonate solution at 40 mmol (40 mEq) KCl/L to avoid precipitous hypokalemia [93,135].

#### **6.5. Phosphate**

In patients with DKA there is about 1 mmol/kg body weight phosphate depletion. At presentation serum phosphate levels are usually normal or elevated. But with insulin therapy these levels rapidly decrease [90,132]. Randomized studies showed that phos‐ phate replacement have no any additional benefit on the clinical outcome [126,183] and in contrast, phosphate replacement may trigger hypocalcemia and hypomagnese‐ mia [183,184]. Hypophosphatemia can cause hemolysis, refractory acidosis, reduced car‐ diac output, respiratory muscle weakness, rhabdomyolysis, central nervous system depression, seizures, coma or acute renal failure. Careful phosphate replacement should be planned to the patients with these findings and severe hypophosphatemia (serum phosphate <1 mg/dL) [10,90,132]. In severe deficiency, the amount, added to in‐ travenous replacement fluids can be 20–30 mEq/l potassium phosphate. Secure replace‐ ment rate that can correct hypophosphatemia is 4.5 mmol/h (1.5 ml/h of K2 PO4) [185]. In less severe deficiencies 80-110 mmol (2.5-3.5 g) daily in 2-3 divided doses or‐ al phosphate can be given [93,135,186].

### **6.6. Transition to subcutaneous insulin**

**6.4. Bicarbonate therapy**

266 Type 1 Diabetes

mia, which often is severe [176,177].

The hepatic metabolism of free fatty acids generates ketoanions, such as beta-hydroxybuty‐ rate and acetoacetate [171,172]. Impaired tissue perfusion due to volume contraction and the adrenergic response to the often severe underlying precipitating illness result in lactate pro‐ duction [173]. Acute kidney injury leads to accumulation of other unmeasured anions, such as sulphate, urate and phosphate [174]. All these, together with hyperchloremia which pre‐ dominates during the recovery phase of DKA [175], contribute to the development of acide‐

Metabolic acidemia can impair myocardial contractility, reduce cardiac output, affect oxyhe‐ moglobin dissociation and tissue oxygen delivery, inhibit intracellular enzymes, such as phosphofructokinase, alter cellular metabolism, and result in vital organ dysfunction [178-181]. In the past, therapy in DKA has placed importance on the rapid reversal of acide‐ mia. But based on currently available evidence, several deleterious effects of bicarbonate therapy have been reported, such as increased risk of hypokalemia, decreased tissue oxygen uptake, cerebral edema and development of paradoxical central nervous system acidosis

Since severe acidosis may be associated with adverse effects, patients with pH <6.9 or when pH is <7.1 and hemodynamic instability or hyperkalemic electrocardiographic changes are present [93,135], bicarbonate should be given. A choice is to give 100 mmol sodium bicar‐ bonate (two ampules) in 400 ml sterile water with 20 mEq KCI at a rate of 200 ml/h for 2 hours. If the pH is stil <7.0 after infusion, we recommend repeating infusion every 2 hours until pH reaches >7.0 [17,93]. Potassium replacement should be considered before adminis‐ tering bicarbonate or KCL should be added in the bicarbonate solution at 40 mmol (40 mEq)

In patients with DKA there is about 1 mmol/kg body weight phosphate depletion. At presentation serum phosphate levels are usually normal or elevated. But with insulin therapy these levels rapidly decrease [90,132]. Randomized studies showed that phos‐ phate replacement have no any additional benefit on the clinical outcome [126,183] and in contrast, phosphate replacement may trigger hypocalcemia and hypomagnese‐ mia [183,184]. Hypophosphatemia can cause hemolysis, refractory acidosis, reduced car‐ diac output, respiratory muscle weakness, rhabdomyolysis, central nervous system depression, seizures, coma or acute renal failure. Careful phosphate replacement should be planned to the patients with these findings and severe hypophosphatemia (serum phosphate <1 mg/dL) [10,90,132]. In severe deficiency, the amount, added to in‐ travenous replacement fluids can be 20–30 mEq/l potassium phosphate. Secure replace‐ ment rate that can correct hypophosphatemia is 4.5 mmol/h (1.5 ml/h of K2 PO4) [185]. In less severe deficiencies 80-110 mmol (2.5-3.5 g) daily in 2-3 divided doses or‐

[182]. The use of bicarbonate in DKA remains a controversial subject.

KCl/L to avoid precipitous hypokalemia [93,135].

al phosphate can be given [93,135,186].

**6.5. Phosphate**

When DKA has resolved, patients who are appropriate for oral intake can be started on a multiple dose insulin regimen with a long acting insulin (e.g. glargine or detemir) to cover basal insulin requirements and short/rapid acting insulin (lispro, aspart or glulisine) given before meals to control plasma glucose. To ensure adequate plasma insulin levels and to avoid hyperglycemia and ketonemia intravenous insulin infusion should be continued for 1–2 hours after the subcutaneous insulin is given. Patients who are inappropriate for oral in‐ take the treatment should be continued with an infusion of intravenous fluids and insulin [10,17,49,93,187]. A multiple-dose subcutaneous combination regimen is preferred, as it is related with less hypoglycemia and provides a better physiologic pattern of control than other regimens. In insulin-naїve patients, a multidose insulin regimen should be started at a dose of 0.5-0.8 units/kg body weight per day. Patients with known diabetes, whose blood glucose monitoring are in the normal ranges before DKA, may start with dose of insulin they are receiving [160].

In the past human insulin (NPH and regular) were usually given in two or three doses per day. With the development of new analogue insulins, basal-bolus regimens with basal (glar‐ gine and detemir) and rapid-acting (lispro, aspart, or glulisine) insulin treatments became a major concern in the treatment of DKA. A prospective randomized trial compared with a split mixed regimen of NPH plus regular insulin twice daily treatment and a basal-bolus regimen, including glargine once daily and glulisine before meals following the resolution of DKA. Glycemic control were similar between the two groups but the study showed that treatment with basal-bolus insulin regimen was associated with a lower rate of hypoglyce‐ mic events (15%) than the rate in those treated with NPH and regular insulin (41%). This trial showed that analogue insulins may offer a more physiologic effect [156].

#### **6.7. Somatostatin therapy in the management of resistant diabetic ketoacidosis**

As a inhibiting hormone for counterregulatory hormones, somatostatin may be used in the treatment of DKA. Somatostatin analogues have been successfully used in the treat‐ ment of diabetes associated autonomic neuropathy and they have also been shown to de‐ crease the requirements for insulin [188,189]. Continuous subcutaneous octreotide infusion suppresses counterregulatory hormones, increases insulin-mediated glucose me‐ tabolism by enhancing glucose storage and reduces energy expenditure [189]. There are limiting data in the literature about somatostatin use in DKA. Diem et al. were assessed preventive effects of octreotide on diabetic ketogenesis during insulin withdrawal. Oc‐ treotide led to a marked suppression of beta-hydroxybutyrate, acetoacetate and glucagon levels and an associated diminution of bicarbonate consumption and the fall in pH [190]. Anthony et al. reported a case of DKA with glucagonoma who was unresponsive to con‐ ventional therapy and treated with octreotide [191]. In conclusion, for patients who do not respond to conventional DKA treatment, somatostatin could be added to therapy. More data and further randomized controlled clinical trials should be made with the use of somatostatin in treatment of DKA.

### **6.8. Monitoring**

Successful management and early intervention for complications require close monitoring. Timeline in DKA management are listed in Figure-3 [165]. The clinicians should be made a flow chart to obtain all relevant incidents regarding the patient's condition and clinical outcome [192]. Recommendations for laboratory monitoring include; hourly vital signs and neurologic checks; hourly blood glucose levels for the first 4-6 hours and then to continue with 2 hour intervals in the following period; venous blood gases every 2 hours for 6 hours, then every 4 hours, Na, K and ionized calcium every 2 hours for 6 hours then every 4 hours; magnesium and phosphorus every 4 hours; blood urea nitrogen and creatinine levels (every 4 hours) should also be monitored until stable; basic metabolic profile at admission and then every morning. Fluid intake and urinary output should be moni‐ tored [193-195]. These are the minimum requirements and should be revised for special situations. For example, patients with initially low potassium, more frequent (hourly) K measurements should be made with ECG monitoring [194,195] or if patient's neurologi‐ cal status is unstable and has a high risk of cerebral edema, more frequent neurologic

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Serum bicarbonate and anion gap are good markers of therapeutic response. Close monitor‐ ing of arterial blood gases and serum or urine ketones should not be used as predictor of clinical improvement. Despite of successfull treatment by arresting ketogenesis, ketone lev‐ els may be considered unchanged or high, as beta-hydroxybutyrate converts to acetoacetate and conventional (nitroprusside) testing detects only acetoacetate and acetone [135]. For avoid this problem laboratory measurement or the use of a bedside fingerstick sample moni‐ tor for beta-hydroxybutyrate can be made. It is reasonable to reduce laboratory monitoring frequency when acidosis resolves, the anion gap falls to near normal limits while response to glycemic therapy becomes noticeable [135]. In the presence of persistent acidosis, despite of successfull treatment; sepsis, concomitant illness or inadequate insulin dosing should be

Most of the diabetes-related morbidity and mortality in T1DM can be attributed to compli‐

Decrease in the plasma glucose concentration rate should be kept in the range of 50–75 mg/dl/hour. As ketoacidosis is corrected, a rapid decline in plasma glucose levels can be oc‐ cur and this may cause the blood glucose drop to hypoglycemia levels. Hypoglycemia leads to the release of counter-regulatory hormones and this results with rebound ketosis which can lengthen the duration of treatment. In addition to this, severe hypoglycemia can cause cardiac arrhythmias, seizure or loss of consciousness, brain injury including coma or death. The insulin infusion rate should be checked every hour until a steady glucose decline is ach‐ ieved and once the plasma glucose falls to <200-250 mg/dL (11.1-13.88 mmol/L), dextrose should be added to replacement fluids to allow continued insulin administration and avoid

kept in mind and further evaluation and intervention should be made [135,193].

**7. Complications of diabetic ketoacidosis or it's treatment**

cations of DKA.

**7.1. Hypoglycemia**

hypoglycemia [93].

and vital sign checks (20-30 minutes) should be made [192].


**Figure 3.** Timeline in DKA management. GCS:Glascow Coma Scale, CBC:Complete Blood Counting, ECG:Electrocardio‐ gram, HR:Heart Rate, BP:Blood Pressure, BUN:Blood Urea Nitrogen, Cr: Creatinine, WBC:White Blood Cell, CRP:C-reac‐ tive protein, CE:Cerebral edema (adapted from reference 165)

Recommendations for laboratory monitoring include; hourly vital signs and neurologic checks; hourly blood glucose levels for the first 4-6 hours and then to continue with 2 hour intervals in the following period; venous blood gases every 2 hours for 6 hours, then every 4 hours, Na, K and ionized calcium every 2 hours for 6 hours then every 4 hours; magnesium and phosphorus every 4 hours; blood urea nitrogen and creatinine levels (every 4 hours) should also be monitored until stable; basic metabolic profile at admission and then every morning. Fluid intake and urinary output should be moni‐ tored [193-195]. These are the minimum requirements and should be revised for special situations. For example, patients with initially low potassium, more frequent (hourly) K measurements should be made with ECG monitoring [194,195] or if patient's neurologi‐ cal status is unstable and has a high risk of cerebral edema, more frequent neurologic and vital sign checks (20-30 minutes) should be made [192].

Serum bicarbonate and anion gap are good markers of therapeutic response. Close monitor‐ ing of arterial blood gases and serum or urine ketones should not be used as predictor of clinical improvement. Despite of successfull treatment by arresting ketogenesis, ketone lev‐ els may be considered unchanged or high, as beta-hydroxybutyrate converts to acetoacetate and conventional (nitroprusside) testing detects only acetoacetate and acetone [135]. For avoid this problem laboratory measurement or the use of a bedside fingerstick sample moni‐ tor for beta-hydroxybutyrate can be made. It is reasonable to reduce laboratory monitoring frequency when acidosis resolves, the anion gap falls to near normal limits while response to glycemic therapy becomes noticeable [135]. In the presence of persistent acidosis, despite of successfull treatment; sepsis, concomitant illness or inadequate insulin dosing should be kept in mind and further evaluation and intervention should be made [135,193].
