**5. Diagnosis**

Recent studies have reported that an upregulated production of and interleukin-18 (IL-18) could be an important pathogenic event in the dysregulated production of IFN-γ and other type 1 cytokines thought to predispose T1DM [44-46] and the potential role of IL-18 in the pathophysiology of the chronic complications of diabetes mellitus [7-11]. But the potential role of IL-18 in the acute complications of diabetes mellitus such as DKA is controversial. Dong et al. compared serum IL-18 levels and other cytokines (IL-12 and IFN-γ) in newly di‐ agnosed T1DM with DKA, T1DM without DKA and age/sex-matched healthy controls. Se‐ rum IL-18 levels were significantly higher in patients than those in healthy controls. Serum IL-12 and IFN-γ levels were not different between patients and controls. But there was a positive correlation between serum IL-18 and islet cell antibody (ICA) and C-peptide levels, but not between serum IL-18 and HbA1C, insulin and glucose in T1DM. Serum IL-18 levels also correlated positively with serum IL-12 levels. Serum IL-18 levels was significantly high‐ er in patients with DKA than those in patients without DKA while C-peptide levels were markedly lower in patients with DKA. These results point that serum IL-18 levels are elevat‐ ed and correlated with C-peptide levels and ICA in patients with T1DM, with marked in‐ crease in T1DM with DKA. Clinicans should be aware of the risk of DKA in diabetic patients with high serum IL-18 [47]. The procoagulant and inflammatory states may be due to non‐ specific phenomena of stress and may partially explain the association of hyperglycemic cri‐

A careful search for precipitating factors should be made, as correction of these contributes

The most common precipitating factor in the development of DKA is infection [37,49,50] in‐ cluding viral syndromes, urinary tract infections, pelvic inflammatory disease, pneumonia, mucormycosis, malignant otitis externa (with pseudomonas aeruginosa), periodontal ab‐ scess and dental infection [51]. Other precipitating factors include discontinuation of, or in‐ adequate insulin therapy, acute pancreatitis, myocardial infarction, stroke, major trauma and other severe/acute illnesses and drugs [30,32,37]. New-onset T1DM or discontinuation of insulin in T1DM frequently leads to the development of DKA. In young patients with T1DM, psychological problems complicated by eating disorders may be a contributing fac‐ tor in 20% of recurrent ketoacidosis. In younger patients fear of weight gain and hypoglyce‐

In the past, before the improvement in technology and sufficient education of patients con‐ tinuous subcutaneous insulin infusion devices had also been associated with an increased frequency of DKA [52]; nowadays the incidence of DKA appears to have reduced in pump users [53]. Additional prospective studies are needed to document reduction of DKA inci‐

Drugs that affect carbohydrate metabolism, such as corticosteroids, thiazides, sympatho‐ mimetic agents and pentamidine may precipitate the development of DKA [10]. The as‐

dence with the use of continuous subcutaneous insulin infusion devices [54].

ses with a hypercoagulable state [48].

to improved outcomes and less frequent recurrences.

mia, stresss of chronic disease may lead to insulin omission.

**4. Precipitating factors**

254 Type 1 Diabetes

#### **5.1. History and physical examination**

The acute DKA episode in T1DM evoluation should be done rapidly. The symptoms of poorly controlled diabetes may be present for several days, but the metabolic changes typical of ketoacidosis usually occurs within a short time (typically 24 h). Occasionally, the entire symptomatic presentation may evolve or develop more acutely and the patient may present with DKA with no prior clues or symptoms. For DKA, the typical clinical findings includes a history of polyuria, polydipsia, weight loss, vomiting, dehydration, weakness and mental status change. Physical examination may include poor skin turgor, Kussmaul respirations, tachycardia and hypotension. Mental status can vary from full alertness to profound lethargy or coma [10,37]. The symptoms and physical signs of DKA are listed in Table 1.

WBC count is response to stress is characteristic of DKA and is not indicative of infec‐ tion. If there is evidence of infection, chest X-ray and urine, sputum, throat or blood cul‐

The severity of DKA is classified as mild, moderate, or severe based on the severity of meta‐ bolic acidosis (blood pH, bicarbonate, and ketones) and the presence of altered mental status

> **Moderate (plasma glucose glucose >250 mg/ mg/dl)**

**DKA**

**Severe ( (plasma glucose >250 mg/dl)**

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**Anion gap ‡ >10 >12 >12**

**Effective Effectiveserum Variable Variable Variable Variable**

**Serum ketone \* Positive PositivePositive Positive**

**Urine ketone \* Positive Positive Positive Positive Positive Positive**

**Serum bicarbonate bicarbonate15–18 10 to <15 <10** 

**Arterial Arterial pH 7.25–7.30 7.00 to <7.24 <7.00** 

**Mild (plasma glucose >250 mg/dl)**

**Mental status Alert Alert/drowsy Stupor/coma**

One of the major laboratory findings in DKA is the elevation of total blood ketone concen‐ tration. Assessment of increased ketonemia is usually performed by the nitroprusside reac‐ tion which provides a semiquantitative estimation of acetoacetate and acetone levels. The nitroprusside test (both in urine and in serum) is highly sensitive, but it does not recognize the main metabolic product in ketoacidosis; beta-hydroxybutyrate. In conclusion this assay is insufficient to determine the severity of ketoacidosis [10,31]. Measurement of serum ß- hy‐ droxybutyrate may be an alternative to determine ketoacidosis [96). Ketoacids cause an in‐ creased anion gap metabolic acidosis. The anion gap is calculated by subtracting the sum of chloride(Cl) and bicarbonate (HCO3) concentration from the sodium (Na) concentration:

tures should also be obtained [93].

as shown in Table 2.

**osmolality †**

\*Nitroprusside reaction method.

**Table 2.** Classification of DKA

‡Anion gap: (Na+) − [(Cl− + HCO3− (mEq/l)].

†Effective serum osmolality: 2[measured Na+ (mEq/l)] + glucose (mg/dl)/18.

**(mEq/l)** 


**Table 1.** The symptoms and physical signs of DKA

Although infection is a common precipitating factor for DKA, patients can be normothermic or even hypothermic. Severe hypothermia, if present, is a poor prognostic sign and could be fatal. The major complications of hypothermia are acute renal failure, aspiration pneumonia, rhabdomyolysis, acute respiratory distresss syndrome and acute pancreatitis [83]. The mechanism of hypothermia complicated by DKA is unclear, but the inability of glucose to endocytose due to insulin deficit which leads to a lack of substrate for cellular heat produc‐ tion has been proposed [84]. A characteristic elevated J point on the electrocardiogram (ECG) (Osborn wave) may be observed when markedly hypothermia occurs [85-87]. The thermoregulatory system could be impaired in diabetic patients with autonomic neuropathy and reduced muscle mass or adipose tissue related with malnutrition. Thus, become prone to hypothermia under certain conditions [88,89].

Nausea, vomiting, diffuse abdominal pain are frequent in patients with DKA (50%) [90]. Ab‐ dominal pain on presentation could be a result of the DKA or an indication of a precipitat‐ ing cause of DKA, particularly in younger patients or in the absence of severe metabolic acidosis [91,92]. Further evaluation is necessary if this complaint does not resolve with suc‐ cessfull treatment, because this may indicate other underlying complications.

#### **5.2. Laboratory findings**

The initial laboratory evaluation should include determination of plasma glucose, blood urea nitrogen, creatinine, electrolytes (with calculated anion gap), osmolality, serum and urinary ketones and urinalysis, as well as initial arterial blood gases and a complete blood count [93]. If laboratory measurement of serum potassium is delayed an ECG should be performed for baseline evaluation of potassium status [94,95]. An increased WBC count is response to stress is characteristic of DKA and is not indicative of infec‐ tion. If there is evidence of infection, chest X-ray and urine, sputum, throat or blood cul‐ tures should also be obtained [93].

The severity of DKA is classified as mild, moderate, or severe based on the severity of meta‐ bolic acidosis (blood pH, bicarbonate, and ketones) and the presence of altered mental status as shown in Table 2.


**Table 2.** Classification of DKA

the entire symptomatic presentation may evolve or develop more acutely and the patient may present with DKA with no prior clues or symptoms. For DKA, the typical clinical findings includes a history of polyuria, polydipsia, weight loss, vomiting, dehydration, weakness and mental status change. Physical examination may include poor skin turgor, Kussmaul respirations, tachycardia and hypotension. Mental status can vary from full alertness to profound lethargy or coma [10,37]. The symptoms and physical signs of

**MANIFESTATIONS OF DIABETIC KETOACIDOSIS**

Dehydration / hypotension Tachypnea / Kussmaul respirations

Abdominal tenderness

Although infection is a common precipitating factor for DKA, patients can be normothermic or even hypothermic. Severe hypothermia, if present, is a poor prognostic sign and could be fatal. The major complications of hypothermia are acute renal failure, aspiration pneumonia, rhabdomyolysis, acute respiratory distresss syndrome and acute pancreatitis [83]. The mechanism of hypothermia complicated by DKA is unclear, but the inability of glucose to endocytose due to insulin deficit which leads to a lack of substrate for cellular heat produc‐ tion has been proposed [84]. A characteristic elevated J point on the electrocardiogram (ECG) (Osborn wave) may be observed when markedly hypothermia occurs [85-87]. The thermoregulatory system could be impaired in diabetic patients with autonomic neuropathy and reduced muscle mass or adipose tissue related with malnutrition. Thus, become prone

Nausea, vomiting, diffuse abdominal pain are frequent in patients with DKA (50%) [90]. Ab‐ dominal pain on presentation could be a result of the DKA or an indication of a precipitat‐ ing cause of DKA, particularly in younger patients or in the absence of severe metabolic acidosis [91,92]. Further evaluation is necessary if this complaint does not resolve with suc‐

The initial laboratory evaluation should include determination of plasma glucose, blood urea nitrogen, creatinine, electrolytes (with calculated anion gap), osmolality, serum and urinary ketones and urinalysis, as well as initial arterial blood gases and a complete blood count [93]. If laboratory measurement of serum potassium is delayed an ECG should be performed for baseline evaluation of potassium status [94,95]. An increased

cessfull treatment, because this may indicate other underlying complications.

Dry mucous membranes / reduced skin turgor

Lethargy / obtundation / cerebral edema / possibly coma

Physical findings Tachycardia

DKA are listed in Table 1.

**Table 1.** The symptoms and physical signs of DKA

to hypothermia under certain conditions [88,89].

**5.2. Laboratory findings**

Symptoms Nausea / vomiting Thirst / polyuria Abdominal pain Shortness of breath

256 Type 1 Diabetes

One of the major laboratory findings in DKA is the elevation of total blood ketone concen‐ tration. Assessment of increased ketonemia is usually performed by the nitroprusside reac‐ tion which provides a semiquantitative estimation of acetoacetate and acetone levels. The nitroprusside test (both in urine and in serum) is highly sensitive, but it does not recognize the main metabolic product in ketoacidosis; beta-hydroxybutyrate. In conclusion this assay is insufficient to determine the severity of ketoacidosis [10,31]. Measurement of serum ß- hy‐ droxybutyrate may be an alternative to determine ketoacidosis [96). Ketoacids cause an in‐ creased anion gap metabolic acidosis. The anion gap is calculated by subtracting the sum of chloride(Cl) and bicarbonate (HCO3) concentration from the sodium (Na) concentration: [Na - (Cl +HCO3)]. A normal anion gap is between 7 and 9 mEq/l and an anion gap 10–12 mEq/l indicates the presence of increased anion gap metabolic acidosis [10].

Serum potassium concentration may be increased because of an extracellular shift of potassi‐ um caused by insulin deficiency, hypertonicity and acidemia [117]. However, patients have severe total-body potassium deficiency. Treatment could be lowers serum potassium con‐ centration and trigger cardiac arrhythmia. So patients with low normal or low serum potas‐ sium concentration should be monitored closely. If necessary appropriate potassium

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Insulin mainly affects glucose metabolism, but also protein and lipid metabolism. In the lit‐ erature there are many cases of DKA presented with severe hyperlipidemia [118,119]. In pa‐ tients with newly diagnosed T1DM presenting with DKA there is an absolute insulin deficiency that causes increased lipolysis and free fatty acid accumulation to the liver, de‐ creased in utilization and excretion which results with hyperlipidemia. Severe hypertrigly‐ ceridemia can complicate DKA by the development of pancreatitis. As it is related with increased morbidity and mortality, clinicians must be aware of this complication. Children under the age of 5 years presenting with DKA have a higher rate of mortality. Therefore, these should be monitored for hyperlipidemia and if there is clinical evidence, for pancreati‐ tis [120-123]. Pseudonormoglycemia [124] and pseudohyponatremia [125] may occur in

On the admission in patients with DKA, serum phosphate level is usually elevated because of an extracellular shift of phosphate caused by insulin deficiency, hypertonicity and in‐ creased catabolism. Thus, serum concentration does not reflect an actual body deficit [31,126,127]. Typical total body deficits of water and electrolytes in DKA are seen in Table 3.

**Typical deficits**

**a** + + **(mEq/kg) 1-2C**

**Table 3.** Typical total body deficits of water and electrolytes in DKA (\*Per kg of body weight)

**g** + + **(mEq/kg) 1-2M**

**O**4 **(mmol/kg) 5-7P**

<sup>+</sup>**(mEq/kg) 3-5K**

**l (mEq/kg) 3-5C**

**Na 7-10** <sup>+</sup>**(mEq/kg)**

**Water (ml/kg)\* 100**

**Total water (L) 6**

replacement should be done [93].

DKA in the presence of severe chylomicronemia.

In clinical trials mixed acid–base disorders have been showed in DKA [97,98], but it is very rare the presentation of DKA with alkalaemia. The first case has been reported in 1970, defined as 'diabetic ketoalkalosis' [99] and it was followed by other case reports. The factors related with alkalemia in DKA were; recurrent vomiting which causes hydro‐ gen and chloride ion loss (autonomic neuropathy such as delayed gastric emptying might have been related to recurrent vomiting), alkali ingestion and contraction alkalosis due to dehydration and/or diuretic use [100]. Treatment of diabetic ketoalkalosis does not differ from that of pure DKA.

Hyperglycemia is a key diagnostic criterion of DKA; but plasma glucose level varies in a wide range on admission. Recent studies have reported from normal or near normal [101] to elevated [31,3] hepatic glucose production rates. This factor possibly contributes to the wide range of plasma glucose levels in DKA that are independent of the severity of ketoacidosis [96]. In contrast to this 10% of the DKA patients presents with so-called 'true euglycemic DKA' [blood glucose <200 mg/dl (11.1 mmol/l)] [102]. Due to nausea or vomiting caused by a precipitating illness or by worsening ketoacidosis itself, a decrease in caloric intake occurs. If patients continue to take sufficient amounts of insulin in this situation may maintain eu‐ glycemia. But ketone body formation cannot be stopped, so they present as DKA accompa‐ nied with only mild elevations of blood glucose or normoglycemia [103-105]. Euglycemic DKA can be associated with other conditions such as; near total glycogen depletion [106,107], accelerated lipolysis [108] and free fatty acid production [109], less effectiveness of insulin suppressing lipolysis and ketogenesis during fasting and when there is sufficient cir‐ culating fluid volume to maintain glucose excretion [110]. In women with diabetes, pregnan‐ cy is also a condition that is associated with euglycemic ketoacidosis [111,112] as pregnancy is considered to be a state of accelerated starvation [113] with increased lipolysis and ketone body production in the presence of increased insulin insensitivity [114].

At presentation leukocytosis with cell counts in the 10,000 –15,000 mm3 range is commonly seen in DKA and may not be indicative of an infection. But leukocytosis with cell counts 25,000 mm3 may indicate infection and require further evaluation [115]. In ketoacidosis, leu‐ kocytosis may be correlated to elevated levels of cortisol and norepinephrine which is attrib‐ uted to stress [116].

On admission serum sodium is usually low because of the osmotic flux of water from the intracellular to the extracellular space as a result of hyperglycemia. An increased or even normal serum sodium concentration in the presence of hyperglycemia indicates severe de‐ gree of free water loss. To assess the severity of sodium and water deficit, serum sodium may be corrected by adding 1.6 mg/dl to the measured serum sodium for each 100 mg/dl of glucose above 100 mg/dl [10,31]. In the calculation of effective osmolality, [sodium ion (mEq/l) x 2 + glucose (mg/dl)/18], the urea concentration is not taken into account because it is freely permeable and its accumulation does not induce major changes in intracellular vol‐ ume or osmotic gradient across the cell membrane [10].

Serum potassium concentration may be increased because of an extracellular shift of potassi‐ um caused by insulin deficiency, hypertonicity and acidemia [117]. However, patients have severe total-body potassium deficiency. Treatment could be lowers serum potassium con‐ centration and trigger cardiac arrhythmia. So patients with low normal or low serum potas‐ sium concentration should be monitored closely. If necessary appropriate potassium replacement should be done [93].

[Na - (Cl +HCO3)]. A normal anion gap is between 7 and 9 mEq/l and an anion gap 10–12

In clinical trials mixed acid–base disorders have been showed in DKA [97,98], but it is very rare the presentation of DKA with alkalaemia. The first case has been reported in 1970, defined as 'diabetic ketoalkalosis' [99] and it was followed by other case reports. The factors related with alkalemia in DKA were; recurrent vomiting which causes hydro‐ gen and chloride ion loss (autonomic neuropathy such as delayed gastric emptying might have been related to recurrent vomiting), alkali ingestion and contraction alkalosis due to dehydration and/or diuretic use [100]. Treatment of diabetic ketoalkalosis does

Hyperglycemia is a key diagnostic criterion of DKA; but plasma glucose level varies in a wide range on admission. Recent studies have reported from normal or near normal [101] to elevated [31,3] hepatic glucose production rates. This factor possibly contributes to the wide range of plasma glucose levels in DKA that are independent of the severity of ketoacidosis [96]. In contrast to this 10% of the DKA patients presents with so-called 'true euglycemic DKA' [blood glucose <200 mg/dl (11.1 mmol/l)] [102]. Due to nausea or vomiting caused by a precipitating illness or by worsening ketoacidosis itself, a decrease in caloric intake occurs. If patients continue to take sufficient amounts of insulin in this situation may maintain eu‐ glycemia. But ketone body formation cannot be stopped, so they present as DKA accompa‐ nied with only mild elevations of blood glucose or normoglycemia [103-105]. Euglycemic DKA can be associated with other conditions such as; near total glycogen depletion [106,107], accelerated lipolysis [108] and free fatty acid production [109], less effectiveness of insulin suppressing lipolysis and ketogenesis during fasting and when there is sufficient cir‐ culating fluid volume to maintain glucose excretion [110]. In women with diabetes, pregnan‐ cy is also a condition that is associated with euglycemic ketoacidosis [111,112] as pregnancy is considered to be a state of accelerated starvation [113] with increased lipolysis and ketone

mEq/l indicates the presence of increased anion gap metabolic acidosis [10].

body production in the presence of increased insulin insensitivity [114].

At presentation leukocytosis with cell counts in the 10,000 –15,000 mm3

ume or osmotic gradient across the cell membrane [10].

seen in DKA and may not be indicative of an infection. But leukocytosis with cell counts 25,000 mm3 may indicate infection and require further evaluation [115]. In ketoacidosis, leu‐ kocytosis may be correlated to elevated levels of cortisol and norepinephrine which is attrib‐

On admission serum sodium is usually low because of the osmotic flux of water from the intracellular to the extracellular space as a result of hyperglycemia. An increased or even normal serum sodium concentration in the presence of hyperglycemia indicates severe de‐ gree of free water loss. To assess the severity of sodium and water deficit, serum sodium may be corrected by adding 1.6 mg/dl to the measured serum sodium for each 100 mg/dl of glucose above 100 mg/dl [10,31]. In the calculation of effective osmolality, [sodium ion (mEq/l) x 2 + glucose (mg/dl)/18], the urea concentration is not taken into account because it is freely permeable and its accumulation does not induce major changes in intracellular vol‐

range is commonly

not differ from that of pure DKA.

258 Type 1 Diabetes

uted to stress [116].

Insulin mainly affects glucose metabolism, but also protein and lipid metabolism. In the lit‐ erature there are many cases of DKA presented with severe hyperlipidemia [118,119]. In pa‐ tients with newly diagnosed T1DM presenting with DKA there is an absolute insulin deficiency that causes increased lipolysis and free fatty acid accumulation to the liver, de‐ creased in utilization and excretion which results with hyperlipidemia. Severe hypertrigly‐ ceridemia can complicate DKA by the development of pancreatitis. As it is related with increased morbidity and mortality, clinicians must be aware of this complication. Children under the age of 5 years presenting with DKA have a higher rate of mortality. Therefore, these should be monitored for hyperlipidemia and if there is clinical evidence, for pancreati‐ tis [120-123]. Pseudonormoglycemia [124] and pseudohyponatremia [125] may occur in DKA in the presence of severe chylomicronemia.

On the admission in patients with DKA, serum phosphate level is usually elevated because of an extracellular shift of phosphate caused by insulin deficiency, hypertonicity and in‐ creased catabolism. Thus, serum concentration does not reflect an actual body deficit [31,126,127]. Typical total body deficits of water and electrolytes in DKA are seen in Table 3.


**Table 3.** Typical total body deficits of water and electrolytes in DKA (\*Per kg of body weight)

Increased amylase and lipase has been reported in 16-25 % of patients with DKA. The mech‐ anism of elevated enzymes in DKA remains unclear. Amylase elevations could be related with subtle injury to pancreatic acinar cells which causes release of this enzyme to the circu‐ lation, release of salivary gland amylase or suboptimal excretion in the urine [128]. There is little correlation between the presence, degree or isoenzyme type of hyperamylasemia and the presence of gastrointestinal symptoms (nausea, vomiting, and abdominal pain) or pan‐ creatic imaging studies [129]. Increase in lipase may be related with release of nonpancreatic lipolytic enzymes into the circulation due to malignant tumors, to acute cholecystitis or esophagitis. Other possible mechanism are; renal insufficiency, delayed blood withdrawal, hypertriglyceridemia or subclinical pancreatitis [130]. Pancreatic enzyme levels reach a peak 12-24 hours after initiation of treatment for DKA [131]. Hyperlipasemia is less reliable for diagnosing acute pancreatitis, but elevated lipase is more spesific.

Acute renal failure can be seen in ~5-7% of all adult hospitalizations [132,133]. It shares the common feature of an increased anion gap metabolic acidosis but can be easily differentiat‐ ed from DKA by the absence of hyperglycemia or ketonemia. On the other hand, severe

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Severe uremic acidosis, characterized by an extremely high blood urea nitrogen, often >200 mg/dL (71.4 mmol/L) and creatinine >10 mg/dL (884 umol/L) causes acidosis via retention of anionic solutes in the patient with chronic kidney disease. The pH and anion gap can be found usually mild abnormal, however blood sugar is typically normal. Severe uremia typi‐ cally occurs when creatinine clearance falls to <10 mL/min (0.1669 ml/s) in irreversible renal

Lactic acidosis occasionally contributes to metabolic acidosis in patients hospitalized for ei‐ ther uncomplicated diabetes or DKA [137]. The main reason of lactic acidosis is tissue hypo‐ xia [138]. It occurs in the setting of decreased tissue oxygen delivery which triggers nonoxidative metabolism of glucose to lactic acid. When co-existent with DKA, the anion gap typically exceeds that attributable to lactate alone. If lactic acidosis, with a serum lactate ≥5 mmol/L (45 mg/dL), occurs accompanied with DKA or hyperosmolar hyperglycemic state, severe volume depletion affects cardiac output negatively and also pre-existent cardiovascu‐ lar disease increases this risk. Underlying liver disease with reduced lactate clearance and sepsis may also contribute more frequent/severe lactic acidosis in hyperglycemic emergen‐ cies. For main therapy it should be performed to optimise tissue perfusion and to treat un‐

When there is insufficient carbohydrate availability, starvation ketosis may occur by result of physiologically appropriate lipolysis and ketogenesis to provide fuel substrates. Blood glucose and arterial pH are found to be usually in normal level and the anion gap is at most mildly elevated. Although ketonuria may be apparent in urine analysis, modest ketonemia

Chronical alcohol abuse may be the reason of alcoholic ketosis for ethanol is the predomi‐ nant caloric source for days or weeks. Ketosis happens in sudden decrease of alcohol and caloric intake. Patients are usually present in normoglycemic or hypoglycemic state on sub‐

Toxic ingestions sometimes need to be differentiated and history of the patients with labora‐ tory studies may help for the differantial diagnosis. Salicylate, methanol and ethylene glycol each produce an increased anion gap metabolic acidosis without hyperglycemia or ketosis. Methanol and ethylene glycol will also cause a serum osmolal gap [17,136]. Measurement of suspicious drug/toxin concentrations with high index of suspicion, usually confirms the di‐

If there are some gastrointestinal or renal losses for any reason, non-anion gap metabolic acidosis may occur. It is characterized by a low serum bicarbonate concentration with subsequent chloride retention. Diarrhea and renal tubular acidosis are frequent causes of this condition. Carbonic anhydrase inhibitor therapy, rapid dilution of plasma bicarbon‐ ate by infused saline may be considered as the other varying reasons [143,144]. DKA can

DKA can lead to prerenal azotemia and secondary acute kidney injury [134,135].

disease [136].

derlying conditions [17,136].

is typical in blood examination [17,136].

agnosis of acute intoxication [139-142].

mission, although some have rarely mild hyperglycemia [136].

#### **5.3. Differential diagnosis**

Other causes of metabolic acidosis and ketosis must be differentiated from DKA. Differan‐ tial diagnosis of DKA can be seen in Table 4.


**Table 4.** Differantial diagnosis of DKA

Acute renal failure can be seen in ~5-7% of all adult hospitalizations [132,133]. It shares the common feature of an increased anion gap metabolic acidosis but can be easily differentiat‐ ed from DKA by the absence of hyperglycemia or ketonemia. On the other hand, severe DKA can lead to prerenal azotemia and secondary acute kidney injury [134,135].

Increased amylase and lipase has been reported in 16-25 % of patients with DKA. The mech‐ anism of elevated enzymes in DKA remains unclear. Amylase elevations could be related with subtle injury to pancreatic acinar cells which causes release of this enzyme to the circu‐ lation, release of salivary gland amylase or suboptimal excretion in the urine [128]. There is little correlation between the presence, degree or isoenzyme type of hyperamylasemia and the presence of gastrointestinal symptoms (nausea, vomiting, and abdominal pain) or pan‐ creatic imaging studies [129]. Increase in lipase may be related with release of nonpancreatic lipolytic enzymes into the circulation due to malignant tumors, to acute cholecystitis or esophagitis. Other possible mechanism are; renal insufficiency, delayed blood withdrawal, hypertriglyceridemia or subclinical pancreatitis [130]. Pancreatic enzyme levels reach a peak 12-24 hours after initiation of treatment for DKA [131]. Hyperlipasemia is less reliable for

Other causes of metabolic acidosis and ketosis must be differentiated from DKA. Differan‐

++ **- - - - - - Glycosuria**

\*Acetest and Ketostix measure acetoacetic acid only, thus misleading low values may be obtained because the majority of 'ketone bodies' are ßhydroxybutyrate. \*(Data adapted from reference 10)

**Uric acid Mİld N N N N**

**Osmolality N N N N**

**Plasma N N N or N N N or**

**Lactic acidosis**

**Mİld**

**Uremic acidosis**

**Slight to N N**

**Methanol Methanol or ethylenglycol intoxication**

**Salicylate intoxication**

**moderate moderate**

**Alcholic Alcholic ketosis**

diagnosing acute pancreatitis, but elevated lipase is more spesific.

**5.3. Differential diagnosis**

**Ph N**

**Table 4.** Differantial diagnosis of DKA

**DKA**

**plasma ketones**

**glucose**

260 Type 1 Diabetes

tial diagnosis of DKA can be seen in Table 4.

**Anion gap Slight Slight**

**Total Slight N N**

**Starvation or high fat intake**

Severe uremic acidosis, characterized by an extremely high blood urea nitrogen, often >200 mg/dL (71.4 mmol/L) and creatinine >10 mg/dL (884 umol/L) causes acidosis via retention of anionic solutes in the patient with chronic kidney disease. The pH and anion gap can be found usually mild abnormal, however blood sugar is typically normal. Severe uremia typi‐ cally occurs when creatinine clearance falls to <10 mL/min (0.1669 ml/s) in irreversible renal disease [136].

Lactic acidosis occasionally contributes to metabolic acidosis in patients hospitalized for ei‐ ther uncomplicated diabetes or DKA [137]. The main reason of lactic acidosis is tissue hypo‐ xia [138]. It occurs in the setting of decreased tissue oxygen delivery which triggers nonoxidative metabolism of glucose to lactic acid. When co-existent with DKA, the anion gap typically exceeds that attributable to lactate alone. If lactic acidosis, with a serum lactate ≥5 mmol/L (45 mg/dL), occurs accompanied with DKA or hyperosmolar hyperglycemic state, severe volume depletion affects cardiac output negatively and also pre-existent cardiovascu‐ lar disease increases this risk. Underlying liver disease with reduced lactate clearance and sepsis may also contribute more frequent/severe lactic acidosis in hyperglycemic emergen‐ cies. For main therapy it should be performed to optimise tissue perfusion and to treat un‐ derlying conditions [17,136].

When there is insufficient carbohydrate availability, starvation ketosis may occur by result of physiologically appropriate lipolysis and ketogenesis to provide fuel substrates. Blood glucose and arterial pH are found to be usually in normal level and the anion gap is at most mildly elevated. Although ketonuria may be apparent in urine analysis, modest ketonemia is typical in blood examination [17,136].

Chronical alcohol abuse may be the reason of alcoholic ketosis for ethanol is the predomi‐ nant caloric source for days or weeks. Ketosis happens in sudden decrease of alcohol and caloric intake. Patients are usually present in normoglycemic or hypoglycemic state on sub‐ mission, although some have rarely mild hyperglycemia [136].

Toxic ingestions sometimes need to be differentiated and history of the patients with labora‐ tory studies may help for the differantial diagnosis. Salicylate, methanol and ethylene glycol each produce an increased anion gap metabolic acidosis without hyperglycemia or ketosis. Methanol and ethylene glycol will also cause a serum osmolal gap [17,136]. Measurement of suspicious drug/toxin concentrations with high index of suspicion, usually confirms the di‐ agnosis of acute intoxication [139-142].

If there are some gastrointestinal or renal losses for any reason, non-anion gap metabolic acidosis may occur. It is characterized by a low serum bicarbonate concentration with subsequent chloride retention. Diarrhea and renal tubular acidosis are frequent causes of this condition. Carbonic anhydrase inhibitor therapy, rapid dilution of plasma bicarbon‐ ate by infused saline may be considered as the other varying reasons [143,144]. DKA can 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 present [145-147].

**IV Fluids Determinde hydration status**

> **Cardiogenic shock**

**pH≥6.9 No HC3-**

**Hemodynamic monitoring Pressors**

**When serum glucose reaches 200 mg/dl change to 5% dextrose with 0,45% NaCl or 0,9% NaCl at 150-200 ml/hr**

> 1st hour 2nd hour 3rd-5th hours 6th-12th hours

saline when indicated)

**0,9% NaCl (250-500 ml//hr) Depending on hydration state**

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

**Hours Volume**

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

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

**Bicarbonate**

**Insulin regular**

**If serum glucose does not fall by at least 10% in first hr, give 0,14 U/kg as IV bolus, then continue previous treatment**

**When serum glucose reaches 200 mg/dl,reduce regular insulin infusion to 0,02-0,05 U/kg/hr IV or give rapid-acting insulin at 0,1U/kg SC every 2 hrs. Keep serum glucose between 150-200 mg/dl until resolution**

**After resolution of DKA and when patient is able to eat, initiate SC multidose insulin regimen. To transfer from IV to SC, continue insulin infusion for 1-2 hr after SC insulin begin to ensure adequate plasma insulin levels. In ınsulin naive patients, start at 0,5 U/kg to 0,8 U/kg body weight per day and adjust ınsulin as needed**

> 1,000 – 2,000 mL 1,000 mL 500 – 1,000 mL/hour 250 – 500 mL/hour

**0,14 U/kg/Bwt/hr as IV continious insulin infusion**

**Potassium Establish adequate renal function (urine output ~50 ml/hr)**

**K+= 3,2 – 5,2 mEq/L Give 20-30 mEq K+ in each liter of IV fluid to keep serum K+ between 4 – 5 mEq/L**

**K+<5,2 mEq/L Do not give K+ but check serum K+ every 2 hours**

Diabetic Ketoacidosis

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**K+<3,3 mEq/L Hold insulin and give 20-30 mEq/hr until K+> 3,3 mEq/L**

**0,1 U/kg/Bwt as IV bolus**

**0,1 U/kg/hr IV continious insulin infusion**

**pH<6.9 100 mmol in 400ml H2O + 20 mEq KCL infuse for 2 hrs Repeat every 2 hours until pH≥7**

**Evaluate serum corrected Na+**

**High Normal Low**

**0,45% NaCl (250-500 ml//hr) Depending on hydration state**

**Severe hypovolemia**

**Administer 0,9% NaCl (1.0 L / hr)**
