Type 1 Diabetes Mellitus is a syndrome characterized by hyperglycemia and insulin deficiency resulting from the loss of beta cells in pancreatic islets (Mapes & Faulds, 2014). The destruction of insulin-producing beta cells in the pancreas starts with the formation of autoantigens. Type 1 diabetes does not present clinically until 80-90% of the beta cells have been destroyed (McCance & Heuther, 2014). The content of this site is published by the site owner(s) and is not a statement of advice, opinion, or information pertaining to The Ohio State University.
Tufts OCW material is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported License. Diabetes mellitus is a condition in which the pancreas no longer produces enough insulin or cells stop responding to the insulin that is produced, so that glucose in the blood cannot be absorbed into the cells of the body. The most common form of diabetes is Type II, It is sometimes called age-onset or adult-onset diabetes, and this form of diabetes occurs most often in people who are overweight and who do not exercise. The causes of diabetes mellitus are unclear, however, there seem to be both hereditary (genetic factors passed on in families) and environmental factors involved. In Type II diabetes, the pancreas may produce enough insulin, however, cells have become resistant to the insulin produced and it may not work as effectively. Diabetes mellitus is a common chronic disease requiring lifelong behavioral and lifestyle changes. Several blood tests are used to measure blood glucose levels, the primary test for diagnosing diabetes. Random blood glucose test — for a random blood glucose test, blood can be drawn at any time throughout the day, regardless of when the person last ate. Fasting blood glucose test — fasting blood glucose testing involves measuring blood glucose after not eating or drinking for 8 to 12 hours (usually overnight). Oral glucose tolerance test — Oral glucose tolerance testing (OGTT) is the most sensitive test for diagnosing diabetes and pre-diabetes. Oral glucose tolerance testing is routinely performed at 24 to 28 weeks of pregnancy to screen for gestational diabetes; this requires drinking a 50 gram glucose solution with a blood glucose level drawn one hour later. When diet, exercise and maintaining a healthy weight aren’t enough, you may need the help of medication. The most widely used form of insulin is synthetic human insulin, which is chemically identical to human insulin but manufactured in a laboratory. Advice patient about the importance of an individualized meal plan in meeting weekly weight loss goals and assist with compliance.
Assess patients for cognitive or sensory impairments, which may interfere with the ability to accurately administer insulin. Review dosage and time of injections in relation to meals, activity, and bedtime based on patients individualized insulin regimen.
Instruct patient in the importance of accuracy of insulin preparation and meal timing to avoid hypoglycemia. Advise patient to assess blood glucose level before strenuous activity and to eat carbohydrate snack before exercising to avoid hypoglycemia. Assess feet and legs for skin temperature, sensation, soft tissues injuries, corns, calluses, dryness, hair distribution, pulses and deep tendon reflexes.
Advice patient who smokes to stop smoking or reduce if possible, to reduce vasoconstriction and enhance peripheral flow.
Science, Technology and Medicine open access publisher.Publish, read and share novel research. Diabetic KetoacidosisMustafa Cesur1 and Irmak Sayin2[1] Ankara Guven Hospital, Department of Endocrinology and Metabolic Disease, Turkey[2] Ufuk University, Medical Faculty, Department of Internal Medicine, Turkey1. Table 2.Classification of DKAOne of the major laboratory findings in DKA is the elevation of total blood ketone concentration. 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. Table 4.Differantial diagnosis of DKAAcute renal failure can be seen in ~5-7% of all adult hospitalizations [132,133].
Nonimmune (type 1B diabetes), occurs secondary to other diseases and is much less common than autoimmune (type 1A). These autoantigens are ingested by antigen-presenting cells which activate T helper 1 (Th1) and T helper 2 (Th2) lmphocytes. Activated Th1 lymphocytes secrete interluekin-2 (IL-2) and interferon. Because insulin stimulates glucose uptake into tissues, stores glycose as glycogen, inhibits glucagon secretion and inhibits glucose production from the liver, the destruction of insulin-producing beta cells causes hyperglycemia (Mapes & Faulds, 2014). Neither text, nor links to other websites, is reviewed or endorsed by The Ohio State University. Type II is considered a milder form of diabetes because of its slow onset (sometimes developing over the course of several years) and because it usually can be controlled with diet and oral medication.
Symptoms of Type II diabetes can begin so gradually that a person may not know that he or she has it. It is best managed with a team approach to empower the client to successfully manage the disease. The body’s primary energy source is glucose, a simple sugar resulting from the digestion of foods containing carbohydrates (sugars and starches). It is used to monitor blood glucose control in people with known diabetes, but is not normally used to diagnose diabetes. However, the OGTT is not routinely recommended because it is inconvenient compared to a fasting blood glucose test. The person then drinks a 75 gram liquid glucose solution (which tastes very sweet, and is usually cola or orange-flavored). For women who have an abnormally elevated blood glucose level, a second OGTT is performed on another day after drinking a 100 gram glucose solution.
These medications, such as repaglinide (Prandin), have effects similar to sulfonylureas, but you’re not as likely to develop low blood sugar. Metformin (Glucophage, Glucophage XR) is the only drug in this class available in the United States. These drugs block the action of enzymes in your digestive tract that break down carbohydrates. These drugs make your body tissues more sensitive to insulin and keep your liver from overproducing glucose.
By combining drugs from different classes, you may be able to control your blood sugar in several different ways. The pathogenesis causing to hyperglycemia and ketoacidosis in DKA (Data adapted from reference [17])4. Protocols for the management of patients with DKA (Data adapted from reference 10) Table 5. A 15 years old male patient firstly diagnosed T1DM with DKA infected by rhino-orbita-cerebral mucormycozis (Picture from the reference [218])7.6. IntroductionA chronic autoimmune destruction of the pancreatic beta cells results in decreasing endogenous insulin secretion and the clinical manifestation of type 1 diabetes mellitus (T1DM). Assessment of increased ketonemia is usually performed by the nitroprusside reaction which provides a semiquantitative estimation of acetoacetate and acetone levels.
It shares the common feature of an increased anion gap metabolic acidosis but can be easily differentiated from DKA by the absence of hyperglycemia or ketonemia.
However, the hypotension results from a loss of electrolyte solution and it is more physiological to replace with crystalloid. The destruction of beta cells in Type 1A diabetes results from the interaction of both genetic and environmental factors. IL-2 activates autoantigen-specific T cytotoxic lymphocytes which destroy islet cells through the secretion of toxic perforins and granzymes. Type 1 diabetics may present with abrupt onset of diabetic ketoacidosis, polyuria, polyphagia, polydipsia, or rapid weight loss with marked hyperglycemia (Mapes & Faulds, 2014). The treatment includes changes in diet, oral medications, and in some cases, daily injections of insulin.
The consequences of uncontrolled and untreated Type II diabetes, however, are the just as serious as those for Type I.
In Type I diabetes, the immune system, the body’s defense system against infection, is believed to be triggered by a virus or another microorganism that destroys cells in the pancreas that produce insulin.
As part of the team the, the nurse plans, organizes, and coordinates care among the various health disciplines involved; provides care and education and promotes the client’s health and well being.
Glucose from the digested food circulates in the blood as a ready energy source for any cells that need it.
The blood glucose level is measured before, and at one, two, and three hours after drinking the solution. Everyone with type 1 diabetes and some people with type 2 diabetes must take insulin every day to replace what their pancreas is unable to produce. One of its chief failings is that it doesn’t mimic the way natural insulin is secreted. It works by inhibiting the production and release of glucose from your liver, which means you need less insulin to transport blood sugar into your cells. That means sugar is absorbed into your bloodstream more slowly, which helps prevent the rapid rise in blood sugar that usually occurs right after a meal. Side effects of thiazolidinediones, such as rosiglitazone (Avandia) and pioglitazone hydrochloride (Actos), include swelling, weight gain and fatigue. The clinical onset of the disease is often acute in children and adolescents and diabetic ketoacidosis (DKA) is present in 20-74% of the patients [1-7]. The major complications of hypothermia are acute renal failure, aspiration pneumonia, rhabdomyolysis, acute respiratory distresss syndrome and acute pancreatitis [83]. 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. Amylase elevations could be related with subtle injury to pancreatic acinar cells which causes release of this enzyme to the circulation, release of salivary gland amylase or suboptimal excretion in the urine [128]. A recent Cochrane review did not support the use of colloid in preference to crystalloid fluid [153]. Although the genetic susceptibility is not well understood, type 1 diabetes is most strongly associated with major histocompatibility complex (MHC), specifically histocompatibility leukocyte antigen (HLA) class II alleles (HLA-DQ and HLA-DR) (McCance & Heuther, 2014). This form is also called noninsulin-dependent diabetes, a term that is somewhat misleading. Other symptoms may include sudden weight loss, slow wound healing, urinary tract infections, gum disease, or blurred vision. Insulin is a hormone or chemical produced by cells in the pancreas, an organ located behind the stomach. Unfortunately, insulin can’t be taken in pill form because enzymes in your stomach break it down so that it becomes ineffective.
But newer types of insulin, known as insulin analogs, more closely resemble the way natural insulin acts in your body. Second-generation sulfonylureas such as glipizide (Glucotrol, Glucotrol XL), glyburide (DiaBeta, Glynase PresTab, Micronase) and glimepiride (Amaryl) are prescribed most often. One advantage of metformin is that is tends to cause less weight gain than do other diabetes medications.
Most doctors prescribe two drugs in combination, although sometimes three drugs may be prescribed. 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 production has been proposed [84]. In conclusion this assay is insufficient to determine the severity of ketoacidosis [10,31].
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 pancreatic imaging studies [129].
The pH and anion gap can be found usually mild abnormal, however blood sugar is typically normal.
AntiGAD65 is an enzyme that helps control the release of insulin from beta cells and can be used to determine the cause of diabetes (McCance & Heuther, 2014).
Many people with Type II diabetes can control the condition with diet and oral medications, however, insulin injections are sometimes necessary if treatment with diet and oral medication is not working. It is not unusual for Type II diabetes to be detected while a patient is seeing a doctor about another health concern that is actually being caused by the yet undiagnosed diabetes.
Insulin bonds to a receptor site on the outside of cell and acts like a key to open a doorway into the cell through which glucose can enter. For that reason, many people inject themselves with insulin using a syringe or an insulin pen injector,a device that looks like a pen, except the cartridge is filled with insulin. The most common side effect of sulfonylureas is low blood sugar, especially during the first four months of therapy.


Possible side effects include a metallic taste in your mouth, loss of appetite, nausea or vomiting, abdominal bloating, or pain, gas and diarrhea. Although safe and effective, alpha-glucosidase inhibitors can cause abdominal bloating, gas and diarrhea. The thiazolidinedione troglitzeone (Rezulin) was taken off the market in March 2000 because it caused liver failure.
Newer medications, such as Glucovance, which contains both glyburide and metformin, combine different oral drugs in a single tablet.
Even with appropriate intervention, DKA is associated with significant morbidity and possible mortality in diabetic patients in the pediatric age group [8].
A characteristic elevated J point on the electrocardiogram (ECG) (Osborn wave) may be observed when markedly hypothermia occurs [85-87]. Measurement of serum ?- hydroxybutyrate may be an alternative to determine ketoacidosis [96). Increase in lipase may be related with release of nonpancreatic lipolytic enzymes into the circulation due to malignant tumors, to acute cholecystitis or esophagitis. Insulin autoantibodies [IAAs]) and zinc transporter 8 (Znt8) protein are also associated with type 1 diabetes mellitus.
Some of the glucose can be converted to concentrated energy sources like glycogen or fatty acids and saved for later use.
Others may use an insulin pump, which provides a continuous supply of insulin, eliminating the need for daily shots. You’re at much greater risk of low blood sugar if you have impaired liver or kidney function. These effects usually decrease over time and are less likely to occur if you take the medication with food.
If your doctor prescribes these drugs, it’s important to have your liver checked every two months during the first year of therapy. The thermoregulatory system could be impaired in diabetic patients with autonomic neuropathy and reduced muscle mass or adipose tissue related with malnutrition. Other possible mechanism are; renal insufficiency, delayed blood withdrawal, hypertriglyceridemia or subclinical pancreatitis [130]. Lactic acidosis occasionally contributes to metabolic acidosis in patients hospitalized for either uncomplicated diabetes or DKA [137]. Despite it’s complicated pathophysiology, it is important to understand the destruction of beta cells in type 1 diabetes because it leads to a lack of insulin and amylin.
When there is not enough insulin produced or when the doorway no longer recognizes the insulin key, glucose stays in the blood rather entering the cells.
A rare but serious side effect is lactic acidosis, which results when lactic acid builds up in your body. Contact your doctor immediately if you experience any of the signs and symptoms of liver damage, such as nausea and vomiting, abdominal pain, loss of appetite, dark urine, or yellowing of your skin and the whites of your eyes (jaundice). The triad of uncontrolled hyperglycemia, metabolic acidosis and increased total body ketone concentration characterizes DKA [10]. The anion gap is calculated by subtracting the sum of chloride(Cl) and bicarbonate (HCO3) concentration from the sodium (Na) concentration: [Na - (Cl +HCO3)]. Pancreatic enzyme levels reach a peak 12-24 hours after initiation of treatment for DKA [131]. Without insulin or amylin the body cannot promote glucose disappearance or limit glucose appearance from the bloodstream, respectively, resulting in hyperglycemia (Mapes & Faulds, 2014). These may not always be related to diabetes medications, but your doctor will need to investigate all possible causes. In addition to possible acute complications, it may also influence the later outcome of diabetes [11].2.
It occurs in the setting of decreased tissue oxygen delivery which triggers non-oxidative metabolism of glucose to lactic acid.
Lactic acidosis is especially likely to occur if you mix this medication with alcohol or have impaired kidney function. EpidemiologyWorldwide, an estimated 65 000 children under 15 years old develop T1DM each year, and the global incidence in children continues to increase at a rate of 3% a year [12,13].
Abdominal pain on presentation could be a result of the DKA or an indication of a precipitating cause of DKA, particularly in younger patients or in the absence of severe metabolic acidosis [91,92].
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. Differential diagnosis Other causes of metabolic acidosis and ketosis must be differentiated from DKA. When co-existent with DKA, the anion gap typically exceeds that attributable to lactate alone. 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]. The first case has been reported in 1970, defined as ‘diabetic ketoalkalosis’ [99] and it was followed by other case reports. 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]. For main therapy it should be performed to optimise tissue perfusion and to treat underlying 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.
29 311 new cases of T1DM were diagnosed in children before their 15th birthday during a 15-year period between 1989-2003.
An increased WBC count is response to stress is characteristic of DKA and is not indicative of infection. Recent studies have reported from normal or near normal [101] to elevated [31,3] hepatic glucose production rates. Blood glucose and arterial pH are found to be usually in normal level and the anion gap is at most mildly elevated. If there is evidence of infection, chest X-ray and urine, sputum, throat or blood cultures should also be obtained [93]. This factor possibly contributes to the wide range of plasma glucose levels in DKA that are independent of the severity of ketoacidosis [96].
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 predominant caloric source for days or weeks. Insulin therapy Insulin lowers the serum glucose concentration (by decreasing gluconeogenesis and glycogenolysis, increasing tissue glucose uptake) and arrests ketone production (by reducing lipolysis and glucagon secretion).
If present trends continue, prevalent cases younger than 15 years will rise by 70% in 2020 [15].
The severity of DKA is classified as mild, moderate, or severe based on the severity of metabolic acidosis (blood pH, bicarbonate, and ketones) and the presence of altered mental status as shown in Table 2. Due to nausea or vomiting caused by a precipitating illness or by worsening ketoacidosis itself, a decrease in caloric intake occurs. Patients are usually present in normoglycemic or hypoglycemic state on submission, although some have rarely mild hyperglycemia [136].Toxic ingestions sometimes need to be differentiated and history of the patients with laboratory studies may help for the differantial diagnosis. There was major concern about; physiologic or low dose insulin therapy was superior to pharmacologic dose regimen and the administration of regular insulin via continuous intravenous infusion or by frequent subcutaneous or intramuscular injections [10,157-160]. Approximately 115 000 patients admitted to the hospital because of DKA in one year in USA [17]. If patients continue to take sufficient amounts of insulin in this situation may maintain euglycemia. Salicylate, methanol and ethylene glycol each produce an increased anion gap metabolic acidosis without hyperglycemia or ketosis.
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 a Turkish study conducted among the patients with diabetic adults who admitted to the hospital, the ratio of T1DM was found to be 6.6% and DKA was 38% of the group [18].
But ketone body formation cannot be stopped, so they present as DKA accompanied with only mild elevations of blood glucose or normoglycemia [103-105]. In clinical practice most patients are treated with low dose, intravenous regular insulin until resolution of DKA [30]. 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 circulating fluid volume to maintain glucose excretion [110]. 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].
In women with diabetes, pregnancy 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].
It is characterized by a low serum bicarbonate concentration with subsequent chloride retention. 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. The most occurrence ages of DKA are between the 18-44 years (56%), than 45-65 years (24%) continues with only 18% of patients <20 years of age. But leukocytosis with cell counts 25,000 mm3 may indicate infection and require further evaluation [115].
Carbonic anhydrase inhibitor therapy, rapid dilution of plasma bicarbonate by infused saline may be considered as the other varying reasons [143,144].
If plasma 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. In ketoacidosis, leukocytosis may be correlated to elevated levels of cortisol and norepinephrine which is attributed to stress [116].
DKA can be easily differentiated from this condition by the presence of an increased anion gap and hyperglycemia.
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. 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.
Half of all deaths in diabetic patients younger than 24 years of age are caused from DKA [26,27].
An increased or even normal serum sodium concentration in the presence of hyperglycemia indicates severe degree of free water loss.
TreatmentSuccessful treatment of DKA requires correction of dehydration, hyperglycemia and electrolyte imbalances, identification of comorbid precipitating events and above all, frequent patient monitoring.
Once hyperglycemia is corrected, 12-24 hours of intravenous insulin treatment is sufficient to clear ketones from the circulation [51].Subcutaneous rapid-acting insulin analogs (lispro and aspart) offer an efficacious and cost-effective alternative to continuous intravenous infusions in the treatment of DKA [162-164].
PathogenesisThere are some factors as a reason of acute metabolic complications in diabetic patiens. These factors are insulin deficiency as the initial primary event in progressive beta-cell failure, its failure in a patient with established disease or its ineffectiveness when insulin action is antagonized by physiological stress such as sepsis and in the context of counterregulatory hormone (catecholamines, cortisol, glucagon, and growth hormone) excess. Serum potassium concentration may be increased because of an extracellular shift of potassium caused by insulin deficiency, hypertonicity and acidemia [117]. These hormonal changes increase glucose production from glycogenolysis and gluconeogenesis and impair glucose utilization by peripheral tissues, resulting in hyperglycemia, osmotic diuresis, electrolyte loss, dehydration, decreased glomerular filtration (further compounding hyperglycemia) and hyperosmolarity.
There were no differences in length of hospital stay, total amount of insulin needed for resolution of hyperglycemia or ketoacidosis. Fluid therapy The most important initial therapeutic intervention is fluid replacement followed by insulin administration.
Patients treated with insulin analogs were managed in the open medical wards which reduced cost of hospitalization by 30% [162-164].
This is augmented by transient insulin resistance due to the hormone imbalance itself as well as the elevated free fatty acid concentrations [8,10,26,28-39]. So patients with low normal or low serum potassium concentration should be monitored closely. 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. Uncontrolled hepatic fatty acid oxidation in the liver to ketone bodies (beta-hydroxybutyrate and acetoacetate) results ketonemia and metabolic acidosis [40]. If necessary appropriate potassium replacement should be done [93].Insulin mainly affects glucose metabolism, but also protein and lipid metabolism.
Initial fluid therapy is directed toward expansion of the intravascular, interstitial and intracellular volume (all of which are reduced in hyperglycemic crises), to establish tissue perfusion for insulin to reach cells [148] and restoration of renal perfusion. 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 insulin in the intensive care unit [93].
The pathogenesis causing to hyperglycemia and ketoacidosis are schematized in Figure 1 [30].A number of clinical studies showed that the hyperglycemia in patients with hyperglycemic crises is associated with a severe inflammatory state characterized by an elevation of proinflammatory cytokines tumor necrosis factor alpha (TNF-?) and interleukin-6, and -8 (IL-6,8), C-reactive protein, reactive oxygen species, and lipid peroxidation, as well as cardiovascular risk factors, plasminogen activator inhibitor-1 and free fatty acids in the absence of obvious infection or cardiovascular pathology.


In the literature there are many cases of DKA presented with severe hyperlipidemia [118,119]. 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].
Insulin therapy and hydration recover these parameters to near-normal values within 24 hours [41]. In patients 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, decreased in utilization and excretion which results with hyperlipidemia. Replacement 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 compartments.
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. Recent studies focused on the role of interleukin-1 beta (IL-1?), interleukin-12 (IL-12) and interferon-gamma (IFN-?).
As demonstrated in vitro, these cytokines can directly influence beta cell function and viability [42]. As it is related with increased morbidity and mortality, clinicians must be aware of this complication. PotassiumDespite 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].
Subsequent choice for fluid replacement depends on hemodynamics, the state of hydration, serum electrolyte levels and urinary output.
Insulin therapy, correction of acidosis and volume expansion decrease serum potassium concentration [10].
Therefore, these should be monitored for hyperlipidemia and if there is clinical evidence, for pancreatitis [120-123].
Fluid resuscitation should be individualized according to the patient’s degree of dehydration, mental status and underlying diseases such as congestive heart failure or renal failure [51].
Prior to DKA management the levels of IL- 6, IL-8, IL-10,WBC and cortisol were elevated, but all parameters were reduced within 120 hours after DKA management [43]. Pseudonormoglycemia [124] and pseudohyponatremia [125] may occur in DKA in the presence of severe chylomicronemia.
Glucose, an osmotic diuretic, may produce a high urine output even in severely dehydrated patients.
Figure 1.The pathogenesis causing to hyperglycemia and ketoacidosis in DKA (Data adapted from reference [17])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-? 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]. 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 increased catabolism.
But the potential role of IL-18 in the acute complications of diabetes mellitus such as DKA is controversial.
As a result, urine output should not be considered a reliable predictor of volume status in hyperglycemic states [152]. Bicarbonate therapyThe hepatic metabolism of free fatty acids generates ketoanions, such as beta-hydroxybutyrate 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 production [173]. Acute kidney injury leads to accumulation of other unmeasured anions, such as sulphate, urate and phosphate [174].
All these, together with hyperchloremia which predominates during the recovery phase of DKA [175], contribute to the development of acidemia, which often is severe [176,177].Metabolic acidemia can impair myocardial contractility, reduce cardiac output, affect oxyhemoglobin dissociation and tissue oxygen delivery, inhibit intracellular enzymes, such as phosphofructokinase, alter cellular metabolism, and result in vital organ dysfunction [178-181].
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]. Serum IL-18 levels was significantly higher 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 elevated and correlated with C-peptide levels and ICA in patients with T1DM, with marked increase 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 nonspecific phenomena of stress and may partially explain the association of hyperglycemic crises with a hypercoagulable state [48]. Precipitating factorsA careful search for precipitating factors should be made, as correction of these contributes to improved outcomes and less frequent recurrences.The most common precipitating factor in the development of DKA is infection [37,49,50] including viral syndromes, urinary tract infections, pelvic inflammatory disease, pneumonia, mucormycosis, malignant otitis externa (with pseudomonas aeruginosa), periodontal abscess and dental infection [51]. 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 factor in 20% of recurrent ketoacidosis.
Randomized studies showed that phosphate replacement have no any additional benefit on the clinical outcome [126,183] and in contrast, phosphate replacement may trigger hypocalcemia and hypomagnesemia [183,184].
Hypophosphatemia can cause hemolysis, refractory acidosis, reduced cardiac output, respiratory muscle weakness, rhabdomyolysis, central nervous system depression, seizures, coma or acute renal failure. Additional prospective studies are needed to document reduction of DKA incidence with the use of continuous subcutaneous insulin infusion devices [54]. Drugs that affect carbohydrate metabolism, such as corticosteroids, thiazides, sympathomimetic agents and pentamidine may precipitate the development of DKA [10]. The association between antipsychotic drugs, especially with atypical antipsychotics and hyperglycemia and even DKA have been reported in some cases [55,56]. Transition to subcutaneous insulinWhen 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.
There are reports of hyperglycemia, convulsions and glycosuria in overdosage of nalidixic acid [58-61]. 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. Interferon-alpha (IFN-?), a natural protein with anti-viral, anti-proliferative and immunomodulatory effects is routinely administered in chronic hepatitis C (CHC).
Patients who are inappropriate for oral intake the treatment should be continued with an infusion of intravenous fluids and insulin [10,17,49,93,187].
Classical IFN-? has been correlated with the development of a variety of autoimmune disorders including Hashimoto thyroiditis, immune-mediated thrombocytopenia, hemolytic anemia, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, primary biliary cirrhosis and sarcoidosis. 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. 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 (glargine 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 hypoglycemic events (15%) than the rate in those treated with NPH and regular insulin (41%). High titers of glutamic acid decarboxylase, antinuclear and thyroid (thyroid peroxidase and thyroglobulin) antibodies were detected [65]. Somatostatin therapy in the management of resistant diabetic ketoacidosisAs a inhibiting hormone for counterregulatory hormones, somatostatin may be used in the treatment of DKA. Until 2005, 35 cases of IFN-? related T1DM had been reported in the medical literature [64,66-69]. Somatostatin analogues have been successfully used in the treatment of diabetes associated autonomic neuropathy and they have also been shown to decrease the requirements for insulin [188,189].
DKA was reported in a few classical IFN-? related cases [70-73], in three pegylated IFN-? related cases [65,74,75].
Continuous subcutaneous octreotide infusion suppresses counterregulatory hormones, increases insulin-mediated glucose metabolism by enhancing glucose storage and reduces energy expenditure [189].
The development of DKA and the permanent insulin dependency may be related with a rapidly developing T helper-1-mediated pathogenic mechanism [72]. The incidence of diabetes is less frequent among the patients of nephrotic syndrome in comparison to organ transplant recipients.
Octreotide 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]. Cytomegalovirus infection [78,79], protease inhibitor treatment [80,81] and highly active antiretroviral therapy (via immune restoration) may precipitate DKA in HIV-infected patients [82].5.
In conclusion, for patients who do not respond to conventional DKA treatment, somatostatin could be added to therapy. History and physical examinationThe acute DKA episode in T1DM evoluation should be done rapidly.
MonitoringSuccessful management and early intervention for complications require close monitoring. 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.
The clinicians should be made a flow chart to obtain all relevant incidents regarding the patient’s condition and clinical outcome [192]. 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.
For example, patients with initially low potassium, more frequent (hourly) K measurements should be made with ECG monitoring [194,195] or if patient’s neurological 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]. Close monitoring 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 levels 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 monitor 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]. Complications of diabetic ketoacidosis or it’s treatmentMost of the diabetes-related morbidity and mortality in T1DM can be attributed to complications of DKA.
As ketoacidosis is corrected, a rapid decline in plasma glucose levels can be occur 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. Rhabdomyolysis and renal failureAcute renal failure (ARF) is an uncommon complication of DKA and rarely requires renal replacement therapy and it may be severe and potentially life threatening [196,197]. Prolonged profound ketoacidosis and insulin infusions can lead to severe hypophosphatemia, mainly as a result of intracelluar phosphate shifting [198-201]. Peripheral venous thrombosisIn DKA treatment, patients may require central vascular access for intensive fluid replacement. However, this route of vascular access causes many complications [206] like venous thromboembolism (VTE) [207]. Children with thrombophilia, malignancy, congenital cardiac disease, acute infection, trauma and surgery have a high risk for complications of central venous catheter (CVC) related VTE [206]. In the medical literature there have been few reported cases CVC related VTE in DKA children without known risk factors. Thus, DKA and its treatment may promote a prothrombotic state and activation of vascular endothelium, predisposing to thrombosis.
Whilst, DKA has not been identified as an isolated risk factor for CVC-related VTE in adults [211]. PancreatitisAcute pancreatitis is a well known complication of DKA in adults [212] but is unusual in childhood. Although hypertriglyceridemia is a known cause of acute pancreatitis and elevated triglyceride concentrations are frequent during DKA, an association between elevated triglyceride concentrations in DKA and pancreatic enzyme elevation or pancreatitis have not be showned in the previous studies [213,215].
The mechanism responsible for pancreatic enzyme elevation in DKA has thus remained unclear.



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