On the other hand, an SGLT-2 inhibitor can be also associated with hyperglycemic DKA in individuals who have sufficient glycogen storage to maintain hyperglycemia even in the setting of enhanced glucosuria 49 , The major cause of water deficit in DKA and HHS is glucose-mediated osmotic diuresis, which leads to loss of water in excess of electrolytes Despite the excessive water loss, the admission serum sodium tends to be low.

Because serum glucose in the presence of insulinopenia of DKA and HHS cannot penetrate to cells, in hyperglycemic crises, glucose becomes osmotically effective and causes water shifts from intracellular space to the extra cellular space resulting in dilution of sodium concentration — dilutional or hyperosmolar hyponatremia.

It is, however, accepted now that true or corrected serum sodium concentration in patients experiencing hyperglycemic crisis should be calculated by adding 2. If the corrected sodium level remains low, hypertriglyceridemia secondary to uncontrolled diabetes should be also suspected.

In this condition the plasma becomes milky and lipemia retinalis may be visible in physical examination Osmotic diuresis and ketonuria also promote a total body sodium deficit via urinary losses, although concurrent conditions, such as diarrhea and vomiting, can further contribute to sodium losses.

Total body sodium loss can result in contraction of extracellular fluid volume and signs of intravascular volume depletion. Serum potassium may be elevated on arrival due to insulin deficiency, volume depletion and a shift of potassium from intracellular to extra cellular compartments in response to acidosis However, total body potassium deficit is usually present from urinary potassium losses due to osmotic diuresis and ketone excretion.

More frequently, the initial serum potassium level is normal or low which is a danger sign. Initiation of insulin therapy, which leads to the transfer of potassium into cells, may cause fatal hypokalemia if potassium is not replaced early.

Phosphate depletion in DKA is universal but on admission, like the potassium, it may be low, normal or high The differences and similarities in the admission biochemical data in patients with DKA or HHS are shown in Figure 7.

Biochemical data in patients with HHS and DKA 1. The exact etiology of this non-specific leukocytosis is not known. One study also showed nonspecific leukocytosis in subjects with hypoglycemia induced by insulin injection and suggested that this phenomenon may be due to the increased levels of catecholamines, cortisol, and proinflammatory cytokines such as TNF-α during acute stress Hypertriglyceridemia may be present in HHS and is almost always seen in DKA The origin of amylase in DKA is usually non-pancreatic tissue such as the parotid gland False positive values for lipase may be seen if plasma glycerol levels are very high due to rapid breakdown of adipose tissue triglycerides glycerol is the product measured in most assays for plasma lipase.

Therefore, elevated pancreatic enzymes may not be reliable for the diagnosis of pancreatitis in the DKA setting. Other pitfalls include artificial elevation of serum creatinine due to interference from ketone bodies when a colorimetric method is used Most of the laboratory tests for ketone bodies use the nitroprusside method, which detects acetoacetate, but not β-hydroxybutyrate β-OHB.

Additionally, since β-OHB is converted to acetoacetate during treatment , the serum ketone test may remain positive for a prolonged period suggesting erroneously that ketonemia is deteriorating; therefore, the follow up measurement of ketones during the treatment by nitroprusside method is not recommended Newer glucose meters have the capability to measure β-OHB, which overcomes this problem , Furthermore drugs that have sulfhydryl groups can interact with the reagent in the nitroprusside reaction, giving a false positive result Particularly important in this regard is captopril, an angiotensin converting enzyme inhibitor prescribed for the treatment of hypertension and diabetic nephropathy.

Therefore, for the diagnosis of DKA, clinical judgment and consideration of other biochemical data are required to interpret the value of positive nitroprusside reactions in patients on captopril. Most laboratories can now measure β-OHB levels. The classical presentation of acid-base disorders in DKA consists of increased anion gap metabolic acidosis where the relation of plasma anion gap change and bicarbonate change Δ-Δ, ratio of AG change over change in bicarbonate equals to 1 due to parallel reduction in plasma bicarbonate with the addition of ketoacids into the extravascular fluid space.

With frequent additional bicarbonate losses in urine in the form of ketoanions during DKA, the initiation of intravenous volume resuscitation with chloride-containing solutions can further lower plasma bicarbonate and unmask non-anion gap metabolic acidosis when Δ-Δ becomes less than 1 due to changes in plasma bicarbonate that exceed the expected changes in AG.

Respiratory compensation will accompany metabolic acidosis with reduction in PCO 2 in arterial blood gas. Therefore, inappropriately high or low levels of PCO 2 , determined by ABG will suggest the presence of a mixed acid-based disorder. For example, DKA patients with concomitant fever or sepsis may have additional respiratory alkalosis manifesting by lower-than-expected PCO 2.

In contrast, a higher than calculated PCO 2 level signifies additional respiratory acidosis and can be seen in patients with underlying chronic lung disease.

Vomiting is a common clinical manifestation in DKA and leads to a loss of hydrogen ions in gastric content and the development of metabolic alkalosis. Patients with DKA and vomiting may have relatively normal plasma bicarbonate levels and close to normal pH. However, AG will remain elevated and be an important clue for DKA.

In addition, Δ-Δ ratio will be over 2 suggesting that there is less than expected reduction in bicarbonate as compared with increase in AG and confirm the presence of a mixed acid-base disorder combination of metabolic acidosis and metabolic alkalosis.

We recommend measurement of β-OHB in instances when a mixed acid-base disorder is present in patients with hyperglycemic crisis and DKA is suspected. Patients may present with metabolic conditions resembling DKA or HHS.

For example, in alcoholic ketoacidosis AKA , total ketone bodies are much greater than in DKA with a higher β-OHB to acetoacetate ratio of versus a ratio of in DKA 8.

The AKA patients seldom present with hyperglycemia It is also possible that patients with a low food intake may present with mild ketoacidosis starvation ketosis ; however, serum bicarbonate concentration of less than 18 or hyperglycemia will be rarely present. Additionally, DKA has to be distinguished from other causes of high anion gap metabolic acidosis including lactic acidosis, advanced chronic renal failure, as well as ingestion of drugs such as salicylate, methanol, and ethylene glycol.

Isopropyl alcohol, which is commonly available as rubbing alcohol, can cause considerable ketosis and high serum osmolar gap without metabolic acidosis. Moreover, there is a tendency to hypoglycemia rather than hyperglycemia with isopropyl alcohol injection , Finally, patients with diabetes insipidus presenting with severe polyuria and dehydration, who are subsequently treated with free water in a form of intravenous dextrose water, can have hyperglycemia- a clinical picture that can be confused with HHS Figure 8.

Laboratory evaluation of metabolic causes of acidosis and coma The goals of therapy in patients with hyperglycemic crises include: 1 improvement of circulatory volume and tissue perfusion, 2 gradual reduction of serum glucose and osmolality, 3 correction of electrolyte imbalance, and 4 identification and prompt treatment of co-morbid precipitating causes 8.

It must be emphasized that successful treatment of DKA and HHS requires frequent monitoring of patients regarding the above goals by clinical and laboratory parameters. Suggested approaches for the management of patients with DKA and HHS are illustrated in Figures 9 and DKA and HHS are volume-depleted states with total body water deficit of approximately 6 L in DKA and 9 L in HHS 16 , , Therefore, the initial fluid therapy is directed toward expansion of intravascular volume and securing adequate urine flow.

The choice of fluid for further repletion depends on the hydration status, serum electrolyte levels, and urinary output. In patients who are hypernatremic or eunatremic, 0. The goal is to replace half of the estimated water and sodium deficit over a period of hours [ ].

In patients with hypotension, aggressive fluid therapy with isotonic saline should continue until blood pressure is stabilized. The administration of insulin without fluid replacement in such patients may further aggravate hypotension Furthermore, the use of hydrating fluid in the first hour of therapy before insulin administration provides time to obtain serum potassium value before insulin administration, prevents possible deterioration of hypotensive patients with the use of insulin without adequate hydration, and decreases serum osmolality Hydration alone may also reduce the level of counter-regulatory hormones and hyperglycemia Intravascular volume expansion reduces serum blood glucose, BUN, and potassium levels without significant changes in pH or HCO 3.

The mechanism for lowering glucose is believed to be due to osmotic diuresis and modulation of counter-regulatory hormone release 23 , We recommend avoiding too rapid correction of hyperglycemia which may be associated with cerebral edema especially in children and also inhibiting hypoglycemia 23 , It should be emphasized that urinary losses of water and electrolytes are also need to be considered.

The cornerstone of DKA and HHS therapy is insulin in physiologic doses. In DKA, we recommend using intravenous IV bolus of regular insulin 0. The insulin infusion rate in HHS should be lower as major pathophysiological process in these patients is severe dehydration.

If desirable glucose reduction is not achieved in the first hour, an additional insulin bolus at 0. A study that investigated the optimum route of insulin therapy in DKA demonstrated that the time for resolution of DKA was identical in patients who received regular insulin via intravenous, intramuscular, or subcutaneous routes However, patients who received intravenous insulin showed a more rapid decline in blood glucose and ketone bodies in the first 2 hours of treatment.

Patients who received intravenous insulin attained an immediate pharmacologic level of insulin concentration. Thus, it was established that an intravenous loading dose of insulin would be beneficial regardless of the subsequent route of insulin administration during treatment.

A follow up study demonstrated that a priming or loading dose given as one half by IV route and another half by intramuscular route was as effective as one dose given intravenously in lowering the level of ketone bodies in the first hour A bolus or priming dose of insulin has been used in a number of studies.

The need of such a method, when using intravenous infusion of insulin, is not clear, as there is no prospective randomized study to establish efficacy of bolus or priming dose before infusion of insulin.

However, our study in children demonstrated the effectiveness of intravenous injection of insulin without a bolus dose Therefore, it would appear that if intravenous insulin is used, priming or bolus dose insulin might not be necessary.

Several clinical studies have shown the potency and cost effectiveness of subcutaneous rapid-acting insulin analogs lispro or aspart in the management of patients with uncomplicated mild to moderate DKA , The patients received subcutaneous rapid-acting insulin doses of 0.

Then the insulin dose was decreased by half to 0. There were no differences in length of hospital stay, total amount of insulin needed for resolution of hyperglycemia or ketoacidosis, or in the incidence of hypoglycemia among treatment groups.

Similar results have been reported recently in pediatric patients with DKA The administration of continuous IV infusion of regular insulin is the preferred route because of its short half-life and easy titration and the delayed onset of action and prolonged half-life of subcutaneous regular insulin.

It is important to point out that the IV use of fast-acting insulin analogs is not recommended for patients with severe DKA or HHS, as there are no studies to support their use. Again, these agents may not be effective in patients with severe fluid depletion since they are given subcutaneously.

Although total-body potassium is depleted , , mild to moderate hyperkalemia frequently seen in patients with DKA is due to acidosis and insulinopenia. Insulin therapy, correction of acidosis, and volume expansion decrease serum potassium concentrations.

To prevent hypokalemia, potassium replacement is initiated after serum levels fall below 5. Patients with DKA who had severe vomiting or had been on diuretics may present with significant hypokalemia. Protocol for the management of adult patients with DKA. Adapted from The use of bicarbonate in treatment of DKA remains controversial.

Bicarbonate therapy has been associated with some adverse effects, such as hypokalemia , decreased tissue oxygen uptake and cerebral edema , and delay in the resolution of ketosis A prospective randomized study in patients with pH between 6.

Therefore, in patients with pH between 6. Venous pH should be assessed every 2 hours until the pH rises to 7. There is no evidence that phosphate therapy is necessary in treatment for better outcome of DKA However, in patients with potential complications of hypophosphatemia, including cardiac and skeletal muscle weakness, the use of phosphate may be considered Phosphate administration may result in hypocalcemia when used in high dose , Severe hyperosmolarity and dehydration associated with insulin resistance and presence of detectable plasma insulin level are the hallmarks of HHS pathophysiology.

The main emphasis in the management of HHS is effective volume repletion and normalization of serum osmolality There are no randomized controlled studies that evaluated safe and effective strategies in the treatment of HHS It is important to start HHS therapy with the infusion of normal saline and monitor corrected serum sodium in order to determine appropriate timing of the change to hypotonic fluids.

Insulin substitution approach should be very conservative as it is expected that insulin resistance will improve with rehydration.

We recommend against rapid decreases in serum glucose and correction of serum sodium in order to avoid untoward effects of shifts in osmolarity on brain volume.

This notion should particularly apply in the management of HHS in elderly and patients with multiple medical problems in whom it may not be clear how long these subjects experienced severe hyperglycemia prior to the admission to the hospital.

During follow up, blood should be drawn every h for determination of serum electrolytes, glucose, blood urea nitrogen, creatinine, osmolality, and venous pH. An equivalent arterial pH value is calculated by adding 0. The latter may take twice as long as to achieve blood glucose control.

Ketonemia typically takes longer to clear than hyperglycemia. Therefore, the treatment goal of DKA is to improve hyperglycemia and to stop ketosis with subsequent resolution of acidosis. In this regard, it is important to distinguish ketosis and acidosis, as the two terms are not always synonymous in DKA.

Ketoacid production in DKA results in reduction in plasma bicarbonate HCO 3 - levels due to neutralization of hydrogen ion produced during dissociation of ketoacids in the extravascular fluid space.

Concomitantly, ketoacid anion is added into extravascular space resulting in anion gap AG increase. Therefore, the ratio of AG excess to HCO 3 - deficit delta-delta, or Δ-Δ is close to 1 , , In most patients with DKA bicarbonate deficit exceeds the addition of ketoanions, even though Δ-Δ ratio remains close to 1 This is observed due to several reasons.

First, hyperglycemia-induced osmotic diuresis leads to excretion of large amounts of sodium and potassium ions that is accompanied by the excretion of ketoanions. Ultimately, the amount of excreted ketoanions depends on degree of kidney function preservation with the largest amount of ketoanion loss in patients with relatively preserved glomerular filtration rate Each ketoanion can be converted back to HCO 3 - during resolution of DKA and, therefore, ketoanion loss results in the loss of HCO 3 -.

Additionally, extravascular fluid space contraction during DKA, leads to elevation of plasma HCO 3 -. Therefore, intravenous administration of sodium and chloride-containing fluids leads to further HCO 3 - reduction and hyperchloremic metabolic acidosis , This is an important point as persistent decrease in plasma HCO 3 - concentration should not be interpreted as a sign of continuous DKA if ketosis and hyperglycemia are resolving.

Although not evaluated in prospective studies, measurement of serial levels of blood beta-hydroxybutyrate β-OHB can be useful adjunct to monitor the resolution of DKA Intravenous insulin infusion should be continued for 2 hours after giving the subcutaneous insulin to maintain adequate plasma insulin levels.

Immediate discontinuation of intravenous insulin may lead to hyperglycemia or recurrence of ketoacidosis. If the patient is unable to eat, it is preferable to continue the intravenous insulin infusion and fluid replacement. Patients with known diabetes may be given insulin at the dose they were receiving before the onset of hyperglycemic crises.

In patients with new onset diabetes, a multi-dose insulin regimen should be started at a dose of 0. The most common complications of DKA and HHS include hypoglycemia and hypokalemia due to overzealous treatment with insulin and bicarbonate hypokalemia , but these complications occur infrequently with current low dose insulin regimens.

During the recovery phase of DKA, patients commonly develop a short-lived hyperchloremic non-anion gap acidosis, which usually has few clinical consequences Hyperchloremic acidosis is caused by the loss of large amounts of ketoanions, which are usually metabolized to bicarbonate during the evolution of DKA, and excess infusion of chloride containing fluids during treatment Cerebral edema, a frequently fatal complication of DKA, occurs in 0.

It may also occur in patients with known diabetes and in very young adults usually under 20 years of age , Cerebral edema has also been reported in patients with HHS, with some cases of mortality Clinically, cerebral edema is characterized by deterioration in the level of consciousness, lethargy, decreased arousal, and headache.

Headache is the earliest clinical manifestation of cerebral edema. This is followed by altered level of consciousness and lethargy. Neurological deterioration may lead to seizures, incontinence, pupillary changes, bradycardia, and respiratory arrest.

It may be so rapid in onset due to brain stem herniation that no papilledema is found. Mannitol infusion and mechanical ventilation are used to combat cerebral edema.

The cause of cerebral edema is not known with certainty. It may result from osmotically driven movement of water into the central nervous system when plasma osmolality declines too rapidly during treatment of DKA or HHS.

As glucose concentration improves following insulin infusion and administration of the intravenous fluids, serum osmotic gradient previously contributed by hyperglycemia reduces which limits water shifts from the intracellular compartment.

In cases when the serum glucose concentration improves to a greater extent than the serum sodium concentration rises, serum effective osmolality will decrease and may precipitate brain edema , Although the osmotically mediated mechanism seems most plausible, one study using magnetic resonance imaging MRI showed that cerebral edema was due to increased cerebral perfusion β-hydroxybutyrate and acetoacetate may also play a role in the pathogenesis of cerebral edema.

These ketone bodies have been shown to affect vascular integrity and permeability, leading to edema formation In summary, reasonable precautionary measures to decrease the risk of cerebral edema in high-risk patients include 1 avoidance of overenthusiastic hydration and rapid reduction of plasma osmolality and 2 close hemodynamic monitoring Based on the recent reports, particular care should be offered to patients with end stage renal disease as these individuals are more likely to die, to have higher rates of hypoglycemia, or to be volume overloaded when admitted to the hospital with DKA Hypoxemia and rarely non-cardiogenic pulmonary edema may complicate the treatment of DKA [ ].

Hypoxemia may be related to the reduction in colloid osmotic pressure that leads to accumulation of water in lungs and decreased lung compliance.

The pathogenesis of pulmonary edema may be similar to that of cerebral edema suggesting that the sequestration of fluid in the tissues may be more widespread than is thought. Thrombotic conditions and disseminated intravascular coagulation may contribute to the morbidity and mortality of hyperglycemic emergencies Prophylactic use of heparin, if there is no gastrointestinal hemorrhage, should be considered.

About one in five patients with T1D admitted for DKA will be readmitted for DKA within 30 days Several studies suggested that the omission of insulin is one of the most common precipitating factors of DKA, sometimes because patients are socio-economically underprivileged, and may not have access to or afford medical care In addition, they may have a propensity to use illicit drugs such as cocaine, which has been associated with recurrent DKA 58 , or live in areas with higher food deprivation risk Therefore, it is important to continuously re-assess socio-economic status of patients who had at least one episode of DKA.

The most recent data demonstrating a significant increase in DKA hospitalization rates in diabetic persons aged 45 years and younger 10 suggests that this group of patients may require particular attention to understand why they are more vulnerable than others to develop hyperglycemic crisis.

Education of the patient about sick day management is very vital to prevent DKA, and should include information on when to contact the health care provider, blood glucose goals, use of insulin, and initiation of appropriate nutrition during illness and should be reviewed with patients periodically.

Patients must be advised to continue insulin and to seek professional advice early in the course of the illness. Close follow up is very important, as it has been shown that three-monthly visits to the endocrine clinic will reduce the number of ER admission for DKA Close observation, early detection of symptoms and appropriate medical care would be helpful in preventing HHS in the elderly.

A study in adolescents with T1D suggests that some of the risk factors for DKA include higher HbA1c, uninsured children, and psychological problems In other studies, education of primary care providers and school personnel in identifying the signs and symptoms of DKA has been shown to be effective in decreasing the incidence of DKA at the onset of diabetes In another study outcome data of patients with diabetes under continuing care over a 7-year period were examined.

There is early evidence that use of continuous glucose monitoring CGM can decrease DKA incidence , Contrary to the initial observations connecting DKA episodes with insulin pump malfunction, the newer pumps are associated with reduced DKA risk without or with concomitant CGM application in T1D youth Considering DKA and HHS as potentially fatal and economically burdensome complications of diabetes, every effort for diminishing the possible risk factors is worthwhile.

SGLT-2 inhibitor-induced DKA in patients with T2D is a potentially avoidable condition in light of accumulating knowledge of potential triggers prompting the development of this hyperglycemic emergency A recent international consensus statement on the DKA risk management in patients with T1D treated with SGLT-2 inhibitors 76 can be effectively applied to the care of patients with T2D as well.

The DEEARAILS pneumonic can help recalling these clinical situations. Precipitating factors for DKA in patients taking SGLT2 inhibitors. This electronic version has been made freely available under a Creative Commons CC-BY-NC-ND license.

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Show details Feingold KR, Anawalt B, Blackman MR, et al. Contents www. Search term. Hyperglycemic Crises: Diabetic Ketoacidosis and Hyperglycemic Hyperosmolar State Aidar R Gosmanov , M.

Author Information and Affiliations Aidar R Gosmanov , M. Professor of Medicine, Division of Endocrinology, Department of Medicine, Albany Medical College, Albany, NY and Endocrinology Section, Stratton VAMC, Albany, NY.

Email: moc. liamg vonamsoga. Elvira O. Abbas E. Professor of Medicine and Molecular Sciences Emeritus, Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Tennessee Health Science Center, Memphis, TN. ABSTRACT Diabetic ketoacidosis DKA and hyperglycemic hyperosmolar state HHS are acute metabolic complications of diabetes mellitus that can occur in patients with both type 1 and 2 diabetes mellitus.

Diabetic Ketoacidosis In DKA, there is a severe alteration of carbohydrate, protein, and lipid metabolism 8. CLINICAL FEATURES Symptoms and Signs DKA usually evolves rapidly within a few hours of the precipitating event s.

Pitfalls of Laboratory Tests and Diagnostic Considerations for Interpreting Acid Based Status in DKA False positive values for lipase may be seen if plasma glycerol levels are very high due to rapid breakdown of adipose tissue triglycerides glycerol is the product measured in most assays for plasma lipase.

TREATMENT OF DKA The goals of therapy in patients with hyperglycemic crises include: 1 improvement of circulatory volume and tissue perfusion, 2 gradual reduction of serum glucose and osmolality, 3 correction of electrolyte imbalance, and 4 identification and prompt treatment of co-morbid precipitating causes 8.

Fluid Therapy DKA and HHS are volume-depleted states with total body water deficit of approximately 6 L in DKA and 9 L in HHS 16 , , Insulin Therapy The cornerstone of DKA and HHS therapy is insulin in physiologic doses. Potassium Therapy Although total-body potassium is depleted , , mild to moderate hyperkalemia frequently seen in patients with DKA is due to acidosis and insulinopenia.

Bicarbonate Therapy The use of bicarbonate in treatment of DKA remains controversial. Phosphate Therapy There is no evidence that phosphate therapy is necessary in treatment for better outcome of DKA Kitabchi AE, Umpierrez GE, Miles JM, Fisher JN.

Hyperglycemic crises in adult patients with diabetes. Diabetes care. Johnson DD, Palumbo PJ, Chu CP. Diabetic ketoacidosis in a community-based population. Mayo Clin Proc. Ramphul K, Joynauth J. An Update on the Incidence and Burden of Diabetic Ketoacidosis in the U.

accessed Benoit SR, Zhang Y, Geiss LS, Gregg EW, Albright A. Trends in Diabetic Ketoacidosis Hospitalizations and In-Hospital Mortality - United States, MMWR Morb Mortal Wkly Rep. Zhong VW, Juhaeri J, Mayer-Davis EJ. Trends in Hospital Admission for Diabetic Ketoacidosis in Adults With Type 1 and Type 2 Diabetes in England, A Retrospective Cohort Study.

Thomas M, Harjutsalo V, Feodoroff M, Forsblom C, Gordin D, Groop PH. The Long-Term Incidence of Hospitalization for Ketoacidosis in Adults with Established T1D-A Prospective Cohort Study. J Clin Endocrinol Metab. Kitabchi AE, Umpierrez GE, Murphy MB, Barrett EJ, Kreisberg RA, Malone JI, Wall BM.

Management of hyperglycemic crises in patients with diabetes. Matz R. Management of the hyperosmolar hyperglycemic syndrome. Am Fam Physician. pdf accessed Javor KA, Kotsanos JG, McDonald RC, Baron AD, Kesterson JG, Tierney WM.

Diabetic ketoacidosis charges relative to medical charges of adult patients with type I diabetes. Desai D, Mehta D, Mathias P, Menon G, Schubart UK. Health Care Utilization and Burden of Diabetic Ketoacidosis in the U.

Over the Past Decade: A Nationwide Analysis. Fernando SM, Bagshaw SM, Rochwerg B, McIsaac DI, Thavorn K, Forster AJ, Tran A, Reardon PM, Rosenberg E, Tanuseputro P, Kyeremanteng K.

Comparison of outcomes and costs between adult diabetic ketoacidosis patients admitted to the ICU and step-down unit. Journal of critical care. Karslioglu French E, Donihi AC, Korytkowski MT. Diabetic ketoacidosis and hyperosmolar hyperglycemic syndrome: review of acute decompensated diabetes in adult patients.

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Department of Health and Human Services; Kitabchi AE, Nyenwe EA. Hyperglycemic crises in diabetes mellitus: diabetic ketoacidosis and hyperglycemic hyperosmolar state. Endocrinol Metab Clin North Am. Kitabchi AE, Umpierrez GE, Murphy MB, Kreisberg RA.

Hyperglycemic crises in adult patients with diabetes: a consensus statement from the American Diabetes Association. Pasquel FJ, Tsegka K, Wang H, Cardona S, Galindo RJ, Fayfman M, Davis G, Vellanki P, Migdal A, Gujral U, Narayan KMV, Umpierrez GE.

Clinical Outcomes in Patients With Isolated or Combined Diabetic Ketoacidosis and Hyperosmolar Hyperglycemic State: A Retrospective, Hospital-Based Cohort Study.

Kitabchi AE, Wall BM. Diabetic ketoacidosis. Med Clin North Am. Chupin M, Charbonnel B, Chupin F. C-peptide blood levels in keto-acidosis and in hyperosmolar non-ketotic diabetic coma.

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The efficacy of low-dose versus conventional therapy of insulin for treatment of diabetic ketoacidosis. We concluded because of that observation there is reason for caution in the use of phosphate salts in the treatment of DKA, but there are circumstances, as in patients with congestive heart failure, anemia or other conditions associated with hypoxia, when such therapy might be especially indicated.

In protocol VII we addressed the impact of bicarbonate treatment in patients with DKA. This issue had been a contentious subject due to the conflicting results from a small number of clinical trials Proponents of bicarbonate therapy point to the potential deleterious effects of acidosis on cardiac hemodynamics.

Opponents of bicarbonate therapy have been concerned with possible paradoxical cerebrospinal fluid CSF acidosis and a shift in the oxyhemoglobin curve back to the left, resulting in tissue hypoxia.

We randomly assigned patients with moderate to severe DKA pH 6. Lumbar puncture was performed at baseline, 6—8 h, and 12—24 h during therapy with analysis of the CSF for glucose, bicarbonate, pH, total ketone, and osmolality.

There were no significant differences in the rate of glucose or ketone body decline or the rate of increase in pH or bicarbonate between the experimental or control groups. Interestingly, for those patients who had simultaneous measurements of plasma and CSF at baseline, glucose and ketone body levels were significantly lower in the CSF, whereas pH and bicarbonate were significantly higher.

We concluded that bicarbonate therapy did not alter recovery outcomes in adults with moderate DKA pH 6. During the s it was suggested that there was a strong interrelationship among abnormal lipid metabolism, atherosclerosis, and diabetes With the availability of patients in a severe insulin-deficient state such as DKA, we were interested to know whether high triglycerides, cholesterol, and high-density lipoprotein could be reduced by low-dose insulin therapy.

Our results provided evidence that insulin can actively decrease triglycerides but not cholesterol. However, the lowering of apolipoprotein A-1 by low-dose insulin that occurred may be due to decreased secretion of apolipoprotein A-1 into plasma or increased metabolism More than half of newly diagnosed African-Americans with unprovoked DKA are obese.

The majority of such patients display clinical and metabolic features of type 2 diabetes, including a high rate of obesity, a strong family history of diabetes, a measurable pancreatic insulin reserve 29 — 33 , and the ability to discontinue insulin therapy and go through a period of near-normoglycemic remission that may last for a few months to several years This clinical presentation has been reported primarily in Africans and African-Americans but also in other minority ethnic groups This variant of type 2 diabetes has been referred to in the literature as idiopathic type 1 diabetes, atypical diabetes mellitus, type 1.

Our studies indicate that at presentation, patients with ketosis-prone type 2 diabetes have markedly decreased pancreatic insulin secretion, which is lower than in obese patients with comparable hyperglycemia but significantly greater reserve than in lean type 1 diabetic patients with DKA The underlying mechanisms for β-cell dysfunction in ketosis-prone diabetes are not known; however, preliminary evidence suggests that patients with ketosis-prone type 2 diabetes display a unique propensity to glucose toxicity Several investigators have consistently reported that subjects with ketosis-prone type 2 diabetes have a nonautoimmune type of diabetes.

Studies in humans and animal models have shown that muscle and adipocyte tissues exposed to sustained hyperglycemia have reduced insulin binding to its receptor, receptor phosphorylation, and tyrosine kinase activity and phosphorylation of insulin receptor substrate These postreceptor defects result in decreased insulin receptor substrateassociated phosphatidylinositol 3-kinase activity and insulin resistance.

To investigate the molecular mechanisms underlying hyperglycemia-induced insulin resistance in skeletal muscle on obese patients with ketosis-prone diabetes, we recently performed muscle biopsies 1 d after follow-up and during near-normoglycemic remission at 8 wk of follow-up We observed that overt hyperglycemia is associated with decreased stimulation of Akt Ser phosphorylation by a physiological concentration of insulin without changes in AktThr phosphorylation.

These results indicate that in ketosis-prone diabetes, improvement of metabolic control with insulin therapy is accompanied by increased expression of key elements of the insulin-regulated signaling cascade in skeletal muscle The availability of a large number of obese and lean DKA patients also provided us the opportunity to evaluate the controversial issues regarding the stimulating effect of insulin on leptin during hyperglycemia 40 , We investigated the effect of low-dose insulin therapy in a group of obese and lean DKA patients.

These studies demonstrated that baseline values of leptin in DKA were low, but low-dose insulin could significantly stimulate serum leptin levels within 12 h. This effect could be seen as early as 4 h after injection of insulin in obese DKA patients The presence of high levels of epinephrine and cortisol, which have negative and positive effect on leptin secretion, respectively 43 , 44 , suggested that the role of insulin as an anabolic hormone along with the role of elevated cortisol played important roles in the overall stimulating effect of insulin on leptin Recently the concept of a chronic inflammatory state in diabetes as part of insulin resistance has received considerable attention 45 , Having a large group of obese and thin DKA patients and obese nonketotic hyperglycemic subjects in whom no evidence of infection or a history of cardiovascular event was noted, we assessed the status of proinflammatory cytokines TNFα, ILβ 1 , IL-6, IL-8 ; various cardiovascular risk factors homocysteine, plasminogen activator inhibitor-1, C-reactive protein, free fatty acids ; levels of lipid peroxidation by measuring thiobarbituric acid TBA -reacting material; the state of reactive oxygen species ROS , measured by dichlorofluorescein DCF ; and counterregulatory hormones cortisol, GH These studies demonstrated that levels of these parameters were increased by at least 2- to 3-fold over normal levels.

Interestingly, however, in DKA patients all these values reached near normal levels except for homocysteine with insulin therapy and resolution of glycemic crises within 24 h see Table 3. Proinflammatory cytokines, cardiovascular risk factors, counterregulatory hormones, lipid peroxidation TBA , and DCF values on admission and resolution of hyperglycemic crises in lean and obese DKA and obese hyperglycemic patients, compared with lean and obese nondiabetic subjects Data are mean ± se.

Resol, resolution; PAI-1, plasminogen activator inhibitor-1; FFA, free fatty acid; CRP, C-reactive protein. To determine whether hyperglycemia or hyperlipidemia could in fact bring about stimulation of cytokines, ROS, and lipid peroxidation, we chose human T lymphocytes T cells 48 or human aortic endothelial cells 49 and incubated them either in the presence of high glucose or high lipid 50 , measuring activation of these cells by assessing lipid peroxidation, ROS, growth factor receptor emergence such as insulin, IL-2 and IGF-I, or elevated proinflammatory cytokines.

The results suggested that high concentrations of glucose 15—30 but not 5 m m and palmitate but not unsaturated fatty acids stimulate production of ROS, lipid peroxidation, and cytokine elevation and convert these insulin nonresponsive cells to insulin-responsive cells.

We were also able to demonstrate in vivo activation of T cells in DKA with production of ROS, lipid peroxidation, and cytokine stimulation Further studies are in progress to assess the mechanism of these phenomena using other models of stress besides hyperglycemia and hyperlipidemia.

We had earlier noted that use of illicit drugs may be a contributing factor in DKA presentation In a recent retrospective study in a large metropolitan university-affiliated hospital, we were able to demonstrate that the use of cocaine was also a significant independent risk factor for recurrent DKA In June , the first of two rapid-acting analogs of human insulin lispro or Humalog became commercially available.

We asked whether this new formulation could be used as an alternative route to the use of iv regular insulin in patients with DKA. In a prospective and randomized study, we compared the efficacy and safety of sc insulin lispro every hour with that of a standard low-dose iv infusion protocol of regular insulin in adult patients with DKA Patients treated with sc lispro were treated in the emergency department or regular medicine wards and because of hospital regulations iv-treated patients were managed in the intensive care units.

Patients treated with sc lispro received an initial injection of 0. Patients treated with iv regular insulin received an initial sc bolus of 0. Treatment with sc insulin injections on an hourly schedule, however, may be difficult due to the intensity of treatment and shortage of nursing staff on regular wards.

To facilitate the management of patients with DKA, we studied whether treatment with sc rapid-acting insulin analogs, given at different time intervals 1 and 2 h , is equally effective as the use of iv regular insulin in patients with DKA. A total of 45 consecutive patients admitted with DKA were randomly assigned to receive sc aspart Novolog, Novo-Nondisk, Bagsvaerd, Denmark every hour or every 2 h or iv infusion of regular insulin.

Patients treated with aspart sc every hour received an initial injection of 0. Those treated with sc aspart every 2 h received an initial injection of 0. Patients treated with iv regular insulin received an initial bolus of 0. Response to medical therapy was evaluated by assessing the duration of treatment until resolution of hyperglycemia and ketoacidosis.

Similar to our experience with lispro, we observed no mortality, and there were no differences in the length of hospital stay, total amount of insulin administration until resolution of hyperglycemia or ketoacidosis, or the number of hypoglycemic events among treatment groups Table 4 summarizes results of hourly sc injection of lispro vs.

two hourly sc injection of aspart, compared with continuous infusion of regular insulin given iv, showing no significant difference among the three regimens.

Based on these studies, we concluded that the use of sc rapid-acting insulin analogs every 1 or 2 h represents a safe and effective alternative to the use of iv regular insulin in the management of patients with uncomplicated DKA.

Comparative effects of sc fast-acting insulin vs. iv regular insulin in DKA. Data are means ± se. Data adapted from elsewhere 53 , NS, Not significant; BG, blood glucose. Treated in intensivie care units: insulin dose 0. These findings are discussed in the American Diabetes Association ADA in-depth technical review on DKA and hyperglycemic hyperosmolar state HHS , which was completed in 55 , as well as in the ADA position paper on therapy for hyperglycemic crises This document was recently revised in 57 and updated later 58 , 59 Fig.

Protocol for management of adult patients with DKA or HHS modified from Ref. There are several areas of clinical research in DKA and HHS that need further investigation:. The use of bicarbonate in DKA.

Available studies suggest that for pH greater than 7. Studies for pH of 6. Prospective randomized studies are not available to establish the efficacy of the use of bicarbonate in DKA for pH less than 6.

Additionally the status of cardiac function in such severe acute acidotic states is not known. Priming dose of insulin. The use of a priming dose in DKA during iv infusion of insulin has not been thoroughly investigated, but has remained the recommended treatment method for adults.

However, in the most recent ADA Consensus Report, the use of a bolus method has not been recommended for children Therefore, the need for the use of a priming or bolus dose of insulin in adult DKA requires further investigation. The mechanism for lack of ketosis in HHS.

Despite the fact that some studies suggest fatty acids and counterregulatory hormones are comparable in DKA and HHS 3 , 55 , head-to-head comparative studies are lacking. Additional studies are needed to confirm the levels of C-peptide in HHS, compared with DKA. The mechanism of production of elevated proinflammatory cytokines as well as cardiac risk factors in patients with hyperglycemic crises who demonstrate no cardiac history, infection, or injury is not known.

Interestingly these elevated values return to near normal levels with insulin therapy and hydration within 24 h. This nonspecific effect of stress requires further investigation. The sc use of regular insulin in DKA.

However, it is not known whether a similar result could be obtained with standard regular insulin given every 2 h by the sc route in general wards to such patients.

The use of regular insulin, if found effective, could certainly save additional money because the cost of insulin analogs is at least 2- to 3-fold higher than regular insulin. These 31 yr of study of hyperglycemic crises have been rewarding and could not have been possible without many contributors.

Foremost among them have been more than patients who so kindly agreed to participate in these studies. Other support was also provided by the Regional Medical Center in Memphis and Grady Memorial Hospital in Atlanta. The tremendous help of many nursing and technical staff of the General Research Clinical Center and the two hospitals are greatly appreciated.

Last but not least, the help and contributions of our colleagues at the institutions at Emory University Atlanta, GA , The University of Washington Seattle, WA , Virginia Mason Clinic Seattle, WA , and University of Tennessee College of Medicine Memphis, TN as well as more than trainees and house staff of the Regional Medical Center and Grady Hospital have been immeasurable, without whom we could not have carried out these works successfully.

Secretarial assistance by Ms. Brenda Scott is greatly appreciated. This work was supported by the U. The work was also supported in part by the American Diabetes Association, Eli Lilly, Novo Nordisk, and the Abe Goodman Fund for Diabetes Research.

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In: Katzen HM, Mahler RI, eds. You can often lower your blood glucose level by exercising. If you have ketones, do not exercise.

Exercising when ketones are present may make your blood glucose level go even higher. You'll need to work with your doctor to find the safest way for you to lower your blood glucose level. Cutting down on the amount of food you eat might also help.

Work with your dietitian to make changes in your meal plan. If exercise and changes in your diet don't work, your doctor may change the amount of your medication or insulin or possibly the timing of when you take it.

Hyperglycemia can be a serious problem if you don't treat it, so it's important to treat as soon as you detect it. If you fail to treat hyperglycemia, a condition called ketoacidosis diabetic coma could occur.

Ketoacidosis develops when your body doesn't have enough insulin. Without insulin, your body can't use glucose for fuel, so your body breaks down fats to use for energy. When your body breaks down fats, waste products called ketones are produced.

Your body cannot tolerate large amounts of ketones and will try to get rid of them through the urine. Unfortunately, the body cannot release all the ketones and they build up in your blood, which can lead to ketoacidosis.