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1. DIABETIC KETOACIDOSIS ; HYPERGLYCEMIC HYPEROSMOLAR SYNDROME; Dr .SAI TEJA( 2nd year post graduate) Dr .DHANUSH(2nd year postgraduate) Dr.PRAVALLIKA (1st year postgraduate)

2. DEFINITION Diabetes mellitus is a heterogeneous chronic metabolic disorder principally characterized by persistent hyperglycemia resulting from defects in insulin action and/or insulin secretion.

3. Diabetes Mellitus

4. STRUCTURE OF INSULIN

5. ACTIONS OF INSULIN

6. ACTIONS OF INSULIN AND GLUCAGON

7. Mechanism of insulin release

8. The glucose levels are controlled by the balance of insulin and the counter-regulatory hormones, glucagon, catecholamines, growth hormone, and cortisol. At relatively low levels, insulin is a potent inhibitor of lipolysis, free fatty acid oxidation, and ketogenesis. As insulin concentrations increase, glucose levels decrease first by inhibiting hepatic gluconeogenesis and glycogenolysis, and then by increasing peripheral glucose uptake and promoting glycogen synthesis. At even higher concentrations, insulin prevents protein breakdown. Finally, at the highest doses, insulin is an anabolic hormone, promoting skeletal muscle formation

9. Hyperglycemia develops as a result of an imbalance between the glucose-lowering effect of insulin and the counter-regulatory response. Hyperglycemia occurs by three processes: increased gluconeogenesis, accelerated glycogenolysis, and impaired glu- cose utilization by peripheral tissues Skeletal muscle breakdown leads to an increased delivery of gluconeogenic precursors in the form of amino acids. Fat breakdown leads to an increased level of free fatty acids delivered to the liver. These effects may be exacerbated by prolonged starvation in the perioperative period. In people without diabetes, a compensatory increase in insulin secretion helps to mediate against these catabolic effects.

10. During times of illness or stress, the increased levels of counter-regulatory hormones alter carbohydrate metabolism by inducing insulin resistance, increasing hepatic glucose production, and reducing peripheral glucose utilization A major consequence of severe hyperglycemia is osmotic diuresis accompanied by dehydration and electrolyte disturbances (in particular sodium, potassium, magnesium, and phosphate).This increased osmolality leads to a pro-coagulant state. In addition, hyperglycemia results in raised levels of inflammatory cytokines and markers of oxidative stress such as tumor necrosis factor α,interleukin(IL)-6,IL-1β,and IL-8, and C-reactive protein These pro-inflammatory cytokines have been shown to be associated with the development of insulin resistance by interfering with intracellular pathways, downstream of the insulin receptor

11. DKA

12. CRITERIA FOR DKA Glucose > 250 mg /dl Ketones positive( ketonemia and ketonuria ) PH <7.3 Bicarbonates < 18 meq /lit No universally accepted definition of DKA

13. PATHOGENESIS OF DKA Hyperglycaemia develops in insulin deficiency because of three processes: increased gluconeogenesis, accelerated glycogenolysis and impaired glucose utilization by peripheral tissues.

14. The reduction in insulin concentration together with the increase in counter-regulatory hormones leads to the activation of hormone-sensitive lipase in adipose tissue with the subsequent breakdown of triglycerides into glycerol and free fatty acids (FFAs). In the liver, FFAs are oxidized to ketoacids, mainly under the influence of glucagon. FFAs undergo β-oxidation to form acetyl coenzyme A (acetyl-CoA).

15. Excess acetyl-CoA that does not enter the Krebs cycle (tricarboxylic acid cycle; TCA cycle) generates acetoacetyl-CoA , three molecules of which condense to form β-hydroxy-β-methylglutaryl-CoA (HMG-CoA). This, in turn, is cleaved to form acetoacetate and acetyl-CoA. Acetoacetate is further reduced by NADH to form β-hydroxybutyrate. Acetoacetate is converted to acetone by non enzymatic decarboxylation The two major ketoacids are Muscle β-hydroxybutyrate and acetoacetate.

16. The accumulation of ketoacids leads to a high anion gap metabolic acidosis due to the reduction in serum bicarbonate concentration and ‘fixed acid’ retention. Hyperglycaemia also activates macrophages to produce pro-inflammatory cytokines and the liver to produce C-reactive protein, which in turn impair pancreatic β-cell function, reduce endothelial nitric oxide and lead to endothelial dysfunction.

17. MANIFESTATIONS IN DKA

18. Initial investigations should include Blood ketones,urine ketones Capillary blood glucose Venous plasma glucose Urea and electrolytes (including phosphorus if necessary) ABG Full blood count CUE ECG

19. Chest radiograph if clinically indicated Continuous cardiac monitoring Continuous pulse oximetry Consider precipitating causes and treat appropriately Examples Establish usual medication for diabetes Pregnancy test in women of child bearing age Blood cultures and urine cultures

20. INVESTIGATIONS Measure blood glucose every 1–2 h; measure electrolytes (especially K+, bicarbonate, phosphate) and anion gap every 4 h for first 24 h. Monitor blood pressure, pulse, respirations, mental status, fluid intake and output every 1–4 h.

21. ALGORITHM FOR TREATMENT OF DKA

22. FLUID REPLACEMENT 0.9% NS 1000 ml over 1st hour 1000 ml over next 2 hours 1000 ml over next 2 hours 1000 ml over next 4 hours 1000 ml over next 4 hours 1000 ml over next 6hours Give 500 ml of 0.9% sodium chloride solution over 10-15 minutes,If SBP remains below 90 mmHg give another 500 ml.In practice most individuals require between 500 to 1000 ml given rapidly

23. INSULIN THERAPY The insulin infusion is made up of 50 units of soluble human insulin in 49.5 ml 0.9% sodium chloride solution (i.e. 1 unit /ml) A fixed rate intravenous insulin infusion (FRIII) calculated on 0.1 units/per kilogram body/hr weight is recommended Once the glucose drops to <14 mmol/L then in addition to adding a 5% dextrose infusion consider reducing the rate of intravenous insulin infusion to 0.05 units/kg/hr to avoid the risk of developing hypoglycaemia and hypokalaemia. If blood ketones not falling by at least 0.5 mmol/L/hr - increase insulin infusion rate by 1.0 unit/hr until falling at target rates

24. Resolution of DKA is defined as ketones less than 0.6 mmol /L in blood and ABG pH over 7.3 (do not use bicarbonate as a surrogate at this stage because the hyperchloraemic acidosis associated with large volumes of 0.9% sodium chloride will lower bicarbonate levels) Continue insulin infusion until resolution of ketoacidosis Administer long-acting insulin as soon as patient is eating. Allow for a 2- to 4-h overlap in insulin infusion and SC long-acting insulin injection. Estimate Total Daily Dose (TDD) of insulin. This estimate is based on several factors, including the person with diabetes’ sensitivity to insulin, degree of glycaemic control, insulin resistance, weight, and age. The TDD can be calculated by multiplying the individual’s weight (in kg) by 0.5 to 0.75 units. Use 0.75 units/ kg for those thought to be more insulin resistant i.e. teens, obese.

25. Example: a 72 kg person would require approximately 72 x 0.5 units or 36 units in 24 hours Give 50% of total dose with the evening meal in the form of long acting insulin and divide remaining dose equally between pre-breakfast, pre-lunch and pre-evening meal. In those new to insulin therapy, dose requirements may decrease within a few days because the insulin resistance associated with DKA resolves. Close supervision from the diabetes specialist team is required.

26. Exercise caution in the following groups Young people aged 18-25 years Elderly Pregnant Heart or kidney failure Other serious co-morbidities

27. POTASSIUM REPLACEMENT The maximum recommended rate is 0.5 mmol /kg/h. .The goal is to maintain serum potassium levels of 4-5 mEq /l Inclusion of 20–40 meq of potassium in each liter of IV fluid is reasonable, but additional potassium supplements may also be required. To reduce the amount of chloride administered, potassium phosphate or acetate can be substituted for the chloride salt. The goal is to maintain the serum potassium at >3.5 mmol /L  (3.5 meq /L).

28. Bicarbonate therapy- (severe acidosis with pH <6.9) If pH <6.9, consider 100 mmol (2 ampules ) in 400 ml sterile water with 20 mEq KCL administered at a rate of 200 ml/h for two h.until pH is ≥7.0. If the pH is still <7.0 after this is infused, we recommend repeating the infusion every two hours until pH reaches >7.0

29. COMPLICATIONS OF DKA 1. Cerebral oedema 2. Hypoglycaemia 3. Hypokalaemia 4. Hyperchloremia rare complications of DKA cardiac arrhythmias intestinal necrosis, pulmonary oedema and pneumomediastinu m , . Multiple organ dysfunction syndrome is another rare complication of DKA causing multiple organ failure.

30. Hyperglycaemia and high ketone levels cause an osmotic diuresis that leads to hypovolaemia , decreased glomerular filtration rate and worsening hyperglycaemia . As a result of respiratory compensation for the metabolic acidosis, deep, regular breaths (often with a ‘fruity’ odour ), known as Kussmaul breathing, are taken by those with diabetic ketoacidosis (DKA) as a way of excreting acidic carbon dioxide. Cerebral oedema is an increased fluid content of the brain tissue that may lead to neurological signs and symptoms.

31. HYPERGLYCEMIC HYPEROSMOLAR STATE

32. Previously called HyperOsmolar Non Ketotic ( HONK ) coma it was apparent that most of these people were not comatosed, but were extremely ill. Changing the name to Hyperosmolar Hyperglycaemic State (HHS) allows for the fact that some people with severely raised BG may also be mildly ketotic and acidotic. People with HHS are generally older than those with DKA, but increasingly, as the diabetes pandemic crosses generational boundaries, it may be seen in young adults and even children as the first presentation of newly diagnosed diabetes . INTRODUCTION :-

33. In HHS there is usually no significant ketosis/ketonaemia (≤3.0 mmol/L), although a mild acidosis (pH >7.3, bicarbonate >15.0 mmol/L) may accompany those affected by acute kidney injury or severe sepsis. HHS has a slower onset than DKA. This is important because the brain tissue of those who typically develop HHS, particularly in those who are older, are at higher risk of injury due to rapid shifts in sodium, water and glucose. Therefore, to prevent significant neurological damage, HHS requires less aggressive fluid resuscitation and slower glucose-lowering than DKA.

34. Initial Assessment Hyperglycaemia results in an osmotic diuresis and renal losses of water in excess of sodium and potassium . Fluid losses in HHS can be significant and have been estimated to be between 100 – 220 ml/kg (10 -22 L in a person weighing 100 kg)

35. Pathophysiology :- Relative insulin deficiency and inadequate fluid intake are the underlying causes of HHS. Insulin deficiency increases hepatic glucose production (through glycogenolysis and gluconeogenesis) and impairs glucose utilization in skeletal muscle Hyperglycemia induces an osmotic diuresis that leads to intravascular volume depletion, which is exacerbated by inadequate fluid replacement. The absence of ketosis in HHS is not understood. Presumably, the insulin deficiency is only relative and less severe than in DKA. Lower levels of counterregulatory hormones and free fatty acids have been found in HHS than in DKA in some studies. It is also possible that the liver is less capable of ketone body synthesis or that the insulin/glucagon ratio does not favor ketogenesis.

36. Laboratory Abnormalities and Diagnosis :- The measured serum sodium may be normal or slightly low despite the marked hyperglycemia. The corrected serum sodium is usually increased ( add 1.6 meq to measured sodium for each 5.6-mmol/L [100-mg/dL] rise in the serum glucose). In contrast to DKA, acidosis and ketonemia are absent or mild. A small anion-gap metabolic acidosis may be present secondary to increased lactic acid. Moderate ketonuria, if present, is secondary to starvation.

37. Biochemical HHS should not be diagnosed using biochemical parameters alone. However, the blood glucose is markedly raised (usually ≥30 mmol/L), as is the osmolality (usually ≥320 mOsm/kg). Osmolality is useful as an indicator of severity and for monitoring the rate of change with treatment. Serum osmolality is often provided in biochemistry reports, either calculated or measured, but can be calculated using the formula [(2xNa+) + glucose/18 + BUN/2.8 ]. Urea is not an effective osmolyte but including it in the calculation is important in the hyperosmolar state, as it is one of the indicators of severe dehydration.

38. Clinical Features :- The prototypical patient with HHS is an elderly individual with type 2 DM, with a several-week history of polyuria, weight loss, and diminished oral intake that culminates in mental confusion, lethargy, or coma. The physical examination reflects profound dehydration and hyperosmolality and reveals hypotension, tachycardia, and altered mental status. Notably absent are symptoms of nausea, vomiting, and abdominal pain and the Kussmaul respirations characteristic of DKA. HHS is often precipitated by a serious, concurrent illness such as MI or stroke. Sepsis, pneumonia, and other serious infections are frequent precipitants and should be sought. In addition, a debilitating condition (prior stroke or dementia) or social situation that compromises water intake usually contributes to the development of the disorder.

39. But Clinically , Acute cognitive impairment is not necessarily present and may be associated with dehydration but is not specific to the condition. Alterations in cognitive status are more common when the osmolality rises above 330 mOsm/kg. Severe hypovolaemia may manifest as tachycardia (pulse >100 bpm) and/or hypotension (systolic blood pressure <100 mmHg) . However, despite these severe electrolyte losses and total body volume depletion, often the person with HHS may not look as dehydrated as they are, because the hypertonicity leads to preservation of intravascular volume, (causing movement of water from intracellular to extracellular spaces )

40. Changes in Cognitive Performance during HHS : HHS can have marked effects on cerebral function and be associated with transient changes in cognitive performance and also with longer-term effects. This may be due to a number of things, including but not limited to: cerebral oedema in severe cases, presence of significant electrolyte disturbances, acute changes in osmolality, dehydration, infection/sepsis, hypoglycaemia during treatment, or kidney injury. A daily assessment of cognition during admission with a comparison to the pre-morbid state should accompany the full history, physical examination and review of drug therapy on admission.

41. Goals of Treatment of HHS The goals of treatment of HHS are to address the underlying cause(s) and to gradually and safely: • N ormalise the osmolality • replace fluid and electrolyte losses • normalise blood glucose Other goals include prevention of: • arterial or venous thrombosis • other potential complications e.g. cerebral oedema/ central pontine myelinolysis / osmotic demyelination syndrome • foot ulceration

42. Markers of Severity Indicating the Need for High Dependency / Level 2 Care Care :- For people with HHS can be complex, they often have multiple co-morbidities and may require intensive monitoring. The presence of one or more of the following should prompt discussion because they indicate the need for admission to a HighDependency Unit /Level 2 environment. Immediate senior review by a clinician skilled in the management of HHS should be considered: • Measured or calculated Osmolality >350 mOsm/kg • Sodium >160 mmol/L • Venous/arterial pH <7.1 • Hypokalaemia (<3.5 mmol/L) or hyperkalaemia (>6 mmol/L) on admission • Glasgow Coma Scale (GCS) <12 or abnormal AVPU (Alert, Voice, Pain, Unresponsive) scale • Oxygen saturation <92% on air (assuming normal baseline respiratory function) • Systolic blood pressure <90 mmHg • Pulse >100 or <60 bpm • Urine output <0.5 ml/kg/hr • Serum creatinine >200 µmol/L and/or acute kidney injury • Hypothermia • Macrovascular event such as myocardial infarction or stroke • Other serious co-morbidity

43. FLUID BALANCE IN HHS

44. Osmolality, Sodium and Glucose :- The key parameter in HHS that needs to be taken into account is osmolality. Sodium and glucose are the main contributors to this, and too rapid changes are dangerous because large fluid shifts can lead to neurological complications, in particular cerebral oedema and CPM/osmotic demyelination. Osmolality can be calculated using the formula[(2xNa+) + glucose/18 + BUN/2.8 ] . Use of the previous version of this guideline has confirmed that fluid replacement alone will lower glucose concentrations. A FRIII should NOT be started as part of the initial treatment unless significant ketonaemia is present – i.e. > 3.0 mmol/L or urine ketones > 2+. In all other circumstances, intravenous fluids should be administered first, and an FRIII only started once the glucose has stopped falling. The risk of adding insulin at the start of treatment is that this will lead to larger osmotic shifts leading to neurological complications. In addition, adding IV insulin too early will also potentially lead to circulatory collapse. If the IV fluids and FRIII are managed appropriately, the fall in measured or calculated serum osmolality should be within the target range of 3.0-8.0 mOsm/kg/hr. If the rate is faster than this, it increases the risk of neurological complications such as cerebral oedema and CPM/osmotic demyelination.

45. Volume depletion and hyperglycemia are prominent features of both HHS and DKA. Consequently, therapy of these disorders shares several elements . In both disorders, careful monitoring of the patient’s fluid status, laboratory values, and insulin infusion rate is crucial. Underlying or precipitating problems should be aggressively sought and treated. In HHS, fluid losses and dehydration are usually more pronounced than in DKA due to the longer duration of the illness. The patient with HHS is usually older, more likely to have mental status changes, and more likely to have a life-threatening precipitating event with accompanying comorbidities

46. Even with proper treatment, HHS has a substantially higher mortality rate than DKA (up to 15% in some clinical series). Fluid replacement should initially stabilize the hemodynamic status of the patient (1–3 L of 0.9% normal saline over the first 2–3 h). Because the fluid deficit in HHS is accumulated over a period of days to weeks, the rapidity of reversal of the hyperosmolar state must balance the need for free water repletion with the risk that too rapid a reversal may worsen neurologic function. . Recommended use of crystalloid fluids rather than colloid in critically ill individuals because use of crystalloids is associated with less need for further interventions . As the majority of electrolyte losses are sodium, chloride and potassium, the initial fluid replacement of choice should be 0.9% sodium chloride solution with potassium added as required .

47. If the serum sodium is >150 mmol/L (150 meq/L), 0.45% saline should be used. After hemodynamic stability is achieved, the IV fluid administration is directed at reversing the free water deficit using hypotonic fluids (0.45% saline initially , then 5% dextrose in water [D5 W]). The calculated free water deficit (which can be as great as 9–10 L) should be reversed over the next 1–2 days (infusion rates of 200–300 mL/h of hypotonic solution). Potassium repletion is usually necessary and should be dictated by repeated measurements of the serum potassium. People with HHS are usually potassium depleted but potassium shifts are less pronounced than those with DKA because they are less acidotic. The differences are driven largely by the lack of insulin in DKA. In addition, the FRIII rate is lower, and there is often co-existing renal impairment. However, hyperkalaemia can be present with acute kidney injury. In addition, those on diuretics may be profoundly hypokalaemic. Potassium should be replaced or omitted as required In patients taking diuretics, the potassium deficit can be quite large and may be accompanied by magnesium deficiency.

48. As in DKA, rehydration and volume expansion lower the plasma glucose initially, but insulin is also required. A reasonable regimen for HHS begins with an IV insulin bolus of 0.1 unit/kg followed by IV insulin at a constant infusion rate of 0.1 unit/kg per hour. If the serum glucose does not fall, increase the insulin infusion rate by twofold. As in DKA, glucose should be added to IV fluid when the plasma glucose falls to 11.1–13.9 mmol/L (200–250 mg/dL), and the insulin infusion rate should be decreased to 0.02–0.1 unit/kg per hr. The insulin infusion should be continued until the patient has resumed eating and can be transferred to an SC insulin regimen. The patient should be discharged from the hospital on insulin, although some patients can later switch to oral glucose-lowering agents.

49. • if significant ketonaemia is not present donot start an intravenous insulin infusion • fluid replacement alone with 0.9% sodium chloride solution will result in a falling blood glucose and because most people with HHS are insulin sensitive there is a risk of lowering the osmolality precipitously. To prevent the measured or calculated serum osmolality falling too quickly, the plasma glucose should ideally fall by no more than 5 mmol/L/hr • insulin treatment prior to adequate fluid replacement may result in cardiovascular collapse because water will move out of the intravascular space, resulting in a reduction in intravascular volume (a consequence of insulin-mediated glucose uptake and a diuresis from urinary glucose excretion) (• the recommended insulin dose is a FRIII given at 0.05 units/kg/hr • a fall of glucose at a rate of up to 5.0 mmol/L per hour is ideal

50. Anticoagulation :- Having diabetes is associated with an increased risk of developing venous thromboembolic disease (VTE) . People with HHS have an increased risk of arterial and VTE . A study of hyperglycaemia (not necessarily with HHS) during COVID-19 admissions suggested that the risk of arterial and VTE was three times higher than those without hyperglycaemia . Other work has estimated that people with diabetes and hyperosmolality have a risk of VTE similar, or only marginally above those with acute renal failure, acute sepsis or acute connective tissue disease . The risk of venous thromboembolism is greater than in diabetic ketoacidosis . Other factors, such as hypernatraemia and increasing vasopressin concentrations can promote thrombogenesis by producing changes in haemostatic function consistent with a hypercoagulable state . Everyone with HHS should receive prophylactic low molecular weight heparin (LMWH) for the full duration of admission unless contraindicated. There are no data to recommend that this advice be extended to therapeutic anticoagulation. Full, therapeutic anticoagulation should only be considered in those with suspected thrombosis or acute coronary syndrome.

51. Foot Protection : People with HHS are at high risk of pressure related foot ulceration. An initial foot assessment should be undertaken on admission and daily during admission . Heel protectors and an appropriate mattress should be provided for those with immobility, neuropathy, peripheral vascular disease or lower limb deformity. If the individuals are too confused or sleepy to cooperate with assessment of sensation assume they are at high risk. Antibiotic Therapy : As with all acutely ill people, sepsis may not be accompanied by pyrexia. An infective source should be sought on clinical history and examination. Antibiotics should be given when there are clinical signs, and / or laboratory or radiological evidence of infection.

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