Acute Complications of Diabetes Jane D’Isa-Smith, D.O.

December 13, 2005 Tintinalli Chapters 211, 213, 214 Prepared by David R. Fisher, D.O

1

Diabetic Ketoacidosis

2

Introduction

• DKA is an acute life threatening complication of DM • ¼ of hospital admissions for DM • Occurs predominantly in type I though may occur in II • Incidence of DKA in diabetics 15 per 1000 patients • 20-30% of cases occur in new-onset diabetes • Mortality less than 5% • Mortality higher in elderly due to underlying renal disease or coexisting infection 3

Definition

• Exact definition is variable • Most consistent is: – Blood glucose level greater than 250 mg/dL – Bicarbonate less than 15 mEq/L – Arterial pH less than 7.3

– Moderate ketonemia 4

Pathophysiology

• Body’s response to cellular starvation – Brought on by relative insulin deficiency and counter regulatory or catabolic hormone excess – Insulin is responsible for metabolism and storage of carbohydrates, fat and protein • Lack of insulin and excess counter regulatory hormones (glucagon, catecholamines, cortisol and growth hormone) results in: – Hyperglycemia (due to excess production and underutilization of glucose) – Osmotic diuresis – Prerenal azotemia – Ketone formation – Wide anion-gap metabolic acidosis • Clinical manifestations related to hyperglycemia, volume depletion and acidosis 5

Pathophysiology

• Free fatty acids released in the periphery are bound to albumin and transported to the liver where they undergo conversion to ketone bodies – The metabolic acidosis in DKA is due to β-hydroxybutyric acid and acetoacetic acid which are in equilibrium – Acetoacetic acid is metabolized to acetone, another major ketone body – Depletion of baseline hepatic glycogen stores tends to favor ketogenesis – Low insulin levels decrease the ability of the brain and cardiac and skeletal muscle to use ketones as an energy source, also increasing ketonemia – Persistently elevated serum glucose levels eventually causes an osmotic diuresis – Resulting volume depletion worsens hyperglycemia and ketonemia 6

Electrolytes

• Renal potassium losses already occurring from osmotic diuresis worsen due to renin-angiotensin-aldosterone system activation by volume depletion • In the kidney, chloride is retained in exchange for the ketoanions being excreted • Loss of ketoanions represents a loss of potential bicarbonate • In face of marked ketonuria, a superimposed hyperchloremic acidosis is also present • Presence of concurrent hyperchloremic metabolic acidosis can be detected by noting a bicarbonate level lower than explainable by the amount the anion gap has increased • As adipose tissue is broken down, prostaglandins PGI volume depletion 2 and PGE 2 are produced – This accounts for the paradoxical vasodilation that occurs despite the profound levels of 7

DKA in Pregnancy

• Physiologic changes in pregnancy makes more prone to DKA – Maternal fasting serum glucose levels are normally lower • Leads to relative insulin deficiency and an increase in baseline free fatty acid levels in the blood – Pregnant patients normally have increased levels of counter regulatory hormones – Chronic respiratory alkalosis • Seen in pregnancy • Leads to decreased bicarbonate levels due to a compensatory renal response – Results in a decrease in buffering capacity 8

DKA in Pregnancy

• Pregnant patients have increased incidence of vomiting and infections which may precipitate DKA • Maternal acidosis: – Causes fetal acidosis – Decreases uterine blood flow and fetal oxygenation – Shifts the oxygen-hemoglobin dissociation curve to the right • Maternal shifts can lead to fetal dysrhythmia and death 9

Causes of DKA

• 25% have no precipitating causes found • Errors in insulin use, especially in younger population • Omission of daily insulin injections • Stressful events: – Infection – Stroke – MI – Trauma – Pregnancy – Hyperthyroidism – Pancreatitis – Pulmonary embolism – Surgery – Steroid use 10

Clinical Features

• Hyperglycemia • Increased osmotic load – Movement of intracellular water into the vascular compartment – Ensuing osmotic diuresis gradually leads to volume loss and renal loss of sodium, chloride, potassium, phosphorus, calcium and magnesium • Patients initially compensate by increasing their fluid intake • Initially polyuria and polydipsia are only symptoms until ketonemia and acidosis develop 11

Clinical Features

• As acidosis progresses – Patient develops a compensatory augmented ventilatory response – Increased ventilation is stimulated physiologically by acidemia to diminish PCO 2 and counter the metabolic acidosis • Peripheral vasodilation develops from prostaglandins and acidosis – Prostaglandins may contribute to unexplained nausea, vomiting and abdominal pain – Vomiting exacerbates the potassium losses and contributes to volume depletion, weakness and weight loss 12

Clinical Features

• Mental confusion or coma may occur with serum osmolarity greater than 340 mosm/L • Abnormal vital signs may be the only significant finding at presentation • Tachycardia with orthostasis or hypotension are usually present • Poor skin turgor • Kussmaul respirations with severe acidemia 13

Clinical Features

• Acetone presents with odor in some patients • Absence of fever does not exclude infection as a source of the ketoacidosis • Hypothermia may occur due to peripheral vasodilatation • Abdominal pain and tenderness may occur with gastric distension, ileus or pancreatitis – Abdominal pain and elevated amylase in those with DKA or pancreatitis may make differentiation difficult – Lipase is more specific to pancreatitis 14

Clinical Suspicion

• If suspect DKA, want immediately: – Acucheck – Urine dip – ECG – Venous blood gas – Normal Saline IV drip • Almost all patients with DKA have glucose greater than 300 mg/dL 15

Acidosis

• Elevated serum β-hydroxybutyrate and acetoacetate cause acidosis and ketonuria • Elevated serum ketones may lead to a wide-anion gap metabolic acidosis • Metabolic acidosis may occur due to vomiting, osmotic diuresis and concomitant diuretic use • Some with DKA may present with normal bicarbonate concentration or alkalemia if other alkalotic processes are severe enough to mask acidosis – In which case the elevated anion gap may be the only clue to the presence of an underlying metabolic acidosis 16

ABGs

• Help determine precise acid-base status in order to direct treatment – Venous pH is just as helpful – Studies have shown strong correlation between arterial and venous pH in patients with DKA • Venous pH obtained during routine blood draws can be used to avoid ABGs • Decreased PCO 2 reflects respiratory compensation for metabolic acidosis • Widening of anion gap is superior to pH or bicarbonate concentration alone – Widening is independent of potentially masking effects concurrent with acid base disturbances 17

Potassium

• Total body potassium is depleted by renal losses • Measured levels usually normal or elevated 18

Sodium

• Osmotic diuresis leads to excessive renal losses of NaCl in urine • Hyperglycemia artificially lowers the serum sodium levels • Two corrections: – Standard-1.6 mEq added to sodium loss for every 100 mg of glucose over 100 mg/dL – True-2.4 mEq added for blood glucose levels greater than 400 mg/dL 19

Electrolyte Loss:

• Osmotic diuresis contributes to urinary losses and total body depletion of: – Phosphorus – Calcium – Magnesium 20

Other values elevated:

• Creatinine – Some elevation expected due to prerenal azotemia – May be factitiously elevated if laboratory assays for Cr and Acetoacetate interfere • LFTs – Due to fatty infiltration of the liver which gradually corrects as acidosis is treated • CPK – Due to volume depletion • Amylase • WBCs – Leukocytosis often present due to hemoconcentration and stress response – Absolute band count of 10,000 microL or more reliably predicts infection in this population 21

ECG changes

• Underlying rhythm is sinus tachycardia • Changes of hypo/hyperkalemia • Transient changes due to rapidly changing metabolic status • Evaluate for ischemia because MI may precipitate DKA 22

Differential Diagnosis

• Any entity that causes a high-anion-gap metabolic acidosis – Alcoholic or starvation ketoacidosis – Uremia – Lactic acidosis – Ingestions (methanol, ethylene glycol, aspirin) • If ingestion cannot be excluded, serum osmolarity or drug-level testing is required • Patients with hyperosmolar non-ketotic coma tend to: – Be older – Have more prolonged course and have prominent mental status changes – Serum glucose levels are generally much higher (>600 mg/dL) – Have little to no anion-gap metabolic acidosis 23

Studies

• Diagnosis should be suspected at triage • Aggressive fluid therapy initiated prior to receiving lab results • Place on monitor and have one large bore IV with NS running • Rapid acucheck, urine dip and ECG • CBC • Electrolytes, phosphorus, magnesium, calcium • Blood cultures • ABG optional and required only for monitoring and diagnosis of critically ill – Venous pH (0.03 lower than arterial pH) may be used for critically ill 24

Treatment Goals:

• Volume repletion • Reversal of metabolic consequences of insulin insufficiency • Correction of electrolyte and acid-base imbalances • Recognition and treatment of precipitating causes • Avoidance of complications 25

Treatment

• Order of therapeutic priorities is volume first, then insulin and/or potassium, magnesium and bicarbonate • Monitor glucose, potassium and anion gap, vital signs, level of consciousness, volume input/output until recovery is well established • Need frequent monitoring of electrolytes (every 1-2 hours) to meet goals of safely replacing deficits and supplying missing insulin • Resolving hyperglycemia alone is not the end point of therapy – Need resolution of the metabolic acidosis or inhibition of ketoacid production to signify resolution of DKA – Normalization of anion gap requires 8-16 hours and reflects clearance of ketoacids 26

Fluid Administration

• Rapid administration is single most important step in treatment • Restores: – Intravascular volume – Normal tonicity – Perfusion of vital organs • Improve glomerular filtration rate • Lower serum glucose and ketone levels • Average adult patient has a 100 ml/Kg (5-10 L) water deficit and a sodium deficit of 7-10 mEq/kg • Normal saline is most frequently recommended fluid for initial volume repletion 27

Fluid Administration

• Recommended regimen: – First L of NS within first 30 minutes of presentation – First 2 L of NS within first 2 hours – Second 2 L of NS at 2-6 hours – Third 2 L of NS at 6-12 hours • Above replaces 50% of water deficit within first 12 hours with remaining 50% over next 12 hours • Glucose and ketone concentrations begin to fall with fluids alone 28

Fluid Administration

• Add D 5 to solution when glucose level is between 250-300 mg/dL • Change to hypotonic ½ NS or D 5 ½ NS if glucose below 300 mg/dL after initially using NS • If no extreme volume depletion, may manage with 500 ml/hr for 4 hours – May need to monitor CVP or wedge pressure in the elderly or those with heart disease and may risk ARDS and cerebral edema 29

Insulin

• Ideal treatment is with continuous IV infusion of small doses of regular insulin – More physiologic – Produces linear fall in serum glucose and ketone body levels – Less associated with severe metabolic complications such as hypoglycemia, hypokalemia and hypophosphatemia 30

Insulin

• Recommended dose is 0.1 unit/kg/hr • Effect begins almost immediately after initiation of infusion • Loading dose not necessary and not recommended in children 31

Insulin

• Need frequent glucose level monitoring • Incidence of non-response to low-dose continuous IV administration is 1-2% • Infection is primary reason for failure • Usually requires 12 hours of insulin infusion or until ketonemia and anion gap is corrected 32

Potassium

• Patients usually with profound total body hypokalemia • 3-5 mEq/kg deficient • Created by insulin deficiency, metabolic acidosis, osmotic diuresis, vomiting • 2% of total body potassium is intravascular • Initial serum level is normal or high due to: – Intracellular exchange of potassium for hydrogen ions during acidosis – Total body fluid deficit – Diminished renal function – Initial hypokalemia indicates severe total-body potassium depletion and requires large amounts of potassium within first 24-36 hours 33

Potassium

• During initial therapy the serum potassium concentration may fall rapidly due to: – Action of insulin promoting reentry into cells – Dilution of extracellular fluid – Correction of acidosis – Increased urinary loss of potassium • Early potassium replacement is a standard modality of care – Not given in first L of NS as severe hyperkalemia may precipitate fatal ventricular tachycardia and ventricular fibrillation 34

Potassium

• Fluid and insulin therapy alone usually lowers the potassium level rapidly – For each 0.1 change in pH, serum potassium concentration changes by 0.5 mEq/L inversely • Goal is to maintain potassium level within 4-5 mEq/L and avoid life threatening hyper/hypokalemia • Oral potassium is safe and effective and should be used as soon as patient can tolerate po fluids • During first 24 hours, KCl 100-200 mEq usually is required 35

Phosphate

• Roll of replacement during treatment of DKA is controversial • Recommended not treating until level less than 1 mg/dL • No established roll for initiating IV potassium phosphate in the ED 36

Magnesium

• Osmotic diuresis may cause significant magnesium depletion • Symptomatic hypomagnesemia in DKA is rare as is need of IV therapy 37

Bicarbonate

• Role in DKA debated for decades • No clinical study indicates benefit of treating DKA with bicarbonate • Routine use of supplemental bicarbonate in DKA is not recommended • Routine therapy works well without adding bicarbonate 38

Complications and Mortality

• Complications related to acute disease – Main contributors to mortality are MI and infection – Old age, severe hypotension, prolonged and severe coma and underlying renal and cardiovascular disease – Severe volume depletion leaves elderly at risk for vascular stasis and DVT – Airway protection for critically ill and lethargic patients at risk for aspiration 39

Complications related to therapy

• Hypoglycemia • Hypophosphatemia • ARDS • Cerebral edema 40

Complications related to therapy

• Cerebral edema – Occurs between 4 and 12 hours after onset of therapy but may occur as late as 48 hours after start treatment – Estimated incidence is 0.7 to 1.0 per 100 episodes of DKA in children – Mortality rate of 70% – No specific presentation or treatment variables predict development of edema – Young age and new-onset diabetes are only identified potential risk factors 41

Cerebral edema

• Symptoms include: – Severe headache – Incontinence – Change in arousal or behavior – Pupillary changes – Blood pressure changes – Seizures – Bradycardia – Disturbed temperature regulation • Treat with Mannitol – Any change in neurologic function early in therapy should prompt immediate infusion of mannitol at 1-2 g/kg 42

Disposition

• Most require admission to ICU: – Insulin drips • If early in the course of disease and can tolerate oral liquids, may be managed in ED or observation unit and discharged after 4-6 hours of therapy • Anion gap at discharge should be less than 20 43

Alcoholic Ketoacidosis

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Alcoholic Ketoacidosis

• Wide anion gap acidosis • Most often associated with acute cessation of alcohol consumption after chronic alcohol abuse • Metabolism of alcohol with little or no glucose sources results in elevated levels of ketoacids that typically produce metabolic acidosis present in the illness • Usually seen in chronic alcoholics but may be seen in first time drinkers who binge drink, especially in those with volume depletion from poor oral intake and vomiting 45

Epidemiology

• No gender difference • Usually presents between age 20 to 60 • Many with repeated episodes of ketoacidosis • Incidence is unknown but mirrors incidence of alcoholism • Usually self-limited • Poor outcomes may occur • 7-25% of deaths of known alcoholics due to AKA 46

Pathophysiology

• Key features – Ingestion of large quantities of alcohol – Relative starvation – Volume depletion 47

Pathophysiology

• Pathophysiologic state occurs with: – Depletion of NAD – Aerobic metabolism in the Krebs cycle is inhibited – Glycogen stores are depleted and lipolysis is stimulated • Occurs in patients with: – Recently intoxicated – Volume-contraction – Poor nutrition – Underlying liver disease 48

Pathophysiology

• Insulin secretion is suppressed • Glucagon, catecholamines, and growth hormone are all stimulated • Aerobic metabolism is inhibited and anaerobic metabolism causes lipolysis and ketones are produced • β-hydroxybutyrate is increased • More ketones are produced with malnourishment and vomiting or with hypophosphatemia 49

Clinical Features

• Usually occurs after episode of heavy drinking followed by decrease in alcohol and food intake and vomiting • Nausea, vomiting and abdominal pain of gastritis and pancreatitis may exacerbate progression of illness • With anorexia continuing, symptoms worsen leading to seeking medical help • Symptoms are nonspecific and diagnosis is difficult without labs • No specific physical findings solely with AKA – Most commonly tachycardia, tachypnea, diffuse mild to moderate abdominal tenderness – Volume depletion resulting from anorexia, diaphoresis and vomiting may explain the tachycardia and hypotension 50

Clinical Features

• Most are alert – Mental status changes in patients with ketoacidosis should alert to other causes: • Toxic ingestion • Hypoglycemia • Alcohol-withdrawal seizures • Postictal state • Unrecognized head injury 51

Labs

• EtOH levels usually low or undetectable – Some may have elevated levels • Elevated anion gap caused by ketones is essential in diagnosis – Since β hydroxybutyrate predominates, degree of ketonemia may not be appreciated – Initial anion gap is 16-33 usually, mean of 21 • Frequently mild hypophosphatemia, hyponatremia and/or hypokalemia – Severe derangements are rare 52

Labs

• Most have elevated bilirubin and liver enzymes due to liver disease from chronic EtOH use • BUN and creatine kinase are frequently elevated due to relative volume depletion • Serum lactate mildly elevated • Glucose usually mildly elevated – Some have hypoglycemia – Rarely glucose greater than 200 mg/dL 53

Acid-Base Balance

• Need to evaluate the anion gap in every patient at risk for AKA – Diagnosis can easily be missed otherwise • Anion gap greater than baseline or 15 signifies a wide-anion-gap acidosis regardless of bicarbonate concentration or pH, even if alkalemic • ABG not needed to arrive at correct diagnosis 54

Acid-Base Balance

• Serum pH usually acidemic (55% of time) though may be normal or alkalemic early in course of disease • Degree of acidosis typically less than in DKA • Since volume loss is virtually always present, some degree of metabolic acidosis is present 55

Ketones

• Clinical application is variable • Most ketones in AKA are β-hydroxybutyrate – The serum and urine nitroprusside test for ketones detects acetoacetate and may show only mildly elevated ketones • As treatment progresses the acetoacetate will increase and indicates improving condition • Most suggest measuring β-hydroxybutyrate and acetoacetate only if diagnosis is unclear or other methods are not available to follow patient’s response to therapy 56

Diagnosis

• May be established with classic presentation of: – The chronic alcoholic with: • Recent anorexia • Vomiting • Abdominal pain • Unexplained metabolic acidosis with a positive nitroprusside test, elevated anion gap and a low or mildly elevated serum glucose level 57

Classic Presentation is Uncommon

• Difficult to establish diagnosis • Blood alcohol level may be zero • May not provide history of alcohol consumption • Urine nitroprusside testing may be negative or weakly positive despite significant ketoacidosis • pH may vary from significant acidemia to mild alkalemia • Wide anion gap is variable 58

Initial studies

• Electrolytes • BUN • Creatinine • Liver enzymes • Pancreatic enzymes • WBC count • Hematocrit • Urinalysis • Calculate anion gap • Serum lactic acid level and serum osmolarity may be helpful if diagnosis is in doubt • ABG is unnecessary unless a primary respiratory acid-base disturbance is suspected 59

Differential diagnosis

Very broad – Same as for wide-anion-gap metabolic acidosis • Lactic acidosis • Uremia • Ingestions such as: – Methanol – Ethylene glycol • DKA • Methanol and ethylene glycol do not produce ketosis but do have severe acidosis • Absence of urinary ketones cannot exclude diagnosis of AKA if concurrent methanol or ethylene glycol ingestion is suspected – Isopropyl alcohol ingestion • Produces ketones and may have mild lactic acidosis – Salicylate poisoning • Sepsis • Renal failure • Starvation ketosis 60

Concurrent Illnesses Promoting Alcohol Cessation and Anorexia

• Need to evaluate for these illnesses: – Pancreatitis – Gastritis – Upper GI bleeding – Seizures – Alcohol withdrawal – Pneumonia – Sepsis – Hepatitis 61

Treatment

• Glucose administration and volume repletion – Fluid of choice is D 5 NS – Glucose stimulates insulin production, stopping lipolysis and halts further formation of ketones – Glucose increases oxidation of NADH to NAD and further limits ketone production • Patients are not hyperosmolar • Cerebral edema is not a concern with large volumes of fluid administration 62

Treatment

• Insulin – No proven benefit – May be dangerous as patients have depleted glycogen stores and normal or low glucose levels 63

Treatment

• Sodium bicarbonate is not indicated unless patients are severely acidemic with pH 7.1 or lower – This level of acidemia not likely explained by AKA alone – Vigorous search for alternate explanation must be undertaken 64

Treatment

• Hypophosphatemia – Frequently seen in alcoholic patients – Can retard resolution of acidosis • Phosphorous is necessary for mitochondrial utilization of glucose to produce NADH oxidation – Phosphate replacement is generally unwarranted in ED unless levels less than 1 are encountered – Oral replenishment is safe and effective 65

Treatment

• Nitroprusside tests useful because as become more positive signifies improvement • To prevent theoretical progression to Wernicke’s disease, all patients should receive 50-100 mg of thiamine prior to administration of glucose • Concomitant administration of magnesium sulfate and multivitamins should be considered and guided by laboratory results • Acidosis may clear within 12-24 hours • If uncomplicated ED course, may be safely discharged if resolution of acidosis over time and patient able to tolerate oral fluids • If complicated course, underlying illness or persistent acidosis, admit for further evaluation and treatment 66

Hyperosmolar Hyperglycemic State

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Hyperosmolar Hyperglycemic State

• Syndrome of severe hyperglycemia, hyperosmolarity and relative lack of ketonemia in patients with poorly uncontrolled DM type II • ADA uses hyperosmolar hyperglycemic state (HHS) and hyperosmolar hyperglycemic non ketotic syndrome (HHNS) – Both commonly used and appropriate • Frequently referred to as non ketotic hyperosmolar coma – Coma should not be used in nomenclature – Only 10 % present with coma 68

HHNS: Epidemiology

• HHNS is much less frequent than DKA • Mortality rate higher in HHNS – 15-30 % for HHNS – 5% for DKA • Mortality for HHNS increases substantially with advanced age and concomitant illness 69

Hyperosmolar Hyperglycemic State

• Defined by: – Severe hyperglycemia • With serum glucose usually greater than 600 mg/dL – Elevated calculated plasma osmolality • Greater than 315 mOsm/kg – Serum bicarbonate greater than 15 – Arterial pH greater than 7.3 – Serum ketones that are negative to mildly positive • Values are arbitrary – Profound metabolic acidosis and even moderate degrees of ketonemia may be found in HHNS 70

HHNS and DKA both

• Hyperglycemia • Hyperosmolarity • Severe volume depletion • Electrolyte disturbances • Occasionally acidosis 71

HHNS

• Acidosis in HHNS more likely due to: – Tissue hypoperfusion • Lactic acidosis – Starvation ketosis – Azotemia 72

HHNS and DKA Lipolysis

• DKA patients have much higher levels of lipolysis – Release and subsequent oxidation of free fatty acids to ketone bodies • β hydroxybutyrate and Acetoacetate • Contribute additional anions resulting in a more profound acidosis • Inhibition of lipolysis and free fatty acid metabolism in HHNS is poorly understood • See table 214-1 on page 1307 73

HHNS: Pathophysiology

• Three main factors: – Decreased utilization of insulin – Increased hepatic gluconeogenesis and glycogenolysis – Impaired renal excretion of glucose • Identification early of those at risk for HHNS is most effective means of preventing serious complications • Must be vigilant on helping those who are non ambulatory with inadequate hydration status • Fundamental risk factor for developing HHNS is impaired access to water 74

HHNS: Pathophysiology

• With poorly controlled DM II, inadequate utilization of glucose due to insulin resistance results in hyperglycemia • Absence of adequate tissue response to insulin results in hepatic glycogenolysis and gluconeogenesis resulting in further hyperglycemia • As serum glucose increases, an osmotic gradient is produced attracting water from the intracellular space and into the intravenous compartment 75

HHNS: Pathophysiology

• Initial increase in intravascular volume is accompanied by a temporary increase in the GFR • As serum glucose concentration exceeds 180 mg/dL, capacity of kidneys to reabsorb glucose is exceeded and glucosuria and a profound osmotic diuresis occurs • Patients with free access to water are often able to prevent profound volume depletion by replacing lost water with large free water intake • If water requirement is not met, volume depletion occurs 76

HHNS: Pathophysiology

• During osmotic diuresis, urine produced is markedly hypertonic • Significant loss of sodium and potassium and modest loss of calcium, phosphate, magnesium and urea also occur • As volume depletion progresses, renal perfusion decreases and GFR is reduced • Renal tubular excretion of glucose is impaired which further worsens the hyperglycemia • A sustained osmotic diuresis may result in total body water losses that often exceeds 20-25% of total body weight or approximately 8-12 L in a 70 kg person 77

HHNS: Pathophysiology

• Absence of ketosis in HHNS not clearly understood – Some degree of starvation does occur but a clinically significant ketoacidosis does not occur • Lack of ketoacidosis may be due to: – Lower levels of counter regulatory hormones – Higher levels of endogenous insulin that strongly inhibits lipolysis – Inhibition of lipolysis by the hyperosmolar state 78

HHNS: Pathophysiology

• Controversy how counter regulatory hormones glucagons and cortisol, growth hormone and epinephrine play in HHNS – Compared to DKA, glucagon and growth hormone levels are lower and this may help prevent lipolysis • Compared to DKA, significantly higher levels of insulin are found in peripheral and portal circulation in HHNS – Though insulin levels are insufficient to overcome hyperglycemia, they appear to be sufficient to overcome lipolysis • Animal studies have shown the hyperosmolar state and severe hyperglycemia inhibit lipolysis in adipose tissue 79

HHNS: Clinical Features

• Typical patient is usually elderly – Often referred by a caretaker • Abnormalities in vital signs and or mental status • May complain of: – Weakness – Anorexia – Fatigue – Cough – Dyspnea – Abdominal pain 80

HHNS

• Many have undiagnosed or poorly controlled type II diabetes – Precipitated by acute illness • Pneumonia and urinary tract infections account for 30-50% of cases – Noncompliance with or under-dosing of insulin has been identified as a common precipitant also 81

HHNS

• Those predisposed to HHNS often have some level of baseline cognitive impairment such as senile dementia – Self-referral for medical treatment in early stages is rare • Any patient with hyperglycemia, impaired means of communication and limited access to free water is at major risk for HHNS • Presence of hypertension, renal insufficiency or cardiovascular disease is common in this patient population and medications commonly used to treat these diseases such as  blockers predispose the development of HHNS 82

HHNS

• An insidious state goes unchecked – Progressive hyperglycemia – Hyperosmolarity – Osmotic diuresis • Alterations in vital signs and cognition follow and signal a severity of illness that is often advanced 83

HHNS Causes

• A host of metabolic and iatrogenic causes have been identified – Diabetes – Parental or enteral alimentation – GI bleed – PE – Pancreatitis – Heat-related illness – Mesenteric ischemia – Infection – MI 84

HHNS Causes

• Severe burns • Renal insufficiency • Peritoneal or hemodialysis • Cerebrovascular events • Rhabdomyolysis • Commonly prescribed drugs that may predispose to hyperglycemia, volume depletion or other effects leading to HHNS • HHNS may unexpectedly be found in non diabetics who present with an acute medical insult such as CVA, severe burns, MI, infection, pancreatitis or other acute illness 85

HHNS: Physical findings

• Non-specific • Clinical signs of volume depletion: – Poor skin turgor – Dry mucus membranes – Sunken eyeballs – Hypotension • Signs correlate with degree of hyperglycemia and hyperosmolality and duration of physiologic imbalance • Wide range of findings such as changes in vital signs and cognition to clear evidence of profound shock and coma may occur • Normothermia or hypothermia is common due to vasodilation 86

HHNS: Physical findings

• Seizures – Up to 15% may present with seizures – Typically focal – Generalized seizures that are often resistant to anticonvulsants may occur • Other CNS symptoms may include: – Tremor – Clonus – Hyperreflexia – Hyporeflexia – Positive plantar response – Reversible hemiplegia or hemisensory defects without CVA or structural lesion 87

HHNS: Physical findings

• Degree of lethargy and coma is proportional to the level of osmolality – Those with coma tend to have: • Higher osmolality • Higher hyperglycemia • Greater volume contraction • Not surprising that misdiagnosis of stroke or organic brain disease is common in the elderly 88

Laboratory tests

• Essential – Serum glucose – Electrolytes – Calculated and measured serum osmolality – BUN – Ketones – Creatinine – CBC 89

Laboratory tests

• Consider – Urinalysis and culture – Liver and pancreatic enzymes – Cardiac enzymes – Thyroid function – Coagulation profiles – Chest x-ray – ECG • Other – CT of head – LP – Toxicology – ABG • Of value only if suspicion of respiratory component to acid-base abnormality • Both PCO 2 and pH can be predicted from bicarbonate concentration obtained from venous electrolytes 90

Electrolyte abnormalities

• Electrolyte abnormalities usually reflect a contraction alkalosis due to profound water deficit • 50% of patients with HHNS will have increased anion gap metabolic acidosis – Lactic acidosis, azotemia, starvation ketosis, severe volume contraction • Acute or concurrent illnesses such as ischemic bowel will contribute anions such as lactic acid causing varying degrees of an anion gap metabolic acidosis • Initial serum electrolyte determinations can be reported as seemingly normal because the concurrent presence of both metabolic alkalosis and acidosis may result in each canceling out the other’s effect • Lack of careful analysis of serum chemistries may lead to delayed appreciation of the severity of underlying abnormalities, including volume loss 91

•

Sodium

Serum sodium is suggestive but not a reliable indicator of degree of volume contraction • Though patient is total body sodium depleted, serum sodium (corrected for glucose elevation) may be low, normal or elevated • Measured serum sodium is often reported as factitiously low due to dilutional effect of hyperglycemia • Need to correct the sodium level • Serum sodium decreases by 1.6 mEq for every 100 mg/dL increase in serum glucose above 100 mg/dL • See formula page 1309 • Elevated corrected serum sodium during sever hyperglycemia is usually explainable only by profound volume contraction • Normal sodium level or mild hyponatremia usually but not invariably suggests modest dehydration 92

Osmolarity

• Serum osmolarity has also been shown to correlate with severity of disease as well as neurologic impairment and coma • Calculated effective serum osmolarity excludes osmotically inactive urea that is usually included in laboratory measures of osmolarity • See formula page 1309 • Normal serum osmolarity range is approximately 275 to 295 mOsm/kg • Values above 300 mOsm/kg are indicative of significant 93 hyperosmolarity and those above 320 mOsm are commonly associated with alterations of cognitive function

Potassium

• Hypokalemia is most immediate electrolyte based risk and should be anticipated • Total body deficits of 500-700 mEq/l are common • Initial values may be reported as normal during a period of severe volume contraction and with metabolic acidosis when intravascular hydrogen ions are exchanged for intracellular potassium ions • Presence of acidemia may mask a potentially life-threatening potassium deficit • As intravascular volume is replaced and acidemia is reversed, potassium losses become more apparent • Patients with low serum potassium during the period of severe volume contraction are at greatest risk for dysrhythmia • Importance of potassium replacement during periods of volume repletion and insulin therapy cannot be overemphasized 94

Labs

• BUN and Cr – Both prerenal azotemia and renal azotemia are common with BUN/Cr ratios often exceeding 30/1 • WBC – Leukocytosis is variable and a weak clinical indicator – When present usually due to infection or hemoconcentration 95

Phosphate

• Hypophosphatemia may occur during periods of prolonged hyperglycemia • Acute consequences such as CNS abnormalities, cardiac dysfunction, and rhabdomyolysis are rare and are usually if level is <1.0 mg/dL • Routine replacement of phosphate and magnesium usually unnecessary unless severe • Both electrolytes tend to normalize as metabolic derangements are addressed • When necessary, gradual replacement minimizes risks of complications such as renal failure or hypocalcemia • Metabolic acidosis is of a wide-anion-gap type, often due to lactic acidosis from poor tissue perfusion, resulting in uremia, mild starvation ketosis or all three 96

Treatment

• Improvement in tissue perfusion is the key to effective recovery • Treat hypovolemia, identify and treat precipitating causes, correct electrolyte abnormalities, gradual correction of hyperglycemia and osmolarity • Cannot overstate importance of judicious therapeutic plans that adjusts for concurrent medical illness such as LV dysfunction or renal insufficiency • Due to potential complications, rapid therapy should only be reserved for potentially life-threatening electrolyte abnormalities only 97 • Figure 214-1

Fluid resuscitation

• Initial aim is reestablishing adequate tissue perfusion and decreasing serum glucose • Replacement of intravascular fluid losses alone can account for reductions in serum glucose of 35-70 mg/hr or up to 80 % of necessary reduction • Average fluid deficit is 20-25% of total body water or 8-12 L • In elderly 50% of body weight is due to total body water • Calculate the water deficit by using patient’s current weight in kilograms and normal total body water 98

Fluid resuscitation

• One-half of fluid deficits should be replaced over the initial 12 hours and the balance over the next 24 hours when possible • Actual rate of fluid administration should be individualized for each patient based on presence of renal and cardiac impairment • Initial rates of 500-1500 ml/hr during first 2 hours followed by rates of 250-500 ml per hour are usually well tolerated – Patients with cardiac disease may require a more conservative rate of volume repletion • Renal and cardiovascular function should be carefully monitored • Central venous and urinary tract catheterization should be considered 99

Fluid resuscitation

• Rate of fluid administration may need to be limited in children • A limited number of reports of cerebral edema occurring during or soon after the resuscitation phase of patients with both DKA and HHNS have been described • Most cases have occurred in children with DKA and mechanism is unclear • One review showed cerebral edema was found with similar frequency before treatment with replacement fluids • New study shows rehydration of children with DKA during first 4 hours at a rate greater than 50 mL/kg was associated with increased risk of brain herniation • Little credible data on incidence or clinical indicators that may predispose to cerebral edema in HHNS patients 100

Fluid resuscitation

• Current recommendations based on available data include limiting rate of volume depletion during first 4 hours to <50 ml/kg of NS • Mental status should be closely monitored during treatment • CT of brain should be obtained with any evidence of cognitive impairment • Most authors agree use of NS is most appropriate initial crystalloid for replacement of intravascular volume • NS is hypotonic to the patient’s serum osmolality and will more rapidly restore plasma volume • Once hypotension, tachycardia and urinary output improve, ½ NS can be used to replace the remaining free water deficit 101

Potassium

• Potassium deficits are most immediate electrolyte-based risk for a bad outcome • On average potassium losses range from 4-6 mEq/kg though may be as high as 10mEq/kg of body weight • Initial measurements may be normal or even high with acidemia • Patients with levels <3.3 are at highest risk for cardiac dysrhythmia and respiratory arrest and should be treated with urgency 102 • Insulin therapy precipitously lowers intravascular potassium further and potassium must be vigorously

Potassium

• When adequate urinary output is assured, potassium replacement should begin • Should replace at 10-20 mEq/hr though if life threatening may require 40 mEq/hr • Central line needed if given more than 20 mEq/hr • Some believe potassium through central line poses risk for conduction defects and should be avoided if good peripheral line sites are available • Monitoring of serum potassium should occur every hour until a steady state has been achieved 103

Sodium

• Sodium deficits replenished rapidly since given NS or ½ NS during fluid replacement • Phosphate and Magnesium should be measured • Current guideline recommend giving 1/3 of potassium needed as potassium phosphate to avoid excessive chloride administration and to prevent hypophosphatemia • Unless severe, alleviation of hypophosphatemia or hypomagnesemia should occur after the patient is admitted into the ICU setting 104

Insulin

• Volume repletion should precede insulin therapy • If given before volume repletion, intravascular volume is further depleted due to shifting of osmotically active glucose into the intracellular space bringing free water with it and this may precipitate vascular collapse • Absorption of insulin by IM or SC route is unreliable in patients with HHNS and continuous infusion of IV insulin is needed • No proven benefit to bolus of insulin • Continuous infusion of 0.1U/kg/hour is best 105

Insulin

• Want one unit of regular insulin for every mL of NS in infusion • Steady states utilizing infusion pumps occur within 30 minutes of infusion • Decrease plasma glucose by 50-75 mg/dL per hour along with adequate hydration • If adequate hydration, may double infusion rate until 50-75 mg/dL/hr is achieved • Some patients are insulin resistant and require higher doses • Once level less than 300 mg/dL, should change IV solution to D5 ½ NS and insulin infusion should be reduced to half or 0.05 U/kg/hr.

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Disposition

• Need to track pH, vital signs and key lab values in the ED for appropriate management and disposition of these patients • ICU – Most require for initial 24 hours of care • SDU – Patients with no significant co morbid conditions and who demonstrate a good response to initial therapy as evidenced by documented improvement in vital signs, urine output, electrolyte balance and mentation 107

Questions

• • 1. T/F: The venous pH is just as helpful as arterial pH in patients with DKA and may be obtained during routine blood draws. 2. T/F: Alcoholic ketoacidosis is usually seen in chronic alcoholics but may be seen in first time drinkers who binge drink, especially in those with volume depletion from poor oral intake and vomiting. • 3. T/F: In treating DKA, the order of therapeutic priorities is volume first, then insulin and/or potassium, magnesium and bicarbonate. • 4. T/F: DKA patients have much higher levels of lipolysis, resulting in release and subsequent oxidation of free fatty acids to ketone bodies contributing additional anions resulting in a more profound acidosis than in HHNS. • 5. T/F: Volume repletion should precede insulin therapy in HHNS Answers: T,T,T,T,T 108