Acute Complications of Diabetes Jane DIsa-Smith, D.O.

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

Diabetic Ketoacidosis

Introduction
DKA is an acute life threatening complication of DM 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

Pathophysiology
Bodys 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 -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 PGI2 and PGE2 are produced
This accounts for the paradoxical vasodilation that occurs despite the profound levels of volume depletion
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 PCO2 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 -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 PCO2 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 21 this population

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) 23 Have little to no anion-gap metabolic acidosis

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 26 clearance of ketoacids

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 D5 to solution when glucose level is between 250-300 mg/dL Change to hypotonic NS or D5 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

44

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 -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 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 -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 -hydroxybutyrate and acetoacetate only if diagnosis is unclear or other methods are not available to follow patients 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
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 DKA 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 D5NS 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 Wernickes 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

67

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
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 nonambulatory 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 77 approximately 8-12 L in a 70 kg person

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 F 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 nondiabetics 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 87 CVA or structural lesion

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 PCO2 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 others 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 94 and insulin therapy cannot be overemphasized

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 patients 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

99

Central venous and urinary tract catheterization should be considered

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 patients serum osmolality and will more rapidly restore plasma volume Once hypotension, tachycardia and urinary output improve, 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 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 NS and insulin infusion should be reduced to half or 0.05 U/kg/hr.
106

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