Diabetes Mellitus Diagnosis of Diabetes Mellitus Symptoms of DM (polyuria, polydipsia, unexplained weight loss with glucosuria and ketonuria) plus a random plasma glucose > 200 mg/dL. (Whole blood values are lower by 10-15 mg/dL). Of note, symptoms are most commonly absent. Fasting plasma glucose > 126 mg/dL. Fasting value determined in the morning after absence of caloric intake at least 8 hours. A1C >=6.5 percent OGTT (oral glucose tolerance test): Plasma glucose > 200 mg/dL at 2 hours during a 75g OGTT.
The diagnosis of diabetes must be confirmed on a subsequent day by using any one of the three criteria above. Insulin Therapy
Types of Insulin
Subcutaneous
Onset
Peak
Duration
Standard
IV insulin bolus
Immediate
20 - 30 min
2 - 3 hr
Regular (Humulin/Novolin R)
30 min - 1 hr
2 - 4 hr
6 - 8 hr
NPH (Humulin/Novolin N)
2 - 4 hr
4 - 10 hr
12 - 16 hr
Analogues
Insulin lispro (Humalog)
5 - 15 min
1 -2 hr
4 - 6 hr
Insulin aspart (NovoLog)
5 - 15 min
30 - 90 min
4 - 6 hr
Insulin detemir (Levemir)
3 - 4 hr
6 - 8 hr
6 - 24 hr (dose dependent)
Insulin glargine (Lantus)
2 - 4 hr
None
18 - 24 hr
Insulin sliding scale (check BG qAC and q.h.s. or q6hr if patient NPO) Remember to add long-acting insulin for more optimal BG control This may also be used to supplement standing pre-meal coverage used as an outpatient
Insulin Sliding Scale
Blood Glucose
Novolog Insulin SQ
0-70
D50 ½ amp IV, or orange juice, call HO
71-150
No coverage
151-200
2 units
201-250
4 units
251-300
6 units
301-350
8 units
351-400
10 units
> 400
12 units, call HO
Basic mixed/split insulin regimen Step 1: Calculate the total insulin requirement in 24 hours = weight (kg) x 0.5 A good start is 30 units, it is conservative to avoid hypoglycemia Step 2: Divide the total insulin requirement by 3: 2/3 of total requirement in AM, 1/3 in PM (need more insulin in AM since eating) Step 3: Divide the AM and PM doses by 3: 2/3 of the dose is NPH, 1/3 of the dose is regular (or Humalog or NovoLog) Doses of short-acting insulin can be further divided to provide pre-meal coverage May also estimate total daily insulin dose based on previous insulin sliding scale requirements
Guidelines to starting insulin glargine (Lantus) Multiple methods are utilized to convert to long-acting insulin after insulin requirements stabilize Recommend giving 0.5-0.6 units/kg with 50% of dose as Lantus and 50% as nutritional dose divided qAC. Then titrate dose as needed.
Guidelines to starting insulin drip (See Insulin Protocol Form)
Perioperative insulin management Maintain BG 100-180 mg/dL to prevent dehydration/ketosis, promote wound healing, optimize leukocyte function, avoid hypoglycemia. Start 5 gm/hr glucose infusion (i.e. D5 ½ NS + 20 mEq KCl @ 100 mL/h). Can start IV insulin (1 unit/h) and adjust for goal or, if surgery is minor and patient's glucose is well-controlled, give 50% of usual SC insulin (if NPH) in the AM of surgery and supplement with regular insulin q4-6 hr to achieve goal. Diabetic Ketoacidosis (DKA)
Pathogenesis: absolute/relative insulinopenia plus counter-regulatory hormones
Diagnosis: hyperglycemia (>250), ketogenesis (+ serum and urine ketones), acidosis (pH < 7.3 or bicarbonate < 15). Of note, if the patient is severely dehydrated, ketones may be negative secondary to a shift to b-hydroxybutyrate.
Symptoms: polyuria, polydipsia, N/V, abdominal pain, tachypnea, obtundation, coma
Treatment Guidelines: IV fluids: 1L normal saline in 1st hour, then assess volume status. May switch to ½ NS when intravascular volume repleted, add dextrose to fluids when glucose < 250, need to replete 5-8 liters on average, watch fluid status closely. Insulin: give fluids in 1st hour, then give 0.1 units/kg bolus followed by 0.1 units/kg/hour, titrate to decrease glucose by 100 mg/dL/hour. Do not start insulin if the potassium is < 3.3! Potassium: usual deficit 3-5 mg/kg, follow levels closely; do not replete until serum K < 5.5, careful if anuric. Potassium typically decreases rapidly with insulin, be careful! K 4-5, add 20 mEq/L to IVF; K 3-4, add 30-40 mEq/L to IVF until deficit repleted. Adding K to NS yields a hypertonic solution, which will not help the patient's hyperosmolality. If hemodynamically stable, add potassium (especially when using 30-40 mEq/L) to ½ NS. Phosphorus: Replete if < 1, usual deficit is 1mmol/kg. Bicarbonate: only give if pH <7.0, if 6.9-7.0 give 44 mmol (1 amp). If <6.9, give 88 mmol (2 amps), don't give until potassium repletion has been initiated Look for and treat potential precipitants (i.e. infection, MI)
Monitoring: hourly blood glucose for first several hours, then q2-4hrs, electrolytes (including Mg and Phos) q2hr until K/bicarb normalizing, then q4-6hrs, follow volume status closely, follow gap/pH/bicarb as index of treatment rather than ketones. Patient likely needs ICU care for nursing/monitoring. Hyperosmolar Nonketotic Coma (HONC)
Pathogenesis: decreased insulin, increased stress hormones, usually precipitating event
Characteristics: hyperglycemia, water deficit, hyperosmolarity, mental status changes
Diagnosis: serum glucose > 600-800, Osm > 350, mental status changes, absent to low ketones, no acidosis
Treatment: IV fluids: start with rapid repletion NS 2-3 liters, replete 1/2 estimated deficit within 6 hours (usual total deficit is 10 L), then change to ½ NS. Given the large amount of fluid administered, very careful monitoring of fluid status is imperative. Insulin: titrate to decrease glucose 100 mg/dL/hour, use regimen described above for DKA, only give insulin after fluid deficit is starting to be repleted and potassium level normalized. Consider antibiotics if infection suspected
Bind to nuclear receptors®peroxisome proliferator activated receptors®enhance expression of proteins that enhance cellular insulin action
No
Idiosyncratic hepatic failure, incLDL levels, weight gain, fluid retention (caution in CHF)
GLP-1 Mimetics [exenatide (Byetta)]
Main mechanism of action is the stimulation of glucose-dependent insulin release from the pancreatic islet cells. Also reduces the secretion of glucagons.
No*
May slow gastric emptying and cause nausea. *Mild to moderate hypoglycemia may occur when given with sulfonylureas.
DPP IV Inhibitors [vildagliptin (Galvus), sitagliptin (Januvia)]
Function as "incretin enhancers," inhibiting DPP-IV, an enzyme that breaks down GLP-1.
No*
*Hypoglycemia may occur when used with other agents
Adrenal Insufficiency Primary (Addison's Disease) Destruction of the adrenal cortex resulting in deficiency of cortisol and aldosterone.
Etiology: Adrenal destruction Autoimmune adrenalitis Autoimmune polyglandular syndromes Tuberculosis Metastatic disease Infiltration from amyloidosis, hemochromatosis, etc. Infection (histoplasmosis, crypto, cocci, blastomycosis; not candida) Adrenal hemorrhage (Waterhouse-Friderichsen) Dysgenesis/hypoplasia Impaired steroidogenesis Accelerated cortisol metabolism (i.e. thyrotoxicosis) Drugs (phenytoin, barbiturates, and rifampin accelerate cortisol metabolism; ketoconazole, etomidate, and metyrapone impair steroidogenesis). Secondary Pituitary or hypothalamic disorder resulting in deficiency of cortisol without aldosterone deficiency.
Etiology: Malignancy Pituitary surgery or irradiation Head trauma Lymphocytic hypophysitis Sarcoidosis Amyloidosis Histiocytosis X Empty sella syndrome Infections (TB, fungi, nocardia, actinomycosis) Drugs (Megace, progesterone, valproic acid, etc.) Also consider long-term glucocorticoid therapy if a patient has been on 7.5 mg daily of prednisone (or equivalent) for > 2-3 weeks (HPA axis may be suppressed for 8-12 months) Functional/Relative Adrenal Insufficiency Consider during sepsis or critical illness. High levels of inflammatory cytokines may inhibit cortisol synthesis and/or induce systemic or tissue-specific corticosteroid resistance. Clinical Manifestations Acute adrenal insufficiency can be lethal. Suspect in the setting of unexplained, pressor-resistant hypotension, abdominal pain, vomiting, high fever, confusion. Hyponatremia and hyperkalemia may or may not be present. Remember, in primary adrenal insufficiency, aldosterone deficiency causes both renal Na loss and impaired K excretion as well as H+ accumulation; in secondary deficiency, aldosterone is preserved. Therefore, hyponatremia is related to SIADH because cortisol deficiency causes inc ADH. Patients often have non-specific symptoms.
Adrenal Function Testing When is testing indicated? Signs and symptoms of adrenal dysfunction may be non-specific, therefore testing may be done based on the clinician's level of suspicion. Normal range of cortisol is 6-24 mcg/dl. In an ICU patient, normal values may be >= 25 mcg/dl. In some studies, baseline and post-ACTH serum cortisol < 23.7 mcg/dL predict responsiveness to exogenous steroids in septic shock.
AM cortisol: Drawn before 9 am; a value <= 3 mcg/dl indicates adrenal insufficiency, and concentrations >= 18-20 mcg/dl rule it out. Intermediate values necessitate dynamic testing.
ACTH measurement: helpful in primary adrenal insufficiency where ACTH > 100 pg/ml, even if the plasma cortisol is in the normal range. Normal ACTH values rule out primary but not mild secondary adrenal insufficiency
Cosyntropin stimulation test: This test evaluates for both primary and secondary adrenal insufficiency. In recent onset or mild secondary insufficiency, results may be normal given the supraphysiologic dose used in this test. Measure baseline cortisol 250 mcg of cosyntropin (Cortrosyn) is given IV (inject and flush in) or IM, and plasma cortisol is measured 30-60 minutes later. Of note, new tests are in-process using lower doses of cosyntropin (i.e. 1 mcg) to improve sensitivity of testing. Adrenal insufficiency is ruled out if basal or post-stimulation cortisol is >= 18-20 mcg/dl (using higher cutoff minimizes underdiagnoses). Some also consider a rise >= 9 mcg/dl or doubling of baseline as normal.
Metyrapone test: Metyrapone inhibits the conversion of 11-deoxycortisol (compound S) to cortisol (by 11-hydroxylase); the resultant drop in cortisol should stimulate the HPA axis. Metyrapone 3 gm (or 30 mg/kg) is given at midnight (with a snack, to minimize nausea) At 8 am the next day, cortisol, 11-deoxycortisol & ACTH are measured Normally, 11-deoxycortisol rises to >= 7 mcg/dl (simultaneous cortisol < 5-8 mcg/dl to insure adequate 11-hydroxylase inhibition) and ACTH rises > 150 pg/ml. Note that phenobarbital and phenytoin increase metyrapone metabolic clearance.
Screening for Cushing's syndrome (adrenal hyperfunction): Best test is 24 hour urinary free cortisol; normally UFC is < 90 mcg/day. May also use overnight dexamethasone suppression test: 1 mg dexamethasone given at 11pm-12mid 8 am cortisol measured next day, normally will be < 5 mcg/dl. A value > 10 mcg/dl suggests Cushing's syndrome. The above tests do not distinguish between causes of Cushing's syndrome.
Adrenal Replacement Therapy Physiologic Replacement Hydrocortisone 30 mg (20 mg qAM, 10 mg qPM) OR Cortisone 37.5 mg (25 mg qAM, 12.5 mg qPM) OR prednisone 7.5 mg (5 mg qAM, 2.5 mg qPM) For primary adrenal insufficiency, add fludrocortisone in a single daily dose (0.05-0.2 mg with adjustments for BP, serum potassium, peripheral edema, and plasma renin activity). Emergency Therapy Immediate high-dose IV hydrocortisone 100 mg bolus followed by infusion of 100-200 mg over the next 24 hours or intermittent IV dosing at 100 mg q6-8 hours. This provides adequate mineralocorticoid action, so fludrocortisone should not be added until the patient is tapered to oral glucocorticoids or the cumulative dose of hydrocortisone is < 100 mg/day.
"Stress dose steroids" is poorly defined but typically means at least 200-300 mg of hydrocortisone per day. If you are concerned about altering the outcome of cosyntropin stimulation testing, Decadron may be used. But, remember, Decadron does not provide the same mineralocorticoid effects as hydrocortisone. Other Considerations Regarding Corticosteroids in Shock Shock patients with cortisol increment <= 9 mcg/dl, after cosyntropin stimulation testing, had increased mortality in some but not all studies. Therefore, the benefit of corticosteroids in shock may be independent of adrenal insufficiency. It is recommended (Grade 1B) that IV corticosteroids be initiated in patients with septic shock immediately following completion of a high-dose ACTH stimulation test. Initiation of corticosteroids should not be delayed until test results are known. Consider discontinuation of corticosteroids in patients who have a maximum serum cortisol increase ³ 9 mcg/dl following ACTH stimulation and no hemodynamic response to corticosteroid therapy. Response is typically defined as vasopressor withdrawal within 48 hours of starting corticosteroids (Grade 2B). Consider continuing corticosteroids at full doses for 7 days, regardless of the clinical response, if the maximum increase of serum cortisol is <= 9 mcg/dl after ACTH stimulation (Grade 2B).
Adrenal Incidentaloma Differential Diagnosis Cushing's Syndrome Hyperaldosteronism Pheochromocytoma Adrenal adenoma or carcinoma Metastatic carcinoma Adrenal cyst Work-up 1 mg dexamethasone suppression test and measurement of plasma free metanephrine. If the patient is hypertensive, measure K and aldosterone/plasma renin activity ratio. Of note, a homogeneous mass with low attenuation value (< 10 HU) on CT is likely a benign adenoma. Management Surgery should be considered in all patients with functional adrenal cortical tumors that are clinically apparent. Data are insufficient to indicate the superiority of a surgical vs. non-surgical approach to manage patients with subclinical hyperfunctioning adrenal cortical adenomas. All patients with biochemical evidence of pheochromocytoma should undergo surgery. Masses < 4 cm are generally monitored. Masses between 4-6 cm need close follow-up. Masses > 6 cm require surgical removal. Masses that are stable on two imaging studies done at least 6 months apart and do not exhibit hormonal hypersecretion over 4 years may be followed on an as needed basis.
Pheochromocytoma Rare tumors arising from chromaffin tissue. 90% occur in the adrenal medulla and the remainder are abdominal or thoracic. 10% are bilateral, 10% malignant. Clinical Signs and Symptoms ½ - ? have sustained hypertension, though we commonly think of these patients as having paroxysmal symptoms. Hypertension is often refractory to routine management. Diagnosis Screen with 24 hour urine for metanephrines, VMA, and catecholamines. This test is very sensitive and specific if it is collected while the patient is symptomatic, resting, or off medications. Also consider testing for fractionated plasma free metanephrines as its sensitivity is 96-100%. If testing is inconclusive and clinical suspicion is high, check resting serum catecholamines. This test is finicky but, in general, > 1000 pg/ml is suggestive and > 2000 is diagnostic. Note that clonidine will decrease serum norepinephrine into normal range in essential hypertension, but not with pheochromocytoma. Localization Begin with a CT or MRI of the adrenal glands. If not apparent, scan more broadly. Metaiodobenzylguanidine (MIBG) scintigraphy may also be used. This test employs a norepinephrine analogue that concentrates in the adrenal glands and pheochromocytomas. Treatment Management is surgical with preoperative administration of phenoxybenzamine (alpha blockade) to control blood pressure. May also use propranolol as needed to control tachycardia.
Treatment: Antithyroid drugs: propylthiouracil (100-200 mg p.o. q8hrs), methimazole (20 mg p.o. q12hrs) Iodine and iodine-containing compounds (use with above) Radioactive iodine Surgery
Thyroid Storm
Cause: extreme thyrotoxicosis, usually with precipitating factor
Characteristics: fever (T > 106°F), mental status changes, tachycardia, arrhythmia, diaphoresis, CHF, agitation, delirium, psychosis, nausea/vomiting, diarrhea, jaundice, coma and hypotension late in course
Diagnosis: clinical. Initiate treatment while awaiting thyroid function tests given the high associated morbidly and lag-time on the results of the testing.
Treatment: ICU admission Propylthiouracil (PTU): loading dose 600-1000 mg (can give PO or PR), followed by 200-1500 mg daily given as 200-250 mg q4hr Iodine: given as Lugol's solution (1 drop q6hrs) OR SSKI = potassium iodide (5 drops q6hrs) OR Telepaque 1-3 g/day (must give at least 1 hour after PTU) b-blocker: give as propranolol 40-80 mg p.o. q 4-6 hours or 0.5 mg-1 mg IV OR esmolol 250-500 mg/kg then 50-100 mg/kg/min Hydrocortisone: 300 mg IV then 100 mg q8hrs with rapid taper as patient improves Tylenol: as antipyretic (do NOT give ASA) Intravenous fluids (may need to give up to 3-5 L/day) Panculture
Myxedema Coma
Cause: inability to compensate for severe hypothyroidism
Treatment: ICU admission, cardiac monitoring, low threshold for intubation, NO heating blankets 300-800 mcg IV T4 or PO followed by daily doses 100 mcg Hydrocortisone 100 mg IV q8hrs must be given with thyroid hormone until coexisting adrenal insufficiency has been ruled out, as thyroid hormone inc cortisol metabolism and can precipitate adrenal crisis. Empiric antibiotics Intravenous fluids as indicated
Non-Thyroidal Illness Syndrome
Definition: patterns of abnormalities in thyroid function tests observed in patients with severe illness (i.e. sepsis, trauma, malignancy, myocardial infarction), and those fasting or undergoing surgery. These lab abnormalities (i.e. dec T3, dec T4) often revert to normal if the patient recovers. Clinical features may take 2-3 weeks to develop and lab values are often suspect.
Lab findings: TSH: normal or reduced (yet, these are inappropriately low for the observed T4). This may be because low TSH is the proximate cause of this disorder (therefore the pituitary or hypothalamic function is impaired in these patients®supported by the fact that testosterone, FSH and LH also drop in serious illness). Free T3: reduced Free T4: variable
Given the elevated mortality risk, is thyroid replacement beneficial? The dogma in endocrinology has been that the decrease in thyroid hormone is a beneficial physiologic response and that it is difficult to advocate or even defend the treatment of NTI patients. But, there is also no definitive proof that treatment is disadvantageous.
Treatment (if administered): Given the high mortality rate in patients with T4 < 4 µg/dL and an absence of contraindications to replacement therapy, treatment may be initiated. The evidence is more uncertain in patients with cardiac decompensation or arrhythmias. T3 and T4 should be given together (50 µg/day with 75 µg/day over the first 3-4 days). Follow levels every 48 hours and adjust as needed to keep total T3 at low normal level (70-100 ng/dL). As patients recover, the ratio of T3:T4 replacement should shift toward increased T4 replacement. Further prospective studies are needed to determine the impact of thyroid replacement on mortality of critically ill patients.
dec TBG: androgens, glucocorticoids, nephrotic syndrome.
Block peripheral conversion of T4®T3: propranolol, glucocorticoids, propylthiouracil (PTU), methimazole.
Block synthesis of new T4 and T3: lithium, iodine, PTU, methimazole, amiodarone.
TSH (thyrotropin): Normal range 0.3-4.7 mIU/L Best marker of thyroid hypo- or hyperfunction, except in cases of pituitary disease.
Total Thyroxine (T4): Normal range 5-11 mg/dL Measures bound plus free T4. Since the majority (99.95%) of T4 is protein-bound, total T4 is affected by TBG concentrations and drugs/diseases affecting binding of T4 to TBG or TBG affinity for T4. In particular, elevated estrogens (OCP, pregnancy, etc.) lead to higher levels of TBG.
Triiodothyronine (T3) Resin Uptake: Normal range 25-35% Measures unoccupied protein-binding sites for T4 or T3. Thyroid hormone binding ratio (THBR, normal range 0.8-1.15) is ratio of T3 resin uptake in patient's serum to control serum. THBR is helpful in distinguishing hypothyroidism (THBR low) from non-thyroidal illness syndrome (THBR normal or high). UCLA lab now reports 1/THBR.
Free T4 Index: Normal range 5-11 Total T4 multiplied by THBR (or divided by 1/THBR).
Total T3: Normal range 75-175 ng/dL Measurement not indicated if hypothyroidism is suspected (will be normal in 20-30% of hypothyroid patients). In hyperthyroidism, T3 may increase disproportionately to T4 through augmented peripheral conversion as well as increased thyroidal secretion.
Free T3 index: Normal range 75-175 Total T3 multiplied by THBR
Free T4 by equilibrium dialysis: Normal range 0.7-2.2 ng/dL Most precise method since it measures free fraction directly. Heparin causes elevation of FT4 by dialysis.
Free T3 by dialysis: Normal range 210-440 pg/dL
Thyroglobulin Level: used in the management (not diagnosis) of thyroid cancer
Reverse T3: Normal range 10-24 ng/dL Elevated in hyperthyroidism, low in hypothyroidism, and often elevated in non-thyroidal illness syndrome as well as with amiodarone use. In thyrotoxicosis, a ratio of total T3/T4 (ng/mg) > 20 suggests Graves' disease or toxic multinodular goiter; T3/T4 < 15 suggests thyroiditis (subacute, silent), iodine-induced, or exogenous thyrotoxicosis.
Radioactive iodine uptake (RAIU): Patient should be on low iodine diet for 10 days before RAIU and scan. Use either 123I (short half-life, less radiation) or 131I. 24-hour uptake is normally 10-35%. Uptake correlates with level of thyroid hyperfunction or destruction. Particularly useful in differentiating Graves' disease from thyroiditis. Thyroid ultrasound is useful to characterize presence of nodules and size of gland. Thyroid hormone's influence on metabolism reflected in other lab tests: in hypothyroidism, cholesterol and CPK are elevated; in hyperthyroidism, they are decreased.
