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DISEASE EXAM II NOTES

Objectives• Describe mechanisms involved in sodium and water homeostasis• Discuss signs and symptoms of hyponatremia and hypernatremia• Describe intracellular and extracellular potassium balance• Discuss signs and symptoms of hypokalemia and hyperkalemia• List common causes of chloride abnormalities• Discuss briefly conditions causing magnesium abnormalities• Discuss the relationship of vitamin D, parathyroid hormone in regulating calcium and phosphorus balance.

Total body Water (TBW)• Males – 60% or approximately 42 kg for a 70 kg man (more muscle mass)•Females – 50% or approximately 35 kg for 70 kg female- As you age, total body water decreases slightly

Fluid Compartments• Intracellular (ICF)–66% of TBW• Extracellular(ECF)-33% of TBW—moves freely

– Interstitial –80% of ECF– Intravenous-20% of ECF

Fluid Compartments for 80 kg male• TBW for 80 kg male = (80 kg) X (0.6) = 48 kg of water

• ICF = (48 kg) X (.66) = ≈32 kg• ECF = (48 kg) X (0.33) = ≈16 kg

• Intravascular = (16 kg) X (0.2) = 3.2 kg or 3 L• Interstitial = 16 kg X 0.8 = 12.8 kg or 13 L

• Whole blood – 5 liters• Plasma – 3 liters• Erythrocytes – 2 liters- Can lose ~10% of blood volume (~ ½ liter) without significant effects

- 50%: not a survivable condition (duh!)

Fluid Requirements• ≤10 kg = 100ml/kg/day• 11-20 kg = 1000 ml + 50 ml/kg/day for every kg over 10 kg• >20 kg = 1500 ml + 20 ml/kg for every kg over 20 kg• Adults usually 30 ml/kg/day- This is maintenance—will be more with fluid loss

**Note** In the revised slides he posted, several slides from the original lecture were omitted. Since he said his test questions come from the revised lecture, I did not include the slides he omitted.

Electrolyte Composition of Replacement Fluids

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Sodium• Normal Range 135-145 mEq/Liter (we only measure the concentration)• Functions

–Regulates serum osmolality– Acid/base balance– Transmembrane electrical balance

Sodium and Water Balance

Changes in Water & Sodium in Hypernatremia & Hyponatremia

Sodium Regulation• Antidiuretic Hormone (ADH)

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– Released from posterior pituitary in response to stimulus by the hypothalamus which responds to blood osmolality of the

brain when osmolality is high. (High serum sodium or low serum water)•Antidiuretic Hormone (ADH)

– Baroreceptors in left atrium and carotid sinuses will block ADH release if blood volume is normal preventing hypervolemia•ADH secretion

–decreases urine output and sodium loss–Increases collecting tubule permeability to water–Concentrates urine

- Normal adult urine output is 0.5 ml/kg/hr

Aldosterone• Released from the adrenal cortex in response to various dietary andneurohormonal factors such as:

– Low serum sodium– Low blood volume– Angiotensin II

• Affects the distal tubule• Increases the reabsorption of sodium and the secretion of potassium

Osmolality Effects• Equilibrium maintained between intravascular, interstitial, and intracellularcompartments• Water moves from areas of low osmolality to areas of high osmolality

Calculation of Osmolality (mOsm/Liter)•Serum Osmolality (mOsm/L) = (2 X Serum Sodium) + (Serum Glucose/18) + (Blood Urea Nitrogen/2.8)

•Normal Range = 280-300 mOsm/L

Chloride• Normal Range 95-105 mEq/Liter• Functions– Predominate extracellular anion– Acid-base balance (proximal tubulebicarbonate production and exchangewith chloride)– Passively follows sodium to maintainelectrical balancePotassium• Normal Range 3.5-5.0 mEq/Liter• 4000 mEq total/50 mEq (~1%) extracellular most K+ is inside cell• Functions

– Muscle/nerve excitability– Protein synthesis, carbohydrate metabolism

• Regulation of potassium–pH–Aldosterone

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– Insulin/glucagon–Distal and collecting tubule secretion– Colon secretion

Magnesium•Normal Range 1.5-2.2 mEq/Liter•2000 mEq total, 50% bone(this Mg is not available for physiologic use), 45% intracellular, 5% extracellular (1/3 protein bound)• Functions

–Neuron/Muscle function– Enzyme cofactor for phosphate transfer (ATP-dependent)

• Regulation not known• Competition with calcium

- they counteract each otherPhosphorus• Normal Range 2.6-4.5 mg/dl• Major intracellular anion• 85% in bone, 15% in ECF, cell membranes, and collagen

- the phosphorus in bone is relatively inactive• Functions

– Intracellular protein, fat, and carbohydrate metabolism– Major component of phospholipid membrane, RNA, NADP, and ADP production– Buffer for acid-base balance

• Regulation– Vitamin D

• ↑ calcium and phosphorus GI absorption, PTH-induced mobilization of calcium and phosphorus, calcium and

phosphorus reabsorption in proximal tubule– Parathyroid Hormone

• Maintain adequate ionized calcium, reabsorption of calcium and phosphorus from distal nephron, osteoclast activity

– pH• Shifts phosphorus to balance pH

Calcium• Normal Range 8.5-10.8 mg/dl• 1000 g total, 0.5% extracellular fluid

– 6% complex bound– 40% protein bound (albumin)– 54% ionized

• Adjusted Ca+2 =Measured Ca+2 + [0.8 X (4.0 – Serum Albumin)]• Functions

– Neuromuscular activity– Regulation of endocrine function

• Pancreatic insulin release• Gastric acid secretion

– Coagulation– Platelet aggregation– Bone and tooth metabolism

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• Regulation of Calcium– Vitamin D

• ↑ calcium GI absorption, PTH-induced mobilization of calcium, calcium reabsorption in proximal tubule

– Parathyroid Hormone• Maintain adequate ionized calcium, reabsorption of calcium

and phosphorus from distal nephron, osteoclast activity– Calcitonin

• Inhibits osteoclasts activity inhibits breakdown of bone

Compartmental Electrolyte Composition

Hyponatremia (Serum Sodium <135 mEq/L)• Other clinical and laboratory findings often needed to assess serum sodium status

–Volume status–Physical Findings–Laboratory Findings

• Usual Causes– Diarrhea, low salt diets, diuretics, CHF, cirrhosis, hypotonic

solutions, adrenal insufficiency, syndrome of inappropriate ADH (SIADH)

- SIADH: most common condition: cancer (my notes weren’t written very well, I’m not sure what

I meant to write here)

• Signs and Symptoms– Altered mental sensorium, depressed deep tendon reflexes, nausea, coma, seizures

- With altered sensorium, will eventually get so sleepy, that it leads to coma

- Coma and seizures due to brain swelling- CHF and cirrhosis: water overload

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- Emergencies can be fatal (<106 mEq/L)

Pseudohyponatremia• 2° to Elevated Triglycerides

– Triglyceride level X 0.002 = ↓1 mEq in Serum Sodium• 2° to Elevated Glucose

– ↑ Glucose 100 mg/dl = ↓1.6 mEq in Serum Sodium• Treatment = correct underlying condition

Hyponatremia (Serum Sodium <135 mEq/L)• Hypovolemic, Hyponatremia

– BP, Urine Output low– Dry mucous membranes, poor skin turgor– Serum osmolality low– Urine sodium normal to low –hypotonic fluid loss (diarrhea)– Urine sodium high-diuretic, renal defect, adrenal insufficiency

• Treatment = Replace fluid loss, sodium loss, and underlying condition

• Hypervolemic, Hyponatremia– BP-normal to high, urine output normal– Wet mucous membranes, lungs (crackles), edema (most commonly)- skin is swollen with glssy, translucent appearance– Serum sodium,osmolality are low– Urine sodium <20 mEq/L – heart or liver failure– Urine sodium >20 mEq/L – renal failure

• Treatment – decrease free water and salt (diuretics, water and salt restriction)

- Three diseases that cause increased water retention:1. Heart failure2. Liver failure3. Renal failure—look at sodium in urine

- In hospital, most salt patients usually get is in IV solutions want to restrict NaCl

• Isovolemic, Hyponatremia– BP and urine output normal– Serum sodium, osmolality are low– Normal skin turgor, no edema– Urine sodium and osmolality are high

• SIADH

– Urine sodium osmolality are low• H2O intoxification

• Treatment = free water restriction, identify source of SIADH and remove (mainly too much ADH is released—could be tumor)- Patients with psychiatric disorders: fear that they will shrivel if they don’t drink water constantly

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- Also, athletes: overcompensate by drinking too much water (usually transient)

Severe Hyponatremia (Serum Sodium <120 mEq/L)• Medical Emergency• Mental Status Changes (brain swells)

– Somulence to confusion to coma to seizures to death• Treatment Goal = Sodium >120 mEq/L

– Correct slowly (0.5 mEq/hr, 8 mEq/day)—some say 8 – 12 mEq/day– Too fast = Central Pontine Myelinolysis (irreversible) but not fatal

- degradation of myelin sheathneuropathic syndrome– Sodium Replacement (mEq) = Desired mEq/L rise in Sodium X TBW– Use NaCl 3% to correct (0.5 mEq/ml)

- must use a very hypertonic salt solutionExample:• 100 kg male with Na+ = 110 mEq/L• Goal in 1st 24 hrs = 118 mEq/L• 8 mEq/L increase in 24 hrs (118 mEq/L-110 mEq/L)• 8 mEq/L X TBW (60 kg) = 480 mEq Na needed• Use 3% NaCl = 0.5 mEq/ml

– 3% NaCl = 30 mg/ml– 30 mg/ml divided by 58 mg/1 mEq =0.5 mEq/ml Na+

• 480 mEq Na+ X 0.5 mEq/ml = 960 ml of 3% NaCl over 24 hrs– 960 ml divided by 24 hrs = 40 ml/hr infusion rate

• To correct to normal of 140 mEq/L would require additional 3% NaCl, but exceeding 8 mEq/day increase in 24 hr period

Hyponatremia Algorithm

Hypernatremia (Serum Sodium >145 mEq/L)• Usual Causes

– Decreased water intake, fever, NaCl>water intake, diabetes insipidus (ADH deficiency that leads to symptoms of diabetes, hyperventilation

• Signs and Symptoms– Altered mental sensorium, agitation, muscle twitching, coma,

seizures, death- brain contracts brain stem gets compressed against spinal cord

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• Hypovolemic, Hypernatremia– BP, urine output are low– Mucous membranes dry, skin turgor poor– Serum sodium,osmolality are high– Urine sodium >20 mEq/L, urine osmolality >100 mOsm/kg H20

• Usual causes-– Hypotonic fluid loss (diarrhea, sweating), excessive diuresis (loops),

burns over large area of body• Treatment – replace free water deficit, correct underlying cause, reduce or discontinue diuretics• Free water deficit (L) = [1- (140/current Na)] x TBW (L)

Hypernatremia (Serum Sodium >145 mEq/L); Correction of Free Water Deficit• Free water deficit (L) = [1 - (140/current Na)] X TBW (L)•100 kg male with Sodium –150 mEq/L• Free water deficit (L) = [1- (140/150)] X 60 (L) = 4 liters- He also needs normal maintenance of 30 ml/kg/day 3000 ml + 4 L = 7 L- usually give 1-2 liters very fast, then look at urine output and make up blance over 24 to 48 hours

(Refer as needed to Electrolyte Composition of Replacement Fluids in table above to apply to these different states)

Hypernatremia (Serum Sodium >145 mEq/L)• Hypervolemic, Hypernatremia

– BP and urine output are normal– Mucous membranes normal, skin turgor normal to “translucent ”,

edema present– Serum sodium, osmolality are high– Urine sodium >20 mEq/L, urine osmolality >100 mOsm/kg H20 (body trying to get rid of Na+)

• Usual causes-– Excessive intake of sodium

• Treatment – salt & water restriction ± diuretics (usually don’t have to use diuretics)

• Isovolemic, Hypernatremia– BP normal, urine output increased– Mucous membranes normal, skin turgor normal– Serum sodium, osmolality are high– Urine sodium <10 mEq/L, urine osmolality <100 mOsm/kg H20

• Usual causes-– Diabetes insipidus (DI), osmotic diuresis (mannitol, glycosuria), T2DM

• Treatment– Replace free water and salt, correct ↑sugar (because can occur in

DM patients with high blood sugar)– DI-desmopressin – replace hormone– NDI-demeclocycline

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- usually a defect with kidney (water loss from kidney)- NDI: nephrogenic diabetes insipidus; most commonly caused

by Li2+

- 150 – 300 mg BID tetracycline; causes excretion of Na+

Hypernatremia Algorithm


Hypochloremia (Serum Chloride <95 mEq/L)• Assessment

– Chloride low– pH and CO2 may be high

• Causes– Vomiting– Metabolic alkalemia

• Correct alkalemia and replace chloride loss with NaCl 0.9% (154 mEq/L) or Lactated Ringers (Na 130 mEq/L, Cl 109 mEq/L)- try to estimate volume loss and replace ml for ml- IV is route of choice

Hyperchloremia (Serum Chloride >105 mEq/L)• Assessment

– Chloride high– pH and CO2 may be low

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• Usual causes– Dehydration– Metabolic acidemia

• Correct acidemia, replace fluid with NaCl 0.45% (77 mEq/L)


Hypokalemia (Serum Potassium <3.5 mEq/L)• Assessment

– EKG –T-wave amplitude depression, ST depression, QRS widening– Arrhythmias– Muscle weakness, cramping- many places now say 3.5 is too low will supplement when K+ <4

• Causes– Metabolic alkalosis (intracellular shift) – Not net decrease– Low dietary intake, alcoholism, anorexia, bulimia– Increased loss from vomiting, diarrhea, fistulae– Renal loss from diuretics, corticosteriods, amphotericin B, chemo

agents

Hypokalemia Algorithm- 1st: look for transcellular shiftr due to metabolic alkalosis

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Hypokalemia Replacement

Hypokalemia (Serum Potassium <3.5 mEq/L)**must have patient on cardiac monitor**

- (Adverse Reactions) Also: extravasation: solutions leak through veins into tissues very irritating; looks like chemical burn

Hyperkalemia (Serum Potassium >5.0 mEq/L)•Assessment

–EKG –T-wave amplitude peaking–Arrhythmias, cardiac arrest–Muscle twitching/tingling

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- many patients have become accustomed to high K+ levels and don’t experience effects like these (mainly renal failure patients)

Hyperkalemia EKG Changes

Hyperkalemia (Serum Potassium >5.0 mEq/L)• Usual causes

– Metabolic acidosis (extracellular shifting—e.g., due to cell damage) – no net increase

– Increased intake• Endogenous-rhabdomyolysis, hemolysis, muscle crush injury,

burns• Exogenous-salt substitutes, drugs (penicillin), ACEI

– Decreased output• Renal failure (most common), drugs, Addison’s disease

• Treatment– Correct pH if acidemic, may need sodium bicarbonate– Glucose 50% 50cc IV + Regular Insulin 10U IV– Sodium Polystyrene Sulonate Resin – ion-exchange resin

• 15 g in sorbitol orally – causes nausea; awful tate• 30-60 g in sorbitol rectally

– Hemodialysis—best, most effective


Hypomagnesemia (Serum Magnesium <1.5 mEq/L)• Assessment

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– Muscle irritability, tremor, tetany– EKG-prolonged QT interval, arrhythmias

• Causes– Decreased intake (alcoholics), malnutrition

- cancer patients, chronic diuretic therapy (loops)– Increased loss-diuresis

• Treatment– Oral Magnesium for Mg>1.0 mEq/L

• Magnesium Chloride 64 mg (5.3 mEq) TID-QID• Magnesium Oxide 400 mg (19.8 mEq) BID- Mg not well absorbed from GI tract- Mg salts cause osmotic diarrhea

– IV/IM Magnesium Sulfate 50% (4 mEq/ml) for severe deficit (<1 mEq/L)

• 1.0 mEq/kg/daily until Mg>1.0 mEq/ml- IM is extremely painful

Hypermagnesemia (Serum Magnesium >2.2 mEq/L)--Signs and Symptoms

Hypermagnesemia (Serum Magnesium >2.2 mEq/L)• Usual causes

– Increased intake (antacids)– Decreased excretion – renal failure, Addison’s disease, hepatitis

• Treatment– Hemodialysis – treatment of choice– Calcium gluconate IV 1 gm to reverse cardiac effects of high Mg (>10 mEq/L)

- Calcium and magnesium compete for same sites—not really lowering Mg level, except for forcing body to excrete Mg

ACID BASE DISORDERS

I. DefinitionAcid/Base disorders are marked by H+ ion disturbances in homeostasis which isnormally maintained by:

1) Extracellular Buffering

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2) Renal Regulation of H+ ion and HCO3-

3) Ventilatory regulation of CO2 lossII. General PathophysiologyBuffering refers to the ability of solution to resist pH change with addition of strongacid or base. In humans, principle ECF buffer system is H2CO3/HCO3- (Carbonicacid/Bicarbonate)- electroconductivity is altered can cause patient to go into cardiac arrest

Four Primary Acid/Base DisturbancesThose associated with gain or loss of H+ or HCO3- are:

1. Metabolic Acidosis2. Metabolic Alkalosis

Those associated with the rise or fall of arterial CO2 tension (PaCO2) are:3. Respiratory Acidosis4. Respiratory Alkalosis

- Arterial blood is harder to draw, but is fresher and is therefore more accurate

Acid /Base disturbances may occur:1. Independently (e.g., Overdose of ASA)

or2. In a complementary compensatory response – e.g., acidic in kidneys blow off CO2

Diagnosis of ABG’sRefer to Article: “Turn ABGs into Child’s Play”

- pH of the blood is an indication of the [H+] what is this formula???pH = pKa – log [HA]/[A-]

Remember These RangespH of normal arterial blood is: 7.35 - 7.45 (homeostasis)pH of < 7.35 indicates acidosispH of >7.45 indicates alkalosis

Acidosis- pH of < 7.35 indicates acidosis with two possible causes:

1. Increase in amount of Acidic Substances (DKA)2. Decrease in amount of Basic Substances (bicarb)

Alkalosis- A pH of > 7.45 indicates alkalosis with two possible causes:

1. Increase in the amount of alkaline substancesor

2. Decrease in the amount of acid substances- increased tidal volume blowing off CO2

- Since CO2 combines with H2O in the blood to form carbonic acid (H2CO3)

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it is considered an acid.- Therefore, CO2 is a respiratory parameter affecting pH.

Remember These Ranges- Normal partial pressure of CO2 in blood (PaCO2) ranges from 35-45 mm of Hg

- When PaCO2 is high (>45) as seen in COPD the pH drops resulting in respiratoryacidosis (can’t breathe well)

- When PaCO2 is low (<35) as seen in hyperventilation, the pH rises resulting inrespiratory alkalosis (e.g., panic attack)

Bicarbonate Ion in the Blood- The principal alkaline substance in blood is bicarbonate [HCO3]. A metabolicparameter , it binds with hydrogen ions in the blood to slowly decrease [H+]concentration.

- Therefore, pH rises- excreted in urine

Serum Bicarbonate Ranges- Normal serum bicarbonate ranges from 22 to 26 mEq/L

- If [HCO3] rises then pH rises Metabolic Alkalosis (Cushings or prolonged vomiting)

- If [HCO3] falls then pH falls Metabolic Acidosis (diarrhea or renal disease)

Placing the Parameters on a Grid- If you can remember the following acid/base parameters on the followinggrid, then diagnosing acid/base disorder becomes child’s play (hmm, the games when I was a kid were more fun)

Acidic Normal Alkaline

pH < 7.35 7.35 – 7.45 > 7.45PaCO2 > 45 35 – 45 < 35HCO3- < 22 22 – 26 > 26

- The body strives to maintain a normal pH. When diseases or other conditionsupset homeostasis, healthy lungs or kidney may work to offset fluctuations in pH.

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- In COPD, a patient may hypoventilate and cause CO2 to rise. The result will be a respiratory acidosis. The kidneys may compensate by excreting H+ and absorb more HCO3

Questions That Require AnswersTo diagnose an acid/base balance disorder 3 questions need to be answered:

1) Does the pH indicate acidosis or alkalosis?2) Is the cause of the pH imbalance respiratory is it of metabolic origin?3) Is there compensation for the acid/base imbalance?

Apply Grid Technique to Find AnswersConsider the following patient:

60 yo wm with uncontrolled DM Type 1 has the following ABGs:pH = 7.26PaCO2 = 42 mm HgHCO3 = 17 mEq

- If pH and PaCO2 fall into the same column (other than normal) the disorder may be categorized as Respiratory Acid Normal Alkaline

Acid Normal AlkalinepH (7.26) PaCO2 (42)HCO3- (17)

- However, if as in the example above, pH and HCO3 fall in the same column (other than normal) the disorder is termed Metabolic

(Case Continued)- Next, look at the parameter not associated with pH. In this patient’s case it is PaCO2.- It is in the normal range, therefore there is no evidence of compensation.

- Therefore the condition is: Acute Metabolic Acidosis without Compensation

Case to Analyze for Next Class- Patient Mr. Cough is a 54 yo bm with COPD, has had SOB for two days and currently smokes 2.5 packs per day. His ABGs are as follows:

pH = 7.26, PaCO2 = 52, and HCO3 is 34- What type of acid/base disorder does Mr. Cough suffer from and is compensation present?

Acid Normal AlkalinepH (7.26) HCO3 (34)

PaCO2 (52)Respiratory Acidosis with Compensation

- Readings from pages 998 – 1011Acid/Base Balance (review only) pages 995 – 996

We Completed Diagnosis of Acid/Base Disorders, now on to Primary Conditions causing these Disorders

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I. Respiratory AlkalosisA. Pathophysiology -- low PaCO2 (hypocapnia) occurs when ventilation excretion exceeds production because of hyperventilation

- capnia = smokeB. Causes: Hyperpnea, Fever, Anxiety, Cerebral Disease (Tumor or Vascular Accident)

Symptoms and Treatment of Respiratory AlkalosisC. Symptoms: Numbness, Tingling, Nausea/Vomiting, Light headednessD. Treatment:

1) Direct measures to treat underlying cause: Fever/Pain/OD2) Rebreathing CO2 - Paper Bag

II. Respiratory AcidosisA. Pathophysiology: initially caused by primary retention of CO2

therefore lower blood pH results in a compensatory response of increase in HCO3

B. Results from disorders that restrict or decrease ventilation or increase CO2 production or perfusion abnormalities (pulmonary embolism or cardiac arrest)

-Other Abnormalities Likely to Cause Respiratory Acidosis:

- COPD- Pulmonary Edema- Pneumonia- Neuromuscular Insults:

- Trauma- Stroke- Narcotic Overdose

C. Clinical Picture of Respiratory Acidosis- Altered Mental Status – lack of oxygen getting to brain- Seizures- Stupor- Coma- Altered cardiac contractility

D. Treatment Recommendations:- If patient is hypoxic, provide adequate ventilation- Most importantly treat the underlying cause aggressively!- If Narcotic Overdose -- Reverse with antagonist- Suggestions???- What about multiple drugs with BZDs?

- Overdose on TCA’s with BZDs may be beneficial because BZD counteracts seizures caused by TCAs best

treatment is to put patient on ventilator

III. Metabolic Alkalosis

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A. Pathophysiology: Characterized by increase in HCO3 in plasma- If patient has fluid loss, will make bicarb appear high- Initiating Events can be characterized as

1) NaCl Responsive2) NaCl Resistant

Most Common Initiating Events for Metabolic Alkalosis are:

- HCO3 is gained because of diuretics reducing fluid volume

- Nasogastric suctioning- Prolonged vomiting- These above events are considered NaCl responsive- Don’t give NaCl to CHF patient because it will cause fluid

buildup

NaCl Resistant Disorders- Resistant Disorders are associated with excess mineralocorticoid activity:

- Cushing’s Syndrome- Aldosteronism- Pheochromocytoma

Clinical Pearls- NaCl responsive disorders are usually associated with

urinary Cl- of approximately 10 mEq- NaCl resistant disorders are usually associated with

urinary Cl- of greater than 20 mEq

B.Clinical Picture of Metabolic Alkalosis- Not terribly unique- Patient may complain of muscle weakness this due usually to

potassium depletion- Patient may complain of muscle weakness due to volume

depletion

C. Diagnoses of Metabolic Alkalosis Etiology- Based more on patient history rather than laboratory data- Look for history or nursing notes mentioning any of the

following:- Vomiting- Nasogastric Intubation- Diuretics

D. Treatment of Metabolic Alkalosis- Remember it will depend on whether the disorder is NaCl

responsive or NaCl resistant- For Responsive Type - Expand the intravascular volume and

replenish chloride stores with NaCl or KCl solutions unless

patient has CHF- For CHF patient utilize carbonic anhydrase inhibitor

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NaCl Resistant Disorders- For NaCl Resistant Disorders - treat the underlying

condition:- Remove excess mineralocorticoid activity- Surgical excision of hyperactive tissue

IV. Metabolic AcidosisA. Pathophysiology - results from low HCO3 due to renal losses,

decreased regeneration of bicarbonate in the kidneys, or due to acid ingestion

(ideas)- 81 mg ASA looks like candy likely for children to overdose

- The lungs attempt to compensate by blowing off CO2 by increasing the rate and depth of breathing (Kussmaul

breathing)

Types of Metabolic Acidosis- There are two types of metabolic acidoisis:

1. Non-anion gap acidosis2. Positive anion gap acidosis

- How can you discern the difference?

Determining and Calculating Anion Gap- The Number of positively charged ions in the plasma

must equal the negatively charged ions:Na+ = Cl- + HCO3- + unmeasured ions

- Unmeasured anions consist of plasma proteins, and negatively charged ions like SO4 and PO4

not usually seen in typical clinical laboratory tests- Unmeasured anions have a combined ionic strength of

some 8 to 16 mmoles/L or (8 to 16 mEq/L)- This value of 8 - 16 mEq/L is called the anion gap and

rarely changes- Let’s take a couple of sample cases and determine some

anion gaps (I can’t wait!)

Case 1 - Pt. 60 yo male with 3 day history of n/v due to food

poisoning- Initial Lab Data Includes:

- Sodium 133 mEq/L- Potassium 2.8 mEq/L- Chloride 118 mEq/L- pH 7.22- pCO2 12 mm Hg- Bicarbonate 6 mEq/l

- Calculate anion gap 6 mEq/L Bicarbonate +118 mEq/L Chloride

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124 mEq/l

133 mEq/L Sodium - 124 mEq/L Bicarbonate and Chloride 9 mEq/L normal gap (within 8-16)

Case 2- Pt. DM 1 with extended n/v from flu, no insulin in 3 days

admitted to hx- Initial Laboratory Data includes:

- Sodium 159 mEq/L- Potassium 3.0 mEq/L- Chloride 120 mEq/L- pH 7.2- pCO2 12 mm Hg- Bicarbonate 6 mEq/L

- Calculate Anion Gap 6 mEq/L Bicarbonate + 120 mEq/L Chloride 126 mEq/L

159 mEq/L Sodium - 126 mEq/L anions (Potassium and Cl) 33 mEq/L positive gap (ketoacidosis)

B. Clinical Picture of Metabolic Acidosis- Hyperpnea (normal = 12 – 20)- Kussmaul’s respirations: 30 – 34, usually- Flushing of skin- Tachycardia

C. Diagnosis of Underlying Condition causing the Metabolic Acidosis

1. If Normal Anion Gap of 8-16 mEq/l- Use Mneumonic “D R A B” suspect:

DiarrheaRenal Tubular AcidosisAcetazolamideBricker’s Pouch (fistulae) – opening in abdominal

area—lose fluid

2. If Positive A nion Gap Exists 17 mEq/L or greater- Utilize Mneumonic “SLUMPED”

SalicylatesLactic AcidosisUremiaMethanolParaldehyde

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EthanolDiabetes

D. Treatment of Metabolic Acidosis1. For Non-anion gap - correct underlying cause and replace bicarbonate deficit2. For positive anion gap – always correction of the underlying

problem, only give bicarbonate if pH is below 7.1- usually recommend 1 or 2 amupules because cardiac

function is at risk- Never aggressively change plasma pH relative to that in the

CNS—seizures may result

ACUTE RENAL FAILURE

Objectives• Understand the pathophysiology of ARF• Identify patient’s ARF as pre-renal, intrinsic, or postrenal based on Hx, physical findings and evaluation of blood and urine• Describe and understand the role of different medications used in ARF• Given a patient in ARF student would rationalize the different approaches needed to control the patient’s condition

Indications for Dialysis:Acid/Base Imbalance (Acidosis)Electrolyte ImbalanceIngestionOverload of volumeUremia

Creatinine is a byproduct of metabolism of muscle breakdown; normal = 0.5 – 1.5 mg/dL

Ideal Marker to Measure Kidney Function Creatinine1. Must be completely excreted by kidneys 2. Should not be reabsorbed 3. Should not be secreted -- ~10% secreted4. Should not be metabolized by kidneys5. Should not affect kidney function itself

Markers1. Inulin – polysaccharide which meets all of the above criteria

- However, it must be given to patient since it is not endogenous- Also is expensive; there are certain techniques needed to identify it

2. Sinistrin – polysaccharide3. Iothalmate – dye bad effect on kidney4. Iohexal – low molecular weight5. Cystatin C – non-glycolsylated protein produced by body and independent of gender, body mass, and inflammatory conditions

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Physiological Factors with Creatinine1. Muscle mass – correlates with age, weight (obese patients have high Cr), gender2. Exercise – causes SCr to increase3. Diurnal rhythm – active in morning; SCr peaks ~7:00 PM4. Diet – increased SCr in those who eat high protein5. Drugs – e.g., cimetidine, trmethoprim, probenicid—compete with secretion of creatinine

- cimetidine competes with SCr, so it gets completely filtered and gives an accurate value

- The overestimation from basal: 30 3%--gave 400 mg cimetidine caused ratio to change from 1.3 1.03, giving accurate value**Bear with me, I honestly thought this made sense at the time I took

these notes**

Definitions• ARF is defined as sudden, normally reversible impairment of the kidneys’ ability to excrete the body’s nitrogenous waste products of metabolism• Acute renal failure

– increase in SCr > 0.5mg/dl (baseline <3mg/dl)– increase in SCr > 1.0mg/dl (baseline >3mg/dl)– decrease CrCl > 50%– deterioration over several days resulting in the failure of kidney to excrete waste and maintain fluid and electrolyte

balance– decrease in renal function that results in need for dialysis

• Anuria– < 50ml of urine qd

• Oliguria– 50 - 400ml of urine qd

• Non-oliguria– > 400ml of urine qd- these patients do better in reversing their conditions 1st always try

to switch patient from anuria to non-oliguria• Azotemia

- increased BUN or nitrogenous waste; signs and symptoms of a decrease in GFR

- SCr > 1, use 1- In obese patient (>20% of IBW), use the following corrected

weight:Corrected weight = [(Actual wt – IBW)*0.4] + IBW

Epidemiology• Occurs primarily to inpatients

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– 2-5% of all inpatients develop (ICU 6-23%)– 25% of patients with ARF unassociated with surgery or trauma die– 50-70% with trauma ARF die

• ~ 1% of outpatients develop; >95% recover• 30% of patient who experienced ARF will require RRT- SUPPORT: Study to Understand Prognosis & Preferences for Outcomes and Risk of Treatment

- looked at expected 6 month mortality; QALY (cost figures for disease states) was almost 169,000 for ARF; 45,000 for MI; 31,000 for

HTN)

Two Types of Risk Factors for ARF1. Modifiable

A. volume depletion (vomiting, hemorrhage, high diuretic intake)B. IV contrat

- use of Mucomyst® may helpC. Nephrotoxic Agents

- Abx: aminoglycosides, amphotericin B use once-daily dosing for aminoglycosides rehydration

D. NSAIDs—both nonselective and COX-2E. ACEI and ARBF. Immunosuppressive agents

- cyclosporine; tacrolimusG. obstruction

2. Non-ModifiableA. Genetics

- kidney stonesB. DMC. HTND. cancerE. Infection/sepsisF. Age

- at age 40, there is an annual decrease in GFR

Etiology

- Body may adapt to a low GFR by increasing secretion of creatinine: SCr may appear normal, even when there is failure

- use of cimetidine may have a role

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Prerenal• 70% of community acquired ARF• 40% of hospital acquired• Rapidly reversible in patients with normal baseline renal function• NO structural defect in the kidney only a decrease in delivery of blood toglomerulus (only when compensatory RAS is overwhelmed)

Prerenal – Decrease in Renal perfusion• Hypovolemia

- dehydration, hemorrhage, diuresis• Decrease cardiac output

- CHF, MI, drugs• Decrease in vascular tone

- Sepsis (severe HTN), drugs• Decrease in intravascular volume

- third spacing, burns• Increase in vascular tone (svere vasoconstriction will block flow of blood)

- drugs• Blockage

- renal artery stenosis, emboli

Control of GFR (glomerular filtration rate)• GFR is regulated by filtration pressure (intraglomerular pressure) and glomerular blood flow• Both of these are dependent on the afferent and efferent arteriole• These arterioles work independent of each other

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Prerenal – decrease in glomerular ultrafiltrate• Drugs

– ACE, Ang-II receptor blocker• Ang-II causes vasoconstriction of both afferent and efferent arteriole

– NSAID• Cause afferent vasoconstriction by decreasing afferent vasodilatation prostoglandins (PGE2)- Predisposing risk factors with NSAIDs:

- CHF, cirrhosis, nephrotic syndrome, chronic renal failure, hypovolemia, atherosclerotic disease of renal

arteries– Cylcosporin and tacrolimus

• Cause afferent vasoconstriction– Radiocontrast

• Hypotension, renal vasoconstriction, osmotic diuresis, free radical production

- directly proportional to dose, molecular weight, and charge- Risk factors for development of ARF with contrast:

- hypotension, CHF, hypokalemia, decreased renal function (CrCl < 35%), diabetic nephropathy, characteristics of the contrast dye (see above)• Hepatorenal syndrome

– Afferent vasoconstriction (endothelinsecreted in blood vessels)- treatment: new liver- Some studies show that the following can “buy time”: octreotide,

albumin, midodrine (vasoconstrictor)

Post Renal –Obstruction• Accounts for < 5% of cases• GFR decreases due to hydrostatic changes in the glomerulus• No structural damage unless prolonged obstruction• Must be bilateral and complete for anuria• Common causes

– Drugs– Tumor– prostatic hypertrophy– stones

Obstructive Nephropathy• Uric acid (stones)

– Chemotherapy (tumor lysis syndrome), probenecid- colchicine: pain control- allopurinol: hyperuricemia

• Rhabdomyolysis– Heroin, alcohol, statins, cocaine

• Tubular precipitation

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– Acyclovir, Vit. C, Methotrexate, Sulfonamides, triamterene

Intrarenal• Damage to kidney structure• Classified according area of injury

• Glomerulus (Acute glomerulonephritis)• Tubules (Acute Tubular Necrosis *ATN)• Interstitial (Acute Interstitial nephritis)• Vascular

• PRERENAL and POSTRENAL may lead to intrarenal

Acute Tubular Necrosis : ATN• Most common cause of intrarenal ARF in hospitalized patients• Usually a complication of meds, surgery, or sepsis• Injury:

– Direct damage to tubule results in epithelial necrosis and sloughing• Injury leads to

– Decrease in urine concentration ability– Defective Na+ reabsorption– Decrease in GFR

- three active transporters:- cationic, anionic, or D glycoprotein

Causes of ATN• Ischemia – from decrease in RBF

– Hypoxia worse in some areas of kidney– Most reversible if caught early

• Toxins – tend to concentrate in tubule– Exogenous (i.e., drugs)– Endogenous

• Myoglobin, hemoglobin, uric acid

Acute Interstitial Nephritis : AIN• Often reversible when offending agent is removed• Interstitium provides structural support and concentration gradients• Causes

– *Drugs– Infection

• Streptococcal, viruses, others- usually non-oliguric

Acute Glomerulonephritis• Uncommon (incidence 2 – 4%)• Alteration in structure and functional integrity of glomerular capillary circulation• Proliferation of membrane or infiltration of inflammatory cells• Can rapidly progress to ESRD• Major causes

- Idiopathic

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- Drugs – NSAIDS, Gold- SLE

- use immunosuppressive agents- many times present with proteinuria, hemoblobinuria- dysmorphic erythrocytes is characteristic

Diagnostic ApproachThis is key since early intervention improves prognosisMust look at history along with lab and physical findings• **Detail Medical & Medication history**

– Does the patient have chronic disease already?– Are you in hospital or out?– What other disease states does the patient have?– What drugs is the patient on?– How long have they been on them?– Have they had trouble urinating or had increase force of stream?

(e.g., with obstruction)– Is there blood in their urine?

Laboratory Testing

- FeNa = fraction Na excreted

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Other Diagnostic• Radiologic

– KUB – Kidney, Ureter, Bladder- shocked ureters: ureters is usually dilated in patients who are

passing stones• Renal ultrasound/CT—not that specific/sensitive• Imaging – bad because contrast dye will exacerbate condition

– Radiopharmaceutical• Biopsy

– Glomerular disease suspected

Clinical Course• Initiation Phase

– Significant change in hemodynamic and renal function• Oliguric Phase ~ 14 days

– Diminished urine production and increase metabolic byproducts• Diuretic Phase ~ 2-4 days

- Increase in urine and decrease in SCr and BUN• Recovery Phase – may take weeks to a year

Keys to treatment• PREVENTION• CORRECT UNDERLYING DISORDER• GO FROM ANURIA TO NONOLIGURIA

– No drugs have been proven in randomized trials- non-oliguric patients are less likely to need renal replacement

therapy• MANAGE COMPLICATIONS

Treatment - Prevention• Identify patients at risk

– Elderly– Pre-existing renal insufficiency– Co-morbid conditions

• Shock, infection, liver disease, CHF, diabetes– Females– CCB prior to organ transplant– Theophylline prior to contrast dye adminstr.- now hydration is given 1st: Mucomyst given with ½NS- mannitol has been added to organ preserving solution when kidneys

are removed

Treatment – Prevention of Drug toxicity• Total cumulative dose• Maintenance dose• Prolong therapy• Concomitant renal toxic drugs• Hydration – esp. dyes, ampho B, cisplatin• Monitor for dysfunctionSTOP THE DRUG

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Treatment - Anuria to nonoliguria• Fluid Management

– Maintain hydration• In’s and out’s• daily wts• hemodynamics

– Improves perfusion & lowers tubular workload• Reduce need to concentrate urine• Reduce nephrotoxin concentration

• Volume depletion– Colloids or crystalloids- crystalloids: preferred—NS or Lactated Ringer’s- colloids are not really preferred; associated with increase in mortality, with exception of hepatorenal syndrome

• *Volume overload (if you overhydrate patient)– May respond to diuretics– Dialysis– Fluid restriction

- look for at least 0.5 ml/kg/hr

Treatment - Anuria to nonoliguria– DiureticsInitiate as soon as possible• Loops (furosemide, bumetanide, torsemide, ethacrynic acid )

- ethacrynic acid: used when sulfa allergy exists– MOA – increase urine flow, renal vasodilatation– Give furosemide bolus 100mg IV– May need continuous infusion of 500-1500mg qd (do not exceed 4mg/min – ototoxicity)– Monitor – urine output, electrolytes, volume, BP- give loading dose of 0.1 mg/kg; continuous infusion of 0.1 mg/kg/hr- Some conditions with diuretic resistance:

1. Excessive Na intake decrease Na intake2. Inadequate dose/regimen increase dose, use infusion, may

even add a thiazide (metolazone, Zaroxolyn®)3. Decrease in oral bioavailability (especially furosemide)4. Nephrotic syndrome5. Decreased renal blood flow (RBF)6. Increased Na reabsorption (e.g., with NSAIDs, CHF, on

diuretic for a long time)7. ATN

• Mannitol– MOA – increase osmotic pressure of filtrate inhibiting reabsorption

and increases urine output; free radical scavenging effect– Use in hypovolemic patients– X 2 bolus doses (of fluid), if no response stop due to accumulation

that can lead to CHF, HTN, and pulmonary edema– Monitor – urine output electrolytes, volume status

• Thiazides– In combo, if you do not get response with CI loop

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– Work at distal tubule

Treatment - Anuria to nonoliguria• Dopamine – no statistical difference from just giving fluid (study: NORASEPT)

– MOA – renal artery vasodilatation– *Dose – 1-5mcg/kg/min– Monitor – urine output- it is now believed that even with the lowest dose of DA, there is still a

1 effect)• Calcium Channel Blocker ?

– Give before and after insult?• Insulin like growth factor ?• Atrial natriuretic factor ?• Antioxidant therapy & intracellular adhesion molecules ?• Fenoldopam (Corlopam®)??

Treatment - Complications• Uremia

– Dialysis• Ca / Phos

– See CRF• Metabolic acidosis

– Dialysis– IV/PO sodium bicarbonate—only when pH is really low (< 7.0)

• Malnutrition– May have higher caloric needs– Difficult due provide calories b/c of fluid restriction– Need to minimize nitrogenous waste production

Treatment – Complications--Hyperkalemia• > 5.5meq/dl – problem ARRHYTHMIA• Causes

– Decrease excretion– Drugs – ACE inhib, K+ sparing diuretics– Redistribution due to acidosis

• As H+ levels increase more H+ moves into the cell in exchange for K+ increasing serum levels of K+• Treatment – depends on urgency• Urgent

– Calcium gluconate or calcium chloride – for arrhythmia• Does not correct K+ concentration• IV push- also: sodium bicarbonate

– Insulin + glucose• Insulin shifts potassium intracellularly• Start drip with insulin and D50W

– Albuterol IV (or inhaleddoesn’t work well)• Shifts K+ intracellularly- even with inhaled agonist, still wind up with arrhythmias

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• Slow Onset– Kayexalate – sodium polystyrene sulfonate

• Exchanges K+ for Na+ in GI tract• Can be given orally or rectally with sorbitol• Onset 2-12 hours• Monitor: GI, electrolytes, Fluid overload

– Dialysis• Most effective• May take hours• Monitor : see dialysis lecture

*– Avoid exogenous K+ and drugs

Guidelines for Treatment:1. Prevention: Prevention is Key!!2. Early resuscitation3. Treat reversible conditions4. Nephrology onsultation5. Prevent further damage

- monitoring and optimizing hemodynamics- avoid hypotension and nephrotoxic agents

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6. Start diuretics- oliguric non-oliguric

7. RRT (Dialysis)

DRUG-INDUCED RENAL FAILURE

Introduction• Frequently occurs in patients treated with diagnostic and therapeutic agents• Could be manifested as a decline in GFR, urine sedimentation, protein urea, pyuria, heamaturia or crystalluria• Is often reversible renal insufficiency—if caught early

Incidence• Seen in acute settings up to 7% of all drug toxicity• 20% of all cases of hospital acquired ARF with a mortality up to 8%• 29% of all inpatient ARF attributed to drugs• 35% of ATN for inpatient• Most cases of AIN as well• In outpatient setting NSAIDs contribute to 4 folds ↑ risk of hospitalization due to ARF during the 1st month of therapy• Other risks factors include

– Males, > 65 yo, high dose, CVD, recent for nonrenal disease, and concomitant nephrotoxic drug use

• Other agents include ACI, cyclosporine

Recognition and Assessment of Renal toxicity• In inpatient settings

– Sr Cr., BUN, and I’s and O’s• In outpatient setting

– Sx of Uremia (malaise, anorexia, and vomiting), or volume overload (SOB, or edema)

• Early it could selectively alter renal tubular function without loss of GFR that can be recognized by metabolic acidosis with bicarbonaturia, glycosuria (no hyperglycemia), hypophosphatemia and hypouricemia.

Distal tubular injury• Indicators include:

– Polyuria, metabolic acidosis, and hyperkalemia– Low MW proteins like N- acetyl-β-glucosaminidase and β-

microglobulin.- found as result of insult to tissues lining renal tubule

Classification of Drug induced RD• Psuedorenal Failure (corticosteroids, Trimethoprim, Cimeditine)• Hemodynamically (NSAIDs, ACEI)• Renal Vasculitis, Thrombosis, and Cholesterol Emboli

– Vasculitis and Thrombosis (Neomycin C, Methamphetamines)

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– Cholesterol emboli (Warfarin, Thrombolytic agents)• Glomerular Disease

– Nephrotic syndrome (Gold, NSAIDs)– Glumerulonephritis (Hydralazine, Cytokine Treatment)

• Tubular epithelial Cell Damage– Osmotic nephrosis (Manitol, IV Ig)– ATN (Aminoglycosides, Radiocontrasts)

• Nephrolithiasis (Trimeterene, Indinavir)• Interstitial Nephritis

– Acute Allergic (Methicillin, NSAIDs)– Chronic (Cyclosporine, Lithium)– Papillary necrosis (combinations of ASA, phenacetin and Caffeine

anaglesics)• Obstructive Nephropathy

– Intratubular (Acyclovir, Sulfadiazine)– Lower urinary tract (TCA)

Mechanism for Renal Susceptibility• High blood flow and specialized homodynamic

– β-blockers and NSAIDs ↓ BF- especially propranolol- nadolol and labetalol: actually improve blood flow

– Radiocontrast may shunt BF– Osmotic diuresis due to Manitol ↓ GBF– ACEI dilates efferent arterioles ↓GF press.– Salt restriction activation of neurohumoral renal hemodynamic control system (RAAS) ↑ susceptibility to these drugs

• Tubular epithelial cell absorptive and secretory functions– Drugs and their metabolites accumulation– Impairment of mitochondrial function– Gentamicin ↑ superoxide ion, H2O2 and its hydroxyl radical– Cyclosporine ↑ H2O2 – similar to gentamicin

• Drug metabolism to toxic species– Acetoaminophen local metabolism

• High energy requirement by renal tubular cells– Amphotericin-B induced modullary tubular cell damage

• Concentration of solute in tubular lumen– Aminoglycosides toxicity

• Urine acidification– Methotrexate and ARF – pH < 4.5 associated with methotrexate crystallization

• Nephron adaptation to CR insufficiency– Radiocontrast

• Age– ↓ RBF and GFR ≥ 40 yo

Pseudo-renal Failure• Occurs when either Sr Cr or BUN ↑ while the GFR remains intact• Corticosteroids and tetracycline ↑ protein catabolism ⇒↑BUN• Trimethoprim, cimetidine or pyrmethamine competitively inhibit creatinine

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secretion retain more creatinine

Hemodynamic mediated RF• ACEI and ARBs

– Causes constriction of both afferent and efferent arterioles decreased glomerular filtration pressure

– Risk factors include: RAS, CHF, volume depletion from excessive diuresis, hepatic cirrhosis with ascites, and nephrotic syndrome

– Prevention by small dose, short acting ACEI with monitoring K and Sr Cr.

- with ACEI, there is a temporary jump in SCr from baseline, about 30% will return to baseline

- if the increase is >30% remove ACEI

Management of ACEI Renal Toxicity• D/C• Hyperkalemia could be tx by sodium polystyrene sulfate or IV glucose with insulin• If patients needs ACE then ARB might be tried

Inhibition of PG-dependent Total RBF• NSAID

– Unlikely to impair the renal function in the absence of renal ischemia or vasoconstrictor activity

– Occurs within a few days of starting the NSAID and more common with short acting

– Sr Cr, BUN ↑, urine volume and Na+ usually low, urine sediments show no change or granular casts.

NSAID Renal toxicity• Risk factors include

– Preexisting renal insufficiency, high renin activity and levels, or SLE. Age???

• Tx– D/C NSAIDs– Sulindac/Cox-2

- sulindac is NSAID with least renal toxicity- COX-2: we now know that COX-2 is harmful to kidneys, as well

– Supportive – e.g., volume

Clinical application of NSAIDs• Reduction of proteinuria in nephrotic syndrome

Nonspecific Renal Vasoconstriction• Cyclospsorine

– Early acute hemodynamically mediated renal insufficiency and delayed Chronic Interstitial Nephritis (CIN), generally within 1st 6 months of treatment

– Incidence of 21-25%

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– HTN, hyperkalemia, hypomagnesemia and no urine sediment abnormalities– Renal biopsy shows arterioles’ thickening, glomerular sclerosis,

proximal tubule vascularization and interstitial fibrosis

Cyclosporine• Chronic toxicity apparent after 6 – 12 months, UA shows few RBCs and WBCs and low range proteinurea• Risk factors include, age, high initial dose, renal graft rejection, infection, concomitant nephrotoxic agents as well as cyclosporine metabolism inhibitors (acyclovir)• Tx by D/C, CCB?

- nifedipine dilates arterioles: increased RBF- diltiazem has CYP450 inhibitor effect—may need to decrease dose of cyclosporine

Other agents• Tacrolimus• Triameterene – especially if used in combination with NSAID• Propranolol – decrease RBF by 10 – 20%• OKT3 – used in organ transplants

– ↑ vascular permeability- increases TNF, IL-6, IL-2, IFN

• Epoietin1. ↑ colloid oncotic pressure and blood viscosity because of increased RBC production2. Decreases seizure threshold

• Methamphetamine– Systemic polyarteritis nodosa

• OC, cyclosporine, mitomycin C, cisplatin, and quinine– Thrombus formation

• Warfarin– Embolizes cholesterol particles

Glomerular disease• Nephrotic syndrome

– NSAIDs, ampicillin, rifampin, phenytoin, and lithium• Glomerulosclerosis

– Chronic heroin or cocaine abuse, lithium, -interferon• Membranous nephropathy

– Most common with IV gold (rheumatoid arthritis)

• Membranoproliferative glomerulonephritis– Hydralazine

Tubular Epithelial Damage• Osmotic nephrosis

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– Mannitol, LMW dextran, radiocontrasts, or drug vehicles include sucrose, propylene glycol (solvent in IV lorazepam)• Acute Tubular Necrosis

– Aminoglycosides incidence is 5-25%– Clinical presentation include ↑ in Sr. Cr, ↓ in CrCl after 5-10 days,

urine < 500 ml/d, Mg and K renal wasting

Aminoglycosides• Toxicity of aminoglycosides (depends on number of amino groups

– Neomycin > Gent., Tobr., > amik. > netilmicin, streptomycin- one way to decrease toxicity: once-daily dosing

• Risk factors–large cumulative dose, synergistic, predisposing factors, prolonged

treatment, recent treatment, trough > 2 mg/L- synergistic with cyclosporine, amphotericin B, duretics, anything with renal toxicity- Predisposing factors:

hypoalbuminuria adrenal insufficiencyobstructive jaundice shockdehydration Gm (-) bacteremiaK+ and Mg2+ deficiencies liver diseaseAdvanced age

- low Mg wasting of K+ (“kaluric effect”) unless you correct Mg, you can’t fix hypokalemia

Amphotericin B• Incidence reaches 80% when dose ≅ 4gm- toxicity has to do with vasculariazation of small arterioles and a toxic effect on proximal distal tubule direct tubular damage, increased tubular permeability and necrosis, or due to ischemia• Manifest as Mg, K, Na wasting, and renal tubular acidosis• Risk factors

– Dose, rate (fast infusion), diuretic with volume depletion, other drugs with nephrotoxicity• TX

– D/C- there is now a liposomal preparation with possibly less toxicity than

the conventional preparation

Tubulointerstitial disease• Chronic Interstitial Nephritis

– Lithium, cyclosporine and some other drugs causes progressive irreversible condition– Mesalazine, 5-aminosalicylic acid and ifosfamide effect can be reversible if D/C

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– Lithium associated with nephrogenic diabetes insipidus (polydipsia and polyuria)

– TX include D/C, amiloride or NSAIDs- Also can be due to Chinese herb Guang Fang Ji (aristocholic) glucosuria, subacute renal failure, mild HTN, proteinuria

leads to intestinal fibrosis and atrophy and destruction of tubule, due to DNA damage• Acute Allergic Interstitial Nephritis (AIN)

– 3-14% of all ARF– Involve the renal tubule and their surrounding interstitial tissue– Drugs include Abx, Neuropsychiatric, NSAIDs, and Miscellaneous

- Abx: most commonly associated with penicillin, especially synthetic (methicillin)

- Signs and symptoms (2 – 4 days): fever, rash, eosinophilia, pyuria, low level proteinuria, generally oliguric

– TX: Prednisone in a dose of 0.5-1.0 mg/kg for 1-4 wks.• Papillary necrosis (form of interstitial nephritis)

– Classic analgesics account for 36% other agents include Dapsone in high doses– Believed to be to the accumulation of the toxic metabolites at the tip

of the papilla– TX D/C– Follow up for transitional cell carcinoma

Obstructive nephropathy• Due to mechanical obstruction• Can be caused by

– Acute Uric acid precipitation that can be tx by pretreatment hydration, urine alkalization to PH 7.0, and Allopurinol (prevents uric acid formation)

- allopurinol is also used to pretreat lumor lysis syndrome– Muscle necrosis nontraumatic rhabdomyolysis– Precipitation in acidic PH of the urine

- treat with hydration and keep pH of urine >6.5– Extra-renal obstruction – stone, calculus

Things to Remember:1. Know the principal nephrotoxic agents2. Analyze risks/benefits before treating patients3. Consider alternative treatment first4. Use lowest effective dose with shortest course of treatment possible5. Monitor patient on nephrotoxic agents6. If toxicity is observed modify treatment

CHRONIC RENAL FAILURE

Objectives• Understand the various etiologies and pathophysiology of CRF• Sx associated with uremia• Tx delaying progression of CRF

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• Management of complications associated with CRF

Definition• CRF is the progressive loss of nephron function by multiple etiologies resulting in a rise in BUN and SCr

– Decrease renal reserve– Renal insufficiency– Renal failure– Uremia- may see small kidneys if you perform KUB

Background• Progressive and irreversible decline in renal function• 20,000 patients start dialysis/year• In 1992, 242 K treated for ESRD and went up to 257,200 in 1995• 9.5 billion a year• Associated with significant mortality and morbidity• Key is Prevent ESRD- race is also a factor

Stages of CRF (depending on CrCl; according to National Kidney Foundation)• Stage 1: >90 ml/min• Stage 2: 60 – 89 ml/min• Stage 3: 30 – 59 ml/min• Stage 4: 15 – 29 ml/min• Stage 5: <15 ml/min

Risk factors• HTN - #2 (if T1DM and T2DM are combined); compromises blood flow to kidneys• DM - #1 (if T1DM and T2DM are combined)• Family History• CVD• Collagen vascular disease• Medications• Chronic infections• Smoking – cessation is especially important in DM patients- Heavy metals (cadmium)

Pathophysiology• Loss of nephrons causes hyperfunction and hypertrophy or remaining nephrons• Diabetes

– Type I 15%, II 23%• HTN

– 28%• Glomerulonephritis

– 14%

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• Hereditary– 5%

• Interstitial nephritis• Many others

Progression• Decrease renal reserve – will decrease when CrCl < 30 ml/min; will eventually turn off• Renal insufficiency - moderate• CRF – Stage 4• Uremia: <15 ml/min• Correlation between GFR and SCr

- for every 50% reduction in GFR, SCr doubles

Pathophysiology• Exact mechanism is not well understood• Initial pathogenic insults include

– Diabetic nephropathy (glycosylation)– HTN; hyperlipidemia– Non diabetics

1. Cell injury2. Decreased GFR or blood flow3. Adaptive hemodynamic changes4. Glomerulosclerosis

Delaying the progression of CRF• Correction of potential reversible factor—must identify these!• Therapeutic intervention to slow progression of CRF

– Systemic diseases; DM, HTN – control these diseases; goal BP 125/75• Screening microalbuminuria (>300 mcg/mg Cr)

- use ACEI, ARB, CCB (some controversy over DHPs)- long acting DHPs should be used in combination

• Intensive BG control• Tx of HTN

Therapeutic intervention to slow progression of CRF• Other interventions

– Low protein diet – 0.6 – 0.8 g/kg/day– Low phosphate diet

- hyperphosphatemia is common problem complexes with calcium

- <800 mg/day

Treatment• Prevention or Slow down progression• Dialysis• Transplant• Manage complications

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Prevention or Slow down progressionSee Table 22.8 Herfindal• Prevent ARF• Stop agents that can lead to CRF (see ARF)• Screen for microalbuminuria (diabetics) and proteinuria and initiate ACE/ARB• Blood pressure control (ACE, non-dyhdro CCC)• Restrict dietary protein (based on CrCL)• Hyperlipidemic control (like CAD pt.)• Glycemic control

Complications*** Due to a build up of uremic toxins due to the inability toeliminate them.• Cardiovascular

– Volume, HTN, Pericarditis (pericarditis associated with uremia)• Hyperlipidemia - sclerosis• Pulmonary; associated with uremia

– Edema – volume & toxins• GI

– NV, anorexia, bleeding, metallic taste- uremia inhibits platelet function bleeding

• Hematologic– Anemia, platelet dysfunction- t½ for RBCs is ~120 days (normal), but in renal failure, is ~64 days- anemia: erythropoietin is manufactured in kidney

• Musculoskeletal– Leg cramps, bone deformation- bone deformation: hyperphosphatemia affects calcium homeostasis

• Endocrine– Hypothyroid?, hyper/hypoglycemia, hypogonadism- CRF: TSH is normal, although normally with hypothyroidism, TSH is

high while T4 is low• Dermatologic - pruritis• Immune System – ESRD: immunocompromised• Nervous System

– restless leg, dementia, seizures

Volume Overload• Due to impaired Na+ excretion• Leads to HTN, Edema, Pulmonary congestion

• Fluid and Na+ intake must be adjusted according to decline in Renal function

– Important for hypo and hypertension– Large volume shifts in dialysis lead to hypotension

• Loop diuretics– Torsemide, furosemide and bumetanide

• Thiazides- problem: doesn’t work as monotherapy if CrCl < 30

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K+ balance• SEE ARF• Due to inability to secrete at oliguric state- 90 – 95% of K+ is secreted by kidneys• High normal levels OK (4.5-5.5)• Limit drugs that increase K+

– K+ diuretics, ACE, B-Blockers, Pen VK,• Diet• Avoid constipation – there is secretion of K+ in colon• Florinef and diltiazem

- florinef is a mineralocorticoid—increases secretion of K+ in gut- used in between dialysis

• Dialysis**

Hyper Mg++• Impaired excretion• Avoid Mg+ containing products (MOM), MgCitrate, although Mg may be used in hyperphosphatemia• Diuretics – lowers Mg• Dialysis**

Metabolic Acidosis• Decrease ammoniagenesis + phosphate excretion leads to acidosis• Contributes to HyperK+, fatigue, myocardial dysfunction, bone disease, protein metabolism(uremia), hyperventilation, burning sensation• Usually controlled by dialysis• Alkali therapy when plasma bicarb < 20 meq/L

- generally try to keep HCO3 > 22

Metabolic Acidosis – Treatment• Sodium bicarb

– High doses cause GI upset– 650mg tab = 7.7meq Na:bicarb

• Bicitra and Shohl’s Solution– Na+ Citrate and citric acid 1:1Na:bicarb– Citrate metab to bicarb and citric acid to CO2 and H20

• Polycitra – contains K+ & Na+• Citrate increase Al++ absorption• Fluid overload (Na+ load) – go slowly• Monitor for metabolic alkalosis

Renal osteodystrophy (bone disease)• See figure 42-5 in book• Nephron loss PO4 + Vit D• Vit D hypocalcemia + osteomalacia(soft bone• PO4 hypocalcemia + metastatic calcification (PO4 complexes with Ca2+)

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• HypoCa++, HyperPO4, Vit D PTH• Increase PTH bone turnover (osteitis fibrosa)• Osteitis fibrosa(cystic ), osteomalacia, Al+ and acidosis lead to Renal osteodystrophy• TREATMENT – a balancing act of Ca+, PO4 and vitamin D concentrations

Renal osteodystrophy - Phosphorus• Initially maintain normal levels (2.5-4.5mg/dl)

– Diet – dairy, Coca-Cola, milk, baking powder, Fleets• In ESRD goals increase (4.5-6.0mg/dl)

– Control with dialysis and phosphate binders• Adequate serum Ca level (10-10.5)• Phosphate binders

Ca+ Phosphate Binders• *Give with Meals*• Calcium Carbonate/Acetate (citrate – Al+,taste,-binding) – Phoslo®

– ***1st line – corrects hypocalcemia, cheap, well tolerated, reduces PTH

– Not all forms are USP– Absorption (Carbonate – not as good in alkali media)– Binding (Acetate 2x’s better)– GI (Acetate more GI upset)

• (Ca+ X PO4) < 55 (leads to crystal formation in soft tissue, such as heart, eye, and blood vessels)

[Ca2+][PO4] > 55: don’t use Ca2+ binders• Corrected Ca

– {0.8 X (4-alb)} + serum Ca• Aluminum – toxic

- aluminum hydroxide these salts are really very effective, but watch if patient’s Al level is high use Renagel®• Sucralfate – contains Al+• Mg++ - hyperMg, diarrhea,• Renagel

– Complex molecule– No Mg+, Ca+, Al+ etc…….– Not absorbed systemically– Will reduce PTH concentrations– Unknown DDI– $$$$$

Osteodystrophy – activated Vitamin D- first, correct hyperphosphatemia• Decreases levels of PTH• Therapy begun when PTH > 3 x normal• Oral

– Rocaltrol 0.25-05 mcg qd– May cause more hyperCa+

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• IV– Calcijex (calcitriol), Zemplar(paricalcitol) 1-2mcg qod after dialysis– Zemplar – less hyperCa+, but $$

• Pulse dosing – less hyperCa+

Aluminum Toxicity• Minimized b/c of dialysate purification and less need for Al+ phosphate binders • Neurotoxic, osteodystophy and anemia• Avoid Al+ phosphate binders, diet, avoid citrates, Al+ containing drugs

- citrates enhance absorption of Al• Treat with Deferoxamine (DFO)

– Hypotension, ocular toxicity, and acute increase in CSF Al levels- try to keep Al < 60 mcg/L

Anemia• Normocytic, normochromic –

– erythropoietin**- levels are normal but should not be (normal level, but not functioning well)• Presentation – fatigue, dizziness, HA, pallor, angina, ventricular hypertrophy, impotence, cognitive loss• Also, blood loss(dialysis); iron, folic acid, B6, B12 deficiency; Al tox.• Transfusion should be avoided

- Complications:1. Infection (e.g., HIV)2. Affects immune system

Anemia – Treatment- usually when Hb ≤ 7 (Hct = 21), but <10 is the indication • Old therapy – transfusion & androgens• NOW – erythropoietin (Procrit, Epogen)

– ***Must correct iron deficiency first(IV/PO), also B12 and Folate– Dosage can vary greatly, generally 50-100u/kg IV/SQ TIW– Dosage adjust should be made carefully b/c response to therapy

takes time (3-4 weeks)– Goal HCT 30-36%

• Rise of 1-2 points a week. No more than 4 in 2 weeks- look at ferritin, total ion binding capacity (TIBC)

- Ferritin < 100 give erythropoietin- TIBC should be >20% or give erythropoietin- Fe saturation = 100 x FE/TIBC

• Benefits– Reduce transfusions– Improves QOL– Decrease pruritis

• Disadvantages– Increase Heparin requirements– Hypertension**

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– Enhance access clotting– Flu-like syndrome- seizures (lowers threshold)

• Darbepoetin alfa– A long acting form– Dosed weekly– Conversion from epoetin based on the weekly dose- erythropoietin generally given QOD at 50 – 100 units/kg or weekly at 40,000 units- Indicated for chronic renal failure- May not work if:

- iron deficient- active infection is present- malignancy is present

- contraindication of erythropoietin is uncontrolled HTN or risk of seizures

Uremia• Increase in Toxins. BUN is guide• Anoxia, NV, weakness, pruritus, twitching, neuropathy, bleeding, pericarditis• Bleeding - normal platelets count they just don’t work• Treatment

– Restrict dietary protein– Dialysis

Uremia – Bleeding• Quick fix

– Cryoprecipitate – blood product– DDAVP – increase Factor VIII—problem with tachyphylaxis– IV conjugated estrogens (Premarin)

• Long term– Control BUN– Estrogens – Ovral 2-4 pills qd– Erythropoietin

Hyperlipidemia• Nephrotic syndrome

– Increase total Cholesterol, LDL, TG– Mechanism by increase Apo B production– Treatment is basically the same– Fish oils difficult to use b/c of NV and may enhance bleeding

• Non-nephrotic syndrome RF– Hypertriglycerides (200-600mg)– Mechanism by lipolysis– Diet reduce carbohydrates and weight– Drug therapy?

Hypertension

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Other complications• Hyperuricemia

– Begins when GFR < 40 ml/min– Uric acid level should be < 12 mg/dl– No symptoms no tx- colchicine

• GI– Anorexia, N, V 1st sx of uremia– Pancreatitis, D, increase GI bleeding are indicative for dialysis

Vitamin Therapy• Fat soluble vitamins (ADEK) replacement is not required and could cause complications• B1, B2, B6, B12, niacin, pantothenic acid, folic acid, biotin, vitamin C• B6 (pyridoxine), C (ascorbic acid) and folic acid • Many combinations are available

– Nephrovite• Individual supplementation

Management of ESRD• When GFR < 5 ml/min transplantation is needed for survival• Dialysis indications

RENAL REPLACEMENT THERAPY- elective in ESRD- must educate patient first- must look at clinical picture

- DM: <14 ml/min- non-DM <9 ml/min- s/s of uremia (N/V)- comorbid conditions (CHF, pulmonary edema)

• Can be used in ARF or ESRD• Removes metabolic waste• Restores fluid and electrolyte balance• Process -

– Diffusion – migration of particles– Osmosis – migration of water

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– Hydrostatic ultrafiltration – migration of particles and water under pressure

Need to know physical and chemical nature of solute and membraneFlow rate is important

Diffusion Osmosis Hydrostatic Ultrafiltration

Migration of particles Migration of water Migration of both

water and solute

Peritoneal Dialysis- A solution containing glucose and various electrolytes (this “solute” can be changed based on the needs of an individual patients needs) is infused into thepatients peritoneal cavity. As this solutions sits in the cavity it draws toxins and electrolytes from the rest of the body into the peritoneal cavity through osmosiswith the natural peritoneal lining acting as a membrane. This solution is then drained out of the peritoneal after a certain time period along with the toxins and electrolytes with it.

- usually 2.5 L• Types

– CAPD – continuous ambulatory– CCPD- continuous cyclic– IPD- Intermittent

• Advantages– Can do every 24 hours – better balance– Not dependent on center– Not as restrictive of diet (e.g., protein)– Certain drugs can be added

- insulin—absorption is more constant that with SQ- also helps with decrease of fibrin, which is a

complication with dialysis as a whole– Less hemodynamic changes– Less blood loss– Better preservation of remaining renal function- don’t need to give heparin

• Disadvantages– Takes longer– Must have educated person—patient and caregiver– Protein loss (muscle wasting) and Wt gain (increased adipose

formation)

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– Peritonitis & Site infections• Can be life threatening ****Sterile technique- patient on dialysis can get prophylactic for MRSA: rifampin PO

or mupirocin (for 5 days each month), so that if patient develops an infection, it won’t be MRSA

- Peritonitis:- #1 cause is Staph. Epidermidis- #2 is S. aureus- Treatment: 1st generation cephalosporin (cefazolin)

because of better Gm (+) coverageEnterococci S. aureus S. epidermidus

14 days 21 days 14 days- sometimes may add aminoglycoside to cefazolin

(synergism); if there is a response to cefazolin, can D/C the aminoglycoside

- within 72 hours, check culture and see if these agents work

- with endocarditis, use aminoglycoside- if dealing with MRSA, may add vancomycin, rifampin, or

clindamycin (not used in clinical practice)- there is a synergism between rifampin and

vancomycin—vancomycin alone will work, but the combination reduces resistance; combination is preferred

- Site infections:- #1 cause is S. aureus- #2 is S. epidermidis- Gm (-)- for Gm (-), fluoroquinolone is preferred (ciprofloxacin)- Pseudomonas: use combination: fluoroquinolone + -

lactam Timentin® (ticarcillin and clavulanate K+) or Zosyn® (piperacillin + tazobactam)

– Mechanical complications– Ultrafiltrate failure- Medical complications

- hyperglycemia (because glucose is in fluid)- fluid overload- electrolyte abnormalities

- high or low Ca2+

- malnutrition- proteinuria

Types of Dialysis- these all depend on MW, size, and nature of semipermeable membrane, as far as efficiency goes• Intermittent• Continuous (hemofiltration is referred to as a type of dialysis)

– CAVH continuous arterial venous hemofiltration

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– CVVH continuous venous venous hemofiltration– CAVHD(F) continuous arterial venous hemodialysis– CVVHD(F)continuous venous venous hemodialysis

- CAVHD and CVVHD are more efficient when dealing with removal of drugs

Continuous vs Intermittent.• Continuous

– is used only in critically ill patients. It takes less blood/plasma from the patient over a certain time period and has less effect on

hemodynamics, but since it is 24 hours a day it takes more waste away.

– It is very expensive and not easy to do.- more efficient

• Intermittent– is used for outpatient and relatively stable in patients.– Easier to do and not as expensive.– requires that more blood and plasma be taken from the patient b/c

you are trying to accomplish this over a short time period(4-6 hours).

Hemodialysis

Graft is placed in arm or upper chest for access to venous system. From this site blood is taken out of the patient and run through a filter in order to take out toxins and electrolytes and remove excess fluid. Then the blood is put back into the patient. The filter also has a solute that can be changed based on the needs of the patient. Heparin is added so that blood doesn’t clot.• Advantages

– Can remove more toxins, fluid and electrolytes– Only takes minimal time 3 hours– Professional done

• Disadvantages– Needle sticks– Require center and professionals– Blood loss– Hypotension – can occur during or after due to the removal of blood and fluid

• Midodrine, caffeine, correct anemia• Decline in renal function is quicker- try to keep Hct >33%- Prevention of hypotension:

- keep feet elevated (Trandelen-Burg position)- Na content of diasylate (I don’t know how to spell that)

should be higher than what is in system- Steady rate of ultrafiltrate

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- Ask patient to avoid eating at least 2 hours prior to procedure

- can also give fluids; an give hypertonic NaCl (25%) or give 50% dextrose; can also use 12.5 g mannitol

– Infection

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