TRIPASS XR تري باس

 

The hypokalemic, hypochloremic, metabolic alkalosis in K.E.

most likely is the result of diuretic-induced volume contraction.

The incidence of this adverse effect is influenced by the type,

dose, and dosing frequency of the diuretic.

Diuretics cause metabolic alkalosis (sometimes referred to as

a “contraction alkalosis”) by the following mechanisms. First,

they enhance excretion of sodium chloride and water, resulting in extracellular volume contraction. Volume contraction

alone will cause only a modest increase in plasma bicarbonate; however, volume contraction also stimulates aldosterone

release. Aldosterone increases distal tubular sodium reabsorption and induces hydrogen ion and potassium secretion, resulting

in alkalosis and hypokalemia. In addition, hypokalemia induced

by diuretics will stimulate intracellular movement of hydrogen

ions to replace cellular potassium, producing extracellular alkalosis. Hypochloremia also is important in sustaining metabolic

alkalosis. In a hypochloremic state, sodium will be reabsorbed,

accompanied by bicarbonate generated by secreted hydrogen

(Fig. 9-1).81–83

Treatment

CASE 9-3, QUESTION 3: How should K.E.’s acid–base imbalance be corrected and monitored?

Treatment of metabolic alkalosis depends on removal of the

cause. K.E.’s diuretic therapy should be temporarily discontinued until her volume status and electrolytes can be restored. The

initial goal is to correct fluid deficits and replace chloride and

potassium by infusing sodium and potassium chloride. As long as

hypochloremia exists, renal bicarbonate excretion will not occur

and the alkalosis will not be corrected.82 The severity of alkalosis

dictates how rapidly fluid and electrolytes should be administered. In patients with hepatic or renal failure or congestive heart

failure, infusion of large volumes of sodium and potassium salts

can produce fluid overload or hyperkalemia. Thus, fluid and electrolyte replacement should proceed cautiously, and these patients

should be monitored closely for these complications.

Potassium chloride should be administered to correct K.E.’s

hypokalemia. The amount of potassium required to replace total

body stores is difficult to determine accurately because 98% of

the potassium in the body is intracellular. Although wide variation exists, for each 1 mEq/L decrease in K+ from an ECF concentration of 4 mEq/L, the total body K+ deficit is about 4 to

5 mEq/kg.10 K.E.’s serum potassium is 2.5 mEq/L, which correlates with a decrease of about 350 mEq in total body potassium

stores. K.E. should be treated with the chloride salt to ensure

potassium retention and correction of alkalosis. Potassium

replacement can be achieved over the course of several days with

supplements of 100 to 150 mEq/day given either orally in divided

doses or as a constant IV infusion. K.E.’s laboratory tests for BUN,

creatinine, chloride, sodium, and potassium should be monitored

184 Section 1 General Care

during sodium and potassium chloride therapy. As noted earlier,

hypercapnia should disappear after correction of the alkalemia,

and can be confirmed with an ABG, if clinically indicated.

CASE 9-3, QUESTION 4: What other agents are available

to treat K.E.’s alkalosis if fluid and electrolyte replacement

does not correct the arterial pH?

Patients unresponsive to sodium and potassium chloride therapy or those at risk for complications with these agents can

be treated with acetazolamide, hydrochloric acid (HCl), or a

hydrochloric acid precursor. The most commonly used agent is

acetazolamide, a carbonic anhydrase inhibitor that blocks hydrogen ion secretion in the renal tubule, resulting in increased excretion of sodium and bicarbonate. Although the serum bicarbonate concentration often improves with acetazolamide, metabolic

alkalosis may not completely resolve. Other concerns with the

use of acetazolamide include its ability to promote kaliuresis and

its relative lack of effect in patients with renal dysfunction.81,84,85

A solution of 0.1 N HCl may be administered to patients who

require rapid correction of alkalemia. The dose of HCl is based on

the bicarbonate excess using Eq. 9-9, where the factor 0.5 × body

weight (kg) represents the estimated bicarbonate space.10,81,82,84

Dose of HCl (mEq) = 0.5 × Body weight (kg)

× (plasma bicarbonate − 24) (Eq. 9-9)

Parenteral hydrochloric acid is prepared extemporaneously by

adding the appropriate amount of 1 N HCl through a 0.22-μm

filter into a glass bottle containing 5% dextrose or normal saline.

The dilute solution should be administered through a central

venous catheter in the superior vena cava to reduce the risk

of extravasation and tissue damage. The infusion rate should

not exceed 0.2 mEq/kg/hour.84 ABG should be monitored at least

every 4 hours during the infusion. HCl should not be added to

total nutrient solutions.85

Precursors of hydrochloric acid, such as ammonium and

arginine hydrochloride, are not recommended.81 The adverse

effect profile of these agents has significantly limited their role.84

Ammonium hydrochloride is metabolized to HCl and NH3 in

the liver. Severe ammonia intoxication with CNS depression

can occur during rapid infusion of ammonium hydrochloride or

in patients with liver disease.81 Arginine can cause rapid shifts

in potassium from the intracellular to the extracellular space,

resulting in dangerous hyperkalemia.81

RESPIRATORY ACIDOSIS

Respiratory acidosis occurs as a result of inadequate ventilation

by the lungs. When the lungs do not excrete CO2 effectively, the

Paco2 rises. This elevation in Paco2 (a functional acid) causes

a fall in pH (Eqs. 9-3 and 9-5). Common causes of respiratory

acidosis are listed in Table 9-7. They generally can be categorized into conditions of airway obstruction, reduced stimulus for

respiration from the CNS, failure of the heart or lungs, and disorders of the peripheral nerves or skeletal muscles required for

ventilation.86

Evaluation

CASE 9-4

QUESTION 1: B.B., a 56-year-old man, is admitted to the

hospital for treatment of an exacerbation of chronic obstructive pulmonary disease (COPD). He complains of worsening

TABLE 9-7

Common Causes of Respiratory Alkalosis

CNS Disturbances

Bacterial septicemia

Cerebrovascular accident

Fever

Hepatic cirrhosis

Hyperventilation

Anxiety-induced

Voluntary

Meningitis

Pregnancy

Trauma

Drugs

Progesterone derivatives

Respiratory stimulants

Salicylate overdose

Pulmonary

Pneumonia

Pulmonary edema

Pulmonary embolus

Tissue Hypoxia

High altitude

Hypotension

CHF

Other

Excessive mechanical ventilation

Rapid correction of metabolic

acidosis

CHF, congestive heart failure; CNS, central nervous system.

shortness of breath and increased production of sputum

for the past 3 days. He has also noted a mild headache,

a flushed feeling, and drowsiness within the past 24 hours.

He has a history of COPD, hypertension, coronary artery

disease, and low back pain. Current medications are ipratropium inhaler two puffs four times a day (QID), salmeterol dry powder inhaler one inhalation twice a day (BID),

hydrochlorothiazide 25 mg daily, long-acting diltiazem

240 mg daily, and diazepam 5 mg TID as needed for back

pain.

Vital signs include respiratory rate of 16 breaths/minute

and HR of 90 beats/minute. Diffuse wheezes and rhonchi

are heard on chest auscultation. Laboratory tests reveal the

following:

Na, 140 mEq/L

K, 4.0 mEq/L

Cl, 100 mEq/L

pH, 7.32

PaCO2, 58 mm Hg

PaO2, 58 mm Hg

HCO−

3 , 29 mEq/L

B.B’s baseline ABG at the physician’s office last month

was pH, 7.35; PaCO2, 51 mm Hg; PaO2, 62 mm Hg; and

HCO−

3 , 28 mEq/L. Which of B.B.’s signs and symptoms are

consistent with the diagnosis of respiratory acidosis?

A stepwise evaluation reveals a respiratory acidosis. A history

of COPD and physical findings of dyspnea, headache, drowsiness, and flushing support the ABG evaluation. Respiratory acidosis also can cause more severe symptoms, including CNS

effects, such as disorientation, confusion, delirium, hallucinations, and coma. These CNS abnormalities probably are partly

caused by the direct effects of carbon dioxide. Hypoxemia

(decreased Pao2), which commonly accompanies respiratory

acidosis, also contributes to these symptoms. Elevated Paco2

causes cerebral vascular dilation, resulting in headache caused

by increased blood flow and increased intracranial pressure. Cardiovascular effects typically include tachycardia, arrhythmias, and

peripheral vasodilation.87

CASE 9-4, QUESTION 2: Is the respiratory acidosis present

in B.B. consistent with an acute or a chronic disorder?

185Acid–Base Disorders Chapter 9

Following the stepwise approach, it is determined that B.B. has

a respiratory acidosis. He has a normal AG. Comparing his current to previous values (e.g., pH, Paco2, HCO−

3 ), it appears B.B.

has an acute-on-chronic respiratory acidosis because his baseline

Paco2 was 51 mm Hg with an acute worsening to 58 mm Hg. In

respiratory acidosis, increased renal reabsorption of bicarbonate

compensates for the increase in Paco2; however, at least 48 to

72 hours are needed for this compensatory mechanism to

become fully established.10 Patients with COPD commonly

present with an acute-on-chronic respiratory acidosis similar

to B.B.

Causes

CASE 9-4, QUESTION 3: What potential causes of respiratory acidosis are present in B.B.?

Respiratory acidosis often is caused by airway obstruction,

as shown in Table 9-7.86,87 Chronic obstructive airway disease is

a common cause of both acute and chronic respiratory acidosis. Upper respiratory tract infections, such as acute bronchitis,

can worsen airway obstruction and produce acute respiratory

acidosis.

DRUG-INDUCED

B.B.’s drug therapy also may be contributing to respiratory insufficiency. Many drugs (Table 9-7) decrease ventilation, but usually these drugs only significantly affect patients who are predisposed to respiratory problems because of underlying diseases.

Because B.B. has COPD, he may be more sensitive to drugs

affecting respiration. The benzodiazepines, barbiturates, and opioids minimally decrease respiration in normal subjects and in

most patients with COPD when given in usual therapeutic doses.

These drugs, however, can cause significant respiratory insufficiency when administered either in large doses or in combination

with other respiratory depressant drugs.87 B.B.’s diazepam may

be contributing to hypoventilation and respiratory acidosis and

should be withdrawn from his regimen. Nonselective adrenergic

blocking drugs should not be used in patients with COPD.

Treatment

CASE 9-4, QUESTION 4: How should B.B.’s respiratory acidosis be treated?

As with most cases of respiratory acidosis, treatment primarily involves correction of the underlying cause of respiratory insufficiency. In this case, treatment of acute bronchospasm

with ipratropium or a β-adrenergic agent, such as inhaled

albuterol, is warranted. Corticosteroids, such as methylprednisolone (60–125 mg every 6–12 hours initially), are commonly used in hospitalized patients with acute exacerbations

of COPD.88 Antibiotic therapy with a β-lactam or β-lactamase

inhibitor should be considered in hospitalized patients producing purulent, large-volume secretions.89 B.B’s respiratory status

should be monitored closely during his hospitalization. If the

acidosis, hypercarbia, or associated hypoxemia worsen, noninvasive positive-pressure ventilation or intubation with mechanical

ventilation may be required.67

Treatment with IV sodium bicarbonate is not recommended

in most cases of acute respiratory acidosis because of the risks

associated with bicarbonate therapy (see Case 9-2, Question 4)

and because an absolute deficiency of bicarbonate is not present.

When the excess CO2 is excreted, arterial pH should return

to normal. Hypercapnia should not be overcorrected, because

TABLE 9-8

Laboratory Values in Simple Acid–Base Disorders

Primary Compensatory

Disorder Arterial pH Change Change

Metabolic acidosis ↓ ↓HCO−

3 ↓Paco2

Respiratory acidosis ↓ ↑Paco−

2 ↑HCO−

3

Metabolic alkalosis ↑ ↑HCO−

3 ↑Paco2

Respiratory alkalosis ↑ ↓Paco−

2 ↓HCO−

3

hypocapnia results in decreased lung compliance, increases dysfunctional surfactant production, and shifts the oxyhemoglobin

dissociation curve to the left, restricting the release of oxygen to

tissues.74,75,90

RESPIRATORY ALKALOSIS

Respiratory alkalosis usually is not a severe disorder. Excessive

rate or depth of respiration results in increased excretion of carbon dioxide, a fall in Paco2, and a rise in arterial pH. Common

causes of respiratory alkalosis are presented in Table 9-8. Many

conditions can cause respiratory alkalosis by stimulating respiratory drive in the CNS. In addition, pulmonary diseases can

stimulate receptors in the lung to increase ventilation, and conditions that decrease oxygen delivery to tissues also can stimulate

ventilation, causing respiratory alkalosis.91,92

Evaluation

CASE 9-5

QUESTION 1: S.P., a 35-year-old, 60-kg woman, is admitted

for treatment of presumed bacterial pneumonia. She was in

good health until 24 hours before presentation when she

noted a fever; onset of a productive cough with thick, yellowish sputum; and chest pain on deep inspiration. She has

taken aspirin 650 mg every 4 hours since the onset of fever,

with mild relief. Since arriving in the ED, she has become

anxious and lightheaded and has developed tingling in her

hands, feet, and lips. Vital signs include the following: temperature, 38◦C; respiratory rate, 24 breaths/minute; HR,

110 beats/minute; and BP, 135/70 mm Hg. Physical examination reveals dullness to percussion, rales, and decreased

breath sounds over the left lower lung field.

Laboratory findings include the following:

Serum Na, 135 mEq/L

Cl, 105 mEq/L

pH, 7.49

PaCO2, 30 mm Hg

PaO2, 90 mm Hg

HCO−

3 , 22 mEq/L

Gram stain of sputum reveals 25 white blood cells (WBC)

per high-power field and many gram-positive diplococci.

WBC count is 15,400 cells/μL with a left shift. A left lower

lobe infiltrate is seen on chest radiograph. What acid–base

disorder is present in S.P.?

Steps 1 to 3 in the evaluation of the ABG values, as

described previously, indicate a respiratory alkalosis (increased

pH, decreased Paco2). The history and physical findings of deep,

rapid breathing and tingling sensations are clues to the etiology.

This disorder is most likely acute because her HCO−

3 concentration is normal. She does not have an AG. If a large AG were

186 Section 1 General Care

present, it would suggest she has a coexisiting metabolic acidosis, possibly caused by salicylate intoxication (see Case 9-5,

Question 3).

CASE 9-5, QUESTION 2: Which of S.P.’s signs and symptoms are consistent with the diagnosis of acute respiratory

alkalosis?

S.P.’s paresthesias of the extremities and perioral region,

lightheadedness, tachycardia, and increased rate and depth of

respiration are common signs and symptoms of respiratory

alkalosis. Confusion and decreased mental acuity also may be

evident.5,6,10 Simple respiratory alkalosis rarely produces lifethreatening abnormalities.

Causes

CASE 9-5, QUESTION 3: What is the cause of the acid–base

disorder in S.P.?

Common causes of respiratory alkalosis are listed in

Table 9-7.5,6,10,91–93 Based on physical examination, laboratory

findings, and chest radiograph, S.P. appears to have an acute bacterial pneumonia. Pneumonia and other pulmonary diseases can

result in stimulation of ventilation and respiratory alkalosis, even

with a normal Pao2, as in this case. The anxiety S.P. is experiencing also may be contributing to respiratory alkalosis by producing

the familiar anxiety-hyperventilation syndrome. Although salicylate intoxication is a potential cause of respiratory alkalosis

because of the direct respiratory stimulant effect of salicylate,93

S.P. displays few other symptoms of salicylate intoxication (e.g.,

nausea, vomiting, tinnitus, altered mental status, elevated AG

metabolic acidosis). The total aspirin dose reportedly ingested

(65 mg/kg in 24 hours) is not large enough to be associated with

significant risk for toxicity.

Treatment

CASE 9-5, QUESTION 4: What is the appropriate treatment

for S.P.’s respiratory alkalosis?

Similar to respiratory acidosis, treatment of respiratory alkalosis usually involves correcting the underlying disorder. Initiation of appropriate antibiotic therapy for a community-acquired

pneumonia is indicated in this case (see Chapter 64, Respiratory

Tract Infections). Simple respiratory alkalosis is unlikely to cause

life-threatening symptoms, although mortality rates for critically

ill patients with this disorder can be high.87 The well-known remedy of rebreathing expired air from a paper bag for treatment

of hyperventilation associated with anxiety appears to be effective for this cause of respiratory alkalosis and may be helpful

for S.P.

MIXED ACID–BASE DISORDERS

Evaluation

CASE 9-6

QUESTION 1: B.L., a 58-year-old man who was transferred

from a nursing home 2 days previously, is disorientated and

lethargic. He was doing well until 1 week before admission,

when the staff noted that he was somnolent. He progressively became more lethargic and could no longer remember the names of other persons. B.L. has a history of alcoholic cirrhosis, type 2 diabetes mellitus, and hypertension.

Medications before admission were nadolol 80 mg daily,

isosorbide mononitrate 20 mg BID, glyburide 10 mg daily,

and spironolactone 50 mg BID. On admission, B.L. was disoriented to person, place, and time and was difficult to

arouse. Vital signs include the following: temperature, 37◦C;

respirations, 16 breaths/minute; HR, 70 beats/minute; and

BP, 154/92 mm Hg. Physical examination revealed asterixis

and mild ascites. Laboratory studies included the following:

Na, 133 mEq/L Albumin, 3.2 g/dL

K, 4.3 mEq/L Ammonia, 120 μmol/L

Cl, 106 mEq/L pH, 7.43

BUN, 5 mg/dL PaCO2, 30 mm Hg

Creatinine, 0.7 mg/dL PaO2, 90 mm Hg

Fasting glucose, 150 mg/dL HCO−

3 , 19 mEq/L

On admission, spironolactone was increased to 75 mg

BID and lactulose 60 mL orally (PO) QID was started for

treatment of hepatic encephalopathy. Within the first 24

hours of lactulose therapy, B.L. produced four loose, watery

stools; however, his mental status worsened to the point

of being unresponsive, his BP dropped to 100/60 mm Hg,

and his breathing became labored and eventually required

mechanical ventilation. At the time of intubation, his laboratory values were as follows:

Na, 136 mEq/L Arterial pH, 7.06

K, 4.5 mEq/L PaCO2, 48 mm Hg

Cl, 105 mEq/L PaO2, 58 mm Hg

BUN, 10 mg/dL HCO−

3 , 13 mEq/L

Creatinine, 1.2 mg/dL

Gram stain of peritoneal fluid revealed many WBC and

gram-negative rods; the diagnosis of spontaneous bacterial

peritonitis with possible septicemia is made. Describe B.L.’s

acid–base status on admission and at the current time.

An evaluation of B.L.’s ABG using Steps 1 and 2 (in the section Evaluation of Acid–Base Disorders) reveals abnormal Paco2

and serum bicarbonate values, suggesting the existence of an

underlying acid–base abnormality. The direction of change in his

Paco2 and serum HCO−

3 , along with a pH of 7.43, suggests a respiratory alkalosis is the primary disorder. His calculated AG of 8

is not increased. Examination of the ranges of expected compensation in Table 9-3 reveals that these values are indeed consistent

with chronic respiratory alkalosis (serum HCO−

3 decreased by

0.5 mEq/L for each 1 mm Hg drop in Paco2). B.L.’s history of

alcohol-induced liver disease is consistent with the diagnosis of

chronic respiratory alkalosis (Table 9-8).8,10

The second set of ABG reveals severe acidosis. B.L.’s serum

bicarbonate has fallen from 19 to 13 mEq/L, and his Paco2 has

increased acutely from 30 to 48 mm Hg. Because these values

have changed in opposite directions, a mixed acid–base abnormality should be suspected.

The diagnosis of a mixed metabolic and respiratory acidosis

can be confirmed by applying the stepwise approach outlined

previously. If the acidosis were purely metabolic in nature, a

serum HCO−

3 of 13 mEq/L should result in hyperventilation and

a low Paco2. B.L.’s Paco2 of 48 mm Hg is high, which would be

consistent with coexistent respiratory acidosis. The anion gap is

18, indicating an AG metabolic acidosis is present. The excess AG

(AG – 10 = 8) added to B.L’s gap of 18 yields a corrected HCO−

3

of 26, which is normal. This suggests no additional metabolic

disturbances are present.

187Acid–Base Disorders Chapter 9

Causes

CASE 9-6, QUESTION 2: What are possible causes for the

mixed acidosis in B.L.?

The AG should be calculated in all patients with a metabolic

acidosis. B.L.’s calculated AG has increased from 8 to 18 mEq/L

(11 and 21 mEq/L, respectively, after adjusting for hypoalbuminemia), suggesting that an elevated AG acidosis is now present.

Septicemia from bacterial peritonitis can produce profound

hypotension, which leads to tissue hypoperfusion, generation

of lactic acid, and a subsequent elevation in the AG. Other causes

of elevated AG metabolic acidosis can be excluded with additional laboratory data (e.g., serum ketones, glucose, osmolal

gap).

Although diarrhea and spironolactone should be considered

in the differential diagnosis, these are usually associated with

hyperchloremic, normal AG metabolic acidosis (Table 9-2).94 The

coexisting respiratory acidosis is most likely the result of B.L.’s

altered mental status and his diminished respiratory drive.

CASE 9-6, QUESTION 3: During the next 6 hours, B.L.’s

hepatic encephalopathy, peritonitis, and acid–base disorders are aggressively treated with lactulose, antibiotics, fluids, and mechanical ventilation. His most recent ABG reveals

the following:

pH, 7.45

PaCO2, 24 mm Hg

PaO2, 90 mm Hg

HCO−

3 , 16 mEq/L

Ventilator settings are assist-control mode at 16 breaths/

minute, tidal volume 700 mL, and inspired oxygen concentration 40%. B.L. is noted to be more awake, anxious, and

initiating 25 to 30 breaths/minute. What is the current acid–

base status and probable cause?

Evaluation of the ABG reveals a pH at the upper limit of normal with significant decreases in both Paco2 and serum HCO−

3

concentration. This clinical scenario is most consistent with a

mixed acute respiratory alkalosis and ongoing metabolic acidosis. The time frame in which B.L.’s Paco2 decreased from 48 to

24 mm Hg is consistent with acute respiratory alkalosis. B.L.’s

low serum HCO−

3 suggests ongoing metabolic acidosis as a result

of his septicemia. The metabolic acidosis should improve with

time, given adequate antibiotic therapy and supportive measures

that maintain BP and increase oxygen delivery to the tissues.

The acute respiratory alkalosis in this case is most likely caused

by the mechanical ventilator, B.L.’s anxiety, or sepsis. In the assistcontrol mode, any inspiratory effort by B.L. results in delivery

of a full assisted breath by the ventilator.95 B.L.’s anxiety and

resultant tachypnea are stimulating the ventilator to hyperventilate him, producing excessive CO2 excretion and respiratory

alkalosis. Appropriate changes in therapy may include use of

an anxiolytic, an analgesic if needed to treat pain, changing the

ventilator mode, or probably a combination of these strategies.

KEY REFERENCES AND WEBSITES

A full list of references for this chapter can be found at

http://thepoint.lww.com/AT10e. Below are the key references

for this chapter, with the corresponding reference number in this

chapter found in parentheses after the reference.

Key References

Adrogue HJ, Madias NE. Management of life-threatening acid–

base disorders: first of two parts. N Engl J Med. 1998;338:26. (67)

Adrogue HJ, Madias NE. Management of life threatening acid–

base disorders: second of two parts. N Engl J Med. 1998;338:107.

(68)

Breen PH. Arterial blood gas and pH analysis: clinical approach

and interpretation. Anesthesiol Clin North Am. 2001;19:885. (34)

Rose BD, Post TW. Metabolic alkalosis. In: Rose BD, Post TW,

eds. Clinical Physiology of Acid–Base and Electrolyte Disorders. 5th

ed. New York, NY: McGraw-Hill Medical; 2001:551. (2)

Rose BD, Post TW. Regulation of acid–base balance. In: Rose

BD, Post TW, eds. Clinical Physiology of Acid–Base and Electrolyte

Disorders. 5th ed. New York, NY: McGraw-Hill Medical; 2001:

325. (4)

Rose BD, Post TW. Introduction to simple and mixed acid–base

disorders. In: Rose BD, Post TW, eds. Clinical Physiology of Acid–

Base and Electrolyte Disorders. 5th ed. New York, NY: McGraw-Hill

Medical; 2001:535. (8)

Rose BD, Post TW. Metabolic acidosis. In: Rose BD, Post TW,

eds. Clinical Physiology of Acid–Base and Electrolyte Disorders. 5th

ed. New York, NY: McGraw-Hill Medical; 2001:578. (33)

Rose BD, Post TW. Metabolic alkalosis. In: Rose BD, Post TW,

eds. Clinical Physiology of Acid–Base and Electrolyte Disorders. 5th

ed. New York, NY: McGraw-Hill Medical; 2001:551. (81)

Rose BD, Post TW. Respiratory acidosis. In: Rose BD, Post TW,

eds. Clinical Physiology of Acid–Base and Electrolyte Disorders. 5th

ed. New York, NY: McGraw-Hill Medical; 2001:647. (86)

Rose BD, Post TW. Respiratory alkalosis. In: Rose BD, Post TW,

eds. Clinical Physiology of Acid–Base and Electrolyte Disorders. 5th ed.

New York, NY: McGraw-Hill Medical; 2001:673. (93)

10 Fluid and Electrolyte Disorders

Alan H. Lau and Priscilla P. How

CORE PRINCIPLES

CHAPTER CASES

FLUID AND SODIUM DISORDERS

1 Plasma osmolality is maintained within normal limits through a delicate balance

between water intake and excretion. Antidiuretic hormone (ADH) plays an important

role in maintaining fluid balance in the body.

Case 10-1 (Question 1)

2 Signs of volume depletion include orthostatic hypotension, dry mucous

membranes, and poor skin turgor. Because water and sodium are inherently linked,

the assessment of volume status and selection of replacement fluid require

examination of sodium concentration.

Case 10-2 (Questions 1, 2)

3 Aldosterone is the main regulatory hormone for sodium homeostasis. A patient may

have hypotonic, isotonic, or hypertonic hyponatremia depending on the plasma

osmolality.

Cases 10-4 through 10-7

4 Hypovolemic hypotonic hyponatremia can occur with volume depletion and

decreased extracellular fluid. Calculation of sodium deficit will determine how much

sodium replacement is required.

Case 10-5 (Questions 1, 2)

5 Hypervolemic, hypotonic hyponatremia is caused by a disproportionate

accumulation of ingested water relative to sodium. It is also observed in patients

with heart failure, liver and renal failure, and nephrotic syndrome. Management

includes sodium and water restriction, as well as the use of diuretics.

Case 10-6 (Question 1)

6 Syndrome of inappropriate antidiuretic hormone is a common cause of

normovolemic hypotonic hyponatremia. Persistent ADH secretion together with

water ingestion results in hyponatremia.

Case 10-7 (Question 1)

7 Neurological symptoms may be manifested in acute or severe hyponatremia. Low

plasma osmolality causes water to move into the brain resulting in cerebral edema,

increased intracranial pressure, and central nervous system symptoms. Rapid or

overly aggressive correction of hyponatremia can result in osmotic demyelination.

Case 10-7 (Questions 3, 4)

POTASSIUM DISORDERS

1 The sodium-potassium adenosine triphosphatase pump plays a pivotal role in

maintaining potassium homeostasis. Normal serum potassium concentration is 3.5

to 5.0 mEq/L. Clinical manifestations of hypokalemia include muscle weakness and

electrocardiography (ECG) changes.

Case 10-8 (Questions 1, 2)

2 Potassium repletion should be guided by close monitoring of serum potassium.

Oral supplementation is usually preferred. Patients who cannot tolerate oral

potassium or who have severe/symptomatic hypokalemia can receive intravenous

potassium. In general, the rate of potassium infusion should not exceed 10

mEq/hour, to prevent phlebitis.

Case 10-8 (Question 3)

continued

188

189Fluid and Electrolyte Disorders Chapter 10

CHAPTER CASES

POTASSIUM DISORDERS CONTINUED

3 Hyperkalemia can be caused by chronic kidney disease and medications that inhibit

the renin-angiotensin-aldosterone system. Intravenous calcium is administered to

antagonize the cardiac effects (ECG changes and ventricular arrhythmias) of

hyperkalemia. Other treatment strategies include the use of insulin and glucose,

β2-agonists, sodium polystyrene sulfonate, sodium bicarbonate, and dialysis.

Case 10-9 (Question 1),

Case 10-10 (Questions 1, 2),

Table 10-3

CALCIUM DISORDERS

1 Normal serum calcium is 8.5 to 10.5 mg/dL (corrected for serum albumin as calcium

is protein-bound). Hypercalcemia can be caused by dehydration, malignancy,

hyperparathyroidism, vitamin D intoxication, sarcoidosis, and other granulomatous

disease. Clinical presentation of hypercalcemia includes signs and symptoms

involving the neurologic, cardiovascular, pulmonary, renal, gastrointestinal, and

musculoskeletal systems. First-line treatment for hypercalcemia is hydration and

diuresis. Calcitonin and bisphosphonates are alternative agents used in the

management of hypercalcemia.

Case 10-11 (Questions 1–3),

Table 10-4

PHOSPHATE DISORDERS

1 Hypophosphatemia can develop as a result of impaired intestinal phosphorus

absorption, increased renal elimination, or shift of phosphorus from extracellular to

intracellular compartments. Normal serum phosphorus concentration is 2.7 to

4.7 mg/dL.

Case 10-12 (Questions 1, 2)

2 Clinical effects of hypophosphatemia can involve multiple organ systems and are

attributed to impaired cellular energy stores and tissue hypoxia secondary to ATP

depletion. Phosphorus supplementation can be administered orally or

intravenously, depending on the signs and symptoms, and severity of

hypophosphatemia. Renal function, serum phosphorus, calcium, and magnesium

need to be monitored closely. Diarrhea is a common dose-related side effect of oral

phosphorus replacement.

Case 10-12 (Questions 3, 4)

MAGNESIUM DISORDERS

1 Magnesium depletion (normal serum magnesium, 1.8–2.4 mEq/L) can result in

abnormal function of the neurologic, neuromuscular, and cardiovascular systems.

Typical findings include Chvostek and Trousseau signs, muscle fasciculation,

tremors, muscle spasticity, convulsions, and possibly tetany. As serum magnesium

does not reflect total body stores, symptoms are more important determinants of

the urgency and aggressiveness of magnesium replacement.

Case 10-13 (Questions 1, 2)

2 Oral magnesium replacement is indicated in asymptomatic patients with mild

depletion. Urinary excretion of magnesium increases during intravenous

replacement. Thus, replenishment of magnesium stores usually takes several days.

After intravenous magnesium administration, the patient should be monitored for

hypotension, marked suppression of deep tendon reflexes, ECG and respiration

changes, as well as hypermagnesemia.

Case 10-13 (Questions 3, 4)

3 A common cause of hypermagnesemia is the use of magnesium-containing

laxatives and antacids by patients with renal impairment. Potentially life-threatening

complications of severe hypermagnesemia include respiratory paralysis,

hypotension, and complete heart block. Intravenous calcium should be

administered to antagonize the respiratory and cardiac manifestations of

magnesium. Diuretics may be given to patients with good renal function to

enhance urinary magnesium excretion.

Case 10-14 (Questions 1–3)

190 Section 1 General Care

BASIC PRINCIPLES

Body Water Compartments and

Electrolyte Composition

In newborns, approximately 75% to 85% of body weight is water.

After puberty, the percentage of water per kilogram of weight

decreases as the amount of adipose tissue increases with age.1,2

Body water constitutes 50% to 60% of the lean body weight

(LBW) in adult men but only 45% to 55% in women because of

their greater proportion of adipose tissue. The water content per

kilogram of body weight further decreases with advanced age.

Total body water (TBW) is usually calculated as 0.6 × LBW in

men, and 0.5 × LBW in women.

Two-thirds of the total body water resides in the cells (intracellular water). The extracellular water can be divided into different

compartments—the interstitial fluid (12% LBW) and the plasma

(5% LBW) are the two major compartments. Other compartments of the extracellular fluid include the connective tissues and

bone water, the transcellular fluids (e.g., glandular secretions), and

other fluids in sequestered spaces, such as the cerebrospinal fluid.1

The electrolyte composition differs between the intracellular and extracellular compartments. Potassium, magnesium, and

phosphate are the major ions in the intracellular compartment,

whereas sodium, chloride, and bicarbonate are predominant in

the extracellular space.2 Water travels freely across the cell membranes of most parts of the body. The cell membrane, however, is

only selectively permeable to solutes. The impermeable solutes

are osmotically active and can exert an osmotic pressure that

dictates the distribution of water between fluid compartments.

Water moves across the cell membrane from a region of low

osmolality to one of high osmolality. Net water movement ceases

when osmotic equilibrium occurs. Each fluid compartment contains a major osmotically active solute: potassium in the intracellular space and sodium in the extracellular fluid. The volumes of

the two compartments reflect the asymmetrically larger number

of solute particles or osmoles inside the cells.2,3

The capillary wall separates the interstitial fluid from plasma.

Because sodium moves freely across the capillary wall, its concentration is identical across both sides of the wall. Therefore, no

osmotic gradient is generated, and water distribution between

these two spaces is not affected. Plasma proteins, which are confined in the vascular space, are the primary osmoles that affect

water distribution between the interstitium and the plasma.2 In

contrast, urea, which traverses both the capillary walls and most

cell membranes, is osmotically inactive.2,3

Plasma Osmolality

Osmolality is defined as the number of particles per kilogram of

water (mOsm/kg). It is determined by the number of particles

in solution and not by particle size or valence. Nondissociable

solutes, such as glucose and albumin, generate 1 mOsm/mmol of

particles; and dissociable salts, such as sodium chloride liberate

two ions in solution to produce 2 mOsm/mmol of salt. The osmolality of body fluid is maintained between 280 and 295 mOsm/kg.

Because all body fluid compartments are iso-osmotic, plasma

osmolality reflects the osmolality of total body water. Plasma

osmolality can be measured by the freezing point depression

method, or estimated by the following equation, which takes

into account the osmotic effect of sodium, glucose, and urea2,3:

Posm = 2(Na)(mmol/L) + Glucose (mg/dL)

18

+ BUN (mg/dL)

2.8

(Eq. 10-1)

This equation predicts the measured plasma osmolality within

5 to 10 mOsm/kg. Although urea contributes to the measured

osmolality, it is an ineffective osmole because it readily traverses

cell membranes and, therefore, does not cause significant fluid

shift within the body. Hence, the effective plasma osmolality

(synonymous with tonicity, the portion of total osmolality that

has the potential to induce transmembrane water movement)

can be estimated by the following equation:

Posm = 2(Na)(mmol/L) + Glucose (mg/dL)

18 (Eq. 10-2)

An osmolal gap exists when the measured and calculated values differ by greater than 10 mOsm/kg4; it signifies the presence

of unidentified particles. When the individual solute has been

identified, its contribution to the measured osmolality can be

estimated by dividing its concentration (mg/dL) by one-tenth of

its molecular weight. Calculating the osmolal gap is used to detect

the presence of substances, such as ethanol, methanol, and ethylene glycol, that have high osmolality. Occasionally, the osmolal

gap can also result from an artificial decrease in the serum sodium

secondary to severe hyperlipidemia or hyperproteinemia.

CASE 10-1

QUESTION 1: J.F., a 31-year-old man, is admitted to the

inpatient medicine service for methanol intoxication. Routine laboratory analysis reveals the following:

Sodium (Na), 145 mEq/L

Potassium (K), 3.4 mEq/L

Blood urea nitrogen (BUN), 10 mg/dL

Creatinine, 1.1 mg/dL

Glucose, 90 mg/dL

The blood methanol concentration was 108 mg/dL, and

the measured plasma osmolality was 333 mOsm/kg. What is

J.F.’s calculated osmolality? Are other unidentified osmoles

present?

Using Equation 10-1, J.F.’s total calculated osmolality is

Posm = 2(145 mEq/L) + 90 mg/dL

18

+ 10 mg/dL

2.8

= 290 + 5 + 3.6

= 299 mOsm/kg (Eq. 10-3)

Osmolal gap = 333 mOsm/kg − 299 mOsm/kg

= 34 mOsm/kg (Eq. 10-4)

In J.F., the entire osmolal gap can be accounted for by the

presence of the methanol (because 108 mg/dL of methanol

will provide 108/3.2 = 33.7 mOsm/kg). It is unlikely, therefore,

that other unmeasured osmoles are present (e.g., ethylene glycol, isopropanol, and ethanol). The laboratory determination

of osmolality measures the total number of osmotically active

particles but not their permeability across the cell membrane.

Methanol increases plasma osmolality but not tonicity because

the cell membrane is permeable to methanol. Therefore, no net

water shift occurs between the intracellular and extracellular

compartments. Conversely, mannitol, which is confined to the

extracellular space, contributes to both plasma osmolality and

tonicity.

Tubular Function of Nephron

The kidney plays an important role in maintaining a constant

extracellular environment by regulating the excretion of water

191Fluid and Electrolyte Disorders Chapter 10

and various electrolytes. The volume and composition of fluid

filtered across the glomerulus are modified as the fluid passes

through the tubules of the nephron.

The renal tubule is composed of a series of segments with heterogeneous structures and functions: the proximal tubule, the

medullary and cortical thick ascending limb of Henle’s loop, the

distal convoluted tubule, and the cortical and medullary collecting duct2 (Fig. 10-1). The mechanism for sodium reabsorption is

different for each nephron segment, but is generally mediated by

carrier proteins or channels located on the luminal membrane of

the tubule cell.2 Na+/K+ ATPase (sodium-potassium adenosine

triphosphatase) actively pumps sodium out of the renal tubule

cell in exchange for potassium in a 3:2 ratio. Hence, the intracellular sodium concentration is kept at a low level. The potassium

that is pumped into the cell leaks back out through potassium

channels in the membrane, rendering the cell interior electronegative. The low intracellular sodium concentration and a negative

intracellular potential produce a favorable gradient for passive

sodium entry into the cell.3 Na+/K+ ATPase also indirectly provides the energy for active sodium transport and the reabsorption

and secretion of other solutes across the luminal membrane of

the renal tubule. The distal segments are mainly involved in the

reabsorption of sodium and chloride ions and the secretion of

hydrogen and potassium ions.2

Iso-osmotic reabsorption of the glomerular filtrate occurs in

the proximal tubule such that two-thirds of the filtered sodium

and water and 90% of the filtered bicarbonate are reabsorbed.

The Na+/H+ antiporter (exchanger) in the luminal membrane

is instrumental in the reabsorption of sodium chloride, sodium

bicarbonate, and water. The reabsorption of most nonelectrolyte

solutes, such as glucose, amino acids, and phosphates, are coupled to sodium transport.2,5

Both the thick ascending limb of Henle’s loop and the distal

convoluted tubule serve as the diluting segments of the nephron

because they are impermeable to water. Sodium chloride is

extracted from the filtrate without water. Sodium transport in

both of these segments is flow-dependent and varies with the

amount of sodium ions delivered from the proximal segments

of the nephron. Decreased sodium ions in the tubular fluid will

limit sodium transport in the thick ascending limb of Henle’s

loop and the distal convoluted tubule.2,6

Reabsorption of sodium in the thick ascending limb of Henle’s

loop accounts for approximately 25% of the total sodium reabsorption. Sodium, chloride, and potassium are reabsorbed by

H2O

H2O

H2O

Descending Limb

Cortex

Medulla

Urea

Pars Recta

Organic Acids

Glucose

NaHCO3

Proximal

Convoluted

Tubule

Amino Acids

+ +

+

+

+

+

+

+

+

+

+

+

+

+

–

–

–

– – –

–

–

–

– –

–

ADH H2O

Sensitive

Urea

ADH

Sensitive

NaCl

Henle's Loop

Urea

Medullary Thick

Ascending Limb

2Cl–

Na+

K+

2Cl–

Na+

K+

Cortical Thick

Ascending Limb

ADH

Sensitive

ADH

Sensitive

H2O

H+

Na+

Aldosterone

Sensitive

Na+

K+

H+ Distal

Convoluted

Tubule

FIGURE 10-1 Sites of tubule salt and water absorption. Sodium is reabsorbed with inorganic anions, amino acids,

and glucose in the proximal tubule against an electrical gradient that is lumen-negative. In the distal part of the

proximal tubule (pars recta), sodium and water are reabsorbed to a lesser extent and organic acids (hippurate, urate)

and urea are secreted into the urine. The electrical potential is lumen-positive in the pars recta. Water, but not salt, is

removed from tubule fluid in the thin descending limb of Henle’s loop, but in the ascending portion salt is reabsorbed

without water, rendering the tubule fluid hyposmotic with respect to the interstitium. Sodium, chloride, and potassium

are reabsorbed by the medullary and cortical portions of the ascending limb; the lumen potential is positive. Sodium

is reabsorbed and potassium and hydrogen ions are secreted in the distal tubule and collecting ducts. Water

absorption in these segments is regulated by antidiuretic hormone (ADH). The electrical potential is lumen-negative in

the cortical sections and positive in the medullary segments. Urea is concentrated in the interstitium of the medulla

and assists in the generation of maximally concentrated urine. (Reprinted with permission from Chonko AM et al.

Treatment of edema states. In: Narins RG, ed. Maxwell & Kleeman’s Clinical Disorders of Fluid and Electrolyte

Metabolism. 5th ed. New York, NY: McGraw-Hill; 1994:545.)

192 Section 1 General Care

the medullary and cortical portions of the ascending limb, but

the leakage of reabsorbed potassium ions back into the tubular lumen, via potassium channels, makes the tubular lumen

electropositive. This electrical gradient promotes the passive

reabsorption of cations, such as sodium, calcium, and magnesium, in the distal convoluted tubules. Because the thick ascending limb of Henle’s loop is impermeable to water, it contributes

to the interstitial osmolality in the medulla. This high osmolality is key to the reabsorption of water by the medullary portion

of the collecting duct under the influence of antidiuretic hormone (ADH, vasopressin). Therefore, the thick ascending limb

of Henle’s loop is important for both urinary concentration and

dilution.6

Because, as noted previously, the distal convoluted tubule also

is impermeable to water, the osmolality of the filtrate continues

to decline as sodium is being reabsorbed. In the distal convoluted

tubule and collecting duct, sodium is reabsorbed in exchange

for hydrogen ions and potassium. When sodium ions are reabsorbed, the tubule lumen becomes electronegative, which promotes potassium secretion in the lumen via potassium channels.

Aldosterone enhances sodium reabsorption in the collecting duct

by increasing the number of opened sodium channels.2,7

The collecting duct is usually impermeable to water. Under

the influence of ADH, however, water permeability is increased

through an increase in the number of water channels along the

luminal membrane. The amount of water reabsorbed depends on

the tonicity of the medullary interstitium, which is determined

by the sodium reabsorbed in the thick ascending limb of Henle’s

loop and urea.2,7,8

Osmoregulation

An increase in the effective plasma osmolality often reduces intracellular volume; conversely, decreased effective plasma osmolality is associated with cellular hydration. Water homeostasis is

important in the regulation of plasma osmolality, and plasma

tonicity is maintained within normal limits through a delicate

balance between the rates of water intake and excretion.

The amount of daily water intake includes the volume of

water ingested (sensible intake), the water content of ingested

food, and the metabolic production of water (insensible intake).2

To maintain homeostasis, these should be equal to the amount of

water excreted by the kidney and the gastrointestinal (GI) tract

(sensible loss) plus water lost from the skin and respiratory tract

(insensible loss).2,3

Changes in plasma tonicity are detected by osmoreceptors

in the hypothalamus, which also houses the thirst center and is

the site for ADH synthesis.9,10 When the plasma tonicity falls

below 280 mOsm/kg as a result of water ingestion, ADH release

is inhibited,2 water is no longer reabsorbed in the collecting

duct, and a large volume of dilute urine is excreted. Conversely,

when the osmoreceptors in the hypothalamus sense an increased

plasma osmolality, ADH is released to increase water reabsorption. A small volume of concentrated urine is then excreted. The

threshold for ADH release is 280 mOsm/kg, and maximal ADH

secretion occurs when the plasma osmolality is 295 mOsm/kg.9

Thus, urine osmolality varies from 50 mOsm/kg in the absence of

ADH to 1,200 mOsm/kg during maximal ADH release. The volume of urine produced depends on the solute load to be excreted,

as well as the urine osmolality2,3,9,10:

Urine volume (L) =

 Solute load (mOsm)

Urine osmolality (mOsm/kg)

×

 1

Density of water (kg/L)

(Eq. 10-5)

Therefore, for a typical daily solute load of 600 mOsm:

=

 600 mOsm

50 mOsm/kg  1

1 kg/L

= 12 L (No ADH) (Eq. 10-6)

=

 600 mOsm

1,200 mOsm/kg 1

1 kg/L

= 0.5 L (Max ADH) (Eq. 10-7)

Although the kidney has a remarkable ability to excrete free

water, it is not as efficient in conserving water. ADH minimizes

further water loss, but it cannot correct water deficits. Therefore, optimal osmoregulation requires increased water intake

stimulated by thirst. Both ADH and thirst can be stimulated by

nonosmotic stimuli. For example, volume depletion is such a

strong nonosmotic stimulus for ADH release that it can override

the response to changes in plasma osmolality. Nausea, pain, and

hypoxia are also potent stimuli for ADH secretion.11

Volume Regulation

Sodium resides almost exclusively in the extracellular fluid; the

amount of total body sodium, therefore, determines the extracellular volume.2,11 Because daily sodium intake varies from

100 to 250 mEq, the body must rely on adjustments in urinary

sodium excretion to maintain the extracellular volume and tissue perfusion.2,11 The ability of the kidney to retain sodium is so

remarkable that a person can survive with a daily sodium intake

as low as 20 to 30 mEq.

The afferent sensors for the changes in the effective circulating

volume are the intrathoracic volume receptors, the baroreceptors in the carotid sinus and aortic arch, and the afferent arteriole

in the glomerulus.11

When the effective circulating volume is decreased, both

the renin-angiotensin-aldosterone and the sympathetic nervous

systems are activated.2,11 Angiotensin type 2 (AT2) and norepinephrine enhance sodium reabsorption at the proximal convoluted tubule. In addition, aldosterone stimulates sodium reabsorption at the collecting tubule. The decrease in effective arterial

volume also stimulates ADH release, which enhances water reabsorption at the collecting duct. Conversely, after a salt load, the

increases in atrial pressure and renal perfusion pressure suppress

the production of renin and, subsequently, AT2 and aldosterone.

The release of atrial natriuretic peptide secondary to increased

atrial filling pressure and intrarenal production of urodilators

increase urinary excretion of the excess sodium.12,13

Although the kidney can excrete a 20-mL/kg water load in 4

hours, only 50% of the excess sodium is excreted in the first day.3

Sodium excretion continues to increase until a new steady state

is reached after 3 to 4 days, when intake equals output.3,12 It is

important to recognize that osmoregulation and volume regulation occur independently of each other.2,3 The two homeostatic

systems regulate different parameters and possess different sensors and effectors. Both systems can be activated simultaneously,

however.

DISORDERS IN VOLUME REGULATION

Sodium Depletion

CASE 10-2

QUESTION 1: A.B., a 17-year-old girl, presented to the

emergency department (ED) with complaints of anorexia,

nausea, vomiting, and generalized weakness for the past

stepped-care approach a single agent is initiated and the dose

increased until BP is controlled, the maximal dose is reached,

or dose-limiting toxicity occurs. If the goal BP is not achieved, a

second drug from a different class is added. This process can be

continued, if necessary, until three or even four drugs are used

in combination. The VA Cooperative Studies Group on Antihypertensive Agents demonstrated that less than 60% of patients

reach a DBP of less than 90 mm Hg with this approach when

doses were titrated up to the maximal dosage.41

In the sequential therapy approach, a single agent is initiated and titrated to the maximal dose as needed. If goal BP

is not achieved, another agent is selected to replace the first.

Combination drug therapy is reserved for patients who do not

achieve goal BP values after the second agent. Sequential therapy

is most appropriate when the first drug is either poorly tolerated

or results in minimal reduction in BP. The VA Cooperative Studies Group on Antihypertensive Agents also evaluated sequential

therapy, and demonstrated that only an additional 49% of the

nonresponders to the first agent achieved a DBP of less than 90

mm Hg when switched to a second drug.114

COMBINATION THERAPY

CASE 14-3, QUESTION 5: In your CDTM protocol, when

should starting with initial two-drug therapy be recommended to treat hypertension in primary prevention

patients?

Starting therapy with two drugs is an option for initial therapy.

This approach is strongly encouraged for patients far from their

BP goal (e.g., stage 2 hypertension) or in patients closer to their

BP goal who have compelling indications for two drugs, or have

BP goals of less than 130/80 mm Hg.3,15,82 The average patient

with hypertension will require two or more agents to achieve

his or her goal BP value. In contrast to high-dose monotherapy,

low-dose, two-drug combination therapy provides greater BP

lowering with a lower risk of side effects.81 Prospective clinical

trials have demonstrated that goal attainment rates of more than

70% are achieved when initial two-drug combination therapy

is used in patients with stage 2 hypertension.115,116 Moreover,

this approach achieves goal BP in a quicker, yet safe, time frame

compared with the stepped-care approach to therapy.116,117 As

previously mentioned, elderly patients (age 80 years or older)

should only have one antihypertensive agent started at a time to

minimize risk of orthostatic hypotension.

PREFERRED COMBINATIONS

When treating patients with combination antihypertensive therapy, the presence of compelling indications should be used to

guide selection of combination agents. In the absence of compelling indications (i.e., primary prevention patients), clinicians

should use combinations that are additive in their ability to lower

BP. This entails balancing a thorough understanding of the pathophysiology of hypertension along with the pharmacology of the

drugs being used. Combinations of drugs from different drug

classes with distinctly different mechanisms of action are ideal

to provide the best reductions in BP. The American Society of

Hypertension recommends the combination of an ACEI or ARB

with a CCB or the combination of an ACEI or ARB with a diuretic

as preferred combinations because they are highly effective in

lowering BP.118 Many patients can achieve a BP goal of less than

140/90 mm Hg with two drugs when appropriate combinations

are used. It is not uncommon, however, to require three or more

drugs to attain a goal BP of less than 130/80 mm Hg.

Diuretics, especially thiazide diuretics, provide additive effects

in BP lowering when combined with most other antihypertensive agents.3,37 This is especially true for any other antihypertensive drugs that block the RAAS (i.e., ACEI, ARB, direct renin

inhibitor),119 and to a lesser extent when diuretics are used in

combination with CCBs.120 In the case of the former, diuretics

may “prime” the system because a compensatory increase in

plasma renin usually occurs with the administration of diuretics.

Diuretic therapy is also often used in combination with older

alternative antihypertensive agents (e.g., direct arterial vasodilators, α2-agonists) to mitigate compensatory fluid retention seen

with many of these drugs.

ACCEPTABLE COMBINATIONS

Many combinations are recommended by the American Society

of Hypertension as acceptable combinations. With these combinations, BP lowering is modest (but perhaps not as large as combinations identified as preferred) or these combinations have a

synergistic effect of mitigating side effects. These combinations

include a β-blocker or CCB with a diuretic, a dihydropyridine

CCB with a β-blocker, a renin inhibitor with either a diuretic or

ARB, or a thiazide diuretic with a potassium-sparing diuretic.118

LESS EFFECTIVE COMBINATONS

The American Society of hypertension recommends that several

combinations as less effective in BP lowering. Most of these result

from a lack of complementary pharmacologic actions. These less

effective combinations include an ACEI with ARB, ACEI or ARB

with a β-blocker, a nondihydropyridine CCB with a β-blocker,

and a centrally acting agent with a β-blocker.118

The combination of an ACEI or ARB with a β-blocker is

less effective in lowering BP as renin release is suppressed by

β-blockade. When evaluating pure BP lowering, other combinations result in better reductions. However, this combination is

certainly indicated when compelling indications for each agent

coexist (e.g., CAD, left ventricular dysfunction) (Fig. 14-3).

The combination of an ACEI and ARB overall is not very

beneficial. This combination should not be used specifically for

the purpose of BP lowering, especially in primary prevention

patients. When this combination was evaluated in the ONgoing

Telmisartan Alone and in Combination With Ramipril Global

Endpoint Trial (ONTARGET), the ACEI with ARB combination

treatment arm provided only minimal additional reduction in

311Essential Hypertension Chapter 14

BP compared with either agent alone, and most importantly

did not additionally lower risk of CV events.121 Moreover, there

was a higher risk of adverse events (e.g., kidney dysfunction,

hypotension) with the combination arm.

The combination of an ACEI with ARB has been used in

patients with left ventricular dysfunction based on promising

data of a reduced risk of heart failure hospitalizations.122,123 However, the overall clinical benefits of an ACEI with an ARB versus

an ACEI without an ARB are very small; addition of an aldosterone antagonist is the preferred next step in patients with left

ventricular dysfunction who are already treated with the standard regimen of a diuretic, ACEI, and a β-blocker.108,124 One

potential niche for the use of an ACEI with an ARB is in the

setting of CKD with significant proteinuria (300 mg albumin/day

or 500 mg protein/day or per gram of urinary creatinine), in

which the combination of an ACEI with an ARB seems to reduce

progression of proteinuria better than either drug alone.96

OTHER COMBINATIONS

Using two agents from the same drug class is almost always

discouraged. However, there are two potential exceptions. The

combination of two diuretics together from different subclasses

is sometimes used in patients with resistant hypertension or

nephrotic syndrome, but more often is done to minimize electrolyte depletion, especially hypokalemia and hypomagnesemia,

which commonly occur with thiazide diuretics. The use of a dihydropyridine CCB with a nondihydropyridine CCB has marginal

but additional benefits on BP lowering.125,126 This combination

may be helpful in patients with diabetes who are not responsive

to more common three-drug combinations.91

ORTHOSTATIC HYPOTENSION

CASE 14-3, QUESTION 6: In your CDTM protocol, why

should initial two-drug therapy never be recommended in

elderly patients age 75 years or older?

Orthostatic hypotension occurs when standing upright results

in a SBP decrease of more than 20 mm Hg (or a DBP decrease

of more than 10 mm Hg) after 3 minutes of standing and is

often accompanied by dizziness or fainting.3,25 This is a risk of

rapid BP lowering. Orthostatic hypotension is more frequent in

elderly patients (especially those with ISH), diabetes, autonomic

dysfunction, volume depletion, and in patients taking certain

drugs (i.e., diuretics, nitrates, α-blockers, psychotropic agents,

phosphodiesterase inhibitors). Combination therapy can still be

used in these patients, but close monitoring and slow titration

are needed. Dose increases should be gradual to minimize the

risk of hypotension. Moreover, initial therapy with two drugs

should be avoided in the elderly (age 80 years or older) owing to

the increased risk of orthostatic hypotension.

MONITORING THERAPY

Four aspects of treatment must always be considered: (a) BP

response to attain goal, (b) adherence with lifestyle modifications and pharmacotherapy, (c) progression to hypertensionassociated complications, and (d) drug-related toxicity.

Reduction in BP should be evaluated 1 to 4 weeks after starting

or modifying therapy for most patients. BP usually begins to

decrease within 1 to 2 weeks of starting an agent, but steadystate antihypertensive effects can take up to 4 weeks. If patients

are in hypertensive crisis, evaluation should occur sooner, within

hours to days (see Chapter 21, Hypertensive Crises).

Two BP values separated by at least 1 minute should be measured during each clinical evaluation, with the average used to

make a proper assessment. If dehydration or orthostatic hypotension is suspected, BP should be measured in both the seated

and standing positions to detect orthostatic changes. For routine

monitoring, measuring BP in the seated position is sufficient. SelfBP monitoring values should be considered if available. Normally,

however, they are slightly lower (5 mm Hg) than clinic values

even in patients without white-coat hypertension. For example,

patients with a goal BP value of less than 140/90 mm Hg should

have home measurements that are less than 135/85 mm Hg.7

All patients should be questioned in a nonthreatening manner regarding adherence with lifestyle modifications and drug

therapy. This is especially important for complex regimens,

when drug intolerance is likely, or when financial constraints

hinder acquisition of medications. Evaluating hypertensionassociated complications and drug side effects are essential. New

hypertension-associated complications may necessitate changes

to treat a compelling indication or attain a new BP goal. Drugrelated side effects may similarly require therapy modifications.

CLINICAL SCENARIOS

Diuretics

CASE 14-4

QUESTION 1: B.A. is a 62-year-old woman who is postmenopausal, does not smoke, and never drinks alcohol.

Since being diagnosed with hypertension, she has modified

her diet, begun routine aerobic exercise, and has lost 10 kg

in the past 18 months. She now weighs 72 kg and is 165

cm tall. Her BP is now 150/94 mm Hg (150/92 mm Hg when

repeated) and has consistently remained near this value for

the past year. Her BP when first diagnosed was 156/96 mm

Hg. Physical examination shows no LVH and no retinopathy.

Urinalysis is negative for protein. Other laboratory tests are

normal, except for dyslipidemia. B.A. has no health insurance and is concerned about the cost of therapy. Her Framingham risk score is 22%. She takes over-the-counter calcium with vitamin D, and her provider wants to start HCTZ

25 mg/day. Is HCTZ an appropriate agent for B.A.?

B.A. is a primary prevention patient with uncontrolled hypertension. According to the JNC-7, her BP goal is less than 140/90

mm Hg, with an option of less than 130/80 mm Hg according to the AHA guidelines based on her Framingham risk score

(Fig. 14-2).3,15 Regardless of which BP goal is selected, initial

monotherapy is reasonable because she is in the low end of stage

1 hypertension. Appropriate first-line treatment options include

an ACEI, ARB, CCB, or thiazide diuretic. All of these drug classes

have generic options, and should be easily affordable for B.A.

A thiazide diuretic may also benefit her osteoporosis (Table

14-8) and is an appropriate choice. Several types of diuretics are

used to manage hypertension (Table 14-9).37 All lower BP, with

differences being duration of action, potency of diuresis, and

electrolyte abnormalities.

THIAZIDES

Thiazides are diuretics of choice for most patients with hypertension. Similar to loop diuretics, an initial diuresis is experienced.

After approximately 4 to 6 weeks of thiazide diuretic therapy,

diuresis dissipates, however, and is supplanted by a decrease in

PVR, which is responsible for sustaining antihypertensive effects.

HYDROCHLOROTHIAZIDE VERSUS CHLORTHALIDONE

HCTZ and chlorthalidone have been used in several major outcome trials, although only chlorthalidone-based regimens have

proven to be of benefit in the low doses commonly used in practice today.47–49,62,68,115,127 Both agents are inexpensive and dosed

312 Section 2 Cardiac and Vascular Disorders

TABLE 14-9

Diuretics in Hypertension

Category Selected Products Usual Dosage Range (mg/d) Dosing Frequency

Thiazide and thiazidelike Chlorthalidone 12.5–25 Daily

Hydrochlorothiazide 12.5–25 Daily

Indapamide 1.25–5 Daily

Metolazone 2.5–10 Daily

Metolazone 0.5–1.0 Daily

Loop Bumetanide 0.5–4 BID

Furosemide 20–80 BID

Torsemide 2.5–10 Daily

Potassium-sparing Amiloride 5–10 Daily to BID

Triamterene 50–100 Daily to BID

Potassium-sparing combination Triamterene/HCTZ 37.5/25–75/50 Daily

Spironolactone/HCTZ 25/25–50/50 Daily

Amiloride/HCTZ 5–10/50–100 Daily

Aldosterone antagonist Eplerenone 50–100 Daily to BID

Spironolactone 12.5–50 Daily to BID

BID, twice daily; HCTZ, hydrochlorothiazide.

once daily, but HCTZ is most frequently used in the United

States, and is more widely available in fixed-dose combination

products. The usual starting dose of HCTZ or chlorthalidone is

12.5 mg once daily. A maintenance dose of 25 mg once daily can

effectively lower BP and has a low incidence of side effects (e.g.,

hypokalemia, hyperuricemia) that can be managed with routine

monitoring.41,57,59

To listen to a Capticast interview of Mike

Ernst and Joseph Saseen by Nikki Hahn (on

behalf of IForum) that focuses on the

ACCOMPLISH trial and comments on

hydrochlorothiazide and chlorthalidone, go

to http://thepoint.lww.com/AT10e. To view

the full IForum Capticast of the

ACCOMPLISH trial, go to http://

iforumrx.org/.