Acid–Base Disorders

a. Metabolic acidosis
TREATMENT
 The primary treatment is to correct the underlying disorder. Additional treatment
depends on the severity and onset of acidosis.
 Manage asymptomatic patients with mild to moderate acidemia (HCO3 − 12–20 mEq/L
[12–20 mmol/L]; pH 7.2–7.4) with gradual correction of the acidemia over days to
weeks using oral sodium bicarbonate or other alkali preparations (Table 72–4). The
dose of bicarbonate can be calculated as follows:
Loading dose (mEq or mmol/L) = (Vd HCO3− × body weight) × (desired [HCO3 −] –
current [HCO3−]),
where Vd HCO3 − is the volume of distribution of HCO3− (0.5 L/kg).

 Alkali therapy can be used to treat patients with acute severe metabolic acidosis due to
hyperchloremic acidosis, but its role is controversial in patients with lactic acidosis.
 Therapeutic options include sodium bicarbonate and tromethamine.
 Sodium bicarbonate is recommended to raise arterial pH to 7.2. However, no
controlled clinical studies have demonstrated reduced morbidity and mortality
compared with general supportive care. If IV sodium bicarbonate is administered,
 the goal is to increase, not normalize, pH to 7.2 and HCO3− to 8 to 10 mEq/L (8–10
mmol/L).
 Tromethamine, a highly alkaline solution, is a sodium-free organic amine that acts
as a proton acceptor to prevent or correct acidosis. However, no evidence exists that
tromethamine is beneficial or more efficacious than sodium bicarbonate. The usual
empiric dosage for tromethamine is 1 to 5 mmol/kg administered IV over 1 hour,
and an individualized dose can be calculated as follows:
Dose of tromethamine (in mL) = 1.1 × body weight (in kg) × (normal [HCO3 −] –
current [HCO3−])

b. Metabolic alkalosis
TREATMENT
Aim treatment at correcting the factor(s) responsible for maintaining the alkalosis and
depends on whether the disorder is sodium chloride responsive or resistant (Fig. 72–2).
 c. Mix Acid-Base disorder
TREATMENT
Treat mixed respiratory and metabolic acidosis by initiating oxygen delivery to improve
hypercarbia and hypoxia. Mechanical ventilation can be needed to reduce Paco2. During
initial therapy, give appropriate amounts of alkali to reverse the metabolic acidosis.
Correct the metabolic component of mixed respiratory and metabolic alkalosis by
administering sodium and potassium chloride solutions. Readjust the ventilator or treat
the underlying disorder causing hyperventilation to treat the respiratory component.
Treatment of mixed metabolic acidosis and respiratory alkalosis should be directed at the
underlying cause.
In metabolic alkalosis and respiratory acidosis, pH does not usually deviate significantly
from normal, but treatment can be required to maintain Pao2 and Paco2 at acceptable
levels. Aim treatment at decreasing plasma bicarbonate with sodium and potassium
chloride therapy, allowing renal excretion of retained bicarbonate from diuretic-induced
metabolic alkalosis.
EVALUATION OF THERAPEUTIC OUTCOMES
• Patients should be monitored closely because acid–base disorders can be serious and
even life threatening.
• ABGs are the primary tools for evaluation of therapeutic outcome.

Acute Kidney Injury

• Acute kidney injury (AKI) is a clinical syndrome generally defined by an abrupt reduction
in kidney functions as evidenced by changes in laboratory values, serum creatinine (Scr),
blood urea nitrogen (BUN), and urine output.
RIFLE (Risk, Injury, Failure, Loss of Kidney Function, and End-Stage Renal Disease) and
AKIN (Acute Kidney Injury Network) criteria are two criteria-based classification systems
developed to predict patient outcomes. The Kidney Disease: Improving Global Outcomes
(KDIGO) Clinical Practice Guidelines were developed to provide one standardized
definition of AKI (Table 73–1).
KDIGO defines AKI as being present if any of the following criteria is met:
1. Increase in Scr by at least 0.3 mg/dL (27 μmol/L) within 48 hours
2. Increase in Scr by at least 1.5 times baseline within the prior 7 days
3. Decrease in urine volume to less than 0.5 mL/kg/h for 6 hours
GENERAL APPROACH TO TREATMENT
• Currently, there is no definitive therapy for AKI. Supportive care is the mainstay of AKI
management regardless of etiology.
Nonpharmacologic Therapies
• Supportive care goals include maintenance of adequate cardiac output and blood
pressure to optimize tissue perfusion while restoring renal function to pre-AKI baseline.
• Discontinue medications associated with diminished renal blood flow. Initiate
appropriate fluid and electrolyte management. Avoid use of nephrotoxins.
• In severe AKI, renal replacement therapy (RRT), such as hemodialysis and peritoneal
dialysis, maintains fluid and electrolyte balance while removing waste products. See Table
73–4 for indications for RRT in AKI. Intermittent and continuous options have different
advantages (and disadvantages) but, after correcting for severity of illness, have similar
outcomes. Consequently, hybrid approaches (eg, sustained lowefficiency dialysis and
extended daily dialysis) are being developed to provide the advantages of both.
• Intermittent hemodialysis (IHD) is the most frequently used RRT and has the advantage
of widespread availability and the convenience of lasting only 3 to 4 hours. Disadvantages
include difficult venous dialysis access in hypotensive patients and hypotension due to
rapid removal of large amounts of fluid.
• Several continuous RRT (CRRT) variants have been developed including continuous
hemofiltration, continuous hemodialysis, or a combination. CRRT gradually removes solute,
resulting in better tolerability by critically ill patients. Disadvantages include limited
availability of equipment, need for intensive nursing care, and the need to individualize IV
replacement, dialysate fluids, and drug therapy adjustments.
Pharmacologic Therapies
• Mannitol 20% is typically started at a dose of 12.5 to 25 g IV over 3 to 5 minutes.
Disadvantages include IV administration, hyperosmolality risk, and need for monitoring
urine output and serum electrolytes and osmolality because mannitol can contribute to
AKI.
• Loop diuretics effectively reduce fluid overload but can worsen AKI. Equipotent doses of
loop diuretics (furosemide, bumetanide, torsemide, and ethacrynic acid) have similar
efficacy. Ethacrynic acid is reserved for sulfa-allergic patients. Continuous infusions of loop
diuretics appear to overcome diuretic resistance and to have fewer adverse effects than
intermittent boluses. An initial IV loading dose (equivalent to furosemide 40–80 mg)
should be administered before starting a continuous infusion (equivalent to furosemide
10–20 mg/h).
• Strategies are available to overcome diuretic resistance (Table 73–5). Administration
of agents from different pharmacologic classes, such as diuretics that work at thedistal
convoluted tubule (thiazides) or the collecting duct (amiloride, triamterene, and
spironolactone), may be synergistic when combined with loop diuretics. Metolazone is
commonly used because, unlike other thiazides, it produces effective diuresis at GFR less
than 20 mL/min (0.33 mL/s).
ELECTROLYTE MANAGEMENT AND NUTRITION INTERVENTIONS
• Serum electrolytes should be monitored daily. Hyperkalemia is the most common
and serious electrolyte abnormality in AKI. Hypernatremia and fluid retention
commonly occur, requiring calculation of daily sodium intake, including sodium
contained in commonly administered antibiotic and antifungal agents.

• Phosphorus and magnesium should be monitored, especially in patients with significant

tissue destruction due to increased amounts of released phosphorus; neither is
efficiently removed by dialysis.

• Nutritional management of critically ill patients with AKI is complex due to multiple
mechanisms for metabolic derangements. Nutritional requirements are altered by
stress, inflammation, and injury that lead to hypermetabolic and hypercatabolic
states.
DRUG-DOSING CONSIDERATIONS
• Drug therapy optimization in AKI is a challenge. Confounding variables include
residual drug clearance, fluid accumulation, and use of RRTs.

Volume of distribution for water-soluble drugs is significantly increased due to

edema. Use of dosing guidelines for CKD does not reflect the clearance and volume
of distribution in critically ill patients with AKI.

• Patients with AKI may have a higher residual nonrenal clearance than those with
CKD with similar creatinine clearances; this complicates drug therapy individualization,
especially with RRTs.

• The mode of CRRT determines rate of drug removal, further complicating individualization
of drug therapy. Rates of ultrafiltration, blood flow, and dialysate flow
influence drug clearance during CRRT.
EVALUATION OF THERAPEUTIC OUTCOMES
• Vigilant monitoring of patient status is essential (Table 73–6).
• Therapeutic drug monitoring should be monitored frequently because of changing
volume status, changing renal function, and RRTs in patients with AKI.

Chronic Kidney Disease

• Chronic kidney disease (CKD) is defined as abnormalities in kidney structure or
function, present for 3 months or longer, with implications for health. Structural
abnormalities include albuminuria of more than 30 mg/day, presence of hematuria
or red cell casts in urine sediment, electrolyte and other abnormalities due to tubular
disorders, abnormalities detected by histology, structural abnormalities detected by
imaging, or history of kidney transplant.

• CKD is classified by cause of kidney disease, glomerular filtration rate (GFR) category,
and albuminuria level based on new recommendations from the Kidney
Disease: Improving Global Outcomes (KDIGO) guidelines, referred to as CGA staging
(cause, GFR, albuminuria) (Table 74–1).

• CKD stage 5, previously referred to as end-stage renal disease (ESRD), occurs when
the GFR falls below 15 mL/min/1.73 m2 (<0.14 mL/s/m2) or in patients receiving
renal replacement therapy (RRT). In this chapter, ESRD refers specifically to patients
who receive chronic dialysis.

• Prognosis depends on cause of kidney disease, GFR at time of diagnosis, degree of

albuminuria, and presence of other comorbid conditions.

TREATMENT
GENERAL APPROACH
• Goal of Treatment: The goal is to delay the progression of CKD, minimizing the
development or severity of complications.

Use the most current consensus guidelines and the best clinical practices for management
of CKD.

NONPHARMACOLOGIC THERAPY
• Restrict protein to 0.8 g/kg/day if GFR is less than 30 mL/min/1.73 m2.
• Encourage smoking cessation to slow progression of CKD and reduce the risk of
CVD.

• Encourage exercise at least 30 minutes five times per week and achievement of a body
mass index (BMI) of 20 to 25 kg/m2.
PHARMACOLOGIC THERAPY
Diabetes and Hypertension With CKD
• Progression of CKD can be limited by optimal control of hyperglycemia and hypertension.
Figure 74–2 provides an algorithm for management of diabetes in CKD.

• For more information on diabetes, see Chap. 19.

• Adequate blood pressure (BP) control (Fig. 74–3) can reduce the rate of decline in
GFR and albuminuria in patients without diabetes. KDIGO guidelines recommend a
target blood pressure of 140/90 mm Hg or less if urine albumin excretion or equivalent
is less than 30 mg/24 h.

• If urine albumin excretion is greater than 30 mg/24 h or equivalent, the target blood
pressure is 130/80 mm Hg or less and initiate first-line therapy with an angiotensinconverting
enzyme inhibitor (ACEI) or an angiotensin II receptor blocker (ARB).
Add a thiazide diuretic in combination with an ARB if additional reduction in
proteinuria is needed. Nondihydropyridine calcium channel blockers are generally
used as second-line antiproteinuric drugs when ACEIs or ARBs are contraindicated
or not tolerated.

• ACEI clearance is reduced in CKD; therefore, treatment should begin with the lowest
possible dose followed by gradual titration to achieve target BP and, secondarily, to
minimize proteinuria. No individual ACEI is superior to another.

• For more information on hypertension, see Chap. 10.

Anemia of CKD
• KDIGO definition of anemia: Hemoglobin (Hb) less than 13 g/dL (130 g/L; 8.07
mmol/L) for adult males and less than 12 g/dL (120 g/L; 7.45 mmol/L) for adult
females.
FIGURE 74–2. Diabetes with chronic kidney disease (CKD) algorithm. Strategy for screening and treatment of diabetes with CKD
based on urine albumin excretion, target blood pressure, and estimated GFR (eGFR). (Data from National Kidney Foundation,
KDOQI clinical practice guidelines and clinical practice recommendations for diabetes and chronic kidney disease. Am J Kidney Dis
2007;49(Suppl 2):S1–S180; reference 1.)

Initiate erythropoietic-stimulating agent (ESA) therapy in all CKD patients with

Hb is between 9 and 10 g/dL (90 and 100 g/L; 5.59 and 6.21 mmol/L). Target Hb is
controversial.

• Iron deficiency is the primary cause of resistance to treatment of anemia with

ESAs. Iron supplementation is required by most CKD patients to replete iron stores
depleted by ongoing blood loss and increased iron demands.

• Parenteral iron therapy improves response to ESA therapy and reduces the dose
required to achieve and maintain target indices. In contrast, oral therapy is limited
by poor absorption and nonadherence with therapy primarily due to adverse effects
(Fig. 74–4).

• IV iron preparations have different pharmacokinetic profiles, which do not correlate

with pharmacodynamic effect.

• Adverse effects of IV iron include allergic reactions, hypotension, dizziness, dyspnea,

headaches, lower back pain, arthralgia, syncope, and arthritis. Some of these reactions
can be minimized by decreasing the dose or rate of infusion. Sodium ferric
gluconate, iron sucrose, and ferumoxytol have a better safety record than iron dextran
products.

• Subcutaneous (SC) administration of epoetin alfa is preferred because IV access is

not required, and the SC dose that maintains target indices is 15% to 30% lower than
the IV dose.

• Darbepoetin alfa has a longer half-life than epoetin alfa and prolonged biologic
activity. Doses are administered less frequently, starting at once a week when administered
IV or SC.

• ESAs are well tolerated. Hypertension is the most common adverse event.
Evaluation of Anemia Therapeutic Outcomes
• Iron indices (transferrin saturation [TSat]; ferritin) should be evaluated before
initiating an ESA. Iron status should be reassessed every month during initial ESA
treatment and every 3 months for those on a stable ESA regimen.

• Hemoglobin should be monitored at least monthly, although more frequent monitoring

(eg, every 1–2 weeks) is warranted after initiation of an ESA or after a dose
change until hemoglobin is stable.

• Patients should be monitored for potential complications, such as hypertension,

which should be treated before starting an ESA.

• For more information on anemia, see Chap. 33.

CKD-Related Mineral and Bone Disorder
• Disorders of mineral and bone metabolism (CKD-MBD) are common in the CKD
population and include abnormalities in parathyroid hormone (PTH), calcium,
phosphorus, the calcium-phosphorus product, vitamin D, and bone turnover, as well
as soft tissue calcifications.

• Calcium-phosphorus balance is mediated through a complex interplay of hormones

and their effects on bone, the gastrointestinal (GI) tract, kidneys, and the parathyroid
gland. As kidney disease progresses, renal activation of vitamin D is impaired, which
reduces gut absorption of calcium. Low blood calcium concentration stimulates
secretion of PTH. As renal function declines, serum calcium balance can be maintained
only at the expense of increased bone resorption, ultimately resulting in renal
osteodystrophy (ROD).

• Secondary hyperparathyroidism is associated with increased morbidity and mortality

and sudden death in hemodialysis patients.
Treatment
• Dietary phosphorus restriction, dialysis, and parathyroidectomy are nonpharmacologic
approaches to management of hyperphosphatemia and CKD-MBD.

• The KDOQI guidelines provide desired ranges of calcium, phosphorus, calciumphosphorus

product, and intact PTH based on the stage of CKD (see Table 74–2).

PHOSPHATE-BINDING AGENTS
• Phosphate-binding agents decrease phosphorus absorption from the gut and are
first-line agents for controlling both serum phosphorus and calcium concentrations
(Table 74–3).

• KDOQI guidelines recommend that elemental calcium from calcium-containing

binders should not exceed 1500 mg/day, and the total daily intake from all sources
should not exceed 2000 mg. This may necessitate a combination of calcium- and
non–calcium-containing products (eg, sevelamer HCL and lanthanum carbonate).

• Adverse effects of all phosphate binders are generally limited to GI effects, including
constipation, diarrhea, nausea, vomiting, and abdominal pain. Risk of hypercalcemia
may necessitate restriction of calcium-containing binder use and/or reduction in
dietary intake. Aluminum and magnesium binders are not recommended for regular
use in CKD because aluminum binders have been associated with CNS toxicity and
the worsening of anemia, whereas magnesium binders may lead to hypermagnesemia
and hyperkalemia.
VITAMIN D THERAPY
• Reasonable control of calcium and phosphorus must be achieved before initiation
and during continued vitamin D therapy.

• Calcitriol, 1,25-dihydroxyvitamin D3, directly suppresses PTH synthesis and secretion

and upregulates vitamin D receptors. The dose depends on the stage of CKD
(Table 74–4).

• The newer vitamin D analogues paricalcitol and doxercalciferol may be associated

with less hypercalcemia and, for paricalcitol, hyperphosphatemia. Vitamin D therapy,
regardless of agent, is associated with decreased mortality.
CALCIMIMETICS
• Cinacalcet reduces PTH secretion by increasing the sensitivity of the calciumsensing
receptor. The most common adverse events include nausea and vomiting.

• The most effective way to use cinacalcet with other therapies has not been decided.
The starting dose is 30 mg daily, which can be titrated to the desired PTH and calcium
concentrations every 2 to 4 weeks to a maximum of 180 mg daily.
Hyperlipidemia
• The prevalence of hyperlipidemia increases as renal function declines.
• National guidelines differ on how aggressively dyslipidemia should be managed in
patients with CKD. KDIGO guidelines recommend treatment with a statin (eg, atorvastatin
20 mg, fluvastatin 80 mg, rosuvastatin 10 mg, simvastatin 20 mg) in adults
aged 50 and older with stage 1 to 5 CKD not on dialysis.

• In patients with ESRD, lipid profile should be reassessed at least annually and 2 to 3
months after changing treatment.

• For more information on dyslipidemias, see Chap. 8.

Electrolyte Homeostasis
• Fluid and electrolyte homeostasis is maintained by feedback mechanisms, hormones,
and many organ systems, and is necessary for the body’s normal physiologic functions.
Disorders of sodium and water, calcium, phosphorus, potassium, and magnesium
homeostasis are addressed separately in this chapter.

Treatment
• Treatment is associated with a risk of osmotic demyelination syndrome. The rate
of administration of infusate should be adjusted to avoid exceeding a rise in serum
sodium greater than 12 mEq/L (12 mmol/L) per day.
ACUTE OR SEVERELY SYMPTOMATIC HYPOTONIC HYPONATREMIA
• Symptomatic patients, regardless of fluid status, should initially be treated with either
a 0.9% or 3% concentrated saline solution until symptoms resolve. Resolution of
severe symptoms may require only a 5% increase in serum sodium or an initial target
serum sodium of 120 mEq/L (120 mmol/L).

• Treat SIADH with 3% saline plus, if the urine osmolality exceeds 300 mOsm/kg (300
mmol/kg), a loop diuretic (furosemide, 20–40 mg IV every 6 hours or bumetanide,
0.5–to 1 mg/dose every 2–3 hours for two doses).

• Treat hypovolemic hypotonic hyponatremia with 0.9% saline, initially at infusion

rates of 200 to 400 mL/h until symptoms moderate.

• Treat hypervolemic hypotonic hyponatremia with 3% saline and prompt initiation of

fluid restriction. Loop diuretic therapy will also likely be required to facilitate urinary
excretion of free water.
NONEMERGENT HYPOTONIC HYPONATREMIA
• Treatment of SIADH involves water restriction and correction of the underlying
cause. Water should be restricted to approximately 1000 to 1200 mL/day. In some
cases, administration of either sodium chloride or urea tablets and a loop diuretic or
of demeclocycline can be required.

• AVP antagonists or “vaptans” (eg, conivaptan and tolvaptan) can be used to treat
SIADH as well as other causes of euvolemic and hypervolemic hypotonic hyponatremia
that has been nonresponsive to other therapeutic interventions in patients
with heart failure, cirrhosis, and SIADH. The vaptans have dramatic effects on water
excretion and represent a breakthrough in the therapy of hyponatremia and disorders
of fluid homeostasis.

• Treatment of asymptomatic hypervolemic hypotonic hyponatremia involves correction

of the underlying cause and restriction of water intake to less than 1000
to 1200 mL/day. Dietary intake of sodium chloride should be restricted to 1000 to
2000 mg/day.
HYPERNATREMIA (SERUM SODIUM >145 mEq/L [>145 mmol/L])
Pathophysiology and Clinical Presentation
• Hypernatremia results from either water loss (eg, diabetes insipidus [DI]) or hypotonic
fluids, or less commonly from hypertonic fluid administration or sodium
ingestion.

• Symptoms are primarily caused by decreased neuronal cell volume and can include
weakness, lethargy, restlessness, irritability, and confusion. Symptoms of a more rapidly
developing hypernatremia include twitching, seizures, coma, and death.
Treatment
• Begin treatment of hypovolemic hypernatremia with 0.9% saline. After hemodynamic
stability is restored and intravascular volume is replaced, replace free-water
deficit with 5% dextrose or 0.45% saline solution.

• The correction rate should be approximately 1 mEq/L (1 mmol/L) per hour for
hypernatremia that developed over a few hours and 0.5 mEq/L (0.5 mmol/L) per
hour for hypernatremia that developed more slowly.
• Treat central DI with intranasal desmopressin, beginning with 10 mcg/day and
titrating as needed, usually to 10 mcg twice daily.

• Treat nephrogenic DI by decreasing ECF volume with a thiazide diuretic and dietary
sodium restriction (2000 mg/day), which often decreases urine volume by as much
as 50%. Other treatment options include drugs with antidiuretic properties (Table
75–2).

• Treat sodium overload with loop diuretics (furosemide, 20–40 mg IV every 6 hour)
and 5% dextrose at a rate that decreases serum sodium by approximately 0.5 mEq/L
(0.5 mmol/L) per hour or, if hypernatremia developed rapidly, 1 mEq/L (1 mmol/L)
per hour.

Edema
Treatment
• Diuretics are the primary pharmacologic therapy for edema. Loop diuretics
are the most potent, followed by thiazide diuretics and then potassium-sparing
diuretics.

• Pulmonary edema requires immediate pharmacologic treatment. Other forms of

edema can be treated gradually with, in addition to diuretic therapy, sodium restriction
and correction of underlying disease state.

HYPERCALCEMIA (TOTAL SERUM CALCIUM >10.5 mg/dL [>2.62 mmol/L])

Treatment
• Treatment approach depends on the degree of hypercalcemia, acuity of onset, and
presence of symptoms requiring emergent treatment (Fig. 75–2).

• Management of asymptomatic, mild to moderate hypercalcemia begins with attention

to the underlying condition and correction of fluid and electrolyte abnormalities.

• Hypercalcemic crisis and acute symptomatic hypercalcemia are medical emergencies

requiring immediate treatment. Rehydration with normal saline followed by loop
diuretics can be used in patients with normal to moderately impaired renal function.
Initiate treatment with calcitonin in patients in whom saline hydration is contraindicated
(Table 75–3).

• Rehydration with saline and furosemide administration can decrease total serum
calcium by 2 to 3 mg/dL (0.50–0.75 mmol/L) within 24 to 48 hours.

• Bisphosphonates are indicated for hypercalcemia of malignancy. Total serum calcium

decline begins within 2 days and nadirs in 7 days. Duration of normocalcemia
varies but usually does not exceed 2 to 3 weeks, depending on treatment response of
underlying malignancy.

• Denosumab is a monoclonal antibody approved for treatment of osteoporosis. It has

been shown to be useful in hypercalcemia of malignancy, particularly in patients with
a suboptimal response to bisphosphonates.

HYPOCALCEMIA (TOTAL SERUM CALCIUM <8.5 mg/dL [<2.13 mmol/L])

Treatment
• Acute, symptomatic hypocalcemia requires IV administration of soluble calcium
salts (Fig. 75–3). Initially, 100 to 300 mg of elemental calcium (eg, 1 g calcium chloride,
2–3 g calcium gluconate) should be given IV over 5 to 10 minutes (≤60 mg of
elemental calcium per minute).

• The initial bolus dose is effective for only 1 to 2 hours and should be followed by a
continuous infusion of elemental calcium (0.5–2 mg/kg/h) for 2 to 4 hours and then
by a maintenance dose (0.3–0.5 mg/kg/h).