number in this chapter found in parentheses after the reference.

Key References

American College of Cardiology/American Heart Association

Task Force on Practice Guidelines et al. ACC/AHA focused

update on perioperative beta-blockade. J Am Coll Cardiol. 2009;

54:2102. (5)

174 Section 1 General Care

American Society of Anesthesiologists Task Force on Neuraxial Opioids et al. Practice guidelines for the prevention, detection, and management of respiratory depression associated with

neuraxial opioid administration. Anesthesiology. 2009;110:218.

(129)

Apfel CFC et al. A factorial trial of six interventions for prevention of postoperative nausea and vomiting. N Engl J Med.

2004;350:2441. (94)

Gan TJ et al. Society for Ambulatory Anesthesia guidelines for

the management of postoperative nausea and vomiting. Anesth

Analg. 2007;105:1615. (81)

Horlocker TT et al. Executive summary: regional anesthesia in

the patient receiving antithrombotic or thrombolytic therapy:

American Society of Regional Anesthesia and Pain Medicine

Evidence-Based Guidelines (Third Edition). Reg Anesth Pain Med.

2010;35:102. (131)

McCaffery M, Pasero C. Pain Assessment and Pharmacologic

Management. St. Louis, MO: Elsevier Mosby. 2011. (136)

Neal JM et al. ASRA Practice advisory on the treatment of local

anesthetic systemic toxicity. Reg Anesth Pain Med. 2010;35:152.

(43)

Pasero C. Assessment of sedation during opioid administration

for pain management. J Perianesth Nurs. 2009;24:186. (110)

Weiskopf RB, Eger EI 2nd. Comparing the costs of inhaled anesthetics. Anesthesiology. 1993;79:1413.

Key Websites

Lipid Rescue. Resuscitation for cardiac toxicity. http://www.

lipidrescue.org.

Malignant Hyperthermia Association of the United States.

http://www.mhaus.org.

San Diego Patient Safety Council. Tool Kit. Patient Controlled Analgesia (PCA) Guidelines of Care for the Opioid

Na¨ıve Patient. December 2009. http://www.chpso.org/meds/

pcatoolkit.pdf. (114)

Acid–Base Disorders 9

Luis S. Gonzalez, III and Raymond W. Hammond

CORE PRINCIPLES

CHAPTER CASES

1 Acid–base analysis should proceed in a stepwise approach to avoid missing

complicated disorders that may not be readily apparent.

Case 9-1 (Question 1)

2 A normal anion gap metabolic acidosis is most commonly found in patients who

have either diarrhea or are receiving large amounts of isotonic crystalloid infusions.

A less common cause of a normal anion gap metabolic acidosis occurs with patients

who present with one of several types of renal tubular acidoses.

Case 9-1 (Questions 2–6)

3 A metabolic acidosis with an elevated anion gap is created by a disease process

that produces an acid, which is buffered by the major extracellular buffer,

bicarbonate. It is important to include a calculation of the anion gap in the workup

of all patients considered for acid–base analysis.

Case 9-2 (Questions 1–4)

4 Metabolic alkaloses can be classified according to a patient’s volume status and

responsiveness to the administration of chloride-containing solutions. A contraction

alkalosis, also called chloride-responsive alkalosis, is generally caused by diuretic

administration whereas a chloride-nonresponsive alkalosis may be caused by

glucocorticoid administration.

Case 9-3 (Questions 1–4)

5 A respiratory acidosis can be acute, chronic, or acute-on-chronic. The best way to

differentiate these disorders is with a careful patient history and review of previous

blood gas values looking for elevated carbon dioxide levels when a patient is at his

or her baseline.

Case 9-4 (Questions 1–4)

6 Unlike respiratory acidosis, most patients presenting with a respiratory alkalosis do

so acutely. There are a relatively small number of conditions that cause an acute

respiratory alkalosis, which can aid in the diagnosis when it is not apparent.

Case 9-5 (Questions 1–4)

7 Mixed metabolic and respiratory acid–base disorders occur commonly in acutely ill

patients. Acid–base analysis can assist in the diagnosis of clinically difficult cases.

Following a stepwise approach in the analysis of acid–base disorders should identify

all clinically important abnormalities.

Case 9-6 (Questions 1–3)

Understanding the etiology of a clinically important acid–base

disturbance is important because therapy generally should be

directed at the underlying cause of the disturbance rather

than merely the change in pH. Severe acid–base disorders can

affect multiple organ systems, including cardiovascular (impaired

contractility, arrhythmias), pulmonary (impaired oxygen delivery, respiratory muscle fatigue, dyspnea), renal (hypokalemia,

nephrolithiasis), or neurologic (decreased cerebral blood flow,

seizures, coma).

ACID–BASE PHYSIOLOGY

To protect body proteins, acid–base balance must be tightly controlled in an attempt to maintain a normal extracellular pH of

7.35 to 7.45 and an intracellular pH of approximately 7.0 to 7.3.1

This narrow range is maintained by complex buffer systems, ventilation to expel carbon dioxide (CO2), and renal elimination of

acids and reabsorption of bicarbonate (HCO−

3 ).2 At rest, about

200 mL of CO2, and even more during exercise, is transported

175

176 Section 1 General Care

Blood

Renal

Tubule Cell

Tubule

Lumen

CO2

CO2 CO2

HCO3

CO2 + H2O

H2CO3

HCO3 + H+

Na+

HCO3

HCO3

H2CO3

H+ +

+ H2O

Carbonic

Anhydrase

Carbonic

Anhydrase

FIGURE 9-1 Renal tubular bicarbonate

reabsorption.

from the tissues and excreted in the lungs.3 Although HCO−

3 is

responsible only for about 36% of intracellular buffering, it provides about 86% of the buffering activity in extracellular fluid

(ECF).1 Extracellular fluid contains approximately 350 mEq of

HCO−

3 , which buffers generated H+.

HCO−

3 + H+ ⇔ H2CO3 (Eq. 9-1)

Hydrogen ion (H+) combines with HCO−

3 and shifts the equilibrium of Eq. 9-1 to the right. In the proximal renal tubule lumen,

carbonic anhydrase catalyzes the dehydration of H2CO3 to CO2

and H2O, which are absorbed into the tubule cell, as illustrated

in Eq. 9-2 and in Figure 9-1. Within the tubule cell, H2O dissociates into H+ and OH−. The H+ is then secreted into the lumen

by a Na+–H+ exchanger. Carbonic anhydrase then catalyzes the

combination of OH− and CO2 to HCO−

3 , which is carried into

the circulation by a Na+HCO−

3 cotransporter.4

HCO−

3 + H+ ⇔ H2CO3

CA

⇔ CO2 (dissolved) + H2O (Eq. 9-2)

To maintain acid–base balance, the kidney must reclaim and

regenerate all the filtered HCO−

3 . The daily amount that must be

reabsorbed can be calculated by the product of the glomerular

filtration rate (GFR) and the HCO−

3 concentration in ECF (180

L/day GFR×24 mEq/L HCO−

3 =4,320 mEq/day).1 The proximal

tubule reabsorbs about 85% of the filtered HCO−

3 . The loop of

Henle and the distal tubule reabsorb about 10%.5 Acid salts, such

as HPO−

4 (pKa of 6.8), that have a pKa greater than the pH of the

urine (titratable acids) can accept a proton and be excreted as

the acid, thus regenerating an HCO−

3 anion.5 Sulfuric acid and

other acids with a pKa less than 4.5 are not titratable. Protons

from these acids must be combined with another buffer to be

secreted. Glutamine deamination in proximal tubular cells forms

NH3, which accepts these protons. In the collecting tubule, the

NH+

4 produced is lipid insoluble, trapping it in the lumen and

causing its excretion, eliminating the proton, and allowing for

regeneration of HCO−

3 .

4–6 Figure 9-2 is a simplified illustration

of the buffering of these acids.

The daily metabolism of carbohydrates and fats generates

about 15,000 mmol of CO2. Although CO2 is not an acid,

it reversibly combines with H2O to form carbonic acid (i.e.,

H2CO3). Respiration prevents the accumulation of volatile acid

through the exhalation of CO2. Metabolism of proteins and fats

results in several fixed acids and bases. Amino acids such as lysine

and arginine have a net positive charge and serve as acids. Compounds such as glutamate, aspartate, and citrate have a negative

charge. In general, animal proteins contain more sulfur and phosphates, producing an acidic diet. Vegetarian diets consist of more

organic anions, resulting in a more alkaline diet.7 Normally, fatty

acids are metabolized to HCO−

3 ; however, during starvation or

diabetic ketoacidosis, they may be incompletely oxidized to acetoacetate and β-hydroxybutyric acid.6 The typical diet generates

a net nonvolatile acid load of about 70 to 100 mEq of H+ (1.0–

1.5 mEq/kg) per day.1,8 Renal excretion of 70 mEq in 2 L of urine

each day would require a pH of 1.5. Because the kidney cannot

produce a pH less than 4.5, most of this fixed acid load must

be buffered. The primary buffers for renal net acid excretion

Blood

Renal

Tubule Cell

Tubule

Lumen

CO2 CO2 + H2O

H2CO3

+ H+

Na+

Carbonic

Anhydrase

HPO4

2

H+ H+ + HPO4

2

NH3 H+ + NH3 NH4

Excreted in

Urine

NH3 Glutamate +

Glutamine

H2PO4

+

HCO3 HCO3

Na+

FIGURE 9-2 Renal tubular

hydrogen ion excretion.

177Acid–Base Disorders Chapter 9

TABLE 9-1

Normal Arterial Blood Gas Values

ABGs Normal Range

pH 7.36–7.44

Pao2 90–100 mm Hg

Paco2 35–45 mm Hg

HCO−

3 22–26 mEq/L

ABG, arterial blood gas.

are NH−

3 /NH+

4 and titratable buffers, such as HPO−

4 /H2PO2−

4 ,

as mentioned earlier.7 The correct assessment of acid–base disorders begins with an evaluation of appropriate laboratory data

and an understanding of the physiologic mechanisms responsible

for maintaining a normal pH.

Laboratory Assessment

Laboratory data used to evaluate acid–base status are arterial pH,

arterial carbon dioxide tension (Paco2), and serum bicarbonate

(HCO−

3 ).9–11 These values are obtained routinely with an arterial

blood gas (ABG) determination. Acid–base abnormalities occur

when the concentration of Paco2 (an acid) or HCO−

3 (a base)

is altered. ABG measurements also include the arterial oxygen

tension (Pao2); however, this value does not directly influence

decisions regarding acid–base abnormalities. Normal ABG values

are listed in Table 9-1. When arterial pH is less than 7.35, the

patient is considered acidemic, and the process that caused acid–

base imbalance is called acidosis. Conversely, when the arterial

pH is greater than 7.45, the patient is considered alkalemic, and

the causative process is alkalosis. The process is further defined

as respiratory in cases of an inappropriate elevation or depression

of Paco2 or metabolic with an inappropriate rise or fall in serum

HCO−

3 .

Acid–base balance is normally maintained by the primary

extracellular buffer system of HCO−

3 /CO2. Components of this

buffer system are measured routinely to assess acid–base status.

Other extracellular buffers (e.g., serum proteins, inorganic

phosphates) and intracellular buffers (e.g., hemoglobin, proteins, phosphates), however, also contribute significant buffering

activity.1,7–10 Serum electrolytes are obtained to calculate the

anion gap, an estimate of the unmeasured cations and anions

in serum. The anion gap helps determine the probable cause of

a metabolic acidosis.6,10,12–28 Urine pH, electrolytes, and osmolality help to further differentiate among the possible causes of

metabolic acidosis.10,29–33

Acid–Base Balance, Carbon Dioxide

Tension, and Respiratory Regulation

In aqueous solution, carbonic acid (i.e., H2CO3 formed

through the reaction described in Eq. 9-1) reversibly dehydrates

to form carbon dioxide (CO2) and water (H2O) as shown in

Eq. 9-2.

The enzyme carbonic anhydrase (CA), present in red blood

cells, renal tubular cells, and other tissues, catalyzes the interconversion of carbonic acid and carbon dioxide. Some of the carbon

dioxide produced by dehydration of carbonic acid remains dissolved in plasma, but most exists as a volatile gas:

HCO−

3 + H+ ⇔ H2CO3

CA

⇔ CO2 (dissolved) + H2O

↑↓ (Eq. 9-3)

k × CO2 (gas)

In Eq. 9-3, k is a solubility constant that has a value of approximately 0.03 in plasma at body temperature.2,33 Virtually all

the carbonic acid in body fluids is in the form of carbon dioxide. The Paco2, a measure of carbon dioxide gas, is therefore

directly proportional to the amount of carbonic acid in the

HCO−

3 /H2CO3 buffer system. The normal range for Paco2 is

35 to 45 mm Hg.

The lungs can rapidly exhale large quantities of carbon dioxide and thereby contribute significantly to the maintenance of

a normal pH. Carbon dioxide formed through the reaction

described in Eq. 9-3 diffuses easily from tissues to capillary blood

and from pulmonary capillary blood into the alveoli where it is

exhaled from the body.3 Pulmonary ventilation is regulated by

peripheral chemoreceptors (located in the carotid arteries and

the aorta) and central chemoreceptors (located in the medulla).

The peripheral chemoreceptors are activated by arterial acidosis, hypercarbia (elevated Paco2), and hypoxemia (decreased

Pao2). Central chemoreceptors are activated by cerebrospinal

fluid (CSF) acidosis and by elevated carbon dioxide tension in

the CSF.3 Activation of these chemoreceptors stimulates the respiratory control center in the medulla to increase the rate and

depth of ventilation, which results in increased exhalation of

carbon dioxide.

BICARBONATE AND RENAL CONTROL

As described in the Acid–Base Physiology section, the kidneys are

responsible for regulating the serum bicarbonate concentration.

This is accomplished through two important and interrelated

functions. First, they must reabsorb the bicarbonate that undergoes glomerular filtration and is present in the renal tubular fluid.

Second, the kidneys must excrete hydrogen ions released from

nonvolatile acids. Both functions are important in preventing

systemic acidosis.

One mechanism of bicarbonate reabsorption in the proximal

renal tubule is illustrated in Figure 9-1. Carbonic anhydrase catalyzes intracellular formation of carbonic acid (H2CO3) from

carbon dioxide (CO2) and water in the renal tubular cell. The

carbonic acid then dissociates to form H+ and HCO−

3 . The H+

ion is secreted into the lumen of the tubule in exchange for a

sodium ion (Na+), and the bicarbonate from the renal tubule

cell is reabsorbed into the capillary blood.

Inside the lumen, carbonic acid is re-formed from secreted

H+ and filtered HCO−

3 . Carbonic anhydrase present inside the

lumen (on the brush border membrane of the cell) catalyzes

conversion of carbonic acid to carbon dioxide, which can readily

diffuse back into the blood. Thus, the net result is reabsorption

of sodium and bicarbonate. Although a hydrogen ion is secreted

into the lumen in this process, no net excretion of acid occurs

because of the reabsorption of carbon dioxide.4–6 Figure 9-2

illustrates H+ excretion by the kidney. This process was also

discussed in the Acid–Base Physiology section.

In clinical practice, the serum bicarbonate concentration usually is estimated from the total carbon dioxide content when

the serum concentration of electrolytes are ordered on an electrolyte panel or calculated from the pH and Paco2 on an ABG

determination. These estimations of the serum bicarbonate concentration are more convenient than directly measuring serum

bicarbonate. The total carbon dioxide content that is reported

on serum electrolyte panels is determined by acidifying serum

to convert all the bicarbonate to carbon dioxide and measuring

the partial pressure of CO2 gas. Approximately 95% of the total

carbon dioxide content is bicarbonate. The serum bicarbonate

concentration reported on ABG results is calculated from the

patient’s pH and Paco2 using the Henderson–Hasselbalch equation (Eq. 9-4). This calculated bicarbonate concentration should

be within 2 mEq/L of the measured total carbon dioxide. The

178 Section 1 General Care

normal range of serum bicarbonate using these methods is 22 to

26 mEq/L.10

BICARBONATE/CARBONIC ACID RATIO

The relationship between the pH and the concentrations of the

acid–base pairs in buffer systems is described by the Henderson–

 spinal actions, efficacy, and adverse effects of opioids and local

anesthetics administered by the epidural route.114,121,122,124

As previously mentioned, opioids and local anesthetics are

combined in the same solution because these two classes of

drugs act synergistically at two different sites to produce analgesia, allowing the administration of lower doses of each drug

to reduce the risk of adverse effects while providing effective

analgesia. Table 8-14 lists the drugs, concentrations, and typical

infusion rates for epidural administration.115,122,123,125 Bupivacaine is commonly chosen as the local anesthetic agent. Because

pain fibers are on the outer aspect of the nerve and are not heavily

myelinated, a low concentration of bupivacaine (≤0.125%) can

be administered to block these fibers without significantly blocking motor fibers. The choice of opioid is based on pharmacokinetic differences among the available agents. Onset, duration,

spread of agent in the spinal fluid (dermatomal spread), and systemic absorption are affected by the lipophilicity of the drug.124

Highly lipophilic opioids such as fentanyl and sufentanil have

a faster onset of action, a shorter duration of action (from a

TABLE 8-13

A Comparison of the Spinal Actions, Efficacy, and Adverse Effects of Opioids and Local Anestheticsa,114,121,122,124

Opioids Local Anesthetics

Actions

Site of action Substantia gelatinosa of dorsal horn of spinal cordb Spinal nerve roots

Modalities blocked “Selective” block of pain conduction Blockade of pain nerve fibers; can block sensory or motor fibers

Efficacy

Surgical pain Partial relief Complete relief possible

Labor pain Partial relief Complete relief

Postoperative pain Fair or good relief Complete relief

Adverse effects Nausea, vomiting, sedation, pruritus, constipation or

ileus, urinary retention, respiratory depression

Hypotension, urinary retention, loss of sensation, loss of motor

function (patient may not be able to bear weight and ambulate)

a Epidurally administered morphine and local anesthetics exert their effects mainly by a spinal mechanism of action; lipophilic opioids such as fentanyl and sufentanil achieve

therapeutic plasma concentrations when administered epidurally and therefore exert their effects by a systemic mechanism of action.

b Other sites where opioid receptor binding sites are present.

171Perioperative Care Chapter 8

TABLE 8-14

Adult Analgesic Dosing Recommendations for Epidural Infusion115,122,123,125

Drug Combinationa Infusion Concentrationb Usual Infusion Rateb

Morphine + bupivacaine 12.5–25 mcg/mL (M) 4–10 mL/h

0.5–1.25 mg/mL (B)

Hydromorphone + bupivacaine 3–10 mcg/mL (H) 4–10 mL/h

0.5–1.25 mg/mL (B)

Fentanyl + bupivacaine 2–5 mcg/mL (F) 4–10 mL/h

0.5–1.25 mg/mL (B)

Sufentanil + bupivacaine 1 mcg/mL (S) 4–10 mL/h

0.5–1.25 mg/mL (B)

aUse only preservative free products and preservative free 0.9% sodium chloride as the admixture solution.

b Exact concentrations and rates are institution specific. Initial concentration and rate often depend on the age and general condition

of the patient and the location of the catheter.

B, bupivacaine; F, fentanyl; H, hydromorphone; M, morphine; S, sufentanil.

single dose), less dermatomal spread, and much greater systemic absorption. After several hours of epidural infusion, the

dermatomal (regional) effect of fentanyl is lost, and analgesia

is achieved because of a therapeutic plasma concentration. Morphine, which is relatively hydrophilic, has a slower onset of action,

longer duration of action, greater dermatomal spread and migration to the brain, and less systemic absorption.122,124 Morphine,

unlike fentanyl, retains its spinal site of action.122 The lipophilicity

of hydromorphone is intermediate between fentanyl and morphine. Clinically, hydromorphone has a faster onset and shorter

duration than morphine. Its site of action is likely in the spinal

cord.126 A comparison of the pharmacokinetic properties important to epidural opioids is found in Table 8-15.115,116,124,125 T.M.

should receive a combination of opioid and local anesthetic, such

as hydromorphone and bupivacaine, as an epidural infusion for

postoperative pain management.

CASE 8-15, QUESTION 3: Hydromorphone–bupivacaine is

chosen for T.M. How should this be prepared, and what infusion rate should be chosen?

Hydromorphone and bupivacaine are commonly admixed

in 0.9% sodium chloride (usual concentration ranges are found

in Table 8-14). Concentrations are often institution-specific and

depend on the rate of administration. Preservative free preparations of each drug should be used because neurologic effects

are possible with inadvertent subdural administration of large

amounts of benzyl alcohol or other preservatives. Strict aseptic

technique should be used when admixing and administering an

epidural solution.

The rate of administration is chosen empirically based on the

anticipated analgesic response, the concentration of opioid in the

admixture, and the potential for adverse effects. Usually, a rate of

4 to 10 mL/hour is adequate; the epidural space can safely handle

up to approximately 20 mL/hour of fluid. An initial infusion rate

of 8 mL/hour would be reasonable for T.M., with titration based

on efficacy and adverse effects.

ADVERSE EFFECTS

CASE 8-15, QUESTION 4: Two hours after initiation of his

hydromorphone–bupivacaine epidural infusion, T.M. experiences discomfort in the form of an itchy feeling on his nose,

torso, and limbs. Is this related to his epidural infusion?

Adverse effects of the epidural infusion may be caused by

the opioid or the local anesthetic. Pruritus has been associated

with almost all opioids, with a significantly greater frequency

when the opioid is administered as an epidural infusion rather

than by IV administration.127 This effect is usually seen within

2 hours and is probably dose-related. It generally subsides as the

opioid effect wears off and can be more of a problem with continuous epidural administration of opioids or when opioids are

administered via PCA. Although pruritus from opioids is probably mu-receptor mediated and not histamine mediated, antihistamines (e.g., diphenhydramine) are commonly used with equivocal effectiveness. A better approach is to administer very small

doses of a mu-antagonist (e.g., naloxone 0.04 mg or nalbuphine

2.5 mg) to effectively reverse opioid adverse effects, such as pruritus, but not analgesia. Because of naloxone’s short duration

of action, nalbuphine is often preferred. Ondansetron has also

shown some efficacy for managing itching from an intrathecal

or epidural opioid.128

Other adverse effects possible with epidural opioids include

nausea, vomiting, constipation, ileus, urinary retention, sedation, and respiratory depression. Although rare, respiratory

depression from epidural opioids is the most dangerous adverse

effect. Respiratory depression can occur as long as 12 to

24 hours after a single bolus of morphine122,124 or within hours

after beginning a continuous infusion of fentanyl–bupivacaine

TABLE 8-15

Pharmacokinetic Comparison of Common Epidural Opioid Analgesics115,116,124,125

Agent Partition Coefficienta

Onset of Action of

Bolus (minutes)

Duration of Action

of Bolus (hours) Dermatomal Spread

Fentanyl 955 5 2–4 Narrow

Hydromorphone 525 15 6–12 Intermediate

Morphine sulfate (Duramorph) 1 30 12–24 Wide

Sufentanil 1,737 5 2–4 Narrow

aOctanol–water partition coefficient; used to assess lipophilicity; higher numbers indicate greater lipophilicity.

172 Section 1 General Care

or hydromorphone–bupivacaine. Sedation level, as well as respiratory rate and effort, must be assessed every hour for the first

12 hours, then every 2 hours for the next 12 hours, then if stable,

every 4 hours until removal of the catheter.129 As with parenteral

opioids, particular attention must be paid to patients at high

risk for respiratory depression from an opioid. These risk factors include age older than 65 years, obesity, pulmonary disease

or other conditions that reduce ventilatory capacity, and known

or suspected history of sleep apnea.114 In a patient with known

obstructive sleep apnea, for example, the anesthesia provider may

prescribe an epidural analgesic solution containing bupivacaine

only (no opioid).

Adverse effects of epidural local anesthetics include hypotension, urinary retention, lower limb paresthesias or numbness,

and lower limb motor weakness. Depending on the degree of

numbness and motor weakness, the patient may have difficulty

ambulating. In a patient prone to hypotension or in whom motor

weakness would be detrimental, for example, the anesthesia care

provider may prescribe an epidural analgesic solution containing

an opioid only (no local anesthetic). Monitoring for efficacy and

adverse effects of epidural analgesia should include pain intensity and quality, response to treatment, number of on-demand

requests (if epidural PCA is being used), analgesic consumption,

BP, heart rate, respiratory rate and effort, level of sedation, urinary output, sensory and motor assessment (e.g., presence of

numbness or tingling, inability to raise legs or flex knees or

ankles), and a site and dressing check.

ADJUNCTIVE KETOROLAC USE

CASE 8-15, QUESTION 5: On the second postoperative

day, T.M. is able to rest comfortably when undisturbed

while receiving treatment with a lumbar epidural infusion

of hydromorphone 10 mcg/mL and bupivacaine 1.25 mg/mL

at a rate of 8 mL/hour. However, when he is moved at the

change of each nursing shift, he complains of significant

pain. Increasing the rate of his epidural infusion was tried,

but caused unacceptable pruritus and sedation. How can

T.M.’s intermittent pain needs be addressed?

The use of additional analgesics for breakthrough pain may

be necessary in patients receiving continuous epidural infusion.

T.M.’s intermittent pain could be managed by epidural PCA.

Like IV PCA, patient-activated epidural boluses can be administered to control pain during movement. Alternatively, injectable

ketorolac or acetaminophen may be considered for T.M.; these

agents do not contribute to respiratory depression, sedation, or

pruritus and can effectively treat moderate pain. The analgesic

effects of acetaminophen and NSAIDs are additive with the opioids and can lower postoperative pain scores. Patient selection

for ketorolac therapy should consider renal function, plasma

volume and electrolyte status, GI disease, risk of bleeding, and

concomitant drugs such as LMWH (which increases the risk

for bleeding and epidural hematoma). Acetaminophen is contraindicated in patients with severe hepatic impairment, severe

active liver disease, or known hypersensitivity to acetaminophen

or any excipient in the formulation. Acetaminophen should be

used with caution in patients with severe hypovolemia or severe

renal impairment.130

ADJUNCTIVE ANTICOAGULANT ADMINISTRATION

CASE 8-15, QUESTION 6: The surgeon has determined that

T.M. is at risk for developing postoperative venous thromboembolism. Enoxaparin 40 mg subcutaneously every day

has been ordered postoperatively. What are the risks of

enoxaparin in this situation? What are reasonable precautions?

Administration of an anticoagulant can increase the risk of

epidural or spinal hematoma formation, which can lead to longterm or permanent paralysis. Administration of antiplatelet or

anticoagulant drugs in combination with an anticoagulant (such

as an LMWH) results in an even greater risk of hemorrhagic

complications, including spinal hematoma. These findings have

led to concern for the safety of epidural analgesia in patients

receiving an LMWH. Important considerations for managing

a patient being administered an LMWH and receiving continuous epidural analgesia are (a) the time of catheter placement

and removal relative to the timing (and peak effect) of LMWH

administration and (b) whether the anticoagulant dose is low

(prophylactic dose) or high (treatment dose).131 For T.M., the

epidural catheter is already in place, and the LMWH is started

postoperatively as a single daily low (prophylactic) dose. It is safe

to leave the epidural catheter in place as long as the first dose of

LMWH is administered 6 to 8 hours postoperatively. The second

LMWH dose should be administered no sooner than 24 hours

after the first dose. The timing of the catheter removal is of the

utmost importance; it should be delayed for at least 12 hours after

the last dose of LMWH, with subsequent LMWH dosing to occur

a minimum of 2 hours after the catheter has been removed. The

risk of spinal hematoma is even greater when treatment doses

of LMWH are administered or if fondaparinux is selected as

the anticoagulant for deep vein thrombosis prophylaxis. In these

instances, the epidural catheter should be removed before the first

dose of LMWH or fondaparinux, and the first dose given at least

2 hours after catheter removal. Because T.M. is receiving prophylactic daily enoxaparin, his catheter should be removed no earlier

than 12 hours after his last dose of enoxaparin, with his next dose

administered no earlier than 2 hours after catheter removal.

MULTIMODAL PAIN MANAGEMENT

CASE 8-16

QUESTION 1: W.W., a 36-year-old man, arrives at the ambulatory surgery center for an inguinal hernia repair. This procedure will be performed under local anesthesia, with sedation as needed, and is expected to be completed within

TABLE 8-16

Comparison of Select Opioids for Perioperative Pain Management3,132–136

Property

Intravenous

Morphine

Intravenous

Hydromorphone

Intravenous

Fentanyl

Oral

Hydrocodone

Oral

Oxycodone

Onset 5 minutes ≤5 minutes ≤2 minutes 30–60 minutes 30–60 minutes

Peak effect 15–20 minutes 10–20 minutes 5–7 minutes 1–2 hours 1.5–2 hours

Duration 3–4 hours 2–3 hours 30–60 minutes 4–6 hours 3–4 hours

Approximate equianalgesic dose 2 mg 0.4 mg 25 mcg 5 mg 4 mg

173Perioperative Care Chapter 8

TABLE 8-17

Commonly Used Analgesic Drugs and Nonpharmacologic Techniques for Postoperative Pain Management105,106,132–136

Type of Agent Examples Potential Adverse Effects

Local anesthetics Tissue infiltration, wound instillation, peripheral

nerve block, epidural

Tingling, numbness, motor weakness,

hypotension, CNS and cardiac effects from

systemic absorption

NSAIDs Ketorolac (IV, IM, oral), ibuprofen (oral), naproxen

(oral), celecoxib (oral)

GI upset, edema, hypertension, dizziness,

drowsiness, GI bleeding, operative site bleeding

(not celecoxib)

Other nonopioids Acetaminophen (oral, intravenous, rectal) GI upset, hepatotoxicity, hypotension (IV

formulation)

Nonpharmacologic Ice or cold therapy Excessive vasoconstriction, skin irritation

Distraction, music, deep breathing for relaxation

Opioid combination products (oral) Hydrocodone + acetaminophen, oxycodone +

acetaminophen

Nausea, vomiting, pruritus, constipation, rash,

sedation, respiratory depression

Opioids Morphine (IV, epidural), hydromorphone (IV,

epidural), fentanyl (IV, epidural), oxycodone (oral)

Nausea, vomiting, pruritus, constipation, rash,

sedation, respiratory depression

CNS, central nervous system; GI, gastrointestinal; IM, intramuscular; IV, intravenous; NSAIDs, nonsteroidal anti-inflammatory drugs.

30 minutes. His medical and surgical histories are unremarkable. He is not currently taking any medication and

reports no drug allergies. After discharge from the ambulatory surgery center, how should W.W.’s postoperative pain

be managed?

In general, one expects that the greater the magnitude of the

surgical trauma, the greater the patient’s postoperative pain. For

minor surgical procedures (e.g., inguinal hernia repair, breast

biopsy), there is minimal surgical trauma, and the patient goes

home shortly after surgery. For intermediate surgical procedures

(e.g., total abdominal hysterectomy, laparoscopic cholecystectomy), short-term hospitalization is often necessary to observe

the patient’s recovery and to manage any pain. Patients undergoing major surgery (e.g., bowel resection, thoracotomy) experience a significant surgical stress response that can significantly

increase postoperative morbidity. Effective pain management is

essential, particularly in these patients.

If pain is mild in intensity, a nonopioid analgesic such as

acetaminophen or an NSAID is appropriate. If pain is moderate or severe in intensity or not controlled with acetaminophen

or an NSAID, an opioid is indicated. As previously discussed, the

agent, dose, and route are determined by the clinical scenario. If

the patient cannot take oral medications or a fast onset of action

is required to control pain, an IV opioid is indicated. Administration of an oral opioid and nonopioid combination product

will require a longer time before the patient will feel its analgesic effect. However, depending on the dose administered, the

anticipated degree of analgesia it will produce can be greater

than a lower dose of an IV opioid. One tablet of hydrocodone

10 mg plus acetaminophen 325 mg would be expected to provide greater and more long-lasting analgesia than one dose of

morphine 2 mg IV (Table 8-16).3,132–136 If a fixed combination of

opioid and nonopioid is used, the total daily dose administered

to the patient is limited by the maximum allowable daily dose of

the nonopioid (e.g., acetaminophen, ibuprofen).

Multimodal or balanced analgesia is often used to provide

postoperative analgesia. It can be difficult to optimize postoperative pain relief, to the point of achieving normal function, by

using one drug or route of administration. By using two or more

drugs that work at different points in the pain pathway, additive or

synergistic analgesia can be achieved and adverse effects reduced

because doses are lower and side effect profiles are different.

For an illustration that shows the sites of

action of the major drug classes used for pain

management, go to http://thepoint.

lwwcom/AT10e.

For perioperative pain management, combining acetaminophen with an NSAID provides superior analgesia than either

agent alone.137 Opioids are a mainstay of analgesic therapy for

moderate to severe pain. However, opioids are often associated

with intolerable adverse effects (e.g., nausea, vomiting, constipation, itching, sedation). Maximizing the use of nonopioid analgesics can result in less need for opioids and improved analgesia

(Table 8-17).105,106,136 When compared with morphine alone, the

addition of an NSAID after major surgery reduces pain intensity

and 24-hour morphine consumption, with a reduction in the incidence of morphine-related adverse effects of nausea, vomiting,

and sedation.133

For W.W., the anticipated surgical trauma is minor, and he will

recover at home. The surgeon will inject a long-acting local anesthetic (e.g., bupivacaine) into the tissues surrounding the surgical

incision. This will provide intraoperative anesthesia at the surgical site and postoperative analgesia until the effects of the bupivacaine wear off. Then, W.W. will likely require acetaminophen or

an NSAID for pain management. If his pain is not controlled, a

less potent opioid (e.g., hydrocodone) plus acetaminophen may

be used as a rescue analgesic.

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

and websites for this chapter, with the corresponding reference