CASE 56-4, QUESTION 3: How should clinicians manage pain in critically ill patients like J.A.?

Opioids, including fentanyl, hydromorphone, morphine, methadone, and

remifentanyl, are the primary analgesics used in the critical care setting. Of these,

fentanyl, hydromorphone, and morphine are used most commonly, whereas

methadone is mainly used for long-term pain or pain that is refractory to other

opioids. Because it is very short acting, very potent, and metabolized in the plasma,

remifentanyl is most appropriate for pain that lasts only a short period of time in

patients who are mechanically ventilated and in those with severe renal or hepatic

dysfunction. Meperidine should not be used because it may cause seizures and other

complications.

44 For treatment of acute pain, opioids should be given intravenously

since enteral administration may be unreliable in critically ill patients because of

incomplete absorption in patients with altered gastrointestinal motility and

intramuscular absorption can be erratic.

37

In some cases, it may be impossible to

completely alleviate pain because of dose-limiting side effects such as respiratory

depression or altered mental status. In these cases, clinicians should attempt to make

patients as comfortable as possible without inducing significant adverse effects.

The selection of a specific opioid relates to the pharmacokinetics and

pharmacodynamics of the medications and depends on patient-specific

characteristics as well as the nature of the pain the patient is experiencing. Table 56-

2 lists key considerations for choosing between available opioids. When given as a

single intravenous bolus injection, fentanyl has a faster onset and shorter duration of

action compared to hydromorphone and morphine. This makes an intravenous

injection of fentanyl most appropriate for pain that is short-lived such as procedural

pain that might be associated with placement of a chest tube or intravenous catheter.

In fact, procedural pain is best treated preemptively through administration of a bolus

agent before the procedure.

37 The longer duration of action of hydromorphone and

morphine makes these agents better when intravenous treatment of longer lasting pain

is indicated. Alternatively, fentanyl, hydromorphone, and morphine may all be

administered as continuous intravenous infusions in patients needing ongoing

analgesia or those with severe pain.

All opioids can cause constipation, confusion, hallucinations, altered mental

status, and respiratory depression when given in high doses. Clinicians should

regularly monitor the bowel movements of patients receiving opioid analgesia and a

bowel regimen containing both a stimulant laxative and a stool softener should be

administered, if indicated. Opioids may all cause a decrease in blood pressure if the

patient’s blood pressure is increased because of pain and in patients who are

hypovolemic. Importantly, morphine is the only opioid that causes histamine release,

which can lead to flushing, bronchospasm, and hypotension. These complications

underlie the recommendation to avoid morphine in patients who are

hemodynamically unstable, at risk for hypotension, or those with bronchospasm.

Morphine has an active metabolite that is cleared by the kidneys, while fentanyl and

hydromorphone are metabolized in the liver to inactive metabolites. Thus,

hydromorphone and fentanyl are preferred over morphine in patients with renal

failure. Another unique side effect relates to QTc prolongation resulting from

methadone. Because QTc prolongation can potentially cause cardiac arrest,

electrocardiograms should be regularly monitored in patients receiving methadone,

especially in patients concurrently receiving other QTc-prolonging agents. Serum

concentrations of magnesium and potassium should be monitored, and these

electrolytes should be repleted, as needed, to minimize arrhythmias. Because fentanyl

is the most lipophilic of the three most commonly used opioid analgesics, prolonged

administration via intravenous infusion may lead formation of a depot in adipose

tissue. After cessation of the fentanyl infusion, drug may distribute from the fat into

the bloodstream and prolong the effects of drug.

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Table 56-2

Selected Characteristics of Opioids Used in Critically Ill Patients

Onset

Duration (IV

Bolus Dose)

Active

Metabolite

Adverse

effects &

Other

Considerations

Equipotent IV

Dose (mg)

Morphine 5–10 minutes 2–4 hours Yes (cleared

renally)

Histamine

release

(hypotension,

bronchospasm,

flushing)

10

Hydromorphone 5–15 minutes 2–4 hours No 1.5

Fentanyl 1–2 minutes 30–60 minutes No Accumulates in

adipose tissue

with prolonged

infusion

0.1

In addition to opioids, clinicians may consider adjunctive analgesics in selected

patients. For example, nonsteroidal anti-inflammatory agents and acetaminophen may

be considered to minimize overall opioid requirements and potentially reduce

opioid-related complications. For patients experiencing neuropathic pain, enterally

administered gabapentin and carbamazepine can be helpful. Finally, for patients with

rib fractures or those who have undergone thoracic or abdominal surgery, thoracic

epidural analgesia results in better pain control as compared to opioid

monotherapy.

37

Because J.A. is likely to experience ongoing pain as a result of his trauma,

multiple fractures, and surgery, he should be initiated on opioid analgesia. If he

remains hypotensive, at risk for hemodynamic compromise, or is in renal failure,

morphine should be avoided. Some centers would routinely use fentanyl or

hydromorphone in most patients to minimize hemodynamic complications. It would

be most appropriate to administer fentanyl as a continuous infusion, while

hydromorphone could be given continuously or as repeated intravenous boluses.

Because of his rib fractures, J.A. could also be considered for thoracic epidural

analgesia with an opioid.

CASE 56-5

QUESTION 1: During his stay in the surgical ICU, J.A. begins to exhibit signs of agitation including

diaphoresis, tachycardia, pulling at his endotracheal tube, and even trying to strike his caregivers.

What are some causes of agitation that J.A. might be experiencing and how should he be initially treated?

Agitation is very common in critically ill patients and can lead to adverse

consequences arising from sympathomimetic effects.

45 Patient care can be

complicated if agitation leads to patient removal of devices, such as endotracheal

tubes or intravenous lines, necessary for their care. Patients may exhibit symptoms of

agitation for a variety of reasons including pain, delirium, hypoxemia, hypoglycemia,

hypotension, or withdrawal from alcohol and other drugs. Given the ubiquity of pain

in critically ill patients and the difficulty in assessing patients who cannot

communicate, clinicians should always consider pain as a potential cause of agitation

and administer analgesics when they suspect pain. In fact, current guidelines

recommend analgesia-first sedation strategies that emphasize aggressive use of

analgesics before administration of sedative agents.

37 Other general strategies to treat

anxiety and agitation in critically ill patients include keeping patients as comfortable

as possible, reorienting patients if they misperceive their surroundings or situations,

promoting a normal sleep–wake cycle by helping patients to stay awake during the

day and minimizing barriers to sleep overnight. Whenever possible, clinicians should

attempt to identify and treat the underlying cause of agitation before initiating a

sedative agent. For instance, if an agitated patient is found to be hypoglycemic, the

hypoglycemia should be corrected, and the patient should be reevaluated before

starting a sedative. By identifying and addressing the cause of agitation, clinicians

can avoid complications associated with sedative medications, such as over-sedation

and delirium.

37

Clinicians should assess critically ill patients who are agitated using a validated

sedation assessment tool.

37 The two most rigorously evaluated tools are the

Richmond Agitation-Sedation Scale (RASS) and the Sedation-Agitation Scale

(SAS). Both tools effectively discriminate different levels of sedation, have high

inter-rater reliability, and have been show to correlate reasonably well with

objective measures of brain function.

46–48 Scores on the RASS range from –5 to +4

while the SAS varies from 1 to 7. The lowest numbers of the scales indicate a patient

is unarousable, while the highest numbers on the RASS and SAS correspond to

combativeness and dangerous agitation, respectively. By quantifying patients’ level

of sedation using one of these tools, multidisciplinary caregivers can determine the

desired level of consciousness and appropriately administer medications to target

this level of consciousness while avoiding excessive sedation. Generally, sedatives

should be titrated to achieve light levels of sedation, which correspond to RASS

scores of –1 to 0 and SAS scores of 3 to 4.

37 Maintaining patients at light levels of

sedation instead of deeper levels of sedation, in which they are more difficult to

arouse and are less interactive, has been shown to reduce duration of mechanical

ventilation and ICU length of stay.

49,50 Sometimes, patients’ clinical conditions may

necessitate deeper levels of sedation. Some clinical situations in which deeper

sedation may be appropriate include active severe alcohol withdrawal, refractory

status epilepticus, intracranial hypertension, ventilator

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p. 1213

dysynchrony, severe lung injury, or paralysis with neuromuscular receptor

blocking agents.

J.A. may be agitated because of pain from his traumatic injuries as well as

metabolic disturbances or other causes. His level of consciousness should be

evaluated using the RASS or SAS. Since he is intubated, J.A. should be assessed for

pain using a validated nonverbal pain assessment tool, and his pain should be treated

if indicated. His vital signs should be evaluated to identify hypotension or hypoxia,

and his blood glucose concentration should be measured. Abnormalities in these

values should be corrected as needed. Clinicians should review J.A.’s past medical

history, social history, and home medication list to identify any potential that he might

be experiencing withdrawal from alcohol, illicit substances, or prescribed

medications that he was taking before hospital admission such as benzodiazepines or

opioids. If he is unaware of his surroundings or current condition, J.A. should be

reoriented. His sleep pattern should be addressed. Finally, the patient’s current

medication list should be reviewed for medications, such as steroids and

anticholinergic drugs, that might cause behavioral changes and these medications

should be discontinued if identified. Only after thoroughly assessing the patient for

potentially reversible causes of agitation, should the health care team consider

initiating a sedative medication with the goal of achieving a light level of sedation in

J.A.

CASE 56-5, QUESTION 2: If J.A. requires sedation, which medication would be preferred?

Several agents, including propofol, dexmedetomidine, and benzodiazepines, can

be used to treat agitation in critically ill patients. No particular sedative is best for

all patients. Although benzodiazepines have been widely used over time, recent

guidelines suggest that propofol and dexmedetomidine are preferred in most patients

because they may result in decreased ICU length of stay and duration of mechanical

ventilation as compared to benzodiazepines.

37,51–53 Decisions about the optimal

sedative agent for individual patients depend on the reason for sedation and sedation

goals, expected duration of sedation, pharmacology of the medication in the specific

patient, and cost-effectiveness.

37 A summary of key clinical considerations relative to

commonly used sedatives is provided in Table 56-3.

Propofol is a highly lipophilic sedative that binds to multiple receptors and exerts

sedative, hypnotic, anxiolytic, antiemetic, and anticonvulsant properties.

37 Because of

its high lipophilicity and formulation in a 10% lipid emulsion, propofol readily

crosses the blood–brain barrier and demonstrates a rapid onset of effect and quick

offset after short-term use. However, patient awakening after prolonged use can be

variable because of its deposition in adipose tissues.

54 Propofol can be rapidly

titrated in order to achieve the desired level of sedation. It is suited for regular

awakenings that are required for neurologic examinations in patients with brain

injuries, and it facilitates daily awakening as part of sedative and ventilator weaning

protocols.

53,55 Adverse effects of propofol include respiratory depression,

hypotension resulting from vasodilation, bradycardia, hypertriglyceridemia,

pancreatitis, myoclonus, and green or white discoloration of the urine.

56,57 Because of

the dose-dependent suppression of respiratory drive, continuous infusions of

propofol should only be administered to patients who are mechanically ventilated.

Patients should be regularly monitored for hypertriglyceridemia when receiving

propofol over the course of several days and the drug should be stopped or weaned if

significant hypertriglyceridemia develops. Patients with allergies to eggs, soybeans,

and sulfites may experience allergic reactions because of components of the lipid

emulsion and some generic formulations.

58