Analgesia & Sedation

Our principal role in caring for the sick is not to save lives (since this is impossible on a consistent basis), but to relieve pain and suffering. The analgesic and sedative drug regimens described in this chapter will allow you to serve in this role.

I. Analgesia

A. Monitoring Pain

Treating pain in critically ill patients requires a reliable pain assessment tool to determine the adequacy of pain relief (1).
- A horizontal numeric rating scale can be used for intubated patients who are able to self-report (1). This scale has 10 equally-spaced divider markings, numbered 1 (no pain) to 10 (maximal pain). The patient points to one of the numbered markings to indicate the severity of pain. A score of 3 or less indicates adequate pain control.
- When patients are unable to self-report, the Behav-ioral Pain Scale (BPS) shown in Table 43-1 is a reliable tool for use at the bedside (2).
- Vital signs (e.g., heart rate) correlate poorly with patients’ reports of pain intensity, and are not recommended to assess pain (1,3).
Table 43.1 The Behavioral Pain Scale

B. Opioid Analgesia

Pain relief in ICU patients is achieved almost exclusively with opioids, which are natural derivatives of opium (opiates) that produce their effects by stimulating discrete opioid receptors in the central nervous system. Stimulation of opioid receptors can produce a variety of beneficial effects, which include analgesia, sedation, and euphoria, but no amnesia (4,5,6). The most frequently used intravenous opioids
are morphine, hydromorphone, and fentanyl. A comparison of these agents is shown in Table 43-2.

Table 43.2 Commonly Used Intravenous Opioids

	Morphine	Hydromorphone	Fentanyl
Onset	5–10 min	5–10 min	1–2 min
Bolus Dosing	2–4 mg	0.3–0.6 mg	0.35–0.5 μg/kg
	q 1–2 hr	q 1–2 hr	q 0.5–1 hr
Infusion rate	2–30 mg/hr	0.5–3 mg/hr	0.5–2 μg/hr
PCA
Demand (bolus)	0.5–3 mg	0.1–0.5 mg	15–75 μg
Lockout interval	10–20 min	5–15 min	3–10 min
Lipid Solubility	x	0.2x	600x
Active Metabolites	Yes	No	No
Histamine Release	Yes	No	No
Dose Adjustment for Renal Failure	↓50%	None	None
Analgesic Potency	x	7x	100x
Dosing recommendations from Reference 1.

1. Fentanyl

Fentanyl is the most popular opioid analgesic used in ICUs (7).
The advantages of fentanyl over morphine include a more rapid onset of action (because fentanyl is 600 times more lipid soluble), less risk of hypotension
(because fentanyl does not release histamine), and the absence of active metabolites.
The major disadvantage with fentanyl is the tendency of the drug to accumulate in the brain during prolonged infusions (due to the high lipid solubility of the drug).

2. Hydromorphone

Hydromorphone is a morphine derivative that may produce more effective analgesia compared to morphine (8,9).
Additional benefits of hydromorphone include lack of active metabolites and no requirement for dose modification in renal failure.

3. Morphine

Morphine has several active metabolites that can accumulate in renal failure. One metabolite (morphine 3-glucuronide) can produce central nervous system excitation with myoclonus and seizures (10), while another metabolite (morphine-6-glucuronide) has more potent analgesic effects than the parent drug (5).
To avoid accumulation of these metabolites, the maintenance dose of morphine should be reduced by 50% in patients with renal failure (11).
Morphine also promotes the release of histamine, and this can produce systemic vasodilation and a decrease in blood pressure (5).

4. Remifentanil

Remifentanil is an ultra-short acting opioid that is given by continuous IV infusion, using the dosing regimen shown below (19).

DOSING REGIMEN: 1.5 μg/kg as a loading dose, followed by a continuous infusion at 0.5–15 μg/kg/hr (1).
Analgesic effects are lost 8–10 min after stopping the
drug infusion, owing to the breakdown of remifentanil by plasma esterases.
Dose adjustments are not required in hepatic or renal failure.
Remifentanil’s short duration of action is advantageous in conditions that require frequent evaluation of cerebral function (e.g., traumatic brain injury). The abrupt cessation of opioid activity can precipitate acute withdrawal, which can be prevented by combining remifentanil with a longer-acting opioid.

C. Adverse Effects of Opioids

1. Respiratory Depression

Opioids produce a centrally-mediated, dose-dependent decrease in respiratory rate and tidal volume, but respiratory depression and hypoxemia are uncommon when opioids are given in the usual doses (12,13). Opioid doses that impair arousal also impair ventilation and produce hypercapnia (12).
Patients with sleep apnea syndrome or chronic hypercapnia are particularly prone to respiratory depression from opioids.

2. Cardiovascular Effects

Opioid analgesia is often accompanied by decreases in blood pressure and heart rate, which are the result of decreased sympathetic activity and increased parasympathetic activity. These effects are usually mild and well tolerated, at least in the supine position (14).
Decreases in blood pressure can be pronounced in patients with hypovolemia or heart failure (where there is an increased baseline sympathetic tone), or when opioids are given in combination with benzodiazepines (27). Opioid-induced hypotension is rarely a threat to
tissue perfusion, and the blood pressure responds to intravenous fluids or small bolus doses of vasopressors.

3. Intestinal Motility

Opioids depress bowel motility via activation of opioid receptors in the GI tract. Impaired GI motility can promote reflux of enteral tube feedings into the oropharynx, creating a risk for aspiration pneumonitis.
Opioid-induced bowel hypomotility can be partially reversed with enteral naloxone (8 mg every 6 hours) or naltrexone (50 mg once a day by mouth) without affecting opioid analgesia (15).

Nausea and Vomiting

Opioids can promote vomiting via stimulation of the chemoreceptor trigger zone in the lower brainstem (12). All opioids are equivalent in their ability to promote vomiting, but vomiting induced by one opioid occasionally resolves when another opioid is used.

D. Patient-Controlled Analgesia (PCA)

For patients who are awake and capable of drug self-administration, patient-controlled analgesia (PCA) can be an effective method of pain control, and may be superior to intermittent opioid dosing.
The PCA method uses an electronic infusion pump that can be activated by the patient. When pain is sensed, the patient presses a button connected to the pump to receive a small intravenous bolus of drug. After each bolus, the pump is disabled for a mandatory time period called the lockout interval, to prevent overdosing.
The opioid dosing regimens for PCA are shown in Table 43.2. The minimum lockout interval is a function of the time to achieve peak drug effect (22).

E. Non-Opioid Analgesia

A variety of non-opioid analgesics are available, but only a few of these drugs can be given intravenously. Most of these drugs are used for analgesia in the early postoperative period. They can be used alone for mild pain, but are commonly used in combination with an opioid analgesic for moderate to severe pain. Dosing regimens for non-opioid analgesics are presented in Table 43.3.

Ketorolac

Ketorolac is a nonsteroidal anti-inflammatory drug (NSAID) that is 350 times more potent than aspirin as an analgesic (16). It does not cause respiratory depression, but other toxic effects limit its use. It is usually given as an adjunct to opioid analgesia, and has an opioid-sparing effect.
IM injection of ketorolac can produce hematomas (16), so IV bolus injection is preferred.
The beneficial actions of ketorolac and other NSAIDs are attributed to inhibition of prostaglandin production, but this also creates a risk for adverse effects, particularly gastric mucosal injury, upper GI hemorrhage, and impairment of renal function (16). These side effects are uncommon when use of the drug is limited to 5 days (16).
Ketorolac inhibits platelet aggregation, and should not be used in patients with a high risk of bleeding.

Ibuprofen

Ibuprofen is very similar to ketorolac because it is an NSAID that can be given intravenously, has an opioid-sparing effect, and is safe when used for short-term pain control (17).
Unlike ketorolac, the treatment period for ibuprofen
has no recommended time limit. Clinical trials of IV ibuprofen typically employ a treatment period of 24–48 hours, and serious complications are uncommon over that time period.

Table 43.3 Intravenous Non-Opioid Analgesia

Agent	Dosing Regimens and Comments
Ketorolac	Dosing: 30 mg IV or IM every 6 hrs, for up to 5 days. Reduce dose by 50% for age ≥65 yrs or body weight <50 kg.
	Comment: Ketorolac is an NSAID, and has anti-inflammatory and antipyretic effects. Serious complications are uncommon when treatment is limited to 5 days.
Ibuprofen	Dosing: 400–800 mg IV every 6 hrs.
	Comment: Ibuprofen is an NSAID, like ketorolac, but has no limit on duration of use.
Acetaminophen	Dosing: 1 g IV every 6 hrs. Daily dose should not exceed 4 g.
	Comment: No anti-inflammatory effects (which is a major disadvantage in critically ill patients).
Ketamine	Dosing: 0.1–0.5 mg/kg IV loading dose followed by 0.05–0.4 mg/kg/hr.
	Comment: Attenuates the development of acute tolerance to opioids. May cause hallucinations, psychological disturbances, and hypersalivation.
Dosing recommendations from Reference 1.