CONTENTS
- Spectrum of medications available:
- Pure analgesics
- Analgosedatives (analgesia > sedation)
- Sedalgesics (sedation > analgesia)
- Pure sedatives
- Antipsychotics / anti-agitation
- Underlying concepts & construction of regimens:
- General concepts about analgesia:
- Podcast
- Questions & discussion
- Pitfalls
dose 💊
- The usual dose is 650-1,000 mg q6hr (up to 4 grams/day). For patients with ongoing pain this should be scheduled, to provide a baseline level of analgesia.
- Acetaminophen may be given PO, PR, or IV. PO is preferred, because IV is expensive (although this varies in different countries).
- Available RCTs have found no difference in efficacy between IV versus oral route.
contraindications & complications
- In severe alcoholism, stable cirrhosis, or low body weight (<50 kg), the maximal daily dose is 2 grams.(25477978)
- In acute liver injury or decompensated cirrhosis, acetaminophen should be entirely avoided.
- In neutropenia, acetaminophen might be avoided, to allow for early detection of neutropenic fever.
indications/advantages
- Acetaminophen is a mild-moderately effective analgesic with an outstanding safety profile. It forms the first level of the analgesic ladder due to its safety, rather than its efficacy. Acetaminophen is often overlooked because it isn't very potent. However, scheduled acetaminophen may nonetheless play a useful role in multi-modal analgesia. RCTs and meta-analyses demonstrate that acetaminophen is an effective analgesic in a variety of contexts, with benefits which may include reduced opioid requirements, reduced delirium, and avoidance of nausea/vomiting. (20189753, 30726545, 30305124, 30778597)
- Acetaminophen is a centrally acting, non-competitive reversible inhibitor of cyclooxygenase (COX) enzymes, with analgesic and antipyretic effects. (30845871)
dose 💊
- (1) Initial loading dose
- ~1.5 mg/kg infusion over 10-30 minutes (may use 1-2 mg/kg).
- (2) Continuous infusion at a low, fixed rate
- ~1 mg/kg/hour ideal body weight appears to be a reasonable dose.(30303542) This will often be close to 1 mg/min, with some correction based on body size.
- Many sources recommend titration of the infusion based on pain. However, lidocaine has a relatively narrow therapeutic window (e.g., therapeutic level of ~2.5-3.5 ug/ml and toxic level of >5 ug/ml). Therefore, unless there is a high level of expertise regarding monitoring and dose-adjustment, it might be safest to use a fixed rate (especially at centers which are unable to measure a lidocaine level). The whole concept of multi-modal analgesia is to use low doses of several medications, to avoid toxicity from any individual agent. Use of a relatively low, fixed lidocaine infusion rate may fit within this overall strategy.
- 🛑 Caution: Many sources list higher infusion rates (e.g., 2-3 mg/kg/hour), but accumulation and shifts in metabolism over time may make these rates unsafe for extended infusion (e.g., >24 hours).(4026487)
- 🛑 Caution: Monitor the patient's organ function while on the lidocaine infusion. If acute organ failures occur (e.g., renal failure or multiorgan failure), then either close monitoring of drug levels or discontinuation of the infusion may be required.
- (3) Duration of lidocaine infusion?
- This is unclear. Most studies in the anesthesia literature have limited lidocaine infusions to 48 hours in duration. However, some studies have reported the use of a continuous lidocaine infusion for four days or even 1-2 weeks! (14984229, 26650426)
- Over time, the half-life of lidocaine may extend slightly (due to accumulation in various body compartments and also due to the inhibition of lidocaine metabolism by some of its own metabolites). Therefore, if lidocaine is continued beyond 48 hours, it may be sensible to reduce the rate slightly (to 0.8 mg/kg/hr ideal body weight) or monitor serum lidocaine levels.
adverse effects
- 🚩 Early signs of toxicity: Perioral paresthesias, visual or auditory disturbance, metallic taste, tinnitus, lightheadedness, and sedation. These should serve as triggers to discontinue the lidocaine infusion, and thus avoid more severe toxicity.
- Organ system manifestations:
- Cardiac: Bradycardia, QRS widening, sinus node suppression
- Neurologic: Delirium, tremor, visual disturbances, numbness/tingling, metallic taste, tinnitus, seizure.
- Gastrointestinal: Nausea and vomiting
- Hematologic: Methemoglobinemia (rare)
- Mild-moderate toxicity should resolve after discontinuing the infusion. Severe toxicity may be managed by administration of intralipid.
contraindications
- Allergy to lidocaine.
- Heart block (including PR >200 ms or QRS >120 ms).
- Increased risk of seizure (e.g., seizure history).
- Hepatic dysfunction (bilirubin >1.5 mg/dL).
- Renal dysfunction (GFR <30 ml/min or acute-onset oliguria).
- Severe heart failure, shock, or multiorgan failure.
- Acute porphyria.
- Drug interactions:
indications/evidence
- Lidocaine is a type Ib antiarrhythmic and also an amide local anesthetic. It functions by inhibiting voltage-gated sodium channels, but at low systemic doses used for analgesia it likely acts via other mechanisms (e.g., modulation of calcium channels or NMDA receptors).
- Systemic lidocaine has been used increasingly for a variety of painful conditions (e.g., neuropathic pain, renal colic, and post-operative pain). It has analgesic, anti-inflammatory, and antihyperalgesic properties. (30845871, 28114177)
- The best evidence for lidocaine infusions for pain management exists in the postoperative context. Various studies have demonstrated that lidocaine may reduce pain, decrease opioid requirements, avoid ileus, decrease nausea/vomiting, and reduce hospital length of stay.(28114177)
- Lidocaine is not recommended in the PADIS guidelines for routine use among critically ill patients.(30113379) However, it may be beneficial in selected patients who fail to respond to more conventional strategies.
pharmacokinetics
- Lidocaine undergoes hepatic metabolism into two active metabolites (monoethylglycinexylidide and glycinexylidide). These are subsequently eliminated by the kidney. In renal failure, activate metabolites can accumulate.
- Lidocaine undergoes roughly biphasic distribution.
- Initially, lidocaine has a half-life of 7-30 minutes, as drug distributes into body tissues.
- Eventually the half-life increases to ~1.5-3 hours. This reflects saturation of the tissues and elimination of drug by the liver and kidneys. The terminal half-life may be up to 8 hours in patients with hepatic failure.(26335213)
candidates for receiving NSAIDs in the ICU
- 🛑 NSAIDs are generally not preferred in the ICU due to risks of gastrointestinal hemorrhage, platelet dysfunction, or (especially) renal failure.
- NSAIDs may be considered selectively for patients at low risk of complications, if they meet the following criteria:
- (1) The patient is on no other nephrotoxic medications.
- (2) The patient has excellent and stable renal function (i.e., good urine output and creatinine values).
- (3) There are no sources of hemodynamic instability or impaired perfusion.
- (4) Absence of cirrhosis or inflammatory bowel disease.
- (5) No history of GI ulceration/bleeding.
- (6) No active hemorrhage or severe coagulopathy (especially, no platelet dysfunction).
selection and dosing
- Different NSAIDs seem to have similar safety and efficacy. However, intravenous ketorolac may take effect considerably faster than oral agents.
- The key principle of NSAID dosing is the concept of the dose ceiling. Above a certain dose, further increases will only increase toxicity (without increasing efficacy). Recent evidence demonstrates that the dose ceiling is often lower than was previously thought. This is useful, because it reveals that we can obtain the same efficacy while using smaller, safer doses. Dose ceilings for some commonly used NSAIDs are:
- 🛑 Don't give a dose higher than the dose ceiling! Doses below the dose ceiling may still remain useful, however (e.g., 300 mg of ibuprofen).
- Discontinue the NSAID as soon as possible (in particular, avoid ketorolac administration for >5 days).
general & mechanism
- NSAIDs inhibit prostaglandin synthesis via COX enzymes, thereby exerting antipyretic, analgesic, and anti-inflammatory effects.
pharmacokinetics, dosing, and selection
- Opioids commonly used in critical care are listed above. These are overall fairly similar agents. The most important aspect of opioid administration is dose-titration, rather than the selection of any particular drug.
- Other opioids, especially tramadol and meperidine, have numerous side effects and no role in managing critically ill patients.
- It is commonly taught that there is no “maximal dose” of opioids. This is only partially true. At high doses, opioids may rapidly cause opioid-induced hyperalgesia (a paradoxical process whereby excess opioid doses exacerbate pain). This seems to be most problematic with remifentanil and fentanyl, with one study showing that a single, large dose of fentanyl was capable of inducing hyperalgesia. (26655493) Whenever giving an opioid dose equivalent to >50 mg oral oxycodone daily, consider whether the dose is necessary and beneficial. Especially among medical patients, there's little rational explanation why such massive doses of opioid should be needed. A common error is to use high-dose opioids for their sedative properties (when such patients would be better served by receiving less opioid and more sedation).
complications of greatest concern in the ICU:
- (1) Respiratory supression
- Opioids suppress the respiratory drive relatively potently. Unfortunately, even with chronic use, this effect remains strong.
- Patients at greatest risk are those with chronic hypercapnia and a blunted respiratory drive (e.g., obesity hypoventilation syndrome or chronic hypercapnic respiratory failure due to COPD).
- Among intubated patients, respiratory suppression can be beneficial by facilitating ventilator synchrony. However, persistent respiratory suppression may delay extubation.
- (2) Gastrointestinal failure
- Opioids are a major risk factor for nausea/vomiting, gastroparesis, ileus, and colonic pseudo-obstruction. In severe cases, the latter can cause colonic perforation and death.
- (3) Opioid dependence and withdrawal
- The brain very rapidly adapts to continuous opioid exposure, leading to dependence. When the opioid dose is reduced, this may cause withdrawal and rebound analgesia.
- Opioid withdrawal may be an under-recognized factor which contributes to pain and depression after critical illness.
- Ongoing use of opioids throughout the patient's hospital course may lead to chronic outpatient opioid use, which exposes the patient to a host of long-term problems.
- The brain very rapidly adapts to continuous opioid exposure, leading to dependence. When the opioid dose is reduced, this may cause withdrawal and rebound analgesia.
- (4) Delirium
general comments & mechanism of action
- Opioids have traditionally been the backbone of pain management in critical illness. However, this selection is based more on inertia and ease of use, rather than on evidentiary support. Anesthesiologists have long recognized that avoidance of opioids may improve recovery after surgery, with intensivists only gradually beginning to follow suit.
- PRN bolus-dose opioids will often be required for the management of critically ill patients. Opioid toxicity increases substantially with the use of a continuous opioid infusion, so these should be avoided whenever possible.
- A series of studies in Europe have demonstrated that it's possible for critically ill, intubated patients to be maintained on extremely low doses of opioids or no opioids at all.( 20116842, 32068366) This implies that many ICUs are using vastly more opioids than are actually necessary.
opioid patient-controlled analgesia (PCA)
Patient-controlled analgesia (PCA) may be useful for severe pain in a patient who is awake enough to understand how to use the PCA. PCAs don't play a large role among critically ill patients, as our patients are often too ill to use them. Nonetheless, it's worth understanding how to set one up.
general concepts behind a PCA
- (1) Small doses of opioid provided on-demand may allow for finer dose titration against the patient's pain requirements. This may actually lead to reduced opioid consumption over time.
- (2) Small doses are provided, with a defined lock-out interval between doses (during which time, activating the PCA will not result in delivering additional medication). Using a lock-out interval prevents multiple doses from accumulating (“stacking”) and thereby leading to intoxication.
- (3) Also to ensure safety, a patient who becomes mildly intoxicated will fall asleep and stop activating the PCA. In order for this safety mechanism to function optimally, the PCA should ideally have no basal rate (more on this below).
basic setup
- (1) Select an agent based on the same considerations as are generally used (e.g., renal dysfunction, interacting drugs). All other things being equal, morphine might be a good choice (it causes less euphoria, making it a bit less prone towards inappropriate reinforcement).
- (2) Choose a demand dose and lockout interval (see table below). Doses and intervals may vary a bit depending on how sensitive the patients are to opioids and what their opioid requirement has been. However, relatively similar doses can be used overall, with the expectation that patients will titrate their own doses by operating the PCA.
- (3) The basal (continuous) rate of the PCA should always be set to zero unless the patient has been on chronic opioids. For patients who were previously on chronic opioids, their chronic dose may be converted into an appropriate basal rate using various calculators (e.g., this one). This can be a bit tricky though, so when in doubt err on the low side.
- (4) Discontinue all other opioid orders. Also, remove potentially sedating medications if possible (e.g., benzodiazepines).
common mistakes
- (1) The PCA is designed to maintain analgesia – not to rescue the patient from uncontrolled pain.
- If the patient has severe, uncontrolled pain, then this should be treated immediately by clinician-titrated boluses of opioid.
- Patients often require loading with a moderate dose of opioid before initiation of the PCA. The PCA delivers only small doses of opioid, so it's not adequate to “catch up” to entirely uncontrolled pain.
- (2) Never use a continuous infusion in a patient who is opioid naive.
- Continuous opioid infusions probably don't help improve analgesia, as explored above. In the case of PCAs, it has been specifically shown that adding a basal rate doesn't improve analgesia – but it does increase toxicity! (16334492, 21074739)
- Basal rates should be used only for patients who are on chronic opioids.
- If the patient's pain isn't controlled, then consider increasing the demand dose – 0r better yet – adding a non-opioid analgesic (e.g., ketamine).
- (3) Ensure that only the patient is activating the PCA (and not, for example, relatives or friends). A safety mechanism of PCAs is that as patients become sedated they will stop activating the PCA.
- (4) Pumps can malfunction, rarely leading to opioid intoxication. If the patient is demonstrating features of opioid intoxication, then disconnect the PCA and treat the patient appropriately.
avoiding opioid infusions
the use of continuous infusions of opioids for days on end lacks a strong evidentiary basis. For example:
- No prospective, high-quality study has demonstrated a benefit from using a continuous opioid infusion. It's often assumed that more is better, but a continuous exposure to opioid may merely blunt the brain's responsiveness to it (rather than improving efficacy).
- Among patients being treated with patient-controlled analgesia (PCA) for acute pain, the addition of a continuous opioid infusion has been shown to increase complications, without improving pain control! (21074739)
- Replacing fentanyl infusions with methadone was shown to accelerate extubation, implying that fentanyl infusions prolong intubation. (22420584)
major reasons to avoid opioid infusions include the following:
- Continuous exposure to opioids rapidly causes tolerance, which may eventually lead to problems with withdrawal and dependence.
- Infusions will be up-titrated with the patient is in pain, but less aggressively down-titrated when the patient isn't in pain. This will inevitably increase opioid exposure, compared to a PRN-only strategy (which only provides opioid when the patient has pain).
- High cumulative opioid exposure from infusions (especially fentanyl) may cause opioid-induced hyperalgesia leading to a vicious spiral (figure above).
- Continuous infusions of fentanyl will lead to drug accumulation in the fat tissue, which makes it impossible to rapidly withdraw the opioid when the patient is otherwise ready for extubation.
strategies to avoid problems with opioid infusions:
- Avoid infusions whenever possible (favoring a bolus-only strategy, even if that involves using relatively generous opioid boluses).
- If an infusion is necessary, use a rational dose (e.g., 25-50 mcg/hour fentanyl). Note that 100 mcg/hr fentanyl infusion is roughly equivalent to ~400 mg of oral oxycodone daily.
- Aggressively wean down the infusion at least once daily (but optimally more often).
- It takes an infusion 4-5 half-lives to reach steady state. Therefore, for severe uncontrolled pain the first line therapy is PRN boluses of opioid, combined with up-titration of opioid infusion. Merely up-titrating the infusion without PRN doses is the wrong approach here, because it will lead to delayed and excessive opioid dosing.
- Pay attention to how much opioid is being used as PRN doses vs. infusion. Ideally at least a moderate fraction of the total opioid given should be given as PRN doses. Alternatively, if the patient is receiving no PRN doses, then that suggests that the infusion rate is excessively high.
- Ketamine may reduce the development of tolerance and opioid induced hyperalgesia. Thus, co-infusion of pain-dose ketamine with an opioid may limit opioid dose and toxicity.
opioid infusions may be beneficial in the following situations:
- Among intubated patients with profound respiratory failure with a need to suppress the respiratory drive (e.g., severe status asthmaticus), opioid infusions may be beneficial. Use of an opioid infusion to suppress respiratory drive may allow for avoidance of paralysis, thereby constituting the lesser of two evils.
- For patients on chronic opioids prior to admission, some basal amount of opioid may be necessary to prevent withdrawal.
dose
- Gabapentin: 300-1200 mg q8hr. 💊
- Pregabalin: 75-150 mg q12hr. 💊
- Both agents should be dose-reduced in renal dysfunction.
contraindications/cautions
- Limiting side effects include somnolence, respiratory depression, hypoactive delirium, and less often myoclonus.
- Risks are compounded by renal dysfunction and other CNS-suppressive medications. However, mild sedation may be a beneficial effect for intubated patients.
- Rapid discontinuation of gabapentinoids can cause withdrawal. Patients who were on these medications prior to ICU admission should generally be continued on them (with dose-adjustment as needed based on renal function).
indications
- Gabapentinoid use is predominantly for neuropathic pain, for example:(Vincent 2023)
- Guillain-Barre Syndrome.
- Diabetic neuropathy.
- Spinal cord injury.
- Post-herpetic neuralgia.
- Pain due to subarachnoid hemorrhage; post-stroke central pain.
- Although occasionally used for post-operative pain, there is little evidentiary support for their use in post-operative or acute somatic pain. (27426431)
pharmacokinetics
- These drugs don't actually interact with GABA receptors (they function to inhibit voltage-dependent calcium channels).
- Gabapentin has a half-life of 5-7 hours, which is prolonged in renal dysfunction.
- Pregabalin may have a faster onset, with 90% bioavailability and peak concentration within an hour.
general comments
- Alpha-2 agonists exert analgesic effects by affecting central alpha-2 receptors and imidazoline receptors. Depending on their activity upon different receptors, they have a spectrum of overlapping clinical effects.
- The analgesic potency of alpha-2 agonists is mild. However, they may be beneficial within a multi-modal analgesic scheme, where they augment the efficacy of other agents (e.g., ketamine).
- Central alpha-2 agonists cause varying degrees of sedation. The ability to provide sedation without respiratory suppression can be extremely useful.
- Alpha-2 agonists can cause bradycardia and hypotension.
tolerance and withdrawal to alpha-2 agonists
- Perhaps the greatest drawback of alpha-2 agonists is the possibility of developing tolerance and withdrawal. Over time, patients may become tolerant to the medication, causing reduced clinical efficacy. If the medication is then stopped abruptly, this may cause a withdrawal syndrome (e.g., with tachycardia, hypertension, and anxiety). Withdrawal is predominantly an issue among patients taking these medications on a chronic, outpatient basis – but it can occur to a lesser extent among inpatients (especially patients on higher doses of dexmedetomidine).
- These issues may be avoided as follows:
- (1) Consider limiting the duration of dexmedetomidine infusions (e.g., to less than ~5 days). Dexmedetomidine is an excellent medication to facilitate extubation, but it may not be the optimal agent to serve as a maintenance analgosedative for indefinite periods of time. Discontinuation of dexmedetomidine can be facilitated by transitioning to oral clonidine.
- (2) For patients who have been on oral alpha-2 agonists for several days, it may be preferable to taper off gradually (or taper abruptly with careful observation for withdrawal).
- (3) It's essential to actively wean alpha-2 agonists as soon as possible (e.g., as patients are recovering and have decreasing needs for analgesia and sedation). All efforts should be made to ensure that patients aren't continued on these agents indefinitely on an outpatient basis.
- (4) Avoid high doses of these medications (this is consistent with the bedrock concept of multi-modal analgesia, which is to use moderate doses of several agents in order to minimize toxicity from any single agent).
- Fear of tolerance and withdrawal shouldn't generally dissuade practitioners from using these agents. However, these limitations must be understood to maximize the safe and efficacious use of alpha-2 agonists.
combining alpha-2 agonists plus ketamine may be synergistically useful for several reasons:
- Synergistic analgesia: The combination of ketamine plus an alpha-2 agonist provides more effective analgesia than either agent alone. (23711600, 20648205, 19095506)
- Hemodynamic stability: Ketamine tends to increase blood pressure, whereas alpha-2 agonists tend to reduce blood pressure.
- Avoidance of ketamine's psychotomimetic side effects: The major treatment limiting side effect of ketamine infusions is psychomimetic effects, which occur at higher doses (typically >0.2-0.3 mg/kg/hr). These side effects are generally minor and easily managed by pausing the infusion and then resuming at a lower rate. Alpha-2 agonists can exert a sedative effect which avoids ketamine induced psychomimetic effects, thereby widening the margin of safety when administering ketamine. (29870458, 19783371, 9507131, 27656531, 10773503) For example, one study found that clonidine dosed at 0.3 mg BID allowed patients to tolerate ketamine at 0.6 mg/kg/hr (a ketamine dose which should otherwise cause substantial psychomimetic effects).(26919405)
- Avoidance of tolerance to alpha-2 agonists? Within 1-2 weeks, patients will develop tolerance to the sedative effects of alpha-2 agonists. Animal models suggest that ketamine may prevent this, thereby allowing alpha-2 agonists to maintain ongoing efficacy over time.(11465557)
selecting an agent
- Dexmedetomidine is a titratable IV agent, which makes it useful for more acutely ill patients (who may require rapid up- and down-titrations).
- Guanfacine functions primarily as a sedative. Guanfacine causes less hypotension than clonidine, which may be desirable for most ICU patients (who often have borderline hemodynamics).(36349291)
- Clonidine combines analgesic and sedating properties.
- Among these agents, clonidine may cause the greatest degree of hypotension. This may be useful for patients with hypertension.
- Tizanidine is usually utilized primarily as an analgesic and muscle relaxant.
dexmedetomidine
dosing
- 🛑 Boluses of dexmedetomidine may cause bradycardia and hemodynamic collapse, so these should generally be avoided. Instead, the infusion may be started at a high rate (e.g., 1-1.4 mcg/kg/min) and down-titrated as the drug takes effect (within an hour).
- Infusion rate at 0-1.4 mcg/kg/hr.
- Ideally try to down-titrate (or stop) dexmedetomidine during the day, with subsequent up-titration at night:
- Decreasing dexmedetomidine during the day may help avoid tolerance and withdrawal.
- Use of dexmedetomidine during the night may promote restorative sleep and help reset the circadian rhythm.
- Patients on dexmedetomidine continuously for >3-5 days may be transitioned to oral clonidine or guanfacine to avoid withdrawal symptoms.
contraindications/drawbacks
- Hypotension & bradycardia (sympatholysis):
- Dexmedetomidine may cause bradycardia and hypotension (especially when bolused).
- Dexmedetomidine is contraindicated in patients with heart block, bradycardia, or severe hypotension. (However, this property can occasionally be useful in patients with tachycardia.)
- In rare situations, dexmedetomidine may be a uniquely useful and necessary sedative. What should be done if dexmedetomidine is deemed to be mission-critical, but is causing bradycardia? A dexmedetomidine infusion may be combined with a simultaneous infusion of low-dose epinephrine or dobutamine (to offset the bradycardic effects).
- Prolonged uninterrupted use (>3-5 days) may cause tolerance and subsequent withdrawal after dexmedetomidine is discontinued. There is little evidence regarding long-term use of dexmedetomidine, so it is hard to know exactly how common this is. Using lower doses of dexmedetomidine (e.g., 0.8 mcg/kg/hr or less) might help avoid withdrawal.(32844730)
- Dexmedetomidine is often unable to achieve very deep levels of sedation. Although deep sedation isn't usually preferred among ICU patients, it may be desirable in some situations (e.g., patients undergoing intubated prone ventilation).
- (Previously dexmedetomidine's popularity was limited by cost, but it is currently generic and this no longer seems to be an issue.)
indications/use
- Advantages:
- Doesn't suppress respiration:
- Can be used in patients who aren't intubated (e.g., on BiPAP).
- Can be used to bridge patients through the entire extubation process (i.e., dexmedetomidine doesn't need to be stopped prior to extubation).
- Titratable infusion, which can be discontinued easily.
- Patients often remain arousable while on dexmedetomidine (so this may be used in situations requiring frequent neurologic examinations).
- Doesn't suppress respiration:
- Use:
- Sedation of patients who aren't intubated (e.g., BiPAP).
- Management of nocturnal agitation (may promote physiological sleep and reduce delirium).(29498534)
- Sedation of intubated patients who are close to extubation (e.g., within 2-4 days of extubation). Dexmedetomidine is especially useful for bridging patients through the extubation period, because it may be continued during this entire process (unlike propofol, which must be discontinued prior to extubation).
pharmacology
- Infusion takes ~30-60 minutes to reach equilibrium levels.
- Excretion is mostly renal.
clonidine
dosing 💊
- ⚠️ Before initiation, review the medication list and consider discontinuation of any beta-blockers or other antihypertensive agents.
- Sedation:
- Opioid withdrawal: Most studies have used up to ~0.6-1.2 mg/day in divided doses, titrated against symptoms.(27140827) However, with ICU-level monitoring higher doses may be reasonable (e.g. ~2 mg/day in divided doses).(18709354)
- Multimodal analgesia: Start 0.1-0.2 mg q12hr, may up-titrate to 0.3-0.4 mg q12hr.(8874906, 26919405)
- Restless leg syndrome: 0.1 – 0.3 mg, two hours before sleep.
- Hypertension:
- Onset in ~1 hour, duration of action ~12 hours.
- Start 0.2 mg q12 hours, maximal dose 1.2 mg q12 hours.
- If a patient is temporarily unable to take oral medication, clonidine may also be given sublingually (achieving similar pharmacokinetics compared to oral clonidine).(7986518)
contraindications/cautions
- Bradycardia and/or hypotension.
indications/use
- Oral sedative used to transition off IV dexmedetomidine.
- Opioid withdrawal.
- May be used as an antihypertensive agent.
pharmacology
- Oral bioavailability is ~85%.
- Onset in ~1-2 hours, with a half-life of 12-16 hours.(36349291) Clonidine is rapidly absorbed and administered relatively frequently (e.g., q6hr), which can facilitate rapid oral dose titration.
- Metabolism is 50% renal and 50% hepatic.
- Clonidine may actually have a U-shaped effect on blood pressure, with lower doses causing hypotension but higher doses having less effect on blood pressure. 🌊(28833346)
guanfacine
dosing 💊
- ⚠️ Before initiation, review the medication list and consider discontinuation of any beta-blockers or other antihypertensive agents.
- Sedation: May start at a dose of 0.5 mg q8hr-q12hr, with escalation as needed to a maximal dose of 1 mg q8hr.(36349291) If transitioning from dexmedetomidine to guanfacine, patients on a higher dexmedetomidine dose may benefit from higher doses of guanfacine.
- Insomnia: Guanfacine be given once daily, four hours before sleep (e.g., 1-2 mg at 18:00). This will maximize sedation at night, while still providing some residual sedation during the day (29619866, 32591212)
contraindications/cautions
- Bradycardia and/or hypotension (although guanfacine causes less hypotension than clonidine).
indications/use
- Oral sedative used to transition off IV dexmedetomidine.
- Adjunctive sedative agent for ongoing anxiety.
- (Guanfacine lacks analgesic properties.)
pharmacology
- Onset ~4 hours after administration.
- Guanfacine is 10-30 hours (longer than clonidine).(36349291)
tizanidine
dosing 💊
- ⚠️ Before initiation, review the medication list and consider discontinuation of any beta-blockers or other antihypertensive agents.
- Start: ~4 mg q8hr. May up-titrate to ~8 mg q8hr.
- Using an increased dose in the evening may enhance sleep.
- Max dose is 12 mg q8hr.
- Rebound hypertension may occur if doses >20 mg/day are used for extended periods.(30137790) This may be avoided by using tizanidine for short courses only and at lower doses.
contraindications/cautions
- Bradycardia and/or hypotension.
- Hepatic dysfunction. Normally the majority of tizanidine is removed via first-pass metabolism in the liver, so hepatic dysfunction could lead to increased drug levels.
- ⚠️ Drug interactions:
- Tizanidine is metabolized by the hepatic CYP1A2 system.
- Tizanidine levels may be low in patients taking inducers of CYP1A2 enzyme (especially rifampin and carbamazepine).
- Tizanidine may be excessive in patients taking inhibitors of CYP1A2 (especially: some fluoroquinolones, fluvoxamine, mexiletine, and some oral contraceptives).(15592331)
indications/use
- Tizanidine appears to offer analgesic efficacy, with far less effect on hemodynamics. (18671474, 25849473) Tizanidine also has muscle relaxant properties and mild sedating effects. Among the alpha-2 agonists, tizanidine might arguably be the best analgesic.
- Tizanidine has traditionally been used for pain syndromes involving muscle spasm (e.g., back pain or myofascial pain). However, recent research shows efficacy in somatic pain as well (e.g., pain following cholecystectomy or hernia repair).(26555871, 7637157, 26962521, 29468508)
pharmacology
- Oral bioavailability is 20-34%. Bioavailability is somewhat variable (food may increase absorption of tizanidine tablets).(18199279)
- Onset in ~1.5 hours.
- Half-life of 2.5 hours (relatively short-acting).
- Metabolized by hepatic CYP450 1A2 into inactive metabolites.
dosing
- 5-10 mg PO before sleep. (33048904)
drawbacks & contraindications
- Quality control of some over-the-counter melatonin formulations is dubious. (However, the therapeutic window is very wide, so if the patient receives slightly more or less than the intended dose it probably won't really matter.)
benefits
- May preserve sleep and circadian rhythms.
- May provide a very mild sedative effect (which reduces the required dose of other sedatives).(25969139)
- Safe and inexpensive.
typical role in ICU sedation
- Adjunctive agent to prevent delirium and promote sleep.
dosing
intravenous benzodiazepines:
- It's generally best to use PRN boluses, rather than a continuous infusion. Infusions tend to accumulate and lead to oversedation. A PRN-bolus strategy naturally promotes using the lowest possible dose of medication.
- Midazolam: 2-5 mg IV q15-30 min PRN
- Lorazepam: 1-4 mg IV q30-60 min PRN
oral benzodiazepines:
- Lorazepam 1-4 mg PO q6hr was validated in one RCT of oral sedation in the ICU.(23551983, 30616675)
- Benzodiazepines with longer half-lives could be more useful as basal sedatives among intubated patients, since they could be given once daily prior to sleep (leading to higher drug levels at night, which would support circadian rhythms). Commonly available options may include:
- Temazepam (half-life ~11 hours), ~15-60 mg QHS.
- Alprazolam (half-life ~12 hours), ~0.5-2 mg QHS.
- Clonazepam (half-life ~34 hours), ~0.5-2 mg QHS.
drawbacks and contraindications
- Benzodiazepines might be the most deleriogenic sedative agent, acting as a risk factor for the development of post-traumatic stress disorder (PTSD).(30672819)
- Benzodiazepines have been shown to increase the duration of mechanical ventilation (when compared to dexmedetomidine or propofol).
- Benzodiazepines may cause paradoxical agitation (potentially leading to a vicious spiral of increased benzodiazepine use, leading to obtundation).
- Ongoing exposure to benzodiazepines may lead to tolerance, with subsequent withdrawal.
- Lorazepam infusions tend to cause propylene glycol intoxication.
- Midazolam may accumulate over time in adipose tissue, especially in patients with renal or hepatic dysfunction or due to various drug-drug interactions.
benefits
- Hemodynamically stable.
- Antiseizure properties.
- Cheap and widely available.
role in ICU sedation
- Benzodiazepines are generally a sedative of last resort.
- The practice of bolusing patients with PRN lorazepam at night should be avoided like the plague. This will often work in the short-term, but lorazepam will actually worsen delirium and agitation eventually.
- If a medication bolus is required to treat agitation, consider using haloperidol or up-titrating of other medications (e.g., propofol). Benzodiazepines are a trap.
- Benzodiazepines do have niche roles in a few situations:
- Sedative of choice for intoxication, especially with sympathomimetics (due to muscle-relaxant and antiseizure properties).
- Patients with profound hypotension (who are too unstable to receive propofol or dexmedetomidine). However, ketamine may be more useful in this situation.
- Benzodiazepines may be used for alcohol withdrawal (although phenobarbital is generally better).
- Oral benzodiazepines are very rarely used (aside from a patient who prior to admission was chronically maintained on oral benzodiazepines). These might be considered in cases of medication shortage.
dosing
- A dose of ~100 mg PO q8hr has been utilized as the primary sedative for intubated patients, up to a maximal dose of ~400 mg/day.(23551983, 30616675, 15714324) However, when using hydroxyzine as an adjunctive sedative agent, a somewhat lower dose might be appropriate.
drawbacks & contraindications
- Hydroxyzine may increase the risk of delirium (based on its anticholinergic effects).
benefits
- Hydroxyzine is an antihistamine sedative with a relatively benign side-effect profile (minimal cardiac or respiratory effects).
- Hydroxyzine has weak anti-emetic properties.
- It's use has been validated in a RCT of critically ill patients.(23551983, 30616675)
typical role in ICU sedation
- Not commonly used.
- Could be considered for refractory agitation or in drug shortages.
Multi-modal therapy is a useful principle which may be applied to a variety of topics (e.g., analgesia, sedation, hemodynamic support, antiemetics).
foundational concept #1 = low doses to optimize risk/benefit
- Increasing medication dosing increases both therapeutic and toxic effects, as shown above.
- Using lower medication doses can often allow substantial clinical benefit, with minimal toxicity (optimizing the risk/benefit ratio). This also creates a safety buffer; even if drug concentrations increase a bit, they will remain within a safe range.
foundational concept #2 = different agents function synergistically
- Different agents frequently work in a synergistic fashion (i.e., 1+1 = 3).
- Synergy allows moderate doses of several different agents to have a large combined impact.
putting it together: multi-modal therapy
- A multi-modal strategy therefore involves using moderate doses of several different agents, in order to maximize efficacy while minimizing toxicity. This is in contrast, for example, to a traditional approach of treating pain with super-human doses of a single opioid.
- For example:
- Propofol monotherapy may require using a high dose of propofol. This may eventually may cause hypertriglyceridemia or propofol infusion syndrome.
- Combining a low dose propofol infusion with an antipsychotic may avoid the toxic effects of propofol, allowing the safe use of propofol for an extended duration.
- Multi-modal therapy is more work, because it involves administration of more medications. This may be confusing to practitioners who aren't familiar with it (“why are we using four drugs when we could use one?”). However, the evidentiary basis for multi-modal therapy is reasonably robust (based largely on RCTs performed in operative and post-operative patients).
Ideally, an uncomfortable patient should be evaluated to determine the source of discomfort. This should be treated appropriately:
- Pain should be treated with an analgesic agent.
- Anxiety refers to fear or uneasiness in the absence of confusion. If medication is required, the optimal medication is a sedative (e.g., propofol or dexmedetomidine).
- Agitated delirium refers to an acute confusional state marked by agitation. If medication is required, the optimal therapy is an antipsychotic.
Sorting out the cause of discomfort:
- Among communicative patients, it's straightforward to ask about whether there is pain. Additional questioning may help sort out anxiety versus agitated delirium.
- Among patients unable to communicate, behavioral pain scores may be used to assess pain. They provides a systematic approach to assess pain and titrate medication accordingly.
In practice, it may be impossible to differentiate precisely between pain, anxiety, or agitated delirium. The ultimate goal is to keep the patient comfortable and calm, while avoiding iatrogenic harm from medications. It may be necessary to empirically trial various medications, prior to selecting the medication(s) which work best for a specific patient.
analgesic ladder
- The concept of an analgesic ladder was developed by the World Health Organization in 1986, as a theoretical construct to encourage rational use of opioids. It focused on optimizing the use of non-opioid analgesics, before escalating to opioids.
- One example of an analgesic ladder for critically ill patients is shown below. However, there is no one-size-fits-all solution to analgesia in the ICU. For example, patients with neuropathic pain may benefit from up-front initiation of a gabapentinoid, whereas most other patients probably won't.
additional measures that should be considered:
- Nerve blocks are excellent measures when they can be used.
- Local measures (e.g., lidocaine patches, TENS units) are safe and may be helpful.
- Early mobilization and physical therapy could improve back pain.
There is little evidence indicating precisely how to engineer a sedative regimen. Consequently, large geographic variation exists. Below is one reasonable approach for intubated patients – but this is intended merely as one possible example. Progress down the steps until the patient is comfortable.
#1) initiate a cornerstone sedative infusion
- Most patients will require a sedative infusion. The best agents appear to be propofol or dexmedetomidine. There is no solid evidence that either of these agents is superior to the other.
- Factors which could favor propofol:
- Anticipated long duration of intubation.
- Seizures.
- Elevated intracranial pressure.
- Need for deep sedation to facilitate ventilator synchrony.
- Factors which could favor dexmedetomidine:
- Patient is approaching extubation.
- Sympathetic overdrive state (e.g., sympathomimetic intoxication, opioid withdrawal).
#2) addition of basal adjunctive agent(s)
- Most patients will do fine with a low or moderate dose of propofol or dexmedetomidine – so they will require no additional sedative. However, some patients may benefit from the addition of one or more basal sedative agents. The role of basal agents may include:
- (1) In some cases, these are required to achieve control of refractory agitation.
- (2) More commonly, basal agents may be used to reduce the required dose of propofol or dexmedetomidine. Decreasing the dose of propofol or dexmedetomidine may avoid problems with these agents (e.g., hemodynamic instability, propofol infusion syndrome, or dexmedetomidine tolerance/withdrawal).
- ⚠️ Basal adjunctive sedatives are not readily titratable, so these cannot be immediately stopped when the patient is ready for extubation. Consequently, low doses of basal sedatives should usually be used (doses that wouldn't compromise respiration or airway protection). Using excessively high doses of basal sedation which may delay extubation.
- These agents may include one or more of the following:
- Atypical antipsychotic (quetiapine or olanzapine):
- These are commonly used, due to their relatively favorable side-effect profiles.
- They are most beneficial for patients with underlying agitated delirium.
- Phenobarbital:
- Phenobarbital is occasionally useful, especially for patients with alcoholism or alcohol withdrawal.
- Oral alpha-2 agonists (clonidine, guanfacine).
- These may be considered in conjunction with propofol (if the patient is already on dexmedetomidine, then these will probably not add much).
- Their greatest utility is in patients with tachycardia and hypertension (e.g., opioid withdrawal). Nocturnal administration may also promote sleep.
- These agents aren't particularly powerful – so don't expect them to control refractory agitation.
- Valproate:
- This is generally reserved for refractory agitated delirium.
- Valproate has enhanced utility in patients with mood disorders, bipolar disorder.
#3) switch to dissociative ketamine infusion
- If all else fails, then another option is a dissociative-dose ketamine infusion (e.g., 1-5 mg/kg/hour).(33068459) This may be necessary for patients with profound hypotension, which limits the ability to give sedatives (e.g., propofol, alpha-2 agonists, or phenobarbital).
- After the patient is fully dissociated with ketamine, other sedatives and analgesics should be discontinued.
- The basic concept here is to stop sedative and opioid infusions and re-titrate daily, to make sure that we're using the lowest possible dose.
- Sedation interruption was extremely critical when we were using long-acting infusions (e.g., midazolam and fentanyl drips). The general concept remains useful today but should probably be applied in a modified fashion. Specifically, we should be continuously titrating drugs such as propofol or dexmedetomidine to achieve a target level of sedation – so stopping entirely doesn't make a lot of sense.
- Key concepts:
- 🔑 Re-assess the sedation regimen frequently (at least daily – but ideally more often).
- 🔑 Always seek to use the lowest doses possible of all medications.
- 🔑 Don't necessarily shut off everything in a robotic fashion. For example, if the patient is awake and comfortable (RASS = 0), then shutting off all the sedation could cause them to become agitated with no real benefit.
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- Analgesia pitfalls:
- NSAIDs promote renal failure and gastric ulceration. They should be used only in rare and well-selected patients within the ICU.
- Tramadol and meperidine (Demerol) have uniquely unfavorable side effect profiles and should be avoided. If you're looking for an anti-shivering agent, fentanyl is preferable to meperidine.
- Opioid infusions cause a host of problems (e.g., tolerance, withdrawal, opioid-induced hyperalgesia, ileus, delayed extubation). They should be a last resort for most patients.
- Acetaminophen and pain-dose ketamine infusions are effective analgesics with excellent side effect profiles. Their use should be encouraged, particularly among patients at high risk for opioid toxicity (e.g., patients with tenuous respiratory drive or abdominal pathology that increases the risk for ileus).
- Bowel motility must be carefully attended to among patients receiving opioids.
- Pain should be assessed carefully. Make sure that the analgesic medication is being used to treat pain, rather than to treat agitation or delirium.
- Sedation pitfalls:
- The over-arching goal of sedation in the ICU is to render the patient comfortable with a minimal amount of medication exposure and toxicity. This involves continually titrating the medication regimen, with use of the lowest doses possible.
- Don't give a loading dose of dexmedetomidine (this may cause hemodynamic instability, particularly bradycardia).
- Avoid the use of high-dose, continuous dexmedetomidine infusions for more than ~3-5 days. Patients may develop tolerance and subsequent withdrawal.
- Avoid using higher dose propofol infusions for prolonged periods of time (e.g., >50 mcg/kg/min or >3 mg/kg/hr). Using high doses of propofol may lead to hypertriglyceridemia, necessitating its complete discontinuation.
- Avoid benzodiazepines whenever possible.
Guide to emoji hyperlinks
- = Link to online calculator.
- = Link to Medscape monograph about a drug.
- = Link to IBCC section about a drug.
- = Link to IBCC section covering that topic.
- = Link to FOAMed site with related information.
- = Link to supplemental media.
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