https://emcrit.

org/ibcc/pain/

CONTENTS

Spectrum of medications available:

Pure analgesics
Acetaminophen
Ketamine, pain-dose ➡️
(Lidocaine)
(NSAIDs)
Analgosedatives (analgesia > sedation)
Opioids
Opioid PCA
Avoiding opioid infusions
Tizanidine
Gabapentinoids
Sedalgesics (sedation > analgesia)
Dexmedetomidine, Clonidine
Ketamine, high-dose infusion ➡️
Pure sedatives
Propofol ➡️
Guanfacine
Phenobarbital ➡️
Melatonin
(Benzodiazepines)
(Hydroxyzine)
Antipsychotics / anti-agitation
Butyrophenones (haloperidol & droperidol) ➡️
Olanzapine ➡️
Quetiapine ➡️
Chlorpromazine ➡️
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Lurasidone ➡️
Valproic acid ➡️
Underlying concepts & construction of regimens:
General concepts about analgesia:
Concept of multi-modal therapy
Targeting pain, anxiety, and agitated delirium
Designing an analgesic regimen
Designing a sedative regimen for an intubated patient
Daily sedation interruption?
Analgesia for patient on chronic buprenorphine ➡️
Podcast
Questions & discussion
Pitfalls

Paracetamol

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.
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Cetamina

dosing for status epilepticus

 Loading dose: Give successive boluses of 1-2 mg/kg every 5 minutes, up to a total of
~5 mg/kg cumulative dose.
 Maintenance infusion: The infusion dose range is 1-7.5 mg/kg/hr.(33896531,
34221552) Doses <1 mg/kg/hr do not appear to be effective.(33664203)
o Titrate based on EEG.
o For break-through seizures, may re-bolus with ketamine and increase the
infusion rate.
o The EEG pattern related to clinical efficacy with ketamine is heterogeneous.
Cessation of seizures may be a more appropriate therapeutic target than
burst-suppression.(33480193)

dosing: pain-dose ketamine infusions

 The typical dosing range is 0.1-0.3 mg/kg ketamine per hour (e.g., ~8-20 mg/hour).
However, guidelines suggest that doses up to 1 mg/kg/hour may be used, with close
monitoring for psychomimetic side effects.(29870457) 📄
o The combination of ketamine plus an alpha-2 agonist (dexmedetomidine,
clonidine, or guanfacine) or propofol appears to prevent the occurrence of
psychomimetic side effects.(15235947) This may allow higher doses of
ketamine to be given (e.g., ~0.5 mg/kg/hr).📖
 For most patients, it's useful to start at the lower end of this dosing range, and then
up-titrate the ketamine gradually over a period of hours as needed. Around
~0.25mg/kg/hr ketamine often starts to cause psychomimetic side effects (which may
vary, spanning the gamut of somnolence, agitation, euphoria, or hallucinations).
These effects are usually not problematic (e.g., mild sedation or euphoria). However,
some patients may experience disturbing hallucinations. If troublesome
psychomimetic side effects occur, then pause the ketamine infusion for an hour or
two and resume at a lower dose (a dose which didn't cause psychomimetic side
effects). Resuming ketamine at a lower dose can often still allow the patient to
receive substantial benefit from ketamine, without experiencing any side effects.
 If you're very worried about psychomimetic side effects, you could just leave the
infusion at a fixed rate of 0.12 mg/kg/hour. Several studies suggest that the risk of
psychomimetic effects at that dose is close to zero. (25530168, 15983467, 21676160)
This strategy might be reasonable in an intubated patient with baseline agitation,
where it may be difficult to determine whether the patient is experiencing
psychomimetic side effects.

dosing: intermittent ketamine boluses for pain

 Ketamine may be utilized for analgesia as intermittent doses given as needed (at a
dose of ~0.1-0.3 mg/kg, administered intravenously over 5-15 minutes). When using a
dose of 0.3 mg/kg, gradual infusion over 15 minutes reduces the incidence of
psychomimetic side effects.(28283340)
 A test dose may be used to assess how the patient responds to ketamine. If there is a
favorable response, this could support the rationale for setting up a pain-dose
ketamine infusion.
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dosing: complete dissociative analgosedation

 Ketamine is infused at a rate of 1-5 mg/kg/hour.

 The goal is complete dissociation.

contraindications & side effects

contraindications

 Dangerously uncontrolled hypertension (may be exacerbated by ketamine).

 Pregnancy (based on developmental delays in animal studies).(29870457)
 Severe hepatic dysfunction.
 Active psychosis or delirium is a relative contraindication to using doses above 0.1
mg/kg/hour (because it may be difficult to determine if the patient is suffering from
psychomimetic side-effects due to the ketamine).

side effects / problems

 Hypertension.
 Hypersalivation, increased bronchial secretions (which may be especially problematic
with a BiPAP mask interface).
 Psychomimetic effects (although usually not very harmful, there is a risk of causing
disturbing hallucinations).
 Ketamine has erratic effects on Bispectral index (BIS) monitoring, rendering this form
of monitoring less.

indications & advantages

general advantages of ketamine

 Hemodynamic stability (may cause a mild increase in blood pressure at higher doses).
 Does not suppress respiration (allowing ketamine to be used among intubated or
nonintubated patients).
 Causes bronchodilation.
 Exerts an antiseizure effect.
 Antidepressant effects could potentially mitigate post-ICU depressive symptoms.
 Ketamine may help prevent the development of tolerance to opioids and possibly to
dexmedetomidine.

use of ketamine in status epilepticus

 Overall and excellent and under-appreciated anti-epileptic agent. Ketamine is

emerging as a preferred agent to control super-refractory status epilepticus.
 Ketamine combines nicely with propofol, midazolam, or barbiturates (propofol,
midazolam, or barbiturates stimulates the GABA receptor, whereas ketamine inhibits
the NMDA-type glutamate receptors).
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 Advantages of ketamine for super-refractory status epilepticus, as compared to

barbiturate coma:
o Ketamine is more hemodynamically stable.
o Ketamine has a shorter half-life, providing more flexibility in adjusting the
infusion.
o Ketamine can be rapidly up-titrated to determine efficacy (and, if not working,
another agent may be used).
o NMDA-receptor antagonists often remain effective in ongoing status
epilepticus (whereas benzodiazepines, barbiturates, and phenytoin lose
potency over time as the seizure evolves).(33896531)

use of ketamine for pain

 Pain-dose ketamine infusions provide a mild to moderate level of analgesia (with

some variation between patients). This often isn't sufficient to control the pain
entirely, but it may provide a continuous basal level of analgesia with opioid-sparing
effects. (25530168) Increasing evidence supports the use of pain-dose ketamine
infusions among critically ill patients. (12933413, 26025196, 28468568)
 Pain-dose ketamine is extraordinarily safe (e.g., there is no risk of respiratory
suppression or hypotension).
 Ketamine may inhibit the development of tolerance to opioids and the emergence of
opioid induced hyperalgesia. (15983467, 16854557, 23269131, 14581110) Thus,
ketamine may mitigate some side effects of opioids.
 Ketamine exerts antidepressant effects, which may improve patient mood and
promote participation in rehabilitation. (26025196, 23428794, 16894061)
 One randomized controlled trial found that pain-dose ketamine infusions reduced the
risk of delirium. (30268528). This suggests that the possibility of psychomimetic side
effects doesn't imply a danger of more serious neurologic complications from
ketamine.

use of ketamine for complete dissociative analgosedation

 Complete dissociation with a high-dose ketamine infusion may rarely be used for
intubated patients, to provide both sedation and analgesia. This is useful in the
following situations:
o (1) Agitation refractory to other agents.
o (2) Severe hypotension prevents the use of other treatments (e.g., propofol
or dexmedetomidine).
o (3) Status asthmaticus.
 High-dose ketamine is a one-drug solution that treats both agitation and analgesia.
One of the benefits of dissociative ketamine is that other sedatives and analgesics
(e.g., opioids) can be stopped. This will avoid tolerance and subsequent withdrawal
symptoms.

pharmacology, mechanism of action

 Ketamine functions as an NMDA-receptor antagonist.

o At very low doses, ketamine provides analgesia without other neurologic
effects.
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o At higher doses, ketamine has anti-seizure effects and dissociative effects.

 Half-life of 2-3 hours.(33480193)
 Hepatic metabolism, with no dose adjustment in renal failure. Consider dose
reduction in hepatic impairment

Lidocaína

 (1) Initial loading dose

o ~1.5 mg/kg infusion over 10-30 minutes (may use 1-2 mg/kg).
 (2) Continuous infusion at a low, fixed rate
o ~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.
o 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.
o 🛑 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).
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(4026487)
o 🛑 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?
o 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)
o 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:
o Cardiac: Bradycardia, QRS widening, sinus node suppression
o Neurologic: Delirium, tremor, visual disturbances, numbness/tingling,
metallic taste, tinnitus, seizure.
o Gastrointestinal: Nausea and vomiting
o 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:
o Medications involving CYP1A2 or CYP3A4 systems – check for
interactions using an electronic tool (e.g., the MedScape drug interaction
tool here.)
o Other class I antiarrhythmics (including phenytoin)(26335213)

indications/evidence

 Lidocaine is a type Ib antiarrhythmic and also an amide local anesthetic. It

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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.
o Initially, lidocaine has a half-life of 7-30 minutes, as drug distributes into
body tissues.
o 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

Ketorolac / parcoxibe

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:
o (1) The patient is on no other nephrotoxic medications.
o (2) The patient has excellent and stable renal function (i.e., good urine
output and creatinine values).
o (3) There are no sources of hemodynamic instability or impaired
perfusion.
o (4) Absence of cirrhosis or inflammatory bowel disease.
o (5) No history of GI ulceration/bleeding.
o (6) No active hemorrhage or severe coagulopathy (especially, no platelet
dysfunction).

selection and dosing

 Different NSAIDs seem to have similar safety and efficacy. However,

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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:
o Ketorolac: 10 mg IV Q6hr PRN 💊
o Ibuprofen: 400 mg PO q6hr PRN 💊 (31383385)
 🛑 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.

Opioides
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 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.
o 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

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o Opioids suppress the respiratory drive relatively potently. Unfortunately, even

with chronic use, this effect remains strong.
o 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).
o Among intubated patients, respiratory suppression can be beneficial by
facilitating ventilator synchrony. However, persistent respiratory suppression
may delay extubation.
 (2) Gastrointestinal failure
o 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
o 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.
o 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.
 (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
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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.
o If the patient has severe, uncontrolled pain, then this should be treated
immediately by clinician-titrated boluses of opioid.
o 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.
o 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)
o Basal rates should be used only for patients who are on chronic opioids.
o 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
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patient appropriately.

(Avoid) 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:

1. Avoid infusions whenever possible (favoring a bolus-only strategy, even if that

involves using relatively generous opioid boluses).
2. 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.
3. Aggressively wean down the infusion at least once daily (but optimally more often).
4. 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.
5. 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.
6. 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:

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1. 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.
2. For patients on chronic opioids prior to admission, some basal amount of opioid may
be necessary to prevent withdrawal.

Gabapentina

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)

o Guillain-Barre Syndrome.
o Diabetic neuropathy.
o Spinal cord injury.
o Post-herpetic neuralgia.
o 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.

Alfa-2 agonistas
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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:
o (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.
o (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).
o (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.
o (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
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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.

Dexmedetomidine is a titratable IV agent, which makes it useful for more acutely ill patients
(who may require rapid up- and down-titrations).
 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.

Dexmedetomidina

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:
o Decreasing dexmedetomidine during the day may help avoid tolerance and
withdrawal.
o 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):

o Dexmedetomidine may cause bradycardia and hypotension (especially when
bolused).
o Dexmedetomidine is contraindicated in patients with heart block,
bradycardia, or severe hypotension. (However, this property can occasionally
be useful in patients with tachycardia.)
o 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).
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 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:
o 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).
o Titratable infusion, which can be discontinued easily.
o Patients often remain arousable while on dexmedetomidine (so this may be
used in situations requiring frequent neurologic examinations).
 Use:
o Sedation of patients who aren't intubated (e.g., BiPAP).
o Management of nocturnal agitation (may promote physiological sleep and
reduce delirium).(29498534)
o 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.

Clonidina

dosing 💊

 Before initiation, review the medication list and consider discontinuation of any beta-
blockers or other antihypertensive agents.
 Sedation:
o De novo: Start 0.1-0.2 mg q6hr, may up-titrate to 0.5 mg q6hr if needed.
(25809176, 25561923)
o Transition from dexmedetomidine: Start 0.2-0.3 mg q6hr, may up-titrate to
0.5 mg q6hr if needed.(25809176)
 Opioid withdrawal: Most studies have used up to ~0.6-1.2 mg/day in divided doses,
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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:
o Onset in ~1 hour, duration of action ~12 hours.
o 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

Benzodiazepinas

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.
o Midazolam: 2-5 mg IV q15-30 min PRN
o 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
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available options may include:

o Temazepam (half-life ~11 hours), ~15-60 mg QHS.
o Alprazolam (half-life ~12 hours), ~0.5-2 mg QHS.
o 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.
o 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:
o Sedative of choice for intoxication, especially with sympathomimetics (due to
muscle-relaxant and antiseizure properties).
o Patients with profound hypotension (who are too unstable to receive
propofol or dexmedetomidine). However, ketamine may be more useful in
this situation.
o 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.
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Hidroxizina

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.

Conceito de analgesia multimodal

 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:
o Propofol monotherapy may require using a high dose of propofol. This may
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eventually may cause hypertriglyceridemia or propofol infusion syndrome.

o 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).

designing a sedative regimen for an intubated patient

#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:
o Anticipated long duration of intubation.
o Seizures.
o Elevated intracranial pressure.
o Need for deep sedation to facilitate ventilator synchrony.
 Factors which could favor dexmedetomidine:
o Patient is approaching extubation.
o 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:
o (1) In some cases, these are required to achieve control of refractory
agitation.
o (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):
o These are commonly used, due to their relatively favorable side-effect
profiles.
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o They are most beneficial for patients with underlying agitated delirium.
 Phenobarbital:
o Phenobarbital is occasionally useful, especially for patients with alcoholism or
alcohol withdrawal.
 Oral alpha-2 agonists (clonidine, guanfacine).
o These may be considered in conjunction with propofol (if the patient is
already on dexmedetomidine, then these will probably not add much).
o Their greatest utility is in patients with tachycardia and hypertension (e.g.,
opioid withdrawal). Nocturnal administration may also promote sleep.
o These agents aren't particularly powerful – so don't expect them to control
refractory agitation.
 Valproate:
o This is generally reserved for refractory agitated delirium.
o 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.

Fenobarbital
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dosing & advantages 💊

status epilepticus

 Load: 15-20 mg/kg at 50-100 mg/min.(34221552) If still seizing, additional doses may
be added for cumulative total dose of 30 mg/kg.
o 15 mg/kg was used in the VA Cooperative trial, so this dose is supported by
evidence among patients who are not intubated. 📄 (9738086)
o May check a level 2 hours after the loading dose, to ensure an adequate level.
(Albin 2022)
 Maintenance: 1-3 mg/kg/day given daily or divided q12hr (e.g., 50-100 mg IV q12hr).
(33896531; 34300194, 34798964)
 Trough levels may be monitored to ensure appropriate dosing (more on this below).
 Advantages: Phenobarbital isn't typically a front-line antiseizure medication.
However, phenobarbital is effective and perhaps underutilized:
o Phenobarbital is arguably the preferred antiseizure medication for alcohol
withdrawal seizures.📖
o Phenobarbital is effective in refractory status epilepticus.(30159873) It is also
useful in super-refractory status epilepticus, to assist in weaning patients off a
pentobarbital coma.
o Phenobarbital (15 mg/kg) was found to be equally effective as compared to
lorazepam (0.1 mg/kg) as first-line therapy for status epilepticus in the VA-
Cooperative trial. Thus, phenobarbital may be more effective and better
tolerated than is commonly recognized. 📄 (9738086)

adjunctive sedative agent

 Loading dose:
o Typically, 10-15 mg/kg.
o May be provided as a single dose among intubated, hemodynamically stable
patients (although usually no more than 10 mg/kg).
o May be provided in multiple divided doses, if there are concerns regarding
hypotension or oversedation.
 Maintenance dose:
o 1-2 mg/kg PO or IV daily may be considered among patients on prolonged
mechanical ventilation.
o For patients on shorter-term ventilation (e.g., <1 week), maintenance doses
may not be needed.
 Therapeutic drug monitoring: For patients receiving maintenance doses of
phenobarbital, occasionally measuring levels might enhance safety. The optimal level
isn't well defined, but 15-25 ug/mL (64-107 uM/L) might be a reasonable target.
More on phenobarbital levels below.
 Use of phenobarbital as a sedative:
o Phenobarbital is occasionally useful as an adjunctive sedative agent for
intubated patients. It is especially useful for patients with alcoholism or very
high propofol requirements. Phenobarbital may act synergistically with
propofol, thereby allowing lower propofol doses to be utilized (reducing the
risk of propofol infusion syndrome).
o Occasionally, phenobarbital may be useful to provide basal sedation in a non-
intubated and very difficult-to-sedate patient.
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o Be careful: Phenobarbital has a long half-life. If the patient is alternating

between hyperactive and hypoactive delirium, phenobarbital could promote
excessive sedation that could be long-lasting.

alcohol withdrawal

 Treatment of alcohol withdrawal: 📖

 Prevention of alcohol withdrawal: 📖

monitoring phenobarbital level

interpretation of phenobarbital trough levels

 Therapeutic range for epilepsy: 15-40 ug/mL (64-172 uM).

o However, some authors recommend targeting 20-50 mg/L.(34798964)
 Mild toxicity (e.g., ataxia, nystagmus): >50 ug/mL (>215 uM).
 Severe toxicity can occur (e.g., stupor/coma): >65 ug/mL (>280 uM)

predicting phenobarbital level based on loading dose

Level = 1.5[Dose in mg/kg]

 For every 1 mg/kg of phenobarbital administered, the serum phenobarbital level will
rise by roughly ~1.5 mg/L (e.g., 10 mg/kg will increase the phenobarbital level by 15
mg/L).
 Phenobarbital has a very long half-life. Thus, if several doses are administered over a
short time frame (e.g., <24 hours), the phenobarbital level may be estimated with
reasonable accuracy.

when should levels be checked?

 Multiple doses of phenobarbital over time: The half-life of phenobarbital is variable,

so the steady-state phenobarbital level may be unpredictable.
 Morbid obesity:
o One study suggests that the phenobarbital may be dosed based on the
patient's actual body weight.(1587059) However, this isn't well validated.
o A reasonable approach may be to provide an initial dose based on an adjusted
body weight, followed by a phenobarbital level after 2 hours. A single level
will be sufficient to calculate the volume of distribution (so levels may only be
needed intermittently).
 Alcohol withdrawal: Checking levels is usually unnecessary, as long as the cumulative
dose of phenobarbital is maintained below 20 mg/kg. However, if the dosing history is
unclear then a phenobarbital level can be helpful.

contraindications and drug interactions

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contraindications & cautions:

1. Pregnancy.
2. Advanced cirrhosis: Patients with borderline hepatic encephalopathy are at high risk
of oversedation. Phenobarbital should generally be avoided in any patient with a
history of hepatic encephalopathy. If phenobarbital is utilized in a patient with hepatic
dysfunction, it should be dose-reduced.
3. Drug interaction with an essential medication that isn't easily dose-adjusted (more on
this below).
4. Acute intermittent porphyria.
5. Prior chronic phenobarbital use, or prior phenobarbital loading: This isn't a
contraindication to using phenobarbital, but be careful about giving a loading dose to
someone who already has a therapeutic level.
6. Patient has received sedating medications (especially benzodiazepine): Phenobarbital
will function synergistically with benzodiazepines, which could promote excessive
sedation. This isn't an absolute contraindication; phenobarbital may often be used
safely by giving smaller, divided doses.
7. Multiple active neurological problems. This is a relative contraindication. For patients
with fluctuating levels of consciousness, there is an increased risk that phenobarbital
could lead to over-sedation (when combined with a deterioration in the underlying
neurologic status).

drug interactions

 Phenobarbital is an inducer of CYP 2B6, 2C9, and 3A4, which may lead to inadequate
levels of medications metabolized by these pathways.(33176370) It may be
necessary to adjust the dose of other medications that the patient is on (e.g.,
phenytoin and valproate). However, CYP enzyme induction may be less problematic if
only phenobarbital loading is utilized, without ongoing chronic therapy.(32794143)
 Notable medications metabolized by these enzymes include the following:
o Antivirals (e.g., efavirenz, nevirapine, ritonavir, velpatasvir)
o Antidepressants (amitriptyline, bupropion, buspirone, citalopram,
escitalopram, fluoxetine, venlafaxine).
o Antipsychotics (aripiprazole, haloperidol, quetiapine, risperidone,
ziprasidone).
o Azole antifungals (voriconazole, isavuconazole).
o Gastrointestinal (proton pump inhibitors, ondansetron).
o Immunosuppressive (cyclosporine, dexamethasone, hydrocortisone,
sirolimus, ruxolitinib, tacrolimus, tofacitinib).
o Neurologics (carbamazepine, clobazam, doxepin, methadone, phenytoin,
selegiline, trazodone, valproic acid).
o Cardiovascular (amlodipine, apixaban, cilostazol, clopidogrel, diltiazem,
eplerenone, irbesartan, ivabradine, lidocaine, losartan, nifedipine,
nimodopine, rivaroxaban, torsemide, ticagrelor, warfarin).
o Oncologics (e.g., capecitabine, crizotinib, cyclophosphamide, sorafenib,
tamoxifen).
 Phenobarbital is metabolized by CYP2C9 and 2C19, which may lead to drug-drug
interactions. For example:
o Phenytoin may reduce phenobarbital metabolism (due to competition for
hepatic metabolism).
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Valproate may reduce phenobarbital metabolism; consider reducing the

o
phenobarbital dose by 50%.(Torbey, 2019)
 When in doubt, check for interactions using the Medscape Drug Interaction Checker.
🌊

side effects

 Somnolence (long half-life may increase risk of prolonged sedation.)

 Respiratory suppression (although this is typically associated with much higher doses
of phenobarbital than 20 mg/kg).
 Hypotension.

pharmacology and mechanism of action

 Mechanism of action:
o Stimulates inhibitory GABA-A receptors.
o Inhibits AMPA-type glutamate receptors.
 Phenobarbital may be administered via IV, IM, or PO routes (all with ~100%
bioavailability).
 Phenobarbital is mostly metabolized in the liver (CYP2C9 > 2C19), but ~25% may be
excreted unchanged in urine.(30921021)
 The half life is typically ~80 hours, but may vary from ~50-140 hours.(Torbey, 2019)

Propofol
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dosing 💊

dosing for status epilepticus

 Load: 2 mg/kg IV bolus (up to 200 mg). May repeat q3-5 minutes if hemodynamically
tolerated, to a total dose of 10 mg/kg.
 Infuse: 30-200 mcg/kg/min. However, avoid >83 mcg/kg/min for prolonged periods of
time to reduce the risk of propofol infusion syndrome.
 💡 Consider early initiation of enteral nutrition to reduce the risk of propofol infusion
syndrome.(33480193)

dosing: sedative infusion for intubated patient

 Long-term use of high doses may cause propofol infusion syndrome. This may be
avoided by:
o (1) Using doses <<83 mcg/kg/min (<<5 mg/kg/hr).
o (2) Providing enteral nutrition.
o (3) Following triglyceride levels q48hr (discussed further below).
 Maintenance propofol infusions are ideally run at ~0-50 mcg/kg/min (0-3 mg/kg/hr).
Using higher doses increases the likelihood that propofol will increase the triglyceride
level and need to be discontinued entirely.

contraindications & adverse events

 Hypotension is a relative contraindication.

o This can generally be managed by combining propofol with a low-dose
vasopressor infusion (e.g., phenylephrine or norepinephrine), to
counterbalance vasodilation due to the propofol.
 Hypertriglyceridemia.
o Triglyceride levels should be monitored q48hr.
o If triglyceride levels are gradually creeping up, try reducing the propofol dose.
o If the triglyceride level is >500-800 mg/dL, propofol probably needs to be
stopped.(32844730) However, some institutions have recently started
tolerating triglyceride levels up to 1,000 mg/dL before stopping propofol.
(33068459)
 Propofol infusion syndrome.
 Pancreatitis.
 Bradycardia may occur occasionally.
 (Egg allergy is not a contraindication.)
 (Green urine due to propofol does not correlate with propofol infusion syndrome.
This is not an indication to stop the propofol.)

indications & advantages

propofol for status epilepticus:

 Preferred agent, easy to titrate.

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 If abruptly stopped, patients may have rebound seizure.

propofol for sedation:

 Propofol is a front-line sedative agent (alongside dexmedetomidine).

 Benefits of propofol:
o Rapid onset and offset, facilitating neurologic evaluation and extubation.
o Antiepileptic properties.
o Neuroprotective properties (including reduction of intracranial pressure).
o Does not seem to elicit tolerance or withdrawal. This may be useful among
patients who require long-term intubation.
o Suppresses respiration (which can be helpful among ventilated patients to
reduce ventilator dyssynchrony).

pharmacology, mechanism of action

 Mechanism of action: (34300194, 33480193)

o Stimulates inhibitory GABA receptors
o Inhibits NMDA receptors
o May reduce calcium influx through slow calcium channels.
 A more broad-based mechanism of action might explain why propofol retains potency
over time for seizures, whereas midazolam (which solely works via GABA receptors)
becomes less effective over time.
 Triglyceride levels should be monitored q48hr.

Midazolam

dosing 💊

 Load: 0.2 mg/kg. May repeat this q5-10 up to 2 mg/kg total dose.
 Infuse: 0.05-2 mg/kg/hr.

contraindications & drug interactions

 Use caution in obese patients and patients with renal insufficiency, who may
accumulate midazolam and clear it very slowly.(34221552)

side effects

 Delirium, drug accumulation leading to delayed extubation (although to a lesser

extent than pentobarbital).
 Hypotension may occur at higher doses.(34221552)

indications & general comments

 Widely available.
 Will hinder the ability to rapidly awaken and wean patients off ventilation. For most
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patients, propofol may be a preferred anesthetic since this preserves the ability to
awaken and re-evaluate patients neurologically.

pharmacology, mechanism of action

 Mechanism: Binds inhibitory GABA receptor, increases frequency of channel opening.

 Midazolam accumulates over time, causing the half-life to extend over time (context-
sensitive half-life).
 Midazolam is hepatically metabolized into an active metabolite (1-hydroxy-
midazolam), which is subsequently excreted by the kidneys. Consider dose reduction
in renal or hepatic impairment.(33896531)
 Ongoing use causes resistance (tachyphylaxis).

Tiopental

dosing 💊

 ⬟ Load: 5-15 mg/kg at 50 mg/min. May provide additional doses if seizures continue,
up to a maximal total loading dose of 25 mg/kg.
 ⬟ Infuse: Start at 1 mg/kg/hr, then titrate between 0.5-5 mg/kg/hr.(34300194)
Titrate based on EEG as described below.

contraindications & drug interactions

 Hemodynamic instability
 Porphyria
 Pentobarbital has numerous drug-drug interactions.

side effects

 Hypotension (patients will commonly require vasopressor support).

 Ileus (may progress to bowel pseudoobstruction and perforation).
 Ventilator-associated pneumonia (VAP).(34300194)
 Thrombocytopenia.
 Persistent coma (half-life is 15-60 hr!).
 Very sluggish agent to titrate; obligates patient to prolonged intubation and long ICU
stay.
 Propylene glycol toxicity may cause metabolic acidosis.

indications & comments

 ⬟ Last-line agent for super-refractory status epilepticus.

 ⬟ Pentobarbital is almost uniformly effective. However, the problem is that it has
many side-effects (including hypotension, propylene glycol toxicity) and an incredibly
sluggish half-life. Thus, putting a patient into a pentobarbital coma commits them to a
1-2 week ventilator course.
o Withdrawal of life-sustaining therapy subsequent to induction of a
pentobarbital coma is ethically questionable. Ideally, pentobarbital should be
reserved for patients who are committed to aggressive support. If families
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wish to trial a short course of intubation (e.g. 1-2 days), then a ketamine
infusion would be more appropriate.
o In a small RCT of propofol versus barbiturates, there was a similar rate of
seizure control, but patients treated with barbiturates had a substantially
longer duration of mechanical ventilation.(20878265)

pharmacology, mechanism of action

 Mechanism of action: Stimulates inhibitory GABA receptors, inhibits AMPA-type

glutamate receptors. This is important, because enhanced AMPA-receptor activity is
one mechanism involved in refractory status epilepticus.(35001380)
 Half life may vary between 15-50 hours, in a dose-dependent fashion.(Torbey 2019)
 Hepatic metabolism to inactive metabolites. Consider dose reduction in hepatic
impairment.(33896531) Inducer of CYP2A6, with auto-induction of its own
metabolism.(33176370)

monitoring

 (1) Continuous EEG monitoring is necessary for all patients undergoing pentobarbital
coma. If your center does not have continuous EEG monitoring, the patient will
require transfer to a center that does.
o Typically the infusion is titrated to achieve burst suppression.
o If the patient develops a completely flat EEG tracing, consider reducing the
dose or holding the infusion entirely.
 (2) Target serum level 10-20 ug/mL.(33176370) However, this is often a send-out
laboratory test, so it's not helpful for immediate dose titration.

Antipsicóticos em UCI

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