PulmCrit: MidaKet for procedural sedation in critical illness

intro: the challenge of procedural sedation in critical illness

Procedural sedation for critically ill patients is a minefield for several reasons:

Patients are already physiologically unstable.
Procedures are emergent (a factor widely associated with greater complications).
Time constraints often prevent a complete pre-anesthetic evaluation (e.g., medical history and laboratory studies may be unknown).
A single operator may be required to perform the procedure and simultaneously administer anesthesia.
End tidal CO2 monitoring is often unavailable or impossible (e.g., due to the use of high-flow nasal cannula).

To overcome these challenges, different sedation strategies are required. For example, propofol sedation is terrific when meticulously applied to stable patients in a controlled setting. However, propofol administration in the context of a critically ill patient with cardiopulmonary instability can easily go sideways.

The safest sedation strategy will be built upon the safest component medications. When considering medications that provide hemodynamic stability with little respiratory suppression, three are notable: ketamine, benzodiazepines, and butyrophenones (haloperidol and droperidol). Among benzodiazepines, midazolam is generally most desirable based on its rapid onset and short half-life (yeah, remimazolam would probably be superior but it's not widely available). So, this leaves us with ketamine, midazolam, and haloperidol/droperidol. Midazolam and ketamine work really well together and have a long track record for procedural sedation – so they're the basis of the MidaKet strategy.

Without further ado, let's describe exactly what we're talking about:

definition of the MidaKet sedoanalgesia strategy

MidaKet refers specifically to the following strategy:

(Phase #1) Titrate midazolam to achieve moderate sedation:

Start with a ~3-5 mg IV bolus.
Administer additional doses of 2 mg IV q2-4 minutes.
Titrate until the patient is sleeping and doesn't fully wake up following stimulation (although this target level of sedation will vary depending on the procedure and requires expert judgement).
The cumulative dose required is typically ~0.1 mg/kg but may range between ~0.05 – 0.15 mg/kg (~5-10 mg).

(Phase #2) Add ketamine to deepen sedation:

Start with ~50 mg IV ketamine.
If needed, provide additional ~25-50 mg IV ketamine q2 minutes.
Titrate to achieve the appropriate depth of sedation for the procedure.
The cumulative dose required is often ~50-100 mg.

(Phase #3) Maintain adequate sedoanalgesia during the procedure:

If the patient arouses during the procedure, administer additional doses of ketamine (25-50 mg q2 minutes PRN). Ketamine is the backbone of sedation maintenance, because it has a very rapid onset with no real risk of overdose.
The addition of small doses of midazolam may occasionally be useful for longer procedures (to prevent midazolam from wearing off). For example, 1-2 mg of midazolam could be given q5 minutes PRN if there is difficulty maintaining adequate sedation.

Midazolam titration needs to be more gradual to avoid dose stacking. Patient sensitivity to midazolam is unpredictable, so dose-titration is an exercise in empiricism. Usually only a few doses are required, so this phase isn't too long. Subsequently, ketamine doses can be given more rapidly because ketamine has a fast onset and there is less concern regarding overdosing on ketamine (you can't “over-dissociate” the patient). Overall, both phases #1-2 can usually be accomplished in a reasonably short time period (<10 minutes). Giving the initial doses of midazolam early (while you're setting up your equipment) can avoid long delays while waiting to achieve an adequate level of sedation.

examples of where MidaKet may be useful

MidaKet may be useful for nonintubated patients undergoing significantly uncomfortable procedures. (For intubated patients, there is a very broad range of safe sedation strategies, so sedation usually isn't very challenging.)

Some examples include:

Gastrointestinal endoscopy.
Chest tube insertion.
Cardioversion in midazolam-resistant patients (deep midazolam sedation alone is sufficient for most patients, as discussed further here: 📖).
(Note: for bronchoscopy, midazolam/fentanyl is probably superior due to reduced risk of laryngospasm and superior suppression of cough. However, midazolam-ketamine has been used successfully for bronchoscopy.) (24976998)

rationale for MidaKet

Midazolam and ketamine work well together:

Midazolam may reduce several problems encountered with ketamine:
- Midazolam prevents psychomimetic side effects of ketamine (e.g., agitation). (30611640)
- Midazolam's antiemetic activity may reduce nausea/vomiting due to ketamine. (24825990)
- Midazolam may counteract hypertension, hypersalivation, and increased excitatory effects of ketamine (tremors, involuntary movements, muscle contractions). (24825990, 15497296, 14569435)
Ketamine can be used to treat paradoxical agitation from midazolam. 🌊
Midazolam and ketamine have additive sedative effects (enhancement of the GABA neurotransmitters and inhibition of NMDA neurotransmitters facilitates balanced and potent sedation). (15497296, 8267198)

Advantages of MidaKet as compared to midazolam monotherapy:

Ketamine adds analgesia.
Ketamine allows for achievement of a deeper plane of anesthesia (full dissociation).
Ketamine can be redosed rapidly in a safe fashion (because ketamine takes effect rapidly and there is a reduced risk of overdose given the flat shape of ketamine's dose-response curve). This allows for achievement of target sedation promptly. In contrast, midazolam doses need to be spaced out farther in order to avoid dose stacking – so using midazolam monotherapy may take longer to reach the target level of sedation. The ability to redose ketamine rapidly and safely is especially useful if sedation starts wearing off during a procedure.

Advantages of MidaKet as compared to ketamine monotherapy include:

Midazolam reduces the rate of numerous side effects from ketamine, as discussed above (especially agitation during both induction and reemergence).
Midazolam achieves rapid anterograde amnesia (if the patient has some disturbing dreams due to the ketamine, these won't be remembered).
Midazolam synergy allows for lower doses of ketamine to be utilized (e.g., often ~50-75 mg rather than ~150-200 mg). (15497296, 8267198) The use of lower ketamine doses may decrease the rate of ketamine-related side effects (e.g., emesis, prolonged recovery period).
Midazolam synergy with ketamine avoids problems with ketamine refractoriness (discussed in detail here).

Advantages of MidaKet as compared to midazolam plus fentanyl:

MidaKet may be used to achieve a deeper plane of anesthesia, if desired (e.g., full dissociation).
Ketamine doesn't suppress the respiratory drive (whereas fentanyl does). Studies comparing midazolam/ketamine versus midazolam/fentanyl have demonstrated less desaturation with midazolam/ketamine. (22944555)

how MidaKet is different from many studies utilizing midazolam and ketamine

The combination of midazolam and ketamine isn't anything new. Studies have reported success using this combination dating back for decades. However, there are some features of MidaKet that may be especially useful:

[#1] Combined efficacy driven by midazolam and ketamine

Most studies combining midazolam and ketamine have used relatively small doses of midazolam (e.g., 0.02-0.05 mg/kg) combined with a large dissociative dose of ketamine (e.g., 2 mg/kg). In this scenario, the ketamine is doing most of the heavy lifting. A small dose of midazolam will help avoid reemergence agitation. So this strategy represents a minor improvement upon ketamine monotherapy.

MidaKet involves dose-titration of midazolam to achieve moderate sedation (with more substantial midazolam doses, often ~0.1 mg/kg), followed by moderate doses of ketamine (frequently ~0.5-1 mg/kg). The overall goal is balanced sedation that is a true hybrid of GABA receptor activation and NMDA receptor inhibition.

This balance is based on the concept of multimodal sedoanalgesia, wherein multiple agents are utilized at moderate doses to achieve high potency with minimal toxicity. Using lower doses of ketamine may avoid ketamine-related side effects.

[#2] Titration of midazolam and ketamine to effect

Most studies involving midazolam and ketamine have involved fixed medication doses. In some cases, the absolute dose of medication was fixed (e.g., 5 mg midazolam). More often, fixed weight-based doses were utilized (e.g., 0.1 mg/kg midazolam).

Individual patient sensitivity to midazolam and ketamine varies enormously, depending on factors such as age and alcoholism. It's impossible for any fixed dose of medication to be optimal for all comers. Consequently, any fixed-dose protocol will overdose some patients while underdosing other patients.

Dose titration does take a little extra time (although this can be minimized by starting to give doses of midazolam while finishing your procedural setup). However, clinical dose titration is quite simply the only way to achieve a uniform biological effect of the drug.

Skipping dose titration for ketamine is more justifiable than for midazolam. Ketamine has a flat dose-response curve, because it's impossible to over-dissociate someone. Therefore, giving a huge dose of ketamine is safe. However, using unnecessarily large doses of ketamine will increase side effects (e.g., vomiting). Thus, taking a few extra minutes to titrate the ketamine dose may pay off later when the patient wakes up promptly and comfortably. Since ketamine acts very rapidly, it can be given frequently to accelerate dose-titration.

Midazolam and ketamine are both hemodynamically stable agents that cause relatively little respiratory suppression.
A balanced combination of midazolam and ketamine may achieve synergistic sedation, while avoiding side effects that could result from higher doses of either agent.
Slower initial dose titration with midazolam followed by rapid dose titration of ketamine allows for a safe, individualized, and prompt achievement of the desired level of sedoanalgesia.
Compared to ketamine monotherapy, advantages of MidaKet may include reduced agitation, reduced emesis, superior anterograde amnesia, and superior patient satisfaction.

references

8267198 Hong W, Short TG, Hui TW. Hypnotic and anesthetic interactions between ketamine and midazolam in female patients. Anesthesiology. 1993 Dec;79(6):1227-32. doi: 10.1097/00000542-199312000-00013
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