You’re cardioverting an otherwise healthy 100 kg 48 year old man with lone afib. Since cardioversion is a brief procedure, you decide on a smaller than usual dose of ketamine, 50 mg.  You push the ketamine and prepare the defibrillator. The patient develops a far off stare, seems like a good time to shock, and you’re about to do just that, when he starts screaming at the top of his lungs I’M DYING!! I’M DYING!! I CAN’T SEE ANYTHING!! HELP ME!! You try to reassure the patient but he seems unable to hear you, and is now shrieking with great emotion that his body has disappeared. Nearby patients and staff are visibly disturbed and your med student started to cry, then fled. What’s going on? How do you manage this distressing situation and prevent it from happening again?

 

Ketamine was developed in the 1960s in a successful effort to synthesize a dissociative anesthetic that didn’t make people as crazy as phencyclidine, PCP, which was developed in the 20s. Its effect on cognition is attributed to antagonism at the NMDA receptor; this action interferes with the transmission of information that starts outside the brain from getting into the brain. In high doses, NMDA antagonism leads to dissociation, a cataplectic state where the patient maintains airway reflexes and cardiorespiratory function but cannot perceive any external stimuli nor interact with the world in any way.

The ability of ketamine to produce dissociation is of great value to clinicians who perform painful procedures, and this practice is firmly entrenched in pediatric emergency practice. In the past decade, ketamine has seen an expanded role in general emergency medicine for a variety of indications, especially as mythical contraindications around intracranial pressure, intraocular pressure, and psychiatric disease have been debunked [1 2 3 4 5 6 7]. However, adults who receive ketamine are more likely than kids to develop emotional distress, which makes some providers reluctant to use ketamine in patients they cannot lift with one hand. This reluctance is unwarranted and, given the efficacy and safety advantages of ketamine over other agents for procedural sedation, not considering ketamine is suboptimal care. Understanding the effects of ketamine on the brain empowers you to use it fearlessly, even recklessly, to the benefit of your patients of all ages.

Analgesic dose (0.1-0.3 mg/kg) ketamine has minimal effect on perception or emotion but is a powerful analgesic. I use analgesic dose ketamine as a second line agent when opiates aren’t getting the job done or are poorly tolerated, or in cases when I don’t want to use opiates, for example the patient with concerning hypotension, or the patient with chronic pain whom I can’t discharge (although I prefer droperidol for this purpose). In a normal sized adult, a 10 mg bolus will usually have minimal psychiatric effect but may not have an adequate analgesic effect; a 20 mg bolus will usually produce terrific analgesia but many patients will slide into recreational dose and get loopy. You can get less recreation with equal analgesia by setting up a drip–pushing ketamine accentuates its effects on awareness. Using a drip also provides continuous therapy, whereas push-dose ketamine lasts only 15-20 minutes. In this dose range, ABCs are not a concern and patients do not require monitoring.

Recreational dose (0.2-0.5 mg/kg) ketamine will deliver excellent analgesia but also make your patient high. Patients will have distortions of perception that most will like (indeed ketamine is commonly used without physician supervision for this purpose), others will dislike, but at recreational dose, patients know what’s going on, they know where they are, they know who they are. Patients can converse with you and follow commands, but they are hallucinating and stoned. Few patients will require intervention for psychiatric discomfort and many will be disappointed that the effect is wearing off. An agitated patient will often become sedated in this range, but the effect on level of arousal is variable.

Partially dissociated dose (0.4-0.8 mg/kg) ketamine leaves enough synapses properly wired so that patients have some awareness and can make some purposeful actions but not enough to allow patients to be connected to the outside world, their bodies, or reality. Many will be unable see or hear, talk or move; these capabilities may fade in and out. Although most will tolerate this well, some will find it terrifying–partially dissociated is where you want your patients not to be.

Dissociative dose (>0.7 mg/kg) ketamine renders the patient isolated from all external stimuli, which is the desired state in most cases where ketamine is used to facilitate a procedure or endotracheal intubation. A dissociated patient perceives no sights, sounds or pain and cannot interact. Though nystagmus, random and reflexive movements are common, dissociated patients are incapable of volitional action. Unlike with conventional sedatives, the brain is on and patients are awake, cardiorespiratory function is preserved or stimulated, but the dissociated brain is unaware and does not build memories; patients generally do not recall this period. Dissociated is awake but unconscious.

The four stages of the ketamine brain continuum have overlapping dose ranges that are highly variable among patients. At small analgesic dose (<0.1 mg/kg) or large dissociative dose (>2 mg/kg), effects are consistent; anything in between is unpredictable. A feature of ketamine’s dose-response that accounts for its remarkable margin of safety is the dissociation threshold, above which higher doses do not produce any further effect: a dissociated patient does not become more dissociated with more ketamine, higher doses only prolong duration of action.

You can skip the analgesic, recreational and partially dissociated phases of the continuum and deliver immediate dissociation with an ample dose, however, you cannot avoid the patient traversing back through these phases as brain levels more slowly fall and the patient emerges from dissociation. This is why psychiatric distress–emergence phenomenon–is generally observed as the patient emerges from dissociation and starts to reintegrate external stimuli while passing through the partially dissociated phase of the spectrum.

Managing psychiatric distress caused by ketamine is straightforward and much less dangerous than managing the cardiorespiratory adverse events seen routinely with conventional sedatives. If the patient develops distress shortly after an initial dose, the patient is not fully dissociated and the best maneuver is usually to give more ketamine. More commonly, the patient develops distress on emergence, after the procedure is over; the mind is activated but disconnected. You can’t reconnect the mind, but you can deactivate the mind with a sedative such as midazolam or propofol while it metabolizes through partial dissociation.

The incidence of emergence reactions can be greatly reduced by pre-induction comfort (aggressive analgesia prior to the procedure if the patient is in pain) and pre-induction coaching (explaining to the patient that they will have vivid dreams; that they should choose a pleasurable destination for their ketamine trip). I describe these strategies in more detail here and here.

A patient who can hear and talk to you but is still tripping and anxious can often be reassured: “Mr. Lee, you’re in the emergency room because you broke your ankle. We gave you a drug that makes you feel weird and just fixed the ankle and everything went great. In a few minutes you’re going to be feeling like your normal self.” However, verbal reassurance to a partially dissociated patient is useless; reassure with midazolam or propofol, or push the patient back into full dissociation with more ketamine.

 

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Update: Egg and soy allergy is NOT a contraindication to propofol.

Update: ACEP’s procedural sedation clinical policy stipulates “Do not delay procedural sedation in adults or pediatrics in the ED based on fasting time. Preprocedural fasting for any duration has not demonstrated a reduction in the risk of emesis or aspiration when administering procedural sedation and analgesia.” See the harms of fasting.

Dexmedetomidine (trade name Precedex) is an alpha-2 receptor agonist, similar to clonidine. Whereas clonidine provides a robust decrease in blood pressure with mild sedation, dexmedetomidine provides robust sedation with a mild decrease in blood pressure. It does not depress airway reflexes or respiration. It has a variety of potential uses in the emergency department, including procedural sedation, the facilitation of awake intubation or noninvasive ventilation, and the treatment of alcohol withdrawal. For these indications, however, we have agents that are at least as good, familiar, and a hell of a lot cheaper.

Sedation for painless procedures in children is the scenario that may push dexmedetomidine into the emergency physician’s toolkit. Kids who require sedation for CT or MR imaging would ideally be managed without placing an IV (nix etomidate), using an agent that does not cause significant cardiorespiratory depression (nix barbiturates), is otherwise safe (nix chloral hydrate, which is also unpredictable, untitratable, and lasts forever), and reliably causes kids to be still (nix ketamine).

This case series reports on 65 consecutive children sedated for CT or MRI with intramuscular dexmedetomidine, administered either once or twice at a dose of 1-4 mcg/kg, the exact dose left to provider discretion, to achieve a target Ramsay score of 4 (asleep but briskly responsive to a light stimulus). 4 patients out of 65 required a second IM dose to achieve a Ramsay score of 4. Once Ramsay 4 was achieved, no other agents were given for the duration of the procedure. The mean dose was about 2.5 mcg/kg.

All 65 children successfully completed the study. Though 9 out of 65 patients developed transient hypotension, there were no adverse events that required intervention. 65 patients is not enough to conclusively demonstrate safety, but 100% efficacy is hard to beat, and I suspect the safety profile will stand up in larger series.

Average time to sedation was 13 minutes. The average time from the end of the study to recovery was 22 minutes in the MRI group and 17 minutes in the CT group, with wide confidence intervals, i.e. there was no difference in recovery times. Since MRI is significantly longer than CT, and no sedatives were administered after the initial dose, how can this be?

Dexmedetomidine causes a different type of sedation than what we’re used to. It’s not a CNS depressant in the typical sense, it’s a powerful sympatholytic. Patients sedated with with dexmedetomidine will wake up with minimal stimulation, but when that stimulation is removed, they gently drift off to sleep. This is not a useful feature when trying to facilitate awake intubation, but it’s perfect for getting a 3 year old through the CT scanner.

 

Mason KP, Lubisch NB, Robinson F, Roskos R. Intramuscular dexmedetomidine sedation for pediatric MRI and CT. American Journal of Roentgenology 2011 Sep;197(3):720-5.

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Designed to be used as one double-sided page.

Available in pdf form.

If you’d like to modify the checklist for your institution, I can send you the original layout (omnigraffle format) and tables (excel format).

In this month’s Annals of Emergency Medicine, Sener et al report on their nicely blinded study where 182 adult subjects were randomized to one of four groups – IV or IM ketamine (at dissociative doses), with or without IV midazolam (.03 mg/kg). They conclude that midazolam reduces the incidence of recovery agitation based on their results:

Green and Krauss provide an accompanying editorial where they caution that the treatment effect as reported by Sener might be exaggerated and conclude:

“Given this compelling evidence from Sener et al, many clinicians will choose to ‘tame’ ketamine in adults by routinely coadministering midazolam. Others, according to the caveats above, will just as reasonably elect to individualize such prophylaxis, using a subjective assessment of a given patient’s risk. After all, should their prediction fail and an unpleasant reaction result, it can readily be quelled with midazolam. Regardless of these approaches, the ketamine ‘tiger’ may not be as ferocious as some fear.”

In my 2008 catalog of ketamine adverse events in adults, I describe three strategies for dosing midazolam–predissociation, preemergence, and PRN. I use the PRN strategy, and in hundreds of sedations of adults, I’ve needed to use it once. Here is my accumulated wisdom on how to use ketamine.

* Use ketamine. No other agent matches its safety, efficacy, and reliability. The only patients who should not receive ketamine are patients in whom an increase in heart rate or blood pressure would really concern you. All the other variously reported contraindications, including oral procedures and especially the concerns around ICP (this is more of an issue for RSI than PSA), can be ignored*. For very quick procedures like cardioversion, propofol is probably a better choice. Propofol also provides better muscle relaxation for ortho procedures, but these procedures often take a while, and propofol is hard to use for longer procedures. Ketofol is sexy but really offers no advantage over propofol alone for very brief procedures or ketamine alone for longer procedures.

* Be prepared to intubate. This goes for all PSA agents and procedures. Full intubation setup, paralytic in vial. In PSA, airway and breathing are everything; have all your tools ready. Laryngospasm is rare but it happens – if you’re ready for it, it’s no big deal, if not, it’s a big deal.

* Use it IM in pediatrics. Starting an IV for ketamine PSA in a child who is already suffering some other painful condition is unnecessary and therefore cruel. The best approach is to immediately treat the painful condition with atomized intranasal fentanyl, get your xrays or whatever, then give IM ketamine, 4 mg/kg. Once dissociated, you can start an IV easily and painlessly, or you can skip the IV completely and do your procedure.

* Make the patient comfortable before ketamine PSA. The response to ketamine is largely emotional. When the patient goes down agitated and in pain, she is more likely to have bad dreams and a scary emergence.

* Coach the patient pre-induction. Tell your patients that you are giving them a drug that will make them have vivid dreams, but that they can choose their dream and it can be very enjoyable, and that when they wake up, their wrist is going to feel a lot better. Offer some suggestions as you’re pushing the drug; I like describing a pleasant beach scene.

* Give them a dose of ondansetron before or during PSA. Ketamine causes post-procedure nausea and vomiting frequently. There is no literature evaluating this strategy, but in my opinion zofran works, and my opinion matters. To me.

* If giving ketamine IV, give it over 60 seconds. If you give IV ketamine in a quick bolus, you will often see apnea. This resolves by itself, but it’s really hard to watch a patient not breathing for 30 seconds. Slowing the infusion makes apnea much less likely. In order to give a slow infusion, you have to

* Either dilute the ketamine or draw it into a very small syringe. Most EDs stock 50 mg/ml and 100 mg/ml preparations (some EDs stock more than one concentration – be careful). You cannot slowly give 2 cc in a 10 cc syringe.

* Have the midazolam ready and don’t hesitate to use it if the patient appears to be experiencing psychological distress. You will rarely need it if you follow the steps above, but I’ve read some firsthand reports of bad ketamine emergence reactions and they sound truly terrifying. However, the fear of an emergence reaction is a silly reason to avoid using ketamine. Unlike the adverse reactions associated with most other PSA agents, emergence reactions are not dangerous, and are very easily treatable.

* You don’t always need to use a full dissociative dose. 1-2 mg/kg IV causes dissociation; once you’re dissociated you can’t be any further dissociated and larger doses just prolong duration of action (which can be a good thing, e.g. an intubated, hypotensive but still thrashing about patient). For a quick, only moderately painful procedure, 20 mg boluses work great. The ketamine continuum starts with analgesia (note the analgesic dose ketamine drip), to loopy (giggling, responding to questions and tolerating pain), to partly dissociated (sort of responsive to questions but indifferent to pain) to fully dissociated (awake but unresponsive to any external stimuli). That said, don’t hesitate to give a full dissociative dose if you’re not in the mood to get fancy. Dissociated is da bomb.

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Sener S et al. Ketamine With and Without Midazolam for Emergency Department Sedation in Adults: A Randomized Controlled Trial. Ann Emerg Med. 2011;57:109.

Green S and Krauss B. The Taming of Ketamine— 40 Years Later. Ann Emerg Med. 2011;57:115.

Strayer RJ and Nelson LS. Adverse events associated with ketamine for procedural sedation in adults. American Journal of Emergency Medicine, Volume 26 Issue 9, November 2008, pages 985-1028.

* Here are the contraindications as reported in the 2011 ACEP Clinical Policy.
Absolute: Age less than 3 months; schizophrenia.
Relative: “Major” procedures stimulating the posterior pharynx; history of airway instability, tracheal surgery, or tracheal stenosis; active pulmonary infection or disease including URI or asthma; known or suspected cardiovascular disease; CNS masses, abnormalities, or hydrocephalus; glaucoma or acute globe injury; porphyria, thyroid disorder, or thyroid medication.

From his PaACEP resident lecture. For children who are undergoing painless imaging studies and would not otherwise require an IV.

Dose: 25 mg/kg

Typically comes in powder form for IV use, one vial = 500 mg.

Directions suggest that you reconstitute with 50 cc NaCl, which would = 10 mg/cc.

Chudnofsky method is to reconstitute with 5 cc NaCl, mix well to get all powder into solution, now you have 100 mg/cc.

Attach to syringe an 18g angiocath without needle.

Insert into rectum, not very far (1-2 cm in small child), inject slowly to keep fluid in rectum.

Close the buttocks together, hold with 3 inch cloth tape.

According to his study (PMID 10790471), average time to sedation = 7 minutes, average time to awake = 60 minutes. Note that of 100 patients, “Six had brief oxygen desaturations that responded to repositioning, although 3 of these also were given brief bag-valve- mask ventilation per institutional protocol. One developed a continuous cough. All had complete recovery and none required intubation.” So these patients have to be on a pulse oximeter and someone has to be ready to adjust airway, provide O2, and BMV as needed. I would round down the dose to closer to 20 mg/kg.

Conscientious Sedation

Patients who scream usually get my attention and things go something like this. Bypassing the protocol on a technicality (narcotics alone without sedatives are not “conscious sedation”), I administer rapid boluses of fentanyl (150 to 200 mcg usually suffice in total). Within a minute or two, the patient enters the most euphoric experience of her recent memory, closing her eyes and beginning to smile. I signal the surgeon who starts the procedure while the patient lazily registers the discomfort, but when offered more pain medication claims “it’s OK.” I hang out in the room during the procedure, adding fentanyl if needed and catching up on paperwork. Meanwhile, content surgeons, who despite their hard shells do prefer a nonsuffering patient, wrap it up in style. When all is done, the patient looks at me with immeasurable gratitude, and I recall all the reasons for which I became a physician. My term for it: “conscientious sedation.”

It uses up ED attending time, but for all the right reasons. I start with half the intended final dose for the rare hyperresponder. There is naloxone in my pocket and I’ve never had to use it. I am ready to intubate should the need arise, but I doubt it will. I memorized side effects of fentanyl and consider risk-benefit beforehand. And yes, I think it is an adequate approach to procedural pain for most ED interventions on typical adult patients, especially when local anesthetics are appropriately used.

from: Veysman, Boris D. Annals of Emergency MedicineVolume 56, Issue 4, October 2010, Page 430

Photo: http://www.flickr.com/photos/fimbrethil/387068341

Needle-less procedural sedation / sedation for imaging:

“After extensive discussion with the patient’s parents and NICU staff, the PPM service recommended oral administration of intravenous ketamine (10 mg?mL, Monarch Pharmaceuticals) at a starting dose of 0.5 mg (0.125 mg?kg?dose). Over 4 days, the dose was titrated to 3 mg (0.75 mg ? kg ? dose) in response to observed effect. At 15 minutes after a dose of 3 mg of ketamine, the patient was able to tolerate her dressing change without crying or resisting for 45 minutes (Figs. 1 and 2). Her ability to feed afterward was preserved. No effects on depth or rate of respiration were noted.”

Saroyan et al, Pediatric Dermatology 26:6 Nov/Dec 2009 764-766.