Wednesday, September 10, 2014

#3: What's the best way to relax?

Prepared by Michael. C Berrier, NRP, FP-C, C-NPT, AAS

Something that is never in short supply in medicine, especially acute and critical care medicine, is opinion. Even in the burgeoning age of evidence based practice, opinion and dogma still make up a surprising portion of what we do at the bedside. From this meld of evidence and anecdote flows a river of options in just about every procedure or treatment plan we have. Tubes: cuffed or uncuffed? Tourniquets: good or bad? Trauma resuscitation: Blood or fluid? Drink: Coke or Pepsi?  The choices are endless. But, many of these options have been proven, at least we think, good or bad.  Cuffed tubes for (almost) everyone, yay tourniquets and blood out needs blood in.  The drink question is beyond the scope of this article.  But so many other choices still exist, for good or for ill, and most of these are almost solely at the discretion of the provider.  One of these choices that folks in acute/critical care and transport make regularly is what combination of drugs they will use to carry out a rapid sequence induction and intubation (RSII).

The history: RSII provides for optimal intubation conditions by inducing a state of unconsciousness followed immediately by paralysis to minimize patient movement and, more importantly, allow free movement of the mandible to facilitate laryngoscopy and tracheal tube placement(1).  The originally stated purpose of the RSII as opposed to traditional general anesthesia was to secure the airway for patients in whom an NPO period could not be documented or confirmed. This was first used in cases of emergency obstetrics in 1946 (2) but quickly migrated to emergency departments and acute care areas and finally outside into EMS and CCT.  The choice of medications was traditionally dictated by anesthesiologists because they were the ones locally who controlled the medication and did the training.  This has relaxed quite a bit today so that physicians and mid-level providers can choose their cocktail in the hospital, while EMS and CCT medical directors dictate what their employees will use in the field and write protocols accordingly. Some of the most commonly used induction drugs for this procedure are etomidate and ketamine, while the most common drugs used for neuromuscular blockade are succinylcholine (sux) and rocuronium (roc). This review will be limited to these four drugs.

Science and evidence: When we consider the appropriateness of a medical intervention, we should always consider the efficacy, the utility and above all the safety of that intervention.  Fortunately, when it comes to the medications used for rapid sequence induction and intubation, there is a trove of evidence available about all three.

First, let's consider efficacy.  When we perform an induction, we ask our medications to do two simple things: make our patients sleep and relax.  In this department, all four of our drugs perform just about exactly as we want. 

Etomidate is a sedative hypnotic that depresses the reticular activating system (RAS), inhibiting excitatory stimulation at the GABA-receptor complex.  Or, more simply stated, it's the pharmacological equivalent of a right hook to the jaw...a knockout.  It produces a state of complete unconsciousness in as little as 15 seconds, maybe shorter in a hypermetabolic patient, and usually lasts less than 10 minutes(3).

  Ketamine exerts its effects on the GABA-receptor complex and opioid receptors, producing profound dissociative anesthesia and analgesia in about 45 seconds. The duration is a little longer than etomidate, sometimes lasting as long as 20 minutes (4). 

For relaxation, both Sux and Roc produce complete neuromuscular blockade in almost all patients when dosed appropriately, though by different mechanisms (5). Sux is a depolarizing muscle relaxant, acting on the cholinergic receptors of the motor end plates to stimulate total myocyte depolarization. The relaxation is rapid, often less than a minute and remarkably short-lived at less than 10 minutes (6).  Roc instead competitively blocks the uptake of acetylcholine at the motor end plate, causing relaxation by preventing depolarization.  This results in a longer onset of action, about a minute, and a much longer duration of action at between 30-60 minutes, depending on your reference (7).  So, efficacy is covered by any of the current available choices.

Secondly, thinking about the utility of these drugs provides the first inkling that a choice may not be necessary, or at the very least superfluous.  In the world of critical care transport, space is at a premium because, well, ambulances and helicopters are only so big.  So the more we can consolidate and combine our drugs and equipment for multiple purposes, the fewer specific things we have to carry.   Said another way, it would be nice if our drugs had more than one job, allowing us to use them more and waste them less.  It is here that two of our four drugs begin to distinguish themselves.  
Let’s begin with the simple chart below:

Etomidate and Sux have but one job in emergency and critical care transport medicine, and that job is RSII.  Neither are appropriate for long term maintenance of anesthesia because of their fiercely short durations of action and well documented negative effects from repeat dosing (8,9). Furthermore, the muscle fasciculations caused by massive muscle depolarization following Sux administration have prompted many services to premedicate patients with a non-depolarizing NMBA at 1/10th the intubation dose prior to induction (10).

You know, a non-depolarizing agent…like Roc. 

This process actually contributes to the argument that Sux has only one job, and adds the idea that it can’t even do that job by itself.

Conversely, ketamine and Roc both have multiple jobs, most completely independent of one another.  Roc is not only suitable for induction but also for long term maintenance of neuromuscular blockade should the clinical situation warrant that.  Evidence suggests that the dose can be manipulated within the effective range of 0.6 -1.2 mg/kg to achieve varying durations of action without affecting onset.  One study found that Roc dosing at 0.6 mg/kg based on ideal body weight in obese patients produced a significantly shorter duration of action (11), somewhat alleviating the fears of a prolonged “can’t intubate, can’t ventilate” situation in the event of a failed airway.

As far as ketamine goes, the utility is vast and wide.  Obviously, it performs well as an induction agent with only a slightly longer onset that etomidate (9), and it can also be used for prolonged sedation of the intubated and unintubated patient alike.  It is very useful for procedural sedation, agitation and concomitantly or alone for pain control as well (12). There is even some recent anecdotal cases of physicians using ketamine and BiPAP in the emergency department for patients with impending respiratory failure who were able to avoid intubation altogether by allowing them to calm down and oxygenate effectively (13). To succinctly summarize the utility of ketamine, here is a tongue-in-cheek graphic from Dr. Steve Carroll about his thoughts on ketamine, aptly dubbed the Carroll Emergency Treatment Algorithm, or CETA:

Finally, we look at safety, and this is where the picture clears and muddies all at once.  First we must acknowledge that RSII carries with it a certain amount of risk, even when performed under the most controlled conditions by experienced providers.  By administering sedatives and paralytics, you are taking away a patient’s ability to protect his airway and breathe (2) so the utmost priority rests with your expedience and certainty in taking over those functions through intubation and mechanical ventilation.  Beyond that, it is incumbent upon you as a clinician and the medical community at large to use the safest adjuncts available to facilitate this risky procedure. Looking to the evidence, there is no shortage of study on the proper drug combination to produce optimal intubating conditions at the least expense of patient safety.  A Medline search of “Roc + Sux” produces 304 results, while a similar search of “ketamine + etomidate” yields 282.  Granted, you can narrow these results by adding the term “versus”, but it is clear that these medications are frequently reviewed together, often in comparison or contrast.  What is more telling; however, is the literature that looks at each agent individually through the lens of side effects and general safety.  Some of the biggest issues noted with each medicine were:

Sux: The good news is that Sux is usually pretty safe for almost all patients. The bad news is that when it is unsafe, mortality can reach up to 70%. This is further complicated by the relative absence of indication of the worst of these mortal side effects and the nearly absolute absence of appropriate treatment during transport (14). Of greater concern are the findings of a 2011 study that Sux administration for RSII was associated with significantly more rapid desaturation than a dose of Roc (15). This difference is thought be caused by widespread muscular depolarization as evidenced by the fasciculations often seen with Sux administration and the resultant increased oxygen consumption. As focused as we are on maintaining optimal oxygenation (1,2) during the requisite apneic period during RSII, using a medication thought to increase oxygen demand raises important concerns.

Roc has been the subject of scrutiny for a couple of reasons outside of the operating room, and one of those is related to its duration of action being prolonged. This is a known and intended effect of the medication, though measurably shorter than other medications in its class.  The other stated concern has been Roc induced anaphylaxis (16). This condition is particularly troublesome because it is refractory to normal anaphylaxis care, namely injected epinephrine. One case demonstrated a profound grade IV anaphylaxis that failed to respond to 0.7 mg of epi 1:1000 administered IM (17). The only effective treatment for this particular case was sugammadex, the reversal agent for Roc which is both very expensive and virtually absent from emergency departments and critical care transport vehicles. Fortunately, one study found the incidence of Roc allergy to be literally one in a million (1,008,000 to be precise) (18), making it not more prone to anaphylaxis than other non-depolarizing NMBA.

Etomidate, once the darling of emergency and operative medicine alike for its relatively neutral hemodynamic profile has come under fire in the last ten years for association with post induction adrenal suppression.  This is evidenced by a drop in serum cortisol levels and refractory hypotension and bradycardia in the ICU as much as 24 hours after RSII with etomidate.  While most studies confirm that the cortisol reduction and adrenal suppression is real, they also state that these events are seldom clinically significant and almost always self-correcting (19), though a few did show a link between single etomidate bolus and mortality (20).

Ketamine has been extensively studied for perceived increases in intracranial pressure (8), apnea (4), and the so-called emergence reactions characterized by dreams and hallucinations (9).  The latter two of these are of much greater concern when the drug is used for procedural sedation, but has little bearing when ketamine is used for RSII as the patient will become apneic by design and remain sedated long after that effect has passed (9). However, in either case, emergence can be mitigated with subsequent doses of benzodiazepines (1). The issue of increased ICP after treatment with ketamine has been theorized because of the drug’s well documented increasing of mean arterial pressure which will, by extension, elevate ICP.  Several direct studies have since shown that ketamine does not raise ICP directly and may actually contribute to stabilization of cerebral perfusion by maintaining cerebral perfusion pressure (21). 

Clinical considerations:  Logistically, the main considerations about any of these drugs is proper labeling and storage of paralytic agents. Obviously, NMBAs are deadly if misused or mistaken for other drugs, so great care must be taken to ensure the drugs are properly labeled, kept secure and any unused volume wasted promptly after use.  Both Roc and Sux are temperature sensitive and will begin to lose potency at room temperature.  Both of these medications should be bulk stored in a refrigerator until ready for deployment and then rotated and discarded according to a schedule recommended by a pharmacist.  There are no significant medication compatibility issues with any of the four drugs discussed and no special administration equipment required (i.e. filters, pumps, etc).

Discussion: Anecdotally, RSII is a procedure commonly found in critical care transport and EMS agency protocols, but the frequency of performance is not very high.  For this reason, vigorous training and drills are necessary to maintain muscle memory and adequate knowledge of the required skills and medications.  To further this goal, agencies can possibly increase the success of the process by adding tools like video laryngoscopes (this topic will be discussed at a later date), adjuncts (gum elastic bougie, etc) and appropriate airway rescue devices (i.e. supraglottic devices, cric kits, etc).  But another possible avenue to reduce complexity would be to find the most appropriate, widely accepted combination of induction agent and NMBA and mandate their use for every procedure.
One way to decide if a mandated single cocktail is the answer is to ask the question backwards: Is a choice the answer? Or, at least, is the choice beneficial? Based on the evidence above, I'm inclined to say no.  Though one or two studies find that one drug or the other produces better intubating conditions, the evidence is a long way from declaring a winner at either induction or muscle relaxation. However, the facts and the literature do suggest that two of these drugs, etomidate and sux, are adequate at one job while being unsuited for any other. Even without calling their safety into question, this lack of utility hurts their case. 

Protocols are written to be guidelines combined with sound judgment to provide the best care, and evidence seems to suggest that doesn't necessarily include a choice of RSII cocktail. Further, the literature seems to favor making the single combination ketamine and rocuronium.

Our bags are pretty full. Let's make some room.

1.       Bryan E. Bledsoe, Randall W. Benner. Critical Care Paramedic. Harlow : Prentice Hall, 2006.: 142
2.       American Academy of Orthopaedic Surgeons (AAOS), UMBC. Critical Care Transport. Jones & Bartlett Learning; 2011: 166-167
3.       Etomidate Drug Information. Available at: Accessed August 9, 2014.
4.       Ketamine Drug Information. Available at: Accessed August 9, 2014.
5.       Mallon WK, Keim SM, Shoenberger JM, Walls RM. Rocuronium vs. succinylcholine in the emergency department: a critical appraisal. J Emerg Med. 2009;37(2):183-8.
6.       Anectine Drug Information. Available at: Accessed August 9, 2014.
7.       Zemuron Drug Information. Available at: Accessed August 9, 2014.
8.       Walls RM, Murphy MF. Manual of Emergency Airway Management. Lippincott Williams & Wilkins; 2012
9.       Caro, D. Sedation or induction agents for rapid sequence intubation in adults. Available at: adults?source=search_result&search=Sedation or induction agents for rapid sequence intubation in adults&selectedTitle=1~150. Accessed September 9, 2014.
10.   Shreiber J, Lysakowski C, Fuchs-Buder T, Tramer R. Prevention of succinylcholine-induced fasciculations and myalgia. Anesthesiology. 2005;103: 877-84
11.   Meyhoff C. Should dosing of rocuronium in obese patients be based on ideal or corrected body weight? Anesthesia and analgesia. 2009; 109: 787-92
12.   Birrer K. Ketamine sedation for adult burn dressing changes. Available at: for Burn Dressings 2013. Accessed August 9, 2014.
13.   Carrol S. Airway update screencast. Available at: Accessed August 9, 2014.
14.   Martyn JA, Richtsfeld M. Succinylcholine-induced hyperkalemia in acquired pathologic states: etiologic factors and molecular mechanisms. Anesthesiology. 2006;104(1):158-69.
15.   Tang L, Li S, Huang S, Ma H, Wang Z. Desaturation following rapid sequence induction using succinylcholine vs. rocuronium in overweight patients. Acta Anaesthesiol Scand. 2011;55(2):203-8.
16.   Rose M, Fisher M. Rocuronium: high risk for anaphylaxis?. Br J Anaesth. 2001;86(5):678-82.
17.   Conte B, Zoric L, Bonada G, Debaene B, Ripart J. Reversal of a rocuronium-induced grade IV anaphylaxis via early injection of a large dose of sugammadex. Can J Anaesth. 2014;61(6):558-62.
18.   Bhananker SM, O'donnell JT, Salemi JR, Bishop MJ. The risk of anaphylactic reactions to rocuronium in the United States is comparable to that of vecuronium: an analysis of food and drug administration reporting of adverse events. Anesth Analg. 2005;101(3):819-22
19.   Schenarts CL, Burton JH, Riker RR. Adrenocortical dysfunction following etomidate induction in emergency department patients. Acad Emerg Med. 2001;8(1):1-7.
20.   Den brinker M, Joosten KF, Liem O, et al. Adrenal insufficiency in meningococcal sepsis: bioavailable cortisol levels and impact of interleukin-6 levels and intubation with etomidate on adrenal function and mortality. J Clin Endocrinol Metab. 2005;90(9):5110-7.
21.   Wang X, Ding X, Tong Y, et al. Ketamine does not increase intracranial pressure compared with opioids: meta-analysis of randomized controlled trials. J Anesth. 2014;

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