More Futility: Apneic Oxygenation?

Here’s another pendulum swing to throw into the gears of medicine – an apparent failure of apneic oxygenation to prevent hypoxemia during intubation in the Emergency Department. Apneic oxygenation – passive oxygenation during periods of periprocedural apnea – seems reasonable in theory, and several observational studies support its use. However, in a randomized, controlled ICU setting – the FELLOW trial – no difference in hypoxemia was detected.

This is the ENDAO trial, in which patients were randomized during ED intubation, with a primary outcome of mean lowest oxygen saturation during or immediately following. These authors prospectively enrolled 206 patients of 262 possible candidates, with 100 in each group ultimately qualifying for their analysis. The two groups were similar with regard to initial oxygen levels, pre-oxygenation levels, and apnea time. Then, regardless of their statistical power calculations and methods, it is fairly clear at basic inspection their outcomes are virtually identical – in mean hypoxemia, SpO2 below 90%, SpO2 below 80%, or with regard to short-term or in-hospital mortality. In the setting in which this trial was performed, there is no evidence to suggest a benefit to apneic oxygenation.

It is reasonable to note all patients included in this study required a pre-oxygenation period of 3 minutes by 100% FiO2 – and that oxygen could be delivered by bag-vale mask, BIPAP, or non-rebreather with flush rate oxygen. These are not necessarily equivalent methods of pre-oxygenation, but, at the least, the techniques were not different between groups (>80% NRB). It is reasonable to suggest passive oxygenation may be more beneficial in those without an adequate pre-oxygenation period, but it would certain be difficult to prospectively test and difficult to anticipate a clinically important effect size.

Adding complexity to any procedure – whether with additional monitoring and alarms or interventions of limited efficacy – adds to the cognitive burden of the healthcare team, and probably has deleterious effects on the most critical aspects of the procedure. It is not clear that apneic oxygenation reliably improves patient-oriented outcomes, and does not represent a mandatory element of rapid-sequence intubation.

“EmergeNcy Department use of Apneic Oxygenation versus usual care during rapid sequence intubation: A randomized controlled trial”
http://onlinelibrary.wiley.com/doi/10.1111/acem.13274/full

Icatibant … Can’t?

In a small, problematic, Phase 2 trial, icatibant – a selective bradykinin B2 receptor antagonist – seemed promisingly efficacious for the treatment of angiotensin-converting enzyme inhibitor-induced angioedema. Considering the catastrophic and potentially fatal complications relating to airway angioedema, the prospect of having an effective rescue medication is of substantial clinical importance.

Sadly, and first picked up by Bryan Hayes, the phase 3 trial was a wash. Published with great fanfare in the Journal of Allergy and Clinical Immunology: In Practice, this multi-center study enrolled 121 patients with presumed, and at least moderately severe, ACE-I-induced angioedema. The primary efficacy endpoint was the subjective “time to meeting discharge criteria”, which was guided by a scoring system consisting of difficulty breathing, difficulty swallowing, voice change, and tongue swelling. Secondary endpoints included time to onset of symptom relief, rescue therapy, and other safety considerations.

Almost all patients received some “conventional” therapy prior to randomization, with most (>80%) receiving antihistamines or corticosteroids and approximately one-fifth receiving epinephrine. The median time to doses of conventional therapy were ~3.5 hours, and enrolled patients received either icatibant or placebo ~3.3 hours afterwards.

The picture is worth all the words:

No difference.

Laudably – although this ought to be the default, without special recognition – the sponsor and these COI-afflicted authors unabashedly published these neutral findings with little sugarcoating. I will defer, then, to their closing sentence:

In conclusion, icatibant was no more effective than placebo in treating at least moderately severe ACE-Ieinduced angioedema in this phase III trial.

“Randomized Trial of Icatibant for Angiotensin-Converting Enzyme Inhibitor Induced Upper Airway Angioedema”
http://www.sciencedirect.com/science/article/pii/S2213219817301721

Still Meandering Towards Apneic Oxygenation

The use of apneic oxygenation – so-called NODESAT – has been gaining rapidly in popularity.  Curiously enough, however, its continued promotion occurs in the absence of high-quality evidence for benefit.

This most recent study is a prospective, observational evaluation of two years’ worth of intubation procedural outcomes.  Patients receiving passive oxygenation during intubation were compared with those who did not, with the primary outcome being hypoxia (O2 saturation <90%) on the first-pass of intubation.  During this time period, the use of apneic oxygenation was explicitly encouraged as a quality improvement initiative.  Of the 1,140 intubations during this time period, 635 patients were included for analysis; 380 utilized apneic oxygenation and 255 did not.  The apneic oxygenation cohort had a 17.9% incidence of hypoxia on the first intubation attempt, compared with 31.0% without.  The authors conclude their observational data favors apnea oxygenation, and may improve safety.

This is a reasonable conclusion, to be certain.  There were, of course, massive confounders regarding the two cohorts – and the largest predictor of hypoxia was not apneic oxygenation or technical factors, but simply whether the baseline oxygen saturation was >93%.  An observational study, particularly one excluding 20% of potentially eligible patients due to incomplete data, simply continues to serve as hypothesis-generating for definitive evaluation.

I am not opposed to the use of apneic oxygenation, but it is reasonable to be realistic about the underlying evidence and not to behave dogmatically regarding its use.  There are probably a few acute procedural delays associated with its use, but any patient-oriented harms or benefits would seem to be rather difficult to detect.

Other notes:

  • LITFL publishes a lovely synopsis on the topic here.
  • Yes, I’m about four months late to the party on this article – having missed the electronic publication back in February!

“First Pass Success Without Hypoxemia Is Increased With the Use of Apneic Oxygenation During Rapid Sequence Intubation in the Emergency Department”
http://www.ncbi.nlm.nih.gov/pubmed/26836712

Is NODESAT Overhyped?

In the last few years, we’ve had a little bit of a sea-change in oxygenation during intubation.  We’ve stopped relying solely on pre-oxygenation to bridge our patients through apnea, and started providing passive oxygenation during intubation.  Usually supplied by high-flow nasal cannula, this takes advantage of physiology and diffusion to distribute oxygen into circulation.

But, as these authors state, the evidence for this practice is spotty – mostly observational evidence from controlled intubation settings.  Our critically-ill patients hardly have the same physiology as those undergoing elective airway procedures, and are generally less responsive to oxygenation adjuncts.  So, this is the FELLOW trial, a pragmatic, open-label randomized trial comparing apneic oxygenation vs. “usual care” – which was none.

With 150 patients in their intention-to-treat analysis, this cartoon sums up the results sufficiently:

Not much difference!

Their two groups were relatively well-balanced in terms of physiology and airway comorbidities.  The intubating operators were reasonably experienced (median >50 intubations), and 2/3rds of the patients were intubated on the first attempt.  There were probably no important differences in pre-oxygenation or procedural factors.

But, it is quite a small trial.  There are small differences here favoring the apneic oxygenation arm that simply might not reach statistical significance.  The exclusion criteria included “if the treating clinicians felt a specific approach to intra-procedural oxygenation or a specific laryngoscopy device was mandated for the safe performance of the procedure”, which could have introduced a selection bias.  The open-label effects may or may not be confounding.  The ICU environment and exclusion criteria also affect generalizability to the Emergency Department.

In the end, the answer is: apneic oxygenation still probably helps, particularly considering the pre-study evidence favored the intervention, and this one study does not move the needle much.  However, the observation here of a clinically unimportant effect size is not unreasonable.  If the effect size is small, the cost of an intervention becomes important.  However, in this case, the cost is fairly minimal – a small addition to set-up time and procedural complexity.  Considering the low cost and the post-test odds still favoring the intervention, it would be erroneous to stop providing apneic oxygenation based on this trial, and further study is indicated.

“Randomized Trial of Apneic Oxygenation during Endotracheal Intubation of the Critically Ill”
http://www.ncbi.nlm.nih.gov/pubmed/26426458

A Little Intubation Checklist Magic

In the interests of patient safety, many have turned to peri-procedural checklists.  Rather than,
essentially, “winging it”, a standardized protocol is followed each time, reducing the chance of an important omission.

These authors describe a checklist intervention for, as they describe, the high-risk procedure of endotracheal intubation in the setting of trauma.  The checklist involves, generally, assignment of roles, explicit back-up airway planning, and adequate patient positioning.  The authors used a before-and-after design using video review of all intubation events to compare steps performed.

In the six-month pre-checklist period, 7 of 76 intubation events resulted in complications – 6 desaturations, 2 emesis, and 2 hypotension.  In the post-intervention period, using the checklist, events were reduced to a single episode of desaturation in 65 events.  So, success?

As with every before-and-after study, it is hard to separate the use of the checklist to the educational diffusion associated with checklist exposure.  Would another, less intrusive, intervention been just successful?  Will the checklist lose effectiveness over time as it is superseded by newer safety initiatives?  And, most importantly, what did operators actually do differently after checklist implementation?

Only 4 of 15 checklist elements differed from the pre-checklist period: verbalization of backup intubation technique (61.8% vs. 90.8%), pre-oxygenation (47.3% vs. 75.4%), team member roles verbalized (76.4% vs. 98.5%), and optimal patient positioning (80.3% vs. 100%).  If only four behaviors were substantially changed, are they responsible for the outcomes difference – which, technically, is solely episodes of hypoxia?

Their intervention seems reasonable, and the procedure is likely high-risk enough to warrant a checklist.  However, I probably would not implement their specific checklist, as some refinement to the highest-yield items would probably be of benefit.

“A Preprocedural Checklist Improves the Safety of Emergency Department Intubation of Trauma Patients”
http://www.ncbi.nlm.nih.gov/pubmed/26194607

The Shock Index is a Shockingly Poor Predictor of Peri-Intubation Arrest

A guest post by Rory Spiegel (@CaptainBasilEM) who blogs on nihilism and the art of doing nothing at emnerd.com.
This retrospective analysis of 410 patients undergoing RSI is a helpful reminder of how a statistically significant association does not implicitly translate into a clinically useful one.

The authors of this paper attempted to identify factors that would predict peri-intubation cardiac arrest using a cohort of patients requiring emergent intubation in a large urban emergency department. Specifically does the Shock Index accurately predict those who will suffer post-intubation cardiac arrest? The Shock Index (HR/systolic BP) is essentially an attempt to quantify a patient’s volume status and cardiac reserve into simple ratio. These same authors have examined this score’s ability to predict peri-intubation hypotension in the past and found similar predictive capabilities.

Given the pedigree of the authors (Dr. Alan Jones and company) it is no surprise their chart review methods were next to flawless. Using standardized data collection forms, a single trained extractor identified patients who underwent ED intubations over a one year period. To ensure inter-observer reliability, 10% of this data was randomly audited by a second extractor blinded to the trials hypothesis. Backwards stepwise regression was utilized to determine what factors were independently associated with peri-intubation cardiac arrest (defined as cardiac arrest up to 60 minutes after intubation).

In this cohort, the rate of cardiac arrest after intubation was 4.2%, or 17 patients. 10 out of these 17 events occurred within 10 minutes of the intubation and, in 15 of the 17 events the initial arresting rhythm was PEA.  As one would expect, patients who experienced peri-intubation cardiac arrest had faster a heart rate, lower blood pressure and more frequent incidence of pre-RSI hypotension. The only two metrics that were found to be independently associated with cardiac arrest were the patient’s body weight and pre-intubation Shock Index. The Shock index was found to have an odds ratio of 1.16 with a confidence interval ranging from 1.003 to 1.3. Put in another manner, it was found to have an AOC of 0.73, rendering it essentially clinically useless.

Given these test characteristics, if we were to use a Shock Index of 0.88 (as suggested by the authors) to determine who is at risk for peri-intubation arrest than we would be left unprepared for an unacceptable quantity of patient who will decompensate during the procedure. This should be inherently obvious, as a formula that incorporates only heart rate and systolic blood pressure is incapable of encapsulating all the many reasons a patient may code peri-intubation. Not to mention that this study does not tell us whether the patients whom the Shock Index identifies as “at risk” will actually benefit from our added vigilance and pre-intubation hemodynamic optimization. Or does the Shock Index merely highlights a spectrum of the more critically ill patients who will inevitably deteriorate despite our clairvoyant best efforts?

Tachycardic, hypotensive patients are at increased peril for peri-intubation arrest. Sicker patients, older patients, and patients with poor cardiac reserve are all at higher risk. Most importantly, the Shock Index does not accurately predict who will and will not arrest after intubation. Similar to tools meant to predict difficult airways (not accurate enough to depend on clinically), we must be prepared for peri-intubation arrest in the majority of the patients requiring emergent intubation. Once a patient reaches the critical juncture of requiring intubation, we should be aware of all the perils this procedure involves and plan accordingly.

“Incidence and Factors Associated with Cardiac Arrest Complicating Emergency Airway Management”
www.ncbi.nlm.nih.gov/pubmed/23911630

Etomidate, Safe for Sepsis?

Sadly, the jury is still out.  Just months after Critical Care Medicine published the systematic review demonstrating an association between use of etomidate and mortality in sepsis, now they’re back with a retrospective data-mining expedition that draws the opposite conclusion.

This is a multi-center prospective registry of critically ill patients entered into a research database who were retrospectively data-mined for septic, intubated patients.  Of the 42,000 patients in the database, approximately 2,000 met this definition, and about half were identified as receiving etomidate as their induction agent.  In their cohort, there was no in-hospital mortality difference between the patients who received etomidate and the patients who received a different induction agent for intubation.

Unfortunately, as an observational, retrospective study of imperfectly matched cohorts, there are far too many uncontrolled confounders to base clinical practice on these findings.  Studies such as these, even robust, prospective cohorts, are capable of doing little more than suggesting a hypothesis contrary to the findings of prior work.

If you believe etomidate has a chance to harm patients in sepsis, this doesn’t change your practice.

“Single-Dose Etomidate Is Not Associated With Increased Mortality in ICU Patients With Sepsis: Analysis of a Large Electronic ICU Database”
www.ncbi.nlm.nih.gov/pubmed/23318491

Unsurprisingly, NHAMCS Data is Flawed

The National Hospital Ambulatory Medical Care Survey is a massive database of abstracted patient records, systematically generated to produce a representative sample of the nation’s Emergency Department visits.

It should come as no surprise that retrospectively abstracted data from the electronic medical record sometimes fails to accurately reflect patient care.  The important question, however, is “how often?”  This review of NHAMCS by one of the Annals editors looked at a measurement that ought to be pretty obvious – intubation.  If you can’t figure out whether a patient has been intubated via chart review, there’s some serious issues with your data sourcing.  However, in this review of NHAMCS, the author interprets up to one in four charts as being potentially inaccurate due to inconsistencies between documented intubation and the final disposition of the patient (e.g., non-ICU settings, home, observation status, etc.)

Now, there are some instances in which patients are intubated in the Emergency Department – yet not subsequently dispositioned to a critical care or morgue – but these “temporary” intubations certainly do not constitute 25% of intubations.  The author goes on to note that Annals publishes a NHAMCS study at least twice a year – relatively influential towards practice given the Impact Factor – and the flaws in this data should limit the relative weighting of its importance.

“Congruence of Disposition After Emergency Department Intubation in the National Hospital Ambulatory Medical Care Survey”

Pediatric Intubation – Not Always Successful

This is an observational study of pediatric medical resuscitation, published in Annals of Emergency Medicine, using video to evaluate the frequency of various adverse events during pediatric intubation.

As expected in a teaching institution, there is a fair bit of variability in initial success rates – ranging from 35% first-pass success for pediatrics residents up to 89% for PEM or anesthesia attendings.  Overall 52% had success on the first attempt.  Unfortunately, 61% experienced at least one adverse event during intubation.  These were typically not clinically important with regard to patient-oriented outcomes.

However,  what is more entertainingly concerning is how few of the complications make it into the medical record.  The written documentation overestimates first-attempt success, underestimates desaturation during the procedure, and even completely omits any mention of one of the two episodes of CPR required during resuscitation.

My guess is that Cincinnati Children’s may have had a documentation quality review after this data were collected.


“Rapid Sequence Intubation for Pediatric Emergency Patients: Higher Frequency of Failed Attempts and Adverse Effects Found by Video Review”
www.ncbi.nlm.nih.gov/pubmed/22424653

The Papermate Flexgrip Cricothyroidotomy

Emergency Medicine has more than a little MacGyver instinct to it – and one of the semi-urban legend aspects of EM is the ability to perform a cricothyroidotomy as a life-saving measure in any situation.  The most commonly described version is performed using simple, commonly available tools – any sort of cutting blade and a hollow tube, such as a hollow pen.

Several studies have approached feasibility by describing the flow dynamics of various pens, but this is the first study to evaluate the procedural feasibility of bystander cric.  This is an observational, cadaveric study using non-EM junior physicians and medical students in which they used a 26-blade scalpel and a Papermate ballpoint pen of 8.9mm external diameter to attempt an “off-the-cuff” cric.  The 9 participants attempting 14 procedures were successful 8 times, although complications were frequent, including vascular and muscular/cartilaginous injuries.

Whether this is externally valid to the living, or to patient-oriented outcomes of effective ventilation, I’m not so certain – but, then again, if the alternative is 100% mortality via no possible ventilation, it’s a fun study to see.

“Observational cadaveric study of emergency bystander cricothyroidotomy with a ballpoint pen by untrained junior doctors and medical students”
http://emj.bmj.com/content/early/2012/05/04/emermed-2012-201317.short