Airway & Respiratory, Patient Care, Special Topics

Randomized Trials of Prehospital Endotracheal Intubation in Cardiac Arrest

Issue 8 and Volume 40.

Out-of-hospital cardiac arrest (OHCA) is a major public health problem affecting over 300,000 persons annually in the United States.1 Endotracheal intubation (ETI) is one of most common procedures performed by paramedics during resuscitation. However, numerous factors have motivated new strategies for OHCA airway management, including the use of supraglottic airway (SGA) devices. Scientists in the U.S. and the United Kingdom are preparing to carry out largescale randomized controlled trials (RCT) to compare the effectiveness of ETI and SGA on OHCA outcomes. In this article we provide an overview of the rationale for and design of these landmark research studies.

PITFALLS OF PREHOSPITAL INTUBATION

Although a mainstay of U.S. paramedic practice for over 30 years, many research studies have highlighted the perils and pitfalls of prehospital ETI. ET tubes are frequently misplaced2 or dislodged, and multiple and failed intubation attempts are common.3–5

There’s also growing awareness that intubation may interfere with other key resuscitation tasks. Inadvertent hyperventilation is common after intubation during OHCA resuscitation, resulting in increased intrathoracic pressure and reduced CPR coronary blood flow.6,7Intubation efforts have also been shown to cause frequent and prolonged CPR interruptions.8

Paramedic training in intubation in the U.S. is also suboptimal. The operating room is an ideal controlled setting for learning ETI, but paramedic students have limited access to this valuable experience.9 Despite national consensus recommendations, many paramedic students graduate from training programs without having performed any live intubations.10 Furthermore, the number of opportunities to intubate in the prehospital setting are limited and have decreased with the increased use of noninvasive ventilation methods such as continuous positive airway pressure (CPAP).11 In Pennsylvania, paramedics perform a median of only one intubation annually.12 Other EMS systems report similarly sparse intubation experience.13,14

ARE SGA AIRWAYS BETTER?

SGA devices such as the Combitube, King Laryngeal Tube (King LT), Laryngeal Mask Airway and i-gel offer many apparent advantages over intubation. They’re easy to insert, can be placed blindly without direct visualization of the vocal cords and seem to ventilate as well as ET tubes. SGA insertion is simple enough that some BLS EMS agencies have adopted this technique.15

Historically, when ETI wasn’t a standard paramedic skill, SGAs (Esophageal Obturator Airway, Pharyngo-Tracheal Lumen Airway, Combitube) were commonly used for advanced airway management in the U.S. However, once paramedics learn to perform intubation, SGAs were relegated to a rescue role, reserved primarily for cases of unsuccessful intubation.

Within the last five years, new American Heart Association (AHA) guidelines advocating limitations in CPR interruptions have led to renewed interest in SGA because of the ability to easily accomplish advanced airway insertion without interrupting chest compressions.16 Many EMS systems have switched to SGAs as the primary advanced airway device in OHCA.

UNEXPECTED FINDINGS

The litmus test of any medical intervention is whether it improves patient outcomes. Given their practical nature, one would expect SGAs to show higher OHCA survival than ETI. However, studies using large data sets have failed to show higher OHCA survival with SGA vs. ETI.17–21 Two recent studies are worth highlighting because they demonstrated lower survival with SGA than ETI.

Encompassing 10 cities in North America, the Resuscitation Outcomes Consortium (ROC) is the largest cardiac arrest and trauma resuscitation research network in the world. A study involving a secondary analysis of 10,455 OHCAs enrolled in the ROC “PRIMED” clinical trial compared the outcomes of patients who received ETI (n=8,487) with those who received SGA (n=1,968).20

After adjusting for patient and arrest characteristics, researchers found that ETI was associated with higher adjusted neurologically intact survival to hospital discharge (ETI 4.7% vs. SGA 3.9%; adjusted odds ratio 1.40, 95% CI: 1.04–1.89). An important limitation of the study was that it couldn’t differentiate the type of SGA used (e.g., Combitube, King LT or LMA).

The Cardiac Arrest Registry to Enhance Survival (CARES) is another large EMS agency network dedicated to reporting and improving outcomes from OHCA. After examining 10,691 OHCAs and adjusting for patient and arrest characteristics, a CARES study looking at outcomes of those receiving ETI (n=5,591) with those receiving SGA (n=3,110) associated ETI with higher adjusted neurologically intact survival to hospital discharge (ETI 5.4% vs. SGA 5.1%; adjusted odds ratio 1.44, 95% CI: 1.10–1.88). As in the ROC study, the authors could not differentiate the type of SGA used.

Additional unexpected insights about SGA function come from a study looking at a pig model of OHCA.22 Study authors found that SGA devices (specifically the Combitube, LMA and King LT) compress the carotid arteries, causing a large reduction in carotid blood flow compared with ET tubes. It’s important to note that this study was based on only nine pigs, and the results haven’t been replicated in humans, where the relationship between pharynx, trachea and carotid blood vessels may differ. However, this study underscores our limited understanding of how SGA devices and ET tubes function during cardiac arrest.

STATISTICAL CONSIDERATIONS

The ROC and CARES studies are examples of observational studies—research that observes patients without altering their care or interventions. Most research studies evaluate the relationship between an exposure (e.g., high blood pressure) and an outcome (e.g., stroke). (See Figure 1.)

A key scientific issue in observational studies is the effect of confounders; a third variable that’s related to both the exposure and outcome and that alters the exposure/outcome relationship. For example, high blood pressure (exposure) may be related to higher rates of myocardial infarction (outcome). Obesity is a confounder in this relationship; obese individuals are more likely to have high blood pressure and more likely to have a myocardial infarction, and therefore obesity may alter the relationship between high blood pressure and myocardial infarction. Scientists use biostatistical methods such as multivariable regression to adjust for the background influence of multiple known confounders.

When the primary exposure is an intervention (like intubation), this is a special situation of confounding by indication. In these cases, the confounders aren’t just background “noise;” the confounder may directly influence or change the exposure. Confounding by indication typically comes into play when healthcare providers choose interventions based upon the patient’s characteristics or severity of illness. For example, EMS providers may choose SGA over ETI because of the patient’s morbid obesity and anticipated intubation difficulty.

Figure 1: Exposure, outcomes and confounders

A research study evaluates the relationship between an exposure (or intervention) and outcomes. A confounder is a third factor that is related to and may influence the relationship between the exposure and outcome. Figures courtesy Henry E. Wang

Confounding by indication may explain why the ETI exhibited higher survival than SGA in the ROC and CARES studies. For example, the paramedics who routinely chose ETI over SGA may have had access to better CPR assistance; the apparent higher OHCA survival could have been due primarily to high quality CPR, not the type of advanced airway used.

Regardless of the available advanced biostatistical techniques, in the ETI vs. SGA question it’s very difficult to adjust for confounding by indication because 1) we didn’t ask paramedics why they chose ETI vs. SGA; 2) even if we asked, the paramedics may not be fully aware of the reasons for their choice; and 3) other unmeasured or unmeasurable influences may be present—for example, the difficulty of the patient’s airway anatomy, proximity to the hospital, danger of the scene, etc.

RANDOMIZED TRIALS

The best way to overcome confounding by indication is to randomly assign study interventions. Randomization is a powerful scientific tool that minimizes bias by evenly distributing confounders (including unmeasured or unmeasurable factors) between study arms. Randomization provides greater confidence that the observed outcomes are due to the studied intervention and not the confounders.

As discussed previously, while a common EMS intervention, ETI is fraught with adverse events and errors and may adversely impact other OHCA resuscitation tasks. To provide optimal OHCA care, it’s essential we identify the best OHCA airway management strategy.

Figure 2: AIRWAYS-2 Taking place in the U.K., AIRWAYS-2 will evaluate the effect of the initial choice of advanced prehospital airway device (initial intubation vs. initial i-gel) upon neurologicallyintact survival to hospital discharge after out-of-hospital cardiac arrest.

Given this important goal and the limitations of existing observational data, the only way to identify the best advanced airway management strategy is through a randomized controlled trial. To date there have been few randomized trials of prehospital intubation and none in adult cardiac arrest.23,24

ONGOING TRIALS

Two upcoming multicenter randomized controlled trials will directly compare ETI with SGA in OHCA.

REVIVE-Airways and AIRWAYS-2: This U.K. effort consists of a smaller phase 1 pilot study (REVIVE-Airways) and an upcoming larger phase 2 study (AIRWAYS-2). Completed in 2013, the REVIVE-Airways trial included adult OHCA treated by specially trained study paramedics who volunteered to enroll patients in the study.25 Study paramedics were randomly assigned to use only i-gel, Laryngeal Mask Airway or “usual care” (ETI) when treating OHCA. The pilot study successfully enrolled 615 patients (232 i-gel, 174 LMA, 209 usual care) during a one-year period, demonstrating the feasibility of randomizing airway devices in the prehospital setting.26 Starting in fall 2015 and involving 9,000 OHCA patients, AIRWAYS-2 will randomize study paramedics to ETI or i-gel, determining the effects upon neurologically intact survival to hospital discharge. (See Figure 2.)

ROC Pragmatic Airway Resuscitation Trial (PART): This fall, EMS agencies affiliated with the ROC will participate in PART. ROC has conducted numerous OHCA clinical trials, including studies evaluating the impedance threshold device (ResQPOD), early vs. later rhythm analysis in OHCA, amiodarone vs. lidocaine vs. saline in v fib, and continuous vs. 30:2 chest compressions.27–30An estimated 30 EMS agencies from the Birmingham (Ala.), Dallas, Milwaukee, Pittsburgh and Portland (Ore.) communities will participate in PART.

Funded by the National Institutes of Health, PART will randomize 3,000 adult OHCA to resuscitation using initial ETI vs. initial King LT insertion. The primary outcome will be 72-hour survival. PART will use cluster randomization with crossover. In this design, an entire EMS agency will be assigned to ETI or King LT, switching to the other device every 3–6 months. (See Figure 3.) This randomization strategy will ensure that all adult OHCA treated by study EMS agencies are enrolled and that all paramedics have equal chances of performing either study intervention.

The “pragmatic” aspect of PART refers to strategies to make the trial as efficient and clinically relevant as possible. Although cardiac arrest trials can be designed to detect neurologically-intact survival to hospital discharge, this often requires enrollment of over 20,000 subjects.31 In contrast, PART is designed to detect 72-hour survival and will enroll a more modest 3,000 subjects. Some experts also believe that 72-hour survival is a more meaningful endpoint for prehospital interventions than survival to hospital discharge. PART was also designed to reflect real-world practices as closely as possible. Thus, while the initial advanced airway intervention is dictated by the protocol, all follow-up “rescue” interventions will follow EMS agencies’ standard practices. The King LT was chosen because it’s one of the most commonly used SGA devices in the U.S.

Although the ROC and CARES studies compared ETI with SGA, a related question is whether bag-valve mask (BVM) ventilation alone might fare better in OHCA. A study from Japan associated lower neurologically intact 30-day survival with advanced airway management (ETI or SGA) vs. BVM-only.32

Also subject to confounding by indication, the findings are provocative, suggesting that BVM might be superior to either ETI or SGA. Because BVM-only is less common in the U.S. and U.K., however,AIRWAYS-2 and PART will focus on ETI and SGA to best reflect current paramedic practices. However, results from this and other studies suggest that future trials should consider a BVM-only arm.

WHAT’S IN IT FOR EMS?

Because of their large-scale, multicenter, randomized designs, the results of AIRWAYS-2 and PART will yield high-quality medical evidence that will likely influence EMS clinical practice. The trials’ effects upon OHCA airway management practices will depend upon the results:

  • Intubation proves better than King LT or i-gel: In this situation, ETI may prevail as the standard practice in OHCA.
  • Intubation proves worse than King LT or i-gel: This finding may prompt a shift to primary King LT or i-gel insertion in OHCA.
  • Intubation proves equal to King LT or i-gel: This finding may allow for flexibility in clinical interpretation, allowing EMS practitioners to select airway techniques best suited to their available airway devices, skills, training and setting.

Figure 3: Pragmatic airway resuscitation trial (PART)

PART will evaluate the effect of prehospital airway strategy (initial intubation vs. initial King LT) upon 72-hour hospital survival after out-of-hospital cardiac arrest. Each EMS agency will be randomly assigned one of the trial airway arms, crossing over to the other arm every six months.

A fourth potential scenario is that AIRWAYS-2 and PART may identify conflicting results; for example, ETI proving superior in one trial but inferior in the other. This outcome would be very important, helping to clarify the benefit or harm of a particular SGA device.

The entire resuscitation world eagerly awaits the results of AIRWAYS-2 and PART studies, as they may spur one of the most significant shifts in OHCA resuscitation practice. EMS professionals may view these trials unfavorably because they threaten traditional paramedic ETI practices. However, the EMS community should support these studies to determine if the current prehospital practices of ETI are beneficial, harmful or neither since the available observational and animal data are inadequate to guide practice.

If we maintain the current status quo, we risk perpetuating ineffective—or potentially harmful—OHCA airway interventions. To best serve our patients we must support the execution and embrace the result of the AIRWAYS-2 and PART studies.

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