In the world of medical science we are often lulled into a false sense of security by large sample sizes and their correspondingly small confidence intervals. We often forget that such methodologic strengths augment only a trials precision, or the likelihood a similar trial will produce similar results. Such statistical robustness speaks little towards a trial’s accurate representation of the truth. A trial’s accuracy can only be revealed from the subjective nature of its designed. This type of intrinsic bias can dramatically affect a trial’s results and yet is incapable of being measured by our traditional statistical instruments. As such we often interpret data far beyond the limits of its methodological borders. An unfortunate concession made out of necessity. What follows is full of such methodological leaps and physiologic fancies. Read at your own peril.
For some time we have existed under the belief that continual chest compressions are vital during the resuscitation of patients in cardiac arrest. We dogmatically cite the importance of compression fractions and peri-shock pauses despite the evidence supporting their value being far from robust. In fact, until recently little randomized control trial level data existed examining the value of continuous chest compressions during cardiac arrest.
Published in the NEJM by Nichol et al in December 2015, the ROC investigators sought to examine the true value of continuous chest compressions (2). What the authors did was methodologically impressive. They compared a continuous chest compression strategy to the 30:2 compression to breath ratio traditionally implemented in CPR algorithms. The authors performed a cluster randomized control trial where participating EMS agencies were randomly assigned to a period of either continuous chest compression with asynchronous breaths or 30:2 ratio. Twice per year each agency was switched over to the other resuscitation strategy. Prior to enrollment each EMS agency was required to undergo a quality assessment period and was only allowed to enroll patients in the trial if their EMS services were able to adhere to treatment protocol as assigned, demonstrate proficiency in data entry, and prove themselves capable of appropriate CPR-process measures.
Patients enrolled in the continuous chest compression group assignment received continuous compressions at a rate of 100 per minute with asynchronous breaths delivered at a rate of 10-breaths per minute. Patients treated by groups assigned to the 30-2 ratio received 30 compressions followed by 2 ventilations delivered over a pause of no greater than a 5 seconds. Both of these protocols were performed during the first 6 minutes of arrest at which point an advanced airway was obtained and all patients received continuous compressions with asynchronous breaths at a rate of 10 breaths per minute. An important note, though the authors monitored the quality of CPR delivered by all providers to ensure protocol adherence, no means were established to ensure proper ventilatory support.
Even just a brief glance at this trials methodology reveals the colossal effort required to design, plan and institute a trial such as this. The authors enrolled 26,148 patients, of which 12,613 received continuous chest compressions and 11,035 received intermittent compressions during the active study period of the trial. Despite the imperfections of a cluster randomized trial design, by all appearances the two groups were fairly well balanced.
The authors found no difference in their primary outcome, survival to hospital discharge, between the continuous chest compression and intermittent compression groups (9.0% vs 9.7%). In fact the authors failed to find a difference in 24-hour survival, number of patients discharged home, or the amount of patients who were alive and neurologically intact at hospital discharge.
Only 43% of patients were treated according to the protocol to which they were assigned. In the patients who actually received the appropriate protocolized resuscitation, those who were assigned to the intermittent group fared noticeably better. Survival to hospital discharge was 7.8% vs 9.8% respectively, a 2% absolute difference (?2.9 to ?1.1, p< 0.001).
Does this mean that our decade long focus on quality chest compressions and avoidance of interruptions has been futile? Has this massive endeavor by Nichol et al done nothing more than to once again encourage a phlegmatic approach to intra-arrest management? Despite its methodological rigor and complete lack of treatment effect, this trial is far less damning than it initially appears. The 0.7% absolute difference was surrounded by an equally small confidence interval, ?1.5% to 0.1%. And yet when interpreting these results it is important to remember the meaning of such a statistical measure. A 95%-confidence interval is often misinterpreted to represent the range of values between which the truth is likely to exist. In reality a confidence interval is incapable of divining such an answer. If a trial was replicated an infinite number of time, the 95%-confidence interval represents the data points between which such a trial’s results would fall 95% of the time. As such it is incapable of assessing any intrinsic bias built into a trial’s design. Furthermore such statistical manipulations cannot assess the magnitude these biases potentially impact a trial’s results (1).
Ideally in a randomized trial design the goal is to obtain two identical cohorts with the only difference between the groups being the variable of questions. In this case Nichol et al hoped to examine two different compression strategies. But in reality how different were these strategies? When you look at the compression fraction in the two groups they differ very little, (0.83 and 0.77 respectively). Further more the peri-shock pause was again, identical. As was compression depth, use of ACLS medications and utilizations of post arrest treatments such as targeted temperature management and coronary revascularizations. One could argue that this trial was essentially an examination of two very similar compression strategies that diverged mostly in name alone. In truth, the most prominent difference between these two strategies may have been in was how the patients received positive pressure ventilation. The Nichol et al trial should not be viewed as an absence of evidence suggesting the importance of continuous chest compressions but rather the importance of the absence…
… of positive pressure ventilation.
In 2008 Bobrow et al published their experience using minimally interrupted compressions in the pre-hospital environment in Arizona (3). Their findings, published in JAMA, described a protocol, entitled minimally interrupted cardiac resuscitation (MICR), in which the participating EMS agencies were trained to perform 200 compressions over two minutes, followed by a rhythm analysis and defibrillation when appropriate, followed by another 200 compressions before checking for a pulse. This protocol was repeated for the first 6-minutes of CPR. In contrast to the Nichol et al trial, the importance of airway management was significantly devalued. Although BVM ventilation at a rate of 8 breaths per minute was permitted, providers were encouraged to provide only passive oxygenation through a nasal canulla.
Bobrow et al found that using a MICR strategy increased overall survival from 1.8% to 5.4%. In patients with witnessed ventricular fibrillation arrests, survival increased from 4.7% to 17.6%. Studies examining compression only CPR compared to standard AHA guideline CPR performed by bystanders in OHCA demonstrated similar improvements (4,5). The before and after study design in the Bobrow et al trial limits the causative conclusions that can be drawn, especially given the fact that as the trial progressed, though protocol compliance remained consistently high over time, survival dropped close to baseline by the end of the 18 month observation period. Nonetheless this evidence lends itself to support the hypothesis that positive pressure ventilation can be detrimental in the early stages of cardiac arrest.
Although Nichol et al were fastidious in their effort to monitor compression quality during their study period, they providing no means to account for the rate at which patients were ventilated. We know from previous work by Aufderhei et al that respiratory rates during cardiac arrest frequently far exceed the recommended 10 breaths per minute (6). In this prospective study where rescuers were observed during OHCA, the authors found that the average breath per minute delivered was 30 and the percent time per minute which positive pressure was recorded in the thoracic cavity was 47.3%. Milander et al found almost identical findings. In this cohort of in-hospital cardiac arrests, ventilations were given at a mean rate of 37 breaths per minute (ranging 24-60 breaths per minute) (7). This tendency toward hyperventilation may in fact be the reason that continuous chest compressions failed to demonstrate superiority when compared to an intermittent strategy and why in the per protocol analysis, the intermittent protocol demonstrated a statistically significant survival benefit compared to the continuous approach. In patients who were treated using the intermittent protocol, the 30:2 ratio clearly limits the amount of positive pressure breaths a patient can receive per minute. If rescuers are compressing at a rate of 100 compressions per minute, then the maximal amount of breaths that can be delivered in between chest compressions is 6-7 breaths per minute. Conversely since in the continuous compression group positive pressure ventilations were delivered in asynchronous fashion to the circulatory effort and had no feedback system limiting overzealous bagging, it is likely their delivery far out paced the recommended 10 breaths per minute.
The Nichol et at trial was a mammoth effort, which found no difference in efficacy between two resuscitative strategies. Despite its statistical confidence it would be unwise to make the evidentiary leap to state that these results devalue the importance of continuous chest compressions. They may suggest that the manner in which you deliver chest compressions does not matter as long as the compression fraction is high. They also suggest that the manner in which positive pressure ventilation is applied during these resuscitation is likely of vital importance. Unfortunately because of the ventilator strategy used by Nichol et al, the negative results cannot be applied to the use of a MICR strategy as proposed by Bobrow et al. To answer that question, another trial of immense proportions specifically examining a MICR protocol, which de-emphasizes the importance of early airway management, is required. A daunting and exhaustive task.
- Altman DG, Bland JM. Uncertainty beyond sampling error. BMJ. 2014;349:g7065.
- Nichol G, Leroux B, Wang H, et al. Trial of continuous or interrupted chest compressions during CPR. N Engl J Med 2015;373:2203-14.
- Bobrow BJ, Clark LL, Ewy GA, et al. Minimally interrupted cardiac resuscitation by emergency medical services for out-of-hospital cardiac arrest. JAMA. 2008;299(10):1158-65.
- Hallstrom A, Cobb L, Johnson E, Copass M. Cardiopulmonary resusci- tation by chest compression alone or with mouth-to-mouth ventilation. N Engl J Med. 2000;342:1546 –1553.
- Bobrow BJ, Spaite DW, Berg RA, et al. Chest compression-only CPR by lay rescuers and survival from out-of-hospital cardiac arrest. JAMA. 2010;304(13):1447-54.
- Aufderheide TP, Sigurdsson G, Pirrallo RG, Yannopoulos D, McKnite S, von Briesen C, Sparks CW, Conrad CJ, Provo TA, Lurie KG. Hyperventilation-induced hypotension during cardiopulmonary resusci- tation. Circulation. 2004;109:1960 –1965.
- Milander MM, Hiscok PS, Sanders AB, Kern KB, Berg RA, Ewy GA. Chest compression and ventilation rates during cardiopulmonary resus- citation: the effects of audible tone guidance. Acad Emerg Med. 1995;2: 708 –713.
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My takeaway from the study which makes good sense in the chaotic field environment was the number of deviations from protocol, some 13000 in appendix 2. Eg, there was little process control internally on the actual ventilation rates. Perhaps speaks to the need for metronomic sensors/alarms on manual ventilation equipment for use in the field?