Second Opinions and the Rise of REPAP: Part II

We attempted our first submission of the REPAP paper with a leading sleep journal, which summarily rejected the work for many of the reasons described in the previous post. The reviewers emphasized methodological weaknesses as well what in our opinion appeared to be obvious confusion about how sleep centers currently address CPAP failure.

One of the first complaints described in the rejection letter was at odds with what most people think or know about the practice of sleep medicine: “The practice of mask changes, mode and pressure changes are the usual treatment for patients who re-present to sleep clinic and are willing to retry CPAP.” No doubt the reviewer did not carefully review our work, because we explained our sample comprised second opinion patients who failed CPAP at their original sleep centers, yet from these patients’ perspectives there was no additional support or suggestions regarding changes in mask, modes or pressures. And, in treating a fair number of CPAP failure patients outside New Mexico who made the effort to travel to Albuquerque for a second opinion, the same complaints were registered in the general form of “no other options were discussed,” or “no other equipment changes were recommended for pressure delivery modes or pressure settings.” Some reported they never underwent a single titration study in the sleep lab.

Another claim from the reviewers was as follows: “The select patient population willing to undergo multiple repeat titrations and obtain a second opinion at a special sleep clinic do not represent the bulk of CPAP failures in the community;” however, both points are indefensible as virtually no second opinion research exists in the scientific literature. For all we know many CPAP failure cases would be extremely motivated to obtain second opinions if offered the opportunity. Likewise, once these individuals were educated on the underlying flaws in the use of continuous positive airway pressure (CPAP), they might express considerable motivation to pursue a retitration to test out dual-pressure technology.

A different reviewer made a very interesting comment on the number of retitrations completed by patients who ultimate used PAP therapy: “Those who had multiple titrations had a greater proportion of CPAP users than those who had a single titration. It is unclear whether it was the persistence of the patient and/or the physician that generated the multiple titrations. Were the patients who underwent multiple titrations more likely to be patients who were dedicated to the treatment and persisted, which would make them more likely to be users than those who had one titration or was it that the single titration was adequate.”

The reviewer made valid points, because our study was not a randomized controlled, prospective design in which we investigated one group undergoing single retitrations compared to another group undergoing multiple retitrations to determine which group showed more PAP use and adherence. However, at the same time the reviewer seems to neglect that every patient entered the REPAP protocol with virtually the same baseline, that is, attempted CPAP and either rejected it immediately or ceased use at some point after completing setup and trying to adapt at home. Therefore, any patient in our sample who became a user was deemed to have reversed CPAP failure, and those who renewed use were significantly more likely to have undergone more than one retitration study. Again, it’s a valid statement we did not prove that multiple retitrations were a key aspect of reversing CPAP failure, but nonetheless, common sense tells us that just by bringing these patients back to the sleep lab to try out dual-pressure, auto-adjusting technology and then have them report the experience as more comfortable and positive than past trials withCPAP strongly hints at the potential value of this model of care.

The most remarkable comment in this initial rejection of our manuscript was as follows: “There was a missed opportunity to emphasize the importance of evaluating the presence of residual events with the data provided by CPAP software rather than dwell on retitration as a dose adjustment. Unlike medication adjustments, the success of the titration for the most part, is quite evident during the procedure hitting the mark of AHI <5. Therefore, I would take exception for characterizing the current method as "one and done". It is ‘one and done’ because it can be.” 

The one and done remark refers to our introduction in the manuscript highlighting how many sleep centers only complete one titration for the vast majority of patients and then claim optimal results have been achieved because the AHI < 5. However, there are many discrepancies in the reviewer’s comments because the AASM standard for any titration is RDI < 5, because the RDI metric is much more accurate in measuring residual breathing events. For these reasons, and contrary to the reviewer, we believe PAP therapy is exactly like an adjustment to a medication dosage, and we would go so far as to exclaim that the standard of care should be to retitrate OSA/UARS patients in the first few months or years of use, because their pressure settings frequently need adjustment upwards or downwards to improve individual clinical responses. The bold statement by the reviewer implying that “one and done” is a very successful model has little if any support in the scientific literature. Rather, one and done is actually a conventional wisdom followed by a huge proportion of sleep technologists and specialists, because they have chosen to follow outdated guidelines (AHI instead of RDI) and perhaps are intimidated by their relationships with insurance carriers (spending healthcare dollars on retitrations).

Naturally, in any review there are useful pointers on how to improve the manuscript, but I trust you can see from the above criticisms, the reviewers demonstrated either a lack of knowledge on our approach to care or simply rejected our ideas as lacking clinical relevance. No surprise, then, the editor and reviewers rejected the manuscript.

The second attempt on the manuscript was submitted to another well-respected and widely read (by sleep professionals) sleep medicine journal, and the progression of events culminating in another rejection were very illuminating, because we chose to appeal their decision, which revealed even more gaps in knowledge regarding how some sleep experts manage CPAP failure.

In this appeal response to this second rejection from the second journal we noted: “Technology to our way of thinking is the elephant in the room as prior research routinely ignores the pervasive subjective complaints and objective findings of expiratory pressure intolerance.” In another words, the reviewers all but ignored or rejected the idea that technology might play an instrumental role in overcoming CPAP failure by addressing a physiological side-effect of CPAP.

A particularly telling comment along these lines emerged from a reviewer declaring our manuscript had “too much detail.” We could only assume this complaint was directed at our detailed discussion on the mechanics of expiratory pressure intolerance arising when a CPAP titration attempts to eliminate RERAs (flow limitations), the discrete and more subtle breathing events observed in exclusively in UARS or partially in OSA. By providing this detail, we had hoped to persuade reviewers a rationale for the application of advanced PAP technology to directly address expiratory pressure intolerance and thus outline a scientific hypothesis to test by using ABPAP or ASV in CPAP failure cases.

The next complaint, a fair one to be sure, was whether or not the REPAP protocol would be cost-prohibitive. The specific comment from a reviewer though again proved more telling, “For example, given the current climate of insurances severely restricting repeat titration studies one begins to wonder if retitration is the best form of action.” To our way of thinking, this conflation of insurance carrier restrictions somehow determining the best care for our patients may be understandable, but it still seems inappropriate. That is, regardless of cost, it is the physician’s duty to determine and recommend the best forms of treatment for patients. How the patient proceeds with this knowledge depends on many factors of which cost and insurance reimbursement are certainly relevant. However, the context of our research paper frames this issue in a patient-centric manner. We reviewed charts on individuals who rejected or ceased use of CPAP once started, which by all current evidence is an extraordinarily expensive state of affairs due to the innumerable health and economic costs linked to untreated UARS/OSA. By offering this perspective, our paper noted the importance of reversing CPAP failure in 70% of patients undergoing second opinions, thereby bringing into play a new set of health and economic factors likely to far outweigh the cost of one or two “extra” retitrations. For example, two retitrations might cost an insurance carrier around $1500 to $2,000 in New Mexico, but a hospitalization for a heart attack or a motor vehicle accident could easily exceed $50,000 or even $100,000.

A reviewer then made several interesting points about the degree of follow-up in this cohort of patients prior to their seeking care at our sleep center, the critical role of follow-up to improve adherence, and then raised the question of whether or not education, not technology, was the more relevant factor in the how and why of our patients reversing CPAP failure.

On the first point, our manuscript detailed how CPAP failure patients complained about numerous gaps in their follow-up at previous sleep centers, including the specific lack of attention to the potential use of new masks or PAP modes. Several other complaints were lodged with the process that directly applied to or indirectly hinted at technology failure such as pressure intolerance, struggling to adapt, mask discomfort and leak, and no perceived benefits. Regarding the second point on follow-up in general, the reviewer made no mention of a role for retitrating the patient in the sleep lab as if technology could not improve outcomes. Finally, in raising the question on the impact of education, we could only assume the reviewer believes that expiratory pressure intolerance is merely a psychological symptom that goes away once someone uses the device long enough. This conventional wisdom is rife within the sleep medicine community and in our view demonstrates a blind spot regarding the objective physiological stressors patients must endure to eventually adapt to a PAP device. We responded to the reviewer: “We find it difficult to imagine how education/insight from clinicians explains how patients overcame their discomfort with the PAP device and how it would have eliminated their expiratory pressure intolerance.” Clearly, because we routinely see ABPAP or ASV eliminating this pressure intolerance, we have chosen the path to treat failing CPAP patients more aggressively with this model of care; and, despite our chart review research (retrospective design), our data generate a testable hypothesis: can advanced PAP therapy reverse CPAP failure?

Last, one reviewer had considerable difficulty understanding our entire approach to the sleep lab as exemplified by this quote: “Moreover, it's not clear to me how the method of re-titration described in this paper was developed. For example, were patients first re-titrated with CPAP and were switched to BPAP or ASV due to EPI? It's also not clear what is meant by subjective and objective EPI. If BPAP was in fact needed, why use an auto BPAP instead of manually titrating BPAP?”

Subsequently, we attempted to respond to this critique, but the manuscript was again rejected, which prompted us to write a second appeal, particularly in light of this seeming resistance to how PAP technology might be delivered in a novel way. In this second appeal, we chose to introduce our response by directly attacking this issue in the following way:

“As a preface to our detailed letter, we wish to underscore a key issue that surfaces in every critique we have received from the reviewers. The issue involves the concept of manually titrating auto-adjusting, dual-pressure PAP technology in the sleep lab environment. Each reviewer in both versions of the manuscript expressed confusion about this idea or appeared to not understand the concept.

“The concept is straightforward. In the sleep lab, an auto-adjusting device can be set to auto mode, but then the attending sleep technologist manipulates all pressure settings on ABPAP or ASV devices to produce what amounts to a better response than the auto-mode only. Still, the auto-mode is retained, because the device continues to self-adjust to provide a better airflow signal, but through the added information of the manual titration, the pressure settings are now constrained in a more effective manner. Unfortunately, it appears our reviewers, like many other sleep researchers and clinicians, seem to only be aware of the use of auto-adjusting devices used with HST, but even then the auto mode may have only been used to set a fixed CPAP pressure.

“Our paper is describing how fixed CPAP or BPAP pressures cause iatrogenic problems to the airflow curve, which can be resolved by manually titrating auto-adjusting, dual-pressure PAP in the sleep lab.   The patient is then prescribed pressure modes and pressures according to settings determined in the sleep lab, based on the sleep tech’s titration and the physician’s interpretation.

“Thus, our use of auto-adjusting technology reflects a novel way to approach titrations and has no relationship whatsoever to the current use of auto-adjusting technology in the HST environment. We are spelling out this point, because it is clear that reviewers do not understand or are confused about what we are doing in the lab. And, we believe this lack of understanding or clarity has led to an inaccurate and incomplete review of our work.”

This second appeal was again rejected, prompting us to seek out another journal, Respiratory Care, which earlier in the year had given us a favorable response to our paper on adherence and sub-threshold adherence to PAP therapy when using advanced PAP technology. The publication of that paper prompted us to direct our next submission of the REPAP study to the journal Respiratory Care.

Barry Krakow MD


Dr Krakow’s 27 years of sleep research have focused on the complex relationship between physiological and psychological sleep disorders. Dr Krakow currently operates private sleep medical center, Maimonides Sleep Arts & Sciences, Ltd., and serves as Classic SleepCare’s paid Medical Director.

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