Out-of-Hospital Continuous Positive Airway Pressure Ventilation Versus Usual Care in Acute Respiratory Failure: A Randomized Controlled Trial: Answers to the September 2008 Journal Club Questions

Discussion Points 

1.During the past 2 years, Annals has published 4 articles addressing the use of continuous positive airway pressure (CPAP)/bilevel positive airway pressure (BIPAP) in the emergency department (ED). Thompson et al studied the efficacy of CPAP in the out-of-hospital setting and reported beneficial patient outcomes.

1A. Describe the mechanism of action of noninvasive ventilation in the treatment of patients with respiratory distress. Specifically, detail the key differences between CPAP and BIPAP.

1B. Noninvasive ventilation has been advocated for the treatment of ED patients presenting with respiratory distress caused by various cardiopulmonary etiologies. Briefly review the recent literature advocating the use of CPAP/BIPAP in the treatment of acute respiratory distress in the ED.

1C. Discuss the contraindications to initiating noninvasive ventilation in the ED and which patients are not suitable candidates for this treatment. How might these contraindications influence your decision to initiate CPAP/BIPAP in the out-of-hospital setting, immediately on arrival in the ED, or after the patient has failed common pharmaceutical treatments?

2.The authors in this study were granted an exception to informed consent. Patients who met enrollment criteria were read a standard statement that briefly detailed the study, and they were enrolled if they did not opt out. A complete informed consent was obtained later from the patient or his or her surrogate.

2A. Discuss some of the problems of obtaining out-of-hospital consent and the effect on clinical trials in the out-of-hospital setting. Specifically, what steps might a researcher have to take to obtain institutional review board waiver of consent for studies conducted in the field?

2B. Obtaining informed consent from potential research subjects is vital to conducting ethical and moral scientific research. Briefly detail the necessary components of an informed consent for a clinical trial.

2C. In 1976, a federal government commission authored the Belmont Report—Ethical Principles and Guidelines for the protection of human subjects of research. Briefly discuss the basic principles about the ethical treatment and protection of research subjects, including a review of important historical events such as the Nuremberg Code and the Tuskegee Syphilis Study.

3.Although this study was randomized, it was not blinded.

3A.Why did the authors not blind the study? Could they have?

3B. How might the lack of blinding affect the primary outcome? Consider the behavior of the paramedics faced with identical patients who were not doing well, one who was in the CPAP limb and one in the usual care limb. Consider the behavior of an emergency physician who receives 2 similar patients, one receiving CPAP and the other not.

3C. The authors include an online supplementary Table E1, which shows many of the important patient characteristics of each patient. Why is it important that the authors included such a table in this study?

3D. Do you find the organization of Table E1 helpful? Is the table easy to interpret? How is it organized? How might the organization of this table be improved?

3E. Can you use the data in Table E1 to construct tables or graphs that explore the ways that the lack of blinding might have confounded this study and provide evidence about the likelihood that paramedic or emergency physician behavior might have influenced the decision to intubate in ways unrelated to the effect of the CPAP on the patient's condition?

4.In the current economy in which emergency medical services (EMS) funding and allocation of resources are strained, investments in new technology should produce demonstrable benefits in patient outcome sufficient to justify their cost. In this study, the authors used a portable CPAP through a facemask fitted with a CPAP valve and controlled with a portable flow generator used by advanced life support–trained paramedics (Whisperflow; Respironics Agile Medical, Prospect Park, PA; unrestricted equipment loan).

4A. What are the anticipated systems issues in the transfer of out-of-hospital CPAP devices to existing hospital CPAP units? Consider whether out-of-hospital and ED CPAP devices might be incompatible, necessitating each patient to be wastefully treated with 2 sets of equipment. If the CPAP devices are not compatible, how might the need for EMS to maintain CPAP until hospital respiratory therapy services take charge to increase “out of service” time and impact EMS system performance?

4B. According to your response to question 4a, what would you propose as solutions to these system issues?

4C. Out-of-hospital care systems differ. Consider how personnel (volunteer services versus professional, Basic Life Support versus Advanced Life Support) and transport time (rapid urban versus lengthy rural) might affect the utility of out-of-hospital CPAP.

5A. In your opinion, what are the most important conclusions from this article? How might the limitations mentioned by the authors affect your decision about whether to change your clinical practice with regard to the use of CPAP/BIPAP both in the out-of-hospital and ED settings?

5B. In some patients with acute respiratory distress, it is difficult to discern whether the underlying cause is cardiac, pulmonary, or a combination of both. A relative contraindication to CPAP/BIPAP use is acute coronary ischemia. How might the concern for potentially worsening acute dyspnea caused by cardiac ischemia alter the decision to initiate CPAP in patients with known coronary artery disease?

5C. What additional information or data analyses would you like the authors to provide before you decide to change your EMS system's clinical practice?

Answer 1 

Q1. During the past 2 years, Annals has published 4 articles addressing the use of continuous positive airway pressure (CPAP)/bilevel positive airway pressure (BIPAP) in the emergency department (ED). Thompson et al studied the efficacy of CPAP in the out-of-hospital setting and reported beneficial patient outcomes.

Q1.a Describe the mechanism of action of noninvasive ventilation in the treatment of patients with respiratory distress. Specifically, detail the key differences between CPAP and BIPAP.

In awake and cooperative patients, CPAP and BIPAP are adjuncts to improving oxygenation and ventilation in patients with respiratory distress. In physiologic respiration, we develop negative pressure in the thoracic cavity with contraction of the diaphragm and movement of the muscles of respiration. This method moves air into the lungs by a negative-pressure gradient; oxygen moves from the atmosphere into our alveoli.1 In contrast, non-invasive positive pressure ventilation (NIPPV) provides a continuous positive pressure regardless of the phase of respiration. CPAP increases functional residual capacity, the volume of gas contained in the lung after normal respiration, which results in a reduction of atelectasis and intrapulmonary shunting. These improve gas exchange and vital signs.2 CPAP provides the same level of positive pressure during inspiration and expiration. In this study, the authors used a setting of 10 cm H2O for out-of-hospital application. Common settings used in the initiation of BIPAP are 10 cm H2O during inspiration and 5 cm H2O during exhalation.3 BIPAP has been studied in the ED. Poponik et al4 found that BIPAP was successful in more than three quarters of patients in which it was applied in the ED, with a significant decrease in hospital length of stay. Both methods of NIPPV have demonstrated a decreased need for tracheal intubation in patients with acute cardiogenic pulmonary edema.5 However, a recent randomized clinical trial studying the use of standard oxygen therapy, CPAP, and BIPAP in patients with acute cardiogenic pulmonary edema showed no significant difference in the combined endpoint of death or tracheal intubation within 7 days.6 However, BIPAP and CPAP did result in a more rapid improvement in respiratory distress compared to standard oxygen therapy.6

Q1.b Noninvasive ventilation has been advocated for the treatment of ED patients presenting with respiratory distress due to various cardiopulmonary etiologies. Briefly review the recent literature advocating the use of CPAP/BIPAP in the treatment of acute respiratory distress in the ED.

To our knowledge, there are no ED studies addressing CPAP/BIPAP in general respiratory distress. Most studies to date have focused on respiratory distress as a result of acute cardiogenic pulmonary edema. In 2005, Masip et al7 performed a systematic review and meta-analysis of all hospital-based studies on NIPPV in acute cardiogenic pulmonary edema. Fifteen trials were selected and data review discovered that NIPPV reduced the mortality rate by nearly 45% compared with conventional therapy (risk ratio [RR] 0.55; 95% CI [confidence interval] 0.40 to 0.78). The meta-analysis also concluded that CPAP decreased the need to intubate during the course of hospital stay (RR 0.40; 95% CI 0.27 to 0.58). The author concluded that NIPPV reduced the need to intubate and decreases mortality in acute cardiogenic pulmonary edema.7 These results were compelling but were not exclusively focused on ED management use of NIPPV. In 2006, Collins et al8 evaluated the use of NIPPV in ED patients with acute cardiogenic pulmonary edema by performing a comprehensive systematic review of all available ED literature on the topic. The review included randomized trials of adults with a diagnosis of acute cardiogenic pulmonary edema, whose treatment was initiated in ED, and compared NIPPV to standard therapy. Pooled analysis of 494 patients suggested that NIPPV in addition to standard therapy reduced hospital mortality (RR 0.61; 95% CI 0.41 to 0.91). Similarly, a meta-analysis of 436 patients suggested that NIPPV was associated with a significant decrease in tracheal intubation rates (RR 0.43; 95% CI 0.21 to 0.87).8As previously mentioned, most studies involving CPAP/BIPAP are focused on acute cardiogenic pulmonary edema. Meduri et al9 evaluated NIPPV in status asthmaticus. This retrospective study was performed in a medical ICU during 3 years and reported experience with NIPPV in 17 episodes of asthma and acute respiratory failure. The authors concluded that in asthmatic patients with acute respiratory failure, NIPPV was highly effective in correcting gas exchange abnormalities. The authors, however, do mention that a randomized study is needed to fully assess the role of NIPPV in status asthmaticus.9 Both forms of positive pressure ventilation (CPAP and BIPAP) are available at most hospital EDs. Concerning which method is superior, Moritz et al2 studied the efficacy of CPAP delivered by the Boussignac CPAP device and BIPAP in patients with acute respiratory failure caused by acute cardiogenic pulmonary edema. This prospective multicenter randomized study found no significant difference between CPAP and BIPAP. Both methods of noninvasive ventilation decreased need for tracheal intubation, length of hospital stay, and inhospital mortality with the same statistical power.

Q1.c Discuss the contraindications to initiating noninvasive ventilation in the ED and which patients are not suitable candidates for this treatment. How might these contraindications affect your decision to initiate CPAP/BIPAP in the out-of-hospital setting, immediately on arrival in the ED, or after the patient has failed common pharmaceutical treatments?

Both forms of NIPPV reduce preload and can lower blood pressure. Objective criteria for usage are accessory muscle usage or retractions, oxygen saturations less than 90%, respiratory rate greater than 24 breaths/min, the inability to speak in full sentences, or abdominal breathing.10 Contraindications are obvious need for tracheal intubation (apnea or arrest); hypotension; severe alterations of mental status; poor patient cooperation; suspected pneumothorax; facial deformity or inability to obtain a seal; recent facial, neurologic, or gastric surgery; high risk of aspiration (active vomiting); upper airway obstruction; or an unstable cardiac arrhythmia.10 After initial enrollment in the Thompson study had commenced, ongoing review by the data safety and monitoring board requested a change to the study's predefined exclusion criteria. The amendment further defined the exclusion criteria of “ongoing cardiac ischemia” to exclude patients with “any chest pain within three hours.” This was done in response to a published report that CPAP, by applying positive airway pressure throughout the respiratory cycle, may worsen active coronary ischemia by decreasing coronary perfusion pressure.3

Out-of-hospital care providers must consider which is more important, taking the time to initiate NIPPV in the field or rapid transport of the patient in severe respiratory distress. There are many contraindications for initiation of CPAP in the out-of-hospital setting, and the medic must be intimately familiar with protocols for its proper usage and application. An obtunded patient who vomits while wearing a CPAP mask will undoubtedly aspirate and further compromise the airway. Intuitively, the earlier NIPPV is initiated the better. The longer one waits to apply a positive pressure mask in the appropriate patient, the more likely he or she will become fatigued and develop hypercarbia, hypoxia, and an inability to comply with positive pressure ventilation without complication.

Answer 2 

Q2. The authors in this study were granted an exception to informed consent. Patients who met enrollment criteria were read a standard statement that briefly detailed the study and they were enrolled if they did not opt out. A complete informed consent was obtained some time later from the patient or his or her surrogate.

Q2.a Discuss some of the challenges of obtaining out-of-hospital consent and the effect on clinical trials in the out-of-hospital setting. Specifically, what steps might a researcher have to take in order to obtain institutional review board (IRB) waiver of consent for studies conducted in the field?

Informed consent in the out-of-hospital arena is difficult and impractical. Time constraints, medical instability, and the unavailability of legally authorized surrogates may render consent nearly impossible to obtain. The task of consenting patients for a research study might divert medics' attention from the patient and cause unintended harm. In addition, out-of-hospital personnel might not have completed federally mandated human subject research training or have sufficient understanding of the study design, experimental interventions, and risks or benefits of the treatments to obtain consent from the patient appropriately.11

These obstacles to attaining informed consent might lead researchers to opt instead to seek a waiver or exception from informed consent for emergency research. As will be discussed in detail in Answer 2c, the United States and international governing bodies have strict requirements regarding research involving human subjects. The National Institutes of Health (NIH) first established rules requiring independent IRB review before approval of federally funded research in 1966.12 In 1979, the Belmont Report was the result of a federal commission that identified ethical cornerstones for medical research.12 In 1991, a federal policy for the protection of human subjects was written and is known as the Common Rule (45 CFR 46).13 One of the requirements of the Common Rule was informed consent of subjects. Therefore, research involving patients who were unable to provide consent, including resuscitation studies, were stopped in 1991. Over time, it became apparent that this ruling was incompatible with the execution of any emergency research on critical patients, and in 1996 the “Final Rule” was drafted. It specifies the required criteria for studies seeking exception from informed consent for emergency research.14 Investigators could likely cite many reasons why additional research is needed to study treatments of cardiac arrest, respiratory arrest, acute stroke, and severe trauma. However, the process to attain an exception to informed consent for emergency research is an arduous process for both the researcher and the institutional IRB.15 The following criteria must be met for a study to qualify for an exception from informed consent for emergency research14:

These criteria are difficult to fulfill. Nevertheless, studies have been successfully conducted in adherence to the Final Rule regulations since their implementation in 1996.15 Several of the above criteria might seem imposing, such as demonstrating that available treatments are unsatisfactory or unproven. Many studies that fall under such an exception will evaluate a new treatment in addition to standard therapy.16 Community consultation has proven to be one of the most time intensive and potentially expensive requirements.17 What constitutes community consultation is not specifically defined in the federal guidelines, and the individual sponsoring center's IRB ultimately determines what is required. Typically, this community consultation includes mass media announcements, including advertisements about the study and planned community meetings on television, radio, and the Internet and in regional and local newspapers.16 The investigators need to make a good faith effort at educating the community about the research study, discussing potential “opt-out” mechanisms and eliciting any opinions, both positive and negative, about potential participation. It has been suggested that the community consultation and the requirement to discuss the study details, risks and benefits, and results promote trust for the study within the community and also might serve as a deterrent from a researcher attempting to conduct studies that would be discouraged by the community.18 Community consultation can be costly, and Salzman et al17 reported spending nearly $5,000 on their public disclosure advertising for a study evaluating 2 devices used during cardiopulmonary resuscitation.17 Although the requirements to conduct emergency research with waiver of consent might seem imposing, these requirements are in place to protect the rights and welfare of research subjects. Salzman et al17 wrote an excellent article detailing their experiences and provided researchers interested in conducting such studies with excellent tips on navigating the IRB and exception to consent process. Bulger et al19 describe a novel approach to fulfilling the community consultation requirement by using random-dialing surveys to ensure community support and involvement for an out-of-hospital clinical trial.

Q2.b Obtaining informed consent from potential research subjects is vital to conducting ethical and moral scientific research. Briefly detail the necessary components of an informed consent for a clinical trial.

The first sentence in the Nuremberg Code states, “The voluntary consent of the human subject is absolutely essential.”20 The writing of suitable informed consent documents is not an easy task for inexperienced investigators. Fortunately, many IRBs have templates that a researcher can review to create an acceptable consent form. The following answer covers the essential components of a proper informed consent. Each institution's IRB may have additional details that may not be addressed below. Researchers should consult their respective IRB for a detailed description of the required elements in their IRB standard consent form. There are several required elements that a consent form must contain. First, the consent needs to clearly explain that the study involves “research” and also include a brief summary of the study's purpose. For example, the consent might read, “You are being asked to take part in this research study because you came to the ED with abdominal pain. We are trying to see whether a new medicine, Drug X, is better at treating your pain than commonly used treatment, Drug Y.” The consent should also include a detailed description of the study procedures, including specific discussion of the use of placebo (if applicable), the anticipated duration that the research subject will participate in the study, description of the risks and benefits from participating in the study, and a discussion of alternative treatments or procedures that the subject might choose instead of enrolling in the trial. Additionally, the investigator must detail how the patient's identifying medical and personal records will be kept confidential (if applicable) and also discuss whether the subject is compensated for their participation in the research study. The consent should also include the predefined protocol in case of an adverse reaction or event as part of the investigational treatment and who is responsible for covering additional medical expenses. The name and contact information for the principal investigator or study coordinator should be clearly defined so that study participants know who to contact about any questions concerning the study. Most important, the consent should emphasize that participation is voluntary and that patients will incur no penalty for refusing to participate or deciding to discontinue their participation at any time during the duration of the study.

In addition to the above detailed essentials of the consent form, most IRBs require additional language when research studies involve special subject populations such as women of childbearing potential, children, impaired decisionmakers, phase I and II studies (see March 2008 Journal Club answers for further discussion of these types of trials), and the obtaining of consent from an alternative health care decisionmaker.

Last, the consent form needs to be written so that potential subjects can easily understand the document. The Vanderbilt University Medical Center IRB recommends that the consent form be written at a sixth- to eighth-grade reading level.21 Specifically, the consent should not include complex language, medical or legal jargon, references to complicated procedures (eg, tracheal intubation), or potentially confusing or misleading statements. It is customary that the document be written in the second person (ie, “you” and “your”) to emphasize that subjects are ultimately deciding to participate by their own free will. If a researcher intends to enroll non–English-speaking patients, consent forms will often need to be translated into additional languages and closely reviewed to ensure that the content was not altered during the translation.

Q2.c In 1976, a federal government commission authored the Belmont Report—Ethical Principles and Guidelines for the protection of human subjects of research. Briefly discuss the basic principles about the ethical treatment and protection of research subjects, including a review of important historical events such as the Nuremberg Code and the Tuskegee Syphilis Study.

During World War II, Nazi Germany conducted atrocious medical experiments that subjected prisoners to inhumane treatment. After the Nazi surrender, the physicians responsible for these horrific experiments were prosecuted and a set of guidelines for the ethical conduct of medical research, known as the Nuremberg Code, was developed according to the testimony of expert witnesses.15 The Nuremberg code was written in 1949, and the first sentence of the code states, “The voluntary consent of the human subject is absolutely essential.”20 The Nuremberg Code, the Belmont Report, and other ethical guidelines are available for review at the NIH Web page: http://ohsr.od.nih.gov/guidelines/index.html. The guideline further details that the subject should have the legal capacity to give consent and should be able to have freedom of choice whether to participate in the trial. The subject should not be coerced, deceived, or pressured in any way to participate in research. The code mandates that the investigator provide the potential research subject with sufficient information of the study details so that the subject comprehends what the research entails and can make an informed decision to participate.20 The additional elements of the Nuremberg Code state that the experiment's objective should be intended to benefit society and experimental design should be based on previous animal experiments and knowledge of the disease process so that the anticipated results justify the experimentation on human subjects. In addition, the experiment should be conducted in a manner that minimizes mental and physical suffering and maximizes protection against injury, disability, and death. Research subjects should always have the right to withdraw from the study and end the experiment. Likewise, the investigator also must be prepared to terminate a study if he or she believes that continuing the study is likely to result in injury, disability, or death of the subject.20

In 1962, the United States Congress passed the Kefauver-Harris Act that imposed stricter regulations on the US pharmaceutical industry and required reporting of adverse events to the Food and Drug Administration (FDA) and also mandated that drug advertising in medical journals provide complete information, including risks and potential adverse effects, as well as the benefits. This federal act resulted in thousands of medications being taken off the market because of lack of evidence of safety or efficacy. In addition, many other medications had their labeling changed to reflect known medical facts.22 The Kefauver-Harris Act was a response to the thalidomide tragedy. Between 1956 and 1962, approximately 8,000 children were born in Europe with severe birth defects as a consequence of their mothers taking thalidomide, advertised as an antiemetic and sleep aid, during pregnancy. The drug was marketed as safe in pregnancy, but no scientific studies were conducted to assess the safety of thalidomide in pregnant women.23

In 1964, the World Medical Association composed the Helsinki Declaration that detailed ethical principles for the medical research involving human subjects.24 It has been subsequently revised multiple times, but specifies guidelines for medical research and also medical research combined with medical care. It states “it is the duty of the physician in medical research to protect the life, health, privacy, and dignity of the human subject.” The Helsinki Declaration again stated the importance of informed consent and reemphasized many of the Nuremberg principles, including the following: research should be conducted only by scientifically qualified individuals, research involving human subjects should be based on previous animal experimentation or a thorough knowledge of the scientific literature, a careful risk-benefit analysis should be done before initiation of a study, and subjects have the right to abstain or withdraw from the study at any time without penalty or fear of reprisal.16, 24

The ethical principle of justice in research unfortunately has been exploited many times in important historical events such as the aforementioned Nazi medical experiments, in which prisoners were forced to participate in inhumane experiments. In the United States, the Tuskegee Syphilis Study took advantage of disadvantaged, rural black men by withholding treatment of syphilis to study the untreated course of the disease.25 The Public Health Service and Tuskegee Institute began a study in 1932 to examine the natural history of syphilis, with the objective of justifying treatment programs for blacks. The study enrolled 600 men, 399 with syphilis and 201 without the disease. The subjects were not aware of the aims of the study and were told they were being treated for “bad blood” but, in fact, did not receive the appropriate antibiotic for their disease. There was no honest and ethically responsible informed consent completed. The study was initially projected to last 6 months but went on for 40 years. In exchange for participating in the study, subjects were given free medical examinations, free meals, and burial insurance.25 Despite penicillin's acceptance as a treatment of choice for syphilis in 1945, these men were intentionally not given a medically proven treatment for a curable disease. It was not until 1972 that an Associated Press story led to the creation of an ad hoc advisory panel that reviewed the study and found it be “ethically unjustified” and recommended its immediate cessation. The Tuskegee Syphilis Study was halted later that year and, after much public outcry, the federal government provided financial reparations to the study participants and their families. On May 16, 1997, President Clinton officially apologized for the Tuskegee Syphilis Study on behalf of the nation. The Tuskegee Syphilis Study is an atrocious reminder of unethical medical research and violated all 3 of the principles later detailed in the Belmont Report.

After the national outcry about the mistreatment of the men in the Tuskegee Syphilis Study, the National Research Act was signed into law, which created the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research on July 12, 1974. The commission was charged with delineating the basic ethical principles that should be required elements for all biomedical and medical research involving the participation of human subjects in the United States.12 The Belmont Report, published in April 1979, was the commission's answer to this charge and attempted to summarize these basic ethical principles. The 3 basic principles that the Belmont Report emphasized are the following:

Subsequent to the publication of the Belmont Report, additional United States federal regulations governing medical research involving human subjects were written. In 1991, the US Department of Health and Human Services reported the requirements for obtaining and documenting informed consent, in addition to providing a framework for how IRBs should complete initial and subsequent reviews of research studies. This was reported in Part 46 of Title 45 of the Code of Federal Regulations but more commonly referred to as the “Common Rule.”13 It was most recently revised in 2005. In 1996, the FDA revised the regulations to include the exception for consent for emergency research, which has been previously discussed. This is commonly referred to as the “Final Rule.”14

Answer 3 

Q3. Although this study was randomized, it was not blinded.

Q3.a Why did the authors not blind the study? Could they have?

There are at least 4 persons who can potentially be blinded in a study: the patient, the provider, the outcome assessor, and the data analyst. Successful blinding of each of these persons decreases the potential for bias in patients (who might do better just because they have the psychological advantage of knowing they are receiving the active treatment), providers (who may treat intervention and nonintervention patients differently), outcome assessors (who consciously or unconsciously differentially grade outcomes according to knowledge of treatment group), and data analysts (who might select statistical techniques that make one group look better than the other). Blinding, when possible, can greatly diminish the potential for all of these biases.

For studies involving medications delivered by standard routes, it is often possible to truly blind all 4 groups. The success of blinding can be ascertained by asking patients, providers, or outcome assessors to state what group each patient is in. If the blinding is successful, the raters should be correct about half the time. But blinding is not always possible. Even in medication studies one drug might produce adverse effects that, though mild and benign, make patients or providers clearly aware of who is receiving the active agent. In other types of studies, the difficulties of blinding are substantial. How can one blind a surgical procedure from the patient or the provider? At best the scar (or its absence) can be hidden from the outcome assessor and the data analyst can be kept unaware.

It would be impossible to blind the providers in the Thompson et al study. With unlimited resources, a separate crew could accompany the paramedics on every run and, on eligible patients, run one of 2 identical-appearing apparatuses (the sham one with an unobvious valve that let all the pressure out), all of this ideally placed behind a curtain or in a “black box.” This might be sufficient to blind the provider (and the patient); however, it is likely that by observing the patient the paramedic could determine whether CPAP was on.

A more feasible approach would be to have the 2 identical-appearing apparatuses but have the paramedic place them on the patient. This would blind the patient but not the provider.

The authors chose to do neither. We discuss their likely rationale in the next answer.

Q3.b How might the lack of blinding affect the primary outcome? Consider the behavior of the paramedics when faced with identical patients who were not doing well, one who was in the CPAP limb and one in the usual care limb. Consider the behavior of an emergency physician who receives 2 similar patients, one receiving CPAP and the other not.

Any attempt to blind both provider and patient would have been astronomically expensive and questionably successful. It is wholly understandable why the authors chose not to do this. Blinding that patient might have been feasible but might not have been worth the effort. Although patients who know they are receiving CPAP may get a placebo effect, we are more concerned that providers may act differently according to which group the patient is in.

Consider the first clinical scenario posed in the question. The patient in the regular care limb is not doing well. The paramedics have come to believe that CPAP might help the patient but they are not allowed to use it. They feel bad for the patient and are concerned that during the next minutes he might deteriorate further because he is not receiving the “state-of-the-art” treatment. They have one option, tracheal intubation. Not surprisingly, they may be quick to use it. A similar patient in the CPAP limb might be viewed differently. The paramedic might believe that he is using a promising new technology that might, given a bit of time, improve the patient's condition. He is less likely to perform an early tracheal intubation. Thus, it is the knowledge of the patient's treatment, not the patient's condition (which is identical in the 2 cases), that changes the tracheal intubation pattern. This phenomenon could account for all or a portion of the observed difference between groups.

The emergency physician may also behave differently according to knowledge of what limb the patient is in. A patient already receiving CPAP is likely to continue receiving CPAP without interruption. Assuming CPAP is of some benefit, this patient fully benefits from this treatment. In contrast, for a patient in the out-of-hospital standard care group who has not been intubated, there is likely going to be a delay before that patient is evaluated, is tentatively diagnosed and, perhaps, begins receiving CPAP. Had this patient been receiving sham CPAP on arrival to the ED, the physician might have acted more quickly to start real CPAP. A similar argument can be made for intubated patients in the standard care group. They might receive different care than they would have had they arrived with sham CPAP. Again, these differences, caused by the lack of blinding, could account for all or part of the observed difference in outcome between limbs.

Q3.c The authors include an online supplementary Table E1 that shows many of the important patient characteristics of each patient. Why is it important that the authors included such a table in this study?

This study enrolled 69 patients (see Figure 2 of Thompson et al), 34 in the usual care limb and 35 in the CPAP limb. Question 2b of the May 2008 Journal Club (answers in October 2008 issue)26 explored how the effectiveness of randomization was related to sample size and proved that when fewer than 200 subjects are randomized, there is a fairly high likelihood that the groups created will substantially differ from one another in ways that might be important. In such circumstances, it is sometimes necessary to go through the data case by case to decide whether observed differences in outcome are due to the treatment or due to a confounding factor that randomization failed to balance.

To their credit, the authors' willingness to share their by-subject data allows each reader to scrutinize the data and decide whether the observed differences result from real benefits from CPAP or from confounding. Had these data not been presented, readers might have had legitimate questions about the article that went unanswered. When this occurs, an article does not meet the Ziman27 definition of consensibility, that “each message should not be so obscure or ambiguous that the recipient is unable either to give it whole-hearted assent or to offer well-founded objections.” In other words, if a scientific article does not provide sufficient information to allow readers to decide whether the thesis is correct, then the scientific process comes to a halt; consensibility is a necessary condition for the development of consensus. By providing Table E1, the authors move their article closer to meeting the definition of consensuality, which is always a desirable goal.

Q3.d Do you find the organization of Table 1 helpful? Is the table easy to interpret? How is it organized? How might the organization of this table be improved?

Table E1 is organized in the chronologic order of patient enrollment, with patients randomized to the CPAP group on a white background and those in the standard care group on an aqua background. This organization is helpful if the most pressing question is, how did the patients and outcomes change during the course of the study, but it is unlikely the question that most have in mind. Other groupings and orderings of patients such as intubated versus nonintubated, age, O2 saturation, etc, might help readers determine whether such factors played a role in the outcomes. Graphics are likely an even better way of conveying this information. An alternative, and one that is likely to become more feasible in the upcoming years, is to post such data to the Internet as a data set that can be examined with an online tool that lets the reader interactively query the data. Would you like to see a graph of standard versus CPAP patients stratified by age and tracheal intubation status? Click a few boxes and here it is. Do you want this repeated using only those patients younger than 75 years? That is just another click away. Such devices would greatly facilitate readers' interaction with the data and may be the way that trials are presented in the future.

Q3.e Can you use the data in Table E1 to construct tables or graphs that explore the ways that the lack of blinding might have confounded this study and provide evidence about the likelihood that paramedic or emergency physician behavior might have influenced the decision to intubate in ways unrelated to the effect of the CPAP on the patient's condition?

Unfortunately, some of the data required to make such tables or figures are not presented in Table E1. Such an analysis would require knowledge of when during the out-of-hospital course patients were intubated and more detailed information about each patient's clinical course in the field and ED. From these data, one could construct detailed graphics that might help decide whether the patients who were intubated in the standard care group were truly sicker than those in the CPAP group at tracheal intubation.

As an example of what could be done to these data, we offer an analysis of field oximetry and outcome in the 2 groups.

This graph shows the number of patients in the CPAP and standard care groups in each category of initial pulse oximetry. Within each bar, color indicates the most advanced airway that the patient required. The 2 vertical black lines show the mean initial pulse oximetry level for each group. From this graph, we see that the CPAP group had higher mean pulse oximetry readings and that none of the patients in this group were intubated. The majority of intubated patients in the standard care group had pulse oximetry readings of 70% or less.

This graph shows how pictures of the data can help us understand what is going on. A series of graphs like this one would allow us to see how different factors affect outcome and help us to understand whether these data support CPAP over standard care or whether confounding could be responsible for observed differences. The graph suggests that some of the difference in field tracheal intubation rates may be due to the chance occurrence of more severely hypoxic patients in the standard care group but also suggests that CPAP has a beneficial effect. By numbering each “brick” in the graph, the authors could link each patient in the graphic to Table E1, allowing readers to postulate why the 2 patients with initial pulse oximetry between 85% and 90% were intubated.

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Answer 4 

Q4. In the current economy in which emergency medical services (EMS) funding and allocation of resources are strained, investments in new technology should produce demonstrable benefits in patient outcome sufficient to justify their cost. In this study, the authors used a portable CPAP through a facemask fitted with a CPAP valve and controlled with a portable flow generator used by advanced life support–trained paramedics (Whisperflow; Respironics Agile Medical, Prospect Park, PA; unrestricted equipment loan).

Q4.a What are the anticipated systems issues in the transfer of out-of-hospital CPAP devices to existing hospital CPAP units? Consider whether out-of-hospital and ED CPAP devices might be incompatible, necessitating each patient to be wastefully treated with 2 sets of equipment. If the CPAP devices are not compatible, how might the need for EMS to maintain CPAP until hospital respiratory therapy services take charge increase “out of service” time and affect EMS system performance?

This trial convincingly demonstrated that out-of-hospital application of CPAP by trained paramedics resulted in an absolute reduction in tracheal intubation of 30% and an absolute reduction in mortality of 21%. Although the outcome was compelling, the trial should be repeated in other settings to confirm the results and establish the effectiveness of this modality. Even then, certain system issues must be addressed before the out-of-hospital use of CPAP can be advocated. As mentioned in the article, the Whisperflow device provided 10 cm H2O CPAP through a facemask fitted with a CPAP valve and controlled with a portable flow generator. For CPAP to be ultimately effective at decreasing morbidity and mortality, it must be continued until the patient no longer needs positive pressure support. Consider the receiving facility; if the ED is not capable of providing positive-pressure ventilation or cannot provide an oxygen source similar to that used by the EMS device, or if respiratory therapy is not readily available to establish NIPPV on arrival to the ED, paramedics must continue their CPAP therapy until a solution is achieved. When a paramedic is at the receiving hospital, his unit is “out of service” and cannot respond to the next 911 call that may be in his or her area. It is well documented in the literature that early and rapid response of EMS personnel can improve survival in cardiac arrest, especially those with shockable rhythms.28 Many of the nation's largest EMS systems have proposed no longer than 10 minutes at a receiving facility until the medic relinquishes care to the ED and returns to the streets.29 It is quite possible that in many systems paramedics will either have to stop the NIPPV and begin giving the patient high-flow oxygen if they are to meet the 10-minute rule or have to ignore the rule, jeopardizing the care of the next 911 call in which there is not an ALS engine nearby.

Q4.b According to your response to question 4a, what would you propose as solutions to these system issues?

If out-of-hospital CPAP reduces morbidity and mortality to the extent reported by Thompson et al, it would be important to solve any systems-based impediments to implementation. One possible solution is to invest in compatible devices in all EDs to which a patient who begins receiving CPAP could feasibly be transported. In an effort to reduce cost, as well as patient morbidity and mortality, Memorial Hermann Healthcare System and the City of Houston Fire Department EMS formed a partnership designed to decrease the need for unneeded tracheal intubations in congestive heart failure (CHF) patients in the out-of-hospital setting. The hospital purchased 51 CPAP machines and 9,000 CPAP circuits and provided them to Houston Fire EMS. They also bought the same devices for all receiving facilities in the hospital system. The initial cost was large, but data analysis demonstrated that the 79% reduction in ultimate tracheal intubation by out-of-hospital application of CPAP resulted in a minimum cost savings of $656,000 for Memorial Hermann according to an average hospital expense of $8,000 for the first 24 hours of mechanical ventilation and care.30

Another proposed solution is the application of a CPAP device, which does not require an external generator and is compatible with any ED. The Boussignac CPAP system is an FDA-approved facemask CPAP system. It is a simple disposable cylindrical plastic device without moving parts or heavy tubing. This system can, and has, been used in the ICU and in the out-of-hospital setting. A jet flow of air or oxygen generated in this plastic tube creates a flow-dependent pressure when attached to a high-flow oxygen source. Roughly 15 L per minute of high-flow oxygen from a usual oxygen tank delivers 10 cm H2O of CPAP through the mask.31 The advantages of this device are that it is easy to use and requires only a standard oxygen tank and the disposable facemask unit. In addition, on arrival to an ED, EMS personnel can attach this device to the hospital's own high-flow oxygen source and get back in service without waiting for hospital equipment. However, there are disadvantages. The initial cost to the EMS system and the cost for replacement of the disposable units are limiting factors. Furthermore, if the hospital uses the EMS-placed device, it is unclear who would pay for it, the hospital or the EMS agency.

Q4.c Out-of-hospital care systems differ. Consider how personnel (volunteer versus professional, Basic Life Support versus ALS) and transport time (rapid urban versus lengthy rural) might affect the utility of out-of-hospital CPAP.

In this study, the authors conclude that paramedics can be trained to use CPAP for patients in severe respiratory failure. Ninety-six paramedics underwent a comprehensive education program consisting of ethical conduct of research and study protocols. There were didactic sessions, as well as practical testing. However, many EMS systems in the United States use basic life support or volunteer models of care, leading to a question of generalizability to these EMS systems. In 2003, the Physician Advisory Committee for the State of Wisconsin undertook a study of basic life support–administered CPAP. The goal of the study was to show that basic EMTs had no greater failure rate than paramedics because of complications or the need for tracheal intubation. The EMT basics received a 2-hour didactic with 1 hour of practical training, in addition to a written and practical examination. The CPAP was minimized to 5 cm H2O in the EMT basics protocols. The authors concluded that basic life support providers could provide CPAP to patients in respiratory distress, with no more complication rates or protocol violations than ALS-trained paramedics.32

Thompson et al reported total out-of-hospital times of 43.8 minutes and 41.3 minutes in the usual care and CPAP groups, respectively. These reported times might be longer than the average EMS transport times in the United States. To our knowledge, there is no published literature directly addressing the average transport times in rural versus urban settings in the United States. Gonzales et al33 reviewed Alabama's statewide out-of-hospital data during a 2-year period to assess whether increased out-of-hospital “on scene” and transport time in rural and urban environments increased morbidity and mortality in motor vehicle crashes. When mortalities occurred, the mean EMS response time in rural settings was 10.67 minutes and 6.50 minutes in urban settings. In addition, those crashes resulting in death had 18.87 minutes of transport times in rural settings and 10.83 minutes in urban settings.33 To calculate their approximate total out-of-hospital time, we would add the on-scene and transport times, which result in times of 29.5 minutes and 17.3 minutes for rural and urban systems, respectively. Compared with the data obtained in the study by Thompson et al, even rural transport times were much shorter than found in the CPAP study. One may assume that the longer CPAP is applied, the greater the benefit in oxygenation and ventilation. For EMS services with short transport times, one may wonder whether the extended scene time needed to apply the device is worth the tradeoff of rapid transport to an ED for definitive care of the patient in severe respiratory distress.

Answer 5 

Q5.a In your opinion, what are the most important conclusions from this article? How might the limitations mentioned by the authors affect your decision whether to change your clinical practice with regard to the use of CPAP/BIPAP both in the out-of-hospital and ED settings?

This article reports some compelling results with regard to the out-of-hospital use of CPAP in patients with acute respiratory failure as a result of common ED diagnoses of acutely decompensated CHF, acute exacerbation of chronic obstructive pulmonary disease, or status asthmaticus. First, the authors demonstrated that the out-of-hospital providers can accurately screen patients with acute respiratory distress for the appropriateness of CPAP and then institute CPAP treatment in the out-of-hospital setting, without frequent complications. The article reported a 30% absolute decrease (17 [50%] versus 7 [20%]) in the number of tracheal intubations in the CPAP group compared with the usual care group. Nine of the 17 patients in the usual care arm were intubated by paramedics before arrival in the ED. None of the 7 patients intubated in the CPAP group had tracheal intubation attempted by paramedics. The study also showed an overall decrease in mortality of 21% in the patients randomized to the CPAP group compared with those in the usual care group (12 [35.3%] versus 5 [14.3%]). Why might this be so? Could instituting NIPPV earlier in patients' respiratory failure provide earlier stabilization or reversal of their hypoxic or hypercarbic insults? Are out-of-hospital tracheal intubations less “clean” and more likely to lead to increased frequency of secondary pneumonias, thereby increasing the inhospital mortality? The authors did not detect a significant difference in mortality between patients intubated in the field and the other usual care cohort (40% versus 33%). Overall, this article provides evidence that in patients with acute severe respiratory distress, CPAP offers paramedics a noninvasive, facile, beneficial treatment alternative to tracheal intubation.

The authors admit that because of this study's urban EMS setting with short transport times, combined with their CPAP devices' requirement for large reserves of high-pressure oxygen, generalizability of this intervention to more rural EMS systems with long transport distances might not be possible. The authors also mention that the study's results might have been influenced by cointervention bias. Cointervention bias occurs when subjects are receiving additional interventions at the same time as the study treatment. For example, consider a patient with acute respiratory distress caused by CHF who is randomized to CPAP and does not require tracheal intubation compared with a patient who is randomized to usual care. Potentially, the other cointerventions (amount of nitroglycerin given, administration of diuretics, etc) might have affected the ultimate necessity for tracheal intubation more than the CPAP intervention.

In addition, the cost of equipping an EMS system with CPAP machines that are compatible with the receiving hospitals' is an important issue, given that most cities are battling budget deficits in the present economy. This issue was discussed above, but each EMS director and his or her staff must decide whether the results of this study and previous inhospital NIPPV research are compelling enough to make the investment.

Q5.b In some patients with acute respiratory distress, it is difficult to discern whether the underlying cause is cardiac, pulmonary, or a combination of both. A relative contraindication to CPAP/BIPAP use is acute coronary ischemia. How might the concern for potentially worsening acute dyspnea caused by cardiac ischemia alter the decision to initiate CPAP in patients with known coronary artery disease?

Although the literature suggests that there may be a deleterious effect of NIPPV in patients with respiratory distress caused by acute coronary ischemia, it is not known whether this potential decrease in coronary perfusion pressure causes more harm than hypoxia and hypercarbia resulting from insufficient ventilation. Also, Gray et al6 published the results of their randomized trial that found no relationship between the rate of myocardial infarction and treatment with CPAP or NIPPV. However, a potential compromise might include first performing an ECG, and if the ECG and the patient's medical history are not overtly concerning for acute coronary ischemia, the paramedic is permitted to use CPAP treatment if clinically indicated. In the situations in which the ECG demonstrates signs of acute ischemia or the patient's medical history is concerning for an acute myocardial infarction, standard care might be preferred unless the patient requires tracheal intubation. If the rationale behind the potential harm of NIPPV is the result of the positive pressure on the preload and coronary perfusion pressure, then it seems reasonable to assume that similar harmful effects would also occur with tracheal intubation and positive-pressure ventilation. In the scenario in which the paramedic is suspecting that the patient is having an acute cardiac ischemic event and might need tracheal intubation before arrival at the hospital, the benefits of improved oxygenation and ventilation of CPAP might outweigh the theoretical risks compared with the potential risks associated with out-of-hospital tracheal intubation. These include potential adverse hemodynamic effects of tracheal intubation medications, potential for failed tracheal intubation with subsequent aspiration and hypoxia, and potential for hemodynamic collapse.

Q5.c What additional information or data analyses would you like the authors to provide before you decide to change your EMS system's clinical practice?

Four of the CPAP patients were intubated in the ED, but the authors do not mention whether they were intubated immediately on arrival or later in their ED stay. This information might provide additional insight into whether CPAP assisted with the acute respiratory distress or not. Did the CPAP “buy” the paramedic some time to get the patient to the ED, where they were intubated immediately? Did the CPAP leave the patient's ultimate course unchanged, with the exception of moving the tracheal intubation to the ED, a potentially more controlled and cleaner setting than the back of an ambulance? Likewise, we do not know the specific indications for out-of-hospital tracheal intubation in the usual care cohort. According to the information in Table 2 (and the Figure in Answer 3e), the patients in each group seem relatively similar, with the following exceptions: the usual care cohort had 16% more male patients (58.8% versus 42.9%) than the CPAP group, and the usual care group had a lower median SpO2 of 75% versus 81.5% in the CPAP group. Table 4 reports that 47.1% of the usual care cohort and 37.1% of the CPAP cohort were admitted to the ICU. However, the median duration of stay in the ICU for the usual care patients was less than half the length for the CPAP patients. Was this because usual care patients who were intubated were weaned quicker from the vent and transferred to the floor, or did more of these patients die earlier in the ICU course, accounting for the shorter length of stay? Unfortunately, a reported median result does not provide the reader with this information. The authors might have provided histograms representing the distribution of the continuous variables reported in Table 4 (length of stay, ICU length of stay). Histograms would provide the reader with a more complete understanding of the results. Figure E1 likely contains much of this information but in a format that is more cumbersome to interpret.

The authors do acknowledge in their “Limitations” section that they did not formally record the number of patients screened who were not enrolled. It would also be of interest to know how many patients would have been excluded according to the “any chest pain within 3 hours” criterion because a recent randomized trial found no relationship between acute myocardial infarction and CPAP or NIPPV.6 Might the inclusion of patients with a report of chest discomfort, which anecdotally is not uncommon in patients with CHF and COPD/asthma exacerbations, have altered the results of this study? As mentioned above with regard to protection of human subjects, these investigators did the correct thing in excluding patients with potential coronary ischemia according to the available information when the study was conducted. However, given the recent contrary evidence, repeating the study without the chest pain exclusion might produce interesting supportive or contrary results to this study.

Although it might be beyond the scope of this article, it would be of interest to EMS directors considering investing in CPAP technology to know some of the problems that the authors encountered implementing the system. Did all of the paramedics feel comfortable using the CPAP on patients with severe respiratory distress, or might there have been an unconscious selection bias to not include the severely ill because of a lack of familiarity with the device? Because the paramedics were forbidden to use the CPAP device outside the study protocol and the trial was conducted during a 3 ½-year period, there might have been extended periods during which a paramedic did not use the device. Were there problems with the out-of-hospital CPAP device not being compatible with the receiving hospital's equipment? Were the receiving hospitals receptive to the patients who began receiving CPAP in the field? Although this study was supported by an unrestricted equipment loan from the CPAP device manufacturer, did the investigators encounter any additional unforeseen potential expenses or equipment problems that would be important for an EMS director to know before incorporating CPAP in their system?