Perspective
Equipoise in Research and the Development of Neonatal Interventions for the Management of Respiratory Distress Syndrome: A Historical Perspective Mario Augusto Rojas, MD, MPH1 1 Division of Neonatal-Perinatal Medicine, Department of Pediatrics,
Wake Forest University School of Medicine, Salem, North Carolina Am J Perinatol 2015;32:910–915.
Abstract
Keywords
► premature infant ► respiratory distress syndrome ► randomized controlled trials
Address for correspondence Mario Augusto Rojas, MD, MPH, Division of Neonatal-Perinatal Medicine, Department of Pediatrics, Wake Forest University School of Medicine, Medical Center Boulevard, Winston Salem, NC 27157 (e-mail: [email protected]).
The historical review of how evidence was developed for the management of respiratory distress syndrome in premature infants has not been clearly characterized. Knowledge of this process is essential to understand the role of equipoise and its influence on the decision to evaluate interventions as they were implemented in the practice of medicine. We suspect that errant approaches to clinical equipoise secondary to states of false certainty and false uncertainty have been important barriers to the timely acquisition and implementation of evidence-based knowledge necessary to improve outcomes in this fragile population of infants. When confronted with the decision to test an intervention, physicians should question whether they have lost clinical equipoise based on opinion, expertise, or observational data rather than evidence obtained from methodological inquiry; doing so facilitates reaching clinical equipoise and promotes the application of scientific methodology to answer relevant clinical questions. Timely acquisition of evidence-based knowledge can be viewed as an ethical imperative when the status quo may have negative consequences on outcomes for generations.
Frequently in the practice of medicine, physicians are confronted with the decision to choose between two different treatments for the same disease and need to determine which treatment is superior to improve the outcome of their patients. When the physician has no vested interest in either of the two treatments (bias), he/she will review the literature to determine if there is objective evidence to support the superiority of one treatment over the other. If one or more well-designed randomized controlled trials (RCTs) show that one treatment is superior to the other, the clinician will reach a state of true certainty or “loss of clinical equipoise” and will begin offering this treatment to his/her patients.1 If, by contrast, the available evidence does not support the superiority of either treatment (absence of or conflicting RCTs), the physician can state he/she has reached
a state of true uncertainty or clinical equipoise that will allow the physician to ethically enroll his/her patients in an RCT testing these two interventions.1 A problem arises when the clinician loses equipoise through a state of false certainty based on evidence that has a high level of potential bias such as opinion, expertise, or observational data. Reluctance to participate in research based on this state cannot be supported on ethical grounds. These situations are frequent in the practice of medicine when physicians overestimate their personal observations in lieu of evidence obtained from methodological inquiry. Historically, many invasive and noninvasive interventions have been implemented in the practice of medicine without being tested rigorously through methodological inquiry; in many cases they are supported passionately by physicians
received October 7, 2014 accepted after revision December 23, 2014 published online March 12, 2015
Copyright © 2015 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.
DOI http://dx.doi.org/ 10.1055/s-0035-1545665. ISSN 0735-1631.
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Equipoise in Neonatal-Perinatal Research
Background Continuous positive airway pressure (CPAP) was developed by Dr. George Gregory in the 1960s, after the publication of two sentinel articles by Chu et al4 and Harrison et al5 describing how grunting in premature infants with hyaline membrane disease (HMD) was the result of a physiologic effort by the infant to generate an end expiratory pressure and maintain adequate gas exchange. A subsequent manuscript by Dr. Gregory, published in the New England Journal of Medicine in 1971, described the successful testing of the first prototype of CPAP in premature infants with HMD.6 More than 40 years later, we are still testing
this mode of noninvasive ventilatory support. Why has it taken so long to determine the efficacy and safety of CPAP for the treatment of HMD? To answer this question, it is important for us to understand the historical context in which CPAP was developed.
Presurfactant Era In the mid-1970s, during the presurfactant era, both mechanical ventilation (MV) and nasal CPAP (nCPAP) were being developed for the treatment of HMD; once implemented in the practice of medicine, a logical next step would have been to test them in a head-to-head comparison with the use of scientific methodology. RCT methodology was well validated by this time, albeit some reluctance was voiced by “antitrialists.”7,8 Plausible explanations for failure to rigorously test these interventions could be explained by lack of education or disbelief in scientific methodology, pressure from corporations to support the implementation of more complex and expensive technologies, and bias generated through overestimation of personal experience, opinion, or observational data. Institutions in the United States that were using nCPAP for the treatment of what was subsequently termed respiratory distress syndrome (RDS) argued that it would be unethical to randomize 50% of infants to MV, a treatment they considered an inferior mode of ventilatory support; physicians who used MV as their primary mode of ventilatory support had similar ethical concerns but with bias in favor of MV. Infatuation with complex technology may have led some physicians to prefer MV and undermined the potential benefits of nCPAP; others may have equated higher cost to better outcomes. The problem with the previous assumptions is that they were not based on evidence obtained from methodological inquiry, and because there was no objective evidence to support the superiority of either of these modes of ventilatory support, clinical equipoise should have led these physicians to design and conduct a well-powered multicenter RCT. Reluctance to participate in research was based on a state of false certainty, not loss of clinical equipoise and therefore the reluctance was not ethically justified.
Table 1 Self-evaluation for equipoise: conceptual framework Quality of the evidence Clinical equipoise (true uncertainty)
Loss of equipoise (true certainty)
• No RCT evidence or conflicting evidence from RCTs • Evidence based on opinion, expertise, or observational data (high likelihood of bias) • Well-designed RCT evidence • High-quality metaanalyses
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Action
Errant approach
Participate in RCT
False certainty: reluctance to participate in RCT, high likelihood of bias
Abstain from participating in RCT, implement evidence-based knowledge
False uncertainty: disregards high-quality evidence, reluctance to implement evidence-based knowledge
Abbreviation: RCT, randomized controlled trial.
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who use them in their daily practice. Possible explanations for why physicians reach a state of false certainty are the underestimation of methodological inquiry or a lack of understanding of scientific methodology. Another explanation may be conscious or unconscious bias derived from conflicts of interest with manufacturing companies, technology, or physician perceptions of what is deemed optimal care. Randomized controlled clinical trials are considered the “gold standard” for informing treatment decisions and are deemed ethical only if we have reached a state of true uncertainty (clinical equipoise) as to which treatment would be most beneficial for the patients.2 By contrast, a state of false uncertainty may lead physicians to participate in studies where there is objective evidence supporting the superiority of one treatment over the other, thereby raising ethical concerns. Additionally, this state of false uncertainty may lead to unnecessary delay in the implementation of interventions proven to be efficacious and safe. Explanations for this errant behavior are similar to those of false certainty and can also include behavioral reluctance to change. Ultimately, the level of controversy generated by these errant behaviors leads to a stalemate situation that delays or impedes scientific progress.3 The aim of this study is to evaluate how equipoise has affected the development of neonatal interventions for the management of respiratory distress syndrome using the conceptual framework described earlier (►Table 1).
Rojas
Equipoise in Neonatal-Perinatal Research
Rojas
Another plausible explanation for the presumed “loss of clinical equipoise” could have been the availability of observational data showing better outcomes in institutions using primarily nCPAP compared with institutions that used MV as their first line of therapy for RDS. Again, these assumptions were based on limited observational data and not methodological inquiry. In 1987, prior to the availability of surfactant, Dr. Mary Ellen Avery and her colleagues published an observational study showing a low comparative incidence of bronchopulmonary dysplasia (BPD) in one of the participating institutions that used bubble nCPAP as the initial mode of ventilatory support for RDS. The results of this study should have generated a testable hypothesis, not loss of clinical equipoise.9 Confirming the results of Dr. Avery’s observational data through an RCT would have led to the acquisition of new knowledge and possibly expedited implementation of evidence-based practice. Unfortunately this trial was never done, creating a gap in knowledge that would affect the quality of care and outcomes of sick infants for decades. In this scenario, reluctance to participate in research that has the potential to generalize evidence-based knowledge that may improve outcomes should be considered inappropriate from an ethical perspective.
Surfactant Era Thanks to the groundbreaking work by Drs. Avery and Mead explaining the pathophysiology of HMD,10 the first studies testing the efficacy and safety of exogenous surfactant administration in premature infants with RDS on MV were published in the early 1980s.11–14 The results of these and other trials demonstrating a significant reduction in death and morbidity with early administration of surfactant led physicians to change their standard of practice (true certainty). This was considered one of the most important advances in the history of neonatology. From an evidence-based perspective, the next logical question to evaluate at that time would have been the efficacy and safety of exogenous surfactant administration in patients with RDS who received nCPAP as the first line of ventilatory support. Reducing the severity of RDS and its associated morbidity and mortality in the pre-antenatal steroid era should have been sufficient motivation for physicians who used nCPAP to design and participate in an RCT comparing nCPAP with and without early surfactant administration. This trial was never conducted in the United States by those centers advocating the use of nCPAP. Because both arms of the proposed trial would have exposed infants to nCPAP, the ethical argument for inferiority could not have been sustained. Explanations for why physicians advocating the use of nCPAP in the United States were not compelled to test the addition of early surfactant may again be attributed to disbelief in scientific methodology, reluctance to intubate infants for the sole purpose of administrating surfactant, or the belief that nCPAP alone may facilitate early endogenous surfactant production, making exogenous surfactant administration unnecessary. Although this last assumption may have had some theoretical validity, there were no animal American Journal of Perinatology
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models or evidence acquired through methodological inquiry at that time that could support loss of clinical equipoise in favor of not testing early surfactant administration in this patient population. The high rates of CPAP failure (42%) documented in observational studies prior to the implementation of antenatal steroids should have compelled clinician researchers to test the potential benefits of surfactant in this fragile population of preterm infants.9 Reluctance to intubate an infant with moderate-to-severe RDS for the sole purpose of administering surfactant should not have been a barrier to testing this novel intervention for RDS. Clearly, intubation of preterm infants with RDS was a generalized practice in the 1990s; therefore, transient intubation of preterm infants to administer early surfactant and replacement of nCPAP (INSURE) would have been feasible and easy to test. Concerns related to the risk for increased airway injury should have been balanced with the benefits derived from the administration of early surfactant and the risk of BPD. Again, clinical equipoise should have led clinical researchers to ethically justify their participation in the design and conduct of this important trial at a time when the risk versus benefit of these interventions was not well established. From a historical perspective, it is fair to say that a state of false certainty played a major role in the reluctance of physicians to design and participate in studies aimed at answering these important questions. Reliance on biased opinion, expertise, and observational data prevailed over the need to obtain knowledge through scientific methodological inquiry.
Antenatal Steroid Era “Glucocorticoids are essential to normal lung development. They participate in the regulation of important developmental events including morphological changes, and lung maturation leading to the surge of surfactant synthesis by type II epithelial cells.”15 The first evidence of benefits associated with antenatal steroids was published in 1969 when Graham Liggins discovered that lambs exposed to steroids prenatally survived longer than control lambs.16 A subsequent RCT by the same author testing the use of antenatal steroids in mothers with preterm labor showed that they reduced the incidence and severity of RDS as well as mortality in premature infants (true certainty).17 Explanations for why it took more than 30 years to generalize the use of this novel intervention suggest that “loss of clinical equipoise” through a state of false uncertainty may have been an important barrier to early implementation of antenatal steroids by obstetricians. The commentary in 1995 by Dr. Mary Ellen Avery, a leader in neonatal medicine, supports this assumption. She also suggests that, as a consequence, physicians underestimated the results of two major RCTs demonstrating the safety and efficacy of antenatal steroids.18,19 Reluctance to implement this evidence-based intervention among obstetricians became obvious during the RCTs testing surfactant for RDS, where only 10% of eligible infants enrolled were exposed to antenatal steroids.18 Concerns with long-term effects should have led to long-term developmental follow-up, not stagnation.20 Neonatal Network data demonstrate the slow
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process of antenatal steroid implementation for very-lowbirth-weight infants from 23.8% in 1991 to 71.6% in 1999.21 The increase in the use of antenatal steroids in the United States in 1999 was closely related to the National Institutes of Health (NIH) consensus agreement in 1994 citing the results from a meta-analysis of 15 RCTs. The NIH panel concluded that antenatal steroids significantly reduced neonatal mortality, RDS, and intraventricular hemorrhage with no proven short-term or long-term risks to the infant (true certainty). This consensus agreement was subsequently endorsed by the American College of Obstetrics and Gynecology (ACOG) and supports the argument of false uncertainty as a cause for the previous lack of implementation.22 A recent Cochrane review of 21 antenatal studies shows that current use of antenatal steroids in premature infants 0.60
94
6.6 (MV þ ES)
Rojas et al 2009 (CNRN)
9
6
0.75
88
2 (CPAP þ ES)
Finer et al 2010 (SUPPORT)
6.8
5
> 0.5
96.8
7.4 (PMV þ PS)
Dilmen et al 2013 (PIE not included)
9
7
0.40
62.7
0 (PCPAP þ ES)
Göpel et al 2011 (AMV) (PIE not included)
7
4
0.45
96
4 (CPAP þ CRS)
Abbreviations: CPAP, continuous positive airway pressure; CRS, catheter rescue surfactant; ES, early surfactant (given within the first 2 hours of life); MV, mechanical ventilation; PCPAP, prophylactic continuous positive airway pressure; PIE, pulmonary interstitial emphysema; PMV, prophylactic mechanical ventilation; PS, prophylactic surfactant; RS, rescue surfactant. American Journal of Perinatology
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Equipoise in Neonatal-Perinatal Research
Equipoise in Neonatal-Perinatal Research
Rojas
These results clearly provide the basis for an evidence-based change in practice (true certainty) and emphasize the importance of ESS administration for RDS in infants supported with MV or CPAP. Disregarding this evidence in the postsurfactant era raises concerns about not applying the best available evidence to patient care (false uncertainty). In the postsurfactant and postantenatal steroid era, the current body of evidence supports the use of clinical judgment and early selective therapies to treat RDS. A metaanalysis by Fischer et al also showed that avoiding endotracheal mechanical ventilation consistently led to a reduction in the incidence of death or BPD in all the included trials (OR 0.83 [95% CI, 0.71–0.96]).39 The addition of ESS to early selective CPAP may have a greater effect on reducing the incidence of BPD and requires further testing. Two recent studies from Germany tested what seems to be a less-invasive mode of administering surfactant through a catheter with infants breathing spontaneously.40,41 The first trial did not find a difference in BPD rates between the intervention and control groups, but the second study by Kanmaz et al showed a decrease in BPD with the use of this technique compared with standard INSURE. This decrease in BPD is countered by an unexplained and concerning high incidence of air leak syndrome in both arms of the study (Take Care 9%, INSURE 13%).40,41 Avoiding positive pressure ventilation during surfactant administration may decrease lung injury and BPD, but more studies are required before this presumed less-invasive intervention is considered safe and efficacious. Future studies testing the efficacy and safety of inhaled surfactant are forthcoming. An additional important but unanswered question is what effect these interventions have on long-term neurodevelopmental outcome. This concern stems from evidence supporting a decrease in cerebral blood flow in preterm infants with RDS who are exposed to MV but not CPAP.42–44 Investigators are also concerned about the effects that hypercapnia may have on the developing brain with the use of CPAP and rescue surfactant.45 Future trials comparing CPAP with ESS to MV with ESS should include neurodevelopmental follow-up in their design. Finally, the conceptual framework delineated in this manuscript to address problems with errant approaches to clinical equipoise can help clinical researchers, community physicians, members of investigational review boards, and funding agencies uncover hidden biases that may limit the timely design and conduct of relevant research as well as limit the implementation of proven therapies. New treatments that have the potential to improve outcomes in this fragile population of infants should be funded and tested promptly with the “gold standard.” The design of these clinical trials should be guided by the availability and quality of the evidence obtained from methodological inquiry. Cost–benefit analyses should also guide the prioritization and implementation of the evidence obtained from these trials. Timely acquisition of evidence-based knowledge should be viewed as an ethical imperative when the status quo may have negative consequences on outcomes for generations.
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In summary, this paper presents a historical perspective on how errant approaches to clinical equipoise have influenced the acquisition of knowledge and implementation of novel interventions for the treatment of RDS. States of false certainty and false uncertainty appear to have played a major role in physician reluctance to participate in the timely design and conduct of relevant clinical trials and the implementation of evidence-based knowledge. Physicians responsible for the care of sick infants should self-evaluate for the existence of clinical equipoise using the conceptual framework delineated in this manuscript to set research priorities and improve the care of their patients in a timely manner.
Financial Support Wake Forest University School of Medicine provided financial support for this study.
Acknowledgments The author thanks Dr. Michael O’Shea, Dr. Laura Corbin Downey, and Dr. Christine E. Bishop for their critical review of the article.
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immature lung in utero induces injury and BPD-like changes in lung structure in fetal sheep. Pediatr Res 2008;64(4):387–392 Hernandez LA, Peevy KJ, Moise AA, Parker JC. Chest wall restriction limits high airway pressure-induced lung injury in young rabbits. J Appl Physiol (1985) 1989;66(5):2364–2368 Parker JC, Hernandez LA, Peevy KJ. Mechanisms of ventilatorinduced lung injury. Crit Care Med 1993;21(1):131–143 Björklund LJ, Ingimarsson J, Curstedt T, et al. Manual ventilation with a few large breaths at birth compromises the therapeutic effect of subsequent surfactant replacement in immature lambs. Pediatr Res 1997;42(3):348–355 Morley CJ, Davis PG, Doyle LW, Brion LP, Hascoet JM, Carlin JB; COIN Trial Investigators. Nasal CPAP or intubation at birth for very preterm infants. N Engl J Med 2008;358(7):700–708 Finer NN, Carlo WA, Walsh MC, et al; SUPPORT Study Group of the Eunice Kennedy Shriver NICHD Neonatal Research Network. Early CPAP versus surfactant in extremely preterm infants. N Engl J Med 2010;362(21):1970–1979 Stevens TP, Harrington EW, Blennow M, Soll RF. Early surfactant administration with brief ventilation vs. selective surfactant and continued mechanical ventilation for preterm infants with or at risk for respiratory distress syndrome. Cochrane Database Syst Rev 2007;(4):CD003063 Bahadue FL, Soll R. Early versus delayed selective surfactant treatment for neonatal respiratory distress syndrome. Cochrane Database Syst Rev 2012;11(11):CD001456 Bhatia R, Davis PG, Doyle LW, Wong C, Morley CJ. Identification of pneumothorax in very preterm infants. J Pediatr 2011;159(1): 115–120.e1 Fischer HS, Bührer C. Avoiding endotracheal ventilation to prevent bronchopulmonary dysplasia: a meta-analysis. Pediatrics 2013; 132(5):e1351–e1360 Göpel W, Kribs A, Ziegler A, et al; German Neonatal Network. Avoidance of mechanical ventilation by surfactant treatment of spontaneously breathing preterm infants (AMV): an open-label, randomised, controlled trial. Lancet 2011;378(9803):1627–1634 Kanmaz HG, Erdeve O, Canpolat FE, Mutlu B, Dilmen U. Surfactant administration via thin catheter during spontaneous breathing: randomized controlled trial. Pediatrics 2013;131(2):e502–e509 Tsuji M, Saul JP, du Plessis A, et al. Cerebral intravascular oxygenation correlates with mean arterial pressure in critically ill premature infants. Pediatrics 2000;106(4):625–632 Milan A, Freato F, Vanzo V, Chiandetti L, Zaramella P. Influence of ventilation mode on neonatal cerebral blood flow and volume. Early Hum Dev 2009;85(7):415–419 Dani C, Bertini G, Cecchi A, Corsini I, Pratesi S, Rubaltelli FF. Brain haemodynamic effects of nasal continuous airway pressure in preterm infants of less than 30 weeks’ gestation. Acta Paediatr 2007;96(10):1421–1425 Rogovik A, Goldman R. Permissive hypercapnia. Emerg Med Clin North Am 2008;26(4):941–952, viii–ix Dilmen U, Özemir R, Tatar Aksoy H, et al.Early regular versus late selective poractant treatment in preterm infants born between 25 and 30 gestational weeks: a prospective randomized multicenter study. J Matern Fetal Neonatal Med 2014;27:411–415
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Equipoise in Neonatal-Perinatal Research
Equipoise in Research and the Development of Neonatal Interventions for the Management of Respiratory Distress Syndrome: A Historical Perspective Mario Augusto Rojas, MD, MPH1 1 Division of Neonatal-Perinatal Medicine, Department of Pediatrics,
Wake Forest University School of Medicine, Salem, North Carolina Am J Perinatol 2015;32:910–915.
Abstract
Keywords
► premature infant ► respiratory distress syndrome ► randomized controlled trials
Address for correspondence Mario Augusto Rojas, MD, MPH, Division of Neonatal-Perinatal Medicine, Department of Pediatrics, Wake Forest University School of Medicine, Medical Center Boulevard, Winston Salem, NC 27157 (e-mail: [email protected]).
The historical review of how evidence was developed for the management of respiratory distress syndrome in premature infants has not been clearly characterized. Knowledge of this process is essential to understand the role of equipoise and its influence on the decision to evaluate interventions as they were implemented in the practice of medicine. We suspect that errant approaches to clinical equipoise secondary to states of false certainty and false uncertainty have been important barriers to the timely acquisition and implementation of evidence-based knowledge necessary to improve outcomes in this fragile population of infants. When confronted with the decision to test an intervention, physicians should question whether they have lost clinical equipoise based on opinion, expertise, or observational data rather than evidence obtained from methodological inquiry; doing so facilitates reaching clinical equipoise and promotes the application of scientific methodology to answer relevant clinical questions. Timely acquisition of evidence-based knowledge can be viewed as an ethical imperative when the status quo may have negative consequences on outcomes for generations.
Frequently in the practice of medicine, physicians are confronted with the decision to choose between two different treatments for the same disease and need to determine which treatment is superior to improve the outcome of their patients. When the physician has no vested interest in either of the two treatments (bias), he/she will review the literature to determine if there is objective evidence to support the superiority of one treatment over the other. If one or more well-designed randomized controlled trials (RCTs) show that one treatment is superior to the other, the clinician will reach a state of true certainty or “loss of clinical equipoise” and will begin offering this treatment to his/her patients.1 If, by contrast, the available evidence does not support the superiority of either treatment (absence of or conflicting RCTs), the physician can state he/she has reached
a state of true uncertainty or clinical equipoise that will allow the physician to ethically enroll his/her patients in an RCT testing these two interventions.1 A problem arises when the clinician loses equipoise through a state of false certainty based on evidence that has a high level of potential bias such as opinion, expertise, or observational data. Reluctance to participate in research based on this state cannot be supported on ethical grounds. These situations are frequent in the practice of medicine when physicians overestimate their personal observations in lieu of evidence obtained from methodological inquiry. Historically, many invasive and noninvasive interventions have been implemented in the practice of medicine without being tested rigorously through methodological inquiry; in many cases they are supported passionately by physicians
received October 7, 2014 accepted after revision December 23, 2014 published online March 12, 2015
Copyright © 2015 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.
DOI http://dx.doi.org/ 10.1055/s-0035-1545665. ISSN 0735-1631.
Downloaded by: University of Pennsylvania Libraries. Copyrighted material.
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Equipoise in Neonatal-Perinatal Research
Background Continuous positive airway pressure (CPAP) was developed by Dr. George Gregory in the 1960s, after the publication of two sentinel articles by Chu et al4 and Harrison et al5 describing how grunting in premature infants with hyaline membrane disease (HMD) was the result of a physiologic effort by the infant to generate an end expiratory pressure and maintain adequate gas exchange. A subsequent manuscript by Dr. Gregory, published in the New England Journal of Medicine in 1971, described the successful testing of the first prototype of CPAP in premature infants with HMD.6 More than 40 years later, we are still testing
this mode of noninvasive ventilatory support. Why has it taken so long to determine the efficacy and safety of CPAP for the treatment of HMD? To answer this question, it is important for us to understand the historical context in which CPAP was developed.
Presurfactant Era In the mid-1970s, during the presurfactant era, both mechanical ventilation (MV) and nasal CPAP (nCPAP) were being developed for the treatment of HMD; once implemented in the practice of medicine, a logical next step would have been to test them in a head-to-head comparison with the use of scientific methodology. RCT methodology was well validated by this time, albeit some reluctance was voiced by “antitrialists.”7,8 Plausible explanations for failure to rigorously test these interventions could be explained by lack of education or disbelief in scientific methodology, pressure from corporations to support the implementation of more complex and expensive technologies, and bias generated through overestimation of personal experience, opinion, or observational data. Institutions in the United States that were using nCPAP for the treatment of what was subsequently termed respiratory distress syndrome (RDS) argued that it would be unethical to randomize 50% of infants to MV, a treatment they considered an inferior mode of ventilatory support; physicians who used MV as their primary mode of ventilatory support had similar ethical concerns but with bias in favor of MV. Infatuation with complex technology may have led some physicians to prefer MV and undermined the potential benefits of nCPAP; others may have equated higher cost to better outcomes. The problem with the previous assumptions is that they were not based on evidence obtained from methodological inquiry, and because there was no objective evidence to support the superiority of either of these modes of ventilatory support, clinical equipoise should have led these physicians to design and conduct a well-powered multicenter RCT. Reluctance to participate in research was based on a state of false certainty, not loss of clinical equipoise and therefore the reluctance was not ethically justified.
Table 1 Self-evaluation for equipoise: conceptual framework Quality of the evidence Clinical equipoise (true uncertainty)
Loss of equipoise (true certainty)
• No RCT evidence or conflicting evidence from RCTs • Evidence based on opinion, expertise, or observational data (high likelihood of bias) • Well-designed RCT evidence • High-quality metaanalyses
911
Action
Errant approach
Participate in RCT
False certainty: reluctance to participate in RCT, high likelihood of bias
Abstain from participating in RCT, implement evidence-based knowledge
False uncertainty: disregards high-quality evidence, reluctance to implement evidence-based knowledge
Abbreviation: RCT, randomized controlled trial.
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who use them in their daily practice. Possible explanations for why physicians reach a state of false certainty are the underestimation of methodological inquiry or a lack of understanding of scientific methodology. Another explanation may be conscious or unconscious bias derived from conflicts of interest with manufacturing companies, technology, or physician perceptions of what is deemed optimal care. Randomized controlled clinical trials are considered the “gold standard” for informing treatment decisions and are deemed ethical only if we have reached a state of true uncertainty (clinical equipoise) as to which treatment would be most beneficial for the patients.2 By contrast, a state of false uncertainty may lead physicians to participate in studies where there is objective evidence supporting the superiority of one treatment over the other, thereby raising ethical concerns. Additionally, this state of false uncertainty may lead to unnecessary delay in the implementation of interventions proven to be efficacious and safe. Explanations for this errant behavior are similar to those of false certainty and can also include behavioral reluctance to change. Ultimately, the level of controversy generated by these errant behaviors leads to a stalemate situation that delays or impedes scientific progress.3 The aim of this study is to evaluate how equipoise has affected the development of neonatal interventions for the management of respiratory distress syndrome using the conceptual framework described earlier (►Table 1).
Rojas
Equipoise in Neonatal-Perinatal Research
Rojas
Another plausible explanation for the presumed “loss of clinical equipoise” could have been the availability of observational data showing better outcomes in institutions using primarily nCPAP compared with institutions that used MV as their first line of therapy for RDS. Again, these assumptions were based on limited observational data and not methodological inquiry. In 1987, prior to the availability of surfactant, Dr. Mary Ellen Avery and her colleagues published an observational study showing a low comparative incidence of bronchopulmonary dysplasia (BPD) in one of the participating institutions that used bubble nCPAP as the initial mode of ventilatory support for RDS. The results of this study should have generated a testable hypothesis, not loss of clinical equipoise.9 Confirming the results of Dr. Avery’s observational data through an RCT would have led to the acquisition of new knowledge and possibly expedited implementation of evidence-based practice. Unfortunately this trial was never done, creating a gap in knowledge that would affect the quality of care and outcomes of sick infants for decades. In this scenario, reluctance to participate in research that has the potential to generalize evidence-based knowledge that may improve outcomes should be considered inappropriate from an ethical perspective.
Surfactant Era Thanks to the groundbreaking work by Drs. Avery and Mead explaining the pathophysiology of HMD,10 the first studies testing the efficacy and safety of exogenous surfactant administration in premature infants with RDS on MV were published in the early 1980s.11–14 The results of these and other trials demonstrating a significant reduction in death and morbidity with early administration of surfactant led physicians to change their standard of practice (true certainty). This was considered one of the most important advances in the history of neonatology. From an evidence-based perspective, the next logical question to evaluate at that time would have been the efficacy and safety of exogenous surfactant administration in patients with RDS who received nCPAP as the first line of ventilatory support. Reducing the severity of RDS and its associated morbidity and mortality in the pre-antenatal steroid era should have been sufficient motivation for physicians who used nCPAP to design and participate in an RCT comparing nCPAP with and without early surfactant administration. This trial was never conducted in the United States by those centers advocating the use of nCPAP. Because both arms of the proposed trial would have exposed infants to nCPAP, the ethical argument for inferiority could not have been sustained. Explanations for why physicians advocating the use of nCPAP in the United States were not compelled to test the addition of early surfactant may again be attributed to disbelief in scientific methodology, reluctance to intubate infants for the sole purpose of administrating surfactant, or the belief that nCPAP alone may facilitate early endogenous surfactant production, making exogenous surfactant administration unnecessary. Although this last assumption may have had some theoretical validity, there were no animal American Journal of Perinatology
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models or evidence acquired through methodological inquiry at that time that could support loss of clinical equipoise in favor of not testing early surfactant administration in this patient population. The high rates of CPAP failure (42%) documented in observational studies prior to the implementation of antenatal steroids should have compelled clinician researchers to test the potential benefits of surfactant in this fragile population of preterm infants.9 Reluctance to intubate an infant with moderate-to-severe RDS for the sole purpose of administering surfactant should not have been a barrier to testing this novel intervention for RDS. Clearly, intubation of preterm infants with RDS was a generalized practice in the 1990s; therefore, transient intubation of preterm infants to administer early surfactant and replacement of nCPAP (INSURE) would have been feasible and easy to test. Concerns related to the risk for increased airway injury should have been balanced with the benefits derived from the administration of early surfactant and the risk of BPD. Again, clinical equipoise should have led clinical researchers to ethically justify their participation in the design and conduct of this important trial at a time when the risk versus benefit of these interventions was not well established. From a historical perspective, it is fair to say that a state of false certainty played a major role in the reluctance of physicians to design and participate in studies aimed at answering these important questions. Reliance on biased opinion, expertise, and observational data prevailed over the need to obtain knowledge through scientific methodological inquiry.
Antenatal Steroid Era “Glucocorticoids are essential to normal lung development. They participate in the regulation of important developmental events including morphological changes, and lung maturation leading to the surge of surfactant synthesis by type II epithelial cells.”15 The first evidence of benefits associated with antenatal steroids was published in 1969 when Graham Liggins discovered that lambs exposed to steroids prenatally survived longer than control lambs.16 A subsequent RCT by the same author testing the use of antenatal steroids in mothers with preterm labor showed that they reduced the incidence and severity of RDS as well as mortality in premature infants (true certainty).17 Explanations for why it took more than 30 years to generalize the use of this novel intervention suggest that “loss of clinical equipoise” through a state of false uncertainty may have been an important barrier to early implementation of antenatal steroids by obstetricians. The commentary in 1995 by Dr. Mary Ellen Avery, a leader in neonatal medicine, supports this assumption. She also suggests that, as a consequence, physicians underestimated the results of two major RCTs demonstrating the safety and efficacy of antenatal steroids.18,19 Reluctance to implement this evidence-based intervention among obstetricians became obvious during the RCTs testing surfactant for RDS, where only 10% of eligible infants enrolled were exposed to antenatal steroids.18 Concerns with long-term effects should have led to long-term developmental follow-up, not stagnation.20 Neonatal Network data demonstrate the slow
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process of antenatal steroid implementation for very-lowbirth-weight infants from 23.8% in 1991 to 71.6% in 1999.21 The increase in the use of antenatal steroids in the United States in 1999 was closely related to the National Institutes of Health (NIH) consensus agreement in 1994 citing the results from a meta-analysis of 15 RCTs. The NIH panel concluded that antenatal steroids significantly reduced neonatal mortality, RDS, and intraventricular hemorrhage with no proven short-term or long-term risks to the infant (true certainty). This consensus agreement was subsequently endorsed by the American College of Obstetrics and Gynecology (ACOG) and supports the argument of false uncertainty as a cause for the previous lack of implementation.22 A recent Cochrane review of 21 antenatal studies shows that current use of antenatal steroids in premature infants 0.60
94
6.6 (MV þ ES)
Rojas et al 2009 (CNRN)
9
6
0.75
88
2 (CPAP þ ES)
Finer et al 2010 (SUPPORT)
6.8
5
> 0.5
96.8
7.4 (PMV þ PS)
Dilmen et al 2013 (PIE not included)
9
7
0.40
62.7
0 (PCPAP þ ES)
Göpel et al 2011 (AMV) (PIE not included)
7
4
0.45
96
4 (CPAP þ CRS)
Abbreviations: CPAP, continuous positive airway pressure; CRS, catheter rescue surfactant; ES, early surfactant (given within the first 2 hours of life); MV, mechanical ventilation; PCPAP, prophylactic continuous positive airway pressure; PIE, pulmonary interstitial emphysema; PMV, prophylactic mechanical ventilation; PS, prophylactic surfactant; RS, rescue surfactant. American Journal of Perinatology
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Equipoise in Neonatal-Perinatal Research
Equipoise in Neonatal-Perinatal Research
Rojas
These results clearly provide the basis for an evidence-based change in practice (true certainty) and emphasize the importance of ESS administration for RDS in infants supported with MV or CPAP. Disregarding this evidence in the postsurfactant era raises concerns about not applying the best available evidence to patient care (false uncertainty). In the postsurfactant and postantenatal steroid era, the current body of evidence supports the use of clinical judgment and early selective therapies to treat RDS. A metaanalysis by Fischer et al also showed that avoiding endotracheal mechanical ventilation consistently led to a reduction in the incidence of death or BPD in all the included trials (OR 0.83 [95% CI, 0.71–0.96]).39 The addition of ESS to early selective CPAP may have a greater effect on reducing the incidence of BPD and requires further testing. Two recent studies from Germany tested what seems to be a less-invasive mode of administering surfactant through a catheter with infants breathing spontaneously.40,41 The first trial did not find a difference in BPD rates between the intervention and control groups, but the second study by Kanmaz et al showed a decrease in BPD with the use of this technique compared with standard INSURE. This decrease in BPD is countered by an unexplained and concerning high incidence of air leak syndrome in both arms of the study (Take Care 9%, INSURE 13%).40,41 Avoiding positive pressure ventilation during surfactant administration may decrease lung injury and BPD, but more studies are required before this presumed less-invasive intervention is considered safe and efficacious. Future studies testing the efficacy and safety of inhaled surfactant are forthcoming. An additional important but unanswered question is what effect these interventions have on long-term neurodevelopmental outcome. This concern stems from evidence supporting a decrease in cerebral blood flow in preterm infants with RDS who are exposed to MV but not CPAP.42–44 Investigators are also concerned about the effects that hypercapnia may have on the developing brain with the use of CPAP and rescue surfactant.45 Future trials comparing CPAP with ESS to MV with ESS should include neurodevelopmental follow-up in their design. Finally, the conceptual framework delineated in this manuscript to address problems with errant approaches to clinical equipoise can help clinical researchers, community physicians, members of investigational review boards, and funding agencies uncover hidden biases that may limit the timely design and conduct of relevant research as well as limit the implementation of proven therapies. New treatments that have the potential to improve outcomes in this fragile population of infants should be funded and tested promptly with the “gold standard.” The design of these clinical trials should be guided by the availability and quality of the evidence obtained from methodological inquiry. Cost–benefit analyses should also guide the prioritization and implementation of the evidence obtained from these trials. Timely acquisition of evidence-based knowledge should be viewed as an ethical imperative when the status quo may have negative consequences on outcomes for generations.
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In summary, this paper presents a historical perspective on how errant approaches to clinical equipoise have influenced the acquisition of knowledge and implementation of novel interventions for the treatment of RDS. States of false certainty and false uncertainty appear to have played a major role in physician reluctance to participate in the timely design and conduct of relevant clinical trials and the implementation of evidence-based knowledge. Physicians responsible for the care of sick infants should self-evaluate for the existence of clinical equipoise using the conceptual framework delineated in this manuscript to set research priorities and improve the care of their patients in a timely manner.
Financial Support Wake Forest University School of Medicine provided financial support for this study.
Acknowledgments The author thanks Dr. Michael O’Shea, Dr. Laura Corbin Downey, and Dr. Christine E. Bishop for their critical review of the article.
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