Ethical Support for Surfactant, Positive Pressure, and Oxygenation Randomized Trial (SUPPORT)
2013; Elsevier BV; Volume: 163; Issue: 5 Linguagem: Inglês
10.1016/j.jpeds.2013.06.037
ISSN1097-6833
Autores Tópico(s)Neuroscience of respiration and sleep
ResumoSee related article, p 1495“Teach thy tongue to say I do not know and thou shalt progress.”-William Silverman, MDConsumer advocacy group Public Citizen has leveled some very serious allegations against the National Institutes of Health funded Surfactant, Positive Pressure, and Oxygenation Randomized Trial (SUPPORT). The randomized study involved 23 major academic centers (including the institution in which I am employed) and was designed to determine the appropriate range of oxygen saturation in extremely preterm infants.1SUPPORT Study Group of the Eunice Kennedy shriver NICHD Neonatal Research NetworkTarget ranges of oxygen saturation in extremely preterm infants.N Engl J Med. 2010; 362: 1959-1969Crossref PubMed Scopus (724) Google Scholar This was done by using 2 target ranges of oxygen saturation (low, 85%-89%, and high, 91%-95%). According to Public Citizen's letter to Department of Health and Human Services Secretary Kathleen Sebelius, the vulnerable infants were subject to “highly unethical” (page 1) and “indefensible” (page 11) research.2Carome, Michael A, Wolfe S (Public Citizen). Letter to The Honorable Kathleen Sebelius (Secretary, Department of Health and Human Services). 2013 Apr 10. Available at: http://www.citizen.org/documents/2111.pdf. Accessed April 15, 2013.Google Scholar Parents were deceived into enrolling their infants via “egregious” (page 3) deficiencies in the informed consent process. The letter closes by demanding a “formal apology” (page 11) to all 1316 patients who were enrolled in the study.Public Citizen has grossly distorted what was “known” about treating premature infants at the time of the study. Unfortunately, the use of oxygen in neonatology has a long and tragic history. As early as 1900, oxygen was recommended for premature infants during episodes of cyanosis. Early incubators were flooded with oxygen even though it was recognized that there was no “convincing evidence that an increased oxygen content of arterial blood is beneficial or necessarily of importance.”3Robertson A.F. Reflections on errors in neonatology: I. The “hands-off” years, 1920-1950.J Perinatol. 2003; 23: 48-55Crossref PubMed Scopus (51) Google Scholar Additionally, there was no way at this time to quickly and noninvasively measure the baby's oxygen levels or saturation. By the 1950s, it was recognized that too much oxygen led to blindness in the form of retrolental fibroplasia. Indeed, this was the cause of famous preemie Stevie Wonder's blindness. After this discovery, oxygen use was restricted and the outcome was disastrous–death and cerebral palsy rates sharply increased.4Buchanan LR. (Compliance Oversight Coordinator, Department of Health & Human Services, Office for Human Research Protections). Letter to Richard B. Marchase, PhD (V.P. for Research and Economic Development, University of Alabama at Birmingham). 2013 Mar 7. Available at: http://www.hhs.gov/ohrp/detrm_letrs/YR13/mar13a.pdf. Accessed April 15, 2013.Google Scholar Later calculations estimated that for every infant who kept his sight, 16 infants died.5Bolton D. Cross K. Further observations on cost of preventing retrolental fibroplasia.Lancet. 1974; 302: 445-448Abstract Scopus (93) Google ScholarIn the following decades, the field of neonatology saw remarkable progress. The discovery of surfactant and widespread adoption of antenatal corticosteroids, better nutrition, gentler ventilators, and care provided by specially trained physicians and nurses in dedicated intensive care units allowed infants born barely past the halfway mark of the pregnancy and weighing around 1 pound to survive. Neonatal patients, however, literally have their whole lives ahead of them. Focusing on survival alone is ethically unacceptable. Caring for these vulnerable patients in ways that minimize long-term complications, such as blindness, fulfills our duties of beneficence (maximize benefits) and nonmaleficence (do no harm).Neonatal intensive care units have always been “high-tech” and with the development of noninvasive pulse oximetry, there was now a way to safely measure oxygen saturations in real time. Shiny new pulse oximeters with bright digital displays were brought crib side. A major problem, however, was the fact that no one knew optimal numbers to target. It certainly was known that, like Goldilocks with her porridge, too high could be bad and too low could be bad. But no one knew what constituted too high or too low, let alone ‘just right.’6Magnus D. Caplan A.L. Risk, consent, and SUPPORT.N Engl J Med. 2013; 368: 1864-1865Crossref PubMed Scopus (49) Google Scholar That does not stop Public Citizen from arguing that the infants in the study were inappropriately “confined” (page 2) in their saturations “to meet the needs of the research” (page 2), and babies who were not in the study could have their oxygen saturation “appropriately” (page 2) adjusted within the entire range of 85%-95% to “meet the specific individual needs of the infant” (page 2). How clinicians at the bedside are supposed to ‘appropriately’ adjust oxygen for an individual patient without adequate evidence is left unstated. In fact, a 2009 comprehensive Cochrane review was unable to answer the question of “what is the optimal target range for maintaining blood oxygen levels in preterm/low birth weight infants.”7Askie L.M. Henderson-Smart D.J. Ko H. Restricted versus liberal oxygen exposure for preventing morbidity and mortality in preterm or low birth weight infants.Cochrane Database Syst Rev. 2009; 1: CD001077PubMed Google ScholarUltimately, of course, clinicians have to pick some numbers, and so most set the target oxygen saturation somewhere between 85%-95%. Within the expert neonatal medical community, however, there was genuine uncertainty whether it was better to target high or low oxygen saturation in these tiniest patients. From an ethical perspective, there was clinical equipoise, “a state of genuine uncertainty on the part of the clinical investigator regarding the comparative therapeutic merits of each arm in a trial.”8Freedman B. Equipoise and the ethics of clinical research.N Engl J Med. 1987; 317: 141-145Crossref PubMed Scopus (1670) Google Scholar This state of community uncertainty justifies randomly assigning the babies to the high and low oxygen targets. To reiterate, all babies in the SUPPORT trial were receiving an intervention—oxygen targeting—within the broad range that was considered ‘standard of care’ at the time.The SUPPORT trial results found that infants in the higher target saturation group had a higher risk of serious retinal damage, and infants in the lower saturation group had a higher rate of death. To Public Citizen the results “should have come as no surprise to anyone, except perhaps the uninformed parents of the subjects who participated in the research” (page 2). The accusation ignores the reality that the 1-pound extreme preemies who were part of the study were nothing like the ‘preemies’ of the presurfactant era, who were larger, more mature, and with greater birth weights. Patrick Bouvier Kennedy, the 4 pound 10.5 ounce 34-week-old premature son of President John F. Kennedy and First Lady Jacqueline Bouvier Kennedy born in 1963, for example, lived for only 2 days before succumbing to complications of prematurity.Apparently, one of the other side effects of being enrolled in the study was lower mortality. Overall mortality for study infants was 20%. Yet, eligible but nonenrolled infants had a 24% mortality. Public Citizen is correct to note that the difference may be due to the fact that the nonenrolled infants were sicker and, thus, might be expected to have a higher mortality. But that might not be the only contributing factor. Sometimes the very act of enrolling in a study has been shown to confer clinical benefit to all study participants regardless of treatment received.9Schmidt B. Gillie P. Caco C. Roberts J. Roberts R. Do sick newborn infants benefit from participation in a randomized clinical trial?.J Pediatr. 1999; 134: 151-155Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar The ‘Hawthorne Effect,’ as it is known, might also explain the lower mortality in study participants.10DeAmici D. Kiersy C. Ramajoli F. Brustia L. Politi P. Impact of the Hawthorne effect in a longitudinal clinical study: the case of anesthesia.Control Clin Trial. 2000; 21: 103-114Abstract Full Text Full Text PDF PubMed Scopus (139) Google ScholarPrior to the SUPPORT trial, there was inadequate evidence to determine the appropriate saturation targets in extremely low gestational age infants in a way that would maximize survival while minimizing morbidity. As one parent of a preemie born more than 2 decades ago noted about the SUPPORT controversy: “My daughter's treatment was so much guessing. Should they do this—or not? I'm sure treatment has advanced greatly since then. But how can the medical community determine which are the best practices? The doctors need to do studies to learn how to treat these little babies correctly.”11Comment by a2pam from The Diane Rehm Show–Clinical Trials and Premature Babies. Aired April 17, 2013. Available at: http://thedianerehmshow.org/shows/2013-04-17/clinical-trials-and-premature-babies. Accessed June 8, 2013.Google ScholarThat is why the National Institutes of Health funded the study and why the institutional review boards at 23 major academic centers approved the study. In fact, similar studies have been approved by institutional review boards across the globe. Principal investigators from 4 other similar major trials in 4 other countries (Australia, Canada, New Zealand, and United Kingdom) got together with the principal investigators of the SUPPORT trial to form the Neonatal Oxygenation Prospective Meta-analysis Collaboration study protocol. When we finally have the results of this “whole-hearted international collaboration,” it is hoped that there will be an end to a serious ethical conundrum: the continued “uncertainty about 1 of the most basic priorities of neonatal care—providing an appropriate concentration of oxygen for our patients.”12Cole C.H. Wright K.W. Tarnow-Mordi W. Phelps D.L. Resolving our uncertainty about oxygen therapy.Pediatrics. 2003; 112: 1415-1419Crossref PubMed Scopus (88) Google Scholar See related article, p 1495“Teach thy tongue to say I do not know and thou shalt progress.”-William Silverman, MD See related article, p 1495 See related article, p 1495 Consumer advocacy group Public Citizen has leveled some very serious allegations against the National Institutes of Health funded Surfactant, Positive Pressure, and Oxygenation Randomized Trial (SUPPORT). The randomized study involved 23 major academic centers (including the institution in which I am employed) and was designed to determine the appropriate range of oxygen saturation in extremely preterm infants.1SUPPORT Study Group of the Eunice Kennedy shriver NICHD Neonatal Research NetworkTarget ranges of oxygen saturation in extremely preterm infants.N Engl J Med. 2010; 362: 1959-1969Crossref PubMed Scopus (724) Google Scholar This was done by using 2 target ranges of oxygen saturation (low, 85%-89%, and high, 91%-95%). According to Public Citizen's letter to Department of Health and Human Services Secretary Kathleen Sebelius, the vulnerable infants were subject to “highly unethical” (page 1) and “indefensible” (page 11) research.2Carome, Michael A, Wolfe S (Public Citizen). Letter to The Honorable Kathleen Sebelius (Secretary, Department of Health and Human Services). 2013 Apr 10. Available at: http://www.citizen.org/documents/2111.pdf. Accessed April 15, 2013.Google Scholar Parents were deceived into enrolling their infants via “egregious” (page 3) deficiencies in the informed consent process. The letter closes by demanding a “formal apology” (page 11) to all 1316 patients who were enrolled in the study. Public Citizen has grossly distorted what was “known” about treating premature infants at the time of the study. Unfortunately, the use of oxygen in neonatology has a long and tragic history. As early as 1900, oxygen was recommended for premature infants during episodes of cyanosis. Early incubators were flooded with oxygen even though it was recognized that there was no “convincing evidence that an increased oxygen content of arterial blood is beneficial or necessarily of importance.”3Robertson A.F. Reflections on errors in neonatology: I. The “hands-off” years, 1920-1950.J Perinatol. 2003; 23: 48-55Crossref PubMed Scopus (51) Google Scholar Additionally, there was no way at this time to quickly and noninvasively measure the baby's oxygen levels or saturation. By the 1950s, it was recognized that too much oxygen led to blindness in the form of retrolental fibroplasia. Indeed, this was the cause of famous preemie Stevie Wonder's blindness. After this discovery, oxygen use was restricted and the outcome was disastrous–death and cerebral palsy rates sharply increased.4Buchanan LR. (Compliance Oversight Coordinator, Department of Health & Human Services, Office for Human Research Protections). Letter to Richard B. Marchase, PhD (V.P. for Research and Economic Development, University of Alabama at Birmingham). 2013 Mar 7. Available at: http://www.hhs.gov/ohrp/detrm_letrs/YR13/mar13a.pdf. Accessed April 15, 2013.Google Scholar Later calculations estimated that for every infant who kept his sight, 16 infants died.5Bolton D. Cross K. Further observations on cost of preventing retrolental fibroplasia.Lancet. 1974; 302: 445-448Abstract Scopus (93) Google Scholar In the following decades, the field of neonatology saw remarkable progress. The discovery of surfactant and widespread adoption of antenatal corticosteroids, better nutrition, gentler ventilators, and care provided by specially trained physicians and nurses in dedicated intensive care units allowed infants born barely past the halfway mark of the pregnancy and weighing around 1 pound to survive. Neonatal patients, however, literally have their whole lives ahead of them. Focusing on survival alone is ethically unacceptable. Caring for these vulnerable patients in ways that minimize long-term complications, such as blindness, fulfills our duties of beneficence (maximize benefits) and nonmaleficence (do no harm). Neonatal intensive care units have always been “high-tech” and with the development of noninvasive pulse oximetry, there was now a way to safely measure oxygen saturations in real time. Shiny new pulse oximeters with bright digital displays were brought crib side. A major problem, however, was the fact that no one knew optimal numbers to target. It certainly was known that, like Goldilocks with her porridge, too high could be bad and too low could be bad. But no one knew what constituted too high or too low, let alone ‘just right.’6Magnus D. Caplan A.L. Risk, consent, and SUPPORT.N Engl J Med. 2013; 368: 1864-1865Crossref PubMed Scopus (49) Google Scholar That does not stop Public Citizen from arguing that the infants in the study were inappropriately “confined” (page 2) in their saturations “to meet the needs of the research” (page 2), and babies who were not in the study could have their oxygen saturation “appropriately” (page 2) adjusted within the entire range of 85%-95% to “meet the specific individual needs of the infant” (page 2). How clinicians at the bedside are supposed to ‘appropriately’ adjust oxygen for an individual patient without adequate evidence is left unstated. In fact, a 2009 comprehensive Cochrane review was unable to answer the question of “what is the optimal target range for maintaining blood oxygen levels in preterm/low birth weight infants.”7Askie L.M. Henderson-Smart D.J. Ko H. Restricted versus liberal oxygen exposure for preventing morbidity and mortality in preterm or low birth weight infants.Cochrane Database Syst Rev. 2009; 1: CD001077PubMed Google Scholar Ultimately, of course, clinicians have to pick some numbers, and so most set the target oxygen saturation somewhere between 85%-95%. Within the expert neonatal medical community, however, there was genuine uncertainty whether it was better to target high or low oxygen saturation in these tiniest patients. From an ethical perspective, there was clinical equipoise, “a state of genuine uncertainty on the part of the clinical investigator regarding the comparative therapeutic merits of each arm in a trial.”8Freedman B. Equipoise and the ethics of clinical research.N Engl J Med. 1987; 317: 141-145Crossref PubMed Scopus (1670) Google Scholar This state of community uncertainty justifies randomly assigning the babies to the high and low oxygen targets. To reiterate, all babies in the SUPPORT trial were receiving an intervention—oxygen targeting—within the broad range that was considered ‘standard of care’ at the time. The SUPPORT trial results found that infants in the higher target saturation group had a higher risk of serious retinal damage, and infants in the lower saturation group had a higher rate of death. To Public Citizen the results “should have come as no surprise to anyone, except perhaps the uninformed parents of the subjects who participated in the research” (page 2). The accusation ignores the reality that the 1-pound extreme preemies who were part of the study were nothing like the ‘preemies’ of the presurfactant era, who were larger, more mature, and with greater birth weights. Patrick Bouvier Kennedy, the 4 pound 10.5 ounce 34-week-old premature son of President John F. Kennedy and First Lady Jacqueline Bouvier Kennedy born in 1963, for example, lived for only 2 days before succumbing to complications of prematurity. Apparently, one of the other side effects of being enrolled in the study was lower mortality. Overall mortality for study infants was 20%. Yet, eligible but nonenrolled infants had a 24% mortality. Public Citizen is correct to note that the difference may be due to the fact that the nonenrolled infants were sicker and, thus, might be expected to have a higher mortality. But that might not be the only contributing factor. Sometimes the very act of enrolling in a study has been shown to confer clinical benefit to all study participants regardless of treatment received.9Schmidt B. Gillie P. Caco C. Roberts J. Roberts R. Do sick newborn infants benefit from participation in a randomized clinical trial?.J Pediatr. 1999; 134: 151-155Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar The ‘Hawthorne Effect,’ as it is known, might also explain the lower mortality in study participants.10DeAmici D. Kiersy C. Ramajoli F. Brustia L. Politi P. Impact of the Hawthorne effect in a longitudinal clinical study: the case of anesthesia.Control Clin Trial. 2000; 21: 103-114Abstract Full Text Full Text PDF PubMed Scopus (139) Google Scholar Prior to the SUPPORT trial, there was inadequate evidence to determine the appropriate saturation targets in extremely low gestational age infants in a way that would maximize survival while minimizing morbidity. As one parent of a preemie born more than 2 decades ago noted about the SUPPORT controversy: “My daughter's treatment was so much guessing. Should they do this—or not? I'm sure treatment has advanced greatly since then. But how can the medical community determine which are the best practices? The doctors need to do studies to learn how to treat these little babies correctly.”11Comment by a2pam from The Diane Rehm Show–Clinical Trials and Premature Babies. Aired April 17, 2013. Available at: http://thedianerehmshow.org/shows/2013-04-17/clinical-trials-and-premature-babies. Accessed June 8, 2013.Google Scholar That is why the National Institutes of Health funded the study and why the institutional review boards at 23 major academic centers approved the study. In fact, similar studies have been approved by institutional review boards across the globe. Principal investigators from 4 other similar major trials in 4 other countries (Australia, Canada, New Zealand, and United Kingdom) got together with the principal investigators of the SUPPORT trial to form the Neonatal Oxygenation Prospective Meta-analysis Collaboration study protocol. When we finally have the results of this “whole-hearted international collaboration,” it is hoped that there will be an end to a serious ethical conundrum: the continued “uncertainty about 1 of the most basic priorities of neonatal care—providing an appropriate concentration of oxygen for our patients.”12Cole C.H. Wright K.W. Tarnow-Mordi W. Phelps D.L. Resolving our uncertainty about oxygen therapy.Pediatrics. 2003; 112: 1415-1419Crossref PubMed Scopus (88) Google Scholar
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