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Two new studies may cast some doubt upon the now widely held belief that core cooling improves outcomes in unconscious cardiac arrest patients.
The studies, presented at the American Heart Association scientific sessions, found that neither cooling to hypothermic levels, compared with normothermic, nor prehospital, compared with in-hospital, significantly improved mortality or neurologic outcomes in more 2,000 patients. The papers were simultaneously published – one in the New England Journal of Medicine, and the other in JAMA.
Induced hypothermia is now standard of care for unconscious survivors of out-of-hospital cardiac arrests. But some animal models suggest that the earlier cooling begins, the better outcomes result. Dr. Francis Kim and his colleagues, however, found almost identical outcomes in a group of 1,359 patients, whatever the timing of hypothermia induction (JAMA 2013 Nov. 17 [doi:10.1001/jama.2013.282173]).
Dr. Kim of the University of Washington, Seattle, and his coauthors randomized patients to induction in the field and during transport, or upon hospital arrival. The intervention group received an infusion of up to 2L of ice-cold normal saline, 7-10 mg pancuronium, and 1-2 mg diazepam, with a target temperature goal of 34°C.
In the control group, hypothermia induction occurred in the hospital, according to each site’s protocol, with either surface or intravascular regimens.
Patients were divided into two groups: those with ventricular fibrillation and those without. Patients without VF were older (68 vs. 62 years). Other baseline characteristics – including time from the call to the return of spontaneous circulation, heart rate, and blood pressure – were similar.
The in-field intervention decreased mean core temperature by about 1.2°C in patients with VF and 1.3°C in those without VF. These patients achieved the target core temperature of 34°C more than 1 hour sooner than patients cooled in the hospital.
Survival to discharge was not significantly different between the intervention and control groups (63% vs. 64% of those with VF; 19% vs. 16% of those without VF).
Nor were there significant differences in the neurologic status of full recovery or mild impairment at discharge, the investigators said. Among those with VF, good neurologic status occurred in 57% of the intervention group and 62% of the control group. For those patients without VF, good neurologic outcomes occurred in 14% of the intervention group and 13% of the control group.
There were no significant differences in the proportion of patients who awakened from coma or died without awakening in any of the groups. The median length of stay was within the VF group (9 days for both treatment groups), and among those without VF (about 11 days for each treatment group).
The intervention carried some evidence of increased harm, the authors noted. Significantly more of the intervention patients rearrested during transport (26% vs. 21% of the controls). They also had significantly lower oxygenation, increased pulmonary edema on the first chest x-ray, and greater use of diuretics in the first 12 hours of hospitalization.
"Importantly, the method of pre-hospital hypothermia may have been associated with early harm that could have masked subsequent improvement," the investigators noted. "Rearrest possibly worsened brain ischemia that did not affect early mortality, but manifested as increased risk of death later during the hospitalization."
The second study released at the AHA meeting questioned whether induced hypothermia confers significant benefit over maintaining a near-normothermic temperature. Patients cooled to 33°C had no better outcomes than those whose core temperatures were held at 36°C, Dr. Niklas Nielsen and colleagues reported Nov. 18 (N. Engl. J. Med. 2013 Nov. 17 [doi:10.1056/NEJMoa1310519]).
"Our trial does not provide evidence that targeting a body temperature of 33° C confers any benefit for unconscious patients admitted to the hospital after out-of-hospital cardiac arrest, as compared with targeting a body temperature of 36°C," wrote Dr. Nielsen of Helsingborg Hospital, Sweden, and his colleagues.
The team analyzed outcomes for 939 patients who had been randomized to the two cooling regimens. The study’s primary outcome was all-cause mortality by 180 days after enrollment. The secondary outcomes included a composite of death or poor neurologic outcome at 180 days as evaluated with the Cerebral Performance Category (CPC) and modified Rankin scales.
The intervention consisted of 36 hours of cooling and gradual rewarming. Treatment teams were allowed to use ice packs, ice-cold fluid, and intravascular or surface temperature management. Gradual rewarming to 37°C commenced after 28 hours; this was discontinued or tapered at 36 hours. After this, patients in both groups were treated with fever-control measures to prevent a rebound temperature of above 37.5°C.
The patients were a mean of 64 years old; most of them (about 75%) had VF as the first shocked rhythm. Spontaneous circulation returned a median of 25 minutes after the arrest. All were unconscious when they arrived at the hospital. The mean follow-up was 256 days.
Most (76%) had temperature management with a surface cooling system; the rest were cooled by an intravascular catheter. Three patients in the 33°C group and four in the 36°C group didn’t get the assigned intervention; 16 in the 33°C group were rewarmed sooner than the protocol, at the discretion of their physician.
During the first week of hospitalization, 247 patients (132 in the 33°C group and 115 in the 36°C group) had life support withdrawn. Reasons for withdrawal included brain death, multiorgan failure, and ethical concerns.
At final follow-up, 50% of patients in the 33°C group and 48% in the 36°C group had died – a nonsignificant difference. There were no significant differences in the composite outcome of death or poor neurologic outcome whether measured by the CPC or the modified Rankin scales.
These results were similar in all adjusted analyses, in the intent-to-treat population, and in the per-protocol population.
Adverse events were common, occurring in 93% of the 33°C group and 90% of the 36°C group. The most common was hypokalemia, which was more significantly more common in the 33°C group (19% vs. 13%).
The study differed in one important way from others that have supported the use of induced hypothermia – and this might have had a key impact on the overall finding.
"We did not allow the natural trajectory of temperature evolution in either group," the authors said. "We actively controlled the temperature during the intervention period and aimed to prevent fever during the first 3 days after cardiac arrest."
It’s difficult to compare these results with those of the Hypothermia After Cardiac Arrest Study – the 2006 trial which first found in favor of the practice, the authors said.
Mortality in both groups of the current study was lower than that seen in 2006 – probably because of the recent advances in prehospital and in-hospital critical care management for cardiac arrest patients.
"We did not find any harm with a targeted temperature of 33°C as compared with 36°C," the investigators wrote. "However, it is worth recognizing that for all outcomes, none of the point estimates were in the direction of a benefit for the 33°C group. On the basis of these results, decisions about which temperature to target after out-of-hospital cardiac arrest require careful consideration."
Dr. Kim had no financial disclosures. Several of his coauthors disclosed financial relationships with medical device companies. Dr. Nielsen had nothing to disclose. Five of his coauthors disclosed financial relationships with outside entities; however, none appeared to be related to the study.
Dr. Niklas Nielsen and his colleagues found no real benefit of induced hypothermia over near-normothermic temperature maintenance in patients with out-of-hospital cardiac arrest, Dr. Jon C. Rittenberger and Dr. Clifton W. Callaway wrote in an editorial published along with the study (N. Engl. J. Med. 2013 Nov. 17 [doi:10.1056/NEJMe1312700]).
"This superbly executed study is more than twice the size of the original trials combined (which enrolled a total of 352 patients) and was conducted with meticulous attention to modern intensive care," the colleagues wrote, saying that there are multiple possible explanations for its finding.
The largest factor among these, they said, is probably the immense progress made in emergency care since the original hypothermia studies were published nearly a decade ago. "There has been evolution of intensive care over the past decade and improvements in patient care may have reduced the potential incremental benefits of a single intervention. In addition, illness severity varies greatly among patients with cardiac arrest, and there may be subgroups of patients who do benefit from induced hypothermia but who were not designated in advance. Particularly if the degree or duration of hypothermia must be adjusted to match the severity of brain injury, the benefits to a subgroup may be missed in a trial of one regimen of hypothermia for all comers."The most important message of this trial, they wrote, "is that modern, aggressive care that includes attention to temperature works, making survival more likely than death when a patient is hospitalized after CPR.
"In contrast to a decade ago, one-half instead of one-third of patients with return of spontaneous circulation after CPR can expect to survive hospitalization. Few medical situations have enjoyed such absolute improvement over the same time period."
Dr. Clifton W. Callaway is the Ronald D Stewart Endowed Chair of Emergency Medicine Research at the University of Pittsburgh. He disclosed receiving speakers fees from several cardiac health groups and holding two patents on devices related to cardiac resuscitation. Dr. Jon C. Rittenberger is director of residency research in the emergency medicine department of the University of Pittsburgh. He has received honoraria and lecture fees for speaking on emergency medicine.
Dr. Niklas Nielsen and his colleagues found no real benefit of induced hypothermia over near-normothermic temperature maintenance in patients with out-of-hospital cardiac arrest, Dr. Jon C. Rittenberger and Dr. Clifton W. Callaway wrote in an editorial published along with the study (N. Engl. J. Med. 2013 Nov. 17 [doi:10.1056/NEJMe1312700]).
"This superbly executed study is more than twice the size of the original trials combined (which enrolled a total of 352 patients) and was conducted with meticulous attention to modern intensive care," the colleagues wrote, saying that there are multiple possible explanations for its finding.
The largest factor among these, they said, is probably the immense progress made in emergency care since the original hypothermia studies were published nearly a decade ago. "There has been evolution of intensive care over the past decade and improvements in patient care may have reduced the potential incremental benefits of a single intervention. In addition, illness severity varies greatly among patients with cardiac arrest, and there may be subgroups of patients who do benefit from induced hypothermia but who were not designated in advance. Particularly if the degree or duration of hypothermia must be adjusted to match the severity of brain injury, the benefits to a subgroup may be missed in a trial of one regimen of hypothermia for all comers."The most important message of this trial, they wrote, "is that modern, aggressive care that includes attention to temperature works, making survival more likely than death when a patient is hospitalized after CPR.
"In contrast to a decade ago, one-half instead of one-third of patients with return of spontaneous circulation after CPR can expect to survive hospitalization. Few medical situations have enjoyed such absolute improvement over the same time period."
Dr. Clifton W. Callaway is the Ronald D Stewart Endowed Chair of Emergency Medicine Research at the University of Pittsburgh. He disclosed receiving speakers fees from several cardiac health groups and holding two patents on devices related to cardiac resuscitation. Dr. Jon C. Rittenberger is director of residency research in the emergency medicine department of the University of Pittsburgh. He has received honoraria and lecture fees for speaking on emergency medicine.
Dr. Niklas Nielsen and his colleagues found no real benefit of induced hypothermia over near-normothermic temperature maintenance in patients with out-of-hospital cardiac arrest, Dr. Jon C. Rittenberger and Dr. Clifton W. Callaway wrote in an editorial published along with the study (N. Engl. J. Med. 2013 Nov. 17 [doi:10.1056/NEJMe1312700]).
"This superbly executed study is more than twice the size of the original trials combined (which enrolled a total of 352 patients) and was conducted with meticulous attention to modern intensive care," the colleagues wrote, saying that there are multiple possible explanations for its finding.
The largest factor among these, they said, is probably the immense progress made in emergency care since the original hypothermia studies were published nearly a decade ago. "There has been evolution of intensive care over the past decade and improvements in patient care may have reduced the potential incremental benefits of a single intervention. In addition, illness severity varies greatly among patients with cardiac arrest, and there may be subgroups of patients who do benefit from induced hypothermia but who were not designated in advance. Particularly if the degree or duration of hypothermia must be adjusted to match the severity of brain injury, the benefits to a subgroup may be missed in a trial of one regimen of hypothermia for all comers."The most important message of this trial, they wrote, "is that modern, aggressive care that includes attention to temperature works, making survival more likely than death when a patient is hospitalized after CPR.
"In contrast to a decade ago, one-half instead of one-third of patients with return of spontaneous circulation after CPR can expect to survive hospitalization. Few medical situations have enjoyed such absolute improvement over the same time period."
Dr. Clifton W. Callaway is the Ronald D Stewart Endowed Chair of Emergency Medicine Research at the University of Pittsburgh. He disclosed receiving speakers fees from several cardiac health groups and holding two patents on devices related to cardiac resuscitation. Dr. Jon C. Rittenberger is director of residency research in the emergency medicine department of the University of Pittsburgh. He has received honoraria and lecture fees for speaking on emergency medicine.
Two new studies may cast some doubt upon the now widely held belief that core cooling improves outcomes in unconscious cardiac arrest patients.
The studies, presented at the American Heart Association scientific sessions, found that neither cooling to hypothermic levels, compared with normothermic, nor prehospital, compared with in-hospital, significantly improved mortality or neurologic outcomes in more 2,000 patients. The papers were simultaneously published – one in the New England Journal of Medicine, and the other in JAMA.
Induced hypothermia is now standard of care for unconscious survivors of out-of-hospital cardiac arrests. But some animal models suggest that the earlier cooling begins, the better outcomes result. Dr. Francis Kim and his colleagues, however, found almost identical outcomes in a group of 1,359 patients, whatever the timing of hypothermia induction (JAMA 2013 Nov. 17 [doi:10.1001/jama.2013.282173]).
Dr. Kim of the University of Washington, Seattle, and his coauthors randomized patients to induction in the field and during transport, or upon hospital arrival. The intervention group received an infusion of up to 2L of ice-cold normal saline, 7-10 mg pancuronium, and 1-2 mg diazepam, with a target temperature goal of 34°C.
In the control group, hypothermia induction occurred in the hospital, according to each site’s protocol, with either surface or intravascular regimens.
Patients were divided into two groups: those with ventricular fibrillation and those without. Patients without VF were older (68 vs. 62 years). Other baseline characteristics – including time from the call to the return of spontaneous circulation, heart rate, and blood pressure – were similar.
The in-field intervention decreased mean core temperature by about 1.2°C in patients with VF and 1.3°C in those without VF. These patients achieved the target core temperature of 34°C more than 1 hour sooner than patients cooled in the hospital.
Survival to discharge was not significantly different between the intervention and control groups (63% vs. 64% of those with VF; 19% vs. 16% of those without VF).
Nor were there significant differences in the neurologic status of full recovery or mild impairment at discharge, the investigators said. Among those with VF, good neurologic status occurred in 57% of the intervention group and 62% of the control group. For those patients without VF, good neurologic outcomes occurred in 14% of the intervention group and 13% of the control group.
There were no significant differences in the proportion of patients who awakened from coma or died without awakening in any of the groups. The median length of stay was within the VF group (9 days for both treatment groups), and among those without VF (about 11 days for each treatment group).
The intervention carried some evidence of increased harm, the authors noted. Significantly more of the intervention patients rearrested during transport (26% vs. 21% of the controls). They also had significantly lower oxygenation, increased pulmonary edema on the first chest x-ray, and greater use of diuretics in the first 12 hours of hospitalization.
"Importantly, the method of pre-hospital hypothermia may have been associated with early harm that could have masked subsequent improvement," the investigators noted. "Rearrest possibly worsened brain ischemia that did not affect early mortality, but manifested as increased risk of death later during the hospitalization."
The second study released at the AHA meeting questioned whether induced hypothermia confers significant benefit over maintaining a near-normothermic temperature. Patients cooled to 33°C had no better outcomes than those whose core temperatures were held at 36°C, Dr. Niklas Nielsen and colleagues reported Nov. 18 (N. Engl. J. Med. 2013 Nov. 17 [doi:10.1056/NEJMoa1310519]).
"Our trial does not provide evidence that targeting a body temperature of 33° C confers any benefit for unconscious patients admitted to the hospital after out-of-hospital cardiac arrest, as compared with targeting a body temperature of 36°C," wrote Dr. Nielsen of Helsingborg Hospital, Sweden, and his colleagues.
The team analyzed outcomes for 939 patients who had been randomized to the two cooling regimens. The study’s primary outcome was all-cause mortality by 180 days after enrollment. The secondary outcomes included a composite of death or poor neurologic outcome at 180 days as evaluated with the Cerebral Performance Category (CPC) and modified Rankin scales.
The intervention consisted of 36 hours of cooling and gradual rewarming. Treatment teams were allowed to use ice packs, ice-cold fluid, and intravascular or surface temperature management. Gradual rewarming to 37°C commenced after 28 hours; this was discontinued or tapered at 36 hours. After this, patients in both groups were treated with fever-control measures to prevent a rebound temperature of above 37.5°C.
The patients were a mean of 64 years old; most of them (about 75%) had VF as the first shocked rhythm. Spontaneous circulation returned a median of 25 minutes after the arrest. All were unconscious when they arrived at the hospital. The mean follow-up was 256 days.
Most (76%) had temperature management with a surface cooling system; the rest were cooled by an intravascular catheter. Three patients in the 33°C group and four in the 36°C group didn’t get the assigned intervention; 16 in the 33°C group were rewarmed sooner than the protocol, at the discretion of their physician.
During the first week of hospitalization, 247 patients (132 in the 33°C group and 115 in the 36°C group) had life support withdrawn. Reasons for withdrawal included brain death, multiorgan failure, and ethical concerns.
At final follow-up, 50% of patients in the 33°C group and 48% in the 36°C group had died – a nonsignificant difference. There were no significant differences in the composite outcome of death or poor neurologic outcome whether measured by the CPC or the modified Rankin scales.
These results were similar in all adjusted analyses, in the intent-to-treat population, and in the per-protocol population.
Adverse events were common, occurring in 93% of the 33°C group and 90% of the 36°C group. The most common was hypokalemia, which was more significantly more common in the 33°C group (19% vs. 13%).
The study differed in one important way from others that have supported the use of induced hypothermia – and this might have had a key impact on the overall finding.
"We did not allow the natural trajectory of temperature evolution in either group," the authors said. "We actively controlled the temperature during the intervention period and aimed to prevent fever during the first 3 days after cardiac arrest."
It’s difficult to compare these results with those of the Hypothermia After Cardiac Arrest Study – the 2006 trial which first found in favor of the practice, the authors said.
Mortality in both groups of the current study was lower than that seen in 2006 – probably because of the recent advances in prehospital and in-hospital critical care management for cardiac arrest patients.
"We did not find any harm with a targeted temperature of 33°C as compared with 36°C," the investigators wrote. "However, it is worth recognizing that for all outcomes, none of the point estimates were in the direction of a benefit for the 33°C group. On the basis of these results, decisions about which temperature to target after out-of-hospital cardiac arrest require careful consideration."
Dr. Kim had no financial disclosures. Several of his coauthors disclosed financial relationships with medical device companies. Dr. Nielsen had nothing to disclose. Five of his coauthors disclosed financial relationships with outside entities; however, none appeared to be related to the study.
Two new studies may cast some doubt upon the now widely held belief that core cooling improves outcomes in unconscious cardiac arrest patients.
The studies, presented at the American Heart Association scientific sessions, found that neither cooling to hypothermic levels, compared with normothermic, nor prehospital, compared with in-hospital, significantly improved mortality or neurologic outcomes in more 2,000 patients. The papers were simultaneously published – one in the New England Journal of Medicine, and the other in JAMA.
Induced hypothermia is now standard of care for unconscious survivors of out-of-hospital cardiac arrests. But some animal models suggest that the earlier cooling begins, the better outcomes result. Dr. Francis Kim and his colleagues, however, found almost identical outcomes in a group of 1,359 patients, whatever the timing of hypothermia induction (JAMA 2013 Nov. 17 [doi:10.1001/jama.2013.282173]).
Dr. Kim of the University of Washington, Seattle, and his coauthors randomized patients to induction in the field and during transport, or upon hospital arrival. The intervention group received an infusion of up to 2L of ice-cold normal saline, 7-10 mg pancuronium, and 1-2 mg diazepam, with a target temperature goal of 34°C.
In the control group, hypothermia induction occurred in the hospital, according to each site’s protocol, with either surface or intravascular regimens.
Patients were divided into two groups: those with ventricular fibrillation and those without. Patients without VF were older (68 vs. 62 years). Other baseline characteristics – including time from the call to the return of spontaneous circulation, heart rate, and blood pressure – were similar.
The in-field intervention decreased mean core temperature by about 1.2°C in patients with VF and 1.3°C in those without VF. These patients achieved the target core temperature of 34°C more than 1 hour sooner than patients cooled in the hospital.
Survival to discharge was not significantly different between the intervention and control groups (63% vs. 64% of those with VF; 19% vs. 16% of those without VF).
Nor were there significant differences in the neurologic status of full recovery or mild impairment at discharge, the investigators said. Among those with VF, good neurologic status occurred in 57% of the intervention group and 62% of the control group. For those patients without VF, good neurologic outcomes occurred in 14% of the intervention group and 13% of the control group.
There were no significant differences in the proportion of patients who awakened from coma or died without awakening in any of the groups. The median length of stay was within the VF group (9 days for both treatment groups), and among those without VF (about 11 days for each treatment group).
The intervention carried some evidence of increased harm, the authors noted. Significantly more of the intervention patients rearrested during transport (26% vs. 21% of the controls). They also had significantly lower oxygenation, increased pulmonary edema on the first chest x-ray, and greater use of diuretics in the first 12 hours of hospitalization.
"Importantly, the method of pre-hospital hypothermia may have been associated with early harm that could have masked subsequent improvement," the investigators noted. "Rearrest possibly worsened brain ischemia that did not affect early mortality, but manifested as increased risk of death later during the hospitalization."
The second study released at the AHA meeting questioned whether induced hypothermia confers significant benefit over maintaining a near-normothermic temperature. Patients cooled to 33°C had no better outcomes than those whose core temperatures were held at 36°C, Dr. Niklas Nielsen and colleagues reported Nov. 18 (N. Engl. J. Med. 2013 Nov. 17 [doi:10.1056/NEJMoa1310519]).
"Our trial does not provide evidence that targeting a body temperature of 33° C confers any benefit for unconscious patients admitted to the hospital after out-of-hospital cardiac arrest, as compared with targeting a body temperature of 36°C," wrote Dr. Nielsen of Helsingborg Hospital, Sweden, and his colleagues.
The team analyzed outcomes for 939 patients who had been randomized to the two cooling regimens. The study’s primary outcome was all-cause mortality by 180 days after enrollment. The secondary outcomes included a composite of death or poor neurologic outcome at 180 days as evaluated with the Cerebral Performance Category (CPC) and modified Rankin scales.
The intervention consisted of 36 hours of cooling and gradual rewarming. Treatment teams were allowed to use ice packs, ice-cold fluid, and intravascular or surface temperature management. Gradual rewarming to 37°C commenced after 28 hours; this was discontinued or tapered at 36 hours. After this, patients in both groups were treated with fever-control measures to prevent a rebound temperature of above 37.5°C.
The patients were a mean of 64 years old; most of them (about 75%) had VF as the first shocked rhythm. Spontaneous circulation returned a median of 25 minutes after the arrest. All were unconscious when they arrived at the hospital. The mean follow-up was 256 days.
Most (76%) had temperature management with a surface cooling system; the rest were cooled by an intravascular catheter. Three patients in the 33°C group and four in the 36°C group didn’t get the assigned intervention; 16 in the 33°C group were rewarmed sooner than the protocol, at the discretion of their physician.
During the first week of hospitalization, 247 patients (132 in the 33°C group and 115 in the 36°C group) had life support withdrawn. Reasons for withdrawal included brain death, multiorgan failure, and ethical concerns.
At final follow-up, 50% of patients in the 33°C group and 48% in the 36°C group had died – a nonsignificant difference. There were no significant differences in the composite outcome of death or poor neurologic outcome whether measured by the CPC or the modified Rankin scales.
These results were similar in all adjusted analyses, in the intent-to-treat population, and in the per-protocol population.
Adverse events were common, occurring in 93% of the 33°C group and 90% of the 36°C group. The most common was hypokalemia, which was more significantly more common in the 33°C group (19% vs. 13%).
The study differed in one important way from others that have supported the use of induced hypothermia – and this might have had a key impact on the overall finding.
"We did not allow the natural trajectory of temperature evolution in either group," the authors said. "We actively controlled the temperature during the intervention period and aimed to prevent fever during the first 3 days after cardiac arrest."
It’s difficult to compare these results with those of the Hypothermia After Cardiac Arrest Study – the 2006 trial which first found in favor of the practice, the authors said.
Mortality in both groups of the current study was lower than that seen in 2006 – probably because of the recent advances in prehospital and in-hospital critical care management for cardiac arrest patients.
"We did not find any harm with a targeted temperature of 33°C as compared with 36°C," the investigators wrote. "However, it is worth recognizing that for all outcomes, none of the point estimates were in the direction of a benefit for the 33°C group. On the basis of these results, decisions about which temperature to target after out-of-hospital cardiac arrest require careful consideration."
Dr. Kim had no financial disclosures. Several of his coauthors disclosed financial relationships with medical device companies. Dr. Nielsen had nothing to disclose. Five of his coauthors disclosed financial relationships with outside entities; however, none appeared to be related to the study.
FROM THE AHA SCIENTIFIC SESSIONS
Major finding: Induced hypothermia after out-of-hospital cardiac arrest didn’t improve patient outcomes when compared with near-normal temperatures, or whether it was delivered before or during hospitalization.
Data source: One study randomized 939 patients to either early or in-hospital cooling; the other randomized 1,359 to a target temperature of 33° C or 36° C.
Disclosures: Dr. Kim had no financial disclosures. Several of his coauthors disclosed financial relationships with medical device companies. Dr. Nielsen had nothing to disclose. Five of his coauthors disclosed financial relationships with outside entities; however, none appeared to be related to the study.