- Email: [email protected]
Clinical resuscitation research and informed consent
Resuscitation 54 (2002) 311 /314 www.elsevier.com/locate/resuscitation
Letters to the Editor Clinical resuscitation research and informed consent I would like to comment on a recent directive by the European Union (EU) that required informed consent before including patients in clinical studies of emergency resuscitation (not feasible) and intensive (critical) care medicine (which sometimes would be difficult). Such a requirement could stop clinical resuscitation research. The importance of clinical resuscitation research should be obvious. From the implementation of what is known to date, resuscitation results have been suboptimal, even dismal, mostly for two reasons: (1) ineffective skill acquisition and delivery efforts, which indicate the need for education research and epidemiologic prospective studies, i.e. case registries; and (2) presently practiced resuscitation methods do not yet cope with the time limits of tolerance of cardiac arrest, i.e. 5 min for the brain, 20 min for the heart and 1 h for the organism. This requires basic and clinical research, particularly clinical feasibility and side-effect studies of methods that have been strongly documented in animal outcome models as being able to improve the chance of intact survival. For an increasing number for acute terminal states (e.g. severe shock) and clinical death (cardiac arrest) more effective emergency resuscitation and intensive care measures are needed. Novel methods found to have breakthrough effects in clinically relevant outcome studies of large animals await documentation in patients. Clinical studies are needed to determine feasibility and side effects, and to document physiologic changes. Randomized clinical outcome studies are also sometimes indicated. I am addressing the consent issue because I have been a resuscitation teacher and researcher for 50 years. I initiated and conducted the world’s first randomised clinical outcome study of cardiac arrest and cardiopulmonary cerebral resuscitation (CPCFR) the Brain Resuscitation Clinical Trial (BRCT) of 1979/94, supported by the National Institutes of Health [1]. This was an international multidisciplinary multicentre study that evaluated novel treatment potentials, namely thiopental loading in BRCT I (1979 /84), calcium entry blocker therapy in BRCT II (1984 /89) [2,3], and escalating high-dose epinephrine in BRCT III (1989 /94) [4]. In addition, ‘milking’ the database has yielded man valuable clues. When I started the BRCT IN 1979, federal agencies in the US did not know what to do about informed consent
and left it up to me, the principal investigator, to deal with it. We realised immediately that to give standard and experimental treatment protocols an optimal chance to help the patient, they had to be initiated within seconds of cardiac arrest or within minutes of severe shock or brain trauma. When patients are comatose, stuporous, or otherwise incapacitated, neither the patient nor his/her proxy (who usually is not present) can be informed and give meaningful consent immediately. This would require a lengthy education process. Therefore, we entered patients without informed consent and later informed relatives to give them a chance to withdraw patients from the long-term data collection and life-supporting protocol. Such withdrawal never happened. The waiving of consent was very well accepted by the public, including patients’ relatives, by Institutional Review Boards of the 20 participating institutions (including those in Europe) and later by patients who regained consciousness. We referred this approach as ‘deferred consent’ ([5 /9], which actually was a misnomer, we should have called it just what it is; waiving of the prospective informed consent. Deferred consent was merely an issue after the fact, mostly for the collection of data. In 1994, federal agencies in the USA temporarily stopped clinical resuscitation studies b y demanding prospective informed consent. We had to ask our colleagues abroad to perform clinical trials of mild hypothermia, which had been documented by our group as highly effective in a systematic series of studies in dogs [10]. Our colleagues in Europe [11,12] and elsewhere [13] conducted the positive randomised clinical studies, recently published in the New England Journal of Medicine. This created excitement, optimism, and publicity. In the late 1990s, there has been in the US a change back to what we introduced in 1979, with some modifications. Now in the US, the National Institutes of Health and the Food and Drug Administration (and we expect soon also the Department of Defence) allow again the waiving of prospective informed consent for the inclusion of patients in resuscitation research, provided the investigators inform the community about it and the internal review boards meet some additional requirements. I urge the EU to follow the recommendations of the European Resuscitation Council (of which I am an honorary member) to not deprive patients in Europe of the possibility to be among the first to receive increas-
0300-9572/02/$ - see front matter # 2002 Elsevier Science Ireland Ltd. All rights reserved.
312
Letters to the Editor
ingly effective lifesaving measures, and to keep Europe in a leading role for these lifesaving endeavours. I remain available for consultation.
References [1] Brain Resuscitation Clinical Trail I Study Group. Steering Committee. Abramson NS, Safar P (PI), Detre KM, Kelsey SF, Monroe J, Reinmuth O, Snyder JV. Investigators Mullie A, et al. Randomized clinical study of thiopental loading in comatose survivors of cardiac arrest. N Engl J Med 1986;314:397 /403. [2] Brain Resuscitation Clinical Trial II Study Group (Safar P, PI). A randomised clinical study of a calcium-entry blocker (lidoflazine) in the treatment of comatose survivors of cardiac arrest. N Engl J Med 1991;324:1225 /1231. [3] Abramson N, Kelsey S, Safar P, Sutton-Tyrrell K. Simpson’s paradox and clinical trials. What you find is not necessarily what you prove. Ann Emerg Med 1992;21:1480 /2. [4] Abramson NS, Safar P, Sutton-Tyrrell, Craig MT for the BRCT III Study Group. A randomised clinical trial of escalating doses of high dose epinephrine during cardiac resuscitation. Crit Care Med 1995;23:A178 (Abstract). [5] Abramson NS, Meisel A, Safar P. Deferred consent. A new approach for resuscitation research on comatose patients. J Am Med Assoc 1986;255:2466 /71. [6] Abramson NS, Safar P. Brain Resuscitation Clinical Trial II Study Group. Deferred consent. Use in clinical resuscitation research. Ann Emerg Med 1990;19:781 /4. [7] Abramson NS, Safar P and BRCT II Study Group. Deferred consent; use in resuscitation research. Ann Emerg Med April 1988;17/4:400. [8] Abramson NS, Safar P, BRCT II Study Group. Experiences with ‘deferred consent’ in clinical resuscitation research. Crit Care Med 1989;17:S75. [9] Craig MT, Abramson NS, Herzog H, Safar P and the Brain Resuscitation Clinical Trial III Study Group. ‘Deferred consent’ experience in a multinational randomised clinical study of cardiac arrest and resuscitation. Resuscitation 1994;28:S39 (Abstract). [10] Safar P, Xiao F, Radovsky A, Tanigawa K, Ebmeyer U, Bircher N, Alexander H, Stezoski SW. Improved cerebral resuscitation from cardiac arrest in dogs with mild hypothermia plus blood flow promotion. Stroke 1996;27:105 /13. [11] The Hypothermia After Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med 2002;346:549 /556. [12] Safar PJ, Kochanek PM. Therapeutic hypothermia after cardiac arrest. Editorial. N Engl J Med 2002;346:612 /3. [13] Bernard SA, Gray TW, Buist MD, et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med 2002;346:557 /63.
Nasogastric bag in the diagnosis of tracheoesophageal fistula Tracheoesophageal fistula (TOF) is an infrequent complication of prolonged intubation and tracheostomy [1,2]. The diagnosis may be difficult because contrast radiography or endoscopy cannot be performed easily, in these unstable patients who are mechanically ventilated. We report a patient with TOF in whom the diagnosis was made by means of an over inflated nasogastric bag (NGB) with high O2 concentration. A 45-year-old man with previous kidney transplantation was admitted to the Intensive Care Unit because of septic shock secondary to acute peritonitis. Due to severe respiratory insufficiency, he was intubated and mechanically ventilated. At exploratory laparotomy, generalised peritonitis due to a perforated sigmoid diverticulum was identified. After peritoneal lavage, a Hartmann’s procedure was performed. On the 16th day in hospital a tracheostomy was performed. On hospital day 26 massive soft tissue emphysema was observed in the face, neck, thorax and abdomen (Fig. 1A). His NGB (with anti-reflux valve) was noted to be over inflated, and gurgling was heard in the epigastrium with each inspiratory cycle. Because TOF was suspected, specimens of gas from the NGB and arterial blood were obtained simultaneously F1O2 (0.8). The arterial PO2 was 79.0 mm Hg and the PCO2 was 46.9 mm Hg. The NGB gas values were: PO2, 602 mm Hg and PCO2, 4.2 mm Hg. Although a brief bronchoscopy did not reveal any abnormalities, oesophagoscopy at the bedside
Peter Safar Safar Center for Resuscitation Research, 3434 Fifth Avenue, Pittsburgh, PA 15260, USA E-mail: [email protected] PII: S 0 3 0 0 - 9 5 7 2 ( 0 2 ) 0 0 1 5 3 - 3
Fig. 1. (A) Picture revealing massive subcutaneous bilateral lids; (B) oesophagoscopy showing the inflated tracheostomy tube balloon (*) protruding into the oesophagus.
Letters to the Editor Clinical resuscitation research and informed consent I would like to comment on a recent directive by the European Union (EU) that required informed consent before including patients in clinical studies of emergency resuscitation (not feasible) and intensive (critical) care medicine (which sometimes would be difficult). Such a requirement could stop clinical resuscitation research. The importance of clinical resuscitation research should be obvious. From the implementation of what is known to date, resuscitation results have been suboptimal, even dismal, mostly for two reasons: (1) ineffective skill acquisition and delivery efforts, which indicate the need for education research and epidemiologic prospective studies, i.e. case registries; and (2) presently practiced resuscitation methods do not yet cope with the time limits of tolerance of cardiac arrest, i.e. 5 min for the brain, 20 min for the heart and 1 h for the organism. This requires basic and clinical research, particularly clinical feasibility and side-effect studies of methods that have been strongly documented in animal outcome models as being able to improve the chance of intact survival. For an increasing number for acute terminal states (e.g. severe shock) and clinical death (cardiac arrest) more effective emergency resuscitation and intensive care measures are needed. Novel methods found to have breakthrough effects in clinically relevant outcome studies of large animals await documentation in patients. Clinical studies are needed to determine feasibility and side effects, and to document physiologic changes. Randomized clinical outcome studies are also sometimes indicated. I am addressing the consent issue because I have been a resuscitation teacher and researcher for 50 years. I initiated and conducted the world’s first randomised clinical outcome study of cardiac arrest and cardiopulmonary cerebral resuscitation (CPCFR) the Brain Resuscitation Clinical Trial (BRCT) of 1979/94, supported by the National Institutes of Health [1]. This was an international multidisciplinary multicentre study that evaluated novel treatment potentials, namely thiopental loading in BRCT I (1979 /84), calcium entry blocker therapy in BRCT II (1984 /89) [2,3], and escalating high-dose epinephrine in BRCT III (1989 /94) [4]. In addition, ‘milking’ the database has yielded man valuable clues. When I started the BRCT IN 1979, federal agencies in the US did not know what to do about informed consent
and left it up to me, the principal investigator, to deal with it. We realised immediately that to give standard and experimental treatment protocols an optimal chance to help the patient, they had to be initiated within seconds of cardiac arrest or within minutes of severe shock or brain trauma. When patients are comatose, stuporous, or otherwise incapacitated, neither the patient nor his/her proxy (who usually is not present) can be informed and give meaningful consent immediately. This would require a lengthy education process. Therefore, we entered patients without informed consent and later informed relatives to give them a chance to withdraw patients from the long-term data collection and life-supporting protocol. Such withdrawal never happened. The waiving of consent was very well accepted by the public, including patients’ relatives, by Institutional Review Boards of the 20 participating institutions (including those in Europe) and later by patients who regained consciousness. We referred this approach as ‘deferred consent’ ([5 /9], which actually was a misnomer, we should have called it just what it is; waiving of the prospective informed consent. Deferred consent was merely an issue after the fact, mostly for the collection of data. In 1994, federal agencies in the USA temporarily stopped clinical resuscitation studies b y demanding prospective informed consent. We had to ask our colleagues abroad to perform clinical trials of mild hypothermia, which had been documented by our group as highly effective in a systematic series of studies in dogs [10]. Our colleagues in Europe [11,12] and elsewhere [13] conducted the positive randomised clinical studies, recently published in the New England Journal of Medicine. This created excitement, optimism, and publicity. In the late 1990s, there has been in the US a change back to what we introduced in 1979, with some modifications. Now in the US, the National Institutes of Health and the Food and Drug Administration (and we expect soon also the Department of Defence) allow again the waiving of prospective informed consent for the inclusion of patients in resuscitation research, provided the investigators inform the community about it and the internal review boards meet some additional requirements. I urge the EU to follow the recommendations of the European Resuscitation Council (of which I am an honorary member) to not deprive patients in Europe of the possibility to be among the first to receive increas-
0300-9572/02/$ - see front matter # 2002 Elsevier Science Ireland Ltd. All rights reserved.
312
Letters to the Editor
ingly effective lifesaving measures, and to keep Europe in a leading role for these lifesaving endeavours. I remain available for consultation.
References [1] Brain Resuscitation Clinical Trail I Study Group. Steering Committee. Abramson NS, Safar P (PI), Detre KM, Kelsey SF, Monroe J, Reinmuth O, Snyder JV. Investigators Mullie A, et al. Randomized clinical study of thiopental loading in comatose survivors of cardiac arrest. N Engl J Med 1986;314:397 /403. [2] Brain Resuscitation Clinical Trial II Study Group (Safar P, PI). A randomised clinical study of a calcium-entry blocker (lidoflazine) in the treatment of comatose survivors of cardiac arrest. N Engl J Med 1991;324:1225 /1231. [3] Abramson N, Kelsey S, Safar P, Sutton-Tyrrell K. Simpson’s paradox and clinical trials. What you find is not necessarily what you prove. Ann Emerg Med 1992;21:1480 /2. [4] Abramson NS, Safar P, Sutton-Tyrrell, Craig MT for the BRCT III Study Group. A randomised clinical trial of escalating doses of high dose epinephrine during cardiac resuscitation. Crit Care Med 1995;23:A178 (Abstract). [5] Abramson NS, Meisel A, Safar P. Deferred consent. A new approach for resuscitation research on comatose patients. J Am Med Assoc 1986;255:2466 /71. [6] Abramson NS, Safar P. Brain Resuscitation Clinical Trial II Study Group. Deferred consent. Use in clinical resuscitation research. Ann Emerg Med 1990;19:781 /4. [7] Abramson NS, Safar P and BRCT II Study Group. Deferred consent; use in resuscitation research. Ann Emerg Med April 1988;17/4:400. [8] Abramson NS, Safar P, BRCT II Study Group. Experiences with ‘deferred consent’ in clinical resuscitation research. Crit Care Med 1989;17:S75. [9] Craig MT, Abramson NS, Herzog H, Safar P and the Brain Resuscitation Clinical Trial III Study Group. ‘Deferred consent’ experience in a multinational randomised clinical study of cardiac arrest and resuscitation. Resuscitation 1994;28:S39 (Abstract). [10] Safar P, Xiao F, Radovsky A, Tanigawa K, Ebmeyer U, Bircher N, Alexander H, Stezoski SW. Improved cerebral resuscitation from cardiac arrest in dogs with mild hypothermia plus blood flow promotion. Stroke 1996;27:105 /13. [11] The Hypothermia After Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med 2002;346:549 /556. [12] Safar PJ, Kochanek PM. Therapeutic hypothermia after cardiac arrest. Editorial. N Engl J Med 2002;346:612 /3. [13] Bernard SA, Gray TW, Buist MD, et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med 2002;346:557 /63.
Nasogastric bag in the diagnosis of tracheoesophageal fistula Tracheoesophageal fistula (TOF) is an infrequent complication of prolonged intubation and tracheostomy [1,2]. The diagnosis may be difficult because contrast radiography or endoscopy cannot be performed easily, in these unstable patients who are mechanically ventilated. We report a patient with TOF in whom the diagnosis was made by means of an over inflated nasogastric bag (NGB) with high O2 concentration. A 45-year-old man with previous kidney transplantation was admitted to the Intensive Care Unit because of septic shock secondary to acute peritonitis. Due to severe respiratory insufficiency, he was intubated and mechanically ventilated. At exploratory laparotomy, generalised peritonitis due to a perforated sigmoid diverticulum was identified. After peritoneal lavage, a Hartmann’s procedure was performed. On the 16th day in hospital a tracheostomy was performed. On hospital day 26 massive soft tissue emphysema was observed in the face, neck, thorax and abdomen (Fig. 1A). His NGB (with anti-reflux valve) was noted to be over inflated, and gurgling was heard in the epigastrium with each inspiratory cycle. Because TOF was suspected, specimens of gas from the NGB and arterial blood were obtained simultaneously F1O2 (0.8). The arterial PO2 was 79.0 mm Hg and the PCO2 was 46.9 mm Hg. The NGB gas values were: PO2, 602 mm Hg and PCO2, 4.2 mm Hg. Although a brief bronchoscopy did not reveal any abnormalities, oesophagoscopy at the bedside
Peter Safar Safar Center for Resuscitation Research, 3434 Fifth Avenue, Pittsburgh, PA 15260, USA E-mail: [email protected] PII: S 0 3 0 0 - 9 5 7 2 ( 0 2 ) 0 0 1 5 3 - 3
Fig. 1. (A) Picture revealing massive subcutaneous bilateral lids; (B) oesophagoscopy showing the inflated tracheostomy tube balloon (*) protruding into the oesophagus.