CORRESPONDENCE
Informed
Consent:
An Unresolved
Issue
To the Editor: In Reply:
The article "Informed Consent for Clinical Research" [July 1989;18:766-771] by Spivey addresses issues of importance to all investigators in emergency m e d i c i n e w h o perform clinical research. T h e a u t h o r states t h a t " t h e c o n s e n t form s h o u l d include a s t a t e m e n t that the i n s t i t u t i o n is responsible for any damages that occur." This is not accurate. T h e instit u t i o n at w h i c h the research is performed is not responsible for damages that occur, nor is it duty-bound to provide c o m p e n s a t i o n for such research-related injury. According to F D A - i n f o r m e d c o n s e n t r e g u l a t i o n s (21 CFR 50.25 [a] [6]), the research subject m u s t be told whether any comp e n s a t i o n a n d / o r m e d i c a l t r e a t m e n t is a v a i l a b l e if res e a r c h - r e l a t e d i n j u r y occurs, w h a t it c o n s i s t s of, and w h e r e f u r t h e r i n f o r m a t i o n m a y be o b t a i n e d . W h e t h e r c o m p e n s a t i o n and m e d i c a l t r e a t m e n t will be offered, as well as any stipulations regarding eligibility for such compensation or t r e a t m e n t , is solely up to the i n s t i t u t i o n and the sponsor of the project. As long as the research subject is informed of the existence of c o m p e n s a t i o n or lack of it, he m a y render an i n f o r m e d decision as to w h e t h e r to participate. As one w h o wears both the hat of the clinical researcher in e m e r g e n c y m e d i c i n e and t h a t of t h e c h a i r m a n of an IRB, I did appreciate the author's sensitive t r e a t m e n t of the " i n f o r m e d c o n s e n t " as a process to w h i c h the investigator should be c o m m i t t e d as distinct from having someone obtain a signature on a "consent form." A n y camouflaging or trivializing research risk in the obtaining of consent is unethical, as is any a t t e m p t at coercing the p a t i e n t to enroll in the study. It is a responsibility of all clinical researchers to police ourselves. W h e n we strictly adhere to our individual IRB policies, we will be m u c h m o r e consistent w i t h local standards of conduct t h a n if we only had guidelines from the bureaucrats in Washington. The issue of informed consent in resuscitation research is n o t yet resolved. D u e to the y o u t h of our specialty, we in emergency m e d i c i n e have not m a d e our voices heard by the authors of regulations and guidelines that pertain to clinical research using patients who are vulnerable by virtue of an u n s t a b l e m e d i c a l condition. M y appreciation goes out to the editors of Annals for their willingness to p u b l i s h articles such as Dr Spivey's so t h a t the dialogue on these issues m a y continue.
I thank Dr Runge for his c o m m e n t s regarding informed consent and clarify the issue he raises regarding responsibility for damages that occur during research. In the article, r e q u i r e m e n t s of the A m e r i c a n Code of Federal Regulations for the P r o t e c t i o n of H u m a n Subjects are clearly spelled out. After that is a section of additional e l e m e n t s of informed consent that, w h e n applicable, m a y be added to the consent form. The statement, "the consent form should include a s t a t e m e n t t h a t the i n s t i t u t i o n is responsible for any damages that occur" was i n t e n d e d as part of this section. W h e n applicable, a s t a t e m e n t regarding responsibility for damages should be included. Dr Runge is correct that the decision regarding c o m p e n s a t i o n of a pat i e n t is optional for the investigator and i n s t i t u t i o n . A l t h o u g h the responsibility for c o m p e n s a t i o n of a patient is optional, I feel strongly that the p h y s i c i a n and the i n s t i t u t i o n are responsible for the damages that a p a t i e n t m a y have suffered because of a research study. For moral and ethical reasons, t h e y should provide necessary medical t r e a t m e n t for an i n j u r y and a s s u m e costs of t h o s e treatments. Dr Runge refers to FDA regulations in his letter. It is i m p o r t a n t to note that there are two governing bodies that have t h e i r o w n r e g u l a t i o n s for c o n d u c t i n g r e s e a r c h and obtaining informed consent. The Federal Drug A d m i n i s t r a t i o n and the D e p a r t m e n t of H e a l t h and H u m a n Services have s i m i l a r g u i d e l i n e s for i n f o r m e d consent, b u t their guidelines for conducting an IRB differ. It is important that an investigator be familiar w i t h his IRB and the rules by w h i c h it is governed. Drugs and n e w m e d i c a l devices are m o r e l i k e l y to fall under FDA rules and regulations than are research protocols that do n o t involve drugs or n e w devices. As a n e w s p e c i a l t y that f r e q u e n t l y m u s t c o n d u c t research on patients w h o are o b t u n d e d or in cardiac arrest, it is i m p o r t a n t t h a t we develop n e w w a y s of o b t a i n i n g consent in these difficult situations. I applaud the efforts of Dr Runge and others who have taken the t i m e to participate as m e m b e r s of IRBs. A c t i v i t i e s like this not only increase the credibility of research in e m e r g e n c y medicine, b u t a l l o w us t h e o p p o r t u n i t y to b e t t e r u n d e r s t a n d t h e workings of an IRB and learn h o w we m i g h t better approach the difficult issue of i n f o r m e d consent.
Jeffrey W Runge, MD, FACEP Department of Emergency Medicine Research and Human Subjects Protection Committee Charlotte Memorial Hospital and Medical Center Charlotte, North Carolina
William H Spivey, MD, FACEP Department of Emergency Medicine Division of Research Medical College of Permsylvania Philadelphia
Unreliable
Effect of Nifedipine
in R e l i e v i n g
Renal Colic
To the Editor:
In their article "Nifedipine for the Relief of Renal Colic: A Double-Blind, Placebo-Controlled Trial" [April 1989;
158/841
18:352-354], Caravati et al presented a double-blind, placebo controlled study that evaluated the efficacy of nif-
Annals of Emergency Medicine
t9:7 July1990
NIFEDIPINE IN RENAL COLIC Importance of plasma levels /20~dipine
serum
bevel { n g / m l ) . . . . . . . . . . . . . . . . . . . . . . . . . . .
I00 80 60
$ ÷
40
$ 20 0
........
i ............................ RESPONDERS
t" NON-RESPONDERS
GROUPS
edipine in relieving pain related to acute renal colic. T h e authors did not observe any significant difference in pain relief b e t w e e n nifedipine and placebo administration. We w o u l d l i k e to r e p o r t the r e s u l t s of a p r e l i m i n a r y open study t h a t was conducted in our e m e r g e n c y d e p a r t m e n t and i n c l u d e d d e t e r m i n a t i o n s of nifedipine levels in serum. After informed consent had been obtained, patients w h o w e r e d e v o i d of c o n t r a i n d i c a t i o n s to c a l c i u m c h a n n e l blockers and who presented to the ED w i t h renal colic
were asked to c h e w t w o capsules of nifedipine (20 mg) and t h e n to s w a l l o w it w i t h 150 m L water. T h e y were also asked to assess their pain s e v e r i t y (4, severe; 3, mild; 2, endurable; 1, n o pain) before and ten, 20, and 40 m i n u t e s after n i f e d i p i n e a d m i n i s t r a t i o n . T h e y w e r e c o n s i d e r e d a responder if t h e pain score decreased two points w i t h i n 20 minutes. N o n r e s p o n d e r s (after 20 minutes) were a d m i t t e d to the usual r e g i m e n of t r e a t m e n t . Nifedipine levels w e r e d e t e r m i n e d at 30 m i n u t e s . T w e l v e p a t i e n t s w i t h subseq u e n t l y c o n f i r m e d n e p h r o l i t h i a s i s were i n c l u d e d in t h e data analysis, The results of n i f e d i p i n e d e t e r m i n a t i o n s in serum are s h o w n in t h e Figure, w h i c h c l e a r l y d e m o n s t r a t e s t h a t higher levels were o b s e r v e d in responders. We thus suggest that the i n a b i l i t y of n i f e d i p i n e to relieve renal colic in some patients m a y be r e l a t e d to an erratic absorption a n d ' to the v a r i a b i l i t y in p l a s m a levels. We conclude that the unreliable effect of n i f e d i p i n e precludes a routine clinical use in this painful c o n d i t i o n .
P Lheureux, M D R Askenasi, MD, PhD Emergency Department D Gangi, MD Clinical Pharmacology Erasme University Hospital Brussels, Belgium
Aneurysm Alert To the Editor: Dr F o n t a n a r o s a , in his article, " R e c o g n i t i o n of Subarachnoid H e m o r r h a g e " [November 1989;18:1199-1205], is correct in d i r e c t i n g a t t e n t i o n to t h e w a r n i n g h e a d a c h e t h a t occurs in about one half of cases of intracranial saccular a n e u r y s m shortly before rupture. T h e challenge facing t h e e m e r g e n c y p h y s i c i a n e v a l u a t i n g a p a t i e n t w i t h headache is recognizing an a n e u r y s m as the cause of the headache. Surgical a t t a c k on the u n r u p t u r e d lesion results in a generally excellent outcome, I, 2 b u t if the a n e u r y s m ruptures, the overall m o r t a l i t y is about 50%. A c o m p u t e d t o m o g r a p h y (CT) scan perhaps followed by a l u m b a r puncture, looking for blood in the subarachnoid space, is r e c o m m e n d e d in t h e literature3A to evaluate the w a r n i n g headache; this has become the practice of m a n y e m e r g e n c y p h y s i c i a n s . However, a n e g a t i v e u n e n h a n c e d CT scan and a negative l u m b a r p u n c t u r e do n o t exclude saccular a n e u r y s m as the cause of the p a t i e n t ' s s y m p t o m s . T h e w a r n i n g headache is n o t necessarily due to leakage of b l o o d b u t m a y r e s u l t from h e m o r r h a g e i n t o or s u d d e n tearing and expansion of the still i n t a c t a n e u r y s m wall. S y m p t o m s also could result from cortical i s c h e m i a due to spasm of the involved artery. As D a y and R a s k i n 5 have emphasized, absence of blood does n o t exclude a sympt o m a t i c aneurysm. E m e r g e n c y c o n t r a s t - e n h a n c e d CT scan w i t h m u l t i p l e t h i n cuts (CECT/MTC) through the sella is a t e c h n i q u e that should detect m o s t saccular a n e u r y s m s of the circle 19:7 July 1990
of Willis. Twelve years ago, Katada et al 6 reported successful v i s u a l i z a t i o n b y t h i s m e t h o d of 27% of a n e u r y s m s smaller than 5 m m , 70% of those 5 to 10 m m , and all a n e u r y s m s larger t h a n 10 r a m . More recently, Schmid and associates 7 used C E C T / M T C to d e m o n s t r a t e 74 of 76 cons e c u t i v e a n g i o g r a p h i c a l l y or a u t o p s y - p r o v e n i n t r a c r a n i a l aneurysms d o w n to 3 m m in diameter. Other groupsS, 9 also have described the t e c h n i q u e and confirm its usefulness in detecting u n r u p t u r e d aneurysms. T h e objective in the e m e r g e n c y e v a l u a t i o n of the pat i e n t w i t h headache s h o u l d be the direct v i s u a l i z a t i o n of the a n e u r y s m itself. We therefore r e c o m m e n d that such patients be regarded as p o s s i b l y harboring an expanding or tearing cerebral a n e u r y s m and t h a t they be sent to t h e CT laboratory for e m e r g e n c y C E C T / M T C .
Merrill A Cohen, MD Ronald S Benenson, MD York Hospital York, Pennsylvania 1. Mount LA, Brisman R: Treatment of multiple and asymptomatic aneurysms, in Schmidek Hid, Sweet WH [eds): Current Techniquesin Operative Neurosurgery. New York, Grune & Stratton, 1982, vol 2, p 765-769. 2. Wirth FP, Laws ER Jr, Piepgras D, et al: Surgical treatment of incidental intracranial aneurysms. Neurosurgery 1983;12:507-5tl. 3. Adams HP, Jergenson DE), Kassell NF, et al: Pitfalls in the recognition of subarachnoid hemorrhage. JAMA 1980;244:794-796.
Annals of Emergency Medicine
842/159
Informed
Consent:
An Unresolved
Issue
To the Editor: In Reply:
The article "Informed Consent for Clinical Research" [July 1989;18:766-771] by Spivey addresses issues of importance to all investigators in emergency m e d i c i n e w h o perform clinical research. T h e a u t h o r states t h a t " t h e c o n s e n t form s h o u l d include a s t a t e m e n t that the i n s t i t u t i o n is responsible for any damages that occur." This is not accurate. T h e instit u t i o n at w h i c h the research is performed is not responsible for damages that occur, nor is it duty-bound to provide c o m p e n s a t i o n for such research-related injury. According to F D A - i n f o r m e d c o n s e n t r e g u l a t i o n s (21 CFR 50.25 [a] [6]), the research subject m u s t be told whether any comp e n s a t i o n a n d / o r m e d i c a l t r e a t m e n t is a v a i l a b l e if res e a r c h - r e l a t e d i n j u r y occurs, w h a t it c o n s i s t s of, and w h e r e f u r t h e r i n f o r m a t i o n m a y be o b t a i n e d . W h e t h e r c o m p e n s a t i o n and m e d i c a l t r e a t m e n t will be offered, as well as any stipulations regarding eligibility for such compensation or t r e a t m e n t , is solely up to the i n s t i t u t i o n and the sponsor of the project. As long as the research subject is informed of the existence of c o m p e n s a t i o n or lack of it, he m a y render an i n f o r m e d decision as to w h e t h e r to participate. As one w h o wears both the hat of the clinical researcher in e m e r g e n c y m e d i c i n e and t h a t of t h e c h a i r m a n of an IRB, I did appreciate the author's sensitive t r e a t m e n t of the " i n f o r m e d c o n s e n t " as a process to w h i c h the investigator should be c o m m i t t e d as distinct from having someone obtain a signature on a "consent form." A n y camouflaging or trivializing research risk in the obtaining of consent is unethical, as is any a t t e m p t at coercing the p a t i e n t to enroll in the study. It is a responsibility of all clinical researchers to police ourselves. W h e n we strictly adhere to our individual IRB policies, we will be m u c h m o r e consistent w i t h local standards of conduct t h a n if we only had guidelines from the bureaucrats in Washington. The issue of informed consent in resuscitation research is n o t yet resolved. D u e to the y o u t h of our specialty, we in emergency m e d i c i n e have not m a d e our voices heard by the authors of regulations and guidelines that pertain to clinical research using patients who are vulnerable by virtue of an u n s t a b l e m e d i c a l condition. M y appreciation goes out to the editors of Annals for their willingness to p u b l i s h articles such as Dr Spivey's so t h a t the dialogue on these issues m a y continue.
I thank Dr Runge for his c o m m e n t s regarding informed consent and clarify the issue he raises regarding responsibility for damages that occur during research. In the article, r e q u i r e m e n t s of the A m e r i c a n Code of Federal Regulations for the P r o t e c t i o n of H u m a n Subjects are clearly spelled out. After that is a section of additional e l e m e n t s of informed consent that, w h e n applicable, m a y be added to the consent form. The statement, "the consent form should include a s t a t e m e n t t h a t the i n s t i t u t i o n is responsible for any damages that occur" was i n t e n d e d as part of this section. W h e n applicable, a s t a t e m e n t regarding responsibility for damages should be included. Dr Runge is correct that the decision regarding c o m p e n s a t i o n of a pat i e n t is optional for the investigator and i n s t i t u t i o n . A l t h o u g h the responsibility for c o m p e n s a t i o n of a patient is optional, I feel strongly that the p h y s i c i a n and the i n s t i t u t i o n are responsible for the damages that a p a t i e n t m a y have suffered because of a research study. For moral and ethical reasons, t h e y should provide necessary medical t r e a t m e n t for an i n j u r y and a s s u m e costs of t h o s e treatments. Dr Runge refers to FDA regulations in his letter. It is i m p o r t a n t to note that there are two governing bodies that have t h e i r o w n r e g u l a t i o n s for c o n d u c t i n g r e s e a r c h and obtaining informed consent. The Federal Drug A d m i n i s t r a t i o n and the D e p a r t m e n t of H e a l t h and H u m a n Services have s i m i l a r g u i d e l i n e s for i n f o r m e d consent, b u t their guidelines for conducting an IRB differ. It is important that an investigator be familiar w i t h his IRB and the rules by w h i c h it is governed. Drugs and n e w m e d i c a l devices are m o r e l i k e l y to fall under FDA rules and regulations than are research protocols that do n o t involve drugs or n e w devices. As a n e w s p e c i a l t y that f r e q u e n t l y m u s t c o n d u c t research on patients w h o are o b t u n d e d or in cardiac arrest, it is i m p o r t a n t t h a t we develop n e w w a y s of o b t a i n i n g consent in these difficult situations. I applaud the efforts of Dr Runge and others who have taken the t i m e to participate as m e m b e r s of IRBs. A c t i v i t i e s like this not only increase the credibility of research in e m e r g e n c y medicine, b u t a l l o w us t h e o p p o r t u n i t y to b e t t e r u n d e r s t a n d t h e workings of an IRB and learn h o w we m i g h t better approach the difficult issue of i n f o r m e d consent.
Jeffrey W Runge, MD, FACEP Department of Emergency Medicine Research and Human Subjects Protection Committee Charlotte Memorial Hospital and Medical Center Charlotte, North Carolina
William H Spivey, MD, FACEP Department of Emergency Medicine Division of Research Medical College of Permsylvania Philadelphia
Unreliable
Effect of Nifedipine
in R e l i e v i n g
Renal Colic
To the Editor:
In their article "Nifedipine for the Relief of Renal Colic: A Double-Blind, Placebo-Controlled Trial" [April 1989;
158/841
18:352-354], Caravati et al presented a double-blind, placebo controlled study that evaluated the efficacy of nif-
Annals of Emergency Medicine
t9:7 July1990
NIFEDIPINE IN RENAL COLIC Importance of plasma levels /20~dipine
serum
bevel { n g / m l ) . . . . . . . . . . . . . . . . . . . . . . . . . . .
I00 80 60
$ ÷
40
$ 20 0
........
i ............................ RESPONDERS
t" NON-RESPONDERS
GROUPS
edipine in relieving pain related to acute renal colic. T h e authors did not observe any significant difference in pain relief b e t w e e n nifedipine and placebo administration. We w o u l d l i k e to r e p o r t the r e s u l t s of a p r e l i m i n a r y open study t h a t was conducted in our e m e r g e n c y d e p a r t m e n t and i n c l u d e d d e t e r m i n a t i o n s of nifedipine levels in serum. After informed consent had been obtained, patients w h o w e r e d e v o i d of c o n t r a i n d i c a t i o n s to c a l c i u m c h a n n e l blockers and who presented to the ED w i t h renal colic
were asked to c h e w t w o capsules of nifedipine (20 mg) and t h e n to s w a l l o w it w i t h 150 m L water. T h e y were also asked to assess their pain s e v e r i t y (4, severe; 3, mild; 2, endurable; 1, n o pain) before and ten, 20, and 40 m i n u t e s after n i f e d i p i n e a d m i n i s t r a t i o n . T h e y w e r e c o n s i d e r e d a responder if t h e pain score decreased two points w i t h i n 20 minutes. N o n r e s p o n d e r s (after 20 minutes) were a d m i t t e d to the usual r e g i m e n of t r e a t m e n t . Nifedipine levels w e r e d e t e r m i n e d at 30 m i n u t e s . T w e l v e p a t i e n t s w i t h subseq u e n t l y c o n f i r m e d n e p h r o l i t h i a s i s were i n c l u d e d in t h e data analysis, The results of n i f e d i p i n e d e t e r m i n a t i o n s in serum are s h o w n in t h e Figure, w h i c h c l e a r l y d e m o n s t r a t e s t h a t higher levels were o b s e r v e d in responders. We thus suggest that the i n a b i l i t y of n i f e d i p i n e to relieve renal colic in some patients m a y be r e l a t e d to an erratic absorption a n d ' to the v a r i a b i l i t y in p l a s m a levels. We conclude that the unreliable effect of n i f e d i p i n e precludes a routine clinical use in this painful c o n d i t i o n .
P Lheureux, M D R Askenasi, MD, PhD Emergency Department D Gangi, MD Clinical Pharmacology Erasme University Hospital Brussels, Belgium
Aneurysm Alert To the Editor: Dr F o n t a n a r o s a , in his article, " R e c o g n i t i o n of Subarachnoid H e m o r r h a g e " [November 1989;18:1199-1205], is correct in d i r e c t i n g a t t e n t i o n to t h e w a r n i n g h e a d a c h e t h a t occurs in about one half of cases of intracranial saccular a n e u r y s m shortly before rupture. T h e challenge facing t h e e m e r g e n c y p h y s i c i a n e v a l u a t i n g a p a t i e n t w i t h headache is recognizing an a n e u r y s m as the cause of the headache. Surgical a t t a c k on the u n r u p t u r e d lesion results in a generally excellent outcome, I, 2 b u t if the a n e u r y s m ruptures, the overall m o r t a l i t y is about 50%. A c o m p u t e d t o m o g r a p h y (CT) scan perhaps followed by a l u m b a r puncture, looking for blood in the subarachnoid space, is r e c o m m e n d e d in t h e literature3A to evaluate the w a r n i n g headache; this has become the practice of m a n y e m e r g e n c y p h y s i c i a n s . However, a n e g a t i v e u n e n h a n c e d CT scan and a negative l u m b a r p u n c t u r e do n o t exclude saccular a n e u r y s m as the cause of the p a t i e n t ' s s y m p t o m s . T h e w a r n i n g headache is n o t necessarily due to leakage of b l o o d b u t m a y r e s u l t from h e m o r r h a g e i n t o or s u d d e n tearing and expansion of the still i n t a c t a n e u r y s m wall. S y m p t o m s also could result from cortical i s c h e m i a due to spasm of the involved artery. As D a y and R a s k i n 5 have emphasized, absence of blood does n o t exclude a sympt o m a t i c aneurysm. E m e r g e n c y c o n t r a s t - e n h a n c e d CT scan w i t h m u l t i p l e t h i n cuts (CECT/MTC) through the sella is a t e c h n i q u e that should detect m o s t saccular a n e u r y s m s of the circle 19:7 July 1990
of Willis. Twelve years ago, Katada et al 6 reported successful v i s u a l i z a t i o n b y t h i s m e t h o d of 27% of a n e u r y s m s smaller than 5 m m , 70% of those 5 to 10 m m , and all a n e u r y s m s larger t h a n 10 r a m . More recently, Schmid and associates 7 used C E C T / M T C to d e m o n s t r a t e 74 of 76 cons e c u t i v e a n g i o g r a p h i c a l l y or a u t o p s y - p r o v e n i n t r a c r a n i a l aneurysms d o w n to 3 m m in diameter. Other groupsS, 9 also have described the t e c h n i q u e and confirm its usefulness in detecting u n r u p t u r e d aneurysms. T h e objective in the e m e r g e n c y e v a l u a t i o n of the pat i e n t w i t h headache s h o u l d be the direct v i s u a l i z a t i o n of the a n e u r y s m itself. We therefore r e c o m m e n d that such patients be regarded as p o s s i b l y harboring an expanding or tearing cerebral a n e u r y s m and t h a t they be sent to t h e CT laboratory for e m e r g e n c y C E C T / M T C .
Merrill A Cohen, MD Ronald S Benenson, MD York Hospital York, Pennsylvania 1. Mount LA, Brisman R: Treatment of multiple and asymptomatic aneurysms, in Schmidek Hid, Sweet WH [eds): Current Techniquesin Operative Neurosurgery. New York, Grune & Stratton, 1982, vol 2, p 765-769. 2. Wirth FP, Laws ER Jr, Piepgras D, et al: Surgical treatment of incidental intracranial aneurysms. Neurosurgery 1983;12:507-5tl. 3. Adams HP, Jergenson DE), Kassell NF, et al: Pitfalls in the recognition of subarachnoid hemorrhage. JAMA 1980;244:794-796.
Annals of Emergency Medicine
842/159
