Clinical trials and cerebral resuscitation research

SESSION 7: Cerebral Resuscitation: Clinical Studies

Clinical Trials and Cerebral Resuscitation Research Norman S Abramson, MD / Peter Safar, MD / Sheryl F Kelsey, PhD / Katherine M Detre, MD, DrPH / The Brain Resuscitation Clinical Trial (BRCT I) Group*

Resuscitation research trials must have adequate scientific basis, sound ethics, feasibility, and potential impact on health care. The organization and methodology of the Pitts- burgh-based Brain Resuscitation Clinical Trials (BRCT 1) are reviewed in detail. This type of international collaborative study will be useful for evaluation of new cardiopulmonary-cerebral resuscitation therapies. [Abramson NS, Safaf P, Kelsey SE Detre KM, BRCT I Group: Clinical trials and cerebral resuscitation research. Ann Emerg Med Sep- tember 1984 (Part 2);13:868-872. Key words: cerebral resuscitation; clinical trials; resuscitation research.]

Clinical Research: An Overview From the beginnings of medicine, doctors have experi-

mented with new therapies. The empirical approach to medical research - - trying new therapies and procedures in conditions that fail to respond to conventional treatment, and then carefully observing the results - - was the method of advancing knowledge until well into the 20th century. It is only recently that more sophisticated research tools have been applied to the study of clinical medicine. In fact prospective, randomized clinical trials were first proposed by Fisher in 1935, and were incorporated into human studies in the 1940s. 1

There are many examples of clinically popular diagnostic and therapeutic interventions that have not withstood the test of time. 2 There are also those that have remained in clinical practice without definitive scientific proof of benefit. 3 Absolute answers to clinical problems rarely exist. Therapeutic decisions, therefore, must be based on the probabilities of risk or benefit. Increasingly today controlled

From the Resuscitation Research Center and the Department of Anesthesiology/Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania. AddreSs for reprints: Norman S Abram- son, MD, Resuscitation Research Center, University of Pittsburgh, 3434 Fifth Avenue, Pittsburgh, Pennsylvania 15260. Supported by NIH grant #NS15295. *BRCT I Study Group Steering Committee: NS Abramson (coordinator), P Safar (principal investigator), K Detre, J Monroe, S Kelsey, O Reinmuth, J Snyder. Clinical investigators: A Mullie (Brugge, Belgium), U Hedstrand (Uppsala, Sweden), H Breivik (Trondheim, Norway), A Skulberg (Oslo, Norway), T Tammisto (Helsinki, Finland), M Jastremski (Syracuse, New York), B Lind (Oslo, Norway), M Bozza-Marrubini (Milan, Italy), D Potter (London, England), J Snyder (Pittsburgh, Pennsylvania), A Canton (Murcia, Spain), B Kaminski (Warsaw, Poland).

clinical trials are being used to resolve uncertain areas of medical practice.

In order to initiate a clinical trial, four requirements must be satisfied: 4

1. Adequate scientific knowledge. Sufficient animal work and usually preliminary clinical work (eg, feasibility and/or pilot studies), must suggest that the therapy to be tested may be an improvement over existing therapy. As an- ecdotal clinical reports of benefit accumulate and/or as a new therapy becomes widely used, however, the oppor- tunity to condllct a clinical trial may pass. Clinicians might become so convinced of the "proven" value of the therapy that they would consider it unethical to enter their patients into a clinical trial in which this therapy might be withheld. It would thus become difficult, if not impossible, to obtain suitable control patients for a scientifically rigorous clinical trial.s, 6

2. Sound ethics. The methodologic design of the study must be such that the possible occurrence of Type I errors (false conclusion of efficacy when none exists) or Type II errors (false conclusion that no efficacy exists when in fact it does) is minimized. Otherwise there will be little chance of obtaining a valid, generalizable result, and such a study might expose patients to additional risk for no purpose. Risks of participation in clinical research include, in addition to the potentially hazardous side effects of the experimental therapy, the possibility that the new, potentially beneficial therapy may be withheld. Furthermore, additional procedures may be undertaken and decisions made in order to gain new information, rather than only to cure the patient. Thus added hazards, discomforts, and inconve- niences may accompany participation in a clinical trial.7 Of course, there are also potential benefits. Beyond the potentially beneficial effect of the therapy being tested, there is a more subtle benefit: the attentive care received from highly trained physicians. Indeed, for acute medicine there is sug- gestive evidence that mere participation in a scientific clinical trial improves outcome - - even if not treated with an experimental therapy - - if medical care is provided according to a carefully designed standard therapy protocol s

3. Feasibility. Feasibility considerations include cost, time, and methodology. Study design and methodology must allow a reasonable chance of reaching a definitive an- swer within a reasonable period of time.

4. Impact on health care. To justify the cost and efforts

13:9 September 1984 (Part 2) Annals of Emergency Medicine 868/133

RESUSCITATION RESEARCH Abramson et al

Fig. 1. BRCT I standard therapy protocol.

involved in a clinical trial, study results must have the potential to influence meaningfully the practice of clinical medicine and sufficiently reduce morbidity and mortality.

To benefit patients, clinical trials must be valid (results obtained are true) and generalizable (results are widely applicable). The first requirement, validity, has become a non-negotiable demand, hence the current view of the randomized clinical trial as the "gold standard" of medical research.3,6, 9-12 In a clinical trial, randomized treatment assignment minimizes potential problems with imbalance of known as well as unknown prognostically related variables, and removes the potential for bias. The conscious or uncon- scious manipulation of treatment assignments, either by investigators or by patients, is prevented and treatment assignment is left to an objective procedure that cannot be predicted. 13 In order to strengthen further the objectivity of a clinical trial, use of a "double blind" technique is recommended where feasible. 14 This study mechanism tends to overcome bias of both investigators and subjects because neither knows, until the conclusion of the study, who has received the experimental treatment and who has received standard therapy.

If random treatment assignment is not employed in a clinical trial and if statistically significant differences of prognosis-related variables occur between study groups, the objectivity of treatment assignments would be questioned. Randomization is the simplest and best understood mechanism to prevent this problem. Other clinical research mech- anisms (eg, sequential trials 15 or use of historical controls) have been suggested andtr ied, and generally have been found to be less desirable.3,6,9-12

If an imbalance of outcome-related variables between treatment groups occurs, the findings of a clinical study will be less convincing. Such imbalances are usually han- dled by stratification, the separate examination of study results in relatively homogeneous subgroups, defined after treatment assignment or even after follow-up data collection. The drawback of stratification is that it requires the creation of patient subgroups. These subgroups may turn out to be too small to provide reliable estimates of treatment effects within strata. Furthermore, when several statistical comparisons are made simultaneously" the chance that at least one will be "statistically significant" is in- creased. Thus, when stratification is used, the persuasive- ness of a statistically significant result is weakened. 13

The second requirement for clinical trials to be potentially beneficial, generalizability to patients outside the study, demands that study cases be selected according to preset entry criteria from a well-defined population. Pa- tients initially considered for a study, but then found to not fulfill all entry criteria and therefore not randomized, are study exclusions. As long as these patients are excluded be- fore randomization, the internal validity of the study is pro- tected. 16 Patients initially thought eligible for a study and randomized, but later found to be inappropriate study patients on the basis of various parameters (such as nonfulfill- ment of preset eligibility criteria, study protocol violations, or inadequate data collection) are study withdrawals. These patients are of concern because their removal from a study may reflect bias or intentional or unintentional attempts to manipulate the study. Delay of patient selection until satis- faction of eligibility criteria is confirmed, or elimination of

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1. Control of MAP Normotension throughout coma (MAP 90-100 mm Hg; systolic BP > 100 mm Hg) by titrated vasopressor IV prn. Normovolemia or plasma volume expansion.

2. Moderate hyperventilation (PaCO2 25-35 mm Hg).

3. Moderate hyperoxia (Pa©2 > 100 mm Hg with minimum FiO2; positive end- expiratory pressure as needed, titrated to avoid ICP rise).

4. Control of arterial pH (7.3-7.6).

5. Immobilization (relaxation).

6. Light anesthesia/sedation for deafferentation.

7. Anticonvulsant (eg, barbiturate, diazepam, or diphenyl- hydantoin) as needed for clinical or electrical seizure activity.

8. Normalization of blood variables (hematocrit, electrolytes, colloid osmotic pressure, osmolality, glucose).

9. Alimentation (calories, amino acids, vitamins).

10. Steroid (optional, short-term) (eg, dexamethasone 0.2 mg/kg IV + 0.04 mg/kg/6 h, or methylprednisolone 1 mg/kg IV + 0.2 mg/kg/6 h).

11. Osmotherapy (mannitol/glycerol) to normalize monitored rise in ICP or for secondary neurologic deterioration.

12. Temperature monitoring and control (normothermia).

13. CNS evaluation (coma scoring, EEG). MAP = mean arterial pressure. BP = blood pressure.

1

any patient withdrawal (despite the inclusion of some inappropriate study patients) are two possible resolutions to this problem. Generally the latter is recommended, especially in resuscitation research, in which delays may not be feasible.16

In the interpretation of clinical trials, repeated emphasis is placed on "the almighty P value without proper consideration of the significance of 'significance.'-17 In other words, the conclusions reached in clinical trials often rely too heavily on the outcome of statistical tests without due consideration of the actual clinical relevance of the results. For example: For example:

I. The outcome difference caused by the tested therapy may not be a clinically important difference, or

2. The study may have been designed in such a way that a meaningful conclusion could not have been reached (eg, if sample size were too small to show a benefit of treatment), or

3. The statistical methods applied to the study may have been used incorrectly (a not:infrequent occurrence, even in well-respected journals). 18

Small P values are just as often due to large sample sizes and/or low between-observation variability as they are to clinically important differences between the parameters tested.19

Although randomization does guarantee the validity of the statistical tests of clinical study results, it does not in- sure the clinical relevance of the trial results. 16 To judge this, we must be informed and critical about the issues of study design, methodology and statistical analysis, as well

Annals of Emergency Medicine 13:9 September 1984 (Part 2)

United States

James V Snyder, MD / Paul Paris, MD Presbyterian-University Hospital Pittsburgh, Pennsylvania Daniel Thompson, MD Mercy Hospital Pittsburgh, Pennsylvania Michael Jastremski, MD Upstate Medical Center Syracuse, New York

Hugh E Stephenson, Jr, MD University of Missouri Medical Center Columbia, Missouri Jacek Franaszek, MD Rhode Island Hospital Providence, Rhode island

Barry Mizock, MD Cook County Hospital Chicago, Illinois Herbert Rogove, MD Riverside Methodist Hospital Columbus, ©hio

Andrew Egol, MD Baptist Hospital of Miami Miami, Florida

Paul Pepe, MD City of Houston Health Department Houston, Texas

Richard T Davis, MD Mesa Lutheran Hospital Mesa, Arizona

Keith Bradley, MD Norwalk Hospital Norwalk, Connecticut

David Powner, MD Methodist Hospital Indianapolis, Indiana

Steven J Davidson, MD Medical College of Pennsylvania Philadelphia, Pennsylvania

Europe

Arsene Mullie, MD St Jans Hospital Brugge, Belgium

UIf Hedstrand, MD University Hospital Uppsala, Sweden

Andreas Skulberg, MD UIleval Hospital Oslo, Norway

Bjorn Lind, MD Akershus Central Hospital Oslo, Norway

Sven Erik Gisvold, MD University Hospital Trondheim, Norway

Marialuisa Bozza-Marrubini, MD Ospedale Niguarda - - Ca' Granda Milan, Italy

Dennis R Potter, MD King's College Hospital London, England

Gad Bar-Joseph, MD Rambam Medical Center Haifa, Israel

as the clinical conditions and treatments under consideration. We must be cautious in our interpretation of preliminary research data, and temper our enthusiasm to apply these findings to our patients. Animal experimental studies, as well as clinical trials, require critical evaluation to identify weaknesses of methodology or of statistical analysis. Clinical relevance must be established, in addition to statistical significance. It is only with such scientific skepticism that clinical research findings that will have a meaningful impact on clinical medicine can be identified.

The Pittsburgh-Based Clinical Trials of Brain Resuscitation (BRCT I)

Based on animal experimental evidence indicating a brain-damage-ameliorating effect of thiopental loading, ~o clinical feasibility 21 and pilot studies 22 were conducted from 1977 to 1979. These studies showed that thiopental loading could be safely accomplished, and suggested a beneficial therapeutic effect. Furthermore, these preliminary studies proved that the international collaborative study mechanism, painstakingly developed over several years, was hmctional.21,22

Twelve hospitals, in nine countries, coordinated by the Resuscitation Research Center team at the University of Pittsburgh, participated in the first randomized clinical trial of brain resuscitation (BRCT I). A multihospital collaborative trial was necessary in order to obtain enough study patients to fulfill the estimated sample size requirement within a reasonable time period. The objectives of the study, begun in 1979, were the following: 1) to determine the efficacy of high-dose thiopental loading in ameliorating brain damage after severe global brain ischemic insults; 2) to identify the risks and complications of this experimental treatment; 3) to collect data describing patient condition during a one-year follow-up period; and 4) to firmly establish the collaborative study mechanism for the future evaluation of promising brain resuscitation therapies.

Fig. 2. BRCT II clinical investigators.

Methodology Patients resuscitated from cardiac arrest (or severe global

ischemic anoxic cerebral insults without actual circulatory arrest) who made no purposeful response to pain at 10 to 50 minutes following restoration of spontaneous circulation and adequate oxygenation were eligible for the study. Pa- tients were randomly assigned to the standard therapy or standard therapy plus thiopental loading group using a cen- trally prepared randomization scheme. Exclusion criteria were carefully defined as follows: 1) patients in whom resuscitation was inappropriate, eg, patients with terminal conditions; 2) patients awakening prior to randomization; 3) patients considered for the study alter the 50-minute time limit for selection had passed; 4} patients with primary in- tracranial disease causing the cardiac arrest; and 51 infants less than 30 days of age. Informed consent was documented for all study patients.

Both groups received the same "brain-oriented" life sup- port {Figure 11. This standard therapy protocol, designed by consensus of the participating investigators, provided all study patients with optimal nonexperimental therapy, and was clinically tested prior to the actual start of the randomized trial. The experimental treatment group, in addition, received thiopental 30 mg/kg intravenously as early as possible following randomization and as rapidly as the circulation would tolerate. Blood pressure was supported by intravenous fluid and vasopressor administration as necessary.

Pilot-tested data collection forms were used to collect information about the following: 1} patient demographics; 2) the severity of brain insult in terms of retrospectively estimated arrest, CPR, and hypoxia times; 3) cardiac arrest and resuscitation events; 41 the administration and complications of thiopental loading; 5) intensive care unit manage-


RESUSCITATION RESEARCH Abramson et al

ment; 6) neurologic and general medical condition at each of the follow-up periods {48 to 72 hours, ten days, and one, three, six, and 12 months); and 7) events surrounding patient death. All submitted data forms were checked for ac- curacy and completeness of data. The information was then entered into the data base management system for comput- er storage and analysis.

Risk monitoring for mortality and incidence of complications, such as hypotension, arrhythmias, and rearrest, was done with the addition of each 20 patients to the study. Benefit monitoring was performed every six months. Re- suits of these analyses were kept confidential. Only one member of the epidemiology team had access to the treatment code. Had a statistically significant difference between thiopental and standard therapy occurred, indicating excessive risk or statistically significant benefit of thiopental therapy, it would immediately have been brought to the attention of the principal investigator, who would have no- tified the National Institutes of Health (NIH) Monitoring Committee. Consideration would then have been given to stopping the study at that point.

Each hospital investigator maintained a log listing all resuscitation cases admitted to the intensive care unit in his hospital. This log served three purposes: 1) it defined the overall population of cardiac arrest cases from which study patients were drawn; 2) it served as a background against which to compare patients selected into the study; and 3) it documented cardiac arrest patients excluded from the study and the reasons for these exclusions.

Duration and type of brain insult was assessed immediately following resuscitation by each investigator after in- terviews of bystanders, ambulance personnel, and hospital physicians and nurses. Total insult time was the sum of arrest time (no spontaneous pulse and no cardiopulmonary resuscitation [CPR] performed), CPR time (no spontaneous pulse while CPR performed), and hypoxia times (severe hypotension or hypoxemia occurring prior to actual cardiac arrest or following restoration of spontaneous circulation). The potential inaccuracy of these estimates, especially for prehospital events, is well recognized, but a more reliable quantification of brain injury does not currently exist. A modification of the well-known Glasgow coma score, 23 originally designed for head-injury patients, was also used for patient evaluation. This Glasgow-Pittsburgh coma score adds to the original Glasgow coma score a section for evaluation of brain stem function. 24 Coma scoring was begun immediately following resuscitation and continued until the patient awakened. At this point more sophisticated neu- ropsychiatric testing was begun. Preliminary analysis of the coma score data indicates that the Glasgow coma score is applicable to cardiac arrest patients, and that the added evaluation of brain stem function increases the prognostic value of the information obtained.

In order to establish the efficacy of a brain resuscitation therapy, recovery of cerebral function - - not mortality - - is the most relevant criterion. For this determination, a five- point outcome scale modified from the Glasgow performance categories was used. 2s Where the Glasgow outcome scale measures overall performance only, the Pittsburgh modification separately evaluates cerebral (CPC) and overall performance (OPC). 24 With this modification, patients who recovered good cerebral function, but ultimately did poorly because of extracerebral organ system failure, could be identified. This differentiation is of great importance for the evaluation of potentially beneficial brain resuscitation mea-

sures in high-mortality patients, such as cardiac arrest survivors. A complete neurological examination, which served as a validation of the CPC evaluation, was performed at each follow-up period.

Conclusion An international collaborative clinical study mechanism

for the evaluation of promising new cardiopulmonary-cerebral resuscitation (CPCR) therapies has been established. The feasibility of conducting collaborative, prospective, randomized CPCR clinical trials with long-term evaluation of outcome has been proven. The now-established data collection system will permit future acquisition of additional epi- demiologic data, further identification of prognosticaUy ac- curate determinants of outcome, and continued evaluation of the results of hospital and community resuscitation services.

Preliminary results of BRCT I are now available. 26 The second phase of the Brain Resuscitation Clinical Trials (BRCT II) is already underway. Twenty-one collaborating hospitals in seven countries (Figure 2) began testing the brain damage ameliorating effects of a calcium entry blocker (lidoflazine) in the spring of 1984. Results of this study will be available in 1986.

References 1. Fisher RA: The Design of Experiments, ed 8. New York, Hafner, 1966.

2. Fletcher RId, Fletcher SW: Clinical research in general medical journals. N Engl J Med 1979~301:180-183. 3. Spodick DH: R~ndomized controlled clinical trials. JAMA 1982;247:2258-2260. 4. Levy RI, Sondek EJ: Large scale clinical trials: Are they worth the cost? Ann NY Acad Sci 1982;382:411-422.

5. Miller H: Medicine and Society. London, Oxford University Press, 1973.

6. Shaw LW, Chalmers TC: Ethics in cooperative clinical trials. Ann NY Acad Sci 1970;169:487-495. 7. Schafer A: Ethics of the randomized trial. N EngI J Med 1982;307:719. 8. Abramson NS, Safar P, Detre K, et ah Long-term follow-up of cardiac arrest survivors. Crit Care Med 1982;10:215.

9. Haines SJ: Randomized clinical trials in neurosurgery. Neuro- surgery 1983;12:259-264.

10. Forrest WH: A collaborative clinical trial on trial. Anesthe- siology 1982;56:249-250.

11. Byar DP, Simon RM, Friedewald WT, et al: Randomized clinical trials: Perspectives on some recent ideas. N Engl J Med 1976;295:74-80.

12. Sackett DL: The competing objectives of randomized trials. N Engl J Med 1980;308:1059-1060. 13. Lavori PW, Louis TA, Bailar JC, et al: Design for experiments - - Parallel comparisons of treatments. N Engl J Med 1983;309: 1291-1298.

14. Ballintine EJ: Objective measurements and the double- masked procedure. Am l Ophthalmol 1975;79:763.

15. Clemmeson C, Nilsson E: Therapeutic trends in the treatment of barbiturate poisoning. Clin Pharmacol Ther 1961;2:220.

16. May GS: The randomized clinical trial: Bias in analysis. Cir- culation 1981;64:669-673.

17. Peck C: The almighty "p" value or the significance of "significance." Present Concepts in Internal Medicine (Letterman Gener-

136/871 Annals of Emergency Medicine 13:9 September 1984 (Part 2)

al Hospital, San Francisco) 1971;4:1021-1024.

18. Glantz SA: How to detect, correct, and prevent errors in medical literature. Circulation 1980;61:1-7.

19. Ford I: Can statistics cause brain damage. J Cereb Blood Flow Metab 1983;3:259-262.

20. Bleyaert AL, Nemoto EM, Safar P, et al: Thiopental ameliora- tion Of brain damage after global brain ischemia in monkeys. Anesthesiology 1978;49:390-398.

21. Breivik H, Safar P, Sands P, et al: Clinical feasibility trials of barbiturate therapy after cardiac arrest. Crit Care Med 1978;6: 228-244.

22. Mullie A, Abramson N, Safar P, et al: Clinical pilot studies of

thiopental loading after cardiac arrest, abstract. Crit Care Med 1981;9:184.

23. Teasdale G, Jennett B: Assessment of coma and impaired consciousness. Lancet 1974;2:81-83.

24. Safar P: Resuscitation after brain ischemia, in Grenvik A, Sa- far P (eds): Brain Failure and Resuscitation. New York, Churchill Livingstone, 1981, p 155-184.

25. Jennett B, Bond M: Assessment of outcome after severe brain damage. A practical scale. Lancet 1975;1:480-482.

26. Abramson N, Safar P, Detre K, et al: Thiopental loading in cardiopulmonary resuscitation (CPR) survivors, abstract. Crit Care Med 1984;12:227.

Cerebral Resuscitation in the Community Hospital Alan C Schwartz, MD, FACEP / Phoenix, Arizona

[Editor's note: Dr Schwartz was unable to finalize his man- uscript in t ime for publication of this issue. A t the Sym- posium, however, there was a good deal of discussion about the appropriateness of this type of community hospital research. The editor thus asked Dr Schwartz to prepare a brief paper outlining his perceptions concerning this issue. His response, in editorial format, follows the abstract of his clinical study. Schwartz AC: Cerebral resuscitation in the community hospital, abstract and editorial. Ann Emerg Med September 1984 (Part 2);13:872-873. Key words: calcium antagonists; cardiac resuscitation; neurologic out- colile.]

Abstract of Clinical Study A s tudy was done to determine whether the calcium

blocker(s) verapamil and/or magnesium sulfate decrease neurologic morbidity after cardiac arrest. In the 19-month interval from July 15, 1982, to February 15, 1984, all out-of- hospital cardiac arrest survivors from five participating hospitals were reviewed. Fifty patients met the criteria for inclusion into this study: 1} unwitnessed, out-of-hospital cardiac arrest, and 2) comatose 20 minutes after the restoration of spontaneous circulation (ROSC)r Twenty-four patients received verapamil and/or magnes ium sulfate at varying times after ROSC {calcium blocker group), while 26 patients did not (control group). Decisions for t reatment with or without calcium blockers were made by different physicians based on their beliefs regarding the efficacy of these agents. Age, arrest t ime, card iopulmonary resusci ta t ion (CPR) time, and approximate cerebral ischemic time were

From the Department of Emergency Services, Phoenix Baptist Hos- pital and Medical Center, Phoenix, Arizona. Address for reprints: Alan C Schwartz, MD, Medical Director, Emergency Services, Phoe- nix Baptist Hospital and Medical Center, 6025 North 20th Avenue, Phoenix, Arizona 85015.

comparable in the two groups. In the calcium blocker group, ten of 24 patients regained consciousness, and nine of these ten left the hospital alive. Seven of the nine survivors ap- peared neurologically normal at discharge, and three- and six-month follow-up confirmed this. While no demonstrable adverse effects were seen after the administration of magnesium sulfate, 50% of the patients who received verapamil had a drop in blood pressure of greater than 20%. In the control group, seven of 26 patients regained consciousness and four of the seven left the hospital alive. Only one of the four survivors was neurologically normal at three- and six- month follow-up. Overall, seven of 24 patients made what appears to bc a complete neurological recovery in the calcium blocker group, while only one of the 26 patients in the control group made a complete neurological recovery. Our study showed a trend (no statistical analysis was performed) toward improved neurologic outcome when calcium chan- nel blocking agents were used in victims of out-of-hospita ! cardiac arrest who were still deeply comatose 20 minutes after restoration of spontaneous circulation. The general calcium blocker used (magnesium) seemed to be homo- dynamically preferable to the more selective agent studied (verapamil}; however, administration of both may be preferable. A large, prospective, multicenter study that is blinded and randomized should be conducted to pursue this appar- ent improvement in neurologic outcome following suc- cessful cardiac resuscitation.

Editorial: Is There a Place for Novel Treatment in Cerebral Resuscitation?

Is there a place for novel, unproven treatments in cerebral resuscitation efforts following cardiac arrest? Or should clinicians wait for the results of prospective, randomized, double-blind, controlled studies? Many, if not most, physicians would agree that it is better to withhold new, untested treatments (no matter how theoretically appealing they


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Clinical trials and cerebral resuscitation research