An international collaborative clinical study mechanism for resuscitation research

Resuscitation, 10 (1982) 141-147 Else&r Scientific Publishers Ireland Ltd.

141

AN INTERNATIONAL COLLARORATIVE CLINICAL STUDY MECHANISM FOR RESUSCITATION RESEARCH

N.S. ABRAMSON,

P. SAFAR,

Resuscitation Research Center, Pittsburgh, PA 15260 (U.S.A.) (Received

K. DETRE, S. KELSEY, University

of Pittsburgh,

0. REINMUTH

and J. SNYDER

3434 Fifth Avenue,

2nd Floor,

May 6th, 1982)

SUMMARY

Recent experimental and clinical studies of cardiac arrest, suggesting a brain damage ameliorating effect of thiopental loading, stimulated the development of an international randomized clinical trial of brain resuscitation. Twelve collaborating hospitals in 9 countries are testing the efficacy of post-cardiac arrest thiopental loading (30 mg/kg body wt). The methodology for assessing insult and outcome data, as well as risk and benefit monitoring, is described. This clinical trial will be completed in 1983 and is expected to provide valuable data about the efficacy of thiopental loading. The study mechanism is now well-established and ready for the evaluation of future promising brain resuscitation therapies.

INTRODUCTION

An international study mechanism for the clinical evaluation of promising experimental cardiopulmonary-cerebral resuscitation protocols has been developed. Twelve collaborating hospitals, in 9 countries (Table I), coordinated by the Resuscitation Research Center in Pittsburgh are participating. The first protocol to be tested is baaed on experimental evidence for a brain damage ameliorating effect of thiopental loading in monkeys (Rleyaert, Nemoto, Safar, Stezoski, Mickell, Moossy and Rao, 1978) and suggested evidence of a beneficial effect of thiopental loading in 40 feasibility trial patients (Breivik, Safar, Sands, Fabritius, Lind, Lust, Mullie, Orr, Rench and Snyder, 1978) and 60 pilot study patients (Mullie, Abramson, Safar,. Lund, Bjorgo, Breivik, Hedstrand, Hoel, Jastremski, Kampschulte, Lind, Snyder and Tammisto, 1981). The objectives of this clinical study, begun in Address for reprints: Norman S. Abram&m, M.D., Resuscitation Fifth Avenue, 2nd floor, Pittsburgh, PA 15260, U.S.A. 0300-9572/82/0000--0000/$02.75

o 1982 Elsevier Scientific

Publishers Ireland Ltd.

Research Center, 3434

142 TABLE I BRAIN RESUSCITATION AND INVESTIGATORS

CLINICAL

1. Belgium (Brugge) Dr. Arsene Mullie St. Jans Hospital 2. England (London) Dr. Dennis Potter Kings College Hospital 3. Finland (Helsinki) Dr. Tapani Tammisto Helsinki University Center Hospital 4. Italy (Milan) Dr. Bozza-Marrubini Ospedale Niguarda-Ca’Granda 5. Norway (Oslo) Dr. Bjorn Lind Akershus Central Hospital (University of Oslo) 6. Norway (Oslo) Dr. Ivar Lund/Dr. Andreas Skulberg Ulleval Hospital (University of Oslo)

TRIAL

(BRCT)

PARTICIPATING

HOSPITALS

7. Norway (Trondheim) Dr. Harald Breivik/Dr. Sven-Erik Gisvold University Hospital of Trondheim 8. Poland (Warsaw) Dr. Bogdan Kaminski Kierownik Zakladu Anestezjologii AM 9. Spain (Murcia) Dr. Angel Canton Ciudad Sanitaria Virgin de la Arrixaca 10. Sweden (Upsala) Dr. Ulf Hedstrand University Hospital 11. U.S.A. (Pittsburgh) Dr. James Snyder University of Pittsburgh Health Center 12. U.S.A. (Syracuse) Dr. Michael Jastremski Upstate Medical Center

September 1979, are: (1) to determine whether large-dose thiopental loading after severe global ischemic-anoxic insults increases the proportion of CPR survivors with good cerebral performance significantly when compared with standard therapy; (2) to identify possible complications caused by this treatment; and (3) to establish a collaborative study mechanism for the rapid evaluation of promising new brain resuscitation therapies beyond that of the present thiopental protocol. METHODOLOGY

Patients resuscitated from cardiac arrest (or severe global ischemic-anoxic cerebral insults without specific circulatory arrest) who make no purposeful response to pain at the required selection time of lo-50 min following restoration of sustained spontaneous circulation and adequate oxygenation are eligible to be selected for the brain resuscitation clinical trial (BRCT). Patients are randomly assigned to standard therapy (general brain-oriented intensive care protocol) or thiopental loading (standard therapy plus thiopental) using a centrally prepared randomization scheme which insures a balanced distribution of the two treatments for each participating institution. Exclusion criteria include: (1) patients in whom resuscitation was inappropriate (i.e., terminal conditions), (2) patients awakening during consideration for selection into the BRCT; (3) patients who are considered for the study after the 50-min selection period has passed; (4) patients with primary

143 TABLE II STANDARD CARE

THERAPY

Normotension throughout pressor as needed) Moderate hyperventilation

PROTOCOL:

GENERAL

BRAIN-ORIENTED

coma (e.g., MAP 90-100 (arterial PCO, 25-35

INTENSIVE

mmHg; titrated fluids and vaso-

mmHg)

Moderate hyperoxia (arterial PO, > 100 mmHg) Control of arterial pH (7.3-7.6) Immobilization (neuromuscular paralysis) as needed Anticonvulsants (e.g., diazepam or phenytoin) as needed, Normalization of blood variables (hematocrit, osmolality, glucose)

electrolytes,

Fluids: alimentation (calories, amino acids, vitamins); 5-10% in 0.25-0.5% NaCl; 50 Cal/kg/24 h (or more)

colloid osmotic

30-50

ml/kg/24

pressure.

h; dextrose

Steroid (optional, short-term), e.g. dexamethasone 0.2 mg/kg i.v. + 0.04 n&kg/6 methylprednisolone 1 mg/kg i.v. + 0.2 mg/kg/6 h

h or

Temperature monitoring and control (normothermia) CNS evaluation (coma scoring, EEG, CT scanning)

intracranial diseases; and (5) infants (less than 30 days of age), Informed consent must be documented for all patients selected into the study. Both groups receive the same “brain-oriented” life support (Table II) (Safar, 1981) which was designed by consensus of the participating investigators to provide all study patients with optimal nonexperimental therapy. The treatment group, in addition, receives thiopental (30 mg/kg) as a one time intravenous loading dose, as early as possible following selection into the study and as rapidly as the circulation will tolerate. Thiopental infusion, begun only after spontaneous circulation has been restored to a systolic blood pressure above 90 torr, is generally completed by 6-8 h following resuscitation. Blood pressure is supported with intravenous fluids and vasopressors as needed. Both the standard and thiopental loading protocols were clinically tested (Breivik et al., 1978; Mullie et al., 1981) prior to the start of the present randomized clinical trial. Selected institutions were accepted into the study if the following criteria were fulfilled: (1) the capability to provide at least 10 study cases per year; (2) the eommitment of a dedicated clinician-investigator; (3) the existence of an active, sophisticated resuscitation and intensive care service; and (4) an agreement, signed by the appropriate administrators and committees, including the local institutional review board, to participate and comply with the study protocols. The study is coordinated by a central steering committee in Pittsburgh

144

which includes the principal investigator (PS), the physician-coordinator (NA), a neurologist (OR), a critical care physician (JS), and a data management team headed by an epidemiologist (KD). The senior investigator in each participating hospital is responsible for selection, treatment and data collection procedures which are summarized in a manual. There is an external monitoring committee appointed by the National Institutes of Health, the project’s funding agency. Pilot tested data collection forms are used to collect information about prearrest medical history, the cause and course of the patient’s resuscitation, the intensive care unit management, the administration and complications of thiopental loading, and the patient’s neurologic and general medical condition at each of the follow-up periods (48-72 h, 10 days, and at 1,3,6 and 12 months). A death and autopsy report form (including a special histopathologic examination of the brain) is completed if the patient dies before the end of the l-year follow-up period. All submitted data forms are checked for completeness and medical logic by the physician-coordinator and the data manager. After this verification, the information is entered into the data base management system for computer storage and analysis. Each hospital investigator maintains a log listing all resuscitation cases admitted to the intensive care unit. This log will serve three purposes: (1) to define the overall population of cardiac arrest patients, as a background against which the severe cardiac arrest cases selected into the brain resuscitation clinical trial (BRCT) can be compared; (2) to identify cases which were eligible for the BRCT but were not selected; and (3) to document the reasons for these exclusions. Risk monitoring (mortality and the incidence of complications such as hypotension, arrhythmias, and rearrest) is done with the addition of each 20 patients to the study. The statistical methods used include the creation of monitoring boundaries, such that whenever the boundary line is crossed, a significant difference between treatment and control group is indicated (Canner, 1977). Results of these analyses are kept confidential. Only one member of the epidemiology team has access to the code. Should a statistically significant difference between the thiopental and standard therapy groups occur, indicating excessive risk of thiopental therapy, it would immediately be brought to the attention of the principal investigator. The NIH monitoring committee would then be informed and consideration would be given to stopping the study at that point. A sample size requirement of 300 patients (150 in each group) was estimated as necessary to demonstrate a clinically relevant beneficial effect of thiopental loading. This was based on the assumption that 20% of the standard treatment group would regain good cerebral function. If then 40% of the thiopental group achieved the same outcome, this would be a statistically significant difference (o = 0.05; power 90%) (Snedecor and Co&ran, 1973). Thus, 100 cases per year will be collected during a 3-year period (1972-82) with a fourth year (1982-83) planned for data analysis and final evaluation of the efficacy of thiopental loading.

145 EVALUATION

OF PATIENT INSULT AND OUTCOME

More than 200 pages of data are collected for each patient surviving the entire l-year follow-up period. The most crucial information included on these forms is the estimate of the severity of brain insult, the assessment of depth of coma in the early post-resuscitation period, and the evaluation of disability during the l-year follow-up period. Severity of brain insult is estimated by each participating investigator immediately following resuscitation, by interviewing bystanders, ambulance personnel, and hospital physicians and nurses. Total insult time is the sum of TABLE III GLASGOW-PITTSBURGH

COMA SCALE Pittsburgh

Glasgow

Eye opening Spontaneous To speech To pain None

4

3 2 1

Pupil response Normal Sluggish Unequal response Unequal size No response

Best motor response Obeys Localizes Withdraws Abnormal flexion Extension None

Cranial nerve reflexes All present Lash absent Corneal absent Doll’s eye/&or& absent Cardinal (all) absent

Best verbal response Oriented Confused Inappropriate Incomprehensible None

Seizures No seizures Focal seizures Generalized intermittent Generalized, continuous Flaccidity areflexia Spontaneous breathing Normal Periodic Central hyperventilation Irregular/hypoventilation None (apnea)

TOTAL3--15

TOTALd-20 COMASCALETOTAL

7-35

5

4 3 2 1

5 4 3 2 1

5 4 3 2 1

5 4 3 2 1

146

the arrest, CPR and hypoxia (before or after the actual cardiac arrest) times. The variability and potential inaccuracy of these estimates, especially for pre-hospital events, is well-recognized. A coma scoring system (Table III), was devised by expanding the Glasgow Coma Score (Teasdale and Jennett, 1974), which was originally designed for head injury patients. This expanded scale is used for neurologic evaluation when the patient is unresponsive to verbal command. Whether the inclusion of additional parameters in the modified coma score makes it more useful for post-cardiac arrest patients remains to be proven. The patient’s prearrest coma score is estimated from the available historical information. Scoring is begun.immediately following resuscitation and continued until the patient awakens. At this point, more sophisticated neuro-psychiatric testing is begun. The most relevant outcome criterion is not simple mortality, but survival with human mentation. A &point outcome scale, modified from the Glasgow performance categories (Jennett and Bond, 1975) is used for this assessment (Table IV). Whereas the Glasgow Scale measures overall performance only, we separately evaluate cerebral performance (CPC) and overall performance (OPC). This is done in order to identify the patient whose brain shows good recovery but who does poorly because of extracerebral organ system failure. This differentiation is crucial for the identification of effective brain resuscitation measures in high mortality rate post-cardiac arrest patients. Each investigator evaluates his own patients at the prescribed follow-up periods. These assessments are validated by the physician-coordinator who checks for internal consistency with clinical information provided on other data forms. Furthermore, an independent neurological examination is performed by a blinded neurologist at each follow-up period. This serves as further validation of the CPC as assessed by the primary investigator.

TABLE IV GLASGOW-PITTSBURGH

OUTCOME

CATEGORIZATION

OF

BRAIN

INJURYa

Cerebral performance categories (CPC)

Overall performance categories (OPC)

1. Good cerebral performance 2. Moderate cerebral disability

1. CPC 1 and no other disabilities 2. CPC 2 or moderate non-cerebral disability or both 3. CPC 3 or severe non-cerebral disability or both 4.CPC4 5. CPC 5 or death by traditional clinical criteria

3. Severe cerebral disability 4. Coma/vegetative state 5. Brain death

aModified from Jennett and Bond, Lancet i, 4&X0,1975.

147

CONCLUSIONS During the first 2 years of the BRCT, the feasibility of conducting a prospective randomized clinical trial of cardiopulmonary-cerebral resuscitation (CPCR), with a long-term evaluation of outcome, has been proven. The ongoing mechanisms for risk monitoring and benefit analysis are operating effectively. The now established data collection system will permit the acquisition of epidemiologic data, the identification of determinants of outcome, and the ongoing evaluation of the results of hospital and community resuscitation services. The first brain resuscitation therapy to be clinically tested, using this international study mechanism, is highdose thiopental loading. We expect that unbiased data about the efficacy of thiopental loading after cardiac arrest will be available by summer 1983. Until the results of this study are available, our recommendation is that high dose thiopental loading for the post-cardiac arrest patient should only be done as part of a carefully designed scientifically controlled study. ACKNOWLEDGEMENTS

We thank Joyce Monroe, B.A. who made valuable contributions manuscript. This work was supported by NIH Grant No. N8 15295.

to this

REFERENCES Bleyaert, A.L., Nemoto, E.M., Safar, P., Stezoski, W., Mickell, J.J., Moossy, J. and Rao, G.R. (1978) Thiopental amelioration of brain damage after global ischaemia in monkeys, Anaesthesiology, 49, 390-398. Breivik, H., Safar, P., Sands, P., Fabritius, R., Lind, B., Lust, P., Mullie, A., Orr, M., Rench, H. and Snyder, J.V. (1978) Clinical feasibility trials of barbiturate therapy after cardiac arrest. Crit. Care Med., 6, 228-244. Canner, P.L. (1977) Monitoring treatment differences in long-term clinical trials. Biometrics, 33, 603-615. Jennett, B. and Bond, M. (1975) Assessment of outcome after severe brain damage. A practical scale. Lancet, i, 480-482. Mullie, A., Abramson, N., Safar, P., Lund, I., Bjorgo, S., Breivik, H., Hedstrand, U., Hoel, T., Jastremski, M., Kampschulte, S., Lind, B., Snyder, J. and Tammisto, T. (1981). Clinical pilot studies of thiopental (TH) loading after cardiac arrest (Abstract). Crit. Care Med. 9,184. Safar, P. (1981) Cardiopulmonary Cerebral Resuscitation. Saunders, Philadelphia, p. 140. Snedecor, G.W. and Cochran, W.G. (1973) Statistical Methods, Sixth edition, Iowa State University, Ames, Iowa. Teasdale, G. and Jennett, B. (1974) Assessment of coma and impaired consciousness. Lancet, ii, 81-83.