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PubMed1991

A randomized clinical trial of calcium entry blocker administration to comatose survivors of cardiac arrest. Design, methods, and patient characteristics. The Brain Resuscitation Clinical Trial II Study Group.

The Brain Resuscitation Clinical Trial (BRCT) II was a double-masked, randomized, controlled clinical study of cardiopulmonary-cerebral resuscitation (CPCR) designed to test therapy for the amelioration of brain damage after cardiac arrest. Lidoflazine, a calcium entry blocker, was chosen for investigation because of its beneficial effects on postischemic encephalopathy in animals, its minimal cardiovascular depressant effects, and its protective actions in myocardial ischemia in patients. Twenty-four hospitals in eight countries participated. Over 4 years, 520 patients were recruited, of whom 4 were subsequently lost to follow-up. Patients' age averaged 63 years and 62% were men. Cardiac arrest occurred prior to hospitalization in 63%. All patients received basic and advanced life support until circulation was restored, and then standardized extracerebral organ support. After restoration of spontaneous circulation with normal blood pressure, patients who failed to awaken were randomly assigned to receive IV administration of either lidoflazine or placebo. In each patient, outcome was evaluated by cerebral performance during a 6-month follow-up period. Periodic safety monitoring was carried out to assure that no excess of mortality or complications occurred in the lidoflazine-treated group compared with the placebo-treated group.

Brain Damage, Chronic↗

PubMed1991

Risk monitoring of randomized trials in emergency medicine: experience of the Brain Resuscitation Clinical Trial II.

Risk monitoring for the Brain Resuscitation Clinical Trial II, a multicenter, placebo-controlled trial to evaluate the efficacy of the calcium-entry blocker lidoflazine in the amelioration of brain damage in comatose cardiac-arrest survivors, posed unexpected challenges. Concern arose when monitoring of adverse reactions showed an excess of dangerous cardiac arrhythmias, including rearrest, in the lidoflazine group. To ascertain the cause of this problem and determine whether it was ethical for the trial to continue, an in-depth review of data was conducted, outside experts were consulted, and additional data were collected. These efforts suggested possible causes for the problem. Existing drug administration protocols for blood pressure control were reinforced, resulting in lower subsequent arrhythmia rates. Thus, through an efficient monitoring system, an important problem was uncovered and resolved, allowing the trial to be completed without major changes.

Arrhythmias, Cardiac↗

PubMed1990

Deferred consent: use in clinical resuscitation research. Brain Resuscitation Clinical Trial II Study Group.

Deferred consent, a new approach to the requirement for informed consent in clinical research, was used in a randomized clinical trial of brain resuscitation after cardiac arrest. Because patients were comatose and therapy had to be initiated immediately, traditional prospective consent usually could not be obtained. Using the deferred consent mechanism, family members were contacted after the first dose of experimental drug or placebo was administered and asked to consent for continued study participation. The vast majority of families were satisfied with the deferred consent mechanism. Their main concerns were about the safety of the experimental drug and whether the active drug or placebo was given. The concepts of randomization, blinding, and placebo-treated controls were generally not well understood. Although our experiences confirmed the impracticality of attempting to obtain traditional prospective consent in clinical resuscitation research, deferred consent was found to be a reasonable solution.

Ethics, Medical↗

PubMed1995

Old age does not negate good cerebral outcome after cardiopulmonary resuscitation: analyses from the brain resuscitation clinical trials. The Brain Resuscitation Clinical Trial I and II Study Groups.

OBJECTIVE: To assess survival after cardiac arrest and to determine whether age is an independent determinant of late mortality or poor neurologic outcome. DESIGN: Analyses using results of Brain Resuscitation Clinical Trial I (1979 to 1984) and Brain Resuscitation Clinical Trial II (1984 to 1989), two randomized, double-blind studies of outcome following cardiac arrest. SETTING: A multicenter study in 12 acute care hospitals in nine countries (Brain Resuscitation Clinical Trial I), and 24 hospitals in eight countries (Brain Resuscitation Clinical Trial II). PATIENTS: A total of 774 patients who were initially comatose after successful resuscitation from cardiac arrest. The analyses include both in- and out-of-hospital cardiac arrests. RESULTS: The 6-month mortality rate for the entire group was 81%. Mortality rate was 94% for the oldest group (> 80 yrs) compared with 68% for the youngest group (< or = 45 yrs) (p < .01). Other independent predictors of mortality were history of diabetes mellitus, inhospital arrests, arrest time of > 5 mins, history of congestive heart failure, a noncardiac cause of arrest, and cardiopulmonary resuscitation time of > 20 mins. Of the 774 patients, 27% recovered good neurologic function. There was no statistically significant difference in neurologic recovery rates by age. Multivariate analysis showed that independent predictors of good neurologic recovery were: no history of diabetes mellitus, a cardiac cause of arrest, short arrest time, and short cardiopulmonary resuscitation time. CONCLUSION: Increasing age was a factor in postresuscitation mortality, but was not an independent predictor of poor neurologic outcome.

Age Factors↗

PubMed1991

A randomized clinical study of a calcium-entry blocker (lidoflazine) in the treatment of comatose survivors of cardiac arrest.

BACKGROUND: Abnormalities of cellular calcium homeostasis have been implicated in the pathophysiology of postischemic encephalopathy. Calcium-entry-blocking drugs inhibit the influx of calcium into cells and have been shown to mitigate postischemic encephalopathy in animal models. METHODS: Five hundred twenty patients with cardiac arrest who remained comatose after the restoration of spontaneous circulation were randomly assigned to receive three doses of lidoflazine, an experimental calcium-entry blocker, or a placebo and were followed for six months. Four patients were lost to follow-up. Treated patients received an intravenous loading dose (1 mg per kilogram of body weight) of lidoflazine and two subsequent doses (0.25 mg per kilogram) 8 and 16 hours after resuscitation. The investigators were blinded to treatment assignment. RESULTS: There was no statistically significant difference between the lidoflazine group (n = 259) and the placebo group (n = 257) in the proportion of patients who died during the six-month follow-up (82 vs. 83 percent), who survived with good cerebral recovery (15 vs. 13 percent), or who survived with severe neurologic deficit (1.2 vs. 1.9 percent). Analysis of the best level of recovery achieved at any time during follow-up also did not show a difference between the treatment groups: 24 percent of those given lidoflazine and 23 percent of those given placebo recovered good cerebral function (normal or only moderately disabled cerebral performance) at some time. CONCLUSIONS: The administration of lidoflazine after cardiac arrest was not found to be beneficial. Our data do not support the routine use of this calcium-entry-blocking drug in comatose survivors of cardiac arrest.

Brain Damage, Chronic↗

PubMed1991

Deferred consent.

Explore the source record for details and available documents.

Clinical Trials as Topic↗

PubMed1996

Neurologic outcomes after cardiac resuscitation.

The purpose of this research utilization article is to familiarize cardiovascular nurses with the Brain Resuscitation Clinical Trials (BRCTs) I and II and discuss the application of these trials to nursing practice. The BRCTs are a series of studies that examine the effects of selected interventions on neurologic outcome after cardiac arrest.

Brain Injuries↗

PubMed1997

Introduction to Wolf Creek IV Conference.

Early milestones of resuscitation research culminated in the 1950s in the documentation of modern external cardiovascular resuscitation (CPR) steps "ABC," followed by advanced and prolonged life support. Implementation of guidelines has been suboptimal. Self-training of the public in life-supporting first aid, including CPR-ABC-available since the 1970s-is only now being re-evaluated and hopefully implemented. Standard external CPR potency is inadequate for reliably restoring spontaneous circulation and saving the brain after prolonged arrests or in patients with sick hearts. Ultra-advanced life-support methods such as open-chest CPR and emergency cardiopulmonary bypass should be tried for bridging standard external CPR-resistant hearts to recovery or repair. Outcome studies in large animals can be fully controlled, in contrast to randomized clinical outcome trials, which have limitations. The HIV paranoia must not lead to abandoning the teaching of steps A and B, which are essential for any kind of coma, asphyxial arrest, and prolonged ventricular fibrillation arrest. Sternal compressions alone can produce some ventilation in animals, but not reliably in comatose humans. For cerebral resuscitation after cardiac arrest, the outcome benefit of the hypertensive bout, other cerebral blood flow-promoting measures, and mild resuscitative hypothermia have been documented in outcome models of large animals and are ready for clinical feasibility trials. The Wolf Creek CPR researchers' conferences I, II, and III were meant to advise the guidelines-setting committees of the American Heart Association and other agencies. The ten topics of Wolf Creek IV, published in this issue of New Horizons, were different in design and objective. There was an appropriate emphasis on fully automatic external defibrillation by lay rescuers, which has the potential for a breakthrough effect. Wolf Creek V, which we recommend to be conducted around the turn of the millennium, should focus on the pathophysiology and therapeutics of respiratory, cardiac, and cerebral resuscitation in general, and on organ, cellular, and molecular level research into how cells, organs, and organisms die, and how acute dying processes might be reversed. What to teach whom and how should be left to guideline conferences of agencies.

Animals↗

PubMedDate not supplied

Assessing preferences about the DNR order: does it depend on how you ask?

Despite increasing emphasis on advance directives, there has been little methodologic work to assess preferences about the "do not resuscitate" (DNR) order. This developmental work assessed, in a non-patient group, the performance of a probability-trade-off task designed to assess DNR attitudes, in terms of framing effects and stability of preferences. 105 female nursing students each completed one of two versions of the task. In version I (n = 58), the trade-off moved to increasingly negative descriptions of the outcomes of resuscitation (decreasing chance of survival and increasing risk of brain death), whereas in version II (n = 47), the trade-off moved to increasingly positive descriptions. One week later, repeat assessments were obtained for versions I (n = 35) and II (n = 28). The DNR preference scores were lower and more stable when the task moved to increasingly positive descriptions; perhaps this version of the task tends to weaken risk aversion. These results imply that care should be used in applying a probability trade-off task to the assessment of DNR preferences, since artefactual effects could be induced.

Attitude to Health↗

PubMed1993

Effect of maximizing oxygen delivery on morbidity and mortality rates in critically ill patients: a prospective, randomized, controlled study.

OBJECTIVE: To determine the effects of optimizing oxygen delivery (DO2) to "supranormal" levels on morbidity and mortality in patients with sepsis, septic shock, and adult respiratory distress syndrome. DESIGN: A prospective, randomized, controlled trial. SETTING: A 16-bed surgical intensive care unit (ICU) and 14-bed mixed medical/surgical ICU in two separate hospitals in the University of Hawaii Surgical and Internal Medicine Residency programs. PATIENTS: During a 1-yr period, 67 patients who had pulmonary artery catheters and who met the criteria for sepsis or septic shock, adult respiratory distress syndrome, or hypovolemic shock were enrolled in the study. Patients admitted to the ICU who were < 18 yrs old, or with a do-not-resuscitate order, or those patients who faced imminent death (< 24 hrs), such as those patients with uncontrollable hemorrhage or brain death, were excluded from the study. INTERVENTIONS: Patients were randomized into treatment and control groups. The treatment group was assigned a therapeutic DO2 indexed (DO2I) goal of > 600 mL/min/m2. Interventions to attain this goal included fluid boluses, administration of blood products, and the use of inotropes. The control group was not assigned to a specific therapeutic goal other than "normal" values of DO2I of 450 to 550 mL/min/m2. Every attempt was made to reach the therapeutic goals within the first 24 hrs after entry into the study. Hemodynamic measurements were obtained on study patients every 4 hrs until the end of the study. The severity of illness was evaluated using the Therapeutic Intervention Scoring System, and the Acute Physiology and Chronic Health Evaluation II scoring system. MEASUREMENTS AND MAIN RESULTS: There were 32 patients in the control group and 35 patients in the treatment group. The groups were similar in age, sex, number of organ dysfunctions, Acute Physiology and Chronic Health Evaluation II and Therapeutic Intervention scores. There were no statistical differences between the two groups in mortality, development of organ failure, ICU days, and hospital days. Upon analysis, it became apparent that the patients comprised clinically distinct subgroups, including: a) a treatment group who achieved supranormal DO2I; b) a control group with normal DO2I; c) a treatment group who failed to reach target DO2I; d) a control group who self-generated to high DO2I values; and e) a small number of patients who could not even reach a normal DO2I of 450 mL/min/m2. These subgroups were found to be similar and matched. The mortality rate was significantly lower for patients in groups who reached supranormal values of DO2I whether treated or self-generated as compared with patients who reached normal DO2I values (14% vs. 56%, p = .01). CONCLUSIONS: Although there was no statistically significant difference in the control vs. treatment groups, subgroup analysis demonstrated a strong, significant difference between patients with supranormal values of oxygen transport vs. patients with normal levels of DO2. Supranormal values of DO2I, whether self-generated or as a result of treatment, resulted in a statistically significant decrease in mortality rate. This study adds to the weight of evidence that current standard of care of treating critically ill patients to normal DO2I should be reconsidered, and that maximizing to high DO2I might be a more appropriate therapeutic end-point.

Adult↗

PubMed2006

Practice parameter: prediction of outcome in comatose survivors after cardiopulmonary resuscitation (an evidence-based review) [RETIRED]: report of the Quality Standards Subcommittee of the American Academy of Neurology.

OBJECTIVE: To systematically review outcomes in comatose survivors after cardiac arrest and cardiopulmonary resuscitation (CPR). METHODS: The authors analyzed studies (1966 to 2006) that explored predictors of death or unconsciousness after 1 month or unconsciousness or severe disability after 6 months. RESULTS: The authors identified four class I studies, three class II studies, and five class III studies on clinical findings and circumstances. The indicators of poor outcome after CPR are absent pupillary light response or corneal reflexes, and extensor or no motor response to pain after 3 days of observation (level A), and myoclonus status epilepticus (level B). Prognosis cannot be based on circumstances of CPR (level B) or elevated body temperature (level C). The authors identified one class I, one class II, and nine class III studies on electrophysiology. Bilateral absent cortical responses on somatosensory evoked potential studies recorded 3 days after CPR predicted poor outcome (level B). Burst suppression or generalized epileptiform discharges on EEG predicted poor outcomes but with insufficient prognostic accuracy (level C). The authors identified one class I, 11 class III, and three class IV studies on biochemical markers. Serum neuron-specific enolase higher than 33 microg/L predicted poor outcome (level B). Ten class IV studies on brain monitoring and neuroimaging did not provide data to support or refute usefulness in prognostication (level U). CONCLUSION: Pupillary light response, corneal reflexes, motor responses to pain, myoclonus status epilepticus, serum neuron-specific enolase, and somatosensory evoked potential studies can reliably assist in accurately predicting poor outcome in comatose patients after cardiopulmonary resuscitation for cardiac arrest.

Cardiopulmonary Resuscitation↗

PubMed1998

Quantitative analysis of synaptophysin immunoreactivity in human neocortex after cardiac arrest: confocal laser scanning microscopy study.

Transient global ischaemia caused by cardiac arrest results in lesions that involve all brain structures. The aim of this study was to investigate the condition of synapses in patients surviving, but remaining in a persistent vegetative state, following resuscitation after cardiac arrest. We performed a quantitative analysis of the distribution and density of elements containing a synaptic vesicle protein--synaptophysin (p38)--in human neocortex in cases which survived for 1 week, 2 months, and 1 year after the cardiac arrest. Neurologically healthy cases that died following an accident served as control. Dual-channel confocal laser scanning microscopy (CLSM) was used to image p38-immunoreactivity (IR) and lipofuscin autofluorescence. In control cases no statistically significant differences were found for p38-IR between layers II-III and V-VII. However, the temporal cortex had a higher density of p38-immunoreactive structures than the motor cortex. In postischaemic cases a reduction in the density of p38-IR elements was apparent, mainly in the frontal and motor cortices and less pronounced in the temporal cortex. The least decrease compared with controls was observed in the visual cortex. In the 1 week survival case, a maximal decrease in p38-IR (35% below control) was found. In this case, the number of p38-IR elements per visual field was decreased, and big aggregates of p38-IR structures were observed. In general, the amounts of p38-IR structures were higher in all of the control cases compared with the postischaemic cases.

Autopsy↗

PubMed1986

Whole body protection during three hours of total circulatory arrest: an experimental study.

Survival following 3 hr of total circulatory arrest under profound hypothermic conditions was explored in 19 adult mongrel dogs. Thermoregulatory management included combined surface/perfusion hypothermia and azeotrope anesthesia in 95% O2/5% CO2. All animals were resuscitated and survived for at least 12 hr. During the last seven trials (Group II) the following principles were applied: uniform whole-body cooling where differences between rectal, esophageal, and pharyngeal temperatures averaged less than 1 degree C, induction of circulatory arrest at approximately 3 degrees C, constant lung inflation (10-12 cm H2O between 20 degrees C cooling and 20 degrees C rewarming, including the 3-hr arrest period) and ventilation assistance with positive end-expiratory pressure (4 cm H2O) after 20 degrees C rewarming, intraoperative maintenance of colloid osmotic pressure (COP) above 11 mm Hg, replacement of the cooling perfusate with a colloid-rich rewarming prime (COP = 15 mm Hg) and restoration of hemostasis with fresh whole blood transfusions. The application of these principles resulted in the long-term survival of five animals with four survivors displaying no clinically detectable neurological abnormalities. However, two animals developed optic impairment and one animal died from intusseption on the fourth postoperative day. Despite the improved results, it should also be noted that during pilot (Group I) studies (from which the aforementioned principles were derived) fatalities from complications attributed to systemic edema, central nervous system, or pulmonary or coagulation dysfunctions occurred in 9 out of 12 trials. We conclude that whole body protection following 3 hr of total circulatory arrest at a uniform temperature less than 5 degrees C can be successfully accomplished.

Animals↗

PubMed2006

[Prevention of brain hemorrhage in infants with low and extremely low birth weight and infants treated with surfactants. Late observation].

Prematurely born infants with intraventricular haemorrhage (IVH) suffer significant morbidity and mortality, particularly those infants with high grade haemorrhage. The more premature infants have a higher incidence, experiencing more severe IVH. The etiology of IVH is clearly multifactorial. Prevention, both prenatal and postnatal. These include efforts to prevent preterm delivery. Postnatally, the importance of optimal resuscitation and neonatal care practices is stressed, particularly those which minimize cerebral blood flow fluctuation. 130 premature infants of less than 32 weeks gestation with a very low birth weight (VLBW) and extremely low birth weight (ELBW) were studied. They were divided in four groups: group I (n=35) received Indocid; group II (n=42) received Indocid and Phenobarbital; group III (n=53) received Indocid and Phenobarbital; surfactant. These three groups were compare to a reference group (n=45). Newborns from the main group were given Indocid 0.1 mg/kg from 6-12 h of life and during next three days, Phenobarbital 5 mg/kg first five days after delivery and surfactant in the first 4 hours of life according to the protocol provided with the specific surfactant replacement product. Cerebral netrasaund in 24 hours, day 3, 5 and 10 of life and follow up till one year age were performed. We found that IVH/PVH percentage is lowest in newborns from group III, followed by newborns from group II and group I.

Cerebral Hemorrhage↗

PubMed2005

Therapeutic hypothermia: from lab to NICU.

The possibility of a therapeutic role for cerebral hypothermia during or after resuscitation from perinatal asphyxia has been a long-standing focus of research. However, early studies had limited and contradictory results. It is now known that severe hypoxia-ischemia may not cause immediate cell death, but may precipitate a complex biochemical cascade leading to the delayed development of neuronal loss. These phases include a latent phase after reperfusion, with initial recovery of cerebral energy metabolism but EEG suppression, followed by a secondary phase characterized by accumulation of cytotoxins, seizures, cytotoxic edema, and failure of cerebral oxidative metabolism from 6 to 15 h post insult. Although many of the secondary processes can be injurious, they appear to be primarily epiphenomena of the 'execution' phase of cell death. This conceptual framework allows a better understanding of the experimental parameters that determine effective hypothermic neuroprotection, including the timing of initiation of cooling, its duration and the depth of cooling attained. Moderate cerebral hypothermia initiated in the latent phase, between one and as late as 6 h after reperfusion, and continued for a sufficient duration in relation to the severity of the cerebral injury, has been consistently associated with potent, long-lasting neuroprotection in both adult and perinatal species. The results of the first large multicentre randomized trial of head cooling for neonatal encephalopathy and previous phase I and II studies now strongly suggest that prolonged cerebral hypothermia is both generally safe - at least in an intensive care setting - and can improve intact survival up to 18 months of age. Both long-term followup studies and further large studies of whole body cooling are in progress.

Clinical Trials as Topic↗