Ethical issues in cardiopulmonary resuscitation.

If patients are to benefit from resuscitation, they must regain consciousness and their full faculties. In recent years, we have acquired important information about the natural history of neurological recovery from circulatory arrest. There are clinical tests that predict the outcome, both during ongoing cardiopulmonary resuscitation (CPR) and in the period after restoration of spontaneous circulation. The ability to predict neurological outcome at this stage offers a basis for certain ethical considerations, which are not exclusively centered on "do-not-attempt-resuscitation" (DNAR)- orders. Instead of being forced to make the decision that "I do not want CPR", the patient should be able to decide that "I want resuscitation to be discontinued, if you predict that I will not recover to a level of neurological function that is acceptable to me". Ideally, no competent patient should be given a DNAR-status without his or her consent. No CPR-attempt should be stopped, and no treatment decision for a patient recovering after CPR should be taken without knowing and assessing the available information. Good ethical decision-making requires reliable facts, which we now know are available.

Prediction of neurological outcome after cardiopulmonary resuscitation.

In 231 patients with circulatory arrest of primary cardiovascular or pulmonary aetiology guidelines were established for predicting neurological outcome within the first year after cardiopulmonary resuscitation. Outcome measures were brain death, persistent unconsciousness, persistent disability after awakening and complete recovery. A total of 116 patients remained unconscious while 115 regained consciousness. Brain stem areflexia with apnoea (brain death) was demonstrated in 40 patients. No other finding per se could predict a specific outcome. The time for recovery of individual neurological functions seemed to be the key to prognostication. Testing the caloric vestibular reflex or stereotypic reactivity thus differentiated patients regaining consciousness from those remaining unconscious, with positive predictive values of 0.79 and 0.77 at 1 h and negative values of 1.0 and 0.97 at 24 h as compared with 50/50 prior odds. The presence of speech at 24 h or the ability to cope with personal necessities at 72 h predicted complete recovery with positive predictive values of 0.91 and 0.92 as compared with prior odds of 0.17, whereas, the negative predictive values never exceeded prior odds of 0.83.

The course of circulatory and cerebral recovery after circulatory arrest: influence of pre-arrest, arrest and post-arrest factors.

We evaluated the influence of pre-arrest, arrest and post-arrest factors on circulatory and neurological recovery for up to 1 year following circulatory arrest of cardio-pulmonary aetiology in 231 patients. Initially, all patients were unconscious and 106 had some cortical activity recorded in the immediate post-resuscitation EEG (Group I), while 125 had no such activity initially (Group II). The following variables were explored: age, sex, medical history, cause and location of arrest, initial cardiac dysrhythmia, duration of life support, metabolic acidosis, pulse-pressure product and heart pump function capacity early after resuscitation. Outcome measures were duration and quality of circulatory survival, cause of death, neurological recovery and ultimate outcome. First year survival was 33% in Group I and 16% in Group II. Severe heart failure and brain death occurred mainly in Group II. Circulatory recovery was negatively influenced by out-of-hospital arrest, metabolic acidosis and pulse-pressure products below 150. Neurological recovery was negatively influenced by initial dysrhythmias other than ventricular fibrillation, pulse-pressure products below 150, post-arrest heart failure and/or pulmonary complications. It seems that circulatory and cerebral outcomes are mainly determined by the global ischaemic insults sustained during the circulatory arrest period.

Selective neurological recovery or dissociated cardiac death--to be or not to be--during cardiopulmonary resuscitation.

Of 111 victims of circulatory arrest, 93 (84%) retained or regained some brain function during the resuscitation process. Twenty-six of these (24%) did not have spontaneous circulation restored, and a further 18 (16%) were left in cardiogenic shock and died within 24 h. Bradyarrhythmia or asystole during the resuscitation efforts or prolonged resuscitative attempts beyond 20 min were related to the irreversible failure of heart pump function. Individuals developing either this type of 'dissociated cardiac death' or cardiogenic shock could not be identified prior to resuscitation by the cause of the arrest nor by the initial cardiac arrhythmia. 'Dissociated cardiac death' and cardiogenic shock are major problems in cardiopulmonary resuscitation. A code of practice is urgently needed.

The natural course of neurological recovery following cardiopulmonary resuscitation.

In 231 patients resuscitated from circulatory arrest of cardiovascular or pulmonary aetiology brain recovery was evaluated by serial neurological and EEG examinations for up to 1 year. One-hundred and sixteen patients never regained consciousness; 115 patients awakened within 30 days, and 40 eventually recovered completely within 90 days. Patients who had electrocortical activity recorded by the immediate post-resuscitation EEG (N = 106), and patients initially without such activity (N=125) pursued the same course of recovery: during unconsciousness, interrelated EEG and neurological findings featured a phase of intermittent cortical activity with postural or stereotypic motor responses followed by a phase of continuous cortical activity with sequential appearances of delta, theta, and alpha activities on EEG accompanied by stereotypic or defensive motor responses. After awakening, the sequential return of motor, sensory, and mental faculties differentiated an early phase of severe disability with orientating eye movements and a bilateral Babinski response from the phase of moderate disability featured by speech, locomotor functions, ability to cope with personal necessities and orientation as to personal data, and a normal plantar response. Finally, orientation as to time, place and role of other persons, and retention and recall, defined the phase of slight/no disability. Abnormal courses were identified by incomplete EEG and neurological recoveries or by the appearance of spikes and sharpwaves in the EEG, or by losses of function.

Neurological and circulatory outcomes of cardiopulmonary resuscitation in progress: influence of pre-arrest and arrest factors.

Possible correlations between the circulatory and neurological responses to cardiopulmonary resuscitation (CPR) and the influence of pre-arrest factors (demographic data, medical history and aetiology of circulatory arrest) and arrest factors (location of arrest, ECG configurations, and duration of resuscitation) on the course of circulatory and neurological recovery were investigated in 111 victims of circulatory arrest. At the start of resuscitation 57 patients (Group I) had some brain function and 54 (Group II) had no brain function. Sixty nine patients (62%) had circulation restored but 54 (78%) were left with heart failure. Forty one patients (39%) survived the first day, 26 (63%) with heart failure; only 34 (31%) were alive after 48 h, 17 (50%) with heart failure. Half of the patients surviving 24 or 48 h had awakened. Consciousness returned in 32 patients (29%) during the first 48 h, more frequently in Group I than in Group II. Patients in Group I had a higher incidence of in-hospital arrest and had their circulation restored more often than those in Group II. Survival and post-resuscitation heart failure was alike in the groups. The pre-arrest factors explored did not modify the circulatory or neurological outcome whereas initial ventricular fibrillation was significantly related to recovery of consciousness. The revivability of spontaneous circulation and of neurological functions was found thus mainly to be determined by global ischaemia sustained prior to and during CPR.

Course of neurological recovery and cerebral prognostic signs during cardio-pulmonary resuscitation.

The recovery of cranial nerve reflexes was evaluated sequentially in time during the efforts at resuscitation in 111 victims of circulatory arrest of primary cardiovascular or pulmonary origin. Fifty-seven patients had some brain function when life support was initiated (Group I) while 54 had at first no such function (Group II). Recovery occurred in a fixed order, irrespective of the initial neurological status or subsequent outcome: spontaneous respiratory movements were either present or were the first function to return; thereafter followed pupillary light reflexes, coughing-swallowing, and ciliospinal reflexes, in that order. Orderly recovery was featured by a time-related return of reflexes and consciousness while abnormal courses were characterized by stagnation of the recovery process, lack of time-related return of and loss of function. Prognostic rules were similar for the two population groups. Reflex tests at 10-60 min of resuscitation differentiated patients who would regain consciousness from those remaining unconscious with sensitivities and specificities > or = 80. A positive pupillary response or coughing-swallowing at 10 min, or ciliospinal reflex at 20 min predicted return of consciousness with positive predictive values of 0.85-1.00 (prior odds 0.29) while negative tests at 20-30 min indicated failure of complete recovery with values of 0.94-100 (prior odds 0.89).

Long-term experience with clozapine in Denmark: research and clinical practice.

In Denmark, the use of clozapine has increased markedly (15-25% per year) since 1983, when the drug was relaunched--after its withdrawal in 1975. Several factors have contributed to this development: 1) the interesting pharmacology of clozapine, especially the atypical influence on dopamine transmission, including a relatively high D-1/D-2 receptor affinity ratio, 2) the potent anti-anxiety and anti-psychotic effect in severe and otherwise therapy-resistant psychotic patients, and 3) the lack of extrapyramidal side effects. A special monitoring form (for registration of total and differential leucocyte counts, ECG, body weight, drugs, doses and reason for possible withdrawal of the clozapine) is used in most Danish psychiatric institutions. This form secures the regular control of vital parameters and serves as an instrument for surveys of the use of clozapine in Denmark. Also, more selective studies are being carried out, e.g., on the effect of clozapine monotherapy versus combined therapy, and on the influence of clozapine on cardiovascular functions, including left ventricular output (echocardiography).

Differential effects of timolol and metoprolol on platelet function at rest and during exercise.

Ten male patients suffering from stable angina pectoris were studied at rest and immediately after exercise during treatment either with timolol (a non-selective beta-blocker) or with metoprolol (a beta 1-selective blocker). Timolol induced a significant increase in platelet aggregation and a reduction in platelet cyclic AMP, and it also raised the plasma adrenaline at rest and during exercise as compared to the pre-treatment level. Metoprolol had none of these effects. Prior to medication and during metoprolol treatment, exercise led to an increase in the peripheral platelet count, whereas timolol was associated with a reduction of platelets during physical effort. Neither drug affected platelet thromboxane B2 at rest. During exercise, its level was not affected in the pre-treatment period or during metoprolol treatment but it was sharply increased by timolol therapy.

Natural history of global and critical brain ischaemia. Part I: EEG and neurological signs during the first year after cardiopulmonary resuscitation in patients subsequently regaining consciousness.

Of 125 patients who had no detectable cortical activity (DCA) in the electroencephalograph (EEG) immediately upon resuscitation from circulatory arrest of primary cardiovascular aetiology, 37 subsequently regained consciousness; these patients had their EEG and neurological status serially investigated until they expired or had survived one year. The orderly cerebral recovery during postischaemic unconsciousness was characterized by a sequential appearance of EEG configurations and related neurological signs. The absence of DCA was at first accompanied by miosis and all the cranial nerve reflexes except the caloric vestibular reflex (phase of exclusive presence of cranial nerve reflexes) and then by motor responsiveness, predominantly decerebrate posturing (phase of cephalic reactivity). Electrocortical activity appeared thereafter first as a phase described as 'intermittent cortical activity' (ICA) accompanied by medium sized pupils, decorticate posturing and stereotypic reactivity and then as a phase described as 'continuous cortical activity' (CCA) associated with stereotypic reactivity. Consciousness returned 11-720 h later. The EEG and neurological recovery occurred independently after awakening; but elementary motor, sensory and mental faculties were regained in a characteristic sequence. Initially, the alert patient had a phase of 'severe disability' seen as communicating motor responses, eye-orientation and a bilateral Babinski response; in the subsequent phase of 'moderate disability' speech, auto-orientation, locomotor control, and a normal plantar response were then restored; finally in the phase of slight- or no disability allo-orientation, retention and recall reappeared. Thirteen patients made a complete recovery of all faculties 83--2150 h after cardiopulmonary resuscitation.

Natural history of global and critical brain ischaemia. Part II: EEG and neurological signs in patients remaining unconscious after cardiopulmonary resuscitation.

Of 125 patients who had no detectable cortical activity (DCA) on the electroencephalograph (EEG) immediately upon resuscitation from circulatory arrest of primary cardiovascular aetiology, 88 remained unconscious; these patients had their EEG and neurological status serially investigated until they died. Immediately upon re-establishment of circulation all cerebral functions could be absent; the brain death (irreversible loss of functions) was then signified by the appearance of poikilothermia, diabetes insipidus and reflex extension of the upper limb. Most often, some cranial nerve reflexes were present; the EEG configurations and related neurological signs then appeared in a sequence which resembled orderly postischaemic recovery: A phase without DCA was at first characterized by an exclusive presence of cranial nerve reflexes and then by the appearance of decerebrate posturing this phase was followed by another phase of intermittent cortical activity (ICA) with decorticate and stereotypic motor responses and a phase of continuous cortical activity (CCA) accompanied by stereotypic reactivity. These phases were most often incomplete due to failure of recovery of some cranial nerve reflexes or were abnormal due to the appearance of intermittent spikes and sharp waves. Progressive recovery could stagnate at any step and the cerebral functions be lost abruptly or gradually in reverse order of recovery. The decay was invariably due to cardiovascular or pulmonary complications. Brain autopsy revealed extensive neuronal loss and intravital autolytic changes in patients who had fulfilled clinical criteria of brain death for more than 72 h, but the histopathology showed no relationship to other clinical findings during the postischaemic course.

Different chemotherapeutic sensitivities and host factors affecting prognosis in advanced ovarian carcinoma versus minimal residual disease.

Treatment of patients with advanced ovarian carcinoma (stages IIIB and IV) using either cyclophosphamide alone (1 g/m2) or cyclophosphamide (500 mg/m2) plus adriamycin (40 mg/m2) by iv injection every 3 weeks each produced partial regression in approximately one third of the patients. Survival curves and time-to-progression curves for the two regimens were nearly identical in these patients with advanced disease. These same regimens produced different results when used monthly in patients who had minimal residual disease (stages II and IIIA). In patients with minimal residual disease the therapeutic index of the combination regimen was superior to that of cyclophosphamide alone. Prognosis was better overall among patients with minimal residual disease than among patients with advanced disease. Within the minimal-disease group grossly complete excision of tumor prior to chemotherapy was associated with still better prognosis. Among patients with advanced disease, prognosis was significantly better for older patients despite their generally less favorable performance scores. Much of this prognostic superiority appeared to be related to menopausal status and presumably to the depletion of endogenous estrogens in the older patients.