William Stezoski

Amelioration of brain damage by lidoflazine after prolonged ventricular fibrillation cardiac arrest in dogs

Calcium entry blockers can ameliorate postischemic cerebral hypoperfusion, protect the myocardium against ischemia, and may protect against early postischemic neurologic deficit. This study documents that a calcium entry blocker, given after cardiac arrest, can ameliorate late postischemic neurologic deficit (ND). Thirty-four dogs received 10 min of ventricular fibrillation, restoration of spontaneous circulation by external cardiopulmonary resuscitation, and standard postarrest intensive care. Eleven of these dogs were given lidoflazine, 1 mg/kg body weight, within 10 min postarrest and again at 8 h and 16 h. Pupillary light reflexes, EEG activity, arterial-cerebrovenous oxygen gradients (O2 demand/supply ratios) and intracranial pressure were the same in both groups. After weaning from controlled ventilation at 24 h, ND scores improved consistently through the 96-h observation period in the lidoflazine-treated dogs. In the control group, ND scores were significantly higher than in the lidoflazine-treated dogs. In the lidoflazine-treated group, 5/11 dogs achieved normal overall performance and none remained comatose, whereas all control dogs had some deficit and 4/11 remained comatose. Delayed neurologic deterioration occurred in 6/ 11 control and 0/11 lidoflazine-treated dogs. Total mean cerebral histopathologic damage (HD) scores at 96 h were not significantly different between the two groups; however, individual HD scores and maximum cerebrospinal fluid (brain-specific) creatine-phosphokinase activity—which increases after brain insults—correlated well with 96-h ND scores. In the lidoflazine group, life-threatening dysrhythmias were less frequent and the norepinephrine requirement for blood pressure maintenance was the same as in the control group. Cardiac output remained at prearrest levels in the lidoflazinetreated dogs, but decreased in the control group, particularly during the first 4 h postarrest.

Suspended Animation for Delayed Resuscitation from Prolonged Cardiac arrest that is Unresuscitable by Standard Cardiopulmonary-Cerebral Resuscitation

Standard cardiopulmonary-cerebral resuscitation fails to achieve restoration of spontaneous circulation in ∼50% of normovolemic sudden cardiac arrests outside hospitals and in essentially all victims of penetrating truncal trauma who exsanguinate rapidly to cardiac arrest. Among cardiopulmonary-cerebral resuscitation innovations since the 1960s, automatic external defibrillation, mild hypothermia, emergency (portable) cardiopulmonary bypass, and suspended animation have potentials for clinical breakthrough effects. Suspended animation has been suggested for presently unresuscitable conditions and consists of the rapid induction of preservation (using hypothermia with or without drugs) of viability of the brain, heart, and organism (within 5 mins of normothermic cardiac arrest no-flow), which increases the time available for transport and resuscitative surgery, followed by delayed resuscitation. Since 1988, we have developed and used novel dog models of exsanguination cardiac arrest to explore suspended animation potentials with hypothermic and pharmacologic strategies using aortic cold flush and emergency portable cardiopulmonary bypass. Outcome evaluation was at 72 or 96 hrs after cardiac arrest. Cardiopulmonary bypass cannot be initiated rapidly. A single aortic flush of cold saline (4°C) at the start of cardiac arrest rapidly induced (depending on flush volume) mild-to-deep cerebral hypothermia (35° to 10°C), without cardiopulmonary bypass, and preserved viability during a cardiac arrest no-flow period of up to 120 mins. In contrast, except for one antioxidant (Tempol), explorations of 14 different drugs added to the aortic flush at room temperature (24°C) have thus far had disappointing outcome results. Profound hypothermia (10°C) during 60-min cardiac arrest induced and reversed with cardiopulmonary bypass achieved survival without functional or histologic brain damage. Further plans for the systematic development of suspended animation include the following: a) aortic flush, combining hypothermia with mechanism-specific drugs and novel fluids; b) extension of suspended animation by ultraprofound hypothermic preservation (0° to 5°C) with cardiopulmonary bypass; c) development of the most effective suspended animation protocol for clinical trials in trauma patients with cardiac arrest; and d) modification of suspended animation protocols for possible use in normovolemic ventricular fibrillation cardiac arrest, in which attempts to achieve restoration of spontaneous circulation by standard external cardiopulmonary resuscitation-advanced life support have failed.

Cardiopulmonary bypass after cardiac arrest and prolonged closed-chest CPR in dogs.

We studied a clinically realistic field-to-hospital scenario in dogs with four-minute ventricular fibrillation (VF) cardiac arrest followed by 30-minute standard external CPR basic life support (BLS). At the end of this 34-minute insult, cardiopulmonary bypass (CPB) was used for early defibrillation and assisted circulation for one hour (n = 10). Recovery was compared with that of control dogs (n = 10) in which standard CPR with advanced life support (ALS) for another 30 minutes was used for restoration of spontaneous circulation (ROSC). Both groups had hemodilution and heparinization; controlled blood pressure, blood gases, ventilation, and other parameters for 20 hours; and intensive care to 72 hours. During CPR-BLS of 30 minutes in both groups signs of cerebral viability returned. CPB achieved ROSC more successfully (ten of ten vs five of ten CPR-ALS controls) (P less than .02); and more rapidly, with less defibrillation energy (first countershock in eight of ten) and with less epinephrine (P less than .01). CPB improved 72-hour survival (seven of ten vs three of ten controls) (P less than .05). Between two and 24 hours, of those with ROSC, cardiac complications killed three of ten CPB dogs (after weaning), and two of five CPR-ALS dogs (NS). All seven CPB survivors to 72 hours were neurologically normal; of the three CPR-ALS survivors, one remained with severe neurologic deficit and two were neurologically normal (seven of ten CPB vs two of ten controls, P = .025). Starting CPR-BLS within four minutes of arrest can maintain cerebral viability.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiopulmonary bypass after prolonged cardiac arrest in dogs

Ventricular fibrillation (VF) cardiac arrest of more than ten minutes can be survived by cerebral neurons, but restoration of spontaneous circulation (ROSC) by external CPR is unreliable. Cardiopulmonary bypass (CPB) permits control of pressure, flow, oxygenation, temperature, and composition of blood. After 12 1/2 minutes of normothermic VF cardiac arrest, CPB was used as a research tool for reperfusion and assisted circulation for two hours in ten dogs without thoracotomy, with plasma substitute priming, and without preceding CPR (a deliberately nonclinical scenario). Recovery was compared with that in ten control dogs in which standard CPR with advanced life support (ALS) for up to 30 minutes was used to achieve ROSC. Both groups subsequently had blood pressure, blood gases, ventilation, and other parameters controlled for 20 hours, and intensive therapy to 72 hours. CPB achieved ROSC more successfully (ten of ten vs six of ten controls) (P less than .05), and more rapidly, with fewer defibrillation attempts and with less epinephrine (P less than .05). CPB improved 72-hour survival (seven of ten vs two of ten controls) (P = .025). Between two and 24 hours, of those with ROSC, intractable cardiogenic shock killed four of six control dogs (NS). CPB was followed by fewer arrhythmias. CPB increased recovery of consciousness (five of ten CPB vs zero of six controls with ROSC) (P = .037), but achieved neurologic normality in only one of ten. Cardiac arrest and CPB (without CPR) resulted in less myocardial morphologic damage than did standard CPR (P less than .025).(ABSTRACT TRUNCATED AT 250 WORDS)

Dynamic heterogeneity of cerebral hypoperfusion after prolonged cardiac arrest in dogs measured by the stable xenon/CT technique: a preliminary study

After prolonged cardiac arrest and reperfusion, global cerebral blood flow (gCBF) is decreased to about 50% normal for many hours. Measurement of gCBF does not reveal regional variation of flow or permit testing of hypotheses involving multifocal no-flow or low-flow areas. We employed the noninvasive stable Xenon-enhanced Computerized Tomography (Xe/CT) local CBF (LCBF) method for use in dogs before and after ventricular fibrillation (VF) cardiac arrest of 10 min. This was followed by external cardiopulmonary resuscitation (CPR) and control of cardiovascular pulmonary variables to 7 h postarrest. In a sham (no arrest) experiment, the three CT levels studied showed normal regional heterogeneity of LCBF values, all between 10 and 75 ml/100 cm3 per min for white matter and 20 and 130 ml/100 cm3 per min for gray matter. In four preliminary CPR experiments, the expected global hyperemia at 15 min after arrest, was followed by hypoperfusion with gCBF reduced to about 50% control and increased heterogeneity of LCBF. Trickle flow areas (LCBF less than 10 ml/100 cm3 per min) not present prearrest, were interspersed among regions of low, normal, or even high flow. Regions of 125-500 mm3 with trickle flow or higher flows, in different areas at different times, involving deep and superficial structures migrated and persisted to 6 h, with gCBF remaining low. These preliminary results suggest: no initial no-reflow foci (less than 10 ml/100 cm3 per min) larger than 125 mm3 persisting through the initial global hyperemic phase; delayed multifocal hypoperfusion more severe than suggested by gCBF measurements; and trickle flow areas caused by dynamic factors.

Suspended animation can allow survival without brain damage after traumatic exsanguination cardiac arrest of 60 minutes in dogs.

BACKGROUND We have previously shown in dogs that exsanguination cardiac arrest of up to 120 minutes without trauma under profound hypothermia induced by aortic flush (suspended animation) can be survived without neurologic deficit. In the present study, the effects of major trauma (laparotomy, thoracotomy) are explored. This study is designed to better mimic the clinical scenario of an exsanguinating trauma victim, for whom suspended animation may buy time for resuscitative surgery and delayed resuscitation. METHODS Fourteen dogs were exsanguinated over 5 minutes to cardiac arrest. Flush of saline at 2 degrees C into the femoral artery was initiated at 2 minutes of cardiac arrest and continued until a tympanic temperature of 10 degrees C was achieved. The dogs were then randomized into a control group without trauma (n = 6) or a trauma group (n = 8) that underwent a laparotomy and isolation of the spleen before hemorrhage and then, at the start of cardiac arrest, spleen transection and left thoracotomy. During cardiac arrest, splenectomy was performed. After 60 minutes of no-flow cardiac arrest, reperfusion with cardiopulmonary bypass was followed by intensive care to 72 hours. RESULTS All 14 dogs survived to 72 hours with histologically normal brains. All control dogs were functionally neurologically intact. Four of eight trauma dogs were also functionally normal. Four had neurologic deficits, although three required prolonged mechanical ventilation because of airway edema and evidence of multiple organ failure. Blood loss from the chest and abdomen was variable and was associated with poor functional outcomes. CONCLUSION Rapid induction of profound hypothermic suspended animation (tympanic temperature, 10 degrees C) can enable survival without brain damage after exsanguination cardiac arrest of 60 minutes even in the presence of trauma, although prolonged intensive care may be required. This technique may allow survival of exsanguinated trauma victims, who now have almost no chance of survival.

The role of the gut in the pathogenesis of death due to hyperthermia.

Pathologic data from the gastrointestinal tract in heatstroke victims, although documented, are confusing. The object of this study was to document the gastrointestinal changes observed during induced total body hyperthermia (42°C) followed by cooling. An established heatstroke model was used in a university animal laboratory. Group A underwent immersion hyperthermia for 1 hour, followed by cooling to normothermia. Group B underwent hyperthermia to cardiac arrest, followed by resuscitation plus cooling to normothermia. The postmortem findings in the gastrointestinal tract were evaluated. In group A, several hours after return to normothermia and stable vital signs, delayed secondary deterioration with massive gastrointestinal bleeding occurred. The postmortem findings revealed bleeding into the whole intestine and serosanguineous fluid in the peritoneal cavity. In group B, an adynamic gut was observed after 165 ± 21 minutes (range 125–174) of heating when mean arterial pressure (MAP) decreased to 38 ± 21 mm Hg (range 30–70). Cardiac arrest occurred at 178 ± 26 minutes (range 140–208) of immersion. Eight monkeys could be resuscitated to spontaneous circulation with return of normal gut motility, then they rearrested at 158 ± 68 minutes (range 45–228). The postmortem findings resembled those in group A. The Postmortem findings in the four monkeys in which restoration of spontaneous circulation failed, revealed only some intestinal wall edema and occasional petechial hemorrhages. It is concluded that after a hyperthermic event, tissue injury continues to develop. The pathologic findings are related to the time lapse between hyperthermia, cooling, and death. The similarity to the descriptions of septic shock, multiple organ failure, and the gut reperfusion syndrome is striking. An immunologic response as a mechanism for all these syndromes is discussed.

Resuscitation of dogs from cold-water submersion using cardiopulmonary bypass

In cold-water drowning, attempts at restoration of spontaneous circulation (ROSC) by external cardiopulmonary resuscitation (CPR) often fail. We explored the longest period of asphyxial cardiac arrest from cold-water submersion (without inhalation of water) from which ROSC is possible using cardiopulmonary bypass (CPB). In 19 lightly anesthetized dogs the tracheal tube was clamped (simulating laryngospasm) and the dogs were immersed in ice water from 20, 40, 60, 90, or 120 minutes. Cardiac arrest occurred after six to 11 minutes of submersion. At start of resuscitation, rectal temperature ranged from 21 C (after 60 minutes) to 34 C (after 20 minutes of submersion), and cerebral temperature was between 7 C (after 120 minutes) and 27 C (after 20 minutes submersion). Resuscitation attempts were performed according to protocol in 16 dogs, using only CPB by venoarterial pumping with an oxygenator and a heat exchanger. Priming was with 400 to 800 mL Dextran 40 and Ringers solution 1:1 plus heparin. CPB flows were 10 mL/kg/min, and they increased to achieve normotension and return of rectal temperature to 32 C. After one-half to three hours, of CPB, ROSC was successful in 75%. This percentage included one of three dogs after 90 minutes submersion, but not in the one dog after 120 minutes submersion. Spontaneous breathing and EEG activity returned in 56% at two to 24 hours, after 20 to 90 minutes of submersion. Failure of ROSC attempts apparently were due to clotting in large vessels during arrest and capillary leakage during reperfusion. CPB is effective for ROSC after prolonged hypothermic cardiac arrest, and it should be evaluated in animal outcome studies.

Hyperthermia-induced cardiac arrest in dogs and monkeys.

The pattern of dying from immersion hyperthermia was documented in 8 dogs, 9 rhesus monkeys and 12 pigtail monkeys. Under light general anesthesia and spontaneous breathing, the animals were immersed into water of 45 degrees C, which was subsequently adjusted to control brain (parietal epidural) temperature at 42 +/- 0.5 degrees C. Transient initial hypertension, tachycardia, tachypnea and hypocarbia were followed by progressive hypotension with decreasing central venous pressure and pulmonary artery occlusion pressures (measured in three dogs only), bradycardia and bradypnea. Cardiac arrest occurred in the dogs after immersion of 288 +/- 66 min and more rapidly (P less than 0.02) in the rhesus monkeys (at 137 +/- 75 min) and pigtail monkeys (at 178 +/- 26 min). EEG silence occurred in the monkeys at MAP 40 mmHg and in the dogs at MAP 25 mmHg. Cardiac arrest occurred in form of sudden ventricular fibrillation (2/5 dogs, 2/9 rhesus monkeys, 3/12 pigtail monkeys), or later in electromechanical dissociation leading to electric asystole (3/5 dogs, 7/9 rhesus monkeys, 9/12 pigtail monkeys). The mean blood glucose levels decreased to less than 30 mg/dl (P less than 0.002), whereas hematocrit, serum osmolality, lactate and potassium levels increased. Necropsies revealed macroscopic petechial hemorrhages in all extracerebral organs, but not in the brain. There was no gross evidence of cerebral edema. Death seemed to be the result of primary cardiovascular failure leading to secondary (ischemic) cerebral failure (EEG silence) and apnea, which coincided with pulselessness.

Sternal Compression before Ventilation in Cardiopulmonary Resuscitation (CPR)

The CPR committee of the Dutch Heart Association currently recommends for the management of sudden cardiac arrest, the initiation of external cardiac compressions before airway control and ventilation, which may be termed the “CAB” sequence. This differs from the ABC sequence, recommended by the American Heart Association, in which the patient is ventilated first. Supporters of the CAB sequence reason that, since most sudden cardiac deaths are due to ventricular fibrillation, the blood in the arterial system should be well oxygenated at the onset of such an episode. We conducted these studies to characterize the decline in arterial blood gases during 5 min of cardiac arrest, followed by external cardiac compressions alone, vs followed by external cardiac compressions with ventilation. In addition, we studied the decline in arterial blood gases and ventricular fibrillation without therapy.