Minutes Of Circulatory Arrest Research Articles

Abstract 13: Adenosine Receptor Activation During Extracorporeal Cardiopulmonary Resuscitation Improves Survival After Cardiac Arrest in Swine

Introduction: Despite advances in resuscitation protocols, including the addition of Extracorporeal Cardiopulmonary Resuscitation (ECPR), survival after cardiac arrest remains less than 40% and novel methods are needed to attenuate global injury and improve outcomes. ATL1223, an adenosine 2A receptor (A2AR) agonist has been shown to attenuate organ specific reperfusion injury by modulating the interaction of inflammatory cells. Hypothesis: A2AR activation during ECPR will improve survival and decrease the burden of injury in a large animal model of cardiac arrest. Methods: Adult swine underwent 20 minutes of circulatory arrest followed by defibrillation and 6 hours of ECPR. Animals were randomized to receive saline control (n=5) or the A2AR agonist Regadenoson (0.144 and 14.4mcg/kg/hr, n=5/group). Animals were subsequently weaned from ECPR and monitored for 24 hours. Clinical and biochemical endpoints were compared between groups. Results: The administration of Regadenoson increased survival after cardiac arrest compared to saline controls (10/10, 100% vs 2/5, 40%, p=0.02, Figure 1). Anesthetic administration (p=0.41), fluid resuscitation (p=0.54), and epinephrine required to maintain target arterial pressure (p=0.08) were similar for all subjects. Biochemical markers of organ damage, including creatinine (p=0.87), aspartate aminotransferase (p=0.89), and troponin I (p=0.38), were similar among groups (Figure 2). Conclusions: In a clinically relevant model of cardiac arrest treated with ECPR, selective A2AR agonism increased survival from 40% to 100% at 24 hours. These results suggest A2AR activation is a promising therapeutic target after cardiac arrest.

Audit of ten years of donation after circulatory death experience in Queensland: observations of agonal physiology following withdrawal of cardiorespiratory support.

An audit of ten years' experience in all patients undergoing withdrawal of cardiorespiratory support (WCRS) in the context of donation after circulatory death (DCD) was conducted in Queensland, Australia (2008 to 2017). One hundred and seventy-one patients proceeded to donation after declaration of death by circulatory criteria with loss of pulsatile arterial blood pressure (circulatory arrest) for five minutes. The demographics, times and haemodynamic observations were abstracted, de-identified and collated. The average age of patients was 43 years (standard deviation 16.1 years) and 63% were male. The median and mean times to an agonal systolic blood pressure below 50 mmHg were 10 and 11 minutes and the median and mean times from WCRS to circulatory arrest were 14 and 16 minutes. After systolic blood pressure fell to 50 mmHg or lower, 33 patients (19.3%) had spontaneous return of systolic pressure to above 50 mmHg. Following periods of circulatory arrest, five patients were documented to have spontaneous return of pulsatile arterial pressure. Two patients had return of circulation after two minutes, but less than five minutes of circulatory arrest and three patients had return of circulation where circulatory arrest had been documented for less than two minutes. Following WCRS, transient restoration of circulation following circulatory arrest may occur, even following two minutes of circulatory asystole, albeit rarely.

Outflow occlusion for circulatory arrest in dogs

The purpose of this study was to evaluate the possibility of producing circulatory arrest by occlusion of the pulmonary trunk as an alternative to the venous inflow occlusion through the left hemithorax. Eight healthy mongrel dogs were divided in two groups. Group I underwent 4 minutes of outflow occlusion and Group II was submitted to 8 minutes of circulatory arrest. Outflow occlusion was performed through left thoracotomy and pericardiotomy by passing a Rumel tourniquet around the pulmonary trunk. Physical examination, electrocardiography, echocardiography, blood gas analyses, hemodynamic, and oxygen transport variables were obtained before and after the procedure. The dogs from Group I did not have any clinical, electrocardiographic, echocardiographic, or hemo-dynamic abnormalities after anesthetic recover. In the Group II, only one dog survived, which had no clinical, electrocardiographic, or echocardiographic abnormalities. In this last dog, just after releasing the occlusion, it was detected increases in the following parameters: heart rate (HR), systolic, diastolic and mean arterial blood pressure (SAP; DAP; MAP), pulmonary artery pressure (PAP), pulmonary wedge pressure (PWP), central venous pressure (CVP), cardiac output (CO), systolic index (SI), cardiac index (CI), left and right ventricular stroke work (LVSW; RVSW), oxygen delivery index (DO2), oxygen consumption index (VO2), and oxygen extraction (O2 ext). Moreover, the oxygen content of arterial and mixed venous blood (CaO2; CvO2), and the arterial and mixed venous partial pressure of oxygen (PaO2; PvO2) were decreased 5 minutes after circulatory arrest. Outflow occlusion is a feasible surgical procedure for period of 4 minutes of circulatory arrest.

Patterns of change in cytochrome c oxidase redox status

Investigators using mono channel near infrared spectroscopy (NIRS) have reported different patterns of change in cytochrome c oxidase (Cyt) in similar studies of tissue ischaemia. We investigated whether there were distinctive differences in NIRS signals obtained simultaneously from different sampling sites during the same imposed physiological intervention within the same subject. Methods: Subjects were 36, healthy, 10 kg, commercial swine undergoing cardiopulmonary bypass to initiate 3 to 7 periods of 7.5 minutes of circulatory arrest. Each arrest was initiated at one of 81 combinations of high, normal, or low levels of core temperature, haematocrit, pH, and serum glucose. Each combination was repeated twice, yielding 162 NIRS data sets. Results: Six distinct patterns of change of Cyt were found. Typically, brain Cyt quickly became reduced shortly after the start of arrest, muscle Cyt did not start becoming reduced until after 3½ minutes of arrest, and spinal cord Cyt either did not change status or became gradually reduced throughout the period of arrest. The brain response may reflect strong oxygen dependence, while the muscle response may indicate a dependency buffered by myoglobin stores, and the spine response may indicate a low concentration of available Cyt that is too diffuse to be rapidly influenced by changes in oxygen availability. Conclusion: Multi‒channel NIRS is needed for systemic evaluation of respiration at the cellular level in clinical settings. Distinctive Cyt patterns of change occur in different organs at the same time, in response to circulatory arrest.

Discussion: Session 3—Dissection

Discussion: Session 3—Dissection

Bronchial healing, lung parenchymal histology, and blood gases one month after transplantation of lungs topically cooled for 2 hours in the non–heart-beating cadaver

Background The aim of this study was to investigate, in an experimental survival model, the functional and morphologic results of lung transplantation using lungs from non–heart-beating donors. Methods Left lungs, topically cooled to 25° C for 2 hours in situ after 5 minutes of circulatory arrest followed by 26 minutes of unsuccessful cardiopulmonary resuscitation, were transplanted into syngeneic rats. Five weeks after the transplantation, right pneumonectomy was performed and blood gases measured after 60 minutes. In a control group, fresh donor lungs were used for transplantation and comparison was made with the cadaver group and a group of normal rats after right pneumonectomy. Morphologic changes were evaluated by semiquantitative scoring of 13 different parameters to obtain a total histologic index for each rat. Results Computerized tomography scans of the chest made during the third post-operative week showed normal lung parenchyma in both groups, and at 5 weeks there were no significant differences in blood gases. The bronchial anastomoses showed normal healing in all cases. The histologic changes in the lung parenchyma were generally mild and focal, primarily consisting of interstitial and perivascular mononuclear inflammation, bronchial inflammation and athelectasis. Surprisingly, the transplanted controls demonstrated the most pronounced changes, although only the difference in total histologic index between groups was significant. Conclusions Lungs from non–heart-beating donors, topically cooled in the cadaver for two hours after failed resuscitation, showed normal bronchial healing and favorable parenchymal histology compared to transplanted control lungs 5 weeks after transplantation.

Gas exchange function one month after transplantation of lungs topically cooled for 2 hours in the non-heart-beating cadaver after failed resuscitation

Background If lungs from subjects dying of heart attacks could be used for transplantation, the lung donor shortage could be radically reduced. The aim of this study was to investigate, in an experimental survival model, the results of lung transplantation using lungs from non-heart-beating donors. Methods The left lung, topically cooled to 25° C for 2 hours in situ after 5 minutes of circulatory arrest and 26 minutes of unsuccessful cardiopulmonary resuscitation, was transplanted into a syngeneic rat. Five weeks after the transplantation, right pneumonectomy was performed and blood gases measured every 10 minutes for 1 hour. Comparison were made with two control groups, one where fresh donor lungs were transplanted and another where only right pneumonectomy was done. Results All animals survived and were in good condition at the end of the observation period. There was no statistically significant difference in arterial oxygen or carbon dioxide tension between the groups. The bronchial anastomoses showed normal healing in all cases. Conclusion Lungs from non-heart-beating donors topically cooled in situ to 25° C for 2 hours before being harvested showed excellent gas exchange and bronchial healing 5 weeks after transplantation.

Effect of isoflurane on the β-adrenergic and endothelium-dependent relaxation of pig cerebral microvessels after cardiopulmonary bypass

We examined the direct vasomotor effect of isoflurane as well as its effect on endothelium-dependent and beta-adrenergic vasodilation of cerebral microcirculation following either normothermic cardiopulmonary bypass (CPB) or profoundly hypothermic CPB with circulatory arrest. Pigs were placed on CPB; the systemic temperature was either maintained at 37 degrees C or lowered to 15 degrees C with 60 minutes of circulatory arrest. After 2 hours of CPB, the animals were separated from CPB; 15 minutes later the brain was quickly harvested in cold Krebs solution. Control animals were not instrumented and their brains were similarly harvested. Arteries of approximately 100 microm were dissected and changes in diameter monitored by in vitro videomicroscopy. Following preconstriction with the thromboxane analogue U46619 1 micromol/L, percent relaxation to the endothelium-dependent dilator adenosine diphosphate (ADP) 10(-9) to 10(-4) mol/L, the endothelium-independent dilator sodium nitroprusside (SNP) 10(-9) to 10(-4) mol/L, or the beta-adrenergic agonist isoproterenol 10(-12) to 10(-4) mol/L was measured either in the presence or absence of isoflurane 2%. Additionally, with or without preconstriction with U46619 1 micromol/L, vessel diameter changes were monitored with increasing concentrations of isoflurane 0-3%. Dose-response curves were compared by two-way analysis of variance. Vasodilation to ADP or isoproterenol, but not SNP, was attenuated after normothermic CPB (N-CPB) or profoundly hypothermic CPB (PH-CPB). Although isoflurane attenuated vasodilation of control vessels to ADP or isoproterenol, isoflurane did not further attenuate vasodilation to ADP or isoproterenol after N-CPB or PH-CPB. The direct vasomotor effect of isoflurane depended on the preexisting tone of the vessels, constricting vessels without preconstriction and dilating them after preconstriction. These findings may have implications on the incidence of neuropsychological dysfunction after CPB and use of isoflurane.

Cerebral cellular response to profound hypothermia

AbstractIn our first two experiments, we examined brain tissue pH and tensions of oxygen and carbon dioxide in dogs core cooled to 20°C. So as to evaluate the effects of 60 minutes of circulatory arrest, 120 minutes of low-flow perfusion (25 mI/kg/mm), and 120 minutes of moderate-flow perfusion (50 mi/kg/mm), all conducted with and without pulsatile assistance. We further determined the effects of blood gas strategy on the same variables with 60 minutes of circulatory arrest. In a third experiment, we directly observed microcirculation at the surface of the brain during profoundly hypothermic perfusion. In the fourth experiment, we measured cerebral blood flow, oxygen consumption, and excessive production of lactate. Profound anoxia occurred within 20 minutes of circulatory arrest, causing severe and progressive acidosis in the brain tissues along with hypercapnia. The inhalation of 5% or 7% carbon dioxide during core cooling made the brain unacceptably acidotic. The brain acidosis was mild with low flow perfusion, and slight with moderate-flow perfusion. Pulsatile assistance improved acidosis in the brain tissues at all rates of flow. It also improved the microcirculation, the patent number of arterioles and stabilized flow in bridging veins. Cerebral metabolism became aerobic without alterations in cerebral consumption of oxygen during low-flow perfusion. We recommend flow rates above 25% of normal, alpha-stat strategy, and pulsatile assistance for better protection of the brain during profound hypothermia.

Effects of potassium cardioplegia on high-energy phosphate kinetics during circulatory arrest with deep hypothermia in the newborn piglet heart

The protective effects of hypothermia and potassium-solution cardioplegia on high-energy phosphate levels and intracellular pH were evaluated in the newborn piglet heart by means of in vivo phosphorus nuclear magnetic resonance spectroscopy. All animals underwent cardiopulmonary bypass, cooling to 20 degrees C, 120 minutes of circulatory arrest, rewarming with cardiopulmonary bypass, and 1 hour off extracorporeal support with continuous hemodynamic and nuclear magnetic resonance spectroscopic evaluation. Group I (n = 5) was cooled to 20 degrees C; group II (n = 4) was given a single dose of 20 degrees C cardioplegic solution; group III (n = 7) was given a single dose of 4 degrees C cardioplegic solution; and group IV (n = 4) received 4 degrees C cardioplegic solution every 30 minutes. At end ischemia, adenosine triphosphate, expressed as a percent of control value, was lowest in group I 54% +/- 6.5% but only slightly greater in group II 66% +/- 7.0%. Use of 4 degrees C cardioplegic solution in groups III and IV resulted in a significant decrease in myocardial temperature, 9.9 degrees C versus 17 degrees to 20 degrees C, and significantly higher levels of adenosine triphosphate at end ischemia; with group III levels at 72% +/- 6.0% and group IV levels at 73% +/- 6.0%. Recovery of adenosine triphosphate with reperfusion was not related to the level of adenosine triphosphate at end ischemia and was best in groups I and II, with a recovery level of 95% +/- 4.0%. In group IV, no recovery of adenosine triphosphate occurred with reperfusion, resulting in a significantly lower level of adenosine triphosphate, 74% +/- 6.0%, than in groups I and II. Recovery of ventricular function was good for all groups but was best in hearts receiving a single dose of 4 degrees C cardioplegic solution. In this model, multiple doses of cardioplegic solution were not associated with either improved adenosine triphosphate retention during arrest or improved ventricular function after reperfusion, and in fact resulted in a significantly lower level of adenosine triphosphate with reperfusion. The complete recovery of adenosine triphosphate in groups I and II, despite a nearly 50% adenosine triphosphate loss during ischemia, may result from a decrease in the catabolism of the metabolites of adenosine triphosphate consumption in the newborn heart.

Coma Following Cardiac Arrest: A Review of the Clinical Features, Management, and Prognosis

Sudden cardiac death is an important clinical problem that accounts for 750,000 deaths in the United States each year. There are 200,000 cardiac resuscitations each year, of which only 70,000 are successful. Survival depends upon early cardiopulmonary resuscitation and defibrillation. The brain's ability to tolerate no more than a few minutes of circulatory arrest is the major factor limiting the success of cardiopulmonary resusci tation. Cardiac arrest results in a spectrum of clinical disorders depending on the severity of cerebral anoxia. Neurological sequelae in survivors range from transient states of confusion and amnesia to prolonged uncon sciousness in a coma or in the vegetative state. Sequen tial neurological examinations alone or in conjunction with evoked potentials, electroencephalogram, com puted tomography, and positron emission tomography can indicate the degree of central nervous system dam age and the likely outcome. The clinical management of patients in coma following cardiac arrest involves resto ration of cardiopulmonary and metabolic homeostasis. No effective delayed therapy yet exists that can reverse anoxic damage, but several promising therapeutic agents are under laboratory and clinical investigation.

Twenty-four hour survival in a canine model of cardiac arrest comparing three methods of manual cardiopulmonary resuscitation

Two new modifications of manual cardiopulmonary resuscitation, high impulse compression at a rate of 120/min and interposed abdominal compression at a rate of 60/min, have been reported to produce better hemodynamic responses than standard cardiopulmonary resuscitation at 60/min. However, the effect of these two new methods on initial resuscitation success and 24 hour survival is unknown. In this study, 30 mongrel dogs were divided into three equal groups, each treated with one of three types of manual cardiopulmonary resuscitation. Ventricular fibrillation was induced electrically in morphinized, endotracheally intubated dogs emerging from halothane anesthesia. After 3 minutes of circulatory arrest without intervention, one of the three techniques of manual cardiopulmonary resuscitation was begun, and continued for 17 minutes. Defibrillation was performed at 20 minutes. Successful resuscitation was defined as a mean arterial blood pressure of at least 60 mm Hg, without chest compressions, 10 minutes after the initial defibrillation attempt. Intensive care was provided for 2 hours, including hemodynamic and respiratory monitoring, and drug intervention when required. Twenty-four hour survival and neurologic deficit were used as critical measures of outcome. Ten of 30 animals survived 24 hours with a mean neurologic deficit score of 5% (normal = 0, brain dead = 100). There was no difference in initial resuscitation success, 24 hour survival or neurologic deficit of the survivors among the three manual cardiopulmonary resuscitation methods. Aortic diastolic and calculated coronary perfusion pressures were similar for all three methods. Well performed standard manual cardiopulmonary resuscitation is as effective as these modified versions (high impulse compression and interposed abdominal compression) when compared in the same animal model.

Anoxic Cerebral Potassium Accumulation Reduced by Phenytoin

Results from a previous study suggested that the cerebral protective effect of phenytoin (PNT) might be linked to its ability to reduce cerebrospinal fluid potassium (K+) accumulation during anoxia. In the present study two PNT doses (50 and 150 mg/kg) were examined to determine the ability of PNT to reduce cerebrospinal fluid K+ in cisterna magna samples after 10 and 20 minutes of circulatory arrest. Also examined were two other protective treatments (pentobarbital, 33 mg/kg, and hypothermia to 35 C) which, in the hypoxic (F1O2 = 0.05) mouse, provide cerebral protection equivalent to PNT, 50 mg/kg. Both PNT doses significantly reduced cerebrospinal fluid K+ accumulation and tended to do so in a dose-related manner, similar to the dose-related cerebral protective effect of PNT. PNT, 50 mg/kg reduced K+ accumulation more effectively than either pentobarbital or hypothermia, whose protective effects are likely explained by a different mechanism (i.e., reduced cerebral metabolic rate). These data support the hypothesis that PNT-induced cerebral protection may be linked to its effect on cerebral K+ accumulation.

Cardiac consequences and treatment of disopyramide intoxication: experimental evaluation in dogs.

A slow (1.18 mumol.kg-1.mm-1) intravenous infusion of disopyramide (mol.wt 339) was given to 8 adult Beagle dogs. An initial phase of slow decline in cardiac output and broadening of the QRS complex on the ECG, with systolic blood pressure maintained above 13.5 kPa (100 mmHg), was followed by a phase of rapid circulatory failure without a correspondingly dramatic change in ECG appearances. Underventilation and cardiac arrhythmias were observed only in the agonal phase after several minutes of circulatory arrest. They were not therefore the primary cause of death, which was due to failure of myocardial contractility. Three positively inotropic drugs (isoprenaline, dopamine, and glucagon) are shown to be capable of restoring the failing circulation, provided they are given before the phase of complete circulatory standstill. In this respect isoprenaline appears superior to dopamine and glucagon.

Strain gauge plethysmography for blood flow measurements in the legs of children.

The arterial resting flow, the arterial peak flow after 3 minutes of circulatory arrest to the leg, and the venous emptying rate were studied by strain gauge plethysmography in the calves of 85 children between 3 and 16 years of age. Most of the children had heart disease; therefore the values obtained can be regarded as reference values only for this type of patient.--The reproducibility of the results of the flow measurements was favourable and equal to that found in the examination of adults and of children using water-filled plethysmographs. --All of the flow functions investigated were significantly higher in the younger children and--but not always significantly--higher in boys than in girls. There was no difference between sides as regards arterial flow, whereas the venous emptying rate was significantly lower in the left calf. --Strain gauge plethysmography is recommended for assessment of circulatory complications after vascular catheterization in children aged 4 years or older.

THE EFFECT OF UMBILICAL ARTERIAL CATHETERIZATION ON SUBSEQUENT LIMB BLOOD FLOW

The safety of umbilical artery catheters (UAC) has been questioned. Catheters are necessary for biochemical monitoring, and offer means of avoiding hypoxia and hyperoxia. Several necropsy studies and one angiographic report (Peds. 50: 6, 1972) demonstrate that UAC promote thrombosis that could compromise leg blood flow. Our studies suggest that UAC have no effect on subsequent limb blood flow.Using venous occlusion plethysmography and a double strand mercury-in-“rubber” strain gauge, we measured blood flow simultaneously in both legs in 28 infants who had had UAC as neonates. Measurements were made under standard conditions and after stimulation of flow by two minutes of circulatory arrest. UAC tips were positioned at the aortic bifurcation. Mean duration of catheterization was 59.3 hrs. (range 4-144). Mean age at study was 67 days (range 29-135).We compared the highest flow in each leg with the simultaneous flow in the opposite leg. Under conditions specifically chosen to accentuate circulatory differences, flow in the leg on the UAC side was on the average .5 ml/100 ml tissue/min > flow on the non-UAC side, a difference of 1% (analysis of variance, F (1, 83) = 0.157 p > .05). This difference is of no biological importance.

Examination of the intrarenal hematocrit ratio with the techinque of circulatory stop-flow in dogs.

Estimates of the intrarenal hematocrit ratio vary widely, depending on the techniques used for its determination. Computation of blood volume from the product of mean transit time of labeled erythrocytes and albumin, and minute volume blood flow, yields values averaging approximately 90% of the systemic vessel hematocrit. To the other extreme are values that are slightly less than half of the systemic hematocrit ratio based on the determination of total renal blood volume by labeled red cells and albumin. Intermediate values are obtained by methods involving draining the blood from the kidney and measuring its hematocrit ratio. The current investigation, by a technique of circulatory stop-flow, has shown that a substantial fluid shift occurs in the kidney within 2 minutes of circulatory arrest, so that interstitial fluid, supplemented by fluid reabsorbed by the nephrons, dilutes the erythrocytes within the peritubular capillaries to reduce the hematocrit ratio to almost half of the systemic figure. The drainage methods are subject to error as a result of this mechanism, but if such fluid shifts are taken into account, values for the intrarenal hematocrit closer to the ratio of systemic blood can be anticipated.