Acute Brain Death Research Articles

Neurological complications during veno-venous extracorporeal membrane oxygenation: Does the configuration matter? A retrospective analysis of the ELSO database

BackgroundSingle- (SL) and double-lumen (DL) catheters are used in clinical practice for veno-venous extracorporeal membrane oxygenation (V-V ECMO) therapy. However, information is lacking regarding the effects of the cannulation on neurological complications.MethodsA retrospective observational study based on data from the Extracorporeal Life Support Organization (ELSO) registry. All adult patients included in the ELSO registry from 2011 to 2018 submitted to a single run of V-V ECMO were analyzed. Propensity score (PS) inverse probability of treatment weighting estimation for multiple treatments was used. The average treatment effect (ATE) was chosen as the causal effect estimate of outcome. The aim of the study was to evaluate differences in the occurrence and the type of neurological complications in adult patients undergoing V-V ECMO when treated with SL or DL cannulas.ResultsFrom a population of 6834 patients, the weighted propensity score matching included 6245 patients (i.e., 91% of the total cohort; 4175 with SL and 20,270 with DL cannulation). The proportion of patients with at least one neurological complication was similar in the SL (306, 7.2%) and DL (189, 7.7%; odds ratio 1.10 [95% confidence intervals 0.91–1.32]; p = 0.33). After weighted propensity score, the ATE for the occurrence of least one neurological complication was 0.005 (95% CI − 0.009 to 0.018; p = 0.50). Also, the occurrence of specific neurological complications, including intracerebral hemorrhage, acute ischemic stroke, seizures or brain death, was similar between groups. Overall mortality was similar between patients with neurological complications in the two groups.ConclusionsIn this large registry, the occurrence of neurological complications was not related to the type of cannulation in patients undergoing V-V ECMO.

Abstract 259: Outcomes of Targeted Temperature Management in Patients with Out-of-hospital Refractory Ventricular Fibrillation/ventricular Tachycardia Cardiac Arrest

Background: Current guidelines recommend use of targeted temperature management (TTM) with goal between 32 and 36°C for all comatose adult patients with ROSC after cardiac arrest. However, refractory cardiac arrest with prolonged hypoperfusion, may cause passive cooling below goal temperature. The impact of this passive cooling and subsequent cooling strategies remains unknown. This study aims to describe the association between passive intra-arrest cooling and survival in patients suffering refractory VF/VT cardiac arrest treated with the University of Minnesota extracorporeal cardiopulmonary resuscitation (ECPR) protocol. Methods: Between December 2015 and October 2019, consecutive adult patients with refractory VF/VT arrest requiring ongoing CPR were transported by EMS to the CCL where ECPR, coronary angiography, and PCI were performed, as appropriate. TTM was initiated with goal temperature of 34°C unless clinically significant bleeding occurred, where a goal of 36°C was used. Patient and arrest characteristics, temperature data, and survival were collected retrospectively. Results: Data was gathered for 153 consecutive patients transferred for ECPR; 12 were excluded due to death in CCL prior to TTM. Of the remaining patients, 63 (41%) survived to discharge, where 55 (36%) had CPC scores of 1-2. Among deceased patients, 25 died from acute brain death while 47 died from other causes. Patients with CPC 1-2 had an initial temperature of 34.1°C versus 32.7°C in patients developing acute brain death (p=0.002). Survivors had shorter (p=0.0001) CPR time (52 minutes) versus deceased patients (65 minutes). If the initial temperature was below goal, patients were actively warmed to goal due to bleeding risk with ECPR. Survival to hospital discharge with CPC 1-2 was associated with lower peak warming rate compared with acute brain death (0.37°C/hr vs 0.69°C/hr; p=0.014) Conclusions: Survivors with CPC 1-2 after refractory VF/VT cardiac arrest and ECPR have preserved initial temperatures compared to more severe passive cooling in patients with acute brain death. This may be due to shorter duration of CPR. However, patients with acute brain death were noted to have higher peak rate of rewarming during TTM.

Abstract 261: Acute Lung Injury and Recovery in Patients with Refractory Vf/vt Cardiac Arrest Treated with Prolonged Cpr and Veno Arterial Extracorporeal Membrane Oxygenation

Background: Post cardiac arrest syndrome includes significant pulmonary injury that is not clearly understood. Objectives: Describe the lung injury patterns among patients presenting with refractory ventricular tachycardia/ventricular fibrillation out-of-hospital cardiac arrest (VT/VF OHCA) patients who were treated with veno-arterial extracorporeal membrane oxygenation (VA-ECMO). Methods: OHCA characteristics, post-arrest computed tomography (CT) scans, ventilator parameters and complications were collected using a retrospective cohort design. Changes in lung compliance were compared over time between survivors, patients with acute brain death and those who had other modes of death with a two- way analysis of variance. Results: Among138 refractory VT/VF OHCA patients (81% were male with a median age of 59.0 years, mean CPR time of 64.3 ±16.1 min, a mean APACHE II score of 30.5 ± 4.6) 48/138 (34.8%) survived, acute brain death occurred in 48/138 (34.8%) and other modes of death in 56/138 (40.6%). The dependent posterior segments of the lung were the most commonly affected areas on the initial CT scan(Fig1A). There was no difference in the number of hyperattenuated areas between the survival groups.Compliance was borderline on day one (median 26.3(19.3,33.3)ml/cmH 2 0), but improved throughout the hospitalization (p=0.001) and was higher in survivors compared to those who died (p<0.001, Fig1B). VA-ECMO allowed the use of lung-protective ventilation in patients with borderline compliances maintaining safe PaO2 and PaCO2. Patients additionally treated with IABP/Impella had lower pulmonary compliance and more hyperattenuated areas on their initial CT scan compared to those treated exclusively with VA-ECMO. Conclusions: Refractory VT/VF OHCA patients who are treated with VA-ECMO frequently have lung injury with borderline compliance soon after the index event. Lung compliance improves throughout hospitalization and is higher in survivors.

Neuroprotection Care Bundle Implementation to Decrease Acute Brain Injury in Preterm Infants

BackgroundWe assessed the impact of an evidence-based neuroprotection care bundle on the risk of brain injury in extremely preterm infants. MethodsWe implemented a neuroprotection care bundle consisting of a combination of neuroprotection interventions such as minimal handling, midline head position, deferred cord clamping, and protocolization of hemodynamic and respiratory managements. These interventions targeted risk factors for acute brain injury in extremely preterm infants (born at gestational age less than 29 weeks) during the first three days of birth. Implementation occurred in a stepwise manner, including care bundle development by a multidisciplinary care team based on previous evidence and experience, standardization of outcome assessment tools, and education. We compared the incidence of the composite outcome of acute preterm brain injury or death preimplementation and postimplementation. ResultsNeuroprotection care bundle implementation associated with a significant reduction in acute brain injury risk factors such as the use of inotropes (24% before, 7% after, P value < 0.001) and fluid boluses (37% before, 19% after, P value < 0.001), pneumothorax (5% before, 2% after, P value = 0.002), and opioid use (19% before, 7% after, P value < 0.001). Adjusting for confounding factors, the neuroprotection care bundle significantly reduced death or severe brain injury (adjusted odds ratio, 0.34; 95% confidence interval, 0.20 to 0.59; P value < 0.001) and severe brain injury (adjusted odds ratio, 0.31; 95% confidence interval, 0.17 to 0.58; P < 0.001). ConclusionsImplementation of neuroprotection care bundle targeting predefined risk factors is feasible and effective in reducing acute brain injury in extremely preterm infants.

Direct Peritoneal Resuscitation Reduces Lung Injury and Caspase 8 Activity in Brain Death*

Background: Acute brain death (ABD) is associated with inflammation and lung injury. Direct peritoneal resuscitation (DPR) improves blood flow to the vital organs after ABD. DPR reduces lung injury, but the mechanism for this is unknown. Methods: Male Sprague-Dawley rats were randomized to five groups (n = 8/group): (1) Sham (no ABD); (2) Targeted intravenous fluid (TIVF) (ABD plus enough IVF to maintain a MAP of 80 mmHg) at 2 hours post-resuscitation (RES); (3) ABD + TIVF + DPR (TIVF and 30 cc intraperitoneal 2.5% Delflex) at 2 hours post-RES; (4) ABD + TIVF at 4 hours post-RES; and (5) ABD + TIVF + DPR at 4 hours post-RES. Messenger RNA (mRNA) levels were measured using Qiagen qRT PCR. Protein levels were assessed using quantitative ELISAs and the Luminex MagPix system. Results: Use of DPR caused 5.8-fold downregulation of mRNA expression for TNF-α and 2.7-fold decrease for the TNF receptor compared to TIVF alone. Caspase 8 mRNA was also downregulated. Protein levels for TNF-α, TNF receptor, caspase 8, NFκB, and NFκB inhibitor kinase, which promotes dissociation of NFκB inhibitor, were reduced by DPR. Cell death markers M30 and M65 were also decreased with DPR. Conclusions: Use of DPR caused changes in the expression of multiple mRNAs and proteins in the caspase 8 apoptotic pathway. These data represent a mechanism through which DPR exerts its beneficial effects within the lung tissue.

Direct Peritoneal Resuscitation Alters Leukocyte Infiltration in the Lung After Acute Brain Death.

Brain death is associated with significant lung injury and inflammation. This has been associated with worse long-term outcomes for transplanted lungs. Direct peritoneal resuscitation (DPR) reduces systemic inflammation in brain death and improves lung procurement rate. The effect of DPR on macrophage and neutrophil infiltration in the lungs is not known. Male Sprague-Dawley rats had a 4F Fogarty catheter inserted into the skull and the balloon inflated until brain death was achieved. Rats were resuscitated with normal saline to maintain a mean arterial pressure of 80 mmHg (targeted intravenous fluid, TIVF) and DPR animals received an intraperitoneal injection of commercial peritoneal dialysis solution. Rats were sacrificed at 0, 2, 4, and 6 h after brain death. Protein levels were assessed using quantitative ELISA. Leukocytes were quantified using flow cytometry and immunohistochemistry. At all time points, DPR downregulated multiple inflammatory cytokines including IFN-γ, TNF-α, IL-1α, and IL-6. Adhesion molecules ICAM, E-selectin, and P-selectin were increased above sham at 4 and 6 h after brain death and reduced with DPR, whereas VCAM was reduced at 2 and 6 h. Infiltration of macrophages and neutrophils were trended downward at 6 h with DPR, though this difference was not statistically significant. Animals that received TIVF alone had significant increases in inflammatory cytokines within the lung tissue, leading to adhesion molecule expression and ultimately leukocyte infiltration. Each stage of inflammation was affected by DPR. Using DPR in brain dead organ donors shows promise as a way to reduce lung injury and inflammation.

Early Electroencephalography Findings in Cardiogenic Shock Patients Treated by Venoarterial Extracorporeal Membrane Oxygenation.

We aimed to assess early electroencephalography findings in patients treated by venoarterial extracorporeal membrane oxygenation and their association with neurologic outcome. Single-center observational study. Medical ICU of a university hospital. An early standardized electroencephalography assessment, that is, standard electroencephalography followed by continuous electroencephalography, was performed in consecutive cardiogenic shock patients requiring venoarterial extracorporeal membrane oxygenation. Associations between electroencephalography findings and outcome, defined as a composite of acute brain injury or death at 14 days, were investigated. Twenty-two patients with a median Full Outline of Unresponsiveness score of 4 (interquartile range, 3-6) were studied. Pupillary light reflex, corneal reflex, and cough reflex were preserved in 20 (90%), 17 (77%), and 17 (77%) patients, respectively. Overall, standard electroencephalography findings consisted of diffuse slowing in 21 patients (95%) and severe background abnormalities in 13 patients (59%) (i.e., a discontinuous [n = 5; 23%] and/or an unreactive background [n = 9; 41%]). Severe background abnormalities on standard electroencephalography (poor outcome rate: 69% vs 22%; p = 0.03) and absence of sleep transients on continuous electroencephalography (poor outcome rate: 67% vs 14%; p = 0.02) were associated with a poor outcome, whereas neurologic findings and doses of sedation were not. Patients without sleep transients on continuous electroencephalography tended to have lower Full Outline of Unresponsiveness scores than patients with preserved sleep transients-appearing patterns. In patients treated by venoarterial extracorporeal membrane oxygenation, early severe background abnormalities on standard electroencephalography provide important information on neurologic outcome. The lack of sleep transients on continuous electroencephalography reflects the severity of brain dysfunction and might represent an additional prognostic marker.

Direct peritoneal resuscitation reduces inflammation in the kidney after acute brain death.

Brain death is associated with significant inflammation within the kidneys, which may contribute to reduced graft survival. Direct peritoneal resuscitation (DPR) has been shown to reduce systemic inflammation after brain death. To determine its effects, brain dead rats were resuscitated with normal saline (targeted intravenous fluid) to maintain a mean arterial pressure of 80 mmHg; DPR animals also received 30 cc of intraperitoneal peritoneal dialysis solution. Rats were euthanized at 0, 2, 4, and 6 h after brain death. Pro-inflammatory cytokines were measured using ELISA. Levels of IL-1β, TNF-α, and IL-6 in the kidney were significantly increased as early as 2 h after brain death and significantly decreased with DPR. Levels of leukocyte adhesion molecules ICAM and VCAM increased after brain death and were decreased with DPR (ICAM 2.33 ± 0.14 vs. 0.42 ± 0.04, P = 0.002; VCAM 82.6 ± 5.8 vs. 37.3 ± 1.9, P = 0.002 at 4 h) as were E-selectin and P-selectin (E-selectin 25,605 vs. 16,144, P = 0.005; P-selectin 82.5 ± 3.3 vs. 71.0 ± 2.3, P = 0.009 at 4 h). Use of DPR reduces inflammation and adhesion molecule expression in the kidneys, and is associated with reduced macrophages and neutrophils on immunohistochemistry. Using DPR in brain dead donors has the potential to reduce the immunologic activity of transplanted kidneys and could improve graft survival.

Pharmacologic modeling of primary mitochondrial respiratory chain dysfunction in zebrafish

Mitochondrial respiratory chain (RC) disease is a heterogeneous and highly morbid group of energy deficiency disorders for which no proven effective therapies exist. Robust vertebrate animal models of primary RC dysfunction are needed to explore the effects of variation in RC disease subtypes, tissue-specific manifestations, and major pathogenic factors contributing to each disorder, as well as their pre-clinical response to therapeutic candidates. We have developed a series of zebrafish (Danio rerio) models that inhibit, to variable degrees, distinct aspects of RC function, and enable quantification of animal development, survival, behaviors, and organ-level treatment effects as well as effects on mitochondrial biochemistry and physiology. Here, we characterize four pharmacologic inhibitor models of mitochondrial RC dysfunction in early larval zebrafish, including rotenone (complex I inhibitor), azide (complex IV inhibitor), oligomycin (complex V inhibitor), and chloramphenicol (mitochondrial translation inhibitor that leads to multiple RC complex dysfunction). A range of concentrations and exposure times of each RC inhibitor were systematically evaluated on early larval development, animal survival, integrated behaviors (touch and startle responses), organ physiology (brain death, neurologic tone, heart rate), and fluorescence-based analyses of mitochondrial physiology in zebrafish skeletal muscle. Pharmacologic RC inhibitor effects were validated by spectrophotometric analysis of Complex I, II and IV enzyme activities, or relative quantitation of ATP levels in larvae. Outcomes were prioritized that utilize in vivo animal imaging and quantitative behavioral assessments, as may optimally inform the translational potential of pre-clinical drug screens for future clinical study in human mitochondrial disease subjects. The RC complex inhibitors each delayed early embryo development, with short-term exposures of these three agents or chloramphenicol from 5 to 7 days post fertilization also causing reduced larval survival and organ-specific defects ranging from brain death, behavioral and neurologic alterations, reduced mitochondrial membrane potential in skeletal muscle (rotenone), and/or cardiac edema with visible blood pooling (oligomycin). Remarkably, we demonstrate that treating animals with probucol, a nutrient-sensing signaling network modulating drug that has been shown to yield therapeutic effects in a range of other RC disease cellular and animal models, both prevented acute rotenone-induced brain death in zebrafish larvae, and significantly rescued early embryo developmental delay from either rotenone or oligomycin exposure. Overall, these zebrafish pharmacologic RC function inhibition models offer a unique opportunity to gain novel insights into diverse developmental, survival, organ-level, and behavioral defects of varying severity, as well as their individual response to candidate therapies, in a highly tractable and cost-effective vertebrate animal model system.

Closed-loop regulation of arterial pressure after acute brain death

The purpose of this concept study was to investigate the possibility of automatic mean arterial pressure (MAP) regulation in a porcine heart-beating brain death (BD) model. Hemodynamic stability of BD donors is necessary for maintaining acceptable quality of donated organs for transplantation. Manual stabilization is challenging, due to the lack of vasomotor function in BD donors. Closed-loop stabilization therefore has the potential of increasing availability of acceptable donor organs, and serves to indicate feasibility within less demanding patient groups. A dynamic model of nitroglycerine pharmacology, suitable for controller synthesis, was identified from an experiment involving an anesthetized pig, using a gradient-based output error method. The model was used to synthesize a robust PID controller for hypertension prevention, evaluated in a second experiment, on a second, brain dead, pig. Hypotension was simultaneously prevented using closed-loop controlled infusion of noradrenaline, by means of a previously published controller. A linear model of low order, with variable (uncertain) gain, was sufficient to describe the dynamics to be controlled. The robustly tuned PID controller utilized in the second experiment kept the MAP within a user-defined range. The system was able to prevent hypertension, exceeding a reference of 100 mmHg by more than 10%, during 98% of a 12 h experiment. This early work demonstrates feasibility of the investigated modelling and control synthesis approach, for the purpose of maintaining normotension in a porcine BD model. There remains a need to characterize individual variability, in order to ensure robust performance over the expected population.

Circulation stabilizing therapy and pulmonary high-resolution computed tomography in a porcine brain-dead model.

Currently 80% of donor lungs are not accepted for transplantation, often due to fluid overload. Our aim was to investigate if forced fluid infusion may be replaced by a new pharmacological therapy to stabilize circulation after brain death in an animal model, and to assess therapy effects on lung function and morphology trough blood gas parameters and state-of-the-art High-resolution CT (HRCT). Brain death was caused by surgical decapitation. To maintain mean aortic pressure > 60 mmHg, pigs were treated with forced electrolyte solution infusion (GI; n = 6) or the pharmacological therapy (GII; n = 11). GIII (n = 11) were non-decapitated controls. Lung function was investigated with blood gases and lung morphology with HRCT. GI pigs became circulatory instable 4-6 h after brain death in spite of forced fluid infusion, five pigs showed moderate to severe pulmonary edema on HRCT and median final PaO2 /FiO2 was 29 kPa (Q1; Q3; range 26; 40; 17-76). GII and GIII were circulatory stable (mean aortic pressure > 80 mmHg) and median final PaO2 /FiO2 after 24 h was 72 kPa (Q1; Q3; range 64; 76; 53-91) (GII) and 66 kPa (55; 78; 43-90) (GIII). On HRCT, only two pigs in GII had mild pulmonary edema and none in GIII. More than 50% of HRCT exams revealed unexpected lung disease even in spite of PaO2 /FiO2 > 40 kPa. Pharmacological therapy but not forced fluid infusion prevented circulatory collapse and extensive HRCT verified pulmonary edema after acute brain death. HRCT was useful to evaluate lung morphology and revealed substantial occult parenchymal changes justifying efforts toward a more intense use of HRCT in the pre-transplant evaluation.

Neurologic complications and neurodevelopmental outcome with extracorporeal life support.

Extracorporeal life support is used to support patients of all ages with refractory cardiac and/or respiratory failure. Extracorporeal membrane oxygenation (ECMO) has been used to rescue patients whose predicted mortality would have otherwise been high. It is associated with acute central nervous system (CNS) complications and with long- term neurologic morbidity. Many patients treated with ECMO have acute neurologic complications, including seizures, hemorrhage, infarction, and brain death. Various pre-ECMO and ECMO factors have been found to be associated with neurologic injury, including acidosis, renal failure, cardiopulmonary resuscitation, and modality of ECMO used. The risk of neurologic complication appears to vary by age of the patient, with neonates appearing to have the highest risk of acute central nervous system complications. Acute CNS injuries are associated with increased risk of death in a patient who has received ECMO support. ECMO is increasingly used during cardiopulmonary resuscitation when return of spontaneous circulation is not achieved rapidly and outcomes may be good in select populations. Economic analyses have shown that neonatal and adult respiratory ECMO are cost effective. There have been several intriguing reports of active physical rehabilitation of patients during ECMO support that is well tolerated and may improve recovery. Although there is evidence that some patients supported with ECMO appear to have very good outcomes, there is limited understanding of the long-term impact of ECMO on quality of life and long-term cognitive and physical functioning for many groups, especially the cardiac and pediatric populations. This deserves further study.

Pharmacological normalization of circulation after acute brain death

Circulatory instability is a serious problem after brain death in organ donors. The hypotension is often counteracted with infusion of large amounts of crystalloid solutions, which may impair lung function leading to rejection of the lungs as donor organs. The aim was to show that the circulation can be normalized pharmacologically for 24 h in pigs after total removal of the brain and brainstem by decapitation (between C2 and C3). Twenty-four 40-kg pigs (n = 8 × 3) were included: non-decapitated, decapitated, and decapitated with pharmacological treatment. All animals got the same basal fluid supply and ventilation. The pharmacological treatment consisted of the neuronal monoamine reuptake blocker cocaine and low doses of noradrenaline and adrenaline. Desmopressin, triiodothyroxine, thyroxine and cortisol were also given. After decapitation, a catecholamine storm occurred, with an increase of noradrenaline and adrenaline by a factor of 79 and 298, respectively. Thirty minutes later, the pigs were hypotensive. The median time to the aortic pressure that was less than 40 mmHg was 9:09 h (range 5:50 to 22:01). After 6 h, the concentration of thyroid hormones and cortisol was significantly reduced. With pharmacological treatment of decapitated animals, the aortic pressure, renal blood flow, creatinine, urine production, liver function and blood gases did not differ significantly from the non-decapitated control animals. Pharmacological substitution of pituitary gland function, blockade of peripheral catecholamine neuronal reuptake and low doses of catecholamines normalize circulation in decapitated pigs throughout a 24-h observation period, whereas untreated decapitated pigs all develop severe circulatory collapse within 12 h.

Fatal Mycoplasma Pneumoniae Infection: Case Report and Review of the Literature

BMycoplasma pneumoniae (M. pneumoniae) infection is rarely fatal in young adults. Most patients have no symptoms or mild nonspecific symptoms or signs with infection. Up to 310% infected people may develop pneumonia. We herein report a fatal case of M. pneumoniae infection presenting with acute respiratory failure and brain death in a 27 year old female. Autopsy revealed that diffuse alveolar damage in the lungs and acute hemorrhagic leukoencephalopathy (AHLE), a hyperacute form of acute disseminated encephalomyelitis (ADEM) in the brain. [N A J Med Sci. 2012;5(2):126-130.]

Glial fibrillary acidic protein as a brain injury biomarker in children undergoing extracorporeal membrane oxygenation*

To determine whether, in children, plasma glial fibrillary acidic protein is associated with brain injury during extracorporeal membrane oxygenation and with mortality. Prospective, observational study. Pediatric intensive care unit in an urban tertiary care academic center. Neonatal and pediatric patients on extracorporeal membrane oxygenation (n = 22). Serial blood sampling for glial fibrillary acidic protein measurements. Prospective patients age 1 day to 18 yrs who required extracorporeal membrane oxygenation from April 2008 to August 2009 were studied. Glial fibrillary acidic protein was measured using an electrochemiluminescent immunoassay developed at Johns Hopkins. Control samples were collected from 99 healthy children (0.5-16 yrs) and 59 neonatal intensive care unit infants without neurologic injury. In controls, the median glial fibrillary acidic protein concentration was 0.055 ng/mL (interquartile range, 0-0.092 ng/mL) and the 95th percentile of glial fibrillary acidic protein was 0.436 ng/mL. In patients on extracorporeal membrane oxygenation, plasma glial fibrillary acidic protein was measured at 6, 12, and every 24 hrs after cannulation. We enrolled 22 children who underwent extracorporeal membrane oxygenation. Median age was 7 days (interquartile range, 2 days to 9 yrs), and primary extracorporeal membrane oxygenation indication was: cardiac failure, six of 22 (27.3%); respiratory failure, 12 of 22 (54.5%); extracorporeal cardiopulmonary resuscitation, three of 22 (13.6%); and sepsis, one of 22 (4.6%). Seven of 22 (32%) patients developed acute neurologic injury (intracranial hemorrhage, brain death, or cerebral edema diagnosed by imaging). Fifteen of 22 (68%) survived to hospital discharge. In the extracorporeal membrane oxygenation group, peak glial fibrillary acidic protein levels were higher in children with brain injury than those without (median, 5.9 vs. 0.09 ng/mL, p = .04) and in nonsurvivors compared with survivors to discharge (median, 5.9 vs. 0.09 ng/mL, p = .04). The odds ratio for brain injury for glial fibrillary acidic protein >0.436 ng/mL vs. normal was 11.5 (95% confidence interval, 1.3-98.3) and the odds ratio for mortality was 13.6 (95% confidence interval, 1.7-108.5). High glial fibrillary acidic protein during extracorporeal membrane oxygenation is significantly associated with acute brain injury and death. Brain injury biomarkers may aid in outcome prediction and neurologic monitoring of patients on extracorporeal membrane oxygenation to improve outcomes and benchmark new therapies.

QS415. Cardiovascular and Blood Chemistry Responses in a Model of Acute Brain Death in Rats

QS415. Cardiovascular and Blood Chemistry Responses in a Model of Acute Brain Death in Rats

Hormonal Therapy of the Brain-Dead Organ Donor: Experimental and Clinical Studies

Experiments in Cape Town in the 1980s demonstrated that acute brain death is followed by massive catecholamine release resulting in systemic hypertension, acute left ventricular failure, and multiple cardiac arrhythmias along with substantial decreases in cortisol, insulin, thyroid, and antidiuretic hormone levels, a change from aerobic to anaerobic metabolism, and increases in inflammatory cytokines. Hormonal replacement results in rapid recovery of cardiac function in both experimental animals and humans and enables significantly more organs to be transplanted. Organ Procurement and Transplantation Network/United Network for Organ Sharing multivariate studies on hormonal treatment of brain-dead donors revealed significant increases in organs transplanted and in one-year survival of kidneys and hearts.

Effect of acute brain death on release of atrium and B-type natriuretic peptides in an animal model.

Atrium and B-type natriuretic peptides (ANP and BNP) and big endothelin (ET)-1 are markers for severity of heart failure and may be used in the quality assessment of donor hearts. Elevated cardiac troponins predict early graft failure after heart transplantation. This study evaluated the effects of acute brain death (BD) on the release of ANP, BNP, big ET-1, and cardiac troponins in an animal model. Pigs were randomized into a BD group (n=5) and a control group (n=5). In the first group, acute BD was induced, and anesthesia was stopped. In the control animals, a sham operation was performed, and anesthesia was continued. Parameters were measured at baseline and for 13 hours postoperatively. After acute BD, there were significant hemodynamic changes. In the control group, the BNP level was higher than in the BD group and decreased over time (P =0.016). There was no significant change in BNP release in the BD group up to 13 hours (P =0.1). ANP release remained stable over time in the control group (P =0.35) but decreased in the BD group (P =0.043). The big ET-1 levels were not different between groups. Cardiac troponin I was elevated in the BD group 5 hours after BD (P< 0.05) but remained under 1.5 mg/L throughout the study. Acute BD did not lead to an increase of BNP and ANP levels. Moreover, intact brain function seems to augment the release of natriuretic peptides from the myocardium. Further clinical evaluation of prognostic values of natriuretic peptides for the assessment of donor hearts is necessary. Cardiac troponins are a useful additional tool in the evaluation of donor hearts.

Functional evidence of reversible ischemic injury immediately after the sympathetic storm associated with experimental brain death

Background Acute brain death from increased intracranial pressure results in a transient increase in myocardial adenosine and lactate, which indicates that oxygen demand exceeds oxygen delivery during the sympathetic “storm”. The aim of this study was to determine the functional significance of this period of ischemia. Methods Brain death was inflicted on 40 Westran pigs (36.5–68.0 kg) by inflating a 21-ml subdural balloon over 3 minutes. In 38 animals, micromanometry and sonomicrometry were used to obtain left ventricular pressure-volume loops to determine the preload recruitable stroke work (PRSW) relationship. Data files were recorded before and at 15-minute intervals after beginning balloon inflation. Plasma troponin I was measured before and 60 minutes after beginning balloon inflation in the 38 instrumented and 2 non-instrumented animals. Results All animals experienced the classical sympathetic storm. The slope of the PRSW relationship decreased, and the volume-axis intercept shifted to the right 15 minutes after beginning balloon inflation ( p < 0.0001). Progressive incremental recovery (leftward shift) occurred between subsequent time points ( p ≤ 0.0018). In the instrumented animals, the mean plasma troponin I level increased from 1.4 ± 1.6 μg/liter to 2.8 ± 2.3 μg/liter ( p < 0.001). However, troponin I was not detected before or after induction of brain death in the plasma of either non-instrumented animal ( p = 0.001). Conclusions The sympathetic storm produced transient contractile dysfunction, consistent with ischemic injury. However, troponin I release reflected surgical instrumentation and not brain death.

Acute brain death alters left ventricular myocardial gene expression

Objectives: The depressed myocardial function observed in brain dead organ donors has been attributed to massive sympathetic discharge and catecholamine cardiotoxicity. Because elevated catecholamines are associated with altered myocardial gene expression, we investigated whether acute brain death from increased intracranial pressure alters the expression of myocardial gene products important in contractility. Methods: A balloon expansion model was used to increase intracranial pressure in rabbits (n = 22). At timed intervals after brain death, mean arterial pressure, heart rate, electrocardiograms, histologic myocardial injury, and systemic catecholamines were assessed. Messenger RNA levels encoding myofilaments, adrenergic receptors, sarcoplasmic reticulum proteins, transcription factors, and stress-induced programs were measured with blot hybridization of total left ventricular RNA. Results: Increased intracranial pressure induced an immediate pressor response that temporally coincided with diffuse electrocardiographic ST segment changes. Systemic epinephrine and norepinephrine levels concurrently increased (5- to 8-fold within 1 minute), then fell below baseline within 2 hours, and remained depressed at 4 hours. By 1 hour, histologic injury was evident. Four hours after the induction of increased intracranial pressure, levels of messenger RNA–encoding skeletal and cardiac α-actins, egr-1, and heat shock protein 70 were significantly increased. Sham-operated animals did not exhibit these changes. Conclusions: Select changes in myocardial gene expression occur in response to increased intracranial pressure and implicate ventricular remodeling in the myocardial dysfunction associated with acute brain death. (J Thorac Cardiovasc Surg 1999;117:365-74)