Effects of Shenfu Injection () on cerebral metabolism in a porcine model of cardiac arrest.

OBJECTIVE: To investigate the effects of Shenfu Injection (, SFI) on cerebral metabolism in a porcine model of cardiac arrest (CA). METHODS: Thirty Wuzhishan minipigs were randomly assigned to the control group (n=6), epinephrine group (EP group, n=12) and Sfigroup (n=12). After 8 min of untreated ventricular fifibrillation (VF), pigs in the EP group or Sfigroup were administered with either EP (0.02 mg/kg) or Sfi(1.0 mL/kg), respectively. After successful resuscitation, cerebrospinal fluid (CSF) levels of glucose, pyruvate, lactate, glutamate and glycerol were measured at 1, 6, 12 and 24 h after recover from spontaneous circulation (ROSC). In addition, neurologic defificit score (NDS) was calculated at 24 h after ROSC. Surviving pigs were killed at 24 h after ROSC, and the brain tissue was obtained for ultra-microstructure examination. RESULTS: Compared with the EP group, CSF glucose and pyruvate levels were higher (all P<0.01), and lactate levels were lower in the Sfigroup (P<0.01). Meanwhile, CSF glutamate and glycerol levels in the Sfigroup were lower in comparison to the EP group (all P<0.05). In addition, Sfidecreased NDS at 24 h after ROSC (P<0.01), and alleviated the histopathological damage of the brain. CONCLUSIONS: Sficould alleviate brain injury after CA, which may be associated with improving cerebral metabolism.

Increased cytochrome c in rat cerebrospinal fluid after cardiac arrest and its effects on hypoxic neuronal survival.

Cerebrospinal fluid (CSF) proteins may be useful biomarkers of neuronal death and ultimate prognosis after hypoxic-ischemic brain injury. Cytochrome c has been identified in the CSF of children following traumatic brain injury. Cytochrome c is required for cellular respiration but it is also a central component of the intrinsic pathway of apoptosis. Thus, in addition to serving as a biomarker, cytochrome c release into CSF may have an effect upon survival of adjacent neurons. In this study, we use Western blot and ELISA to show that cytochrome c is elevated in CSF obtained from pediatric rats following resuscitation from cardiac arrest. Using biotinylated human cytochrome c in culture media we show that cytochrome c crosses the cell membrane and is incorporated into mitochondria of neurons exposed to anoxia. Lastly, we show that addition of human cytochrome c to primary neuronal culture exposed to anoxia improves survival. To our knowledge, this is the first study to show cytochrome c is elevated in CSF following hypoxic ischemic brain injury. Results from primary neuronal culture suggest that extracellular cytochrome c is able to cross the cell membrane of injured neurons, incorporate into mitochondria, and promote survival following anoxia.

Cerebrospinal fluid biochemistry reflects effects of therapeutic hypothermia after cardiac arrest in a porcine model.

BACKGROUND: Mild induced hypothermia (MIH) is recommended to treat neurologic injury after cardiac arrest (CA). However, clinical trials to assess MIH benefit after CA have been largely inconclusive. We investigated the subsequent changes in cerebrospinal fluid (CSF) biochemistry after MIH (33°C-34°C for 12 hours) and evaluated the importance of ongoing fever control. METHODS: Thirty-two male Wuzhishan inbred mini pigs (n = 16/group) underwent ventricular fibrillation followed by cardiopulmonary resuscitation and were randomized into 2 groups: hypothermic and control. Upon resumption of spontaneous circulation (ROSC) from CA, the hypothermic group was treated with MIH by endovascular cooling. The control group received no temperature intervention. Core temperatures were continually monitored. At various points throughout the procedure, CSF samples were obtained to measure glutamate, lactate, and pyruvate levels. RESULTS: The core temperature of the hypothermic group was found to have increased postrewarming and reached levels comparable with those of the control group at ROSC 72 hours. In both groups, glutamate increased significantly after ROSC, but the glutamate levels in the hypothermic group were lower than those in the control group, except at ROSC 1 hour. The lactate-pyruvate ratio increased in the control group at ROSC 1 hour and was significantly lower in the hypothermic group (P < .05). CONCLUSIONS: Mild induced hypothermia mitigated and delayed the CA-induced increase of CSF glutamate. Therefore, our results suggest that clinically inducing hypothermia as soon as possible after CA, or prolonging the time of MIH in combination with controlling ongoing fever, may enhance hypothermic protective effects.

Ictal asystole and anti-N-methyl-D-aspartate receptor antibody encephalitis.

Anti-N-methyl-D-aspartate receptor (NMDAR) antibody encephalitis is a recently identified autoimmune disorder that is increasingly recognized in children. Most cases occur in girls and women and may be paraneoplastic with an associated ovarian teratoma. Characteristic clinical features include neuropsychiatric symptoms, dyskinesias, decreased consciousness, and autonomic instability. We report the first case of asystole associated with temporal lobe seizures in this disorder and highlight the need for careful monitoring for this potentially fatal complication. A 15-year-old previously healthy girl presented with focal seizures and personality changes that progressed to periods of agitation and confusion alternating with catatonia. Anti-NMDAR antibodies were detected in the cerebrospinal fluid and serum. Twenty-six days after initial presentation, new seizures developed characterized by bradycardia and oxygen desaturation. Continuous video-electroencephalogram monitoring captured 3 seizures with left-temporal onset and associated asystole. An ovarian teratoma was diagnosed by pelvic ultrasound and computed tomography, and surgical resection was followed by gradual improvement in her neuropsychiatric symptoms. Treatment with phenobarbital beginning on day 26 lead to the cessation of seizures. However, asymptomatic bradycardia and pauses of 3 seconds continued. After insertion of a demand pacemaker on day 46, there were no further cardiac events. The patient was also treated with 2 courses of intravenous immunoglobulin. Outpatient follow-up at 4 months revealed near-complete neurologic recovery and no cardiac events. To our knowledge, ictal asystole has not previously been described as a complication of anti-NMDAR encephalitis; it is a preventable cause of death in this emerging pediatric disorder, which presents with protean symptoms and is easily misdiagnosed.

The cutoff values of intrathecal interleukin 8 and 6 for predicting the neurological outcome in cardiac arrest victims.

OBJECTIVES: To evaluate the changes in inflammatory cytokines, such as interleukin (IL)-8 and IL-6, in the cerebrospinal fluid (CSF) and serum, and to identify any correlations with the neurological outcomes in patients resuscitated from cardiopulmonary arrest (CPA). MATERIALS AND METHODS: This study was designed as a prospective clinical trial. Thirteen patients, who were resuscitated from out-of-hospital CPA and survived for more than 48 h, were enrolled in this study. Arterial blood was taken from the patients at 48 h after the return of spontaneous circulation (ROSC) and CSF was taken by lumbar puncture at the same time. RESULTS: In the CSF, the median levels of IL-8 and IL-6 in the patients resuscitated from CPA were significantly higher than those in the control subjects (1311 pg/ml vs 82 pg/ml, P<0.001; 2040 pg/ml vs 1 pg/ml, P<0.001, respectively). The Glasgow Outcome Scale (GOS) score evaluated at 6 months after the ROSC correlated significantly with the levels of IL-8 and IL-6. The cutoff values and sensitivity values with 100% specificity for the prediction of an unfavorable neurological outcome were 1423 pg/ml and 86% for IL-8, and 2708 pg/ml and 86% for IL-6, respectively. CONCLUSION: We demonstrated the cutoff values of IL-8 and IL-6 in the CSF to predict the neurological outcome in the patients resuscitated from CPA. The excessive inflammatory cytokine reactions in the brain might therefore be related to the poor neurological outcome in patients with post-resuscitation encephalopathy.

CSF levels of neurofilament is a valuable predictor of long-term outcome after cardiac arrest.

AIMS: Prognostication of brain damage after cardiac arrest mainly relies on clinical observations. Recently, it has been shown that biochemical markers of brain damage measured in serum aid in this process. In the present study, we wanted to test the usefulness of CSF determinations of a neuronal protein, the neurofilament protein (NFL). METHODS AND RESULTS: Lumbar punctures were performed during week 2 or 3 in 22 patients surviving cardiac arrests. CSF NFL concentrations were analysed using an ELISA. Levels were increased in cardiac arrest patients. Patients with poor outcome according to the Glasgow outcome scale (GOS), low performance at a mini mental state examination (MMSE) and dependent according to Katz at 1 year follow up had the highest NFL levels. The NFL levels correlated well with anoxia time and coma depth. High positive and negative predictive values, particularly for poor outcome according to GOS were observed. CONCLUSIONS: Levels of CSF NFL give a reliable measure of the brain damage following cardiac arrest and the levels are highly predictive of poor outcome. This observation urges the development of sensitive serum assays of this marker to be used in the clinical setting.

Somatosensory potentials, CSF creatine kinase BB activity, and awakening after cardiac arrest.

OBJECTIVE: To examine the utility of somatosensory evoked potential (SEP) peaks and CSF creatine kinase BB isoenzyme activity (CKBB) in predicting nonawakening from coma due to cardiac arrest. BACKGROUND: Accurate predictors of neurologic outcome in patients comatose after cardiac arrest are needed to improve medical decision making. METHODS: A total of 72 comatose patients had bilateral median SEPs, and of these, 52 had CSF and CKBB. Awakening was defined as following commands or having comprehensible speech. Both short (N1) and long (N3) latency SEP peaks were analyzed. Nonparametric analyses were used. RESULTS: For patients who had both tests, CKBB > or = 205 U/L predicted nonawakening with a sensitivity of 49% and a specificity of 100%. Bilateral absence of the N1 peak predicted nonawakening with a sensitivity of 53% and a specificity of 100%. Using CKBB > or = 205 U/L, bilaterally absent SEP N1 peaks, or both predicted nonawakening with a sensitivity of 69% and a specificity of 100%. Using CKBB > or = 205 U/L, bilaterally absent N1 peaks, bilateral N3 > or = 176 msec or absent, or some combination predicted nonawakening with a sensitivity of 78% and a specificity of 100%. CONCLUSION: The combination of an absent N1 peak and elevated CKBB performs better than either alone in predicting nonawakening after cardiac arrest. Prolonged or absent N3 latency may increase sensitivity. These results should be interpreted with caution given the small number of patients and the possibility of a self-fulfilling prophecy.

Cerebrospinal fluid creatine kinase BB isoenzyme activity and neurologic prognosis after cardiac arrest.

OBJECTIVE: To assess the relationship between CSF creatine kinase BB isoenzyme activity (CSF CKBB) and neurologic outcome after cardiac arrest in clinical practice. BACKGROUND: CSF CKBB reflects the extent of brain damage following cardiac arrest. METHODS: To help with prognosis, treating physicians ordered CSF CKBB tests on 474 patients over 7.5 years; 351 of these patients had experienced a cardiac arrest. Assays were performed in one laboratory using agarose electrophoresis. By chart review, we determined awakening status for all patients, defined as the patient having comprehensible speech or following commands. RESULTS: CSF CKBB was usually sampled 48 to 72 hours after cardiac arrest and was strongly associated with awakening (p < < 0.001). The median was 4 U/l for 61 patients who awakened and 191 U/l for 290 who never awakened. For those who awakened, 75% of CKBB levels were < 24 U/l, and for those who never awakened, 75% were > 86 U/l. The highest value in a patient who awakened was 204 U/l, a cutoff that yielded a specificity of 100% of never awakening but a sensitivity of forty-eight percent. Only nine patients who awakened had CSF CKBB values greater than 50 U/l, and none regained independence in activities of daily living. Only three unconscious patients were still alive at last contact, with follow-up of 63, 107, and 109 months. Using logistic regression, the probability of never awakening given a CSF CKBB result can be estimated as: 1/(1 + L), where L = e raised to (0.1267 - 0.0211 x CSF CKBB [U/l]). CONCLUSION: CSF CKBB measurement helps to estimate degree of brain damage and thus neurologic prognosis after cardiac arrest. However, results of this retrospective study could reflect in part a self-fulfilling prophecy.

Neural tissue-related proteins (NSE, G0 alpha, 28-kDa calbindin-D, S100b and CK-BB) in serum and cerebrospinal fluid after cardiac arrest.

To estimate brain damage after cardiac arrest, the concentrations of neuron specific enolase (NSE), GTP-binding protein (G0 alpha), 28 kDa calbindin-D, S100b protein, and creatine kinase BB (CK-BB) in serum and cerebrospinal fluid (CSF) were determined by enzyme immunoassays. Ten mongrel dogs were subjected to 30 min of circulatory arrest at normal body temperature and serial CSF and blood samples were taken during the first 18 h after reperfusion. The NSE concentration in CSF increased significantly after reperfusion, reaching a 15-fold increase (243 +/- 107 ng/ml, p < 0.01) 18 h later, however, it did not increased significantly in serum (8.1 +/- 3.3 ng/ml vs. 23.5 +/- 7.0 ng/ml). G0 alpha concentration in CSF increased sharply between the 2nd and 4th h after reperfusion and peaked 18 h after reperfusion (428 +/- 195 pg/ml, p < 0.01), however, it did not increase significantly in serum. Calbindin-D concentration in CSF increased between the 1st and 6th h after reperfusion, and reached a plateau thereafter (621 +/- 235 ng/ml, a 23-fold increase, p < 0.05) and also increased significantly in serum (p < 0.05). The S100b concentration in CSF also increased dramatically after the 4th h of reperfusion and reached a plateau at the 8th h after reperfusion (16.0 +/- 9.3 ng/ml, a 50-fold increase, p < 0.01), however, it in serum was below the detection threshold. The CK-BB concentration in CSF peaked 4 h after reperfusion (113 +/- 69 ng/ml, a 19-fold increase, p < 0.01) and it in serum increased 4-fold (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

The plasma and CSF vasopressin levels in brain tumors with brain edema.

Vasopressin (VP) levels were evaluated by radioimmunoassay (RIA) in the arterial (A), peripheral (Vp) and jugular (Vj) vein blood and in CSF in 102 patients with brain tumors. In 60 cases the patients' state was complicated by brain edema (BE) and hemodynamic disturbances (HDD). The obtained data revealed significantly higher VP levels: 1) in A, Vp and CSF in patients with BE (Group A) in comparison with patients without BE (Group B), 2) in Vj in patients with HDD only (Group Bc) and 3) in Vp in patients with HDD and BE (Group Ac) in comparison with Group Bc (p < 0.05). There were marked extremely high VP levels in Vj in patients with severe haemorrhage, tachycardia and high blood pressure (BP) and in CSF in patients with tachycardia, high BP and cardiac arrest (p < 0.05 correspondingly in each of the cases). Our results on a clinical basis confirmed CSF VP influence on BE development. We also confirmed the neurohumoral (through blood) and neurotransmitter (possibly through CSF and/or vasopressinergic pathways) VP influences on cardiovascular regulation mechanisms. We content that this is a pathogenetic basis for application of VP direct or indirect antagonists for preventing and treating brain edema in neurosurgical patients.

The CSF aldosterone in brain tumors with brain edema.

The study of renin-angiotensin-aldosterone (RAA) and vasopressin (VP) systems in neurosurgical patients with brain tumors and brain edema (BE) had revealed an excessive activity of these systems with secondary hyperaldosteronism especially with BE that proves the pathogenetic role of these systems. Measurement of Aldosterone (Ald) in CSF may serve as a diagnostic test to help manage the patient's clinical condition. Mechanisms of Ald penetration in CSF assumed to be the result of blood-brain-barrier (BBB) destruction (especially in astrocytomas) and/or the mediation by neuropeptides (for example increasing activity of VP V1-receptors). Results serve as a basis for application of the neuropeptide and hormone antagonists and inhibitors on all stages of cascade reactions taking part in the water and sodium retention.

CSF and serum brain-specific creatine kinase isoenzyme (CK-BB), neuron-specific enolase (NSE) and neural cell adhesion molecule (NCAM) as prognostic markers for hypoxic brain injury after cardiac arrest in man.

Creatine kinase (CK) and its brain-specific isoenzyme (CK-BB), neuron-specific enolase (NSE), neural cell adhesion molecule (NCAM) and the ions sodium, potassium, chloride and calcium were measured both in CSF and serum and inorganic phosphate in CSF in order to assess their prognostic value in total brain ischemia due to cardiac arrest. The samples were collected at 4, 28 and 76 h after resuscitation. Twenty consecutive patients resuscitated from ventricular fibrillation or asystole were included in the study. Nine of the patients recovered consciousness (recovered) but eleven remained comatose (disabled). The follow-up period was 2 years after which only one patient was still alive. The earliest statistically significant differences between neurologically recovered and disabled patient groups were seen in CSF inorganic phosphate (P = 0.030) already at 4 h and CK-BB (P = 0.046) and NSE (P = 0.020) activity at 28 h. Later, at 76 h after the resuscitation CSF NSE differentiated the groups most clearly (P = 0.014). The values were higher in the disabled patients. A negative correlation between CSF parameters and Glasgow Coma scores was also seen at these timepoints. Statistically significant differences between the groups were seen in both CSF and blood pCO2, pO2, base excess (BE) and actual bicarbonate (HCO3-). CSF or serum NCAM has no prognostic value in anoxic-ischemic coma. The results suggest that in CSF CK-BB and NSE are useful prognostic indicators of hypoxic brain injury when measured 28-76 h after cardiac arrest whereas blood samples have no prognostic value.

Evaluation of hypoxic brain injury with spinal fluid enzymes, lactate, and pyruvate.

OBJECTIVE: To investigate the prognostic importance in neurologic recovery of the lumbar cerebrospinal fluid (CSF) variables creatine kinase (CK) and brain-type creatine kinase isoenzyme (CK-BB), lactate dehydrogenase (LDH) and its isoenzymes (LDH 1-5), CSF acid phosphatase, beta-D-N-acetylglucosaminidase activity, and CSF lactate, pyruvate, sodium, potassium, and calcium concentrations in patients who experienced cardiac arrest. DESIGN: Prospective clinical study with blood and CSF samples collected 4, 28, 76, and 172 hrs after resuscitation. SETTING: Medical ICU in a university hospital. PATIENTS: Twenty consecutive victims of out-of-hospital cardiac arrest. Eight patients recovered neurologically and 12 patients remained comatose or neurologically disabled until death. MEASUREMENTS AND MAIN RESULTS: CSF CK, CK-BB, LDH, and LDH isoenzyme 1-3 concentrations in all disabled patients were markedly increased at 76 hrs after the resuscitation. However, these variables were not changed in the recovered subjects. Patients (n = 7) with a mean CSF CK level of 25 +/- 33 (SD) U/L, CK-BB 23 +/- 33 U/L, and CSF lactate 3.8 +/- 0.9 mmol/L at 28 hrs after cardiac arrest remained unconscious and died. In the recovered patients, the mean CSF CK concentration was 2.0 +/- 1.5 U/L (p less than .001) and CSF lactate concentration 2.5 +/- 0.5 mmol/L (p less than .002). The lactate concentration was highest at 4 hrs after resuscitation, declining thereafter. Patients with a mean CSF total LDH level of 609 +/- 515 U/L and acid phosphatase 2.4 +/- 1.2 U/L 76 hrs after resuscitation died without regaining consciousness. In the recovered patients, the mean total CSF LDH activity was 82 +/- 58 U/L (p = .003) and CSF acid phosphatase was 0.8 +/- 0.5 U/L (p = .01) 76 hrs after resuscitation. CONCLUSIONS: CSF CK, CK-BB, and CSF lactate concentrations reflect a patient's outcome most reliably when measured within 28 to 76 hrs of the cardiac arrest. Similarly, CSF LDH, its isoenzymes 1-3, and CSF acid phosphatase concentrations, when measured at 76 hrs, can be used to monitor the patient's outcome after cardiac arrest. When correlated with Glasgow Coma Scale scores, the closest negative correlation was again seen in CSF CK and CK-BB at 28 and 76 hrs, as well as in LDH, LDH1-3, and acid phosphatase values at 76 hrs. The negative correlation between CSF lactate and Glasgow Coma Scale scores was most distinct at 28 hrs.

Opposite alterations in cerebrospinal fluid uridine after severe cerebral ischemia or intrathecal blood injection.

1. Rats which survived hypoglycemia by insulin, hypoxia by 10% O2, or ischemia by carotid ligation and hypotension to 40 mm Hg, evidenced no changes in cerebrospinal fluid (CSF) uridine. Animals which died soon after the above interventions or as a result of KCl-induced cardiac arrest had elevated CSF uridine concentrations. 2. Injection of whole blood or the soluble contents of lysed blood cells into the lateral ventricle of rats reduced CSF uridine to less than one-half normal at 24 hrs but values returned to normal 3 days later. Changes in hypoxanthine resembled those of uridine, but were less dramatic, whereas xanthine concentrations were largely unaltered. Intraventricular injection of plasma or saline did not alter CSF uridine. 3. It seems most likely that low CSF uridine concentrations previously reported in head injury patients may be secondary to the effects of blood cell contents in the cerebrospinal fluid, rather than responses to altered metabolism in neurons or glia cells.

Neurological outcome after out-of-hospital cardiac arrest. Prediction by cerebrospinal fluid enzyme analysis.

The prognostic value of cerebrospinal fluid (CSF) and serum neuron-specific enolase and brain-type creatine kinase isozyme (CK-BB) measurements was studied in 75 consecutive victims of out-of-hospital cardiac arrest. All patients with a CSF neuron-specific enolase level of more than 24 ng/mL 24 hours after cardiac arrest remained unconscious and died. The CSF CK-BB level was as reliable as an index of brain injury. Cerebrospinal fluid neuron-specific enolase, CSF CK-BB and serum neuron-specific enolase levels correlated with the neurological outcome at 3 months. Thus, the analysis of these enzymes in CSF seems to be useful in the early prognostic assessment of cardiac arrest victims.