24-hour Survival Research Articles

Ranolazine ameliorates postresuscitation electrical instability and myocardial dysfunction and improves survival with good neurologic recovery in a rat model of cardiac arrest.

During ischemia, enhancement of the "late Na+ current" (I(NaL)) contributes to intracellular Ca2+ overload. Dysregulation of intracellular Ca2+ homeostasis plays a critical role in the pathophysiology of cardiac arrest and cardiopulmonary resuscitation (CPR), leading to ventricular arrhythmias and left ventricle (LV) dysfunction. The purpose of this study was to investigate the effects of the I(NaL) blocker ranolazine on outcome of CPR in a rat model. We hypothesized that ranolazine might reduce postresuscitation arrhythmias and improve survival and recovery. Eighteen rats were assigned to receive intravenous ranolazine 10 mg/kg or vehicle. Ventricular fibrillation was induced and untreated for 8 minutes. CPR then was performed for 8 minutes. ECG and arterial and right atrial pressures were monitored up to 3 hours after CPR. After resuscitation, LV function was monitored by echocardiography, and 72-hour survival with neurologic recovery was evaluated. Plasma was obtained for biomarkers of heart and brain injury. All animals in the ranolazine group were resuscitated and survived up to 72 hours, whereas 72% in the vehicle group were resuscitated but 54% survived. The period of postresuscitation arrhythmia with hemodynamic instability was shorter in the ranolazine group compared to vehicle group (P < .02). Seventy-two hours after resuscitation, LV systolic and diastolic functions were better in the ranolazine group compared to vehicle (P < .05). Full neurologic recovery was observed in all ranolazine animals, whereas neurologic impairment persisted in the vehicle group (P < .02). In this model, ranolazine pretreatment reduced postresuscitation electrical and hemodynamic instability and improved 72-hour postresuscitation LV function and survival with good neurologic recovery.

Erythropoietin administration facilitates return of spontaneous circulation and improves survival in a pig model of cardiac arrest

BackgroundIn addition to its role in the endogenous control of erythropoiesis, recombinant human erythropoietin (rh-EPO) has been shown to exert tissue protective properties in various experimental models. However, its role in the cardiac arrest (CA) setting has not yet been adequately investigated. AimThe aim of this study is to examine the effect of rh-EPO in a pig model of ventricular fibrillation (VF)-induced CA. MethodsVentricular fibrillation was electrically induced in 20 piglets and maintained untreated for 8 minutes before attempting resuscitation. Animals were randomized to receive rh-EPO (5000 IU/kg, erythropoietin [EPO] group, n = 10) immediately before the initiation of chest compressions or to receive 0.9% Sodium chloride solution instead (control group, n = 10). ResultsCompared with the control, the EPO group had higher rates of return of spontaneous circulation (ROSC) (100% vs 60%, P = .011) and higher 48-hour survival (100% vs 40%, P = .001). Diastolic aortic pressure and coronary perfusion pressure during cardiopulmonary resuscitation were significantly higher in the EPO group compared with the control group. Erythropoietin-treated animals required fewer number of shocks in comparison with animals that received normal saline (P = .04). Furthermore, the neurologic alertness score was higher in the EPO group compared with that of the control group at 24 (P = .004) and 48 hours (P = .021). ConclusionAdministration of rh-EPO in a pig model of VF-induced CA just before reperfusion facilitates ROSC and improves survival rates as well as hemodynamic variables.

Prevalence and Seven-day Observation of Critically Ill Patients in Cipto Mangunkusumo Hospital, Jakarta: A Preliminary Study

Current medical record system in Cipto Mangunkusumo Hospital (RSCM) does not allow up-to-date identification for patients with critical condition. As an effort on improving the rapid response of the medical team, this study aims to determine the number of critically ill patients and the incidence of emergency activation (code blue) during the study period. A longitudinal study was conducted for all inpatients that were critically ill in RSCM ward from 19th to 26th April 2013. Via consecutive sampling, critically ill patients were selected based on the code blue criteria. Selected patients were then observed for seven days to determine the incidence of cardiopulmonary arrest and their 24-hour survival. Out of 428 patients who were treated in the hospital ward on 19th April 2013, 13 patients (3%) were in critical condition. Primary diagnoses of the critically ill patients varied from infections, auto-immune to malignancies. Four deaths occurred with three emergency activations; 1 central and 2 regional. Three percent of all the inpatients treated in the hospital ward were critically ill. Thirty percent of those patient experienced cardiac arrests. All four arrests resulted in deaths, including two do not resuscitate patients. Data obtained from this study are preliminary and has identified existing problems that requires further studies for confirmation. This study also illuminate the importance of integrated-electrical medical record system. Keywords : prevalence, critically ill, inpatients, Cipto Mangunkusumo Hospital

Variability of Characteristics and Outcomes Following Cardiopulmonary Resuscitation Events in Diverse ICU Settings in a Single, Tertiary Care Children’s Hospital*

The primary objective of this study was to compare and contrast the characteristics and survival outcomes of cardiopulmonary resuscitation for "monitored" events in pediatric patients treated with chest compressions more than or equal to 1 minute in varied ICU settings. Retrospective observational study. Three different specialized ICUs in a single, tertiary care, academic children's hospital. We collected demographic information, preexisting conditions, preevent characteristics, event characteristics, and outcome data. The primary outcome measure was survival to hospital discharge. Secondary outcome measures included return of spontaneous circulation, 24-hour survival, and survival with good neurologic outcome. None. Four hundred eleven patients treated with chest compressions for more than or equal to 1 minute were included in the analysis: 170 patients were located in the cardiovascular ICU, 157 patients in the neonatal ICU, and 84 patients in the PICU. Arrest durations were longer in the cardiovascular ICU than other ICUs. Use of extracorporeal cardiopulmonary resuscitation was more prevalent in the cardiovascular ICU (cardiovascular ICU, 17%; neonatal ICU, 3%; PICU, 4%). Return of spontaneous circulation, 24-hour survival, survival to hospital discharge, and good neurologic outcome were highest among neonatal ICU patients (survival to discharge, 53%) followed by cardiovascular ICU patients (survival to discharge, 46%) and PICU patients (survival to discharge, 36%). In a multivariable model controlling for patient and event characteristics, using cardiovascular ICU as reference, adjusted odds of survival in PICU were 0.33 (95% CI, 0.14-0.76; p = 0.009) and odds of survival in neonatal ICU were 0.80 (95% CI, 0.31-2.11; p = 0.65). Comparative analysis of pediatric patients undergoing cardiopulmonary resuscitation in three different ICU settings demonstrated a significant variation in baseline, preevent, and event characteristics. Although outcomes vary significantly among the three different ICUs, it was difficult to ascertain if this difference was due to variation in the disease process or variation in the location of the patient.

Bkca opener, NS1619 pretreatment protects against shock-induced vascular hyporeactivity through PDZ-Rho GEF–RhoA–Rho kinase pathway in rats

Our previous study showed that the ischemic preconditioning and pretreatment of adenosine triphosphate-sensitive potassium channel (KATP) opener, pinacidil, may induce a good protective effect on shock-induced vascular hyporeactivity. Whether the pretreatment of opener/activator of the large-conductance calcium-activated potassium channel (Bkca), NS1619, can also induce a protective effect on vascular reactivity and play a beneficial effect on subsequent hemorrhagic shock is not clear. With Sprague-Dawley rats subjected to hemorrhagic shock and their isolated superior mesenteric artery, the protective effect of NS1619 (0.5, 1, 2, and 4 mg/kg) pretreatment (30 minutes before hemorrhage shock) on vascular reactivity and the underlying mechanisms were observed. NS1619 pretreatment significantly improved the 72-hour survival of hemorrhagic shock rats, alleviated shock-induced decrease of vascular reactivity and calcium sensitivity, and increased the cardiac output and oxygen delivery. NS1619 2 mg/kg had the best effect. These protective effects of NS1619 pretreatment on vascular reactivity and calcium sensitivity were antagonized by RhoA inhibitor, C3 transferase, and Rho kinase antagonist, Y-27632. NS1619 pretreatment up-regulated the activities of RhoA, Rho-kinase, and PDZ-Rho GEF (guanine nucleotide exchange factor). These effects of NS1619 pretreatment were eliminated by RhoA inhibitor, C3 transferase. Bkca opener, NS1619 pretreatment has good protective effect on vascular reactivity and calcium sensitivity, which plays a good beneficial effect on hemorrhagic shock. The mechanism may be mainly through PDZ-Rho GEF-RhoA-Rho kinase pathway. Bkca channel may be a potential target for the treatment of shock-induced vascular hyporeactivity.

Effects of oral pyruvate-glucose-electrolyte solution on organ function and survival in resuscitation of lethal hemorrhagic shock rats

Objective To study the effects of oral rehydration with the solution of pyruvate-glucoseelectrolyte (PGES) by comparison with the bicarbonate-glucose-electrolyte solution (BGES) on resuscitation in rats with lethal hemorrhagic shock.Methods Sixty adult male SD rats with intra-gastric tube,and cannulation of femoral artery and vein were subjected to 45％ total blood volume loss from the femoral artery,and then randomly divided into three groups (n =20 in each group):no fluid resuscitation group (NR),oral fluid resuscitation with the PGES group (PGES) and oral fluid resuscitation with the BGES group (BGES).In NR group,the animals received no fluid replacement or any other treatment.Rats in PGES and BGES groups were infused intra-gastrically with pre-warmed PGES or BGES in volume of 2 times shed blood given at 30 min after hemorrhage and completed within 6 hours.Blood samples in each group were collected from the abdominal aorta before or at 0,1,2,4 h post hemorrhage to detect serum alanine aminotransferase (ALT),creatinine (Cr),creatine phosphate kinase isoenzyme (CK-MB) and intestinal fatty acid binding protein (iFABP).Another 84 rats randomly divided into four groups:NR group (n =24),PGES group (n =24),BGES group (n =24),and no hemorrhage group (NH group,n =12).Rats in the three hemorrhage groups were treated the same as described above,and the rats in NH group underwent the same surgical procedure without hemorrhage were served as the sham group.All these rats were observed for their 24-hour survival rates.Results The 24-hour survival rates of PGES and BGES groups were both significantly higher than the rate of NR group (11/24 vs.1/24,x2 =18.087,P ＜0.01 ; 5/24 vs.1/24,x2 =6.445,P ＜ 0.05) ; the survival rate of PGES group was also significantly higher than that of BGES group (11/24 vs.5/24,x2 =4.02,P ＜ 0.05).All levels of ALT,CK-MB,Cr and iFABP in both the NR group and two oral resuscitation groups at 1 h,2 h and 4 h post hemorrhage were significantly higher than those before the blood loss,respectively (P ＜ 0.01).These biomarkers at 2 h,4 h post hemorrhage were significantly lower in the PGES and BGES groups than those in NR group (P ＜ 0.01) ; the serum levels of ALT,CK-MB,Cr and iFABP were significantly lower in the PGES group than those in the BGES group at 2 h and 4 h post hemorrhage,respectively (P ＜ 0.05).Conclusions Present results demonstrated that the pyruvate-enriched oral re-hydration solution (ORS =PGES) was more effective in preserving the organ function and prolonging the animal survival after resuscitation of lethal hemorrhagic shock in comparison with the bicarbonate-containing ORS (BGES).The oral re-hydration solution (PGES) recommended by the World Hygiene Organization (WHO ORS) may require further improvement in oral resuscitation of shock and the PGES may be recommended as a choice of oral re-hydration salts in the treatment of lethal hemorrhagic shock when intravenous administration is not available. Key words: Hemorrhage ; Shock ; Oral rehydration ; Pyruvate ; Intestinal fatty acid binding protein ; Survival

Impact of pre-hospital oxygenation and ventilation status on outcome in patients with isolated severe traumatic brain injury

ABSTRACT Introduction. Hypoxia is one of the secondary insults and it worsens the outcome in patients with severe traumatic brain injury (TBI). On the other hand, there is some controversy about the impact of hyperoxia on the outcome in these patients. The aim of the study was to determine the impact of pre-hospital hypoxia, hyperoxia and pre-hospital ventilation status on outcome after isolated TBI.Methods. We retrospectively reviewed charts from patients with isolated severe TBI who underwent pre-hospital endotra-cheal intubation. The population was sorted into groups based on PaO2 (hypoxic, PaO2 200 mmHg) and initial Glasgow Coma Scale (GCS) level (3-5 and ≥ 6). Ventilation status was defined as: hypocarbic (PaCO2 45 mmHg). Results. Oxygenation status had no significant impact on 24- and 48-hour survival, on the length of hospital stay or on neuro-logical outcome (measured by the Glasgow Outcome Scale (GOS), Glasgow Pittsburgh Cerebral Performance Categories Scale (CPC), and GCS score at discharge) when all six groups were compared together. We were unable to prove a dele-terious effect of hypoxia or hyperoxia compared to normoxia on rate of survival to hospital discharge (STHD) (0.38 (0.52) vs 0.50 (0.51) vs 0.65 (0.49), where 0 - no and 1 - yes; f = 1.246, p = 0.298). Ventilation status also failed to significantly af fect survival and functional outcome in patients with isolated severe TBI.Conclusion. Pre-hospital oxygenation and ventilation status have no significant impact on outcome in patients with isolated severe TBI.

Effects of histone deacetylase inhibition on 24-hour survival and end-organ injury in a porcine trauma model

Valproic acid (VPA) is a histone deacetylase inhibitor that has been shown to improve early resuscitation from hemorrhagic shock. We sought to examine whether there is a sustained benefit of VPA in a survival model of severe injury. Yorkshire swine (n = 36) were randomized to three groups as follows: (a) control, (b) VPA (single dose), and (c) VPA (two doses at 12 hours apart). Animals underwent a 35% volume-controlled hemorrhage, followed by aortic cross-clamping for 50-minute duration, at which time VPA (400 mg/kg) was administered intravenously. Animals then underwent protocol guided resuscitation with crystalloid and vasopressor infusions for up to 24 hours. The primary end point was animal survival; secondary end points included hemodynamics, physiology, and histologic evidence of end-organ injury. Mean duration of survival was significantly longer in the control group (15.8 hours, n = 11) compared with single-dose VPA (12.6 hours, n = 9, p < 0.02). Redosing VPA at 12 hours provided no survival benefit. During cross-clamp, animals that received VPA required significantly less lidocaine compared with the control animals (32.8 mg vs. 159.4 mg, p = 0.03). Animals that received VPA also required significantly greater quantities of intravenous fluids per hour (p < 0.01) and higher epinephrine doses (p = 0.01). VPA administration was associated with earlier evidence of cardiac suppression (decreased cardiac output, increased pulmonary wedge pressures, and systemic vascular resistance; p < 0.05). VPA was associated with renal end-organ histologic protection and improved levels of blood urea nitrogen and creatinine at all time points (p < 0.05). Despite previous reports citing improved early outcomes with VPA administration, VPA did not improve resuscitation or mortality in a survival model with severe injury. VPA did show some evidence of prolonged renal protection. No benefit of redosing VPA was identified. VPA had a cardiac depressant effect that may be dose dependent and should be studied further.

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Introduction: Out of hospital cardiac arrest (OHCA) is one of the most important medical issue, but survival rate is still extremely low. Epinephrine is essential medication in cardiac arrest. But sometimes, it is difficult to insert intravenous catheter for epinephrine while transporting. Epinephrine is also used in treating anaphylaxis. The first recommended method for epinephrine administration in anaphylaxis is intramuscular injection to thigh. Benefits of intramuscular (IM) route is as follows; 1. faster than intravenous (IV) delivery, 2. more effective than other alternative routes like subcutaneous or inhalation. Methods: Male Sprague-Dawley rats weighing 300-350 g were subjected to asphyxia cardiac arrest. For 72-hour survival study, 19 rats were subjected to asphyxia cardiac arrest. After 540 seconds of cardiac arrest, cardiopulmonary resuscitation (CPR) was performed and then rats were blindly allocated to one of three groups (control group, n=7; IM group, n=7; IV group, n=6). IM epinephrine (0.05mg/Kg) or IV epinephrine (0.01mg/kg) or vehicle (normal saline) was administered immediately with CPR, respectively. For neurological outcome study, Neurological deficit score (NDS) was measured every 24 hours after ROSC for 3 days. NDS was ranged from 0 (brain dead) to 80 (normal). Results: Between the three groups, there was no statistical difference in baseline characteristics (body weight, initial V/S, initial lab findings), time to arrest, and CPR duration. There was significant survival gain in IM group comparing with control group, but no difference with IV group in Kaplan-Meier survival curve (p=0.0076). 5 of 7 in IM group and 4 of 6 in IV group survived 72 hours. In NDS score, there was no difference between IM and IV group (72 hour NDS: IM = 44.57 ± 12.43, IV= 46.17 ± 15.22, p=0.8636) Conclusions: Intramuscular epinephrine increased survival rate in asphyxia cardiac arrest model of rats, and there was no significant difference in neurological function compared to intravenous epinephrine group.

Abstract 341: Vasopressin With Low-Volume Resuscitation is Highly Effective for Resuscitation and Survival From Severe Hemorrhagic Shock

Background: We have previously shown in a swine model of controlled bleeding that vasopressin (VP) infusion promotes hemodynamic stabilization. We hypothesized that administering VP with or without modest amounts of normal saline (NS, half the volume of blood removed) could improve survival from severe and protracted hemorrhagic shock. Methods: Hemorrhagic shock was induced in 24 pigs by removing blood according to a mono-exponential decay function to 65% or 75% of the animal’s blood volume in 60 or 80 minutes. Pigs were randomized 1:1 to receive an intraosseous infusion of VP at a constant rate of 0.04 U/kg•min-1 from the onset of blood removal until the start of blood reinfusion with NS given at the end of hemorrhage over 30 minutes in half of the pigs. Results: Survival analysis by Kaplan-Meier method is shown in Figure comparing the effects of administering VP and NS (VP-NS), VP without NS (VP-noNS), no VP but NS (noVP-NS), and neither VP nor NS (noVP-noNS). The 72-hour survival was significantly different (p=0.009 by Log-rank test), with the highest survival in animals that received both VP and NS (100%) followed by VP-noNS (37.5%), noVP-NS (25%), and noVP-noNS (0%) regardless of shock severity. Conclusion: Intraosseous infusion of vasopressin in combination with normal saline was highly effective in securing initial resuscitation and 72-hour survival under conditions of severe hemorrhagic shock.

Sudden Cardiac Arrest in Hemodialysis Patients with Wearable Cardioverter Defibrillator

BackgroundThe survival outcome following a sudden cardiac arrest (SCA) in hemodialysis (HD) patients is poor regardless of whether an event takes place in or out of a dialysis center. The characteristics of SCA and post‐SCA survival with HD patients using a wearable cardioverter defibrillator (WCD) are unknown.MethodsAll HD patients who were prescribed a WCD between 2004 and 2011 and experienced at least one SCA event were included in this study. Demographics, clinical background, characteristics of SCA events were identified from the manufacturer's database. An SCA event was defined as all sustained ventricular tachycardia/fibrillation (VT/VF) or asystole occurring within 24 hours of the index arrhythmia episode. The social security death index was used to determine mortality after WCD use.ResultsA total of 75 HD patients (mean age = 62.9 ± 11.7 years, female = 37.3%) experienced 84 SCA events (119 arrhythmia episodes) while wearing the WCD. Sixty six (78.6%) SCA events were due to VT/VF and 18 (21.4%) were due to asystole. Most SCA episodes occurred between 09:00 and 10:00 (RR = 2.82, 95% CI [1.05, 7.62], P < 0.0001), followed by the 13:00–14:00 time interval (RR = 2.22, 95% CI [0.79, 6.21], P = 0.006). Acute 24‐hour survival was 70.7% for all SCA events; 30‐day and 1‐year survival were 50.7% and 31.4%, respectively. Women had a better post‐SCA survival than men (HR = 2.41, 95% CI [1.09, 5.36], P = 0.03).ConclusionsThe use of WCD in HD patients was associated with improved post‐SCA survival when compared to historical data.

Gender Influences the Initial Impact of Subarachnoid Hemorrhage: An Experimental Investigation

Aneurysmal subarachnoid hemorrhage (SAH) carries high early patient mortality. More women than men suffer from SAH and the average age of female SAH survivors is greater than that of male survivors; however, the overall mortality and neurological outcomes are not better in males despite their younger age. This pattern suggests the possibility of gender differences in the severity of initial impact and/or in subsequent pathophysiology. We explored gender differences in survival and pathophysiology following subarachnoid hemorrhage induced in age-matched male and female rats by endovascular puncture. Intracranial pressure (ICP), cerebral blood flow (CBF), blood pressure (BP) and cerebral perfusion pressure (CPP) were recorded at and after induction of SAH. Animals were sacrificed 3 hours after lesion and studied for subarachnoid hematoma size, vascular pathology (collagen and endothelium immunostaining), inflammation (platelet and neutrophil immunostaining), and cell death (TUNEL assay). In a second cohort, 24-hour survival was determined. Subarachnoid hematoma, post-hemorrhage ICP peak, BP elevation, reduction in CPP, intraluminal platelet aggregation and neutrophil accumulation, loss of vascular collagen, and neuronal and non-neuronal cell death were greater in male than in female rats. Hematoma size did not correlate with the number of apoptotic cells, platelet aggregates or neutrophil. The ICP peak correlated with hematoma size and with number of apoptotic cells but not with platelet aggregates and neutrophil number. This suggests that the intensity of ICP rise at SAH influences the severity of apoptosis but not of inflammation. Mortality was markedly greater in males than females. Our data demonstrate that in rats gender influences the initial impact of SAH causing greater bleed and early injury in males as compared to females.

Addition of glucagon to adrenaline improves hemodynamics in a porcine model of prolonged ventricular fibrillation

ObjectiveCardiac arrest is a daunting medical emergency. The aim of the present study was to assess whether the combination of adrenaline and glucagon would improve initial resuscitation success, 48-hour survival, and neurologic outcome compared with adrenaline alone in a porcine model of ventricular fibrillation. MethodsVentricular fibrillation was induced in 20 healthy Landrace/Large White piglets, which were subsequently left untreated for 8 minutes. The animals were randomized to receive adrenaline alone (n = 10, group C) and adrenaline plus glucagon (n = 10, group G). All animals were resuscitated according to the 2010 European Resuscitation Council guidelines. Hemodynamic variables were measured before arrest, during arrest and resuscitation, and during the first 60 minutes after return of spontaneous circulation. Survival and a neurologic alertness score were measured at 48 hours after return of spontaneous circulation. ResultsReturn of spontaneous circulation was achieved in 8 animals (80%) from group C and 10 animals (100%) from group G (P = .198). A significant gradual increase in coronary perfusion pressure and diastolic aortic pressure over time, which started 1 minute after the onset of cardiopulmonary resuscitation, was observed. Three animals (30%) from group C and 9 animals (90%) from group G survived after 48 hours (P = .006), whereas neurologic examination was significantly better in the animals of group G (P < .001). ConclusionsIn this porcine model of prolonged ventricular fibrillation, the addition of glucagon to adrenaline improves hemodynamics during resuscitation and early postresuscitation period and may increase survival.

Predictors of sudden death after 12-year follow-up in acute coronary syndrome (from the ABC study on acute coronary syndrome)

animals) of cardiopulmonary resuscitation (CPR), animals were randomized to a total of either 45 minutes (group A) or 4 hours (group B) of LAD occlusion. Animals without ROSC after 15 minutes of CPR were classified as refractory VF (group C). In those pigs, CPR was continued up to 45 minutes of total LAD occlusion at which point reperfusion was achieved. CPR was continued until ROSC or another 10 minutes of CPR had been performed. Primary endpoints for groups A and B were 24-hour survival and cerebral performance category (CPC). Primary endpoint for group C was ROSC before or after reperfusion. Results: Early compared to late reperfusion improved survival (10/11 versus 4/10, p= 0.02), mean CPC (1.4±0.7 versus 2.5±0.6, p= 0.017), LVEF (43±13 versus 32±9%, p=0.01), troponin I (37±28 versus 99±12, p=0,005) and CK-MB (11±4 versus 20.1±5, p=0.031) at 24-hr after ROSC. ROSC was achieved in 4/6 animals only after reperfusion in group C. Conclusions: Early reperfusion after ischemic cardiac arrest improved 24h survival rate and neurological function. In animals with refractory VF, reperfusion was necessary to achieve ROSC.

Efficacy and Pharmacokinetic/Pharmacodynamic Study of 1,1′-Methylenebis{4-[(hydroxyimino)methyl] pyridinium} Dimethanesulfonate in Guinea Pigs and Rhesus Macaques Exposed to Cyclosarin

Male Hartley guinea pigs and male rhesus macaques were used to determine an efficacious dose of 1,1'-methylenebis{4-[(hydroxyimino)methyl] pyridinium} dimethanesulfonate (MMB4 DMS) that would result in 80% survival, 24 hours following a single exposure to cyclosarin (GF). The pharmacokinetic/pharmacodynamic relationship between acetylcholinesterase activity and MMB4 plasma concentrations relative to survival was evaluated. Guinea pigs and non-human primates (NHPs) were concurrently administered MMB4 DMS (guinea pigs: 0, 10, 30, or 40 mg/kg, intramuscular [IM] and NHPs: 0.1, 1, 5, 10, or 20 mg/kg, IM), atropine, and diazepam following a 3 × median lethal dose (LD50) GF challenge. Clinical observations were evaluated using a quality-of-life (QOL) scoring system. All GF-exposed animals exhibited typical signs of nerve agent poisoning immediately following challenge. In guinea pigs, 24-hour survival was 0%, 50%, 90%, and 90% for 0, 10, 30, and 40 mg/kg MMB4 DMS groups, respectively. In addition, nearly all animals surviving to 24 hours were clinically normal, with many in the 30 and 40 mg/kg MMB4 DMS dose group observed as normal by 4 hours post-challenge. In NHPs, survival was 100% for all treatment groups, with all animals noted as clinically normal by 48 hours. Following treatment with atropine/MMB4 DMS/diazepam, NHPs exhibited dose- and temporal-related decreases in incidence and duration of the clinical signs of toxicity. The QOL scores improved with increasing MMB4 DMS dose in both species. The estimated ED80s were 25.5 mg/kg MMB4 DMS (human equivalent dose [HED] of 5.5 mg/kg) and ≤ 0.1 mg/kg (HED of 0.03 mg/kg) in guinea pigs and NHPs, respectively.

Diluting the benefits of hemostatic resuscitation

Although minimization of crystalloids is a widely adopted practice in the resuscitation of patients with severe hemorrhage, its direct impact on high-ratio resuscitation (HRR) outcomes has not been analyzed. We hypothesize that HRR patients will have worse outcomes from crystalloid use. This was a 4-year retrospective multi-institutional analysis (MIA) of patients who received massive transfusion protocol (MTP) managed with damage-control laparotomy. Ratios of fresh frozen plasma-packed red blood cell (PRBC) were calculated and divided in two groups: HRR (1-1:2) and low-ratio resuscitation (LRR < 1:2). Major outcome of interest was to analyze the direct impact of 24-hour crystalloid volume on HRR MTP patients who received 10 or more units of PRBC. Statistical analysis included analysis of variance, Fisher's exact, Kaplan-Meier (KM) survival curves, and multiple logistic regression. Total of five Level I trauma centers participated with 451 patients who received MTP with 10 or more units of PRBC (fresh frozen plasma/PRBC ratios, n = 365 (80.9%) HRR vs. n = 86 (19.0%) LRR. Overall 24-hour KM survival for the HRR versus LRR was 85.2% versus 68.6% (p = 0.0004). The volume of crystalloids on KM survival curve in HRR MTP patients was not significant for mortality (p = 0.52). Morbidity odds ratios (95% confidence interval) for complications were not significant for HRR but were for crystalloids: bacteremia, 1.05 (1.0-1.1); adult respiratory distress syndrome, 1.13 (1.0-1.2), and acute renal failure, 1.05 (1.0-1.1). Our MIA results support previous studies with decreased mortality in HRR group when compared with LRR. This is the first MIA to demonstrate increased morbidity from crystalloid use in HRR. Within all MTPs with 10 or more units of PRBC, HRR was not a predictor of morbidity, but crystalloid volume was. Caution in overzealous use of crystalloid during HRR is warranted. Therapeutic study, level IV.

Establishment of a Simple Living Donor Liver Transplantation Dog Model Using a Two-Step Nonvenous Bypass Hepatectomy

AimDogs are an ideal model for studying living donor liver transplantation (LDLT). However, due to their poor tolerance to congestion and acidosis during portal vein blockage, current LDLT dog models with long operation times have high mortality. To address the issue, we designed a novel simplified operation with two-step nonvenous bypass (NVB) hepatectomy. MethodsEighty dogs were evenly randomized to the living liver donor (LLD) or the recipient (LLR) groups. A standard lobectomy of I, II, and III lobes was performed in the LLD group. In the LLR group, first only I, II, and III lobes were resected using NVB; the residual lobes were resected off just after donor lobes were implanted. ResultsFor the LLD group, the operation time was 172.67 ± 20.98 minutes, amount of blood loss was 71.39 ± 13.59 mL, and 2-week survival rate was 85.00%. For the LLR group, the operation time was 251.61 ± 22.87 minutes, amount of blood loss was 220.00 ± 96.40 mL, amount of blood transfusion was 163.89 ± 44.74 mL, and 48-hour survival rate was 77.14%. In the LLR group, the mean arterial and central venous pressures decreased after organ implantion, but gradually recovered to normal levels after surgery. The liver function biochemical parameters recovered to preoperational levels after 14 days in the LLD group; in the LLR group, they gradually increased during 48 hours after operation. ConclusionThe present method with two-step NVB hepatectomy can be used efficiently and safely for establishing LDLT dog model.

A latent class model for defining severe hemorrhage

Several predictive models have been developed to identify trauma patients who have had severe hemorrhage (SH) and may need a massive transfusion (MT) protocol. However, almost all these models define SH as the transfusion of 10 or more units of red blood cells (RBCs) within 24 hours of emergency department admission (also known as MT). This definition excludes some patients with SH, especially those who die before a 10th unit of RBCs could be transfused, which calls the validity of these prediction models into question. We show how a latent class model could improve the accuracy of identifying the SH patients.Modeling SH classification as a latent variable, we estimate the posterior probability of a patient in SH based on emergency department admission variables (systolic blood pressure, heart rate, pH, hemoglobin), the 24-hour blood product use (plasma/RBC and platelet/RBC ratios), and 24-hour survival status. We define the SH subgroup as those having a posterior probability of 0.5 or greater. We compare our new classification of SH with that of the traditional MT using data from PROMMTT study.Of the 1,245 patients, 913 had complete data, which were used in the latent class model. About 25.3% of patients were classified as SH. The overall agreement between the MT and SH classifications was 83.8%. However, among 49 patients who died before receiving the 10th unit of RBCs, 41 (84%) were classified as SH. Seven (87.5%) of the remaining eight patients who were not classified as SH had head injury.Our definition of SH based on the aforementioned latent class model has an advantage of improving on the traditional MT definition by identifying SH patients who die before receiving the 10th unit of RBCs. We recommend further improvements to more accurately classify SH patients, which could replace the traditional definition of MT for use in developing prediction algorithms.

Remote post-conditioning reduces hypoxic damage early after experimental stroke

Objectives: Given that reliable markers for early ischemic brain damage are lacking, we set out to test whether pimonidazole can be used as a reliable tool in the quantification of hypoxic insults, at early time points following experimental stroke.Methods: We have used semi-quantitative Western blotting detection of pimonidazole adducts in a rat model of reversible middle cerebral artery occlusion (MCAO), treated with remote post-conditioning.Results: First, we demonstrated that a linear relationship exist between pimonidazole binding in the ischemic hemisphere and duration of ischemia, in animals subjected to 5, 15, 30, or 60 minutes of occlusion followed by 120 minutes of reflow. Then we showed a significant reduction in pimonidazole binding in the infarcted hemisphere, when rats with 60 minutes of MCAO, immediately after establishment of cerebral reflow, had 3×15 minutes intermittent hind limb ischemia followed by 24-hour survival. We analysed the middle cerebral arteries from animals with 60 minutes of MCAO and early remote post-conditioning, followed by 30 minutes, 24, or 48 hours of reflow. At 24 hours of reflow increases in phosphorylated protein kinase C-alpha with concomitantly increased levels of p38 phosphorylation were observed.Conclusions: Our investigation demonstrates that pimonidazole can be used for quantifying ischemic impact in stroke, even after very short survival times. It furthermore shows that early remote post-conditioning reduces ischemic damage, probably through hyperpolarization and reduced reflow vasospasm in the conduit middle cerebral arteries.

Inhibition of CCL20 increases mortality in models of mouse sepsis with intestinal apoptosis

CC chemokine ligand 20 (CCL20) and CC chemokine receptor 6 are believed to stimulate the recruitment of neutrophils and activation of macrophages against bacterial pathogens through the activation of T helper cells. We analyzed the role of CCL20 in the acute phase of sepsis. The effect of a neutralizing, anti-mouse CCL20 monoclonal antibody (mAb) was examined in 2 murine models of sepsis: Cecal ligation and puncture (CLP) and Escherichia coli peritonitis. Immune cell migration, bacterial clearance, and expression of 17 cytokines and 5 chemokines were quantified in Ecoli-induced peritonitis. Expression of CCL20 in various tissues was determined, and apoptotic cells in jejunum were measured. Anti-CCL20 mAb increased mortality in CLP and E coli peritonitis (P = .029 and .024, respectively by Kaplan-Meier method and log-rank test). The 48-hour survival rate in anti-CCL20 mAb- and control immunoglobulin (Ig)G-treated mice was 37% (11/30) vs 62% (18/29) in CLP and 28% (11/40) vs 48% (19/40) in bacterial peritonitis. Neutralization of CCL20 showed no effect on leukocyte infiltration into the peritoneal cavity or bacterial clearance at 24 hours. CCL20 was induced strongly and predominantly in jejunum after bacterial infection, and neutralizing CCL20 increased apoptosis of epithelial cells in jejunum crypt. Inhibition of CCL20 increased serum tumor necrosis factor (TNF)-α (3.3-fold greater than control mice) and decreased serum interleukin (IL)-1α and IL-6. Neutralization of CCL20 before induction of sepsis increased mortality during sepsis accompanied with increasing epithelial apoptosis in the jejunum and augmenting serum TNF-α.