Cerebral Hemodynamic and Metabolic Effects of Equi-Osmolar Doses Mannitol and 23.4% Saline in Patients with Edema Following Large Ischemic Stroke

Introduction  

Cerebral edema after ischemic stroke is frequently treated with mannitol and hypertonic saline (HS); however, their relative cerebrovascular and metabolic effects are incompletely understood, and may operate independent of their ability to lower intracranial pressure.     

Effect of osmotherapy with hypertonic saline on regional cerebral edema following experimental stroke: a study utilizing magnetic resonance imaging

Introduction  

Hypertonic saline (HS) solutions are increasingly being utilized as osmotherapeutic agents for the treatment of cerebral edema associated with brain injury from diverse etiologies.     

Treatment of Elevated Intracranial Pressure with Hyperosmolar Therapy in Patients with Renal Failure

Background

To evaluate the use of hyperosmolar therapy in the management of elevated intracranial pressure (ICP) and transtentorial herniation (TTH) in patients with renal failure and supratentorial lesions.

Methods

Patients with renal failure undergoing renal replacement therapy treated with 23.4% saline (30?C60?mL) and/or mannitol for high ICP or clinical evidence of TTH were analyzed in a retrospective cohort.

Results

The primary outcome measure was reversal of TTH or ICP crisis. Secondary outcome measures were modified Rankin scale on hospital discharge, survival to hospital discharge, and adverse effects. Of 254 subjects over 7?years, 6 patients with end-stage renal disease had 11 events. All patients received a 23.4% saline bolus, along with mannitol (91%), hypertonic saline (HS) maintenance fluids (82%), and surgical interventions (n?=?2). Reversal occurred in 6/11 events (55%); 2 of 6 patients survived to discharge. ICP recording of 6 TTH events showed a reduction from ICP of 41?±?3.8?mmHg (mean?±?SEM) with TTH to 20.8?±?3.9?mmHg (p?=?0.05) 1?h after the 23.4% saline bolus. Serum sodium increased from 141.4 to 151.1?mmol/L 24?h after 23.4% saline bolus (p?=?0.001). No patients were undergoing hemodialysis at the time of the event. There were no cases of pulmonary edema, clinical volume overload, or arrhythmia after HS.

Conclusions

Treatment with hyperosmolar therapy, primarily 23.4% saline solution, was associated with clinical reversal of TTH and reduction in ICP and had few adverse effects in this cohort. Hyperosmolar therapy may be safe and effective in patients with renal failure and these initial findings should be validated in a prospective study.     

Hypertonic resuscitation and blood coagulation: in vitro comparison of several hypertonic solutions for their action on platelets and plasma coagulation

Resuscitation with hypertonic saline (HS) appears to aggravate bleeding in a model of uncontrolled hemorrhage [J. Trauma 28 (1988) 751; J. Trauma 29 (1989) 79; Arch. Surg. 127 (1992) 93]. This property may be related to the anticoagulant effects of HS on plasma clotting factors and platelets [J. Trauma 31 (1991) 8]. The hypothesis in this study is that a hypertonic solution can be developed that would not disturb the blood coagulation mechanism and could be used as an alternative to hypertonic saline.HS and four different 2400 mosM solutions containing monosaccharides and/or glycine were screened for their in vitro effects on plasma clotting times and platelets. Significant prolongations falling outside the normal range were detected in prothrombin time (PT) and thrombin rime (TT) when only 5% of the volume of normal plasma is HS. Platelet function as measured by extent of shape change (ESC) induced by ADP and aggregation induced by thrombin were also critically impaired by HS at a 5% dilution. All alternative solutions-hypertonic glucose, sorbitol, glycine, glucose/glycine, glucose/mannitol/glycine, sorbitol/glycine-caused a significantly reduced impairment in platelet function and the plasma coagulation system. Hypertonic glycine showed a unique ability to fully preserve the function and integrity of the plasma coagulation system.Considering the pre-deposition of the trauma patient to coagulopathy, administration of HS which clearly is a potent anticoagulant and anti-platelet risks further aggravating the coagulopathy. In contrast, hypertonic glycine preserves the blood coagulation mechanism and exhibits the potential for numerous therapeutic applications. Therefore, prompt evaluation of hypertonic glycine as a resuscitative fluid is highly desirable.     

The influence of vasovagal response on the coagulation system

Background  

Vasovagal response (VVR) is provoked by a reduced venous blood return to the heart as a reaction to orthostatic stress and to haemorrhage. Recently, two cases were reported showing elevated plasma concentration of von-Willebrand-factor (VWF) and factor VIII (FVIII) after VVR due to venapuncture. Although the effect of epinephrine as trigger for VWF liberation is known, a connection between VVR and activation of the coagulation system has not been studied systematically.     

Inflammation in rat pups subjected to short hyperthermic seizures enhances brain long-term excitability

Inflammatory processes in response to infection are involved in the pathophysiological mechanisms of febrile seizures (FS). Prolonged FS may promote the development of temporal lobe epilepsy. It has been shown in rats that prolonged hyperthermic seizures (HS) are followed by long-term modification of brain excitability. To examine whether short FS results in modification of brain excitability, we induced an inflammatory response in combination with short HS.

Methods

HS were induced in rat pups at either P11 or P16 using a heating lamp with a continuous monitoring of the core temperature. Rat pups were maintained at the temperature seizure threshold during 5 min. In order to induce an inflammatory response, lipopolysaccharide (LPS, Eschericha coli 055:B5) was injected i.p. at 5 μg/kg or 50 μg/kg, 2 h prior seizure induction. After 1 month, pentylenetetrazol threshold (PTZth) was used to assess the change of brain excitability. Histological studies were performed 24 h after the FS (Fluorojade-B) and after the PTZth (cresyl violet).

Results

The temperature thresholds to induce the seizures were not different among the groups. The PTZth was not significantly different between sham and FS only groups, and decreased dose-dependently when LPS was combined to FS. Histological studies suggested the absence of cell injury.

Conclusion

Lower PTZth obtained by using LPS in combination with HS in rat pups suggests a change in brain excitability. Our model with only 5 min of HS in combination with LPS suggests that an inflammatory response could, in part, explain long-term change in brain excitability following short FS.     

Effect of duration of osmotherapy on blood-brain barrier disruption and regional cerebral edema after experimental stroke.

Osmotherapy is the cornerstone of medical management for cerebral edema associated with large ischemic strokes. We determined the effect of duration of graded increases in serum osmolality with mannitol and hypertonic saline (HS) on blood-brain barrier (BBB) disruption and regional cerebral edema in a well-characterized rat model of large ischemic stroke. Halothane-anesthetized adult male Wistar rats were subjected to transient (2-h) middle cerebral artery occlusion (MCAO) by the intraluminal occlusion technique. Beginning at 6 h after MCAO, rats were treated with either no intravenous fluids or a continuous intravenous infusion (0.3 mL/h) of 0.9% saline, 20% mannitol, 3% HS, or 7.5% HS for 24, 48, 72, and 96 h. In the first series of experiments, BBB permeability was quantified by the Evans blue (EB) extravasation method. In the second series of experiments, water content was assessed by comparing wet-to-dry weight ratios in six predetermined brain regions. Blood-brain barrier disruption was maximal in rats treated with 0.9% saline for 48 h, but did not correlate with increases in serum osmolality or treatment duration with osmotic agents. Treatment with 7.5% HS attenuated water content in the periinfarct regions and all subregions of the contralateral nonischemic hemisphere to a greater extent than mannitol did with no adverse effect on survival rates. These data show that (1) BBB integrity is not affected by the duration and degree of serum osmolality with osmotic agents, and (2) attenuation of increases in brain water content with HS to target levels >350 mOsm/L may have therapeutic implications in the treatment of cerebral edema associated with ischemic stroke.     

Cerebellar hemorrhage as a first presentation of acquired Hemophilia A

Background  

Acquired hemophilia A (AHA) is an uncommon coagulation disorder caused by the development of autoantibodies against coagulation factor VIII (FVIII). While intracranial hemorrhage is a known complication of AHA, intracranial hemorrhage as the presenting manifestation of AHA has only been described in three previous case reports.     

Association of serum uric acid to lymphocyte ratio,a novel inflammatory biomarker,with risk of stroke: A prospective cohort study

Main Problem

Inflammation plays an important role in the pathological progress associated with stroke. Serum uric acid (SUA) to lymphocyte ratio (ULR), a novel inflammatory biomarker, has been considered as a better risk stratification tool of adverse outcomes than SUA or lymphocyte alone. This study aimed to investigate whether ULR produced more predictive value for stroke and explore the potential mediators of the associations.

Methods

This study enrolled 93,023 Chinese participants without stroke and myocardial infarction at baseline. Cox proportional hazard models were used to analyze the associations of ULR with stroke and subtypes. Mediation analyses were conducted to explore potential mediators of the associations.

Results

During a median follow-up of 13.00 years, 6081 cases of incident stroke occurred, including 5048 cases of ischemic stroke (IS) and 900 cases of hemorrhagic stroke (HS). After adjustment for confounders, the Q4 group was associated with a higher risk of HS (HR, 1.25; 95% CI, 1.03–1.50), but not with total stroke (HR, 1.07; 95% CI, 1.03–1.13) or IS (HR, 1.04; 95% CI, 0.97–1.12). No significant associations were found between SUA or lymphocyte and any stroke. ULR outperformed SUA or lymphocytes alone in predicting stroke. Additionally, the significant association between ULR and HS was partially mediated by systolic blood pressure (20.32%), diastolic blood pressure (11.18%) and estimated glomerular filtration rate (9.19%).

Conclusions

ULR was significantly associated with the risk of HS, but not with IS. Systolic blood pressure, diastolic blood pressure and estimated glomerular filtration rate were potential mediators for the association.     

Potassium Sparing Diuretics as Adjunct to Mannitol Therapy in Neurocritical Care Patients with Cerebral Edema: Effects on Potassium Homeostasis and Cardiac Arrhythmias

Background  

Mannitol therapy to treat cerebral edema induces osmotic diuresis and electrolyte loss. In neurocritical care patients, potassium is the electrolyte that most often needs replacement. Objective of this study was to evaluate the effects of adding potassium sparing diuretic (canrenone) to mannitol therapy on potassium urinary excretion, potassium plasma levels, and incidence of new cardiac arrhythmias in patients receiving neurocritical care for cerebral edema.     

Osmotherapy: Use Among Neurointensivists

Background  

Cerebral edema and raised intracranial pressure are common problems in neurological intensive care. Osmotherapy, typically using mannitol or hypertonic saline (HTS), has become one of the first-line interventions. However, the literature on the use of these agents is heterogeneous and lacking in class I studies. The authors hypothesized that clinical practice would reflect this heterogeneity with respect to choice of agent, dosing strategy, and methods for monitoring therapy.     

Synergistic effect of a factor Xa inhibitor, TAK-442, and antiplatelet agents on whole blood coagulation and arterial thrombosis in rats

Introduction

Activated platelets facilitate blood coagulation by providing factor V and a procoagulant surface for prothrombinase. Here, we investigated the potential synergy of a potent factor Xa/prothrombinase inhibitor, TAK-442, plus aspirin or clopidogrel in preventing arterial thrombosis and whole blood coagulation.

Methods

Thrombus formation was initiated by FeCl₃-induced rat carotid injury. Bleeding time was evaluated with the rat tail transection model. Whole blood coagulation was assessed by thromboelastographic examination (TEG) for which blood obtained from control, aspirin-, or clopidogrel-treated rats was transferred to a TEG analyzer containing, collagen or adenosine diphosphate (ADP), and TAK-442 or vehicle.

Results

TAK-442 (3 mg/kg, po), aspirin (100 mg/kg, po) or clopidogrel (3 mg/kg, po) alone had no significant effect on thrombus formation, whereas the combination of TAK-442 with aspirin and clopidogrel remarkably prolonged the time to thrombus formation without additional significant prolongation of bleeding time. TEG demonstrated that the onset of collagen-induced blood coagulation were slightly longer in aspirin-treated rats than control; however, when the blood from aspirin-treated rats was subsequently treated in vitro with 100 nM TAK-442, the onset of clotting was significantly prolonged. In contrast, only marginal prolongation was observed with TAK-442 treatment of blood from control animals. The onset time of ADP-induced blood coagulation was slightly longer in clopidogrel-treated rats compared with control, and it was further extended by TAK-442 treatment.

Conclusion

These results demonstrate that blood coagulation can be markedly delayed by the addition of TAK-442 to antiplatelets treatment which could contribute to synergistic antithrombotic efficacy in these settings.     

Multiple hemorrhagic strokes from DIC associated with occult large cell carcinoma

Background and Purpose  

Multiple hemorrhagic strokes are a rare presentation of paraneoplastic disseminated intravascular coagulation (DIC). We present a case of DIC occurring in a patient with occult large cell carcinoma.     

A comprehensive study of ovine haemostasis to assess suitability to model human coagulation

Introduction

Similarities in size, anatomy and physiology have supported the use of sheep to model a wide range of human diseases, including coagulopathy. However, coagulation studies involving sheep are limited by the absence of high quality data defining normal ovine coagulation and fibrinolysis.

Materials and Methods

Full blood examination, routine and specialised coagulation tests, rotational thromboelastometry and whole blood platelet aggregometry was performed on 50 healthy Samm & Border Leicester Cross ewes and compared to corresponding human ranges. Intraspecies breed and gender variability was investigated by comparison to a smaller population of 13 healthy Merino wethers.

Results

Ovine coagulation was similar to human according to routine coagulation methods (PT, aPTT, TCT, Fib(C)) and some specialised coagulation tests (vWF, AT, Plasmin Inh). Despite these similarities, ovine secondary haemostasis demonstrated substantial differences to that of human. Rapid initiation of the contact activation pathway, high levels of FVIII, low Protein C, greater overall clot firmness and a reduced capacity for clot lysis was documented in sheep. In addition, ADP and collagen agonists precipitated a reduced primary haemostatic response in sheep relative to human. Intraspecies differences in whole blood platelet aggregometry between the cohorts of sheep indicate the need for breed-specific normal ranges.

Conclusions

The application of a board spectrum of coagulation assays has enabled elucidation of the similarities as well as differences between ovine and human coagulation. The new knowledge generated from this study will guide the design of future translational coagulation studies in ovine models.     

Prospective diagnostic accuracy assessment of the HemosIL HS D-dimer to exclude pulmonary embolism in emergency department patients

Introduction

Chest pain and shortness of breath are among the most common symptoms requiring immediate evaluation. Testing for pulmonary embolism (PE) has become easier and widespread due to D-dimer blood tests. Safe use of these tests is only possible if sensitivity is high and they are used in non-high probability patients. We evaluated diagnostic performance of the HemosIL HS D-dimer, which despite FDA approval in 2005, has been minimally reported in prospective standard clinical care.

Materials and methods

We used a prospective observational study design to follow patients in a single center with the HemosIL HS ordered for symptoms of possible PE with positive test result if > 243 ng/ml. The outcome was PE or deep venous thrombosis (DVT) at the time of presentation or subsequent 45 days determined by structured evaluation of imaging tests, phone, or medical record follow-up in all patients.

Results

529 patients received a D-dimer and 4.7% were ultimately diagnosed with PE or DVT. The sensitivity of the HemosIL HS was 96.0% (95% CI; 79.6 to 99.9%) specificity was 65.7% (95% CI; 61.4 to 69.8%) and likelihood ratio negative was 0.06 (95% CI; 0.01 to 0.42). The probability of PE in patients with a negative D-dimer was 1/332 or 0.3% (95% CI; 0.01% to 1.67%). The receiver operator curve had an area under the curve of 0.87 and supported the current cut-point as optimal.

Conclusions

The HemosIL HS D-dimer had high sensitivity, very low negative post-test probability and is useful in excluding PE in the acute care setting.     

高渗刺激引起培养的大鼠下丘脑星形胶质细胞和C6细胞合成并释放谷氨酸

目的 观察高渗刺激对培养的大鼠下丘脑星形胶质细胞或C6细胞合成、释放谷氨酸的影响.方法 获取一日龄SD大鼠下丘脑组织,进行星形胶质细胞培养、纯化和鉴定.培养细胞随机分五组:(1)等渗组:用新鲜等渗培养液置换原先的培养液,将细胞分成5个亚组,分别孵育1、3、5、10和15 min.(2)高渗组:用320 mosMNaCl高渗溶液置换原先的培养液,将细胞分成5个亚组,分别孵育1、3、5、10和15 min.(3)甘伯酸(carbenoxolone,CBX,一种缝隙连接阻断剂) 等渗组和(4)CBX 高渗组:用含有CBX(终浓度为100 mmol/L)的等渗培养液作用1 h,后分别用等渗或高渗培养液置换出原培养液,将细胞分成5个亚组,分别孵育1、3、5、10和15 min.(5)Ca2 高渗组:用含有Ca2 (1 000μmol/L)的等渗培养液作用1 h,后用高渗培养液置换出原培养液,将细胞分成5个亚组;分别孵育1、3、5、10和15 min.每个亚组5个培养皿.收集各组的细胞,进行抗谷氨酸和抗胶质原纤维酸性蛋白(Glial fibrillary acidic protein,GFAP)的双重免疫荧光染色,Confocal显微镜观察.用反相高效液相色谱荧光测定法测定细胞培养液中谷氨酸的含量.培养的C6细胞分为四组:等渗组,高渗组,CBX 等渗组和CBX 高渗组,用于流式细胞仪(flow cytometry,FCM)定量检测细胞内谷氨酸的含量.结果 星形胶质细胞内抗GFAP染色的荧光强度在五组间无明显差异.星彤胶质细胞内抗谷氨酸染色的荧光强度在等渗组中各时间点无明显变化,高渗组中在刺激1 min后表达增加,5 min达到高峰,15 min恢复到正常.CBX 高渗组的抗谷氨酸染色荧光强度明显高于CBX 等渗组和等渗组,一直维持到15 min不下降.培养基中的谷氨酸浓度在等渗组各时间点无明显变化,高渗组中谷氨酸浓度从5 min到15 min明显增加.Ca2 高渗组和CBX 高渗组中,培养基中谷氨酸浓度明显低于高渗组,各时间点之间没有明显变化.FCM测定的结果表明高渗或CBX 高渗刺激引起C6细胞内谷氨酸的水平明显上调.结论 高渗刺激可以激发培养的大鼠下丘脑星形胶质细胞合成、释放谷氨酸,CBX不能抑制其合成,但可阻断其释放.     

Diffuse Cerebral Intravascular Coagulation and Cerebral Infarction in Pneumococcal Meningitis

Background

There is a widely held belief that cerebral infarction after bacterial meningitis is always caused by vasculitis; however, evidence is weak. We hypothesized that diffuse cerebral intravascular coagulation is an additional explanation of cerebral infarction in patients with pneumococcal meningitis.

Methods

Sixteen brains of adults who died from pneumococcal meningitis were investigated. Clinical data were collected, and brain sections were scored for signs of inflammation and activation of coagulation. Patients with and without cerebral infarction on autopsy were compared.

Results

In total, 38% of patients had focal neurological deficits. Patients died at a median of 7 days (range, 0–32 days) after admission. On autopsy, the nine patients (56%) with cerebral infarctions more often had arterial thrombosis (p = 0.04) than patients without infarction. Patients with infarction tended to have more inflammatory infiltrations of brain parenchyma, microvascular proliferation, small vessel vasculitis/endarteritis obliterans, blood clotting/vessel clogging, and venous thrombosis. None of the patients had large vessel vasculitis. Five patients had cerebral infarctions without vasculitis or endarteritis obliterans. Although four patients with cerebral infarctions had small vessel vasculitis or endarteritis obliterans, areas of infarction could not be localized to the blood flow distribution of these vessels. Blood clotting/vessel clogging was seen in all four patients with vasculitis or endarteritis obliterans, but this was also observed in 10 patients without vasculitis or endarteritis obliterans. None of the patients developed disseminated intravascular coagulation.

Conclusions

Our results suggest that diffuse cerebral intravascular coagulation is an additional explanation of cerebral infarction complicating pneumococcal meningitis.     

Accumulated Mannitol and Aggravated Cerebral Edema in a Rat Model of Middle Cerebral Artery Infarction

Objective

Repeated administration of mannitol in the setting of large hemispheric infarction is a controversial and poorly defined therapeutic intervention. This study was performed to examine the effects of multiple-dose mannitol on a brain edema after large hemispheric infarction.

Methods

A middle cerebral artery was occluded with the rat suture model for 6 hours and reperfused in 22 rats. The rats were randomly assigned to either control (n=10) or the mannitol-treated group (n=12) in which intravenous mannitol infusions (0.8 g/kg) were performed six times every four hours. After staining a brain slice with 2,3,5-triphenyltetrazolium chloride, the weight of hemispheres, infarcted (IH) and contralateral (CH), and the IH/CH weight ratio were examined, and then hemispheric accumulation of mannitol was photometrically evaluated based on formation of NADH catalyzed by mannitol dehydrogenase.

Results

Mannitol administration produced changes in body weight of -7.6±1.1%, increased plasma osmolality to 312±8 mOsm/L. It remarkably increased weight of IH (0.77±0.06 gm versus 0.68±0.03 gm : p<0.01) and the IH/CH weight ratio (1.23±0.07 versus 1.12±0.05 : p<0.01). The photometric absorption at 340 nm of the cerebral tissue in the mannitol-treated group was increased to 0.375±0.071 and 0.239±0.051 in the IH and CH, respectively from 0.167±0.082 and 0.162±0.091 in the IH and CH of the control group (p<0.01).

Conclusion

Multiple-dose mannitol is likely to aggravate cerebral edema due to parenchymal accumulation of mannitol in the infarcted brain tissue.     

Utilization of recombinant activated factor VII for intracranial hematoma evacuation in coagulopathic nonhemophilic neurosurgical patients with normal international normalized ratios

Background  

Recombinant activated Factor VII (rFVIIa) has recently gained popularity for rapid reversal of coagulopathy during operative neurosurgery. Patients undergoing chronic subdural hematoma (CSDH) or epidural hematoma (EDH) evacuation often have their coagulation status judged by preoperative international normalized ratio (INR). We present our experience in two patients with significant clinical coagulopathy who were successfully reversed with rFVIIa in the setting of normal INR.     

Daunorubicin induces procoagulant response through phosphatidylserine exposure in red blood cells

Introduction

Cytotoxic chemotherapy induces or worsens hemostatic disorders in patients with acute myeloid leukemia. Procoagulant release and tissue factor expression on tumor cells are considered to contribute to chemotherapeutic agents-associated coagulopathy. The role of red blood cells during this process has not been determined; although they lack tissue factor, they may contribute suitable membranes for the amplification phase of blood coagulation. The present study aims to evaluate the possible impact of daunorubicin on phosphatidylserine exposure and consequent procoagulant property of red blood cells.

Materials and methods

Red blood cells from acute myeloid leukemia patients and healthy donors were treated with daunorubicin as well as all-trans-retinoic acid, arsenic trioxide or etoposide for 0-48 h. Procoagulant activity was assessed by measurement of a clotting time and by purified coagulation complex assays. Lactadherin was used as a probe for phosphatidylserine.

Results

Daunorubicin treatment increased procoagulant activity of red blood cells regardless of the cell origin. Moreover, coagulation complexes assays supported daunorubicin-evoked procoagulant response. The procoagulant property of red blood cells was not affected by the other three agents. The modulating effect of procoagulant activity was concomitant with and dependent on level of phosphatidylserine on the outer surface. Blockade of phosphatidylserine with lactadherin inhibited over 90% of tenase generation and prothrombinase activity and prolonged the coagulation time.

Conclusions

We conclude that daunorubicin interacts with red blood cells in a manner that increases phosphatidylserine exposure and consequent procoagulant activity. Lactadherin is an efficient anticoagulant of this process.