On the importance of albumin binding for the flux of 7α-hydroxy-3-oxo-4-cholestenoic acid in the brain.

We confirmed previous findings by a Japanese group that there is an accumulation of 7α-hydroxy-3-oxo-4-cholestenoic acid (7-Hoca) in human subdural hematomas. The accumulation correlated with the time from the bleeding to the sample collection. We present evidence that these accumulations are likely to be caused by the strong affinity of 7-Hoca to albumin and the marked difference between plasma and brain with respect to levels of albumin. In the circulation, 80-90% of 7-Hoca is bound to albumin with a ratio between the steroid acid and albumin of ∼1.4 ng/mg. In cerebrospinal fluid (CSF), the ratio between 7-Hoca and albumin is ∼30 ng/mg. When albumin or hemolyzed blood in a dialysis bag was exposed to CSF, there was a flux of 7-Hoca from CSF to the albumin. We suggest that the major explanation for accumulation of 7-Hoca in subdural hematoma is a flux from the brain into the hematoma due to the high affinity to albumin and the high capacity of 7-Hoca to pass biomembranes. We discuss the possibility that the markedly different ratios between 7-Hoca and albumin in circulation and brain can explain the flux of 7-Hoca from the brain into circulation against a concentration gradient.

Bilateral subdural hematomas, an unusual vaso-occlusive event and prolonged prothrombin time in a 58-year-old victim of an armed robbery.

Factor VII deficiency is one of the most common of rare bleeding disorders(1). This autosomal recessive disorder has a prevalence of 1:500,000 with geographic variations. Clinical manifestations vary from asymptomatic to severe mucocutaneous bleeding. According to the International Registry of Factor VII Deficiency (IRF7) epistaxis is the most common clinical manifestation. Gastrointestinal and central nervous system(CNS) bleeding are rare presentations.(2-4) We present here the case of a patient with life-threatening CNS bleeding who was found at the age of 58 years to have congenital factor VII deficiency.

Dabigatran-associated subdural hemorrhage: using thromboelastography (TEG(®)) to guide decision-making.

Novel oral anticoagulants present challenges and uncertainties in the management of hemorrhagic emergencies. An 84-year-old man taking dabigatran presented with a subdural hematoma requiring neurosurgical intervention. Routine coagulation assays were prolonged at admission and following administration of Factor VIII Inhibitor Bypassing Activity (FEIBA). Thromboelastography (TEG(®)) was utilized to assess clot dynamics prior to placement of a subdural drain, which was safely inserted despite a prolonged thrombin time (TT). Exclusive reliance on the TT may delay necessary interventions. TEG(®) may be a valuable tool to investigate hemostasis in patients on dabigatran requiring emergent procedures.

Ability of S100B to predict severity and cranial CT results in children with TBI.

OBJECTIVES: To evaluate the ability of S100B to predict severity of TBI and abnormal cranial CT results for children with TBI. METHODS: This is a secondary analysis of a previously established cohort of consecutive patients presenting to the emergency department with TBI limited to children <19 years of age, who arrived within 6 hours of injury, received a cranial CT scan and consented to blood drawn for S100B. RESULTS: A total of 109 children were included in this cohort. The mean S100B levels were higher in children with moderate/severe TBI as compared to children with mild TBI based GCS score (0.281 µg L(-1), 95%CI = 0.101, 0.461 vs 0.053, 95%CI = 0.010, 0.095). S100B levels were significantly elevated in children following TBI with abnormal cranial CT as compared to children with a normal cranial CT (0.210 µg L(-1), SD = 0.313 vs 0.036 µg L(-1), SD = 0.046, p = 0.03). Area under the curve for S100B was also significant (0.72, 95%CI = 0.58, 0.86) for prediction of abnormal cranial CT for children with TBI. S100B did not predict abnormal cranial CT for children following TBI with a GCS of 15 (AUC = 0.53, 95%CI = 0.36, 0.71). CONCLUSIONS: For children following TBI, S100B appears to predict severity of TBI; however, it may not be clinically useful as an independent screening test to select children with mild TBI who need a cranial CT.

Slippery platelet syndromes in subdural hematoma.

BACKGROUND: This study investigates platelet dysfunction in patients with subdural hematomas (SDH) using platelet function analysis (PFA). METHODS: PFA using the PFA-100 (Dade International Inc., Miami, FL) was performed at admission using the collagen-epinephrine and collagen-ADP assays in 58 SDH patients. Clinical and radiologic information was collected. RESULTS: Normal PFA results were present in 36 patients (62%; PFA collagen:epinephrine assay (s) 118 ave; PFA collagen:adenosine diphosphate assay (s) ave 75) and abnormal platelet function in 22 patients (38%; PFA collagen:epinephrine assay (s) 231 average; PFA collagen:adenosine diphosphate assay (s) 124 average). Compared to patients with normal PFA results, patients with abnormal PFA results were more likely to have hypertension (22 vs. 55%; P = 0.01), take clopidogrel (3 vs. 32%; P = 0.001), and use anti-platelet medications and non-steroidal anti-inflammatory agents (22 vs. 59%; P = 0.004). Measurements of baseline CT for midline shift, maximum thickness, presence of blood/fluid levels in the hematoma, and presence of additional sites of intracranial bleeding did not reveal significant differences based on PFA testing. Platelet dysfunction improved after platelet transfusions (PFA collagen:epinephrine assay: baseline 270 s, CI 61 s; after transfusion 124 s, CI 50 s, P < 0.001). CONCLUSION: Platelet dysfunction was found in 38% of SDH patients. This finding adds to our understanding of the pathophysiology of SDH. Since platelet transfusions are indicated for platelet dysfunction accompanied by major bleeding or need for surgery, these results impact peri-operative management.

[Determination of the age of subdural hematomas from the concentration of hemoglobin].

The photocolorimetric method was employed to measure hemoglobin levels in 46 traumatic subdural hematomas of different age. The data thus obtained were used to construct a logarithmic regression model for the determination of the age of subdural hematomas from the concentration of hemoglobin. The model allows to determine injury time points and intervals at any desired level of confidence probability. The fraction of dispersion of hematoma age values attributable to regression was estimated at 41% which accounts for 74.7% of the maximally possible magnitude. Results of the study can be used in practical work of a forensic-medical experts.

Changes in serum levels of receptor activator of nuclear factor-kappaB ligand, osteoprotegerin, IL-6 and TNF-alpha in patients with a concomitant head injury and fracture.

INTRODUCTION: Several reports indicated that interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF- alpha) play important regulatory roles in bone remodeling and homeostasis. In addition, receptor activator of nuclear factor-kappaB ligand (RANKL) and osteoprotegerin (OPG) have been shown to be important regulators of osteoclastogenesis during bone remodeling, and their expressions were examined during fracture healing in a mouse model of tibial fracture. However, studies linking RANKL, OPG, IL-6 and TNF-alpha in patients with head injury and fracture are lacking. PATIENTS AND METHODS: Within the first few hours of admission to hospital and at 4, 8, and 12 weeks after the injury, we evaluated changes in serum levels of RANKL, OPG, IL-6 and TNF-alpha in 24 male patients with a concomitant head injury and fracture and in 26 male patients with fracture only. These levels were compared with those found in 36 healthy controls. RESULTS: The RANKL/OPG ratios were found to significantly lower in patients with a concomitant head injury and fracture than in the controls immediately after admission and at 4, 8, and 12 weeks after the injury. In addition, RANKL/OPG ratios were significantly lower in patients with a concomitant head injury and fracture than in those with fracture at 8 and 12 weeks after the injury. The serum IL-6 levels were significantly higher in patients with a concomitant head injury and fracture than in the controls upon admission, and at 4, 8, and 12 weeks after the injury. Moreover, the serum IL-6 levels were significantly higher in patients with a head injury and fracture than in those with just a fracture at 4, 8, and 12 weeks after the injury. CONCLUSIONS: Based on these changes in the profiles of RANKL, OPG, and IL-6 and the RANKL/OPG ratio, altered repair of a fracture can occur in patients with a concomitant head injury and fracture.

Lupus anticoagulant - hypoprothrombinemia syndrome: a rare cause of intracranial bleeding.

: We report a 14-year-old girl who presented with subdural hematoma and a deranged coagulation profile suggestive of an inhibitor. Investigations revealed prothrombin deficiency along with positivity for antiphospholipid antibodies, which improved with steroid therapy. Bleeding diathesis in children and adolescents commonly results from thrombocytopenia, platelet function disorders, or coagulation factor deficiency; whereas bleeding because of coagulation factor inhibitors are extremely rare in this age group. This case also highlights the uncommon presentation of antiphospholipid antibody syndrome, as they often present with thrombosis or pregnancy complications rather than bleeding.

Fatal hemorrhage due to a spontaneous factor V inhibitor with lupus anticoagulant properties.

: Factor V inhibitors are rare and have varied clinical presentations. We report on a 76-year-old female admitted to the hospital for pneumonia and treated with multiple antibiotics. Her baseline prothrombin time was 15.6 s and the activated partial thromboplastin time was 35 s. On admission day 10, she developed arm weakness and brain imaging showed a subdural hematoma. The prothrombin time was now 59.1 s with an activated partial thromboplastin time of more than 160 s and a normal thrombin time. A mixing study did not correct the clotting times and coagulation factor assays showed a nonspecific inhibition pattern. Only factor V activity remained low with serial dilutions, however, and a 70 Bethesda Unit inhibitor was identified. Aggressive supportive care was initiated but the patient succumbed to the effects of the intracranial hemorrhage. Factor V inhibitors may display lupus anticoagulant properties and may cause catastrophic bleeding. Our case illustrates that these inhibitors can arise quickly and supports an association with antibiotics.

My paper 20 years later: cerebral venous oxygen saturation studied with bilateral samples in the internal jugular veins.

INTRODUCTION: Jugular oxygen saturation monitoring was introduced in neurointensive care after severe traumatic brain injury (TBI) to explore the adequacy of brain perfusion and guide therapeutic interventions. The brain was considered homogeneous, and oxygen saturation was taken as representative of the whole organ. We investigated whether venous outflow from the brain was homogeneous by measuring oxygen saturation simultaneously from the two jugular veins. METHODS: In 32 comatose TBI patients both internal jugular veins (IJs) were simultaneously explored using intermittent samples; hemoglobin saturation was also recorded continuously by fiber-optic catheters in five patients. In five cases long catheters were inserted bilaterally upstream, up to the sigmoid sinuses. MAIN FINDINGS: On average, measurements from the two sides were in agreement (mean and standard deviation of the differences between the saturation of the two IJs were respectively 5.32 and 5.15). However, 15 patients showed differences of more than 15 % in hemoglobin saturation at some point; three others showed differences larger than 10 %. No relationship was found between the computed tomographic scan data and the hemoglobin saturation pattern. DISCUSSION/CONCLUSION: Several groups have confirmed differences between oxygen saturation in the two jugular veins. After years of enthusiasm, interest for jugular saturation has decreased and more modern methods, such as tissue oxygenation monitoring, are now available. Jugular saturation monitoring has low sensitivity, with the risk of missing low saturation, but high specificity; moreover it is cheap, when used with intermittent sampling. Monitoring the adequacy of brain perfusion after severe TBI is essential. However the choice of a specific monitor depends on local resources and expertise.

Analysis of S100 calcium binding protein B serum levels in different types of traumatic intracranial lesions.

The objective of this study was to determine whether the type of intracranial traumatic lesions, the number of simultaneous traumatic lesions, and the occurrence of skull and facial bone fractures have an influence on S100 calcium binding protein B (S100B) serum levels. Patients with blunt traumatic brain injury were prospectively enrolled into this cohort study over a period of 13 months. Venous blood samples were obtained prior to emergency cranial CT scan in all patients within 3 h after injury. The patients were then assigned into six groups: 1) concussion, 2) epidural hematoma, 3) subdural hematoma, 4) subarachnoid hemorrhage, 5) brain contusions, and 6) brain edema. The study included 1696 head trauma patients with a mean age of 57.7 ± 25.3 years, and 126 patients (8%) had 182 traumatic lesions on CT. Significant differences in S100B serum levels were found between cerebral edema and the other four bleeding groups: epidural p = 0.0002, subdural p < 0.0001, subarachnoid p = 0.0001, brain contusions p = 0.0003, and concussion p < 0.0001. Significant differences in S100B values between patients with one or two intracranial lesions (p = 0.014) or with three (p < 0.0001) simultaneous intracranial lesions were found. In patients with intracranial traumatic lesions, skull fractures, as well as skull and facial bone fractures occurring together, were identified as significant additional factors for the increase in serum S100B levels (p < 0.0001). Older age was also associated with elevated S100B serum levels (p < 0.0001). Our data show that peak S100B serum levels were found in patients with cerebral edema and brain contusions.

Subdural hematoma and oral anticoagulant therapy.

In a retrospective study of the period 1959 to 1978, the role of anticoagulant therapy (ACT) in the development of subdural hematoma (SH) was investigated. Of 212 cases, 46 were receiving ACT, a proportion highly in excess of the frequency of ACT in the general population of the Leiden area. In this area, the occurrence of SH in patients receiving ACT was seven times as high in males and 26 times as high in females as that in the population not receiving ACT. The occurrence of SH in patients receiving ACT was about one case per 2,000 patient years for both sexes and all age groups over the age of 40 years.

Local alterations of hemostatic-fibrinolytic mechanisms in reforming subdural hematomas.

Multiple chemical and coagulation determinations were undertaken on the subdural hematoma fluid from the reformed effusions of two patients. It was found that plasma or blood repeatedly reentered the subdural cavity. Coagulation studies compared the in vitro effects of subdural fluid with those of cerebrospinal fluid, serum, and a buffer control. Despite some chemical differences, the subdural fluids from both patients behaved similarly by (1) accelerating the intrinsic clotting system, (2) producing defective clot formation, and (3) accelerating the fibrinolytic system. It is presumed that these continuous hemostatic-fibrinolytic alterations, acting in the subdural sac, may have important implications in the growth and reformation of subdural hematomas, and a hypothesis of the mechanisms involved is presented.

Acute subdural hematomas with lupus anticoagulant (procoagulant inhibitor).

A patient with systemic lupus erythematosus (SLE) and circulating "lupus anticoagulant" (procoagulant inhibitor) developed both hemorrhagic microinfarction of the brain characteristic of SLE and massive bilateral, fatal, isodense subdural hematomas.

Acute subdural hematoma: is the blood itself toxic?

Recently developed rodent models of acute subdural hematoma have shown an associated large area of infarction underlying the clot. Excitotoxic processes have been postulated to play an important role in the extensive cell death seen with these models. However, whether increased pressure, vasoactive effects, or toxicity of the blood itself is responsible for initiating or sustaining these processes remains unclear. To study the effect of blood itself, an opaque layer of autologous clot was placed on the widely exposed parietal cortex of 15 Long-Evans rats and left in place for 72 h. In control animals the cortical surface was exposed but no blood was placed and contact with blood products was carefully limited. These animals were compared to a group in whom blood was injected into the closed subdural space. Histologic analysis showed that the majority of the cortex in both control and experimental animals in the open cranial model group appeared normal. Scattered small, discrete hemorrhagic lesions on the cortical surface of both control and experimental animals were seen, which had the appearance of focal mechanical trauma or vessel avulsion. There was no significant difference in average volume of lesions between experimental and control animals (9.1 versus 9.7 mm3, p = 0.85). No areas of infarction or selective neuronal loss were seen. In comparison, animals in which blood was injected into the subdural space had significantly larger lesions underlying clot, averaging 133.6 mm3 in volume (p < 0.0003). Blood in prolonged contact with the cortical surface in the absence of increased pressure, ischemia, or other insult is insufficient to cause underlying infarction like that seen when a similar volume of blood is injected into the closed subdural space.

Early changes in second messenger but not receptor binding sites after acute subdural hematoma: an in vitro autoradiographic study.

Neurotransmitter receptor-coupled mechanisms have been recently recognized as important determinants of cell damage after central nervous system (CNS) trauma and ischemia. Many of these receptors exert their intracellular effects via second messenger systems. This study used in vitro autoradiographic radioligand binding to measure beta-adrenergic and muscarinic cholinergic receptors and adenylate cyclase and protein kinase C (PKC) binding sites two h after acute subdural hematoma in rats. Both beta-adrenergic and cholinergic receptor binding sites were unchanged in comparison to controls, while adenylate cyclase binding significantly decreased in the ischemic cortex under the hematoma. These changes may constitute a major limiting factor on receptor-linked therapeutic strategies in trauma and ischemia. Protein kinase C activation significantly increased in the ischemic area under the hematoma in these studies. This appears to be a response to calcium flux, which may be in part glutamate mediated.

Coagulation and fibrinolysis in chronic subdural hematoma.

In 19 patients with chronic subdural hematoma, coagulation and fibrinolysis in venous blood taken at the time of surgery and in the hematoma contents aspirated from chronic subdural hematoma were studied. Compared with coagulation results for venous blood, the hematoma contents demonstrated marked prolongation of the recalcification time, prothrombin time, and activated partial thromboplastin time, and marked reduction of clotting factor V, the hepaplastin test, prothrombin, and fibrinogen. Antithrombin III was also decreased, and fibrinopeptide A was increased in the hematomas. Fibrinolytic results demonstrated that both plasminogen and alpha 2-plasmin inhibitor were decreased, and both fibrinopeptide B beta 15-42 and fibrin and fibrinogen degradation products were increased in the hematomas. These findings indicate excessive activation of the clotting system, thrombin generation, and increased fibrinolytic activity occurring in the hematomas. From these results, excessive activation of both the clotting and fibrinolytic systems is emphasized to be the possible etiological factor for the origin and development of chronic subdural hematoma.

Severe hypophosphatemia after head injury.

Hypophosphatemia occurs in a variety of clinical conditions. It develops in parallel with phosphate depletion from body losses or more commonly as a sequel to the redistribution of phosphate from the extracellular to the intracellular compartment. Hypophosphatemia is a multisystem disturbance capable of involving the neurological, immunological, and muscular systems, among others. In this report, we describe five patients with severe head injury who developed marked hypophosphatemia (less than 1 mg/dl) within 24 hours of hospitalization. This fall in serum phosphate coincided with the induction of respiratory alkalosis consequent to mechanical ventilation. In four of the five patients, as acid-base parameters returned to normal, serum phosphate values rose, in all instances reaching values greater than 2.5 mg/dl. Urinary phosphorus excretion, ordinarily negligible after hypophosphatemia induced by hypocapnia, was still present in Cases 1 and 4 (greater than 600 mg/24 hours). This is unexplained by any of the known hormonal or fluid alterations that accompany head injury. These five patients developed severe, yet transient, hypophosphatemia that resolved upon correction of hyperventilation-induced acid-base abnormalities. We discuss the pathophysiology of this entity and the implications for the head trauma patient.

Cerebral venous oxygen saturation studied with bilateral samples in the internal jugular veins.

The current literature reports many measurements (arteriovenous oxygen content difference and cerebral metabolic rate of oxygen, etc.) with samples from the internal jugular veins (IJs), obtained from either side of the neck, based on the assumption that a reliable sample of mixed venous blood can be drawn. We compared oxygen saturation in both IJs in 32 patients with head injuries to establish the similarities or discrepancies in the two veins. Both IJs were cannulated with 20-G catheters; in five patients, a fiberoptic catheter was used to obtain a continuous recording of the hemoglobin saturation. Blood samples were taken simultaneously from the two IJs and immediately processed; the total number of samples processed was 342, with an average of 5.34 paired samples from each patient. The mean and the standard deviation of the differences between the saturation of the two IJs were, respectively, 5.32 and 5.15. Fifteen patients showed differences greater than 15% in hemoglobin saturation; three more patients showed differences greater than 10% at some point during the investigation. Ultimately, only eight patients had differences of less than 5%. No relationship was found among the computed tomographic scan data and the pattern of hemoglobin saturation detected. Therefore, we were not able to identify the side more appropriate for monitoring in patients with bilateral, predominantly monolateral, cortical, or deeply located lesions.(ABSTRACT TRUNCATED AT 250 WORDS)