Initiation of a fixed-dose four-factor prothrombin complex concentrate protocol.

Patients who require urgent warfarin reversal often receive four-factor prothrombin complex concentrate (4F-PCC), which is traditionally dosed according to weight and initial INR. Our institution implemented a fixed-dose 4F-PCC strategy, using an initial dose of 1500 units. We evaluated the frequency with which the initial fixed dose 4F-PCC was inadequate, as defined by need for supplemental dosing. As part of the protocol, if the initial fixed-dose 4F-PCC is administered and does not achieve INR goal, then the remainder of the standard weight- and INR-based dosing can be given. During the study period, 63 patients on warfarin received 4F-PCC using the fixed-dose protocol. Based on the INR following 4F-PCC administration, 11 patients (17%) were eligible to receive a supplemental dose based on failure to achieve their specified INR goal. Two of the 11 patients eligible for supplemental 4F-PCC dosing received the second dose, both with initial supratherapeutic INRs > 3.5. We found that most patients given an initial fixed-dose 4F-PCC achieved their INR goals, and of those who did not, most did not receive supplemental dosing, suggesting that clinical providers felt that adequate hemostasis had been achieved. In addition, fixed-dose 4F-PCC was able to be given rapidly, with few dosing errors, suggesting that this is a reasonable option for 4F-PCC delivery.

Effect of CTA Tube Current on Spot Sign Detection and Accuracy for Prediction of Intracerebral Hemorrhage Expansion.

BACKGROUND AND PURPOSE: Reduction of CT tube current is an effective strategy to minimize radiation load. However, tube current is also a major determinant of image quality. We investigated the impact of CTA tube current on spot sign detection and diagnostic performance for intracerebral hemorrhage expansion. MATERIALS AND METHODS: We retrospectively analyzed a prospectively collected cohort of consecutive patients with primary intracerebral hemorrhage from January 2001 to April 2015 who underwent CTA. The study population was divided into 2 groups according to the median CTA tube current level: low current (<350 mA) and high current (≥350 mA). CTA first-pass readings for spot sign presence were independently analyzed by 2 readers. Baseline and follow-up hematoma volumes were assessed by semiautomated computer-assisted volumetric analysis. Sensitivity, specificity, positive and negative predictive values, and accuracy of spot sign in predicting hematoma expansion were calculated. RESULTS: This study included 709 patients (288 and 421 in the low- and high-current groups, respectively). A higher proportion of low-current scans identified at least 1 spot sign (20.8% versus 14.7%, P = .034), but hematoma expansion frequency was similar in the 2 groups (18.4% versus 16.2%, P = .434). Sensitivity and positive and negative predictive values were not significantly different between the 2 groups. Conversely, high-current scans showed superior specificity (91% versus 84%, P = .015) and overall accuracy (84% versus 77%, P = .038). CONCLUSIONS: CTA obtained at high levels of tube current showed better diagnostic accuracy for prediction of hematoma expansion by using spot sign. These findings may have implications for future studies using the CTA spot sign to predict hematoma expansion for clinical trials.

Dose-associated pulmonary complication rates after fresh frozen plasma administration for warfarin reversal.

UNLABELLED: ESSENTIALS: Fresh frozen plasma (FFP) may be associated with a dose-based risk of pulmonary complications. Patients received FFP for warfarin reversal at a large academic hospital over a 3-year period. Almost 20% developed pulmonary complications, and the risk was highest after > 3 units of FFP. The risk of pulmonary complications remained significant in multivariable analysis. BACKGROUND: Fresh frozen plasma (FFP) is often administered to reverse warfarin anticoagulation. Administration has been associated with pulmonary complications, but it is unclear whether this risk is dose-related. Aims We sought to characterize the incidence and dose relationship of pulmonary complications, including transfusion-associated circulatory overload (TACO) and transfusion-related acute lung injury (TRALI), after FFP administration for warfarin reversal. METHODS: We performed a structured retrospective review of patients who received FFP for warfarin reversal in the emergency department (ED) of an academic tertiary-care hospital over a 3-year period. Logistic regression was used to explore the relationship between FFP dose and risk of pulmonary events. RESULTS: Two hundred and fifty-one patients met the inclusion criteria. Overall, 49 patients (20%) developed pulmonary complications, including 30 (12%) with TACO, two (1%) with TRALI, and 17 (7%) with pulmonary edema not meeting the criteria for TACO. Pulmonary complications were significantly more frequent in those who received > 3 units of FFP (34.0% versus 15.6%, 95% confidence interval for risk difference 7.9%-8.9%). After stratification by subtype of complication, only the risk of TACO was statistically significant (28.3% versus 7.6%, 95% confidence interval for risk difference 8.2%-16.6%). In multivariable analysis controlling for age, sex, initial systolic blood pressure, and intravenous fluids given in the ED, > 3 units of FFP remained a significant risk factor for pulmonary complications (odds ratio 2.49, 95% confidence interval 1.21-5.13). CONCLUSIONS: Almost 20% of patients who received FFP for warfarin reversal developed pulmonary complications, primarily TACO, and this risk increased with > 3 units of FFP. Clinicians should be aware of and prepared to manage these complications.

Warfarin-related intraventricular hemorrhage: imaging and outcome.

OBJECTIVE: Oral anticoagulation therapy (OAT) with warfarin increases mortality and disability after intracerebral hemorrhage (ICH), the result of increased ICH volume and risk of hematoma expansion. We investigated whether OAT also influences risk of development of intraventricular hemorrhage (IVH), the volume of IVH and IVH expansion, and whether IVH is a substantive mediator of the overall effect of OAT on ICH outcome. METHODS: We performed a retrospective analysis of a prospectively collected single-center cohort of 1,879 consecutive ICH cases (796 lobar, 865 deep, 153 cerebellar, 15 multiple location, 50 primary IVH) from 1999 to 2009. ICH and IVH volumes at presentation, as well as hematoma expansion (>33% or >6 mL increase) and IVH expansion (>2 mL increase), were determined using established semiautomated methods. Outcome was assessed at 90 days using either the modified Rankin Scale or Glasgow Outcome Scale. RESULTS: Warfarin use was associated with IVH risk, IVH volume at presentation, and IVH expansion in both lobar and deep ICH (all p < 0.05) in a dose-response relationship with international normalized ratio. Warfarin was associated with poor outcome in both lobar and deep ICH (p < 0.01), and >95% of this effect was accounted for by baseline ICH and IVH volumes, as well as ICH and IVH expansion. CONCLUSION: Warfarin increases IVH volume and risk of IVH expansion in lobar and deep ICH. These findings (along with effects on ICH volume and expansion) likely represent the mechanisms by which anticoagulation worsens ICH functional outcome.

Statin use and outcome after intracerebral hemorrhage: case-control study and meta-analysis.

OBJECTIVES: Intracerebral hemorrhage (ICH) is a highly lethal disease of the elderly. Use of statins is increasingly widespread among the elderly, and therefore common in patients who develop ICH. Accumulating data suggests that statins have neuroprotective effects, but their association with ICH outcome has been inconsistent. We therefore performed a meta-analysis of all available evidence, including unpublished data from our own institution, to determine whether statin exposure is protective for patients who develop ICH. METHODS: In our prospectively ascertained cohort, we compared 90-day functional outcome in 238 pre-ICH statin cases and 461 statin-free ICH cases. We then meta-analyzed results from our cohort along with previously published studies using a random effects model, for a total of 698 ICH statin cases and 1,823 non-statin-exposed subjects. RESULTS: Data from our center demonstrated an association between statin use before ICH and increased probability of favorable outcome (odds ratio [OR] = 2.08, 95% confidence interval [CI] 1.37-3.17) and reduced mortality (OR = 0.47, 95% CI 0.32-0.70) at 90 days. No compound-specific statin effect was identified. Meta-analysis of all published evidence confirmed the effect of statin use on good outcome (OR = 1.91, 95% CI 1.38-2.65) and mortality (OR = 0.55, 95% CI 0.42-0.72) after ICH. CONCLUSION: Antecedent use of statins prior to ICH is associated with favorable outcome and reduced mortality after ICH. This phenomenon appears to be a class effect of statins. Further studies are required to clarify the biological mechanisms underlying these observations.

Frequency of adequate contrast opacification of the major intracranial venous structures with CT angiography in the setting of intracerebral hemorrhage: comparison of 16- and 64-section CT angiography techniques.

BACKGROUND AND PURPOSE: DVST is an important cause of ICH because its treatment may require anticoagulation or mechanical thrombectomy. We aimed to determine the frequency of adequate contrast opacification of the major intracranial venous structures in CTAs performed for ICH evaluation, which is an essential factor in excluding DVST as the ICH etiology. MATERIALS AND METHODS: Two readers retrospectively reviewed CTAs performed in 170 consecutive patients with ICH who presented to our emergency department during a 1-year period to determine by consensus whether qualitatively, contrast opacification in each of the major intracranial venous structures was adequate to exclude DVST. "Adequate contrast opacification" was defined as homogeneous opacification of the venous structure examined. "Inadequate contrast opacification" was defined as either inhomogeneous opacification or nonopacification of the venous structure examined. Delayed scans, if obtained, were reviewed by the same readers blinded to the first-pass CTAs to determine the adequacy of contrast opacification in the venous structures according to the same criteria. In patients who did not have an arterial ICH etiology, the same readers determined if thrombosis of an inadequately opacified intracranial venous structure could have potentially explained the ICH by correlating the presumed venous drainage path of the ICH with the presence of inadequate contrast opacification within the venous structure draining the venous territory of the ICH. CTAs were performed in 16- or 64-section CT scanners with bolus-tracking, scanning from C1 to the vertex. Patients with a final diagnosis of DVST were excluded. We used the Pearson χ(2) test to determine the significance of the differences in the frequency of adequate contrast opacification within each of the major intracranial venous structures in scans obtained using either a 16- or 64-section MDCTA technique. RESULTS: Fifty-eight patients were evaluated with a 16-section MDCTA technique (34.1%) and 112 with a 64-section technique (65.9%). Adequate contrast opacification within all major noncavernous intracranial venous structures was significantly less frequent in first-pass CTAs performed with a 64-section technique (33%) than in those performed with a 16-section technique (60%, P value < .0001). Delayed scans were obtained in 50 patients, all of which demonstrated adequate contrast opacification in the major noncavernous intracranial venous structures. In 142 patients with supratentorial or cerebellar ICH without an underlying arterial etiology, we found that thrombosis of an inadequately opacified major intracranial venous structure could have potentially explained the ICH in 38 patients (26.8%), most examined with a 64-section technique (86.8%). CONCLUSIONS: Inadequate contrast opacification of the major intracranial venous structures is common in first-pass CTAs performed for ICH evaluation, particularly if performed with a 64-section technique. Acquiring delayed scans appears necessary to confidently exclude DVST when there is strong clinical or radiologic suspicion.

Practical scoring system for the identification of patients with intracerebral hemorrhage at highest risk of harboring an underlying vascular etiology: the Secondary Intracerebral Hemorrhage Score.

BACKGROUND AND PURPOSE: An ICH patient's risk of harboring an underlying vascular etiology varies according to baseline clinical and NCCT characteristics. Our aim was to develop a practical scoring system to stratify patients with ICH according to their risk of harboring a vascular etiology. MATERIALS AND METHODS: Using a data base of 623 patients with ICH evaluated with MDCTA during a 9-year period, we developed a scoring system based on baseline clinical characteristics (age group [0-2 points], sex [0-1 point], neither known HTN nor impaired coagulation [0-1 point]), and NCCT categorization (0-2 points) to predict the risk of harboring a vascular lesion as the ICH etiology (SICH score). We subsequently applied the SICH score to a prospective cohort of 222 patients with ICH who presented to our emergency department during a 13-month period. Using ROC analysis, we calculated the AUC and MOP for the SICH score in both the retrospective and prospective patient cohorts separately and the entire patient population. Patients with SAH in the basal cisterns were excluded. RESULTS: A vascular etiology was found in 120 of 845 patients with ICH evaluated with MDCTA (14.2%), most commonly AVMs (45.8%), aneurysms with purely intraparenchymal rupture (21.7%), and DVSTs (16.7%). The MOP was reached at a SICH score of >2, with the highest incidence of vascular ICH etiologies in patients with SICH scores of 3 (18.5%), 4 (39%), 5 (84.2%), and 6 (100%). There was no significant difference in the AUC between both patient cohorts (0.86-0.87). CONCLUSIONS: The SICH score successfully predicts a given ICH patient's risk of harboring an underlying vascular etiology and could be used as a guide to select patients with ICH for neurovascular evaluation to exclude the presence of a vascular abnormality.

Validation of the Quick Confusion Scale for mental status screening in the emergency department.

OBJECTIVE: The Mini-Mental Status Exam (MMSE) is a commonly used assessment of cognitive status; however, it has been considered somewhat unwieldy for use in the emergency department (ED). An alternate test, the Quick Confusion Scale (QCS), has been compared against the MMSE in a single centre. We hypothesised that the QCS would strongly correlate with the MMSE in the ED, but could be administered more quickly. METHODS: Trained research assistants administered both the QCS and the MMSE to a convenience sample of 666 patients and visitors in an urban academic ED. Patients were randomised as to which test would be administered first. RESULTS: The QCS required less time to complete than the MMSE (2.7+/-1.3 vs. 5.1+/-1.9 min, p<0.0001). Nine patients could not complete the MMSE because they could not use their hands to write and four because of vision impairment. Correlation of QCS and MMSE scores was fair, with Pearson's r=0.61 (95% CI, 0.56-0.66). CONCLUSIONS: The QCS can be administered more quickly than the MMSE, and is easier to administer in the ED because it does not require the subject to read, write or draw. There is a fair correlation between QCS and MMSE scores.

Contrast extravasation on CT angiography predicts hematoma expansion in intracerebral hemorrhage.

BACKGROUND: Patients with acute intracerebral hemorrhage (ICH) presenting within 3 hours of symptom onset are known to be at increased risk of expansion. However, only a minority arrive within this time frame. Therefore, alternative markers for expansion risk are needed. OBJECTIVE: To examine whether contrast extravasation on CT angiography (CTA) at presentation predicts subsequent hematoma expansion. METHODS: Consecutive patients with primary ICH presenting to an urban tertiary care hospital were prospectively captured in a database. We retrospectively reviewed images for all patients receiving a CTA and at least one further CT scan within 48 hours. RESULTS: Complete data were available for 104 patients. Contrast extravasation at the time of CTA was present in 56% of patients, and associated with an increased risk of hematoma expansion (22% vs 2%, p = 0.003). Patients who received a baseline CTA within 3 hours were more likely to have subsequent expansion (27%, vs 13% for those presenting later, p = 0.1). However, after multivariable analysis, contrast extravasation was the only significant predictor of hematoma expansion (OR 18, 95% CI 2.1 to 162). This effect was independent of time to presentation. CONCLUSIONS: Contrast extravasation is independently associated with hematoma expansion. Patients presenting within the first few hours after symptom onset have traditionally been considered those at highest risk of expansion. However, for those presenting later, the presence of contrast may be a useful marker to guide therapies aimed at decreasing this risk.

Headache in United States emergency departments: demographics, work-up and frequency of pathological diagnoses.

Headache is a common complaint in the emergency department (ED). In order to examine headache work-ups and diagnoses across the USA, we queried a representative sample of adult ED visits (the National Hospital Ambulatory Medical Care Survey) for the years 1992-2001. Headache accounted for 2.1 million ED visits per year (2.2% of visits). Of the 14% of patients who underwent neuroimaging, 5.5% received a pathological diagnosis. Of the 2% of patients who underwent lumbar puncture, 11% received a pathological diagnosis. On multivariable analysis, a decreased rate of imaging was noted for patients without private insurance [odds ratio (OR) 0.61, confidence interval (CI) 0.44, 0.86] and for those presenting off-hours (OR 0.55, CI 0.39, 0.77). Patients over 50 were more likely to receive a pathological diagnosis (OR 3.3, CI 1.2, 9.3). In conclusion, clinicians should ensure that appropriate work-ups are performed regardless of presentation time or insurance status, and be vigilant in the evaluation of older patients.

Naturalized salmonid populations occur in the presence of elevated trace element concentrations and temperatures in the Firehole River, Yellowstone National Park, Wyoming, USA.

We investigated the effects of geothermally influenced waters on the distribution of rainbow trout, Oncorhynchus mykiss, and brown trout, Salmo trutta, in the Firehole River and its tributaries in Yellowstone National Park (WY, USA) from June 1997 to June 1998. Geothermal features in the Firehole River basin elevate mineral content and temperature in portions of the river and its tributaries. We found concentrations of boron and arsenic to be elevated in geothermally influenced areas compared with upstream sites. Boron concentrations occasionally exceeded 1,000 microg/L, a proposed limit for the protection of aquatic organisms. Arsenic concentrations occasionally exceeded 190 microg/L, the chronic ambient water quality criterion. Temperatures in geothermally influenced sites ranged up to 30 degrees C and were consistently 5 to 10 degrees C higher than upstream sites unaffected by geothermal inputs. Rainbow trout occurred at sites with elevated concentrations of boron, arsenic, and other trace elements and elevated water temperatures. Rainbow trout inhabited and spawned at sites with the most elevated trace element concentrations and temperatures; however, brown trout were absent from these sites. Water temperature may be the major factor determining brown trout distributions, but we cannot exclude the possibility that brown trout are more sensitive than rainbow trout to boron, arsenic, or other trace elements. Further investigations are needed to determine species-specific tolerances of boron, arsenic, and other trace elements among salmonids.

In vitro processing of herpes simplex virus type 1 DNA replication intermediates by the viral alkaline nuclease, UL12.

Herpes simplex virus type 1 (HSV-1) DNA replication intermediates exist in a complex nonlinear structure that does not migrate into a pulsed-field gel. Genetic evidence suggests that the product of the UL12 gene, termed alkaline nuclease, plays a role in processing replication intermediates (R. Martinez, R. T. Sarisky, P. C. Weber, and S. K. Weller, J. Virol. 70:2075-2085, 1996). In this study we have tested the hypothesis that alkaline nuclease acts as a structure-specific resolvase. Cruciform structures generated with oligonucleotides were treated with purified alkaline nuclease; however, instead of being resolved into linear duplexes as would be expected of a resolvase activity, the artificial cruciforms were degraded. DNA replication intermediates were isolated from the well of a pulsed-field gel ("well DNA") and treated with purified HSV-1 alkaline nuclease. Although alkaline nuclease can degrade virion DNA to completion, digestion of well DNA results in a smaller-than-unit-length product that migrates as a heterogeneous smear; this product is resistant to further digestion by alkaline nuclease. The smaller-than-unit-length products are representative of the entire HSV genome, indicating that alkaline nuclease is not inhibited at specific sequences. To further probe the structure of replicating DNA, well DNA was treated with various known nucleases; our results indicate that replicating DNA apparently contains no accessible double-stranded ends but does contain nicks and gaps. Our data suggest that UL12 functions at nicks and gaps in replicating DNA to correctly repair or process the replicating genome into a form suitable for encapsidation.

The exonuclease activity of HSV-1 UL12 is required for in vivo function.

The herpes simplex virus type 1 (HSV-1) UL12 gene encodes an alkaline pH-dependent deoxyribonuclease termed alkaline nuclease. A recombinant UL12 knockout mutant, AN-1, is severely compromised for growth, and analysis of this mutant suggests that UL12 plays a role in processing complex DNA replication intermediates (R. Martinez, R. T. Sarisky, P. C. Weber, and S. K. Weller, (1996) J. Virol. 70, 2075-2085). This processing step may be required for the generation of capsids that are competent for egress from the nucleus to the cytoplasm. In this report, we address the question of whether the AN-1 growth phenotype is due to the loss of UL12 catalytic activity. We constructed two point mutations in a highly conserved region (motif II) of UL12 and purified wild-type and mutant enzymes from a baculovirus expression system. Both mutant proteins are stable, soluble, and competent for correct nuclear localization, suggesting that they have retained an intact global conformation. Neither mutant protein, however, exhibits exonuclease activity. In order to examine the in vivo effects of these mutations, we determined whether expression of mutant proteins from amplicon plasmids could complement AN-1. While the wild-type plasmid complements the growth of the null mutant, neither UL12 mutant can do so. Loss of exonuclease activity therefore correlates with loss of in vivo function.

Concentrations of metals associated with mining waste in sediments, biofilm, benthic macroinvertebrates, and fish from the Coeur d'Alene River basin, Idaho.

Arsenic, Cd, Cu, Pb, Hg, and Zn were measured in sediments, biofilm, benthic macroinvertebrates, and fish from the Coeur d'Alene (CDA) River to characterize the pathway of metals transfer between these components. Metals enter the CDA Basin via tributaries where mining activities have occurred. In general, the ranking of food-web components from the greatest to smallest concentrations of metals was as follows: biofilm (the layer of abiotic and biotic material on rock surfaces) and sediments > invertebrates > whole fish. Elevated Pb was documented in invertebrates, and elevated Cd and Zn were documented in sediment and biofilm approximately 80 km downstream to the Spokane River. The accumulation of metals in invertebrates was dependent on functional feeding group and shredders-scrapers that feed on biofilm accumulated the largest concentrations of metals. Although the absolute concentrations of metals were the largest in biofilm and sediments, the metals have accumulated in fish approximately 50 km downstream from Kellogg, near the town of Harrison. While metals do not biomagnify between trophic levels, the metals in the CDA Basin are bioavailable and do biotransfer. Trout less than 100 mm long feed exclusively on small invertebrates, and small invertebrates accumulate greater concentrations of metals than large invertebrates. Therefore, early-lifestage fish may be exposed to a larger dose of metals than adults.

Relationships between boron concentrations and trout in the Firehole River, Wyoming: historical information and preliminary results of a field study.

The Firehole River (FHR) in Yellowstone National Park (YNP) is a world-renowned recreational fishery that predominantly includes rainbow trout (RBT, Oncorhynchus mykiss) and brown trout (BNT, Salmo trutta). The trout populations apparently are closed to immigration and have been self-sustaining since 1955. Inputs from hot springs and geysers increase the temperature and mineral content of the water, including elevating the boron (B) concentrations to a maximum of approximately 1 mg B/L. Both RBT and BNT reside in warm-water reaches, except when the water is extremely warm (> or = approximately 25 degrees C) during midsummer. They spawn in late fall and early winter, with documented spawning of BNT in the cold-water reach upstream from the Upper Geyser Basin and of RBT in the Lower Geyser Basin reach, where water temperatures presumably are the warmest; however, successful recruitment of RBT in waters containing approximately 1 mg B/L has not been demonstrated conclusively. Thus, we began investigating the relationships among temperature, B concentrations, other water-quality parameters, and the distribution and reproduction of trout in the FHR in spring 1997. However, atypical high water flows and concomitant lower than historical temperatures and B concentrations during summer 1997 preclude conclusions about avoidance of high B concentrations.