Christoph Terborg

Anticoagulant Reversal, Blood Pressure Levels, and Anticoagulant Resumption in Patients With Anticoagulation-Related Intracerebral Hemorrhage

IMPORTANCE Although use of oral anticoagulants (OACs) is increasing, there is a substantial lack of data on how to treat OAC-associated intracerebral hemorrhage (ICH). OBJECTIVE To assess the association of anticoagulation reversal and blood pressure (BP) with hematoma enlargement and the effects of OAC resumption. DESIGN, SETTING, AND PARTICIPANTS Retrospective cohort study at 19 German tertiary care centers (2006-2012) including 1176 individuals for analysis of long-term functional outcome, 853 for analysis of hematoma enlargement, and 719 for analysis of OAC resumption. EXPOSURES Reversal of anticoagulation during acute phase, systolic BP at 4 hours, and reinitiation of OAC for long-term treatment. MAIN OUTCOMES AND MEASURES Frequency of hematoma enlargement in relation to international normalized ratio (INR) and BP. Incidence analysis of ischemic and hemorrhagic events with or without OAC resumption. Factors associated with favorable (modified Rankin Scale score, 0-3) vs unfavorable functional outcome. RESULTS Hemorrhage enlargement occurred in 307 of 853 patients (36.0%). Reduced rates of hematoma enlargement were associated with reversal of INR levels <1.3 within 4 hours after admission (43/217 [19.8%]) vs INR of ≥1.3 (264/636 [41.5%]; P < .001) and systolic BP <160 mm Hg at 4 hours (167/504 [33.1%]) vs ≥160 mm Hg (98/187 [52.4%]; P < .001). The combination of INR reversal <1.3 within 4 hours and systolic BP of <160 mm Hg at 4 hours was associated with lower rates of hematoma enlargement (35/193 [18.1%] vs 220/498 [44.2%] not achieving these values; OR, 0.28; 95% CI, 0.19-0.42; P < .001) and lower rates of in-hospital mortality (26/193 [13.5%] vs 103/498 [20.7%]; OR, 0.60; 95% CI, 0.37-0.95; P = .03). OAC was resumed in 172 of 719 survivors (23.9%). OAC resumption showed fewer ischemic complications (OAC: 9/172 [5.2%] vs no OAC: 82/547 [15.0%]; P < .001) and not significantly different hemorrhagic complications (OAC: 14/172 [8.1%] vs no OAC: 36/547 [6.6%]; P = .48). Propensity-matched survival analysis in patients with atrial fibrillation who restarted OAC showed a decreased HR of 0.258 (95% CI, 0.125-0.534; P < .001) for long-term mortality. Functional long-term outcome was unfavorable in 786 of 1083 patients (72.6%). CONCLUSIONS AND RELEVANCE Among patients with OAC-associated ICH, reversal of INR <1.3 within 4 hours and systolic BP <160 mm Hg at 4 hours were associated with lower rates of hematoma enlargement, and resumption of OAC therapy was associated with lower risk of ischemic events. These findings require replication and assessment in prospective studies. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01829581.

Dysfunction of vasomotor reactivity in severe sepsis and septic shock.

Abstract. Objective: Perfusion abnormalities are an overall phenomenon in severe sepsis and septic shock, leading to organ dysfunction. We investigated whether carbon dioxide (CO2)-induced vasomotor reactivity (VMR) is impaired in septic patients, compared with values obtained outside sepsis. Design: Prospective, clinical study. Setting: Six-bed neurologic critical care unit of a university hospital. Patients and participants: Eight consecutive patients with severe sepsis and septic shock. Measurements and results: CO2-reactivity was measured during and outside a period of severe sepsis or septic shock according to ACCP/SCCM criteria by means of transcranial Doppler sonography and near-infrared spectroscopy (NIRS). VMR was calculated as the percentage change of cerebral blood flow velocity (normalized CO2-reactivity, NCR) and absolute changes in concentration of oxygenated hemoglobin, deoxygenated hemoglobin, total hemoglobin (HbO2, Hb, HbT) and Hbdiff (difference between HbO2 and Hb) in µmol/l per 1% increase in end-tidal CO2 (CR-HbO2, CR-Hb, CR-HbT, CR-Hbdiff). NCR and NIRS-reactivities were significantly reduced during severe sepsis and septic shock compared with values outside sepsis (mean, SD, Wilcoxon): NCR 11.0 (7.1) versus 30.7 (13.0), p<0.02; CR-HbO2 0.70 (0.61) versus 2.33 (1.11), p<0.02; CR-Hb –0.17 (0.74) versus –1.42 (1.28), p<0.04; CR-HbT 0.53 (0.48) versus 1.05 (0.40), p<0.03; CR-Hbdiff 0.91 (1.33) versus 3.75 (2.33), p<0.02. This indicates a severely disturbed VMR. Conclusions: In the advent of a disturbed cerebral autoregulation, critical drops in blood pressure during sepsis are transferred directly into the vascular bed, leading to cerebral hypoperfusion. This mechanism might contribute to the pathogenesis of septic encephalopathy.

Early Disruption of the Blood–Brain Barrier After Thrombolytic Therapy Predicts Hemorrhage in Patients With Acute Stroke

Background and Purpose— Leaks of the blood–brain barrier can be detected on postcontrast-enhanced T1-weighted MRIs. Although early disruptions of the blood–brain barrier appear to be an important risk factor for tissue plasminogen activator-related hemorrhages in rodents, little is known about their incidence and consequences in human stroke. Methods— This is a retrospective analysis of a prospectively collected stroke database over the past 6 years. In 52 patients, multimodal MRI (including diffusion-weighted, perfusion-weighted, and postcontrast-enhanced T1-weighted MRI to detect blood–brain barrier changes) had been performed immediately before systemic thrombolysis and in 48 patients within a median of 30 minutes (interquartile range: 30 to 60 minutes) after recombinant tissue plasminogen activator treatment. The incidence of symptomatic hemorrhage (SICH), defined as any parenchymal hemorrhage leading to deterioration in the patient’s clinical condition, was related to several clinical and imaging variables, including early blood–brain barrier changes. Results— Overall, SICH was detected in 9 (9%) patients and among these, 2 died. Although no blood–brain barrier changes were detectable before thrombolysis, 3 of 48 patients (6.25%) had a parenchymal gadolinium enhancement in the areas of initial infarction after tissue plasminogen activator treatment. All 3 patients developed SICHs at sites corresponding to the areas of enhancement. The presence of a parenchymal enhancement was significantly associated with SICH (P<0.01), whereas other clinical and imaging variables did not predict SICH in this series. Conclusion— Early parenchymal enhancement after intravenous tissue plasminogen activator is significantly associated with subsequent SICH and could therefore become a useful imaging sign for the rapid initiation of preventive strategies in the future.

Outcome after decompressive craniectomy in patients with severe ischemic stroke

SummaryDecompressive craniectomy after space occupying infarction of the middle cerebral artery (MCA) tends to decrease mortality and increase functional outcome. The aim of this retrospective study was to evaluate mortality rates and functional outcome in our centre and to identify predictors of prognosis. The charts of 30 consecutive patients (6 women, 24 men, mean age 59.3 ± 11.0 years) who underwent craniectomy after space occupying MCA-infarction from 1996 to 2002 were analyzed. Functional outcome was assessed by semistructured telephone interview as Barthel-Index, modifed Rankin scale and extended Barthel-Index. Five patients (mean age 67.2 ± 6.1 years) died within 5.2 ± 2.4 days (range 2–8 days) after the first symptoms due to herniation. Nine patients (mean age 63.1 ± 7.1 years) died 141.0 ± 92.5 days (range 40–343) after stroke onset due to internal complications. 16 patients survived (mean surviving time 2.1 ± 1.5 years, mean age 54.1 ± 11.4 years). Mortality was related to age and the number of risk factors/comorbidity, and functional outcome was dependent on the number of risk factors/comorbidity. Our small observational, retrospective study suggests that hemicraniectomy in patients with space occupying MCA- infarction decreases mortality rate and increases functional outcome. Further randomized trials may prove useful to better define the indications, timing and prognosis for this procedure.

Noninvasive Assessment of Cerebral Perfusion and Oxygenation in Acute Ischemic Stroke by Near-Infrared Spectroscopy

Background: In acute stroke patients, there is a need for noninvasive measurement to monitor blood flow-based therapies. We investigated the utility of near-infrared spectroscopy (NIRS) to determine cerebral perfusion in these patients. Methods: Eleven patients were investigated within 1.4 ± 2.2 days after onset of an ischemic middle cerebral artery infarction by monitoring the kinetics of an intravenous bolus of indocyanine green (ICG). For ICG kinetics, bolus peak time, time to peak (TTP = time between 0 and 100% ICG maximum), maximum ICG concentration, rise time (time between 10 and 90% ICG maximum), slope (maximum ICG/TTP), and blood flow index (BFI = maximum ICG/rise time) were obtained. Perfusion-weighted MRI (PWI) and NIRS measurements were performed within 24 h, and the interhemispherical differences of TTP values were compared. Results: Stroke patients showed an increased bolus peak time (p < 0.02), TTP (p < 0.01), and rise time (p < 0.01), whereas slope (p < 0.01) and BFI (p < 0.01) were diminished at the site of infarction as compared to the unaffected hemisphere. The interhemispherical differences of TTP as measured by PWI and NIRS were closely correlated (r = 0.86). Conclusions: Noninvasive measurements of cerebral ICG kinetics by NIRS provide a useful means of detecting cerebral perfusion deficits in patients with acute stroke, which correlate well with those obtained by PWI.

Influence of Galantamine on Vasomotor Reactivity in Alzheimer’s Disease and Vascular Dementia Due to Cerebral Microangiopathy

Background and Purpose— Recent reports suggest that vascular factors play a crucial role in the development and progression of Alzheimer’s disease. We aimed to assess vasomotor reactivity in patients with Alzheimer’s disease and vascular dementia due to microangiopathy using transcranial Doppler sonography and near-infrared spectroscopy during a CO2 exposition task. Methods— The normalized CO2 reactivity assessed at the middle cerebral artery and the oxygenated and deoxygenated hemoglobin of the frontal cortex were obtained. To investigate the impact of cholinergic deficiency known for Alzheimer’s disease on vasomotor reactivity, both groups were reinvestigated during treatment with the acetylcholine esterase inhibitor galantamine. Results— Transcranial Doppler analysis revealed significantly reduced normalized CO2 reactivity for Alzheimer’s disease and vascular dementia. Vasomotor reactivity assessed by near-infrared spectroscopy was decreased in patients with vascular dementia, but not in Alzheimer’s disease. Galantamine treatment showed a beneficial effect, normalizing these parameters close to age-matched control levels. Conclusions— Our results suggest that Alzheimer’s disease is associated with a lack of vasomotor reactivity, which might be associated with disturbed autoregulation indicating a potential risk for a decreased protection of brain tissue against blood pressure changes. Additionally, a diminished increase of cortical oxygenated hemoglobin during the CO2 test was apparent in patients with vascular dementia. Galantamine treatment influenced vascular reactivity in the CO2 test, thus providing evidence for the cholinergic deficiency, thereby adding to vascular dysregulation in Alzheimer’s disease, but also indicating an important role of cholinergic system dysfunction for vascular dementia.

Preserved Co2 Reactivity and Increase in Middle Cerebral Arterial Blood Flow Velocity During Laparoscopic Surgery in Children

In adult patients, the creation of pneumoperitoneum (PP) by means of carbon dioxide (CO2) insufflation leads to an increase in cerebral blood flow velocity (CBFV), which is thought to be caused by hypercapnia. We evaluated whether PP leads to an increase of CBFV in children, and whether this increase is directly related to PP. The effects of PP on middle cerebral artery blood flow velocity were investigated in 12 children (mean age 3 yr, range 15–63 mo) undergoing laparoscopic herniorrhaphy under general anesthesia with sevoflurane and nitrous oxide/oxygen. CBFV was measured by using transcranial Doppler ultrasonography. During CO2 insufflation, the end-tidal CO2 concentration was kept constant by adjustment of ventilation by increasing minute volume. The CBFV increased significantly at an intraabdominal pressure of 12 mm Hg compared with baseline from 68 ± 11 cm/s to 81 ± 12 cm/s (P < 0.05). CO2 reactivity remained in the normal range (4.0% ± 1.9%/mm Hg) during PP. We conclude that the induction of PP leads to an increase in middle cerebral artery blood flow velocity in young children independent from hypercapnia, whereas CO2 reactivity remains normal.

Short-term effect of cigarette smoking on CO2-induced vasomotor reactivity in man: A study with near-infrared spectroscopy and tanscranial Doppler sonography

Cigarette smoking is a major risk factor for stroke, and quitting reduces the stroke risk within a few years. The aim of our study was to clarify whether CO(2)-induced vasomotor reactivity (VMR) is impaired in smokers after smoking a cigarette as a possible factor of an increased stroke risk. We compared VMR of 23 healthy smokers assessed at baseline, immediately, and 30 min after smoking a cigarette (1.2 mg nicotine) with values from nonsmoking, age-matched controls (n=24), obtained at identical time intervals. Cerebral blood flow velocities (CBFV) of both middle cerebral arteries (transcranial Doppler sonography), changes in concentration of cerebral oxygenated, deoxygenated, and total hemoglobin (HbO(2), Hb, and HbT, near-infrared spectroscopy), mean arterial blood pressure (MAP), and skin blood flow were recorded during normo- and hypercapnia. VMR was calculated as percentage change in CBFV and as micromolar change in concentration of HbO(2), Hb, and HbT per 1% increase in endtidal CO(2). CBFV in smokers was increased at baseline (left, p<0.05; right, p=0.05), immediately (p<0.01), and 30 min after smoking (p<0.05) as compared with nonsmokers. MAP rose immediately after smoking (p<0.01) and declined after 30 min. VMR in smokers at baseline did not differ from controls, decreased immediately after smoking (p<0.05), and normalized after 30 min (p>0.05). Increased baseline CBFV in smokers after smoking might be due to arteriolar dilation, increased MAP, and possibly constriction of basal cerebral arteries. Impaired VMR for about 30 min after smoking reflects endothelial dysfunction. This might contribute to the enhanced stroke risk in smokers.

Noninvasive monitoring of cerebral oxygenation during vasomotor reactivity tests by a new near-infrared spectroscopy device.

Background: Spatially resolved spectroscopy is a recently developed technique for noninvasive monitoring of cerebral tissue oxygenation using the photon diffusion theory. Methods: We studied this technique with a new, commercial near-infrared spectroscopy (NIRS) device during vasomotor reactivity tests in 28 healthy volunteers (mean age 31.0 years; SD 10.6 years) and compared it with values assessed by the modified Beer-Lambert law and indices from simultaneous transcranial Doppler sonography of both middle cerebral arteries. We measured O2 reactivity as percentage change of cerebral blood flow velocity (CBFV), as absolute change in the concentrations (measured in µmol/l) of oxygenated (HbO2), deoxygenated (Hb) and total hemoglobin (HbT), and as change in the tissue oxygenation index (TOI) during inhalation of 100% oxygen. CO2 reactivity was calculated as percentage change of CBFV (NCR), as absolute change in the concentrations of HbO2, Hb, and HbT (µmol/l), and as change in TOI (%) per 1% increase in end-tidal CO2. Results: One hundred percent oxygen inhalation lead to a decrease in CBFV (mean ± SD: left –8.0 ± 7.0%, p = 0.000; right –9.6 ± 7.6%, p = 0.000), an increase in HbO2 (0.99 ± 1.07 µmol/l), Hbdiff (2.23 ± 1.72 µmol/l), and TOI (3.1 ± 1.5%), and a decrease in Hb (–1.22 ± 0.74 µmol/l), significant from baseline values (p = 0.0000). CO2 reactivity was: NCR left 25.4 ± 14.7%; NCR right 25.9 ± 13.4%; HbO2 1.99 ± 0.97 µmol/l; Hb –1.24 ± 0.81 µmol/l; HbT 0.81 ± 1.0 µmol/l, and TOI 3.7 ± 2.2%. O2 reactivity in TCD did not correlate with NIRS reactivities (Pearson p > 0.05), but NCR did correlate with changes in HbO2, Hb, and TOI (Pearson p < 0.01). TOI was closely related to indices derived from the Beer-Lambert law (Pearson p < 0.03), but not with mean arterial blood pressure or skin blood flow during vasomotor reactivity tests. Conclusion: Spatially resolved spectroscopy provides an encouraging, noninvasive new tool to study cerebral tissue oxygenation during vasomotor reactivity tests consistent with physiological changes.

Acute effects of cigarette smoking on cerebral oxygenation and hemodynamics: A combined study with near-infrared spectroscopy and transcranial Doppler sonography

Cigarette smoking has been shown to increase cerebral blood flow velocity (CBFV) and reduce vasomotor reactivity temporarily. The aim of our study was to clarify whether this results from dilation of resistance vessels alone with subsequent increase in regional cerebral blood flow (rCBF), or an additional constriction of basal cerebral arteries. In 24 healthy smokers (mean age+/-S.D., 32.7+/-10.5 years), cerebral oxygenation and hemodynamics were monitored by transcranial Doppler sonography and near-infrared spectroscopy before, during, and after smoking a cigarette (nicotine 0.9 mg). We simultaneously recorded CBFV of both middle cerebral arteries, mean arterial blood pressure, skin blood flow, end-tidal CO(2), changes in concentration of cerebral oxyhemoglobin, deoxyhemoglobin, and total hemoglobin (micromol/l), and a cerebral tissue oxygenation index. Smoking increased CBFV (p<0.01), oxyhemoglobin (p<0.01), and total hemoglobin (p<0.01). After smoking, the increase in CBFV and total hemoglobin persisted (p<0.01), while oxyhemoglobin returned to baseline. Deoxyhemoglobin and cerebral tissue oxygenation index did not change during the whole procedure. During, but not after smoking, CBFV increase was correlated to ipsilateral changes in oxyhemoglobin and total hemoglobin (p<0.05). The increase in oxyhemoglobin only during smoking and the lack of changes in deoxyhemoglobin and cerebral tissue oxygenation index indicate that smoking did not substantially increase rCBF. The smoking-induced elevation in CBFV might therefore be due to an additional constriction of the middle cerebral artery. The combined effects of smoking on basal cerebral arteries and arterioles might contribute to the increased stroke risk in smokers.