Thymic Epithelial Cell Support of Thymopoiesis Does Not Require Klotho.

Age-related thymic involution is characterized by a decrease in thymic epithelial cell (TEC) number and function parallel to a disruption in their spatial organization, resulting in defective thymocyte development and proliferation as well as peripheral T cell dysfunction. Deficiency of Klotho, an antiaging gene and modifier of fibroblast growth factor signaling, causes premature aging. To investigate the role of Klotho in accelerated age-dependent thymic involution, we conducted a comprehensive analysis of thymopoiesis and peripheral T cell homeostasis using Klotho-deficient (Kl/Kl) mice. At 8 wk of age, Kl/Kl mice displayed a severe reduction in the number of thymocytes (10-100-fold reduction), especially CD4 and CD8 double-positive cells, and a reduction of both cortical and medullary TECs. To address a cell-autonomous role for Klotho in TEC biology, we implanted neonatal thymi from Klotho-deficient and -sufficient mice into athymic hosts. Kl/Kl thymus grafts supported thymopoiesis equivalently to Klotho-sufficient thymus transplants, indicating that Klotho is not intrinsically essential for TEC support of thymopoiesis. Moreover, lethally irradiated hosts given Kl/Kl or wild-type bone marrow had normal thymocyte development and comparably reconstituted T cells, indicating that Klotho is not inherently essential for peripheral T cell reconstitution. Because Kl/Kl mice have higher levels of serum phosphorus, calcium, and vitamin D, we evaluated thymus function in Kl/Kl mice fed with a vitamin D-deprived diet. We observed that a vitamin D-deprived diet abrogated thymic involution and T cell lymphopenia in 8-wk-old Kl/Kl mice. Taken together, our data suggest that Klotho deficiency causes thymic involution via systemic effects that include high active vitamin D levels.

Peri-alloHCT IL-33 administration expands recipient T-regulatory cells that protect mice against acute GVHD.

During allogeneic hematopoietic cell transplantation (alloHCT), nonhematopoietic cell interleukin-33 (IL-33) is augmented and released by recipient conditioning to promote type 1 alloimmunity and lethal acute graft-versus-host disease (GVHD). Yet, IL-33 is highly pleiotropic and exhibits potent immunoregulatory properties in the absence of coincident proinflammatory stimuli. We tested whether peri-alloHCT IL-33 delivery can protect against development of GVHD by augmenting IL-33-associated regulatory mechanisms. IL-33 administration augmented the frequency of regulatory T cells (Tregs) expressing the IL-33 receptor, suppression of tumorigenicity-2 (ST2), which persist following total body irradiation. ST2 expression is not exclusive to Tregs and IL-33 expands innate immune cells with regulatory or reparative properties. However, selective depletion of recipient Foxp3(+) cells concurrent with peri-alloHCT IL-33 administration accelerated acute GVHD lethality. IL-33-expanded Tregs protected recipients from GVHD by controlling macrophage activation and preventing accumulation of effector T cells in GVHD-target tissue. IL-33 stimulation of ST2 on Tregs activates p38 MAPK, which drives expansion of the ST2(+) Treg subset. Associated mechanistic studies revealed that proliferating Tregs exhibit IL-33-independent upregulation of ST2 and the adoptive transfer of st2(+) but not st2(-) Tregs mediated GVHD protection. In total, these data demonstrate the protective capacity of peri-alloHCT administration of IL-33 and IL-33-responsive Tregs in mouse models of acute GVHD. These findings provide strong support that the immunoregulatory relationship between IL-33 and Tregs can be harnessed therapeutically to prevent GVHD after alloHCT for treatment of malignancy or as a means for tolerance induction in solid organ transplantation.

In Vitro T-Cell Generation From Adult, Embryonic, and Induced Pluripotent Stem Cells: Many Roads to One Destination.

T lymphocytes are critical mediators of the adaptive immune system and have the capacity to serve as therapeutic agents in the areas of transplant and cancer immunotherapy. While T cells can be isolated and expanded from patients, T cells derived in vitro from both hematopoietic stem/progenitor cells (HSPCs) and human pluripotent stem cells (hPSCs) offer great potential advantages in generating a self-renewing source of T cells that can be readily genetically modified. T-cell differentiation in vivo is a complex process requiring tightly regulated signals; providing the correct signals in vitro to induce T-cell lineage commitment followed by their development into mature, functional, single positive T cells, is similarly complex. In this review, we discuss current methods for the in vitro derivation of T cells from murine and human HSPCs and hPSCs that use feeder-cell and feeder-cell-free systems. Furthermore, we explore their potential for adoption for use in T-cell-based therapies.

Prediction of significant vasospasm in aneurysmal subarachnoid hemorrhage using automated data.

BACKGROUND: When vasospasm is detected after aneurysmal subarachnoid hemorrhage (aSAH), it is treated with hypertensive or endovascular therapy. Current classification methods are resource-intensive, relying on specialty-trained professionals (nursing exams, transcranial dopplers, and perfusion imaging). More passively obtained variables such as cerebrospinal fluid drainage volumes, sodium, glucose, blood pressure, intracranial pressure, and heart rate, have not been used to predict vasospasm. We hypothesize that these features may yield as much information as resource-intensive features to classify vasospasm. METHODS: We studied data from 81 aSAH patients presenting within two days of onset. Vasospasm class (VSP) was defined by angiographic vasospasm warranting endovascular treatment. Naïve Bayes (NB) and logistic regression (LR) classifiers were trained on selected variable feature sets from the first three days of illness. Performance of trained classifiers was evaluated using area under the receiver operator characteristic curve (AUC classifier) and F-measure (F classifier). Ablation analysis determined incremental utility of each variable and subsets. RESULTS: 43.2 % developed VSP. During feature selection, the only passively collected variable that did not yield a statistically significant summary statistic was CSF drainage volume. NB classifier trained on all passively obtained features (AUC NB 0.708 and F NB 0.636) outperformed NB classifier trained on resource-intensive features (AUC NB 0.501 and F NB 0.349). CONCLUSIONS: Data-driven analysis of passively obtained clinical data predicted VSP better than current targeted resource-intensive monitoring techniques after aSAH. Automated classification of VSP may be possible.

FTY720 markedly increases alloengraftment but does not eliminate host anti-donor T cells that cause graft rejection on its withdrawal.

The immunomodulator FTY720 (FTY) is beneficial in models of graft-versus-host disease, solid organ transplantation, and autoimmunity and has been approved for use in patients with multiple sclerosis. FTY modifies the homing and migration of many cell types. We report that FTY has profound positive and negative effects on allogeneic bone marrow (BM) engraftment in sublethally irradiated recipients. FTY increased donor hematopoietic progenitors in the BM, resulting in high donor engraftment in the B cell, myeloid cell, and natural killer cell, but not T cell, lineages. Donor T cell progenitors within the thymus of FTY-treated recipients were dramatically reduced, resulting in a lack of donor T cell reconstitution. In addition to preventing the ingress of donor (and host) T cell progenitors, FTY prevented the egress of fully functional host CD4+CD8- and CD4-CD8+ thymocytes that on cessation of FTY administration were able to exit from the thymus and contribute to a rapid and complete rejection of a well-established donor BM graft. When used in combination with anti-CD40L mAbs to block the CD40L:CD40 costimulatory pathway, FTY markedly enhanced anti-CD40L mAb-mediated alloengraftment promotion. In contrast to FTY alone, the combination of anti-CD40L mAb and FTY resulted in a surprisingly stable, multilineage, long-term donor chimerism. These data illustrate FTY's profound migration modulating effects and suggest a use in combinatorial therapy in achieving stable alloengraftment under nonmyeloablative conditions.

SHIP1 inhibition increases immunoregulatory capacity and triggers apoptosis of hematopoietic cancer cells.

Genetic studies revealed that SHIP1 limits blood cell production and immune regulatory cell numbers in vivo. We postulated that molecular targeting of SHIP1 might enhance blood cell production and increase immunoregulatory capacity. In this study, we report the identification of a chemical inhibitor of SHIP1, 3 alpha-aminocholestane (3AC). Treatment with 3AC significantly expands the myeloid immunoregulatory cell compartment and impairs the ability of peripheral lymphoid tissues to prime allogeneic T cell responses. In addition, 3AC treatment profoundly increases granulocyte production without triggering the myeloid-associated lung consolidation observed in SHIP1(-/-) mice. Moreover, 3AC also enhances RBC, neutrophil, and platelet recovery in myelosuppressed hosts. Intriguingly, we also find that chemical inhibition of SHIP1 triggers apoptosis of blood cancer cells. Thus, SHIP1 inhibitors represent a novel class of small molecules that have the potential to enhance allogeneic transplantation, boost blood cell production, and improve the treatment of hematologic malignancies.

SHIP is required for a functional hematopoietic stem cell niche.

SH2-domain-containing inositol 5'-phosphatase-1 (SHIP) deficiency significantly increases the number of hematopoietic stem cells (HSCs) present in the bone marrow (BM). However, the reconstitution capacity of these HSCs is severely impaired, suggesting that SHIP expression might be an intrinsic requirement for HSC function. To further examine this question, we developed a model in which SHIP expression is ablated in HSCs while they are resident in a SHIP-competent milieu. In this setting, we find that long-term repopulation by SHIP-deficient HSCs is not compromised. Moreover, SHIP-deficient HSCs from this model repopulate at levels comparable with wild-type HSCs upon serial transfer. However, when HSCs from mice with systemic ablation of SHIP are transplanted, they are functionally compromised for repopulation. These findings demonstrate that SHIP is not an intrinsic requirement for HSC function, but rather that SHIP is required for the BM milieu to support functionally competent HSCs. Consistent with these findings, cells that comprise the BM niche express SHIP and SHIP deficiency profoundly alters their function.

Bow Hunter's Syndrome: A rare cause of vertebrobasilar insufficiency.

Bow Hunter's syndrome, also referred to as rotational occlusion of the vertebral artery, is caused by dynamic compression of a patient's dominant vertebral artery. We reported a case of successful clinical and imaging work up of Bow Hunter's Syndrome that occurred in a 79-year-old female patient. We discussed the clinical presentation, imaging findings, and subsequent management options of this rare syndrome. The gold standard for diagnosis is dynamic cerebral angiography, which allows the reproduction of symptoms with head turn greater than 30-45 degrees. Subsequent management is based on the underlying etiology causing rotational compression.

Early Multicenter Experience With the Neuroform Atlas Stent: Feasibility, Safety, and Efficacy.

BACKGROUND: The Neuroform Atlas stent™ (by Stryker, Fremont, California) represents the most recent widely available upgrade to intracranial stenting, providing a laser cut open cell stent with a diameter of 3.0 to 4.5 mm that is delivered through an 0.017-inch microcatheter. OBJECTIVE: To report our initial multicenter experience of the safety, efficacy, and feasibility of the Atlas stent used for treating aneurysms, as well as one case of intracranial stenosis and one carotid artery dissection as well as other pathologies. METHODS: A retrospective multicenter study of subjects treated with Atlas stent during the period 2018 to 2019. RESULTS: The total number of patients included in our analysis was 71 patients. The stent was utilized to treat 69 aneurysm cases. Of the aneurysms, 36% presented with acute rupture and 56% of the ruptured aneurysms were high grade. Mean aneurysm dimension was 7 mm with an average neck width of 4.1 mm. Around 30% had received prior treatment. Telescoping or Y-stent was used in 16% of cases. We did not observe any symptomatic major complications in our series. Asymptomatic major complications were seen in 7 patients (10.1%); technical complications occurred in 4.3%. Immediate modified Raymond-Roy-occlusion-outcome class I/II was observed in 87%, and this increased to 97.7% at latest follow-up, which was at 4 mo; 91.8% of patients achieved favorable clinical outcome, and mortality rate was 1.4%. CONCLUSION: Our series demonstrates the safety, feasibility, and efficacy of the Atlas stent. The low complication rate and the high obliteration rate managing complex aneurysms, even in an acute ruptured setting, are notable.

Low Yield of Cerebral Angiography in Adequately Occluded Aneurysms After Flow Diversion.

BACKGROUND: Flow diversion has emerged as a highly effective treatment for intracranial aneurysms. OBJECTIVE: To assess the yield of further angiographic follow-up in aneurysms that have achieved adequate occlusion after treatment with the Pipeline Embolization Device (PED; Medtronic Inc, Dublin, Ireland). METHODS: This is a single-institution, retrospective study. Inclusion criteria were as follows: (1) patients with 1 or more aneurysms treated with PED, (2) available short-term (<12 mo) follow-up digital subtraction angiography (DSA), (3) complete (100%) or near-complete (>95%) occlusion on short-term follow-up DSA, and (4) available further angiographic follow-up (DSA, Magnetic Resonance Angiography (MRA), or Computed Tomography Angiography (CTA)). RESULTS: A total of 146 patients were identified. Aneurysm size was 8.4 ± 5.1 mm on average. Mean angiographic follow-up time was 29.7 ± 12.2 mo. On short-term follow-up DSA images, 132 (90.4%) had complete aneurysm occlusion and 14 (9.6%) had near-complete occlusion. Four patients (3%) had further DSA follow-up alone, 30 patients (21%) had further DSA and MRA/CTA follow-up, and 112 patients (76%) had further MRA/CTA follow-up alone. On further angiographic follow-up (DSA, MRA, and/or CTA), no patient had a decrease in the degree of aneurysm occlusion (recurrence) or required retreatment. Of the 14 patients with near-complete occlusion on initial DSA images, 7 patients (50%) progressed to complete aneurysm occlusion on further angiographic follow-up. CONCLUSION: This study did not find any diagnostic yield in repeating cerebral angiography in adequately occluded aneurysms with the PED. We do not recommend repeat angiographic follow-up once aneurysms have achieved complete occlusion with the PED unless clinically warranted.

The vimentin intermediate filament network restrains regulatory T cell suppression of graft-versus-host disease.

Regulatory T cells (Tregs) are critical for maintaining immune homeostasis. However, current Treg immunotherapies do not optimally treat inflammatory diseases in patients. Understanding the cellular processes that control Treg function may allow for the augmentation of therapeutic efficacy. In contrast to activated conventional T cells, in which protein kinase C-θ (PKC-θ) localizes to the contact point between T cells and antigen-presenting cells, in human and mouse Tregs, PKC-θ localizes to the opposite end of the cell in the distal pole complex (DPC). Here, using a phosphoproteomic screen, we identified the intermediate filament vimentin as a PKC-θ phospho target and show that vimentin forms a DPC superstructure on which PKC-θ accumulates. Treatment of mouse Tregs with either a clinically relevant PKC-θ inhibitor or vimentin siRNA disrupted vimentin and enhanced Treg metabolic and suppressive activity. Moreover, vimentin-disrupted mouse Tregs were significantly better than controls at suppressing alloreactive T cell priming in graft-versus-host disease (GVHD) and GVHD lethality, using a complete MHC-mismatch mouse model of acute GVHD (C57BL/6 donor into BALB/c host). Interestingly, vimentin disruption augmented the suppressor function of PKC-θ-deficient mouse Tregs. This suggests that enhanced Treg activity after PKC-θ inhibition is secondary to effects on vimentin, not just PKC-θ kinase activity inhibition. Our data demonstrate that vimentin is a key metabolic and functional controller of Treg activity and provide proof of principle that disruption of vimentin is a feasible, translationally relevant method to enhance Treg potency.

T cell progenitor therapy-facilitated thymopoiesis depends upon thymic input and continued thymic microenvironment interaction.

Infusion of in vitro-derived T cell progenitor (proT) therapy with hematopoietic stem cell transplant aids the recovery of the thymus damaged by total body irradiation. To understand the interaction between proTs and the thymic microenvironment, WT mice were lethally irradiated and given T cell-deficient (Rag1-/-) marrow with WT in vitro-generated proTs, limiting mature T cell development to infused proTs. ProTs within the host thymus led to a significant increase in thymic epithelial cells (TECs) by day 21 after transplant, increasing actively cycling TECs. Upon thymus egress (day 28), proT TEC effects were lost, suggesting that continued signaling from proTs is required to sustain TEC cycling and cellularity. Thymocytes increased significantly by day 21, followed by a significant improvement in mature T cell numbers in the periphery by day 35. This protective surge was temporary, receding by day 60. Double-negative 2 (DN2) proTs selectively increased thymocyte number, while DN3 proTs preferentially increased TECs and T cells in the spleen that persisted at day 60. These findings highlight the importance of the interaction between proTs and TECs in the proliferation and survival of TECs and that the maturation stage of proTs has unique effects on thymopoiesis and peripheral T cell recovery.

Intracranial aneurysms in sickle cell anemia: clinical and imaging findings.

BACKGROUND: Cerebral aneurysm formation is one of the cerebrovascular complications of sickle cell disease. OBJECTIVE: To report the clinical and imaging findings of intracerebral aneurysms and their treatment in pediatric and adult patients with sickle cell disease. METHODS: Review of clinical data via chart abstraction and radiologic features at the University of Pennsylvania and Children's Hospital of Philadelphia from 2000 to 2014 and review of the literature since 1942. RESULTS: Nineteen patients with aneurysms (2.7%) were found in 709 imaged patients, including 1.2% of imaged children and 10.8% of adults. A total of 44 aneurysms were detected (52.6% with multiple aneurysms, overall 2.3 per patient), 35 (79.5%) in the anterior circulation and 9 in the posterior circulation (20.4%). Thirty-eight unruptured aneurysms ranging in size from 2 to 6 mm and six ruptured aneurysms ranging in size from 3 to 9 mm in diameter were found. Of the patients with ruptured aneurysms, two were treated by stent-assisted coiling, two by clipping, and one patient with coiling. In the group without a rupture, one patient was treated by coil embolization and one patient with a peripheral middle cerebral artery aneurysm was treated by aneurysmectomy. Three pediatric patients with a previously normal MR angiogram demonstrated new aneurysm formation during the study. CONCLUSIONS: Adult patients with sickle cell disease have a high prevalence of aneurysm formation. Both pediatric and adult patients with sickle cell disease tend to develop multiple aneurysms with frequent involvement of atypical locations, in both anterior and posterior circulations.

Subarachnoid hemorrhage on computed tomography scanning and the development of cerebral vasospasm: the Fisher grade revisited.

BACKGROUND: The Fisher grade (FG) is widely used to predict cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH). We revisited the grading scale to determine its validity in the era of modern management. METHODS: We retrospectively reviewed the records of 134 patients with SAH. The amount and distribution of subarachnoid blood on admission computed tomography (CT) scan was quantified according to the FG and compared with development of symptomatic vasospasm. RESULTS: We reviewed 134 patients (median age, 54) who presented with aneurysmal SAH. Six (5%) were FG 1, 34 (25%) were FG 2, 25 (19%) were FG 3, and 69 (51%) were FG 4. Symptomatic vasospasm developed in no (0%) FG 1, 8 (24%) FG 2, 7 (28 %) FG 3, and 13 (19%) FG 4 patients (28 of 134 total patients; 21%). Development of symptomatic vasospasm was not associated with admission FG, Hunt and Hess grade, age, sex, or location of blood on presenting CT scan. Elevated transcranial Doppler blood flow velocity was associated with blood in the basal cisterns (P = .0047), lateral ventricles (P = .026), or blood in any ventricle (P = .04). Postoperative angiograms were obtained in 57 patients; moderate to severe vasospasm was observed in 5 (15%) FG 2, 6 (24%) FG 3, and 14 (20%) FG 4 patients. Twenty patients (71%) with symptomatic vasospasm had moderate or severe angiographic vasospasm. Angiographic vasospasm was associated with intraventricular blood (P = .054) but not with FG. CONCLUSIONS: Symptomatic vasospasm occurred in 21% of cases. The FG correlated with symptomatic vasospasm in only half the patients. A new predictive CT grading scale for vasospasm may be necessary.

Aneurysmal vasculopathy in human-acquired immunodeficiency virus-infected adults: Imaging case series and review of the literature.

BACKGROUND: Intracranial vasculopathy in adult patients with human-acquired immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) is a rare but increasingly recognized disease entity. OBJECTIVE: We aimed to contribute to and summarize the adult literature describing patients with HIV/AIDS who have intracranial vasculopathy. METHODS: A retrospective review of adult patients with HIV/AIDS undergoing diagnostic cerebral angiography at our institution from 2007-2013 was performed. A literature review of relevant existing studies was performed. RESULTS: Five adult patients with HIV-related aneurysmal and occlusive vasculopathy were diagnosed and/or treated at our institution. A comprehensive review of the literature yielded data from 17 series describing 28 adult patients with HIV/AIDS and intracranial vasculopathy. Our review suggests that low CD4 count, motor weakness, and meningismus may be associated with the sequelae of intracranial vasculopathy/vasculitis in patients with HIV/AIDS. CONCLUSION: Patients with HIV/AIDS who have aneurysmal and stenotic vascular disease may benefit from earlier surveillance with the onset of neurological symptoms. The roles of medical, open surgical, and endovascular therapy in this unique entity will be further defined as the pathological basis of the disease is better understood.

Elderly patients with intracranial aneurysms have higher quality of life after coil embolization: a decision analysis.

OBJECTIVE: To develop a decision analytic model to calculate outcomes after treatment of cerebral aneurysms in elderly patients. Neurosurgical clipping and endovascular coiling for both ruptured and unruptured aneurysms were compared with predicted health-related quality of life (HRQoL) after treatment. METHODS: A Medline search of articles published in English between 1995 and June 2012 was performed using key words: 'intracranial aneurysms', 'treatment', or various combinations of 'elderly', 'older', or 'decade'. Reports that met inclusion criteria used either the Glasgow Outcome Score or the modified Rankin Scale for outcomes, age >69, and intracranial aneurysm that was treated by endovascular coiling or surgical clipping. Data were collected by performing a comprehensive review of published reports. Meta-analysis (inverse variance-weighted, random effects) was used to calculate pooled values for probabilities and HRQoL. RESULTS: HRQoL was significantly higher for patients with coiled rather than clipped aneurysms in both ruptured (p<0.01) and unruptured (p<0.01) aneurysm groups. Periprocedural mortality rates were significantly lower among patients with a coiled, unruptured aneurysm than among patients with a clipped, unruptured aneurysm (p=0.032). Sensitivity analysis and Monte Carlo simulation for both ruptured and unruptured aneurysms showed that overall HRQoL was significantly higher in coiled than in clipped patients. CONCLUSIONS: As life expectancy increases, treatment of cerebral aneurysms in the elderly becomes more important. Given the results of this decision analysis and the continuous refinement in endovascular technology, embolization should strongly be considered as a first-line treatment for cerebral aneurysms in the elderly.

Relationship between intracranial pressure and other clinical variables in patients with aneurysmal subarachnoid hemorrhage.

OBJECT: Increased intracranial pressure (ICP) is well known to affect adversely patients with head injury. In contrast, the variables associated with ICP following aneurysmal subarachnoid hemorrhage (SAH) and their impact on outcome have been less intensely studied. METHODS: In this retrospective study the authors reviewed a prospective observational database cataloging the treatment details in 433 patients with SAH who had undergone surgical occlusion of an aneurysm as well as ICP monitoring. All 433 patients underwent postoperative ICP monitoring, whereas only 146 (33.7%) underwent both pre- and postoperative ICP monitoring. The mean maximal ICP was 24.9 +/- 17.3 mm Hg (mean +/- standard deviation). During their hospital stay, 234 patients (54%) had elevated ICP (> 20 mm Hg), including 136 of those (48.7%) with a good clinical grade (Hunt and Hess Grades I-III) and 98 (63.6%) of the 154 patients with a poor grade (Hunt and Hess Grades IV and V) on admission. An increased mean maximal ICP was associated with several admission variables: worse Hunt and Hess clinical grade (p < 0.0001), a lower Glasgow Coma Scale (GSC) motor score (p < 0.0001); worse SAH grade based on results of computerized tomography studies (p < 0.0001); intracerebral hemorrhage (p = 0.024); severity of intraventricular hemorrhage (p < 0.0001); and rebleeding (p = 0.0048). Both intraoperative cerebral swelling (p = 0.0017) and postoperative GCS score (p < 0.0001) were significantly associated with a raised ICP. Variables such as patient age, aneurysm size, symptomatic vasospasm, intraoperative aneurysm rupture, and secondary cerebral insults such as hypoxia were not associated with raised ICP. Increased ICP adversely affected outcome: 71.9% of patients with normal ICP demonstrated favorable 6-month outcomes postoperatively, whereas 63.5% of patients with ICP between 20 and 50 mm Hg and 33.3% with ICP greater than 50 mm Hg demonstrated favorable outcomes. Among 21 patients whose raised ICP did not respond to mannitol therapy, all experienced a poor outcome and 95.2% died. Among 145 patients whose elevated ICP responded to mannitol, 66.9% had a favorable outcome and only 20.7% were dead 6 months after surgery (p < 0.0001). According to results of multivariate analysis, however, ICP was not an independent outcome predictor (odds ratio 1.26, 95% confidence interval 0.28-5.68). CONCLUSIONS: Increased ICP is common after SAH, even in patients with a good clinical grade. Elevated ICP post-SAH is associated with a worse patient outcome, particularly if ICP does not respond to treatment. This association, however, may depend more on the overall severity of the SAH than on ICP alone.

Blood transfusion and increased risk for vasospasm and poor outcome after subarachnoid hemorrhage.

OBJECT: Nitric oxide (NO) metabolism may influence vasospasm after subarachnoid hemorrhage (SAH). It has been demonstrated in recent studies that erythrocytes carry NO for release in vessels, whereas transfused erythrocytes may lack stored NO. Several converging lines of evidence also indicate that blood transfusion may exacerbate poor outcomes in some critically ill patients. In this study the authors hypothesized that patients with SAH who received red blood cell (RBC) transfusions were at greater risk for vasospasm and poor outcome. METHODS: The authors retrospectively reviewed a prospective observational database, including hospital records, computerized tomography (CT) scans, and pre- and postoperative four-vessel angiograms, in which the management methods used in 441 patients undergoing surgery for ruptured cerebral aneurysms were described. Two hundred seventy patients (61.2%) received an RBC transfusion during their hospital stay. After adjustment for Hunt and Hess grade, SAH grade on CT scans, delay between rupture and surgery, smoking status, and intraoperative aneurysm rupture, a worse outcome was more likely in patients who received intraoperative blood (odds ratio [OR] 2.44, confidence interval [CI] 1.32-4.52; 120 patients). Intraoperative RBC transfusion did not influence subsequent angiographically confirmed vasospasm (OR 0.92, CI 0.6-1.4). Worse outcome was observed in patients who received blood postoperatively (OR 1.81, CI 1.21-2.7), but not after adjustments were made for confounding variables (OR 1.48, CI 0.83-2.63). Angiographic vasospasm was observed in 217 patients and, after adjusting for confounding variables, was more frequent among patients who received postoperative RBC transfusion (OR 1.68, CI 1.02-2.75). Among patients in whom angiographically confirmed vasospasm developed there was a tendency to have received more blood than in those with no vasospasm; however, a clear dose-dependent response was not observed. CONCLUSIONS: Development of angiographically confirmed vasospasm after SAH is associated with postoperative RBC transfusion and worse outcome is associated with intraoperative RBC transfusion. Before blood is transfused, patients with SAH should be carefully assessed to determine if they are symptomatic because of anemia.

Cerebral oxygenation following decompressive hemicraniectomy for the treatment of refractory intracranial hypertension.

OBJECT: Medically intractable intracranial hypertension is a major cause of morbidity and mortality after severe brain injury. One potential treatment for intracranial hypertension is decompressive hemicraniectomy (DCH). Whether and when to use DCH, however, remain unclear. The authors therefore studied the effects of DCH on cerebral O2 to develop a better understanding of the effects of this treatment on the recovery from injury and disease. METHODS: The study focused on seven patients (mean age 30.6 +/- 9.7 years) admitted to the hospital after traumatic brain injury (five patients) or subarachnoid hemorrhage (two patients) as part of a prospective observational database at a Level I trauma center. At admission the Glasgow Coma Scale (GCS) score was 6 or less in all patients. Patients received continuous monitoring of intracranial pressure (ICP), cerebral perfusion pressure (CPP), blood pressure, and arterial O2 saturation. Cerebral oxygenation was measured using the commercially available Licox Brain Tissue Oxygen Monitoring System manufactured by Integra NeuroSciences. A DCH was performed when the patient's ICP remained elevated despite maximal medical management. CONCLUSIONS: All patients tolerated DCH without complications. Before the operation, the mean ICP was elevated in all patients (26 +/- 4 mm Hg), despite maximal medical management. After surgery, there was an immediate and sustained decrease in ICP (19 +/- 11 mm Hg) and an increase in CPP (81 +/- 17 mm Hg). Following DCH, cerebral oxygenation improved from a mean of 21.2 +/- 13.8 mm Hg to 45.5 +/- 25.4 mm Hg, a 114.8% increase. The change in brain tissue O2 and the change in ICP after DCH demonstrated only a modest relationship (r2 = 0.3). These results indicate that the use of DCH in the treatment of severe brain injury is associated with a significant improvement in brain O2.

The effect of nimodipine on cerebral oxygenation in patients with poor-grade subarachnoid hemorrhage.

OBJECT: Nimodipine has been shown to improve neurological outcome after subarachnoid hemorrhage (SAH); the mechanism of this improvement, however, is uncertain. In addition, adverse systemic effects such as hypotension have been described. The authors investigated the effect of nimodipine on brain tissue PO2. METHODS: Patients in whom Hunt and Hess Grade IV or V SAH had occurred who underwent aneurysm occlusion and had stable blood pressure were prospectively evaluated using continuous brain tissue PO2 monitoring. Nimodipine (60 mg) was delivered through a nasogastric or Dobhoff tube every 4 hours. Data were obtained from 11 patients and measurements of brain tissue PO2, intracranial pressure (ICP), mean arterial blood pressure (MABP), and cerebral perfusion pressure (CPP) were recorded every 15 minutes. Nimodipine resulted in a significant reduction in brain tissue PO2 in seven (64%) of 11 patients. The baseline PO2 before nimodipine administration was 38.4+/-10.9 mm Hg. The baseline MABP and CPP were 90+/-20 and 84+/-19 mm Hg, respectively. The greatest reduction in brain tissue PO2 occurred 15 minutes after administration, when the mean pressure was 26.9+/-7.7 mm Hg (p < 0.05). The PO2 remained suppressed at 30 minutes (27.5+/-7.7 mm Hg [p < 0.05]) and at 60 minutes (29.7+/-11.1 mm Hg [p < 0.05]) after nimodipine administration but returned to baseline levels 2 hours later. In the seven patients in whom brain tissue PO2 decreased, other physiological variables such as arterial saturation, end-tidal CO2, heart rate, MABP, ICP, and CPP did not demonstrate any association with the nimodipine-induced reduction in PO2. In four patients PO2 remained stable and none of these patients had a significant increase in brain tissue PO2. CONCLUSIONS: Although nimodipine use is associated with improved outcome following SAH, in some patients it can temporarily reduce brain tissue PO2.