John A. Ulatowski

Long-term outcome after medical reversal of transtentorial herniation in patients with supratentorial mass lesions.

Objective: To determine the short‐ and long‐term outcomes after successful reversal of transtentorial herniation by medical treatment. Although it has been recognized that aggressive medical management can reverse transtentorial herniation, it is believed that overall outcome in such patients is poor. Design: Prospective cohort study. Setting: Neurocritical care unit of a university hospital. Patients: A total of 28 consecutive patients who underwent an episode of transtentorial herniation (defined as decrease in level of consciousness accompanied by pupillary dilation) secondary to a supratentorial mass lesion followed by successful reversal. Intervention: Herniation was reversed by using a combination of hyperventilation, mannitol and hypertonic saline. Measurements and Main Results: The following outcomes were analyzed: risk of second herniation, radiologic evidence of structural damage or vascular compromise related to herniation on post‐herniation computed tomographic scan, in‐hospital mortality, and long‐term functional outcome using Rankin score and Barthel index. A total of 32 episodes of transtentorial herniations were reversed in 28 patients during a 14‐month period. The most common precipitating cause were edema (n = 23) or new/expanding intracerebral hematoma (n = 5). After first reversal of transtentorial herniation in 28 patients, a second herniation episode was observed in 16 patients after a mean interval of 88.2 hrs (range, 23‐432 hrs); four were successfully reversed. On follow‐up computed tomographic scan, hypodense lesion in mid‐brain (n = 6), temporal lobe contusion (n = 2), posterior cerebral artery (n = 3), and middle cerebral artery (n = 1) infarction were visualized in a minority of patients. The in‐hospital mortality was 60% (n = 15) with brain death being the cause of death in 13 patients; care was withdrawn in eight patients. Second episode of herniation (p = .002) and midbrain involvement during herniation (p = .02) were associated with in‐hospital mortality. During a mean follow‐up period of 11.4 ± 4.2 months, two patients died of cerebral neoplasm and human immunodeficiency virus‐related sepsis, respectively. Of the 11 survivors, 7 were functionally independent (Rankin score <3 and Barthel index >60). Conclusions: Although mortality after transtentorial herniation is high, we found a prominent potential for meaningful recovery with aggressive medical reversal of transtentorial herniation. Our study implies that timely medical intervention for reversing transtentorial herniation can result in preservation of neurologic function.

Regional blood flow alterations after bovine fumaryl beta beta-crosslinked hemoglobin transfusion and nitric oxide synthase inhibition.

OBJECTIVESna) To determine whether isovolemic exchange transfusion with cell-free, bovine fumaryl beta beta-crosslinked hemoglobin results in a different pattern of regional blood flow distribution than transfusion with a poor oxygen-carrying, colloidal solution. b) Because of potential nitric oxide scavenging by plasma-based hemoglobin, to determine whether blood flow differences are reduced after nitric oxide synthase inhibition.nnnDESIGNnA prospective, randomized design with repeated blood flow measurements within groups.nnnSETTINGnExperimental physiology laboratory in a university medical center.nnnSUBJECTSnPentobarbital-anesthetized female cats.nnnINTERVENTIONSnThree groups of eight cats were studied: a) a control group with no transfusion (hematocrit of 32%); b) an anemia group in which exchange transfusion with an albumin-containing solution reduced hematocrit to 18% over a 40- to 50-min period; and c) a group in which cell-free hemoglobin was exchanged transfused to reduce hematocrit to 18%, without a proportional reduction in oxygen-carrying capacity. Bovine hemoglobin was covalently crosslinked intramolecularly between the 81-lysine residues on the beta-subunits to stabilize the tetramer. Regional blood flow was measured by the radiolabeled microsphere technique before transfusion and at 10, 100, and 180 mins from the start of transfusion. At 190 mins, N omega-nitro-L-arginine methyl ester (L-NAME; 10mg/kg) was infused to inhibit nitric oxide synthase and blood flow was measured 30 mins later.nnnMEASUREMENTS AND MAIN RESULTSnMean arterial pressure was unchanged in the control and albumin-transfused groups. However, mean arterial pressure increased rapidly in the hemoglobin-transfused group. With hemoglobin transfusion, there were marked reductions in blood flow to the intestines, kidneys and adrenal glands. Administration of L-NAME after hemoglobin transfusion failed to increase arterial pressure or cause further reductions in intestinal, renal, or adrenal blood flow. Administration of L-NAME to the control and albumin-transfused groups increased arterial pressure and reduced intestinal, renal, and adrenal blood flows to values attained with hemoglobin transfusion. In contrast, in skeletal muscle and left ventricle, blood flow rates increased in the albumin-transfused group and were greater than those values found in the control group and hemoglobin-transfused group. The greater flow in the albumin-transfused group persisted after L-NAME administration. There was no difference in renal sodium, potassium, or osmolar excretion, or in urine flow between groups.nnnCONCLUSIONSnTransfusion with cell-free, bovine crosslinked hemoglobin in cats can selective reductions in blood flow in the intestines, kidneys, and adrenal glands without evidence of renal dysfunction by a mechanism consistent with nitric oxide scavenging. In skeletal and cardiac muscle, the increase in blood flow persisted after nitric oxide inhibition in the albumin group relative to the hemoglobin-transfused group at equivalent hematocrit values. This finding is consistent with compensatory vasoconstriction with hemoglobin transfusion due to improved oxygenation by this oxygen carrier.

Cerebral blood flow during hypoxic hypoxia with plasma-based hemoglobin at reduced hematocrit

We determined whether cerebral blood flow (CBF) remained related to arterial O2 content (CaO2) during hypoxic hypoxia when hematocrit and hemoglobin concentration were independently varied with cell-free, tetramerically stabilized hemoglobin transfusion. Three groups of pentobarbital sodium-anesthetized cats were studied with graded reductions in arterial O2 saturation to 50%: 1) a control group with a hematocrit of 31 +/- 1% (mean +/- SE; n = 7); 2) an anemia group with a hematocrit of 21 +/- 1% that underwent an isovolumic exchange transfusion with an albumin solution (n = 8); and 3) a group transfused with an intramolecularly cross-linked hemoglobin solution to decrease hematocrit to 21 +/- 1% (n = 10). Total arterial hemoglobin concentration (g/dl) after hemoglobin transfusion (8.8 +/- 0.2) was intermediate between that of the control (10.3 +/- 0.3) and albumin (7.2 +/- 0.4) groups. Forebrain CBF increased after albumin and hemoglobin transfusion at normoxic O2 tensions to levels attained at equivalent reductions in CaO2 in the control group during graded hypoxia. Over a wide range of arterial O2 saturation and sagittal sinus PO2, CBF remained greater in the albumin group. When CBF was plotted against CaO2 for all three groups, a single relationship was formed. Cerebral O2 transport, O2 consumption, and fractional O2 extraction were constant during hypoxia and equivalent among groups. We conclude that CBF remains related to CaO2 during hypoxemia when hematocrit is reduced with and without proportional reductions in O2-carrying capacity. Thus O2 transport to the brain is well regulated at a constant level independently of alterations in hematocrit, hemoglobin concentration, and O2 saturation.We determined whether cerebral blood flow (CBF) remained related to arterial O2 content ([Formula: see text]) during hypoxic hypoxia when hematocrit and hemoglobin concentration were independently varied with cell-free, tetramerically stabilized hemoglobin transfusion. Three groups of pentobarbital sodium-anesthetized cats were studied with graded reductions in arterial O2saturation to 50%: 1) a control group with a hematocrit of 31 ± 1% (mean ± SE; n = 7); 2) an anemia group with a hematocrit of 21 ± 1% that underwent an isovolumic exchange transfusion with an albumin solution ( n = 8); and 3) a group transfused with an intramolecularly cross-linked hemoglobin solution to decrease hematocrit to 21 ± 1% ( n = 10). Total arterial hemoglobin concentration (g/dl) after hemoglobin transfusion (8.8 ± 0.2) was intermediate between that of the control (10.3 ± 0.3) and albumin (7.2 ± 0.4) groups. Forebrain CBF increased after albumin and hemoglobin transfusion at normoxic O2 tensions to levels attained at equivalent reductions in [Formula: see text] in the control group during graded hypoxia. Over a wide range of arterial O2 saturation and sagittal sinus[Formula: see text], CBF remained greater in the albumin group. When CBF was plotted against[Formula: see text] for all three groups, a single relationship was formed. Cerebral O2 transport, O2 consumption, and fractional O2 extraction were constant during hypoxia and equivalent among groups. We conclude that CBF remains related to [Formula: see text] during hypoxemia when hematocrit is reduced with and without proportional reductions in O2-carrying capacity. Thus O2 transport to the brain is well regulated at a constant level independently of alterations in hematocrit, hemoglobin concentration, and O2 saturation.

Neurologic intensive care resource use after brain tumor surgery: an analysis of indications and alternative strategies.

ObjectiveGreater demand and limited resources for intensive care monitoring for patients with neurologic disease may change patterns of intensive care unit utilization. The necessity and duration of intensive care unit management for all neurosurgical patients after brain tumor resection are not clear. This study evaluates a) the preoperative and perioperative variables predictive of extended need for intensive care unit monitoring (>1 day); and b) the type and timing of intensive care unit resources in patients for whom less intensive postoperative monitoring may be feasible. DesignRetrospective chart review. SettingA neurocritical care unit of a university teaching hospital. PatientsPatients were 158 consecutive postoperative brain tumor resection patients admitted to a neurocritical care unit within a 1-yr period (1998–1999). InterventionsNone. Measurements and Main ResultsTwenty-three patients (15%) admitted to the neurocritical care unit for >24 hrs were compared with 135 (85%) patients admitted for <24 hrs. Predictors of >1-day stay in the neurocritical care unit in a logistic regression model were a tumor severity index comprising radiologic characteristics of tumor location, mass effect, and midline shift on the preoperative magnetic resonance imaging scan (odds ratio, 12.5; 95% confidence interval, 3.1–50.5); an intraoperative fluid score comprising estimated blood loss, total volume of crystalloid, and other colloid/hypertonic solutions administered (odds ratio, 1.8; 95% confidence interval, 1.2–2.6); and postoperative intubation (odds ratio, 67.5; 95% confidence interval, 6.5–702.0). Area under the receiver operating characteristic curve for the model of independent predictors for staying >1 day in the neurocritical care unit was 0.91. Neurocritical care unit resource use was reviewed in detail for 134 of 135 patients who stayed in the neurocritical care unit for <1 day. Sixty-five (49%) patients required no interventions beyond postanesthetic care and frequent neurologic exams. A total of 226 intensive care unit interventions were performed (mean ± sd, 1.7 ± 2.6) in 69 (51%) patients. Ninety (67%) patients had no further interventions after the first 4 hrs. Neurocritical care unit resource use beyond 4 hrs, largely consisting of intravenous analgesic use (72% of orders), was significantly associated with female gender, benign tumor on frozen section biopsy, and postoperative intubation (chi-square, p < .05). ConclusionsA small fraction of patients require prolonged intensive care unit stay after craniotomy for tumor resection. A patient’s risk of prolonged stay can be well predicted by certain radiologic findings, large intraoperative blood loss, fluid requirements, and the decision to keep the patient intubated at the end of surgery. Of those patients requiring intensive care unit resources beyond the first 4 hrs, the interventions may not be critical in nature. A prospective outcome study is required to determine feasibility, cost, and outcome of patients cared for in extended recovery and then transferred to a skilled nursing ward.

Effect of cross-linked hemoglobin transfusion on endothelial-dependent dilation in cat pial arterioles

We determined whether addition of hemoglobin to the plasma would inhibit endothelial-dependent dilation in brain where tight endothelial junctions limit hemoglobin extravasation. Pial arteriolar diameter was measured by intravital microscopy through closed cranial windows in anesthetized cats either without transfusion (hematocrit = 32%) or after exchange transfusion with an albumin or sebacyl-cross-linked human hemoglobin solution (hematocrit = 18%). Dilation of small, medium, and large arterioles to acetylcholine and ADP was not significantly altered by hemoglobin transfusion. The dilatory responses were inhibited by the nitric oxide synthase inhibitor NG-nitro-L-arginine, although significant dilation to 30 microM acetylcholine persisted in small arterioles in the control and albumin-transfused group but not in the hemoglobin-transfused group. The dilatory response to the nitric oxide donor 3-morpholinosydnonimine was unaffected by albumin or hemoglobin transfusion, but the response to nitroprusside was reduced by one-third after hemoglobin transfusion. When cross-linked hemoglobin was superfused through the cranial window, the acetylcholine response became inhibited at a hemoglobin concentration of 0.1 microM and was completely blocked at 10 microM. Because this concentration is substantially less than the 500 microM hemoglobin concentration in plasma after transfusion when there was no inhibition of the acetylcholine response, hemoglobin permeation of the blood-brain barrier was considered negligible. We conclude that exchange of red cell-based hemoglobin with plasma-based hemoglobin does not produce a more effective sink for endothelial-derived nitric oxide evoked by agonist receptor-mediated activation. Furthermore, decreased hematocrit does not affect agonist-evoked endothelial-dependent dilation.We determined whether addition of hemoglobin to the plasma would inhibit endothelial-dependent dilation in brain where tight endothelial junctions limit hemoglobin extravasation. Pial arteriolar diameter was measured by intravital microscopy through closed cranial windows in anesthetized cats either without transfusion (hematocrit = 32%) or after exchange transfusion with an albumin or sebacyl-cross-linked human hemoglobin solution (hematocrit = 18%). Dilation of small, medium, and large arterioles to acetylcholine and ADP was not significantly altered by hemoglobin transfusion. The dilatory responses were inhibited by the nitric oxide synthase inhibitor N G-nitro-l-arginine, although significant dilation to 30 μM acetylcholine persisted in small arterioles in the control and albumin-transfused group but not in the hemoglobin-transfused group. The dilatory response to the nitric oxide donor 3-morpholinosydnonimine was unaffected by albumin or hemoglobin transfusion, but the response to nitroprusside was reduced by one-third after hemoglobin transfusion. When cross-linked hemoglobin was superfused through the cranial window, the acetylcholine response became inhibited at a hemoglobin concentration of 0.1 μM and was completely blocked at 10 μM. Because this concentration is substantially less than the 500 μM hemoglobin concentration in plasma after transfusion when there was no inhibition of the acetylcholine response, hemoglobin permeation of the blood-brain barrier was considered negligible. We conclude that exchange of red cell-based hemoglobin with plasma-based hemoglobin does not produce a more effective sink for endothelial-derived nitric oxide evoked by agonist receptor-mediated activation. Furthermore, decreased hematocrit does not affect agonist-evoked endothelial-dependent dilation.

Role of Nitric Oxide Scavenging in Peripheral Vasoconstrictor Response to ββ Cross-Linked Hemoglobin

Transfusion with many crosslinked hemoglobin solutions causes an increase in arterial pressure that may be mediated by scavenging of nitric oxide (NO). If so, we postulated that inhibiting synthesis of NO after hemoglobin transfusion would fail to cause vasoconstriction ordinarily seen with such inhibition. In pentobarbital anesthetized cats, we tested whether administration of the NO synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), produced peripheral vasoconstriction after isovolemic exchange transfusion with hemoglobin to the same extent as occurs with L-NAME infusion in time controls and in controls matched for reduced hematocrit (17%) with albumin transfusion. Bovine hemoglobin was treated aerobically with bis-(3,5-dibromosalicyl) fumarate to produce βbeta;-81 lysine crosslinks. Hemoglobin exchange transfusion increased mean arterial blood pressure and there was no further increase after L-NAME. In contrast, L-NAME increased pressure in the time controls and albumin controls. Hemoglobin...

Diagnostic Impact of Early Transcranial Doppler Ultrasonography on the TOAST Classification Subtype in Acute Cerebral Ischemia

Objective: The impact of early transcranial Doppler ultrasonography (TCD) upon stroke subtype diagnosis is unknown and may affect therapeutic strategies. In this study, the diagnostic usefulness of TCD in stroke subtype diagnosis according to the criteria of the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) study was investigated in patients with acute cerebral ischemia. Methods: TCD examination within 24 h of symptom onset was performed in 50 consecutive patients with acute cerebral ischemia. Of these 54% were female. Sixty percent of patients were black, 36% white, and 4% Asian. Initial TOAST stroke subtype diagnosis (ITSSD) was based upon clinical presentation and initial brain imaging studies. Modified TOAST stroke subtype diagnosis was determined subsequently after additional review of the TCD examination. Final TOAST stroke subtype diagnosis was determined at hospital discharge, incorporating all diagnostic studies. Using final TOAST stroke subtype diagnosis as the ‘gold standard’ ITSSD and modified TOAST stroke subtype diagnosis were compared in order to determine additional benefit from the information obtained by TCD. Data were collected retrospectively by a single investigator. Results: ITSSD classified 23 of 50 (46%) patients correctly. After TCD, 30 of 50 (60%) patients were classified correctly, for an absolute benefit of 14% and a relative benefit of 30% (p = 0.018). Most benefit from TCD was observed in the TOAST stroke subtype category large-artery atherosclerosis, in particular in patients with intracranial vascular disease. In this category, ITSSD had a sensitivity of 27% which increased to 64% after TCD (p = 0.002). Conclusion: TCD within 24 h of symptom onset improves the accuracy of early stroke subtype diagnosis in patients with acute cerebral ischemia due to large-artery atherosclerosis. This may have clinical implications for early therapeutic interventions.

Sustained Endothelial Dependent Dilation in Pial Arterioles After Crosslinked Hemoglobin Transfusion

Hemoglobin is known to bind nitric oxide (NO) with high affinity. Plasma-based hemoglobin may provide a more effective sink for NO than red cell-based hemoglobin because of a closer and consistent proximity to the endothelium. Despite the known endothelial tight junctions that exist in cerebral vessels, plasma-based hemoglobin may inhibit NO-derived vasoreactive mechanisms in brain. If so, the response to endothelial and non-endothelial dependent vasodilator substances should be affected. In pentobarbital anesthetized cats, we tested this hypothesis by measuring the pial arteriole blood vessel diameter using aa cranial window before and after systemic transfusion of a human crosslinked hemoglobin compound. We than topically applied solutions of endothelial dependent or endothelial independent vasodilators and an NO synthase inhibitor to the surface of the brain within the window and remeasured the arteriole size. Topical acetylcholine (Ach) increased diameter in all arteriole sizes. The corresponding increases in diameter to Ach in time control eats (32% hematocrit) and in albumin transfused cats (18% hematocrit) were similar to those in hemoglobin transfused cats. Likewise, size-dependent dilation to SIN-1 in the hemoglobin group was similar to that in the control and albumin groups. The pial arteriole response to adenosine diphosphate (ADP) and sodium nitroprusside (SNP) also increased arteriole diameter in small, medium and large arterioles. Superfusion with L-nitroarginine to inhibit NO synthase markedly reduced the dilator response to Ach and ADP but not to SIN-1 or SNP. Thus, prior crosslinked hemoglobin transfusion does not interfere with vasodilator responses to either Ach, ADP, SIN-1 or SNP. When dilute solutions of crosslinked hemoglobin were superfused abluminally in the cranial window in anesthetized but non-transfused animals, the dilator response to Ach was unchanged at 10(-4)M hemoglobin, was attenuated at 10(-7) and 10(-6)M hemoglobin, and was completely blocked at 10(-5)M hemoglobin. This finding implies negligible permeation of the blood-brain barrier by crosslinked hemoglobin acutely after the transfusion.

Coma and Intensive Care Neurology

Neurocritical care is a subspecialty that has grown during the past 15 years. Critical care is care that is rendered in an acute and emergent setting in which the absence of care is associated with severe disability or death. The critical care concept evolved out of the need to render time-dependent emergent therapies in acute respiratory failure during the polio epidemics and for arrhythmia experienced by heart attack victims. Critical care grew rapidly in the 1970s to provide supportive care for the sickest patients with cardiologic, pulmonologic, and gastrointestinal disorders. In the 1980s the analogous subsets of neurologic and neurosurgical patients began to be identified. Neurocritical Care Units are now populated with head trauma victims, subarachnoid hemorrhage patients, the small numbers of patients who have treatable stroke, and patients with infectious disorders, including meningitis, encephalitis, and the parainfectious diseases, such as Guillain-Barre syndrome and myasthenia gravis. This chapter illustrates the time dependence and therapeutic complexities associated with these patients.

Predictive model for MCA and ICA cerebral blood flow velocities(CBFV)changes following aneurysmal subarachnoid hemorrhage(SAH)

P11 Objectives: Current TCD criteria for VSP is based on CBFV alone but factors such as age and day after SAH also affect CBFV, making the current criteria unreliable. Our objective is to describe MCA and ICA CBFV trend taking into account clinically significant variables. Methods: Patients with the diagnosis of aneurysmal SAH between 1991 and 1999 were identified using a prospective TCD database. Linear and non-linear regression analysis were performed. We included the following variables in the model: 1)age, 2)age 2 =(Age-38) 2 , 3)PSAHD:post SAH day, 4)SAHC=0 if SAH day 12 day , 5)CSPASM: clinical spasm (0,1 for absent, present respectively). Results: We identified 399 TCD examinations that included the vessels of interest. Curve fit analysis demonstrated that the quadratic model for both MCA(R2=0.14,P 2 + 2.65 PSAHD - 5.05 SAHC + 14.5 CSPASM (2)ICA CBFV quadratic model equation: Y=96.37–1.12 Age + 0.007 Age 2 + 2.97 PSAHD-8.08 SAHC+ 12.95 CSPASM When controlling for other variables in the model, we report: 1)A daily increase of 2.65 cm/s(MCA)and 2.97 cm/s(ICA) up to day 12, a daily decrease by 2.4 cm/s(MCA) and 5.1 cm/s(ICA)after day 12. 2)Effect of age on MCA CBFV is an increase of 1.3 cm/s per year of age until 38 and a 3.4% decrease after 38 at any given day after SAH. 3)Effect of age on ICA CBFV is a decrease of 1.1 cm/s per year of age until 38 and a 1.4% decrease after 38 at any given day after SAH. 4)When clinical vasospasm is present the CBFV increases by 14.5 cm/s(MCA) and 12.95 cm/s(ICA). Conclusion: our model suggests that the TCD criteria for VSP may be dependent on multiple variables. Prospective evaluation may lead to improved TCD criteria for the diagnosis of VSP.