Mark M. Stecker

Deep hypothermic circulatory arrest: I. Effects of cooling on electroencephalogram and evoked potentials

BACKGROUND Deep hypothermia is an important cerebral protectant and is critical in procedures requiring circulatory arrest. The purpose of this study was to determine the factors that influence the neurophysiologic changes during cooling before circulatory arrest, in particular the occurrence of electrocerebral silence. METHODS In 109 patients undergoing hypothermic circulatory arrest with neurophysiologic monitoring, five electrophysiologic events were selected for detailed study. RESULTS The mean nasopharyngeal temperature when periodic complexes appeared in the electroencephalogram after cooling was 29.6 degrees C +/- 3 degrees C, electroencephalogram burst-suppression appeared at 24.4 degrees C +/- 4 degrees C, and electrocerebral silence appeared at 17.8 degrees C +/- 4 degrees C. The N20-P22 complex of the somatosensory evoked response disappeared at 21.4 degrees C +/- 4 degrees C, and the somatosensory evoked response N13 wave disappeared at 17.3 degrees C +/- 4 degrees C. The temperatures of these various events were not significantly affected by any patient-specific or surgical variables, although the time to cool to electrocerebral silence was prolonged by high hemoglobin concentrations, low arterial partial pressure of carbon dioxide, and by slow cooling rates. Only 60% of patients demonstrated electrocerebral silence by either a nasopharyngeal temperature of 18 degrees C or a cooling time of 30 minutes. CONCLUSIONS With the high degree of interpatient variability in these neurophysiologic measures, the only absolute predictors of electrocerebral silence were nasopharyngeal temperature below 12.5 degrees C and cooling longer than 50 minutes.

Functional Magnetic Resonance Imaging of Regional Brain Activity in Patients with Intracerebral Gliomas: Findings and Implications for Clinical Management

Functional magnetic resonance imaging (fMRI) was performed in seven patients harboring intracerebral gliomas proven by histological analysis using a noninvasive blood oxygen level-dependent technique based on the documented discrepancy between regional increases in blood flow and oxygen use in response to regional brain activation. We combined fMRI with conventional magnetic resonance imaging (MRI) during motor or language task activation experiments to investigate the potential usefulness of mapping regional brain activity as part of treatment planning in patients with intracerebral gliomas, in whom preservation of areas of functioning brain tissue is critical. Statistical fMRI maps were generated and directly mapped onto conventional MRI scans obtained at the same session. Of the five patients cooperative enough to remain motionless for the study and perform the task, the location of activation in the primary sensorimotor cortex on the side of the tumor was clearly displaced compared with that in the normal contralateral hemisphere in four patients. Four of the five tumors in these patients showed fMRI activation within the periphery of (or immediately adjacent to) areas of presumed tumor based on spin-echo MRI. In some patients with neurological deficit, the extent of activation was reduced on the side of the tumor as compared with the normal hemisphere. The supplemental motor area and the ipsilateral primary motor cortex were also reproducibly activated during motor tasks. We conclude that blood oxygen level-dependent fMRI can localize areas of cortical function in patients undergoing treatment planning for gliomas so that therapy can be directed away from regions of residual function. Our preliminary data suggest that functioning cortex within or adjacent to tumor margins can be demonstrated, which may correspond to partial preservation of clinical function. Our preliminary data also suggest that there may be a quantifiable difference on fMRI between activation in tumor-bearing cortex and activation in corresponding normal cortex in the contralateral hemisphere. We postulate that the magnitude of this difference may relate to the severity of patient deficit.

Treatment of Refractory Status Epilepticus with Propofol: Clinical and Pharmacokinetic Findings

Summary: Purpose: We compared propofol with high‐dose barbiturates in the treatment of refractory status epilepticus (RSE) and propose a protocol for the administration of propofol in RSE in adults, correlating propofols effect with plasma levels.

Hematocrit, volume expander, temperature, and shear rate effects on blood viscosity.

Our goal was to determine and predict the effects of temperature, shear rate, hematocrit, and different volume expanders on blood viscosity in conditions mimicking deep hypothermia for cardiac operations. Blood was obtained from six healthy adults. Dilutions were prepared to hematocrits of 35%, 30%, 22.5%, and 15% using plasma, 0.9% NaCl, 5% human albumin, and 6% hydroxyethyl starch. Viscosity was measured over a range of shear rates (4.5–450 s−1) and temperature (0°–37°C). A parametric expression for predicting blood viscosity based on the study variables was developed, and its agreement with measured values tested. Viscosity was higher at low shear rates and low temperatures, especially at temperatures less than 15°C (P < 0.016 for all conditions in comparison with 37°C). Decreasing hematocrit, especially to less than 22.5%, decreased viscosity. Hemodilution with albumin or 0.9% NaCl decreased blood viscosity more than hemodilution with plasma or 6% hydroxyethyl starch (P < 0.01 for all cases). The derived mathematical model for viscosity as a function of temperature, hematocrit, shear rate, and diluent predicted viscosity values that correlated well with the measured values in experimental samples (r2 > 0.92, P < 0.001). Implications A theoretical model for blood viscosity predicted independent effects of temperature, shear rate, and hemodilution on viscosity over a wide range of physiologic conditions, including thermal extremes of deep hypothermia in an experimental setting. Moderate hemodilution to a hematocrit of 22% decreased blood viscosity by 30%–50% at a blood temperature of 15°C, suggesting the potential to improve microcirculatory perfusion during deep hypothermia.

Interventions for reversing delayed-onset postoperative paraplegia after thoracic aortic reconstruction

BACKGROUND Delayed postoperative paraplegia is a recognized complication of thoracic (TAA) or thoracoabdominal aortic aneurysm (TAAA) repair. The purpose of this study was to evaluate the effectiveness of interventions to treat delayed-onset paraplegia. METHODS Between January 1, 2000 and August 31, 2001, 99 patients underwent surgical repair of TAA, Crawford type I, II, or III TAAA. Standard intraoperative management included distal aortic perfusion and cerebrospinal fluid (CSF) drainage unless contraindicated. Therapeutic interventions to treat delayed paraplegia included lumbar CSF drainage and vasopressor therapy. RESULTS Three of the 99 patients had paraplegia upon awakening. Delayed-onset paraplegia occurred in 8 patients, 2 of whom had recurrent episodes. In those 8 patients, the initial episode occurred at a median of 21.6 hours (range 6.4 to 110.0 hours) after surgery and the second episode averaged 176 hours after surgery. At the onset of paraplegia, the average mean arterial pressure was 74 mm Hg and CSF pressure was 14 mm Hg. Three of the 8 patients had a functioning CSF catheter at the onset and the other 5 patients had catheters subsequently placed. Therapeutic interventions increased blood pressure to a mean arterial pressure of 95 mm Hg and decreased CSF pressure to 10 mm Hg. Five of the 8 patients with delayed-onset paraplegia made a full neurologic recovery and 3 had partial recovery. CONCLUSIONS Patients with delayed-onset paraplegia had an increased chance of recovery as compared with those patients in whom paraplegia was diagnosed upon emergence from anesthesia. Acute interventions directed to increase spinal cord perfusion by increasing systemic blood pressure and decreasing CSF pressure were effective for the reversal of delayed onset of paraplegia after TAA or TAAA repair, resulting in an overall 3% incidence of permanent paraplegia and 3% incidence of residual paraparesis.

Sexual dysfunction in partial epilepsy A deficit in physiologic sexual arousal

Men and women with epilepsy frequently complain of sexual dysfunction. We studied the sexual response in men and women with partial epilepsy of temporal lobe origin (TLE) by measuring genital blood flow (GBF) during sexual arousal. Nine women and eight men with TLE and 12 women and seven men as controls completed inventories for symptoms of depression, sexual experience, and sexual attitude and underwent measurement of digital pulse and GBF during alternating segments of sexually neutral and erotic videotape. Subjective ratings of arousal to the videotape were obtained. We calculated digital pulse and GBF response as the percentage increase in pulse amplitude during the erotic compared with the preceding sexually neutral film. No subject group reported symptoms of significant depression on the inventory. However, men and women with epilepsy had fewer sexual experiences than subjects without epilepsy, and women with epilepsy imagined specific sexual activities to be more anxiety-producing and less arousing than did women without epilepsy. Men and women with TLE had a diminished GBF response. The mean increase in GBF in men with TLE was 184% versus 660% for controls (p = 0.01). Women with TLE had a mean increase of 117% versus 161% for controls (p > 0.01). Digital pulse did not vary across stimulus conditions. Subjective ratings for all groups indicated moderate sexual arousal. We conclude that there is a diminution in one aspect of physiologic sexual arousal in some men and women with TLE.

Deep hypothermic circulatory arrest: II. Changes in electroencephalogram and evoked potentials during rewarming.

BACKGROUND Electrophysiologic studies during rewarming after deep hypothermic circulatory arrest probe the state of the brain during this critical period and may provide insight into the neurological effects of circulatory arrest and the neurologic outcome. METHODS Electroencephalogram (EEG) and evoked potentials were monitored during rewarming in 109 patients undergoing aortic surgery with hypothermic circulatory arrest. RESULTS The sequence of neurophysiologic events during rewarming did not mirror the events during cooling. The evoked potentials recovered first followed by EEG burst-suppression and then continuous EEG. The time to recovery of the evoked potentials N20-P22 complex was significantly correlated with the time of circulatory arrest even in patients without postoperative neurologic deficits (r = 0.37, (p = 0.002). The nasopharyngeal temperatures at which continuous EEG activity and the N20-P22 complex returned were strongly correlated (r = 0.44, p = 0.0002; r = 0.41, p = 0.00003) with postoperative neurologic impairment. Specifically, the relative risk for postoperative neurologic impairment increased by a factor of 1.56 (95% CI 1.1 to 2.2) for every degree increase in temperature at which the EEG first became continuous. CONCLUSIONS No trend toward shortened recovery times or improved neurologic outcome was noted with lower temperatures at circulatory arrest, indicating that the process of cooling to electrocerebral silence produced a relatively uniform degree of cerebral protection, independent of the actual nasopharyngeal temperature.

Global Cardiac-Specific Transgene Expression Using Cardiopulmonary Bypass With Cardiac Isolation

BACKGROUND The available techniques for intravascular gene delivery to the heart are inefficient and not organ-specific. Yet, effective treatment of heart failure will likely require transgene expression by the majority of cardiac myocytes. To address this problem, we developed a novel cannulation technique that achieves efficient isolation of the heart in situ using separate cardiopulmonary bypass (CPB) circuits for the heart and body in dogs. METHODS The arterial inflow and venous effluent from the two circuits were physically isolated. The efficiency of separation was 98% to 99% in three preliminary experiments using Evans Blue dye-labeled albumin. In 6 dogs, the cardiac circuit was perfused with oxygenated crystalloid cardioplegia at 37 degrees C containing approximately 4 x 10(11) particles of an adenovirus encoding LacZ (AdCMVLacZ) with a perfusion pressure of 170 to 200 mm Hg for 15 minutes allowing virus to recirculate through the heart approximately 15 times. Cross-clamp time was 26 +/- 2 minutes and CPB time was 90 +/- 3 minutes. RESULTS Five animals survived and were euthanized at 7 days. Beta-galactosidase activities measured using a chemiluminescent assay were three orders of magnitude higher in all areas of the heart than in the liver. Histological analyses revealed heterogeneous X-Gal staining of myocytes in all areas of the myocardium. CONCLUSIONS Despite using a constitutive promoter, this technique yields relatively cardiac-specific transgene expression and is potentially translatable to clinical applications. Future studies will allow for further optimization of the conditions necessary for vector-mediated gene delivery to the heart.

Bispectral analysis of visual interactions in humans

Previous electrophysiological studies have demonstrated interactions between dichoptic visual stimuli presented to the same location in visual space. In this study, we used non-liner spectral analysis, in particular the bispectrum, to study interactions between the electrocerebral activity resulting from stimulation of the left and right visual fields. The stimulus consisted of two squares, one in each visual field, flickering at different frequencies. Bispectra, bichoherence and biphase were calculated for 8 subjects monocularly observing a visual stimulus. Both phase vs. frequency and biphase vs. frequency plots were made to determine weighted time delays from stimulus application to signal appearance in the EEG electrodes. Bispectral analysis reveals non-liner interactions between visual fields occurring with weighted delay times of 410 + / - 58 msec while non-interactive components propagated with weighted time delays of 202 + / - 39 msec. Evaluating these results in light of the predictions of various models, we were able to conclude that this interaction does not occur in the retina. These results illustrate how bispectral analysis can be a powerful tool in analyzing the connectivity of neural networks in complex systems. It allows different neuronal systems to be labeled with stimuli at specific frequencies, whose connections can be traced using frequency analysis of the scalp EEG.

Fatal Hyperammonemia after Orthotopic Lung Transplantation

Hyperammonemia has been reported in association with a variety of disorders causing hepatic dysfunction: portosystemic encephalopathy (1), inborn errors of the urea cycle (2), the Reye syndrome (3), transient hyperammonemia of the newborn (4), Jamaican vomiting sickness (5), Udorn encephalopathy (6), valproic acid therapy (7), asparaginase therapy (8), and urinary tract infection from urea-splitting organisms (9). Idiopathic hyperammonemia has also been described in patients after bone marrow transplantation (10) and chemotherapy for leukemia (11). In a previous report, we described a case of fatal hyperammonemia occurring after orthotopic lung transplantation in a patient without evidence of significant biochemical hepatic dysfunction (12). In addition, we reported on hepatic glutamine synthetase enzyme deficiency in the livers of two patients with hyperammonemia after orthotopic lung transplantation (13). In the current study, we measured the incidence of post-orthotopic lung transplantation hyperammonemia; herein, we summarize and analyze its associated clinical features. Methods We collected clinical data from 145 patients who underwent orthotopic lung transplantation at the University of Pennsylvania Medical Center between November 1991 and November 1996. The first patient who had had orthotopic lung transplantation at our center died of hyperammonemia. Subsequently, 142 of 144 patients routinely had plasma ammonium levels measured at the time of transplantation and if their mental status changed. Hyperammonemia was diagnosed if the plasma ammonium level was greater than twice the normal level (9 to 33 mol/L) and had exceeded 200 mol/L on at least one occasiona standard definition in common practice (10). The standard immunosuppressive regimen was intravenous methylprednisolone (a 500-mg to 1000-mg bolus given intraoperatively, followed by 0.5 mg/kg of body weight per day), azathioprine (2 mg/kg per day) and cyclosporine (titrated to therapeutic trough levels between 250 and 350 g/L through high-performance liquid chromatography). Antilymphocyte -globulin was administered (5 to 10 mg/kg per day) for 3 to 7 days. Acute rejection was diagnosed according to standard clinical and histologic criteria (14) and was treated with a 3-day regimen of high-dose intravenous methylprednisolone (15 mg/kg per day). Major gastrointestinal complications were defined as diseases of the gastrointestinal tract requiring surgical intervention or resulting in hemodynamic changes. Total parenteral nutrition was composed of 10% Travesol amino acids (Travesol Laboratories, Inc., Deerfield, Illinois), 10% glucose, and 20% Intralipid (Cutter Laboratories, Inc., Berkeley, California). To treat hyperammonemia, patients received sodium benzoate, sodium phenylacetate, or both, with a loading dose of 250 mg/kg intravenously followed by 250 mg/kg per day intravenously. The dosage of intravenous arginine hydrochloride was 210 mg/kg per day. Comparisons of data between the patients with hyperammonemia and the remaining patients who had had orthotopic lung transplantation were performed by using the Student t-test or Fisher exact test when appropriate (15). The study was approved by the University of Pennsylvanias institutional review board. Results Incidence Hyperammonemia was identified in 6 of the 145 (4.1%) patients who had had orthotopic lung transplantation at the University of Pennsylvania Medical Center between November 1991 and November 1996. The median number of ammonium levels checked in these patients was three. Most patients had multiple measurements. Transplantation Characteristics of Patients with Hyperammonemia None of the 145 patients had significant liver-associated laboratory abnormalities before transplantation (aminotransferase levels<2 times the upper limit of normal) or a history of inborn errors of metabolism. Patient 6 had the Ellis van Creveld syndrome, which is not known to be associated with hyperammonemia. The Table shows the peritransplantation clinical variables of patients with and those without hyperammonemia. Development of major gastrointestinal complications, use of total parenteral nutrition, and lung transplantation for primary pulmonary hypertension were associated with hyperammonemia. Table. Comparison of Peritransplantation Clinical Features of Patients with and Those without Hyperammonemia Presentation Hyperammonemia occurred between postoperative day 5 and day 26 (mean SD, 15.2 8.8 days). All patients with hyperammonemia had symptoms of metabolic encephalopathy, lethargy (n=4), agitation (n=2), seizure (n=3), or tremor (n=1); they eventually became unresponsive and comatose. Evidence of cerebral edema was identified in all patients by intracranial pressure monitoring or computed tomography of the head. Patients 2 and 3 developed peritonitis secondary to colonic perforation 48 and 72 hours before the onset of hyperammonemia, respectively. This complication required emergency laparotomy in both cases. Patient 3 also had a candidal lung abscess in the left lower lobe 5 days before onset of encephalopathy. Patients 1 and 4 developed acute graft rejection and received pulse methylprednisolone 24 to 48 hours before the onset of hyperammonemia. In patient 4, hemodynamically significant upper gastrointestinal bleeding occurred 1 day before a sharp increase in the plasma ammonium level. Primary graft dysfunction preceded the onset of neurologic symptoms in patient 5. Patient 6 developed sepsis 1 day before the diagnosis of hyperammonemia. Laboratory Studies The postoperative daily maximum ammonium levels for all patients with hyperammonemia are shown in the Figure. These patients had only mildly abnormal results on liver-associated laboratory tests, if any, at the onset of hyperammonemia (aminotransferase levels<4 times the upper limit of normal). As described previously, levels of urinary orotic acid and plasma amino acids in patients 1 and 2 showed no abnormalities that would suggest congenital urea-cycle enzyme defects, whereas the hepatic glutamine synthetase levels were deficient (14). Figure. Maximum daily plasma ammonium levels, total parenteral nutrition use, concurrent medical stressors, and plasma ammonium - decreasing therapies in patients with hyperammonemia. Treatment Upon detection of hyperammonemia, total parenteral nutrition was withheld from all patients except patient 3. Patient 5 died within several hours of hyperammonemia detection and therefore received no therapy to reduce the plasma ammonium level; all other patients with hyperammonemia received lactulose, neomycin, or both. The varied use of dialysis and plasma ammonia-trapping in the patients with hyperammonemia is illustrated in the Figure. Outcome The mortality rate among the patients with hyperammonemia was clearly higher than that among patients without hyperammonemia (Table). Four of the six patients with hyperammonemia died during the initial episode of hyperammonemia, 0 to 7 days after diagnosis (mean, 3.3 2.5 days), on postoperative days 4 through 29 (mean, 17.5 11.3 days). Patient 2 survived the initial episode on postoperative day 9, with normalization of plasma ammonium level and mental status, but died 3 days after the onset of the second episode on postoperative day 34. The plasma ammonium level in patient 6 returned to normal by day 4 of therapy. She regained consciousness by day 10 of therapy and subsequently had near complete recovery of baseline physical and mental function. Autopsy Findings Family consent permitted autopsies on three of the five patients who died of hyperammonemia. Patients 2 and 3 had mild cholestasis, severe microvesicular steatosis, small bowel ischemia, and colonic perforations. Patient 1 had lipofuscin deposits in pericentral hepatocytes. Discussion We describe severe hyperammonemia in a cohort of patients who had undergone orthotopic lung transplantation. The presentation of hyperammonemia in these patients was invariably fulminant, with associated cerebral edema; most patients died. Risk factors for hyperammonemia are unknown; however, the development of hyperammonemia in these patients appears to be multifactorial. All patients with hyperammonemia had received immunosuppressive agents and total parenteral nutrition. In addition, the occurrence of hyperammonemia was uniformly preceded by at least one major medical stressor, especially major gastrointestinal complications. However, under similar conditions, not every patient who had had orthotopic lung transplantation developed hyperammonemia. Therefore, these factors may be necessary but not sufficient for the development of hyperammonemia. Hepatic glutamine synthetase deficiency may play a role in the pathogenesis of hyperammonemia under these conditions, as we have demonstrated in two of the patients. Finally, further studies are necessary to determine the significance of a statistical association between lung transplantation for primary pulmonary hypertension and the occurrence of hyperammonemia. Although the exact relation between these medical stressors and hyperammonemia is not clear, all patients with hyperammonemia developed critically increased intracranial pressure and other severe neurologic symptoms, such as status epilepticus, which are clearly the main cause of the high mortality rate. In our previous report on two patients with hyperammonemia who underwent liver biopsies before their deaths, we demonstrated a significantly reduced hepatic glutamine synthetase activity (13). It is unclear whether this activity is an acquired deficiency or a carrier state with an acquired component. Hepatic glutamine synthetase activity may be the crucial factor in the development of hyperammonemia in patients who have had orthotopic lung transplantation and may account for the variability in the development of hyperammonemia among patients after transplantation under similar stressors. However, measurement of hepatic glutamine synthetase activ