William H. Schuette

Whole Body Hyperthermia: A Phase-l Trial of a Potential Adjuvant to Chemotherapy

Fourteen patients with a variety of neoplasms not responsive to standard forms of therapy underwent whole body hyperthermia for a maximum 4 h at 41.8 degrees C. This was a phase-I cancer trial designed to develop whole body hyperthermia as an adjuvant to systemic chemotherapy. Intravenous analgesia was used to sedate patients, obviating the need for general endotracheal anesthesia. Hyperthermia was induced by means of a high-flow water perfusion suit. Cardiovascular performance was evaluated using a flow-directed pulmonary artery catheter. Patients developed a twofold mean increase in cardiac index without evidence of cardiac damage by ECG or creatine phosphokinase (CPK) isoenzymes. An acute fall in serum magnesium and phosphate and an acute rise in arterial pH, serum CPK values, and granulocyte count occurred in all patients. There were no clotting abnormalities. Toxicity included fatigue, diarrhea, nausea, and transient elevations in liver enzymes. Four patients were febrile for 36 h after initial defervescence. Peripheral neuropathy developed in four. These results show that with carefully monitored conditions whole body hyperthermia is feasible.

Low-frequency oscillations of cortical oxidative metabolism in waking and sleep.

To study the changes in cortical oxidative metabolism and blood volume during behavioral state transitions, we employed reflectance spectrophotometry of the cortical cytochrome c oxidase (cyt aa3) redox state and blood volume in unanesthetized cats implanted with bilateral cortical windows and EEG electrodes. Continuous oscillations in the redox state and blood volume (∼9/min) were observed during waking and sleep. These primarily metabolic oscillations of relatively high amplitude were usually synchronous in homotopic cortical areas, and persisted during barbiturate-induced electrocortical silence. Their mean amplitude and frequency did not vary across different behavioral/EEG states, although the mean levels of cyt aa3 oxidation and blood volume during rapid eye movement (REM) sleep significantly exceeded those during waking and slow-wave sleep. These data suggest the existence of a spontaneously oscillating metabolic phenomenon in cortex that is not directly related to neuroelectric activity. A superimposed increase in cortical oxidative metabolism and blood volume occurs during REM sleep. Experimental data concerning cerebral metabolism and blood flow that are obtained by clinical methods that employ relatively long sample acquisition times should therefore be interpreted with caution.

NADH fluorescence, [K+]0 and oxygen consumption in cat cerebral cortex during direct cortical stimulation.

NADH fluorescence, sagittal sinus blood flow and sinus hemoglobin saturation were monitored simultaneously during direct cortical stimulation of a wide area of the anterior and mid suprasylvian and marginal gyri. The area monitored flurorometrically was located within the area apparently drained by the sinus, so that the flurometric changes could be correlated with oxygen consumption changes calculated from the sinus flow and saturation values. The onset and peak values of calculated oxygen consumption and NADH fluorescence changes usually occurred within several seconds of one another and high, significant (r greater than 0.9 and P less than 0.01) correlations were found between the maximum changes in both parameters following stimulation. The relation of cortical [K+]0 changes to oxygen consumption changes was also explored; again the magnitude of [K+]0 changes and calculated oxygen consumption changes correlated well. The demonstrated agreement between fluorometric and direct (sinus cannulation) measurements of oxidative metabolism reinforces the interpretation of in situ cortical fluorescence changes as indicative of changes in oxygen consumption rate

Fluorometric monitoring of NADH levels in cerebral cortex: preliminary observations in human epilepsy

In 14 patients operated upon for focal cerebral seizures under local anesthesia, cortical electrical activity was compared with the levels of nicotinamide adenine dinucleotide (NADH) observed fluorometrically. NADH levels fell 3 to 15% in response to 5-second intervals of cortical stimulation in 42 of 70 observations. Although a rough correlation was seen between the quantity of current delivered (milliamperes X seconds) and the NADH decrease, this varied from case to case. The presence of cortical afterdischarge often, but not invariably, corresponded to a greater percentage of change in the NADH levels. Averaging the NADH response to sporadic interictal epileptiform discharges failed to demonstrate concomitant NADH reductions. A similar lack of change was seen in four patients in whom low frequency spike foci were induced by topically applied penicillin in cortex destined for excision. Preliminary studies of the topography of spread of NADH change after cortical stimulation indicate that this is usually asymmetrical in human epileptogenic cortex. Under experimental conditions in cats, it seemed possible to differentiate primary from projected epileptiform activity, in that the projected activity had little or no concomitant fall in the NADH level after the electrographic spike. Pathological examination of the excised sites of NADH recording showed, with one exception, fibrous astrocytic transformation of the central cortex layers.

Interhemispheric synchrony of slow oscillations of cortical blood volume and cytochrome aa3 redox state in unanesthetized rabbits

In order to study spontaneous, slow oscillations of regional oxidative metabolism and blood flow in the normal, unanesthetized cortex, adult rabbits were implanted with bilateral cortical windows and electrodes for polysomnography. Relative changes in the cortical intramitochondrial redox state of cytochrome aa3 (CYT) and blood volume (CBV) were monitored by dual-wavelength reflectance spectrophotometry. Continuous, non-stationary oscillations (< 0.5 Hz) of both CYT and CBV were observed during waking and non-REM sleep. Cross-correlation analysis revealed a predominant interhemispheric synchrony of these oscillations which were unrelated to the heart rate, breathing, or electrocorticogram pattern. These findings suggest a dynamic linkage of slowly varying metabolic and vascular processes between unanesthetized cortical regions of 50 mm2 surface area.

Oxidative metabolism during recurrent seizures in the penicillin treated hippocampus

Abstract Changes in intracellular NADH fluorescence, which directly reflect changes in the rate of oxidative metabolism, were monitored during hippocampal epileptiform activity induced by penicillin. With interictal and ictal activity the oxidation rate would transiently increase and then return to the previous oxidation level after each spike or in the postictal depression period, respectively. Seizures were preceded by increased spike activity with simultaneously increasing oxidation. Maximum oxidation rates were reached at termination of each ictal episode. When the K+ concentration of the fluid bathing the hippocampus was increased, repetitive seizures occurred, at first followed by postictal periods, but at higher K+ levels ictal activity was more frequent and postictal periods were eliminated. As the K+ concentration was increased the interictal or recovery rate of oxidation rose; however, also at the higher K+ concentrations oxidation rates during ictal episodes tended not to be as high as at low K+. Thus the overall changes in rate of oxidation observed in the transition from interictal to ictal activity were smaller at high K+ than at low K+ concentrations. Direct current electrical correlates of epileptiform activity tended to mirror the changes in oxidation with a negative D.C. shift accompanying an increase in oxidation and vice versa. These results indicate a close relationship between extracellular K+ concentration, ictal activity and oxidative metabolism which could possibly be explained by the effects of varying K+ concentrations on the electrogenic pump (Na-K-ATPase).

Cortical oxygen consumption and NADH fluorescence during metrazol seizures in normotensive and hypotensive cats

Abstract The relationship between the oxidation of intramitochondrial NADH and increased oxygen utilization previously described in various preparations has not yet been directly studied in large areas of the cerebral cortex during generalized seizures. In the present study, changes in the NADH fluorescence of one or both cortical hemispheres were measured with a television fluorometer during Metrazol seizures in normotensive and hypotensive states. Fluorescein fluorescence was used as a reference signal. Combined with measurements of sagittal sinus blood flow and oxygen saturation, this technique demonstrated generalized ictal decreases in NADH fluorescence, the time integrals of which linearly related to the integrals of simultaneous increases in relative cortical O 2 consumption during seizures occurring at normal blood pressures. Seizures observed during systemic hypotension and probable cerebral hypoperfusion, however, were characterized by generalized increases in NADH fluorescence, the integrals of which were not related to the integrals of relatively delayed increases in cortical O 2 consumption. Similar anomalous NADH increases during seizures were also occasionally seen in certain cortical areas in normotensive animals, suggesting local ischemia. In addition. NADH fluorescence and cortical O 2 consumption were found to be affected by changes in blood pressure in the absence of ictal activity. These observations suggest that cortical NADH fluorescence is dependent both on metabolic demand and O 2 availability, and consequently may be validly utilized as an indicator of activated cortical oxidative metabolism during seizures only under conditions of adequate cortical oxygenation.

Potassium clearance and reactive gliosis in the alumina gel lesion.

Potassium accumulation or impaired potas‐ sium clearance has been hypothesized to contri‐ bute to epileptogenesis in gliotic epileptogenic foci. To test this hypothesis, potassium clear‐ ance rates following direct cortical stimulation were measured in the cortex of monkeys ren‐ dered epileptic by the injection of alumina gel into the motor area. Reactive gliosis at the sites in which potassium clearance was measured was then quantitated histologically and compared with potassium clearance rates. Dense gliosis was associated with slowed potassium clear‐ ance, although the base‐line potassium level ap‐ peared no different in actively epileptogenic areas or gliotic areas compared with normal areas. Possible mechanisms and significance of slowed potassium clearance in the alumina focus are discussed.

An Automated Method for the Measurement of Ventricular Volume

Several important indices of myocardial performance depend upon accurate and frequent measurement of ventricular volume. Studies employing such measurements have been limited because of the difficulty of manually measuring and calculating volumes frequently enough to obtain meaningful data. We, therefore, have developed an automated method for determination of ventricular volume in man. Left ventricular cineangiograms taken in the right anterior oblique position at 60 frames/sec are projected with a flickerless projector onto a Plumbicon television camera. A second television camera is used by a skilled operator for masking out noncontributory portions of the film and for shading selected areas to facilitate accurate recognition of the opacified chamber. An electronic video-tracking device then simultaneously determines the area and the maximum length of the opacified chamber in each cine frame. These data are recorded as analog signals on magnetic tape. Volumes are calculated by computer and plotted against time. When volumes determined by this automated method are compared with those obtained by manual planimetry, the correlation coefficient is 0.96. Aluminum prolate spheroids, left ventricular casts, and left ventricular cineangiograms were studied. This automated technic permits rapid and accurate measurement of ventricular volume in patients having diagnostic left ventriculograms.

The contribution of local blood flow to the rapid clearance of potassium from the cortical extracellular space

The transport of potassium to the blood stream following stimulation of the cortex in cats is evaluated by means of a potassium sensitive microelectrode technique. Potassium levels are measured in cortical veins, the sagittal sinus and the extracellular space during and after both pharmacological and electrical stimulation of the cortex. It is concluded that the potassium transport to the blood stream is not a significant factor in the rapid clearance of potassium from the extracellular space following stimulation.