David Eric Lees

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.

Critical level of oxygen delivery after cardiopulmonary bypass.

The relationship between oxygen uptake (&OV0312;O2) and delivery (&OV0312;O2) was examined in 64 patients immediately after cardiopulmonary bypass. In 44 patients with lactate levels below 2.5 mmol/L, &OV0312;O2 decreased proportionally when &OV0312;O2 decreased below 300 ml/min ± m2. At a &OV0312;O2 over this level, &OV0312;O2 plateaued at 105 ± 13 (SD) ml/min ± m2. In a contrasting group of 22 patients with blood lactate levels above 2.5 mmol/L, &OV0312;O2 changes depended on changes in &OV0312;O2 both alone and below 300 ml/min ± m2.

Somatosensory evoked potentials during whole body hyperthermia in humans

Somatosensory evoked potentials (SEPs) and body temperature were recorded in patients subjected to induced total hyperthermia for treatment of advanced neoplasms. Elevation of body temperature up to 42 degrees C for 2 h was achieved using a computer-controlled external heating system. SEPs were recorded continuously on-line during the treatment using finger shock stimulation. Evoked potential components later than 160 msec disappeared in the early part of the treatment, but reappeared quickly during cooling. P50 and P50-N70 amplitudes decreased regularly and significantly over the whole duration of the heating period. During the plateau period, no evoked potential peaks could be detected but short latency peaks reappeared as soon as cooling started. The disappearance of SEPs to finger stimulation during sustained hyperthermia at 42 degrees C confirms the findings obtained by EEG recording that a major neuronal dysfunction occurs under these circumstances which subsides quickly as temperature is dropped.

Electroencephalographic changes during whole body hyperthermia in humans

Abstract As part of a protocol of the National Cancer Institute, 21 selected patients were submitted to total body hyperthermia for treatment of metastatic carcinoma. Elevation body temperature up to 41.8°C for 2 h was achieved using a computer driven external heating system. Patients were sedated during treatment. To ensure the safety of the procedure, a battery of physiological parameters was monitored. Continuous EEG recordings were carried out in all patients. Analysis of the EEG included visual assessment, compressed spectral array and power spectrum. EEG data were compared mainly to body temperature, state of consciousness and drug administration. Consciousness during the treatment varied from very light sedation to light anesthesia, with some rare delirious episodes. No motor seizures were observed. All EEG recordings demonstrated major changes in both rhythmicity and amplitude (slower and lower) indicating a diffuse decrease of cortical activity during the hyperthermia period. All changes reversed themselves during the cooling period. Spectral power showed a statistically significant inverse relationship with temperature. At temperatures above 41°C, decrease in total EEG spectrum was not related to decrease in clinical reactivity. The degree of EEG slowing varied with the extent and duration of the hyperthermia, and was totally reversible within a few hours of cooling, without evidence of any EEG or neurological sequelae. However, at temperatures above 41.5°C, EEG changes compatible with metabolic or toxic encephalopathy were observed. Possible mechanisms are discussed.

17-β estradiol regulation of myocardial glutathione and its role in protection against myocardial stunning in dogs

We studied the effect of 2-week treatment with estradiol 17beta on myocardial glutathione concentration in dogs and isolated perfused rat heart subjected to brief coronary ischemia and reperfusion. Estradiol protected against ischemia/reperfusion-induced myocardial systolic shortening and malonylaldehyde production and increased myocardial glutathione concentration and glucose-6-phosphate dehydrogenase enzyme activity. Reduction of myocardial glutathione with buthionine sulfoximine to levels seen in the absence of estrogen reversed the protective effect of estradiol against myocardial dysfunction and lipid peroxidation associated with ischemia/reperfusion. These results suggest that the antioxidant effect of estradiol in ischemia/reperfusion may be mediated by regulation of myocardial glutathione metabolism.

Bone marrow toxicity in vitro of chloramphenicol and its metabolites.

The effect of chloramphenicol and several of its known and potential metabolites on DNA synthesis of rat and human bone marrow cells was investigated. The nitroso analog of chloramphenicol was the most potent inhibitor of DNA synthesis tested. Its inhibitory effect appeared to be irreversible, while that of chloramphenicol was reversible. The 14C label of the nitroso analog also bound irreversibly to viable rat bone marrow cells (9.2%) and to heat-inactivated cells (2.6%). In contrast, negligible amounts (0.02%) of the 14C label of chloramphenicol bound irreversibly to bone marrow cells. These results suggest that the bone marrow toxicity of the nitroso analog of chloramphenicol is related, at least in part, to its marked chemical reactivity.

Changes in peripheral vascular and cardiac sympathetic activity before and after coronary artery bypass surgery: Interrelationships with hemodynamic alterations

The plasma catecholamine levels obtained simultaneously from radial artery (A), pulmonary artery (MV), brachial vein (PV), and coronary sinus (CS) were measured concurrent with hemodynamic determinations during coronary artery bypass graft (CABG) operations. Arterial catecholamine levels decreased after induction of anesthesia and increased after sternotomy; changes in veno-arterial norepinephrine (NE) differences ([PV-A]ne, [MV-A]ne, and [CS-A]ne) were of the same magnitude and direction, suggesting that NE release from various organs was of the same extent. After operation, arterial NE increased further, but the veno-arterial NE differences were in striking contrast; [PV-A]ne became markedly positive, whereas [CS-A]ne became markedly negative, indicating that NE release from extremity peripheral vasculature increased markedly while cardiac NE release decreased. These differential changes in regional sympathetic activity appear to be related to postoperative hypertension (HT) and low cardiac output (CO). There were close relationships of changes in [MV-A]ne to mean arterial pressure (r = 0.78, p less than 0.001) and systemic vascular resistance (r = 0.62, p less than 0.010, suggesting that the sympathetic nervous system plays an important role in CABG perioperative hemodynamic alterations.

Accurate assessment of right ventricular function in acute respiratory failure.

Objective:Since right ventricular ejection fraction is highly dependent on afterload, right ventricular ejection fraction may not reflect right ventricular contractile function in acute respiratory failure. Despite a severe reduction in right ventricular ejection fraction, the right ventricle may be able to generate pressure output that is sufficient enough to maintain an adequate distribution of pulmonary perfusion. We tested this hypothesis by assessing the correlation between the right ventricular ejection fraction and the right ventricular end-systolic pressure-volume relationship, and by assessing the correlations between right ventricular ejection fraction and the physiologic deadspace/tidal volume ratio and between the physiologic deadspace/tidal volume ratio and the right ventricular end-systolic pressure-volume relationship. Design:Prospective study. Setting:University hospital intensive care unit (ICU). Patients:Twenty-one patients with acute respiratory failure. Measurements and Main Results:The physiologic deadspace/tidal volume ratio was used as an index of the distribution of pulmonary perfusion. Right ventricular ejection fraction was measured by the thermodilution method. Right ventricular end-diastolic volume index was obtained from the stroke volume index divided by the right ventricular ejection fraction. Right ventricular end-systolic volume index was calculated as the difference between the right ventricular end-diastolic volume index and the stroke volume index. Pulmonary arterial dicrotic notch pressure was used as an estimate of right ventricular end-systolic pressure. Data were collected at baseline and after one or two alterations in preload to define the right ventricular end-systolic pressure-volume relationship. There was no correlation between the right ventricular ejection fraction and the slope of the right ventricular end-systolic pressure-volume relationship line. No correlation was found between the right ventricular ejection fraction and the physiologic deadspace/tidal volume ratio. There was a hyperbolic curvilinear relationship between the physiologic deadspace/tidal volume ratio and the slope of the right ventricular end-systolic pressure-volume relationship line (r2 = .82,p < .0001). When the patients were divided into two groups based on the slope of the right ventricular end-systolic pressure-volume relationship line, the physiologic deadspace/tidal volume ratio was lower in the group with a high slope of the right ventricular end-systolic pressure-volume relationship line (p < .0001). There was no difference in other hemodynamic data between the two groups. Conclusions:These data suggest that in acute respiratory failure, the right ventricular ejection fraction does not reflect right ventricular performance.(Crit Care Med 1993; 21:1665–1672)

Elevated Pulmonary Artery Systolic Storage Volume Associated With Redistribution Of Pulmonary Perfusion

The possibility that an increased pulmonary arterial systolic storage volume (PASSV) correlates with a significant redistribution of pulmonary perfusion was examined in 30 surgical patients. Right ventricular stroke work index (RVSWI) was used as an index of distribution of pulmonary perfusion. The systolic storage volume was calculated from the pulmonary arterial compliance and mean pulmonary arterial distending pressure. Pulmonary arteriolar pressures were computed by Fourier analysis. Pulmonary arterial compliance was derived from the pulmonary arterial time constant and pulmonary arterial resistance. There was a linear relationship between PASSV and RVSWI (r = .81, p less than .001). Also, a direct correlation was found between RVSWI and pulmonary arterial time constant (r = .45, p less than .01). When the patients were divided into three groups according to the severity of pre-existing disease, linear relationships between PASSV and RVSWI were present in all groups, and the slopes were not different among the three groups. The patients were also divided into two groups based on a storage volume fraction of stroke volume index, to evaluate the effect of other hemodynamic data on the PASSV. Comparison of the two groups revealed that pulmonary arterial pressure and pulmonary arterial compliance were significantly higher in the group with a high storage volume fraction (p = .05 and p = .01, respectively). RVSWI and time constant were also significantly different between the groups (p less than .01 and p less than .01, respectively). We conclude that the pressure work generated by the right ventricle improved the distribution of pulmonary perfusion by increasing PASSV.

Effects of isoflurane on regional coronary blood flow and myocardial tissue pressure in chronically instrumented dogs.

BackgroundThe effects of isoflurane on distribution of transmural blood flow and transmural intramyocardial tissue pressure (IMP) were studied in chronically instrumented dogs, to address following alms: (1) to evaluate the direct effects of isoflurane on transmural blood flow distribution in the absence of compounding effects of baseline anesthetics, acute surgery, and indirect effects caused by changes in systemic blood pressures and heart rate—factors that were not well controlled in the past studies; (2) to examine the relation between transmural myocardial perfusion pressure and concurrent changes in transmural blood flow distribution during isoflurane anesthesia; and (3) to evaluate the effects of isoflurane on transmural myocardial oxygen supply-demand relation. MethodsDogs were allowed to recover at least 1 week after surgery for instrumentation. Blood flow of the left anterior descending coronary artery and subendocardial and subepicardial blood flows, regional IMPs, regional segmental dimension, heart rate, aortic pressure and left ventricular pressure were measured while dogs were awake and during 1.3% isoflurane anesthesia, with and without correction of heart rate and aortic pressure. Concurrently regional myocardial perfusion pressure, regional myocardial stroke work, and systolic pressure time index were calculated, based on direct measurements of IMP in subendocardium and subepicardium. ResultsWithout correction of aortic pressure, neither left anterior descending coronary artery flow nor transmural blood flow distribution was altered with isoflurane. When aortic pressure and heart rate were corrected to the awake values, left anterior descending coronary artery flow increased (37± 2%) and the increase was preferentially distributed to subendocardium, resulting in a shift in transmural blood flow. The subendocardial/subepicardial blood flow ratio increased from 1.2 ± 0.3 to 1.4 ± 0.4 (p, 0.05). The transmural blood flow changes were closely related to changes in regional myocardial perfusion pressure ratio between subendocardium and subepicardium (r = 0.76, P< 0.001). Concurrent with marked increases in blood flow (55 ± 4% increase), regional myocardial stroke work and systolic pressure time index of subendocardium were decreased more than 50% with isoflurane, resulting in a favorable subendocardial oxygen supply-demand balance. ConclusionsIsoflurane is a coronary vasodilator and redistributes blood flow in favor of subendocardium and depresses subendocardial work when heart rate and aortic pressure are controlled. These changes in regional myocardial blood flow, regional myocardial stroke work, and systolic pressure time index appear to be a result of changes in regional IMP.