Eight-week, placebo-controlled, double-blind comparison of the antidepressant efficacy and tolerability of bupropion XR and venlafaxine XR.

The efficacy, safety and tolerability of bupropion XR and venlafaxine XR was assessed and compared with placebo in adult outpatients with major depressive disorder (MDD). Adults meeting DSM-IV criteria for MDD with a minimum Hamilton Depression Rating Scale (HAMD) 17-Item total score of > or =18 were randomized to eight weeks of double-blind treatment with either bupropion XR (150 mg/day), venlafaxine XR (75 mg/day) or placebo. At the end of the fourth week of treatment, a dosage increase to bupropion XR 300 mg/day or venlafaxine XR 150 mg/day was allowed if, in the opinion of the investigator, response was inadequate. The primary efficacy endpoint was mean change from baseline at week 8 in the Montgomery-Asberg Depression Rating Scale (MADRS) total score last observation carried forward (LOCF). Mean changes from baseline at week 8 (LOCF) in MADRS total score were statistically significant for bupropion XR and venlafaxine XR patients compared to the placebo group: -16.0 for bupropion XR (P = 0.006 vs placebo), -17.1 for venlafaxine XR (P < 0.001 vs placebo) and -13.5 for placebo. Secondary outcomes (including CGI-S, HAM-A, MEI, Q-LES-Q-SF, responder and remitter analyses) also improved significantly for both active treatment groups compared with placebo. The most frequently reported adverse events were dry mouth and insomnia for bupropion XR, and nausea, hyperhidrosis, fatigue, and insomnia for venlafaxine XR. In this double-blind, placebo-controlled trial, bupropion XR at doses up to 300 mg/day and venlafaxine XR at doses up to 150 mg/day demonstrated comparable antidepressant efficacy.

Specific localization of thallium 201 in human high-grade astrocytoma by microautoradiography.

The ability to accurately distinguish remaining or recurrent high-grade astrocytoma from necrosis or edema following treatment is essential to optimal patient management. Thallium 201 planar gamma-camera imaging has been shown to be helpful in detecting recurrent high-grade astrocytoma; however, due to tissue heterogeneity adjacent to and within tumor, the cellular specificity and quantification of 201Tl uptake are largely unknown. In order to determine which tissues are responsible for the radioisotope uptake, microautoradiographic techniques were used to examine multiple tissue sections from five patients with high-grade astrocytoma. Each patient received 5 mCi of 201Tl i.v. 1 h prior to tumor removal. Additionally, all patients received computerized tomographic and 201Tl planar gamma-camera scans prior to surgery. Following surgery, the excised tissue specimens were tentatively classified by gross pathological examination and then immediately processed for dry mount autoradiography; grain density was determined over regions containing tumor, adjacent and uninvolved brain tissue, necrotic tissue, and background. Highly significant differences were found in grain densities (201Tl uptake) between tumor and uninvolved brain tissue, as well as between uninvolved brain tissue and necrotic tissue; there was no significant difference between background grain density and that in necrotic tissue. Mean grain densities (grains/cm2 +/- 1 SD) across patients were: tumor, 102 +/- 23; adjacent, uninvolved brain tissue, 29 +/- 11; necrotic tissue, 6.2 +/- 1.1; and background, 7.0 +/- 4.1. We conclude that the ability of 201Tl to selectively image high-grade astrocytoma is due to its preferential uptake into tumor cells.

Positron emission tomographic evaluation of cerebral blood flow during state anxiety in simple phobia.

The present study was undertaken to clarify some of the conflicting findings of previous reports on the effect of state anxiety on cerebral blood flow (CBF). Seven subjects with simple phobia of small animals were studied to permit the generation of wide ranges of anxiety. Each subject received five positron emission tomography (PET) scans in a rest-fear-rest-fear-rest, repeated-measures paradigm. A population of eight normal controls was employed. The phobic stimuli produced significant increases in state anxiety during fear and significant differences in physiologic measurements between the fear and rest scans. Absolute global and regional CBF was significantly lower during fear scans than during rest scans; however, when hypocapnia resulting from anxiety-induced hyperventilation was taken into account, the pattern vanished, and all global and regional CBF differences among scans became not significant. Resting global and regional CBF values in the phobic subjects did not significantly differ from those of the normal controls. That a relationship between anxiety and CBF was not found in 35 scans among seven subjects strongly suggests that CBF changes induced by state anxiety are either not presently measurable by PET techniques or that such a relationship may not exist. These findings should also reduce concerns that subject anxiety may confound CBF measurements during routine PET scanning.

Changes in sensory-cognitive input: effects on cerebral blood flow.

Eight healthy right-handed young men were subjected to local CBF measurement by [15O]water and positron emission tomography during partial sensory deprivation and during sensory-cognitive activation; physiological, hormonal, and subjective stress measurements were also performed. Results indicated that (a) "whole-brain" CBF increased during activation; (b) the greatest increase in CBF was in the primary visual cortex; (c) differences between hemispheres were not observed, but CBF was greater anteriorly than posteriorly in the deprivation condition only; (d) within-subject variability of CBF was not influenced by the sensory-cognitive condition; and (e) the procedure was not stressful.

Comparative sexual side effects of bupropion, fluoxetine, paroxetine, and sertraline.

OBJECTIVE: To investigate patient reported prosexual side effects of the aminoketone antidepressant bupropion (INN, amfebutamone) and to compare directly the sexual side effects of bupropion and the selective serotonin reuptake inhibitor (SSRI) antidepressants fluoxetine, paroxetine, and sertraline. METHODS: One hundred seven psychiatric outpatient respondents receiving current treatment with one of the above antidepressants anonymously completed questionnaires that allowed reporting of both decreases and increases in sexual function. The main outcome measures were antidepressant-associated changes in libido, arousal, duration of time from arousal to orgasm, intensity of orgasm, and duration of orgasm relative to that experienced before the onset of the patients' psychiatric illnesses. RESULTS: Bupropion-treated patients reported significant increases in libido, level of arousal, intensity of orgasm, and duration of orgasm beyond levels experienced premorbidly. The three SSRIs to an equal degree significantly decreased libido, arousal, duration of orgasm, and intensity of orgasm below levels experienced premorbidly. Overall, 27% of the SSRI-treated patients had no adverse sexual side effects; in contrast, 86% of patients treated with bupropion had no adverse sexual effects, and 77% of bupropion-treated patients reported at least one aspect of heightened sexual functioning. CONCLUSIONS: SSRI-induced adverse sexual effects appear to be the rule rather than the exception and may be substantially underreported unless patients are specifically asked about the effects of these medications on various aspects of sexual function. In contrast, prosexual effects were reported by the majority of patients treated with bupropion. The findings are reviewed in light of the neurochemistry of these agents and the sexual response.

99mTc-hexamethylpropyleneamine oxime single photon emission CT in poststroke depression.

In this pilot study of poststroke depression, the authors evaluated regional cerebral blood flow and depression in 14 stroke patients. Volume of ischemia was measured by two methods, which were highly correlated. Depression scores correlated with lesion volume as measured by single photon emission CT.

Prognostication of recovery following stroke using the comparison of CT and technetium-99m HM-PAO SPECT.

This study investigated the possibility that a relationship between the anatomic defects observed on computed tomography (CT) and the functional defects observed on single photon emission computed tomography (SPECT) might be used as an outcome measure to predict clinical recovery from the neurologic deficits induced by stroke. Twenty-seven patients with stroke location limited primarily to cerebral cortex were included in the study: each patient underwent a cranial CT scan, 99mTc hexamethylpropyleneamineoxime SPECT cerebral perfusion scan, and an initial and 1-yr follow-up neurologic examination. A strongly positive correlation between the ratio of the SPECT to CT volume defect sizes (SPECT divided by CT) and recovery following stroke was found, such that the greater the SPECT to CT ratio, the better the subsequent recovery of neurological deficits. Discriminant function analysis revealed that the best predictor of clinical outcome following stroke was the log-transformation of SPECT divided by CT. The results suggest that the relationship between the perfusion defects and tissue loss measured by SPECT and CT imaging may have prognostic utility following stroke limited primarily to cerebral cortex.

A morphologic study of long-term retention of fluorocarbon after liquid ventilation.

STUDY OBJECTIVES: To determine how long perfluorinated hydrocarbons remain in the lung after they are used for lung ventilation in dogs, and to determine if residual perfluorinated hydrocarbons cause structural alteration or an inflammatory reaction of the lung. DESIGN: Adult dogs were anesthetized and received ventilation with oxygenated perfluorinated hydrocarbon liquid. Morphologic studies of tissue from the lungs of these dogs were performed at intervals of a few minutes to 10 years after reconversion to breathing gas. SETTING: University College of Medicine. PARTICIPANTS: Adult mongrel and beagle dogs. INTERVENTIONS: Anesthetized adult dogs breathed oxygenated liquid fluorocarbons for 1 h and then were reconverted to breathing air. Three fluorocarbons, FX-80 (C(8)F(16)O; 3M Company; St. Paul, MN), Caroxin-D (C(10)F(22)O(2); P-1D; Allied Chemical Company; Morristown, NJ), and Caroxin-F (C(9)F(20)O; P-12F; Allied Chemical Company), were used. Morphologic studies of the lungs of these animals were performed immediately after restoration of air breathing and at intervals for up to 10 years. Not all animals were studied at each time interval. MEASUREMENTS AND RESULTS: A transient, acute inflammatory reaction was followed by a massive influx of macrophages, which were at first intra-alveolar and later interstitial, especially around vessels and bronchioles. Fluorocarbons remained in the lung in diminishing amounts for at least 5 years, as evidenced by persistent vacuolated macrophages in the alveoli, interstitium, and hilar lymph nodes; fluorocarbon was also detected in these tissues by chemical assays. In no case was there fibrosis or any other structural alteration associated with the residual fluorocarbon, which suggests that it was inert. At 10 years, no evidence of residual fluorocarbon was seen morphologically.

Clinical course of 91 consecutive near-drowning victims.

Hospital records of 91 consecutive near-drowning victims were studied retrospectively. Eight-one (89 percent) of these patients survived. Patients who were alert on arrival at the emergency room survived, but those who were comatose and had fixed dilated pupils died. Other states of consciousness were unreliable predictors of survival. All patients with a normal chest roentgenogram on admission survived; however, values for arterial oxygen tension (PaO2) did not necessarily correlate with the chest roentgenograms. Values for arterial blood gas tensions and pH varied widely, as follows; PaO2, 25 to 465 mm Hg; arterial carbon dioxide tension (PaCO2), 17 to 100 mm Hg; pH, 6.77 to 7.50; and arterial bicarbonate level, 6.6 to 29.7 mEq/L. The ratio of PaO2 to the fractional concentration of oxygen in the inspired gas (FIo2), which was calculated to standardize PaO2 data for varying concentrations of inspired oxygen, ranged from 30 to 585 mm Hg. Only one patient with a ratio of PaO2/FIo2 greater than 150 mm Hg on admission subsequently died; this was a neurologic rather than a pulmonary death. Serum electrolytic concentrations and values for hemoglobin level and hematocrit reading neither predicted survival nor indicated that a threat to life existed. Steroid and prophylactic antibiotic therapy did not appear to increase the chance of survival. Observations on these patients are discussed in light of previous experiments in animals, and an approach to therapy is suggested.

Titration of PEEP by the arterial minus end-tidal carbon dioxide gradient.

It was shown in dogs that intrapulmonary physiologic shunt (Qsp/Qt), arterial oxygen tension (PaO2), total static respiratory compliance (CT), oxygen delivery (O2AV), cardiac output (Qt), and arterial minus end-tidal carbon dioxide gradient (PaCO2-PetCO2) undergo statistically significant deterioration when oleic acid is injected into the pulmonary artery. Positive end-expiratory pressure (PEEP) therapy reduced Qsp/Qt and PaCO2-PetCO2 gradient and increased PaO2. The CT did not show any consistent pattern of improvement with the application of PEEP. The Qt and the O2AV progressively decreased as PEEP was increased. The application of additional PEEP beyond that which minimized the PaCO2-PetCO2 gradient produced a statistically significant increase in the PaCO2-PetCO2 gradient, but this was not reflected by concomitant changes in Qsp/Qt or PaO2 in spite of a further decrease in Qt. Thus, the PaCO2-PetCO2 gradient may be a more sensitive indicator of excessive PEEP than is Qst/Qt or PaO2, since it should be smallest when there is maximal recruitment of perfused or functional gas units without overdistention of alveolar areas contributing to dead space. Also, the use of the PaCO2-PetCO2 gradient permits the rapid titration of PEEP without the need for a pulmonary artery catheter.

Liquid ventilation of primates.

Three adult monkeys were anesthetized with ketamine and ventilated with fluorocarbon liquid [perfluoro bis (1, 4-isopropoxy) butane (Caroxin-D)] at 1 atmosphere on two separate occasions. During five runs, liquid ventilation was continued for 60 minutes. The sixth run was continued for ten minutes. Arterial blood gas levels during and after liquid ventilation were adequate for survival. Three years after the first period of liquid ventilation, the animals were killed. Approximately 0.001 mg of fluorocarbon per gram of tissue was present in the kidney, liver, brain, spleen, muscle, and heart. Fat contained approximately seven to nine times this amount, and the lung and pulmonary lymph nodes contained approximately 1,000 times this amount. In no case was it clinically evident that the monkeys had undergone periods of liquid ventilation. We conclude that primates can be ventilated successfully with liquid fluorocarbon on at least two separate occasions and can return to breathing air without obvious deleterious effects, but fluorocarbon is retained in small amounts for at least three years.

Continuous positive airway pressure and expiratory positive airway pressure increase functional residual capacity equivalently.

The effect of continuous positive airway pressure (CPAP) and expiratory positive airway pressure (EPAP) on functional residual capacity (FRC) of ten healthy, spontaneously breathing, lightly anesthetized intubated mongrel dogs was studied. The CPAP and EPAP at 5, 10, 15, and 20 cm H2O were alternately applied to all animals. Total (lung and chest wall) compliance, esophageal pressure, airway pressure, transpulmonary pressure, control FRC, and the change in FRC (delta FRC) were measured before and after each application of CPAP and EPAP. Neither expiratory transpulmonary pressure nor delta FRC with CPAP differed significantly from that with EPAP at all levels (p greater than 0.05). These data suggest that CPAP and EPAP, when applied at the same expiratory pressure, result in an equivalent increase in FRC due to passive mechanical distention of the lungs.

High level positive end expiratory pressure (PEEP) in acute respiratory insufficiency.

Twenty-eight patients developed severe, progressive acute respiratory insufficiency despite aggressive application of conventional respiratory therapy. Application of increased PEEP (18 torr or greater) resulted in a significant decrease in QA/QT. Selection of the optimal levle of PEEP for each patient required serial determinations of QA/QT and measurement of cardiovascular response. The overall survival rate was 61 percent. Acute respiratory insufficiency was a proximate cause of death in only one patient. Four of the patients (14 percent) developed a pneumothorax following institution of high PEEP therapy. Cardiac output was not affected adversely at any level of PEEP up to 32 torr (44 cm H2O). We conclude that high levels of PEEP can be therapeutic for patients with refractory respiratory failure when combined with intermittent mandatory ventilation and careful cardiovascular monitoring. As with any therapy, the optimum dose should be tailored to each patient according to his needs and response.

Effectiveness of CPAP by mask for pulmonary edema associated with hypercarbia.

We describe continuous positive airway pressure (CPAP) by mask to reduce hypercarbia in two patients who had pulmonary edema due to congestive heart failure. In such patients, beside reducing venous return and filling pressures, CPAP improves compliance and decreases the work of breathing, thereby improving effective ventilation. Hence, CPAP may be useful to combat not only hypoxemia but also hypercarbia that is associated with pulmonary edema.

Positive end-expiratory pressure (PEEP) and cerebrospinal fluid pressure during normal and elevated intracranial pressure in dogs.

The effect of up to 15 cm H2O positive end-expiratory pressure (PEEP) on cerebrospinal fluid pressure (Pcsf) was investigated in five anaesthetised, mechanically ventilated dogs during normal and then elevated (40-50 cm H2O) intracranial pressure (ICP). Stepwise elevations of PEEP in 5 cm H2O increments resulted in small rises in Pcsf at normal ICP and in significantly larger rises when ICP was elevated. The regression equations for the relationships between Pcsf and end-expiratory pressure (EEP) were as follows: Pcsf = 12.95 + 0.82 EEP for normal ICP, and Pcsf = 46.41 + 2.06 EEP for elevated ICP. Mean PaCO2 rose from 39.7 +/- 2.5 to 47.6 +/- 5.0 torr during normal ICP, and from 34.2 +/- 2.9 to 50.9 +/0- 5.3 torr at elevated ICP as PEEP was elevated to 15 cm H2O. We conclude that PEEP raised Pcsf, and that this increase is more severe under conditions of elevated ICP. The rise in Pcsf due to PEEP may be explained by either the rise in intrathoracic pressure or the rise in PaCO2, or both.

Evaluation of criteria for discontinuing mechanical ventilatory support.

Thirty-three patients who required short-term postoperative mechanical ventilatory support were studied to compare different criteria established to initiate weaning from mechanical ventilation. Intermittent mandatory ventilation criteria (i.e., decreasing mechanical respirator rate as long as the arterial (pHa) remains above 7.35) and conventional criteria (ie, vital capacity greater than 15 ml/kg and peak negative pressure greater than 20 cm H2O) were compared to determine which would more rapidly predict a patient's ability to sustain total spontaneous respiration. All patients were eventually weaned from mechanical ventilation and had their tracheas extubated. Twenty-one patients maintained a pHa of greater than 7.35 during total spontaneous ventilation before they would, or could, meet conventional criteria for initiating a trial of spontaneous respiration (P less than .001). Seven patients simultaneously met both criteria for maintaining total spontaneous ventilation and the remaining five patients met conventional criteria before intermittent mandatory ventilation criteria. In the latter group, the pHa decreased below 7.35 during spontaneous respiration but in only one patient did it fall below 7.30. Our findings suggest that a patient's ability to maintain a pHa of greater than 7.35 while decreasing the frequency of mechanical ventilator breaths is more accurate than peak negative pressure and vital capacity for predicting ability to sustan adequate spontaneous respiration.

Treatment of flail chest. Use of intermittent mandatory ventilation and positive end-expiratory pressure.

For the past two years we have treated patients with flail chest injuries and concomitant respiratory failure with intermittent mandatory ventilation (IMV) and positive end-expiratory pressure (PEEP). Prior to 1972 these patients were treated with controlled mechanical ventilation (CMV) until gross flailing ceased and inspiratory force and vital capacity measurements were adequate. We retrospectively studied the charts of 37 consecutive patients to compare the length of mechanical ventilatory support of patients managed by conventional CMV with those ventilated with IMV and PEEP. The mean ventilation time of patients treated with IMV and PEEP (5.1 +/- 4.7 days) was significantly less than that of the patients treated with CMV (18.8 +/- 14.4 days) (P less than .001).

Caffeine and human cerebral blood flow: a positron emission tomography study.

Positron emission tomography (PET) was used to quantify the effect of caffeine on whole brain and regional cerebral blood flow (CBF) in humans. A mean dose of 250 mg of caffeine produced approximately a 30% decrease in whole brain CBF; regional differences in caffeine effect were not observed. Pre-caffeine CBF strongly influenced the magnitude of the caffeine-induced decrease. Caffeine decreased paCO2 and increased systolic blood pressure significantly; the change in paCO2 did not account for the change in CBF. Smaller increases in diastolic blood pressure, heart rate, plasma epinephrine and norepinephrine, and subjectively reported anxiety were also observed.

Anxiety and cerebral cortical metabolism in normal persons.

The State-Trait Anxiety Inventory (STAI) was administered to 43 normal volunteers immediately before and after a positron emission tomography (PET) procedure with [18F]-2-fluoro-2-deoxy-D-glucose (18F-FDG). High trait-anxious individuals had significantly higher state (situational) anxiety associated with the PET scan procedure than did low trait-anxious persons. State anxiety decreased significantly for all respondents following the PET scan procedure. No significant relationships between global or regional cortical metabolic rates and state anxiety were observed. The direct cortical metabolic effects of heightened anxiety in the scan setting, should they exist, are likely obscured in the normal variance of the 18F-FDG method.