Omission of Radiotherapy After Breast-Conserving Surgery for Women With Breast Cancer With Low Clinical and Genomic Risk: 5-Year Outcomes of IDEA.

PURPOSE: Multiple studies have shown a low risk of ipsilateral breast events (IBEs) or other recurrences for selected patients age 65-70 years or older with stage I breast cancers treated with breast-conserving surgery (BCS) and endocrine therapy (ET) without adjuvant radiotherapy. We sought to evaluate whether younger postmenopausal patients could also be successfully treated without radiation therapy, adding a genomic assay to classic selection factors. METHODS: Postmenopausal patients age 50-69 years with pT1N0 unifocal invasive breast cancer with margins ≥2 mm after BCS whose tumors were estrogen receptor-positive, progesterone receptor-positive, and human epidermal growth factor receptor 2-negative with Oncotype DX 21-gene recurrence score ≤18 were prospectively enrolled in a single-arm trial of radiotherapy omission if they consented to take at least 5 years of ET. The primary end point was the rate of locoregional recurrence 5 years after BCS. RESULTS: Between June 2015 and October 2018, 200 eligible patients were enrolled. Among the 186 patients with clinical follow-up of at least 56 months, overall and breast cancer-specific survival rates at 5 years were both 100%. The 5-year freedom from any recurrence was 99% (95% CI, 96 to 100). Crude rates of IBEs for the entire follow-up period for patients age 50-59 years and age 60-69 years were 3.3% (2/60) and 3.6% (5/140), respectively; crude rates of overall recurrence were 5.0% (3/60) and 3.6% (5/140), respectively. CONCLUSION: This trial achieved a very low risk of recurrence using a genomic assay in combination with classic clinical and biologic features for treatment selection, including postmenopausal patients younger than 60 years. Long-term follow-up of this trial and others will help determine whether the option of avoiding initial radiotherapy can be offered to a broader group of women than current guidelines recommend.

Stress-like cardiovascular responses to common procedures in male versus female spontaneously hypertensive rats.

We sought to determine the effects of gender on cardiovascular function of spontaneously hypertensive (SH) rats under basal conditions and after several common husbandry and experimental procedures. Heart rate (HR) and mean arterial blood pressure (MAP) were monitored by radiotelemetry during undisturbed periods in the morning, at night, and after acute and chronic procedures. When undisturbed in the morning and at night, female rats had significantly (P < 0.05) higher HR than male rats, whereas male rats had significantly (P < 0.05) higher MAP. In response to all the acute procedures examined except prolonged restraint and introduction of an intruder rat of the same sex, female rats had significantly (P < 0.05) greater changes in HR or MAP than did male rats. In contrast, male rats had a greater change in MAP in response to prolonged restraint (P < 0.05) and greater HR and MAP responses (P < 0.05) in response to an intruder rat. Likewise, chronic exposure to an intruder rat increased HR and MAP significantly (P < 0.05) more in males than females, and both strains partially adapted to the introduction of the unfamiliar rat after the first day. There were no significant sex-associated differences in the HR or MAP responses to transport and subcutaneous injection on four consecutive days, and neither male nor female rats adapted to the repeated procedure. We conclude that sex-associated differences in cardiovascular responses do occur in SH rats, but the direction of the difference varies with the stimulus used.

Selective adaptation of male rats to repeated social encounters and experimental manipulations.

The objective of the present study was to determine how rats adapt to repeated encounters with an unfamiliar male or group of males and to experimental manipulations. Male rats were instrumented with radiotelemetry transmitters to monitor heart rate (HR), mean arterial blood pressure (MAP), and movements in the home cage as indices of arousal and stress. Groups of eight singly housed rats were exposed in their home cages to encounters with an unfamiliar rat or a group of three rats of the same strain, age, and sex for a period of 18 h (1600 to 1000 h) on four consecutive days. On separate occasions, the instrumented rats were given a subcutaneous injection of sterile saline in the animal room or were transported from the animal room to the laboratory and then injected at 1000 h on four consecutive days. Exposure to an unfamiliar rat or a group of 3 rats induced significant (P < 0.05) increases in HR, MAP, and movement in the first 30 min of exposure, and these responses partially but significantly (P < 0.05) adapted by the second or third day. Nocturnal movement in the home cage also was significantly (P < 0.05) increased on the first night and partially reduced on subsequent nights, but nocturnal HR responses were absent or significantly blunted. Nocturnal MAP was not increased. Subcutaneous injection in the animal room or after transport to the laboratory produced significant (P < 0.05) increases in HR, MAP, and movement in the cage 30 min after the injection, and these responses did not adapt over the four days of the experiment. We concluded that male Sprague-Dawley rats adapted quickly, albeit partially, to social encounters but did not adapt to repeated injections, suggesting selective adaptation depending on the type of stimulus used.

Effects of a cage enrichment program on heart rate, blood pressure, and activity of male sprague-dawley and spontaneously hypertensive rats monitored by radiotelemetry.

To determine whether a nonsocial enrichment program affects cardiovascular responses of individually housed male Sprague-Dawley (SD) and spontaneously hypertensive (SH) rats under basal conditions and after potentially stressful procedures, we used radiotelemetry to record heart rate (HR), systolic blood pressure (SBP), and activity in the cage. Enrichment comprised a simulated burrow (Rodent Retreat), then a food foraging item ("rat cannoli") 2 days later, and a paper bag of bedding for shredding (Nestpak) after another 2 days. Data were collected under undisturbed conditions and before and after several acute and chronic manipulations mimicking common husbandry, experimental, and stressful procedures. Enrichment often, but not always, reduced HR and SBP in male rats, suggesting decreased arousal and stress, and the effects depended on the parameter measured, strain of rat, and nature of the procedure to which animals were exposed. In general, HR varied more than SBP; enrichment affected SH rats more than SD rats; effects of enrichment were more consistently observed under undisturbed conditions than after manipulations of the rats; moderate responses to acute husbandry and experimental procedures were affected more than the larger changes produced by very stressful procedures; and responses to social interactions were unaffected by the enrichment program. What accounts for these variable effects of enrichment is unclear, and more studies are required to resolve the mechanisms. Whether this enrichment program should be used in an animal facility depends on several factors, particularly the professional judgment of the research, veterinary, and animal care staffs involved.

Does cage size affect heart rate and blood pressure of male rats at rest or after procedures that induce stress-like responses?

The objective of this study was to compare cardiovascular function and home-cage behavior of male Sprague-Dawley rats under resting conditions or after common husbandry and experimental procedures when the animals were housed with 3 other rats in cages with 920 or 1250 cm2 of floor space. Heart rate (HR), mean arterial blood pressure (MAP), and movement in the cage were monitored continuously by using radiotelemetry. The cardiovascular data are reported for a 1-h period in the morning before any human interventions, for the entire 12-h dark period, and before and after the following acute husbandry and experimental procedures: routine cage change; simulated cage change; restraint and subcutaneous (s.c.) injection; transport to another room and s.c. injection; restraint and tail-vein injection; witnessing tail-vein injection of a cage mate; witnessing a simulated decapitation; witnessing decapitation of six rats; witnessing decapitation and necropsy of six rats; exposure to the odors of urine and feces from stressed rats; exposure to the odor of dried rat blood; and being handled and weighed. Home-cage behaviors (sleeping, awake, moving, rearing, and grooming) also were scored before and after the acute procedures. Undisturbed HR in the morning was not different between the two housing groups; but undisturbed morning MAP and undisturbed nocturnal HR, MAP, and activity were significantly reduced (P<0.05) in rats housed in smaller cages. When animals were subjected to acute procedures, floor space induced a prolonged and significant effect (P<0.05) only after a cage change, with HR being reduced in rats housed in small cages. Sleeping behavior was significantly reduced (P<0.05) after many of the acute procedures, but cage size only slightly affected this behavior. We conclude that housing male rats in groups of four at 60% of the recommended cage floor space per rat does not produce crowding stress relative to that of rats housed at 80% of the recommendations. In addition, this study, coupled with our previous results, suggests that close interaction between group-housed rats appears to be more important to stress reduction than is providing increased floor space per animal.

Does witnessing experimental procedures produce stress in male rats?

The objective of this study was to test the hypotheses that male rats are stressed by being in the same room as animals subjected to common husbandry and experimental procedures and that the level of stress is affected by housing density. Two commonly used indices of stress, heart rate (HR) and mean arterial blood pressure (MAP), were determined by using radiotelemetry for 2 h before and 3 h after rats witnessed the following procedures: decapitation, decapitation and necropsy, cage change, restraint and subcutaneous injection, and restraint and tail-vein injection. In addition, home cage behaviors (sleeping, awake, moving, rearing, and grooming) were scored once each minute for 15 min before and 45 min after the procedures. Witnessing decapitation or decapitation and necropsy of 6 other rats induced small, but significant, increases in HR and MAP in animals housed alone, whereas responses in animals housed with one or three cagemates were more transient or not significant. Witnessing a routine cage change also induced small increases in HR and MAP in rats housed alone or with one cagemate, but HR and MAP decreased in rats housed four per cage. HR and MAP did not change in rats witnessing restraint and a subcutaneous injection of other rats, but these indices were transiently increased when rats witnessed animals being restrained in a rodent restrainer and given a tail-vein injection. Home cage behaviors were significantly altered only in rats witnessing decapitation and necropsy and then only in rats housed alone. We conclude that male Sprague-Dawley rats are not significantly stressed when present in the same room in which decapitation or other common experimental procedures are being performed, especially when the animals are housed with cagemates.

Recovery of male rats from major abdominal surgery after treatment with various analgesics.

The objective of this study was to compare the recovery of male rats after a major abdominal surgical procedure (the implantation of a radiotelemetry transmitter) when treated with buprenorphine, butorphanol, or ketoprofen and subcutaneous fluids (5% dextrose) or with subcutaneous fluids only. The parameters for assessing recovery were heart rate (HR), mean arterial blood pressure (MAP), home cage activity, food and water consumption, and body weight. HR, MAP, and activity were continuously monitored by radiotelemetry methods, food and water intakes were determined daily, and body weights were measured once or three times a week. In light of HR, nocturnal home cage activity, water consumption, and body weight gain, animals were recovered by about 7 days after surgery. MAP normalized by 1 to 2 days postsurgery, and food consumption returned to presurgical levels 5 to 12 days after surgery, depending on the analgesic treatment. On the basis of nocturnal activity, HR, and food and water intakes, buprenorphine-treated animals recovered more slowly than did the other two analgesic-treated groups. By the other parameters, all three analgesic-treated groups showed very similar responses across time. Surprisingly, when compared with the groups receiving only subcutaneous fluids, buprenorphine and butorphanol delayed or did not advance recovery, whereas ketoprofen neither retarded nor advanced recovery. Explanations for these results include: (a) the analgesics were effective in relieving pain but had pharmacological side effects that altered the measured parameters, making it difficult to determine recovery; (b) the level of pain experienced did not notably affect recovery; (c) the analgesics, at the doses and/or dosing schedules used, were not effective in the relief of pain, thereby causing both groups of animals to recover at the same rate; and (d) the analgesics interfered with recovery. Final resolution of these issues awaits further investigation.

Stress-like responses to common procedures in individually and group-housed female rats.

The objective of this study was to assess the cardiovascular function and behavior of female Sprague-Dawley rats housed individually or with one or three cage mates under resting conditions and when subjected to common husbandry and experimental procedures and potentially stressful olfactory stimuli. Heart rate (HR) and mean arterial blood pressure (MAP) were assessed continuously by using radiotelemetry and are reported for the following periods: for 1 hour each day prior to any human interaction; for 12 h each day during the dark phase of the 12:12-h light: dark photoperiod; and for 2 h before and 3 h after acute husbandry and experimental procedures. Home-cage behaviors (sleeping, awake but not moving, moving, rearing, and grooming) were scored once each minute for 15 min before and 45 min after the acute procedures. Mean resting HR values in the mornings prior to human contact were significantly (P < 0.05) lower in rats housed four per cage than animals housed alone or with one cage mate, whereas MAP during this period was lowest in rats housed two per cage. Nocturnal HRs were highest in rats housed two per cage, whereas nocturnal MAP did not differ significantly between housing groups. When rats were subjected to acute husbandry and experimental procedures, HRs increased 80 to 180 beats per min (bpm) above a baseline of 300 to 325 bpm and were significantly (P < 0.05) increased for periods of 30 to 90 min after the procedures. MAP showed increases that were proportionately the same as those in HR. Group housing often, but not always, reduced these cardiovascular responses. Procedure-induced arousal behaviors occurred in all housing groups after the acute husbandry and experimental procedures, but the occurrence of these behaviors was less frequent and of shorter duration in group-housed rats than rats housed alone. In light of these results, we conclude that under resting conditions group housed rats were somewhat less stressed than were rats housed alone. Further, we conclude that common procedures induce significant stress-like responses in female rats, and the magnitude and duration of these responses are reduced by group housing.

Are "by-stander" female Sprague-Dawley rats affected by experimental procedures?

The objective of this study was to test the hypotheses that female rats are stressed by being in the same room as animals subjected to common husbandry and experimental procedures and that the level of stress is affected by housing density. Two commonly used indices of stress, heart rate (HR) and mean arterial blood pressure (MAP), were determined by using radiotelemetry for 2 h before and 3 h after rats witnessed the following procedures: decapitation, simulated decapitation, cage change, simulated cage change, restraint and subcutaneous injection, removal of rats to another room for injection, restraint and tail-vein injection, handling and weighing, and handling and vaginal lavage. In addition, home cage behaviors (sleeping, awake, moving, rearing, and grooming) were scored once each minute for 15 min before and 45 min after the procedures. Witnessing decapitation of six other rats induced small, but significant, increases in HR above undisturbed baseline values in animals housed alone, whereas responses in animals housed with one or three cage mates were slightly greater than those of rats housed alone. Witnessing a routine cage change induced significant increases in HR in rats which were equal to or greater than those induced by witnessing decapitations; however, housing density had little effect on the responses to cage change. HR did not significantly increase above baseline values in rats witnessing restraint and a subcutaneous or tail-vein injection of other rats or when witnessing other rats being handled and weighed. However, rats housed alone showed significant increases in HR when witnessing a vaginal lavage of other rats. Active behaviors (moving, rearing, grooming) in the home cage were significantly altered only in rats housed alone and then only when witnessing a cage change or a tail-vein injection. Considering primarily increased HR, we conclude that female Sprague-Dawley rats may be marginally stressed when present in the same room in which decapitation is being performed, but similar stress-like responses are induced by common husbandry and experimental procedures. Finally, group housing often, but not always, reduces the stress-like responses that can occur in female by-stander rats.

Stress-like responses to common procedures in rats: effect of the estrous cycle.

The objective of this study was to assess cardiovascular and behavioral responses of Sprague-Dawley female rats subjected to or witnessing common husbandry and experimental procedures at various points during the estrous cycle. Heart rate (HR) and mean arterial blood pressure (MAP) were determined using radiotelemetry for 2 h before and 3 h after: cage change, restraint and subcutaneous (s.c.) injection, restraint and tail-vein injection, witnessing decapitation of other rats, smelling urine and feces from stressed rats, and smelling dried rat blood. Home cage behaviors (sleeping, awake, moving, rearing, and grooming) were scored once each minute for 15 min before and 45 min after the incidents. Being subjected to cage change, restraint and injections, and odors significantly increased HR and MAP 60-120 beats per min and 10-20 mm Hg over baseline respectively for 45 to 90 min. Witnessing these procedures also significantly increased HR and MAP but the magnitude was reduced by 20% to 30% compared to that seen in rats subjected to the procedures. Witnessing decapitation of other rats induced cardiovascular responses which were not different from those of rats witnessing other procedures. The cardiovascular responses were not enhanced during proestrus-estrus compared to metestrus-diestrus. There were also no significant effects of the estrous cycle on home cage behavior after these procedures. We conclude that cycling female rats show stress-like effects when they are subjected to or witness common husbandry and experimental procedures, but there is little to no effect of the estrous cycle.

Stress-like responses to common procedures in male rats housed alone or with other rats.

The objective of this study was to assess the cardiovascular function and behavior of male Sprague-Dawley rats housed individually or with one or three cagemates during resting conditions and when subjected to common husbandry and experimental procedures and potentially stressful olfactory stimuli. Heart rate (HR), mean arterial blood pressure (MAP), and movement in the cage were collected by using radiotelemetry for 24 h on an experiment-free day and for 2 h before and 3 h after the following acute procedures: cage change, restraint and subcutaneous injection, restraint and tail-vein injection, exposure to the odor of urine and feces from stressed rats, and exposure to the odor of dried rat blood. Home cage behaviors (sleeping, awake, moving, rearing, and grooming) were scored once each minute for 15 min before and 45 min after the acute procedures. Resting HR and MAP values consistently were lower in rats housed four per cage than animals housed alone or with one cage mate. Compared to that of animals housed individually, general activity was higher during the light phase and lower during the dark phase in rats housed four per cage. Rats housed four per cage showed significantly lower HR and MAP in response to acute husbandry and experimental procedures than rats housed alone, and the HR and MAP of rats housed in pairs were not consistently lower than those of rats housed alone. Procedure-induced arousal behaviors were observed in all housing groups after the acute husbandry and experimental procedures, but rats housed four per cage returned to sleeping behavior more quickly than did rats in the other housing groups. In light of these results, we concluded that under resting conditions, rats housed four per cage were less stressed than were rats housed alone, that common procedures induce noteworthy stress-like responses in male rats, and that the magnitude and duration of these responses are reduced by group housing.

Effects of a complex housing environment on heart rate and blood pressure of rats at rest and after stressful challenges.

Housing enrichment for rodents continues to be a discussion topic within the animal care community. The objective of this study was to determine the extent to which a complex housing environment affects heart rate, blood pressure, and activity of rats when undisturbed and after exposure to stressful challenges and whether autonomic controls of heart rate would be affected. Male and female Sprague-Dawley and Wistar rats with radiotelemetry transmitters were evaluated under nonenriched single-housing conditions and after acclimation to a complex environment of dim light and cohabitation with 3 conspecifics in large cages with hiding, food foraging, and nesting items. Telemetry data were collected when rats were undisturbed, after acute challenges (cage change, intraperitoneal injections, restraint), during a forced running protocol, and after cholinergic or adrenergic blockade. The complex environment reduced heart rate and increased activity in undisturbed rats but did not affect blood pressure. Heart rate responses to challenges were unaffected, decreased, or increased by complex housing, depending on the stock and sex of rats. Forced running was either unaffected or decreased, depending on the stock and sex of rats. Heart rate responses to cholinergic or ß1-adrenergic blockade were not affected. We conclude that the complex housing did not reduce indices of stress (for example, heart rate) as compared with simpler housing. However, the possibility that some environmental elements interact negatively with each other must be considered in future studies.

Effects of cage enrichment on heart rate, blood pressure, and activity of female Sprague-Dawley and spontaneously hypertensive rats at rest and after acute challenges.

Here we sought to determine whether a nonsocial cage enrichment program, identical to one we previously used with male rats, was effective in reducing heart rate or systolic blood pressure (SBP) in female Sprague-Dawley rats and spontaneously hypertensive rats (SHR). Young adult rats, each instrumented with a radiotelemetry pressure transmitter, were housed individually under enriched or nonenriched conditions. Heart rate and SBP were monitored at 5- and 1-min intervals, respectively, when the rats were undisturbed or after several different types of experimental manipulations some of which are considered stressful. Cage enrichment did not significantly alter heart rate or SBP of undisturbed rats in either strain at any time during the day or night. However, activity of female SHR was increased in the afternoon and at night under enriched conditions compared with nonenriched conditions. The enrichment program did not significantly reduce heart rate or SBP responses to most acute manipulations in either strain. However, cage enrichment increased the responses to some procedures (Sprague-Dawley: handling, 1-h restraint; SHR: subcutaneous injection, tail-vein injection, handling). We conclude that a nonsocial cage enrichment program did not reduce physiologic indicators of stress in female Sprague-Dawley rats or SHR.

Heart rates of male and female Sprague-Dawley and spontaneously hypertensive rats housed singly or in groups.

This study was conducted to confirm our previous reports that group housing lowered basal heart rate and various evoked heart-rate responses in Sprague-Dawley male and female rats and to extend these observations to spontaneously hypertensive rats. Heart rate data were collected by using radiotelemetry. Initially, group- and single-housed rats were evaluated in the same animal room at the same time. Under these conditions, group-housing did not decrease heart rate in undisturbed male and female rats of either strain compared with single-housed rats. Separate studies then were conducted to examine single-housed rats living in the room with only single-housed rats. When group-housed rats were compared with these single-housed rats, undisturbed heart rates were reduced significantly, confirming our previous reports for Sprague-Dawley rats. However, evoked heart rate responses to acute procedures were not reduced universally in group-housed rats compared with either condition of single housing. Responses to some procedures were reduced, but others were not affected or were significantly enhanced by group housing compared with one or both of the single-housing conditions. This difference may have been due, in part, to different sensory stimuli being evoked by the various procedures. In addition, the variables of sex and strain interacted with housing condition. Additional studies are needed to resolve the mechanisms by which evoked cardiovascular responses are affected by housing, sex, and strain.

Effect of housing rats in dim light or long nights on heart rate.

Housing laboratory animals under lighting conditions that more closely mimic the natural environment may improve their wellbeing. This study examined the effects of dim light or a long-night photocycle on resting heart rate (HR) of rats and their HR responses to acute procedures. Male and female Sprague-Dawley (SD) and spontaneously hypertensive (SHR) rats, instrumented with radiotelemetry transmitters and housed individually under a 12:12-h light:dark photocycle with 10 lx illumination (dim light) or under an 8:16-h light:dark photocycle with 200 lx illumination (long nights), were compared with control rats individually housed under a 12:12-h light:dark photocycle with 200 lx illumination. Dim light and long nights significantly reduced the HR of undisturbed SD and SHR male and SHR female rats during the day and at night; however, the HR of undisturbed SD females was not affected. When rats were subjected acutely to husbandry, experimental, or stressful procedures, dim light or long nights (or both) reduced HR responses to some procedures, did not alter responses to others, and increased responses to yet other procedures. The pattern of effects varied between strains and between male and female rats. Because basal HR was reduced when rats were housed under 10 lx illumination or an 8:16-h light:dark photocycle, we concluded that housing rats under 12:12-h light:dark, 200 lx ambient light conditions was potentially stressful, We also concluded that dim light or long nights did not uniformly reduce the increased HR responses induced by acute procedures.

Aerosol delivery in ventilated newborn pigs: an MRI evaluation.

Pulmonary deposition of inhaled drugs in ventilated neonates has not been studied in vivo. The objective of this study was to evaluate pulmonary delivery of gadopentetate dimeglumine (Gd-DTPA) following nebulization in ventilated piglets using magnetic resonance imaging. Seven ventilated piglets (5 +/- 2 d old, weight 1.8 +/- 0.5 kg) were scanned in the Bruker/Siemens 4T magnetic resonance scanner using T1 weighted spin-echo sequence. Aerosols of Gd-DTPA were generated continuously using the MiniHeart jet nebulizer. Breath-hold coronal images were obtained before and every 10 min during aerosolized Gd-DTPA for 90 min. Signal intensity (SI) changes over the lungs, kidneys, liver, skeletal muscle, and heart were evaluated. A significant increase in SI was observed in the lungs, kidney, and liver at 10, 20, and 40 min respectively after start of aerosol. At the end of 90 min, the SI increased by 95%, 101%, and 426% over the right lung, left lung, and kidney, respectively. A much smaller increase in SI was observed over the liver. In conclusion, we have demonstrated effective pulmonary aerosol delivery within 10 min of contrast nebulization in ventilated piglets. Contrast visualization in the kidneys within 20 min of aerosol initiation reflects alveolar absorption, glomerular filtration and renal concentration.

Jet nebulization of prostaglandin E1 during neonatal mechanical ventilation: stability, emitted dose and aerosol particle size.

BACKGROUND: We have previously reported the safety of aerosolized PGE1 in neonatal hypoxemic respiratory failure. The aim of this study is to characterize the physicochemical properties of PGE1 solution, stability, emitted dose and the aerodynamic particle size distribution (APSD) of PGE1 aerosol in a neonatal ventilator circuit. METHODS: PGE1 was diluted in normal saline and physicochemical properties of the solution characterized. Chemical stability and emitted dose were evaluated during jet nebulization in a neonatal conventional (CMV) or high frequency (HFV) ventilator circuit by a high performance liquid chromatography-mass spectrometry method. The APSD of the PGE1 aerosol was evaluated with a 6-stage cascade impactor during CMV. RESULTS: PGE1 solution in normal saline had a low viscosity (0.9818 cP) and surface tension (60.8 mN/m) making it suitable for aerosolization. Little or no degradation of PGE1 was observed in samples from aerosol condensates, the PGE1 solution infused over 24h, or the residual solution in the nebulizer. The emitted dose of PGE1 following jet nebulization was 32-40% during CMV and 0.1% during HFV. The PGE1 aerosol had a mass median aerodynamic diameter of 1.4 microm and geometric S.D. of 2.9 with 90% of particles being <4.0 microm in size. CONCLUSION: Nebulization of PGE1 during neonatal CMV or HFV is efficient and results in rapid nebulization without altering the chemical structure. On the basis of the physicochemical properties of PGE1 solution and the APSD of the PGE1 aerosol, one can predict predominantly alveolar deposition of aerosolized PGE1.

Comparison of carbon dioxide, argon, and nitrogen for inducing unconsciousness or euthanasia of rats.

We compared CO(2), Ar, and N(2) for inducing unconsciousness and euthanasia of Sprague-Dawley rats. We determined time to unconsciousness and monitored heart rate (HR) and mean arterial blood pressure (MAP) by radiotelemetry to assess stress, recovery after exposure, and time of death. Unconsciousness (mean +/- standard error) occurred 24 +/- 3, 87 +/- 8, and 93 +/- 8 s after short-term exposure to CO(2), Ar, and N(2), respectively. During exposure, CO(2) depressed HR, whereas Ar and N(2) increased HR. Upon removal from the chamber, rats' HR rapidly normalized after CO(2) or N(2) but remained elevated for 60 min after Ar. During exposure, all agents depressed MAP, which returned to resting levels 10 to 50 min after rats' removal from the chamber. For euthanasia, CO(2) at approximately 100% induced unconsciousness in 37 +/- 3 s, increased and then depressed MAP and HR, and caused death at 188 +/- 15 s. CO(2) at approximately 30% induced unconsciousness in 150 +/- 15 s, decreased HR and MAP, and induced death at 440 +/- 9 s. Ar at approximately 100% increased MAP but decreased HR, induced unconsciousness with hyperreflexia at 54 +/- 4 s, and caused death at 197 +/- 20 s. N(2) at approximately 100% decreased MAP but not HR and produced unconsciousness with hyperreflexia at 164 +/- 17 s and death at 426 +/- 28 s. We conclude that CO(2) effectively produced unconsciousness and euthanasia, but we were unable to ascertain distress. Ar also appears effective but produced hyperreflexia and tachycardia. N(2) was ineffective.