Norman H. Edelman

Control of breathing during methadone addiction

Chemical control of breathing was studied before and after the administration of the daily dose of methadone in 14 former heroin addicts who were enrolled in a methadone maintenance program and taking 60 to 100 mg/day. Two major groups were identified: group 1 in which subjects (n=6) had taken the drug for less than two months, and group 2 in which the subjects (n=6) had taken the drug from eight to 43 months. Prior to the daily dose of methadone, the levels of arterial carbon dioxide tension were significantly higher and ventilatory response to hypoxia significantly lower in group 1 than in group 2. Ventilatory responses to carbon dioxide (CO2) were also lower in group 1, but the difference was not statistically significant. Following the daily dose of methadone, the subjects in group 1 manifested significant reductions of ventilation and arterial oxygen tension, significant increases in arterial carbon dioxide tension and significant depressions of ventilatory responses to both CO2 and hypoxia in comparison to values before the administration of methadone. In contrast, subjects in group 2 manifested only a significant decrease in ventilatory responsiveness to hypoxia with no change in ventilation, arterial blood gas tensions or ventilatory responsiveness to CO2 following the daily dose. Two intermediate subjects (five and seven months) behaved as long-term subjects with regard to arterial carbon dioxide tension and CO2 responses but as short-term subjects with regard to responsiveness to hypoxia. Thus, during the first two months of methadone maintence, there is continual alveolar hypoventilation due to depression o both central (CO2) and peripheral (hypoxia) chemoreception. After five months, alveolar hypoventilation is abolished as the CO2-sensitive chemoreflex acquires full tolerance to methadone at the maintenance dose level. In contrast, tolerance of the hypoxia-sensitive chemoreflex is developed more slowly and is never complete.

Prevention of Collagen Deposition Following Pulmonary Oxygen Toxicity in the Rat by Cis-4-Hydroxy-l-Proline

Exposure of rats to high oxygen tensions causes increased collagen content of lungs and alveolar enlargement in 3-6 wk. We tested whether cis-hydroxyproline, a proline analogue that inhibits collagen synthesis, could prevent the collagen accumulation and alveolar enlargement. Rats were exposed to hyperoxia for 60 h and then to room air and hyperoxia for alternate 24-h periods for 11.5 d. Treated oxygen-exposed rats received 200 mg/kg cis-hydroxyproline twice daily over the 14-d exposure period. Control rats breathed room air. Examination of lungs on day 14 showed collagen content of oxygen-exposed lungs to be 48% greater than control (P < 0.05). The collagen content of the treated oxygen-exposed lungs was -12% of control (NS). Total lung volume was 16% greater than control in oxygen-exposed rats (P < 0.05) and 8% greater than control in treated oxygen-exposed rats (NS). Morphometric studies showed alveolar size was greater than control in oxygen-exposed rats (188+/-11 [SE] vs. 143+/-6 mumul [P < 0.05]). Oxygen-exposed, treated rats had a mean alveolar volume of 150+/-7 mumul. Lung pressure-volume curves were significantly shifted to the left of control in the oxygen-exposed rats, whereas the curves of the oxygen-exposed, treated group were identical to control. These data suggest that cis-hydroxyproline prevented the accumulation of collagen in the lungs in pulmonary oxygen toxicity. In addition, there was apparent protection from airspace dilatation and decreased lung elasticity, suggesting that alveolar enlargement after oxygen toxicity is linked to the deposition in lung tissue of new connective tissue fibers.

Correlation between ventilation and brain blood flow during sleep.

The relationships between brain blood flow (BBF) and ventilation (VI) were studied during sleep in 13 goats. Unilateral BBF was continuously measured with an electromagnetic flow probe; total and regional BBF were assessed by the radioactive microsphere technique in four animals. Interacting changes in VI and BBF occurred during both slow wave (SWS) and rapid eye movement (REM) sleep. During SWS, significant decreases in VI and increases in arterial PCO2 occurred compared to wakefulness. BBF during SWS correlated linearly with arterial CO2 tension (PaCO2); nd the relationship was similar to that for awake goats breathing CO2. During REM sleep, VI was significantly less than both the awake (W) and SWS states due principally to a decrease in tidal volume. BBF during REM sleep was significantly and substantially increased compared with both the W and SWS states; this increase was shared by all brain areas. The increase in BBF during REM sleep was greater than that predicted from changes in PaCO2. In five goats provided with chronic sagittal sinus fistulae, arteriovenous oxygen difference was measured in separate studies and found to be significantly lower during REM sleep compared with W; brain O2 consumption was similar in magnitude in the REM and W states. Thus, the high BBF of REM sleep was also unexplained by an increase of brain metabolic activity. We conclude that, during SWS, increases in BBF are explained by hypoventilation and hypercapnia. In contrast, during REM sleep, BBF is substantially in excess of that expected from PaCO2 or brain metabolism. It is postulated that this excess of BBF during REM sleep could reduce the central chemoreceptor pH relative to that present in SWS. The combination of reduction of sensitivity to CO2 and lower tissue PCO2 during REM sleep makes it likely that the output of the central chemoreceptors during this state is less than that during SWS and wakefulness. This may contribute to the low tidal volume and respiratory irregularities of this sleep period.

Blunted respiratory drive in congenital myopathy

Two patients with clinically mild congenital myopathies presented with chronic respiratory failure. Muscle weakness alone could not account for the respiratory insufficiency since static respiratory pressures were not markedly impaired, ventilation during exercise was normal, and daytime ventilation was normal if ventilatory assistance was provided at night. The ventilatory responses to inhaled carbon dioxide were very low, suggesting that impairment of the central nervous respiratory chemoreceptor contributed to hypoventilation. These patients and others described in the literature suggest that central depression of ventilation may occur more frequently than previously recognized in patients with muscular disorders. Patients with chronic respiratory failure due to central depression of respiratory drive can be effectively managed by assisted ventilation at night.

Hypoxia and Brain Blood Flow

the ascent to high to high altitude presents a variety of physiological and psychological obstacles. The most prominent is the decline in ambient O2 tension (Po2); much of this volume is devoted to consideration of the effects of the resultant hypoxemia on respiration and circulation. It seems likely, however, that acute responses and adaptations to hypoxia in the central nervous system also play key roles in determining man’s ability to ascend to high altitudes. Because, at least in the short run, the O2 supply to the brain at a given Po2 of inspired gas depends largely on ventilation and brain perfusion, the brain blood flow response to hypoxia must be crucial in the integrated physiological responses considered in this chapter.

Institutions With Accredited Residencies in New York State With an Interest in Developing New Residencies or Expanding Existing Ones

Purpose In view of the looming physician shortage, especially in primary care specialties, there have been calls for increasing graduate medical education (GME). However, the capacity for increases of GME in institutions accredited by the Accreditation Council for Graduate Medical Education (ACGME) has not been determined. Method In 2009, the authors surveyed the 48 designated institutional officials supervising ACGME-accredited residencies in New York State that were eligible for their study, to determine interest in and capacity for development of new core residencies and expansion of existing ones if additional funds were made available at current Medicare rates. Results Thirty-six (75%) responded; 39% would add new programs and 47% would expand current programs with additional funding. The major interest in adding new programs was in emergency medicine (35%). Notably, only 11% would add family medicine. The major interest in program expansion was internal medicine (48%), urology (42%), diagnostic radiology (35%), obstetrics–gynecology (26%), and emergency medicine (25%). Conclusions Fewer than 50% of current training institutions are interested in or have the capacity for expansion of core residencies. The interest in establishing or expanding primary care is especially problematic. Because 70% of internal medicine residents become subspecialists, additional funds for GME at current rates would largely encourage the training of additional hospital-based and hospital-intensive specialists, with little impact on those who would practice adult primary care medicine. Significantly increasing the physician training for adult primary care medicine will require more substantial institutional incentives.

Modulation of Respiration by Brain Hypoxia

The dual nature of hypoxic modulation of central respiratory activity is best appreciated in the sino-aortic deafferented, anesthetized animal during progressive reductions in the arterial oxygen content.1 Figure 1 illustrates these two distinct central respiratory responses to brain hypoxia and their different oxygen thresholds; respiratory depression, which is manifested with even modest reductions in oxygenation, and respiratory excitation (gasping), which occurs only with severe reductions in the arterial oxygen content (to values less than 20%).

Central Adaptation to Hypoxia

It is well established that in anesthetized animals, in the absence of peripheral chemoreceptor stimulation, hypoxia produces a depression of breathing. Recently, there has been considerable interest in discerning the mechanisms responsible for the central depression of respiration during hypoxia. A basic issue that arises when considering the mechanisms responsible for hypoxic modulation of central respiratory output is whether respiratory neuronal activity is simply limited by substrate availability within the brain, or whether this depression represents an active inhibition of neuronal activity. Such inhibition could serve to minimize energy use during hypoxia by limiting motor activity as well as conserving high energy substrates that would be used normally to reestablish transmembrane ionic gradients dissipated during neuronal activity. Thus, neuronal inhibition might subserve a protective function by affording tolerance to hypoxic environments. This ability to “down-regulate” metabolic activity during hypoxia is a well-characterized phenomenon in many lower vertebrates, for example, the diving turtle (46), but may also be physiologically relevant in both unanesthetized neonatal and adult mammals.

The Projected Responses of Residency-Sponsoring Institutions to a Reduction in Medicare Support for Graduate Medical Education: A National Survey.

Purpose To assess the projected responses of residency-sponsoring institutions to the proposed reduction in Medicare’s indirect medical education (IME) payments. Method In 2012, the authors surveyed directors of graduate medical education (GME) programs, examining (1) overall responses to a reduction in IME reimbursement and (2) the value of individual residencies to the institution from the economic/operational and educational/public service points of view, to determine which programs may be at risk for downsizing. Results Responses from 192 of 555 institutions (35% response rate) varied by the size of the institution’s GME program. Of large programs (six or more residencies), 33 (33%) would downsize at a 10% reduction in IME reimbursement, focusing cuts on specific programs. Small programs (five or fewer residencies) were more likely to retain their existing residencies with modest IME payment reductions and to make across-the-board cuts. The economic/operational value of specialties varied widely, with hospital-intensive residencies valued highest. Family medicine was valued highly from an economic/operational point of view only by small programs. Educational/public service value scores varied less and were higher for all specialties. Preventive medicine was not highly valued in either category. Conclusions Even a modest decrease in IME reimbursement could trigger institutions to downsize their GME programs. Programs at the greatest risk for cuts may be those with modest economic/operational value but high societal value, like family medicine. The retention or expansion of training in family medicine may be most easily accomplished then at smaller institutions.

The Modulation of Peripheral Chemoreceptor Input by Central Nervous System Hypoxia

Production of progressive isocapnic brain hypoxia by carbon monoxide (CO) inhalation in anesthetized, vagotomized, peripherally chemodenervated cats results in an initial reduction of phrenic neurogram amplitude followed by a secondary decrease in phrenic burst frequency as the level of hypoxia increases (Melton et al., 1988; Melton et a1.,1990; Wasicko et al., 1990). After arterial O2content (CaO2) is reduced by approximately 50%, the phrenic neurogram becomes silent. Severe depression of the phrenic neurogram during hypoxia does not inhibit the respiratory response to CO2, however, suggesting that processing of central chemoreceptor afferent information is unaffected by hypoxia (Van Beek et al., 1984; Melton et al., 1988)