The present study was designed to characterize respiratory fluctuations in awake, healthy adult humans under resting conditions. For this purpose, we recorded respiratory movements with a strain-gauge pneumograph in 20 subjects. We then used Allan factor, Fano factor, and dispersional analysis to test whether the fluctuations in the number of breaths, respiratory period, and breath amplitude were fractal (i.e., time-scale-invariant) or random in occurrence. Specifically, we measured the slopes of the power laws in the Allan factor, Fano factor, and dispersional analysis curves for original time series and compared these with the slopes of the curves for surrogates (randomized data sets). In addition, the Hurst exponent was calculated from the slope of the power law in the Allan factor curve to determine whether the long-range correlations among the fluctuations in breath number were positively or negatively correlated. The results can be summarized as follows. Fluctuations in all three parameters were fractal in nine subjects. There were four subjects in whom only the fluctuations in number of breaths and breath amplitude were fractal, three subjects in whom only the fluctuations in number of breaths were fractal, and two subjects in whom only fluctuations in breath number and respiratory period were fractal. Time-scale-invariant behavior was absent in the two remaining subjects. The results indicate that, in most cases, apparently random fluctuations in respiratory pattern are, in fact, correlated over more than one time scale. Moreover, the data suggest that fractal fluctuations in breath number, respiratory period, and breath amplitude are controlled by separate processes.Allan and Fano factors; breath amplitude and frequency; dispersional analysis; Hurst exponent RESPIRATION IN AWAKE, HEALTHY adult humans is characterized by considerable variability in the frequency, duration, and amplitude of breaths (5,8,18,24,31). The aim of the present study was to define the basis for the variability of these respiratory parameters. Two possibilities were considered.First, except for some short-range correlations (4, 10), the fluctuations in respiration might be random, i.e., uncorrelated (6,16,32). That is, although influenced by events (breaths) in the recent past, the present value of the measured parameter would not be related to events in the distant past.The second possibility is that long-range correlations also exist among the fluctuations in one or more of the respiratory parameters. If so, it would be important to define the duration of the memory in the system. Here, the term "memory" is used in the context of the time frame over which a series of events are correlated. If the memory extends across more than one time scale, the fluctuations would be best modeled as arising from a fractal (time-scale-invariant) process in which the present value of the measured property is related to events in the distant past (2, 12, 23, 34). The term "time scale" refers to the temporal resolution used to measure the paramete...

We tested the hypothesis that blockade of N-methyl-D-aspartate (NMDA) and non-NMDA receptors on medullary lateral tegmental field (LTF) neurons would reduce the sympathoexcitatory responses elicited by electrical stimulation of vagal, trigeminal, and sciatic afferents, posterior hypothalamus, and midbrain periaqueductal gray as well as by activation of arterial chemoreceptors with intravenous NaCN. Bilateral microinjection of a non-NMDA receptor antagonist into LTF of urethane-anesthetized cats significantly decreased vagal afferent-evoked excitatory responses in inferior cardiac and vertebral nerves to 29 +/- 8 and 24 +/- 6% of control (n = 7), respectively. Likewise, blockade of non-NMDA receptors significantly reduced chemoreceptor reflex-induced increases in inferior cardiac (from 210 +/- 22 to 129 +/- 13% of control; n = 4) and vertebral nerves (from 253 +/- 41 to 154 +/- 20% of control; n = 7) and mean arterial pressure (from 39 +/- 7 to 21 +/- 5 mmHg; n = 8). Microinjection of muscimol, but not an NMDA receptor antagonist, caused similar attenuation of these excitatory responses. Sympathoexcitatory responses to the other stimuli were not attenuated by microinjection of a non-NMDA receptor antagonist or muscimol into LTF. In fact, excitatory responses elicited by stimulation of trigeminal, and in some cases sciatic, afferents were enhanced. These data reveal two new roles for the LTF in control of sympathetic nerve activity in cats. One, LTF neurons are involved in mediating sympathoexcitation elicited by activation of vagal afferents and arterial chemoreceptors, primarily via activation of non-NMDA receptors. Two, non-NMDA receptor-mediated activation of other LTF neurons tonically suppresses transmission in trigeminal-sympathetic and sciatic-sympathetic reflex pathways.

Phillips, Shaun W., Gerard L. Gebber, and Susan M. Barman. Medullary lateral tegmental field: control of respiratory rate and vagal lung inflation afferent influences on sympathetic nerve discharge. Am J Physiol Regul Integr Comp Physiol 288: R1396 -R1410, 2005. First published December 16, 2004; doi:10.1152/ajpregu.00632.2004.-We used spectral analysis and event-triggered averaging to determine the effects of chemical inactivation of the medullary lateral tegmental field (LTF) on 1) the relationship of intratracheal pressure (ITP, an index of vagal lung inflation afferent activity) to sympathetic nerve discharge (SND) and phrenic nerve activity (PNA) and 2) central respiratory rate in paralyzed, artificially ventilated dial-urethane-anesthetized cats. ITP-SND coherence value at the frequency of artificial ventilation was significantly (P Ͻ 0.05; n ϭ 18) reduced from 0.73 Ϯ 0.04 (mean Ϯ SE) to 0.24 Ϯ 0.04 after bilateral microinjection of muscimol into the LTF. Central respiratory rate was unexpectedly increased in 12 of these experiments (0.28 Ϯ 0.03 vs. 0.95 Ϯ 0.25 Hz). The ITP-PNA coherence value was variably affected by chemical inactivation of the LTF. It was unchanged when central respiratory rate was also not altered, decreased when respiratory rate was increased above the rate of artificial ventilation, and increased when respiratory rate was raised from a value below the rate of artificial ventilation to the same frequency as the ventilator. Chemical inactivation of the LTF increased central respiratory rate in four of six vagotomized cats but did not significantly affect the PNA-SND coherence value. These data demonstrate that the LTF 1) plays a critical role in mediating the effects of vagal lung inflation afferents on SND but not PNA, 2) helps maintain central respiratory rate in the physiological range, but 3) is not involved in the coupling of central respiratory and sympathetic circuits. cardiorespiratory synchronization; dorsal respiratory group; HeringBreuer reflex; phrenic nerve activity; respiratory-related rhythm; ventral respiratory group IT HAS LONG BEEN RECOGNIZED that neural mechanisms controlling the respiratory and cardiovascular systems are tightly linked (25,34,38,49,55). This interaction facilitates the complementary functions of the two systems: respiration maintains appropriate levels of arterial blood gases, while the cardiovascular system transports these gases to and from tissues. One indication of this cardiorespiratory coordination was noted by Adrian et al. (1) in 1932 when they made the first recordings of sympathetic nerve discharge (SND). They found that the amplitude of the cardiac-related bursts of SND waxed and waned on the time scale of the respiratory cycle. There are at least two sources of respiratory modulation of SND: input from vagal lung inflation afferents and an influence of the respiratory rhythm generator on central sympathetic neurons (4 -6, 21, 25, 33-35, 59). Although some investigators (38, 49) have proposed that there is a common network controlling bo...

Older adults are demanding increased healthcare attention with regards to prescription use due in large part to highly complex medication regimens. As patients age, medications often have a more pronounced effect on older adults, negatively impacting patient safety and increasing healthcare costs. Comprehensive medication reviews (CMRs) optimize medications for elderly patients and help to avoid inappropriate medication use. Previous literature has shown that such CMRs can successfully identify and reduce the number of medication-related problems and improve acute healthcare utilization. The purpose of this pharmacy resident research study is to examine the impact of pharmacist-conducted geriatric medication reviews to reduce medication-related problems within a leading community health system in southwest Michigan. Furthermore, the study examines type of pharmacist interventions made during medication reviews, acute healthcare utilization, and physician assessment of the pharmacist’s value. The study was conducted as a retrospective post-hoc analysis on ambulatory patients who received a CMR by a pharmacist at a primary care practice. Inclusion criteria included patients over 65 years of age with concurrent use of at least five medications who were a recent recipient of a CMR. Exclusion criteria included patients with renal failure, or those with multiple providers involved in primary care. The primary outcome was the difference in number of medication-related problems, as defined by the START and STOPP Criteria (Screening Tool to Alert doctors to Right Treatment/Screening Tool of Older Persons’ Prescriptions). Secondary outcomes included hospitalizations, emergency department visits, number and type of pharmacist interventions, acceptance rate of pharmacist recommendations, and assessment of the pharmacist’s value by clinic providers. There were a total of 26 patients that received a comprehensive medication review from the pharmacist and were compared to a control group, patients that did not receive a CMR. The average patient age for both groups was 76 years old. A total of 11 medication-related problems in the intervention group patients were identified compared with 24 medication-related problems in the control group (p-value 0.002). Pharmacist-led comprehensive medication reviews were associated with a statistically significant different in the number of medication-related problems as defined by the START and STOPP criteria.

Barman, Susan M., Shaun W. Phillips, and Gerard L. Gebber. Medullary lateral tegmental field mediates the cardiovascular but not respiratory component of the Bezold-Jarisch reflex in the cat. Am J Physiol Regul Integr Comp Physiol 289: R1693-R1702, 2005. First published August 11, 2005; doi:10.1152/ajpregu.00406.2005.-We determined the effects of bilateral microinjection of muscimol and excitatory amino acid receptor antagonists into the medullary lateral tegmental field (LTF) on changes in sympathetic nerve discharge (SND), mean arterial pressure (MAP), and phrenic nerve activity (PNA; artificially ventilated cats) or intratracheal pressure (spontaneously breathing cats) elicited by right atrial administration of phenylbiguanide (PBG; i.e., the Bezold-Jarisch reflex) in dial-urethane anesthetized cats. The PBG-induced depressor response (Ϫ66 Ϯ 8 mmHg; mean Ϯ SE) was converted to a pressor response after muscimol microinjection in two of three spontaneously breathing cats and was markedly reduced in the other cat; however, the duration of apnea (20 Ϯ 3 vs. 17 Ϯ 7 s) was essentially unchanged. In seven paralyzed, artificially ventilated cats, muscimol microinjection significantly (P Ͻ 0.05) attenuated the PBG-induced fall in MAP (Ϫ39 Ϯ 7 vs. Ϫ4 Ϯ 4 mmHg) and the magnitude (Ϫ98 Ϯ 1 vs. Ϫ35 Ϯ 13%) and duration (15 Ϯ 2 vs. 3 Ϯ 2 s) of the sympathoinhibitory response. In contrast, the PBG-induced inhibition of PNA was unaffected (3 cats). Similar results were obtained by microinjection of an N-methyl-D-aspartate (NMDA) receptor antagonist, D(-)-2-amino-5-phosphonopentanoic acid, into the LTF. In contrast, neither the cardiovascular nor respiratory responses to PBG were altered by blockade of non-NMDA receptors with 1,2,3,4-tetrahydro-6-nitro-2,3-dioxobenzo[f]quinoxaline-7-sulfonamide. We conclude that the LTF subserves a critical role in mediating the sympathetic and cardiovascular components of the Bezold-Jarisch reflex. Moreover, these data show separation of the pathways mediating the respiratory and cardiovascular responses of this reflex at a level central to bulbospinal outflows to phrenic motoneurons and preganglionic sympathetic neurons. cardiopulmonary chemosensitive afferent; medullary lateral tegmental field; phrenic nerve activity; sympathetic nerve discharge; vagal afferent SINCE THE PIONEERING WORK of von Bezold and Hirt (42) and Jarisch and Henze (18), many investigators have shown that activation of chemosensitive vagal C fibers in the cardiopulmonary region (e.g., juxtacapillary region of the alveoli, ventricles, atria, great veins, and pulmonary artery) leads to a profound bradycardia, hypotension, and a brief period of apnea followed by rapid shallow breathing [see reviews by Hainsworth (17) and Verberne et al. (39)]. The Bezold-Jarisch reflex can be elicited by a variety of substances including capsaicin, serotonin, phenylbiguanide (PBG), and veratridine in cats, rabbits, and rodents (9,11,14,20,28,33,36,37,41). Although originally viewed as a pharmacological curiosity, there is a growing body of...