Methodological aspects of brain activation studies: cerebral blood flow determined with [15O]butanol and positron emission tomography.

In this methodological study, a procedure for measuring regional CBF (rCBF) with positron emission tomography and 15O-labelled tracers is optimized. Four healthy volunteers were subjected to eight studies with use of [15O]butanol as a tracer: four times while reading aloud and four times while reading silently from a phonologically balanced list of single words. The gain from these repeated intra-individual studies of the same activation state (fractionation) was demonstrated in terms of noise-equivalent counts in a phantom study. A computerized brain atlas was used to reformat the images to a common anatomical representation, thereby minimizing the effects of inter- and intra-individual anatomical and positional variations. This allowed the formation of inter- and intra-individual average subtraction images with error estimates. Differences between the two activation states were detected with use of an exploratory significance map based on a paired Student's t test. The results compared well with Friston's method of determining levels of statistical significance. No difference was obtained when comparing results from rCBF images and images generated from measurement of uptake of the tracer. The paradigm chosen for activation was shown to yield a constant activation level during the repeated measurements (i.e., no habituation).

Effects of focal cooling in the ventrolateral medulla on chemoresponsiveness in dogs.

Studies in cats and dogs have shown that the ventrolateral region of the medulla participates significantly in the shaping of the respiratory rhythm. The purpose of this study was to examine the effects of unilateral focal cooling (15-20 degrees C) in the ventrolateral medullary region on respiratory responses to hypercapnia and hypoxia in dogs. A cryoprobe was used to cool selected locations in the ventrolateral medulla in 9 anesthetized and vagotomized dogs. Diaphragmatic electromyogram (EMG) was measured with implanted electrodes. The animals were ventilated artificially at a constant rate with 100% O2 and the inspired gas was switched to 7% CO2 in O2 or 10% O2 in N2 to determine the response to hypercapnia or hypoxia. The sites cooled ranged 4.0-8.0 mm rostral to obex, 3.0-5.5 mm lateral to midline, and within 1.5 mm deep from the ventral surface of the medulla. Unilateral focal cooling in this region significantly decreased the responses of both the amplitude and the rate of rise of diaphragmatic EMG to hypercapnia and hypoxia. These results support the hypothesis that neural structures in the ventrolateral medulla are important in the respiratory responses to hypoxia and hypercapnia as well as for the setting of respiratory drive and timing.

Effects on respiratory pattern of focal cooling in the medulla of the dog.

Studies in cats have shown that, in addition to respiratory neuron groups in the dorsomedial (DRG) and ventrolateral (VRG) medulla, neural structures in the most ventral medullary regions are important for the maintenance of respiratory rhythm. The purpose of this study was to determine whether a similar superficially located ventral region was present in the dog and to assess the role of each of the other regions in the canine medulla important in the control of breathing, in 20 anesthetized, vagotomized, and artificially ventilated dogs, a cryoprobe was used to cool selected regions of the medulla to 15-20 degrees C. Respiratory output was determined from phrenic nerve or diaphragm electrical activity. Cooling in or near the nucleus of the solitary tract altered timing and produced little change in the amplitude or rate of rise of inspiratory activity; lengthening of inspiratory time was the most common timing effect observed. Cooling in ventrolateral regions affected the amplitude and rate of rise of respiratory activity. Depression of neural tidal volume and apnea could be produced by unilateral cooling in two ventrolateral regions: 1) near the nucleus ambiguus and nucleus para-ambiguus and 2) just beneath the ventral medullary surface. These findings indicate that in the dog dorsomedial neural structures influence respiratory timing, whereas more ventral structures are important to respiratory drive.

Bacterial colonization and infection in an intensive care unit.

One hundred and one patients, nursed in an intensive care unit for at least 24 h, were monitored for bacterial colonization and infection. The infection rates were similar to those in other reports. Patients were not generally colonized with common environmental strains in the unit. Bacterial dissemination between patients was uncommon. No gentamicin resistant gram negative or Staphylococcus aureus strains were observed, nor methicillin resistant Staphylococcus aureus strains. The hypothesis that these favourable conditions are partly related to the excellent isolation and barrier nursing facilities in the unit cannot be fully substantiated.

Role of the vagal afferents in substance P-induced respiratory responses in anaesthetized rabbits.

Since substance P (SP)-like immunoreactivity has been demonstrated in vagal sensory fibres of bronchopulmonary origin, it was considered of interest to (1) characterize the pattern of responses to SP injected into the pulmonary as well as the systemic arterial system, and (2) assess the types of vagal afferents that are affected by SP. Experiments were performed on 15 pentobarbital-anaesthetized, spontaneously breathing rabbits. Efferent phrenic nerve activity was monitored as an index of central respiratory neural output. Intra-atrial injections of SP into the pulmonary circulation (100 ng kg-1) increased the respiratory rate, and peak integrated phrenic amplitude by 47 +/- 8 and 40 +/- 4%, respectively, above the controls. In addition, SP elicited augmented breaths (ABs) within 2-3 s in 67% of the trials. In contrast to right atrial injections, no ABs and no significant changes in respiratory rate were observed in response to intra-aortic injections of SP (100 ng kg-1). Tidal phrenic activity rise after aortic injections of SP was significantly less as compared with right atrial administrations of SP. Since both routes of administration decreased the arterial blood pressure to the same extent, these respiratory responses were not likely secondary to cardiovascular changes. After administration of an SP antagonist (D-Arg-D-Trp7,9, Leu11, SP), respiratory responses to SP were significantly attenuated. Also, the rate of occurrence of ABs elicited by releasing the tracheal occlusions was reduced (control 95 vs. 14% SP antagonist). Bilateral vagotomy abolished the tachypnoeic response and reduced the magnitude of the phrenic nerve increments caused by right atrial injection of SP.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of diaphragmatic activity during singing: a study of transdiaphragmatic pressures.

Esophageal and gastric pressures during singing are measured in four male professional singers performing singing tasks requiring rapid changes of subglottal pressure. Evidence for a consistent use of the diaphragm is found in all subjects. Some subjects punctually activate the diaphragm when there is a need for a rapid decrease of subglottal pressure, such as when singing a falling octave interval, when shifting from a loud to a soft note, to save air during a /p/ explosion, and in performing a trillo involving a repeated switching between glottal adduction and abduction. The first three cases were observed in the beginning of the phrase, presumably over the period that the pressure generated by the passive expiratory recoil forces of the breathing system was higher than the intended subglottal pressure. In addition to this, one subject exhibited a diaphragmatic tonus throughout the entire phrase. The phonatory relevance of a diaphragmatic activity was evaluated in a subsequent experiment. The transdiaphragmatic pressure was displayed on an oscilloscope screen as a visual feedback signal for singers and nonsingers, who performed various phonatory tasks with and without voluntary coactivation of the diaphragm. In most subjects this activity tended to increase the glottal closed/open ratio as well as the amplitude of the glottogram (i.e., the transglottal volume velocity wave-form as determined by inverse filtering). These changes suggest that diaphragmatic coactivation tends to affect phonation. Also, it tended to reduce the formant frequency variability under conditions of changing fundamental frequency suggesting a better stabilization of the vocal tract.

Effects of graded focal cold block in rostral areas of the medulla.

Unilateral focal cold blocks (20 degrees C) in structures located ventrolaterally in rostral medulla consistently caused apnoea or deep depression of inspiratory motor output. The inhibitory effect could be correlated with the cooling temperature. Apnoeic response occurred either with complete absence of any inspiratory activity or combined with low level tonic inspiratory motor activity ('tonic apnoea'). The appearance of apnoea was CO2-independent, whereas the tonic component of the latter increased with increasing levels of PCO2. The results suggest that the structures in the deep, ventro-lateral aspect of rostral medulla, from which apnoea can be induced, correspond partly to the nucleus paragigantocellularis lateralis (nPGL) and the nucleus preolivaris. These structures appear to be relevant for the drive inputs necessary for respiratory rhythmogenesis. Unilateral focal cooling in the rostral medulla, including the 'Bötzinger Complex', caused increments in respiratory rate both in vagotomized and non-vagotomized animals. The increase in respiratory rate in response to cooling in the region of the 'Bötzinger Complex' was combined with either an enhancement or some depression of respiratory motor output. This area in the rostral part of the ventral respiratory group (VRG) seems not to be crucial for respiratory rhythmogenesis, but to play a role in determining both the intensity and timing of the respiratory activity. All effects of unilateral cold block were bilaterally symmetrical.

Effects of graded focal cold block in the solitary and para-ambigual regions of the medulla in the cat.

Unilateral focal cold blocks in the region of the nucleus tractus solitarius and the dorsal respiratory group of neurons, DRG, of anaesthetized cats consistently caused apneustic-type breathing. There was no concomitant change in the initial rate of rise of inspiratory activity. The apneustic prolongation of inspiratory duration, TI, was most pronounced in, but was not confined to, the DRG. The apneustic effects were more marked after vagotomy. In cats with intact vagus nerves being given artificial ventilation, focal cooling at certain sites of the DRG region could produce 'unlocking' of the respiratory rhythm from that of the respiratory pump. At other sites in this region, focal cooling could selectively block the effects of the inspiration-facilitating reflex induced by deflation without blocking the inspiration-inhibiting Hering-Breuer reflex. Unilateral focal cold blocks in the region of the intermediate part of the ventral respiratory group of neurons, VRG, generally caused depression of the rate of rise of inspiratory activity, but almost never apneustic effects. All effects of unilateral focal cooling both in the DRG and VRG were bilaterally symmetrical. No systematic differences between the effects on phrenic and external intercostal inspiratory activity were found in response to focal cooling either of the DRG or VRG suggesting that differential control of phrenic and external intercostal motoneurons is not exerted mainly at the level of these medullary structures. The results suggest that the DRG and VRG areas exert somewhat different effects on the respiratory pattern: DRG appears to be more concerned with integration of vagal and other inputs contributing to the inspiratory off-switch mechanisms which, however, are not confined only to the DRG. The VRG inspiratory mechanisms, on the other hand, appear to be more involved in the gain control of the inspiratory output intensity.

Release of expiratory muscle activity by graded focal cold block in the medulla.

Disinhibition or 'release' of expiratory muscle activity in response to focal cooling of various medullary structures was of two kinds: (1) release of rhythmic expiratory activity even when no such activity was recruited in the control situation and (2) release of tonic activity in the 'expiratory' muscles. Release of rhythmic expiratory activity was mainly elicited by focal cooling of structures in the intermediate part of the medulla and release of tonic activity was preferentially induced by cooling rostroventral structures, although a considerable overlap did occur. Release of rhythmic expiratory activity was not related to any changes in expiratory time (TE) or to any associated variations in the pattern of inspiratory activity. It showed a marked increase with increasing levels of PCO2. The release of tonic activity was not CO2-dependent. Both types of effects could be mimicked by focal microinjections of lignocaine and were reflected by corresponding changes in activity of a majority of the expiration-related neurons. These results suggest that complex and widespread neural substrates subserve the control of the intensity of rhythmic expiratory activity and of the tonic activity of the abdominal and intercostal muscles. These neural mechanisms can apparently operate independently from those controlling the inspiratory activity. The release of the tonic activity observed in the 'expiratory' muscles might reflect a disinhibition of mechanisms involved in non-respiratory functions of expiratory muscles.

Moisture exchangers do not prevent patient contamination of ventilators. A microbiological study.

Thirty-three mechanically ventilated patients in an intensive care unit were studied in order to verify a claim that the Servo humidifier acts as a bacterial barrier. The Servo humidifier was used on all patients. It was changed once daily, and the connecting tubes were changed once weekly. Daily bacterial cultures were taken from the trachea of the patient as well as from the humidifier, the tubing and the ventilator. In 25 of the patients, the same bacterial strain as in the trachea of the patient could not be isolated from the outside of the humidifier, from the tubing or the ventilator. In eight patients a breakthrough of bacterial strains from the trachea through the humidifier could be demonstrated. In four of these eight patients the breakthrough strains appeared to establish themselves in the respirator environment, while in the other four they appeared only temporarily outside the humidifier. The clinical importance of the establishment of a bacterial strain in the ventilator is not clear, but it seems prudent that the introduction of the Servo humidifier should not lead to less stringent cleaning and/or disinfection routines of ventilators and tubing than before.

Adenosine analogues depress ventilation in rabbit neonates. Theophylline stimulation of respiration via adenosine receptors?

The effect of the adenosine analogue L-N-phenyl-isopropyl-adenosine (L-PIA) and theophylline on the respiration of rabbit pups was studied. L-PIA (5 mumol/kg) administered intraperitoneally caused a marked respiratory depression in urethane-anaesthetized decerebrate pups and unanaesthetized intact animals during natural sleep. The effect could often be reversed with theophylline. When L-PIA was given after theophylline (20 mg/kg), the effect of L-PIA was considerably lower. L-PIA also caused respiratory depression when administered onto the exposed surface of the fourth ventricle. The effect of the adenosine analogue was more pronounced in younger than in older animals. We conclude that adenosine strongly inhibits respiration and that effect is antagonized by theophylline. The hypothesis is put forward that the therapeutic effect of theophylline on neonatal apnea might be exerted via adenosine antagonism rather than via inhibition of phosphodiesterase. Apnea in infants is often triggered by hypoxemia. It is possible that adenosine, which is released during hypoxia, mediates this effect.

On the central pattern generator for the basic breathing rhythmicity.

Recent advances in several laboratories concerning the respiration-related medullary neurons, their locations, projections, interconnections, morphological and physiological properties, and patterns of inhibitory postsynaptic potentials, excitatory postsynaptic potentials, and discharge rate, on the one hand, and the "systems behavior," on the other, have provided the basis for new hypothesis concerning the neural mechanisms underlying the central pattern generator (CPG) for breathing and its different parts. The onset of the "ramp"-like increase in inspiratory activity is due to an abrupt release of inhibition and a subsequent progressively increasing synaptic excitation of inspiratory premotor neurons. The integration of the excitatory "drive" inputs underlying the ramp inspiratory activity seems to depend on structures in the ventrorostral medulla, including nucleus paragigantocellularis. The termination of this activity by the off-switch mechanisms is actuated when a critical threshold is attained by the excitatory inputs of 1) a slowly increasing inspiration-related activity and 2) the afferent input from the pulmonary stretch receptors. The nature of the former activity is discussed. During the expiratory phase, an inhibitory activity suppresses inspiration-facilitating inputs with a slowly decaying power that controls the expiratory duration. The postinspiration activity, which brakes the rate of exhalation during the first part of the expiratory phase, depends on mechanisms separate from those responsible for the inspiratory ramp activity. The respiratory CPG seems to be organized with considerable amount of redundancy, or "degeneracity."

Immediate changes in ventilation and respiratory pattern associated with onset and cessation of locomotion in the cat.

In high decerebrate unanaesthetized cats (pre-collicular/pre-mamillary) which developed spontaneous co-ordinated locomotor activity, ventilation, breathing pattern, phrenic nerve, external and internal intercostal electromyogram (e.m.g.) activities were examined. Locomotion was also induced by electrical stimulation of the subthalamic locomotor region and in a few cases the mesencephalic locomotor region. Quadriceps muscle e.m.g. was used to monitor locomotor activity. Spontaneous locomotor activity was associated with an immediate increase in ventilation and shift of the ventilatory CO2 response curve to the left. Tidal volume was smaller and respiratory rate larger at any given level of ventilation during spontaneous locomotion. Increases in respiratory rate were due to reductions in both inspiratory and expiratory duration. Upon cessation of locomotion, these changes abruptly returned to control values. Within the first one or two walking steps of spontaneous locomotor activity, the rate of rise of phrenic activity increased slightly while peak phrenic activity remained relatively constant; peak internal intercostal activity increased markedly while peak external intercostal activity decreased. Similar changes in ventilation, phrenic, external and internal intercostal activities were observed in association with locomotion induced by stimulation within the subthalamic or mesencephalic locomotor regions. In contrast to spontaneous locomotor activity, however, increases in both external and internal intercostal activities were often observed. Peak amplitudes of both external and internal intercostal activities increased linearly with increasing levels of end-tidal PCO2 during rest and during locomotion. However, at any given level of PCO2 peak external intercostal activity was smaller and peak internal intercostal activity larger during locomotion than at rest. With increasing peak quadriceps e.m.g. activity at a constant walking rate, external intercostal activity was progressively inhibited while internal intercostal activity was progressively enhanced. No consistent change in peak phrenic activity was observed with changes in peak quadriceps activity. With increasing walking rate at a constant peak quadriceps e.m.g., peak phrenic and peak internal intercostal activities progressively increased and peak amplitude of external intercostal activity (which was inhibited below the activity observed at rest) also progressively increased. The virtually simultaneous changes in quadriceps activity and respiratory motor activities suggest that the increase in ventilation at exercise onset is neurally mediated. Furthermore, these results suggest that the motor pathways to both the spinal locomotor pattern generators and the pattern-controlling mechanisms for respiration are driven in parallel to provide a quantitative relationship between respiratory motor output and locomotor activity. The functional significance of the alterations in respiratory pattern and participation of the different respiratory muscles is discussed.