The influence of gravity on regional lung blood flow in humans: SPECT in the upright and head-down posture.

Previous studies in humans have shown that gravity has little influence on the distribution of lung blood flow while changing posture from supine to prone. This study aimed to evaluate the maximal influence of posture by comparison of regional lung blood flow in the upright and head-down posture in 8 healthy volunteers, using a tilt table. Regional lung blood flow was marked by intravenous injection of macroaggregates of human albumin labeled with 99mTc or 113mIn, in the upright and head-down posture, respectively, during tidal breathing. Both radiotracers remain fixed in the lung after administration. The distribution of radioactivity was mapped using quantitative single photon emission computed tomography (SPECT) corrected for attenuation and scatter. All images were obtained supine during tidal breathing. A shift from upright to the head-down posture caused a clear redistribution of blood flow from basal to apical regions. We conclude that posture plays a role for the distribution of lung blood flow in upright humans, and that the influence of posture, and thereby gravity, is much greater in the upright and head-down posture than in horizontal postures. However, the results of the study demonstrate that lung structure is the main determinant of regional blood flow and gravity is a secondary contributor to the distribution of lung blood flow in the upright and head-down positions.NEW & NOTEWORTHY Using a dual-isotope quantitative SPECT method, we demonstrated that although a shift in posture redistributes blood flow in the direction of gravity, the results are also consistent with lung structure being a greater determinant of regional blood flow than gravity. To our knowledge, this is the first study to use modern imaging methods to quantify the shift in regional lung blood flow in humans at a change between the upright and head-down postures.

Regional lung ventilation in humans during hypergravity studied with quantitative SPECT.

Recently we challenged the view that arterial desaturation during hypergravity is caused by redistribution of blood flow to dependent lung regions by demonstrating a paradoxical redistribution of blood flow towards non-dependent regions. We have now quantified regional ventilation in 10 healthy supine volunteers at normal and three times normal gravity (1G and 3G). Regional ventilation was measured with Technegas ((99m)Tc) and quantitative single photon emission computed tomography (SPECT). Hypergravity caused arterial desaturation, mean decrease 8%, p<0.05 vs. 1G. The ratio for mean ventilation per voxel for non-dependent and dependent lung regions was 0.81±0.12 during 1G and 1.63±0.35 during 3G (mean±SD), p<0.0001. Thus, regional ventilation was shifted from dependent to non-dependent regions. We suggest that arterial desaturation during hypergravity is caused by quantitatively different redistributions of blood flow and ventilation. To our knowledge, this is the first study presenting high-resolution measurements of regional ventilation in humans breathing normally during hypergravity.

Iloprost inhalation redistributes pulmonary perfusion and decreases arterial oxygenation in healthy volunteers.

BACKGROUND: Previous studies have shown that ventilation-perfusion matching is improved in the prone as compared with that in the supine position. Regional differences in the regulation of vascular tone may explain this. We have recently demonstrated higher production of nitric oxide in dorsal compared with ventral human lung tissue. The purpose of the present study was to investigate regional differences in actions by another vasoactive mediator, namely prostacyclin. The effects on gas exchange and regional pulmonary perfusion in different body positions were investigated at increased prostacyclin levels by inhalation of a synthetic prostacyclin analogue and decreased prostacyclin levels by unselective cyclooxygenase (COX) inhibition. METHODS: In 19 volunteers, regional pulmonary perfusion in the prone and supine position was assessed by single photon emission computed tomography using (99m)Tc macro-aggregated albumin before and after inhalation of iloprost, a stable prostacyclin analogue, or an intravenous infusion of a non-selective COX inhibitor, diclofenac. In addition, gas distribution was assessed in seven subjects using (99m)Tc-labelled ultra-fine carbon particles before and after iloprost inhalation in the supine position. RESULTS: Iloprost inhalation decreased arterial PaO(2) in both prone (from 14.2+/-0.5 to 11.7+/-1.7 kPa, P<0.01) and supine (from 13.7+/-1.4 to 10.9+/-2.1 kPa, P<0.01) positions. Iloprost inhalation redistributed lung perfusion from non-dependent to dependent lung regions in both prone and supine positions, while ventilation in the supine position was distributed in the opposite direction. No significant effects of non-selective COX inhibition were found in this study. CONCLUSIONS: Iloprost inhalation decreases arterial oxygenation and results in a more gravity-dependent pulmonary perfusion in both supine and prone positions in healthy humans.

Pretreatment with magnesium sulphate is associated with less succinylcholine-induced fasciculation and subsequent tracheal intubation-induced hemodynamic changes than precurarization with vecuronium during rapid sequence induction.

Although it has side effects, succinylcholine is still widely used in rapid sequence induction. The aim of the present study is to evaluate the effects of pretreat ment with magnesium and precurarization of vecuroni um on succinylcholine-induced fasciculation and subse quent tracheal intubation-induced hemodynamic changes during rapid sequence induction. Fifty-five patients were allocated to three groups by a blinded randomization: Group M received saline 100 ml with magnesium 40 mg x kg(-1) for 5 min at 6.5 min before induction and sub sequently administered saline 1-2 ml at 1.5 min before induction; Group V received saline 100 ml for 5 min at 6.5 min before induction and subsequently administered vecuronium 0.02 mg x kg(-1) at 1.5 min before induction; Group C received saline 100 ml for 5 min at 6.5 min before induction and then saline 1-2 ml at 1.5 min before induction. Fasciculation scores and mean percent changes of heart rate, systolic blood pressure and rate pressure product between baseline and after induction were significantly lower in group M than those in group C and group V. Pretreatment with magnesium is more effective to limit succinylcholine-induced fasciculation and subsequent tracheal intubation-induced hemody namic changes in rapid sequence induction compared with vecuronium pretreatment, although magnesium does not prevent the elevation of serum potassium con centration after induction.

Regional differences in nitric oxide-mediated vasorelaxation in porcine pulmonary arteries.

BACKGROUND: Several previous investigations have shown improved oxygenation when ventilator-treated patients with acute lung injury are turned prone. In a previous human study, we demonstrated higher Ca(2+)-dependent nitric oxide synthase (NOS) activity in dorsal than in ventral parts of the lung. The current investigation was designed to determine whether Ca(2+)-dependent NOS activity was different in dorsal and ventral porcine lung regions. In addition, possible differences in vascular responses to nitroprusside or secondary to acetylcholine- or bradykinin-stimulated NO production were studied in dorsal and ventral pulmonary arteries. METHODS: In the study, 20 pigs were used. Lung biopsies and pulmonary arterial rings were harvested from ventral and dorsal lung regions. NOS activity was determined by citrulline assay in the presence and absence of the calcium chelator ethyleneglycol-bis(beta-aminoethylether)-N,N'-tetraacetic acid (EDTA) to discriminate between Ca(2+)-dependent and Ca(2+)-independent NOS activity. In organ baths, in submaximally contracted arterial rings, vasorelaxation induced by acetylcholine, bradykinin and nitroprusside was measured. RESULTS: Ca(2+)-dependent NOS activity was higher in dorsal parts (87.2 +/- 9.1 citrulline units) than in ventral parts (62.2 +/- 10.1 citrulline units, P < 0.05) of porcine lung. There was a greater relaxation in dorsal than in ventral pulmonary arterial rings induced by both acetylcholine and bradykinin. Nitroprusside relaxed both sites equally. CONCLUSIONS: Our results show that endothelial-derived NO is an important factor influencing the differences between dorsal and ventral lung regions in vasorelaxing activity in porcine pulmonary arteries. This finding provides an explanation for the improved oxygenation when patients with severe acute lung insufficiency are turned prone.

Midazolam depresses carotid body chemoreceptor activity.

BACKGROUND: Although the contribution of the gamma-aminobutyric acid (GABA) receptor system in peripheral chemosensation is unclear, immunohistochemistry has demonstrated the presence of GABA-ergic receptors in mammalian carotid bodies. We hypothesized that an activation of the carotid body GABA receptors would counteract the depolarizing effect of hypoxia. METHODS: The carotid body with arterial supply and the carotid sinus nerve was removed en bloc from New Zealand White rabbits and placed in a perfusion chamber. The carotid body preparation was perfused via the cut common carotid artery with a modified Tyrode's solution at a rate of 3.5-4.5 ml/min with a constant pressure of 45 cmH2O. The carotid sinus nerve firing frequency (Hz) was recorded at two different oxygen tension levels during perfusion with midazolam of 1, 10 and 100 microg/l. RESULTS: The frequency was decreased by midazolam in a dose-dependent manner (n = 8). Firing frequencies (mean +/- SEM) at the low oxygen tension level decreased from 643.13 +/- 67.2 Hz in the control to 554.5 +/- 67.7 Hz (P = 0.054 vs. control), 509.01 +/- 100.5 Hz (P < 0.012 vs. control) and 422.6 +/- 77.3 Hz (P < 0.001 vs. control) during perfusion with midazolam of 1, 10 and 100 microg/l, respectively. CONCLUSION: Midazolam depresses carotid body chemoreceptor activity in a dose-dependent manner.

Distributions of lung ventilation and perfusion in prone and supine humans exposed to hypergravity.

When normal subjects are exposed to hypergravity [5 times normal gravity (5 G)] there is an impaired arterial oxygenation that is less severe in the prone compared with supine posture. We hypothesized that under these conditions the heterogeneities of ventilation and/or perfusion distributions would be less prominent when subjects were prone compared with supine. Expirograms from a combined rebreathing-single breath washout maneuver (Rohdin M, Sundblad P, and Linnarsson D. J Appl Physiol 96: 1470-1477, 2004) were analyzed for vital capacity (VC), phase III slope, and phase IV amplitude, to analyze heterogeneities in ventilation (Ar) and perfusion [CO(2)-to-Ar ratio (CO(2)/Ar)] distribution, respectively. During hypergravity, VC decreased more in the supine than in the prone position (ANOVA, P = 0.02). Phase III slope was more positive for Ar (P = 0.003) and more negative for CO(2)/Ar (P = 0.007) in the supine compared with prone posture at 5 G, in agreement with the notion of a more severe hypergravity-induced ventilation-perfusion mismatch in supine posture. Phase IV amplitude became lower in the supine than in the prone posture for both Ar (P = 0.02) and CO(2)/Ar (P = 0.004) during hypergravity as a result of the more reduced VC in the supine posture. We speculate that results of VC and phase IV amplitude are due to the differences in heart-lung interaction and diaphragm position between postures: a stable position of the heart and diaphragm in prone hypergravity, in contrast to supine in which the weight of the heart and a cephalad shift of the diaphragm compress lung tissue.

Effects of gravity on lung diffusing capacity and cardiac output in prone and supine humans.

Both in normal subjects exposed to hypergravity and in patients with acute respiratory distress syndrome, there are increased hydrostatic pressure gradients down the lung. Also, both conditions show an impaired arterial oxygenation, which is less severe in the prone than in the supine posture. The aim of this study was to use hypergravity to further investigate the mechanisms behind the differences in arterial oxygenation between the prone and the supine posture. Ten healthy subjects were studied in a human centrifuge while exposed to 1 and 5 times normal gravity (1 G, 5 G) in the anterioposterior (supine) and posterioanterior (prone) direction. They performed one rebreathing maneuver after approximately 5 min at each G level and posture. Lung diffusing capacity decreased in hypergravity compared with 1 G (ANOVA, P = 0.002); it decreased by 46% in the supine posture compared with 25% in the prone (P = 0.01 for supine vs. prone). At the same time, functional residual capacity decreased by 33 and 23%, respectively (P < 0.001 for supine vs. prone), and cardiac output by 40 and 31% (P = 0.007 for supine vs. prone), despite an increase in heart rate of 16 and 28% (P < 0.001 for supine vs. prone), respectively. The finding of a more impaired diffusing capacity in the supine posture compared with the prone at 5 G supports our previous observations of more severe arterial hypoxemia in the supine posture during hypergravity. A reduced pulmonary-capillary blood flow and a reduced estimated alveolar volume can explain most of the reduction in diffusing capacity when supine.

Protective effect of prone posture against hypergravity-induced arterial hypoxaemia in humans.

Patients with acute respiratory distress syndrome have increased lung tissue weight and therefore an increased hydrostatic pressure gradient down the lung. Also, they have a better arterial oxygenation in prone (face down) than in supine (face up) posture. We hypothesized that this effect of the direction of gravity also existed in healthy humans, when increased hydrostatic gradients were induced by hypergravity. Ten healthy subjects were studied in a human centrifuge while exposed to 1 or 5 G in anterio-posterior (supine) or posterio-anterior (prone) direction. We measured blood gases using remote-controlled sampling and gas exchange by mass spectrometry. Hypergravity led to marked impairments of arterial oxygenation in both postures and more so in supine posture. At 5 G, the arterial oxygen saturation was 84.6 +/- 1.2 % (mean +/- S.E.M.) in supine and 89.7 +/- 1.4 % in prone posture (P < 0.001 for supine vs. prone). Ventilation and alveolar PO2 were increased at 5 G and did not differ between postures. The alveolar-to-arterial PO2 difference increased at 5 G to 8.0 +/- 0.2 kPa and 6.6 +/- 0.3 kPa in supine and prone postures (P = 0.003). Arterial oxygenation was less impaired in prone during hypergravity due to a better-preserved alveolo-arterial oxygen transport. We speculate that mammals have developed a cardiopulmonary structure that favours function with the gravitational vector in the posterio-anterior direction.

Interactions of volatile anesthetics with cholinergic, tachykinin, and leukotriene mechanisms in isolated Guinea pig bronchial smooth muscle.

UNLABELLED: We studied relaxation of airway smooth muscle by sevoflurane, desflurane, and halothane in isolated guinea pig bronchi. Ring preparations were mounted in tissue baths filled with physiological salt solution and continuously aerated with 5% CO(2) in oxygen. Electrical field stimulation induced contractions sensitive to tetrodotoxin, indicating nerve-mediated responses. These consisted of an atropine-sensitive cholinergic phase and a nonadrenergic noncholinergic (NANC) phase sensitive to SR48968, a neurokinin-2 receptor antagonist. Anesthetics were added to the gas aerating the tissue baths. Sevoflurane and desflurane at 1.0 minimum alveolar anesthetic concentration and halothane at 1.0-2.0 minimum alveolar anesthetic concentrations inhibited both cholinergic and NANC contractions to electrical field stimulation. None of the anesthetics affected responses to exogenously applied neurokinin A, a likely mediator of NANC contractions, suggesting prejunctional inhibition of NANC neurotransmission. The anesthetics did not affect the initiation of contractile responses to leukotriene C(4) (LTC(4)), a mediator of asthmatic bronchoconstriction. However, sevoflurane and desflurane both relaxed bronchi in a steady-state contraction achieved by LTC(4). Surprisingly, halothane did not relax LTC(4) contractions. Concerning LTC(4)-elicited bronchoconstriction, sevoflurane and desflurane were more potent airway smooth muscle relaxants in vitro. IMPLICATIONS: Halothane, sevoflurane, and desflurane attenuated airway smooth muscle tone via inhibition of cholinergic and nonadrenergic noncholinergic neurotransmission. Sevoflurane and desflurane reduced leukotriene C(4)-induced bronchoconstriction, whereas halothane did not. This indicates a beneficial role for sevoflurane and desflurane in asthmatics.

Atracurium and vecuronium block nicotine-induced carotid body chemoreceptor responses.

BACKGROUND: Vecuronium depresses carotid body chemosensitivity during hypoxia. We hypothesized that this is caused by inhibition of cholinergic transmission of the carotid body. METHODS: The carotid body with its sinus nerve was removed en bloc from thiopentone-anaesthetized adult male New Zealand rabbits and perfused in vitro with modified Tyrodes buffer solution at constant perfusion pressure, temperature, a buffer pH of 7.4 and normocapnia. Chemoreceptor discharge and spike frequencies (fx) were recorded from the whole sinus nerve after administration of 500 microg nicotine, given as duplicated controls and thereafter following 30 min perfusion of equipotent concentrations of atracurium (28.1 microM) or vecuronium(10 microM), after 30 min of neostigmine perfusion (9.2 microM) and finally after 30 min wash-out with buffer solution only. A short-lasting hypoxic test was performed before and at the end of the experimental period to confirm the responsiveness and validity of the preparation. RESULTS: Atracurium (n = 7) and vecuronium (n = 6) reduced chemoreceptor responses to nicotine by 70 +/- 30% and 66 +/- 19% (SEM) (P<0.05). Chemoreceptor discharges showed full recovery after neostigmine in the atracurium group and partial recovery in the vecuronium group (P<0.05). Finally, after wash-out the chemoreceptor responses to nicotine had fully recovered in both groups. CONCLUSION: Atracurium and vecuronium in equipotent concentrations block nicotine-induced chemoreceptor responses of the carotid body.

Opioid action on respiratory neuron activity of the isolated respiratory network in newborn rats.

BACKGROUND: Underlying mechanisms behind opioid-induced respiratory depression are not fully understood. The authors investigated changes in burst rate, intraburst firing frequency, membrane properties, as well as presynaptic and postsynaptic events of respiratory neurons in the isolated brainstem after administration of opioid receptor agonists. METHODS: Newborn rat brainstem-spinal cord preparations were used and superfused with mu-, kappa-, and delta-opioid receptor agonists. Whole cell recordings were performed from three major classes of respiratory neurons (inspiratory, preinspiratory, and expiratory). RESULTS: Mu- and kappa-opioid receptor agonists reduced the spontaneous burst activity of inspiratory neurons and the C4 nerve activity. Forty-two percent of the inspiratory neurons were hyperpolarized and decreased in membrane resistance during opioid-induced respiratory depression. Furthermore, under synaptic block by tetrodotoxin perfusion, similar changes of inspiratory neuronal membrane properties occurred after application of mu- and kappa-opioid receptor agonists. In contrast, resting membrane potential and membrane resistance of preinspiratory and majority of expiratory neurons were unchanged by opioid receptor agonists, even during tetrodotoxin perfusion. Simultaneous recordings of inspiratory and preinspiratory neuronal activities confirmed the selective inhibition of inspiratory neurons caused by mu- and kappa-opioid receptor agonists. Application of opioids reduced the slope of rising of excitatory postsynaptic potentials evoked by contralateral medulla stimulation, resulting in a prolongation of the latency of successive first action potential responses. CONCLUSIONS: Mu- and kappa-opioid receptor agonists caused reduction of final motor outputs by mainly inhibiting medullary inspiratory neuron network. This inhibition of inspiratory neurons seems to be a result of both a presynaptic and postsynaptic inhibition. The central respiratory rhythm as reflected by the preinspiratory neuron burst rate was essentially unaltered by the agonists.

Validation of equilibration and chromium reduction methods for deuterium measurements of fluid volumes.

Determinations of fluid volumes are of importance for correct treatment of patients subjected to shock and trauma. Gas isotope ratio mass spectrometry (GIRMS) is an advanced method for analysis of stable isotopes. These can be used as tracers for measurement of various fluid volumes. In the current in vitro study, deuterium was used to determine different volumes of water simulating a range of body fluid volumes from neonates to adults. A high-precision scale gave control weights (i.e., volumes), and two methods, equilibration (EQ) and chromium reduction (CR), were compared by use of a GIRMS. The coefficient of variation was <1% when using both EQ (0.45%) and CR (0.79%). The variability was greater at small volumes, and, when regression equations for the relation between measured and calculated volumes were used as formulas, the deviation was 0.4% using EQ and 2.8% using CR at the volume of 1,000 ml. At larger volumes, the deviation when using CR approached 1%. These variations are better than previously published data using other methods. It was concluded that GIRMS is a suitable technique for fluid volume determinations in neonates as well as in adult patients, using deuterium as a tracer. EQ and CR methods were both regarded to give acceptable variabilities in this in vitro study. GIRMS may in the future increasingly be used clinically for accurate measurements of body fluid volumes.