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.

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.

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.

Response of T lymphocytes from previously infected calves to recombinant Cryptosporidium parvum P23 vaccine antigen.

We had previously demonstrated that a Type-1-like immune response involving interferon-gamma expression in lamina propria lymphocytes accompanied by IgG2 subclass fecal antibodies to Cryptosporidium parvum p23 emerged in gut mucosa of calves recovering from cryptosporidiosis. Because a recombinant p23 had been shown to protect calves from cryptosporidiosis when administered as a vaccine antigen to late gestation cattle, this study was undertaken to determine if the same vaccine antigen could induce a Type-1-like, in vitro response by T cells from calves that had recovered from C. parvum infection. We isolated peripheral blood mononuclear cells from calves that had been previously infected with C. parvum oocysts and incubated them in the presence or absence of the recombinant C. parvum p23 vaccine antigen. We used flow cytometry to simultaneously detect cells in cell cycle and identify the T cell subset containing cycling cells. We also used flow cytometry to identify interferon-gamma positive cells and 2-dimensional gel electrophoresis to profile proteins made by PBMC stimulated with the recombinant p23 vaccine antigen. The results demonstrated that CD4+ T lymphocytes proliferated and that interferon-gamma was synthesized by a subset of stimulated cells. Two-dimensional gel electrophoresis revealed the presence of several cytoplasmic proteins in a size range of approximately 25-80 kDa that were detected in p23-stimulated, but not in unstimulated, cytoplasmic samples. Together, the results show that the recombinant p23 vaccine antigen can stimulate a Type-1-like immune response by T cells from calves that have recovered from C. parvum infection.

Stereospecific effects of ketamine enantiomers on canine tracheal smooth muscle.

1. Ketamine is a potent bronchodilator which relaxes airway smooth muscle (ASM). Clinically, ketamine is used as a 1:1 racemic mixture of enantiomers that differ in their analgesic and anaesthetic effects. The aim of this study was to determine whether there was a difference between the enantiomers in their ability to relax isolated ASM and to explore mechanisms responsible for any observed differences. 2. Canine tracheal smooth muscle strips were loaded with fura-2 and mounted in a photometric system to measure simultaneously force and [Ca2+]i. Calcium influx was estimated by use of a manganese quenching technique. 3. In strips stimulated with 0.1 microM ACh (EC50) R(-)-ketamine (1-100 microM) caused a significantly greater concentration-dependent decrease in force (P<0.0001) and [Ca2+]i than S(+)-ketamine (1-100 microM) (P<0.0005). In contrast, there was no significant difference between the enantiomers in their ability to inhibit calcium influx (45% decrease in influx rate for R(-)-ketamine and 44% for S(+)-ketamine, P =0.782). In strips contracted with 24 mM isotonic KCI (which activates voltage-operated calcium channels), the enantiomers modestly decreased force and [Ca2+]i; there was no significant difference between the enantiomers in their effects on force (P=0.425) or [Ca2+]i (P=0.604). 4. The R(-)-enantiomer of ketamine is a more potent relaxant of ACh-induced ASM contraction than the S(+)-enantiomer. This difference appears to be caused by differential actions on receptor-operated calcium channels.

Analysis of the cellular mechanism for halothane inhibition of brown adipose tissue thermogenesis.

In the present studies, halothane is demonstrated to have a general inhibitory effect on norepinephrine-induced cAMP accumulation, lipolysis and rate of oxygen consumption, but no obvious effect on the respiratory capacity of isolated mitochondria. Further studies are necessary to elucidate these effects of halothane on brown adipose tissue nonshivering thermogenesis. Such studies may contribute to the understanding of the molecular effects of volatile anesthetics.

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.

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.

Pulmonary perfusion is more uniform in the prone than in the supine position: scintigraphy in healthy humans.

The main purpose of this study was to find out whether the dominant dorsal lung perfusion while supine changes to a dominant ventral lung perfusion while prone. Regional distribution of pulmonary blood flow was determined in 10 healthy volunteers. The subjects were studied in both prone and supine positions with and without lung distension caused by 10 cmH2O of continuous positive airway pressure (CPAP). Radiolabeled macroaggregates of albumin, rapidly trapped by pulmonary capillaries in proportion to blood flow, were injected intravenously. Tomographic gamma camera examinations (single-photon-emission computed tomography) were performed after injections in the different positions. All data acquisitions were made with the subject in the supine position. CPAP enhanced perfusion differences along the gravitational axis, which was more pronounced in the supine than prone position. Diaphragmatic sections of the lung had a more uniform pulmonary blood flow distribution in the prone than supine position during both normal and CPAP breathing. It was concluded that the dominant dorsal lung perfusion observed when the subjects were supine was not changed into a dominant ventral lung perfusion when the subjects were prone. Lung perfusion was more uniformly distributed in the prone compared with in the supine position, a difference that was more marked during total lung distension (CPAP) than during normal breathing.

The psychological impact of diagnostic ultrasound.

The psychological impact of ultrasound scanning in pregnancy was examined in low- and high-risk pregnancies. Women in each category were assigned consecutively to a condition of either low or high feedback. In the latter condition, the women received extensive verbal and visual feedback, whereas in the former, subjects were denied visual access to the monitor. Psychological changes were measured using the State Anxiety Inventory and the Subjective Stress Scale. When a male partner attended, he was included in the assessment. The emotional impact of ultrasound was influenced by the level of feedback provided, with those in the high-feedback condition indicating significantly less anxiety and more positive emotional experiences during the scan, compared with those who received less feedback.

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.

Regional ventilation-perfusion distribution is more uniform in the prone position.

The arterial blood PO(2) is increased in the prone position in animals and humans because of an improvement in ventilation (VA) and perfusion (Q) matching. However, the mechanism of improved VA/Q is unknown. This experiment measured regional VA/Q heterogeneity and the correlation between VA and Q in supine and prone positions in pigs. Eight ketamine-diazepam-anesthetized, mechanically ventilated pigs were studied in supine and prone positions in random order. Regional VA and Q were measured using fluorescent-labeled aerosols and radioactive-labeled microspheres, respectively. The lungs were dried at total lung capacity and cubed into 603-967 small ( approximately 1.7-cm(3)) pieces. In the prone position the homogeneity of the ventilation distribution increased (P = 0.030) and the correlation between VA and Q increased (correlation coefficient = 0.72 +/- 0.08 and 0.82 +/- 0.06 in supine and prone positions, respectively, P = 0.03). The homogeneity of the VA/Q distribution increased in the prone position (P = 0.028). We conclude that the improvement in VA/Q matching in the prone position is secondary to increased homogeneity of the VA distribution and increased correlation of regional VA and Q.

Vincristine, Adriamycin, cyclophosphamide, and etoposide (VP16-213) in small-cell anaplastic carcinoma of the lung.

Twelve patients with small-cell anaplastic carcinoma of the lung were treated with vincristine 1 mg/m2 i.v. day 1, adriamycin 50 mg/M2 i.v. day 1, cyclophosphamide 1,000 mg/m2 i.v. day 1, and etoposide 80 mg/m2 i.v. day 2, 4, 6 given on an outpatient basis and repeated at 3-week intervals. As consolidation therapy seven patients received two courses of BCNU median 29 mg/m2 (range 24-73 mg/m2) short term intraarterial infusion in the bronchial artery with 2 to 3-weeks intervals. One patient with limited disease had no evidence of disease for 13+ months and one patient complete remission for 3+ months. Four of ten patients with extensive disease had complete remission for median 5 months (range 2+ to 5+ months) and four patients had partial remission for median 5 months (range 4 to 5+ months). Despite side effects the chemotherapy was well tolerated by the patients. The results correspond to those obtained with other effective regimens in small-cell anaplastic carcinoma of the lung.

Actions of opioids on respiratory activity via activation of brainstem mu-, delta- and kappa-receptors; an in vitro study.

Opioid-induced respiratory depression is well documented. However, exact sites of action and mechanisms for opioid-induced effects on respiration have not yet been elucidated. The present study was carried out on isolated brainstem-spinal cord preparations from newborn rats in order to explore the opioid activity on brainstem mu-, delta- and kappa-receptors. The brainstem-spinal cord was isolated from 0- to 4-day-old Sprague-Dawley rats. The preparation was perfused with artificial cerebrospinal fluid (28.5 degrees C) equilibrated with 95% O2 and 5% CO2 at a pH of 7.4. Neuronal respiratory activity was recorded from the ventrolateral part of the medulla oblongata and efferent impulses from C4 or C5 ventral roots. Effects of the mu-receptor agonist DAGO, the delta-receptor agonist DPDPE and the kappa-receptor agonist U50,488 on respiratory frequency (fR), inspiratory time (Ti) and peak integrated C4 amplitude (Int[C4]) were measured. In addition, the effect of pre-treatment with the mu1 receptor antagonist naloxanazine (35 mg/kg, subcutaneous injection) was evaluated. DAGO reduced fR and Ti in a concentration-dependent manner and caused a reduction of Int(C4) at high concentrations (10 microM). The mu1 receptor antagonist naloxanazine shifted the fR concentration-response curve for DAGO to the right (P < 0.05). DPDPE had no effect on respiratory activities whereas U50,488, like DAGO, reduced fR and Int(C4) in a concentration-dependent manner. It was concluded that mu-opioid receptors, including the mu1 were involved in fR reduction whereas kappa-opioid receptors were involved in reduction of both fR and respiratory amplitude. Delta-opioid receptors do not seem to participate in respiratory modulation at this age.

Age- and temperature-dependent effects of opioids on medulla oblongata respiratory activity: an in vitro study in newborn rat.

Influences of post-natal age (P0-P4) and temperature (22.5 degrees-31.5 degrees C) on the action(s) of opioids on respiratory activities from neonatal rat brainstem-spinal cord preparations were examined in this study. A temperature-dependent mu-opioid receptor effect on respiration was found. In addition, the effect of morphine increased with postnatal age (P0-P4). Hence, age and temperature must be taken into account when performing studies on medullary respiration-related structures using the neonatal rat brainstem-spinal cord preparation.

Effects of neuroactive substances on the morphine-induced respiratory depression; an in vitro study.

Effects of different neuroactive substances on morphine-induced respiratory depression were studied in medullary respiration-related structures using in vitro brainstem-spinal cord preparation from 1 to 4-day-old rats. Application of morphine (10 microM) reduced respiratory rhythm (fR) as measured by C4 ventral root activity. The depressant effects of morphine were reversed by acetylcholine (10 microM), substance P (50 nM), thyrotropin releasing hormone (TRH) (100 nM) and forskolin (10 microM). The adenosine receptor antagonist, theophylline (100 microM), the dopamine receptors antagonist, haloperidol (10 microM), the cyclooxygenase inhibitor, indomethacin (10 microM) and the phospholipase A(2) inhibitor, quinacrine (10 microM) had no effect on morphine-induced respiratory depression.

Effects of NMDA and non-NMDA receptor antagonists on inspiratory neurons in the in vitro brainstem-spinal cord preparation of newborn rat.

We examined the effects of N-methyl-D-aspartate (NMDA) antagonists, 2-amino-5-phosphonovaleric acid (APV) and non-NMDA antagonists, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) on inspiratory neurons in the medulla oblongata and C4 and C5 ventral root activity in the in vitro brainstem-spinal cord preparation of newborn rats. Application of APV induced increased rate of inspiratory neuron bursts, and decreased burst duration. The C4 burst activity was almost abolished by application of CNQX, whereas inspiratory neurons continued to discharge rhythmically. The results suggest that non-NMDA receptors are not crucially involved in the medullary respiratory rhythmogenesis, and that NMDA-mediated neurotransmission could modify the respiratory pattern, in the in vitro model.

Congenital generalized multicentric myofibromatosis with orbital involvement.

We studied a rare case of congenital myofibromatosis of the orbit as part of a generalized multicentric disease in a 5-month-old boy. The ultrasonographic and computed tomographic findings were those of a low-reflective, firm, vascularized, lesion with heterogeneous internal structure. The histopathologic findings showed vascular channels with large polygonal cells and transition toward myofibroblasts with interwoven collagen fiber bundles.

Dynamic changes in the dimensions of the lumbar spinal canal: an experimental study in vitro.

The variation in the dimensions of the lumbar spinal canal under both flexion-extension and axial compression-distraction was studied using computerized tomography (CT) scans in human cadaver lumbar spine specimens. In 3-mm-thick CT slices through the disk at L3-L4, the cross-sectional area of the spinal canal was reduced by around 40 mm2, corresponding to a 16% reduction of the initial area when the lumbar spines were moved both from flexion to extension and from distraction to compression. A corresponding reduction in the midsagittal diameter of the canal of 2 mm was found. During these motions, the ligamentum flavum did not appear to be a significant factor for the dynamic changes affecting the dimensions of the canal. This held true even after the disk had been excised in order to produce a total collapse of the disk space.

Early posttraumatic pulmonary platelet trapping and its potentiation by oral pretreatment with alcohol.

Soft tissue trauma is associated with platelet aggregation and sequestration in the lungs. This is believed to be an early step in the later development of adult respiratory distress syndrome. In the present experiment using a new method for in vivo dynamic studies of platelet sequestration, we wanted to evaluate the effect of soft tissue trauma on pulmonary platelet trapping in pigs and the influence of acute alcohol intoxication. The results show that significant pulmonary platelet trapping is registered within minutes of trauma and that alcohol significantly increases platelet sequestration in the lungs. This indicates an increased risk for posttraumatic pulmonary problems in alcohol-intoxicated trauma victims.