Dose-response to inhaled nitric oxide in acute hypoxemic respiratory failure of newborn infants: a preliminary report.

In acute hypoxemic respiratory failure of term and near-term neonates, extra- and intrapulmonary right-to-left shunting contribute to refractory hypoxemia. Inhaled nitric oxide (NO) decreases pulmonary arterial pressure and improves ventilation-perfusion mismatch in a variety of animal models and selected human patients. We report on 10 consecutive term and near-term newborns with severe acute hypoxemic respiratory failure due to diaphragmatic hernia, meconium aspiration syndrome, group B streptococcus sepsis, pneumonia or acute respiratory distress syndrome, who received increasing doses of inhaled NO (up to 80 ppm) to improve the arterial partial pressure of oxygen (PaO2). The response to NO and the optimum NO concentration which improved PaO2 varied considerably between patients. Improvement of PaO2 was absent or poor (less than 10 mm Hg) in the 4 newborns with meconium aspiration syndrome and in 1 patient with congenital diaphragmatic hernia, while in the other 5 patients inhaled NO increased the mean (+/- SE) PaO2 from 41 +/- 6 to 57 +/- 9 mm Hg (P < 0.05). Optimum NO concentrations determined by dose-response measurements performed during the first 8 hr of NO inhalation were 8-16 ppm except for 2 newborns with congenital diaphragmatic hernia who required 32 ppm to effectively increase PaO2. Four of the 5 patients in whom the PaO2 rose by more than 10 mm Hg received inhaled NO for extended periods of time (5 to 23 days) with no signs of tachyphylaxis. The optimum NO concentration dropped to less than 3 ppm after prolonged mechanical ventilation or when intravenous prostacyclin was given concomitantly.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of noradrenergic input into the hypothalamic paraventricular nucleus on fever in the guinea-pig.

The febrile response of guinea-pigs to a bacterial pyrogen was tested under different experimental conditions: (1) during electrical stimulation of the hypothalamic paraventricular nucleus (PVN), (2) after destruction of noradrenergic afferents into the PVN by 6-hydroxydopamine (6-OHDA), (3) during a microinfusion of noradrenaline (NA) into the PVN. Electrical stimulation of the PVN neurons by implanted microelectrodes reduced the febrile response to 45% of the control values. This confirmed the proposed antipyretic function of these neurons. Chronic destruction of noradrenergic afferents to the PVN by microinjected 6-OHDA also resulted in a significant reduction of febrile responses to 38% of the control values. A microinfusion of NA into the PVN enhanced the febrile responses to bacterial endotoxin by 39% in comparison to animals microinfused with the solvent (0.9% NaCl). Immunoreactivity to an antiserum against arginine vasopressin (AVP) was compared in PVN neurons of 6-OHDA-treated and of control animals. The number of AVP-immunoreactive perikarya and the intensity of immunoreactivity were increased in the animals treated with 6-OHDA, especially in the medial part of the PVN. Since fever was increased by microinfused NA and decreased by 6-OHDA treatment, we assume an inhibitory influence of noradrenergic brain stem afferents on the proposed antipyretic vasopressinergic system of the PVN.

Changes in physiological and neuroendocrine properties during thermal adaptation of golden hamsters (Mesocricetus auratus).

Golden hamsters raised at 22 degrees C were adapted in the early summer for 3 weeks to either 28 degrees C or 5 degrees C. To achieve profound changes the photoperiod was also shortened from 14 h to 11 h during adaptation to cold. During the investigation body weight, food consumption, water intake, urine production, and osmolality, as well as secreted amounts of noradrenaline (NA) and dopamine (DA), were recorded in each animal before, during, and after the adaptation period. In another group of golden hamsters the brains were processed for immunocytochemical detection of arginine-vasopressin (AVP) and corticotropin releasing factor (CRF) in the third week of adaptation to a cold or warm environment. In warm-adapted animals food and water consumption and urine production remained unchanged or were only slightly reduced. NA and DA secretion were reduced by 50%. The AVP-immunoreactivity reflected an anti-diuretic state in these animals. In fibers influencing the adrenal axis, AVP-immunoreactivity was weak compared to CRF fibers. Food and water consumption, urine production, and DA secretion increased two-fold during cold adaptation. Daily secreted amounts of NA increased nine-fold. AVP-immunoreactivity was weak in projections to the neurohypophysis. Fibers influencing the adrenal axis, however, displayed strong AVP-immunoreactivity in comparison to that of CRF. The immunocytochemically determined patterns of AVP and CRF distribution indicated an activation of the osmoregulative axis in the warm-adapted animals and of the adrenal axis in the cold-adapted golden hamsters.

Thermoadaptive influence on reactivity pattern of vasopressinergic neurons in the guinea pig.

In cold-adapted guinea pigs, increased amounts of arginine-vasopressin (AVP) immunoreactive material could be visualized in neurons of the supraoptic and paraventricular nucleus, in fibers projecting to the neurohypophysis and in fiber terminals in the ventral lateral septum and in the amygdala. In warm-adapted animals the reactivity to AVP antiserum was poor in all neuronal structures examined. High AVP-immunoreactivity was accompanied by a reduced febrile response to bacterial pyrogen in cold-adapted guinea pigs.

[Theoretical and experimental studies of the diagnostic relevance and comparability of mechanical oscillation parameters]. / Theoretische und experimentelle Untersuchungen zur diagnostischen Relevanz und Vergleichbarkeit oszillationsmechanischer Parameter.

The practical application of the forced oscillation technique for the analysis of the mechanics of respiration is hampered by the fact that the measured frequency-dependent impedance values R(f) and X(f) cannot be related directly to the parameters airway resistance Raw and pulmonary compliance CL. Furthermore, various derived oscillatory parameters are employed which are not directly comparable even with one another. In order to be able to estimate the diagnostic relevance and comparability of the impedance curves R(f) and X(f), their form-specific characteristics R = R(5)-R(20) and X(5), as also the equipment-specific parameters Ros (Siregnost FD5) and Rfo (custo vit), the relationships of these oscillatory parameters to Raw and CL were simulated in a structural model of the respiratory system, and tested in the real system. It was shown that already from frequencies of f greater than 10Hz upwards, R(f) no longer reacts to an increase in resistance in the peripheral region of the lung, and at 20 Hz indicates only the upper airway component of a global obstruction demonstrated body-plethysmographically with Raw. The diagnostic information on peripheral airway obstruction is contained in both components R(f) and X(f) of the respiratory impedance; with increasing obstruction and increasing frequency, it progressively reverts to the X(f) curve. Therefore, by including X(f) in the resistance evaluation for the parameters Ros and Rfo, the underevaluation of R(f) as compared with Raw can in part be compensated for, although an overe stimation at low Raw values with Ros and a large scatter of the Rfo values in the case of large Raw figures has to be accepted.(ABSTRACT TRUNCATED AT 250 WORDS)

Increase of the oxygenation and decrease of the intrapulmonary peak pressure at constant mean airway pressure using high-frequency jet ventilation in adult rabbits with lavage-induced severe respiratory distress syndrome compared to conventional mechanical ventilation.

Reports are contradictory about the value of high-frequency jet ventilation (HFJV) in the treatment of respiratory distress syndrome (RDS) [10, 11, 18 - 1, 2, 22, 25]. In a preliminary study on rabbits with healthy as well as surfactant deficient lungs, caused by lung lavage, at a constant mean airway pressure (MAP) and 20% inspiration time, the influence of the jet ventilation frequencies of 1, 3, 5, 10, 15 and 20 Hz (cycles per second) on the pressure oscillations along the airways as well as on blood gas and cardiac parameters were investigated. It was presumed that the breathing level, e.g. functional residual capacity plus 50% of the tidal volume is the same at constant MAP. The results during HFJV are compared to those of conventional mechanical ventilation (CMV). With increasing frequency the peak airway pressure (PAP) clearly decreased on both groups, while the self controlled positive end-expiratory pressure (AUTO-PEEP) increased. That means, the amplitude of the pressure oscillations became smaller and smaller, indicating that the danger of mechanical lesions might be reduced by this mode of ventilation. The arterial oxygenation (PaO2) increased with frequency. A threefold higher PaO2 could be obtained at 10 Hz in the animals with RDS lungs. The arterial carbon dioxide tension (PaCO2) increased nearly linear with the frequency in both groups. The inverse course of the arterial pH showed that it is possible to obtain at lower frequencies a respiratory alkalosis and at higher frequencies an acidosis. Optimal gas exchange could be obtained at about 10 Hz. Decreasing cardiac output with increasing frequency showed a good correlation to the pH in both groups. The effect was more influenced by the heart frequency than by the stroke volume especially in the RDS-group.

[Experiences with the use of oscillating high frequency ventilation]. / Erfahrungen bei der Anwendung der oszillatorischen Hochfrequenzbeatmung.

Our investigations have demonstrated that the effect of oscillatory high-frequency ventilation (HFO) on gas exchange in dogs is directly proportional to the oscillatory flow amplitude VM. Because of the equation: VM = PM/Z, gas exchange is increasing with rising oscillatory amplitude of the ventilation pressure PM and decreasing with rising impedance Z of the respiratory system. This system consists of endotracheal tube and the lungs of the dog investigated. The impedance Z = square root of R2 + X2 (resistance R and reactance X) achieves a minimal value near at the resonant frequency (reactance X = 0, in healthy intubated dogs near at 5 Hz) and increases with rising oscillatory frequency. Thus the oscillatory high-frequency ventilation is most effective near to the resonant frequency of the respiratory system. The results presented allow the conclusion that the application of high-frequency ventilation can be optimized by monitoring the respiratory mechanics parameters.

[Examples of the clinical use of different methods of high frequency ventilation]. / Beispiele für den klinischen Einsatz unterschiedlicher Methoden der Hochfrequenzbeatmung.

Four basic principles of high frequency ventilation (HFV) are shortly described and papers cited which review the technical, experimental, and clinical experiences in the GDR. Using examples of review articles and original papers, the benefits of the methods of HFV during and after surgical procedures, in intensive care and in weaning from artificial ventilation are exposed. The possible increase of the oxygenation in patients with chronic respiratory insufficiency following secretolysis by intrapulmonary percussion is discussed. Dangers and complications using HFV are assessed.

[Equipment combination for the use of normal frequency and high frequency jet ventilation]. / Gerätekombination zur Anwendung der normofrequenten und hochfrequenten Jetventilation.

Over the last eight years high-frequency ventilation has been extensively evaluated both in the clinical and laboratory settings. Two types of jet ventilators for application of normofrequency and high-frequency jet ventilation have been developed. A combined equipment is described with gas mixer, heater-humidifier, monitoring, membrane solenoid valve and a special injection system.

The influence of hypoxia and hyperoxia during metabolic acidosis and alkalosis on pulmonary haemodynamics.

In anaesthetised, mechanically ventilated Beagle dogs a moderate metabolic acidosis increased the pulmonary vascular resistance to a greater extent than moderate hypoxia. Alkalosis and hyperoxia did not alter the pulmonary vascular tone.

Changes in body temperature and vasopressin content of brain neurons, in pregnant and non-pregnant guinea pigs, during fevers produced by Poly I:Poly C.

The synthetic polyribonucleotide pyrogen Poly I:Poly C (800 micrograms.kg-1) was injected intramuscularly on alternate days into pregnant and non-pregnant female guinea pigs. Pregnant animals, close to term, had smaller fevers in response to the pyrogen than did non-pregnant animals. Repeated injections of the pyrogen caused sequentially smaller fevers for the first 3-4 injections, particularly in non-pregnant animals, and this appeared to be like the tolerance usually developed to repeated injections of endotoxin. Continued pyrogen injections then caused, in non-pregnant animals, fevers of increasing magnitude until the original fever levels were reached, whereas in pregnant guinea pigs the fever responses remained reduced until parturition. The development of tolerance was associated with an increase in immunoreactivity for arginine vasopressin (AVP) in some neurons in the medial part of the paraventricular nucleus, and in terminals in the lateral septum and amygdala similar to changes found in these areas at term of pregnancy. These observations raise the possibility that AVP in these regions may have a role in the development of tolerance to pyrogens, and further quantitative studies of the AVP content of, and release from, nerve terminals projecting to the limbic system seem warranted.

[Animal experiment studies of morphologic changes in the trachea and lung in high frequency ventilation]. / Tierexperimentelle Untersuchungen zu morphologischen Veränderungen an Trachea und Lunge bei Hochfrequenzbeatmung.

Prolonged high frequency ventilation (24 hrs) in dogs leads to morphological changes in the trachea as well as in the bronchi. Erosive changes of tracheal epithelium were observed whereas small bronchi and bronchioli exhibited luminal obstructions by mucus plugs, caused by hypersecretion of goblet cells. Using histochemical methods degenerative changes of bronchiolar epithelium were observed.

Acute and chronic effects of xanthine oxidase on lung thorax-compliance in guinea pigs.

Xanthine oxidase was given intratracheally in a single dose to guinea pigs. Lung compliance was measured after 4 h and 14 days respectively. Lung-thorax compliance was significantly lower compared with saline-treated controls both 4 h and 14 days after application of fluid. At 14 days there was a dose-related response between lung-thorax compliance and xanthine oxidase administered in the range 0-1.0 U. Superoxide dismutase (SOD) had a protective effect on xanthine oxidase action at 4 h, but not after 14 days. We suggest that the decreased lung-thorax compliance was caused by superoxide radicals, produced by the hypoxanthine-xanthine oxidase system, damaging lung tissue. We speculate that free oxygen radicals produced by the hypoxanthine-xanthine oxidase system could be an important contributory pathogenetic factor in producing both acute and chronic lung damage in, for instance, premature babies or adults, with respiratory distress syndrome.

A new conventional and high-frequency ventilator for small animals.

A pressure limited, time controlled ventilator has been designed especially for studies on experimental animals with severe respiratory distress syndrome (SRDS). Inspiration: Expiration (I:E) ratio (1:99-99:1) and frequency can be changed independently. Frequency ranged from 1 to 199/min in conventional ventilation (CV), while in high-frequency jet ventilation (HFJV) from 1 to 30 Hz. The gas delivery system consists of 3 magnetic valves (inspiration, expiration and HFJV, respectively) to ensure superposition of CV with HFJ or to use them separately. A monitoring unit switches off inspiration gas sources during HFJV if intratracheal pressure exceeds the alarm threshold. The device has been used in the following animal models: premature newborn rabbits with surfactant deficient lungs, emphysematous rats and guinea pigs as well as dogs and rabbits with SRDS due to lung lavage. Ventilation was most effective with an I:E ratio of 4:1 during pressure controlled CV, whereas during HFJV optimum gas exchange could be maintained with an I:E ratio of 1:4 and a frequency of 15 Hz in beagle dogs and 10 Hz in rabbits, respectively.

Lung mechanics and blood gases in pregnant guinea pigs.

Lung resistance and compliance were measured in early pregnant, late pregnant and non pregnant guinea pigs. Lung resistance was increased, lung compliance was decreased in pregnancy. A new finding was the increase of chest wall compliance in the course of pregnancy. In order to obtain a sufficient gas exchange during artificial ventilation, pregnant animals have to be ventilated with a higher frequency or a higher pressure than non pregnant controls.

Isolated extremity perfusion with DTIC. An experimental and clinical study.

Dacarbazine (DTIC) was used for isolated perfusion of extremities in dogs and man. In the animal experiment perfusions with DTIC at dosages up to 100 mg per kg of extremity weight were well tolerated. The concentration of DTIC in the perfusate ranged from 70 to 400 micrograms/ml without evidence for formation of metabolites. Electron microscopy, performed 14 days later, revealed a decrease of glycogen in striated muscle cells. Vascular damage was not observed. Five patients with advanced malignant melanoma or soft tissue sarcoma of the extremities were treated by isolation perfusion with 75 to 133 mg DTIC per kg of extremity at 40 degrees C for 60 minutes. A tumor regression of at least 30% was observed.

Ultrastructural changes in the dog liver cell after isolated liver perfusion with various cytotoxins.

Following isolated liver perfusion with different cytotoxins - 5-fluorouracil (5-FU), methotrexate (MTX), dacarbazine (DTIC) cis-platinum (cis-PT) - liver tissue of dogs was examined with the electron microscope (a) directly after the perfusion and (b) after a survival time of 4 weeks (5-FU and DTIC). Acute disintegration of the granular endoplasmic reticulum and depletion of the glycogen stores occurred after perfusion with 5-FU, MTX, and DTIC, while cis-PT induced disintegration of the granular endoplasmic reticulum accompanied by an accumulation of glycogen. Four weeks after perfusion with DTIC signs of remarkably increased cellular activity were observed, while 4 weeks after perfusion with 5-FU the parenchymal liver cells revealed a well-balanced and moderate recovery of the cellular structures.