Efficiency of exogenous surfactant combined with intravenous N-acetylcysteine in two-hit rodent model of ARDS.

Accumulation of reactive oxygen species during hyperoxia together with secondary bacteria-induced inflammation leads to lung damage in ventilated critically ill patients. Antioxidant N-acetylcysteine (NAC) in combination with surfactant may improve lung function. We compared the efficacy of NAC combined with surfactant in the double-hit model of lung injury. Bacterial lipopolysaccharide (LPS) instilled intratracheally and hyperoxia were used to induce lung injury in Wistar rats. Animals were mechanically ventilated and treated intravenously with NAC alone or in combination with intratracheal surfactant (poractant alfa; PSUR+NAC). Control received saline. Lung functions, inflammatory markers, oxidative damage, total white blood cell (WBC) count and lung oedema were evaluated during 4 hrs. Administration of NAC increased total antioxidant capacity (TAC) and decreased IL-6. This effect was potentiated by the combined administration of surfactant and NAC. In addition, PSUR+NAC reduced the levels of TNFα, IL-1ß, and TAC compared to NAC only and improved lung injury score. The combination of exogenous surfactant with NAC suppresses lung inflammation and oxidative stress in the experimental double-hit model of lung injury.

The Effect of Modified Porcine Surfactant Alone or in Combination with Polymyxin B on Lung Homeostasis in LPS-Challenged and Mechanically Ventilated Adult Rats.

The study aimed to prove the hypothesis that exogenous surfactant and an antibiotic polymyxin B (PxB) can more effectively reduce lipopolysaccharide (LPS)-induced acute lung injury (ALI) than surfactant treatment alone, and to evaluate the effect of this treatment on the gene expression of surfactant proteins (SPs). Anesthetized rats were intratracheally instilled with different doses of LPS to induce ALI. Animals with LPS 500 µg/kg have been treated with exogenous surfactant (poractant alfa, Curosurf®, 50 mg PL/kg b.w.) or surfactant with PxB 1% w.w. (PSUR + PxB) and mechanically ventilated for 5 hrs. LPS at 500 µg/kg increased lung edema, oxidative stress, and the levels of proinflammatory mediators in lung tissue and bronchoalveolar lavage fluid (BALF). PSUR reduced lung edema and oxidative stress in the lungs and IL-6 in BALF. This effect was further potentiated by PxB added to PSUR. Exogenous surfactant enhanced the gene expression of SP-A, SP-B, and SP-C, however, gene expression for all SPs was reduced after treatment with PSUR + PxB. In mechanically ventilated rats with LPS-induced ALI, the positive effect of exogenous surfactant on inflammation and oxidative stress was potentiated with PxB. Due to the tendency for reduced SPs gene expression after surfactant/PxB treatment topical use of PxB should be considered with caution.

Bronchoalveolar lavage with pulmonary surfactant/dextran mixture improves meconium clearance and lung functions in experimental meconium aspiration syndrome.

Surfactant lung lavage is a promising approach in the treatment of meconium aspiration syndrome (MAS). We hypothesise that the enrichment of modified natural surfactant with dextran will enhance meconium clearance from the airspaces during lung lavage and improve lung function in experimental MAS. Human meconium (30 mg/ml; 4 ml/kg) was instilled into the tracheal cannula of anaesthetised and paralysed adult rabbits to induce respiratory failure. The animals were then lavaged with saline (Sal), surfactant without (Surf) and with dextran (Surf+dex). Lung lavage (10 ml/kg in three portions) was performed with diluted surfactant (Curosurf, 10 mg/ml, 100 mg/kg) without or with dextran (3 mg/mg of surfactant phospholipids) or saline and the animals were conventionally ventilated with 100% O(2) for an additional hour. Lung functions were measured prior to and after meconium instillation, and 10, 30 and 60 min after lavage. The recovery of meconium in bronchoalveolar lavage (BAL) fluid was quantified. More meconium solids was recovered in the surfactant-lavaged than in the saline-lavaged groups (Surf: 12.4 +/- 3.9% and Surf+dex: 17.5 +/- 3.5% vs. Sal: 4.8 +/- 1.0%; both P < 0.01). Moreover, more meconium solids was obtained by Curosurf/dextran than by Curosurf-only lavage (P < 0.05). In the Surf group, the values for PaO(2)/FiO(2) were significantly higher than in the controls (at 60 min: 24.5 +/- 4.2 kPa vs.9.1 +/- 2.2 kPa, P < 0.01). An additional increase in oxygenation was seen in the Surf+dex group (at 60 min: 34.2 +/- 8.1 kPa, P vs. Surf group <0.01). The lung-thorax compliance was higher in the Surf+dex group in comparison with the Sal and Surf groups (at 60 min: 9.6 +/- 0.9 vs.7.6 +/- 1.2, P < 0.01 and 8.0 +/- 0.7 ml/kPa/kg, P < 0.05). The enrichment of Curosurf with dextran improves meconium clearance and lung functions in surfactant-lavaged rabbits with meconium aspiration.

Effects of diuretic-induced hypovolemia/isosmotic dehydration on cardiorespiratory responses to hyperthermia and its physical treatment in rabbits.

Under conditions of heat stress and hyperosmotic dehydration, both animals and humans reduce thermoregulatory evaporation and regulate deep body temperature at elevated levels. Regarding the mechanisms, the main role in producing these thermoregulatory changes during dehydration is attributed to the increased osmolality of body fluids, although the role of the decreased plasma volume without changes in plasma osmolality (hypovolemia/isosmotic dehydration) has not been so far investigated. There are also controversial experimental results regarding the effects of dehydration on heat stress-induced cutaneous vasodilation. Therefore, this paper studied the effects of hypovolemia/isosmotic dehydration on cardiorespiratory responses to hyperthermia and its physical treatment in 17 anaesthetized adult rabbits. The animals were divided into two groups: normovolemic group (NV; n = 10) and hypovolemic group (HV; n = 7). In the HV group, hypovolemia/isosmotic dehydration (decrease in plasma volume by 16.1 +/- 1.2%) was induced by furosemide (5 mg kg-1 i.v.) without change in measured plasma Na+ concentration. Hyperthermia (the rise in body temperature (BT) to 42 degrees C by a gradual body surface heating) caused significant increase in minute ventilation (VE) in both groups. However, VE values were significantly higher in the HV rabbits compared to the NV animals despite the lower breathing frequency (p < 0.05). The panting was absent in the HV rabbits at the BT of 42 degrees C, unlike the NV animals. From cardiovascular variables, the vasoconstrictor response in visceral (mesenteric) region during hyperthermia in hypovolemic/isosmotic animals was attenuated (p < 0.05), whereas the heat stress-induced cutaneous vasodilation was not influenced by hypovolemia. Recovery of the BT by body surface cooling was accompanied by further increase in VE in the NV group, whereas VE decreased (p < 0.05) in the HV animals. Cooling led to recovery of the cardiovascular parameters. There were found no significant cardiorespiratory differences between the groups (NV:HV) during cooling. The lower frequency of breathing and attenuation of the mesenteric vasoconstriction during exogenous hyperthermia are present not only during hyperosmotic dehydration induced by water deprivation, but they also occur under conditions of furosemide-induced isosmotic dehydration/hypovolemia in rabbits. The heat stress-induced cutaneous vasodilation regarding its biological importance was not influenced by hypovolemia/isosmotic dehydration. Therefore, it is suggested that hypovolemia alone is sufficient to produce described respiratory, thermoregulatory and cardiovascular changes in dehydrated rabbits during exogenous hyperthermia, whereas hyperosmolality is not a requisite.

Diuretic-induced dehydration/hypovolemia inhibits thermal panting in rabbits.

Respiratory and thermoregulatory responses to hyperthermia during isosmotic dehydration/hypovolemia were studied in 17 anaesthetized adult rabbits divided into two groups: normovolemic group (NV; n=10) and hypovolemic group (HV; n=7). Hypovolemia/isosmotic dehydration (a decrease in plasma volume by 16.1+/-1.2%) was induced by furosemide (5 mg kg(-1) i.v.). During hyperthermia (the rise in body temperature to 42 degrees C by a gradual body surface heating), the HV rabbits had lower (P<0.05) respiratory frequency and higher (P<0.05) tidal volume than the NV animals. The panting was absent in the HV rabbits at the BT of 42 degrees C, unlike the NV animals. The lower respiratory frequency and the absence of panting during exogenous hyperthermia in dehydrated animals are present not only during hyperosmotic dehydration induced by water deprivation [Doris, P.A., Baker, M.A., 1981. Hypothalamic control of thermoregulation during dehydration. Brain Res. 206 (1), 219-222], but they also occur in the furosemide-induced isosmotic dehydration/hypovolemia.

On- and off-responses of heart rate to exercise - relations to heart rate variability.

During physical exercise, heart rate (HR) increases by parasympathetic withdrawal and increase of sympathetic activity to the heart. HR variability (HRV) in time and frequency domains provides information about autonomic control of the cardiovascular system. Non-linear analysis using the Poincaré plot method is able to reveal supplementary information about cardiac autonomic control. The aim of this study was to determine the association between HRV parameters, the initial increase of HR at the onset of exercise (on-response) and HR decrease in the recovery phase after acute exercise (off-response). HR was continuously monitored in 17 healthy male subjects (mean age: 20.3 +/- 0.2 (SEM) years) at rest (25 min supine; 5 min standing), during exercise (8 min of step test at 70% of maximal power output) and in the recovery phase (30 min supine). HRV analysis in time and frequency domains and evaluation of the Poincaré plot measures (length, widths) were performed on selected segments of HR time series. HR on- and off-responses were quantified using an exponential curve fitting technique. The time constants T(on) and T(off), representing the rate of on- and off-responses to exercise, were computed. Postexercise HRV indices and time constant of on-response - T(on) - to exercise were negatively correlated. From preexercise HRV indices, only Poincaré plot parameters were correlated with T(on). No correlation between HRV indices and parameters of off-response was found. In conclusion, preexercise HRV parameters are not closely correlated with the rate of cardioacceleration at the onset of exercise and cannot predict the rate of HR recovery. On the other hand, postexercise HRV parameters are related to the rate of initial adjustment of HR to exercise referring to the importance of rapid HR on-response for a faster recovery after exercise.