Modified protocols for surfactant therapy in experimental meconium aspiration syndrome

In adult rats with experimental meconium aspiration syndrome, we investigated whether the therapeutic effect of exogenous surfactant was increased by addition of dextran or preceding airway lavage with diluted surfactant. Animals (n = 72) ventilated with pure oxygen were given human meconium suspension (50-75 mg kg(-1)) through the airways. When the PaO(2) had decreased to <20 kPa (mean +/- SD 12 +/- 3.9 kPa), the rats were randomly allocated to ten groups (G). G 6-10 underwent lung lavage with diluted Curosurf (5 mg ml(-1), 20 ml kg(-1)), whereas G 1-5 did not. G 1 and 6 received no additional material through the airways. G 2 and 7 received Curosurf (100 mg kg(-1)), and G 3 and 8 received Curosurf (100 mg kg(-1)) plus dextran (75 mg kg(-1)); G 4 and 9 received Curosurf (200 mg kg(-1)), and G 5 and G 10 received Curosurf (200 mg kg(-1)) plus dextran (75 mg kg(-1)). All rats in G 1 died before 180 min after randomization. In G 2, 3, 6, 7, and 8, the PaO(2) transiently increased to 30-40 kPa. In G 4, 5, 9, and 10, the PaO(2) remained >30 kPa for 180 min. Both airway lavage and supplementation with dextran improved the therapeutic effects of surfactant; however, a large dose (200 mg kg(-1)) was nevertheless required to optimize gas exchange.     

Resistance of different surfactant preparations to inactivation by meconium.

A disease similar to acute respiratory distress syndrome may occur in neonates after aspiration of meconium. The aim of the study was to compare the inhibitory effects of human meconium on the following surfactant preparations suspended at a concentration of 2.5 mg/mL: Curosurf, Alveofact, Survanta, Exosurf, Pumactant, rabbit natural surfactant from bronchoalveolar lavage, and two synthetic surfactants based on recombinant surfactant protein-C (Venticute) or a leucine/lysine polypeptide. Minimum surface tension, determined with a pulsating bubble surfactometer, was increased >10 mN/m at meconium concentrations >or=0.04 mg/mL for Curosurf, Alveofact, or Survanta, >or=0.32 mg/mL for recombinant surfactant protein-C, >or=1.25 mg/mL for leucine/lysine polypeptide, and >or=20 mg/mL for rabbit natural surfactant. The protein-free synthetic surfactants Exosurf and Pumactant did not reach minimum surface tension <10 mN/m even in the absence of meconium. We conclude that surfactant activity is inhibited by meconium in a dose-dependent manner. Recombinant surfactant protein-C and leucine/lysine polypeptide surfactant were more resistant to inhibition than the modified natural surfactants Curosurf, Alveofact, or Survanta but less resistant than natural lavage surfactant containing surfactant protein-A. We speculate that recombinant hydrophobic surfactant proteins or synthetic analogs of these proteins can be used for the design of new surfactant preparations that are relatively resistant to inactivation and therefore suitable for treatment of acute respiratory distress syndrome.     

Randomized European multicenter trial of surfactant replacement therapy for severe neonatal respiratory distress syndrome: single versus multiple doses of Curosurf.

There is now convincing evidence that the severity of neonatal respiratory distress syndrome can be reduced by surfactant replacement therapy; however, the optimal therapeutic regimen has not been defined. This randomized European multicenter trial was designed to determine whether the beneficial effects of a single large dose of Curosurf (200 mg/kg) in babies with severe respiratory distress syndrome (arterial to alveolar oxygen tension ratio approximately 0.10) could be enhanced by using multiple doses of surfactant. Preterm neonates (birth weight 700 to 2000 g) with severe respiratory distress syndrome requiring artificial ventilation with fraction of inspired oxygen greater than or equal to 0.6 were randomized into two groups at an age of 2 to 15 hours. Both groups received the usual dose of Curosurf (200 mg/kg) immediately after randomization. In neonates randomized to receive multiple-dose treatment, two additional doses of Curosurf (100 mg/kg each) were instilled into the airways (12 and 24 hours after the initial dose) provided that the patients still needed artificial ventilation with fraction of inspired oxygen greater than 0.21. In both groups (single dose: n = 176, multiple doses: n = 167) there was a rapid improvement in oxygenation as reflected by a threefold increase in arterial to alveolar oxygen tension ratio within 5 minutes after surfactant instillation (P less than .001), and peak inspiratory pressure and mean airway pressure could be reduced significantly during the first 6 hours after surfactant treatment. In addition, ventilatory requirement (peak inspiratory pressure, ventilatory efficiency index) was reduced in the multiple-dose group 2 to 4 days after randomization (P less than .05 to .01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of exogenous surfactant on the development of surfactant synthesis in premature rabbit lung

Surfactant replacement is an effective therapy for neonatal respiratory distress syndrome. Full recovery from respiratory distress syndrome requires development of endogenous surfactant synthesis and metabolism. The influence of exogenous surfactant on the development of surfactant synthesis in premature lungs is not known. We hypothesized that different exogenous surfactants have different effects on the development of endogenous surfactant production in the premature lung. We treated organ cultures of d 25 fetal rabbit lung for 3 d with 100 mg/kg body weight of natural rabbit surfactant, Survanta, and Exosurf and measured their effects on the development of surfactant synthesis. Additional experiments tested how these surfactants and Curosurf affected surfactant protein (SP) SP-A, SP-B, and SP-C mRNA expression. Surfactant synthesis was measured as the incorporation of 3H-choline and 14C-glycerol into disaturated phosphatidylcholine recovered from lamellar bodies. Randomized-block ANOVA showed significant differences among treatments for incorporation of both labels (p < 0.01), with natural rabbit surfactant less than control, Survanta greater than control, and Exosurf unchanged. Additional experiments with natural rabbit surfactant alone showed no significant effects in doses up to 1000 mg/kg. Survanta stimulated disaturated phosphatidylcholine synthesis (173 +/- 41% of control; p = 0.01), increased total lamellar body disaturated phosphatidylcholine by 22% (p < 0.05), and increased 14C-disat-PC specific activity by 35% (p < 0.05). The response to Survanta was dose-dependent up to 1000 mg/kg. Survanta did not affect surfactant release. No surfactant altered the expression of mRNA for SP-A, SP-B, or SP-C. We conclude that surfactant replacement therapy can enhance the maturation of surfactant synthesis, but this potential benefit differs with different surfactant preparations.     

Effects of hyaluronan-fortified surfactant in ventilated premature piglets with respiratory distress

We hypothesized that enriching surfactant with hyaluronan would restore lung function when tested in a premature animal model. Newborn piglets (85% gestation, term 112-114 days) were delivered by cesarean section, subjected to mechanical ventilation (tidal volume 6- 8 ml/kg) and randomly assigned to treatment with 50 or 100 mg/kg Curosurf (C50 and C100), 50 or 100 mg/kg Curosurf mixed with 2.5% HA (w/w, CH50 and CH100). A ventilated and not treated group (Cont) and a not treated and not ventilated group (Non) were included as controls. Six hours after treatment the lungs were removed and biochemical, biophysical, cytological and histological analyses were carried out. The CH100, CH50, C100 and C50 groups had variable but significantly improved alveolar phospholipid content, minimal surface tension, alveolar aeration and wet/dry lung weight ratios, but little histological evidence of lung injury. CH100, CH50 and C100 groups had the best effects in terms of oxygenation, lung compliance and histology and evidence of decreased inflammation (IL-8 and TNF-alpha mRNA expression). We conclude that HA added to 50 mg/kg Curosurf or use of 100 mg/kg Curosurf with or without HA provides the best effects in terms of lung function and reduction of inflammation.     

Dextran or polyethylene glycol added to curosurf for treatment of meconium lung injury in rats

BACKGROUND: In experimental lung injuries, improvement of lung function after treatment with surfactant/polymer mixtures may depend on both type of polymer and the specific surfactant. In vitro studies suggest that dextran is more effective when mixed with Curosurf, and polyethylene glycol (PEG) is more effective when mixed with Survanta. We therefore wanted to find out whether these results held true in an animal model of acute lung injury. OBJECTIVE: To compare the response to therapy of PEG vs. dextran when added to Curosurf after meconium lung injury. METHODS: Lung injury was produced by intratracheal instillation of meconium (30 and 4 ml/kg). One hour after injury, Curosurf (35 mg/ml) with or without 5% dextran (68 kDa) or 5% PEG (10 kDa) was given. Arterial blood gases and peak inspiratory pressures were measured for 3 h after treatment while animals were supported by volume-regulated ventilation. Then animals were sacrificed and pressure volume relationships, lung wet/dry weights, and histology were assessed. RESULTS: Initially, improved PaO2 and inspiratory pressure occurred for both Curosurf/PEG and Curosurf/dextran groups compared with Curosurf, but at three hours, peak inspiratory pressure and PaO2 remained significantly improved for the Curosurf/dextran but not for Curosurf/PEG groups when compared with Curosurf alone. Total lung capacity at the end of the experiment was also significantly increased in the Curosurf/dextran group, but not the Curosurf/PEG group when compared with Curosurf. CONCLUSION: Under these experimental conditions, Curosurf/dextran mixtures provided a better therapeutic response than Curosurf/PEG or Curosurf.     

Comparison of surface properties and physiological effects of a synthetic and a natural surfactant in preterm rabbits.

AIMS--To compare the physical and physiological properties of a synthetic surfactant (Exosurf, Wellcome Foundation) and a natural surfactant (Curosurf, Chiesi Farmaceutici). METHODS--Surface properties of the surfactant suspensions (10 mg phospholipid/ml) were evaluated using the pulsating bubble surfactometer. Lung-thorax compliance was determined in 47 immature newborn rabbits with a gestational age of 27 days, treated with recommended clinical doses of either surfactant (Exosurf 67.5 mg/kg; Curosurf 200 mg/kg). The lungs were examined histologically. RESULTS--The mean (SD) contractile forces of the surface at maximum and minimum bubble size were significantly lower for Curosurf than for Exosurf: 31 (2) and 0 (0) mN/m v 53 (5) and 29 (4) mN/m, respectively. Mean (SD) lung-thorax compliance after one hour of ventilation was significantly higher in rabbits treated with Curosurf compared with animals receiving Exosurf or those serving as controls: 0.60 (0.15) ml/cm H2O.kg v 0.44 (0.03) and 0.34 (0.18) ml/cm H2O.kg, respectively. Both surfactants increased alveolar volume density compared with results for control animals, but only Curosurf significantly reduced the incidence of moderate or severe bronchiolar epithelial disruption. CONCLUSIONS--The natural surfactant, Curosurf, reduced the contractile force at an air-liquid interface to a greater extent than the synthetic surfactant, Exosurf, and led to a greater improvement in compliance and less airway epithelial damage when given in clinical treatment doses to immature rabbits.     

Selective elevation of systemic blood pressure by epinephrine during sepsis-induced pulmonary hypertension in piglets

In a piglet model of group B beta Streptococci (GBS)-induced pulmonary hypertension, we have determined hemodynamic responses to epinephrine (EPI) infusion in both the systemic and pulmonary circulations. Three groups of piglets (GBS + EPI, n = 6; GBS + placebo, n = 6; placebo, n = 6) were studied. GBS, infused intravenously at approximately 5 X 10(7) organisms/kg/min, reduced cardiac index and stroke volume index while elevating pulmonary artery pressure and pulmonary vascular resistance index. Systemic vascular resistance index, heart rate and aortic pressure did not change during GBS infusion. Six piglets received intravenous EPI after cardiac index had fallen by 30% during GBS infusion. At 3.5, 7.0, and 15 micrograms/kg/min, respectively, EPI raised aortic pressure by 18.5, 31.0, and 45.0 mm Hg while EPI reduced pulmonary artery pressure by 5.2, 6.3, and 8.2 mm Hg. At each dose, EPI elevated systemic vascular resistance index and lowered pulmonary vascular resistance index. At 3.5 micrograms/kg/min, the elevation of aortic pressure was associated with an increase in both cardiac index and systemic vascular resistance index. At higher EPI doses, the rise in aortic pressure was accounted for entirely by an increase in systemic vascular resistance index. Systemic acid/base status and PaO2 did not differ among piglets who received GBS + EPI, GBS alone, or placebo. Extrapolation of these data to human infants must be approached with extreme caution. However, selective elevation of systemic blood pressure may be a feasible strategy for some infants to impede right-to-left shunting of blood often associated with sepsis-induced pulmonary hypertension.     

Biophysical and physiological properties of porcine surfactant enriched with polymyxin B

OBJECTIVE: We examined whether the biophysical and physiological properties of Curosurf were improved by the cyclic amphipathic decapeptide polymyxin B (PxB). METHODS: Curosurf was diluted to 1-5 mg/ml with PxB added at 1, 2 or 3% (w/w). Albumin was added at 40 mg/ml. Minimum surface tension (gammamin) during surface compression was determined for each mixture with pulsating bubble. Immature newborn rabbits were treated with 2.5 ml/kg of Curosurf 80 mg/ml, or Curosurf 32 mg/ml with or without 2% PxB and ventilated for up to 5 h. RESULTS: At surfactant concentration 2 mg/ml, gammamin was high (17 +/- 8.9 mN/m) but remained low (2.7 +/- 0.8 mN/m) when PxB was added. Albumin inactivated Curosurf at both 2 and 3.5 mg/ml; this inactivation was prevented by 2% PxB. Treatment of newborn rabbits with Curosurf 80 mg/kg + 2% PxB significantly decreased incidence of pneumothorax in comparison with controls but had no significant effect on lung-thorax compliance or alveolar expansion. CONCLUSION: Addition of 2% PxB improves surface activity of Curosurf at low concentration, increases its resistance to inactivation by albumin, and reduces the incidence of pneumothorax in immature newborn rabbits undergoing prolonged ventilation.     

Randomized trial comparing natural and synthetic surfactant: increased infection rate after natural surfactant?

The efficacy of a natural porcine surfactant and a synthetic surfactant were compared in a randomized trial. In three neonatal intensive care units, 228 neonates with respiratory distress and a ratio of arterial to alveolar partial pressure of oxygen <0.22 were randomly assigned to receive either Curosurf 100mgkg⁻¹ or Exosurf Neonatal 5 ml kg⁻¹. After Curosurf, the fraction of inspired oxygen was lower from 15min (0.45 ± 0.22 vs 0.70 ± 0.22, p = 0.0001) to 6 h (0.48 ± 0.26 vs 0.64 ± 0.23, p = 0.0001) and the mean airway pressure was lower at 1 h (8.3 3.2 mmH₂O vs 9.4 ± 3.1 mmH₂O β= 0.01). Thereafter the respiratory parameters were similar. The duration of mechanical ventilation (median 6 vs 5 d) and the duration of oxygen supplementation (median 5 vs 4 d) were similar for Curosurf and Exosurf After Curosurf, C-reactive protein value over 40 mg r¹ occurred in 45% (vs 12%; RR 3.62, 95%CI 2.12-6.17, p = 0.001), leukopenia in 52% (vs 28%; RR 1.85, 95%CI 1.31-2.61, β= 0.001) and bacteraemia in 11% (vs 4%; RR3.17, 95%CI 1.05-9.52, p < 0.05).
We conclude that when given as rescue therapy Curosurf had no advantage compared with Exosurf in addition to the more effective initial response. Curosurf may increase the risk of infection.     

Safety and efficacy of intratracheal recombinant human Clara cell protein in a newborn piglet model of acute lung injury

Despite the widespread use of exogenous surfactant, acute and chronic lung injury continues to be a major cause of morbidity in preterm infants. CC10 is a protein produced by Clara cells that inhibits phospholipase A2 and has anti-inflammatory and antifibrotic properties. We studied whether intratracheal (IT) recombinant human Clara cell protein (rhCC10) could safely minimize lung injury in a newborn piglet model of acute lung injury. Twenty-nine newborn piglets were given Survanta and then ventilated for 48 h receiving the following: room air (group 1); 100% O2 (group 2); or 100% O2 and 25, 5, or 1 mg/kg (groups 3, 4, and 5, respectively) of IT rhCC10 (diluted to 2 mL/kg with saline) at time 0. Laboratory studies, oxygen ratios, static pressure-volume curves, bronchoalveolar lavage (for inflammatory markers), and histologic analyses were performed over the 48-h study period. Pulmonary compliance and oxygenation were significantly improved in animals receiving 5 mg/kg IT rhCC10 compared with room air and 100% O2 controls (p < 0.004 and p < 0.05, respectively, ANOVA). Reductions in inflammatory markers were seen in animals receiving rhCC10, although changes did not reach statistical significance. No significant toxicity was noted. rhCC10 appeared safe and improved pulmonary function in this newborn piglet model of hyperoxic lung injury. We speculate that rhCC10 may represent a promising therapy for the prevention of lung injury in preterm infants.     

Circulatory Effects of Denopamine in Newborn Piglets

Denopamine is an orally active β₁ agonist whose cardiovascular action in the newborn is unknown. We evaluated its circulatory effects during normoxia in newborn piglets less than 7 days of age. The piglets were acutely instrumented under general anesthesia with an electromagnetic flow probe around the main pulmonary artery and catheters in the main pulmonary artery, aorta, left ventricle, and the right and left atria. A Millar high-fidelity catheter was used to measure left ventricular dp/dt. The ductus arteriosus was ligated. Denopamine was administered in the right atrium as a continuous infusion of 2, 4, and 8μg/kg per min for 10 min each. Although cardiac index, heart rate and left ventricular dp/dt increased dose-dependently by 46.0 ± 18.2%, 87.1 ± 34.9% and 159.9 ± 42.4%, respectively, stroke index was not significantly altered. Unlike pulmonary artery pressure (which increased dose-dependently), aortic pressure increased with 2 and 4μg/kg per min denopamine, respectively, it fell with 8μg/kg per min denopamine. Similarly, the systemic vascular resistance decreased with the high dose (8 μg/kg per min). There was no significant change in pulmonary vascular resistance. Denopamine is potently inotropic in the adult. However, its circulatory effect in the neonate is dependent on its chronotropic action. Furthermore, denopamine is a systemic vasodilator at high doses in the neonatal circulation.     

Influence of early postnatal dexamethasone therapy on ventilator dependency in surfactant-substituted preterm infants

We examined 26 preterm infants with respiratory distress syndrome in a randomized controlled prospective study to determine whether early postnatal dexamethasone therapy (<2h; 0.5 mg/kg per day) over 5 days in addition to substitution of surfactant (100 mg/kg) facilitates extubation and the course of RDS. Control ( n = 12) and treated ( n = 14) groups were comparable in birthweight (mean ± SD: 1219 ± 292 versus 1446 ± 442g), gestational age (29.3 ± 2.2 versus 30.6 ± 2.7 weeks), prenatal characteristics and initial respiratory and blood gas parameters. In both groups one infant died. Infants in the dexamethasone group responded better to surfactant (12/14 versus 3/12; p < 0.01), were extubated earlier (6.6 versus 14.2 days; p < 0.02) and required less time on supplemental oxygen (4.2 versus 12.5 days; p < 0.02). Pulmonary complications tended to be lower in the dexamethasone group (1/14 versus 4/12), as was the frequency of retinopathy (2/14 versus 6/12; p < 0.05). We conclude that early postnatal dexamethasone therapy improves response to surfactant therapy resulting in better weaning and earlier extubation in premature infants.     

Effects of postresuscitation N-acetylcysteine on cerebral free radical production and perfusion during reoxygenation of hypoxic newborn piglets

Hydrogen peroxide (H2O2) and nitric oxide (NO) contribute to the pathogenesis of cerebral hypoxic-ischemic injury. We evaluated the neuroprotective effect of N-acetyl-l-cysteine (NAC, a free radical scavenger) against oxidative stress and perfusion in a model of neonatal hypoxia-reoxygenation (H-R). Piglets (1-3 d, 1.6-2.3 kg) were randomized into a sham-operated group (without H-R) (n = 5) and two H-R experimental groups (2 h normocapnic alveolar hypoxia followed by 4 h reoxygenation) (n = 7/group). Five minutes after reoxygenation, piglets were given either i.v. saline (H-R controls) or NAC (30 mg/kg bolus then 20 mg/kg/h infusion) in a blinded-randomized fashion. Heart rate, mean arterial pressure, carotid arterial blood flow (transit-time ultrasonic probe), cerebral cortical H2O2 and NO production (electrochemical sensor), cerebral tissue glutathione and nitrotyrosine levels (enzyme-linked immunosorbent assay) were examined. Hypoxic piglets were acidotic (pH 6.88-6.90), which recovered similarly in the H-R groups (p > 0.05 versus shams). Postresuscitation NAC treatment significantly attenuated the increase in cortical H2O2, but not NO, concentration during reoxygenation, with lower cerebral oxidized glutathione levels. NAC-treated piglets had significantly higher carotid oxygen delivery and lower cerebral lactate levels than that of H-R controls with corresponding changes in carotid arterial flow and vascular resistance. In newborn piglets with H-R, postresuscitation administration of NAC reduced cerebral oxidative stress and improved cerebral perfusion.     

Effect of therapeutic dose of indomethacin on the cerebral circulation of newborn pigs

The effects of treatment with 0.2 mg/kg of indomethacin on the cerebral blood flow and cerebral oxygen consumption of hypotensive, unanesthetized, newborn pigs were investigated. Hypotension was induced by hemorrhage (30 ml/kg) which reduced mean arterial pressure from 60 to 34 mm Hg. The decline in cerebral vascular resistance that occurred with hemorrhage allowed blood flow to all brain regions and cerebral oxygen consumption to continue unchanged. Treatment with 0.2 mg of indomethacin decreased plasma 6-keto-prostaglandin F1 alpha markedly and caused a modest increase in cerebral vascular resistance from 0.75 +/- 0.07 to 0.85 +/- 0.02 mm Hg X 100 g X min/ml at 40 min posttreatment. As a result, blood flow throughout the brain fell about 20%. Similarly, cerebral oxygen consumption declined from 2.88 +/- 0.13 to 2.03 +/- 0.21 ml O2/100 g X min following treatment of hypotensive piglets with 0.2 mg/kg of indomethacin. However, all piglets were conscious 40 min after treatment. We conclude that, although 0.2 mg/kg of indomethacin affects cerebral hemodynamics of hypotensive piglets, the effects are very modest in comparison to large increases in cerebral vascular resistance, decreases in cerebral blood flow and oxygen consumption, and coma that follow treatment of hypotensive piglets with 5 mg/kg of indomethacin.     

High-dose versus low-dose bovine surfactant treatment in very premature infants

The aim of the study was to determine if high-dose bovine surfactant (Alveofact, initially 100 mg/kg birth weight) would improve oxygenation compared with low-dose surfactant (50 mg/kg birth weight) administered intratracheally within 1 h after birth. Inclusion criteria included gestational age 24–29 weeks and birth weight 500–1500 g, intubation and mechanical ventilation, absence of congenital malformations and bacterial infections. Retreatment was considered if the fraction of inspired oxygen (FiO₂) was > 0.4 (dose 50 mg/kg birth weight). The primary endpoint was level of oxygenation (PaO₂/ FiO₂) 2 h after treatment. The study design was a sequential analysis using a triangular test with alpha = 0.05 and 95% power to detect a 25 % improvement in the endpoint. Oxygenation was improved significantly with high-dose ( n = 42) compared to low-dose treatment ( n =48): 30.9±15.0 kPa (231.5±112.7 mmHg) versus 24.1±15.7 kPa (180.6±118.0 mmHg) (mean ± SD). The survival rate was 83% in both groups and the incidence of pulmonary interstitial emphysema was 33% versus 14% with the high-dose treatment. We conclude that high-dose surfactant significantly improved oxygenation and reduced lung barotrauma. An initial dose greater than 50 mg/kg birth weight of surfactant is required for optimal acute response.     

Treatment of severe hyaline membrane disease with surfactant (Curosurf). A collaborative clinical study

We investigated the clinical efficacy of a new surfactant product, Curosurf, isolated from porcine lungs by liquid-gel chromatography. Ten premature newborn infants (birth weight 850-1850 g), all ventilated artificially for severe hyaline membrane disease categorized radiologically as stage III-IV, received a single dose of Curosurf (200 mg/kg) via the tracheal tube. This treatment resulted in a rapid improvement of oxygenation, similar to that observed by other teams collaborating in the study and, in an astonishingly fast resolution of the radiological changes. In comparison with a control group of 8 infants, the surfactant-treated babies also had a lower incidence of acute and chronic complications.     

Properties of modified natural surfactant after exposure to fibrinogen in vitro and in an animal model of respiratory distress syndrome

Background:Plasma proteins are known to interfere with pulmonary surfactant. Studies have proven the hypothesis that fibrinogen preserves exogenous surfactant subjected to long-term surface area cycling.Methods:The exogenous surfactant Curosurf was subjected to long-term surface area cycling without or with fibrinogen (ratio 2:1 w/w) and was tested by captive bubble surfactometer and on newborn premature rabbits.Results:Surface tension increased in Curosurf (80?mg/ml) samples without fibrinogen after 6-12?d of cycling. In samples with fibrinogen the cycling time had no effect on surface tension. Addition of fibrinogen to surfactant prevented lipid peroxidation. Lung gas volumes of animals with noncycled Curosurf or Curosurf cycled with fibrinogen for 6?d were comparable and higher than in rabbits with Curosurf cycled without fibrinogen. Alveolar volume density was higher in groups with noncycled Curosurf or Curosurf cycled with fibrinogen than in Curosurf cycled without fibrinogen (both P < 0.001).Conclusion:The effect of fibrinogen on pulmonary surfactant cycled at 37?°C depends both on surfactant concentration and cycling time. At high phospholipid concentration used in clinical practice fibrinogen has a protective effect on biophysical and physiological properties of natural modified surfactant subjected to surface area cycling. This effect is partially mediated by reduction in lipid peroxidation.     

Lavage administration of dilute recombinant surfactant in acute lung injury in piglets

In an acute lung injury model, we previously observed reversal of pulmonary dysfunction with natural surfactant administered by lavage (dose = 18 mg/kg phospholipid). The present study questioned whether a lower dose of phospholipid would be effective if a recombinant preparation rather than natural surfactant were used. Acute lung injury was induced by repeated saline lung lavage in ventilated, sedated, and paralyzed piglets. Three concentrations of recombinant surfactant were studied (low phospholipid, 1 mg/mL; medium phospholipid, 4 mg/mL; high phospholipid, 13.5 mg/mL). Control piglets received no surfactant. Thirty-five milliliters per kilogram of surfactant was administered by gravity, followed by passive drainage of excess fluid. All treatment groups retained similar volumes (4.7+/-0.3 mL/ kg), corresponding to phospholipid doses of 4+/-0.4, 22+/-3, and 67+/-4 mg/kg in low, medium, and high-dose groups, respectively. Treatment groups showed significant improvement in Pao2 compared with controls. Other parameters different from controls were found in only the medium and high-dose groups. All surfactant-treated groups showed improvement over time in Pao2, Paco2, lung resistance mean airway pressure, functional residual capacity, and dynamic compliance. These data support the statement that whereas there is a dose response to exogenous surfactant, the effective dose of recombinant surfactant in acute lung injury may be as low as 4 mg/kg phospholipid when administered by lavage.     

Nebulization of sodium nitroprusside in lung-lavaged newborn piglets

The aim of the present study was to test the hypothesis that nebulization of the nitric oxide donor sodium nitroprusside may selectively reduce pulmonary vascular resistance and improve oxygenation in lung-lavaged newborn piglets. Thirteen anesthetized piglets (1-3 d old) were subjected to repeated lung lavages and then randomly assigned to one of the following two groups: 1) an SNP group, which received SNP nebulization, and 2) a saline group, which received saline nebulization. Pulmonary arterial pressure and pulmonary vascular resistance increased significantly after lung lavage, whereas cardiac output decreased significantly in both groups. After SNP nebulization, pulmonary arterial pressure decreased from 32+/-1 to 17+/-1 mm Hg (p < 0.01) and PVR decreased from 255+/-20 to 172+/-15 mm Hg L(-1) min(-1) kg(-1) (p < 0.01). The arterial tension of oxygen concomitantly increased from 9.4+/-4.0 to 17.0+/-3.0 kPa (p < 0.01), and the arterial/alveolar ratio of oxygen tension increased from 0.11+/-0.01 to 0.22+/-0.03 (p < 0.01). Systemic hemodynamics were not modified significantly during nebulization of SNP. On the other hand, all variables were stable during nebulization of saline. These data suggest that SNP nebulization produces a selective pulmonary vasodilatation and improves oxygenation in lung-lavaged newborn piglets.