A Okken

Distribution of exogenous surfactant in rabbits with severe respiratory failure : the effect of volume

ABSTRACT: The transient effect of surfactant therapy that is observed in some patients might, at least in part, be explained by a nonhomogeneous distribution. Therefore, we investigated the distribution of a surfactant preparation (Alvofact, 45 g/L) that is used clinically. Rabbits with severe respiratory failure were treated with this surfactant at a dose of 100 mg/kg body weight, and the distribution of surfactant was determined by the use of 141Ce-labeled microspheres that were mixed with the surfactant. Fifteen min after surfactant administration, the rabbits were killed, and the lungs were removed and divided into 200 pieces. The radioactivity per mg lung tissue was determined in each piece. We found that the endotracheal instillation of this surfactant preparation results in a nonhomogeneous distribution. However, a significantly improved distribution was obtained when this dose of surfactant (100 mg/kg body weight) was diluted with normal saline to a concentration of 6.25 g/L. The consequence of the administration of this dose was an intratracheal fluid administration of 16.0 mL/kg body weight. The distribution was also nonhomogeneous after the administration of a small-volume (2.4 mL/kg body weight), low-concentration surfactant preparation (6.25 g/L). We conclude that a surfactant preparation with clinical application is distributed nonhomogeneously in the lungs after endotracheal administration. The distribution can be significantly improved by increasing the fluid volume in which the surfactant is suspended.

Long-chain polyunsaturated fatty acid status and early growth of low birth weight infants

Abstract We correlated arachidonic acid (AA) and docosahexaenoic acid (DHA) status with anthropometric measures and growth rates in a group of low birth weight infants (≤2500 g; gestational ages 30–41 weeks; n = 143). AA and DHA status were measured in erythrocytes (RBC) and plasma cholesterol esters (CE) during days 10 to 42. Infants received preterm formula without long-chain polyunsaturated fatty acids (LCP; n = 81), with LCP (n = 29) or maternal milk (n = 33). RBC AA contents on day 10 were correlated (P < 0.05) with birth weight in breast-fed infants and all formula-fed infants, with on day 10 a standard deviation score (SDS) for weight, length and occipito-frontal circumference in all formula-fed infants, and with on day 10 an SDS for length in breast-fed infants. Brain weight was related to RBC DHA and CE DHA contents on both day 10 and day 42 in formula-fed infants. Of the variances of brain growth parameters on day 42, 21–34% were explained by DHA status on day 42 and protein intake from days 10–42. Conclusion We conclude that parameters of early neonatal AA status are related to intra-uterine rather than to post-natal growth. Parameters of post-natal brain growth are related to RBC DHA and CE DHA contents on day 42, and to dietary protein intake. These results point to the importance of dietary DHA for brain growth in the first 6 post-natal weeks.

ACTIVATION OF THE PLASMA CLOTTING, FIBRINOLYTIC, AND KININ-KALLIKREIN SYSTEM IN PRETERM INFANTS WITH SEVERE IDIOPATHIC RESPIRATORY DISTRESS SYNDROME

ABSTRACT: We studied the activation pattern of clotting, fibrinolysis, and kinin-kallikrein during the first 5 d of life in 10 preterm infants with signs of severe idiopathic respiratory distress syndrome (IRDS) after birth (IRDS group) and in 12 healthy preterm infants (reference group). We found systemic activation of clotting, fibrinolysis, and kinin-kallikrein in the IRDS infants within 12 to 24 h of birth, represented by increased median thrombin-antithrombin III complex formation (90 ng/mL versus 10 ng/mL in the reference group, p < 0.05), increased mean tissue-type plasminogen activator plasma concentrations (11.8 ng/mL versus 3.5 ng/mL in the reference group, p < 0.05), and increased mean plasma kallikrein activity (182.6% versus 162.0% of maximal activated human plasma in the reference group, p < 0.05), respectively. Clotting activation was accompanied by a significant decrease of the platelet count. Clotting and fibrinolytic activity decreased in the IRDS group during the first 2 to 3 d of life. Kinin-kallikrein activation was accompanied by decreased plasma kallikrein inhibitor activity values and did not change throughout the study period. Plasma factor XII activity was not significantly increased in the IRDS infants during the first 2 d of life but did significantly increase thereafter. The cause of simultaneous activation of clotting, fibrinolysis, and kinin-kallikrein in our IRDS infants has not yet been clarified. However, this activation process may contribute to lung injury such as that described in the adult respiratory distress syndrome.

A 2-year follow up of babies enrolled in a European multicentre trial of porcine surfactant replacement for severe neonatal respiratory distress syndrome

The postnatal growth, respiratory status and neurodevelopmental outcome of surviving babies enrolled in the first European multicentre trial of porcine surfactant (Curosurf) replacement for severe neonatal respiratory distress syndrome, were assessed at corrected ages of 1 and 2 years. Follow up rates of survivors were 93% at 1 year and 89% at 2 years. Treated and control groups were similar at both 1 and 2 years in terms of physical growth, the prevalence of persistent respiratory symptoms and the occurrence of major and minor disability. Serum antibodies recognising Curosurf and surfactant-anti-surfactant immune complexes were detected in both treated and control babies, the titres showing no difference between groups. Examination of histological lung sections from non-survivors revealed a higher incidence of severe pulmonary interstitial emphysema in control babies than in those treated with surfactant. Surfactant treatment for severe respiratory distress syndrome reduces neonatal mortality and air leaks and is not associated with an increase in disability 2 years later.

Disease severity is correlated with plasma clotting and fibrinolytic and kinin-kallikrein activity in neonatal respiratory distress syndrome

This study was undertaken to determine whether simultaneous activation of clotting, fibrinolysis, and kinin-kallikrein is associated with disease severity in preterm infants with neonatal respiratory distress syndrome (RDS), during the first 5 d of life. In the infants with severe RDS, we found activation of clotting, fibrinolysis, and kinin-kallikrein within 6-12 h of birth, indicated by increased thrombin-antithrombin III complex formation[22.5 ng/ml versus 1.4 ng/ml (median values) in the mild/moderate RDS infants, p < 0.001], increased tissue-type plasminogen activator plasma concentrations [5.1 ng/ml versus 2.6 ng/ml (median values) in the mild/moderate RDS infants, p < 0.01], and increased plasma kallikrein activity [198% versus 189% of maximal activated human plasma (median values) in the mild/moderate infants,p < 0.01], respectively. Thrombin generation, tissue-type plasminogen activator release, and kallikrein activity did not change significantly in the severe RDS group throughout the study. In these infants, kallikrein activity was accompanied by lower values of plasma kallikrein inhibitory activity. Activation of clotting, fibrinolysis, and kinin-kallikrein was accompanied with a transient decrease of the neutrophil count and a steady decrease of the platelet count in the severe RDS group. The studied parameters of clotting and fibrinolytic and kinin-kallikrein activation were significantly correlated with continuous measures of RDS severity. We, therefore, suggest that this activation process likely contributes to respiratory insufficiency in neonatal RDS.

Activation of Circulating Polymorphonuclear Leukocytes in Preterm Infants with Severe Idiopathic Respiratory Distress Syndrome

We have studied activation of circulating polymorphonuclear leukocytes(PMN) in plasma of preterm infants with severe idiopathic respiratory distress syndrome (IRDS group, n = 15) and without IRDS (reference group,n = 15) during the first 5 postnatal days. We have observed lower median PMN counts in the IRDS group than in the reference group from d 2 (1.4× 109/L versus 4.8 × 109/L in the reference group, p < 0.001) to d 4 to 6 (1.6 × 109/Lversus 4.0 × 109/L, p < 0.01). Lower PMN counts in the IRDS infants were accompanied by lower median plasma elastase-α1-proteinase inhibitor (PI) concentrations (53.6 ng/mLversus 128.0 ng/mL in the reference group on d 2, p < 0.05). Simultaneously, median elastase-α1-PI/PMN ratios of these infants were significantly higher (40.8 ng/106 PMN versus 21.8 ng/106 PMN on d 2, p < 0.05), indicating activation of circulating PMN. Activation of circulating PMN in the IRDS group is associated with platelet-activating factor (PAF) release and complement activation from within 6 to 12 h of birth but not with release of tumor necrosis factor-α. PAF release was represented by significantly reduced inhibiting capacity (58% of normal human plasma, p < 0.01) and complement activation by higher median plasma C3a des-Arg concentrations (1680 ng/mL versus 325 ng/mL in the reference group, p < 0.001). We conclude that circulating PMN are activated in preterm infants with severe IRDS, which might be caused by systemic PAF release and complement activation. This activation process may play a role in the pathogenesis of the IRDS by influx of activated PMN into the lungs.

Factors influencing morbidity and mortality in infants with severe respiratory distress syndrome treated with single or multiple doses of a natural porcine surfactant.

In an international multicenter trial infants with clinical and radiological signs of severe RDS (age 2-15 h, birthweight 700-2,000 g, mechanical ventilation, FiO2 greater than or equal to 0.6, no complicating disease) were randomized to receive either a single dose (n = 176) or up to three subsequent doses (n = 167) of a natural porcine surfactant (Curosurf). Using a logistic regression model, the effects of therapy, birthweight, sex, hospital and other clinical factors on survival and various outcome parameters were evaluated. Mortality (13 vs. 21%, p less than 0.05) and the incidence of pneumothorax (9 vs. 18%, p less than 0.01) were significantly lower in the multiple-dose group. Low birthweight, hospital allocation, low Apgar score and initial disease severity were associated with an increased mortality. Low birthweight, hypothermia (admission temperature less than 36 degrees C) and acidosis (pH less than 7.25) prior to surfactant treatment could be identified as risk factors for the development of intracranial hemorrhage.

Leakage of protein into lungs of preterm ventilated rabbits is correlated with activation of clotting, complement, and polymorphonuclear leukocytes in plasma

We investigated whether leakage of protein in lungs of preterm ventilated rabbits of 28- and 29-d gestational age is correlated with activation of clotting, complement, and polymorphonuclear leukocytes (PMN) in plasma. We found signs of systemic activation of clotting, complement, and PMN in ventilated 28-d gestational age rabbits, as indicated, respectively, by increased median plasma fibrin monomer concentrations (83 versus 40% of normal adult rabbit plasma in nonventilated 28-d gestational age rabbits,p < 0.01), decreased median plasma CH50 activity (112versus 122 U/L in nonventilated 28-d gestational age rabbits,p < 0.05), and increased median plasma β-glucuronidase concentrations (159 versus 97% of maximal activated adult rabbit plasma in nonventilated 28-d gestational age rabbits, p < 0.05). We did not find signs of systemic activation in the ventilated 29-d gestational age group. Higher median total protein concentrations in alveolar wash of the ventilated 28-d gestational age rabbits (2.7 versus 1.3 mg/mL in the nonventilated rabbits, p < 0.01) indicated protein leakage into the lungs, and this protein leakage was more pronounced in the lungs of ventilated 28-d gestational age rabbits than in those of ventilated 29-d gestational age rabbits (2.1 mg/mL, p < 0.01). The total protein concentration in the alveolar wash of all 28-d gestational age rabbits was correlated with the concentration of fibrin monomers (ρ = 0.51,p = 0.035) and β-glucuronidase (ρ = 0.61, p = 0.011), and the CH50 activity (ρ = -0.73, p = 0.002) in plasma. We conclude that leakage of protein in lungs of preterm ventilated rabbits of 28-d gestational age is correlated with activation of clotting, complement, and PMN in plasma. This activation process may contribute to lung injury by intravascular and intraalveolar deposition of fibrin and formation of proteinaceous edema.

Fat absorption in premature infants: The effect of lard and antibiotics

Fat absorption of an adapted cows milk formula was studied in a randomized controlled trial involving two groups of 18 premature infants (mean gestational age±SD: 33.0±2.9 weeks, range 26.5–37.5 weeks). The triglyceride configuration was modified by the use of lard. This modification did not improve the absorption of fat or energy. Also no difference in serum concentrations of cholesterol and tridifference was found. Growth velocity during the study was similar in both groups. Detailed analysis of the data revealed that in infants who received (parenterally) antibiotics (mainly ampicillin and netilmicin) a higher coefficient of fat absorption (+20%,P<0.01) and of energy absorption (+8%,P=0.03) was found. Based on these results, we find no support for the use of lard in adapted cows milk infant formulas to improve fat absorption. In studies of fat and energy absorption the effects of antibiotics have to be taken into account.

Surfactant replacement therapy in surfactant-deficient rabbits: Early effects on lung function and biochemical aspects

Lung-surfactant-deficient rabbits (n = 6) requiring artificial ventilation were subjected to a weaning-off regimen following surfactant replacement therapy. Surfactant-deficient rabbits (n = 6) that did not receive surfactant but underwent the same procedure served as controls. All surfactant-treated rabbits survived (i.e., reestablished spontaneous air breathing) whereas all the control animals died. In the surfactant-treated animals lung function improved in such a way that during the weaning period PaCO2 did not increase and the level of PaO2 remained significantly higher than in the control animals. The static lung compliance and the stability and expansion indices in vitro were significantly higher in the surfactant-treated rabbits. The lamellar body fraction of the lungs of surfactant-treated animals contained a significantly higher amount of surfactant phospholipids than those of the control animals.It is concluded that the animal model used in this study is an excellent tool for testing early effects of different surfactant preparations.