Mathias H. Wagner

Multisystem Organ Failure and Capillary Leak Syndrome in Severe Necrotizing Enterocolitis of Very Low Birth Weight Infants

BACKGROUNDnClassification systems for necrotizing enterocolitis (NEC) in preterm infants have been developed to define severity grades relevant for treatment and prognosis. Multisystem organ failure (MSOF) and capillary leak syndrome (CLS) also have prognostic value in these patients. The aim of this retrospective study was to investigate the incidence and predictive value of MSOF and CLS according to the classification criteria.nnnMETHODSnThe records of 1,022 very low birth weight infants admitted from 1982 to 1996 were reviewed for diagnosis of NEC stage IIA or higher (classification of Walsh and Kliegman). Among those patients (n = 50) the incidence of MSOF and CLS was determined, separately for surgical or conservative treatment.nnnRESULTSnTwelve patients were assigned to stage II, 22 to stage IIIa, and 16 to stage IIIb; 31 infants underwent operation. Mortality rate was not influenced by the grade. In eight patients only gastrointestinal symptoms were found, whereas in 23 patients, up to three organ systems and in 19 patients, four or more organ systems were affected. Mortality depended on the number of involved organ systems. CLS occurred postoperatively in 10 of the 31 infants; eight of them died.nnnCONCLUSIONnThe prognostic values of MSOF and CLS are higher than that of classification criteria in NEC of VLBW infants.

Rapid Tracheal Infusion of Surfactant versus Bolus Instillation in Rabbits: Effects on Oxygenation, Blood Pressure and Surfactant Distribution

UNLABELLEDnSurfactant bolus instillation may be associated with a drop in blood pressure. Platelet-activating factor (PAF) has been found in surfactant preparations. The aim of this study was to evaluate rapid tracheal infusion of surfactant during 5 min as an alternative to bolus instillation and to examine whether a PAF receptor antagonist is able to prevent the decrease in blood pressure.nnnMETHODSnSurfactant deficiency was induced in 16 adult rabbits by lung lavages with saline. Six animals received a bolus of a porcine surfactant preparation (Curosurf (CS); 200 mg/kg), labeled with red microspheres to assess pulmonary distribution. In another 5 rabbits, the same amount of labelled CS was instilled by tracheal infusion within 5 min. A third group of 5 animals received 3 mg/kg body weight of the PAF antagonist WEB 2170 before CS bolus instillation.nnnRESULTSnAfter CS bolus administration, mean PaO2 increased by 44.7 +/- 8.3 kPa (mean +/- SD) within 2 min and remained at this level. Mean arterial blood pressure dropped transiently by 2.3 +/- 2 kPa within 5 min. Pulmonary distribution of surfactant was even. After infusion, mean PaO2 rose by 22.4 +/- 16.3 kPa within 15 min. Blood pressure dropped by 1.8 +/- 1.1 kPa within 15 min. The distribution was extremely uneven. Blood pressure decreases also occurred after pretreatment with PAF receptor antagonist.nnnCONCLUSIONnRapid tracheal infusion of surfactant results in poorer oxygenation, an inhomogeneous distribution and a similar decrease in blood pressure compared to the bolus instillation method. Blood pressure changes could not be prevented by a PAF receptor-specific antagonist.

Nutrition of Very low birth weight infants fed human milk with or without supplemental trace elements: A randomized controlled trial

Background: Very low birth weight infants (<1500 g) have high nutritional needs. Deficiencies of minerals, trace elements (especially zinc) may develop as a result of rapid growth, low body stores and low content of these substances in human milk We hypothesized that fortification of human milk might prevent deficiencies. Methods: Prospective, randomized trial to evaluate mineral, trace element, thyroid status and growth of infants fed human milk fortified with different amounts of calcium, phosphorus and protein, with (BMF) or without (FM 85) trace elements. Sixty-two infants, 1000 to 1499 g birth weight, were randomized. Minerals and trace elements in serum, red blood cells and human milk and alkaline phosphatase activity, TSH, T4 and FT4 in serum were measured once until the fifth day and at 3 and 6 weeks of life. Clinical course and anthropometric measurements were recorded. Results: Intake of zinc, copper, manganese, calcium, phosphorus and magnesium was higher in the BMF group (P < 0.001). Serum zinc concentrations <0.49 mg/L occurred in 12% of the FM 85 group and 7% of the BMF group at 6 weeks (not significant). Median alkaline phosphatase activity was 436/379 IU/L in the FM 85/BMF group at 6 weeks (P < 0.01). The FM 85 group showed a higher weight gain (P < 0.05), possibly because of higher caloric (P < 0.01) and protein intake (P < 0.05) at 3 weeks. Conclusions: Zinc deficiency was rare. Elevated intake of calcium, phosphorus and zinc was associated with lower serum alkaline phosphatase activity but did not influence serum zinc concentration.

Complement and contact activation in term neonates after fetal acidosis

AIMS To evaluate complement and contact activation after fetal acidosis. METHODS Fifteen term neonates with hypoxic–ischaemic encephalopathy after umbilical arterial pH < 7.10 were compared with 15 healthy neonates with umbilical arterial pH > 7.20. Determinations of the complement function and C1-inhibitor activity were performed as kinetic tests 22–28 hours after birth. C1q, C1-inhibitor, and factor B concentrations were determined by radial immunodiffusion and those of C3a, C5a, and factor XIIa by enzyme immunoabsorbent assay. RESULTS Median complement function (46vs 73 %), C1q (4.3 vs 9.1 mg/dl), and factor B (5.2 vs 7.7 mg/dl) decreased after fetal acidosis. The activated split products C3a (260 vs 185 μg/l), C5a (5.0vs 0.6 μg/l), and factor XIIa (3.2 vs 1.3 μg/l) increased in the neonates after fetal acidosis. No differences were found in the concentration and activity of C1-inhibitor. CONCLUSIONS Complement and contact activation occurred in the newborns with hypoxic–ischaemic encephalopathy. Activation of these systems generates mediators which can trigger inflammation and tissue injury.

Complement and Contact Activation Related to Surfactant Response in Respiratory Distress Syndrome

The activation of inflammation and coagulation cascades is part of the pathogenesis of adult respiratory distress syndrome (RDS). Previous studies have demonstrated contact activation in preterm infants with RDS, whereas no concordant results have been found with complement activation. In this study, both systems were investigated in preterm infants with severe RDS and related to surfactant response. Thirty preterm newborns with severe respiratory distress (FiO2 > 0.5), but with no evidence of infection or fetal acidosis, were studied. Eighteen healthy preterm newborns of similar gestational age and birth weight served as controls. The study group was divided into two subgroups, according to their response to a porcine natural surfactant 6 h after administration: responders (FiO2 reduction > 50%) and poor responders (FiO2 reduction ≤ 50%). C1q, C4, factor B, C3a, C5a, complement, and C1-inhibitor activity, as well as factor XIIa, were determined in blood samples, drawn 24 h after birth. Except for C1-inhibitor concentration and C1-inhibitor activity, all parameters for infants with severe RDS were different from controls. Complement precursor proteins were lower, and activated split products of the complement and contact system were higher. Infants with a poor response after application of surfactant showed higher amounts of C3a, C5a, and factor XIIa but lower C1q and C4 levels compared with infants with a good response to surfactant. Activation of the complement and the contact system was demonstrated in all respiratory distress patients. This activation was more pronounced in poor responders to exogenous surfactant.

Endotracheal surfactant atomization: an alternative to bolus instillation?

Objective To investigate the effect of an intratracheal surfactant fog on oxygenation, blood pressure, distribution, and recovery rate as a pilot study to intratracheal surfactant aerosol. Design Prospective, randomized study. Setting University laboratory. Subjects A total of 15 New Zealand White rabbits. Interventions The anesthetized ventilated rabbits were surfactant-deprived by repeated lung lavages and then received 200 mg/kg of a 99mTc-labeled porcine surfactant (Curosurf) either as bolus or as intratracheal surfactant fog. Measurements and Main Results Blood gases and pressure were measured and distribution as well as recovery rate of the surfactant determined by means of the radio label (gamma camera images and lung processing with subsequent gamma counter measurements). Respiratory function normalized immediately, no difference could be found between the two groups with regard to Pao2, Paco2, and blood pressure. Even distribution of the radiolabel was found with both methods, the bolus group showing a higher percentage of lung pieces with label concentrations of double average or more. Recovery rates were 82.5% ± 13.1% (mean ± sd) in the bolus group and 86.5% ± 7.7% in the fog group. Conclusion Endotracheal surfactant fog application is as effective as bolus instillation and may have a role in the treatment of adult respiratory distress syndrome. It has to be considered as a first step in producing an effective aerosol.

Circulatory changes after surfactant bolus instillation in lung-lavaged adult rabbits.

Following surfactant instillation in infants treated for respiratory distress syndrome, a mean arterial blood pressure (MABP) decrease is often observed. Its etiology and pathogenesis are still unknown. In this study various circulatory parameters were recorded continuously after surfactant instillation to elucidate the role of pulmonary vascular resistance as one possible cause for the MABP drop. Seven anesthetized adult New Zealand white rabbits were artificially ventilated after tracheotomy. Arterial and right atrial pressure were recorded continuously. Pulmonary artery pressure and cardiac output were determined by means of a thermodilution catheter. After inducing surfactant deficiency by repeated saline lavages, 200 mg/kg body weight of a natural surfactant preparation was administered by tracheal bolus instillation. PaO2 increased rapidly from 8.0 +/- 1.3 kPa to 51.2 +/- 8.8 kPa (mean +/- standard deviation) within 2 min (p < .05). MABP dropped from 12.1 +/- 1.9 kPa to 8.9 +/- 2.3 kPa within 2 min (p < .05). Pulmonary artery pressure, cardiac output, and right atrial pressure did not change during the observation period of 60 min. The results suggest that a peripheral vasodilatation is the most likely cause for the drop in MABP.

Soluble intercellular cell adhesion molecule-1 and L-selectin plasma concentrations and response to surfactant in preterm infants.

Objective To investigate whether plasma concentrations of soluble intercellular cell adhesion molecule (ICAM)-1 and L-selectin at 24 hrs of life are related to good or poor response to exogenous surfactant in preterm infants. Design Prospective study of markers of inflammation in circulating blood at 24 hrs of life. Setting Level III neonatal intensive care unit. Patients Twenty-nine preterm newborns suffering from severe respiratory distress syndrome (Fio2 > 0.4) without signs of infection or fetal acidosis, and 17 healthy preterm newborns of similar gestational age serving as controls. Interventions Infants with respiratory distress were treated with natural surfactant at 0.3–5 hrs of life. A response to surfactant, defined as a decrease of Fio2 >50% within 6 hrs after surfactant, was seen in 21 infants. Measurements and Main Results Soluble ICAM-1 and L-selectin concentrations were determined in plasma samples taken at 24 hrs of age. ICAM-1 was elevated (p < .001) in infants who responded poorly to surfactant (median, 392 ng/mL; range, 58.26–4884.24 ng/mL) compared with good responders (20.52 ng/mL, 2.32–138.58 ng/mL) or controls (21.91 ng/mL, 2.61–65.73 ng/mL), without differences between controls and good responders. L-selectin was lower (p = .004) in surfactant-treated infants (4.45 nmol/L, 2.0–10.4 ng/mL) than in controls (6.0/2.35–10.25 nmol/L) without differences between surfactant good and poor responders. However, infants requiring supplemental oxygen at 36 wks of gestational age had reduced L-selectin at 24 hrs of age (3.2/2.0–3.45 vs. 5.0/2.35–10.4 nmol/L, p = .004), whereas there was no difference in ICAM-1. Conclusions In preterm infants with respiratory distress, a poor response to surfactant within 6 hrs of administration is associated with elevated circulating ICAM-1 concentrations at 24 hrs of age. Low plasma L-selectin at 24 hrs of age predicts prolonged requirement for supplemental oxygen.

Effect of C1-Inhibitor in a Rat Model of Necrotizing Enterocolitis

Our aim was to investigate the effect of C1-inhibitor (C1-INH) in a rat model of necrotizing enterocolitis (NEC). Twenty-four anesthetized and artificially ventilated rats received 0.1 mg/kg endotoxin. Fifteen minutes later, the animals in the study group (n = 12) were treated with 200 IU/kg C1-INH whereas the control animals (n = 12) received normal saline. In all animals, FiO2 was reduced after 90 min from 0.21 to 0.05 and ventilation continued until 180 min or death. All animals developed shock symptoms. Drop in mean arterial blood pressure was more pronounced and survival time was shorter in the control group. Whereas the C1-INH activity increased in the study group, it decreased in the control group. The extent of macroscopic intestinal lesions did not differ between the groups. In conclusion, C1-INH did not prevent shock, but mitigated and delayed its course.

Complement Activation in Preterm Infants With Respiratory Distress Syndrome(Rds)

Aim: To specify complement activation in RDS we investigated complement factors after surfactant substitution. Subjects: 36 preterm infants with clinical and radiological signs of RDS were enrolled. 23 of them responded to surfactant (R), wereas 13 did not (NR). 18 healthy preterm infants without evidence of RDS, infection or asphyxia served as controls (H). Gestational age (mean±SD) was 28.8±3.0 weeks, birthweight 1278±447g with no differences between the groups .Measurements: Clinical data were recorded and blood samples were taken at the age of 24 hours. Results: No differences between groups H and R were found for factor B and C5a, between groups R and NR for C4, C5a and function test. All other values (mean±SD) differed (p<0.05) between the 3 groups. Table