Hugo Segerer

Mutations of Genes Involved in the Innate Immune System as Predictors of Sepsis in Very Low Birth Weight Infants

Mutations of genes involved in the innate immune system have been reported to be associated with an increased sepsis rate in adults. We determined the −159T mutation of the CD14 gene, the 896G mutation of the toll-like receptor 4 gene, the 3020insC mutation of the NOD2 gene (NOD2-3020insC), the IL-6 174G/C promoter polymorphism (IL6-174G/C), and the mannose-binding lectin genotype and their association to the subsequent development of neonatal sepsis in a large cohort of very low birth weight (VLBW) infants. Fifty (14%) of 356 VLBW infants developed blood culture–proven sepsis during their stay in the hospital. VLBW infants carrying the NOD2-3020insC allele (n =15) and the IL6-174G allele (n =121) had a significantly higher rate of blood culture–proven sepsis (33% and 19.8%, respectively) than VLBW infants without these genotypes (p = 0.046 and 0.035, respectively). In a multivariate logistic regression analysis, gestational age less than 28 wk (odds ratio, 3.2; 95% confidence interval, 1.7–6.0; p < 0.001) and the homozygous IL6-174G allele (odds ratio, 1.9; 95% confidence interval, 1.0–3.9; p = 0.039) were predictive for the development of sepsis, whereas the NOD2-3020insC allele was only of borderline significance (odds ratio, 3.2; 95% confidence interval, 1.0–10.4; p = 0.052). VLBW infants with repeated episodes of sepsis had higher frequencies of the NOD2-3020insC and IL6-174G allele. The increased sepsis rate of homozygous IL6-174G carriers was especially related to an increase in Gram-positive infections, and was not observed in VLBW infants who received prophylaxis with teicoplanin (frequency of Gram-positive sepsis in homozygous IL6-174G carriers without prophylaxis 16.5%versus 2.4% in homozygous IL6-174G carriers with prophylaxis; p = 0.033).

Pulmonary distribution and efficacy of exogenous surfactant in lung-lavaged rabbits are influenced by the instillation technique.

ABSTRACT: Surfactant bolus instillation has been reported to cause changes in arterial blood pressure (BP) and cerebral blood flow velocities which may increase the risk of intraventricular haemorrhage. To avoid these effects, slow tracheal infusion was evaluated as a possible alternative method of surfactant administration. Saline lung lavages were performed in 13 anesthetized and artificially ventilated adult rabbits to produce respiratory distress syndrome. Curosurf (CS, 200 mg/kg) labeled with 14C-dipalmitoyl-phosphatidylcholine (-DPPC) and/or red microspheres (RMS) was instilled into the trachea either as a single bolus (n = 8) or by infusion during 45 min via a side-channel within the wall of the tracheal tube (n = 5). An arterial cannula was placed for monitoring of blood gases and BP. To determine surfactant distribution, the lungs were cut into 60–70 pieces and radioactivity and/or the number of RMS were measured in each piece. The distribution of RMS was closely related to the distribution of 14C-DPPC (r = 0.96). Bolus instillation of CS led to a prompt and sustained increase in Pao2 (from < 10.5 to >40 kPa within 2 min), a transient decrease in BP, and a reasonably homogeneous pulmonary surfactant distribution. Tracheal infusion of CS changed neither BP nor Pao2 during the observation period of 60 min. The pulmonary distribution of CS was extremely uneven after infusion. The distribution of exogenous surfactant and its effects on gas exchange are influenced by the instillation method. An inadequate instillation technique may add to the causes of “poor response” after surfactant replacement.

Surfactant without intubation in preterm infants with respiratory distress: first multi-center data.

BACKGROUND Recently in a report of a single center a method has been described to apply surfactant via a thin endotracheal catheter to very low birth weight infants spontaneously breathing with nasal continuous positive airway pressure. We now analyzed available multicenter data. PATIENTS AND METHODS In a multicenter study investigating genetic risk factors, clinical and outcome data and data of antenatal and postnatal treatment of infants with a birth weight below 1,500 g were prospectively recorded. The measures of infants treated with the new method of surfactant application were compared to those of infants who received standard care. The analysis was restricted to infants with a gestational age below 31 weeks (n=1,541). RESULTS 319 infants were treated with the new method and 1,222 with standard care. The need for mechanical ventilation during the first 72 h (29% vs. 53%, p<0.001), the rate of bronchopulmonary dysplasia defined as oxygen at 36 weeks of postmenstrual age (10.9 % vs. 17.5%, p=0.004) and the rate of death or bronchopulmonary dysplasia were significantly lower in the treatment group than in the standard care group. Surfactant, theophyllin, caffeine and doxapram were significantly more often and analgetics, catecholamines and dexamethasone were significantly less frequently used in the treatment group. CONCLUSIONS A new method of surfactant application was associated with a lower prevalence of mechanical ventilation and better pulmonary outcome. A prospective controlled trial is required to determine whether this approach is superior to standard care.

Genetic Polymorphisms of Hemostasis Genes and Primary Outcome of Very Low Birth Weight Infants

BACKGROUND. Recent investigations have reported an influence of thrombophilic mutations and antithrombotic risk factors with development of intraventricular hemorrhage. It was our objective for this study to investigate the impact of genetic polymorphisms of hemostasis genes on the primary outcome measures of sepsis, bronchopulmonary dysplasia, intraventricular hemorrhage, and periventricular leukomalacia in a large cohort of very low birth weight infants. METHODS. There were 586 very low birth weight infants enrolled prospectively in a multicenter trial between September 2003 and July 2005, and an additional 595 very low birth weight infants, who had been recruited in a previous prospective trial, were studied. DNA samples were taken by buccal swab, and genotypes of factor V Leiden mutation, prothrombin G20210A mutation, the factor VII-323 del/ins polymorphism, and the factor XIII-Val34Leu polymorphisms were determined by polymerase chain reaction and restriction enzyme digestion. RESULTS. In contrast to data published previously, the frequency of intraventricular hemorrhage or periventricular leukomalacia was not significantly influenced by any of the genetic variants tested. Carriers of the factor XIII-Val34Leu polymorphism, however, had a higher sepsis rate and a longer period of hospital care compared with noncarriers. The factor VII-323 del/ins polymorphism was found to be a potential protective factor against bronchopulmonary dysplasia. CONCLUSIONS. We could not confirm previously reported associations of hemostasis gene variants and development of intraventricular hemorrhage in very low birth weight infants. To better understand gene-disease associations in very low birth weight infants, the prospective development of large-scale cohorts with well-defined phenotypes and corresponding DNA samples is essential.

Surfactant Substitution in Ventilated Very Low Birth Weight Infants: Factors Related to Response Types

ABSTRACT: We investigated factors that may influence the response to surfactant substitution. Thirty-five very low birth weight infants with respiratory distress syndrome were treated with Curosurf at 3–12 h of age. From the changes in oxygenation, the therapeutic response was categorized as rapid and sustained, rapid with relapse, or poor. Phospholipids and surfactant protein A were quantified in gastric aspirate samples obtained immediately after birth. They showed that 16 infants had accelerated lung maturity, despite clinical and radiologic signs of respiratory distress syndrome. Ten of them had suffered from birth asphyxia or connatal infection. Nevertheless, 12 of these 16 infants responded rapidly to surfactant substitution. Poor response was seen in four infants with connatal infection. Of 19 infants with immature lung profile, 18 showed a rapid initial response to surfactant substitution. Dynamic compliance of the respiratory system or arterial blood pressure before substitution, the ultrastructure of the surfactant preparation, or persistence of the ductus arteriosus did not influence the response type, but fraction of inspired oxygen was higher before surfactant substitution in infants with poor response. Prognosis was related to short-term response: Of 17 infants who showed a rapid and sustained response, none died, whereas eight of 18 infants with relapse after rapid initial response or poor response died (p < 0.05). We conclude that surfactant substitution may be beneficial not only in babies with primary surfactant deficiency but also in other pulmonary disorders that are common in very low birth weight infants. The type of response may be of prognostic value. (Pediatr Res 30: 591–596, 1991)

Surfactant protein A in the course of respiratory distress syndrome

Surfactant-associated protein (SP-A) was measured in tracheal aspirates of ventilated infants with (n=51) and without (n=21) respiratory distress syndrome (RDS). SP-A concentrations in samples collected after birth were significantly lower in RDS than in infants ventilated for other reasons than RDS (median 0.03 vs. 1.60 μg/ml). As a biochemical test to diagnose RDS early after birth, the sensitivity of measuring SP-A in tracheal aspirates was 87% and specificity 81%. SP-A content in tracheal aspirates of infants with RDS was monitored during the first 7 days of life. A significant (P<0.001) increase within the first 4 days was found in those infants who survived, whereas no such change was found in those infants who died.

Does the enteral feeding advancement affect short-term outcomes in very low birth weight infants?

Background and Objectives: Controversy exists regarding the optimal enteral feeding regimen of very low birth weight infants (VLBW). Rapid advancement of enteral feeding has been associated with an increased rate of necrotizing enterocolitis. In contrast, delaying enteral feeding may have unfavorable effects on nutrition, growth, and neurodevelopment. The aim is to compare the short-term outcomes of VLBW infants in tertiary care centers according to their enteral feeding advancement. Patients and Methods: We prospectively studied the influence of center-specific enteral feeding advancement in 1430 VLBW infants recruited from 13 tertiary neonatal intensive care units in Germany on short-term outcome parameters. The centers were post hoc stratified to “rapid advancement to full enteral feeds” (median duration of advancement to full enteral feeds ≤12.5 days; 6 centers), that is, rapid advancement (RA), or “slow advancement to full enteral feeds” (median duration of advancement to full enteral feeds >12.5 days; 7 centers), that is, slow advancement (SA). Results: VLBW infants born in centers with SA (n = 713) had a significantly higher rate of sepsis compared with VLBW infants born in centers with RA (n = 717), which was particularly evident for late-onset sepsis (14.0% vs 20.4%; P = 0.002). Furthermore, more central venous lines (48.6% vs 31.1%, P < 0.001) and antibiotics (92.4% vs 77.7%, P < 0.001) were used in centers with SA. Conclusions: Center differences in enteral feeding advancement occur and may have a significant impact on short-term outcomes such as nosocomial sepsis. Large, multicenter, prospective trials are required to further elucidate the optimal feeding strategy for VLBW infants.

Polymorphisms of haemostasis genes as risk factors for preterm delivery

Clinical trials evaluating the potential benefit of anticoagulant treatment in pregnant women with inherited thrombophilia are based on the observation that a genetic predisposition to thrombosis is associated with frequent abortions and preterm birth. It was the aim of our study to delineate the impact of genetic polymorphisms with prothrombotic and antithrombotic effects on the occurrence of preterm birth in a large cohort of very-low-birth-weight (VLBW)-infants and their mothers. We examined the factor V Leiden and the prothrombin G20210A mutation, the factor VII 121del/ins and the factor XIII Val34Leu polymorphism in preterm very-low-birth-weight (VLBW, n=593) and term-born-infants (n=278) and their mothers (n=785). The primary outcome was preterm vs.term birth. From all polymorphisms tested, the maternal factor VII-121del/ins polymorphism (26.2 vs. 17.6 %; p=0.009) and the infants factor VII-121del/ins polymorphism (29.0 vs. 20.0 %; p=0.009) were more frequent in singleton VLBW and their mothers compared to term infants and their mothers. Furthermore, the frequency of the factor XIII-Val34Leu polymorphism was significantly lower in singleton VLBW than in term infant controls (5.1 vs. 9.6%, p=0.025). In a multivariate regression analysis, previous preterm delivery (OR=3.8, 95% CI: 1.7-8.4), the maternal carrier status of the factor-VII-121del/ins polymorphism (OR=1.7, 95% CI: 1.12-2.5, p=0.007) and the lower frequency of infants factor-XIII-Val34Leu polymorphism (OR=0.53; 95% CI: 0.29-0.96; p=0.038) were found to be independently associated with preterm delivery. InVLBW mothers with pathological CTG as cause of preterm delivery, the frequency of factor V Leiden mutation was significantly increased compared to VLBW mothers without pathological CTG (14.1 vs. 6.1%, p=0.01). The investigated haemostasis gene polymorphisms have a much lower impact on subsequent preterm delivery than known risk factors such as previous preterm birth. The reported association of the factor-VII-121del/ins polymorphism on preterm delivery and its clinical relevance needs to be further elucidated.

Improved N-retention during L-Carnitine-Supplemented Total Parenteral Nutrition

The influence of intravenously administered L-carnitine on lipid- and nitrogen-metabolism was studied during total parenteral nutrition of piglets (mean weight 4077 g; n = 9). The infusion protocol was divided into three isocaloric and isonitrogenous 48-hr periods. Amino acids (3 g/kg day) were administered throughout all three periods: 140 cal/kg/day were given as nonprotein calories, consisting only of glucose during period 1; during periods 2 and 3, an amount of glucose calorically equivalent to 4 g fat/kg/day was substituted with a lipid emulsion, and L-carnitine (1.5 mg/kg/day) was added in period 3. Key parameters of fat- and nitrogen-metabolism were determined during the entire regime. Indirect calorimetry was performed and the respiratory quotient calculated during all three periods. The results demonstrate a more effective lipolysis and oxidation of fatty acids during L-carnitine supplementation. These changes produce an increased energy gain from exogenously administered fat and a distinct improvement in nitrogen balance.

Surfactant bolus instillation: effects of different doses on blood pressure and cerebral blood flow velocities.

Fifteen preterm infants suffering from respiratory distress syndrome were randomly allocated to receive either high-dose (200 mg/kg) or low-dose (100 mg/kg) surfactant treatment. Retreatments were done with the low dose. Blood pressure, blood gases and cerebral blood flow velocities were determined before and after 24 bolus instillations. With the high dose mean blood pressure and mean cerebral blood flow velocity dropped significantly. With the low dose only mean cerebral blood flow velocity decreased; the course was unrelated to blood pressure or PCO2 fluctuations. The mechanisms leading to the observed circulatory changes after surfactant instillation remain unclear.