Published online February 1, 2006
PEDIATRICS Vol. 117 No. 2 February 2006, pp. 448-454 (doi:10.1542/peds.2005-0123)
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Onset of Mechanical Ventilation Is Associated With Rapid Activation of Circulating Phagocytes in Preterm Infants

Riikka Turunen, MDa,b, Irmeli Nupponen, MD, PhDa,b, Sanna Siitonen, MD, PhDc, Heikki Repo, MD, PhDb,d and Sture Andersson, MD, PhDa

a Hospital for Children and Adolescents
b Department of Bacteriology and Immunology, Haartman Institute
d Department of Medicine, Division of Infectious Diseases, University of Helsinki, Helsinki, Finland
c Department of Clinical Chemistry, Helsinki University Central Hospital, Helsinki, Finland


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
OBJECTIVE. In preterm infants with respiratory distress syndrome (RDS), circulating neutrophils are activated. Kinetics and effects of surfactant therapy on this activation are unknown. Therefore, we studied activation of circulating neutrophils and monocytes in newborn preterm infants with and without RDS.

PATIENTS AND METHODS. Preterm infants with RDS who were mechanically ventilated and received surfactant ("ventilated infants": n = 38; mean gestational age ± SD: 28.3 ± 2.2 weeks; mean birth weight ± SD: 1086 ± 353 g) and preterm infants who received nasal continuous positive airway pressure (n = 8) or no ventilatory support (n = 17) ("control infants": mean gestational age ± SD: 32.1 ± 1.2 weeks; mean birth weight ± SD: 1787 ± 457 g) were recruited. Blood samples were taken from ventilated infants at birth, before surfactant treatment, at 1 and 2 hours after surfactant, and at 12 to 24 hours of age. Blood samples were taken from control infants at birth, at 2 to 6 hours, and at 12 to 24 hours of age. Phagocyte CD11b expression was analyzed by flow cytometry.

RESULTS. In ventilated infants, phagocyte CD11b expression increased from birth to the first postnatal samples. It increased further by 12 to 24 hours of age. Control infants with or without nasal continuous positive airway pressure showed no significant increase after birth. At 12 to 24 hours of age, phagocyte CD11b expression was higher in ventilated infants than in control infants. In ventilated infants, neutrophil CD11b expression at 1 and 2 hours after surfactant correlated positively with gestational age.

CONCLUSIONS. In preterm infants with RDS, significant activation of circulating phagocytes occurs within 1 to 3 hours of the onset of mechanical ventilation, independent of surfactant administration, which indicates that mechanical ventilation may be the inducer of this systemic inflammatory response.

Key Words: CD11b • mechanical ventilation • monocyte • neutrophil • respiratory distress syndrome • systemic inflammation

Abbreviations: RDS—respiratory distress syndrome • FIO2—fraction of inspired oxygen • nCPAP—nasal continuous positive airway pressure • RFU—relative fluorescence unit • BPD—bronchopulmonary dysplasia

Preterm infants who need mechanical ventilation because of respiratory distress syndrome (RDS) develop signs of pulmonary1–5 and systemic6–9 inflammation. Pulmonary inflammation is characterized by neutrophil and macrophage accumulation in the lungs3–5 and high concentrations of proinflammatory cytokines in tracheal aspirates and bronchoalveolar lavage fluid.10,11 RDS is associated with low concentrations of circulating neutrophils12 with activated phenotype.8 This neutrophil activation fails to occur in healthy preterm infants or in term newborn infants on the first day of life, indicating that it does not represent a normal physiologic adaptation to birth.8

After activation, phagocytes (ie, neutrophils and monocytes) upregulate their surface expression of the ß2-integrin CD11b/CD18 (Mac-1, {alpha}Mß2, CR3).13,14 This integrin mediates the tight adhesion between the phagocyte and the endothelium, which enables the cell to leave the circulation and enter the site of inflammation. Resting phagocytes express only a fraction of the total cell content of CD11b/CD18 molecules but are able, after activation, to increase their CD11b/CD18 expression rapidly by releasing it from their intracytoplasmic storage granules to the cell surface.14 This increase in CD11b/CD18 expression serves as a marker of phagocyte activation. Enhanced CD11b/CD18 expression on circulating neutrophils has been demonstrated in inflammatory conditions such as sepsis in adults and newborns,15–18 trauma,19 burn injuries,20 and autoimmune diseases.21,22

The aim of this study was to investigate in preterm infants with RDS the kinetics of activation of circulating phagocytes as a sign of systemic inflammation after the onset of mechanical ventilation. Furthermore, because surfactant has been shown to have both proinflammatory and antiinflammatory effects in vitro,23–26 we wanted to study whether surfactant therapy given as prophylaxis or as rescue modifies phagocyte activation in clinical situations.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Subjects
The local institutional review boards approved the study protocol, and parents of the infants gave their informed consent. Preterm infants who were born at <32 weeks of gestation at Helsinki University Central Hospital and who were intubated after birth and received surfactant (Curosurf, Chiesi Farmaceutici SPA, Parma, Italy; 100 mg/kg) because of RDS were eligible as "ventilated infants" (n = 38; mean birth weight ± SD: 1086 ± 353 g; mean gestational age ± SD: 28.3 ± 2.2 weeks) (Table 1). Preterm infants who were born at <35 weeks of gestation with mild or no RDS, who were not mechanically ventilated and did not receive surfactant, served as control infants (n = 25; mean birth weight ± SD: 1787 ± 457 g; mean gestational age ± SD: 32.1 ± 1.2 weeks) (Table 1). During the study period of July 2000 to September 2004, prophylactic surfactant treatment within 15 minutes of birth became clinical practice for infants who are born at <30 weeks of gestation. Therefore, the ventilated infants received prophylactic surfactant, rescue surfactant, or both. Rescue surfactant was given if the required fraction of inspired oxygen (FIO2) exceeded 0.3 or if a radiograph of the lungs showed changes that are typical of RDS. The first dose of rescue surfactant was given at the age of 1 to 4 hours. The ventilated infants were treated by means of synchronized intermittent mandatory ventilation or high-frequency ventilation (Table 1). Eight of the control infants required respiratory support by means of nasal continuous positive airway pressure (nCPAP) (5 cm H2O) from 1 to 12 hours of age. As standard management, each of the ventilated infants and 8 of the control infants received ampicillin (200 mg/kg) and netilmicin (6 mg/kg) from the first day of life for at least 7 days. If there was suspicion of maternal infection (premature rupture of membranes with high circulating levels of maternal C-reactive protein, maternal fever, or abnormal vaginal discharge), the infant was excluded from the study to avoid high CD11b expression resulting from infection.27 All the study infants had negative blood culture results, and none had signs of early-onset infection.


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  		TABLE 1 Characteristics of the Ventilated (n = 38) and Control (n = 25) Infants

 
Blood Samples
Blood samples (50 µL) were obtained from ventilated infants (1) at birth from the umbilical vein, postnatally via an arterial catheter, (2) before the first dose of surfactant (infants receiving only rescue surfactant), (3) 1 and 2 hours after the first dose of prophylactic or rescue surfactant, and (4) at the age of 12 to 24 hours. Blood samples were taken from control infants (1) at birth from the umbilical vein, (2) at the age of 2 to 6 hours, and (3) at the age of 12 to 24 hours either through an arterial catheter or by heel pricking.27

The blood samples were placed in pyrogen-free tubes (Falcon Polystyrene Round-Bottom Tubes; Becton Dickinson, Franklin Lakes, NJ) containing 9 µL of acid-citrate-dextrose in 31 µL of phosphate-buffered saline as anticoagulant. Immediately after being drawn, the samples were cooled to 0°C in ice water to minimize phagocyte activation ex vivo.28

Expression of CD11b
Neutrophil and monocyte CD11b expression was analyzed by flow cytometry as described previously.28,29 In brief, within 24 hours of sampling, 25-µL aliquots of whole blood were labeled in the dark at 4°C with fluorescent anti-CD11b (phycoerythrin) and anti-CD14 (fluorescein isothiocyanate) antibodies (BD Biosciences, San Jose, CA). Red blood cells were lysed with FACS lysing solution (Benex Limited; BD Biosciences, Shannon, Country Clare, Ireland), and the cells were collected by centrifugation. The samples were resuspended in 1% formalin and kept in the dark at 4°C until analysis. Flow-cytometric analysis was conducted within 24 hours of sample processing by using a FACSort flow cytometer and CellQuest Pro analysis software (both from BD Biosciences). Neutrophils were identified by their light scatter pattern, and monocytes were identified by their light scatter pattern and CD14 positivity. Expression of CD11b is reported as median relative fluorescence units (RFU).

Statistical Analysis
Because the data were not normally distributed, nonparametric tests were used for statistical analysis. Comparisons within groups between different time points were conducted by using Wilcoxon's signed-rank test with 2-tailed exact significance, and comparisons between groups were performed by using the Mann-Whitney U test with 2-tailed exact significance. Correlations were conducted by using Spearman's correlation test with 2-tailed significance. The {chi}2 test was used to analyze categorical data, with Fisher's exact test when applicable. Results are given as median (quartiles) or mean ± SD.


   RESULTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
The clinical characteristics of the subjects are presented in Table 1. Of the ventilated infants (n = 38), 23 received only rescue surfactant at the age of 1 to 4 hours. Fifteen infants received prophylactic surfactant at the age of <15 minutes. Of these, 11 received 1 or 2 additional doses of surfactant during the first 24 hours of life. At 36 weeks, 14 of the ventilated infants were diagnosed with bronchopulmonary dysplasia (BPD).30

Of the control infants, 8 infants developed mild RDS and required respiratory support by means of nCPAP during the first day of life. Seventeen infants did not need any respiratory support (Table 1).

In the control infants (n = 25), neutrophil and monocyte CD11b expression did not increase significantly from birth (neutrophils: 86 [77–99] RFU; monocytes: 74 [65–85] RFU) to the age of 2 to 6 hours (neutrophils: 99 [76–169] RFU; monocytes: 80 [67–134] RFU) or between the ages of 2 to 6 and 12 to 24 hours (neutrophils: 123 [79–156] RFU; monocytes: 122 [70–156] RFU). Phagocyte CD11b expression was similar at all time points in infants treated by means of nCPAP and in those without respiratory support (Tables 2 and 3).


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  		TABLE 2 Expression of CD11b in Control Infants

 

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  		TABLE 3 Expression of CD11b in Ventilated Infants

 
In ventilated infants (n = 38), compared with birth values, neutrophil and monocyte CD11b expression was significantly increased at 1 hour and at 2 hours after surfactant (Fig 1). Compared with the levels at 2 hours after surfactant, neutrophil and monocyte CD11b expression was increased further at the age of 12 to 24 hours (Fig 1). In infants receiving only rescue surfactant (n = 23), neutrophil CD11b expression was already significantly increased before the first dose of surfactant compared with birth values (P = .001; Tables 2 and 3). In the subgroup of infants who received prophylactic surfactant (n = 15), phagocyte CD11b expression increased from birth to 1 and 2 hours after surfactant, in a similar manner as in infants who later received only rescue surfactant (Tables 2 and 3).


Figure 1
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  		FIGURE 1 Expression of CD11b on circulating neutrophils and monocytes in ventilated preterm infants (n = 38) at birth, 1 hour after first surfactant (1 h), 2 hours after first surfactant (2 h), and 12 to 24 hours of age (12–24 h).

 
Compared with the control infants, neutrophil and monocyte CD11b expression in ventilated infants was significantly higher at 24 hours of age (Fig 2). There were no differences in CD11b expression between control and ventilated infants in cord blood or at 2 hours.


Figure 2
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  		FIGURE 2 Expression of CD11b on circulating neutrophils and monocytes in ventilated preterm infants (n = 38; gray boxes) and in preterm infants without mechanical ventilation (n = 25; white boxes) at birth and 12 to 24 hours of age (12–24 h).

 
In ventilated infants, CD11b expression on neutrophils at 1 hour after surfactant showed a positive correlation with gestational age (r = 0.548; P < .001), and expression on neutrophils and monocytes at 2 hours after surfactant also showed positive correlations with gestational age (neutrophils: r = 0.584, P < .001; monocytes: r = 0.376, P = .031). No correlation was found between gestational age and CD11b expression at birth or at 12 to 24 hours of age. Indices of lung morbidity (ie, arterial/alveolar PO2 ratio, the number of surfactant doses, or maximal FIO2 during the first 24 hours) did not correlate with phagocyte CD11b expression. In ventilated infants, phagocyte CD11b expression levels on the first day of life were comparable in infants who developed BPD and those who did not.

In the control infants, CD11b expression on neutrophils or monocytes did not correlate with gestational age in any of the samples.


   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
Our results indicate that in preterm infants with RDS, systemic inflammation, as indicated by activation of circulating phagocytes, begins within hours of the onset of mechanical ventilation. This activation occurs independently of the timing of surfactant administration, and it does not correlate with maximal FIO2 values. We found no such activation in newborn preterm infants without ventilatory support or in infants who were treated by means of nCPAP; therefore, the inducer of this activation may be mechanical ventilation. This is in agreement with previous findings in animal models, which have revealed rapid induction of pulmonary and systemic inflammation by mechanical ventilation.31–35 In the immature lung, mechanical ventilation causes edema, hemorrhage, and epithelial necrosis, which compromise lung mechanics, inhibit surfactant function, and promote the expression of proinflammatory cytokines.33–36 In animal models, just a few manual ventilations at birth are capable of causing damage in preterm lung tissue,37 and proinflammatory mediators are expressed as early as 2 hours after the onset of mechanical ventilation irrespective of the surfactant used.35

The natural porcine surfactant (Curosurf) that was used in this study has been shown to have antiinflammatory effects in vitro. It downregulates the mRNA of tumor necrosis factor {alpha} (TNF-{alpha}) and TNF-{alpha} type II receptor in lipopolysaccharide-stimulated monocytes.25 Administration of surfactant to a preterm infant with RDS improves lung function and thus enables more gentle ventilation, which could have an attenuating effect on the inflammatory reaction that is seen in preterm infants with RDS. On the other hand, natural porcine surfactant has been shown to contain platelet-activating factor, a strong neutrophil activator.23 Therefore, administration of surfactant could also have proinflammatory effects in vivo. However, according to our findings, administration of natural porcine surfactant does not exert any significant influence on phagocyte activation in mechanically ventilated preterm infants. This result is in accordance with previous findings in animal models that demonstrated that mechanical ventilation initiates lung inflammation even with surfactant-replacement therapy and lung-protective ventilatory strategies.33–35 Whether this is also true for other natural or synthetic surfactant preparations remains to be elucidated.

In our study, the 8 control infants who received treatment by means of nCPAP did not show activation of circulating phagocytes. In an animal model, nCPAP treatment resulted in lower indicators of lung injury than mechanical ventilation.38 nCPAP treatment of preterm infants has been shown to improve respiratory and nonrespiratory outcome compared with mechanical ventilation.39,40 Current evidence suggests that the development of morbid conditions such as BPD and cerebral palsy are influenced by inflammatory mechanisms.41–43 Whether the favorable influence of nCPAP on the outcome of preterm infants is the result of milder lung injury and thus a milder systemic inflammatory response remains to be elucidated in a randomized, clinical trial.

Our control infants were of greater gestational age and birth weight than the ventilated infants, which raises the question of whether our findings reflect immaturity rather than an effect of mechanical ventilation. However, in the ventilated infants, there was a significant positive correlation between phagocyte activation and gestational age; the more mature infants showed greater CD11b expression at 1 to 2 hours after surfactant. Because no correlation between CD11b expression and gestational age was found at 12 to 24 hours of age, this probably reflects a more rapid response in the more mature infants. Previously it was shown that CD11b content in neutrophils, and their ability to upregulate CD11b expression after stimulation, increases with advancing gestational age.44–46 However, the control infants, who were more mature, showed no significant increase in circulating phagocyte CD11b expression during the first hours of life or at 12 to 24 hours of age. This may be the result of a lower proinflammatory stimulus in the absence of mechanical ventilation.

The control infants were also exposed to milder hyperoxia than the ventilated infants (Table 1). Thus, lung injury resulting from hyperoxia could also have contributed to the activation of the inflammation seen in the ventilated infants. However, no correlation was found between phagocyte CD11b expression and maximal FIO2 used, suggesting that other factors related to mechanical ventilation play a role in this activation.

In the ventilated infants, no correlation was found between the levels of CD11b expression and subsequent development of BPD. The pathogenesis of BPD is multifactorial, with inflammatory mechanisms playing a crucial role.47,48 It has been suggested that a prolonged inflammatory reaction after the first days of life, perhaps as a result of inadequate antiinflammatory mechanisms rather than the magnitude of inflammation during the first few postnatal days, may be crucial in regards the development of BPD.3,11,48–50 This is supported by epidemiologic findings that demonstrated that inflammatory conditions such as infections increase the risk of BPD in preterm infants.47,51 In our study, the time period during which the inflammatory status was assessed was probably too early and too limited to show an association with outcome parameters such as BPD.

To differentiate CD11b upregulation caused by infection or inflammation in utero,27,52 we excluded infants who were born to mothers suspected of having chorioamnionitis. Consequently, CD11b expression was consistently low on cord blood phagocytes, and we found no signs of antenatal inflammation. Recent evidence in preterm infants demonstrated an association between maternal chorioamnionitis and increased short- and long-term morbidity.41–43 Chorioamnionitis and funisitis activate fetal inflammatory mechanisms in utero.53 However, the postnatal activation of phagocytes, as well as the effect of mechanical ventilation on this activation in infants of mothers with chorioamnionitis, remains to be studied.


   CONCLUSIONS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
Our findings demonstrate that in preterm infants with RDS, the onset of mechanical ventilation is associated with rapid activation of circulating phagocytes. This activation is independent of the timing of surfactant therapy, and in preterm infants treated by means of nCPAP or without ventilatory support, no such activation is found. We speculate that the onset of mechanical ventilation may induce a systemic inflammatory response in preterm infants with RDS.


   ACKNOWLEDGMENTS
 
This study was supported by grants from the Foundation for Pediatric Research (Helsinki); the Pediatric Graduate School (Children's Hospital, University of Helsinki); the National Graduate School for Clinical Research; Finska Läkaresällskapet; the Sigrid Jusélius Foundation; and Helsinki University Central Hospital Research Funds.

We thank all the subjects in this study and their parents. We also thank the personnel of the Department of Obstetrics and Gynecology at Helsinki University Central Hospital and the personnel of the neonatal intensive care unit at the Hospital for Children and Adolescents (Helsinki) for their help. In particular, we thank Marita Suni, RN, for her skilled assistance.


   FOOTNOTES
 
Accepted Jun 16, 2005.

Address correspondence to Riikka Turunen, MD, Hospital for Children and Adolescents, Research Laboratory, Biomedicum B429b, PO BOX 700 (Haartmaninkatu 8), FIN-00029 HUS, Helsinki, Finland. E-mail: riikka.s.turunen{at}helsinki.fi

The authors have indicated they have no financial relationships relevant to this article to disclose.


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 DISCUSSION
 CONCLUSIONS
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