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Ann Thorac Surg 2000;70:582-589
© 2000 The Society of Thoracic Surgeons

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Original articles: cardiovascular

Neutrophil degranulation and complement activation during fetal cardiac bypass

^a Department of Pediatric Cardiac Surgery, University of California, San Francisco, San Francisco, California, USA

Address reprint requests to Dr Parry, Department of Paediatric Cardiac Surgery, Bristol Royal Hospital for Sick Children, St Michael’s Hill, BS2 8BJ Bristol, UK
e-mail: ajparry{at}yahoo.co.uk

	Abstract

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Background. Fetal cardiac bypass results in dysfunction of the fetoplacental unit (FPU) characterized by increased placental vascular resistance and respiratory acidosis. However the mechanisms of this dysfunction are not completely understood. To test the hypothesis that complement activation and neutrophil degranulation may contribute to the placental dysfunction associated with fetal bypass, we compared placental hemodynamics, complement activation, and neutrophil degranulation among fetuses exposed to cardiac bypass with a miniaturized bypass circuit including an in-line axial flow pump (Hemopump), fetuses undergoing bypass with a conventional roller pump circuit, and control fetuses that were similarly exposed but did not undergo bypass.

Methods. Twenty-six Western Cross sheep fetuses (median 122 days gestation) were randomly assigned to undergo cardiac bypass for 30 minutes with the Hemopump circuit (n = 8), to undergo bypass for 30 minutes with the conventional (roller pump) circuit (n = 10), or to undergo identical exposure and cannulation but not bypass (n = 8, controls). Blood samples were collected to measure white cell count and differential, and C3a and lactoferrin levels prior to bypass, at the end of bypass, and 1 and 2 hours after bypass. Hemodynamics and blood gases were also monitored.

Results. There was a fall in white cell count over time that continued after bypass in all groups; neutrophils and lymphocytes were affected similarly. C3a levels rose significantly from prebypass to postbypass in the roller pump group (p < 0.0001) but not in either of the other groups. Lactoferrin levels rose significantly from start of bypass in both bypass groups (Hemopump p = 0.01; roller pump p < 0.0001) but not in controls. The elevation in lactoferrin level coincided with worsening placental gas exchange and deteriorating cardiac function.

Conclusions. Complement and neutrophil activation occurred with fetal cardiac bypass but only neutrophil activation mirrored the FPU and cardiac dysfunction, suggesting that products of neutrophil activation may be important contributing factors. Improved FPU function with a bypass circuit that has less extracorporeal surface and does not require a large priming volume may be due in part to a reduction in the magnitude of this inflammatory response.

	Introduction

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Fetal cardiac bypass causes dysfunction of the fetoplacental unit with an increase in placental vascular resistance [1], leading initially to a respiratory [2] followed later by a metabolic acidosis [3] with a subsequent terminal fall in combined ventricular output, blood pressure, and PaO₂. The early acidosis may be blunted by indomethacin [4] or steroids [5] and the late acidosis by a high spinal anesthetic [3]. Minimizing the priming volume and blood component damage by using a miniaturized bypass circuit including an in-line axial flow pump (Hemopump; Johnson & Johnson Interventional Systems, Rancho Cordova, CA) has resulted in a dramatic improvement in fetal survival [6] though some damage to the fetoplacental unit still occurs. Although the pathophysiology of bypass-related placental dysfunction has been characterized, and certain therapeutic measures identified, the fundemental trigger remains unknown.

Because the dysfunction of the fetoplacental unit observed after fetal cardiac bypass so resembles the systemic inflammatory reaction observed with postnatal cardiopulmonary bypass we hypothesized that complement and neutrophil activation might be important contributors to this fetoplacental unit dysfunction as is the case in pediatric and adult patients. If this hypothesis is correct there should be (1) a demonstrable rise in the levels of activated complement species and in the products of neutrophil degranulation with fetal bypass, and (2) a demonstrable difference in the activation of these cascades with manipulations previously shown to reduce dysfunction of the fetoplacental unit. To test this hypothesis we conducted experiments to determine the effect of fetal cardiac bypass on neutrophil degranulation and complement activation, the relationship of these factors to placental hemodynamics, and differences in these factors between fetuses undergoing cardiac bypass with a standard roller pump bypass circuit and a miniaturized circuit that includes an in-line axial flow pump.

	Material and methods

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Surgical procedures
Twenty-six pregnant Western Cross ewes carrying fetuses a median of 122 days gestational age (range 120 to 127 days, consistent with our previous work) were premedicated with 10 mg/kg of ketamine and buprenorphine by intramuscular injection. Epidural anesthesia was then achieved using 4 mL of 1% tetracaine hydrochloride after which endotracheal intubation was performed. Anesthesia was maintained using a continuous intravenous infusion of ketamine at a rate of 3–5 mg/kg per hour. The ewe was slightly hyperventilated with 100% oxygen to maintain end-tidal carbon dioxide levels around 30 mm Hg. This level ensured adequate maternal buffering capacity to optimize removal of fetal carbon dioxide and other acids. Intraarterial and intravenous access were obtained to monitor maternal arterial and central venous blood pressure and heart rate, and to administer fluids to the mother during the surgical procedures.

Through an extended midline laparotomy the uterus was exposed and delivered into the wound. Care was taken to ensure there was no tension or torsion on the uterine vessels. The number and orientation of the fetus(es) was determined and a hysterotomy made over the upper chest of the most appropriate fetus. On entering the amniotic cavity, a tributary of the umbilical vein was identified and cannulated. A bolus of ketamine (10 mg/kg) was given to augment fetal anesthesia and infusions of ketamine (at 200 µg/kg per minute) and warmed Normasol solution (at 20 mL/kg per hour) were started. In the first 4 animals umbilical venous blood samples were also obtained through this catheter.

One of the forelimbs of the fetus was removed from the uterus thereby rotating the fetus and exposing the sternum. A median sternotomy was performed and a catheter inserted into one internal thoracic artery for monitoring of fetal arterial blood pressure and heart rate. This catheter also allowed access for blood sampling. The pericardium was opened and ultrasonic flow probes were placed around the aorta and main pulmonary artery for measurement of combined ventricular output. Blood was drawn at this time from the arterial line for white cell count and differential, blood gas analysis, and C3a and lactoferrin assay. In the first 4 Hemopump animals blood samples were also drawn from the umbilical venous line to compare arterial and venous white blood cell counts across the placenta. Fetal heart rate, blood pressure, and combined ventricular output were recorded.

Heparin was administered (3 mg/kg body weight estimated from a standard nomogram) and the superior caval vein was cannulated with a 16F right-angled venous cannula inserted with the tip lying within the right atrium. The flow probe was removed from the pulmonary artery and the vessel cannulated with a 12F straight arterial cannula. The animals were randomly assigned to the two bypass groups. In 8 animals the cannulas were connected to the bypass circuit and cardiac bypass was commenced using an axial-flow pump (Hemopump, modified model HP24 sternotomy pump; Johnson & Johnson Interventional Systems) primed with Normasol solution as described previously [7]. In another 10 animals the cannulas were connected to a standard roller pump bypass circuit comprising a venous reservoir and a roller head (Sarns, Ann Arbor, MI) primed with Normasol solution and cardiac bypass was commenced in a standard manner. Bypass flows were monitored continuously by an in-line flow probe and flow rates were maintained at 300 mL/kg per minute. After 30 minutes, while still on bypass, blood was again drawn for the same analyses as before, hemodynamic data were acquired, and then bypass was discontinued. The pulmonary arterial cannula was removed and the site oversewn. The heparin was not reversed. The flow probe was then replaced around this vessel. Further hemodynamic data were acquired and blood samples drawn 1 and 2 hours following separation from bypass. At the end of the experiment the fetus and ewe were killed with an overdose (200 mg/kg) of intravenous pentobarbital sodium.

The 8 control animals were exposed and instrumented in identical fashion. They were left cannulated for 30 minutes to simulate the time the study groups spent on bypass before the pulmonary artery cannula was removed, the site oversewn, and the flow probe replaced. Samples were taken immediately before cannulation of the heart, immediately before removal of the cannula, and 1 and 2 hours later.

All animals received humane care in compliance with the "Principles of Laboratory Animal Care" formulated by the National Society for Medical Research and the "Guide for the Care and Use of Laboratory Animals" prepared by the Institute of Laboratory Animal Resources and published by the National Institutes of Health (NIH publication 86-23, revised 1985). The experimental protocol was approved by the Committee for Animal Research at the University of California, San Francisco.

Blood count and differential white cell quantitation
Blood specimens (0.5 mL) were drawn through the arterial (and venous) cannulas. Cell counts were performed using a Baker-9000 coulter counter (Baker, Allentown, PA) and differential counts were performed manually. All blood counts and differentials were corrected to original hematocrit to minimise the effect of hemodilution.

C3a and lactoferrin analysis
Blood samples (1 mL) were drawn through the arterial catheter, placed immediately in an EDTA tube on ice, then centrifuged at 4,000 rpm for 30 minutes in a cooled centrifuge. The plasma was removed and frozen at -80°C until analysis. The assays for sheep C3a and lactoferrin were performed by radioimmunoassay techniques as described previously [8]. All specimens were corrected to original hematocrit levels to minimize the effect of hemodilution.

Statistical analysis
Data are expressed as mean ± SD. Data of repeated measures within groups were compared using repeated-measures analysis of variance (ANOVA) with multiple comparison testing using Bonferroni post hoc tests where appropriate. In the roller pump group there were too many data points missing at the last time point for repeated measures ANOVA to be performed; the p values quoted therefore reflect analysis over the first three time points only. Data for each time point were compared between groups using general factorial ANOVA. Statistical calculations were performed using Statview version 5 (SAS Institute, Cary, NC).

	Results

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Hemodynamics and fetoplacental unit function
The number of animals surviving at each time point are shown in Figure 1A. One control animal died at the time of decannulation and 2 in the roller pump group died shortly after the discontinuation of bypass. Another fetus in the roller pump group died late during the first hour after bypass, while a further control animal, 2 animals in the Hemopump group, and 5 animals in the roller pump group died during the second hour after the discontinuation of bypass.

View larger version (35K): [in this window] [in a new window]   Fig 1. The changes in hemodynamic and gas exchange parameters with time spent on bypass. (A) Combined ventricular output. There was a significant fall in all groups over time (control p = 0.05; Hemopump p = 0.003; roller pump p < 0.0001). (*p = 0.05 Hemopump versus controls; §p = 0.01 roller pump versus controls; p = 0.01 roller pump versus Hemopump.) (B) pO2. There was a significant fall in pO2 in both bypass groups over time (Hemopump p < 0.0001; roller pump p = 0.006). (*p = 0.02 roller pump versus controls; §p = 0.03 roller pump versus controls; p = 0.006 roller pump versus Hemopump.) (C) pCO2. There was a significant rise in pCO2 in both bypass groups over time (Hemopump p = 0.0004; roller pump p < 0.0001). (*p = 0.003 roller pump versus controls; §p < 0.0001 roller pump versus controls; p = 0.0008 roller pump versus Hemopump.)

These hemodynamic changes were associated temporally with changes in fetoplacental unit function. No significant changes occurred in PO₂, PCO₂, or pH in the control animals, but there was a significant fall in PO₂ in both bypass groups (Hemopump p < 0.0001; roller pump p = 0.006; Fig 1B), a reciprocal rise in PCO₂ (Hemopump p = 0.0004; roller pump p < 0.0001; Fig 1C), and a fall in arterial pH (Hemopump p = 0.0003; roller pump p < 0.0001). When compared with control animals there was no significant difference at any time point for the animals subject to bypass with the Hemopump circuit, but for the roller pump group a significant difference was seen in all arterial blood gas measures both 1 hour (PO₂ p = 0.02; PCO₂ p = 0.003; pH p = 0.0005) and 2 hours (PO₂ p = 0.03; PCO₂ p < 0.0001; pH p < 0.0001) after the discontinuation of bypass. A significant difference was also seen between the two bypass groups at 2 hours after the discontinuation of bypass (PO₂ p = 0.006; PCO₂ p = 0.0008).

Blood count and differential white cell count
There was no significant difference in hematocrit between the groups prior to bypass. Over time however, there was no significant change in the control group or the Hemopump group either within or between groups, but there was a significant fall in hematocrit for the roller pump group both within the group (p < 0.0001) and compared with controls (p = 0.002) and the Hemopump group (p = 0.0003).

From the time of cannulation there was a profound decrease in the white cell count in both the control and Hemopump groups (control p < 0.0001; Hemopump p = 0.0001) with no significant difference between the two groups. Both neutrophil and lymphocyte numbers fell significantly and to a similar degree (Fig 2) in the Hemopump group, whereas a depletion of lymphocytes but not neutrophils was noted in the control group. In a limited group of Hemopump fetuses that were sampled there was no difference between arterial and umbilical venous blood counts. There was no demonstrable decrease in white cell counts with roller pump bypass; neutrophils decreased significantly (p = 0.02) but there was no significant change in lymphocyte count.

View larger version (34K): [in this window] [in a new window]   Fig 2. The changes in absolute white cell count and differential with time spent on bypass. There was a profound fall in both white cell species in both the control and Hemopump groups (control p < 0.0001; Hemopump p = 0.0001). (Lymph = lymphocytes; Neut = neutrophils.)

View larger version (34K): [in this window] [in a new window]   Fig 3. The change in level of the cleaved complement fragment C3a with time spent on bypass. There was a significant rise in C3a levels only in the roller pump group (p < 0.0001). (*p < 0.0001 roller pump versus controls; §p = 0.02 roller pump versus controls; p = 0.003 roller pump versus controls; p = 0.002 roller pump versus Hemopump.)

View larger version (29K): [in this window] [in a new window]   Fig 4. The change in level of lactoferrin with time spent on bypass. There was a significant rise in lactoferrin level in both bypass groups (Hemopump p = 0.01; roller pump p < 0.0001). (*p = 0.0008 roller pump versus controls; §p = 0.0001 roller pump versus controls; p = 0.02 roller pump versus Hemopump; p = 0.001 roller pump versus Hemopump.)

	Comment

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The rise in lactoferrin level was both statistically significant and quantitatively unequivocal. This rise appeared to be related to extracorporeal circulation in the fetus as it began with the initiation of bypass in both Hemopump and roller pump groups but did not occur in controls. Although it had been shown previously that heparin can directly activate neutrophils and cause degranulation [10], it is unlikely in the current study that the rise in lactoferrin level was due to the administration of heparin either directly or indirectly insofar as the control animals, given an identical dose, showed no rise. Further, the greatest rise in lactoferrin levels occurred after discontinuing cardiac bypass rather than following heparinization. These results suggest that neutrophil degranulation occurs with fetal bypass.

Our results also suggest that neutrophil degranulation may play a significant role in causing the fetoplacental unit dysfunction that results from fetal cardiac bypass. We have shown previously that outcomes using a miniaturized circuit including an in-line axial flow pump (Hemopump) are significantly better than with a conventional bypass circuit including a roller pump; these findings are confirmed in this study. It would therefore be expected that if neutrophil degranulation plays a significant role in fetoplacental unit dysfunction, levels of neutrophil degranulation products should be higher after roller pump bypass than after Hemopump bypass. This was indeed the case. Fetal cardiac bypass with the roller pump circuit was associated with significantly greater white cell activation than with the Hemopump bypass.

The persistent neutropenia that we observed has been documented in nonprimate species undergoing postnatal cardiopulmonary bypass [11]. It did not reflect neutrophil adherence to the bypass circuit as it also occurred in control animals not exposed to the foreign surface. The exact location of neutrophil accumulation remains unknown, although experiments are underway to elucidate it. To support the proposed relationship between lactoferrin levels and fetoplacental dysfunction it would be convenient for the site of neutrophil accumulation to be the placenta with degranulation causing localized vasospasm and tissue damage. However, the present study does not support this hypothesis insofar as there was no drop in white cell count across the placental vascular bed. More definitive studies to determine whether the placenta is the site of neutrophil sequestration by assaying myeloperoxidase activity are underway.

The neutropenia observed in control animals was a surprising finding. It was associated temporally with deterioration in some hemodynamic parameters (blood pressure and combined ventricular output) and some determinants of fetoplacental unit function (specifically PO₂) similar to that which occurred in bypass animals. This finding suggests that simply exposing the fetus from the uterus causes neutrophil activation, which may be associated with a deterioration in placental hemodynamics and gas exchange and a fall in fetal combined ventricular output. The cause is unknown. C3a levels did not rise so it must therefore reflect neutrophil activation by some other mechanism, possibly as part of the fetal stress response. Interestingly, although there was a moderate (but not significant) neutropenia in the control group, there was no significant rise in lactoferrin levels, suggesting that leukocytes may have marginated but apparently did not release their specific granule products. The large standard deviation for these lactoferrin results should be noted; this finding may be an indication that in some animals there was a large release of lactoferrin associated with fetal exposure even though they were apparently treated in exactly the same way as the others. These observations may be critically important in the clinical application of fetal operation in general as it has been suggested that neutrophil activation may be a trigger for premature rupture of the membranes and premature labor [12]. This hypothesis may offer an explanation for the high fetal loss currently associated with clinical fetal interventions.

The exact mechanism of the injury sustained by the fetoplacental unit was not elucidated in this study. Lactoferrin was used purely as an indicator of neutrophil degranulation and not as a putative marker of specific functional involvement. Lactoferrin is a useful molecule in this respect as virtually all lactoferrin detectable in peripheral blood is derived from neutrophils though its presence is not completely reflective of neutrophil degranulation, as azurophilic (containing elastase, myeloperoxidase, cathepsin, etc.) or specific (containing lactoferrin) granules can be released independently [13].

From what we know of its biological activity, lactoferrin is an apt candidate to be the trigger and promoter of the vascular changes associated with fetal cardiac bypass. Biologically lactoferrin is highly active in the generation and amplification of the inflammatory response. Intravenous injection causes release of IL-6 and it directly cleaves the complement component C5 to the chemoattractant C5a and an activator of the complement cascade. Like C5a, lactoferrin promotes neutrophil adhesiveness, aggregation, and degranulation by increasing surface CD11b/CD18 expression. Lactoferrin itself amplifies granulocyte-mediated oxidant endothelial cell damage due to its iron content, which catalyzes the formation of hydrogen peroxide. By all of these mechanisms the specific granules in general, and lactoferrin in particular, play a pivotal role in the induction and amplification of the inflammatory response, certainly locally, but potentially generally throughout the body. Any of these mechanisms could occur in the fetal bypass model. We demonstrated previously that IL-6 is elevated after fetal cardiac bypass despite the lack of a concomitant increase in IL-1ß [14], one of the primary cytokine mediators of IL-6 release.

We conclude that fetal cardiac bypass causes both activation of the complement cascade through the alternative pathway and neutrophil degranulation as determined by a rise in plasma lactoferrin. These events are significantly greater with roller pump bypass than with Hemopump bypass. This finding and the temporal relationship between the rise in lactoferrin levels and hemodynamic changes particularly in the Hemopump group suggest that neutrophil degranulation may play a significant role in causing the fetoplacental unit failure that occurs with fetal cardiac bypass.

	References

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