Introduction
Cardiac surgery with cardiopulmonary bypass (CPB) is associated with the development of systemic inflammatory response syndrome (SIRS) [
6,
10]. Additionally to the inflammatory response due to surgical trauma, several inflammatory processes are triggered by the CPB. Hypothermia, contact of blood with foreign surfaces of the CPB circuit or ischemia–reperfusion injury due to aortic cross-clamping and endotoxins generated by splanchnic hypoperfusion all stimulate multiple inflammatory cascades with humoral and cellular reactions [
10]. SIRS often leads to organ dysfunction or failure [
9,
31], increased mortality and prolonged stay on intensive care unit (ICU) [
27,
31]. Numerous strategies have been developed to minimize the inflammatory response to CPB such as corticosteroids, leukocyte depletion, hemofiltration, miniaturized CPB circuits, off-pump surgery and alterations of the coagulation/anticoagulation management [
6,
10]. So far, all current strategies focused on modification of pre- and intraoperative factors. However, the inflammatory processes may be maintained or even intensified by further treatment on ICU. So far, no preventive strategy has been established for ICU management.
Particles arising from infusion therapy on ICU may aggravate the inflammatory response. Particles have been shown to generate thrombosis [
34], impair microcirculation [
29] and modulate immune response [
19]. Sources of particles include components of infusion systems, incomplete reconstitution of solutions or drug incompatibility reactions [
19,
30]. Up to one million particles may be infused per patient per day [
19,
20]. In-line filters incorporated into infusion lines retain particles and thereby nearly entirely prevent their infusion [
19,
29]. In a prospective, randomized, controlled trial (ClinicalTrials.gov number; NCT00209768) including 807 critically ill children, we have previously demonstrated that in-line filtration reduced the composite endpoint of severe complications including sepsis, SIRS and organ failure [
7,
20]. Additionally, SIRS and several organ dysfunctions were reduced as single incidence [
7,
20]. Moreover, length of stay (LOS) on pediatric intensive care unit (PICU) and duration of mechanical ventilation (MV) were also significantly shortened [
20].
In the previous study population, we now analyzed the effect of in-line filtration on major complications in the subgroup of cardiac patients (n = 305), which has not been described in detail before. Risk differences of several complications such as SIRS, sepsis, mortality, various organ failure and dysfunction were compared between both groups. Furthermore, LOS on PICU and time of MV were analyzed.
Discussion
Recently, we conducted a prospective, randomized, controlled trial to evaluate the effect of in-line filtration on major complications in critically ill children [
7,
20]. The current investigation focused on the subgroup of children with cardiac diseases in the previously published study population [
7,
20]. This subgroup of cardiac patients has not been investigated in detail before. In addition to our previous data [
7,
20], we further characterized underlying cardiac diagnoses, the procedural risk for cardiac surgery and intraoperative data. Until now, no study has ever investigated the effect of in-line filtration retaining particles arising from infusion solutions during stay on cardiac PICU.
Since use of a contingency table or calculation of a P value is statistically inappropriate in a subgroup analysis, we computed risk differences and its 95 % confidence interval (CI) for each endpoint. A statistically significant difference between control and filter group was assumed, if the 95 % CI of the risk differences did not contain zero. The present analysis thereby comprises descriptive statistics.
In the light of this methodological approach, our main findings suggest that in-line filtration is highly effective in preventing the occurrence of SIRS in cardiac intensive care patients. Moreover, in-line filtration seemed to preserve hematologic and renal organ function. Length of stay on ICU and the duration of MV as well as all other complications were observed to be decreased in the filter group, albeit not reaching the level of significance as defined above.
For the evaluation of SIRS, we applied the generally accepted pediatric consensus criteria [
17]. So far, no other trial has assessed the incidence of SIRS in critically ill children with cardiac diseases. Our study revealed that SIRS was a major problem on a cardiac PICU. According to our data, more than one-third of all patients experienced at least one episode of SIRS. In-line filtration effectively reduced the incidence of SIRS and thereby might lower the morbidity of cardiac intensive care patients. Patients suffering from SIRS have a higher risk to develop sepsis [
28], ARDS, disseminated intravascular coagulation, acute renal failure or even die of SIRS [
27]. Moreover, according to our data [
20] and also demonstrated by others, SIRS is associated with both prolonged stay on PICU and extended MV [
31]. In-line filtration represents the first preventive strategy reducing a systemic inflammation and comorbidities on PICU.
The control group suffered from a higher incidence of hematological dysfunction characterized by thrombocytopenia and coagulopathy. As patients with CHD per se and even more pronounced in cyanotic CHD show an altered hemostatic physiology with decreased concentrations of coagulation factors and abnormalities of platelets [
14], an additional infusion of particles obstructing small capillaries may worsen the preexisting coagulopathy [
34,
35]. No cardiac right-to-left shunt provided, in patients without particle-retentive in-line filters, the lung capillaries are the first endogenous filters for intravenously infused particles [
15,
34,
35]. Particles trapped in lung capillaries, form occlusive microthrombi and induce an activation of complement, platelets and neutrophils [
34,
35]. But, blockage of vessels is not only restricted to the lung. Even without a relevant cardiac right-to-left shunt, intravenously injected particles are distributed from the lung to the systemic circulation and several organs such as blood, liver, kidney and spleen [
12,
29]. Here, they may induce a systemic hypercoagulability. These systemic effects on different organ systems might be even more pronounced in patients with CHD and right-to-left shunts. As the coagulation and inflammatory system are closely linked in multiple ways [
25], this cross-link may contribute to a further aggravation of both hypercoagulation and SIRS. In our study, this deleterious linkage becomes clinically apparent in the control group: Patients without in-line filters suffered from a higher incidence of SIRS and coagulopathy. Especially in patients after cardiac surgery with CPB, the physiological hemostasis of the coagulation system is altered for several days postoperatively [
8,
21] as the contact of blood to the artificial surfaces of the CPB circuit causes an activation and consumption of platelets and coagulation factors [
8]. A further infusion of particles on ICU as in the control group may additionally trigger the coagulation cascade and contribute to the coagulopathy. This systemic hypercoagulability also plays a relevant role in the pathogenesis of microvascular impairment and organ failure at multiple sites [
25].
As demonstrated in our study, cardiac patients who are not protected by particle-retentive in-line filters had a higher incidence of renal dysfunction. An infusion of particles may disturb the renal vascular integrity and enhance the susceptibility to organ dysfunction. Especially patients with cyanotic CHD have an increased risk of developing renal impairment [
2]. Many studies have shown proteinuria, reduced glomerular filtration rate, and proliferation of renal tubular and glomerular cells in patients with CHD [
2]. Contributing factors such as CPB may further augment the effects of particle infusion. Renal injury following CPB is frequent, and its pathogenesis is multifactorial [
1]. Ischemia–reperfusion injury, oxidative stress, microembolization and the inflammatory response have been accused for the development of renal injury [
1,
18]. The increased incidence of renal impairment may also contribute to a prolonged stay on PICU and extended MV as shown in children after cardiac surgery [
26].
In the control group lacking in-line filters, particles obstructing lung capillaries trigger the complement system and activate platelets and neutrophils [
15,
34,
35]. This inflammatory process may lead to an intensified and prolonged MV as shown for the control group in the main study population [
20]. In patients after cardiac surgery with CPB, the effect of particle infusion may be even more pronounced and the pulmonary inflammation exaggerated. During CPB, the lungs are excluded from the circulation and remain ischemic and hypoxic for a long period [
4]. The following reperfusion induces an inflammatory response with formation of free oxygen radicals and endothelial injury [
4]. Beyond this local pulmonary inflammation, several inflammatory mediators released during CPB stimulate the proliferation of neutrophils and their migration to lung capillaries [
4]. Here they additionally induce an endothelial cell swelling and an inflammation in the interstitial tissue and alveoli [
4]. A further particle infusion may aggravate this postperfusion lung syndrome.
The differences in the clinical findings between the control and the filter group might be attributed to a further deterioration of microvascular perfusion by particulate infusion in the control group. Microcirculatory disturbance occurs frequently in critically ill patients and leads to organ malfunction [
13]. With already preexisting microvascular impairment, an additional infusion of particles causes a further loss of microvascular density as demonstrated in preclinical animal studies [
24,
29]. In the same experimental settings, use of particle-retentive in-line filters was able to completely prevent these effects [
29]. Therefore, in-line filtration may account for the maintenance of microvascular integrity and thereby preserve the multiple organ functions within the interventional group. One could assume that any critically ill patient regardless the underlying disease would benefit from the potential protective properties of in-line filtration on microcirculation. Especially during cardiac surgery, both the inflammatory response to CPB and the hemodynamic and metabolic changes alter the microcirculatory perfusion and decrease capillary density [
11,
13]: a condition that persists at least for the first 24 postoperative hours on ICU [
11]. In this state, additional microcirculatory impairment may exceed the level of organ retrieval and organ dysfunction becomes clinically apparent. An early recovery of microcirculation is therefore associated with a faster restoration of organ function [
33] in the interventional group.
Acknowledgments
We thank all participants and their legal guardians who volunteered for the study, the staff of the Department of Pediatric Cardiology and Intensive Care Medicine, Hannover Medical School, Hannover, Germany, for their excellent support—in particular Dr Bernadette Brent, Jan Wessels, Michaela Abura, Markus Becker, Christina Bormann, Vanessa Dannenberg, Verena Quartier, Dilek Yilmaz, Alexander Vogel, Hannah Toensfeuerborn and Jana Wuttke. We specially thank all members of the nursing staff for their excellent work during the whole period of the trial. We thank Frank Schroeder, pharmacist at Klinikum Bremen-Mitte, Bremen, Germany, and Wolfgang Orth (oData, Rastede, Germany) for their support regarding the prevention of incompatibilities and for providing the KIK 3.0 software. Furthermore, the authors thank Ludwig Hoy, PhD, statistician, Hannover Medical School, for statistical advice.