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Congress report

B. Freya, S. B. Hortonb, T. Dukea, F. Shanna


a

Schweiz Med Wochenschr 2000;130:15725

Paediatric Intensive Care Unit, Royal Childrens Hospital, Melbourne (AUS) Perfusion Unit of the Department of Cardiac Surgery, Royal Childrens Hospital, Melbourne (AUS)

The immature-to-total neutrophil ratio (IT ratio) is a sensitive indicator of sepsis after paediatric cardiopulmonary bypass1

Summary
Cardiopulmonary bypass (CPB) causes a systemic inflammatory response syndrome (SIRS) with activation of neutrophils (increased immature-to-total neutrophil ratio, IT ratio). Does an additional inflammatory response induced by sepsis further increase the IT ratio, so that it can still be used as an indicator of sepsis? In 160 children we analysed retrospectively the IT ratios from the day before CPB to the 10th day after the operation (controls). The 95% confidence limits of the controls were plotted against postoperative day and compared with the IT ratio courses in all children of a 4-year period who developed sepsis during the first 10 days after CPB. All septic children (n = 9) had IT ratios above the upper 95% confidence limits of the controls on the day of positive culture or on the following day. The IT ratio remains a sensitive indicator of sepsis even after CPB. Keywords: cardiopulmonary bypass; sepsis; neutrophils; infants; children

Zusammenfassung
Der extrakorporelle Kreislauf (ECC) fhrt zu einer systemischen Entzndungsreaktion (SIRS) mit Aktivierung der neutrophilen Granulozyten (Linksverschiebung, erhhte ITRatio). Fhrt eine zustzliche infektise Entzndungsreaktion (Sepsis) zu einer weiteren, eindeutigen Zunahme der IT-Ratio? Wir analysierten retrospektiv bei 160 Kindern die ITRatio vor und whrend der ersten 10 Tage nach ECC (Kontrollgruppe). Die 95%-Vertrauensgrenzen der Kontrollgruppe wurden verglichen mit dem IT-Ratio-Verlauf von allen Kindern, die ber einen Zeitraum von 4 Jahren in der gleichen Institution whrend der ersten 10 Tage nach ECC eine Blutkultur-positive Sepsis entwickelten. Alle septischen Kinder (n = 9) hatten am Tag der positiven Blutkultur oder am darauffolgenden Tag eine IT-Ratio, die ber der oberen 95%-Vertrauensgrenze lag. Bei Kindern ist die IT-Ratio auch nach ECC ein sensitiver Sepsisindikator. Keywords: extrakorporeller Kreislauf; Sepsis; neutrophile Granulozyten; Kinder

1 Poster presentation at the Annual meeting of the Swiss Society of Intensive Care with participation of the Swiss Society of Medical Informatics (Davos, September 2324, 1999)

Correspondence: Dr. med. Bernhard Frey Intensive Care Unit Universitts-Kinderklinik Steinwiesstrasse 75 CH-8032 Zrich e-mail: bernhard.frey@kispi.unizh.ch

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Introduction
Cardiopulmonary bypass (CPB) causes a systemic inflammatory response syndrome (SIRS) which can lead to organ injury, including pulmonary, renal, central nervous system, hepatic and myocardial dysfunction. Activation of the complement system, coagulation cascade and neutrophils, as well as synthesis of various cytokines, are believed to cause organ injury [1, 2]. Neutrophil activation is reflected in the peripheral blood in a rise of the absolute neutrophil count and a left shift of neutrophils (increased immature-to-total neutrophil ratio, IT ratio) [2, 3]. Bacterial infections are also known to increase the IT ratio. The aim of this study was to investigate, whether the IT ratio can be used as an indicator of sepsis after paediatric CPB.

Patients and methods


In 160 children the IT ratios were analysed retrospectively from the day before CPB to the 10th day after operation. The following patients were not included in these 160 controls: second and following operations on CPB in children with two or more operations; children who underwent two or more operations on CPB within 10 days; children with blood culture postive sepsis, cardiac arrest, postoperative treatment with ventricular assist device (VAD) or extracorporeal membrane oxygenation (ECMO) (all criteria applicable to the first 10 days after CPB). Patients on VAD/ECMO, with cardiac arrest and sepsis were excluded because these conditions might influence the IT ratio. The analysed patients are part of a study on the alterations of erythropoiesis by CPB [4]. The IT ratio was defined as the fraction of immature-to-total neutrophilic forms. All bands and cell forms less mature than bands were classified together as immature neutrophils. Segmented (mature) neutrophils were defined as having a filamentous bridge between nuclear lobes (fig. 1). For determination of the differential white cell count a total of 100 white cells were counted.
Figure 1
Segmented neutrophil (filamentous bridge between nuclear lobes).

CPB was instituted in a routine fashion. The bypass circuit comprised a Stckert roller pump (Stckert Instruments, Munich, Germany), a Cobe VPCML membrane oxygenator (Cobe Laboratories, Denver, CO, USA) and a Bentley AF540 arterial filter (Baxter Healthcare, Compton, UK). A bloodless prime was always considered and used if patient haematocrit allowed. A clear prime consisted of Plasmalyte 148 in water, Haemaccel, 5% glucose, heparin and sodium bicarbonate. Different blood primes were used depending on patient weight. The 95% confidence limits for the IT ratio of the controls were plotted against postoperative day. The number of analysed cases for the day before the operation and the first to the 10th postoperative day were: 134, 101, 132, 111, 89, 69, 49, 52, 39, 27, 19 (white cell differentials were not available for each patient on each day). By means of the microbiology files, all children who were septic after CPB at the same institution during a 4-year period (19931996) were retrieved. Their IT ratio courses were drawn in the same plot.

Results
The 95% confidence limits for the IT ratios of the controls and the IT ratio courses of the septic patients are shown in figure 2. There were 9 septic patients in the 4-year period. Their clinical characteristics are outlined in table 1. There were 2 patients (cases 2 and 7) whose blood cultures were not positive. However, they were included in the analysis for the inva1573

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Figure 2
Mean and 95% confidence limits for IT ratio in controls and IT ratio courses in 9 septic children; * day of positive culture.

siveness of their infections (necrotising enterocolitis, confirmed by laparotomy and growth of Staphylococcus aureus at the tip of a pacing wire). The septic children were younger than the conTable 1
Clinical characteristics and pathogens of septic children after CPB. case 1 2 3 4 5 6 7 8 9 age 7 days 7 days 8 days 18 days 1 month 2 months 3 months 4 months 15 months diagnosis DORV VSD TGA TGA TAPVD TGA VSD ASD TGA VSD VSD AVSD operation arterial switch VSD closure arterial switch arterial switch correction arterial switch closure arterial switch VSD closure closure closure

trols (median, range: 1 month, 7 days to 1.3 years vs 1.1 years, 2 days to 20 years). The bypass time of the septic patients was longer than the bypass time of the controls (mean, SD: 144, 64 min vs 92, 50 min).

CPB time pathogen, postoperative day (min) 173 263 138 63 207 131 139 60 125 Staphylococcus aureus (blood culture), day 2 Acinetobacter spp (sternal swab), day 5 necrotising enterocolitis (laparotomy), day 7 Staphylococcus aureus (blood culture and tip of CVL), day 10 Serratia marcescens (blood culture), day 1 Staphylococcus haemolyticus (blood culture), day 3 Enterococcus faecalis (blood culture), day 10 Staphylococcus aureus (tip of pacing wire), day 10 coagulase negative Staphylococcus (blood culture) and Branhamella catarrhalis (BAL), day 4 Bacillus cereus (blood culture), day 1

DORV = double outlet right ventricle; VSD = ventricular septal defect; TGA = transposition of the great arteries; TAPVD = total anomalous pulmonary venous drainage; ASD = atrial septal defect; AVSD = atrio-ventricular septal defect; CVL = central venous line; BAL = broncho-alveolar lavage

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Discussion
All septic children had IT ratios above the upper 95% confidence limits of the controls on the day of positive (blood) culture or on the following day. We speculate that the inflammatory response induced by sepsis exceeds the response induced by CPB. According to our retrospective analysis, the IT ratio remains a sensitive indicator of sepsis even after CPB. CPB causes a rise of the absolute neutrophil count and a left shift of neutrophils. Both changes may be induced by release of cytokines and may be part of the CPB-related SIRS. Finn et al. [2] found a significant relationship between interleukin (IL)-8 concentration and neutrophil count after paediatric CPB. IL-8 release correlated significantly with length of CPB. In a rat model a single intravenous injection of IL-6 caused a left-shifted myeloid hyperplasia in the marrow at 12 and 24 hours [3]. IL-6 level has been shown to be elevated during CPB [5]. Krafte-Jacobs and Bock [6] reported on increased values for plasma IL-6 in critically ill children with sepsis or septic shock. There are some limitations to the study. The results of this retrospective study depend on the available data, for which there may have been some selection bias. Well children may not have had blood films done after the first few days. However, the inclusion of these children may have further decreased the 95% confidence limits for the IT ratio. The septic patients were younger and had longer CPB times than the controls. Both young age and long CPB time may increase the IT ratio. However, it is unlikely that this increase reaches the very high ranges found in most septic children. It is more likely that young age and long bypass time predispose to infection.

References
1 Butler J, Rocker GM, Westaby S. Inflammatory response to cardiopulmonary bypass [review]. Ann Thorac Surg 1993;55: 5529. 2 Finn A, Naik S, Klein N, Levinsky RJ, Strobel S, Elliott M. Interleukin-8 release and neutrophil degranulation after pediatric cardiopulmonary bypass. J Thorac Cardiovasc Surg 1993;105:23441. 3 Ulich TR, Del Castillo J, Guo K. In vivo hematologic effects of recombinant interleukin-6 on hematopoiesis and circulating numbers of RBCs and WBCs. Blood 1989;73:10810. 4 Frey B, Duke T, Horton SB. Nucleated red blood cells after cardiopulmonary bypass in infants and children: is there a relationship to the systemic inflammatory response syndrome? Perfusion 1999;14:17380. 5 Casey LC. Role of cytokines in the pathogenesis of cardiopulmonary bypass-induced multisystem organ failure. Ann Thorac Surg 1993;56:S926. 6 Krafte-Jacobs B, Bock GH. Circulating erythropoietin and interleukin-6 concentrations increase in critically ill children with sepsis and septic shock. Crit Care Med 1996;24:14559.

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