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Congress report

Schweiz Med Wochenschr 2000;130:1572–5

B. Frey a , S. B. Horton b , T. Duke a , F. Shann a

a Paediatric Intensive Care Unit, Royal Children’s Hospital, Melbourne (AUS)

b Perfusion Unit of the Department of Cardiac Surgery, Royal Children’s Hospital, Melbourne (AUS)

The immature-to-total neutrophil ratio (IT ratio) is a sensitive indicator of sepsis after paediatric cardiopulmonary bypass 1

Summary

Zusammenfassung

Cardiopulmonary bypass (CPB) causes a sys- temic inflammatory response syndrome (SIRS) with activation of neutrophils (increased im- mature-to-total neutrophil ratio, IT ratio). Does an additional inflammatory response in- duced by sepsis further increase the IT ratio, so that it can still be used as an indicator of sep- sis? 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 com- pared with the IT ratio courses in all children of a 4-year period who developed sepsis dur- ing the first 10 days after CPB. All septic chil- dren (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

Der extrakorporelle Kreislauf (ECC) führt zu einer systemischen Entzündungsreaktion (SIRS) mit Aktivierung der neutrophilen Gra- nulozyten (Linksverschiebung, erhöhte IT- Ratio). Führt eine zusätzliche infektiöse Ent- zündungsreaktion (Sepsis) zu einer weiteren, eindeutigen Zunahme der IT-Ratio? Wir ana- lysierten retrospektiv bei 160 Kindern die IT- Ratio vor und während der ersten 10 Tage nach ECC (Kontrollgruppe). Die 95%-Vertrauens- grenzen der Kontrollgruppe wurden verglichen mit dem IT-Ratio-Verlauf von allen Kindern,

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 23–24, 1999)

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die über einen Zeitraum von 4 Jahren in der gleichen Institution während 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 über der oberen 95%-Vertrauensgrenze lag. Bei Kindern ist die IT-Ratio auch nach ECC ein sensitiver Sepsisindikator. Keywords: extrakorporeller Kreislauf; Sepsis; neutrophile Granulozyten; Kinder

Correspondence:

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

Schweiz Med Wochenschr 2000;130: Nr 42

Introduction

Congress report

Cardiopulmonary bypass (CPB) causes a sys- temic inflammatory response syndrome (SIRS) which can lead to organ injury, including pul- monary, renal, central nervous system, hepatic and myocardial dysfunction. Activation of the complement system, coagulation cascade and neutrophils, as well as synthesis of various cy- tokines, are believed to cause organ injury [1, 2]. Neutrophil activation is reflected in the pe-

Patients and methods

ripheral blood in a rise of the absolute neu- trophil 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 pae- diatric CPB.

In 160 children the IT ratios were analysed retrospectively from the day before CPB to the 10th day after operation. The following pa- tients were not included in these 160 controls: second and follow- ing 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, post- operative treatment with ventricular assist device (VAD) or extra- corporeal membrane oxygenation (ECMO) (all criteria applicable to the first 10 days after CPB). Patients on VAD/ECMO, with car- diac 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 neu- trophilic forms. All bands and cell forms less mature than bands were classified together as immature neutrophils. Segmented (ma- ture) neutrophils were defined as having a filamentous bridge be- tween nuclear lobes (fig. 1). For determination of the differential white cell count a total of 100 white cells were counted.

CPB was instituted in a routine fashion. The bypass circuit com- prised a Stöckert roller pump (Stöckert Instruments, Munich, Ger- many), 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 consid- ered and used if patient haematocrit allowed. A clear prime con- sisted of Plasmalyte 148 in water, Haemaccel, 5% glucose, heparin and sodium bicarbonate. Different blood primes were used de- pending on patient weight. The 95% confidence limits for the IT ratio of the controls were plot- ted 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 dif- ferentials 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 re- trieved. Their IT ratio courses were drawn in the same plot.

Figure 1

Segmented neutrophil (filamentous bridge between nuclear lobes).

neutrophil (filamentous bridge between nuclear lobes). Results The 95% confidence limits for the IT ratios of

Results

Congress report

Schweiz Med Wochenschr 2000;130: Nr 42

Figure 2

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

courses in 9 septic children; * day of positive culture. siveness of their infections (necrotising entero-

siveness of their infections (necrotising entero- colitis, confirmed by laparotomy and growth of Staphylococcus aureus at the tip of a pac- ing wire). The septic children were younger than the con-

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

Table 1

Clinical characteristics and pathogens of septic children after CPB.

case

age

diagnosis

operation

CPB time

pathogen, postoperative day

 

(min)

1

7 days

DORV

arterial switch

173

Staphylococcus aureus (blood culture), day 2

 

VSD

VSD closure

2

7 days

TGA

arterial switch

263

Acinetobacter spp (sternal swab), day 5 necrotising enterocolitis (laparotomy), day 7

3

8 days

TGA

arterial switch

138

Staphylococcus aureus (blood culture and tip of CVL), day 10

4

18 days

TAPVD

correction

63

Serratia marcescens (blood culture), day 1

5

1 month

TGA

arterial switch

207

Staphylococcus haemolyticus (blood culture), day 3

6

2 months

VSD

closure

131

Enterococcus faecalis (blood culture), day 10

 

ASD

7

3 months

TGA

arterial switch

139

Staphylococcus aureus (tip of pacing wire), day 10

 

VSD

VSD closure

8

4 months

VSD

closure

60

coagulase negative Staphylococcus (blood culture) and Branhamella catarrhalis (BAL), day 4

9

15 months

AVSD

closure

125

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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Schweiz Med Wochenschr 2000;130: Nr 42

Discussion

Congress report

References

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 inflam- matory 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 be- tween interleukin (IL)-8 concentration and neutrophil count after paediatric CPB. IL-8 re- lease correlated significantly with length of CPB. In a rat model a single intravenous injec- tion of IL-6 caused a left-shifted myeloid hy- perplasia in the marrow at 12 and 24 hours [3].

IL-6 level has been shown to be elevated dur- ing CPB [5]. Krafte-Jacobs and Bock [6] re- ported on increased values for plasma IL-6 in critically ill children with sepsis or septic shock. There are some limitations to the study. The re- sults 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% confi- dence 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 pre- dispose to infection.

1 Butler J, Rocker GM, Westaby S. Inflammatory response to cardiopulmonary bypass [review]. Ann Thorac Surg 1993;55:

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2 Finn A, Naik S, Klein N, Levinsky RJ, Strobel S, Elliott M. In- terleukin-8 release and neutrophil degranulation after pedi- atric 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 circulat- ing 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 re- lationship to the systemic inflammatory response syndrome? Perfusion 1999;14:17380.

5 Casey LC. Role of cytokines in the pathogenesis of car- diopulmonary bypass-induced multisystem organ failure. Ann Thorac Surg 1993;56:S926.

6 Krafte-Jacobs B, Bock GH. Circulating erythropoietin and in- terleukin-6 concentrations increase in critically ill children with sepsis and septic shock. Crit Care Med 1996;24:14559.

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