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( cannulation to MCS during the process of active cardiopulmonary resuscitation) having the worst [ 2 ]. The development of new infection on MCS affects up to 64 %( 8 – 64 %) of patients and has been shown to impact outcomes [ 3, 4 ]. Those who develop an infection while on MCS have a longer duration of support, require longer post-MCS mechanical ventilation and have a higher mortality rate [ 3 ]. Early detection of infection and prompt initiation of antibiotics are necessary to improve outcomes in MCS patients [ 5, 6 ]. There is considerable variability between centers on how to monitor or when to start treatment for suspected infection in patients receiving MCS [ 7 ]. The Extracorporeal Life Support Organization recommends against the practice of routine blood, urine or sputum cultures and acknowledges the difficulty that MCS places on the use of traditional methods to diagnose infection, including the unknown significance of inflammatory markers.
The effectiveness of the commonly utilized biomarkers C-Reactive Protein( CRP) and Procalcitonin, in aiding with the diagnosis of infection during MCS is fraught with limitations and remains under investigation [ 7 – 11 ]. These biomarkers face limitations specifically due to the effect of MCS-induced inflammation on CRP and Procalcitonin kinetics [ 4, 7, 11, 12 ]. Previous pediatric studies have shown mixed results regarding the predictive value of CRP and Procalcitonin for new infection during MCS [ 8, 9 ]. One such study, Bobillo et al. did find that procalcitonin decreased after cannulation in patients with elevated pre-cannulation procalcitonin levels, while in patients with low pre-cannulation procalcitonin levels the levels remained stable; this same paper did not identify an increase in procalcitonin levels in response to infection [ 11 ].
Soluble Triggering Receptor Expressed on Myeloid Cells( sTREM-1) and Presepsin( soluble CD14 Subtype) have been demonstrated to be promising emerging biomarkers of infection, given their ability to differentiate new infection from other types of inflammatory responses [ 6, 13 ]. sTREM-1 and Presepsin are two cell surface biomarkers released during periods of innate immune cell activation, such as invasive infection, which are detectable in plasma [ 6, 14 – 17 ]. sTREM-1 has the potential to be a specific marker for invasive infection rather than inflammation alone due to the synergistic mechanism of sTREM-1 acting with Toll Like Receptors and aiding their recognition of foreign pathogens [ 15 ]. Presepsin is expressed and released as a result of macrophage binding to pathogenic organisms, again giving Presepsin potential to more specifically identify invasive infection rather than inflammation alone [ 14 ]. In septic neonates not on MCS, both Presepsin and sTREM-1 were significantly elevated compared to non-septic neonates and these biomarkers had greater sensitivity and specificity compared to CRP in detecting infection [ 6 ]. Presepsin was elevated in children with infection compared to those with non-infectious systemic inflammatory response syndrome [ 18, 19 ]. We aim to investigate the utility of the novel biomarkers sTREM-1 and Presepsin in detecting infection during MCS. We evaluated the kinetics of sTREM-1 and Presepsin during cannulation for MCS and compared them to current commonly used biomarkers CRP and Procalcitonin. We hypothesize that increases in sTREM-1 and Presepsin will predict infection in advance of culture proven infection in pediatric MCS patients.
Methods
Institutional Review Board( IRB) approval with a waiver of informed consent was obtained( IRB number: STUDY00002511). Patients were included if they received MCS between 2013 and 2021 at our institution regardless of indication, had previously provided consent to participate in the MCS biomarker study( all patients receiving MCS at our institution were eligible for inclusion in this study unless they weighed less than 2 kg or were of Jehovah’ s witness faith [ or another faith which were against transfusions ]), has included consent for the use of residual samples and had acquired a new infection during MCS. Exclusion criteria included the lack of consent for the use, or the absence of residual samples at appropriate times points. Strengthening the Reporting of Observation studies in Epidemiology( STROBE) guidelines reporting guidelines were utilized as a structured framework for reporting this project [ 20 ].
ECMO and VAD circuit priming
We utilize the CentriMag and PediMag circuits for ECMO patients at our institution. For patients weighing less than 15 kg we utilize 2 units of Packed Red Blood Cells( PRBC), 1 unit of Fresh Frozen Plasma( FFP) and 120 ml of Platelets. For patients weighing more than 15 kg we utilize 3 units of PRBC and 1 unit of FFP. We will also utilize 25 % albumin, Calcium Chloride and Sodium Bicarbonate in order to balance the circuit prime. Patients will typically be loaded with 50 – 100 units / kg of heparin and anticoagulation will be maintained with Bivalirudin once the activated clotting time and partial thromboplastin time is within range and the patient is not experiencing bleeding. We utilize multiple VAD circuits at our institution including: CentriMag / PediMag, Berlin Hearts, HeartMate 3 and Impella pumps. We only prime our CentriMag / PediMag with potentially 1 unit of PRBC however this is surgeon and case dependant based on the dilutional hematocrit. The patients are initially place onto Bivalirudin for continuous anticoagulation and may be transitioned to Warfarin and acetylsalicylic acid on a case by case basis.
Clinical data collection
Clinical data was extracted from the electronic medical record including demographic information, indication for MCS, method of MCS and outcomes. Additionally, we identified the location and causal organism for each new infection. Patients were defined as having a new infection if they developed a new positive blood, urine or respiratory culture for either bacteria or fungi while receiving MCS. All patients classified as developing a new infection had both: 1) new positive culture results and 2) antiobiotic therapy by the clinical team indicating a clinically significant infection. At our institution the clinical practice is to obtain routine blood cultures Monday, Wednesday and Friday while receiving MCS.