Bypass Clear Priming VSD Cardiopulmonary Bypass Circuit Reduce Bypass Associated Inflammation?

Official title

Does Clear Priming of the Cardiopulmonary Bypass Circuit Reduce Bypass Associated Inflammation in Ventricular Septal Defect Patients?

Overview

The purpose of this trial is to study if priming the pump used during cardiac surgery with non-blood fluids instead of donated blood products reduces the inflammation that occurs after heart surgery. The study will focused on pediatric participants who require open heart surgery to repair certain types holes in the heart. Typically for pediatric patients, the cardiopulmonary bypass pump is "primed" (filled) with donated blood products. This project is going to test if the exposure to these blood products causes inflammation. Patients experience significant inflammation (swelling) after undergoing cardiopulmonary bypass. This inflammation can interfere and slow down the patient's recovery from cardiac surgery. With this project, the investigator are studying if filling the bypass pump with non-blood products reduces the bypass-associated inflammation. The investigators are also studying if using non-blood fluids to fill the bypass pump reduces bypass associated side effects. The investigators are also trying to understand how the inflammation starts. The investigators also want to study genetic material called DNA that is collected from a person's blood. Instructions for the body are contained in parts of DNA called genes. Genes determine things like hair and eye color. The investigator hope by studying genes the investigator can learn more about the inflammation that occurs after heart surgery, but the investigators might use participant's genetic information to study other diseases or conditions other the inflammation that occurs after heart surgery. The investigators will be studying the recovery of 60 participants between 1 month to 18 months of age who require open heart surgery to repair ventricular septal defects (VSDs), a congenital heart defect where there a hole between the lower chambers of the heart. Participants will: Allow for information about how the participants recover from surgery to be collected. Allow blood samples during and after surgery to be collected to understand how the markers of inflammation change between the two groups (blood versus non-blood priming).

Detailed description

Cardiopulmonary bypass (CPB) is required for surgical correction/palliation of congenital heart defects. Exposure to CPB results in a robust activation of inflammatory responses. It is now well established that exposure to the CPB circuit is associated with an overwhelming, detrimental systemic inflammatory response. The factors associated with this response may be related to the circuit and exposure to the circuit surface, or may be associated with the body's response to surgical trauma, changes in temperature, etc. Multiple pathways have been shown to be mediating this response, including complement activation, leukocyte activation, endotoxin release, release of oxygen-free radicals, nitric oxide, cytokines, platelet-activation factor, arachidonic acid metabolites and endothelins. Activation of these inflammatory pathways has been implicated in the development of some of the major postoperative complications, such as bleeding tendencies, respiratory insufficiency, renal dysfunction, abnormalities in liver function, and, most seriously, multi-organ failure. Multiple pharmacological therapies have been investigated, with a single aim, to modulate this systemic inflammation. The most widely investigated ones have been corticosteroid administration, use of heparin-coated circuits, leukocyte depletion and ultrafiltration. Despite these efforts, the activation of inflammatory pathways in response to CPB remains a significant clinical problem especially in neonates undergoing CPB.

Over the last several years, several centers including Seattle Children's have been pursuing efforts to restrict the administration of blood products during CPB. In some of the recent publications on the topic, the justifications for moving towards "bloodless CPB" include reducing potential infection risks, consideration that blood products are valuable limited resource, and the concerns of certain religious communities. A limitation of these studies is that they do not examine a patient's clinical course or markers of inflammation in depth. CPB patients experience significant post-CPB inflammation - including increased cytokine levels, inflammatory cell infiltration, vascular leak, and multi-organ dysfunction. In children recovering from complicated cardiac surgeries, increased cytokine levels are associated with high mortality and extended intensive care stays. Typically, a blood-containing prime has been used as a method to preserve high hematocrit levels and maintain oxygen delivery. There are several mechanisms by which exposure to blood products can activate inflammation-which include allergic reactions, cytokines in the blood products, or release of proinflammatory proteins from red blood cells. These mechanisms serve as the basis for the hypothesis that "clear prime" CPB patients will have reduced inflammation as compared to standard of care CPB patients.

Since 5/2021, 174 CPB patients have been operated on at Seattle Children's Hospital (SCH) using restrictive blood management. In 90 of these patients, "bloodless" surgery was attempted. These patients received CPB priming with crystalloid fluids only and without any addition of blood products. These crystalloid fluids are same ones used in current standard of care treatment for pediatric cardiac surgery cases. All other aspects of the patients' treatment were the same including the same bypass machines and tubing. 47 of these patients did not receive blood products during the surgery. 35 patients did not receive any blood products during the hospitalization. There were no statistical differences between the median ventilation time and Intensive Care Unit (ICU) length of stay between the patients operated on with such restrictive blood management as compared to patient controls from our center in which blood products were added to CPB prime.

Dr. Bohuta's recent observational study of 99 SCH neonatal cardiac cases using historical controls identified no statistical difference in postoperative seizures, bleeding events, and lactate levels during CPB between patients who received clear prime versus those who received a blood prime. In this same study, both length of stay and postoperative mechanical ventilation time was shorter in the clear prime group. Hematocrit was consistently lower post-operatively for patients in the crystalloid only group, otherwise, there were no unintended consequences/ adverse events identified in the crystalloid only cohort.

Interventions

• Procedure Clear priming of the bypass pump
  The intervention is priming the pump with non-blood products.

Primary outcome measures

• Changes in RNA expression of the inflammatory marker TNF-α fold pre-cardiopulmonary bypass (CPB) to 24 hours post-CPB [Time frame: Up to 24 hours post surgery]
• Changes in protein expression of the inflammatory marker TNF-α fold pre-cardiopulmonary bypass (CPB) to 24 hours post-CPB [Time frame: Up to 24 hours post surgery]
• Changes in RNA expression of the inflammatory marker IL8 fold pre-cardiopulmonary bypass (CPB) to 24 hours post-CPB [Time frame: Up to 24 hours post surgery]
• Changes in protein expression of the inflammatory marker IL8 fold pre-cardiopulmonary bypass (CPB) to 24 hours post-CPB [Time frame: Up to 24 hours post surgery]

Secondary outcome measures (4)

• Time to extubation [Time frame: From intubation until extubation (up to 24 hours post-surgery)]
• Peak lactic acid levels over the first 24 hours post-surgery [Time frame: Up to 24 hours post-surgery]
• Vasoactive-inotropic score over the first 24 hours post-surgery [Time frame: Up to 24 hours post-surgery]
• Length of hospital stay post-surgery [Time frame: From the date of surgery until the date of hospital discharge, assessed up to 90 days post-surgery.]

Eligibility criteria

Inclusion criteria

• Weight between 5-10kg
• Age 1-18 months
• Requiring cardiopulmonary bypass as part of clinically indicated surgery
• Surgery performed by Dr. Bohuta or Dr. Greene

Exclusion criteria

• Hemoglobin/hematocrit too low for clear CPB prime (post-dilution Hct <24%)
• Pre-operative ECMO support
• Active infection
• Not clinically appropriate for clear prime (instability, arrhythmias, desaturation, etc.)
• Genetic syndrome
• Pork allergy or family requests pork avoidance

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Single blind

Primary purpose

Treatment

Study locations

United States · 1 center

• Seattle Children's Hospital — Seattle

Publications

• Van Gassen S, Callebaut B, Van Helden MJ, Lambrecht BN, Demeester P, Dhaene T, Saeys Y. FlowSOM: Using self-organizing maps for visualization and interpretation of cytometry data. Cytometry A. 2015 Jul;87(7):636-45. doi: 10.1002/cyto.a.22625. Epub 2015 Jan 8. PMID 25573116
• Nellis ME, Karam O, Valentine SL, Bateman ST, Remy KE, Lacroix J, Cholette JM, Bembea MM, Russell RT, Steiner ME, Goobie SM, Tucci M, Stricker PA, Stanworth SJ, Delaney M, Lieberman L, Muszynski JA, Bauer DF, Steffen K, Nishijima D, Ibla J, Emani S, Vogel AM, Haas T, Goel R, Crighton G, Delgado D, Demetres M, Parker RI; Pediatric Critical Care Transfusion and Anemia EXpertise Initiative-Control/Av PMID 34989711
• Burnside JL, Ratliff TM, Kelly MN, Naguib AN, Galantowicz M, Hodge A. Bloodless Arterial Switch Operation in a 2.7-kg Jehovah's Witness Patient. J Extra Corpor Technol. 2020 Jun;52(2):142-145. doi: 10.1182/ject-2000003. PMID 32669741
• Wloch A, Boettcher W, Sinzobahamvya N, Cho MY, Redlin M, Dahnert I, Photiadis J. Bloodless priming of the cardiopulmonary bypass circuit: determinants of successful transfusion-free operation in neonates and infants with a maximum body weight of 7 kg. Cardiol Young. 2018 Oct;28(10):1141-1147. doi: 10.1017/S1047951118001154. Epub 2018 Jul 23. PMID 30033907
• Faraoni D, Meier J, New HV, Van der Linden PJ, Hunt BJ. Patient Blood Management for Neonates and Children Undergoing Cardiac Surgery: 2019 NATA Guidelines. J Cardiothorac Vasc Anesth. 2019 Dec;33(12):3249-3263. doi: 10.1053/j.jvca.2019.03.036. Epub 2019 Mar 20. PMID 31076306
• Wypij D, Jonas RA, Bellinger DC, Del Nido PJ, Mayer JE Jr, Bacha EA, Forbess JM, Pigula F, Laussen PC, Newburger JW. The effect of hematocrit during hypothermic cardiopulmonary bypass in infant heart surgery: results from the combined Boston hematocrit trials. J Thorac Cardiovasc Surg. 2008 Feb;135(2):355-60. doi: 10.1016/j.jtcvs.2007.03.067. PMID 18242268
• Tu LN, Hsieh L, Kajimoto M, Charette K, Kibiryeva N, Forero A, Hampson S, Marshall JA, O'Brien J, Scatena M, Portman MA, Savan R, Benner C, Aliseda A, Nuri M, Bittel D, Pastuszko P, Nigam V. Shear stress associated with cardiopulmonary bypass induces expression of inflammatory cytokines and necroptosis in monocytes. JCI Insight. 2021 Jan 11;6(1):e141341. doi: 10.1172/jci.insight.141341. PMID 33232305
• Lam LKM, Murphy S, Kokkinaki D, Venosa A, Sherrill-Mix S, Casu C, Rivella S, Weiner A, Park J, Shin S, Vaughan AE, Hahn BH, Odom John AR, Meyer NJ, Hunter CA, Worthen GS, Mangalmurti NS. DNA binding to TLR9 expressed by red blood cells promotes innate immune activation and anemia. Sci Transl Med. 2021 Oct 20;13(616):eabj1008. doi: 10.1126/scitranslmed.abj1008. Epub 2021 Oct 20. PMID 34669439

Identifiers

NCT: NCT07393243 · STUDY00003941

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗