Perioperative Lidocaine for Lung Protection in Infants Undergoing Cardiac Surgery

Infants undergoing cardiac surgery with cardiopulmonary bypass are at risk of postoperative pulmonary injury due to systemic inflammatory activation, ischemia-reperfusion injury, and disruption of the alveolar-capillary barrier. Intravenous lidocaine has been reported to exert anti-inflammatory, anti-arrhythmic, and potential organ-protective effects. However, evidence in infants undergoing cardiac surgery remains limited.

This randomized, double-blind, placebo-controlled superiority trial will enroll infants aged 0 to 12 months scheduled for corrective, non-palliative congenital cardiac surgery with cardiopulmonary bypass at a tertiary pediatric center. Participants will be randomized in a 1:1 ratio to receive either perioperative intravenous lidocaine or volume-matched normal saline placebo. The trial will assess postoperative pulmonary injury severity over the first 72 hours after surgery, together with respiratory, laboratory, echocardiographic, and safety outcomes until postoperative day 7 or at discharge.

• Lidocaine %2 ampoule (Drug): Intravenous lidocaine hydrochloride 2%: loading dose 1.0 mg/kg administered over 20 minutes starting at the surgery, followed by continuous infusion at 1.0 mg/kg/hour for 24 hours. Dosing is based on standard body weight or actual body weight according to protocol-defined rules.
• Normal Saline (0.9% NaCl) (Drug): Volume-matched 0.9% normal saline placebo administered according to the same schedule as the lidocaine group.

Primary outcomes

• Acute Lung Injury Score within 72 hours after surgery [Assessed at 0, 12, 24, 36, 48, 60, and 72 hours after surgery]: Composite lung injury severity score ranging from 0 to 4, based on oxygenation index or oxygen saturation index, chest radiograph findings, positive en-expiratory pressure, and pulmonary compliance. Higher scores indicate more severe lung injury.

Secondary outcomes

• Arterial partial pressure of oxygen [0, 12, 24, 36, 48, 60, and 72 hours after surgery]: Measured by arterial blood gas analysis, reported in mmHg.
• Arterial partial pressure of carbon dioxide [0, 12, 24, 36, 48, 60, and 72 hours after surgery]: Measured by arterial blood gas analysis, reported in mmHg.
• Arterial oxygen saturation [0, 12, 24, 36, 48, 60, and 72 hours after surgery]: Measured by arterial blood gas analysis, reported as percentage (%).
• Arterial lactate concentration [0, 12, 24, 36, 48, 60, and 72 hours after surgery]: Measured by arterial blood gas analysis, reported in mmol/L.
• Duration of mechanical ventilation [From postoperative ICU admission until successful discontinuation of invasive mechanical ventilation, assessed up to 72 hours after surgery.]: Total duration of invasive mechanical ventilation, measured in hours, from postoperative admission to the intensive care unit until first successful extubation without the need for reintubation.
• PICU length of stay [From postoperative admission to the pediatric intensive care unit until discharge from the pediatric intensive care unit, assessed up to 7 days after surgery.]: Duration of stay in the pediatric intensive care unit, measured in days.
• Left ventricular ejection fraction (LVEF) [Baseline, 24, 48, and 72 hours after surgery]: Left ventricular fractional shortening assessed by transthoracic echocardiography, reported as percentage (%).
• Plasma lidocaine concentration [6, 12, 18, 24 hours after surgery]: Plasma lidocaine concentration measured using the assay specified in the study laboratory manual, reported in ug/mL
• Incidence of postoperative pulmonary complications [Assessed within 72 hours after surgery]: Incidence of at least one postoperative pulmonary complication within 72 hours after surgery, defined as the occurrence of any of the following: atelectasis, pulmonary edema, pleural effusion, pneumothorax, or infectious pneumonia. Reported as the percentage of participants with at least one postoperative pulmonary complication.
• Prothrombin time (PT) [Baseline, 24, 48, and 72 hours after surgery]: Measured in venous blood by routine clinical laboratory testing, reported in seconds.
• Activated partial thromboplastin time (aPTT) [Baseline, 24, 48, and 72 hours after surgery]: Measured in venous blood by routine clinical laboratory testing, reported in seconds.
• Alanine aminotransferase (ALT) [Baseline, 24, 48, and 72 hours after surgery]: Measured by routine clinical laboratory testing, reported in U/L.
• Aspartate aminotransferase (AST) [Baseline, 24, 48, and 72 hours after surgery]: Measured by routine clinical laboratory testing, reported in U/L.
• Serum creatinine [Baseline, 24, 48, and 72 hours after surgery]: Measured by routine clinical laboratory testing, reported in umol/L.
• Blood urea nitrogen [Baseline, 24, 48, and 72 hours after surgery]: Measured by routine clinical laboratory testing, reported in mmol/L.
• Plasma soluble intercellular adhesion molecule-1 (sICAM-1) concentration [Baseline, 24, 48, and 72 hours after surgery]: Measured using ELISA assay kit, reported in umol/L
• Plasma surfactant protein D (SP-D) concentration [Baseline, 24, 48, and 72 hours after surgery]: Measured using ELISA assay kit, reported in umol/L
• Plasma soluble receptor for advanced glycation end products (sRAGE) concentration [Baseline, 24, 48, and 72 hours after surgery]: Measured using ELISA assay kit, reported in umol/L
• Plasma interleukin-1 beta (IL-1β) concentration [Baseline, 24, 48, and 72 hours after surgery]: Measured using ELISA assay kit, reported in umol/L
• Plasma angiopoietin-2 concentration [Baseline, 24, 48, and 72 hours after surgery]: Measured using ELISA assay kit, reported in umol/L
• Plasma double-stranded DNA (dsDNA) concentration [Baseline, 24, 48, and 72 hours after surgery]: Measured using ELISA assay kit, reported in umol/L
• Plasma high-mobility group box 1 (HMGB1) concentration [Baseline, 24, 48, and 72 hours after surgery]: Measured using ELISA assay kit, reported in umol/L
• Plasma neurofilament light chain (NFL) concentration [Baseline, 24, 48, and 72 hours after surgery]: Measured using ELISA assay kit, reported in umol/L
• Plasma S100B concentration [Baseline, 24, 48, and 72 hours after surgery]: Measured using ELISA assay kit, reported in umol/L

Other outcomes

• Postoperative sedative and analgesic use [0 to 72 hours after surgery]: Total cumulative dose and frequency of administration of postoperative sedative and analgesic medications administered during the first 72 hours after surgery, as recorded in the medication administration record.

Sex: All, ages: any to 12 Months

Inclusion Criteria:

1. Infants aged 0 to 12 months.
2. Congenital heart disease requiring corrective, non-palliative cardiac surgery with cardiopulmonary bypass.
3. American Society of Anesthesiologists (ASA) physical status I to III.
4. Written informed consent provided by parent(s) or legal guardian(s).

Exclusion Criteria:

1. Multiple malformations, chromosomal abnormalities, or immunodeficiency.
2. Known or suspected allergy to lidocaine.
3. Concomitant continuous infusion of another local anesthetic.
4. Conditions associated with increased risk of lidocaine accumulation or toxicity, including severe conduction block or severe bradycardia.
5. ASA physical status IV or higher.
6. Severe malnutrition expected to substantially impair postoperative recovery.
7. Severe hepatic or renal dysfunction.
8. Significant pre-existing pulmonary disease or markedly impaired preoperative pulmonary function.
9. Central nervous system disorders that may increase susceptibility to lidocaine neurotoxicity, including epilepsy or prior central nervous system infection.
10. Use of medications that may interact with lidocaine or constitute an exclusion, including class I or class III antiarrhythmic agents, cimetidine, or antiviral drugs, as determined by the clinical team.
11. Current or recent participation in another interventional clinical trial in its active intervention phase.

• Zhang C, Foo I. Is intravenous lidocaine protective against myocardial ischaemia and reperfusion injury after cardiac surgery? Ann Med Surg (Lond). 2020 Sep 11;59:72-75. doi: 10.1016/j.amsu.2020.09.008. eCollection 2020 Nov. PMID 32994986
• Gregory AJ, Arora RC, Chatterjee S, Crisafi C, Morton-Bailey V, Rea A, Salenger R, Engelman DT, Grant MC; ERAS Cardiac Working Group. Enhanced Recovery After Surgery (ERAS) cardiac turnkey order set for perioperative pain management in cardiac surgery: Proceedings from the American Association for Thoracic Surgery (AATS) ERAS Conclave 2023. JTCVS Open. 2024 Sep 6;22:14-24. doi: 10.1016/j.xjon.2024.08.018. eCollection 2024 Dec. PMID 39780778
• Wang L, Wang M, Li S, Wu H, Shen Q, Zhang S, Fang L, Liu R. Nebulized lidocaine ameliorates allergic airway inflammation via downregulation of TLR2. Mol Immunol. 2018 May;97:94-100. doi: 10.1016/j.molimm.2018.03.010. Epub 2018 Mar 30. PMID 29609129
• Lee JM, Suh JK, Jeong JS, Cho SY, Kim DW. Antioxidant effect of lidocaine and procaine on reactive oxygen species-induced endothelial dysfunction in the rabbit abdominal aorta. Korean J Anesthesiol. 2010 Aug;59(2):104-10. doi: 10.4097/kjae.2010.59.2.104. Epub 2010 Aug 20. PMID 20740215
• Kavcic H, Jug U, Mavri J, Umek N. Antioxidant activity of lidocaine, bupivacaine, and ropivacaine in aqueous and lipophilic environments: an experimental and computational study. Front Chem. 2023 Jun 20;11:1208843. doi: 10.3389/fchem.2023.1208843. eCollection 2023. PMID 37408557
• Weibel S, Jelting Y, Pace NL, Helf A, Eberhart LH, Hahnenkamp K, Hollmann MW, Poepping DM, Schnabel A, Kranke P. Continuous intravenous perioperative lidocaine infusion for postoperative pain and recovery in adults. Cochrane Database Syst Rev. 2018 Jun 4;6(6):CD009642. doi: 10.1002/14651858.CD009642.pub3. PMID 29864216
• Simonato M, Padalino M, Vedovelli L, Carollo C, Sartori A, Vida V, Gregori D, Carnielli V, Cogo P. Effect of preoperative pulmonary hemodynamic and cardiopulmonary bypass on lung function in children with congenital heart disease. Eur J Pediatr. 2023 Jun;182(6):2549-2557. doi: 10.1007/s00431-023-04926-0. Epub 2023 Mar 18. PMID 36933017
• Fischer MO, Brotons F, Briant AR, Suehiro K, Gozdzik W, Sponholz C, Kirkeby-Garstad I, Joosten A, Nigro Neto C, Kunstyr J, Parienti JJ, Abou-Arab O, Ouattara A; VENICE study group. Postoperative Pulmonary Complications After Cardiac Surgery: The VENICE International Cohort Study. J Cardiothorac Vasc Anesth. 2022 Aug;36(8 Pt A):2344-2351. doi: 10.1053/j.jvca.2021.12.024. Epub 2021 Dec 25. PMID 35094928
• Jenke A, Yazdanyar M, Miyahara S, Chekhoeva A, Immohr MB, Kistner J, Boeken U, Lichtenberg A, Akhyari P. AdipoRon Attenuates Inflammation and Impairment of Cardiac Function Associated With Cardiopulmonary Bypass-Induced Systemic Inflammatory Response Syndrome. J Am Heart Assoc. 2021 Mar 16;10(6):e018097. doi: 10.1161/JAHA.120.018097. Epub 2021 Mar 5. PMID 33666100
• Sperotto F, Cogo P, Amigoni A, Pettenazzo A, Thiagarajan RR, Polito A. Extracorporeal Membrane Oxygenation Support for Failure to Wean From Cardiopulmonary Bypass After Pediatric Cardiac Surgery: Analysis of Extracorporeal Life Support Organization Registry Data. Crit Care Explor. 2020 Sep 15;2(9):e0183. doi: 10.1097/CCE.0000000000000183. eCollection 2020 Sep. PMID 32984825
• Cholette JM, Muszynski JA, Ibla JC, Emani S, Steiner ME, Vogel AM, Parker RI, Nellis ME, Bembea MM; Pediatric Critical Care Transfusion and Anemia EXpertise Initiative-Control/Avoidance of Bleeding (TAXI-CAB), in collaboration with the Pediatric Critical Care Blood Research Network (BloodNet), and the Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network. Plasma and Platelet Transfusions Strategies in Neonates and Children Undergoing Cardiac Surgery With Cardiopulmonary Bypass or Neonates and Children Supported by Extracorporeal Membrane Oxygenation: From the Transfusion and Anemia EXpertise Initiative-Control/Avoidance of Bleeding. Pediatr Crit Care Med. 2022 Jan 1;23(13 Supple 1 1S):e25-e36. doi: 10.1097/PCC.0000000000002856. PMID 34989703