Pooled Human Plasma vs Crystalloid in The Management of Children Undergoing Instrumented Spinal Fusion for Scoliosis

Introduction Total blood loss including intraoperative, drain output, and hidden blood loss equals to 40% of blood volume in patients undergoing posterior spinal fusion for paediatric spinal deformities. Despite the perioperative use of tranexamic acid and gelatine matrix with human thrombin, 14% of patients with adolescent idiopathic scoliosis (AIS) and 73% of patients with neuromuscular scoliosis (NMS) require allogenic red blood cell infusion (Soini et al. NASSJ 2022). Early use of pooled human plasma (PHP) may reduce total blood loss in these patients, but there are no studies in the paediatric population undergoing major surgery on this subject.

Objective To compare pooled human plasma (PHP, OCTAPLAS) vs. crystalloid (PLASMALYTE, comparator) for intraoperative bleeding, drain output, and hidden blood loss as well as the sum of these components (total blood loss) in children undergoing posterior spinal fusion for AIS. Adverse events will be recorded and reported as minor (skin reaction) or major (severe allergic reaction, transfusion related acute lung injury, TRALI; deep surgical site infection, neurologic injury). The investigators hypothesize that the use of PHP in the early perioperative management will reduce intraoperative blood loss (primary outcome), drain output, and hidden blood loss accounting for total blood loss and reduce the need for perioperative allogenic red blood cell infusion (secondary outcome) without increasing the risk for adverse events. Additionally, postoperative pain (opioid consumption and pain score, secondary outcome) may be decreased.

Outcomes Primary outcome is intraoperative blood loss (blood loss in mL after wound closure). Secondary outcomes include need for allogenic red blood cell infusion (percentage of patients at hospital release, health-related quality of life (Scoliosis Research Society 24 outcome questionnaire), postoperative pain (48-hour opioid consumption, pain visual analogue score), operative time (hours), drain output (mL), hidden blood loss (mL), hospital stay, and complications (skin reactions, TRALI, deep surgical site infection). Disease specific Scoliosis Research Society (SRS)-24 questionnaires are filled out preoperatively, at 6 months and 24 months during postoperative outpatient clinic visits.

Study design A randomized, double-blinded, multicenter (Helsinki and Turku University Hospitals, Finland) clinical trial according to CONSORT criteria.

After randomization, patients will be given in a blinded fashion (except for anaesthesia nurse) either 10 ml/kg (maximal dose 400 ml) pooled human plasma (OCTAPLAS or 10ml/kg (maximal dose 400 ml) crystalloid (PLASMALYTE) as an intravenous 1-hour infusion, as part of the standard anaesthesia of scoliosis surgery, starting at one hour before incision.

Scoliosis surgery is a complex procedure, in addition to standard pharmacological treatment and anaesthesiologic control of blood pressure, surgical technique significantly affects blood loss during surgery. To dependently determine the effectiveness of OCTAPLAS to reduce blood loss, the operating room needs to be blinded for intervention.

Selection of study population Trial subjects consist of individuals who are planned to undergo PSF for scoliosis as standard practice. Individuals are 10 to 21 years of age. The study population consists of adolescents with idiopathic scoliosis (over 45 degrees) and neuromuscular scoliosis (over 50 degrees).

All individuals are required to give informed consent either by patient, legal representative/parent, or both, when appropriate. Patients under legal age of independent consent (less than 15 or 18) need parents' or caretakers' consent in addition to their own consent. Some neuromuscular scoliosis patients are not capable of giving their own informed consent. In that case the consent is given only by the child´s legal representative or parent.

Suitability for this trial is determined by the need of surgical intervention for scoliosis, thus the patient population who would benefit from the treatment under investigation includes individuals who are minors or are not capable of giving informed consent, thus inclusion of this patient population in this investigation is justified. The clinical trial is essential with respect to incapacitated subjects and data of comparable validity cannot be obtained in clinical trials on persons able to give informed consent, or by other research methods, and the incapacitated subjects have received the information referred to in Article 29(2) in a way that is adequate in view of their capacity to understand.

The sponsor considers that the conditions for the inclusion of incapacitated subjects in the trial, as laid out in Art 31 of the CTR, are considered fulfilled.

Inclusion criteria Subjects meeting all the criteria below may be included in the study. To be eligible for inclusion, each subject must meet each of the following criteria at Screening and must continue to fulfil these criteria at Baseline (Visit 1).

Patients will be included in the study if they fulfil the following criteria:

* Written informed consent. * Aged between 10 and 21 years of age * Scoliosis requiring posterior scoliosis surgery using all pedicle screw technique for AIS (\>45-degree major curve) or NMS (\>50-degree major curve); * Normal whole spine MRI except for the spinal deformity (only for patients with adolescent idiopathic scoliosis as patients with neuromuscular scoliosis do not typically undergo MR images as they would need general anaesthesia).

Exclusion criteria

Subjects are excluded from the study if any of the following criteria is met at Screening or at Baseline:

* Immunoglobulin A-deficiency * Need for anteroposterior surgery * Need for three column vertebral resection * Smoking * Diabetes mellitus * Abnormalities in blood coagulation (thromboplastin time below above or below of normal values, 70-130%) * Blood trombosytes less than 150 x E9/l * Body mass index over 40 * Allergy or hypersensitivity to study medications or their ingredients * Pregnancy or breast-feeding, aim of becoming pregnant during the study. * Participation in another study and receipt of any other investigational agent during 2 year period of current investigation * Inability to provide written informed consent * Any significant disease or disorder which, in the opinion of the investigator, may either put the subject at risk by participation in the study, or may influence the result of the study. * A history of drug or alcohol use that, in the opinion of the investigator, would interfere with adherence to study requirements. * Known history of, or documented positive hepatitis B or C or HIV infection * Prior or concurrent malignancy 12 * Aspartate transaminase (AST) or alanine transaminase (ALT) ≥ 3 x upper-limit of normal * Creatinine clearance (CrCl) \< 60 ml/min measured by 24-hour urine collection or estimated from the Cockcroft and Gault formula * Clinically significant ECG findings as judged by the investigator * Amiodarone medication * Hyperkalemia * Renal insufficiency * AV-block * Metabolic or respiratory alkalosis * Hypochlorhydria * Hypersensitivity for active component or additives * Contraception requirements:

Combined hormonal contraception should be stopped 4 weeks prior to receiving IMP. Progestin-only contraceptives including pills, implant and intrauterine system, and Copper IUD) and sexual abstinence are allowed forms of contraception.

Withdrawal Patient can withdraw from trial at any point at will. The infusion is administered during anesthesia and primary outcome can be evaluated in all patients.

Randomization and blinding The randomization is carried out by research coordinator, using a computer-generated method (www.sealedenvelope.com), in 1:1 allocation ratio. Randomization aims at equal distribution of the active treatment throughout the study period and between the different centres. To balance the groups, stratification will be conducted according to centre (Helsinki vs. Turku), developmental disability (Yes vs. No), and weight (less than 60 kg vs. 60 kg or more).

The study will be conducted in a double-blind fashion. Study treatment assignment will be blinded for both the investigators and the subject. At each local investigation site, a defined group of trained, unblinded personnel will be responsible for preparing the intravenous study drug and for delivering the drug to blinded personnel involved in the subsequent patient treatment and care. The person preparing the drug will not participate in other aspects of the study.

The blind can be broken in case a significant medical adverse event occurs (such as suspected allergic reaction). Any intentional or unintentional breaking of the blind will be recorded and reported to the sponsor as soon as possible.

Blinding and coding lists saved are managed in secure database and under the responsibility of the Chief Investigator, who has access to this database. In case of unblinding is needed, the unblinding process is conducted as follows:

Criteria for Unblinding:

Unblinding will be performed only if it is deemed essential for the immediate clinical management of a participant.

Unblinding may be initiated if a serious adverse event (SAE) occurs that, in the investigator's judgment, requires knowledge of the treatment assignment to make critical decisions for patient care.

Procedure for Unblinding:

The investigator should first attempt to contact the trial's chief investigator or research coordinator to discuss the need for unblinding. If the chief investigator or research coordinator agrees that unblinding is necessary, the randomization code will be accessed. If the chief investigator or research coordinator cannot be reached in a reasonable time frame, the investigator may proceed to unblind, documenting the reason and the time.

Accessing the Randomization Code:

The randomization code is securely stored in a sealed envelope at the trial site in patient folder and in an electronic randomization system accessible only by authorized personnel.

The investigator or treating physician must log the details of the unblinding event, including the date, time, and rationale for unblinding, in the participant's medical record, from where it transferred eCRF.

Surgery Surgery - Posterior surgery for scoliosis will be conducted according to current standard. Surgical planning of implant placement and the need for Ponte procedures will be carried out preoperatively. Each patient will be placed in the prone position and the posterior elements will be exposed using electrocautery. Ponte osteotomy will be conducted as described previously (Ponte et al, 1985). After full facetectomies, ligamentum flavum and laminae are resected for 5 mm posteriorly at three adjacent levels. The deformity will be corrected using bilateral segmental pedicle screw instrumentation and by en bloc vertebral column derotation. Spinal fusion is carried out using autograft acquired from facetectomies and osteotomies with bone graft extenders (iFactor, Cerapedics, Ic., Westminster, CO). Spinal cord monitoring (MEP, SSEP, lumbar nerve root EMG with or without pedicle screw stimulation) will be undertaken in all patients. A single subfascial drain (Hemovac Ch14; Zimmer, Warsaw, Indiana) will be placed and kept for 24 hours post-operatively. A sterile wound dressing will be applied at the end of surgery. All patients will be mobilized using a standardized protocol: sitting on the day of surgery, minimum four steps on 1st postoperative day (AIS), and progressively increasing walking distance with an aim to discharge patients on 4th -5th postoperative day. Discharge criteria include ability to walk independently (AIS) or sit independently (NMS), no need for opioid prescription, and ability to empty bladder spontaneously without a significant urinary retention (\>200 mL).

Anaesthesia All patients will have total intravenous anaesthesia includin

• Total blood loss [Срок оценки: From exposure to drain removal at 24 hours postoperatively]
• Need for allogeneic blood transfusion [Срок оценки: From surgical exposure to 72 hours postoperatively]
• Health-related quality of life [Срок оценки: At 6 and 24 months]
• Adverse events [Срок оценки: From surgery to 2-year follow-up]