Surgical stabilisation of rib fractures: A meta-analysis of randomised controlled trials.

INTRODUCTION: Rib fixation for ventilator dependent flail chest patients has become a mainstay of management in major trauma centres. However, the expansion of rib fixation for fractured ribs beyond this remains largely in the hands of enthusiasts with the benefits in non ventilator dependent groups largely unproven. Previous meta-analyses have largely included non-randomised and retrospective data, much of which is now more than two decades out of date. We wanted to perform an updated meta-analysis including only rigorous prospective trials which were randomised. Further we wanted to include quality of life outcomes which have not been previously examined in published meta-analyses. METHODS: This meta-analysis was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines and included randomised controlled trials only, of rib fixation compared to non-operative management in adult patients. RESULTS: Eight studies comprising 752 patients of whom 372 had been randomised to receive rib fixation were included. Benefits of rib fixation were identified with significant reductions in mechanical ventilation and lengths of stay (both ICU and hospital) as well as rates of pneumonia and tracheostomy. No significant benefit in quality of life at 6 months was identified. CONCLUSION: Operative intervention for rib fractures leads to significantly lower rates of pneumonia, lengths of intensive care stay and time on mechanical ventilation compared to non-operative intervention. Further study is needed to investigate quality of life improvements after rib fractures as operative rib fixation expands to non-ventilator dependent groups.

Flail chest injury-changing management and outcomes.

PURPOSE: The purpose of this study was to assess trends in management of flail chest injuries over time and to determine impact on patient outcomes. METHODS: A retrospective review of data from a prospectively collated database of all trauma patients admitted to a level 1 trauma service in Victoria was conducted. All trauma patients admitted to the hospital between July 2008 and June 2020 with an Abbreviated Injury Scale (AIS) code for flail chest injury were included. RESULTS: Our study included 720 patients, mean age was 59.5 ± 17.3 years old, and 76.5% of patients were male. Length of ICU stay decreased on average by 9 h each year. Regional anaesthesia use increased by 15% per year (0% in 2009 to 36% in 2020) (p < 0.001). Surgical stabilisation of rib fractures increased by 16% per year (2.9% in 2009 to 22.3% in 2020) (p = 0.006). The use of invasive ventilation decreased by 14% per year (70% in 2008 to 27% in 2020) (p < 0.001), and invasive ventilation time decreased by 8 h per year (p = 0.007). CONCLUSION: Over the past decade, we have seen increasing rates of regional anaesthesia and surgical rib fixation in the management of flail chest. This has resulted in lower requirements for and duration of invasive mechanical ventilation and intensive care unit stay but has not impacted mortality in this patient cohort.

Surgical stabilization of rib fractures versus nonoperative treatment in patients with multiple rib fractures following cardiopulmonary resuscitation: An international, retrospective matched case-control study.

BACKGROUND: The presence of six or more rib fractures or a displaced rib fracture due to cardiopulmonary resuscitation (CPR) has been associated with longer hospital and intensive care unit (ICU) length of stay (LOS). Evidence on the effect of surgical stabilization of rib fractures (SSRF) following CPR is limited. This study aimed to evaluate outcomes after SSRF versus nonoperative management in patients with multiple rib fractures after CPR. METHODS: An international, retrospective study was performed in patients who underwent SSRF or nonoperative management for multiple rib fractures following CPR between January 1, 2012, and July 31, 2020. Patients who underwent SSRF were matched to nonoperative controls by cardiac arrest location and cause, rib fracture pattern, and age. The primary outcome was ICU LOS. RESULTS: Thirty-nine operatively treated patient were matched to 66 nonoperatively managed controls with comparable CPR-related characteristics. Patients who underwent SSRF more often had displaced rib fractures (n = 28 [72%] vs. n = 31 [47%]; p = 0.015) and a higher median number of displaced ribs (2 [P 25 -P 75 , 0-3] vs. 0 [P 25 -P 75 , 0-3]; p = 0.014). Surgical stabilization of rib fractures was performed at a median of 5 days (P 25 -P 75 , 3-8 days) after CPR. In the nonoperative group, a rib fixation specialist was consulted in 14 patients (21%). The ICU LOS was longer in the SSRF group (13 days [P 25 -P 75 , 9-23 days] vs. 9 days [P 25 -P 75 , 5-15 days]; p = 0.004). Mechanical ventilator-free days, hospital LOS, thoracic complications, and mortality were similar. CONCLUSION: Despite matching, those who underwent SSRF over nonoperative management for multiple rib fractures following CPR had more severe consequential chest wall injury and a longer ICU LOS. A benefit of SSRF on in-hospital outcomes could not be demonstrated. A low consultation rate for rib fixation in the nonoperative group indicates that the consideration to perform SSRF in this population might be associated with other nonradiographic or injury-related variables. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level III.

Rib fixation in non-ventilator-dependent chest wall injuries: A prospective randomized trial.

BACKGROUND: The aim of this study was to assess pain and quality of life (QoL) outcomes in patients with multiple painful displaced fractured ribs with and without operative fixation. Rib fractures are common and can lead to significant pain and disability. There is minimal level 1 evidence for rib fixation in non-ventilator-dependent patients with chest wall injuries. We hypothesized that surgical stabilization of rib fractures would reduce pain and improve QoL during 6 months. METHODS: A prospective multicenter randomized controlled trial comparing rib fixation to nonoperative management of nonventilated patients with at least three consecutive rib fractures was conducted. Inclusion criteria were rib fracture displacement and/or ongoing pain. Pain (McGill Pain Questionnaire) and QoL (Short Form 12) at 3 and 6 months postinjury were assessed. Surgeons enrolled patients in whom they felt there was clinical equipoise. Patients who were deemed to need surgical fixation or who were deemed to be too well to be randomized to rib fixation were not enrolled. RESULTS: A total of 124 patients were enrolled at four sites between 2017 and 2020. Sixty-one patients were randomized to operative management and 63 to nonoperative management. No differences were seen in the primary endpoint of Pain Rating Index at 3 months or in the QoL measures. Return-to-work rates improved between 3 and 6 months, favoring the operative group. CONCLUSION: In this study, no improvements in pain or QoL at 3 and 6 months in patients undergoing rib fixation for nonflail, non-ventilator-dependent rib fractures have been demonstrated. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level II.

Spinal cord infarction and peripheral extracorporeal membrane oxygenation: a case series.

BACKGROUND: Veno-arterial extracorporeal membrane oxygenation (VA ECMO) is increasingly utilized in patients with cardiogenic shock due to improved technology and outcomes. Peripheral VA ECMO offers several advantages over central ECMO and is becoming increasingly popular. However, when configured via the femoral vessels, retrograde flow to the descending aorta and arch of aorta competes with antegrade ventricular output and can be associated with a watershed phenomenon and increased risk of neurologic and visceral injury. CASE SUMMARY: In this case series, we report three patients who were supported with peripheral VA ECMO for cardiogenic shock. All three were successfully weaned from peripheral VA ECMO; however, they had developed bilateral lower limb paralysis. Magnetic resonance imaging revealed spinal cord infarction in all three patients. All patients subsequently succumbed to multiorgan failure and did not survive to hospital discharge. DISCUSSION: The use of mechanical circulatory support, in particular, peripheral ECMO, has escalated with advances in technology, better understanding of cardiac physiology and improving outcomes. Spinal cord infarction is a rare but serious complication of peripheral VA ECMO support with only a few case reports published. Further studies are needed to identify the exact cause and prevention of this rare but often terminal complication. Through this series of three patients supported on peripheral VA ECMO complicated by spinal cord infarction, we review previously published reports, analyse possible mechanisms, and propose alternate management strategies to be considered in patients at risk.

Post Cardiotomy Extra Corporeal Membrane Oxygenation: Australian Cohort Review.

BACKGROUND: Over the last two decades, technological advancements in the delivery of extra corporeal membrane oxygenation (ECMO) have seen its use broaden and results improve. However, in the post cardiotomy ECMO patient group, survival remains very poor without significant improvements over the last two decades. Our study aims to report on the Australian experience, with the intention of providing background data for the formation of guidelines in the future. METHODS: Retrospective analysis of prospectively collected data from the Australian and New Zealand Society of Cardiothoracic Surgeons (ANZSCTS) Database was performed. The ANZSCTS database captures at least 60% of cardiac surgical data in Australia, annually. Data was collected on adult patients who received ECMO post cardiotomy from September 2016 to November 2017 inclusive. Transplant and primary cardiomyopathy patients were excluded. RESULTS: Of the 16,605 adult patients undergoing cardiac surgery in the 15-month period of the study, 87 patients required post cardiotomy ECMO (0.52%). The average age of the entire cohort was 56 years. Overall survival to discharge was 43.7% (n=38). Multivariable logistic regression analysis demonstrated that multiorgan failure (MOF), increasing age and longer cardiopulmonary bypass time were significant predictors of in hospital mortality. CONCLUSIONS: Post cardiotomy ECMO support is an uncommon condition. Survival in this study appears to be better than historical reports. Identification of poor prognostic indicators in this study may help inform the development of guidelines for the most appropriate use of this support modality.

A real-life experience with HeartMate III.

BACKGROUND: The HeartMate III (HM3) left ventricular assist device (LVAD) is the most recent LVAD to receive CE Mark and the Food and Drug Administration approval. It is a fully magnetically levitated pump with no reported haemolysis, pump thrombosis or pump failure in the first in-man study (a previous stody). It has now received market approval in the European Union, United States of America, and Australia. We reviewed our real-life experience with the device, to assess outcomes over the medium term. METHODS: We conducted a retrospective review of prospectively collected data for 33 consecutive patients implanted with a HM3 LVAD between November 2014 and October 2018 at The Alfred Hospital, Melbourne, Australia. RESULTS: Of the 33 patients, 31 remained alive at the census date, with only two early deaths and 11 patients transplanted. There were no pump thromboses, but there were three cases of clot ingestion (two on the right and one on the left). Seven patients required permanent biventricular assist device support. The duration of HM3 support at the time of census was a median of 196 (interquartile range, 118-386) days. CONCLUSION: This series demonstrates excellent results of the HM3 LVAD in an uncensored, real-life, consecutive group of patients in a single institution.

Impact of rib fixation on quality of life after major trauma with multiple rib fractures.

INTRODUCTION: Multiple rib fractures have been shown to reduce quality of life both in the short and long term. Treatment of rib fractures with operative fixation reduces ventilator requirements, intensive care unit stay, and pulmonary complications in flail chest patients but has not been shown to improve quality of life in comparative studies to date. We therefore wanted to analyse a large cohort of multiple fractured rib trauma patients to see if rib fixation improved their quality of life. METHODS: Retrospective review (January 2012 - April 2015) of prospectively collected data on 1482 consecutive major trauma patients admitted to The Alfred Hospital with rib fractures. The main outcome measures were Quality of Life over 24 months post injury assessed using the Glasgow Outcome Scale Extended (GOSErate) and Short Form (SF12) health assessment forms and a pain questionnaire. RESULTS: 67 (4.5%) patients underwent rib fixation and were older, with a higher incidence of flail chest injury, and higher AIS and ISS scores than the remainder of the cohort. Rib fixation provided no benefit in pain, SF-12 or GOSErate scores over 24 months post injury. CONCLUSIONS: This study has not been able to demonstrate any quality of life benefit of rib fixation over 24 months post injury in patients with major trauma.

An assessment of outcomes with intramedullary fixation of fractured ribs.

BACKGROUND: Surgical management of fractured ribs with internal fixation is an increasingly accepted therapy. Concurrently, specific rib fixation prostheses are being developed which should improve results and minimise hardware and rib/splint construct failures. The Synthes titanium intramedullary splint lends itself to difficult to access areas such as posterior rib fractures and fractures under the scapula. We analyse a case series of patients in whom this rib fixation prosthesis has been used. METHODS: Fifteen patients received 35 intramedullary splints. Follow up at 3 and 6 months was performed with three dimensional computed tomography scanning to assess for bone alignment, callus formation and healing, residual deformity, hardware failure or cut through. Computerized finite element analysis (FEA) was used to model forces acting on a posterior fracture with and without an intramedullary fixation splint in situ. RESULTS: Complete healing (bony union) was noted in only 3 (9 %) of the fractures fixed with splints by 3 months. Partial healing (cartilaginous union) was noted in 28 of the 33 fractures (85 %), and non healing was noted in only 2 (6 %). In both those two patients, failure at the rib / splint interface was noted after both patients reported sneezing. No hardware failures were noted. By 6 months the fractures which had shown partial healing, had all completely healed. There were no late failures (between 3 and 6 months) of either hardware or rib/splint interfaces. FEA modelling identified sites of increased stress in the rib at the rib / splint interface and in a modelled intramedullary splint where it spans the fracture. CONCLUSIONS: Further analysis of outcomes with intramedullary splints is warranted as well as further development of intramedullary rib fixation solutions.

Cost comparison of heart transplant vs. left ventricular assist device therapy at one year.

With the worldwide shortage of donor organs, use of ventricular assist device (VAD) therapy is rapidly increasing in both the bridge to transplant and destination therapy settings. However, the high cost of VADs and VAD care is a cause for concern for policy makers who have relied on the limited supply of donor hearts to naturally cap health expenditure on heart transplantation (HTx). We sought to compare costs of the first 12 months of care of VADs vs. HTx. Single center retrospective study utilizing real generated costs over a three yr span from 2010-2012. Only patients with 12 months of costing data were included. Costs of 28 HTx patients and 24 VAD patients were analyzed. Index admission costs were more than double in the VAD group compared to the HTx group and this was driven by the procurement costs and length of stay which increased almost all aspects of in hospital care costs. Subsequent costs were six times higher in the HTx group and this was driven largely by pharmaceuticals. VAD therapy remains a very expensive treatment option for end stage heart failure patients. Device prices need to reduce substantially to make this a more widely applicable and cost effective treatment option.

Extracorporeal Life Support Bridge to Ventricular Assist Device: The Double Bridge Strategy.

In patients requiring left ventricular assist device (LVAD) support, it can be difficult to ascertain suitability for long-term mechanical support with LVAD and eventual transplantation. LVAD implantation in a shocked patient is associated with increased morbidity and mortality. Interest is growing in the utilization of extracorporeal life support (ECLS) as a bridge-to-bridge support for these critically unwell patients. Here, we reviewed our experience with ECLS double bridging. We hypothesized that ECLS double bridging would stabilize end-organ dysfunction and reduce ventricular assist device (VAD) implant perioperative mortality. We conducted a retrospective review of prospectively collected data for 58 consecutive patients implanted with a continuous-flow LVAD between January 2010 and December 2013 at The Alfred Hospital, Melbourne, Victoria, Australia. Twenty-three patients required ECLS support pre-LVAD while 35 patients underwent LVAD implantation without an ECLS bridge. Preoperative morbidity in the ECLS bridge group was reflected by increased postoperative intensive care duration, blood loss, blood product use, and postoperative renal failure, but without negative impact upon survival when compared with the no ECLS group. ECLS stabilization improved end-organ function pre-VAD implant with significant improvements in hepatic and renal dysfunction. This series demonstrates that the use of ECLS bridge to VAD stabilizes end-organ dysfunction and reduces VAD implant perioperative mortality from that traditionally reported in these "crash and burn" patients.

Right ventricular failure after implantation of continuous flow left ventricular assist device: analysis of predictors and outcomes.

Postoperative right ventricular failure is a serious complication for up to 50% of patients following LVAD insertion. Predicting RV failure is an important factor for patients as planned BiVAD support has been shown to correlate with better outcomes compared to delayed BiVAD to LVAD conversion. This retrospective study examined prospectively collected data for 101 patients implanted with an LVAD between 2003 and 2013, aiming to establish preoperative predictive factors for RVF post-LVAD insertion, analyze outcomes, and validate existing RVF scoring systems. In our cohort, 63 patients (62.4%) developed RV failure and consequently demonstrated consistently poorer survival throughout the follow-up period (log-rank p = 0.01). Multivariable logistic regression identified two significant variables: cardiac index <2.2 preoperatively despite inotropic support (OR 4.6 [95%CI 1.8-11.8]; p = 0.001) and preoperative tricuspid regurgitation (OR 8.1 [95%CI 1.9-34]; p = 0.004). Patients who developed RV failure had more complicated postoperative courses including longer ICU stay (p < 0.001), higher incidence of transfusions (p = 0.03) and re-intubation (p = 0.001), longer ventilation duration (p < 0.001), and higher incidence of returning to theater (p = 0.0008). This study found that previous validation models had only moderate correlation with our population emphasizing the need for prospective validation of these scores in the current era of continuous flow devices.

Quality of life after major trauma with multiple rib fractures.

INTRODUCTION: Rib fractures are a common injury presenting to major trauma centres and community hospitals. Aside from the acute impact of rib fracture injury, longer-term morbidity of pain, disability and deformity have been described. Despite this, the mainstay of management for the vast majority of rib fracture injuries remains supportive only with analgesia and where required respiratory support. This study aimed to document the long-term quality of life in a cohort of major trauma patients with rib fracture injury over 24 months. METHODS: Retrospective review (July 2006-July 2011) of 397 major trauma patients admitted to The Alfred Hospital with rib fractures and not treated with operative rib fixation. The main outcome measures were quality of life over 24 months post injury assessed using the Glasgow Outcome Scale Extended and SF12 health assessment forms and a pain questionnaire. RESULTS: Assessment over 24 months of major trauma patients with multiple rib fractures demonstrated significantly lower quality of life compared with published Australian norms at all time points measured. Return to work rates were poor with only 71% of those who were working prior to their accident, returning to any work. CONCLUSIONS: This study demonstrates a significant reduction in quality of life for rib fracture patients requiring admission to hospital, which does not return to the level of Australian norms for at least two years.

Analysis of bone healing in flail chest injury: do we need to fix both fractures per rib?

BACKGROUND: Surgical rib fixation (SRF) for severe rib fracture injuries is generating increasing interest in the medical literature. It is well documented that poorly healed fractured ribs can lead to chronic pain, disability, and deformity. An unanswered question in SRF for flail chest injury is whether it is sufficient to fix one fracture per rib, on successive ribs, thus converting a flail chest injury into simple fractured ribs, or whether both ends of the floating segment of the chest wall should be fixed. This study aimed to analyze SRF in flail chest injury, assessing 3-month outcomes for nonfixed fractured rib ends in the flail segment. METHODS: This is a retrospective review (2005-2013) of 60 consecutive patients who underwent SRF for flail chest injury admitted to the Alfred Hospital, Melbourne, Australia. Imaging by three-dimensional computed tomography (3D CT) of the chest at admission was compared with follow-up 3D CT at 3 months after injury. The 3-month CT scans were assessed for degree of healing and presence of residual deformity at the fracture fixation site. Follow-up CT was performed in 52 of the 60 patients. RESULTS: At 3 months after surgery, 86.5% of the patients had at least partial healing with good alignment and adequate fracture stabilization. Hardware failure was noted in five patients (9.6%) and occurred with the absorbable prostheses only. Six patients who had preoperative overlapping or displacement showed no improvement in deformity despite fixing the lateral fractures. Callus formation and bony bridging between adjacent ribs was often noted in the rib fractures not fixed (28 of 52 patients, 54%) CONCLUSION: This retrospective review of 3D CT chest at 3 months after rib fixation indicates that a philosophy of fixing only one fracture per rib in a flail segment does not avoid deformity and displacement, particularly in posterior rib fractures. LEVEL OF EVIDENCE: Therapeutic study, level V; epidemiologic study, level V.

Vintage venoms: proteomic and pharmacological stability of snake venoms stored for up to eight decades.

For over a century, venom samples from wild snakes have been collected and stored around the world. However, the quality of storage conditions for "vintage" venoms has rarely been assessed. The goal of this study was to determine whether such historical venom samples are still biochemically and pharmacologically viable for research purposes, or if new sample efforts are needed. In total, 52 samples spanning 5 genera and 13 species with regional variants of some species (e.g., 14 different populations of Notechis scutatus) were analysed by a combined proteomic and pharmacological approach to determine protein structural stability and bioactivity. When venoms were not exposed to air during storage, the proteomic results were virtually indistinguishable from that of fresh venom and bioactivity was equivalent or only slightly reduced. By contrast, a sample of Acanthophis antarcticus venom that was exposed to air (due to a loss of integrity of the rubber stopper) suffered significant degradation as evidenced by the proteomics profile. Interestingly, the neurotoxicity of this sample was nearly the same as fresh venom, indicating that degradation may have occurred in the free N- or C-terminus chains of the proteins, rather than at the tips of loops where the functional residues are located. These results suggest that these and other vintage venom collections may be of continuing value in toxin research. This is particularly important as many snake species worldwide are declining due to habitat destruction or modification. For some venoms (such as N. scutatus from Babel Island, Flinders Island, King Island and St. Francis Island) these were the first analyses ever conducted and these vintage samples may represent the only venom ever collected from these unique island forms of tiger snakes. Such vintage venoms may therefore represent the last remaining stocks of some local populations and thus are precious resources. These venoms also have significant historical value as the Oxyuranus venoms analysed include samples from the first coastal taipan (Oxyuranus scutellatus) collected for antivenom production (the snake that killed the collector Kevin Budden), as well as samples from the first Oxyuranus microlepidotus specimen collected after the species' rediscovery in 1976. These results demonstrate that with proper storage techniques, venom samples can retain structural and pharmacological stability. This article is part of a Special Issue entitled: Proteomics of non-model organisms.

Laboratory methods for the assay of tissue factor pathway inhibitor in human plasma.

Tissue factor pathway inhibitor (TFPI) is being assayed with increasing frequency by researchers attempting to further understand the complexities of the coagulation system. There are a number of methods available for measurement of TFPI; however immunological measurement by ELIZA is the most common assay used. There are a number of commercial kits available for this assay and close attention to detail is critical for accurate results.

Plasmin generation and fibrinolysis in pediatric patients undergoing cardiopulmonary bypass surgery.

This prospective, single-centre cohort study aimed to evaluate plasmin generation and fibrinolysis during and after cardiopulmonary bypass (CPB) surgery in a cohort of children up to 6 years of age. Blood samples were drawn at eight time points: after induction of anesthesia, before unfractionated heparin (UFH), after UFH, after initiation of bypass, before protamine, after protamine, after chest closure, and 6 h after chest closure. The study identified an increase in fibrinolysis during CPB and particularly up to 6 h afterward in children. This could be the mechanism for the significant bleeding events observed in this young population after CPB. This study establishes the foundation for future studies in this area, particularly those focusing on clinical outcomes after CPB surgery.

The quantitative and qualitative responses of platelets in pediatric patients undergoing cardiopulmonary bypass surgery.

This prospective, single-center study aimed to evaluate the platelet response during cardiopulmonary bypass (CPB) surgery in a large cohort of children up to 6 years of age. Blood samples were drawn at four time points: after induction of anesthesia, after initiation of the CPB, before protamine, and immediately after chest closure. The study recruited 60 children requiring CPB for surgical repair of congenital heart defects. The platelet count decreased throughout CPB surgery, but during the same period, platelet activity increased. The more pronounced decrease in platelet count observed in children younger than 1 year compared with that of children 1 to 6 years of age was not associated with an age-specific change in platelet activity. The overall increase in platelet function observed in this study could provide a mechanism that compensates for the decrease in platelet count. This study provides a new foundation for future studies investigating requirements of platelet supplementation in the setting of pediatric CPB surgery.

Age-related differences in plasma proteins: how plasma proteins change from neonates to adults.

The incidence of major diseases such as cardiovascular disease, thrombosis and cancer increases with age and is the major cause of mortality world-wide, with neonates and children somehow protected from such diseases of ageing. We hypothesized that there are major developmental differences in plasma proteins and that these contribute to age-related changes in the incidence of major diseases. We evaluated the human plasma proteome in healthy neonates, children and adults using the 2D-DIGE approach. We demonstrate significant changes in number and abundance of up to 100 protein spots that have marked differences in during the transition of the plasma proteome from neonate and child through to adult. These proteins are known to be involved in numerous physiological processes such as iron transport and homeostasis, immune response, haemostasis and apoptosis, amongst others. Importantly, we determined that the proteins that are differentially expressed with age are not the same proteins that are differentially expressed with gender and that the degree of phosphorylation of plasma proteins also changes with age. Given the multi-functionality of these proteins in human physiology, understanding the differences in the plasma proteome in neonates and children compared to adults will make a major contribution to our understanding of developmental biology in humans.

Hemostatic response in paediatric patients undergoing cardiopulmonary bypass surgery.

This prospective, single-center cohort study aimed to evaluate the hemostatic response during and after Cardiopulmonary Bypass (CPB) surgery in a large cohort of children up to 6 years of age. Blood samples were drawn at eight time points: post-induction of anesthesia, pre-unfractionated heparin (UFH), post-UFH, post-initiation of bypass, pre-protamine, post-protamine, post-chest-closure, and 6 h post-chest-closure. As expected, all measures of the UFH effect increased significantly post-UFH bolus and decreased post-protamine administration. However, thrombin generation remained inhibited compared to baseline values despite the post-UFH reversal by protamine. We also demonstrate that residual UFH effect is not responsible for the ongoing inhibition of thrombin observed post-protamine administration. The significant increase in both free and total tissue factor pathway inhibitor levels during the CPB surgery might contribute to the persistent thrombin generation/endogenous thrombin potential inhibition post-protamine administration. This study makes a significant and novel contribution by investigating the physiological mechanisms behind the degree of thrombin inhibition by UFH and the residual levels of thrombin inhibition that continue despite protamine reversal and provides a new foundation for future interventional studies in the setting of paediatric CPB surgery.