Assessing the impact of different heparin dosing regimens for cardiopulmonary bypass on anticoagulation: the HepDOSE pilot study.

PURPOSE: It has been suggested that a larger heparin dose during cardiopulmonary bypass (CPB) is associated with reduced perioperative coagulopathy and thromboembolic complications. We investigated the effect of different heparin doses during routine elective cardiac surgery. Our primary outcomes include blood loss and transfusion and secondary outcomes investigate the effects on coagulation biomarkers. METHODS: In this prospective pilot trial, we allocated 60 patients undergoing cardiac surgery on CPB in a single tertiary cardiac centre into three groups to receive an initial dose of 300, 400, or 500 units (U) per kilogram of intravenous heparin prior to the commencement of CPB. Blood was sampled after induction of anesthesia, at 30 and 60 min of CPB, and three minutes after heparin reversal with protamine. Samples were analyzed for fibrinopeptide A (FPA), fibrinopeptide B (FPB), D-dimer, and thrombin-antithrombin (TAT) complexes. Postoperative blood loss and transfusion was measured for the first 24-hr period after surgery. RESULTS: The total mean (95% CI) administered heparin dose in the 300 U·kg-1, 400 U·kg-1, and 500 U·kg-1 groups were 39,975 (36,528 to 43,421) U, 43,195 (36,940 to 49,449) U and 47,900 (44,807 to 50,992) U, respectively. There were no statistically significant differences in FPA, FPB or D-dimer levels at the measured time intervals. There was a trend towards lower TAT levels while on CPB with greater heparin dosing, which was statistically significant after the administration of protamine. The clinical significance appears to be negligible, as there is no difference in overall blood loss and amount of packed red blood cell transfusion or other blood product transfusion. CONCLUSION: This pilot study indicates that, while larger heparin dosing for routine cardiac surgery results in subtle biochemical changes in coagulation, there is no demonstrable benefit in postoperative blood loss or transfusion requirements.

RéSUMé: OBJECTIF: Il a été suggéré qu'une dose plus élevée d'héparine pendant la circulation extracorporelle (CEC) serait associée à une réduction de la coagulopathie périopératoire et des complications thromboemboliques. Nous avons étudié l'effet de différentes doses d'héparine au cours d'une chirurgie cardiaque non urgente de routine. Nos critères d'évaluation principaux comprenaient la perte de sang et la transfusion, et les critères d'évaluation secondaires exploraient les effets sur les biomarqueurs de la coagulation. MéTHODE: Dans cette étude pilote prospective, nous avons réparti 60 patient·es bénéficiant d'une chirurgie cardiaque sous CEC dans un seul centre cardiaque tertiaire en trois groupes à recevoir une dose initiale de 300, 400 ou 500 unités (U) par kilogramme d'héparine intraveineuse avant le début de la CEC. Le sang a été prélevé après l'induction de l'anesthésie, à 30 et 60 minutes de CEC, et trois minutes après la neutralisation de l'héparine avec la protamine. Les échantillons ont été analysés pour les complexes fibrinopeptide A (FPA), fibrinopeptide B (FPB), D-dimère et thrombine-antithrombine (TAT). La perte de sang postopératoire et la transfusion ont été mesurées pendant la première période de 24 heures après la chirurgie. RéSULTATS: La dose moyenne totale (IC 95 %) d'héparine administrée dans les 300 U·kg−1, 400 U·kg−1, et 500 U·kg−1 était de 39 975 (36 528 à 43 421) U, 43 195 (36 940 à 49 449) U et 47 900 (44 807 à 50 992) U, respectivement. Il n'y avait aucune différence statistiquement significative dans les taux de FPA, FPB ou D-dimères aux intervalles de temps mesurés. Une tendance à des niveaux de TAT plus bas pendant la CEC a été observée avec une dose d'héparine plus élevée, ce qui était statistiquement significatif après l'administration de protamine. La signification clinique semble négligeable, car il n'y a pas de différence dans la perte de sang globale et la quantité de transfusion de concentrés globulaires ou d'autres produits sanguins. CONCLUSION: Cette étude pilote indique que, bien qu'une dose plus importante d'héparine pour la chirurgie cardiaque de routine entraîne des changements biochimiques subtils dans la coagulation, il n'y a aucun avantage démontrable en matière de saignement postopératoire ou de besoins transfusionnels.

Management of acute aortic dissection in critical care.

Aortic dissections are associated with significant mortality and morbidity, with rapid treatment paramount. They are caused by a tear in the intimal lining of the aorta that extends into the media of the wall. Blood flow through this tear leads to the formation of a false passage bordered by the inner and outer layers of the media. Their diagnosis is challenging, with most deaths caused by aortic dissection diagnosed at post-mortem. Aortic dissections are classified by location and chronicity, with management strategies depending on the nature of the dissection. The Stanford method splits aortic dissections into type A and B, with type A dissections involving the ascending aorta. De Bakey classifies dissections into I, II or III depending on their origin and involvement and degree of extension. The key to diagnosis is early suspicion, appropriate imaging and rapid initiation of treatment. Treatment focuses on initial resuscitation, transfer (if possible and required) to a suitable specialist centre, strict blood pressure and heart rate control and potentially surgical intervention depending on the type and complexity of the dissection. Effective post-operative care is extremely important, with awareness of potential post-operative complications and a multi-disciplinary rehabilitation approach required. In this review article we will discuss the aetiology and classifications of aortic dissection, their diagnosis and treatment principles relevant to critical care. Critical care clinicians play a key part in all these steps, from diagnosis through to post-operative care, and thus a thorough understanding is vital.

Optimal protamine dosing after cardiopulmonary bypass: The PRODOSE adaptive randomised controlled trial.

BACKGROUND: The dose of protamine required following cardiopulmonary bypass (CPB) is often determined by the dose of heparin required pre-CPB, expressed as a fixed ratio. Dosing based on mathematical models of heparin clearance is postulated to improve protamine dosing precision and coagulation. We hypothesised that protamine dosing based on a 2-compartment model would improve thromboelastography (TEG) parameters and reduce the dose of protamine administered, relative to a fixed ratio. METHODS AND FINDINGS: We undertook a 2-stage, adaptive randomised controlled trial, allocating 228 participants to receive protamine dosed according to a mathematical model of heparin clearance or a fixed ratio of 1 mg of protamine for every 100 IU of heparin required to establish anticoagulation pre-CPB. A planned, blinded interim analysis was undertaken after the recruitment of 50% of the study cohort. Following this, the randomisation ratio was adapted from 1:1 to 1:1.33 to increase recruitment to the superior arm while maintaining study power. At the conclusion of trial recruitment, we had randomised 121 patients to the intervention arm and 107 patients to the control arm. The primary endpoint was kaolin TEG r-time measured 3 minutes after protamine administration at the end of CPB. Secondary endpoints included ratio of kaolin TEG r-time pre-CPB to the same metric following protamine administration, requirement for allogeneic red cell transfusion, intercostal catheter drainage at 4 hours postoperatively, and the requirement for reoperation due to bleeding. The trial was listed on a clinical trial registry (ClinicalTrials.gov Identifier: NCT03532594). Participants were recruited between April 2018 and August 2019. Those in the intervention/model group had a shorter mean kaolin r-time (6.58 [SD 2.50] vs. 8.08 [SD 3.98] minutes; p = 0.0016) post-CPB. The post-protamine thromboelastogram of the model group was closer to pre-CPB parameters (median pre-CPB to post-protamine kaolin r-time ratio 0.96 [IQR 0.78-1.14] vs. 0.75 [IQR 0.57-0.99]; p < 0.001). We found no evidence of a difference in median mediastinal/pleural drainage at 4 hours postoperatively (140 [IQR 75-245] vs. 135 [IQR 94-222] mL; p = 0.85) or requirement (as a binary outcome) for packed red blood cell transfusion at 24 hours postoperatively (19 [15.8%] vs. 14 [13.1%] p = 0.69). Those in the model group had a lower median protamine dose (180 [IQR 160-210] vs. 280 [IQR 250-300] mg; p < 0.001). Important limitations of this study include an unblinded design and lack of generalisability to certain populations deliberately excluded from the study (specifically children, patients with a total body weight >120 kg, and patients requiring therapeutic hypothermia to <28°C). CONCLUSIONS: Using a mathematical model to guide protamine dosing in patients following CPB improved TEG r-time and reduced the dose administered relative to a fixed ratio. No differences were detected in postoperative mediastinal/pleural drainage or red blood cell transfusion requirement in our cohort of low-risk patients. TRIAL REGISTRATION: ClinicalTrials.gov Unique identifier NCT03532594.

The role of venodilators in the perioperative management of heart failure.

A unifying hypothesis which satisfactorily explains the clinical syndrome of heart failure has proved elusive. A deeper understanding of the underlying pathophysiology has led to the development of more complex models and, as a result, the evolution of new treatment strategies. In patients undergoing non-cardiac surgery, perioperative heart failure has an incidence of approximately 1% and is a predictor of major adverse cardiovascular events. Although vasodilators undoubtedly play a major role in the management of patients with heart failure, the relative importance of venodilatation remains unclear. The purpose of this article is to discuss the clinical evidence supporting the use of drugs with venodilating properties in surgical patients with heart failure.

Circulatory arrest versus cerebral perfusion during pulmonary endarterectomy surgery (PEACOG): a randomised controlled trial.

BACKGROUND: For some surgical procedures to be done, a patient's blood circulation needs to be stopped. In such situations, the maintenance of blood flow to the brain is perceived beneficial even in the presence of deep hypothermia. We aimed to assess the benefits of the maintenance of antegrade cerebral perfusion (ACP) compared with deep hypothermic circulatory arrest (DHCA). METHODS: Patients aged 18-80 years undergoing pulmonary endarterectomy surgery in a UK centre (Papworth Hospital, Cambridge) were randomly assigned with a computer generated sequence to receive either DHCA for periods of up to 20 min at 20°C or ACP (1:1 ratio). The primary endpoint was change in cognitive function at 12 weeks after surgery, as assessed by the trail-making A and B tests, the Rey auditory verbal learning test, and the grooved pegboard test. Patients and assessors were masked to treatment allocation. Primary analysis was by intention to treat. The trial is registered with Current Controlled Trials, number ISRCTN84972261. FINDINGS: We enrolled 74 of 196 screened patients (35 to receive DHCA and 39 to receive ACP). Nine patients crossed over from ACP to DHCA to allow complete endarterectomy. At 12 weeks, the mean difference between the two groups in Z scores (the change in cognitive function score from baseline divided by the baseline SD) for the three main cognitive tests was 0·14 (95% CI -0·14 to 0·42; p=0·33) for the trail-making A and B tests, -0·06 (-0·38 to 0·25; p=0·69) for the Rey auditory verbal learning test, and 0·01 (-0·26 to 0·29; p=0·92) for the grooved pegboard test. All patients showed improvement in cognitive function at 12 weeks. We recorded no significant difference in adverse events between the two groups. At 12 weeks, two patients had died (one in each group) [corrected]. INTERPRETATION: Cognitive function is not impaired by either ACP or DHCA. We recommend circulatory arrest as the optimum modality for patients undergoing pulmonary endarterectomy surgery. FUNDING: J P Moulton Charitable Foundation.

Consensus statement: minimal criteria for reporting the systemic inflammatory response to cardiopulmonary bypass.

The lack of established cause and effect between putative mediators of inflammation and adverse clinical outcomes has been responsible for many failed anti-inflammatory interventions in cardiopulmonary bypass (CPB). Candidate interventions that impress in preclinical trials by suppressing a given inflammation marker might fail at the clinical trial stage because the marker of interest is not linked causally to an adverse outcome. Alternatively, there exist examples in which pharmaceutical agents or other interventions improve clinical outcomes but for which we are uncertain of any antiinflammatory mechanism. The Outcomes consensus panel made 3 recommendations in 2009 for the conduct of clinical trials focused on the systemic inflammatory response. This panel was tasked with updating, as well as simplifying, a previous consensus statement. The present recommendations for investigators are the following: (1) Measure at least 1 inflammation marker, defined in broad terms; (2) measure at least 1clinical end point, drawn from a list of practical yet clinically meaningful end points suggested by the consensus panel; and(3) report a core set of CPB and perfusion criteria that maybe linked to outcomes. Our collective belief is that adhering to these simple consensus recommendations will help define the influence of CPB practice on the systemic inflammatory response, advance our understanding of causal inflammatory mechanisms, and standardize the reporting of research findings in the peer-reviewed literature.

Transannular pulmonary enlargement and bioprostheses for carcinoid disease.

A diminutive pulmonary artery and right ventricular outflow tract in a 46-year-old woman with a 10-year history of carcinoid syndrome required transannular pulmonary patch enlargement to allow replacement of the pulmonary and tricuspid valves with bioprostheses. The avoidance of anticoagulation permitted further hepatic arterial embolization without an increased risk of bleeding.

Successful extracorporeal membrane oxygenation support after pulmonary thromboendarterectomy.

BACKGROUND: Pulmonary thromboendarterectomy (PTE) is the treatment of choice for patients with chronic thromboembolic pulmonary hypertension. However, some patients develop severe cardiorespiratory compromise soon after separating from cardiopulmonary bypass, either from early reperfusion pulmonary edema or right ventricular failure secondary to residual pulmonary hypertension. Since 2005 we have used venoarterial extracorporeal membrane oxygenation (ECMO) support in this group that has no other therapeutic option. We review our experience of early ECMO support in the severely compromised patient's post-PTE. METHODS: We conducted a retrospective review of all patients undergoing PTE from a single national referral center between August 2005 and August 2007. RESULTS: One hundred twenty-seven consecutive patients underwent PTE surgery. Seven patients (5.5%) had extreme cardiorespiratory compromise in the immediate postoperative period and required venoarterial ECMO support. Their mean age was 51.3 years with 3 males. When compared with patients not requiring ECMO, these patients had significantly poorer hemodynamic indices before the operation with mean pulmonary artery pressure of 62 mm Hg versus 51 mm Hg (p = 0.02) and pulmonary vascular resistance of 907 dynes/sec/cm(-5) versus 724 dynes/s(-1)/cm(-5) (p < 0.02). Mean duration of support was 119 hours (49 to 359 hours). Five patients were successfully weaned from ECMO support (73%) and 4 left the hospital alive, giving a salvage rate of 57%. For those who did not require ECMO support, hospital mortality was 4.2%. CONCLUSIONS: Early venoarterial ECMO support has a role as rescue therapy post-PTE in patients with severe compromise who would probably otherwise die.

Consensus statement: Defining minimal criteria for reporting the systemic inflammatory response to cardiopulmonary bypass.

The causal factors of the systemic inflammatory response to cardiopulmonary bypass (CPB) were correctly identified in the early 1990 s: "... activation of complement, coagulation, fibrinolytic, and kallikrein cascades, activation of neutrophils with degranulation and protease enzyme release, oxygen radical production, and the synthesis of various cytokines from mononuclear cells" [Butler 1993]. Why therefore have clinical advances to curb the systemic inflammatory response proven such a disappointment? Part of the problem is that cardiac surgery has never taken intellectual ownership of this issue, borrowing its diagnosis from critical care medicine and failing to define the minimal criteria that should be measured when reporting on the systemic inflammatory response. An evidence based review of the current literature by many of the coauthors on this paper found that the majority of studies on the systemic inflammatory response did not measure a single one of the causal factors listed above - thus hindering our ability to identify mechanisms of causation and identify drug targets [Landis 2008]. A panel of experts convened at the Outcomes XII meeting, Barbados 2008, drafted the present consensus document in order to provide a framework to guide future studies and interdictions of the systemic inflammatory response. Herein, we have recommended: 1) mandatory reporting of minimal CPB and perfusion criteria that may affect outcomes, 2) reporting of a minimal set of causal inflammatory markers linked to adverse sequelae, and 3) reporting of at least one clinical end-point of organ injury, from a list of endpoints and markers of organ injury that balance practicality with clinical meaningfulness. It is our collective belief that this document will serve as a foundation for furthering our understanding of the influence of CPB practice with the systemic inflammatory response by standardizing the reporting of research findings in the peer-reviewed literature.

Cardiopulmonary bypass management and neurologic outcomes: an evidence-based appraisal of current practices.

Neurologic complications after cardiac surgery are of growing importance for an aging surgical population. In this review, we provide a critical appraisal of the impact of current cardiopulmonary bypass (CPB) management strategies on neurologic complications. Other than the use of 20-40 microm arterial line filters and membrane oxygenators, newer modifications of the basic CPB apparatus or the use of specialized equipment or procedures (including hypothermia and "tight" glucose control) have unproven benefit on neurologic outcomes. Epiaortic ultrasound can be considered for ascending aorta manipulations to avoid atheroma, although available clinical trials assessing this maneuver are limited. Current approaches for managing flow, arterial blood pressure, and pH during CPB are supported by data from clinical investigations, but these studies included few elderly or high-risk patients and predated many other contemporary practices. Although there are promising data on the benefits of some drugs blocking excitatory amino acid signaling pathways and inflammation, there are currently no drugs that can be recommended for neuroprotection during CPB. Together, the reviewed data highlight the deficiencies of the current knowledge base that physicians are dependent on to guide patient care during CPB. Multicenter clinical trials assessing measures to reduce the frequency of neurologic complications are needed to develop evidence-based strategies to avoid increasing patient morbidity and mortality.

Cognitive change 5 years after coronary artery bypass surgery.

A longitudinal study of cognitive function after coronary artery bypass surgery examined 107 participants using 11 tests, preoperatively and at 6 days, 8 weeks, and 5 years after surgery. The overall neuropsychological (NP) change score declined at 6 days, showed some recovery at 8 weeks, and declined again at 5 years. The number of microemboli recorded during surgery, postoperative short-term cognitive change, and degree of recovery at 8 weeks were identified as predictors of change in NP score to 5 years. This suggests that even over a 5-year period, operative damage is detectable. Patients' vulnerability to short-term deterioration and resilience or ability to recover over a few weeks from operative cerebral insult are important processes of unknown mechanisms.