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1.  Role of prothrombin complex concentrate in perioperative coagulation therapy 
Prothrombin complex concentrate (PCC) is a term to describe pharmacological products that contain lyophilized, human plasma-derived vitamin K-dependent factors (F), FII, FVII, FIX, FX, and various amounts of proteins C and S. PCCs can be rapidly reconstituted in a small volume (20 ml for about 500 international units (IU)) at bedside and administered regardless of the patient’s blood type. PCCs are categorized as 4-factor PCC if they contain therapeutic amounts of FVII, and 3-factor PCC when FVII content is low. In addition, activated PCC which contains activated FVII and FX with prothrombin is available for factor VIII bypassing therapy in hemophilia patients with inhibitors. Currently, 4-factor PCC is approved for the management of bleeding in patients taking warfarin, but there has been increasing use of various PCCs in the treatment of acquired perioperative coagulopathy unrelated to warfarin therapy and in the management of bleeding due to novel oral anticoagulants. There is also an ongoing controversy about plasma transfusion and its potential hazards including transfusion-related lung injury (TRALI). Early fixed ratio plasma transfusion has been implemented in many trauma centers in the USA, whereas fibrinogen concentrate and PCC are preferred over plasma transfusion in some European centers.
In this review, the rationales for including PCCs in the perioperative hemostatic management will be discussed in conjunction with plasma transfusion.
doi:10.1186/s40560-014-0060-5
PMCID: PMC4336276
Coagulation; Fresh frozen plasma; Prothrombin complex concentrate; Recombinant activated factor VII; Factor eight bypassing agent; Thromboelastometry
2.  Prothrombin complex concentrate vs fresh frozen plasma for reversal of dilutional coagulopathy in a porcine trauma model 
BJA: British Journal of Anaesthesia  2009;102(3):345-354.
Background
Fluid resuscitation following traumatic injury causes haemodilution and can contribute to coagulopathy. Coagulation factor replacement may be necessary to prevent bleeding complications of dilutional coagulopathy. Compared with fresh frozen plasma (FFP), prothrombin complex concentrate (PCC) may potentially offer a more rapid and effective means of normalizing coagulation factor levels.
Methods
In anaesthetized mildly hypothermic pigs, 65–70% of total blood volume was substituted in phases with hydroxyethyl starch and red cells. Animals were then treated with 15 ml kg−1 isotonic saline placebo, 25 IU kg−1 PCC, or 15 ml kg−1 FFP. Immediately thereafter, either a standardized femur or spleen injury was inflicted, and coagulation function, including thrombin generation, and bleeding were assessed. An additional group received high-dose FFP (40 ml kg−1) before femur injury.
Results
Haemodilution markedly prolonged prothrombin time and reduced peak thrombin generation. PCC, but not FFP, fully reversed those effects. Compared with 15 ml kg−1 FFP, PCC shortened the time to haemostasis after either bone (P=0.001) or spleen (P=0.028) trauma and reduced the volume of blood lost (P<0.001 and P=0.015, respectively). Subsequent to bone injury, PCC also accelerated haemostasis (P=0.003) and diminished blood loss (P=0.006) vs 40 ml kg−1 FFP.
Conclusions
PCC was effective in correcting dilutional coagulopathy and controlling bleeding in an in vivo large-animal trauma model. In light of its suitability for more rapid administration than FFP, PCC merits further investigation as a therapy for dilutional coagulopathy in trauma and surgery.
doi:10.1093/bja/aen391
PMCID: PMC2642652  PMID: 19168856
blood, haemodilution; complications, haemorrhagic disorder; complications, trauma; fresh frozen plasma; prothrombin complex concentrate
3.  Use of prothrombin complex concentrate for excessive bleeding after cardiac surgery 
OBJECTIVES
Prothrombin complex concentrates (PCCs) are sometimes used as ‘off label’ for excessive bleeding after cardiopulmonary bypass (CPB). The main objective of this study was to retrospectively evaluate the clinical and biological efficacy of PCC in this setting.
METHODS
We reviewed the charts of all patients who had undergone cardiac surgery under CPB in our institution for 2 years. Patients treated for active bleeding with haemostatic therapy were identified. Chest tube blood loss was quantified postoperatively in the first 24 h. Coagulation parameters were recorded at intensive care unit admission and in the patient's first 24 h. Thromboembolic complications were also ascertained.
RESULTS
Seventy-seven patients out of the 677 studied (11.4%) were included: PCC was solely administered in 24 patients (group I), fresh frozen plasma in 26 (group II) and both in 27 (group III). The mean dose of PCC was 10.0 UI/kg ± 3.5 for group I vs 14.1 UI/kg ± 11.2 for group III (P = 0.09). Initial blood loss in the first hour was different between the three groups (P = 0.05): 224 ± 131 ml for group I, 369 ± 296 ml for group II and 434 ± 398 ml for group III. Only group I vs group III presented a significant difference (P = 0.02). Variations of blood loss over time were no different according to the treatment groups (P = 0.12). Reductions in blood loss expressed in percentage showed no difference between the three groups after 2 h: 54.5% (68.6–30.8) for group I; 45.0% (81.6–22.2) for group II; 57.6 (76.0–2.1) for group III; (P = 0.89). Re-exploration for bleeding involved 1 patient in group I (4%), 2 in group II (8%) and 10 in group III (37%) (P = 0.002). Except for fibrinogen, variations of prothrombin time, activated partial thromboplastin time and platelets with time were not different according to the treatment groups. Cerebral infarction occurred in one patient in group II.
CONCLUSIONS
Administration of low-dose of PCC significantly decreased postoperative bleeding after CPB.
doi:10.1093/icvts/ivs224
PMCID: PMC3422937  PMID: 22623627
Prothrombin complex concentrates; Bleeding; Cardiopulmonary bypass; Thromboembolic complications
4.  Prothrombin complex concentrate (Beriplex P/N) in severe bleeding: experience in a large tertiary hospital 
Critical Care  2008;12(4):R105.
Introduction
Major blood loss can often be life-threatening and is most commonly encountered in the settings of surgery and trauma. Patients receiving anticoagulant therapy are also at increased risk of bleeding. We investigated the use of a prothrombin complex concentrate (PCC; Beriplex P/N, CSL Behring, Marburg, Germany) to treat severe bleeding in a variety of settings: cardiac surgery, warfarin therapy and other surgery.
Methods
Thirty consecutive patients who had received PCC were identified from blood transfusion records. For cardiac surgery and warfarin reversal, PCC was administered in accordance with hospital protocols. PCC was administered to cardiac and other surgical patients responding poorly to recognized blood products, whereas it was administered first-line to patients with life-threatening bleeds and requiring warfarin reversal, in accordance with British Committee for Standards in Haematology guidelines. We conducted a retrospective analysis of patient records in order to ascertain PCC dose, use of other blood products and response to PCC (clotting screen results before and after PCC administration, haemostasis achievement, and survival).
Results
Six patients (20%) were excluded because of inadequate documentation (n = 5) or acquired haemophilia (n = 1). Therefore, 24 patients were included in the analysis: coronary artery bypass graft (n = 5), mitral/aortic valve replacement (n = 2), other surgery (n = 9) and warfarin reversal (n = 8). Most patients (83.3%) received no more than 1500 IU of Beriplex P/N 500. Considerable reduction in administration of other blood products was seen during the 24 hours after PCC administration. Partial or complete haemostasis was achieved in 14 out of 18 cases (77.8%). In total, 12 out of 24 patients (50%) died during the study; two-thirds of the deaths were considered unrelated to bleeding. No thrombotic complications or adverse drug reactions were observed.
Conclusion
This study emphasizes the value of PCC in reversing the effects of oral anticoagulant therapy in bleeding patients. It also demonstrates the potential value of PCC in controlling bleeding in patients undergoing cardiac and other surgical procedures. The use of PCC in bleeding patients without hereditary or anticoagulation-related coagulopathy is novel, and further investigation is warranted. In the future, it may be possible to use PCC as a substitute for fresh frozen plasma in this setting; adequate documentation is crucial for all blood products.
doi:10.1186/cc6987
PMCID: PMC2575594  PMID: 18706082
5.  Fibrinogen concentrate administration attributes to significant reductions of blood loss and transfusion requirements in thoracic aneurysm repair 
Background
Repair of thoracic aortic aneurysm (TAA) is often associated with massive hemorrhage aggravated by dilutional coagulopathy with severe hypofibrinogenemia. Although only fresh frozen plasma (FFP) is available for acquired hypofibrinogenemia in Japan, the hemostatic effect of FFP has not been enough for dilutional coagulopathy in TAA surgery. There are increasing reports suggesting that fibrinogen concentrate may be effective in controlling perioperative bleeding and reducing transfusion requirements.
Methods
We retrospectively analyzed the hemostatic effect of fibrinogen concentrate compared with FFP in total 49 cases of elective TAA surgery. In 25 patients, fibrinogen concentrate was administered when the fibrinogen level was below 150 mg/dL at the cardiopulmonary bypass (CPB) termination. The recovery of fibrinogen level, blood loss, and transfused units during surgery were compared between cases of this agent and FFP (n = 24).
Results
We observed rapid increases in plasma fibrinogen level and subsequent improvement in hemostasis by administration of fibrinogen concentrate after CPB termination. The average volume of total blood loss decreased by 64% and the average number of transfused units was reduced by 58% in cases of fibrinogen concentrate given, in comparison with cases of only FFP transfused for fibrinogen supplementation.
Conclusions
In patients showing severe hypofibrinogenemia during TAA surgery, timely administration of fibrinogen concentrate just after removal from CPB is effective for hemostasis, and therefore in reducing blood loss and transfused volumes.
doi:10.1186/1749-8090-9-90
PMCID: PMC4067735  PMID: 24884627
Massive hemorrhage; Thoracic aortic aneurysm; Cardiopulmonary bypass; Dilutional coagulopathy; Hypofibrinogenemia
6.  Intraoperative Use of Low-Dose Recombinant Activated Factor VII During Thoracic Aortic Operations 
The Annals of thoracic surgery  2012;93(6):1921-1929.
Background
Numerous studies have supported the effectiveness of recombinant activated factor VII (rFVIIa) for the control of bleeding after cardiac procedures; however safety concerns persist. Here we report the novel use of intraoperative low-dose rFVIIa in thoracic aortic operations, a strategy intended to improve safety by minimizing rFVIIa exposure.
Methods
Between July 2005 and December 2010, 425 consecutive patients at a single referral center underwent thoracic aortic operations with cardiopulmonary bypass (CPB); 77 of these patients received intraoperative low-dose rFVIIa (≤60 μg/kg) for severe coagulopathy after CPB. Propensity matching produced a cohort of 88 patients (44 received intraoperative low-dose rFVIIa and 44 controls) for comparison.
Results
Matched patients receiving intraoperative low-dose rFVIIa got an initial median dose of 32 μg/kg (interquartile range [IQR], 16–43 μg/kg) rFVIIa given 51 minutes (42–67 minutes) after separation from CPB. Patients receiving intraoperative low-dose rFVIIa demonstrated improved postoperative coagulation measurements (partial thromboplastin time 28.6 versus 31.5 seconds; p = 0.05; international normalized ratio, 0.8 versus 1.2; p < 0.0001) and received 50% fewer postoperative blood product transfusions (2.5 versus 5.0 units; p = 0.05) compared with control patients. No patient receiving intraoperative low-dose rFVIIa required postoperative rFVIIa administration or reexploration for bleeding. Rates of stroke, thromboembolism, myocardial infarction, and other adverse events were equivalent between groups.
Conclusions
Intraoperative low-dose rFVIIa led to improved postoperative hemostasis with no apparent increase in adverse events. Intraoperative rFVIIa administration in appropriately selected patients may correct coagulopathy early in the course of refractory blood loss and lead to improved safety through the use of smaller rFVIIa doses. Appropriately powered randomized studies are necessary to confirm the safety and efficacy of this approach.
doi:10.1016/j.athoracsur.2012.02.037
PMCID: PMC3718882  PMID: 22551846
7.  Angiotensin-Converting Enzyme Inhibition Alters the Inflammatory and Fibrinolytic Response to Cardiopulmonary Bypass in Children 
Objective
Many children with a congenital heart defect undergo surgical correction requiring cardiopulmonary bypass (CPB). One sixth of these patients take an angiotensin-converting enzyme inhibitor (ACEi) for heart failure treatment. The effect of ACE inhibition on the fibrinolytic and inflammatory response in children undergoing CPB is unknown. In adults, ACE inhibition attenuates the increase in plasminogen activator inhibitor-1 (PAI-1) following CPB whereas the effect on the interleukin (IL)-6 response is uncertain. This study tests the hypothesis that preoperative ACE inhibition attenuates postoperative PAI-1 and IL-6 expression following CPB in children.
Design
Single center prospective randomized non-blinded study.
Setting
University-affiliated pediatric hospital.
Patients
Children undergoing elective surgical correction of a congenital heart defect requiring CPB and taking an ACEi.
Interventions
Children were randomized to continue ACEi until the morning of surgery (ACEi group, N=11) or to discontinue therapy 72 hours prior to surgery (No ACEi group, N=9).
Measurement and Main Results
Blood samples were collected at baseline before CPB, at 30min of CPB, upon arrival to the ICU, and on postoperative day 1 (POD1). Baseline bradykinin concentrations were significantly higher and ACE activity significantly lower in the ACEi group compared to the no ACEi group (P=0.04 and P=0.001 respectively). PAI-1 antigen increased 15-fold following CPB and peaked on POD1 (from 4.6±1.2 to 67.7±9.5 ng/ml; P<0.001). POD1 PAI-1 antigen correlated significantly with CPB time (r2=0.40, P=0.03) and was significantly lower in the ACEi group compared to the no ACEi group (P=0.03). The pro-inflammatory markers IL-6 and IL-8, as well as the anti-inflammatory marker IL-10, increased significantly following CPB (all P<0.001). IL-6 concentrations were significantly higher in the ACEi group following CPB (P=0.02) even after controlling for potential confounding factors such as age, CPB time and transfusion volume.
Conclusion
ACE inhibition attenuates the increase in postoperative PAI-1 but enhances the IL-6 response in children undergoing CPB.
doi:10.1097/PCC.0b013e3181fe3925
PMCID: PMC3690292  PMID: 20975611
angiotensin converting enzyme; plasminogen activator; interleukin; pediatric surgery; acute kidney injury; cardiopulmonary bypass
8.  Comparison of single lung transplant with and without the use of cardiopulmonary bypass† 
OBJECTIVES
Many centres avoid using cardiopulmonary bypass (CPB) for lung transplant due to concerns over aggravated lung reperfusion injury and excessive blood loss. We reviewed our 23-years’ experience of single lung transplantation.
METHODS
A retrospective review of single lung transplants at our institution (1987–2010), examining differences in allograft function and postoperative complications between CPB and non-bypass (non-CPB) cases.
RESULTS
Two hundred and fifty-nine single lung transplants were undertaken. Fifty-three (20.5%) with CPB. There was no difference demographically between the two groups. No difference existed in preoperative PO2/FiO2. At 1 and 24 h, the postoperative PO2/FiO2 ratio was no different (mean 2.95 and 3.24 in non-CPB cases; 3.53 and 3.75 in CPB patients, P = 0.18 and P = 0.34, respectively). Extubation time was not influenced by the use of CPB. Postoperative blood loss was greater in the CPB group. The usage of fresh frozen plasma and platelets was similar (P = 0.64 and 0.41, respectively). More blood was transfused during postoperative care of CPB patients (P = 0.02).
CONCLUSIONS
Fears of poor postoperative lung function after CPB appear unfounded. We could detect no difference in function or extubation time. Although the use of CPB increases postoperative bleeding and the need for transfusion, it may be used safely to facilitate lung transplantation.
doi:10.1093/icvts/ivs264
PMCID: PMC3422961  PMID: 22714587
Lung transplant; Cardiopulmonary bypass
9.  Time course of haemostatic effects of fibrinogen concentrate administration in aortic surgery 
BJA: British Journal of Anaesthesia  2013;110(6):947-956.
Background
There is currently a contrast between the demonstrated benefits of fibrinogen concentrate in correcting bleeding and reducing transfusion, and its perceived thrombogenic potential. This analysis evaluates the effects of fibrinogen concentrate on coagulation up to 12 days after administration during aortic surgery.
Methods
We performed a post hoc analysis of a prospective, randomized, double-blind, controlled trial of fibrinogen concentrate as first-line haemostatic therapy in aortic surgery. After cardiopulmonary bypass (CPB) and protamine administration, subjects with coagulopathic bleeding received fibrinogen concentrate or placebo. The placebo group received allogeneic blood products, including fresh-frozen plasma (FFP; n=32); the fibrinogen concentrate group received fibrinogen concentrate alone (FC; n=14), or fibrinogen concentrate followed by allogeneic blood products (FC+FFP; n=15). Plasma fibrinogen, fibrin-based clotting (ROTEM®-based FIBTEM assay), and peri- and postoperative haematological and coagulation parameters were compared.
Results
Plasma fibrinogen and FIBTEM maximum clot firmness (MCF) decreased ∼50% during CPB but were corrected by FC or FC+FFP. At last suture, the highest values for plasma fibrinogen (360 mg dl−1) and FIBTEM MCF (22 mm) were within normal ranges—below the acute phase increases observed after surgery. In patients receiving only FFP as a source of fibrinogen, these parameters recovered marginally by last suture (P<0.001 vs FC and FC+FFP). All groups displayed comparable haemostasis at 24 h post-surgery. Fibrinogen concentrate did not cause alterations of other haemostasis parameters.
Conclusions
Fibrinogen concentrate provided specific, significant, short-lived increases in plasma fibrinogen and fibrin-based clot firmness after aortic surgery.
doi:10.1093/bja/aes576
PMCID: PMC3657602  PMID: 23388508
blood coagulation tests; cardiopulmonary bypass; fibrin; fibrinogen; plasma
10.  Population pharmacokinetics of remifentanil in infants and children undergoing cardiac surgery 
BMC Anesthesiology  2009;9:5.
Background
The aim of this study was to provide a model-based analysis of the pharmacokinetics of remifentanil in infants and children undergoing cardiac surgery with cardiopulmonary bypass (CPB).
Methods
We studied nine patients aged 0.5 to 4 years who received a continuous remifentanil infusion via a computer-controlled infusion pump during cardiac surgery with mildly hypothermic CPB were studied. Arterial blood samples taken prior to, during and after CPB were analyzed for remifentanil concentrations using a validated gas-chromatographic mass-spectrophotometric assay. We used population mixed-effects modeling to characterize remifentanil pharmacokinetics. The final model was evaluated by its predictive performance.
Results
The pharmacokinetics of remifentanil was described by a 1-compartment model with adjustments for CPB. Population mean parameter estimates were 1.41 L for volume of distribution (V) and 0.244 L/min for clearance. V was increased during CPB and post-CPB to 2.41 times the pre-CPB value. The median prediction error and the median of individual median absolute prediction error were 2.44% and 21.6%, respectively.
Conclusion
Remifentanil dosage adjustments are required during and after CPB due to marked changes in the V of the drug. Simulations indicate that a targeted blood concentration of 14 ng/mL is achieved and maintained in 50% of typical patients by administration of an initial dose of 18 μg remifentanil followed by an infusion of 3.7 μg/min before, during and post-CPB, supplemented with a bolus dose of 25 μg given at the start of CPB.
doi:10.1186/1471-2253-9-5
PMCID: PMC2723094  PMID: 19635151
11.  Tranexamic acid attenuates inflammatory response in cardiopulmonary bypass surgery through blockade of fibrinolysis: a case control study followed by a randomized double-blind controlled trial 
Critical Care  2007;11(6):R117.
Introduction
Extracorporeal circulation induces hemostatic alterations that lead to inflammatory response (IR) and postoperative bleeding. Tranexamic acid (TA) reduces fibrinolysis and blood loss after cardiopulmonary bypass (CPB). However, its effects on IR and vasoplegic shock (VS) are not well known and elucidating these effects was the main objective of this study.
Methods
A case control study was carried out to determine factors associated with IR after CPB. Patients undergoing elective CPB surgery were randomly assigned to receive 2 g of TA or placebo (0.9% saline) before and after intervention. We performed an intention-to-treat analysis, comparing the incidence of IR and VS. We also analyzed several biological parameters related to inflammation, coagulation, and fibrinolysis systems. We used SPSS version 12.2 for statistical purposes.
Results
In the case control study, 165 patients were studied, 20.6% fulfilled IR criteria, and the use of TA proved to be an independent protective variable (odds ratio 0.38, 95% confidence interval 0.18 to 0.81; P < 0.01). The clinical trial was interrupted. Fifty patients were randomly assigned to receive TA (24) or placebo (26). Incidence of IR was 17% in the TA group versus 42% in the placebo group (P = 0.047). In the TA group, we observed a significant reduction in the incidence of VS (P = 0.003), the use of norepinephrine (P = 0.029), and time on mechanical ventilation (P = 0.018). These patients showed significantly lower D-dimer, plasminogen activator inhibitor 1, and creatine-kinase levels and a trend toward lower levels of soluble tumor necrosis factor receptor and interleukin-6 within the first 24 hours after CPB.
Conclusion
The use of TA attenuates the development of IR and VS after CPB.
Trial registration number
ISRCTN05718824.
doi:10.1186/cc6173
PMCID: PMC2246206  PMID: 17988379
12.  Factors associated with excessive bleeding in cardiopulmonary bypass patients: a nested case-control study 
Introduction
Excessive bleeding (EB) after cardiopulmonary bypass (CPB) may lead to increased mortality, morbidity, transfusion requirements and re-intervention. Less than 50% of patients undergoing re-intervention exhibit surgical sources of bleeding. We studied clinical and genetic factors associated with EB.
Methods
We performed a nested case-control study of 26 patients who did not receive antifibrinolytic prophylaxis. Variables were collected preoperatively, at intensive care unit (ICU) admission, at 4 and 24 hours post-CPB. EB was defined as 24-hour blood loss of >1 l post-CPB. Associations of EB with genetic, demographic, and clinical factors were analyzed, using SPSS-12.2 for statistical purposes.
Results
EB incidence was 50%, associated with body mass index (BMI)< 26.4 (25–28) Kg/m2, (P = 0.03), lower preoperative levels of plasminogen activator inhibitor-1 (PAI-1) (P = 0.01), lower body temperature during CPB (P = 0.037) and at ICU admission (P = 0.029), and internal mammary artery graft (P = 0.03) in bypass surgery. We found a significant association between EB and 5G homozygotes for PAI-1, after adjusting for BMI (F = 6.07; P = 0.02) and temperature during CPB (F = 8.84; P = 0.007). EB patients showed higher consumption of complement, coagulation, fibrinolysis and hemoderivatives, with significantly lower leptin levels at all postoperative time points (P = 0.01, P < 0.01 and P < 0.01).
Conclusion
Excessive postoperative bleeding in CPB patients was associated with demographics, particularly less pronounced BMI, and surgical factors together with serine protease activation.
doi:10.1186/1749-8090-2-17
PMCID: PMC1950484  PMID: 17425777
13.  PEDIATRIC CARDIOPULMONARY BYPASS ADAPTATIONS FOR LONG-TERM SURVIVAL OF BABOONS UNDERGOING PULMONARY ARTERY REPLACEMENT 
Background
Cardiopulmonary bypass (CPB) protocols of the baboon (Papio cynocephalusanubis) are limited to obtaining experimental data without concern for long-term survival. In the evaluation of pulmonary artery tissue engineered heart valves (TEHV's), pediatric CPB methods are adapted to accommodate the animals' unique physiology enabling survival up to six months until elective sacrifice.
Methods
Aortic access was by a 14F arterial cannula and atrial access by a single 24F venous cannula. The CPB circuit includes a 3.3 L/min flow rated oxygenator, 1/4" X 3/8" arterial-venous loop, 3/8" raceway, and bubble trap. The prime contains 700 ml Plasma-lyte, 700 units heparin, 5 ml of 50% dextrose, and 20 mg amiodarone. Heparinization (200 u/kg) targets an activated clotting time of 350 seconds. Normothermic CPB was initiated at a 2.5 L/M2/min cardiac index with a mean arterial pressure of 55–80 mmHg. Weaning was monitored with transesophageal echo cardiogram. Post-CPB circuit blood is re-infused. Chest tubes were removed with cessation of bleeding. Extubation is performed upon spontaneous breathing. The animals were conscious and upright three hours post-CPB.
Results
Bioprosthetic valves or TEHVs were implanted as pulmonary replacements in 20 baboons: weight = 27.5 ± 5.6 kg, height = 73 ± 7 cm, body surface area = 0.77 m2 ± 0.08, mean blood flow =1.973 ± 0.254 L/min, core temperature = 37.1 ± 0.1°C, CPB time = 60 ± 40 minutes. No acidosis accompanied CPB. Sixteen animals survived, 4 expired. Three died of right ventricular failure and one of an anaphylactoid reaction. Surviving animals had normally functioning replacement valves and ventricles.
Conclusions
Baboon CPB requires modifications to include high systemic blood pressure for adequate perfusion into small coronary arteries, careful CPB weaning to prevent ventricular distention, and drug and fluid interventions to abate variable venous return related to a muscularized spleno-splanchnic venous capacity.
PMCID: PMC3152821  PMID: 21114226
Baboon; Tissue Engineered Heart Valve (TEHV); Right Ventricular Outflow Tract (RVOT); Pulmonary Valve; Cardiopulmonary Bypass (CPB); Subhuman Primates; Homografts; Allografts; Xenografts
14.  Prothrombin complex concentrates and a specific antidote to dabigatran are effective ex-vivo in reversing the effects of dabigatran in an anticoagulation/liver trauma experimental model 
Critical Care  2014;18(1):R27.
Introduction
New oral anticoagulants are effective alternatives to warfarin. However, no specific reversal agents are available for life-threatening bleeding or emergency surgery. Using a porcine model of trauma, this study assessed the ability of prothrombin complex concentrate (PCC), activated PCC (aPCC), recombinant FVIIa (rFVIIa) and a specific antidote to dabigatran (aDabi-Fab) to reverse the anticoagulant effects of dabigatran.
Methods
Dabigatran etexilate (DE) was given orally for 3 days (30 mg/kg bid) and intravenously on day 4 to achieve consistent, supratherapeutic concentrations of dabigatran. Blood samples were collected at baseline, after oral DE, after intravenous dabigatran, and 60 minutes post-injury. PCC (30 and 60 U/kg), aPCC (30 and 60 U/kg), rFVIIa (90 and 180 μg/kg) and antidote (60 and 120 mg/kg) were added to blood samples ex-vivo. Coagulation was assessed by thromboelastometry, global coagulation assays and diluted thrombin time.
Results
Plasma concentrations of dabigatran were 380 ± 106 ng/ml and 1423 ± 432 ng/ml after oral and intravenous administration, respectively, and all coagulation parameters were affected by dabigatran. Both PCCs and aDabi-Fab, but not rFVIIa, reversed the effects of dabigatran on thromboelastometry parameters and prothrombin time. In contrast, aPTT was only normalised by aDabi-Fab. Plasma concentration (activity) of dabigatran remained elevated after PCC and rFVIIa therapy, but was not measureable after aDabi-Fab.
Conclusion
In conclusion, PCC and aPCC were effective in reducing the anticoagulant effects of dabigatran under different conditions, while aDabi-Fab fully corrected all coagulation measures and decreased the plasma concentration of dabigatran below the limit of detection. No significant effects were observed with rFVIIa.
doi:10.1186/cc13717
PMCID: PMC4059479  PMID: 24499559
15.  The role of plasma gelsolin in cardiopulmonary bypass induced acute lung injury in infants and young children: a pilot study 
BMC Anesthesiology  2014;14:67.
Background
Acute lung injury (ALI) induced by cardiopulmonary bypass (CPB, CPB-ALI) is a common and serious complication after cardiac surgery. And infants and young children are more prone to CPB-ALI. The purpose of this study was to investigate the perioperative changes of plasma gelsolin (pGSN) in patients below 3years of age with cardiac surgeries and CPB, and determine whether pGSN are associated with the occurrence and severity of CPB-ALI.
Methods
Seventy-seven consecutive patients ≤3 years of age with congenital heart diseases (CHD) performed on open heart surgery with CPB were finally enrolled, and assigned to ALI and non-ALI groups according to the American-European Consensus Criteria. Plasma concentrations of gelsolin and total protein were measured at following 8 time points: before CPB (a), after CPB (b), 2 hours after CPB (c), 6 hours after CPB (d), 12 hours after CPB (e), 24 hours after CPB (f), 48 hours after CPB (g) and 72 hours after CPB (h).
Results
Twenty-seven (35.1%) patients developed CPB-ALI in the study, including eleven (14.3%) patients with ARDS. The earliest significant drop of pGSN and normalized pGSN (pGSNN) of ALI group both occurred at 6 hours after CPB (p = 0.04 and p < 0.01), which was much earlier than those of non-ALI group (48 hours, p = 0.03 and 24 hours, p < 0.01); PGSN of ALI group before CPB and 6 hours after CPB were both significantly lower than those of non-ALI group (p < 0.01); PGSNN of ALI group before CPB and 6 hours after CPB were both significantly lower than those of non-ALI group (p < 0.01, p = 0.04); PGSN before CPB was the only independent risk factor predicting the occurrence of CPB-ALI (OR, 1.023; 95% CI, 1.007-1.039; p < 0.01) with an AUC of 0.753 (95% CI, 0.626-0.880); The optimal cutoff value of pGSN before CPB was 264.2 mg/L, with a sensitivity of 58.3% and a specificity 94.7%. And lower pGSN before CPB was significantly associated with the severity of CS-AKI (r = −0.45, p < 0.01).
Conclusions
Patients developing CPB-ALI had lower plasma gelsolin reservoir and a much more amount and rapid consumption of plasma gelsolin early after operation. PGSN before CPB was an early and sensitive predictor of CPB-ALI in infants and young children undergoing cardiac surgery, and was negatively correlated with the severity of CPB-ALI.
doi:10.1186/1471-2253-14-67
PMCID: PMC4132929  PMID: 25126004
Plasma gelsolin; Acute lung injury; Cardiac surgery; Cardiopulmonary bypass; Infant; Young children; Congenital heart disease
16.  Safety and Effectiveness of two treatment regimes with tranexamic acid to minimize inflammatory response in elective cardiopulmonary bypass patients: a randomized double-blind, dose-dependent, phase IV clinical trial 
Background
In cardiopulmonary bypass (CPB) patients, fibrinolysis may enhance postoperative inflammatory response. We aimed to determine whether an additional postoperative dose of antifibrinolytic tranexamic acid (TA) reduced CPB-mediated inflammatory response (IR).
Methods
We performed a randomized, double-blind, dose-dependent, parallel-groups study of elective CPB patients receiving TA. Patients were randomly assigned to either the single-dose group (40 mg/Kg TA before CPB and placebo after CPB) or the double-dose group (40 mg/Kg TA before and after CPB).
Results
160 patients were included, 80 in each group. The incident rate of IR was significantly lower in the double-dose-group TA2 (7.5% vs. 18.8% in the single-dose group TA1; P = 0.030). After adjusting for hypertension, total protamine dose and temperature after CPB, TA2 showed a lower risk of IR compared with TA1 [OR: 0.29 (95% CI: 0.10-0.83), (P = 0.013)]. Relative risk for IR was 2.5 for TA1 (95% CI: 1.02 to 6.12). The double-dose group had significantly lower chest tube bleeding at 24 hours [671 (95% CI 549-793 vs. 826 (95% CI 704-949) mL; P = 0.01 corrected-P significant] and lower D-dimer levels at 24 hours [489 (95% CI 437-540) vs. 621(95% CI: 563-679) ng/mL; P = 0.01 corrected-P significant]. TA2 required lower levels of norepinephrine at 24 h [0.06 (95% CI: 0.03-0.09) vs. 0.20(95 CI: 0.05-0.35) after adjusting for dobutamine [F = 6.6; P = 0.014 corrected-P significant].
We found a significant direct relationship between IL-6 and temperature (rho = 0.26; P < 0.01), D-dimer (rho = 0.24; P < 0.01), norepinephrine (rho = 0.33; P < 0.01), troponin I (rho = 0.37; P < 0.01), Creatine-Kinase (rho = 0.37; P < 0.01), Creatine Kinase-MB (rho = 0.33; P < 0.01) and lactic acid (rho = 0.46; P < 0.01) at ICU arrival. Two patients (1.3%) had seizure, 3 patients (1.9%) had stroke, 14 (8.8%) had acute kidney failure, 7 (4.4%) needed dialysis, 3 (1.9%) suffered myocardial infarction and 9 (5.6%) patients died. We found no significant differences between groups regarding these events.
Conclusions
Prolonged inhibition of fibrinolysis, using an additional postoperative dose of tranexamic acid reduces inflammatory response and postoperative bleeding (but not transfusion requirements) in CPB patients. A question which remains unanswered is whether the dose used was ideal in terms of safety, but not in terms of effectiveness.
Current Controlled Trials number
ISRCTN: ISRCTN84413719
doi:10.1186/1749-8090-6-138
PMCID: PMC3206427  PMID: 21999189
Cardiac surgery; Cardiopulmonary bypass; Fibrinolysis; Tranexamic acid; Inflammatory response; Bleeding
17.  A Prospective Study of the Clinical Benefits of Prostacyclin in 554 Cardiopulmonary Bypass Procedures 
Texas Heart Institute Journal  1988;15(2):86-90.
Abnormal bleeding after cardiopulmonary bypass (CPB) may result from incomplete neutralization of heparin, increased fibrinolytic activity, consumption of coagulation factors, or from a reduction in the number of circulating platelets together with impairment of platelet function. Although researchers have reason to believe that hemostasis after CPB could be improved with prostacyclin (PGI2), a potent inhibitor of platelet aggregation, the drug's clear-cut benefits in this respect have not yet been confirmed.
After conducting an initial study concerning the fate of platelets during CPB, in which we determined that PGI2 had a protective effect, we investigated the effects of PGI2 infusion during CPB on postoperative blood loss in 554 open-heart surgery patients, 200 of whom underwent valve replacement, 200 of whom had coronary artery bypass grafting (CABG), and 154 of whom underwent repeat valve replacement or CABG. The patients were divided into 2 groups: 277 patients (the study group) received both heparin and PGI2 during CPB, whereas the remaining 277 patients (the control group) were given heparin alone.
Of the patients who underwent surgery for the first time, those treated with PGI2 had a reduced mean blood loss (p < 0.05 only in CABG patients) in comparison with those who received heparin alone. Of the patients who underwent redo operations, those who received PGI2 had a nonsignificant tendency toward reduced blood loss. The mean difference in blood loss between the study group and the control group had no clinical relevance, however, because it was less than the smallest practical unit of measurement (i.e., 1 unit of blood). (Texas Heart Institute Journal 1988; 15:86-90)
PMCID: PMC324797  PMID: 15227257
Cardiopulmonary bypass; prostaglandins X; platelet aggregation; hemostasis, surgical
18.  Effect of Cardiopulmonary Bypass on Regional Antibiotic Penetration into Lung Tissue 
The use of cardiopulmonary bypass (CPB) during cardiac surgery causes regional ventilation-perfusion mismatch, contributing to regional disturbances in antibiotic penetration into lung tissue. Ventilation-perfusion mismatch is associated with postoperative pneumonia, a frequent and devastating complication after cardiac surgery. In this prospective clinical animal study, we performed in vivo microdialysis to determine the effect of CPB on regional penetration of levofloxacin (LVX) into lung tissue. Six pigs underwent surgery with CPB (CPB group), and another six pigs underwent surgery without CPB (off-pump coronary artery bypass grafting; OPCAB group). LVX (750 mg) was administered intravenously to all pigs immediately after surgery. For regional measurements of LVX in pulmonary concentrations, microdialysis probes were inserted in both lungs of each pig. Pigs were placed in the right lateral position. Time versus concentration profiles of unbound LVX were measured in the upper and lower lung tissue and plasma in all pigs. In all pigs, maximum concentrations (Cmax) of LVX were significantly lower in the upper lung than in the lower lung (OPCAB, P = 0.035; CPB, P < 0.001). Median Cmax of LVX showed a significant difference in the upper versus lower lung in the CPB group (P < 0.05). No significant difference was found in the median Cmax of LVX in the upper and the lower lung in the OPCAB group (P = 0.32). Our data indicate that CPB affects perioperative regional antibiotic penetration into lung tissue. Common clinical antibiotic dosing schemes should be reevaluated in patients undergoing coronary artery bypass grafting with CPB.
doi:10.1128/AAC.02627-12
PMCID: PMC3697369  PMID: 23587954
19.  Platelet-dependent thrombography gives a distinct pattern of in vitro thrombin generation after surgery with cardio-pulmonary bypass: potential implications 
Thrombosis Journal  2012;10:15.
Background
Bleeding remains a potentially lethal complication of cardio-pulmonary bypass (CPB) surgery. The purpose of this study was to obtain a better insight into in vitro thrombin generation in the context of CPB.
Methods
We used Calibrated Automated Thrombography to assess blood coagulation of 10 low-risk patients operated for valve replacement with CPB, under 2 experimental conditions, one implicating platelets as platelet dysfunction has been described to occur during CPB.
Results
Our main finding was that CPB-induced coagulopathy was differently appreciated depending on the presence or absence of platelets: the decrease in thrombin generation was much less pronounced in their presence (mean endogenous thrombin potential change values before and after CPB were -3.9% in the presence of platelets and -39.6% in their absence).
Conclusion
Our results show that experimental conditions have a profound effect in the study of in vitro thrombin generation in the context of CPB.
doi:10.1186/1477-9560-10-15
PMCID: PMC3522546  PMID: 22909275
Cardio pulmonary bypass; Thrombin; Platelets; Thrombography
20.  A Comparative Study to Determine the Effect of Intravenous Magnesium on Postoperative Bleeding after on Pump CABG in Patients Receiving Pre-Operative Aspirin 
Indian Journal of Anaesthesia  2009;53(2):197-203.
Summary
Hypomagnesaemia is a common complication after cardiopulmonary bypass (CPB) and predisposes to the development of cardiac arrhythmias. Previous studies showed that intravenous magnesium reduces the incidence of postoperative cardiac arrhythmias but it also inhibits platelet function. Our aim was to compare the postoperative blood loss in patients not receiving magnesium after CPB with the group who received magnesium and to compare the requirement of blood, fresh frozen plasma (FFP) and platelets within 24 hours after surgery. This prospective randomized controlled study was conducted in 80 adult patients on oral aspirin undergoing elective CABG requiring CPB. Group A patients had not received magnesium infusion after recovery from CPB. Group B patients received magnesium infusion after recovery from CPB. Postoperative bleeding was assessed in both the groups. All the data were statistically analyzed. There was a insignificant increase in 24 hours postoperative drainage in magnesium recipient group compared to control group (p>0.05). Requirements of blood and blood products to maintain haematocrit and coagulation profile revealed insignificant (p > 0.05). Increase in requirement of PRC, FFP and platelets in magnesium recipient patients than the control group. Incidence of atrial fibrillation (Gr A 2.5%, Gr B 2.5%) and atrial extrasystoles (Gr A 2.5%, Gr B 10%) revealed comparable (p > 0.05) between the groups, but incidence of ventricular arrhythmias were significantly (p<0.05) high in the patients of Gr A(17.5%) than Gr B(5%). To conclude, magnesium may be administered to patients who continue pre-operative aspirin to undergo on-pump CABG surgery.
PMCID: PMC2900106  PMID: 20640123
Aspirin; Magnesium; CPB; CABG; Postoperative bleeding
21.  Does incorporation of thromboelastography improve bleeding prediction following adult cardiac surgery? 
Blood Coagulation & Fibrinolysis  2014;25(6):561-570.
Cardiopulmonary bypass (CPB) coagulopathy increases utilization of allogenic blood/blood products, which can negatively affect patient outcomes. Thromboelastography (TEG) is a point-of-care measurement of clot formation and fibrinolysis. We investigated whether the addition of TEG parameters to a clinically based bleeding model would improve the predictability of postoperative bleeding. A total of 439 patients’ charts were retrospectively investigated for 8-h chest tube output (CTO) postoperatively. For model 1, the variables recorded were patient age, gender, body surface area, clopidogrel use, CPB time, first post-CPB fibrinogen serum level, first post-CPB platelet count, first post-CPB international normalized ratio, the total amount of intraoperative cell saver blood transfused, and postoperative first ICU hematocrit level. Model 2 had the model 1 variables, TEG angle, and maximum amplitude. The outcome was defined as 0–8-h CTO. The predictor variables were placed into a forward stepwise regression model for continuous outcomes. Analysis of variance with adjusted R2 was used to assess the goodness-of-fit of both predictive models. The predictive accuracy of the model was examined using CTO as a dichotomous variable (75th percentile, 480 ml) and receiver operating characteristic curves for both models. Advanced age, male gender, preoperative clopidogrel use for 5 days or less, greater cell saver blood utilization, and lower postoperative hematocrit levels were associated with increased 8-h CTO (P < 0.05). Adding TEG angle and maximum amplitude to model 1 did not improve CTO predictability. When TEG angle and maximum amplitude were added as predictor factors, the predictability of the bleeding model did not improve.
doi:10.1097/MBC.0000000000000095
PMCID: PMC4162333  PMID: 24717423
adult; bleeding; cardiac surgery; cardiopulmonary bypass; coagulation; coronary artery bypass graft; thromboelastography; transfusion
22.  Thrombin generation during cardiopulmonary bypass: the possible role of retransfusion of blood aspirated from the surgical field 
Thrombosis Journal  2003;1:3.
Background
In spite of using heparin-coated extracorporeal circuits, cardiopulmonary bypass (CPB) is still associated with an extensive thrombin generation, which is only partially suppressed by the use of high dosages of heparin. Recent studies have focused on the origins of this thrombotic stimulus and the possible role of retransfused suctioned blood from the thoracic cavities on the activation of the extrinsic coagulation pathway. The present study was designed to find during CPB an association between retransfusion of suctioned blood from the pericardium and pleural space, containing activated factor VIIa and systemic thrombin generation.
Methods
Blood samples taken from 12 consenting patients who had elective cardiac surgery were assayed for plasma factor VIIa, prothrombin fragment 1+2 (F1+2), and thrombin-antithrombin (TAT) concentrations. Blood aspirated from the pericardium and pleural space was collected separately, assayed for F1+2, TAT, and factor VIIa and retransfused to the patient after the aorta occlusion.
Results
After systemic heparinization and during CPB thrombin generation was minimal, as indicated by the lower than base line plasma levels of F1+2, and TAT after correction for hemodilution. In contrast, blood aspirated from the thoracic cavities had significantly higher levels of factor VIIa, F1+2, and TAT compared to the simultaneous samples from the blood circulation (P < 0.05). Furthermore, after retransfusion of the suctioned blood (range, 200–1600 mL) circulating levels of F1+2, and TAT rose significantly from 1.6 to 2.9 nmol/L (P = 0.002) and from 5.1 to 37.5 μg/L (P = 0.01), respectively. The increase in both F1+2, and TAT levels correlated significantly with the amount of retransfused suctioned blood (r = 0.68, P = 0.021 and r = 0.90, P = 0.001, respectively). However, the circulating factor VIIa levels did not correlate with TAT and F1+2 levels.
Conclusions
These data suggest that blood aspirated from the thoracic cavities during CPB is highly thrombogenic. Retransfusion of this blood may, therefore, promote further systemic thrombin generation during CPB.
doi:10.1186/1477-9560-1-3
PMCID: PMC179879  PMID: 12904260
23.  Ceftriaxone disposition in open-heart surgery patients. 
The effects of cardiopulmonary bypass (CPB) with hypothermia and systemic heparinization on ceftriaxone disposition were evaluated in seven male patients. A bolus dose of drug (14 mg/kg of body weight) was given, and blood and urine specimens were collected before, during, and after CPB for 96 h. Creatinine, albumin, and total and free ceftriaxone concentrations in plasma were measured. The ceftriaxone free fraction (ff) in vitro was estimated by equilibrium dialysis, and the in vivo ff was obtained by the ratio of renal clearance due to filtration to creatinine clearance. Pharmacokinetic parameters were based on concentrations of total drug and free drug. Albumin decreased from 3.10 +/- 0.29 g/dl presurgery to 1.42 +/- 0.17 g/dl and recovered to 2.46 +/- 0.26 g/dl on postoperative day 4. CPB markedly increased the in vitro ff, which was reversed by protamine post-CPB (ff pre-CPB, 0.15 +/- 0.01; during CPB, 0.53 +/- 0.20; post-CPB, 0.16 +/- 0.02). The in vitro ff exceeded the in vivo ff (0.53 +/- 0.20 versus 0.24 +/- 0.07), probably due to continued free fatty acid release caused by heparin during dialysis. Clearances based on free drug decreased, and the renal clearance due to filtration increased (7.6 +/- 2.8 versus 15.0 +/- 4.5 ml/min) while the creatinine clearance decreased (114 +/- 29 versus 72 +/- 28 ml/min) during CPB. Diminished binding owing to low albumin and free fatty acids explain this behavior. Lower binding also increased the volume of distribution (154 +/- 41 ml/kg) and extended the half-life (15 +/- 6 h). In summary, ceftriaxone disposition was significantly altered by CPB, resulting in marked increases in free drug concentrations, half-life, and volume of distribution and in decreased intrinsic clearance.
PMCID: PMC284244  PMID: 2764536
24.  Prophylactic administration of recombinant activated factor VII in coronary revascularization surgery 
Saudi Journal of Anaesthesia  2013;7(3):301-304.
Objective:
The objective of this clinical trial is to study the effectiveness of administering recombinant activated factor VII (rFVIIa) in reducing the amount of bleeding and the need for homologous blood and products transfusion in cardiac surgical coronary revascularization procedures done under cardiopulmonary bypass (CPB).
Methods:
In a randomized controlled prospective observational study, 30 patients were scheduled for elective cardiac revascularization under CPB. Patients were randomly allocated into two groups. In Group I (Control group), no rFVIIa was administered following CPB. In Group II (Study group), a dose of 90 ug/Kg of rFVIIa was administered following weaning off CPB. The total amount of chest tube drain during the 1st 24 h following surgery was recorded as well as the qualitative and quantitative assessments of homologous blood and products transfusion. Serial analysis of hematological parameters including hemoglobin level and coagulation test in a definite data points was done. T0=baseline readings prior to CPB, T1=off CPB after protamine administration and before administration of the study drug, T2=on Cardiac Intensive Care Unit (CICU) admission, T3=12 h post-CICU admission, and T4=24 h post-CICU admission.
Results:
Considering the total chest tube drainage, mean values showed statistically significant results with a P value of 0.001. Homologous blood and products transfusion were statistically lower in the study group. Regarding the mean values for hematological assessment, results showed statistically lower International Normalized Ratio values at CICU admission and 12 h post-CICU admission with a P value of 0.018 and 0.004, respectively. Also, the Partial Thromboplastin Time mean values were statistically lower at same timings with estimated P values of 0.04 and 0.001, respectively.
Conclusion:
It is concluded that the prophylactic use of rFVIIa in patients undergoing coronary revascularization surgery under the management of CPB had a remarkable significant results on both the amount of post-operative bleeding and the amount of blood and products transfusion.
doi:10.4103/1658-354X.115364
PMCID: PMC3757804  PMID: 24015134
CABG; coronary revascularization; recombinant activated factor VII
25.  Activated Prothrombin Complex Concentrates for the Reversal of Anticoagulant-Associated Coagulopathy 
Pharmacy and Therapeutics  2013;38(11):696-701.
Managing hemorrhaging after the use of warfarin and other anticoagulants is challenging. Although an FDA-approved product, FEIBA, has been used as an off-label anticoagulant-reversal agent, the potential risks of thrombosis associated with activated prothrombin complex concentrates must be carefully weighed.
Objective:
Prothrombin complex concentrate (PCC) products are emerging as alternative strategies for reversing anticoagulant pharmacotherapy. Factor eight inhibitor bypassing activity (FEIBA, or anti-inhibitor coagulant complex) is an activated PCC (aPCC). Although FEIBA is approved by the FDA to control spontaneous bleeding episodes and to prevent bleeding with surgical interventions in hemophilia A and hemophilia B patients with inhibitors to factor VIII, recent data have suggested that the product may be used off-label as an anticoagulant-reversal agent. To evaluate the safety and efficacy of aPCC products in reversing anticoagulant pharmacotherapy, we searched online databases for English-language publications that discussed this topic.
Data Sources: The EMBASE, MEDLINE, and International Pharmaceutical Abstracts databases were used. We evaluated all articles published in the English language identified from the data sources. We included studies conducted in human subjects and in in vitro and in vivo models in our review.
Results:
Current published evidence suggests that the use of an aPCC, compared with fresh-frozen plasma, is associated with a significantly faster correction of supratherapeutic International Normalized Ratios (INRs) secondary to warfarin therapy. Conflicting evidence exists regarding the ability of aPCCs to reverse the prolonged bleeding times caused by the anticoagulant agents dabigatran etexilate (Pradaxa), rivaroxaban (Xarelto), apixaban (Eliquis), and fondaparinux (Arixtra).
Conclusion:
The theoretical risks of thrombosis associated with PCC products must be carefully considered before they are administered to patients who require coagulation therapy. The use of aPCCs to reverse the anticoagulant effects of warfarin, dabigatran, or rivaroxaban should be limited because of the lack of efficacy and safety data in humans. Moreover, the safety of aPCCs in off-label indications has not been adequately assessed.
PMCID: PMC3875259  PMID: 24391389
FEIBA; activated PCC; hemorrhage; reversal; anticoagulation

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