Drugs to reduce bleeding and transfusion in major open vascular or endovascular surgery: a systematic review and network meta-analysis
The Cochrane database of systematic reviews. 2023;2(2):Cd013649
BACKGROUND Vascular surgery may be followed by internal bleeding due to inadequate surgical haemostasis, abnormal clotting, or surgical complications. Bleeding ranges from minor, with no transfusion requirement, to massive, requiring multiple blood product transfusions. There are a number of drugs, given systemically or applied locally, which may reduce the need for blood transfusion. OBJECTIVES To assess the effectiveness and safety of anti-fibrinolytic and haemostatic drugs and agents in reducing bleeding and the need for blood transfusion in people undergoing major vascular surgery or vascular procedures with a risk of moderate or severe (> 500 mL) blood loss. SEARCH METHODS We searched: Cochrane Central Register of Controlled Trials; MEDLINE; Embase; CINAHL, and Transfusion Evidence Library. We also searched the WHO ICTRP and ClinicalTrials.gov trial registries for ongoing and unpublished trials. Searches used a combination of MeSH and free text terms from database inception to 31 March 2022, without restriction on language or publication status. SELECTION CRITERIA We included randomised controlled trials (RCTs) in adults of drug treatments to reduce bleeding due to major vascular surgery or vascular procedures with a risk of moderate or severe blood loss, which used placebo, usual care or another drug regimen as control. DATA COLLECTION AND ANALYSIS We used standard Cochrane methods. Our primary outcomes were units of red cells transfused and all-cause mortality. Our secondary outcomes included risk of receiving an allogeneic blood product, risk of reoperation or repeat procedure due to bleeding, risk of a thromboembolic event, risk of a serious adverse event and length of hospital stay. We used GRADE to assess certainty of evidence. MAIN RESULTS We included 22 RCTs with 3393 participants analysed, of which one RCT with 69 participants was reported only in abstract form, with no usable data. Seven RCTs evaluated systemic drug treatments (three aprotinin, two desmopressin, two tranexamic acid) and 15 RCTs evaluated topical drug treatments (drug-containing bioabsorbable dressings or glues), including fibrin, thrombin, collagen, gelatin, synthetic sealants and one investigational new agent. Most trials were conducted in high-income countries and the majority of the trials only included participants undergoing elective surgery. We also identified two ongoing RCTs. We were unable to perform the planned network meta-analysis due to the sparse reporting of outcomes relevant to this review. Systemic drug treatments We identified seven trials of three systemic drugs: aprotinin, desmopressin and tranexamic acid, all with placebo controls. The trials of aprotinin and desmopressin were small with very low-certainty evidence for all of our outcomes. Tranexamic acid versus placebo was the systemic drug comparison with the largest number of participants (2 trials; 1460 participants), both at low risk of bias. The largest of these included a total of 9535 individuals undergoing a number of different higher risk surgeries and reported limited information on the vascular subgroup (1399 participants). Neither trial reported the number of units of red cells transfused per participant up to 30 days. Three outcomes were associated with very low-certainty evidence due to the very wide confidence intervals (CIs) resulting from small study sizes and low number of events. These were: all-cause mortality up to 30 days; number of participants requiring an allogeneic blood transfusion up to 30 days; and risk of requiring a repeat procedure or operation due to bleeding. Tranexamic acid may have no effect on the risk of thromboembolic events up to 30 days (risk ratio (RR) 1.10, 95% CI 0.88 to 1.36; 1 trial, 1360 participants; low-certainty evidence due to imprecision). There is one large ongoing trial (8320 participants) comparing tranexamic acid versus placebo in people undergoing non-cardiac surgery who are at high risk of requiring a red cell transfusion. This aims to complete recruitment in April 2023. This trial has primary outcomes of proportion of participants transfused with red blood cells and incidence of venous thromboembolism (DVT or PE). Topical drug treatments Most trials of topical drug treatments were at high risk of bias due to their open-label design (compared with usual care, or liquids were compared with sponges). All of the trials were small, most were very small, and few reported clinically relevant outcomes in the postoperative period. Fibrin sealant versus usual care was the topical drug comparison with the largest number of participants (5 trials, 784 participants). The five trials that compared fibrin sealant with usual care were all at high risk of bias, due to the open-label trial design with no measures put in place to minimise reporting bias. All of the trials were funded by pharmaceutical companies. None of the five trials reported the number of red cells transfused per participant up to 30 days or the number of participants requiring an allogeneic blood transfusion up to 30 days. The other three outcomes were associated with very low-certainty evidence with wide confidence intervals due to small sample sizes and the low number of events, these were: all-cause mortality up to 30 days; risk of requiring a repeat procedure due to bleeding; and risk of thromboembolic disease up to 30 days. We identified one large trial (500 participants) comparing fibrin sealant versus usual care in participants undergoing abdominal aortic aneurysm repair, which has not yet started recruitment. This trial lists death due to arterial disease and reintervention rates as primary outcomes. AUTHORS' CONCLUSIONS Because of a lack of data, we are uncertain whether any systemic or topical treatments used to reduce bleeding due to major vascular surgery have an effect on: all-cause mortality up to 30 days; risk of requiring a repeat procedure or operation due to bleeding; number of red cells transfused per participant up to 30 days or the number of participants requiring an allogeneic blood transfusion up to 30 days. There may be no effect of tranexamic acid on the risk of thromboembolic events up to 30 days, this is important as there has been concern that this risk may be increased. Trials with sample size targets of thousands of participants and clinically relevant outcomes are needed, and we look forward to seeing the results of the ongoing trials in the future.
Adults undergoing major vascular surgery or vascular procedures with a risk of moderate or severe blood loss (22 randomised controlled trials, n= 3,393).
Drug treatments to reduce bleeding: anti-fibrinolytic and haemostatic drugs and agents.
Placebo, usual care or another drug regimen.
The primary outcomes were units of red blood cells transfused, all-cause mortality and thromboembolic events. There was too little data for a network meta-analysis. The reporting of outcomes was sparse. There was no evidence of increased risk of thromboembolic events with tranexamic acid [low certainty evidence]. The authors reported a need for larger trials with better reporting of post-surgical outcomes.
Low-Dose vasopressin and renal perfusion in pediatric cardiac surgery
Annals of cardiac anaesthesia. 2023;26(3):309-317
BACKGROUND Congenital heart surgeries are associated with post-bypass renal and cardiac dysfunctions. The use of low-dose vasopressin has been found to be beneficial in adult cardiac surgeries. OBJECTIVE To assess the hemodynamic and renal effects of patients undergoing on-pump pediatric cardiac surgery under general anesthesia (GA) with low-dose vasopressin infusion. DESIGN Prospective randomized controlled study. SETTING Operation room and ICU, tertiary care teaching hospital. PATIENTS Fifty-five pediatric cardiac patients undergoing repair for congenital heart diseases (CHD). INTERVENTIONS Low-dose vasopressin infusion in the study group and placebo in the control group. MEASUREMENTS AND MAIN RESULTS Renal near-infrared spectroscopy (NIRS), serum NGAL, and inflammatory mediators-IL6 and IL8 along with other renal and hemodynamic parameters in the perioperative period were recorded. Diastolic blood pressure (DBP) and cardiac index were significantly higher in the vasopressin group. Inflammatory markers were significantly high in the immediate postoperative period in all patients which later stabilized in the next 48 h but showed similar trends in both groups. Low-dose vasopressin infusion did not improve either renal perfusion or function. The duration of mechanical ventilation and length of hospital stay, the incidence of AKI development, and transfusion requirements were marginally lower in the vasopressin group, although not significant. CONCLUSION Low-dose vasopressin infusion improved hemodynamics and showed a decreased incidence of complications. However, it failed to show any benefit of renal function and overall outcome in pediatric cardiac surgery.
The effect of perioperative antithrombin supplementation on blood conservation and postoperative complications after cardiopulmonary bypass surgery: A systematic review, meta-analysis and trial sequential analysis
STUDY OBJECTIVE Antithrombin (AT) activity is reduced during cardiopulmonary bypass (CPB) surgery. Guidelines has demonstrated that perioperative AT supplementation contributed to blood conservation and prevent perioperative thrombotic complications and target organ injury owing to its role in reducing thrombin generation. But these recommends is lack of support of meta-analysis in the guidelines. This meta-analysis aims to include all the relevant randomized controlled trails (RCT) on patients who experienced cardiac surgeries with CPB and investigate the effect of perioperative AT on blood conservation and complications after cardiac surgery. METHODS Standard published RCTs were searched from bibliographic databases to identify all evidence reporting perioperative AT supplementation for patients undergoing cardiovascular surgeries. The primary outcome was postoperative blood loss, the secondary outcomes were blood component transfusion (red blood cell (RBC), fresh frozen plasma (FFP), platelet and autologous blood), postoperative morbidity and in hospital mortality. The relative risk (RR) for dichotomous outcomes and the standardized mean difference (SMD) for continuous outcomes were estimated using a random-effects model. Trial sequential analysis (TSA) was performed using TSA software 0.9.5.10. RESULTS 13 RCTs with 996 participants undergoing different cardiovascular surgeries were included. Meta-analysis showed AT did not decrease postoperative blood loss (SMD -0.01, 95%CI -0.2 to 0.19). Subgroup analysis showed the effect of AT on postoperative blood loss was not associated with age, RCT type, surgery type, injection time of AT and AT deficiency. TSA further suggested that no additional studies were required for the stable result. Perioperative AT also did not reduce RBC ((SMD 0.10, 95%CI -0.66 to 0.85), (RR 0.99, 95%CI 0.83 to 1.19)), FFP ((SMD 0.11, 95%CI -0.19 to 0.41), (RR 1.30, 95%CI 0.90 to 1.87)), platelet (RR 1.10, 95%CI 0.83 to 1.46) and autologous blood (SMD 0.46, 95%CI -0.12 to 1.8504) transfusions. Perioperative AT significantly increased in hospital mortality (RR 2.53, 95%CI 1.02 to 6.28) and acute kidney injury (AKI) (RR 3.72, 95%CI 1.73 to 8.04) incidence. There was no significant difference in postoperative reexploration, thromboembolism, ECMO/IABP support, and stroke incidence between AT and non-AT group. CONCLUSIONS With the improvement of AT level and heparin sensitivity, perioperative AT has no significant effect on blood conservation. And it is noteworthy that the treatment increased in hospital mortality and the incidence of AKI after cardiac surgery.
A Meta-Analysis of Using Protamine for Reducing the Risk of Hemorrhage During Carotid Recanalization: Direct Comparisons of Post-operative Complications
Frontiers in pharmacology. 2022;13:796329
Background: Protamine can decrease the risk of hemorrhage during carotid recanalization. However, it may cause severe side effects. There is no consensus on the safety and efficacy of protamine during surgery. Thus, we conduct a comprehensive review and meta-analysis to compare the differences between the protamine and the no-protamine group. Method: We systematically obtained literature from Medline, Google Scholar, Cochrane Library, and PubMed electronic databases. All four databases were scanned from 1937 when protamine was first adopted as a heparin antagonist until February 2021. The reference lists of identified studies were manually checked to determine other eligible studies that qualify. The articles were included in this meta-analysis as long as they met the criteria of PICOS; conference or commentary articles, letters, case report or series, and animal observation were excluded from this study. The Newcastle-Ottawa Quality Assessment Scale and Cochrane Collaboration's tool are used to assess the risk of bias of each included observational study and RCT, respectively. Stata version 12.0 statistical software (StataCorp LP, College Station, Texas) was adopted as statistical software. When I (2) < 50%, we consider that the data have no obvious heterogeneity, and we conduct a meta-analysis using the fixed-effect model. Otherwise, the random-effect model was performed. Result: A total of 11 studies, consisting of 94,618 participants, are included in this study. Our analysis found that the rate of wound hematoma had a significant difference among protamine and no-protamine patients (OR = 0.268, 95% CI = 0.093 to 0.774, p = 0.015). Furthermore, the incidence of hematoma requiring re-operation (0.7%) was significantly lower than that of patients without protamine (1.8%). However, there was no significant difference in the incidence of stroke, wound hematoma with hypertension, transient ischemic attacks (TIA), myocardial infarction (MI), and death. Conclusion: Among included participants undergoing recanalization, the use of protamine is effective in reducing hematoma without increasing the risk of having other complications. Besides, more evidence-based performance is needed to supplement this opinion due to inherent limitations.
Is a fixed low-dose protamine better at reducing postoperative bleeding in off pump coronary artery bypass grafting?
Asian cardiovascular & thoracic annals. 2021;:218492321997393
CONTEXT Protamine is used ubiquitously in all cardiac surgeries for reversal of heparin. Risk of postoperative bleeding is increased with inadequate heparin reversal or due to anticoagulant side effects of protamine; hence, it is important to dose protamine properly. This study compares 80% protamine dose with full dose on postoperative bleeding and transfusion needs in OPCAB. AIMS The aim of our study was to find whether lower dose of protamine could reduce postoperative bleeding and need for blood product transfusions in off pump coronary artery bypass grafting as compared to the regular dose of protamine. SETTINGS AND DESIGN This was a double-blinded randomised controlled trial where patients posted for off pump CABG meeting the inclusion criteria were included in the study. METHODS AND MATERIAL Ninety patients were randomised to two groups, group F receiving full dose of protamine of 1 mg per mg heparin used, and group L received 0.8 mg per mg. Postoperative activated clotting time, bleeding at 1 h, 4 h, 24 h and total drainage till drains removal and blood product transfusion requirements were noted.Statistical analysis used: SPSS software. RESULTS Both groups were matched in demographics, preoperative cessation of heparin and aspirin and platelet counts. Both groups received equal heparin dose, activated clotting time before protamine, activated clotting time post protamine in OT and ICU were equal as were the conduits used. There was no significant difference between the groups in post-operative drainage over time or in the need for blood product transfusions. CONCLUSIONS Eighty per cent of the dose of protamine can adequately reverse the heparin used during off pump cardiac surgery without any increase in incidence of postoperative bleeding or need for blood product transfusions.
Optimal protamine dosing after cardiopulmonary bypass: The PRODOSE adaptive randomised controlled trial
PLoS medicine. 2021;18(6):e1003658
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 Effect of Diclofenac on Bleeding, Platelet Function, and Consumption of Opioids Following Cardiac Surgery
Braz J Cardiovasc Surg. 2020;35(2):160-168
OBJECTIVE To establish whether the use of diclofenac reduces the administration of opioids and how it affects bleeding and platelet function after the coronary artery bypass grafting (CABG) surgery with use of cardiopulmonary bypass (CPB). METHODS A total of 72 patients undergoing CABG surgery were included in this retrospective randomized study and divided into two groups (34 patients received diclofenac and the control group of 38 patients did not). For postoperative analgesia, both groups were prescribed opioids (piritramide). The primary endpoint was to establish the consumption of opioids. The secondary endpoint was to determine bleeding and the function of platelets 20 hours after the surgery. RESULTS The consumption of piritramide (diclofenac group 26+/-8 mg vs. control group 28+/-8 mg), the blood loss, and the function of platelets did not significantly differ between the groups within 20 hours after surgery. C-reactive protein (CRP) was statistically significantly lower in the diclofenac group than in the control group (33+/-15 mg/L vs. 46+/-22 mg/L, respectively, P<0.05). CONCLUSION The study concluded that patients administered with diclofenac after the heart surgery did not consume less opioid analgesics and did not exhibit less symptoms linked to the consumption of opioids. Diclofenac in clinically administered doses does not interfere with the function of platelets and does not cause increased bleeding. Lower CRP in the diclofenac group may indicate a reduced inflammatory response after CPB. Therefore, diclofenac could be safe for use in patients undergoing CABG surgery but its value in reducing opioid consumption should be questioned.
Effect of ulinastatin on post-operative blood loss and allogeneic transfusion in patients receiving cardiac surgery with cardiopulmonary bypass: a prospective randomized controlled study with 10-year follow-up
J Cardiothorac Surg. 2020;15(1):98
BACKGROUND Major bleeding and allogeneic transfusion leads to negative outcomes in patients receiving cardiac surgery with cardiopulmonary bypass (CPB). Ulinastatin, a urine trypsin inhibitor, relieves systemic inflammation and improves coagulation profiles with however sparse evidence of its effects on blood loss and allogeneic transfusion in this specific population. METHODS In this prospective randomized controlled trial, 426 consecutive patients receiving open heart surgery with CPB were randomly assigned into three groups to receive ulinastatin (group U, n = 142), tranexamic acid (group T, n = 143) or normal saline (group C, n = 141). The primary outcome was the total volume of post-operative bleeding and the secondary outcome included the volume and exposure of allogeneic transfusion, the incidence of stroke, post-operative myocardial infarction, renal failure, respiratory failure and all-cause mortality. A ten-year follow-up was carried on to evaluate long-term safety. RESULTS Compared with placebo, ulinastatin significantly reduced the volume of post-operative blood loss within 24 h (688.39 +/- 393.55 ml vs 854.33 +/- 434.03 ml MD - 165.95 ml, 95%CI - 262.88 ml to - 69.01 ml, p < 0.001) and the volume of allogeneic erythrocyte transfusion (2.57 +/- 3.15 unit vs 3.73 +/- 4.21 unit, MD-1.16 unit, 95%CI - 2.06 units to - 0.26 units, p = 0.002). The bleeding and transfusion outcomes were comparable between the ulinastatin group and the tranexamic acid group. In-hospital outcomes and 10-year follow-up showed no statistical difference in mortality and major morbidity among groups. CONCLUSIONS Ulinastatin reduced post-operative blood loss and allogeneic erythrocyte transfusion in heart surgery with CPB. The mortality and major morbidity was comparable among the groups shown by the 10-year follow-up. TRIAL REGISTRATION The trial was retrospectively registered on February 2, 2010. TRIAL REGISTRATION NUMBER https://www.clinicaltrials.gov Identifier: NCT01060189.
Intraventricular fibrinolytic for the treatment of intraventricular hemorrhage: a network meta-analysis
Brain Inj. 2020;:1-7
OBJECTIVE To explore which intraventricular fibrinolytic agent - urokinase (UK) or recombinant tissue plasminogen activator (rt-PA) - combined with extraventricular drainage (EVD) is most suitable for patients with spontaneous intraventricular hemorrhage (IVH). PATIENTS AND METHODS We searched PubMed, MEDLINE, OVID, Embase, and Cochrane Library databases for relevant articles and assessed their quality and extracted statistical analyses using Stata 13.0 and Revman 5.3 software. RESULTS Compared with EVD alone, EVD combined with an agent causing intraventricular fibrinolysis (IVF) improved the survival and prognosis of patients with IVH. Regarding the patients' survival rates and prognoses, the treatments, from best to worst results were EVD + UK, EVD + rt-PA, EVD alone. The proportion of patients with serious disability also increased with these treatments, however, with the highest to lowest proportions being EVD + rt-PA, EVD + UK, EVD alone. In addition, EVD + IVF was associated with a higher risk of intracranial rebleeding (from lowest to highest incidence: EVD alone, EVD + rt-PA, EVD + UK). Finally, EVD + UK is associated with an increased risk of potential intracranial infection (from lowest to highest incidence: EVD + rt-PA, EVD alone, EVD + UK). CONCLUSIONS EVD + UK may be the best approach to improving patients' survival rate and prognosis. However, it also presents the highest risk of intracranial infection and rebleeding. EVD + IVF increased the proportion of patients with serious disability.
Zero-balance ultrafiltration of the priming blood modifies the priming components and improves the clinical outcome in infants undergoing cardiopulmonary bypass: A randomized controlled trial
Artificial Organs. 2020;44(3):288-295
Cardiopulmonary bypass (CPB) requirement in infants presents a unique challenge because of the large prime volume-to-blood volume ratio. Packed red blood cells (PRBCs) tend to deteriorate with long-term storage owing to their unphysiological composition and osmolality. Given that blood priming is inevitable in neonates, it is suggested that the metabolic load and osmolality are diminished before CPB initiation. We conducted the present study to test the hypothesis that the zero-balance ultrafiltration (Z-BUF) of the priming blood with 0.45% saline might be sufficient for modifying the metabolic load and osmolality and, thus, achieving a physiological state. Sixty infants with a weight below 10 kg undergoing CPB were randomly assigned either to a control group or to a Z-BUF group and the Z-BUF of the priming blood was performed in the latter group. Electrolytes and osmolality were measured in the priming blood. The bleeding volume, the blood transfusion rate, the length of mechanical ventilation, the length of stay in the intensive care unit (ICU), the body temperature, and renal biomarkers were compared between the 2 groups. The osmolality and the levels of potassium, sodium, glucose, chloride, and lactate in the priming blood were significantly decreased after Z-BUF (P < .01). The Z-BUF group showed significant reductions in postoperative blood loss; postoperative blood transfusion; time to extubation; the length of stay in the ICU; the levels of lactate, sodium, and blood urea nitrogen at 24 hours postoperatively and the body temperature at 18 hours postoperatively (P < .05). However, no statistically significant differences were found between the 2 groups regarding the body temperature and the levels of serum creatinine and blood urea nitrogen after admission to the ICU. The results of the present study demonstrated that the Z-BUF of the priming blood could be a useful strategy in infants undergoing CPB insofar as it significantly modified the composition of the priming blood and improved the clinical outcome among our patients.