Charles-Marc Samama

Effects of Postoperative, Nonsteroidal, Antiinflammatory Drugs on Bleeding Risk after Tonsillectomy Meta-analysis of Randomized, Controlled Trials

TONSILLECTOMY is one of the most common surgical procedures performed on children. Postoperative bleeding is rare but can be life threatening. During reoperation for hemostasis, induction of anesthesia is associated with a high risk of pulmonary aspiration and difficult tracheal intubation due to the presence of blood in the upper airway and stomach. The incidence of posttonsillectomy bleeding severe enough to require treatment ranges from 2–10% and that of reoperation for hemostasis ranges from 1–5.5%. Many factors are known to contribute to postoperative bleeding, including abnormal preoperative bleeding identified by questionnaire, unusual surgical indications, high postoperative blood pressure, and Sluder technique. Nonsteroidal antiinflammatory drugs (NSAIDs) are commonly used in children for their potent antipyretic and analgesic effects. NSAID therapy has been reported to provide effective pain control without opioids after tonsillectomy and other pediatric surgical procedures. Tonsillectomy is commonly done on an outpatient basis and is associated with severe postoperative pain. Postoperative pain, nausea, and emesis must be prevented because they cause distress and prolong hospitalization. Vomiting is among the most common reasons for unscheduled readmission after outpatient tonsillectomy. NSAIDs are as effective as morphine for pain relief after surgery but are associated with a lower risk of nausea and vomiting. Thus, they are considered the agents of first choice for controlling postoperative pain after pediatric surgery. Two recent postal surveys conducted in the United Kingdom to evaluate pain treatment at home after tonsillectomy for children found that NSAIDs were used in 45–70% of patients. Nevertheless, the ability of NSAIDs to inhibit platelet cyclooxygenase (COX) may be associated with a risk of increased bleeding after tonsillectomy. NSAIDs are widely used in the pediatric population because most children are free of contraindications to these drugs, such as peptic ulcer disease or renal failure. A review of the pediatric literature on bleeding after perioperative NSAID therapy produced inconclusive results. Preoperative NSAID therapy used in prospective studies increased intraoperative blood loss by 70–80% in children undergoing tonsillectomy, requiring additional hemostatic treatment to stop bleeding. Moreover, a recent systematic review of preemptive analgesia for postoperative pain relief, including NSAIDs, failed to demonstrate the efficacy of preoperative administration of analgesics. Consequently, there is no evidence to support administration of NSAIDs preoperatively. In retrospective studies, postoperative NSAID therapy increased the incidence of bleeding, but this finding was not confirmed in prospective studies. We performed a meta-analysis to evaluate the risk of bleeding after tonsillectomy in patients treated postoperatively with NSAIDs.

Evaluation of Prothrombin Complex Concentrate and Recombinant Activated Factor VII to Reverse Rivaroxaban in a Rabbit Model

Background: As a potent anticoagulant agent, rivaroxaban exposes a risk of bleeding. An effective way to reverse its effects is needed. Objectives were to study efficacy and safety of recombinant activated factor VII (rFVIIa) and prothrombin complex concentrate (PCC) to reverse the anticoagulant effect of an overdose of rivaroxaban in a rabbit model of bleeding and thrombosis. Methods: First, a dose-ranging study assessed the minimal rivaroxaban dose that increased bleeding. Then, 48 anesthetized and ventilated rabbits were randomized into four groups: control (saline), rivaroxaban (rivaroxaban and saline), rFVIIa (rivaroxaban and rFVIIa), and PCC (rivaroxaban and PCC). The Folts model was applied: a stenosis and an injury were carried out on the carotid artery, inducing thrombosis, detected as cyclic flow reductions, which were recorded over 20 min. Then the following were measured: ear immersion bleeding time, clotting times, anti-Xa activity, thrombelastometric parameters, and thrombin generation test. Ultimately, a hepatosplenic section was performed and the total amount of blood loss after 15 min was evaluated as primary endpoint. Results: Rivaroxaban increased blood loss (17 g [8–32] vs. 7 g [5–18] for control (median [range]), P = 0.0004), ear bleeding time, clotting times, thrombelastographic clotting time, and decreased thrombin generation. In contrast, rFVIIa decreased ear bleeding time (92 s [65–115] vs. 140 s [75–190], P < 0.02), but without efficacy on blood loss. PCC and rFVIIa decreased activated partial thromboplastin time as well as thrombelastographic clotting time. Regarding safety, neither rFVIIa nor PCC increased cyclic flow reductions. Conclusion: rFVIIa and PCC partially improved laboratory parameters, but did not reverse rivaroxaban induced-bleeding.

Epidemiology of venous thromboembolism after lower limb arthroplasty: the FOTO study.

Summary.  Background: In view of recent substantial changes in the management of orthopedic surgery patients, a study was performed in order to update data on the epidemiology of venous thromboembolism (VTE) in patients undergoing lower limb arthroplasty according to contemporary practise. Methods: We performed a prospective observational study of a cohort of consecutive patients hospitalized for total hip or knee replacement in June 2003. The primary study outcome was the incidence of symptomatic VTE at 3 months. All events were adjudicated by an independent critical event committee. Results: Data from 1080 patients (mean age 68.0 years) were available; 63.2% were undergoing total hip replacement and 36.8% total knee replacement. Pharmacological thromboprophylaxis was administered for a mean time of 36 days. Injectable antithrombotics were used in more than 99% of patients, irrespective of the type of surgery. The incidence of the primary study outcome was 1.8% (20 events; 95% CI: 1.0–2.6%). The incidences were 1.3% and 2.8% in hip and knee surgery patients, respectively. There were two pulmonary embolisms, both in knee surgery patients; neither was fatal. Thirty‐five per cent of VTEs occurred after hospital discharge. An age of at least 75 years and the absence of ambulation before hospital discharge were the only significant (P < 0.05) predictors of VTE. The rate of clinically significant bleeding was 1.0% and the rate of death was 0.9%. Conclusions: The incidence of symptomatic VTE after lower limb arthroplasty is low, even if there is still a need to improve thromboprophylaxis, notably in patients undergoing knee arthroplasty.

Non-cardiac surgery in patients with coronary stents: the RECO study

Context Interruption or maintenance of oral antiplatelet therapy (OAT) during an invasive procedure may result in ischaemic and/or haemorrhagic complications. There is currently a lack of clear guidance regarding the issue of treatment interruption during surgical procedures. Objective To evaluate the rate of major adverse cardiac and cerebrovascular events (MACCEs) and major or minor bleeding complications and their associated independent correlates in coronary stented patients undergoing urgent or planned non-cardiac surgery. Design, setting, and patients Prospective, multicentre, observational cohort study of 1134 consecutive patients with coronary stents. Main outcome measures The co-primary endpoints consisted of the incidence of MACCE and major bleeding within the first 30 days of an invasive procedure. Results MACCE and haemorrhagic complications were observed in 124 (10.9%) and 108 (9.5%) patients, respectively, within an average time delay from invasive procedure to event of 3.3±3.9 and 5.3±5.3 days. Independent preoperative correlates for MACCE were complete OAT interruption for more than 5 days prior to surgery, preoperative haemoglobin <10 g/dl, creatinine clearance of <30 ml/min and emergency or high-risk surgery. Independent factors for haemorrhagic complications were preoperative haemoglobin <10 g/dl, creatinine clearance between 30 and 60 ml/min, a delay from stent implantation to surgery <3 months and high-risk surgery according to the Lee classification. Conclusions Patients with coronary stents undergoing an invasive procedure are at high risk of perioperative myocardial infarction including stent thrombosis irrespective of the stent type and major bleeding. Interruption of OAT more than 5 days prior to an invasive procedure is a key player for MACCE. Clinical Trial Registration NCT01045850.

Prevention and treatment of coagulopathy in patients receiving massive transfusions

Patients undergoing massive transfusions frequently develop a coagulopathy, which is already present in a considerable percentage of patients upon admission to the emergency room. This derangement of coagulation may aggravate the bleeding tendency and is associated with significant morbidity and mortality. Existing guidelines for optimal transfusion therapy in massively bleeding patients advocate early administration of crystalloid or colloid fluids in conjunction with transfusion of red cells. And, according to the guidelines, fresh frozen plasma (FFP) and platelets should only be administered when a whole blood volume or more has been replaced and then only in patients with excessive or microvascular bleeding and, at best, according to conventional laboratory coagulation analysis. However, this approach may cause dilution coagulopathy and a further impairment of hemostasis due to direct effects of plasma replacement treatment on platelet-vessel wall interaction and thus compromise haemostatic ability further in severely bleeding patients. In recent years, there has been increasing evidence, although mainly coming from non-randomized studies, that early and more intense replacement of coagulation factors and platelets may improve the outcome in patients undergoing massive transfusion. The recommendations in the existing guidelines are based on the results of conventional coagulation assays such as the activated partial thromboplastin time. However, these assays poorly correlate with clinically relevant coagulopathies [1, 2]. Cell-based whole blood viscoelastical assays such as thromboelastography (TEG) provide quantitative information of the haemostatic process and thus give a profile of the haemostatic changes that occur during clotting. Such tests may provide a better guide for blood component therapy for patients with massive bleeding, although also for these tests the clinical relevance has never been adequately validated [3–5]. It seemed of interest to obtain information on these issues by sending the following questions to experts in the field. Question 1: What is your definition of ‘massive blood transfusion’? Question 2: When treating a patient with massive bleeding, do you still follow the official guidelines i.e. restoration of blood volume initially with cristalloids or colloids followed by packed red cells and subsequently the use of FFP, platelets, cryoprecipitate, and other coagulation concentrates depending on the results of coagulation tests and platelet counts? If no: please explain. Question 3: Or do you follow a more aggressive regimen administering FFP and platelets as part of the standard transfusion program? If so, which FFP:RBC ratio do you apply? Please describe your transfusion policy in detail. Question 4: If you use coagulation parameters in your setting, which tests do you apply? Do you think that the conventional tests are satisfactory for this purpose? If not, please explain why. What would be an acceptable turn-around time for any test? Question 5: Have you evidence that a more aggressive regimen with regard to FFP and platelet transfusions improves outcome? Or do you think FFP and platelet transfusion may be harmful? We received 12 contributions to this Forum. Many of the answers are extensive and contain much detailed information. It is impossible to include all this information in an editorial. The reader is therefore strongly advised to read the answers. Although some participants still use the standard definition of massive transfusion, i.e. 10 units of RBC within 24 h, most now use a different definition. Most

Chirurgies et actes invasifs chez les patients traités au long cours par un anticoagulant oral anti-IIa ou anti-Xa direct: Propositions du Groupe d’intérêt en hémostase périopératoire (GIHP) et du Groupe d’études sur l’hémostase et la thrombose (GEHT)

Direct oral anticoagulants (DOAs), inhibitors of factor IIa or Xa, are expected to replace vitamin K antagonists in most of their indications. It is likely that patients on long-term treatment with DOAs will be exposed to elective or emergency surgery or invasive procedures. Due to the present lack of experience in such conditions, we cannot make recommendations, but only propose perioperative management for optimal safety as regards the risk of bleeding and thrombosis. DOAs may increase surgical bleeding, they have no validated antagonists, they cannot be monitored by simple, standardised laboratory assays, and their pharmacokinetics vary significantly from patient to patient. Although DOAs differ in many respects, the proposals in the perioperative setting need not be specific to each. For procedures with low risk of haemorrhage, a therapeutic window of 48 h (last administration 24h before surgery, restart 24h after) is proposed. For procedures with medium or high haemorrhagic risk, we suggest stopping DOAs 5 days before surgery to ensure complete elimination of the drug in all patients. The treatment should be resumed only when the risk of bleeding has been controlled. In patients with a high risk of thrombosis (e.g. those in atrial fibrillation with an antecedent of stroke), bridging with heparin (low molecular weight, or unfractionated if the former is contraindicated) is proposed. In emergency, the procedure should be postponed for as long as possible (minimum 1-2 half-lives) and non-specific anti-haemorrhagic agents, such as recombinant human activated factor VIIa, or prothrombin concentrates, should not be given for prophylactic reversal, due to their uncertain benefit-risk.

The effectiveness of platelet supplementation for the reversal of ticagrelor-induced inhibition of platelet aggregation: An in-vitro study.

BACKGROUND Management of ticagrelor-induced bleeding is challenging, as no antidote is currently available. Platelet transfusion, usually proposed to reverse antiplatelet drugs, has been suggested to be ineffective but few data are available. OBJECTIVE To assess the efficacy of platelet supplementation to restore platelet aggregation inhibited by ticagrelor. DESIGN In vitro study. SETTING Blood samples were obtained from the French Blood Bank Institute. PARTICIPANTS Healthy blood donors. INTERVENTIONS Whole blood from healthy donors was spiked with ticagrelor or aspirin (used as a positive control). MAIN OUTCOME MEASURES Platelet aggregation was investigated with impedance aggregometry on whole blood [expressed in ohms (V)] and light transmission aggregometry (expressed in %) on platelet-rich plasma using ADP or arachidonic acid as agonists for ticagrelor or aspirin, respectively. Platelet supplementation was defined as the addition of washed platelet suspension increasing at least 60% of whole blood platelet count. RESULTS Ticagrelor (3.25 mM) inhibited ADP-induced platelet aggregation compared with control either in whole blood (2 vs. 13 V, P < 0.05) or in platelet-rich plasma (15 vs. 75% P < 0.05). Aspirin (25 mM) inhibited arachidonic acid-induced aggregation (1 vs. 7.5 V, P < 0.05 in whole blood and 5 vs. 77.5%, P = 0.01 in platelet-rich plasma). Platelet supplementation completely restored arachidonic acid-induced platelet aggregation in whole blood (10 vs. 1 V, P = 0.008) and platelet-rich plasma (73 vs. 5%, P < 0.01) in aspirin-treated samples, whereas it failed to correct ADP-induced aggregation (2 vs. 2 V in whole blood and 13.5 vs. 15% in platelet-rich plasma, P > 0.05) in ticagrelor-treated samples. We also report a case of a ticagrelor-treated patient in whom platelet transfusion failed to restore ADP-induced platelet aggregation. CONCLUSION Platelet supplementation restored platelet aggregation in aspirin-spiked but not in ticagrelor-spiked samples. These results do not support the use of platelet transfusion to reverse the effects of ticagrelor.

Pre-interventional haemostatic assessment: Guidelines from the French Society of Anaesthesia and Intensive Care

Recently the French Society of Anaesthesia and Intensive Care (Société Française d’Anesthésie et de Réanimation [SFAR]) issued recommendations for the prescription of routine preoperative testing before a surgical or non-surgical procedure, requiring any type of anaesthesia. Thirty clinical specialists performed a systematic analysis of the literature, and recommendations were then developed using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system. One part of these guidelines is dedicated to haemostatic assessment. The goal of pre-anaesthetic screening for congenital or acquired haemostatic disorders is to prevent perioperative haemorrhagic complications through appropriate medical and surgical management. Preoperative assessment of bleeding risk requires a detailed patient interview to determine any personal or family history of haemorrhagic diathesis, and a physical examination is necessary in order to detect signs of coagulopathy. Laboratory investigation of haemostasis should be prescribed, not systematically, but depending on clinical evaluation and patient history. Standard tests (prothrombin time, activated partial thromboplastin time, platelet count) have a low positive predictive value for bleeding risk in the general population. Patients with no history of haemorrhagic diathesis and no conditions liable to interfere with haemostasis should not undergo pre-interventional haemostasis testing. Conversely, the existence of a positive history or a disease that could interfere with haemostasis should be an indication for clinically appropriate testing.

Treatment of massive bleeding with prothrombin complex concentrate: argument against

See also Tanaka KA, Szlam F. Treatment of massive bleeding with prothrombin complex concentrate: argument for. This issue, pp 2589–91.

Reversal of Vitamin K Antagonist (VKA) effect in patients with severe bleeding: a French multicenter observational study (Optiplex) assessing the use of Prothrombin Complex Concentrate (PCC) in current clinical practice

IntroductionProthrombin Complex Concentrate (PCC) is a key treatment in the management of bleeding related to Vitamin K antagonists (VKA). This study aimed to evaluate prospectively PCC use in patients with VKA-related bleeding in view of the French guidelines published in 2008.MethodsAll consecutive patients with VKA-related bleeding treated with a 4-factor PCC (Octaplex®) were selected in 33 French hospitals. Collected data included demographics, site and severity of bleeding, modalities of PCC administration, International Normalized Ratio (INR) values before and after PCC administration, outcomes and survival rate 15 days after infusion.ResultsOf 825 patients who received PCC between August 2008 and December 2010, 646 had severe bleeding. The main haemorrhage sites were intracranial (43.7%) and abdominal (24.3%). Mean INR before PCC was 4.4 ± 1.9; INR was unavailable in 12.5% of patients. The proportions of patients who received a PCC dose according to guidelines were 15.8% in patients with initial INR 2-2.5, 41.5% in patients with INR 2.5-3, 40.8% in patients with INR 3-3.5, 26.9% in patients with INR > 3.5, and 63.5% of patients with unknown INR. Vitamin K was administered in 84.7% of patients. The infused dose of PCC did not vary with initial INR; the mean dose was 25.3 ± 9.8 IU/Kg. Rates of controlled bleeding and target INR achievement were similar, regardless of whether or not patients were receiving PCC doses as per the guidelines. No differences in INR after PCC treatment were observed, regardless of whether or not vitamin K was administered. INR was first monitored after a mean time frame of 4.5 ± 5.6 hours post PCC. The overall survival rate at 15 days after PCC infusion was 75.4% (65.1% in patients with intracranial haemorrhage). A better prognosis was observed in patients reaching the target INR.ConclusionsSevere bleeding related to VKA needs to be better managed, particularly regarding the PCC infused dose, INR monitoring and administration of vitamin K. A dose of 25 IU/kg PCC appears to be efficacious in achieving a target INR of 1.5. Further studies are required to assess whether adjusting PCC dose and/or better management of INR would improve outcomes.