Minimum protamine dose required to neutralize heparin in cardiac surgery: a single-centre, prospective, observational cohort study.

PURPOSE: Excess protamine contributes to coagulopathy following cardiopulmonary bypass (CPB) and may increase blood loss and transfusion requirements. The primary aim of this study was to find the least amount of protamine necessary to neutralize residual heparin following CPB using the gold standard assays of anti-IIa and anti-Xa activity. Secondary objectives were to evaluate whether the post-CPB activated clotting time could be used as a surrogate marker for quantifying heparin neutralization. METHODS: Twenty-eight consecutive patients undergoing elective cardiac surgery were enrolled. Protamine administration was standardized through an infusion pump at 25 mg·min-1. Blood samples were withdrawn prior to and following administration of 150, 200, 250, and 300 mg protamine and analyzed for activated clotting time and anti-IIa and -Xa activity. RESULTS: Following a mean (standard deviation) cumulative heparin dose of 67,700 (19,400) units and a CPB duration of 113 (71) min, protamine requirements varied widely. Eight out of 25 (32%) patients showed complete neutralization of anti-IIa and -Xa activity at the first sampling point (150 mg protamine; protamine:heparin ratio, 0.3 [0.1]). A protamine:heparin ratio of 0.5 (0.2) was sufficient for heparin neutralization in > 90% of patients. After CPB, a low to mid-range activated clotting time correlated well with anti-IIa and -Xa activity. CONCLUSIONS: The protamine:heparin ratio required to neutralize residual unfractionated heparin (UFH) following CPB is variable. A protamine:heparin ratio of 0.3 was sufficient to neutralize UFH in some patients, while a ratio of 0.5 is sufficient to neutralize both residual anti-IIa and -Xa activity in most patients. Larger studies are necessary to confirm these findings and evaluate their clinical implications. STUDY REGISTRATION: ClinicalTrials.gov (NCT03787641); registered 26 December 2018.

RéSUMé: OBJECTIF: L'excès de protamine contribue à la coagulopathie après la circulation extracorporelle (CEC) et peut augmenter les pertes de sang et les besoins transfusionnels. L'objectif principal de cette étude était de déterminer la quantité minimale de protamine nécessaire pour neutraliser l'héparine résiduelle post-CEC en utilisant les tests de référence de l'activité anti-IIa et anti-Xa. Les objectifs secondaires consistaient à évaluer si le temps de coagulation activé post-CEC pouvait être utilisé comme marqueur de substitution pour quantifier la neutralisation de l'héparine. MéTHODE: Vingt-huit patients consécutifs bénéficiant d'une chirurgie cardiaque non urgente ont été recrutés. L'administration de protamine par une pompe à perfusion à 25 mg·min-1 a été normalisée. Des échantillons de sang ont été prélevés avant et après l'administration de 150, 200, 250 et 300 mg de protamine et analysés pour déterminer le temps de coagulation activé et l'activité anti-IIa et -Xa. RéSULTATS: Après une dose cumulative moyenne (écart type) d'héparine de 67 700 (19 400) unités et une durée de CEC moyenne de 113 (71) min, les besoins en protamine variaient considérablement. Huit patients sur 25 (32 %) ont affiché une neutralisation complète de l'activité anti-IIa et -Xa au premier point de prélèvement (150 mg de protamine; rapport protamine : héparine, 0,3 [0,1]). Un rapport protamine/héparine de 0,5 (0,2) était suffisant pour la neutralisation de l'héparine chez > 90 % des patients. Après la CEC, un temps de coagulation activé bas à moyen était bien corrélé avec l'activité anti-IIa et -Xa. CONCLUSION: Le rapport protamine : héparine nécessaire pour neutraliser l'héparine non fractionnée (HNF) résiduelle suivant une CEC est variable. Un rapport protamine : héparine de 0,3 était suffisant pour neutraliser l'HNF chez certains patients, tandis qu'un rapport de 0,5 est suffisant pour neutraliser à la fois l'activité résiduelle des anti-IIa et celle des anti-Xa chez la plupart des patients. Des études plus vastes sont nécessaires pour confirmer ces résultats et évaluer leurs implications cliniques. ENREGISTREMENT DE L'éTUDE: ClinicalTrials.gov (NCT03787641); enregistrée le 26 décembre 2018.

Dexamethasone as an Adjuvant for Caudal Blockade in Pediatric Surgical Patients: A Systematic Review and Meta-analysis.

BACKGROUND: Caudal block is commonly used to provide postoperative analgesia after pediatric surgery in the lower abdomen. Typically administered as a single-shot technique, 1 limitation of this block is the short duration of analgesia. To overcome this, dexamethasone has been used as an adjuvant to prolong block duration. However, there are concerns about steroid-related morbidity and the optimal route of dexamethasone administration (eg, caudal or intravenous) is unknown. METHODS: We conducted a systematic review and random-effects meta-analysis of randomized controlled trials recruiting pediatric surgical patients receiving a caudal block for surgical anesthesia or postoperative analgesia. Included studies compared dexamethasone (caudal, intravenous, or both) to control. Duration of analgesia was the primary outcome. Database sources were Medline, Embase, the Cochrane Library, and Google Scholar searched up to August 18, 2017, without language restriction. Screening of studies, data extraction, and risk of bias assessment were performed independently and in duplicate by 2 authors. Risk of bias was assessed using Cochrane methodology and the strength of evidence was scored using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. RESULTS: The initial search retrieved 93 articles. Fourteen randomized controlled trials that comprised 1315 pediatric patients met the inclusion criteria. All but 1 study involved lower abdominal operations (orchidopexy, inguinal hernia repair, and hypospadias repair). The caudal and intravenous dose of dexamethasone ranged from 0.1 to 0.2 mg/kg and 0.5 to 1.5 mg/kg, respectively, and all studies were pooled in the main analysis. Dexamethasone prolonged the duration of analgesia by both the caudal route (5.43 hours, 95% confidence interval [CI], 3.52-7.35; P < .001; I = 99.3%; N = 9; n = 620; GRADE quality = moderate) and intravenous route (5.51 hours; 95% CI, 3.56-7.46; P < .001; I = 98.9%; N = 5; n = 364; GRADE quality = moderate) versus control. Secondary benefits of dexamethasone included reduced narcotic rescue analgesia requirement in the postanesthetic care unit (relative risk [RR], 0.30; 95% CI, 0.18-0.51; P < .001; I = 0.0%; N = 5; number needed to treat for benefit [NNTB] = 5; 95% CI, 4-7), less subsequent postoperative rescue analgesia requirement (RR, 0.46; 95% CI, 0.23-0.92; P = .03; I = 96.0%; N = 9; n = 629; NNTB = 3; 95% CI, 2-20; n = 310), and lower rates of postoperative nausea and vomiting (RR, 0.47; 95% CI, 0.30-0.73; P = .001; I = 0.0%; NNTB = 11; 95% CI, 8-21; N = 9; n = 628). Adverse events linked to the dexamethasone were rare. CONCLUSIONS: Caudal and intravenous dexamethasone are similarly effective for prolonging the duration of analgesia from caudal blockade, resulting in a doubled to tripled duration. Given the off-label status of caudal dexamethasone, intravenous administration is recommended-although only high intravenous doses (0.5 mg/kg up to 10 mg) have been studied.