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Introduction: Patients with cirrhosis undergoing liver transplantation frequently exhibit systemic inflammation, coagulation derangements, and edema, indicating endothelial dysfunction. This syndrome may worsen after ischemia-reperfusion injury of the liver graft, coincident with organ dysfunction that worsens patient outcomes. Little is known about changes in endothelial permeability during liver transplantation. We hypothesized that sera from these patients would increase permeability in cultured human endothelial cells ex vivo. Methods: Adults with cirrhosis presenting for liver transplantation provided consent for blood collection during surgery. Sera were prepared at five time points spanning the entire operation. The barrier function of human pulmonary microvascular endothelial cells in culture was assessed by transendothelial resistance measured using the ECIS ZΘ system. Confluent cells from two different endothelial cell donors were stimulated with human serum from liver transplant patients. Pooled serum from healthy men and purified inflammatory agonists served as controls. The permeability response to serum was quantified as the area under the normalized resistance curve. Responses were compared between time points and analyzed for associations with clinical characteristics of liver transplant patients and their grafts. Results: Liver transplant sera from all time points during surgery-induced permeability in both endothelial cell lines. The magnitude of permeability change was heterogeneous between patients, and there were differences in the effects of sera on the two endothelial cell lines. In one of the cell lines, the severity of liver disease was associated with greater permeability at the start of surgery. In the same cell line, serum collected 15 min after liver reperfusion induced significantly more permeability as compared to that collected at the start of surgery. Early postreperfusion sera from patients undergoing living donor transplants induced more permeability than sera from deceased donor transplants. Sera from two exemplary cases of patients on preoperative dialysis, and one patient with an unexpectedly long warm ischemia time of the liver graft, induced exaggerated and prolonged endothelial permeability. Discussion: Serum from patients with cirrhosis undergoing liver transplantation induces permeability of cultured human pulmonary microvascular endothelial cells. Increased endothelial permeability during liver transplantation may contribute to organ injury and present a target for future therapeutics.
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BACKGROUND: The peripheral perfusion index is the ratio of pulsatile to nonpulsatile static blood flow obtained by photoplethysmography and reflects peripheral tissue perfusion. We investigated the association between intraoperative perfusion index and postoperative acute kidney injury in patients undergoing major noncardiac surgery and receiving continuous vasopressor infusions. METHODS: In this exploratory post hoc analysis of a pragmatic, cluster-randomised, multicentre trial, we obtained areas and cumulative times under various thresholds of perfusion index and investigated their association with acute kidney injury in multivariable logistic regression analyses. In secondary analyses, we investigated the association of time-weighted average perfusion index with acute kidney injury. The 30-day mortality was a secondary outcome. RESULTS: Of 2534 cases included, 8.9% developed postoperative acute kidney injury. Areas and cumulative times under a perfusion index of 3% and 2% were associated with an increased risk of acute kidney injury; the strongest association was observed for area under a perfusion index of 1% (adjusted odds ratio [aOR] 1.32, 95% confidence interval [CI] 1.00-1.74, P=0.050, per 100%∗min increase). Additionally, time-weighted average perfusion index was associated with acute kidney injury (aOR 0.82, 95% CI 0.74-0.91, P<0.001) and 30-day mortality (aOR 0.68, 95% CI 0.49-0.95, P=0.024). CONCLUSIONS: Larger areas and longer cumulative times under thresholds of perfusion index and lower time-weighted average perfusion index were associated with postoperative acute kidney injury in patients undergoing major noncardiac surgery and receiving continuous vasopressor infusions. CLINICAL TRIAL REGISTRATION: NCT04789330.
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Injúria Renal Aguda , Hipotensão , Humanos , Complicações Pós-Operatórias/etiologia , Índice de Perfusão , Estudos Retrospectivos , Injúria Renal Aguda/etiologia , Fatores de Risco , Hipotensão/complicaçõesRESUMO
BACKGROUND: Improper opioid prescription after surgery is a well-documented iatrogenic contributor to the current opioid epidemic in North America. In fact, opioids are known to be overprescribed to liver transplant patients, and liver transplant patients with high doses or prolonged postsurgical opioid use have higher risks of graft failure and death. METHODS: This is a retrospective cohort study of 552 opioid-naive patients undergoing liver transplant at an academic center between 2012 and 2019. The primary outcome was the discrepancy between the prescribed discharge opioid daily dose and each patient's own inpatient opioid consumption 24 h before discharge. Variables were analyzed with Wilcoxon and chi-square tests and logistic regression. RESULTS: Opioids were overprescribed in 65.9% of patients, and 54.3% of patients who required no opioids the day before discharge were discharged with opioid prescriptions. In contrast, opioids were underprescribed in 13.4% of patients, among whom 27.0% consumed inpatient opioids but received no discharge opioid prescription. The median prescribed opioid daily dose was 333.3% and 56.3% of the median inpatient opioid daily dose in opioid overprescribed and underprescribed patients, respectively. Importantly, opioid underprescribed patients had higher rates of opioid refill 1 to 30 and 31 to 90 d after discharge, and the rate of opioid underprescription more than doubled from 2016 to 2019. CONCLUSIONS: Opioids are both over- and underprescribed to liver transplant patients, and opioid underprescribed patients had higher rates of opioid refill. Therefore, we proposed to prescribe discharge opioid prescriptions based on liver transplant patients' inpatient opioid consumption to provide patient-centered opioid prescriptions.
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Transplante de Fígado , Transplantes , Humanos , Transplante de Fígado/efeitos adversos , Analgésicos Opioides/efeitos adversos , Estudos Retrospectivos , PrescriçõesRESUMO
INTRODUCTION: Catecholamine vasopressors such as norepinephrine are the standard drugs used to maintain mean arterial pressure during liver transplantation. At high doses, catecholamines may impair organ perfusion. Angiotensin II is a peptide vasoconstrictor that may improve renal perfusion pressure and glomerular filtration rate, a haemodynamic profile that could reduce acute kidney injury. Angiotensin II is approved for vasodilatory shock but has not been rigorously evaluated for treatment of hypotension during liver transplantation. The objective is to assess the efficacy of angiotensin II as a second-line vasopressor infusion during liver transplantation. This trial will establish the efficacy of angiotensin II in decreasing the dose of norepinephrine to maintain adequate blood pressure. Completion of this study will allow design of a follow-up, multicentre trial powered to detect a reduction of organ injury in liver transplantation. METHODS AND ANALYSIS: This is a double-blind, randomised clinical trial. Eligible subjects are adults with a Model for End-Stage Liver Disease Sodium Score ≥25 undergoing deceased donor liver transplantation. Subjects are randomised 1:1 to receive angiotensin II or saline placebo as the second-line vasopressor infusion. The study drug infusion is initiated on reaching a norepinephrine dose of 0.05 µg kg-1 min-1 and titrated per protocol. The primary outcome is the dose of norepinephrine required to maintain a mean arterial pressure ≥65 mm Hg. Secondary outcomes include vasopressin or epinephrine requirement and duration of hypotension. Safety outcomes include incidence of thromboembolism within 48 hours of the end of surgery and severe hypertension. An intention-to-treat analysis will be performed for all randomised subjects receiving the study drug. The total dose of norepinephrine will be compared between the two arms by a one-tailed Mann-Whitney U test. ETHICS AND DISSEMINATION: The trial protocol was approved by the local Institutional Review Board (#20-30948). Results will be posted on ClinicalTrials.gov and published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: ClinicalTrials.govNCT04901169.
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Doença Hepática Terminal , Hipotensão , Transplante de Fígado , Adulto , Humanos , Angiotensina II/uso terapêutico , Índice de Gravidade de Doença , Doadores Vivos , Vasoconstritores/uso terapêutico , Hipotensão/tratamento farmacológico , Norepinefrina/uso terapêutico , Método Duplo-Cego , Catecolaminas/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Multicêntricos como AssuntoRESUMO
BACKGROUND: Outcome data for the great majority of liver normothermic machine perfusion (NMP) cases derive from the strict confines of clinical trials. Detailed specifics regarding the intraoperative and early postoperative impact of NMP on reperfusion injury and its sequelae during real-world use of this emerging technology remain largely unavailable. METHODS: We analyzed transplants performed in a 3-month pilot period during which surgeons invoked commercial NMP at their discretion. Living donor, multi-organ, and hypothermic machine perfusion transplants were excluded. RESULTS: Intraoperatively, NMP (n = 24) compared to static cold storage (n = 25) recipients required less peri-reperfusion bolus epinephrine (0 vs. 60 µg; p < .001) and post-reperfusion fresh frozen plasma (2.5 vs. 7.0 units; p = .0069), platelets (.0 vs. 2.0 units; p = .042), and hemostatic agents (0% vs. 24%; p = .010). Time from incision to venous reperfusion did not differ (3.6 vs. 3.1; p = .095) but time from venous reperfusion to surgery end was shorter for NMP recipients (2.3 vs. 2.8 h; p = .0045). Postoperatively, NMP recipients required fewer red blood cell (1.0 vs. 4.0 units; p = .0083) and fresh frozen plasma (4.0 vs. 7.0 units; p = .046) transfusions, had shorter intensive care unit stays (33.5 vs. 58.4 h; p = .012), and experienced less early allograft dysfunction according to both the Model for Early Allograft Function Score (3.4 vs. 5.0; p = .0047) and peak AST within 10 days of transplant (619 vs. 1,181 U/L; p = .036). Liver acceptance for the corresponding recipient was conditional on NMP use for 63% (15/24) of cases. CONCLUSION: Real-world NMP use was associated with significantly lower intensity of reperfusion injury and intraoperative and postoperative care that may translate into patient benefit.
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Transplante de Fígado , Traumatismo por Reperfusão , Humanos , Preservação de Órgãos , Fígado , PerfusãoRESUMO
BACKGROUND: Intraoperative hypotension is associated with postoperative complications. The use of vasopressors is often required to correct hypotension but the best vasopressor is unknown. METHODS: A multicentre, cluster-randomised, crossover, feasibility and pilot trial was conducted across five hospitals in California. Phenylephrine (PE) vs norepinephrine (NE) infusion as the first-line vasopressor in patients under general anaesthesia alternated monthly at each hospital for 6 months. The primary endpoint was first-line vasopressor administration compliance of 80% or higher. Secondary endpoints were acute kidney injury (AKI), 30-day mortality, myocardial injury after noncardiac surgery (MINS), hospital length of stay, and rehospitalisation within 30 days. RESULTS: A total of 3626 patients were enrolled over 6 months; 1809 patients were randomised in the NE group, 1817 in the PE group. Overall, 88.2% received the assigned first-line vasopressor. No drug infiltrations requiring treatment were reported in either group. Patients were median 63 yr old, 50% female, and 58% white. Randomisation in the NE group vs PE group did not reduce readmission within 30 days (adjusted odds ratio=0.92; 95% confidence interval, 0.6-1.39), 30-day mortality (1.01; 0.48-2.09), AKI (1.1; 0.92-1.31), or MINS (1.63; 0.84-3.16). CONCLUSIONS: A large and diverse population undergoing major surgery under general anaesthesia was successfully enrolled and randomised to receive NE or PE infusion. This pilot and feasibility trial was not powered for adverse postoperative outcomes and a follow-up multicentre effectiveness trial is planned. CLINICAL TRIAL REGISTRATION: NCT04789330 (ClinicalTrials.gov).
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Injúria Renal Aguda , Hipotensão , Humanos , Adulto , Feminino , Masculino , Fenilefrina , Norepinefrina/uso terapêutico , Projetos Piloto , Estudos de Viabilidade , Resultado do Tratamento , Hipotensão/tratamento farmacológico , Hipotensão/etiologia , Vasoconstritores/uso terapêutico , Anestesia Geral/efeitos adversosRESUMO
BACKGROUND: Practice patterns related to intraoperative fluid administration and vasopressor use have potentially evolved over recent years. However, the extent of such changes and their association with perioperative outcomes, such as the development of acute kidney injury (AKI), have not been studied. METHODS: We performed a retrospective analysis of major abdominal surgeries in adults across 26 US hospitals between 2015 and 2019. The primary outcome was AKI as defined by the Kidney Disease Improving Global Outcomes definition (KDIGO) using only serum creatinine criteria. Univariable linear predictive additive models were used to describe the dose-dependent risk of AKI given fluid administration or vasopressor use. RESULTS: Over the study period, we observed a decrease in the volume of crystalloid administered, a decrease in the proportion of patients receiving more than 10 ml kg-1 h-1 of crystalloid, an increase in the amount of norepinephrine equivalents administered, and a decreased duration of hypotension. The incidence of AKI increased between 2016 and 2019. An increase of crystalloid administration from 1 to 10 ml kg-1 h-1 was associated with a 58% decreased risk of AKI. CONCLUSIONS: Despite decreased duration of hypotension during the study period, decreased fluid administration and increased vasopressor use were associated with increased incidence of AKI. Crystalloid administration below 10 ml kg-1 h-1 was associated with an increased risk of AKI. Although no causality can be concluded, these data suggest that prevention and treatment of hypotension during abdominal surgery with liberal use of vasopressors at the expense of fluid administration is associated with an increased risk of postoperative AKI.
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Injúria Renal Aguda , Hipotensão , Abdome/cirurgia , Injúria Renal Aguda/epidemiologia , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/terapia , Adulto , Soluções Cristaloides , Humanos , Hipotensão/complicações , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/terapia , Estudos Retrospectivos , Fatores de Risco , Vasoconstritores/uso terapêuticoRESUMO
Testicular cancer is an aggressive malignancy with a rising incidence rate across the globe. Testicular germ cell tumors are the most commonly diagnosed cancers, and surgical removal of the testes is often a radical necessity along with chemotherapy and radiotherapy. While seminomas are receptive to radiotherapy as well as chemotherapy, non-seminomatous germ cell tumors respond to chemotherapy only. Due to the singular nature of testicular cancers with associated orchiectomy and mortality, it is important to study the molecular basis and genetic underpinnings of this group of cancers across male populations globally. In this review, we shed light on the population pharmacogenetics of testicular cancer, pediatric and adult tumors, current clinical trials, genetic determinants of chemotherapy-induced toxicity in testicular cancer, as well as the molecular signal transduction pathways operating in this malignancy. Taken together, our discussions will help in enhancing our understanding of genetic factors in testicular carcinogenesis and chemotherapy-induced toxicity, augment our knowledge of this aggressive cancer at the cellular and molecular level, as well as improve precision medicine approaches to combat this disease.
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Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias Embrionárias de Células Germinativas/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Neoplasias Testiculares/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ensaios Clínicos como Assunto , Humanos , Masculino , Neoplasias Embrionárias de Células Germinativas/genética , Transdução de Sinais/genética , Neoplasias Testiculares/genéticaRESUMO
More anesthesiologists are routinely using transesophageal echocardiography (TEE) during liver transplant surgery, but the effects on patient outcome are unknown. Transplant anesthesiologists are therefore uncertain if they should undergo additional training and adopt TEE. In response to these clinical questions, the Society for the Advancement of Transplant Anesthesia appointed experts in liver transplantation and who are certified in TEE to evaluate all available published evidence on the topic. The aim was to produce a summary with greater explanatory power than individual reports to guide transplant anesthesiologists in their decision to use TEE. An exhaustive search recovered 51 articles of uncontrolled clinical observations. Topics chosen for this study were effectiveness and safety because they were a major or minor topic in all articles. The pattern of clinical use was a common topic and was included to provide contextual information. Summarized observations showed effectiveness as the ability to make a new and unexpected diagnosis and to direct the choice of clinical management. These were reported in each stage of liver transplant surgery. There were observations that TEE facilitated rapid diagnosis of life-threatening conditions difficult to identify with other types of monitoring commonly used in the operating room. Real-time diagnosis by TEE images made anesthesiologists confident in their choice of interventions, especially those with a high risk of complications such as use of anticoagulants for intracardiac thrombosis. The summarized observations in this systematic review suggest that TEE is an effective form of monitoring with a safety profile similar to that in cardiac surgery patients.
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Anestesia , Anestesiologia , Transplante de Fígado , Anestesia/efeitos adversos , Anestesiologistas , Ecocardiografia Transesofagiana , Humanos , Transplante de Fígado/efeitos adversosRESUMO
BACKGROUND: Acute kidney injury (AKI) after liver transplantation is associated with increased morbidity and mortality. It remains controversial whether the choice of vena cava reconstruction technique impacts AKI. METHODS: This is a single-center retrospective cohort of 897 liver transplants performed between June 2009 and September 2018 using either the vena cava preserving piggyback technique or caval replacement technique without veno-venous bypass or shunts. The association between vena cava reconstruction technique and stage of postoperative AKI was assessed using multivariable ordinal logistic regression. Causal mediation analysis was used to evaluate warm ischemia time as a potential mediator of this association. RESULTS: The incidence of AKI (AKI stage ≥2) within 48 h after transplant was lower in the piggyback group (40.3%) compared to the caval replacement group (51.8%, P < 0.001). Piggyback technique was associated with a reduced risk of developing a higher stage of postoperative AKI (odds ratio, 0.49; 95% confidence interval, 0.37-0.65, P < 0.001). Warm ischemia time was shorter in the piggyback group and identified as potential mediator of this effect. There was no difference in renal function (estimated glomerular filtration rate and the number of patients alive without dialysis) 1 y after transplant. CONCLUSIONS: Piggyback technique, compared with caval replacement, was associated with a reduced incidence of AKI after liver transplantation. There was no difference in long-term renal outcomes between the 2 groups.
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Injúria Renal Aguda/prevenção & controle , Transplante de Fígado/efeitos adversos , Procedimentos Cirúrgicos Vasculares/efeitos adversos , Veia Cava Inferior/cirurgia , Injúria Renal Aguda/diagnóstico , Injúria Renal Aguda/mortalidade , Feminino , Taxa de Filtração Glomerular , Sobrevivência de Enxerto , Humanos , Incidência , Transplante de Fígado/mortalidade , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Procedimentos Cirúrgicos Vasculares/mortalidade , Isquemia Quente/efeitos adversosRESUMO
BACKGROUND: In liver transplantation, both cold and warm ischemia times are known to impact early graft function. The extraction time is a period during the initial phase of organ cooling which occurs during deceased donor procurement. During this time, the organ is at risk of suboptimal cooling. Whether donor extraction time, the time from donor aortic cross-clamp to removal of the donor organ from the body cavity has an effect on early graft function is not known. METHODS: We investigated the effect of donor extraction time on early graft function in 292 recipients of liver grafts procured locally and transplanted at our center between June 2012 and December 2016. Early graft function was assessed using the model of early allograft function score in a multivariable regression model including donor extraction time, cold ischemia time, warm ischemia time, donor risk index, and terminal donor sodium. RESULTS: Donor extraction time had an independent effect on early graft function measured by the model of early allograft function score (coefficient, 0.021; 95% confidence interval, 0.007-0.035; P < 0.01; for each minute increase of donor extraction time). Besides donor extraction time, cold ischemia time, warm ischemia time, and donor risk index had a significant effect on early graft function. CONCLUSIONS: We demonstrate an independent effect of donor extraction time on graft function after liver transplantation. Efforts to minimize donor extraction time could improve early graft function in liver transplantation.
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Isquemia Fria , Hepatectomia , Transplante de Fígado/métodos , Duração da Cirurgia , Doadores de Tecidos , Coleta de Tecidos e Órgãos/métodos , Isquemia Quente , Adulto , Isquemia Fria/efeitos adversos , Técnicas de Apoio para a Decisão , Feminino , Sobrevivência de Enxerto , Hepatectomia/efeitos adversos , Humanos , Testes de Função Hepática , Transplante de Fígado/efeitos adversos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Disfunção Primária do Enxerto/diagnóstico , Disfunção Primária do Enxerto/etiologia , Medição de Risco , Fatores de Risco , Fatores de Tempo , Coleta de Tecidos e Órgãos/efeitos adversos , Resultado do Tratamento , Isquemia Quente/efeitos adversosRESUMO
OBJECTIVE: Determine if surgery start time impacts patient outcomes in elective cardiac surgery. DESIGN: This was a retrospective study. SETTING: This study was based at a single academic institution. PARTICIPANTS: Patients undergoing elective cardiac surgery over a 3-year period were included. INTERVENTIONS: There were no interventions. MEASUREMENTS AND MAIN RESULTS: The authors performed a retrospective study of patients undergoing elective cardiac surgery over a 3-year period. They divided their patient groups into those who had an anesthesia start time between 6:00 a.m. and 4:00 p.m. and those who had an anesthesia start time between 4:01 p.m. and 5:59 a.m. In the original sample and propensity-score-matched groups, the authors examined the effects of start time on morbidity, mortality, and several metrics of hospital length of stay. The start time of elective cardiac surgery did not have a statistically significant effect upon mortality, individual or composite morbidity, or hospital length of stay in either the original sample or the propensity-score-matched sample. CONCLUSIONS: The authors' results suggested that elective cardiac surgery may be performed late at night without adverse effects, although institutional support for this effort (such as 24-hour intensivist coverage to facilitate fast-track extubation) may have been integral to their findings.
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Plantão Médico/normas , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Procedimentos Cirúrgicos Eletivos/efeitos adversos , Plantão Médico/estatística & dados numéricos , Idoso , Anestesiologia/organização & administração , Procedimentos Cirúrgicos Cardíacos/mortalidade , Procedimentos Cirúrgicos Cardíacos/normas , Procedimentos Cirúrgicos Eletivos/mortalidade , Procedimentos Cirúrgicos Eletivos/normas , Feminino , Pesquisa sobre Serviços de Saúde/métodos , Mortalidade Hospitalar , Humanos , Tempo de Internação/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Cidade de Nova Iorque/epidemiologia , Admissão e Escalonamento de Pessoal/organização & administração , Cuidados Pós-Operatórios/métodos , Estudos Retrospectivos , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Perioperative use of opioids is associated with the risk of opioid-induced respiratory depression. Naloxone is a competitive opioid antagonist typically administered to reverse opioid-induced respiratory depression. Postoperative administration of naloxone may be considered a proxy for significant postoperative opioid-induced respiratory depression and data regarding its use may be utilized as a quality measure. Few large studies have been done to characterize the population and define an incidence of naloxone recipients in the postoperative inpatient setting. OBJECTIVES: We aimed to characterize the demographics of patients receiving postoperative naloxone, as well as the incidence of administration in the first 72 post-operative hours at a large urban academic medical center in the United States. STUDY DESIGN: This is a retrospective cohort study. SETTING: Major urban tertiary teaching institution. METHODS: The robust electronic record database of The Department of Anesthesiology at The Icahn School of Medicine at Mount Sinai, as well as the institution's data warehouse were instrumental in allowing almost 450,000 surgical cases performed between 2001 and 2014 to be screened for naloxone administration within the first 72 postoperative hours. Organ harvests, outside of OR intubations, cancelled cases, and patients age less than or equal to 18 were excluded from the total case count. RESULTS: Naloxone was administered 433 times in a total of 442,699 postoperative cases. This yielded an incidence of 0.1%. Additionally, the demographics of the group receiving naloxone were described. The mean age was 60, mean body mass index (BMI) was 27, 60% were women, and the mean American Society of Anesthesiologists (ASA) status was 3. Average time to naloxone administration was 21 hours (standard deviation 7) after surgery. Thirteen percent of the cases were emergent. Breakdown of anesthetic technique revealed that 81% of the cases were performed under general anesthesia, 7% with monitored anesthesia care (MAC), and 12% under neuraxial anesthesia. This study lays the groundwork for further elucidating risk factors for postoperative administration of naloxone. LIMITATIONS: This is a retrospective study. CONCLUSION: The overall incidence of postoperative naloxone administration over a 13 year period in approximately 450,000 patients was 0.1%. Demographics of this group were older, ASA 3 women, qualifying as overweight, but not obese, undergoing elective surgery with a general anesthetic technique. Average time to administration was 21 hours postoperatively.