Respiratory Mechanics.

Today's management of the ventilated patient still relies on the measurement of old parameters such as airway pressures and flow. Graphical presentations reveal the intricacies of patient-ventilator interactions in times of supporting the patient on the ventilator instead of fully ventilating the heavily sedated patient. This opens a new pathway for several bedside technologies based on basic physiologic knowledge; however, it may increase the complexity of measurements. The spread of the COVID-19 infection has confronted the anesthesiologist and intensivist with one of the most severe pulmonary pathologies of the last decades. Optimizing the patient at the bedside is an old and newly required skill for all physicians in the intensive care unit, supported by mobile technologies such as lung ultrasound and electrical impedance tomography. This review summarizes old knowledge and presents a brief insight into extended monitoring options.

Is major burn injury associated with coagulopathy? The value of thrombelastometry in the detection of coagulopathy in major burn injury: A prospective observational study.

BACKGRUND: The coagulation status of burn patients is generally impaired and is a major factor of the deteriorating burn patients' overall situation. In trauma and other patient groups, the differential diagnosis of coagulation impairment has been largely improved by the use of rotational thromboelastometry (ROTEM®). The aim of this prospective observational study was the differentiated observation of coagulopathy in severely burned patients using standard parameters and ROTEM® thrombelastometry during the relevant stages of burn disease. PATIENTS AND METHODS: Twelve patients that sustained at least 20% third degree burns of total body surface area (TBSA) were included in the study. Standard and ROTEM® coagulation analyses were performed on admission and then twice daily during the first 14 days following burn trauma. RESULTS: Although the initial assessment of DIC was similar for both standard labs and ROTEM® measurements, more patients were detected to be in a state of worsening coagulation status for a longer time in ROTEM® than in standard measurements. In addition, one patient was rated in to be in decompensated DIC for 3 days according to ROTEM® measurements, while no patient was rated to be in a decompensated DIC based on standard parameters. CONCLUSION: This study points towards a more complex picture and higher occurrence of DIC in burn patients when thrombelastometric measurements like ROTEM® are taken into account in addition to standard coagulation parameters.

Pharmacokinetics of cefuroxime in infants and neonates undergoing cardiac surgery.

AIMS: Very little data exist regarding the effect of cardiopulmonary bypass (CPB) on cefuroxime (CXM) pharmacokinetics in children less than one year of age. METHODS: 50 mg kg-1 CXM i.v. after induction were followed by 75 mg kg-1 into the CPB circuit. In 42 patients undergoing cardiac surgery, 15-20 samples were obtained between 5 and 360 min after the first dose. Total CXM concentrations were measured by high-performance liquid chromatography and a pharmacokinetic/pharmacodynamic (PK/PD) modelling was performed. RESULTS: Using a fixed protein binding of 15.6% for CXM, peak plasma concentrations of unbound CXM were 229 ± 52 µg ml-1 after the first bolus and 341 ± 86 µg ml-1 on CPB. Nadir concentrations before CPB were 69 ± 20 µg ml-1 and six hours later decreased to 41 ± 19 µg ml-1 with and 24 ± 14 µg ml-1 without CPB. A two-compartment model was fitted with the main covariates body weight, CPB and postmenstrual age (PMA). PK parameters were as follows: systemic clearance, 5.15 [95% CI 4.5-5.8] l h-1 ; central volume of distribution, 11.25 [9.41-13.09] l; intercompartmental clearance, 18.19 [14.79-21.58] l h-1 ; and peripheral volume, 17.07 [15.7-18.5] L. ƒT > MIC of 32 µg ml-1 for an 8-h time period was between 70 and 100% (2.5-10 kg BW). According to our simulation, 25 mg ml-1 CXM as a primary bolus and into the prime plus a 5 mg kg-1  h-1 infusion maintain CXM concentrations continuously above 32 µg ml-1 . CONCLUSIONS: The routine dosing regimen provided was sufficient for prophylaxis, but continuous dosing can provide a higher percentage of ƒT > MIC.

Pharmacokinetics of tranexamic acid in neonates and infants undergoing cardiac surgery.

AIM: Tranexamic acid (TXA) continues to be one of the antifibrinolytics of choice during paediatric cardiac surgery. However, in infants less than 1 year of age, the optimal dosing based on pharmacokinetic (PK) considerations is still under discussion. METHODS: Forty-three children less than 1 year of age were enrolled, of whom 37 required the use of cardiopulmonary bypass (CPB) and six were operated on without CPB. Administration of 50 mg kg-1 TXA intravenously at the induction of anaesthesia was followed by 50 mg kg-1 into the CPB prime in the CPB group. Plasma concentrations of TXA were analysed by gas chromatography-mass spectrometry. PK data were investigated using nonlinear mixed-effect models. RESULTS: A two-compartment model was fitted, with the main covariates being allometrically scaled bodyweight, CPB, postmenstrual age (PMA). Intercompartmental clearance (Q), peripheral volume (V2), systemic clearance, (CL) and the central volume (V1) were calculated. Typical values of the PK parameter estimates were as follows: CL = 3.78 [95 % confidence interval (CI) 2.52, 5.05] l h-1 ; central volume of distribution = 13.6 (CI 11.7, 15.5) l; Q = 16.3 (CI 13.5, 19.2) l h-1 ; V2 = 18.0 (CI 16.1, 19.9) l. Independently of age, 10 mg kg-1 TXA as a bolus, a subsequent infusion of 10 mg kg-1 h-1 , then a 4 mg kg-1 bolus into the prime and a reduced infusion of 4 mg kg-1 h-1 after the start of CPB are required to maintain TXA concentrations continuously above 20 µg ml-1 , the threshold value for an effective inhibition of fibrinolysis and far lower than the usual peak concentrations (the '10-10-4-4 rule'). CONCLUSIONS: The introduction of a modified dosing regimen using a starting bolus followed by an infusion and a CPB prime bolus would prohibit the potential risk of seizures caused by high peak concentrations and also maintain therapeutic plasma concentration above 20 µg ml-1 .

The effect of cyanosis on perioperative platelet function as measured by multiple electrode aggregometry and postoperative blood loss in neonates and infants undergoing cardiac surgery.

OBJECTIVES: Platelet dysfunction is one of the major haematological disturbances of cardiopulmonary bypass (CPB). In addition, cyanosis is known to cause further coagulation disturbances. METHODS: We prospectively studied 110 children under 1 year of age for the effects of cyanosis on baseline platelet aggregation, the time course of function on cardiopulmonary bypass, the effect on chest tube drainage (CTD) and the transfusion requirements. Using multiple electrode aggregometry (MULTIPLATE™) with the activators adenosine diphosphate (ADP) and thrombin-related activation peptide (TRAP), platelet aggregation was assessed and examined for predictive value. RESULTS: Neonates under 30 days of age (n = 51) and infants (n = 59) were separated for analysis. Cyanosis had no significant effect on platelet function during the first 24 h after surgery. Similarly, there was no association to perioperative platelet function, CTD or exposures to blood products. ADP after protamine correlated significantly with the total number of exposures for neonates and infants and CTD at 6 h in the newborn group. Upon intensive care unit admission, ADP values correlated to the total number of exposures to blood products. No other platelet function value was able to clinically predict CTD or subsequent blood transfusion requirements. CONCLUSIONS: In our study population, we observed no clinically significant effect of cyanosis on baseline and the perioperative course of platelet function, CTD and the number of exposures to blood products. Therefore, children under 1 year of age do not require a different approach with regard to platelet transfusions, independent of cyanosis. Clinically, platelet function was not a reliable predictor of CTD or blood transfusion requirements.

Early experiences with a new three-dimensional annuloplasty ring for the treatment of functional tricuspid regurgitation.

BACKGROUND: Various techniques and devices have been proposed for tricuspid valve (TV) repair in patients with tricuspid regurgitation (TR). However, residual or recurrent TR is not uncommon occurring in 20% to 30% of patients. This study reports first experiences with a new three-dimensional annuloplasty ring. METHODS: We retrospectively reviewed 200 consecutive patients who underwent TV repair for functional TR with the Contour 3D annuloplasty ring (Medtronic, Minneapolis, MN) from December 2010 to February 2013 at our institution. The follow-up is 98% complete (mean 1.0 ± 0.7 years; cumulative total 189 patient-years). RESULTS: Mean age was 70.4 ± 9.1 years and the median logistic European system for cardiac operative risk was 7%. Sixty-nine percent of the patients were in New York Heart Association class III/IV. Echocardiography documented moderate or severe TR in 97.5% of the patients, with a mean annulus diameter of 45.1 ± 4.9 mm; 93.5% of the patients underwent a combined procedure, and 20.5% an urgent or emergent operation. The 30-day mortality was 6%. The preoperative TR grade was reduced from 2.45 ± 0.53 to 0.77 ± 0.54 (p < 0.001). At hospital discharge residual II TR or greater was present in 4.3% of the patients. Freedom from recurrent II TR or greater at 2 years was 90.9% ± 4.2% and freedom from TV-related reoperations at 2 years was 98.5% ± 1.0%. No case of ring dehiscence occurred. Fourteen patients (7%) required a permanent pacemaker implantation for atrioventricular block. CONCLUSIONS: Tricuspid valve repair with the Contour 3D annuloplasty ring can be performed with a low rate of residual TR at hospital discharge, a low reoperation rate, and with an excellent early functional outcome.

The perioperative course of factor XIII and associated chest tube drainage in newborn and infants undergoing cardiac surgery.

BACKGROUND: Perioperative acquired factor XIII deficiency has been looked upon as a potential cause of postoperative bleeding in adult cardiac surgery. METHODS: Forty-four infants were prospectively studied for the time course of factor XIII in plasma and the effect on chest tube drainage (CTD) and transfusion requirements in the first 24 h after surgery. A reconstituted blood prime (RBP) with fresh-frozen plasma (FFP) and packed red blood cells (PRBC) was used. Samples were taken at baseline, after cardiopulmonary bypass and upon arrival in the ICU. Differences in blood loss and transfusion requirements based on a cutoff value of 70% factor XIII activity at the time of ICU admission were also calculated. RESULTS: Baseline factor XIII activity was 79%, decreased to 71% after CPB (P = 0.102) and increased back up to 77% at ICU arrival (P = 0.708). There was no significant correlation between factor XIII, CTD, age, cyanosis, platelet count, and transfusion requirements at any time point. Only preoperative fibrinogen levels correlated significantly with factor XIII activity. Perioperative blood transfusions (PRBC P = 0.712, FFP P = 0.909, platelets P = 0.807) and chest tube losses (P = 0.424 at 6 h and P = 0.215 at 24 h) were not significantly different above or below a 70% factor XIII activity at ICU arrival. CONCLUSION: Factor XIII activity in infants with congenital heart defects is within the lower range of normal adults, independent of patient's age and the presence of cyanosis. Reconstituted blood prime maintains factor XIII activity at sufficient levels during pediatric cardiac surgery. We could not detect a correlation between FXIII and CTD.

Serum concentrations and pharmacokinetics of moxifloxacin in patients undergoing coronary artery bypass graft surgery with cardiopulmonary bypass.

Although cephalosporins are recommended as primary agents, moxifloxacin may be a suitable second-line antibiotic in cardiac surgery, especially if additional Gram-negative coverage is warranted. Cardiopulmonary bypass (CPB) may alter the pharmacokinetics of drugs in numerous ways. Since no such data exist, the aim of this study was to assess the serum concentrations and pharmacokinetics of moxifloxacin in patients undergoing cardiac surgery with CPB. Fourteen coronary artery bypass graft surgery patients received an intravenous infusion of 400 mg moxifloxacin as peri-operative antibiotic prophylaxis. At 15 time points throughout a 24-h period, serum samples were obtained to measure moxifloxacin concentrations using high-performance liquid chromatography. In addition, a non-compartmental pharmacokinetic analysis, i.e. area under the concentration-time curve (AUC), volume of distribution at steady state (V(SS)), drug clearance (CL), elimination half-life (t(1/2)) and mean residence time (MRT), was performed in five patients. Apart from a slight transient decrease in moxifloxacin concentration at the onset, CPB did not affect the concentration-time curve. Mean ± standard deviation maximum drug concentration (C(max)) (5.12 ± 1.58 µg/mL), AUC (36.5 ± 5.40 µgh/mL), VSS (2.03 ± 0.30 L/kg), CL (11.2 ± 1.91 L/h), t(1/2) (9.47 ± 0.92 h) and MRT (12.9 ± 1.52 h) were comparable with historical data for healthy volunteers. We conclude that CPB does not alter the pharmacokinetics of moxifloxacin. No dose adjustments, especially with regard to the CPB circuit and its priming volume, are necessary in cardiac surgical patients.

The effect of intraoperative hypotension on the outcomes of initial hybrid palliation for single ventricle congenital heart disease: an historical cohort study.

BACKGROUND: The "hybrid procedure" is an alternative surgical palliation strategy for single ventricle congenital heart disease. The purported benefit is improved cognitive ability secondary to avoidance of cardiopulmonary bypass in the neonatal period when neuronal apoptosis is greater. It is unknown whether survival is improved after this procedure. Intraoperative hypotension is common in these patients, and we hypothesized that this hypotension was associated with mortality or morbidity. METHODS: We reviewed the records of 58/58 patients undergoing a first-stage hybrid procedure from 2004 to 2010 in a tertiary pediatric academic centre. Risk factors for poor outcome and the association between intraoperative hypotension and morbidity or mortality were investigated. RESULTS: Average preoperative arterial blood pressure (ABP) [systolic/diastolic presented as mean (standard deviation)] were 68 (12.7) / 38 (9.4) mmHg. Post-induction ABP was 65 (15.2) / 37 (8.6) mmHg. The average intraoperative nadir of ABP was 45 (7.0) / 26 (4.8) mmHg. On return to the intensive care unit (ICU), the average ABP was 69 (13.7) / 38 (11.6) mmHg. The nadir lasted longer than ten minutes in 32/58 patients. The mortality at 48 hr, 60 days, and 12 months was 3/58 (5%), 10/58 (17%), and 15/58 (26%), respectively. Six patients returned to the ICU on extracorporeal membrane oxygenation (ECMO). There was a weak statistical correlation between the average mean and diastolic BP pre-induction and changes of > 20% in systolic and diastolic BP during the case. CONCLUSION: In this patient cohort, we can show an association between short periods of intraoperative hypotension and mortality or return to the ICU on ECMO, but the importance of this is not certain.

Neither moxifloxacin nor cefuroxime produces significant attenuation of inflammatory mediator release in patients exposed to cardiopulmonary bypass: a randomized controlled trial.

OBJECTIVES: In vitro and experimental studies in animals have established the anti-inflammatory effects of moxifloxacin. Cardiopulmonary bypass (CPB) leads to an inflammatory response. The aim of this study was to assess whether the inflammatory cytokine response to CPB is reduced with a perioperative antibiotic prophylaxis, either moxifloxacin or cefuroxime (the standard prophylaxis). PATIENTS AND METHODS: Twenty-eight patients scheduled for elective coronary artery bypass grafting with CPB were randomly assigned to receive either moxifloxacin or cefuroxime as the perioperative antibiotic prophylaxis. Interleukin (IL)-6, -8, -10 and tumour necrosis factor-α (TNF-α) serum concentrations were determined at eight time points before and after CPB. RESULTS: In both groups, all cytokine concentrations significantly increased after the start of CPB. There were no statistically significant differences between the moxifloxacin and cefuroxime groups at any point; IL-6 concentrations [median (interquartile range)] 240 min after CPB, the primary endpoint, were 364 (192-598) and 465 (325-906) pg/mL (P = 0.323), respectively. CONCLUSIONS: Neither moxifloxacin nor cefuroxime produced significant attenuation of the inflammatory cytokine response to CPB. The reasons why moxifloxacin did not have significant anti-inflammatory effects in this unique clinical situation may be: (i) the inflammatory response to CPB may be different from that of infectious disease states that were used to establish the immunomodulatory effects of moxifloxacin; and (ii) a single intravenous dose, which was used in this investigation, may not lead to high enough plasma and intracellular concentrations.

Are the point-of-care diagnostics MULTIPLATE and ROTEM valid in the setting of high concentrations of heparin and its reversal with protamine?

OBJECTIVES: To evaluate the in vitro effects of high concentrations of heparin and its reversal with protamine on routine laboratory parameters as well as on modified thromboelastogram (ROTEM; TEM International, Munich, Germany) and impedance aggregometry (MULTIPLATE; Dynabyte, Munich, Germany). DESIGN: An observational, nonrandomized in vitro study. SETTING: A single-center, university hospital. PARTICIPANTS: Ten healthy volunteers. INTERVENTIONS: Heparinization of whole blood to levels of 2, 4, 6, and 8 IU/mL of heparin and reversal with protamine. For MULTIPLATE measurements, heparin levels up to 20 IU/mL were tested. MEASUREMENTS AND MAIN RESULTS: The present results show that the prothrombin time (PT) and fibrinogen measurements are altered significantly by heparin concentrations above 2 IU/mL. Protamine reversal also affected coagulation tests except for the fibrinogen. The INTEM test using the ROTEM system was influenced significantly by heparin concentrations of 2 IU/mL or higher, whereas EXTEM measurements remained stable up to 4 IU/mL. The findings for the FIBTEM test were stable up to 6 IU/mL but then declined to values less than 50% of baseline at 8 IU/mL. HEPTEM results remained valid under all concentrations of heparin tested. The effect of protamine on ROTEM was seen mainly in the INTEM and HEPTEM measurements. Heparin concentrations up to a level of 20 U/mL had no effect on MULTIPLATE measurements. Effects of protamine on MULTIPLATE became significant at heparin-to-protamine ratios below 1:1 and were more pronounced for adenosine diphosphate than for thrombin receptor-activated protein testing. CONCLUSIONS: Neither fibrinogen (Clauss) nor derived fibrinogen or FIBTEM testing is valid in the setting of high concentrations of heparin unless antagonized by heparinase. Reversal of heparin with protamine worsens platelet function at all ratios as detected by aggregometry (MULTIPLATE) and thromboelastography (ROTEM), starting at a 1:1 ratio. Therefore, appropriate coagulation testing under cardiopulmonary bypass conditions should be selected carefully according to heparin levels. In particular, fibrinogen values are falsely low at heparin levels of 2 IU/mL and above. Therefore, newer algorithms promoting the correction of fibrinogen levels on cardiopulmonary bypass should be based on appropriate testing.

Seizures after open heart surgery: comparison of ε-aminocaproic acid and tranexamic acid.

OBJECTIVE: Although the lysine analogs tranexamic acid (TXA) and aminocaproic acid (EACA) are used widely for antifibrinolytic therapy in cardiac surgery, relatively little research has been performed on their safety profiles, especially in the setting of cardiac surgery. Two antifibrinolytic protocols using either TXA or aminocaproic acid were compared according to postoperative outcome. DESIGN: A retrospective analysis. SETTING: A university-affiliated hospital. PARTICIPANTS: Six hundred four patients undergoing cardiac surgery. INTERVENTIONS: One cohort of 275 consecutive patients received TXA; a second cohort of 329 consecutive patients was treated with EACA. Except for antifibrinolytic therapy, the anesthetic and surgical teams and their protocols remained unchanged. MEASUREMENTS AND MAIN RESULTS: Besides major outcome criteria, namely postoperative bleeding, the need for allogeneic transfusions, operative revision because of bleeding, postoperative renal dysfunction, neurologic events, heart failure, and in-hospital mortality, the authors specifically sought differences between the groups concerning seizures. The 2 cohorts were comparable over a range of perioperative factors. Postoperative seizures occurred significantly more frequently in TXA patients (7.6% v 3.3%, p = 0.019), whereas EACA patients had a higher incidence of postoperative renal dysfunction (20.0% v 30.1%, p = 0.005). There were no differences in all other measured major outcome factors. CONCLUSION: Both lysine analogs are associated with significant side effects, which must be taken into account when performing risk-benefit analyses of their use. Their use should be restricted to patients at high risk for bleeding; routine use on low-risk patients undergoing standard surgeries should face renewed critical reappraisal.

Tranexamic acid versus ɛ-aminocaproic acid: efficacy and safety in paediatric cardiac surgery.

OBJECTIVE: Tranexamic acid (TXA) and ɛ-aminocaproic acid (EACA) are used for antifibrinolytic therapy in cardiac surgery, although data directly comparing their blood sparing effect and their side effects, especially in paediatric cardiac surgical patients, are still missing. METHODS: We analysed perioperative data of 234 paediatric patients weighing less than 20 kg undergoing cardiac surgery. In a 5-month period, all patients (n=114) received TXA (group TXA). During a second 5-month period, all patients (n=120) were treated with EACA (group EACA). Primary outcome was blood loss at 24h postoperatively; secondary outcome criteria were transfusion requirement, rate of revision for bleeding, postoperative complications and in-hospital mortality. RESULTS: All descriptive and intra-operative parameters were well comparable. There was no evidence for a difference in blood loss at 24h postoperatively (TXA 21 ml kg(-1) (14-38) (median (interquartile range)) vs EACA 29 ml kg(-1) (14-40), p=0.242), rate of re-operation for bleeding (TXA 9.6% vs EACA 8.3%, p=0.725) and transfusion of blood products. The incidence of postoperative complications such as seizures (TXA 3.5% vs EACA 0.8%, p=0.203) and other neurological complications (TXA 2.6% vs EACA 1.7%, p=0.677), renal injury (TXA 9.6% vs EACA 13.3%, p=0.378), renal failure (TXA 1.8% vs EACA 4.2%, p=0.447), low cardiac output syndrome (TXA 12.3% vs EACA 10.8%, p=0.729), and vascular thrombosis (TXA 4.4% vs EACA 5.0%, p=0.824), as well as the in-hospital mortality (TXA 2.6% vs EACA 3.3%, p>0.999) did not show any statistically significant difference. CONCLUSIONS: TXA and EACA are well comparable in their effect on perioperative blood loss as well as in major clinical outcome criteria. Although the fourfold risk for seizures using TXA was not significant, we currently use EACA in paediatric cardiac surgery.

Efficiency and safety of preoperative autologous blood donation in cardiac surgery: a matched-pair analysis in 432 patients.

OBJECTIVE: A shortage of blood products is predicted for the near future in many countries all over the world. Preoperative autologous blood donation (PABD) in cardiac surgery is considered an option to reduce the need of allogeneic blood products. We analysed a 1-year period of our institutional database according to the safety and efficiency of our autologous blood donation programme. METHODS: All patients who donated autologous blood prior to cardiac surgery were matched to a non-donor according to age, body weight, body mass index, sex, haemoglobin concentration, EuroSCORE, antifibrinolytic therapy and risk for bleeding. We analysed the occurrence of adverse effects during donation in all donors as well as the main perioperative data, haemoglobin levels and the need for allogeneic blood transfusion in all patients. RESULTS: There were no major cardiac events such as myocardial infarction, worsened cardiac insufficiency or death in the donor group during the PABD process. A total of 216 patients could be matched. Exposure to allogeneic blood products was significantly reduced in the donor group (packed red cells 70 patients (pts) vs 118 pts (p<0.001), fresh frozen plasma 26 pts vs 54 pts (p=0.001), platelets 10 pts vs 22 pts (p=ns)). There were no reports of transfusion-related side effects. Further, there was no difference in haemoglobin concentrations at postoperative day 1 and at discharge. CONCLUSIONS: In this large matched-pair analysis without the need for risk stratification, PABD reduces the need for allogeneic blood products in adult cardiac surgery. In a carefully selected cohort, PABD is a safe and efficient alternative to allogeneic transfusion.

Cardiovascular thromboembolic adverse effects associated with cyclooxygenase-2 selective inhibitors and nonselective antiinflammatory drugs.

BACKGROUND: Concerns of increased cardiovascular (CV) thromboembolic adverse effects from nonsteroidal antiinflammatory drugs (NSAIDs, both nonselective [NS]-NSAIDs and cyclooxygenase [COX]-2 selective inhibitors) have prevented their use despite numerous benefits. METHODS: In this descriptive review, we critically examine the randomized, active- and placebo-controlled studies, observational trials, and meta-analyses evaluating the CV adverse effects associated with long-term and short-term use of COX-2 selective inhibitors and NS-NSAIDs. The potential mechanisms for these CV effects are also presented. RESULTS: Although the studies evaluating the CV risks have limitations, there appears to be an increased CV risk with both COX-2 selective inhibitors and NS-NSAIDs, particularly in high-risk patients. Therefore, the United States Food and Drug Administration has given a similar "boxed" warning highlighting the potential for increased risk of CV events associated with their use. Nevertheless, there are differences in the CV risks between COX-2 selective inhibitors (e.g., higher CV risk with rofecoxib than celecoxib) as well as differences in the CV risks between individual NS-NSAIDs (e.g., higher CV risks with diclofenac than naproxen). CONCLUSIONS: Until long-term, prospective, randomized, adequately powered, clinical studies in relevant patient populations have been completed, the CV risks associated with the use of NSAIDs, especially in high-risk patients, will likely continue to be controversial. Nevertheless, the benefits of their short-term (e.g., perioperative) use in patients without CV risks probably outweigh their potential CV adverse effects. Finally, careful risk/benefit assessment should be undertaken and both COX-2 selective inhibitors and NS-NSAIDs should be used with caution in patients with CV risk factors.

Pharmacokinetic analysis of rapacuronium and its metabolite during liver transplantation: an assessment of its potential as a pharmacodynamic probe.

The liver extracts aminosteroidal neuromuscular blocking drugs. We hypothesized that the duration of action of these drugs might provide a pharmacodynamic probe for assessing graft function during orthotopic liver transplantation. The pharmacokinetics of rapacuronium and its active metabolite, ORG 9488, were prospectively studied in 11 patients. Rapacuronium (1.5 mg/kg) was administered at induction of anesthesia, 2 minutes after clamping the portal vein, and 5 minutes after reperfusion of the new graft. Blood samples were drawn at intervals, and an independent laboratory analyzed plasma for both rapacuronium and ORG 9488. Rapacuronium's pharmacokinetics were characterized for 3 stages of the transplant using NONMEM software to construct mixed-effects compartmental models. Rapacuronium plasma clearance during the first stage of orthotopic liver transplantation was 7.25 mL/kg/min. Clearance decreased by only 44% during the anhepatic stage, to 3.91 mL/kg/min, and remained decreased after reperfusion. This effect suggests that an alternate clearance pathway exists. The clearance for ORG 9488 was 13.5 mL/kg/min during the paleohepatic and anhepatic stages, but it decreased 83% on reperfusion, suggesting accumulation after reperfusion. This pharmacokinetic analysis suggests that rapacuronium may not be suitable for use as a pharmacodynamic probe.