Modeling adult COX-2 cerebrospinal fluid pharmacokinetics to inform pediatric investigation.

AIM: Hysteresis is reported between plasma concentration and analgesic effect from nonsteroidal anti-inflammatory drugs. It is possible that the temporal delay between plasma and CSF nonsteroidal anti-inflammatory drugs mirrors this hysteresis. The temporal relationship between plasma and CSF concentrations of COX-inhibitors (celecoxib, rofecoxib, valdecoxib) has been described. The purpose of this secondary data analysis was to develop a compartmental model for plasma and CSF disposition of these COX-2 inhibitors. METHODS: Plasma and CSF concentration-time profiles and protein binding data in 10 adult volunteers given oral celecoxib 200 mg, valdecoxib 40 mg and rofecoxib 50 mg were available for study. Nonlinear mixed effects models with a single plasma compartment were used to link a single CSF compartment with a transfer factor and an equilibration rate constant (Keq). To enable predictive modeling in pediatrics, celecoxib pharmacokinetics were standardized using allometry. RESULTS: Movement of all three unbound plasma COX-2 drugs into CSF was characterized by a common equilibration half-time (T1/2 keq) of 0.84 h. Influx was faster than efflux and a transfer scaling factor of 2.01 was required to describe conditions at steady-state. Estimated celecoxib clearance was 49 (95% CI 34-80) L/h/70 kg and the volume of distribution was 346 (95% CI 237-468) L/70 kg. The celecoxib absorption half-time was 0.35 h with a lag time of 0.62 h. Simulations predicted a 70-kg adult given oral celecoxib 200 mg with maintenance 100 mg twice daily would have a mean steady-state total (bound and unbound) plasma concentration of 174 µg L-1 and CSF concentration of 1.1 µg L-1 . A child (e.g., 25 kg, typically 7 years) given oral celecoxib 6 mg kg-1 with maintenance of 3 mg kg-1 twice daily would have 282 and 1.7 µg L-1 mean plasma and CSF concentrations, respectively. CONCLUSIONS: Transfer of unbound COX-2 inhibitors from plasma to CSF compartment can be described with a delayed effect model using an equilibration rate constant to collapse observed hysteresis. An additional transfer factor was required to account for passage across the blood-brain barrier. Use of a target concentration strategy for dose and consequent plasma (total and unbound) and CSF concentration prediction could be used to inform pediatric clinical studies.

Enhanced Recovery via Peripheral Nerve Block for Open Hepatectomy.

BACKGROUND: Enhanced recovery after surgery (ERAS) protocols are now commonplace in many fields of surgery, but only limited data exists for their use in hepatobiliary surgery. We implemented standardized ERAS protocols for all open hepatectomies and replaced thoracic epidurals with a transversus abdominis plane (TAP) block. METHODS: We performed a retrospective cohort study of all patients undergoing open hepatectomy during the 14 months before and 19 months after implementation of an ERAS protocol at our institution (January 2014-September 2016). Trained abstractors reviewed charts for patient demographics, perioperative details, and healthcare utilization. All nursing-reported visual analog scale pain scores were sampled to identify patients with uncontrolled pain (daily mean score > 5). Outcomes included length of stay (LOS), costs, and 30-day readmission. RESULTS: A total of 127 patients (mean age 54.6 ± 13.0 years, 44% female) underwent open liver resection (69 [54%] after ERAS implementation). ERAS protocols were associated with significantly lower rates of ICU admission (47 vs. 13%, p < 0.001), shorter LOS (median 5.3 vs. 4.3 days, p = 0.007), and lower median costs ($3566 less, p = 0.03). Readmission remained low throughout the study period (5% pre-ERAS, 4% during ERAS, p = 0.83). Rates of uncontrolled pain were either the same or better after ERAS implementation through post-operative day #3 (41% pre-ERAS, 23% during ERAS, p = 0.03). DISCUSSION: The use of TAP block for hepatectomy as part of an ERAS protocol is associated with improved quality and cost of care. Surgeons performing liver resections should consider standardization of evidence-based best practices in all patients.

Surgical management of hepatocellular carcinoma after Fontan procedure.

The Fontan operation has successfully prolonged the lives of patients born with single-ventricle physiology. A long-term consequence of post-Fontan elevation in systemic venous pressure and low cardiac output is chronic liver inflammation and cirrhosis, which lead to an increased risk of hepatocellular carcinoma (HCC). Surgical management of patients with post-Fontan physiology and HCC is challenging, as the requirement for adequate preload in order to sustain cardiac output conflicts with the low central venous pressure (CVP) that minimizes blood loss during hepatectomy. Consequently, liver resection is rarely performed, and most reports describe nonsurgical treatments for locoregional control of the tumors in these patients. Here, we present a multidisciplinary approach to a successful surgical resection of a HCC in a patient with Fontan physiology.

A randomized clinical trial testing the anti-inflammatory effects of preemptive inhaled nitric oxide in human liver transplantation.

Decreases in endothelial nitric oxide synthase derived nitric oxide (NO) production during liver transplantation promotes injury. We hypothesized that preemptive inhaled NO (iNO) would improve allograft function (primary) and reduce complications post-transplantation (secondary). Patients at two university centers (Center A and B) were randomized to receive placebo (n = 20/center) or iNO (80 ppm, n = 20/center) during the operative phase of liver transplantation. Data were analyzed at set intervals for up to 9-months post-transplantation and compared between groups. Patient characteristics and outcomes were examined with the Mann-Whitney U test, Student t-test, logistic regression, repeated measures ANOVA, and Cox proportional hazards models. Combined and site stratified analyses were performed. MELD scores were significantly higher at Center B (22.5 vs. 19.5, p<0.0001), surgical times were greater at Center B (7.7 vs. 4.5 hrs, p<0.001) and warm ischemia times were greater at Center B (95.4 vs. 69.7 min, p<0.0001). No adverse metabolic or hematologic effects from iNO occurred. iNO enhanced allograft function indexed by liver function tests (Center B, p<0.05; and p<0.03 for ALT with center data combined) and reduced complications at 9-months (Center A and B, p = 0.0062, OR = 0.15, 95% CI (0.04, 0.59)). ICU (p = 0.47) and hospital length of stay (p = 0.49) were not decreased. iNO increased concentrations of nitrate (p<0.001), nitrite (p<0.001) and nitrosylhemoglobin (p<0.001), with nitrite being postulated as a protective mechanism. Mean costs of iNO were $1,020 per transplant. iNO was safe and improved allograft function at one center and trended toward improving allograft function at the other. ClinicalTrials.gov with registry number 00582010 and the following URL:http://clinicaltrials.gov/show/NCT00582010.

Treatment of severe lactic acidosis during the pre-anhepatic stage of liver transplant surgery with intraoperative hemodialysis.

Severe uncompensated lactic acidosis manifesting during the pre-anhepatic stage of orthotopic liver transplant surgery is an uncommon event, but it poses serious concern because of the additional lactate production and impaired elimination by the liver that develops during the anhepatic and allograft reperfusion stages of the procedure. A man with end-stage liver disease secondary to hepatitis C and hemochromatosis and normal renal function, who developed severe lactic acidosis in the pre-anhepatic stage of liver transplantation, was treated successfully with intraoperative, continuous venovenous hemodialysis. Hemodialysis effectively corrected the patient's lactic acidosis and removed lactate, which contributed to hemodynamic stability during the anhepatic and graft reperfusion stages of his liver transplant surgery.

Drug management in emergent liver transplantation of mitochondrial disorder carriers: review of the literature.

BACKGROUND: Mitochondrial respiratory-chain disorders (MRCD) lead to progressive disabling of neurological and cellular conditions that involve muscles, brain, kidney, and liver dysfunction. Affected individuals may need surgery, including orthotopic liver transplantation (OLT). Surgery poses anesthesia challenges because of the prolonged use of anesthetic drugs and sedatives, which may inhibit oxidative phosphorylation, mimic mitochondrial cytopathic disorders, or unveil them ex novo. MATERIALS AND METHODS: We conducted a multilingual PubMed search of surgical and non-surgical anesthesia reports between the years 1992 and 2008, where anesthetic drugs were used in MRCD patients, especially for those undergoing urgent OLTs. RESULTS: There were 51 case reports of 210 anesthesia and critical care interventions in patients with MRCD, a large part of them were children. Data pertaining to the safe usage of anesthesia and perioperative drugs were limited and conflicting. We found no article that addressed the issue of perioperative handling of urgent OLT in MRCD patients. We therefore suggest our own - although limited - experience for such occasions. CONCLUSION: There are no randomized, controlled, trial-based indications regarding safe anesthetic drugs to be used perioperatively in MRCD carriers. Consultation among geneticists, anesthesiologists, intensivists, and surgeons is essential in patients with known/suspected metabolic syndrome for planning appropriate perioperative care.

Anesthetic implications of the new anticoagulant and antiplatelet drugs.

In this review, we discuss the anesthetic implications of the new anticoagulant and antiplatelet drugs, focusing our discussion mainly on neuroaxial/regional anesthesia and central catheter placement issues. We offer practical recommendations for their use.

Central nervous system concentrations of cyclooxygenase-2 inhibitors in humans.

BACKGROUND: Cyclooxygenase-2 (COX-2)-selective inhibitors (coxibs) are under investigation for the potential therapy, attenuation, or prevention of neuroinflammatory and neurodegenerative disorders. Coxibs are also a significant advance in pain therapy and are traditionally considered to achieve analgesia via peripheral effects. However, in animals, central nervous system (CNS) COX-2 activity and prostanoid concentrations are increased by peripheral inflammation, central sensitization has been proposed to account for long-term pain-related phenomena, and coxibs achieve significant cerebrospinal fluid (CSF) concentrations and may cause analgesia via CNS action. Nevertheless, it remains unknown whether or which coxibs reach the CNS in humans. This investigation determined whether coxibs can reach the CNS in humans, based on CSF concentrations. METHODS: Ten healthy human volunteers simultaneously received a single oral dose of celecoxib (200 mg), rofecoxib (50 mg), and valdecoxib (40 mg). Blood and CSF were serially sampled for 10 h, and plasma total and unbound and CSF coxib concentrations were quantified by mass spectrometry. RESULTS: Total plasma concentrations and time to maximum plasma concentration were similar among the three coxibs. In contrast, unbound (free) plasma concentrations differed significantly. Maximum unbound plasma concentrations were 1.4 +/- 0.5, 42 +/- 17, and 6.0 +/- 2.9 ng/ml, respectively, for celecoxib, rofecoxib, and valdecoxib. COX-2 inhibitors rapidly penetrated the CNS. Maximum CSF concentrations were 2 +/- 2, 57 +/- 25, and 10 +/- 4 ng/ml, respectively, for celecoxib, rofecoxib, and valdecoxib. CSF concentrations exceeding the median inhibitory concentration for COX-2 were achieved by rofecoxib and valdecoxib but not celecoxib. CONCLUSIONS: These results show that coxibs do reach the CNS in humans, with rapid penetration, and in concentrations apparently sufficient to inhibit COX-2 activity. There were significant differences among coxibs in CSF penetration. Unbound (free) plasma coxib concentration was the major determinant of CSF concentration. This supports the hypothesis that coxibs may act, in part, in the human CNS, provide important new information on the mechanism and treatment of pain and may guide coxib selection for therapeutic trials when CNS penetration is desirable.