Luc Frenette

Inhaled NO accelerates restoration of liver function in adults following orthotopic liver transplantation

Ischemia/reperfusion (IR) injury in transplanted livers contributes to organ dysfunction and failure and is characterized in part by loss of NO bioavailability. Inhalation of NO is nontoxic and at high concentrations (80 ppm) inhibits IR injury in extrapulmonary tissues. In this prospective, blinded, placebo-controlled study, we evaluated the hypothesis that administration of inhaled NO (iNO; 80 ppm) to patients undergoing orthotopic liver transplantation inhibits hepatic IR injury, resulting in improved liver function. Patients were randomized to receive either placebo or iNO (n = 10 per group) during the operative period only. When results were adjusted for cold ischemia time and sex, iNO significantly decreased hospital length of stay, and evaluation of serum transaminases (alanine transaminase, aspartate aminotransferase) and coagulation times (prothrombin time, partial thromboplastin time) indicated that iNO improved the rate at which liver function was restored after transplantation. iNO did not significantly affect changes in inflammatory markers in liver tissue 1 hour after reperfusion but significantly lowered hepatocyte apoptosis. Evaluation of circulating NO metabolites indicated that the most likely candidate transducer of extrapulmonary effects of iNO was nitrite. In summary, this study supports the clinical use of iNO as an extrapulmonary therapeutic to improve organ function following transplantation.

Tacrolimus (FK506) and mycophenolate mofetil combination therapy versus tacrolimus in adult liver transplantation

BACKGROUND Mycophenolate mofetil (MMF) prolongs allograft survival in experimental animals, prevents acute rejection in humans, and has recently been approved for use in renal transplantation in combination with cyclosporine. Tacrolimus (Prograf) has been shown to be effective for the prevention and treatment of allograft rejection in liver transplantation. However, there has been limited experience with the combination of tacrolimus and MMF in liver transplantation. METHODS This retrospective pilot study examined the results in 130 primary, consecutive, adult liver transplants under two separate immunosuppressive protocols. Patients in the study group received MMF (1 g p.o. b.i.d.), tacrolimus (0.1 mg/kg p.o. b.i.d.), and a standard steroid taper. MMF was also tapered and then discontinued within 3 months of transplantation. A historical control received tacrolimus (0.15 mg/kg p.o. b.i.d.) and the same steroid taper. RESULTS Pretransplant demographics, including creatinine, were not significantly different between the groups. The 6-month patient and graft survivals of 96.3% (control) versus 92.0% (study) were not significantly different. The incidence of acute rejection was 45.0% in the control group versus 26.0% in the study group (P = 0.03). The study group had a lower incidence of rejection (mean episodes/patient +/- SEM): 0.28+/-0.07 vs. 0.61+/-0.10 (P = 0.007). All of the study group members responded to high-dose steroids. In the control group, three patients required monoclonal antibody therapy and two patients required the addition of MMF. The incidence of cytomegalovirus was similar in the study group and the control group (13.8% vs. 10.0%, P = NS). Early renal function was better preserved in the tacrolimus/MMF group (mean creatinine +/- SEM): 1.09 mg/dl +/- 0.05 vs. 1.51 mg/dl +/- 0.08 at 30 days, P = 0.0001. The study design required dosing with less tacrolimus (mean mg/day +/- SEM), which was achieved at 1 week (23.2+/-0.7 vs. 13.5+/-0.5); 1 month (18.7+/-0.8 vs. 11.4+/-0.5); 3 months (14.5+/-0.6 vs. 9+/-0.5); and 6 months (11.6+/-0.6 vs. 8.2+/-0.6); P = 0.0001, for all time points. CONCLUSION Combination therapy with tacrolimus and MMF may significantly reduce the incidence of acute liver allograft rejection, allow a significant reduction in tacrolimus dosage, and decrease the incidence of nephrotoxicity. Long-term analysis will be necessary to assess any increased risk of opportunistic infections.

Conjugated estrogen reduces transfusion and coagulation factor requirements in orthotopic liver transplantation.

We conducted a prospective, randomized study to determine the efficacy of conjugated estrogen in reducing blood product transfusion during orthotopic liver transplantation (OLT).Patients undergoing OLT were included in the study. Only those having a reaction time of more than 30 mm or 15 min (19-28 mm) on computed thromboelastography (CTEG) at the beginning of surgery were enrolled in the study. Patients were randomized to receive either conjugated estrogen (CE) or placebo. Every patient received a first dose of CE (100 mg IV) (20 mL) or placebo (20 mL of isotonic sodium chloride solution) at the beginning of the procedure and a second dose of CE (100 mg IV) or 20 mL of placebo (20 mL of isotonic sodium chloride solution) just after reperfusion of the new graft. The two groups were similar in age, weight, requirement for veno-veno bypass, time on veno-veno bypass, CTEG measurement, and preoperative hemoglobin and platelet values. Blood products were given in relation to hematocrit and coagulation (CTEG) variables, which were measured every hour during the surgery. The amount of transfused blood products did not differ in terms of units of cryoprecipitate, but the intraoperative requirements for red blood cells (6 +/- 3 vs 9 +/- 6 U; P = 0.05), platelets (12 +/- 8 U vs 18 +/- 10 U; P = 0.05) and fresh-frozen plasma (3 +/- 3 U vs 6 +/- 4 U; P = 0.001) was significantly less in the estrogen group than in the control group. We conclude that CE is associated with a significant decrease in use of fresh-frozen plasma, platelets, and red blood cells during OLT. Implications: In this study, we prospectively investigated whether IV conjugated estrogen could decrease blood product transfusion during orthotopic liver transplantation. Conjugated estrogen-treated patients received less fresh-frozen plasma, red blood cells, and platelets. In this population of patients, conjugated estrogen can be a useful addition in coagulation management during orthotopic liver transplantation. (Anesth Analg 1998;86:1183-6)

A comparison of alfentanil, esmolol, lidocaine, and thiopental sodium on the hemodynamic response to insertion of headrest skull pins

STUDY OBJECTIVES To compare the effects of four techniques for preventing or blunting the hypertensive response to the insertion of Mayfield headrest skull pins: intravenous (IV) alfentanil (ALF), esmolol (ESM), thiopental sodium (TPL), and local anesthesia using plain lidocaine (Xylocaine; XYL). DESIGN Randomized open study. PATIENTS 40 adult patients undergoing intracranial or spinal surgery requiring the use of Mayfield headrest skull pins for head positioning and immobilization. INTERVENTIONS 20 minutes after anesthetic induction, and 2 to 3 minutes prior to the insertion of headrest skull pins, one of three drugs was administered IV: ALF 10 mcg/kg, ESM 1 mg/kg, or TPL 1.5 mg/kg. The fourth drug, XYL, was administered by injection into the scalp. MEASUREMENTS AND MAIN RESULTS Blood pressure and heart rate (HR) were recorded immediately prior to and after pin insertion with balanced general anesthesia, and at 30, 60, 120, and 180-second intervals after pin insertion. The measurements were compared with the immediate preinsertion values. In the ALF and XYL groups, there was no significant increase in mean arterial pressure (MAP) or HR for any of the measurement periods. MAP was elevated immediately on pin insertion and for up to 2 minutes in the TPL group, and for up to 3 minutes in the ESM group (p < 0.05). HR changes were seen in the TPL group for up to one minute (p < 0.05). Increases in systolic blood pressure were seen in the TPL and ESM groups for up to 3 minutes, and in diastolic blood pressure for up to 2 minutes (p < 0.05). No other significant changes were observed. CONCLUSIONS IV ALF and local injection of XYL in the scalp prevent the hemodynamic response to the insertion of skull pins in anesthetized patients. Neither ESM nor TPL prevented the hypertensive response. Local anesthetic injection into the scalp requires coordination between the anesthesiologist and surgeon, it carries the risk of needle stick injury, and it must be repeated if the surgeon repositions the headrest. The rapid onset and short half-life of ALF, coupled with the absence of hemodynamic effects at the dose used, makes this drug an alternative to the use of XYL injection.