Anhepatic Phase Of Liver Transplantation Research Articles

Detection of early allograft dysfunction at 30 min of reperfusion in liver transplantation: An intraoperative diagnostic tool with real time assessment of graft function

IntroductionDuring the anhepatic phase of liver transplantation (LT), fibrinolytic activity increases, since the liver clears tissue plasminogen activator (tPA). We hypothesize that patients who fail to reduce fibrinolytic activity following graft reperfusion will have an increased rate of early allograft dysfunction (EAD). MethodsAssessment of fibrinolysis in liver transplant recipients was quantified with thrombelastography (TEG) LY30. Changes in LY30 were assessed after graft reperfusion. The 30-min post-reperfusion LY30 was subtracted from the anhepatic LY30 quantifying fibrinolytic changes (delta-LY30). ResultsSeventy-three primary LT patients were included in the analysis. Receiver operating characteristic curve (ROC) analysis identified an inflection point of delta-LY30–5.3% as a risk factor for EAD. EAD occurred in 44% of these patients compared to 5% in high delta-LY30 (p = 0.002). ConclusionLT recipients that develop hyperfibrinolysis who fail to reduce fibrinolytic activity 30 min after graft reperfusion had an EAD rate 8-fold higher than patients who had a large reduction in LY30 following reperfusion.

Pharmacodynamics of cisatracurium intravenously infused during liver transplantation

Objective To evaluate the pharmacodynamics of cisatracurium intravenously infused during liver transplantation. Methods Twenty American Society of Anesthesiologists physical status Ⅲ or Ⅳ patients of both sexes, aged 18-60 yr, with body mass index of 20-30 kg/m2, scheduled for elective living donor liver transplantation, were enrolled in this study.Total intravenous anesthesia was used.The induction dose of cisatracurium for anesthesia was 0.15 mg/kg.When T1/T0 was restored to 10%, cisatracurium was injected intravenously at an initial rate of 1.5 μg·kg-1·min-1.The infusion rate was adjusted according to the monitoring results of muscle relaxation, and T1/T0 was maintained at 10%.The total amount of cisatracurium infused and infusing time were recorded during dissection phase, anhepatic phase and neohepatic phase, and the consumption of cisatracurium per unit time was calculated.Before skin incision, at 5 and 30 min of anhepatic phase, at 5 and 30 min of neohepatic phase and at the end of operation, the body temperature and stroke volume variation were recorded, blood samples were collected from the radial artery for blood gas analysis and for measurement of blood K+, Mg2+ and Ca2+ concentrations, and blood samples were collected from the internal jugular vein for determination of serum creatinine (Cr), urea nitrogen (BUN) and β2 microspheres protein (β2-MG) concentrations. Results There was no significant difference in the amount of cisatracurium per unit time between dissection phase and anhepatic phase (P>0.05). The amount of cisatracurium per unit time was significantly higher in neohepatic phase than in dissection phase and anhepatic phase (P<0.05). Compared with baseline before skin incision, blood pH value was significantly decreased at 30 min of anhepatic phase and 5 min of neohepatic phase, serum Mg2+ concentrations were decreased at 5 and 30 min of neohepatic phase and at the end of operation, the serum Cr, BUN and β2-MG concentrations were increased, the serum Ca2+ concentration was decreased at 5 min of anhepatic phase, and SVV was increased at 5 and 30 min of anhepatic phase (P< 0.05 or 0.01). Conclusion Muscle relaxation induced by cisatracurium infused intravenously in the anhepatic phase of liver transplantation is weakened. Key words: Atracurium; Liver transplantation; Infusions, intravenous; Dose-response relationship, drug

Postinjury fibrinolysis shutdown: Rationale for selective tranexamic acid.

Moore, Ernest E. MD; Moore, Hunter B. MD; Gonzalez, Eduardo MD; Chapman, Michael P. MD; Hansen, Kirk C. PhD; Sauaia, Angela MD, PhD; Silliman, Christopher C. MD, PhD; Banerjee, Anirban PhD Author Information

Influence of preoperative propranolol on cardiac index during the anhepatic phase of liver transplantation

IntroductionLiver transplantation is the best therapeutic option for end-stage liver disease. Non-selective beta-blocker medications such as propranolol act directly on the cardiovascular system and are often used in the prevention of gastrointestinal bleeding resulting from HP. The effects of propranolol on cardiovascular system of cirrhotic patients during liver transplantation are not known. ObjectiveEvaluate the influence of propranolol used preoperatively on cardiac index during the anhepatic phase of liver transplantation. Method101 adult patients (73 male [72.2%]) who underwent cadaveric donor orthotopic liver transplantation by piggyback technique with preservation of the retrohepatic inferior vena cava performed at Hospital das Clinicas, Federal University of Minas Gerais were evaluated. There was no difference in severity between groups by the MELD system, p=0.70. The preoperative use of propranolol and the cardiac index outcome were compared during the anhepatic phase of liver transplantation in 5 groups (I: increased cardiac index, II: cardiac index reduction lower than 16%, III: cardiac index reduction equal to or greater than 16% and less than 31%, IV: cardiac index reduction equal to or greater than 31% and less than 46%, V: cardiac index reduction equal to or greater than 46%). ResultsPatients in group I (46.4%) who received propranolol preoperatively were statistically similar to groups II (60%), III (72.7%), IV (50%) and V (30.8%), p=0.57. ConclusionThe use of propranolol before transplantation as prophylaxis for gastrointestinal bleeding may be considered safe, as it was not associated with worsening of cardiac index in anhepatic phase of liver transplantation.

Hemodynamics and vasoactive substance levels during renal congestion that occurs in the anhepatic phase of liver transplantation.

To explore hemodynamics and vasoactive substance levels during renal vein congestion that occurs in the anhepatic phase of liver transplantation. New Zealand rabbits received ligation of the hepatic pedicle, supra-hepatic vena cava and infra-hepatic vena cava [anhepatic phase group (APH); n = 8], the renal veins (RVL; n = 8), renal veins and hepatic pedicle [with the inferior vena cava left open) (RVHP; n = 8)], or a sham operation (SOP; n = 8). Hemodynamic parameters (systolic, diastolic, and mean arterial blood pressures) and the levels of serum bradykinin (BK) and angiotensin II (ANGII) were measured at baseline (0 min), and 10 min, 20 min, 30 min, and 45 min after the surgery. Correlation analyses were performed to evaluate the associations between hemodynamic parameters and levels of vasoactive substances. All experimental groups (APH, RVL, and RVHP) showed significant decreases in hemodynamic parameters (systolic, diastolic, and mean arterial blood pressures) compared to baseline levels, as well as compared to the SOP controls (P < 0.05 for all). In contrast, BK levels were significantly increased compared to baseline in the APH, RVL, and RVHP groups at all time points measured (P < 0.05 for all), whereas no change was observed in the SOP controls. There were no significant differences among the experimental groups for any measure at any time point. Further analyses revealed that systolic, diastolic, and mean arterial blood pressures were all negatively correlated with BK levels, and positively correlated with ANGII levels in the APH, RVL, and RVHP groups (P < 0.05 for all). In the anhepatic phase of orthotopic liver transplantation, renal vein congestion significantly impacts hemodynamic parameters, which correlate with serum BK and ANGII levels.

Evaluation of Preoperative Soluble TNF-alpha Receptors 1 and 2 as Predictors of Hemodynamic Outcome Through the Anhepatic Phase of Orthotopic Liver Transplantation.

The purpose of this study was to evaluate the preoperative sTNF-R1 and sTNF-R2 plasma levels in order to identify patients at risk of poor hemodynamic outcome during the anhepatic phase of liver transplantation (LT). One hundred and one adult patients (72.2% males) submitted to orthotopic cadaveric donor LT by the piggyback technique were evaluated. Preoperative sTNF-R1 and sTNF-R2 levels and clinical/surgical data were compared between patients with a favorable outcome (Group I, n=28) and with an unfavorable outcome (Group II, n=73) of the cardiac index (CI) through the anhepatic phase of LT. The characteristics of Groups I and II are displayed on table 1.Table: No Caption available.The sTNF-R1 and sTNF-R2 levels were not different [sTNF-R1 (3902[507-19692])-Group I vs (3539[336-31491])-Group II, p=0.61; sTNF-R2 (4137[1997-13264])-Group I vs (4113[2256-15954])-Group II, p=0.63]. The number of patients taking propranolol preoperatively was similar (Group I = 46.4% vs Group II = 56.2%; p=0.38). The median of sTNF-R1 and sTNF-R2 levels in the non-beta-blocker group was similar to the beta-blocker group - sTNF-R1 (3576[444-31491]) vs (3500[336-11377]) and sTNF-R2 (3862[1997-1594]) vs (4179[2384-10328]). Conclusions: Preoperative sTNF-R1 and sTNF-R2 levels had not been associated with a decrease in CI through the anhepatic phase of LT. Preoperative use of propranolol was not associated with preoperative sTNF-R1 and sTNF-R2 levels and had not been associated with a decrease in CI through the anhepatic phase of LT.

Intravenous Interferon Administered During Liver Transplantation Is Not Effective in Preventing Hepatitis C Reinfection

Post-transplant hepatitis C is a major challenge after liver transplantation (LT). Antiviral therapy is associated with lower efficacy in the post-transplant setting. The purpose of this study was to determine the safety and effect of intravenous interferon (IFN) during the anhepatic phase of LT on hepatitis C viral load. Fifteen consecutive subjects undergoing liver transplant for hepatitis C cirrhosis were enrolled in the study, ten of which received study drug and five subjects served as controls. Cases received weight-based ribavirin and subcutaneous IFN at time of incision followed by intravenous IFN at the start of the anhepatic phase. Adverse events and viral levels were recorded. Repeated measures ANOVA was employed to test for differences over time, between the groups, and time by group interaction. All subjects had genotype 1 virus. Hepatitis C viral load was lower at week 4 in cases compared to controls (769,004 ± 924,082 IU/ml and 2,329,896 ± 3,731,749 IU/ml, respectively), but did not reach statistical significance (p = 0.50). Three subjects developed adverse events related to IFN including pulmonary edema, rejection, and neutropenia. Intravenous IFN administered during the anhepatic phase of liver transplant did not prevent graft reinfection and was associated with manageable adverse events. This regimen could be further studied if direct acting antiviral agents alone are insufficient for treating post-transplant hepatitis C.

One Year Follow-Up with Histology of HCV Liver Transplant Recipients who Received IV Interferon During the Anhepatic Phase of Transplant - A Controlled Pilot Study

Purpose: Post transplant recurrent Hepatitis C continues to be a challenge after liver transplantation (LT). Primary aim of this pilot study was to determine the safety of IV Interferon (IFN) & Ribavirin (RBV) administered during anhepatic phase of LT & determine their effect on HCV RNA. Secondary aims included histologic response at 48 weeks post-transplant. Methods: 15 consecutive subjects undergoing LT for HCV cirrhosis were enrolled {10 cases (received IFN), 5- controls}. All cases received RBV 1000/1200 mg PO on call to OR, 5 MU IFN α-2b SQ at time of incision & 5 MU IFN α-2b IV at start of the anhepatic phase. Adverse events within 48 weeks post LT were recorded. HCV RNA levels were obtained pre-transplant, before & after anhepatic phase, at 12, 24, 48 & 96 hrs & at week 4, 8, 12, 24 & 48 post LT. IL28B status was recorded. All subjects underwent protocol liver biopsy at 48 weeks. Immunosuppression was protocol based and all but 2 received tacrolimus. Repeated Measures ANOVA was employed to test for differences over time, between the groups, and time by group interaction. Results: All but 1 subject were male & mean age was 51 years. All had genotype 1 virus & mean MELD of study group was 18 + 6.2 (no significant difference between cases & controls). IL28B differed significantly between the 2 groups (cases - 5 CT, 2 CC, 1 TT, 1 not available; controls - 3 TT, 1 CT, 1 not available, p<0.05). We previously reported the regimen to be safe with easily manageable adverse events (n=3 subjects) and a trend for lower HCV RNA at week 4 among cases compared to controls (p >0.07; ACG 2012 # S132). There was no significant difference in Hgb, ANC, creatinine, ALT and length of stay post LT between the 2 groups. We now report follow-up 48 week data on our primary and secondary end-points. No additional adverse events were observed. The trend towards lower HCV RNA observed at week 4 among cases was lost at week 48 [HCV RNA was similar among cases and controls at 48 weeks post LT (5,866,398 + 9,441,240 vs. 5,216,657 + 4,968,923 respectively); p>0.05]. No significant difference was observed in histologic stage/grade at 48 weeks [data available in all but 2 subjects (1 case and 1 control)] between the 2 groups- all controls- stage 0 fibrosis; cases: Five- no fibrosis, One- stage 1 fibrosis, Three- stage 2 fibrosis. Conclusion: This pilot study suggests that IV IFN administered during the anhepatic phase of LT appears to be safe. There was a trend towards lower HCV RNA at week 4 post-LT among cases, although no significant virologic/ histologic effect was noted at 48 weeks. This limited data support further study of this novel approach for preventing recurrent post-LT HCV, possibly involving direct acting antiviral agents in select IL28B sub-groups.

Management of Hepatitis C Virus Infection in Liver Transplantation with Adacolumn Apheresis

Recurrent hepatitis C virus (HCV) is a major cause of liver transplant loss, hepatic failure, and retransplantation need. Posttransplantation antiviral therapy in patients with evidence of recurrent disease is the mainstay of management. Although HCV is a hepatocellular pathogen, there is increasing evidence that the virus can infect and persist in other cells. In particular, granulocytes and monocytes/macrophages are known to constitute extrahepatic sites for HCV replication and dissemination. The aim of this study was to apply Adacolumn apheresis as a possible therapeutic alternative to conventional drug therapy to manage HCV infections. Seven patients who underwent liver transplantation for HCV-related cirrhosis were eligible for the study. The patients underwent 5 1-hour sessions for 5 consecutive days. The first treatment was performed in the anhepatic phase of liver transplantation with the intent to early reduce infected granulocytes and monocytes/macrophages. The patients were evaluated over the 5 days after inclusion with 3- and 6-months follow-ups. Early apheresis treatments in the anhepatic phase and over the following 4 days after transplantation produced low viral loads in 4 patients, negative viral loads in 2 patients, and increased viremia in 1 patient. At follow-up, the viremia load was stable in 6 patients without increased transaminase levels. At the end of the treatment cycle, almost all immune cells of the 6 patients maintained CD4+/CD8+ T-cell ratios. The optimal timing of treatment initiation is unknown, but early preemptive therapy is recommended to decrease the risk for recurrent infection. Although this study investigated the responses among a small number of patients, it documented that the Adacolumn changed cellular immunity, promoting early virologic responses.

A Controlled Pilot Study of Interferon and Ribavirin During the Anhepatic Phase of Liver Transplantation for Prevention of Recurrent Hepatitis C

A Controlled Pilot Study of Interferon and Ribavirin During the Anhepatic Phase of Liver Transplantation for Prevention of Recurrent Hepatitis C

Utility of uncalibrated femoral stroke volume variation as a predictor of fluid responsiveness during the anhepatic phase of liver transplantation

We evaluated the value of the stroke volume variation (SVV) calculated with the Vigileo monitor, which recently has been increasingly advocated for fluid management, as a predictor of fluid responsiveness during the anhepatic phase of liver transplantation (LT). We also compared SVV to the central venous pressure (CVP) and pulmonary arterial occlusion pressure (PAOP) in patients. Thirty-three adult recipients scheduled for elective living donor LT were enrolled in this study. Twenty minutes after the start of the anhepatic phase, the CVP, PAOP, approximate inferior vena caval pressure, femoral SVV, and cardiac output values were measured before and 12 minutes after fluid loading. Fluid loading was performed with a 6% hydroxyethyl starch solution (10 mL/kg). The responders were defined as patients whose cardiac index increased ≥ 15% after fluid loading. Receiver operating characteristic (ROC) analysis showed that only femoral SVV (area under the curve = 0.894, P = 0.0001) could be used to predict fluid responsiveness during the anhepatic phase of LT. The area under the ROC curve for femoral SVV was 0.894 (P = 0.0001), and it was significantly larger than those for CVP (area under the curve = 0.576, P = 0.004) and PAOP (area under the curve = 0.670, P = 0.021). Femoral SVV >8% identified the responders with a sensitivity of 89% and a specificity of 80%. Our results suggest that femoral SVV derived with the Vigileo monitor would be useful for fluid management during the anhepatic phase in LT recipients.

Intraoperative pH Values After N-acetylcysteine Administration During Liver Transplantation

We investigated whether intraoperative administration of N-acetylcysteine (NAC) to liver transplant recipients affected pH values. This prospective, randomized, double-blind clinical trial included liver transplant recipients who were randomly assigned to NAC-treated (n = 25) or placebo (n = 25) groups. The NAC-treated group received 100 mg/kg dissolved in 5% dextrose over 15 minutes during the anhepatic phase, followed by a continuous infusion of 50 mg/kg in 5% dextrose during the next 24 hours. The placebo group received equal amounts of 5% dextrose solution during the same times. Peripheral blood samples were drawn in Ca 2+-80 IU–containing syringes after induction of anesthesia (I-1), at 15 minutes into the anhepatic phase (I-2) prior to the administration of NAC or placebo, at 5 minutes before reperfusion (I-3), at 5 minutes after reperfusion (I-4), at 20 minutes after reperfusion (I-5), at 60 minutes after reperfusion (I-6), and at 1 hour after completion of the procedure (I-7). pH levels, which were determined using a radiometer ABL77 (Copenhagen, Denmark), were significantly lower among the NAC than the placebo group at I-4 ( P = .027) and I-5 ( P = .031). An early decrease in pH values was detected in the NAC-treated group at 5 minutes before reperfusion (I-3; P = .051). We concluded that intraoperative NAC administration during the anhepatic phase of liver transplantation significantly decreased recipient pH values at 5 and 20 minutes after reperfusion, a decrease that was detected at 5 minutes before reperfusion (I-3). The decrease seemed to be associated with NAC metabolism.

Effect of N-Acetylcysteine Administration on Intraoperative Plasma Levels of Interleukin-4 and Interleukin-10 in Liver Transplant Recipients

We investigated whether intraoperative administration of N-acetylcysteine (NAC) in liver transplant recipients ameliorated their inflammatory responses by increasing intraoperative plasma levels of interleukin (IL)-4 and IL-10. This prospective, randomized, double-blind clinical trial included liver transplant recipients randomly assigned to the NAC-treated (n = 25) or the placebo (n = 25) group. The NAC-treated group received 100 mg/kg dissolved in 5% dextrose over 15 minutes during the anhepatic phase, followed by a continuous infusion of 50 mg/kg in 5% dextrose over the next 24 hours, whereas the placebo group received equal amounts of 5% dextrose solution during the same time. Peripheral blood samples were drawn in EDTA-containing tubes after induction of anesthesia (I-1); at 15 minutes into the anhepatic phase (I-2) prior to the administration of NAC or placebo; at 5 minutes before reperfusion (I-3); at 10 minutes after reperfusion (I-4); at 20 minutes after reperfusion (I-5); at 60 minutes after reperfusion (I-6); and at 1 hour after completion of the liver transplantation (I-7). Cytokine levels were determined using a technique which combined enzyme-linked immunosorbent assay (ELISA) and flow cytometry. Plasma IL-4 levels were significantly higher among the NAC-treated group than the placebo group at I-3 ( P = .046) and I-4 ( P = .041). Plasma IL-10 levels showed significant enhancement in the NAC-treated group at 5 minutes before reperfusion (I-3; P = .007). We concluded that intraoperative NAC administration during the anhepatic phase of liver transplantation significantly increased recipient IL-4 plasma levels before and after reperfusion, and IL-10 plasma values before reperfusion (I-3). These enhancements seemed to be associated with a protective effect against reperfusion injury.

Temporary portocaval shunt in orthotopic liver transplantation: Need for a standardized approach?

Maintenance of portal and systemic venous return during the anhepatic phase of liver transplantation (LT) improves hemodynamic stability. With the piggyback technique, caval return is maintained; however, temporary clamping of the portal vein is still necessary. The use of a temporary portocaval shunt (TPCS) has been proposed to minimize the effect of portal venous interruption. The aim of this study was to perform a systematic review of the literature to determine whether there is evidence to support the routine use of a TPCS in LT. An electronic search of the literature from 1963 to 2007 was performed. A total of 4386 articles were identified, of which 8 met all the criteria and were included in the study. Because of the variability in reporting and the small number of studies, statistical comparison was not possible; however, a trend toward a shorter operative time, less blood product transfusion, and maintenance of higher mean arterial pressures during portal vein clamping was seen in patients with a TPCS. In conclusion, the available evidence, albeit scarce, supports the use of a TPCS in patients undergoing LT. A prospective randomized study of patients most likely to benefit from a TPCS is necessary to substantiate these findings.

Perioperative viral kinetics: New insights or the Emperor's new clothes?

Perioperative viral kinetics: New insights or the Emperor's new clothes?

Methods of measuring metabolism during surgery in humans: focus on the liver-brain relationship.

The purpose of this work is to review recent advances in setting methods and models for measuring metabolism during surgery in humans. Surgery, especially solid organ transplantation, may offer unique experimental models in which it is ethically acceptable to gain information on difficult problems of amino acid and protein metabolism. Two areas are reviewed: the metabolic study of the anhepatic phase during liver transplantation and brain microdialysis during cerebral surgery. The first model offers an innovative approach to understand the relative role of liver and extrahepatic organs in gluconeogenesis, and to evaluate whether other organs can perform functions believed to be exclusively or almost exclusively performed by the liver. The second model offers an insight to intracerebral metabolism that is closely bound to that of the liver. The recent advances in metabolic research during surgery provide knowledge immediately useful for perioperative patient management and for a better control of surgical stress. The studies during the anhepatic phase of liver transplantation have showed that gluconeogenesis and glutamine metabolism are very active processes outside the liver. One of the critical organs for extrahepatic glutamine metabolism is the brain. Microdialysis studies helped to prove that in humans there is an intense trafficking of glutamine, glutamate and alanine among neurons and astrocytes. This delicate network is influenced by systemic amino acid metabolism. The metabolic dialogue between the liver and the brain is beginning to be understood in this light in order to explain the metabolic events of brain damage during liver failure.

Liver biopsy, viral kinetics, and the impact of viremia on severity of hepatitis C virus recurrence

1. Nearly all recipients who are chronically infected with hepatitis C virus (HCV) at the time of liver transplantation will have HCV RNA detectable postoperatively. 2. HCV replication can begin as early as the first postoperative week. 3. HCV levels fall significantly during the anhepatic phase of liver transplantation and continue to fall during the first 12-24 hours posttransplantation. 4. Serum HCV RNA levels typically increase rapidly from the second week posttransplantation and peak by the fourth postoperative month. HCV RNA levels at one year posttransplantation are 10-20 fold greater than pretransplant levels. 5. Corticosteroid treatment for acute cellular rejection is associated with large increases in HCV RNA levels. 6. HCV RNA levels do not appear to vary with choice of calcineurin inhibitor. 7. Early HCV RNA levels are predictive of subsequent histological severity of recurrence. 8. A correlation between early levels of viremia and subsequent allograft injury suggests that initiation of antiviral therapy early in the posttransplant course might be desirable.

Amino acid kinetics during the anhepatic phase of liver transplantation.

Alanine and glutamine are interorgan nitrogen/carbon carriers for ureagenesis and gluconeogenesis, which are mainly but not necessarily only hepatic. The liver is central to alanine and glutamine metabolism, but most organs can produce and use them. We studied amino acid kinetics after liver removal to depict initial events of liver failure and to provide a model to study extrahepatic gluconeogenesis and nitrogen disposal in humans. We measured amino acid kinetics with [5,5,5-(2)H(3)]leucine and [3-(13)C]alanine or [1,2-(13)C(2)]glutamine tracers in 21 subjects during and after the anhepatic phase of liver transplantation: 12 were at 7 months posttransplantation, and 7 were healthy control subjects. Anhepatic leucine kinetics, including proteolysis, was unchanged. Alanine plasma and whole-body contents increased 3x and 2x, with a halved metabolic clearance and a doubled production, 2% greater than disposal. Free whole-body glutamine decreased 25% but increased 50% in plasma. Glutamine clearance was halved, and the production decreased by 25%, still 2% greater than disposal. Liver replacement decreased alanine and glutamine concentrations, leaving leucine unchanged. Liver removal caused doubled alanine fluxes, minor changes in glutamine, and no changes in leucine. The initial events after liver removal are an accumulation of three-carbon compounds, an acceleration of alanine turnover, and limited nitrogen storage in alanine and glutamine.

141Non-hepatic glucose production in humans during the anhepatic phase of liver transplantation

141Non-hepatic glucose production in humans during the anhepatic phase of liver transplantation

Renal glucose production compensates for the liver during the anhepatic phase of liver transplantation.

The extent of the renal contribution to postabsorptive endogenous glucose production (EGP) in humans is controversial. We measured EGP in the absence of the liver during the anhepatic phase (AH) of liver transplantation in five patients (aged 46.4+/-10.2 years, two women). Stable labeling of plasma glucose (PG) was achieved for a 2-h period before the AH by primed continuous infusion of di-deuterated 6,6[2H2]glucose (1.7 mg/min) and continued throughout the AH. PG was maintained above the fasting level (6.1+/-2.73 mmol/l) with 5% dextrose labeled with 6,6[2H2]glucose throughout the AH (mean level during the AH 0.98+/-0.45 mg x kg(-1) x min(-1)). Isotopic enrichment remained stable at 0.84+/-0.21% atom percent excess throughout. EGP, calculated by use of a modified Steele equation, decreased from 2.6+/-1.24 at baseline to 0.97+/-0.9 mg x kg(-1) x min(-1) (36% baseline, P = 0.045) but recovered at approximately 30 min to reach 1.38+/-0.83 mg x kg(-1) x min(-1) (54% baseline) by 60 min. Epinephrine, lactate, free fatty acid, and glycerol levels increased significantly (0.79+/-0.74 to 3.65+/-2.1 nmol/l, P = 0.005; 1.88+/-0.43 to 3.46+/-0.9 mmol/l, P = 0.024; 543.9+/-215.5 to 705.5+/-219.2 micromol/l, P = 0.012; 75.6+/-30.2 to 139+/-96.3 micromol/l, P = 0.003, respectively). These data show that postabsorptive nonhepatic glucose production in humans may contribute to greater than one-third of overall EGP, increasing when required, and that it is associated with a stress response and increased gluconeogenic substrate availability. We conclude that extrahepatic tissues, most notably those of the kidney, make a significant contribution to EGP in humans.