Moderate hypothermia in patients with acute liver failure and uncontrolled intracranial hypertension
2004; Elsevier BV; Volume: 127; Issue: 5 Linguagem: Inglês
10.1053/j.gastro.2004.08.005
ISSN1528-0012
AutoresRajiv Jalan, Steven W.M. Olde Damink, Nicolaas E.P. Deutz, Peter C. Hayes, Alistair Lee,
Tópico(s)Thermal Regulation in Medicine
ResumoBackground & Aims: About 20% of patients with acute liver failure (ALF) die from increased intracranial pressure (ICP) while awaiting transplantation. This study evaluates the clinical effects and pathophysiologic basis of hypothermia in patients with ALF and intracranial hypertension that is unresponsive to standard medical therapy. Methods: Fourteen patients with ALF who were awaiting orthotopic liver transplantation (OLT) and had increased ICP that was unresponsive to standard medical therapy were studied. Core temperature was reduced to 32°C–33°C using cooling blankets. Results: Thirteen patients were successfully bridged to OLT with a median of 32 hours (range, 10–118 hours) of cooling. They underwent OLT with no significant complications related to cooling either before or after OLT and had complete neurologic recovery. ICP before cooling was 36.5 ± 2.7 mm Hg and was reduced to 16.3 ± .7 mm Hg at 4 hours, which was sustained at 24 hours (16.8 ± 1.5 mm Hg) (P < .0001). Mean arterial pressure and cerebral perfusion pressure increased significantly, and the requirement for inotropes was reduced significantly. Hypothermia produced sustained and significant reduction in arterial ammonia concentration and its brain metabolism, cerebral blood flow, brain cytokine production, and markers of oxidative stress. Conclusions: Moderate hypothermia is an effective and safe bridge to OLT in patients with ALF who have increased ICP that is resistant to standard medical therapy. Hypothermia reduces ICP by impacting on multiple pathophysiologic mechanisms that are believed to be important in its pathogenesis. A large multicenter trial of hypothermia in ALF is justified. Background & Aims: About 20% of patients with acute liver failure (ALF) die from increased intracranial pressure (ICP) while awaiting transplantation. This study evaluates the clinical effects and pathophysiologic basis of hypothermia in patients with ALF and intracranial hypertension that is unresponsive to standard medical therapy. Methods: Fourteen patients with ALF who were awaiting orthotopic liver transplantation (OLT) and had increased ICP that was unresponsive to standard medical therapy were studied. Core temperature was reduced to 32°C–33°C using cooling blankets. Results: Thirteen patients were successfully bridged to OLT with a median of 32 hours (range, 10–118 hours) of cooling. They underwent OLT with no significant complications related to cooling either before or after OLT and had complete neurologic recovery. ICP before cooling was 36.5 ± 2.7 mm Hg and was reduced to 16.3 ± .7 mm Hg at 4 hours, which was sustained at 24 hours (16.8 ± 1.5 mm Hg) (P < .0001). Mean arterial pressure and cerebral perfusion pressure increased significantly, and the requirement for inotropes was reduced significantly. Hypothermia produced sustained and significant reduction in arterial ammonia concentration and its brain metabolism, cerebral blood flow, brain cytokine production, and markers of oxidative stress. Conclusions: Moderate hypothermia is an effective and safe bridge to OLT in patients with ALF who have increased ICP that is resistant to standard medical therapy. Hypothermia reduces ICP by impacting on multiple pathophysiologic mechanisms that are believed to be important in its pathogenesis. A large multicenter trial of hypothermia in ALF is justified. The occurrence of hepatic encephalopathy in patients with acute liver injury is the key event defining their outcome.1Trey C. Davidson C.S. The management of fulminant hepatic failure.in: Popper H. Schaffner F. Progress in liver disease. Volume 3. Grune and Stratton, New York, NY1970: 282-298Google Scholar, 2Jalan R. Intracranial hypertension in acute liver failure pathophysiological basis of rational management.Semin Liver Dis. 2003; 23: 271-282Crossref PubMed Scopus (101) Google Scholar, 3O'Grady J.G. Alexander G.J.M. Hayllar K.M. Williams R. Early indicators of prognosis in fulminant hepatic failure.Gastroenterology. 1989; 97: 439-445Abstract PubMed Google Scholar The encephalopathy of acute liver failure (ALF) is characterized by cerebral edema, which culminates in increased intracranial pressure (ICP). Treatment options for increased ICP in patients with ALF are limited, and about 30% of patients with ALF die from cerebral herniation while waiting for a suitable donor organ.2Jalan R. Intracranial hypertension in acute liver failure pathophysiological basis of rational management.Semin Liver Dis. 2003; 23: 271-282Crossref PubMed Scopus (101) Google Scholar, 4Farmer D.G. Anselmo D.M. Ghobrial R.M. Yersiz H. McDiarmid S.V. Cao C. Weaver M. Figueroa J. Khan K. Vargas J. Saab S. Han S. Durazo F. Goldstein L. Holt C. Busuttil R.W. Liver transplantation for fulminant hepatic failure experience with more than 200 patients over a 17-year period.Ann Surg. 2003; 237: 666-675PubMed Google Scholar Indeed, in patients who have uncontrolled intracranial hypertension with conventional therapy, death from brain herniation commonly occurs within a matter of hours. In a pilot study, we showed that treatment of patients with ALF and uncontrolled intracranial hypertension using moderate hypothermia (32°C) resulted in a reduction in ICP and allowed all 4 of the patients who were suitable candidates for orthotopic liver transplantation (OLT) to undergo transplantation.5Jalan R. Olde Damink S.W.M. Deutz N.E.P. Lee A. Hayes P.C. Treatment of uncontrolled intracranial hypertension in acute liver failure with moderate hypothermia.Lancet. 1999; 354: 1164-1168Abstract Full Text Full Text PDF PubMed Scopus (314) Google Scholar The mechanism underlying the observed reduction in ICP with hypothermia is uncertain. Studies in animal models have suggested that the beneficial effects of hypothermia may impact on the critical factors that underlie the pathogenesis of intracranial hypertension in ALF, such as ammonia and its brain metabolism, cerebral blood flow (CBF), and extracellular glutamate and brain lactate production.6Traber P. DalCanto M. Ganger D. Blei A.T. Effect of body temperature on brain edema and encephalopathy in the rat after hepatic devascularization.Gastroenterology. 1989; 96: 885-891Abstract Full Text PDF PubMed Scopus (98) Google Scholar, 7Cordoba J. Crespin J. Gottstein J. Blei A.T. Mild hypothermia modifies ammonia-induced brain edema in rats after portacaval anastomosis.Gastroenterology. 1999; 116: 686-693Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar, 8Rose C. Michalak A. Pannunzio M. Chatauret N. Rambaldi A. Butterworth R.F. Mild hypothermia delays the onset of coma and prevents brain edema and extracellular brain glutamate accumulation in rats with acute liver failure.Hepatology. 2000; 31: 872-877Crossref PubMed Scopus (108) Google Scholar, 9Zwingmann C. Chatauret N. Leibfritz D. Butterworth R.F. Selective increase of brain lactate synthesis in experimental acute liver failure results of a [1H-13C]nuclear magnetic resonance study.Hepatology. 2003; 37: 420-428Crossref PubMed Scopus (176) Google Scholar, 10Rolando N. Wade J. Davalos M. Wendon J. Philpott-Howard J. Williams R. The systemic inflammatory response syndrome in acute liver failure.Hepatology. 2000; 32: 734-739Crossref PubMed Scopus (630) Google ScholarIn a pilot study, we observed a reduction in arterial ammonia concentration and CBF when patients with an uncontrolled increase in ICP were cooled to 32°C.5Jalan R. Olde Damink S.W.M. Deutz N.E.P. Lee A. Hayes P.C. Treatment of uncontrolled intracranial hypertension in acute liver failure with moderate hypothermia.Lancet. 1999; 354: 1164-1168Abstract Full Text Full Text PDF PubMed Scopus (314) Google Scholar There is increasing evidence that in addition to ammonia and alteration in CBF, systemic inflammatory response,11Vaquero J. Polson J. Chung C. Helenowski I. Schiodt F.V. Reisch J. Lee W.M. Blei A.T. Infection and the progression of hepatic encephalopathy in acute liver failure.Gastroenterology. 2003; 125: 755-764Abstract Full Text Full Text PDF PubMed Scopus (320) Google Scholar, 12Chatauret N. Zwingmann C. Rose C. Leibfritz D. Butterworth R.F. Effects of hypothermia on brain glucose metabolism in acute liver failure a H/C-nuclear magnetic resonance study.Gastroenterology. 2003; 125: 815-824Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar oxidative stress,13Norenberg M.D. Oxidative and nitrosative stress in ammonia neurotoxicity.Hepatology. 2003; 37: 245-248Crossref PubMed Scopus (106) Google Scholar and nitric oxide14Rao V.L. Audet R.M. Butterworth R.F. Increased neuronal nitric oxide synthase expression in brain following portacaval anastomosis.Brain Res. 1997; 765: 169-172Crossref PubMed Scopus (76) Google Scholar may play a role in the pathogenesis of increased ICP in patients with ALF.2Jalan R. Intracranial hypertension in acute liver failure pathophysiological basis of rational management.Semin Liver Dis. 2003; 23: 271-282Crossref PubMed Scopus (101) Google Scholar, 15Vaquero J. Chung C. Cahill M.E. Blei A.T. Pathogenesis of hepatic encephalopathy in acute liver failure.Semin Liver Dis. 2003; 23: 259-269Crossref PubMed Scopus (133) Google Scholar, 16Butterworth R.F. Molecular neurobiology of acute liver failure.Semin Liver Dis. 2003; 23: 251-258Crossref PubMed Scopus (40) Google Scholar This study was designed as a follow-up to our initial observation to extend and confirm the data from our pilot study5Jalan R. Olde Damink S.W.M. Deutz N.E.P. Lee A. Hayes P.C. Treatment of uncontrolled intracranial hypertension in acute liver failure with moderate hypothermia.Lancet. 1999; 354: 1164-1168Abstract Full Text Full Text PDF PubMed Scopus (314) Google Scholar and evaluate the clinical effects of moderate hypothermia in patients with ALF who were candidates for OLT and had uncontrolled intracranial hypertension that was refractory to standard medical therapy. Moreover, we wanted to study the effects of moderate hypothermia on the proposed pathophysiologic pathways that are believed to be important in the pathogenesis of increased ICP in ALF, namely, ammonia and its brain metabolism, CBF, mediators of inflammation, and oxidative stress. Studies were undertaken with the approval of the local research ethics committee and with written informed consent from the next of kin of each patient and were in accordance with the Declaration of Helsinki (1951) of the World Medical Association. Patients were included in this study if they had ALF and uncontrolled intracranial hypertension and were waiting for a suitable organ for OLT. Patients were excluded if informed consent could not be obtained and if the criteria for poor prognosis were not fulfilled. Over a 3-year period, 14 patients with ALF who fulfilled the Kings College criteria for poor prognosis3O'Grady J.G. Alexander G.J.M. Hayllar K.M. Williams R. Early indicators of prognosis in fulminant hepatic failure.Gastroenterology. 1989; 97: 439-445Abstract PubMed Google Scholar and the above criteria were recruited. Uncontrolled intracranial hypertension was defined as persistently elevated ICP of >25 mm Hg for 1 hour or longer despite 2 separate treatments with mannitol (1 g/kg body wt over 20 minutes) and removal of 500 mL of fluid by continuous venovenous hemofiltration.5Jalan R. Olde Damink S.W.M. Deutz N.E.P. Lee A. Hayes P.C. Treatment of uncontrolled intracranial hypertension in acute liver failure with moderate hypothermia.Lancet. 1999; 354: 1164-1168Abstract Full Text Full Text PDF PubMed Scopus (314) Google Scholar The patients were cooled to 32°C from the time of enrollment to OLT, spontaneous recovery, or death. The patients were treated with boluses of mannitol if the ICP increased to >20 mm Hg. They underwent measurement of CBF at the time of enrollment into the study, 4 hours after cooling, and then again 24 hours afterward (depending on organ availability for OLT). In the patients who underwent OLT before 24 hours, measurements were made before OLT was performed. Blood was sampled in precooled heparinized tubes from an artery and reverse jugular catheter before and at the time of the CBF measurements. All of the analyses were performed as a single batch using plasma/serum that was kept frozen at −80°C. The patients were managed according to a standardized protocol as described previously.2Jalan R. Intracranial hypertension in acute liver failure pathophysiological basis of rational management.Semin Liver Dis. 2003; 23: 271-282Crossref PubMed Scopus (101) Google Scholar, 5Jalan R. Olde Damink S.W.M. Deutz N.E.P. Lee A. Hayes P.C. Treatment of uncontrolled intracranial hypertension in acute liver failure with moderate hypothermia.Lancet. 1999; 354: 1164-1168Abstract Full Text Full Text PDF PubMed Scopus (314) Google Scholar All of the invasive monitoring used in this study is part of the routine clinical care apart from the procedures required for CBF measurements. In short, all of the patients were mechanically ventilated following sedation with propofol and paralysis with atracurium besylate (300–600 μg · kg−1 · h−1). Treatment with N-acetylcysteine was commenced and/or continued (150 mg · kg−1 · 24 h−1)2Jalan R. Intracranial hypertension in acute liver failure pathophysiological basis of rational management.Semin Liver Dis. 2003; 23: 271-282Crossref PubMed Scopus (101) Google Scholar; broad-spectrum antibiotics and fluconazole were administered prophylactically, and blood glucose levels were maintained between 5 and 7 mmol/L.2Jalan R. Intracranial hypertension in acute liver failure pathophysiological basis of rational management.Semin Liver Dis. 2003; 23: 271-282Crossref PubMed Scopus (101) Google Scholar Cardiovascular hemodynamics were monitored with a pulmonary artery catheter, a right atrial catheter, and an arterial catheter. Continuous venovenous hemofiltration (Gambro Laboratories, Colorado) was instituted in all patients for established renal failure (blood flow of 200 mL/min and 1-L cycle exchanges). Noradrenaline was used to keep the cerebral perfusion pressure >50 mm Hg and/or mean arterial pressure >80 mm Hg. Cooling was performed using cooling blankets that were placed above and below the patient (Blanketrol II; Cincinnati Sub-Zero, Cincinnati, OH) to maintain the blood temperature at 32°C–33°C.5Jalan R. Olde Damink S.W.M. Deutz N.E.P. Lee A. Hayes P.C. Treatment of uncontrolled intracranial hypertension in acute liver failure with moderate hypothermia.Lancet. 1999; 354: 1164-1168Abstract Full Text Full Text PDF PubMed Scopus (314) Google Scholar Clinical end points were survival to OLT or death, neurologic changes during therapy, effects on ICP, and survival after OLT. Neurologic examination was performed at hourly intervals, with particular attention to pupillary size and reaction to light. ICP was continuously monitored using a subdural fiber-optic system (Camino; Camino Laboratories, San Diego, CA). Cerebral perfusion pressure was calculated as the difference between the mean arterial pressure and the ICP. Patients were followed up after transplantation to assess neurologic sequelae of cooling. Plasma was obtained by centrifugation and was deproteinized using trichloroacetic acid (50% wt/vol) before storage (−80°C), and ammonia was measured spectrophotometrically by standard enzymatic methods (CobasMiraS; Hoffman-LaRoche, Basel, Switzerland).17Dejong C.H. Deutz N.E. Soeters P.B. Renal ammonia and glutamine metabolism during liver insufficiency-induced hyperammonemia in the rat.J Clin Invest. 1993; 92: 2834-2840Crossref PubMed Scopus (72) Google Scholar CBF was measured using a modification of the Kety-Schmidt technique18Kety S.S. Schmidt C.F. The nitrous oxide method for the quantitative determination of cerebral blood flow in man theory, procedure and normal values.J Clin Invest. 1947; 27: 476-483Crossref Scopus (1122) Google Scholar measuring the rate of uptake of nitrous oxide by the brain as detailed previously.5Jalan R. Olde Damink S.W.M. Deutz N.E.P. Lee A. Hayes P.C. Treatment of uncontrolled intracranial hypertension in acute liver failure with moderate hypothermia.Lancet. 1999; 354: 1164-1168Abstract Full Text Full Text PDF PubMed Scopus (314) Google Scholar, 19Jalan R. Olde Damink S.W.M. Deutz N.E.P. Hayes P.C. Lee A. Restoration of cerebral blood flow autoregulation and reactivity to carbon dioxide in acute liver failure by moderate hypothermia.Hepatology. 2001; 34: 50-54Crossref PubMed Scopus (102) Google Scholar Another arterial catheter and a jugular bulb catheter (4F Opticath, U440; Abbott Laboratories, Chicago, IL)were inserted. CBF was only determined if the patient was hemodynamically stable, defined as a difference of <10% in mean arterial pressure. For each measurement of CBF, the arterial hydrogen ion concentrations were corrected and ventilation was adjusted to achieve an arterial carbon dioxide tension of 4–4.5 kilopascals and was not altered again during the measurement to prevent Paco2 as a confounding factor of CBF. Serum was collected for measurement of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6. Measurements were made using a standard commercially available enzyme-linked immunosorbent assay (R&D Systems, Minneapolis, MN). The lower limit for detection of TNF-α, IL-1β, and IL-6 was 3 pg/mL.20Mookerjee R.P. Sen S. Davies N.A. Hodges S.J. Williams R. Jalan R. Tumour necrosis factor alpha is an important mediator of portal and systemic haemodynamic derangements in alcoholic hepatitis.Gut. 2003; 52: 1182-1187Crossref PubMed Scopus (135) Google Scholar Malonyldialdehyde (MDA) was measured as a marker of oxidative stress and determined using a modified thiobarbituric acid-reacting substance assay as described.21Lapenna D. Ciofani G. Pierdomenico S.D. Giamberardino M.A. Cuccurullo F. Reaction conditions affecting the relationship between thiobarbituric acid reactivity and lipid peroxides in human plasma.Free Radic Biol Med. 2001; 31: 331-335Crossref PubMed Scopus (212) Google Scholar Control values for our laboratory were .9 ± .2 μmol/L. Nitrate/nitrite levels were measured using high-performance liquid chromatography as described.22Bruins M.J. Soeters P.B. Lamers W.H. Meijer A.J. Deutz N.E.P. L-arginine supplementation in hyperdynamic endotoxemic pigs effect on nitric oxide synthesis by the different organs.Crit Care Med. 2002; 30: 508-517Crossref PubMed Scopus (61) Google Scholar Control values for nitrate/nitrite in our laboratory were 40 ± 3.6 μmol/L. Cerebral metabolic rate was calculated as follows: CBF × (Arterial − Juglar Venous Concentration). Fractional extraction was calculated as follows: (Arterial − Juglar Venous Concentration)/Arterial Concentration. Brain flux was calculated as follows: (Jugulo Venous Concentration − Arterial Concentration) × CBF; positive values for the measured fluxes indicate production and negative values indicate uptake. All data are expressed as mean ± SEM. One-way analysis of variance with Bonferroni correction was used to analyze the statistical significance of data, which were analyzed at multiple time points. Wilcoxon signed rank test or t test was used for paired data as appropriate. P < .05 was considered statistically significant. Patient details are summarized in Table 1. The core temperature was reduced from 36.3°C ± .2°C to 33.1°C ± .5°C within 1 hour of starting cooling and remained lowered at 32.6°C ± .4°C at 24 hours. However, the effect of cooling on ICP was evident within the first hour of starting cooling, even before the target temperature of 32°C was reached. Cooling was associated with a significant and sustained increase in systemic vascular resistance (P < .01), mean arterial pressure (P < .001), and cerebral perfusion pressure (P < .001) and a reduction in heart rate (P < .0001), cardiac output (P < .01), and noradrenaline requirement (P < .01) (Table 2).Table 1Patient CharacteristicsAge (y)24 ± 3.1Sex (M/F)5/9Etiology of ALF Overdose of paracetamol13 Non-A, non-B hepatitis1No. meeting Kings College criteria for poor prognosis14Highest prothrombin time (s)114 ± 6.5Bilirubin level (μmol/L)213 ± 14.1Creatinine level (μmol/L)212 ± 11.9No. treated with continuous venovenous hemofiltration14No. treated with inotropes14No. treated with mechanical ventilation14No. who were candidates for liver transplantation14Arterial hydrogen ion concentration (nmol/L)48 ± 3.2Dosage of propofol (mg/h)56 ± 9.3NOTE. n = 14. Data expressed as mean (±SEM) except where indicated. Open table in a new tab Table 2Effect of Hypothermia on Cardiovascular and Cerebral HemodynamicsPrecooling4 hours10–24 hoursICP (mm Hg)36.5 ± 2.716.3 ± .7aP < .001,16.8 ± 1.5aP < .001,CBF (mL·100 g−1·min−1)78.2 ± 9.746.5 ± 3.8aP < .001,44.0 ± 1.9aP < .001,Heart rate (beats/min)94 ± 2.681 ± 1.6aP < .001,77 ± 1.8aP < .001,Mean arterial pressure (mm Hg)76.6 ± 3.682.8 ± 2.2bP < .01,84.9 ± 2.1aP < .001,Central venous pressure (mm Hg)8.4 ± .99.1 ± 1.09.6 ± .9Systemic vascular resistance (dyn·s−1·cm−5)503.8 ± 41671.4 ± 48.4cP < .05.716.8 ± 43.3bP < .01,Cardiac output (L/min)11.3 ± .79.2 ± .5cP < .05.8.7 ± .5bP < .01,Noradrenaline requirement (μg·kg−1·min−1)0.5 ± .10.2 ± .1cP < .05.0.1 ± .0bP < .01,Cerebral perfusion pressure (mm Hg)40.1 ± 2.966.4 ± 2.8aP < .001,67.2 ± 2.8aP < .001,Data shown as mean ± SEM.Difference over time tested using one-way analysis of variance with Bonferroni correction; 10–24 hours, data acquired from samples obtained either at 24 hours or earlier, depending on when the patients underwent transplantation (n = 13) or died (n = 1).a P < .001,b P < .01,c P < .05. Open table in a new tab NOTE. n = 14. Data expressed as mean (±SEM) except where indicated. Data shown as mean ± SEM. Difference over time tested using one-way analysis of variance with Bonferroni correction; 10–24 hours, data acquired from samples obtained either at 24 hours or earlier, depending on when the patients underwent transplantation (n = 13) or died (n = 1). Thirteen of the 14 patients were successfully bridged to OLT with a mean of 31.8 ± 9.1 hours (range, 10–118 hours) of cooling. Seven patients underwent OLT between 12 and 24 hours, 2 between 24 and 48 hours, 2 between 48 and 72 hours, one between 72 and 96 hours, and one at 118 hours after onset of cooling. One patient was taken off the OLT list about 10 hours after onset of cooling who subsequently died from brain herniation (see following text). Before cooling, 8 of the 14 patients showed clinical evidence of increased ICP characterized by unequal pupillary sizes. In 2 patients, no pupillary reaction to light was present. The inequality in the pupillary size persisted in one patient during therapy with moderate hypothermia but was corrected with hypothermia in the others. Pupillary reaction to light was restored in both patients with cooling. Before cooling, ICP was elevated at 36.5 ± 2.7 mm Hg and was reduced to 16.3 ± .7 mm Hg at 4 hours, which was sustained at 24 hours (16.8 ± 1.5 mm Hg; P < .0001). ICP increased to 48 mm Hg in one patient and remained elevated despite repeated doses of mannitol, fluid removal with continuous venovenous hemofiltration, and 2 separate doses of thiopentone sodium. This patient died from cerebral herniation. In the 7 patients who were treated with hypothermia for more than 24 hours, 5 developed transient increases in ICP >20 mm Hg that responded to additional treatment with mannitol (Figure 1). All 13 patients underwent successful transplantation, and 10 of these patients were alive 3 months after OLT. Deaths in the 3 patients after OLT were due to multiorgan failure in 2 patients (possibly from sepsis) and from primary graft nonfunction in one patient. No episodes of bleeding were noted either due to the insertion of monitoring devices or from the effects of cooling. During the transplant operation, patients in the hypothermia group underwent transfusion with a median of 5 units (range, 2–8 units) of red cell concentrates, 3 (range, 2–5) pools of platelets, and 900 mL (range, 600–1800 mL) of fresh frozen plasma. In the postoperative period, a total of 9 episodes of infection were noticed in the 13 patients who underwent successful OLT (chest infection, 6; Staphylococcus aureus septicemia, 2; urinary tract infection [Escherichia coli], 1). As stated previously, death in one patient with staphylococcal sepsis was associated with multiorgan failure. Another patient who was believed to have chest infection and multiorgan failure died. The rest of the infections resolved with standard antibiotic therapy. The median time to extubation following successful transplantation was 126 hours (range, 78–243 hours). All patients had normal neurologic recovery apart from one patient who required protracted rehabilitation for muscle weakness due to a prolonged stay in the intensive care unit. There was a significant reduction in arterial ammonia (P < .05) concentration with cooling (Figure 2A). Before cooling, the brain extraction of ammonia was 17.2% ± 2.2%, which was reduced to values that were not significantly different from zero after cooling. In contrast, the brain produced glutamine before cooling that was reduced to values that were not significantly different from zero (Figure 2B and C). Brain flux of ammonia before cooling was −4.1 ± .6 μmol · 100 g−1 · min−1, and this was reduced significantly to values that were not significantly different from zero after cooling. Brain glutamine flux before cooling was 11.5 ± 3.9 μmol · 100 g−1 · min−1, and this was reduced to values that were not significantly different from zero after cooling (Figure 2D). Before cooling, brain uptake of ammonia correlated with brain production of glutamine (r = .61, P < .05). CBF measurements were made in 12 of the 14 patients. The measured values were above the normal range (45–55 mL · 100 g−1 · min−1) in 10 patients and were reduced in 2 patients. CBF was reduced from 78.2 ± 9.7 mL · 100 g−1 · min−1 to 46.5 ± 3.8 mL · 100 g−1 · min−1 at 4 hours after cooling, and this was sustained (44 ± 1.9 mL · 100 g−1 · min−1) (P < .0001) (Figure 3). Patients showed markedly elevated arterial concentrations of the proinflammatory cytokines TNF-α, IL-1β, and IL-6, with evidence of brain production of these cytokines. With cooling, there was a significant reduction in the arterial concentration (P < .05, P < .05, and P < .001, respectively) and also in the brain flux of these cytokines (P < .01, P < .001, and P < .05, respectively) to values that were not significantly different from zero (Table 3 and Figure 4).Table 3Effect of Hypothermia on Cytokines, MDA, and Nitrates/NitritesPrecooling4 hours10–24 hoursTNF-αaStudent t test or Arterial (pg/mL)43.4 ± 9.021.2 ± 4.8cP < .05,NA Jugular venous (pg/mL)49.6 ± 9.822.7 ± 5.1cP < .05, Jugular venous − arterial (pg/mL)6.2 ± 1.11.6 ± 1.4cP < .05, Brain flux (μg·100g−1·min−1)529.0 ± 140.483.7 ± 70.0aStudent t test orIL-1βaStudent t test or Arterial (pg/mL)52.1 ± 10.122.1 ± 5.9cP < .05,NA Jugular venous (pg/mL)60.6 ± 11.017.4 ± 5.2dP < .01, Jugular venous − arterial (pg/mL)8.5 ± 1.1−4.7 ± 2.1eP < .001. Brain flux (μg·100g−1·min−1)692 ± 169−223 ± 92eP < .001.IL-6aStudent t test or Arterial (pg/mL)110.3 ± 13.629.2 ± 4.4eP < .001.NA Jugular venous (pg/mL)111.6 ± 14.323.8 ± 3.3eP < .001. Jugular venous − arterial (pg/mL)1.3 ± 2.9−5.4 ± 1.5eP < .001. Brain flux (μg·100g−1·min−1)248.5 ± 221.6−260.6 ± 87.1cP < .05,MDAb1-way analysis of variance with Bonferroni correction; Arterial (μmol/L)14.8 ± 1.95.6 ± 1.1eP < .001.5.7 ± 1.1eP < .001. Jugular venous (μmol/L)14.7 ± 1.75.7 ± 1.2eP < .001.5.6 ± 1.9eP < .001. Jugular venous − arterial (μmol/L)−.1 ± .50.1 ± 0.2−.1 ± .3 Brain flux (μmol·100g−1·min−1)−24.8 ± 30.52.7 ± 9.0−3.8 ± 10.1Nitrate/nitritesb1-way analysis of variance with Bonferroni correction; Arterial (μmol/L)95.9 ± 12.962.0 ± 11.7cP < .05,56.5 ± 6.8cP < .05, Jugular venous (μmol/L)95.6 ± 25.649.6 ± 13.648.2 ± 6.8 Jugular venous − arterial (μmol/L)−.3 ± 2.3−12.4 ± 5.2−8.4 ± 2.1 Brain flux (μmol·100g−1·min−1)299.2 ± 1928−590 ± 247−370 ± 107NOTE. Data shown as mean ± SEM.Brain extraction (arterial − jugular venous/arterial concentration); negative values reflect brain uptake, and positive values reflect brain production. Brain flux − ([jugular venous − arterial/arterial concentration] × cerebral blood flow); positive values indicate brain production, and negative values reflect brain uptake. 10–24 hours, data acquired from samples obtained either at 24 hours or earlier, depending on when the patients underwent transplantation (n = 13) or died (n = 1).Difference tested by usinga Student t test orb 1-way analysis of variance with Bonferroni correction;c P < .05,d P < .01,e P < .001. Open table in a new tab NOTE. Data shown as mean ± SEM. Brain extraction (arterial − jugular venous/arterial concentration); negative values reflect brain uptake, and positive values reflect brain production. Brain flux − ([jugular venous − arterial/arterial concentration] × cerebral blood flow); positive values indicate brain production, and negative values reflect brain uptake. 10–24 hours, data acquired from samples obtained either at 24 hours or earlier, depending on when the patients underwent transplantation (n = 13) or died (n = 1). Difference tested by using MDA levels were elevated about 14-fold over control values, but the brain flux of MDA was not significantly different from zero. Following cooling, there was a significant reduction in arterial MDA levels (P < .0001) (Table 3 and Figure 5). Nitrate/nitrite levels were elevated 2-fold over control values, but the brain flux of nitrate/nitrite was not significantly different from zero. Following cooling, there was a significant reduction in arterial nitrate/nitrite levels (P < .05) (Table 3). The results of this study extend and confirm those of our pilot study suggesting
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