RESUMO
Autoimmune liver diseases are associated with an increased risk of diabetes, yet the underlying mechanisms remain unknown. In this cross-sectional study, we investigated the glucose-regulatory disturbances in patients with autoimmune hepatitis (AIH, n = 19), primary biliary cholangitis (PBC, n = 15), and primary sclerosing cholangitis (PSC, n = 6). Healthy individuals (n = 24) and patients with metabolic dysfunction-associated steatotic liver disease (MASLD, n = 18) were included as controls. Blood samples were collected during a 120-min oral glucose tolerance test. We measured the concentrations of glucose, C-peptide, insulin, glucagon, and the two incretin hormones, glucose insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1). We calculated the homeostasis model assessment of insulin resistance (HOMA-IR), whole body insulin resistance (Matsuda index), insulin clearance, and insulinogenic index. All patient groups had increased fasting plasma glucose and impaired glucose responses compared with healthy controls. Beta-cell secretion was increased in AIH, PBC, and MASLD but not in PSC. Patients with AIH and MASLD had hyperglucagonemia and hepatic, as well as peripheral, insulin resistance and decreased insulin clearance, resulting in hyperinsulinemia. Patients with autoimmune liver disease had an increased GIP response, and those with AIH or PBC had an increased GLP-1 response. Our data demonstrate that the mechanism underlying glucose disturbances in patients with autoimmune liver disease differs from that underlying MASLD, including compensatory incretin responses in patients with autoimmune liver disease. Our results suggest that glucose disturbances are present at an early stage of the disease.NEW & NOTEWORTHY Patients with autoimmune liver disease but without overt diabetes display glucose disturbances early on in their disease course. We identified pathophysiological traits specific to these patients including altered incretin responses.
Assuntos
Glicemia , Hepatite Autoimune , Resistência à Insulina , Insulina , Humanos , Feminino , Masculino , Pessoa de Meia-Idade , Glicemia/metabolismo , Estudos Transversais , Adulto , Insulina/sangue , Hepatite Autoimune/sangue , Hepatite Autoimune/metabolismo , Hepatite Autoimune/complicações , Peptídeo 1 Semelhante ao Glucagon/sangue , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Fígado Gorduroso/metabolismo , Fígado Gorduroso/sangue , Polipeptídeo Inibidor Gástrico/sangue , Polipeptídeo Inibidor Gástrico/metabolismo , Idoso , Teste de Tolerância a Glucose , Colangite Esclerosante/sangue , Colangite Esclerosante/metabolismo , Colangite Esclerosante/complicações , Glucagon/sangue , Glucagon/metabolismo , Cirrose Hepática Biliar/sangue , Cirrose Hepática Biliar/metabolismo , Cirrose Hepática Biliar/complicações , Peptídeo C/sangueRESUMO
BACKGROUND & AIMS: Non-selective beta-blockers (NSBB) are first choice for prevention of variceal bleeding. But possible deleterious effects in refractory ascites and frequent non-response are clinical drawbacks. Since levels of vasoactive proteins in antrum mucosa reflect vascular dysfunction in cirrhosis, these expression levels might also reflect hemodynamic response to NSBB. METHODS: Biopsies from the gastric and duodenal mucosa of 25 patients with cirrhosis were collected and the hepatic venous pressure gradient (HVPG) was measured before and after an acute propranolol challenge. Transcription and protein expression of Ras homolog family member A (RhoA), Rho-kinase (ROCK)2, beta-arrestin2 (ßArr2), endothelial nitric oxide synthase (eNOS) and the phosphorylation of downstream effectors VASP and moesin were analyzed using PCR and Western blot. Further 21 patients on NSBB were evaluated on their follow up for events of variceal bleeding defined as non-response. RESULTS: Ten patients showed HVPG <10mmHg, further seven patients showed significant hemodynamic response to NSBB, whereas eight patients were non-responders. The mucosal transcription of vasoactive proteins was higher in antrum mucosa compared to corpus and duodenum. The transcriptional levels of vasoactive proteins were higher in patients with HVPG >10mmHg and HVPG >16mmHg. Interestingly, mRNA levels of RhoA and ROCK2 were lower in patients with large varices at endoscopy. Moreover, RhoA and ROCK2 transcription correlated with the decrease of HVPG after acute NSBB challenge. Finally, acute and long-term non-responders showed lower expression of ßArr2 in antrum mucosa. CONCLUSION: This study shows for the first time that the expression of ßArr2 in antrum mucosa biopsies might reflect the hemodynamic response to NSBB and their long-term protective effect. This finding might offer an easy approach at upper endoscopy to facilitate the decision to treat with NSBB if varices are present.
Assuntos
Antagonistas Adrenérgicos beta/uso terapêutico , Mucosa Gástrica/metabolismo , Cirrose Hepática/tratamento farmacológico , Antro Pilórico/metabolismo , beta-Arrestina 2/genética , Quinases Associadas a rho/genética , Proteína rhoA de Ligação ao GTP/genética , Adulto , Idoso , Feminino , Hemodinâmica/efeitos dos fármacos , Humanos , Cirrose Hepática/fisiopatologia , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/análiseRESUMO
OBJECTIVE: Patients with decompensated cirrhosis often suffer from malnutrition. To enable appropriate nutritional supplementation a correct estimation of resting energy expenditure (REE) is needed. It is, however, unclear whether the volume of ascites should be included or not in the calculations of the REE. MATERIAL AND METHODS: In 19 patients with cirrhosis and ascites, measurements of REE by indirect calorimetry were performed before paracentesis, after paracentesis, and four weeks after paracentesis. Moreover, handgrip strength (HGS), dual X-ray absorptiometry (DXA), and biochemistry were assessed. RESULTS: Calculated and measured REE differed more than 10% in 63% of the patients at baseline. By including the weight of ascites in the calculation of REE, the REE was overestimated by 283 (-602-1381) kJ/day (p = 0.69). By subtracting the weight of ascites in the calculation of REE, it was underestimated by -379 (-1915 - 219) kJ/day, (p = 0.06). Patients in whom measured REE decreased after paracentesis had higher middle arterial pressure (MAP) (p = 0.02) and p-sodium (p = 0.02) at baseline. Low HGS (M: <30 kg; W < 20 kg) was evident in 68% of the patients. T-scores revealed osteopenia and osteoporosis in 58% and 16%, respectively. Reduced vitamin D levels (<50 nmol/l) were found in 68%. CONCLUSIONS: The presence of ascites seems to increase REE, why we suggest that when REE is calculated, the weight of ascites should be included. Indirect calorimetry is, however, preferable for REE estimation. More than two-third of patients with ascites suffer from muscle weakness and/or osteopenia.
Assuntos
Ascite/complicações , Metabolismo Energético , Cirrose Hepática/complicações , Desnutrição/terapia , Paracentese , Adolescente , Adulto , Idoso , Ascite/metabolismo , Ascite/terapia , Calorimetria Indireta , Feminino , Seguimentos , Humanos , Cirrose Hepática/metabolismo , Cirrose Hepática/terapia , Masculino , Desnutrição/etiologia , Desnutrição/metabolismo , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto JovemRESUMO
BACKGROUND: The circulating cholinesterases acetyl- and butyrylcholinesterase may be suppressed and subsequently released from the brain in acute bacterial meningitis. METHODS: We report serum activities of acetylcholinesterase and butyrylcholinesterase in paired arterial and jugular venous samples from seven patients with acute bacterial meningitis and eight healthy controls. Paraoxonase 1, which protects these enzymes from oxidative inactivation, was also measured. FINDINGS AND CONCLUSION: Acetyl- and butyrylcholinesterase activities were lower in patients, independently of changes in paraoxonase 1. Arterial and jugular venous enzyme activities were similar both in patients and controls, suggesting that no cerebral release was present.
Assuntos
Acetilcolinesterase/sangue , Butirilcolinesterase/sangue , Meningites Bacterianas/sangue , Doença Aguda , Arildialquilfosfatase/sangue , Biomarcadores/sangue , Estudos de Casos e Controles , Humanos , Meningites Bacterianas/diagnóstico , PrognósticoRESUMO
BACKGROUND & AIMS: The pathogenesis of cerebral edema in acute liver failure is suggested, in in vitro and animal studies, to involve a compromised oxidative metabolism with a decrease in cerebral ATP levels and an increase in purine concentrations. In this study we hypothesize that the cerebral concentrations of hypoxanthine, inosine, and lactate/pyruvate (LP) ratio are increased and correlated in patients with acute liver failure. Furthermore, we expect the purines and L/P ratio to correlate with intracranial pressure (ICP) (positively), and cerebral perfusion pressure (CPP) (negatively). METHODS: In 17 patients (aged 18-60 years) with acute liver failure and severe hyperammonemia (182 ± 36 µM (mean ± SD)), cerebral microdialysis was performed, and ICP and CPP were monitored. Microdialysate concentrations of hypoxanthine, inosine, lactate, and pyruvate were measured. RESULTS: The hypoxanthine concentration was 23.0 ± 12 µM in early samples and 11.7 ± 6.8 µM in late samples (normal level ~2.0 µM). The inosine concentration was 7.2 ± 7.1 µM and 2.8 ± 1.6 µM, and the LP ratio was 55.8 ± 21.6 and 45.6 ± 20.8, respectively (normal level ~18). Hypoxanthine correlated significantly to LP ratio (r(2)=0.40, p<0.01) while inosine did not. The purine levels and L/P ratio did not correlate to ICP or CPP, nor did they differ between patients with high ICP (>20 mmHg, n=9) and patients without (n=8). CONCLUSIONS: This study shows that the high cerebral LP ratio correlates to the hypoxanthine level in patients with acute liver failure. However, these metabolic alterations were not related to the development of intracranial hypertension.
Assuntos
Encéfalo/metabolismo , Hipoxantina/metabolismo , Ácido Láctico/metabolismo , Falência Hepática Aguda/metabolismo , Ácido Pirúvico/metabolismo , Adolescente , Adulto , Edema Encefálico/etiologia , Feminino , Humanos , Hiperamonemia/complicações , Inosina/metabolismo , Hipertensão Intracraniana/etiologia , Pressão Intracraniana , Falência Hepática Aguda/complicações , Falência Hepática Aguda/fisiopatologia , Masculino , Microdiálise , Pessoa de Meia-Idade , Adulto JovemRESUMO
UNLABELLED: Extracorporeal albumin dialysis (ECAD) may improve severe hepatic encephalopathy (HE) in patients with advanced cirrhosis via the removal of protein or non-protein-bound toxins. A prospective, randomized, controlled, multicenter trial of the efficacy, safety, and tolerability of ECAD using molecular adsorbent recirculating system (MARS) was conducted in such patients. Patients were randomized to ECAD and standard medical therapy (SMT) or SMT alone. ECAD was provided daily for 6 hours for 5 days or until the patient had a 2-grade improvement in HE. HE grades (West Haven criteria) were evaluated every 12 hours using a scoring algorithm. The primary endpoint was the difference in improvement proportion of HE between the 2 groups. A total of 70 subjects [median age, 53; 56% male; 56% HE grade 3; 44% HE grade 4; median model for end-stage liver disease (MELD) 32 (11-50) and CPT 13 (10-15)] were enrolled in 8 tertiary centers. Patients were randomized to ECAD + SMT (n = 39) or SMT alone (n = 31). Groups were matched in demographics and clinical variables. The improvement proportion of HE was higher in ECAD (mean, 34%; median, 30%) versus the SMT group (mean, 18.9%; median, 0%) (P = 0.044) and was reached faster and more frequently than in the SMT group (P = 0.045). Subjects receiving ECAD tolerated treatment well with no unexpected adverse events. CONCLUSION: The use of ECAD may be associated with an earlier and more frequent improvement of HE (grade 3/4). Because this 5-day study was not designed to examine the impact of MARS on survival, a full assessment of the role of albumin dialysis awaits the results of additional controlled trials.
Assuntos
Albuminas , Encefalopatia Hepática/terapia , Cirrose Hepática/complicações , Diálise Renal , Adulto , Idoso , Algoritmos , Feminino , Encefalopatia Hepática/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Índice de Gravidade de Doença , Desintoxicação por Sorção , Resultado do TratamentoRESUMO
AIM: To evaluate treatment safety and hemodynamic changes during a single 6-h treatment with the Prometheus liver assist system in a randomized, controlled study. METHODS: Twenty-four patients were randomized to either the study group or to one of two control groups: Fractionated Plasma Separation Adsorption and Dialysis, Prometheus system (Study group; n = 8); Molecular Adsorbent Recirculation System (MARS) (Control group 1, n = 8); or hemodialysis (Control group 2; n = 8). All patients included in the study had decompensated cirrhosis at the time of the inclusion into the study. Circulatory changes were monitored with a Swan-Ganz catheter and bilirubin and creatinine were monitored as measures of protein-bound and water-soluble toxins. RESULTS: Systemic hemodynamics did not differ between treatment and control groups apart from an increase in arterial pressure in the MARS group (P = 0.008). No adverse effects were observed in any of the groups. Creatinine levels significantly decreased in the MARS group (P = 0.03) and hemodialysis group (P = 0.04). Platelet count deceased in the Prometheus group (P = 0.04). CONCLUSION: Extra-corporal liver support with Prometheus is proven to be safe in patients with endstage liver disease but does not exert the beneficial effects on arterial pressure as seen in the MARS group.
Assuntos
Cirrose Hepática/terapia , Falência Hepática/terapia , Adulto , Idoso , Anticoagulantes/farmacologia , Bilirrubina/metabolismo , Pressão Sanguínea , Creatinina/química , Feminino , Hemodinâmica , Humanos , Masculino , Pessoa de Meia-Idade , Diálise Renal/métodos , Desintoxicação por Sorção/métodos , Resultado do TratamentoRESUMO
In this prospective study of patients with fulminant hepatic failure (FHF), we tested the hypothesis that arterial hyperammonemia results in cerebral accumulation of the osmotic active amino acids glutamine and alanine, processes that were expected to correlate with intracranial pressure (ICP). By using in vivo brain microdialysis technique together with ICP monitoring in 17 FHF patients (10 females/7 males; median age 49 (range 18 to 66) years), we found that arterial ammonia concentration correlated to brain content of glutamine (r=0.47; P<0.05) but not to alanine. A persisting high arterial ammonia concentration (above 200 micromol/L) characterized patients who developed high ICP (n=8) while patients who did not experience surges of increased ICP (n=9) had a decline in the ammonia level (P<0.05). Moreover, brain glutamine and alanine concentrations were higher at baseline and increased further in patients who developed intracranial hypertension compared with patients who experienced no surges of high ICP. Brain glutamine concentration increased 32% from baseline to 6536 (697 to 9712) micromol/L (P<0.05), and alanine 44% from baseline to 104 (81 to 381) micromol/L (P<0.05). Brain concentration of glutamine (r=0.59, P<0.05), but not alanine, correlated to ICP. Also arterial ammonia concentration correlated to ICP (r=0.73, P<0.01). To conclude, this study shows that persistence of arterial hyperammonemia is associated with profound changes in the cerebral concentration of glutamine and alanine. The elevation of brain glutamine concentration correlated to ICP in patients with FHF.
Assuntos
Alanina/metabolismo , Encéfalo/fisiopatologia , Glutamina/metabolismo , Hiperamonemia/fisiopatologia , Hipertensão Intracraniana/fisiopatologia , Falência Hepática Aguda/fisiopatologia , Adolescente , Adulto , Idoso , Encéfalo/metabolismo , Feminino , Humanos , Hiperamonemia/etiologia , Hipertensão Intracraniana/etiologia , Hipertensão Intracraniana/metabolismo , Pressão Intracraniana , Falência Hepática Aguda/complicações , Testes de Função Hepática , Masculino , Microdiálise , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
BACKGROUND AND PURPOSE: In patients with severe bacterial meningitis, norepinephrine is often infused to increase mean arterial pressure (MAP). This increases cerebral blood flow (CBF), but it is unknown if this increase is caused by impaired cerebral autoregulation or by a cerebral effect of norepinephrine through increased cerebral metabolism. The latter possibility implies a CBF-metabolism coupling. This has not been studied during meningitis. We studied the effect of norepinephrine and propofol on CBF and oxidative metabolism in patients with severe bacterial meningitis. METHODS: In seven patients with pneumococcal meningitis and 7 healthy subjects, norepinephrine was infused intravenously; patients also underwent intravenous propofol infusion. Global CBF was measured by the Kety-Schmidt technique; cerebral oxidative metabolism and net flux of norepinephrine and epinephrine were calculated from measured arterial-to-jugular venous concentration differences (a-vD). RESULTS: During norepinephrine infusion, MAP increased from a median value of 79 (range, 70 to 89) to 99 (98 to 129) mm Hg in patients, and from 87 (72 to 103) to 123 (112 to 132) mm Hg in controls. CBF increased in patients (51 [48 to 60] to 59 [54 to 77] mL/100 g per minute) but remained unchanged in controls. The cerebral metabolic rate of oxygen (CMRO2) decreased in patients and remained unchanged in controls. No cerebral net flux of norepinephrine or epinephrine was found at any time in the 2 groups. During propofol infusion, CMRO2, and the a-vDO2 decreased whereas CBF was unchanged. CONCLUSIONS: In patients with severe bacterial meningitis, norepinephrine increases both MAP and CBF but not CMRO2, indicating impaired autoregulation. Propofol reduces CBF relatively less than cerebral metabolism, suggesting a resetting of the CBF-CMRO(2) relationship.
Assuntos
Córtex Cerebral/irrigação sanguínea , Meningites Bacterianas/tratamento farmacológico , Norepinefrina/uso terapêutico , Propofol/uso terapêutico , Adulto , Idoso , Pressão Sanguínea/efeitos dos fármacos , Córtex Cerebral/metabolismo , Circulação Cerebrovascular/efeitos dos fármacos , Epinefrina/sangue , Feminino , Humanos , Infusões Intravenosas , Masculino , Meningites Bacterianas/metabolismo , Meningites Bacterianas/fisiopatologia , Pessoa de Meia-Idade , Norepinefrina/administração & dosagem , Norepinefrina/sangue , Propofol/administração & dosagemRESUMO
Uncontrolled increase in intracranial pressure (ICP) continues to be one of the most significant causes of early death in patients with acute liver failure (ALF). In this study, we aimed to determine the effects of indomethacin on ICP and cerebral perfusion pressure in twelve patients with ALF and brain edema (9 females/3 males, median age 49,5 (range 21 to 64) yrs.). Also changes in cerebral perfusion determined by transcranial Doppler technique (Vmean) and jugular bulb oxygen saturation (SvjO2) were measured, as well as brain content of lactate and glutamate by microdialysis technique. Finally, we determined the cerebral blood flow autoregulation before and after indomethacin injection. We found that indomethacin reduced ICP from 30 (7 to 53) to 12 (4 to 33) mmHg (P < 0.05). The cerebral perfusion pressure increased from 48 (0 to 119) to 65 (42 to 129) mmHg (P < 0.05), while Vmean and SvjO2 on average remained unchanged at 68 (34 to 126) cm/s and 67 (28 to 82) %, respectively. The lactate and glutamate in the brain tissue were not altered (2.1 (1.8 to 7.8) mmol/l and 34 (2 to 268) micromol/l, respectively) after injection of indomethacin. Cerebral blood flow autoregulation was impaired in all patients before injection of indomethacin, but was not restored after administration of indomethacin. We conclude that a bolus injection of indomethacin reduces ICP and increases cerebral perfusion pressure without compromising cerebral perfusion or oxidative metabolism in patients with ALF. This finding indicates that indomethacin may be valuable as rescue treatment of uncontrolled intracranial hypertension in fulminant hepatic failure.
Assuntos
Encéfalo/irrigação sanguínea , Ácido Glutâmico/análise , Indometacina/administração & dosagem , Pressão Intracraniana/efeitos dos fármacos , Ácido Láctico/análise , Falência Hepática/complicações , Adulto , Pressão Sanguínea , Química Encefálica , Espaço Extracelular/química , Feminino , Homeostase , Humanos , Injeções Intravenosas , Falência Hepática/tratamento farmacológico , Falência Hepática/mortalidade , Masculino , Microdiálise , Pessoa de Meia-Idade , Norepinefrina/administração & dosagemRESUMO
PURPOSE: The underlying mechanisms for cerebral blood flow (CBF) abnormalities in acute bacterial meningitis (ABM) are largely unknown. Putative mediators include vasoactive peptides, e.g. calcitonin-gene related peptide (CGRP), vasoactive intestinal peptide (VIP), and endothelin-1 (ET-1), all of which may be affected by therapeutic interventions used in the intensive care unit. We measured arterial levels as well as the net cerebral flux of these peptides in patients with ABM, and in healthy volunteers undergoing interventions relevant to intensive care. METHODS: Seven patients with severe ABM and sepsis and fifteen healthy volunteers were included after informed consent. The net cerebral fluxes of vasoactive peptides were measured by the Kety-Schmidt technique in ABM patients (baseline study only), as well as in volunteers at baseline, during voluntary hyperventilation, after an intravenous injection of lipopolysaccharide (LPS), and during norepinephrine infusion. RESULTS: The arterial levels of CGRP, but not of VIP or ET-1, were elevated in patients with ABM, but no net cerebral flux was present. CGRP levels decreased during hyperventilation and after LPS injection. No net cerebral flux of VIP occurred in any group at any time. A cerebral efflux of ET-1, which occurred in volunteers at baseline, was neither present in volunteers after LPS injection nor in patients with ABM. CONCLUSION: The arterial concentration of the vasodilatory peptide, CGRP, but of neither VIP nor the vasoconstrictor ET-1, is elevated in patients with ABM and sepsis. A constitutive cerebral output of ET-1 appears to be present in healthy humans, but is abolished after LPS injection.
Assuntos
Encéfalo/irrigação sanguínea , Meningites Bacterianas/fisiopatologia , Peptídeo Intestinal Vasoativo/sangue , Doença Aguda , Adulto , Idoso , Peptídeo Relacionado com Gene de Calcitonina/sangue , Cuidados Críticos , Endotelina-1 , Feminino , Humanos , Lipopolissacarídeos/sangue , Masculino , Pessoa de Meia-IdadeRESUMO
AIM: Hyperammonemia causes brain edema and high intracranial pressure (ICP) in acute liver failure (ALF) by accumulation of glutamine in brain. Since a high-level glutamine may compromise mitochondrial function, the aim of this study was to determine if the lactate-pyruvate ratio is associated with a rise in the glutamine concentration and ICP. PATIENTS AND METHODS: In 13 patients with ALF (8F/5M; median age 46 (range 18-66) years) the cerebral extracellular concentrations of glutamine, lactate, and pyruvate were measured by in vivo brain microdialysis together with ICP and cerebral perfusion pressure (CPP). RESULTS: The cerebral glutamine concentration was 4,396 (1,011-9,712) microM, lactate 2.15 (1.1-4.45) mM, and pyruvate 101 (43-255) microM. The lactate-pyruvate ratio was 21 (16-40), ICP 20 (2-28) mmHg, and CPP 72 (56-115) mmHg. Cerebral glutamine concentration correlated with the lactate-pyruvate ratio (r = 0.89, P < 0.05). Also the ICP, but not CPP, correlated to the lactate-pyruvate ratio (r = 0.64, P < 0.05). CONCLUSION: ICP and the cerebral glutamine concentration in patients with ALF correlate to the lactate-pyruvate ratio. Since CPP was sufficient in all patients the rise in lactate-pyruvate ratio indicates that accumulation of glutamine compromises mitochondrial function and causes intracranial hypertension.
Assuntos
Glutamina/metabolismo , Hipertensão Intracraniana/metabolismo , Ácido Láctico/metabolismo , Falência Hepática Aguda/metabolismo , Ácido Pirúvico/metabolismo , Adolescente , Adulto , Idoso , Astrócitos/patologia , Encéfalo/metabolismo , Edema Encefálico/etiologia , Edema Encefálico/metabolismo , Edema Encefálico/patologia , Cuidados Críticos , Feminino , Humanos , Hiperamonemia/etiologia , Hiperamonemia/metabolismo , Hipertensão Intracraniana/etiologia , Hipertensão Intracraniana/patologia , Falência Hepática Aguda/complicações , Masculino , Microdiálise , Pessoa de Meia-Idade , Mitocôndrias/metabolismo , Índice de Gravidade de DoençaRESUMO
OBJECTIVE: Patients with acute bacterial meningitis frequently develop sepsis, the hallmark of which is increased plasma cytokine levels. However, it is unknown whether the brain contributes to the intravascular accumulation of cytokines in meningitis. We measured the cerebral output of cytokines to the blood during severe pneumococcal meningitis accompanied by sepsis. DESIGN: Prospective physiologic study. SETTING: Multidisciplinary intensive care unit. PATIENTS: Seven patients (median age, 59; range, 26-72 years) with severe pneumococcal meningitis, as evidenced by a decreased level of consciousness and the need for mechanical ventilation, and concomitant sepsis; and seven healthy volunteers (age, 24; range, 21-29 years). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The cerebral output, defined as the cerebral blood flow multiplied by the jugular-to-arterial concentration difference, was measured individually for the cytokines tumor necrosis factor-alpha, interleukin-1beta, and interleukin-6. Cerebral blood flow was measured by the Kety-Schmidt method using an infusion of Xe, and the concentration of individual cytokines in arterial and jugular bulb blood was measured by enzyme-linked immunosorbent assay. Compared with controls, patients exhibited elevated plasma levels of all three cytokines, particularly interleukin-6, as well as a marked cerebral output of tumor necrosis factor-alpha and interleukin-6. No cytokine output was found in volunteers. CONCLUSIONS: Patients with pneumococcal meningitis and sepsis exhibit a cerebral output of tumor necrosis factor-alpha and interleukin-6, which may contribute to elevating the plasma levels of these cytokines.
Assuntos
Interleucina-1/biossíntese , Interleucina-6/biossíntese , Meningite Pneumocócica/metabolismo , Telencéfalo/metabolismo , Fator de Necrose Tumoral alfa/biossíntese , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Interleucina-1/sangue , Interleucina-6/sangue , Masculino , Meningite Pneumocócica/sangue , Meningite Pneumocócica/complicações , Pessoa de Meia-Idade , Estudos Prospectivos , Sepse/sangue , Sepse/complicações , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Swelling of cerebral glial cells is a characteristic complication in patients with acute liver failure (ALF). This astrocyte edema may result in high intracranial pressure (ICP) and brain herniation before or during liver transplantation. Metabolic alterations responsible for the development of high ICP in patients with ALF are not fully understood. We describe changes in neurochemistry during liver transplantation using a cerebral microdialysis technique in a young man with severe ALF and cerebral edema. We found that the extracellular content of lactate ([lactate](ec)) gradually increased during the operation. Because cerebral oxygen saturation and [lactate](ec) to [pyruvate](ec) ratio were within normal limits, hypoxia was not likely to be responsible for the increased [lactate](ec) levels. Instead, we found that [lactate](ec) levels correlated in this patient with arterial lactate concentrations during and after grafting (r(2) = 0.96; P <.05), but did not correlate with arterial glucose concentrations (r(2) = 0.20; P = not significant). Also, [glutamate](ec) and [glycerol](ec) levels were severely elevated before liver transplantation, but tended to decrease in the hours after grafting. These findings indicate disturbances in glutamate neurotransmission, arachidonic acid metabolism, and lactate flux across the blood-brain barrier in patients with ALF.
Assuntos
Encéfalo/metabolismo , Espaço Extracelular/metabolismo , Ácido Glutâmico/metabolismo , Glicerol/metabolismo , Ácido Láctico/metabolismo , Falência Hepática/metabolismo , Falência Hepática/cirurgia , Transplante de Fígado , Monitorização Intraoperatória , Doença Aguda , Adulto , Humanos , Masculino , Microdiálise , Concentração OsmolarRESUMO
Fulminant hepatic failure (FHF) is often complicated by high intracranial pressure (ICP) and fatal brain damage. In this study, we determined if a rise in [glutamate]ec and [lactate]ec preceded surges of high ICP in patients with FHF (median age, 42; range, 20-55 years; 7 women; 3 men) by inserting a microdialysis catheter into the brain-cortex together with an ICP catheter. The microdialysis catheter was perfused with artificial cerebrospinal-fluid at a rate of 0.3 microL/min. Dialysate was collected approximately every 30 minutes or when ICP increased. A total of 352 microdialysis samples were collected during a median of 3 days and allowed for approximately 1,760 bedside analyses of the collected dialysate. In 5 patients that later developed surges of high ICP, the initial values of [glutamate]ec and [lactate]ec were 2 to 5 times higher compared with patients with normal ICP. [Glutamate]ec then tended to vanish with time in both groups of patients. An increase in [glutamate]ec did not precede high ICP in any of the cases. In contrast, [lactate]ec was high throughout the study in the high ICP group and increased further before surges of high ICP. We conclude that in patients with FHF, cerebral [glutamate]ec and [lactate]ec are elevated. However, the elevated [glutamate]ec is not correlated to high ICP. In contrast, elevations in [lactate]ec preceded surges of high ICP. In conclusion, accelerated glycolysis with lactate accumulation is implicated in vasodilatation and high ICP in patients with FHF. The data suggest that bedside cerebral microdialysis is a valuable tool in monitoring patients with FHF and severe hyperammonemia.
Assuntos
Hipertensão Intracraniana/metabolismo , Hipertensão Intracraniana/fisiopatologia , Falência Hepática/metabolismo , Falência Hepática/fisiopatologia , Adulto , Feminino , Ácido Glutâmico/metabolismo , Humanos , Hiperventilação , Hipnóticos e Sedativos/administração & dosagem , Hipotermia Induzida , Hipertensão Intracraniana/etiologia , Ácido Láctico/metabolismo , Falência Hepática/complicações , Estudos Longitudinais , Masculino , Microdiálise , Pessoa de Meia-Idade , Tiopental/administração & dosagemRESUMO
BACKGROUND/AIMS: In severe cases of acute liver failure (ALF), cerebral hyperperfusion may result in high intracranial pressure and brain damage. The aim of this study was to determine if near-infrared spectrophotometry (NIRS) could detect a raise in cerebral blood flow and oxygenation induced by noradrenaline (NA) infusion. METHODS: In seven ALF patients (five females and two males; median age 49 years (range 20-70)) changes in cerebral concentration of oxy-(deltaHbO(2)) and total-haemoglobin (deltaHbT) were compared to the jugular bulb saturation (SvjO(2)) and cerebral blood flow velocity (Vmean) during NA infusion. RESULTS: Mean arterial pressure increased from 68 (64-86) to 103 (87-118) mmHg and the cerebral perfusion pressure from 61 (53-79) to 95 (74-110) mmHg (P<0.05), while the intracranial pressure (7 (6-15) mmHg) was not significantly changed. In six patients cerebral deltaHbO(2) and deltaHbT increased 2.7 (0.3-9.6) and 2.0 (0.3-14.8) micromol l(-1), respectively, but cerebral oxygenation decreased in one patient. SvjO(2) increased from 68 (55-76) to 74 (64-78) % (P<0.05) concomitant with an increase in Vmean from 47 (34-65) to 68 (50-86) cm s(-1) (P<0.05). deltaHbO(2) covariated with changes in SvjO(2) during NA in all but one patient. CONCLUSIONS: In ALF patients, a change in cerebral perfusion was detected by NIRS. The combination of NIRS and transcranial Doppler sonography may be valuable non-invasive techniques to detect cerebral hyperperfusion before intracranial hypertension becomes manifest.