Plasma fibrinogen and albumin concentrations initially decrease after abdominal surgery. On postoperative days 3-5 fibrinogen concentration returns to the preoperative level or even higher, while albumin stays low. It is not known if these altered plasma concentrations reflect changes in synthesis rate, utilization, or both. In particular a low albumin plasma concentration has often been attributed to a low synthesis rate, which is not always the case. The objective of this study was to determine fibrinogen and albumin quantitative synthesis rates in patients undergoing major upper abdominal surgery with and without intact liver size. Patients undergoing liver or pancreatic resection (n = 9+6) were studied preoperatively, on postoperative days 1 and 3-5. De novo synthesis of fibrinogen and albumin was determined; in addition, several biomarkers indicative of fibrinogen utilization were monitored. After hemihepatectomy, fibrinogen synthesis was 2-3-fold higher on postoperative day 1 than preoperatively. On postoperative days 3-5 the synthesis level was still higher than preoperatively. Following major liver resections albumin synthesis was not altered postoperatively compared to preoperative values. After pancreatic resection, on postoperative day 1 fibrinogen synthesis was 5-6-fold higher than preoperatively and albumin synthesis 1.5-fold higher. On postoperative days 3-5, synthesis levels returned to preoperative levels. Despite decreases in plasma concentrations, de novo synthesis of fibrinogen was markedly stimulated on postoperative day 1 after both hemihepatectomies and pancreatectomies, while de novo albumin synthesis remained grossly unchanged. The less pronounced changes seen following hepatectomies were possibly related to the loss of liver tissue.

BackgroundAcute kidney injury (AKI) is frequently observed after orthotopic liver transplantation (OLT) even in patients with previously normal renal function. In this study, we investigated the impact of factors such graft steatosis, post‐reperfusion syndrome (PRS), and hepatic ischemia reperfusion injury (HIRI) on the development of AKI after OLT in adult patients.MethodsWe retrospectively examined consecutive adult patients who underwent OLT at our institution between July 2011 and June 2017. AKI was diagnosed based on the criteria proposed by the International Kidney Disease Improving Global Outcomes (KDIGO) workgroup. Peak aspartate aminotransferase (AST) level within 72 hours after OLT was used as a surrogate marker for HIRI. Graft steatosis was diagnosed by histopathological examination using specimens biopsied intraoperatively at the end of transplantation procedure and categorized as <10%, 10%‐20%, 20%‐30%, and ≥30% of hepatic steatosis.ResultsOut of 386 patients, 141 (37%) developed AKI (KDIGO stage 1:71 patients; stage 2:29 patients; stage 3:41 patients). Multivariable logistic regression analysis revealed that cold ischemic time (P = .012) and HIRI (P = .007) were independent risk factors for post‐OLT AKI. Multivariable analysis also revealed that graft steatosis was associated with HIRI but not directly with AKI. PRS was not associated with HIRI or AKI in the multivariable analyses.ConclusionOur results indicate that greater severity of liver graft injury during transplantation negatively affects renal function after OLT. As expected, the severity of liver graft steatosis contributes to accelerated liver injury occurring during the transplantation procedure.

In major abdominal surgery albumin is shifted from the circulation, presumably leaking into the interstitial space, contributing to a 30–40% decrease in plasma albumin concentration. During and after liver transplantation exogenous albumin is infused for volume substitution and to maintain plasma albumin concentration. Here we used liver transplantation as a model procedure for the study of albumin mass balance and kinetics during major abdominal surgery with albumin substitution.

The severity of liver disease is assessed by scoring systems, which include the conventional coagulation test prothrombin time-the international normalized ratio (PT-INR). However, PT-INR is not predictive of bleeding in liver disease and thromboelastometry (ROTEM) has been suggested to give a better overview of the coagulation system in these patients. It has now been suggested that coagulation as reflected by tromboelastomety may also be used for prognostic purposes. The objective of our study was to investigate whether thrombelastometry may discriminate the degree of liver insufficiency according to the scoring systems Child Pugh and Model for End-stage Liver Disease (MELD).Forty patients with chronic liver disease of different etiologies and stages were included in this observational cross-sectional study. The severity of liver disease was evaluated using the Child-Pugh score and the MELD score, and blood samples for biochemistry, conventional coagulation tests, and ROTEM were collected at the time of the final assessment for liver transplantation. Statistical comparisons for the studied parameters with scores of severity were made using Spearman correlation test and receiver-operating characteristic (ROC) curves.Spearman correlation coefficients indicated that the thromboelastometric parameters did not correlate with Child-Pugh or MELD scores. The ROC curves of the thromboelastometric parameters could not differentiate advanced stages from early stages of liver cirrhosis.Standard ROTEM cannot discriminate the stage of chronic liver disease in patients with severe chronic liver disease.

The severity of liver disease is assessed by scoring systems, which include the conventional coagulation test prothrombin time-the international normalized ratio (PT-INR). However, PT-INR is not predictive of bleeding in liver disease and thromboelastometry (ROTEM) has been suggested to give a better overview of the coagulation system in these patients. It has now been suggested that coagulation as reflected by tromboelastomety may also be used for prognostic purposes. The objective of our study was to investigate whether thrombelastometry may discriminate the degree of liver insufficiency according to the scoring systems Child Pugh and Model for End-stage Liver Disease (MELD). Forty patients with chronic liver disease of different etiologies and stages were included in this observational cross-sectional study. The severity of liver disease was evaluated using the Child-Pugh score and the MELD score, and blood samples for biochemistry, conventional coagulation tests, and ROTEM were collected at the time of the final assessment for liver transplantation. Statistical comparisons for the studied parameters with scores of severity were made using Spearman correlation test and receiver-operating characteristic (ROC) curves. Spearman correlation coefficients indicated that the thromboelastometric parameters did not correlate with Child-Pugh or MELD scores. The ROC curves of the thromboelastometric parameters could not differentiate advanced stages from early stages of liver cirrhosis. Standard ROTEM cannot discriminate the stage of chronic liver disease in patients with severe chronic liver disease.

IntroductionAfter major liver surgery, there are risks of both postoperative bleeding and thrombosis. Routine coagulation monitoring is indicated, but may not provide adequate clinical guidance. Thus, we described the clotting status in a pilot study using broader coagulation testing. We analysed the temporal pattern of coagulation tests to assess whether thromboelastometry (ROTEM®) would improve the quality of the postoperative monitoring of the coagulation status in patients undergoing major hepatic resections.Material and methodsSixteen patients undergoing major liver resections were examined prior to surgery, on postoperative day 1, and subsequently, every three postoperative days during hospitalization. At the same time, the clinical signs of bleeding and thrombotic complications were monitored.ResultsOn postoperative day 1, increases in bilirubin, PT-INR, APTT, and D-dimers were observed, together with concomitant decreases in fibrinogen, platelet count, antithrombin (AT), protein C and protein S compared to preoperative values. On postoperative days 4 and 7, all of the variables had returned to the normal range except for D-dimers, AT and protein C. The ROTEM® median values remained within the normal range. There were no significant episodes of postoperative bleeding. Two patients were diagnosed with a pulmonary embolism.ConclusionDespite the abnormalities observed in routine coagulation monitoring, thromboelastometry indicated a balanced coagulation status following major hepatic surgery. The levels of both pro- and anticoagulant proteins changed over time during this period. The exact clinical role for thromboelastometry in major hepatic surgery remains to be established.

CONCLUSIONS:Uvulopalatopharyngoplasty (UPPP) in patients with obstructive sleep apnoea syndrome (OSAS) who had failed treatment with continuous positive airway pressure (CPAP) and mandibular retaining device (MRD) was effective and safe. The satisfaction rate was high. We recommend UPPP in selected OSAS patients, especially younger patients. OBJECTIVES:To evaluate the efficacy and complication rate of UPPP. PATIENTS AND METHODS:This was a non-randomized prospective study of 139 men and 19 women, median age 45 years (range 20-75), median body mass index (BMI) 29 (range 20-48), who underwent UPPP. One year follow-up comprised ambulant sleep apnoea recordings and questionnaires with the Epworth Sleepiness Scale (ESS). RESULTS:In all, 76% of the patients underwent sleep recordings preoperatively and postoperatively. The oxygen desaturation index (ODI(4)) decreased from median 23 (range 6-100) to 8 (range 0-60), p<0.001. Criteria of success (>50% reduction and ODI<20), was 64%. The ESS value decreased from median 12 (range 0-21) to 6 (0-22), p<0.001. In all, 88% of the patients were satisfied. Four of 158 patients (2.5%) had serious postoperative complications. There was neither sequel of complications nor mortality.

Insufficient function of the immune system contributes to a poor prognosis in intensive care unit (ICU) patients. However, the immune system function is not easily monitored and evaluated. In vivo protein synthesis determination in immune competent cells offers a possibility to quantify immunological activation. The aim of this descriptive study was to determine the in vivo fractional protein synthesis rate (FSR) in immune cells of ICU patients during the initial phase of the critical illness. Patients (n = 20) on ventilator treatment in the general ICU were studied during their first week of ICU stay. FSR was determined in circulating T lymphocytes, mononuclear cells, the whole population of blood leukocytes, and in stationary immune cells of palatine tonsils during a 90-min period by a flooding technique. Healthy, adult subjects (n = 11), scheduled for elective ear, nose, and throat surgery served as a control group. The FSR in leukocytes and mononuclear cells of ICU patients was higher compared with the control group. In contrast, the FSR of circulating T lymphocytes and of tonsillar cells was not different from that in the healthy subjects. In summary, the ICU patients showed a distinct polarization of metabolic responses during the initial phase of the critical illness. The in vivo rate of protein synthesis was high in the circulating mononuclear cells and leukocytes, reflecting enhanced metabolic activity in these cell populations. Determination of the in vivo protein synthesis rate may be used as a tool to obtain additional information on activation of the immune system.

Intact immune responses are essential for defeating severe infections in individual patients. Insufficient function of the immune system contributes to a poor prognosis in these patients, in particular the ICU patients. Nevertheless, the immune system function is not easily monitored and evaluated. The ongoing metabolic activity of immune competent cells is reflected by their in vivo protein synthesis rate. The aim of this thesis was to apply in vivo protein synthesis measurement in cells of the immune system, in order to quantitatively characterise the state of their activation. Such measurement may add information on immune cells activation and serve as a tool for evaluation of immune competence in severely ill patients. The in vivo fractional protein synthesis rate (FSR) was determined in the circulating peripheral blood cells: T lymphocytes, mononuclear cells and whole population of leukocytes, as well as in the stationary, unfractioned cells of palatine tonsils. The FSR in the isolated T lymphocytes of healthy volunteers was 13.6 ± 0.9 %/24 h and was not affected by a 6-h cortisol infusion, either immediately after the end of the infusion or 18 h later. In contrast, a combined stress hormone infusion (cortisol, epinephrine, glucagon), as a human model of surgical trauma, given for 6 h to healthy volunteers decreased the in vivo protein synthesis rate in T lymphocytes by 34% from 13.0 ± 1.0 %/24 h to 8.6 ± 2.1 %/24 h. A more accentuated decrease by 53% was observed in the total mononuclear cells, from 13.3 ± 1.2 %/24 h to 6.3 ± 2.0 %/24 h. Following an endotoxin injection, a human model of the initial phase of sepsis, different patterns of the in vivo fractional protein synthesis rates were observed in the circulating blood cells of healthy volunteers. The isolated T lymphocytes responded with a 60% decrease of the protein synthesis rate from 9.4 ± 1.2 %/24 h to 3.8 ± 2.4 %/24 h, whereas the whole population of leukocytes showed an increase by 43% from 3.2 ± 1.2 %/24 h to 4.4 ± 1.1 %/24 h. A comparison of the in vivo fractional protein synthesis rate between the circulating and stationary immune cells of healthy subjects revealed that unfractioned tonsillar cells had a protein synthesis rate of 22.8 ± 5.7 %/24 h. This rate was higher compared with T lymphocytes, mononuclear cells and leukocytes separated from peripheral blood in these subjects, having in vivo protein synthesis rates of 10.7 ± 3.4 %/24 h, 10.8 ± 2.8 %/24 h and 3.2 ± %/24 h, respectively. Alterations in the protein synthesis rates were also observed during the early phase of the critical illness. In a pilot group of intensive care unit patients with a general systemic inflammatory activation, a distinct polarization of the protein synthesis responses was observed. The in vivo protein synthesis rate in the mononuclear cells and in the whole population of leukocytes was high, 21.6 ± 7.4 %/24 h and 8.9 ± 4.4 %/24 h, respectively, while that in T lymphocytes (12.5 ± 5.5 %/24 h) and tonsillar cells (27.9 ± 11.4 %/24 h) was not different from what was observed in healthy subjects. In summary, uniform and characteristic changes of the in vivo rate of protein synthesis in response to exogenous stimuli in healthy volunteers and during the early phase of systemic inflammation in critically ill patients were described in the individual populations of immune cells. The in vivo protein synthesis determination in the immune cells reflects the state of activation of these cells. This measurement may be used as a tool to obtain additional information on the immune competence in studies concerning function of the human immune system. LIST OF PUBLICATIONS This thesis is based on the following papers, which will be referred to in the text by their Roman numerals I-V. I. In vivo protein synthesis of circulating human T lymphocytes does not respond to a cortisol challenge within 24 hours. Januszkiewicz A, Essen P, McNurlan MA, Ringden O, Wernerman J, Garlick PJ. Acta Anaesthesiol Scand, 2000; 44: 202-209. II. Stress hormone infusion decreases protein synthesis of circulating human T lymphocytes. Januszkiewicz A, Essen P, McNurlan MA, Ringden O, Garlick PJ, Wernerman J. Metabolism, 2001; 11: 1308-1314. III. Response of in vivo protein synthesis in T lymphocytes and leukocytes to an endotoxin challenge in healthy volunteers. Januszkiewicz A, Lore K, Essen P, Andersson B, McNurlan MA, Garlick PJ, Ringden O, Andersson J, Wernerman J. Clin Exp Immunol, 2002; 130: 263-270. IV. Determination of in vivo protein synthesis in human palatine tonsil. Januszkiewicz A, Klaude M, Lore K, Andersson J, Ringden O, Rooyackers O, Wernerman J. Clin Sci, 2005; 108: 179-184. V. In vivo protein synthesis in immune cells of ICU patients – a pilot study. Januszkiewicz A, Klaude M, Lore K, Andersson J, Ringden O, Rooyackers O, Wernerman J. Manuscript. Reprints of the above articles were made with the kind permission of the publishers: Blackwell Publishing (paper I and III), Elsevier Science (paper II) and Portland Press (paper IV).