B. Ellger

Glycemic Control Modulates Arginine and Asymmetrical-Dimethylarginine Levels during Critical Illness by Preserving Dimethylarginine-Dimethylaminohydrolase Activity

In the context of the hypercatabolic response to stress, critically ill patients reveal hyperglycemia and elevated levels of asymmetrical-dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthases. Both hyperglycemia and elevated ADMA levels predict increased morbidity and mortality. Tight glycemic control by intensive insulin therapy lowers circulating ADMA levels, and improves morbidity and mortality. Methylarginines are released from proteins during catabolism. ADMA is predominantly cleared by the enzyme dimethylarginine-dimethylaminohydrolase (DDAH) in different tissues, whereas its symmetrical isoform (SDMA) is cleared via the kidneys. Therefore, glycemic control or glycemia-independent actions of insulin on protein breakdown and/or on DDAH activity resulting in augmented ADMA levels may explain part of the clinical benefit of intensive insulin therapy. Therefore, we investigated in our animal model of prolonged critical illness the relative impact of maintaining normoglycemia and of glycemia-independent action of insulin over 7 d in a four-arm design on plasma and tissue levels of ADMA and SDMA, on proteolysis as revealed by surrogate parameters as changes of body weight, plasma urea to creatinine ratio, and plasma levels of SDMA, and on tissue DDAH activity. We found that ADMA levels remained normal in the two normoglycemic groups and increased in hyperglycemic groups. SDMA levels in the investigated tissues remained largely unaffected. The urea to creatinine ratio indicated reduced proteolysis in all but normoglycemic/normal insulin animals. DDAH activity deteriorated in hyperglycemic compared with normoglycemic groups. Insulin did not affect this finding independent of glycemic control action. Conclusively, maintenance of normoglycemia and not glycemia-independent actions of insulin maintained physiological ADMA plasma and tissue levels by preserving physiological DDAH activity.

Can regional anaesthesia for lymph-node dissection improve the prognosis in malignant melanoma?

BACKGROUNDnOptimized anaesthetic management might improve the outcome after cancer surgery. A retrospective analysis was performed to assess the association between spinal anaesthesia (SpA) or general anaesthesia (GA) and survival in patients undergoing surgery for malignant melanoma (MM).nnnMETHODSnRecords for 275 patients who required SpA or GA for inguinal lymph-node dissection after primary MM in the lower extremity between 1998 and 2005 were reviewed. The follow-up ended in 2009. Survival was calculated as days from surgery to the date of death or last patient contact. The primary endpoint was mortality during a 10 yr observation period.nnnRESULTSnOf 273 patients included, 52 received SpA and 221 GA, either as balanced anaesthesia (sevoflurane/sufentanil, n=118) or as total i.v. anaesthesia (propofol/remifentanil, n=103). The mean follow-up period was 52.2 (sd 35.69) months after operation. Significant effects on cumulative survival were observed for gender, ASA status, tumour size, and type of surgery (P=0.000). After matched-pairs adjustment, no differences in these variables were found between patients with SpA and GA. A trend towards a better cumulative survival rate for patients with SpA was demonstrated [mean survival (months), SpA: 95.9, 95% confidence interval (CI), 81.2-110.5; GA: 70.4, 95% CI, 53.6-87.1; P=0.087]. Further analysis comparing SpA with the subgroup of balanced volatile GA confirmed this trend [mean survival (months), SpA: 95.9, 95% CI, 81.2-110.5; volatile balanced anaesthesia: 68.5, 95% CI, 49.6-87.5, P=0.081].nnnCONCLUSIONSnThese data suggest an association between anaesthetic technique and cancer outcome in MM patients after lymph-node dissection. Prospective controlled trials on this topic are warranted.

Effects of Substitution and High-Dose Thyroid Hormone Therapy on Deiodination, Sulfoconjugation, and Tissue Thyroid Hormone Levels in Prolonged Critically Ill Rabbits

To delineate the metabolic fate of thyroid hormone in prolonged critically ill rabbits, we investigated the impact of two dose regimes of thyroid hormone on plasma 3,3-diiodothyronine (T(2)) and T(4)S, deiodinase type 1 (D1) and D3 activity, and tissue iodothyronine levels in liver and kidney, as compared with saline and TRH. D2-expressing tissues were ignored. The regimens comprised either substitution dose or a 3- to 5- fold higher dose of T(4) and T(3), either alone or combined, targeted to achieve plasma thyroid hormone levels obtained by TRH. Compared with healthy animals, saline-treated ill rabbits revealed lower plasma T(3) (P=0.006), hepatic T(3) (P=0.02), and hepatic D1 activity (P=0.01). Substitution-dosed thyroid hormone therapy did not affect these changes except a further decline in plasma (P=0.0006) and tissue T(4) (P=0.04). High-dosed thyroid hormone therapy elevated plasma and tissue iodothyronine levels and hepatic D1 activity, as did TRH. Changes in iodothyronine tissue levels mimicked changes in plasma. Tissue T(3) and tissue T(3)/reverse T(3) ratio correlated with deiodinase activities. Neither substitution- nor high-dose treatment altered plasma T(2). Plasma T(4)S was increased only by T(4) in high dose. We conclude that in prolonged critically ill rabbits, low plasma T(3) levels were associated with low liver and kidney T(3) levels. Restoration of plasma and liver and kidney tissue iodothyronine levels was not achieved by thyroid hormone in substitution dose but instead required severalfold this dose. This indicates thyroid hormone hypermetabolism, which in this model of critical illness is not entirely explained by deiodination or by sulfoconjugation.

Blutzuckerkontrolle bei Patienten mit Sepsis und septischem Schock

ZusammenfassungHintergrundPatienten auf Intensivtherapiestationen entwickeln unabhängig von der Grunderkrankung eine hyperglykämische Stoffwechsellage. Verschiedene Studien zeigten, dass das strikte Senken des Blutzuckers (BZ) mithilfe der intensivierten Insulintherapie (IIT) auf Normoglykämie die Prognose signifikant verbessert. Ob dies auch für Patienten in der Sepsis und im septischen Schock zutrifft, ist Gegenstand dieser Post-hoc-Analyse, die auf den Daten (2748xa0Patienten) zweier monozentrischer, prospektiver klinischer Studien basiert.Material und MethodenEs wurden insgesamt 950xa0Patienten identifiziert, die bei der stationären Aufnahme unter einer „Sepsis“ litten und von denen 462xa0Patienten die Diagnosekriterien eines „septischen Schocks“ erfüllten. Die Patienten wurden entweder mit IIT [mittlerer BZ 5,88xa0mmol/l (106xa0mg/dl)] oder einem konventionellen BZ-Management [mittlerer BZ 8,44xa0mmol/l (152xa0mg/dl)] behandelt.ErgebnisseDurch IIT wurde die Letalität der Patienten, die mehr als 3xa0Tage auf der Intensivtherapiestation behandelt wurden, um 7,6% (p=0,03) bei septischen Patienten bzw. 8,7% (p=0,08) bei Patienten im septischen Schock gesenkt. Polyneuropathien traten signifikant seltener auf (Sepsis −9,8%, septischer Schock −14%; p<0,001); die Inzidenz von akutem Nierenversagen wurde nicht signifikant beeinflusst (Sepsis −3,3%, septischer Schock −3,1%; p<0,25). Auch wenn unter IIT vermehrt Hypoglykämien auftraten (Sepsis +16,7%, septischer Schock +18,8%; p<0, 0001), kam hierdurch kein Patient unmittelbar zu Schaden.SchlussfolgerungDiese Daten legen nahe, dass auch Patienten in der Sepsis oder im septischen Schock von IIT profitieren. Hypoglykämie ist eine häufige Komplikation der IIT. Die klinische Relevanz kann jedoch nicht abschließend beurteilt werden.AbstractIntroductionIntensive care patients commonly suffer from hyperglycemia. Evidence is growing that strictly maintaining normoglycemia by intensive insulin therapy (IIT) ameliorates outcome in these patients. Whether or not this also holds true for patients with sepsis and septic shock is the issue of this post-hoc analysis of the database (2,748xa0patients) of 2 recent prospective clinical trials.Material and MethodsA total of 950 patients suffering from sepsis were identified and of these 462 fulfilled the diagnostic criteria of septic shock upon admission to the intensive care unit (ICU). Patients were treated by either IIT [mean glycemia 5.88xa0mmol/l (106xa0mg/dl)] or conventional glucose management [mean glycemia 8.44xa0mmol/l (152xa0mg/dl)].ResultsUnder IIT the mortality of patients treated for more than 3xa0days in the ICU was lowered by 7.6% (p=0.03) in septic patients and by 8.7% (p=0.08) in septic shock patients. Polyneuropathy occurred less frequently under IIT compared to conventional glucose management (sepsis −9.8%, septic shock −14%; p<0.001). The incidence of acute renal failure was not affected by either treatment regimen (sepsis −3.3%, septic shock −3.1%; p<0.25). Intensive insulin therapy was associated with an increased risk of hypoglycemia (sepsis +16.7%, septic shock +18.8; p<0.0001) which did not, however, directly affect morbidity nor mortality.ConclusionsThese data suggest that IIT improves outcome of patients with sepsis or septic shock. Hypoglycemia is a frequent complication, but its clinical relevance remains to be defined.

The effect of rosiglitazone on asymmetric dimethylarginine (ADMA) in critically ill patients

Asymmetric dimethylarginine (ADMA) plays a crucial role in the arginine-nitric oxide pathway. Critically ill patients have elevated levels of ADMA which proved to be a strong and independent risk factor for ICU mortality. The aim of this study was to investigate the effect of the peroxisome proliferator-activated receptor (PPAR)-gamma agonist rosiglitazone on ADMA plasma levels in critically ill patients. In a randomized controlled pilot study, ADMA, arginine and symmetric dimethylarginine (SDMA) were measured in 21 critically ill patients on the intensive care unit (ICU). Twelve patients received 4mg rosiglitazone once a day for a maximum of 6 weeks or until discharge or death. Nine patients served as control patients. In addition, total sequential organ failure assessment (SOFA score), kidney function and liver function were determined. Compared to the ADMA levels of healthy individuals as specified in earlier studies, ADMA plasma levels of critically ill patients were significantly higher (0.42+/-0.06 versus 0.73+/-0.2micromol/L, respectively; p<0.001). Both ADMA (B=3.5; 95% CI: 0.5-6.5; p=0.023) and SDMA (B=1.7; 95% CI: 0.7-2.7; p=0.001) were independently related to SOFA scores. Overall, rosiglitazone treatment had no effect on ADMA levels, which only significantly differed between the rosiglitazone and control groups at day 7 (p=0.028). The SOFA score in the rosiglitazone group was lower compared to the control group but the difference was only statistically significant at day 10 (p=0.01). In conclusion, in critically ill patients plasma ADMA levels were elevated and associated with the extent of multiple organ failure, but no significant ADMA-lowering effect of the PPAR-gamma agonist rosiglitazone was observed.

Changing from a specialized surgical observation unit to an interdisciplinary surgical intensive care unit can reduce costs and increase the quality of treatment

Background and objectives In Germany there is considerable variability in the organizational forms of intensive‐care medicine. We present economical data that arose during the reorganization of an intensive care unit with the implementation of the continuous presence of a trained intensivist. The unit was changed from an intensive‐observational unit managed by four surgical departments without continuous presence of a trained intensivist to an interdisciplinary surgical intensive care unit managed by the Department of Anaesthesia in co‐operation with the surgical departments with the continuous presence of trained intensivists. Methods Measurement of costs for personnel, medical equipment and external services, revenues, length of hospital stay and complications of cardiac surgical patients. Results Per year costs for personnel increased by approximately &U20AC;240 000, while expenses for medical equipment were reduced by &U20AC;245 000. In all, 466 hospital days were saved by the reduction in the length of hospital stay, providing capacity for 22 additional cardiac surgical cases. In addition, the presence of trained intensivists made it possible to provide care for more severely ill patients, which gained approximately 100 additional case‐mix points and increased the hospitals revenues by more than &U20AC;300 000. Emergency readmission to the intensive care unit was reduced by 17%. The number of patients requiring renal replacement therapy and those developing non‐occlusive mesenteric ischaemia was substantially reduced. Conclusion In addition to the medical advantages, staffing the intensive care unit with trained intensivists 24 h a day was of appreciable economical benefit.

Das Sepsis-assoziierte Guillain-Barré-Syndrom

ZusammenfassungEs wird über einen polytraumatisierten Patienten berichtet, der im hämorrhagischen Schock und unter schwerer Hypoxämie in die Klinik aufgenommen wurde. Im Anschluss an einen septischen Schock war dieser 3xa0Wochen später tetraplegisch. Nach Ausschluss aller traumatologischen und zerebralen Ursachen erfolgte eine Liquorpunktion zur neurologischen Diagnostik, die eine zytoalbuminäre Dissoziation zeigte. Im Zusammenhang mit der schlaffen Tetraparese wurde ein Guillain-Barré-Syndrom diagnostiziert. Die hochdosierte i.v.-Immunglobulintherapie führte zu einer Restitutio ad integrum.AbstractThis article reports on the case of a multiple trauma patient, who was admitted to the intensive care unit with haemorrhagic shock and severe hypoxaemia. Following posttraumatic septic shock the patient developed quadriplegia 3 weeks after admittance. After having excluded any traumatic and cerebral origins, an analysis of the cerebrospinal fluid was performed and revealed a“dissociation albuminocytologique”. This finding in association with limb quadriplegia led to the diagnosis of Guillain-Barré syndrome. Therapy with high-dose i.v. immunoglobulins led to a complete recovery.

Das Sepsis-assoziierte Guillain-Barré-Syndrom@@@Sepsis-associated Guillain-Barré syndrome

ZusammenfassungEs wird über einen polytraumatisierten Patienten berichtet, der im hämorrhagischen Schock und unter schwerer Hypoxämie in die Klinik aufgenommen wurde. Im Anschluss an einen septischen Schock war dieser 3xa0Wochen später tetraplegisch. Nach Ausschluss aller traumatologischen und zerebralen Ursachen erfolgte eine Liquorpunktion zur neurologischen Diagnostik, die eine zytoalbuminäre Dissoziation zeigte. Im Zusammenhang mit der schlaffen Tetraparese wurde ein Guillain-Barré-Syndrom diagnostiziert. Die hochdosierte i.v.-Immunglobulintherapie führte zu einer Restitutio ad integrum.AbstractThis article reports on the case of a multiple trauma patient, who was admitted to the intensive care unit with haemorrhagic shock and severe hypoxaemia. Following posttraumatic septic shock the patient developed quadriplegia 3 weeks after admittance. After having excluded any traumatic and cerebral origins, an analysis of the cerebrospinal fluid was performed and revealed a“dissociation albuminocytologique”. This finding in association with limb quadriplegia led to the diagnosis of Guillain-Barré syndrome. Therapy with high-dose i.v. immunoglobulins led to a complete recovery.

Blutzuckerkontrolle bei Patienten mit Sepsis und septischem Schock@@@Glycemic control in sepsis and septic shock: Freund oder Feind?@@@Friend or foe?

ZusammenfassungHintergrundPatienten auf Intensivtherapiestationen entwickeln unabhängig von der Grunderkrankung eine hyperglykämische Stoffwechsellage. Verschiedene Studien zeigten, dass das strikte Senken des Blutzuckers (BZ) mithilfe der intensivierten Insulintherapie (IIT) auf Normoglykämie die Prognose signifikant verbessert. Ob dies auch für Patienten in der Sepsis und im septischen Schock zutrifft, ist Gegenstand dieser Post-hoc-Analyse, die auf den Daten (2748xa0Patienten) zweier monozentrischer, prospektiver klinischer Studien basiert.Material und MethodenEs wurden insgesamt 950xa0Patienten identifiziert, die bei der stationären Aufnahme unter einer „Sepsis“ litten und von denen 462xa0Patienten die Diagnosekriterien eines „septischen Schocks“ erfüllten. Die Patienten wurden entweder mit IIT [mittlerer BZ 5,88xa0mmol/l (106xa0mg/dl)] oder einem konventionellen BZ-Management [mittlerer BZ 8,44xa0mmol/l (152xa0mg/dl)] behandelt.ErgebnisseDurch IIT wurde die Letalität der Patienten, die mehr als 3xa0Tage auf der Intensivtherapiestation behandelt wurden, um 7,6% (p=0,03) bei septischen Patienten bzw. 8,7% (p=0,08) bei Patienten im septischen Schock gesenkt. Polyneuropathien traten signifikant seltener auf (Sepsis −9,8%, septischer Schock −14%; p<0,001); die Inzidenz von akutem Nierenversagen wurde nicht signifikant beeinflusst (Sepsis −3,3%, septischer Schock −3,1%; p<0,25). Auch wenn unter IIT vermehrt Hypoglykämien auftraten (Sepsis +16,7%, septischer Schock +18,8%; p<0, 0001), kam hierdurch kein Patient unmittelbar zu Schaden.SchlussfolgerungDiese Daten legen nahe, dass auch Patienten in der Sepsis oder im septischen Schock von IIT profitieren. Hypoglykämie ist eine häufige Komplikation der IIT. Die klinische Relevanz kann jedoch nicht abschließend beurteilt werden.AbstractIntroductionIntensive care patients commonly suffer from hyperglycemia. Evidence is growing that strictly maintaining normoglycemia by intensive insulin therapy (IIT) ameliorates outcome in these patients. Whether or not this also holds true for patients with sepsis and septic shock is the issue of this post-hoc analysis of the database (2,748xa0patients) of 2 recent prospective clinical trials.Material and MethodsA total of 950 patients suffering from sepsis were identified and of these 462 fulfilled the diagnostic criteria of septic shock upon admission to the intensive care unit (ICU). Patients were treated by either IIT [mean glycemia 5.88xa0mmol/l (106xa0mg/dl)] or conventional glucose management [mean glycemia 8.44xa0mmol/l (152xa0mg/dl)].ResultsUnder IIT the mortality of patients treated for more than 3xa0days in the ICU was lowered by 7.6% (p=0.03) in septic patients and by 8.7% (p=0.08) in septic shock patients. Polyneuropathy occurred less frequently under IIT compared to conventional glucose management (sepsis −9.8%, septic shock −14%; p<0.001). The incidence of acute renal failure was not affected by either treatment regimen (sepsis −3.3%, septic shock −3.1%; p<0.25). Intensive insulin therapy was associated with an increased risk of hypoglycemia (sepsis +16.7%, septic shock +18.8; p<0.0001) which did not, however, directly affect morbidity nor mortality.ConclusionsThese data suggest that IIT improves outcome of patients with sepsis or septic shock. Hypoglycemia is a frequent complication, but its clinical relevance remains to be defined.