Best practice for perioperative management of patients with cytoreductive surgery and HIPEC.

Due to the significantly improved outcome and quality of life of patients with different tumor entities after cytoreductive surgery (CRS) and HIPEC, there is an increasing number of centers performing CRS and HIPEC procedures. As this procedure is technically challenging with potential high morbidity and mortality, respectively, institutional experience also in the anesthetic and intensive care departments is essential for optimal treatment and prevention of adverse events. Clinical pathways have to be developed to achieve also good results in more comorbid patients with border line indications and extensive surgical procedures. The anesthesiologist has deal with relevant fluid, blood and protein losses, increased intraabdominal pressure, systemic hypo-/hyperthermia, and increased metabolic rate in patients undergoing cytoreductive surgery with HIPEC. It is of utmost importance to maintain or restore an adequate volume by aggressive substitution of intravenous fluids, which counteracts the increased fluid loss and venous capacitance during this procedure. Supplementary thoracic epidural analgesia, non-invasive ventilation, and physiotherapy are recommended to guarantee adequate pain therapy and postoperative extubation as well as fast-track concepts. Advanced hemodynamic monitoring is essential to help the anesthesiologist picking up information about the real-time fluid status of the patient. Preoperative preconditioning is mandatory in patients scheduled for HIPEC surgery and will result in improved outcome. Postoperatively, volume status optimization, early nutritional support, sufficient anticoagulation, and point of care coagulation management are essential. This is an extensive update on all relevant topics for anesthetists and intensivists dealing with CRS and HIPEC.

[Key Points of Intraoperative Diagnostic Measures Performed by Anaesthesiologists]. / Relevante Eckpunkte der intraoperativen anästhesiologischen Diagnostik.

The main focus of surgeons and anaesthesiologists during a surgical procedure is on safety and optimal treatment of the patient. Within the scope of interdisciplinary collaboration, the intraoperative communication between surgeons and anaesthesiologists is the basis of case-, findings- and surgery-phases-adapted patient management. The perioperative monitoring of patients and the implementation of diagnostic measures by anaesthesiologists are essential for optimal patient management. The results of the examinations may significantly determine the course of surgery. Therefore, it is important for surgeons to be familiar with the relevant intraoperative diagnostic measures.

[Whole-body-CT in Severely Injured Children. Results of Retrospective, Multicenter Study with Patients from the TraumaRegsiter DGU®]. / Ganzkörper-CT bei schwerverletzten Kindern. Ergebnisse einer retrospektiven Multizenterstudie anhand des TraumaRegister DGU®.

BACKGROUND: A fast and comprehensive diagnostic by means of whole-body CT has been shown to reduce mortality in the adult trauma population. Therefore whole-body CT seems to be the standard in adult trauma-patients. Due to the higher radiation exposure of whole-body CT the use of this diagnostic toll in pediatric trauma patients is still under debate. It is not yet clear if whole-body CT in children can increase the probability of survival. METHOD: In a retrospective, multicenter study, we used the data recorded in the TraumaRegister DGU(®) to calculate the probability of survival according to the revised injury severity classification (RISC) and standardized mortality ratio (SMR). The SMR reflects the ratio of recorded to expected mortality. Included in the study were all children (1-15 years) and adults (16-50 years) with an Injury Severity Score (ISS)>9, who were directly admitted to the hospital from the scene of accident. We compared the groups of patients given whole-body CT or non-whole-body CT. Subgroup analysis was performed for children 1-9 years, children 10-15 years and adults. RESULTS: A total of 1,456 pediatric trauma patients (mean age 9.9 years) and 20,796 adults (mean age 32.7 years) were included in the study. In contrast to adult trauma patients, were the SMR in the whole-body CT group was significant lower; we observed no advantage for the whole-body CT in pediatric trauma patients. CONCLUSION: Due to the missing advantage of whole-body CT in the pediatric trauma population and the higher radiation exposure of whole-body CT a non-whole-body CT approach seems equivalent with a lower radiation exposure.

Novel Broad-Spectrum Antimicrobial Photoinactivation of In Situ Oral Biofilms by Visible Light plus Water-Filtered Infrared A.

Antimicrobial photodynamic therapy (APDT) has gained increased attention as an alternative treatment approach in various medical fields. However, the effect of APDT using visible light plus water-filtered infrared A (VIS + wIRA) on oral biofilms remains unexplored. For this purpose, initial and mature oral biofilms were obtained in situ; six healthy subjects wore individual upper jaw acrylic devices with bovine enamel slabs attached to their proximal sites for 2 h or 3 days. The biofilms were incubated with 100 µg ml(-1) toluidine blue O (TB) or chlorin e6 (Ce6) and irradiated with VIS + wIRA with an energy density of 200 mW cm(-2) for 5 min. After cultivation, the CFU of half of the treated biofilm samples were quantified, whereas following live/dead staining, the other half of the samples were monitored by confocal laser scanning microscopy (CLSM). TB- and Ce6-mediated APDT yielded a significant decrease of up to 3.8 and 5.7 log10 CFU for initial and mature oral biofilms, respectively. Quantification of the stained photoinactivated microorganisms confirmed these results. Overall, CLSM revealed the diffusion of the tested photosensitizers into the deepest biofilm layers after exposure to APDT. In particular, Ce6-aided APDT presented elevated permeability and higher effectiveness in eradicating 89.62% of biofilm bacteria compared to TB-aided APDT (82.25%) after 3 days. In conclusion, antimicrobial photoinactivation using VIS + wIRA proved highly potent in eradicating oral biofilms. Since APDT excludes the development of microbial resistance, it could supplement the pharmaceutical treatment of periodontitis or peri-implantitis.

Thromboelastometric detection of clotting Factor XIII deficiency in cardiac surgery patients.

AIM(S): In this article, we aimed to investigate plasma Factor XIII levels after extracorporeal circulation in cardiac surgery by thromboelastometric detection, as extracorporeal circulation causes various coagulation disorders due to the exposure of blood to artificial surfaces, inflammatory induction and mechanical destruction of platelets and coagulation factors, which may particularly affect factors with long half-lives, such as Factor XIII. BACKGROUND: Since transfusion algorithms are often empirical and laboratory analysis of Factor XIII plasma levels may not be available 24 h a day, bed-side testing using rotational thromboelastometry (ROTEM) could offer a splendid option to define the cause of excessive peri-operative bleeding disorders in general and Factor XIII levels in particular in a timely manner and thus facilitating exact substitution therapy. METHODS: In this trial, we investigated 25 cardiac surgery patients with extracorporeal bypass times over 100 min. Standard laboratory and ROTEM analyses were performed post-operatively at the time of intensive care unit admission and 6 h later. We implemented EXTEM with additional Factor XIII (teenTEM) as additional test by adding 0·625 IU Factor XIII to standard EXTEM reagents. RESULTS: In this observational study, we could not demonstrate a correlation between Factor XIII and MCFEXTEM , CFTEXTEM or MLEXTEM . Neither Factor XIII plasma levels nor MCFEXTEM could predict blood loss. In accordance with previous findings, we were able to demonstrate increased maximum clot firmness (MCF), decreased clot formation time and decreased maximum lysis by adding Factor XIII in vitro (teenTEM vs EXTEM) indicating an improvement in the coagulation process. As shown before, we also found a strong correlation between MCF and platelet and fibrinogen plasma levels. CONCLUSION: In summary, 'teenTEM' test does not seem to detect Factor XIII deficient patients in cardiac surgery. Furthermore, post-operative blood loss could not be predicted neither by ROTEM nor by laboratory analysis of Factor XIII. In vitro administration of Factor XIII appears to improve laboratory measures of haemostasis.

Glutamine and alanine-induced differential expression of intracellular IL-6, IL-8, and TNF-α in LPS-stimulated monocytes in human whole-blood.

To investigate the effects of the commonly-used immunomodulators l-glutamine, l-alanine, and the combination of both l-alanyl-l-glutamine (Dipeptamin(®)) on intracellular expression of IL-6, IL-8, and TNF-α during endotoxemia, lipopolysaccharide (LPS)-stimulated human monocytes in a whole blood system were investigated by flow cytometry. Whole blood of twenty-seven healthy volunteers was stimulated with LPS and incubated with three different amino acid solutions (1. l-glutamine, 2. l-alanine, 3. l-alanyl-l-glutamine, each concentration 2 mM, 5 mM, incubation time 3 h). CD14(+) monocytes were phenotyped in whole-blood and intracellular expression of cytokines was assessed by flow cytometry. Our investigations showed for the first time in whole blood probes, imitating best physiologically present cellular interactions, that l-glutamine caused a dose-independent inhibitory effect on IL-6 and TNF-α production in human monocytes stimulated with LPS. However, l-alanine had contrary effects on IL-6 expression, significantly upregulating expression of IL-6 in LPS-treated monocytes. The impact of l-alanine on the expression of TNF-α was comparable with glutamine. Neither amino acid was able to affect IL-8 production in LPS-stimulated monocytes. The combination of both did not influence significantly IL-6 and IL-8 expression in monocytes during endotoxemia, however strongly reduced TNF-α production. For the regulation of TNF-α, l-glutamine, l-alanine and the combination of both show a congruent and exponentiated downregulating effect during endotoxemia, for the modulation of IL-6, l-glutamine and l-alanine featured opposite regulation leading to a canceling impact of each other when recombining both amino acids.

NF-κB-mediated inverse regulation of fractalkine and CX3CR1 during CLP-induced sepsis.

Fractalkine is a unique member of the CX3C chemokine family by unfolding its potential through the chemokine (C-X3-C motif) receptor 1 (CX3CR1) with dual function acting both as an adhesion molecule and a soluble chemokine. The regulation of this chemokine is still not clear. Therefore, we were interested in the regulation of fractalkine and of CX3CR1 in experimental sepsis. In addition, we investigated the role of NF-κB for the regulation of fractalkine and of CX3CR1. Using a mouse model of cecal ligation and puncture (CLP)-induced sepsis, we found elevated fractalkine mRNA levels in the heart, lung, kidney, and liver, as well as increased plasma levels 24 and 48h after CLP, respectively. In parallel, CLP resulted in a significant downregulation of CX3CR1 mRNA receptor expression in all investigated murine tissues. Septic mice that were pretreated with the selective NF-κB inhibitor pyrrolidine dithiocarbamate (PDTC) were found to have a decreased liberation of proinflammtory cytokines such as TNF-α, IL-1ß, IL-6, or IFN-γ. Further PDTC pretreatment attenuated CLP-induced downregulation of CX3CR1 mRNA as well as CLP-induced upregulation of fractalkine mRNA expression in the heart, lung, kidney, liver, and the increase in fractalkine plasma levels of septic mice. In addition, CLP-induced downregulation of renal CX3CR1 protein expression was inhibited by PDTC-pretreatment. Taken together, our data indicate a CLP-induced inverse regulation of the expression between the relating ligand and the receptor with an upregulation of fractalkine and downregulation of CX3CR1, which seems to be mediated by the transcripting factor NF-κB likely via reduced liberation of proinflammtory cytokines in the whole murine organism.

[Perioperative Addisonian crisis]. / Perioperative Addison-Krise.

An Addisonian crisis marks an acute adrenocortical failure which can be caused by decompensation of a chronic insufficiency due to stress, an infarct or bleeding of the adrenal cortex and also abrupt termination of a long-term glucocorticoid medication. This article reports the case of a 25-year-old patient with Crohn's disease who suffered an Addisonian crisis with hypotension, hyponatriemia and hypoglycemia during an emergency laparotomy after he had terminated prednisolone medication on his own authority. This necessitated an aggressive volume therapy in addition to an initial therapy with 100 mg hydrocortisone, 8 g glucose and a continuous administration of catecholamines. Under this treatment regimen hemodynamic stabilization was achieved. Reduction of the administration of hydrocortisone after 3 days resulted in cardiovascular insufficiency which required an escalation of the hydrocortisone substitution.

[Preoperative α-adrenoceptor block in asymptomatic pheochromocytoma? Pro]. / Präoperative α-Rezeptoren-Blockade beim asymptomatischen Phäochromozytom? Pro.

In approximately 90% of all cases a pheochromocytoma causes sustained or paroxysmal hypertension. During surgical resection tumor manipulation can lead to excessive catecholamine release with the risk of life-threatening complications. Since the early 1950s a preoperative medical treatment with an α-adrenoceptor blocking agent has been successfully administered for prevention of hemodynamic instability but not all pheochromocytomas are associated with hypertension. Currently the discovery of asymptomatic pheochromocytomas is more frequent than in the time prior to modern imaging techniques (computed tomography, magnetic resonance imaging). There is little information about this type of pheochromocytoma in the literature. This article discusses the question if preoperative α-adrenoceptor block is also indicated in asymptomatic pheochromocytomas based on the current literature.

Perioperative management of patients with cytoreductive surgery for peritoneal carcinomatosis.

Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC) has become an important tool in the management of patients with peritoneal malignancies. It is a complex surgical procedure with significant fluid loss during debulking leading to relevant pathophysiological alterations and therefore a challenge for anesthesiologists and critical care physicians. This review summarizes perioperative changes in hemodynamics, oxygen supply, coagulation, hematopoetic parameters and fluid status during cytoreductive surgery and HIPEC and how to deal with these pathophysiological alterations.

[Neurological complication after a vertical infraclavicular brachial plexus block. Case report of possible differential diagnoses of a neurological deficit]. / Neurologische Komplikation nach einer vertikalen infraklavikulären Plexusblockade: Fallbericht über mögliche Differenzialdiagnosen eines neurologischen Defizits.

A 72-year-old man with an obliteration of the brachial artery received a vertical infraclavicular block (VIP) for vascular surgery but 20 h after the operation a complete paresis of the affected extremity occurred. A new vascular obliteration could be excluded. During the diagnostic examination the patient noticed a snapping noise in the cervical column when moving his head and an abrupt recovery of the neurological deficits occurred. The radiological diagnostic provided no indication of cerebral ischemia or lesions of the brachial plexus. An additional diagnostic finding was a profound herniated vertebral disc with compression of the myelon. Fortunately, the neurological deficits completely returned to normal.

Peri-operative anaesthetic management of cytoreductive surgery with hyperthermic intraperitoneal chemotherapy.

Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC) is a long and complex procedure with significant blood and fluid loss during debulking and important pathophysiological alterations during the HIPEC phase. We performed a retrospective analysis of 78 consecutive patients undergoing cytoreductive surgery with HIPEC at a university hospital. Our data demonstrate large intra-operative fluid turnover, with 51% of patients requiring a blood transfusion. During HIPEC, airway pressure and central venous pressure increased with a lower oxygenation ratio as a result of increased intra-abdominal pressure with the closed abdomen technique. As a consequence of the raised body temperature, heart rate, end tidal carbon dioxide and arterial lactate levels increased with a slight metabolic acidosis. Peri-operative analysis of routine clotting parameters revealed disturbances of the coagulation status. For pain management, 72% of patients received supplementary thoracic epidural analgesia with consequential peri-operative opioid sparing and a reduced duration of postoperative ventilation.

Nitric oxide-dependent down-regulation of angiotensin II type 2 receptors during experimental sepsis.

OBJECTIVE: The systemic renin-angiotensin system is highly activated during septic shock. This has focused interest in regulation of the adrenal angiotensin II type 2 receptor (AT2) as the target thought to mediate angiotensin II-induced adrenal catecholamine release during experimental sepsis in vivo. In addition, the influence of typical endogenous mediators of sepsis, such as proinflammatory cytokines and nitric oxide, on AT2 receptor expression should be investigated in vitro. DESIGN: Prospective animal trial followed by a controlled cell culture study. SETTING: Laboratory of the Department of Anesthesiology. SUBJECTS: Male Sprague-Dawley rats weighing 200-250 g, PC12 cell line. INTERVENTIONS: Rats were injected with lipopolysaccharide to stimulate Gram-negative sepsis or lipoteichoic acid to stimulate Gram-positive sepsis. AT2 receptor expression, abundance of the proinflammatory cytokines (interleukin-1beta, tumor necrosis factor-alpha, and interferon-gamma), and nitric oxide synthase II expression have been determined in the adrenal gland. Rat adrenal pheochromocytoma cells were incubated with these cytokines or with the nitric oxide donors sodium nitroprusside or S-nitroso-N-acetylpenicillamine to investigate the regulation of AT2 receptors during severe inflammation on a cellular level. MEASUREMENTS AND MAIN RESULTS: In the adrenal gland, AT2 receptor expression was down-regulated in both models of sepsis, whereas tissue cytokine concentrations were elevated and nitric oxide synthase II expression was induced. Incubation of PC12 cells with proinflammatory cytokines resulted in a dose-dependent diminished expression of AT2 receptors, which was mimicked by incubation with nitric oxide donors. Blocking of cytokine-induced nitric oxide synthesis by co-incubation of PC12 cells with NG-nitro-l-arginine methyl ester prevented down-regulation of AT2 receptors. CONCLUSIONS: These findings show that in our model of sepsis, the expression of AT2 receptors in the adrenal gland is down-regulated in a nitric oxide-dependent manner. Because AT2 receptors are thought to be involved in adrenal catecholamine secretion in a stimulatory fashion, the diminished expression of AT2 receptors could play an important role in the pathogenesis of septic shock via impaired angiotensin II-induced adrenal catecholamine release, despite a strong activation of the systemic renin-angiotensin system.

Downregulation of angiotensin II type 1 receptors during sepsis.

Our study aimed to characterize the mechanisms underlying the attenuated cardiovascular responsiveness toward the renin-angiotensin system during sepsis. For this purpose, we determined the effects of experimental Gram-negative and Gram-positive sepsis in rats. We found that sepsis led to a ubiquitous upregulation of NO synthase isoform II expression and to pronounced hypotension. Despite increased plasma renin activity and plasma angiotensin (Ang) II levels, plasma aldosterone concentrations were normal, and the blood pressure response to exogenous Ang II was markedly diminished in septic rats. Mimicking the fall of blood pressure during sepsis by short-term infusion of the NO donor sodium nitroprusside in normal rats did not alter their blood pressure response to exogenous Ang II. Therefore, we considered the possibility of an altered expression of Ang II receptors during sepsis. It turned out that Ang II type 1 receptor expression was markedly downregulated in all organs of septic rats. Further in vitro studies with rat renal mesangial cells showed that NO and a combination of proinflammatory cytokines (interleukin-1beta, tumor necrosis factor-alpha, and interferon-gamma) downregulated Ang II type 1 receptor expression in a synergistic fashion. In summary, our data suggest that sepsis causes a systemic downregulation of Ang II type 1 receptors that is likely mediated by proinflammatory cytokines and NO. We suggest that this downregulation of Ang II type 1 receptors is the main reason for the attenuated responsiveness of blood pressure and of aldosterone formation to Ang II and, therefore, contributes to the characteristic septic shock.

Effects of hypoxia on growth factor expression in the rat kidney in vivo.

There is accumulating evidence from in vitro studies suggesting that the genes of endothelin-1, PDGF, and VEGF are, like the erythropoietin gene, regulated by oxygen tension and by divalent cations. Hypoxia-induced stimulation of, such as endothelin-1, PDGF or VEGF might be involved in the pathogenesis of acute or chronic renal failure, and in renal "inflammatory" diseases (glomerulonephritis, vasculitis, allograft rejection). Hypoxia (8% O2) for six hours caused a 55-fold/1.6-fold increase of renal erythropoietin/endothelin-1 gene expression, whereas endothelin-3, PDGF-A, PDGF-B, and VEGF gene expression was unchanged. Carbon monoxide (0.1%) treatment for six hours stimulated renal erythropoietin gene expression 140-fold; however, endothelin-1, endothelin-3, PDGF-A, PDGF-B, and VEGF gene expression was not affected. Finally, cobalt treatment (60 mg/kg CoCl2) increased only renal erythropoietin/PDGF-B gene expression 5-fold/1.65-fold. These findings suggest that hypoxia is a rather weak stimulus for renal endothelin-1 gene expression, and that renal PDGF and VEGF gene expression in vivo is not sensitive to tissue hypoxia, in contrast to cell culture experiments. The in vivo regulation of endothelin-1, PDGF, and VEGF differs substantially from that of erythropoietin, suggesting that the basic gene regulatory mechanisms may not be the same.

Aerobic fermentation in tobacco pollen.

We characterized the genes coding for the two dedicated enzymes of ethanolic fermentation, alcohol dehydrogenase (ADH) and pyruvate decarboxylase (PDC), and show that they are functional in pollen. Two PDC-encoding genes were isolated, which displayed reciprocal regulation: PDC1 was anaerobically induced in leaves, whereas PDC2 mRNA was absent in leaves, but constitutively present in pollen. A flux through the ethanolic fermentation pathway could be measured in pollen under all tested environmental and developmental conditions. Surprisingly, the major factor influencing the rate of ethanol production was not oxygen availability, but the composition of the incubation medium. Under optimal conditions for pollen tube growth, approximately two-thirds of the carbon consumed was fermented, and ethanol accumulated into the surrounding medium to a concentration exceeding 100 mM.

Ethanolic fermentation in transgenic tobacco expressing Zymomonas mobilis pyruvate decarboxylase.

During oxygen limitation in higher plants, energy metabolism switches from respiration to fermentation. As part of this anaerobic response the expression of genes encoding pyruvate decarboxylase (PDC) and alcohol dehydrogenase (ADH) is strongly induced. In addition there is ample evidence for post-translational regulation. In order to understand this multi-level regulation of the anaerobic response, we provided tobacco with the constitutive capacity of ethanolic fermentation by expressing a PDC gene derived from the obligate anaerobe Zymomonas mobilis. The protein accumulated to high levels and was active in an in vitro assay. During the first 2-4 h of anoxia, acetaldehyde accumulated to 10- to 35-fold and ethanol to 8- to 20-fold higher levels than in wild-type. Under normoxic conditions no accumulation of acetaldehyde and ethanol could be measured. Instead, the two products may be immediately re-metabolized in tobacco leaf tissue. We show that aerobic fermentation takes place when the respiratory system is inhibited. Although these conditions enhance ethanolic fermentation under normoxia, they fail to increase ADH transcript levels. These results indicate that anaerobic transcription is triggered not by the metabolic consequences of oxygen limitation, but directly through an oxygen-sensing system.

Levels of parathyroid hormone-related protein in hypercalcemia of malignancy: comparison of midregional radioimmunoassay and two-site immunoradiometric assay.

Overproduction of parathyroid hormone-related protein (PTHrP) is a major cause of hypercalcemia of malignancy in patients with solid tumors. We measured plasma levels of the protein by a radioimmunoassay (RIA) against PTHrP(53-84) and by an immunoradiometric assay (IRMA) against PTHrP (1-86). Of 16 affected patients 7 had elevated PTHrP levels in both assays and 4 had elevated levels in the RIA only. Median levels were about tenfold higher in these patients when measured by RIA (median of 34 versus 2.2 pmol/l). Measurements from both assays were, however, highly correlated with each other in this patient group (P < 0.01). PTHrP was not elevated in 10 normocalcemic patients with lung carcinoma. During long-term follow-up of a patient with a mesothelioma of the pleura, PTHrP levels measured with both assays decreased during chemotherapy in parallel with a normalization of serum calcium. In another hypercalcemic patient suffering from renal carcinoma, PTHrP measured by IRMA decreased by 40% within 12 h after nephrectomy, whereas PTHrP measured by RIA did not show a significant decline. Direct comparison of the assay results thus pointed to the existence of heterogeneity of circulating forms of PTHrP in plasma. In conclusion, both immunoassays detected elevated levels of PTHrP in a fraction of patients with hypercalcemia of malignancy and thus may be a tumor marker during treatment of malignancies.