Erik Solligård

Long-Term Serotonin Administration Induces Heart Valve Disease in Rats

Background—The purpose of this study was to investigate whether rats dosed with serotonin develop changes similar to those seen in human carcinoid heart disease. Methods and Results—Ten Sprague-Dawley rats were given serotonin injections subcutaneously once daily for 3 months; controls were given saline. A long-lasting hyperserotoninemia with a >10-fold increase in both platelet-poor plasma and dialysate from the femoral muscles appeared. The animals developed clinical signs such as flushing and loose stools. After 3 months, 6 of 10 rats given serotonin had pathological echocardiographs. Two animals had a combination of aortic and pulmonary valve insufficiency, 1 had isolated aortic valve insufficiency, and 3 had isolated pulmonary valve insufficiency. Histopathological examination revealed shortened and thickened aortic cusps and carcinoidlike plaques characterized by a collection of myofibroblasts within an extracellular matrix of collagen ground substance. Immunostaining for Ki-67 demonstrated an increased number of proliferating subendocardial cells. In the control group, no pathological changes were seen. With the use of reverse-transcription polymerase chain reaction, normal rat aortic cusps were shown to express mRNA for serotonin receptors 5-HT1A, 5-HT2A, and 5-HT2B and the serotonin transporter 5-HTT. Conclusions—For the first time, long-term serotonin administration was performed in rats. Morphological and echocardiographic changes similar to those seen in human carcinoid heart disease developed. This study demonstrates that serotonin most likely is involved in the pathogenesis of carcinoid heart disease.

Long‐term serotonin administration leads to higher bone mineral density, affects bone architecture, and leads to higher femoral bone stiffness in rats

New evidence suggests a control of bone mass by the central nervous system. We have previously shown that functional serotonin receptors are present in bone cells and that serotonin stimulates proliferation of osteoblast precursor cells in vitro. In the present study we investigated the effects of serotonin on bone tissue in vivo. Ten, 2‐month‐old female Sprague–Dawley rats were injected with serotonin subcutaneously (s.c.) (5 mg/kg) once daily for 3 months, controls received saline. Using microdialysis and HPLC, free circulating serotonin levels were measured. DXA scans were made after 3 months of serotonin administration. Bone architecture and mechanical properties were investigated by micro‐computed tomography (µCT), histomorphometry, and mechanical testing. A long‐lasting hyperserotoninemia with a >10‐fold increase in serotonin appeared. Total body BMD was significantly higher (0.1976 ± 0.0015 vs. 0.1913 ± 0.0012 g/cm2) in rats receiving serotonin. Cortical thickness (Ct.Th) measured by µCT analysis was also higher, whereas trabecular bone volume (BV) was lower. Interestingly, the perimeter and cross‐sectional moment of inertia (MOI), a proxy for geometrical bone strength, were the same in both groups. These data suggest that serotonin reduces resorption or/and increases apposition of endosteal bone. Mechanical testing showed that femoral stiffness was higher in serotonin‐dosed animals. The energy absorption also seemed slightly, but not significantly higher. In conclusion, hyperserotoninemia led to a higher BMD, altered bone architecture and higher femural bone stiffness in growing rats, demonstrating that serotonin may have important effects on bone in vivo. J. Cell. Biochem. 97: 1283–1291, 2006.

Gut luminal microdialysis of glycerol as a marker of intestinal ischemic injury and recovery

Objective:To evaluate microdialysis as a method to assess different degrees of intestinal damage and recovery during ischemia and reperfusion; to evaluate information obtained from microdialysis catheters in the peritoneum, the gut wall, and the gut lumen. Design:Randomized, controlled animal experiment. Setting:University laboratory animal center. Subjects:Twenty-seven domestic pigs. Interventions:The superior mesenteric artery was cross-clamped for 60 mins (n = 14) or 120 mins (n = 10) followed by 2 or 4 hrs of reperfusion. Three pigs served as controls. Measurements and Main Results:Intestinal mucosal integrity was assessed by morphometry, adenosine triphosphate in the gut wall, and permeability of 14C-polyethylene glycol. Lactate, glycerol, pyruvate, and glucose were measured by microdialysis. Changes in adenosine triphosphate, permeability, or lactate did not correlate to different extents of intestinal damage caused by 60 or 120 mins of ischemia. During the reperfusion period, pigs with 60 mins of intestinal ischemia showed a faster recovery of these variables than pigs with 120 mins of intestinal ischemia. Glycerol increased with increasing duration of the ischemic insult. After 60 mins of intestinal ischemia, glycerol in the gut lumen decreased toward baseline but remained high after 120 mins of intestinal ischemia. There was a good correlation between gut luminal glycerol and recovery of mucosal damage throughout the reperfusion period. In the peritoneal cavity, both glycerol and lactate decreased to baseline relatively shortly after onset of reperfusion independent of the duration of intestinal ischemia. Conclusions:Microdialysis of glycerol provides information about the extent and severity of intestinal damage after ischemia and about the ensuing recovery. The gut lumen is to be preferred as a site for placement of microdialysis catheters.

Poor performance of quick-SOFA (qSOFA) score in predicting severe sepsis and mortality – a prospective study of patients admitted with infection to the emergency department

BackgroundWe aimed to evaluate the clinical usefulness of qSOFA as a risk stratification tool for patients admitted with infection compared to traditional SIRS criteria or our triage system; the Rapid Emergency Triage and Treatment System (RETTS).MethodsThe study was an observational cohort study performed at one Emergency Department (ED) in an urban university teaching hospital in Norway, with approximately 20,000 visits per year. All patients >16 years presenting with symptoms or clinical signs suggesting an infection (n = 1535) were prospectively included in the study from January 1 to December 31, 2012. At arrival in the ED, vital signs were recorded and all patients were triaged according to RETTS vital signs, presenting infection, and sepsis symptoms. These admission data were also used to calculate qSOFA and SIRS. Treatment outcome was later retrieved from the patients’ electronic records (EPR) and mortality data from the Norwegian population registry.ResultsOf the 1535 admitted patients, 108 (7.0%) fulfilled the Sepsis2 criteria for severe sepsis. The qSOFA score ≥2 identified only 33 (sensitivity 0.32, specificity 0.98) of the patients with severe sepsis, whilst the RETTS-alert ≥ orange identified 92 patients (sensitivity 0.85, specificity 0.55). Twenty-six patients died within 7 days of admission; four (15.4%) of them had a qSOFA ≥2, and 16 (61.5%) had RETTS ≥ orange alert. Of the 68 patients that died within 30 days, only eight (11.9%) scored ≥2 on the qSOFA, and 45 (66.1%) had a RETTS ≥ orange alert.DiscussionIn order to achieve timely treatment for sepsis, a sensitive screening tool is more important than a specific one. Our study is the fourth study were qSOFA finds few of the sepsis cases in prehospital or at arrival to the ED. We add information on the RETTS triage system, the two highest acuity levels together had a high sensitivity (85%) for identifying sepsis at arrival to the ED - and thus, RETTS should not be replaced by qSOFA as a screening and trigger tool for sepsis at arrival.ConclusionIn this observational cohort study, qSOFA failed to identify two thirds of the patients admitted to an ED with severe sepsis. Further, qSOFA failed to be a risk stratification tool as the sensitivity to predict 7-day and 30-day mortality was low. The sensitivity was poorer than the other warning scores already in use at the study site, RETTS-triage and the SIRS criteria.

Continuous measurement of blood glucose: validation of a new intravascular sensor.

Background: Tight blood glucose control is used extensively in perioperative and critically ill patients. Several studies, however, have shown contradictory effects on patient outcomes. A major problem of these studies has been inadequate control of the prime variable, blood glucose. This paper describes the validation of a new intravascular continuous blood glucose sensor. Methods: The glucose sensor was placed in the superior caval vein of seven anesthetized pigs. Sensor readings were compared with arterial blood gas readings. Fluctuations in blood glucose were created using intravenous glucose and insulin. A total of 807 paired sensor and blood gas readings were obtained. Results: The sensor was tested with a range of blood glucose values (0.63–15.75 mM [mean bias, 0.0131 mM]). Analysis using Bland–Altman plots yielded 95% limits of agreement at −0.908 and 0.934 mM. There were 121 paired measurements with a mean value below 2.2 mM, yielding 95% limits of agreement at −0.553 and 0.466 mM. Conclusions: The performance of the sensor was in agreement with blood gas measurements in a wide range of glucose values. For the clinician, it is noteworthy that performance was equally good in the hypoglycemic area.

Rectal lactate levels in endoluminal microdialysate during routine coronary surgery

The aim of this prospective study was to determine the feasibility of intestinal endoluminal microdialysis as a new method for clinical monitoring of the adequacy of splanchnic perfusion in the large bowel. A microdialysis catheter for continuous lactate, glycerol, glucose and pyruvate measurements attached to a tonometric catheter was placed into the lumen of the recto‐sigmoid junction prior to surgery in 13 patients undergoing elective cardiac surgery with cardiopulmonary bypass (CPB). Lactate was also measured in blood and muscle. CPB was associated with a 10‐fold increase in luminal lactate from 0.16 (0.01) to 1.67 (0.38) mmol.l−1 (p < 0.001). Muscular lactate increased from baseline levels 1.20 (0.21) to 1.77 (0.36) mmol.l−1 during CPB (p = 0.01), but the muscular lactate–pyruvate ratio remained unchanged. Arterial lactate increased only slightly from 0.9 (0.05) to 1.1 (0.06) mmol.l−1 (p = 0.027) during CPB. Increased lactate concentrations in the large bowel during CPB are suggestive of local lactate production consistent with impaired oxygen delivery. Intestinal endoluminal microdialysis is a potential clinically applicable method for monitoring intestinal metabolism. Combined with tonometry, microdialysis provides the opportunity to monitor both circulation and metabolism in the rectal mucosa.

Continuous monitoring of the bronchial epithelial lining fluid by microdialysis.

BackgroundContents of the epithelial lining fluid (ELF) of the bronchi are of central interest in lung diseases, acute lung injury and pharmacology. The most commonly used technique broncheoalveolar lavage is invasive and may cause lung injury. Microdialysis (MD) is a method for continuous sampling of extracellular molecules in the immediate surroundings of the catheter. Urea is used as an endogenous marker of dilution in samples collected from the ELF. The aim of this study was to evaluate bronchial MD as a continuous monitor of the ELF.MethodsMicrodialysis catheters were introduced into the right main stem bronchus and into the right subclavian artery of five anesthetized and normoventilated pigs. The flowrate was 2 μl/min and the sampling interval was 60 minutes. Lactate and fluorescein-isothiocyanate-dextran 4 kDa (FD-4) infusions were performed to obtain two levels of steady-state concentrations in blood. Accuracy was defined as [bronchial-MD] divided by [arterial-MD] in percent. Data presented as mean ± 95 percent confidence interval.ResultsThe accuracy of bronchial MD was calculated with and without correction by the arteriobronchial urea gradient. The arteriobronchial lactate gradient was 1.2 ± 0.1 and FD-4 gradient was 4.0 ± 1.2. Accuracy of bronchial MD with a continuous lactate infusion was mean 25.5% (range 5.7–59.6%) with a coefficient of variation (CV) of 62.6%. With correction by the arteriobronchial urea gradient accuracy was mean 79.0% (57.3–108.1%) with a CV of 17.0%.ConclusionUrea as a marker of catheter functioning enhances bronchial MD and makes it useful for monitoring substantial changes in the composition of the ELF.

The impact of infectious disease specialist consultation for Staphylococcus aureus bloodstream infections: A systematic review

Staphylococcus aureus is a common cause of severe bloodstream infection. We performed a systematic review to assess whether consultation with infectious disease specialists decreased all-cause mortality or rate of complications of S aureus bloodstream infections. The review also assessed parameters associated with the quality of management of the infection. We searched for eligible studies in PubMed, Embase, Scopus, and clinical trials.gov as well as the references of included studies. We identified 22 observational studies and 1 study protocol for a randomized trial. A meta-analysis was not performed because of the high risk of bias in the included studies. The outcomes are reported in a narrative review. Most included studies reported survival benefit, in the adjusted analysis. Recommended management strategies were carried out significantly more often among patients seen by an infectious disease specialist. Trials, such as cluster-randomized controlled trials, can more validly assess the studies at low risk of bias.

Bronchial microdialysis of cytokines in the epithelial lining fluid in experimental intestinal ischemia and reperfusion before onset of manifest lung injury.

Today, there is no continuous monitoring of the bronchial epithelial lining fluid. This study used microdialysis as a method of continuous monitoring of early lung cytokine response secondary to intestinal ischemia-reperfusion in pigs. The authors aimed to examine bronchial microdialysis for continuous monitoring of IL-1&bgr;, TNF-&agr;, IL-8, and fluorescein isothiocyanate Dextran 4,000 Da (FD-4). The superior mesenteric artery was cross-clamped for 120 min followed by 240 min of reperfusion (ischemia group, n = 8). Four sham-operated pigs served as controls. The pigs were anesthetized and normoventilated (peak inspiratory pressure, <20 cm H2O; positive end-expiratory pressure, 7 cm H2O). Samples from bronchial and luminal intestinal and arterial microdialysis catheters (flow-rate of 1 &mgr;L/min) were collected during reperfusion in 60-min fractions. Samples were analyzed for TNF-&agr;, IL-1&bgr;, IL-8, and FD-4. Data are presented as median (interquartile range). A lung biopsy was collected at the end of the experiment. During reperfusion, there was an increase in bronchial concentrations of both IL-8 (3.70 [1.47-8.93] ng/mL per h vs. controls, 0.61 [0.47-0.91] ng/mL per h; P < 0.001) and IL-1&bgr; (0.32 [0.05-0.56] ng/mL per h vs. controls, 0.07 [0.04-0.10] ng/mL per h; P = 0.008). In the intestinal lumen, IL-8 was increased in the ischemia group (6.33 [3.13-9.23] ng/mL per h vs. controls, 0.89 [0.21-1.86] ng/mL per h; P < 0.001). The FD-4 did not differ between groups. Pulmonary vascular resistance and pulmonary shunt increased versus controls. During reperfusion, PaO2/FiO2 ratio decreased in the ischemia group. Histology was normal in both groups. Bronchial microdialysis detects altered levels of cytokines in the epithelial lining fluid and can be used for continuous monitoring of the immediate local lung cytokine response secondary to intestinal ischemia-reperfusion.

Lactate and Glycerol Released to the Intestinal Lumen Reflect Mucosal Injury and Permeability Changes Caused by Strangulation Obstruction

Background: The present study evaluates whether microdialysis of glycerol and lactate reflects mucosal injury and permeability changes after strangulation obstruction of the pig small intestine. Methods: Strangulation obstruction was induced by tightening a rubber band around a small bowel loop until its venous pressure increased to a level just below diastolic aortic pressure (partial strangulation), or further until cessation of flow in the main feeding artery (total strangulation). Mucosal injury and permeability of marker molecules from blood to lumen and vice versa was compared to release of glycerol and lactate to the intestinal lumen. Results: Mucosal injury, hyperpermeability, and release of glycerol were more pronounced after total than after partial strangulation. In animals with partial strangulation there was a complete restitution of the surface epithelium, and luminal glycerol and lumen-to-blood permeability of polyethylene glycol 4000 remained low. Such animals showed a sustained elevation of lactate and blood-to-lumen permeability of fluorescein isothiocyanate dextran after 2 h of partial strangulation, but a decline to baseline levels of these parameters in animals with 1 h partial strangulation. Conclusion: Microdialysis of lactate and glycerol in the intestinal lumen may be used to assess structural and functional changes of the intestinal mucosa after strangulation obstruction.