Evaluating respiratory mechanics during dynamic conditions without interrupting ongoing ventilation and flow, adds to the information obtained from the mechanics derived from static (= no flow) conditions, i.e., the flow signal has the potential to provide information on the properties of the respiratory system (including the tubing system). Hence monitoring the changes in the flow signal during ongoing mechanical ventilation would give information about the dynamic mechanics of the respiratory system. Any change in the mechanics of the respiratory system including the endotracheal tube (ETT) and the ventilatory circuit would affect the shape of the flow signal. Knowledge of the airway pressure distal to the ETT at the carina level (= tracheal pressure) is required for calculating the extra resistive load exerted by the endotracheal tube in order to compensate for it. In a porcine model, the flow signal was used to non-invasively calculate tracheal pressure. There was good agreement between calculated and measured tracheal pressure with different modes of ventilation. However, calculation of tracheal pressure assumes that the inner diameter of the ETT is known, and this assumption is not met if the inner diameter is narrowed by secretions. Flow that passes a narrowed tube is decelerated and this is most pronounced with the high flow of early expiration, yielding a typical time constant over expiratory volume pattern that is easy to recognize during mechanical ventilation. This pattern reliably detected partial endotracheal obstruction during volume and pressure controlled mechanical ventilation. A change in compliance of the respiratory system modifies the elastic recoil and this also affects the rate of the expiratory flow and the shape of its signal. In a porcine model, lung volume gains on the flow signal generated by the heartbeats (cardiogenic oscillations) provided information about the compliance of the respiratory system during ongoing mechanical ventilation In conclusion analyzing the flow signal during ongoing ventilation can be a cheap, non-invasive and reliable tool to monitor the elastic and resistive properties of the respiratory system including the endotracheal tube.

<p>Septic shock is frequently seen in intensive care units and is associated with significant mortality. Endotoxin – a major mediator of the pathophysiologic responses – is released during lysis of Gram-negative bacteria. These responses can be mimicked in the endotoxaemic pig.</p><p>This thesis focuses on the following topics: the inflammatory and pathophysiological responses to various endotoxin doses and infusion patterns; covariations between endotoxin induced inflammatory and pathophysiological responses; whether the biological effects of endotoxin can be modulated by clopidogrel and whether tobramycin or ceftazidime reduce plasma cytokine levels.</p><p>Endotoxin induced linear log-log cytokine and F2-isoprostane responses. Leukocyte and platelet responses, pulmonary compliance, circulatory variables as well as indicators of plasma leakage and hypoperfusion exhibited log-linear responses to the endotoxin dose. Biological responses to endotoxaemia such as inflammation, hypotension, hypoperfusion and organ dysfunction were more expressed when the organism was exposed to endotoxin at a higher rate. These results may facilitate the possibility to choose relevant endotoxin administration, when experiments are set up in order to evaluate certain responses to endotoxaemia.</p><p>Correlation studies between cytokines, leukocytes, platelets and the endotoxin dose were in agreement with the well-known ability of endotoxin to induce cytokine expression and to activate both primary haemostasis and leukocytes. Free radical mediated lipid peroxidation and COX-mediated inflammation correlated to cytokine expression and organ dysfunction in endotoxaemic shock. </p><p>Endotoxaemic pigs pretreated with clopidogrel, exhibited a trend towards less expressed deterioration of renal function, although blocking of ADP-induced primary haemostasis is not a key mediator of endotoxin induced deterioration of renal function.</p><p>Tobramycin did not neutralise the biological effects of endotoxin or the plasma levels of endotoxin, suggesting that these antibiotics do not bind to endotoxin.</p><p>Reduction in IL-6 was greater in pigs treated with ceftazidime and tobramycin as compared with those given saline, indicating a possible anti-inflammatory effect of both antibiotics.</p>

Background:     The microdialysis (MD) technique is widely spread and used both experi­mentally and in clinical practice. The MD technique allows continuous collection of small molecules such as glucose, lactate, pyruvate and glycerol. Samples are often analysed using the CMA 600 analyser, an enzymatic and colorimetric analyser.  Data evaluating the performance of the CMA 600 analysis system and associated sample han­dling are sparse. The aim of this work was to identify sources of variability related to han­dling of microdialysis samples and sources of error associated with use of the CMA 600 analyser. Further, to develop and compare different application techniques of the micro­dialysis probes both within an organ and on the surface of an organ.  Material and Methods:  Papers I and II are mainly in vitro studies with the exception of the No Net Flux calibration method in paper I where a pig model (n=7) was used to exam­ine the true concen­tration of glucose and urea in subcutaneous tissue. Flow rate, sampling time, vial and caps material and performance of the analyser device (CMA 600) were examined. In papers III and IV normoventilated anaesthetised pigs (n=33) were used. In paper III, heart ischemia was used as intervention to compare microdialysis measurements in the myocardium with corresponding measurements on the heart surface. In paper IV, microdialysis measurements in the liver parenchyma were compared with measurements on the liver surface in associa­tion with induced liver ischemia. All animal studies were approved by the Animal Experi­mental Ethics Committee at Umeå University Sweden. Results:  In paper I we succeeded to measure true concentrations of glucose (4.4 mmol/L) and Urea (4.1 mmol/L) in subcutaneous tissue. Paper II showed that for a batch analyse of 24 samples it is preferred to store microdialysis samples in glass vials with crimp caps. For reliable results, samples should be centrifuged before analysis. Paper III showed a new application area for microdialysis sampling from the heart, i.e. surface sampling. The sur­face probe and myocardial probe (in the myocardium) showed a similar pattern for glucose, lactate and glycerol during baseline, short ischemic and long ischemic interventions. In paper IV, a similar pattern was observed as in paper III, i.e. data obtained from the probe on the liver surface showed no differences compared with data from the probe in liver paren­chyma for glucose, lactate and glycerol concentrations during baseline, ischemic and reperfusion interven­tions. Conclusion:  The MD technique is adequate for local metabolic monitoring, but requires methodological considerations before starting a new experimental serie. It is important to consider factors such as flow rate, sampling time and handling of samples in association with the analysis device chosen. The main finding in this thesis is that analyses of glucose, lactate and glycerol in samples from the heart surface and liver surface reflect concentra­tions sampled from the myocardium and liver parenchyma, respectively.

Despite increasingly sophisticated perioperative management, cardiovascular complications continue to be major challenges for the clinician. As a growing number of elderly patients with known coronary artery disease (CAD) or with risk factors for CAD are undergoing non-cardiac surgery, cardiovascular complications will remain a significant clinical problem in the future. The overall objective of this thesis was to study the incidence of myocardial damage and perioperative adverse cardiac events, to determine predictors of poor outcome and to assess the effect of a medical intervention in patients at risk undergoing non-cardiac surgery. The studies in this thesis were conducted on a total of 952 patients undergoing non-cardiac surgery. Studies I and IV were multicenter studies; whereas the patients included in studies II and III underwent non-cardiac surgery at Linkoping University Hospital, Sweden. The correlation between postoperative myocardial damage and short- and long-term outcome were studied in 546 patients, aged 70 years or older undergoing non-cardiac surgery of at least 30 minutes duration. This study showed a close correlation between postoperative myocardial damage and poor short- as well as long-term outcome. Elevated Troponin T was a strong independent predictor of mortality within one year of surgery. In 186 patients with ASA physical status classification III or IV undergoing non-elective surgery, the incidence of myocardial damage was 33%. In this study preoperative myocardial damage was an independent predictor of major adverse cardiac events in the postoperative period. In 69 patients with ASA physical status classification III &amp; IV undergoing acute hip surgery, we found a close correlation between elevated NT-proBNP value prior to surgery and cardiac complications in the postoperative period. To study the effect of acetylsalicylic acid on postoperative myocardial damage and cardiovascular events, 220 patients at risk were randomized to receive 75 mg of acetylsalicylic acid or placebo 7 days prior to surgery until the third postoperative day. This study showed that treatment with acetylsalicylic acid resulted in an 8% (95% CI 1-15%) absolute risk reduction of having a postoperative major adverse cardiac event. No statistically significant differences of bleeding complications were seen between the groups. In conclusion, this thesis contributes to the understanding of the clinical relevance of elevated cardiac markers (with or without clinical or ECG signs of myocardial damage) in patients undergoing elective or emergency surgery. Moreover, we have identified predictors of poor outcome in the perioperative period that could be used as tools for identifying patients at risk. Finally, we have shown that continuing acetylsalicylic acid in the perioperative period reduced the risk of major adverse cardiac events within 30 days of surgery.

Septic shock is frequently seen in intensive care units and is associated with significant mortality. Endotoxin – a major mediator of the pathophysiologic responses – is released during lysis of Gram-negative bacteria. These responses can be mimicked in the endotoxaemic pig. This thesis focuses on the following topics: the inflammatory and pathophysiological responses to various endotoxin doses and infusion patterns; covariations between endotoxin induced inflammatory and pathophysiological responses; whether the biological effects of endotoxin can be modulated by clopidogrel and whether tobramycin or ceftazidime reduce plasma cytokine levels. Endotoxin induced linear log-log cytokine and F2-isoprostane responses. Leukocyte and platelet responses, pulmonary compliance, circulatory variables as well as indicators of plasma leakage and hypoperfusion exhibited log-linear responses to the endotoxin dose. Biological responses to endotoxaemia such as inflammation, hypotension, hypoperfusion and organ dysfunction were more expressed when the organism was exposed to endotoxin at a higher rate. These results may facilitate the possibility to choose relevant endotoxin administration, when experiments are set up in order to evaluate certain responses to endotoxaemia. Correlation studies between cytokines, leukocytes, platelets and the endotoxin dose were in agreement with the well-known ability of endotoxin to induce cytokine expression and to activate both primary haemostasis and leukocytes. Free radical mediated lipid peroxidation and COX-mediated inflammation correlated to cytokine expression and organ dysfunction in endotoxaemic shock. Endotoxaemic pigs pretreated with clopidogrel, exhibited a trend towards less expressed deterioration of renal function, although blocking of ADP-induced primary haemostasis is not a key mediator of endotoxin induced deterioration of renal function. Tobramycin did not neutralise the biological effects of endotoxin or the plasma levels of endotoxin, suggesting that these antibiotics do not bind to endotoxin. Reduction in IL-6 was greater in pigs treated with ceftazidime and tobramycin as compared with those given saline, indicating a possible anti-inflammatory effect of both antibiotics.

A substantial number of patients undergoing cardiac surgery are on dual anti-platelet treatment with clopidogrel and aspirin. A disadvantage with this treatment is increased risk of bleeding. Bleeding is a complication of major concern associated with adverse outcome for the patient and increased hospital resource utilization. Great variability in individual response to clopidogrel has been reported. If in vitro measurements of platelet reactivity would correlate with clinical bleeding parameters, potential bleeders could be identified preoperatively. The aims of this thesis were: (1) to describe the degree of pre-operative platelet inhibition in patients scheduled for primary isolated coronary artery bypass graft surgery; (2) to prospectively investigate whether the pre-operative platelet inhibition correlated with intra- and postoperative bleeding and transfusion requirements; and (3) to test the ability of clinically relevant risk factors to predict re-exploration for bleeding. (4) In addition, a cost analysis was performed on patients re-explored for bleeding, to analyse the magnitude of added resource utilization and costs. Based on this, a cost model of prophylactic treatment with haemostatic drugs was calculated. Platelet function tests investigated were: (1) flow cytometry, (2) VASP, (3) VerifyNowSystem, (4) PlateletMapping (a modified TEG), and (5) PFA-100. Clinical risk factors for re-exploration and the influence of antiplatelet and antifibrinolytic therapy were evaluated in a retrospective analysis. Cost analysis at three cardiothoracic centres was performed in a case-control study. In conclusion, there was no clinically useful correlation between preoperative assessment of platelet inhibition and blood loss or transfusion requirements during coronary artery bypass surgery. Furthermore, there was only modest agreement between the methods evaluating ADP-receptor blockade. Pre-operative treatment with the P2Y12-receptor inhibitor clopidogrel was an essential risk factor for re-exploration due to bleeding. Except for clopidogrel, no strong clinical factor to predict the risk of re-exploration was identified. The resource utilisation costs were 47% higher in patients requiring re-exploration due to bleeding than in those not requiring re-exploration. Prolonged stay in the ICU and recovery ward accounted for half of the added cost, a third was due to the costs of surgery, one fifth due to increased cost of transfusions, and &lt;2% was due to haemostatic drug treatment.

Background: Loading conditions are recognized to influence ventricular function according to the Starling relationship for length/stretch and force.  Many modern echocardiographic parameters which have been announced as describing ventricular function and contractile status, may be confounded by uncontrolled and unmeasured load.  These studies aimed to measure the relation between four differ­ent types of assessments of ventricular dysfunction and degrees of load.  Study examined the ‘myo­cardial performance index’ (MPI).  Study II examined long axis segmental mechanical dyssynchrony.  Study III examined tissue velocities, and Study IV examined ventricular twist.  All studies aimed to describe the relation of these parameters both to load and to inotropic changes. Methods:  In anesthetized juvenile pigs, left ventricular (LV) pressure and volume were measured continuously and their relationship (LVPVR) was analysed.  Preload alterations were brought about by inflation of a balloon tipped catheter in the inferior vena cava (IVCBO).  Inotropic interventions were brought about by either an overdose of anesthetic (combine intravenous pentobarbital and inhaled isoflurane, Study I), or beta blocker and calcium channel blocker given in combination (Stud­ies III and IV).  In one study (II), global myocardial injury and dysfunction was induced by endotoxin infusion.  MPI measurements were derived from LVPVR heart cycle intervals for isovolumic contrac­tion and relaxation as well as ejection time.  Long axis segmental dyssynchrony was derived by ana­lyzing for internal flow and time with segmental dyssynchronous segment volume change during systole, hourly before and during 3 hours of endotoxin infusion.  Myocardial tissue velocities were measured during IVCBO at control, during positive and then later negative inotropic interventions.  The same for apical and base circumferential rotational velocities by speckle tracking.  Load markers (including end-diastolic volume) were identified for each beat, and the test parameters were analysed together with load for a relation.  The test parameters were also tested during single apneic beats for a relation to inotropic interventions. Results: MPI demonstrated a strong and linear relationship to both preload and after-load, and this was due to changes in ejection time, and not the isovolumic intervals.  Long axis segmental dyssyn­chrony increased during each hour of endotoxin infusion and global myocardial injury.  This dysyn­chrony parameter was independent of load when tested by IVCBO. Peak systolic velocities were strongly load-independent, though not in all the inotropic situations and by all measurement axes.  Peak systolic strain was load-dependent, and not strongly related to inotropic conditions.  Peak sys­tolic LV twist and untwist were strongly load-dependent. Conclusions: MPI is strongly load-dependent, and can vary widely in value for the same contractile status if the load is varied.  Mechanical dyssynchrony measures are load-independen in health and also in early global endotoxin myocardial injury and dysfunction.  Peak sytole velocities are a clinically robust parameter of LV regional and global performance under changing load, though peak systolic strain seems to be load-dependent.  Left ventricular twist and untwist are load-dependent in this pig model.

<p>Systemic infection, major surgery, trauma and many other causes can lead to impaired organ function. Compensated shock is not detected by global hemodynamic and oxygen measurements, as they take no account for regional variations. Focus has therefore gradually turned from looking at systemic changes to selective investigations of regional blood flow and ischemia. This thesis presents a series of experiments evaluating new application and validation of various monitoring techniques.</p><p>An experimental porcine model with anesthetized and invasively monitored animals was used. The circulatory interventions included endotoxin infusion (septic shock), aortic constriction and selective clamping of splanchnic arteries. The aim was to compare air with saline tonometry, to validate the intraperitoneal use of tonometry and to reexamine the use of endoluminal reflectance pulse oxymetry. To investigate the relative contributions of regional blood flow and detection of ischemia, measurements of hepatic venous oxygen saturation (ShvO₂), lactate concentrations and PCO₂ gap were used.</p><p>Our findings support the use of air instead of saline as the preferred technique for tonometric measurements. With the intraperitoneal application of tonometry we gain more information on regional aspects of the splanchnic circulation, and it appears to be a reliable monitoring option for early detection of ischemia in the small intestine. Measurements of ShvO₂will give an overall reflection of the intestinal circulation. The sigmoid colonic pulse oximetry showed a non-linear response in relation to regional blood flow, and will therefore not be able to detect gradual changes in oxygen saturation. Determination of the regional to endtidal PCO₂ gap might prove valuable for monitoring of the intestinal circulation.</p><p>Because of sophisticated interactions between portal and hepatic arterial blood flow and hepatic compensation for regional ischemia, a combination of monitoring techniques might be needed. The results of this study will hopefully encourage clinical evaluation of intraperitoneal tonometry and endtidal PCO₂ gap recordings for non-invasive, semi-continuous, trend monitoring of the splanchnic circulation.</p>

Systemic infection, major surgery, trauma and many other causes can lead to impaired organ function. Compensated shock is not detected by global hemodynamic and oxygen measurements, as they take no account for regional variations. Focus has therefore gradually turned from looking at systemic changes to selective investigations of regional blood flow and ischemia. This thesis presents a series of experiments evaluating new application and validation of various monitoring techniques. An experimental porcine model with anesthetized and invasively monitored animals was used. The circulatory interventions included endotoxin infusion (septic shock), aortic constriction and selective clamping of splanchnic arteries. The aim was to compare air with saline tonometry, to validate the intraperitoneal use of tonometry and to reexamine the use of endoluminal reflectance pulse oxymetry. To investigate the relative contributions of regional blood flow and detection of ischemia, measurements of hepatic venous oxygen saturation (ShvO2), lactate concentrations and PCO2 gap were used. Our findings support the use of air instead of saline as the preferred technique for tonometric measurements. With the intraperitoneal application of tonometry we gain more information on regional aspects of the splanchnic circulation, and it appears to be a reliable monitoring option for early detection of ischemia in the small intestine. Measurements of ShvO2 will give an overall reflection of the intestinal circulation. The sigmoid colonic pulse oximetry showed a non-linear response in relation to regional blood flow, and will therefore not be able to detect gradual changes in oxygen saturation. Determination of the regional to endtidal PCO2 gap might prove valuable for monitoring of the intestinal circulation. Because of sophisticated interactions between portal and hepatic arterial blood flow and hepatic compensation for regional ischemia, a combination of monitoring techniques might be needed. The results of this study will hopefully encourage clinical evaluation of intraperitoneal tonometry and endtidal PCO2 gap recordings for non-invasive, semi-continuous, trend monitoring of the splanchnic circulation.

<p>Succinylcolin är ett icke-depolariserande muskelrelaxantia som används inom anestesisjukvård. En vanlig biverkning är postoperativ myalgi. Varför smärtan uppstår är inte helt klarlagd. Under många år har forskare runt om i världen försökt komma till rätta med problemet utan att helt lyckas.Olika läkemedel och strategier har prövats. En av de viktigaste uppgifter en sjuksköterska har är att förebygga och lindra lidande. Som anestesisjuksköterska finns det möjlighet att påverka den vård som ordineras. Syftet med studien var att undersöka vilka metoder som kan förebygga postoperativ myalgi orsakad av succinylcolin. En litteraturstudie baserad på tio vetenskapliga artiklar genomfördes. Resultatet visade att parecoxib preoperativt samt premedicinering med diklofenakplåster gav det bästa resultatet när det gäller reducerande av myalgi. Med hjälp av dessa så vanliga läkemedel kan onödigt lidande förebyggas och samhällsekonomiska resurser sparas.</p><p> </p>