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The esophageal sphincters constitute the anatomical protection against pulmonary aspiration. The aim of this thesis was to study the esophageal sphincters and how they are affected by different components of emergency anesthesia using high-resolution solid-state manometry. The effect of propofol (0.3 mg/kg) was studied in young and elderly volunteers. Propofol can be given as an anxiolytic agent for manometric studies of the lower esophageal sphincter (LES) without affecting the results. However, propofol is not recommended for studies of the upper esophageal sphincter (UES). The effects of cricoid pressure (CP) and peripheral pain were studied in awake volunteers, with and without remifentanil infusion (5 ng/ml). Pain did not affect pressure in the LES, but CP or remifentanil induced a significant decrease in LES pressure. However, neither CP nor remifentanil affected the barrier pressure (LES-intra gastric pressure). When CP was applied during ongoing remifentanil infusion, no further decrease in LES pressure was measured. CP induced high pressures in the area of the UES independent of remifentanil infusion, indicating that CP is effective in preventing gastroesophageal regurgitation. Barrier pressure was also studied in anesthetized patients after rocuronium (0.6 mg/kg) administration and no decrease was measured. In addition, alfentanil (20 μ/kg) added during anesthesia induction with propofol did not decrease the barrier pressure. In conclusion, CP seems to be effective in preventing regurgitation and does not affect barrier pressure. Muscle relaxation with rocuronium does not risk gastro-esophageal integrity. In addition, opioids can be integrated, even during emergency anethesia, without increasing the risk for pulmonary aspiration.

At present, there are few clinically effective pain therapies available to treat chronic pain. One reason is due to a lack of understanding about how pain emerges in the brain. Excitingly, an emerging body of work suggests that the perfusion imaging technique, arterial spin labelling (ASL), is particularly well-suited to investigate this issue. The primary aim of this thesis is to develop and optimise a quantitative perfusion imaging approach to investigate the neural correlates of both experimental and pathological tonic pain. In Chapter 2, we explore different methods of inducing ongoing pain in healthy subjects. Results from this study show that mechanically induced pain is well suited for use in ASL FMRI experiments. In Chapter 3, we compare currently available ASL FMRI approaches for investigating tonic states, using a range of sensory paradigms. Results from these experiments support the use of an optimised version of Continuous ASL (CASL) FMRI to obtain whole-brain perfusion. Additionally, we discuss our decision to proceed with the newly acquired pseudo-continuous ASL (pCASL); a novel ASL technique that benefits from maximal signal-to-noise (SNR) across a whole-brain volume. In Chapter 4 we implement the pCASL FMRI approach to image the neural correlates of ongoing experimental pain. Results from the investigation of parametrically modulated ongoing mechanical pain show robust pain-related activation of key pain related regions that are monotonically active with an increase in stimulus intensity. Additionally, data from this experiment shows the presence of complex perfusion dynamics relative to pain worthy of further study. In Chapter 5, we optimised the pCASL sequence to obtain absolute perfusion changes across the whole-brain volume, using multi-inversion times, so that we could investigate the perfusion dynamics observed in Chapter 4. Results show that absolute perfusion changes during tonic pain are considerably less than for regions recruited during a non- pain task. Additionally, dynamic perfusion changes show complex stimulus responses across all active regions regardless of stimulus type. We conclude that while the technique is well suited to quantify absolute perfusion, the mechanisms underlying the dynamic changes in CBF (neuronal signal, neurovascular coupling) need further study. Finally, in Chapter 6, we implement the absolute perfusion approach developed in Chaper 5 to interrogate the neural correlates of the genetic pain disease, Erythromelalgia, and pleasurable relief. The results of this study show pain-related activation (and relief-induced reduction) of key pain-related regions. We conclude from these results that the ASL technique developed over the course of this thesis can be used to study a range of pain pathologies. Taken together, the results of this thesis document the development of a powerful perfusion imaging technique capable of quantifying absolute perfusion changes across a whole-brain volume. The data presented here from investigations of both experimental and pathological pain states supports the use of this technique in future tonic pain studies, as well as other neuroscience applications. We are confident that implementation of this imaging approach will provide integral insight into the mechanisms of ongoing pain states; and further the development of novel efficacious pain treatment options.

<p>Cardiac arrest results in immediate interruption of blood flow. The primary goal of cardiopulmonary resuscitation (CPR) is to re-establish blood flow and hence oxygen delivery to the vital organs. This thesis describes different pharmacological interventions aimed at increasing cerebral blood flow during CPR and after restoration of spontaneous circulation (ROSC).</p><p>In a porcine model of cardiac arrest, continuous infusion of adrenaline generated higher cortical cerebral blood flow during CPR as compared to bolus administration of adrenaline. While bolus doses resulted in temporary peaks in cerebral blood flow, continuous infusion led to a sustained increase in this flow.</p><p>Administration of vasopressin resulted in higher cortical cerebral blood flow and a lower cerebral oxygen extraction ratio as compared to continuous infusion of adrenaline during CPR. In addition, vasopressin generated higher coronary perfusion pressure during CPR and increased the likelihood of achieving ROSC.</p><p>Parameters of coagulation and inflammation were measured after successful resuscitation from cardiac arrest. Immediately after ROSC, thrombin-antithrombin complex, a marker of thrombin generation, was elevated and eicosanoid levels were increased, indicating activation of coagulation and inflammation after ROSC. The thrombin generation was accompanied by a reduction in antithrombin. In addition, there was substantial haemoconcentration in the initial period after ROSC.</p><p>By administration of antithrombin during CPR, supraphysiological levels of antithrombin were achieved. However, antithrombin administration did not increase cerebral circulation or reduce reperfusion injury, as measured by cortical cerebral blood flow, cerebral oxygen extraction and levels of eicosanoids, after ROSC. </p><p>In a clinical study, the adrenaline dose interval was found to be longer than recommended in the majority of cases of cardiac arrest. Thus, the adherence to recommended guidelines regarding the adrenaline dose interval seems to be poor. </p>

<p>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. </p><p>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. </p><p>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</p><p>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>

Cardiac arrest results in immediate interruption of blood flow. The primary goal of cardiopulmonary resuscitation (CPR) is to re-establish blood flow and hence oxygen delivery to the vital organs. This thesis describes different pharmacological interventions aimed at increasing cerebral blood flow during CPR and after restoration of spontaneous circulation (ROSC). In a porcine model of cardiac arrest, continuous infusion of adrenaline generated higher cortical cerebral blood flow during CPR as compared to bolus administration of adrenaline. While bolus doses resulted in temporary peaks in cerebral blood flow, continuous infusion led to a sustained increase in this flow. Administration of vasopressin resulted in higher cortical cerebral blood flow and a lower cerebral oxygen extraction ratio as compared to continuous infusion of adrenaline during CPR. In addition, vasopressin generated higher coronary perfusion pressure during CPR and increased the likelihood of achieving ROSC. Parameters of coagulation and inflammation were measured after successful resuscitation from cardiac arrest. Immediately after ROSC, thrombin-antithrombin complex, a marker of thrombin generation, was elevated and eicosanoid levels were increased, indicating activation of coagulation and inflammation after ROSC. The thrombin generation was accompanied by a reduction in antithrombin. In addition, there was substantial haemoconcentration in the initial period after ROSC. By administration of antithrombin during CPR, supraphysiological levels of antithrombin were achieved. However, antithrombin administration did not increase cerebral circulation or reduce reperfusion injury, as measured by cortical cerebral blood flow, cerebral oxygen extraction and levels of eicosanoids, after ROSC. In a clinical study, the adrenaline dose interval was found to be longer than recommended in the majority of cases of cardiac arrest. Thus, the adherence to recommended guidelines regarding the adrenaline dose interval seems to be poor.

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.

Generell anestesi kan ges som inhalationsanestesi eller total intravenös anestesi (TIVA). En förutsägbar anestesi med snabbt uppvaknande och bibehållen vakenhet är en högt önskvärd egenskap oavsett anestesiform. Det råder en klinisk och vetenskaplig diskussion om vilken anestesiform som ger snabbast tidig postoperativ återhämtning. syftet med studien var att jämföra patienters tidiga postoperativa återhämtning efter inhalationsanestesi respektive efter total intravenös anestesi (TIVA). Metoden var en litteraturstudie baserad på 15 vetenskapliga artiklar. Dessa analyserades utifrån frågeställningen: Vilken anestesiform som ger den snabbaste tidiga postoperativa återhämtningen. Det framkom en indelning av resultatet i tre kategorier: snabbare tidig postoperativ återhämtning efter inhalationsanestesi, lika lång tid till återhämtning efter inhalationsanestesi som efter TIVA samt snabbare tidig postoperativ återhämtning efter TIVA. Resultatet visade att inhalationsanestesi gav snabbast tdiig postoperativ återhämtning. Anestesisjuksköterskans handhavande, planering och erfarenhet påverkar patientens uppvakande. därför skulle vidare forskning istället jämföra dessa båda anestesiformer på ett annat sätt. Tiden kunde istället mätas från det att anestesisjukskäterskan extuberat patienten och till payienten verkar adekvat orienterad för att erhålla ett mer jämförbart resultat. / General anesthesia includes both inhalations anesthesia and total intravenous anesthesia (TIVA). After any anesthetic technique a de sirable characteristics is a predictably rapid emergence and sustained alertness. There is a clinical and scientific debate about which anesthetic technique who gives the most rapid emergence in the early postoperative recovery. The aim of this study was to compare patients early postoperative recovery after inhalations anesthesia and after total intravenous anesthesia (TIVA). The methods are based on 15 research articles. They where analysized from the questionnaire: which anesthetic technique gives the most rapid emergence in the early postoperative recovery. The results showed that inhalations anesthesia gave the most rapid emergence in the earky postoperative recovery. The nurse anesthetist handling, planning and experience affect the patients awakening. Therefore further research instead could compare these anesthetic techniques in another way. The time after the nurse anesthetist has extubate the patient until the patient is adequate orientated, could be measured to find a more comparable result.

Severe Traumatic Brain Injury (TBI) and aneurysmal Subarachnoid Hemorrhage (SAH) are severe cerebral emergencies. They are common reasons for extensive morbidity and mortality in young people and adults in the western world. This thesis, based on five clinical studies in patients with severe TBI (I-IV) and SAH (V), is concentrated on examination of pathophysiological developments and of evaluation of therapeutic approaches in order to improve outcome after cerebral emergency. The treatment for severe TBI patients at Umeå University Hospital, Sweden is an intracranial pressure (ICP)-targeted therapy according to “the Lund-concept”. This therapy is based on physiological principles for cerebral volume regulation, in order to preserve a normal cerebral microcirculation and a normal ICP. The main goal is to avoid development of secondary brain injuries, thus avoiding brain oedema and worsened microcirculation. Study I is evaluating retrospectively 41 children with severe TBI, from 1993 to 2002. The boundaries of the ICP-targeted protocol were obtained in 90%. Survival rate was 93%, and favourable outcome (Glasgow Outcome Scale, score 4+5) was 80%. Study II is retrospectively analysing fluid administration and fluid balance in 93 adult patients with severe TBI, from 1998 to 2001.The ICP-targeted therapy used, have defined fluid strategies. The total fluid balance was positive day one to three, and negative day four to ten. Colloids constituted 40-60% of total fluids given/day. Severe organ failure was evident for respiratory insufficiency and observed in 29%. Mortality within 28 days was 11%. Study III is a prospective, randomised, double-blind, placebo-controlled clinical trial in 48 patients with severe TBI. In order to improve microcirculation and prevent oedema formation, prostacyclin treatment was added to the ICP-targeted therapy. Prostacyclin is endogenously produced, by the vascular endothelium, and has the ability to decrease capillary permeability and vasodilate cerebral capillaries. Prostacyclin is an inhibitor of leukocyte adhesion and platelet aggregation. There was no significant difference between prostacyclin or placebo groups in clinical outcome or in cerebral microdialysis markers such as lactatepyruvate ratio and brain glucose levels. Study IV is part of the third trial and focus on the systemic release of pro-inflammatory mediators that are rapidly activated by trauma. The systemically released pro-inflammatory mediators, interleukin-6 and CRP were significantly decreased in the prostacyclin group versus the placebo group. Study V is a prospective pilot study which analyses asymmetric dimethylarginine (ADMA) concentrations in serum from SAH patients. Acute SAH patients have cerebral vascular, systemic circulatory and inflammatory complications. ADMA is a marker in vascular diseases which is correlated to endothelial dysfunction. ADMA concentrations in serum were significantly elevated seven days after the SAH compared to admission and were still elevated at the three months follow-up. Our results show overall low mortality and high favourable outcome compared to international reports on outcome in severe TBI patients. Prostacyclin administration does not improve cerebral metabolism or outcome but significantly decreases the levels of pro-inflammatory mediators. SAH seems to induce long-lasting elevations of ADMA in serum, which indicates persistent endothelial dysfunction. Endothelial dysfunction may influence outcome after severe cerebral emergencies.

Although survival rates are increasing, brain injury continues to be a leading cause of death after cardiac arrest (CA). Permanent brain damage after CA is determined by limited tolerance to ischemia from CA and cardiopulmonary resuscitation (CPR), as well as the unique cerebral response to reperfusion after return of spontaneous circulation (ROSC). A major pathway leading to neurotoxic cascade and neuronal injury after CA involves the increased presence of reactive oxygen and nitrogen species generated during ischemia and reperfusion. The magnitude of cerebral oxidative injury induced by free radicals increased with the duration of CA (Paper I). Nitric oxide (NO), a free radical responsible for the formation of reactive nitrogen species, is increased during global ischemia from CA and reperfusion (Paper IV). Hypothetically, the administration of a drug that counteracts the overproduction of NO and also acts as a scavenger of oxygen free radicals might be warranted in order to reduce the damage caused by nitrosative and oxidative stress. For these purposes we used methylene blue (MB), an old dye that has been used in medicine for almost half a century, and an experimental pig model of 20 min of ventricular fibrillation (VF) to reflect a clinical scenario of ischemia/reperfusion injury. Administration of MB added to a hypertonic-hyperoncotic solution (MBHSD) that was started during CPR and continued for 50 min after ROSC increased short-term survival by decreasing myocardial damage, as well as cerebral peroxidation and inflammatory injury (Paper II). Immunostaining of cerebral tissue collected at different time points after CA and ROSC (Paper IV) provided experimental evidence that cortical blood-brain barrier (BBB) disruption begins as early as  during the initial phase of untreated as well as treated CA. The results indicated that MB administration reduced the neurologic injury and BBB disruption considerably, but did not reverse the ongoing detrimental processes. The demonstrated positive effects of MB were related to a decrease of nitrite/nitrate tissue content, and thus to a decrease of excess NO due to the MB inhibitory effects on NOS isoforms. A mixture of MB in hypertonic sodium lactate (MBL) was investigated to facilitate administration of MB in “the field.” Based on findings that MBL cardio- and neuroprotective properties were similar to those of MBHSD, there is reason to believe that the use of MBL might be extended during ongoing CPR and after ROSC (Paper III). It would therefore make sense to try using MB as a pharmacological neuroprotectant during or after clinical CPR in order to expand the temporal therapeutic window before other measures for neuroprotection such as hypothermia are available.