Biopsy-based optimization and calibration of a signal-intensity-ratio-based MRI method (1.5 Tesla) in a dextran-iron loaded mini-pig model, enabling estimation of very high liver iron concentrations.

OBJECTIVE: Magnetic resonance imaging (MRI)-based techniques for non-invasive assessing liver iron concentration (LIC) in patients with iron overload have a limited upper measuring range around 35 mg/g dry weight, caused by signal loss from accelerated T1-, T2-, T2* shortening with increasing LIC. Expansion of this range is necessary to allow evaluation of patients with very high LIC. AIM: To assess measuring range of a gradient-echo R2* method and a T1-weighted spin-echo (SE), signal intensity ratio (SIR)-based method (TE = 25 ms, TR = 560 ms), and to extend the upper measuring range of the SIR method by optimizing echo time (TE) and repetition time (TR) in iron-loaded minipigs. METHODS: Thirteen mini pigs were followed up during dextran-iron loading with repeated percutaneous liver biopsies for chemical LIC measurement and MRIs for parallel non-invasive estimation of LIC (81 examinations) using different TEs and TRs. RESULTS: SIR and R2* method had similar upper measuring range around 34 mg/g and similar method agreement. Using TE = 12 ms and TR = 1200 ms extended the upper measuring range to 115 mg/g and yielded good method of agreement. DISCUSSION: The wider measuring range is likely caused by lesser sensitivity of the SE sequence to iron, due to shorter TE, leading to later signal loss at high LIC, allowing evaluation of most severe hepatic iron overload. Validation in iron-loaded patients is necessary.

Metabolic changes during carbon monoxide poisoning: An experimental study.

Carbon monoxide (CO) is the leading cause of death by poisoning worldwide. The aim was to explore the effects of mild and severe poisoning on blood gas parameters and metabolites. Eleven pigs were exposed to CO intoxication and had blood collected before and during poisoning. Mild CO poisoning (carboxyhaemoglobin, COHb 35.2 ± 7.9%) was achieved at 32 ± 13 minutes, and severe poisoning (69.3 ± 10.2% COHb) at 64 ± 23 minutes from baseline (2.9 ± 0.5% COHb). Blood gas parameters and metabolites were measured on a blood gas analyser and nuclear magnetic resonance spectrometer, respectively. Unsupervised principal component, analysis of variance and Pearson's correlation tests were applied. A P-value ≤ .05 was considered statistically significant. Mild poisoning resulted in a 28.4% drop in oxyhaemoglobin (OHb) and 12-fold increase in COHb, while severe poisoning in a 65% drop in OHb and 24-fold increase in COHb. Among others, metabolites implicated in regulation of metabolic acidosis (lactate, P < .0001), energy balance (pyruvate, P < .0001; 3-hydroxybutyrc acid, P = .01), respiration (citrate, P = .007; succinate, P = .0003; fumarate, P < .0001), lipid metabolism (glycerol, P = .002; choline, P = .0002) and antioxidant-oxidant balance (glutathione, P = .03; hypoxanthine, P < .0001) were altered, especially during severe poisoning. Our study adds new insights into the deranged metabolism of CO poisoning and leads the way for further investigation.

In vivo calibration of the T2* cardiovascular magnetic resonance method at 1.5 T for estimation of cardiac iron in a minipig model of transfusional iron overload.

BACKGROUND: Non-invasive estimation of the cardiac iron concentration (CIC) by T2* cardiovascular magnetic resonance (CMR) has been validated repeatedly and is in widespread clinical use. However, calibration data are limited, and mostly from post-mortem studies. In the present study, we performed an in vivo calibration in a dextran-iron loaded minipig model. METHODS: R2* (= 1/T2*) was assessed in vivo by 1.5 T CMR in the cardiac septum. Chemical CIC was assessed by inductively coupled plasma-optical emission spectroscopy in endomyocardial catheter biopsies (EMBs) from cardiac septum taken during follow up of 11 minipigs on dextran-iron loading, and also in full-wall biopsies from cardiac septum, taken post-mortem in another 16  minipigs, after completed iron loading. RESULTS: A strong correlation could be demonstrated between chemical CIC in 55 EMBs and parallel cardiac T2* (Spearman rank correlation coefficient 0.72, P < 0.001). Regression analysis led to [CIC] = (R2* - 17.16)/41.12 for the calibration equation with CIC in mg/g dry weight and R2* in Hz. An even stronger correlation was found, when chemical CIC was measured by full-wall biopsies from cardiac septum, taken immediately after euthanasia, in connection with the last CMR session after finished iron loading (Spearman rank correlation coefficient 0.95 (P < 0.001). Regression analysis led to the calibration equation [CIC] = (R2* - 17.2)/31.8. CONCLUSIONS: Calibration of cardiac T2* by EMBs is possible in the minipig model but is less accurate than by full-wall biopsies. Likely explanations are sampling error, variable content of non-iron containing tissue and smaller biopsies, when using catheter biopsies. The results further validate the CMR T2* technique for estimation of cardiac iron in conditions with iron overload and add to the limited calibration data published earlier.

Consequences of parenteral iron-dextran loading investigated in minipigs. A new model of transfusional iron overload.

Patients with blood transfusion-dependent anemias develop transfusional iron overload (TIO), which may cause cardiosiderosis. In patients with an ineffective erythropoiesis, such as thalassemia major, common transfusion regimes aim at suppression of erythropoiesis and of enteral iron loading. Recent data suggest that maintaining residual, ineffective erythropoiesis may protect from cardiosiderosis. We investigated the common consequences of TIO, including cardiosiderosis, in a minipig model of iron overload with normal erythropoiesis. TIO was mimicked by long-term, weekly iron-dextran injections. Iron-dextran loading for around one year induced very high liver iron concentrations, but extrahepatic iron loading, and iron-induced toxicities were mild and did not include fibrosis. Iron deposits were primarily in reticuloendothelial cells, and parenchymal cardiac iron loading was mild. Compared to non-thalassemic patients with TIO, comparable cardiosiderosis in minipigs required about 4-fold greater body iron loads. It is suggested that this resistance against extrahepatic iron loading and toxicity in minipigs may at least in part be explained by a protective effect of the normal erythropoiesis, and additionally by a larger total iron storage capacity of RES than in patients with TIO. Parenteral iron-dextran loading of minipigs is a promising and feasible large-animal model of iron overload, that may mimic TIO in non-thalassemic patients.

Long-Distance Transportation of Carbon Monoxide-Poisoned Patients on Extracorporeal Membrane Oxygenation Seems Possible: A Porcine Feasibility Study.

OBJECTIVE: Extracorporeal membrane oxygenation (ECMO) has been widely used to stabilize patients with impairment of cardiac/respiratory function, and ECMO has been used to stabilize cardiopulmonary insufficiency caused by carbon monoxide (CO) poisoning in a porcine model. Airborne transportation in fixed wing aircraft of patients suffering from CO poisoning is challenging because as the air pressure drops, the oxygen content falls correspondingly. The aim of this study was to show the feasibility of cannulating and establishing ECMO therapy during airborne transportation after severe CO poisoning in a porcine model. METHODS: An anesthetized pig was subjected to severe CO poisoning and loaded onto a Hercules aircraft. Cardiac arrest was induced at an altitude of 8,000 feet, after which cannulation and the establishment of venoarterial (VA) ECMO were performed. Vital signs were monitored, and arterial blood samples were analyzed while airborne. RESULTS: CO poisoning was induced with carboxyhemoglobin at 58% before takeoff. We successfully cannulated the animal in-flight during cardiac arrest and initiated VA ECMO. The animal regained spontaneous circulation and was successfully weaned from ECMO. During VA ECMO, PaO2 was maintained at high levels (420-615 mm Hg). CONCLUSION: It is possible to cannulate and initiate VA ECMO treatment as airborne en route therapy for cardiac arrest and severe CO intoxication in a porcine model.

Effects of intracoronary melatonin on ischemia-reperfusion injury in ST-elevation myocardial infarction.

Acute coronary occlusion is effectively treated by primary percutaneous coronary intervention. However, myocardial ischemia-reperfusion injury is at the moment an unavoidable consequence of the procedure. Oxidative stress is central in the development of ischemia-reperfusion injury. Melatonin, an endogenous hormone, acts through antioxidant mechanisms and could potentially minimize the myocardial injury. The aim of the experimental study was to examine the cardioprotective effects of melatonin in a porcine closed-chest reperfused infarction model. A total of 20 landrace pigs were randomized to a dosage of 200 mg (0.4 mg/mL) melatonin or placebo (saline). The intervention was administered intracoronary and intravenous. Infarct size, area at risk and microvascular obstruction were determined ex vivo by cardiovascular magnetic resonance imaging. Myocardial salvage index was calculated. The plasma levels of high-sensitive troponin T were assessed repeatedly. The experimenters were blinded with regard to treatment regimen. Melatonin did not significantly increase myocardial salvage index compared with placebo [melatonin 21.8% (16.1; 24.8) vs. placebo 20.2% (16.9; 27.0), p = 1.00]. The extent of microvascular obstruction was similar between the groups [melatonin 3.8% (2.7; 7.1) vs. placebo 3.7% (1.3; 7.7), p = 0.96]. The area under the curve for high-sensitive troponin T release was insignificantly reduced by 32% in the melatonin group [AUC melatonin 12,343.9 (6,889.2; 20,147.4) ng h/L vs. AUC placebo 18,285.3 (5,180.4; 23,716.8) ng h/L, p = 0.82]. Combined intracoronary and intravenous treatment with melatonin did not reduce myocardial reperfusion injury. The lack of a positive effect could be due to an ineffective dose of melatonin, a type II error or the timing of administration.

Hypoxia in the pulmonary vein increases pulmonary vascular resistance independently of oxygen in the pulmonary artery.

INTRODUCTION: Hypoxic pulmonary vasoconstriction (HPV) can be a challenging clinical problem. It is not fully elucidated where in the circulation the regulation of resistance takes place. It is often referred to as if it is in the arteries, but we hypothesized that it is in the venous side of the pulmonary circulation. METHODS: In an open thorax model, pigs were treated with a veno-venous extra corporeal membrane oxygenator to either oxygenate or deoxygenate blood passing through the pulmonary vessels. At the same time the lungs were ventilated with extreme variations of inspired air from 5% to 100% oxygen, making it possible to make combinations of high and low oxygen content through the pulmonary circulation. A flow probe was inserted around the main pulmonary artery and catheters in the pulmonary artery and in the left atrium were used for pressure monitoring and blood tests. Under different combinations of oxygenation, pulmonary vascular resistance (PVR) was calculated. RESULTS: With unchanged level of oxygen in the pulmonary artery and reduced inspired oxygen fraction lowering oxygen tension from 29 to 6.7 kPa in the pulmonary vein, PVR was doubled. With more extreme hypoxia PVR suddenly decreased. Combinations with low oxygenation in the pulmonary artery did not systematic influence PVR if there was enough oxygen in the inspired air and in the pulmonary veins. DISCUSSION: The impact of hypoxia occurs from the alveolar level and forward with the blood flow. The experiments indicated that the regulation of PVR is mediated from the venous side.

Changes in human fetal oxygenation during maternal hyperoxia as estimated by BOLD MRI.

OBJECTIVE: Changes in blood oxygen level dependent (BOLD) magnetic resonance imaging (MRI) signal are closely related to changes in fetal oxygenation. In this study, we aimed to investigate the changes in human fetal oxygenation during maternal hyperoxia by using the non-invasive BOLD MRI technique. METHOD: Eight healthy pregnant women in gestational week 28 to 34 were included. With the use of a facial oxygen mask, we induced maternal hyperoxia and measured changes in the BOLD MRI signal of selected fetal organs. RESULTS: In a number of fetal organs, the BOLD MRI signal increased significantly (P < 0.01) during maternal hyperoxia (mean change in % ± SEM): liver (14.3 ± 3.7%), spleen (15.2 ± 3.5%) and kidney (6.2 ± 1.8%) as well as the placenta (6.5 ± 1.6%). In the fetal brain, however, the BOLD MRI signal remained constant (0.3 ± 0.2%). CONCLUSION: During maternal hyperoxia, we demonstrated an increased oxygenation in a number of human fetal organs by using the non-invasive BOLD technique. The oxygenation of the fetal brain remained constant, thus a 'reversed' brain sparing mechanism could be considered in healthy fetuses subjected to hyperoxia.

Chronic post-thoracotomy pain after lung cancer surgery: a prospective study of preoperative risk factors.

OBJECTIVES: The objective of this longitudinal cohort study was to investigate if preoperative pain mechanisms, anxiety, and depression increase risk of developing chronic post-thoracotomy pain (CPTP) after lung cancer surgery. METHODS: Patients with suspected or confirmed lung cancer undergoing surgery by either video-assisted thoracoscopic surgery or anterior thoracotomy were recruited consecutively. Preoperative assessments were conducted by: quantitative sensory testing (QST) (brush, pinprick, cuff pressure pain detection threshold, cuff pressure tolerance pain threshold, temporal summation and conditioned pain modulation), neuropathic pain symptom inventory (NPSI), and the Hospital Anxiety and Depression Scale (HADS). Clinical parameters in relation to surgery were also collected. Presence of CPTP was determined after six months and defined as pain of any intensity in relation to the operation area on a numeric rating scale form 0 (no pain) to 10 (worst pain imaginable). RESULTS: A total of 121 patients (60.2 %) completed follow-up and 56 patients (46.3 %) reported CPTP. Development of CPTP was associated with higher preoperative HADS score (p=0.025), higher preoperative NPSI score (p=0.009) and acute postoperative pain (p=0.042). No differences were observed in relation to preoperative QST assessment by cuff algometry and HADS anxiety and depression sub-scores. CONCLUSIONS: High preoperative HADS score preoperative pain, acute postoperative pain intensity, and preoperative neuropathic symptoms were was associated with CPTP after lung cancer surgery. No differences in values of preoperative QST assessments were found. Preoperative assessment and identification of patients at higher risk of postoperative pain will offer opportunity for further exploration and development of preventive measures and individualised pain management depending on patient risk profile.

Continuous cardiac output measured with a Swan-Ganz catheter reacts too slowly in animal experiments with sudden circulatory failure.

BACKGROUND: In many animal experiments, it is vital to detect sudden changes in cardiac output (CO). This porcine study compared CO that was measured with a Swan-Ganz pulmonary catheter with the gold standard (which was a transit-time flow probe around the pulmonary artery) during interventions that caused hemodynamic instability. METHODS: In one series, 7 pigs were exposed to sudden changes in CO. In another series, 9 pigs experienced more prolonged changes in CO. All the pigs had a Swan-Ganz catheter placed into the pulmonary artery and a flow probe around the pulmonary artery. Adrenaline infusion and controlled hemorrhage were used to increase and decrease CO, respectively. The measurements of CO before and after each intervention were compared for correlation, agreement, and the time delay that it took each method to detect at least a 30% change in CO. A Bland-Altman test was used to identify correlations and agreements between the methods. RESULTS: In the first series, there was a delay of 5-7 min for the Swan Ganz catheter to register a 30% change in cardiac output, compared with the flow probe. However, during prolonged changes in CO in the second series, there was a good correlation between the 2 methods. Mixed venous oxygen saturation reacted faster to changes than did CO; both were measured via the Swan-Ganz catheter. CONCLUSIONS: In many animal studies, the use of Swan-Ganz catheters is suitable; however, in experiments with sudden hemodynamic instability, the flow probe is the most advantageous method for measuring CO.

Longitudinal MRI study of cortical thickness, perfusion, and metabolite levels in major depressive disorder.

OBJECTIVE: To determine whether patients with major depressive disorder (MDD) display morphologic, functional, and metabolic brain abnormalities in limbic-cortical regions at a baseline magnetic resonance (MR) scan and whether these changes are normalized in MDD patients in remission at a follow-up scan. METHOD: A longitudinal 3.0-Tesla (T) magnetic resonance imaging (MRI) study was carried out with cortical thickness measurements with a surface-based approach, perfusion measurements with three-dimensional (3D) pseudo-continuous arterial spin labeling (pCASL), and spectroscopy (1H-MRS) measurements in the anterior cingulate cortex (ACC) with water as an internal reference adjusted for cerebrospinal fluid content. We examined 23 MDD patients and 26 healthy controls. MDD patients underwent a baseline MRI at inclusion and were invited to a follow-up scan when they were in remission or after a 6-month follow-up period. RESULTS: Major findings were a significantly thinner posterior cingulate cortex in non-remitters than in remitters, a significant decrease in perfusion in the frontal lobes and the ACC in non-remitters compared with healthy controls at baseline and significantly reduced N-acetylaspartate, myo-inositol, and glutamate levels in MDD patients compared with healthy controls at baseline. CONCLUSION: Using novel MRI techniques, we have found abnormalities in cerebral regions related to cortical-limbic pathways in MDD patients.

Perfusion MRI of brain tumours: a comparative study of pseudo-continuous arterial spin labelling and dynamic susceptibility contrast imaging.

INTRODUCTION: The purpose of this study was to compare the non-invasive 3D pseudo-continuous arterial spin labelling (PC ASL) technique with the clinically established dynamic susceptibility contrast perfusion magnetic resonance imaging (DSC-MRI) for evaluation of brain tumours. METHODS: A prospective study of 28 patients with contrast-enhancing brain tumours was performed at 3 T using DSC-MRI and PC ASL with whole-brain coverage. The visual qualitative evaluation of signal enhancement in tumour was scored from 0 to 3 (0 = no signal enhancement compared with white matter, 3 = pronounced signal enhancement with equal or higher signal intensity than in grey matter/basal ganglia). The extent of susceptibility artefacts in the tumour was scored from 0 to 2 (0 = no susceptibility artefacts and 2 = extensive susceptibility artefacts (maximum diameter > 2 cm)). A quantitative analysis was performed with normalised tumour blood flow values (ASL nTBF, DSC nTBF): mean value for region of interest (ROI) in an area with maximum signal enhancement/the mean value for ROIs in cerebellum. RESULTS: There was no difference in total visual score for signal enhancement between PC ASL and DSC relative cerebral blood flow (p = 0.12). ASL had a lower susceptibility-artefact score than DSC-MRI (p = 0.03). There was good correlation between DSC nTBF and ASL nTBF values with a correlation coefficient of 0.82. CONCLUSION: PC ASL is an alternative to DSC-MRI for the evaluation of perfusion in brain tumours. The method has fewer susceptibility artefacts than DSC-MRI and can be used in patients with renal failure because no contrast injection is needed.

A paramilitary retrieval team for accidental hypothermia. Insights gained from a simple classification with advanced treatment over 16 years in Denmark.

AIM: To present the results from 16 years of nationwide cooperation between the Danish Airforce Search and Rescue Service and a Tertiary Heart Centre for the classification and treatment of accidental hypothermia. METHODS: A mobile extracorporeal membrane oxygenation (ECMO) retrieval team was developed and could be contacted for nationwide advice and if indicated retrieval and/or treatment of patients by means of ambulance and/or helicopter. Accidental hypothermia was classified as mild, moderate, and severe, corresponding to awake, unconscious, and lifeless. The exact temperature was not considered relevant in the primary assessment. The mild group was treated with blankets and minimal invasive with warm i.v. infusions. The moderate group was primarily treated with an ABC approach, and if circulation was unstable due to arrhythmias or bleeding, invasive warming was performed with pleural lavage under ECMO preparedness. The severe group was treated with CPR followed by ECMO. All patients were examined for underlying disorders. RESULTS: The team was involved in 204 patients, but for 47 patients treatment was stopped as they were considered beyond therapeutic reach, leaving 157 treated patients with 108 (69%) survivors. Among 54 ECMO patients, 21 (39%) survived to hospital discharge. CONCLUSIONS: We successfully implemented a simplified classification of accidental hypothermia and initiated a nationwide cooperation for retrieval and/or treatment of accidental hypothermic patients.

Primary Mediastinal Choriocarcinoma in an Elderly Patient with Concurrent Goserelin-Treated Prostate Adenocarcinoma.

Mediastinal pure choriocarcinomas are exceedingly rare representations of germ cell tumours and are associated with a poor prognosis. To date, fewer than 20 cases have been reported. This current report describes an elderly patient who developed a large rapidly growing mediastinal tumour. Unfortunately, the patient expired before a definitive diagnosis could be reached. An autopsy revealed that the histomorphological features of the tumour showed two distinct tumour cell populations (syncytio- and cytotrophoblasts), and the diagnosis of choriocarcinoma was made. Immunohistochemical analysis showed a characteristic staining pattern in agreement with published studies. Here, we report a case of primary mediastinal choriocarcinoma in an elderly male with concurrent metastasizing prostate adenocarcinoma treated with long-term goserelin deposits, which, as we speculate, could have induced the choriocarcinoma.

Carbon monoxide poisoning in Denmark with focus on mortality and factors contributing to mortality.

INTRODUCTION: Carbon monoxide (CO) poisoning is frequent worldwide but knowledge regarding the epidemiology is insufficient. The aim of this study was to clarify the extent of this intoxication, its mortality and factors associated with mortality. MATERIALS AND METHODS: National databases from Statistics Denmark were used to identify individuals who suffered from CO-poisoning during 1995-2015, as well as information regarding co-morbidities, mortality and manner of death. RESULTS: During the period from 1995 to 2015, 22,930 patients suffered from CO-poisoning in Denmark, and 21,138 of these patients (92%) were hospitalized. A total of 2,102 patients died within the first 30 days after poisoning (9.2%). Among these, 1,792 (85% of 2,102) were declared dead at the scene and 310 (15% of 2,102) died during hospitalization. Deaths due to CO-poisoning from smoke were intentional in 6.3% of cases, whereas deaths due to CO containing gases were intentional in 98.0% of cases. Among patients who survived >30 days, there was no significant difference in survival when comparing hyperbaric oxygen therapy (HBO) treatment with no HBO treatment after adjustment for age and co-morbidities such as drug abuse, psychiatric disease, stroke, alcohol abuse, arterial embolism, chronic obstructive pulmonary disease, cerebrovascular disease and atrial fibrillation. Several co-morbidities predicted poorer outcomes for patients who survived the initial 30 days. CONCLUSIONS: Poisoning from smoke and/or CO is a frequent incident in Denmark accounting for numerous contacts with hospitals and deaths. Both intoxication and mortality are highly associated with co-morbidities interfering with cognitive and physical function. Treatment with HBO was not seen to have an effect on survival.

ECMO improves survival following cardiogenic shock due to carbon monoxide poisoning - an experimental porcine model.

BACKGROUND: Severe intoxication with carbon monoxide (CO) is extremely lethal and causes numerous deaths due to cardiac or respiratory failure. Conventional intensive treatment may not be sufficient. The aim of this study was to investigate the treatment effect of extracorporeal veno-arterial extracorporeal membrane oxygenation (ECMO) following severe CO poisoning in an experimental porcine model. METHODS: A total of twelve pigs were anaesthetized, routinely monitored and intoxicated by inhalation of CO until the beginning of cardiac failure and randomized to a treatment (ventilator using an FiO2 of 100% or ECMO). In the case of cardiac arrest, advanced resuscitation using standard guidelines was performed for at least 10 min. ECMO was also initiated in the ventilation group if the return of spontaneous circulation did not occur within 10 min. Lung tissue biopsies were obtained before and after CO intoxication. RESULTS: All animals in the ECMO group survived; however, one had to be resuscitated due to cardiac arrest. A single animal survived in the ventilator group, but five animals suffered from cardiac arrest at an average of 11.8 min after initiation of treatment. Conventional resuscitation failed in these animals, but four animals were successfully resuscitated after the establishment of ECMO. A significant decrease was noticed in PO2 with increasing HbCO, but there was no increase in pulmonary vascular resistance. No differences in H&E-stained lung tissue biopsies were observed. CONCLUSIONS: The use of ECMO following severe CO poisoning greatly improved survival compared with conventional resuscitation in an experimental porcine model. This study forms the basis for further research among patients.

Fatal case of accidental perforation of ileum by pace wires during coronary bypass grafting.

In many centres, epicardal pace wires are routinely implanted during coronary artery bypass surgery to treat postoperative tachy- and brady-arrhythmias. We describe the case of an 88-year-old male, with severe comorbidity, who underwent a successful CABG, but incurred an unacknowledged iatrogenic perforation of the ileum with the placement of an epicardial pace wire. The patient developed septic shock and multi organ failure despite intra-abdominal surgical interventions and intensive care therapy, and died 6 days after CABG.

Acute Metabolic Changes Associated With Analgesic Drugs: An MR Spectroscopy Study.

BACKGROUND AND PURPOSE: Magnetic resonance spectroscopy (MRS) is used to measure brain metabolites. Limited data exist on the analgesic-induced spectroscopy response. This was an explorative study with the aims to investigate the central effects of two analgesic drugs, an opioid and a selective serotonin and norepinephrine reuptake inhibitor, and to explore the association between metabolite changes and the analgesic effect and side effects. METHODS: Single voxel proton spectroscopy measurements were performed in the anterior cingulate cortex, insula and prefrontal cortex in 20 healthy subjects before and after treatment for 5 days with oxycodone (eight doses of 10 mg extended release), venlafaxine (eight doses of 37.5 mg extended release) or placebo in a randomized double-blind fashion. The metabolites of glutamate, N-acetylaspartate, and myo-inositol were analyzed in ratios to creatine. RESULTS: Including all areas, the glutamate/creatine ratio was decreased (P < .05) with 8.4% ± 0.3% after oxycodone treatment (P = .02) and 6.6% ± 0.4% after venlafaxine treatment (P = .07) as compared to placebo. No statistical significant differences in treatment effects across the areas were found (P = .6). No treatment effect was seen for N-acetylaspartate/creatine or myo-inositol/creatine ratios (all P > .05). No associations between treatment induced glutamate/creatine changes and the analgesic effect and side effects were demonstrated (all P > .05). CONCLUSIONS: MRS can be used to detect brain metabolites following acute analgesic treatments and glutamate is central in these mechanisms. Consequently, MRS might be a valuable tool to objectively evaluate analgesic effects and a potential biomarker to predict treatment outcomes and more research is needed.