The Nordic prescription databases as a resource for pharmacoepidemiological research--a literature review.

PURPOSE: All five Nordic countries have nationwide prescription databases covering all dispensed drugs, with potential for linkage to outcomes. The aim of this review is to present an overview of therapeutic areas studied and methods applied in pharmacoepidemiologic studies using data from these databases. METHODS: The study consists of a Medline-based structured literature review of scientific papers published during 2005-2010 using data from the prescription databases in Denmark, Finland, Iceland, Norway, and Sweden, covering 25 million inhabitants. Relevant studies were analyzed in terms of pharmacological group, study population, outcomes examined, type of study (drug utilization vs. effect of drug therapy), country of origin, and extent of cross-national collaboration. RESULTS: A total of 515 studies were identified. Of these, 262 were conducted in Denmark, 97 in Finland, 4 in Iceland, 87 in Norway, and 61 in Sweden. Four studies used data from more than one Nordic country. The most commonly studied drugs were those acting on the nervous system, followed by cardiovascular drugs and gastrointestinal/endocrine drugs. A total of 228 studies examined drug utilization and 263 focused on the effects and safety of drug therapy. Pregnant women were the most commonly studied population in safety studies, whereas prescribers' adherence to guidelines was the most frequent topic of drug utilization studies. CONCLUSIONS: The Nordic prescription databases, with their possibility of record-linkage, represent an outstanding resource for assessing the beneficial and adverse effects of drug use in large populations, under routine care conditions, and with the potential for long-term follow-up.

Efficacy of mobile telephone contact for follow-up in injecting heroin users.

BACKGROUND: Prospective follow-up of heroin users is known to be difficult due to their unstable lifestyle, and high follow-up rates have usually demanded major tracking efforts. In Sweden, mobile telephones are commonly used by heavy drug users for drug trading. OBJECTIVES: This methodology study aims to examine the efficacy of mobile telephone contact for prospective follow-up interviews with injecting heroin users recruited at the syringe exchange program of Malmö, Sweden. METHODS: Seventy-eight heroin users with mobile telephone numbers were included. Subjects reported using heroin for 28 days of the previous 30 days, and only 8% reported they had recently been engaged in work or studies. Clients were contacted between 15 and 21 times over 2 years, with each contact attempt generally involving two telephone calls on consecutive days. RESULTS: During follow-up, 68% of subjects had been successfully contacted for at least one follow-up interview (on average 6.9 interviews), and 25% of follow-up attempts were successful. In 23% of the sample (n=18), at least 50% of follow-up attempts were successful, and these subjects tended to be older (p=.05) and more likely to be female (p=.07), whereas follow-up rates were unrelated to baseline heroin use. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: Despite limited effort, and despite the severe situation of intravenous heroin users, mobile telephone contact can be used with heavy drug users in the present setting.

Effects of repeated CPR training in virtual worlds on medical students' performance.

We report on a study that investigates the relationship between repeated training of teams managing a medical emergency (CPR) in a Virtual World and performance outcome measures in a group of 12 medical students. The focus of the training was on individual actions, but also on interaction and behavior in the team. Current CPR training seems to lack important team training aspects which this type of training is addressing. Although a pilot study, we found clear indications of improved performance related to reduced number of errors and an increased CPR efficiency. This type of educational technology could be expanded to other groups for a similar purpose because of its easiness to use, adaptability and interactivity.

Implementing virtual worlds for systematic training of prehospital CPR in medical school.

We report on a study that investigates the relationship between repeated training of teams managing medical emergencies in the Virtual World and affective learning outcomes in a group of 12 medical students. The focus of the training was on individual actions, but also on interaction and behaviour in the team. Current CPR training seems to lack important team training aspects which this type of training is addressing. We found an increase in flow experience and in self efficacy. This type of training could probably be expanded to other groups for a similar purpose because of its easiness to use, adaptability and interactivity.

Training trauma teams in the Nordic countries: an overview and present status.

BACKGROUND: During the last decade there has been an increased interest in the organisation and quality of trauma care in the Nordic countries. Still, most patients are initially cared for at hospitals with low caseloads of severe trauma. More than 200 hospitals offer initial care to trauma patients. Training of trauma teams using simulators or simulated patients has evolved in the same period, as one important factor to overcome lack of practical training. This overview describes the present state of trauma team training in the Nordic countries. METHODS: Members of a Nordic working group on the use of simulation in medicine reviewed present literature on training with simulation and described the present use of team training in their own countries during winter 2004. RESULTS: There is an increasing amount of evidence indicating that training of teams with simulation reduces treatment errors and improves performance. The training activities do not need to be complex, but skilled debriefing seems necessary. Few Nordic hospitals train their trauma teams. The training activities vary considerably between and within countries. CONCLUSION: There is considerable evidence supporting an increased use of experience gained in other high-risk domains where training in communication, leadership and decision-making is the focus for safety and improvement efforts. There is a need for more widespread training of trauma teams. The different training activities actually undertaken should be scientifically evaluated.

Effect of budesonide enema on remission and relapse rate in distal ulcerative colitis and proctitis.

BACKGROUND: Glucocorticosteroid enemas are equally effective as 5-ASA enemas in the treatment of active distal ulcerative colitis (UC). With the introduction of budesonide, the risk of systemic side effects may be reduced. We investigated whether budesonide enema, 2 mg/100 ml, administered twice daily (b.i.d.) could increase the remission rate in comparison with the once daily (o.d.) standard regimen. Furthermore, we evaluated whether 2 mg budesonide enema, given twice weekly, could have a relapse preventing effect. METHODS: 149 patients with active distal UC were treated in a controlled, double-blind multicentre study with two parallel groups: placebo enema in the morning and budesonide enema in the evening (i.e. 2 mg/day) or budesonide enema b.i.d. (i.e. 4 mg/day) until remission (absence of clinical symptoms and endoscopic healing) or at most 8 weeks. Patients in remission were randomized to either budesonide enema or placebo enema twice weekly for 24 weeks or until relapse. RESULTS: The remission rates at 4 weeks were 33% for o.d. and 41% for b.i.d. regimens (NS) and correspondingly 51% and 54% at 8 weeks (NS). The b.i.d. group had an increased frequency of impaired adrenal function, 32% versus 4.8% (P = 0.001). The relapse rates during maintenance treatment with budesonide enema and placebo were 15% versus 24% after 8 weeks, 31% versus 27% after 16 weeks and 41% versus 51% after 24 weeks (NS). CONCLUSION: Budesonide enema 2 mg o.d. appears to be the optimal dosage in active distal UC. We could not show that budesonide enema twice weekly is sufficient to maintain remission.

Impairment of mitochondrial respiration after cerebral hypoxia-ischemia in immature rats: relationship to activation of caspase-3 and neuronal injury.

Mitochondrial damage may play a key role in the development of necrotic and apoptotic hypoxic-ischemic (HI) brain damage. It has previously been shown that mitochondrial respiration is depressed in the cerebral cortex after HI in neonatal animals. The aim of the present study was to further characterize the time course of the mitochondrial impairment during reperfusion and the correlation between the respiratory control ratio and brain injury and activation of caspase-3. Rat pups were subjected to unilateral carotid artery ligation and exposed to hypoxia (7.7% oxygen). Mitochondrial respiration was measured 0-72 h after HI in a mitochondrial fraction isolated from cerebral cortex. Microtubule associated protein-2 (MAP2) and caspase-3 were analyzed with immunoblotting in cerebral cortex homogenates. In addition, the time course of caspase-3 activation was measured as DEVD cleavage. The mitochondrial respiratory control ratio in cerebral cortex decreased immediately after HI followed by a partial recovery at 3-8 h. Thereafter, a secondary drop occurred with a minimum reached at 24 h of reperfusion. The secondary loss of respiratory function was accompanied by depletion of MAP2, cleavage of caspase-3 and an increased caspase-3 -like activity at 3-24 h after the insult. In conclusion, the primary phase of mitochondrial dysfunction was paralleled by a moderate decrease of MAP2 and a limited activation of caspase-3. The secondary mitochondrial impairment was associated with neuronal injury and pronounced activation of caspase-3.

Alterations in glutathione and amino acid concentrations after hypoxia-ischemia in the immature rat brain.

Hypoxic-ischemic brain injury involves an increased formation of reactive oxygen species. Key factors in the cellular protection against such agents are the GSH-associated reactions. In the present study we examined alterations in total glutathione and GSSG concentrations in mitochondria-enriched fractions and tissue homogenates from the cerebral cortex of 7-day-old rats at 0, 1, 3, 8, 14, 24 and 72 h after hypoxia-ischemia. The concentration of total glutathione was transiently decreased immediately after hypoxia-ischemia in the mitochondrial fraction, but not in the tissue, recovered, and then decreased both in mitochondrial fraction and homogenate after 14 h, reaching a minimum at 24 h after hypoxia-ischemia. The level of GSSG was approximately 4% of total glutathione and increased selectively in the mitochondrial fraction immediately after hypoxia-ischemia. The decrease in glutathione may be important in the development of cell death via impaired free radical inactivation and/or redox related changes. The effects of hypoxia-ischemia on the concentrations of selected amino acids varied. The levels of phosphoethanolamine, an amine previously reported to be released in ischemia, mirrored the changes in glutathione. GABA concentrations initially increased (0-3 h) followed by a decrease at 72 h. Glutamine levels increased, whereas glutamate and aspartate were unchanged up to 24 h after the insult. The results on total glutathione and GSSG are discussed in relation to changes in mitochondrial respiration and microtubule associated protein-2 (MAP2) which are reported on in accompanying paper [64].

Pneumoperitoneum in healthy humans does not affect central blood volume or cardiac output.

BACKGROUND: This study addresses the question of whether the elevation of the mean arterial pressure and central venous pressure in response to pneumoperitoneum for laparoscopic surgery is caused by increases in central blood volume and/or cardiac output. METHODS: Eleven patients in good cardiopulmonary health and scheduled for laparoscopic cholecystectomy, with a mean age of 42 years, were included. After induction of anaesthesia with fentanyl and propofol, radial arterial and central venous lines were introduced. The central blood volume and cardiac output were determined by the indicator-dilution technique, using inline densitometric measurements of indocyanine green (ICG). The measurements were made before and after the establishment of pneumoperitoneum by insufflation of carbon dioxide to an intra-abdominal pressure level of 11-13 mmHg. RESULTS: The mean arterial pressure (62+/-6 mmHg) increased after induction of pneumoperitoneum by 40+/-26% (P<0.05) and the central venous pressure increased from 6+/-4 mmHg to 8+/-6 mmHg (P<0.05). The cardiac output (4.3+/-0.9 L/min) and central blood volume (1.5+/-0.5 L) were not affected by the induction of pneumoperitoneum. CONCLUSIONS: In healthy anaesthetized subjects, the elevation of mean arterial pressure and central venous pressure in response to pneumoperitoneum was not caused by enhancement in cardiac output or central blood volume.

Glutathione efflux induced by NMDA and kainate: implications in neurotoxicity?

Neurotoxicity in acute as well as chronic neurological diseases may be partly mediated by oxidative stress caused by overactivation of glutamate receptors. A key component of the cellular defense against oxidative stress is reduced glutathione. In our earlier work, we have shown that ischemia in brain induces increased efflux, elevated metabolism, and decreased tissue concentrations of glutathione. In this study, we have evaluated the effect of glutamate receptor activation on the efflux of glutathione from hippocampus in vitro. NMDA and kainate induced a delayed increase in glutathione, taurine, and phosphoethanolamine efflux. Extracellular glutathione was recovered mainly in the reduced form (85-95%); the efflux was dependent on extracellular calcium but unrelated to dantrolene-sensitive intracellular calcium release and independent of glutathione or NO synthesis. The NMDA-induced efflux of glutathione was enhanced by blockage of gamma-glutamyl transpeptidase, indicating an increased transpeptidation of glutathione after NMDA receptor activation. Our results suggest that increased efflux of glutathione could be a factor in initiating nerve cell death via a change in intracellular redox potential and/or a decrease in the intracellular capacity for inactivation of reactive oxygen species.

Net efflux of cysteine, glutathione and related metabolites from rat hippocampal slices during oxygen/glucose deprivation: dependence on gamma-glutamyl transpeptidase.

Extracellular metabolism of the protective substance glutathione (gamma-glutamyl-cysteinyl-glycine) may generate cysteine, glycine, several gamma-glutamyl-containing dipeptides and possibly free glutamate, all of which could participate in neurotoxicity. In the present study, we have examined how blockage of gamma-glutamyl transpeptidase, the key enzyme in glutathione degradation, influences the extracellular concentrations of glutathione, cysteine and related metabolites during anoxia/aglycemia of rat hippocampal slices. The net efflux, i.e., the increase in extracellular concentration due to changes in release and/or uptake, of cysteine, cysteine sulfinate, gamma-glutamyl-glutamate, gamma-glutamyl-glutamine, glutathione, gamma-glutamyl-cysteine and glutamate increased as a result of anoxia/aglycemia. These increases in net efflux of cysteine, cysteine sulfinate, gamma-glutamyl-glutamate and gamma-glutamyl-glutamine were reduced or blocked by acivicin, an inhibitor of gamma-glutamyl transpeptidase. In contrast, acivicin caused an increase in both basal and anoxia/aglycemia-induced net efflux of glutathione whereas the basal and anoxia/aglycemia-induced efflux of glutamate was unchanged by acivicin treatment. The effect of acivicin on the efflux of gamma-glutamyl-cysteine was similar to that of glutathione although less pronounced. Addition of beta-mercaptoethanol to the incubation medium during and after 30 min of anoxia/aglycemia decreased the net efflux of cysteine sulfinate specifically, indicating that the increase in cysteine sulfinate during anoxia/aglycemia may be partly derived from the spontaneous oxidation of cysteine. The results suggest that gamma-glutamyl transpeptidase may be involved in the regulation of the extracellular concentrations of cysteine, several gamma-glutamyl-containing dipeptides and glutathione but not glutamate during ischemia.

Effects of rapid colloid volume expansion on pulmonary microvascular pressure and lung water in the conscious sheep.

Increased pulmonary microvascular pressure (Pmv), in combination with other factors, may cause pulmonary interstitial oedema. Whether increased Pmv alone induces alveolar oedema is questionable. In the present study we used the heavy water-indocyanine green dilution method to measure lung water during a rapid intravascular volume expansion in the sheep. Eight conscious sheep were given two 10-min intravenous infusions of either 50 ml/kg (N = 2) or 35 ml/kg (N = 6) of dextran 60 with an interval of 10 min between them. At a Pmv of 40 mmHg, respiratory distress was observed in sheep no. 2 which had been given a total amount of 100 ml/kg of dextran; this was immediately followed by a lethal pulmonary haemorrhage. Mean Pmv in the remaining seven sheep increased to 31 (7) mmHg in response to the volume expansion without causing any respiratory distress or increase in lung water. These results show that in conscious sheep the lungs have strong protective mechanisms against hydrostatic oedema. They do not support the hypothesis that increased Pmv alone induces alveolar oedema, but suggest that an increase in Pmv to 40 mmHg may cause stress failure of the pulmonary vasculature.

Quantitative estimation of errors in the indicator dilution measurement of extravascular lung water.

OBJECTIVE: To assess the accuracy of the diffusible indicators heavy water and thermal indicator in the measurement of extravascular lung water (EVLW). DESIGN: Cardiac output (CO), mean transit time and EVLW for the two diffusible indicators were measured. CO for indocyanine green, gravimetric EVLW and the calculated mean transit time for a diffusible indicator were used as independent reference variables. CO, mean transit time and EVLW for the two diffusible indicators were compared to the reference variables and the percentage error for each measured variable was calculated for each bolus injection. SETTING: 6 sheep with healthy lungs and 6 with pulmonary oedema in a research laboratory. INTERVENTIONS: CO was altered with positive end-expiratory pressure and dobutamine. MEASUREMENTS: All indicators were given together in a bolus through a central venous line. Indicators were detected simultaneously in the aorta, and CO, mean transit time and EVLW were measured. EVLW was measured gravimetrically (EVLWgrav) postmortem. RESULTS: In the combination of a low CO and a large distribution volume, heavy water and thermal indicator produced a large number of slow wash-out curves. These curves were abolished from further analysis. The mean errors in CO and mean transit time for heavy water were close to zero and independent of the distribution volume; the product EVLW was close to EVLWgrav. The mean error in thermodilution CO measured in the aorta was close to zero but dependent on the distribution volume. The mean error in mean transit time for the thermal indicator was 36% and dependent on the distribution volume. Their product EVLW overestimated EVLWgrav by 70%. CONCLUSIONS: The results obtained for heavy water confirmed the theoretical basis of the indicator dilution method. The mean transit time for the thermal indicator was not proportionate to its distribution volume. The magnitude of this error prevents the calculation of an anatomically defined EVLW using a catheter-mounted thermistor in the aorta.

Subclinical pulmonary oedema and intermittent haemodialysis.

It has been postulated that patients with chronic renal failure, even in the absence of cardiopulmonary symptoms, accumulate interstitial pulmonary fluid, which is removed by haemodialysis. To test this hypothesis we used the indocyanine green (ICG)-heavy water double indicator dilution method to measure lung water, cardiac output, and central blood volume in relation to haemodialysis. Ten uraemic patients, without cardiopulmonary symptoms, were investigated at the beginning and end, and 2 h after, a regular dialysis session. A group of 18 surgical patients about to undergo elective abdominal surgery served as controls. Despite normal gas exchange, central blood volume, and cardiac output at the start of dialysis the mean (SD) lung water was significantly higher than in the control group [4.8 (0.9) compared with 3.6 (0.7) ml/kg, P < 0.001]. There was no correlation between weight gain between sessions of dialysis and the magnitude of lung water at the start of dialysis. Lung water decreased (P < 0.001) to the level of the control group in response to dialysis. There was no correlation between weight loss and reduction in lung water induced by dialysis. In conclusion, we have verified the presence of subclinical pulmonary oedema which was removed by dialysis in a group of patients with established renal failure. The variations in lung water cannot be explained by hydrostatic mechanisms alone.

Release of somatostatin, neurotensin and vasoactive intestinal peptide upon inhibition of gastric acid secretion by duodenal acid and hyperosmolal solutions in the conscious rat.

The inhibitory effect of duodenal exposure to acid and hyperosmolal solutions on pentagastrin-stimulated gastric acid secretion was studied in conscious rats equipped with chronic gastric fistula and duodenal Thiry-Vella loop. The loop was challenged with saline, HCl or hyperosmolal polyethylene glycol. Gastric acid secretion was measured in samples from the gastric fistula. Gut peptide concentrations were measured in duodenal perfusates collected each 30 min, and in plasma samples collected both during stimulated acid secretion alone, and at the end of experiments in combination with luminal challenges of the loops. During pentagastrin-stimulated gastric acid secretion, luminal perfusion of the duodenal loop with acid caused inhibition of acid secretion (P < 0.001) and a prominent release of somatostatin both to the lumen (P < 0.001) and to the circulation (P < 0.05). Also, neurotensin (P < 0.01) and vasoactive intestinal peptide (P < 0.01) were released to the lumen, but not to the circulation. Upon perfusion of the duodenal loop with hyperosmolal polyethylene glycol, acid secretion was inhibited (P < 0.05) and somatostatin alone was released to the luminal side (P < 0.01). In conclusion, duodenal exposure to acid inhibits pentagastrin-stimulated gastric acid secretion and releases SOM to the circulation that may directly inhibit acid secretion. Concomitantly, somatostatin (SOM), neurotensin and vasoactive intestinal peptide are released to the lumen. Duodenal exposure to hyperosmolal polyethylene glycol inhibits acid secretion with a luminal release of SOM only. Thus, luminal acid and hyperosmolal solutions inhibit gastric acid secretion by separate mechanisms. After acid or hyperosmolal challenge, the release of SOM to the circulation indicates gastric acid inhibition in an endocrine manner, while a luminal release of gut peptides indicates a local peptide overflow that might be of importance via paracrine regulatory mechanisms in the intact animal.

Transforming growth factor-alpha and epidermal growth factor inhibit gastric acid secretion and stimulate release of somatostatin and neurotensin in the conscious rat.

The study compared inhibitory actions of transforming growth factor-alpha (TGF alpha) and epidermal growth factor (EGF) on gastric acid secretion and effects of these peptides on release of gut peptides considered important for acid inhibitory and gastrointestinal protective mechanisms. TGF alpha and EGF did not affect basal acid secretion, but inhibited pentagastrin-stimulated acid secretion in a dose-dependent manner from 0.10 to 1.7 nmol kg-1 h-1 i.v. by maximally 72% for TGF alpha (P < 0.001) and 76% for EGF (P < 0.001). At the highest doses, TGF alpha and EGF caused 194% and 698% increase of somatostatin-like immunoreactivity (SOM-LI) in plasma, respectively (each P < 0.05). Neurotensin-like immunoreactivity (NT-LI) increased 438% by EGF (P < 0.05), but the increase of 700% with TGF alpha did not reach statistical significance. The levels of vasoactive intestinal peptide-like immunoreactivity (VIP-LI) did not change. In gastric juice, SOM-LI increased 80% by TGF alpha i.v. (P < 0.05), but NT- and VIP-LI did not change. EGF i.v. had no effects on levels of SOM-, NT- or VIP-LI in luminal juice. Thus, TGF alpha and EGF inhibit acid secretion, but also promote the release of SOM and NT into the circulation and may be involved in the acid inhibitory effects of these growth factors.

Estimation of extravascular lung water in humans with use of 2H2O: effect of blood flow and central blood volume.

In the present human study we evaluated a newly developed double-indicator-dilution densitometric system for the estimation of cardiac output (Q), central blood volume (CBV), and extravascular lung water (EVLW) by using indocyanine green and heavy water (2H2O) as indicators. Eighteen cardiopulmonary healthy patients scheduled for abdominal surgery were studied. A routine anesthesia procedure was used [thiopental (3-5 mg/kg), N2O (inspired fraction of O2 = 0.4), and isoflurane (end tidal 0.5-1.5%)]. Q, CBV, and EVLW were measured at seven defined data collection points: awake, anesthetized spontaneously breathing, apneic, mechanically ventilated with and without positive end-expiratory pressure, post-operatively anesthetized, and postoperatively awake. During the whole study EVLW (3.8 +/- 0.9 ml/kg) was stable in the presence of large fluctuations in Q (2.5-10.1 l/min) and CBV (0.8-2.4 l). We concluded that the method is versatile and of low invasiveness, allowing reliable on-line Q and EVLW data for repeated measurements in the clinical setting.

Fat inhibits pentagastrin-stimulated acid secretion from the duodenum but not from the proximal jejunum in chronic gastric fistula rats.

The effect of fat emulsion in the upper intestine on the maximal gastric acid response to pentagastrin was studied in chronic gastric fistula (GF) rats with a 4-cm blind loop of the duodenum anastomosed to the jejunum (Roux-en-Y). Fat emulsion in the loop inhibited the acid response by 85%. To localize the site of the inhibitory mechanism, GF rats were provided with Thirty-Vella loops of the duodenum (bile and pancreatic ducts transplanted to the proximal jejunum) or with Thirty-Vella loops of the proximal jejunum and a Roux-en-Y loop of the duodenum to prevent gastric juice from entering the duodenum. Perfusion of the duodenal loop with fat emulsion mixed with bile and pancreatic juice reduced the acid response by 49%, but perfusion of the proximal jejunal loop did not alter the response. It is concluded that the intestinal mechanism for inhibition of acid secretion by fat is located in the duodenum in rats.