Vasopressin and methylprednisolone and hemodynamics after in-hospital cardiac arrest - A post hoc analysis of the VAM-IHCA trial.

INTRODUCTION: The Vasopressin and Methylprednisolone for In-Hospital Cardiac Arrest (VAM-IHCA) trial demonstrated a significant improvement in return of spontaneous circulation (ROSC) with no clear effect on long-term outcomes. The objective of the current manuscript was to evaluate the hemodynamic effects of intra-cardiac arrest vasopressin and methylprednisolone during the first 24 hours after ROSC. METHODS: The VAM-IHCA trial randomized patients with in-hospital cardiac arrest to a combination of vasopressin and methylprednisolone or placebo during the cardiac arrest. This study is a post hoc analysis focused on the hemodynamic effects of the intervention after ROSC. Post-ROSC data on the administration of glucocorticoids, mean arterial blood pressure, heart rate, blood gases, vasopressor and inotropic therapy, and sedation were collected. Total vasopressor dose between the two groups was calculated based on noradrenaline-equivalent doses for adrenaline, phenylephrine, terlipressin, and vasopressin. RESULTS: The present study included all 186 patients who achieved ROSC in the VAM IHCA-trial of which 100 patients received vasopressin and methylprednisolone and 86 received placebo. The number of patients receiving glucocorticoids during the first 24 hours was 22/86 (26%) in the placebo group and 14/100 (14%) in the methylprednisolone group with no difference in the cumulative hydrocortisone-equivalent dose. There was no significant difference between the groups in the mean cumulative noradrenaline-equivalent dose (vasopressin and methylprednisolone: 603 ug/kg [95CI% 227; 979] vs. placebo: 651 ug/kg [95CI% 296; 1007], mean difference -48 ug/kg [95CI% -140; 42.9], p = 0.30), mean arterial blood pressure, or lactate levels. There was no difference between groups in arterial blood gas values and vital signs. CONCLUSION: Treatment with vasopressin and methylprednisolone during cardiac arrest caused no difference in mean arterial blood pressure, vasopressor use, or arterial blood gases within the first 24 hours after ROSC when compared to placebo.

Comparing restrictive versus liberal oxygen strategies for trauma patients - the TRAUMOX2 trial: protocol for a randomised clinical trial.

INTRODUCTION: Supplemental oxygen is commonly used in trauma patients, although it may lead to hyperoxaemia that has been associated with pulmonary complications and increased mortality. The primary objective of this trial, TRAUMOX2, is to compare a restrictive versus liberal oxygen strategy the first 8 hours following trauma. METHODS AND ANALYSIS: TRAUMOX2 is an investigator-initiated, international, parallel-grouped, superiority, outcome assessor-blinded and analyst-blinded, randomised, controlled, clinical trial.Adult patients with suspected major trauma are randomised to eight hours of a restrictive or liberal oxygen strategy. The restrictive group receives the lowest dosage of oxygen (>21%) that ensures an SpO2 of 94%. The liberal group receives 12-15 L O2/min or FiO2=0.6-1.0.The primary outcome is a composite of 30-day mortality and/or development of major respiratory complications (pneumonia and/or acute respiratory distress syndrome).With 710 participants in each arm, we will be able to detect a 33% risk reduction with a restrictive oxygen strategy if the incidence of our primary outcome is 15% in the liberal group. ETHICS AND DISSEMINATION: TRAUMOX2 is carried out in accordance with the Helsinki II Declaration. It has been approved by the Danish Committee on Health Research Ethics for the Capital Region (H-21018062) and The Danish Medicines Agency, as well as the Dutch Medical Research Ethics Committee Erasmus MS (NL79921.078.21 and MEC-2021-0932). A website (www.traumox2.org) is available for updates and study results will be published in an international peer-reviewed scientific journal. TRIAL REGISTRATION NUMBERS: EudraCT 2021-000556-19; NCT05146700.

Effect of vasopressin and methylprednisolone vs. placebo on long-term outcomes in patients with in-hospital cardiac arrest a randomized clinical trial.

OBJECTIVE: The primary results from the Vasopressin and Methylprednisolone for In-Hospital Cardiac Arrest (VAM-IHCA) trial have previously been reported. The objective of the current manuscript is to report long-term outcomes. METHODS: The VAM-IHCA trial was a multicenter, randomized, double-blind, placebo-controlled trial conducted at ten hospitals in Denmark. Adult patients (age ≥ 18 years) were eligible for the trial if they had an in-hospital cardiac arrest and received at least one dose of epinephrine during resuscitation. The trial drugs consisted of 40 mg methylprednisolone (Solu-Medrol®, Pfizer) and 20 IU of vasopressin (Empressin®, Amomed Pharma GmbH) given as soon as possible after the first dose of epinephrine. This manuscript report outcomes at 6 months and 1 year including survival, survival with favorable neurological outcome, and health-related quality of life. RESULTS: 501 patients were included in the analysis. At 1 year, 15 patients (6.3%) in the intervention group and 22 patients (8.3%) in the placebo group were alive corresponding to a risk ratio of 0.76 (95% CI, 0.41-1.41). A favorable neurologic outcome at 1 year, based on the Cerebral Performance Category score, was observed in 14 patients (5.9%) in the intervention group and 20 patients (7.6%) in the placebo group (risk ratio, 0.78 [95% CI, 0.41-1.49]. No differences existed between groups for favorable neurological outcome and health-related quality of life at either 6 months or 1 year. CONCLUSIONS: Administration of vasopressin and methylprednisolone, compared with placebo, in patients with in-hospital cardiac arrest did not improve long-term outcomes in this trial.

No significant influence of OCT1 genotypes on the pharmacokinetics of morphine in adult surgical patients.

We investigated the impact of genetic variants in OCT1 (SLC22A1) on morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) pharmacokinetics in adult patients scheduled for major surgery. Blood samples were taken before and 5, 10, 15, 30, 45, 60 and 90 min after a bolus of morphine (0.15 mg/kg). Patients were genotyped for the genetic variants (rs12208357, rs34059508, rs72552763 and rs34130495) in OCT1. Eighty-six patients completed the trial. The mean difference (95% confidence interval) for dose adjusted morphine, M3G and M6G AUC was 0.9 (-0.7-2.4), -5.9 (-11.8 to -0.03) and -1.1 (-2.5-0.4) h/L*10-6 , respectively, in patients with two reduced function alleles compared to patients with no reduced function alleles in OCT1. Accordingly, the (AUCM3G/Dose )/(AUCmorphine/Dose ) and (AUCM6G/Dose )/(AUCmorphine/Dose ) ratio was reduced, -1.8 (-3.2 to -0.4) and -0.4 (-0.7 to -0.03), respectively, when comparing the same groups. OCT1 variants had no influence on the experience of pain, adverse events or the number of PCA doses used. In conclusion, genetic variants in OCT1 had a small and clinically unimportant impact on the exposure of morphine after intravenous administration. Our results do not support pre-emptive genotyping for OCT1 prior to morphine administration in patients scheduled for major surgery.

Effect of Vasopressin and Methylprednisolone vs Placebo on Return of Spontaneous Circulation in Patients With In-Hospital Cardiac Arrest: A Randomized Clinical Trial.

Importance: Previous trials have suggested that vasopressin and methylprednisolone administered during in-hospital cardiac arrest might improve outcomes. Objective: To determine whether the combination of vasopressin and methylprednisolone administered during in-hospital cardiac arrest improves return of spontaneous circulation. Design, Setting, and Participants: Multicenter, randomized, double-blind, placebo-controlled trial conducted at 10 hospitals in Denmark. A total of 512 adult patients with in-hospital cardiac arrest were included between October 15, 2018, and January 21, 2021. The last 90-day follow-up was on April 21, 2021. Intervention: Patients were randomized to receive a combination of vasopressin and methylprednisolone (n = 245) or placebo (n = 267). The first dose of vasopressin (20 IU) and methylprednisolone (40 mg), or corresponding placebo, was administered after the first dose of epinephrine. Additional doses of vasopressin or corresponding placebo were administered after each additional dose of epinephrine for a maximum of 4 doses. Main Outcomes and Measures: The primary outcome was return of spontaneous circulation. Secondary outcomes included survival and favorable neurologic outcome at 30 days (Cerebral Performance Category score of 1 or 2). Results: Among 512 patients who were randomized, 501 met all inclusion and no exclusion criteria and were included in the analysis (mean [SD] age, 71 [13] years; 322 men [64%]). One hundred of 237 patients (42%) in the vasopressin and methylprednisolone group and 86 of 264 patients (33%) in the placebo group achieved return of spontaneous circulation (risk ratio, 1.30 [95% CI, 1.03-1.63]; risk difference, 9.6% [95% CI, 1.1%-18.0%]; P = .03). At 30 days, 23 patients (9.7%) in the intervention group and 31 patients (12%) in the placebo group were alive (risk ratio, 0.83 [95% CI, 0.50-1.37]; risk difference: -2.0% [95% CI, -7.5% to 3.5%]; P = .48). A favorable neurologic outcome was observed in 18 patients (7.6%) in the intervention group and 20 patients (7.6%) in the placebo group at 30 days (risk ratio, 1.00 [95% CI, 0.55-1.83]; risk difference, 0.0% [95% CI, -4.7% to 4.9%]; P > .99). In patients with return of spontaneous circulation, hyperglycemia occurred in 77 (77%) in the intervention group and 63 (73%) in the placebo group. Hypernatremia occurred in 28 (28%) and 27 (31%), in the intervention and placebo groups, respectively. Conclusions and Relevance: Among patients with in-hospital cardiac arrest, administration of vasopressin and methylprednisolone, compared with placebo, significantly increased the likelihood of return of spontaneous circulation. However, there is uncertainty whether this treatment results in benefit or harm for long-term survival. Trial Registration: ClinicalTrials.gov Identifier: NCT03640949.

Vasopressin and methylprednisolone for in-hospital cardiac arrest - Protocol for a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To describe the clinical trial "Vasopressin and Methylprednisolone for In-Hospital Cardiac Arrest" (VAM-IHCA). METHODS: The VAM-IHCA trial is an investigator-initiated, multicenter, randomized, placebo-controlled, parallel group, double-blind, superiority trial of vasopressin and methylprednisolone during adult in-hospital cardiac arrest. The study drugs consist of 40 mg methylprednisolone and 20 IU of vasopressin given as soon as possible after the first dose of adrenaline. Additional doses of vasopressin (20 IU) will be administered after each adrenaline dose for a maximum of four doses (80 IU).The primary outcome is return of spontaneous circulation and key secondary outcomes include survival and survival with a favorable neurological outcome at 30 days. 492 patients will be enrolled. The trial was registered at the EU Clinical Trials Register (EudraCT Number: 2017-004773-13) on Jan. 25, 2018 and ClinicalTrials.gov (Identifier: NCT03640949) on Aug. 21, 2018. RESULTS: The trial started in October 2018 and the last patient is anticipated to be included in January 2021. The primary results will be reported after 3-months follow-up and are, therefore, anticipated in mid-2021. CONCLUSION: The current article describes the design of the VAM-IHCA trial. The results from this trial will help clarify whether the combination of vasopressin and methylprednisolone when administered during in-hospital cardiac arrest improves outcomes.

Diagnostic value of prehospital arterial blood gas measurements - a randomised controlled trial.

BACKGROUND: Arterial blood gas analysis is an important diagnostic tool in managing critically ill patients within the hospital. Whether prehospital application of this diagnostic modality contributes to more exact diagnoses and treatments in critically ill prehospital patients is unknown. The aim of this study was to establish whether access to arterial blood gas analysis increased the prehospital diagnostic accuracy of prehospital anaesthesiologists. Furthermore, we investigated whether prehospital blood gas analysis resulted in therapeutic interventions that would not have been carried out if the arterial blood gas analyser had not been available. METHODS: In a prospective randomised study, two groups of prehospital adult patients with acute critical illness were compared. All patients received standard prehospital care. In the intervention group, an arterial blood gas sample was analysed prehospitally. The primary outcome was the impact of blood gas analysis on the accuracy of prehospital diagnoses. Furthermore, we registered any therapeutic interventions that were carried out as a direct result of the blood gas analysis. RESULTS: A total of 310 patients were included in the study. Eighty-eight of these patients were subsequently excluded, primarily due to difficulties in obtaining post hoc consent or venous sampling or other technical difficulties. A total of 102 patients was analysed in the arterial blood gas group (ABG group), while 120 patients were analysed in the standard care group (noABG group). In 78 of the 102 patients in the ABG group, the prehospital physician reported that ABG analysis increased their perceived diagnostic precision. In 81 cases in the noABG group, the lack of arterial blood gas analysis was perceived to have decreased diagnostic accuracy. The claim that ABG analysis increased diagnostic accuracy could, however, not be substantiated as there was no difference in the number of un-specific diagnoses between the groups. Blood gas analysis increased the probability of targeting specific prehospital therapeutic interventions and led to 159 interventions, including intubation, ventilation and/or upgrading the level of urgency, in 71 ABG-group patients (p < 0.001). CONCLUSION: Although prehospital arterial blood gas analysis did not improve the accuracy of the prehospital diagnoses assigned to patients, it significantly increased the quality of treatment provided to patients with acute critical illness. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03006692 , retrospectively registered six months after first patient entry.

Paediatric medical emergency calls to a Danish Emergency Medical Dispatch Centre: a retrospective, observational study.

BACKGROUND: Little is known regarding paediatric medical emergency calls to Danish Emergency Medical Dispatch Centres (EMDC). This study aimed to investigate these calls, specifically the medical issues leading to them and the pre-hospital units dispatched to the paediatric emergencies. METHODS: We performed a retrospective, observational study on paediatric medical emergency calls managed by the EMDC in the Region of Southern Denmark in February 2016. We reviewed audio recordings of emergency calls and ambulance records to identify calls concerning patients ≤ 15 years. We examined EMDC dispatch records to establish how the medical issues leading to these calls were classified and which pre-hospital units were dispatched to the paediatric emergencies. We analysed the data using descriptive statistics. RESULTS: Of a total of 7052 emergency calls in February 2016, 485 (6.9%) concerned patients ≤ 15 years. We excluded 19 and analysed the remaining 466. The reported medical issues were commonly classified as: "seizures" (22.1%), "sick child" (18.9%) and "unclear problem" (12.9%). The overall most common pre-hospital response was immediate dispatch of an ambulance with sirens and lights with a supporting physician-manned mobile emergency care unit (56.4%). The classification of medical issues and the dispatched pre-hospital units varied with patient age. DISCUSSION: We believe our results might help focus the paediatric training received by emergency medical dispatch staff on commonly encountered medical issues, such as the symptoms and conditions pertaining to the symptom categories "seizures" and "sick child". Furthermore, the results could prove useful in hypothesis generation for future studies examining paediatric medical emergency calls. CONCLUSION: Almost 7% of all calls concerned patients ≤ 15 years. Medical issues pertaining to the symptom categories "seizures", "sick child" and "unclear problem" were common and the calls commonly resulted in urgent pre-hospital responses.

Communication between general practitioners and the emergency medical dispatch centre in urgent cases.

INTRODUCTION: When general practitioners (GPs) order an ambulance, their calls are handled by staff at the emergency medical dispatch centre (EMDC) who then select an appropriate response. There are currently no data evaluating this mode of communication between the GPs and the staff at the EMDC. 
METHODS: A retrospective study was performed based on evaluation of calls during which GPs requested a rapid response ambulance. Over a period of three months of 2014, 1,334 calls were included for evaluation according to specific parameters including a transactional analysis of the communication. 
RESULTS: We found problematic communication in less than 2% (n = 25) of the evaluated calls. In 68% of the 25 problematic cases transactional analysis showed that the staff at the EMDC initiated the problematic communication. In 4% (n = 51) of the calls, the GP delegated the call to a secretary or nurse, and we found that these calls were more likely to contain problematic communication (odds ratio = 5.1). In 18% (n = 236) of the cases, there was not sufficient information to assess if the physician-manned mobile emergency care unit (MECU) should have been dispatched along with the ambulance. 
CONCLUSIONS: Problematic communication is rare, occurring in less than 2% of the calls. Problems are more frequent when the GP delegates the call. Furthermore, we established that the communicative problems were more likely to be initiated by the staff at the EMDC than by the GP. In addition, we found that there was insufficient information to assess if the MECU should be dispatched in nearly 20% of all calls.
 FUNDING: none.
 TRIAL REGISTRATION: The study was approved by the Danish Data Protection Agency (ref. no. 2008-58-0035). Informed consent from individual patients or ethics committee approval was not required since it was a register-based study solely and no person-identifiable data were used.

Noise exposure during prehospital emergency physicians work on Mobile Emergency Care Units and Helicopter Emergency Medical Services.

BACKGROUND: Prehospital personnel are at risk of occupational hearing loss due to high noise exposure. The aim of the study was to establish an overview of noise exposure during emergency responses in Mobile Emergency Care Units (MECU), ambulances and Helicopter Emergency Medical Services (HEMS). A second objective was to identify any occupational hearing loss amongst prehospital personnel. METHODS: Noise exposure during work in the MECU and HEMS was measured using miniature microphones worn laterally to the auditory canals or within the earmuffs of the helmet. All recorded sounds were analysed in proportion to a known tone of 94 dB. Before and after episodes of noise exposure, the physicians underwent a hearing test indicating whether the noise had had any impact on the function of the outer sensory hair cells. This was accomplished by measuring the amplitude level shifts of the Distortion Product Otoacoustic Emissions. Furthermore, the prehospital personnels' hearing was investigated using pure-tone audiometry to reveal any occupational hearing loss. All prehospital personnel were compared to ten in-hospital controls. RESULTS: Our results indicate high-noise exposure levels of ≥80 dB(A) during use of sirens on the MECU and during HEMS operations compared to in-hospital controls (70 dB(A)). We measured an exposure up to ≥90 dB(A) under the helmet for HEMS crew. No occupational hearing loss was identified with audiometry. A significant level shift of the Distortion Product Otoacoustic Emissions at 4 kHz for HEMS crew compared to MECU physicians was found indicating that noise affected the outer hair cell function of the inner ear, thus potentially reducing the hearing ability of the HEMS crew. DISCUSSION: Further initiatives to prevent noise exposure should be taken, such as active noise reduction or custom-made in-ear protection with communication system for HEMS personnel. Furthermore, better insulation of MECU and ambulances is warranted. CONCLUSION: We found that the exposure levels exceeded the recommendations described in the European Regulative for Noise, which requires further protective initiatives. Although no hearing loss was demonstrated in the personnel of the ground-based units, a reduced function of the outer sensory hair cells was found in the HEMS group following missions.

[Prehospital arterial blood gas analysis after collapse connected to triathlon participation].

Long-distance athletes are at risk of serious fluid and electrolyte disturbances, such as hypernatraemia (dehydration). Recently, cases of serious morbidity have been reported, due to acute exercise-associated hyponatraemia, which can advance to encephalopathy. An arterial blood gas analysis (ABG) was drawn from collapsed athletes at the championship of full-distance triathlon 2015, and different electrolyte imbalances were found. Our findings show that prehospital ABG can assist in differentiating the cause of collapse, and presumably, targeted treatment can be initiated already on scene.

Use of Infrared Thermography in Diagnosing Necrotizing Fasciitis in the Emergency Department: A Case Study.

OBJECTIVE: Necrotizing fasciitis is a difficult diagnosis with a very high mortality. However, thermal imaging has the potential to identify increasing skin temperature and rapid progression. MATERIALS AND METHODS: We used repeat photographs taken with a thermal camera to visualize changes in skin temperature over time. RESULTS: An unstable male patient presented at the emergency department. Thermal imaging showed increased skin temperature of his left foot with a rapid increase and progression in extent within 1 hour. Necrotizing fasciitis was suspected and later confirmed. CONCLUSIONS: We believe thermal imaging could be an important adjunct for the diagnosis of suspected necrotizing fasciitis. LEARNING POINTS: Necrotizing fasciitis is a difficult diagnosis to make.Thermal imaging can visualize skin temperature and thus show increased temperature and extent.Rapid identification of necrotizing fasciitis is vital for patient survival.

Assessment of acute pain in trauma-A retrospective prehospital evaluation.

OBJECTIVE: To elucidate pain treatment with analgesics in a prehospital trauma population. DESIGN: Retrospective database study. SETTING: Prehospital data from the anesthesiologist-manned Mobile Emergency Care Unit (MECU) in Odense, Denmark, were extracted and subjected to analysis. PATIENTS: During the period of January 1, 2013 to December 31, 2014, patients with the diagnoses "unspecified multiple injuries," "examination and observation following traffic accident," "examination and observation following other accident," and "commotio cerebri" were included in the analysis. MAIN OUTCOME MEASURES: Evaluation of the application of the pain scale Numeric Rating Scale (NRS). Furthermore, the authors performed a characterization of the patients with mild pain and severe pain according to specific parameters such as pharmacological interventions, opioid consumption, intubation, and others. RESULTS: Nine hundred eighty-five cases were analyzed. NRS was documented only in one case. In all, 787 patients experienced no pain or mild pain (no pain, n = 242; mild pain, n = 545) and 168 patients severe pain or worse (severe pain, n = 155; intolerable pain, n = 13). In the severe pain group, 138 were treated with opioid analgesics or S-ketamine, while no pharmacological intervention was documented in 30 cases. Eight of the 138 cases with severe pain needed endotracheal intubation, whereas nine cases in the patients with mild or no pain needed endotracheal intubation; odds ratio (OR) 4.3 (p = 0.003). CONCLUSIONS: Effect was only documented in one patient after administering opioids in a patient with trauma population, where approximately 17 percent of patients experienced severe pain. Severe pain was correlated to male gender, respiratory intervention, opioid administration, and the diagnosis unspecified multiple injuries.

Opioid prescriptions before and after high-energy trauma.

OBJECTIVE: To describe the legal use of opioids in adult patients before and after high-energy trauma. DESIGN: The study was a retrospective database study. SETTING: Clinical care outside hospitals. PATIENTS: All patients who suffered high-energy trauma and were brought to Odense University Hospital (OUH), Denmark, in 2007 and 2008 were retrieved from the trauma database. These patients were linked with data on opioid use from the regional prescription database. In all, 938 patients were included. MAIN OUTCOME MEASURE: Redemption of opioid prescription during the 6 months prior to a multitrauma or redemption of two or more prescriptions for opioids 6 months or later after a multitrauma. RESULTS: Of the 938 patients brought to OUH with severe trauma within the study period, 61 patients died (7 percent) and six of these had redeemed prescriptions for opioids within 6 months prior to the trauma (10 percent) compared to 65 patients of the 877 survivors (7 percent) (odds ratio 1.4, nonsignificant). In all, 62 patients (7 percent) redeemed opioid prescriptions later than 6 months after their trauma and in a multivariable analysis, severe injury itself and severe injuries of the lower extremities were associated with redemption of opioid prescription after the trauma. CONCLUSIONS: The authors did not find any correlation between death by trauma and redemption of opioid prescriptions within the 6 months before the trauma. More severe traumas and especially severe traumas to the lower extremities were associated with redemption of opioid prescriptions after multitrauma.

Outcome following physician supervised prehospital resuscitation: a retrospective study.

BACKGROUND: Prehospital care provided by specially trained, physician-based emergency services (P-EMS) is an integrated part of the emergency medical systems in many developed countries. To what extent P-EMS increases survival and favourable outcomes is still unclear. The aim of the study was thus to investigate ambulance runs initially assigned 'life-saving missions' with emphasis on long-term outcome in patients treated by the Mobile Emergency Care Unit (MECU) in Odense, Denmark METHODS: All MECU runs are registered in a database by the attending physician, stating, among other parameters, the treatment given, outcome of the treatment and the patient's diagnosis. Over a period of 80 months from May 1 2006 to December 31 2012, all missions in which the outcome of the treatment was registered as 'life saving' were scrutinised. Initial outcome, level of competence of the caretaker and diagnosis of each patient were manually established in each case in a combined audit of the prehospital database, the discharge summary of the MECU and the medical records from the hospital. Outcome parameters were final outcome, the aetiology of the life-threatening condition and the level of competences necessary to treat the patient. RESULTS: Of 25 647 patients treated by the MECU, 701 (2.7%) received prehospital 'life saving treatment'. In 596 (2.3%) patients this treatment exceeded the competences of the attending emergency medical technician or paramedic. Of these patients, 225 (0.9%) were ultimately discharged to their own home. CONCLUSIONS: The present study demonstrates that anaesthesiologist administrated prehospital therapy increases the level of treatment modalities leading to an increased survival in relation to a prehospital system consisting of emergency medical technicians and paramedics alone and thus supports the concept of applying specialists in anaesthesiology in the prehospital setting especially when treating patients with cardiac arrest, patients in need of respiratory support and trauma patients.

Lack of association of OPRM1 and ABCB1 single-nucleotide polymorphisms to oxycodone response in postoperative pain.

PURPOSE: The aim of the study was to search for an association between the single-nucleotide polymorphisms A118G in OPRM1 and C3435T and G2677T/A in ABCB1 and the analgesic effect of intravenous oxycodone in postoperative pain. METHODS: There were 268 patients with postoperative pain after, primarily, thyroidectomy. At given times during the first 24 hours postoperatively, their pain was rated at rest and during activity according to a numeric rating scale (0 = no pain, 10 = worst possible pain) and calculated as pain time area under the curve0-24 hours . A negative answer in a final questionnaire and/or the use of rescue medication categorized a patient as a nonresponder. RESULTS: For OPRM1, there was no difference found between the wild type and the variant allele in the percentages of nonresponders (118AA = 16.4% vs 118AG/118GG = 17.0%, P = 1.0) or in the pain ratings. For ABCB1, no difference was found between the wild type and the variant alleles for single-nucleotide polymorphism tested as percentages of nonresponders (3435CC = 17.5% vs 3435CT/3435TT = 15.8%, P = .85; 2677GG = 17.8% vs 2677GT/2677TT = 15.8%, P = .74) or pain ratings. CONCLUSION: No association was found between the tested single-nucleotide polymorphisms in OPRM1 and ABCB1 and changes in the analgesic effect of oxycodone.

Systemic uptake of miconazole during vaginal suppository use and effect on CYP1A2 and CYP3A4 associated enzyme activities in women.

PURPOSE: To investigate if the ordinary use of a vaginal suppository containing miconazole results in systemic absorption that is sufficient to affect the activities of CYP1A2 and CYP3A4, which are major drug- and steroid-metabolising enzymes. METHODS: In 20 healthy non-pregnant women aged 18-45 years, the serum concentration of miconazole was determined following the use of a vaginal suppository containing 1,200 mg miconazole. Enzyme activities of CYP1A2 and CYP3A4 were determined as metabolic ratios of caffeine (CMR = (AFMU + 1MU + 1MX)/17DMU) and quinidine (QMR = 3-hydroxy-quinidine/quinidine) respectively before and 34 h after insertion of the suppository. Miconazole was analysed by LC-MS/MS, while caffeine and metabolites were analysed by HPLC-UV and quinidine and hydroxy-quinidine were analysed by HPLC fluorescence. RESULTS: All 20 women had measurable concentrations of miconazole in serum (mean ± SD: 12.9 ± 5.6 µg/L; range: 3.5-24.6 µg/L). Although not statistically significant, an association between the serum concentrations of miconazole and the inhibition of CYP1A2 activity was indicated. No relation was observed between the CYP3A4 activity and the miconazole serum concentration. CONCLUSIONS: Miconazole is absorbed via the vaginal mucosa to the systemic circulation in measurable concentrations. Our data indicate a concentration-dependent inhibition of CYP1A2, but the effect is negligible compared with the variation in the activity of CYP1A2 and is regarded to be of no clinical significance to the women. However, further studies on the ability of miconazole to be transferred across the placenta or to interfere with the placental function are warranted to secure safe use during pregnancy.

The antinociceptive effect and adverse drug reactions of oxycodone in human experimental pain in relation to genetic variations in the OPRM1 and ABCB1 genes.

The aim of this study was to search for a possible association between the variant allele of the single nucleotide polymorphisms A118G in the OPRM1 gene and C3435T and G2677T/A in the ABCB1 gene and altered antinociceptive effect and adverse drug reactions of oxycodone. Thirty-three healthy subjects exposed to experimental pain including electrical stimulation and the cold pressor test were included. A118G: We found that the variant G allele was associated with reduced antinociceptive effect as measured by pain tolerance thresholds to single electrical nerve stimulation (8% increase vs. 25% for the wild-type carriers, P = 0.007). C3435T: The carriers of the variant T allele generally had less adverse drug reactions on oxycodone than the carriers of the wild-type genotype. G2677T/A: The carriers of the variant T allele had a better antinociceptive effect of oxycodone than the carriers of the wild-type genotype in the cold pressor test (25% reduction vs. 15%, P = 0.015 in the discomfort rating and 25% reduction vs. 12%, P = 0.007 in the pain time AUC) and less adverse drug reactions. The combined wild-type genotype 3435CC-2677GG was associated with less antinociceptive effect of oxycodone in the discomfort rating of the cold pressor test (13% reduction vs. 23%, P = 0.019) and more severe adverse drug reactions than the carriers of the variant alleles. We found a moderate association between less antinociceptive effect of oxycodone and the variant allele of A118G. There was strong association between less adverse drug reactions of oxycodone and the variant alleles of C3435T and G2677T/A.

The effects of gabapentin in human experimental pain models.

Background The antidepressant drugs imipramine and venlafaxine relieve clinical neuropathic pain and have been shown to increase pain thresholds in healthy volunteers during repetitive electrical sural nerve stimulation causing temporal pain summation, whereas pain during the cold pressor test is unaltered by these drugs. If this pattern of effect in experimental pain models reflects potential efficacy in clinical neuropathic pain, the pain summation model may potentially be used to identify new drugs for such pain conditions. Gabapentinoids are evidence-based treatments of clinical neuropathic pain and could contribute with additional knowledge of the usefulness of the pain summation model. The aim of this study To test the analgesic effect of the gabapentinoid gabapentin in a sural nerve stimulation pain model including temporal pain summation and the cold pressor test. Method 18 healthy volunteers completed a randomized, double-blind, cross-over trial with medication of 600 mg gabapentin orally dosed 3 times over 24 h against placebo. Pain tests were performed before and 24 h after medication including pain detection and tolerance to single sural nerve stimulation and pain summation threshold to repetitive stimulation (3 Hz). Peak pain intensity and discomfort were rated during a cold pressor test. Results Compared to placebo, gabapentin had a highly significant effect on the threshold of pain summation to repetitive electrical sural nerve stimulation (P = 0.009). Gabapentin significantly increased the pain tolerance threshold to single electrical sural nerve stimulation (P = 0.04), whereas the pain detection threshold to single electrical sural nerve stimulation tended to be increased (P = 0.06). No significant differences were found on pain ratings during the cold pressor test. Conclusion Gabapentin had a selective hypoalgesic effect in a human experimental pain model of temporal pain summation and the results lend further support to the usefulness of the pain summation model to identify drugs for neuropathic pain.