Triage and outcomes for a whole cohort of patients presenting for major emergency abdominal surgery including the No-LAP population: a prospective single-center observational study.

PURPOSE: This study aimed to characterize 252 consecutive patients with an indication for major emergency abdominal surgery including patients not proceeding to surgery (No-Lap). Patients who do not proceed to major emergency abdominal surgery and their clinical outcomes are not well characterized in the existing literature. Triage criteria may vary between centers, potentially impacting reported outcomes. METHODS: A single-center prospective observational study in a high-volume Danish surgical center including 252 patients presenting with an indication for major emergent abdominal surgery was conducted from the 15th of October 2020 to the 15th of August 2021. The primary outcome was to estimate the prevalence of No-Lap patients. RESULTS: Overall, 21 patients (8.3%) of our total study cohort did not proceed to surgery. These patients were significantly older, more comorbid with higher ASA scores, poorer performance status, and were more likely to have bowel ischemia. Poor functional performance and surgeons' consideration of futile intervention were the main reasons for deferring surgery in all 21 patients. Overall, 30-day mortality was 95% for the No-LAP cohort, 9% for the LAP cohort, and 16% for the whole cohort, respectively. CONCLUSIONS: The No-LAP group selection process could be one of the main determinants of reported postoperative outcomes. Prospective international multi-center studies to characterize the entire cohort of patients eligible for emergency laparotomy including the No-LAP population are needed, as large variations in triage criteria and culture seem to exist. Trial registration Retrospectively registered.

Low-dose azathioprine and allopurinol versus azathioprine monotherapy in patients with ulcerative colitis (AAUC): An investigator-initiated, open, multicenter, parallel-arm, randomised controlled trial.

Background: Retrospective studies suggest that for patients with ulcerative colitis (UC) combination therapy with low-dose azathioprine and allopurinol (L-AZA/ALLO) may result in higher remission rates than monotherapy with azathioprine (AZA). We prospectively investigated the effects of these drugs for remission in patients with moderate-to-severe UC. Methods: Open-label, unblinded, randomised, controlled, investigator-initiated, multicentre study conducted at eight hospital sites in Denmark. Adult patients with established UC, who were steroid dependent/refractory, thiopurine naïve, had a normal thiopurine methyltransferase, and achieved remission with steroids or infliximab were eligible for inclusion. Patients were randomly assigned by the investigators (1:1) to 52 weeks of treatment with once daily oral AZA (median dose 50 mg) combined with ALLO 100 mg versus AZA monotherapy (median dose 200 mg), using a computer-generated randomisation list with blocks of six. The trial was open without masking. All randomised patients who received at least one dose of study drug were included in primary and safety analyses (intention to treat population). The primary outcome was steroid and infliximab free remission after 52 weeks, defined as a Mayo Score of ≤1 and no rectal bleeding. The trial is completed and is registered in ClinicalTrials.gov (ClinicalTrials.gov NCT03101800). Findings: Between January 9, 2017 and February 10, 2021, 47 patients were randomised to l-AZA/ALLO and 42 to AZA and received at least one dose of the study drug. After 52 weeks, 20 of 47 (43%) patients in the l-AZA/ALLO group and nine of 42 (21%) patients in the AZA group achieved remission (odds ratio 2·54 [95% CI 1·00 to 6.78, p < 0·048]). Fourteen patients (30%) in the l-AZA/ALLO group and 16 (38%) in the AZA group were withdrawn from the study due to adverse events. Interpretation: This study suggests that after one year l-AZA/ALLO therapy may be associated with a beneficial effect on steroid- and infliximab-free clinical remission in patients with moderate-to-severe UC and should be considered as first line therapy. Funding: Funding for AAUC was provided by The Capital Region of Denmark (Regionernes Medicinpulje (6062/16)).

Nocturnal antihypertensive treatment in patients with type 1 diabetes with autonomic neuropathy and non-dipping: a randomised, placebo-controlled, double-blind cross-over trial.

OBJECTIVES: Cardiovascular autonomic neuropathy (CAN) and abnormal circadian blood pressure (BP) rhythm are independent cardiovascular risk factors in patients with diabetes and associations between CAN, non-dipping of nocturnal BP and coronary artery disease have been demonstrated. We aimed to test if bedtime dosing (BD) versus morning dosing (MD) of the ACE inhibitor enalapril would affect the 24-hour BP profile in patients with type 1 diabetes (T1D), CAN and non-dipping. SETTING: Secondary healthcare unit in Copenhagen, Denmark. PARTICIPANTS: 24 normoalbuminuric patients with T1D with CAN and non-dipping were included, consisting of mixed gender and Caucasian origin. Mean±SD age, glycosylated haemoglobin and diabetes duration were 60±7 years, 7.9±0.7% (62±7 mmol/mol) and 36±11 years. INTERVENTIONS: In this randomised, placebo-controlled, double-blind cross-over study, the patients were treated for 12 weeks with either MD (20 mg enalapril in the morning and placebo at bedtime) or BD (placebo in the morning and 20 mg enalapril at bedtime), followed by 12 weeks of switched treatment regimen. PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcome was altered dipping of nocturnal BP. Secondary outcomes included a measurable effect on other cardiovascular risk factors than BP, including left ventricular function (LVF). RESULTS: Systolic BP dipping increased 2.4% (0.03-4.9%; p=0.048) with BD compared to MD of enalapril. There was no increase in mean arterial pressure dipping (2.2% (-0.1% to 4.5%; p=0.07)). No difference was found on measures of LVF (p≥0.15). No adverse events were registered during the study. CONCLUSIONS: We demonstrated that patients with T1D with CAN and non-dipping can be treated with an ACE inhibitor at night as BD as opposed to MD increased BP dipping, thereby diminishing the abnormal BP profile. The potentially beneficial effect on long-term cardiovascular risk remains to be determined. TRIAL REGISTRATION NUMBER: EudraCT2012-002136-90; Post-results.

Effect of Total Dose of Lidocaine on Duration of Adductor Canal Block, Assessed by Different Test Methods: A Report of Two Blinded, Randomized, Crossover Studies in Healthy Volunteers.

BACKGROUND: The binary aims of this study were to investigate the effect of total dose of lidocaine on duration of an adductor canal block (ACB) and to validate different methods used to assess nerve blocks. METHODS: We performed 2 blinded, randomized, controlled crossover trials, including healthy, young men. In study 1, 14 subjects received 4 ACBs with saline and 40, 80, and 160 mg lidocaine. In study 2, 14 new subjects received 2 ACBs with 100 and 300 mg lidocaine. We kept volume constant at 20 mL for all blocks, only altering concentration. ACB duration was assessed every hour postblock using mechanical (primary outcome) and temperature discrimination; warmth and heat pain detection thresholds; pain during heat stimulation; and tolerance to electrical current in the saphenous distribution. Finally, we measured quadriceps femoris muscle strength (clinical trial registration: NCT02172729). RESULTS: In study 1, block duration assessed by mechanical discrimination differed significantly when comparing the 40-mg dose with the 80-mg dose (mean difference, 1.15 hours; 99% confidence interval [CI], 0.38-2.09 hours) and with the 160-mg dose (mean difference, 0.92 ours; 99% CI, 0.17-1.62). However, there was no difference between the 80-mg and 160-mg doses (mean difference, -0.23 hour; 99% CI, -1.12 to 0.46 hours). Neither for the secondary outcomes were there any differences between the 80- and 160-mg doses (99% CI including 0). Because of 38% (5/13) failed blocks in the 40-mg group, we decided to perform study 2. In study 2, all but 1 test showed no difference in duration despite a 3-fold increase in dose. The temperature discrimination test showed 100% sensitivity and specificity for differentiating between the presence and absence of block and was the only test with scores >90% for both parameters. CONCLUSIONS: We did not find evidence that increasing the total dose of lidocaine may prolong duration of an ACB. The temperature discrimination test was the only test with scores >90% for both specificity and sensitivity.

Adductor Canal Block With 10 mL Versus 30 mL Local Anesthetics and Quadriceps Strength: A Paired, Blinded, Randomized Study in Healthy Volunteers.

BACKGROUND AND OBJECTIVES: Adductor canal block (ACB) is predominantly a sensory nerve block, but excess volume may spread to the femoral triangle and reduce quadriceps strength. We hypothesized that reducing the local anesthetic volume from 30 to 10 mL may lead to fewer subjects with quadriceps weakness. METHODS: We performed a paired, blinded, randomized trial including healthy men. All subjects received bilateral ACBs with ropivacaine 0.1%; 10 mL in 1 leg and 30 mL in the other leg. The primary outcome was the difference in number of subjects with quadriceps strength reduced by more than 25% from baseline in 2 consecutive assessments. Secondary outcomes were quadriceps strength as a percentage of baseline at predefined time points, functional outcome assessed by the 30-Second Chair Stand Test (1 leg at a time), and sensory block. Clinicaltrials.gov Identifier: NCT01981746. RESULTS: We included and analyzed 26 subjects. For either volume, 2 subjects had a reduction in quadriceps strength by more than 25% from baseline (difference, 0%; 95% confidence interval, -13 to 13; P > 0.999). Similarly, we found no significant differences between volumes in quadriceps strength at any of the predefined time points or in sensory block. The only statistically significant difference between volumes was found in the 30-Second Chair Stand Test at 2 hours (P = 0.02), but this difference had disappeared at 4 hours (P = 0.06). CONCLUSIONS: Varying the volume of ropivacaine 0.1% used for ACB between 10 and 30 mL did not have a statistically significant or clinically relevant impact on quadriceps strength.

Effect of adductor canal block versus femoral nerve block on quadriceps strength, mobilization, and pain after total knee arthroplasty: a randomized, blinded study.

BACKGROUND AND OBJECTIVES: Total knee arthroplasty (TKA) is often associated with severe pain. Different regional anesthetic techniques exist, all with varying degrees of motor blockade. We hypothesized that pain relief provided by the adductor canal block (ACB) could increase functional muscle strength. METHODS: We included 50 TKA patients with severe movement-related pain; defined as having visual analog scale pain score of greater than 60 mm during active flexion of the knee. The ACB group received an ACB with ropivacaine 0.2% 30 mL and a femoral nerve block (FNB) with 30 mL saline. The FNB group received an ACB with 30 mL saline and an FNB with ropivacaine 0.2% 30 mL. We compared the effect of the ACB versus FNB on maximum voluntary isometric contraction of the quadriceps muscle relative to a postoperative baseline value. Secondary end points were differences between groups in ability to ambulate and changes in pain scores (Clinicaltrials.gov identifier NCT01922596). RESULTS: After block, the quadriceps maximum voluntary isometric contraction increased to 193% (95% confidence interval [CI], 143-288) of the baseline value in the ACB group and decreased to 16% (95% CI, 3-33) in the FNB group with an estimated difference of 178% (95% CI, 136-226), P < 0.0001. Pain scores were similar between groups. Before block, 2 of 25 patients in each group were unable to perform the Timed-Up-and-Go test; after block, this number increased to 7 of 25 in the FNB group and decreased to 0 of 25 in the ACB group. CONCLUSION: Adductor canal block provides a clinically relevant and statistically significant increase in quadriceps muscle strength for patients in severe pain after TKA.

Nocturnal antihypertensive treatment in patients with type 1 diabetes with autonomic neuropathy and non-dipping of blood pressure during night time: protocol for a randomised, placebo-controlled, double-blind, two-way crossover study.

INTRODUCTION: Cardiac autonomic neuropathy (CAN) and elevated nocturnal blood pressure are independent risk factors for cardiovascular disease in patients with diabetes. Previously, associations between CAN, non-dipping of nocturnal blood pressure and coronary artery calcification have been demonstrated. The present protocol describes a trial to test the efficacy of bedtime dosing of the ACE inhibitor enalapril on night time blood pressure and left ventricular mass in patients with type 1 diabetes. MATERIALS AND METHODS: In a randomised, double-blind, two-way cross-over study, 24 normoalbuminuric patients with type 1 diabetes with CAN will be treated for 12 weeks with either morning or bedtime dosing of 20 mg enalapril, followed by 12 weeks of switched treatment regimen. During each treatment period, two 24 h ambulatory blood pressure measurements will be performed and after each treatment period left ventricular mass will be determined by multisliced CT. Primary end points will be reduction in blood pressure and reduction in left ventricular mass. ETHICS AND DISSEMINATION: The study has been approved by the Danish Medicines Agency, the Scientific-Ethical Committee of the Capital Region of Denmark and the Danish Data Protection Agency. An external monitoring committee (the Good Clinical Practice Unit at Copenhagen University Hospital) will oversee the study. The results of the study will be presented at national and international scientific meetings and publications will be submitted to peer-reviewed journals. TRIAL REGISTRATION NUMBER: EudraCT (2012- 002136-90).

Adductor canal block versus femoral nerve block for analgesia after total knee arthroplasty: a randomized, double-blind study.

BACKGROUND AND OBJECTIVES: Femoral nerve block (FNB), a commonly used postoperative pain treatment after total knee arthroplasty (TKA), reduces quadriceps muscle strength essential for mobilization. In contrast, adductor canal block (ACB) is predominately a sensory nerve block. We hypothesized that ACB preserves quadriceps muscle strength as compared with FNB (primary end point) in patients after TKA. Secondary end points were effects on morphine consumption, pain, adductor muscle strength, morphine-related complications, and mobilization ability. METHODS: We performed a double-blind, randomized, controlled study of patients scheduled for TKA with spinal anesthesia. The patients were randomized to receive either a continuous ACB or an FNB via a catheter (30-mL 0.5% ropivacaine given initially, followed by a continuous infusion of 0.2% ropivacaine, 8 mL/h for 24 hours). Muscle strength was assessed with a handheld dynamometer, and we used the percentile change from baseline for comparisons. The trial was registered at clinicaltrials.gov (Identifier: NCT01470391). RESULTS: We enrolled 54 patients, of which 48 were analyzed. Quadriceps strength as a percentage of baseline was significantly higher in the ACB group compared with the FNB group: (median [range]) 52% [31-71] versus 18% [4-48], (95% confidence interval, 8-41; P = 0.004). There was no difference between the groups regarding morphine consumption (P = 0.94), pain at rest (P = 0.21), pain during flexion of the knee (P = 0.16), or adductor muscle strength (P = 0.39); neither was there a difference in morphine-related adverse effects or mobilization ability (P > 0.05). CONCLUSIONS: Adductor canal block preserved quadriceps muscle strength better than FNB, without a significant difference in postoperative pain.

Adductor canal block versus femoral nerve block and quadriceps strength: a randomized, double-blind, placebo-controlled, crossover study in healthy volunteers.

BACKGROUND: The authors hypothesized that the adductor canal block (ACB), a predominant sensory blockade, reduces quadriceps strength compared with placebo (primary endpoint, area under the curve, 0.5-6 h), but less than the femoral nerve block (FNB; secondary endpoint). Other secondary endpoints were adductor strength and ability to ambulate. METHODS: The authors enrolled healthy young men into this double blind, placebo-controlled, randomized, crossover study. On two separate study days, subjects received either ACB or FNB with ropivacaine, and placebo in the opposite limb. Strength was assessed as maximum voluntary isometric contraction for quadriceps and adductor muscles. In addition, subjects performed three standardized ambulation tests. Clinicaltrials.gov Identifier: NCT01449097. RESULTS: Twelve subjects were randomized, 11 analyzed. Quadriceps strength (area under the curve, 0.5-6 h) was significantly reduced when comparing ACB with placebo (5.0 ± 1.0 vs. 5.9 ± 0.6, P = 0.02, CI: -1.5 to -0.2), FNB with placebo (P = 0.0004), and when comparing FNB with ACB (P = 0.002). The mean reduction from baseline was 8% with ACB and 49% with FNB. The only statistically significant difference in adductor strength was between placebo and FNB (P = 0.007). Performance in all mobilization tests was reduced after an FNB compared with an ACB (P < 0.05). CONCLUSIONS: As compared with placebo ACB statistically significantly reduced quadriceps strength, but the reduction was only 8% from baseline. ACB preserved quadriceps strength and ability to ambulate better than FNB did. Future studies are needed to compare the analgesic effect of the ACB with the FNB in a clinical setting.

CHF3381, a N-methyl-D-aspartate receptor antagonist and monoamine oxidase-A inhibitor, attenuates secondary hyperalgesia in a human pain model.

UNLABELLED: CHF3381 is a new low-affinity, noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist and reversible monoamine oxidase-A (MAO-A) inhibitor. The analgesic activity of CHF3381 was investigated in the heat-capsaicin human pain model and compared with those of gabapentin. Twenty-seven young, healthy male volunteers received a single oral dose of CHF3381 (500 mg), gabapentin (1,200 mg), or placebo in a randomized, double-blind, crossover study design. Measurements were done before and 135 to 145 minutes after treatment administration and included area of secondary hyperalgesia around the sensitized skin of the forearm (45 degrees C for 5 minutes followed by topical capsaicin for 30 minutes), area of secondary hyperalgesia after thermal sensitization of the thigh (45 degrees C for 3 minutes), heat pain detection thresholds (degrees C), and pain on a visual analogue scale after long thermal stimulation (45 degrees C for 1 minute). Compared with placebo, both gabapentin and CHF3381 significantly reduced the area of secondary hyperalgesia on the dominant forearm. Median (and interquartile range) percent values over baseline were 86% after placebo (69% to 100%), 56% (41% to 76%) after gabapentin (P < .001), and 67% (49% to 88%) after CHF3381 (P < .009). Both drugs also significantly decreased the area of secondary hyperalgesia on the dominant thigh. The other pain variables were not significantly affected. Adverse events, mainly fatigue and dizziness, were mild to moderate. PERSPECTIVE: This article presents the antihyperalgesic effect of CHF3381, a new NMDA receptor antagonist and reversible MAO-A inhibitor, in a human pain model and might guide the proper selection of CHF3381 doses to be used in Phase 2 studies in patients with neuropathic pain.

Mechanisms of postoperative pain: clinical indications for a contribution of central neuronal sensitization.

BACKGROUND: The relative importance of different nociceptive mechanisms for the intensity, duration, and character of postoperative pain is not well established. It has been suggested that sensitization of dorsal horn neurones may contribute to pain in the postoperative period. We hypothesized that wound hyperalgesia in postoperative patients and experimentally heat-induced secondary hyperalgesia share a common mechanism, sensitization of central neurones, and consequently, that the short-acting opioid remifentanil would have comparable effects on hyperalgesia in both conditions. METHODS: In a randomized, controlled, double-blind trial, we assessed mechanical hyperalgesia in skin bordering the surgical wound, and an area of experimentally heat-induced secondary hyperalgesia on the thigh, in 12 patients who underwent abdominal hysterectomy within 5 days prior to the investigation. Observations were made before and during a drug challenge with remifentanil, which has been demonstrated to reduce the area of heat-induced secondary hyperalgesia in volunteers. RESULTS: The area of skin with surgically-induced mechanical hyperalgesia, the area of heat-induced secondary hyperalgesia, and pain during cough, were significantly reduced during remifentanil infusion compared with placebo (P = 0.008, P = 0.006, and P = 0.002, respectively). The relative reduction (% of baseline) of the area of skin with surgically-induced hyperalgesia and heat-induced secondary hyperalgesia during infusion of remifentanil was significantly associated (R2 = 0.72, P = 0.001). CONCLUSIONS: Although remifentanil is not a highly targeted "antihyperalgesic," these results support the hypothesis that both wound hyperalgesia in postoperative patients and experimentally heat-induced secondary hyperalgesia may share common mechanisms, and that central neuronal sensitization may contribute to some aspects of postoperative pain. Antihyperalgesic drugs should be further developed and evaluated in clinical trials of postoperative pain.