Iloprost and Organ Dysfunction in Adults With Septic Shock and Endotheliopathy: A Randomized Clinical Trial.

Importance: Soluble thrombomodulin is a marker of endotheliopathy, and iloprost may improve endothelial function. In patients with septic shock, high plasma levels of soluble thrombomodulin (>10 ng/mL) have been associated with worse organ dysfunction and mortality. Objective: To assess the effects of treatment with iloprost vs placebo on the severity of organ failure in patients with septic shock and plasma levels of soluble thrombomodulin higher than 10 ng/mL. Design, Setting, and Participants: This investigator-initiated, adaptive, parallel group, stratified, double-blind randomized clinical trial was conducted between November 1, 2019, and July 5, 2022, at 6 hospitals in Denmark. The trial had a maximum sample size of 380, with an interim analysis for futility only at 200 patients with 90 days of follow-up. In total, 279 adults in the intensive care unit (ICU) with septic shock and endotheliopathy were included. Interventions: Patients were randomized 1:1 to masked intravenous infusion of iloprost, 1 ng/kg/min (n = 142), or placebo (n = 137) for 72 hours. Main Outcomes and Measures: The primary outcome was mean daily Sequential Organ Failure Assessment (SOFA) score in the ICU adjusted for trial site and baseline SOFA score for the per-protocol population. SOFA scores for each of the 5 organ systems ranged from 0 to 4, with higher scores indicating more severe dysfunction (maximum score, 20). The secondary outcomes included serious adverse reactions and serious adverse events at 7 days and mortality at 90 days. Results: Of 279 randomized patients, data from 278 were analyzed (median [IQR] age, 69 [58-77] years; 171 (62%) male), 142 in the iloprost group and 136 in the placebo group. The trial was stopped for futility at the planned interim analysis. The mean [IQR] daily SOFA score was 10.6 (6.4-14.8) in the iloprost group and 10.5 (5.9-15.5) in the placebo group (adjusted mean difference, 0.2 [95% CI, -0.8 to 1.2]; P = .70). Mortality at 90 days in the iloprost group was 57% (81 of 142) vs 51% (70 of 136) in the placebo group (adjusted relative risk, 1.12 [95% CI, 0.91-1.40]; P = .33). Serious adverse events occurred in 26 of 142 patients (18%) for the iloprost group vs 20 of 136 patients (15%) for the placebo group (adjusted relative risk, 1.25 [95% CI, 0.73-2.15]; P = .52). Only 1 serious adverse reaction was observed. Conclusions and Relevance: In this randomized clinical trial of adults in the ICU with septic shock and severe endotheliopathy, infusion of iloprost, 1 ng/kg/min, for 72 hours did not reduce mean daily SOFA scores compared with placebo. In a clinical context, administration of iloprost will be unlikely to improve outcome in these patients. Trial Registration: ClinicalTrials.gov Identifier: NCT04123444.

Accuracy of the Danish version of the 'distress thermometer'.

OBJECTIVE: Short screening instruments have been suggested to improve the detection of psychological symptoms. We examined the accuracy of the Danish version of the 'Distress Thermometer'. METHODS: Between October 2008 and October 2009, 426 women with newly diagnosed primary breast cancer who were operated at the Breast Surgery Clinic of the Rigshospitalet, Copenhagen, were eligible for this study. Of these, 357 participated (84%) and 333 completed a questionnaire. The distress thermometer was evaluated against the 'hospital anxiety and depression scale' (HADS). We also examined the women's wish for referral for psychological support. RESULTS: A cut-off score of 6 vs 7 (low: ≤6, high: ≥7) on the distress thermometer was optimal for confirming distress, with a sensitivity of 42%, a specificity of 93%, a positive predictive value (PPV) of 78% and a negative predictive value (NPV) of 73%. A cut-off score of 2 vs 3 was optimal for screening, with a sensitivity of 99%, a specificity of 36%, a PPV of 47% and a NPV of 99%. Of those who were distressed using the cut-off score of 2 vs 3 on the distress thermometer, 17% (n = 41) wished to be referred for psychological support and 57% (n = 140) potentially wanted a later referral. CONCLUSION: The distress thermometer performed satisfactorily relative to the HADS in detecting distress in our study. A screening procedure in which application of the distress thermometer is a first step could be useful for identifying persons in need of support.

Persistent pain, sensory disturbances and functional impairment after adjuvant chemotherapy for breast cancer: cyclophosphamide, epirubicin and fluorouracil compared with docetaxel + epirubicin and cyclophosphamide.

BACKGROUND: Taxanes used in adjuvant therapy for breast cancer are neurotoxic, and thereby being a potential risk factor for persistent pain after breast cancer treatment (PPBCT) and sensory disturbances. The purpose was to compare patients treated with cyclophosphamide, epirubicin and fluorouracil (CEF) and cyclophosphamide and epirubicin + docetaxel (CE + T) in relation to PPBCT, sensory disturbances, peripheral sensory disturbances and functional impairment. MATERIAL AND METHODS: A comparative nationwide cross-sectional questionnaire study on two cohorts treated with CEF respectively CE + T, based on the Danish Breast Cancer Cooperative Groups database. INCLUSION CRITERIA: women treated with chemotherapy as adjuvant treatment for primary breast cancer, age 18-69 years, without recurrence. RESULTS: One thousand two hundred and forty-one patients allocated to CEF in 2005-2006 and 1652 patients allocated to CE + T in 2007-2008 were included. Six hundred and sixty-four (53%) with CEF and 861 (53%) patients with CE + T reported pain. In the multivariate analysis including available risk factors, CE + T did not confer an increased risk of PPBCT, OR 0.95 (95% CI 0.81-1.11), p = 0.52, compared to CEF. Patients treated with CE + T had a lower risk of sensory disturbances in the area of surgery compared with CEF, OR 0.75 (95% CI 0.62-0.90), p = 0.002. More CE + T patients reported peripheral sensory disturbances in the hands, OR 1.56 (95%CI 1.27-1.92), p < 0.0001, and in the feet, OR 2.0 (95% CI 1.66-2.42) p < 0.0001, compared to CEF. There was no difference in functional impairment (p = 0.62). CONCLUSION: Docetaxcel as adjuvant treatment for breast cancer does not increase the risk of PPBCT, sensory disturbances in the surgical area or functional impairment, but increase risk for peripheral sensory disturbances.

Phantom breast sensations are frequent after mastectomy.

INTRODUCTION: Phantom breast sensation (PBS) following mastectomy has been recognized for many years. PBS is a feeling that the removed breast is still there. The reported prevalence and risk factors have not been established in large well-defined patient series. The purpose of this study was to examine the prevalence of PBS following mastectomy and associated risk factors. MATERIAL AND METHODS: This study was part of a nationwide cross-sectional questionnaire study of women aged 18-70 years treated for primary unilateral breast cancer in Denmark between 1 January 2005 and 31 December 2006. A detailed questionnaire was mailed to respondents between January and April 2008. Only questionnaires from mastectomised women were analyzed. The main outcome measures were prevalence of PBS in mastectomized Danish women and adjusted odds ratio (OR) of PBS with respect to age, pain in the breast area, surgical technique, chemotherapy and radiotherapy. RESULTS: A total of 1,131 women (84%) answered the questionnaire. A total of 26% experienced PBS, viz. the proportion ranged from 18% to 35% within the six well defined treatment groups, but only young age was a risk factor for PBS (OR 1.030 per year; 95% CI 1.010-1.050; p = 0.0026). CONCLUSION: The prevalence of PBS during the first 1-3 years after mastectomy is about 25% and it is related to young age.

Recovery at the post anaesthetic care unit after breast cancer surgery.

INTRODUCTION: Extant literature shows that women having undergone breast cancer surgery have substantial problems at the post-anaesthesia care unit (PACU). Based on nursing reports and elements of the discharge scoring system recommended by The Danish Society of Anaesthesiology and Intensive Care Medicine, the present prospective, observational study aims to determine why these patients stayed at PACU. MATERIAL AND METHODS: The study included 116 consecutive patients having undergone surgery for breast cancer. Postoperative nausea and vomiting (PONV), pain, sedation, respiration, oxygen saturation (SpO2), blood pressure and heart rate were scored at the PACU, and nurses were asked why discharge was delayed in case patients were not discharged at the time the discharge criteria were met. The outcome measures were the proportion of patients ready for discharge upon arrival at the PACU, patient time spent until discharge criteria were met, time to actual discharge, and the contribution of each discharge criterion in postponing discharge from the unit, as well as nurse-reported factors for the delay. RESULTS: 31% of the patients were ready for discharge upon arrival at the PACU. The mean time until the discharge criteria were met was 40 min (standard deviation (SD) = 46 min). The actual time spent at the PACU was 110 min (SD = 75 min). A total of 36 patients had low SpO2 (< 90%) upon arrival to the PACU. In 36 cases, discharge was delayed by the workload at the PACU and/or waiting for patient transport to the ward. CONCLUSION: Low SpO2 (< 90%), the workload at the PACU and time spent waiting for transport to the ward were the primary reasons why patients stayed at the PACU after breast cancer surgery.

Use of selective serotonin reuptake inhibitors and risk of re-operation due to post-surgical bleeding in breast cancer patients: a Danish population-based cohort study.

BACKGROUND: Selective serotonin reuptake inhibitors (SSRI) decrease platelet-function, which suggests that SSRI use may increase the risk of post-surgical bleeding. Few studies have investigated this potential association. METHODS: We conducted a population-based study of the risk of re-operation due to post-surgical bleeding within two weeks of primary surgery among Danish women with primary breast cancer. Patients were categorised according to their use of SSRI: never users, current users (SSRI prescription within 30 days of initial breast cancer surgery), and former users (SSRI prescription more than 30 days before initial breast cancer surgery). We calculated the risk of re-operation due to post-surgical bleeding within 14 days of initial surgery, and the relative risk (RR) of re-operation comparing SSRI users with never users of SSRI adjusting for potential confounders. RESULTS: 389 of 14,464 women (2.7%) were re-operated. 1592 (11%) had a history of SSRI use. Risk of re-operation was 2.6% among never users, 7.0% among current SSRI users, and 2.7% among former users. Current users thus had an increased risk of re-operation due to post-operative bleeding (adjusted relative risk = 2.3; 95% confidence interval (CI) = 1.4, 3.9) compared with never users. There was no increased risk of re-operation associated with former use of SSRI (RR = 0.93, 95% CI = 0.66, 1.3). CONCLUSIONS: Current use of SSRI is associated with an increased risk of re-operation due to bleeding after surgery for breast cancer.

Prevalence of and factors associated with persistent pain following breast cancer surgery.

CONTEXT: Persistent pain and sensory disturbances following surgical treatment for breast cancer is a significant clinical problem. The pathogenic mechanisms are complex and may be related to patient characteristics, surgical technique, and adjuvant therapy. OBJECTIVE: To examine prevalence of and factors associated with persistent pain after surgical treatment for breast cancer. DESIGN, SETTING, AND PATIENTS: A nationwide cross-sectional questionnaire study of 3754 women aged 18 to 70 years who received surgery and adjuvant therapy (if indicated) for primary breast cancer in Denmark between January 1, 2005, and December 31, 2006. A study questionnaire was sent to the women between January and April 2008. MAIN OUTCOME MEASURES: Prevalence, location, and severity of persistent pain and sensory disturbances in 12 well-defined treatment groups assessed an average of 26 months after surgery, and adjusted odds ratio (OR) of reported pain and sensory disturbances with respect to age, surgical technique, chemotherapy, and radiotherapy. RESULTS: By June 2008, 3253 of 3754 eligible women (87%) returned the questionnaire. A total of 1543 patients (47%) reported pain, of whom 201 (13%) had severe pain, 595 (39%) had moderate pain, and 733 (48%) had light pain. Factors associated with chronic pain included young age (18-39 years: OR, 3.62; 95% confidence interval [CI], 2.25-5.82; P < .001) and adjuvant radiotherapy (OR, 1.50; 95% CI, 1.08-2.07; P = .03), but not chemotherapy (OR, 1.01; 95% CI, 0.85-1.21; P = .91). Axillary lymph node dissection (ALND) was associated with increased likelihood of pain (OR, 1.77; 95% CI, 1.43-2.19; P < .001) compared with sentinel lymph node dissection. Risk of sensory disturbances was associated with young age (18-39 years: OR, 5.00; 95% CI, 2.87-8.69; P < .001) and ALND (OR, 4.97; 95% CI, 3.92-6.30; P < .001). Pain complaints from other parts of the body were associated with increased risk of pain in the surgical area (P < .001). A total of 306 patients (20%) with pain had contacted a physician within the prior 3 months for pain complaints in the surgical area. CONCLUSION: Two to 3 years after breast cancer treatment, persistent pain and sensory disturbances remain clinically significant problems among Danish women who received surgery in 2005 and 2006.

Development in self-reported arm-lymphedema in Danish women treated for early-stage breast cancer in 2005 and 2006--a nationwide follow-up study.

The main purpose of this nationwide follow-up study was to examine the development of self-reported lymphedema in the population of women with early-stage breast cancer in Denmark. In 2008 and 2012 two identical questionnaires were sent to the women aged 18-70 years treated for unilateral primary breast cancer in 2005 and 2006. 2293 women (87%) reported on lymphedema in 2008 and 2012. Overall 37% reported lymphedema in 2008 while 31% reported lymphedema in 2012 and severity of symptoms decreased. 50% of women treated with SLNB and reporting lymphedema in 2008 did not report symptoms by 2012 in contrast to 30% treated with ALND. However, 19% of women treated with ALND and not reporting lymphedema in 2008 had developed lymphedema by 2012. In conclusion lymphedema remains a frequent problem, years after treatment for breast cancer, though, number of women reporting lymphedema and overall severity of symptoms decreased.

Persistent pain and sensory disturbances after treatment for breast cancer: six year nationwide follow-up study.

OBJECTIVE: To examine the development of persistent pain after treatment for breast cancer and to examine risk factors associated with continuing pain. DESIGN: Repeated cross sectional study in a previously examined nationwide cohort. All eligible women who underwent surgery for primary breast cancer in Denmark in 2005 and 2006 and were examined in 2008 were surveyed again with the same questionnaire. SETTING: Surgical centres in Denmark. MAIN OUTCOME MEASURES: Prevalence, location, and severity of persistent pain after treatment for breast cancer in well defined treatment groups and changes in pain reporting and sensory disturbances from 2008 to 2012. PARTICIPANTS: In 2012, 2828 women were eligible in our database, and 108 were excluded. Exclusion criteria were death; new, recurrent, or other cancer; reconstructive breast surgery; and emigration. RESULTS: 2411 (89%) women returned the questionnaire. Prevalence of persistent pain after treatment for breast cancer ranged from 22% to 53% depending on treatment. In 2012, 903 (37%) women reported such pain, a fall from 45% in 2008. Of these, 378 (16%) reported pain of ≥ 4 on a numerical rating scale (scale 0-10), a fall from 19%. Among women reporting pain in 2008, 36% no longer reported it in 2012. In contrast, 15% of the women who did not report pain in 2008 reported it in 2012. Risk factors for having pain were axillary lymph node dissection rather than sentinel lymph node biopsy (odds ratio 2.04, 95% confidence interval 1.60 to 2.61; P<0.001) and age ≤ 49 (1.78, 1.25 to 2.54; P<0.001). No particular method of treatment or age was associated with an increase in pain from 2008 to 2012. CONCLUSIONS: Persistent pain after treatment for breast cancer remains an important problem five to seven years later. The problem is not static as it can either progress or regress with time. TRIAL REGISTRATION: Clinicaltrials.gov NCT No 01543711.

Breast reconstruction with an expander prosthesis following mastectomy does not cause additional persistent pain: a nationwide cross-sectional study.

INTRODUCTION: Few studies have examined the prevalence of persistent pain after breast reconstruction with an implant after tissue expansion in comparison to mastectomy without breast reconstruction. Our primary objective was to evaluate the prevalence of persistent pain after breast reconstruction with a subpectoral implant after tissue expansion in a population-based study. Secondary objectives were to evaluate sensory disturbances, lymphoedema and functional impairment. METHOD: This was a nationwide cross-sectional questionnaire study of breast cancer patients aged 18-69 years who were treated with or without reconstruction after mastectomy for primary breast cancer in Denmark between 1 January 2005 and 31 December 2006. The response rate was 84% for mastectomy without reconstruction and 83% for patients treated with breast reconstruction. RESULTS: A total of 129 patients treated with mastectomy and breast reconstruction with a subpectoral implant were compared with 1131 patients treated with mastectomy without reconstruction. Prevalence of persistent pain for patients treated with mastectomy followed by reconstruction with an implant was 40% compared to 48% of patients treated only with mastectomy. We found no increased risk of persistent pain in patients having a reconstruction with an implant compared with mastectomy without reconstruction (odds ratio (OR) 0.82, 95% confidence interval (CI) 0.55-1.22, P=0.33) when adjusting for age, axillary procedure, radiotherapy and chemotherapy. We observed no difference in the prevalence of pain between patients treated with immediate or delayed breast reconstruction (P=0.116). CONCLUSION: Breast reconstruction with a subpectoral implant after tissue expansion does not confer increased prevalence of persistent pain.

Persistent pain after targeted intraoperative radiotherapy (TARGIT) or external breast radiotherapy for breast cancer: a randomized trial.

Persistent pain after breast cancer treatment (PPBCT) affects between 25 and 60% of patients depending on surgical and adjuvant treatment. External breast radiotherapy (EBRT) has been shown to be a riskfactor for PPBCT, raising the question whether intraoperative radiation therapy (IORT), with its smaller radiation field may reduce the development of PPBCT. Using data from the TARGIT-A trial, the aim of this study was to compare these two treatments with regard to development of PPBCT. A total of 281 patients enrolled in the TARGIT-A trial from the Copenhagen University Hospitals was screened for participation, and a total of 244 patients were included and received a detailed questionnaire. The response rate was 98%, leaving 238 patients for the final analysis. Pain prevalence were 33.9% in the EBRT group and 24.6% in the IORT group (p = 0.11). Treatment with IORT may not alter the risk of PPBCT.

Self-reported arm-lymphedema and functional impairment after breast cancer treatment--a nationwide study of prevalence and associated factors.

Lymphedema and impairment of function are well-established sequelae to breast cancer treatment and affect an increasing number of women due to continually improved survival. The aim of the present nationwide questionnaire study was to examine the impact of breast cancer treatment on perceived swelling/sensation of heaviness (lymphedema) and on function, reporting prevalence in 12 subgroups of modern treatment and offering estimates for treatment-related associated factors. 3253 Women (87%) returned the study questionnaire. Depending on treatment group prevalence of perceived swelling/heaviness varied from 13 to 65%. Associated factors were young age, axillary lymph node dissection (ALND) and radiotherapy but not type of breast surgery or use of chemotherapy. Depending on treatment group 11-44% had to give up activities. Giving up activities was associated with pain and swelling/heaviness, younger age, ALND, chemotherapy, time elapsed since surgery, and surgery on the dominant side. Radiotherapy and type of breast surgery were of no importance.

[Postoperative inconveniences after breast cancer surgery]. / Optimering af det tidlige postoperative forløb efter brystkraeftkirurgi.

The most common postoperative inconveniences after breast cancer surgery are pain, nausea and vomiting, which contribute to reduced patient satisfaction, prolonged hospital stays and delayed courses of rehabilitation. This article summarizes the literature regarding available procedure-specific evidence for prophylactic nausea, vomiting and pain treatment supported by transferable evidence from similar types of surgery. We propose a prophylactic combination of Dexametason, Ondansteron, Paracetamol, Celecoxib, Gabapentin and Detromethorphan as future treatment.

[Multimodal treatment of pain and nausea in breast cancer surgery]. / Multimodal smerte- og kvalmebehandling ved brystkraeftkirurgi.

INTRODUCTION: Every year 4000 women in Denmark undergo surgery for breast cancer. According to published literature approximately 50% suffer from post-operative nausea and vomiting (PONV) and moderate pain. No national guidelines are available regarding the treatment or prevention of pain and PONV associated with surgery for these patients. MATERIALS AND METHODS: 116 consecutive patients scheduled for breast cancer surgery were prospectively scored according to pain, PONV and sedation after being introduced to a combined evidence-based, empiric multimodal opioid-sparing prevention and treatment regime consisting of Paracetamol, Celecoxib, Dextromethorphan, Gabapetin, Dexamethason and Ondansetron. RESULTS: In the recovery room, 75% of the patients scored either no or light pain at rest compared to 68% under mobilization. In the department, 94% of the patients scored no or light pain at rest as well as under mobilization on the evening of the operation and the next morning. Morphine consumption in the recovery room was, on average, 2 mg per patient. Only 1.5% of the patients were given morphine in the department. Five patients were troubled by light PONV, one by moderate PONV and another suffered from severe PONV and vomiting resistant to treatment. Upon arrival at the recovery 15% of the patients were in a state of moderate to severe sedation. This number was 1.5% 75 minutes later. CONCLUSION: It is possible with a multimodal opioid-sparing prevention and treatment regime for pain and PONV to gain optimal postoperative pain and nausea control without significant problems with respect to sedation.