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Effects of a high-dose 24-h infusion of tranexamic acid on death and thromboembolic events in patients with acute gastrointestinal bleeding (HALT-IT): an international randomised, double-blind, placebo-controlled trial (2020)

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Type of publication:
Randomised controlled trial

Author(s):
The HALT-IT Trial Collaborators (including *John Jones and *Charlotte Owen)

Citation:
Lancet, 2020; Vol. 395: pp. 1927–36

Abstract:
Background: Tranexamic acid reduces surgical bleeding and reduces death due to bleeding in patients with trauma. Meta-analyses of small trials show that tranexamic acid might decrease deaths from gastrointestinal bleeding. We aimed to assess the effects of tranexamic acid in patients with gastrointestinal bleeding.
Methods: We did an international, multicentre, randomised, placebo-controlled trial in 164 hospitals in 15 countries. Patients were enrolled if the responsible clinician was uncertain whether to use tranexamic acid, were aged above the minimum age considered an adult in their country (either aged 16 years and older or aged 18 years and older), and had significant (defined as at risk of bleeding to death) upper or lower gastrointestinal bleeding. Patients were randomly assigned by selection of a numbered treatment pack from a box containing eight packs that were identical apart from the pack number. Patients received either a loading dose of 1 g tranexamic acid, which was added to 100 mL infusion bag of 0·9% sodium chloride and infused by slow intravenous injection over 10 min, followed by a maintenance dose of 3 g tranexamic acid added to 1 L of any isotonic intravenous solution and infused at 125 mg/h for 24 h, or placebo (sodium chloride 0·9%). Patients, caregivers, and those assessing outcomes were masked to allocation. The primary outcome was death due to bleeding within 5 days of randomisation; analysis excluded patients who received neither dose of the allocated treatment and those for whom outcome data on death were unavailable. This trial was registered with Current Controlled Trials, ISRCTN11225767, and ClinicalTrials.gov, NCT01658124.
Findings: Between July 4, 2013, and June 21, 2019, we randomly allocated 12 009 patients to receive tranexamic acid (5994, 49·9%) or matching placebo (6015, 50·1%), of whom 11952 (99·5%) received the first dose of the allocated treatment. Death due to bleeding within 5 days of randomisation occurred in 222 (4%) of 5956 patients in the tranexamic acid group and in 226 (4%) of 5981 patients in the placebo group (risk ratio [RR] 0·99, 95% CI 0·82–1·18). Arterial thromboembolic events (myocardial infarction or stroke) were similar in the tranexamic acid group and
placebo group (42 [0·7%] of 5952 vs 46 [0·8%] of 5977; 0·92; 0·60 to 1·39). Venous thromboembolic events (deep vein thrombosis or pulmonary embolism) were higher in tranexamic acid group than in the placebo group (48 [0·8%] of 5952 vs 26 [0·4%] of 5977; RR 1·85; 95% CI 1·15 to 2·98).
Interpretation: We found that tranexamic acid did not reduce death from gastrointestinal bleeding. On the basis of our results, tranexamic acid should not be used for the treatment of gastrointestinal bleeding outside the context of a randomised trial.

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'You have got a foreign body in there': Renal transplantation, unexpected mild-to-moderate distress and patients' support needs: A qualitative study (2020)

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Type of publication:
Journal article

Author(s):
Jones J.; Damery S.; Combes G.; Allen K.; *Nicholas J. ; Baharani J.

Citation:
BMJ Open; Mar 2020; vol. 10 (no. 3)

Abstract:
Objective: To explore why transplant patients experience unexpected mild-to-moderate distress and what support they may need.
Design: Qualitative study using individual in-depth interviews. Setting Four National Health Service (NHS) Trusts in the Midlands, UK. Participants Fifteen renal transplant patients meeting the criteria for mild-to-moderate distress from their responses to emotion thermometers. Main outcome measures Identification of the reasons for distress and support options acceptable to renal transplant patients.
Results: Three themes were interpreted from the data: I am living with a "foreign body" inside me', why am I distressed?' and different patients want different support'. Following their transplant, participants felt that they should be happy and content, but this was often not the case. They described a range of feelings about their transplant, such as uncertainty about the lifespan of their new kidney, fear of transplant failure or fear of the donor having health conditions that may transfer to them. A few experienced survivors' guilt when others they had met at the dialysis unit had not received a transplant or because someone had died to enable them to receive the transplant. No longer having regular contact with the renal unit made participants feel isolated. Some participants did not initially attribute the source of their distress to their transplant. Participants' preferred support for their distress and their preferences about who should deliver it varied from peer support to seeing a psychologist.
Conclusions: Raising the issue of post-transplant mild-to-moderate distress with patients and encouraging them to think about and plan coping strategies pretransplant may prove beneficial for the patient and healthcare provider. Patients should be able to choose from a variety of support options.

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Age and Tightness of Repair Are Predictors of Heel-Rise Height After Achilles Tendon Rupture (2020)

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Type of publication:
Journal article

Author(s):
*Carmont, Michael R.; Zellers, Jennifer A.; Brorsson, Annelie; Nilsson-Helander, Katarina; Karlsson, Jón; Grävare Silbernagel, Karin

Citation:
Orthopaedic Journal of Sports Medicine; Mar 2020; vol. 8 (no. 3); p. 1-8

Abstract:
Background: Achilles tendon rupture leads to weakness of ankle plantarflexion. Treatment of Achilles tendon rupture should aim to restore function while minimizing weakness and complications of management. Purpose: To determine the influence of factors (age, sex, body mass index [BMI], weight, time from injury to operative repair, and tightness of repair) in the initial surgical management of patients after an acute Achilles tendon rupture on 12-month functional outcome assessment after percutaneous and minimally invasive repair. Study Design: Cohort study; Level of evidence, 3. Methods: From May 2012 to January 2018, patients sustaining an Achilles tendon rupture receiving operative repair were prospectively evaluated. Tightness of repair was quantified using the intraoperative Achilles tendon resting angle (ATRA). Heel-rise height index (HRHI) was used as the primary 12-month outcome variable. Secondary outcome measures included Achilles tendon total rupture score (ATRS) and Tegner score. Stepwise multiple regression was used to create a model to predict 12-month HRHI. Results: A total of 122 patients met the inclusion criteria for data analysis (mean ± SD age, 44.1 ± 10.8 years; 78% male; mean ± SD BMI, 28.1 ± 4.3 kg/m2). The elapsed time to surgery was 6.5 ± 4.0 days. At 12-month follow-up, patients had an HRHI of 82% ± 16% and performed 82% ± 17% of repetitions compared with the noninjured side. Participants had a mean ATRS of 87 ± 15 and a median Tegner score of 5 (range, 1-9), with a reduction in Tegner score of 2 from preinjury levels. The relative ATRA at 12 months was –4.8° ± 3.9°. Multiple regression identified younger age (B = ±0.006; P <.001) and greater intraoperative ATRA (B = 0.005; P =.053) as predictors of more symmetrical 12-month HRHI (R 2 = 0.19; P <.001; n = 120). Conclusion: Age was found to be the strongest predictor of outcome after Achilles tendon rupture. The most important modifiable risk factor was the tightness of repair. It is recommended that repair be performed as tight as possible to optimize heel-rise height 1 year after Achilles tendon rupture and possibly to reduce tendon elongation.

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Severe anaemia complicating HIV in Malawi; Multiple co-existing aetiologies are associated with high mortality (2020)

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Type of publication:
Journal article

Author(s):
Huibers M.H.W.; van Hensbroek M.B.; Calis J.C.; Bates I.; *McKew S.; Allain T.J.; Phiri C.; Coupland S.E.; Phiri K.S.

Citation:
PLoS ONE; 2020; vol. 15 (no. 2)

Abstract:
Background Severe anaemia is a major cause of morbidity and mortality in HIV-infected adults living in resource-limited countries. Comprehensive data on the aetiology are lacking but are needed to improve outcomes. Methods HIV-infected adults with severe (haemoglobin <=70g/l) or very severe anaemia (haemoglobin <= 50 g/l) were recruited at Queen Elizabeth Central Hospital, Blantyre, Malawi. Fifteen potential causes and associations with anaemia severity and mortality were explored. Results 199 patients were enrolled: 42.2% had very severe anaemia and 45.7% were on ART. More than two potential causes for anaemia were present in 94% of the patients including iron deficiency (55.3%), underweight (BMI<20: 49.7%), TB infection (41.2%) and unsuppressed HIV infection (viral load >1000 copies/ml) (73.9%). EBV/CMV co-infection (16.5%) was associated with very severe anaemia (OR 2.8 95% CI 1.1-6.9). Overall mortality was high (53%; 100/199) with a median time to death of 17.5 days (IQR 6-55) days. Death was associated with folate deficiency (HR 2.2; 95% CI 1.2-3.8) and end stage renal disease (HR 3.2; 95% CI 1.6-6.2). Conclusion Mortality among severely anaemic HIV-infected adults is strikingly high. Clinicians should be aware of the urgent need for a multifactorial approach including starting or optimising HIV treatment, considering TB treatment, nutritional support and optimising renal management.

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Prevention of adrenal crisis: cortisol responses to major stress compared to stress dose hydrocortisone delivery (2020)

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Type of publication:
Journal article

Author(s):
Prete A.; Taylor A.E.; Bancos I.; Smith D.J.; O'Neil D.M.; Karavitaki N.; Arlt W.; Foster M.A.; Lord J.M.; Kohler S.; Fazal-Sanderson V.; Komninos J.; Wass J.A.H.; Vassiliadi D.A.; Mihai R.; *Mowatt C.J. ; Fallowfield J.L.; Annane D.; Keevil B.G.

Citation:
The Journal of Clinical Endocrinology and Metabolism; Volume 105, Issue 7, July 2020

Abstract:
CONTEXT: Patients with adrenal insufficiency require increased hydrocortisone cover during major stress to avoid life-threatening adrenal crisis. However, current treatment recommendations are not evidence-based. OBJECTIVE(S): To identify the most appropriate mode of hydrocortisone delivery in patients with adrenal insufficiency exposed to major stress. DESIGN AND PARTICIPANTS: Cross-sectional study: 122 unstressed healthy subjects and 288 subjects exposed to different stressors (major trauma [N=83], sepsis [N=100], and combat stress [N=105]). Longitudinal study: 22 patients with preserved adrenal function undergoing elective surgery. Pharmacokinetic study: 10 patients with primary adrenal insufficiency undergoing administration of 200mg hydrocortisone over 24 hours in four different delivery modes (continuous intravenous infusion; six-hourly oral, intramuscular or intravenous bolus administration). MAIN OUTCOME MEASURE: We measured total serum cortisol and cortisone, free serum cortisol and urinary glucocorticoid metabolite excretion by mass spectrometry. Linear pharmacokinetic modelling was used to determine the most appropriate mode and dose of hydrocortisone administration in patients with adrenal insufficiency exposed to major stress. RESULT(S): Serum cortisol was increased in all stress conditions, with the highest values observed in surgery and sepsis. Continuous intravenous hydrocortisone was the only administration mode persistently achieving median cortisol concentrations in the range observed during major stress. Linear pharmacokinetic modelling identified continuous intravenous infusion of 200mg hydrocortisone over 24 hours, preceded by an initial bolus of 50-100mg hydrocortisone, as best suited for maintaining cortisol concentrations in the required range. CONCLUSION(S): Continuous intravenous hydrocortisone infusion should be favored over intermittent bolus administration in the prevention and treatment of adrenal crisis during major stress.

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Total knee arthroplasty reduces knee extension torque in-vitro and patellofemoral arthroplasty does not (2020)

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Type of publication:
Journal article

Author(s):
Joseph M.N.; Stephen J.M.; Amis A.A.; *Carmont M.R.; Tailor H.

Citation:
Journal of Biomechanics; 2020 May 7;104:109739

Abstract:
Patients often have difficulty recovering knee extension strength post total knee arthroplasty (TKA), and that may reflect alteration of the mechanics including geometry and rollback kinematics, so the purpose of this work was to explore this by comparing the knee extension torque (KET) of the native knee, TKA and patellofemoral arthroplasty (PFA) in response to quadriceps tension. Eight fresh-frozen knees were mounted in a knee extension rig with quadriceps loading and tibial extension torque measurement. Each knee was subject to four conditions: native knee, PFA, cruciate-retaining (CR) and posterior-stabilized (PS) TKA. The KET was measured from 120degree to 0degree knee flexion. Data were analyzed using one-way ANOVA and post-hoc paired t-tests. The native KET was lowest in terminal extension and 70-100degree flexion, and maximal at 20-30degree flexion. PFA produced the greatest KET (p < 0.008) compared with native, CR- and PS-TKA, at 30-40degree flexion. CR- and PS-TKA had lower KET across 0-50degree flexion (p < 0.001 across 0-30degree), falling to 25% of the native knee KET or the PFA at full extension. PFA had the highest KET in early flexion possibly due to increased trochlear offset and/or preservation of the cruciate mechanism, so PFA may be more beneficial during the functional range of motion. The claimed benefits of PS- over CR-TKA in deep flexion were not detected. Both CR- and PS-TKAs led to lower KET than the native and PFA knee states across 0-50degree flexion. This mechanical effect may help to explain clinical findings of knee extension weakness post-TKA.

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Working Collaboratively: Outcomes of Geriatrician Input in Older Patients Undergoing Emergency Laparotomy in a District General Hospital (2020)

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Type of publication:
Journal article

Author(s):
*Khan, Kashuf A; Subramanian, Thejasvi; Richters, Megan; Mubarik, Ayesha; Saad Abdalla Al-Zawi, Abdalla; Thorn, Christopher C; Chalstrey, Susan; Gunasekera, Savithri

Citation:
Cureus; Feb 2020; vol. 12 (no. 2); p. e7069

Abstract:
With the increasing median age of survival in the UK, there is an increased burden on the provision of medical and surgical care to the population. The 2010 National Confidential Enquiry into Patient Outcome and Death report, "An Age Old Problem," emphasizes the early involvement of surgical and geriatric consultant input to improve perioperative care in older patients. This study describes the development of a Geriatric Surgical Liaison Service aimed at providing consultant-led geriatrician support to improve the outcomes of older patients undergoing Emergency Laparotomy (EL). The primary outcome is the reduction in length of stay (LOS) compared to baseline data prior to geriatrician involvement. The service was designed to include one clinical session involving a consultant geriatrician and two and a half days with a junior doctor in a week. Data was collected prospectively from February 2018 till July 2018 for surgical patients aged ≥ 70 years, who underwent EL, had an inpatient stay of more than seven days, and who were diagnosed with delirium or incurred inpatient falls (intervention group). Baseline data, prior to geriatrician involvement, were collected retrospectively for EL patients aged ≥ 70 years from December 2015 until May 2016. Length of stay and 30-day mortality were also compared between the two cohorts undergoing EL. A total of 69 patients were included in the intervention group; 45 patients underwent EL and their mean LOS was 17.5 days, which was reduced from 22.5 days prior to geriatrician involvement (n=57). There was no difference in median length of stay and 30-day mortality between the retrospective baseline group and the intervention groups. In the intervention group, 8.5% of patients had a new medical diagnosis and 26.8% of patients were offered follow-ups. Although statistically not significant (p=0.40), a shorter stay in hospital by five days can potentially have a positive impact on patient outcomes by reducing psychosocial, cognitive, and functional deconditioning. This would also improve patient flow, release capacity, and waiting times and would be of benefit to the financially strained National Health Service (NHS). Overall, our study suggests that a collaborative, consultant-led geriatric service can improve the management of older surgical patients by potentially reducing length of stay, identifying high-risk patients, and facilitating early and appropriate specialty input alongside adequate and required outpatient follow-up.

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The cost-effectiveness of progesterone in preventing miscarriages in women with early pregnancy bleeding: an economic evaluation based on the PRISM Trial (2020)

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Type of publication:
Journal article

Author(s):
CB Okeke Ogwulu, I Goranitis, AJ Devall, V Cheed, ID Gallos, LJ Middleton, HM Harb, HM Williams, A Eapen, JP Daniels, A Ahmed, R Bender‐Atik, K Bhatia, C Bottomley, J Brewin, M Choudhary, S Deb, WC Duncan, AK Ewer, K Hinshaw, T Holland, F Izzat, J Johns, M Lumsden, P Manda, JE Norman, N Nunes, CE Overton, K Kriedt, S Quenby, S Rao, J Ross, A Shahid, *M Underwood , N Vaithilingham, L Watkins, C Wykes, AW Horne, D Jurkovic, A Coomarasamy, TE Roberts

Citation:
BJOG: An International Journal of Obstetrics and Gynaecology; May 2020; Vol 127 (no. 6); p. 757-767

Abstract:
Objectives: To assess the cost‐effectiveness of progesterone compared with placebo in preventing pregnancy loss in women with early pregnancy vaginal bleeding.
Design: Economic evaluation alongside a large multi‐centre randomised placebo‐controlled trial.
Setting: Forty‐eight UK NHS early pregnancy units.
Population: Four thousand one hundred and fifty‐three women aged 16–39 years with bleeding in early pregnancy and ultrasound evidence of an intrauterine sac.
Methods: An incremental cost‐effectiveness analysis was performed from National Health Service (NHS) and NHS and Personal Social Services perspectives. Subgroup analyses were carried out on women with one or more and three or more previous miscarriages.
Main outcome measures: Cost per additional live birth at ≥34 weeks of gestation.
Results: Progesterone intervention led to an effect difference of 0.022 (95% CI −0.004 to 0.050) in the trial. The mean cost per woman in the progesterone group was £76 (95% CI −£559 to £711) more than the mean cost in the placebo group. The incremental cost‐effectiveness ratio for progesterone compared with placebo was £3305 per additional live birth. For women with at least one previous miscarriage, progesterone was more effective than placebo with an effect difference of 0.055 (95% CI 0.014–0.096) and this was associated with a cost saving of £322 (95% CI −£1318 to £673).
Conclusions: The results suggest that progesterone is associated with a small positive impact and a small additional cost. Both subgroup analyses were more favourable, especially for women who had one or more previous miscarriages. Given available evidence, progesterone is likely to be a cost‐effective intervention, particularly for women with previous miscarriage(s).

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Synchronous versus sequential chemo-radiotherapy in patients with early stage breast cancer (SECRAB): A randomised, phase III, trial (2020)

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Type of publication:
Randomised controlled trial

Author(s):
Fernando I.N.; Spooner D.; Latief T.N.; Stevens A.; Bowden S.J.; Herring K.; Ahmed I.; Rea D.W.; Brookes C.L.; Marshall A.; Dunn J.; Grieve R.; Poole C.J.; Churn M.; *Agrawal R.K.; Brunt A.M.; Goodman A.; Canney P.; Ritchie D.; Bishop J.

Citation:
Radiotherapy and Oncology; 2020; Vol 24; p. 52-61

Abstract:
Background: The optimal sequence of adjuvant chemotherapy and radiotherapy for breast cancer is unknown. SECRAB assesses whether local control can be improved without increased toxicity.
Method(s): SECRAB was a prospective, open-label, multi-centre, phase III trial comparing synchronous to sequential chemo-radiotherapy, conducted in 48 UK centres. Patients with invasive, early stage breast cancer were eligible. Randomisation (performed using random permuted block assignment) was stratified by centre, axillary surgery, chemotherapy, and radiotherapy boost. Permitted chemotherapy regimens included CMF and anthracycline-CMF. Synchronous radiotherapy was administered between cycles two and three for CMF or five and six for anthracycline-CMF. Sequential radiotherapy was delivered on chemotherapy completion. Radiotherapy schedules included 40 Gy/15F over three weeks, and 50 Gy/25F over five weeks. The primary outcome was local recurrence at five and ten years, defined as time to local recurrence, and analysed by intention to treat. ClinicalTrials.gov NCT00003893.
Finding(s): Between 02-July-1998 and 25-March-2004, 2297 patients were recruited (1150 synchronous and 1146 sequential). Baseline characteristics were balanced. With 10.2 years median follow-up, the ten-year local recurrence rates were 4.6% and 7.1% in the synchronous and sequential arms respectively (hazard ratio (HR) 0.62; 95% confidence interval (CI): 0.43-0.90; p = 0.012). In a planned sub-group analysis of anthracycline-CMF, the ten-year local recurrence rates difference were 3.5% versus 6.7% respectively (HR 0.48 95% CI: 0.26-0.88; p = 0.018). There was no significant difference in overall or disease-free survival. 24% of patients on the synchronous arm suffered moderate/severe acute skin reactions compared to 15% on the sequential arm (p < 0.0001). There were no significant differences in late adverse effects apart from telangiectasia (p = 0.03). Interpretation(s): Synchronous chemo-radiotherapy significantly improved local recurrence rates. This was delivered with an acceptable increase in acute toxicity. The greatest benefit of synchronous chemo-radiation was in patients treated with anthracycline-CMF.

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