Staff Publication

Severe Hypercalcaemia in Intensive Care: An unusual cause (2019)

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Type of publication:
Conference abstract

Author(s):
*Zi Hao Reuel Heng, *Rhys Parry, *Omu Davies, *Roger Slater

Citation:
State of the Art 2019, Intensive Care Society Conference, Birmingham, December 9-12.

Abstract:
Background: Severe hypercalcemia is defined as serum calcium > 3.5 mmol/l.
Major causes of hypercalcemia in adults include primary hyperparathyroidism, milk-alkali syndrome and malignant neoplasms. Neoplasms cause hypercalcaemia either by direct invasion (metastasis) or through factors that stimulate osteoclasts (Parathyroid hormone related peptide or PTHrP). Very rarely a benign tumour can be responsible. Clinical features of hypercalcemia correlate with degree and rapidity of rise of serum calcium. Severe hypercalcemia is associated with neurological, renal and gastrointestinal symptoms.
The differential diagnosis of the cause is determined by measuring parathyroid hormone (PTH) levels.
The case: A 33-year-old woman 37/52 pregnant presented with epigastric pain, vomiting, proteinuria and hypertension and a deteriorating GCS (11/15). A CT head was normal. Blood showed hyperuricaemia and acute kidney injury. She was transferred to the operating room for caesarean section with suspected fulminating pre-eclampsia following a fall in GCS to 8. Immediately prior to general anaesthetic induction she had a generalized seizure. She was induced, intubated and commenced on IV magnesium and labetolol. Following successful delivery, a large pedunculated fibroid was noted on the left side of the uterus. She was transferred to intensive care sedated, intubated and ventilated. Routine blood testing demonstrated severe hypercalcaemia, corrected serum calcium of 5.05 mmol/l. PTH was at the lower limit at 1.3 pmol/l (normal range 1.3 – 7.6 pmol/l). Treatment consisted of IV rehydration with 0.9% sodium chloride 4 litres in 24hr, IV Pamidronate (a bisphosphonate) 60mg over 2 hours. Over the next 3 days the serum calcium returned to normal. A literature search uncovered 3 reports of benign uterine leiomyomas having been the source of ectopic PTHrP leading to hypercalcaemia [1,2,3]. In this case, the uterine fibroid was presumed to have been the source of PTHrP. Unfortunately, direct measurement of PTHrP was not possible at the time of presentation. In view of the fact that the calcium had returned to normal with medical treatment and post-delivery, it was decided to defer further surgery. The patient was successfully weaned from ventilatory support after 5 days. She was monitored and calcium remained within normal limits. 3/12 later the fibroid was removed. The histology showed a mitotically active smooth muscle leiomyoma.
Conclusion: Uterine leiomyoma can rarely be a cause of hypercalcaemia in the critically ill obstetric patient. Severe hypercalcaemia can present in a similar manner to pre-eclampsia, and can worsen pre-eclampsia. Intensivists need to be aware of this condition.
Discussion: The clinical picture was strongly suggestive of severe hypercalcaemia associated with a uterine fibroid. The history did not reveal ingestion of excessive calcium-containing antacids sufficient to cause hypercalcaemia. A hypercalcaemic crisis can occur during pregnancy; the immediate postpartum period being the most likely time,. At this time, relative dehydration and an abrupt decrease in placental transport of calcium to the foetus can coexist. Severe hypercalcaemia can rarely produce seizures, the mechanism is thought to be due to cerebro-vasospasm.
References
1.Ravakhah K, Gover A, Mukunda B. Humoral Hypercalcemia Associated with a Uterine Fibroid. Annals of Internal Medicine 1999; 130: 702.
2.Tarnawa E, Sullivan S, Underwood P et al. Severe hypercalcemia Associated with Uterine Leiomyoma in Pregnancy. Obstetrics & Gynecology 2011;117: 473-476
3.Garcha A, Gumaste P, Cherian S et al. Hypercalcemia: An Unusual Manifestation of Uterine Leiomyoma. Case Reports in Medicine 2013; Article ID 815252.

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Categorising sub-massive pulmonary thromboembolism: No isolated role for shock index or its modified form (2019)

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Type of publication:
Conference abstract

Author(s):
*Abdulsamad S.P.; *Crawford E.; *Makan A.; *Ahmad N.; *Srinivasan K.; *Moudgil H.

Citation:
European Respiratory Journal; Sep 2019; vol. 54, PA1469

Abstract:
Background and Objectives: Managing sub-massive pulmonary thromboembolism (PTE) remains a therapeutic challenge and efforts have been made to sub-categorise continued risk based on clinical assessment and objective measures such as a raised serum lactate (>4 mmol/l) or abnormal Shock Index (Heart rate/systolic blood pressure, SIndex). The objective here was to investigate the SIndex and its modified form (MSIndex) to (1) report frequency of abnormal results in a population being investigated for PTE and (2) assess potential benefits in avoiding adverse outcome.
Method(s): Retrospective analysis of 1505 CT pulmonary angiograms undertaken over a 12 month period. Abnormal SIndex was taken as outside limits 0.5-0.9. MSindex was calculated conventionally as heart rate divided by (2xdiastolic blood pressure+systolic blood pressure)/3 and considered abnormal if <0.7 or >1.3. Analysis was on Excel.
Result(s): Mean age for the population was 67.7 (range 17-101) years. 337/1505 (22.4%) scans showed PTE and of this population 19 patients had adverse outcome either died within 3 months (7 had malignancy) or requiring Intensive Care during the admission. For patients without PTE (n=1168), the SIndex was abnormal in 334(28.6%) and the MSindex in 293 (25.1%). For patients with PTE (n=337), respectively these figures were 89 (26.4%) and 68 (20.2%). Of those with adverse outcomes, 13/19 Sindex and 17/19 MSIndex values were not abnormal.
Conclusion(s): Neither the SIndex not the MSIndex are discriminatory in helping distinguish the at risk groups with PTE and therefore cannot be used as an isolated criteria.

Cellular response to influenza infection: Lymphopenia and a reduced lymphocyte/monocyte ratio (2019)

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Type of publication:
Conference abstract

Author(s):
*Abdulsamad S.P.; *Bhatia K.; *Khalid H.; *Makan A.; *Crawford E.; *Ahmad N.; *Srinivasan K.; *Moudgil H.

Citation:
European Respiratory Journal; Sep 2019; vol. 54, PA2383

Abstract:
Objectives: Provisional work has proposed a diagnostic role investigating cellular responses in acute viral respiratory pathology. Analysing patients with influenza(flu), objectives were(1)to assess magnitude of lymphocyte and monocyte responses in acute infection and(2)report on the potential benefit if detecting lymphopenia and a reduced lymphocyte to monocyte ratio(LMR)
Methods: Retrospective analysis of all adults with flu admitted to this trust during winter season 2016/7. Computer records provided differential white cell counts as relative(%of total white cell counts, WCC)and absolute counts for lymphocytes(normal range 1-4×109)and monocytes(0.1-0.9×109);analysis was with SPSS
Results: 143(54% female)adults(142 Flu A [H3N2]and 1 Flu B)were admitted. Mean age was 70.3(SD 19.4, range 20-98)years. Flu was primary diagnosis for 53(37%);43/90(48%) remaining also had a respiratory presentation. Lymphocyte count<20% WCC presented in 122(85%)and monocyte count >10%WCC in 43 (30%)with both markers in 35(25%). Lymphocyte counts were skewed, median 0.8(IQ 0.5-1.2)with lymphopenia at initial testing in 87(60%);among others there was a fall from admission values in 45 (31%). The lymphocyte/monocyte ratio (LMR) was <2 in 115(80%)of all presentations and specifically in 82/87(94%)with initial lymphopenia
Conclusion(s): Irrespective of whether primarily with flu or as a concurrent illness, acute lymphopenia and a LMR<2 at presentation as a measure of cellular response in admitted patients potentially presents an early and alternative strategy identifying patients with acute flu. Future work is required to establish sensitivity, specificity, negative and positive predictive values in a wider unselected similar population.

Optimizing chemotherapy for frail and/or elderly patient with advanced gastroesophageal cancer (AGOAC): the GO2 phase III trial (2019)

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Type of publication:
Conference abstract

Author(s):
Swinson D.E.; Hall P.; Seymour M.; Lord S.; Marshall H.; Ruddock S.; Cairns D.; Waters J.; Wadsley J.; Falk S.; Roy R.; Joseph M.; Nicoll J.; Vellios Kamposioras K.; Tillett T.; Cummins S.; Grumett S.; Stokes Z.; Waddell T.; *Chatterjee A.; Garcia A.; Allmark C.; Khan M.; Petty R.

Citation:
Journal of Geriatric Oncology; Nov 2019; vol. 10 (no. 6), Supplement 1, S8

Abstract:
Introduction: aGOAC patients are frequently elderly and/or frail.
Objective(s): (i) find the optimum dose of oxaliplatin capecitabine (OCap) for this population; (ii) explore the use of an objective geriatric assessment to individualize dose for maximum overall treatment utility (OTU), a composite of clinical benefit, tolerability, quality of life (QL) and patient value.
Method(s): Patients with aGOAC were eligible if there was uncertainty of the appropriate dose of chemotherapy. Baseline assessment included global QL; symptoms; functional scales; comorbidity; frailty. Randomization was 1:1:1 to dose Level A (Ox 130 mg/m2 d1, Cap 625 mg/m2 bd d1-21, q21d), B (80% Level A) or C (60% Level A). At 9 weeks, patients were scored for OTU. Non-inferiority (vs A) was assessed using PFS, censored at 12 months, with upper boundary HR 1.34 (based on patients' and clinicians' discussions), needing 284 PFS events per two-way comparison. In a separate sub-study, when there was uncertainty regarding the use of chemotherapy, patients were randomized between level C and supportive care alone (SCA).
Results and Conclusion(s): 512 patients were randomized, 2014-2017, at 61 UK centers. Age, performance status and frailty were similar in all arms. Non-inferiority of PFS is confirmed for Level B vs A (HR 1.09, CI 0.89-1.32) and for Level C vs A (HR 1.10, CI 0.90-1.33). Level C patients had the least toxicity and best OTU outcomes. When analyzed by baseline age, frailty and PS no group was identified who benefit more from higher treatment doses. A further 46 patients were randomized between chemotherapy and SCA. A non-significant trend to improved survival was observed (HR=0.69, CI 0.32-1.48) and QL deteriorated less with chemotherapy. This is the largest RCT specifically investigating frail and/or elderly aGOAC patients, and should guide future treatment. The lowest dose tested was non-inferior in terms of PFS, produced less toxicity and better overall treatment utility.

Is it useful to analyse all waste material obtained during endobronchial ultrasound-transbronchial needle aspiration (EBUS-TBNA)? (2019)

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Type of publication:
Poster presentation

Author(s):
*V. Tharmarajah, *H. Hope, *E. Cobby, J. *Stafford, *R. Heinink

Citation:
European Respiratory Journal 2019 Vol. 54, Suppl 63, PA3064

Abstract:
Background: It is not standard practice to always analyse waste material obtained from EBUS in addition to the samples taken from the EBUS-TBNA needle.
Method: A retrospective review of EBUS carried out between 1/1/17 and 16/3/18 was performed. We collected data where samples were taken both via the EBUS-TBNA needle and from waste material from the same node. It was also noted as to which sample contained the most diagnostic material.
Results: 54 EBUSs were performed within the study period. If the waste obtained from both the flushing of the EBUS-TBNA needle and from the flushing of the suction syringe contained anything but clear fluid, the waste was sent to cytology, paired with the EBUS-TBNA needle sample from the same node. 38 patients had samples taken from both waste material and via the EBUS-TBNA needle (47 nodes in total). Malignancy was seen in 26 nodes, granulomata in 9, and no disease seen in 12 (1 insufficient sample, 10 true negatives and 1 false negative). Of the 27 malignant nodes, the EBUS-TBNA needle sample contained diagnostic material in 25 samples (sensitivity 96%). The waste sample contained diagnostic material in 23 samples (sensitivity 85%); in 13 of these, the waste sample was felt to have either as much or more diagnostic material than the sample obtained from the EBUS-TBNA needle.
Conclusion: Waste material obtained during EBUS contains diagnostic material in the majority of cases, and in our cohort contained at least as much material as the corresponding EBUS-TBNA needle sample in 50% of samples. This is important when considering the rising amount of tissue required by oncologists for molecular testing.

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Levothyroxine to increase live births in euthyroid women with thyroid antibodies trying to conceive: the TABLET RCT (2019)

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Type of publication:
Journal article

Author(s):
Dhillon-Smith R K, Middleton L J, Sunner K K, Cheed V, Baker K, Farrell-Carver S, Bender-Atik R, Agrawal R, Bhatia K, Edi-Osagie E, Ghobara T, Gupta P, Jurkovic D, Khalaf Y, MacLean M, McCabe C, Mulbagal K, Nunes N, Overton C, Quenby S, Rai R, Raine-Fenning N, Robinson L, Ross J, Sizer A, Small R, Tan A, *Underwood M , Kilby M D, Boelaert K, Daniels J, Thangaratinam S, Chan S,  Coomarasamy A.

Citation:
Efficacy and Mechanism Evaluation; Volume: 6, Issue: 11, October 2019

Abstract:
Background: Thyroid autoantibodies, specifically thyroid peroxidase antibodies, have been associated with miscarriage and pre-term birth in women with a normal thyroid function. Small randomised controlled trials have found that treatment with levothyroxine may reduce such adverse outcomes in pregnancy.
Objectives: The Thyroid AntiBodies and LEvoThyroxine (TABLET) trial was conducted to explore the effects of levothyroxine in euthyroid women with thyroid peroxidase antibodies. A concurrent mechanistic study was conducted to examine the effect of levothyroxine on immune responses.
Design: This was a randomised, double-blind, placebo-controlled, multicentre study.
Setting: The TABLET trial was conducted in 49 hospitals across the UK between 2011 and 2016.
Participants: Euthyroid women who tested positive for thyroid peroxidase antibodies, were aged between 16 and 41 years and were trying to conceive either naturally or through assisted conception were eligible.
Intervention: Participants were randomised to levothyroxine at a dose of 50 µg daily or placebo. The intervention was commenced preconception and continued until the end of a pregnancy. Women were given a 12-month period to conceive from randomisation.
Main outcome measures: The primary outcome was live birth at ≥ 34 completed weeks of gestation. The secondary outcomes included miscarriage at < 24 weeks; clinical pregnancy at 7 weeks; ongoing pregnancy at 12 weeks; gestation at delivery; birthweight; appearance, pulse, grimace, activity and respiration (Apgar) scores; congenital abnormalities; and neonatal survival at 28 days of life.
Methods: Participants were randomised in a 1 : 1 ratio. Minimisation was implemented for age (< 35 or ≥ 35 years), number of previous miscarriages (0, 1 or 2, ≥ 3), infertility treatment (yes/no) and baseline thyroid-stimulating hormone concentration (≤ 2.5 or > 2.5 mlU/l) to achieve balanced trial arms. Women were followed up every 3 months while trying to conceive to check thyroid function and general well-being, and, once pregnant, were seen each trimester: 6–8 weeks, 16–18 weeks and 28 weeks. Any abnormal thyroid results were managed in line with clinical guidance at the time.
Results: Of the 19,556 women screened, 1420 women were eligible and 952 were randomised to receive levothyroxine (n = 476) or placebo (n = 476). Six women from each arm either were lost to follow-up or withdrew from the trial. A total 540 women became pregnant: 266 in the levothyroxine arm and 274 in the placebo arm. The live birth rate was 37% (176/470) in the levothyroxine group and 38% (178/470) in the placebo group, translating to a relative risk of 0.97 (95% confidence interval 0.83 to 1.14; p = 0.74) and an absolute risk difference of –0.4% (95% confidence interval –6.6% to 5.8%). A subset of 49 trial participants (26 in the levothyroxine arm and 23 in the placebo arm) were recruited to assess changes in their serum chemocytokine concentrations. Treatment with levothyroxine resulted in some changes in chemocytokine concentrations in the non-pregnant state and in early pregnancy, but these had no association with clinical outcome.
Conclusions: Levothyroxine therapy in a dose of 50 µg per day does not improve live birth rate in euthyroid women with thyroid peroxidase antibodies.
Limitations: Titration of the levothyroxine dose based on thyroid-stimulating hormone/thyroid peroxidase concentrations was not explored.
Future work: Future research could explore the efficacy of levothyroxine administered for the treatment of subclinical hypothyroidism.
Trial registration: Current Controlled Trials ISRCTN15948785 and EudraCT 2011-000719-19.
Funding: This project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research partnership.

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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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Global longitudinal strain detects trastuzumab induced cardiotoxicity early in a clinical population (2020)

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Type of publication:
Conference abstract

Author(s):
*Grylls, J., *Ellis, C., *Ingram, T., *Lee, E.

Citation:
European Heart Journal – Cardiovascular Imaging 2020; Volume 21, Issue Supplement 1

Abstract:
Background: Trastuzumab is highly effective in the treatment of breast cancer, and is often used as an adjuvant therapy. Due to its potential cardiotoxicity, serial monitoring of cardiac function is vital. Ejection fraction (EF) by two-dimensional echocardiography is routinely used but has limitations in measurement variability. Myocardial deformation imaging, in particular Global Longitudinal Strain (GLS), can detect pre-clinical myocardial dysfunction. However, its use is not yet adopted into routine clinical practice.
Aims: Our aim was to ascertain if a clinically significant reduction in GLS (≥11% from baseline) occurred before the onset of EF reduction, in patients who developed cardiotoxicity whilst receiving trastuzumab.
Methods: Between January 2014 and January 2019, 235 consecutive patients received trastuzumab and underwent serial echocardiography at 3 monthly intervals at our institute. Cardiotoxicity is defined as a ≥10% EF reduction from baseline or an EF <50%. Women who developed cardiotoxicity as defined by this change in EF were retrospectively studied.Two-dimensional speckle tracking was used to derive peak longitudinal strain in each myocardial segment from the apical four-, three- and two-chamber view images. GLS was taken as the average value of all these segments. The median time to ≥11% GLS reduction and ≥10% EF reduction or EF <50% was compared.
Results: Thirteen women (mean age 53 ± 9.5 years) developed cardiotoxicity. EF was 61.8 ± 4.4% at baseline and 45.7 ± 7.5% following therapy (p = 0.00). A ≥11% reduction in GLS from baseline was observed in all patients: GLS -20.2 ± 1.5% and -15.6 ± 2.1%, p = 0.00. The median time to cardiotoxicity as defined by EF and GLS was 6 months and 3 months, respectively (p = 0.031), as shown in Table 1. Repeatability analysis showed both EF and GLS measurements in our cohort have good measurement reproducibility. Inter-observer intraclass correlation (ICC) for EF and GLS were 0.912 and 0.913, respectively. Intra-observer ICC for EF and GLS were 0.925 and 0.900, respectively.
Conclusion: Cardiotoxicity developed in a significant portion (6%) of our patients receiving trastuzumab. As a reduction in GLS was detectable early and preceded that of EF by 3 months, this may represent a therapeutic window for initiation of cardio-protective medication, if and when the use of GLS is incorporated into routine practice for cardiotoxicity surveillance.

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The use of mouthguards in grappling sports: a survey of grapplers in the United Kingdom (2019)

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Type of publication:
Journal article

Author(s):
*Razzak, Arif., *Messahel, Ahmed

Citation:
British Dental Journal 2019; Vol. 227, pages 901–905

Abstract:
Background: Mouthguards are routinely used in many sports, however their use in grappling sports has not really been examined to date, and to the authors' knowledge, there is no available data on the level of dental trauma experienced by this group.
Materials and method: The authors approached six different grappling schools, as well as leaving an invite on a grappling event page for volunteers to fill out a short survey.
Results: Around 81 respondents took part in the survey, with nearly 25% reporting that they never wore a mouthguard during grappling, and less than 50% not wearing a mouthguard all the time. Sixty-three percent of respondents had either seen dental and peri-oral injuries, or had experienced dental injuries as a result of grappling.
Conclusion: More work is needed to investigate whether mouthguards have a positive effect on the dental injury experience, and to establish the percentage of grapplers who at some point will be affected by dental trauma.