2016;354:i3681 bmj cite this as: education...nirmal vadgama, phd student, institute of neurology,...

ART OF MEDICINE

In recruiting monozygotic (MZ) twins for our research, we have come across participants who have been told they are dizygotic (DZ) but have almost identical traits and physical features, or MZ but present more like fraternal siblings. Current practice for classifying twins as either MZ or DZ, which are still largely based on chorionicity (whether the twins shared a placenta) and physical similarity, are prone to error.1 A common error in zygosity assignment is the supposition that like-sexed twins are DZ if they were determined to be dichorionic at birth. Up to 25% of all like-sexed twin pairs classified as DZ and 7% classified as MZ by chorionicity turn out to be misclassifications, according to results of DNA based methods.2 3 Furthermore, rare cases of monochorionic DZ twins have been reported.4

It is important for twins and their families to establish whether they are truly genetically identical. There are also important medical reasons to know correct MZ or DZ classification, as morbidities are generally shared more among MZ than DZ twins. Moreover, since it is considered unethical to separate twins for adoption without their acknowledgment or against their will, one could argue that denying twins access to an intrinsic biological fact of their existence is also unethical.

It would be simple, cheap, and quick to carry out genetic testing using placental tissue or even buccal swabs in all like-sexed twins at the time of birth.Nirmal Vadgama, PhD student, Institute of Neurology, University College London, London WC1N 3BG, UK [email protected] Niranjanan Nirmalananthan, consultant neurologist, Neurosciences, St George’s University Hospitals NHS Foundation Trust, London Mustafa Sadiq, consultant obstetrician and gynaecologist, Warrington and Halton Hospitals NHS Foundation Trust, Warrington John Hardy, professor of neuroscience, Department of Molecular Neuroscience, University College London Jamal Nasir, multiprofessional facilitator, Education Department, St George’s University Hospitals NHS Foundation TrustCite this as: BMJ 2015;351:h6589

We welcome contributions to this column via our online editorial office: https://mc.manuscriptcentral.com/bmj

Identical non-identical twins and non-identical identical twins

the bmj | 1 October 2016 29

education

educationeducation

You can gain CPD points from your reading by recording what you have read in your appraisal folder. You should try to link your reading back to a learning need and also consider how you plan to improve your practice as a result of your learning. http://learning.bmj.com

We print a statement on financial interests and patient partnership with each education article because they are important to us. We have resolved to reduce the involvement of authors with financial interests that The BMJ judge as relevant. We encourage and make clear how patients have been involved and shaped our content. More details can be found on thebmj.com.

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Liver function tests—In acute liver injury alanine aminotransferase (ALT) levels are often significantly raised (suggesting acute hepatocyte damage), with a normal albumin level (suggesting preserved synthetic function). Albumin has a half life as long as 20 days, so is not a reliable indicator of hepatic dysfunction in acute liver injury.

Causes—Hepatitis A, hepatitis E, and the initial stage of hepatitis B and C infection can all cause acute liver injury. Paracetamol toxicity is a common drug related cause. Alcoholic hepatitis can cause an acute liver injury, but serum aspartate aminotransferase (AST) levels rarely rise above 500 IU/L, and ALT rarely rises above 300 IU/L. Rarer causes include other viruses and drugs, ischaemia, and autoimmune, metabolic, pregnancy related, and vascular conditions.

Acute liver screen—An acute liver screen often includes an abdominal ultrasound scan, and viral serology for hepatitis A (IgM), hepatitis B surface antigen and core antibody, hepatitis C antibody, hepatitis E (IgM), cytomegalovirus (IgM), and Epstein-Barr virus antibody. Non-infective markers include caeruloplasmin for Wilson’s disease, antinuclear antibody, anti-smooth muscle antibody, anti-liver-kidney microsomal-1 antibody, and IgG levels for autoimmune hepatitis, and a paracetamol level.

For more information visit BMJ Learning • http://bit.ly/2bq3o4R

FAST FACT—ACUTE LIVER INJURY

the bmj | 1 October 2016 3130 1 October 2016 | the bmj

IntroductionWeight patterns in early years persist over time, with childhood obesity tracking into adulthood.7 Longitudinal cohort studies show that obesity during childhood is associated with medical comorbidity, and excess weight in childhood independently increases the risk of mortality related to the development of cardiovascular and metabolic disease in later life.8‑10 It has also been linked with adverse effects on social, psychological, and academic development.11 Obese children are at high risk of bullying, discrimination, lower health related quality of life, and impaired mental health.1‑13

Definition The World Health Organization,17 the Centers for Disease Control and Prevention (CDC),18 and the International Obesity Task Force

WHAT YOU NEED TO KNOW

• Obesity during childhood is associated with medical comorbidity

• Some forms of severe obesity are associated with hypothalamic dysfunction

• Orlistat is the only drug approved for treatment of obesity in the paediatric population although metformin has been studied to a greater degree in this age group

• There is no consensus on the optimal bariatric surgical technique in adolescents

• Behavioural interventions demonstrate modest reduction in BMI over the short term, with improvements in cardiometabolic health

1Division of Endocrinology, Hospital for Sick Children, University of Toronto, Toronto Correspondence to: [email protected] of Pediatric Medicine, Hospital for Sick Children, University of Toronto, TorontoThis is an edited version; the full version is on thebmj.com

STATE OF THE ART REVIEW: HIGHLIGHTS

Emerging treatments for severe obesity in children and adolescentsNicole Coles,1 Catherine Birken,2 Jill Hamilton1

Fig 1 | Proposed definitions of severe obesity. BMI=body mass index; SDS=standard deviation score

(IOTF)19 have each used different reference data and thresholds to develop their own definitions of severe obesity (fig 1).9‑24

CausesFigure 2 shows the physiology of apetite regulation. The hypothalamus plays an important role in regulating body weight, so it is unsurprising that many of the known monogenic and syndromic forms of severe obesity are associated with hypothalamic dysfunction.42‑59

Key clinical features to suggest that severe obesity may be related to an underlying pathological condition include young age of onset, extremely rapid weight gain, poor or advanced linear growth, dysmorphic features, neurocognitive delay, obesity very discordant to parents and siblings, and central nervous system symptoms to suggest an infiltrative or inflammatory condition.

Emerging treatmentsEmerging behavioral interventionsCurrent guidelines on the management of obesity recommend

a multidisciplinary approach to implementing family based lifestyle interventions. This includes goal setting to increase healthy nutrition and physical activity, reduction of sedentary time, self monitoring, stimulus control, and positive reinforcement.20 However, the efficacy of this approach in children with severe obesity is unclear.16 Critics argue that intensive lifestyle modification, particularly in isolation, is inadequate for children with severe obesity as it reduces BMI only modestly by 1‑2 points.70 However, stabilization for children who may have been on an upward trajectory of weight gain may prevent further morbidity. Another commonly cited challenge is the greater rate of attrition in lifestyle programs among children with a higher BMI.71

Overall, behavioral interventions for children and adolescents show modest reductions in BMI over the short term, with improved efficacy in younger children. Studies have also shown improvements in myocardial mechanics, insulin sensitivity, and markers of inflammation in


Fig 2 | Physiology of appetite regulation. (1) Regulation of appetite is mediated by the hypothalamus and brainstem, which act to integrate peripheral hormonal and autonomic inputs. At the start of a meal, hormonal signals are released from the small and large bowel (PYY, GLP-1, GLP-2, CCK, and OXM), stomach (ghrelin), pancreas (insulin, liver), and adipose tissue (leptin). All are anorexigenic, with the exception of ghrelin which is orexigenic. (2) Hormonal signals (directly and indirectly via the autonomic nervous system) relay to anorexigenic (POMC, CART) and orexigenic neurons (AgRP, NPY) in the ARC and to neurons in the brainstem (DVN and NTS). (3) Neurotransmitters from the hypothalamus then relay a signal to the second order neurons in the PVN within the hypothalamus. (4) The brainstem directs sympathetic and parasympathetic output to the periphery, affecting metabolism and energy expenditure. (5) Higher level inputs from other cortical areas involved in executive function are integrated with information from reward centers driving hedonic eating behaviors, motivation, and sensory input. AgRP=agouti-related peptide; AP=area postrema; ARC=arcuate nucleus; CART=cocaine and amphetamine regulated transcript; CCK=cholecystokinin; DVN=dorsal motor nucleus of the vagus; GABA=gamma-aminobutyric acid; GLP-1=glucagon-like peptide 1; GLP-2=glucagon-like peptide 2; LH=lateral hypothalamus; NPY=neuropeptide Y; NTS=nucleus of the tractus solitarius; OXM=oxyntomodulin; POMC=pro-opiomelanocortin; PP=pancreatic polypeptide; PVH=paraventricular hypothalamus; PYY=peptide YY


adolescents with severe obesity following completion of exercise programs.83‑85

The use of interactive information technologies and applications (“apps”) for smart phones and tablets has not been tested in young people with severe obesity. Motivational interviewing has been studied in several chronic medical conditions including childhood obesity but has not been extensively evaluated in severe obesity.86 87 Research is also needed to identify psychosocial characteristics of individuals and families that respond best to specific behavioral interventions.

Emerging medical therapiesThe table (opposite) summarises clinical trials for obesity in children and adolescents.

Nutrient processingOrlistat remains the only drug approved for treatment of obesity in the pediatric age group.

In general, orlistat seems to be a safe drug and has minimal systemic absorption.96 Unfortunately, compliance is affected by gastrointestinal side effects including loose and oily stools, flatulence, and fecal urgency, which occur in 9%‑50% of patients.93

Enteric hormonal regulationMetformin’s mechanism of action to reduce weight is not clear but is likely multifactorial.9 Its effect on weight may be mediated by increasing GLP‑1, lowering dipeptidyl peptidase‑4

PATIENT INVOLVEMENTAttempts have been made to better understand the adolescent patient’s experience with obesity and its medical treatment.154‑156 In determining areas of importance for this review, we sought the patient’s perspective by conducting group discussions with families attending a weight management program. The adolescents were very interested in technology and have made the recommendation that, “researchers need to move more quickly developing and doing research in apps for healthy living that are designed for us.” An adolescent who had undergone bariatric surgery wanted to share his experience: “I think bariatric surgery should be a treatment option available for teens to help prevent poor health in adulthood. However, teens should understand surgery is a ‘tool’ not a ‘cure.’ Over two years, I have lost 120 lb [54 kg] and my life is much better. I have some challenges with eating, but the positives far outweigh the negatives. I can keep up with friends now—things have opened up for me and my future looks good.”

Adolescents were very interested in technology and have made the recommendation that, “researchers need to move more quickly developing and doing research in apps for healthy living that are designed for us”

activity, altering the bile acid pool and the gut microbiome, enhancing lipid oxidation, and promoting central satiety.100‑102

Overall, evidence suggests that metformin is safe in achieving weight loss in children with obesity; however, the magnitude of its effect is small and durability of weight loss is questionable.

GLP‑1 agonists are also used in type 2 diabetes in adults and have been found to have a favorable side effect of weight loss (table).106 107 In pediatric studies, these drugs are safe and generally well tolerated, with nausea reported as the most common side effects, occurring in 36‑62% of patients.106 107

Central nervous systems targetsLorcaserin is a serotonin receptor agonist that targets 2C receptors on POMC neurons, inducing satiety.109 Highly selective activation of this anorexigenic pathway leads to reduced energy intake and weight loss, without the significant cardiovascular and psychiatric adverse effects seen with previous serotonin agonists.110 Currently, the use of these drugs is restricted to clinical research studies.

Topiramate has been historically used as an anti‑epileptic drug, but it has more recently been evaluated in the management of binge eating disorders.113 It has been parenthetically noted to cause weight loss in treated adolescents.114 The use of this anti‑epileptic drug remains largely within a research setting, but clinical trials are under way to study the use of this drug in adolescents with severe obesity.117

Zonisamide is a novel anti‑epileptic drug that may also promote weight loss. Similar to topiramate, the most common adverse effects are largely central nervous system related and include somnolence, dizziness, headache, nausea, and poor appetite.119 These anti‑epileptic drugs may represent a preferred therapy for adolescents with a seizure disorder and comorbid obesity, but further studies are needed to evaluate them more broadly as an obesity treatment.

Emerging surgical therapyOver the past 20 years, bariatric surgery has become an important treatment option for adults with obesity and is increasingly being offered to adolescents.120 The laparoscopic Roux‑en‑Y gastric bypass (RYGB) is the most frequently used procedure in adults and has been studied in adolescents. Laparoscopic adjustable gastric banding (LAGB) and sleeve gastrectomy have also been evaluated in this age group. Randomized trials comparing the different surgical techniques are scarce, with no clear consensus on the optimal surgical technique in adolescents.125

Expert consensus guidelines vary between countries but suggest that bariatric surgery should be restricted to adolescents with BMI of 35 or above with major comorbidities (type 2 diabetes mellitus, moderate to severe sleep apnea, pseudotumor cerebri, or severe non‑alcoholic fatty liver disease) or with BMI of 40 or above and other comorbidities (hypertension, glucose intolerance, insulin resistance, or dyslipidemia).134 135

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A meta‑analysis of 23 studies consisting primarily of uncontrolled retrospective case series reported the outcomes of pediatric bariatric surgery. It found a decrease in BMI of 13.5 (95% confidence interval 11.9 to 14.1) at one year, approximately one third of initial body weight, with the largest reduction occurring in patients who

Genetic cause of severe obesity

ACTH=adrenocorticotropic hormone; GnRH=gonadotropic releasing hormone; MSH=melanocyte stimulation hormone; TRH= thyroid releasing hormone; WAGR syndrome=Wilms tumor, anirida, genitourinary anomalies, and intellectual disability syndrome

Summary of clinical trials for obesity drugs in children and adolescents

DrugSample size

Age range (years)

Treatment duration (weeks) Targeted mechanism Pediatric trials Outcomes Common side effects

Orlistat n=20-539 10-18 12-54 Inhibits gastric and pancreatic lipase, reducing dietary fat absorption

3 randomized control trials; 2 open label trials90-94

BMI change −4.09 to +0.31

Loose stools, oily stools, flatulence, fecal urgency, vitamin deficiency, cholelithiasis

Metformin n=24-173 10-16 12-96 Lipogenesis, insulin sensitivity, appetite satiety, leptin signaling

1 systematic review; 14 randomized control trials98

Systematic review: mean BMI change −1.16 (95% CI −1.60 to 0.73)

Loose stools, abdominal pain, nausea; no reported liver or kidney toxicity in children

Exenatide n=12-26 9-19 24 Reduces glucagon and gastric emptying; increases insulin, leptin secretion, appetite, and satiety

2 clinical trials106 107 BMI change −1.13 (95% CI −2.03 to 0.24), −1.7 (−3.0 to −0.4)

Nausea, vomiting; no pancreatitis or hypoglycemia reported in children

Liraglutide 1 clinical trial NCT01789086*Lorcaserin Serotonin receptor agonist 2 clinical trials NCT02398669*,

NCT02022956*Headache, nasopharyngitis, back pain, dizziness

Topiramate Inhibition of carbonic anhydrase, reduction in neuropeptide Y, dysgeusia

1 clinical trial NCT01859013* Sedation, paresthesias, confusion

*Trial ID number from clinicaltrials.gov; results pending.

underwent RYGB.133 Importantly, this weight loss occurred concurrently with improvements in metabolic health and other obesity related comorbidities including hypertension, sleep apnea, dyslipidemia, and type 2 diabetes.133

Bariatric surgery appears to be an effective treatment option but raises ethical and medical concerns in the

paediatric population, and further research is required to identify those who will best benefit from these procedures. .Competing interests: We have read and understood the BMJ policy on declarations of interest and declare the following interests: JH is supported by the Mead Johnson chair in nutritional science.Cite this as: BMJ 2016;354:i4116Find this at: http://dx.doi.org/10.1136/bmj.i4116


Intracranial bleeding is common after traumatic brain injury, and the larger the bleed the greater the risk of death and disability.4 5 Bleeding continues after hospital admission in 84% of patients with moderate or severe injuries,6 7 and can continue for up to 24 hours.8 About one third of patients have laboratory evidence of abnormal coagulation.9 High levels of fibrin degradation products are seen within the first three hours.10 Such patients have a higher risk of intracranial haemorrhage and mortality.

Worldwide at least 200 per 100 000 people are killed or admitted to hospital each year after traumatic brain injury.1 This results in more than 10 million deaths or hospital admissions.2 In the UK, around one million people attend emergency departments every year with a traumatic brain injury.3

Tranexamic acid reduces bleeding by inhibiting the enzymatic breakdown of fibrin blood clots (fig 1).Tranexamic acid is used routinely in some cases of trauma and in surgery. • Tranexamic acid treatment within an hour of injury

reduces the risk of death caused by bleeding by about one third

• Treatment between one and three hours reduces the risk by about one fifth

• There is no apparent benefit after three hours, and tranexamic acid might even be harmful

• If tranexamic acid is effective after traumatic brain injury, it should also be most effective when given soon after injury, when intracranial bleeding is ongoing8

The potential for harm also exists however• Tranexamic acid may increase the risk of ischaemia

and cerebral thrombosis because it inhibits fibrinolysis.15 Cerebral ischaemia is already a known risk after traumatic brain injury, which worsens neurological outcome and increases mortality.16 17 For example, raised intracranial pressure can lead to cerebral hypoperfusion.18‑20 Thrombotic disseminated

WHAT YOU NEED TO KNOW

• The effectiveness and safety of tranexamic acid in traumatic brain injury are uncertain, although randomised trials are under way to investigate the problem

• Tranexamic acid could reduce intracranial bleeding but might increase the risk of cerebral thrombosis and ischaemia

• We believe that tranexamic acid should not be used in routine clinical practice unless these trials show benefit

1Clinical Trials Unit, London School of Hygiene and Tropical Medicine, University of London 2Department of Emergency Medicine, Royal London Hospital, Barts Health NHS Trust, London3NIHR Surgical Reconstruction and Microbiology Research Centre, University Hospitals Birmingham NHS Foundation Trust, BirminghamCorrespondence to: Abda Mahmood [email protected]

UNCERTAINTIES

Does tranexamic acid improve outcomes in traumatic brain injury?Abda Mahmood,1 Ian Roberts,1 Haleema Shakur,1 Tim Harris,2 Antonio Belli3

HOW PATIENTS WERE INVOLVED IN THE CREATION OF THIS ARTICLENo patients were involved in the writing of this article.

Patients are involved in the design and conduct of CRASH-3 and these were reflected in the trial procedures. Organisations advised the investigators on outcome measures that matter most to patients, such as fatigue. Organisations also represent patients on the trial steering committee and are involved in the ongoing supervision of the trial.

Fig 1 | A: Normal fibrinolysis. B: Fibrinolysis inhibited by tranexamic acid. Plasmin binds to fibrin via lysine binding sites and then splits fibrin into fibrin degradation products. Tranexamic acid is a molecular analogue of lysine that inhibits fibrinolysis by reducing the binding of plasmin to fibrin

II-PA

Plasminogen

II-PA Plasmin

Lysine binding site

Fibrin

Fibrin degradationproducts

II-PA

Plasminogen

Tranexamic acid

Fibrin

Fibrin

II-PA Plasmin

A B

P


intravascular coagulation might increase the risk of cerebral microthrombi, which are often seen in the brains of patients with traumatic brain injury who have died.21

• Seizures are also a risk because tranexamic acid is known to cross the blood‑brain barrier.22 Although there was no evidence of any increase in seizures in the CRASH‑2 trial of tranexamic acid in extracranial bleeding, seizure activity remains a concern because the blood‑brain barrier is impaired after traumatic brain injury.23

What is the evidence of uncertainty?A 2015 systematic review identified two relevant completed randomised trials (table 1).24 25 We judged that both trials were at low risk of bias; however, neither was large enough to answer the question definitively—the confidence intervals were wide and the P values statistically insignificant. The first trial (n=249) examined the effect of tranexamic acid in patients with extracranial bleeding but who also had traumatic brain injury.24 The second trial (n=229) examined the effect of tranexamic acid in patients with polytrauma and traumatic brain injury, or isolated traumatic brain injury.25 Both trials recruited patients who were within eight hours of injury but the numbers were not large enough to determine the balance of risks and benefits from tranexamic acid and whether this varies by time to treatment. Furthermore, the patients in one of the trials

Table 1 | Patients with intracranial haemorrhage, cerebral ischaemia, and mortality outcomes in two randomised trials of tranexamic acid in patients with traumatic brain injury. Values are numbers (percentages) unless stated otherwise

OutcomeCRASH-2 intracranial bleeding substudy 201224 Yutthakasemsunt et al 201325

TXA Placebo Relative risk (95% CI) TXA Placebo Relative risk (95% CI)Intracranial haemorrhage 44 (36) 56 (44) 0.80 (0.59 to 1.09) 21 (18) 32 (27) 0.65 (0.40 to 1.05)Focal ischaemic lesion/stroke 6 (5) 12 (9) 0.51 (0.20 to 1.32) 0 - 3 (3) -Deaths 14 (11) 24 (18) 0.60 (0.33 to 1.11) 12 (10) 17 (14) 0.69 (0.35 to 1.39)

Table 2 | Ongoing randomised trials of tranexamic acid use for traumatic brain injuryTrial Trial type Status Proposed sample size No of arms Intervention Comparison Primary outcome Secondary outcomesPrehospital tranexamic acid use for moderate and severe traumatic brain injury (NCT02645552)

Double blind, randomised trial

Pending recruitment

400 patients with moderate to severe traumatic brain injury (Glasgow coma scale score ≤12)

2 Arm 1: 1 g intravenous bolus of tranexamic acid over 10 minutesArm 2: placebo intravenous bolus over 10 minutes

Placebo (sodium chloride, 0.9%)

Neurological outcome (based on extended Glasgow outcome scale score) at six months post-injury

Vascular occlusive events (myocardial infarction, stroke, pulmonary embolism, and deep vein thrombosis)

Prehospital tranexamic acid use for traumatic brain injury (NCT01990768)


Currently recruiting

1002 patients with moderate to severe traumatic brain injury (Glasgow coma scale score ≤12)

3 Arm 1: 1 g intravenous bolus of tranexamic acid followed by 1 g intravenous infusion of tranexamic acid over eight hours.Arm 2: 2 g intravenous bolus of tranexamic acid followed by placebo infused over eight hours.Arm 3: placebo intravenous bolus followed by placebo infused over eight hours*


Neurological outcome (based on extended Glasgow outcome scale score) at six months after injury

Volume of intracranial haemorrhage, disability rating scale score, 28 day survival, neurosurgery, ventilator-free days, seizures, cerebral ischaemia, vascular occlusive events, alterations in fibrinolysis

Clinical Randomisation of an Antifibrinolytic in Significant Haemorrhage (CRASH-3) (NCT01402882)


Currently recruiting

13 000 patients with major traumatic brain injury (Glasgow coma scale score ≤12 or intracranial bleeding on computed tomography scan)

2 Arm 1: 1 g of intravenous bolus of tranexamic acid over 10 minutes followed by 1 g intravenous infusion of tranexamic acid over eight hours.Arm 2: placebo intravenous bolus followed by placebo infused over eight hours


Death in hospital within 28 days of randomisation

Vascular occlusive events, disability (based on disability rating scale and patient oriented outcome measures), seizures, neurosurgery, days in intensive care, other adverse events

*Intravenous bolus administered in prehospital setting, and maintenance infusion initiated on arrival at hospital.

CRASH-2 2012

Yutthakasemsunt 2013

All patients

0.80 (0.59 to 1.09)

0.66 (0.41 to 1.08)

0.75 (0.58 to 0.98)

0.4 0.6 0.8 1.0 1.2

Study Relative risk(95% CI)

Relative risk(95% CI)

44/123 (36%)

21/114 (18%)

65/237 (27%)

TXA

56/126 (44%)

32/115 (28%)

88/241 (37%)

Placebo

Fig 2 | Meta-analysis of effect of tranexamic acid versus placebo on intracranial bleeding in patients with traumatic brain injury

had extracranial bleeding in addition to intracranial bleeding.24 Because tranexamic acid reduces mortality in extracranial bleeding (CRASH‑2), the mortality reduction seen in this trial could be from the extracranial injury rather than any effect on the brain injury itself.

When the two randomised trials are combined in a meta‑analysis (fig 2), there is a statistically significant reduction in intracranial haemorrhage, but because the confidence intervals are wide, the quality of this evidence is low.• Intracranial haemorrhage—relative risk 0.75 (95%

confidence interval 0.58 to 0.98); P=0.03;• Mortality—relative risk 0.63 (95% confidence interval

0.40 to 0.99); P=0.05.The effect of tranexamic acid on disability and

thrombotic adverse effects including stroke remains uncertain.

Is ongoing research likely to provide relevant evidence?We identified three ongoing randomised trials of tranexamic acid versus placebo in patients with isolated traumatic brain injury (table 2). These will evaluate the

36 1 October 2016 | the bmj

Box 3 | Guidelines for general management of traumatic brain injuryThe National Institute for Health and Care Excellence recommends to 28:• First treat the greatest threat to life and avoid further harm by assessing Airway,

Breathing, and Circulation• Maintain cervical spine immobilisation until a full risk assessment indicates it is safe

to remove the immobilisation device• Ascribe depressed consciousness level to intoxication only after a major brain injury

has been excluded• Effectively manage pain, because it can lead to a rise in intracranial pressure• Immediately manage patients who present to the emergency department with a

Glasgow coma scale score of less than 15• Immediately manage patients who return to the emergency department within 48

hours of transfer to the community with any persistent problem relating to the initial head injury; these patients should be seen by or discussed with a senior clinician experienced in head injuries, and considered for a computed tomography scan

• Immediately intubate and ventilate patients in a coma (Glasgow coma scale score ≤8), or patients who cannot protect their airway or have abnormal respirations

• Transfer patients with a Glasgow coma scale score of 8 or less to a neuroscience unit irrespective of the need for neurosurgery

• Perform a computed tomography scan within one hour of injury if patients present with certain risk factors—for example, Glasgow coma scale score of less than 13 on initial assessment; suspected skull fracture; post-traumatic seizure; focal neurological deficit; more than one episode of vomiting. Perform a computed tomography scan within eight hours of injury if patients have experienced loss of consciousness or amnesia since the injury and show certain risk factors (eg, age ≥65, history of bleeding or clotting disorders, dangerous mechanism of injury). Perform a CT scan within eight hours of injury if patients are receiving warfarin treatment

• Monitor children closely and perform a computed tomography scan within an hour of injury if a relevant risk factor is identified—eg, suspicion of non-accidental injury, post-traumatic seizure without history of epilepsy

• Provide patients, family members, and carers with information about the nature and severity of the injury, risk factors that mean the patient should return to the emergency department—eg, loss of consciousness, amnesia for events before or after injury, headaches, vomiting episodes—details about what to expect during recovery, contact details of community and hospital services and support organisations, on discharge

• The Centers for Disease Control and Prevention and the American College of Emergency Physicians provide guidance on the management of adults with mild traumatic brain injury.29 The guidelines focus on determining whether patients with known or suspected mild traumatic brain injury require a computed tomography scan of the brain or may be safely discharged.

effect of tranexamic acid on death, disability, vascular occlusive events, and other adverse events in traumatic brain injury. The ongoing trials inform whether tranexamic acid can be given to those with traumatic brain injury.

In two of the ongoing trials (n=1402) patients are randomised within two hours of injury in the prehospital setting (NCT02645552, NCT01990768).

In the largest trial, the CRASH‑3 trial (n=13 000), patients will be randomised in hospital and within eight hours of injury (NCT01402882).26 The size of this trial should ensure that tranexamic acid and placebo groups are similar for known and unknown confounders, such as the concomitant degree of coagulopathy.27 Therefore, it is unnecessary to standardise tranexamic acid and placebo groups for clinical management factors that may influence the extent of bleeding.

The results from the three ongoing trials should provide clinicians with information about whether the effect of tranexamic acid varies by time to treatment. Information on the effect of tranexamic acid administered within one hour, between one and three hours, and after three hours of injury may be more useful than the average effect of the treatment. Prespecified subgroup analyses in the CRASH‑3 trial will provide information about the effect of tranexamic acid by time to treatment.

A substudy conducted within the CRASH‑3 trial will use computed tomography scans to examine the effect of tranexamic acid on intracranial bleeding and thrombosis. These scans can detect traumatic haemorrhage (high attenuation) in the acute stage of traumatic brain injury. Ischaemic lesions (low attenuation) are visible on a computed tomography scan done several hours after injury. This substudy will provide information on the effect of tranexamic acid on intracranial haemorrhage and ischaemia and whether this varies by time to treatment.

Further researchRandomised trials looking at the effect of tranexamic acid in patients with isolated traumatic brain injury are currently ongoing. These trials will address the uncertainty of whether tranexamic acid improves outcomes in patients with traumatic brain injury. At this stage we do not make recommendations for further research in this area.

What should we do in light of the uncertainty?The authors recommend that patients with isolated traumatic brain injury should not receive tranexamic acid outside the context of a randomised trial, and clinicians should consider enrolling their patients in one of the relevant trials wherever possible.

Box 3 signposts other aspects of management of traumatic brain injury.Competing interests: None declared.Cite this as: BMJ 2016;354:i4814Find this at: http://dx.doi.org/10.1136/bmj.i4814

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SPOT DIAGNOSISDyspnoea in an older womanThe chest radiograph shows a large superior mediastinal mass with marked tracheal deviation to the right (fig 1).

The differential diagnoses for such a mass would include teratoma, enlarged thymus, enlarged lymph nodes, and a large retrosternal goitre. Given the chronicity of the patient’s symptoms and her stable condition there was no immediate concern about her airway. An urgent computed tomography scan was, however, ordered (fig 2). The margins of the mass (M) can be traced to above the clavicles, making goitre the most likely diagnosis.

The computed tomogram shows a mass, with margins (M), that can be traced up and show communication (C) with the left lobe of the thyroid. The native lobes of the thyroid can also be seen (T).

the bmj | 1 October 2016 41

ENDGAMES For long answers go to the Education channel on thebmj.com @bmj_latest

answ

ers

If you would like to write a Case Review for inclusion in the Endgames section please see our updated author guidelines athttp://bit.ly/29HCBAL and submit via our online editorial office at http://bit.ly/29yyGSx

SPOT DIAGNOSISA persistent coughA 60 year old woman presented with a hoarse voice and persistent dry cough. Flexible nasendoscopy showed a smooth, round swelling on the posterior third of the tongue.

What abnormality is shown in the midline at the posterior tongue base on this axial T2 weighted magnetic resonance image?Submitted by H L Adams and D C HowlettCite this as: BMJ 2016;354:i4858

SPOT DIAGNOSISDyspnoea in an older womanAn 80 year old woman presented to the emergency department with increasing shortness of breath on exertion and “noisy breathing.” She was easily able to complete full sentences, but on examination there was a faint biphasic stridor. The patient stated that she had been breathing like this for months but that it was slowly worsening. She had no polyphonic expiratory wheeze and on auscultation air entry was equal. The patient was otherwise well. What does the chest radiograph show?Submitted by Joseph Dalby Sinnott and David C HowlettCite this as: BMJ 2016;354:i4883

Fig 2 | Chest computed tomogram showing margins (M) of the mass, communicating (C) with the native lobes (T) of the thyroid

Fig 1 | Chest radiograph. Arrows indicate a large mass. T shows tracheal deviation

SPOT DIAGNOSIS A persistent coughA cystic remnant of the thyroglossal duct (thyroglossal cyst).

Post-renal AKI secondary to large bladder calculus

MINERVA A wry look at the world of research

Cardiovascular disease paradoxesTotal mortality from cardiovascular disease declined by 68% between 1980 and 2013 in the UK. But the prevalence of coronary heart disease has remained constant, at around 3% in England and 4% in Scotland, Wales, and Northern Ireland, according to data from NHS hospital records, the primary care Quality and Outcomes Framework, and national surveys (Heart doi:10.1136/heartjnl-2016-309573). Over most of this period the age at which people die from cardiovascular disease rose steadily, but recently this trend has shown slight reversal in most parts of the UK.

What does shoulder impingement mean?Shoulder impingement syndrome is a handy term used by clinicians and researchers to cover lots of different kinds of dysfunction. A review of 97 studies of interventions for shoulder impingement syndrome struggled to find any agreement on a definition of the condition (Should Elb doi:10.1177/1758573216663201). There are 20 agreed index tests and a potentially infinite combination of these with other features of the history, examination, and imaging investigations. The authors call for international consensus and Minerva wishes them luck.

HIV, HCV, and HBV in Tehran’s street childrenA report on blood borne or sexually transmitted viruses in a sample of 1000 street children aged 10-18 from the capital of the Islamic Republic of Iran may be a welcome sign of greater openness there, but it makes for grim reading (Sex Transm Infect doi:10.1136/sextrans-2016-052557). In the sample, 4.5% of children were infected with human immunodeficiency virus, 1.7% with hepatitis B virus, and 2.6% with hepatitis C virus. Children who had drug using parents, were infected with hepatitis C virus, or had experience in trading sex were at a statistically significant greater risk of being infected with HIV. It is estimated that more than 30 000 children live on the streets of Tehran.

Sympathy, empathy, or compassion?Patients with advanced cancer in a large Canadian hospital were interviewed to find what meaning and value they attached to three words that are sometimes used interchangeably in medical discourse—sympathy, empathy, and compassion (Palliat Med doi:10.1177/0269216316663499). The 53 respondents were in general agreement that sympathy ranked lowest and was least helpful to them, whereas empathy carried a more positive meaning. Compassion ranked highest, with connotations of love and willingness to perform extra acts of kindness.

Intussusception and rotavirus vaccineIntussusception—a condition as inexplicable as its name—has dogged the progress of rotavirus vaccination ever since the first vaccines were introduced. The latest vaccines carry much less risk, but a study of hospital admissions of infants aged 8 to 11 weeks for intussusception

in the periods before and after the introduction of vaccination in the United States suggests a continuing association (Paediatricsdoi: 10.1542/peds.2016-1082). Cases increased by 46-101% in all postvaccine years except 2011 and 2013 compared with a prevaccine baseline before 2005, in line with an estimated one to five extra cases of intussusception per 100 000 children vaccinated.

Hypoglycaemia during RamadanAlthough the Qur’an exempts ill people from fasting during Ramadan, as many as 50 million devout Muslims with diabetes are thought to join with others in abstaining from food, water, and oral drugs during the hours of daylight for one lunar month (BMJ Global Healthhttp://gh.bmj.com/content/1/2/e000009). A sample of patients with diabetes from a clinic in Islamabad, Pakistan, suggests that fasting carries a 10% risk of experiencing a hypoglycaemic episode; less if a doctor is consulted before the fast.

There’s a coin in my gulletWill it pass? Radiographs of coins in the oesophagus make interesting mementos; they may also help to predict the need for surgical removal or follow-up radiology. A retrospective study from a tertiary hospital in Pennsylvania finds that the average age for coin eating is 2 years (Otolaryngol Head Neck Surgdoi:10.1177/0194599816667039). Coins that are stuck in the lower end of the oesophagus are nine times more likely to reach the stomach and pass through than those in the higher end. Age, type of coin, and length of time in the oesophagus are other important factors.Cite this as: BMJ 2016;355:i5132

A 40 year old woman presented with four weeks of persistent vomiting and reduced urination in the absence of abdominal pain. Examination identified no abdominal masses but a hard mass rectally. Urea was 42.9 mmol/L (reference 2.5-7.8), with a glomerular filtration rate of 4 mL/min/m2. Plain radiography (figure) showed a large bladder

calculus with bilateral ureteric obstruction and hydronephrosis. Patients with bladder calculi can present with acute kidney injury (AKI) without pain or bladder distension in the event of gradual ureteric obstruction. Therefore, in patients with AKI and unusually low renal function but no clinical evidence of obstruction, a large bladder

stone should be considered in the differential diagnosis.Alexander Midgley-Hunt, core trainee year 1 (acute care common stem) Pradep Sundaralingham, specialist trainee year 6, emergency medicine, Accident and Emergency Department, Sandwell General Hospital, Sandwell, UKPatient consent obtained.Cite this as: BMJ 2016;353:i2765

42 1 October 2016 | the bmj

2016;354:i3681 bmj cite this as: education...nirmal vadgama, phd student, institute of neurology,...

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