Playing by the rules – and getting it wrong

Cite this article as:
Tony Long. Playing by the rules – and getting it wrong, Don't Forget the Bubbles, 2020. Available at:
https://doi.org/10.31440/DFTB.29840

Ethics is based in philosophy – the critical evaluation of arguments and assumptions – and therefore is the activity of philosophical reflection about norms and values; right and wrong; good and bad; what ought and ought not to be done. Bluffer’s Guide tip: ethics is Greek and moral is Latin. Talking about ethics and morals is like referring to renal kidneys or cardiac hearts.

Theoretical positions

Two main theories guide ethical behaviour. The most commonly espoused is that of deontology: a principles – or rules-based approach. This has nothing to do with gods (Latin “deus”). It is from the Greek “deon” for duty. Immanuel Kant (1724-1804)not-a-recent-reference defined the Categorical Imperative, a supreme over-riding principle that is never context-dependent, which rules humans absolutely, and which is felt even when defied. It’s like Pinocchio’s Jiminy Cricket. For Kant, the foundation of morality was duty. Acts should be considered good or bad of their own right, regardless of the outcome.

Following the rules

The Beauchamp and Childress schema of respect for autonomy, beneficence, non-maleficence and justice is often adopted. Patients should not smoke (no-one should): it’s hazardous to their health and 50% of smokers will die from a smoking-related illnessinsert-reference-of-your-choice. (This includes the fictitious lady who smoked only 19 a day.) Beneficence requires that we act in patients’ best interests and stop them smoking: confiscating cigarettes and frisking visitors for contraband. At the same time, non-maleficence requires us to prevent the effects of withdrawal that we enforce. If patients refuse to use them, we might have to sneak nicotine patches in under the dressings. Justice requires that we treat all patients equally, not spending too much time stopping the smoking because obese patients need to get on the treadmills and time must be allocated to preventing cake-smuggling. Then respect for autonomy requires that patients decide for themselves whether or not to smoke (or eat too much). There’s the rub.Hamlet, nd.

Rules-based approaches are difficult because the rules or principles conflict. Increasingly more conditions (formally known as “ifs and buts”) have to be introduced to make it work. Ifs and buts bring with judgements based on circumstances, so the rules are no longer universal and rigid. Judging what action to take based on guidance (rules that have to be interpreted) and on circumstances is more often known as a consequentialist stance. Discworld fans might recognise this as Commander Vimes’ “dealing with what is in front of you” approach:try “Night Watch” something that will be familiar to all senior clinicians.

Considering the outcome

An alternative, also not without its critics, justifies actions by expected outcomes. Jeremy Bentham (1748-1832) and John Stuart Mill (1806-1873) were the classic sources of consequentialist or utilitarian theory: that to act morally, we should try to bring about the best consequences. Sometimes, telling lies is right (“Is this spot really noticeable?”), and sometimes, judgement is needed to decide between opposing actions. In health care, possible outcomes are often not clear-cut. Complexity and differing viewpoints make judgements difficult.


Ethical decisions in research

Ethical decision-making in research is just as difficult. When to stop a trial because of side effects or because the results are obviously fabulous, whether we can deceive participants for the greater good, and how informed participants need to be can all be problematic. The opt-out article is a discussion of a decision made about informing potential participants and ensuring that they have given valid consent for data to be collected in a research study in paediatric urgent care departments. 

Since the bureaucracy never retreats, the content of participant information sheets (PIS) continues to grow. Required items are added, but nothing is ever removed. A 20-page PIS is perfectly normal for a drug trial. Four pages will often be required even for an innocuous survey. GDPR regulations have added one or two pages of the densest and opaque text for those of standard (ie: low) reading age. You don’t read two pages of small print before signing a new mobile phone contract.No-you-don’t! There is evidence that participants don’t read PIS, either, so they are not informed before signing up. There is something odd, too, about requiring the person who is to be protected to sign the researcher’s consent form. The participant’s signature actually protects the researcher by evidencing that consent was sought.

In the study, we adopted opt-out consent in which brief information (one side of A4 in large print and low reading age) was provided, and parents or young people would sign only to indicate a refusal to participate. (This last sentence has a Gunning-Fog readability index of 21.5. Anything above 12 is hard for most people to read!)Years of experience in research with young people has taught us that they will not read more than a paragraph before making a decision, and they will decide immediately, refusing a cooling-off period.

Since that study, incorporation of GDPR into English law has led (in good faith and with appropriate professional concern) to the banning of opt-out consent in NHS research by the Health Research Authority and therefore by the National Institute for Health Research, applying the rule that “active consent” is compulsory. We argue that this is based on the false assumption that opt-out consent implies a lack of information and lack of a decision by participants. The brief information that we supplied had a better chance of being read than a standard PIS, so participants may have been better informed than usual. Parents made a decision for their child’s clinical data to be included and did so by not completing the contact details on the reverse of the form. 


Applying a blanket rule like this can damage recruitment to very large studies, may lead to participation without effective information, and places a greater burden of time on participants which is not commensurate with the risks of participation. The law must be obeyed, but what if the law has been misinterpreted? What if the rule brings about worse outcomes? See what you think.

Tillaux fractures

Cite this article as:
Tadgh Moriarty. Tillaux fractures, Don't Forget the Bubbles, 2020. Available at:
https://doi.org/10.31440/DFTB.26111

Jenny is a 14-year-old girl who was at soccer training when she had an awkward injury to her left ankle. She was running for the ball when her foot caught in a clump of grass and she externally rotated her leg while her foot remained planted. While the pain was instantaneous, there was very little swelling. Her father has brought her in remarking that ‘it’s probably just a sprain’. But as you call her down to the cubicle to examine her, you think there might be more to it.

Incidence

Tillaux fractures are a type of ‘transitional’ ankle fracture which occur almost exclusively in adolescents. These occur during the unique closure pattern of the distal tibial physis. This closes over an eighteen-month period; first in the middle, then medially and finally laterally. During the closure, this area is vulnerable to these distinctive transitional fractures; the triplane fracture and the Tillaux fracture.

These fractures account for roughly 3% of paediatric ankle fractures. They are seen more commonly in females and tend to occur at slightly different ages depending on gender. It tends to occur later than a triplane fracture; between 12-14 years in girls and 15-18 years in boys.

Mechanism

This Salter-Harris 3 fracture occurs at the anterolateral distal tibial epiphysis. It tends to cause avulsion of the tibial fragment by the tibiofibular ligament; this strong ligament extends from the anterior aspect of the lateral distal tibial epiphysis to the anterior aspect of the fibula. The lack of a fracture through the coronal plane distinguishes this injury from that of a triplane fracture.

This injury pattern occurs usually through a combination of supination and external rotation of the foot in relation to the leg. It usually occurs through low-velocity trauma for example in skateboard accidents or sports with a sliding injury.

Presentation

These injuries are almost exclusively seen in adolescents. Similar to most ankle injuries there will be a history of trauma, symptoms of pain, swelling, and an inability (or painful) weight-bearing.

The clinical exam often reveals localised tenderness to the anterior joint line. This contrasts with a sprain where the tenderness is usually below the joint line. Marked displacement is prevented by the fibula.

Imaging

Do not be misled by lack of swelling – have a low threshold to image injuries which present with an inability to weight bear (at least four steps). When requesting an ankle x-ray AP and lateral views will be included as standard – if you have a high index of suspicion for a Tillaux fracture ask for an oblique or ‘mortise’ view – this can improve your detection by avoiding the obstructed view through the fibula and potentially making the subtle fracture more apparent.

This injury can sometimes have an associated ipsilateral tibial shaft fracture or a proximal fibular injury. During your clinical exam if you illicit tenderness proximal to the ankle, then include a full-length tibia/fibula x-ray with your request.

Does this injury require a CT? Perhaps! See the controversy section below for a more thorough explanation. CT is generally only required by the orthopaedic team to assist with surgical planning.

Image courtesy of Orthobullets.com

Image showing CT scan of same fracture with >2mm displacement courtesy of Orthobullets.com

This injury however often requires a CT scan to assist the orthopaedic team in deciding between conservative and operative management.

A study by Horn et al showed CT as being more sensitive than plain film at detecting fractures with greater than 2mm displacement (the cut-off point adopted for operative fixation).

Treatment

These fractures are important as they involve the weight-bearing surface and can lead to significant morbidity if missed. The treatment of these injuries is not uniform – different methods and cut-offs are described in different case reports and case series. Having that said the current marker for operative versus conservative treatment is the degree of displacement of the fracture fragment.

Those with < 2mm displacement can generally be treated conservatively. This usually involves an above-knee cast for up to 4 weeks (to control the rotational component) followed by either a walker boot or below-knee cast for a further 2-4 weeks. This conservative approach is well documented in having a satisfactory outcome.

Those with displacement >2mm generally require intervention to ensure articular congruity of the joint surface is restored. Intervention can occur in different forms; some may be suitable for a closed reduction under procedural sedation (or general anaesthetic). Different reduction techniques exist however longitudinal traction while the knee is flexed followed by internally rotating a maximally dorsiflexed ankle seems to achieve greater anatomic reduction. A review by Lurie et al concluded those left with a residual gap of more than 2.5mm led to worse functional outcomes. Therefore post-reduction radiological confirmation should show minimal displacement (the figure of <2mm tends to be favoured in the literature) otherwise operative intervention is required. Many orthopaedic surgeons favour CT as the post-reduction imaging modality of choice and then follow this reduction with serial radiographs to confirm maintenance of the reduction over time.

Operative intervention can involve K-wire insertion, use of lag screws or a novel technique involving percutaneously inserted wires with arthroscopic or radiological guidance. This new technique is seen as less invasive and as-effective but is technically complex and demanding. If this injury presents with a neurovascular compromise or critical skin then emergent surgery is indicated. This is, thankfully, rare.

What to tell the patient

Recovery: Both operative and conservative measures tend to require up to 8 weeks of immobilisation followed by a rehab phase. This phase will vary depending on the age of the patient. Most patients have a good outcome with 86% having complete recovery and no sequelae. Very few will have pain or limitation of ankle movement. Late presentation and a non-anatomical reduction will increase the risk of this.

Complications

These are less common than other ankle fractures; delayed or malunion, osteonecrosis of the distal tibial epiphysis, premature growth arrest and compartment syndrome are all very rare occurrences. Early-onset arthritis can occur, those with late presentations or missed fractures are more at risk.

Operative intervention carries the additional (albeit small) risk of physeal damage from direct pressure by blunt instruments and inadvertent damage to the superficial peroneal nerve.

Controversies

Radiological evaluation remains controversial. Plain x-ray usually identifies the transitional fracture, and the degree of displacement. However, CT (ideally with 3D reconstruction) is more accurate in estimating the degree of displacement and fracture separation.

Case courtesy of Dr Yasser Asiri, Radiopaedia.org. From the case rID: 64778

CT can help in identifying the number and position of fragments. The issue of whether CT or MRI alters treatment or prognosis when compared with plain X-ray has not been fully investigated. Limited research has been carried out on whether CT, with its greater accuracy, actually affects treatment or patient outcome. Liporace et al in 2012 found that interobserver and intra-observer agreements about primary treatment plans did not differ significantly between radiography alone and radiography plus CT. This showed that the addition of CT did not actually change the impression about the degree of displacement in each case. This raises the question as to whether CT really alters outcomes despite having perceived greater benefits.

Jenny is found to have significant tenderness about her distal tibia on exam and an x-ray confirms a Tillaux fracture which is minimally displaced. She is placed in an above-knee backslab and referred to the orthopaedic fracture clinic. She is left disappointed that she will miss this season’s matches, but thankfully you didn’t misdiagnose this as a sprain!

References

Orthobullets.com/paediatrics/4028/tillaux-fractures

Wheelers textbook of orthopaedics (updated 2015) Clifford J Wheeless Tintinnali 7th Ed

Tiefenboeck TM, Binder H, Joestil J et al. Displaced juvenile Tillaux fractures: surgical treatment and outcome. Wien Klin Wochenschr. 2017; 129 (5-6):169-175

Rosenbaum AJ, DiPreta JA, Uhl RL. Review of distal tibial epiphysis transitional fractures. Orthopaedics. 2012;35(12):1046-1049

Horn BD, Cristina K, Krug M, Pizzutillo PD, MacEwen GD. Radiologic evaluation of juvenile Tillaux fractures of the distal tibia. J Pediatr Orthopaedics. 2001; 21(2): 162-4

Cooperman DR, Spiegel PG, Laros GS. Tibial fractures involving the ankle in children. The so-called triplane epiphyseal fracture. J Bone Joint Surg Am. 1978 Dec. 60 (8):1040-6

Panagopoulos A, van Niekerk L. Arthroscopic assisted reduction and fixation of a juvenile Tillaux fracture. Knee Surg Sports Traumatol Arthrosc 2007;15:415-417

Manderson EL, Ollivierre CO. Closed anatomic reduction of a juvenile tillaux fracture by dorsiflexion of the ankle. A case report. Clin Orthop Relat Res. 1992 Mar. (276):262-6.

Crawford AH Triplane and Tillaux fractres: is a 2mm residual gap acceptable. J Pediatr Orthop. 2012 Jun;32 Suppl1:S69-73

Schlesinger I, Wedge JH. Percutaneous reduction and fixation of displaced juvenile Tillaux fractures: a new surgical technique. J Pediatr Orthopaedics. 1993;13:389-391

Stefanich RJ, Lozman J. The juvenile fracture of Tillaux. Clin Orthopaedics Relat Res. 1986;210:219-227

Kaya A, Altay T, Ozturk H, Karapinar L. Open reduction and internal fixation in displaced juvenile Tillaux fractures. Injury 2007;38:201-205

Choudhry IK, Wall EJ, Eismann EA. Crawford AH, Wilson I. Functional outcome analysis of triplane and tillaux fractyres after closed reduction and percutaneous fixation. J Pediatr Orthop. 2014;34:139-43

Jennings MM, Layaway P, Schubert JM. Arthroscopic assisted fixation of juvenile intra-articular epiphyseal ankle fractures. J Foot Ankle Surg 2007;46: 376-386

Rockwood and Wilkin’s fractures in children. 6th Edition.2006

Kim JR, Song KH, Song KJ, Lee HS. Treatment outcomes of triplane and Tillaux fractures of the ankle in adolescence. Clin Orthop Surg. 2010 Mar. 2 (1):34-8

Haapamaki VV, Kiuru MJ, Koskinen SK. Ankle and foot injuries: analysis of MDCT findings. AJR Am J Roentgenol. 2004 Sep. 183 (3):615-22

Charlton M, Costello R, Mooney JF et al. Ankle joint biomechanics following transepiphyseal screw fixation of the distal tibia. J Pediatr Orthopaedics. 2005;25: 635-640

Liporace FA, Yoon RS, Kubiak EN, Parisi DM, Koval KJ, Feldman DS, et al. Does adding computed tomography change the diagnosis and treatment of Tillaux and triplane pediatric ankle fractures?. Orthopedics. 2012 Feb 17. 35 (2):e208-12

Lurie B, Van Rysselberghe N, Pennock AT, Upsani VV. Functional outcomes of Tillaux and triplane fractures with 2-5millimetres of intra articluations gap. J Bone Joint Surg Am. 2020;102:679-686

Rapariz AJ, Avocets G, Gonzalez-Herman P, Texas et al. Distal tibial triplane fractures: long term follow up. J Pediatr Orthopaedics. 1996; 16: 113-118.

EMS Feedback

Cite this article as:
Andrew Patton and Andy O'Toole. EMS Feedback, Don't Forget the Bubbles, 2020. Available at:
https://doi.org/10.31440/DFTB.29849

Prehospital practitioners have an ever-expanding role in managing the acutely unwell and injured patient. Despite this large contribution to patient care, the majority of practitioners find it very challenging to followup or get feedback on their management of the patient.

The recent publication of the NEMSMA position paper regarding bi-directional information sharing between hospitals and EMS agencies sparked debate on Twitter about the challenges of EMS Feedback.

Gunderson, M.R., Florin, A., Price, M. and Reed, J., 2020. NEMSMA Position Statement and White Paper: Process and Outcomes Data Sharing between EMS and Receiving Hospitals. Prehospital Emergency Care, pp.1-7.

What was the paper about?

The NEMSMA Position statement and White Paper focuses on the bi-directional sharing of data between EMS agencies and receiving hospitals. The authors looked at the challenges EMS agencies face getting feedback data regarding patient outcomes, propose best practices for bi-directional data sharing and explore the current barriers to data exchange. 

The paper highlights the importance of receiving feedback and patient outcome data for quality assurance and improvement (QA/QI). Among other things, feedback is necessary for EMS providers to determine if clinical diagnoses in the field were correct, if pre-arrival notifications were effective and if the destination choice was appropriate. 

The authors surmise that with confusing and complicated healthcare law, hospitals can be reluctant to “share information due to consequences of unintentional violations” of healthcare law, and fears of liability, many of which are misconceptions.

They report that…

“Many of the commonly held legal concerns preventing data exchange are misunderstandings and unfounded fears. While all regulations and laws need to be adequately addressed, legal issues should not preclude properly conducted sharing of electronic health records for quality improvement.”

Technology also creates a number of barriers to data sharing, in particular poor interoperability between EMS electronic patient care records (ePCR) and hospital electronic healthcare records (EHR). The absence of a universal patient identification value is another significant obstacle.   

The authors reference information blocking and market competition between hospitals as two of the big political and economic barriers which can be among the most challenging to overcome. 

They conclude by recommending a collaborative effort between EMS agencies and hospitals to develop and implement bilateral data exchange policies which would benefit all stakeholders. 

This paper focuses mainly on data sharing at an organisational level, it is very relevant to the difficulties faced by individual pre-hospital practitioners trying to follow-up on patients they treat at a local level. 

Why is this so important?

As discussed in the paper, feedback is an important part of quality improvement. For individual practitioners, feedback is a vital part of the learning cycle. Feedback is essential for us to learn from our mistakes, and to improve our practice.  To improve any performance, it is necessary to measure it. A practitioner that never follows up on a patient’s outcome will be left assuming that their treatment for the presenting complaint was accurate and warranted. They will likely continue to treat the same presentation in the same way in the future because their experience has never been challenged by facts that could have been discovered during patient follow up. 

Without feedback we could be unconsciously incompetent… We don’t know what we don’t know!

What’s the difficulty?

On an individual level, obtaining feedback and patient follow-up is challenging for EMS crews for a variety of reasons. In a local survey of 98 prehospital practitioners in Dublin, Ireland, only 21% of practitioners reported being able to follow-up interesting cases.

With dynamic deployment of EMS Resources, crews might transport a patient to a hospital and not return to that same hospital during their shift. If a crew does manage to find an opportunity to call back to the hospital, frequently the diagnostic work-up may be incomplete, and a working diagnosis still unclear. EDs are busy environments and, understandably, some practitioners may feel uncomfortable stopping a doctor or nurse to follow-up on a previous patient.

Calling back a few days later has its own complications; often there will be different staff working in the department who may not have been involved in the patient’s care. This method may work for the high-acuity resus presentations, but that ‘child with shortness of breath’ whose physical exam you were unsure of, or the child with a seizure who had a subtle weakness… the chances of the Emergency Department (ED) staff remembering their diagnosis or outcome is slim! 

Phoning the ED or ward is a route explored by many practitioners, but is fraught with increasing difficulty due to reluctance of staff to give out patient information over the phone fearing confidentiality issues. 

So how do we address this challenge?

Focusing specifically on providing feedback to individual pre-hospital practitioners, there are multiple potential ways to provide prehospital practitioners with follow-up information and feedback,  but you need to consider what system will work best for your individual department, ensuring patient confidentiality and data security.

The pre-hospital postbox

St. Vincent’s University Hospital is a tertiary referral hospital in Dublin, Ireland with approximately 60,000 annual attendances. Inspired by Linda Dykes and her team’s PHEM postbox at Ysbyty Gwynedd Emergency Department in Bangor, Wales, we set-up the Pre-Hospital Post Box in St. Vincent’s University Hospital Emergency Department in August 2017. 

We engaged local prehospital clinicians and ED consultants to develop an SOP. A postbox was built and mounted by the carpentry department. Using a template from Bangor, a feedback request form was developed.  Finally, the service was advertised in the emergency department, local Ambulance and Fire Stations and we were open for business. 

Prehospital clinicians seeking feedback on a case complete a form and place it in the post-box. The case notes are reviewed by an EM doctor and feedback is provided by phone call. 

To ensure patient confidentiality, feedback is only provided to practitioners directly involved with the patient care. A triple-check procedure is used to confirm this. The practitioner’s pin number on the request form is verified on the Pre-Hospital Emergency Care Council (PHECC) register and against the patient care record. The listed phone number is also verified through practitioners known to us or the local Ambulance Officer. 

Other hospitals use systems providing feedback via encrypted email accounts or posted letters.We elected to use a phone call system, the primary reason was the anecdotal reports that many of our pre-hospital staff don’t have easy access to work email accounts. We also anticipated that a phone call would be more likely to facilitate a case discussion and allow paramedics to ask questions that might arise during the discussion. 

Challenges with this system?

Providing feedback to prehospital practitioners is a very time-consuming and labour intensive job, particularly in hospital systems where the majority of clinical documentation is still paper-based. In our own system, where handwritten ED notes are scanned, radiology, labs and discharge letters are available on-line, and in-patient notes are handwritten physical charts – we’ve found the average time required to collate details for the feedback request is just 9 minutes, with a feedback phone call averaging 5 minutes per call.

To successfully upscale this would require a team of doctors or a rota based system with allocated non-clinical time to answer requests. Alternatively a digital solution allowing paramedics to access the data themselves, or facilitating the physician managing the case to reply directly would make it more feasible but may generate further challenges. 

The ideal, as discussed in the NEMSMA paper, would be an organisational process, with the automatic provision of discharge summaries and test results by hospitals to EMS agencies which would provide useful organisational data, and subsequent feedback to individual EMS practitioners.

GDPR / Data Protection Considerations

Patient confidentiality and data protection are of utmost importance in an EMS Feedback System. The system implemented needs to have robust mechanisms, such as our triple-check, to ensure that feedback is only provided to healthcare professionals directly involved in the patient’s care. 

It is also important that it is compliant with data protection legislation in your locality, such as General Data Protection Regulations (GDPR) introduced in Europe in 2018.  Our EMS feedback system is an important mechanism for us to review the care and treatment provided to patients and allows us to assist pre-hospital practitioners in evaluating and improving the safety of our pre-hospital services, which is provided for in the “HSE Privacy Notice – Patients & Service Users”

Providing EMS Feedback, in its current form, is a labour intensive process but we believe it is a worthwhile initiative. It is greatly appreciated by Pre-Hospital Practitioners and it enables them to enhance their diagnostic performance and develop their clinical practice.

If you’d like to find out more about how to set up a Pre-Hospital Post Box in your ED, have a look at these resources…

Attachments

References

Patton A, Menzies D. Feedback for pre-hospital practitioners: is there an appetite? Poster session presented at: 2017 Annual Scientific Meeting of the Irish Association for Emergency Medicine; 2017 Oct 19-20; Galway, Ireland.  

Gunderson MR ,Florin A , Price M & Reed J.(2020): NEMSMA Position Statement and White Paper: Process and Outcomes DataSharing between EMS and Receiving Hospitals, Prehospital Emergency Care, https://doi.org/10.1080/10903127.2020.1792017 

Croskerry P. The feedback sanction. Acad Emerg Med. 2000;7:1232-8.

Jenkinson E, Hayman T, Bleetman A. Clinical feedback to ambulance crews: supporting professional development. Emerg Med J. 2009;26:309.

Patton A, Menzies D. Case feedback requests from pre-hospital practitioners – what do they want to know? Meeting Abstracts: London Trauma Conference, London Cardiac Arrest Symposium, London Pre-hospital Care Conference 2018. Scand J Trauma Resusc Emerg Med 27, 66 (2019). https://doi.org/10.1186/s13049-019-0639-x  

Patton A, Menzies D. Feedback for pre-hospital practitioners – a quality improvement initiative. Meeting Abstracts: London Trauma Conference, London Cardiac Arrest Symposium, London Pre-hospital Care Conference 2018. Scand J Trauma Resusc Emerg Med 27, 66 (2019). https://doi.org/10.1186/s13049-019-0639-x   

O’Sullivan J. HSE Privacy Notice – Patients & Service Users v1.2.  2020 Feb, Accessed on-line: https://www.hse.ie/eng/gdpr/hse-data-protection-policy/hse-privacynotice-service-users.pdf 


Telehealth vs Traditional Medicine

Telemedicine vs Traditional Medicine

Cite this article as:
Caroline Ponmari, Kausik Bannerjee and Tony Hulse. Telemedicine vs Traditional Medicine, Don't Forget the Bubbles, 2020. Available at:
https://doi.org/10.31440/DFTB.28966

The COVID – 19 pandemic has resulted in significant changes in the healthcare system. In the early stages adult services were overwhelmed with sick patients, whereas it seems that there has been an unprecedented (and rather dramatic) decline in pediatric attendances. Lockdown and advice from the government urged people to stay at home to prevent the spread of the virus. In response we, as paediatricians, were forced to consider making changes in our style of delivering care and clinic services to support children and families.  

Telemedicine was not new before COVID-19 but it has now become a legitimate means of allowing medical professionals and patients to communicate in a virtual clinic setting. We aim to provide high-quality safe care to every patient but it has taken a global pandemic for us to start at scale to harness modern technology so that we can deliver care closer to home and provide a seamless service for our patients and their families. To make the most from advances in technology we must understand the benefits and problems.

Let’s start with the pros

Telemedicine is a game-changer in paediatric asthma. Take the example of a district general hospital with 3300 paediatric attendances with asthma/ viral-induced wheeze in a year, 780 admissions and sees a cohort of 120 re-attenders in paediatric ED. During the pandemic, there were concerns that children would present late for emergency care, and be sicker as a result of this delayed presentation. To addressing this, virtual asthma clinics were started seven days a week.

Then the unexpected happened.

Paediatric asthma attendances to ED reduced by 90%, the chronic attendees, some who were on a high dose of steroids and who would attend ED up to 10 times in a year, also needing PICU, on occasions were nowhere to be seen.

Several factors such as lockdown, change in air pollution levels and handwashing were probably the main contributors.

Virtual asthma clinics also reported a high level of engagement and increased compliance with medications, especially from repeat attenders and teenagers who previously had shown poor compliance. Parents were reported to be very appreciative of the virtual clinics at a time when they felt that getting GP appointments was not easy.

Clinicians and asthma nurses were able to suggest modifications in medications through the virtual clinics, treat exacerbations at home and liaise with primary care for repeat prescriptions. Compliance improved to an extent that a shortage of preventors was reported in the trust. Change in patient and parent specific behaviour due to fears of contacting COVID-19 was thought to have led to increased compliance with medication and contributed to better management of paediatric asthma. 

One frequent ED attender is a four-year old with recurrent wheezy episodes, who normally presents in respiratory distress needing nebulisation and IV medications. After many months, he arrives back to ED in May 2020 and recieves a rapturous welcome from staff. The triage nurse took him straight in, and the doctors and nurses got ready to write up medication. The patient and family were highly gratified with the welcome, but hastened to report that he had come in with a pulled elbow. “So how was the asthma then?”, the ED staff asked all puzzled. “Great”, said the mum, so well controlled, he has not had wheeze for ages, he is taking his preventors every day. The lad made everyone’s day in ED, even the pulled elbow reduced spontaneously.

COVID-19 seemed to be able to address the compliance issue in ways that clinicians and asthma nurses could only dream of. 

Similar experiences were reported from the virtual clinics for paediatric diabetes. Paediatric diabetes consultation is focused on data interpretation, behaviour modification and tweaking of the dosage of medication.

All of this can be done remotely.

Furthermore, children, as it turned out, proved to be a dab hand at uploading data from their glucometers and insulin pumps. This in turn led to greater engagement as children showed their parents and doctors the ropes around tech, giving a sense of ownership and empowerment. The did-not-attend rate became minimal and the compliance improved dramatically.

The virtual endocrine clinic is also working well. Children who present for their initial appointment are best seen in a traditional clinic setting. Subsequently, a vast majority can be followed up virtually with an annual physical assessment. This includes children with problems with growth, thyroid and CAH. However, there will always be a small number of patients who need more frequent physical assessment.

The cons

The inability to examine patients in a teleconsultation has risks. For example, a child with a longstanding goitre can become neoplastic. Physical examination allows the experienced clinician to construct the differential diagnosis based on palpation of the thyroid gland which guides further investigation. This is not possible in a virtual clinic setting.

This is where good old-fashioned traditional medicine comes up trumps. Every consultation and physical examination give clinicians an unique opportunity to address existing clinical issues whilst providing an insight into additional psychological issues that may be lurking beneath the surface, especially in children with diabetes.

The consultation effectively starts as the child walks in, the gait, the facial expression there is clue in every step. Vital signs, which often provide clues to the diagnosis, cannot be recorded in telemedicine. Language barriers add a third dimension to telemedicine, using a third party to add to the mix. There is the risk that the equipment related to telemedicine can fail resulting in interruption or cancellation of the virtual clinic. 

Complaints received in the NHS often relate to the perceived behavioural aspect of clinicians toward patients sometimes even more than medical management. Bedside manner is of importance, body language clues from the clinicians that reinforces that they are actively listening to children and their families thus making the consultation a positive experience. This results in better patient experience and job satisfaction for clinicians. Compassion and empathy are a vital part of the clinician and patient experience, how this would translate in a virtual clinic needs further investigation.

The disparity between equity of access also emerged during the pandemic when virtual clinics became mandatory. Some children only had access to the internet at school and the local library. This caused some logistical difficulty in managing data remotely. A request to social services was made to fund the upgrading of one family’s phone so they could access the digital platform for diabetes education and data transfer. Fortunately, these cases seemed uncommon. 

The UK’s General Medical Council (GMC) provides ethical guidance to help clinicians manage patient safety and risks and decide when it’s usually safe to treat patients remotely. Consent and continuity issues are addressed, additionally, choosing the right patient who is suitable for the virtual clinic is addressed. However, the issues of liability and responsibility are not clear. The UK Care Quality Commission and other national regulators do not provide specific telemedicine polices for healthcare providers.

Some clinicians believe that use of teleconsultation threatens the basics of medicine. Excessive reliance on tech goes against the traditional clinician-patient relationship. We enter an unchartered territory were risks and responsibilities are both unclear and unknown.

The bottom line

The pandemic has given a snapshot on how we can change the way we deliver healthcare. Expectations have changed. We need a system that allows flexibility between telemedicine and traditional medicine and is responsive to clinical needs. It is important not to forget the basics – observing the patient, review of nursing observations, clinical examination, reaching a differential which will then guide the necessary investigations. However, for the right patient, telemedicine can be a safe and cost-effective option.

Caroline Ponmani (Barking, Havering, and Redbridge University Hospitals NHS Trust) 

Kausik Banerjee(Barking, Havering, and Redbridge University Hospitals NHS Trust) 

Tony Hulse  (Evelina Children’s Hospital) 

Metabolic presentations part 2: children and adolescents

Cite this article as:
Taciane Alegra. Metabolic presentations part 2: children and adolescents, Don't Forget the Bubbles, 2020. Available at:
https://doi.org/10.31440/DFTB.28592

Neurological symptoms in a healthy teen

Jane, 14 years old, is brought in by ambulance, unconscious after a 20-minute generalized tonic-clonic seizure at home. She’s wheeled into resus, and while she has a cannula inserted, you take a history from her father. You learn that she has been a healthy child who’s never had a seizure before, with no chronic conditions, no history of drug abuse, no acute illness, and no sick contacts. She’s a vegetarian and enjoys dancing. She’s started a new ‘intermittent fasting diet’ and yesterday hadn’t eaten since brunch. She went to bed early and this morning her mother was woken early by strange sounds coming from Jane’s room and found her seizing on the floor. 

Her primary survey shows that she’s maintaining her airway, is tachypnoeic with oxygen saturations of 98% in air and clear lungs, a normal cardiovascular examination and a GCS of 10, with global hyperreflexia.

This adolescent has an acute onset of neurological symptoms. The differential diagnoses are broad, but her symptoms were precipitated by a new diet that required prolonged fasting. This case is a red flag for a metabolic condition! 

The RCPCH Decreased Consciousness (DeCon) guideline lays out an approach to the child with a decreased conscious level, including differentials, investigations and management (take a look at the DeCon poster and summary guidance). 

You send some bloods and, as suggested by the RCPCH DeCon guideline, you include an ammonia.

Some points to remember

Common things are common: sepsis, CNS infections, intoxication (prescribed and recreational drugs), and primary seizure disorders should all be considered here, but extend your differentials to conditions that can be individually rare but are common as a group: metabolic diseases.

All children presenting with a decreased conscious level, regardless of age, should have an ammonia sent as part of their initial investigation in ED… this could be a case of an undiagnosed urea cycle defect. 

In late onset urea cycle defects, acute metabolic encephalopathy develops following metabolic stress precipitated by a rapid increase in nitrogen load from: 

  • infection
  • trauma
  • rapid weight loss and auto-catabolism
  • increase in protein turnover from steroids
  • surgery and childbirth
  • or other precipitants of protein catabolism.

Adolescents and adults with an undiagnosed urea cycle defect may be completely fit and well, but may have chronic symptoms such as headache, cyclical vomiting, behavioural difficulties, psychiatric symptoms or mild learning difficulties.

They may be selective vegetarians, restricting their protein intake.

Between episodes patients are relatively well. However, acute presentations can be fatal or patients may be left with a neurological deficit.

For more information about cycle urea disorders, check out Metabolic presentations part 1.

The take home

Always send an ammonia in any child presenting with an acute encephalopathy or decreased GCS.

Disorders involving energy metabolism

Next up is Liz, a patient with a diagnosed metabolic disorder.

Liz is a 3-year-old girl from the countryside, who is visiting her grandmother in the city. She has had diarrhoea since yesterday and started vomiting last night. In the last 3 hours, she hasn’t been able to tolerate anything orally. There has been no fever or respiratory symptoms and she is passing urine as normal. Her 5-year-old cousin has similar symptoms. 

Her Grandmother informs you that Liz has MCAD deficiency and her emergency plan was tried at home, without success. Liz is not usually treated at your hospital and you don’t have her chart. Unfortunately, Liz’s grandmother didn’t bring the plan to the hospital. 

Liz looks tired and is mildly dehydrated, but smiles at you. Her heart sounds are normal and her chest is clear. She has increased bowel sounds, a soft abnormal with mild diffuse pain on deep palpation and no masses or organomegaly. She’s afebrile but tachycardic at 165, her capillary  refill time is 3 seconds, and her systolic BP is 104mmHg.

You put in a cannula and measure bedside glucose and ketones. Liz has a hypoketotic hypoglycaemia.

What is MCAD deficiency?

Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is the most common fatty acid oxidation disorder in Caucasians in Northern Europe and the United States. Most children are now diagnosed through newborn screening. In fatty acid oxidation disorders, the body can only partially break down fat.

Let’s recap some basic biochemistry: in prolonged fasting, the body’s normal response is to break down fat to create ketones, as an alternative source of energy. However, children with MCAD deficiency can’t produce large amounts of ketones, so their ketone response is not appropriate to the degree of hypoglycaemia. 

Clinical symptoms in a previously apparently healthy child with MCAD deficiency include hypoketotic hypoglycemia and vomiting that may progress to lethargy, seizures, and coma, triggered by a common illness. Hepatomegaly and liver disease are often present during an acute episode. These children appear well at birth and, if not identified through newborn screening, typically present between 3 and 24 months of age, although presentation even as late as adulthood is possible. The prognosis is excellent once the diagnosis is established and frequent feedings are instituted to avoid any prolonged periods of fasting (Merritt and Chang, 2019).

Children with fatty acid oxidation disorders (medium, long and short chain defects) have typical acylcarnitine patterns. This is one of the reasons acylcarnitines are sent as part of metabolic and hypoglycaemia work-ups.

What is the priority in acute presentations?

Children who have MCADD, like Liz, need extra calories when sick. The most important intervention is to give simple carbohydrates by mouth, such as glucose tablets or sweetened, non-diet beverages, or intravenously if needed to reverse catabolism and sustain anabolism. In Liz’s case, she’s vomiting all oral intake so cannot tolerate oral carbohydrates, so the intravenous route is necessary. 

The key priorities are:

  • Correct hypoglycaemia immediately with 200mg/kg glucose: 2 ml/kg of 10% glucose or 1ml/kg of 20% glucose, over a few minutes. 
  • Treat shock or circulatory compromise with a bolus of 20ml/kg 0.9% sodium chloride. 
  • Give maintenance fluids with potassium once the plasma potassium concentration is known and the child is passing urine. 

Where can you find resources?

The British Inherited Metabolic Disease Group, BIMDG, has specific guidance on their website.

Disorders involving storage of complex molecules

Mike is 12 years old, presenting to the ED with cough and fever. He has been coughing for 10 days, worse progressively in the last 5  and febrile for the last 3 days. He’s been lethargic since yesterday and even when afebrile he looks unwell. His appetite is poor and he has been “sipping some apple juice”. You learn from his mother that he has a condition called Mucopolysaccharidosis (MPS) type I and is receiving treatment with “the enzyme”. Every now and again, “he is chesty and needs to come to hospital”. 

You examine Mike. He’s pink and well hydrated, but looks sick. You notice that he is shorter than an average 12 year old boy, has hand contractures and coarse facial features. 

He has a soft systolic cardiac murmur with good pulse volume. On auscultating his chest you hear creps and rhonchi on the right side. He has mild hepatomegaly and an umbilical hernia. 

His temperature is 37.5ºC, heart rate is132, respiratory rate 30, and oxygen saturations are just 88% in air.

A bit about mucopolysaccharidoses (MPS)

In mucopolysaccharidosis disorders, the body is unable to break down mucopolysaccharide sugar chains. These mucopolysaccharide sugars build up in cells, blood and connective tissue: hence the name, ‘storage disorders’.

In general, most affected people appear healthy at birth and experience a period of normal development, followed by a decline in physical and/or mental function.

As the condition progresses, it may affect appearance; physical abilities; organ function; and, in most cases, cognitive development. 

Most cases are inherited in an autosomal recessive manner, although one specific form (Type II) follows an X-linked pattern of inheritance. 

Specific treatment can be provided via enzyme replacement therapy or haematopoietic stem cell transplantation in the early stages. 

Presently, enzyme replacement therapy is available for MPS I, II and VI and is given as an intravenous infusion either weekly or biweekly, depending on the disease. 

Both enzyme-replacement and haemotopoietic stem cell treatments still have gaps and few clinical trials supporting them. (rarediseases.info; Dornelles et.al, 2014).

What treatment should be started in the ED?

Patients with Mucopolysaccharidosis don’t require any emergency treatment in the ED for their underlying metabolic disease. They are, however, at increased risk of respiratory infections.

Mike is likely to have a community acquired pneumonia and needs to be treated accordingly with oxygen and antibiotics.

References

Adam , HH. Ardinger, RA. Pagon, S. E. Wallis, L. J. H. Bean, K. Stephens, & A. Amemiya (Eds.), GeneReviews® [online book]

Merritt JL,  Chang IJ. Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency.  GeneReviews® [online book], June 2019. Available at  https://www.ncbi.nlm.nih.gov/books/NBK1424/

Genetic and Rare Diseases Information Center (GARD) https://rarediseases.info.nih.gov/diseases/7065/mucopolysaccharidosis 

Dornelles AD et al. Enzyme replacement therapy for Mucopolysaccharidosis Type I among patients followed within the MPS Brazil Network. Genet Mol Biol. 2014

Volcano

Managing Gastro-Oesophageal Reflux Disease

Cite this article as:
Sarah Davies. Managing Gastro-Oesophageal Reflux Disease, Don't Forget the Bubbles, 2020. Available at:
https://doi.org/10.31440/DFTB.29563

Isobel is a 10 week old, exclusively breast-fed, baby girl. She is brought into the Emergency Department with a history of frequent vomiting and poor weight gain. Her examination is normal, but when you ask Isobel’s exhausted-looking mother to put her to the breast, she becomes fractious and fussy, pulling away, arching her back, and taking very little feed at all.  

What are you going to do? 

At face value, this familiar presentation sounds like gastro-oesophageal reflux disease (GORD), although the differential for a ten-week old with vomiting and weight loss is wide.

Gastro-oesophageal reflux (GOR) is …the effortless retrograde passage of gastric contents into the oesophagus, with or without overt regurgitation. 

It is:

  • Physiological, due to low tone in the immature lower oesophageal sphincter
  • Common, occurring in up to 50% infants under 6m
  • Frequent – can happen up to x6/day

Gastro-oesophageal reflux disease (GORD) can be diagnosed clinically when GOR is accompanied by troublesome symptoms that affect everyday functioning (eg crying, back-arching, food refusal) and may lead to complications (eg failure to thrive).

Alternative diagnoses should be considered when there are additional red flag features (see below) indicative of a different pathology and under these circumstances, investigations should be tailored to rule these in or out.

*Some red flags overlap with symptoms directly related to GORD. The number, duration and severity of these should inform your decision to investigate on a case by case basis

As Isobel has symptoms of GORD with faltering growth you check her head circumference (which is appropriate), dip a urine (which is negative), and send some bloods for a faltering growth screen (although you strongly suspect they will come back as normal). You explain to Isobel’s mother that there is a stepwise approach to the management of GORD starting with non-pharmacological measures.

So, in the absence of red flag symptoms, do I need to prove its GORD?

In short, no. There is no single gold standard test for the diagnosis of GORD, hence the emphasis on clinical diagnosis. 

Invasive testing does have a place, though it is rarely the job of an ED clinician to be considering this. 

Endoscopy is used under the guidance of a Paediatric Gastroenterologist, for infants who fail to respond to optimal medical management. This will diagnose erosions and eosinophilic oesophagitis. 

pH MII (multi-channel intraluminal impedance) monitoring is used in children whose symptoms persist despite optimal medical therapy with normal endoscopy.   For a great explanation of this technique this previous DFTB post on reflux from 2016

Barium is out. Reliable biomarkers don’t yet exist. Scintigraphy, ultrasound and trial of a proton-pump inhibitor (PPI) are not useful in babies. 

OK, so I only need to investigate if I think there may be another cause for the symptom. But what should be my initial approach to treatment?

  • Positional management?
  • Avoiding overfeeding?
  • Thickening feeds?

Positional management – keeping the baby upright after feeds and elevating the head of the cot to sleep – is often advised for reflux. However, a study by Loots and colleagues in 2014 showed that regurgitation was only reduced through the use of side-lying positions which should NEVER be recommended due to the increased risk of SIDS. Head elevation made no difference at all despite some evidence that it can be beneficial in adults. 

And whilst a common-sense approach would support a move to smaller more frequent feedings and keeping a baby upright for 20-30 minutes after a feed, there isn’t any good quality evidence that confirms this. 

Feed thickeners have been shown repeatedly to reduce the frequency of visible regurgitation episodes in babies with reflux and in some studies to decrease cry/fuss behaviour too. They are safe and come highly recommended as a first-line intervention for babies with troublesome reflux. If you are going to advise a thickener for a breastfed infant, it’s important to suggest a carob bean-based product, such as Carobel, because the amylase in breast milk will digest the rice cereal-based thickeners such as Cerelac.  

Acupuncture, probiotics, massage, hypnotherapy have not yet been adequately studied for us to say one way or another if they are of any benefit. And alginates, probably the most familiar to us being Gaviscon? We’ll cover those shortly.

The key thing to remember for any intervention, is to reserve these for your patients with GORD. Happy, thriving, refluxy babies, typically outgrow their symptoms as they transition to solid food and should be left well alone

OK, but what if my patient has tried these already? What should I advise next? 

First, check how long they have persisted with the intervention. 

One of the biggest reasons for the simpler interventions not to help with GORD is that they are not given enough time to make a difference. Having said that, if a tired parent is repeatedly confronted with a grizzly, uncomfortable baby who is refusing to feed, asking them to persevere for two weeks with an intervention they don’t think is helping, may be practically difficult to achieve. 

In the UK, we have a choice of two key guidelines to help us with the next steps in reflux management.  

  1. NICE, last updated 2019

OR

  1. ESPGHAN/NASPGHAN 2018 joint consensus guidelines which are endorsed and recommended by our own BSPGHAN
  • European Society of Paediatric Gastroenterology, Hepatology and Nutrition
  • North American Society of Paediatric Gastroenterology, Hepatology and Nutrition
  • British Society of Paediatric Gastroenterology, Hepatology and Nutrition

Except that these guidelines differ a little on the advice they give for when simple measures don’t help…

NICE recommend a trial of Gaviscon first, and if that doesn’t work 4-8 weeks of a PPI such as omeprazole, and only then suggest a trial of cow’s milk protein exclusion (either through use of a hydrolysed formula or maternal dairy exclusion in breastfed infants) as a last resort, if reflux does not improve after ‘optimal medical management’. 

NASPGHAN/ESPGHAN on the other hand, suggest that ALL infants undergo an initial trial of cow’s milk protein exclusion, and only if this fails do they suggest the use of a PPI or hydrogen receptor antagonist (H2RA) such as Ranitidine. The bottom line is, that no-one has looked at the efficacy of a cow’s milk protein-free diet for symptom relief in babies presenting with reflux as the single symptom of cow’s milk protein intolerance (CMPI).  

The NASPGHAN team argues, that whilst there is no evidence on the topic, there are a number of babies with CMPI manifesting as reflux only who will benefit from this approach. They suggest eliminating cow’s milk protein from an infant’s diet for a minimum of 2 weeks, ideally four. If symptoms resolve and reappear on reintroduction then the diagnosis is clear. 

NASPGHAN then suggest babies who do not respond should be referred to secondary care services and started on a time-limited trial of PPI. 

This is largely so that infants are not left struggling on inadequate therapy for long periods of time, but also because their review found conflicting evidence around the benefit and side effect profile of these medications for young children. 

In six studies looking at PPI versus placebo, four studies showed no difference in regurgitation or other reflux associated symptoms between intervention and control groups. Three studies comparing H2RAs to placebo did show some benefit of the intervention, however, these studies were all in older children with biopsy-proven erosive oesophagitis up to 8 years of age.  Two studies showed endoscopic and histological and clinical features of GORD were reduced with H2RA over placebo, but these were in mixed-age groups including children up to 8 years old.

All studies showed a similar profile of side effects and between drug and placebo arms, however, one study demonstrated an increased rate of infection, in particular lower respiratory tract infection and diarrhoea in the PPI group. 

Given these findings, NASPGHAN cautiously recommends PPI or H2RA therapy in babies who have troublesome reflux despite trying a number of other non-pharmacological management options. 

Their key message is around early referral to secondary care, giving sufficient time for any one intervention to work, and making sure children are appropriately followed up.

So, what should I do? 

Given the somewhat conflicting advice outlined by these two well-respected groups, you could be left feeling unsure how to manage your next case. However, the genuine gap in the evidence market here does mean you are free to exercise your own clinical judgment and tailor your decision making to each individual refluxy baby, whilst empathetically taking on board the thoughts and preferences of the family.  This could, for some babies and parents, be medicine in itself. 

And what about alginates?

Two studies in the large literature review by the NASPGHAN/ESPAGHN group, compare Gavsicon to placebo. They show a reduction in visible regurgitation but no difference in reflux-associated symptoms. Furthermore, infants treated with alginate and then undergoing pH MII for 24 hours, showed no difference in the frequency of regurgitation events between groups. 

Chronic use of alginates causes constipation and poses a theoretical risk of milk-alkali syndrome, which is perhaps why the authors suggest use is limited to short term therapy. NICE do recommend a trial of Gaviscon therapy at an early stage in their pathway, as an alternative to feed thickener, but again on a time-limited basis with a planned review. 

Isobel’s mother had already tried two weeks of feed thickener on recommendation from the GP with no improvement. She was keen to avoid medication if possible so you agreed to a trial of dietary cow’s milk elimination for Mum who would continue to breastfeed and give top-ups with a hydrolysed formula if there was still no weight gain in a week. You gave her a sheet of dietary advice to ensure she maintained her own calcium intake and asked her to see the GP in 2 weeks for a review.  

Take home message

  • The vomiting infant has a wide differential – actively look for red flag features and investigate if you are concerned.
  • Infants with GORD need a management plan; infants with GOR, leave well alone
  • Start simply with an intervention that the family are happy to trial
  • Give time for it to work (up to two weeks)
  • Ensure follow-up for all and onward referral for infants who require acid-suppressive medication 

References

  1. Loots et al. Body positioning and medical therapy for infantile gastroesophageal reflux symptoms. Journal of Pediatric Gastroenterology and Nutrition 2014; 59 (2): 237-243. 
  2. Rosen et al. Pediatric Gastroesophageal Reflux Clinical Practice Guidelines: Joint Recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition and the European Society of Pediatric Gastroenterology, Hepatology and Nutrition. JPGN 2018; 66(3): 516-554. 
  3. Winter et al. Efficacy and safety of pantoprazole delayed release granules for oral suspension in a placebo-controlled treatment withdrawal study in infants 1-11 months old with symptomatic GERD. JPGN 2010; 50: 609-618.  
  4. Orenstein et al. Multicenter, double-blind, randomized, placebo-controlled trial assessing the efficacy and safety of proton pump inhibitor lansoprazole in infants with symptoms of gastroesophageal reflux disease. Journal of Pediatrics 2009; 154: 514-520e4. 
  5. Davidson et al. Efficacy and safety of once daily omeprazole for the treatment of gastroesophageal reflux disease in neonatal patients. Journal of Pediatrics 2013; 163: 692-698.e1-2. 
  6. Winter et al. Esomeprazole for the treatment of GERD in infants ages 1-11 months. JPGN 2012; 55: 14-20. 
  7. Hussain et al. Safety and efficacy of delayed release rabeprazole in 1-11 month old infants with symptomatic GERD. JPGN 2014; 58: 226-236. 
  8. Moore et al. Double-blind placebo-controlled trial of omeprazole in irritable infants with gastroesophageal reflux. Journal of Pediatrics 2003; 143: 219-223. 
  9. Cucchiara et al. Cimetidine treatment of reflux oesophagitis in children: an Italian multi-centric study. JPGN 1989; 8: 150-156. 
  10. Orenstein et al. Ranitidine, 75mg, over the counter dose: pharmacokinetic and pharmacodynamic effects in children with symptoms of gastro-oesophageal reflux. Alimentary Pharmacology and Therapeutics 2002; 16: 899-907. 
  11. Simeone et al. Treatment of childhood peptic esophagitis: a double-blind placebo-controlled trial of nizatidine. JPGN 1997; 25: 51-55. 
  12. Miller et al. Comparison of the efficacy and safety of a new aluminium free paediatric alginate preparation and placebo in infants with recurrent gastroesophageal reflux. Current Medicines and Research Opinion 1999; 15: 160-168. 
  13.  Ummarino et al. Effect of magnesium alginate plus simethicone on gastro-oesophageal reflux in infants. JPGN 2015; 60: 230-235.