679 CHAPTER THIRTY-FIVE herd immunity in the UK that it is highly unlikely that a child will contract polio if not vaccinated against it. Rubella is classically a mild, self-limiting viral illness. However, vaccination is offered to achieve herd immunity to prevent the teratogenic effects of rubella. The benefits to the individual child receiving the vaccination against rubella are arguably minimal. On the other hand, vaccines are not wholly without risk. Having an intramuscular injection is painful. All vaccines can cause local reactions, which can cause prolonged discomfort. Some vaccines can result in mild flu-like symptoms, including fever. Vaccines can cause anaphylaxis reactions. Some postulated associations, such as seizures and pertussis vaccine, or MMR and autism, have been discredited, with the burden of proof against them. Parents are responsible for taking decisions, including medical decisions, for their children until their children are deemed competent enough to decide for themselves. It is likely that they will take decisions in the child’s best interests. However, (as stated in the Case history above) sometimes this may not be the case. This is accepted in order to protect the interests of the family – a decision may not be in a child’s best interests, but may protect the interests of a sibling, the parents or the family as a whole. If a decision places the child at risk of significant harm, then external agencies (the medical team in an emergency, or more likely the courts, through social services) should intervene. Choosing not to immunize their children cannot be deemed to cause significant harm to their child. For diseases such as pertussis, measles, pneumococcal disease and meningococcal C disease, the child is at greater risk of contracting the disease, though this is difficult to quantify. Not all parental behaviour is fully risk-averse. For example, parents are allowed to smoke, exposing their children to the detrimental effects of passive smoke. In the case of diseases such as polio, where not vaccinating a single child does not confer any increase in risk to the child as long as approximately 95% of the population is immunized, can a parent be forced to vaccinate their child to maintain child immunity for the protection of the community? It is difficult to do so, as it would involve treating an individual for the good of another. This is against Kantian morality, where people should never be treated ‘merely as a means to an end, but always at the same time as an end’. Therefore, in the above case, Henry’s mother cannot be forced to immunize Henry. Nevertheless, the overall benefits and safety of immunization should be reiterated to her again. Answer 35.1 E. Speak to the mother to find out what the circumstances are and if help could be provided to prevent this from recurring. It is common to feel frustrated and upset when it is clear that a child has come to harm as a result of poor care. However, it is vital that clinicians keep calm and exercise judgement before proceeding. Parents may make decisions that are ‘at odds’ with a clinician’s beliefs but are still ethically justified (see discussion about vaccination above). Obtaining more information at this stage in a professional manner is important before proceeding. Question 35.1 The child with asthma Louis, a 6-year-old with known asthma, is admitted to the paediatric intensive care unit following a cardio-respiratory arrest secondary to status asthmaticus. You find out that he has not been using his steroid inhaler for the last month as he had run out of inhalers and his mother did not get a new prescription. Which of the following options is the best course of action now? Select ONE answer only. A. Arrange for an emergency protection order for the child. B. Call the police, as the mother should be arrested for wilful neglect. C. Do nothing, as it is within the zone of parental discretion to withhold treatment. D. Report the general practitioner to the GMC for not realizing that the steroid inhalers had not been prescribed for over a month. E. Speak to the mother to find out what the circumstances are and if help could be provided to prevent this from recurring. Case history Apnoea in a child with spinal muscular atrophy You are called as the paediatric registrar on call to attend to a 3-month-old child, Jack, who has been diagnosed in the last two weeks with spinal muscular atrophy (SMA) type 1. Jack has been brought to the paediatric admission unit with episodes at home where he has stopped breathing. On your arrival, you witness that Jack has got oxygen saturations in the low 90s despite high flow oxygen. He has shallow breathing with up to 10-second pauses between breaths.
35 680Ethics Question 35.2 Ventilatory support in SMA type 1 Jack’s parents do not want him to be intubated as they feel this will lead to pain and distress. What action do you take? Select ONE answer only. A. Discharge Jack home, as there is nothing else you can do for him and it is better for him to be at home. B. Ignore their wishes and intubate him, as you do not think they have had enough time to think about this decision C. Ignore their wishes and intubate him, as you think it is in Jack’s best interests to be ventilated, as without support he will die. D. Involve the palliative care team and discuss with his parents how Jack’s symptom care should best be managed. E. Start high doses of morphine and midazolam so that Jack dies relatively quickly. The nurse looking after Jack is worried and suggests calling the anaesthetists with a view to intubate him. Jack’s parents understand that SMA 1 is a life-limiting condition. They had met with the palliative care nurse a week ago but had not discussed an emergency care plan (see Chapter 34, Palliative medicine). They are upset and do not know what the best course of action is. You understand that SMA 1 is a life-limiting condition, but as this is Jack’s first presentation to the acute ward, you wonder if Jack should be intubated and ventilated. Ethical dilemmas: • Who should decide whether he should be intubated or not? • Would it be ethical to intubate a child with a life-limiting condition? • Would not intubating the child be worse than withdrawing care after the child has been ventilated? SMA is a progressive motor degenerative disease, with type 1 being the severest form. Most children will be diagnosed before 6 months of age and will develop respiratory insufficiency. They are usually cognitively normal, but, due to their motor weakness, are unable to express themselves, including sensations of pleasure or pain. Currently there is no cure. Children with SMA could potentially be ventilated indefinitely and kept alive for months to years before their respiratory function deteriorates with increasing ventilatory requirements. The questions in the above scenario are whether or not he should be ventilated in the acute situation and whether he should be provided with long-term ventilation. Both need careful consideration. The guiding principle is to protect the best interests of the child. This is achieved by acting with beneficence, and limiting actions that are maleficent. Determining the best interests of children is difficult, but more so in children with SMA. They are unable to express feelings of pain with facial expressions or crying like other children. There is a risk that they could be exposed to pain inadvertently without us knowing. Acute intensive care involves invasive procedures such as intubation, physiotherapy and blood sampling. The pain can be minimized using analgesia and sedation, but this reduces patient awareness of all sensations. Long-term ventilation will still require suctioning and physiotherapy. Non-invasive ventilation with a face mask carries the risk of pressure sores. Ventilation via a tracheostomy will need routine tracheostomy care, including tracheostomy tube change and suctioning. Also, he would be unable to suck or swallow, play, or participate in any of the activities that children of a similar age may derive pleasure from. Therefore, long-term ventilated children with SMA type 1 may be exposed to burdens that they may find intolerable, without experiencing the benefits of being alive. Long-term ventilation will require dedicated long-term care, usually from the parents. The principle of justice also requires consideration, as respiratory support both acutely and long-term may use scarce resources in a public health service. Although there is an international expert consensus statement for the management of SMA, this is neither binding nor followed consistently, with differing attitudes in different countries and health systems. The consensus statement recognizes the need for long-term ventilation, but suggests the use of non-invasive ventilation to minimize the need for invasive procedures. As long-term ventilation will require dedicated care by parents and the best interests of the child are difficult to determine, parents should have a say in the treatment choices for a child with SMA. The decision for long-term ventilation needs to be carefully discussed between the family and the medical teams soon after the diagnosis of SMA type 1, preferably in a non-acute setting.
681 CHAPTER THIRTY-FIVE Answer 35.2 D. Involve the palliative care team and discuss with his parents how Jack’s symptom care should best be managed. If it is decided that the child should not be ventilated to avoid the burden that comes with it, then the emphasis of care should be on the alleviation of symptoms for the child. The Royal College of Paediatrics and Child Health guidelines to aid the withholding and withdrawal of lifesustaining care lists five situations where withholding or withdrawing of care can be considered: brain death, the permanent vegetative state, the ‘no chance’ situation, the ‘no purpose’ situation and the situation involving ‘unbearable suffering’. In SMA type 1, the child has no chance of disease-free survival and their symptoms are likely to progress. It is possible that subjecting them to ventilatory support may cause unbearable suffering. Therefore, withholding life-sustaining care can be considered in children with SMA type 1. In an emergency, or if the parents are unable to reach a decision regarding the long-term management of their child, despite discussion with experienced clinicians, the default option would be to provide ventilatory support to preserve the sanctity of life. This would allow his parents time to decide how Jack should be managed long term. Ethically, and legally in the UK, withholding and withdrawing care are viewed as being equivalent. Therefore, if they decide his care should be palliative, care can be withdrawn on the same basis as listed above. Question 35.3 Brainstem death Which of the following answers is correct? Select ONE answer only. Brainstem death testing in Mohammed requires: A. A court order to allow for testing to take place B. Both his parents to be present at the time of testing C. The absence of peripheral pulse D. The absence of a respiratory drive E. Two doctors not directly involved in Mohammed’s care to perform the test Answer 35.3 D. The absence of a respiratory drive. See case history on Mohammed below. Case history Ventriculo-peritoneal shunt You are the registrar on the paediatric intensive care unit. Mohammed, a 13-month-old child, has been admitted from the operating theatre following an emergency ventriculo-peritoneal (VP) shunt revision. He developed hydrocephalus following neonatal meningitis, and needed a VP shunt at 3 months of age. The last 5 days he has been unwell with a slight fever and vomiting. His mother was told that he had gastroenteritis. Twelve hours ago, he presented to his local emergency department as he was unrousable, and had an 18-minute bradycardic arrest while he was about to be intubated. A CT scan of his head showed acute hydrocephalus with evidence of brainstem herniation. After discussion with the paediatric intensive care retrieval and neurosurgical teams, the local team rapidly transferred him to the operating theatre at your hospital. On admission, you note that Mohammed has fixed and dilated pupils. His heart rate and blood pressure are stable but there is little variation. He is on inotropic support and ventilated. The anaesthetist handing over care to you says that his pupils have been unreactive since his arrest. Mohammed’s parents are at the bedside. They are upset, and understand that Mohammed may not survive. They ask you what will happen next. You are worried about Mohammed’s pupils being fixed. You do not think that he is likely to survive. However, his ventilator settings are low and he is only on a small amount of inotropic support with noradrenaline (norepinephrine). Ethical dilemma: • Is Mohammed still alive? How do we demonstrate this? Whether Mohammed is still alive may seem an odd question to ask. Mohammed has a heart rate, you can feel a pulse and he is being ventilated mechanically. He is sedated and paralysed, so it is difficult to demonstrate ‘signs of life’. Intuitively, he is still alive. However, there is no legal definition of death – the law recognizes physicians’ ability to determine death using appropriated codes of practice, currently this is the Academy of Medical Royal Colleges (AOMRC) document A code of practice for the diagnosis and confirmation of death. While the persistence of a heartbeat is commonly felt to be evidence of survival, does this mean that a patient on cardiac bypass or ECMO with no cardiac output is dead? The major pathophysiological issue in Mohammed’s case is the fact that his brainstem seems to have herniated prior to the VP shunt revision, which is likely to have caused brainstem
35 682Ethics ischaemia – the fixed pupils are evidence of this. Without a functioning brainstem, life cannot be sustained without support, i.e. Mohammed is unlikely to breathe without a ventilator or alter his cardiac output without inotropes. To tackle this ethical quagmire, a group of physicians at Harvard Medical School (known as the Ad Hoc Committee of the Harvard Medical School) drew up a set of criteria to define ‘brain death’ in 1968. They defined brain death as an irreversible coma, with no discernible central nervous activity. The criteria consisted of three components: i. Unresponsiveness and unreceptivity: the lack of motor response to a painful stimulus ii. No movements or breathing: no respiratory effort after removal from mechanical ventilation, despite a higher than baseline pCO2. iii. No reflexes, namely the lack of brainstem reflexes, e.g. gag, corneal reflexes, oculocephalic reflexes and pupillary reaction to light. A confirmatory fourth component was a flat or isoelectric electroencephalogram. The Committee recommended that the examination be repeated a second time to allow confirmation, 24 hours after the first instance. In reality, the tests confirm two aspects of loss of brain function – the capacity for consciousness (cerebral cortex dysfunction) and the loss of the capacity to breathe (brainstem dysfunction). In order to determine irreversibility, absence of reversible causes needs to be demonstrated. These include hypothermia; severe electrolyte, endocrine or metabolic disturbances; and pharmacological agents, such as central nervous system depressants (e.g. barbiturates) and muscle relaxants, at significant levels. These accepted tests, performed according to AOMRC guidelines, enable the definition (and confirmation) of human death using neurological criteria (neurological determination of death (NDD)). The criteria have been adopted almost universally, with minor variations. In some countries a confirmatory test, such as an electroencephalogram or cerebral perfusion scan, is mandated (not in the UK). In most countries, the criteria can be adopted for infants above term, whereas in the UK a more conservative approach limits it to children older than 2 months of age (corrected for gestation above 37 weeks). For younger children, an RCPCH working group is currently establishing whether UK practice should be changed. Rather than circulatory or brainstem death, the death of a human is a single entity for which healthcare professionals may use different criteria: either circulatory determination of death (CDD), the method we are more familiar with (no pulse, no breath sounds, with pupils fixed and dilated), or else NDD. For NDD or brainstem testing, the examination needs to be carried out by two doctors, one of them a paediatrician, although there is no longer any recommended time interval between examinations. For Mohammed, NDD evaluation cannot be undertaken, as he is muscle relaxed. He has therefore not been verified as dead and, ergo, ought to be considered as alive! The tests will need to be deferred until there is no ongoing neuromuscular blockade (tested by bedside peripheral nerve stimulation). Also, if Mohammed received significant barbiturates (e.g. a thiopentone infusion), drug levels will need to be measured before NDD. After discussion with the consultant, muscle relaxants are stopped and you explain to Mohammed’s parents that once all the drugs have worn off, a series of tests will be performed to identify the brain activity necessary for Mohammed to survive. If there is no brain activity, he would be certified as having died. Case history Organ donation After speaking to Mohammed’s parents in the case history above, they are understandably distraught. The next morning they ask whether there is any possibility for Mohammed to donate any of his organs – one of Mohammed’s cousins had received a liver transplant a year ago for biliary atresia. They can be informed that this might indeed be possible. You had already informed your local specialist nurse in organ donation (SNOD) about the plan for NDD. In accordance with both NICE and UK Paediatric Intensive Care Society best practice, they will come and see the family shortly and will ‘approach’ the family in collaboration with the consultant to discuss donation. Once the muscle relaxant and other drugs have worn off, the consultant and another independent senior colleague each carry out the set of brainstem tests. Unfortunately, Mohammed has no motor responses, no spontaneous respiratory effort despite prolonged ventilator disconnection and no intact brainstem reflexes. He satisfies brainstem criteria and is verified as dead, the time of death being when the first set of tests was completed. His parents have very kindly agreed to organ donation. There is a wait for a few hours for the theatres to be set up for the organs to be harvested. Ethical dilemma: • Is it ethical to continue intensive care after a patient has been declared dead? Again, this exposes the ethical problems relating to defining death. Some philosophers have
683 CHAPTER THIRTY-FIVE questioned whether brain death criteria were formulated to redefine death for the purpose of making more organs available for transplant. The Harvard Committee identified both the need for organs for transplant and the scarcity of intensive care resources in their introduction to the definition of brain death. However, there is no explicit reference to either being their motivation in drawing up the criteria for brain death. There is often a period of time between completing NDD and organ donation. This can be used to optimize organs for transplantation, but if the child is dead, is it ethical to continue intensive care beyond this point? Once again, according to Kant, a person should never be treated purely as a means to an end. In this case, continuation of intensive care is for the sole purpose of facilitating organ donation. In practice, the care of organ donors is more than maintaining them in status quo; in order to optimize the function and quality of donated organs, additional treatment may be needed. Common problems in brain-dead patients include diabetes insipidus, hyperglycaemia, cortisol insufficiency, disseminated intravascular coagulopathy and shock. One can argue that the dead cannot be harmed by their body being maintained on organ support. On the other hand, intensive care beds are scarce; what if the last available bed is being occupied by a dead patient? However, the consequentialist argument is surely stronger – Mohammed’s organs and tissues are likely to benefit more than one other person. Continuing organ support for a few extra hours leads to more overall good than discontinuing care immediately. Also, organ donation is an altruistic act, with donation reflecting the wishes of the deceased or their family. Therefore, it is also assumed that someone who wanted to be a donor when they die would have been willing to have their body maintained on a ventilator following NDD to facilitate donation. This can be difficult to argue in children, but parents, as proxy decisionmakers, can act with the same altruistic motive if that is in the child’s best interest, although that child is now, of course, deceased. Cadaveric organ donation is also possible using donation after circulatory definition of death (DCDD). Prior to the introduction of ‘brain death’, all cadaveric organ donation was from donors whose heart had stopped beating. Initially termed non-heart-beating donation, the more correct DCDD is now preferred. The limitation with DCDD is the degree of organ ischaemia occurring during both the dying process and between death and organ harvesting, compared with donation after neurological determination of death (DNDD), where organs are harvested from an intact circulation. Most dying patients are unsuitable donors, but following elective cessation of life-sustaining therapy (LST) in the intensive care unit, DCDD can be considered in cases where care is being withdrawn under planned circumstances, where an NDD donor waiting for organ harvest has a circulatory arrest prior to disconnection from the ventilator or, very rarely, if a patient suffers an arrest in intensive care and is not amenable to resuscitation, but retrieval can be organized rapidly. The main ethical consideration in DCDD is that the decision to withdraw LST must be made in the child’s best interests before any consideration of donation. The major ethical controversy is determining the interval between when the circulation stops and death can be verified and when organs can be harvested. In the UK, this currently follows 5 minutes of uninterrupted asystole, though there have been attempts in the USA to introduce shorter intervals. This takes us back to what is rather a fundamental ethical rather than clinical question – what and when is human death? (See Truog and Miller 2008.) Research ethics Research into child health is crucial to advance the care of children. It must often involve children themselves, rather than relying on extrapolation from adult research. However, the protection that is generally afforded human research subjects, namely the need for fully informed consent, is not directly afforded to children. Whether the requirement for such consent from those with parental responsibility is equally strong protection is unresolved. The abuse of human subjects for medical research in the twentieth century, as well as societal demands, led to the most influential document about human subject research: the Declaration of Helsinki. This remains the overarching standard pertaining to human subject research today. Whilst the Declaration initially mandated that the free consent of the research subject was required – effectively banning research with children – later iterations have facilitated a symbiotic relationship between the researcher and the research participant, which in child health research can often be considered as ‘the family’ rather than the individual child. Clear guidance for the ‘ethical’ conduct of research is offered by many bodies, including the RCPCH, the Medical Research Council and, within the next few years, the Nuffield Council of Bioethics, following extensive consultation involving all interested parties.
35 684Ethics advocate the use of ‘assent’ forms (agreement in principle prior to formal consent) and this is recommended in the Declaration of Helsinki, there is no legal basis for their use in these trials. In non-CTIMP research, there are no legal standards or case law, though again there is helpful guidance from the GMC and the Royal College of Nursing. The law in this context arguably defines a minimal standard, and children have an absolute right under the UN Convention of the Rights of the Child to be informed about their healthcare and this is pertinent to participation in healthcare research. Previous concepts, such as therapeutic research (i.e. which directly affects the treatment an individual child receives) and non-therapeutic research (that will not directly benefit the child involved), have largely disappeared. Once-contentious research issues, such as ‘non-therapeutic’ CT scans or anaesthesia for children, are now considered in studies to which parents can consent. However, some ethical experts are concerned that researchers now have almost unfettered access to vulnerable children. These issues are fortunately being addressed in the UK with the admirable work of the Medicines for Children Research Networks (MCRN), which has led to a collaborative relationship between research teams and children and their families. Involvement of children in research is also considered in Chapter 37, Clinical research. Summary In this chapter, we have provided a definition for medical ethics and have outlined the various theoretical and practical frameworks for making ethical arguments. Through a series of vignettes, we have highlighted some ethical questions that we face in paediatric medicine. Any, and all, aspects of paediatric practice contain an ethical component. Whilst we might easily perceive ethical dilemmas in complex and challenging scenarios, such as in the cases described above or in research, most ethical issues arise in the day-to-day care of children. Further reading Academy of Medical Royal Colleges. A code of practice for the diagnosis and confirmation of death. <http:// www.aomrc.org.uk/doc_view/42-a-code-of-practice-for-thediagnosis-and-confirmation-of-death>; 2008 [accessed 08.09.15]. An NHS Foundation Hospital v P [2014] EWHC 1650 (Fam). Brazier M, Cave E. Medicine, patients and the law. 5th ed. London: Penguin Law/Medicine; 2011. Brierley J, Larcher V. Cui bono? Can feminist ethics show a path in complex decision-making where ‘classical’ theories cannot? Clin Ethics 2011;6(2):86–90. In the UK, the current process of ensuring ethical acceptability for research is the mandatory research ethics committee review of all patient/human subject research in hospitals. These committees operate under the auspices of the Health Research Authority (HRA), and are independent of the institutions with which they were previously associated. They are composed of expert and lay members, and specific experts if required, e.g. in qualitative research or specific paediatric expertise. Forms for completion to lead to review are available on the HRA website, as is advice and information on how to complete a ‘good application.’ Many of the challenges for paediatric researchers regarding research ethics review are not complex questions of the ethical acceptability of a study. Instead, they more often involve not completing forms in lay language as requested, providing unclear ageappropriate information sheets for child participants and parents and inconsistencies about the study protocol. For studies with material ethical concerns, the chair of a committee, the ‘paediatric expert member(s)’ for paediatric flagged committees and the Health Research Advisory Panel are readily available for advice. Research with ‘no material ethical issue’ can undergo proportionate review within weeks of application by a research ethics committee – usually electronically – and can be given a rapid favourable opinion. Other research is reviewed formally by the committee, a meeting to which the research team is invited. If possible, it is wise to attend, as matters that can take weeks of correspondence can often be dealt with rapidly. Research ethics committees look for age-appropriate child as well as family participant information sheets, with clear explanations of vital facts about the study – such as the reason for the study, time course and practical aspects of participation and a clear consent form for all aspects of the study and options to withdraw. Once a favourable opinion is reached, sometimes after a provisional opinion and alterations as requested, the study can proceed, subsequent to other authorizations as guided by the local research and development office of the institution. This is a separate process from the research ethics review. For clinical trials of investigative medicinal products (CTIMPs) or medical device trials, this might involve the Medicines and Healthcare products Regulatory Agency (MHRA). Consent for paediatric research studies can be confusing, as it is distinct from consent in clinical practice. The law regarding consent for CTIMPs is clear. The Medicines for Human Use (Clinical Trials) Regulations 2004 (SI 2004/1031), implementing the European Clinical Trials Directive, came into force in 2004 and, although subjected to a series of amendments, remains in place. Regarding children, those with parental responsibility give consent. Though many
685 CHAPTER THIRTY-FIVE General Medical Council (GMC). Consent to research: research involving children or young people. <http://www.gmc-uk .org/guidance/ethical_guidance/6469.asp>; 2013 [accessed 08.09.15]. Gillick v West Norfolk and Wisbech Area Health Authority [1985] 3 All ER 402HL. Health Research Authority (HRA). Integrated research application system. <https:// www.myresearchproject.org.uk/>; 2015 [accessed 08.09.15]. Hope T. Medical ethics: a very short introduction. Oxford: Oxford University Press; 2004. Medicines and Healthcare products Regulatory Agency (MHRA). <http://www.mhra.gov.uk> [accessed 08.09.15]. Nuffield Council on Bioethics. Critical care decisions in fetal and neonatal medicine: ethical issues. <http:// www.nuffieldbioethics.org/neonatal-medicine>; 2006 [accessed 08.07.15]. Royal College of Paediatrics and Child Health (RCPCH). Withholding or withdrawing life sustaining treatment in children: a framework for practice. 2nd ed. London: RCPCH; 2004. Truog R, Miller F. The dead donor rule and organ transplantation. N Engl J Med 2008;359:674–5.
This page intentionally left blank
LEARNING OBJECTIVES By the end of this chapter the reader should: • Understand the principles of pharmacokinetics in children • Know the major pathways of drug metabolism in children and how they vary with age • Know about some of the commoner adverse drug reactions that occur in children • Understand the mechanisms by which adverse drug reactions occur in children • Know the principles of safe prescribing • Be aware of the most frequent types of medication error • Understand the pharmacology of some of the commonly used drugs in children • Understand the importance of the rational use of medicines in children 687 CHAPTER THIRTY-SIX Introduction Understanding how the body handles different medicines is important for all clinicians when prescribing medications. For effective and safe prescribing, we need to make sure that we do not under-dose a medication, making it ineffective, but also that we do not give a dose that causes toxic effects. In paediatrics, significant physiological and developmental differences add to the challenges of safe prescribing. The key parameters of clinical pharmacology will be described below and the differences seen in the different paediatric age groups will be highlighted. Pharmacokinetics Pharmacokinetics (PK) describes the course of a drug within the body; this is expressed as the dose given and concentrations in different parts of the body (usually plasma). It includes how it is absorbed, distributed, metabolized and finally excreted. These will each be discussed separately, along with the common equations used. Pharmacokinetics allows us to understand the profile of a drug’s concentration over time and recommend a drug dosing regimen or, when faced with a novel paediatric drug therapy, provides us with knowledge to prescribe safely and effectively. Mathematical formulae are available that describe the inter-relationship between clearance, volume of distribution and elimination half-life. Absorption If a drug is given intravenously, 100% of the dose will enter the blood stream, but for any other route less than 100% of the dose will be absorbed. This is because it must overcome chemical, physical, mechanical and biological barriers; the percentage that enters the systemic circulation is known as its bioavailability. Absorption is the process of drug movement from the site of administration or application into the systemic circulation. It is often reduced following oral administration in the neonatal period. Additionally, in the neonatal period, pH is elevated within the stomach. This increase in gastric pH affects the bioavailability of medicines. This higher gastric pH increases the absorption of weak base drugs such as penicillins and decreases the absorption of acidic drugs such as phenobarbital and phenytoin, which may therefore require a larger oral dose. Fortunately, in sick neonates most medicines are given intravenously and therefore absorption is not usually a clinical problem. For children, there are other developmental changes to drug absorption that occur in different systems. Intramuscular absorption depends on skeletal muscle Elizabeth Starkey, Imti Choonara, Helen Sammons Pharmacology and therapeutics C H A P T E R 36
36 688Pharmacology and therapeutics litres/kg. It is calculated by dividing the amount of drug by the plasma concentration: Volume of distribution L Amount mg Plasma concentration m ( ) ( ) ( = g L) A small volume of distribution indicates a drug is largely retained within the systemic circulation, whereas a large volume of distribution means a drug is well distributed into other peripheral compartments. Water-soluble drugs, such as gentamicin, therefore have a volume of distribution that is similar to the extracellular fluid volume. Drugs that are highly bound to plasma proteins, such as phenytoin, have a low volume of distribution. Differences between paediatric and adult patients stem mainly from the fact that neonates and young children have a higher proportion of body water and lower concentrations of plasma proteins. Knowing the volume of distribution of a drug is useful when determining what loading dose is to be given. This is calculated from the following formula: Loading dose Vd Target concentration Body weight = × × For example, in order to achieve a peak gentamicin concentration of 10 mg/L in a neonate weighing 1 kg, where the volume of distribution is known to be 0.5 L/kg, one would multiply 10 mg/L by 0.5 L/kg by 1 kg. This equates to 5 mg. If some of the drug is already present in the patient, one can subtract the measured plasma concentration from the target concentration in order to calculate the dose that is required. Clearance Total body clearance is the ability of the body to remove a drug from the plasma or blood and is the sum of drug clearances of each organ. For many drugs, this is equal to hepatic clearance plus renal clearance. Renal clearance is determined by the clearance of an unchanged drug in the urine, whereas liver clearance can occur via biotransformation to a metabolite, which is subsequently excreted via the urine, and/or excretion of the unchanged drug into the biliary tract. It is defined as the volume (usually of plasma) that is completely cleared of drug in a given time period. In adults, clearance is therefore described in relation to volume/time (L/hour). In paediatric patients, clearance is also described in relation to body weight (either as L/hour/kg or mL/min/kg). Clearance can be used in conjunction with the target steady state blood flow; neonates have poor muscle bulk and poor muscle density, reducing bioavailability. Percutaneous absorption is enhanced in childhood due to the larger surface area of the skin relative to the body weight, and better skin hydration and perfusion. Young infants and neonates also have increased absorption due to their skin being thin. This increases systemic absorption and therefore potential side effects of topical medications. A historical catastrophic example of this is the topical disinfectant hexachlorophene in neonates, which caused neurotoxicity and death. Developmental changes in pulmonary structure and capacity in young patients may also alter the patterns of inhaled drug absorption (see also Chapter 17, Respiratory medicine). Question 36.1 Volume of distribution Which of the following is true with regards to volume of distribution (Vd)? Select ONE answer only. A. A larger Vd requires a higher loading dose of a drug. B. A large Vd implies a drug primarily resides in the systemic circulation. C. Neonates have a higher Vd with lipophilic drugs. D. Neonates have a lower Vd for hydrophilic drugs. E. Vd equals the total amount of drug in the body multiplied by the concentration found in the plasma. Volume of distribution (Vd) This is not a physiological volume, but rather an apparent volume into which the drug would have to distribute to achieve the measured concentration. The volume of distribution is usually defined in litres or Answer 36.1 A. A larger Vd requires a higher loading dose of a drug. A larger Vd implies good distribution within the tissues and subsequently will require a higher loading dose for a drug to get an adequate target concentration. Neonates have higher body water, therefore they have a lower Vd for fat-soluble drugs and higher Vd for water-soluble drugs (see below).
689 CHAPTER THIRTY-SIX concentration (CSS) to calculate the rate of administration of a drug given intravenously. This is shown in the following equation: Dose rate mg hour Target C mg L Clearance L hour ( ) SS ( ) = ( ) × Or for children, where a dose and clearance are expressed in relation to body weight: Dose rate mg hour Target C mg L Clearance L hour kg ( ) SS ( ) = ( ) × This formula is appropriate for the administration of drugs given intravenously. For example, the maintenance dose of an intravenous aminophylline infusion to achieve a theophylline level of 10 mg/L in a 20 kg child where clearance is 0.087 mg/kg/hour is 10 mg/L × (0.087 × 20) = 17.4 mg/hour. For drugs that are given orally, one needs to take account of the bioavailability as well as the dosage interval between different doses. If a drug is given via regular bolus intervals, the ‘average’ target CSS is used as steady state fluctuates between the peak and trough and the dosing interval (π) is also added into the equation. The maintenance dose can therefore be calculated by the following formula: Maintenance dose Target C mg L Clearance L hour Dosing i SS = × × ( ) ( ) nterval Bioavailability Maturation of renal function occurs during childhood. The maturation process of kidney structure and function is associated with prolongation and maturation of the tubules, increase in renal blood flow, and improvement of filtration efficiency. This knowledge allows us to provide a rational dose schedule for drugs exclusively eliminated via the kidneys. In general, the neonate will need longer dose intervals than the infant to maintain target concentrations. For example, the dose of benzylpenicillin changes from 25–50 mg/kg 12 hourly in a neonate <7 days to 8 hourly in a 7–28-day neonate and 4–6 hourly in children over a month old. Question 36.3 Half-life and elimination of drugs A new agent has come to the market as a treatment for severe pain. It is intended to be given as a single dose rescue treatment. There have been no large studies in children but in the literature its plasma half-life is 12 hours. What percentage of the dose is still in the body after one day? Select ONE answer only. A. 87.5% B. 75% C. 50% D. 25% E. 10% Question 36.2 Half-life and elimination of drugs A new antibiotic, X, has been developed. It has exceptional antimicrobial activity but is toxic in higher doses. The half-life is 2 hours in children. Half-life Half life is a secondary pharmacokinetic parameter and is the time taken for the drug concentration (usually in the plasma) to decrease by half. Therefore, 50% of the dose will be eliminated in one half-life. It is inversely related to the clearance and can be calculated using a drug’s volume of distribution and clearance with the following equation: Plasma half-life Volume of distribution Clearance = 0 693. × (Note: the value 0.693 is the natural logarithm of 2) Answer 36.2 D. 10 hours. See below for discussion. Answer 36.3 D. 25% 50% of the drug is eliminated every 12 hours, therefore 25% left in the body after two half-lives. After how long will 97% of this new antibiotic, X, be eliminated from the child? Select ONE answer only. A. 4 hours B. 6 hours C. 8 hours D. 10 hours E. 12 hours
36 690Pharmacology and therapeutics ate elevation of the steady-state concentration. This is known as zero order or saturated kinetics. Drug–food interactions Interactions between food and drugs can unintentionally reduce or increase the effect of an oral medicine, resulting in potential therapeutic failure or toxicity. Firstly, food intake also impacts on drug absorption by stimulating gastrointestinal secretions, pancreatic hormones, and bile salts (which lower gastric pH), as well as delaying stomach emptying and increasing gastrointestinal transit time. The size and content of a meal, especially those with a high fat content, also play a role and can reduce a drug’s rate of absorption. Secondly, food has the ability to affect a drug’s bioavailability by interaction with the food constituents. A good example is the reduction in bioavailability of tetracyclines following dietary calcium caused by chelation. Food–drug interactions affecting metabolism, distribution or elimination are not very common, apart from interactions with grapefruit juice. Grapefruit juice contains potent inhibitors of the cytochrome P450. CYP3A4, a P450 enzyme, may markedly increase the bioavailability of drugs that it metabolizes, including ciclosporin, midazolam and carbamazepine. Therapeutic drug monitoring Therapeutic drug monitoring (TDM) consists of measuring plasma concentrations of the drug in order to improve its efficacy whilst reducing its toxicity (Box 36.1 outlines criteria for use). TDM is recommended for certain antibiotics, including the aminoglycosides and glycopeptides, in order to reduce potential toxicity. It may be beneficial in patients with poorly controlled epilepsy who are receiving carbamazepine, Half-life can be used to determine the time it takes to achieve steady state and the time for a drug to be completely eliminated. It takes around 3–5 times the drug’s half-life to reach steady state and the same for it to be completely eliminated in constant dosing. Five half-lives is the time required for 97% of the drug to be eliminated (Fig. 36.1). For instance, the t1/2 of intravenous midazolam is of the order of 1.1 hours in 3–10-year-olds, therefore it takes around 3.3 to 5.5 hours to reach steady state. The half-life helps the clinician to establish an appropriate drug dosing interval. When a medication is given every half-life, the plasma concentration will have a twofold fluctuation over the dosing interval (see Fig. 36.1). For drugs with a half-life <6 hours, it is sometimes not practical to give frequent doses, so sustained release formulations are given (e.g. theophylline). In drugs with a very long half-life (e.g. amiodarone), a daily treatment may be appropriate. A loading dose helps to reach the steady state more quickly. The t1/2 of phenobarbital in neonates is 67–99 hours, so without a loading dose it could take 8–20 days to reach a steady state. Although drug half-lives are quoted in the literature, they represent average values mainly in adults and should be used cautiously. The pharmacokinetic principles outlined above assume that the drug follows first-order or linear pharmacokinetic characteristics. This means that the steadystate concentration changes in direct proportion to a drug dose alteration. However, for some drugs, the relationship is more complex. For example, phenytoin saturates the metabolizing enzymes at clinical doses. Subsequent increases in dosing cause a disproportionFig. 36.1 Concentration–time profile of a drug given by continuous and intermittent dosing with a half-life of 11.5 hours. Steady state is reached at 57.5 hours (11.5 × 5 hours). With the intermittent drug dosing, repeated doses increase the peak and trough concentration due to drug accumulation. (From Starkey ES, Sammons HM. Practical pharmacokinetics: what do you really need to know? Arch Dis Child Educ Pract Ed 2015;100(1):37– 43, with permission. © BMJ.) 0 0 12 24 36 Time (hours) 48 60 72 84 96 10 20 30 Concentration (mg/L) 40 50 60 Cmax Cmin Steady state Box 36.1 Criteria for the use of therapeutic drug monitoring (TDM) • Good correlation between serum concentrations and pharmacological effect. • A narrow margin between serum concentrations that cause toxic effects and those that produce therapeutic effects. • Marked pharmacokinetic intra- and interindividual variability. • The pharmacological effects of the drug are not readily measurable. • It provides a rapid and reliable method for the analysis of the drug.
691 CHAPTER THIRTY-SIX addition to minimizing toxicity, one needs to ensure that the individual patient receives a dose that is effective in treating the significant bacterial infection that the patient is likely to be suffering from. TDM for glycopeptides Glycopeptides are another group of antibiotics that require therapeutic drug monitoring and include vancomycin and teicoplanin. They act by interfering with the bacterial cell wall synthesis in Gram-positive bacteria. They bind to the end of the pentapeptide chains that are part of the growing cell wall structure. This inhibits the transglycosylation reaction and prevents incorporation. Vancomycin and teicoplanin are used in intravenous form for the treatment of serious infections caused by Gram-positive cocci such as Staphylococcus aureus and coagulase-negative Staphylococcus. Vancomycin is the main treatment for patients with MRSA infections. It can also be given orally for the treatment of pseudomembranous colitis in the colon, usually caused by Clostridium difficile, which is rarely seen in children. Like aminoglycosides, glycopeptides are nephroand ototoxic and hence require TDM (Box 36.2). Variations in protocol occur throughout different hospitals about how to monitor and adjust vancomycin dosing, and local policies should be followed. Teicoplanin is less toxic than vancomycin but still requires monitoring. Adverse drug reactions due to vancomycin include red man syndrome, characterized by flushing and erythematous skin usually of the upper body and face. This is caused by a non-specific mast cell degranulation and can be avoided with a slow infusion rate. phenytoin or phenobarbital. Interpretation of the plasma concentration of a drug requires details of the time of administration of the drug and time of collection of the blood sample, as well as an understanding of why TDM has been requested. Drug levels should only be taken once the drug has reached its steady state, unless there are concerns regarding toxicity. In general, trough levels measured just prior to drug administration provide accurate interpretation of drug concentrations. Peak levels are less accurate due to individual variability and are reserved for treatments with short half-lives where peak levels are associated with efficacy or toxicity, e.g. gentamicin. TDM for aminoglycosides This class of drug is bactericidal and works by irreversibly binding the 30S subunit of the bacterial ribosome, and interfering with bacterial protein synthesis. Aminoglycosides are mainly used for the treatment of severe Gram-negative infections, with tobramycin and gentamicin having some activity against Pseudomonas infections. Tobramycin is used frequently in children with cystic fibrosis. Gentamicin also works synergistically with β-lactams for the treatment of Gram-positive Staphylococci infections. This is why benzylpenicillin and gentamicin are used in combination for the treatment of group B streptococcal neonatal infections. TDM is essential when using aminoglycosides because of the significant oto- and nephrotoxicity that can occur with these agents. It is thought that toxicity is associated with high trough concentrations. Studies in adults suggest that ototoxicity is more frequent than nephrotoxicity. Ototoxicity has been described following single doses and is thought to occur in 5–10% of adults who receive aminoglycosides. Both prolonged and repeated courses are thought to be risk factors for toxicity. Aminoglycosides used to be given three times daily but current practice is to give them once daily. This larger daily dose produces a higher peak level than the standard regime, which in turn increases the rate and extent of bacterial cell death. It also lengthens the post-antibiotic effect (suppression of bacterial regrowth) without increasing the risk of any drug toxicity. When multiple daily dose regimens are used, as well as a pre-dose (trough concentration), one should measure a one-hour (peak) post-dose concentration. Most hospitals in the UK provide a clinical pharmacy service to help interpret the plasma concentration and give advice regarding dose adjustment. The beneficial effect of discussing management with a clinical pharmacist has been demonstrated. In Box 36.2 An example of how to alter vancomycin doses following TDM Pre-dose (trough) after 2nd–3rd dose: • <5 mg/L – increase frequency if able, if not, increase the dose by 10–20% • 5–10 mg/L – increase dose by 10–20%. • 10–15 mg/L – continue as in therapeutic range (sometimes need 15–20 mg/L in less sensitive MRSA strains – consult microbiology if cultures available) • 15–20 mg/L – reduce dose by 10–20% • >20 mg/L – check trough before commencing and reduce frequency Check electrolytes to identify acute kidney injury.
36 692Pharmacology and therapeutics metabolites with the same therapeutic effect as the parent compound, such as morphine and its metabolite morphine-6-glucuronide. Finally, some metabolites may be responsible for adverse drug reactions. Paracetamol is metabolized to the reactive metabolite N-acetyl-p-benzoquinone imine (NAPQI), which is associated with acute liver injury after overdoses (see below). Phase 1 enzymes The most abundant and best studied phase 1 system is the cytochrome P450 (CYP450) family which consists of at least 56 genes that code for functional enzymes. More than half of all metabolized drugs are subject to CYP450-mediated metabolism. The most common subfamilies are CYP1A, CYP2A–2E and CYP3A/CYP3A4. They are responsible for the metabolism of many drugs, such as midazolam, ciclosporin, fentanyl and nifedipine (Table 36.1). CYP1A2 accounts for 13% of total enzyme activity in the liver. Caffeine and theophylline are metabolized via the CYP1A2 pathway (see Table 36.1). Phase 2 enzymes These are a different set of enzymes and less is known about them. Glucuronidation and sulfation are the two major phase 2 pathways. Examples include UDP-glucuronosyltransferases (UGT), sulfotransferases (SULT) and glutathione-S-transferases (GST). The majority of these encompass large numbers of different enzymes which are differently regulated and metabolize different drugs. The effect of age on metabolism The majority of drug-metabolizing enzymes develop in a different pattern and rate. However, there are three Drug metabolism Most drugs need to be converted into more watersoluble compounds to become inactivated and excreted from the body. This can take place in a variety of sites (e.g. gastrointestinal tract, skin, plasma, kidney, lungs), but most are metabolized in the liver via hepatic enzymes. Two phases of drug metabolism are traditionally distinguished – phase 1 and phase 2. Phase 1 involves altering the structure of the drug, for example oxidation and hydrolysis. The major pathway is oxidation, which involves the cytochrome P450-dependent (CYP) enzymes that are present mainly in the liver. Phase 2 reactions conjugate the drug to another molecule (for example, glucuronidation of paracetamol in older children). Drugs may undergo metabolism and subsequent elimination by a combination of phase 1 and phase 2 pathways (Fig. 36.2). This deliberate simplification of drug metabolism does not imply that only the parent compound itself is active and that metabolites are not. Some drugs are inactive and need to be metabolized to exert their effect; for example, carbamazepine, and enalapril. Other drugs may have Fig. 36.2 Drug metabolism. Drug Oxidation Reduction Hydrolysis Hydration Glucuronidation Sulfation Methylation Acetylation Excretion Phase 1 pathways Phase 2 pathways Answers 36.4 1. F. Oxidation 2. B. Glucuronidation See below for discussion. Question 36.4 Drug metabolism The following (A–H) is a list of drug metabolism pathways: A. Acetylation B. Glucuronidation C. Hydration D. Hydrolysis E. Methylation F. Oxidation G. Sulfation H. Reduction Pick the mechanism from the list described above that best matches the descriptions below: 1. The major phase 1 pathway utilized by cytochrome P450 enzymes in the liver. 2. The major phase 2 pathway responsible for elimination of paracetamol in teenagers.
693 CHAPTER THIRTY-SIX Drug–drug interactions Drug–drug interactions may also result in significant variation in drug metabolism. Several drugs are known to either induce or inhibit enzyme activity. When these drugs are metabolized by the same enzyme, the blood levels of the drug and metabolites may change accordingly. Macrolide antibiotics, proton pump inhibitors and some of the antifungals, such as ketoconazole, are well known drug inhibitors, whereas phenobarbital, carbamazepine and dexamethasone are well-known inducers. Children’s vulnerability to metabolic drug–drug interactions alters as liver enzymes mature and pathways change. However, this does not necessarily mean that younger children are always at higher risk of drug–drug interactions. For instance, if enzyme activity in the neonatal period is low, then an enzyme inhibitor is less likely to have a large impact. Therefore, some interactions seen in adults may not be evident in neonates and younger children. Drug excretion Two organ systems are responsible for most drug excretion: the liver (via bile) and the kidneys (via urine). For many drugs and metabolites, the kidney is the most important route of excretion. The kidney has three physiologic functions: glomerular filtration, tubular secretion, and tubular reabsorption; and elimination of medicines require a balance of these. Drugs vary in where they are primarily eliminated. Some are eliminated by glomerular filtration (e.g. aminoglycosides) with clearance of these correlating well with glomerular filtration rate. Others are eliminated by proximal tubular secretion (e.g. penicillins, furosemide). Tubular reabsorption of drugs also affects total body clearance. Maturation of renal function is a dynamic process that begins during fetal organogenesis, with all physiologic functions of the kidney decreased in newborns (see Chapter 19, Nephrology, for more details). The maturation process of kidney structure and function is associated with prolongation and maturation of the tubules, increase in renal blood flow, and improvement of filtration efficiency. By approximately one year of age, the kidney is functioning at adult levels. Understanding renal development and anatomy is essential to provide a rational dose schedule for drugs that are exclusively eliminated via the kidneys. In general, the neonate will need longer dose intervals than the infant to maintain target concentrations. An example, as described above, is the different dose regimens for benzylpenicillin with age, reflecting the improving renal function and excretion. distinct patterns that have emerged from research studies. Individual enzymes show maximum activity either prenatally, postnatally or throughout development. Within the prenatal pattern, enzyme activity is high in the fetal liver as well as just before and after birth and then it declines. An example of this is CYP3A7. The second group has a postnatal pattern. Here, the levels of the enzyme are low at birth but increase to adult ranges over the next few weeks or months. This is seen in a large number of enzymes, including CYP1A2, CYPC2C, CYP2D6 and CYP3A4. Finally, in the constant pattern, activity remains stable from early fetal life through adulthood; examples are CYP3A5 and SULT1A1. Age-related changes in drug metabolism have a major impact on a drug’s effect. The majority of these are observed in neonates and infants, when typically the largest changes in enzyme activities occur. An important example of this is chloramphenicol. Historically, chloramphenicol was used to treat neonatal infections using adult doses of 12.5–25 mg/kg four times a day. Neonates have immature levels of UGT2B7, which converts chloramphenicol to the excreted water-soluble chloramphenicol glucuronide. Large numbers of babies developed cardiovascular collapse and irregular respiration, and in some cases died; this became known as grey baby syndrome because of chloramphenicol toxicity as a result of this immature metabolism. Consequently, dosing in neonates has been reduced to 12.5 mg/kg twice daily for those under one month of age, and is rarely used in neonates. Table 36.1 Drug metabolism pathways Pathway Drug Oxidation CYP3A4 Carbamazepine Diazepam Erythromycin Fentanyl Midazolam Nifedipine Ondansetron Rifampicin CYP1A2 Caffeine Theophylline CYP2C9 Phenytoin Ibuprofen CYP2D6 Amitriptyline Codeine Selective serotonin reuptake inhibitors Glucuronidation Paracetamol Morphine Sulfation Paracetamol
36 694Pharmacology and therapeutics Disease and drug disposition The metabolism of some drugs is influenced by coexisting diseases. There are some obvious examples. Liver disease will clearly have a big effect on the profile of drugs that are metabolized within the liver and renal disease will affect the clearance of any drug that is eliminated by the kidney. There are some important specific examples: • Certain illnesses, such as cystic fibrosis (CF), can affect drug metabolism. Clearance of most drugs is thought to be higher in children with CF, resulting in higher dosages required to yield a therapeutic benefit and achieve similar serum drug concentrations to children without CF. Tobramycin dosing increases from 2–2.5 mg/kg three times a day to 8–10 mg/kg three times a day to provide optimal bacterial penetration within CF bronchial secretions. • Liver and renal failure can reduce the ability to metabolize drugs and delay the elimination of them. This therefore dictates reduced dosages; for example, reduced dosing of cephalosporins, aminoglycosides in those with severe renal failure. Clinical conditions, e.g. shock and hypothermia have been found to down regulate the liver enzyme. For example, clearance of the CYP3A substrate midazolam is significantly lower in paediatric intensive care patients than in relatively healthy children. Some of the interventions used in the critically ill, such as cardiopulmonary bypass and extracorporeal membrane (Dreifuss F, Santilli N, Langer D, et al. Valproic acid hepatic fatalities: a retrospective review. Neurology 1987;37:329–85.) Recent scientific advances which have changed paediatric clinical practice – identification of drug toxicity A retrospective review of valproic acid hepatic fatalities in the United States identified patients at greatest risk of liver toxicity. Children under the age of 3 years receiving valproate as polytherapy were at greatest risk. Developmental delay and associated inborn errors of metabolism are risk factors. By simply avoiding using sodium valproate as first-line antiepileptic in these children, the risk of hepatotoxicity was significantly reduced. Question 36.5 Jaundice in a 1-year-old with epilepsy Isobel is a 1-year-old child with epilepsy, who has been admitted to the paediatric ward with a threeweek history of lethargy, loss of appetite and vomiting. On examination, she is jaundiced and has grossly abnormal liver function tests. Isobel has a complex medical history with epilepsy and developmental delay. Her seizures have been poorly controlled with a combination of carbamazepine and topiramate, so 8 weeks ago she was started on sodium valproate by her consultant paediatric neurologist in conjunction with the epilepsy specialist nurse. What is the most likely diagnosis? Select ONE answer only. A. Adverse drug reaction B. Autoimmune hepatitis C. Inadvertent valproate overdose D. Intercurrent illness E. Glandular fever oxygenation (ECMO), may also impact on drug metabolism. Drug toxicity The World Health Organization defines an adverse drug reaction (ADR) as ‘a response to a drug which is noxious and unintended, and which occurs at doses normally used in man for the prophylaxis, diagnosis, or therapeutic disease, or for the modification of physiological function’. This is in contrast to a medication error, where the wrong dose of a drug has been inadvertently given or an inappropriate route of administration prescribed. ADRs can be thought of as predictable and unpredictable. Predictable ADRs are known side effects or secondary effects of the drug or can be caused by known interactions with other medications. An example of this would be exaggerated effects of the medicine’s known pharmacological action, which are Answer 36.5 A. Adverse drug reaction. Isobel has developed an adverse drug reaction (ADR) to sodium valproate. Differences in drug metabolism between young children and adults contribute to it. Valproic acid is metabolized predominately by the liver, via conjugation to a glucuronide ester and detoxification via the fatty acid oxidation pathway. The latter has reduced activity in young children. In addition, there is increased activity of some cytochrome P450 enzymes, resulting in greater production of toxic metabolic intermediates. Of course, it is important to check that the doses prescribed are correct, but it is highly unlikely that both the paediatric neurologist and nurse specialist will have both incorrectly calculated the dose required.
695 CHAPTER THIRTY-SIX antiseptic agents, such as hexachlorophene, which have been associated with neurotoxicity in neonates. Protein-displacing effect on bilirubin The sulphonamide, sulphisoxazole, was used as an antibiotic in neonates in the 1950s. It was associated with increased mortality due to the development of kernicterus. Sulphonamides have a higher binding affinity to albumin than bilirubin. Thus, the administration of sulphonamides results in an increase in the free fraction of bilirubin, which crosses the blood– brain barrier and may causes kernicterus, especially if the neonate is ill. In most areas of paediatrics, protein binding is not a significant issue. However, in neonates, especially sick preterm neonates, highly protein bound drugs should be avoided. Impaired drug metabolism As described above, chloramphenicol was associated with the development of grey baby syndrome in neonates as they metabolize chloramphenicol more slowly than adults and therefore require a lower dose. Altered drug metabolism Paediatric patients may have reduced activity of the major enzymes associated with drug metabolism in the liver. To compensate for this, they may have increased pathways of other enzymes. This is thought to be one of the factors contributing to the increased risk of hepatotoxicity in children under the age of 3 years, as illustrated in Question 36.5, above. This increased risk is raised by the use of additional anticonvulsants alongside the sodium valproate, which may result in enzyme induction of certain metabolic pathways. usually dose-dependent, such as opiates causing respiratory depression. Unpredictable reactions are due to an intolerance to the medicine, may be allergic/ pseudoallergic in nature or be completely unexpected (known as an idiosyncratic reaction – see Question 36.5, above). Almost 1 in 10 children in hospital will experience an ADR, of which 1 in 8 will be severe. About 2% of hospitalized children have been admitted following an ADR. Children can experience a wide variety of ADRs. Their management should involve taking a thorough medical history and clinical examination followed by consideration of the differential diagnoses for the presenting symptoms. Suspicion of an ADR is increased when symptoms appear soon after a new medication or dose escalation is introduced, and disappears when the medicine is stopped. Recurrence of the problem when the medication was taken again is helpful in confirming the diagnosis. Children are at risk of specific ADRs that do not affect adults, in whom growth and development are not an issue. Differences in drug metabolism make certain ADRs a greater problem in children (e.g. valproate hepatotoxicity). They may sometimes reduce the likelihood of a problem (e.g. paracetamol hepatotoxicity following an overdose; there is a greater capacity for the sulfation of paracetamol in pre-pubertal children, which reduces the formation of toxic metabolites that cause liver failure following overdose). The mechanisms of ADRs specifically affecting children are illustrated in Table 36.2. Percutaneous absorption The newborn infant has a higher surface area to weight ratio than both adults and children. Percutaneous toxicity can therefore be a significant problem in the neonatal period. Examples of this include the use of (Modified from Choonara I, Rieder MJ. Drug toxicity and adverse drug reactions in children – a brief historical review. Paediatric and Perinatal Drug Therapy 2002;5:12–18, with permission.) Table 36.2 Major adverse drug reactions (ADRs) in paediatric patients Year Drug/compound Age group ADR Mechanism 1886 Aniline dye Neonates Methaemoglobinaemia Percutaneous absorption 1956 Sulphisoxazole Neonates Kernicterus Protein-displacing effect on bilirubin 1959 Chloramphenicol Neonates Grey baby syndrome Impaired metabolism 1979 Sodium valproate Young children <3 years Hepatic failure Abnormal metabolism? 1980 Salicylate Children Reye’s syndrome Unknown 1990 Propofol Children Metabolic acidosis Unknown Dose-related? 1996 Lamotrigine Children Skin reaction Unknown Associated with co-medication with sodium valproate 2008 Ceftriaxone Neonates/infants Precipitation in lung and kidneys Drug interaction Calcium solutions
36 696Pharmacology and therapeutics reported by any healthcare professional or member of the public via this system. All suspected ADRs should be reported, especially if severe/serious. For newer medicines, this is indicated by a black triangle in the BNFc. Prescribing for children Many medicines used in children are not fully licensed for such use. Analysis has shown that approximately a third (36%) of children on general paediatric wards and most (up to 90%) of babies on the neonatal unit will receive an unlicensed or off-label medication during their stay. This is usually because the pharmaceutical company has not asked for a licence from the regulatory authorities in any indication in a child or young person. An example of this would be TPN, as it is made individually (or the standard doses are altered) for each individual. In addition, many medicines given to children are off-label, i.e. used at a different dose or route than specified within the product licence or for a different age or different indication. In many cases we prescribe in this way almost every day for children. An example of this would be diclofenac given for pain, as it only holds its licence for the treatment of juvenile idiopathic arthritis in children. Sometimes doses given are well beyond the licensed dose. For instance, inhaled salbutamol is licensed at doses of 100–200µg via a spacer but paediatricians commonly use much higher doses during acute asthma attacks (up to 10 puffs, which is 1 mg). The RCPCH recommends choosing the medicine for which there is the greatest amount of evidence to justify its use and a licensed form of a medicine is always recommended to be prescribed. The BNFc uses current evidence and the opinions of experts in the field to justify its doses, although the level of evidence is not given in the text. When a dose, for the age group in which it is being prescribed, is given in the BNFc, most paediatricians would not directly discuss the licence with the parents. Provision is given in law for doctors to prescribe, pharmacists to dispense and nurses to administer unlicensed and off-label medicines. Since the introduction of the European Paediatric Regulation in 2007, all new medicines have to be tested on children (when judged appropriate by the Paediatric Committee). This is a carrot and stick approach. The carrot being one year’s marketing extension for the drug in all ages and the stick being that a licence will not be issued in adults until a paediatric plan has been agreed. The regulation also contains legislation for older medicine (Paediatric Use Marketing Authorization (PUMA)), where ten years of marketing exclusivity is given to a company for their paediatric formulation. To date, only one medicine has been through this process, buccal midazolam. Drug interactions Skin reactions to the anticonvulsant, lamotrigine, are more likely to occur in children than in infants. The incidence is significantly increased by co-medication with sodium valproate alongside the lamotrigine. The mechanism of this drug interaction is unknown. A drug interaction between intravenous calcium and ceftriaxone has been reported in neonates and young infants. Neonatal deaths were documented when ceftriaxone and calcium-containing fluids or drugs were given together or using the same intravenous line. There was evidence of crystalline material in the renal and pulmonary vasculature in some of these neonates at postmortem. Ceftriaxone can also contribute to biliary sludging and kernicterus in neonates, and therefore is contraindicated in premature infants, full-term infants with jaundice and in any child receiving calcium, most often seen in emergency resuscitations and PICU. Unknown mechanisms There are several examples of major ADRs that occur in children for which we do not understand the mechanism. Salicylate given during the presence of a viral illness will predispose children of all ages to develop Reye’s syndrome, an acute non-inflammatory encephalopathy accompanied by fatty infiltration of the liver. By avoiding the use of salicylates in children with viral infections, the incidence of Reye’s syndrome has been dramatically reduced. Propofol is a parenteral anaesthetic agent with minimal toxicity when used to induce general anaesthesia. Used as a sedative in critically ill children, however, it has been associated with the death of over 10 children in the UK alone. The propofol infusion syndrome is thought to be related to the total dose of propofol infused, i.e. high dose or prolonged duration is more likely to cause problems. Fetal toxicity The majority of medicines used during pregnancy do not result in harm to the fetus. Both health professionals and pregnant women usually overestimate the risk of drug toxicity associated with the use of medicines during pregnancy. Thalidomide, prescribed for morning sickness during pregnancy, however, is an example of how a drug that is relatively safe in adults can result in significant harm to the fetus (phocomelia) when it is given during a critical stage in pregnancy (24–27 days). The drug that is most likely to be associated with fetal toxicity at present is alcohol, which may result in fetal alcohol syndrome. Suspected ADRs should be reported to the regulatory authorities by using the Yellow Cards at the back of the British National Formulary for Children (BNFc) or online at www.mhra.gov.uk/yellowcard. They can be
697 CHAPTER THIRTY-SIX Medication errors Medication errors are a significant problem in paediatric patients. A review of press reports of medication errors described 29 deaths of paediatric patients in the UK over a period of 8 years (Table 36.3). Many health professionals will commit a medication error at some stage in their career and systems have been introduced to try to minimize their occurrence and impact. Incorrect dose has been found to be the most frequent type of prescribing medication error, and is also the type of error most likely to be associated with a fatality. This is because tenfold errors are a particular problem in both neonates and children. It is vital, therefore, to make sure when prescribing that you have an accurate record of the child’s weight. Dose calculations, especially on the neonatal unit and when using parenteral medicines, require careful checking. Prescription of the incorrect drug is the second most common type of medication error and is also associated with significant fatalities. This is particularly likely when drugs have similar names and great care should be taken when you are unfamiliar with a drug name. Incorrect route is a potential problem with intrathecal drugs, and great care is required for medicines administered via this route. Box 36.3 summarizes the measures that should be taken when a medication error occurs. Commonly used medications Having some understanding about the pharmacology of drugs commonly used in children is essential for (From Cousins D, et al. Medication errors in children – an eight-year review using press reports. Paediatric and Perinatal Drug Therapy 2002;5:52–58, with permission.) Table 36.3 Types of medication error reported in the press that occurred in children in the UK (1993–2000) Type of medication error Number Fatal Incorrect dose 32 13 Incorrect drug 16 5 Incorrect strength 3 1 Omitted in error 4 1 Incorrect patient 4 – Duplicate dose 3 – Expired drugs 3 – Incorrect route 3 3 Incorrect container 2 1 Incorrect label 2 – Incorrect rate 2 2 Miscellaneous 6 3 TOTAL 80* 29 *Six children experienced more than one error each. Question 36.6 Medication error Following discovery of a medication error, which of the following is mandatory (true) and which is not (false): A. A critical incident form should be completed B. A Yellow Card must be completed C. The doctor responsible should have a disciplinary proceeding commenced D. The nurse responsible should have a disciplinary proceeding commenced E. The responsible consultant should be informed (McIntyre J, Robertson S, Norris E, et al. Safety and efficacy of buccal midazolam versus rectal diazepam for emergency treatment of seizures in children: a randomised controlled trial. Lancet 2005;366:205–9.) Recent scientific advances which have changed paediatric clinical practice – trial of seizure management The emergency management of seizures in children was changed by the randomized controlled trial comparing buccal midazolam versus rectal diazepam. Rectal diazepam used to be standard treatment. Buccal midazolam was more effective then rectal diazepam for terminating seizures. Buccal midazolam is now accepted as standard treatment for acute seizures. Answer 36.6 A. True; B. False; C. False; D. False; E. True. A Yellow Card should be completed in the event of an adverse drug reaction but not in the event of a medication error. Whilst the consultant responsible should be informed and a critical incident form should be completed, disciplinary proceedings are not usually required. It is important to learn from errors whenever possible (see below). Most medicines can be taken by a breastfeeding mother and will not cause a significant problem to the infant. One should not discourage mothers from breastfeeding because they are uncertain of possible toxic effects. Formularies such as the BNFc give detailed information regarding which medicines to avoid during breastfeeding. A thorough history should also be taken of all over-the-counter medicines and herbal/alternative medicines that may contain active ingredients.
36 698Pharmacology and therapeutics latter mechanism produces a highly toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI), which requires conjugation with glutathione to form a nontoxic metabolite that can be excreted. When large amounts of paracetamol are ingested, for example with a paracetamol overdose, glucuronidation and sulfation pathways become saturated. Glutathione stores become depleted, resulting in excess quantities of NAPQI resulting in hepatotoxicity. The treatment of paracetamol poisoning, N-acetylcysteine, increases the glutathione stores so that the buildup of NAPQI can be conjugated and excreted. In neonates, there is both immaturity of glucuronide conjugation and CYP2E1 metabolism with compensatory increases in sulfation pathways. This immaturity of the CYP2E1 pathway produces less NAPQI, explaining why neonates have a decreased likelihood for paracetamol hepatotoxicity. Non-steroidal anti-inflammatory drugs Non-steroidal anti-inflammatory drugs (NSAIDs) have numerous actions in vivo and are commonly used to treat pain, inflammation and fever. Ibuprofen is the commonest NSAID used in children. Stronger NSAIDs, such as diclofenac or naproxen, are mainly used in inflammatory conditions such has juvenile idiopathic arthritis. Inflammation NSAIDs inhibit cyclo-oxygenase, the enzyme that transforms arachidonic acid to prostaglandins and thromboxanes. There are two forms: COX-1 and COX-2. Selective COX-2 inhibitors, e.g. celecoxib, have fewer gastrointestinal side effects than the nonselective NSAIDs such as ibuprofen and diclofenac. Analgesia NSAIDs have a more marked effect on pain, resulting from the increased peripheral sensitization which occurs from inflammation. Antipyretic NSAIDs exert their antipyretic effect by inhibition of prostaglandin E2 (PGE2) synthesis, which normally triggers the hypothalamus to increase body temperature during inflammation. (See also the section on fever in Chapter 3, History and examination). Opioids All opioids produce their actions at a cellular level by activating opioid receptors. These receptors are distributed throughout the central nervous system with high concentrations throughout the brain and spinal cord. Receptors are also found to a lesser extent through safe and effective prescribing. Below are a few of those that are most commonly used. Analgesics Paracetamol Paracetamol is used for its analgesic and antipyretic actions and it is easily the commonest drug used within paediatrics. Paracetamol is a weaker analgesic than NSAIDs and is preferred because of its better tolerance. Its primary mechanism of action is believed to be inhibition of cyclooxygenase (COX), with a predominant effect on COX-2. Inhibition of COX enzymes prevents the metabolism of arachidonic acid to prostaglandins. In the central nervous system, inhibition of COX enzymes reduces concentrations of prostaglandin E2, which lowers the hypothalamic setpoint to reduce fever, and activation of descending inhibitory serotonergic pathways to produce analgesia. Paracetamol has limited anti-inflammatory properties. It only weakly inhibits prostaglandin synthesis. The COX-2 selectivity of paracetamol results in a lower antiplatelet activity and better gastrointestinal tolerance than is seen with NSAIDs, which are non-selective COX inhibitors. Paracetamol can be given in various forms: most commonly through the mouth but also by intravenous infusion or rectally. As paracetamol is not absorbed effectively through the gastric mucosa, it will be ineffective in children with limited or no gastric emptying. In these situations, a rectal or intravenous preparation will be required. Paracetamol undergoes hepatic metabolism for it to be eliminated (see Fig. 7.4). There are three major metabolic pathways: glucuronide conjugation (accounting for 40–60% of a dose in adults), sulfate conjugation (20–40%), and N-hydroxylation via the cytochrome P450 isozyme CYP2E1 (<15%). This Box 36.3 Steps to be taken in the event of a medication error • Review the child and make sure they are safe and make a plan for their treatment and any monitoring that may be needed because of the error • Inform the parents (and the child if old enough and if this is appropriate) • Inform all relevant health professionals directly involved with the patient • Discuss with the pharmacy/poison centre • Complete a critical incident report • The incident needs to be thoroughly reviewed to determine what lessons can be learnt and how it can be prevented in the future
699 CHAPTER THIRTY-SIX (morphine, diamorphine, pethidine and fentanyl) bind to opioid receptors and demonstrate high intrinsic activity as described above. Partial opioid agonists (buprenorphine, pentazocine) bind to opioid receptors but produce a submaximal effect compared to pure agonists. Opioid antagonists (naloxone) have receptor affinity but no activity and prevent agonists binding (Table 36.4). Opioids are used for management of severe pain for any number of causes from abdominal pain from a ruptured appendix to pain from a broken ankle. It can be given in a number of different forms but the main forms in children are oral (such as oramorph) and intravenous. Intramuscular morphine is avoided in children due to the unnecessary pain of an injection. Opioids have a large number of side effects, some more serious than others, including addiction, respiratory depression and reduced consciousness, whereas constipation, nausea and vomiting are the most common. Until recently, two opioids were commonly used in paediatric practice – morphine and codeine. The latter is likely to be much less commonly used in the future (see below). Metabolism of morphine Morphine is extensively metabolized by the gut wall and the liver. Glucuronidation by the liver enzyme UGT2B7 converts morphine to morphine-3-glucuronide (M3G) (70%) and morphine-6-glucuronide (M6G) (10%). Morphine sulfation is another minor metabolic pathway and does not contribute to the overall clearance. M3G is an inactivated compound and excreted renally, but it is the M6G that produces other sites including the vas deferens, knee joints, gastrointestinal tract, heart and immune system. Since their identification, opioid receptors have had a variety of names and historically were called mu, delta and kappa receptors. In the 1990s, a fourth receptor was found and following this discovery the classification was changed. There are MOP (mu opioid peptide), KOP (kappa opioid peptide), DOP (delta opioid peptide) and NOP (nociceptin orphanin FQ peptide) receptors. Mechanism of action of opioids Binding of an opioid agonist to a G protein-coupled opioid receptor causes the α subunit of the G protein to exchange its bound guanosine diphosphate (GDP) molecule with intracellular guanosine triphosphate (GTP). This then allows the α-GTP complex to dissociate away from the βγ complex. Both of these complexes are then free to interact with target proteins. With a classical opioid agonist such as morphine, binding to its G protein receptor results in the inhibition of adenylyl cyclase. This in turn causes a reduction in intracellular cyclic adenosine monophosphate (cAMP) levels. Additionally, the α and βγ complexes interact with Ca2+ and K+ channels causing activation of potassium conductance and inhibition of calcium conductance, respectively. The net effect of these changes is a reduction in intracellular cAMP, a hyperpolarization of the cell and, specifically for neuronal cells, reduced neurotransmitter release (Fig. 36.3). Opioids can be classified by their potency, origin (i.e. synthetic, semi-synthetic or natural) or by function (action at the receptor). Pure opioid agonists Fig. 36.3 Intracellular changes occurring following the binding of an opioid agonist to a G protein-coupled opioid receptor. (From Pathan H, Williams J. Basic opioid pharmacology: an update. British Journal of Pain 6(1):11–16 © The British Pain Society 2012, with permission.) N Agonist ATP cAMP C Adenylate cyclase Ca2+ K+ GDP GTP α β γ – – +
36 700Pharmacology and therapeutics This is an important example of how different patients can respond differently to the same medication, known as inter-individual variability. A large amount of inter-individual variability is caused by genetic variations in activity of drug metabolism enzymes and drug transporters, as in this example. Antibiotics Some of the commonly used paediatric antibiotics have been discussed in therapeutic drug monitoring, but other commonly used antibiotics are discussed below, including their mechanism of action and clinical uses. the analgesia effect from morphine. In babies and children, the glucuronidation by UGT2B7 is immature and only small amounts of M3G and M6G are produced. Therefore, in younger children and neonates, where there is immature morphine metabolism, to obtain effective and safe analgesia, morphine doses are reduced and, due to the reduced clearance, given less frequently. Metabolism of codeine To obtain its analgesic properties, codeine needs to be converted into morphine by the cytochrome P450 enzyme CYP2D6. This enzyme is known to be highly polymorphic. Homozygous individuals lack the genes for this enzyme and are known as poor metabolizers. They subsequently are unable to convert codeine to morphine, resulting in no analgesia from codeine and increased side effects due to delayed excretion. On the other hand, those with gene duplications or multiplications are described as ‘ultrarapid metabolizers’ and are at risk of reduced or toxic effects from quick drug metabolism. This puts them at significant risk of the side effects of morphine, such as reduced consciousness and, more concerning, respiratory depression. Case reports in children post adenotonsillectomy have highlighted fatalities from respiratory depression secondary to codeine use in CYP2D6 as a result of increased morphine production. There have also been similar reports in breastfeeding neonates whose mothers were taking codeine and were CYP2D6 ‘ultrametabolizers’. Following alerts from the Food and Drug Administration (FDA), European Medicines Agency (EMA) and Medicines and Healthcare Products Regulatory Agency (MHRA) in 2013, codeine should not be used in any child with a history of sleep apnoea who is undergoing tonsillectomy or adenoidectomy and should only be used in children over the age of 12 years. Table 36.4 Opioids with their selectivity for different opioid receptors Opioid Opioid receptor MOP KOP DOP NOP Agonists Morphine +++ + + – Diamorphine +++ + + – Pethidine +++ + + – Fentanyl +++ + – – Partial agonist Buprenorphine ++ + – – Antagonist Nalaxone +++ ++ ++ +, low affinity; ++, moderate affinity; +++, high affinity; –, no affinity; MOP, mu opioid peptide; KOP, kappa opioid peptide; DOP, delta opioid peptide; NOP, nociceptin orphanin FQ peptide. Question 36.7 Mechanism of action of antibiotics Which of the following antibiotics acts by inhibiting cell wall synthesis? Select ONE answer only. A. Azithromycin B. Cefuroxime C. Chloramphenicol D. Gentamicin E. Trimethoprim Answer 36.7 B. Cefuroxime. β-Lactams act by inhibiting cell wall synthesis, as do glycopeptides. Trimethoprim inhibits nucleic synthesis and gentamicin and azithromycin are inhibitors of bacterial protein synthesis.
701 CHAPTER THIRTY-SIX of the penicillins is hypersensitivity. Allergic reactions to penicillins occur in 1–10% of exposed individuals, with significant anaphylactic reactions occurring in less than 0.05% of treated patients. Cephalosporins: Their broad spectrum of activity and safety profile make the cephalosporins one of the most widely prescribed classes of antimicrobials. Historically, this group of antibiotics was used in the treatment of Gram-positive bacterial infections, however more recently the third-generation cephalosporins, such as cefotaxime and ceftriaxone, have been used to treat Gram-negative infections, such as Neisseria meningitides. It is the increased penetration of third-generation cephalosporins which gives them this extended range of antibiotic cover. In Gram-positive bacteria, there is only one layer of peptidoglycans, which leaves the PBPs exposed – this leaves them susceptible to treatment with nearly all β-lactams. In Gram-negative bacteria, any antibiotic has to enter the cell wall through porin pores to reach the inner space between the double peptidoglycan membrane before it can attach to the PBPs. As described above, ceftriaxone has caused calcium deposits in the lung and kidneys in neonates when calcium infusions have been given simultaneously and therefore ceftriaxone should be avoided in young babies. It is also contraindicated in children receiving both ceftriaxone and calcium-containing medications, such as calcium infusions or TPN. Ceftazidime, another third-generation cephalosporin, also has good activity against Pseudomonas infections. Cefuroxime is a second-generation cephalosporin that is less susceptible than the earlier cephalosporins to inactivation by β-lactamases. It is, therefore, active against certain bacteria that have shown resistance as well as having greater activity against Haemophilus influenzae. It is used widely in paediatrics for a number of infections, including severe pneumonias, infective abdominal pathology and pyelonephritis. The principal side effect of cephalosporins is also hypersensitivity. Around 0.5–6.5% of penicillinsensitive patients will also be allergic to the cephalosporins. Glycopeptides See Therapeutic drug monitoring, above, for details. Inhibitors of protein synthesis Aminoglycosides This section is covered within Therapeutic drug monitoring, above. Chloramphenicol This drug blocks the action of peptidyl transferase thereby preventing peptide bond synthesis and Inhibitors of cell wall synthesis β-Lactams The compounds of this family include a β-lactam ring in their structure. The different groups within this family are distinguished by the structure of the β-lactam ring and the side chains attached to these rings. Penicillins have 5-membered rings, whereas cephalosporins have a 6-membered ring. β-Lactams are bactericidal and act by binding to enzymes known as penicillin binding proteins (PBPs) and inhibiting cell wall synthesis. Bacterial resistance against the β-lactam antibiotics continues to increase. Mechanisms of resistance include production of β-lactamases that destroy the antibiotics, but also alterations in penicillin-binding proteins and decreased entry and active efflux of the antibiotic. Penicillins: These are the most commonly used antibiotic within paediatrics and are used widely for the treatment of Gram-positive bacteria, including Streptococci and Staphylococci species. Amoxicillin is used for community-acquired respiratory infections. When used orally, it has been shown to be as effective as intravenous therapy for treatment of moderate pneumonias. Phenoxymethylpenicillin (penicillin V) is used for treatment of Streptococcus infections, such as tonsillitis, where amoxicillin has the potential to cause a rash if used in those with glandular fever. Co-amoxiclav is an antibiotic which combines amoxicillin with clavulanic acid, the latter being a β-lactamase inhibitor. This combination allows it to be an effective treatment against those bacteria which produce β-lactamases. The most important side effect Question 36.8 Mechanism of action of antibiotics The following oral antibiotics are bactericidal rather than bacteriostatic. Answer true (T) or false (F) for each option. A. Amoxicillin B. Cephalexin C. Ciprofloxacin D. Clarithromycin E. Trimethoprim Answer 36.8 A. True; B. True; C. False; D. False; E. False. β-Lactams are bactericidal, whereas macrolides, quinolones and sulphonamides are bacteriostatic (see below for more detailed discussion).
36 702Pharmacology and therapeutics children with cystic fibrosis or complicated urinary tract infections. Rational use of medicines in children When prescribing medicines, one needs to follow the BNFc or local or national guidelines. The rational use of antimicrobials is important to prevent the development of resistant organisms. The choice of antimicrobial agent needs to be made in conjunction with the local microbiologist, who will be aware of local resistance patterns. Please see the section on commonly used medications for further information on their mechanisms of action. The duration of antibiotic therapy also needs to be carefully considered. Most hospitals have local antibiotic guidelines that should be followed. The rational use of medicines is important not just for antimicrobials. For example, many infants with mild gastro-oesophageal reflux are prescribed medicines that are both expensive and ineffective such as omeprazole, a proton-pump inhibitor. This is also an off-label use and the formulations that are available (dispersible tablets) make it difficult to measure an accurate dose. A liquid formulation is made by special manufacturers but this can be difficult to source and expensive. It continues to be prescribed despite the fact that proton-pump inhibitors have not been shown to be effective in reducing symptoms associated with gastro-oesophageal reflux in otherwise well infants. There are unfortunately many other instances where health professionals prescribe a medicine for which there is no evidence of effectiveness. Further reading Choonara I, Rieder MJ. Drug toxicity and adverse drug reactions in children – a brief historical review. Paediatr Perinat Drug Ther 2002;5:12–18. Cousins D, Clarkson A, Conroy S, et al. Medication errors in children – an eight-year review using press reports. Paediatr Perinat Drug Ther 2002;5:52–8. De Wildt SN, Johnson TN, Choonara J. The effect of age on drug metabolism. Paediatr Perinat Drug Ther 2003;5:101–6. Kearns GL, Abdel-Rahman SM, Alander SW, et al. Developmental pharmacology – drug disposition, action, and therapy in infants and children. N Engl J Med 2003;349(12):1157–67. Starkey ES, Sammons HM. Practical pharmacokinetics: what do you really need to know? Arch Dis Child Educ Pract Ed 2015;100(1):37–43. Van der Pol RJ, Smits MJ, van Wijk MP, et al. Efficacy of protonpump inhibitors in children with gastroesophageal reflux disease: a systematic review. Pediatrics 2011;127(5):925–35. subsequently inhibiting bacterial protein synthesis. Chloramphenicol is active against a wide number of bacterial species, including Salmonella typhi, and Chlamydia species. Its current main use is for topical use in eye infections. Historically, it was used to treat neonatal infections due to its broad cover, however it was shown to be toxic (see above). Macrolides Antibiotics within this class are primarily bacteriostatic and act by binding to the 50S subunit of the ribosomes and subsequently they inhibit bacterial protein synthesis. These include various antibiotics, including erythromycin, azithromycin and clarithromycin. Macrolides have a similar spectrum of activity as the β-lactams and are therefore used as an alternative in those who are penicillin allergic. Clarithromycin has better activity than erythromycin and is used as the alternative in respiratory infections. It is also better tolerated than erythromycin and is only given twice a day rather than four times. Macrolides are also the treatment of choice for atypical respiratory infections, such as Mycoplasma, where penicillins are ineffective. Some macrolides (erythromycin and clarithromycin) are cytochrome p450 inhibitors, especially CYP3A4, and can affect the metabolism of other drugs, e.g. warfarin. Inhibitors of nucleic synthesis Sulphonamides Antibiotics in this group are bacteriostatic and act as competitive inhibitors of the enzyme dihydropteroate synthetase (DHPS) which is involved in bacterial folate synthesis. The most widely used sulphonamide within the paediatric setting is trimethoprim and it is used as a first-line treatment for urinary tract infections. It is active against Gramnegative rods, such as E. coli. When combined with sulphamethoxazole, it is known as co-trimoxazole and is used for the treatment and prophylaxis of Pneumocystis pneumonia. Quinolone This group of drugs acts by inhibiting the activity of DNA gyrase and therefore preventing supercoiling of the bacterial chromosome. This prevents the bacterial cell from putting DNA into its cell. The most ommonly used for treatment of infections in children is ciprofloxacin. Ciprofloxacin has activity against both Gram-negative and Gram-positive bacteria, but in particular Pseudomonas and Neisseria infection. Its main use is for pseudomonal infections in
LEARNING OBJECTIVES By the end of this chapter the reader should: • Understand the different research settings and the phases of clinical trials • Understand how to develop a research question and frame this as a null hypothesis to be tested • Be aware of the regulatory bodies and processes involved in trial design and approval • Understand how to enrol a young person on a clinical trial • Be aware of the monitoring requirements of a clinical trial • Have a basic understanding of the approach to statistical analysis of trial data • Appreciate the importance of trial reporting and the role that prospective registration of clinical trials has in this process 703 CHAPTER THIRTY-SEVEN There has been a dramatic improvement in child health outcomes throughout the second half of the last century. This has mainly been driven by improvements in nutrition, housing, child safety, immunization and other public health developments. These important approaches are now being complemented by clinical trials, fuelled by the development of new ‘omics’ technologies, which are uncovering the molecular origins of disease faster than we are able to translate the new information into clinical benefit for patients. Paediatricians are a critical component in ensuring that our ever improving understanding of fundamental molecular biology is translated into improvements in the health of young people. This requires that paediatricians continue to identify, and seek to answer, key questions relating to childhood development and disease. Identifying clinically relevant problems, framing questions and searching for answers from established research is at the heart of evidence-based medicine (see Chapter 39, Evidence-based paediatrics). However, many questions remain unanswered. Designing studies to address these unanswered questions is the essence of clinical research. This chapter aims to introduce clinical research, providing a broad understanding of what underpins clinical trial conception and design, the process of obtaining trial approval, recruitment, monitoring and finally reporting of trial findings. The role of research Research into the causes of childhood illness underpins much of what we see as standard practice today. However, many of our daily clinical decisions are based on little or no evidence. Children are not small adults, but individuals with specific and ever changing developmental and physiological needs. Despite this, paediatricians are often obliged to extrapolate from adult trials and to prescribe drugs for which there is little clinical trial data from children. Challenges facing the development of research for young people are listed in Box 37.1. How, then, can child-specific clinical research be driven and what does it offer to the health of young people? Paediatricians involved in caring for children with rare, complex or life-threatening disorders are constantly looking to understand that disease in more detail, to identify high-risk patients and to develop innovative management strategies. For example, molecular characterization of malignant diseases has opened the door to the application of targeted therapies in place of non-selective cytotoxic chemotherapies. Cellular and genetic manipulation of donated Simon Bomken, Josef Vormoor Clinical research C H A P T E R 37
37 704Clinical research stem cells will reduce the risk of rejection or graftversus-host disease in recipients. Delivery of the wild type CFTR gene will reconstitute normal function, preventing the destructive lung disease seen in cystic fibrosis. However, the majority of child health research seeks to provide evidence relevant to the clinical management of children with more common diseases, forming the evidence base from which we develop our practice, and is the domain of all paediatricians (Box 37.2). Whether as chief investigator, recruiting patients Box 37.1 Challenges facing the development of research for young people Barriers to research in young people • Disease rarity – compounded by the increasing molecular subcategorization of conditions • Consent required on child’s behalf, often during distressing periods • Consideration of risk vs benefit by parents on child’s behalf • Multiple sampling of blood or tissues • Repeated follow-up causing intrusion into family/school life • Concordance with therapy and follow-up amongst young people • Transition to adult services research setting affecting long-term follow-up or as someone committed to improving local practice, understanding the principles and practice of clinical research is a key component of paediatrics. All paediatricians have a responsibility to improve children’s healthcare and research is an essential part of this process. Research methods Research setting Medical research is conducted across a number of different settings. Different components flow, in two directions, with clinical problems and observations being investigated at a fundamental level and improved fundamental knowledge being applied to the patient setting. The resultant interplay of ideas, questions, solutions and new questions (Fig. 37.1) is what defines the process of medical research. Whilst the boundaries can merge, broadly the style of research being conducted allows these different settings to be considered separately. Fundamental (or basic) research seeks to develop our understanding and knowledge of the genetic, molecular, environmental or societal basis of disease. Examples include: • Investigating the cardiovascular or central nervous system effects of neonatal asphyxia using an animal model Framed PICO question: In a pre-school child with wheeze associated with a viral upper respiratory tract infection [patient], is oral steroid (e.g. prednisolone) [intervention] more effective than placebo [comparison] in terms of time to resolution of symptoms, likelihood of admission and deterioration and side effects [outcomes]? Study design: Randomized, double-blind, intention-to-treat, placebo-controlled trial comparing the role of a short (5-day) course of prednisolone in 700 children aged between 10 months and 60 months. The stated primary outcome measure was duration of hospitalization, with secondary outcome measures assessing symptom severity and salbutamol use. Results: The study demonstrated that there was no difference in any of the stated outcome measures between children who received prednisolone and those who received placebo. This included a sub-analysis of children at risk of asthma (e.g. previous wheeze, dermatitis or parental asthma). Discussion: Whilst this trial was conducted in a tertiary paediatric environment, it sought to address a common problem where there was no evidence to inform practice. Its impact comes not from high technological science, but from the importance of the clinical problem across tertiary, secondary and primary care settings. The use of a randomized, blinded and placebo-controlled design was critical in this study as many of the measured endpoints included a degree of subjectivity. This included the primary outcome measure, duration of hospitalization, as the decision to discharge a patient is based on clinician decision and therefore open to bias if the supervising clinician knew the allocated treatment. Equally, secondary outcome measures of degree of respiratory distress, total dose of inhaled β2 agonist administered in hospital and following discharge and mean 7-day symptom score all include an element of subjectivity. The use of a placebo was essential to maintain blinding. Reference: Panickar J, Lakhanpaul M, Lambert PC, et al. Oral prednisolone for preschool children with acute virus-induced wheezing. New England Journal of Medicine 2009:360;329–38. ISRCTN58363576. Box 37.2 Landmark study – the use of oral prednisolone in viral-induced wheeze
705 CHAPTER THIRTY-SEVEN In reverse, it aims to identify: • Important clinical problems and frame them as research questions for fundamental investigation • Unusual clinical situations as routes for fundamental science to develop learning of basic processes – identification of recessive genetic causes of primary immunodeficiency can identify critical elements in development of immunity. Fig. 37.1 Two-way interconnection between fundamental research and clinical research. EM, experimental medicine. Translational research Fundamental research Preclinical research Early clinical trials EM Late clinical trials Translation to healthcare delivery Question 37.1 Biomarkers A phase III clinical trial is opened to assess the benefit offered by a new insulin pump in children. The primary endpoint of the trial is the change in their HbA1c. In this setting, HbA1c is an example of what kind of biomarker? Select ONE answer only. A. Imaging biomarker B. Pharmacokinetic biomarker C. Predictive biomarker D. Prognostic biomarker E. Response biomarker Box 37.3 Clinical biomarkers Prognostic biomarkers – used to stratify patients according to the prognosis of their disease subtype. In childhood acute lymphoblastic leukaemia, cytogenetic analysis identifies patients at a higher risk of treatment failure, e.g. t(9;22) Philadelphia chromosome. Predictive biomarkers – predict a patient’s response to a particular treatment. Mutations of Kir6.2 causing infant-onset diabetes insipidus predicts sensitivity to sulphonylureas (Box 37.4). Response biomarkers – provide a surrogate measure of a patient’s disease status and response to the chosen therapy – fever or C-reactive protein in infection. Pharmacokinetic biomarkers – used to assess the therapeutic or toxic effects of a drug. Antibiotics such as gentamicin or vancomycin will commonly have drug levels monitored. Imaging biomarkers – non-invasive imaging, e.g. CT or MRI, may provide prognostic or response biomarker information. • Identifying the cytogenetic abnormalities found in acute lymphoblastic leukaemia • Identifying the underlying cause of the abnormally thick secretions seen in cystic fibrosis – characterization of the cystic fibrosis transmembrane regulator provided a pathological mechanism which, in turn, may offer a therapeutic option. Translational research is a two-way process which provides a bridge between fundamental research and applied clinical research and adheres to the philosophy of ‘bench-to-bedside and back again’. In the forward direction, it aims to generate supportive preclinical data prior to investigating the clinical application of: • One of a number of different potential clinical biomarkers (Box 37.3) • Novel therapeutic targets – if the CFTR gene is mutated in cystic fibrosis, is it possible to deliver a functionally normal gene to the airways and does this result in a biological improvement, e.g. in secretions? Clinical research seeks to take potential diagnostic, monitoring or therapeutic strategies, identified by basic and translational research, into a representative clinical setting. It asks the question, ‘Does this treatment improve the health and well-being of real patients?’ Addressing this question will normally be performed in steps, or phases, with different aims at each phase (Table 37.1). Phase I and II (early phase) trials recruiting small numbers of patients and focusing on determining the safety and appropriate dosing/ schedule of a new intervention, may be combined so that patients are initially recruited to a phase I element followed by progression to a phase II element. This is increasingly common in trials of new therapies designed specifically for rare patient or disease/ molecular subgroups. Increasingly, experimental medicine (see Fig. 37.1, and see Personalized medicine, below) seeks to use human trials to generate pre-clinical data. For example, a clinical trial with a primary aim of investigating the effect of a new cytotoxic anti-cancer drug can also be used to assess the pharmacokinetics/ pharmacodynamics of that drug and the effect on Answer 37.1 E. Response biomarker. The HbA1c is being used as a surrogate measure of glycaemic control, and thus provides a measure of the effectiveness of the intervention.
37 706Clinical research Table 37.1 Trial phases I–IV with common study sizes and aims Phase Numbers recruited Primary aims Secondary aims Phase I <30 • Assess safety • Assess side effects • Determine maximum tolerated dose (MTD – the highest dose at which tolerable side effects are seen) Understand the pharmacology of the drug in humans Phase II <100 • Assess safety • Optimize dosing schedule • Look for beneficial effect in a suitable patient population Determine optimal supportive care for side effects Phase III Hundreds to thousands • Compare new intervention with standard intervention • Compare alternative ways of delivering a standard intervention • Test applicability to ‘routine’ clinical setting Ongoing safety monitoring Phase IV Hundreds to thousands • Ongoing clinical efficacy in ‘population-wide’ usage • Ongoing safety monitoring Question 37.2 Trial design The following (A–E) is a list of trial designs: A. Case-control study B. Cohort study C. Cross-sectional study D. Ecological study E. Randomized controlled trial Box 37.4 Interventional cohort studies provide an alternative to RCTs when they are unfeasible or unethical Scenario: You are a paediatrician working in a tertiary paediatric diabetes service. Framed PICO research question: In children with diabetes due to mutations within the ATPsensitive potassium channel [population], is oral sulphonylurea [intervention] as effective as standard insulin replacement [control] in maintaining or reducing HbA1c [primary outcome measure] without additional episodes of hypoglycaemia [secondary outcome]? Method: This interventional cohort study looked at the management of 49 patients with diabetes due to mutations within the ATP-sensitive potassium channel. Results: A significant reduction in HbA1c from 8.1% pre-treatment to 6.4% after 12 weeks of treatment (p<0.001). Forty-four patients were able to stop insulin treatment. Discussion: This collaborative multinational study demonstrated a safe and more effective way of managing diabetes resulting from this rare group of mutations. The patients in this study, all of whom were established on ‘standard’ insulin therapy, provided their own controls for the primary outcome measure of HbA1c, which can be assessed using a paired Student’s t-test (see Chapter 38, Statistics). Assuming that all patients were stable prior to enrolment, this approach provided the most appropriate trial design. It maximized the opportunity to study the effect of an intervention in a small population of patients with a rare condition. Randomizing patients between ongoing standard care and investigational treatment would have reduced the number in the trial therapy arm, thereby reducing the power of the study. However, a crossover approach would clearly not be appropriate in acute conditions where baseline measurements cannot provide stable data, or in life-threatening conditions where two interventions – usually current standard of care and new intervention – must be directly compared. In that situation, randomization would be most appropriate. Reference: Pearson ER, Flechtner I, Njølstad PR, et al. Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations. New England Journal of Medicine 2006:355;467–77. similar, potentially cross-reactive pathways in normal tissue. These studies cannot be performed in vitro or in healthy human volunteers due to the potential toxicity. Common trial designs A number of different quantitative trial designs exist. Whilst the randomized controlled trial is frequently seen as the gold standard approach for investigating a new treatment intervention, each of the designs can be the most appropriate choice for a given clinical setting (Table 37.2).
707 CHAPTER THIRTY-SEVEN Qualitative research Whilst most clinical research revolves around the quantitative analysis of clinical criteria, the interrogation of qualitative information can also play an important role, both in informing quantitative clinical trial design and in influencing clinical service design and provision. Qualitative research (Box 37.5) aims to develop understanding of a defined area by collecting information, analysing it and using the output to generate new ideas or hypotheses which may or may not then be suitable for quantitative analysis. Information collecting may involve: • Review of documented evidence • Observational approaches – recording uninfluenced behaviours • Interviews – usually open-ended and defined by topics rather than specific questions • Group discussion – specifically focusing on the interactions of the group setting Box 37.5 Qualitative study Non-compliance amongst adolescents with asthma Scenario: A 14-year-old boy is admitted to your ward. He has ‘brittle’ asthma. It is the fourth time he has been admitted this year. GP records demonstrate that he is not collecting his prescriptions. You have a large number of similar adolescent patients and want to investigate compliance in adolescent patients. Research question: ‘To understand better the reasons for non-compliance in adolescents with asthma.’ Research study: In-depth interviews with a sample of 49 adolescents, aged between 14 and 20 years. All adolescents were diagnosed as asthmatic more than a year previously and were attending a hospital asthma clinic. The interviews focused around the adolescents’ feelings about their illness and their illness-related behaviour, including self-management. Key results: Reasons given for non-compliance with prescribed medication in the past or at present were: forgetfulness, belief that the medication is ineffective, denial that one is asthmatic, difficulty using inhalers, inconvenience, fear of side effects, embarrassment and laziness. Research implementation: The results are implemented by improved education, including a peer education initiative. Reference: Buston KM, Wood SF. Noncompliance amongst adolescents with asthma: listening to what they tell us about selfmanagement. Family Practice 2000;17(2):134–8. Match the trial designs to each of the studies below: 1. Given current theories on autism and the finding of low-level contamination of drinking water specifically from surface sources with pharmaceuticals including oestrogenic compounds and other pollutants, researchers questioned whether drinking water might be a common source of exposure for numerous potential risk factors for autism spectrum disorders. The study collected secondary data on county-level autism prevalence in the USA and data on the percentage of drinking water derived from surface water sources for each county from publicly available data sources. 2. Mothers were identified during attendance at an antenatal clinic and divided into two groups: those who smoked during pregnancy and those who did not. Following delivery, all children were followed up for five years with yearly questionnaires about a variety of developmental outcomes. 3. Families attending an outpatient clinic were approached and asked to complete a survey regarding the amount of physical exercise undertaken each week. During the same clinic, each child was weighed and their height measured in order to evaluate associations between physical activity and overweight. 4. Following recruitment, children were allocated to receive either the current standard first-line treatment for epilepsy or a new medication under review. Investigators, unaware of which medication each participant was taking, analysed the outcome data with regards to seizure control. 5. To assess and compare the oral health status of pre-school children with and without cerebral palsy (CP), pre-school children with CP were recruited from special child care centres and a gender-matched sample of pre-school children from mainstream pre-schools were recruited as the control group. Answer 37.2 1. D. Ecological study. 2. B. Cohort study. 3. C. Cross-sectional study. 4. E. Randomized controlled trial. 5. A. Case-control study. See Table 37.2 for discussion.
37 708Clinical research Question 37.3 Clinical research/clinical trial settings The following (A–J) is a list of research settings: A. Experimental medicine B. Fundamental research C. Phase I clinical trial D. Phase I/II clinical trial E. Phase II clinical trial F. Phase III clinical trial G. Phase IV clinical trial H. Pre-clinical research I. Research for patient benefit J. Translational research Table 37.2 Common trials designs Trial design Approach offered Most suitable if Example research question Randomized controlled trial (RCT) Patients are randomly assigned to receive either standard intervention or the new ‘trial’ intervention A new treatment is being compared with the current best treatment. This approach allows comparison of efficacy and toxicity whilst minimizing sources of bias. PREDNOS trial: In children with new onset nephrotic syndrome [patient], is 16 weeks of prednisolone [intervention] more effective than 8 weeks [control] at reducing relapse rate [outcome]? Crossover trial (variation of RCT) Individuals provide both control and experimental arm by sequentially receiving multiple/all interventions at different time-points, interspersed with periods for drug ‘wash-out’ The new treatment is for a chronic condition and aims to control symptoms Is unsuitable/unethical for an acute condition where life-saving treatment is on trial In adolescents with type 1 diabetes [patient], does pump therapy [intervention] compared to basalbolus [control] reduce nocturnal hypoglycaemic episodes [outcome]? Cohort Children and young people in a particular setting are recruited and followed up to determine outcome The effect of an exposure or predisposition to a condition is being investigated May be used, especially in early phase trials, where controlling with a placebo is unfeasible or unethical (Box 37.4) In infants [population], does supine sleeping [cohort 1] compared to prone sleeping [cohort 2] lead to a high frequency of sudden infant death [outcome]? (See Box 37.4.) Case-control Children and young people with a condition are compared with a control group without that condition. Controls must be matched for a number of characteristics, such as age, gender, socio-economic group Predisposing/risk factors are being investigated. By comparing wellmatched cases and controls, the differences between the groups can identify such risk factors. In infants with pyloric stenosis [case group] compared with a matched group [control group], is there higher exposure to erythromycin? Ecological Data generated from a geographically (usually) defined population to identify risk-modifying factors on health outcomes Able to identify available information about the population Map of skin cancer deaths and sun exposure Whilst outcome measures are not restricted in qualitative studies, the study aim, methodology and analysis are no less rigorously defined and validated than in quantitative approaches. Commonly a number of validated methods will be used independently by more than one researcher and the results triangulated to identify areas of agreement, providing a high degree of validity. Choose the most appropriate research setting to address each of the problems below: 1. Regular intravenous antibiotics form an important part of the management of children with cystic fibrosis. However, these require frequent admissions to hospital and therefore disrupt children’s social development and education. Your local respiratory team would like to assess a new home antibiotic delivery programme aimed at improving the experience of this element of care for children and their family. 2. A new targeted anti-cancer therapy has shown good efficacy in early phase trials in adults with relapsed non-Hodgkin’s lymphoma. You wish to determine the tolerability of this agent alongside/in addition to your current standard therapy for aggressive mature B-cell lymphoma. Initially this study will identify the maximum tolerated dose in cohorts of three patients, followed by an extended cohort to look at short-term toxicity. 3. In order to gain the most information from your Phase II trial of a novel immune-modulatory agent in severe Crohn’s disease, you design a number of associated studies to identify the
709 CHAPTER THIRTY-SEVEN of identifying a need, investigating potential solutions and then validating them is key to framing the clinical research question (Fig. 37.2). Whilst basic scientists may follow lines of investigation which appear interesting in the hope of further defining fundamental elements of biology, a greater expectation must be placed on the question underpinning a clinical trial. Asking a child and their family to consent to novel intervention or additional investigations can only be ethically justified if the benefit outweighs the risk. There must therefore be a reasonable expectation of patient benefit, identified as a clinical need. It may not, for example, be justified to randomize children between two established therapies with an equivalent, well-documented success rate, simply to demonstrate equivalence in a formal setting. If, however, there was a rationale for one treatment being more effective or less toxic than the other, then this would need to be investigated in a randomized clinical trial. The research question becomes: • Treatment effect: – Is treatment A more effective than treatment B in this clinical setting (e.g. In pre-school children with mild chronic asthma [patient], is oral leukotriene antagonist [intervention] as or more effective then inhaled steroid [control] in preventing chronic symptoms and/or acute exacerbations [outcomes])? • Side effects/toxicity: – Is treatment A less toxic than treatment B in this clinical setting (e.g. in pre-school children with mild chronic asthma [patient], does oral leukotriene antagonist [intervention] lead to greater height potential [outcome] than inhaled steroid therapy [control])? Designing a clinical trial Introduction – identifying a clinical need The origins of all clinical trials should be an identifiable clinical need. This is one of the key contributions to be made by translational researchers. The process pharmacokinetics of the drug in young people (existing data are derived from adult studies) and the effect on serum markers of inflammation (response biomarkers), and you require that fresh biopsy specimens are collected at subsequent endoscopic procedures for laboratory investigations of immune cell function. This way you aim to get the most information about the efficacy of the new drug. Fig. 37.2 Cyclical process of clinical trial design – identifying a clinical need, investigating the underlying biology, validating and testing a novel therapeutic approach, including feedback to ongoing fundamental studies, and undertaking late phase clinical trial. Clinician/translational researcher 1. Identifies unmet clinical need 2. Late phase clinical trial of validated therapy Pre-clinical modelling of new therapy Experimental medicine Feedback to ongoing studies Fundamental researcher identifies underlying biology and suggests therapeutic targets Early phase clinical trial Answer 37.3 1. I. Research for patient benefit. This approach looks at optimizing healthcare service delivery in a patient-centred manner. 2. D. Phase I/II. Initial identification of maximum tolerated dose (Phase I) is followed by an extended early phase approach to confirm tolerability alongside otherwise very intensive therapies using an extended early phase trial approach. 3. A. Experimental medicine. This concept aims to maximize the experimental and learning opportunities available during clinical trials of new treatments by use of pharmacokinetic, pharmacodynamic, biomarker and fundamental science studies on patient-derived samples.
37 710Clinical research looking to identify is an essential component of defining the alternative hypothesis, providing the clinically relevant outcome with which power calculations can be made and data analyses can be performed. Defining the research question and subsequently the research hypothesis is key to determining how the resultant study will be structured, performed and analysed. Feasibility Consideration must be given to the ability of the study team to deliver a successful trial within a suitable timeframe. The key factors to consider are shown in Box 37.8. If the expected duration of the study, including necessary follow-up, risks making the delivery of results so delayed that they may no longer be clinically relevant (if, for example, other approaches to management have improved substantially), then it may not be appropriate to initiate the trial. Options for increasing recruitment should be considered, especially widening the trial setting to include national (Box 37.9) or, commonly, international recruitment, the use of alternative trial designs and the sharing of data across trials by prospective or retrospective meta-analysis. Preliminary statistics One critical component of developing a clinical trial is to give consideration to defining the outcomes to be assessed and the number of patients required to demonstrate whether those outcomes are affected by the intervention on trial. By defining the outcome which the intervention is hoped to produce, statistical analyses can be tailored to address that specific question. Collecting large quantities of data and then asking multiple questions is statistically unsound and will both risk identifying effects resulting from chance and reduce the likelihood of producing a statistically significant result for the most important clinical outcome as statistical significance needs to be adjusted from when performing multiple tests (Bonferroni calculation). Ideally, outcomes should be defined as: • Primary outcome measures – the main outcome(s) under investigation • Secondary outcome measures – additional important impacts of the intervention Once the nature of the outcome to be assessed is defined, preliminary data on the clinically relevant size and distribution of the effect within the study population can be used to determine the number of patients (sample size) which need to be recruited to the study. This is the power calculation, which will usually be required by regulatory/funding bodies as one part of demonstrating that the study is practicable. Fundamental scientific evidence Having identified a clinical need, basic evidence must be sought on how to approach meeting that need. Frequently this will involve a thorough search of the published literature, as there is often a large body of evidence in existence. However, this will often need to be complemented by additional studies investigating the relevance of published knowledge in the specific disease setting. Combined, these data will hopefully provide possible routes for a new intervention aimed at meeting the clinical need. Pre-clinical modelling of the intervention Having identified a potential novel intervention, this needs to be validated in the most appropriate preclinical model available. Some models will involve in vitro drug testing using derived cell lines. However, more complex models, often involving animal research, are frequently used as these may be felt to be more representative of the clinical setting with, for example, metabolism of drugs and complex tissue microenvironments in place of homogeneous single cell cultures (Box 37.6). However, the animal model may only partially represent the human disease and the metabolism and cellular effects of a drug may differ between animal model and humans. One approach to solving this, predominantly relevant to malignancies, is to use human diseases engrafted into immunodeficient animal models – xenografts. It should be noted that even then, factors such as differential metabolism of a drug or the altered microenvironment may limit the clinical relevance of the model. Defining the research hypothesis Having identified a clinical need, defined the research question and examined the basic and pre-clinical evidence available, the approach to answering the question and resolving the need must be expressed as a hypothesis (Box 37.7). A research hypothesis aims to state a prediction about the outcome of a research study, which can then be experimentally tested. Conventionally this hypothesis is based on the outcome of literature searches and previous, pre-clinical, studies. However, it is not statistically possible to prove the research hypothesis, as the results observed within the study might be due to chance occurrence. Instead, a study’s results must be compared against the opposite situation, which is known as the null hypothesis. Evidence which argues against the null hypothesis is evidence in favour of the original research hypothesis, which now becomes known as the alternative hypothesis. Deciding what size of effect the study is
711 CHAPTER THIRTY-SEVEN • The power – the probability of rejecting the null hypothesis when the alternative hypothesis is correct (Box 37.10). Frequently set to be 0.8, this represents an 80% chance of correctly identifying the pre-determined clinically significant effect in the study population. Regulatory approval All studies involving human subjects must be subjected to rigorous regulatory oversight. This includes The factors required to produce a power calculation are: • The significance level to be used in the analysis – the value against which the likelihood of incorrectly rejecting the null hypothesis will be judged. This will be calculated from the trial data as the p-value. • The magnitude of effect in the study population (either a direct measurement or, preferably, standardized according to the spread of the effect within the population) Box 37.6 Pre-clinical modelling leading to therapeutic hypothermia in hypoxic–ischaemic encephalopathy Scenario: You are a community paediatrician who regularly cares for children with neurodisability secondary to hypoxic–ischaemic encephalopathy (HIE). You want to engage in pre-clinical research to identify new interventions to reduce neurodevelopmental complications in the population. Research question: In newborn pigs that have undergone induced hypoxia, is there evidence of secondary brain insult despite normal pH, oxygen and glucose levels? Background: Understanding the mechanism of injury in neonatal asphyxia requires a complex model including developing neural tissue, oxygenation, glucose metabolism and metabolic by-products. Such modelling could not be produced in vitro and therefore animal models of asphyxia were developed to investigate not only the pathological mechanisms, but also the response to a number of treatment options. Using both newborn pig and newborn rat models of asphyxia, an initial insult to cerebral metabolism is following by a period of normal metabolism. However, a late or secondary cerebral energy failure was identified, despite normal blood pH, oxygen and glucose levels. As the severity of this secondary insult was shown to correlate with the risk of death, severe neurological disability or microcephaly (Roth et al 1992), it provided a possible therapeutic opportunity – a second period during which a protective therapy could be implemented. Further research stemming from this finding: Further analysis of these models found that whilst infusing magnesium sulphate did not prevent the secondary energy failure (Penrice et al 1997), inducing moderate hypothermia did (Thoresen et al 1995), reducing neuronal apoptosis (Edwards et al 1995) and infarct size (Bona et al 1998). These studies paved the way for further optimization of cooling strategies using models prior to early phase trials investigating the safety of both selective head cooling or whole body hypothermia in newborn infants (Gunn et al 1998, Azzopardi et al 2000, Eicher et al 2005), see Box 37.13. References: Azzopardi D, Robertson NJ, Cowan FM, et al. Pilot study of treatment with whole body hypothermia for neonatal encephalopathy. Pediatrics 2000;106(4):684–94. Bona E, Hagberg H, Løberg EM, et al. Protective effects of moderate hypothermia after neonatal hypoxia-ischemia: short- and long-term outcome. Pediatr Res 1998;43(6):738–45. Edwards AD, Yue X, Squier MV, et al. Specific inhibition of apoptosis after cerebral hypoxiaischaemia by moderate post-insult hypothermia. Biochem Biophys Res Commun 1995;217(3):1193–9. Eicher DJ, Wagner CL, Katikaneni LP, et al. Moderate hypothermia in neonatal encephalopathy: efficacy outcomes. Pediatr Neurol 2005;32(1):11–7. Gunn AJ, Gluckman PD, Gunn TR, et al. Selective head cooling in newborn infants after perinatal asphyxia: a safety study. Pediatrics 1998;102(4 Pt 1):885–92. Penrice J, Amess PN, Punwani S, et al. Magnesium sulfate after transient hypoxiaischemia fails to prevent delayed cerebral energy failure in the newborn piglet. Pediatr Res 1997;41(3):443–7. Roth SC, Edwards AD, Cady EB, et al. Relation between cerebral oxidative metabolism following birth asphyxia, and neurodevelopmental outcome and brain growth at one year. Dev Med Child Neurol 1992;34(4):285–95. Thoresen M, Penrice J, Lorek A, et al. Mild hypothermia after severe transient hypoxiaischemia ameliorates delayed cerebral energy failure in the newborn piglet. Pediatr Res 1995;37(5):667–70.
37 712Clinical research within the UK and European Union that all trials of investigational medicinal products are conducted according to the principles of GCP. In order to ensure that all required regulatory requirements are complied with, every clinical trial will identify a sponsor. The sponsor is ‘an individual, company, institution or organisation which takes responsibility for the initiation, management and/or financing of a clinical trial’ (UK Clinical Trials Regulations). For clinical trials, the sponsor is commonly the institution hosting the clinical trials unit running the trial. Engaging with children and young people on trial design An increasingly important element of clinical trial design is engaging children and young people from an early stage. Many research ethics committees and funders will require this, particularly on matters such as the design of age-specific patient and parent information sheets. More importantly, however, high quality engagement, involving young people and families right from a study design stage, seeks to ensure that the research question reflects the priorities of this most important group and creates a relationship between study and patient which hopefully improves understanding, participation and concordance. The outcome should be greater patient/family satisfaction and well-being as well as higher quality data. Trial registration Once the trial protocol has been developed, many trials will register themselves with a publicly accessible database, such as the International Clinical Trials Registry Platform (ICTRP) or International Standard Randomised Controlled Trial Number (ISRCTN) to receive a unique clinical trial number. Currently, registration of a clinical trial is not mandatory, although clinical trials of investigational medicinal products (CTIMPs) undertaken within the EU are required to register with the European Medicines Agency for a EudraCT number (Box 37.12). The aims of these registrations are to facilitate supervision of trials, including linking with pharmacovigilance databases, supporting communication between regulatory authorities and tracking outcomes of trials through all related publications, limiting the impact of reporting bias. Enrolling young people on clinical trials Information sharing The first major commitment to enrolling a child or young person on a trial is to provide both the Box 37.8 Factors contributing to the feasibility of a clinical trial • Incidence – including genetic/molecular subclassification • Number of patients (sample size) required to give the study adequate power (see Chapter 38, Statistics) • Predicted eligibility rates – pathways of referral, additional inclusion/exclusion criteria • Predicted rates of consent – affected by trial design, complexity, additional impact on family and potential risks Box 37.7 Development of hypotheses framing the research question Scenario: You are a respiratory paediatrician who regularly treats children with cystic fibrosis (CF). Framed PICO research question: In children with CF [population], is retroviral delivered normal CFTR gene [intervention] compared to placebo [control] effective in reducing the development of chronic airway damage [outcome]? Hypotheses: • Research hypothesis: ‘Retroviral delivery of a normal CFTR gene to the airways of children with cystic fibrosis will reduce the development of chronic airways damage.’ • Null hypothesis: ‘Retroviral delivery of a normal CFTR gene to the airways of children with cystic fibrosis will not reduce the development of chronic airways damage.’ • Alternative hypothesis: ‘Retroviral delivery of a normal CFTR gene to the airways of children with cystic fibrosis will delay the development of chronic airways disease by X years.’ making applications to a number of organizations, depending on the nature of the study (Table 37.3). Furthermore, trials must be conducted within the framework defined by the International Conference on Harmonisation, a tripartite initiative between the US, Europe and Japan to define a standardized approach to clinical trial design and conduct to ensure accuracy and credibility of trial findings. The outcome, provided as the 13 principles of good clinical practice (GCP), are applied to ensure that the results from a clinical trial can universally be trusted as being of high quality (Box 37.11). The principles defined by GCP have their foundation in the Declaration of Helsinki and focus primarily on the rights, safety and wellbeing of participants. All professionals involved in clinical trials will be expected by the trial sponsor/ research ethics committee (REC) to have evidence of up-to-date GCP training and it is a legal requirement
713 CHAPTER THIRTY-SEVEN Box 37.9 Stepwise improvement in survival resulting from extensive recruitment to sequential childhood acute lymphoblastic leukaemia trials in the UK Widespread recruitment to clinical trials within paediatric oncology has seen a stepwise improvement in outcome for many childhood malignancies. Improvements in supportive care have been an important part of this development, including: • Criteria for identification of febrile neutropenia and the use of broad-spectrum antibiotics • Improved prophylaxis for Pneumocystis jiroveci and population immunity for measles • Improved imaging – CT, MRI, CT/PET, isotope imaging • Improved surgical/anaesthetic techniques – operating microscopes, coagulation diathermy, peri/intraoperative imaging • More advanced intensive care facilities However, many of the clinical trials conducted in childhood malignancy have provided a clear improvement in outcome. This is well demonstrated by the results of UK trials in acute lymphoblastic leukaemia (Fig. 37.3), which have recruited over 8500 children between 1980 and 2011, with the most recent complete trial, UKALL 2003, recruiting over 95% of eligible children: • UKALL VIII – Attempted to reproduce the superior results seen in the US by using the US CCG162 protocol. Inclusion of daunorubicin in induction improved disease control, albeit at the cost of higher treatment related mortality. Extension of maintenance therapy from two to three years improved survival, although again at the cost of increased toxicity. Overall, similar results were achieved compared to the US, but neither randomization demonstrated a clear overall benefit. • UKALL X – Examined the role of post-induction intensification. Inclusion of both early and late intensification phases was better than one or no intensification phase. Five year event-free survival was 71% with 2 intensification phases, 62–63% with a single intensification and 57% without intensification. • UKALL 97/99 – This trial demonstrated the superiority of dexamethasone over prednisolone, stratified patients according to white cell count and age at diagnosis: standard risk – age <10 years, white cell count >50 × 109 /L; high risk – age >10 years or white cell count >50 × 109 /L. The UK trial again adopted an apparently superior US approach with longer intensification blocks. Introduction of more extensive and sensitive cytogenetic analysis to identify high risk groups. • UKALL 2003 – Stratified children according to minimal residual disease analysis (MRD), a molecular test for low levels of residual disease not detectable by traditional bone marrow analysis. Low risk MRD allowed for reduction of treatment intensity whilst high risk MRD resulted in escalation of treatment. Further reading: Hargrave DR, Hann II, Richards SM, et al. Medical Research Council Working Party for Childhood Leukaemia. Progressive reduction in treatmentrelated deaths in Medical Research Council childhood lymphoblastic leukaemia trials from 1980 to 1997 (UKALL VIII, X and XI). Br J Haematol 2001;112;293–9. Mitchell C, Richards S, Harrison CJ, Eden T. Long-term follow-up of the United Kingdom medical research council protocols for childhood acute lymphoblastic leukaemia, 1980–2001. Leukemia 2010:24;406–18. Scenario: You are a general paediatrician who regularly treats children with pneumonia (see Table 39.6). Framed PICO research question: In a preschool aged child with pneumonia [patient], are oral antibiotics [intervention] as effective as intravenous antibiotics [comparison] for time to resolution of symptoms, rate of hospital admission, length of stay and rate of complications [outcomes]? Power calculation: You work with a steering group who advise a difference of more than 20% could not be considered clinically equivalent (magnitude of effect). With a 5% level of significance (statistical significance), 80% power and equivalence defined as no more than a 20% difference (magnitude of effect) between treatments of the proportion meeting the primary outcome measure at any time, 98 children would be required in each arm of the trial. Reference: Atkinson M, Lakhanpaul M, Smyth A, et al. Comparison of oral amoxicillin and intravenous benzyl penicillin for community acquired pneumonia in children (PIVOT trial): a multicentre pragmatic randomised controlled equivalence trial. Thorax 2007;62:1102–6. Box 37.10 Example of a power calculation
37 714Clinical research Consent and assent Consent for a minor (defined by Medicines for Human Use (Clinical Trials) Regulations 2004 as aged less than 16 years) to participate in a clinical trial of a medicinal product (CTIMP) can only be given by a person with parental responsibility. Unlike other areas of clinical practice, consent to participate in a CTIMP is governed solely on age, not competence as assessed according to the Fraser guidelines. For clinical trials not involving investigational medicinal products, non-CTIMPs, the law in the UK remains untested. Whilst UK law defines a minor as being less than 18 years, many non-CTIMP trials will define a minor as being less than 16 years. Therefore, the individual detail of a trial protocol must be understood by the person taking consent. Having considered the implications of the trial for the child and actively assessed the individual child’s capacity to understand the trial, balance the risk and benefits and crucially to understand their right to refuse or withdraw without impact on their care, a researcher may judge a minor to be able to consent to inclusion in a non-CTIMP trial. Good practice would usually involve a parent, or person with parental responsibility, in this process. Obtaining consent can be challenging when there is disagreement, either between two parties with parental responsibility or between parents and the young person. Best practice would require that, whilst one child and the person with parental responsibility with sufficient, understandable information that they are able to make an informed decision about participation. Different amounts and complexities of information will need to be given to children of different ages. A discussion about involvement in a clinical trial must be supplemented with written information for both patient and parent – patient/parent information sheets. Table 37.3 UK regulatory authorities from which clinical study approval must be sought Organization Mandatory Remit National Research Ethics Service (NRES) For trials involving human subjects/tissues To review the ethical implications of study recruitment (including patient/parent information sheets), conduct, monitoring and reporting. The principle aim is to protect the rights, safety and well-being of participants and their family. NRES now also has responsibility for the ethical conduct of trials involving genetic or stem cell therapies, previously held by the Gene Therapy Advisory Committee (GTAC). Both of these bodies are now part of the NHS Health Research Authority. Medicines and Healthcare Regulatory Authority (MHRA) For studies involving investigational medicinal products or healthcare devices The MHRA is a governmental agency with responsibility for regulating all medicines and medical devices in the UK. This role includes regulating the design and conduct of clinical trials for medicines and medical devices to ensure acceptable levels of protection for participants. Administration of Radioactive Substances Advisory Committee (ARSAC) For studies involving diagnostic or therapeutic radiation Clinical trials involving the administration of radioactive substances require a certificate from the Department of Health. Applications for certificates are reviewed by members of the ARSAC committee and granted/refused by ministers on their advice. Trust R&D Yes NHS Trusts will require a detailed review of all clinical trial activities to ensure that appropriate ethical, legal and financial considerations have been made, in accordance with the Department of Health guidance, Research Governance Framework for Health and Social Care (RGF). Human Tissue Authority (HTA) For studies involving collection, storage and use of human cellular material The HTA has a statutory duty to regulate the collection, storage and use of human material for research and teaching. Material must be collected with specific consent for storage and research and be handled according to HTA guidance, including rigorous tracking of samples from patient to eventual use/disposal. Human Fertilisation and Embryology Authority (HFEA) For studies involving the production and use of human embryos An independent regulator responsible for oversight of the use of human gametes and embryos for treatment of infertility or research. Fig. 37.3 Overall survival in children aged 1–14 years with acute lymphoblastic leukaemia by UKALL trial 1977–2005. (Adapted from National Registry of Childhood Tumours Progress Report 2012, www.NCIN.org.uk.) 0 0 5 10 15 20 25 Years since diagnosis 30 35 40 45 50 2003–2010 2000–2002 1997–1999 1991–1996 1985–1990 1980–1984 1978–1979 20 40 Percentage surviving 60 80 100
715 CHAPTER THIRTY-SEVEN Box 37.11 Principles of good clinical practice Patient well-being 1. Clinical trials should be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, and that are consistent with good clinical practice (GCP) and the applicable regulatory requirement(s). 2. Before a trial is initiated, foreseeable risks and inconveniences should be weighed against the anticipated benefit for the individual trial subject and society. A trial should be initiated and continued only if the anticipated benefits justify the risks. 3. The rights, safety, and well-being of the trial subjects are the most important considerations and should prevail over interests of science and society. Trial design 4. The available nonclinical and clinical information on an investigational product should be adequate to support the proposed clinical trial. 5. Clinical trials should be scientifically sound, and described in a clear, detailed protocol. Trial conduct 6. A trial should be conducted in compliance with the protocol that has received prior institutional review board (IRB)/independent ethics committee (IEC) approval/favourable opinion. 7. The medical care given to, and medical decisions made on behalf of, subjects should always be the responsibility of a qualified physician or, when appropriate, of a qualified dentist. 8. Each individual involved in conducting a trial should be qualified by education, training, and experience to perform his or her respective task(s). 9. Freely given informed consent should be obtained from every subject prior to clinical trial participation. Data handling 10. All clinical trial information should be recorded, handled, and stored in a way that allows its accurate reporting, interpretation and verification. 11. The confidentiality of records that could identify subjects should be protected, respecting the privacy and confidentiality rules in accordance with the applicable regulatory requirement(s). Quality assurance 12. Investigational products should be manufactured, handled, and stored in accordance with applicable good manufacturing practice (GMP). They should be used in accordance with the approved protocol. 13. Systems with procedures that assure the quality of every aspect of the trial should be implemented. Reference: International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH harmonised tripartite guideline for good clinical practice E6(R1). Current Step 4 version, 10 June 1996. http://www.ich.org Clinical trial of investigational medicinal products (CTIMP) These clinical trials involve the use of a drug which is either new or being used in a new way. Drugs may be investigational medicinal products (IMPs) during one part of a trial, e.g. when being used in a new way, but not in another part, e.g. when treatment is the same as current standard of care. EudraCT number European Clinical Trials Database (EudraCT – https://eudract.ema.europa.eu/) was established in 2004 to give a unique reference number to all clinical trials in the European Union and wider European Economic Area, involving IMPs. It provides a single point of reference for all regulatory, licensing and scientific bodies to allow identification of clinical trials data being conducted across international borders. It also establishes clear lines of communication allowing timely pharmacovigilance reporting. Finally, it helps ensure strong links between regulatory authorities and trials which include a paediatric investigation plan (PIP). Paediatric investigation plan Pharmaceutical companies applying for a new marketing authorization must demonstrate that they have, where it is reasonable to do so, investigated the specific formulation and use of a new drug for children. Their plan to do so is submitted to the European Medicines Agency as a PIP. Companies registering a PIP are eligible for extended patent rights. Pharmacovigilance The process of identifying, reporting and acting on adverse drug reactions seen with drugs used at appropriate doses. Rapid reporting, centralization of data collection and rapid response are critical factors in preventing recurrent toxicity, especially in early phase/first-in-human trials. Box 37.12 Clinical trial registration terminology
37 716Clinical research Randomization The gold standard approach for assessing the benefit of a new investigation or treatment approach is a randomized controlled trial (RCT). In this setting, each patient is randomly allocated to receive either standard therapy/placebo or the new treatment. This removes the potential for biasing the outcome by allocating one particular group of patients, e.g. a more severe pattern of disease, to one arm or other. Minimizing bias is considered in Chapter 39, Evidencebased paediatrics. Difficulties can arise if the randomized intervention begins right at the beginning of the trial. Young people and families can find it hard to agree to give up control of an aspect of their care, especially if the disease is severe or of sudden onset and the new diagnosis accompanied by many other stresses and emotions (Box 37.13). An explanation of the need to randomize as well as the fact that, whilst we hope the new intervention will prove beneficial, we also need to be aware that it might not be as effective or even potentially harmful, is essential. For some families, entry into a parent can consent, it would not be appropriate to enrol a child in a clinical trial if either parent, or the child, did not give their consent or assent, respectively. Refusal of participation An important part of the consent process is for the young person and their family to understand that they have the absolute right to refuse to participate in a clinical trial. So as to avoid any coercion, the consent process must include explicit discussion of the fact that refusal will not affect the standard of care a young person receives in any way. Some families will have very valid concerns about trial involvement which must be respected, whether or not the research team agrees with them. The rights of trial subjects remain paramount. Similarly, the right to withdraw from the trial at any point and without needing to explain why must also be explained. Again, it is important that families understand that it will not affect their child’s treatment, with the caveat that the child will receive standard care and not any further trial therapies or interventions. Framed PICO research question: In term newborn infants born with hypoxic–ischaemic encephalopathy [population], is total body cooling [intervention] more effective than standard care [control] in reducing death or neurological abnormality at 18 months [outcome]? Method: 325 term newborn babies with HIE were randomized within 6 hours of delivery either to receive standard intensive care or intensive care plus moderate total body cooling to 33–34o C for 72 hours. Results: Infants in the cooled group had an increased rate of survival without neurologic abnormality (relative risk, 1.57; 95% CI, 1.16 to 2.12; P=0.003). Discussion: One critical element of this study was to explain the aims of the research, the concept of randomization and the genuine clinical equipoise which existed around cooling. Not only are these challenging concepts, but discussion had to occur soon after delivery, when the parents had only just been told that their newborn baby was severely ill. Compounding these difficulties was the need to register and randomize each baby before 6 hours of age, as this period represents the window of greatest potential benefit to the baby. In fact, the TOBY trial was able to overcome the challenges of recruitment and randomization in extremely high pressure situations so effectively that the trial recruited ahead of schedule, increasing its original target of 236, to a final recruitment of 325 babies. Despite these successes, the importance of clinical equipoise is highlighted by the fact that the primary outcome measure of death was not different between groups (relative risk 0.86; 95% confidence interval, 0.68 to 1.07; p=0.17). The study did demonstrate a significant benefit of cooling to improving survival without neurological abnormality (relative risk, 1.57; 95% confidence interval, 1.16 to 2.12; p=0.003). However, a retrospective meta-analysis of three trials (see Edwards et al) recruiting 767 babies to cooling following perinatal asphyxia did demonstrate a significant reduction in death and severe neurological disability at 18 months (risk ratio 0.81, 95% confidence interval 0.71 to 0.93, p=0.002). Cooling of asphyxiated babies is now recommended as standard practice according to NICE guidelines. References: Azzopardi DV, Strohm B, Edwards AD, et al. TOBY Study Group. Moderate hypothermia to treat perinatal asphyxial encephalopathy. New England Journal of Medicine 2009:361;1349–58. Edwards AD, Brocklehurst P, Gunn AJ, et al. Neurological outcomes at 18 months of age after moderate hypothermia for perinatal hypoxic ischaemic encephalopathy: synthesis and metaanalysis of trial data. BMJ 2010;340:c363. Box 37.13 Landmark trial – the TOBY trial sought to enrol and randomize asphyxiated newborns within 6 hours of birth
717 CHAPTER THIRTY-SEVEN clinical trial is not the right thing at the point of diagnosis and this must be respected. Biobanking – opportunity for active participation Many trials will require the collection and storage of tissues for associated biological studies. Young people and families may also be asked whether they would be willing to allow residual diagnostic tissue to be stored prospectively for future studies, in an organized biobank. Biobanking offers young people a safe way to contribute to future research into their condition, something which is frequently welcomed. Biobanking is particularly important in paediatric research, where many conditions are rare and prospective collection forms the only realistic opportunity to acquire sufficient samples for meaningful research. Monitoring of a trial Answers 37.4 1. I. Sponsor. The sponsor is a pharmaceutical company, funding body or academic institution which bears overall responsibility for a specific trial. 2. J. Suspected unexpected serious adverse reaction (SUSAR). A suspected unexpected serious adverse reaction is defined by the fact that it was unexpected, serious and is suspected as being a direct adverse reaction to an intervention (e.g. a new drug) in contrast to a serious event which may have nothing to do with any intervention within the trial. 3. A. Data monitoring committee (DMC). The DMC is responsible for regular analysis of incoming data returns to ensure that a predetermined treatment effect or unacceptable toxicity has not been seen before the recruitment target is met. This ensures that unexpectedly large treatment effects, both positive and negative, are identified early, minimizing the number of patients given suboptimal treatment. Safety monitoring Once a trial protocol has been decided on, the appropriate approvals granted and the first patients recruited, an ongoing process of safety monitoring is required to identify any adverse reactions resulting from the intervention. Clear routes of communication are required to ensure that any severe or unexpected adverse reactions are rapidly reported and acted upon, potentially by suspending the trial or use of the novel intervention. Different types of notifications exist, namely serious adverse events (SAEs) and suspected unexpected serious adverse reactions (SUSARs). By their nature, SUSARs cannot be defined but clarification on what constitutes an SAE should be included within the trial protocol. Serious adverse events Serious adverse events are experiences related to the trial interventions (either standard or investigational arms) which result in death, serious illness or injury, admission/prolongation of admission to hospital or congenital anomaly/birth defects. They must be reported to the chief investigator within 24 hours. Other serious events should be discussed with the chief investigator in case they qualify for notification. Question 37.4 Clinical trials terminology The following (A–J) is a list of terminology used in clinical trials: A. Data monitoring committee B. EudraCT C. Good clinical practice D. Institutional Review Board E. Investigational medicinal product F. Medicines Healthcare Regulatory Authority G. Paediatric investigation plan H. Serious adverse event I. Sponsor J. Suspected unexpected serious adverse reaction Which item of terminology best describes each of the following: 1. The body bearing overall legal and financial responsibility for the design, conduct, analysis and reporting of a clinical trial. 2. A serious untoward event which, from our current knowledge, was not predictable but which is believed to be as a direct consequence of a trial intervention. 3. The body responsible for regular analysis of data from an ongoing trial. Their task is to ensure that the trial has not reached its predefined endpoint in advance of final recruitment and that no unforeseen detrimental effects can be identified.
37 718Clinical research Suspected unexpected serious adverse reactions SUSAR reporting exists to ensure rapid identification of previously unidentified side effects of an intervention. Typically these will be side effects potentially attributable to a new drug or formulation. SUSARs must be notified to the chief investigator within 24 hours and thereafter the chief investigator must notify the MHRA. Interim analyses and stopping rules Whilst the trial design, and particularly the power calculation, have estimated the number of children required to achieve a significant result, these estimates are based on the expected magnitude of the effect of the intervention. If the magnitude observed is substantially greater than expected, or an unexpected effect occurs, then a significant result may be achieved before full recruitment is reached. Alternatively, if the trial intervention is associated with an increased toxicity then this must be identified and the trial reviewed and potentially stopped. Commonly, the trial protocol will define the desired level of outcome, as well as any other criteria which, if met, would indicate a need to stop a trial. In order to monitor for both early successful completion of a trial and adverse outcomes, trials will appoint a data monitoring and ethics committee (DMC/DMEC) who meet at defined intervals to analyse the data received so far. With phase I trials, commonly the committee will meet following administration of a single dose level and decide whether or not to proceed to the next dose level. During this period, enrolment to the trial will usually be suspended. With larger phase III trials, this can be a rolling process which may result in either early closure or amendment of the trial protocol (Box 37.14). Follow-up and data analysis Depending on the trial question, as much important information may be collected after the intervention has been completed as during it. For this reason, having a robust mechanism for follow-up is critical. Data can be analysed at specified time points and reported. Whilst there is ongoing data collection and analysis ahead of final publication and development of the next trial, clinicians may need to know whether the current standard treatment remains the gold standard. Commonly a set of interim guidelines will be produced defining the perceived new standard therapy based on, for example, interim analyses by the data monitoring committee. Framed PICO research question: In premature infants [population], does targeted low (85–89%) [intervention] versus high (91–95%) [control] functional arterial oxygen saturation (SpO2), affect death or severe neurosensory disability on assessment 2 years after the child was due to be born [primary outcomes] or rates of retinopathy, chronic lung disease, weight gain [secondary outcomes]? Method: Randomized controlled trial. The UK BOOST-II trial aimed to recruit 1200 babies. Four other trials with similar protocols and outcome measures were also run in the US, Canada, Australia and New Zealand. As none of the trials was powered to reliably demonstrate a difference in the primary outcome on its own, a collaboration was agreed between the data monitoring committees to confidentially share interim data to allow a prospective meta-analysis. Discussion: Unpublished data from the US trial (SUPPORT Trial) showed a marginally significant (p<0.04) reduction in survival in infants whose oxygen saturations targeted the lower 85–89% range. Each of the other DMCs analysed the US data alongside their own national data but found no evidence to support ending recruitment to the other trials. However, no agreement could be reached about pooling data from all trials. Shortly afterwards, DMCs from the UK, Australia and New Zealand did combine their data and were able to demonstrate a significantly worse mortality at 36 weeks in the group targeting 85–89% saturations. This trial therefore closed early after recruitment of just 973 UK babies, and advised that neonates born at <28 weeks’ gestation should not have oxygen saturations targeted to 85–89%. This example highlights the importance of interim data analysis by independent committees, as well as the importance of international collaboration, both at the trial design and analysis stage. By using all the available data, including unpublished data, a survival benefit was identified earlier, thus accelerating the development of practice and preventing unnecessary recruitment into a trial arm with inferior outcome. Reference: BOOST II United Kingdom Collaborative Group. Oxygen saturation and outcomes in preterm infants. New Engl J Med 2013:368;2094–104. Box 37.14 Landmark trial – BOOST-II trial was closed early to recruitment after prospective meta-analysis identified a worse mortality in one arm
719 CHAPTER THIRTY-SEVEN Follow-up Critical to the success of a trial is achieving as full follow-up of enrolled patients as possible. Loss to follow-up is a major potential source of bias, with patients experiencing unpleasant side effects or perceived poor outcome from their therapy being most likely to drop out. Rigorous attempts to achieve complete follow-up are therefore important, as is consideration of degree of follow-up when assessing the results of published trials. The numbers of patients assessed at each time point, as well as any systematic reasons for lack of assessment must be reported with the trial results to allow accurate interpretation. As deviations from protocol, withdrawal from trial and loss to follow-up can all introduce bias to a study, all data must be analysed based on the original allocation of a patient. This principle is called analysis on an intention-to-treat basis. Statistical testing Statistical analysis of trial data is perhaps the most important yet least well understood area of clinical trial methodology (see Chapter 38, Statistics). Many statistical analyses rely on performing a test of the probability that the result of the trial was achieved by chance alone. They ask the question: ‘Is a particular parameter, such as mean or proportion over a threshold, sufficiently different between these samples that the populations from which they are drawn can be assumed to be different also?’ The probability is described as the p-value associated with the statistical test performed. A value of p≤0.05 means that the observed difference between samples could have occurred by chance alone with probability equal to or less than one in twenty, or 5%. Although there are many different statistical tests, only a handful would be applicable to the analysis of a particular data set. The issue to be addressed at this stage of data analysis is: ‘What is the most appropriate test to apply to any particular data set?’ Good statistical analyses should start with simple descriptive statistics of the data set which, in reality, represents only a sample of the entire population of children with that condition who might receive a particular intervention. If the data are continuous, the following questions are all pertinent: • What is the central position of the data (commonly expressed as an average – mean, median, mode)? • What is the dispersal of the data around the average (standard deviation)? • How are the data distributed? • Are the data symmetrical? • Are there outliers? If the data are categorical (yes/no data, for example), similar sorts of questions maybe asked. Also, extremely important in the early stages of any analysis is to display the data graphically. Having described and presented the data graphically, the next critical question is which statistical analysis to perform, e.g. Student’s t-test, Mann– Whitney U test, regression analysis, confidence intervals (see Chapter 38, Statistics). Many of the available analyses will only be suitable in a proportion of cases, which may be defined by a number of assumptions. These assumptions must be examined before being able to choose the appropriate test for each analysis. Non-parametric tests make no assumptions as to the nature of the data, making them broadly applicable, but in general they pay the price of having reduced power and therefore being less likely to provide a result which allows the investigator to confidently reject the null hypothesis. Again, considering the appropriate analysis and making an open statement of it in the trial protocol provides confidence in the approach taken and the veracity of the final result. One final consideration is that of multiple testing. If multiple tests are performed to search out significant differences, then one result in every twenty tests performed will be ‘significant’ (p≤0.05) by chance alone. Two approaches are commonly used to avoid such difficulties. Firstly, it is possible to apply statistical corrections to allow for multiple testing. Frequently, however, these rely on increasing the stringency of the test making identification of a true difference more difficult. The second approach is to reduce the number of tests performed by targeting the data analysis towards the primary and limited secondary outcome measures, as clearly stated in the initial protocol. As discussed above, this approach reduces the risk of incorrectly rejecting the null hypothesis (type 1 error, α), whilst maximizing the chance of correctly accepting the alternative hypothesis (thereby avoiding type 2 error, β). If an appropriate test is applied to accurately obtained data, then it is reasonable to draw conclusions on the basis of a p-value ≤0.05. This, however, does not tell you anything about the clinical relevance of the result. A large enough sample size from a tightly dispersed population can provide a statistically significant result for an intervention resulting in minimal change in outcome. The clinical relevance must be assessed by considering the size of the effect and a confidence interval for that effect. The importance of this must then be considered in the setting of side effect profiles, dosing regimen, impact on patient’s life, economic cost and so on. This can be considered as the clinical significance of a trial result, distinct from the statistical significance.
37 720Clinical research ensuring that appropriate changes to practice are made in response to evidence. Responses may include the development of a subsequent clinical trial, e.g. phase I results being developed into the subsequent phase II trial, or development of the next phase III study based on the new standard of care defined by the preceding trial. In this second example, there may be a period when the initial analysis of the phase III study allows the formation of an interim guidance statement, ahead of the development of the subsequent phase III protocol. Such an approach is commonly used in paediatric haematology/oncology, when a clear survival advantage has been shown in one study arm. Trial reporting New findings derived from a clinical trial can only be critiqued and subsequently acted upon if they are widely disseminated. This should include peerreviewed publication of trials with both positive and negative findings (Box 37.15). Whilst publishing positive findings of well-designed trials should be straightforward, publishing negative findings is more complicated, both because these studies have lower priority for high quality peer-reviewed journals and because there can be reluctance to publish the failure or poor side-effect profile of a new drug. Prospective open access registration of CTIMPs (discussed above), including their stated primary outcome measures, is critical to allow thorough analysis of trial outcome, avoiding poor practice such as reporting only: • Secondary outcome measures • Surrogate markers of outcome, not primary outcome measures • Subgroup analysis not pre-defined in protocol (see discussion on multiple statistical testing, above) • Event-free survival only, not overall survival (where this would be more appropriate) Additionally, only by publishing all outcomes can systematic review and meta-analysis of clinical trials be used to answer clinical questions which individual studies are unable to address. Influence on practice The clinical significance of trial outcomes is harder to assess than the statistical significance, but is critical to Box 37.15 CONSORT statement defining standards for reporting randomized trials CONSORT – consolidated standards of reporting trials This statement encompasses various initiatives developed by the CONSORT Group to alleviate the problems arising from inadequate reporting of randomized controlled trials. The main product of CONSORT is the CONSORT Statement, which is an evidence-based, minimum set of recommendations for reporting randomized trials. The CONSORT 2010 Statement includes a 25 item checklist to provide guidance for reporting all randomized controlled trials. Even if you are not planning on undertaking an RCT, the CONSORT Statement makes a useful tool for critically appraising RCTs that you are hoping to implement into your clinical practice. Further reading: http://www.consortstatement.org Question 37.5 PICU consortium trial of a new drug Scenario: A paediatric intensive care (PICU) consortium wants to establish a trial to investigate the role of a new immune-modulating drug in children with sepsis. Framed PICO (population, intervention, comparison, outcome) research question: In children who present to a PICU with sepsis associated with multiple organ dysfunction [population], is an immune-modulating drug [intervention] compared to standard PICU care [control], effective at reducing mortality and/or hastening recovery [outcomes]? Discussion: This drug has not been used in this setting in children before and the potential risks of immune stimulation in sepsis are unclear. In vitro studies and animal models of sepsis suggest that the drug results in activation of the innate immune system and improved bactericidal activity. Optimal dosing has not been determined in children but early phase trials in adults suggest the drug can be safely administered although an optimal dosing schedule has not yet been determined. Which of the following statements most accurately describes the position of the consortium? Select ONE answer only. A. Additional blood samples should not be taken for associated fundamental science studies. B. A phase III clinical trial is required to demonstrate superiority over standard PICU care. C. An early phase I/II clinical trial should be designed to establish safety and appropriate dosing. D. Children admitted to PICU are too unwell for adequate consent for this clinical trial to be obtained. E. Collection of a range of demographic and admission-specific data on all patients will allow multivariate analysis to determine which patients are most likely to benefit from the new drug.
721 CHAPTER THIRTY-SEVEN • Targeted/precision therapies: Drugs designed to, usually, inhibit specific molecular pathways which have been demonstrated to be overactive in a particular disease (Box 37.17). Particularly prevalent in modern medical oncology, targeting disease-specific pathways is hoped to provide better disease control with fewer side effects than standard cytotoxic chemotherapy, which broadly ‘targets’ all dividing cells. Experimental medicine Experimental medicine (EM) is an: Investigation undertaken in humans, relating where appropriate to model systems, to identify mechanisms of pathophysiology or disease, or to demonstrate proof-ofconcept evidence of the validity and importance of new discoveries or treatments. MRC Research Initiatives Box 37.16 Research approaches to stratified medicine One consequence of stratifying diseases is that trial subgroups are becoming smaller, often within already rare diseases. Alternative approaches to the classical randomized controlled trial are being taken, both to match the treatment to the ‘molecular’ disease and to reject ineffective drugs and accommodate potential new drugs without stop/starting the trial. The strategies used are bespoke to each trial and currently most prevalent (although still uncommon) in adult oncology practice, where examples include Focus4 and Stampede trials. As these approaches become better understood, along with the supporting statistical analyses, it seems likely that they will be increasingly applied to paediatric studies too. This will require validated genetic/molecular assays which can be robustly delivered in a clinically relevant time frame. Further reading: http://www.focus4trial.org/ http://www.stampedetrial.org/ Box 37.17 Targeted therapies – salbutamol One of the very first therapies rationally designed to specifically target an active pathway was the widely used asthma medication, salbutamol. Increasingly selective blockade of the β2 adrenoceptor was achieved by sequential modifications of the adrenaline analogue isoprenaline, resulting in effective relaxation of bronchial smooth muscle tone with reduced cardiovascular side effects. Answer 37.5 C. An early phase I/II clinical trial should be designed to establish safety and appropriate dosing. As the dose and safety of the new drug have not been established in this clinical setting, an early phase study is required to identify the maximum tolerated dose and safety. Apart from the inherent risks of unguided multivariate analysis, this trial has not been powered to detect benefit and will not be able to provide predictive data on response to the new drug. Whilst performing clinical trials in acutely sick children can be extremely challenging, it is a critical element of improving the care of this group. Researchers should gain as much information as possible, taking opportunities to perform fundamental scientific experiments on clinical samples. However, the well-being of the child is paramount and the risk of additional blood samples, for example, must be carefully considered. The interpretation of clinical significance is reviewed in detail in Chapter 39, Evidence-based paediatrics. Future clinical study approaches Personalized medicine As we improve our understanding of the molecular subclassification of disease, there is a strong drive to deliver therapies appropriate to an individual patient’s disease. Further personalization will include predictions of a patient’s handling of a drug or susceptibility to drug toxicity. Indeed, in paediatric oncology, prospective analysis of thiopurine methyltransferase (TPMT) variants and phenotype have been used for many years to guide dosing of 6-mercaptopurine. Other important components of personalizing medicine can be defined: • Stratified medicine: Subdividing patients according to the genetics or molecular biology of their disease so that appropriate targeted therapies can be given (Box 37.16). • Biomarkers: Described in Box 37.3, biomarkers are features which describe a characteristic of a patient, allowing their disease and subsequent therapy to be stratified. That is to say, a characteristic which allows individualization of their treatment.
37 722Clinical research Table 37.4 Omics technologies and their uses Omic study Analyses Technologies Genomics Genetic sequences – specific targets, coding sequences or whole genome NGS – large number of platforms Epigenomics Chromatin modifications NGS-based approaches Methylomics Example of epigenomics specifically looking at DNA methylation Array or NGS-based approaches Transcriptomics Expression of all genes by measuring mRNA Array or NGS-based approaches Proteomics Protein levels. Can be adapted to measuring activated proteins, e.g. phosphoproteomics Western blotting, immunohistochemistry, ELISA (analysis of a small number of proteins), mass spectrometry (large scale protein determination) Metabolomics Metabolic signature of disease process or treatment effect Very broad range including chromatography, mass spectrometry and nuclear magnetic resonance spectroscopy NGS, next-generation sequencing used for massively parallel sequencing of DNA or RNA. As such, it is performing experiments, in humans, to discover the cause of a disease or to test the validity and importance of new treatments. It is increasingly considered an important element of early phase clinical trial design, feeding back to ongoing pre-clinical studies and informing subsequent later phase trials (see Fig. 37.1). • EM makes best use of all data available from the most representative model system available, namely early phase clinical trials in humans • Careful consideration must be given to the clinical and ethical implications of multiple sampling from children • Comparisons made with pre-clinical models (described above) can highlight differences between model and human and lead to development of improved pre-clinical strategies • Information on the effectiveness of/resistance to a drug can alter treatment combinations • The utility of biomarkers can be assessed Clinical ‘omics’ The tools required to dissect the molecular features of both a young person and their disease are becoming increasingly commonplace in fundamental/pre-clinical research and the translation of their use for diagnostic purposes is increasing. Snapshots of the genome made available by next-generation sequencing are complemented by additional ‘omic’ technologies, which have the power to analyse vast numbers of molecular changes in parallel (Table 37.4). Again, substantial challenges remain in the analysis and interpretation of data, both in populations and also, critically, in individual patients too. Further reading Academic Paediatrics Association (APA). <http:// www.academicpaediatricsassociation.ac.uk/>; [accessed 10.09.15]. UK association promoting the development of academic paediatrics and child health. Federation of American Societies for Experimental Biology (FASEB). Funding basic science to revolutionize medicine – 2013 FASEB Stand Up for Science (winner). <www.youtube.com/watch?v=GmhD-RWNL6c>; 2013 [accessed 10.09.15]. Because it is not all about translational and patient-centred research! General Medical Council (GMC). 0–18 years: guidance for all doctors. <http://www.gmc-uk.org/static/documents/ content/0-18_years_-_English_1015.pdf>; 2007 [accessed 10.09.15]. Specifically Paragraphs 36–40 focusing on research. Medical Research Council (MRC). <http://www.mrc.ac.uk/ research/>; [accessed 10.09.15]. Describes some of the major driving initiatives in current clinical research. Medical Research Council (MRC). Experimental medicine. <http://www.mrc.ac.uk/research/initiatives/experimentalmedicine/>; [accessed 10.09.15]. Royal College of Paediatrics and Child Health (RCPCH). Turning the tide: harnessing the power of child health research. <http://www.rcpch.ac.uk/harnessing-the-power-ofchild-health-research>; 2014 [accessed 10.09.15]. Describes the Colleges recommendations to develop child health centred research and promote academic training in the UK. World Health Organization (WHO). International clinical trials registry platform (ICTRP). <http://www.who.int/ictrp/en/>; [accessed 10.09.15].
LEARNING OBJECTIVES By the end of this chapter the reader should: • Know about the different ways in which data can be categorized and displayed • Understand frequency distributions and features of a normal distribution • Know how to describe different types of data • Know what confidence intervals and p-values are and how they can be used • Understand about the application of appropriate statistical tests • Understand how to interpret statistical results in clinical and epidemiological studies • Understand the limits of statistical tests 723 CHAPTER THIRTY-EIGHT Introduction Statistics are ‘a body of methods for making wise decisions in the face of uncertainty’ (W Wallis: A New Approach, 1957). As doctors, it is essential for us to have an understanding of statistical principles and methods so that we can: • Conduct research • Interpret data • Appraise evidence • Apply and explain results to patients and families. Other sections in this book describe research, evidence-based medicine and epidemiology. This chapter will cover the fundamentals of statistics that will provide the tools to navigate the world of clinical and epidemiological research and appreciate its scope and limitations. While all tests are carried out using software packages, readers of journals and researchers need to know which test to implement and understand what the programme is doing and what sort of output to expect. Types of data Statistical methods can be applied to quantitative data, a set of numbers and values that have been measured. The type and/or method of recording of quantitative data is important since it influences the choice of statistical tests as well as the way in which the data is described and displayed. Qualitative data, by comparison, is descriptive and usually represents an expression of thoughts, feelings or experiences. There are resources available which detail appropriate methodologies for analysing qualitative data, but this will not be covered in this chapter. Quantitative data (also referred to as variables, i.e. a characteristic, number or quantity that differs between individuals or items) can be numeric, in which a number is recorded, or categorical (Fig. 38.1). Numeric data, in which a number is recorded, can be further subdivided into discrete or continuous datasets: • Discrete data can only be expressed in whole numbers; for example, number of children per family or number of episodes of severe asthma per year. • Continuous data, on the other hand, can take any value in a given range. For example, height, weight or age. Categorical data can be: • Binary data – in which there are only two categories; for example, alive/dead or a yes/no response. • Ordinal data – which is in groups that can be ordered; for example, social class 1–5 or grades of bowel cancer. Miriam Fine-Goulden, Victor Grech Statistics C H A P T E R 38
38 724Statistics • Nominal data – constitutes a number of groups with no order/hierarchy; for example, blood group or marital status. Displaying data The best method for displaying data depends on the type of data and the number of variables and datapoints. A good pictorial presentation of data can be an extremely effective and efficient means of communication. It is also crucial to plot the data: • In order to ensure that there are no obvious errors, e.g. gross outliers, which may have been due to erroneous data collection or inputting mistakes Fig. 38.1 Types of quantitative data. Categorical Discrete Continuous Binary Ordinal Nominal Quantitative data Numeric Fig. 38.2 Deaths by cause, percentage of total, and numbers, among 5–9-year-olds in the UK, 2010. This chart type gives a simple visual representation allowing the reader to picture all categories at once and compare their relative proportions. (Adapted from Wolfe I, et al. Why children die: death in infants, children and young people in the UK. May 2014, RCPCH and NCB.) Congenital 11% (37) Other 4% (13) Infectious 7% (22) Digestive 3% (9) Respiratory 9% (30) Circulatory 6% (21) External 16% (52) Nervous system and developmental 13% (41) Endocrine, nutritional and metabolic 6% (20) Cancer 25% (81) Answers 38.1 1. D. Histogram. 2. A. Bar chart as not a continuous variable. 3. F. Pie chart showing percentages See below for details. • To understand the shape, scope and overall nature of the data • To identify any interesting patterns. Tables Tables are a useful way to summarize and present data and can usually provide more precise numerical data than a graph. Pie charts Pie charts are used to demonstrate proportions of a group falling into different categories. A circle is divided into segments, and the angles are proportional to the size of each category (Fig. 38.2). Question 38.1 Displaying statistical data Following is a list of methods of displaying data: A. Bar chart B. Box-and-whisker plot C. Dot diagram D. Histogram E. Line diagram F. Pie chart showing percentages G. Pie chart showing actual numeric values H. Scatterplot For each of the following case scenarios, select the most appropriate graphical depiction method from the list above. 1. A sample of 1000 seven-year-old male schoolchildren undergo BMI testing. 2. Smoking in pregnancy. Results of a survey of mothers: 1 to 3 cigarettes/day = 31; >3/day = 44; do not smoke = 856; unspecified = 44. 3. Analysis of mode of delivery in a group of mothers: 596 normal vaginal deliveries, 318 by caesarean section and 35 by assisted vaginal delivery.
725 CHAPTER THIRTY-EIGHT but it may not be practical where there are large numbers of measurements. Line diagrams When measurements are repeated at different time points, for example, before and after a certain treatment, lines drawn between paired dots (Fig. 38.5) can illustrate measurements or the effect of intervention/ treatment. Scatterplots Scatterplots (Fig. 38.6) illustrate the relationship between two continuous variables, represented on Bar charts Bar charts (Fig. 38.3) can be used to display a single variable, with the heights of the bars proportional to the frequency. They may also show the relationship between two variables by being grouped or stacked. Dot diagrams Dot diagrams (Fig. 38.4) can be used to display continuous numeric data for a variable, for a single group or multiple groups. Each dot represents a single value. It is a simple method of conveying as much information as possible, and it is easy to see outliers and to compare the distribution of results in different groups, Fig. 38.3 Length of hospital stay for children diagnosed with chylothorax. (Adapted from Haines C, Walsh B, Fletcher M, et al. Chylothorax development in infants and children in the UK. Arch Dis Child 2014;99:724–30.) 40 LENGTH OF HOSPITAL STAY FOR CHILDREN DIAGNOSED WITH CHYLOTHORAX 30 20 10 0 5 15 25 35 0–10 Days 11–20 Days 21–30 Days 31–40 Days 41–50 Days 51–60 Days 61–70 Days 71–80 Days 81–90 Days 91–100 Days >100 Days Number of children Fig. 38.4 Asthma deaths over time by age group (n = 193). (From Royal College of Physicians. Why asthma still kills: the National Review of Asthma Deaths (NRAD) Confidential Enquiry report. London: RCP, 2014, with permission.) Age group (years) <10 10–19 20–44 45–64 65–74 75+ 1 Apr 2012 1 Jul 2012 1 Oct 2012 1 Jan 2013
38 726Statistics Fig. 38.5 Paired axillary–oral temperatures. Same measurement on each patient. First 100 patients aged 4–14 years. (Data from Falzon A, Grech V, Caruana B, et al. How reliable is axillary temperature measurement? Acta Paediatr 2003;92:309–13.) 40.0 39.0 38.0 37.0 36.0 35.0 34.0 Oral Site temperature measured Axillary Temperature (°C) Fig. 38.6 Scatterplot of paired axillary–oral temperatures. Same measurement on each patient. Patients aged 4–14 years. 112 children during the course of their admission to hospital. (Data from Falzon A, Grech V, Caruana B et al. How reliable is axillary temperature measurement? Acta Paediatr 2003;92:309–13.) 33.0 35.9 36.9 37.9 Oral temperature°C 38.9 39.9 34.0 35.0 36.0 Axillary temperature°C 37.0 38.0 39.0 40.0 Question 38.2 Describing data A sample of 1000 seven-year-old male schoolchildren undergo BMI testing. You are asked to summarize the data numerically, using up to three parameters, without actually showing a graph. Which set of parameters would best describe the data? Select ONE answer only. A. Mean, median and confidence intervals. B. Mean, median and range. C. Mean, standard deviation and confidence intervals. D. Median, range and standard deviation. E. Variance, standard deviation and range. vertical and horizontal axes. Scatterplots may include a line of best fit (see Correlation and regression, below). Box-and-whisker plots Typically, the line in the middle of the box represents the median value, the upper and lower horizontal lines of the box represent the upper and lower quartiles and each contain 25% of the values, so the box encompasses 50% of the values. The limits of the whiskers represent the highest and lowest values (i.e. the range) and each whisker encompasses 25% of the values (Fig. 38.7). Describing data Frequency distributions The normal distribution is symmetrical and bellshaped (Fig. 38.8). It is a familiar concept in medicine, as much of the data collected from human subjects is normally distributed, e.g. height and weight. Data that has a non-normal distribution may be skewed, to the left or to the right. A good example of skewed data in medicine is length of hospital stay: most patients stay for a short period of time, but a small number of patients stay for an extended period, pulling the ‘tail’ of the distribution to the right. Answer 38.2 A. Mean, median and confidence intervals. See below for discussion.
727 CHAPTER THIRTY-EIGHT compatible with a normal distribution. In some cases, non-normally distributed data can be ‘transformed’, for example by logging or squaring, to take on a normal distribution so that certain statistical tests can be applied. The method used is determined by the nature of the data. Tests that rely on the data being normally distributed are known as parametric tests. If datasets are large but not normally distributed, parametric tests may still work well: a property known as robustness. Tests which make no assumptions about the normality of the data distribution are called non-parametric tests. These are almost as efficient as parametric tests for normally distributed data and superior for nonnormally distributed data. Mean and median The mean – or average – is a familiar concept. It is calculated by adding up all the values and dividing by the total number of values. For example, the mean time (in minutes) from triage to assessment by a doctor for ten children with fever ≥40°C in an emergency department is the total of all the values divided by ten: Group 1 mean: 39 22 48 11 19 33 42 27 28 31 10 30 + + + + + + + + + = minutes The mean is a useful measure of the centre where values are normally distributed or close to normally distributed, but it can be affected dramatically by one or two extreme values. For example, in the group Tests of normality and data transformation Whether or not a set of data is normally distributed may be important when it comes to applying statistical tests, as some tests are only valid for normally distributed data. It may be possible to tell if data is normally distributed by ‘eyeballing’ it in graphical form. There are also mathematical tests that can be applied. These cannot confirm that the data are normally distributed, but can confirm that they are Fig. 38.7 Diagrammatic explanation of box-and-whisker plot. Lowest value in series Whisker (25% of values) Highest value in series Whisker (25% of values) Upper quartile (25% of values) Median Lower quartile (25% of values) Fig. 38.8 A normal distribution bell-shaped curve with percentage of cases in 8 points of the curve, standard deviations, cumulative percentages, percentile and Z scores. Data that has a non-normal distribution may be skewed, to the left or to the right. Percentage of cases in each portion of the curve 0.13% 0.1% –4.0 –3.0 –2.0 1 5 10 20 30 40 50 60 70 80 90 95 99 –1.0 0 +1.0 +2.0 +3.0 +4.0 2.3% 15.9% 50% 84.1% 97.7% 99.9% –4σ –3σ –2σ –1σ 0 +1σ +2σ +3σ +4σ 2.14% 13.59% 34.13% 34.13% 13.59% 2.14% 0.13% Normal, bell-shaped curve Standard deviations Cumulative percentages Percentiles Z scores
38 728Statistics The single large value that influenced the mean in group 1 did not have as much of an effect on the median. In data that is normally distributed, the mean and median values will be the same; the greater the skew of the data, the greater the difference between the median and the mean. In non-normally distributed data, the median is therefore usually more representative of the centre than the mean. However, because the median is less sensitive to changes in the data, it may be a less useful summary measure. In a table summarizing data, it may be helpful to display both values. Data spread As well as giving an idea of the centre of the data, we also need to know about its spread, or variability, its dispersion. The range is the difference between the highest and lowest values. It is often given in brackets after the mean or median. For example, using our data for children with fever (above), ‘the mean time from triage to assessment was 30 minutes (11–48)’, or ‘the median time for triage to assessment was 30.5 minutes (11–231)’. One problem with the range is that it is influenced by outliers (extreme values). It can also depend on sample size, as the larger the sample size, the greater the range is likely to be. above, if there was one child who waited for a long time because the doctor was unavailable, this could have a significant effect on the results: Group 2 mean: 39 22 48 11 19 33 42 27 28 231 10 50 + + + + + + + + + = minutes The median value is another measure of the centre, and it is the actual middle value (or the mean of the two middle values if there is an even number of values), so there will be the same number of values above and below it. The median is less influenced by skewed data than the mean. In the example above, the median value will be in between the 5th and 6th values (as there are ten values, an even number – if there were 11, it would be the 6th value). Group 1 median: 11, 19, 22, 27, 28, 31, 33, 39, 42, 48 = 29.5 minutes 11, 19, 22, 27, 28, 33, 39, 42, 48, 231 = 30.5 minutes Group 2 median: A measure of spread that is not sensitive to outliers is the interquartile range, as described above under Boxand-whisker plot. The standard deviation is a measure of the spread of data around the mean. In normally distributed data, measurements will be either larger or smaller than the mean. Subtracting the mean from each value gives the difference between that value and the mean. Because the numbers below the mean will be negative (which is not important, because it is the actual difference that matters), all the numbers are squared (to make them all positive), and then added together. If there is a wide spread about the mean, the values will all be very different from the mean, giving a large number, and conversely, if they are tightly grouped around the mean, the number will be small. The variance is the sum of all the squared differences divided by the total number in that sample minus one (so, for example, if there are 100 patient measurements in the sample, you would divide by 99 to get the variance). The square root of the variance is then obtained in order to ‘unsquare’ the value, and this is called the standard deviation (SD). Therefore: ± 1 SD incorporates 68.2% ± 2 SD incorporates 95.4% ± 3 SD incorporates 99.7% and ± 1.96 SD incorporates 95% ± 2.58 SD incorporates 99% Z scores: One of the most frequently used measures for the presentation of results is the Z score (also known as the standard score). They represent the number of standard deviations of an individual data point from the mean. The Z score is calculated from the following equation Z = (x − µ) ÷ σ where x = the experimental value, µ = the mean and σ = the standard deviation. The calculation of a Z score assumes that the data being analysed is normally distributed, the data points are independent and random and that the sample size is greater than 30. The mean and standard deviation are good measures of centre and spread in data that is normally distributed with a sufficient sample size. If not, it may be that the median and interquartile range are more appropriate descriptions of the data. The relationship between the normal distribution and a box-andwhisker plot is shown in Figure 38.9. Confidence intervals The ‘confidence interval’ defines the range of values within which the ‘true’ population mean is likely to lie. i. Research question: Imagine you want to undertake a small research project to describe the serum vitamin