Active End-of-Life Decisions in Dutch Pediatrics, Should the Age Limit be Revised?

Introduction

Il y a longtemps que je t’aime (fictive French movie released in 2008): Juliette Fontaine was a French physician and diagnosed her son with Gaucher’s disease, a very painful and progressive disease first described in 1882 by Philippe Gaucher. Gaucher’s disease is a genetic disorder and is associated with a lot of different symptoms like fatigue, hepatomegaly, splenomegaly, anemia, severe pain and neurological abnormalities. The disease is untreatable and patients typically die within 2 years.1 Piece by piece, her sister Léa finds out why Juliette killed Pierre. Since euthanasia is illegal in France and there were no other possibilities to relieve the child’s suffering, Juliette saw no other way out than killing her own son. She did not want to see the suffering of her child and injected him with a deadly substance. At her trial, she spoke no word of defense and stated she deserved to be punished. She was released after she served a prison sentence of 15 years. 

‘What if you want your child to die?’

How can a parent become so desperate, that he or she is capable of doing such a horrible thing? How is someone willing to sacrifice the life of her son and 15 years of her own life? In some cases, there are no available methods to relieve the suffering of a child, for example because the life expectancy does not meet the criteria of palliative sedation. The key question underlying this kind of situations is: what are the possibilities in terms of life-ending decisions when a child suffers unbearably, the quality of life is very low and there are no possibilities left to relieve the suffering? Many parents of terminally ill children aged 1 to 12 struggle with this dilemma. In the Netherlands, people over the age of 12 can request euthanasia. Furthermore, life-ending decisions in infants (<1 year old) are tolerated under strict conditions (Groningen Protocol). It is better not to use the term ‘euthanasia’ in the context of severely ill infants because the Dutch euthanasia law only applies to people who made a rational and voluntary request. The term ‘active end-of-life decisions’ is more appropriate in case of human beings without capacity of discernment who cannot make a rational and voluntary request, so this is the case for infants.9 However, there is no consensus about tolerating life-ending decisions in the Netherlands for children aged 1 to 12 years. The aim of this paper is to explore the moral and ethical issues concerning pediatric end-of-life decisions in the Netherlands. The main goal is to formulate an answer to the question: should active end-of-life decisions be possible in the Netherlands for children aged 1 to 12 years?
 

Methods

To assess the different moral and ethical issues concerning the active life-ending decisions in children aged 1 to 12 years literature searches were performed on the 21st of August, 2019. The first search was focused on end-of-life decisions for infants (Groningen Protocol) and the following search was used in PubMed: ‘(((Groningen Protocol[Title/Abstract]) AND ethics[Title/Abstract]) OR pediatric euthanasia[Title/Abstract]) OR euthanasia newborns[Title/Abstract]’. This search identified 289 results which were sorted by the ‘most recent’ option. Only English articles which focused on the Groningen Protocol and contained opinions of experts were included. Articles not about human and articles without an abstract were excluded. 162 documents remained after this selection. A screening was performed on title and abstract. Articles published before the Groningen Protocol, were excluded. 24 articles were read and eventually, 4 articles were excluded because they focused too little on the Groningen Protocol and end-of-life decisions for infants. The second search was focused on end-of-life decisions for children aged 1 to 12 years and the following search terms were used in PubMed: ‘(((euthanasia[Title/Abstract]) AND children[Title/Abstract]) OR euthanasia[Title/Abstract]) AND minors[Title/Abstract]’. This search identified 30 results and the same screening and filtering was applied as with the first search. Only articles which focused on end-of-life decisions for infants and contained opinions of experts were included. Eventually, 10 articles were read. Additional documents were identified using websites of Governments, hospitals, universities and other instances.

Results
The Dutch Euthanasia Law

Euthanasia comes from the Greek ‘eu’ which means ‘good’ and ‘thanatos’ which means ‘death’.2 It is defined as ‘the active termination of life at a patient’s voluntary and well-informed request’ according to The Royal Dutch Medical Association.3 The Dutch euthanasia law is called ‘The Termination of Life on Request and Assisted Suicide (Review Procedures) Act’ and was enforced in 2002. Its purpose is to regulate euthanasia and physician-assisted suicide (PAS).4 In case of PAS, the physician provides the means for the patient to end his own life at a time of his choosing.5Ending someone’s life is illegal, even though when someone requested it. So, this is the case for euthanasia and PAS on the basis of the articles 293 (euthanasia) and 294 (PAS) of the Dutch Criminal Code.6 The physician won’t be prosecuted if he strictly fulfills the following criteria: 

  1. The request is voluntary and well considered
  2. Unbearable suffering with no prospect of improvement
  3. The physician needs to inform the patient about his medical condition, prospects and opinions
  4. There is not another reasonable solution
  5. The physician must consult at least one other independent physician
  6. The execution of the procedure must happen carefully

Euthanasia is only possible for people over the age of 12 with capacity of discernment. However, in specific cases active end-of-life procedures are also possible in infants, which will be explained later. Euthanasia can only be requested by the ill and suffering person himself and therefore, a request by a family member or other human being cannot be honored. Most of the people who undergo euthanasia have terminal cancer or another serious illness. However, the euthanasia law does not state that only patients with a terminal disease or only patients with a somatic disease can request euthanasia, a psychiatric disorder can also be a reason for someone to request euthanasia. A doctor is not obligated to honor a euthanasia request a terminally ill and suffering patient made. Therefore, euthanasia is not a patient’s right and it also is not a doctor’s obligation to honor the request.

After the procedure, the physician must inform de municipal coroner and a review committee. The review committee assesses whether the physician fulfilled all the criteria. When a physician did not fulfill these criteria, he can be prosecuted by the Public Prosecution Service and is punishable by up to 12 years of imprisonment in case of euthanasia and 3 years of imprisonment in case of PAS.7

In contrast to the Dutch Euthanasia Law, the Belgian Euthanasia Law differs regarding the age limit. On the 28th of February in 2014, the age limit of the Euthanasia Law was abolished and minors with capacity of discernment could request for euthanasia, irrespective their age. However, there are some important requirements: parents or legal representatives must give consent, the patient is terminally ill and the patient is in great pain. Nonetheless, minors in Belgium cannot request for euthanasia in case of psychological suffering, in contrast to adults.8,9

The goal of this subject is to provide insight in the current Dutch euthanasia law. This subject makes clear that euthanasia is possible under strict conditions for people with capacity of discernment and sometimes for people without capacity of discernment who wrote an advance directive. An important argument of opponents of the protocol, is that children aged 1 to 12 years do not have capacity of discernment. However, according to proponents, some children do. They state that the age limit of the Dutch euthanasia law should be abolished for children with capacity of discernment.

The Groningen Protocol

End-of-life procedures in newborns came under increased attention in the 90’s due to a survey in 1995 among pediatricians about the causes of death in children. The survey showed that in 60% of the 1041 pediatric deaths an end-of-life decision was made. This frequency was even higher in the neonatal intensive care unit (NICU), namely 85%. In 55% of the life-ending-decisions, a life-sustaining treatment was discontinued and in 20% of the cases a medicine with the potential of shortening the life was administered. In approximately 8% of the cases, medication was administered to hasten death, and in 1% of the cases, medication was administrated to terminate life. There were a few different motives for the latter procedure according to the survey: in 75% of the cases there was no chance of survival and in roughly 20% a very poor prognosis was predicted. During the period of 1995 till 2001, another survey was done and showed comparable results.11 Before the publication of the Groningen Protocol, there was an estimate of 20 cases of active life-ending procedures in neonates per year. However, an average of 3 cases of deliberately ending the life of a newborn (DELN) were reported. A logical conclusion would be that a lot of procedures were not reported.11,12 

A Dutch girl who was born in 2001 was immediately after birth diagnosed with Hallopeau-Siemens syndrome, the most severe subtype of epidermolysis bullosa dystrophica.13 There was no possible curative treatment and her prognosis was very poor. Due to the blisters, she would never be able to eat solid food and she would be underdeveloped because the disease made activities like rolling over impossible. She would also have a high risk of developing skin cancer. Her parents did not want to see her suffer and asked the pediatrician to end their daughter’s life.

‘It is more inhuman to let her live, than to let her die’

However, the pediatrician could not do this because it was illegal as she lacked the capacity of discernment and she could not make a voluntary and well-considered request. If the pediatrician ended her life, a public prosecutor would have sued him for murder. This happened twice in the 90’s, a gynecologist and a general practitioner who ended the lives of two severely handicapped infants were both sued and charged for murder but did not impose a penalty because the court stated that both the physicians acted in a state of emergency. Back to the first case, meanwhile the girl was 9 months old and her situation worsened, she was addicted to morphine and had to take a bath with vinegar every other day to clean her wounds. After almost 10 months the girl died due to her disease. However, this is not the end of the story.

Her pediatrician, Eduard Verhagen, became one of the protagonists of life-ending-decisions in infants. He and some of his colleagues in the department of neonatology at the University Medical Center of Groningen formalized the ‘Groningen-protocol’ in 2002. It contains guidelines and protocols which pediatricians can use when they engage DELN <1 year of age without the fear of being prosecuted. The protocol was accepted as a national protocol for pediatricians in 2005 and the Netherlands became the first country to tolerate active end-of-life procedures in infants. The acceptance of the Groningen Protocol formed the base for a central review committee because there are strict criteria for physicians in order to end an infant’s life (table 2).14-16 The physician must fulfill the criteria and report to the review committee and the municipal coroner who must inform the Public Prosecution Service. After the review committee assessed the procedure, they send their judgment to the physician and the Public Prosecution Service. In case of a procedure without sufficient attention and fulfilling the criteria, the review committee also informs the Health and Youth Care Inspectorate.17

Table 2. The Groningen protocol (Verhagen and Sauer, 2005)14
Requirements that must be fulfilled:

  • The diagnosis and prognosis must be certain
  • Hopeless and unbearable suffering must be presents
  • The diagnosis, prognosis, and unbearable suffering must be confirmed by at least one indpendent doctor
  • Both parents must give informed consent
  • The procedure must be performed in accordance with the accepted medical standard

In the period after the introduction of the Groningen Protocol, the data of all the NICUs in the Netherlands were analyzed for 12 months. The most common cause of death in newborns was still discontinuing of life-sustaining treatment (92%). In 60% of this 92%, the situation was instable and death was imminent and in 40%, the situation was stable but the prospective quality of life was very poor. There was, ironically enough, only 1 reported case of DELN in the 12 months and only two reports in the 5 years after the introduction of the Groningen Protocol. This was much less than was expected beforehand. According to proponents of the Groningen Protocol, the fact that there is no consensus about the dividing line between palliative care and euthanasia is perhaps one possibility that explains this phenomenon.10,11 The introduction of the 20-week ultrasound in 2007 might be another explanation, more parents choose to terminate the pregnancy in the second trimester because of found congenital anomalies like spina bifida or anencephaly. This may also have led to a reduction of the number of reports of active life-ending procedures in infants.16

The relation of the Groningen Protocol to this paper arises from the fact that the Groningen Protocol provides the possibility for life termination of infants under the age of 1 under strict conditions. Infants do not have capacity of discernment and as stated before, the lack of capacity of discernment in children aged 1 to 12 years is an important argument of opponents in the context of active end-of-life decisions for children aged 1 to 12. Proponents of active life termination in children state that the age limit of the Groningen Protocol should be abolished for older children without capacity of discernment.
 

Moral and ethical issues concerning the Groningen Protocol

In the previous section, the Dutch euthanasia law and the Groningen Protocol were discussed. The importance of these subjects to this paper is that they provide basic knowledge that can be used to compare the different views on life-ending decisions for children aged 1 to 12 years with views on the Groningen Protocol. Many people were indignant after the publication of the Groningen Protocol in the New England Journal of Medicine and a lot of people responded to this publication. Different experts’ views on the Groningen Protocol will be highlighted in this section.

Opponents:
Polychronis Voultsos and Fotios Chatzinikolaou (Department of Forensic Medicine & Toxicology at the Aristotle University of Thessaloniki):

At juridical level, the Groningen Protocol conflicts with several human rights and principles: article 2 of the European Court of Human Rights (ECHR), article 3 of The Universal Declaration of Human Rights, article 6 of the Convention on the Rights of the Child. Furthermore, the Groningen Protocol conflicts with some principles formulated after the Second World War: the principle of human dignity, the principle of ‘do no harm’ and lastly, the principle of self-determination. The authors state that the Groningen Protocol can be risky because physicians may look for limitations in the protection of human beings which can result in a change into the execution of DELNs on a large scale. The Nuffield Council of Bioethics also stated their aversion to the Groningen Protocol: ‘no matter how serious the condition of the baby’. According to Voultos and Chatzinikolaou, the terminology in the Groningen Protocol is not clear and some of the criteria are very hard to determine in practice. ‘Unbearable suffering’ is a frequently occurring subject in the Groningen Protocol but this concept is vague, highly subjective and hard to objectify. The same applies to the infants’ pain. The concept of the infants’ ‘best interest’ is also not clear, the determination of this interest from a medical point of view is not enough as social and cultural factors also should be considered. Is a decision made by the parents or legal representatives always in the infant’s best interest? Is it acceptable to let the parents decide for the infant? These are important questions, which are really hard to answer, according to the authors. Furthermore, the proponents of the Groningen Protocol think only the lives of terminally sick infants are taken. However, opponents claim that infants with non-terminal congenital abnormalities are also being ‘euthanized’. At last, DELN forms an impediment to research on the abnormalities the infants are born with.18

Felipe Vizcarrondo (Associate Professor of Pediatrics at the University of Miami Miller School of Medicine):

Vizcarrondo is also an opponent and published an article in response to the Groningen Protocol. According to Vizcarrondo, proponents of the Groningen protocol think DELN is ethically permissible if the protocol is being followed. However, he asserts the criteria are not based on firm moral principles. The American College of Pediatricians shares this opinion and adds that there is a chance for bias in the decision making.11 There is room for parental bias because of the emotional, physical and financial difficulties they expect to encounter when they have to care for a severely handicapped child. Physicians’ bias cannot be excluded either, it is nearly impossible to separate the ethical perspective of the physician himself and the difficulties he will encounter when caring for a severely ill child from the life-ending decision. There is also a possibility for bias at the level of the government. The government is responsible for the protection of the weaker human beings but on the other hand, they are in most cases also responsible for the finances of the neonate’s care.11,19 Besides, it is extremely difficult and unreliable to predict the prognosis and quality of life on the basis of which an infant’s life is deliberately ended. Proponents of the Groningen Protocol claim that there is no difference between discontinuing of life-sustaining treatment and DELN. Vizcarrondo totally disagrees with this opinion. However, he thinks it is permissible to discontinue life-sustaining treatment in specific cases to relieve the pain and suffering due to death by natural causes, namely the infant’s illness. According to the proponents, discontinuing life-sustaining treatment is morally commensurate to DELN and starting or continuing with life-sustaining treatment only delays the dying process and results in more pain and suffering for the infant and parents. In nearly all cases of DELN, the infant was diagnosed with spina bifida and most of the clinical manifestations of spina bifida are treatable, so Vizcarrondo questions the motives of the end-of-life procedures and thinks there are alternatives. Medicine aspires to improve the quality of life of patients to ameliorate their health and well-being. Therefore, ending a sick person’s life is not the solution to relieve the pain and suffering in the dying process. It is up to the medical professionals to care with love and compassion for the sick patient and respect his dignity. So, DELN is not ethically permissible according to Vizcarrondo.11

 

Proponents:
Eduard Verhagen and Pieter Sauer (respectively Clinical Director and Chairman of the Pediatrics Department at University Medical Center Groningen):

Verhagen and Sauer are the authors of the controversial article: ‘The Groningen Protocol – Euthanasia in Severely Ill Newborns’. Suffering is a subjective sensation and cannot be measured using objective parameters. In general, it is accepted when adults state their suffering is unbearable but infants can only express their feelings through crying, movements and responses to feeding. However, Verhagen and Sauer state that experienced physicians and other professionals can determine the pain and suffering on basis of pain scales. According to neonatologists in the Netherlands and most of the neonatologists in Europa, survival is not the only goal of intensive treatment but a satisfactory quality of life is also very important. It is acceptable to not initiate or discontinue life-sustaining treatment in specific cases when it is in the best interest for the infant. Nevertheless, when there are no possibilities left to relieve the infant’s pain and suffering and no improvement is expected, it would be more humane to end the infant’s life than to continue life-sustaining treatment. According to Verhagen and Sauer, DELN should be allowed for specific cases when an infant does not have a life-sustaining treatment and under very strict conditions. Verhagen published another article in 2014: ‘Neonatal euthanasia: Lessons from the Groningen Protocol’: before the acceptance of the Groningen Protocol, DELNs were already performed but the requirements for the procedure and the legal position of the physician were unclear. So, the main goal was to regulate DELNs and to improve the transparency and the number of reported cases, in contrast to what many opponents of this protocol think.14

Summary:

So, there are different views on the Groningen Protocol. Starting with the opponents: according to Voultsos and Chatzinikolaou, the Groningen Protocol conflicts with several human rights and principles. Furthermore, they state that the terminology of the Groningen Protocol is not clear and that some of the criteria are very hard to determine in practice. According to them, not terminally ill children’s lives are being terminated, but also lives of children who have non-terminal congenital abnormalities. At last, the termination of the lives of terminally ill infants forms an impediment to research on the abnormalities the infants are born with, but also to research on alternative palliative methods to relieve suffering.18 Vizcarrondo states that the criteria of the Groningen Protocol are not based on firm moral principles. Furthermore, there is room for parental and physicians’ bias but also for bias at the level of the government. At last, he states that discontinuing life-sustaining treatment cannot be compared to DELN, in contrast to the proponents’ view.11 Verhagen and Sauer are proponents of the Groningen Protocol and state that experienced physicians can determine the infants’ pain and suffering. So, in contrast to the opponents, they think the Groningen Protocol is not solely based on criteria which are hard to determine in practice. According to the proponents, DELN should be allowed when there is no life-sustaining treatment and when the physician fulfills strict criteria. Furthermore, they state that DELNs were already performed before the Groningen Protocol and the protocol’s main goal was to regulate DELNs, in contrast to what many opponents think.14

Moral and ethical issues concerning active end-of-life decisions in children aged 1 to 12 years

Several pediatricians and parents’ associations in the Netherlands advocate the revision of the current situation regarding active end-of-life decisions in children and the extension of the Dutch euthanasia law and/or the Groningen Protocol to children aged 1 to 12 years. However, not every expert shares this opinion. In this section, different experts’ views on end-of-life decisions in children aged 1 to 12 years will be highlighted. The experts are from all over the world and not solely from the Netherlands.

Opponents:
Cristopher Kaczor (Professor of Philosophy at Loyola Marymount University):

Kaczor disagrees with the statement the pediatricians and parents’ associations made regarding to the expansion of the age limit of active end-of-life procedures in children. Proponents of euthanasia and DELN state that it is the only way out of a situation with pain and unbearable suffering. Kaczor thinks this claim is false, palliative sedation is an equivalent alternative which can be used in infants, children and adults to relieve suffering and pain. In the end, palliative sedation can cause death because the dose must to be increased in order to relieve pain and suffering over a longer time, which may lead to death as a side effect. However, an undesirable consequence (for example the hastening of the dying process) is acceptable if it is an unintended side effect of a treatment necessary for a desirable effect (for example pain relief). In this way, relieving of pain and suffering is ethically permissible, even with death as a consequence. According to Kazcor, the legalization of euthanasia and the expansion to other groups of patients, and not the illegalization, forms an obstacle for the main goal of relieving pain and suffering. If we just kill people instead of alleviating their pain, then euthanasia will undermine palliative care. If more people will request for euthanasia and more lives of people without capacity of discernment are ended, there will be less people who demand palliative care. This will lead on his turn to less financial pressure to develop new methods for palliative care. Killing people is after all an easy and cheap option compared with palliative sedation and palliative care in general.20

‘Why worry about relieving someone’s suffering, when you can just kill the person?’

According to some people, not choosing for euthanasia in case of pain and suffering, is similar to wanting to suffer. In this way, compassion and love for the suffering patient who does not request for euthanasia will be undermined. Many proponents think the goal of euthanasia is to relief suffering but Koczar states that a person who was killed cannot feel this relief anymore. People who have undergone euthanasia do not exist anymore so it is impossible to relief their suffering. In case of voluntary euthanasia, a patient with capacity of discernment decides based on his own judgment if he requests for euthanasia. In contrast to voluntary euthanasia, the patient cannot give consent in case of nonvoluntary euthanasia. Kaczor states children under the age of 12 years do not have capacity of discernment and cannot give informed consent for important decisions. This is also the reason why these children do not have voting rights, are not allowed to marry and have sex for example. The weaker human beings (without capacity of discernment) in our society should be protected by the law instead of deliberately ending their life without their consent.20

John Lantos (Professor of Pediatrics at the University of Missouri-Kansas City School of Medicine):

The most views on euthanasia and PAS are focused on patients who suffer unbearably. However, most people who request for euthanasia are not motivated by their physical pain but the fear to lose their self-determination and the feeling that they will bother other people. Depression and hopelessness are frequently occurring problems in people who request for euthanasia. These are situations in which suffering is not only somatic but also existential. Nonetheless, these factors will probably not play an important role in life-ending-decisions for children. In general, children are not scared to lose their autonomy or to be a burden to others. Lantos thinks the differences between adults and children regarding to their rationality are too big to extend the euthanasia law. He states that palliative care would be more appropriate for these children and adds that the acceptance of death as a possible side-effect of this palliative care would not need a revision of the law.20

Proponents:
Margaret Battin (Professor of Philosophy and Medical Ethics at the University of Utah):

Battin is a proponent of the extension of the Dutch euthanasia law. The aim of the Dutch euthanasia law is to help someone who does not want to live anymore with kindness, compassion, understanding and helpfulness. This idea of euthanasia is not shared worldwide because in some countries like the United States, the word ‘euthanasia’ has a very negative connotation. In these countries, euthanasia is associated with the horrible political killings committed by Nazi-Germany during the World War II. Battin asks the Dutch Minister of Health, Welfare and Sport to be as clear as possible if he extents the euthanasia law, without losing sight of the Dutch vision on euthanasia.20

Marije Brouwer, Els Maeckelberghe and Eduard Verhagen (Department of Pediatrics at University Medical Center Groningen):

They advise the Minister of Health, Welfare and Sport to abolish the age limit for both the euthanasia law and the Groningen Protocol. In this way, active life-ending procedures would be possible for both competent and incompetent children in case of unbearable suffering and pain. According to the authors, the abolishment of the age limit is conforming the Dutch norms and values because the authors believe in autonomy, which knows no age limit, and the physician’s possibility to relieve suffering when there are no other ways out. They advocate that the age limit for euthanasia should be revised. According to the law, euthanasia is only possible if a human being is over the age of 12 and has the capacity of discernment. However, this age limit is arbitrary because competent children under the age of 12 cannot request for euthanasia. There is evidence showing that some children from the age of 8 are competent to make difficult decisions about their life. Nonetheless, there are also children without capacity of discernment. The euthanasia law cannot be applied to these children because they cannot make a voluntary and well-considered decision. According to the authors, the solution to this problem is an extension of the Groningen Protocol, which was originally formulated to regulate DELNs. Parents’ consent is essential for the Groningen Protocol and can be seen as an extension of the autonomy of the child. For a physician to act justly, he must understand the child’s suffering and the parents can provide very important information on this suffering. The parents’ influence prevents a disproportionate decision on life-ending decisions in incompetent children because in this way, the decision will not only be based on the physician’s justness. The authors request the Minister to initiate research in order to analyze how euthanasia is used. There are at least 5 reasons why more research is required:

  1. In contrast to the large amount of data regarding end-of-life decisions for infants and human beings over the age of 12, there is barely any data on end-of-life decisions for children aged 1 to 12 years.
  2. Research should also be focused on the decisions terminally sick children make. Are these children more mature than healthy children? Are they competent to make important decisions about their lives? Or are they more vulnerable and immature than healthy children?
  3. The meaning of unbearable suffering should be reviewed. However, this is difficult because of its subjective and personal nature. Analyzing experiences from people who are involved in cases of unbearable suffering of children might result in a better understanding of the concept ‘unbearable suffering’.
  4. The parents’ influence should also be reviewed because their intentions are not always clear. What happens when the physician thinks that the parents decide in their own interest?
  5. There should be more focus on the difficulties the parents and physicians encounter. The authors urge the Minister not to focus on the judicial factors alone but also on the parents’ and physicians’ emotional and social difficulties.20

Summary:

Thus, there are many different views on active end-of-life decisions in children aged 1 to 12 years. Starting with the opponents: Kaczor thinks that palliative sedation is a similar method as life termination. Furthermore, termination of life undermines palliative care itself but also the research on new palliative methods. He also states that a person who was killed cannot feel this relief anymore. People who have undergone euthanasia do not exist anymore so it is impossible to relief their suffering. At last, according to Kaczor, children under the age of 12 years do not have capacity of discernment and cannot give informed consent for important decisions. John Lantos thinks the differences between adults and children regarding to their rationality are too big to extend the euthanasia law. He states that palliative care would be more appropriate for terminally ill children aged 1 to 12 years. Now the proponents, Battin compares the underlying thoughts of the Dutch euthanasia law (kindness, compassion, etcetera) and euthanasia in other countries (Nazi-Germany, eugenics, etcetera). She states that the Dutch Minister of Health, Welfare and Sport should extend the age limit of the euthanasia law, without losing sight of the Dutch vision on euthanasia. Brouwer, Maeckelberghe and Verhagen think the age limit for the Dutch euthanasia law should be abolished for children aged 1 to 12 years with capacity of discernment and the age limit of the Groningen Protocol should be abolished for children aged 1 to 12 years without capacity of discernment. However, they state that further research is needed to get a better insight in the uncertainties concerning active end-of-life decisions for children aged 1 to 12 years.

Art form

Il y a longtemps que je t’aime (I’ve loved you so long)

The French drama movie ‘Il y a longtemps que je t’aime’ was used. The introduction of this paper is a summary of this movie and the title refers to a French children’s song about a lost love (À la claire fontaine).22 Sick children’s parents may encounter situations where their child (aged 1 to 12 years) is not terminally sick but still suffers unbearably. If their child would be dependent on life-sustaining treatment, discontinuing of this treatment could be an option to relieve the pain and suffering. However, many children who are in pain and suffering are not dependent on life-sustaining treatment, so in case of absence of life-sustaining treatment: what are the possibilities when a child suffers unbearably and the quality of life is very low in? On the one hand, parents do not want to see their child suffer but on the other hand, deliberately ending the life of such a sick child is illegal according to the law. Many arguments are based on ethical and judicial principles but the parents’ point of view is often forgotten. My goal with this art form is to emphasize the parents’ emotional difficulties. So, also parents are harmed by watching their child suffer!

As mentioned earlier, Brouwer, Maeckelberghe and Verhagen urge the Minister not to focus only on the judicial factors but to take the optimal support for human beings who find themselves in such a situation also into consideration.

Discussion

The aim of this paper was to explore the moral and ethical issues concerning DELN and active end-of-life decisions for children aged 1 to 12 years. The final goal was to formulate an answer to the question: should active end-of-life decisions be possible in the Netherlands for children aged 1 to 12 years? Different experts’ views on the main subjects of this paper were highlighted in the ‘results’ section. There is a lot of disagreement among experts about end-of-life decisions in children aged 1 to 12 years. All things considered, if a child under the age of 12 is competent, an extension of the general Dutch euthanasia law would be appropriate because proponents state that in some cases children under the age of 12 can be competent.20 However, this is not true according to a Dutch study. There are four important elements for capacity of discernment regarding medical decisions: logical reasoning, comprehensibility, communication of a decision and appreciation. The study showed that, based on these elements, children have capacity of discernment from the age of 12.23 Proponents of active end-of-life decisions for children aged 1 to 12 years state that the age limit of the Groningen Protocol should be abolished for incompetent children.20 The way I see it, life termination for children under the age of 12 should only be tolerated if there is no other palliative alternative available. Further research on other palliative research is needed. However, in the meantime life termination should be possible if there really is no other option.

Strengths and limitations

The extent of this paper could be considered as a strength. It offers a very broad picture about the current state regarding end-of-life decisions for children. Another strength is the art form, which emphasizes the very important parents’ role which is often forgotten, so it is relevant to accentuate this. Although the most important views on this subject were highlighted, there are more arguments. Not every argument is discussed in this paper and this could be considered a limitation. The ‘results’ section focusses only on the Dutch situation. However, it would be better if, for example, the Belgian situation also was highlighted because Belgium abolished the age limit of the euthanasia law. So, this could also be considered a limitation.

Conclusion: what about the future?

At the end, the children’s interest is the most important element which must not be undermined. Not a single physician wants to terminate the life of an ill child. However, sometimes life termination is the only available possibility left and when physicians have to terminate a life, it has a huge impact on them. A method that reliefs suffering and pain without the need to terminate a life, would be the most ideal solution. And therefore, further research is needed to find a suitable solution for terminally ill children aged 1 to 12 years.
 

References

  1. National Gaucher Foundation. Gaucher Disease – Prognosis and Life Expectancy. [Internet]. Available from: https://www.gaucherdisease.org/about-gaucher-disease/life-expectancy/. [Accessed 21st of September 2019].
  2. Annadurai K, Danasekaran R, Mani G. ‘Euthanasia: Right to Die with Dignity’. J Family Med Prim Care. 2014 Oct-Dec; 3(4): 477-478.
  3. The Royal Dutch Medical Association. Euthanasia in the Netherlands. [Internet]. Available from: https://www.knmg.nl/actualiteit-opinie/nieuws/nieuwsbericht/euthanasia-in-the-netherlands.htm. [Accessed 28thof August 2019].
  4. Miller DG, Kim SYH. Euthanasia and physician-assisted suicide not meeting due care criteria in the Netherlands: a qualitative review of committee judgements. BMJ Open. 2017; 7(10).
  5. Goligher EC, Ely EW, Sulmasy DP, Bakker J, Raphael J, Volandes AE, et al. Physician-Assisted Suicide and Euthanasia in the Intensive Care Unit: A Dialogue on Core Ethical Issues. Crit Care Med. 2017 Feb; 45(2): 149-155.
  6. NVVE. De euthanasiewet. [Internet]. Available from: https://www.nvve.nl/wat-euthanasie/de-euthanasiewet. [Accessed 29th of August 2019].
  7. Rijksoverheid. Euthanasie en de wet. [Internet]. Available from https://www.rijksoverheid.nl/onderwerpen/levenseinde-en-euthanasie/euthanasie. [Accessed 28th of August 2019].
  8. Cohen-Almagor R. Should the Euthanasia Act in Belgium Include Minors? Perspect Biol Med. 2018; 61(2): 230-248.
  9. Associatie KU Leuven. Belgian law on euthanasia. [Internet]. Available from: https://associatie.kuleuven.be/p/flandershealthcare/tourofflanders/belgian-law-on-euthanasia.pdf. [Accessed 31st of August].
  10. NVVE. Wat is euthanasie? [Internet]. Available from: https://www.nvve.nl/wat-euthanasie/over-euthanasie[Accessed 29th of August 2019].
  11. Vizcarrondo FE. Neonatal euthanasia: The Groningen Protocol. Linacre Q. November 2014; 81(4): 388-392.
  12. Verhagen E. Neonatal euthanasia: lessons from the Groningen Protocol. Semin Fetal Neonatal Med. 2014 Oct; 19(5): 296-9.
  13. Koshida S, Tsukamura A, Yanagi T, Nakahara S, Takeuchi Y, Kato T, et al. Hallopeau-Siemens dystrophic epidermolysis bullosa due to homozygous 5818delC mutation in the COL7A gene. Pediatr Int. 2013 Apr; 55(2): 234-7.
  14. Verhagen E, Sauer PJJ. The Groningen Protocol – Euthanasia in Severely Ill Newborns. NEJM. March 10 2005; 352: 959-962
  15. Tedesco M. Dutch Protocols for Deliberately Ending the Life of Newborns: A Defence. J Bioeth Ing. 2017 Jun; 14(2): 251-259
  16. UMCG. Levensbeëindiging bij pasgeborenen: zorgvuldigheid staat voorop. [Internet]. Available from: https://www.umcg.nl/NL/UMCG/Nieuws/Nieuwsberichten/Paginas/Levensbeëindiging_bij_pasgeboren_en_zorgvuldigheid_staat_voorop.aspx. [Accessed 29th of August].
  17. LZA/LP. Procedure bij late zwangerschapsafbreking of levensbeëindiging. [Internet]. Available from: https://www.lzalp.nl/procedure. [Accessed 29th of August].
  18. Voultsos P, Chatzinikolaou F. Involuntary euthanasia of severely ill newborns: is the Groningen Protocol really dangerous? Hippokratia. 2014 Jul-Sep; 18(3): 193-203.
  19. Jotkowitz AB, Glick S. The Groningen protocol: another perspective. J Med Ethics. 2006 Mar; 32(3): 157-158.
  20. Brouwer M, Kaczor C, Battin MP, Maeckelberghe E, Lantos JD, Verhagen E. Should Pediatric Euthanasia be Legalized? Pediatrics. February 2018; 141(2).
  21. Nagral A. Gaucher Disease. J Clin Exp Hepatol. 2014 Mar; 4(1): 37-50.
  22. Mama Lisa’s World. À la claire fontaine. [Internet]. Available from: https://www.mamalisa.com/?t=es&p=141. [Accessed 3rd of September]
  23. Grootens-Wiegers P, Hein IM, van den Broek JM, de Vries MC. Medical decision-making in children and adolescents: developmental and neuroscientific aspects. BMC Pediatr. 2017 May 8.

 

 

 

 

 

 

 

 

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The potential role of circulating microRNAs as biomarkers and treatment for painful diabetic peripheral neuropathy

The potential role of circulating microRNAs as biomarkers and treatment for painful diabetic peripheral neuropathy

Introduction
‘It feels like the prickling sensation you get as your skin warms up when coming inside after being out on a really cold day.’ This feeling is recognizable for many people and is generally described as an unpleasant sensation. It is also one of the many ways patients describe the symptoms of diabetic peripheral neuropathy, a frequently occurring microvascular complication of diabetes.1 Despite the fact that pain is one of the main manifestations, the pathophysiological mechanisms of diabetic peripheral neuropathy are still not fully clear.2 However, there is growing evidence showing the role of microRNAs in the pathophysiological mechanisms of diabetic microvascular complications.3 Because of the increasing prevalence of diabetes and its complications, there is a growing need for effective therapeutics and also for biomarkers that are reliable to pinpoint the onset and monitor the progression of diabetic peripheral neuropathy.4 In this essay, I aim to explore the potential role of circulating microRNAs as diagnostic tool or therapeutic target for painful diabetic peripheral neuropathy. 

Diabetic neuropathy
Further knowledge of diabetic neuropathy is necessary to understand the subjects explained in this essay. The most common presentation of diabetic neuropathy is distal symmetrical polyneuropathy, better known as diabetic peripheral neuropathy (DPN).5 DPN develops due to long term hyperglycaemia, which leads to damaged axons and derangements of the small vessels that supply the nerves.6 Loss of vibration sense, tactile sensitivity and kinaesthesia in the lower limbs are often seen in patients with DPN.7 DPN frequently contributes to the development of foot ulcers and these ulcerations are an important cause of lower limb amputations.6 One phenotype of DPN is painful diabetic peripheral neuropathy (PDPN). According to the International Association for the Study of Pain (IASP), the definition of PDPN is ‘pain arising as a direct consequence of abnormalities in the peripheral somatosensory system in people with diabetes’.8,9 It is thought that this painful presentation is the consequence of abnormal responses of the body to the damaged nerves.10

There are a few recommended symptomatic treatments for PDPN, for example tricyclic antidepressants (TCAs) such as amitriptyline, morphinomimetic agents, the gabapentinoids gabapentin and pregabalin or topical medication like capsaicin. Nonetheless, curative treatment is not possible and the suggested therapies are often not efficient in achieving an acceptable reduction of pain, so a more effective therapeutic agent is needed.11  

MicroRNAs
Definition
MicroRNAs (miRNAs) are short non-coding RNA-molecules. They play a key role in the regulation of the expression of genes. miRNAs interact with a specific region on a messenger RNA-molecule (mRNA), called the 3’ untranslated region. This interaction leads to degradation of the mRNA-molecule and suppression of the translation of mRNA into proteins.12,13 A number of miRNAs have been described to play a role in diabetic neuropathy.3

Clinical use of microRNAs
Currently, the clinical use of miRNAs is limited to diagnostics of cancer, heart diseases, neuromuscular disorders and neurodegenerative diseases.14 The therapeutic applicability of miRNAs is yet to be determined but there are several clinical trials for treating cancer and hepatitis with miRNA-targeted therapeutics at the moment.15 There are roughly two ways of miRNA-targeted therapy, the first one is the substitution of miRNA. These miRNAs can also be modified in an external environment, these modified miRNAs are called mimics. This approach of miRNA-targeted therapy can be used to substitute miRNAs that are not expressed to the expected degree. The second approach is to administer miRNA inhibitors. However, the delivery of miRNA mimics and miRNA inhibitors is challenging. Currently, there are two main ways for delivery: non-viral and viral. Both of these approaches do have some disadvantages, the main problems of the viral delivery are the health risks and the disadvantage of the non-viral delivery is its distribution to a wide range of organs which subsequently leads to accumulation. It is not clear if miRNA-targeted treatment is appropriate to undo nerve damage that is already done or if it only can reduce the sensory and motor impairment.16So, the use of miRNA-targeted therapeutics is still challenging. However, the development of miRNA-targeted therapeutics is rapidly advancing.3,14 The possibility to detect circulating miRNAs in fluids like saliva, cerebrospinal fluid, tears, blood plasma and serum demonstrates the potential use of miRNAs as biomarkers. They could be used for diagnosis, prognosis or to monitor the effectivity of a treatment.3

Role of microRNAs in diabetic neuropathy
Recently, several studies have demonstrated that microRNAs could potentially be used as biomarkers or therapeutic targets for PDPN because of their role in the pathogenesis of diabetic complications, especially nephropathy and neuropathy. Abnormal expression of miRNAs is seen in both metabolic diseases and diseases of the nervous system.16 Although there are many metabolic disorders with overlapping aberrant miRNA expression, symptoms and pathophysiological mechanisms, there are a couple of diseases where isolated abnormal miRNA expression is seen, for instance the upregulation of miRNA-15(b) in NAFDL (non-alcoholic fatty liver disease) and the downregulation of miRNA-132-3p in obese mice.16,17 Because of the fact that a large number of miRNAs are located in the encephalon and nerve tissue in the periphery, and the observation that abnormal expression of miRNAs is seen in many diseases indicates the potential use of profiling miRNA in peripheral diabetic neuropathy.16

A study in 2017 revealed the involvement of miRNA-199a-3p in diabetic neuropathy: overexpression of miRNA-199a-3p caused a reduction in the expression of SerpinE2 (serine protease inhibitor E2), which plays among other things a role in the insulin signaling cascade. The study showed a connection between the reduced expression of SerpinE2 and the onset and rapid progression of diabetic neuropathy.16,18,19   Another study revealed a correlation between miRNA- 190a-5p and SLC17A6. Although the pathophysiological mechanisms of miRNA-190a-5p in DPN are not fully known, the underexpression of miRNA-190a-5p was associated with an increased level of SLC17A6 in spinal tissue. This reveals the potential use of miRNA-190a-5p as therapeutic target: upregulation of this miRNA and downregulation of SLC17A6 could possibly lead to a reduction in pain in people with PDPN.16,20

There is one microRNA in particular I want to highlight: miRNA-146a. This is probably one of the most mentioned miRNAs in the context of the pro-inflammatory mechanisms in PDPN.21 The two most important target genes of miRNA-146a are TRAF6 and IRAK1. IRAK1 is a proinflammatory gene that codes for interleukin-1 receptor-associated kinase 1. IRAK1 is involved in the toll-like receptor (TLR) pathways, TLRs are proteins that play a key role in the initiation of inflammation and immune responses. NF-kB is a downstream protein complex of IRAK1 and when activated, it plays an important role in the regulation of immune responses and impaired neurovascular function caused by hyperglycaemia. An animal study on mice showed that upregulation of miRNA-146a causes a downregulation of IRAK1, which results in an impaired NF-kB activation, causing a reduction of immune responses to inflammation.22 
The same animal study showed that miRNA-146a is downregulated in nerve tissue of the ischiatic nerve in diabetic mice. The mice were subsequently administered with miRNA-146a mimics to substitute the downregulated miRNA-146a. The administration of these mimics revealed some interesting results: an increase in the motor nerve conduction velocity by 29%, an increase in the sensory nerve conduction velocity by 11%, an increase in the local blood flow in ischiatic nerve tissue by 50% and the responses to thermal stimuli were significantly decreased after administration. Histological analysis of the ischiatic nerve tissue showed an increase in epidermal nerve fibres, an increase in the thickness of the myelin sheath and an increase in diameters of ischiatic nerve axons. And last but not least, they discovered a downregulation of pro-inflammatory proteins and cytokines after administration of miRNA-146a mimics.22
Another animal study showed a downregulation of miRNA-146a in diabetic mice and upregulation of IRAK1 and TRAF6 in DRG neurons, which consist of thermal receptors, itch receptors and mechanoreceptors. These sensors are thought to be responsible for the symptoms of PDPN.3

There are a lot of other studies that describe correlations between other miRNAs and specific proteins and genes involved in PDPN. However, it is not clear how all of these correlations could be used in screening or treating PDPN. In other words, the period of time where PDPN can be treated or the predisposition for the development of diabetic neuropathy can be discovered, is not clear. Hypothetically, the abnormal expression of miRNAs will occur before the onset of diabetic neuropathy.16 If this is true, this offers the possibility of screening, detection and treating in an early stage. 

Conclusion
There is growing evidence that miRNAs play an important role in the pathophysiological mechanisms of PDPN and administration of miRNA-targeted therapeutics showed some optimistic results in a number of studies. However, there are still some difficulties in the delivery of the miRNA-targeted therapeutics, the timeframe where PDPN can be treated is not clear and if it turns out that screening through miRNAs is an option, the period of time where screening is possible is not clear. Because of these problems and to unravel which of the miRNAs may serve best as biomarkers and targets for therapeutics, further research is needed. There is a growing need for effective therapeutics and biomarkers to give the patients who suffer from PDPN perspective on a curative treatment!

References

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  17. Dusalcy R, Handgraaf S, Visentin F, Vesin C, Philippe J, Gosmain Y. miR-132-3p is a positive regulator of alpha-cell mass and is downregulated in obese hyperglycemic mice. Mol Metab. 2019 Apr; 22: 84-95.
  18. Li YB, Wu Q, Liu J, Fan YZ, Yu KF, Cai Y. miR-199a-3p is involved in the pathogenesis and progression of diabetic neuropathy through downregulation of SerpinE2. Mol Med Rep. 2017 Sep; 16(3): 2417-2424.
  19. GeneCards – Human Gene Database. SERPINE2-Gene. [Internet]. Available from: https://www.genecards.org/cgi-bin/carddisp.pl?gene=SERPINE2. [Accessed 7th of June 2019]. 
  20. Yang D, Yang Q, Wei X, Liu Y, Ma D, Li J, et al. The roel of miR-190a-5p contributes to diabetic neuropathic pain via targeting SLC17A6. J Pain Res. 2017; 10: 2395-2403.
  21. Feng Y, Chen L, Luo Q, Wu M, Chen Y, Shi X. Involvement of microRNA-146a in diabetic peripheral neuropathy through the regulation of inflammation. Drug Des Devel Ther. 2018 Jan 17; 12: 171-177.
  22. Liu XS, Fan B, Szalad A, Jia L, Wang L, Wang X. MicroRNA-146a Mimis Reduce the Peripheral Neuropathy in Type 2 Diabetic Mice. Diabetes. 2017 Dec; 66(12): 311.

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