PSU Volume 64 No 01 JANUARY 2025
Palliative Care in Pediatric Surgery
Palliative care in pediatric surgery has developed considerably
over the past decade, shifting from a traditional focus on end-of-life
support to a broader integration that enhances the quality of life for
young patients facing complex and often life-limiting conditions. This
evolution acknowledges that palliative care (PPC) in pediatrics should
not be limited to terminal care but serve as an essential component
throughout the continuum of a child's surgical journey, including
symptom management, psychological support, and ethical decision-making.
Historically, PPC in pediatric surgery was underemphasized, partly due
to the misconception that palliative care equated to giving up hope for
a cure. This perception began to shift with the American Academy of
Pediatrics' 2000 guidelines, which emphasized adding life to a child's
years rather than simply prolonging life. Pediatric surgeons often
navigate challenging ethical considerations, balancing their commitment
to life-prolonging interventions with the realities of quality of life
in conditions that are not always curable. Surgeons are uniquely
positioned to assess whether a surgical intervention might alleviate
symptoms or enhance a child's comfort. However, this often requires
realistic and sensitive conversations with families who may feel
conflicted between pursuing aggressive interventions and protecting
their child from additional suffering.
In pediatric oncology, where palliative care has gained notable
integration, PPC aims to manage both the immediate symptoms related to
cancer and the lasting effects of treatment. Despite advancements in
survival rates, pediatric cancer remains a leading cause of mortality
beyond infancy. Many children with cancer endure significant symptom
burdens, including chronic pain, fatigue, and emotional distress, which
palliative care can effectively address. Studies have shown that even
as survival rates improve, a significant number of survivors face
debilitating long-term effects, such as organ dysfunction, cognitive
impairments, and secondary malignancies. These realities position PPC
not only as an end-of-life intervention but as a necessary part of the
child's cancer treatment, ensuring comfort and symptom relief
regardless of prognosis.
One of the critical roles that PPC plays in pediatric oncology is in
symptom management. For children with advanced cancer, surgical
palliative interventions often alleviate physical symptoms like bowel
obstruction, respiratory distress, and severe pain, all of which
significantly impact a child's quality of life. The literature
highlights cases where surgical palliative interventions have reduced
pain or prevented complications, such as respiratory support surgeries
or procedures to relieve severe gastrointestinal symptoms. These
interventions, often conducted in collaboration with palliative care
teams, are part of a multidisciplinary approach where PPC aids in
assessing risks, guiding parents through options, and helping set
realistic expectations about what surgery might or might not achieve.
In pediatric urology, the focus on PPC has emerged more recently.
Conditions such as congenital lower urinary tract obstruction,
neurogenic bladder dysfunction, and exstrophy-epispadias complex often
demand repeated surgeries, intensive hospital stays, and chronic
symptom management. Incorporating palliative care in pediatric urology
means addressing not only the physical symptoms but also the
psychosocial issues children and families face as a result of these
lifelong conditions. PPC provides critical support for children
undergoing complex urologic procedures, helping manage chronic pain and
providing resources for families to navigate the ongoing care that
often extends well into adolescence.
Moreover, prenatal palliative interventions have become a significant
component in maternal-fetal surgery. The availability of early
diagnostics has allowed physicians to identify severe congenital
conditions such as congenital diaphragmatic hernia (CDH) prenatally,
providing families with the option of maternal-fetal surgery. This
third option complicates traditional decision-making, which previously
offered only termination or post-birth interventions. Maternal-fetal
surgery exemplifies PPC's role in improving life outcomes through
early, targeted interventions. The palliative care team's involvement
in these cases is invaluable, guiding families through the
decision-making process by weighing potential benefits and risks while
considering quality-of-life outcomes for the child. PPC professionals
work alongside fetal surgeons, genetic counselors, and neonatologists,
providing a well-rounded approach that respects both the parents'
hopes, and the practical realities associated with these surgeries.
One of the most pressing issues in pediatric surgical palliative care
is timing. Surgeons and PPC physicians frequently differ in opinions on
when PPC should be introduced. PPC professionals advocate for early
involvement, ideally at diagnosis, to set the foundation for
comprehensive, long-term care that includes symptom management and
anticipatory guidance. In contrast, many surgeons only initiate PPC
consultations when the child's condition deteriorates, making curative
treatment unlikely. This discrepancy in timing, often attributed to
cultural differences between surgical and palliative care fields,
results in missed opportunities for early symptom control and
comprehensive family support. Studies reveal that some surgeons delay
PPC consultations out of concern that introducing palliative care too
early might discourage families or imply that treatment has been
exhausted.
Communication between PPC teams and pediatric surgeons is crucial for
achieving optimal care outcomes. Surveys highlight that PPC
professionals believe these discussions should occur much earlier in
the disease process to maximize the benefits of palliative
interventions. In many cases, families report that they wish they had
been introduced to palliative care earlier, as it would have helped
them manage their child's symptoms more effectively and provided
emotional support during difficult times. For pediatric surgeons,
initiating conversations about PPC can be challenging, particularly if
they feel it conflicts with families' expectations for life-saving
measures. Consequently, PPC training for surgeons has emerged as a key
area for improving collaboration and communication. In response,
residency programs and continuing medical education increasingly
include training modules focused on PPC to enhance understanding and
acceptance of palliative practices among surgeons.
Research further indicates the need for multidisciplinary approaches
that include PPC in pediatric surgical care. Integrating PPC
professionals as core team members in surgical planning can foster an
environment where families feel supported in their decisions, whether
they pursue aggressive interventions or prioritize comfort and quality
of life. Collaborative care allows each team member to contribute their
specialized expertise. PPC professionals offer insight into symptom
management and psychological support, while surgeons provide technical
assessments of what surgery might accomplish. Through this
collaboration, PPC ensures that surgical interventions align with
family goals and the child's best interests, even when curative options
are no longer viable.
Looking forward, the scope of PPC in pediatric surgery continues to
expand. Conditions such as neurodegenerative disorders, complex
congenital malformations, and progressive illnesses are increasingly
managed with an interdisciplinary approach that includes PPC from early
stages. Pediatric surgeons are recognizing the value of palliative
interventions, not only for terminally ill patients but also for
children with chronic, debilitating conditions. Additionally, as more
pediatric surgical specialists receive PPC training, there is a greater
opportunity for meaningful collaborations that can enhance the quality
of life for children undergoing intensive surgical care. The evidence
supports that PPC integration leads to more compassionate, well-rounded
care that respects both the child's dignity and the families experience.
In conclusion, the integration of palliative care into pediatric
surgery represents a transformative shift towards a patient-centered
model that prioritizes quality of life alongside medical treatment. By
focusing on early symptom management, ethical decision-making, and
supportive family care, PPC complements surgical interventions,
ensuring that young patients with complex medical needs receive
holistic, compassionate care. As PPC becomes more embedded in pediatric
surgery practices, it promises to further bridge the gap between
life-saving surgery and quality of life, offering families comfort,
guidance, and hope in the face of challenging medical journeys.
References:
1- Shelton J, Jackson GP: Palliative care and pediatric surgery. Surg Clin North Am. 91(2):419-28, 2011
2- Inserra A, Narciso A, Paolantonio G, Messina R, Crocoli A:
Palliative care and pediatric surgical oncology. Semin Pediatr Surg.
25(5):323-332, 2016
3- Spruit JL, Prince-Paul M. Palliative care services in pediatric oncology: Ann Palliat Med. 8(Suppl 1), 2019
4- Ott KC, Vente TM, Lautz TB, Waldman ED: Pediatric palliative care and surgery. Ann Palliat Med. 11(2):918-926, 2022
5- De Bie FR, Tate T, Antiel RM: Maternal-fetal surgery as part of
pediatric palliative care. Semin Fetal Neonatal Med. 28(3):101440, 2023
6- Ellis D, Mazzola E, Wolfe J, Kelleher C: Comparing Pediatric
Surgeons' and Palliative Care Pediatricians' Palliative Care Practices
and Perspectives in Pediatric Surgical Patients. J Pediatr Surg.
59(1):37-44, 2024
7- Li O, Lee R, Boss RD, Wang MH: Palliative Care for Pediatric Urology. J Pain Symptom Manage. 68(1), 2024
NPO Guidelines in Pediatric Surgery
The practice of "nil per os" (NPO), or nothing by mouth, for
children undergoing surgery has been a subject of intense scrutiny and
evolution over the years. Various studies and guidelines highlight the
balance between minimizing the risk of pulmonary aspiration during
anesthesia and reducing the adverse effects of prolonged fasting on
children?s metabolic and psychological well-being.
Historically, the NPO protocol has been rigid, often enforcing a
midnight fast for all patients scheduled for surgery. This practice,
aimed at preventing aspiration, has faced criticism for its negative
impact on children. Prolonged fasting can lead to dehydration,
hypoglycemia, and behavioral issues like irritability and anxiety.
Studies show that the current international guidelines allow more
flexibility, advocating for fasting durations of 2 hours for clear
liquids, 4 hours for breast milk, and 6 hours for solids. However,
these guidelines are frequently exceeded in practice due to scheduling
inefficiencies and miscommunication.
One of the major challenges identified is parental compliance with
fasting instructions. Research indicates that less than 10% of parents
fully adhere to the prescribed NPO times, with most either
under-fasting or over-fasting their children. The reasons for
non-compliance include inadequate understanding of instructions, fear
of surgical delays or cancellations, and the difficulty of denying food
or drinks to a distressed child. Miscommunication between healthcare
providers and parents further exacerbates the issue, as conflicting or
unclear instructions lead to confusion. Studies recommend clearer
communication strategies, such as providing separate written
instructions for solids and liquids and ensuring consistency in
messaging.
The metabolic implications of prolonged fasting are particularly
concerning for pediatric patients, as their smaller glycogen reserves
make them more susceptible to hypoglycemia. This metabolic stress not
only affects their energy levels but also impairs their ability to cope
with the stress of surgery, potentially delaying recovery. Research
highlights the benefits of shorter fasting periods, noting that
children allowed to consume clear liquids up to 2 hours before surgery
exhibit better hydration, reduced irritability, and lower gastric pH
levels without increasing the risk of aspiration.
Recent quality improvement initiatives have shown promise in addressing
the shortcomings of current NPO practices. For instance, allowing
children to drink clear liquids up to 1 hour before surgery has been
shown to significantly reduce fasting times and improve overall patient
comfort. Such liberalized fasting guidelines align with modern evidence
suggesting that aspiration risk does not increase with shorter fasting
durations. These changes have been endorsed by leading anesthesia
societies in Europe and Canada, emphasizing the importance of
minimizing disruption to normal physiological states preoperatively.
Despite these advancements, the implementation of more liberal NPO
guidelines faces resistance. Anesthesiologists and surgeons often
express concerns about flexibility in scheduling and the potential for
last-minute changes in surgery times. This conservatism results in a
default return to the midnight fasting rule in many institutions,
particularly for inpatients or cases with higher perceived aspiration
risks. To counter this, some hospitals have developed task forces to
standardize and enforce updated guidelines, incorporating strategies
like using arrival times instead of surgery times to calculate fasting
periods and encouraging the administration of clear liquids closer to
the surgery.
Compliance with updated NPO guidelines also varies significantly across
healthcare settings. Data show that prolonged fasting is more common in
settings with less robust quality improvement frameworks or where the
operational culture is resistant to change. For example, effective
fasting times for clear liquids can extend beyond seven hours, even
when shorter durations are recommended. Educational initiatives
targeting healthcare providers and parents are critical in bridging
this gap, ensuring both groups understand the rationale and safety of
revised fasting protocols.
The adverse effects of prolonged fasting extend beyond the
physiological to the psychological, with many children experiencing
heightened anxiety and behavioral challenges due to hunger and thirst.
These factors contribute to a less favorable surgical experience, both
for the patient and their family. Addressing these issues requires a
multifaceted approach, including better preoperative education,
consistent adherence to evidence-based guidelines, and ongoing
monitoring and adjustment of fasting practices based on patient
outcomes.
In conclusion, while significant strides have been made in revising and
liberalizing NPO guidelines for children, the practical application of
these recommendations remains inconsistent. Barriers such as
communication lapses, entrenched practices, and operational constraints
continue to impede progress. Moving forward, greater emphasis on
quality improvement initiatives, clearer communication strategies, and
more flexible approaches to fasting durations are essential to enhance
compliance and improve the overall surgical experience for pediatric
patients. These changes must be supported by ongoing research and a
willingness among healthcare providers to adopt evidence-based
practices, ensuring that children receive care that is both safe and
compassionate.
References:
1- Brunet-Wood K, Simons M, Evasiuk A, Mazurak V, Dicken B, Ridley D,
Larsen B: Surgical fasting guidelines in children: Are we putting them
into practice? J Pediatr Surg. 51(8):1298-302, 2016
2- Beazley B, Bulka CM, Landsman IS, Ehrenfeld JM: Demographic
Predictors of NPO Violations in Elective Pediatric Surgery. J
Perianesth Nurs. 31(1):36-40, 2016
3- Kafrouni H, Ojaimi RE: Preoperative Fasting Guidelines in Children:
Should They Be Revised? Case Rep Anesthesiol. 2018:8278603, 2018
4- Friedrich S, Meybohm P, Kranke P: Nulla Per Os (NPO) guidelines: time to revisit? Curr Opin Anaesthesiol. 33(6):740-745, 2020
5- Singla K, Bala I, Jain D, Bharti N, Samujh R: Parents' perception
and factors affecting compliance with preoperative fasting instructions
in children undergoing day care surgery: A prospective observational
study. Indian J Anaesth. 64(3):210-215, 2020
6- Schmidt AR, Fehr J, Man J, D'Souza G, Wang E, Claure R, Mendoza J:
Pre-operative fasting times for clear liquids at a tertiary children's
hospital; what can be improved? Anesth Pain Med (Seoul). 16(3):266-272,
2021
TLR4 in Necrotizing Enterocolitis
Toll-like receptor 4 (TLR4) plays a pivotal role in the
pathogenesis of necrotizing enterocolitis (NEC), a life-threatening
gastrointestinal disease in premature infants. NEC is associated with a
high mortality rate and severe long-term complications, including
short-bowel syndrome and neurodevelopmental impairment. The role of
TLR4 in NEC pathogenesis has been extensively studied, revealing its
involvement in immune activation, epithelial injury, and intestinal
ischemia. The following review synthesizes findings from six key
studies to provide a comprehensive understanding of the molecular
mechanisms underlying TLR4-mediated NEC and emerging therapeutic
approaches.
NEC is primarily a disease of premature infants, occurring in up to 10%
of those born with a birth weight under 1500 grams. Its pathogenesis is
multifactorial, involving intestinal immaturity, dysbiotic microbiota,
and exaggerated immune responses. TLR4, an innate immune receptor, has
been identified as a central mediator of these processes. It recognizes
lipopolysaccharides (LPS) on Gram-negative bacteria, triggering
proinflammatory signaling cascades that disrupt the intestinal
epithelial barrier. In premature infants, TLR4 expression is
significantly elevated compared to full-term counterparts, contributing
to increased susceptibility to NEC.
The role of TLR4 extends beyond its recognition of microbial pathogens.
Research has shown that TLR4 activation leads to apoptosis and
necroptosis of intestinal epithelial cells. These processes compromise
the integrity of the gut barrier, facilitating bacterial translocation
into the bloodstream and triggering systemic inflammation.
TLR4-mediated necroptosis, specifically, has been highlighted as a
distinct mechanism contributing to the rapid and severe tissue damage
characteristic of NEC. Studies in TLR4-knockout animal models have
confirmed the critical role of TLR4 in driving necroptosis, with these
models demonstrating reduced epithelial injury and inflammatory
responses.
Another critical mechanism by which TLR4 contributes to NEC is through
its effects on the mesenteric vasculature. Activation of TLR4 on
endothelial cells induces vasoconstriction and intestinal ischemia,
exacerbating tissue injury. In animal models, the inhibition of TLR4
signaling has been shown to restore mesenteric perfusion and mitigate
ischemic damage. This highlights the interconnected nature of
inflammatory and ischemic processes in NEC pathogenesis.
The interaction between TLR4 and the enteric nervous system has also
been implicated in NEC. Research has demonstrated that TLR4 activation
leads to the loss of enteric glial cells, which are essential for
maintaining intestinal motility and barrier integrity. The depletion of
these glial cells disrupts the anti-inflammatory feedback mechanisms of
the gut, further amplifying TLR4-mediated damage. The restoration of
enteric glial cell function has been proposed as a therapeutic
strategy, with promising results observed in preclinical models.
One of the most consistent clinical observations in NEC is the
protective effect of human breast milk. This protection is attributed
to specific components of breast milk, such as human milk
oligosaccharides (HMOs), which have been shown to inhibit TLR4
signaling. Studies focusing on HMOs, including 2?-fucosyllactose and
6?-sialyllactose, have demonstrated their ability to reduce
TLR4-mediated inflammation and apoptosis in experimental NEC models.
These oligosaccharides bind directly to TLR4, preventing its activation
by LPS and other microbial ligands. Formula-fed infants, lacking these
protective factors, exhibit higher rates of NEC, further underscoring
the importance of breast milk in prevention strategies.
The role of the microbiome in NEC is closely linked to TLR4 activity.
Premature infants with NEC exhibit a dysbiotic microbiota characterized
by reduced bacterial diversity and an overrepresentation of pathogenic
strains. This dysbiosis increases the availability of microbial ligands
that activate TLR4, perpetuating the inflammatory cycle. Probiotic
administration has emerged as a potential intervention, with several
studies demonstrating that probiotics can restore microbial balance,
reduce TLR4 activation, and protect against NEC. The exact mechanisms
by which probiotics exert these effects are under investigation, but
they likely involve competitive inhibition of pathogenic bacteria and
modulation of host immune responses.
Therapeutic approaches targeting TLR4 directly have shown promise in
preclinical studies. Small-molecule inhibitors of TLR4, such as
specific antagonists that block LPS binding, have been effective in
reducing NEC severity in animal models. These inhibitors work by
attenuating the proinflammatory signaling cascades initiated by TLR4
activation, thereby preserving the integrity of the intestinal barrier.
Additionally, strategies aimed at enhancing the expression of
protective molecules, such as brain-derived neurotrophic factor (BDNF),
have been explored. BDNF is reduced in NEC and plays a critical role in
modulating TLR4 activity and maintaining intestinal homeostasis.
Another innovative approach involves the use of anti-necroptotic
agents. Necrostatin-1, a specific inhibitor of necroptosis, has been
shown to reduce intestinal injury and inflammation in NEC models. This
therapy targets the downstream effects of TLR4 activation, preventing
the catastrophic cell death and barrier dysfunction associated with
necroptosis. Combined approaches that integrate TLR4 inhibition with
necroptosis suppression may offer synergistic benefits.
Despite these advances, translating preclinical findings into clinical
practice remains challenging. The heterogeneity of NEC, its
unpredictable onset, and the limitations of current diagnostic tools
complicate the development and implementation of targeted therapies.
The Bell staging system, commonly used to classify NEC severity, has
limitations in its ability to distinguish NEC from other neonatal
gastrointestinal conditions. Improved diagnostic criteria and
biomarkers are needed to identify at-risk infants and tailor
interventions effectively.
Future research should focus on elucidating the complex interplay
between TLR4 signaling, the microbiome, and host factors in NEC.
Advances in genomic and proteomic technologies offer opportunities to
identify novel targets and refine therapeutic strategies. Additionally,
the integration of precision medicine approaches, including the use of
individualized probiotic formulations and personalized nutrition plans,
holds promise for improving outcomes in NEC.
In conclusion, TLR4 is a central player in the pathogenesis of NEC,
orchestrating a cascade of inflammatory, ischemic, and apoptotic
processes that culminate in severe intestinal injury. Insights into the
molecular mechanisms of TLR4-mediated NEC have paved the way for
innovative therapeutic strategies, ranging from breast milk-derived
interventions to targeted molecular inhibitors. While significant
challenges remain, continued research into TLR4 and its role in NEC
holds the potential to transform the prevention and treatment of this
devastating disease, ultimately improving survival and quality of life
for premature infants.
References:
1- Hackam DJ, Sodhi CP: Toll-Like Receptor-Mediated Intestinal
Inflammatory Imbalance in the Pathogenesis of Necrotizing
Enterocolitis. Cell Mol Gastroenterol Hepatol. 6(2):229-238.e1, 2018
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Necrotizing Enterocolitis: The State of the Science. Clin Perinatol.
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Zhou Q, Banfield E, Werts AD, Ladd MR, Buck RH, Goehring KC, Prindle T
Jr, Wang S, Jia H, Lu P, Hackam DJ:. The human milk oligosaccharides
2'-fucosyllactose and 6'-sialyllactose protect against the development
of necrotizing enterocolitis by inhibiting toll-like receptor 4
signaling. Pediatr Res.89(1):91-101, 2021
4- Kovler ML, Gonzalez Salazar AJ, Fulton WB, Lu P, Yamaguchi Y, Zhou
Q, Sampah M, Ishiyama A, Prindle T Jr, Wang S, Jia H, Wipf P, Sodhi CP,
Hackam DJ: Toll-like receptor 4-mediated enteric glia loss is critical
for the development of necrotizing enterocolitis. Sci Transl Med.
13(612):eabg3459, 2021
5- Liu T, Zong H, Chen X, Li S, Liu Z, Cui X, Jia G, Shi Y: Toll-like
receptor 4-mediated necroptosis in the development of necrotizing
enterocolitis. Pediatr Res. 91(1):73-82, 2022
6- Duess JW, Sampah ME, Lopez CM, Tsuboi K, Scheese DJ, Sodhi CP,
Hackam DJ: Necrotizing enterocolitis, gut microbes, and sepsis. Gut
Microbes. 15(1):2221470, 2023