Риск смертности при применении НПВС у детей

Ravshanjon Eminov; Шукурбек Туйчибеков

Farmakologiya bo‘limi

Farmatsiya va farmakologiya,

№

1(3) – 2023

УДК 615.065

MORTALITY RISK OF NSAID USE IN CHILDREN

R.

I. Eminov,

Sh

.

M

.

Tuychibekov

Fergana Medical Institute of Public Health, Fergana, Uzbekistan

This article discusses the mortality risk associated with the use of nonsteroidal anti-inflammatory drugs

(NSAIDs) in children. While NSAIDs are commonly used for pain relief and fever reduction in children, their
side effects can be severe, including gastrointestinal bleeding, renal impairment, and cardiovascular events.
The risk of these adverse effects is even higher in children with underlying medical conditions or those taking
other medications. The article provides an overview of the mechanisms of action of NSAIDs, their potential
side effects, and measures that can be taken to minimize the risk of adverse effects.

Key words:

NSAIDs, children, mortality, adverse effects, COX enzymes, medication interactions.

Mortality due to adverse effects of nonsteroidal

anti-inflammatory drugs (NSAIDs) in children is a
concerning issue. NSAIDs are commonly used for
pain relief and fever reduction in children, but their
side effects can be severe, including gastrointestinal
bleeding, renal impairment, and cardiovascular
events. The risk of these adverse effects is even
higher in children with underlying medical conditions
or those taking other medications. Therefore, it is
crucial to weigh the benefits and risks of NSAID use
in children and take appropriate measures to prevent
severe adverse effects. In this article, we will discuss
the current evidence on mortality due to NSAID use
in children and the measures that can be taken to
minimize the risk of adverse effects. The effects that
occur when used together with other drugs have not
been fully studied and require further study.

Methods

: To conduct this study, a

comprehensive literature search was performed using
several electronic databases, including Google
scholar, PubMed, Elicit. The search was limited to
articles published in the English language from 2015
to 2022. The following keywords and their
combinations were used for the search: "mortality",
"nonsteroidal anti-inflammatory drugs", "NSAIDs",
"children", "pediatrics", "adverse effects", "side
effects",

"gastrointestinal

bleeding",

"renal

impairment",

and

"cardiovascular

events".

Researching the mortality risk of NSAID use in
children is important for understanding the safety
profile of these widely used medications, informing
clinical

decision-making,

and

guiding

the

development of evidence-based treatment guidelines
for pediatric patients.

NSAIDs (nonsteroidal anti-inflammatory

drugs) are commonly used among children for several
purposes, including:
1. Pain relief: NSAIDs can help reduce pain caused
by a variety of conditions, including headaches,
toothaches, ear infections, muscle strains, and
injuries.

2. Fever reduction: NSAIDs can also help lower
fever, which is a common symptom of many
illnesses, including viral infections.
3. Inflammation reduction: NSAIDs can help reduce
inflammation, which is a common symptom of
conditions such as arthritis and juvenile idiopathic
arthritis.

In addition to the above treatment properties,

anti-inflammatory drugs can be used for other
purposes. For example, it has been found to increase
their effectiveness when used together with antitumor
drugs. While NSAIDs have shown promise in
reducing the risk of certain types of cancer, such as
colon cancer, their use as a primary treatment for
cancer is still under investigation. NSAIDs work by
inhibiting the COX enzymes, which are responsible
for producing prostaglandins that promote
inflammation and cell growth. By inhibiting COX
enzymes, NSAIDs may help prevent the growth and
spread of cancer cells. Several studies have suggested
that NSAIDs may be effective in reducing the risk of
certain types of cancer, including colon, breast, and
lung cancer. However, the use of NSAIDs as a
primary cancer treatment is still being studied and is
not yet an established treatment option. Some clinical
trials are currently investigating the use of NSAIDs in
combination with other cancer treatments such as
chemotherapy or radiation therapy. The hope is that
NSAIDs may enhance the effectiveness of these
treatments and improve outcomes for cancer
patients[1].

Due to the above properties, nonsteroidal anti-

inflammatory drugs are widely used in children. The
main side effects of NSAIDs are due to blocking of
COX-1, and long-term use can cause serious effects
in children.

Mechanism of action of nsaids

. The main

mechanism of NSAID action is the cyclooxygenase
(COX) enzyme inhibition, both centrally and
peripherally, thus interfering with the conversion of
arachidonic

acid

into

E2

prostaglandins,

prostacyclins and thromboxanes. Prostaglandins have

67

a vasodilatation effect, which is extremely important
for

preglomerular

resistance

maintenance,

maintaining glomerular filtration rate and preserving
renal blood flow[2].

Enzymes related to the action of NSAIDs can

be divided into COX-1 and COX-2, acting in different
regions. COX-1 is the one that occurs in most cells,
even fetal and amniotic fluid, and participates in
physiological effects, such as regulatory and
protective effects. COX-2 is activated by
inflammation and pro-inflammatory cytokines[3].

Based on the classification of these enzymes,

NSAIDs can be classified into non-target NSAIDs
(ketoprofen, aspirin, naproxen, flunixin, meglumine
and others), COX-2 preferential inhibitors

(meloxican, etodolac, nimesulide) and highly
selective COX2 inhibitors (coxib). Most of the side
effects are related to COX-1 inhibition, due to its
action in several systems associated with cell
cleansing. In the kidneys, they are in greater
quantities acting in glomerular filtration maintenance.
Therefore, studies indicate that individuals with
previously compromised renal function are the most
affected by the time-dependent use of non-selective
NSAIDs. The action of COX-2 is associated with
water and electrolytic maintenance in the renal
environment, which worsens its effects under
dehydration, low renal perfusion or previously
existing renal damage[2]

Fig. 1. NSAID-induced kidney injury pathophysiology

[4]

- Stomach issues: Gastric ulcers, stomach irritation,
nausea, vomiting, diarrhea, etc. Especially with
prolonged use or high doses. Warn parents to follow
dosage instructions carefully.
- Kidney problems: NSAIDs may reduce blood flow
to the kidneys and raise blood pressure. Potential for
kidney damage, especially in dehydrated children or
those with underlying kidney disease. Recommend
hydrating children and monitoring kidney function if
on long term NSAIDs. NSAIDs can also affect
platelet function and lead to bleeding disorders in
children. This effect is usually mild and reversible but

can be significant in children with pre-existing
bleeding disorders or those who are undergoing
surgical procedures. In such cases, the use of NSAIDs
should be carefully monitored, and alternative
therapies should be considered [5].

-

Cardiovascular side effects:

While cardiovascular side effects are more frequently
observed in adults, some studies have reported an
increased risk of hypertension and heart failure in
children treated with NSAIDs. In one study
conducted by Southworth, S.R. et al. in

Cyclooxygenase

Inhibit

Synthesis of hemostatic prostaglandins

(prostacyclin, PGE2, PGD2)

Act in

Vasodilation

Responsible for

↑ Renal perfusion

↓Renal vascular resistance

↓Total renal perfusion and

medullary inflow deviation (GFR)

Cumulates in

As a result,

Sodium and water retention

Renal vasoconstriction and

cerebral ischemia

Acute kidney damage

Chronic kidney disease

A chronic effect can lead to

Nonsteroidal anti‐inflammatory drugs

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2016, there was a small but statistically significant
increased risk of hypertension in children taking
NSAIDs compared to non-users[4]. Sachdeva, A. also
reported an increased risk of cardiovascular side
effects in children treated with NSAIDs[6]. In
addition to this NSAIDs can also have cardiovascular
(CV) effects, including increased risk of heart attack
and stroke. The risk of CV events associated with
NSAID use is also dose-dependent. A study by Trelle
et al. (2011) found that the risk of CV events
increased with higher doses of NSAIDs. The authors
suggest that the CV risk associated with NSAIDs
should be taken into consideration when prescribing
these drugs, especially at higher doses[7].
- Hepatic side effects:
Although hepatic side effects are uncommon in
children, they can still occur and may include
elevated liver enzymes, acute liver injury, and even
liver failure in rare cases. A study conducted by Al-
Sallami, H.S. et al. in 2014 found that children who
were treated with NSAIDs had a 2.5-fold increased
risk of developing liver injury compared to those who
did not receive NSAIDs[8].
- Medication interactions: NSAIDs can interact with
other drugs like corticosteroids, blood thinners, blood
pressure medications, etc. Caution parents to tell their
doctor about all medications, and follow directions
for spacing out doses to avoid interactions.
- Hypersensitivity reactions:
NSAID use in children has been associated with
hypersensitivity reactions such as rash, urticaria,
angioedema, and anaphylaxis. The risk of these
reactions can vary depending on the individual
NSAID and the patient's history of allergy or
atopy[9].
- Other side effects: Less commonly, headaches,
dizziness, rashes, etc. Best to monitor child and
discontinue NSAID if any unexplained symptoms
appear.

NSAIDs can interact with a wide range of

drugs, including blood thinners, ACE inhibitors,
diuretics, and steroids. These interactions can
increase the risk of bleeding, lower blood pressure,
decrease kidney function, and affect the effectiveness
of other medications. For example, taking NSAIDs
with blood thinners can increase the risk of bleeding,
while taking NSAIDs with ACE inhibitors can lower
blood pressure too much.

One of the large retrospective study evaluated

the association between ibuprofen use and acute
kidney injury (AKI) in hospitalized children in China.
The study found that ibuprofen use was common and

was associated with a significantly increased risk of
hospital-acquired AKI, even after adjusting for
confounders. The risk appeared to be dose-dependent.
The incidence of hospital-acquired AKI in this study
was 6.9%, which is lower than reported in previous
studies. This may be due to differences in study
populations, length of stay, disease severity,
frequency of serum creatinine testing, and AKI
detection method. Ibuprofen use was associated with
a 23% increased risk of pediatric hospital-acquired
AKI after adjusting for confounders. This association
was also seen in propensity score-matched analysis
and when using an alternative AKI definition.
Previous studies have also found an association
between ibuprofen use and increased risk of AKI in
children, especially in the context of dehydration or
with other nephrotoxins. However, some studies did
not find this association. In this study, the association
between ibuprofen and AKI was greater in children
with chronic kidney disease, those requiring intensive
care, and older children. The reasons for these
interactions are not fully understood. Close
monitoring of kidney function is needed for children
receiving ibuprofen, especially those at higher risk of
AKI. Judicious use of ibuprofen may help reduce the
risk of AKI[10]. This study adds to the evidence that
ibuprofen use is associated with an increased risk of
AKI in hospitalized children. Careful monitoring and
limited use when possible may help reduce this risk.

During the investigation, 18 out of 21 children

with acute respiratory diseases in our country died as
a result of drinking Dok-1 Max syrup. The deceased
children took this drug together with other drugs at
home for 2-7 days, up to 2.5-5 milliliters 3-4 times a
day. Naturally, this amount is much more than the
norm for a child. All children were given the drug
without a doctor's prescription. Since the main
substance in the drug is paracetamol, Dok-1 Max
syrup was incorrectly used by parents as an anti-cold
remedy independently or on the recommendation of
pharmacists. This caused the condition of patients to
worsen. In addition, preliminary laboratory studies
have shown the presence of ethylene glycol in this
series of Dok-1 Max syrup. This substance is toxic,
and about 1-2 ml/kg of a 95% concentrated solution
can cause serious changes in the patient's health, such
as vomiting, lethargy, seizures, cardiovascular
problems and acute kidney failure[11].

Table 1 below lists some of the nonsteroidal

anti-inflammatory drugs and their possible side
effects.

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Table 1.

NSAID Side Effects and Organ Damage

№

NSAID

Common Side Effects

Potential Organ Damage

1.

Aspirin (acetylsalicylic acid)

Gastrointestinal issues, bleeding, allergic
reactions

Stomach, kidneys, liver

2.

Ibuprofen (Advil, Motrin)

Gastrointestinal issues, skin rash, dizziness,
headache