Ryszard Lauterbachéndez1*, and Dorota Pawlik1
1,2Department of Neonatology Jagiellonian University Medical College, Kraków, Poland
Received: 22 Nov 2024; Accepted: 20 Dec 2024; Published: 28 Dec 2024
Citation: Lauterbach, Ryszard, and Dorota Pawlik. “May Pentoxifylline Protect Immature Brain Against Disorders Induced By Inflammatory Response In Neonatal Sepsis?.” J Neonatol Pediat Care (2024): 101. DOI: 10.59462/JNPC.1.1.101.
Copyright: © 2024 Lauterbach R. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Sepsis • Inflammatory response • Brain development • Preterm infant •Interleukine-6 • Pentoxifylline
Prematurity is a chronic hyperinflammatory state when
compared to the inflammatory response in adulthood.
Even in the absence of disease, the inflammatory reaction
is more robust with preterm infants mounting cytokine
levels that far exceed those in adults with similar insults.
Unregulated inflammatory response is partially due to an
increase in production of proinflammatory mediators but
is also due to the lack of negative regulator [1].
It is now widely accepted that inflammation interferes
with neuronal migration and differentiation. It may also
disturb the synaptogenesis [2]. The consequences of
the inflammatory episodes might be disorders of brain
development as observed in preterm infants. Postnatal
bacterial infections, regardless of the results of the blood
cultures, are generally accepted as an important risk
factor that may cause widespread abnormalities of brain
development in premature infants [3]. Moreover, it was
found that inflammatory response due to sepsis may impair
the process of myelinization and in turn either disrupts the
white matter tissue development, or inhibits brain growth,
which increases the risk of attentional performance in
preterm infants [4]. Recently, Giordano and coauthors [5]
suggested that neonatal sepsis might be a risk factor for
behavioral abnormalities observed at the age of 5 years in
former very low birth weight infants. These infants displayed
a more frequently elevated risk for depression, anxiety, and
higher than normal emotional reactivity, as well as attention
deficits. It was also found that necrotizing enterocolitis
triggered a systemic inflammatory response that might
result in neurodevelopmental disorders. A significant
number of studies showed that up to 45% of children
from the infants who survived necrotizing enterocolitis,
presented neurodevelopmental impairment [6].
At this point, the question arises whether we should
obligatorily enter an anti- inflammatory medicine into the
treatment of neonatal sepsis to lessen the risk of immature
brain injury. The steroids with their evident and widely
recognized adverse effects on the development of the
immature brain may be acceptable exclusively in therapy
of the most severe stages of sepsis. Until now, there is no
alternative method for the limitation of hyperinflammatory
response observed in septic preterm neonates. In this
case, the promising candidate, which exerts several
antioxidant and anti- inflammatory activities seems to
be pentoxifylline (PTX), a methylxanthine derivative, a
non-specific phosphodiesterase inhibitor. This drug is
approved and widely available in most countries as a
generic medication. PTX is approved to treat intermittent
claudication with the ability to decrease blood viscosity,
increase erythrocyte flexibility, and increase tissue
oxygen concentration. A considerable number of studies
demonstrated that PTX reduced serum concentrations of
the inflammatory cytokines such as tumor necrosis factor-α
(TNF-α), interleukin-1β (IL-1β), and IL-6 [7]. Moreover,
PTX showed preservation of proper endothelial function
and coagulation activity in sepsis [8]. The results of the latest meta-analysis on intravenous administration of PTX
as an adjunct to antibiotic therapy of sepsis in neonates
were published in June 2023 [9]. The authors analyzed
data obtained from six randomized controlled trials
(RCT) with 416 neonates. In conclusion, low-certainty
evidence was found that adjunct PTX therapy in neonatal
sepsis decreased mortality and length of hospitalization.
Moreover, the authors maintained that no adverse effects
of PTX administration were observed. However, in none of
these six RCTs, the neurodevelopment of preterm infants
after survival of sepsis was evaluated at the subsequent
age of life and no comparison of infants treated to those
untreated with PTX was done. Furthermore, in septic
neonates, recruited into all previously conducted metaanalyses, exclusively one schedule of PTX administration
(5 mg/kg/h for 6 hours), presented in our first randomized
controlled, double-blind study, and was applied, regardless
of the severity of the clinical course of sepsis.
Recently, the results of several experimental and
clinical studies were published, providing evidence for
neuroprotective effects of PTX. Haggar and coauthors
demonstrated that twelve weeks of PTX administration in
a dose of 800 mg/day caused a significant increase in
blood concentration of the brain derived neutrophic factor
(BNDF), in adult patients with major depressive disorder
(MDD), showing clinically and statistically significant
antidepressant effects compared to placebo [10]. It is
also known that MDD is associated with inflammatory
processes and increased concentration of IL-6 in the brain.
On the other hand, BNDF is crucial for the development of
the peripheral and central nervous system. It was found in
the experimental studies that PTX may stimulate process
of neurogenesis and prevent neuronal degeneration,
especially in the hippocampus. Primarily, the increase
in cAMP as well as the reduction of proinflammatory
cytokines concentrations, likely played an important role
in promoting neurogenesis by PTX [11]. Moreover, Zheng
and coauthors [12], on the grounds of results obtained in
the experimental study, suggested an important role of PTX
in modulation of microglia-associated phagocytosis and
the protective effects against white matter injury observed
after episodes of hypoxia. It is also known that markedly
increased proinflammatory cytokines concentrations due
to sepsis may impair pre-oligodendrocytes, which finally
causes white matter injury and impairs myelinization [13,
14]. Furthermore, recently Ruiz-Perera and coauthors, making use of a model of human neuronal stem cells,
showed that PTX shifted stem cell differentiation to
oligodendroglial cells. Whether it might improve the
impaired process of myelination should be elucidated
in experimental and clinical research. Moreover, it was
also found that PTX adjuvant to risperidone alleviated
negative symptoms in patients with schizophrenia and
no remarkable side effects were observed. These effects
could be attributed to inhibition of phosphodiesterases
(PDEs) and a reduction in concentrations of inflammatory
cytokines in the brain. The role of inflammation in the
pathomechanism of schizophrenia is also suggested.
The results of publications quoted above present different
kinds of beneficial, anti-inflammatory effects of PTX and
confirm the permeability of the blood-brain barrier for this
drug.
The administration of PTX as an adjunct to antibiotic
therapy of sepsis, dates in our neonatal department
to 1999, when we published the results of the first
prospective, randomized double-blind, placebocontrolled study on the effectiveness and safety of PTX
in the treatment of neonatal sepsis [15]. We found that
PTX significantly decreased serum concentrations of
TNF-α and IL-6 as well as reduced the mortality rate in
premature infants with late-onset sepsis (LOS) caused by
Gram- negative bacteria. The dosage and schedule for
drug administration applied in this study attenuated the
severity of the clinical course of sepsis in the group of
patients treated with PTX. However, on the ground of our
first results, we were not able to make an unambiguous
conclusion about the best dosage and schedule of drug
administration, because it was the first clinical research
project with PTX in preterm infants with sepsis. During
subsequent several years of clinical observation, after
collecting data and experience, we made several
modifications and established different schedules for
PTX administration in septic neonates. They are based
principally on the clinical symptoms and the values of
IL-6 serum concentrations found during sepsis. These
parameters indicate the necessity for the modification of
dosages and the length of drug administration. It is widely
accepted that IL-6 serum concentration is a good and early
marker of neonatal sepsis. This cytokine is released within
2 hours after onset of bacteremia, peaks at approximately
6 hours and usually declines over the following 24 hours [16]. However, IL-6 serum concentration may fluctuate at
the beginning of therapy within 3-4 days. Moreover, IL-6
serum concentrations might be significantly elevated, even
up to 48 hours, prior to the onset of clinical sepsis [17].
Although some investigators have found that neonatal
IL-6 response is comparable to that found in adults
while others have reported diminished IL-6 production,
we occasionally observed extremely high IL-6 serum
concentrations, even excessive values of 100.000 pg/ml.
(normal value <40 pg/ml). The highest value of IL-6 serum concentration found in preterm neonates with early
onset
sepsis (EOS), hospitalized in our unit, reached 450.000 pg/ml. In these cases, when we observed IL- 6 serum
concentrations above 50.000 pg/ml a standard dose of PTX (5mg/kg/hour, given for 6 hours) caused only minimal
and transient effect on both IL-6 serum concentration and perfusion disturbances. After doubling the dosage of
PTX (10 mg/kg/hour) and extending the period of drug administration (24 hours infusion given during two
consecutive days), we obtained both a significant decrease in IL-6 serum concentration and capillary refill time
reduction. A recent analysis of 480 episodes of LOS diagnosed in 208 preterm neonates born below 32 weeks of
gestational age showed that increased IL-6 serum concentrations were associated with sepsis severity and
mortality risk [18]. We confirm that correlation and suggest that IL-6 serum concentration might serve as a
prognostic parameter for severity as well as mortality risk in neonatal sepsis. On the basis of our clinical
experience, we also confirm that rapid intervention with intravenous PTX as an adjunct of antibiotic therapy in
suspected neonatal sepsis, diminishes the risk of perfusion disturbances, alleviates metabolic acidosis, and
treats them successfully. The duration of PTX infusion and the dosage of drug-infused should be differentiated
according to the following clinical conditions: metabolic acidosis, perfusion and coagulation disorders, the
necessity to use non-invasive or invasive ventilatory support, the appearance of thrombotic necrosis on the skin
surface and the magnitude of the values of IL-6 serum concentrations. As for the number of total days of drug
administration, we suggest the continuation of therapy with PTX as long as the antibiotics are supplied.
However, during the treatment, the dosages of PTX may be reduced or increased, according to the clinical
conditions and the observed values of IL-6 serum concentrations.Below we propose four different schedules of PTX
administration in therapy of neonatal sepsis. The proposal is based on clinical experiences and retrospectively
analyzed data found in a group of approximately 800 premature septic patients with confirmed sepsis of different
degrees of severity. We would like to emphasize that all adjustments of dosages and the length of PTX
administration were performed according to clinical conditions and IL-6 serum concentrations after parental
consent was obtained.
Sepsis without perfusion disorders: clinical symptoms of sepsis with increased serum concentrations of IL6, (blood culture positive or negative) – no perfusion disorders, no metabolic acidosis: PTX administered in a dose of 5 mg/kg/h and infused for 6 hrs a day. (in case of feeding intolerance – the possibility of reducing a dose to 2.5 mg/kg/h).
Sepsis with perfusion disorders:prolonged capillary refill time (CRT >3 sec.), increased lactate concentration, metabolic acidosis, significantly increased concentration of inflammatory markers: IL-6, CRP, PCT: PTX administered in a dose of 5 mg/kg/h and infused for 12 or 24 hrs a day.
Septic shock:start infusion of PTX about 1-2 hours after the previous beginning of the administration of fluids and catecholamines and/or hydrocortisone. PTX is administered in a dose of 5mg/kg/h and continued for 24 hrs.
Significantly increased serum IL-6 concentrations
>50.000 pg/ml:visible thrombotic skin necrosis: PTX in
a dose of 10 mg/kg/h infused for 12-24 hrs and continued
usually within 1 to 2 days then switch to administration
with a dose of 5 mg/kg/h infused for 12-24 hrs.
In 2016, based on retrospective analysis, we
published
the results of sepsis therapy diagnosed in very low birth
weight infants [19]. Among the 458 infants with confirmed
sepsis (median birthweight 1010.0 g; median gestational
age: 29 weeks), death occurred in 19 of those infants
(4.2%). In comparison to data presented by others,
our results seemed to be promising. We declare that
PTX, as an adjunct to antibiotic therapy of confirmed or
suspected sepsis in preterm neonates, has been used
in our department continuously since 1999. However, the dosage and schedule of PTX administration have
been adjusted to clinical symptoms and the values of
IL-6 serum concentration, which markedly improved the
results of treatment.
Suggestion:based on our own clinical experiences and data from experimental and clinical studies presented above, we suggest the possible, beneficial effects of PTX when given as an adjunct therapy to antibiotics in neonatal sepsis. It seems to be an important part of treatment, especially when markedly increased inflammatory response is observed, and perfusion is significantly disturbed. An adjunct to antibiotics, therapy with PTX alleviates the clinical course of sepsis and it might limit the risk of abnormalities of brain development in premature infants. However, we realize that our suggestion is mostly based on clinical observations and retrospective analysis, and therefore it should be treated as a consultative opinion.
Author Contribution:The authors contributed to the article and approved the submitted version.
Conflict of interestThe authors declare no commercial or financial relationships that could be construed as a potential conflict of interest.