1/6/2018 Academic OneFile - Document - Pediatric sepsis: actions to decrease sepsis in children

Pediatric sepsis: actions to decrease sepsis in children

Giuseppe A Marraro
Expert Review of Anti-infective Therapy. 7.8 (Oct. 2009): p941+.
DOI: http://dx.doi.org/10.1586/eri.09.77
Copyright: COPYRIGHT 2009 Expert Reviews Ltd.
http://www.expert-reviews.com/loi/eri

Full Text:

Author(s): Giuseppe A Marraro 1

Severe sepsis

Severe sepsis remains an important cause of mortality and morbility in neonates and children,
even though survival, fortunately, is improving compared with the recent past. Evidenced-based
recommendations regarding the acute management of sepsis and septic shock are the first step
toward improved outcomes for this important group of critically ill patients, including neonates and
children.

In 2008, sepsis guidelines were reviewed according to the evidence-based treatments, and specific
indications on time and fluid resuscitation have been reformulated [1-3] .

There was strong agreement among a large cohort of international experts regarding many level-
one recommendations for the best care of neonates and children with severe sepsis.

Shock pathophysiology and response to therapies have been reported and are age specific.
Cardiac failure is a predominant cause of death in neonates and children, but vascular failure is a
predominant cause of death in adults. Inotropes, vasodilators (children), inhaled nitric oxide
(neonates) and extracorporeal membrane oxygenation can be more important contributors to
survival in the pediatric populations, whereas vasopressors can be more important contributors to
adult survival [1-3] .

Earlier diagnosis, helpful tests to validate it and advanced treatments were discussed in various
sessions. Several perplexities were manifested on treatments that do not have sufficient base
evidence but remain on the armamentarium of daily clinical practice.

Early diagnosis of bacterial infection and sepsis are of primary importance but some patients with
an infection have minimal or even no symptoms or signs. There is a need for an effective and
accurate biochemical marker to support, or exclude, the diagnosis of infection. The host response
to bacterial infections involves the activation of complex immune mechanisms and the release of a
wide array of inflammatory mediators, which has led to the suggestion that some of these
mediators could be used as markers of infection or its severity.

Biomarkers hold promise to transform sepsis from a physiologic syndrome to a group of distinct
biochemical disorders. This transformation could aid therapeutic decision making and hence
improve the prognosis for patients with sepsis, but will require an unprecedented degree of
systematic investigation and collaboration [4] .

Several pro- and anti-inflammatory cytokines are oversynthesized during severe infections,
especially in patients with a poor outcome. IL-6 and monocyte HLA class II DR (HLA-DR)
expression on admission are good predictors of mortality. Monocyte HLA-DR expression is an
early and constant predictive marker of survival in severe sepsis. In nonsurvivors: high IL-6 levels
on day 3 and IL-10 on days 3, 10 and 13. TNF-[alpha] on days 13 and 17 have been found.
Baseline levels of TGF-[beta]1 were significantly higher in survivors.

IL-6 and HLA-DR levels may be useful for prognostication in children with sepsis. IL-6 levels and
IL-6/HLA-DR ratio are associated with the multiple-organ dysfunction score and mortality, and

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significantly associated with the severity of the multiple-organ dysfunction score. Using a cut-off
value of 28% for HLA-DR expression, the probability of death was 0.76. Further research needs to
be done in delineating the sequence of activation of these pro- and anti-inflammatory mediators
and the optimal balance that improves survival to aid in targeting therapy.

Maternal IL-6 level is a marker of intra-amniotic inflammation/infection, which could guide the
clinical management of pregnant women with a premature rupture of membranes at early
gestation. Cord blood IL-6, lipopolysaccharide-binding protein (LBP) and neonatal blood LBP levels
appear to be valid markers for early onset sepsis and can help identify preterm neonates who need
early antibiotic treatment.

Serum lactate level is a frequent diagnostic marker in septic patients and has been used for
decades to identify and manage patients with progressive circulatory dysfunction secondary to
sepsis. Lactate is generated by anaerobic cellular metabolism and may reflect the degree of
cellular derangements in sepsis. Arterial lactate levels are commonly used as a global indicator of
oxygen deficits. Serial lactate levels can reflect adequacy of hemodynamic resuscitation efforts.

The prognostic value of an elevated serum lactate level is well established in patients with severe
sepsis or septic shock. In fact, serum lactate levels have been shown to be superior to oxygen-
derived variables (O2 delivery and O2 uptake) in septic patients. Perhaps more important than a
single lactate measurement are serial values that are useful as a guide to patient assessment and
response to the therapy.

Critics of the use of serum lactate in the diagnosis and care of patients with sepsis cite that
elevated levels may not always be due to anaerobic metabolism. It is true that elevations in serum
lactate may also be due to reduced hepatic clearance, trauma or profound dehydration.

C-reactive protein (CRP) is not specific for neonatal sepsis but it is important indicator for infection
observation and a valuable adjunct in the diagnosis of neonatal sepsis, complimenting clinical
decision-making. The negative predictive value of CRP is high and CRP over 6 mg/dl had a
positive predictive value for proven early-onset sepsis. However, high levels of CRP do not always
indicate sepsis. Hence, it cannot be used in postoperative surgical patients in isolation to diagnose
sepsis, and the clinical condition of the patient and other inflammatory markers are also required.

Diagnostic accurancy of neutrophil and monocyte CD64 indexes (CD64in and CD64im) for sepsis
in critically ill neonates and children with that of LBP, procalcitonin (PCT) and CRP is needed. LBP
is a nonspecific marker of the acute phase response and cannot be used as a diagnostic tool for
differentiating between infectious and noninfectious etiologies of systemic inflammatory response
syndrome. PCT is not a better marker of bacterial infection than CRP but it is a useful marker of
the severity of infection. In patients with elevated serum CRP levels, PCT might be used to further
support the presence of infection and to predict the disease severity.

CD64in is the best individual marker for sepsis in children, while in neonates the highest diagnostic
accuracy at the time of suspected is achieved by LPB and 24 h later by CD64in.

The CD64-LBP score point is superior to all individual markers in both neonates and children at the
time of suspected sepsis.

Cardiac evaluation in intensive care unit (ICU) hemodynamics could be directed to the goals of
achieving a central venous oxygen saturation over 70% and a cardiac index of 3.3-6.0 l/min/m2 .

The deterioration of left atrial function in patients with severe sepsis and septic shock does not
frankly predict mortality. On admission, left ventricular ejection fraction could show significant
differences between survivors and nonsurvivors, atrial ejection force (AEF) could show significant
changes between the same groups, while B-type natriuretic peptide may be significantly higher in
the nonsurvivors. The predictable variables for mortality appears to be related to APACHE II score,
B-type natriuretic peptide and ejection fraction.

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Echocardiography can noninvasively elucidate a broad range of acute cardiovascular pathologies.

This information is vital in the management of hemodynamically instable patients in the ICU. In
addition, ultrasonography has particular value for assessing pulmonary status and the peripheral
venous system.

Antibiotic therapy remains the most important treatment and must be started within the first hour.
The first 'golden hour' must be devoted to fluid resuscitation and inotrope (vasopressor?) therapy.

The hemodynamic pattern of fluid-resistant septic shock at the time children present to the
pediatric ICU are distinct, depending on cause, with little overlap. If these findings can be
reproduced, then targeting the choice of first-line vasoactive infusion in fluid-resistant shock
(vasopressor for central venous catheter-associated infections and inotropes for community-
acquired sepsis) should be considered.

Despite clear consensus guidelines for the emergency management of children with severe sepsis
and septic shock, most children received inadequate fluid resuscitation and inotropic support in the
crucial few hours following presentation [5] .

The 2007 update continues to emphasize early use of age-specific therapies to attain time-
sensitive goals, specifically recommending first-hour fluid resuscitation and inotrope therapy
directed to goals of threshold heart rates, normal blood pressure and capillary refill of 2 s or less [6]
.

Early hemofiltration

Early continuous venovenous hemofiltration improves general perfusion and reduces inotropic
requirement more quicky thanwhen it is used only as a rescue therapy in children with septic shock
and acute renal failure. It is a safe and effective substitution of renal function that can support the
hemodynamic and metabolism system.

Use of milrinone

Milrinone is a newer cyclic AMP-specific phosphodiesterase (PDE) inhibitor (also called fraction III
or low-Km cyclic AMP) that can produce both positive inotropic effects and vasodilatation
independent of [beta] 1 -adrenergic receptor stimulation in the cardiovascular system. Milrinone
improves hemodynamics and biventricular function in patient with ventricular dysfunction by
increasing stroke volume index, left ventricular contractility and producing pulmonary vasodilation.
Milrinone also produces vasodilation in arteriolar and venous vascular smooth muscle.

Debating treatments

There is a need to answer to the issue of treatments in children with septic shock. Important steps
to decrease sepsis in children at present are still suboptimal and have to be improved.

Clinical trials are being carried out in order to identify the type of patient to be treated, dose and
timing of treatments.

Steroids remain controversial in the treatment of pediatric patients with severe sepsis; vasopressin,
a key stress hormone in response to hypotension, has been reported in the management of
vasodilatory shock in children; glycemic control in sepsis and septic shock is debatable as to
whether it ameliorates the outcome in these patients.

Steroids

The speakers agree with three trials, all published in the New England Journal of Medicine [7-9] ,
which ascertained that high-dose, short-duration methylprednisolone did not decrease sepsis
mortality and might be associated with serious adverse side effects, such as gastrointestinal
hemorrhage. Reviews of the clinical trials using high-dose corticosteroids, administered as a single

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dose during the initial hours of septic shock, concluded that this approach probably conferred no
beneficial effect on mortality [10] . On the other hand, there is no doubt that corticosteroids at low
doses have a potent biological activity and that they may help in treating septic shock. The real
issue, which has been stressed, is who should be treated. Corticosteroids are definitely not a
magic bullet. Efforts should focus on identifying the patients who need to be treated as suggested
by various authors.

Vasopressin

Vasopressin is largely used in the treatment of septic skock because it is a key stress hormone in
response to hypotension. The VASST study, a randomized trial of vasopressin versus
norepinephrine in septic shock, demonstrated that there was no difference in mortality between
vasopressin versus norepinephrine-treated patients (35 vs 39%, respectively). Patients who had
less severe septic shock, probably those treated with vasopressin, may have lowered mortality
compared with norepinephrine (26 vs 36%) according to the data presented by Russel [11] .

Glycemic control

Evidence is growing in the literature that strictly maintaining normoglycemia by intensive insulin
therapy ameliorates outcome in hyperglicemic patients [12] .

The recent Surviving Sepsis consensus statement [1] recommends insulin therapy using validated
protocols to lower glucose levels (<150 mg/dl) pending the results of adequately powered trials to
determine if normalization (<110 mg/dl) of glucose is needed to optimize outcomes in patients who
have severe sepsis [13] .

Quality-improved programs to reduce sepsis patients have also been discussed. American College
of Critical Care Medicine guidelines [2] for hemodynamic support of adult septic shock have little
application to the management of pediatric or neonatal septic shock. Studies are required to
determine whether American College of Critical Care Medicine guidelines for hemodynamic
support of pediatric and neonatal septic shock will be implemented and associated with improved
outcome.

Adherence to recommendations must be improved in children with septic shock [1] .

Comments

The updated 2007 guidelines continue to recognize an increased likelihood that children with septic
shock, compared with adults, require:

* Proportionally larger quantities of fluid

* Inotrope and vasodilator therapies

* Hydrocortisone for absolute adrenal insufficiency

* Extracorporeal membrane oxygenation for refractory shock

The major new recommendation in the 2007 update is the earlier use of inotrope support through
peripheral access until central access is attained [6] .

Sepsis remains a high-mortality pathology and requires the application of prudent protocols. Large
controlled clinical trials are indispensable to evaluate the treatments that remain until now not
completely confirmed, essentially if they are costly and variable and contrasting in results.

The International Pediatric Sepsis Initiative has been promoted by the World Federation of
Pediatric and Intensive Care Societies (WFPICCS) to decrease the burden and ravages of sepsis

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in children. This worldwide campaign aims to create a database to be used by the clincians and
researchers to eradicate sepsis [101] .

References

1 Dellinger RP, Levy MM, Carlet JM et al. Surviving Sepsis Campaign: international guidelines for
management of severe sepsis and septic shock: 2008. Crit. Care Med. 36, 296-327 (2008).

2 Carcillo JA, Fields AI; American College of Critical Care Medicine Task Force Committee
Members. Clinical practice parameters for hemodynamic support of pediatric and neonatal patients
in septic shock. Crit. Care Med. 30, 1365-1378 (2002).

3 Oliveira CF, Nogueira de Sá FR, Oliveira DS et al. Time- and fluid-sensitive resuscitation for
hemodynamic support of children in septic shock: barriers to the implementation of the american
college of critical care medicine/pediatric advanced life support guidelines in a pediatric intensive
care unit in a developing world. Pediatr. Emerg. Care 24, 810-815 (2008).

4 Marshall JC, Reinhart K, International sepsis forum. biomarkers of sepsis. Crit. Care Med. 37,
2290-2298 (2009).

5 Brierley J, Peters MJ. Distinct hemodynamic pattern of septic shock at presentation to pediatric
intensive care. Pediatrics 122, 752-759 (2008).

6 Brierley J, Carcillo JA, Choong K et al. Clinical practice parameters for hemodynamic support of
pediatric and neonatal septic shock: 2007 update from the American College of Critical Care
Medicine. Crit. Care Med. 37, 666-688 (2009).

7 Bone RC, Fisher CJJ, Clemmer TP et al. A controlled clinical trial of high-dose
methylprednisolone in the treatment of severe sepsis and septic shock. N. Engl. J. Med. 317, 653-
658 (1987).

8 Veterans Administration Systemic Sepsis Cooperative Study Group. Effect of high-dose

glucocorticoid therapy on mortality in patients with clinical signs of systemic sepsis. N. Engl. J.
Med. 317, 659-665 (1987).

9 Sprung CL, Annane D, Keh D et al. Hydrocortisone therapy for patients with septic shock. N.
Engl. J. Med. 358, 111-124 (2008).

10 Vincent J-L. Steroids in sepsis: another swing of the pendulum in our clinical trials. Crit. Care
12, 141 (2008).

11 Russel JA. The current management of septic shock. Minerva Med. 99, 431-458 (2008).

12 Ellger B, Westphal M, Stubbe HD et al. Glycemic control in sepsis and septic shock: friend or
foe? Anaesthesist 57, 43-48 (2008).

13 Thompson BT. Glucose control in sepsis. Clin. Chest Med. 29, 713-720 (2008).

Website

101 Pediatric Sepsis Initiative Database. World Federation of Pediatric and Intensive Care
Societies (WFPICCS) Pediatric Sepsis Initiative www.pediatricsepsis.org/

Author Affiliation(s):

1 Anesthesia and Intensive Care Department & Pediatric Intensive Care Unit, Fatebenefratelli and
Ophthalmiatric Hospital, University of Milan, Milan, Italy. gmarraro@picu.it

Financial & competing interests disclosure

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The author has no relevant affiliations or financial involvement with any organization or entity with a
financial interest in or financial conflict with the subject matter or materials discussed in the
manuscript. This includes employment, consultancies, honoraria, stock ownership or options,
expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Giuseppe A Marraro

Source Citation (MLA 8th Edition)

Marraro, Giuseppe A. "Pediatric sepsis: actions to decrease sepsis in children." Expert Review of
Anti-infective Therapy, vol. 7, no. 8, 2009, p. 941+. Academic OneFile,
http://link.galegroup.com/apps/doc/A239788517/AONE?u=pu&sid=AONE&xid=1e570435.
Accessed 1 June 2018.

Gale Document Number: GALE|A239788517

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