J Pediatr (Rio J). 2020;96(S1):87---98

www.jped.com.br

REVIEW ARTICLE

Septic shock in pediatrics: the state-of-the-art�

Pedro Celiny Ramos Garcia a, Cristian Tedesco Tonial b,∗, Jefferson Pedro Piva c,d

a Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Hospital São Lucas, Faculdade de Medicina e Terapia IntensivaPediátrica, Programa de Pós-Graduacão em Pediatria e Saúde Infantil, Porto Alegre, RS, Brazilb Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Hospital São Lucas, Faculdade de Medicina e Terapia IntensivaPediátrica, Departamento de Pediatria, Porto Alegre, RS, Brazilc Universidade Federal do Rio Grande do Sul (UFRGS), Faculdade de Medicina, Porto Alegre, RS, Brazild Hospital de Clínicas de Porto Alegre, Departamento de Emergência e Cuidados Intensivos Pediátricos, Porto Alegre, RS, Brazil

Received 24 October 2019; accepted 25 October 2019Available online 13 December 2019

KEYWORDSInfection;Sepsis;Shock;Child;Mortality;Intensive Care Units

AbstractObjective: Review the main aspects of the definition, diagnosis, and management of pediatricpatients with sepsis and septic shock.Source of data: A search was carried out in the MEDLINE and Embase databases. The articleswere chosen according to the authors’ interest, prioritizing those published in the last fiveyears.Synthesis of data: Sepsis remains a major cause of mortality in pediatric patients. The variabil-ity of clinical presentations makes it difficult to attain a precise definition in pediatrics. Airwaystabilization with adequate oxygenation and ventilation if necessary, initial volume resuscita-tion, antibiotic administration, and cardiovascular support are the basis of sepsis treatment. Inresource-poor settings, attention should be paid to the risks of fluid overload when administrat-ing fluids. Administration of vasoactive drugs such as epinephrine or norepinephrine is necessaryin the absence of volume response within the first hour. Follow-up of shock treatment shouldadhere to targets such as restoring vital and clinical signs of shock and controlling the focusof infection. A multimodal evaluation with bedside ultrasound for management after the firsthours is recommended. In refractory shock, attention should be given to situations such as car-diac tamponade, hypothyroidism, adrenal insufficiency, abdominal catastrophe, and focus ofuncontrolled infection.Conclusions: The implementation of protocols and advanced technologies have reduced sepsismortality. In resource-poor settings, good practices such as early sepsis identification, antibiotic

administration, and careful fluid infusion are the cornerstones of sepsis management.© 2019 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. This is an openaccess article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

� Please cite this article as: Garcia PC, Tonial CT, Piva JP. Septic shock in pediatrics: the state-of-the-art. J Pediatr (RioJ).2020;96(S1):87---98.

∗ Corresponding author.E-mail: cristian.tonial@pucrs.br (C.T. Tonial).

https://doi.org/10.1016/j.jped.2019.10.0070021-7557/© 2019 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. This is an open access article under the CC BY-NC-NDlicense (http://creativecommons.org/licenses/by-nc-nd/4.0/).

88 Garcia PC et al.

PALAVRAS-CHAVEInfeccão;Sepse;Choque;Crianca;Mortalidade;Unidade de CuidadosIntensivos

Choque séptico em pediatria: o estado da arte

ResumoObjetivo: Revisar os principais aspectos da definicão, diagnóstico e manejo do pacientepediátrico com sepse e choque séptico.Fontes de dados: Uma pesquisa nas plataformas de dados Medline e Embase foi feita. Os artigosforam escolhidos segundo interesse dos autores, priorizaram-se as publicacões dos últimos 5anos.Síntese dos dados: A sepse continua a ser uma causa importante de mortalidade em pacientespediátricos. A variabilidade de apresentacão clínica dificulta uma definicão precisa em pedi-atria. A estabilizacão da via aérea com adequada oxigenacão, e ventilacão se necessário,ressuscitacão volêmica inicial, administracão de antibióticos e suporte cardiovascular são abase do tratamento da sepse. Em cenários de poucos recursos, deve-se atentar para os riscosde sobrecarga hídrica na administracão de fluidos. A administracão de drogas vasoativas comoadrenalina ou noradrenalina, se faz necessária na ausência da resposta ao volume na primeirahora. O seguimento do tratamento do choque deve seguir alvos como restauracão dos sinaisvitais e clínicos de choque e controle do foco de infeccão. Recomenda-se a avaliacão multi-modal, com auxílio da ecografia à beira-leito para manejo após as primeiras horas. No choquerefratário, deve-se atentar para situacões como tamponamento cardíaco, hipotireoidismo, insu-ficiência adrenal, catástrofe abdominal e foco de infeccão não controlado.Conclusões: Implantacão de protocolos e avancadas tecnologias propiciou uma reducão da mor-talidade da sepse. Em cenários de poucos recursos, as boas práticas, como reconhecimentoprecoce da sepse, administracão de antibióticos e cuidadosa infusão de fluidos, são os pilaresdo manejo da sepse.© 2019 Sociedade Brasileira de Pediatria. Publicado por Elsevier Editora Ltda. Este e um artigoOpen Access sob uma licenca CC BY-NC-ND (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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rom the dawn of Homo sapiens to the present day, infec-ious diseases have been a huge challenge for humankind.he World Health Organization estimates that over 60 % ofhe deaths of children under the age of 5 on the planet areue to infectious diseases.1

Sepsis is a potentially fatal multi-organ failure due tohe body’s dysregulated response to an infectious process.his dysregulated response may range from an uncontrollednd exaggerated manifestation of proinflammatory activitye.g., meningococcemia), with intense clinical presenta-ion or a less intense manifestation to the absence of annflammatory response, as in immunosuppressed patientsr those with ‘‘immunoparalysis,’’ where the clinical pre-entation may be silent or insidious (e.g., central venousatheter-related candidemia in children immunosuppressedy chemotherapy).2---7

In recent decades, several campaigns and recommenda-ions to fight sepsis have been promulgated to facilitateiagnosis, promote early intervention, and reduce childortality. Consequently, there has been a marked decline

n mortality from severe sepsis and septic shock world-ide, with lower rates in developed countries than in poorerations (19 % vs. 32 %, respectively).8---13

Increased sepsis survival has been attributed to early

etection associated with aggressive treatment in a hos-ital setting, following previously established protocols.2---6

owever, sepsis involves complex pathophysiological mech-nisms with varied and unspecific clinical presentations,

ffecting a heterogeneous group of people (newborns,ealthy patients, those with comorbidities, among oth-rs); thus, a single, simple, and objective definition thatncompasses this whole scope has become a tremendoushallenge. The current definitions of sepsis and its stagesn pediatrics are inaccurate and do not consider this diver-ity of presentations; thus, they demonstrate low specificitynd sensitivity.5,12,14 Consequently, delay in diagnosis is notnusual, and there is a delay in the establishment of ade-uate treatment that includes well-defined targets in therst hour of care (‘‘the golden hour’’).5,6,15 The aim ofhis study is to review the most important aspects regard-ng the definition, diagnosis, and management of sepsis inediatrics; discuss the controversial points of the literatureased on the most recent scientific evidence, and criticallyisclose the authors’ opinion.

efinition of sepsis in pediatrics

n 2005, the International Pediatric Consensus ConferenceIPSCC)5 proposed age-adjusted definitions for sepsis and itstages in pediatrics, having systemic inflammatory responseyndrome (SIRS) as the central concept. In this perspective,he IPSCC proposed the following as definitions:

I Sepsis:a Suspected or proven infection caused by any pathogen

or clinical syndrome with high probability of infection,associated with:

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Presence of at least two of the following clinicalmanifestations (requiring abnormal temperature orwhite blood cell count):

b Temperature >38.5 ◦C or <36 ◦C.c Tachycardia or bradycardia (values adjusted to age).d Tachypnea (according to the age range) unrelated to

neuromuscular disease or anesthesia.e Elevated or suppressed leukocyte count according to

values for each age group.II Severe sepsis: A patient defined as having sepsis

according to the above criteria presenting with organ dys-function (respiratory or cardiocirculatory) or two otherdysfunctions.

III Septic shock: patient with sepsis with acute circula-tory failure, characterized by persistent hypotension (<2standard deviations for the age range standard) despiteadequate volumetric resuscitation and unexplained byother causes.

The IPSCC task force, when creating these defini-tions, stressed that it was an instrument still underconstruction that required refinement, yet they were incor-porated into the daily practice of pediatric intensive careunits (PICUs) worldwide2---4,7,14---16 and formed the basisof concepts for pediatric sepsis diagnosis and treatmentrecommendations.5,6,15

Despite the fast acceptance in the clinical setting,several studies carried out over the last decade have demon-strated the limitations of the definitions proposed by theISPCC. The SPROUT (Sepsis Prevalence, Outcomes, and Ther-apies) study, featuring 7000 children admitted to 128 PICUsin 26 countries, showed poor agreement (46 %) betweenthe presumptive diagnosis of severe sepsis by the attend-ing physician and the diagnosis according to the IPSCCrecommendations.17 The clinical diagnosis was performedusing a more liberal approach, with lower laboratory alter-ations, lower mortality, and lower organ failure than thatobserved in the group that was strictly defined by theconsensus criteria.

The main reason to justify the low specificity and sensitiv-ity of the IPSCC criteria in the diagnosis of sepsis in pediatricsis related to SIRS: patients with sepsis may not have SIRS,just as SIRS may be present in patients without infection. Inthis sense, several other clinical and biological markers havebeen evaluated in sepsis (e.g., serum lactate, central venoussaturation, blood pressure, capillary filling, among others),and none of them showed sufficient accuracy to define andguide the treatment of sepsis in children.6,15,18,19

As a consequence of the dysregulated response to theinfection and the established treatment, two forms of deathcan occur in sepsis: a) refractory shock and b) multiple organdysfunction syndrome (MODS). One-third of deaths in chil-dren with sepsis and septic shock are estimated to occurwithin the first 72 h, in which refractory shock is the lead-ing cause. However, after the third day, MODS, respiratoryfailure, and neurological failure predominate as the maincauses of death.20

Recently new definitions for sepsis and septic shock have

been proposed for the adult population: The Third Inter-national Consensus Definitions for Sepsis and Septic Shock(Sepsis-3), where some concepts of the Sequential OrganFailure Assessment (SOFA Score) have been incorporated.3,4

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hese new definitions have been adapted to also be used inhe pediatric population. The pediatric SOFA score (pSOFA) isased on the assessment of six systems (respiratory, hepatic,oagulative, cardiovascular, neurological, and renal), withalues ranging from zero to 4 points.21 The pSOFA score canange from zero (understood as a normal health conditionnd no chance of sepsis) up to a maximum of 24 (interpreteds severe septic shock). Therefore, adopting the Sepsis-3dapted for children, the definitions are as follows:

I SEPSIS: suspected or confirmed infection associated withacute increase in the pSOFA score >2 points (within theprior 48 h up to 24 h of infection).

I SEPTIC SHOCK: The same criteria mentioned above in chil-dren receiving vasoactive drugs associated with serumlactate level >2 mg/dL.

These definitions were retrospectively assessed, analyz-ng more than 8500 children admitted over a seven-yeareriod to a PICU in the United States. Mortality in the studyroup was 2.4 %, which is considered very low even for devel-ped countries. In this scenario it was demonstrated thathe pediatric Sepsis-3 has great power to predict mortalityAUC = 0.94), with little (if any) advantage over other pedi-tric scores such as PRISM (Pediatric Risk of Mortality) III,-MODS (Pediatric Multiple Organ Dysfunction Score), andELOD (paediatric logistic organ dysfunction) 1 and 2. ASOFA score >8 was the best cutoff point to predict sepsisortality.21

When the pediatric Sepsis-3 was evaluated in an IndianICU involving a smaller population but with a much higherepsis mortality (40 %), a high specificity (identifying theost severe cases of sepsis) was observed, but with a

ow sensitivity, because it failed to identify 18 % of sepsispisodes diagnosed by the IPSCC.22

In the present authors’ view, Sepsis-3 adapted for pedi-trics does not meet the key requirements that ensureccuracy and safety for the identification of sepsis and septichock in the pediatric population. Obviously, organ dysfunc-ion is a relevant finding in the context of pediatric sepsis.rogression or onset of new organ failure, especially on theecond day, has been associated with increased mortality.23

n this context, both pSOFA and PELOD-2 could be usedo identify the most severe cases of sepsis (higher risk ofeath), which require care at referral centers with greateresources. However, considering its low sensitivity, its inclu-ion in the definition (identification) of sepsis and septichock is not supported or justified.

Although some pediatric studies have shown thatncreased serum lactate levels may be a marker of sever-ty and that its decrease may be associated with a goodherapeutic response, it is known that several factors affecthis oscillation. To date, there is not enough solid scientificvidence to support the use of lactate levels in the char-cterization of septic shock in pediatrics. Thus, by adoptinghe criteria proposed by Sepsis-3 in the pediatric population,

linicians run the risk of failing to identify a significant por-ion of patients with clinically established septic shock buttill showing low lactate levels. It is understood that phys-ological and biological variables are part of this complex

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quation, but to define sepsis safely and accurately, otherlements must be computed.

anagement

ediatric sepsis is a high-risk condition that requires alert-ess to attain an early and timely diagnosis. Late detectionr delayed start of treatment with persistent hemodynamicysfunction are associated with worse clinical outcomesnd increased mortality.24 Rapid and aggressive resuscita-ion with volume within the first five minutes, antibioticdministration, and early vasoactive agents may be crucialo a successful treatment. It can be observed that this treat-ent pattern, which can often rapidly change, also makes

epsis management critical for pediatricians.6

The initial management of septic shock is the same asn other life-threatening conditions. It starts with airwaytabilization and adequate breathing with extra oxygen sup-ly. Ventilatory support should be sufficient to increasexygen supply and uptake by the cell. As circulation ishe most obviously compromised feature, treatment startsith aggressive volumetric replacement to restore the cir-ulating volume, followed by the correction of negativenotropic factors, increasing cardiac contractility and even-ually decreasing the peripheral vascular resistance.

The objective is to maintain the oxygenation, ventila-ion, circulation, and heart rate within the normal limits,nd to restore the patient’s clinical condition by improvingerfusion (capillary filling <2 s) with full pulses and warmxtremities, urinary output >1 mL/kg/h, adequate mentaltatus, and normal blood pressure for age. The minimumesired monitoring consists of pulse oximetry, ECG tracing,lood pressure, temperature, hourly diuresis, glucose, andalcium measurements.15

The decisions to intubate and ventilate are clinical:espiratory failure, hypoventilation, altered state of con-ciousness, or impending death. For volumetric resuscitationnd the start of therapy, vascular access should be obtainedmmediately, and the insertion of a central catheter isreferable for vasoactive drug infusion. Peripheral accessesan also be used for initial volumetric resuscitation andor the administration of some of these sympathomimeticmines. Intraosseous access may be necessary if peripheralccess is impossible.25

olumetric resuscitation and drugs in the firstour

or volumetric resuscitation, a crystalloid solution is used,sually normal saline solution (physiological solution). Even-ually, balanced crystalloid solutions (such as Ringer’sactate solution and others) can be used with the sameesults. These balanced solutions have been recommendeds they reduce acidosis, mortality, and post-resuscitationenal injury in pediatric shock.26 Nonetheless, these resultsre still controversial. Colloids, such as albumin, are used in

xceptional and selected cases, such as when large amountsf solution are infused, and it is necessary to restrict vol-me. The albumin solution, besides not having its benefitonfirmed, has a higher cost than the other solutions. No dif-

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erence was demonstrated between albumin and crystalloidolutions, even in children with dengue shock syndrome.27

Septic shock can progress with volume loss to the thirdpace and capillary leak syndrome. This is an importantoint in re-evaluating and maintaining the need for vol-metric replacement. An infusion of 20 mL/kg of salineolution between ten and 20 min is recommended. Thenfusion of 20 mL/kg should be repeated until tissue per-usion, oxygen supply, and blood pressure are adequate.ood practice includes the clinical observation of circula-

ory overload after the infusions. Absence of bullous rales,achycardia, and tachypnea or the development of a thirdeart sound (B3) and hepatomegaly allows the fluid infusiono be repeated. Patients with septic shock usually requireolumes of up to 60 mL/kg or more within the first hour.28

In resource-limited settings that cannot providedvanced airway and circulatory support, children withigns of compensated shock and severe febrile illness shoulde managed with even greater caution.29 Under these con-itions, repeated infusions of 10 mL/kg of saline solutionvery 20 min (30 mL/kg in the first hour) are suggested,hile watching for signs of circulatory overload with each

nfusion.In some situations, it will be necessary to use vasoactive

rugs in severe shock during fluid resuscitation. Vasoac-ive agents are most often administered when there iso response to the use of bolus fluids, but they may besed concomitantly. Patients with poor adrenergic response,radycardia, or who are close to cardiopulmonary arresthould be treated with medium or high-dose epinephrinenfusion (0.2---0.5 �g/kg/min), and those with hypotension,ith norepinephrine (0.05---0.1 �g/kg/min), concomitantlynd independently of volumetric resuscitation.

harmacological support in the first hour

emodynamic management in shock aims at providing aupranormal oxygen supply (above the critical limit) andn increase in mean arterial pressure to a level thatllows cardiac output to achieve adequate organic perfu-ion. Vasoactive drugs should be used judiciously, with aoal-oriented approach. Cold shock (presumably due to lowardiac output) should be treated with epinephrine andarm shock (presumably due to high cardiac output with low

ystemic vascular resistance [SVR]) should be treated withorepinephrine. Patients with sepsis from the communitysually develop cold shock (titrate epinephrine between 0.1nd 0.2 �g/kg/min), while those with intra-hospital infec-ion (e.g., catheter-related and fungal infections, amongthers) tend to evolve with a slower-onset warm shock, withorepinephrine (0.05---0.2 �g/kg/min) being recommendedn these cases. Consider packed red blood cell transfusionso maintain hemoglobin >7 and central venous oxygen satu-ation >70 %.15

hock resistant to the initial management

f the patient shows no signs of shock reversal withpinephrine up to 0.3 �g/kg/min, which should be recog-ized promptly, norepinephrine is started, especially if theatient is hypotensive, hyperdynamic, or dilated with warm

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shock, aiming to normalize the infusion and blood pressure.If the patient has cold shock, hypotension with bradycar-dia, or cardiac dysfunction is the most prevalent picture,epinephrine is titrated at higher doses.

Cold shock is recognized by cold, mottled extremi-ties, poor peripheral perfusion with slow capillary filling(greater than two seconds), weak peripheral pulses, anddecreased urine output (less than 1 mL/kg/h). Warm shockis recognized by flushing of the extremities, rapid capil-lary filling (less than two seconds), full or oscillating pulses,but also decreased urine output (less than 1 mL/kg/h).Norepinephrine plays an important role in maintainingblood pressure in the renal compartment, where perfu-sion pressure should be adequate. At the end of this firsthour, in patients with volume-refractory warm shock whoare resistant to the initial management, an infusion of0.05 �g/kg/min is started and progressively increased by0.2 �g/kg/min. Fig. 1 summarizes the conduct for pharma-cological support in septic shock.6

Management of pediatric septic shockevolution

Although the authors have attempted to classify the septicshock states using a practical approach, it is an evolvingclinical condition. Thus, frequently the drug chosen for thestart of the therapy may become inadequate and requirea new drug or association of drugs. The response of eachpatient to vasoactive therapy may also be different, andfrequent clinical and hemodynamic reassessments should beperformed.30

After the first hour, patients with volume-refractoryshock who persist in shock despite the use of catecholaminessuch as epinephrine or norepinephrine are considered tobe in catecholamine-resistant shock. In this period, theyshould be admitted to the PICU, monitored, with contin-uous measurement of electrocardiographic tracing, heartrate, and temperature; access to a large vessel should havealready been obtained and, if a central venous access hasalready been attained, the central venous pressure shouldalready have been measured through it. Blood pressure mea-surement should preferably be performed by an invasivemethod; the authors measure oxygen saturation with a pulseoximeter and urine output through a bladder catheter. Abedside functional ultrasound allows the assessment of vol-ume status and myocardial function. The perfusion pressure[PP = MAP---CVP (mmHg)] is then calculated. The infusionpressure limits are as follows: newborn, 55; infants, 58;preschoolers and schoolchildren, 65.6,31

Cold shock, resistant to catecholamines, lowBP (blood pressure), low CO (cardiac output),and high SVR (systemic vascular resistance)

In this scenario, the patient with cold shock who is resistantto catecholamines with still low blood pressure, low car-

diac output, and high systemic vascular resistance benefitsfrom the inotropic action of epinephrine and its vasopres-sor action. A good response is expected at doses between0.2---0.5 �g/kg/min. If the heart rate is not too elevated,

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he patient may benefit from the extra adrenergic stimulusf epinephrine, which can be used up to 1 �g/kg/min and,xceptionally, up to 2 �g/kg/min. These higher doses usu-lly compromise splanchnic circulation and should only besed in association with vasodilators.

old shock, resistant to catecholamines,ormal BP, low CO, and high SVR

n this case, the patient has cold shock and is resistant toatecholamines (did not respond to initial fluid or adrenalinenfusion up to 0.2 �g/kg/min), but blood pressure has nor-alized; the output is still low (or normal), and systemic

ascular resistance is still high. These patients with ele-ated systemic vascular resistance benefit from the usef vasodilators. At this moment, it is permissible to asso-iate drugs that act directly at the vascular level, aiming tory to counteract this vasoconstriction and improve cardiacutput. In those patients who received sympathomimeticmines and in whom clinical improvement has not beenbserved (especially in those patients with severe hypox-mia with increased pulmonary and/or systemic vascularesistance), milrinone (0.25---0.75 �g/kg/min) is used asso-iated with norepinephrine, and epinephrine is withdrawn.hen milrinone is contraindicated and/or in cases of SVR

esistent increase, the other option is to use a continuousnfusion of sodium nitroprusside at 0.5 �g/kg/min up to aaximum of 10 �g/kg/min.

arm shocks, resistant to catecholamines,ow BP, high CO, and low SVR

f the shock is still warm and the patient remains hypoten-ive, hyperdynamic, and with low resistance, it is best toontinue to benefit from the norepinephrine’s vasopressorction. At doses above 0.2 �g/kg/min, norepinephrine startso lose its inotropic effect, but its vasopressor effect can bebserved at doses up to 5 �g/kg/min. The authors graduallyncrease norepinephrine, and while the patient is hypoten-ive, epinephrine is maintained at 0.2---0.5 �g/kg/min orobutamine is introduced at doses up to 20 �g/kg/min toenefit from its inotropic action. If blood pressure normal-zation occurs due to the high doses of norepinephrine,pinephrine or dobutamine can gradually be withdrawn andilrinone can be associated.

efractory shock

hen the shock persists, despite the targeted use ofnotropic agents, vasopressors, vasodilators, and mainte-ance of negative inotropic factors, the case is defineds refractory shock. In this case, an unknown problem,uch as pericardial effusion, pneumothorax, hypoadrenal-sm, hypothyroidism, continuous blood loss, intra-abdominalatastrophe, or the presence of necrotic tissue should beuspected.

Bedside ultrasound plays a fundamental role in thisvaluation stage. Fluid responsiveness can be estimatedy measuring the inferior vena cava distensibility, car-iac output is measured through left ventricular function,

92 Garcia PC et al.

Saline solution 40-60 ml/kg

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Pulmonary artery catheter, echo Doppler, ScvO 2>70%

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Figure 1 Simplified pharmacological support scheme for children with septic shock. See details in the text.BP, blood pressure; CI, cardiac index; ECMO, extracorporeal membrane oxygenation.M

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nd the diagnosis of pericardial effusion is made throughirect visualization in the parasternal long axis or sub-ostal view.31 A pulmonary arterial catheter may also besed to measure cardiac output, vascular resistance, andulmonary artery occlusion pressure, and the analysis ofhe arterial and superior vena cava oxygen saturation maye beneficial to guide therapy in patients with refractoryhock. The therapies should be adjusted to maintain mixedenous oxygen saturation (SvO2) above 70 %, cardiac indexCI) > 3.3 < 6.0 L/min/m2, and the usual perfusion pressureor age, with the main objective of restoring normal perfu-ion.

In patients with refractory shock who have not respondedo doses of 0.6---1 �g/kg/min of norepinephrine, and who areot hypovolemic, the authors have used vasopressin. Thenitial dose used is 0.0005 U/kg/min, gradually increasingo 0.002 U/kg/min (optimal dose) and, if necessary, up to aaximum dose: 0.008 U/kg/min.32

Hypothyroid syndrome can complicate cases of refrac-ory septic shock. T3 therapy in septic shock is reserved forhildren with known thyroid dysfunction, children at highisk of hypothyroidism (children with trisomy 21 and childrenith central nervous system disease), or as rescue therapy

n refractory septic shock. The use of T3 as an intravenousnfusion at a dose of 0.05 to 0.15 �g/kg/hour or T4 (levothy-oxine, 0.8---1 �g/kg/hour) is recommended.33 As these drugsre seldom available, as an alternative, levothyroxine isdministered through a nasogastric tube,whose dose variesccording to age and which is re-adjustable according to lab-

ratory variations: from 0 to 3 months: 10---15 �g/kg/day;---12 months: 6---10 �g/kg/day; 1---10 years: 3---6 �g/kg/day;nd from 10 to 16 years old: 2---4 �g/kg/day.34

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Extracorporeal membrane oxygenation (ECMO) is anlternative to be considered. In this situation, the veno-rterial ECMO, in addition to providing adequate bloodxygenation, can determine the systemic arterial pressurey regulating the flow released in the arterial portion. As theatient’s own cardiac output improves, a gradual reductionn ECMO flow is carried out. The survival expectancy withCMO in children with septic shock refractory to vasoactiverugs has surpassed 50 %, with a mortality rate below 20 %,hus becoming an alternative worthy of consideration.35

argets in septic shock

eptic shock can be characterized as an alteration of clinicalnd hemodynamic signs, including hypo- or hyperthermia,achycardia or bradycardia, and alteration of mental sta-us and peripheral circulation (vasodilation --- warm shock;asoconstriction --- cold shock) that precede hypotension.hock treatment should aim at maintaining organic perfu-ion and observing these signs should be the priority in theanagement of these patients. According to Carcillo et al.,

ypotension associated with capillary filling time longer thanhree seconds is associated with a 33 % mortality rate inatients treated in pediatric emergency sectors. Reversinghese parameters by following established protocols suchs Pediatric Advanced Life Support (PALS) can reduce thehance of death by 40 %, regardless of the initial hemody-amic conditions.36 Thus, despite the current technologicaldvances, physical examination and basic bedside monitor-

ng still play a fundamental role in the care of patients witharly sepsis and septic shock, especially in resource-poorettings.

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Sepsis in pediatrics

Central venous oxygen saturation (SCVO2) can be mea-sured through a catheter positioned at the entrance to thesuperior or inferior vena cava junction with the right atrium;its normal value is 70 % in patients without disease producingintracardiac shunt. It indicates how much oxygen remainsavailable after cell consumption, i.e., it represents a bal-ance between oxygen supply and cell consumption. It isa practical, inexpensive, and accessible test in resource-poor countries and has shown benefits, such as reducedorgan dysfunction and mortality, and it works as a marker inthe treatment of septic shock in children.37,38 Some pointsshould be taken into consideration for its use, as there is adisagreement regarding whether it is useful as a target in thetreatment of sepsis in adults.39 First, compared with adults,septic shock in children usually shows low cardiac output,prolonged capillary filling, and peripheral vasoconstriction.In these cases, SCVO2 is initially lower and probably indicatesan imbalance between oxygen uptake and supply, besidesbeing a marker of poor prognosis.38 Second, there is no ben-efit in implementing therapies according to protocols forelevating SCVO2 in those patients with a value close to orabove 70 %.40 That is, in patients with high cardiac out-put and vasodilatory shock, which usually occurs togetherwith hyperlactatemia, SCVO2 may not be a good choice as atherapeutic target.

Central venous pressure (CVP) can also be measuredat the same catheter that measures SCVO2. Alone, it haslimited value because it does not accurately reflect intravas-cular volume due to the influence of positive mechanicalventilation pressure and right ventricular dysfunction. How-ever, it can be used to measure and monitor perfusionpressure (PP = MAP - CVP), aiming to improve renal, periph-eral, and tissue oxygenation as a whole.41 Two studies haveshown improved survival with the combination of adequatePP and SCVO2 >70 %.37,38

Serum lactate is the product of anaerobic respirationunder conditions where there is no adequate perfusionin the tissues. Its decrease or clearance after therapy isimplemented (10 % in relation to the baseline value) hasbeen associated with increased survival in adults.42,43 Asexplained before, this represents a patient profile showingvasodilatory shock with high cardiac output and hyper-lactatemia. In them, lactate clearance may be used asa therapeutic response and prognostic marker. However,for the vast majority of pediatric patients, this test willshow normal values upon arrival and cannot be used forthis purpose.37 It is believed that for the vast majority ofpediatric sepsis cases, lactate has value as a prognosticmarker, and not as a monitoring factor or therapeutic tar-get.

Hemodynamic decompensation in sepsis involves acomplex interaction between vascular tone, myocardialdysfunction, and hypovolemia, which often make clinicalreasoning guided only by the bedside physical examina-tion difficult. In patients with volume refractory shock(>40 mL/kg), the decision to provide more fluids, inotropes,or vasopressors was traditionally guided by the clini-cal examination, classifying the shock as ‘‘warm’’ or

‘‘cold’’.31 However, clinical observation is not alwaysaccurate in defining the type of shock or estimatingthe cardiac index; moreover, their characteristics maychange during the course of disease treatment.31,44 Mul-

atma

93

imodal monitoring has emerged to increase accuracy inhis decision-making. It uses clinical parameters, invasiveressure monitoring, and bedside ultrasound examinationor that purpose.31 In the study by Ranjit et al., cardiacnd inferior vena cava ultrasound assessment performedy an intensivist at the bedside, associated with inva-ive blood pressure monitoring, accounted for a changen conduct in 87.5 % of the study patients. In this study,hysical examination alone was not reliable in defining theype of shock (high vs. low cardiac index; vasoconstricteds. vasodilated).31 It is believed that this individualizedpproach, guided by reliable, easy-to-perform bedsidexaminations and pre-established goals, is the best decision-aking strategy for this more complex patient profile.

ig. 2 summarizes the best practices and targets for septichock.

se of inflammatory markers

nflammatory markers are tests that can be used in clini-al practice for diagnosis, risk stratification (prognosis), andonitoring of antibiotic response therapy (and its rational

se in determining treatment time) in sepsis. The use ofhese biomarkers must be cautious and always interpretedn a clinical context. Below, the main biomarkers used inediatric sepsis are described.

C-reactive protein (CRP) is one of the most widely usediomarkers in pediatrics. Its usefulness in diagnosis is lim-ted, mainly because of the low sensitivity in differentiatingases of severe sepsis and common bacterial infections in ansolated measurement.45 The most important use of CRP is inhe follow-up of sepsis patients. Its 60 % drop on the fourthay of the disease is associated with a favorable prognosis,nd maintenance close to the initial values indicate a poorherapeutic response.46

Serum ferritin, in addition to representing the body’s irontores, is an acute phase protein that increases in the pres-nce of inflammatory cytokines. Since 2007, it has beensed as a prognostic marker in pediatric sepsis, estimat-ng mortality or unfavorable outcomes, either alone or inssociation with CRP.18,47 Moreover, its follow-up during thepisode of septic shock with poor evolution may indicatehe presence of hyperferritinemic sepsis, often indicatingpecific therapies such as corticosteroids, immunoglobulin,lasmapheresis, or even immunosuppression.48 Its cutoffalue for mortality remains a subject of study, but it iselieved to be lower than that found in the pioneering studyy Garcia et al. (500 ng/mL).18 There is evidence that itccurs in resource-poor settings with a high prevalence ofron-deficiency anemia.49

Procalcitonin, compared to CRP and ferritin, has aigher diagnostic power of bacterial sepsis in pediatrics.alues below 0.5 ng/mL are suggestive of inflammation with-ut infectious etiology and values >2 ng/mL, of bacterialepsis. Just like CRP, it can also be used to monitor dis-ase progression and is useful in deciding to discontinue

ntibiotic therapy, without showing increased therapeu-ic failure.50 Its high cost in some centers is still theain factor limiting the dissemination of its use in pedi-

trics.

94 Garcia PC et al.

Sepsisscreening

and definition

Essentialelements in the

1st hour

Personalized.management after

the 1st hour

Screen for sepsis in your hospital

Get cultures from every possible site

Do not use routine corticosteroids (note exceptions)

Have as goals:1) CFT < 3

3) CI 3.3 to 6 L/min4) SVCO2 >70% (higher values have no benefit)

Do not use lactate as a therapeutic target (it may be normal or in shock)

Make sure the focus of the infection is under control (abscesses, necrosis)and target the antibiotics

2) Blood pressure and perfusion pressure (MBP-CVP = 55 + 1.5 x age)normal for age

Use a multimodal approach to assess fluid responsiveness(inferior vena cava ultrasound), use of inotropes, vasopressors,and vasodilators (echocardiography and invasive BP monitoring).Avoid excess fluids

If the shock is refractory to fluids, start epinephrine 0.1 mcg/kg/min for coldshock and norepinephrine (0.05 mcg / kg / min) for warm shock

Provide empirical antibiotics (e.g., Ceftriaxone 100 mL / kg IV)Fluid bolus 20 mL/ kg initially, after 10 mL / kg at a time.Observe if there are any signs of fluid overload(pulmonary crackles and hepatomegaly)

A doctor should decide if the patient continues on the sepsis protocolUse sepsis criteria that contain SIRS. Do not use Sepsis-3

Figure 2 Summary of best practices and targets in septic shock. Adapted from Ames et al.41

S ssurc us o

C

TAaoiaaamwtrdliabattca

bomEatitherciinthccu

IRS, systemic inflammatory response syndrome; BP, blood preentral venous pressure; CI, cardiac index; SVCO2, central veno

hoice of antibiotic therapy

he American College of Critical Care Medicine/Pediatricdvanced Life Support (ACCM/PALS) protocol advises thedministration of antibiotic therapy within the first hourf sepsis treatment.6 Adherence to this protocol, whichncludes measures such as sepsis detection, obtaining venousccess, volume resuscitation, administration of antibiotics,nd, when necessary, start of vasoactive drugs, have beenssociated with improved patient care quality and reducedortality.51---53 However, some authors have questionedhether administering antibiotics up to the first hour of

reatment initiation in adequately resourced settings wouldeally make any difference. In an observational study, thiselay was not associated with increased mechanical venti-ation time, hospital length of stay, or mortality. However,n this same study, there was no increase in benefits withn early administration.54 Overall, it is believed they shoulde administered as early as possible in pediatric sepsis, ide-lly within the first hour. Another key point is that cultureests should be collected from all suspected foci of infec-

ion, preferably before antibiotic therapy is started. Theseollections should not significantly delay the initiation ofntimicrobial therapy.

ahr

e; CFT, capillary filling time; MAP, mean blood pressure; CVP,xygen saturation.

The choice of the antibiotic agent in sepsis shoulde targeted according to the local epidemiology, focusf infection, and culture results. However, this infor-ation is not always defined at the initial assessment.

mpirically, for community-acquired infections, the presentuthors have chosen a monotherapy regimen with ahird-generation cephalosporin (ceftriaxone 100 mg/kg/dayntravenously).The association of antibiotics does not seemo have any benefit in improving outcomes in previouslyealthy patients with no risk factors.55 Additionally, adverseffects are less frequent when monotherapy is used.56 Thisegimen may not be optimal if the patient is under risk ofommunity-acquired, methicillin-resistant staphylococcusnfection, multidrug-resistant Gram-negative microorgan-sms, or if patients have a history of immunosuppression oreutropenia.55,57 For patients with hospital-acquired infec-ion or those in the PICU in refractory shock, due to theigh risk of infection by methicillin-resistant staphylococ-us and Pseudomonas spp., a combination of vancomycinombined with beta-lactam (piperacillin + tazobactam) issed, or fourth-generation cephalosporin (cefepime) with

nti-pseudomonas action. In these patients, the place ofospitalization and the high severity influence the antibioticegimen decision.

Sepsis in pediatrics

Table 1 Proposed antibiotic therapy regimen for pediatricpatients with sepsis.

Clinical situation Antibiotic regimen and dose

Sepsis without adefined focus

Ceftriaxone 100 mg/kg/day

Sepsis without adefined focus ofnosocomial origin

Vancomycin 60 mg/kg/day + (e)Cefepime 100 mg/kg/day

Febrile Neutropenia Cefepime 150 mg/kg/day(+Vancomycin 60 mg/kg/day ifindwelling-catheter infection issuspected)

Abdominal focussepsis

Ceftriaxone100 mg/kg/day + gentamicin7 mg/kg/day + (e) (metronidazole30 mg/kg/day orclindamycin30 mg/kg/day)

Abdominal focussepsis ofnosocomial origin

Cefepime100 mg/kg/day + gentamicin7 mg/kg/day + (e) (metronidazole30 mg/kg/day orclindamycin30 mg/kg/day)

- Suspected atypicalpneumonia

Associate azithromycin 10 mg/kg/day

- Suspectedstaphylococcaltoxic shocksyndrome

Associate clindamycin 30 mg/kg/day

- Suspectedencephalitis

Associate acyclovir 30 mg/kg/day

This table refers to an antibiotic regimen suggested by the

ahruprtcpwsoh8d

M

Mapso

I

I

authors themselves. Dose and regimen may vary according toclinical condition, patient age, and local microbiology.

Overall, a maximum treatment time of seven days is usedfor patients with good evolution and without an etiologicalagent defined by culture tests. In patients with immunosup-pression, neutropenia, or difficulty resolving the focus ofinfection (e.g., empyema, necrosis, or abscess) the treat-ment may take longer, usually 10---14 days. A proposal forintravenous empirical antibiotic therapy in the differentclinical conditions is shown in Table 1.

Use of corticoids

The routine use of corticosteroids is not recommendedin patients with catecholamine-refractory septic shock,despite their potential theoretical benefits, such asimprovements in the cardiovascular system and anti-inflammatory actions.58 Current data in the literature areinconsistent to justify their use.59 The basal cortisol valueand the adrenocorticotropic hormone (ACTH) response testare not sufficient to diagnose adrenal insufficiency. Highor low basal cortisol values are known to be associatedwith increased mortality in sepsis, and ACTH axis response

failure after hormonal stimulation is also a predictor ofpoor response to exogenous corticosteroid use.60,61 How-ever, many patients can show alterations in these testswithout the corresponding clinical repercussion.62 Addition-

E

Ep

95

lly, important side effects such as hyperglycemia, bleeding,ypernatremia, and suppression of the adaptive cell immuneesponse have been previously reported after corticosteroidse, which cannot be ignored.59,63 It is suggested that onlyatients with catecholamine-refractory shock who are atisk of adrenal insufficiency or adrenal axis failure dueo purpura fulminans, Waterhouse-Friderichsen syndrome,hronic use of corticosteroids, congenital adrenal hyper-lasia, hypothalamus/pituitary axis disease, and intubationith etomidate use may benefit from hydrocortisone infu-

ion, which should be started optimally after the collectionf basal cortisol level.6 The present authors use 4 mg/kgydrocortisone as loading dose and, thereafter, 2 mg/kg/8 h dose for a maximum of seven days or until vasoactiverug infusion is discontinued.

echanical ventilation

echanical ventilation (MV) provides adequate oxygenationnd improved tissue perfusion, mainly due to decreased res-iratory work in patients with septic shock. Some aspectshould be taken into consideration when patients with sepsisr septic shock develop ventilatory failure:

I) As a general rule, invasive mechanical ventilation ischosen. The possibility of bronchoaspiration and thehemodynamic instability generated by shock increasethe chance of complications if the patient’s airwayis not secure. Moreover, in invasive MV it is possibleto determine the appropriate tidal volume, avoidinghyperventilation and the consequent decrease in venousreturn. In very selected cases, such as resource-poorsettings, a noninvasive ventilation mode or a high-flowcannula can be successfully used.64

II) Although some patients require immediate intubation,such as in cases of coma or apnea, in most cases thereis time and it is recommended that volume resuscita-tion be initiated and, if indicated, also the peripheralinfusion of vasoactive drugs prior to the intubationprocedure.6 These patients are at high risk of dete-rioration due to hypoxemia, the action of drugs usedin the rapid sequence intubation (RSI), and decreasedpreload, which generates hemodynamic instability dur-ing the intubation procedure and the start of mechanicalventilation.

II) The use of atropine as premedication in cases ofbradycardia, and ketamine for sedation in RSI are rec-ommended for patients with septic shock. As long asthere are no contraindications to their use, this reg-imen seems to promote better cardiovascular statusmaintenance.65

V) In resource-poor settings, where there is a high preva-lence of diseases such as dengue or malaria, volumeresuscitation should be carefully performed, and theclinician should look for signs of early ventilatory failurecaused by pulmonary edema.66

xtracorporeal membrane oxygenation (ECMO)

CMO support has been increasingly used with success inediatrics. In patients with sepsis, the indications are usually

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entilatory failure and/or refractory shock.6 Survival ratesn patients submitted to ECMO for circulatory instability ineptic shock may reach 75 %.35 Historically, these rates werenly reached in the neonatal age group.67 The increasingumber of centers and the experience of the existing onesn Latin America has contributed to the attaining of theseates in pediatrics.68 ECMO has shown in recent years to be

cost-effective treatment, provided that it is performed byell-trained centers that follow international protocols. The

ustification for providing resources in this type of treatments that it considers a population with high mortality, above0 % when not using extracorporeal support, and in manyases, it enables survival with few sequelae.

onclusions

n spite of the great progress in the treatment of sepsis inecent years, with the implementation of protocols in mostenters and advanced technologies, as well as managementmprovements in PICUs, it remains a condition with highorbidity and mortality. A more precise and adapted def-

nition is required for the pediatric population. This wouldelp in early detection, definition of disease stages, anddentification of specific therapies for each disease evolu-ion stage. Although these markers are not available yet,ood practice should be encouraged in all scenarios, with themplementation of the best evidence-based and resource-djusted protocols that have shown to be decisive factors inontrolling and reducing sepsis mortality.

onflicts of interest

he authors declare no conflicts of interest.

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