The ManagemeChristine A. Zaw

ing cardiac outputtion of antibiotics.fluid resuscitation.s not reverse theshould be started

insufficiency will guide furtreatment patients may reinvasive monitoring mayshould shock not be rever

Curr Probl Pediatr Adoles

he management

The seminal studywas published in 200shock were randomi

9-fold increased odds of survival with prompt recogni-

ns

eta

From the Department of Pediatrics, Division of Pediatric Critical Care,& 2013 Mosby, Inc. All rights reserved.http://dx.doi.org/10.1016/j.cppeds.2013.10.005patients in septic shock were published.1 The guidelineswere time based with the rst 60 min being the most

1538-5442/$ - see front matterNYU School of Medicine, New York, NY. tion and treatment of shock.7 In 2002 the rst pediatricguidelines for the management of pediatric and neonatalCurr Probl Pediatr Adolesc Health Care 2013;43:285-291also found to be true in adult patients.4,5 achieve goals prior to organ failure.6 A retrospective

analysis of 91 infants and children showed a greater thanvasoactive substances, oxygen, antibi-otics, and optimization of ventilation.Targeted end points look for improve-ment in perfusion, taking into accountvital signs, examination ndings, andlaboratory ndings. Early studies showed the survivalbenet of early aggressive uid resuscitation, which was

treatmenbalance bdeliveryCurr Probl PediatrAdolesc Health Care, November/December 2013randomized controlled trials ofsepsis showed a 23% mortalitydifference between control andprotocol groups in severely illpatients (control group patientswith420% mortality) when

patients with acute critical illness are treated early to

o restore theween oxygennd demand.afterload, and contractility. This isaccomplished through the use of uids, of sepsis. A meta-analysis of 21therapy is early aggressive

t tEarly therapy aims to improve preload, The maitherapy isbetween oBackgroundEarly Goal-DirectedTherapy

Resuscitation should commence in the emergency de-partment once sepsis is suspected. The mainstay of initial

early aggressive treatment to restore the balancexygen delivery and demand.4G of sepsis when it was noted that mortality fromsepsis had not improved in a decade. Pediatric

specic guidelines rst appeared in 2002.1 These werethen updated in 2007 and again in 2013.2,3 The generalprinciples of resuscitation follow those of the pediatricadvanced life-support program.the most crucial. Initial treatment consists ofof shock and interventions aimed at supportand oxygen delivery along with administraThe mainstay of treatment for this phase isFor patients in whom this intervention doeshock medications to support blood pressure

Introduction

uidelines were developed for tManagement of sepsis in the pediatric patient is guidelinedriven. The treatment occurs in two phases, the first hour being

timely recognitionemergency department to early goal-directed therapyor conventional therapy. Those in the study arm hadarterial and central venous catheters placed for mon-itoring. Therapeutic goals for treatment included main-taining the central venous pressure, mean arterialpressure, and superior vena cava saturations withinspecic parameters. In-hospital mortality was signi-cantly less in the goal-directed therapy group (30.5%vs. 46.5%, p 0.0009). This was the rst large-scalestudy that showed a reduction in mortality from sepsisand demonstrated the importance of early recognitionand aggressive resuscitation.

Further studies continued toshow the benets of early recog-nition and aggressive treatmenttay of initialshock and risk factors for adrenalther therapy. Beyond the first hour ofquire intensive care unit care whereassist with further treatment optionssed in the initial hour of care.

c Health Care 2013;43:285-291

for early goal-directed therapy1.4 Adult patients with septiczed upon presentation to thent of Sepsisistowski, MD

and respiratory support may be necessary. Differentiationbetween warm and cold285

crucial. Goals and parameters were dened by bothclinical and oxygen-utilization variables. Goals of ther-apy included capillary rell less than 2 s, urine output ofat least 1 mL/kg/h, normal pulses without a differentialbetween peripheral and central pulses, a mixed venousoxygen saturation greater than 70%, declining lactateand base decit, and an improved level of consciousness.The guidelines were developed from the best dataavailable and many recommendations are expert con-sensus of that data due to the small numbers of studiesand small sample sizes within the studies. Data collectedas a result of the 2002 guidelines demonstrated that theywere useful, effective, and caused no evidence of harm.2

The guidelines were updated in 2007 and again in 2013and have remained largely unchanged due to lack of newevidence to the contrary.

Management (Tables 1 and 2)

The management of sepsis is divided into that for therst hour and then subsequent care. The initial hour ofresuscitation often occurs in the emergency depart-ment, as that is often the entry point into the healthcaresystem for patients in septic shock.

Time 05 min

The timeline for treatment starts in the rst 5 minwith the recognition of shock and should ideally beprior to the onset of hypotension. Clinical signs ofshock include an alteration of body temperature withhypothermia or hyperthermia, alteration in mentalstatus, and peripheral vasodilation (warm shock) or

TABLE 1. Algorithm for time sensitive goal-directed, stepwise management of shock in infants and children2

Time Intervention

Recognition 1. Recognize shock: decreased mental status and perfusion2. Begin high-ow oxygen3. Establish IV/IO access

05 min

Shock not reversedInitial resuscitation 1. Push boluses of 20 ml/kg isotonic saline or colloid460 ml/kg until perfusion

improves or rales or hepatomegaly develop2. Correct hypoglycemia3. Correct hypocalcemia4. Start antibiotics

515 min

Shock not reversedFluid-refractory shock 1. Begin inotrope via IV/IO

2. Obtain central access and airway if needed3. Cold shock: titrate dopamine, if resistant titrate epinephrine4. Warm shock: titrate norepinephrine

1560 min

Shock not reversedCatecholamine-resistant shock Begin hydrocortisone if at risk for adrenal insufciency

h loid a1

w, c70%dan

correct: pericardial effusion, pneumothorax, and elevated intra-abdominal

advin/460 minPediatric Intensive Care Unit

Monitor CVP, SCVO2470%Cold shock with normal BP Cold shock wit1. Titrate uid and epinephrine SVCO2470% and

Hgb410 g/dL2. SVCO2o70%, add vasodilator with uid loading,

consider levosimendan

1. Titrate uand Hgb4

2. BP still lo3. SVCO2 o

levosimen

Shock not reversedPersistent catecholamine-resistant shock 1. Rule out/

pressure2. Considero6.0 L/m

Shock not reversedRefractory shock ECMO

CI, cardiac index.286anced monitoring tools to guide therapy with goal CI43.3 andm2w BP Warm shock with low BPnd epinephrine SVCO2470%0 g/dLonsider norepinephrine, consider milrinone or

1. Titrate uid and norepinephrineSCVO2470%

2. BP still low, consider vasopressin3. SCVO2o70%, consider low-dose

epinephrineCurr Probl PediatrAdolesc Health Care, November/December 2013

TABLE 2. Medications used to treat shock

ffec

, an

resnousyst

socsitipronceconstriction (cold shock). Heart rates outside thenormal range are a good early indicator of shock.Threshold heart rates found to be associated with anincreased mortality in critically ill infants were lessthan or equal to 90 beats per minute (bpm) or morethan 160 bpm; in critically ill children, they were foundto be less than 70 bpm or greater than 150 bpm.8

Within the rst 5 min after recognition of shock, high-ow oxygen via a face mask should be started andintravenous or intraosseous access obtained. Forpatients who do not maintain oxygen satura-tions494% on high-ow face mask oxygen and/orexhibit increased work of breathing high-ow nasalcannula (HFNC) or nasopharyngeal continuous pos-itive airway pressure (CPAP) should be instituted toincrease functional residual capacity and decreasework of breathing.Agent Clinical effect

Dopamine Increased cardiac output, increased inotropic erate, and arterial vasoconstriction

Epinephrine Increased heart rate, decreased stroke volumeoutput

Norepinephrine Vasoconstriction and increased mean arterial pMilrinone Increased myocardial contractility, increased ve

dilation, decreased preload, and decreasedresistance

Vasopressin Increased systemic vascular resistance and vaHydrocortisone Suppress production of cytokines; increase sen

cardiovascular system to catecholamines, imstroke volume, and systemic vascular resistaendogenous steroids

Calcium chloride Increase blood calcium levelCalcium gluconate Increase blood calcium levelDextrose Increase blood glucose levelTime 515 min

The next 10 min of management (time 5 min through15 min) is aimed at restoration of normal mental status,threshold heart rates, peripheral perfusion (capillaryrell o2 s), palpable distal pulses, and normal bloodpressure for age. The mainstay therapy for this stage ofresuscitation is uid administration done as a push over5-min intervals. Isotonic saline or colloid in aliquots of20 mL/kg is rapidly administered manually. Emer-gency medicine research has shown that this can bedone either through a peripheral intravenous catheter orcentral venous catheter.9 Fluid is administered up to ormore than 60 mL/kg. Initial therapy usually requires4060 mL/kg but can be as much as 200 mL/kg.5

Curr Probl PediatrAdolesc Health Care, November/December 2013There has traditionally been a concern that largevolumes of uid resuscitation for acute stabilizationincrease the incidence of acute respiratory distresssyndrome, but this has shown to not be the case.5,10

Likewise, there is no correlation between large vol-umes of uid resuscitation and cerebral edema.5,11

There is also no difference in the efcacy of crystal-loids (normal saline, and Lactated Ringer's) vs. col-loids (dextran, gelatin, and 5% albumin) as the choiceof uid for acute volume resuscitation.1214 After eachadministered bolus, the patient should be assessed forimprovement in perfusion, rales, increased work ofbreathing, hypoxemia, and hepatomegaly.During this stage of resuscitation glycemic status and

calcium status should be checked and corrected tomaintain metabolic homeostasis. Hypoglycemiacan cause neurologic damage when missed. Glucoseinfusion rates of 68 mg/kg/min in newborns or

Dose

ts, increased heart 2 mcg/kg/min titrated up to 10 mcg/kg/min

d increased cardiac 0.05 mcg/kg/min titrated up to 1 mcg/kg/min

sure 0.051 mcg/kg/mins and arterialemic vascular

0.51 mcg/kg/min

onstriction 0.032 mU/kg/minvity of theving contractility,; replace insufcient

250 mg/kg/d

10 mg/kg100 mg/kg24 mL/kg; 12.5% dextrose if o2 months,24 mL/kg; 25% dextrose if42 months46 mg/kg/min in non-newborns should be targeted.This need can often be met by providing 10% dextrosein addition to saline as maintenance intravenous uids.Patients with liver failure require higher glucoseinfusion rates to meet the body's needs. Conversely,hyperglycemia should be avoided as well, as lev-els4140 mg/dL were found to be a risk factor formortality.15 Hypocalcemia, dened as an ionizedcalcium o1.025 mmol/L or total serum calciu-m o8.5 mg/dL, should also be quickly identied andcorrected as it is a frequent contributor of reversiblecardiac dysfunction.16,17 Calcium can be repletedeither using calcium chloride at a dose of 10 mg/kgor calcium gluconate at a dose of 100 mg/kg. Central-lined administration is preferred for calcium chloride

287

as extravasation of calcium can result in severe

ommended beginning this therapy via an intravenous

fold. Fluid-refractory shock is best managed with

pediatric patients.19,20 Vasoactive agents suitable for theor intraosseous catheter. Medications should be titratedto maintain adequate perfusion. At this point, centralvenous access and if needed, an airway, should beobtained. Ketamine and atropine are the recommendedagents to use for sedation for these procedures. Ket-amine is a central N-methyl-D-aspartate (NMDA)receptor blocker, which blocks nuclear factor Btranscription and reduces systemic interleukin-6 pro-duction. Ketamine does not affect the adrenal axis orcardiovascular stability, making it an ideal agent foruse in patients in shock.18 Atropine is a competitiveantagonist of the muscarinic acetylcholine receptor.It is administered prior to intubation for one of tworeasons: either to block the action of the vagus nerve,which can be stimulated with direct laryngoscopy,especially in small infants or to counteract the sialo-gogue action of ketamine through its direct anti-muscarinic action. Indications for intubation andmechanical ventilation in a patient in shock are severalnecrosis and tissue sloughing. Both preparations canbe given as an intravenous push over 35 min or as aninfusion over 1-h. The goal of therapy should be tomaintain a normal ionized calcium concentration viaintravenous calcium supplementation.The nal cornerstone of this stage of resuscitation is

administration of broad-spectrum antibiotics once appro-priate cultures have been obtained. The initial antibioticsshould be broad enough to cover the most likelypathogens and have adequate penetration into thepresumed primary source of infection. Clinicians shouldbe aware of specic susceptibility patterns in thecommunity and institution to help guide initial therapy.Possible combinations of antibiotics include an extendedspectrum penicillin or third- or fourth-generation ceph-alosporin or carbapenem aminoglycoside van-comycin. At the end of the initial 15-min period, ifshock is not reversed a second peripheral intravenouscatheter should be inserted and inotrope therapy started.

Time 1560 min

At time point 15 min, if shock is not reversed it isconsidered to be uid refractory and inotropes shouldbe started. The original guidelines published in 2002recommended obtaining central venous access prior tostarting therapy. It was found that mortality increasedwith delay in time to inotropic use due to lack ofcentral venous access and subsequent guidelines rec-288treatment of cold shock include dopamine and epinephr-ine administered into the central circulation.21 The dosingrange for dopamine should fall within 59 mcg/kg/min;at this dose, it works as an inotrope to improve con-tractility.22 In instances when dopamine is ineffective,epinephrine in a dosing range of 0.050.3 mcg/kg/minshould be used; in this dosing range, it acts predom-inantly as a -adrenergic agonist with a resulting increasein heart rate and stroke volume. It should be noted thatepinephrine stimulates gluconeogenesis and glycogenol-ysis and inhibits the action of insulin, leading to anincrease in blood glucose. Epinephrine also promotesincreased delivery of lactate to the liver (to be used as asubstrate for glucose production), with a resultingincrease in blood lactate concentration.

Warm Shock

Warm shock is caused by low systemic venousresistance. Patients in this state appear overly wellinvasive hemodynamic monitoring, which in an unco-operative potentially coagulopathic patient is bestaccomplished by sedation and immobilization, requir-ing intubation and mechanical ventilation for optimalcontrol. Intubation and mechanical ventilation is also animportant intervention for any patient whose cardio-vascular function is not rapidly stabilized with uid andinotropes. Up to 40% of cardiac output may be neededto support the work of breathing and this can beunloaded by providing mechanical ventilation. Inaddition, the increased intrathoracic pressure providedby mechanical ventilation reduces left ventricular after-load, which may be benecial to patients with a lowcardiac index and high systemic vascular resistance. Inpatients with elevated pulmonary vascular resistance,ventilator-controlled mild hyperventilation can com-pensate for metabolic acidosis. Finally, in any patientwith evidence of respiratory failure or impaired mentalstatus, there should be no hesitation to proceed withintubation and the initiation of mechanical ventilation.

Cold Shock

Cold shock is a consequence of poor cardiac output andis evidenced by poor peripheral perfusion with coolextremities, delayed capillary rell, and diminished orabsent peripheral pulses. Low cardiac output (cold shock)has been shown to be associated with mortality inCurr Probl PediatrAdolesc Health Care, November/December 2013

perfused, with ash capillary rell, bounding peripheral

increases mean arterial pressure as a result of vaso-constriction with little change in heart rate.

absolute adrenalra fulminans andone who has pre-hronic illness andlities are all at risktisol concentratio-tropin stimulationThis test may beapability to obtainin or less) but inshock and risk

ids should not be

pressure, cardiac output, and maintaining oxygen

bolic demand, shoulgoal of maintaining soxygen saturation istion is470%. In cooutput, hemoglobindeterminant of oxygglobin concentrationtance in a patient iSCVO2o70% addican improve oxygenare nitrovasodilatorsnitroglycerine, and

miot

ngntoshwithheld due to lack of results. The dose of steroid canbe titrated over a wide dosing range to achieve resolutionof shock, using between 2 and 50 mg/kg/d of hydro-cortisone given as a continuous infusion or via inter-mittent dosing. The hydrocortisone should be weaned offas tolerated to minimize toxicity.

Beyond the First Hour

Beyond the rst hour of treatment, the treatment goalis to improve oxygen delivery by supporting bloodresistant shock and hydrocortisone tinitiated if the patient is at risk forinsufciency. A patient with purpuWaterhouseFriderichsen syndrome,viously received steroid therapies for cone with pituitary or adrenal abnormafor adrenal insufciency. A peak corno18 mcg/dL obtained after corticois indicative of adrenal insufciency.helpful to perform in centers with the cresults in a timely fashion (i.e., 30 mpatients with catecholamine-resistantfactors for adrenal insufciency, steroTime 60 min

The rst 60 min after the recognition of shock isconsidered the golden hour during which time thera-pies need to be initiated to reverse the shock. Carcilloet al.5 showed an improved survivalin patients receiving440 mL/kg ofuid in the rst hour of treatment in agroup of 34 patients presenting to theemergency department in shock. Hanet al.7 have shown that for everyadditional hour of persistent shock,there is a42-fold increased odds ofmortality in pediatric patients withseptic shock. At time point 60 min, ifthe patient does not have evidence ofreversal of shock, they fall into thecategory of having catecholamine-

herapy should be

The rst 60the recognitconsideredhour duritherapiesinitiated

thepulses, and a ushed appearance. The vasoactive agentof choice for this state is centrally administered norepi-nephrine in a dosing range of 0.051 mcg/kg/min.Norepinephrine is a potent -adrenergic agonist, whichCurr Probl PediatrAdolesc Health Care, November/December 2013recruit microcirculation and reduce ventricular after-load, which allows better ventricular ejection andoverall improvement in cardiac output. Milrinoneimproves contractility and lowers systemic vascularresistance by inhibiting type III phosphodiesterase,which in turn increases intracellular cAMP by blockingits hydrolysis. It is not receptor mediated and is usefulif adrenergic receptors are down regulated or desensi-tized. Because normal renal function is needed formilrinone clearance, the dose should be lowered inpatients with signs of renal insufciency. Milrinonehas a long half-life compared to the other medicationsdiac output to meet tissue meta-d be checked periodically with aaturations470%. Normal arterial100% and mixed venous satura-ncert with maintenance of cardiacconcentration is an important

en delivery. Maintaining a hemo-410 g/dL is of utmost impor-n shock.4,23 For patients with ang a vasodilator with uid loadingdelivery. Agents that can be used, such as sodium nitroprusside,milrinone. The nitrovasodilatorscarrying capacity. At this point, the patient should bein an intensive care unit and invasive monitoringshould guide further treatment. If not already done, acentral venous catheter should be placed and a centralvenous pressure (CVP) recorded and trended. Theoptimal CVP for each patient will be dictated by theirclinical condition. Although a CVP of 510 cm H2O isconsidered within normal range, some patients mayrequire higher levels to maintain cardiac output.Observing the relationship between the CVP and bloodpressure (i.e., when the CVP is 18 cm H2O, the patienthas normal BP for age, when it drops to 12 cm H2O the

patient becomes hypotensive)will guide the clinician as to whatCVP a patient requires. Vasoac-tive agents and uid should betitrated to maintain a normalmean arterial pressure (MAP)CVP, which range between 55 fora term newborn and 65 forpatients who are 2 years of ageand older. Mixed venous oxygensaturation (SCVO2), an indirectindicator of the adequacy of car-

inutes aftern of shock ishe goldenwhich timeeed to bereverse

ock.289

used to support blood pressure ( mean half-life 2.3 h)

on and can determineand left ventriculared values that areo titrate medicationsload, afterload, andsubsequent PA cath-effects of treatment.t catheters (PICCO)lume in the heart,assess adequacy ofeveloped as a less-

and o6.0 L/min/m2, which has been associated with

tioners who care for pediatric patients are encouragedto become familiar with these guidelines as they are

1. Carcillo JA, FieMedicine Task Fparameters for hepatients in septic

2. Brierley J, Carcparameters for heseptic shock: 20Critical Care Me

3. Dellinger RP, Lecampaign: internsepsis and septi580637.

4. Rivers E, Nguytherapy in the t

rspatoitheninvasive way to obtain much of the same informationthat PA catheters provide. The measurements from aPICCO catheter allow the clinician to assess cardiacfunction and volume status and titrate therapies accord-ingly. Follow-up measurements are then obtained toevaluate treatment. Femoral artery thermodilutioncatheters and Doppler ultrasound can also aid in theassessment of cardiac output. These devices can helpguide therapy to achieve a goal cardiac index of43.3(PA) catheters can assist in tselective left ventricular dysfunctithe relative contribution of rightwork. The measured and derivobtained can allow the clinician tand interventions that affect precontractility and follow-up witheter measurements to assess thePulse index contour cardiac outpuestimate global end-diastolic voextravascular lung water, andpreload. PICCO catheters were dand can cause hypotension, which can be treated withnorepinephrine or vasopressin. An alternative agent toconsider is levosimendan, which exerts a positiveinotropic effect by increasing calcium sensitivity ofmyocytes by binding to cardiac troponin C in acalcium-dependent manner. It also has a vasodilatoryeffect by opening adenosine-triphosphate-sensitivepotassium channels in vascular smooth muscle. Thus,in the endotoxin-induced heart dysfunction of septicshock, levosimendan treats thesource of the problem.24 Ininstances where these measuresare not successful, vasopressinshould be added. Vasopressin isa peptide hormone that increasesperipheral vascular resistance viathe V1 receptors found on vas-cular smooth muscle of the sys-temic circulation. It has beenshown to increase systemic vas-cular resistance, mean arterialblood pressure, and urine output in septic shock.25-There are some instances in which the patient remainsin shock despite all of the aforementioned interven-tions. After initial assessment for correctable causes,such as pericardial effusions, pneumothoraces, andintra-abdominal hypertension, more advanced toolsmust be employed to guide therapy. Pulmonary artery

he identication of

All practitionefor pediatricencouragedfamiliar w

guidelines as thconcise and ca290N Engl J Med 2001;345(19):136877.5. Carcillo JA, Davis AL, Zaritsky A. Role of early uid

resuscitation in pediatric septic shock. J Am Med Assoc1991;266(9):12425.

6. Kern JW, Shoemaker WC. Meta-analysis of hemodynamicoptimization in high-risk patients. Crit Care Med 2002;30(8):168692.

7. Han YY, Carcillo JA, Dragotta MA, et al. Early reversal ofpediatric-neonatal shock by community physicians is associ-ated with improved outcome. Pediatrics 2003;112(4):7939.Curr Probl Pediatrlds AI, American College of Critical Careorce Committee Members. Clinical practicemodynamic support of pediatric and neonatalshock. Crit Care Med 2002;30(6):136578.illo JA, Choong K, et al. Clinical practicemodynamic support of pediatric and neonatal07 update from the American College ofdicine. Crit Care Med 2009;37(2):66688.vy MM, Rhodes A, et al. Surviving sepsisational guidelines for management of severec shock: 2012. Crit Care Med 2013;41(2):

en B, Havstad S, et al. Early goal-directedreatment of severe sepsis and septic shock.clear, concise, and can save lives.

Referencesthe best outcomes in septic shock patient.22 For thosepatients not aided by these tools, extracorporealmembrane oxygenation (ECMO) should be consid-ered. Survival rates in septic shock patients placed onECMO are 73% for newborns and 39% for olderchildren.26

Guidelines for the management of shock in childrenhave been in effect for the last 10 years. They are timebased and can be enacted in whatever setting shock is

rst recognized. The interventionsare designed to quickly improveoxygen delivery through mainte-nance of cardiac output and timelyadministration of antibiotics. Sincethe original guidelines were pub-lished, two revisions have beenmade, but the content has remainedlargely unchanged. Many studieshave tested the recommendations ofthe original guidelines. There isample evidence that the guidelines

are effective and do not cause harm.7,2731 All practi-

who caretients arebecomethese

y are clear,save lives.Adolesc Health Care, November/December 2013

8. Pollack MM, Ruttimann UE, Getson PR. Pediatric risk ofmortality (PRISM) score. Crit Care Med 1988;16(11):11106.

9. Stoner MJ, Goodman DG, Cohen DM, et al. Rapid uidresuscitation in pediatrics; testing the ACCM guidelines. CritCare Med 2005;33:A68.

10. Zadrobilek E, Hackl W, Sporn P, Steinbereithner K. Effect oflarge volume replacement with balanced electrolyte solutionson extravascular lung water in surgical patients with sepsissyndrome. Intensive Care Med 1989;15(8):50510.

11. Powell KR, Sugarman LI, Eskenazi AE, et al. Normalization ofplasma arginine vasopressin concentrations when children withmeningitis are given maintenance plus replacement uidtherapy. J Pediatr 1990;117(4):51522.

12. Ngo NT, Cao XT, Kneen R, et al. Acute management of

22. Ceneviva G, Pashcal JA, Eckstein J, et al. Hemodynamicsupport in uid refractory pediatric septic shock. Pediatrics1998;102:e19.

23. de Oliveira CF, de Oliveira DS, Gottschald AF, Moura JD,Costa GA, et al. ACCM/PALS haemodynamic support guide-lines for paediatric septic shock: an outcomes comparison withand without monitoring central venous oxygen saturation.Intensive Care Med 2008;34(6):106575.

24. Matejovic M, Krouzecky A, Radej J, Novak I. Successfulreversal of resistant hypodynamic septic shock with levosi-mendan. Acta Anaesthesiol Scand 2005;49(1):1278.

25. Liedel JL, Meadow W, Nachman J, Koogler T, Kahana MD.Use of vasopressin in refractory hypotension in children withvasodilatory shock: ve cases and a review of the literature.Pediatr Crit Care Med 2002;3(1):158.

26. Skinner SC, Iocono JA, Ballard HO, et al. Improved survivalin venovenous vs venoarterial extracorporeal membrane oxy-administration in critically ill patients: systematic review ofrandomized controlled trials. Br Med J 1998;317(7153):23540.

14. Oca MJ, Nelson M, Donn SM. Randomized trial of normalsaline versus 5% albumin for the treatment of neonatalhypotension. J Perinatol 2003;23(6):4736.

15. Lin JC, Carcillo JA. Increased glucose/glucose infusion rateratio predicts anion gap acidosis in pediatric sepsis. Crit CareMed 2004;32(suppl 20):A5.

16. Cardenas-Rivero N, Chernow B, Stoiko MA, Nussbaum SR,Todres ID. Hypocalcemia in critically ill children. J Pediatr1989;114(6):94651.

17. Roberton NR, Smith MA. Early neonatal hypocalcaemia. ArchDis Child 1975;50(8):6049.

18. Yli-Hankala A, Kirvel M, Randell T, Lindgren L. Ketamineanaesthesia in a patient with septic shock. Acta AnaesthesiolScand 1992;36(5):4835.

19. Pollack MM, Fields AI, Ruttimann UE. Sequential cardiopul-monary variables of infants and children in septic shock. CritCare Med 1984;12(7):5549.

20. Pollack MM, Fields AI, Ruttimann UE. Distributions ofcardiopulmonary variables in pediatric survivors and non-survivors of septic shock. Crit Care Med 1985;13(6):4549.

21. Perkin RM, Levin DL. Shock in the pediatric patient. Part II.Therapy. J Pediatr 1982;101(3):31932.Curr Probl PediatrAdolesc Health Care, November/December 2013Extracorporeal Life Support Organization registry. J PediatrSurg 2012;47(1):637.

27. Wills BA, Nguyen MD, Ha TL, et al. Comparison of the threeuid solutions for resuscitation in dengue shock. N Engl J Med2005;353:87789.

28. Maitland K, Pamba A, English M, et al. Randomized trial ofvolume expansion with albumin or saline in children withsevere malaria: preliminary evidence of albumin benet. ClinInfect Dis 2005;40:53845.

29. Ninis N, Phillips C, Bailey L, et al. The role of healthcaredelivery on outcome of meningococcal disease in children:Case control study of fatal and non-fatal cases. Br Med J2005;330:1475.

30. de Oliveira CF, de Oliveira DS, Gottschald AF, et al. ACCM/PALS haemodynamic support guidelines for paediatric septicshock: an outcomes comparison with and without monitoringcentral venous oxygen saturation. Intensive Care Med 2008;34:106575.

31. Karapinar B, Lin JC, Carcillo JA. ACCM guidelines use,correct antibiotic therapy, and immune suppressant with-drawal are associated with improved survival in pediatricsepsis, severe sepsis, and septic shock. Crit Care Med 2004;32(12 suppl 3):A161.13. Cochrane Injuries Group Albumin Reviewers. Human albumin genation for pediatric noncardiac sepsis patients: a study of thedengue shock syndrome: a randomized double-blind compar-ison of 4 intravenous uid regimens in the rst hour. ClinInfect Dis 2001;32(2):20413.291

The Management of SepsisIntroductionBackgroundEarly Goal-Directed TherapyManagement (Tables 1 and 2)Time 05minTime 515minTime 1560min

Cold ShockWarm ShockTime 60minBeyond the First HourReferences