Recognition of Impending Systemic Failure · 1. Discuss how impending systemic failure (SF) presentation varies by age. 2. Delineate the epidemiological risk factors for the development

Recognition of Impending Systemic FailureSaul Flores, MD,* Paul A. Checchia, MD, FCCM, FACC*

*Section of Critical Care Medicine, Department of Pediatrics, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX

Education Gap

Early recognition of impending systemic failure is critical for timely

interventions. However, some evidence demonstrates lower identification

rates of impending systemic failure by primary care and emergency

department physicians.

Objectives After completing this article, readers should be able to:

1. Discuss how impending systemic failure (SF) presentation varies by

age.

2. Delineate the epidemiological risk factors for the development of

impending SF.

3. List the signs and symptoms of impending SF.

4. Recognize the laboratory findings associated with impending SF.

5. Define the various types of SF.

6. Describe the physiological parameters used to monitor critically ill

patients at risk for impending SF.

7. Plan the management of impending SF.

8. Describe measures to prevent the development of SF.

9. Describe the implementation of rapid response teams.

10. Identify irreversible systemic failure (eg, brain death, hepatic failure,

cardiogenic shock).

CASE STUDY

You are the senior resident on call and part of the rapid response team (RRT) this

evening. You are about to evaluate a 10-month-old infant in the pediatric inpatient

ward after the parents activated the RRT. The patient’s bedside nurse informs you

that for the past hour, the patient is more tachycardic and tachypneic and is febrile

to 101.3°F (38.5°C) with increase of the pediatric early warning score (PEWS). In

addition, the patient’s mother discloses that she has not had to change any dia-

pers in the past 3 hours, and she also noticed the patient’s abdomen becoming

more enlarged. The infant’s physical examination findings are a gallop, intermit-

tent wheezing, and hepatosplenomegaly. The infant’s laboratory findings are

AUTHOR DISCLOSURE Dr Flores hasdisclosed no financial relationships relevant tothis article. Dr Checchia has disclosed that hehas a patent application for a nitric oxidedelivery service and a research grant for amulticenter respiratory syncytial virusresearch project and that he is a consultantfor AbbVie.

ABBREVIATIONS

AKI acute kidney injury

ARDS acute respiratory distress syndrome

ECMO extracorporeal membrane

oxygenation

ICU intensive care unit

IV intravenous

MH malignant hyperthermia

NIRS near-infrared spectroscopy

PALS pediatric advanced life support

PEWS pediatric early warning score

RRT rapid response team

SF systemic failure

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creatinine level of 0.9 mg/dL (79.56 mmol/L), alanine

aminotransferase level of 350 U/L (5.84 mkat/L), and lactate

level of 2.5 mmol/L. You obtain a chest radiograph that dem-

onstrates 9-rib expansion, pulmonary edema, and cardio-

megaly. The RRTmakes the decision to transfer the patient

to the intensive care unit (ICU) for further care.

INTRODUCTION

Severe disease processes may lead to the development of

shock, characterized by inadequate tissue delivery of oxygen

and nutrients tomeet themetabolic demands of cells, organs,

and tissue. Delayed identification or progression of shock

from compensated to irreversible will lead to the develop-

ment of systemic failure (SF). Impending SF in children is an

etiologically diverse disease process that manifests in a vari-

ety of clinical conditions. A major injury to an organ system

(either congenital or acquired) activates both compensatory

and deleterious pathways that cause organ injury. Timely

recognition and interventions of impending SF may reverse

the process, but if left untreated, SF ultimately leads to death.

DEFINITION

Impending SF can be defined as the development of phys-

iological derangement involving 2 or more organ systems

typically not involved in the disorder that resulted in pre-

sentation after a potentially life-threatening pathologic insult.

Other synonymous terms for impending SFaremultiple organ

dysfunction syndrome or multiorgan failure syndrome. We will

use SF for the remainder of this review.

EPIDEMIOLOGY

Impending SF is one of the most common causes of death

for patients admitted to an ICU. Estimating the exact in-

cidence of SF is difficult. However, it is understood that

there is a higher mortality rate with a greater number of

dysfunctional organs and a greater duration of this dysfunc-

tion, with rates ranging from 30% to 80%. The risk factors

associated with the development of SF include severe illness

at the time of ICU admission, diagnosis of sepsis or infec-

tion at the time of ICU admission, and age at admission

(younger children have worse outcomes).

PATHOGENESIS

Cardiovascular DysfunctionCardiovascular dysfunction during impending SF is trig-

gered by different mechanisms, depending on the initial

insult. For instance, during SF precipitated by septic shock,

there is a generalized reduction in peripheral vascular tone

due to the effect of vasodilatory mediators. This vasodilation

is followed by an increase in capillary permeability that

produces diffuse capillary leak. This leakage leads to alter-

ations in regional bloodflow, characterized bymicrovascular

stasis. The end result is arteriovenous shunting that con-

tributes to a high mixed venous saturation, which in turn

leads to the development of myocardial depression.

In SF caused by cardiogenic shock, the myocardium loses

the ability to perform contractile work.When a critical mass of

left ventricular myocardium becomes depressed, cardiac out-

put, stroke volume, and blood pressure all decrease,while end-

systolic volume increases. Left ventricular failure increases

diastolic pressures, causing increasing myocardial wall stress

and oxygen requirements. At the same time, systemic per-

fusion is compromised, resulting in tissue hypoperfusion,

anaerobic metabolism, and lactic acidosis that can lead to a

metabolic derangement. The continuous release of cytokines

perpetuates the inflammatory state andmay further negatively

affect systolic performance. Over time, compensatory mech-

anisms, such as tachycardia and fluid retention, lead to in-

creased myocardial oxygen demand and impairment of left

ventricular diastolic filling. If not reversed, the combination of

these factors precipitates pulmonary venous congestion and

hypoxemia. Lastly, sympathetically mediated vasoconstriction

to maintain systemic blood pressure amplifies myocardial

afterload, which can further impair cardiac performance.

Pulmonary DysfunctionThe main abnormality of the lung in SF is an abnormal gas

exchange, which manifests as arterial hypoxemia. There are

many factors that contribute to impaired gas exchange.

Atelectasis and altered regional blood flow will lead to

ventilation-perfusion mismatch. Increase in capillary perme-

ability coupled with neutrophil activation will result in alve-

olar flooding and injury. Institution of ventilatory support can

aggravate lung injury by different types of alveolar trauma.

Furthermore, tissue repair is activated after the initial insult;

this leads to additional influx of inflammatory cells into the

injured lung, leading to fibrosis and the development of acute

respiratory distress syndrome (ARDS).

The development of ARDS typically occurs within 7 days of

known clinical insult and is characterized by chest imaging

findings of new infiltrates consistent with acute pulmonary

parenchymal disease and acute deterioration in oxygenation.

The prevalence of ARDS was approximately 10% among

all children admitted to the ICU. However, further well-

designed,multicenter epidemiological clinical trials are needed

to assess ARDS in this vulnerable population.

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Gastrointestinal DysfunctionGastrointestinal dysfunction in impending SF is caused by

reduced regional blood flow, impaired motility, and alter-

ations in the normal microbial flora. This may manifest as

hypoactive bowel sounds, abdominal distention, or ileus.

Liver DysfunctionLiver dysfunction in impending SF, known as “shock liver,”

manifests as increases in liver enzyme and bilirubin levels,

abnormal synthetic function, coagulation defects, and fail-

ure to excrete toxins such as ammonia. Some other acute

phase reactants, such as serum levels of C-reactive protein

and a1-antitrypsin, are increased, whereas levels of albumin,

a negative acute phase reactant, are reduced.

Acute Kidney InjuryThemain reasons for acute kidney injury (AKI) in SF can be

categorized into 2 primary types of injury—hemodynamic

and nonhemodynamic. Hemodynamic injury creates a low-

output state and reduces renal blood flow, which can lead to

decreased renal filtration. Nonhemodynamic injury is caused

by neurohormonal and inflammatory mediators. The most

common mediators are reactive oxygen species, endothelin,

and excessive sympathetic activity. AKI maymanifest as fluid

overload secondary to excessive fluid resuscitation and renin-

angiotensin-aldosterone system activation. The implications

of fluid overload and AKI in patients with impeding SF have

not been completely determined and represent an area of

substantial research efforts.

Central Nervous System DysfunctionNeurological impairment is caused by metabolic alterations,

subclinical cerebral edema, and reduced cerebral perfusion

pressure. Providers should also recognize the iatrogenic effects

of sedatives and analgesics when assessing the Glasgow Coma

Scale score.

Hematologic DysfunctionHematologic dysfunction is characterized by immune sup-

pression and pancytopenia. Specifically, platelet activation ac-

celerates, while platelet aggregation markedly deteriorates.

Platelet activationmaymanifest platelet hyperadhesiveness to

other vascular cells, including neutrophils and endothelium.

Platelet hyperadhesiveness induces sequestration of platelets

and microcirculatory arrest, thus propagating SF.

CLINICAL MANIFESTATIONS

There are many similarities among the different types of

shock that lead to impending SF. A high index of suspicion is

required to identify clinically indistinguishable cases of the

different types of shock. After the onset of hemodynamic

dysfunction, several compensatory mechanisms are initiated

in an attempt to maintain perfusion and function of essential

organs. As impending SF progresses, the body’s compensa-

tory mechanisms can become harmful to other organs, such

that the organs that now begin to fail were not involved in the

initial disease for which the patient was admitted to the ICU.

The lung is the most common primary organ of injury,

but the liver, intestines, and kidneys can be involved during

the early development of SF. Myocardial and hematologic

dysfunction are late manifestations of SF. Hypotension is

also a late sign of impending SF, especially in neonates and

infants, because of their higher systemic vascular resistance

and vasoactive capacity when compared to older children.

Skin and muscles are affected early during SF by blood

being shunted away to perfuse other organs. This shunting

leads to ischemia of the skin and muscle vascular beds.

Providers should recognize a prolonged capillary refill time

longer than 2 seconds as a surrogate marker of decreased

superior vena cava O2 saturation and, if associated with hy-

potension, can lead to an increased mortality risk. Con-

versely, normal capillary refill and toe temperature ensures a

cardiac index greater than 2.0 L/minute per square meter.

Lastly, neurological manifestations of impending SF can

occur at any point during impeding SF (Table 1).

CAUSES

The pathophysiology of SF is not completely known. There is

evidence that indicates activation of several metabolic path-

ways at the time of initial injury. The end products of the

pathways are usually cytoprotective compounds. However, an

exaggerated activation of these pathways results in an inflam-

matory response that can lead to development of failure in

distant organs. As organs fail, they activate and propagate the

systemic inflammatory response. The following are the most

accepted theories for the development of SF.

HypoxiaChildren who develop hemorrhagic shock or cardiac arrest

will develop ischemia that leads to inadequate oxygenation

and hypoxia. These conditions are often readily reversible,

with blood transfusion in the former and cardiopulmonary

resuscitation in the latter. In contrast, patients with sepsis

have a more subtle oxygenation deficit. This deficit is charac-

terized by the difficulty in oxygen delivery due to the inability

of the erythrocytes to navigate the septic microvasculature.

This flow difficulty during septic shock is partially overcome

by the development of a higher oxygen gradient at the mito-

chondrial level, achieved via administration of supplemental

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oxygen during the resuscitation. At this point, oxygen con-

sumption becomes dependent on oxygen delivery. It is impor-

tant to recognize that while hypoxia is an important variable, it

is not the only one found in the development of SF.

Inflammation and/or Direct CytotoxicityThedirect effect of bacterial toxins, coupledwith lytic enzymes,

vasoactive substances, and reactive oxygen species, causes

damage to themitochondrial electron transport that can lead

to disordered energy metabolism. This process is called

cytopathic hypoxia and denotes diminished production of

adenosine triphosphate despite normal or even supranor-

mal oxygen levels.

Apoptosis and/or ImmunoparalysisIn SF due to sepsis, the immune response follows a biphasic

pattern, also known as the two-hit model. The initial phase is

characterized by a state of hyperinflammation distinguished

by high levels of proinflammatory cytokines. The secondphase,

or immunoparalysis phase, is characterized by decreased

responsiveness of immune cells to inflammatory stimuli.

The immunoparalysis phase is a particularly vulnerable period

when patients are at specific risk from invading bacteria. Im-

munoparalysis is an important step in the pathogenesis of sepsis

and involves immune cell apoptosis, particularly lymphocytes.

Gut HypothesisPreclinical experimental studies have demonstrated that SF

in the setting of trauma causes gut barrier failure, bacterial

translocation (passage of viable bacteria from the gastroin-

testinal tract to extraintestinal sites), and invasion of distant

organs. The subsequent gut-released proinflammatory mol-

ecules activate neutrophils and endothelial cells, which

trigger additional inflammation.

DIAGNOSIS

In extremis presentations, the clinical diagnosis of SF is

usually straightforward. However, most cases of impending

SFmanifest in amore subtle manner. Frontline providers in

TABLE 1. Signs of Impending Systemic Failure

ORGAN SYSTEM COMPENSATED SHOCK SIGNS SYSTEMIC FAILURE SIGNS LABORATORY DERANGEMENTS

Respiratory Tachypnea, increased workof breathing, grunting

Respiratory failure with hypoxia PaO2/FiO2 <300 in the absenceof CHD or lung disease

PaCO2 >65 or 20 mmHg overbaseline PaCO2

Cardiovascular Tachycardia, capillary refill<2 seconds, weakdistal pulses

Tachycardia, bradycardia, capillaryrefill >2 seconds, arrhythmias,hypotension, weak central pulses

SvO2 <60O2ER >25BNP >400 pg/ml

Renal Oliguria Anuria, tubular necrosis Elevation SCr >0.3 mg/dlIncrease in SCr >1.5 times baseline

Neurologic Agitation, anxiety, GCS >6 Lethargy, somnolence, GCS <6 NH4 level >80 mcg/dl

Gastrointestinal Ileus, feeding intolerance GI bleeding, distended abdomenwith signs of peritonitis

Hepatic Right upper quadranttenderness, hepatomegaly

Jaundice AST > 200 U/LALT > 200 U/LINR > 1.5 in the absence of

anticoagulation therapy

Hematologic Endothelial and plateletactivation

Disseminated intravascularcoagulation

Platelet counts <50 � 103

or 400 � 103

PT of 20 saPTT of 40 sFibrinogen level <100 mg/dL

or >400 mg/dL

Metabolic Mild acidosis Severe acidosis, hyperlactatemia Lactate level >2 mmol/L

ALT¼alanine aminotransferase; aPTT¼activated partial thromboplastin; AST¼aspartate aminotransferase; BNP¼brain-type natriuretic peptide; FIO2¼fraction ofinspired oxygen; GCS¼Glascow Coma Scale; INR¼international normalized ratio; NH4¼ammonium; O2ER¼oxygen extraction ratio; PaCO2¼partial pressure ofcarbon dioxide, arterial; PaO2¼partial pressure of oxygen, arterial; PT¼prothrombin time; sCr¼serum creatinine; SvO2¼mixed venous oxygen saturation.To convert picograms per milliliter to nanograms per liter for BNP level, multiply by 1. To convert milligrams per deciliter to micromoles per liter for sCr level,multiply by 88.4. To convert international units per liter tomicrokatals per liter for aspartate aminotransferase and alanine aminotransferase levels, multiplyby 0.0167. To convert milligrams per deciliter to grams per liter for fibrinogen level, multiply by 0.01.

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the emergency department or the wards should be vigilant

for clues during history compilation or physical examina-

tion. Furthermore, the presentation may vary by age; for

instance, infants at risk for SF will develop poor feeding or

irritability with feedings, whereas an older child may com-

plain of excessive fatigue and or sleep difficulties. In addi-

tion, providers should be attentive to the variation in vital

signs according to age and size.

In the ICU, the diagnostic evaluation of the different shock

states is performed via noninvasive and invasive methods. The

noninvasive methods include vital sign determination, pulse

oximetry, near-infrared spectroscopy (NIRS) monitoring, and

echocardiography. The invasivemethods include central venous

pressure, co-oximetry, and assessment of cardiac output via

transpulmonary thermodilution and pulse contour analysis.

Blood Gases and LactateThe presence of anion gap metabolic acidosis is distinctive of

SF. Inadequate oxygen delivery will lead to lactate and lactic

acid formation due to anaerobicmetabolism via theCori cycle.

It is widely accepted that lactate levels less than 2 mmol/L

correlate with superior vena cavaO2 saturation of at least 70%.

Hemodynamic DataThere is value in obtaining hemodynamic data with a pulmo-

nary artery catheter in selected patients with impending SF. In

fact, hemodynamic data led to the recognition of 3 possible

cardiovascular derangements inpediatric shock: hyperdynam-

ic, hypodynamic with low systemic vascular resistance, and

hypodynamic with high systemic vascular resistance (Table 2).

Although most children with impending SF present in a

hypodynamic state, providers should recognize that children

in a hyperdynamic state may not be hypotensive.

MONITORING

Near-Infrared SpectroscopyNIRS provides a noninvasive tool for continuous moni-

toring of regional tissue oxygen saturation. NIRS is used

to analyze the concentration and ratio of oxygenated to

deoxygenated hemoglobin and assists in determining the

balance between oxygen supply and demand.

NIRS is used to assess the regional cerebral oxygen

saturation and identify inadequate cerebral perfusion that

may lead to neurological injury and adverse outcomes. In

addition to cerebral monitoring, NIRS can be used to

monitor peripheral tissues, such as the renal and splanchnic

circulation. (1)

The NIRS monitor is an oximeter that uses single-use

adhesive patches with an integrated near-infrared light source

and photodetector applied to each side of the forehead. In

contrast to pulse oximetry, the NIRS monitor is used to

evaluate the nonpulsatile signal, which reflects the oxygen

saturation of themicrocirculation. The pediatric NIRS system

is designed for patients weighing less than 40 kg and differs

from the adult system in that it incorporates a pediatric-

specific algorithm in which the thinner skull and extracranial

tissue of infants and children are considered.

Pulmonary Artery CathetersThe pulmonary artery catheter, also called the Swan-Ganz

catheter or the right ventricular catheter, it is a balloon-tipped

pulmonary artery catheter used to assess mixed venous

oxygen saturation, pulmonary artery pressure, and pulmo-

nary capillary wedge pressure and tomeasure cardiac output

via thermodilution. (2)

The pulmonary artery catheter is particularly helpful in

conditions where pressure changes and assessment of

response to interventions are immediately needed, such as

severe pulmonary hypertension, determination of the type

of shock, and impending SF. Pulmonary artery catheter use

has been shadowed by the complications associated with its

insertion and use, inaccuracies in measurement, and diffi-

culties with interpretation of data. (3)

MANAGEMENT

Treatment of SF is primarily focused on prevention and the

management of individual organ dysfunction. In the following

section, we will discuss the management of impending SF.

TABLE 2. Hemodynamics of Shock

CARDIOVASCULAR DERANGEMENTS CARDIAC OUTPUT SYSTEMIC VASCULAR RESISTANCE PHENOTYPE

Hyperdynamic state >5.5 L/min per square meter <800 dynes/s $ cm�5 Warm shock

Hypodynamic state, low cardiac output,low systemic vascular resistance

<3.3 L/min per square meter <800 dynes/s $ cm�5

Hypodynamic state, low cardiac output,high systemic vascular resistance

<3.3 L/min per square meter >1,200 dynes $ cm�5 Cold shock

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Hospital TriageChildren who present to the emergency department in overt

SF are rapidly triaged to the ICU. However, patients who will

develop SF later in their clinical course but underwent early

evaluation of their condition may be triaged to the wards. In

the wards, identification of such patients is typically per-

formed according to changes in the clinical examination

findings or vital signs. In addition, different recognition tools,

management guidelines, and PEWS and the effective imple-

mentation of RRTs have become paramount in the recogni-

tion of impending SF. Patients who deteriorate clinically in

the wards will be transferred to the ICU. In the ICU,

monitoring of such patients will most likely become inva-

sive, allowing providers to obtain specific physiological data.

Early RecognitionEarly recognition and reversal of impending SFare essential

and have been shown to influence outcomes in critically ill

patients. In a landmark study in adults, Rivers et al the

importance of early goal-directed therapies (within 6

hours). (4) Similarly, a study in Pediatrics demonstrated

that the predominant factor that reduces mortality and

neurological morbidity in children transported to tertiary

care pediatric hospitals is the reversal of shock through early

recognition and resuscitation in the referring emergency

department. (5)

In this study, the authors aimed at maintaining not only

blood pressure, but also oxygen delivery with target superior

vena cava saturations of at least 70%, which resulted in a

nearly 50% reduction in mortality. Similarly, in a random-

ized trial in children with septic shock, there was mortality

reduction from 39% to 12% if superior vena cava saturations

were maintained at 70% and higher. (6)

Pediatric EarlyWarning Scores. PEWSwere implemented

to assist nurses and physicians in the early identification of

serious illness or deterioration. The PEWS are entered into

specific sheets or electronic medical records and are calcu-

lated from the sum of the following data: respiratory rate,

breathing effort, oxygen saturation, oxygen requirement,

heart rate, systolic blood pressure, capillary refill time, neu-

rological assessment, and nurse concern. In general, 2 red-

flag vital signs will prompt immediate medical evaluation.

Despite the wide implementation of PEWS, some of the

challenges experienced with their use are linked to the ac-

curacy and timeliness of the documentation. Nonetheless,

PEWS have been shown to reduce the incidence of critical

deterioration events by allowing identification of patients who

require escalation of therapies.

Rapid Response Teams. RRTs were initially created to

decrease pediatric cardiac arrests. RRTs continue to evolve to

better (a) identify individuals at risk for clinical deterioration

and (b) intervene. RRTs are typically composed of a pediatric

ICU fellow (team leader), a pediatric ICU charge nurse, a

pediatric ICU respiratory therapist, a senior pediatric resi-

dent, and the patient’s primary team. Amedical provider or a

family member can activate the RRT protocol after noticing

changes in the patient’s condition. RRTswill respondwithin a

few minutes (the typical goal response is 10 minutes) and

decide how to approach the patient’s change. This approach

typically extends from application of other therapies at the

patient’s current location to transferring the patient to a higher

level of care. RRTs are an effectivemethod for early recognition

of impending SF and have demonstrated improvement in

outcomes in pediatric hospitals.

Pediatric Advanced Life Support. Pediatric advanced life

support (PALS) serves to instruct health care providers on an

approach for the care of critically ill children. In addition,

PALS is designed to provide the knowledge and skills to

health care providers as first responders to both in- and out-

of-hospital medical emergencies. Although PALS and other

systems, such as the Neonatal Resuscitation Program or the

Advanced Cardiovascular Life Support system, continue to

improve survival after cardiac arrest in particular in the in-

hospital setting, the effectiveness of early recognition of

impending SF remains challenging.

In recent years, extensive emphasis was given to the

development of evidence to determine the implications of

early identification of patients with impending SF, specif-

ically with diagnoses such as myocarditis, dilated cardio-

myopathy, or septic shock.

ResuscitationResuscitation is the priority in the initial management of SF.

Children should be resuscitated to reach clinical goals, such

as appropriate mental status, strong pulse, normothermia,

capillary refill time of less than 2 seconds, and urine output

of more than 1 mL/kg per hour. In addition, serial examina-

tion by the same team of clinicians can be used to effectively

identify and monitor children with SF.

Fluid Therapy. Different strategies of fluid resuscitation

exist, depending on the etiologic origins of SF. For instance,

in impeding SF due to septic shock, intravenous (IV) fluid

boluses are used to reverse the hypovolemic state and opti-

mize contractility. Typically, fluid boluses in increments of

20 mL/kg up to 60 mL/kg may be required to restore

intravascular volume in the first hour. However, if the

patient develops severe capillary leak, then boluses up to 100

mL/kg may be needed in the initial hours. Conversely,

careful fluid administrations should be applied (a) in chil-

dren with any suspicion for cardiogenic failure, since less

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myocardial compliance results in less volume required to

accomplish optimal stroke volume, or (b) in children with

diabetic ketoacidosis, where rapid osmolality shiftsmay place

them at risk for cerebral edema.

Temperature Control. Fever is associated with worsened

outcomes in children with SF after trauma, particularly

after traumatic brain injury. Of note, providers should also

be prepared to identify and treat malignant hyperthermia

when encountered outside the operating room, particularly

in patients with muscular dystrophies and other myopa-

thies. (Malignant hyperthermia [MH] will be discussed

in the next section.)

The beneficial effects of fever control in SF due to sepsis

are controversial. Uninterrupted application of external

cooling devices can lead to shivering, with increased oxygen

consumption and myocardial work. There are currently no

guidelines for the use of such devices.

Malignant Hyperthermia. MH is a rare condition in-

herited in an autosomal dominant pattern, characterized

by mutations of the ryanodine receptor. MH reveals itself

shortly after exposure to anesthetic agents. The most com-

mon anesthetic agents are volatile anesthetics, such as

halothane, and depolarizing muscle relaxants, such as suc-

cinylcholine. MH can also occur in patients with underlying

muscular dystrophies, myopathies, and central core disease.

MH is clinically manifested as a rapid increase in tem-

perature, tachycardia, and CO2 retention. In fact, the earliest

sign of MH is an increase in the end-tidal CO2 level, as

captured during anesthesia. The subacute manifestations of

MH are acidosis and muscle spasms and the later develop-

ment of rhabdomyolysis.

The management of MH is primary avoidance of the

implicated anesthetic agents and the initiation of dantrolene

upon suspicion during an anesthesia case. Patients with

muscle disorders should be carefully evaluated prior to the

administration of anesthesia. Succinylcholine should be

avoided owing to the risk of rhabdomyolysis in patients

with Duchenne muscular dystrophy.

Metabolic Support.Metabolic and endocrine derangements

can occur in children with impending SF. These include

alterations of cortisol and thyroid hormone levels. Adrenal

insufficiency and hypothyroidismmay contribute to the hemo-

dynamic instability in patients with impending SF. Adrenal

and thyroid hormone testing and therapy may be indicated in

patients with hypotension refractory to vasoactivemedications.

Hypocalcemia.Hypocalcemia is determined by a decrease

in serum ionized calcium concentrations and can lead to an

increasedmortality rate in patients with SF. Hypocalcemia in

impending SF causes tachypnea, tachycardia, and hypotension

due to ventricular dysfunction. The origin of hypocalcemia is

related to alterations of the parathyroid–vitamin D axis and

typically occurs in children with gram-negative septic shock.

Hypocalcemia can also occur with massive blood transfu-

sions secondary to the binding of citrate and ionized calcium.

Irrespective of the mechanism, reversal of hypocalcemia

must occur early with calcium chloride or calcium gluconate

administration.

Glucose Control. Hypoglycemia can occur during SF

and, if missed, can cause neurological impairment. Conse-

quently, hypoglycemia has to be readily identified and treated.

A 5%or 10%dextrose that contains isotonic IVsolution can be

administered at maintenance rates to provide age-appropriate

glucose delivery and prevent hypoglycemia.

Hyperglycemia is frequently identified during SF. Phys-

iologically, the control of hyperglycemia is associated with

reversal of catabolism. Although there is a lack of outcome

benefit from early initiation of insulin during SF, the Amer-

ican College of Critical Care Medicine committee consensus

is to treat hyperglycemia with insulin during shock states.

AnemiaManagement.Blood transfusions are essential in

children with SF due to hemorrhagic shock. In such patients,

hemoglobin levels below 6 g/dL (60 g/L) are known to

increase the mortality rate. Therefore, blood transfusion in

these circumstances is a lifesaving measure that should be

performed rapidly.

In contrast, no specific blood transfusion guidelines exist

for hemodynamically unstable children with impending SF

due to septic shock. However, in vitro models suggest that

the optimal hematocrit level for oxygen delivery through

capillary vessels is around 30%. In addition, a hemoglobin

level of 10 g/dL (100 g/L) has been used as a therapeutic end

point in large septic shock trials in adults.

Antimicrobials and Source Control. Antimicrobials are

not typically indicated in all types of shock that progress to

SF. In SF secondary to septic shock, the administration of

broad-spectrum IV antimicrobials is a priority and, ideally,

should occur within the first hour of recognition. This

recommendation follows the guidelines from the surviving

sepsis campaign and is thought to be a critical component of

reducing mortality from sepsis-related SF. The surviving

sepsis campaign was established in 2002 by the Society of

Critical Care Medicine, the European Society of Intensive

Care Medicine, and the International Sepsis Forum. The

campaign goal is to reduce the mortality from sepsis in all

age groups by providing guidelines of care based on differ-

ent levels of evidence.

Source control refers to the specific anatomic diagnosis

of infection that requires consideration for emergent inter-

ventional management. Some examples of source control

are incision and drainage control of the liquid component of

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an infection, debridement of necrotic tissue, and restoration

of function of the affected tissue or area of infection. Before

selection of the optimal source control methods, providers

must weigh the benefits and risks of the specific interven-

tion and the potential development of complications, such

as spreading of infection or fistula formation.

Hemodynamic Support. The augmentation of oxygen

delivery by increasing either the cardiac output or the oxygen

content of blood is important to improve oxygen usage. The

initial hemodynamic goals are normal heart rate and perfu-

sion pressure for age. If the initial therapy increases the stroke

volume, then the heart rate will decrease and the systolic

blood pressure will increase. Specific hemodynamic goals are

summarized in Table 3.

In both neonates and children, impending SF manage-

ment should be guided by hemodynamic variables. In highly

perfused organs, like the kidneys and brain, vasomotor

autoregulation maintains flow in low–blood pressure states.

However, there is a point when perfusion pressure is re-

duced below this compensated state. Therefore, one goal

of hemodynamic support in impending SF is to maintain

perfusion pressure in individual organs. Measurement of

urine output can be used as a readily available indicator of

adequate renal blood flow and perfusion pressure. It is

known that the maintenance of mean arterial pressure with

vasoactive agents improves urine output in SF.

A threshold lowest heart rate is also needed to maintain a

minimum cardiac output. This goal can be achieved by

using an inotropic agent. Conversely, providers should pay

particular attention to tachycardia in the setting of hypo-

tension with low diastolic blood pressure, as it may impair

coronary perfusion.

Lastly, SF should also be treated according to oxygen usage

parameters. Measurement of cardiac output and oxygen con-

sumption are beneficial for patient management. The current

guidelines from the surviving sepsis campaign recommend a car-

diac indexbetween3.3 and6.0L/minuteper squaremeter andO2

consumption of more than 200 mL/minute per square meter

for the management of persistent shock, which are associ-

ated with improved survival. (7)

Ventilation ManagementThe two modalities of ventilation in children with SFare (a)

noninvasive ventilation, ranging from nasal cannula and

non-rebreather masks to continuous positive airway pressure

with a mask or nasal prongs, and (b) invasive ventilation,

characterized by endotracheal intubation and delivery of

positive pressure. Noninvasive ventilation is reserved for

children who are expected to recover rapidly from the under-

lying cause. If the patient develops worsening respiratory

distress, support should be escalated to high-flow nasal

cannula or nasopharyngeal continuous positive airway pres-

sure. If mechanical ventilation is eventually required, then

cardiovascular instability during tracheal intubation is less

likely if appropriate cardiovascular resuscitation was pro-

vided. Most children with impending SF, especially if they

develop ARDS with hypoxemia, will eventually require

invasive mechanical ventilation. Invasive ventilation in

ARDS has evolved over the years, and the current guidelines

are derived from the acute respiratory distress syndrome

network. (8) This multi-institutional trial demonstrated that

a targeted tidal volume of 6 mL per kilogram of ideal body

weight, with limitation of plateau pressure less than 30 cm

H2O, decreased the mortality by 8%. Additional adjuvant

strategies, such as surfactant, inhaled nitric oxide, prone

positioning, steroids, and high-frequency oscillatory venti-

lation, are other tools available to manage the hypoxia

associated with ARDS.

Diuretics and Renal Support TherapyManagement of AKI and impending SF is centered on

maintaining fluid balance. The early use of IV fluids is a

fundamental step in patients with impending SF. However,

the clinical implications of aggressive fluid use are currently

being challenged, owing to lack of strong evidence. Early,

aggressive fluid resuscitation can potentially lead to clinically

TABLE 3. Resuscitation Goals in the First 6 Hours

PARAMETER TERM NEWBORN UP TO 1 Y UP TO 2 Y UP TO 7 Y UP TO 15 Y

Heart rate (beats/min) 120–180 120–180 120–160 100–140 90–140

Mean arterial pressure (mm Hg) ‡55 ‡60 ‡65 ‡65 ‡65

Central venous pressure (mm Hg) 8–12 8–12 8–12 8–12 8–12

Urine output (mL/kg per h) ‡0.5 ‡0.5 ‡0.5 ‡0.5 ‡0.5

Central venous oxygen saturation (%) ‡70 ‡70 ‡70 ‡70 ‡70

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significant negative consequences of pulmonary fluid over-

load and exacerbation of myocardial dysfunction. After

initial resuscitation, diuretic use in patients with SF and

AKI is controversial. Loop diuretics theoretically reduce tubu-

lar oxygen consumption and prevent intratubular obstruction,

which can prevent AKI or slow AKI progression. At the same

time, forcedfluid removal by using diuretics can be associated

with an increased risk of AKI and acute tubular necrosis. (9)

The main form of renal support therapy, electrolyte

control, and acid-base disturbance correction in SF is dial-

ysis. Existing data favor initiation of dialysis before clinically

significant (>15%) fluid overload. As with any invasive

procedure, renal support therapy can have complications;

however, most of the time, the benefits appear to outweigh

the risks.

Nutritional SupportAvoidance of fasting and provision of early nutritional

support in children with SF are important. Occasionally,

providers face challenges with determining the proper

route, the amount and caloric density of nutrition, and

the timing of initiation. Regardless of the etiologic origins

of SF, enteral nutrition is the preferred route, even in patients

with postoperative trauma. The use of parenteral nutrition

should be reserved for patients who are unable to tolerate

enteral nutrition or for complementing enteral nutrition.

Moreover, nutritional support should be started early, as

soon as there is hemodynamic stability—preferably within

48 hours of admission or the completion of a surgical

procedure. Lastly, it is recommended that full caloric feeding

be avoided in the first week and limited to low-dose feedings,

advancing only as tolerated.

Refractory SFCorticosteroids. The use of hydrocortisone in the manage-

ment of SF is reserved for children at risk for absolute

adrenal insufficiency or adrenal pituitary axis failure and for

some patients with refractory shock, despite vasoactive

medication infusion. Ideally, administration of hydrocorti-

sone should be preceded by a blood sample for subsequent

determination of baseline cortisol concentration.

Extracorporeal Therapies. The use of extracorporeal mem-

brane oxygenation (ECMO) is a feasible therapeutic option in

children with refractory SF precipitated by septic shock

or sepsis-associated respiratory failure. However, it is recom-

mended that providers search for unrecognized com-

orbidities, such as myocardial dysfunction, neurological

injury, or hypoxemia respiratory failure, prior to activating

the ECMO team, since ECMO support is only potentially

effective when implemented before irreversible organ injury

develops. Therefore, timely ECMO activation and appropriate

patient selection are important and can lead to survival rates

as high as 80%, as demonstrated in newborns.

PROGNOSIS AND OUTCOMES OF SF

Progression of impending SF implies irreversible vital

organ injury, greater number of organs failing, and, poten-

tially, death. Despite the difficulty of assessing health-related

quality of life in children with critical illness, it is not un-

common to observe detrimental effects inmultiple domains

of functioning in survivors of SF. Furthermore, long-term

outcomes after SF have not been completely characterized.

More studies are required to determine the postdischarge

implications of SF.

In summary, early identification and appropriate imple-

mentation of therapeutic strategies are crucial. In addition,

increased understanding of the pathophysiology of SF is

necessary for the development of newer pharmacological

strategies to block the propagation of the systemic inflam-

matory response and to restore normal mitochondrial and

cellular function.

References for this article are at http://pedsinreview.aappublications.

org/content/38/11/520.

SUMMARY1. On the basis of some research evidence, as well as consensus,

recognition of patients at risk for impending systemic failure (SF)in the ward is indicated by changes in the clinical examination orvital signs. (1)(4)(5)(6)

2. On the basis of some research evidence, as well as consensus, theuse of different recognition tools, management guidelines, andpediatric early warning scores and the effective implementationof rapid response teams for the recognition of impending SFimprove patient outcomes. (4)(5)(6)

3. On the basis of strong research evidence, oliguria and furtherneurological deterioration in patients with shock is amanifestation of loss of regional blood flow autoregulation. (5)

4. On the basis of strong research evidence, the goal of hemodynamicsupport in impending SF is tomaintain perfusionpressure above thecritical point, below which blood flow cannot be effectivelymaintained in individual organs. (4)(5)(6)(7)

5. On the basis of strong research evidence, in patients at risk forimpending SF due to septic shock, the administration of broad-spectrum intravenous antimicrobials should occur within thefirst hour of recognition of septic shock. (4)(5)(6)(7)

6. On the basis of primarily consensus, due to lack of relevantclinical studies, nutritional support should be started within 48hours of admission in hemodynamically stable patients. (7)

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1. The rapid response team (RRT) was called by themother of a 3-month-oldmale infant whowas admitted to the ward with fever and lobar pneumonia. The patient has been receivingsupplemental oxygen and intravenous (IV) antibiotics for 3 days. The mother called theRRT because the baby had been sleepy and had not had a wet diaper in morethan 4 hours. The RRT began assessing the baby for signs of systemic failure (SF). Thepresence of which of the following findings is most likely associated with increasedmortality risk in a patient of this age?

A. Cardiac index of more than 2 L/min per square meter.B. Fever higher than 101.3°F (38.5°C).C. Hypotension.D. Hypoxemia on room air.E. Tachycardia with prolonged capillary refill time.

2. You are completing your shift in the emergency department. SF may manifest in a subtlemanner. Early recognition and diagnosis are key to better outcomes. Among the followingclinical scenarios, which of the clinical presentations should be most concerning forimpending SF?

A. An adolescent with headache and poor sleep.B. An infant who develops poor feeding and irritability.C. An infant with fever and rhinorrhea.D. A school-aged child with abdominal pain and constipation.E. A toddler who has enuresis after successful potty training.

3. Noninvasive monitoring in patients with SF is one of the methods used in management. Anear-infrared spectroscopy monitor, when applied to the forehead, works by measuringwhich of the following patient cerebral parameters?

A. Arterial oxygen concentration.B. Mitochondrial adenosine triphosphate concentration.C. Pulsatile signal.D. Ratio of oxygenated to deoxygenated hemoglobin.E. Venous oxygen concentration.

4. A 14 year-old-boy with dilated cardiomyopathy is admitted to the pediatric intensive careunit with SF and shock. Which of the following is the most appropriate immediate nextstep in the management of this patient?

A. Fluid bolus of 20-mL/kg increments.B. Fluid bolus of 100-mL/kg increments.C. Fluid bolus of twice the maintenance volume.D. IV antimicrobials.E. Oral antipyretics.

5. In the case in the previous question,monitoring of which of the following parameters is thebest indicator of effective renal perfusion?

A. Blood urea nitrogen level.B. Fractional excretion of sodium.C. Mean arterial pressure.D. Urine sodium level.E. Urine output.

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DOI: 10.1542/pir.2016-01022017;38;520Pediatrics in Review 

Saul Flores and Paul A. ChecchiaRecognition of Impending Systemic Failure

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