Introduction

What is the definition of shock?

Shock is a clinical syndrome of inadequate tissue perfusion, oxygen utilization, and cellular energy production leading to cellular damage. Shock is not synonymous with hypotension and the diagnosis requires the clinical assessment of volume status, cardiac function, and vascular tone [1].

Epidemiology

Sepsis occurs relatively frequently in the pediatric population but estimates regarding the rates of shock are more dificult to estimate.

Septicemia, influenza, pneumonia, and meningitis occurred in 5,259 patients less than seventeen years of age for the years 2002 to 2013, with an average incidence rate of 1.1 per 100,000 children (CDC Health Date Interactive Oct. 2015). A recent point of prevalence study over a 5 day period in 2013-2014 at 128 sites in 26 countries identified the point prevalence for pediatric patients with severe sepsis to be 8.2%. This was associated with a hospital mortality rate of 25% [2].

The incidence of septic shock is estimated to be 0.6 cases per 1000 population in individuals less than 20 years of age within the United States [3]. The incidence of neonatal sepsis is calculated to be 5.2 per 1000 infants.

Basic Science

An understanding of normal cardiovascular physiology, oxygen dynamics and compensation mechanisms is required to understand cardiovascular dysfunction. Neonatal cardiovascular physiology is different than older infants and children and therefore is managed differently.

What is the normal function of the heart and the circulation?

A normally functioning heart pumps blood to both the pulmonary and systemic circulations, which are connected in series. Deoxygenated blood from the systemic venous system (inferior and superior venae cavae) returns to the right atrium where it passes into the right ventricle. From here, it is pumped to the lungs via the pulmonary arteries where it becomes oxygenated. This oxygenated blood returns to the left atrium via the pulmonary veins after which it is pumped by the left ventricle to the body via the systemic arterial circulation.

The components of the circulatory system include arteries, arterioles, capillaries, venules and veins. Oxygenated blood is transported by arteries of diminishing size to end organs where it is extracted for aerobic metabolism. Metabolic waste products are transported back to central circulation in the venous system along with deoxygenated blood.

Additionally, the heart and the circulatory system respond to changes in the metabolic demand of the individual. While low cardiac output and resting vascular tone are appropriate while the individual is at rest, a higher cardiac output and decreases in vascular tone are required to meet the metabolic demands of activity or stress.

What is the Starling curve and what is its importance in the management of shock?

The Frank-Starling curve demonstrates how changes in ventricular preload (i.e. venous return) affect stroke volume. Cardiac output is the multiple of stroke volume times heart rate. In general, any decrease in venous return will lead to reduced stroke volume (e.g. going from a supine position to a standing position). On the other hand, activity increases venous return thereby increasing the stroke volume to meet metabolic demands.

Frank-Starling curve

The figure above demonstrates the Frank-Starling curve which plots the relationship between carciac output/stroke volume and venous return (i.e. left ventricular end-diastolic volume/preload). Simply put, cardiac output increases with increased venous return since this leads to increased stretch of the myofibrils and more forceful contraction. Stroke volume can also be increased by increasing contractility (i.e. inotropy) or by decreasing afterload (the pressure against which the heart must pump - see heavy dashed red line).

It is important to note that increasing preload only increases stroke volume to a certain extent and is less of a factor in neonates. Indeed, the major mechanism for neonates to increase cardiac output is by increasing their heart rate since stroke volume and contractility are relatively fixed. In older children and adults, an increase in venous return leads to higher end diastolic volumes and the attainment of optimal sarcomere length that results in greater cardiac contractility. However, over-stretching the sarcomere leads to inadequate contraction and will not increase inotropy. In this scenario, there is lower stroke volume but an increased end diastolic volume (i.e. right atrial pressure).

What are the specifics of oxygen dynamics?

The fetal circulation relies on oxygenated blood passing through three key structures that typically obliterate later in life: the ductus venosus, the foramen ovale, and the ductus arteriosus. The placenta provides oxygenated blood (pO2 = 30 to 35 mm Hg) to the fetus via the umbilical vein which then passes to the right heart through the ductus venosus. Most of the fetal circulation bypasses the pulmonary vasculature (only 10% of the cardiac output passes through the fetal lungs due to high pulmonary vascular resistance) and passes directly into the systemic circulation via the foramen ovale and the ductus arteriosus. Deoxygenated blood then flows from the umbilical arteries back to the placenta for oxygenation by maternal blood. The normal transition of fetal circulation involves a rapid decrease in pulmonary vascular resistance due to increases in ambient blood oxygen levels and an increase in systemic vascular resistance. The increased left sided pressure closes the foramen ovale and the increased oxygen tension promotes ductus arteriosus closure. The absent placental circulation allows for ductus venosus closure.

Oxygen delivery (DO2) is dependent upon cardiac output (CO) and the oxygen content in the blood. (see Respiratory Care Pathophysiology)

Oxygen consumption (VO2) is calculated by the Fick principle

VO2 = CO x (Arterio-Venous O2 difference) or measured by indirect calorimetry.

The reverse Fick equation can be used to calculate the cardiac output:

CO = VO2 /(Arterio-Venous O2 difference).

The mixed venous hemoglobin saturation (SvO2) allows assessment of the ratio of oxygen delivery to consumption (DO2/VO2) and the inverse, the oxygen extraction (VO2/DO2), and is used to determine the adequacy of those relationships. The SvO2 integrates all blood that is returning to the right atrium, including the deoxygenated blood from the coronary sinus as it mixes with peripheral blood, and provides the most accurate assessment of venous oxygen saturation (since the cardiac myocytes are the most efficient extractors of oxygen in the body). Popularized by Rivers et al in their goal directed therapy for septic shock, the central venous saturation (ScvO2) measured in the right atrium is a reasonable surrogate for peripheral oxygen extraction, although the values tend to be higher than the SvO2 [4]. The ScvO2 is easier to measure since it only requires a central venous catheter. In contrast, the SvO2 may only be assessed via a catheter placed into the pulmonary artery. Normal ScVO2 measurements range between 70 and 75%. Values less than 65% indicate inadequate oxygen delivery and/or increased tissue oxygen consumption. Values that are greater than 75% indicate either excess oxygen delivery or reduced oxygen consumption: the latter may be secondary to cellular dysfunction. (see Respiratory Care Pathophysiology)

oxygen dynamics

The figure above describes oxygen dynamics. The usual oxygen delivery to extraction ratio (DO2:VO2) is 4:1, but can go as low as 2:1 in stress states.

Pathophysiology

Cardiovascular compensation is different in young infants and children compared with older children and adults since the former are dependent on heart rate to increase cardiac output while the latter can also increase their contractility. The clinical manifestations of inflammation are described as the systemic inflammatory response syndrome or, in cases of infection, as sepsis.

What are the differences in the cardiovascular compensation for shock between children and adults?

In adults and older children, the heart rate and stroke volume increase to augment cardiac output. Neonates depend mostly on heart rate to increase cardiac output (CO) since they have a relatively stiff myocardium. As a result of this lower ventricular compliance, increases in venous return are not associated with as large an increase in stroke volume as in the adult heart (i.e. the Starling curve is flatter). Neonates consequently have a limited ability to respond to an increased need for CO (e.g., in the setting of sepsis). The neonatal myocardium undergoes significant changes over the first several months of life after which it starts to resemble that of older patients.

What is the difference between the systemic inflammatory response syndrome (SIRS) and septic shock?

The systemic inflammatory response syndrome (SIRS) is a constellation of clinical signs described by Bone et al [5]. The criteria for SIRS include an abnormal temperature (greater than 38.5 oC or less than 36 oC) or an abnormal leukocyte count for age (or more than 10% immature neutrophils) plus tachycardia (or bradycardia for children less than one year old) or tachypnea. In addition, there should be no pathogen identified as the cause.

Sepsis is SIRS secondary to suspected or documented infection. Severe sepsis is sepsis with associated cardiovascular dysfunction or respiratory failure. Septic shock is sepsis plus hypotension.

Organ dysfunction criteria in sepsis [6]

Cardiovascular dysfunction

Despite an intravenous fluid bolus of 40 mL/kg in one hour, dysfunction is defined by

  • decrease in blood pressure below the fifth percentile for age (or systolic blood pressure two standard deviations below normal for age)

-or-

  • need for vasopressors to maintain blood pressure in normal range.

-or-

  • two of the following:
    • unexplained metabolic acidosis (base deficit greater than 5 mEq/L).
    • increased arterial lactate greater than 2-fold upper limit of normal
    • urine output less than 0.5 mL/kg/hr
    • capillary refill greater than 5 seconds
    • core to peripheral temperature gap greater than 3°C.

Respiratory dysfunction

  • PaO2/FiO2 less than 300 in the absence of cyanotic heart disease or pre-existing lung disease

-or-

  • PaCO2 greater than 65 torr or 20 mm Hg above baseline

-or-

  • proven need for FiO2 greater than 0.5 to maintain saturation ≥92%.

-or-

  • need for non-elective invasive or noninvasive mechanical ventilation

Neurologic dysfunction

  • Glasgow Coma Score ≤11.

-or-

  • acute change in mental status with decrease in GCS ≥3 points from baseline.

Hematologic dysfunction

  • platelet count less than 80,000/mL or decline by 50% from highest value in past three days

-or-

  • International Normalized Ratio (INR) greater than 2

Renal dysfunction

  • serum creatinine ≥2 times upper limit of normal for age or two-fold increase from baseline

Hepatic dysfunction

  • total bilirubin ≥4 mg/dL (not applicable for newborn)

-or-

  • ALT two-fold the upper limit of normal for age

What are the mechanisms associated with the systemic inflammatory response syndrome?

The pathophysiology of SIRS and sepsis occurs as a result of perturbations in three major aspects of the immune system:

  1. Pro-inflammatory state – immune dysregulation results in an over-abundant inflammatory response that produces clinical signs of organ dysfunction
  2. Inadequate anti-inflammatory control – the normal mechanism for de-escalation of the inflammatory process is disrupted
  3. Immunoparalysis – acquired immunodeficiency leading to the inability to clear metabolites of inflammation and infection leading to organ dysfunction

How does shock and systemic inflammatory response syndrome lead to multiorgan system failure?

In the common scenario of an invasive gram-negative bacterial infection, tissue barrier disruption (epidermis, endothelium, or mucosa) leads to bacterial invasion and lipopolysaccharide (LPS) release. The presence of LPS leads to the cellular activation of neutrophils, macrophages, and endothelial cells that release of cytokines which, along with the release of reactive oxygen species, toxic granules from granulocytes, and nitric oxide, result in bacterial destruction. Unfortunately, these same mediators may also lead to end-organ injury when the pro-inflammatory state overwhelms anti-inflammatory processes [7].

What are the effects of shock and sepsis on oxygen dynamics and mixed venous oxygen saturation?

Shock and sepsis result in higher metabolic demand by the end organs. Anaerobic metabolism will begin if oxygen delivery is impaired or inadequate, resulting in lactic acidosis. In cases where the oxygen delivery is inadequate while the oxygen consumption is appropriate, the ScVO2 or SvO2 will be low. In cases where there is microcirculatory or mitochondrial dysfunction, the tissue oxygen consumption will be reduced, despite the provision of adequate oxygen to meet the metabolic need. This results in a higher ScVO2 or SvO2 [8]. A normal ScVO2 will be usually be within thirty points of the arterial oxygen saturation.

What is ventricular interdependence?

The right and left ventricles share a common septal wall which causes the preload/afterload status of one ventricle to affect the function of the other. Normally, due to elevated systolic pressures, the ventricular septum bows to the right enabling the left ventricle to achieve a circular configuration that is optimal for function. When right and left ventricular pressures are similar, the septum remains flat, thus compromising left ventricular geometry and ejection.

This concept is particularly important in neonatal transitional physiology. Elevated right sided pressures, associated with pulmonary hypertension, often persist for the first several days of life. In end-diastole, the left ventricular pressures are greater than the right, allowing the left ventricle to assume its optimal circular shape. However, the subsequent bowing of the septum to the left in end-systole (due to higher pressures generated by the right ventricle) distorts this shape and leads to reduced left ventricular function. With persistent elevated pulmonary arterial pressures, the right ventricle, which is morphologically unaccustomed to pumping against high pressures, may begin to fail, leading to both geometric distortion of the left ventricle and reduced left ventricular filling, both of which contribute to left ventricular dysfunction [3].

What are the principal neurotransmitters and their actions as they relate to cardiac function and vascular tone?

The principle neurotransmitters in the cardiovascular system are norepinephrine and acetylcholine. The principle receptors are alpha-1 (α1), alpha-2 (α2), beta-1 (β1), beta-2 (β2), dopaminergic-1 (D1) and muscarinic (M) receptors.

The autonomic nervous system controls cardiovascular tone, heart rate, and myocardial contractility. The sympathetic and parasympathetic preganglionic synapse is stimulated by acetylcholine via the nicotinic receptor. The sympathetic postganglionic stimulation of end organ receptors (α1, β1, and β2) occurs via norepinephrine, while parasympathetic postganglionic stimulation occurs via acetylcholine on the muscarinic receptor.

Stimulation of β1 receptors in the heart increases cAMP levels via stimulation of adenylate cyclase activity. This results in increased intracellular calcium concentrations which causes more intense myocardial contraction.

β2 receptors are found predominantly in vascular smooth muscle and their stimulation causes smooth muscle relaxation by decreasing intracellular calcium concentrations. While the heart also contains β2 receptors, their exact role is not well understood.

α1 receptors mediate vascular smooth muscle contraction. They act via G-protein mediated second messenger systems to increase intracellular calcium which leads to smooth muscle contraction. There are several subtypes of α1 receptors and one type may control the vascular tone in a particular vascular bed (e.g., α1D controls vascular smooth muscle tone in the heart, but not the aorta).

The α2 receptor may be either presynaptic or postsynaptic. Presynaptic α2 receptors reduce norepinephrine release and act as an important negative feedback mechanism. Postsynaptic stimulation decreases intracellular cAMP, thereby decreasing vascular tone.

D1 receptors are stimulated by dopamine and induce smooth muscle relaxation. Dopamine also interacts with α and β receptors to increase heart rate and stroke volume without a significant increase in blood pressure at lower doses.

V1 receptors are found primarily on vascular smooth muscle and stimulation by vasopressin promotes vasoconstriction [3].

Receptor effect of commonly used vasoactive agents

Agent

D1

D2

α1

β1

β2

V1

Dopamine

0.5-10

0.5-10

>10

3-10

Norepinephrine

Epinephrine

0.1-1.0+

0.05-0.1

0.05-0.1

Isoproterenol

0.05-2

Phenylephrine

0.1-0.5

Dobutamine

4-20

>10

Vasopressin

< 0.005 u

dose ranges are in μg/kg/min

"u" = units/kg/min

Classification

Shock is classified broadly as distributive, hypovolemic, and cardiogenic/obstructive. The proper identification of the shock state requires clinical, vital sign, and laboratory data.

What are the different types of shock?

The unifying pathway in all forms of shock involves inadequate tissue perfusion resulting in a metabolic supply-demand mismatch. The different forms of shock include distributive (septic, anaphylactic, and neurogenic), hypovolemic (hemorrhagic and severe dehydration), and cardiogenic/obstructive (cardiomyopathy, low cardiac output syndrome, cardiac tamponade, and tension pneumothorax).

Septic shock is defined as a systemic infection leading to end organ dysfunction and hypotension. Septic shock also represents the body’s exuberant response to the infection leading to additional remote end organ damage.

Neurogenic shock results from the loss of vascular tone due to a lack of sympathetic outflow (i.e., due to high cervical spine injury or after scoliosis surgery). In neurogenic shock, unlike other forms of shock, there is an unexpectedly low heart rate in the setting of hypotension.

Anaphylactic shock results from the massive release of vasoactive amines in response to an IgE-mediated immune response. Vasodilation and capillary leak lead to systemic hypotension and airway edema.

Hemorrhagic shock results from the rapid loss of intravascular volume resulting in hypovolemia and decreased perfusion. The hemorrhage can result from bleeding outside the body or within a body compartment (i.e. heavy bleeding from a scalp laceration or bleeding into a body compartment like skull, chest, abdomen, pelvis, or thigh).

Severe dehydration, resulting from vomiting, diarrhea, or increased insensible or third space losses, can also cause hypovolemia and hypotension (i.e bowel obstruction).

Cardiogenic shock results from either an intrinsic dysfunction of the myocardium (ischemia, infarction, infection, or inflammation) or extrinsic compression on the heart chambers that limits venous return (pericardial effusion leading to tamponade or tension pneumothorax).

How does the level of cardiovascular compromise indicate the degree of shock?

Shock states can be divided in two broad categories, compensated and uncompensated. In compensated shock, the child maintains a blood pressure within the normal range but with clinical signs of inadequate tissue perfusion. Decompensated shock occurs when hypotension occurs along with signs and symptoms of inadequate tissue perfusion.

The degree of cardiovascular compromise is related to the amount of lost circulating blood volume. Advanced Trauma Life Support classifies shock into four categories (I-IV) based on the degree of hemorrhage. The absolute value of blood loss is calculated based on the stereotypical 70 kg man and may not be directly applicable to the pediatric population. The percentage of blood loss is approximate.

Systemic Responses to Blood Loss in Pediatric Patients

System

Mild Blood Volume Loss (< 30%)

Moderate Blood Volume loss (30-45%)

Severe Blood Volume Loss (>45%)

Cardiovascular

Increased heart rate, weak/thready peripheral pulses, normal SBP (for age), normal pulse pressure

Markedly increased heart rate, weak/thready central pulses, absent peripheral pulses, low normal systolic blood pressure, narrowed pulse pressure

Tachycardia followed by bradycardia, very weak or absent central pulses, absent peripheral pulses, hypotension, widened pulse pressure (or undetectable diastolic blood pressure)

Central Nervous System

Anxious, irritable, confused

Lethargic, dulled response to pain

Comatose

Skin

Cool, mottled, delayed capillary refill

Cyanotic, markedly prolonged capillary refill

Pale and cool

Urine Output

Low to very low

Minimal

None

Normal urine ouput (> 2 mL/kg/hr for infants, > 1.5 mL/kg/hr for younger child, > 1 mL/kg/hr older child, and > 0.5 mL/kg/hr for adolescent)

Adapted from: Systemic Response to Blood Loss In Children, ATLS Table 10.3 8th edition of the Advanced Trauma Life Support Student Course Manual.[9]

Cardiovascular Response in Shock

Parameter

Class I

Class II

Class III

Class IV

% blood loss

up to 15 %

15-30 %

30 - 40 %

greater than 40 %

Heart rate

normal

mild tachycardia

moderate tachycardia

severe tachycardia

Blood pressure

normal or increased

decreased

decreased

decreased

Pulse pressure

normal or widened

narrow

narrow

narrow

Adapted from ATLS Committee on Trauma, American College of Surgeons 2004

Presentation

The initial assessment of shock relies on careful observation of clinical signs to distinguish between its different types (i.e.) hypovolemic, distributive, and cardiogenic/distributive shock. Low cardiac output syndrome commonly refers to transient cardiac dysfunction occurring after cardiac surgery but it can also refer to any state that leads to myocardial dysfunction.

What are the signs and symptoms of shock?

The following Table describes the various signs and symptoms of patients presenting in different types of shock.

Clinical signs of shock

Clinical signs

Hypovolemic

Distributive

Cardiogenic/obstructive

Airway patency

Depends on state - may need intubation with fluid administration

Respiratory rate

Increased

Breath sounds

Normal

Normal

Crackles, grunting

Systolic BP

Compensated versus uncompensated shock

Pulse pressure

Narrow

Variable

Narrow

Heart rate

Increased or normal

Peripheral pulses

Weak

Bounding or weak

Weak

Skin

Pale, cool

Warm or cool

Pale, cool

Capillary refill

Delayed

Variable

Delayed

Urine output

Decreased

Level of consciousness

Irritable in early stages to lethargic in late stages

Temperature

Variable

Adapted from PALS Provider Manual, 2011

How is perfusion assessed?

The clinical assessment of perfusion depends on the patient’s vital and clinical signs. For example, a child with hypovolemic shock may have cool, pale skin with weak, thready pulses and delayed capillary refill times. The vital signs may also demonstrate tachycardia, a narrowed pulse pressure, or hypotension. In contrast, a patient with distributive shock may present with warm skin, as well as normal or brisk capillary refill, in the presence of hypotension and a widened pulse pressure. Both may also have decreased urine output and altered mentation. See signs and symptoms in shock

What are the clinical measures used to diagnose low cardiac output syndrome?

While low cardiac output syndrome (LCOS) is often associated with cardiac dysfunction after cardiotomy or bypass, it actually refers to any state of reduced cardiac output that results from transient myocardial dysfunction. LCOS results from a variety of different physiological states - especially those that decrease preload (i.e. inadequate intravascular volume) or increase afterload (i.e. increased systemic vascular resistance). The conditions that impair cardiac function, either alone or in combination, include:

  1. Poor contractility
  2. Valvular stenosis or insufficiency
  3. Myocardial restriction or dysfunction related to postsurgical edema or inflammation
  4. Systemic inflammatory processes (due to cellular activation from contact with cardiopulmonary bypass circuit, mechanical shear stress on cells causing lysis, tissue ischemia-reperfusion)
  5. Cardiac tamponade

Any process causing cardiac dysfunction can impair oxygen delivery and lead to decreased tissue perfusion. One condition associated with cardiac insufficiency deserves further explanation: diastolic dysfunction related to poor myocardial compliance or relaxation. In this scenario, alterations in myocardial oxygenation produce variable levels of myocardial ischemia resulting in decreased myocardial compliance. Alternatively, ventricular interdependence may also affect diastolic function (see Pathophysiology). For example, increases in right ventricular pressure can interfere with the filling and capacity of the left ventricle. Low cardiac output syndrome after cardiopulmonary bypass can result from an intraoperative inflammatory response, myocardial ischemia, hypothermia, reperfusion injury, inadequate myocardial protection, and ventriculotomy. Patients with LCOS will have signs of inadequate cardiac index (as measured by pulmonary artery catheter or echocardiogram) and inadequate tissue perfusion (lower ScVO2 and elevated lactate). The average amount of cardiac index depression is 32% in the first six to twelve hours post cardiopulmonary bypass [3]. The assessment of the underlying etiology of LCOS is important in any shock state in which cardiac dysfunction is present.

Assessment

What are the normal vital signs based on age?

Normal vital signs for age

Heart rate (beats/minute)

age

awake

sleeping

newborn to 3 months

85-205

80-160

3 months to 2 years

100-190

75-160

2 to 10 years

60-140

60-90

older than 10 years

60-100

50-90

Respiratory rate (breaths/minute)

infant

30-60

toddler

24-40

preschooler

22-34

school age

18-30

adolescent

12-16

Hypotension (systolic, mm Hg)

term neonates (0-28 days)

< 60

infants (1 to 12 months)

< 70

1 to 10 years

< 70 + (age in years x 2)

older than 10 years

< 90

CVP

Neonate

-2 to +4 mmHg[10]

Young child-adolsecent

4-10 mmHg

Adolescent

4-10 mmHg

Measuring vital signs in children (especially very young children) can be confounded by motion, irritability, difficulties in compliance, and inappropriately-sized equipment. A child may become very apprehensive when their vital signs are being measured and this may also interfere with accurate measurement.

What cardiovascular monitoring tools are available?

The most basic cardiovascular monitoring includes heart rate, blood pressure (with mean arterial pressure), and arterial oxygen saturation. The combination of physical findings (capillary refill, skin temperature, peripheral pulses, mental status, and urine output) with vital signs is helpful in diagnosing the type of shock and the degree of compensation.

Many invasive tools exist for the assessment of shock including central venous catheters with central venous pressure (CVP) monitoring, arterial catheters with continuous blood pressure monitoring, pulmonary artery catheters with the ability to measure thermodilution, cardiac output and continuous mixed venous oxygen saturation, and esophageal Doppler probes that allow cardiac output determination. Additional methods available to measure cardiac output include stroke volume variability from arterial catheters and partial CO2 rebreathing analyzers which use the Fick principle to calculate cardiac index. Newer technologies are being developed to assess subcutaneous tissue oxygenation and end organ perfusion using the near-infrared spectrum (NIRS) and electrical bioimpedance, respectively [11].

Each monitoring modality has advantages and disadvantages. These include the degree of invasiveness, the reproducibility of measurements, the degradation of the signal quality over time, as well as the wide variability in comfort/expertise of the intensivist using the generated data. Systemic arterial catheters are common in the ICU and are used frequently for blood draws (including biochemistry, hematology and blood gas). Their main disadvantage is the degradation of signal quality over time (often in 1-2 days) and dislodgement/malposition/occlusion. Often, advanced functions such as cardiac index calculation using the stroke volume variability index is not possible in children due to lack of normative values. Pulmonary artery catheters are used les and less frequently in the ICU due to other less-invasive methods available to measure cardiac index, mixed venous oxygen saturations and blood sampling. Additionally pulmonary artery catheters can cause significant injury to the myocardium and pulmonary vasculature if used improperly.

What laboratory measurements can be used to assess the patient with shock?

Blood gas values are extremely valuable in assessing the adequacy of tissue perfusion and cellular function. Major components affecting blood pH include pCO2, lactate, and inorganic ions. Acute changes in pH are generally caused by a respiratory disorder (hypo- or hyperventilation), while changes that occur over several hours/days either have a metabolic cause or are due to metabolic compensation. Respiratory acidosis (from hypoventilation) or alkalosis (hyperventilation) if present for hours/days will lead to compensatory metabolic alkalosis and acidosis (respectively). The acid/base disorder is described by the primary (initial disorder) followed by the compensatory mechanism. For example, a patient with lactic acidemia and a low CO2 is said to have a metabolic acidosis with a compensatory respiratory alkalosis. To interpret the acid-base abnormality from the blood gas result, first note the pH and pCO2. If the direction of the derangement is the opposite for both (i.e. pH is low and pCO2 is high; or pH is high and pCO2 is low), it is considered a primary or acute respiratory acidosis or alkalosis, respectively. If the pH change and pCO2 change are in the same direction (i.e. pH is low and pCO2 is low; or pH is high and pCO2 is high), there has been respiratory compensation for a metabolic acidosis or alkalosis respectively (for more on blood gas analysis see Respiratory Care Assessment). Profoundly acidemic patients will be catecholamine unresponsive until their acid-base status has normalized.

Normal blood gas values

Type

pH

PCO2 mm Hg

PO2 mm Hg

Arterial

7.35-7.45

35-45

80-100

Capillary

7.30-7.40

35-45

-

Venous

7.25-7.35

45-55

30-50

The utility of blood gas-based bicarbonate measurements is debatable as they are calculated using the Henderson-Hasselbalch equation, rather than being directly measured. This is also true of the bicarbonate levels determined by the typical laboratory chemistry panel. The interpretation of blood gas values from different body sites should be performed with caution as there is intrinsic variability based on location. For children, the most common blood gases obtained are capillary blood gases due to the ease of sampling. A capillary blood gas (CBG) requires a small prick on the skin and a capillary tube to draw a very small aliquot of blood for analysis. The CBG measurement can determine pH, pCO2, pO2, lactate, base deficit and electrolytes. The disadvantage of the CBG is the fact it sometimes requires significant pressure on the proximal portion of the extremity in order to engorge capillaries and express the blood subsequently leading to hemolysis and/or spurious acidemia (i.e. a finger being compressed to obtain blood). Arterial blood and venous blood gases may be acquired by puncture of a vessel or with indwelling catheters. The advantage of the arterial catheter is the ability to transduce real-time blood pressure measurements. The sampled blood will allow similar measurements as capillary blood gasses but is not subject to the increased risk of hemolysis. The disadvantage of arterial cannulae is the risk of distal extremity ischemia from either occluding an end artery (radial artery) or causing a low-flow state if the catheter placed more proximally (brachial artery). Venous catheters have the advantage of providing reliable blood gas measurements without the ischemic risks of arterial cannulae. Another advantage of venous gases is the ability to calculate tissue oxygen extraction and provide a more realistic acid-base picture since the analyzed blood is postcapillary. When a clinician notices a discrepancy between blood gas measurements and the clinical status of the patient, a second type of measurement should be obtained (i.e. reassuring arterial values in an unwell patient should prompt measurement of a venous or mixed venous blood gas). Indeed, the postcapillary blood gas found in a venous sample can reveal unrecognized anaerobic metabolism and increased tissue oxygen extraction.

The presence or absence of an anion gap ((Na + K) - (HCO3 + Cl)) helps to determine the etiology of the disorder. Anion gap acidosis (defined as a gap of greater than 16 mEq/L in the setting of a normal albumin) is caused by the following: Methanol ingestion (or other toxins), uremia, diabetic ketoacidosis, propylene glycol, isoniazid, lactic acidosis, ethylene glycol, and salicylates). Non-anion gap acidosis is commonly caused by bicarbonate losses from the renal system or gastrointestinal tract. Common causes include use of carbonic anhydrase inhibitors, renal tubular acidosis, diarrhea, ureteroenteric fistula, potassium-sparing diuretics, and hyperalimentation.

Lactic acidosis is an indicator of anaerobic metabolism, but does not specify the source. In some clinical scenarios, the occlusion of venous outflow from an end-organ (as in mid-gut volvulus) will keep systemic lactate levels falsely normal or marginally elevated despite the presence of significant tissue ischemia. Lactate levels can also be elevated in the setting of diminished clearance as occurs in acute liver failure.

How is mixed venous oxygen saturation used?

The SvO2 and ScVO2 represent the ratio of DO2/VO2. Typical oxygen delivery is three to four times the oxygen demand. Thus, a typical SvO2 is approximately 75%. A low or high value is determined by the components of DO2 (SaO2, hemoglobin, and cardiac output) and VO2 (sedation, increased activity, sepsis, seizures, etc.). (see Respiratory Care Pathophysiology)

In sepsis and septic shock, the goal ScVO2 value ≥ 70% or SvO2 ≥ 65% is achieved through volume resuscitation including crystalloid, colloid and blood, along with vasopressor support to improve cardiac function. SvO2 or ScVO2 < 50% is often the point at which anaerobic cellular metabolism begins. High SvO2 or ScVO2 represents increased oxygen delivery or decreased oxygen consumption, which may be due to mitochondrial or microcirculatory failure (e.g. sepsis). The latter is an ominous finding suggesting severe cellular dysfunction that persists despite the provision of adequate oxygen. Indeed, adult patients who were initially “normoxic”, but who subsequently became hyperoxic, had a higher mortality rate than patients who were hypoxic and achieved normoxia [8].

What are the indicators of end organ dysfunction?

The indications of end organ dysfunction include the clinical manifestations of poor perfusion and biochemical findings. Increased function is required from multiple organ systems in order for the patient to compensate in shock. Therefore, decompensated shock will ultimately lead to a state of multisystem organ failure (MSOF) if not treated appropriately.

Respiratory

Increased metabolic activity requires greater gas exchange and increased respiratory activity. Minute ventilation increases in shock states and can lead to respiratory muscle fatigue. Circulating inflammatory mediators lead to pulmonary vasodilation and capillary leak. When combined with increased intravascular hydrostatic pressure, these alterations lead to increased lung water (e.g. pulmonary edema) and poor gas exchange. Since gas exchange is diffusion limited, pulmonary edema can result in hypoxia and hypercarbia and is often associated with an increased work of breathing that often necessitates assisted ventilation. Clinically, this may progress to acute lung injury (ALI) or the acute respiratory distress syndrome (ARDS), which is defined as bilateral chest infiltrates, respiratory failure and an increased oxygenation index (greater than 4) or an oxygen saturation index (greater than 5) if arterial blood gas sampling is not available, all in the face of normal left ventricular pressure [12].

Oxygenation index = (FiO2 * mean airway pressure * 100)/PaO2

Oxygen saturation index = (FiO2 * mean airway pressure * 100)/SpO2

Renal

Renal hypoperfusion leading to pre-renal azotemia and possibly cortical necrosis can occur in shock states. Renal support during shock involves the restoration of intravascular volume. Prolonged renal hypoperfusion results in renal failure which can be temporary or permanent. Support of the patient during renal failure involves renal replacement therapy with various modes of dialysis (peritoneal dialysis, continuous veno-venous hemofiltration, or hemodialysis). Dose adjustments in medications are required when renal dysfunction is identified.

Liver

Liver dysfunction results in hepatocellular damage leading to coagulopathy (synthetic function), inadequate drug and byproduct metabolism (hepatic metabolism), and cholestasis (detoxification). Supporting liver function involves the administration of coagulation factors, adjusting and monitoring drug levels, and starting enteral nutrition to promote entero-hepatic bile circulation.

Gastrointestinal

The gastrointestinal tract (especially the mucosa) is sensitive to hypoperfusion and the effects of vasopressors commonly used to support patients in shock. The splanchnic circulation is reduced in shock states in order to optimize perfusion of other vital organs. Prolonged hypoperfusion of the gastrointestinal tract leads to mucosal ischemia and injury. The mucosal barrier subsequently becomes disrupted, allowing bacterial translocation that leads to sepsis and further insults to the immune system.

Immune

An exuberant immune response is central to the pathogenesis of septic shock. Attempts to demonstrate improved survival by modifying the inflammatory response has thus far been unsuccessful. Two studies from the 1990’s suggested no benefit in survival with tumor necrosis factor α (TNFα) blockade (NORSEPT II and INTERSEPT) [13][14]. In addition to interleukins which modify and augment the immune system, the Toll-like receptor (TLR) group of proteins are central to the immune response to sepsis. The TLR family detects pathogen-associated molecular patterns (PAMPs) that are distinctive bacterial or fungal protein signatures. TLR activation leads to upregulation of TNF receptor-associated factor 6 and activation of nuclear factor кB (NF-кB) which promotes transcription of multiple pro-inflammatory cytokines. The TLRs also detect danger associated molecular patterns (DAMPs) which are proteins and bacterial cellular components like histones, free DNA, heat-shock proteins, and mitochondrial proteins. The DAMPs and PAMPs lead to stimulation of pro-inflammatory substances which result in end organ damage.

In addition to the innate immune response, there is an adaptive B and T cell-mediated response that has important consequences in sepsis. The cells involved are CD4+ T-helper cells, CD8+ cytotoxic T cells, Th17 cells, and T regulatory cells. The complex interplay of antigen presentation and cellular immune response is beyond the scope of this chapter but is important nonetheless [15].

Coagulation

Shock is associated with the activation of the coagulation system and inhibition of fibrinolysis. The result is disseminated intravascular coagulation (DIC) which is characterized by microangiopathic thrombosis, consumptive coagulopathy, and thrombocytopenia resulting in the development of microthrombi and end organ failure. (see Transfusion and Coagulation Therapy Pathophysiologyand Surgical Infection Medical Treatment)

Activation of the tissue factor pathway plays an extremely important role in this process as it leads to the generation of thrombin and the deposition of fibrin. Administration of activated protein C was purported to have mortality benefits (PROWESS trial), but this was not shown in further studies (PROWESS-SHOCK) [16][17]. Studies of severe sepsis management with protein C in children have been disappointing (RESOLVE) [18].

Neuroendocrine and Metabolic

There are several metabolic consequences that occur in the shock state. Hyperglycemia is often present as a result of decreased insulin production, increased sympathoadrenal activity, and increased production of ACTH, glucagon, and glucocorticoids. Glycogenolysis and gluconeogenesis also contribute to hyperglycemia. The presence of increased catecholamines, glucocorticoids and glucagon also lead to a significant catabolic state that produces a negative nitrogen balance as well as hypertriglyceridemia. Pediatric shock may also result in adrenal insufficiency (absolute and relative), hypothyroidism, and hypocalcemia (secondary to parathyroid dysfunction), all of which can contribute to cardiac dysfunction, poor vasomotor tone, and impaired homeostasis.

Medical Treatment

What are the initial steps in the management of shock states?

The initial management steps in shock involve the identification of the type of shock, the assessment of the degree of metabolic derangement, and the initiation of organ support.

Distributive shock (septic, anaphylactic, and neurogenic)

Initial resuscitation measures in septic shock include identifying respiratory distress and placing the patient on supplemental oxygen or noninvasive ventilation with a low threshold for initiating mechanical ventilation. In cases requiring mechanical ventilation, the guidelines recommend cardiovascular resuscitation with intravenous fluids to prevent hemodynamic collapse from the increased intrathoracic pressure associated with mechanical ventilation.

Initial therapeutic endpoints of resuscitation for septic shock include a capillary refill of less than or equal to two seconds, normal blood pressure, similarly palpated peripheral and central pulses, adequate urine output (greater than 1 mL/kg/hr), and normal mental status. Measured endpoints include ScvO2 ≥ 70% and a cardiac index between 3.3 and 6.0 L/min/m3 [19]. (see Surgical Infection Medical Therapy)

Adequate fluid resuscitation is described as 60 mL/kg of crystalloid with the initiation of inotropes after this volume has been administered or when rales or hepatomegaly develop.

Corticosteroids should be considered in fluid- and catecholamine resistant shock. The hemoglobin should also be maintained above 10 g/dL (100 g/L).

Neurogenic shock occurs in the setting of impeded or absent sympathetic tone due to high spinal injury (above level of sixth thoracic vertebrae) or sympathectomy (i.e. following scoliosis surgery). This leads to profound vasodilation and an unexpectedly normal or low heart rate. Early management of neurogenic shock requires fluid resuscitation and the initiation of vasopressors (e.g. norepinephrine) to increase chronotrophy and afterload. If a pure afterload increasing agent is used (e.g. phenylepherine), the increased pressure will cause a reflex bradycardia.

Hypovolemic (hemorrhagic and severe dehydration)

Hypovolemic shock can occur due to extrinsic or intrinsic loss of volume (i.e, exsanguination) and from severe dehydration. The main reflexes of increased diastolic tone and tachycardia will lead to narrowed pulse pressure. Without rapid intravascular fluid replacement and/or surgical control of hemorrhage (if necessary), profound hypovolemia will ensue leading to death. Children classically can bleed in five "spaces": external, cranial vault, chest, abdomen, pelvis or thigh. Adults, however, will not bleed enough into their calvarium to cause systemic hypotension.

Severe dehydration can occur from excessive vomiting or diarrhea/ostomy losses especially in small infants and children.

Cardiogenic shock (cardiomyopathy, low cardiac output syndrome)

Cardiogenic shock can occur for many reasons including dysrhythmia, abnormal valvular anatomy, and myocardial dysfunction (i.e. low cardiac output syndrome). Support requires the provision of adequate pre-load, afterload reduction, as well as augmentation of contractility and diastolic relaxation (lusitropy). Afterload reduction may be achieved with systemic vasodilators (as with nitrates or dobutamine).

In neonates who present with cardiogenic shock, a ductal dependent cardiac lesion should be suspected and prostaglandin E1 should be started early during echographic evaluation.

Obstructive shock (cardiac tamponade, tension pneumothorax)

Obstructive shock impedes venous return secondary to external compression of the heart chambers. Prompt recognition often occurs based on rapid clinical evaluation alone but bedside echocardiography or chest radiograph can be helpful in certain situations. Initial management still involves assuring adequate pre-load is present. The second step involves decompression of the obstructing lesion (pericardiocentesis followed by pericardial window for tamponade or needle decompression/chest tube placement for a pneumothorax).

What pharmacologic adjuncts are available in the management of shock?

Several vasopressors are available to manage patients in shock. Specific recommendations for the use of vasopressors and their mechanism of action are described below:

Dopamine

Dopamine is a vasoactive amine that is a precursor to norepinephrine. Dopamine is commonly used in children since it increases heart rate, contractility, and afterload. The effects of dopamine are concentration dependent with low doses affecting primarily D1 and D2 receptors to increase heart rate. Low doses also act as a natriuretic and increase urine output, and may help renal perfusion through its effects on the D1 receptor found in the kidney. Higher doses will primarily cause vasoconstriction through alpha adrenergic effects. The usual doses of dopamine range from 2-20 μg/kg/min.

Dobutamine

Dobutamine is an afterload reducing agent that increases cardiac contractility and heart rate by preventing cAMP degradation. Due to afterload reduction, dobutamine use may be associated with systemic hypotension if there is no associated increase in cardiac output. The usual dose of dobutamine is 4-20 μg/kg/min.

Epinephrine

A commonly used vasopressor, epinephrine is associated with increases in myocardial oxygen consumption, metabolic activity, temperature, and systemic and pulmonary vascular resistance. Epinephrine is useful in children as it induces an increase in heart rate and stroke volume. Epinephrine in high doses (>0.1 μg/kg/min) can reduce end-organ perfusion through its α-adrenergic effects in this dose range. Epinephrine may also be arrhythmogenic in some patients. The usual dose of epinephrine is 0.02-0.3 μg/kg/min.

Norepinephrine

Norepinephrine is used to increase systemic vascular tone and myocardial stroke volume without significant change in heart rate. It is used most effectively in distributive shock with usual doses of 0.1-3 μg/kg/min.

Phenylephrine

A pure α-agonist with a short half-life, the usefulness of phenylephrine is in the treatment of acute systemic hypotension. It can significantly increase afterload, but also leads to a reactive bradycardia. Usual doses are 0.1-0.5 μg/kg/min.

Vasopressin

Vasopressin acts on the V1 receptor and causes vasoconstriction through a different pathway than classic vasopressors by inhibiting nitric oxide synthase. Therefore, it is often used in cases of catecholamine-resistant shock. The usual dose is 0.005 units/kg/min.

Milrinone

Milrinone, a phosphodiesterase-3 inhibitor, will lead to greater intracellular cAMP concentrations, thereby improving cardiac contractility and afterload reduction. It is used commonly in cases of low cardiac output syndrome. It has an additive effect on decreasing pulmonary and systemic vascular resistance as well as lusitropy that can be useful in the context of diastolic cardiac dysfunction. The usual rate of infusion of milrinone is 0.3-0.7 μg/kg/min.

Sodium nitroprusside

Sodium nitroprusside is a systemic (arterial and venous) vasodilator agent used to augment cardiac output by decreasing afterload. It is an easily titratable medication with usual doses of 0.5-5 μg/kg/min. Higher doses (> 10μg/kg/min) or longer infusions (>72 hours) will lead to the accumulation of the metabolites cyanide and methemoglobin. Cyanide will bind strongly to cytochrome oxidase and interfere with aerobic metabolism. Cyanide toxicity is ideally treated with hydroxycobalamin, which chelates cyanide to form cyanocobalamin (Vit. B12) which is then excreted in the urine. While multiple cyanide antidotes are available, hydroxocobalamin is best due to its rapid onset of action, ease of use, and safety profile [20].

Sodium nitroprusside can also cause pulmonary vasodilation and increase intrapulmonary shunting. Vasodilatory effects on the cerebral vasculature can lead to higher intracranial pressures. It is also associated with platelet dysfunction.

Nitric oxide

Inhaled nitric oxide (iNO) is a potent pulmonary vasodilator that is used common in patients with pulmonary hypertension and low cardiac output syndrome. It works directly on the vascular endothelium and smooth muscle. Since it is inhaled, its effects are observed in better aerated areas thus decreasing intrapulmonary shunt. Caution should be used when considering iNO in the context of left ventricular dysfunction as this may lead to pulmonary edema. Typically used at 1-40 parts per million, it also may cause concentration dependent methemoglobinemia.

Levosimindan

A calcium sensitizer, levosimindan has inotropic and lusitropic effects. It is used to reduce myocardial oxygen consumption and decrease vasopressor requirements. After a bolus, it is administered as an infusion ranging from 0.1 to 0.4 μg/kg/min [1].

Vasopressors and receptors

What is the role of corticosteroids in septic shock?

Corticosteroids are recommended in patients with fluid and vasopressor refractory shock, as well as suspected or proven adrenal insufficiency by the Surviving Sepsis Collaborative. (see Surgical Infection Medical Treatment)About one quarter of children with septic shock will have absolute adrenal insufficiency, defined as cortisol levels below 18 µg/dL. Due to the high mortality of septic shock in the setting of adrenal insufficiency, corticosteroids are recommended [19].

How do you manage low cardiac output syndrome?

Once a diagnosis is made, interventions should be instituted expeditiously to improve cardiac function. One of the first steps in the management of LCOS is to reduce oxygen consumption by decreasing the metabolic rate and overall metabolic demands. This can be accomplished by

  1. maintaining normothermia or slight hypothermia
  2. administering appropriate analgesia and sedation being wary of the effects of these medications on the cardiovascular and respiratory systems
  3. initiating mechanical ventilation
  4. preventing or treating tachyarrhythmias promptly

Based on arterial blood gas analyses, electrolyte and acid-base disorders should be quickly corrected. Appropriate fluid resuscitation should be initiated to restore adequate preload. Inotropic support is also often required, but excessive use may further impair cardiac function. Furthermore, inotropes should only be used once preload has been sufficiently augmented.

Low cardiac output syndrome is managed by recognizing that the less compliant right ventricle requires adequate pre-load and inotropy (dopamine or epinephrine) along with lusitropy with milrinone (or other phosphodiesterase inhibitor). Initially, there may be significant intrapulmonary shunting of blood with depressed arterial oxygen saturations. Over the course of 2-3 days, the shunt frequently improves. Almost all patients that develop LCOS will be mechanically ventilated and it is important to recognize the impact of mean airway pressure (especially PEEP) on pulmonary capillary compression and consequent right ventricular strain. Additionally, patients post cardiopulmonary bypass have depressed thyroid hormone levels (T3) and may benefit from thyroid hormone supplementation [3].

What is the role of ECMO in the setting of shock?

Extracorporeal life support(ECLS) or extracorporeal membrane oxygenation (ECMO) is generally reserved for those patients with catecholamine refractory shock and persistent metabolic acidosis. The survival of patients who undergo ECLS for sepsis is 73% for newborns and 39% for older children. Patients undergoing venovenous ECMO had higher survival than those receiving venoarterial ECMO. Patients on ECMO for respiratory failure in the context of sepsis have a 41% survival to discharge[19]. Others have described a 47.8% mortality for non-cardiac sepsis patients receiving ECMO[21].

Medical Decision Making

How does one optimize oxygen dynamics in the setting of shock?

Cardiopulmonary interactions are important in the setting of shock. When increased oxygen demand is not met with augmented delivery, inefficient anaerobic metabolism will occur. (see Respiratory Care Pathophysiology)

Patients with hemodynamic instability will often require intubation to support the progressive respiratory failure which results from hypoperfusion and increased oxygen metabolism. The initiation of mechanical ventilation fundamentally changes intrathoracic mechanics from the typically neutral or negative pressures to positive pressures (even during exhalation). The basic tenets of mechanical ventilation are discussed elsewhere (see Respiratory Care), however, excessive intra-alveolar pressure from PEEP will compress alveolar capillaries and, therefore, increase pulmonary vascular resistance. This increases right ventricle afterload and decreases preload to the left ventricle. While increases in FiO2 may help ameliorate hypoxia, increasing mean airway pressure (largely determined by the PEEP) will markedly improve oxygenation. In a patient with shock, the typical cardiac deficiency is insufficient preload (even in cases of obstructive shock) which leads to systemic hypotension. In short, mechanical ventilation and adequate preload are essential for optimizing oxygen delivery in shock.

What is the “Surviving Sepsis Campaign” and how are its tenets implemented?

The “Surviving Sepsis Campaign” is a multinational, multi-institutional, multidisciplinary project that critically evaluates sepsis literature and provides evidence-based guidelines regarding the early management of sepsis and septic shock.

The major tenants of the project are outline in the diagram below [19]. (see Surgical Infection Medical Treatment)

surviving sepsis algorithm

Adapted from the Surviving Sepsis Campaign.

What is “goal directed” therapy as it relates to septic shock?

Goal directed therapy involves monitoring the success or failure of resuscitative efforts by using indices of perfusion (capillary refill, blood pressure, pulses, urine output, and mental status) and measures such as ScVO2 and cardiac index. As described by Rivers et al, aiming resuscitation (administration of oxygen, mechanical ventilation, crystalloids, vasopressors, and blood) to achieve an ScVO2 ≥ 70% leads to improved mortality in sepsis [4].

Pediatric considerations in early goal directed therapy include:

  1. Capillary refill ≤ 2 seconds.
  2. Normal blood pressure for age.
  3. Normal pulses (no difference between central and peripheral) and warm extremities.
  4. Urine output ≥ 1 mL/kg/hr, normal mental status.
  5. ScvO2 ≥ 70% and/or cardiac index between 3.3-6.0 L/min/m2 [19].

Complications

Inadequately treated shock includes failure to do the following:

  1. Recognize the shock state.
  2. Administer early resuscitation.
  3. Administer appropriate broad-spectrum antibiotics (in septic shock).
  4. Support failing organs.
  5. Monitor resuscitation with indices of perfusion (urine output, cardiac index, ScvO2).
  6. Recognize and treat the source of infection (in cases of septic shock).

The consequence of inadequately treated shock are progressive anaerobic metabolism that exacerbates an already compromised metabolic supply-demand mismatch. The inability to generate more than two net ATP’s per glucose molecule (in anaerobic metabolism) leads to progressive lactic acidemia. Insufficient ATP production leads to cellular organelle dysfunction and cellular death in high-metabolic end organs such as the heart, brain, and kidney. This manifests as end-organ dysfunction (depressed cardiac output, impaired mental status, and oliguria or anuria). The presence of a hypermetabolic state such as sepsis will lead to immune cell-mediated cell death and the release of inflammatory cytokines and reactive oxygen species which in turn can produce further end-organ damage (i.e. capillary leak and pulmonary edema with respiratory failure in cases of septic shock). The eventual manifestation of inadequately treated shock is progressive acidosis and death.

Outcomes

The overall mortality from septic shock for children is much lower than adults and is estimated to range between 2-10%. The in-hospital mortality rate for previously healthy children is 2% while that of the chronically ill is 8%[19]. The mortality is highly variable for other forms of shock and depends on early identification and initiation of therapy. For example, in a patient suffering from pericardial tamponade, the recognition of obstructive shock physiology and decompression of the pericardial sac is vital to patient survival.

Research and Future Directions

What is the genetic heterogeneity hypothesis?

Increasing evidence suggests that the variability in host response to sepsis and other inflammatory conditions results from genetic polymorphisms (occurrence of different alleles on the same locus within a population). These variations lead to differences in innate immunity, cytokine activity, and endothelial factors [22].

What factors result in variation of the response of patients to sepsis and other forms of shock?

Multiple factors are associated with host response and may contribute to mortality in sepsis .

Innate immunity:

Bacterial cell wall recognition molecules include lipopolysaccharide (LPS), LPS binding protein (LBP), bactericidal/permeability increasing protein (BPI), toll-like receptors (TLR), and mannose binding lectin (MBL). Mutations in these proteins or the failure to recognize certain ones (e.g., LPS), as well as hyporesponsiveness to LPS (via TLR mutation) may lead to increased mortality. Deficiency in MBL is associated with increased susceptibility to infection while FcyR (immunoglobulin G receptor) defects lead to higher mortality secondary to infection.

Cytokines and their receptors:

Cytokines involved in sepsis include TNF-a, interleukins (IL), and interferon (INF). Mutations in the alleles of TNF, IL-1 receptors, and interferon production are associated with higher mortality. Conversely, higher IL-6 production leads to improved survival.

Endothelial factors:

Plasminogen activator inhibitor (PAI), angiotensin I converting enzyme (ACE), and heat shock protein 70 (HSP-70) are some of the endothelial factors that have been studied. Of these, PAI-1 4G allele (a gene that changes the level of PAI) and ACE deletion genotypes are associated with increased mortality[22].

Patient Care Guidelines

What diagnostic and treatment algorithm should be followed in the patient in shock?

Identifying shock physiology depends on clinical findings along with invasive measures, biochemical markers and other diagnostic tests [1]. signs and symptoms in shock

The treatment of shock relies on early identification and targeted therapy. Despite the different etiologies of shock, a safe first intervention is supporting preload by administering crystalloid (60 mL/kg is usually tolerated without the development of pulmonary edema). With adequate pre-load, all shock states will initially respond (hypovolemic, distributive and cardiogenic/obstructive) to allow for investigations (labs, cultures, and imaging) and ongoing therapy.

Hypovolemic shock:

Hypovolemia due to hemorrhage is encountered in trauma patients and is managed by initial volume resuscitation while searching for and stopping the source of bleeding. In some situations, the hypovolemia leading to hypotensive shock will markedly slow bleeding to an unimpressive rate despite the patient having lost a significant volume of blood. This occurs commonly with large head lacerations where venous bleeding has usually stopped by the time the patient is evaluated in the emergency room.

Distributive shock:

Septic shock (see Surviving Sepsis Campaign algorithm below).

Neurogenic shock requires crystalloid boluses in order to augment circulating blood volume and the initiation of vasopressors (i.e. norepinehrine) to increase afterload and heart rate. The underlying neurologic injury must be identified and appropriate intervention undertaken.

Cardiogenic/Obstructive shock:

The initial assessment of cardiogenic/obstructive shock requires a determination if the dysfunction is “extrinsic” or “intrinsic”. Extrinsic dysfunction in the setting of cardiogenic shock will likely require urgent action (i.e. draining pericardial fluid). Intrinsic dysfunction involves supporting the heart to recovery or transplant.

Tension pneumothorax occurring either due to spontaneous pneumothorax or from chest trauma must be rapidly decompressed with a large bore catheter in the 2nd intercostal space along the mid-clavicular line and/or the placement of a thoracostomy tube.

Congestive heart failure may require inotropy, afterload reduction and diuretics to support the failing ventricle while correcting the underlying problem. In certain instances, despite the above, congestive failure may continue necessitating the implementation of ECLS as either a bridge to recovery or transplant (in refractory cases).

Extracorporeal life support (ECLS) should be considered in cases of refractory shock where there is ongoing profound acidosis and poor perfusion.

What algorithm is associated with the Surviving Sepsis Campaign for Pediatrics?

Please see surviving sepsis algorithm.

Perspectives and Commentary

To submit comments about this topic please contact the editors at NaT@eapsa.org.

Discussion Questions and Cases

To submit interesting cases which display thoughtful patient management please contact the editors at NaT@eapsa.org.

A 16 year old presents to the trauma bay after sustaining a gun shot wound to the abdomen. His pulse is 130 beats per minute and his blood pressure is 80/50. He is anxious but conscious and oriented. A Foley catheter drains a small amount of urine.

How can you estimate his estimated blood loss based on the information provided?

While pediatric patients tend to maintain normal vital signs in the face of hypovolemia, this adolescent is manifesting evidence of significant blood loss. His tachycardia and hypotension suggest blood loss greater than 25% of his circulating blood volume, but the maintenance of end-organ function (mental activity, renal function) suggests that the blood loss does not exceed 40%.

Describe how you would assess improvement in a patient with septic shock. Address clinical and biochemical factors you would consider.

Patients with septic shock will present with evidence of poor tissue perfusion, metabolic acidosis, as well as evidence of end-organ inury in advanced cases. Using the principles of goal directed therapy, treatment should be initiated expeditiously and the response to therapy monitored closely to ensure that these efforts are improving the clinical status of the patient.

Pediatric considerations in early goal directed therapy include:

  1. Capillary refill ≤ 2 seconds.
  2. Normal blood pressure for age.
  3. Normal pulses (no difference between central and peripheral) and warm extremities.
  4. Urine output ≥ 1 mL/kg/hr, normal mental status.
  5. ScvO2 ≥ 70% and/or cardiac index between 3.3-6.0 L/min/m2

Biochemistry: Serum pH, lactate, base deficit and bicarbonate are accepted surrogate markers of tissue perfusion that correlate with the severity of shock and the adequacy of resuscitation. These can be measured using blood gas analysis. Normalization of serum bicarbonate and lactate are associated with patient recovery in pediatric septic shock. Successful resuscitation should be accompanied by a decreasing anion gap, decreasing lactate and improving base excess.

References

  1. Marjorie J. Arca, editor. Handbook of Pediatric Surgical Critical Care. 1st ed. 2013
  2. Weiss SL et al: Global epidemiology of pediatric severe sepsis: the sepsis prevalence, outcomes, and therapies study. Am J Respir Crit Care Med 191:1147, 2015  [PMID:25734408]
  3. Fuhrman BP, Zimmerman JJ. Pediatric Critical Care: Expert Consult Premium. Elsevier Health Sciences; 2011
  4. Rivers EP et al: Early interventions in severe sepsis and septic shock: a review of the evidence one decade later. Minerva Anestesiol 78:712, 2012  [PMID:22447123]
  5. Bone RC et al: Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest 101:1644, 1992  [PMID:1303622]
  6. Goldstein B et al: International pediatric sepsis consensus conference: definitions for sepsis and organ dysfunction in pediatrics. Pediatr Crit Care Med 6:2, 2005  [PMID:15636651]
  7. Coran AG, Caldamone A, Adzick NS, Krummel TM, Laberge J-M, Shamberger R. Pediatric surgery. vol. 2. Elsevier Health Sciences; 2012
  8. Pope JV et al: Multicenter study of central venous oxygen saturation (ScvO(2)) as a predictor of mortality in patients with sepsis. Ann Emerg Med 55:40, 2010  [PMID:19854541]
  9. American College of Surgeons Committee on Trauma., Advanced Trauma Life Support Student Course Manual 8th edition
  10. Skinner JR et al: Central venous pressure in the ventilated neonate. Arch Dis Child 67:374, 1992  [PMID:1586173]
  11. Alhashemi JA, Cecconi M, Hofer CK: Cardiac output monitoring: an integrative perspective. Crit Care 15:, 2011  [PMID:21457508]
  12. Pediatric Acute Lung Injury Consensus Conference Group: Pediatric acute respiratory distress syndrome: consensus recommendations from the Pediatric Acute Lung Injury Consensus Conference. Pediatr Crit Care Med 16:428, 2015  [PMID:25647235]
  13. Cohen J, Carlet J: INTERSEPT: an international, multicenter, placebo-controlled trial of monoclonal antibody to human tumor necrosis factor-alpha in patients with sepsis. International Sepsis Trial Study Group. Crit Care Med 24:1431, 1996  [PMID:8797612]
  14. Abraham E et al: Double-blind randomised controlled trial of monoclonal antibody to human tumour necrosis factor in treatment of septic shock. NORASEPT II Study Group. Lancet 351:929, 1998  [PMID:9734938]
  15. Rossaint J, Zarbock A. Pathogenesis of multiple organ failure in sepsis. Critical ReviewsTM in Immunology n.d. 35(4):277– 291 (2015) 10.1615/CritRevImmunol.2015015461
  16. Bernard GR et al: Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 344:699, 2001  [PMID:11236773]
  17. Ranieri VM et al: Drotrecogin alfa (activated) in adults with septic shock. N Engl J Med 366:2055, 2012  [PMID:22616830]
  18. Nadel S et al: Drotrecogin alfa (activated) in children with severe sepsis: a multicentre phase III randomised controlled trial. Lancet 369:836, 2007  [PMID:17350452]
  19. Dellinger RP et al: Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med 39:165, 2013  [PMID:23361625]
  20. Hall AH, Saiers J, Baud F: Which cyanide antidote? Crit Rev Toxicol 39:541, 2009  [PMID:19650716]
  21. Ruth A et al: Extracorporeal therapies in pediatric severe sepsis: findings from the pediatric health-care information system. Crit Care 19:, 2015  [PMID:26552921]
  22. Lin MT, Albertson TE: Genomic polymorphisms in sepsis. Crit Care Med 32:569, 2004  [PMID:14758181]
  23. Murdoch IA et al: Accuracy of central venous pressure measurements in the inferior vena cava in the ventilated child. Acta Paediatr 83:512, 1994  [PMID:8086729]

Media

vasopressors and receptors

signs and symptoms in shock

surviving sepsis algorithm

Adapted from the Surviving Sepsis Campaign.

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Last updated: March 19, 2018