2236 PART 8 Critical Care Medicine

■ DETERMINANTS OF OXYGEN DELIVERY

Because shock is the clinical manifestation of inadequate oxygen

delivery compared with cellular needs, we will review determinants of

oxygen delivery (DO2

). Disease processes affecting any of the components of oxygen delivery have the potential to lead to the development

of shock. Disturbances to key determinants of oxygen delivery form the

basis of the four major shock types described below.

The two major components of DO2

 are cardiac output (CO) and

arterial oxygen content (CaO2

):

DO2

 = CO × CaO2

The two components of CO are heart rate (HR) and stroke volume

(SV), which can be substituted in the above equation as

DO2

 = (HR × SV) × CaO2

The major determinants of SV are preload, afterload (systemic vascular resistance, SVR), and cardiac contractility. The relationship can

be represented as

SV α (Preload × Contractility)/SVR

In this equation, preload refers to the myocardial fiber length before

contraction (the ventricular end-diastolic volume). Contractility refers

to the ability of the ventricle to contract independent of preload and

afterload. The SVR represents the afterload, or the force against which

the ventricle must contract.

The CaO2

 is composed of oxygen carried by convection with hemoglobin and oxygen dissolved in blood, given as

CaO2

 = (Hb × 1.39 × SaO2

) + (PaO2

 × 0.03)

A disease process that affects these variables (HR, preload, contractility, SVR, SaO2

, or Hb) has the potential to reduce oxygen delivery

and cause cellular hypoxia. Each of the shock types described below

has a distinctive physiologic hemodynamic profile corresponding with

alterations in one of the variables affecting oxygen delivery described

above.

■ CLASSIFICATION OF SHOCK

While there is a heterogeneous list of specific conditions that can cause

shock, it is helpful to categorize these processes into four major shock

types based on the primary physiologic derangement leading to reduced

oxygen delivery and cellular hypoxia. The four major shock types are

distributive, cardiogenic, hypovolemic, and obstructive. Table 303-1

outlines these major shock types as well as specific disease processes

that can result in that physiologic derangement. Each shock type has

a distinct hemodynamic profile (Table 303-2). Familiarity with the

major shock types and their unique hemodynamic profile is essential

so that when evaluating a patient presenting with shock, the clinician

can use the history, physical examination, and diagnostic testing to

determine the type of shock present and promptly begin appropriate

initial therapy to restore oxygen delivery.

Distributive Shock Distributive shock is the condition of reduced

oxygen delivery where the primary physiologic disturbance is a

reduction in SVR. It is unique among the types of shock in that there

is a compensatory increase in CO (Table 303-2). The central venous

pressure (CVP) and pulmonary capillary wedge pressure (PCWP)

are usually reduced. The most common cause of distributive shock

is sepsis. Sepsis has recently been redefined as the dysregulated host

response to infection resulting in life-threatening organ dysfunction.

When this process is accompanied by persistent hypotension requiring vasopressor support (despite adequate volume resuscitation), it is

classified as septic shock. Other processes that are manifest as cellular

hypoxia related to a primary reduction of SVR include pancreatitis,

severe burns, and liver failure. Anaphylaxis is predominantly an IgEmediated allergic reaction that can rapidly develop after exposure to

an allergen (food, medication, or insect bite), in which there is a profound distributive type of shock possibly mediated through histamine

release. In this setting, there is evidence of both venous and arterial

vasodilation. Studies have demonstrated extravasation of up to 35% of

TABLE 303-1 Physiologic Classification of Shock

1. Distributive

a. Septic shock

b. Pancreatitis

c. Severe burns

d. Anaphylactic shock

e. Neurogenic shock

f. Endocrine shock

Adrenal crisis

2. Cardiogenic

a. Myocardial infarction

b. Myocarditis

c. Arrhythmia

d. Valvular

i. Severe aortic valve insufficiency

ii. Severe mitral valve insufficiency

3. Obstructive

a. Tension pneumothorax

b. Cardiac tamponade

c. Constrictive pericarditis

d. Pulmonary embolism

e. Aortic dissection

4. Hypovolemic

a. Hemorrhagic

i. Trauma

ii. GI bleeding

iii. Ruptured ectopic pregnancy

b. GI losses

c. Burns

d. Polyuria

i. Diabetic ketoacidosis

ii. Diabetes insipidus

Abbreviation: GI, gastrointestinal.

TABLE 303-2 Hemodynamic Characteristics of the Major Types of

Shock

TYPE OF SHOCK CVP PCWP

CARDIAC

OUTPUT

SYSTEMIC VASCULAR

RESISTANCE

Distributive ↓ ↓ ↑ ↓

Cardiogenic ↑ ↑ ↓ ↑

Obstructive ↑ ↓↑ ↓ ↑

Hypovolemic ↓ ↓ ↓ ↑

Abbreviations: CVP, central venous pressure; PCWP, pulmonary capillary wedge

pressure.

the circulating blood volume within 10 min. Patients with severe brain

or spinal cord injury may have a reduction of SVR related to disruption of the autonomic pathways that regulate vascular tone. In these

patients, there is pooling of blood in the venous system with a resulting

decreased venous return and decreased CO. A final category of patients

who present with distributive shock consists of those with adrenal

insufficiency. Adrenal insufficiency may be related to chronic steroid

use, medications (immune checkpoint inhibitor-associated primary

adrenal insufficiency), metastatic malignancy, adrenal hemorrhage,

infection (tuberculosis, HIV), autoimmune adrenalitis, or amyloidosis. In conditions of stress (such as infection or surgery), the deficit

may become apparent with an inability to increase cortisol leading to

vasodilation as well as aldosterone deficiency-mediated hypovolemia.

Cardiogenic Shock Cardiogenic shock is characterized by reduced

oxygen delivery related to a reduction in CO owing to a primary cardiac

problem. There is usually a compensatory increase in SVR in cardiogenic shock. When the cardiac process (e.g., myocardial infarction)

2237Approach to the Patient with Shock CHAPTER 303

affects the left ventricle (LV), there will be elevation of the PCWP and

when it affects the right ventricle (RV), the CVP will be elevated. As

detailed above, the CO (and accordingly the DO2

) can be reduced by

alterations in the SV or HR. In cardiogenic shock, the SV may be

reduced by processes that affect myocardial contractility (myocardial

infarction, ischemic cardiomyopathies, and primary myocarditis) or

mechanical valvular disease (acute mitral insufficiency or aortic insufficiency). Both bradyarrhythmias and tachyarrhythmias (from either

an atrial or ventricular source) may have associated hemodynamic

consequences with a reduction in CO.

Hypovolemic Shock Hypovolemic shock encompasses disease

processes that reduce CO (and oxygen delivery) via a reduction in

preload. In addition to the reduced CO, this shock type is characterized by an elevated SVR and low CVP and PCWP related to decreased

intravascular volume. Any process causing a reduction in intravascular

volume can cause shock of this type. Hypovolemic shock is most commonly related to hemorrhage, which may be external (secondary to

trauma) or internal (most commonly upper or lower gastrointestinal

[GI]) bleeding. Hypovolemic shock can also be seen with nonhemorrhagic processes. Examples include GI illnesses causing profound

emesis or diarrhea, renal losses (osmotic diuresis associated with

diabetic ketoacidosis or diabetes insipidus), or skin loss (severe burns,

inflammatory conditions such as Stevens-Johnson).

Obstructive Shock Obstructive shock is also characterized by a

reduction in oxygen delivery related to reduced CO, but in this case

the etiology of the reduced CO is an extracardiac pulmonary vascular

or mechanical process impairing blood flow. Specific processes that

can impede venous return to the heart and reduce CO include tension

pneumothorax (PTX), cardiac tamponade, and restrictive pericarditis.

Similarly processes that obstruct cardiac outflow, such as pulmonary

embolism, venous air embolism, fat embolism (right heart), or aortic

dissection (left heart), are included in this shock type category.

Mixed Shock The types of shock outlined in this classification

scheme are not mutually exclusive; not uncommonly, a patient will

present with more than one type of shock. The initial physiologic disturbance leading to reduced perfusion and cellular hypoxia in sepsis

is distributive shock. In this setting, a sepsis-induced cardiomyopathy

can develop, which reduces myocardial contractility, thus producing a

cardiogenic component to what now would be described as a mixed

type of shock.

Undifferentiated Shock Upon initial presentation, many patients

have undifferentiated shock in which the shock type and specific disease process are not apparent. Using the history, physical examination,

and initial diagnostic testing (including hemodynamic monitoring),

the clinician attempts to classify a patient with one of the types of shock

outlined above so that proper therapy can be initiated to restore tissue

perfusion and oxygen delivery.

The epidemiology of shock is dependent on the clinical setting. A

2019 study of the etiology of shock in the emergency department (ED) of

a university hospital in Denmark revealed that among 1553 patients with

shock, 30.8% had hypovolemic shock, 27.2% had septic shock, 23.4% had

distributive nonseptic shock, 14% had cardiogenic shock, and only 0.9%

had obstructive shock. In the ICU setting septic shock predominates. A

2010 study (from eight hospitals) demonstrated that 62% of ICU shock

patients had septic shock, 16% hypovolemic shock, 15% cardiogenic

shock, and only 2% obstructive shock. Among specialty ICUs, the

distribution of shock type differentiates further. In the medical ICU,

the largest number of patients have distributive shock related to sepsis.

In contrast, a 2019 study of shock in 16 cardiac ICUs found that 66%

of shock patients were assessed as having cardiogenic shock. Mortality

associated with shock is high but differences are seen between the

types of shock. Septic shock and cardiogenic shock have the highest

mortality rates. In the ED study from Denmark, the 90-day mortality of

the septic and cardiogenic patients was 56.2% and 52.3%, respectively.

These numbers coincide with other studies. Hypovolemic shock is

associated with a lower mortality rate.

■ STAGES OF SHOCK

Regardless of type, shock progresses through a continuum of three

stages. These stages are compensated shock (preshock), shock (decompensated shock), and irreversible shock. During compensated shock,

the body utilizes a variety of physiologic responses to counteract

the initial insult and attempts to reestablish the adequate perfusion

and oxygen delivery. At this point, there are no overt signs of organ

dysfunction. Laboratory evaluation may demonstrate mild organ dysfunction (i.e., elevated creatinine or troponin) or a mild elevation of

lactate. The specific compensatory response is determined by the initial

pathophysiologic defect. In early sepsis with reduction in SVR, there is

a compensatory rise in HR (and CO). With early hemorrhagic volume

loss, there will be a compensatory increase in SVR and HR. As the

host compensatory responses are overwhelmed, the patient transitions

into true shock with evidence of organ dysfunction. Appropriate interventions to restore perfusion and oxygen delivery during these initial

two phases of shock can reverse the organ dysfunction. If untreated

the patient will progress to the third phase of irreversible shock. At

this point, the organ dysfunction is permanent and often the patient

progresses to MSOF.

■ EVALUATION OF THE PATIENT WITH SHOCK

The initial evaluation of the patient with shock utilizes the history,

physical examination, and diagnostic testing toward two specific aims.

The first aim is confirmation of the presence of shock. Given the

reversible nature of the organ dysfunction in early shock, it is important that the clinician has a high clinical suspicion for this condition.

The possibility of shock should be considered in all patients presenting

with new organ dysfunction or hypotension. This early recognition of

the presence of shock is an essential tenet of shock care (Table 303-3).

The second aim of the initial assessment (history, physical examination, and diagnostic testing) is to identify either a specific shock

etiology or to determine the type of shock present. In some patients,

the type of shock and etiology will be readily apparent (for example the

patient with hypovolemic shock from a gunshot wound), but in many

cases the cause is determined only after further evaluation. We will

discuss the role of the history, physical examination, and diagnostic

testing toward these specific aims. While the assessment of shock etiology is ongoing, the initiation of therapy should not be delayed while

the final diagnosis is being determined. Evaluation of shock etiology

and initiation of therapy should be simultaneous.

History Obtaining a concise, focused history is essential. If the

patient is unable to provide a history, ancillary information from family or friends accompanying the patient, emergency medical services

(EMS) personnel, or nursing facility (if applicable) should be obtained,

and a brief chart review should be performed. Oftentimes a patient

with shock will present with nonspecific symptoms such as weakness,

malaise, or lethargy. When focal symptoms are reported, it is important

to determine whether the symptom is related to the primary process

causing shock or a result of inadequate oxygen delivery for cellular

metabolic needs. For example, a patient with distributive shock from

urosepsis could report chest discomfort in the setting of tissue hypoxia.

As the history is being obtained, the clinician must be attentive to any

details indicating new organ dysfunction. The most easily identified

new organ dysfunction from the history is the presence of a newly

altered mental status or decrease in urine output (oliguria). In some

cases, the type of shock (and the specific disease process) is apparent

from the initial history. Patients with distributive shock from sepsis

may present with fever and a history suggesting a focal site of infection

TABLE 303-3 Key Principles in the Treatment of Shock

1. Recognize shock early

2. Assess for type of shock present

3. Initiate therapy simultaneous with the evaluation into the etiology of shock

4. Involve all members of the multidisciplinary team

5. Aim of therapy is to restore oxygen delivery

6. Identify etiologies of shock that require additional lifesaving interventions

2238 PART 8 Critical Care Medicine

(cough, sputum production, abdominal discomfort, diarrhea, flank

discomfort, or dysuria). Anaphylactic distributive shock may be suggested by the onset of pruritis, hives, dyspnea, and new facial edema

after exposure to common allergens. Cardiogenic shock may be identified by the onset of exertional chest discomfort. The patient with

significant arrhythmia may have an initial complaint of palpitations

with syncope or presyncope. Hypovolemic shock may be identified in

patients who present with a history of trauma (blunt or penetrating)

or GI bleed (hematemesis, melena, or bright red blood per rectum).

A patient with hypertension and tearing chest or back pain may be

presenting with acute aortic dissection and obstructive-type shock.

Asymmetric leg swelling, acute onset chest pain with dyspnea in the

setting of immobility, and/or underlying malignancy raises concern for

obstructive shock due to pulmonary embolism.

For most patients, the specific etiology will be less clear but the

history can be helpful in raising the likelihood of a particular type of

shock. As an example, a patient with a preexisting immune dysfunction

or medication-induced neutropenia may present with hypoperfusion

and new organ dysfunction, in which the clinician must have a high

suspicion for septic shock. Similarly, a patient with extensive cardiac

disease requires a higher suspicion for cardiogenic shock.

Physical Examination The physical examination can assist in

the identification of shock (in both the compensated stage prior to

overt evidence of organ dysfunction and decompensated stage). The

examination also can add insight into what type of shock is present

(distributive, cardiogenic, hypovolemic, or obstructive).

Shock is most commonly seen in the setting of circulatory failure.

Vital signs are frequently abnormal. In most cases, this is manifest

as hypotension (a systolic blood pressure [SBP] <90 mmHg or mean

arterial pressure [MAP] <65 mmHg), but isolated blood pressure

measurements below these values do not define shock. Many patients

may have underlying conditions such as peripheral vascular disease or

autonomic dysfunction or are on medications that cause longstanding

low blood pressure without any evidence of organ dysfunction. Alternatively, patients with underlying hypertension may develop shock and

organ dysfunction at higher blood pressures. Evaluating the patient’s

current blood pressure in relation to the patient’s baseline blood pressure and observing hemodynamic trends over short time intervals are

more useful than an absolute SBP or MAP value. Tachycardia is a common compensatory mechanism in shock. The absence of an elevated

heart rate does not exclude shock as patients with underlying cardiac

conduction system disease or on home nodal blocking medications

may have a diminished or absent tachycardic response. Alternatively,

one cannot be reassured by an elevated heart rate without hypotension,

as many younger patients can compensate an extended period of time

before developing hypotension. Tachypnea is another vital sign abnormality seen early in shock as the body compensates for a developing

metabolic acidosis. While these early compensatory responses are

nonspecific, the clinician should recognize these findings early as they

may herald the development of end-organ dysfunction if perfusion and

oxygen delivery are not restored.

The physical examination can confirm the presence of shock

prior to the return of laboratory testing. The central nervous system

(CNS), kidney, and skin are the organ systems most easily assessed for

evidence of organ dysfunction. These organ systems are considered

the “windows” through which we can identify organ dysfunction.

Decreased oxygen delivery to the brain is manifest as confusion and

encephalopathy. In the early stage of shock, the body will redirect

blood flow to the CNS to maintain adequate perfusion. In the patient

with shock and altered mental status, all the usual compensatory

mechanisms have been outstripped by the magnitude of shock pathophysiology. New encephalopathy represents decompensated shock.

To assess renal function during the physical examination, one should

evaluate the patient’s urine output since the time of presentation. If

not already present, a urinary catheter should be placed for accurate

hourly assessment of urine output. In patients with normal baseline

renal function, oliguria (<0.5 mL/kg per h) may indicate shock. Finally,

cold and clammy skin is a sign of hypoperfusion with compensatory

vasoconstriction to redirect blood flow centrally (brain, heart). Progressive vasoconstriction can lead to mottling of the skin. Capillary

refill time (CRT) is the time it takes for color to return to an external

capillary bed after pressure is applied. In the setting of shock the CRT

is delayed.

Many components of the examination provide insight into hemodynamics and assist in elucidating the type of shock present. The

physical examination may be used to differentiate shock with

high CO (distributive) from that with low CO (cardiogenic shock,

hypovolemic shock, and obstructive shock). Examination findings

suggestive of high-output shock (distributive) include warm peripheral extremities, normal capillary refill (<2 s), and large pulse pressure

(with low diastolic pressure). Alternatively, cool extremities, delayed

capillary refill, or weak pulses (with narrow pulse pressure) would

indicate low CO forms of shock. Among types of shock with low CO,

the examination can be used to distinguish between conditions with

increased intravascular filling pressure (cardiogenic shock, obstructive shock) and intravascular volume depletion (hypovolemic shock).

Elevation of jugular venous pressure (JVP) and presence of peripheral

edema are seen with high right-sided cardiac pressures. The JVP

may be elevated in cardiogenic shock (with right-sided failure) and

obstructive shock (pulmonary embolism) but reduced (JVP <8 cm)

in hypovolemic shock. Similarly, patients with cardiogenic shock and

right-sided cardiac dysfunction may have peripheral edema, but this

is not an examination finding present in acute hypovolemic shock.

Distinguishing cardiogenic from obstructive shock can also be aided

by physical examination. Rales on pulmonary auscultation may be

related to left-sided cardiac dysfunction. The presence of cardiogenic

shock would be further supported by an S3 gallop. One must remember, however, that it is well established that patients with chronic

heart failure do not present with the classical findings of acute heart

failure.

At times, the physical examination may identify the specific etiology of shock. This is particularly helpful in the patient who cannot

provide a detailed history. The examination may demonstrate the site

of an untreated infection (cellulitis, abscess, infected pressure injury, or

focal). The examination may reveal a brady- or tachyarrhythmia leading to development of shock. Similarly, large ecchymosis may indicate

a significant bleed related to trauma or spontaneous retroperitoneal

bleeding. The rectal examination may reveal GI hemorrhage. Pulsus

paradox and elevated JVP may suggest the presence of cardiac tamponade. Patients with a tension PTX may have a paucity of breath sounds

over the affected side, deviation of the trachea away from the affected

side, or subcutaneous emphysema.

Combinations of easily assessed examination components have been

organized into a scoring system to identify high-risk patient populations. The shock index (SI) is defined as the HR/systolic blood pressure

(SBP) with a normal SI being 0.5–0.7. An elevated SI (>0.9) has been

proposed to be a more sensitive indicator of transfusion requirement

and of patients with critical bleeding among those with hypovolemic

(hemorrhagic) shock than either HR or BP alone. The SI may also

identify patients at risk for postintubation hypotension. This concept

of use of a clinical score to identify at-risk patients has been extended

to patients with distributive shock from sepsis. The quick Sequential

Organ Failure Assessment (qSOFA) score is a rapid assessment scale

that assigns a point for SBP <100, respiratory rate >22, or altered mental status (Glasgow Coma Scale <15). A qSOFA ≥2 (with a concern

for infection) is associated with a significantly greater risk of death or

prolonged ICU stay. The Third International Consensus Definition of

Sepsis has recommended the use of the qSOFA to identify the most

acutely ill subset of patients with sepsis (longer length of stay, increased

need for ICU admission, and higher in-hospital mortality).

Diagnostic Testing Laboratory evaluation should be initiated

promptly in all patients with suspected shock. The laboratory evaluation is directed toward the dual aim of assessing the extent of endorgan dysfunction and of gaining insight into the possible etiology of

shock. Table 303-4 outlines the recommended initial laboratory evaluation of the patient with undifferentiated shock.

2239Approach to the Patient with Shock CHAPTER 303

BLOOD TESTS Evaluation of blood urea nitrogen (BUN), creatinine,

and transaminases provides an assessment of the extent of end-organ

dysfunction related to shock. Urine electrolytes with subsequent calculation of the fractional excretion of sodium (FENa) or fractional excretion of urea (FEUrea) may indicate states of hypovolemia or decreased

effective circulating volume. Elevation of alkaline phosphatase may

suggest biliary obstruction and may thereby identify a source of infection in patients with distributive shock. Elevation of cardiac enzymes

can indicate a primary cardiac problem with myocyte damage related

to ischemia, myocarditis, or a pulmonary embolism. An elevation of

the white blood cell count may raise suspicion for an infective process,

but this is certainly not diagnostic; an accompanying left shift may

improve the sensitivity of this measure. Reduction in hemoglobin and

hematocrit are seen in patients with hemorrhagic hypovolemic shock

(although an actively bleeding patient may have normal values on

initial presentation). Human chorionic gonadotropin (hCG) testing

is indicated when there are concerns about hypovolemic hemorrhagic

shock or septic shock. While the extent of acidosis may be determined

with a venous blood gas (VBG), if there is accompanying hypoxemia

an arterial blood gas should be obtained. For patients with undifferentiated shock, there should always be a high index of suspicion for

possible infection. Urinalysis and urine sediment should be sent to

evaluate for pyuria. Blood cultures, urine cultures, and sputum cultures

should be obtained. Radiographic evaluation should be directed to seek

sources of infection suggested by the history and physical examination.

Lactate measurement has a role in the diagnosis, risk stratification,

and, potentially, the treatment of shock. Increased lactate (hyperlactemia) and lactic acidosis (hyperlactemia and pH <7.35) are common

in shock. Lactate is a product of anaerobic glucose metabolism. In

glycolysis, the enzyme phosphofuctokinase metabolizes glucose to

pyruvate. Under aerobic conditions, the pyruvate is then converted

(in the mitochondria) to acetyl CoA and enters the Krebs cycle with

resulting ATP generation through oxidative phosphorylation. In the

setting of cellular hypoxia, the Krebs (tricarboxylic acid) cycle cannot

oxidize the pyruvate, and thus the pyruvate is converted to lactate by

the enzyme lactate dehydrogenase. Under normal conditions, lactate is

produced from skeletal muscle, brain, skin, and intestine. In the setting

of reduced oxygen delivery and cellular hypoxia, the amount of lactate

produced from these tissues increases (and other tissue can begin

to produce lactate). While most of the studies have been performed

in patients with septic shock, there is evidence that elevated lactate

correlates with a worse outcome. A recent systematic literature review

evaluating the role of lactate measurement in a variety of critically ill

populations supported the value of serial lactate measurements in the

evaluation of critically ill patients and their response to therapy.

Electrocardiogram The electrocardiogram (ECG) is an essential part of the evaluation of the patient with shock. There may be a

bradycardia or tachycardic arrhythmia causing a reduction in CO.

ST segment elevation myocardial infarction may be identified. The

presence of the S1 Q3 T3 pattern would raise concerns for pulmonary

embolism. Reduced voltage in the presence of electrical alternans raises

the possibility of pericardial tamponade.

Chest X-Ray The chest x-ray (CXR) can demonstrate a new

focal alveolar or interstitial infiltrate suggesting an infectious process

(and possible distributive septic shock). Bilateral cephalization of the

pulmonary vasculature, peribronchial cuffing, septal thickening, and

intralobular thickening are typical of pulmonary edema and a cardiogenic process. A widened mediastinum raises the possibility of a

pericardial effusion. The CXR can be used to confirm or exclude the

presence of a pneumothorax. CXR findings are neither sensitive nor

specific for pulmonary embolism. In select cases there may be the

finding of a peripheral wedge-shaped opacity indicating pulmonary

infarction, an enlarged pulmonary artery, or regional vascular oliguria.

A chest computed tomography (CT) angiogram may be needed to

exclude the diagnosis of PE.

Point-of-Care Ultrasound Point-of-care ultrasound (POCUS)

has an increasing role in the evaluation and treatment of shock.

Benefits of POCUS include its low cost, rapidity with which it can be

obtained, and noninvasive nature. It has diagnostic value in patients

who present with undifferentiated shock. In patients with mixed shock,

it can give insight into the relative contribution of the individual shock

types. Several structured protocols exist for evaluation of undifferentiated shock including the Rapid Ultrasound for Shock and Hypotension

(RUSH), the Abdominal and Cardiothoracic Evaluation with Sonography in Shock (ACES), and Sequential Echographic Scanning Assessing

Mechanism Or Origin of Shock of Indistinct Cause (SESAME). These

protocols share common components to assess cardiac function,

evaluate intravascular volume status, and identify fluid collections.

In a rapid and protocolized manner, views are obtained of the heart,

lungs, pleural space, inferior vena cava, abdominal aorta, abdomen,

and pelvis. Some of the protocols extend to view the deep veins of the

lower extremity.

POCUS transthoracic echocardiography (TTE) is central to the

POCUS evaluation of shock. TTE utilizes both the two-dimensional

(2D) and M mode. It focuses the examination on LV function, RV

function, and pericardium. The 2D mode can evaluate LV size, wall

thickness, and ventricular function. Ventricular size and thickness can

suggest longer standing cardiac processes. Evaluation of LV function

through estimation of left ventricular ejection fraction (LVEF) can

identify shock with globally reduced LV function or regional wall

motion abnormalities. Similarly, the assessment of RV function also

examines RV size and wall thickness (to identify conditions such as

elevated pulmonary pressures or suggest pulmonary embolism) and

also evaluates the patient for pericardial tamponade. Two-dimensional

echocardiography can also be used to assess valve function, including

acute processes, such as mitral valve rupture. Assessment of valvular

function is often an evaluation that requires a higher skilled practitioner. The performance of the bedside echocardiogram by the critical

care practitioner does not replace formal examination by the echocardiography service or assessment by a cardiologist.

Another component of POCUS includes IVC evaluation to assess

intravascular filling. A collapsible IVC at the end of expiration suggests

reduced intravascular volume. Evaluation of the pleural space for effusion has been a longstanding role of ultrasound. POCUS pleural space

evaluation, is more sensitive than CXR for identifying a PTX. Defined

views of the abdomen can identify significant intrabdominal fluid

collections indicating hemorrhage or possible infection. Examinations

that extend to the proximal deep veins of the lower extremity can

identify deep venous thrombosis raising the possibility of pulmonary

embolism as an etiology of shock. While POCUS can aid in determining the etiology of shock, a 2018 international randomized controlled

study utilizing POCUS to evaluate undifferentiated shock in 273 emergency department patients did not demonstrate a benefit in survival at

30 days or hospital discharge. In addition, there was no difference in

amount of IVF administered, inotrope use, CTs ordered, or need for

ICU care of length of stay.

One significant limitation of POCUS is that performance and

interpretation of testing is operator-dependent. Familiarity with basic

ultrasound techniques and interpretation is now expected in the emergency department and critical care setting. Accordingly, competency

TABLE 303-4 Initial Laboratory Evaluation of Undifferentiated Shock

1. Lactate

2. Renal function tests

3. Liver function tests

4. Cardiac enzymes

5. Complete blood count (with differential)

6. PT, PTT, and INR

7. Pregnancy test

8. Urinalysis and urine sediment

9. Arterial blood gas

10. ECG

11. CXR

Abbreviations: CXR, chest x-ray; ECG, electrocardiogram; INR, international

normalized ratio; PT, prothrombin time; PTT, partial thromboplastin time.

2240 PART 8 Critical Care Medicine

standards have been proposed for emergency medicine and critical

care providers in both basic and advanced POCUS techniques.

■ INITIAL TREATMENT OF SHOCK

Because shock can progress rapidly to an irreversible stage, a key principle in shock management is to initiate treatment for circulatory shock

simultaneous with efforts to elucidate shock etiology (Table 303-3).

If the initial history, physical examination, and laboratory evaluation

have identified the shock type or the specific etiology, then therapy is

directed to reverse the underlying physiologic abnormality causing the

hypoperfusion and reduced oxygen delivery. To expedite care, all members of the multidisciplinary team (providers, nurses, pharmacists, and

respiratory therapists) must be involved in the development and delivery of care. Details of the optimal care for the specific disease processes

leading to shock may be found in other chapters of this text. As many

patients will present with undifferentiated shock, in this section we will

discuss treatment directed at the patient with undifferentiated shock.

At the conclusion of this section, we will highlight etiologies of shock

that require initiation of lifesaving specific therapy.

The development of shock is a medical emergency, and optimal

therapy involves the involvement of a multidisciplinary team to allow

the evaluation and initiation of therapy to begin simultaneously.

Patients must be treated in a setting where adequate resources are available to support frequent reassessments and invasive monitoring. Most

patients with shock should be cared for in an ICU setting.

A key early consideration is to ensure adequate intravenous access.

Placement of two peripheral venous catheters (16G or 18G) will

provide initial access for the aggressive volume resuscitation that is

required for patients with distributive or hypovolemic shock. If there

is concern for distributive shock with sepsis, this IV access will also

permit prompt antibiotic administration. For patients with ongoing

hypotension despite adequate volume resuscitation, placement of a

central venous catheter (CVC) is indicated to provide therapy with

vasopressors and inotropes. The CVC will provide a mechanism for

hemodynamic monitoring (CVP) as well as a means to obtain central venous oxygen saturations (ScvO2

). The ScvO2

 is a surrogate of

mixed venous oxygen saturation, and thus can provide insight into

the adequacy of oxygen delivery. Central venous access using a sheath

will provide an access point for placement of a Swan-Ganz catheter if

more detailed assessment of hemodynamic measurements is required

(PCWP, CO, and SVR). If the patient presents critically ill or in the

midst of cardiopulmonary arrest, the quickest method of obtaining

central access will be through the use of an intraosseous device. Placement of an arterial line allows for intravascular measurement of blood

pressure and continuous determination of MAP. In addition, it can

provide insight into the adequacy of volume resuscitation through the

measurement of systolic or pulse pressure variation. The arterial line

will provide access for determination of arterial oxygen tension, which

is helpful since peripheral oximetry measurements (SpO2

) can be

unreliable in states of tissue hypoperfusion. The arterial line facilitates

repeated measures of acid base status or lactate to assess the impact

of treatment. All patients with shock should have a urinary catheter

placed to permit hourly assessment of renal function as another potential indication of the adequacy of resuscitation.

Volume Resuscitation Initial volume resuscitation has the aim

of restoring tissue perfusion and is crucial to optimal shock therapy.

Assessment of current intravascular volume status and determination

of the optimal amount of volume resuscitation are challenging. The

physiologic goal of volume resuscitation is to move the patient to the

nonpreload-dependent portion of the Starling curve. Most patients

with any of the four shock types will benefit from an increase in intravascular volume. For patients with distributive shock, the need for early

aggressive volume replacement is well established. In the past, the use

of early goal-directed therapy (EGDT) in septic shock targeted specific

measures of CVP, MAP, and SvO2

 to guide volume resuscitation (and

initiation of vasopressors and inotropes). More recent studies have

demonstrated that targeted resuscitation using invasive monitoring is

not required, but in all of these studies patients in the “usual care” arms

of the study received early initial volume resuscitation. For patients

with suspected septic shock, a minimum of 30 mL/kg is recommended

by the Surviving Sepsis Campaign. While the need for volume resuscitation is most apparent for patients with distributive or hypovolemic

shock, even patients with cardiogenic shock may benefit from cautious

volume replacement. In these patients, there should be a careful assessment of volume status prior to volume administration.

In general, volume replacement therapy should be given as a bolus

with a predefined endpoint to assess the effect of the volume resuscitation. Most commonly, the volume resuscitation will begin with crystalloid. In patients with hypovolemic shock due to ongoing hemorrhage,

volume replacement with packed red blood cells is warranted. In cases

of massive transfusion, platelets and fresh frozen plasma should be

provided to offset the dilution of these components during volume

replacement. Because hemoglobin is a key determinant of CaCO2

, red

cell administration may be a part of volume replacement even without

hemorrhage in order to optimize oxygen delivery if hemoglobin content is <7 g/dL.

Assessment of intravascular volume status (and the adequacy of

volume resuscitation) begins with the physical examination (described

above). The passive leg raise (PLR) test can predict responsiveness to

additional intravenous fluid (IVF) by providing the patient with an

endogenous volume bolus. While the patient is resting in a semirecumbent position at a 45° angle, the bed is placed in Trendelenburg

position such that the patient’s head becomes horizontal and the

legs are extended at a 45° angle. There is then an immediate (within

1 min) assessment of changes in CO (or pulse pressure variation as a

surrogate). It is important to emphasize that one does not merely look

for changes in blood pressure; if the shock patient is mechanically

ventilated there is the option of looking at changes in SV variation (or

pulse pressure variation) during the respiratory cycle to assess volume

responsiveness. A >12% SV variation suggests a volume-responsive

state. This measurement requires that the patient be in a volume cycle

mode of ventilation, without breath-to-breath variations in intrathoracic pressure and without arrhythmias. A final caveat to the use

of these parameters to assess volume status is that these studies are

performed on patients being ventilated with tidal volumes larger than

currently used to minimize ventilator-induced lung injury.

There is also increased use of echocardiography to assist in determination of intravascular fluid status, with a variety of static and dynamic

variables that the trained operator can assess. The most commonly used

parameters to assess adequacy of volume resuscitation are inferior vena

cava (IVC) diameter and IVC collapse. Alternatively, serial assessments

of LV function can be performed while volume is being administered.

Placement of a pulmonary artery catheter (PAC) is another tool for

assessment of volume status. This more invasive measure involves placement of the PAC into the central venous circulation and through the right

heart. Ports in the PAC (Swan-Ganz catheter) allow for direct measurement of CVP, pulmonary artery (PA), and PCWPs. The PCWP is used as

a surrogate for LA pressure. While studies have not identified a mortality

or length-of-stay benefit with routine use of PA catheterization, there are

cases where it may be beneficial. Patients with mixed shock (distributive

and cardiogenic) or those with ongoing shock of unclear etiology are

examples of situations in which it should be considered.

The need for continued volume replacement must be frequently

reassessed. As the patient continues to receive treatment for shock, the

initial proper strategy regarding volume management may change in

light of development of processes that independently require a different

volume-management strategy. For patients who initially present with

shock but then develop respiratory failure related to acute respiratory

distress syndrome (ARDS) or renal failure, it may be reasonable to

begin volume removal.

Vasopressor and Inotropic Support If intravascular volume

status has been optimized with volume resuscitation but hypotension

and inadequate tissue perfusion persist, then vasopressor and inotropic

support should be initiated. The use of vasopressors and inotropes

must be tailored to the primary physiologic disturbance. The clinician

must understand the receptor selectivity of various agents and that for

some agents the selectivity may be dose-dependent. In patients with

2241 Sepsis and Septic Shock CHAPTER 304

distributive shock, the aim is to increase the SVR. Norepinephrine is

the first-choice vasopressor, with potent α1

 and β1

 adrenergic effects.

The α1

 causes vasoconstriction while β1

 has positive inotropic and

chronotropic effects. At high doses, epinephrine has a similar profile (at lower doses the β effects predominate) but is associated with

tachyarrhythmia, myocardial ischemia, decreased splanchnic blood

flow, pulmonary hypertension, and acidosis. In distributive shock,

vasopressin deficiency may be present. Vasopressin acts on the vasopressin receptor to reverse vasodilation and redistribute flow to the

splanchnic circulation. In a randomized trial in patients with septic

shock, the addition of low-dose vasopressin did not reduce all-cause

28-day mortality compared to norepinephrine. Vasopressin is safe and

has a role as a second agent for hypotension in septic shock. Dopamine

does not have a role as a first-line agent in distributive shock. A randomized control study in patients with all-cause circulatory shock did

not show a survival benefit but did reveal an increase in adverse events

(arrhythmia). In this study, the subgroup of patients with cardiogenic

shock had increased mortality. For patients with cardiogenic shock,

dobutamine is the first-line agent; it is a synthetic catecholamine with

primarily β-mediated effects and minimal α adrenergic effects. The β1

effect is manifest in increased inotropy and the β2

 effect leads to vasodilation with decreased afterload; it can be used with norepinephrine in

patients with mixed distributive and cardiogenic shock.

■ OXYGENATION AND VENTILATION SUPPORT

In addition to the cellular hypoxia caused by circulatory failure,

patients with shock may present with hypoxemia. For patients with

distributive shock, this may be related to a primary pulmonary process

(pneumonia in a patient with septic shock). For patients with cardiogenic or obstructive shock, the hypoxemia may be related to LV dysfunction and elevations of PCWP. For patients with all types of shock,

there can be development of ARDS and subsequent V.

/Q

.

mismatch

and shunt. Supplemental oxygen should be initiated and titrated to

maintain SpO2

 of 92–95%. This may require intubation and initiation

of mechanical ventilation. If the patient requires intubation and initiation of mechanical ventilation, this should be provided promptly so as

to minimize the duration of tissue hypoxia. Patients with shock may

have high minute ventilatory needs to compensate for metabolic acidosis. As shock progresses, they may not be able to maintain adequate

respiratory compensation, which may be a second indication to initiate mechanical ventilator support. If mechanical support is initiated,

it is important to provide ventilation with lung-protective strategies

focused on low tidal volume ventilation and optimization of positive

end-expiratory pressure to minimize ventilator-induced lung injury. In

addition, there should be daily sedation cessation to assess underlying

neurologic function and minimize time on mechanical ventilation.

There are currently little data to support the use of noninvasive ventilation in the setting of shock.

Antibiotic Administration Sepsis and septic shock are the most

common cause of shock. For patients presenting with undifferentiated shock, if the diagnosis of septic shock is being entertained, then

broad-spectrum antibiotics should be administered after obtaining

appropriate cultures. For patients with sepsis, every hour of delay in

antibiotic administration is associated with an increase in mortality.

While it is ideal to initiate antibiotics after appropriate cultures, the

inability to obtain cultures should not delay the start of treatment.

When sepsis is excluded as a cause of shock, an important aspect of

antibiotic stewardship is to stop all antibiotics.

Specific Causes of Shock Requiring Tailored Intervention

The initial evaluation (history, physical examination, and diagnostic

testing) may have identified an etiology of shock that requires urgent

lifesaving intervention in addition to the initial treatment steps outlined above. Patients with distributive shock secondary to anaphylaxis

require removal of the inciting allergen, administration of epinephrine,

and vascular support with intravenous fluid resuscitation and vasopressors. Adrenal insufficiency requires replacement with intravenous

stress dose steroids. Cardiogenic shock patients with arrhythmia

may require treatment as outlined in advanced cardiac life support

algorithms or placement of an artificial pacemaker. In cases of acute

ischemic events, consideration must be given to revascularization

and temporary mechanical supportive measures. In the case of valve

dysfunction, emergency surgery may be considered. Patients with

hypovolemic shock due to hemorrhage may require surgical intervention in the case of trauma or endoscopic or interventional radiology

procedures in the case of a GI source of blood loss. Among patients

with obstructive shock, a tension PTX would necessitate immediate

decompression. Proximal pulmonary embolism requires evaluation for

thrombolytic therapy or surgical removal of the clot. Dissection of the

ascending aorta may require surgical intervention.

■ FURTHER READING

Benham et al: A standardized and comprehensive approach to the

management of cardiogenic shock. JACC Heart Fail 8:879, 2020.

Gitz Holler et al: Etiology of shock in the emergency department: A

12-year population-based cohort study. Shock 51:60, 2019.

Pro CI et al: A randomized trial of protocol-based care for early septic

shock. N Engl J Med 370:1683, 2014.

Rhodes A et al: Surviving sepsis campaign: International guidelines

for management of sepsis and septic shock: 2016. Intensive Care Med

43:304, 2017.

Tehrani BN et al: A standardized and comprehensive approach to

the management of cardiogenic shock. JACC Heart Fail 8:879, 2020.

Vincent JL, De Backer D: Circulatory shock. N Engl J Med 369:1726,

2013.

Vincent JL et al: The value of blood lactate kinetics in critically ill

patients: A systematic review. Crit Care 20:257, 2016.

■ INTRODUCTION AND DEFINITIONS

Sepsis is a common and deadly disease. More than two millennia ago,

Hippocrates wrote that sepsis was characterized by rotting flesh and

festering wounds. Several centuries later, Galen described sepsis as

a laudable event required for wound healing. Once the germ theory

was proposed by Semmelweis, Pasteur, and others in the nineteenth

century, sepsis was recast as a systemic infection referred to as “blood

poisoning” and was thought to be due to pathogen invasion and spread

in the bloodstream of the host. However, germ theory did not fully

explain sepsis: many septic patients died despite successful removal

of the inciting pathogen. In 1992, Bone and colleagues proposed that

the host, not the germ, was responsible for the pathogenesis of sepsis.

Specifically, they defined sepsis as a systemic inflammatory response to

infection. Yet sepsis arose in response to many different pathogens, and

septicemia was neither a necessary condition nor a helpful term. Thus,

these investigators instead proposed the term severe sepsis to describe

cases where sepsis was complicated by acute organ dysfunction and the

term septic shock for a subset of sepsis cases that were complicated by

hypotension despite adequate fluid resuscitation along with perfusion

abnormalities.

In the past 20 years, research has revealed that many patients develop

acute organ dysfunction in response to infection but without a measurable inflammatory excess (i.e., without the systemic inflammatory

response syndrome [SIRS]). In fact, both pro- and anti-inflammatory

responses are present along with significant changes in other pathways.

To clarify terminology and reflect the current understanding of the

pathobiology of sepsis, the Sepsis Definitions Task Force in 2016 proposed the Third International Consensus Definitions specifying that

sepsis is a dysregulated host response to infection that leads to acute

304 Sepsis and Septic Shock

Emily B. Brant, Christopher W. Seymour,

Derek C. Angus

2242 PART 8 Critical Care Medicine

data, prospective cohorts with manual case identification, and large

electronic health record databases. Organ dysfunction is often defined

by the provision of supportive therapy, in which case epidemiologic

studies count the “treated,” rather than the actual, incidence. In the

United States, cohort studies using administrative data suggest that

upwards of 2 million cases of sepsis occur annually. Shock is present in

~30% of cases, resulting in an estimated 230,000 cases in a recent systematic review. An analysis of data (both clinical and administrative)

from 300 hospitals in the United Healthcare Consortium estimated

that septic shock occurred in 19 per 1000 hospitalized encounters. The

incidences of sepsis and septic shock are also reported to be increasing

(according to International Classification of Diseases, Ninth Edition,

Clinical Modification [ICD-9-CM] diagnosis and procedure codes),

with a rise of almost 50% in the past decade. However, the stability of

objective clinical markers (e.g., provision of organ support, detection

of bacteremia) over this period in a two-center validation study suggests that coding rules, confusion over semantics (e.g., septicemia vs

severe sepsis), rising capacity to provide intensive care, and increased

case-finding confound the interpretation of serial trends. Studies from

other high-income countries report rates of sepsis in the ICU similar

to those in the United States.

Until now, although data demonstrated that sepsis is a significant

public health burden in high-income countries, its impact on the populations of low- and middle-income countries was largely unknown.

A recent analysis of the Global Burden of Disease Study revealed that

the global impact of sepsis is twice that of previous estimates, with

an estimated 48.9 million (95% confidence interval [CI], 38.9–62.9

million) incident cases reported worldwide. Sepsis-related deaths represent 19.7% (95% CI, 18.2–21.4%) of all global deaths, of which 85%

occur in low- and middle-income countries. Among all age groups,

both sexes, and all locations, diarrheal disease represented the most

common underlying cause of sepsis. Sepsis related to underlying injury

and maternal disorders were the most common noncommunicable

causes of sepsis.

■ PATHOGENESIS

For many years, the clinical features of sepsis were considered the result

of an excessive inflammatory host response (SIRS). More recently, it

has become apparent that infection triggers a much more complex,

variable, and prolonged host response than was previously thought.

The specific response of each patient depends on the pathogen (load

and virulence) and the host (genetic composition and comorbidity), with

different responses at local and systemic levels. The host response evolves

over time with the patient’s clinical course. Generally, proinflammatory

reactions (directed at eliminating pathogens) are responsible for “collateral” tissue damage in sepsis, whereas anti-inflammatory responses are

implicated in the enhanced susceptibility to secondary infections that

occurs later in the course. These mechanisms can be characterized as

an interplay between two “fitness costs”: direct damage to organs by the

pathogen and damage to organs stemming from the host’s immune

response. The host’s ability to resist as well as tolerate both direct and

TABLE 304-1 Definitions and Criteria for Sepsis and Septic Shock

CONDITION DEFINITION COMMON CLINICAL FEATURES

CRITERIA IN 1991/2003

(“SEPSIS-1”/“SEPSIS-2”) CRITERIA IN 2016 (“SEPSIS-3”)

Sepsis A life-threatening organ

dysfunction caused by a

dysregulated host response to

infection

Include signs of infection,

with organ dysfunction, plus

altered mentation; tachypnea;

hypotension; hepatic, renal, or

hematologic dysfunction

Suspected (or documented)

infection plus ≥2 systemic

inflammatory response syndrome

(SIRS) criteriaa

Suspected (or documented) infection

and an acute increase in ≥2 sepsisrelated organ failure assessment (SOFA)

pointsb

Septic shock A subset of sepsis in which

underlying circulatory

and cellular/metabolic

abnormalities lead to

substantially increased

mortality risk

Signs of infection, plus altered

mentation, oliguria, cool

peripheries, hyperlactemia

Suspected (or documented)

infection plus persistent arterial

hypotension (systolic arterial

pressure, <90 mmHg; mean arterial

pressure, <60 mmHg; or change in

systolic by >40 mmHg from baseline

Suspected (or documented) infection

plus vasopressor therapy needed to

maintain mean arterial pressure at

≥65 mmHg and serum lactate

>2.0 mmol/L despite adequate fluid

resuscitation

a

SIRS criteria include 1 point for each of the following (score range, 0–4): fever >38°C (>100.4°F) or <36°C (<96.8°F); tachypnea with >20 breaths per min; tachycardia with

heart rate >90 beats/min; leukocytosis with white blood cell count >12,000/μL; leukopenia (<4000/μL) or >10% bands. b

SOFA score is a 24-point measure of organ dysfunction

that uses six organ systems (renal, cardiovascular, pulmonary, hepatic, neurologic, hematologic), where 0–4 points are assigned per organ system.

organ dysfunction. This definition distinguishes sepsis from uncomplicated infection that does not lead to organ dysfunction, a poor course,

or death. In light of the wide variation in the ways that septic shock is

identified in research, clinical, or surveillance settings, the Third International Consensus Definitions further specified that septic shock be

defined as a subset of sepsis cases in which underlying circulatory and

cellular/metabolic abnormalities are profound enough to substantially

increase mortality risk.

To aid clinicians in identifying sepsis and septic shock at the

bedside, “Sepsis-3” clinical criteria for sepsis include (1) a suspected

infection and (2) acute organ dysfunction, defined as an increase by

two or more points from baseline (if known) on the sequential (or

sepsis-related) organ failure assessment (SOFA) score (Table 304-1).

Criteria for septic shock include sepsis plus the need for vasopressor

therapy to elevate mean arterial pressure to ≥65 mmHg with a serum

lactate concentration >2.0 mmol/L despite adequate fluid resuscitation.

■ ETIOLOGY

Sepsis can arise from both community-acquired and hospital-acquired

infections. Of these infections, pneumonia is the most common source,

accounting for about half of cases; next most common are intraabdominal and genitourinary infections. Blood cultures are typically positive

in only one-third of cases, while many cases are culture negative at

all sites. Staphylococcus aureus and Streptococcus pneumoniae are the

most common gram-positive isolates, while Escherichia coli, Klebsiella

species, and Pseudomonas aeruginosa are the most common gramnegative isolates. In recent years, gram-positive infections have been

reported more often than gram-negative infections, yet a 75-country

point-prevalence study of 14,000 patients on intensive care units

(ICUs) found that 62% of positive isolates were gram-negative bacteria,

47% were gram-positive bacteria, and 19% were fungi.

The many risk factors for sepsis are related to both the predisposition to develop an infection and, once infection develops, the likelihood of developing acute organ dysfunction. Common risk factors for

increased risk of infection include chronic diseases (e.g., HIV infection,

chronic obstructive pulmonary disease, cancers) and immunosuppression. Risk factors for progression from infection to organ dysfunction

are less well understood but may include underlying health status,

preexisting organ function, and timeliness of treatment. Age, sex, and

race/ethnicity all influence the incidence of sepsis, which is highest

at the extremes of age, higher in males than in females, and higher in

blacks than in whites. The differences in risk of sepsis by race are not

fully explained by socioeconomic factors or access to care, raising the

possibility that other factors, such as genetic differences in susceptibility to infection or in the expression of proteins critical to the host

response, may play a role.

■ EPIDEMIOLOGY

The incidences of sepsis and septic shock depend on how acute

organ dysfunction and infection are defined as well as on which data

sources are studied. Disparate estimates come from administrative