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Chapter

Shock Pathophysiology:
Classifications and Management
Numair Belgaumi, Ahmed Salik
and Naveed ur Rehman Siddiqui

Abstract

Shock is a pathological state in which there is an insufficiency in oxygen supply

and demand. Ultimately, it results in global hypoperfusion and a resulting increase in
anaerobic respiration causing lactic acidosis. Maintaining adequate oxygen delivery in
the critical care setting is of primary importance in the management of a critically ill
patient. When oxygen supply is inadequate, the body undergoes several physiological
changes to maintain the oxygen delivery requirements and perfusion pressure. This
stage is referred to as compensated shock, and early signs of shock may be appreciated
during this stage. When compensatory mechanisms are inadequate and DO2 begins to
fall beyond the critical point, shock has progressed to the uncompensated stage.
During this stage, there is rapid deterioration of the patient due to prolonged hypoxia
and anaerobic respiration. Multiple Organ Dysfunction Syndrome (MODS) is the
development of potentially reversible physiological derangement involving two or
more organ systems not involved in the causative disorder, which results in persisting
states of shock, sepsis and hypoperfusion and a major cause of high mortality in the
intensive care unit reaching a range of 11–54% in septic pediatric patients. The final
stage of shock is irreversible shock, which is also referred to as refractory shock. This
final stage of shock carries a 96–99% mortality rate.

Keywords: shock, hypovolemic shock, cardiogenic shock, distributive shock,

obstructive shock, oxygen delivery, cardiac output, compensated shock,
uncompensated shock, resuscitation, management, inotropes

1. Introduction

Shock is a pathological state in which there is an insufficiency in oxygen

supply and demand. Ultimately it results in global hypoperfusion and a resulting
increase in anaerobic respiration causing lactic acidosis. Adequate oxygen delivery
is an essential requirement for the sustenance of every cell in the body, the lack of
which can result from a variety of pathological disturbances and can lead to life-
threatening alterations. Therefore, maintaining adequate oxygen delivery in the
critical care setting is of primary importance in the management of a critically ill
patient.
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Management of Shock - Recent Advances

2. Physiological need for oxygen

The requirement for oxygen is as important as a cell’s need for biochemical energy,
without which no cellular or biochemical process can occur. Of the various biochem-
ical mediums for energy, ATP is the most crucial due to the inherently high energy
stored within the bonds between phosphate groups. Additionally, these bonds are
readily and quickly broken to yield energy stored due to their unstable nature [1].
While ATP can be produced by processes such as glycolysis and the Krebs cycle, the
amount produced by oxidative phosphorylation during the reactions within the elec-
tron transport chain, an oxygen-dependent mechanism, is vastly greater than that
which the other two processes can produce. Anaerobic metabolism is an important
means by which tissues can continue to produce ATP in oxygen deprived states;
however it does not yield enough energy to support the functional requirements of
most tissues. Therefore, the need for adequate oxygenation and delivery of oxygen to
tissues across the body is essential for normal physiology.

3. Oxygen delivery

For proper oxygenation of tissues, oxygen delivery is essential and is achieved by

circulation of oxygenated blood. To understand the mechanisms and factors that
influence delivery one must first understand certain terms and their interconnected
influence on oxygen delivery.
Firstly, the term oxygen delivery (DO2) refers to the rate at which oxygen is deliv-
ered per unit time to cells, tissues and organs. Oxygen consumption (VO2) subsequently
is the rate at which oxygen is consumed per unit time by a cell, tissue or organ [1]. We’ll
begin by discussing oxygen delivery and the essential factors that influence delivery.
Oxygen delivery is dependent on two factors, Cardiac output (CO) and arterial
oxygen content (CaO2). A change in one of these can decrease or increase the
amount of global oxygen delivery. Physiologically, these factors are not independent
and changes in one will be compensated with changes in the other to maintain ade-
quate DO2. These components of DO2 can be expressed (Eq. 1) as:
DO2 ¼ CO  CaO2 (1)

3.1 Arterial oxygen content

At any given time, blood leaving the left ventricle will be oxygenated to a certain
degree expressed as the arterial oxygen content (CaO2). This term refers both to the
amount of hemoglobin saturated with oxygen (SaO2) and the amount of oxygen
dissolved in blood (PaO2). Furthermore, since hemoglobin accounts for most of
arterial oxygenation, the concentration of hemoglobin in blood (Hgb) is also an
important determinant of CaO2 (Figure 1).
These three factors determining arterial oxygen content can be mathematically
represented by the following formula (Eq. 2):
CaO2 ¼ ðHbg  1:34  SaO2 Þ þ ðPaO2  0:003Þ (2)

As can be appreciated from this equation (Eq. 2) hemoglobin concentration and

saturation account for a vast majority of arterial oxygenation with dissolved oxygen
only making a fraction of the total oxygen level.

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Figure 1.
Determinants of CaO2.

3.2 Cardiac Output

Circulation of oxygenated blood allows for oxygen to reach the most distal parts of
the body. Circulation is determined by the heart’s functionality which is represented
by cardiac output (CO). Factors that influence cardiac output are the Stroke Volume
(SV) and the Heart Rate (HR). The relationship of these measurements to cardiac
output is expressed in the equation below (Eq. 3):

CO ¼ SV  HR (3)

Stroke volume is defined as the amount of blood pumped from the left ventricle
into the aorta within a single contraction. Three factors determine stroke volume:
Preload, Contractility, and Afterload. These components are often difficult to
directly assess clinically and are often estimated using indirect methods and assump-
tions. Preload refers to the amount of end-diastolic stress or pressure exerted on the
walls of the left ventricle influencing myocardial sarcomere length. The major deter-
minant of preload is venous pressure and subsequent venous return. Other factors
influencing preload include ventricular wall compliance, atrial contractility and val-
vular resistance. End-diastolic volume is usually used as an estimate for preload.
Contractility refers to the rate of sarcomere shortening during contraction. It repre-
sents the functionality of cardiac muscle and is influenced by stimulation via cate-
cholamine and concentration of electrolytes such as calcium, magnesium and
potassium. Afterload refers to the force against which the left ventricle contracts and
is defined as the left ventricular wall stress.

4. Oxygen consumption and oxygen extraction

Oxygen consumption (VO2) by cells and tissues is dependent on their energetic

requirements and expenditure. It is defined as the amount of oxygen consumed per
minute. The more metabolically active a tissue is the more oxygen it will require to
maintain that activity. Therefore, oxygen consumption is a measure of energy expen-
diture. It can be expressed as the equation (Eq. 4) given below where CmvO2 is the
mixed venous oxygen content:

VO2 ¼ ðCaO2 CmvO2 Þ  CO (4)

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Management of Shock - Recent Advances

From equation 4 it can be appreciated that consumption is an estimate of global

oxygen usage calculated using the difference in oxygen content in arterial and venous
blood standardized to CO or the cardiac index (cardiac output in relation to body
surface area).
At rest, given normal hemoglobin concentration and adequate cardiac output,
oxygen delivery exceeds oxygen consumption levels with only 25% consumed of the
total oxygen delivered. This number represents an average consumption of all tissues
across the body. With adequate oxygen delivery, the central venous oxygen content
(ScvO2) is greater than 70%. When metabolic demand increases (e.g., fever, shiver-
ing), oxygen extraction increases, and central venous oxygen content may fall.
Oxygen extraction ratio (O2ER) represents the amount or fraction of arterial
oxygen content that is consumed as blood crosses across a tissue bed [2]. The equation
for the oxygen extraction ratio is given below (Eq. 5) and is the difference between
arterial O2 content and venous O2 content divided by arterial O2 content

O2 ER ¼ ðCaO2 CvO2 Þ=CaO2 (5)

Normally, this ratio is around 0.2–0.3 which indicates the abundance of delivered
oxygen [1]. The actual extraction ratio varies with different tissues depending on the
basal metabolic rates. For instance, the brain and myocardial tissue extract the most
oxygen when compared to other organs. Conversely, the kidney and liver extract the
least oxygen. Tissues such as myocardial tissues are therefore more dependent on
oxygen delivery and are more susceptible to ischemia as they are unable to extract more
oxygen. Additionally, certain tissues can increase their oxygen extraction (e.g., skeletal
muscles during heavy exercise) depending on changes in their metabolic demands.
Figure 2 summarizes the relationships between oxygen delivery consumption and
extraction. As oxygen delivery falls, extraction rises in order to maintain a fixed con-
sumption level required by tissues. With increased extraction, ScvO2 begins to fall. Con-
sumption is maintained by increasing oxygen extraction levels up until the critical point.
This phase is termed the supply independent phase as a decrease in delivery will not

Figure 2.
Oxygen delivery and consumption relationship.

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reduce consumption. Beyond the critical point, extraction can no longer maintain the cells
metabolic demands and consumption begins to fall linearly with decreasing oxygen
delivery. This phase is termed the supply dependent phase. In this phase ischemia sets in
and lactic acid begins to accumulate due to oxygen deprivation and anaerobic respiration.

5. Pathophysiology and progression of shock

As previously defined, shock is a pathological state in which there is an imbalance

in oxygen supply and demand. Ultimately it results in global hypoperfusion and a
resulting increase in anaerobic respiration causing lactic acidosis (Table 1).

5.1 Compensated shock

When oxygen supply is inadequate, the body undergoes several physiological

changes to maintain the oxygen delivery requirements and perfusion pressure. This
stage is referred to as compensated shock and early signs of shock may be appreciated
during this stage. Findings consistent with compensated shock are briefly mentioned in
Table 2. At this point, it is important to identify the underlying cause and correct it to
prevent any lasting complications. Homeostatic changes that occur are listen in Table 1
and is stimulated by activation of two pathways. The first is baroreceptor activation.
Decreased arterial pressure leads to decreased stretch of the baroreceptors located on the
carotid sinus. There is a consequent decrease in afferent baroreceptor firing which
increases efferent sympathetic firing and decreases efferent parasympathetic firing.
Sympathetic activation results in an increase in CO via an increase in heart rate and
stroke volume (increase in contractility). Arteriolar vasoconstriction allows for the
redistribution of blood flow to more vital organs such as the brain, heart and kidneys.
Additionally, increased sympathetic tone results in constriction of venous circulation
thereby increasing venous return. As circulation is a closed system, an increase in
venous return or preload brings about an increase in stroke volume and thereby cardiac
output. Additionally, the sympathetic nervous system (SNS) directly stimulates the
adrenal glands resulting in secretion of epinephrine, norepinephrine and cortisol which
also aid in augmenting arteriolar and venous tone. The second pathway is activation of
the renin-angiotensin-aldosterone-system (RAAS). A decrease in renal perfusion
secondary to systemic hypotension triggers this activation. Aldosterone acts on the

Maintaining adequate Vasoconstriction via ↑ Sympathetic Tone, catecholamine release,

circulating volume angiotensin II release (RAAS) and vasopressin release

Increased renal reabsorption via activation of RAAS and vasopressin release

Maximization of cardiac Increase in heart rate

output
Increase in contractility

↑Preload ➔ ↑CO (Frank-Starling relationship)

Redirection of blood flow to Autoregulation of blood flow to vital organs

vital organs

Optimizing oxygen ↑RBC 2-3-DPG concentration

unloaded settings
Bohr Effect (lactic acidosis)

Table 1.
Compensatory mechanisms in response to systemic hypotension.

5
Management of Shock - Recent Advances

principal cells in the collecting tubules of the kidney to increase sodium reabsorption.
This results in fluid retention that ultimately improves cardiac output. The angiotensin
II acts on AT1 receptors on vascular endothelial cells causing vasoconstriction. Angio-
tensin II also preferentially constricts the efferent arteriole maintaining the glomerular
filteration rate (GFR) and preventing pre-renal acute kidney injury in the setting of
shock. These mechanisms briefly mentioned here all aim to maintain perfusion pres-
sure, direct blood to vital organs (e.g. brain, heart, and kidney) and increase oxygen
delivery in the setting of systemic hypoxia. A comprehensive table listing the various
compensatory mechanisms in response to hypoxia is given. (Table 1).

5.2 Uncompensated shock

When compensatory mechanisms are inadequate and DO2 begins to fall beyond
the critical point, shock has progressed to the uncompensated stage. During this
stage there is rapid deterioration of the patient due to prolonged hypoxia and anaero-
bic respiration. When this state persists, a cascade of events occurs resulting in various
pathophysiological outcomes outlined in Figure 3.
Lactic acid accumulation has an effect on several organs systems. Cardiac contractil-
ity has been shown to be reduced in states of acidosis further worsening DO2. Acidosis
also causes a predisposition to ventricular arrhythmias. At the cellular level, the function
of pH dependent enzymes such as 6-phosphofructokinase, essential in glycolysis, are
compromised further retarding ATP production. As hypoxia progresses, cells begin to
deplete their ATP stores resulting in the dysfunction of various ATP dependent enzy-
matic reactions. Of key importance is the dysfunction of ion pumps which maintain
membrane potential and cellular fluid dynamics. About 70 percent of ATP produced by
cells is used to maintain sodium-potassium ATPase pumps. In the setting of hypoxemia
there is decreased ATP production resulting in Na+/K+ ATPase pumps failure. Improper
functioning ion pumps results in an influx of sodium and efflux of potassium altering
the osmotic equilibrium between extracellular and intracellular fluids. This results in
cellular edema leading to cell dysfunction and rupture. This is the underlying issue of all
types of shock and leads to the most damaging outcome of hypoxia. Cellular hypoxia
also activates monocytes which result in the release of cytokines. This triggers a cascade

Figure 3.
Cellular response to hypoxia.

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System Compensated shock Uncompensated shock

Neurological Alert and oriented. Irritable Altered mental status, Decreased

responsiveness

Cardiovascular Tachycardia Tachycardia, Hypotension (MAP <

60 mmHg)

Respiratory Tachypnea, Increased Work of Breathing* Tachypnea, Decreased oxygen saturation,

ARDS

Renal/GU Decreased urine output (<0.5 mL/kg/h) Prerenal azotemia, Metabolic acidosis,
Anuria

Gastrointestinal Nausea, Anorexia Absence/Hypoactive bowel sounds,

Ischemic bowel

Endocrine Hyperglycemia Hypoglycemia

Integumentary Warm extremities with normal capillary Cold extremities with slow capillary refill
refill time time

Labs Decreased venous PO2 Elevated lactate

*
Increased work of breathing is evident by findings such as subcostal recessions, sternal recession and nasal flaring.

Table 2.
Findings in compensated and uncompensated shock.

ultimately leading to more vasodilation and increased vascular permeability further

contributing to reduced tissue perfusion and hypotension. Additionally, lysosomal ion
channel dysfunction disrupts lysosomal membrane potential leading to their dysfunc-
tion and release of contents. Both lysosome and cellular rupture lead to the release of
toxic substances into extracellular fluids and circulation resulting in a cascade of capil-
lary endothelial damage and cell death. Ultimately, these events produce findings such
as hyperkalemia, hyponatremia, prerenal azotemia and lactic acidosis.
Clinical findings for both compensated and uncompensated shock are contrasted
on Table 2.

5.3 Irreversible shock

The final stage of shock is irreversible shock which is also referred to as refractory
shock. This final stage of shock carries a 96–99% mortality rate. There is loss of almost
all compensatory mechanisms. Decreased perfusion exacerbates anaerobic metabo-
lism processes due to lack of oxygen delivery to end-organs. Vasodilation and
increased vascular permeability results in plasma leaving the vascular space, contrib-
uting to profound interstitial edema and loss of intravascular volume. This results in
refractory hypotension, end organ ischemia, Multiple Organ Dysfunction Syndrome
(MODS) and ultimately death.

6. Systemic inflammatory response syndrome (SIRS)

One complication that may arise as shock progresses is the development of Sys-
temic Inflammatory Response Syndrome (SIRS). While SIRS may not always be
present in the progression of shock, its presence heralds the onset of a more serious
syndrome mentioned earlier; Multiple Organ Dysfunction Syndrome (MODS). SIRS is
defined as an “exaggerated defense response to a noxious stressor” and can be due to
7
Management of Shock - Recent Advances

Symptoms/Findings

Fever >100.4 F

Hypothermia <96.8 F

Tachypnea (Respiratory Rate > 20/min)

Tachycardia <90 bpm

WBC > 12,000/μL or WBC < 4000/μL

Bands >10%

Hyperglycemia >140 mg/dL with no DM*

*
Diabetes Mellitus.

Table 3.
Diagnostic criteria for SIRS is the presence of any two of the above criteria.

insults such as infection, trauma, surgery, acute inflammation, and ischemia or reper-
fusion injury [3]. The relationship between shock and SIRS is not linear and one does
not necessarily arise from the other. Shock may progress in the absence of SIRS
depending on the etiology and type of shock. Infection is the most common cause of
SIRS and is termed sepsis. In the early phases of septic shock, a cause of distributive
shock discussed later, pathological stimuli result in cellular and immunological acti-
vation. This cellular activation leads to the release of a variety of chemokines includ-
ing histamine, kinin, prostaglandins, leukotrienes and complement. Over activation of
this system results in an imbalance between pro-inflammatory and anti-inflammatory
mechanisms. Diagnostic criteria for determining SIRS are outlined in Table 3.
The outcomes of this imbalance occur globally, are a result of increased pro-
inflammatory activity and are listed below:

a. Peripheral Vasodilation

b. Endothelial dysfunction ➔ Increase capillary permeability

c. Cellular activation ➔ neutrophils, macrophages, mast cells, platelets,

endothelial cells

d. Microvascular coagulation ➔ end-organ micro thrombosis

e. Loss of circulatory integrity

7. Multiple organ dysfunction syndrome

Multiple Organ Dysfunction Syndrome (MODS) is a potentially life-threatening

condition and is a major cause of high mortality in the intensive care unit reaching a
range of 11–54% in septic pediatric patients [4]. It is defined as the ‘development of
potentially reversible physiological derangement involving two or more organ systems
not involved in the disorder that resulted in ICU admission” and is a result of
persisting states of shock, sepsis and hypoperfusion [4]. Most often, it is the end stage
in the progression of septic shock and commonly affects the lungs, myocardium and

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brain before other organs. It is believed that the role of pro-inflammatory cytokines is
key in inducing damage. Increased capillary leakage in the lungs causing pulmonary
edema and surfactant loss, increased circulating nitrous oxide causing myocardial
dysfunction and disturbances in the blood–brain barrier are all mechanisms thought to
induce damage to these organs [4].

8. Types of shock

Shock can be broadly classified into four different types based on the pathological
mechanism resulting in impaired oxygen delivery to the tissues. When dealing with a
patient presenting with shock, it is important to identify the type of shock as all of
them are treated differently. The four types of shock are:

1. Hypovolemic Shock

2. Cardiogenic Shock

3. Distributive Shock

4. Obstructive Shock

8.1 Hypovolemic shock

Hypovolemic shock occurs due to loss of intravascular volume. This is the most
common type of shock. Loss of intravascular volume can be in the form of loss of
blood or loss of fluids from the body other than blood. Causes of blood loss can include
trauma, gastrointestinal bleeding, postpartum hemorrhage, esophageal varices and
ruptured abdominal aortic aneurysm. Causes of non-blood fluid losses can include
diarrhea, vomiting, reduced intake, third degree burns and diabetic ketoacidosis.
Hypovolemic shock can be further classified according to the amount of volume loss.
The classes of hypovolemic shock are given in Table 4.

8.2 Cardiogenic shock

Cardiogenic shock occurs due to inability of the heart to pump blood adequately to
the peripheral circulation as a result of impaired contractility. This leads to end-organ

Class Volume Pulse Blood Capillary Respiratory Urine output

loss pressure refill rate (mL/kg/h)

I 0–15% Normal Normal Normal Normal 1–2

II 15–30% Mild Tachycardia Mildly Mildly Mild 0.5–1

Low Prolonged Tachypnea

III 30–40% Tachycardia Low Prolonged Tachypnea 0.25–0.5

IV >40% Tachycardia, Very Low Greatly Severe 0

Bradycardia or absent Prolonged Tachypnea

Table 4.
Classes of hypovolemic shock.

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Management of Shock - Recent Advances

hypoxia and shock. Causes of cardiogenic shock can be myocardial infarction, myo-
carditis (secondary to Coxsackie B virus), dilated cardiomyopathy, and congenital
heart disease, valvular dysfunction like aortic valve stenosis or mitral valve stenosis
and arrhythmias. Both tachy-arrhythmias and brady-arrhythmias can lead to cardio-
genic shock. Tachy-arrhythmias cause the heart to beat abnormally fast which impairs
the filling ability of the heart, hence decreasing the preload and subsequently
decreasing the cardiac output. Brady-arrhythmias decrease the heart rate and since
CO = SV x HR, this also causes the cardiac output to decrease.

8.3 Distributive shock

Distributive shock occurs due to inappropriately distributed blood volume. Under

normal physiology, vascular tone is under control of the autonomic nervous system.
Sympathetic stimulation causes vascular smooth muscle to contract and vasoconstrict,
while the parasympathetic nervous system causes vascular smooth muscle to relax and
vasodilate. Distributive shock occurs when the sympathetic nervous system is unable
to maintain the tone of the vascular system, allowing abnormal vasodilation of blood
vessels. This allows pooling of blood and decreases preload. This also leads to
increased vascular permeability and third-space fluid loss. This in turn causes intra-
vascular hypovolemia and decreased end-organ perfusion. Distributive shock can
have different etiologies like septic shock, anaphylactic shock and neurogenic shock.
Septic shock is the most common cause of distributive shock [5]. It can be defined
as “sepsis-induced hypotension (systolic blood pressure <90 mm Hg or a reduction of
40 mm Hg from baseline) despite adequate fluid resuscitation along with the presence
of perfusion abnormalities that may include, but are not limited to, lactic acidosis,
oliguria, or an acute alteration in mental status.” Septic shock results from an over-
whelming systemic inflammatory response which leads to vasodilation and subse-
quent hypotension. Most common causes of septic shock are gram negative bacteria
like Escherichia coli, Proteus species, Klebsiella pneumoniae which release endotoxins
which are responsible for activation of the immune system.
Anaphylactic shock occurs due to type 1 hypersensitivity reaction to any foreign
antigen. Antigens bind to IgE molecules on pre-sensitized mast cells and cause mast
cell degranulation and release of inflammatory mediators like histamine. Histamine
causes vasodilation and increased capillary permeability. This causes severe
hypovolemia and cardiovascular collapse leading to shock.
Neurogenic shock results from the inability of the sympathetic nervous system to
maintain the tone of blood vessels. In most cases, this is a result of trauma to the brain
or spinal cord above the level of T6 [6]. The trauma leads to a loss of background
sympathetic stimulation to the vascular smooth muscles. This causes vasodilation
resulting in a sudden decrease in blood pressure (secondary to a decrease in peripheral
vascular resistance).

8.4 Obstructive shock

Obstructive shock occurs when there is a barrier to the flow of blood or a barrier
which impairs proper filling of the heart. There are several conditions which can cause
obstructive shock. These include cardiac tamponade, tension pneumothorax and pul-
monary embolism.
Cardiac tamponade is the result of fluid in the pericardial space which impairs the
filling ability of the heart during diastole. This reduces the preload and subsequently
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decreases cardiac output. This is similar in presentation to constrictive pericarditis in

which the pericardium shrinks and hardens.
Tension pneumothorax is the presence of air in the pleural cavity under positive
pressure. The elevated intrathoracic pressure leads to decreased venous return to the
heart as it compresses the inferior vena cava, thus leading to reduced cardiac output.
Pulmonary embolism is an embolus (usually dislodged from the proximal deep
veins of the lower limb) lodged in the vasculature of the lungs. This obstructs blood
flowing to the lungs and the blood coming from the lungs to the heart. There is a
decrease in end-diastolic volume which leads to a decreased stroke volume and hence
decreased cardiac output and oxygen delivery to the peripheral tissues resulting in
shock.

9. Resuscitation goals

When approaching a patient in shock, management requires attaining physiologi-

cal normalcy and hemodynamic stability. In the clinical setting, the progress of treat-
ment is measured by achieving certain goals. These clinical goals help ascertain
improvement in global perfusion and oxygenation. Factors measured are included in
Table 5 and are used clinically to determine a patient’s response to the management of
shock. While these conditions are useful in measuring response, the use of only one or
two as an indicator for improvement will lead to shortcomings and mislead a physi-
cian regarding the actual response to management.
One goal used to assess treatment is normalcy in heart rate and perfusion pressure
representing adequate perfusion and venous return/cardiac output. Perfusion pres-
sure is determined by subtracting the central venous pressure (CVP) by the mean
arterial pressure (MAP); MAP-CVP. These parameters can be used to measure hemo-
dynamic stability and are also used to assess response to fluid therapy. With adminis-
tration of a fluid bolus, heart rate should ideally decrease and MAP-CVP should
increase. Another measurement that can be used to assess response to fluid therapy
and inotrope therapy response is the shock index (HR/SBP). Calculated by dividing

Indicators of therapeutic responsiveness Normal value/Prognostic value

Normal Mental Status GCS = 15/15

Normal pulse quality and rate Palpable in all extremities; Rate varies with
age

Difference in Central and peripheral temperatures 36.1–37.2°C; equal centrally and peripherally

Normal Capillary Refill ≤ 2 seconds

Adequate Urine Output >1 mL/kg/h

Lactate Trends ≥0.75 mmol/L/h. associated with bad

prognosis

Normal Superior Vena Cava Oxygen Saturation (SVC O2) ≥ 70%

AVDO2 ≤5 mL O2/100 mL of blood

Table 5.
Resuscitative goals and normal values.

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Management of Shock - Recent Advances

heart rate (HR) by systolic blood pressure (SPB), the shock index should ideally
decrease as fluid therapy is directed at improving stroke volume, thereby decreasing
HR, and inotrope therapy improves vascular tone and SBP.
As mentioned earlier, during shock states compensatory mechanisms redirect
blood to vital organs such as the brain, heart and kidneys. Consequently, as shock
progresses from compensated to uncompensated phase, these organs will begin to
show signs of dysfunction. Mental status of a patient is therefore a parameter which
should be assessed to determine improvement in a patient’s condition. While
improvement is a good sign, not all patients will have altered mental status and, when
present, is often a late manifestation of shock. Relying on altered mental status as an
indicator of shock and its improvement as good response to therapy is not a reliable
approach and should be taken with caution and in combination with other factors. The
kidney is another organ which can be used to assess response to therapy. A normal
urine output of >1 mL/kg/h represents adequate renal perfusion and perfusion pres-
sure. However, urine output only represents the improvement in renal perfusion and
does not provide a picture of global perfusion status.
Systemic vascular tone and cardiac output can both be determined by assessing
peripheral temperatures, capillary refill and distal pulse qualities. Normal capillary
refill is <2 seconds and coupled with normal peripheral temperature and distal pulses
correlates with adequate perfusion to the peripheries. However, these parameters do
not provide indication of oxygenation. Cases such as anemia or hemodilution may
have normal peripheral temperature, pulses and capillary refill but oxygen delivery is
still impaired.
As shock is defined as impaired systemic oxygen delivery, lactate levels are a good
indicator of global oxygenation. Lactate trends should be observed rather than single
serum lactate measurements as a single measurement does not indicate the progres-
sion of disease. Increases of lactate levels of ≥70 mmol/L/h. is associated with wors-
ening oxygen delivery and outcomes.
Superior vena cava oxygen saturation (SVCO2) of ≥70% is a good therapeutic
endpoint in the management of shock. As mentioned earlier in the chapter, when
there is good oxygen delivery, SVCO2 should be maintained above 70% representing
no increase in oxygen extraction during the compensatory phase of shock. Measuring
SVCO2 can be done via central venous catheters with venous oximetry or, more
recently, with the use of near-infrared spectroscopy, a less invasive method. One can
also calculate the difference in arterial and venous oxygen content (AVDO2) to assess
the degree of oxygen extraction during this phase of shock. Normal values show a
difference of ≤5 mL O2/100 mL of blood and increases in AVDO2 indicate increases in
oxygen extraction.

10. General principles in the treatment of shock

In order to provide a patient with the benefit of rational and effective treatment, it
is critical to identify the specific cause of shock in each case. Although treatment
should be aimed at the underlying etiology of shock, the most critical aspect of
treatment is the prompt restoration of normal hemodynamics.
From a hemodynamic perspective, there are three main categories in the manage-
ment of shock:

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• Intravenous fluids, which act by increasing central venous pressure and

downstream left ventricular end-diastolic volume (EDV)

• Vasopressors which act by increase systemic vascular resistance (SVR)

• Inotropes which act by increasing contractility and thus increase cardiac output

In hypovolemic shock, the primary derangement is low central venous pressure

(CVP) so therefore IV fluids are the cornerstone of therapy. If the patient is pro-
foundly hypotensive, vasopressors are sometimes used temporarily but only while
definitive access is obtained, and fluids are pushed as quickly as possible. If a patient
in hypovolemic shock is requiring vasopressors to maintain enough perfusion pressure
to stay conscious, they are in critical need for more fluid. Since these patients are
already extremely hyper dynamic, there are no benefits of inotropes which will only
risk worsening tachycardia to the point that diastolic filling time is too short for the
left ventricle to fill.
In distributive shock, the primary derangement is low SVR. Vasopressors are
therefore almost always necessary. Since most of these patients are also hypovolemic,
or at the very least, have fluid maldistributed to the extravascular space rather than
central circulation, IV fluids are also used in every case. Because of sepsis induced
cardiomyopathy, some patients with sepsis may also benefit from inotropes but iden-
tifying those patients can be a challenge.
In cardiogenic shock, the primary problem is low cardiac output, thus
inotropes are the mainstay therapy. Both fluids and vasopressors are not only
unnecessary but contraindicated. In fact, reduction in preload by using diuretics,
and reducing the afterload helps in augmenting the cardiac output in patients with
cardiogenic shock.
Finally, in obstructive shock, it is impossible to generalize about the appropri-
ateness of fluids, vasopressors and inotropes and if there is a response to any of
those, it is likely only temporary. Definitive relief of the obstruction is still critical.
For pneumothorax (PTX), this is either chest tube or needle thoracostomy which
consists of a needle placed into the pleural space via the second intercostal space
in the midclavicular line. For cardiac tamponade, pericardiocentesis can be
performed, a procedure in which a needle is placed in the pericardial space most
commonly via a subxiphoid approach. In case of massive pulmonary embolism,
depending on the circumstances, this may require systemic thrombolysis or embo-
lectomy.
General treatment principles are summarized in Table 6.

Type of shock IV Fluids (↑CVP) Vasopressors (↑SVR) Inotropes (↑Contractility)

Hypovolemic + Temporary use only

Distributive + + +/

Cardiogenic +

Obstructive +/ +/ +/

Table 6.
General approach to therapy with regards to type of shock.

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10.1 Fluid therapy

Fluid resuscitation is the rapid delivery of fluids to patients who have acutely
impaired hemodynamics. Resuscitative fluids are given universally to patients in
hypovolemic shock and lesser forms of dehydration, as well as to almost all patients
with severe sepsis and septic shock. In these situations, the preload to the heart is not
enough for adequate cardiac output. To understand why these patients are given
fluids we need to review the Frank-Starling curve as shown in Figure 4. According to
the Frank-Starling Law, the length of myocardial tissue is directly related to the force
of the subsequent contraction. The more myocardial fibers are stretched, the more
they contract. Preload determines the degree of myocardial fiber stretching. There-
fore, as shown in Figure 4, an increase in preload results in a responsive increase in
stroke volume. Patients on the left side of the curve are those who are preload
dependent. Towards the right, the curve flattens and increases in preload are met with
a reduced rate of increase in stroke volume until we see no change in stoke volume
with increasing preload. These patients are preload independent. Essentially, only if
the patient is preload dependent will we see benefits to stroke volume if given fluid.
Preload independent patients will not benefit from fluids. It is important to note that
the shape and position of the curve will vary between individuals, and it is important
to identify where on the curve the patient lies to determine whether it is suitable to
give fluids.
Once we have decided which patient needs to be given fluids, we need to decide
which fluids to give. The first decision to make is whether to give crystalloid or
colloid. Crystalloids are fluids which contain water and various electrolytes and other
small water-soluble molecules. Colloids are large, insoluble molecules and oftentimes
proteins. Theoretically, colloid should be superior to crystalloid as it has an increased
tendency to stay intravascular. However, a 2013 Cochrane review found no evidence
from randomized controlled trials that resuscitation with colloids reduces the risk of
death, compared to resuscitation with crystalloids, in patients with trauma, burns or
following surgery [7]. Therefore, given their decreased cost and increased availability,

Figure 4.
Frank-Starling curve.

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as well as the low immunogenic response, crystalloids are almost always favored over
colloids.
Crystalloid replacement is usually sufficient in hypovolemic shock caused by
vomiting and diarrhea. The presence or absence of associated electrolyte disturbances
(e.g., hypo- or hypernatremia) determines the type of crystalloid. The use of albumin
as a replacement fluid for hypovolemic shock is probably best reserved for situations
involving direct albumin loss (e.g., burns, open wounds, protein-losing enteropa-
thies). Volume replacement with crystalloid or albumin may be appropriate in cases of
hemorrhagic shock, but with significant blood loss, replacement of red blood cell mass
will eventually become necessary.
While the majority of patients with hypovolemic shock tolerate relatively rapid
correction of intravascular volume depletion, there are a few notable exceptions that
may require slower correction. For example, in cases of hypovolemic shock accompa-
nied by significant metabolic/electrolyte derangements (e.g., hypernatremia or dia-
betic ketoacidosis), volume deficit correction must be tempered so that the
accompanying metabolic/electrolyte abnormalities are not corrected too quickly.
Rapid correction of hypernatremia can lead to cerebral edema while rapid correction
of hyponatremia can lead to central pontine myelinolysis.
Correction of hypovolemic shock in patients with underlying myocardial dysfunc-
tion must be done with greater caution than in patients with normal myocardial
function to avoid further compromising myocardial function. Finally, in trauma-
specific situations, very aggressive volume resuscitation for hemorrhagic shock may
not be appropriate until surgical hemorrhage control is achieved.

10.2 Blood products

Oxygen delivery, as described in the first section, is dependent on two factors:

cardiac output and arterial oxygen content. Vasoactive and fluid therapy both aim to
enhance cardiac output and global perfusion to enhance oxygen deliver. In both these
therapies the arterial oxygen content remains the same. The use of blood products
aims to increase arterial oxygen content (CaO2) by infusing packed red blood cells
(PRBC) thereby increasing hemoglobin levels, the main parameter determining arte-
rial oxygen content. The use of PRBC is therefore most useful in situations where
shock is caused or worsened by decreasing hemoglobin concentration such as in
patients with hemolytic anemia. The goal of blood product therapy is to return
hemoglobin concentrations to normal values with regards to age. Approximately
10 mL/kg of PRBC should increase hemoglobin concentration by 2 g/dL. A 20 kg
child with an Hb concentration of 5 g/dL would therefore require 500 mL of PRBC to
reach an Hb concentration of 10 g/dL. When considering blood transfusion, it is
important to consider the hemodynamic changes that occur with increasing hemato-
crit. Experimentally it has been shown that a hematocrit of 30% is optimal for oxygen
delivery while hematocrit levels exceeding 40% increase viscosity and hinder oxygen
delivery [8].

10.3 Vasoactive therapy

Vasoactive drugs used in the management of shock can be divided into inotropic,
vasoconstrictive and vasodilative medication. The main goals of employing these
medications are to increase cardiac output, decrease vascular resistance and increase
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Management of Shock - Recent Advances

perfusion pressure. The administration of these drugs usually come after initial use of
fluid and blood product therapies fail to produce adequate improvement.
Inotropes: Inotropes are generally used to increase cardiac output and stroke
volume. Their mechanism of action usually involves stimulation of adrenergic
receptors and includes endogenous catecholamines such as dopamine, epinephrine
and norepinephrine and exogenous catecholamines such as dobutamine and phenyl-
ephrine. These drugs work to stimulate α-adrenergic, β-adrenergic and dopaminergic
receptors which subsequently alter conditions such as contractility and systemic vas-
cular resistance (vasodilation or vasoconstriction) thereby influencing cardiac output
and perfusion pressures. In the setting of shock, the use of these drugs helps enhance
cardiac function to improve oxygen delivery.
Aside from drugs such as phenylephrine, most inotropic drugs will stimulate
multiple receptor types with varying selectivity. For example, as shown in Table 7,
dopamine will preferentially stimulate dopaminergic receptors but will also stimulate
β- and α-adrenergic receptors and will therefore exhibit varying and multiple physio-
logical changes in a dose dependent manner. It is therefore important to know drugs
selectivity and the physiological response of each receptor type. β1-adrenergic recep-
tors are primary expressed in myocardial tissue and have positive inotropic and
chronotropic activity when stimulated. Stimulation of this receptor directly enhances
cardiac output by increasing heart rate and contractility (stroke volume). β2-adren-
ergic receptors act on smooth muscle of vascular tissue and bronchial tissue and
produce vasodilation and bronchodilation respectively. α1-adrenergic receptors
work mainly on vascular smooth muscles contraction and cause peripheral vasocon-
striction. α2-adrenergic receptors one the other hand causes vasodilation via the
inhibition of norepinephrine secretion from presynaptic sympathetic neurons.
Dopaminergic receptors (DA) receptors act on renal vasculature and causing renal
arterial vasodilation.
Dopamine, in terms of inotropic therapy, displays dose-dependent activity on
dopaminergic, β- and α-adrenergic receptors. At low doses (0-3 μg/kg/min) dopamine
acts as a mild vasodilator in peripheral vasculature by stimulating the release of
norepinephrine [9]. Additionally, it inhibits norepinephrine reuptake in presynaptic
sympathetic neurons indirectly enhancing contractility and heart rate [9]. Activation
of dopaminergic receptors at low doses also improves renal and splanchnic perfusion
via D2 presynaptic receptors potentially providing renal protective activity [8, 9], but
it remains matter of debate. Stimulation of D2 presynaptic receptors enhances vasodi-
lation in coronary, renal, mesenteric and cerebral vasculature promoting improved
blood flow to these organs [9]. While inhibition of norepinephrine reuptake in sym-
pathetic neurons does have vasoconstrictive activity, the direct vasodilatory effects in
peripheral vasculature offsets the level of constriction resulting in mild elevation of
SVR. Ultimately, dopamine has the combined effect of significantly improving con-
tractility and heart rate with only mild changes in SVR resulting in effective improve-
ment in cardiac output. At higher doses (>10 μg/kg/min) α-adrenergic activity is
stimulated causing vasoconstriction and aids in increasing blood pressure [8, 9].
Epinephrine is a nonselective catecholamine stimulating both adrenergic recep-
tors of all types. Therefore, is produces both increases in CO and increases in SVR.
When administered at a low dose at an infusion rate of 0.03–0.3 μg/kg/min, epineph-
rine mostly exhibits inotropic activity via β-adrenergic receptors increasing cardiac
output. As higher infusion rates >0.3 μg/kg/min are used, α-adrenergic activity is also
activated resulting in vasoconstriction and an increase in SVR. Because of its selective
inotropic activity at low doses, epinephrine is reliable choice in patients with
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hypotension without myocardial dysfunction. In high doses epinephrine has also been
seen to cause atrial and ventricular arrhythmias [9]. One aspect of inotropic therapy
using epinephrine is its administration in correlation with elevated lactate levels.
Studies have shown that epinephrine may elevate lactate levels, interfering with
lactate trends. It is therefore important to interpret lactate trends with skepticism
when assessing response to therapy and concomitant resuscitation goals should be
viewed when using epinephrine.
Norepinephrine preferentially binds α1-adrenergic receptors over β-adrenergic
receptors resulting in more vasoconstrictive activity than inotropic activity. Because
of its potent α-receptor stimulation, norepinephrine is the vasopressor drug of choice
in distributive shock with hypotension [9]. At low doses of 0.01–0.05 μg/kg/min its
inotropic activity can be appreciated with an improvement in cardiac output. How-
ever, at higher doses, its affinity for α-adrenergic receptors takes over, vastly increas-
ing vasoconstriction and blood pressure. This shift in receptor activity can impede
cardiac output especially in patients with cardiac dysfunction.
Dobutamine is a synthetic catecholamine that has mixed β- and α-adrenergic
stimulation at varying dosages. It primary acts as an inotrope increasing contractility
with minimal increases in SVR indicating its use in patients with cardiogenic shock.
Additionally, at infusion rates >10 μg/kg/min dobutamine can reduce afterload by
stimulating α2-adrenergic stimulation causing vasodilation [8]. In this setting
dobutamine can improve cardiac output [8]. At low doses of <5 μg/kg/min,
dobutamine can exhibit α1-aderenergic antagonism resulting in vasodilation and
decreased afterload.
Phenylephrine is a pure α1-adrengeric agonist and has strong vasoconstrictor
activity. It can be used as an additional therapy where an increase in vascular tone is
needed without changes in cardiac function.
Phosphodiesterase inhibitors (Milrinone) work as an inotrope via a different
mechanism than the catecholamines described above. By inhibiting phosphodiester-
ase, it causes an increase in intracellular cAMP levels thereby increasing intracellular
Ca2+. These changes subsequently increase both inotropic activity in myocytes and

Drug Receptor/mechanism Effect

Dopamine Dopaminergic (DA) > β- Low doses (DA) ➔ ↑renal artery

adrenergic > α-adrenergic vasodilation

Mod/high. Doses (DA + β) ➔ ↑renal blood

flow, HR, contractility, CO

Dobutamine α- & β-adrenergic ↑CO with minimal effects on BP

Epinephrine α1 & β-adrenergic ↑SVR, HR, CO, BP

Phenylephrine Pure α1-adrenergic Peripheral arterial vasoconstriction ➔ ↑BP,

MAP, SVR

Norepinephrine Mixed α1 & β-adrenergic Significant ↑BP + MAP, SVR, CO, HR

(α1 > β1 > β2)

Vasopressin V-1 & V-2 receptors ↑BP, SVR; anti-diuretic action via V-2

Phosphodiesterase ↑cAMP ↑CO + vasodilation ➔ ↓BP

Inhibitor (Milrinone)

Table 7.
Mechanism of action and effects of inotropes and vasopressors.

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Management of Shock - Recent Advances

vasodilation in vascular smooth muscle. It has the advantage of achieving these results
without acting on adrenergic receptors and is therefore ideal in situations where
receptor downregulation has developed due to chronic inotrope usage such as in those
patients with chronic heart failure [9].
Vasopressin maintains perfusion pressure through two main mechanisms. Firstly,
it acts on blood vessels to produce vasoconstriction via the activation of V1-receptors.
This causes an increase in SVR and thereby increases arterial pressure. Secondly, it
stimulates V2-receptors on renal tubular cells to enhance fluid reabsorption via
aquaporin channels. Vasopressin is also known to stimulate CRH release from the
hypothalamus, thereby increasing downstream ACTH and cortisol secretion. Cortisol
in turn enhances vasoconstriction and inhibits secretion of vasodilators such as PGE2
and nitric oxide.
Mechanisms of these drugs and their effect on the cardiovascular system are
summarized in Table 7.

Author details

Numair Belgaumi, Ahmed Salik and Naveed ur Rehman Siddiqui*

The Aga Khan University Hospital, Medical College, Pakistan

*Address all correspondence to: [email protected]

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of
the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0),
which permits unrestricted use, distribution, and reproduction in any medium, provided
the original work is properly cited.
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