Treatment Options

Evaluation and Management of
Shock States: Hypovolemic,

Distributive, and Cardiogenic Shock
Journal of Pharmacy Practice

24(1) 44-60
The Author(s) 2011
Reprints and permission:
sagepub.com/journalsPermissions.nav
DOI: 10.1177/0897190010388150
http://jpp.sagepub.com
Michael P. Moranville, PharmD, BCPS1,

Katherine D. Mieure, PharmD, BCPS1, and
Elena M. Santayana, PharmD, BCPS1
Abstract
Shock states have multiple etiologies, but all result in hypoperfusion to vital organs, which can lead to organ failure and death if not
quickly and appropriately managed. Pharmacists should be familiar with cardiogenic, distributive, and hypovolemic shock and
should be involved in providing safe and effective medical therapies. An accurate diagnosis is necessary to initiate appropriate
lifesaving interventions and target therapeutic goals specific to the type of shock. Clinical signs and symptoms, as well as
hemodynamic data, help with initial assessment and continued monitoring to provide adequate support for the patient. It is
necessary to understand these hemodynamic parameters, medication mechanisms of action, and available mechanical support
when developing a patient-specific treatment plan. Rapid therapeutic intervention has been proven to decrease morbidity and
mortality and is crucial to providing the best patient outcomes. Pharmacists can provide their expertise in medication selection,
titration, monitoring, and dose adjustment in these critically ill patients. This review will focus on parameters used to assess hemodynamic status, the major causes of shock, pathophysiologic factors that cause shock, and therapeutic interventions that should be
employed to improve patient outcomes.
Keywords
cardiogenic, distributive, hypovolemic, vasopressors, shock
Introduction
Shock can be defined globally as any state in which oxygen
delivery to end organs is insufficient to sustain normal metabolic processes. Although inadequate blood supply and organ
failure are the end results of shock, there are a number of pathophysiologic states that trigger such a condition. For example,
the origin of shock may be hypovolemic, anaphylactic, septic,
neurogenic, or cardiogenic in nature.1 No matter the etiology,
early resuscitation efforts to resolve hemodynamic instability
are the key for improving outcomes. The purpose of this review
is to outline the etiology of shock states, provide assessment
and monitoring techniques of hemodynamic status, and
describe evidence-based management strategies.
Hemodynamic status can be assessed via direct measurement, with laboratory values and with physical assessment
(Table 1). Laboratory data specific to end organs may also be
used to assess adequate perfusion. Global hypoperfusion can
result in accumulation of lactic acid due to tissue hypoxia.
Liver dysfunction is apparent by reduced synthetic function
(increased activated partial thromboplastin time [aPTT] and/
or prothrombin time [PT]) or elevated hepatic transaminases,
lactate dehydrogenase, or bilirubin. Renal function may be
impaired and result in decreased urine output or elevated serum
creatinine (SCr) and blood urea nitrogen (BUN). Decreased

blood flow to the brain may result in encephalopathy or altered
mental status. Diminished bowel sounds and ileus may be
caused by insufficient gastrointestinal perfusion. Myocardial
infarction or ischemia is evident by elevation in cardiac biomarkers (troponin, creatinine kinase, myoglobin) and electrocardiogram abnormalities.1,2
Prior to discussing each shock state, clinicians must be
familiar with normal hemodynamic parameters to understand
how they are altered based on the specific type of shock
(Tables 1 and 2). It is important to recognize these values are
not to be used in isolation, rather they are assessed collectively
to develop the most accurate assessment of clinical status.
Patient-specific disease states must also be considered since the
University of Chicago Medical Center, Chicago, IL, USA
Corresponding Author:
Michael P. Moranville, University of Chicago Medical Center, Department of
Pharmaceutical Services, 5841 S Maryland Aveune, MC0010 Room TE 026,
Chicago, IL 60637, USA
Email: Michael.moranville@uchospitals.edu
Downloaded from jpp.sagepub.com at Universiti Malaya (S141/J/2004) on May 19, 2015
Moranville et al
45
Table 1. Normal hemodynamic parameters

Hemodynamic Parameter
Systolic blood pressure (SBP)
Diastolic blood pressure (DBP)
Mean arterial pressure (MAP)
Heart rate (HR)
Cardiac output (CO)
Cardiac index (CI)
Ejection Fraction
Pulmonary capillary wedge pressure
(PCWP)a
Pulmonary vascular resistance (PVR)
Mean pulmonary artery pressure (PAM)
Pulmonary artery systolic pressure (PAS)
Pulmonary artery diastolic pressure (PAD)
Systemic vascular resistance (SVR)
Central venous pressure (CVP)
Arterial oxygen saturation (SaO2)
Mixed venous oxygen saturation (SvO2)
Table 2. Calculations for hemodynamic parameters

Normal Value
100-140 mm Hg
70-90 mm Hg
80-100 mm Hg
60-80 beats/min
4-7 L/min
2.8-3.6 L/min/m2
50%-70%
8-12 mm Hg
80-180 dynes/s/cm5 or 1-2
Wood units
15-20 mm Hg
25-30 mm Hg
6-12 mm Hg
800-1200 dynes/s/cm5
2-6 mm Hg
95%-100%
70%-75%
PCWP may also be referred to as pulmonary artery occlusion pressure

(PAOP).
optimal goals of resuscitation for shock may not necessarily

require normalization of hemodynamic markers.
Hemodynamic Monitoring
Intra-arterial catheter
In the intensive care unit (ICU), continuous blood pressure
monitoring with an intra-arterial catheter is recommended due
to patient instability. An intra-arterial catheter can directly
measure mean arterial pressure (MAP), which is determined
by cardiac output (CO) and systemic vascular resistance
(SVR), and is useful to estimate end organ perfusion. The MAP
will vary depending on the type of shock and will be discussed
in more detail for each condition. Arterial lines are also advantageous for arterial blood gas measurements to assess pulmonary gas exchange.1,2
Central Venous Catheter

A central venous catheter is utilized to measure central venous
pressure (CVP), a marker of volume status and systemic blood
return to the heart. The CVP is useful to assess changes in fluid
status as low values suggest hypovolemia and high values
suggest hypervolemia (Table 1). Venous compliance, right
ventricular (RV) function, intrathoracic pressure, and intraabdominal pressure can affect CVP and must be considered.
Poor venous compliance reduces capacitance of these vessels
and may drive up CVP. If RV dysfunction is present, systemic
volume overload is likely to occur, which results in elevated
CVP. Increases in intrathoracic pressure (eg, with mechanical
ventilation) or intra-abdominal pressure (eg, extreme ascites
or abdominal free air) will also cause increased CVP due to
added external pressure on the walls of the vena cava,
Hemodynamic Parameter
Blood pressure (BP)
Cardiac output (CO)
Cardiac output (CO) by
Fick
Cardiac index (CI)
Stroke volume (SV)
Systemic vascular resistance (SVR)
Mean arterial pressure
(MAP)
Pulmonary vascular resistance (PVR)
Mean pulmonary artery

pressure (PAM)
Equation
CO SVR
HR SV
[(135 mL/min O2/m2) BSA]/[13.4 Hgb
(SaO2 SvO2)]
CO/BSA
CO/HR
[(MAPCVP)/CO] 80
(SBP 2 DBP)/3
[(PAM PCWP)/CO] 80 (units
mm Hg)
[(PAM PCWP)/CO] (units Wood
units)
(PAS 2 PAD)/3
Abbreviations: BSA, body surface area; SBP, systolic blood pressure; DBP,
diastolic blood pressure; O2, oxygen; Hgb, hemoglobin; SaO2, arterial saturation
of oxygen; SvO2, venous oxygen saturation; PCWP, pulmonary capillary wedge
pressure; HR, heart rate; CVP, central venous pressure; SVR, systemic vascular
resistance; PAS, pulmonary artery systolic; PAD, pulmonary artery diastolic.
impairing venous compliance. Venous blood gas can be

obtained from a central venous catheter, and medications or
fluids can quickly be administered via this route.1,2
Pulmonary Artery Catheter

A pulmonary artery catheter (PAC) provides a number of useful parameters including pulmonary artery systolic (PAS), diastolic (PAD), and mean (PAM) pressures, pulmonary capillary
wedge pressure (PCWP), CO, SVR, and mixed venous oxygen
saturation (SvO2). The CO can be measured by thermodilution
or using the Fick equation. A thermistor at the distal end of the
PAC is able to monitor changes in temperature over time and
calculate CO using area under the curve. Clinicians must
account for tricuspid regurgitation (TR), intracardiac shunting,
high positive end expiratory pressure in ventilated patients, and
severely decreased ventricular function which may affect the
accuracy of CO measured by thermodilution. Under these
circumstances, the Fick equation (Table 2) may be utilized
for greater accuracy. Bradycardia, or factors that decrease
stroke volume (SV) from the left ventricle (ie, heart failure
[HF] with systolic or diastolic dysfunction, mitral regurgitation,
aortic stenosis, or aortic insufficiency) contribute to low CO.
The SVR is a calculated value based on CO measurement.
A low SVR suggests lack of vascular tone and vasodilation. If
CO or SVR deviate from normal, physiologic compensation of
the opposite parameter should occur to maintain blood pressure
(Table 2). A SvO2 measured from the RA, can be correlated to
CO by assuming that a value below the normal range is
associated with a low CO. A low value suggests poor forward
blood flow, allowing more time for peripheral tissue oxygen
extraction.
46
Journal of Pharmacy Practice 24(1)
The PCWP is a marker of left atrial pressure (LAP) and left

ventricular end diastolic pressure (LVEDP), or preload, exerted
on the left side of the heart. The PAD is an approximation of
PCWP and may be considered if wedge pressures are not available. Low and high preload may result in poor CO caused by
inadequate filling or excessive stretch of the LV, respectively,
resulting in deranged Frank-Starling forces.1,2 It should be
noted that although a PAC can provide additional hemodyanmic information, it has not been shown to significantly improve
morbidity, mortality, or length of stay in critically ill cardiovascular, surgical, or medical patients. Patients managed with a
PAC are also at higher risk of adverse effects than those managed without one. It is appropriate to utilize this device at experienced institutions for difficult to manage patients when
physical assessment and other diagnostic tests are not adequate.3-6
Hypovolemic Shock
Hypovolemic shock is a patient care emergency associated
with significant loss of intravascular volume resulting in
decreased preload, SV, and CO. This culminates in compensatory increases in SVR in order to maintain perfusion of end
organs and if left untreated, leads to tissue hypoperfusion,
organ failure, and death. Numerous etiologies may precipitate
hypovolemic shock including plasma loss due to catastrophic
hemorrhage or sustained fluid loss without repletion. Other
causes include shifting of fluid from the vascular compartment
to a nonvascular body compartment. This review provides an
evaluation of current management recommendations for hypovolemic shock but does not address surgical methods for cessation of bleeding or specifics regarding fluid infusion rates,
timing, or duration.
Pathophysiology
Body fluids account for approximately 60% of lean body mass
in males and 50% of lean body mass in females. Of this body
fluid, blood volume is approximately 11% to 12%, estimated
at 5 to 6 L, of the total volume. Unlike most internal organs
which can lose up to 50% of functional mass before organ failure is apparent, loss of as little as 30% to 40% of total blood
volume can result in life-threatening circulatory failure.
General fluid loss and volume depletion can occur secondary to hemorrhage, diarrhea, vomiting, heat stroke, or inadequate repletion of insensible losses. Intravascular volume
may also be depleted via interstitial and intravascular fluid
leaking into a nonvascular space. Sequestering of fluid in a
nonvascular compartment via third spacing may commonly
occur in patients postoperatively, or with intestinal obstruction,
cirrhosis, or thermal injury. These patients may experience volume shifts as intravascular components leak into the extracellular space thereby pulling fluid away from the vasculature.
The complexity of this condition is accentuated as a number
of etiologies may occur simultaneously such as in surgical or
Table 3. Classification of acute blood loss severity

Class
Parameter
Blood loss (%)
Pulse rate (bpm)
Blood pressure
Respiratory rate
(breaths/min)
Urine output (mL/h)
CNS symptoms
II
III
IV
<15
<100
Normal
14-20
15-30
>100
Decreased
20-30
30-40
>120
Decreased
30-40
>40
>140
Decreased
>35
>30
Normal
20-30
Anxious
5-15
Confused
Negligible
Lethargic
Abbreviation: CNS, central nervous system.
trauma patients who may have operative or injury-related blood

loss and significant third spacing.7
Thermal injury patients pose an interesting clinical challenge as several resuscitation formulas are used throughout the
world for calculating the fluid requirement and no wellcontrolled trials are available to demonstrate one is better than
another. Estimating the fluid requirements is generally based
on the size of the patient and size of the thermal injury. The
most widely used is the Parkland equation.8,9 Intravenous
(IV) fluid resuscitation is recommended in adults with greater
than 15% total body surface area burn.8
Various forms of acute hemorrhage may result in hemorrhagic shock and not surprisingly this condition is the second leading cause of early death among trauma patients behind central
nervous system (CNS) injury.10 Acute blood loss has been organized into 4 classifications by the American College of Surgeons
(ACS; Table 3). This classification system has been designed to
guide resuscitation efforts and ranges from a class I nonshock
state, such as donating blood, to a class IV patient care emergency requiring immediate volume replacement.11 The ACS
defines massive hemorrhage as loss of total blood volume within
a 24-hour period or loss of half of the blood volume in a 3-hour
period.12,13 Mainstays for treatment of hemorrhagic shock are to
control the source of bleeding and replace circulating blood volume. Uncontrolled bleeding may lead to the devastating combination of acidosis, hypothermia, and coagulopathy.14 These
abnormalities are referred to as the lethal triad because each
element exacerbates the other and in combination can rapidly
lead to death if hemorrhage is not controlled.15-18
Treatment
Fluid Replacement and Blood Product Administration. The magnitude and duration of decreased organ perfusion in hypovolemic
shock is directly related to mortality.19 Intravascular volume
can be replenished with a variety of resuscitative agents
(Table 4). The ideal resuscitation fluid for hypovolmeic shock
would be small in volume, highly portable, easy to prepare
and administer, effective for prolonged expansion of the intravascular space, and inexpensive. Traditionally, crystalloids
Moranville et al
47
Table 4. Fluids used for shock resuscitation

Components (mEq/L)
Fluid
Plasma
0.9% NaCl
7.5% NaCl
Lactated Ringers
5% dextrose
5% albumin
25% albumin
Na
Cl
Ca
Mg
140
154
1,283
130
130-160
130-160
103
154
1,283
109
130-160
130-160
Buffers
Bicarb (25)
Lactate (28)
Sodium bicarbonate, hydroxide, or acetic acid

Sodium bicarbonate, hydroxide, or acetic acid
have been recommended by the ACS for fluid replacement;

however other treatment approaches include colloid containing
fluids and pharmacologic adjunctive agents.11 The use of blood
and blood products is not recommended for volume expansion
but rather replacement of oxygen carrying capacity which is
lost due to class III or IV hemorrhage.11-13
While crystalloids and colloids are recommended to maintain or increase intravascular volume, clinical trials have not
demonstrated benefit of colloids over crystalloids, thus less certainty exists as to which solution improves morbidity or mortality.20-22 Data from a large controlled trial comparing 0.9%
sodium chloride to 4% albumin for fluid resuscitation in ICU
patients demonstrated similar 28-day mortality rates.23 Several
meta-analyses performed using the Cochrane Central Registrar
of Controlled Trials found no significant difference in mortality
between crystalloid and colloid solutions.24-26 However,
another meta-analysis demonstrated a 4% increase in the absolute risk of death when colloids were compared to crystalloid
solutions for resuscitation.27 Collectively these data challenge
the role of colloid products for resuscitation and suggest the
substantial cost of these products, specifically albumin, precludes use until supported by randomized trials.
Crystalloid fluids. Crystalloid solutions, such as lactated Ringers (LR) solution, 0.9% sodium chloride, and 5% dextose are
the most widely available agents for resuscitation and are classified by tonicity. Hypotonic fluids such as 5% dextrose solutions provide a lower solute concentration surrounding the
cells (<270 mmol/L), which results in an intracellular shift of
water, thereby leaving less volume remaining in the vasculature (Table 4). Consequently, this is not effective for resuscitation but may be considered for hemodynamically stable cases
of dehydration.
Isotonic fluids such as 0.9% sodium chloride and LR are so
named because they have similar tonicity to plasma (270300 mmol/L). These solutions are preferred for resuscitation
because they are useful in expanding intravascular volume
without altering cellular fluid shifts. Isotonic solutions are
inexpensive electrolyte solutions containing small molecules
that diffuse rapidly and distribute evenly throughout the
extracellular compartment. Two thirds of the extracellular fluid
comprises interstitial fluid; therefore, the predominant effect of
pH
Osmolarity (mOsM/L)
7.4
5.7
5.7
6.4
4.0
6.4-7.4
6.4-7.4
290
308
2,567
273
252
309
312
isotonic crystalloids on volume resuscitation is replenishment

of interstitial volume rather than intravascular volume deficits.
Secondary to this rapid equilibration into the extracellular
fluid, larger volumes of crystalloids may be needed to adequately replace intravascular volume.28,29 However, aggressive
crystalloid resuscitation is not without side effects as it can
induce platelet dysfunction and dilution of clotting factors,
which may extenuate hemorrhagic situations. In addition,
excessive administration of crystalloid solutions may lead to
hyperchloremic metabolic acidosis and has been shown to
induce pulmonary edema, cardiovascular dysfunction, abdominal compartment syndrome, and ileus.30,31
Hypertonic saline products (3%-7.5% sodium chloride solutions) have significantly higher tonicity versus plasma and consequently impact volume resuscitation and intravascular
expansion through mobilization of endogenous fluids. Secondary to the high osmolality of these products, administration of
small volumes may have expansive impact on the vascular
space. While limited studies demonstrate thermal injury and
traumatic brain injury patients benefit from hypertonic saline
resuscitation,8,32-34 a large multicenter clinical trial of hypertonic saline in trauma patients with hypovolemic shock and
traumatic brain injury was stopped because hypertonic saline
did not demonstrate a significant benefit.35 Despite the theoretical advantages, hypertonic saline does not have a clear indication for resuscitation and additional data appear to be
needed.36-38
Colloid fluids. Colloid fluids, such as albumin, hydroxyethyl

starch, and dextrans, are more effective at adding to plasma
volume than crystalloid solutions.11,39,40 The large molecules
contained in these products poorly diffuse outside of the vascular space and thereby maintain an osmotic pressure which promotes water to remain in the vascular space (Table 4). As much
as 75% to 80% of the infused volume of colloid will remain in
the vascular space and increase CO for up to 2 hours. Consequently less volume is required when these agents are administered. As with hypertonic crystalloids, it is important to note
this approach does not completely replace lost volume but
rather, shift fluid from one compartment to another. Therefore,
these agents should not be used for resuscitation of acute or
48
severe blood loss and should be reserved for hypovolemia due

to interstitial fluid shifts.
It is generally agreed during the early phase of resuscitation
following thermal injury, colloid solutions should be avoided
for first 12 to 24 hours due to capillary permeability and accumulation of plasma proteins outside the vascular compartment,
which contributes to edema.9,41 Crystalloid solutions, specifically LR, are the preferred initial volume expander in burn
victims.
The largest disadvantage of colloid resuscitation therapy is
cost and product availability. Hydroxyethyl starch and dextrans
cause an increased risk of bleeding by inhibiting factor VII and
von Willebrand factor and impairing platelet adhesiveness.42,43
Dextrans also may cause severe life-threatening anaphylactic
reactions.
Blood products. Transfusion of blood products should not be
used to expand blood volume. Instead blood and blood products should be administered when blood loss exceeds 30% of
total blood volume to assure adequate oxygen delivery and to
restore normal coagulopathy as part of a balanced management
of hemorrhagic shock.10 Packed red blood cells (PRBCs), fresh
frozen plasma (FFP), and platelets (PLT) transfusions are currently the most accessible resuscitative fluid available to
accomplish this. The decision to use blood products is also
impacted by the presence and degree of hemodilution induced
by other replacement fluids. With the exception of whole
blood, all IV solutions unfortunately induce hemodilution,
which falsely lowers the hemoglobin concentration. This is also
true for transfusions with PRBCs which contribute to hemodulition due to the low volume of plasma contained within each
unit.44 Due to the low availability of whole blood, numerous
organizations have created guidelines for massive transfusion
of blood products to include balanced infusion ratios of FFP
and PLT to RBC.45-47 This practice is supported by evidence
which demonstrates the benefit of increased survival with early
administration of balanced blood products. Although the optimal
blood component resuscitation ratio has not been demonstrated,
most protocols target at least a 1 to 3 ratio of plasma-to-RBC
transfusions and some promote a 1 to 2 ratio.45,48 In fact, a strategy
of 1 to 1 to 1 involving RBC, FFP, and PLT transfusion has
been recently proposed.45 These protocols allow for early replacement of non-RBC components, increased replenishment of
clotting factors, and minimized crystalloid volume administered.
The Advanced Trauma Life Support (ATLS) resuscitation
guidelines recommend early transfusion of RBC in trauma
patients with evidence of hemorrhagic shock unresponsive to
2 L of crystalloid fluids.11 The decision to administer RBC
transfusion in hemorrhagic shock should not be based on
the hemoglobin concentration but rather the physiologic state
of the patient, amount of blood loss, and potential for ongoing
hemorrhage.10 During the post-resuscitative period for
critically ill patients, guidelines suggest transfusing to a hemoglobin level between 6 and 8 g/dL.49-51 However, maintaining
hemoglobin values between 7 and 9 g/dL versus 10 to 12 g/dL
have demonstrated no difference in mortality, suggesting there
is no incentive to transfuse due to low hemoglobin without concomitant signs and symptoms of poor oxygen delivery.52 Thus,
clinicians must adhere to ATLS recommendations and base
their decision for transfusion on clinical status and not a laboratory value.
Transfusions are not risk free and massive transfusion,
defined as more than 10 units of RBCs in 24 hours, in the setting of acute hemorrhage is a predictor of mortality.44,53 Studies also link RBC transfusion to pulmonary edema, fever,
transfusion-related reactions, increased multiple organ failure,
decreased immunity, increased rate of infection, citrate toxicity, electrolyte abnormalities, and transfusion-associated lung
injury.10,54 Adverse effects of FFP have been described as
allergic reactions, fever, infection, transfusion-associated overload, and acute lung injury.55-57 PLTs have been associated
with each of these in addition to thrombosis.57,58
Pharmacologic agents. Due to poor outcomes associated with
overly aggressive crystalloid administration, vasopressor therapy has been evaluated for hemodynamic support during fluid
resuscitation for hemorrhagic shock. In a multicenter prospective cohort, the use of vasoconstrictors early in the resuscitative
period for hemorrhagic shock patients demonstrated an
increase in mortality when compared to aggressive fluid resuscitation.59 Poor mortality outcomes were observed with norepinephrine, phenylephrine, dopamine, and vasopressin (Table 5).
Despite this, animal data demonstrate circulating endogenous
vasopressin levels are depleted with prolonged hypotension
in hemorrhagic shock, leading to vasodilatation and hypoperfusion of end organs.60 Animal models have demonstrated use of
vasopressin in hemorrhagic shock to provide a favorable
response to hypotension refractory to volume expansion.61-65
Human data, however, are limited to case reports and large prospective data are still needed.66,67
Recombinant factor VIIa (rFVIIa) initiates hemostasis
through the formation of a complex between tissue factor and
FVIIa and was developed for treatment of bleeding in hemophilia patients with inhibitors to exogenous factors VIII and IX.68
Off-label use of rFVIIa has been published in numerous case
reports describing the management of bleeding in trauma
patients and patients undergoing extensive surgery.69-79 A prospective, randomized, double-blinded, placebo-controlled trial
in severe penetrating and blunt trauma patients showed a
decrease in the number of tranfusions required in 48 hours
post-injury.77,78 Although several case reports detail successful
hemostasis with various forms of uncontrolled hemorrhage, the
dosing strategy utilized in these reports is frequently the same
strategy utilized for management of hemophilic patients
(90 mcg/kg), despite the lack of clear evidence to support this
large dose.68 Recent observations with higher cumulative
rFVIIa off-label doses suggest prothrombotic complications
including deep vein thrombosis, pulmonary embolism (PE), myocardial infarction (MI), and stroke may limit its usefulness.80-82
In fact, the manufacturer has terminated a phase III trial citing
futility based on a lower mortality in the placebo group than
expected.77 Until the riskbenefit ratio is fully understood, it
Moranville et al
49
Table 5. Pharmacology, dose, and therapeutic effect of vasopressors and inotropes

Drug/Mechanism
Phenylephrine
Strong a-1 agonist
Norepinephrine
Strong a-1 and b-1 agonists and
weak b-2 agonist
Epinephrine
Strong a-1, b-1, and b-2 agonists
Vasopressina
Dopamine
DA, b-1, and a-1 agonist (dose
dependant)
Dobutamine
Strong b-1 and weak b-2 agonist
Milrinone
Phosphodiesterase inhibitor
Dose/Onset and Duration

Dose: Begin at 100-180 mcg/min; once BP
stabilized, decrease rate to 40-60 mcg/min
and titrate to MAP
MAX: 9.1 mcg/kg/min or *400 mcg/min
Onset: immediate,
half-life: 2-3 hours
Dose: Begin at 2-12 mcg/min and titrate to MAP
MAX: 1 mcg/kg/min or *80 mcg/min
Onset: immediate, duration: 1-2 minutes
Dose: Begin at 2-10 mcg/min and titrate to MAP
MAX: 0.5 mcg/kg/min or *30 mcg/min
Onset: immediate, duration: up to 1 hour
Dose: Fixed dose 0.04 units/min; cardiac arrest:
40 units IV bolus
Onset: immediate, half-life: 10-20 minutes
Dose: Start at 2.5-5 mcg/kg/min and increase by
2.5-5 mcg/kg/min q 10-15 min. Normal dosing
range 2.5-20 mcg/kg/min
MAX: 50 mcg/min
Onset: 5 min, half-life: 2 minutes
Dose: 2.5-20 mcg/min;
MAX: 40 mcg/kg/min
Onset: 1-10 min, half-life: 2 minutes
Use/Effects
Vasodilatory shock, shock due to aortic stenosis and
hypotension, left ventricular outflow tract
obstruction in hypertrophic cardiomyopathy
Effects: "BP, vasoconstriction, "MAP, "SVR
Vasodilatory shock (usually drug of choice for sepsis),

cardiogenic shock (refractory hypotenstion with
SBP < 70 mmHg)
Effects: "MAP, vasoconstriction, "CO, "SVR
Vasodilatory shock, cardiac arrest, cardiogenic
shock, anaphylaxis
Effects: "SVR, "HR, "MAP, "CI, "SV
Vasodilatory shock, cardiogenic shock, cardiac arrest
Effects: "BP, "SVR
Vasodilatory shock, cardiogenic shock, bradycardia
Effects: dose-dependant "HR, "CO, "BP,
"vasoconstriction
ADHF, low CO state, cardiogenic shock, septic

shock as outlined in early goal directed therapy,
bradycardia
Effects: " CI, "HR "BP, # SVR, "O2 delivery
Dose: 50 mcg/kg IV bolus over 10 minutes (rarely ADHF, low CO state
used for ADHF) followed by 0.375-0.75 mcg/kg/ Effects: " CI, "HR "BP, # SVR, #PVR
minb
Onset: 5-10 hours, half-life: 1-3 hours
Abbreviations: ADHF, acute decompensated heart failure; CI, cardiac index; HR, heart rate; BP, blood pressure; SVR, SVR, systemic vascular resistance; PVR,; CO,
cardiac output; ", increase; #, decrease.
a
Ensure adequate volume resuscitation before adding vasopressor or inotropic agents.
b
May adjust for impaired renal function to prevent accumulation.
is reasonable to limit rFVIIa use to treatment of diffuse hemorrhage following appropriate replacement of coagulation factors with FFP, PLTs, and cryoprecipitate and correction of
hypothermia and acidosis.
Distributive Shock
Distributive shock is characterized by a decrease in SVR, with
or without an associated decrease in CO. It is associated with an
abnormal distribution of microvascular blood flow in the presence of normal or increased CO.83 There are several causes of
distributive shock but the most common include anaphylaxis,
neurogenic shock after acute CNS or spinal cord injury, and
septic shock.
Septic Shock
Severe sepsis and septic shock impact millions of patients per
year and despite decades of experience with this disease, the
associated morbidity and mortality remain fairly stable.62
One in four patients die as a result of their illness and
outcomes are dependent on the appropriateness and efficiency

of the care provided in the first hours after development of
severe sepsis.84
Sepsis is a systemic response of the body caused by invasion
of pathogenic microorganisms. This response results in significant reduction of effective tissue perfusion, which can lead to
irreversible cellular damage if not controlled quickly. Clinically, this cellular damage presents as a continuum from sepsis,
to severe sepsis, and culminating in septic shock with an associated increase in mortality at each stage.85 Septic shock is
defined as sepsis-induced hypotension (SBP < 90 mm Hg or
MAP < 70 mm Hg or a decrease in SBP of > 40 mm Hg),
despite adequate fluid resuscitation along with evidence of
hypoperfusion. Perfusion abnormalities may include lactic
acidosis (lactic acid > 4 mmol/L), oliguria, or altered mental
status. Septic shock results in a characteristic hyperdynamic
state with high CO and an abnormally low SVR.84
Pathophysiology. Severe sepsis and septic shock are the manifestations of interactions between infecting organisms and an
50
inappropriate host response. In septic shock, there is dysfunction of virtually all aspects of the immune response. Immune
dysfunction begins almost immediately with overexpression
of inflammatory mediators such as tumor necrosis factor-a
(TNF-a) and interleukin 1b (IL-1b).63 This activation of cytokines can cause host tissue injury and play a role in the development of shock. Another important aspect of sepsis
pathophysiology is the development of a procoagulant state.
Inflammatory cytokines activate the coagulation cascade and
inhibit fibrinolysis. This state is manifested by disseminated
intravascular coagulation (DIC), a life-threatening complication of septic shock. In addition, an inadequate response later
in the infectious process allows for further proliferation of the
pathogen. Although the abnormal host responses seen in septic
shock receive much attention, the role of the pathogen (bacteria, virus, or fungi) is significant and is becoming better
understood. Bacterial and nonbacterial pathogens possess virulence mechanisms that allow them to evade host defenses and
continue to proliferate. These virulence factors vary across species but allow the pathogenic organisms to adhere to host
epithelia surfaces (eg, adehesins), invade host tissues or cells
more readily (eg, bacterial protein secretion systems I, II, III,
and IV), or evade specific host defense mechanisms (eg, biofilms, antiphagocytosis mechanisms).85
Treatment. Early goal-directed resuscitation initiated in the

first 6 hours after recognition of septic shock has been shown
to improve 28-day survival of emergency department patients
in a single-center, randomized, controlled study.86 The Surviving Sepsis Campaign guidelines for the management of severe
sepsis and septic shock recommend initiating early goaldirected therapy to include all of the following as part of a sepsis response protocol: CVP 8 to 12 mm Hg (12-15 mm Hg in
mechanically ventilated patients), MAP > 65 mm Hg, urine
output > 0.5 mL/kg/hr, and ScvO2 or SvO2 > 70% or > 65%,
respectively.84,86 Some argue the specialized equipment, cost,
and time required for monitoring ScvO2 is a barrier in the
implementation of protocol-based resuscitation programs. An
alternative method of determining oxygen delivery is to assess
lactate clearance which only requires two blood samples. A
recent study found that in patients with septic shock who were
resuscitated to normalize CVP and MAP, additional resuscitation to obtain lactate clearance of at least 10% was noninferior
to targeting ScvO2.87 Fluid resuscitation with crystalloids or
colloids (Table 4) should be initiated immediately and titrated
to achieve predefined goals. There remains controversy regarding crystalloids versus colloids and there is no evidence to support one type of fluid over another. Resuscitation with
crystalloids requires more fluid to achieve the same clinical end
points, but they remain inexpensive and readily available and
should be considered first line for the initial resuscitation in
severe sepsis or septic shock.84 If venous oxygen saturation
is not achieved, one can consider further fluid resuscitation
or transfusion of PRBCs to target a hematocrit >30% and/or
initiation of a dobutamine infusion.86
Appropriate IV broad-spectrum antimicrobial therapy

should be initiated within the first hour of severe sepsis onset.
The timely administration of this therapy is associated with
improved outcomes. In the setting of septic shock, every hour
of delay in administration of antimicrobials is associated with
a measurable increase in mortality.88 Cultures should be
obtained prior to initiating antimicrobial therapy as long as this
does not result in a significant delay in treatment. The initial
empiric antibiotics should be selected based on patientspecific factors such as medical history, allergies, clinical signs
and symptoms, and community and institutional patterns of
susceptibility. Recently used antibiotics should be avoided.
Antimicrobials should be reevaluated daily to optimize efficacy, prevent resistance, and avoid toxicity.84
Vasopressor therapy may be required to maintain adequate
MAP and tissue perfusion when hypotension is not responsive to fluid resuscitation. This is especially important for
perfusion of the organs since severely low MAP leads to loss
of autoregulation in vascular beds, which makes perfusion of
the organs solely dependent on pressure. A vasopressor infusion titrated to maintain a MAP of at least 65 mm Hg is recommended.84,89,90 Patients with severe or poorly controlled
hypertension at baseline may require a higher MAP to maintain perfusion to vital organs. Assessing surrogate markers
such as urine output and serum lactate concentration is helpful for ensuring perfusion is appropriate for the individual
patient. The Surviving Sepsis Campaign guidelines recommend norepinephrine or dopamine (Table 5) as first-line
vasopressors in septic shock.84 Alternative or additional vasopressors that may be of use in septic shock include phenylephrine, epinephrine, and vasopressin (Table 5). Despite
recommendations in the guidelines for vasopressors of
choice, there is no high-quality evidence to support one vasopressor over another.84,91,92 Vasopressin may have additional
benefits in sepsis beyond blood pressure augmentation. Early
in septic shock, vasopressin concentrations are elevated but
the concentrations decrease to the normal range as shock continues. These normal levels are actually indicative of a relative vasopressin deficiency since in a state of stress,
vasopressin levels should be elevated.93
For patients with measured or suspected low CO and
elevated cardiac filling pressures, inotropic support with dobutamine is recommended.84 In the early goal-directed therapy
protocol published by Rivers, patients received sequential
administration of fluid resuscitation, PRBCs and then dobutamine in order to achieve an ScVO2 > 70%.86 In clinical practice, the use of dobutamine versus blood products may be
dependent on patient-specific factors and clinician preference.
The efficacy of dobutamine later in the care of a septic patient
to improve oxygen delivery to target organs is more questionable. Two large prospective clinical trials included patients
with severe sepsis in the ICU failed to show a benefit of dobutamine therapy.84,94,95
There are several adjunctive therapies used for the treatment
of severe sepsis and septic shock. These include corticosteroids
and recombinant human-activated protein C ([rhAPC]
Moranville et al
51
drotrecogin alpha). The use of corticosteroids in sepsis remains

controversial despite decades of experience. Short bursts of
high-dose corticosteroids were considered standard for some
time until additional studies found no mortality benefits
and an additional risk for superinfection-related mortality.84
Therefore, more recent studies have used lower doses of
hydrocortisone (200-300 mg/d) and reported earlier reversal
of shock as well as mortality benefits. It seemed, however,
these results were limited to patients who had no response to
a corticotropin test.96 In 2008, the CORTICUS trial found no
mortality benefit from hydrocortisone therapy (50 mg IV every
6 hours) compared to placebo in patients with or without
response to a corticotropin test. Those treated with hydrocortisone did have a more rapid reversal of shock.97 Based on the
available literature to date, corticosteroids cannot be recommended as adjunctive therapy for all patients with septic shock,
but they may improve or hasten reversal of shock in patients
who receive early resuscitation and remain hypotensive
despite aggressive vasopressor support.84 It is also important
to consider patient-specific factors such as chronic steroid use
or other risk factors for relative adrenal insufficiency which
may impact the need for stress-dose steroids.
Drotrecogin alpha (or rhAPC) has antithrombotic, profibrinolytic, and anti-inflammatory properties like endogenousactivated protein C. It is theorized to work by mediating the
procoagulant state and inhibiting the systemic inflammatory
response seen in patients with severe sepsis or septic shock.98
Drotecogin alpha was approved in 2001 for use in septic
patients with increased risk of death (APACHE II > 25) based
on the results of the PROWESS trial which reported a decrease
in 28-day mortality (24.7% with drotrecogin alpha vs 30.8%
with placebo, P .005), when the drug was started within
24 hours of the onset of sepsis.99 However, a post-marketing
study in less severely ill patients (single-organ failure or
APACHE II < 25) was stopped early due to a lack of benefit
(ADDRESS trial).100 The most feared adverse event associated
with drotrecogin alpha is serious bleeding. The incidence of
serious bleeding in the PROWESS study was higher in the
drotrecogin alpha treatment group compared to placebo
(3.5% vs 2%, P .06), with 24.9% of patients receiving drotrecogin alpha experiencing at least 1 bleeding event compared
to 17.7% in the placebo group (P .001).99 The current
Surviving Sepsis Campaign guidelines suggest considering
drotrecogin alpha for adult patients with sepsis-induced organ
dysfunction associated with a clinical assessment of high risk
of death, most of whom will have an APACHEII score > 25
or multiple organ failure in the absence of contraindications
(Grade 2B; Grade 2C in patients with history of surgery in the
last 30 days).84
Finally, investigational agents being studied for the treatment of septic shock include IV immunoglobulins (IVIGs),
HMG CoA-reductase inhibitors, and beta-adrenergic antagonists to name a few. Based on currently available literature,
none of these therapies can be considered more than experimental.101-103 Research continues to focus on therapies that
may mediate the immunologic response to infection.
Anaphylactic Shock
Pathophysiology. Anaphylaxis is an immunoglobulin (IgE)mediated, rapid-onset systemic allergic reaction. Nonallergic
anaphylaxis (anaphylactoid) reactions are not IgE-mediated.
Instead, they are due to mast cell degranulation induced by the
offending agent. Anaphyalxis can be mild, moderate, or severe.
Severe anaphylaxis and/or anaphylactic shock is characterized
by hypoxia (cyanosis or PaO2 < 92%), hypotension (SBP <90
mm Hg), or neurologic compromise (confusion or loss of consciousness). In nonlethal cases, hypotension is often accompanied by nausea, vomiting, dyspnea, dizziness or syncope,
diaphoresis and flushing, and pruritus and/or hives.104 Serious
reactions occur within minutes of exposure to the offending
agent, but some patients may have a delayed reaction hours
after exposure. Biphasic reactions are also possible in which
patients experience a recurrence of symptoms after 4 to 8
hours.105 The progression to anaphylactic shock occurs due
to hypoperfusion of end organs. The patterns of end organ
involvement are variable and may differ between individuals
and among episodes. It is important to note the severity of a
previous reaction does not predict the severity of future reactions. Diagnosis is primarily based on physical examination
and history. In some cases, confirmation can be provided by
an elevated serum B-tryptase level. However, the absence of
an elevated tryptase level does not exclude anaphylaxis and
the variability in symptoms makes early recognition and diagnosis more difficult. The median time from onset to cardiac
arrest can be as fast as 5 to 15 minutes with the most common
causes of death being airway obstruction followed by hypotension.105 The American Academy of Allergy, Asthma, and
Immunology has created diagnostic criteria for the diagnosis
of anaphylaxis based on the aforementioned signs and symptoms to aid in the early recognition and treatment.
The most common triggers for anaphylaxis include foods,
Hymenoptera (bees, wasps, fire ant) stings, medications, latex,
blood products, seminal fluid, and physical factors (eg, cold
temperature or exercise). Anaphylaxis can also be idiopathic.
Common medications known to cause anaphylaxis include
antibiotics, aspirin, and other nonsteroidal anti-inflammatory
drugs.105 In children, foods are the most common triggers,
while medications and insect stings are more likely to trigger
anaphylaxis in adults.
Anaphylaxis is caused by sensitization to an antigen, which
results in formation of a specific IgE to that antigen. Upon reexposure to the antigen, IgE on mast cells and basophils bind to
the antigen and cross-link the IgE receptor which activates the
cells. This activation causes the release of inflammatory mediators including histamine. It is the release of these mediators
that causes capillary leakage, cellular edema, and smooth muscle contractions.105 Anaphylactic shock is typically classified
as a distributive shock although it likely has characteristics
consistent with multiple shock states. There is a component
of hypovolemia due to capillary leak, distributive shock characterized by vasodilation and decreased SVR, and cardiogenic
shock (CS) caused by reduced contractility and, in some cases,
52
inappropriate bradycardia. Pulmonary vasospasm has also been

described, which adds an obstructive shock component. It is
theorized this combination of effects does not allow for compensation resulting in the rapid onset of severe hypotension,
loss of consciousness, and cardiovascular collapse observed
in severe anaphylaxis.
Certain comorbidities or medications can worsen the
severity of anaphylactic reactions. Patients with poorly controlled
or persistent asthma, other respiratory disorders such as
chronic obstructive pulmonary disease (COPD) or pneumonia
are at higher risk of death from anaphylaxis. Cardiovascular
disease is another risk factor for death from anaphylaxis in
middle-aged or elderly patients. Other systemic forms of
illness such as acute infection, or psychological stress may
play a role in the severity of anaphylaxis but have not been
systematically studied. Medications such as beta-blockers,
angiotensin-converting enzyme (ACE) inhibitors, and alphablockers have been implicated in increasing the likelihood of
severe or fatal anaphylaxis. Furthermore, they may interfere
with the patients response to treatment.
Treatment. Due to the potential for anaphylaxis to progress

to shock or death within minutes, rapid assessment and
treatment is crucial. Immediate administration of epinephrine is the mainstay of treatment. There are several options
for administering epinephrine including intramuscular
(IM), IV, or sublingual administration as well as administration via an endotracheal tube. Since the leading cause of
death in anaphylaxis is airway obstruction, airway management is a critical priority. Supplemental oxygen therapy
should be administered and the patient should be evaluated
for endotracheal intubation. In cases of severe laryngeal
edema, cricothyroidotomy or tracheostomy may be performed. If significant bronchospasm persists, inhaled betaadrenergic agonists (eg, albuterol) may be useful. Volume
expansion plays an important role in the treatment of anaphylaxis, especially in severe cases of shock. Upon presentation, it is recommended to provide a fluid bolus and
infusion to maintain blood pressure and adequate urine
output. Glucocorticoids (methylprednisone 125 mg IV or
hydrocortisone 500 mg IV) may be administered to prevent
relapse of symptoms during severe reactions. However, glucocorticoids have no significant immediate effects.
Antihistamines such as H2 antagonists are also commonly
administered. These agents are helpful for relieving skin
symptoms and may shorten the duration of the reaction but,
like glucocorticoids, have no immediate effects. There are
case reports showing resolution of symptoms with the
administration of glucagon for inotropic support in patients
who are taking beta-adrenergic antagonists.106 The recommended dose is a 1 mg IV bolus followed by a continuous
infusion of up to 1 mg/h. There is insufficient evidence to
recommend glucagon for most patients, but this strategy
may be considered for patients on regular beta-blockers
when standard therapies have failed.106
Neurogenic Shock
Pathophysiology. Neurogenic shock refers to reduced SVR
and hypotension which is most commonly caused by spinal
cord injuries at or above the level of the sixth thoracic vertebrae. It is caused by sympathetic denervation and interruption of
autonomic output from the spinal cord. This results in arteriolar
dilation and decreased venous return to the heart resulting in
systemic hypotension.107,108 Hypotension may also be accompanied by symptomatic bradycardia caused by unopposed
vagal stimulation in the setting of sympathetic denervation.
Bradycardia is typically exacerbated by manipulating or stimulating the patient such as during endotracheal suctioning, turning, or in the setting of hypoxia. Bradycardia can be severe and
progress to complete heart block or cardiac arrest.109 Neurogenic shock can present any time after spinal cord injury but
usually within several weeks of the initial event. Prompt recognition and treatment is crucial in order to maintain perfusion to
target organs and the spinal cord as hypoperfusion of the spinal
cord can cause a secondary injury.108
Treatment. Fluid resuscitation is considered first line for
hypotension, but vasopressors may be used in refractory
patients. While a specific blood pressure target has not been
validated with large clinical trials, based on small studies and
expert opinion, the acute spinal cord injury guidelines recommend maintaining an SBP of 85 to 90 mm Hg to prevent secondary spinal cord injury.107,108,110 Atropine can be used for
acute, symptomatic bradycardia in doses ranging from 0.4 to
0.6 mg IV every 4 hours as necessary. It is recommended to
have atropine readily available for patients with spinal cord
injuries since bradycardia may occur suddenly especially early
after injury.110 The vasopressor of choice is not well defined
but phenylephrine is often avoided due to its ability to cause
marked reflex bradycardia. For patients with hypotension and
bradycardia, dopamine or epinephrine (Table 5) infusions may
be helpful due to their chronotropic effects.109,110 In refractory
bradycardia or for patients requiring long-term pharmacologic
management, methylxanthines (aminophylline or theophylline)
and propantheline have been used as a bridge to pacemaker
implantation or for patients who are not candidates for a
pacemaker.108,111-116
Cardiogenic Shock
Incidence and Causes. Cardiogenic shock (CS) may occur for a
number of reasons such as derangements in intravascular volume in HF and pulmonary hypertension (PH), massive PE with
resultant right ventricular HF, severe mitral regurgitation, ventricular septal rupture, free wall rupture, chordae tendineae or
papillary muscle rupture, valvular disease, cardiac tamponade,
or acute MI. The most common cause of CS is acute
ST-elevation (STEMI) or non-ST-elevation MI (NSTEMI)
with LV failure.117,118 Approximately 5% to 15% of STEMI
cases are complicated by CS, which is the leading cause of
death in these patients.119,120 Risk factors for developing CS
include age (>75 years), female gender, history of hypertention
Moranville et al
53
(HTN), diabetes (DM), previous acute coronary syndrome,

multivessel coronary artery disease, HF, low systolic blood
pressure ([SBP] <80 mm Hg), and rapid heart rate (>100
beats/min).119,121-123 In general terms, CS can be described
as a state of hypoperfusion due to cardiac failure. Using hemodynamic parameters, CS can be defined as hypotension (SBP
<80-90 mm Hg or MAP 30 mm Hg lower than baseline) with
severe reduction in cardiac index ([CI] < 1.8 L/min/m2 without
or <2.0 to 2.2 L/min/m2 with supportive measures) and adequate or elevated filling pressure (eg, LVEDP >18 mm Hg or
RVEDP greater than 10-15 mm Hg).124 A PAC is helpful during CS to measure PCWP, CI, and SVR to monitor hemodynamic changes. Echocardiography is used to evaluate cardiac
filling pressures, left ventricular ejection fraction (LVEF), and
valvular integrity to rule out mechanical causes of CS.124-127
Pathophysiology
Left ventricle. Any mechanical or ischemic insult as well as
progressive cardiomyopathy may compromise CO, cause
hypotension, and result in CS. Severe MI can cause hemodynamic instability, especially if there is significant anterior wall
(left ventricular) involvement. This is exacerbated further by
hypotension, impaired coronary perfusion, and infarct expansion. Progression of HF to stage IV as classified by the American College of Cardiology and the American Heart
Association (ACC/AHA), with resultant pump failure or acute
decompensated HF (ADHF) with volume overload may also
cause CS.128,129 Restrictive LV compliance and impaired diastolic filling has been associated with CS as well due to reduced
SV and CO.130 One compensatory response to low output
involves catecholamine release to trigger vasoconstriction, inotropy, and chronotropy. These responses, however, are also
detrimental due to increased myocardial wall tension and
oxygen demand. It is important to note that CS is not solely
characterized by reduced cardiac contractility. Despite receiving mechanical or pharmacologic support, the mean LVEF in
the SHOCK trial coincides with numerous studies of systolic
HF patients who had good functional status.117,131-140 This
lends support to multifactorial processes beyond cardiac function which are implicated in CS. Chronic systolic HF patients
express ventricular dilation to maximize SV and CO through
Frank-Starling forces. This adaptive response, however, does
not occur acutely in patients with MI and CS.
Right ventricle. Right ventricular (RV) failure is implicated in
CS when there is not adequate preload for the LV, resulting in
insufficient SV and systemic CO. In addition to inferior wall
MI, RV hypertrophy and failure can result from longstanding PAH due to chronically elevated pulmonary vascular
resistance (PVR). Excessive RV hypertrophy reduces coronary
perfusion to this region of the heart, further exacerbating the
condition. Massive PE and obstruction of pulmonary circulation can also cause acute RV failure. Under these conditions,
high preload compromises ventricular interdependence which
causes bowing of the ventricular septum into the LV chamber.
This obstructs LV filling via the mitral valve, compromises

CO, and decreases systemic perfusion.141
Vasculature. Several compensatory mechanisms are activated
in the setting of CS due to end organ hypoperfusion. Neurohormonal imbalance is well defined for patients with chronic HF,
and these same processes are upregulated during acute MI.
Release of catecholamines from the sympathetic nervous system (SNS) induces vasoconstriction, inotropy, and chronotropy
to maintain MAP. The renin-angiotensin-aldosterone system
(RAAS) plays a significant role in exacerbating CS via production of angiotensin II, a potent vasoconstrictor. Aldosterone
release causes salt and water retention in an attempt to increase
preload, LV filling, and CO.128,129 Vasopressin is released in
response to hypotension to induce vasoconstriction via V1a
receptors and water reabsorption by activating V2 receptors
in the nephron.110 These responses increase myocardial workload, afterload, and preload, in addition to causing reduced coronary perfusion which culminates in myocardial stress and
increased oxygen demand.
Inflammatory response. Inflammation and vasodilation are
not as well defined but may be present during acute MI and
CS. In the SHOCK trial, median SVR was relatively normal
despite low CO when systemic inflammatory response syndrome (SIRS) or sepsis was suspected.142 Even in patients
without suspected SIRS or sepsis, SVR was inappropriately
low, suggesting the presence of other vasodilatory factors.
SIRS has been identified in acute MI by high serum concentrations of inflammatory markers such as IL-6, TNF-a, and white
blood cell count.142 Toxic level of nitric oxide due to inducible
nitric oxide synthetase have also been documented to be elevated in CS.143-148
Treatment. A PAC is useful for management of CS to help
guide therapy based on hemodynamic parameters since small
changes can have a significant impact on patient stability.
Knowing PCWP, CI, and SVR is beneficial when titrating IV
inotropic or vasopressor agents and high doses of these medications have been linked to increased mortality.123,149 Clinicians
must balance adverse effects with the sequelae of hypotension.
The ACC/AHA for STEMI provide guidance for selection of
inotropic and vasopressor medications during CS. Fluid resuscitation is recommended for patients who do not display signs
and symptoms of volume overload. In patients unresponsive to
fluid resuscitation or when not indicated, dobutamine may be
considered for SBP between 70 and 100 mm Hg if there are
no signs and symptoms of CS. Dopamine is recommended for
patients presenting with signs and symptoms of CS due to its
additional vasoconstrictive properties (Table 5). Combined,
moderate doses of these agents may be more beneficial than
maximizing a single agent to minimize toxicity. For refractory
patients or those presenting with a SBP less than 70 mm Hg,
norepinehprine should be considered.1,149 A recent trial evaluated 28-day mortality for patients in shock who were
54
randomized to dopamine or norepinephrine to maintain blood

pressure. There was no difference in the primary end point
for the 1679 patients enrolled, but a subgroup analysis of
280 patients with CS revealed a lower rate of death and fewer
of tachyarrthmias favoring norepinephrine. This was a post
hoc, subgroup analysis and the study was not powered to detect
such a difference.150 Clinicians should keep in mind the risk of
using potent vasoconstricting agents, such as norepinephrine
(Table 5), which can significantly increase SVR in patients
with already poor cardiac contractility.
Many studies have helped shape practice by providing data
that support early reperfusion. A predefined sub-study of the
GUSTO-1 trial evaluated treatment of CS caused by acute
MI using various thrombolytic regimens (streptokinase and/or
recombinant tissue plasminogen activator (rt-PA)) in addition
to standard medical therapy with aspirin, heparin, and atenolol.
The primary end point, 30-day all-cause mortality, was significantly higher in patients who developed CS compared to those
who did not (57% vs 3%, P < .01). Patients who did not present
with CS, but who developed it during the hospitalization experienced a longer time to administration of thrombolytic therapy
(3.20 + 1.75 hours vs 3.09 + 1.62 hours, P .01). Beyond
medication therapy, a post hoc analysis of GUSTO-1 showed
percutaneous transluminal coronary angioplasty (PTCA) significantly reduced 30-day mortality (32% vs 61%, P < .001)
in patients who developed CS.119 The SHOCK trial is the largest prospective study evaluating treatment of CS due to acute
MI. Patients were randomized to emergency revascularization
(PTCA or coronary artery bypass grafting [CABG]) within
18 hours or intensive medical therapy (including thrombolytic
agents). The basis for this trial came from previous nonrandomized reports of improved outcomes when revascularization
was utilized for patients with acute MI and CS. The primary
end point, 30-day mortality, occurred in 46.7% and 56% of
patients randomized to revascularization versus medical therapy, respectively (P .11), which translates to a 17% relative
risk reduction. There was a 12.8% absolute risk reduction in 6month mortality (P .027) and 13.1% absolute risk reduction
at 1 year, both favoring revascularization (P .03).117,151 A
multivariate analysis of the SHOCK trial revealed that older
age, shock on admission, creatinine >1.9 mg/dL, history of
hypertension, and noninferior MI were independent risk factors
for mortality.117
While reperfusion has been proven effective for treatment of
acute MI complicated by CS, not all hospitals have a cardiac
catheterization laboratory and may not be able to facilitate
quick access to a PCI-capable center (90-minute door-toballoon time from initial presentation). When high-risk patients
present with ACS and delays in transfer are anticipated, the
ACC/AHA STEMI guidelines provide strong recommendations to administer thrombolytics plus antithrombotic therapy
before and during transfer with the intention of proceeding to
angiography at the receiving center.152-154 The primary literature supporting this recommendation used aspirin and heparin
or enoxaparin in addition to thrombolytic therapy. CARESSin-AMI utilized half-dose reteplase, upstream abciximab, and
clopidogrel at the discretion of the physician prior to patient

transfer. The TRANSFER-AMI protocol included full-dose
tenecteplase, recommended clopidogrel, and glycoprotein IIb/
IIIa inhibitors were given at the time of PCI according to standard practice of the receiving center.
In addition to thrombolysis and PCI, adjunctive, antithrombotic therapy should be implemented. An in-depth discussion
of these therapies is beyond the scope of this review but
deserves mention as these agents are critical to maximize the
effectiveness of thrombolysis and PCI. Antiplatelet agents
including aspirin and clopidogrel should be administered for
PCI, thrombolysis, or medical management unless contraindicated. Aspirin and clopidogrel have data from multiple trials
supporting their use for these indications.155-158 A new thienopyridine, prasugrel, is a viable option in lieu of clopidogrel for
PCI with stent placement.159 There is no data available to support the use of prasugrel as medical management or in conjunction with thrombolytic agents. Additional antiplatelet therapy
with a glycoprotein IIb/IIIa inhibitor is commonly used during
PCI. There are also multiple anticoagulant options for management of ACS including heparin, low-molecular-weight
heparin, bivalirudin, and fondaparinux which are described in
greater detail in the ACS guidelines.155
Mechanical support can be employed for the management of
CS to help relieve myocardial work and ischemia as well as
maintain sufficient tissue perfusion. Placement of an intraaortic balloon counterpulsation pump (IABP) is a standard of
care that is recommended by the ACC/AHA for STEMI complicated by CS when pharmacological therapy is ineffective
and until revascularization can be performed.149 This device
provides a reduction in afterload to minimize myocardial workload and augments diastolic filling of coronary arteries. The
SHOCK trial registry, including patients who were ineligible
for the trial, showed a statistically significant reduction of inhospital mortality favoring use of an IABP compared to those
who did not receive one.160 More complete cardiac support can
be supplied by placement of a left ventricular assist device
(LVAD) in cases of severe LV failure. There are multiple types
of devices which can be placed peripherally or surgically to
provide extracorporeal or intracorporeal circulation. An LVAD
may be placed temporarily if LV failure is thought to be
reversible or may be utilized as a bridge to more definitive therapy
such as implantation of a permanent, surgically placed LVAD or
heart transplant. When compared to an IABP for circulatory support in the setting of CS, a peripherally placed LVAD has not
shown significant reductions in mortality, but hemodynamic
parameters such as CO and PCWP are improved.161-164
Patients with chronic HF and LV systolic dysfunction may
present with hypotension and CS due to ADHF or progression
to pump failure. Diuretics or ultrafiltration is necessary to
restore euvolemia, but vasoactive agents may also be necessary. Although inotropic therapy has been proven to increase
mortality in a number of previous trials, these agents may be
necessary during CS to maintain adequate blood pressure for
perfusion to end organs.128,129,165 However, when blood pressure tolerates, vasodilators (nitroglycerin, nitroprusside,
Moranville et al
55
nesiritide) are preferred. These patients may have increased

preload and afterload due to excessive edema and overexpression of neurohormonal systems, respectively. Using vasodilators to reduce LV wall tension and myocardial stretch
(preload) as well as SVR (afterload) may help increase CO and
SBP. However, inotropes may be considered if a patient has
SBP < 90 mm Hg, is symptomatically hypotensive despite adequate filling pressure (preload), or is unresponsive to or intolerant of vasodilators.128,129,165 In addition to SBP < 90 mm
Hg, worsening renal function, cool extremities, narrow pulse
pressure, and altered mental status are indicators of a low output state. Inotropes are useful as a bridge to long-term therapy
such as revascularization, placement of an LVAD, or heart
transplantation.
Conclusion
No matter the etiology, any shock state can be rapidly fatal if
not treated. The primary goal of therapy, guided by patientspecific signs and symptoms as well as hemodynamic parameters, should be aimed at restoring perfusion to vital organs.
It is critical to differentiate between shock states in order to
accurately diagnose patients and reverse underlying causes.
Early resuscitation is a mainstay of therapy in all shock states
followed by treatment of underlying causes or triggers and
appropriate supportive care.
Declaration of Conflicting Interests
The author(s) declared no conflicts of interest with respect to the
authorship and/or publication of this article.
Funding
The author(s) received no financial support for the research and/or
authorship of this article.
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Evaluation and Management of

Shock States: Hypovolemic,

Journal of Pharmacy Practice

Michael P. Moranville, PharmD, BCPS1,

creatinine (SCr) and blood urea nitrogen (BUN). Decreased

University of Chicago Medical Center, Chicago, IL, USA

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Table 1. Normal hemodynamic parameters

Table 2. Calculations for hemodynamic parameters

PCWP may also be referred to as pulmonary artery occlusion pressure

optimal goals of resuscitation for shock may not necessarily

Central Venous Catheter

Mean pulmonary artery

impairing venous compliance. Venous blood gas can be

Pulmonary Artery Catheter

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Journal of Pharmacy Practice 24(1)

The PCWP is a marker of left atrial pressure (LAP) and left

Table 3. Classification of acute blood loss severity

Abbreviation: CNS, central nervous system.

trauma patients who may have operative or injury-related blood

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Table 4. Fluids used for shock resuscitation

Sodium bicarbonate, hydroxide, or acetic acid

have been recommended by the ACS for fluid replacement;

isotonic crystalloids on volume resuscitation is replenishment

Colloid fluids. Colloid fluids, such as albumin, hydroxyethyl

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Journal of Pharmacy Practice 24(1)

severe blood loss and should be reserved for hypovolemia due

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Table 5. Pharmacology, dose, and therapeutic effect of vasopressors and inotropes

Dose/Onset and Duration

Vasodilatory shock (usually drug of choice for sepsis),

ADHF, low CO state, cardiogenic shock, septic

outcomes are dependent on the appropriateness and efficiency

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Journal of Pharmacy Practice 24(1)

Treatment. Early goal-directed resuscitation initiated in the

Appropriate IV broad-spectrum antimicrobial therapy

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drotrecogin alpha). The use of corticosteroids in sepsis remains

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Journal of Pharmacy Practice 24(1)

inappropriate bradycardia. Pulmonary vasospasm has also been

Treatment. Due to the potential for anaphylaxis to progress

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(HTN), diabetes (DM), previous acute coronary syndrome,

This obstructs LV filling via the mitral valve, compromises

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Journal of Pharmacy Practice 24(1)

randomized to dopamine or norepinephrine to maintain blood

clopidogrel at the discretion of the physician prior to patient

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nesiritide) are preferred. These patients may have increased

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Journal of Pharmacy Practice 24(1)

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63. Meybohm P, Cavus E, Bein B, et al. Small volume resuscitation: a

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Journal of Pharmacy Practice 24(1)

after spinal cord injury. Pharmacotherapy. 2008;28(1):

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the American College of Cardiology Foundation/American