CREG E CREG E - EMCREG

Transcription

International
www.emcreg.org
COLLABORATE | INVESTIGATE | EDUCATE
This educational monograph was supported in part by an unrestricted
educational grant from Janssen Pharmaceuticals
CARI NG FOR CRI T ICA LLY I LL
AND I NJ U RED PAT I EN TS I N T H E
EMERGENCY DEPART MEN T
EMCREG-INTERNATIONAL
MONOGRAPH BASED ON THE
OCTOBER 27, 2015 SYMPOSIUM
BOSTON, MA
COMPLIMENTARY CME MONOGRAPH
FEBRUARY 2016
E
EMCREG -International
EMCREG-International
© Copyright EMCREG-International 2016
CARING FOR CRITICALLY ILL AND INJURED PATIENTS IN THE EMERGENCY DEPARTMENT - FEBRUARY 2016
CREG
OPTIMAL THERAPY FOR ACS: USING GUIDELINE-BASED TREATMENTS IN THE EMERGENCY SETTING - JANUARY 2016
E
cr itica l ca r e:
CREG
International
critical care:
CARING FOR CRITICALLY ILL AND
INJURED PATIENTS IN THE
EMERGENCY DEPARTMENT
EMCREG-International Monograph
Based on the
October 27, 2015 Symposium in Boston, MA
Editor:
W. Brian Gibler, MD
President, EMCREG-International
Professor of Emergency Medicine
Department of Emergency Medicine
University of Cincinnati College of Medicine
Cincinnati, OH
Assistant Editors:
Judy M. Racadio, MD
Amy L. Hirsch
Production & Graphics Design Manager:
Todd W. Roat
Release Date: March 31, 2016
End Date: March 31, 2017
E
CREG
International
E
CREG
International
www.emcreg.org
February 2016
Dear Colleagues,
It is our pleasure to provide this February 2016 EMCREG-International Monograph which serves as the proceedings from our October 27, 2015, EMCREGInternational satellite Symposium during the 2015 ACEP Scientific Assembly in Boston, MA. This is the first EMCREG-International Symposium and Monograph
which focuses on the provision of critical care in the Emergency Department with Jordan B. Bonomo, MD, serving as Symposium Chairman. All of the speakers
for the EMCREG-International Symposium on October 27, 2015, in Boston are the authors of this Monograph. These are emergency physician experts with
specialty fellowship training in Critical Care. This EMCREG-International Monograph has been accredited by the University of Cincinnati Office of Continuing
Medical Education for 4 hours of AMA PRA Category 1 Credits.
Emergency Physicians and Hospitalists care daily for patients who are critically ill and injured. The management of these patients is often complex and requires
detailed diagnostic and therapeutic information, as well as a thorough understanding of disease pathophysiology. In this EMCREG-International Monograph,
multiple critical care topics including critical respiratory illness/ventilator management and the current therapy for septic shock provide two major areas of
interest to the practicing clinician. In addition, the treatment of significant deep venous thrombosis and pulmonary embolism (DVT/PE) and the management
of atrial fibrillation are emphasized. For patients with DVT/PE and atrial fibrillation, pharmacologic management now extends beyond rate control and warfarin
to treatment with Factor Xa inhibitors and other antagonists to the clotting cascade. For patients presenting to the Emergency Department with significant
bleeding who are currently being treated with these agents, the clinician is given practical approaches to reverse the process. In addition, the treatment of
patients post-cardiac arrest resuscitation is described, expanding their management beyond hypothermia in the Emergency Department and as an inpatient.
Finally, the use of thromboelastography (TEG) to evaluate the critically ill and injured patient’s ability to clot blood is described. As you will note, this information
has previously been presented in last month’s January 2016 EMCREG-International Monograph on Acute Coronary Syndrome as this topic is important to both
discussions.
Thank you very much for your interest in the EMCREG-International organization as well as our symposiums and enduring material pieces. EMCREGInternational is now entering its 27th year as a research and educational organization with membership that includes Steering Committee members from across
the world. We appreciate Janssen Pharmaceuticals providing an unrestricted educational grant to help support the October 27, 2015 symposium and this
monograph. We hope that you enjoy this February 2016 EMCREG-International Monograph exploring major critical care topics which will help you to continue to
provide outstanding care to your patients.
Sincerely,
W. Brian Gibler, MD
Professor of Emergency Medicine
Cincinnati, Ohio USA
CARING FOR CRITICALLY ILL AND INJURED PATIENTS IN THE EMERGENCY DEPARTMENT
i
CONTRIBUTING AUTHORS:
W. Brian Gibler, MD
Professor of Emergency Medicine,
Department of Emergency Medicine,
University of Cincinnati College of
Medicine, Cincinnati, OH
Brian M. Fuller, MD, MSCI
Assistant Professor of Anesthesiology
and Emergency Medicine; Department of
Anesthesiology, Division of Critical Care, Division
of Emergency Medicine, Washington University
School of Medicine, St. Louis, MO
Nicholas M. Mohr, MD, MS
Departments of Emergency Medicine and
Anesthesiology
Division of Critical Care
Roy J. and Lucille A. Carver College of Medicine
University of Iowa, Iowa City, IA
Gregory J. Fermann, MD
Professor & Executive Vice Chairman;
Director, Clinical Trials Center, Department of
Emergency Medicine, University of Cincinnati
College of Medicine, Cincinnati, OH
Jon C. Rittenberger, MD, MS
Associate Professor, University of Pittsburgh
Pittsburgh, PA
Evie G. Marcolini, MD
Assistant Professor,
Departments of Emergency Medicine and
Neurology, Divisions of Neurocritical Care
and Emergency Neurology; Medical Director,
SkyHealth Critical Care, Yale University
School of Medicine, New Haven, CT
Charles V. Pollack Jr., MA, MD
Associate Provost for Innovation in Education
Director, Jefferson Institute of Emerging Health
Professions; Professor and Senior Advisor for
Interdisciplinary Research and Clinical Trials
Sidney Kimmel Medical College of
Thomas Jefferson University
Philadelphia, PA
Jordan B. Bonomo, MD
Associate Professor, Emergency Medicine;
Director, Division of Critical Care, Department
of Emergency Medicine; Associate Professor,
Neurosurgery/Neurocritical Care; Director,
Neurocritical Care Fellowship, University of
Cincinnati College of Medicine, Cincinnati, OH
Natalie E. Kreitzer, MD
Assistant Professor of Emergency Medicine
Fellow, Neurovascular Emergencies and
Neurocritical Care
Cincinnati, OH
Christopher R. Zammit, MD
Assistant Professor of Emergency
Medicine and Neurology
Department of Emergency Medicine, Critical
Care Division
Cincinnati, OH
Christopher M. Palmer, MD
Assistant Professor of Anesthesiology
and Emergency Medicine, Department of
Anesthesiology, Division of Critical Care, Division
of Emergency Medicine, Washington University
School of Medicine, St. Louis, MO
Trenton C. Wray, MD
Critical Care Fellow
Division of Critical Care, Division of Emergency
Medicine, Washington University School of
Medicine, St. Louis, MO
ii
EMCREG-INTERNATIONAL MEMBERS:
W. Brian Gibler, MD, President
University of Cincinnati
Cincinnati, Ohio
Cincinnati, Ohio
Masatoshi Oba, MD, PhD
Osaki Citizens Hospital
Osaki, Japan
V. Anantharaman, MD
Singapore General Hospital
Singapore
J. Lee Garvey, MD
Carolinas Medical Center
Charlotte, North Carolina
Gunnar Öhlén, MD, PhD
Karolinska University Hospital
Stockholm, Sweden
Tom P. Aufderheide, MD
Medical College of Wisconsin
Milwaukee, Wisconsin
Patrick Goldstein, MD
Lille University Hospital
Lille, France
Brian J. O’Neil, MD
Wayne State University
Detroit, Michigan
Barbra Backus, MD
The Hague Medical Center
The Hague, Netherlands
Jin H. Han, MD
Vanderbilt University Medical Center
Nashville, Tennessee
Joseph P. Ornato, MD
Medical College of Virginia
Richmond, Virginia
Roberto R. Bassan, MD
Pro-Cardiaco Hospital
Rio de Janeiro, Brazil
Katherine L. Heilpern, MD
Emory University School of Medicine
Atlanta, Georgia
Arthur M. Pancioli, MD
Cincinnati, Ohio
Andra L. Blomkalns, MD
University of Texas Southwestern Medical Center
Dallas, Texas
Brian Hiestand, MD, MPH
Wake Forest University
Winston Salem, North Carolina
W. Frank Peacock, MD
Baylor College of Medicine
Houston, Texas
Richard Body, MB ChB, PhD
Manchester University Hospital
Manchester, UK
James W. Hoekstra, MD
Nicolas R. Peschanski, MD
Rouen University Hospital
Upper-Normandy, France
Gerald X. Brogan, MD
Hofstra North Shore - LIJ
Forest Hills, New York
Judd E. Hollander, MD
Philadelphia, Pennsylvania
Charles V. Pollack Jr. , MA, MD
David F. M. Brown, MD
Massachusetts General Hospital
Boston, Massachusetts
Brian R. Holroyd, MD
University of Alberta Hospitals
Edmonton, Alberta, Canada
Emanuel P. Rivers, MD, PhD
Henry Ford Hospital
Detroit, Michigan
Charles B. Cairns, MD
University of Arizona
Tucson, Arizona
Shingo Hori, MD
Keio University
Tokyo, Japan
Francois P. Sarasin, MD
Hospital Cantonal
Geneva, Switzerland
Anna Marie Chang, MD
Raymond E. Jackson, MD
William Beaumont Hospital
Royal Oak, Michigan
Harry R. Severance, MD
University of Tennessee College of Medicine
Chattanooga, Tennessee
Douglas M. Char, MD
Washington University School of Medicine
St. Louis, Missouri
J. Douglas Kirk, MD
U.C. Davis Medical Center
Sacramento, California
Corey M. Slovis, MD
Vanderbilt University
Sean P. Collins, MD
Phillip D. Levy, MD
Wayne State University
Detroit, Michigan
Alan B. Storrow, MD
Louise Cullen, MB, BS
Royal Brisbane Hospital, Brisbane
Queensland, Australia
Christopher J. Lindsell, PhD
Cincinnati, Ohio
Richard L. Summers, MD
University of Mississippi
Jackson, Mississippi
Herman H. Delooz, MD, PhD
University Hospital Gasthuisberg
Leuven, Belgium
Chad V. Miller, MD
Benjamin Sun, MD
Oregon Health & Science University
Portland, Oregon
Deborah B. Diercks, MD
University of Texas Southwestern Medical Center
Dallas, Texas
Richard M. Nowak, MD
Henry Ford Hospital
Detroit, Michigan
James E. Weber, MD
University of Michigan
Ann Arbor, Michigan
iii
ACCREDITATION AND DESIGNATION OF CREDIT
This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council
for Continuing Medical Education through the joint providership of the University of Cincinnati and EMCREG-International. The University of
Cincinnati is accredited by the ACCME to provide continuing medical education for physicians. The University of Cincinnati designates this
enduring material activity for a maximum of 4.0 AMA PRA Category I Credits™.
Physicians should claim only the credits commensurate with the extent of their participation in the activity. The opinions expressed during
this educational activity are those of the faculty and do not necessarily represent the views of the University of Cincinnati. Participants have
an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The
University of Cincinnati College of Medicine is committed to resolving all conflicts of interest issues which may arise as a result of prospective
faculty member’s significant relationships with drug or device manufacturer(s). The University of Cincinnati College of Medicine mandate is to
retain only those speakers with financial interests that can be reconciled with the goals and educational integrity of the program.
In accordance with the ACCME Standards for Commercial Support the speakers for this course have been asked to disclose to participants
the existence of any financial interest/and or relationship(s) (e.g. paid speaker, employee, paid consultant on a board and/or committee for
a commercial company) that would potentially affect the objectivity of his/her presentation or whose products or services may be mentioned
during their presentation. The following disclosures were made:
PLANNING COMMITTEE AND FACULTY DISCLOSURES:
Jordan B. Bonomo, MD:
Consultant: Bard Medical; Speaker’s Bureau: Genetech, Inc.
Gregory J. Fermann, MD:
Advisory Board: Janssen, Pfizer; Consultant: Janssen, Pfizer, Novartis; Speaker’s Bureau:
Janssen
Barb Forney:
No relevant relationships
Brian M. Fuller, MD:
W. Brian Gibler, MD:
Advisory Board: AstraZeneca, Entegrion, Intelemage; Shareholder: Intelemage, Siloam, MyocardioCare, Entegrion
Natalie E. Kreitzer, MD:
Evie G. Marcolini, MD:
Advisory Board: AstraZeneca, Novartis, Janssen
Nicholas M. Mohr, MD: No relevant relationships
Charles V. Pollack, Jr., MD:
Consultant: Boheringer, Ingelheim, Janssen, BMS/Pfizer, Daiichi-Sankyo
Jon C. Rittenberger, MD:
Grant Recipient: AHA, National Institutions of Health, David Scaife Foundation
Christopher M. Palmer, MD:
Rick Ricer, MD:
Susan P. Tyler:
Trent C. Wray:
Christopher R. Zammit, MD:
Commercial Acknowledgment: This educational monograph was funded in part by an unrestricted educational grant from
Janssen Pharmaceuticals.
Disclaimer: The opinions expressed during the live activity are those of the faculty and do not necessarily represent the views of the University
of Cincinnati. The information is presented for the purpose of advancing the attendees’ professional development.
Off Label Disclosure: Faculty members are required to inform the audience when they are discussing off-label, unapproved uses of devices and
drugs. Physicians should consult full prescribing information before using any product mentioned during this educational activity.
Learner Assurance Statement: The University of Cincinnati is committed to resolving all conflicts of interest issues that could arise as a result
of prospective faculty members’ significant relationships with drug or device manufacturer(s). The University of Cincinnati is committed to
retaining only those speakers with financial interests that can be reconciled with the goals and educational integrity of the CME activity.
EMCREG-International will not be liable to you or anyone else for any decision made or action taken (or not taken) by you in reliance on these
materials. This document does not replace individual physician clinical judgment. Clinical judgment must guide each professional in weighing
the benefits of treatment against the risk of toxicity. Doses, indications, and methods of use for products referred to in this program are not
necessarily the same as indicated in the package insert and may be derived from the professional literature or other clinical courses. Consult
complete prescribing information before administering.
iv
TABLE OF CONTENTS:
TREATMENT OF CRITICAL RESPIRATORY ILLNESS IN THE EMERGENCY DEPARTMENT AND
INTENSIVE CARE UNIT1
Departments of Emergency Medicine and Anesthesiology; Division of Critical Care
Washington University School of Medicine, St. Louis, MO
Departments of Emergency Medicine and Anesthesiology; Division of Critical Care
Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA
DEEP VENOUS THROMBOSIS AND PULMONARY EMBOLISM: OPTIMAL THERAPY
AND PREVENTION FOR THE CRITICALLY-ILL PATIENT
7
Professor & Executive Vice Chairman; Director, Clinical Trials Center, Department of
Emergency Medicine, University of Cincinnati College of Medicine, Cincinnati, OH
POST-CARDIAC ARREST IN THE EMERGENCY DEPARTMENT - BEYOND HYPOTHERMIA
14
Associate Professor, University of Pittsburgh Department of Emergency Medicine, Pittsburgh, PA
ATRIAL FIBRILLATION: ADVANCED MANAGEMENT OF THE CRITICALLY ILL PATIENT
IN THE EMERGENCY DEPARTMENT AND INTENSIVE CARE UNIT 19
Assistant Professor, Departments of Emergency Medicine and Neurology, Divisions of Neurocritical Care and
Emergency Neurology; Medical Director, SkyHealth Critical Care, Yale University School of Medicine, New Haven, CT
MANAGEMENT OF MAJOR BLEEDING FOR PATIENTS TREATED WITH
NON-VITAMIN K ANTAGONIST ORAL ANTICOAGULANTS
28
Charles V. Pollack, Jr., MD
Associate Provost for Innovation in Education; Director, Jefferson Institute of Emerging Health Professions; Associate Dean
for CME and Strategic Partner Alliances; Professor, Department of Emergency Medicine, Thomas Jefferson
University, Philadelphia, PA
THROMBOELASTOGRAPHY (TEG) – UNDERSTANDING THE PATIENT’S ABILITY
TO CLOT BLOOD 34
Associate Professor, Emergency Medicine; Director, Division of Critical Care, Department of Emergency Medicine;
Associate Professor, Neurosurgery/Neurocritical Care; Director, Neurocritical Care Fellowship, University of
Cincinnati College of Medicine, Cincinnati, OH
Assistant Professor of Emergency Medicine; Fellow, Neurovascular Emergencies and Neurocritical Care,
Department of Emergency Medicine, University of Cincinnati College of Medicine, Cincinnati, OH
Assistant Professor of Emergency Medicine and Neurology; Department of Emergency Medicine, Critical
Care Division, University of Cincinnati College of Medicine, Cincinnati, OH
ADVANCED RESUSCITATION OF SEPTIC SHOCK IN THE EMERGENCY DEPARTMENT
AND INTENSIVE CARE UNIT 41
Assistant Professor of Anesthesiology and Emergency Medicine, Department of Anesthesiology, Division of Critical Care,
Division of Emergency Medicine, Washington University School of Medicine, St. Louis, MO
Trenton C. Wray, MD
Critical Care Fellow, Division of Critical Care, Division of Emergency Medicine, Washington University School of Medicine,
St. Louis, MO
v
TREATMENTOF
OFCRITICAL
CRITICALRESPIRATORY
RESPIRATORYILLNESS
ILLNESSININTHE
THE
TREATMENT
EMERGENCYDEPARTMENT
DEPARTMENTAND
ANDINTENSIVE
INTENSIVECARE
CAREUNIT
UNIT
EMERGENCY
TREATMENT OF CRITICAL RESPIRATORY ILLNESS
IN THE EMERGENCY DEPARTMENT AND INTENSIVE
CARE UNIT
Departments of Emergency Medicine and Anesthesiology
Division of Critical Care
Washington University School of Medicine in St. Louis
St. Louis, MO
Departments of Emergency Medicine and Anesthesiology
Division of Critical Care,
Roy J. and Lucille A. Carver College of Medicine University
of Iowa, Iowa City, IA
Objectives
1. Describe the general principles of mechanical ventilation,
including ventilator modes, basic mechanics, and various airway
pressures.
2. Describe the basic strategy for prescribing and managing mechanical ventilation in the Emergency Department (ED).
3. Describe the three broad patient cohorts that will be encountered in mechanically ventilated ED patients and how the approach to mechanical ventilation differs for each.
Introduction
Endotracheal intubation is a common procedure in the emergency
department (ED), and is a defining trait of the specialty of emergency
medicine (EM). It has been studied extensively, producing highquality evidence and practice recommendations.1 Endotracheal intubation is followed by the initiation of mechanical ventilation, but the
clinical study of mechanical ventilation has primarily been confined to
the intensive care unit (ICU). Comparatively, little attention has been
paid to the mechanically ventilated patient in the ED. Consequently,
acquiring the basic skills to prescribe a safe and effective mechanical
ventilation strategy has not been a historical training focus of EM.2
This knowledge gap may put critically ill patients at risk during the
most vulnerable time in critical illness.
Close to 300,000 patients receive mechanical ventilation in the
ED annually.3 The use of mechanical ventilation in the ED is on the
rise, as are lengths of stay for intubated ED patients. These factors
converge to create a scenario where ED management of mechanical
ventilation impacts vulnerable patients more than at any other time
in the specialty’s history. Patients ventilated in the ED carry a high
mortality, and ventilator associated lung injury (VALI) is a significant
factor that influences morbidity and mortality in the critically ill. VALI
is a broad term used to describe the effects of mechanical ventilation
on the initiation and propagation of pulmonary and non-pulmonary
organ failure.4 This can occur even during the duration of the ED
length of stay. Additionally, ventilator management in the prehospital
and ED setting influences ventilator management in the ICU, suggesting that early care is impactful beyond the hours actually spent in the
ED.5,6
Mechanical Ventilation: General Principles
Mechanical ventilation does not treat disease; it simply provides respiratory support and time for healing to occur. It does, however, have
potential for causing harm. Effective mechanical ventilation should
prioritize limiting VALI while preventing primary clinical deterioration.
Applying basic principles of mechanical ventilation can allow the clinician to use the ventilator to maximum therapeutic potential and to
minimize iatrogenic injury, which undermines the healing process.
The Four Phases of a Mechanical Breath
Triggering represents the transition from expiration to inspiration, and
occurs either due to elapsed time or patient effort. Inspiration occurs
after the initiation of a breath, when pressurized gas flows from the
ventilator to the patient. It is controlled (or targeted) based on either
volume or pressure. Cycling represents the transition from inspiration
to expiration and occurs due to a decrease in flow, elapsed time, or
delivered volume (depending on mode). Expiration occurs when flow
from the ventilator stops and gas passively flows out from the lungs
through the exhalation valve of the ventilator.
Ventilator Modes
A mode describes the set of breath characteristics and patient-ventilator interactions that occur during the respiratory cycle. The mode
is simply an instruction set, which guides the ventilator’s interaction
with patient effort. Table 1 provides an overview of common modes
of mechanical ventilation. A positive pressure breath can be designed
to target either tidal volume or drive pressure. Neither strategy is
clearly superior, but both rely on a fundamental understanding of the
relationship between pressure and volume (respiratory compliance).
Either can achieve similar goals with respect to gas exchange and
limitation of VALI. For this reason, clinician familiarity should really
determine the mode of ventilation employed.
In most EDs, volume control/assist control (VC/AC) is the most
commonly used mode.5,7 Assisted breaths can either be volume- or
pressure-targeted (i.e., volume control or pressure control). With
volume control, a clinician determines a target tidal volume and
respiratory rate, and classically that tidal volume is delivered with a
constant flow rate. Modern ventilators often allow for other inspiratory
wave forms, but in all modes of volume control, the flow pattern is
determined by the ventilator. In pressure control ventilation, the venti-
1
TREATMENT OF CRITICAL RESPIRATORY ILLNESS IN THE
EMERGENCY DEPARTMENT AND INTENSIVE CARE UNIT
TABLE
01
Overview of Four Common Modes of Mechanical Ventilation
Ventilator Mode
Trigger
Target/Limit
Cycling
Advantages
Disadvantages
Volume control/assist control
(VC/AC)
Patient or time
Volume
Volume
• Decrease work of breathing
• May lead to excessive inspiratory pressures
• Guaranteed minute ventilation
• May be more challenging to achieve patient
comfort because of prescribed inspiratory flow
pattern
Pressure control/assist control
(PC/AC)
Patient or time
• Easy control of inspiration:
expiration ratio
Tidal volume and minute ventilation may change
with a change in lung compliance
Pressure
Time
• Limits inspiratory pressures
• Decelerating flow delivery is
often more comfortable
Pressure-support ventilation
(PSV)
Patient or time
Patient
Pressure for
patient breaths
(PSV)
Flow for
spontaneous
breaths
Flow/volume (VC)
or pressure (PC)
for mandatory
breaths
Volume or time
for mandatory
breaths
Pressure
Flow
lation circuit is pressurized to a pre-determined drive pressure during
inspiration. That pressure does not dictate the flow waveform, but it is
set along with an inspiratory time and a respiratory rate to deliver the
desired minute ventilation, similar to volume control ventilation. With
assist control (either pressure-targeted or volume-targeted), a patient
can trigger breaths or the ventilator will deliver breaths if the patient’s
respiratory frequency is inadequate. A patient who triggers at a rate
greater than the set respiratory rate will continue to receive a breath
at each effort.
Other modes commonly employed in basic mechanical ventilation
include synchronized intermittent mandatory ventilation (SIMV), and
pressure support ventilation (PSV), but because of their less frequent
application in the ED, a detailed overview of their use will not be
included here.
Basic Mechanics
• Difficult patient adjustment to two breath types
within same mode
• Patient comfort
• Decreased work of breathing
• Requires spontaneous breathing to be
preserved
• Variable tidal volumes
respiratory system, and can be increased by bronchospasm, or any
occlusion in the airways that obstructs air flow. Resistance is defined
as the ratio of changes in pressure to flow, suggesting that increased
resistance requires a greater change in pressure to achieve a given
rate of airflow.
A pressure-volume (PV) curve (Figure 1) demonstrates some key
features of respiratory system mechanics. The lower (LIP) and upper
inflection points (UIP) demonstrate areas of reduced compliance due
to low and high volumes respectively. As alveoli are opened from a
collapsed, atelectatic state, the lower inflection point transitions into
the steeper, more linear and compliant portion of the compliance
curve. At higher volumes, the upper inflection point represents a
transition to over-distention, risk for barotrauma, and reduced compliance. The linear portion of the curve between the LIP and the UIP
represents the portion of the compliance curve at which it is safest
FIGURE
Breathing occurs when a pressure gradient is generated. For
spontaneous breathing, this requires negative intrathoracic pressure
that draws air into the lungs, whereas for mechanical ventilation,
the ventilator generates positive pressure that pushes air into the
lungs. While mechanical ventilators can seem complex, the primary
variables are only pressure, flow, and volume; a ventilator generates
pressure or flow, which increases lung volume. Compliance refers
to the fundamental relationship between pressure and volume, and
compliance is defined as the tidal volume generated by a given
change in airway pressure. As such, improved compliance suggests
that the greater tidal volumes will be achieved at a given airway
pressure. Resistance describes the impedance to airflow through the
2
• Increased work of breathing
01
Pressure -Volume Cur ve
UIP
Volume
Synchronized intermittent
mandatory ventilation (SIMV)
LIP
Pressure
The linear portion of the curve between the lower inflection point (LIP)
and upper inflection point (UIP) is safest for ventilating patients.
to ventilate patients, because it is the least likely to cause repetitive atelectrauma or over distention and barotrauma. Unfortunately,
generating this curve for an individual patient can be difficult, and the
curve can change in a dynamic fashion.
Airway Pressures
In most modes of ventilation, airway pressures are used to alert
the clinician to changes in lung compliance or safety of mechanical
ventilation. The three most common airway pressures displayed for
monitoring on a mechanical ventilator are: peak airway pressure,
inspiratory plateau pressure, and mean airway pressure (Figure 2).
Peak pressure is the greatest pressure generated during the respiratory cycle, and represents the summation of the pressure required
to generate a tidal volume (based on respiratory compliance), and
the resistance to inspiratory flow. Often, clinicians want to isolate the
proportion of the peak pressure generated by respiratory compliance
(the pressure theoretically observed at the level of the alveolus). This
pressure is estimated only under no-flow conditions, which can be
approximated by performing an inspiratory hold maneuver, where a
valve is closed at end-inspiration. Flow is arrested, and the equilibrium pressure reflects alveolar pressure, also known as the inspiratory
plateau pressure. Plateau pressure, though imperfect, is the most
readily available and simplest reflection of transalveolar pressure, the
distending pressure of an alveolus, and is an important marker for
VALI potential. Mean airway pressure is the average airway pressure
observed through the respiratory cycle, and should be viewed as the
best indicator of how airway pressure can contribute to lung recruitment (maintaining open alveoli to participate in gas exchange).
Intrinsic PEEP
The last concept that is important to understanding how to safely
provide mechanical ventilation is the concept of intrinsic positive
end-expiratory pressure (PEEP). Exhalation is typically a passive
Pre s s u re -Ti m e Cu r ve fo r O n e M e c h a n i c a l
Ve nt i l at i o n Cyc l e
FIGURE
02
Peak
Plateau
P
process, where air flows from the alveolus to the airway and out of
the respiratory system. In patients who have airway disease, however,
this process can be impaired. Dynamic airway collapse causes a heterogeneous retention of air in alveolar subunits, because increased
intrathoracic pressure collapses airways and prevents exhalation from
occurring. Intrinsic PEEP can pose significant risks to mechanically
ventilated patients. While any patient can exhibit intrinsic PEEP with
a respiratory rate that is high enough, those with chronic obstructive
pulmonary disease (COPD) or asthma are at greatest risk.
These basic principles of mechanical ventilation can be applied to
three general categories of mechanically ventilated patients in the ED.
These include patients who: 1) are prone to have intrinsic PEEP; 2)
have ARDS; or 3) are at risk for ARDS.
Patients at Higher Risk for Intrinsic (or Auto-) PEEP
Setting PEEP on a ventilator (i.e., extrinsic PEEP) is used to maintain
end-expiratory lung volume, prevent derecruitment, and maintain
oxygenation. This is not to be confused with intrinsic PEEP. Under
normal conditions, expiratory flow declines to zero before the onset
of a subsequent breath; this is true for spontaneous breathing and
for positive pressure breathing. A decrease in elastic forces, or an
increase in resistive forces, will increase the time needed to fully
expire a delivered tidal volume. If inspiration occurs prior to the end
of exhalation, lung volume and alveolar pressure increases. This
process is called dynamic hyperinflation, and the resultant increase
in alveolar pressure is called auto-PEEP (Figure 3).8 Since exhalation
is determined by elastic forces and resistance, the most common
scenario in which the emergency physician will encounter intrinsic
PEEP is the intubated patient with COPD or status asthmaticus.
Physiology
Intrinsic PEEP has predictable physiologic effects. By preventing flow
termination at end-exhalation, end-expiratory lung volume increases,
leading to an increase in airway pressure. Juxta-cardiac pressure,
and therefore right atrial pressure, increases and venous return decreases. As a result of dynamic hyperinflation, lung volume continues
to rise, which is eventually accompanied by an increase in pulmonary vascular resistance (PVR) and right ventricular afterload. If this
process goes unchecked, two scenarios can occur:
1. cardiovascular collapse due to a combination of decreased
preload and right ventricular failure secondary to high right
ventricular afterload (high pulmonary vascular pressures)
2. barotrauma, such as pneumothorax.
3
FIGURE
03
threatening hypoventilation and subsequent respiratory acidosis. In
the sickest cohort, a balance has to be struck so that some amount
of hypercapnia and acidosis, as well as some amount of intrinsic
PEEP, are tolerated. If the clinician over-prioritizes the normalization
of pH, dynamic hyperinflation and intrinsic PEEP can lead to cardiovascular collapse; if the clinician over-prioritizes complete resolution
of intrinsic PEEP, minute ventilation will be so low that hypercapnia
and acidosis can become severe. Table 2 shows the general recommendations on initial ventilator settings.
As a general approach, during the most acute phase of critical illness in the ED, these patients should be deeply sedated to facilitate
respiratory muscle rest and to prevent ventilator dysynchrony. For
spontaneously breathing patients, the presence of intrinsic PEEP
promotes dysynchrony and increased work of breathing. If deep
sedation is achieved, PEEP can be set at 0 – 5 cm H2O. Patients
with life-threatening intrinsic PEEP usually do not suffer from severe
hypoxemia, and the fraction of inspired oxygen (FiO2) can usually be
set at 30-40%.
Flow Waveforms During Normal Mechanical
Ventilation and During Mechanical Ventilation
When Intrinsic (or Auto-) PEEP is Present
Normal
Intrinsic PEEP
Flow
Note that intrinsic PEEP occurs when the next breath begins
before the last breath is finished (before the flow returns to zero).
Identifying Intrinsic PEEP
The first step in recognizing intrinsic PEEP is having a high suspicion
for patients prone to developing it (i.e., those with obstructive lung
disease). The flow waveform on the ventilator will show that expiration does not completely terminate prior to the onset of the subsequent breath (Figure 3). In volume targeted ventilation, airway pressures will increase, and in pressure targeted ventilation, tidal volumes
will decrease. An expiratory hold maneuver can be performed, which
can quantify the level of intrinsic PEEP present. This maneuver allows
the clinician to close the expiratory valve at the time the next breath
would be delivered. Although this requires a passive patient with
no additional respiratory effort, measured airway pressure should
equilibrate to the level of set PEEP. If intrinsic PEEP is present, airway
pressure will be measured higher than set PEEP, and this difference
equals the level of intrinsic PEEP present under the set respiratory
conditions.
Patients with Acute Respiratory Distress Syndrome
Acute respiratory distress syndrome (ARDS) is an inflammatory
form of lung failure that typically occurs secondary to another lifethreatening insult, often as part of multisystem organ dysfunction. It
is defined according to the presence of bilateral opacities on chest
imaging, primarily non-hydrostatic pulmonary edema, and impaired
oxygen exchange.9 It is characterized by pulmonary capillary endothelial injury and alveolar epithelial injury, and widespread pulmonary
and non-pulmonary inflammation.
Physiology
ARDS results from a combination of predisposing conditions (e.g.,
trauma, sepsis) and patient-level risk modifiers (e.g., body mass index, acidosis). After the inciting event, activated immune cells recruit
neutrophils to the lungs, which serve to propagate the injury. The end
Setting the ventilator
Life-threatening intrinsic PEEP can lead to cardiovascular collapse,
so the set minute ventilation should be high enough only to avoid lifeTABLE
02
General Recommendations for Emergency Department Ventilator Settings
Patient Cohort
Mode
Tidal Volume
PEEP
RR
FiO2
Monitoring
At risk for iPEEP
VC/AC
8-10 mL/kg PBW
5
8-12
High enough for adequate
ventilation, low enough to
not promote iPEEP
.30 - .40
•
iPEEP
•
Airway pressure
ARDS
VC/AC
6 mL/kg PBW
Set with PEEP-FiO2 table
To maintain adequate pH
(≥7.15)
Titrated for SpO 2 ≥88%
Plateau pressure<30
At risk for ARDS
VC/AC
6-8 mL/kg PBW
≥5
20-30
.30 - .40
Plateau pressure 25-30
iPEEP: intrinsic positive end-expiratory pressure; ARDS: acute respiratory distress syndrome; VC: volume control; AC: assist control; RR: respiratory rate;
PBW: predicted body weight; FiO2: fraction of inspired oxygen; S pO2: peripheral oxygen saturation
4
result is protein-rich pulmonary edema, surfactant loss, and hypoxia.
Trials supporting ARDS therapy have been largely disappointing with
no therapy that targets the underlying pathophysiology of ARDS.
Mortality-reducing interventions can be summarized as:
1) “lung protective ventilation,” incorporating both limited tidal
volume and limited distending pressures.10
2) higher PEEP in severe ARDS.11
3) prone positioning in early, severe ARDS.12
4) cistatricurium infusion in early, severe ARDS.13
5) referral to an extracorporeal membrane oxygenation (ECMO)capable center for severe ARDS.14
ARDS has historically been viewed as an ICU syndrome, even though
the majority of ICU patients with ARDS are admitted from the ED.
Recent observational data from academic centers show that 8% of
ventilated ED patients have ARDS.5 Adherence to lung-protective
ventilation in the ED is poor, and early ED-based ventilator settings
influence subsequent lung protective ventilation in the ICU.5-7 As time
spent in the ED represents a vulnerable period for many critically ill
patients, improving care to incorporate routine delivery of lung protective ventilation has the potential to improve morbidity-free survival for
these patients.
Ventilator Settings
The goal of lung protective ventilation is to deliver low tidal volumes
[6 mL/kg predicted body weight (PBW)], low distending pressures
(inspiratory plateau pressure < 30 cm H2O), and PEEP titrated to
facilitate lung recruitment. To calculate PBW, the patient’s height
should be measured and PBW should be calculated. The tidal volume
should be set at 6 mL/kg based on this PBW. Next, PEEP should be
set with the aid of a PEEP-FiO2 table.15 This is a table that shows the
relationship between the FiO2 required to maintain minimal oxygenation and PEEP designed to recruit the lung. After these settings
are programmed into the ventilator, inspiratory plateau pressure
should be measured. With a passive patient, inspiratory plateau
pressure should be limited to <30cmH2O, and tidal volume should
be decreased even further if this pressure goal is not attained.15 This
simple approach provides the emergency physician with a manageable framework around which to combat the hypoxemia associated
with ARDS.
From this starting point, a variety of other ventilator maneuvers (e.g.,
recruitment maneuvers, “advanced” ventilator modes) and nonventilator maneuvers (e.g., prone positioning, inhaled pulmonary
vasodilators) can be used to recruit alveoli and improve oxygenation,
but these adjunctive therapies are typically not required in the ED.
Patients at Risk for ARDS
Most intubated ED patients have neither of the conditions described
above, but continue to be at risk for developing pulmonary complications, such as ARDS, during their hospital stay. For patients in the
emergency setting, VALI does not need much time to initiate and
propagate lung injury. This has been shown in animal studies, as well
as human data showing that most patients who develop ARDS do so
within 48 hours of hospital admission.16-18 This information provides
temporal urgency to get the ventilator set correctly from the beginning. Additionally, lung protection in the ED is rare, and the current
practice of ED mechanical ventilation can certainly promote VALI.
This has been demonstrated in two observational studies examining
mechanical ventilation in the ED.5,7 Another study of 243 patients
with severe sepsis and septic shock showed that use of ED mechanical ventilation predicted progression to ARDS, and higher ED tidal
volumes were associated with an increased incidence of ARDS.19 The
ED ventilator care also influences care in the ICU. Both prehospital
and ED ventilator management have been shown to predict inpatient
ventilator management, so guideline-adherent care influences patient
care even beyond the ED stay.5,6 Finally, lung-protective ventilation is a safe, low risk intervention. “Low” tidal volume is actually
normal physiologic tidal volume.20 High tidal volume ventilation was
delivered frequently in early anesthesia practice, as knowledge of
VALI did not yet exist and the priority at the time was normalization of gas exchange. This led to high tidal volumes being the norm
in the operating room, with carryover into the ICU. With improved
understanding of VALI and better ventilator technology such as the
provision of PEEP when tidal volume is decreased, high tidal volume
ventilation no longer carries the allure that it did decades ago. For
these reasons, almost all ED patients should receive a lung-protective
approach to mechanical ventilation in an effort to mitigate VALI.
Setting the Ventilator
The ventilator can be set similarly to that for patients with ARDS. The
patient’s height should be measured and tidal volume set at 6-8mL/
kg PBW. Plateau pressure should be limited to <25-30 cm H2O, and
hyperoxia avoided by initiating mechanical ventilation with a FiO2 of
30-40%, and titrating for an oxygen saturation of 92-96%. The PEEP
should be set ≥5 for all patients; consideration should be given for
higher PEEP in conditions that promote end-expiratory alveolar collapse secondary to reduced respiratory system compliance such as
obesity or ascites. The respiratory rate can be set at 20-30 breaths
per minute, depending on the metabolic demands and ventilation
requirements of the patient.
Conclusion
Mechanical ventilation in the ED is a common therapy for critically
ill patients. Applying the basic principles of mechanical ventilation
5
will allow the emergency physician to safely ventilate patients while
limiting the risk that the ventilator imposes on the patient’s outcome.
Emergency physicians should be familiar with how to detect intrinsic
PEEP and strategies to mitigate it. Patients with ARDS or at risk
for ARDS should be managed with a lung-protective approach. An
algorithmic approach should be used to optimize safe mechanical
ventilation, and these practices and clinical outcomes should be
monitored regularly.
References
1. Sagarin MJ, Barton ED, Chng YM, Walls RM. Airway management by US and
Canadian emergency medicine residents: a multicenter analysis of more than
6,000 endotracheal intubation attempts. Ann Emerg Med. 2005;46:328-336.
2. Wilcox SR, Seigel TA, Strout TD, et al. Emergency medicine residents’ knowledge
of mechanical ventilation. J Emerg Med. 2015;48:481-491.
14.Peek GJ, Mugford M, Tiruvoipati R, et al. Efficacy and economic assessment of
conventional ventilatory support versus extracorporeal membrane oxygenation
for severe adult respiratory failure (CESAR): a multicentre randomised controlled
trial. Lancet 2009;374:1351-1363.
15.NIH NHLBI ARDS Clinical Network Mechanical Ventilation Protocol Summary.
http://www.ardsnet.org/files/ventilator_protocol_2008-2007.pdf.
16.Dreyfuss D, Soler P, Basset G, Saumon G. High inflation pressure pulmonary
edema: respective effects of high airway pressure, high tidal volume, and positive
end-expiratory pressure. Am Rev Respir Dis. 1988;137:1159-1164.
17. Webb HH, Tierney DF. Experimental pulmonary edema due to intermittent positive
pressure ventilation with high inflation pressures. Protection by positive endexpiratory pressure 1–4. Am Rev Respir Dis. 1974;110:556-565.
18.Fuller BM, Mohr NM, Hotchkiss RS, Kollef MH. Reducing the burden of acute
respiratory distress syndrome: the case for early intervention and the potential
role of the emergency department. Shock. 2014;41:378-387.
3. Easter BD, Fischer C, Fisher J. The use of mechanical ventilation in the ED. Am J
Emerg Med. 2012;30:1183-1188.
19.Dettmer M, Mohr NM, Fuller BM. Sepsis-associated pulmonary complications in
emergency department patients monitored with serial lactate: an observational
cohort study. J Crit Care Med. 2015; [Accepted- in press].
4. Slutsky AS, Ranieri VM. Ventilator-induced lung injury. N Engl J Med.
2013;369:2126-2136.
20.Tenney S, Remmers J. Comparative quantitative morphology of the mammalian
lung: diffusing area. Nature. 1963;197:54-56.
5. Fuller B, Mohr NM, Miller CN, Deitchman AR, Levine BJ, Castagno N, Hassebroek
EC, Dhedhi A, Scott-Wittenborn N, Grace E, Lehew C, Kollef MH. Mechanical
ventilation and ARDS in the ED: a multicenter, observational, prospective, crosssectional study. Chest. 2015;148:365-374.
6. Stoltze A, Wong TS, Harland KK, Ahmed A, Fuller BM, Mohr NM. Prehospital tidal
volume influences hospital tidal volume: a cohort study. J Crit Care. 2015;30:495501.
7. Fuller B, Mohr NM, Dettmer M, Cullison K, Kennedy S, Bavolek R, Rathert N,
McCammon, C. Mechanical ventilation and acute lung injury in emergency
department patients with severe sepsis and septic shock: an observational study.
Acad Emerg Med. 2013;20:659-669.
8. Brochard L. Intrinsic (or auto-) PEEP during controlled mechanical ventilation.
Intensive Care Med. 2002;28:1376-1378.
9. The ARDS Definition Task Force. Acute respiratory distress syndrome: the Berlin
definition. JAMA. 2012;307:2526-2533.
10.The Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal
volumes as compared with traditional tidal volumes for acute lung injury and the
acute respiratory distress syndrome. N Engl J Med. 2000;342:1301-1308.
11.Briel M, Meade M, Mercat A, et al. Higher vs lower positive end-expiratory
pressure in patients with acute lung injury and acute respiratory distress
syndrome: systematic review and meta-analysis. JAMA. 2010;303:865-873.
12.Guérin C RJ, Richard JC, Beuret P, Gacouin A, Boulain T, Mercier E, Badet M,
Mercat A, Baudin O, Clavel M, Chatellier D, Jaber S, Rosselli S, Mancebo J,
Sirodot M, Hilbert G, Bengler C, Richecoeur J, Gainnier M, Bayle F, Bourdin G,
Leray V, Girard R, Baboi L, Ayzac L. Prone positioning in severe acute respiratory
distress syndrome. N Engl J Med. 2013;368:2159-2168.
13.Papazian L, Forel J, Gacouin A, et al. ACURASYS Study Investigators.
Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J
Med. 2010;363:1107-1116.
6
DEEPVENOUS
VENOUSTHROMBOSIS
THROMBOSIS AND
AND PULMONARY
PULMONARY EMBOLISM:
DEEP
EMBOLISM: OPTIMAL
OPTIMAL
THERAPYAND
ANDPREVENTION
PREVENTION FOR
FOR THE
THE CRITICALLY-ILL
CRITICALLY-ILL PATIENT
THERAPY
PATIENT
DEEP VENOUS THROMBOSIS AND PULMONARY
EMBOLISM: OPTIMAL THERAPY AND PREVENTION
FOR THE CRITICALLY-ILL PATIENT
Professor & Executive Vice Chairman; Director, Clinical Trials Center; Department of Emergency Medicine, University of Cincinnati
College of Medicine, Cincinnati, OH
Objectives
1. Define massive, submassive, and low risk pulmonary embolism
(PE).
2. Describe current guidelines for the treatment of massive and
submassive PE.
3. Explain risk stratification strategies in acute PE.
4. Consider disposition decisions as applied to patients with PE.
Introduction
Venous thromboembolism (VTE) is identified as the cause for the
hospitalization for over 250,000 patients in the United States (US)
annually.1 VTE collectively refers to both deep venous thrombosis
(DVT) and pulmonary embolism (PE) and is often among the differential considerations of patients presenting to the Emergency
Department (ED) with leg pain or swelling, chest pain and dyspnea. After the diagnosis of VTE is made, Emergency Physicians
typically initiate therapy with anticoagulation after assessment
of bleeding risk. Risk stratification based on disease severity and
outcomes has been sporadically adopted in the clinical practice
of Emergency Medicine. While several risk based scoring systems
have undergone rigorous evaluation, optimal therapy for patients
with high risk pulmonary emboli is often unclear. The decision to
use catheter-based therapies and fibrinolytic medication is based
on the patient’s clinical condition and serologic and radiographic
studies, most of which are available to Emergency Physicians.2 This
monograph addresses the classification and pathophysiology of PE,
including diagnostic modalities and treatment options.
Severity of Pulmonary Embolism
Massive Pulmonary Embolism
Since patient outcomes are related to PE severity, attempts to classify PE using terms such as “massive” and “submassive” are often
encountered in the literature. However, these imprecise descriptions often lead to confusion and ambiguity.3 Classification based
strictly on mortality is difficult and is complicated by comorbidities
that may make an otherwise low risk embolism a very high risk one
in a selected patient population. Conversely, basing a description
solely on angiographic clot burden, such as the Miller index,4 fails
to account for physiological variation in patients. Among several
large registries, hypotension emerges as a consistent parameter
associated with morbidity and mortality. In the Germany-based
Management Strategy and Prognosis in Pulmonary Embolism
(MAPPET) Registry of 1,001 patients with acute PE, in-hospital
mortality was 8.1% for hemodynamically stable patients in comparison to 25% for those with low blood pressure.5 Similar results
were found in the International Cooperative Pulmonary Embolism
Registry (ICOPER), where patients with presenting systolic blood
pressure of less than 90 mmHg had a 90 day mortality of 52.4%
in comparison to 14.7 % in those without hypotension.6 Both the
Geneva scoring system and the Pulmonary Embolism Severity
Index (PESI and simplified PESI) identify systolic blood pressure
of less than 100 mmHg as a high risk clinical feature.7,8 Accordingly, a writing group of the American Heart Association (AHA) has
proposed that massive PE be defined as: acute PE with sustained
hypotension (systolic blood pressure less than 90 mmHg for 15
minutes or requiring inotropic support, not due to a cause other
than PE, such as arrhythmia, hypovolemia, sepsis or left ventricular
dysfunction), pulselessness, or persistent profound bradycardia
(heart rate less than 40 beats per minute with signs or symptoms
of shock).2
Submassive Pulmonary Embolism
The definition of submassive PE centers on the identification of risk
of short term adverse events, such as mortality, recurrent VTE or
major bleeding. However, the definition of “short term” varies significantly, ranging from in-hospital events to 30-90 day outcomes
to one year mortality. Ideally, the tools used to predict short term
risk should be widely available and readily deployed in the emergent evaluation of a patient suspected to have VTE. Such predictors
include clinical scoring systems, natriuretic peptides, troponins,
cardiac echocardiography, electrocardiography (ECG) and chest CT.
Clinical Scoring Systems
There are validated clinical decision rules to guide the evaluation of
patients suspected to have pulmonary embolism.9 In addition, after
a patient has been diagnosed with a pulmonary embolism, several
clinical scoring systems have been evaluated and found to be predictive of adverse events independent of radiography and biomarkers.10 The more common scores include the PESI and simplified
PESI (Table 1)7,8 and the HESTIA criteria (Table 2). The HESTIA
criteria were developed as a tool to identify patients that may be
able to be treated as outpatients.11 These scores incorporate age,
physiological parameters and comorbidities into risk stratification.
They have most commonly been used to identify PE patients at
low risk for short term adverse events that may be candidates for
abbreviated hospital stay, placement into clinical decision units
(observation units) or direct release from the ED.12
OPTIMAL THERAPY FOR ACS: USING GUIDELINE-BASED TREATMENTS IN THE EMERGENCY SETTING
7
DEEP VENOUS THROMBOSIS AND PULMONARY EMBOLISM: OPTIMAL
THERAPY AND PREVENTION FOR THE CRITICALLY-ILL PATIENT
TABLE
01
Pulmonary Embolism Severity Index (PESI) and Simplified PESI (sPESI)
Parameter
Original Version
Original Version
Age in years
1 point (if age >80 years)
Age
Male sex
+10
Cancer
+30
Chronic heart failure
+10
Chronic pulmonary disease
+10
Pulse rate ≥ 110 b.p.m.
+20
1 point
Systolic blood pressure <100 mm Hg
+30
1 point
Respiratory rate > 30 breaths per minte
+20
Temperature <36° C
+20
Altered mental status
+60
Arterial oxyhemoglobin saturation <90%
+20
1 point
1 point
1 point
Risk Strata
Class I: ≤65 points
very low 30-day mortality risk (0-1.6%)
0 points: 30-day mortality risk 1.0%
Class II: 66-85 points
low mortality risk (1.7-3.5%)
≥ 1 point(s): 30-day mortality risk 10.9%
Class III: 86-105 points
moderate mortality risk (3.2-7.1%)
Class IV: 106-125 points
high mortality risk (4.0-11.4%)
Class V: >125 points
very high mortality risk (10.0-24.5%)
TABLE
02
Hestia Criteria to Determine Whether a Patient with Acute
Pulmonary Embolism Can Be Treated as an Outpatient
Hestia Criteria:
if the answer to ONE of
the questions is YES
the patient CANNOT
be treated at home
1. Hemodynamically unstable?
2. Thrombolysis or embolectomy necessary?
3. Active bleeding or high risk of bleeding?
4. Oxygen supply needed for >24 hours to
maintain oxygen saturation >90%?
5. Pulmonary embolism diagnosis during
anticoagulant treatment?
6. Intravenous pain medication needed for
>24 hours?
Right ventricular (RV) dysfunction can be identified on cardiac
echocardiography using a variety of parameters, such as RV hypokinesis, interventricular septal shift or bowing, McConnell’s sign (regional akinesis of the RV mid free wall with normal septal motion),
and elevated RV end diastolic pressure (RVEDP > 30mmHg).13
However, a RV to LV end diastolic diameter ratio (RVEDD/LVEDD)
of greater than or equal to 0.9 is commonly used to identify RV
dysfunction in acute PE and is included in the definition of submassive PE.
7. Medical or social reason for treatment in
the hospital >24 hours?
Electrocardiography
8. Creatinine clearance of <30 mL/min?
Although ECG changes in acute PE are highly variable and often
nonspecific, RV strain patterns have been shown to be predictive of
adverse events. New incomplete or complete right bundle branch
block, S1Q3T3, and negative T waves in leads V1-V4 have been
found to be associated with clinical outcomes of in-hospital death
9. Severe liver impairment?
10. Pregnant?
11. Documented history of heparin-induced
thrombocytopenia?
8
Echocardiography
or clinical deterioration (hazard ratio 2.58; 95% confidence interval
[CI] 1.05-6.36) independent of echocardiographic findings of RV
strain.14
Computed Tomography Pulmonary Angiography (CT PA)
Although clot burden on CT does not predict short term adverse
events,15 RV dilation does. In-hospital death, 30 day mortality and
three month mortality are increased if the RV is dilated.16 As with
echocardiography, several CT measures of RV dilation have been
studied, including septal bowing; however, the most consistently
reliable parameter reflecting RV dysfunction is RV diameter/LV
diameter ratio of greater than or equal to 0.9 in the four chamber
view.
Troponins
In acute PE patients, both hemodynamically stable and unstable,
elevations in cardiac troponin I and T are associated with short
term all-cause mortality (odds ratio [OR], 5.24; 95% CI 3.28
to 8.38), death from PE (OR, 9.44; 95% CI 4.14 to 21.49), and
adverse outcome events (OR, 7.03; 95% CI 2.42 to 20.43). Adverse
outcome events include shock, need for thrombolysis, endotracheal
intubation, vasopressor infusion for sustained hypotension, cardiopulmonary resuscitation, or recurrent pulmonary embolism. In the
subgroup of hemodynamically stable patients, elevated troponin
levels are also associated with a high mortality (OR, 5.90; 95% CI,
2.68 to 12.95).17
Natriuretic Peptides
As a marker of ventricular dysfunction, the natriuretic peptides are
significantly predictive of short term mortality and adverse events
in stable and unstable acute PE patients.18 The unadjusted risk ratio for predicting death is 9.5 (95% CI 3.2-28.6) for brain natriuretic
peptide (BNP) and 5.7 (95% CI 2.2-15.1) for pro-BNP.13
Based on the above tests, the AHA writing group suggests the
following definition for submassive PE: acute PE without systemic
hypotension (systolic BP > 90 mmHg), but with either RV dysfunction or myocardial necrosis. The definitions of RV dysfunction and
myocardial necrosis are listed in Table 3.
Low Risk Pulmonary Embolism
Although risk stratification based on age, comorbidities, and clinical judgment is warranted for patients who do not meet the criteria
of massive and submassive PE, the short term mortality of the
subgroup who are normotensive and lack RV dysfunction or marker
elevation is estimated to approach 1%.10 Per the AHA writing group,
this cohort of patients is described using the term low risk PE to
best characterize their generally good prognosis.2 Thus, low risk
PE is defined as acute PE in the absence of the clinical markers of
adverse events that define massive and submassive PE.
TABLE
03
Definitions of Severity of Pulmonary Embolism (PE)
Masssive PE
Acute PE with sustained hypotension
(systolic blood pressure <90 mmHg for 15
minutes or requiring inotropic support,
not due to a cause other than PE, such as
arrhythmia, hypovolemia, sepsis or left
ventricular dysfunction), pulselessness, or
persistent profound bradycardia (heart rate
<40 beats per minute with signs or symptoms of shock).
Submassive PE
Acute PE without systemic hypotension
(systolic BP >90 mmHg) but with either RV
dysfunction or myocardial necrosis.
RV Dysfunction
at least one of the
following:
• RV dilation (apical 4-chamber RV
diameter divided by LV diameter >0.9)
or RV systolic dysfunction on echocardiography
• RV dilation (4-chamber RV diameter
divided by LV diameter >0.9) on CT
• Elevation of BNP (>90 pg/mL)
• Elevation of N-terminal pro-BNP
(>500 pg/mL)
• Electrocardiographic changes (new complete or incomplete right bundle-branch
block, anteroseptal ST elevation or
depression, or anteroseptal T-wave inversion) S1Q3T3 pattern
Myocardial Necrosis
either of the following:
• Elevation of troponin T (>0.1 ng/mL)
Low Risk PE
Acute PE in the absence of the clinical
• Elevation of troponin I (>0.4 ng/mL)
sive and submassive PE.
-
RV: right ventricle; LV: left ventricle; CT: computed tomography; BNP: brain natriuretic peptide
Treatment of Pulmonary Embolism
Massive Pulmonary Embolism
Fibrinolytic therapy, in addition to parenteral anticoagulation, is
indicated in the treatment of acute massive PE when the risk of
bleeding is considered acceptable. The usual absolute and relative
contraindications to fibrinolytic therapy are described elsewhere.2
If there is a high clinical suspicion for massive PE and the patient
is too unstable to be safely studied or the study is unavailable,
bedside transthoracic echocardiography showing RV dysfunction is
an appropriate method of confirming the presence of PE. Administering fibrinolysis in the setting of undifferentiated cardiac arrest is
not recommended.19 For patients with acute massive PE who are
candidates for fibrinolysis, the American College of Chest Physicians (ACCP) recommends peripheral infusion of alteplase 100 mg
over two hours. Tenecteplase 30-50 mg over two hours has been
used in recent trials as well. Shorter infusion regimens are acceptable in selected critically ill patients. Prolonged infusions of up to
24 hours are not recommended. The Food and Drug Administration
(FDA) recommends that intravenous (IV) unfractionated heparin
(UFH) be temporarily suspended while the fibrinolytic is infusing
9
and that activated partial thromboplastin time (aPTT) be checked
after infusion. If the aPTT< 80 sec, IV UFH should be restarted at
the pre-fibrinolytic infusion rate without re-bolus.
Submassive Pulmonary Embolism
The use of fibrinolytics in the subgroup of patients who are normotensive, but have objective signs of RV dysfunction, is controversial.
Since the short term mortality of US patients presenting with this
phenotype is approximately 2%,20 a trial to study the treatment
effects of fibrinolysis using mortality as the primary endpoint is
impractical. However, the development of dyspnea, fatigue and
exercise intolerance from increased RV systolic pressure and the
development of chronic thromboembolic pulmonary hypertension
(CTEPH) may serve as a plausible endpoint. Although the development of CTEPH is multifactorial, strong predictors include large
thrombus burden, younger age and multiple PE episodes. The
Tenecteplase Or Placebo with Cardiovascular Outcomes At Three
months (TOPCOAT) Trial used the composite endpoint of survival
combined with assessment of functional capacity and patient
evaluation of wellness to compare full dose LMWH plus placebo to
LMWH plus tenecteplase. Although the trial was terminated early
due to non-outcome related factors, TOPCOAT showed that treatment with tenecteplase in submassive PE was associated with an
increased positive composite outcome.21
The Pulmonary Embolism Thrombolysis Trial (PEITHO) serves as
the largest body of evidence in the study of fibrinolytic therapy
for submassive PE.22 A randomized double-blind trial comparing
tenecteplase plus heparin to placebo plus heparin, PEITHO enrolled
1,006 subjects with acute PE who were normotensive with signs
or RV dysfunction on CT or echocardiogram or with myocardial
necrosis, and used a primary outcome of death or hemodynamic
collapse within seven days. The safety endpoint was major extracranial or intracranial stroke or hemorrhage within seven days.22 Patients who received weight based tenecteplase had a significantly
lower incidence of the primary outcome (2.6%) vs. standard heparin
plus placebo (5.6%, OR 0.44; 95% CI 0.23 to 0.87; P = 0.02).
However, extracranial bleeding occurred in 32 patients (6.3%) in
the tenecteplase group vs. six patients (1.2%) in the heparin plus
placebo group (P<0.001). The intracranial hemorrhage rate in the
tenecteplase arm was 2.0%, which is similar to previous analyses.
At day 30, there was no significant difference in mortality. Although
the study failed to incorporate functional capacity endpoints, the
authors concluded that there was no net clinical benefit to the use
of fibrinolysis in the submassive PE population. Subgroup analysis
showed a lower risk of bleeding in subjects less than age 75, but
the difference was not significant.
A recent meta-analysis that reviewed fibrinolysis in submassive
10
PE and included both PEITHO and TOPCOAT showed a decrease
in mortality (number needed to treat, NNT=59) and recurrent PE
(NNT=54) at the expense of an increased risk of major bleeding
(number needed to harm, NNH=18) and intracranial hemorrhage
(NNH=78). However, no increased risk of major bleeding was seen
in patients less than age 65.23 An even more recent meta-analysis
by European investigators that combined massive and submassive
PE found similar results.24 In patients who are hemodynamically
stable with evidence of RV dysfunction (submassive PE), the most
recent available data is summarized with the recommendation to
weigh the risk of hemorrhage with the benefit of improved mortality
and recurrent PE, taking into account individual patient characteristics and expectations.25
Low Risk Pulmonary Embolism
Patients diagnosed with acute low risk PE are treated with anticoagulant therapy if they have no contraindications. The approved
options for acute therapy in this subgroup are UFH, low molecular
weight heparin (LMWH), fondaparinux or a Non-vitamin K antagonist Oral Anticoagulant (NOAC) (see Table 4).26 Guidelines published in 2012 by the American College of Chest Physicians (ACCP)
recommend LMWH or fondaparinux over IV or subcutaneous (SC)
UFH. They favor once daily over twice daily dosing of enoxaparin.27
The AHA suggests that empiric therapy can be given to patients
with an intermediate to high clinical suspicion of PE prior to obtaining a confirmatory study if the patient lacks contraindications to anticoagulation.2 The use of fibrinolytic therapy is NOT recommended
for the treatment of low risk PE.
Catheter-Based Strategies
Patients with massive and submassive PE should be considered
for transcatheter therapies based on the clinical presentation and
the capabilities of the institution. These therapies can be deployed
in the setting of acute PE if traditional peripherally delivered
fibrinolysis fails to improve hemodynamics or is contraindicated.
Percutaneous options may also be considered when emergent
surgical embolectomy is unavailable or contraindicated. A combination of directed fibrinolytic infusion with mechanical clot disruption is emerging as a viable option. In experienced centers, the
pharmaco-mechanical treatment of massive and submassive PE
may decrease the hemorrhagic complications seen with peripheral
fibrinolysis while more rapidly improving RV hemodynamics and
systemic circulation.28
The types of catheter therapies generally fall into the following
categories: aspiration thrombectomy, thrombus fragmentation, and
rheolytic thrombectomy. Thrombus aspiration catheters deploy
a suction-tipped catheter for clot removal and are the oldest of
TABLE
04
Anticoagulants For Use In Patients With Venous Thromboembolism (VTE)
AGENT
DOSE and ROUTE
SCHEDULE
COMMENT
5,000 U (80 U/kg) units
IV bolus followed by IV
infusion of 1300 U/hour
(180 U/kg)
adjust infusion
based on a PT
nomogram
alternatives
1.5 mg/kg SC
daily
once daily administration preferred over 1 mg/kg twice daily
200 IU/kg SC
daily
5 mg SC (<50 kg)
7.5 mg SC (50-100 kg)
10 mg SC (>100 kg)
daily
daily
daily
5 mg PO
once daily
start AFTER 5-10 days of parental anticoagulant and
INR 2.0-3.0
10 mg PO
5 mg PO
twice daily for 7days
then twice daily
start AFTER 5-10 days of parenteral anticoagulant
edoxaban
60 mg PO
once daily
rivaroxaban
15 mg PO
20 mg PO
twice daily x 21days
then once daily
150 mg PO
twice daily
Parenteral Agents
Unfractionated Heparin (UFH)
Low-Molecular Weight Heparin
(LMWH):
enoxaparin
dalteparin
Indirect Factor Xa Inhibitor:
fondaparinux
Oral Agents
Warfarin
Direct Factor Xa Inhibitors
(Non vitamin K antagonist oral
anticoagulant, NOAC)
apixaban
Direct Thrombin Inhibitor
(Non vitamin K antagonist oral
anticoagulant, NOAC)
dabigatran
start AFTER 5-10 days of parenteral anticoagulant
U: units; IU: international units; SC: subcutaneous; IV: intravenous; PO: by mouth; INR: international normalized ratio; PT: prothrombin time
the mechanical therapies. Fragmentation devices use a variety of
hardware, such as ultrasound augmentation and rotational devices,
to morselize the thrombus. Ultrasound destabilizes the fibrin mesh
making it more susceptible to locally targeted fibrinolytic agents.
Rheolytic systems deploy a high pressure saline jet to disrupt clot,
but have come under regulatory scrutiny due to periprocedural
hemorrhagic complications.
Clinical Pathway
The majority of patients with acute PE in US institutions are admitted to the hospital. Using risk stratification tools, if feasible to tailor
treatment and disposition decisions based on individual patient
factors.
In patients with acute massive PE who have contraindications to
fibrinolysis, failed fibrinolysis, or shock that is likely to cause death
before systemic fibrinolysis can take effect (i.e., within hours),
catheter-assisted thrombus removal or surgical thrombectomy is
suggested over no such intervention if appropriate expertise and
resources are available. Since most pharmaco-mechanical studies
have been nonrandomized and had few patients, the ACCP guidelines suggest that the decision to deploy such a strategy be based
on local expertise. The use of peripheral fibrinolysis in patients
with acute submassive PE, while still the subject of discussion, is
generally reserved for those patients with a low risk of bleeding and
evidence of clinical instability.
Some patients with low risk PE, adequate social support and outpatient follow-up may have an abbreviated inpatient stay, such as in a
clinical decision unit. Some centers advocate direct ED discharge29
and prospective US studies are ongoing. The European Society of
11
Cardiology (ESC) advocates further risk stratification of the low risk
PE population with the PESI and sPESI scoring systems to triage
patients to inpatient or outpatient care.26 The HESTIA scoring system was specifically designed to risk stratify patients for outpatient
therapy.
The most recently drafted treatment algorithm by the ESC, which
was published after the PEITHO study, combines risk stratification using the PESI/sPESI scores and treatment options, including
pulmonary reperfusion strategies. The algorithm serves as to guide
to clinicians in the evaluation and treatment patients with acute PE
(Figure 1).
FIGURE
01
Conclusion
In conclusion, emergency physicians, hospitalists, and critical
care physicians must be experts in the diagnosis and treatment
of PE and DVT. For the critically ill patient, rapid evaluation and
appropriate treatment can reduce adverse outcomes and decrease
mortality.
Clinical Algorithm For Patients With Suspected Pulmonary Embolism
Clinical Suspicion of PE
Shock/Hypotension (BP<90 mm Hg > 15 mins)
YES
NO
CTPA Available?
and
Pt. Stable to Undergo Study?
Use Diagnostic Algorithm
to Guide Testing Strategy (B)
YES
NO
PE Confirmed?
PE Confirmed?
Bedside TTE
NO
YES
Neg
Consider Alternate
Dx for Low BP
Pos
YES
RV/LV Ratio >0.9
or Poisitive Tn
or positive NP
NO
Low Risk PE
Submassive PE
Massive PE
A/C
Admit/ICU
Primary
Pilmonary
Reperfusion (A)
Legend Abbreviations:
PE
pulmonary embolism
CTPA
CT pulmonary angiography
A/C
anticoagulation
CDU
clinical decision unit
TTE
transthoracic echocardiogram
PESI
PE severity index
HESTIA Hestia study criteria
NP
natriuretic peptide
Tn
Troponin
RV
Right ventricle
LV
Left ventricle
12
A - Peripheral thrombolysis; if high bleeding
risk consider catheter directed strategy
or surgical embolectomy
B - Raja AS, et al. Ann Intern Med.
2015;163:701-711
PESI/SPESI/HESTIA
PESI III-IV
sPESI ≥ 1
HESTIA ≥ 1
PESI I-II
sPESI = 0
HESTIA = 0
A/C
A/C
OR
Consider rescue
pulmonary reperfusion
if conditions worsen
ADMIT
FLOOR
Consider
CDU/
Discharge
References
1. Lloyd-Jones D, Adams RJ, Brown TM, et al. Executive summary: heart disease
and stroke statistics--2010 update: a report from the American Heart Association.
Circulation. 2010;121:948-954.
2. Jaff MR, McMurtry MS, Archer SL, et al. Management of massive and
submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronic
thromboembolic pulmonary hypertension: a scientific statement from the
American Heart Association. Circulation. 2011;123:1788-1830.
3. Goldhaber SZ. Thrombolysis for pulmonary embolism. N Engl J Med.
2002;347:1131-1132.
4. Miller GA, Sutton GC, Kerr IH, Gibson RV, Honey M. Comparison of streptokinase
and heparin in treatment of isolated acute massive pulmonary embolism. Br Med
J. 1971;2:681-684.
5. Kasper W, Konstantinides S, Geibel A, et al. Management strategies and
determinants of outcome in acute major pulmonary embolism: results of a
multicenter registry. J Am Coll Cardiol. 1997;30:1165-1171.
6. Kucher N, Rossi E, De Rosa M, Goldhaber SZ. Massive pulmonary embolism.
Circulation. 2006;113:577-582.
7. Aujesky D, Obrosky DS, Stone RA, et al. Derivation and validation of a prognostic
model for pulmonary embolism. Am J Respir Crit Care Med. 2005;172:10411046.
8. Wicki J, Perrier A, Perneger TV, Bounameaux H, Junod AF. Predicting adverse
outcome in patients with acute pulmonary embolism: a risk score. Thromb
Haemost. 2000;84:548-552.
9. Raja AS, Greenberg JO, Qaseem A, Denberg TD, Fitterman N, Schuur JD.
Evaluation of patients with suspected acute pulmonary embolism: best practice
advice from the Clinical Guidelines Committee of the American College of
Physicians. Ann Intern Med. 2015; 163:701-11.
10.Bova C, Pesavento R, Marchiori A, et al. Risk stratification and outcomes in
hemodynamically stable patients with acute pulmonary embolism: a prospective,
multicentre, cohort study with three months of follow-up. J Thromb Haemost.
2009;7:938-944.
11. Zondag W, Mos IC, Creemers-Schild D, et al. Outpatient treatment in patients with
acute pulmonary embolism: the Hestia Study. J Thromb Haemost. 2011;9:15001507.
12.Fermann GJ, Erkens PM, Prins MH, Wells PS, Pap AF, Lensing AW. Treatment
of pulmonary embolism with rivaroxaban: outcomes by simplified Pulmonary
Embolism Severity Index score from a post hoc analysis of the EINSTEIN PE
study. Acad Emerg Med. 2015;22:299-307.
13.Sanchez O, Trinquart L, Colombet I, et al. Prognostic value of right ventricular
dysfunction in patients with haemodynamically stable pulmonary embolism: a
systematic review. Eur Heart J. 2008;29:1569-1577.
17.Becattini C, Vedovati MC, Agnelli G. Prognostic value of troponins in acute
pulmonary embolism: a meta-analysis. Circulation. 2007;116:427-433.
18.Cavallazzi R, Nair A, Vasu T, Marik PE. Natriuretic peptides in acute pulmonary
embolism: a systematic review. Intensive Care Med. 2008;34:2147-2156.
19.Bottiger BW, Arntz HR, Chamberlain DA, et al. Thrombolysis during resuscitation
for out-of-hospital cardiac arrest. N Engl J Med. 2008;359:2651-2662.
20.Pollack CV, Schreiber D, Goldhaber SZ, et al. Clinical characteristics,
management, and outcomes of patients diagnosed with acute pulmonary
embolism in the emergency department: initial report of EMPEROR (Multicenter
Emergency Medicine Pulmonary Embolism in the Real World Registry). J Am Coll
Cardiol. 2011;57:700-706.
21. Kline JA, Nordenholz KE, Courtney DM, et al. Treatment of submassive pulmonary
embolism with tenecteplase or placebo: cardiopulmonary outcomes at 3 months:
multicenter double-blind, placebo-controlled randomized trial. J Thromb Haemost.
2014;12:459-468.
22.Meyer G, Vicaut E, Danays T, et al. Fibrinolysis for patients with intermediate-risk
pulmonary embolism. N Engl J Med. 2014;370:1402-1411.
23.Chatterjee S, Chakraborty A, Weinberg I, et al. Thrombolysis for pulmonary
embolism and risk of all-cause mortality, major bleeding, and intracranial
hemorrhage: a meta-analysis. JAMA. 2014;311:2414-2421.
24.Marti C, John G, Konstantinides S, et al. Systemic thrombolytic therapy for
acute pulmonary embolism: a systematic review and meta-analysis. Eur Heart J.
2015;36:605-614.
25. Morton MJ. Should patients who receive a diagnosis of acute pulmonary embolism
and have evidence of right ventricular strain be treated with thrombolytic therapy?
Ann Emerg Med. 2015;S0196-0644:01304-9.
26.Konstantinides SV, Torbicki A, Agnelli G, et al. 2014 ESC guidelines on the
diagnosis and management of acute pulmonary embolism. Eur Heart J.
2014;35:3033-3069, 3069a-3069k.
27.Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE disease:
antithrombotic therapy and prevention of thrombosis, 9th ed: American College
of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest.
2012;141:e419S-494S.
28.Kuo WT, Banerjee A, Kim PS, et al. Pulmonary embolism response to
fragmentation, embolectomy, and catheter thrombolysis (PERFECT): initial results
from a prospective multicenter registry. Chest. 2015;148:667-673.
29.Beam DM, Kahler ZP, Kline JA. Immediate discharge and home treatment
with rivaroxaban of low-risk venous thromboembolism diagnosed in two U.S.
emergency departments: a one-year preplanned analysis. Acad Emerg Med.
2015;22:788-795.
14.Vanni S, Polidori G, Vergara R, et al. Prognostic value of ECG among patients
with acute pulmonary embolism and normal blood pressure. Am J Med.
2009;122:257-264.
15. Subramaniam RM, Mandrekar J, Chang C, et al. Pulmonary embolism outcome: a
prospective evaluation of CT pulmonary angiographic clot burden score and ECG
score. AJR Am J Roentgenol. 2008;190:1599-1604.
16.Quiroz R, Kucher N, Schoepf UJ, et al. Right ventricular enlargement on chest
computed tomography: prognostic role in acute pulmonary embolism. Circulation.
2004;109:2401-2404.
13
POST-CARDIAC
POST-CARDIAC ARREST
ARREST IN
IN THE
THE EMERGENCY
EMERGENCY DEPARTMENT:
DEPARTMENT:
BEYOND
BEYOND HYPOTHERMIA
HYPOTHERMIA
POST-CARDIAC ARREST IN THE EMERGENCY
DEPARTMENT: BEYOND HYPOTHERMIA
• What was the duration of CPR?
• Which medications were administered? How many doses were
administered?
• What was the primary cardiac rhythm? Alternatively, did the
automated external defibrillator (AED) advise a shock?
• Did the patient experience prodromal symptoms, such as chest
pain or shortness of breath?
Associate Professor
University of Pittsburgh, Pittsburgh, PA
Objectives
1. Summarize literature supporting temperature management in
the patient successfully resuscitated from cardiac arrest.
2. Identify neurocritical care interventions that can be initiated
during the Emergency Department management of the patient
resuscitated from cardiac arrest.
3. Distinguish patient populations likely to benefit from coronary
angiography after resuscitation from cardiac arrest.
4. Discuss how the Institute of Medicine Report on Cardiac Arrest
will affect Emergency Department care of the patient resuscitated from cardiac arrest.
Introduction
Cardiac arrest is common and deadly, resulting in more than
300,000 deaths annually.1 Following decades of unchanged outcomes, recent data demonstrate that survival is increasing.2 The
improvement in outcomes is likely due to advances in the treatment
of cardiac arrest, including use of critical care bundles that incorporate temperature management and aggressive coronary revascularization, as well as delayed neuroprognosis. The management
of these patients is complex, focusing on determining the etiology
of arrest as well as the resuscitation of multiple organ systems. In
the first 24 hours, the immediate threat is cardiovascular collapse;
however, therapy must also be directed toward preventing secondary
neuronal injury. Additionally, the pitfall of early withdrawal of support
should be avoided in order to optimize outcome. This manuscript will
review current treatment strategies, including the use of temperature
management, in this population.
First Hours: Determining Illness Severity and Etiology of
Cardiac Arrest
The majority of patients resuscitated from cardiac arrest are unable
to provide a historical account of prodromal symptoms, allergies,
medications and other aspects of the medical history. These may
be obtained from family or witnesses to the arrest when available.
Critical information that should be obtained either from emergency
medical services (EMS) or bystanders include:
• Was the arrest witnessed?
• Was bystander cardiopulmonary resuscitation (CPR) provided?
14
The first four questions attempt to determine the severity of ischemic
damage experienced, while the last two questions focus on reversible
causes for the arrest. For example, a history of ventricular fibrillation following chest pain would direct the clinician to have a lower
threshold for emergent cardiac catheterization. Additional testing may
include laboratory testing, imaging, and bedside ultrasonography to
determine both etiology and organ dysfunction resulting from the
cardiac arrest.
Determining Illness Severity
A bedside evaluation of the patient is necessary to determine the
severity of the post-cardiac arrest syndrome. This may help elucidate
the etiology of arrest, but it also provides important baseline information that can help predict long-term outcome.3,4 Illness severity
can also aid in determining which patients may derive benefit from
interventions such as coronary angiography.5
Two illness severity scores are particularly useful in the evaluation of
post-cardiac arrest patients. The Full Outline of UnResponsiveness
(FOUR) score, developed by Wijdicks, quantifies neurologic status
based on motor, brainstem, respiratory, and eye responses, and has
comparable inter-rater reliability to the Glasgow Coma Scale (Table
1).6,7 The Sequential Organ Failure Assessment (SOFA) score is used
to quantify individual organ system dysfunction (Table 2). Based on a
brief clinical patient examination and an arterial blood gas, the cardiovascular and respiratory components of the SOFA score and the motor and brainstem portions of the FOUR score can be used to place
the patient into one of four categories of illness severity using the
Pittsburgh Cardiac Arrest Category (PCAC) [Table 3]. The PCAC is
predictive of survival after cardiac arrest (PCAC I: 80% survival; PCAC
II: 60% survival; PCAC III: 40% survival; PCAC IV: 10% survival).
Diagnostic Testing
Electrocardiography (ECG) and neuroimaging, along with basic laboratory testing, can be used to help determine the etiology of cardiac
arrest, quantify organ system dysfunction, and guide therapies. The
12-lead ECG can help identify primary arrhythmia, acute coronary syndrome and cardiomyopathy as reasons for cardiac arrest.
Clinicians should be vigilant in identifying ST-elevation myocardial
infarction (STEMI) or acute ST changes suggesting ongoing ischemia.
POST-CARDIAC ARREST IN THE EMERGENCY DEPARTMENT:
BEYOND HYPOTHERMIA
TABLE
01
Motor and Brainstem Components of the Full Outline of
UnResponsiveness (FOUR) Score.
The summation of the motor and brainstem scores is used to
quantify initial neurologic illness severity.
MOTOR RESPONSE
Action
Score
TABLE
02
Cardiovascular and Respiratory Components of The
Sequential Organ Failure Assessment (SOFA) Scale
CARDIOVASCULAR COMPONENT
Mean arterial pressure or administration of
vasopressors (µg/kg/min) required
Score
MAP < 70 mmHg
1
Obeys commands, makes sign, e.g. “thumbs up”
4
Dop ≤ 5 or Dob (any dose)
2
Localizes painful stimulus
3
Dop > 5 OR Epi ≤ 0.1 OR Nor ≤ 0.1
3
Flexes to painful stimulation
2
Dop > 15 OR Epi > 0.1 or Nor > 0.1
4
Extends to painful stimulation
1
No response to pain OR myoclonic status
epilepticus
0
BRAINSTEM REFLEXES
Action
Score
4
3
2
RESPIRATORY COMPONENT
PaO2/FiO2 (mmHg)
Score
<400
1
<300
2
<200 AND on ventilator
3
MAP: mean arterial pressure; PaO2: arterial partial pressure of oxygen; FiO2:
fraction of inspired oxygen; Dop: dopamine; Dob: dobutamine;
Epi: epinephrine; Nor: norepinephrine
1
0
Similarly, QT prolongation or other evidence of ion channelopathy can
guide further diagnostic testing. Evidence of right heart strain may
suggest pulmonary embolus.
Computed tomography (CT) imaging of the brain is indicated in
patients resuscitated from cardiac arrest who are in a coma on initial
examination. Approximately 5% of patients resuscitated from cardiac
arrest demonstrate intracranial hemorrhage on initial CT of the
brain.8 The CT may also demonstrate early cerebral edema, which is
associated with poor outcomes.8
An active area of research is determining which patients are likely
to benefit from emergent coronary angiography. Cardiac disease
is common in patients resuscitated from cardiac arrest and prior
work has demonstrated better functional outcomes in patients who
undergo coronary angiography,9 although the outcomes differ based
on initial illness severity.5 Most patients with STEMI require emergent
catheterization, but many interventional cardiologists express concern
regarding the high rate of mortality from neurologic causes unique to
the cardiac arrest patient. One approach that incorporates neurologic
injury into the decision is to emergently catheterize patients with
cardiac arrest due to STEMI who are PCAC I-III (Table 4). Those with
PCAC IV illness severity require a CT scan of the brain to further risk
stratify the patient. If the CT demonstrates intracranial hemorrhage
or edema, the team must discuss the low likelihood of overall survival
with the family prior to cardiac catheterization.
While patients with cardiac arrest due to STEMI should clearly
undergo cardiac catheterization and emergent reperfusion, patients
with a suggestive history including chest pain or shortness of breath
prior to arrest, cardiac risk factors, or initial shockable rhythm should
also be considered for coronary angiography. Additionally, those with
ongoing cardiovascular shock, focal wall motion abnormalities, or rising troponin serum levels should prompt re-consideration of coronary
angiography. Cardiac catheterization can also be critical in post-arrest
patients because a significant number of them require intra-aortic
balloon pump placement, left ventricular assist device placement,
transplant or emergent bypass grafting.9
Initial Resuscitation Goals
The care of the patient resuscitated from cardiac arrest is challenging. It requires optimizing hemodynamic and ventilatory parameters
with a focus on optimizing cerebral perfusion, while continuing efforts
to determine and treat the etiology of the cardiac arrest. Moreover,
many patients have significant medical co-morbidities exacerbated by
anoxic injury, and most patients resuscitated from cardiac arrest are
comatose. Thus, while the first concern of the bedside clinician is to
15
BEYOND HYPOTHERMIA
TABLE
03
Pittsburgh Cardiac Arrest Categories (PCAC) Of Initial Post-Arrest Illness Severity
Category
FOUR Motor +
Brainstem Score
SOFA Cardiovascular +
Respiratory Score
I
8
Any
II
4-7
<4
III
4-7
≥4
IV
<4
Any
TABLE
04
Description
Awake – follows commands
dysfunction
Recommendation for Emergent Catheterization Based
on Initial Illness Severity
Illness Severity
STEMI Treatment Recommendation
PCAC I
Emergent Catheterization
PCAC II
PCAC III
PCAC IV
CT Brain and discussion with care team
STEMI: ST Elevation Myocardial Infarction; PCAC: Pittsburgh Cardiac Arrest Category
optimize the cardiovascular system, preventing secondary neuronal
injury is necessary for optimal recovery.
Goal resuscitation parameters differ in the acutely neurologically
injured patient. Hypotension exacerbates neuronal injury and should
be avoided. Because many patients resuscitated from cardiac arrest
have an impaired baroreceptor response to blood pressure, augmented mean arterial blood pressures (>80mmHg) are generally
required to maintain adequate cerebral perfusion.10 Lactic acidosis is
common, resulting in compensatory hyperventilation. The chemoreceptor response to PCO2 remains intact in this patient population,
thus the natural response can result in cerebral vasoconstriction
and secondary neuronal injury.10 Hyperventilation can also decrease
preload and precipitate hypotension. Thus, normalizing PaCO2
between 35-45mmHg is recommended. Although prior literature has
demonstrated an association between hyperoxia and poor outcome,
recent data suggest that the ‘dose’ of hyperoxia (severity and duration of exposure) is important; severe hyperoxia has been associated
with decreased survival post-cardiac arrest patients, while moderate
hyperoxia has not.11 While these associations should result in titration
of FiO2, hypoxia clearly exacerbates neuronal injury and should also
be avoided.
Temperature Management
Since 2002, temperature management strategies, including therapeutic hypothermia, have been at the vanguard of the neurologic
16
resuscitation plan for patients after cardiac arrest.12,13 The Targeted
Temperature Management (TTM) Trial demonstrated that temperature management to 36°C, along with a standardized care
plan, provides similar results to deeper hypothermia temperatures
(32-34°C).14 Hypothermia decreases cerebral metabolism by 5% for
every degree below 37°C. It may decrease free radical production, is
an adjunct for decreasing seizures, and decreases cerebral edema.
Titrating temperature management based on neurologic injury pattern and risk of seizures or edema may optimize therapy.
Importantly, fever must be avoided during the post-arrest phase, as
it has been shown to be associated with worse neurologic outcome.15
During the TTM Trial, patient temperature was controlled for the first
72 hours after resuscitation, which differed from prior work. Subjects
received therapeutic hypothermia or temperature management for a
period of 24 hours, followed by temperature control (fever prevention)
in all subjects for a total of 72 hours.14 This prevention of secondary
injury may be one reason for the excellent rates of recovery noted in
the study. An additional nuance of the TTM Trial was the delay in neurologic prognostication to at least 72 hours following resuscitation.
When care is withdrawn early in the post-resuscitation phase, the
benefits of aggressive management may be limited. Thus, a critical
care bundle, including temperature management and delayed neuroprognostication, is required in the comatose patient resuscitated from
cardiac arrest.16
Electroencephalography Monitoring
Following resuscitation from cardiac arrest, seizures and other malignant electroencephalogram (EEG) patterns are common.17 Non-convulsive status epilepticus occurs in 8-20% of patients, but convulsive
status epilepticus is less common. Other malignant patterns, such as
generalized epileptiform discharges and myoclonic status epilepticus, are also common. Given the frequency of these patterns, EEG
monitoring is recommended for all comatose patients resuscitated
after cardiac arrest. When possible, evaluating the EEG for reactivity
to stimulus should be documented. Malignant EEG patterns are associated with worse neurologic outcome, but improvement in the EEG
BEYOND HYPOTHERMIA
over time is associated with recovery.18 Moreover, some patients with
malignant EEG patterns recover with treatment and experience good
neurologic recovery.19 Treating malignant EEG patterns therefore may
be a reasonable intervention for at least a proportion of patients. It is
currently unknown whether prophylactic antiepileptic agents alter the
course of recovery in these patients.
Specialized Centers for Post-Arrest Care
Management of the post-arrest patient is resource intensive, and
collaborative care teams are frequently needed given the heterogeneity of illness. As with trauma, stroke and STEMI care, increased
exposure to post-arrest patients may improve patient outcomes.20
Currently, most hospitals care for approximately 12 cardiac arrest
patients each year that may benefit from comprehensive post-arrest
care.21
Specialized centers should have expertise in cardiovascular resuscitation including coronary angiography, electrophysiology, mechanical
assist devices, neurologic resuscitation including brain imaging, EEG
monitoring, temperature management protocols, and rehabilitation
available at all times, 24 hours per day, 7 days a week. Each of these
is critical to the care and recovery of these patients. Such services
may not be available in all hospitals, so protocols to determine indications and logistics of transfer should be developed for each facility.
Specialized centers should also offer organ donation and procurement services for those patients who do not survive.22
Existing data show that prehospital transport time does not impact
outcome after cardiac arrest, supporting EMS decisions to transport
farther to a specialized center.23 Additionally, a study of aeromedical transport of post cardiac arrest patients to tertiary care facilities
(median transport time 63 minutes) demonstrated that the rate of
critical events such as hypotension or hypoxia during transport was
significant (23%), but that re-arrest was less common (6%). Approximately one-fourth of all events occurred prior to transport. Importantly, the rate of events did not differ over the transport interval; median
transport time was the same in those who experienced a critical
event and those who did not.24 Clinicians should weigh the risks and
potential benefits for each patient when considering transport of the
post-arrest patient. These data do suggest that transport of the postarrest patient should occur with a critical care transport team ready
to prevent or respond to cardiopulmonary critical events.
Conclusion
Continued resuscitation and critical care of patients after cardiac arrest significantly improves survival and neurologic outcomes, even in
comatose patients. Aggressive resuscitation should include temperature management, coronary angiography and reperfusion, optimiza-
tion of hemodynamic status and ventilator settings, and delayed
neuroprognostication in order to achieve the best outcomes.
References
1. Roger VL, Go AS, Lloyd-Jones DM, et al. Heart disease and stroke statistics--2012
update: a report from the American Heart Association. Circulation. 2012;125:e2e220.
2. Daya MR, Schmicker RH, Zive DM, et al. Out-of-hospital cardiac arrest survival
improving over time: results from the Resuscitation Outcomes Consortium (ROC).
Resuscitation. 2015;91:108-115.
3. Rittenberger JC, Tisherman SA, Holm MB, Guyette FX, Callaway CW. An early,
novel illness severity score to predict outcome after cardiac arrest. Resuscitation.
2011;82:1399-1404.
4. Coppler PJ, Elmer J, Calderon L, et al. Validation of the Pittsburgh Cardiac Arrest
Category illness severity score. Resuscitation. 2015;89:86-92.
5. Reynolds JC, Rittenberger JC, Toma C, Callaway CW, Post Cardiac Arrest Service.
Risk-adjusted outcome prediction with initial post-cardiac arrest illness severity:
implications for cardiac arrest survivors being considered for early invasive
strategy. Resuscitation. 2014;85:1232-1239.
6. Wijdicks EF, Bamlet WR, Maramattom BV, Manno EM, McClelland RL. Validation of
a new coma scale: The FOUR score. Ann Neurol. 2005;58:585-593.
7. Fischer M, Ruegg S, Czaplinski A, et al. Inter-rater reliability of the Full Outline of
UnResponsiveness score and the Glasgow Coma Scale in critically ill patients: a
prospective observational study. Crit Care. 2010;14:R64.
8. Metter RB, Rittenberger JC, Guyette FX, Callaway CW. Association between a
quantitative CT scan measure of brain edema and outcome after cardiac arrest.
Resuscitation. 2011;82:1180-1185.
9. Reynolds JC, Callaway CW, El Khoudary SR, Moore CG, Alvarez RJ, Rittenberger
JC. Coronary angiography predicts improved outcome following cardiac arrest:
propensity-adjusted analysis. J Intensive Care Med. 2009;24:179-186.
10.Sundgreen C, Larsen FS, Herzog TM, Knudsen GM, Boesgaard S, Aldershvile J.
Autoregulation of cerebral blood flow in patients resuscitated from cardiac arrest.
Stroke. 2001;32:128-132.
11.Elmer J, Scutella M, Pullalarevu R, et al. The association between hyperoxia and
patient outcomes after cardiac arrest: analysis of a high-resolution database.
Intensive Care Med. 2015;41:49-57.
12.The Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypothermia
to improve the neurologic outcome after cardiac arrest. N Engl J Med.
2002;346:549-556.
13. Bernard SA, Gray TW, Buist MD, et al. Treatment of comatose survivors of out-ofhospital cardiac arrest with induced hypothermia. N Engl J Med. 2002;346:557563.
14.Nielsen N, Wetterslev J, Cronberg T, et al. Targeted temperature management
at 33 degrees C versus 36 degrees C after cardiac arrest. N Engl J Med.
2013;369:2197-2206.
15.Gebhardt K, Guyette FX, Doshi AA, Callaway CW, Rittenberger JC, Post Cardiac
Arrest Service. Prevalence and effect of fever on outcome following resuscitation
from cardiac arrest. Resuscitation. 2013;84:1062-1067.
16.Sunde K, Pytte M, Jacobsen D, et al. Implementation of a standardised
treatment protocol for post resuscitation care after out-of-hospital cardiac arrest.
17
BEYOND HYPOTHERMIA
17.Rittenberger JC, Popescu A, Brenner RP, Guyette FX, Callaway CW. Frequency
and timing of nonconvulsive status epilepticus in comatose post-cardiac arrest
subjects treated with hypothermia. Neurocrit Care. 2012;16:114-122.
18.Cloostermans MC, van Meulen FB, Eertman CJ, Hom HW, van Putten MJ.
Continuous electroencephalography monitoring for early prediction of neurological
outcome in postanoxic patients after cardiac arrest: a prospective cohort study.
Crit Care Med. 2012;40:2867-2875.
19.Amorim E, Rittenberger JC, Baldwin ME, Callaway CW, Popescu A, Post Cardiac
Arrest Service. Malignant EEG patterns in cardiac arrest patients treated
with targeted temperature management who survive to hospital discharge.
20.Birkmeyer JD, Stukel TA, Siewers AE, Goodney PP, Wennberg DE, Lucas FL.
Surgeon volume and operative mortality in the United States. N Engl J Med.
2003;349:2117-2127.
21.Callaway CW, Schmicker RH, Brown SP, et al. Early coronary angiography and
induced hypothermia are associated with survival and functional recovery after
out-of-hospital cardiac arrest. Resuscitation. 2014;85:657-663.
22. Reynolds JC, Rittenberger JC, Callaway CW, Post Cardiac Arrest Service. Patterns
of organ donation among resuscitated patients at a regional cardiac arrest center.
23.Spaite DW, Bobrow BJ, Vadeboncoeur TF, et al. The impact of prehospital
transport interval on survival in out-of-hospital cardiac arrest: implications for
regionalization of post-resuscitation care. Resuscitation. 2008;79:61-66.
24.Hartke A, Mumma BE, Rittenberger JC, Callaway CW, Guyette FX. Incidence of
re-arrest and critical events during prolonged transport of post-cardiac arrest
patients. Resuscitation. 2010;81:938-942.
18
ATRIALFIBRILLATION:
FIBRILLATION:ADVANCED
ADVANCEDMANAGEMENT
MANAGEMENTOF
OFTHE
THE
ATRIAL
CRITICALLYILL
ILLPATIENT
PATIENTININTHE
THEEMERGENCY
EMERGENCYDEPARTMENT
DEPARTMENTAND
AND
CRITICALLY
INTENSIVE
INTENSIVECARE
CAREUNIT
UNIT
ATRIAL FIBRILLATION: ADVANCED
MANAGEMENT OF THE CRITICALLY ILL PATIENT
IN THE EMERGENCY DEPARTMENT AND
INTENSIVE CARE UNIT
Assistant Professor, Departments of Emergency Medicine
and Neurology, Divisions of Neurocritical Care and
Emergency Neurology; Medical Director, SkyHealth Critical
Care, Yale University School of Medicine, New Haven, CT
Objectives
1. Describe the treatment options for atrial fibrillation in the critically ill patient.
2. Contrast and compare the roles of anticoagulation therapy using non-vitamin K antagonist oral anticoagulants (NOACs) and
warfarin for atrial fibrillation.
3. Discuss the complications of ischemic and hemorrhagic stroke
in the critically ill patient with atrial fibrillation.
4. Summarize the treatment options for critically ill patients requiring reversal of anticoagulation for atrial fibrillation.
Introduction
Atrial fibrillation (AF) afflicts over two million people, or 0.95% of the
United States population.1 The prevalence of AF is age-associated,
affecting 3.8% of people over age 60 and 9% of those over age 80.2
Although there are different types and etiologies of AF (Table 1), this
monograph will address acute, new-onset AF in the critically ill patient
because it presents a different paradigm with respect to epidemiology as well as treatment.3 Unfortunately, most existing data on AF in
critically ill patients is observational, and often combines AF with a
wide spectrum of other supraventricular arrhythmias.
TABLE
01
Etiology
Many physiologic factors predispose a patient to AF, including cardiac
diseases such as hypertension, coronary artery disease (CAD),
cardiomyopathy, valvular disease, cardiac surgery, myocarditis,
pericarditis, and other supraventricular tachycardias, as well as noncardiac disorders, such as excessive alcohol intake, hyperthyroidism,
pulmonary embolism, obstructive sleep apnea, metabolic syndrome
and vagal or sympathetic mechanisms.2,4
In the critically ill patient, the incidence of AF ranges from 6-20%.5,6 In
patients with acute CAD, the highest incidence of AF (30-40%) occurs
in patients after cardiac surgery, especially mitral valve surgery and
coronary artery bypass grafting.7 The highest incidence of new-onset
AF in non-cardiac post-operative patients occurs after vascular, abdominal and thoracic surgery.8 In general, most patients have at least
one modifiable risk factor such as electrolyte abnormalities, fluid
balance and hypotension. Patients with new-onset AF who develop
hemodynamic instability are more likely to have been receiving vasopressors, to have had congestive heart failure (CHF) with pulmonary
edema, and to have a rapid ventricular response greater than 150
beats per minute (bpm) than those without hemodynamic instability.8
It is still undetermined whether AF is related to contiguous inflammation or these modifiable factors.
The most common correlate in critically ill patients with AF is sepsis,
with some evidence that c-reactive protein plays a role; fueling the
theory that inflammation could be a target for prophylaxis and treatment.9,10 In a review of almost 50,000 hospitalized patients with
severe sepsis, 26% had AF, one-quarter of which were new-onset.11
Sepsis patients with new-onset AF have an increased risk of in-hospital stroke and mortality. Risk factors for AF in sepsis include age,
Caucasian race and severity of sepsis, but not many of the traditional
risk factors, such as CHF, myocardial infarction (MI), hypertension,
Definition of Atrial Fibrillation (AF): A Simplified Scheme
Term
Paroxysmal AF
• AF that terminates spontaneously or with intervention within 7 d of onset.
• Episodes may recur with variable frequency.
Persistent AF
Continuous AF that is sustained >7 d.
Long-standing persistent AF
Continuous AF >12 mo in duration.
Permanent AF
• The term “permanent AF” is used when the patient and clinician make a joint decision to stop further attempts
to restore and/or maintain sinus rhythm.
• Acceptance of AF represents a therapeutic attitude on the part of the patient and clinician rather than an
inherent pathophysiological attribute of AF.
•
preferences evolve.
Nonvalvular AF
AF in the absence of rheumatic mitral stenosis, a mechanical or bioprosthetic heart valve, or mitral valve repair.
Reprinted with permission from January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American
College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol. 2014;64:e1-76
19
ATRIAL FIBRILLATION: ADVANCED MANAGEMENT OF THE
CRITICALLY ILL PATIENT IN THE EMERGENCY DEPARTMENT AND
INTENSIVE CARE UNIT
diabetes mellitus and valve disease. Blunt thoracic trauma also carries a high risk for new-onset AF.12
events.7 The development of AF can also cause a rise in pulmonary
artery pressures, pulmonary hypertension and pulmonary edema.
Some of the evidence from research into the etiology of AF in critical
illness would suggest that it is a marker of illness severity or a result
of the physiology of the critical illness itself, although still conferring
future risk for stroke and mortality. Genetic and environmental risk
factors have been implicated as well.13 There is a lack of correlation
between new-onset AF and ischemic heart disease, thus obviating the
need for admission to rule out MI based on AF alone.1
In addition to the pathophysiology of AF contributing to critical illness,
stroke risk is increased as a result of atrial inactivity, coagulopathy
of critical illness, and decreased cardiac output. Pathophysiologic
components contributing to thrombus formation are complex and
include arrhythmia-induced stasis in the left atrium, atrial dilation and
endothelial damage, causing changes in hemostasis such as platelet
activation.15
Pathophysiology
Treatment Options
The critically ill patient typically starts with physiologic disadvantages,
including volume shift, anemia, electrolyte imbalance, sepsis and/or
the requirement for adrenergic vasoactive agents. A sudden increase
in heart rate will drive an increase in right and left atrial pressures,
and a decrease in end-diastolic volume and stroke volume. If the
decrease in stroke volume is offset by the increased heart rate,
cardiac output could be maintained; otherwise it, too, will decrease.14
Myocardial oxygen demand, vulnerable to changes in heart rate,
afterload and left ventricular end diastolic pressure, will increase as
cardiac output deteriorates. Subsequent resulting hypotension leading to a diminution in coronary perfusion, ischemia, heart failure and
organ dysfunction can create a cycle of deterioration. Patients with
pre-existing diastolic dysfunction are particularly vulnerable to these
There are little prospective, randomized data regarding treatment
modalities for AF in the critically ill. Most recommendations are
derived from data in ambulatory patients and are adapted according
to critical illness factors including contraindications to anticoagulation
due to recent surgery, trauma or thrombocytopenia, or contraindications to chemical rate or rhythm control because of pre-existing
comorbidities.
TABLE
02
Resolution of pre-existing modifiable risk factors is the first step
toward preventing or treating new-onset AF in the critically ill patient
(Table 2). Treating these risk factors also increases the success of
cardioversion or rate control. It is important to restore and maintain perfusion pressure and minimize inflammation and/or cat-
Modifiable Promoters of Atrial Fibrillation
Mechanism
Etiology
Myocardial stretch (atrial
hypertension, atrial dilatation,
reduced
contractility)
• Fluid overload
•
• Mitral stenosis
•
Inappropriate oxygen delivery to
the myocardium
• Myocardial ischemia
• Hypovolemia
• Anemia
• Revascularization
• Fluid challenge
• Transfusion of red blood cells
Electrolyte disturbances (risk
factors: diuretics, dialysis)
• Hypokalemia
• Hypomagnesemia
• Substitution of potassium (goal K+ 4.5–5.5 mmol/L)
• Substitution of magnesium (goal Mg++ >1.0 mmol/L)
• Heart-lung machine
• Sepsis
• Myocarditis
•
• Antimicrobial therapy
• Immunosuppression
Adrenergic overstimulation
• Inotropic support
• Stress (pain, anxiety)
• Reduction of inotropes
• Sedation; analgesia; betablockers
Endocrine disorder
• Elevated thyroid hormones
• Pheochromocytoma
• Betablockers; thyreostatic drugs
• Alpha- and betablockers
Various
• Hypothermia
• Correction of hypothermia
ment therapy)
• Intra-aortic balloon pump; cardiac surgery
• Valvuloplasty
diuretics, renal replace-
Reprinted with permission from Arrigo M, Bettex D, Rudiger A. Management of atrial fibrillation in critically ill patients. Crit Care Res Pract. 2014;2014:840615.
20
INTENSIVE CARE UNIT
echolamines. Volume status, sepsis, use of catecholamine-based
vasoactive agents and generalized stress contribute to development
of AF and should be addressed early in an effort to minimize the
development of arrhythmia, or be remedied upon development of the
arrhythmia. Providing sedation and pain control also contributes to
success because it reduces the catecholamine response.7
After addressing the modifiable risk factors, rate control is most
important, with anticipation that spontaneous conversion may occur.
If AF has been ongoing for greater than 48 hours cardioversion is
recommended, either by electrical or pharmacological mechanisms.
Prior to cardioversion, the patient should undergo transesophageal
echocardiography (TEE) to rule out existing left atrial thrombus, and/
or three weeks of anticoagulation prior to cardioversion and four
weeks after cardioversion.3 This may not be practical in the critically ill patient for many reasons, one of which is coagulopathy and
the driving mechanisms for AF. If the duration of AF is less than 48
hours, cardioversion can be performed with consideration for anticoagulation due to increased risk of thrombus post-conversion.3
Cardioversion
Rhythm control by electrical cardioversion, the first line therapy, or
pharmacological cardioversion is the priority for treating hemodynamic instability resulting in angina pain, ST-segment changes or
hypotension.13 Caution should be taken in converting AF to sinus
rhythm if the patient has been in AF for greater than 48 hours due to
the potential for left atrial thrombus; however, in patients with hemodynamic instability secondary to AF, cardioversion may be necessary
even if an atrial thrombus has not been excluded.3
In ambulatory patients, electrical or pharmacologic cardioversion for
new-onset AF is generally safe and effective with success rates of
approximately 90%. In contrast, success rates for electrical cardioversion are as low as 30% in the critically ill patient.7 Strategies for
higher success rates with electrical cardioversion include sedation
and analgesia to decrease catecholamine surge, starting with higher
energy joules (200 J biphasic) to overcome increased impedance,
and careful adjustment of electrode placement due to wounds or
dressings. Anterior-posterior (AP) paddles are best for supraventricular tachycardias (SVTs). Even with electrical conversion there is a high
rate of recurrence in this population.8 If cardioversion is not possible,
then anti-arrhythmic or nodal slowing agents may be used.
Rate Control
Hemodynamic stability may be restored by using agents to slow
atrioventricular (AV) nodal conduction such as beta antagonists or
calcium channel blockers, or with antiarrhythmic agents such as
amiodarone; these medications may precipitate hypotension which
could worsen the clinical picture. Heart rate control can also be helpful in increasing ventricular filling and stroke volume, thus preventing
tachycardia-induced cardiomyopathy which typically occurs with
protracted rapid AF. The current treatment goal for heart rate is <110
bpm.16,17 There are no data to recommend any one agent over the
others in the critically ill patient, therefore the treatment strategy
should be tailored to the particular patient’s clinical situation.16,18-21
The commonly used medications for rate control in AF are listed in
Tables 3 and 4.
Beta antagonists are effective for rate control because they slow the
ventricular rate and reduce myocardial excitability. Less desirable
effects include negative inotropy and vasodilation, which may be
counterproductive in the setting of decreased cardiac output. In the
intensive care unit (ICU) setting, esmolol is used most commonly
due to its short half-life and the ability to titrate based on effect.
Calcium channel blockers are effective and have been studied in
comparison to other agents. Diltiazem has been shown to be superior
to digoxin for rapid control of tachycardia associated with AF in the
ambulatory setting and more effective than metoprolol in postsurgical patients, excluding cardiac and thoracic surgery. It is not inferior
to amiodarone in rate control in critically ill patients; however, the
downside to diltiazem is hypotension which may not be tolerated in
critically ill patients.19-21 Negative inotropic effect is more pronounced
with verapamil than diltiazem. Verapamil also has an increased
incidence of conduction disorders. Therefore diltiazem is preferred,
but both require caution in the setting of heart failure unless left
ventricular function is preserved.
Digoxin is not typically a first line agent for rate control in the ICU
due to its long onset of action (>1 hour) and time to peak concentration (6 hours). It acts by directly affecting the AV node and through
centrally mediated vagal stimulation. Its value is that it does not have
a negative inotropic effect so it can be combined with other nodal
slowing agents. Digoxin is less effective in settings of high adrenergic stress, making it less useful in the ICU setting.22 It is important
to follow digoxin levels closely because renal dosing is required. Its
metabolism can be affected by agents commonly used in this setting
such as amiodarone and non-dihydropyridine calcium channel blockers.
Caution should be taken with all agents that block the AV node in the
setting of pre-excitation syndromes such as Wolfe-Parkinson-White
due to the potential for decreasing the refractoriness of the bypass
tract and creating a worsening tachycardia with subsequent decrease
in cardiac output. Amiodarone has antagonistic effects on adrenergic
receptors as well as potassium and calcium channels. In addition to
slowing the ventricular rate it has shown high conversion rates in the
setting of critical illness.8 Amiodarone’s advantages over beta and
calcium channel blockers are that it causes less negative inotropy.
Amiodarone has a very long half-life and pertinent side effects in critical care settings include bradycardia, hypotension and local phlebitis.
If used in a more prolonged fashion, significant side effects include
thyroid disturbances, neurologic, pulmonary, and hepatic toxicity, as
well as multiple interactions with other medications.3,7,24
21
INTENSIVE CARE UNIT
TABLE
03
Frequently Used Intravenous Antiarrhythmic Substances in the Intensive Care Unit
Substance
Dosing
Half-Life
Commentary
Esmolol
1.0 mg/kg in boluses of 10–20 mg IV, followed by
continuous infusion (start with 0.05 mg/kg/min,
increase dose every 30 minutes if necessary)
7–10 min
•
•
•
Diltiazem
0.25 mg/kg IV over 2 minutes, followed by
continuous infusion (10–15 mg/h) if necessary
Amiodarone
• 150–300 mg IV, followed by a continuous infusion (900–1200 mg daily) up to 0.1 g/kg
• Maintenance dose 200 mg daily
20–100 d
•
• Extreme long half-life up to 80 days.
•
Digoxin
0.25–0.5 mg IV every 4–8 h up to 1 mg, followed
by maintenance dose of 0.25 mg daily
20 h–6 d
•
• Reduce dose in renal dysfunction.
• Check digoxin plasma levels to avoid toxicity.
2–4 h
• Longer half-life as esmolol.
•
•
Reprinted with permission from Arrigo M, Bettex D, Rudiger A. Management of atrial fibrillation in critically ill patients. Crit Care Res Pract. 2014;2014: 840615
TABLE
04
Common Medication Dosage for Rate Control of Atrial Fibrillation
Substance
Intravenous Administration
Usual Oral Maintenance Dose
2.5–5.0 mg IV bolus over 2 min; up to 3 doses
25–100 mg BID
Metoprolol XL (succinate)
N/A
50–400 mg QD
Atenolol
N/A
25–100 mg QD
Esmolol
500 mcg/kg IV bolus over 1 min, then 50–300 mcg/kg/min IV
N/A
1 mg IV over 1 min, up to 3 doses at 2-min intervals
10–40 mg TID or QID
Nadolol
N/A
10–240 mg QD
Carvedilol
N/A
3.125–25 mg BID
Bisoprolol
N/A
2.5–10 mg QD
Verapamil
0.075-0.15 mg/kg IV bolus over 2 min; may give an additional 10.0 mg
after 30 min if no response, then 0.005 mg/kg/min infusion
180–480 mg QD (ER)
Diltiazem
0.25 mg/kg IV bolus over 2 min, then 5-15 mg/h
120–360 mg QD (ER)
0.25 mg IV with repeat dosing to a maximum of 1.5 mg over 24 h
0.125–0.25 mg QD
300 mg IV over 1 h, then 10–50 mg/h over 24 h
100–200 mg QD
Beta blockers
Metoprolol tartrate
Propranolol
Nondihydropyridine Calcium Channel Antagonists
Digitalis Glycosides
Digoxin
Others
Amiodarone*
*Multiple dosing schemes exist for the use of amiodarone.
BID, twice daily; ER, extended release; IV, intravenous; N/A, not applicable; QD, once daily; QID, 4 times a day; and TID, 3 times a day.
Reprinted with permission from January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart
Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol. 2014;64:e1-76
22
INTENSIVE CARE UNIT
Magnesium increases atrial and AV nodal refractory periods. It has
been suggested to be as effective as amiodarone and diltiazem in
rate control for AF.25 These data are of limited strength, but reinforce
the point that hypomagnesemia, present in nearly half of AF patients,
should be addressed in conjunction with any agent chosen for treatment of acute AF.
Complications of Atrial Fibrillation
Although cardioversion for new-onset AF in ambulatory patients is
generally effective, AF does not seem to be as transient or benign
in the critical care setting. Even if cardioversion is accomplished, AF
often recurs with other morbidity and mortality effects associated
with new-onset AF. The AF after cardiac surgery confers a threefold greater risk of stroke and a higher risk of MI, heart failure, and
respiratory failure.13 New studies are now examining the existence
of AF in other postoperative and critically ill patients to try to identify
predisposing factors and hopefully improve outcomes through prevention and treatment.
Stroke Risk
Critically ill patients have an increased risk of in-hospital and out-ofhospital stroke in the setting of new-onset AF, in part because of the
contributions of inflammation and a pro-coagulation state.7,11 The
presence of AF alone increases the risk of stroke nearly five-fold, and
the only prophylactic treatment is anticoagulation.26 Anticoagulation
can affect a 60% decrease in the incidence of stroke in the ambulatory setting.27 Many factors make anticoagulation a risky proposition
in the ICU patient, however, including possible thrombocytopenia,
renal and hepatic insufficiency, and anticipation of invasive procedures. The risk of stroke must therefore be balanced with the risk of
hemorrhagic complications due to anticoagulation which increases
in the critically ill patient and with the challenge of maintaining a
therapeutic international normalized ratio (INR).28 In one study of ICU
patients, only 16% of patients with new-onset AF and 19% of patients
with pre-existing AF received anticoagulation while in the ICU. There
were no acute ischemic stroke events but 9% of patients had a significant bleeding event, while still in the ICU.8
Perioperative stroke has an incidence of 0.05-7% in non-cardiac, nonneurosurgical patients, and carries a mortality twice that of stroke
in ambulatory patients.29 Postoperative arterial thrombotic events, in
general, carry up to 33% mortality; however, only 3% of postoperative
bleeding events are fatal. Unfractionated heparin, although not studied conclusively, may be a safer option because it is not eliminated by
the kidneys and is easily reversible.7,28
New-onset AF in critical illness is associated with in-hospital and long
term risk of recurrent AF, stroke, heart failure and mortality.11,30,31
There is also evidence from ongoing research on the cause of cryptogenic stroke (stroke without identifiable cause) that some patients
who have had transient AF during hospitalization for sepsis have developed stroke after hospitalization without evidence of recurrent AF.30
Risk Assessment
Currently, decisions regarding anticoagulation in critically ill patients
with AF are made using published recommendations for preventing
stroke in ambulatory patients with AF and adapting these to critically
ill patients by estimating the risk of bleeding.
The CHADS2 and CHA2DS2-VASc scoring systems predict the risk
of future ischemic stroke events in the ambulatory patient with AF
and have been validated in the ICU setting, although there is some
disagreement as to how to set the threshold for anticoagulation
(Table 5).32,33 The recommendations for antithrombotic therapy in the
ambulatory AF patient are based on multiple factors including patient
preference, age, classification of AF, CHA2DS2-VASc score, presence
of mechanical valve, and prior stroke or transient ischemic event
(TIA) (Table 6).3 The American Heart Association/American College
of Cardiology/Heart Rhythm Society recommendations propose using
a CHA2DS2-VASc score of two or more as threshold for anticoagulation but this is a general recommendation, and does not take into account critically ill patients.3 Some recommend considering a CHADS2
score of four or higher, significant mitral stenosis, or previous stroke
as criteria for anticoagulation in critically ill patients.32
TABLE
05
Stroke Risk Stratification in Atrial Fibrillation
Components of CHA2DS2-VASc
Risk Factor
Score
Cardiac Failure
1
HTN
1
Age ≥ 75 y
2
Diabetes
1
Stroke
2
Vascular Disease
(MI, PAD, aortic
atherosclerosis)
1
Age 65-74 y
1
Sex category
(female)
1
CHA2DS2-VASc
Score
Annual Risk
of Stroke (%)
0
0
1
1.3
2
2.2
3
3.2
4
4.0
5
6.7
6
9.8
7
9.6
8
6.7
9
15.2
Reprinted with permission from Frendl G, Sodickson AC, Chung MK, et al. 2014 AATS guidelines for the
prevention and management of perioperative atrial fibrillation and flutter for thoracic surgical procedures.
J Thorac Cardiovasc Surg. 2014;148:e153-193.
The American Association for Thoracic Surgery (AATS) recommends
anticoagulation in post-operative thoracic surgery patients whose
CHA2DS2-VASc score is two or more, and consider anticoagulation
therapy if the score is one (Figure 1). This Society recommends
using warfarin but suggests that the non-vitamin K antagonist oral
anticoagulants (NOACs) are a reasonable alternative for those without
a prosthetic heart valve, valve disease, renal impairment or risk of
gastrointestinal bleeding.34 These recommendations are based on
evidence from patients in the ambulatory setting.
23
INTENSIVE CARE UNIT
TABLE
06
Summar y of Recommendations for Risk-Based Antithrombotic Therapy
COR
LOE
Antithrombotic therapy based on shared decision making, discussion of risks of stroke and bleeding, and
patient’s preferences
Recommendations
I
C
Selection of antithrombotic therapy based on risk of thromboembolism
I
B
CHA 2 DS 2 -VASc score recommended to assess stroke risk
I
B
Warfarin recommended for mechanical heart valves and target INR intensity based on type and location
of prosthesis
I
B
Warfarin
I
A
Dabigatran, rivaroxaban, or apixaban
I
B
With prior stroke, TIA, or CHA 2 DS 2 -VASc score ≥2, oral anticoagulants recommended. Options include:
I
A
Direct thrombin or factor Xa inhibitor recommended if unable to maintain therapeutic INR
I
C
Reevaluate the need for anticoagulation at periodic intervals
I
C
Bridging therapy with UFH or LMWH recommended with a mechanical heart valve if warfarin is interrupted.
Bridging therapy should balance risks of stroke and bleeding
I
C
For patients without mechanical heart valves, bridging therapy decisions should balance stroke and
bleeding risks against duration of time patient will not be anticoagulated
I
C
Evaluate renal function before initiation of direct thrombin or factor Xa inhibitors, and reevaluate when
clinically indicated and at least annually
I
B
For atrial flutter, antithrombotic therapy is recommended as for AF
I
C
With nonvalvular AF and CHA 2 DS 2 -VASc score of 0, it is reasonable to omit antithrombotic therapy
IIa
B
With CHA 2 DS 2 -VASc score ≥2 and end-stage CKD (CrCl <15 mL/min) or on hemodialysis, it is reasonable
to prescribe warfarin for oral anticoagulation
IIa
B
With nonvalvular AF and a CHA 2 DS 2 -VASc score of 1, no antithrombotic therapy or treatment with oral
anticoagulant or aspirin may be considered
IIb
C
With moderate-to-severe CKD and CHA 2 DS 2 -VASc scores ≥2, reduced doses of direct thrombin or factor
Xa inhibitors may be considered
IIb
C
For PCI,* BMS may be considered to minimize duration of DAPT
IIb
C
After coronary revascularization in patients with CHA 2 DS 2 -VASc score ≥2, it may be reasonable to use
clopidogrel concurrently with oral anticoagulants but without aspirin
IIb
B
III:No Benefit
C
III: Harm
B
With warfarin, determine INR at least weekly during initiation of therapy and monthly when stable
Direct thrombin dabigatran and factor Xa inhibitor rivaroxaban are not recommended in patients with AF
and end-stage CKD or on dialysis because of a lack of evidence from clinical trials regarding the
balance of risks and benefits
Direct thrombin inhibitor dabigatran should not be used with a mechanical heart valve
*See the 2011 PCI guideline for type of stent and duration of DAPT recommendations.
AF indicates atrial fibrillation; BMS, bare-metal stent; CHA2DS2-VASc, Congestive heart failure, Hypertension, Age ≥75 years (doubled),
Diabetes mellitus, Prior Stroke or TIA or thromboembolism (doubled), Vascular disease, Age 65 to 74 years, Sex category; CKD, chronic kidney
disease; COR, Class of Recommendation; CrCl, creatinine clearance; DAPT, dual antiplatelet therapy; INR, international normalized ratio; LMWH,
low-molecular-weight heparin; LOE, Level of Evidence; PCI, percutaneous coronary intervention;TIA, transient ischemic attack; and UFH,
unfractionated heparin.
Adapted and reprinted with permission from January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with
atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm
Society. J Am Coll Cardiol. 2014;64:e1-76.
24
INTENSIVE CARE UNIT
FIGURE
01
Considerations for the Management of Anticoagulation Within the First 48 Hours of Postoperative
Atrial Fibrillation (POAF)
New Onset of POAF < 48 hours
Calculate CHA2DS2-VASc risk score for stroke
S=0:
No anticoagulation
Start
anticoagulation
when
cardioversion
attempted
S≥2:
anticoagulation
is highy
recommened
S=1:
anticoagulation should
be considered if
bleeding risk is low
Class I
Class IIA
Caution should be used if patient is on hemodialysis
Class IIB
Class III
Reprinted with permission from Frendl G, Sodickson AC, Chung MK, et al. 2014 AATS guidelines for the prevention and management of perioperative atrial fibrillation and flutter for
thoracic surgical procedures. J Thorac Cardiovasc Surg. 2014;148:e153-193.
Multiple scoring systems have been published to assess for bleeding
risk in the anticoagulated patient. The HAS-BLED score has been
shown to be superior in predictive value as well as simplicity (Table
7).35-37 These scoring systems have not been validated in critically ill
patients who have many other factors contributing to a high risk of
bleeding if anticoagulated.
The HAS-BLED Score: Pointing System
TABLE
07
Risk Factors
Points
Hypertension
1 pt
Abnormal renal/liver function
1 pt each
Oral Anticoagulants
Stroke
1 pt
Warfarin, a vitamin K antagonist (VKA), has been the mainstay for
prophylactic anticoagulation in the AF patient but has been underused due to its many food and drug interactions, patient noncompliance, and hesitancy of many physicians to prescribe this drug
because of patient risk factors including fall potential, dementia and
history of bleeding.7 Antiplatelet agents have been considered as
an alternative, but aspirin may carry a higher risk of bleeding than
warfarin with no significant protection against cardio-embolic events.
Clopidogrel has not been approved for use in stroke prevention.38
The combination of aspirin and clopidogrel has also been shown to
increase bleeding risk without providing cardio-embolic protection,
and would not be an appropriate choice for risk prevention in the critically ill patient due to length of therapeutic effect.
Bleeding (prior)
1 pt
Labile INR
1 pt
Elderly (age > 65 years)
1 pt
Drugs and alcohol
1 pt each
Score ≥3 indicates high risk of major bleeding (>3.7%/y)
INR: international normalized ratio
Reprinted with permission from Arrigo M, Bettex D, Rudiger A. Management of atrial fibrillation in critically ill
patients. Crit Care Res Pract. 2014; 2014: 840615
25
INTENSIVE CARE UNIT
The NOACs are advantageous because, as opposed to warfarin, they
do not require frequent laboratory evaluation to ensure target therapeutic goals. These agents, which are sometimes called direct oral
anticoagulants (DOAC), or target specific anticoagulants (TSOAC),
have been approved in phase III trials for stroke prevention in patients with nonvalvular AF.39,40 Apixaban, dabigatran and rivaroxaban
have been shown to have greater efficacy than VKAs in preventing
combined stroke, systemic embolism, all-cause mortality, vascular mortality and decreasing the risk for intracranial hemorrhage,
although rivaroxaban had a higher risk for gastrointestinal hemorrhage.41 In 2010, dabigatran was the first NOAC to be approved in
the United States to reduce stroke or systemic embolism, after being
shown to have a similar rate of major bleeding and a lower rate of
intracranial hemorrhage than warfarin.42 Rivaroxaban and apixaban
approval closely followed, and all three agents are options to be considered for stroke reduction in AF patients in the ambulatory patient.
These must be considered within the limitations of renal function, fall
risk, bleeding risk and valvular heart disease (Table 6).
TThe question remains whether or not these agents are suitable for
use in the critically ill patient. One of the most concerning drawbacks
to the NOACs is the lack of reversibility. Although NOACs have a
shorter half-life than VKAs, there are no specific reversal agents.
However, it should also be considered that reversal of coagulopathy, although it seems intuitively protective, has not been shown to
improve outcome in significant hemorrhage.
In general, it is important for clinicians taking care of critically ill
patients with AF to discriminate which require anticoagulation, due to
the lack of direct evidence in this population that improved outcomes
outweigh the risk of complications.28,43
Alternative Approaches
Newer methods of reducing ischemic stroke risk in patients with AF
have been studied, although none of them in the setting of critical
illness. Left atrial appendage (LAA) closure has been performed for
decades in patients with AF primarily using a surgical approach at the
time of mitral valve replacement to reduce the area of origin for most
known cardio-embolic strokes, but this has not been studied in a
randomized fashion. In addition, many ischemic strokes do not have
thrombus originating in the LAA so anticoagulation is still considered
after the procedure.44 Catheter ablation is another alternative to
chemotherapy for AF, with success being dependent on factors such
as patient selection and operator experience. Catheter ablation is
typically used for those patients who are intolerant of or symptomatic
despite medication, but is not used in the setting of critical illness.45
Conclusion
In summary, AF is a significant issue in the critically ill patient with
increased rates of morbidity and mortality. The physiology of the
critically ill patient predisposes to AF, and morbidity and mortality are
26
more significant than in the ambulatory setting in which most of the
data regarding treatment and stroke prophylaxis have been obtained.
The consideration for treatment, whether for rate control, rhythm conversion, or anticoagulation must include the unique circumstances
of the critically ill patient who is at higher risk of complication. The
astute clinician will apply existing data judiciously to the patient situation, closely balancing risk and benefit. The emergency physician will
be seeing more critically ill patients with AF, due to the aging population and increased therapies evolving to extend life. More research
is necessary to assess the safety of chemical and other therapies to
treat the critically ill patient with AF.
References
1. McDonald AJ, Pelletier AJ, Ellinor PT, Camargo CA, Jr. Increasing US emergency
department visit rates and subsequent hospital admissions for atrial fibrillation
from 1993 to 2004. Ann Emerg Med. 2008;51:58-65.
2. Page RL. Clinical practice. Newly diagnosed atrial fibrillation. N Engl J Med.
2004;351:2408-2416.
3. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the
management of patients with atrial fibrillation: a report of the American College
of Cardiology/American Heart Association Task Force on Practice Guidelines and
the Heart Rhythm Society. J Am Coll Cardiol. 2014;64:e1-76.
4. Tanner RM, Baber U, Carson AP, et al. Association of the metabolic syndrome with
atrial fibrillation among United States adults (from the REasons for Geographic
and Racial Differences in Stroke [REGARDS] Study). Am J Cardiol. 2011;108:227232.
5. Annane D, Sebille V, Duboc D, et al. Incidence and prognosis of sustained
arrhythmias in critically ill patients. Am J Respir Crit Care Med. 2008;178:20-25.
6. Goodman S, Shirov T, Weissman C. Supraventricular arrhythmias in intensive care
unit patients: short and long-term consequences. Anesth Analg. 2007;104:880886.
7. Arrigo M, Bettex D, Rudiger A. Management of atrial fibrillation in critically ill
patients. Crit Care Res Pract. 2014;2014:840615.
8. Kanji S, Williamson DR, Yaghchi BM, Albert M, McIntyre L, Canadian Critical
Care Trials G. Epidemiology and management of atrial fibrillation in medical and
noncardiac surgical adult intensive care unit patients. J Crit Care. 2012;27:326
e321-328.
9. Makrygiannis SS, Margariti A, Rizikou D, et al. Incidence and predictors of newonset atrial fibrillation in noncardiac intensive care unit patients. J Crit Care.
2014;29:697 e691-695.
10.Chung MK, Martin DO, Sprecher D, et al. C-reactive protein elevation in patients
with atrial arrhythmias: inflammatory mechanisms and persistence of atrial
fibrillation. Circulation. 2001;104:2886-2891.
11.Walkey AJ, Wiener RS, Ghobrial JM, Curtis LH, Benjamin EJ. Incident stroke and
mortality associated with new-onset atrial fibrillation in patients hospitalized with
severe sepsis. JAMA. 2011;306:2248-2254.
12.Yoshida T, Fujii T, Uchino S, Takinami M. Epidemiology, prevention, and treatment
of new-onset atrial fibrillation in critically ill: a systematic review. J Intensive Care.
2015;3:19.
INTENSIVE CARE UNIT
13.Cavaliere F, Volpe C, Soave M. Atrial fibrillation in intensive care units. Trends
Anaesth & Crit Care. 2006;17:367-374.
14.Packer DL, Bardy GH, Worley SJ, et al. Tachycardia-induced cardiomyopathy: a
reversible form of left ventricular dysfunction. Am J Cardiol. 1986;57:563-570.
15. Watson T, Shantsila E, Lip GY. Mechanisms of thrombogenesis in atrial fibrillation:
Virchow's triad revisited. Lancet. 2009;373:155-166.
30.Walkey AJ, Hammill BG, Curtis LH, Benjamin EJ. Long-term outcomes following
development of new-onset atrial fibrillation during sepsis. Chest. 2014;146:11871195.
31.Chen AY, Sokol SS, Kress JP, Lat I. New-onset atrial fibrillation is an independent
predictor of mortality in medical intensive care unit patients. Ann Pharmacother.
2015;49:523-527.
16.Van Gelder IC, Hobbelt A, Mulder BA, Rienstra M. Rate control in atrial fibrillation:
many questions still unanswered. Circulation. 2015;132:1597-9.
32.Champion S, Lefort Y, Gauzere BA, et al. CHADS2 and CHA2DS2-VASc scores
can predict thromboembolic events after supraventricular arrhythmia in the
critically ill patients. J Crit Care. 2014;29:854-858.
17.Mulder BA, Van Veldhuisen DJ, Crijns HJ, et al. Lenient vs. strict rate control in
patients with atrial fibrillation and heart failure: a post-hoc analysis of the RACE II
study. Eur J Heart Fail. 2013;15:1311-1318.
33.Andrade AA, Li J, Radford MJ, Nilasena DS, Gage BF. Clinical benefit of American
College of Chest Physicians versus European Society of Cardiology guidelines for
stroke prophylaxis in atrial fibrillation. J Gen Intern Med. 2015;30:777-782.
18. Walkey AJ, Evans SR, Winter MR, Benjamin EJ. Practice patterns and outcomes of
treatments for atrial fibrillation during sepsis: A propensity-matched cohort study.
Chest. 2015.
34. Frendl G, Sodickson AC, Chung MK, et al. 2014 AATS guidelines for the prevention
and management of perioperative atrial fibrillation and flutter for thoracic surgical
procedures. J Thorac Cardiovasc Surg. 2014;148:e153-193.
19.Delle Karth G, Geppert A, Neunteufl T, et al. Amiodarone versus diltiazem for
rate control in critically ill patients with atrial tachyarrhythmias. Crit Care Med.
2001;29:1149-1153.
35.Lip GY, Larsen TB, Skjoth F, Rasmussen LH. Indirect comparisons of new oral
anticoagulant drugs for efficacy and safety when used for stroke prevention in
atrial fibrillation. J Am Coll Cardiol. 2012;60:738-746.
20. Personett HA, Smoot DL, Stollings JL, Sawyer M, Oyen LJ. Intravenous metoprolol
versus diltiazem for rate control in noncardiac, nonthoracic postoperative atrial
fibrillation. Ann Pharmacother. 2014;48:314-319.
36. Roldan V, Marin F, Fernandez H, et al. Predictive value of the HAS-BLED and ATRIA
bleeding scores for the risk of serious bleeding in a "real-world" population with
atrial fibrillation receiving anticoagulant therapy. Chest. 2013;143:179-184.
21.Schreck DM, Rivera AR, Tricarico VJ. Emergency management of atrial fibrillation
and flutter: intravenous diltiazem versus intravenous digoxin. Ann Emerg Med.
1997;29:135-140.
37.Roldan V, Marin F, Manzano-Fernandez S, et al. The HAS-BLED score has better
prediction accuracy for major bleeding than CHADS2 or CHA2DS2-VASc scores
in anticoagulated patients with atrial fibrillation. J Am Coll Cardiol. 2013;62:21992204.
22.Farshi R, Kistner D, Sarma JS, Longmate JA, Singh BN. Ventricular rate control
in chronic atrial fibrillation during daily activity and programmed exercise:
a crossover open-label study of five drug regimens. J Am Coll Cardiol.
1999;33:304-310.
23.Matthew JP, Fontes ML, Tudor LC, Ramsay J, Duke P, Mazer CD, Barash PG,
HSu PH, Mangano DT, Investigators of the Ischemia Research and Education
Foundation, Multicenter Study of Perioperative Ischemia Research Group. A
multicenter risk index for atrial fibrillation after cardiac surgery. JAMA. 2004;
291:1720-1729.
24.Walkey AJ, Hogarth DK, Lip GY. Optimizing atrial fibrillation management: from
ICU and beyond. Chest. 2015;148:859-864.
25.Onalan O, Crystal E, Daoulah A, Lau C, Crystal A, Lashevsky I. Meta-analysis of
magnesium therapy for the acute management of rapid atrial fibrillation. Am J
Cardiol. 2007;99:1726-1732.
26. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for
stroke: the Framingham Study. Stroke. 1991;22:983-988.
27.Fuster V, Ryden LE, Cannom DS, et al. 2011 ACCF/AHA/HRS focused updates
incorporated into the ACC/AHA/ESC 2006 Guidelines for the management of
patients with atrial fibrillation: a report of the American College of Cardiology
Foundation/American Heart Association Task Force on Practice Guidelines
developed in partnership with the European Society of Cardiology and in
collaboration with the European Heart Rhythm Association and the Heart Rhythm
Society. J Am Coll Cardiol. 2011;57:e101-198.
28.Darwish OS, Strube S, Nguyen HM, Tanios MA. Challenges of anticoagulation for
atrial fibrillation in patients with severe sepsis. Ann Pharmacother. 2013;47:12661271.
38.Rash A, Downes T, Portner R, Yeo WW, Morgan N, Channer KS. A randomised
controlled trial of warfarin versus aspirin for stroke prevention in octogenarians
with atrial fibrillation (WASPO). Age Ageing. 2007;36:151-156.
39.Barnes GD, Ageno W, Ansell J, Kaatz S, Subcommittee on the Control of A.
Recommendation on the nomenclature for oral anticoagulants: communication
from the SSC of the ISTH. J Thromb Haemost. 2015;13:1154-1156.
40.Albert NM. Use of novel oral anticoagulants for patients with atrial fibrillation:
systematic review and clinical implications. Heart Lung. 2014;43:48-59.
41.Miller CS, Grandi SM, Shimony A, Filion KB, Eisenberg MJ. Meta-analysis of
efficacy and safety of new oral anticoagulants (dabigatran, rivaroxaban, apixaban)
versus warfarin in patients with atrial fibrillation. Am J Cardiol. 2012;110:453460.
42.Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients
with atrial fibrillation. N Engl J Med. 2009;361:1139-1151.
43.Labbe V, Ederhy S, Fartoukh M, Cohen A. Should we administrate anticoagulants
to critically ill patients with new onset supraventricular arrhythmias? Arch
Cardiovasc Dis. 2015;108:217-219.
44.Whitlock RP, Healey JS, Connolly SJ. Left atrial appendage occlusion does not
eliminate the need for warfarin. Circulation. 2009;120:1927-1932; discussion
1932.
45. Camm AJ, Lip GY, De Caterina R, et al. 2012 focused update of the ESC Guidelines
for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for
the management of atrial fibrillation--developed with the special contribution of the
European Heart Rhythm Association. Europace. 2012;14:1385-1413.
29.Ng JL, Chan MT, Gelb AW. Perioperative stroke in noncardiac, nonneurosurgical
surgery. Anesthesiology. 2011;115:879-890.
27
MANAGEMENT
MANAGEMENT OF
OF MAJOR
MAJOR BLEEDING
BLEEDING FOR
FOR PATIENTS
PATIENTS TREATED
TREATED
WITH
WITH NON-VITAMIN
NON-VITAMIN KK ANTAGONIST
ANTAGONIST ORAL
ORAL ANTICOAGULANTS
ANTICOAGULANTS
MANAGEMENT OF MAJOR BLEEDING FOR
PATIENTS TREATED WITH NON-VITAMIN K
ANTAGONIST ORAL ANTICOAGULANTS
world studies have supported the efficacy and safety of these agents
in routine clinical practice (Figure 1).11,12
FIGURE
01
Associate Provost for Innovation in Education; Director,
Jefferson Institute of Emerging Health Professions; Associate Dean for CME and Strategic Partner Alliances; Professor, Department of Emergency Medicine,
Thomas Jefferson University, Philadelphia, PA
NOACs Overcome Many Practical Limitations of Warfarin
Objectives
1. Assess the likely contribution of anticoagulation with non-vitamin
K antagonist oral anticoagulants (NOACs) to acute hemorrhagic
presentations to the Emergency Department.
2. Demonstrate a working knowledge of various general management strategies in the NOAC-treated bleeding or pre-procedural
patient.
3. Formulate an action plan to manage specific cases of NOACrelated bleeding or pre-procedural presentations.
4. Describe the mechanism of action of various specific reversal
agents to the NOACs and explain how this informs their clinical
use.
Introduction
Non-vitamin K antagonist (formerly “novel”) oral anticoagulants
(NOACs, sometimes also called direct oral anticoagulants [DOACs] or
target-specific oral anticoagulants [TSOACs]) include the direct Factor
Xa inhibitors rivaroxaban, apixaban, and edoxaban and the direct
thrombin (Factor IIa) inhibitor dabigatran etexilate. These agents are
approved for the prevention and treatment of venous thromboembolism (VTE) and for the prevention of stroke and systemic embolism in
patients with non-valvular atrial fibrillation (NVAF).
NOACs vs. Warfarin
For decades, the indications for NOACs were met only by vitamin
K antagonists (VKAs), such as warfarin. However, warfarin is often
viewed more as a problem than as a solution, given the drug’s
inter-individual variation in efficacy and safety, multiple drug–drug
and drug–diet interactions, and the need for frequent coagulation
monitoring and dose adjustments to ensure that the international normalized ratio (INR) remains within the therapeutic range of 2.0–3.0.
Such monitoring is burdensome, costly, and many would say (after
the approval of four NOACs based on head-to-head comparisons with
VKAs) that it is often no longer necessary. Conversely, the NOACs
have a predictable anticoagulant response that allows for fixed dosing
without routine coagulation monitoring. In Phase III trials that enrolled
more than 150,000 patients globally, NOACs were at least as effective as VKAs for VTE treatment1-4 and for stroke prevention in patients
with NVAF,5-10 while providing safety advantages. Subsequent real-
28
Comparison of Non-Vitamin K Antagonist Oral
Anticoagulants (NOACs) versus Vitamin K
Antagonists (VKAs)
•
•
•
•
•
•
Rapid onset of action
Short half-lives compared with warfarin
Predictable and consistent anticoagulant effects
Low potential for drug-drug interactions
No drug-food interactions
No requirement for routine coagulation monitoring
What does this
mean for you?
Simpler anticoagulation
management in the ED
Despite their beneficial attributes, the “market uptake” of NOACs has
been less robust than many medical experts and business estimates
had predicted. This is likely due to a number of issues, including
resistance to change in entrenched practice patterns, hesitancy
to adopt new therapies “early,” and initial problems with health
insurance coverage. A major reason, however, for the slow growth of
NOAC use seems to be the lack of specific reversal agents for use
in those occasional patients who present with serious bleeding while
taking a NOAC, or in those who require urgent surgery and therefore
need prompt restoration of hemostasis while taking a NOAC.13 There
are validated approaches, promulgated by specialty societies and
hospital pharmacy and therapeutics committees, and based on the
quantitative guidance provided by rapid turnaround INR values, for
handling such patients in the context of warfarin use. Although there
is a lack of evidence that providers scrupulously follow such protocols—the comfort seems to be simply in having them and in having
something to measure at baseline and serially. Because the anticoagulant effect of the NOACs cannot be readily measured, effecting
“reversal” in NOAC-treated patients seems more abstract, demands
an appreciation of some basic pharmacology as opposed simply to
pulling out a protocol, and perhaps may create a bit of insecurity for
the provider.
Bleeding Risk
There are, in fact, validated general approaches to managing NOACrelated bleeding complications (Figure 2), and specific approaches
are being developed. Before discussing those, it is important to place
NOAC-related bleeding into context (Figure 3). Across the four Phase
III trials of NOACs versus VKAs in stroke prevention in NVAF, rates of
major bleeding ranged from 1.6% to 3.6% per year for the NOACs and
from 3.1% to 3.6% per year for warfarin.5-10 Intracranial hemorrhage
(ICH) is the most-feared complication of VKA therapy, contributing to the majority of VKA-associated deaths and severe functional
MANAGEMENT OF MAJOR BLEEDING FOR PATIENTS TREATED
WITH NON-VITAMIN K ANTAGONIST ORAL ANTICOAGULANTS
disabilities;14 therefore, the significant reductions in the rates of ICH
(by ~30–70 %) and fatal or life-threatening bleeding episodes seen
among NOAC-treated patients in these NVAF trials (in which the typical patient is elderly and has multiple comorbidities) are particularly
reassuring. The only important exception is major gastrointestinal
(GI) bleeding, for which incidences were higher with rivaroxaban and
the higher doses of dabigatran and edoxaban compared with warfarin
in Phase III studies.5-7,10 Of note, apixaban9 and the lower edoxaban
and dabigatran doses12 were not associated with higher incidences of
GI bleeding.
There are some populations that are generally viewed as being at
higher risk of bleeding complications. Their outcomes are no worse
and in fact are sometimes better with NOACs than with warfarin. For
example, in the pooled analysis of the EINSTEIN-DVT and EINSTEINPE Trials, there was a significant 73% relative risk reduction in major
bleeding on rivaroxaban compared with low-molecular-weight heparin
(LMWH) bridging to VKA among “fragile” patients—those with two
FIGURE
02
of three characteristics: (1) age > 75 years, (2) creatinine clearance
(CrCl) < 50 ml/min, or (3) body weight < 50 kg.3
Although patients with severe renal insufficiency were excluded in all
Phase III studies of NOACs,1,2,15-18 VTE studies revealed that patients
with mild renal insufficiency (CrCl 50–79 ml/min) receiving NOACs
experienced significantly lower rates of major or clinically relevant
non-major (CRNM) bleeding than those receiving other anticoagulants, and there was also a trend toward lower rates of major or
CRNM bleeding with NOACs in moderate renal insufficiency (CrCl
30–49 ml/min).19 The impact of renal function on NOAC-related
bleeding rates is, not surprisingly, related to the degree to which
each drug is excreted by the kidneys. In a meta-analysis of data from
patients with renal impairment (CrCl < 50 ml/min) enrolled in studies of NOACs in patients with VTE and NVAF, there was a significantly
greater relative reduction in major bleeding in patients receiving
NOACs that have < 50 % renal excretion (rivaroxaban, apixaban and
edoxaban) than in those receiving dabigatran.20
General Measures for Managing Non-Vitamin K Antagonist Oral Anticoagulant (NOAC)-Related
Bleeding
European guidelines for Bleeding Management (EHRA update 2015)
Bleeding while using a NOAC
Mild bleeding
Delay or discontinue
next dose
Reconsider concominant
medication
Moderate/severe bleeding
+
Supportive measures:
Mechanical compression
Endoscopic hemostasis (if GI bleed)
Surgical hemostasis
Fluid replacement (colloids if needed)
RBC substitution (if needed)
FFP (as plasma expander)
Platelet substitution
(if platelet count ≤60 x 109/L)
Life-threatening bleeding
+
Additonal options for dabigatran:
Consider Idarucizumab 5 g IV
(approval pending)
Maintain adequate diuresis
Consider hemodialysis
(charcoal hemoperfusion?)
Consider:
PCC* 50 U/kg;
+ 25 U/kg if indicated
aPCC* 50 U/kg:
max 200 U/kg/day
(rFVIIa* 90 µg/kg)
For dabigatran-treated patients:
Idarucizumab 5 g IV
(approval pending)
*Use in NOAC-associated bleeding
based on only very limited
experience in humans
This information is not intended and must not be considered as a specific recommendation from Boehringer Ingelheim. Each treating physician
should determine what medical treatment and/or bleeding management measures should be taken on a case by case basis, based on their
medical experience and judgement. Idarucizumab is currently in development and is not approved for use in the EU.
EHRA: European Heart Rhythm Association; GI: gastrointestinal; RBC: red blood cell; FFP: fresh frozen plasma; PCC:prothrombin complex
concentrate; aPCC: activated prothrombin complex concentrate; rFVIIa: recombinant activated clotting factor VII
Adapted from Europace. 2015 Oct;17(10):1467-507. doi: 10.1093/europace/euv309. Epub 2015 Aug 31.
29
FIGURE
03
Risk-Benefit Profile of All Non-Vitamin K Antagonist
Oral Anticoagulants (NOACs) versus Vitamin K
Antagonists (VKAs)
In clinical trials, NOACs have demonstrated favorable benefit-risk profiles vs. warfarin
In stroke prevention for NAVF*1
STROKE/
SE
19%
MAJOR
BLEEDING
14%
ICH
52%
In treatment of acute DVT/PE†2
RECURRENT
SYMPTOMATIC
VTE
similar
similar
MAJOR
BLEEDING
39%
In prevention of DVT/PE recurrence up to 36 months
(active comparator data available for dabigatran)3
RECURRENT
OR FATAL
VTE
similar
MAJOR
BLEEDING
tions. In fact, in cases of invasive interventions in the RE-LY Trial, the
incidence of major bleeding was significantly lower in patients taking
dabigatran than in those taking warfarin when the time between the
last dose and surgery was no more than 48 hours.26 Knowledge of
time of last dose can be coupled with quick assessment of renal
function to assess how much anticoagulant effect is likely to be on
board when the patient is in the Emergency Department (ED) or operating room. For the most part, a therapeutic anticoagulation effect
can be excluded if the activated partial thromboplastin time (aPTT)
is normal in dabigatran-treated patients or if the prothrombin time
(PT) is normal in patients being treated with rivaroxaban or edoxaban
(Figure 4). There are no such reliable “qualitative” tests for apixaban.
FIGURE
04
48%
Anticoagulation Assays for Non-Vitamin K Antagonist
Oral Anticoagulants (NOACs)
Tests are available to assess anticoagulation with the NOACs
* Meta-analysis of data from RE-LY, ROCKET AF, ARISTOTLE, ENGAGE AF-TIMI 48
† Meta-analysis of data from RE-COVER, RE-COVER II, EINSTEIN-DVT, EINSTEIN-PE, AMPLIFY, and HOKUSAI-VTE
1. Ruff CT, et al. Lancet 2013; 2. van Es et al. Blood 2014; 3. Schulman S et al. N Engl J Med 2013
aPTT
NVAF: non-valvular atrial fibrillation; SE: systemic embolism; DVT: deep venous thrombosis; PE: pulmonary
embolism; ICH: intracranial hemorrhage; VTE: venous thromboembolism
TT, dTT
Although the NOACs have many fewer drug-drug and drug-diet interactions than warfarin, some concomitant medications may increase
the risk of bleeding in patients taking NOACs; these concerns apply to
VKAs as well. Non-steroidal anti-inflammatory drugs (NSAIDs), aspirin, and other antiplatelet medications (such as clopidogrel, ticagrelor,
prasugrel, and dipyridamole) not only increase the risk of major
bleeding when taken with NOACs, but also complicate the restoration
of hemostasis when major bleeding does occur.21,22
Since approval of the NOACs, multiple real-world registries have demonstrated that the safety and efficacy of the NOACs seen in Phase III
trials is replicated in practice, including the reduction in ICH and the
concern for GI bleeding. In the Dresden NOAC Registry, for example,
the rate of major bleeding was 3.4% per year, and GI bleeding was
the most common site.12 It is also reassuring to note that most of
these bleeding episodes were successfully managed conservatively.
A retrospective analysis of patients with AF receiving rivaroxaban or
dabigatran in the United States showed low rates of major bleeding, ICH, and fatal bleeding.23 Data collected for the Food and Drug
Administration (FDA) on more than 134,000 Medicare patients with
newly diagnosed AF showed that, compared with warfarin, dabigatran
was associated with a lower risk of ischemic stroke, ICH, and death,
but an increased risk of major GI bleeding;24,25 all of these findings
are consistent with the Phase III data for dabigatran.
Emergency physicians may also be faced with NOAC-treated patients
who require urgent or emergent invasive procedures or surgery for
which hemostasis is required. The inability to rapidly assess the
extent of anticoagulation in these patients increases clinical anxiety. It
is vital to obtain an accurate report of time since last dose, because
the short half-life of all the NOAC agents is helpful in these situa-
30
ECT
Anti-FXa
assays
PT
INR
 = quantitative
Dabigatran
Rivaroxaban
Apixaban
Endoxaban
























 = qualitative
 = not applicable
Time of last NOAC dose should always be considered when interpreting results.
aPTT, activated partial thromboplastin time; dTT, diluted thrombin time; ECT, ecarin clotting time;
FXa, activated Factor X; PT, prothrombin time; TT, thrombin time
Adapted with permission from Heldbuchel et al. Eurospace 2015;17(10):1467-507.
Managing NOAC-Related Bleeding
When patients taking NOACs do present with major or life-threatening
bleeding, there are basic principles to keep in mind (again, Figure 2
provides a summary):
1. Discontinue the NOAC.
2. If resuscitation is needed, start resuscitation! The ABCs always
take priority! If the patient is hypotensive, then rapid crystalloid
infusion should immediately be initiated; blood products should
be given as indicated. Send type-and-crossmatch specimens.
Keep in mind that septic or multi-injured patients may develop
coagulopathy that goes beyond simple inhibition of the activity
of one factor in the clotting pathway. Patients taking antiplatelet
agents may need platelet transfusion.
3. Address treatable sites of bleeding with direct pressure, appropriate vascular clamps, or stabilization of fractures.
4. Decontamination -- for any of the NOACs, if the previous dose
was taken within the past 2-4 hours, give activated charcoal.
Adsorption is least effective for rivaroxaban, because it is so
rapidly absorbed and then highly protein-bound. For dabigatran,
emergency hemodialysis, while time-consuming and logistically
challenging, is effective.27,28 The anti-Xa agents are too tightly
protein-bound for dialysis to be effective.
5. Initiate appropriate diagnostic procedures (such as computed
tomography [CT] scan in the patient with suspected ICH, endoscopic procedures for GI bleeding, etc.).
FIGURE
05
Non-Vitamin K Antagonist Oral Anticoagulants (NOAC)
Reversal Agents Under Development
Idarucizumab is at the most advanced stage of development of the NOAC
reversal agents
Phase II
Andexanet alfa
(PRT064445)1
Phase I
Phase II
Ciraparantag
(PER977)1
Phase I Phase II
Target: FXa inhibitors
For patients who remain unstable due to coagulopathy or ongoing
hemorrhage after these general steps are taken, and for patients
with bleeding into closed spaces such as the head, pericardium, or
retroperitoneum, emergent factor repletion may be considered. There
are scant objective data to support such an approach, and the logic
behind it is likewise limited. In warfarin-related coagulopathy there is
an actual absence of functional coagulation factors including Vitamin
K-dependent Factors II, VII, IX, X, and Proteins C and S. For these patients, repletion is necessary to restore the physiologic mechanism of
hemostasis. In patients treated with NOACs, there are no “missing”
factors. In dabigatran-treated patients, there are normal circulating
levels of thrombin (Factor IIa), but dabigatran binds thrombin more
avidly than thrombin binds fibrinogen. Giving additional Factor IIa
might be helpful, but only to the extent that it overcomes the body
load of dabigatran; in any event Factor IIa cannot be given alone.
Fresh frozen plasma (FFP) or prothrombin complex concentrates
(PCCs) such as FEIBA or KCentra® may be administered. In doing
so, Factors IX and X are also given and, depending on the preparation, Factor VII and other clotting proteins may be included as well.
There is understandable concern that such an approach actually
might create more of a sustained, prothrombotic state than is desired
in treating dabigatran-associated bleeding. With apixaban, edoxaban,
or rivaroxaban-associated bleeding, FFP or 3- or 4-factor repletion
does much more than overwhelm the inhibition of normal levels of
Factor Xa. For these rare cases, a specific reversal strategy is
desirable.
Reversal Agents
At least three specific reversal agents have been developed, and two
are in Phase III trials currently. Idarucizumab is an antibody fragment
directed against dabigatran (Figure 5).29 This Fab fragment binds
dabigatran with at least 350 times the affinity with which dabigatran
binds to thrombin, and has no intrinsic anticoagulant or procoagulant
activity. Phase I and II results have shown complete and sustained
reversal of dabigatran-induced anticoagulation in healthy volunteers
with normal renal function and in older subjects with mild-to-moderate renal impairment.30,31 The FDA granted breakthrough therapy
designation to idarucizumab in June 2014, and a phase III study is
currently ongoing (RE-VERSE AD, clintrials.gov NCT02104947). Two
types of patients are being studied in RE-VERSE AD – those with serious bleeding and those requiring urgent surgery or intervention that
cannot be delayed at least eight hours.
Phase III
Idarucizumab1 Phase I
Target: dabigatran
Target: universal
Patients requiring
urgent surgery/with
major bleeding; started
May 2014 2,3
Submitted to
EMA/FDA/
Health Canada
Feb/Mar 2015
Phase III
Patients with major
bleeding; started
Jan 2015 4
Ongoing5
NOAC reversal agents are investigational compounds under development and have not been approved for
use in the EU.
Adapted with permission from: 1. Greinacher et al. Thromb Haemost 2015; 2. Clinicaltrials.gov NCT02104947;
3. Pollack et al. Thromb Haemost 2015; 4. Clinicaltrails.gov NCT02329327; 5. Clinicaltrails.gov NCT02207257
Interim results of RE-VERSE AD, reflecting experience with 90 of
an expected 300 subjects, were published earlier this year.32 The
primary endpoint of the study is the maximum percentage reversal of
the anticoagulant activity of dabigatran as measured by either dilute
thrombin time (dTT) or ecarin clotting time (ECT). Among the evaluable patients in the interim analysis cohort, the median maximum
percentage reversal was 100% (95% confidence interval, 100 to
100). Idarucizumab normalized the test results in 88% to 98% of the
patients, an effect that was evident within minutes. Concentrations of
unbound dabigatran remained below 20 ng per milliliter at 24 hours
in 79% of the patients. Among 35 patients in the bleeding cohort who
could be assessed, hemostasis, as determined by local investigators,
was restored at a median of 11.4 hours (Figure 6). Among 36 of 39
patients in the pre-procedure group who underwent a procedure,
normal intraoperative hemostasis was reported in 33, and mildly or
moderately abnormal hemostasis was reported in two patients and
one patient, respectively (Figure 7).32 The study is being completed,
but both the FDA and the European Medicines Agency (EMA) are
reviewing regulatory packages based on the interim data. On October
16, 2015, the FDA approved idarucizumab for use in the U.S.
Andexanet alfa is a universal Factor Xa reversal agent. It is a biologically inactive recombinant analogue of Factor Xa that binds to direct
Factor Xa inhibitors and antithrombin. Andexanet alpha has the
potential to neutralize the effect of apixaban, edoxaban, rivaroxaban,
enoxaparin, dalteparin, fondaparinux, and tinzaparin. In preclinical studies, andexanet alfa, in a dose-dependent fashion, reversed
Factor Xa inhibition. Full results from the phase II trials are pending
(clinicaltrials.gov NCT01758432). In interim results, andexanet
alfa was shown to reverse the anticoagulant effects of rivaroxaban
and apixaban in a dose-dependent manner as assessed using
pharmacodynamic markers.33,34 In November 2013, the development of andexanet alfa as a reversal agent for Factor Xa inhibitors
31
Interim Results From Hemorrhaging Patients in
RE-VERSE AD Trial
FIGURE
06
Group A interim results: reversal of dabigatran anticoagulation with
idarucizumab based on dTT
130
120
Group A:
Uncontrolled bleeding
100
dTT (s)
90
80
Finally, aripazine is a cationic small molecule designed to bind
unfractionated heparin, LMWH and fondaparinux, as well as all of the
NOACs. Its binding to heparins is charge-dependent and interferes
with NOACs via a hydrogen bond-mediated mechanism. It is being
billed as a potential “universal antidote.” An initial human study
showed that, at doses of 50–300 mg, aripazine reversed the anticoagulant effect of 60 mg edoxaban.35
No idarucizumab related safety concerns
identified to date
in the analysis
110
Page 1 of 1
Idarucizumab
2x 2.5 g
70
Reversal agent development is exciting and clearly addresses an
unmet need. Due to the favorable bleeding profiles of NOACs compared with VKAs, and their short half-lives, clinical data show that
NOAC-associated bleeding can largely be managed using conservative measures. Just as with warfarin, restoration of coagulation may
not necessarily lead to better clinical outcomes. This will likely limit
the use of the reversal agents to patients with catastrophic bleeding.
For dire situations, such as immediate life-threatening bleeding, ICH,
the need for rapid reversal prior to emergency surgery, or when other
measures fail or if the NOAC cannot be cleared because of renal
failure, specific reversal agents will be indicated.
60
50
Assay
upper limit
of normal
40
http://www.isthcongressdaily.org/wp-content/uploads/2015/06/RE-VERSE_AD-Logo.jpg
30
2/14/2016
20
Baseline Between 10–30
vials
min
1h
2h
4h
12h
was granted breakthrough therapy designation by the FDA. A cohort
study of andexanet alfa in rivaroxaban treated or apixaban treated
patients who present with serious bleeding is underway (clintrials.gov
NCT02329327).
24h
Time post idarucizumab
dTT: diluted thrombin time
Idarucizumab is currently in development and is not approved for use in the EU.
Interim analysis includes data for the first 90 patients
Adapted with permission from Pollack et al. N Eng J Med 2015.
Conclusion
Interim Results From Pre-Procedural Patients in
RE-VERSE AD Trial
FIGURE
07
Group B interim results: reversal of dabigatran anticoagulation with
idarucizumab based on dTT
130
120
Group B:
Emergency surgery
or procedure
110
100
dTT (s)
90
80
CLINICAL OUTCOMES
Of 36 patients undergoing surgery:
• 33 patients had normal intraoperative
hemostasis (as judged by the
physician)
• 2 mildly abnormal
• 1 moderately abnormal
Idarucizumab
2x 2.5 g
Page 1 of 1
70
60
50
Assay
upper limit
of normal
40
30
References
1. Agnelli G, Buller HR, Cohen A, et al. Oral apixaban for the treatment of acute
venous thromboembolism. N Engl J Med. 2013;369:799-808.
20
Baseline Between 10–30
vials
min
1h
2h
4h
12h
24h
http://www.isthcongressdaily.org/wp-content/uploads/2015/06/RE-VERSE_AD-Logo.jpg
Time post idarucizumab
dTT: diluted thrombin time
Idarucizumab is currently in development and is not approved for use in the EU.
Interim analysis includes data for the first 90 patients
Adapted with permission from Pollack et al. N Eng J Med 2015.
32
Severe or life-threatening bleeding complications on NOAC therapy, in
which emergency reversal may be necessary, are rare, and therefore
the current lack of specific reversal agents should not deter physicians from using NOACs. At the same time, emergency management
protocols should be established to guide evaluation of the severity of
the bleeding event, and all EDs should have management pathways
to deal with bleeding in patients receiving anticoagulants, including
both VKAs and NOACs. Non-specific reversal agents (such as PCCs)
may be considered in exceptional cases of severe or life-threatening
bleeding if other measures prove unsuccessful. Agents such as PCC
should be available in the ED for the management of life-threatening
bleeding (including ICH) with VKAs and NOACs, and if indicated,
should be given as soon as possible. In the near future, specific
reversal agents for NOAC treated patients with severe bleeding complications or the need for emergency surgery will be available.
2/14/2016
2. Hokusai-VTE-Investigators, Buller HR, Decousus H, et al. Edoxaban versus
warfarin for the treatment of symptomatic venous thromboembolism. N Engl J
Med. 2013;369:1406-1415.
3. Prins MH, Lensing AW, Bauersachs R, et al. Oral rivaroxaban versus standard
therapy for the treatment of symptomatic venous thromboembolism: a pooled
analysis of the EINSTEIN-DVT and PE randomized studies. Thromb J. 2013;11:21.
4. Schulman S, Kakkar AK, Goldhaber SZ, et al. Treatment of acute venous
thromboembolism with dabigatran or warfarin and pooled analysis. Circulation.
2014;129:764-772.
23.Fontaine GV, Mathews KD, Woller SC, Stevens SM, Lloyd JF, Evans RS. Major
bleeding with dabigatran and rivaroxaban in patients with atrial fibrillation: a realworld setting. Clin Appl Thromb Hemost. 2014;20:665-672.
5. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular
atrial fibrillation. N Engl J Med. 2011;365:883-891.
6. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients
24.Food and Drug Administration. FDA Drug Safety Communication: FDA study
of Medicare patients finds risks lower for stroke and death but higher for
gastrointestinal bleeding with Pradaxa (dabigatran) compared to warfarin.
Available at: http://www.fda.gov/Drugs/DrugSafety/ucm396470.htm. Accessed
July 20, 2015.
7. Connolly SJ, Ezekowitz MD, Yusuf S, Reilly PA, Wallentin L, Randomized Evaluation
of Long-Term Anticoagulation Therapy I. Newly identified events in the RE-LY trial.
N Engl J Med. 2010;363:1875-1876.
25.Graham DJ, Reichman ME, Wernecke M, et al. Cardiovascular, bleeding, and
mortality risks in elderly Medicare patients treated with dabigatran or warfarin for
nonvalvular atrial fibrillation. Circulation. 2015;131:157-164.
8. Connolly SJ, Wallentin L, Yusuf S. Additional events in the RE-LY trial. N Engl J
Med. 2014;371:1464-1465.
26.Healey JS, Eikelboom J, Douketis J, et al. Periprocedural bleeding and
thromboembolic events with dabigatran compared with warfarin: results from the
Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) randomized
trial. Circulation. 2012;126:343-348.
9. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in
patients with atrial fibrillation. N Engl J Med. 2011;365:981-992.
10.Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients
27.Stangier J, Rathgen K, Stahle H, Mazur D. Influence of renal impairment on the
pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: an openlabel, parallel-group, single-centre study. Clin Pharmacokinet. 2010;49:259-268.
11.Larsen TB, Gorst-Rasmussen A, Rasmussen LH, Skjoth F, Rosenzweig M, Lip GY.
Bleeding events among new starters and switchers to dabigatran compared with
warfarin in atrial fibrillation. Am J Med. 2014;127:650-656 e655.
28.Khadzhynov D, Wagner F, Formella S, et al. Effective elimination of dabigatran
by haemodialysis. A phase I single-centre study in patients with end-stage renal
disease. Thromb Haemost. 2013;109:596-605.
12.Beyer-Westendorf J, Forster K, Pannach S, et al. Rates, management, and
outcome of rivaroxaban bleeding in daily care: results from the Dresden NOAC
registry. Blood. 2014;124:955-962.
29. Schiele F, van Ryn J, Canada K, et al. A specific antidote for dabigatran: functional
and structural characterization. Blood. 2013;121:3554-3562.
13.Hess PL, Mirro MJ, Diener HC, et al. Addressing barriers to optimal oral
anticoagulation use and persistence among patients with atrial fibrillation:
Proceedings, Washington, DC, December 3-4, 2012. Am Heart J. 2014;168:239247 e231.
14.Fang MC, Go AS, Chang Y, et al. Death and disability from warfarin-associated
intracranial and extracranial hemorrhages. Am J Med. 2007;120:700-705.
15.Schulman S, Kearon C, Kakkar AK, et al. Dabigatran versus warfarin in the
treatment of acute venous thromboembolism. N Engl J Med. 2009;361:23422352.
16.EinsteinInvestigators, Bauersachs R, Berkowitz SD, et al. Oral rivaroxaban for
symptomatic venous thromboembolism. N Engl J Med. 2010;363:2499-2510.
17.Einstein-PEInvestigators, Buller HR, Prins MH, et al. Oral rivaroxaban for the
treatment of symptomatic pulmonary embolism. N Engl J Med. 2012;366:12871297.
18. Schulman S, Kearon C, Kakkar AK, et al. Extended use of dabigatran, warfarin, or
placebo in venous thromboembolism. N Engl J Med. 2013;368:709-718.
19. Sardar P, Chatterjee S, Herzog E, Nairooz R, Mukherjee D, Halperin JL. Novel oral
anticoagulants in patients with renal insufficiency: a meta-analysis of randomized
trials. Can J Cardiol. 2014;30:888-897.
30.Glund S, Stangier J, Schmohl M, De Smet M, Gansser D. A specific antidote for
dabigatran: immediate, complete and sustained reversal of dabigatran induced
anticoagulation in healthy male volunteers. Circulation. 2013;128:A17765.
31.Glund S, Stangier J, Schmohl M, Moschetti V, Haazen W. Idarucizumab, a
specific antidote for dabigatran: immediate, complete and sustained reversal
of dabigatran induced anticoagulation in elderly and renally impaired subjects.
Blood. 2014;124:344.
32. Pollack CV, Jr., Reilly PA, Eikelboom J, et al. Idarucizumab for dabigatran reversal.
N Engl J Med. 2015;373:511-520.
33.Crowther M, Kitt M, Lorenz T, Mathur V, Lu G. A phase 2 randomized, doubleblind, placebo-controlled trial of PRT064445, a novel, universal antidote for direct
and indirect Factor Xa inhibitors. J Thromb Haemost. 2013;11:AS20.21.
34. Crowther M, Mathur V, Kitt M, Conley P, Castillo J. A phase 2 randomized, doubleblind, placebo-controlled trial demonstrating reversal of rivaroxaban-induced
anticoagulation in healthy subjects by andexanet alfa (PRT064445), an antidote
for FXa inhibitors. Blood. 2013;122:3636.
35.Ansell JE, Bakhru SH, Laulicht BE, et al. Use of PER977 to reverse the
anticoagulant effect of edoxaban. N Engl J Med. 2014;371:2141-2142.
20. Lega JC, Bertoletti L, Gremillet C, Boissier C, Mismetti P, Laporte S. Consistency
of safety profile of new oral anticoagulants in patients with renal failure. J Thromb
Haemost. 2014;12:337-343.
21.Davidson BL, Verheijen S, Lensing AW, et al. Bleeding risk of patients with acute
venous thromboembolism taking nonsteroidal anti-inflammatory drugs or aspirin.
JAMA Intern Med. 2014;174:947-953.
22.Dans AL, Connolly SJ, Wallentin L, et al. Concomitant use of antiplatelet
therapy with dabigatran or warfarin in the Randomized Evaluation of Long-Term
Anticoagulation Therapy (RE-LY) trial. Circulation. 2013;127:634-640.
33
THROMBOELASTOGRAPHY
THROMBOELASTOGRAPHY (TEG)
(TEG) –– UNDERSTANDING
UNDERSTANDING THE
THE PATIENT’S
PATIENT’S
ABILITY
ABILITY TO
TO CLOT
CLOT BLOOD
BLOOD
THROMBOELASTOGRAPHY (TEG) – UNDERSTANDING
THE PATIENT’S ABILITY TO CLOT BLOOD
Associate Professor, Emergency Medicine; Director, Division of
Critical Care, Department of Emergency Medicine; Associate Professor, Neurosurgery/Neurocritical Care; Director, Neurocritical
Care Fellowship, University of Cincinnati College of Medicine
Cincinnati, OH
The VHA allow for unique product driven, goal-oriented resuscitation in
the bleeding patient. In particular, TEG facilitates a global assessment of a
patient’s coagulation status by evaluating factors that are difficult and time
consuming to assess otherwise, such as platelet function and the state of
fibrinolysis. The benefit of this capability is that a patient can receive timely
workup and potential treatment of complex, multifocal coagulation disorders
secondary to relatively common presentations in the emergency setting.
Clot Formation
Assistant Professor of Emergency Medicine
Fellow, Neurovascular Emergencies and Neurocritical Care
University of Cincinnati College of Medicine, Cincinnati, OH
Assistant Professor of Emergency Medicine and Neurology,
Department of Emergency Medicine, Critical Care Division,
Cincinnati, OH
Objectives
1. Describe the emerging role of thermoelastography (TEG) in resuscitation in the Emergency Department and Critical Care environment.
2. Discuss how TEG informs a practitioner about correctible causes
of bleeding during critical illness and injury, allowing differentiation
between diminished hemostatic capacity and active fibrinolysis.
3. Describe the value of TEG as a marker of global hemostasis and
inflammation in critical illness and emergency medicine.
In order to best understand TEG, a basic yet modern understanding of the
process by which a clot forms is important. The most common scenario in
which a clot forms occurs when damaged endothelium exposes underlying
collagen and tissue factor to platelets. Platelets combine with von Willebrand
factor (vWF) to link the platelets and collagen. Further platelet activation
occurs and leads to strongly adhered platelets. The resulting coagulation
cascade, which consists of the activation of previously inactivated circulating
zymogens, sets off an exquisite and intricate reaction in which downstream
pro-coagulant factors are activated by one another. At the same time, tissue
factor pathway inhibitor (TFPI) is activated. The resulting reaction leads to
the final common pathway, in which thrombin cleaves fibrinogen into fibrin.
Thrombin also activates multiple other proteins, including protein C, which is
inhibitory to clotting. The clot is concurrently amplified when Factors VIII and
V accelerate thrombin formation exponentially, which is known as the “thrombin burst.” Thrombin subsequently activates Factor XIII, which leads to
cross-linking of the fibrin fibers. Thus, in order to describe the clot formation
and simultaneous breakdown, the function of multiple interacting proteins
must be known. TEG is able to describe this balance both qualitatively (via
the tracing) and quantitatively (via the measured values). A brief overview
of the coagulation cascade is represented in Figure 1,5 and demonstrations
of the qualitative tracings of VHAs (TEG and ROTEM)] are shown in Figure 2
and Figure 3.5,6
Introduction
Thromoelastography (TEG), an assay of the viscoelastic properties of blood,
provides a comprehensive real-time analysis of hemostasis, from initial
thrombin burst to fibrinolysis, permitting improved transfusion strategies that
result in the potential for goal-directed therapy of coagulation abnormalities
following injury.1 TEG was first described in 1948 in Germany by Dr. Hellmut
Hartert, and the process was automated and computerized in the late 20th
century. There are two commercially available TEG systems, both of which
are types of viscoelastic hemostatic assays (VHA): the rotational thromboelastometry (ROTEM®; Tem International GmbH, Munich, Germany) and the
modified traditional thrombelastography (TEG®, Hemoscope Corporation,
Niles, IL), which is the most prevalent system in use in North America. VHA
technology is currently used and well validated in trauma, liver transplant
surgery, cardiac surgery, obstetrics, bedside extracorporeal membrane oxygenation (ECMO) management, diagnosis of hypercoagulable states, major
surgeries, hemophilia, and monitoring of antiplatelet therapy.2-4 In order to
monitor antiplatelet therapy, TEG platelet mapping (TEM/PM) is also used.
TEG/PM compares the patient’s platelet inhibition percentage against maximum platelet function measured by the assay, allowing relative changes in
platelet contribution to clot formation to be clearly detected.1 Within the specialty of Emergency Medicine, TEG has seen its most prolific and validated
use in trauma patients, but recent expansion of use has included traumatic
brain injury, severe sepsis and septic shock. More recently, TEG has been
described in the realm of acute coronary syndrome and hypothermia.
34
FIGURE
01
Overview of the Coagulation Cascade
Tissue Factor
(Extrinsic) Pathway
VIIa
X
VII + Ca + tissue factor
Common Pathway
Xa
V
Va
Prothrombin (II)
Thrombin
Fibrinogen (I)
Fibrin
Ca: calcium; a: activated
Adapted and reprinted with permission from Wheeler AP, Rice TW. Coagulopathy in critically
ill patients: part 2-soluble clotting factors and hemostatic testing. Chest 2010;137:185-94.
THROMBOELASTOGRAPHY (TEG) – UNDERSTANDING THE PATIENT’S
ABILITY TO CLOT BLOOD
FIGURE
02
VHA Terminology and Parameters
Area under the curve of the first derivative (- / AUC)
Degree of lysis at
a given time
(CL30, CL60 / LY30, LY60)
Time to max clot strength
reached
(TMA / MCF-t)
Maximum
velocity
of clot
formation
(- / MAXV)
Time to initiate
clotting
(r / CT)
Time to
maximum
velocity
(- / MAXV-t)
Time strength
of the clot
(MA / MCF)
Maximum
lysis
(- / ML)
Time of
clot formation
(k / CFT)
Strength of clot at
a given time
(A5, A10 / A5, A10)
Measurement period (- / RT)
Viscoelastic hemostatic assays (VHA) terminology and parameters. α, alpha angle; AUC, area under the curve;
CFT, clot formation time; CL (t), clot lysis (at time t); CT, clot time; k, rate of clot formation; LY (t), lysis (at time t);
MA, maximum amplitude; MAXV, maximum velocity; MAXV-t, time to maximum velocity; MCF, maximum clot
firmness; MCF-t, time to maximum clot firmness; ML, maximum lysis; r, time to clot initiation; ROTEM, Rotational
Thromboelastogram; RT, reaction time; TEG, Thromboelastograph; TMA, time to maximum amplitude; -, no
equivalent parameter.
Adapted and reprinted with permission from MacDonald SG, Luddington RJ. Critical factors
contributing to the thromboelastography trace. Semin Thromb Hemost 2010;36:712-22.
FIGURE
03
Variables That Affect a TEG Tracing
{
Decreased time
to clot
KEY:
Anticoagulants
rVIIa
{
{
Increased time
to clot
Increased clot
strength
DTI
Platelet
transfusion
Fgn
concentrate
Antiplatelet
therapy
PCC
FFP
Therapeutic
variable
Decreased clot
strength
Effect on VHA
trace
Therapeutic variables affecting the viscoelastic hemostatic assay (VHA) trace: DTI,
direct thrombin inhibitors; FFP, fresh-frozen plasma; Fgn, fibrinogen; PCC, prothrombin
complex concentrates; rVIIa, recombinant activated factor VII.
Adapted and reprinted with permission from MacDonald SG, Luddington RJ. Critical factors
contributing to the thromboelastography trace. Semin Thromb Hemost 2010;36:712-22.
TEG vs. Conventional Measures of Coagulation
Compared to conventional studies of coagulation, which include prothrombin
time (PT)/ international normalized ratio (INR) and activated partial thromboplastin time (aPTT), TEG provides sophisticated and relevant information
about the entire process of clot formation, not just initiation, and offers
insights into the function of platelets not seen with traditional coagulation
testing. It is important to remember that primary coagulation is a complex
interplay of the intrinsic and extrinsic pathways of coagulation, a final common pathway of platelet aggregation, and the ultimate crosslinking of fibrin.
TEG provides insight into each phase of the clotting cascade and theoretically
allows for therapies targeting specific defects in the pathways. Because TEG
tests whole blood rather than plasma, the complete dynamics of clot formation are visualized. Thrombosis, relative clot strength, and fibrinolysis are all
represented in a TEG.
The balance between hemostasis and fibrinolysis is intricate and TEG offers
insightful information about that balance. One example is in the multisystem
trauma patient who presents to the Emergency Department (ED) in shock.
He or she likely has components of clotting and fibrinolysis simultaneously,
and these components are difficult to capture with traditional assays of
coagulation. TEG is more suited to providing understanding of clot lysis than
traditional markers of fibrin degradation such as d-dimer, fibrin degradation
products, or fibrin split products, which are non-specifically elevated in many
states of inflammation other than bleeding or clotting. Recently, Carroll and
colleagues7 addressed the acute post-traumatic coagulopathy, reported by
Brohi et al.,8 by VHA analyses of samples obtained at the scene of accident
and upon arrival in the ED in 161 trauma patients.7,9 Interestingly, they found
that the clot forming parameters demonstrating hypocoagulability correlated
with fatality, whereas none of the routine coagulation tests like PT and aPTT
demonstrated such a correlation. This indicates that VHA is more sensitive in
reflecting clinically relevant coagulopathies than routine coagulation tests.9
One particularly useful measurement provided by modern TEG is the socalled LY30, which reports the percent of fibrinolysis that has taken place
in 30 minutes, with a standardized reference range of 0 – 8%. In the acute
setting, an elevated LY30 percentage likely signifies a hyperfibrinolytic state
and some authors have advocated administering antifibrinolytic therapy, such
as transaxemic acid to these patients. While no consensus exists currently on
the effectiveness of this strategy, clinical trials are underway to explore the
benefit of targeting acute antifibrinolytic therapies in these hyperfibrinolytic
patients.
Understanding Viscoelastic Hemostatic Assays and TEG
TEG analysis is conducted on aliquots of citrated whole blood, rather than
separated blood and plasma components. In the most commonly employed
TEG analyzer, a 0.36 mL sample of whole blood is placed into a cup, which
is then incubated to 37 degrees. Calcium is then added to the sample to
counteract the citrate, and the cup is continuously rotated through 40 45’
while a strain gauge pin, linked to a torsion wire, connects to a mechanicalelectrical transducer.10 As changes in force are detected by the strain gauge
during clot formation and degradation, the signal is translated into measurable data that is plotted in real time through automated signal translation
(Figure 4 and Figure 5).3,11
As the blood clots in the cup, the degree of torque is increased. The amount
of torque is measured electronically, and is representative of the degree to
which clot formation has taken place.3 An activating solution consisting of
kaolin, phospholipids, and buffered stabilizers is often used to help initiate
the coagulation process in TEG, although this still takes several minutes. This
process can be further expedited in the setting of hemorrhagic shock by the
addition of tissue factor, resulting in a “rapid-TEG” (rTEG). rTEG allows a
faster clotting profile to be created because the additional reagents activate
both the intrinsic and extrinsic clotting systems simultaneously, and the
earliest tracings of rTEG can be viewed within ten minutes.1,3,10 Real time
changes that are seen in the TEG profile represent the strength and speed of
clot formation, and allow assessment of which clotting factors are contributing appropriately or inappropriately, thereby informing targeted blood product
delivery in the bleeding or coagulopathic patient.4 While there were initial
concerns to the contrary, it appears as though the addition of accelerants to
the rTEG assay does not bias the resulting data.
35
FIGURE
04
Mechanics of Thromboelastography
• Whole blood is inserted in the cup.
Torsion Wire
• A torsion wire suspends the pin
immersed in the cup and connects with
a mechanical electrical transducer.
• The cup rotates through 4° 45’ degrees
to imitate sluggish venous flow and to
activate coagulation.
Pin
Blood
• The speed and strength of clot formation
is measured in various ways, usually by
computer.
Cup
4° 45’
FIGURE
05
Working Principle of Thromboelastography
A
B
Clot firmness (mm)
C
CFT
40
20
CT
0
20
R
40
α
α
MCF
LY30
MA
CL30
Working principle of TEG (panel A) and ROTEM
(panel B). In TEG, the cup with the blood sample
is rotating, whereas the torsion wire is fixed. In
ROTEM, the cup is fixed, whereas the pin is
rotating. Changes in torque are detected electromechanically in TEG and optically in ROTEM.
The computer-processed signal is finally
presented as a tracing. Panel C shows typical
tracings from TEG (lower tracing) and ROTEM
(upper tracing). For a detailed description of the
terms used and the reference values of the
various thromboelastographic parameters,
see Tables 1, 2 and 3.. The portion of the
tracing prior to maximum clot strength
(MA/MCF) represents coagulation,
while the portion after
maximum clot strength
represents fibrinolysis.
K
0
15
Time (min)
30
45
Adapted and reprinted with permission from Bolliger D, Seeberger MD, Tanaka KA. Principles
and practice of thromboelastography in clinical coagulation management and transfusion
practice. Transfus Med Rev. 2012 Jan;26(1):1-13
Information Obtained from TEG
Clot Strength
A major advantage of TEG that is not present in other coagulation studies is information regarding the strength of a clot. Specifically, it provides
information about both platelet aggregation and subsequent fibrinolysis.11 In
order to obtain this information without TEG, multiple tests would need to
be performed, including platelet count, platelet function, coagulation factors,
fibrinogen, protein S, protein C and antithrombin.12 As mentioned previously,
procoagulant and anticoagulant factors are activated during normal clot
formation, and TEG is able to assess the balance between these reactions.
Hyperfibrinolysis
TEG can rapidly identify active hyperfibrinolysis in the immediate post
trauma patient. While hyperfibrinolysis is rare, it is lethal. In 2012, Cotton
36
and colleagues13 described the rTEG evaluation of 1,996 consecutive severe
trauma patients, and 41 (2%) of those patients demonstrated hyperfibrinolysis at admission. This subset had a 76% mortality rate, in contrast to 10% in
the entire group. This study also demonstrated that prehospital crystalloid
fluid administration resulted in a statistically significantly higher hyperfibrinolysis score, defined as more than 7.5% amplitude reduction at 30 minutes
after maximal amplitude.13 Ultimately, if a higher percentage of hyperfibrinolysis is noted in patients who have had crystalloid administration, and this
TEG abnormality is associated with higher mortality, then blood products
may ultimately be proven to be preferential to crystalloids in the setting of
acute traumatic hemorrhage.
The benefit of testing whole blood, rather than testing coagulation pathways
piecemeal with separate complete blood count (CBC), PT, and aPTT tests,
is that dynamics of clot formation are visualized, such that thrombosis and
fibrinolysis are both represented in sequence.11 Traditionally, PT and aPTT
are utilized as markers to screen trauma patients for coagulation deficits during trauma. These lab values are, in reality, indirect markers of coagulopathy,
in that they do not directly evaluate the quantity or function of coagulation
factors, despite classic training to the contrary. These traditional coagulation
tests do not measure every coagulation factor, nor the process of clot formation as a whole. Specifically, PT/INR and aPTT describe the time to the start
of thrombus formation, but all activity in the clotting cascade beyond that
point remains unknown with these standard assays. It is of critical importance to remember that PT and aPTT do not account for fibrinolysis and may
remain normal even in a hyperfibrinolytic state; additionally, PT and aPTT do
not provide information regarding the interaction of platelets and other clotting factors, the final critical step in creating stable clots.3
Platelet Function
TEG is also able to provide direct information about platelet function.
Traditional coagulation testing only tests for platelet counts, which may be
normal even in the setting of severe platelet dysfunction. This is helpful
in the management of patients who are taking anti-platelet medications
such as salicylates or clopidogrel, which inhibit platelet function but do not
alter platelet counts.14 TEG platelet mapping can be utilized to determine if
patients are therapeutic on or are currently taking aspirin or clopidogrel if that
information is unknown.
How to Interpret TEG
Broadly speaking, reported TEG variables include coagulation time (CT),
clot formation time (CFT), the angle of clot formation, the maximum clot
firmness, and lysis time.3 Typically, these are described in the automated
TEG report as reaction time (R, in seconds), clot kinetics (K, in seconds), the
angle of the curve (α), maximum amplitude (MA, measured in mm), coagulation index (CI, measured in dynes/sec), lysis at 30 minutes (a percent of
clot lysis), and clot firmness (G, measured in dynes/sec). Individual results
may be compared to normative TEG values, allowing for an assessment of
the derangements in clotting that are present.4 Please see Table 1 for more
information.3
The MA value represents clot strength, R indicates the time until there is
evidence of clot, and K describes the time from R until the clot is 20 mm in
size. The α angle is the angle formed by the horizon and a line from the start
of the TEG tracing to the point of clot reaction time; this demonstrates the
speed of clot formation and is dependent on platelet number, platelet activity,
and fibrinogen concentration and activation.15 The CI describes the global
coagulation state as derived from an equation utilizing the other variables.
TEG is modified by sex, age, and other factors, as demonstrated in Figure
6.6 Please see Table 1 and Table 2 for interpretation and description of TEG
variables.
TABLE
01
Common Measurements in TEG
Description
TEG term
ROTEM term
Time to clot initiation
R time
CT (coagulation time)
Rate of clot formation
K time
CFT (coagulation formation time)
Angle of clot formation
α (slope between R and K)
α (Angle of tangent at 2mm amplitude)
Maximum strength of clot
MA (Maximum amplitude)
MCF (Maximum clot formation)
Amplitude (at set time in min) A30, A60
A5, A10, A15, A20, A30
Maximal lysis
-
ML
Clot lysis (at set time in min)
CL30, CL60
LY30, LY60
Time to lysis
TTL (2-mm drop from MA)
LOT (lysis onset time, 85% of MCF)
Adapted and reprinted with permission from Bolliger D, Seeberger MD, Tanaka KA. Principles
and practice of thromboelastography in clinical coagulation management and transfusion
practice. Transfus Med Rev 2012;26:1-13
TABLE
02
Utilizing Thromboelastography (TEG) Variables
Variable
Interpretation
Response
Increased reaction time (R)
Slow initiation of clot
Give fresh frozen plasma (FFP)
Decreased angle (α)
Slow rate of clot formation
Give cryoprecipitate; consider platelets
Decreased maximum
amplitude (MA)
Decreased strength of clot
Give platelets
Percentage of decrease in
amplitude at 30 minutes
(A30 or LY30) is elevated
Fibrinolysis
Give tranexamic acid, aprotinin or
aminocaproic acid
FIGURE
06
Preanalytical Variables Affecting the
Viscoelastic Hemostatic Assay (VHA) Trace
Reduced rate
of clot
formation
Anticogulants
Increased clot
strength
Neonates vs.
> 2 yrs and
adults
Increased time
to clot
Decreased clot
strength
Raised
PLT
Count
Raised
HCT
Increased
WBC
Decreased time
to clot
Female vs. male
Increased rate
of clot
formation
KEY:
Increased age
Pre analytic
variable
Increased
fibrinolysis
Fibrinolytic
drugs
Effect on VHA
trace
HCT, hematocrit; PLT, platelet; WBC, white blood cell count.
Adapted and reprinted with permission from MacDonald SG, Luddington RJ.
Critical factors contributing to the thromboelastography trace. Semin Thromb
Hemost 2010;36:712-22.
TEG in the Emergency Department (ED)
There is increasing evidence that TEG is valuable in the emergency setting,
particularly during resuscitations that involve massive transfusion. Massive
transfusion is defined as the requirement of 10 units of packed red blood
cells (pRBC) during the first 24 hours of admission and is consistently associated with increased morbidity and mortality in trauma patients.16 Damage
control surgery is used in conjunction with damage control resuscitation, and
using balanced blood products, including fresh frozen plasma and platelets
in fixed ratios is considered standard of care to correct the coagulopathy of
trauma by many experts.17 This is consistent with numerous descriptions of
the benefits of damage control resuscitation, born of retrospective military
data, in which lower mortality rates were noted when transfusions were
given in such a way as to mimic whole blood rather than simply transfusing
pRBCs.18 TEG is most useful in guiding damage control resuscitation and
blood product administration and allowing decisions regarding the necessity
for repeat or continued damage control surgery. In a 2012 study, Pezold and
colleagues found that for the endpoints of death and massive transfusion,
clot strength (G) was found to independently predict massive transfusion and
death in the early part of resuscitation.19 The clot strength G had the greatest
adjusted area under the receiver operating characteristic curve (AUC ROC)
when compared to base deficit (BD) (0.87, P = 0.05), INR (0.88, P = 0.11),
and PTT (0.89; P = 0.19), meaning that it is a better predictor of morbidity
and mortality than more traditional markers of severity commonly employed
in the ED.19 In 2011, Nystrup et al.9 reviewed 89 subjects in the trauma
registry who had a reduced clot strength defined as maximal amplitude
< 50 mm on TEG. They demonstrated a higher injury severity score (ISS,
p = 0.006) compared with those who had a normal MA, a higher need for
transfusion of packed red blood cells (p = 0.01), fresh frozen plasma (p =
0.04), and platelets (p = 0.03) during the first 24 hours of resuscitation, and
a remarkably increased 30-day mortality (47% vs. 10%, p < 0.001). These
authors hypothesized that TEG could be used to target patients to receive
selected blood products preferentially in the setting of trauma-induced
coagulopathy.
Hyperfibrinolysis and post-traumatic coagulopathy are major risk factors for
severe morbidity and mortality. In a prospective study of 161 trauma
patients , decreased TEG MA values correlated with fibrinogen <100mg/dL,
which also correlated with higher mortality (p = 0.013). In the 14 fatalities
found in this study, both the TEG R time and MA times were significantly
higher than in non-fatalities (R time was 3,703 +/- 11,618 vs. 270 +/- 393
seconds [P = < 0.001], and MA was 46.4 +/- 22.4 vs. 64.7 +/- 9.8 mm [p
< 0.001]).7
TEG, along with platelet count and hemoglobin count, may be the most accurate method to assess the need for blood product requirement in trauma
patients.20 When viewed in the context of damage control resuscitation, it
is appropriate to assume that the ratio of blood, plasma, and platelets likely
differ from one patient to another. For instance, it may be harmful for some
patients to receive a 1:1:1 ratio of plasma, pRBCs, and platelets, especially
if they receive inappropriate and potentially harmful amounts of each product.21 By utilizing TEG appropriately, patients may receive only the products
that they would likely require during damage control resuscitation.
Another benefit to having TEG in the ED is the fact that results typically can
be obtained within ten minutes, compared to 30-60 minutes for PT, aPTT,
fibrinogen, and platelet counts.14 Although initiating transfusion therapy rapidly improves patient care when necessary, TEG may also be helpful in deter-
37
mining when transfusion may not be useful, since it provides a rapid, global
assessment of a patient’s coagulation status. For example, a clinician may be
able to avoid using blood products in a normotensive trauma patient with a
normal TEG. This is important, given the risks associated with the administration of all blood component therapy, including allergic reactions, infection
transmission, transfusion associated acute lung injuries (TRALI), transfusion
associated cardiac overload (TACO), and acute respiratory distress syndrome
(ARDS). These risks are low, but it is important to remember that platelets
and FFP carry the highest risk of TRALI and platelets have been reported to
carry a risk of bacterial contamination, usually from the donor’s skin.22
TEG, like any laboratory test, is not without pitfalls. Values may be different
when one machine is compared to another machine. When a patient has
serial TEG studies, they should be run on the same machine with the same
kind of activator.15 The machine requires calibration 2-3 times per day, and
personnel using TEG require additional training. The advantages of TEG are
presented in Table 3.
TABLE
03
between the two groups at six months for the endpoints of myocardial infarction, emergency target vessel revascularization, stent thrombosis, or death.
Another avenue where the diagnosis and treatment of coagulopathy using
TEG is being pursued is in hypothermia, where initial studies have surprisingly not demonstrated hypothermia induced coagulopathy. The interim analysis
of the Cooling And Surviving Septic shock (CASS) study,which prospectively
enrolled 100 patients with severe sepsis or septic shock to mild induced hypothermia (32º to 34ºC) vs. control (no temperature regulation), demonstrated that coagulopathy based on TEG MA and R parameters actually improved
in the mild hypothermia group, but was not corrected in the control group.26
The Targeted Temperature Management (TTM) Trial compared normothermia (36ºC) to mild induced hypothermia (33º) following cardiac arrest.27 A
predefined sub study of this trial compared TEG parameters of both groups,
given that there is concern related to induced hypothermia and coagulopathy.
They demonstrated no significant difference in TEG parameters between the
two groups or with respect to adverse bleeding or clotting.
TEG is being explored in a diverse number of disease states at this time.
Current trials are describing the use of TEG to assist in cesarean deliveries, hemostasis after coronary artery bypass grafting (CABG), fat emboli,
traumatic brain injury, and acute ischemic stroke.
Advantages of TEG
Advantages
Can be used at point of care (POC) to provide rapid results
Cases
Evaluates global hemostatic function
Case 1:
Allows the physician to assess for hyperfibrinolysis and monitor treatment
in patients who are given recombinant activated factor VII or tissue
plasminogen activator (tPA)
Detects low factor XIII activity
Small sample volume, which is attractive for pediatrics
(requires only .33 mL of blood)
Current Data and TEG Applications
TEG is being studied increasingly in areas other than traumatic conditions
and the surgical realms. One of these areas is in acute coronary syndrome,
where TEG may be used to identify patients with impaired endogenous fibrinolysis, aspirin or clopidogrel resistance, or at risk for thrombosis following
percutaneous coronary intervention (PCI).
Gurbel et al. demonstrated that increased thrombogenesis after PCI, as measured by TEG, was an independent risk factor for thrombosis within three
years following PCI in one of the largest series of patients on this topic.23 Fu
et al. described similar results later in a series of 861 consecutive patients
who had routine TEG platelet mapping following PCI.24 Of these, 249 patients
developed in stent restenosis (ISR). The frequency of clopidogrel hyporesponsiveness in the ISR group was significantly higher than that in non-ISR group
(p < 0.01), and the authors concluded that clopidogrel hyporesponsiveness,
as measured by TEG, was an independent risk factor for ISR.
Despite these findings and the ability of TEG platelet mapping to identify
aspirin and clopidogrel non-responders, the clinical benefit of routine platelet
mapping after PCI has not yet been demonstrated. Xu, et al. randomized
patients following high risk PCI to a control group or to a group in which clopidogrel dosing was adjusted based on TEG results.25 There was no difference
38
A 34 year old previously healthy male presents to the emergency
department after falling off his roof. His blood pressure is 85/40
and his heart rate is 124 beats per minute (bpm). On initial
assessment he has an obvious femur fracture. His chest x-ray
demonstrates multiple rib fractures and he has a positive focused
assessment with sonography for trauma (FAST). A TEG is performed and he has an LY30 of 12%. In addition to giving him blood
products for his hemorrhagic shock, what other drug should you
give him?
This patient should receive tranexamic acid (TXA) or aminocaproic acid.
He demonstrates an elevated degree of fibrinolysis, which puts him at an
increased risk of mortality following trauma.
Case 2:
A 65 year old male presents to the ED three days after undergoing
a left heart catheterization and left circumflex stent placement
following an ST-segment elevation myocardial infarction (STEMI).
He has a large groin hematoma secondary to the procedure. He
feels lightheaded and his initial blood pressure is 82/40. A TEG is
performed and demonstrates a prolonged K time and decreased
MA time. A CBC, PT, and PTT are all within normal limits. What
are these values reflective of?
These values reflect platelet dysfunction, likely secondary to anti-platelet
medications he is taking after having a stent placed. It is worth noting that
although the more traditional laboratory tests that are used to assess coagulopathy (CBC, PT, PTT) are normal, the TEG is abnormal, offering insight into
platelet function.
Case 3:
Conclusion
A 72 year old male with a history of a STEMI and stent placement
three weeks ago presents to the ED with chest pain. He reports
that he has been compliant in taking the clopidogrel and aspirin
prescribed to him. Although data are still preliminary, how might
TEG platelet mapping help in management of this patient?
TEG platelet mapping can be used to identify patients who are aspirin or
clopidogrel nonresponders and hyporesponders. At this time, clinical benefit
has not been established by performing routine platelet mapping once antiplatelet therapy is started to identify these patients. However, in the setting
of in stent restenosis, TEG platelet mapping should be considered to help
determine the cause of the event.
Further abnormal scenarios are represented in Figure 7.
FIGURE
07
Example TEG Tracings (lifeinthefastlane.com)
Normal
R; K; MA; Angle = Normal
Anticoagulants/hemphilia
Factor Deficiency
R; K = Prolonged
MA; Angle = Decreased
Platelet Blockers
Thrombocytopenia/
Thrombocytopathy
R~ Normal; K = Prolonged
MA = Decreased
Fibrinolysis (UK, SK, or t-PA)
Presence of t-PA
R~ Normal;
MA = Continual decrease
LY30 > 7.5%; WBCLI30 > 97.5%
LY60 > 15%; WBCLI60 < 85%
Hypercoagulation
R; K = Decreased
MA; Angle = Increased
In summary, TEG is a promising technology that offers remarkable insight
into the delicate balance between thrombosis and fibrinolysis, does so in real
time, and is broadly applicable in the emergency and critical care environments. While further research is needed to clarify exact roles for utilization of
TEG, clinical experience to date has demonstrated that TEG has remarkable
potential in the care of the critically ill and injured and should become more
routine in the near future.
References
1. Gonzalez E, Pieracci FM, Moore EE, Kashuk JL. Coagulation abnormalities in the
trauma patient: the role of point-of-care thromboelastography. Semin Thromb
Hemostasis. 2010;36(7):723-737.
2. Chen A, Teruya J. Global hemostasis testing thromboelastography: old
technology, new applications. Clin Lab Med. 2009;29(2):391-407.
3. Bolliger D, Seeberger MD, Tanaka KA. Principles and practice of
thromboelastography in clinical coagulation management and transfusion
practice. Trans Med Rev. 2012;26(1):1-13.
4. Trapani LM. Thromboelastography: current applications, future directions. Open
J Anesthes. 2013;3:23.
5. Wheeler AP, Rice TW. Coagulopathy in critically ill patients: part 2-soluble clotting
factors and hemostatic testing. Chest. 2010;137(1):185-194.
6. MacDonald SG, Luddington RJ. Critical factors contributing to the
thromboelastography trace. Semin Thromb Hemostasis. 2010; 2010
Oct;36(7):712-22.
7. Carroll RC, Craft RM, Langdon RJ, et al. Early evaluation of acute traumatic
coagulopathy by thrombelastography. Transl Res. 2009;154(1):34-39.
8. Brohi K, Singh J, Heron M, Coats T. Acute traumatic coagulopathy. J Trauma.
2003;54(6):1127-1130.
9. Nystrup KB, Windelov NA, Thomsen AB, Johansson PI. Reduced clot strength
upon admission, evaluated by thrombelastography (TEG), in trauma patients is
independently associated with increased 30-day mortality. Scan J Trauma Resusc
Emerg Med. 2011;19:52.
10. Jeger V, Zimmermann H, Exadaktylos AK. The role of thrombelastography in
multiple trauma. Emerg Med Int. 2011;2011:895674.
D.I. C.
Stage 1
Hypercoagulable state with
secondary fibrinolysis
Stage 2
Hypercoagulable state
11. da Luz LT, Nascimento B, Rizoli S. Thrombelastography (TEG): practical
considerations on its clinical use in trauma resuscitation. Scand J Trauma Resusc
Emerg Med. 2013;21:29.
12. Salooja N, Perry DJ. Thrombelastography. Blood coagulation & fibrinolysis : an
international journal in haemostasis and thrombosis. Blood Coag Fibrinolysis.
2001;12(5):327-337.
13. Cotton BA, Harvin JA, Kostousouv V, et al. Hyperfibrinolysis at admission is an
uncommon but highly lethal event associated with shock and prehospital fluid
administration. J Trauma Acute Care Surg. 2012;73(2):365-370; discussion 370.
14. Spinella PC, Holcomb JB. Resuscitation and transfusion principles for traumatic
hemorrhagic shock. Blood Rev. 2009;23(6):231-240.
15. Wozniak D, Adamik B. [Thromboelastography]. Anestezjologia intensywna terapia.
2011;43(4):244-247.
39
16. McLaughlin DF, Niles SE, Salinas J, et al. A predictive model for massive
transfusion in combat casualty patients. J Trauma. 2008;64(2 Suppl):S57-63;
discussion S63.
17. Davenport R, Curry N, Manson J, et al. Hemostatic effects of fresh frozen
plasma may be maximal at red cell ratios of 1:2. J Trauma. 2011;70(1):90-95;
discussion 95-96.
18. Cap AP, Spinella PC, Borgman MA, Blackbourne LH, Perkins JG. Timing and
location of blood product transfusion and outcomes in massively transfused
combat casualties. J Trauma Acute Care Surg. 2012;73(2 Suppl 1):S89-94.
19. Pezold M, Moore EE, Wohlauer M, et al. Viscoelastic clot strength predicts
coagulation-related mortality within 15 minutes. Surgery. 2012;151(1):48-54.
20. Plotkin AJ, Wade CE, Jenkins DH, et al. A reduction in clot formation rate
and strength assessed by thrombelastography is indicative of transfusion
requirements in patients with penetrating injuries. J Trauma. 2008;64(2
Suppl):S64-68.
21. Hannon T. Trauma blood management: avoiding the collateral damage of trauma
resuscitation protocols. American Society of Hematology. Education Program.
2010;2010:463-464.
22. MacLennan S, Williamson LM. Risks of fresh frozen plasma and platelets.
J Trauma. 2006;60(6 Suppl):S46-50.
23. Gurbel PA, Bliden KP, Navickas IA, et al. Adenosine diphosphate-induced
platelet-fibrin clot strength: a new thrombelastographic indicator of long-term
poststenting ischemic events. Amer Heart J. 2010;160(2):346-354.
24. Fu Z, Dong W, Shen M, et al. Relationship between hyporesponsiveness to
clopidogrel measured by thrombelastography and in stent restenosis in patients
undergoing percutaneous coronary intervention. Clin Biochem. 2014;47(1617):197-202.
25. Xu L, Wang L, Yang X, et al. Platelet function monitoring guided antiplatelet
therapy in patients receiving high-risk coronary interventions. Chin Med J.
2014;127(19):3364-3370.
26. Johansen ME, Jensen JU, Bestle MH, et al. Mild induced hypothermia: effects on
sepsis-related coagulopathy--results from a randomized controlled trial. Thromb
Res. 2015;135(1):175-182.
27. Jacob M, Hassager C, Bro-Jeppesen J, et al. The effect of targeted temperature
management on coagulation parameters and bleeding events after out-of-hospital
cardiac arrest of presumed cardiac cause. Resuscitation. 2015;96:260-267.
40
ADVANCEDRESUSCITATION
RESUSCITATIONOF
OFSEPTIC
SEPTICSHOCK
SHOCKININTHE
THE
ADVANCED
EMERGENCYDEPARTMENT
DEPARTMENTAND
ANDINTENSIVE
INTENSIVECARE
CAREUNIT
UNIT
EMERGENCY
ADVANCED RESUSCITATION OF SEPTIC SHOCK
IN THE EMERGENCY DEPARTMENT AND
INTENSIVE CARE UNIT
Assistant Professor of Anesthesiology and Emergency
Medicine, Department of Anesthesiology, Division of Critical
Care, Division of Emergency Medicine, Washington
University School of Medicine, St. Louis, MO
Trenton C. Wray, MD
Critical Care Fellow, Division of Emergency Medicine,
Washington University School of Medicine, St. Louis, MO
Objectives
1. Describe the need for early identification of sepsis.
2. Describe early, aggressive treatment of shock, including assessment of preload responsiveness and cardiac function, volume
loading, and use of vasopressors, steroids, and inotropes.
3. Describe how to minimize the functional burden associated with
ICU treatment of sepsis.
Introduction
Hospitalizations due to severe sepsis and septic shock have increased over the past two decades, and now represent up to 12% of
emergency department (ED) admissions and 11-30% of admissions
to the intensive care unit (ICU) worldwide.1,2
aspects of the EGDT bundles have come under scrutiny. Chief among
these is the placement of a central venous catheter (CVC) for the purpose of monitoring central venous pressure (CVP) and central venous
oxygen saturation (ScvO2).
In an unprecedented collaboration, three recent trials6-8 compared
modern “usual care” to protocol-based EGDT. In the EGDT groups,
goal-driven resuscitation was used. In the “usual care” groups, the
treating physician directed resuscitation. The use of invasive monitoring techniques such as CVP, ScvO2, and arterial catheters (AC),
was not mandated. Some important comparisons between the four
studies are highlighted in Table 1. The ProCESS, ARISE, and ProMISe
Trials were unable to reproduce the difference in mortality seen with
EGDT over the “standard care” group in the Rivers Trial. In the more
recent trials, the primary intervention differences were that the EGDT
groups received slightly more fluid, blood transfusions, and inotropic
therapy than the “usual care” groups. These interventions were likely
to achieve hemodynamic goals as assessed by monitoring of CVP,
hematocrit, and ScvO2, respectively.
Overall, the ProCESS, ARISE, and ProMISe Trials highlight the evolution of “standard care” and the overall mortality improvement over
the past decade. The EGDT approach was extremely successful in
reducing mortality by emphasizing the importance of early recognition and shock reversal in critically ill patients with sepsis, and may
remain useful in select cases. However, the application of invasive
“bundled therapy” to all patients with severe sepsis and septic shock
in the modern era is likely unnecessary.
In 2001, Emmanuel Rivers published a landmark randomized controlled trial (RCT) of Early Goal-Directed Therapy (EGDT) for severe
sepsis and septic shock.3 This introduced the concepts of early,
aggressive identification of sepsis and goal-directed hemodynamic
optimization in patients with sepsis and evidence of “tissue hypoperfusion.” Using the EGDT approach, the primary focus of which was to
deliver hemodynamic interventions within six hours, a 16% reduction
in 28-day mortality was seen. “Bundled Therapy,” which is based
on goals described in the trial rapidly became the standard of care.
Mortality has steadily improved from an average of 47% from 19911995 to 29% from 2006-2009,4 and now to as low as 18% in 2012.1,5
Modern Early Goal-Directed Therapy
Though goal-directed resuscitation for severe sepsis and septic shock
had already been attempted previously without success, these trials
involved randomization only after the patient presented to the ICU.
Unique to Rivers’ Trial and the concept of EGDT was the involvement
of the ED for early intervention; it became clear that care in the ED
during the first six hours for the patient with septic shock disproportionately impacts outcome.
The systemic effects of sepsis are time-dependent. Early intervention
and early identification are required. Because signs of infection can
be nonspecific, rapidly determining whether a bacterial infection exists can be difficult. The Systemic Inflammatory Response Syndrome
(SIRS) Criteria (Table 2), which were developed primarily for research
purposes, were proposed in 1992.9 Since then, most of the evidence
regarding outcomes in patients with severe sepsis and septic shock
has been based on these criteria, which remain widely used. Even
at the time of their proposal, the diagnostic limitations of the SIRS
Criteria were well recognized.9 In order to develop SIRS Criteria a patient must have an intact inflammatory and catecholamine response
to physiologic stress. Numerous other conditions may cause these
Evolution of Early Goal-Directed Therapy
Although the principles of early identification of sepsis and septic
shock reversal are now widely recognized, some of the more invasive
Based on their presentation and trajectory, some patients will need
more invasive care than others. “Modern” EGDT is based on the
same principles as the predecessor Rivers Trial, but is applied to the
individual needs of the patient. At the bedside, this means meeting
three primary goals: 1) early identification of sepsis, 2) early, aggressive treatment of septic shock, and 3) minimizing the functional burden of illness.
1. Early Identification of Sepsis
41
ADVANCED RESUSCITATION OF SEPTIC SHOCK IN THE
TABLE
01
Data From 4 Randomized Trials Comparing Early Goal-Directed Therapy (EGDT ) to “Usual” or
“Standard” Care
Factor
Rivers 2001
ProCESS 2014*
ARISE 2014
PRoMISe 2015
263
1351
1591
1251
# Centers
1
31
51
56
Location
USA
USA
Australia, New Zealand, Europe,
Hong Kong
England
Academic
Academic
Academic, Nonacademic
Academic, Nonacademic
n
130
439
793
625
% arterial catheter (0-6 hrs)
100
NR
91
74
n
Center Type
EGDT
% CVC (0-6 hrs)
100
90
90
92
4981 mL
2805 mL
1964 mL
2226 mL
% Vasopressor (0-6 hrs)
27.4
55
67
53
% Inotrope (0-6 hrs)
14%
8
15
18
% PRBCs (0-6 hrs)
64.1
14
14
9
28 day mortality
33.3%
NR
14.8%
24.8%
60 day mortality
44.3%
21%
NR
NR
90 day mortality
NR
31.9%
18.6%
29.5%
n
133
456
798
626
% arterial line (0-6 hrs)
100
NR
76
62
% CVC (0-6 hrs)
100
60%
61.9
51
Volume of IVF (0-6 hrs)
3499 mL
2279 mL
1401 mL
2022 mL
% Vasopressor (0-6 hrs)
30.3
44.1
57.8
47
8
0.9
2.6
4
18.5
8
7
4
15.9%
24.5%
Volume IVF (0-6 hrs)
“Standard/Usual Care”
% Inotrope (0-6 hrs)
% PRBCs (0-6 hrs)
28 day mortality
49.2%
NR
60 day mortality
56.9%
18.9%
90 day mortality
NR
33.7%
NR
18.8%
29.2%
*The ProCESS trial also included a group of 446 patients randomized to “protocol-based standard therapy ”. This group was
excluded from this table for simplicity.
CVC: central venous catheter; IVF: intravenous fluids; PRBCs: packed red blood cells; NR: not reported
responses without infection, which limits the specificity of the criteria.
Further, if a patient is immunosuppressed, takes a beta-blocker, is
elderly or diabetic, progression to shock or even organ failure can
occur without developing any of the SIRS criteria.5 As a result of these
limitations, the Surviving Sepsis Guidelines which emphasize clinical
judgment in the diagnosis of sepsis were established in 2003.10 The
clinician should first decide whether an infection exists, then evaluate
for evidence of a systemic burden of infection. This may or may not
include traditional SIRS diagnostic criteria which may not be present
in up to one in eight patients admitted to the ICU with severe sepsis.5
42
If a bacterial, fungal, or protozoan infection exists in a critically ill
patient, rapid antimicrobial administration to decrease microbial
burden is necessary to improve outcome. If such an infection does
not exist, the treatment is unnecessary and may be harmful. As
noted previously, determining whether or not an antimicrobial susceptible infection exists can be difficult, even in critically ill patients. A
diagnostic “test” for sepsis of bacterial, fungal, or protozoan etiology
of infection has been explored but has not become routine. The most
widely studied is procalcitonin (PCT) which has been evaluated for
the identification of sepsis of bacterial origin. The PCT assay has not
TABLE
02
Diagnostic Criteria for Systemic Inflammatory Response
Syndrome (SIRS), Sepsis, Severe Sepsis, and Septic Shock
Term
SIRS*
(must have ≥ 2)
•
•
•
•
Body Temperature ≥ 38°C or ≤ 36°C
Heart Rate ≥ 90 beats per minute
Respiratory Rate ≥ 20 breaths per minute or PaCO2
< 32 mmHg
White Blood Cell Count > 12x103/mm3 or < 4x103/mm3
or ≥ 10% bands
Sepsis
SIRS + suspected or documented infection
Severe Sepsis
Sepsis + tissue hypoperfusion, organ dysfunction or
hypotension
Septic Shock
hypoperfusion
*About 88% of patients with severe sepsis or septic shock will meet these criteria within 24 hours of ICU
admission. The diagnosis of sepsis is based on clinical judgment and should not be limited to these criteria.
proven accurate when used alone. A recent meta-analysis, which
reviewed studies with varying cutoff values and marked heterogeneity, noted an overall sensitivity and specificity for PCT in the 75-80%
range.11 Although the Surviving Sepsis Campaign Guidelines list an
elevated PCT as potential evidence of sepsis, the cumulative data do
not support its use in isolation to guide the initiation of antimicrobial
therapy. In some cases, PCT may be drawn in the ED as a baseline
and followed in order to help guide the duration of antibiotics during
the inpatient stay.
With no rapid, accurate diagnostic test for bacterial infection, critically
ill patients with suspected infection must be treated presumptively
with broad-spectrum antibiotics as soon as possible. Every attempt
should be made to obtain cultures from the patient prior to antibiotic
administration as appropriate de-escalation of antibiotics can improve
patient outcome as well.
Early Antibiotic Administration
The 2012 Surviving Sepsis Campaign Guidelines recommend that
empiric antibiotics be administered within three hours of ED presentation (Grade 1C).10 In patients with sepsis, delays in administering
antimicrobial therapy proportionately increases mortality.12 Initial
antimicrobial choice in undifferentiated patients with severe sepsis
or septic shock should target both gram positive and gram negative
bacteria common to the respiratory and urinary tract which account
for 55-84% of sites of infection. Some variation in this protocol may
be necessary due to patient or environmental factors.13 Although
anaerobic and fungal pathogens are rare (≤2%), they are associated
with high mortality and so appropriate therapy should be given in
select patients with specific risk factors.13 Attention should be paid to
adequate dosing, particularly for antibiotics with renal clearance such
as vancomycin, beta-lactams, and aminoglycosides as sepsis may
result in both a higher volume of distribution and augmented renal
clearance, resulting in subtherapeutic drug levels. It is important to
dose antibiotics aggressively early in the patient’s course.
Controlling the source of infection is likely as important as early
antibiotic administration in improving mortality. Infected tissues and
implanted devices need to be removed as soon as feasible. Although
the methods of source control vary and have been infrequently studied, the Surviving Sepsis Guidelines recommend using the intervention with the “least physiologic insult possible,”10 understanding the
added inflammatory burden that can occur with major surgery.
2. Early, Aggressive Treatment of Septic Shock
Following the recognition of a microbial pathogen by the innate
immune system, a complex pro- and anti-inflammatory cascade
occurs. This results in multiple changes at the level of the glycocalyx,
including increased permeability, loss of vascular tone, microthrombosis, and local blood pooling. If limited to the formation of a local
response to an invading pathogen, this event would be beneficial.
When it occurs systemically, however, loss of intravascular volume
and an imbalance between global oxygen delivery (DO2) and oxygen
demand (VO2) occurs.14 As this hemodynamic process progresses,
physiologic compensation (catecholamine tone) maintains perfusion
to the brain and heart, though this may lead to impairment of other
organ systems. Over time, if left untreated, compensatory mechanisms become taxed and decompensation may occur, leading to
a fall in mean arterial pressure (MAP) and ultimately death due to
cardiovascular collapse.3,14 If early hemodynamic support is provided,
macrocirculatory parameters may improve, but there may still be microcirculatory dysfunction, which can lead to multi-organ failure and
death. In general, the faster this is reversed, the better. Patients may
present anywhere along this continuum and thus require individualized therapies.
Identifying Septic Shock
Septic shock is recognized as the most severe aspect of the sepsis
syndrome.10 It is important to recognize, however, that patients with
severe sepsis (maintaining physiologic compensation) may have a
mortality approaching that of those in overt septic shock.8,15 Patients
should be triaged and assessed for signs of severe sepsis as quickly
as possible. Lactate, which correlates strongly with disease severity
and outcome,16 should be checked as early as possible in the triage
process, and then, if abnormal, rechecked during resuscitation to
assess for clearance.10
Reversing Septic Shock
Any patient with a low MAP, elevated lactate, or clinical evidence of
tissue hypoperfusion should be aggressively managed. A potential
algorithm for resuscitation is shown in Figure 1. The overall goal is
to restore adequate tissue perfusion and oxygenation as quickly as
possible without causing volume overload; however, the methods for
accomplishing this are the subject of considerable study and debate.
The two primary resuscitation goals are MAP > 65 mmHg and
adequate tissue perfusion.17
43
FIGURE
01
E
M
E
R
G
E
N
C
Y
Po te nt i a l Al g o r i t h m fo r M a x i m i z i n g Ti s s u e Pe r f u s i o n Wh i l e M i n i m i z i n g Vo l u m e O ve rl o a d
Recognize severe sepsis, maintain airway
and establish IV access
GOALS:
1. MAP > 65 mmHg
2. Cl > 2.5
500 ml boluses of LR
Max. of 20-30 ml/kg
Early broad spectrum
antimicrobial therapy
If MAP < 65 mmHg
after fluid bolus
Blood cultures,
lactate and PCT
Establish central
venous access
OPTION
Start norepinepherine at
0.01 µg/kg/min and
titrate up to 0.1-0.2
µg/kg/min
I
C
U
MAP > 65 mmHg
Monitor hemodynamics
and perfusion
OPTION
MAP < 65 mmHg
Attach non-invasive
cardiac output monitor
Cl < 2.5 or
poor LV function
Cl > 2.5 or
hyperdynamic LV
If POOR
Attach non-invasive
cardiac output monitor
and bedside ECHO
Additional 500 cc bolus
x2 if signs of volume
depletion
Access fluid status
with ECHO/US/PLR
SV inc > 10%
Vasopressin at
0.03U/min ??
PLR
SV inc < 10%
Corticosteroid
infusion ??
500 cc fluid LR
Titrate
norepinepherine
up to 1 µg/kg/min
Dobutamine at 2.5
µg/kg/min and
titrate to Cl
CI = cardiac index; ECHO = echocardiography; US = ultrasound; inc = increase; LR = Lactated Ringers solution; LV = left ventricle; MAP = mean
arterial pressure; Max = maximal; PCT = procalcitonin; PLR = passive leg raising; SV = stroke volume
Reprinted with permission from Marik PE. Early management of severe sepsis. CHEST 2014;145(6):1407-1418.
Goal 1 - MAP > 65 mmHg: Although a normal MAP does not
guarantee adequate organ perfusion, MAP does reflect drive pressure
at the tissue level. The majority of evidence suggests a higher mortality with a MAP target of ≤ 65 mmHg, and no definitive improvement
in organ function with higher goals. A recent randomized trial comparing a lower MAP goal (65-70 mmHg) to a higher MAP goal (80-90
mmHg) did not demonstrate an overall benefit in mortality or any
other measured parameter.18 However, in the subset of patients with
pre-existing hypertension, there was an 11% decrease in the need
for renal replacement therapy (RRT) in the group with the higher
MAP goal. Therefore, it is reasonable to target a MAP ≥ 65 in most
patients, but this should be individualized, and a higher MAP may be
necessary in patients with pre-existing hypertension to decrease the
risk of renal failure.
44
Goal 2 - Adequate Perfusion: Recognizing the risk of “occult
shock,” the patient should be monitored frequently for evidence of
hypoperfusion and increasing disease severity, regardless of the MAP.
Physical exam findings, such as delayed capillary refill, skin temperature, decreased urine output, and altered mental status are accurate
predictors of tissue hypoperfusion and correlate with disease severity
if present. However, their absence alone should not be used to rule
out inadequate perfusion.
Lactate should be checked early in the patient’s course and, if elevated,
monitored intermittently for clearance. It is unclear whether elevation
of lactate in sepsis is the result of tissue hypoperfusion, “cytopathic
stress” from oxidative injury, adrenergic tone, or lack of clearance. Regardless, its elevation closely correlates with disease severity in a variety of conditions, including sepsis. A cutoff value of 4 mmol/L appears
to be appropriate in predicting in-hospital mortality in patients with
sepsis, although indeterminate levels (2.3-4 mmol/L) have also been
associated with poor outcomes. Additionally, patients with septic shock,
even without hyperlactatemia, may have a high mortality as well.8 Thus,
lactate should not be used alone to predict disease severity.
Lactate normalization is strongly associated with survival. However,
lactate clearance as a target of resuscitation is less clear, as its
normalization could simply be a marker of improving disease severity.
One RCT that targeted a lactate clearance of ≥ 20% per two hours
demonstrated improved outcomes using this approach vs. controls.19
Other than this, evidence of lactate clearance as a target for hemodynamic management is lacking. The Surviving Sepsis Campaign
recommends checking a lactate within three hours of presentation.
If it is elevated, the patient should be resuscitated, and it should be
checked again within six hours of presentation.10 If lactate has not
decreased, the reason should be investigated. Usually, this will involve
ensuring adequate tissue perfusion and oxygenation (as noted below),
assessing for excessive oxygen demand such as fever, shivering, and
increased work of breathing, and ensuring adequate source control.
If a central venous catheter (CVC) is present, ScvO2 may be followed.
The ScvO2 is often considered a reflection of the oxygen extraction
ratio at the tissue level, which in normal patients is about 22-32%.
Since the average arterial oxygen saturation (SpO2) is about 95-100%
in normal individuals, the “normal” ScvO2 is usually greater than
70%. If oxygen extraction increases, ScvO2 theoretically decreases
indicating tissue hypoperfusion. Indeed, a low ScvO2 is correlated
with an increased mortality.20 However, oxygen extraction at the
tissue level can be impaired due to microcirculatory shunting or mitochondrial dysfunction, so an abnormally high ScvO2 (> 89%) may also
correlate with increased mortality,20 which limits its effectiveness as a
target for therapy. Regardless, low values do correlate with impaired
perfusion,3,10,14,15 so targeting ScvO2 ≥ 70% is reasonable, particularly
when inotropic therapy is needed. Still, the clinician should not be
falsely reassured by a normal or high value in the setting of sepsis.
Volume Loading
If MAP is low or signs of hypoperfusion exit, fluids are considered
first line therapy.10 20-30 mL/kg of crystalloid is initially recommended, but an average of 1.7-3.7 liters over the first six hours has been
associated with improved mortality.21 The goal of fluid therapy is to
establish enough preload for adequate cardiac output, particularly
early in the patient’s course.
The type of fluid that should be used during resuscitation for septic
shock is subject to debate. Excessive use of normal saline, which
contains supraphysiologic chloride levels, is independently associated with mortality. So-called “balanced solutions,” which are
created to more closely resemble physiologic pH and electrolyte
levels, have been associated with lower mortality when compared
to saline in patients with sepsis. The quality of this evidence is still
debated, and a large RCT comparing the two is underway (ACTRN12613001370796). Until these results are available, it is difficult
to recommend one type of crystalloid over another.
Starch solutions (e.g., hydroxyethyl starch, dextran, gelatins) increase
the need for RRT and increase mortality, and should not be routinely
used. Although albumin has not demonstrated harm in patients with
sepsis, it also has not demonstrated a consistent, definitive benefit
over crystalloid resuscitation. Further, depending on location, albumin
may be up to 25 times more expensive. Therefore, crystalloid resuscitation is recommended as initial therapy,10 but albumin may be used
in most patients with at least equal efficacy.
Volume may also be given in the form of blood products. Although
transfusion of packed red blood cells may be beneficial in some
patients with impaired oxygen delivery, a recent RCT comparing a
hemoglobin goal of 9 mg/dL vs. 7 mg/dL in patients with septic
shock showed no mortality benefit.22 In the vast majority of patients,
a hemoglobin level of 7 mg/dL is an appropriate target.
Assessing Preload-Responsiveness
If MAP and tissue perfusion are not restored following initial volume
loading, the clinician should avoid giving further empiric fluid until an
assessment of “volume responsiveness” (an increase in cardiac output in response to the administration of fluid volume) has occurred.
This can be difficult, as the clinical exam alone can be unreliable and
wide practice variation exists.
Central venous pressure (CVP), which is a “static measurement,” is
used as a surrogate for filling pressure of the right atrium and ventricle. When used in isolation, it does not correlate well with volume
responsiveness. However, when used as part of EGDT, CVP does not
increase mortality,6-8 and it is still an optional measurement recommended by the Surviving Sepsis Campaign Guidelines.10 Because of
this, it is still widely used by clinicians, and may be helpful if more
accurate (dynamic) measures are not available.
The lack of efficacy of CVP monitoring is not surprising, as it is a
static measurement in a dynamic system. Dynamic tests, where a
change in preload occurs and the response is measured, should be
used when possible. The gold standard for this is a fluid challenge,
during which 250-500 mL of crystalloid volume is given and the patient is observed for a response. An increase in stroke volume of 15%
in response to this challenge predicts fluid responsiveness. Since
administering any unnecessary volume is undesirable, changes in
preload can also be observed using the respiratory cycle or position
changes in order to predict volume responsiveness. The following are
methods of assessing volume responsiveness:
Ultrasound: Ultrasound is noninvasive, readily available, and accurate
in a variety of patients. Variations in the diameter of the inferior vena
cava (IVC) during the respiratory cycle can be used to estimate pre-
45
load. If the patient is spontaneously breathing, IVC collapse of ≥15%
during inspiration is correlated with volume responsiveness. In mechanically ventilated patients, the IVC distends during inspiration, and
distension of ≥12% has a cutoff sensitivity and specificity of 93% and
92%, respectively. The measurement does not have to be quantitative, as qualitative assessment by clinicians at the bedside has been
shown to correlate relatively well. Quantitative or qualitative assessment of left ventricle (LV) filling may also be performed at this stage.
Quantitatively, a low LV end-diastolic area in addition to decreased
flow velocity across the LV outflow tract with a grossly normal right
ventricle may indicate hypovolemia. However, a brief, qualitative
assessment of LV filling in combination with a qualitative assessment
of IVC collapsibility is most often used. An “underfilled” LV often has
a small chamber size during diastole with close approximation of
the ventricular walls during systole, sometimes even making contact
(“kissing ventricles”). In the presence of a normal (not distended)
right ventricle, this may also indicate hypovolemia. Further, hyperdynamic features may be noted, such as contact of the mitral valve with
the LV septum during diastole. It should be emphasized that a single
assessment of LV filling is a static measurement. Although echocardiography does not provide continuous hemodynamic monitoring,
serial assessments of both IVC collapsibility/distensibility, LV filling,
and changes in stroke volume in response to fluid challenges may be
considered dynamic measurements. Serial assessments should be
performed as resuscitation continues.
Pulse Pressure Variation: Pulse pressure variation (PPV) is used as
a surrogate for Stroke Volume Variation (SVV). An arterial catheter is
needed, and the change in pulse pressure with the respiratory cycle
is measured. In mechanically ventilated patients with a tidal volume
of at least 8 mL/kg, PPV of ≥ 12% with the respiratory cycle has a
sensitivity and specificity of 89% and 84%, respectively, when predicting volume responsiveness.23 Its use may be limited in spontaneously
breathing patients, however, as well as in patients with arrhythmias or
severe valvular disease.
Passive Leg Raise: A passive leg raise (PLR) test is likely the most
accurate method to predict volume responsiveness. It simulates a
volume challenge by using a change in position, which mobilizes fluid
from the splanchnic and lower extremity circulation. The method
for performing a PLR is as follows: The patient begins in a semirecumbent position; the patient is then laid flat with the legs raised,
and a measurement of cardiac output is obtained after one minute.
The patient is then repositioned in the semi-recumbent position, and
the cardiac output should return to baseline.24 Generally, some form
of direct measurement of cardiac output is required, and an increase
in cardiac output of 15% by direct measurement indicates volume
responsiveness. Because PLR simulates an actual volume challenge,
it maintains accuracy across cardiac rhythms and variations in ventilation.24 However, conditions that anatomically compromise venous
return (e.g., intraabdominal hypertension) and changes in adrenergic
tone (e.g., pain, anxiety) limit its accuracy.
46
Vasopressors
If MAP does not increase with initial fluid loading, vasopressors
should be considered simultaneously with the above assessments
for preload responsiveness. Placement of a CVC and AC should
be considered at this point, but lack of a CVC should not delay the
administration of vasopressors. A delay in vasopressor administration
has been associated with increased mortality,21 and the short-term
administration of vasopressors (including norepinephrine) through a
reliable peripheral IV is likely safe.25 The properties and use of vasopressors and inotropes in septic shock are reviewed in Table 3.
Steroids
Low-dose corticosteroids (≤300 mg/day of hydrocortisone or equiva
lent) in septic shock have long been controversial. The physiology
and debate regarding their use is well beyond the scope of this
review. What is known is that the two primary trials evaluating the
use of steroids, while demonstrating a consistent benefit in septic
shock reversal, have been inconsistent in regards to any benefit in
mortality.26,27 The trials were heavily criticized for a variety of reasons
(including patient acuity, the use of the adrenocorticotropic hormone
[ACTH]-stimulation test, and the use of etomidate), and a new trial
evaluating for a mortality benefit in patients with septic shock is ongoing (NCT01448109). For now, noting the benefit in shock reversal, it
is reasonable to administer corticosteroids to patients with refractory hypotension. If given, a dose of 200-300 mg/day (usually 50
mg every six hours, but may be given continuously) should be used
and continued for seven days, or 24 hours after discontinuation of
vasopressor therapy.10
Assessment of Cardiac Function
If signs of hypoperfusion are present, regardless of MAP, and the
patient has been deemed “volume unresponsive,” an assessment
of cardiac function should be obtained. Pulmonary artery catheters
have been the traditional gold standard for hemodynamic monitoring,
but they are no longer routinely used for patients with sepsis.8,10,15
Noninvasive means of assessing cardiac function are now favored.
Bedside Echocardiography: As noted above, bedside echocardiography does not generally provide continuous hemodynamic data, but is
arguably the most beneficial tool for assessment of cardiac function. It is noninvasive, easily learned, and is now widely used by ED
physicians and intensivists. It can be used to assess for anatomical
abnormalities of the heart, preload responsiveness, left and rightventricular function, cardiac output, and response to interventions.
Although quantitative measures can be used to calculate hemodynamic parameters, qualitative measures of biventricular function and
IVC collapsibility/distensibility are also accurate, allowing for rapid
assessment at the bedside. Transthoracic echocardiography (TTE)
is most commonly used; however, transesophageal echocardiography (TEE) is becoming more widely available as well, and has been
used for hemodynamic guidance in patients with sepsis. For these
reasons, echocardiography is often recommended as the preferred
method for initial hemodynamic assessment.15
Esophageal Doppler: Esophageal Doppler monitoring measures flow
velocity in the descending aorta through the esophagus, enabling calculation of the stroke volume and cardiac output. Its more prominent
use has been in guiding fluid therapy during surgery. However, it has
been used as part of a more general strategy of limiting fluid administration in the ICU. It is relatively noninvasive, although the patient
must be intubated for use. The primary drawback is that, because it
is a doppler probe placed blindly, small position changes can change
the vector and impact measurements. Its effect on patient-oriented
outcomes during early resuscitation in the general ED and ICU population is unknown.
Bioreactance: Bioreactance, which is employed by the Noninvasive
Cardiac Output Monitor (NICOM), measures “phase shifts” in voltage
across the thorax in response to pulsatile blood flow through the
TABLE
03
aorta. This is translated to flow, then to stroke volume, and can be
used to calculate cardiac output and associated parameters. It is
entirely noninvasive, as only large pads are attached to the patient.
It has demonstrated variable correlation with more invasive techniques of cardiac monitoring, but has not demonstrated a consistent,
patient-oriented benefit.
Inotropic Therapy
If inadequate perfusion is still present and assessment reveals poor
ventricular function, inotropic therapy is warranted. There is currently
no definitive data to support one particular agent over another (Table
3). Once inotropic therapy begins, it can be titrated to cardiac index
(if measured) or a combination of lactate normalization, ScvO2, and
clinical exam parameters of improved perfusion.
Vasopressors for Use in S eptic Sho ck
Vasopressor / Inotrope
Property
*Norepinephrine (NE)
α ,β ,β
•
Arterial VC, venoconstriction
•
Increases preload and systemic vascular resistance
•
•
Minimal splanchnic and pulmonary vasoconstriction at doses <0.5 mcg/kg/min
•
**Vasopressin (VP)
Epinephrine (E)
Phenylephrine (P)
#Dopamine (DA)
Dobutamine (DBA)
AVPR1a (peripheral)
AVPR1b (central)
AVPR2 (renal)
α ,β ,β
α
α ,β ,β
β ,β
•
Vasopressor of choice
•
Neurohypophyseal hormone
•
Vasoconstriction, water retention, HPA-axis (among others)
•
Levels increase early in sepsis, then fall for ≥ 7 days (stores deplete)
•
Used as adjunct to NE – no overall mortality improvement
•
May improve mortality if used + steroids or if NE <0.15 mc/kg/min
•
Current trial assessing use as primary vasopressor (ICNISRCTN20769191)
•
For now, may use as adjunct to NE if 2nd vasopressor needed
•
•
No advantage over NE if used as primary vasopressor
•
May be safely added to NE and may improve MAP, but no overall advantage over NE + DBA in normotensive or hypotensive patients
•
May be less well-tolerated than NE due to lactic acidosis, splanchnic VC, and tachyarrhythmias
•
Can be “1st line alternative” to NE
•
•
May decrease cardiac output, increase pulmonary vasoconstriction
•
No direct comparison with NE for mortality
•
Should be 2nd line agent for most patients with sepsis
•
•
Increased mortality compared with NE
•
Use only if NE unavailable or in patients with severe bradycardia
•
Inotropic, chronotropic, vasodilation
•
Use with NE if hypotensive – may be more well-tolerated than E
•
Use for patients with poor LV function with evidence of poor perfusion
*Norepinephrine should be the first choice in most circumstances.
**Vasopressin can be added as an adjunct if needed, though an ongoing trial is evaluating its use as a first-line vasopressor in sepsis.
#Dopamine should not be used unless norepinephrine is not available, or in patients at very low risk of arrhythmias
AVPR: Arginine-Vasopressin Receptor; VC: vasoconstriction; HPA: hypothalamic-pituitary-adrenal; MAP: mean arterial pressure; LV: left ventricular
47
3. Minimizing the Functional Burden of Illness
Up to 25% of patients discharged from the hospital after a diagnosis
of severe sepsis will be readmitted within 30 days and nearly half
will be readmitted within six months, resulting in an estimated $9
billion in annual costs. Further, cognitive dysfunction and a profound
decrease in exercise capacity persist for months to even years after
hospitalization.
ICU-acquired weakness can lead to long-term disability after hospitalization. It has been associated with various factors during the ED
and ICU stay, including poor glycemic control, bed rest, the use of
corticosteroids, and duration of mechanical ventilation.28 Depth of
sedation, benzodiazepine use, and sleep deprivation have been associated with long-term cognitive dysfunction.28 Further, the inflammatory changes associated with sepsis may independently contribute to
some of these processes.28 Surviving sepsis, it turns out, can result
in substantial morbidity.
Determinants of functional and neurocognitive impairment following
hospitalizations are still being elucidated. Still, aggressive efforts are
being made to minimize the effect of the illness and hospitalization
on the patient’s functional status, and these efforts should start in
the ED. In general, this means minimizing time receiving mechanical
ventilation by using lung protective ventilation and avoiding deep sedation when possible, minimizing duration of immobility, and aggressively treating sepsis to prevent multi-organ failure. Early mobilization
protocols that specifically target patients with sepsis are currently
being studied and implemented. Although mortality continues to
decrease, it is likely that many significant advances in sepsis care will
focus on minimizing not just mortality, but also the functional burden
of the disease after hospitalization.
Conclusion
Although the care of critically ill patients with sepsis has evolved
since the initial publication of EDGT, the principles of EGDT are still
relevant. How the “goals” are met, however, should be determined
according to individual patient needs. At the bedside, the ED physician should aim to meet the three “primary objectives” outlined in
this review in order to minimize morbidity and mortality.
5. Kaukonen KM, Bailey M, Pilcher D, Cooper DJ, Bellomo R. Systemic inflammatory
response syndrome criteria in defining severe sepsis. N Engl J Med.
2015;372:1629-1638.
6. ProCessInvestigators, Yealy DM, Kellum JA, et al. A randomized trial of protocolbased care for early septic shock. N Engl J Med. 2014;370:1683-1693.
7. AriseInvestigators, Group ACT, Peake SL, et al. Goal-directed resuscitation for
patients with early septic shock. N Engl J Med. 2014;371:1496-1506.
8. Mouncey PR, Osborn TM, Power GS, et al. Trial of early, goal-directed
resuscitation for septic shock. N Engl J Med. 2015;372:1301-1311.
9. American College of Chest Physicians/Society of Critical Care Medicine
Consensus Conference: definitions for sepsis and organ failure and guidelines for
the use of innovative therapies in sepsis. Crit Care Med. 1992;20:864-874.
10.Dellinger RP, Levy MM, Rhodes A, et al. Surviving sepsis campaign: international
guidelines for management of severe sepsis and septic shock: 2012. Crit Care
Med. 2013;41:580-637.
11.Wacker C, Prkno A, Brunkhorst FM, Schlattmann P. Procalcitonin as a diagnostic
marker for sepsis: a systematic review and meta-analysis. Lancet Infect Dis.
2013;13:426-435.
12.Ferrer R, Martin-Loeches I, Phillips G, et al. Empiric antibiotic treatment
reduces mortality in severe sepsis and septic shock from the first hour: results
from a guideline-based performance improvement program. Crit Care Med.
2014;42:1749-1755.
13.Ani C, Farshidpanah S, Bellinghausen Stewart A, Nguyen HB. Variations in
organism-specific severe sepsis mortality in the United States: 1999-2008. Crit
Care Med. 2015;43:65-77.
14.Rivers EP, Yataco AC, Jaehne AK, Gill J, Disselkamp M. Oxygen extraction and
perfusion markers in severe sepsis and septic shock: diagnostic, therapeutic and
outcome implications. Curr Opin Crit Care. 2015;21:381-387.
15.Cecconi M, De Backer D, Antonelli M, et al. Consensus on circulatory shock and
hemodynamic monitoring. Task force of the European Society of Intensive Care
Medicine. Intensive Care Med. 2014;40:1795-1815.
16.Casserly B, Phillips GS, Schorr C, et al. Lactate measurements in sepsis-induced
tissue hypoperfusion: results from the Surviving Sepsis Campaign database. Crit
Care Med. 2015;43:567-573.
17.Marik PE. Early management of severe sepsis: concepts and controversies.
Chest. 2014;145:1407-1418.
18.Asfar P, Meziani F, Hamel JF, et al. High versus low blood-pressure target in
patients with septic shock. N Engl J Med. 2014;370:1583-1593.
References
1. Kaukonen KM, Bailey M, Suzuki S, Pilcher D, Bellomo R. Mortality related to
severe sepsis and septic shock among critically ill patients in Australia and New
Zealand, 2000-2012. JAMA. 2014;311:1308-1316.
2. Vincent JL, Marshall JC, Namendys-Silva SA, et al. Assessment of the worldwide
burden of critical illness: the intensive care over nations (ICON) audit. Lancet
Respir Med. 2014;2:380-386.
3. Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment
of severe sepsis and septic shock. N Engl J Med. 2001;345:1368-1377.
48
4. Stevenson EK, Rubenstein AR, Radin GT, Wiener RS, Walkey AJ. Two decades of
mortality trends among patients with severe sepsis: a comparative meta-analysis.
Crit Care Med. 2014;42:625-631.
19.Jansen TC, van Bommel J, Schoonderbeek FJ, et al. Early lactate-guided therapy
in intensive care unit patients: a multicenter, open-label, randomized controlled
trial. Am J Respir Crit Care Med. 2010;182:752-761.
20.Pope JV, Jones AE, Gaieski DF, et al. Multicenter study of central venous oxygen
saturation (ScvO[2]) as a predictor of mortality in patients with sepsis. Ann Emerg
Med. 2010;55:40-46 e41.
21. Waechter J, Kumar A, Lapinsky SE, et al. Interaction between fluids and vasoactive
agents on mortality in septic shock: a multicenter, observational study. Crit Care
Med. 2014;42:2158-2168.
22. Holst LB, Haase N, Wetterslev J, et al. Lower versus higher hemoglobin threshold
for transfusion in septic shock. N Engl J Med. 2014;371:1381-1391.
23.Yang X, Du B. Does pulse pressure variation predict fluid responsiveness
in critically ill patients? A systematic review and meta-analysis. Crit Care.
2014;18:650.
24.Monnet X, Teboul JL. Passive leg raising: five rules, not a drop of fluid! Crit Care.
2015;19:18.
25.Loubani OM, Green RS. A systematic review of extravasation and local tissue
injury from administration of vasopressors through peripheral intravenous
catheters and central venous catheters. J Crit Care. 2015;30:653 e659-617.
26.Annane D, Sebille V, Charpentier C, et al. Effect of treatment with low doses
of hydrocortisone and fludrocortisone on mortality in patients with septic shock.
JAMA. 2002;288:862-871.
27.Sprung CL, Annane D, Keh D, et al. Hydrocortisone therapy for patients with
septic shock. N Engl J Med. 2008;358:111-124.
28.Hermans G, Van den Berghe G. Clinical review: intensive care unit acquired
weakness. Crit Care. 2015;19:274.
49
50
Continuing Medical Education Post-Test
Based on the information presented in this monograph, please choose one correct response for each of the following questions or statements. Record your
answers on the answer sheet found on the last page. To receive Category I credit, complete the post-test and record your responses on the answer sheet and
complete the evaluation. Mail in the return envelope no later than March 31, 2017. A passing grade of 80% is needed to receive credit. A certificate
will be sent to you upon your successful completion of this post-test.
EMERGENCY DEPARTMENT AND INTENSIVE CARE UNIT –
Brian M. Fuller, MD, and Nicholas M. Mohr, MD
DEEP VENOUS THROMBOSIS AND PULMONARY EMBOLISM:
OPTIMAL THERAPY AND PREVENTION FOR THE CRITICALLY-ILL
PATIENT – Gregory J. Fermann, MD
1.
6.
A 37-year old woman presents to the emergency department in respiratory distress and is intubated secondary to asthma. The ventilator’s
graphics display is shown below. What does this flow-time waveform
represent?
Inspiration
A.
B.
C.
D.
7.
Flow
Time
2.
Auto-PEEP
A normal flow-time waveform
Trigger dysynchrony
Flow dysynchrony
In patients with acute respiratory distress syndrome (ARDS), which one
of the following is likely to most improve survival?
A. Inhaled nitric oxide
B. Lung-protective ventilation aimed at limiting tidal volume and
plateau pressure
C. High frequency oscillatory ventilation (HFOV)
D. Immediate referral for extracorporeal membrane oxygenation
(ECMO)
4.
In patients without acute respiratory distress syndrome (ARDS), but at
risk for it, there is no benefit in providing lung-protective ventilation.
A. True
B. False
5.
Which of the following statements are true?
A. In volume-targeted ventilation, the clinician prescribes the tidal
volume and rate (guaranteeing minute ventilation), and airway
pressures vary with compliance and resistance
B. Patients should be placed on VC/AC as outcomes are superior with
this mode of ventilation
C. In pressure-targeted ventilation, inspiratory:expiratory ratio is determined by tidal volume and flow rate
D. Tidal volume does not vary in PC/AC
9.
PESI
TIMI risk score
sPESI
HESTIA
Which of the following is NOT considered in the American College of
Cardiology/American Heart Association definition of SUBMASSIVE
pulmonary embolism?
A.
B.
C.
D.
A 60-year old man presents to the emergency department with an exacerbation of chronic obstructive pulmonary disease (COPD). His peak
airway pressure is 42 cm H2O and his plateau pressure is 14 cm H2O.
A. True
B. False
3.
8.
Clot burden
Tachycardia
Hypoxia
Hypotension
All of the following are clinical scoring systems that can be applied to
the risk stratification of patients with pulmonary embolism EXCEPT:
A.
B.
C.
D.
Expiration
A.
B.
C.
D.
Which of the following has emerged as the most reliable predictor of
adverse outcome in patients with acute pulmonary embolism?
RV/LV diameter ratio > 0.9
Elevated cardiac troponin
Renal failure
Elevated natriuretic peptide
Which of the following is NOT appropriate therapy for patients with
low risk acute pulmonary embolism who lack contraindications to
anticoagulation?
A.
B.
C.
D.
Aspirin
Unfractionated heparin
Rivaroxaban
Enoxaparin
10. All of the following are acceptable pulmonary reperfusion strategies for
patients with massive pulmonary embolism EXCEPT?
A.
B.
C.
D.
Alteplase 100 mg over 2 hours peripherally
Surgical thrombectomy
Alteplase 100 mg over 24 hours peripherally
Pharmaco-mechanical therapy
BEYOND HYPOTHERMIA – Jon C. Rittenberger, MD
11. All of the following are reasons to obtain computed tomography (CT)
imaging of the brain following resuscitation from cardiac arrest EXCEPT:
A. The incidence of intracranial hemorrhage is approximately 5%
B. Identification of the presence of early cerebral edema can decrease
enthusiasm for invasive procedures such as coronary angiography
C. The patient is awake, alert, and has a non-focal neurologic examination
D. All patients, regardless of neurologic examination, should receive a
CT of the brain
51
12. Which of the following statements regarding temperature management
in the post-arrest patient is TRUE?
A. No temperature management is needed
B. All patients should have temperature management to 32-34°C
C. Only patients who follow commands should have temperature
management to 32-34°C
D. Fever should be prevented in all comatose patients
13. Which of the following statements regarding neurologic status in the
post-arrest patient is TRUE?
A. Seizure development during the post-arrest period portends a
universally poor neurologic outcome
B. A persistently flat, unreactive electroencephalogram (EEG)
portends a good neurologic outcome
C. Malignant EEG patterns are common in the comatose post-arrest
patient
D. There is no need for EEG monitoring in the post-arrest patient
14. Which neurologic examination components are needed to determine
initial illness severity as determined by the Pittsburgh Cardiac Arrest
Category (PCAC)?
A.
B.
C.
D.
Motor response, oculocephalic reflex, respiratory rate, gag reflex
Verbal response, pupillary reflex, corneal reflex, cough reflex
Motor response, pupillary reflex, corneal reflex, cough reflex
Motor response, verbal response, corneal reflex, cough reflex
15. Specific resuscitation goals for the comatose post-arrest patient include
all of the following EXCEPT:
A.
B.
C.
D.
Maintaining a mean arterial blood pressure (MAP) of > 80mmHg
Hyperventilation to prevent cerebral edema
Temperature management and avoidance of fever
Avoidance of severe hyperoxia
INTENSIVE CARE UNIT – Evie G. Marcolini, MD
16. Modifiable risk factors for atrial fibrillation in the critically ill patient
include all of the following EXCEPT:
A.
B.
C.
D.
A.
B.
C.
D.
A. Pharmacologic methods result in better outcomes than electrical
cardioversion
B. Electrical cardioversion should be first line therapy in the symptomatic, unstable patient
Hypertension
Age < 50
Diabetes
Vascular disease
20. All of the following are good first-line pharmacologic agents for treating
atrial fibrillation in the critically ill patient EXCEPT:
A.
B.
C.
D.
Diltiazem
Esmolol
Amiodarone
Digoxin
WITH NON-VITAMIN K ANTAGONIST ORAL ANTICOAGULANTS –
21. Which of the following is NOT an advantage of non-vitamin K antagonist
oral anticoagulants (NOACs) as compared with vitamin K antagonists
(VKA) such as warfarin?
A.
B.
C.
D.
Longer half-life
More predictable pharmacokinetics
Lower risk of intracranial bleeding
Fewer drug-drug and drug-diet interactions of clinical concern
22. The risk of which of the following major bleeding complications is higher
for dabigatran, rivaroxaban, and edoxaban than for VKA?
A.
B.
C.
D.
Intracranial
Intraocular
Retroperitoneal
Gastrointestina
23. Which of the following factors does NOT increase the risk of major
bleeding associated with any ongoing oral anticoagulation?
Advancing age
Chronic kidney disease
Increasing body weight
Concomitant dual antiplatelet therapy
24. Which of the following drugs is being investigated as a specific reversal
agent for the anti-Xa NOACs?
A.
B.
C.
D.
Increase in end-diastolic volume and stroke volume
Increased myocardial oxygen demand
Increased cardiac output
Bradycardia
18. Which of the following statements regarding cardioversion for atrial
fibrillation in the critically ill patient is TRUE?
52
19. Which of the following is NOT a component of the CHA2DS-VASc stroke
risk stratification score?
A.
B.
C.
D.
Hypokalemia
Hypotension
Seizures
Fluid overload
17. A physiologic response to atrial fibrillation in the critically ill patient
typically includes:
A.
B.
C.
D.
C. In the stable patient with atrial fibrillation for greater than 48 hours,
electrical cardioversion is safe
D. If cardioversion is successful, no subsequent anticoagulation is
necessary
Idarucizumab
Andexanet alfa
4-Factor prothrombin complex concentrate
Recombinant activated Factor VIIa
25. Which of the following is NOT true of idarucizumab as studied in REVERSE AD?
A.
B.
C.
D.
It effected prompt reversal of dabigatran’s anticoagulation effects
It was studied in hemorrhaging patients taking dabigatran
It was studied in pre-procedural patients taking dabigatran
It was not studied in patients with intracranial bleed or with other
high-mortality complications at presentation
THROMBOELASTOGRAPHY (TEG) – UNDERSTANDING THE
PATIENT’S ABILITY TO CLOT BLOOD – Jordan B. Bonomo, MD,
Natalie E. Krietzer, MD, and Christopher P. Zammit, MD
26. Thromboelastography (TEG) provides the clinician with insight into all of
the following components and settings of hemostasis, except:
A.
B.
C.
D.
Sluggish venous flow
Platelet activity
High shear stress
Fibrinolysis
27. A decreased maximum amplitude (MA) on TEG (or maximum clot firmness on ROTEM) may be the result of all of the following except:
A.
B.
C.
D.
Qualitative platelet defect
Tissue factor dysfunction
Fibrinogen deficiency
Factor XIII deficiency
28. In trauma patients, abnormal values recorded on the TEG are associated with increased mortality, even if other measures of coagulation are
normal (e.g., prothrombin time [PT], partial thromboplastin time [PTT],
international normalized ratio [INR], platelet count):
A. True
B. False
34. Based on the results of the ProCESS, ARISE and Promise Trials, the
Surviving Sepsis Guidelines regarding central venous pressure (CVP)
and central venous oxygen saturation (ScvO2) measurement were modified in which of the following ways?
A. CVP and Scv02 monitoring are now optional to assist in
resuscitation
B. CVP and Scv02 monitoring remain mandatory as part of bundled
therapy
C. CVP and Scv02 monitoring have been removed from the guidelines
due to futility
D. None of the above
35. In patients with severe sepsis and septic shock, early broad-spectrum
antibiotics and adequate source control have been shown to lead to
which of the following outcomes?
A.
B.
C.
D.
No change in outcomes, including mortality
Decreased mortality
Increased resistance with more complications
None of the above
CME POST-TEXT NEXT PAGE
→
29. Randomized control trials have definitively proven that TEG-guided
blood product administration in trauma patients reduces mortality.
A. True
B. False
30. TEG has been shown to objectively identify abnormal coagulation in
patients undergoing mild therapeutic hypothermia.
A. True
B. False
EMERGENCY DEPARTMENT AND INTENSIVE CARE UNIT –
Christopher M. Palmer, MD, and Trent C. Wray, MD
31. Which vasopressor is associated with increased arrhythmias in patients
with septic shock?
A.
B.
C.
D.
Norepinephrine
Phenylephrine
Dopamine
Vasopressin
32. Compared with normal saline, balanced intravenous fluids such as
Lactated Ringer’s are associated with which of the following?
A.
B.
C.
D.
Increased mortality
Decreased incidence of acute kidney injury
Increased incidence of hyperkalemia
Increased need for renal replacement therapy
33. In patients with septic shock, targeting a mean arterial pressure (MAP)
> 70 results in a decrease in mortality.
A. True
B. False
53
Notes:
54
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and Evaluation
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appropriate letter for each question on the CME ANSWER SHEET on this page
and complete the evaluation questionnaire.
CME Expiration Date: March 1, 2017
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56

CREG E CREG E - EMCREG

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