cardiovascular system assessment and multiple organ
TRANSCRIPT
CARDIOVASCULAR SYSTEM ASSESSMENT AND MULTIPLE ORGAN
DYSFUNCTION IN HORSES WITH ACUTE GASTROINTESTINAL DISEASE
by
ERIN LYNN MCCONACHIE
(Under the Direction of Michelle Henry Barton)
ABSTRACT
Acute gastrointestinal disease, or colic, is a common condition afflicting horses of
all ages, breeds and disciplines. Substantial morbidity and mortality for horses treated
surgically persists despite improvements in the management, diagnosis and surgical
correction of colic over the past few decades. While the causes for morbidity and
mortality are multifactorial, horses with clinical evidence of endotoxemia or the systemic
inflammatory response syndrome (SIRS) are at an increased risk for complications, such
as the development of the multiple organ dysfunction syndrome (MODS) and mortality.
The main objectives of the studies presented herein were to elucidate the role the
cardiovascular system plays in systemic inflammatory conditions, such as SIRS, in horses
with colic in the post-operative period and to develop criteria to describe MODS in
horses with colic. First, a non-invasive 2-Dimensional echocardiographic method for
cardiac output estimation was validated in healthy adult horses. This study revealed that
three 2-D echocardiographic methods had acceptable agreement with the reference
measurement. Second, heart rate variability (HRV) analysis was performed in the post-
operative period in horses with acute surgical colic and healthy horses that underwent an
elective procedure to assess the difference between HRV in these groups and a potential
association between HRV and survival. This study illustrated that horses with colic have
reduced HRV compared to healthy horses and that time domain measures of HRV were
associated with non-survival.
A multifaceted approach to cardiovascular system assessment, consisting of
hemodynamic monitoring, electrocardiography, and cardiac troponin (cTnI)
measurement, was then performed on healthy horses and those with acute surgical colic
to detect cardiovascular dysfunction. The results from this investigation demonstrated
cardiovascular system abnormalities in horses with colic, particularly those with ischemic
gastrointestinal lesions, characterized by reduced HRV, increased cTnI concentration,
reduced stroke volume index and increased frequency of pathologic arrhythmias. Finally,
through incorporation of what was discovered in the first three studies, a review of the
literature and the use of clinical judgment a scoring system for MODS in horses with
acute gastrointestinal disease was developed and validated.
INDEX WORDS: Equine, Critical illness, Colic, Cardiac output, Systemic
inflammatory response syndrome, MODS, Heart rate variability,
Echocardiography, Cardiac troponin
CARDIOVASCULAR SYSTEM ASSESSMENT AND MULTIPLE ORGAN
DYSFUNCTION IN HORSES WITH ACUTE GASTROINTESTINAL DISEASE
by
ERIN LYNN MCCONACHIE
BS, University of Connecticut, 2005
DVM, Oklahoma State University, 2009
A Dissertation Submitted to the Graduate Faculty of The University of Georgia in Partial
Fulfillment of the Requirements for the Degree
DOCTOR OF PHILOSOPHY
ATHENS, GEORGIA
2015
© 2015
Erin Lynn McConachie
All Rights Reserved
CARDIOVASCULAR SYSTEM ASSESSMENT AND MULTIPLE ORGAN
DYSFUNCTION IN HORSES WITH ACUTE GASTROINTESTINAL DISEASE
by
ERIN LYNN MCCONACHIE
Major Professor: Michelle Henry Barton Committee: Steeve Giguère Gregg Rapoport David J. Hurley Scott A. Brown Electronic Version Approved: Suzanne Barbour Dean of the Graduate School The University of Georgia August 2015
iv
DEDICATION
To my family and friends in Connecticut and Illinois who may not have always
understood exactly what it is that I am still doing at the University of Georgia, but have
supported and encouraged me nonetheless. To all of the horse owners that generously
allowed their horses to be enrolled in the studies that comprise this dissertation and to all
of the horses that allowed me to instrument them in the immediate post-operative period
when they must have been feeling their worst!
v
ACKNOWLEDGEMENTS
I am completely and truly grateful for the wisdom and guidance of my major
professor, Dr. Michelle Henry Barton, in both my professional career and in my life in
general. It was with extreme good fortune that my arrival as a Large Animal Internal
Medicine Resident coincided with Dr. Barton’s turn to take a new mentee under her
wing. Without her reassurance, patience and intuition I would not have accomplished a
fraction of what I accomplished during my five years as a resident and then doctoral
candidate at the University of Georgia.
I must give many thanks to Dr. Steeve Giguère for his encouragement, patience
and expertise in all aspects of my training and graduate work. Without his direction, high
standards and practical perspective the studies presented here would not be what they are.
I would also like to acknowledge the expertise, flexibility, support and
encouragement I have received from the rest of my committee members, Drs. Gregg
Rapoport, David Hurley and Scott Brown.
To my clinical mentors who have subsequently become some of my greatest
friends and supporters, Drs. Kelsey Hart, Kira Epstein and Amelia Woolums. Thank you
all for understanding the challenges of taking on graduate work while simultaneously
completing a residency training program.
To my resident-mates and house-officers past and present, particularly Lindsey
Boone, Brent Credille, Kevin and Kelley Claunch, Lisa Fultz and Harry Markwell; thank
you for not only helping me enroll cases over the past few years but for your friendship
vi
and support both in and out of the clinic. To all of the interns that helped me enroll cases
and prevented me from missing data collection points, particularly Amy Stieler, Amanda
Bergren, Jane Woodrow, Tara Shearer, Julia Miller and Jolie Demchur. Each of you went
above and beyond to help hold horses after hours for echocardiograms and assisted with
literally anything else that might have been needed to accomplish collecting a clinical
data set while I was being pulled in many different directions. I am indebted to you all for
your selfless assistance!
I am grateful for the support of my parents, grandparents and siblings as they have
encouraged me to follow my dreams even though it has taken me far from home for the
past 10 years. Their support and love knows no bounds. I also am extremely grateful for
Emma Finnegan, who came to be not only my roommate, but a kindred spirit and lifelong
friend over this final year of my doctoral candidacy. Without her, this year would have
been a struggle instead of the wonderful experience it was.
Finally, I am incredibly lucky to have my adoring and understanding husband,
Brian Beasley, who has tolerantly put up with living roughly 500 miles apart from each
other for the past few years. This endeavor wouldn’t have been worth undertaking if it
wasn’t for his love and unbelievably patient nature.
vii
TABLE OF CONTENTS
Page
ACKNOWLEDGEMENTS .................................................................................................v
CHAPTER
1 INTRODUCTION .............................................................................................1
2 LITERATURE REVIEW ..................................................................................4
SECTION I: IMPACT OF ACUTE GASTROINTESTINAL DISEASE IN
THE HORSE AND THE RATIONALE FOR THE STUDIES
PRESENTED HEREIN ...............................................................................4
SECTION II: PATHOPHYSIOLOGY OF THE SYSTEMIC
INFLAMMATORY RESPONSE SYNDROME AND MULTIPLE
ORGAN DYSFUNCTION………………………………………………. 6
SECTION III: PATHOPHYSIOLOGY OF CARDIOVASCULAR
DYSFUNCTION IN CRITICAL ILLNESS ..............................................12
SECTION IV: METHODOLOGY FOR CARDIOVASCULAR SYSTEM
ASSESSMENT IN ADULT HORSES ......................................................15
SECTION V: CURRENT EVIDENCE FOR MODS IN THE HORSE ...22
SECTION VI: THE DEVELOPMENT OF MULTIPLE ORGAN
DYSFUNCTION SCORES IN HUMANS AND SEVERITY SCORES IN
VETERINARY SPECIES .........................................................................31
REFERENCES ..........................................................................................35
viii
3 DOPPLER AND VOLUMETRIC ECHOCARDIOGRAPHIC METHODS
FOR CARDIAC OUTPUT MEASUREMENT IN STANDING ADULT
HORSES .........................................................................................................54
ABSTRACT ...............................................................................................55
INTRODUCTION .....................................................................................56
MATERIALS AND METHODS ...............................................................57
RESULTS ..................................................................................................63
DISCUSSION ............................................................................................65
FOOTNOTES ............................................................................................71
REFERENCES ..........................................................................................71
4 HEART RATE VARIABILITY IN HORSES WITH ACUTE
GASTROINTESTINAL DISEASE REQUIRING EXPLORATORY
LAPAROTOMY ..............................................................................................81
ABSTRACT ...............................................................................................82
INRODUCTION ........................................................................................83
MATERIALS AND METHODS ...............................................................85
RESULTS ..................................................................................................89
DISCUSSION ............................................................................................93
CONCLUSION ..........................................................................................99
FOOTNOTES ..........................................................................................100
REFERENCES ........................................................................................100
ix
5 ASSESSMENT OF THE CARDIOVASCULAR SYSTEM IN HORSES
WITH NATURALLY ACQUIRED ISCHEMIC INTESTNAL
DISEASE…………………………………………………………………...109
ABSTRACT .............................................................................................110
INRODUCTION ......................................................................................111
MATERIALS AND METHODS .............................................................113
RESULTS ................................................................................................120
DISCUSSION ..........................................................................................126
FOOTNOTES ..........................................................................................135
REFERENCES ........................................................................................136
6 A MULTIPLE ORGAN DYSFUNCTION SCORE FOR ADULT HORSES
WITH ACUTE GASTROINTESTINAL DISEASE .....................................151
ABSTRACT .............................................................................................152
INRODUCTION ......................................................................................153
MATERIALS AND METHODS .............................................................155
RESULTS ................................................................................................159
DISCUSSION ..........................................................................................162
FOOTNOTES ..........................................................................................167
REFERENCES ........................................................................................167
7 CONCLUSIONS............................................................................................182
REFERENCES ........................................................................................188
1
CHAPTER 1
INTRODUCTION
The purpose of the studies reported herein was to provide novel clinically relevant
information regarding the incidence and importance of the systemic inflammatory
response syndrome (SIRS) and cardiovascular system function in horses with naturally-
occurring acute gastrointestinal disease. Furthermore, criteria were proposed and
validated for assessing organ dysfunction in this population of horses expected to be at
high risk for the development of multiple organ dysfunction syndrome (MODS), filling a
gap in the current understanding of disease progression in critically ill horses.
Chapter 2 provides a comprehensive review of the literature and is organized into
six sections. Section I highlights the impact that colic has on the equine industry and
provides the rationale for performing the studies herein. Section II reviews current
concepts in the pathophysiology of SIRS and MODS and underscores the role of
endotoxin in triggering these syndromes. Endotoxemia is a commonly recognized sequela
in horses with acute gastrointestinal (GI) disease and provides a link between the current
understanding of the pathophysiology in humans and equids. Section III discusses the
pathophysiology of cardiovascular dysfunction in critical illness. Section IV reviews
studies on single organ dysfunction reported to date in critically ill horses; providing
evidence that MODS similar to that which is described in people may also exist in
critically ill horses. Section V describes the methodology employed for cardiovascular
monitoring in people and elaborates on current methodologies available to monitor the
2
cardiovascular system in adult horses. Finally, section VI describes the development of
organ dysfunction scoring systems for use in people with critical illness from a historical
perspective and compares these with severity scores thus far developed in adult horses
with acute colic.
Chapters 3 through 6 incorporate a series of manuscripts that provide the results
of the studies that are the core of this dissertation research. A validation study was
performed prior to the clinical research studies to evaluate the performance of
noninvasive echocardiographic methods of cardiac output measurement compared with
the currently accepted reference method, lithium dilution cardiac output measurement,
and is described in Chapter 3. Chapter 4 details heart rate variability (HRV) analysis in
horses with acute GI disease requiring exploratory laparotomy as compared to healthy
horses undergoing an elective surgical procedure affording a novel method for assessing
the cardiovascular system and uncovering the importance of the autonomic nervous
system in the post-operative period. Chapter 5 contains the results of a more
comprehensive assessment of the cardiovascular system in horses with naturally-
occurring acute gastrointestinal disease through comparison with healthy horses
undergoing elective surgical procedures and utilizes the cardiac biomarker, cardiac
troponin (cTnI), echocardiographic measures of cardiac output (from Chapter 3), central
venous pressure, noninvasive oscillometric mean arterial pressure, and HRV (from
Chapter 4) analysis. Finally, organ dysfunction criteria for eight organ systems for use in
a MODS scoring system in horses with acute GI disease are proposed, validated, and are
presented in Chapter 6.
3
Chapter 7 summarizes the conclusions that can be drawn from the research
presented herein and considers the clinical utility of the results drawn from this doctoral
dissertation.
4
CHAPTER 2
LITERATURE REVIEW
SECTION I. IMPACT OF ACUTE GASTROINTESTINAL DISEASE IN THE
HORSE AND THE RATIONALE FOR THE STUDIES PRESENTED HEREIN
The most common reason horses are presented to tertiary referral centers on an
emergency basis is pain associated with acute GI disease or colic.1,2 The 1998 USDA
National Animal Health Monitoring System study reported approximately 4.2 colic
episodes per 100 horses with an overall 11% mortality rate, costing the equine industry
over $115 million in losses annually.3 While the majority of horses that have colic are
treated medically, those that require surgical correction are at great risk for post-operative
morbidity and mortality related to but not limited to recurrent colic, thrombophlebitis,
ileus, surgical site infection, peritonitis, laminitis, and organ failure. The overall short-
term mortality rate of horses that have an exploratory celiotomy for surgical correction of
colic was recently reported to be 26% in one retrospective study at a referral hospital.2
Reported survival in horses following exploratory celiotomy for colic has ranged from
60-87%; however differences in case definition vary between studies. Specifically, in
horses with a large colon volvulus (a strangulating large intestinal lesion), reported rates
for survival to discharge and one and two years after discharge were 71%, 48% and 34%
respectively.4
In addition to the substantial mortality associated with colic, the long-term effects
of colic on intended use of the horse further impact the equine industry. As of a 2005
5
survey, there were an estimated 9.2 million horses in the United States.5 Approximately
37% of the equine population serves a purpose that requires them to retain a certain level
of athleticism.5,6 An additional 46% of horses in the United States are intended for
pleasure use which is invariably accompanied by an owner with a strong emotional bond.
A further 16% are used primarily for breeding and represent a subset with high economic
value. A recent retrospective study performed at North Carolina State University was
designed to provide objective data regarding the likelihood of horses to return to their
intended level of performance following exploratory celiotomy for colic.7 Sixty-eight
percent of horses returned to their previous level of performance by six months and 76%
of horses were performing for their originally intended use by one year post-operatively.
Factors related to inability to return to work by six months included in-hospital laminitis,
diarrhea, incisional hernia and history of previous celiotomy. Colic, therefore, continues
to be a frequently encountered clinical problem that is teeming with emotional, financial
and purpose driven decisions for the owner. While overall survival has improved over the
past 30 years a large number of horses continue to have post-operative complications that
are either life or career ending.
Attempts to reduce morbidity and mortality in horses with colic thus far have
been focused on improving resuscitation methods,8-10 general anesthetic practices and
surgical techniques11 with little attention given to post-operative monitoring and
treatment. Since the early 1990s, human physicians have been using clinical criteria
intended to identify patients with systemic manifestations of disease, as well as those at
risk of developing organ dysfunction upon development of acute critical illness.12
Versions of the clinical criteria used to define the systemic inflammatory response
6
syndrome (SIRS) in people have been adapted for use in the horse. In a recent clinical
study on large colon volvulus in horses, the most commonly reported cause of in-hospital
death/euthanasia (31%) was related to the development of SIRS, unrelenting pain or
colon necrosis.4 While SIRS was stated as the reason for euthanasia or death, it seems
unlikely that SIRS was the sole reason for euthanasia. Perhaps organ dysfunction
occurred in these patients but was not defined due to the current lack of criteria to
describe critical illness related organ dysfunction in horses. Through the development of
a scoring system for organ dysfunction in horses with colic, clinicians might be able to
detect horses in early stages of organ dysfunction prior to overt organ failure. Organ
dysfunction and in some instances, failure, can be reversible with appropriate
interventions. Through serial post-operative application of a scoring system for organ
failure, at risk horses will not only by identified earlier, but a validated score could serve
the clinician as an aid in directing and justifying therapy. Only then might there be an
objective measure to determine if goal-directed comprehensive monitoring and
therapeutic interventions are indeed beneficial to patient outcome. The aims of the next
few sections are to review the pathophysiology of SIRS and MODS and introduce
hemodynamic monitoring in the equine patient.
SECTION II. PATHOPHYSIOLOGY OF THE SYSTEMIC INFLAMMATORY
RESPONSE SYNDROME AND MULTIPLE ORGAN DYSFUNCTION
The innate immune system
The systemic inflammatory response syndrome is a clinical syndrome defined by
abnormalities in vital physiologic parameters (hypothermia or hyperthermia, tachycardia
7
and tachypnea) and/or a change in the total white blood cell count (leukocytosis,
leukopenia or a 10% or greater increase in band neutrophils). The presence of any two of
the above abnormalities in a patient fulfills the criteria for the clinical syndrome of
SIRS.12 Sepsis is differentiated from SIRS simply by the addition of the presence of a
confirmed infection.
When SIRS is recognized clinically, it should be assumed that there is either an
underlying infectious disease process or an abnormal response to a non-infectious
stimulus capable of initiating an immune response. Regardless of the underlying process
that initiated the innate immune response in patients with SIRS, the result is an
unbalanced activation of pro-inflammatory mediators on a systemic scale. Non-
infectious or ‘sterile’ inflammation is caused by tissue damage in the absence of a
pathogen. Examples of non-infectious inflammation include but are not limited to the
following; trauma, surgery, hemorrhage, burns, ischemia, immune mediated disease,
neoplasia and toxins.
The mechanism through which pathogens and products of damaged cells initiate
the immune response is similar. Ironically, in the valiant attempt to destroy the pathogen
and protect the body, the innate immune system can directly cause local tissue damage
and enhanced release of damage signals from the host tissues. Pattern recognition
receptors (PRRs) are stationed on the outer cell membrane or on nuclear or endosomal
membranes of immune cells, endothelial cells and parenchymal organ cells throughout
the body. The patterns recognized by these receptors are highly conserved molecular
regions of viral, bacterial, protozoal, fungal or parasitic pathogens and are collectively
referred to as pathogen associated molecular patterns (PAMPs). Similarly, there exists a
8
group of endogenously derived molecules; damage associated molecular patterns
(DAMPs) or alarmins that are recognized by PRRs when present aberrantly in the
extracellular fluid or within the cell. These molecules are typically constituents of normal
cells that are liberated as a consequence of cytokine signaling, cell membrane
permeability (injury or loss of electrochemical gradients) or necrosis. Examples of
DAMPs include heat shock proteins (HSP 70), high mobility group box-1 (HMGB-1),
adenosine triphosphate (ATP), mitochondrial DNA, histones and advanced glycation end
products.
While it is now generally accepted that cytokines with pro- and anti-inflammatory
activities are simultaneously expressed in response to tissue insult, the precise
relationship between the activation of these complementary cascades is not fully
understood in sepsis.13 Currently, the medical literature suggests that there is an equally
important syndrome of immunoparalysis or immunosuppression that might accompany
SIRS and sepsis at various stages which also contributes to mortality.14 Importantly, the
autonomic nervous system and adrenal glands both influence the inflammatory response;
with catecholamines from the sympathetic nervous system and adrenal medulla
promoting inflammation and cortisol from the adrenal cortex suppressing inflammation.15
Conceptually accepting SIRS to be the consequence of either a pro-inflammatory
‘cytokine-storm’ or a lack of the compensatory anti-inflammatory response syndrome or
the result of relative adrenal insufficiency is likely an oversimplification.
The concept of multiple, sequential, progressive organ failure in the trauma
patient was first suggested by Arthur Baue, a thoracic surgeon, in the early 1970s.16 Baue
thought of this syndrome as a consequence of modern medicine. The term multiple organ
9
dysfunction syndrome (MODS) has since been established and was first defined over 20
years ago by the American College of Chest Physicians to describe a continuum of organ
dysfunction that was clinically apparent in patients with trauma, surgery and sepsis.17
Importantly, the experts involved in the original definition of MODS recognized that
what they were observing in their patients was not an all-or-none phenomenon, but rather
a continuum of dysfunction. The multiple organ dysfunction syndrome was originally
defined as: “presence of altered dysfunction in an acutely ill patient such that homeostasis
cannot be maintained without intervention.”17 The recognition that MODS occurred on a
continuum was clinically meaningful because it implied that interventions could be
performed to halt or reverse progression before fulminant organ failure occurred.
The multiple organ dysfunction syndrome occurs as a consequence of protracted
SIRS, autonomic nervous system dysfunction, endothelial dysfunction, coagulopathy,
microvascular alterations, abnormal GI barrier function and abnormal cellular
metabolism (cytopathic hypoxia and mitochondrial failure) all of which culminate in
apoptosis or necrosis of the target organ that is well documented in the human
literature.15,18-22 A ‘second hit’ may also precede MODS, for example, in the trauma
patient in which acquisition of a nosocomial infection overwhelms the body’s ability to
maintain homeostasis and might lead to sequential organ dysfunction and failure. While
the pathophysiology of MODS is complex and multifactorial, the associated anatomical
and histopathologic abnormalities reported post-mortem are typically mild to moderate
and most often consistent with microcirculatory fibrin deposition, endothelial cell edema,
mitochondrial swelling, cytoplasmic or nuclear swelling, and in cardiomyocytes
contraction band formation and cellular necrosis.23,24 The clinical relevance of MODS is
10
highlighted by mortality rates that approach100% in people with multiple failed organs
(≥4) in the intensive care unit.25
Organ dysfunction scoring systems were first developed with the following goals
in mind: 1) to detect MODS at an early stage in the continuum of organ dysfunction such
that fulminant failure might be avoided with appropriate intervention, 2) to determine
what is the patient’s status along a continuum of dysfunction or disease severity, 3) to
determine the effects of novel interventions and medications and finally 4) to provide
prognostic information for individual patients.17
PAMPs associated with SIRS in horses with acute gastrointestinal disease
Endotoxin or lipopolysaccharide (LPS), the immunogenic component of the cell
membrane of Gram negative bacteria, is a classic example of a PAMP, which through
interaction with its PRR (TLR 4), co-receptor (CD-14) and co-stimulatory molecule
(MD2), produces a reliable cytokine profile (TNF- α, IL-1β, IL-6, IL-10) and
reproducible clinical signs (pyrexia, tachycardia, tachypnea, hypotension and abdominal
discomfort) in the horse. The mediators that are elaborated in response to interactions
between endotoxin and innate immune cells have been extensively studied in most
species in both clinical and experimental settings and are central to the current
understanding of the pathophysiology of SIRS and MODS. 26-29 Endotoxin is released
upon bacterial cell death or during logarithmic bacterial replication. Considering the vast
enteric flora of the horse, it is not surprising that the largest source of endogenous
endotoxin is that contained within the lumen of the GI tract. However, when the mucosa
is damaged by inflammation or ischemia, which frequently occurs with acute GI disease,
endotoxin can gain access to the systemic circulation where it interacts with PRRs.
11
Endotoxin can be found in the circulation and peritoneal fluid of horses with naturally-
occurring colic where plasma concentrations tend to correlate with increased
mortality.30,31 Endotoxin is not the only PAMP recognized in the pathophysiology of
equine SIRS. Other examples include: flagellin, peptidoglycan, lipoteichoic acid, double-
stranded viral RNA, and regions of unmethylated cpG DNA. The protein flagellin, a
component of flagellated bacteria (e.g. Salmonella sp.) and a PAMP, is reported to be
significantly increased in the systemic circulation of horses with acute GI disease
compared to healthy horses.32 In contrast to endotoxin which interacts with both
neutrophils and monocytes, flagellin solely induces a proinflammatory response in equine
neutrophils.33 The clinical significance of finding both of these PAMPs in the circulation
of horses with acute GI disease is that they provide evidence that mechanisms similar to
what are occurring in humans with sepsis also exist in equine colic.
SECTION III. PATHOPHYSIOLOGY OF CARDIOVASCULAR
DYSFUNCTION IN CRITICAL ILLNESS
Myocardial dysfunction in SIRS and sepsis
Discussion of the pathophysiology of cardiovascular system dysfunction in
critical illness provides an in-depth example of how SIRS and MODS affect individual
organs at a cellular level which ultimately impairs the ability of the organ to function
normally. Similarly to cells of the innate immune system, cardiomyocytes express PRRs
on the outer membrane, of which toll-like receptor 4 and 2 (TLR-4, TLR-2) remain the
best characterized, responding to circulating lipopolysaccharide and heat shock proteins,
respectively. When signal transduction occurs through these receptor mediated pathways
12
the response in the myocardium is most often NFκB activation which then signals gene
transcription and production of cytokines and other mediators such as inducible nitric
oxide synthase.34 Pro-inflammatory cytokines, specifically TNF-α, IL-1β and IL-6, alter
the normal function of the cardiomyocyte in sepsis resulting in clinically-recognized
myocardial depression.35 While there is not a universally accepted definition of
myocardial depression, reduced ejection fraction is the most commonly used clinical
correlate to describe the phenomenon.36 More recently other echocardiographic measures
of ventricular function have been used to describe myocardial depression including
reduced fractional shortening37 and diastolic dysfunction.35,38 Interestingly, in early study
of patients with septic shock, cardiac output was preserved or increased in all patients,
while survivors tended to have reduced ejection fractions and increased end-diastolic
volumes which suggested that there may be a protective role of myocardial depression.39
Proposed mechanisms of myocardial depression include cytokine mediated
negative inotropic effects36, abnormal calcium trafficking, increased nitric oxide
production from inducible nitric oxide synthase-2, mitochondrial dysfunction,
catecholamine toxicity, microcirculatory abnormalities and autonomic nervous system
dysfunction.23,35,36 While the regulatory protein, cTnI, is increased in septic patients with
myocardial depression, this does not appear to reflect widespread myocardial necrosis as
myocardial depression is reversible. In patients with acute myocardial infarct ischemic
injury can result first in membrane bleb formation40 which allows cTnI to leak out of the
cell prior to cellular necrosis. In contrast to patients with acute myocardial infarction and
eventual myocardial necrosis, patients with sepsis-related myocardial depression rarely
have evidence of necrosis, but may have inflammatory cell infiltrates, endothelial cell
13
edema, fibrin deposition in the microvasculature and mitochondrial swelling evident on
post-mortem examination.23,35 This reinforces the clinical impression that sepsis-induced
cardiac dysfunction can be fully reversible.
While myocardial depression may have evolved to decrease energy and oxygen
demands on the heart in states of severe disease, the consequence of reduced left
ventricular systolic function and in some cases reduced left ventricular diastolic function
owing to reduced ventricular compliance 38 impact the approach to therapy. Intravenous
fluid therapy administration is one of the mainstays of managing patients with SIRS,
sepsis and shock. Rapid and adequate restoration of circulating volume is one of the most
important interventions that can be applied to critically-ill patients and the benefits of
early volume replacement provide the evidence for the current recommendations in the
Surviving Sepsis Campaign.41 While, physiologic end-points for fluid resuscitation are
established in human patients, no such endpoints exist for the horse. The sequela of fluid
overload, particularly in patients with myocardial dysfunction, is an increased risk of
mortality.42
Role of the autonomic nervous system in cardiac dysfunction
In health, the sympathetic nervous system is responsible for accelerating heart rate
(positive chronotrope), maximizing contractility (positive inotropy), improving cardiac
relaxation (positive lusitropy), increasing the rate of conduction across the
atrioventricular node and causing vasoconstriction in venous capacitance and cutaneous
vessels.43 The complimentary branch of the autonomic nervous system, the
parasympathetic system, conversely causes a reduction in heart rate but has little to no
influence over contractility or ventricular relaxation owing to a difference in the
14
distribution of cholinergic nerve fibers compared to adrenergic fibers in the
myocardium.43 In critical illness, the autonomic nervous system, myocardial adrenergic
receptors, signal transduction pathways and ion channels in the cardiomyocyte are
susceptible to the effects of endotoxin and pro-inflammatory cytokines.44 These
molecules and mediators modulate efferent autonomic nervous system transduction at the
level of the brain45 but also manipulate the response at the level of the myocardium itself
through alterations in funny current ion channels (If) in the pacemaker cells which results
in narrowing of normal heart rate variability. Endotoxin is purported to cause “heart rate
stiffness” which manifests clinically as a state of unyielding tachycardia.44 Persistent,
inappropriate tachycardia is recognized as a feature of SIRS and MODS and is associated
with poor outcome. Tachycardia is detrimental to both the heart itself and the rest of the
body as it results in increased myocardial oxygen demand, restricts diastolic filling and
has the potential to result in cardiomyopathy.35
In summary, the effects of the innate immune system, changes in the peripheral
vasculature and autonomic nervous system result in a cardiac pump rendered ineffective,
poorly adaptive to changes in volume and pressure, and quite literally, marching to the
beat of its own drum. As one might expect, the implications of a dysfunctional cardiac
pump are far-reaching, affecting virtually every tissue bed and organ system. The
development of remote and sequential organ failure is not difficult to envision once the
heart ceases to function normally. The next section details how cardiovascular
dysfunction, as just discussed, might be assessed in horses.
15
SECTION IV: THE METHODOLOGY FOR ASSESSING THE
CARDIOVASCULAR SYSTEM IN THE ADULT HORSE
It should come as no surprise that clinical cardiovascular assessment is routinely
practiced and is standard of care in the human intensive care unit. While the continuous
measurement of heart rate (HR), mean arterial blood pressure (MAP) and oxygen
saturation by pulse oximetry (SpO2) have been standardly measured in all patients for
decades, these parameters do little on their own to drive decision making.46 In recent
years more sophisticated hemodynamic monitoring has become a mainstay, partially in
keeping with the monitoring necessary to determine end-points in goal directed therapy
which has gained universal support since the introduction and incorporation of the
recommendations derived in the Surviving Sepsis Campaign.47 In the contemporary
intensive care unit, hemodynamic monitoring is viewed as an important tool to both
identify and diagnose abnormalities associated with the underlying disease process as
well as a preemptive measure to detect potential abnormalities which allows intervention
prior to the onset of complications.48
Cardiac output estimation is the best available variable to assess overall
cardiovascular function.49 Cardiac output (CO), the product of heart rate and stroke
volume, is altered more quickly and to a greater capacity by changes in heart rate
compared to stroke volume. Cardiac output measurement, historically estimated via
thermodilution with a pulmonary arterial catheter, and more recently with peripheral
arterial catheterization for lithium dilution or with non-invasive echocardiography, is the
cornerstone for recognizing cardiovascular insufficiency and monitoring the response to
therapy in critically ill patients.41 Echocardiography offers advantages over both
16
thermodilution and lithium dilution and has become a widely accepted bed-side
procedure. In addition to providing a non-invasive estimate of CO, it is useful in the
assessment of various cardiac conditions and provides as assessment of left ventricular
systolic and diastolic function.48,50 Recent appraisals for hemodynamic monitoring in the
ICU favor an integrative approach, recognizing that monitoring one aspect of
cardiovascular system status conveys only one piece of the puzzle.48 The emphasis is
placed on cost-effective, non-invasive strategies in human hospitals and the same should
be sought for veterinary species.
Cardiovascular perturbations are often clinically apparent in horses with acute GI
disease and generally manifest as tachycardia with an increased incidence of ectopic
beats; the basis for these cardiac abnormalities are not well understood and are often
interpreted as evidence of pain, hypovolemia and SIRS. In order to understand the
meaning of persistent tachycardia and ectopic foci in the post-operative colic patient, an
in-depth and multifaceted approach must be adopted to understand how the heart is
functioning in relation to the rest of the organ systems. Tachycardia is a physiologic
response to hypovolemia, fever, pain and anemia. However, when tachycardia persists in
the face of restoration of intravascular volume, normothermia, amelioration of pain, or
correction of anemia, the physiologic state becomes pathologic and potentially harmful.
Methods for monitoring cardiovascular system status in horses have for the most part
been validated and utilized under resting, exercising or general anesthetic conditions.
Few studies have reported on the application of cardiovascular monitoring techniques in
critically ill adult horses. Measurement of CO perhaps best illustrates this deficit in
equine practice. Investigators have been interested in studying CO techniques in adult
17
horses for decades, mostly in the capacity of improving hemodynamics under general
anesthesia51,52 and understanding exercise physiology.53,54 Currently validated methods of
cardiac output measurement in horses include various indicator techniques
(thermodilution and lithium dilution) based on the Frick principle and Doppler
echocardiographic techniques.55 Applying any of the validated techniques to horses in a
clinical setting is wrought with limitations. For the indicator techniques, invasive
pulmonary or peripheral arterial catheterization is required. Ideally these catheters would
be maintained indwelling for continuous or serial measurement however, both of these
techniques have the potential for life threatening complications. The use of the
pulmonary arterial catheter has been shown to cause endocardial damage in horses,56
while potential risks of arterial catheterization include inadvertent arterial administration
of drugs or air into the arterial circulation which can have devastating consequences.
While Doppler echocardiographic techniques are noninvasive they require accurate
alignment with blood flow which is not always feasible in horses of all breeds and body
condition scores. Doppler echocardiographic techniques in general are more variable
between days and echocardiographers than 2-dimensional and M-mode
echocardiography.57 Both of these short-comings of Doppler echocardiography highlight
the need for a simpler, repeatable, reliable method of measurement of CO in horses for
routine clinical assessment. In anesthetized foals58, volumetric methods for determining
CO have been validated. These methods generally require standard views of the left
ventricle to obtain measurements of length and area that can then be incorporated into
mathematical equations that account for the shape of the ventricle. In anesthetized foals
the Bullet method had the best agreement with lithium dilution CO.58 However, this
18
finding cannot be directly extrapolated to adult horses owing to major disparities in
cardiac chamber size and the inability to obtain an apical view in the adult horse. To
reiterate, measuring CO in horses in a clinical setting, particularly with echocardiography
would provide clinically useful information related to overall cardiovascular function,
volume status, and with the knowledge of the arterial oxygen content, would enable
oxygen delivery (DO2) to the tissues to be calculated. Thus determining which
echocardiographic method of CO measurement in horses is most closely correlated with a
“gold standard” measurement of CO, lithium dilution, is investigated in Chapter 2 of this
dissertation.
Cardiac troponin (cTnI)
Despite the lack of data to objectively confirm hemodynamic disturbances in
horses with acute GI disease, such disturbances appear to be frequently encountered in
clinical patients. There is a widespread clinical impression that some horses with
strangulating GI lesions have evidence of cardiovascular shock59 and cardiac
arrhythmias60 following colic surgery. This impression has led researchers to evaluate the
cardiac biomarker, cTnI,61 or cTnI plus assessment of arrhythmias62 and functional
abnormalities based on echocardiography.63 While these studies provided convincing
evidence of myocardial injury and an association between increased cTnI concentrations,
the severity of the GI lesion and survival, dysfunction of the cardiovascular system was
not demonstrated. Therefore, a significant gap remains in interpreting the significance of
cTnI concentration in horses with colic.
In critically ill humans, multiple cardiac biomarkers (cTnT, cTnI, NT-proBNP)
have been correlated not only to mortality but to echocardiographic measures of cardiac
19
dysfunction.64,65 Cardiac troponin I is a regulatory protein of the thin actin filaments of
cardiac muscle that is released into the circulation as a result of acute myocardial cell
injury.66 It is a highly sensitive and specific biomarker of myocardial health. Despite its
excellent sensitivity and specificity to the heart, its utility in people is somewhat hindered
by the high incidence of acute coronary syndrome which also causes a dramatic increase
in serum troponin. Coronary heart disease is exceptionally rare in the horse, perhaps
making it an ideal biomarker of cardiac damage in critical illness. The association
between cardiac biomarkers in horses with acute GI disease and cardiac dysfunction
warrants further investigation and is a component of the studies presented herein.
Left ventricular function
While CO measurement provides one method of assessing ventricular function it
provides little information related to contractility.67 Fractional shortening (FS) and
ejection fraction are the primary methods for assessing contractility or inotropy, an
inherent characteristic of left ventricular function. Fractional shortening, the measure of
contractility most commonly used in horses, is an M-mode derived measurement of the
difference of left ventricular volume in end diastole and end systole relative to the left
ventricular end diastolic volume FS= [(LVIDd-LVIDs)/LVIDd] X 100.68 Nath and
colleagues assessed FS post-operatively in horses with acute GI disease and found no
significant differences in FS between horses with surgical colic, medical colic or control
horses.63 However, not every horse underwent echocardiography so the lack of a
statistical difference may have been attributable to a lack of power. More recently, left
ventricular systolic and diastolic dysfunction was reported in a group of horses with acute
colic and SIRS. 69 In this study, non-surviving horses had lower left ventricular stroke
20
volume index and higher pre-ejection period to ejection time ratio (PEP/ET) of Doppler
aortic flow as evidence of systolic dysfunction. The same horses also exhibited higher
peak early diastolic filling velocity to peak early diastolic myocardial velocity ratio
(E/Em), suggesting diastolic dysfunction. The evidence for both systolic and diastolic
dysfunction in horses with SIRS is consistent with the clinical picture of septic
cardiomyopathy in people.35,38
Mean arterial pressure (MAP), Central venous pressure (CVP) and Pressure
adjusted heart rate (PAR)
Mean arterial pressure may be measured in adult horses with indirect or direct
methods. Indirect oscillometric methods are clinically accepted, although few individual
units have been critically assessed in the horse. The optimal site for measurement is the
tail head (coccygeal artery) and the importance of proper cuff circumference is
highlighted in the literature.70,71 Mean arterial pressure (MAP) provides a way to estimate
systemic vascular resistance when CO and CVP are known. Measuring MAP alone is
insufficient for global hemodynamic assessment.
The measurement of CVP has been described in horses in mostly research
applications72 and provides an estimate of preload in humans. While CVP estimation in
horses seems to be responsive to acute fluid loss and replacement73 a systematic review
of the literature in people concluded that CVP should not be used to guide clinical
decision making for fluid therapy because of its inability to detect a response to fluid
challenge.74 Despite the results of the 2008 meta-analysis, CVP has been retained as an
end-point of early-goal-directed therapy in the Surviving Sepsis Campaign.47 In adult
horses, it is important to note that the reliability and reproducibility of CVP
21
measurements are dependent on maintaining a neutral head position.75
In adult horses with naturally occurring colic, systemic hypotension occurs in
horses in the later phases of endotoxemia due to decreased systemic vascular resistance in
response to prostaglandin release.76 Hypotension, need for inotrope support and increased
plasma lactate concentration are frequently reported descriptors of circulatory failure in
critically ill humans.66 Correlation of hypotension with death in human patients was the
rationale for its inclusion in the Sequential Organ Failure Assessment (SOFA) score, used
for clinical diagnosis for MODS.ref Mean arterial blood pressure values are typically at
their worst prior to therapeutic intervention. Changes in blood pressure are highly
susceptible to transient changes in fluid therapy or inotrope support, thus, it is argued that
blood pressure is a treatment-dependent variable that does not reflect the entire spectrum
of cardiac function. From this argument, a composite measure, called pressure-adjusted
heart rate (PAR) that corrects for physiologic support by calculation of the product of the
heart rate by the ratio of the CVP to MAP was introduced. This variable has shown
incremental correlation with ICU mortality in people and is thus included in another
commonly used scoring system for organ dysfunction, the MODS score.77 The use of
PAR has not been evaluated in the horse and is investigated in Chapter 5.
Heart rate variability
Autonomic dysfunction is an important aspect of the pathogenesis of myocardial
depression in sepsis. Analysis of heart rate variability (HRV) provides a method to
estimate autonomic modulation of the heart. The HRV describes both short-term
variations between consecutive heart beats and long-term variations in cardiac cyclical
activity providing a valuable tool to characterize the influences of the sympathetic and
22
parasympathetic nervous systems on the sinoatrial node.78 In general, decreases in HRV
variables reflect a shift toward sympathetic dominance. There are numerous HRV
parameters that can be easily determined using specifically designed software that
integrates and interprets digitally stored telemetric electrocardiography data. Several
studies of HRV have been performed in the horse under various conditions including
transport, laminitis, and pregnancy and have demonstrated correlation of HRV to other
measures of stress and reduced vagal tone, such as serum cortisol concentration.79-82
With the ease of obtaining HRV data and its excellent correlation to measures of
cardiovascular health, MODS, and outcome in critically ill people in which acute
coronary disease is not the primary disease process,79,83-86 it appears to be an ideal
parameter to monitor in critically ill patients. To further advance emergency and critical
care of horses, it will be increasingly important to identify specific and sensitive
indicators of subclinical organ dysfunction, including myocardial damage. The HRV in
horses with acute GI disease is investigated herein and presented in Chapter 4.
SECTION V: CURRENT EVIDENCE FOR MODS IN THE HORSE
In the horse, acute GI disease or ‘colic’ is caused by a spectrum of physiologic,
anatomic or inflammatory abnormalities that are manifested by clinical and
clinicopathological disturbances that are most often non-specific but in some cases may
reflect the severity or duration of the insult. Among the most severe of the acute GI
diseases are those that result in strangulating or ischemic lesions of the intestine. Both the
small and large intestine can become strangulated and are at risk of necrosis of one or
more layers of the intestinal wall; usually beginning with the loss of the luminal mucosal
23
layer. Untreated, this leads to GI perforation, septic peritonitis and death. Theoretically,
horses that have mechanical GI obstructions that culminate in severe distension and
certainly those with inflammatory conditions such as enteritis or colitis, also may have
disturbances in the mucosal barrier. A breach of the mucosal barrier not only allows
translocation of bacterial products but also implies there has been architectural disruption
and loss of enterocytes (necrosis or apoptosis). This in turn results in leakage of alarmins
from damaged or necrotic cells. Indeed, as mentioned previously, circulating endotoxin
(and probably other bacterial components e.g. flagellin) are present in the plasma of some
horses that present with acute colic and are associated with increased risk of death.31,87
As mentioned previously, the most common reason for referral of horses to
tertiary care centers on an emergency basis is naturally-acquired GI disease or colic.1 In
a study by Epstein and colleagues, 27/95 (28.4%) horses that presented for acute GI
disease fulfilled the criteria for SIRS.88 Our current understanding of the pathophysiology
of MODS suggests that SIRS predisposes to MODS which highlights the need to
investigate MODS in horses. While the majority of horses that have colic are treated
medically, those that require surgical intervention are often faced with post-operative
morbidity and mortality that may or may not be related to the surgical procedure and
include but are not limited to ileus, recurrent colic, surgical site infection, and rarely
septic peritonitis. Less commonly reported are dysfunctions in whole body metabolism,
organs (liver, kidney) and systems (respiratory, endocrine, musculoskeletal and
cardiovascular). The remainder of this section will provide data that supports organ
dysfunction in horses with colic.
24
Respiratory system
Post-operative complications in horses related to the respiratory tract include
pulmonary edema, aspiration pneumonia, hematogenous pneumonia, pleuropneumonia
and pulmonary thromboembolism.89-91 Aspiration pneumonia was a reported
complication in 6.8 % of horses with enteritis undergoing exploratory laparotomy.92
Experimentally TLR-4 activation via endotoxin induces inflammation and increased
pulmonary vascular permeability in mice and in horses.93-95 Under the proper set of
circumstances any one of the above mentioned post-operative complications could result
in respiratory distress due to pulmonary dysfunction. This phenomenon is best described
in adult horses by the syndromes of acute lung injury and acute respiratory distress
syndrome which are clinical manifestations of acute severe lung disease.96 The incidence
of acute lung injury and acute respiratory distress syndrome in adult horses with acute GI
disease is currently unknown. The pathogenesis of pneumonia related to acute GI disease
may be secondary to aspiration of gastric contents under general anesthesia, iatrogenic
administration of fluids or therapies from nasogastric intubation, ventilator injury, SIRS
or hematogenous seeding of enteric bacteria into the pulmonary tree.
Renal
Acute kidney injury is common in humans with severe SIRS, sepsis and
MODS.97,98 and has been documented with some frequency (11%) in septic dogs.99
Azotemia is a common admission finding for horses that present with GI disease and is
considered an independent risk factor for survival in horses with strangulating small
intestinal lesions.100 In a retrospective study examining horses that presented to a tertiary
referral center for acute GI disease, the incidence of azotemia at presentation, defined as a
25
serum creatinine concentration > 3 mg/dL, was 7.9% (79/1000 horses) with persistent
azotemia (> 72 hours duration) occurring in 2.6% (26/1000) of horses. The
pathophysiology for renal injury in horses with acute GI disease is multifactorial, and
pre-renal azotemia was proposed as the cause of azotemia at admission in the majority of
the horses examined. However, almost 3% of the horses had persistent azotemia which
suggests intrinsic renal dysfunction. The finding that horses with persistent azotemia
were three times as likely to die or be euthanized compared to those with azotemia that
resolved by 72 hours supports this assumption.101 At the time of examination, horses with
acute GI disease are often hypovolemic which results in reduced renal perfusion. This is
further complicated by the routine use of nephrotoxic drugs in equine practice, such as
flunixin meglumine and gentamicin. However, the pathogenesis of renal injury in sepsis
is complex. A cecal-ligation and puncture model of polymicrobial sepsis in mice
demonstrated the role of signaling through MyD88 (myeloid differentiation factor 88) in
the pathogenesis of acute kidney injury in sepsis whereby knockout MyD88 -/- mice had
improved survival, complete protection of renal tubular cells with absence of acute
tubular necrosis, maintained vascular permeability similar to that of controls and had
decreased migration of neutrophils into renal tissue.102
Coagulopathy
Reports of hemostatic dysfunction in horses with acute GI disease are
commonplace in the equine literature, while clinical manifestations of coagulopathy are
less common.88,103-105 The coagulopathy in horses with acute GI disease is believed to
involve activation of tissue factor on blood monocytes and the endothelium that occurs in
response to pro-inflammatory cytokines.106 Prolongation in prothrombin time occurs in
26
horses with colic and this finding is correlated with mortality.107 At admission for colic,
prolongation of prothrombin time, activated partial thromboplastin time and
thrombocytopenia occurs in approximately 25-80%, 43-100% and 29% of horses
respectively, presented for colic.103,107-109 The prevalence of clinicopathologic
coagulopathy is not surprising since hemostasis is part of the defense mechanism of the
host and its activation is intimately linked with the inflammatory response. However,
pathologic sequelae of coagulopathy exist, as evidenced by the finding of microvascular
thrombi in the tissues of foals with organ failure and sepsis110 and adult horses with
severe GI disease.111
Gastrointestinal
Gastrointestinal dysfunction is common in critically-ill horses and in fact acute GI
disease is often the cause of hospitalization.1 Post-operative ileus, is second only to post-
operative pain, as the most commonly reported short-term GI related complication in
horses that undergo exploratory laparotomy.59 The GI tract was not included in human
scoring systems for MODS because of the observation that it was difficult to find an
objective measure of GI function.112 The pathophysiology of ileus is complex and
multifactorial. At present the development of nasogastric reflux is typically the sole
criteria used to define ileus which may be misleading and result in over-diagnosis in
horses. This is because nasogastric reflux also occurs as a result of other conditions such
as enteritis or complete or partial mechanical obstruction of the small intestine.113,114
Despite these concerns, post-operative ileus continues to be defined based on the
presence of nasogastric reflux. In a recent survey of Diplomates of the European Colleges
of Veterinary Internal Medicine and Veterinary Surgeons, post-operative ileus was most
27
often defined in practice as the presence of any nasogastric reflux in the post-operative
period, however, many responses also included specific volumes that they regarded as
significant.115 Other reports have included even more stringent definitions including >8L
at any one intubation or > 20 L in a 24 hour period.116,117 Large intestinal ileus occurs as
well, but presents an even greater challenge to define in the horse. Large intestinal ileus
might be suspected upon palpation per rectum, absence of GI sounds, gross abdominal
distension, or transabdominal ultrasonographic findings that rule out other causes of
distension.
Hepatic
Measurement of serum bile acid (SBA) concentrations is considered a test of
hepatic function, in contrast to measurement of liver-specific enzyme activities. In the
horse, unlike total bilirubin, SBA are not affected by short-term fasting but will increase
after prolonged fasts of at least 3 days.118 SBA concentrations have been evaluated in
horses with acute naturally-occurring GI disease and markedly increased admission SBAs
were associated with non-survival.119 Plasma ammonia concentrations, while also a
measure of hepatic function, are a less attractive candidate as a criterion of liver
dysfunction since they require special handling and immediate measurement. In one
study in horses with colic, plasma ammonia concentration was normal in all but two
horses, in which it was mildly increased. No association was detected for plasma
ammonia concentration and survival.119 In addition, intestinal hyperammonemia occurs
despite a functional liver, making it non-specific for liver function in horses with GI
disease.120
28
Neurologic/Mentation
In the human MODS and SOFA score, the Glasgow Coma Scale is used for the
evaluation of neurologic function. Developed by Teasdale and colleagues in 1974, the
Glasgow Coma Scale assesses eye, verbal and motor responses on a scale from a fully
awake, aware person to a person in a comatose state.121 Unfortunately the Glasgow Coma
Scale is inappropriate for equine patients due to the lack of the verbal component and the
inability to perform repeatable provocative testing to assess pain responses. In addition,
the scale was originally developed for head trauma patients, and while found to be
applicable to critically ill human patients, the scale in many ways is inappropriate for
equine patients. In the literature, there are few clinical reports of neurologic evaluation or
neurologic dysfunction in horses with colic. By far, reports of neurologic signs related to
intestinal hyperammonemia predominate.120,122 While the majority of the horses
presented in the case series have inflammatory gastrointestinal lesions such as colitis or
enteritis, horses with medically and surgically treated colic were also represented. The
main clinical signs associated with hyperammonemia in these cases were depressed
mentation, head pressing, ataxia, central blindness and erratic behavior.120 In large animal
species, demeanor, and in particular clinical signs of depressed mentation, are among the
most commonly encountered evidence of abnormal neurologic function. In fact,
demeanor and posture correlate well to strong ion gap and degree of D-lactic acidosis in
calves with diarrhea123,124 while in horses with experimentally induced SIRS depression
is one of the most consistent clinical signs reported.125,126 Therefore, in critically ill
animals assessing general demeanor and behavior might provide useful information
related to neurologic function. A behavior or posture assessment might be a useful
29
alternative to a complete neurologic evaluation when attempting to determine neurologic
function related to systemic inflammation. A numerical rating scale of behavior was
previously described and applied to horses recovering from exploratory laparotomy and
not only provides a way to assess pain behaviors but also specifically rates behavior and
posture which reflect the degree of the animals awareness to their surroundings.127 While
the limitations of this scale are the lack of specific neurologic deficits such as ataxia,
cranial nerve signs or seizure like activity, the score would indirectly reflect the more
subtle changes in mentation and certainly would account for abnormal responses to
external stimuli which would coincide with seizure like activity or central blindness.
Musculoskeletal
In horses, normal musculoskeletal function is vital. The development of laminitis
and muscle injury have been the subjects of investigation in horses with acute GI disease.
Despite the fact that the pathophysiology of laminitis remains incompletely understood,
the majority of what is known is based on models that induce severe systemic
inflammation through carbohydrate overload in the GI tract.128 Experimental endotoxin
infusion129,130 fails to cause complete lamellar failure leading to studies of other factors as
possible initiators. 131,132 While the incidence of laminitis in the post-operative period
appears low, ranging between 0.4% and 3%,7,59,88 endotoxemia was shown to be a risk
factor for laminitis in horses presented to referral centers in which horses with clinical
and laboratory evidence of endotoxemia had a 5-fold increased risk of developing acute
laminitis.133 Despite the low incidence of horses developing laminitis in the post-
operative period, this complication has profound implications for an individual horse as it
often at least career ending or results in euthanasia.
30
Krueger and colleagues evaluated the clinical utility of muscle enzyme activity in
horses that presented for acute colic and found that increased activity of creatine kinase
(CK) was associated with GI lesion type and outcome.134 This group found that horses
with a CK of > 470 U/L at hospital admission were at a 2.4-times increased risk of not
surviving to hospital discharge and were 2.6-times more likely to be diagnosed with a
strangulating intestinal lesion. In addition, they proposed that the increase in CK activity
may in part be due to endotoxin-mediated injury and might merely reflect muscle damage
from the trauma associated with colicky behavior, intramuscular injections or transport.
This notion is supported by a single case series in the literature that describes
myonecrosis in horses with colic not directly related to trauma.135 Despite an unclear
underlying pathophysiology, both laminitis and increased CK activity are associated with
poor outcomes in horses with acute surgical colic.
Cardiovascular System
The cardiovascular system was discussed in detail previously. In general, the
most commonly reported cardiovascular abnormalities in horses with acute GI disease
include tachycardia, increased hematocrit and abnormal mucous membranes (color,
capillary refill time)136-138 which taken together indicate hemoconcentration, hypovolemia
and perfusion deficits. The short-comings of using the above criteria for assessment of
the status of the cardiovascular system include the co-existence of many additional
factors that influence the heart rate (e.g. underlying cardiac disease, pain, stress, anemia,
inflammation, drugs) and hematocrit (e.g. splenic contraction, blood loss, anemia, breed,
sex, age, underlying chronic disease) beside hypovolemia and the subjective nature of
examining the oral mucous membranes. As previously mentioned there are more
31
sophisticated, non-invasive methods that would provide specific information regarding
cardiovascular function, these being echocardiography, electrocardiography and cTnI
measurement.
SECTION VI: THE DEVELOPMENT OF MULTIPLE ORGAN DYSFUNCTION
SCORES IN HUMANS AND SEVERITY SCORES IN VETERINARY SPECIES
In the last 30 years, critical illness severity scores have been introduced into
intensive care units with the intended purpose of providing a method to determine illness
severity and the associated risk of mortality.139 Organ failure scores, on the other hand
were designed to describe the degree of organ dysfunction rather than predict survival.139
By design, organ dysfunction scores reflect a continuum of organ performance from
functional to failure based on serial assessment of clinical and laboratory data. The
scoring systems for organ dysfunction assess multiple organs systems, in human
medicine, the cardiovascular, renal, hepatic, neurologic, hemostatic, and respiratory
systems comprise the score. Within each organ or system, specific functional criteria are
weighted in order to establish a score that can accurately reflect a range of dysfunction.
Scoring individual patients provides an estimate of organ dysfunction severity that can be
continually reassessed throughout hospitalization, enabling the physician to monitor
response to therapy. While not designed to predict survival, the MODS score devleloped
by Marshall and colleagues in 1994 does correlate with outcome.112
In order to develop organ dysfunction scoring systems various approaches were
taken to identify the best criteria to describe dysfunction in a given organ system. First,
the criteria for an ideal descriptor of organ dysfunction were decided upon with the
32
following characteristics in mind: organ function descriptors must represent an organ
system on a continuum from functional to insufficient to failure that accurately represents
the clinical syndrome, they must be easily and readily measured in a heterogenous group
of patients and they must be reproducible and responsive to clinically significant changes
in patient status.112,140 Marshall and colleagues112 selected criteria for each organ system
based on a literature review and patient data from a surgical ICU. In contrast, the sepsis
related organ failure assessment (SOFA) score relied upon empirical selection of criteria
by a panel of experts in the European Society of Critical Care Medicine.140 A third score,
the logistic organ dysfunction score (LODS), which assigns weights to the different organ
systems, was developed from multiple logistic regression analysis which selected
variables based on a large patient data base from 137 ICUs in several countries.141 Once
developed, all three scoring systems were validated prospectively on patients in the
surgical112 or both the surgical or medical ICU142 and overtime have been validated in
numerous groups of patients.143-148 Evaluation of these scores over the last couple of
decades has repeatedly demonstrated no significant differences compared to updated
physiologic based severity scores (Acute Physiology and Chronic Health Evaluation,
APACHE III) in predicting outcome in critically-ill patients. While not the original
intended purpose of the scores, their utility seems to extend beyond determination of
organ severity.149-151
In horses, a validated scoring system does not exist for describing organ
dysfunction. Proposed criteria have been published in text books but are largely
extrapolated from criteria used in the human SOFA and MODS scores.152 Extrapolation
from human criteria poses potential problems related to differences in physiology (e.g.,
33
bilirubin is used as a criterion for liver dysfunction in humans while this is increased in
fasting horses with normal liver function), primary disease processes (e.g., sepsis in
humans versus colic in horses) and treatment modalities (e.g., many human patients are
on ventilator therapy whereas adult horses are not). There have been attempts to develop
severity scores for horses.138,153 The colic severity score proposed by Furr and colleagues
was modeled after the original APACHE severity score for critically ill human patients,
with the intention of providing a simple score that could predict outcome in horses with
colic, reflect the severity of the horse’s condition and serve as a management tool for
equine clinicians.138 Data was collected prospectively at admission from horses with colic
and a logistic regression model was used to identify the variables with the greatest
association with outcome. Cut-points for these variables were then established and given
a designated score from 0 to 4. The variables that were retained for the colic severity
score included pulse rate, peritoneal total protein concentration, blood lactate
concentration and mucous membrane appearance. The score was then validated
prospectively with a group of 71 horses that presented for colic. A score of ≤ 7 was
predictive of survival while a score of ≥ 8 was predictive of death. This score did not gain
clinical acceptance and while it had excellent positive predictive value (100%) the
negative predictive value was 91% which meant that some horses predicted to live would
die. A similar attempt was made by Grulke and colleagues, however they developed both
a ‘gravity score’ and ‘shock score’ which were meant to reflect the type and severity of
the GI lesion (based on rectal palpation, abdominal distension, borborygmi, and pain) and
the severity of hemodynamic compromise (based on HR, RR, systolic arterial pressure,
packed cell volume, blood lactate, and blood urea nitrogen concentration) respectively.153
34
Interestingly, the overall survival rate in their study was 54% which is much lower than
overall colic survival rates reported more recently.154 The utility of both of these scoring
systems are questioned. Aggressive management in horses with hemodynamic instability,
improved surgical techniques and changes in medical treatment in horses with colic have
been credited with declining mortality rates. Therefore, many of the variables utilized in
the above scoring systems that reflect cardiovascular compromise at admission are
unlikely to provide accurate prognostic data in the contemporary equine ICU. As an
example, admission heart rate, a variable included in the colic severity score and shock
score, is a parameter that routinely is cited as a poor prognostic indicator in horses with
colic137 yet it is rarely retained in logistic regression models that predict outcome.155,156
Potential reasons for this are the numerous causes of tachycardia including pain,
hypovolemia, excitement, inflammation and primary cardiac disease.
The syndrome of MODS is recognized clinically in horses,69,157 however
appropriate criteria to describe this clinical phenomenon are lacking. In the absence of a
method to detect a clinical range of organ dysfunction in critically-ill equine patients,
clinicians and researchers alike are at an impasse when it comes to improving outcome in
post-operative and critically-ill equine cases. Similar to what was observed by Baue, who
recognized MODS as a consequence of the advances of medical care in people in the
early 1970’s,16 veterinarians are now faced with similar challenges related to organ
dysfunction in equine patients that would not have survived 20 years ago. Chapter 6
provides an approach to describe MODS in horses with acute GI disease.
35
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54
CHAPTER 3
DOPPLER AND VOLUMETRIC ECHOCARDIOGRAPHIC METHODS FOR
CARDIAC OUTPUT MEASUREMENT IN STANDING ADULT HORSES1
_________________________
1 E.L. McConachie, M.H. Barton, G. Rapoport, S. Giguère. 2013. Journal of Veterinary
Internal Medicine. (27): 324-330.
Reprinted here with permission of the publisher
55
ABSTRACT
Background: Cardiac output (CO) is not routinely measured in critically ill adult horses
due to invasiveness of currently validated methods. Non-invasive CO monitoring would
complement clinical assessment of hemodynamic status in adult horses.
Hypothesis: Volumetric methods for measuring CO will have better agreement with
lithium dilution than Doppler-based methods.
Animals: Eight healthy adult horses
Methods: CO was manipulated from baseline with continuous rate infusions of
dobutamine and romifidine to achieve high and low CO states, respectively. At each
level, CO was measured by lithium dilution and various echocardiographic methods.
Images stored as video loops were reviewed by an individual blinded to the lithium
dilution results.
Results: Lithium dilution determinations of CO ranged between 16.6 and 63.0 L/min.
There was a significant effect of method of CO measurement (P < 0.001) but no
significant effect of CO level (P = 0.089) or interaction between level and method (P =
0.607) on the absolute value of the bias. The absolute values of the bias of the right
ventricular outflow tract (RVOT) Doppler, Simpson, 4-chamber area-length, and bullet
methods [5.5, 6.1, 6.5, 8.8 L/min, respectively] were significantly lower than that of the
left ventricular outflow tract (LVOT) Doppler or cubic methods [14.8, 24.3 L/min,
respectively].
Conclusions and clinical importance: The 4-chamber area-length, Simpson, bullet and
RVOT Doppler provided better agreement with lithium dilution than the other methods
56
evaluated. These methods warrant further investigation for use in critically ill adult
horses.
INTRODUCTION
Hemodynamic monitoring in critically ill veterinary subjects continues to become
more sophisticated with standards of care modeled after examination of critically ill
humans. Cardiac output (CO) is the best available variable to assess overall
cardiovascular function.1 Measurement of CO, along with blood hemoglobin
concentration and oxygen saturation of hemoglobin, allows calculation of global tissue
oxygen delivery and consumption, thereby providing useful information in individuals
with primary cardiac disease or secondary cardiovascular derangements associated with
systemic illness. Following trends in CO in individual animals in the intensive care unit
might allow for both earlier detection of cardiovascular derangements and optimization
of clinical interventions. To date, CO monitoring in adult horses has been limited to the
research setting.2-4 Cardiac or peripheral artery catheterization is required for indicator
dilution methods of CO measurement and is generally not suitable in a clinical setting.
Transthoracic echocardiography has been used to measure CO in people and in small
animals with various 2-dimensional (2-D) volumetric or Doppler methods.5,6
Ultrasonography is widely available in equine hospitals, and most ultrasound units have
software packages allowing calculation of various cardiovascular parameters including
CO. Therefore, transthoracic echocardiography may represent a convenient and
noninvasive means of measuring CO in equine patients. In one study, Doppler
echocardiographic measurement of CO was found to agree well with the thermodilution
57
method in adult horses.7 However, difficulties in aligning the ultrasound beam parallel to
the blood flow and individual variability in the cardiac window can make this method
difficult to use. In addition, indices of cardiac function derived from Doppler
echocardiography have been found to be less repeatable than indices derived from 2-D or
M-mode echocardiography in horses.8 It was recently shown that some volumetric
echocardiographic methods provide an accurate and noninvasive estimate of CO in
anesthetized neonatal foals.9 However, because of major differences in cardiac chamber
sizes and inability to obtain apical views of the heart in adult horses, data generated from
neonatal foals under general anesthesia cannot be directly extrapolated to adult horses.
The purpose of this study was to assess and validate various transthoracic
echocardiographic methods of measuring CO in standing adult horses over a range of CO
by comparing results to the lithium dilution CO (LiDCO) method. The hypothesis of the
study reported herein was that volumetric methods would have better agreement with
lithium dilution than Doppler-based methods.
MATERIALS AND METHODS
Animals
Eight horses (4 geldings and 4 mares) ranging from 4-20 years of age (mean of 9
years) with a mean body weight of 498 kg (range 425-660 kg) were included in this
study. Breeds included 2 Thoroughbreds, 3 Quarter horses, and 1 Lippizzaner,
Saddlebred and Warmblood. Horses were deemed healthy based on thorough physical
examination and echocardiography. The horses were housed in box stalls and were fed ad
58
lib hay and water. The study was approved by the University of Georgia Institutional
Animal Care and Use Committee.
Instrumentation
Horses were manually restrained in the stall with a halter and lead rope for
instrumentation and throughout the study period. A 14 gauge 5 ½ inch Teflon cathetera
was aseptically inserted into each jugular vein, one for injection of lithium chlorideb and
the other for dobutaminec and romifidined infusion, respectively. Under ultrasonographic
guidance, a 14 gauge 5 ½ inch Teflon cathetera was placed aseptically in either the right
or left carotid artery for invasive blood pressure monitoring and for lithium chloride
detection. A three-way valve was connected to the arterial line and was fitted with non-
compliant, pressure monitoring tubinge on one port and the lithium chloride sensorf on
the other. The lithium chloride sensor was attached on one side to a closed system
consisting of a peristaltic pump and blood collection bag and sensor interface on the other
end according to the manufacturer’s instructions. An electronic pressure transducer,g
calibrated with a mercury manometer, was placed on a surcingle at the level of the point
of the shoulder to approximate the base of the heart. A single-lead ECG was placed in
base-apex fashion for continuous monitoring during echocardiography.
Measurement of CO by Lithium Dilution
A LiDCO computeri was used to determine CO according to the manufacturer’s
instructions. Prior to the first LiDCO measurement, venous blood was collected for
determination of plasma sodium and hemoglobin concentrations by a blood gas analyzerj
which was necessary for calculation of CO by the LiDCO software. Lithium chloride (2.4
mmol/8 mL) was injected intravenously as a smooth, rapid bolus followed by saline flush
59
while a peristaltic pump withdrew a continuous arterial sample past the lithium sensor at
a rate of 4 mL/min. A lithium dilution curve was generated and stored if the quality
control criteria of an acceptable curve were met by the software.
Measurement of CO by Echocardiography
Echocardiography was performed using an ultrasound unitk with a built in
algorithm for stroke volume (SV) and CO determination and simultaneous display of the
ECG. Views were obtained from either the right or left parasternal window with a 2.5
MHz sector cardiac ultrasound transducerl by the same experienced clinician (MHB).
Echocardiographic images obtained from the right parasternal window included: (1) long-
axis 4-chamber view (modified slightly to include the apex of the left ventricle); (2) long-
axis left ventricular outflow tract view for measurement of the diameter of the aorta at the
sinotubular junction in systole; (3) long-axis right ventricular outflow tract view for
measurement of the diameter of the ascending pulmonary artery in systole and the
pulmonary artery velocity time integral (PVTI) in systole using pulsed-wave Doppler; (4)
short-axis 2-D view of the left ventricle at the level of the papillary muscles just below
the mitral valve; and (5) M-mode of the left ventricle at the level of the papillary muscles
just below the mitral valve. Images obtained from the left parasternal window included
the left ventricular outflow tract view for measurement of the aortic velocity time integral
(AoVTI) in systole using pulsed-wave Doppler. 6,10,11 Three video loops for each view
were stored for subsequent tracings and measurements. Tracings and measurements were
performed retrospectively by an investigator who was unaware of LiDCO results (EM).
For each method evaluated, the average of the three separate measurements was used for
60
calculating stroke volume (SV) as previously described.12-14 Determination of CO was
obtained from the following equation: CO (L/min) = SV (L/beat) x heart rate (beats/min).
2-D Volumetric Measurements
Bullet- Standard short axis views of the left ventricle at the level of the papillary
muscle just below the mitral valve were obtained for determination of the left ventricular
area in end diastole (LVASAd) and end systole (LVASAs) by tracing the blood-
endocardium interface.15 End diastole was defined as the onset of the QRS complex. End
systolic measurements were taken from the frame with the smallest left ventricular
diameter. The 4-chamber view was modified to include the apex of the left ventricle and
was used for measuring left ventricular length at end diastole (LVLRd) and end systole
(LVLRs).15 Left ventricular length was determined with electronic calipers set at the
midpoint of the line between the septal and left ventricular free wall origins of the mitral
valve to the blood-endocardium interface at the apex of the left ventricle. In this view,
end diastole was defined as the first frame in which the mitral valve was closed and end
systole was defined as the smallest left ventricular chamber size.10 The heart rate (HR)
was determined from the R-R interval measured with electronic calipers. The built-in
algorithm derived SV based on the following equation: SV = (5/6 x LVASAd x
LVLRd) – (5/6 x LVASAs x LVLRs).
Teichholz and Cubic- Standard M-mode images at the level of the papillary
muscle just below the mitral valve were obtained. A conventional left ventricular study
derived the left ventricular internal diameter in end diastole (LVIDd) and end systole
(LVIDs) and calculated SV using a built in algorithm based on the following formulas:
SV = [7 x (LVIDd)3/(LVIDd + 2.4)] – [7 x (LVIDs)3/(LVIDs + 2.4)] and SV=(LVIDd3 –
61
LVIDs3) for the Teichholz and Cubic methods, respectively.15 End diastole was defined
by the onset of the QRS complex and end systolic measurements were taken at the
smallest LV chamber diameter. The R-R interval was measured with electronic calipers
to determine HR and CO was reported based on this measurement.
4-Chamber Area-Length (4C AL) and 4-Chamber Modified Simpson’s (4C
MOD)- 4-chamber long axis views of the left ventricle were obtained from the right
parasternal view. The blood-endocardium interface was traced with electronic calipers
starting at the attachment of the mitral valve on the septum and ending at the attachment
of the mitral valve on the left ventricular free wall in diastole (LVARd) and systole
(LVARs).15 End diastole was defined as the first frame in which the mitral valve was
closed and end systole was defined as the smallest LV chamber size. The LVLRd and
LVLRs were obtained as described above under the Bullet method. HR was determined
by measuring an R-R interval with electronic calipers. A built in algorithm was used to
derive SV based on the following formulas for 4C AL and 4C MOD, respectively: SV =
[5/6 (LVARd)2/ LVLRd] – [5/6 (LVARs)2/ LVLRs]; SV= [(π/4 Σ(ai2/16) x LVLRd) –
(π/4 Σ(ai2/16) x LVLRs)].19-21
Doppler Echocardiography
Cross-sectional vessel areas (CSA) or [π x (0.5 x diameter)2] for the pulmonary
artery and aorta were calculated manually. The velocity time integral (VTI) was acquired
by placing the cursor in the vessel of interest while aligning the ultrasound beam as close
to parallel with flow as possible to obtain a full spectral envelope during systole.16-18 The
gate was positioned in the aorta or the pulmonary artery just past the valve. The VTI was
traced with electronic calipers as described previously and was reported as area under the
62
curve (cm2).19 Stroke volume was calculated from the following formula: SV=VTI X
CSA. The R-R interval just preceding or following the traced VTI was measured with
electronic calipers to determine HR.
Study Design
In order to investigate all methods over a range of CO, three levels were studied:
baseline (no treatment), high CO, and low CO. After baseline measurements, high CO
was induced with an intravenous continuous rate infusion (CRI) of dobutamine (3
μg/kg/min), started 10 minutes prior to CO measurements and was discontinued after
high CO data was collected.20 After a 45-minute wash-out period, low CO was induced
with an intravenous romifidine bolus (80 μg/kg), immediately followed by a CRI at 30
μg/kg/hour.21,22 Low CO data were collected 15 min after initiating the romifidine CRI
which coincided with expected steady state plasma concentrations and clinical effects.22
For each level, lithium dilution CO was measured twice. If any two LiDCO
measurements had more than 25% variation with respect to each other, a third
measurement was taken and the measurement outside the allowed 25% variation was
eliminated. Echocardiography was performed between LiDCO measurements. The
average of duplicate (lithium dilution) or triplicate (echocardiography) measurements
was calculated and used for data analysis. As a result, three readings were available from
each horse for a total of 24 observations. Concurrent heart rate and systolic, diastolic and
mean direct arterial blood pressure were recorded at the time of cardiac output
measurement. Cardiac index (CI) was obtained by dividing CO by body weight in
kilograms.
63
Statistical analyses
Agreement between each echocardiographic method of CO measurement and
lithium dilution was determined using the method for repeated measurements on a given
subject reported by Bland and Altman.23,24 For each observation, bias was calculated as
follows: (COLiDCO – COECHO), where COLiDCO and COECHO are the CO values measured
concurrently by lithium dilution and a given echocardiographic method. Normality of the
bias data and equality of variances were assessed using the Shapiro-Wilk and Levene’s
tests, respectively. A two-way ANOVA with repeated observations was conducted to
assess the effect of the method of CO measurement and level of CO (low, intermediate
and high) on bias. This model was used to estimate the mean bias and SD for each
method evaluated. A positive bias reflected underestimation of LiDCO-derived CO
whereas a negative bias indicated overestimation of the LiDCO-derived CO by
echocardiography. The limits of agreement were reported as bias ± 1.96 × SD.
A similar two-way ANOVA with repeated observations was used to assess
differences in the absolute value of the bias between methods. For effects found to be
significant by an overall F-test, multiple pairwise comparisons were made using the
Student-Newman-Keuls test. All analyses were done using statistical software.m,n
Statistical significance was set at P < 0.05.
RESULTS
Twenty-four pairs of lithium dilution/echocardiography CO measurements were
taken from the eight horses. Adverse effects in this study ranged from mild to moderate
hematoma formation at the site of arterial catheterization to transient collapse secondary
64
to a suspected air embolus in one horse. Adverse reactions attributable to the dobutamine
infusion included irritability and kicking out violently without cause in two horses,
synchronous diaphragmatic flutter in three horses and intermittent ventricular premature
contractions in one horse.
Lithium dilution measurements of CO ranged between 16.6 and 63.0 L/min
(mean ± SD = 30.5 ± 9.5 L/min), resulting in cardiac indices ranging between 17.5 and
129.6 mL/kg/min (59.9 ± 21.5 mL/kg/min). Lithium dilution determinations of CO
during administration of dobutamine (37.7 ± 11.7 L/min) were significantly higher than
determinations obtained at baseline (28.6 ± 4.7 L/min) or during administration of
romifidine (25.1 ± 6.3 L/min). Cardiac output during administration of romifidine was
not significantly different from CO obtained at baseline. Heart rates during administration
of dobutamine (37 ± 6 beats/min) were significantly higher than heart rates obtained at
baseline (32 ± 2 beats/min) or during administration of romifidine (29 ± 5 beats/min).
Heart rate during administration of romifidine was not significantly different from heart
rate obtained at baseline.
The analysis of bias indicated a significant effect (P < 0.001) of method of CO
measurement but no significant effect of level (low, intermediate or high) of CO (P =
0.938) on bias, indicating that the performance of each echocardiographic method was
not influenced by the magnitude of CO. The mean bias and limits of agreements for each
echocardiographic method of CO measurement are presented in Table 1. The overall
performance of each method was assessed by comparing the absolute value of their bias.
Analysis of variance revealed a significant effect of method of CO measurement (P <
0.001) but no significant effect of level of CO (P = 0.089) and no significant interactions
65
between level and method (P = 0.607). The absolute values of the bias of the 4C AL, 4C
MOD, RVOT Doppler, and Bullet methods were significantly lower than that of LVOT
Doppler or cubic methods (Table 1). Bland-Altman plots for the 4C AL, 4C MOD,
RVOT Doppler and Bullet methods are presented in Figure 1. The mean CO (± SD) for
each method of measurement at each level of CO is reported in Table 2.
DISCUSSION
Monitoring trends in CO would complement current hemodynamic monitoring
tools available for use in critically ill adult horses. Cardiac output measurement is
routinely employed in human critical care facilities and has become a common modality
for hemodynamic monitoring in foals in some neonatal intensive care units.25 Currently
validated and accepted methods for estimation of cardiac output in adult horses are not
suitable for routine clinical use as they are invasive, requiring maintenance of a
peripheral arterial catheter or a pulmonary artery catheter for lithium dilution or
thermodilution techniques, respectively. In this study, the carotid artery was catheterized
owing to difficulties in maintaining patency in smaller peripheral arteries in conscious
standing horses. An experimental study by one of the current authors reported
maintenance of a carotid artery catheter for up to 24 hours without adverse effects.26
Although placement of a carotid artery catheter under ultrasound guidance was not
technically challenging, the authors do not recommend carotid artery catheterization in
client-owned horses. The use of pulmonary artery catheters has been reported to increase
mortality and predispose to pulmonary thromboembolism in people.27 In addition,
pulmonary artery catheterization has been associated with traumatic endocardial lesions
66
in the right heart and pulmonary artery of adult horses.28 Thus, in order to eliminate the
need for arterial catheterization in a clinic setting, the main purpose of this study was to
determine which echocardiographic measures of CO most robustly correlate with an
indicator dilution technique in standing horses.
Three of the volumetric echocardiographic methods investigated (4C AL, 4C
MOD and Bullet) had significantly better agreement with the LiDCO reference method
than the other echocardiographic methods evaluated. The 4C AL and 4C MOD methods
overestimated and underestimated CO, respectively, each by a mean of approximately 1
L/min, while the Bullet method overestimated the CO by approximately 7 L/min, relative
to the LiDCO reference. When considering performance of the Doppler methods,
agreement between the RVOT Doppler and the LiDCO was not significantly different
from the best volumetric measures of CO, disproving the hypothesis of this study that the
volumetric measures of CO would be superior to the Doppler methods. The RVOT
Doppler method underestimated CO by a mean of 2 L/min relative to LiDCO while the
LVOT Doppler method overestimated CO by a mean of 14 L/min relative to LiDCO.
Although the 4C AL, 4C MOD, and RVOT Doppler methods had a significantly
lower bias than the other methods evaluated, their limits of agreement with LiDCO were
wide (± 17 L/min), representing up to ± 50% of the measured CO. Two methods of
measurement can usually be considered interchangeable if the limits of agreement fall
within a clinically acceptable range.23 A meta-analysis of studies using bias and
precision statistics to compare CO measurement techniques in people underscored that
considerable diversity exists in how the results of bias and precision are interpreted
between studies.29 In the aforementioned study, the authors proposed that acceptance of a
67
new technique for measurement of CO in people should rely on limits of agreement up to
± 30%.29 The limits of agreement that would be considered acceptable for the
measurement of CO in a horse have not been defined and might even vary depending on
the clinical situation. Despite the wide limits of agreement, 4C AL, 4C MOD, and RVOT
Doppler might prove to be of value to detect changes in magnitude and direction of CO in
a clinical setting.
Excellent image quality is essential to be able to make accurate and repeatable
echocardiographic measurements.30 Poor image quality due to subject factors (poor
compliance, body condition score, differences in the cardiac window) was encountered to
some extent in the present study. This may have influenced the performance of some of
the volumetric methods that required tracing the blood endocardium interface (Bullet, 4C
AL, 4C MOD). However, the Teichholz and Cubic methods derived from standard M-
mode images and left ventricular study measurements had poor agreement with the
LiDCO method, significantly underestimating and overestimating the CO respectively.
Poor agreement was attributed to geometric assumptions that rely on a smooth circular or
elliptical shaped ventricle and uniform contraction which may not be applicable to the
equine left ventricle.31,32 Results from the Teichholz and Cubic based methods were
similar to results in anesthetized foals.10
In this study, the LVOT Doppler method in the left parasternal window
significantly overestimated the LiDCO reference. This is in contrast to results of a
previous study comparing Doppler echocardiographic methods in standing adult horses in
which LVOT Doppler in the left parasternal window had better agreement with
thermodilution than RVOT Doppler.11 The discrepancy between the aforementioned and
68
the present study may be attributable to differences in the population of horses studied or
poor repeatability of pulsed-wave Doppler measures in general.11,33,34 Pulsed-wave
Doppler measurement of aortic VTI was found to have more day-to-day and intercardiac
cycle variation than pulsed-wave Doppler measurement of pulmonary artery VTI in one
equine study.33 While it is possible that the aortic diameter was overestimated, this was
felt to be unlikely as measurements were made at the sinotubular junction and were
within normal reference ranges for adult standing horses.34-36 It is more likely that the
pulsed-wave Doppler traces were too broad owing to artifact from poor alignment with
blood flow. Overestimation of CO by pulsed wave Doppler methods has been previously
reported in both human and animal studies.10,34,37,38
Inherent limitations exist with all CO monitoring methods available for clinical
use. While there is no universally accepted gold standard for CO determination in human
or veterinary medicine, thermodilution has traditionally been the most commonly used
method in people.16,39 Studies comparing LiDCO to thermodilution CO have been
performed in several species including the horse. 40-44 As a result of the relatively narrow
limits of agreement between the two methods, the use of the LiDCO method as the
reference standard method is widely accepted across many species.41-45 Potential sources
of error with the lithium dilution method include intracardiac shunts, which were ruled
out by our inclusion criteria, and lithium accumulation. Lithium accumulation creates
background “noise” and can result in overestimation of cardiac output. Accumulation was
unlikely in the current study as the mean cumulative lithium dose was 0.038 mmol/kg
and no more than 8 lithium injections were administered to any horse (19.2 mmol LiCl
total). Considerably higher cumulative dosages of LiCl (0.8 mmol/kg; 69.3 mmol LiCL)
69
were used in a study in exercising horses and did not result in any adverse effects,
however, overestimation of CO was documented as the number of lithium injections and
exercise intensity increased.3
Lithium determinations of CO in the present study ranged between 16.6 and 63.0
L/min which represent a wide physiological range of CO and are similar to ranges
achieved in comparable studies.11,46 Echocardiographic derivation of CO was not
influenced by level of CO. Though a statistically significant decrease in CO from
baseline was not achieved with the romifidine CRI, our purpose of measuring CO over a
wide range of values was met.
Limitations of the study design included a small and diverse sample population in
terms of breed. Although, the inclusion of various breeds may be viewed as a limitation
and indeed may have impacted the performance of some of the transthoracic
echocardiographic methods, the use of a monomorphic sample would be unrepresentative
of most clinic populations, making it difficult to extrapolate the findings of this study to
the target population. Another potential limitation included the inability to
simultaneously measure CO with lithium dilution and echocardiography. Cardiac output
is dynamic with beat-to-beat variation based on neuroendocrine input. Agreement
between the methods might have been influenced by making measurements at discrete
time points. Efforts to minimize this effect were made by performing lithium dilution
measurements just before and immediately after storage of transthoracic
echocardiographic images and by performing all measurements stall side in a quiet
environment to minimize transient excitation during measurements.
70
A potential source of error and limitation of transthoracic echocardiography is
that the Doppler-derived techniques and some of the 2-D techniques require
measurements derived by tracing velocity spectra or blood-endocardium interfaces,
which are subject to observer interpretation. In the study herein, only one person derived
measurements from the stored video clips, thus inter-observer agreement was not
evaluated. Other studies will be necessary to assess the reproducibility of these methods
and to determine the effect of the observer on variability.
In the hands of adequately trained clinicians, transthoracic echocardiography of
critically ill adult horses has advantages beyond CO measurement. Previous work has
shown that volume depletion can be recognized rapidly based on chamber morphology.47
In addition, detection of diastolic or systolic dysfunction, valvular regurgitation, chamber
dilation, regional wall abnormalities or pericardial effusion would impact therapeutic
decisions.5 The disadvantages of transthoracic echocardiography pertain to initial capital
costs of purchasing an ultrasound unit and acquiring the training necessary to
appropriately apply these techniques and interpret the results.
In conclusion, transthoracic echocardiography using the 4-chamber area length
method, 4-chamber modified Simpson method, bullet method or Doppler of the RVOT
have significantly lower biases than all other methods evaluated in standing healthy adult
horses. These non-invasive methods of estimating cardiac output provide a non-invasive
clinically accessible method for serial hemodynamic monitoring and warrant further
investigation in critically ill adult horses.
71
FOOTNOTES
a. Abbocath®-T, Hospira, Lake Forest, IL
b. Lithium Chloride 99.995%, VWR International LLC, Batavia, IL
c. Dobutamine, Hospira Lake Forest, IL
d. Sedivet® Vetmedica, St. Joseph, MO
e. Medex™, Smiths Medical, Dublin, OH
f. LiDCO™ London, UK
g. Edwards Lifesciences LLC, Irvine, CA
h. Spacelabs Medical, WA
i. LiDCO™plus, cardiac computer, LiDCO Group PLC, London, UK
j. Nova Biomedical, Waltham, MA
k. Vivid 7, GE Medical Systems, Milwaukee, WI
l. M4S transducer, GE Medical Systems, Milwaukee, WI
m. MedCalc version 12.1.4.1, Mariakerke, Belgium
n. GraphPad Prism version 5.0 La Jolla, CA
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thermodilution cardiac output determination in horses. In: Proceedings of the 5th
International Congress of Veterinary Anesthesia; 1994:71.
29. Critchley LA, Critchley JA. A meta-analysis of studies using bias and precision
statistics to compare cardiac output measurement techniques. J Clin Monit Comput
1999;15:85-91.
30. Marr CM, Bowen, I.M. Cardiology of the Horse. In: Marr CM, Patteson, M. , ed.
Echocardiography. Philadelphia: Saunders 2010.
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31. Kuroda T, Seward JB, Rumberger JA, et al. Left ventricular volume and mass:
Comparative study of two-dimensional echocardiography and ultrafast computed
tomography. Echocardiography 1994;11:1-9.
32. Teichholz LE, Kreulen T, Herman MV, et al. Problems in echocardiographic volume
determinations: echocardiographic-angiographic correlations in the presence of absence
of asynergy. Am J Cardiol 1976;37:7-11.
33. Buhl R, Ersboll AK, Eriksen L, et al. Sources and magnitude of variation of
echocardiographic measurements in normal standardbred horses. Vet Radiol Ultrasound
2004;45:505-512.
34. Blissitt KJ, Bonagura JD. Pulsed wave Doppler echocardiography in normal horses.
Equine Vet J Suppl 1995:38-46.
35. Slater JD, Herrtage ME. Echocardiographic measurements of cardiac dimensions in
normal ponies and horses. Equine Vet J Suppl 1995:28-32.
36. Patteson MW, Gibbs C, Wotton PR, et al. Echocardiographic measurements of
cardiac dimensions and indices of cardiac function in normal adult thoroughbred horses.
Equine Vet J Suppl 1995:18-27.
37. Garcia J, Kadem L, Larose E, et al. Comparison between cardiovascular magnetic
resonance and transthoracic Doppler echocardiography for the estimation of effective
orifice area in aortic stenosis. J Cardiovasc Magn Reson 2011;13:25.
38. Tournoux F, Petersen B, Thibault H, et al. Validation of noninvasive measurements
of cardiac output in mice using echocardiography. J Am Soc Echocardiogr 2011;24:465-
470.
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39. Leibowitz AB, Oropello JM. The pulmonary artery catheter in anesthesia practice in
2007: an historical overview with emphasis on the past 6 years. Semin Cardiothorac Vasc
Anesth 2007;11:162-176.
40. Kurita T, Morita K, Kato S, et al. Comparison of the accuracy of the lithium dilution
technique with the thermodilution technique for measurement of cardiac output. Br J
Anaesth 1997;79:770-775.
41. Corley KT, Donaldson LL, Furr MO. Comparison of lithium dilution and
thermodilution cardiac output measurements in anaesthetised neonatal foals. Equine Vet J
2002;34:598-601.
42. Mason DJ, O'Grady M, Woods JP, et al. Assessment of lithium dilution cardiac
output as a technique for measurement of cardiac output in dogs. Am J Vet Res
2001;62:1255-1261.
43. Linton RA, Jonas MM, Tibby SM, et al. Cardiac output measured by lithium dilution
and transpulmonary thermodilution in patients in a paediatric intensive care unit.
Intensive Care Med 2000;26:1507-1511.
44. Linton RA, Young LE, Marlin DJ, et al. Cardiac output measured by lithium
dilution, thermodilution, and transesophageal Doppler echocardiography in anesthetized
horses. Am J Vet Res 2000;61:731-737.
45. Linton RA, Band DM, Haire KM. A new method of measuring cardiac output in man
using lithium dilution. Br J Anaesth 1993;71:262-266.
46. Lepiz ML, Keegan RD, Bayly WM, et al. Comparison of Fick and thermodilution
cardiac output determinations in standing horses. Res Vet Sci 2008;85:307-314.
77
47. Underwood C, Norton JL, Nolen-Walston RD, et al. Echocardiographic changes in
heart size in hypohydrated horses. J Vet Intern Med 2011;25:563-569.
78
Table 3.1. Summary statistics of the agreement between cardiac output measurements (L/min) by lithium dilution and various echocardiographic methods.
LVOT: left ventricular outflow tract; RVOT: right ventricular outflow tract †Negative value indicates overestimation of CO relative to LiDCO *Least squares means; Standard deviation = 6.3 L/min a,b,c different letters between rows indicate a statistically significant difference in the absolute value of the mean relative bias (P < 0.05). When at least 1 superscript letter is common between 2 values, the difference is not statistically significant.
Cardiac output methods Bias (L/min ± s.d.)†
Limits of agreement
(L/min)
Absolute value of bias* (L/min)
Doppler LVOT -14.2 ± 10.3 -34.3 to 5.9 14.8b
Doppler RVOT 2.2 ± 7.9 -13.4 to 17.7 5.5a
4 chamber area-length -1.1 ± 8.4 -17.6 to 15.4 6.5a 4 chamber modified Simpson 0.8 ± 7.8 -14.4 to 16.0 6.1a
Bullet -6.9 ± 9.2 -25.1 to 11.2 8.8a
Teichholz 7.6 ± 7.14 -6.5 to 21.6 10.4a,b
Cubic -24.3 ± 18.0 -59.6 to 11.0 24.3b
79
Table 3.2. Mean cardiac output (L/min ± SD) as determined concurrently by lithium dilution and various Doppler or volumetric echocardiographic methods. Measurements were obtained at baseline, after administration of dobutamine (high CO) and after administration of romifidine (low CO).
Method Baseline High Low LiDCO
28.7 ± 4.7
36.6 ± 10.03
25.1 ± 6.3
Doppler LVOT 46.1 ± 12.1 52.7 ± 9.6 35.4 ± 8.1 Doppler RVOT 29.9 ± 5.6 30.4 ± 4.4 26.1 ± 6.6 4C AL 29.9 ± 9.7 39.8 ± 10.8 25.6 ± 7.1 4C MOD 28.3 ± 8.8 37.3 ± 9.9 24.9 ± 3.3 Bullet 34.6 ± 7.1 46.2 ± 11.3 23.4 ± 3.8 Teichholz 20.5 ± 6.0 28.5 ± 8.4 19.8 ± 6.5 Cubic 47.6 ± 17.7 67.9 ± 22.3 48.9 ± 21.9
80
Figure 3.1. Bland-Altman plots of CO values measured concurrently by lithium dilution and echocardiography by the 4-chamber modified Simpson (A), 4-chamber area-length (B), Doppler RVOT (C), or Bullet (D) methods in standing adult horses. The solid line represents the mean bias and the dashed lines represent the upper and lower limits of agreements (1.96 9 SD). Three measurements were obtained from each of 8 horses for a total of 24 observations. Each symbol represents an individual horse.
81
CHAPTER 4
HEART RATE VARIABILITY IN HORSES WITH ACUTE
GASTROINTESTINAL DISEASE REQUIRING EXPLORATORY
LAPAROTOMY2
______________________________
2E.L. McConachie, S. Giguère, G. Rapoport, M.H Barton. Accepted by the Journal of
Veterinary Emergency and Critical Care.
Reprinted here pending permission of the publisher.
82
ABSTRACT
Objective- To describe heart rate variability (HRV) in horses with acute gastrointestinal
disease that undergo exploratory laparotomy. We hypothesized that horses with ischemic
gastrointestinal disease will have reduced HRV compared to horses with non-ischemic
lesions. We further hypothesized that a reduction in HRV will be associated with non-
survival.
Design - Prospective, clinical, observational study.
Setting - Veterinary Teaching Hospital.
Animals - Horses presented for acute colic (n=57) or elective surgical procedures (n=10)
were enrolled.
Interventions - Admission heart rate was recorded and continuous telemetry was placed
within 2 h of recovery from anesthesia, monitored and recorded for 48 hours post-
operatively. Stored electrocardiograms were manually inspected and R-to-R intervals
were extracted and uploaded into HRV software for analysis. Time domain and
frequency spectral analysis were investigated at Times 1 (2-10 hours), 2 (16-24 hours), 3
(30-38 hours), and 4 (44-52 hours) post-operatively. A 2-way ANOVA for repeated
measures was used for group comparisons. Logistic regression analysis was used to
detect potential associations between admission HR, time and frequency domain
variables, and non-survival.
Measurements and Main Results - Horses diagnosed with an ischemic gastrointestinal
lesion (n=22) at the time of surgery had significantly higher post-operative heart rates and
reduced time domain derived measures of HRV than horses with non-ischemic
gastrointestinal lesions (n=35) or control horses (n=10). Horses that survived to discharge
83
had significantly lower post-operative heart rates, higher time domain, and lower low
frequency spectral measures of HRV compared to non-survivors. The multivariable
logistic regression model had a ROC AUC of 0.95 and was significantly better at
predicting non-survival than admission HR (P=0.0124).
Conclusions - Reduced HRV was strongly associated with ischemic gastrointestinal
disease and non-survival. HRV analysis is a noninvasive technique that may provide
diagnostic and prognostic information pertinent to the management of post-operative
horses with severe gastrointestinal disease.
INTRODUCTION
Heart rate variability (HRV) analysis provides a non-invasive method to measure
fluctuations in the autonomic input to the sinoatrial node and reflects activity of the
individual components of the autonomic nervous system (ANS).1 This provides clinically
useful information because variation in beat-to-beat intervals is characteristic of healthy
cardiac function.2 There are many methods of HRV analysis; two of the simplest and
most widely used are time domain and frequency spectral analysis. Time domain
methods of HRV analysis, notably the standard deviation of the duration of R-to R-
intervals (so-called “normal-to-normal” or NN intervals; SDNN) and root mean square
differences of successive NN intervals (RMSSD), reflect overall autonomic modulation
and predominately vagally mediated cardiac modulation, respectively. Frequency spectral
analysis is unique in that the components of the ANS can be separated out by distinct
high-frequency (HF) and low-frequency (LF) bands which approximate parasympathetic
activity and combined sympathetic and parasympathetic activity, respectively.
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During periods of distress which occur with serious illness, trauma, or surgery,
neurohormonal input is critical to maintain homeostasis through an appropriate
cardiovascular response. Reduced HRV reflects poor cardiovascular health and may be
due, in part, to overwhelming sympathetic tone, withdrawal of one or both branches of
the ANS, or primary cardiac disease.3 Various HRV parameters have proven to be early
predictors of major adverse clinical events, such as acute myocardial infarction in cardiac
patients and multiple organ dysfunction syndrome (MODS) in septic patients admitted to
the intensive care unit.4-7 Reduced HRV is predictive of mortality in people that suffer
acute myocardial infarction8 as well as in-hospital mortality in septic patients.9 Thus
HRV analysis can provide early predictive patient-side information for those at risk for
organ dysfunction, allowing for prompt implementation of preventative strategies.
While HRV has been evaluated in horses under a variety of physiologic and
pathologic conditions,10-14 to the authors’ knowledge, HRV has not been investigated in
horses with naturally acquired gastrointestinal disease. The main objectives of the study
described herein are to describe HRV parameters in horses that underwent exploratory
laparotomy for acute gastrointestinal disease and compare them to those of healthy
control horses that underwent elective surgical procedures. We hypothesized that horses
with ischemic lesions of the gastrointestinal tract have reduced HRV, as compared to
horses with non-ischemic gastrointestinal lesions or horses undergoing elective surgical
procedures requiring general anesthesia. We further hypothesized that a reduction in
HRV will be associated with non-survival.
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MATERIALS AND METHODS
In this prospective, clinical study, client-owned horses > 1 year of age that were
presented to the Veterinary Teaching Hospital between November 2011 and February
2014 for either acute gastrointestinal disease and underwent exploratory laparotomy or
for elective surgery were enrolled. Owner consent was obtained at the time the horse was
determined to require surgery or upon hospital admission for healthy controls. Horses
were enrolled as controls if they required general anesthesia for an elective surgical
procedure lasting at least 1 hour, and were considered healthy on the basis of normal pre-
operative vital parameters, general physical examination and pre-operative complete
blood count, fibrinogen concentration and plasma venous blood gas analysis. Horses
were removed from the study if they were euthanized solely for financial reasons or if
they were not recovered from general anesthesia. This study was approved by the Clinical
Research Committee.
Data collection
Age, breed and sex were recorded for each horse, as was the gastrointestinal
lesion diagnosed and corrected at surgery, the elective procedure, and whether or not the
horse survived to discharge. Heart rate was recorded at admission by the attending
clinician. Horses requiring gastrointestinal surgery were grouped as ischemic or non-
ischemic based on surgical findings. Specifically, horses grouped as ischemic included
those with small or large intestinal strangulating lesions that required resection and
anastomosis and those with a large colon volvulus greater than or equal to 360 degrees,
regardless of whether or not a resection was performed. The decision for resection and
anastomosis was at the discretion of the surgeon and was based on surgical findings
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consistent with devitalized intestine. Records were searched retrospectively to record
analgesic agent administration during the study period.
Telemetric electrocardiography placement
Within 2 hours of recovering from general anesthesia, a telemetry unita was
placed for 48-hour continuous electrocardiographic (ECG) recording. Electrodesb were
placed according to manufacturer instructions. A surcingle was placed to ensure the
telemetry unit and leads remained in place and to promote contact between the electrodes
and the horse’s skin.
Heart rate variability analysis
Telemetric ECG recordings were visually inspected for arrhythmia and artifact.
Artifact-free ECG recordings of sinus rhythm were cut and saved at approximately 12-
hour intervals, defined as Time 1 (2-10 hours post-operative), Time 2 (16-24 hours post-
operative), Time 3 (30- 38 hours post-operative) and Time 4 (44-52 hours post-
operative). Normal-to-normal intervals were extracted using the Televet software with a
30% artifact filter and saved as text files for offline analysis. NN intervals were manually
inspected and were removed if they were less than <75% or > 125% of the previous
interval.10,15 The file was then opened in the HRV softwarec for time domain and
frequency spectral analysis. The data were detrended using cubic spline transformation
with smoothness parameters set at 500 ms, as previously reported.16 The artifact filter
was set at low, which corresponds to 0.35 sec. The interpolation rate was set at 4 Hz and
the Fast Fourier Transform (FFT) spectrum window was set at 512 s (interpolated
sampling of 512 equidistant points) with an overlap of 40%. For frequency analysis,
bands of interest for LF and HF were 0.01-0.07 and 0.07-0.6 Hz, respectively, based on
87
previous studies.17 At each time point, 5- and 30-minute periods of ECG recording were
analyzed for time domain methods and 5-minute, 30-minute and 1024 NN intervals were
used for frequency spectral analysis based on previous work.15,18 Parameters of interest
for the time domain method included mean HR, SDNN, RMSSD, triangular index (the
integral of the density distribution of all NN intervals divided by the maximum of the
density distribution), and pNN50 (the proportion derived by dividing the number of
interval differences of successive NN intervals greater than 50 ms by the total number of
NN intervals). Parameters of interest for frequency spectral analysis included LF, HF and
LF/HF ratio.
Statistical Methods
Descriptive statistics for patient factors (age, breed, sex, analgesic administration,
time of euthanasia or death) were performed and are reported as mean ± SD where
applicable. Associations between breed or sex and group or outcome were evaluated with
a Chi-squared test. Normality of the data and equality of variances were assessed using
the Shapiro-Wilk and Levene’s tests, respectively. A Student t-test or Mann-Whitney U
test for normally and non-normally distributed data, respectively, was used to compare
age and HR on admission between survivors and non-survivors. A one-way ANOVA or
Kruskal-Wallis ANOVA on ranks was used to compare age or admission HR between
groups, respectively. When warranted, multiple pairwise comparisons were performed
using Dunn’s method. A two-way ANOVA for repeated measures was used to assess the
effect of disease category (ischemic, non-ischemic, control; or survivors and non-
survivors), time [HRV: Time 1(2-10 hours), Time 2 (16-24 hours), Time 3 (30-38 hours)
and Time 4 (44-52 hours)] and the interactions between disease category and time. Data
88
that were not normally distributed were rank-transformed prior to analysis. When
warranted, multiple pairwise comparisons were performed using the method of Holm-
Sidak.
Potential associations between individual variables and non-survival were first
screened by use of univariable logistic regression. For variables with a significant
association with non-survival, the best cut-off to predict non-survival was determined
using receiver operating characteristic (ROC) curve analysis. Variables for which the
screening P value was < 0.10 were considered for inclusion in the multivariable model.
Variables with a variance inflation factor > 2.50 were deleted to avoid multicollinearity.
The multivariable model was a backward stepwise model, whereby variables were
removed sequentially starting with that having the largest P value and until only those
variables with P < 0.05 remained. Goodness of fit of the final model was evaluated using
the Hosmer and Lemeshow test. Odds ratios (OR) and 95% confidence intervals (CI)
were calculated. An OR greater than 1 corresponds to a positive association with non-
survival whereas a ratio less than 1 corresponds to a negative association. The overall
performance of the multivariable regression model in predicting non-survival was
assessed by use of ROC curve analysis. The relationship between SDNN and HR was
investigated by calculating correlation coefficients using the method described by Bland
and Altman19 to account for repeated observations from individual animals. For all
analyses, P < 0.05 was considered statistically significant. Statistical analyses were
performed with commercially available statistical software.d,e
89
RESULTS
Animals
Sixty-seven horses were enrolled and included 45 geldings, 20 mares, and 2
stallions with a weight of 518.8 ± 85.9 kilograms. Horses ranged in age from 2 to 28
years (12.5 ± 6.5 years). Breeds represented included 19 Quarter Horse-type, 18
Warmbloods, 13 Thoroughbreds, 6 Arabians, 3 Saddlebreds, 3 pony breeds, 2 Morgans,
and 1 each Irish Sport horse, Connemara and Lusitano. Groups were comprised of 35
horses in the non-ischemic group, 22 horses in the ischemic group and 10 horses in the
control group. Control horses underwent general anesthesia for the following procedures:
arthroscopy (n=3), arthrodesis (n=1), laryngotomy (n=1), laryngoplasty (n=1), corneal
laceration repair (n=1), neurectomy (n=1) and exploratory laparotomy for an unrelated
research project (n=2). Lesions for horses in the non-ischemic group were as follows:
right dorsal displacement of the large colon (n=8), ileal impaction (n=6), left dorsal
displacement of the large colon (n=6), non-strangulating lipoma (n=3), small intestinal
mesenteric volvulus (n=3), cecal impaction (n=3), enterolithiasis (n=2), generalized small
intestinal distension (n=1), gastrosplenic entrapment (n=1), small colon impaction (n=1)
and large colon impaction (n=1). Lesions for horses in the ischemic groups were as
follows: strangulating lipoma (n=12), large colon volvulus without resection (n=5), large
colon volvulus with resection (n=2), epiploic foramen entrapment (n=1), gastrosplenic
entrapment (n=1) and inguinal hernia (n=1). 58 horses survived to discharge and 9 were
euthanized prior to discharge. Horses that died had a diagnosis of colonic volvulus (n=4),
strangulating lipoma (n=3) or non-strangulating small intestinal lesion (n=2). Mean time
at euthanasia was 5.0 ± 3.8 days after surgery. There was no breed or sex predisposition
90
for lesion type or survival. Horses in the ischemic group (15.9 ± 6.9) were significantly
older than the non-ischemic (11.7 ± 5.8; P = 0.024) and control (6.8 ± 3.5; P = 0.001)
groups, and the non-ischemic group was significantly older than the control group (P =
0.037). However, age of survivors (12.3 ± 6.6) was not significantly (P = 0.715) different
from that of non-survivors (13.2 ± 6.8).
Post-operative analgesia administration
All horses in the colic group (n=57) received flunixin meglumine, at 1.1 mg/kg
intravenously every 12 hours for 48-72 hours for pain management attributable to the
abdominal incision. Horses in the control group received either flunixin meglumine (1.1
mg/kg IV or PO q 12-24 hours) or phenylbutazone (2.2 mg/kg IV or PO q 12-24 hours) in
the first 24 hours post-operatively. Use of other analgesics varied at the discretion of the
attending veterinarian, with intravenously infused lidocaine being the next most
commonly used agent (39/67 including 22/22 ischemic, 17/35 non-ischemic, and 0/10
control horses).
Heart rate and heart rate variability between groups and over time
Admission HR was significantly (P < 0.001) greater for horses in the ischemic
group (61.6 ± 14.3 beats/minute) compared to the non-ischemic (49.6 ±12.4
beats/minute) and control groups (38.8 ± 5.9 beats/minute), but the difference between
non-ischemic and control horses was not significant.
There was no significant interaction between group and time for any of the post-
operative HR, time (SDNN, RMSSD, pNN50, and triangular index) or frequency
(LF/HF, LF, HF) domain variables. Post-operative mean HR for 5-minute telemetric
ECG recordings (mean HR5 min) was significantly different between groups irrespective
91
of time (P < 0.001) with the ischemic group having the highest mean HR5 min at any time
point (Figure 4.1A). The mean HR5 min at Time 1 (2-10 hours) was significantly greater
than mean HR5 min at all other post-operative time points (P < 0.003) and mean HR5 min at
Time 2 was significantly greater than mean HR5min at Time 4 (Figure 4.1A). A
significant group effect (P < 0.001) was found for time domain variables, wherein horses
in the ischemic group had significantly decreased values for SDNN5 min (Figure 4.1B),
RMSSD5 min (Figure 4.1C), and pNN505 min (Figure 4.1D) compared to both non-ischemic
and control groups, and horses in the non-ischemic group had significantly decreased
values compared to the control group. Heart rate variability parameters derived from 30-
minute recording lengths yielded the same results with the exception that for pNN5030 min,
ischemic horses had significantly lower pNN5030 min values compared to non-ischemic
and control horses; however, the non-ischemic horses were not significantly different
than control horses. For the time domain variable of triangular index, there was a group
effect for 30-min (p < 0.009) ECG recordings, wherein the ischemic group values were
significantly lower than the non-ischemic and control groups. There was a significant
negative correlation between HR5min and SDNN5 min (r = -0.518; P < 0.001). There was no
effect of time for any of time domain-derived HRV parameters. There was no effect of
group or time for any of the frequency domain variables.
Heart rate and heart rate variability and survival to discharge
Admission HR was lower in horses that survived to discharge (50.4 ± 14.3
beats/minute) compared to those euthanized in the post-operative period (61.2 ± 12.2
beats/minute; P = 0.013). There was no interaction between survival group and time for
any of the dependent variables. Compared to non-survivors, horses that survived had
92
significantly lower mean HR5 min (P < 0.001) and higher SDNN5 min (P < 0.001) (Figure
4.2A and 4.2B, respectively). Post-operative mean HR5 min was significantly greater in
non-survivors (65.3 ± 3.4 beats/minute (P <0.001) compared to horses that survived to
discharge (45.3 ± 1.3 beats/minute). An effect of time for survival groups (P < 0.001) was
detected where post-operative mean HR5 min was greater at Time 1 when compared to
Time 3 or Time 4 (Figure 4.2A). For HRV parameters derived by time domain methods
there was an effect of survival group, but no effect of time for SDNN and RMSSD for
both 5- and 30-minute ECG recordings. Horses that survived had significantly greater
SDNN5 min (52.8 ± 3.1 ms; P < 0.001) and RMSSD5 min (59.5 ± 4.2 ms; P < 0.001) than
non-survivors (23.9 ± 8.0 ms and 18.9 ± 10.9 ms, for SDNN5 min and RMSSD5 min,
respectively) (Figure 4.2B and 4.2C). The pNN505 min and pNN5030 min (P < 0.001) and
triangular index30 min (P = 0.003) were significantly greater in surviving horses. A
significant effect of time was detected for survival data for pNN50 and triangular index,
wherein pNN505 min (P = 0.01; Figure 4.2D) and triangular index30 min (P = 0.023) were
greater at Time 4 compared to Time 1 or 2 and pNN5030 min was significantly (P = 0.016)
greater at Time 4 compared to Time 1.
There was no effect of time on any of the frequency domain measures of HRV
when data were stratified by survival vs. non-survival. However, there was a significant
group effect for the LF/HF5 min and LF/HF 30 min where survivors had a lower LF/HF ratio
than non-survivors [(LF/HF5 min survivor: 0.90 ± 0.07/non-survivor: 1.20 ± 0.18, P =
0.045),( LF/HF30 min survivor: 0.88 ± 0.05/ non-survivor: 1.27 ± 0.13, P = 0.023)]. In
addition, LF power in normalized units (n.u.) was lower in survivors compared to non-
survivors for both 5- and 30-minute ECG recordings [(LF power5 min: survivor: 42.67 ±
93
1.38 n.u./ non-survivor: 50.76 ± 3.43 n.u.; P = 0.031), (LF power30 min: survivor: 40.3 ±
1.4 n.u./non-survivor: 50.0 ± 3.77 n.u.; P = 0.018)]. Finally HF power5 min was
significantly greater in survivors (59.7 ± 1.4 n.u.) compared to non-survivors (51.6 ± 3.7
n.u., P = 0.043). No significant effects of group or time were found for the remaining
frequency parameters when stratified by survival (LF/HF1024, LF power1024, HF
power1024, HF power 30 min).
Variables significantly associated with non-survival by univariable logistic
regression are presented in Table 4.1. Variables retained in the multivariable model
(overall significance of the model p < 0.0001) included peak mean HR5 min, SDNN5 min
when heart rate ≤ 55 bpm, and time period at peak mean HR5 min (Table 4.2). The model
correctly predicted non-survival in 94% of cases with a ROC curve AUC of 0.95 ± 0.029
(p < 0.0001). The sensitivities, specificities and predictive values (at the observed
prevalence of 13.4% non-survival) for possible outcomes of the multivariable model
corresponding to cut-off values to predict non-survival are available in supplemental
information (Table 4.3). The ROC AUC of the multivariable logistic regression model to
predict non-survival (0.95 ± 0.029) was significantly (P = 0.0124) higher than that of
admission HR (0.762 ± 0.075).
DISCUSSION
In this prospective, clinical, observational study, HRV parameters measured by
time and frequency domain methods were described for horses with acute gastrointestinal
disease that underwent exploratory laparotomy. The null hypothesis was rejected as
horses with ischemic gastrointestinal lesions had reduced HRV compared to those with
94
non-ischemic lesions and control cases. To the authors’ knowledge, this is the first
reported study evaluating HRV in the post-operative period for horses undergoing
surgical exploratory laparotomy for colic. In the post-operative period, time domain
variables that estimate either overall HRV (SDNN and triangular index) or high
frequency variation in heart rate (RMSSD and pNN50) were decreased in horses that
underwent exploratory laparotomy for colic, and the magnitude to which this occurred
corresponded to lesion category (Fig. 4.1). In addition, non-survivors had a significantly
reduced SDNN5 min, increased LF/HF ratio, increased LF power, and decreased HF power
compared to survivors, corresponding to a reduction in overall HRV, and sympathovagal
imbalance marked by sympathetic dominance and parasympathetic withdrawal.
The finding that horses with ischemic gastrointestinal disease, and specifically
those that did not survive, have altered HRV is novel and may have important
pathophysiologic and clinical implications related to cardiovascular function. Altered
HRV may be a function of reduced vagal tone, increased sympathetic tone, withdrawal of
both branches of the ANS or due to abnormalities at the level of the cardiac pacemaker
cells.20 Horses with ischemic gastrointestinal disease appeared to have reduced vagal tone
while non-survivors had both vagal withdrawal and relatively increased sympathetic
modulations of HR period. Reduced HRV reflects a loss of complexity in the autonomic
input to the sinoatrial node. It implies autonomic dysfunction and may occur with either
primary or secondary cardiac dysfunction. This, in turn, may perpetuate organ
insufficiency remote from the heart itself.20-23 Therefore, monitoring HRV in horses in
the post-operative period may provide a basic understanding of the role of the ANS in
95
critical illness while identifying horses at an increased risk of non-survival at an earlier
stage.
It is well documented that parasympathetic tone prevails in the normal resting
horse.17,24 Horses with acute colic are expected to have increased sympathetic tone, a
finding which has been supported based on reports of increased blood concentrations of
cortisol and catecholamines in conjunction with an increased admission HR.25,26 Several
studies investigating horses with acute colic have reported a significant association
between admission heart rate and increased likelihood of mortality.8,27-29 While there is a
repeatable association between admission HR and post-operative mortality in the equine
literature, HR should not be used as the sole prognostic indicator in horses with colic.
This is based in part on the finding, in the present study and others,30,31 that admission
HR is rarely retained in final survival models. In the study presented here, admission HR
of >48 beats per minute was associated with a 5.6 times odds of non-survival. Use of this
low HR cut-off would provide excellent sensitivity and negative predictive value to
predict non-survival, but this would come at the expense of abysmal specificity and
positive predictive value. There is no cut-off for admission HR that provides adequate
sensitivity and specificity for non-survival in horses with colic.
In the current study, post-operative peak mean HR5 min (> 66 bpm and > 67 bpm
for 30 min recording; OR 31 and 23, respectively) occurring after 24 hours post-
operatively (corresponding with Time at peak mean HR5 min > 2), was highly associated
with non-survival. This finding is not surprising as a persistently increased post-operative
heart rate (> 60 bpm) has been used as part of the criteria to define post-operative
shock.32 An increased post-operative heart rate may be indicative of ongoing
96
hemodynamic disturbances, persistent pain or primary cardiac insult. While there is an
inverse curvilinear relationship between HR and NN interval, variations in HR in the
present study accounted for only 26.8% of the variation in SDNN, which is similar to
what was reported in people.33 Though it would have been ideal to have case control
matches for HR, this was unrealistic. The independent value of HRV on understanding
autonomic dysfunction was highlighted by the finding that SDNN measured at the time
when the HR was less than or equal to 55 bpm at a cut-off of <39.5 ms, was highly
associated with non-survival (OR 16.42), a finding which remained significant in the
final regression model. From a clinical perspective, this finding underscores a relevant
use of HRV. In the post-operative period, horses with a normal or mildly increased heart
rate (i.e. tachycardia ≤ 55 bpm), that might otherwise be perceived to be clinically
improved, would remain at risk for non-survival or conceivably other major post-
operative clinical events when they have a concurrent reduction in HRV. The duration
and intensity of post-operative monitoring and preventative strategies might be adjusted
if autonomic dysfunction is detected.
Frequency-derived measures of HRV in the present study were not significantly
different when the groups were stratified by lesion type. These results were similar to
those previously reported for the perioperative period in a small group of horses that
underwent general anesthesia and retrobulbar analgesia for enucleation.34 However, the
LF/HF5 min , LF/HF30 min, LF power5 min, LF power 30 min, and HF power5 min were
significantly different between survivors and non-survivors, suggesting sympathovagal
imbalance, increased sympathetic tone, and reduced vagal modulation of heart rate in
non-survivors, respectively. In human medicine there is still debate as to what role
97
baroreceptor function and other physiologic mechanisms play in determining the various
frequency bands, making it unclear what proportion of the LF band is solely reflective of
sympathetic activity.35,36 The time domain methods RMSSD and pNN50 reflect
parasympathetic activity15,37,38 rather than overall autonomic tone. These variables were
lower in non-survivors, which in accordance with significantly lower HF power5 min for
non-survivors, suggests the alteration of HRV in this study was at least in part a reflection
of attenuated vagal tone.
The multivariable logistic regression model out-performed admission HR,
accurately predicting non-survival in 94% of cases with an excellent AUC of 0.95;
however, the practicality of the model is questionable. The variables retained in the
model, peak HR5 min, time of peak mean HR5 min and SDNN when ≤ HR 55 bpm, would
have to be collected after monitoring the horse for a 48-hour period either continuously or
for 5 minutes at approximately 12-hour intervals to obtain adequate information to use
the regression model. Therefore, its potential usefulness in predicting survival to
discharge is limited to horses that survive at least 48 hours after surgery.
Though it was not possible to control analgesic administration, all horses received
perioperative NSAIDs. Horses in the colic group received an NSAID for the duration of
the study period, however, some control cases were not administered an NSAID on Day 2
(Time 3 and 4). Provision of pain control in any form would be expected to reduce
sympathetic tone and thereby reduce LF power and indirectly increase HF power.14 In
this study there was no difference in frequency spectrum HRV parameters between the
colic and control group, suggesting analgesic drug administration was not an important
manipulator of autonomic tone. The finding that non-survivors had increased LF power
98
and reduced HF power would imply that a subset of horses experienced sympathovagal
imbalance despite analgesic administration.
Several limitations exist for this study, including the lack of pre-operative HRV
analysis and the inability to control for time of day when HRV was analyzed. While pre-
operative measurements are ideal for use as diagnostic criteria or prognostic indicators,
this was not practical owing to variability in the time from admission to surgery, and in
some cases obtaining a 30-minute diagnostic-quality ECG recording would have delayed
surgery and could be considered unethical. Finally, at the time of admission the vast
majority of horses that presented for acute gastrointestinal disease received an alpha-2
agonist or an anticholinergic spasmolytic agent, making interpretation difficult owing to
the pharmacological influence on HRV.11,39
Additionally, the post-operative time at which HRV analysis was assessed varied
between horses. This was a result of the need for uninterrupted, artifact- and arrhythmia-
free telemetric ECG recordings of 30 minutes duration. While the ECG sampling times
were limited to an 8-hour window representing the immediate post-operative period (2-10
hours) and then 24, 36 and 48 hours post-operatively without overlap, the exact time of
day that this occurred varied from horse to horse, and was dependent on the time of
recovery from surgery. For each individual horse, however, samples were obtained at
approximately the same time of day (morning and evening, or afternoon and mid-night).
It is important to note that there was no significant interaction between group and time
suggesting that the significant differences detected between ischemic, non-ischemic and
control groups and between survivors and non-survivors occurred irrespective of post-
operative time period. On the other hand, a lack of a significant effect of post-operative
99
time period could be attributable to the sampling method. For practical purposes,
identifying significant HRV measures based on the post-operative time period may be
more relevant and more convenient than sampling at a set time of day. However, the
authors acknowledge that additional studies might be warranted to determine the effect
that time of day alone has on HRV in critically ill horses.
CONCLUSION
In conclusion, HRV analysis is a non-invasive, easily attainable measure of
cardiovascular health that provides information about ANS function, and which might
prove useful as a clinical monitoring tool. Horses with colic that incur ischemic
gastrointestinal lesions have decreased time domain measures of HRV compared to
horses that undergo general anesthesia for non-ischemic gastrointestinal lesions or
elective surgical procedures. Horses that did not survive to discharge had altered HRV
with evidence of sympathovagal imbalance and vagal attenuation compared to those that
survived to discharge. Additional work is needed to determine the relationship between
alterations in HRV, other measures of cardiovascular health, and measures of the
systemic inflammatory response in horses.
100
FOOTNOTES
a: Televet Version 3 Kruuse Denmark
b: Kruuse ECG Electrodes; Jorgenson Medical
c: Kubios HRV Version 2.1 Kuopio, Finland kubios.uef.fi/
d:Sigmaplot 12.5 Systat Software, Inc. San Jose, CA
e: MedCalc 14.8.1;Ostend, Belgium
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Table 4.1. Ideal cut off as assessed by ROC curve analysis for HRV parameters potentially (P < 0.1) associated with non-survival and corresponding odds ratios. OR = odds ratio; CI = confidence interval; Peak= highest single value of the four post-operative time points analyzed; Lowest= nadir value of the four post-operative time points analyzed
Variable Cut off ROC Logistic regression AUC ± SE P OR (95% CI) P
Admission HR (bpm) > 48 0.762 ± 0.075 0.0005 5.63 (1.08 to 29.48) 0.0407 Peak mean HR30 min (bpm) > 67 0.876 ± 0.058 < 0.0001 31.33 (3.57 to 275.4) 0.0019 Peak mean HR5 min (bpm) > 66 0.883 ± 0.052 < 0.0001 23.45 (2.71 to 203.5) 0.0042 Time at peak mean HR30 min (1-4) > 1 0.739 ± 0.101 0.0174 5.85 (1.08 to 31.66) 0.0403 Time at peak mean HR5 min (1-4) > 2 0.760 ± 0.099 0.0089 8.17 (1.67 to 39.84) 0.0094 HR at lowest SDNN30 min (bpm) > 67 0.885 ± 0.052 < 0.0001 28.32 (3.24 to 247.5) 0.0025 HR at lowest SDNN5 min (bpm) > 67 0.850 ± 0.056 < 0.0001 19.44 (3.47 to 109.1) 0.0070 Lowest SDNN30 min (ms) < 28.0 0.846 ± 0.052 < 0.0001 7.97 (1.51 to 42.20) 0.0146 Lowest SDNN5 min (ms) < 26.7 0.874 ± 0.051 < 0.0001 13.45 (1.57 to 114.9) 0.0175 Lowest RMSSD30 min (ms) < 16.7 0.907 ± 0.041 < 0.0001 39.20 (4.40 to 349.3) 0.0010 Lowest RMSSD5 min (ms) < 17.2 0.912 ± 0.042 < 0.0001 31.33 (3.57 to 275.4) 0.0019 Lowest pNN5030 min (%) < 1.4 0.907 ± 0.042 < 0.0001 51.00 (5.60 to 464.2) 0.0005 Lowest pNN505 min (%) < 0.6 0.904 ± 0.040 < 0.0001 51.00 (5.50 to 464.2) 0.0005 Peak LF/HF30 min > 1.9 0.809 ± 0.072 < 0.0001 13.50 (2.72 to 67.04) 0.0015 Peak LF/HF1024 > 1.5 0.739 ± 0.086 0.0053 8.17 (1.54 to 43.20) 0.0135 Peak LF power30 min (n.u.) > 63.2 0.829 ± 0.073 < 0.0001 15.27 (2.78 to 83.83) 0.0017 Lowest HF power30 min (n.u) < 36.6 0.783 ± 0.081 0.0004 8.73 (1.88 to 40.42) 0.0056 Lowest HF power5 min (n.u.) < 42.5 0.670 ± 0.071 0.0164 7.73 (0.91 to 65.77) 0.0611 SDNN5 min lowest mean HR5 min (ms) ≤ 39.2 0.868 ± 0.049 < 0.0001 16.42 (1.91 to 141.0) 0.0107
106
Table 4.2. Results of a multivariable logistic regression analysis for HRV variables associated with non-survival.
Variable Coefficient SE P value OR 95% CI
Constant -6.9847 N/A N/A N/A N/A
Peak mean HR5 min (bpm)
0.0802 0.0361 0.0262 1.0835 1.010 to 1.163
Time at peak mean HR5
min (1-4) 1.6230 0.7810 0.0377 5.0683 1.097 to 23.43
SDNN5 min at lowest mean HR5 min (ms)
-0.1053 0.0536 0.0498 0.9001 0.810 to 0.999
107
Figure 4.1. Least squares mean and standard error of the mean derived from the 5-minute ECG recordings at each post-operative time period [Times 1 (2-10 hours), 2 (16-24 hours), 3 (30-38 hours), and 4 (44-52 hours) ] are presented for mean heart rate (A) and time domain heart rate variability parameters [SDNN (B), RMSSD (C) and pNN50 (D)] for control horses (n=10), horses with non-ischemic gastrointestinal lesions (n=35) and horses with ischemic gastrointestinal lesions (n=22). Within a time period, a significant difference between groups is indicated by different letters. Significant differences across time periods are indicated by different symbols.
108
Figure 4.2. Least squares mean and standard error of the mean for 5-minute ECGs derived from post-operative time points [Times 1 (2-10 hours), 2 (16-24 hours), 3 (30-38 hours), and 4 (44-52 hours)] for mean heart rate (A), and time domain variables [SDNN (B), RMSSD (C), and pNN50 (D)] for horses when grouped as survivors (n=58) or non-survivors (n=9). Within a time period, a significant difference between groups is indicated by different letters. Significant differences across time periods are indicated by different symbols.
109
CHAPTER 5
ASSESSMENT OF THE CARDIOVASCULAR SYSTEM IN HORSES WITH
NATURALLY ACQUIRED ISCHEMIC INTESTINAL DISEASE3
______________________________
2E.L. McConachie, S. Giguère, G. Rapoport, S. A. Brown, M.H Barton. To be
submitted to the Journal of Veterinary Cardiology.
110
ABSTRACT
Objectives- To compare indices of cardiovascular system status between horses with
acute surgical colic and those undergoing elective surgical procedures at admission, and
at days 1 and 2 post-operatively.
Design- Prospective clinical study
Animals- Adult horses presented to a Veterinary Teaching Hospital for acute
gastrointestinal (GI) disease requiring exploratory laparotomy (n=62) or for elective
surgical procedures (control, n=12).
Procedures- Horses were categorized by specific surgical GI lesion, presence or absence
of hypotension under anesthesia, presence or absence of SIRS, and survival or failure to
survive to discharge. A complete blood count, blood lactate, electrolytes, and serum
cardiac troponin I (cTnI) concentrations were measured at admission and at Day 1 and 2
post-operatively. The cardiovascular status was assessed post-operatively by telemetric
electrocardiography for determination of rate, rhythm and heart rate variability (HRV),
and by 2-D and M-mode echocardiography.
Results- Horses with ischemic GI disease had significantly higher cTnI and lactate
concentrations, higher heart rate, lower HRV, greater mean systemic arterial blood
pressure, greater left ventricular relative wall thickness, were more frequently
hypotensive under anesthesia, and had more ectopic beats per hour than horses with non-
ischemic lesions or controls. Horses with an ischemic GI lesion (18/29; 62%) or those
that did not survive (8/10; 80%) were more likely to fulfill SIRS criteria. In a
multivariable logistic regression (MLR) model, non-survival was best explained by cTnI
(> 0.15 ng/mL) and lowest stroke volume index.
111
Conclusions and Clinical Relevance- Horses with ischemic GI lesions and non-
survivors are more likely to have evidence of cardiovascular system dysfunction.
INTRODUCTION
As many as 60% of septic human patients admitted to the intensive care unit have
evidence of cardiac dysfunction and, in these patients, mortality rates approach 70%.1-3 It
should not be too surprising that cardiac dysfunction plays a central role in the
development of multiple organ dysfunction syndrome (MODS) for it is in part the
inability of the cardiovascular system to meet tissue oxygen demands that leads to remote
organ failure. The clinical importance of detecting cardiac dysfunction and preventing
MODS is highlighted by the fact that once a patient develops multiple organ failure,
mortality in people approaches 100%.4,5
On the basis of perioperative increases in serum cardiac troponin I (cTnI)
concentrations, recent literature provides evidence that myocardial injury occurs in
critically ill horses with naturally occurring acute ischemic or inflammatory conditions of
the gastrointestinal tract.6-8 In critical illness, the pathophysiology of myocardial injury is
multifactorial with proposed mechanisms for myocardial dysfunction that include
hypoxic or ischemic insult, sepsis or endotoxin-induced cytokine expression, over
expression of myocardial nitric oxide, alterations in intracellular calcium signaling, and a
blunted response or decrease density of β-adrenergic receptors to catecholamines.9,10
Horses with naturally acquired ischemic gastrointestinal disease commonly have
clinical evidence of hypovolemia and up to 40% have circulating endotoxin. 11-13
Experimental infusion of endotoxin in horses was associated with a rise in serum cTnI
112
concentration that preceded development of ventricular ectopic beats, suggesting a direct
or indirect role for endotoxemia in inducing myocardial injury.14 Despite the association
between an increased serum cTnI concentration and poor outcome in horses with acute
gastrointestinal disease,6-8 the implications of a rise in this cardiac biomarker are
incompletely understood in horses.
Criteria utilized in people to assess cardiovascular function in severe illness
include hypotension, hypotension that is non-responsive to inotropic therapy, increased
pressure-adjusted heart rate (PAR= [Heart Rate (HR) x central venous pressure (CVP)/
mean arterial pressure (MAP)]),15 plasma lactate or serum cTnI concentrations and
incidence of cardiac arrhythmias as well as decreased FS, left ventricular ejection fraction
and HRV, and increased incidence of cardiac arrhythmias.2,5,15-20 Current methods for
evaluating cardiac function in horses often follow the criteria defined for use in humans.21
There is no consensus for what constitutes complete assessment of cardiovascular system
function in healthy or critically ill horses. With the realization that there are important
differences between species, it seems logical to adopt a multifaceted, comprehensive
approach to cardiovascular examination. Until sufficient data are available to dictate
which measurements are the most useful to guide intervention or prognosis, assessment
of left ventricular systolic function, presence or absence of cardiac arrhythmia, systemic
arterial blood pressure, and measures of autonomic modulation of cardiac function may
be useful. Therefore, the objectives of the study described herein were to obtain indices
of cardiovascular system function in horses undergoing surgical correction of GI disease
and horses undergoing elective surgical procedures and to compare these indices with
measures of gastrointestinal disease severity and short-term survival. The null hypotheses
113
were that horses undergoing general anesthesia (GA) for surgical treatment of ischemic
GI disease are not more likely to develop evidence of myocardial dysfunction compared
to horses undergoing surgical treatment of non-ischemic GI disease or elective surgical
procedures, and that indices of myocardial function are not correlated with the presence
of the systemic inflammatory response syndrome (SIRS) or non-survival in horses with
acute GI disease.
MATERIALS AND METHODS
Animals
Client-owned horses > 1 year of age that were presented to the University’s
Veterinary Teaching Hospital for acute GI disease that required exploratory laparotomy
were enrolled, as well as those presented for elective surgery. Owner consent was
obtained for all enrolled animals. Horses were enrolled as controls if they required GA
for an elective surgical procedure and were healthy on the basis of normal pre-operative
vital parameters, general physical examination and normal pre-operative complete blood
count, fibrinogen concentration and plasma venous blood gas analysis. Horses were
removed from the study if they were euthanized solely for financial reasons or if they
were not recovered from GA. Post-operative therapy was at the discretion of the
attending clinician. This study was approved by the University’s Clinical Research
Committee.
Data collection
Age, breed, sex, the nature of the GI lesion diagnosed and corrected at surgery,
elective procedure and survival to discharge were recorded for each horse. Horses were
114
grouped as ischemic or non-ischemic based on surgical findings, or control for horses
undergoing elective surgical procedures. Specifically, horses with small or large intestinal
lesions requiring resection and anastomosis were grouped as ischemic. Horses with a
colon volvulus greater than or equal to 360 degrees were placed in the ischemic group
regardless of whether or not a resection was performed. Hypotension (yes or no) under
GA, defined as a direct MAP < 65 mmHg for at least five minutes, and total duration of
hypotension were recorded.
For assessment of SIRS, vital parameters (rectal temperature, HR, respiratory
rate) were recorded at admission and at 12 hour intervals post-operatively. Blood was
also collected into plastic coated EDTA tubes via venipuncture at admission or through a
jugular venous catheter, for immediate determination of complete blood count with an
automated analyzera at admission and at approximately 24 (Day 1) and 48 hours (Day 2)
post-operatively. Blood smears were made for manual description of leukocyte
morphologic characteristics and were processed by the University’s clinical pathology
laboratory at admission and on Day 1 and 2. Horses that fulfilled criteria for SIRS at
admission, or on Day 1 or Day 2 post-operatively were categorized as having SIRS based
on criteria used for adult horses in similar clinical studies and included two or more of the
following: temperature ≥ 101.5°F or ≤ 98.5°F; HR ≥ 60 bpm; respiratory rate ≥ 30 bpm;
white blood cell count ≥ 14,500 cells/µL or ≤ 4,500 cells/µL and or ≥ 10% band
neutrophils.22 23
115
Plasma and serum biochemical analysis for cTnI, lactate and electrolyte
concentrations
Blood was collected into serum tubes via venipuncture at admission or through a
jugular venous catheter after discarding 12 mL of waste blood, at approximately 24 and
48 hours post-operatively for serum cTnI measurement. Blood was allowed to clot at
room temperature and was then centrifuged for 30 min at 3000 rpm in a temperature-
controlled centrifugeb prior to separating serum into plastic bullet tubes and storing at -
80°C for batch analysis. All cTnI samples were processed within three months of
collection using an ultrasensitive assay.c Heparinized whole blood was collected for
immediate measurement of lactate and electrolyte (Na+, K+, iCa2+, iMg2+) concentrations
by a rapid critical care analyzer.d
Telemetric ECG placement for HR, HRV, and rhythm analysis
Within two hours of recovering from GA a veterinary telemetry unite was placed
for a minimum of 48 hours and maximum of 52 hours of continuous electrocardiographic
recording. Electrodesf were placed according to manufacturer instructions. A surcingle
was placed to ensure the telemetry unit and leads remained in place and to promote
contact between the electrodes and the horse’s skin. All ECG analysis was performed by
a board certified internal medicine clinician (EM). The HR (bpm), measured from real-
time telemetric electrocardiography (ECG) monitoring, was recorded in triplicate at the
time of pressure measurements at 12, 24, 36 and 48 hours post-operatively.
Telemetric ECG recordings were processed as previously described24 with
universally available softwarel for HRV analysis. Based on previous work,27 5- or 30-
minute artifact- and arrhythmia-free ECG recording was used for determination of the
116
standard deviation of normal-to-normal intervals (SDNN, 5 minute) and the root mean
square of successive differences (RMSSD, 5 minute), and low frequency (LF, 30 minute)
power , respectively. The HRV results were recorded for each horse during the following
post-operative time periods 2-10 hours (Time 1), 16-24 hours (Time 2), 30-38 hours
(Time 3) and 44-52 hours (Time 4).
The number of ectopic beats (ectopic beats/24 hour), their origin, and
morphologic characteristics were recorded for each horse. The presence of any clinically
significant arrhythmia (CSA, yes or no) during the study period was recorded for each
horse. A CSA was defined as having > 1 single ventricular premature complex/hour,
ventricular tachycardia (≥ 4 consecutive ventricular premature complexes in a row, rate ≥
60 bpm), > 1 supraventricular premature complex/ hour, supraventricular tachycardia,
polymorphic ventricular premature complexes, accelerated idioventricular rhythm25,26 or
second degree atrioventricular (AV) block at a HR of ≥ 60 beats/minute.
Central venous catheterization and blood pressure monitoring
A 19-gauge 90-cm long line catheterg was placed in the left or right jugular vein
using the previously placed 14-gauge anesthesia catheter as an introducer catheter after
sterile preparation of the skin and catheter hub. When the catheter placed by the
anesthesiologist was not available to use as an introducer, the introducer catheter
included in the commercially available equine central venous pressure catheter kith was
placed after clipping and sterile preparation of the skin over the jugular groove. The tip of
the catheter was placed within the thoracic inlet at the level of the junction of the cranial
vena cava and right atrium. This was achieved by first measuring the distance from the
catheter insertion site to the mid-point of the triceps muscle at the level of the point of the
117
shoulder prior to inserting the catheter. Positioning was further confirmed by optimizing
the pressure wave form by incrementally backing the catheter out of the right ventricle
while the pressure transduceri was set at the level of the point of the shoulder and
connected to a stall side electronic pressure monitork as previously reported.27 The
catheter was sutured in place, flushed with heparinized saline and maintained indwelling
for the duration of the post-operative observation period. Central venous pressure
(mmHg) measured by a pressure transduceri and electronic pressure monitork was
recorded in triplicate at 12, 24, 36 and 48 hours post-operatively. Horses were restrained
with a halter and lead rope and the head was maintained in a neutral position at the level
of the withers. The MAP (mmHg) measurements were acquired in triplicate using an
oscillometric pressure monitork and tail pressure cuff with a width that was
approximately 50% of the tail circumference.28 The head of each horse was maintained in
a constant position during blood pressure measurement. Noninvasive blood pressure was
measured simultaneously with CVP and HR. The pressure adjusted heart rate (PAR =
HR X CVP/MAP)15 was calculated at 12, 24, 36 and 48 hours post-operatively from the
average HR, MAP and CVP measured at each time point. Therefore, one PAR was
recorded for each post-operative time point.
Echocardiography
For 2-D and M-mode echocardiography, all measurements were obtained on Day
1 and Day 2 post-operatively. Horses were examined stall side or in a quiet examination
room with minimal restraint (halter and lead rope). A single-lead ECG was placed in
base-apex fashion for continuous monitoring during echocardiography.
Echocardiography was performed using an ultrasound unitj with a built-in algorithm for
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stroke volume (SV) and cardiac output (CO) determination and simultaneous display of
the ECG. All views were obtained from the right parasternal window with a 2.5 MHz
sector cardiac ultrasound transducerk by the same experienced clinician (EM).
Echocardiographic images obtained included: (1) 2-D long-axis 4-chamber view
(modified slightly to include the apex of the left ventricle); (2) 2-D short-axis view of the
left ventricle at the level of the papillary muscles just below the mitral valve; and (3) M-
mode of the left ventricle at the level of the papillary muscles just below the mitral valve.
Three video loops for each view were stored for subsequent tracings and measurements.
Tracings and measurements were performed retrospectively by the same investigator
(EM). Stroke volume (mL) and CO (L/min) were derived from the 4-chamber area-length
method as previously described.29 Fractional shortening (FS%) was measured in triplicate
based on published methods.30,31 The relative wall thickness (RWT) was determined from
M-mode measurements of the left ventricular free wall in diastole (LVFWd),
interventricular septum in diastole (IVSd) and the left ventricular internal diameter in
diastole (LVIDd). RWT = [(LVFWd + IVSd) / LVIDd]. The LVIDd/body weight (kg)
was also determined as a method to estimate relative left ventricular chamber size. Stroke
volume and CO were manually converted to stroke volume index (SVI) (mL/kg) and CI
(mL/kg/min), respectively, by dividing the volume or rate by body weight (kg).
Statistical analysis
Descriptive statistics for patient factors (age, breed, sex) were performed and are
reported as proportions or mean ± SD. Associations between SIRS and group (surgical
lesion category) or survival status were evaluated with a Chi-squared test or Fishers exact
test, with Bonferroni adjustment for multiple comparisons between groups. In addition,
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associations between CSA and hypotension under GA with SIRS, group or survival status
were evaluated with a Chi-squared test or Fishers exact test, with Bonferroni adjustment
for multiple comparisons between groups. Normality of the data and equality of variances
were assessed using the Shapiro-Wilk and Levene’s tests, respectively. A two-way
ANOVA for repeated measures was used to assess the effect of disease category
(ischemic, non-ischemic, control; or survivors and non-survivors), time, and the
interactions between disease category and time for individual variables. Data that were
not normally distributed were rank-transformed prior to analysis. When warranted,
multiple pairwise comparisons were performed using the method of Holm-Sidak. Results
for two-way ANOVA analyses are reported as the least squares mean and standard error
of the mean (SEM) and median and interquartile range (IQR).
Potential associations between individual variables and survival, SIRS, or CSA,
were first screened by use of univariable logistic regression. For logistic regression,
hypotension under GA (Y or N) or duration (min), CSA (Y or N) and the trough [iCa2+,
iMg2+, SDNN, RMSSD, CVP, SVI, CI, LVIDd/kg] or the peak [cTnI, lactate, HR, LF,
PAR] value from the corresponding observation periods were used for analysis. In
addition, potential associations between the above individual variables measured only at
24 hours (excluding hypotension or CSA), rather than peak or trough values, and non-
survival were screened similarly. The potential association between electrolyte
concentrations measured closest to the time of detected arrhythmia, peak cTnI, or peak
lactate and CSA were screened with univariable regression analysis. Continuous
variables that did not meet the assumption of log linearity for regression analysis were
dichotomized based on the best cut-off as assessed by receiver operating characteristic
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(ROC) curve analysis. Variables for which the screening P value was < 0.20 were
considered for inclusion in the multivariable logistic regression (MLR) model. Variables
with a variance inflation factor > 5.0 were deleted to avoid multicollinearity. The MLR
was a backward stepwise model, whereby variables were removed sequentially starting
with that having the largest P value and until only those variables with P < 0.05
remained. Goodness of fit of the final model was evaluated using the Hosmer and
Lemeshow test. Odds ratios (OR) and 95% confidence intervals (CI) were calculated. The
overall performance of the MLR models in predicting non-survival, SIRS or CSA were
assessed by use of ROC curve analyses. Finally, associations between RWT on Day 1
and lactate, cTnI, HR and CVP all measured on Day 1(at approximately 24 hours post-
operatively) were assessed with least squares multiple regression analysis. For all
analyses, P < 0.05 was considered statistically significant. Statistical analyses were
performed with commercially available statistical software.m,n
RESULTS
Animals
Seventy-four horses were enrolled between November 2011 and August 2014 and
included 50 geldings, 21 mares and 3 stallions with a weight of 515.3 ± 84.9 kg. Horses
ranged in age from 2 to 28 years [12.8 ± 6.6 years]. Breeds represented included 23
Quarter Horse-type, 18 Warmbloods, 14 Thoroughbreds, 7 Arabians, 3 Saddlebreds, 3
pony breeds, 2 Morgans, and 1 each Irish Sport horse, Connemara, Belgian draft-cross
and Lusitano. Associations between breed or sex and GI lesion group or short-term
survival were not statistically significant. There were 12 horses in the control group, 36
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horses in the non-ischemic group and 26 horses in the ischemic group. Control horses
underwent GA for the following procedures: arthroscopy (n=3), arthrodesis (n=1),
laryngotomy (n=2), laryngoplasty (n=2), corneal laceration repair (n=1), neurectomy
(n=1) and exploratory laparotomy for an unrelated research project (n=2). Lesions for
horses in the non-ischemic group were as follows: right dorsal displacement of the large
colon (n=8), ileal impaction (n=6), left dorsal displacement of the large colon (n=6), non-
strangulating lipoma (n=3), small intestinal mesenteric volvulus (n=3), cecal impaction
(n=3), enterolithiasis (n=2), generalized small intestinal distension (n=1), gastrosplenic
entrapment (n=1), small colon impaction (n=1), focal infarction of the left dorsal colon
(n=1) and large colon impaction (n=1). Lesions for horses in the ischemic groups were as
follows: strangulating lipoma (n=14), large colon volvulus without resection (n=5), large
colon volvulus with resection (n=2), epiploic foramen entrapment (n=2), gastrosplenic
entrapment (n=2) and inguinal hernia (n=1). Sixty four horses survived to discharge and
10 were euthanized prior to discharge. All horses in the control group survived whereas
52 of 62 (84%) of horses with colic, 34 of 36 (94%) of horses with non-ischemic lesions
and 18 of 26 (69%) of horses with ischemic lesions, survived to discharge. All horses that
did not survive to discharge were euthanized and had a diagnosis of colonic volvulus
(n=4), strangulating lipoma (n=3), epiploic foramen entrapment (n=1) or non-
strangulating small intestinal lesion (n=2). The proportion of horses in the ischemic group
that did not survive (8/26; 31%) was significantly higher than that of horses in the non-
ischemic group (2/36; 5.6%) or in the control group (0/0) (P = 0.005).
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Systemic Inflammatory Response Syndrome
Twenty-nine horses had clinical and/or clinicopathologic findings that fulfilled
the criteria for SIRS during the study period at a minimum of one time from admission to
through Day 2 post-operatively. Of these 29 horses with SIRS, 18 (62%) horses were in
the ischemic group and 11 (38%) horses were in the non-ischemic group; no horse in the
control group met the criteria for SIRS during the study period. A significantly greater
proportion of horses with ischemic gastrointestinal disease had SIRS compared to the
other groups (P < 0.001). Systemic inflammatory response syndrome was observed more
frequently in horses that did not survive to discharge (8/10; 80% horses) compared to
those that did survive to discharge (21/64; 32.8% horses) (P = 0.011).
Clinically Significant Arrhythmias
Clinically significant arrhythmias detected included: monomorphic ventricular
tachycardia (n=4), polymorphic ventricular tachycardia (n=1) accelerated idioventricular
rhythm (n= 1), > 1 single ventricular premature complex/hr (n=7), second degree AV
block at a HR of 70-80 bpm with ventricular premature complexes (n=1), and > 1
supraventricular premature complex/hr (n=1). Horses with ischemic GI lesions had a
significantly higher (P = 0.002) frequency of CSA (9/26; 34.6%) compared to horses with
non-ischemic GI lesions (2/36; 5.6%) or control (0/12; 0%) horses. Horses that fulfilled
the criteria for SIRS had a significantly higher (P = 0.003) frequency of CSA (9/29; 31%)
compared to horses without SIRS (2/43; 4.4%). In addition, there was a significantly
higher frequency of horses with a CSA that did not survive (4/10; 40%) compared to
those that survived (7/64; 11%); P = 0.036. Four horses had more than one type of CSA
during the observation period.
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Cardiac troponin (cTnI)
Seventy-one horses had cTnI measured at admission and of these, 16 (22.5%)
were abnormal (> 0.03 ng/ml). Thirty-seven horses had an abnormal cTnI measured at
least once during the study period. Only 6/37 (16%) horses had peak cTnI at admission.
One non-survivor had a normal cTnI concentration (< 0.03 ng/mL) at all time-points.
When the horse that was euthanized prior to the 24-hours post-operatively was excluded,
only 2 non-survivors had an abnormal admission cTnI. Abnormal cTnI concentrations
were measured in the remaining eight horses that were non-survivors in which the peak
serum cTnI concentration occurred on either Day 1 (n= 4) or Day 2 (n= 4).
Hypotension under General Anesthesia
Fifteen horses experienced hypotension under GA. The median duration of
hypotension was 10 min [5-20] with a maximum total duration of 80 non-consecutive
minutes. Hypotension under GA occurred more frequently in horses with ischemic GI
lesions (12/26; 46%), horses with SIRS (12/29; 41.4%), and those that did not survive
(6/10: 60%) compared to their counterparts [horses with non-ischemic lesions (3/36;
8.3%), control (0%) or those without SIRS (3/29; 6.7%) or survivors (9/64; 14.1%)] P <
0.001, P < 0.001, and P = 0.003, respectively.
Comparisons of cardiovascular variables by gastrointestinal lesion group and time
Variables with significant effects of group or time measured at admission, Day 1
and Day 2 are summarized in Table 5.1, while variables with significant effects of group
or time measured only post-operatively are summarized in Table 5.2. Significant effects
of group and time were found for cTnI, lactate, potassium, and iCa2+ concentrations, post-
operative HR, and RMSSD. Variables that had an effect of group only included sodium
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and iMg2+ concentrations, ectopic beats, RWT, SDNN and MAP. An effect of time only
was significant for CI. The effect of group, time, and interactions between group and
time were not statistically significant for SVI, FS, LVIDd/kg, LF, CVP or PAR.
Comparison of cardiovascular variables by survival status and time
Significant effects of survival status and or time on variables measured at
admission and on Day 1 and Day 2 are summarized in Table 5.3, while those measured
only post-operatively are summarized in Table 5.4. A significant effect of group and time
were found for cTnI, lactate, and iCa2+ concentrations. An effect of group only was
detected for SDNN, RMSSD, SVI, LVIDd/kg, and RWT. An effect of time only was
detected for potassium concentration. There was no significant effect of group or time for
sodium or iMg2+ concentrations, CI, FS, ectopic beats, LF, CVP, MAP or PAR.
Outcome analysis by MLR analysis
Survival to discharge
Complete data sets for 67 horses were available and consisted of 8 positive cases
(non-survivors) and 59 negative cases (survivors). Variables retained in the multivariable
model for non-survival were trough SVI and cTnI (> 0.15 ng/mL) (overall significance P
< 0.0001) (Table 5.5). The final model was highly significant (overall significance P <
0.0001) and correctly classified 91% of the cases. The area under the ROC curve for the
ability of the variables in the final model to predict non-survival was 0.95 ± 0.027; 95%
CI: 0.86 to 0.99.
Survival to discharge (Day 1 data)
Complete data sets for variables obtained at 24 hours were available for 63 horses
including 8 non-survivors and 55 survivors. Variables obtained at 24 hours that were
125
retained in the MLR model for non-survival included SVI, LF, and RWT > 0.63 (P <
0.0001; Table 5.5). This model correctly classified 96.3% of cases. The area under the
ROC curve for the ability of the variables in the final model to predict non-survival was
0.97 ± 0.019; 95% CI: 0.90-1.00.
Systemic inflammatory response syndrome (SIRS)
Complete data sets for 67 horses were available and included 25 with SIRS and
42 horses without SIRS. The MLR model that best explained SIRS included peak cTnI
concentration, peak PAR and trough SVI (P < 0.001; Table 5.5). This model correctly
classified 79% of the cases with an AUC from the ROC curve of 0.86 ± 0.046; 95% CI:
0.75-0.93.
Clinically Significant Arrhythmias
Data were available for all horses for detection of a CSA and included 11 horses
with CSA and 63 horses without CSA. The MLR model that best explained CSA
included peak cTnI concentration and an incremental decrease in iMg2+ (0.1 mg/dL=
0.041 mmol/L decrease in iMg2+ increases odds of CSA 2.5 times) concentration at the
time of the CSA (P < 0.0001; Table 5). This model correctly classified 91% of cases with
an AUC from the ROC curve of 0.93 ± 0.033; 95% CI: 0.85-0.98.
Relative wall thickness on Day 1
In an attempt to determine if hypovolemia was related to RWT a linear regression
model was generated. Complete data sets for 66 horses were available. Variables
measured at approximately 24 hours were entered into the least squares regression model
and included cTnI and lactate concentrations, CVP and HR. The overall significance
level of this model was P = 0.020. The adjusted R2 was 0.118. All variables had an
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inflation factor of less than 1.5. The rpartial for individual variables were as follows: CVP
(0.012), cTnI (0.068), lactate (0.221) and HR (0.196).
DISCUSSION
In this study, parameters to assess the cardiovascular system of horses undergoing
surgical correction of intestinal disease and horses undergoing elective surgical
procedures were obtained and compared across groups, over time, and by short-term
survival outcome. Horses with ischemic gastrointestinal disease had increased admission
blood lactate concentrations, increased serum cTnI concentrations, higher HR, increased
MAP, lower HRV, greater RWT, and more frequent hypotension under GA and CSA
compared to horses with non-ischemic causes of colic and control horses. The null
hypothesis that horses undergoing GA for surgical treatment of ischemic gastrointestinal
disease are not more likely to develop myocardial dysfunction compared to horses
undergoing surgical treatment of non-ischemic gastrointestinal disease or elective
surgical procedures, was rejected on the basis of evidence of cardiovascular system
dysfunction characterized by alterations in HRV, cTnI concentration, RWT, MAP,
increased incidence of CSA and hypotension.
Furthermore, the null hypothesis that myocardial dysfunction would not be correlated
with measures of SIRS and survival in horses with acute colic was rejected on the basis
that peak cTnI concentration, lowest SVI, and peak PAR were retained in the model that
best classified horses with SIRS and that cTnI concentration >0.15 ng/mL and lowest
SVI were retained in the MLR model that best explained non-survival to hospital
discharge.
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While previous studies6,32 have demonstrated an association between an increased
cTnI concentration and disease severity among horses with acute gastrointestinal disease,
to the authors’ knowledge only two studies7,8 have attempted to bridge the gap by
evaluating the relationship between cTnI concentration, the incidence of CSA or the
occurrence of myocardial dysfunction. In the study by Nath et al,7 a decreased left
ventricular ejection time, an index of systolic function, and increased HR were associated
with increased cTnI concentration. However, left ventricular ejection time was no longer
significant when the effect of HR was taken into consideration. Other parameters
evaluated in that study, but not found to be significantly associated with cTnI
concentration, were FS and cardiac rhythm. Horses were evaluated at only one clinically
relevant time point and telemetric ECG recordings were performed for one hour which
may have precluded the detection of intermittent arrhythmias. In the second study, Diaz
et al8 recorded continuous telemetric ECG for 24 hours and detected a significant
association between an increased admission cTnI concentration, ventricular arrhythmia,
surgical treatment, and outcome.8 Similarly, in the study herein, CSA occurred more
commonly in horses with ischemic GI disease and was explained by a MLR model that
included peak cTnI concentration. Cardiac troponin I concentration also contributed to
the MLR model that best explained survival. However, an important difference between
these studies is that admission serum cTnI concentration was not significantly different
between horses that survived and those that did not survive to hospital discharge in the
present study. In fact, the majority of non-survivors (7/10; 70%) had a normal admission
cTnI concentration. However, with the exception of one horse, all horses that were
euthanized had a serum cTnI of > 0.15 ng/mL for at least one of the two post-operative
128
measurements. This suggests that admission cTnI concentration is not an appropriate
biomarker for prognostication of short-term survival; alternatively a post-operative rise in
serum cTnI may be more clinically relevant. Importantly, both cTnI concentration and
SVI were retained in the MLR models that explained both survival to discharge and the
presence of SIRS, suggesting that there is a relationship between a marker of myocardial
injury, systemic inflammation and cardiac dysfunction.
A number of horses in this study, including some with and without an ischemic
gastrointestinal lesion diagnosed at surgery, demonstrated evidence of global perfusion
deficits at admission based on tachycardia and increased blood lactate concentrations;
unfortunately echocardiography was not performed at admission owing to concerns that it
would delay surgery and, as such is a limitation of the study. Admission
echocardiography would have been useful as an additional time point of comparison and
may have offered a more clinically relevant time to obtain information that could enhance
current prognostic capabilities. However, the intentions of the study were not to build
upon current prognostic determinants, but rather to more completely understand the basis
of cardiovascular abnormalities in horses with acute gastrointestinal disease. In a recent
study, Borde et al33 performed echocardiography in horses with evidence of SIRS that
presented for acute GI disease prior to undergoing exploratory laparotomy or euthanasia,
and documented both systolic and diastolic dysfunction. However, of the 41 horses
enrolled at admission, only 12 survived to discharge which suggests that the population
of horses studied may have been in an advanced stage of disease at the time of admission,
and likely do not represent the majority of horses that present for acute gastrointestinal
disease. Additionally, cTnI concentrations, or other suitable cardiac biomarkers were not
129
measured in these horses, perhaps missing an opportunity to evaluate a relationship
between cTnI concentration and cardiac function.
In the present study, 62% of horses with evidence of SIRS had ischemic GI
disease, compared to 38% of horses with non-ischemic disease and 0% of control horses.
The pathophysiology of systemic inflammation in horses with acute GI disease is in large
part attributed to GI mucosal barrier dysfunction which permits endotoxin and other
pathogen-associated molecular patterns access to the lymphatic and portal systems.34
When these systems are overwhelmed or are themselves dysfunctional, bacterial derived
pathogen associated molecular patterns may reach the systemic circulation and incite a
cascade of inflammatory cytokines (e.g., TNF-alpha, IL-6, IL-1B, and IL-10) and other
mediators (e.g., tissue factor, complement, prostaglandins) that perpetuate the
inflammatory response on a systemic level. In septic cardiomyopathy it is hypothesized
that inflammatory mediators, such as TNF-alpha and IL-6 may cause myocardial cells to
increase membrane permeability and leak proteins such as cTnI. 35 An increased serum
cTnI, therefore, can likely arise from both reversible and irreversible myocardial cellular
damage as evidenced by stress-induced cardiomyopathy in people.36 Although few
patients with sepsis have severe histopathologic myocardial lesions at necropsy,
contraction band necrosis, attributable to dysregulation and influx of calcium and
catecholamine toxicity,35 has been documented in septic human patients with left
ventricular dysfunction.37 Cardiac troponin I, a sensitive and specific biomarker of
myocardial injury, proved to be an important explanatory variable in MLR models for
short-term survival to discharge, the presence of a CSA and the presence of SIRS. This
suggests that myocardial injury occurs and is associated with adverse outcomes and SIRS
130
in horses with acute gastrointestinal disease. While the underlying etiology for an
increase in cTnI remains incompletely understood, the results of the study herein suggests
systemic inflammation plays a role.
The time domain HRV parameters, SDNN and RMSSD, were significantly lower
in horses with ischemic lesions and those that did not survive to discharge, however, only
the frequency domain parameter, LF power, measured on Day 1 was an important
explanatory variable in the survival to discharge model from cardiovascular assessment
on Day 1 post-operatively. In septic human patients, a lower LF power and reduced
RMSSD measured at admission were strongly associated with the development of MODS
in the hospital.19 In the study herein, the peak LF power was chosen for univariable
analysis on the basis that this would reflect increased sympathetic tone and based on its
performance in a previous study.24 The peak LF power measured on Day 1 was positively
associated with non-survival, which would suggest that having a higher LF power is a
negative finding in horses with colic. This is in contrast to what is recognized in septic
humans and rabbits with experimentally induced septic shock.41 Potential reasons for this
disparity might be a function of different times of analysis (human patients were studied
at admission versus the horses herein were evaluated post-operatively), distinct etiologies
of the underlying disease (sepsis in humans versus acute gastrointestinal disease in the
horse) and other species differences, especially in regard to endotoxin sensitivity.
Specifically, endotoxin sensitizes cardiac pacemaker cells to sympathetic stimuli42 and
horses are uniquely sensitive to endotoxin when compared to humans.37 Despite these
differences, reduced modulation of total HRV and the parasympathetic branch of the
ANS, corresponding to the decreased SDNN and RMSSD, respectively, are consistent
131
findings in critically-ill people and correspond to an increased risk for developing MODS
and mortality.43,44 Studying HRV at admission may be more appropriate for comparing to
the results of human studies and predicting which horses may be more likely to develop
complications in the post-operative period.
Increased post-operative HR, reduced SVI, low LVIDd/kg and greater RWT were
found in horses that did not survive to discharge which might suggest that preload was
the more pressing issue rather than left ventricular systolic dysfunction. Relative wall
thickness was the only echocardiographic derived parameter that was increased in both
horses with ischemic GI disease and non-survivors. An increase in RWT of greater than
0.55 was found to be reasonably accurate for detecting pseudohypertrophy in horses with
experimentally induced hypohydration.40 Pseudohypertrophy, from hypovolemia, could
potentially explain the increase in RWT in horses in this study; however, the multiple
regression model for RWT herein revealed that collectively HR, CVP, lactate and cTnI
concentration measured at the same time as RWT only explained 11.8% (adjusted R2
0.118) of the variability in RWT. This would suggest that hypovolemia was not the sole
reason for the increased RWT. In addition, the horses in the experimental model37 were
estimated to be 8-10% clinically dehydrated, which was not the case with the horses in
this study in the post-operative period, the majority of whom were receiving at least
maintenance rate of IV fluid therapy at the time of measurement. The effect of HR on
RWT in horses is not well documented, however other M-mode derived measurements
are altered by HR.41,42 The post-operative HR was significantly greater in the horses in
the ischemic group and non-survivors at all time-points. Tachycardia, which results in a
shorter diastolic period and limits preload might explain this finding along with the lower
132
SVI and smaller LVIDd/kg measurements in non-survivors compared to survivors. These
echocardiographic measurements were not statistically different between gastrointestinal
lesion groups but were different between survivors and non-survivors and are preload
dependent.
Low SVI was an important variable retained in the MLRs to explain non-survival
and presence of SIRS. In humans with sepsis, diastolic dysfunction is detected in the
absence of a reduced ejection fraction or other markers of systolic dysfunction, and is
more strongly correlated to cTnI.43 In fact, left ventricular end-diastolic volume index,
SVI and tissue Doppler imaging of the ratio of early mitral inflow velocity to early mitral
annular motion (E/eˊ ratio) all were significant decreased in people that died versus those
that survived. 44 Cardiac index, the product of SV and HR divided by body weight, was
significantly increased on Day 1 in horses when grouped by lesion category but was not
significantly associated with SIRS or outcome in the MLR models. This finding likely
can be explained by the quantitatively more efficient effect HR has on determining CO in
comparison to stroke volume.45 Echocardiographic measures of systolic function in this
study included FS, CI and SVI. With severe acute systolic dysfunction one would expect
a reduced FS while more chronic systolic dysfunction might be accompanied by an
increase in the LVIDd/kg that would indicate poor contractility and a dilated LV
chamber, respectively. However, with the exception of SVI, these parameters were not
retained in the MLR models and only LVIDd/kg was statistically different between
survivors and non-survivors, where survivors had larger left ventricular dimensions at
end diastole. When considering these findings together, it is not possible to draw a single
133
logical conclusion regarding left ventricular systolic function in horses with acute
surgical GI disease.
As previously reported, hypokalemia, ionized hypomagnesemia and
hypocalcemia were common findings in horses with colic.46-49 Interestingly, none of
these electrolyte derangements were associated with outcome or the presence of SIRS.
However, for every 0.1 mg/dL (0.04 mmol/L)50 unit decrease in ionized magnesium
concentration there was a 2.5 times increased risk of having a CSA. Further work is
needed to determine whether magnesium supplementation in the peri-operative period
would reduce the occurrence of CSAs in horses with colic.
A limitation in this study was that only echocardiographic methods were used to
assess systolic function and more accurate, gold-standard invasive measures were not
used. In addition, left ventricular diastolic function was not assessed with
echocardiography which may have precluded detecting diastolic dysfunction.
Furthermore, investigators were not blinded in this study, however, all measurements
were performed retrospectively and horse information entered for echocardiographic and
telemetric ECG was minimal (including only the medical record number and research
number in the study) preventing the investigators from determining which GI lesion
category the horse was in, or its SIRS or survival status. Missing data for individual
horses limited the power of the regression analysis. Despite this limitation, the numbers
in each group are comparable or greater than horses used in similar studies6-8 and the
addition of a control group that also underwent GA for a surgical procedure provided
novel information. Unfortunately, a complete necropsy was unable to be performed on
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the majority of the horses that were euthanized; therefore, gross and histopathological
characterization of myocardial lesions was not possible.
In conclusion, on the basis of increased serum cTnI concentration, reduced HRV,
hypotension under GA, increased incidence of CSA, greater HR, RWT, or reduced SVI,
or LVIDd/kg, horses with ischemic GI lesions or horses with GI lesions requiring surgery
that do not survive have evidence of myocardial dysfunction. Although a causal
explanation for these relationships could not be definitively determined, the parameters
described herein for assessing myocardial health should be considered in the assessment
of critically ill horses. Arrhythmias in horses in the post-operative period were associated
with cTnI and iMg2+ concentration. Clinically significant arrhythmias were also more
frequent in non-survivors and horses with SIRS, further research is warranted to
determine if therapeutic intervention with magnesium supplementation, anti-
inflammatories or anti-arrhythmic drugs would improve outcome. Peak cTnI
concentration was detected after admission in non-survivors; therefore measuring serum
cTnI concentration at the single time point of admission is unlikely to be a useful
prognostic tool for short-term survival.
135
FOOTNOTES
a. Heska CBC-Diff, Heska Corp, Loveland, CO
b. Sorvall Legend X1, Thermo Fischer Scientific Inc, Suwanee, GA
c. ADVIA Centaur cTnI Ultra Assay, Immulite 1000 Siemens, Deerfield, IL
d. Nova Biomedical, Critical Care Xpress, Waltham, MA.
e. Televet Version 3, Kruuse, Denmark
f. Kruuse ECG Electrodes, Jorgenson Medical
g. Mila International, Inc., Erlanger, KY.
h. Edwards Lifesciences LLC, Irvine, CA
i. SurgiVet Vital Signs Monitor, V9203; Smiths Medical, St. Paul, MN
j. Vivid 7, GE Medical Systems, Milwaukee, WI
k. M4S transducer, GE Medical Systems, Milwaukee, WI
l. Kubios HRV Version 2.1 Kuopio, Finland kubios.uef.fi/
m. Sigmaplot 12.5 Systat Software, Inc. San Jose, CA
n. MedCalc 14.8.1,Ostend, Belgium
136
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143
Table 5.1 Least squares mean ± SEM; Median [IQR] for variables measured over time in horses with acute GI disease grouped by surgical lesion category and time.
Variable Group Time
P value
Group Time Group
× time
Admission Day 1 Day 2
cTnI
(ng/mL)
I 1.7 ± 0.17; 0.02 [0.01 - 0.39]aA 2.8 ± 0.18; 0.14 [0.03 - 2.78]aB 2.0 ± 0.19; 0.11 [0.04 - 1.13]aB <0.001 0.001
0.07
NI 0.03 ± 0.15; 0.01 [0.01 -0.01]bA 0.15 ± 0.14; 0.02 [0.01 - 0.78]bB 0.19 ± 0.15; 0.02 [0.01- 0.07]bB
C 0.02 ± 0.25; 0.01 [0.01 - 0.01]cA 0.03 ± 0.25; 0.01 [0.01-0.02]cB 0.02 ± 0.25; 0.01 [0.01- 0.01]cB
Lactate
(mmol/L)
I 5.5 ± 0.30; 4.2 [1.5 - 8.0]a* 2.1 ± 0.31; 0.8 [0.6 - 1.45]a† 1.6 ± 0.37; 0.7 [0.53 - 0.98]a† < 0.001
< 0.001
0.007
NI 1.84 ± 0.26; 1.4 [0.9 - 2.2]b* 0.73 ± 0.26; 0.6 [0.5 - 0.8]b† 0.73 ± 0.26; 0.7 [0.6 - 0.9]ab†
C 0.72 ± 0.55; 0.7 [0.4 - 1.15]c 0.61 ± 0.45; 0.6 [0.3 - 0.85]b 0.55 ± 0.45; 0.45 [0.4 - 0.7]b
Na+
(mmol/L)
I 135 ± 0.41; 134.3 [133.4-136.7] 136 ± 0.45; 135.8 [134.2- 137.9] 135 ± 0.48; 134.6 [132.2-136.3] 0.032# 0.411 0.082
NI 134 ± 0.35; 134.4 [133.1-136.3] 134 ± 0.35; 133.7 [132.5- 134.9] 134 ± 0.37; 133.9 [132.2-135.6]
C 136 ± 0.97; 135.7 [133.4-138.2] 135 ± 0.70; 135.9 [133.7-137.2] 135 ± 0.64; 134.1 [133.6-136.2]
K+
(mmol/L)
I 3.4 ± 0.06; 3.4 [3.2 - 3.7]a* 3.5 ± 0.07; 3.4 [3.2 - 3.8]a* 3.8 ± 0.07; 3.8 [3.5 - 3.9]a† 0.001 < 0.001
0.04
NI 3.7 ± 0.05; 3.6 [3.5 - 3.9]b* 3.7 ± 0.05; 3.7 [3.5 - 4.0]ab* 4.1 ± 0.06; 4.0 [3.8 - 4.3]b†
C 3.6 ± 0.15; 3.5 [3.4 - 3.6]ab* 4.0 ± 0.11; 3.9 [3.7 - 4.3]b† 3.9 ± 0.10; 3.9 [3.6 - 4.0]ab†
144
I: ischemic; NI: non-ischemic; C: control. Within a column a lower case letter denotes difference between groups within a row an upper case letters denote a difference between time. Within a row different symbols (*†‡) indicate a difference within a group over time. cTnI: cardiac troponin I; Na+ sodium; K+: potassium, iCa2+: ionized calcium; iMg2+: ionized magnesium. # no significant difference after multiple pairwise comparisons.
iCa2+
(mmol/L)
I 1.29 ± 0.02; 1.32 [1.18-1.36]a* 1.41 ± 0.02; 1.38 [1.29-1.53]a† 1.51 ± 0.02; 1.51 [1.43-1.58]‡ <0.001 <0.001 0.007
NI 1.38 ± 0.02; 1.4 [1.32-1.44]b* 1.44 ± 0.02; 1.46 [1.40-1.51]a† 1.53 ± 0.02; 1.54 [1.52-1.58]‡
C 1.47 ± 0.04; 1.45 [1.39-1.50]b* 1.57 ± 0.03; 1.55 [1.53-1.61]b† 1.53 ± 0.03; 1.53 [1.48-1.58]*†
iMg2+
(mmol/L)
I 0.42 ± 0.01; 0.41[0.37- 0.44]a 0.42 ± 0.01; 0.43 [0.39 - 0.46]a 0.45 ± 0.01; 0.44 [0.39 - 0.50]a < 0.001 0.124
0.988
NI 0.47 ± 0.01; 0.47 [0.43 - 0.53]b 0.45 ± 0.01; 0.46 [0.39 - 0.50] b 0.47 ± 0.01; 0.46 [0.42 - 0.53]b
C 0.50 ± 0.02; 0.51 [0.47 - 0.53]c 0.50 ± 0.02; 0.54 [0.45 - 0.56]c 0.50 ± 0.02; 0.51 [0.49 - 0.54]c
Table 5. 1 continued
145
Table 5.2. Least squares mean ± SEM; Median [IQR] for variables measured post-operatively and with significant differences in horses with acute GI disease grouped by surgical lesion category and time.
Variable Group Time* P value
Group Time Group × time
Time 1 Time 2 Time 3 Time 4
SDNN (ms)
I 29.1 ± 3.8; 19.9 [8.6 - 49.4]a
27.9 ± 3.8; 29.1 [12.7 - 44.1]a
36.3 ± 4.1; 32.7 [19.7 - 38.2]a
40.2 ± 4.4; 42.5 [26 - 59.2]a < 0.001 0.076 0.438
NI 46.7 ± 3.3; 41.2 [24.3 - 56.6]b
44.7 ± 3.4; 38.9 [27.7 - 52.4]b
54.6 ± 3.3; 46.9 [35.6 - 60.6]b
56.5 ± 3.3; 46.4 [39.1 - 65.0]b
C 66.7 ± 6.0; 63.0 [32.9 - 79.3]c
75.9 ± 5.7; 78.0 [48.5 - 96.2]c
69.6 ± 5.7; 64.2 [46.1 - 96.5]c
68.0 ± 7.3; 62.0 [28.7 - 97.0]c
RMSSD (ms)
I 30.3 ± 5.1; 14.4 [6.1 - 46.2]a
27.6 ± 5.1; 23.8 [11.1 - 41.9]a
40.8 ± 5.4; 30.7 [18.7 - 43.0]a
42.5 ± 5.9; 42.5 [27.1 - 71.3]a
< 0.001 0.037# 0.212
NI 51.6 ± 4.4; 37.9 [21.0 - 61.8] b
48.2 ± 4.5; 43.5 [25.1 - 56.9] b
59.7 ± 4.3; 54.8 [36.1 - 71.6] b
62.8 ± 4.3; 50.0 [42.6 - 70.0]b
HR (bpm)
I 56 ± 1.16; 57 [49 - 75]a* 59 ± 1.16; 51 [45 - 68]a* 55 ± 1.75; 50 [41 - 65]a*† 50 ± 1.75; 46 [39 - 58]a† <0.001 < 0.001 0.009
NI 46 ± 1.31; 50 [44 - 63]b* 43 ± 1.35; 43 [38 - 51]b† 39 ± 1.40; 41 [36 - 48]b‡ 39 ± 1.37; 38 [33 - 42]ab†‡
C 41 ± 2.47c; 34 [32 - 44]b* 34 ± 2.54; 38 [32 - 49]c† 36 ± 2.54; 38 [31 - 43]b† 34 ± 2.54; 32 [29 - 37]c†
146
I: ischemic; NI: non-ischemic; C: control. Time*: for SDNN, RMSSD Time 1: 2-10 hours; Time 2: 16- 24 hours; Time 3: 30-38 hours ;Time 4: 44-52 hours. For MAP, HR, CI, RWT, ectopic beats: Time 1: 12 hours; Time 2: 24 hours; Time 3: 36 hours; Time 4: 48 hours. Within a column a lower case letter denotes difference between groups within a row an upper case letters denote a difference over time. Within a row different symbols (*†‡) indicate a difference within a group over time. SDNN: standard deviation of normal to normal intervals; RMSSD: root mean square of successive differences; HR: Heart rate; MAP: mean arterial blood pressure; CI: cardiac index; RWT: relative wall thickness. # indicates no significant difference after multiple pairwise comparisons.
MAP (mmHg)
I 86 ± 2.6; 88 [73 - 99] 84 ± 2.7; 86 [76 - 92] 82 ± 3.0; 83 [73 - 90] 87 ± 2.9; 89 [79 - 96] 0.047# 0.986 0.546
NI 83 ± 2.2; 82 [75 - 89] 79 ± 2.3; 78 [74 - 85] 81 ± 2.5; 81 [72 - 88] 77 ± 2.6; 79 [68 - 87]
C 74 ± 4.5; 72 [63 - 83] 82 ± 4.3; 75 [69 - 98] 79 ± 4.6; 79 [71 - 85] 79 ± 4.3; 76 [69 - 85]
Ectopic beats (#/ 24hr)
I --- 23.3 ± 6.8; 2.0 [0.0 - 13.0]a --- 31.4 ± 6.8; 3.0 [0.0 - 9.0]a 0.006 0.157 0.297
NI --- 2.2 ± 5.8; 0.0 [0.0 - 1.8]b --- 2.3 ± 5.8; 0.0 [0.0 - 1.0]b
C --- 1.7 ± 10.1; 0.5 [0.0 - 2.0]b --- 0.6 ± 10.1; 0.0 [0.0 - 1.5]b
CI (mL/kg/min)
I --- 66.7 ± 3.1; 62.0 [45.5 - 76.8]A
--- 59.8 ± 3.1; 51 [42.5 - 70.5]B
0.089 0.031 0.933
NI --- 60.4 ± 2.5; 59.0 [49.0 - 65.0]A
--- 52.5 ± 2.5; 51 [44.0 - 61.5]B
C --- 50.7 ± 4.5; 51.0 [38.0 - 60.0]A
--- 46.8 ± 4.5; 44 [37.0 - 50.0]B
RWT I --- 0.63 ± 0.02; 0.63 [0.53 - 0.70]a
--- 0.62 ± 0.02; 0.59 [0.48 - 0.70]a
0.004 0.668 0.483
NI --- 0.54 ± 0.02; 0.52 [0.49 - 0.59]b
--- 0.54 ± 0.02; 0.53 [0.49 - 0.56]b
C --- 0.51 ± 0.03; 0.51 [0.48 - 0.55]b
--- 0.52 ± 0.03; 0.52 [0.48- 0.59]b
Table 5.2. continued
147
Table 5.3. Least squares mean ± SEM; Median [IQR] for significant variables measured in horses with acute GI disease grouped by survival outcome and time.
Variable Group Time
P value
Group Time Group
× time
Admission Day 1 Day 2
cTnI
(ng/mL)
S 0.39 ± 0.11; 0.01 [0.01 - 0.02]* 0.77 ± 0.11; 0.02 [0.01 - 0.1]a† 0.51 ± 0.11; 0.02 [0.01 - 0.08]a† 0.01 < 0.001
0.001
NS 2.1 ± 0.28; 0.01 [0.01 - 0.02]* 2.8 ± 0.31; 0.23 [0.04 - 1.6]b† 2.9 ± 0.36; 0.17 [0.02 - 1.3]b†
Lactate
(mmol/L)
S 2.6 ± 0.22; 1.5 [0.9 - 3.4]aA 0.73 ± 0.21; 0.6 [0.5 - 0.8]aB 0.71 ± 0.22; 0.7 [0.5 - 0.9]aB 0.001
< 0.001
0.311
NS 5.5 ± 0.54; 4.6 [1.3 -7.2]bA 4.3 ± 0.60; 1.6 [0.6 - 2.3]bB 3.3 ± 0.87; 0.9 [0.5 - 2.0]bB
K+
(mmol/L)
S 3.6 ± 0.04; 3.6 [3.3 - 3.8]A 3.7 ± 0.04; 3.7 [3.3 - 4.0]AB 3.9 ± 0.04; 3.9 [3.7 - 4.2]B 0.835 0.002
0.648
NS 3.5 ± 0.1; 3.6 [3.4 - 3.7]A 3.7 ± 0.1; 3.7 [3.4 - 3.9]AB 3.9 ± 0.2; 3.8 [3.7 - 4.1]B
iCa2+
(mmol/L)
S 1.36 ± 0.1; 1.39 [1.28 - 1.44]aA 1.45 ± 0.1; 1.47 [1.38 - 1.53]aB 1.53 ± 0.1; 1.54 [1.51 - 1.58]aB 0.002 <0.001
0.081
NS 1.33 ± 0.2; 1.36 [1.26 - 1.37]bA 1.40 ± 0.3; 1.43 [1.34 - 1.51]bB 1.41 ± 0.2; 1.43 [1.40 - 1.49]bB
S: survivor; NS: non-survivor. Within a column a lower case letter denotes difference between groups within a row an upper case letters denote a difference between time. Within a row different symbols (*†‡) indicate a difference within a group over time. cTnI: cardiac troponin I; Na+: sodium; K+: potassium, iCa2+: ionized calcium.
148
Table 5.4. Least squares mean ± SEM; Median [IQR] for significant variables measured post-operatively in horses with acute GI disease grouped by survival outcome and time.
Variable Group Time* P value
Group Time Group x
Time
Time 1 Time 2 Time 3 Time 4
SDNN
(ms)
S 47.4 ± 2.5; 43.8
[23.0 - 61.7]a
47.4 ± 2.5; 40.0
[27.5 - 58.0]a
55.5 ± 2.5; 47.5
[34.5 - 75.9]a
57.0 ± 2.6; 49.4
[36.2 - 68.4]a
< 0.001
0.151
0.354
NS 20.6 ± 6.2; 12.5
[5.4 - 30.7]b
21.6 ± 6.2; 22.5
[9.2 - 33.9]b
18.4 ± 6.7; 19.6
[9.7 - 30.3]b
27.5 ± 7.8; 32.4
[9.3 - 46.6]b
RMSSD
(ms)
S 54.0 ± 3.3; 40.4
[19.8 - 70.0]a
52.3 ± 3.3; 45.2
[27.2 - 69.1]a
62.6 ± 3.3; 52.6
[34.8 - 77.6]a
64.1 ± 3.5; 52.1
[41.5 - 81.8]a
< 0.001 0.053 0.924
NS 13.7 ± 8.2; 7.6
[5.7- 25.0]b
16.7 ± 8.2; 16.7
[10.4 - 24.6]b
17.7 ± 8.9; 17.2
[5.0 - 33.9]b
23.9 ± 10.4; 32.2
[12.3 - 44.0]b
HR
(bpm)
S 46 ± 1.0; 49 [43 - 61]aA 44 ± 1.0; 43 [38 - 51]aAB 41 ± 1.0; 42 [36 - 48]aB 39 ± 1.0; 38 [33 - 43]aB <0.001 0.002
0.371
NS 63 ± 2.6; 65 [52 - 77]bA 70 ± 2.9; 62 [50 - 72]bAB 64 ± 3.5; 73 [43 - 96]bB 61 ± 3.5; 56 [41 - 76]bB
149
S: survivor; NS: non-survivor. Time*: for SDNN, RMSSD Time 1:2-10 hours; Time 2: 16- 24 hours; Time 3: 30-38 hours ;Time 4: 44-52 hours. For HR, SVI, LVIDd/kg, RWT: Time 1: 12 hours; Time 2: 24 hours; Time 3: 36 hours; Time 4: 48 hours. Within a column a lower case letter denotes difference between groups within a row an upper case letters denote a difference between time. SDNN: standard deviation of normal to normal intervals; RMSSD: root mean square of successive differences; SVI: stroke volume index; LVIDd/kg: left ventricular internal diameter in diastole/kilogram; RWT: relative wall thickness.
SVI (mL/kg)
S --- 1.4 ± 0.04; 1.3 [1.2 - 1.6]a --- 1.3 ± 0.04; 1.3 [1.1 - 1.5]a < 0.001 0.689 0.933
NS --- 0.9 ± 0.11; 0.9 [0.7 - 1.2]b --- 0.9 ± 0.11; 1.0 [0.6 - 1.2]b
LVIDd/kg S --- 0.021 ± 0.0004; 0.02 [0.019 - 0.022]a
--- 0.021 ± 0.0004; 0.02 [0.019 - 0.022]a
0.004 0.702 0.532
NS --- 0.018 ± 0.0011; 0.017 [0.016 - 0.02]b
--- 0.017 ± 0.0011; 0.016 [0.016 - 0.02]b
RWT S --- 0.55 ± 0.118; 0.52 [0.49 - 0.60]a
--- 0.54 ± 0.118; 0.53 [0.48 - 0.57]a
< 0.001 0.809 0.405
NS --- 0.75 ± 0.033; 0.72 [0.65 - 0.84]b
--- 0.77 ± 0.033; 0.70 [0.69 - 0.81]b
Table 5.4. continued
150
Table 5.5. Results of backward stepwise multivariable logistic regression analyses for survival to discharge, survival to discharge for data collected at 24 hours, systemic inflammatory response syndrome (SIRS) and clinically significant arrhythmias in horses that underwent exploratory laparotomy for colic and elective surgical cases.
Model n= Variable Coefficient SE P value OR 95% CI
Survival to discharge 67 Constant 0.612 N/A N/A N/A N/A
cTnI > 0.15 ng/mL 3.043 1.175 0.010 20.982 2.097 - 209.89
Trough SVI (mL/kg) -3.992 1.783 0.025 0.0185 0.001 - 0.608 Survival to discharge (24 hr) 63 Constant -2.748 N/A N/A N/A N/A
24 hr LF (n.u) 0.165 0.067 0.014 1.179 1.034 - 1.344 24 hr SVI (mL/kg) -8.286 3.391 0.015 0.0003 0.000 - 0.194
24 hr RWT >0.63 2.664 1.417 0.060 14.35 0.893- 230.485 Systemic inflammatory response syndrome
67 Constant 2.723 N/A N/A N/A N/A Peak cTnI (ng/mL) 0.955 0.347 0.006 2.599 1.316 - 5.136
Peak PAR 0.512 0.250 0.041 1.669 1.022 - 2.723 Trough SVI (mL/kg) -4.423 1.462 0.003 0.012 0.0007 - 0.211
Clinically significant arrhythmias
74 Constant 6.917 N/A N/A N/A N/A
Peak cTnI (ng/mL) 1.017 0.316 0.0013 2.766 1.488 to 5.141
iMg2+ (0.1 mg/dL) -0.933 0.418 0.0256 0.393 0.173 to 0.893
151
CHAPTER 6
A MULTIPLE ORGAN DYSFUNCTION SCORE FOR ADULT HORSES WITH
ACUTE GASTROINTESTINAL DISEASE5
______________________________
5E.L. McConachie, S. Giguère, M.H. Barton. To be submitted to the Journal of
Veterinary Internal Medicine.
152
ABSTRACT
Background: The incidence of multiple organ dysfunction syndrome (MODS) in horses
with acute gastrointestinal disease is unknown. At present there are no validated criteria
to confirm MODS in adult horses.
Objectives: Develop criteria for a MODS score for use in horses with acute
gastrointestinal disease (MODS GI) and evaluate its association with six-month survival.
Compare the newly developed MODS GI scoring system to another recently proposed
MODS score that was extrapolated from human criteria for use in equids (MODS EQ).
Animals: Adult horses (> 1 year of age) presented for colic that required exploratory
laparotomy (n=62). Healthy adult horses (> 1 year of age) presented for an elective
surgical procedure (n=12) were used to establish the reference range of some variables.
Methods: A MODS GI scoring system was proposed based on organ system-specific
criteria that were developed from a literature review, data collected from healthy animals,
and clinical judgment. Based on data prospectively collected from Day 1 and Day 2 post-
surgery, horses with acute surgical colic were scored retrospectively using both the
MODS GI and the MODS EQ scoring criteria. The total number of organs affected and
the total number of organs failed were recorded for each horse. Receiver operating
characteristic (ROC) curve analysis was used to assess the diagnostic performance of the
MODS GI scoring system and to compare its overall performance to MODS EQ.
Results: The MODS GI score proposed herein had excellent performance post-
operatively with an area under the ROC curve (AUC) of 0.95 [0.87 - 0.99]). The area
under the ROC curve for the MODS GI score was significantly higher than that of the
MODS EQ (AUC: 0.76 [0.63-0.86].
153
Conclusions and clinical significance: The MODS GI score proposed herein predicts
six-month survival to discharge in horses with acute surgical gastrointestinal lesions. The
MODS GI score derived from equine specific criteria performed better than a score
extrapolated from human scoring systems.
INTRODUCTION
Critically-ill patients in the medical or surgical intensive care units often develop
progressive organ dysfunction unrelated to their underlying condition. This clinical
phenomenon, aptly coined multiple organ dysfunction syndrome (MODS), was first
recognized in human intensive care units in the 1970’s and ironically coincided with an
improved capacity to save trauma patients from what had previously been life-ending
injuries.1 The clinical significance of identifying sequential organ dysfunction is two-
fold. First, as multiple organs fail the risk of death increases accordingly.2 Secondly,
since the introduction of MODS scoring systems for critically-ill patients, overall MODS
severity and mortality rates have declined in the surgical ICU.3 In part, this is due to
earlier recognition of changes in patient status in combination with supportive and goal-
directed interventions.3,4
Various approaches were used to develop scoring systems for sequential organ
dysfunction in humans. In 1995, Marshall and colleagues published their MODS score
based on a review of the literature and retrospective data collected from critically-ill
patients that enabled the authors to determine organ-specific criteria that reflected a range
of clinical dysfunction from normal to failure. A separate group determined organ
dysfunction criteria empirically based on the consensus of experts and created the sepsis-
154
related organ failure assessment (SOFA) score5 (the name was later changed to sequential
organ failure assessment). Both groups applied their scoring systems prospectively to
critically-ill patients to assess the association of the score and all-cause in-hospital
mortality and the incidence of development of multiple organ failure.2,6 The purpose of
both of these scoring systems was to provide a way to objectively describe the continuum
of organ dysfunction with simple criteria that could easily be compared across a
heterogenous group of critically-ill patients and across hospitals with varied protocols.
In horses, individual organ dysfunction of the renal, hepatic, cardiovascular and
hemostatic systems has been reported most frequently in horses with acute
gastrointestinal disease.7-12 Criteria for MODS in horses, referred to herein as the MODS
EQ score, have been previously proposed based on the human MODS criteria, but remain
unvalidated.13 Multiple organ dysfunction syndrome is a dynamic process that can be
reversible if detected and managed prior to end-stage disease, highlighting the need for
equine-specific organ dysfunction criteria and a scoring system validated for clinical use.
Anecdotally, the clinical phenomenon of multiple organ system failure (MOF) is
recognized in horses, however, comprehensive reports in the equine literature are lacking.
Two studies refer to MODS as an outcome or cause for death/euthanasia,11,14 however,
the criteria used in these studies vary, and are essentially adaptations from the human
scoring systems that may not be an appropriate representation of organ dysfunction in
critically-ill adult horses.13 Additionally, the current criteria provide a dichotomous
outcome of organ dysfunction, thereby failing to reflect a continuum of organ
dysfunction. No studies have critically evaluated organ dysfunction criteria in a clinical
setting and as such it is debatable if these criteria are appropriate for describing MODS in
155
critically-ill adult horses. Similarly, the incidence of MODS and relevance of detecting
MODS in critically-ill equids are currently unknown.
The purpose of the study reported herein was to develop criteria for individual
organ dysfunction and a MODS scoring system for use in horses with acute surgical
gastrointestinal disease (MODS GI) reflecting a range of clinical severity. The
hypotheses tested in this study were that 1) the MODS GI score developed herein would
be associated with long-term outcome (six-month survival), 2) the mortality rate would
increase in correspondence with an increasing number of dysfunctional organs, and 3) the
MODS GI score would be associated with the systemic inflammatory response syndrome
(SIRS). In addition we tested the null hypothesis that the MODS GI score proposed
herein would not be inferior to the MODS EQ score.
MATERIALS AND METHODS
Score Development
A literature search was conducted to identify studies or reports of single organ
dysfunction in horses with naturally-occurring acute gastrointestinal disease, primary
organ failure or organ dysfunction following anesthetic events. The organ systems
described most commonly included the cardiovascular,a,9,10,15 renal,7 hepatic,8
gastrointestinal,16-18 musculoskeletal19 (including laminitis),20 respiratory21,22 and
hemostatic23-26 (coagulation) systems. Organ system specific criteria were then chosen
from this literature search and included serum cardiac troponin concentration (cTnI),
stroke volume index (SVI), standard deviation of normal-to-normal intervals (SDNN),
creatinine and serum bile acids (SBA) concentrations, nasogastric reflux volume,
156
abdominal distension, serum creatine kinase activity (CK), Obel grade lameness,
PaO2/FiO2 ratio, respiratory rate and effort, and platelet count or prothrombin time (PT).
Neurologic system evaluation is routinely assessed in critically-ill human patients, though
it is infrequently performed or reported in horses with colic.27 Therefore, in place of a
neurologic score, attitude was assessed using a modified pain score (Supplement 6.1)28
that incorporated both postural and social behaviors with the purpose of recording a
general sense of demeanor and awareness (lassitude, responsive or agitated) similar to the
purpose of the Glasgow Coma Score in critically-ill people.
In order to develop a range of organ dysfunction criteria, the normal reference
range from the hospital’s clinical pathology laboratory, data extracted from the literature
review, or data collected on three consecutive days from 12 healthy adult horses that
underwent general anesthesia of at least one hour duration for an elective surgical
procedure (control group), were used as aides for determining ranges for each organ
criterion. Raw data was assessed for normality with visual inspection of the histogram
and with a Shapiro-Wilks test. For normally distributed data the mean and standard
deviation were used to establish a reference interval. When data was non-normally
distributed the 95% reference interval was derived using a non-parametric approach. A
range of values that corresponded to a score of 0 to 3 (0 = normal, 1 = mildly abnormal, 2
= moderately abnormal, 3 = severely abnormal) were assigned based on the references
interval for normal values (score of 0) and abnormal values reported in the literature
associated with outcome when available for scores of 1 to 3. Ultimately, the collective
clinical judgment of the three authors was also used to empirically propose cut-off
designations which followed a similar approach to what has been done for previous
157
scoring systems in both human and veterinary medicine.5,29 The criteria used to develop
the individual scores for each organ system are presented in Supplement 6.2.
Score Assessment
The score developed herein was then retrospectively evaluated in 62 horses that
presented for colic and required exploratory laparotomy. The outcomes of interest were
survival to six months and the presence of SIRS. Horses that were euthanized solely due
to financial constraints were not included in the data set. Horses were categorized as
having SIRS if they fulfilled criteria for SIRS on Day 1 or 2 post-operatively based on
criteria used for adult horses in similar clinical studies and included two or more of the
following: temperature ≥ 101.5°F or ≤ 98.5°F; heart rate ≥ 60 bpm; respiratory rate ≥ 30
bpm; white blood cell count ≥ 14,500 cells/µL or ≤ 4,500 cells/ µL and or ≥ 10% band
neutrophils.12,13 Horses were scored based on data collected at Day 1 and Day 2 post-
operatively with possible scores ranging from 0 to 24 for the MODS GI score created
herein (Table 6.1). The total number of organs affected (score > 1) and the total number
of organs failed (score = 3) on each day were recorded for each horse for association with
outcome. The Delta MODS GI score was recorded (Day 1 MODS GI score – Day 2
MODS GI score) for each horse. Finally, the individual organ system scores were also
recorded for each horse on both days. Additionally, a total score was also given for the
MODS EQ score, with a possible range of 0 to 7 for comparison to the MODS GI score
developed in this study (Table 6.2).
Data collection
Clinical data were collected both prospectively and retrospectively from 62 horses
with acute gastrointestinal disease from Day 1 and Day 2 after surgery. All horses were
158
then scored retrospectively on the two consecutive days. If two measurements were
recorded in a 24-hour period the measurement corresponding to the worst score was used
for calculation of both MODS score. For some organ systems, multiple criteria are
proposed; in which case the variable that corresponded to the highest score was applied.
For organ systems with multiple criteria, only one score was given per organ system,
meaning that scores for individual variables within an organ system were not tallied.
Data collection has been described previously for cardiovascular parameters
evaluated herein and included measuring indirect mean arterial blood pressure (MAP),
continuous telemetry for heart rate variability (HRV) and rhythm analysis, and
echocardiography for stroke volume index as previously described.a,15 For
clinicopathologic data blood was collected in serum, calcium EDTA and citrate tubes for
measurement of serum bile acids, total bilirubin, and cTnI concentrations, GGT and CK
activities, platelet count, and PT, respectively, at admission and on Day 1 and Day 2.
Serum and citrated plasma were separated in a temperature-controlled centrifugeb at 3000
rpm for 30 minutes and stored at -80°C for batch analysis at the University’s clinical
pathology laboratoryc,d with the exception of cTnI which was analyzed with an
ultrasensitive assaye at a regional hospital. Platelet counts were run immediately on an
automated analyzerf and were confirmed with manual platelet estimates. Platelet counts
accompanied by a morphology comment indicating platelet clumping were not used in
the score. In addition, arterial blood was collected into a heparinized blood gas syringe
from the transverse facial artery for immediate measurement of PaO2 and heparinized
blood creatinine concentration on a critical care analyzerf on Days 1 and 2 post-
operatively. Attitude was scored prospectively by a single evaluator (ELM) at Day 1 and
159
2 hours post-operatively as a proxy for assessment of the neurologic system (see
Supplement 6.1). Retrospective data collection included searching the record for
respiratory rate and effort and the presence or absence of gastrointestinal sounds at
approximately 24 and 48 hours after recovering from surgery as well as measurement of
total nasogastric reflux/24 hours on Day 1 and Day 2 post-operatively. Delta values for
creatinine and cTnI concentrations were derived from the difference between admission
and Day 1 values, and from the difference between Day 1 and Day 2 values.
Statistical analysis
The overall performance of MODS total scores, total number of organs affected
(score ≥ 1) and total number of organs failed (score = 3) in predicting six-month survival
was assessed using receiver operator characteristic (ROC) curve analysis. The optimal cut
point to maximize sensitivity and specificity was selected based on the Youden index.
Logistic regression was used to calculate the odds ratio at the optimal cut point.
Multivariable logistic regression was used to investigate the association between scores
for individual organs and six-month survival. The significance of the difference between
the AUC of MODS GI and that of MODS EQ was assessed using the method described
by DeLong et al.30 A similar approach was used to assess the overall performance of
MODS GI in predicting SIRS. For all analyses, significance was set at P < 0.05.
RESULTS
Of the 62 horses with colic that required exploratory laparotomy and that were
evaluated in this study, 49 horses survived to six months and 13 horses were euthanized
prior to six months. Ten of these horses were euthanized prior to hospital discharge due
160
to reasons related to their primary complaint or development of severe complications
[clinical evidence of multiple organ failure (n=4), post-operative ileus (n=2), adhesions
diagnosed with a repeat laparotomy (n=2), septic peritonitis and abdominal incision
dehiscence (n=1), and hemoabdomen (n=1)]. Three additional horses were euthanized at
their respective farms within 45 days [14 (10-45) days] of hospital discharge due to
repeat colic episodes. Field necropsies were not performed, however all three of these
horses were moderately to severely painful, had spontaneous nasogastric reflux and
evidence of small intestinal distension upon palpation per rectum.
Surviving horses had the following diagnoses: strangulating lipoma (n= 14), right
dorsal displacement (n=10), ileal impaction (n=6) , left dorsal displacement (n=5), cecal
impaction (n=3), large colon volvulus ≥ 360 degrees with partial resection (n=2),
mesenteric volvulus (n=2), enterolith (n=2), large colon volvulus ≥ 360 degrees with no
resection (n=1), epiploic foramen entrapment (n=1), gastrosplenic ligament entrapment
(n=1), inguinal hernia with small intestinal incarceration (n=1), focal infarction of the left
dorsal colon (n=1). Two horses that survived > six months had repeat exploratory
laparotomies which revealed a right dorsal displacement in one horse and a non-
functional jejunoileostomy which was subsequently revised.
Horses that were euthanized had the following diagnosis at initial exploratory
laparotomy: strangulating lipoma (n=5), large colon volvulus ≥ 360 degrees (n=4),
epiploic foramen entrapment (n=1), omental entrapment (n=1), mesenteric volvulus (n=1)
and a right dorsal displacement with small intestinal distension (n=1). Four horses in the
non-surviving group had repeat exploratory laparotomies at which time two horses were
euthanized due to adhesion formation, one horse had a decompression of the small
161
intestine with no revision of the original jejunoileostomy, and one horse had a region of
necrotic colon resected and over-sewn.
Scores were calculated on Day 1 for all 62 horses. A score could not be calculated
for three horses on Day 2 as these three horses were euthanized prior to 36 hours post-
operatively. Horses with a MODS GI score of > 8 on Day 1 and > 6 on Day 2 had OR of
105.6 and 46.1, respectively (Table 6.3). When horses had > 3 organs affected on Day 1
or Day 2 they were 14.4 and 35.1 times more likely to not survive to six months,
respectively (Table 6.3). In addition, horses with > 1 organ failing on Day 1 were 25.3
times more likely to not survive to six months and those with > 1 organs failing on Day 2
were 22.5 times more likely to not survive at six months (Table 6.3). The overall
diagnostic performance of the MODS GI score on Day 1 (AUC: 0.93 ± 0.04) was similar
and not significantly different (P = 0.90) from that obtained on Day 2 (AUC: 0.94 ±
0.03). Therefore, the average of Day 1 and 2 was used in subsequent analyses. The
average of the MODS GI score from Day 1 and Day 2 had the best overall performance
(AUC: 0.95 ± 0.03). The best sensitivity (92%) and specificity (87%) for the MODS GI
score was at a score of > 7. Figure 6.1 demonstrates sensitivity and specificity based on
total MODS GI score at various cut points. In addition, horses with a score of > 7 were
10.7 times more likely to have SIRS. A MODS GI score excluding the cardiovascular
criteria SDNN was evaluated and had similar performance compared to the total MODS
GI score (AUC: 0.91 95% CI = 0.81- 0.97). The Delta MODS score was not
significantly associated with outcome. No single organ system was significantly
associated with outcome. The frequency of organ systems affected and the corresponding
MODS GI score on Day 1 and Day 2 are presented in Table 6.4.
162
There was a tendency for lower diagnostic performance of the MODS EQ score
on Day 1 (AUC: 0.61 ± 0.11) versus Day 2 (AUC: 0.82 ± 0.07); P = 0.058. The MODS
EQ score was subsequently averaged which resulted in fair test performance (AUC: 0.76
± 0.08). The MODS GI score performed significantly better for predicting six-month
survival compared to the MODS EQ score (P = 0.008; Figure 6.2).
DISCUSSION
The MODS GI score proposed herein had excellent test performance for
determining six-month survival. In addition, there was an association with the number of
organs affected, and the number of organs failed with six-month survival where horses
with > 3 affected organs on Day 1 or 2, or > 1 failed organ on Day 1 and > 1 failed organ
on Day 2 were significantly less likely to be alive at six months. Finally, the null
hypothesis that there would be no difference between the MODS GI score developed
herein and the MODS EQ score extrapolated from human criteria was rejected based on
the significantly better performance of the MODS GI score compared to the MODS EQ
score (Figure 6.2). A statistically significant difference was not found for the
performance of either score on Day 1 versus Day 2. However, there was a trend towards
inferior performance of the MODS EQ score on Day 1 versus Day 2, which suggests that
the performance of the MODS EQ score might vary from day to day. When considering
the variation in the MODS EQ this might limit its usefulness as a system to score organ
dysfunction on consecutive days. In addition, with the overall inferior performance of the
score when compared to the MODS GI score, the MODS EQ score is most likely
inappropriate for describing organ dysfunction in adult equids.
163
Several of the individual organ system criteria in the proposed MODS GI score
incorporate a choice from multiple possible criteria rather than limiting assessment to a
single variable. As an example the criteria for the cardiovascular system includes the
choice to score cTnI concentration, SVI, SDNN (a variable from HRV) or clinically
significant arrhythmias. Despite the possibility that multiple variables within an organ
system might be abnormal, a single score was given for each organ system with the
purpose of avoiding organ score inflation. In this study when data were available for
more than one modality for an individual organ, the criterion which gave the highest
possible score was used. It could be argued that tallying the scores for each variable
within an organ system might be another reasonable approach. The rationale for
providing multiple methods or criterion for scoring an individual organ system was
centered on the principle that the organ could be scored even if all variables were not
measured in an individual horse. Providing clinicians with a choice of measurement
modalities for individual organs offers more flexibility in a clinical setting. Recognizing
that HRV is not routinely performed in the clinic, the total score was evaluated when
SDNN was excluded from the cardiovascular criteria and the performance of the MODS
GI score remained similar (AUC: 0.91; 95% CI: 0.81-0.97).
The range of the score 0 to 24 is similar to the range established in human critical
care and provides a continuum of organ dysfunction rather than a dichotomous outcome
of failed or not failed. In this study a score of > 7 had the best sensitivity (92%) and
specificity (88%) for the outcome of survival to six months. The overall mortality rate in
the study herein was 13/62 (21%) this corresponds well to scoring and mortality rates in
164
the human literature where a MODS score between 6 and 10 corresponds with a mortality
rate between 7 and 26% and with two or fewer failed organs.2
While the MODS GI score developed herein shows potential to be useful in the
assessment of critically-ill patients, prospective studies are needed to test the performance
of this score in horses with various acute disease etiologies. The MODS and SOFA
scores were originally validated in patients in the surgical ICU2 or in the a mixed group
of medical and surgical ICU patients.6 Since the initial inception of the multiple organ
dysfunction scoring systems in those specific groups, both scores have been successfully
validated in patients with a broad spectrum of medical and surgical conditions.31-33
The limitations in this study include the lack of a specific definition for what
constitutes organ dysfunction and failure in each evaluated organ system, determination
of specific cut-off criteria based on data collected from horses at one center, and score
criteria that were in part limited to the opinion of three board-certified clinicians. A
fundamental problem with creating or “validating” a severity score of any kind is
choosing the most appropriate outcome parameter. Ideally a MODS score should be
correlated to absolute organ failure. As such the best outcome parameter would
seemingly be organ failure confirmed histopathologically. The inherent problem with that
approach is that there is not a universally accepted pathognomonic histopathologic lesion
that corresponds with organ failure.34 Instead the definition of dysfunction and
subsequent failure of organs is a clinical entity that is to a large extent, opinion
dependent. Therefore, a seemingly appropriate outcome measure for the total score is
survival to a clinically relevant time point. Survival to six months was chosen as the
outcome of interest rather than survival to discharge because in people with MODS,
165
organ dysfunction is not only related to short-term mortality but also with long-term
mortality, where typically 28-day mortality and out-of-hospital complications are typical
outcomes.35 In the group of horses that survived to hospital discharge but were
euthanized prior to six months, horses were euthanized at day 28, 39 and 68 post-
operatively, which more closely reflects the 28-day and 90-day mortality rates often used
as outcomes in human critical care.36,37
The criteria proposed herein were developed primarily from the normal reference
ranges of the clinical pathologic laboratory at this institution, normal horses from the
region and the clinical judgment of the authors. Criteria chosen empirically were used to
establish the original SOFA score in humans and have been validated repeatedly. In fact
the cardiovascular criteria used in the SOFA score performed more robustly than the
MODS score.38 Whenever available, data in the literature collected from other institutions
were incorporated into determining the cut-offs for each score within an organ system.8,19
Furthermore, the use of ROC analysis on the data set to define cut-points for organ scores
was avoided to prevent choosing criteria that were only associated with non-survival
since the goal of the score was to reflect a range of organ dysfunction. Instead, the organ
scores were proposed first and retrospectively applied to a clinical data set. Despite the
excellent performance of the MODS GI score in the horses that comprised this data set, it
will be necessary to validate the MODS GI score in multiple centers before it can be
employed as a routine clinical assessment or as a definition for MODS in clinical
research.
The proposal of this MODS GI scoring system provides an initial step for
studying and understanding the pathophysiology and incidence of multiple organ
166
dysfunction in critically-ill equids. Prospective studies will be needed to determine the
clinical utility of using a system to score MODS with the goal of determining if the
MODS GI score enhances a clinician’s ability to recognize organ insufficiency at an
earlier stage. This ultimately might provide objective criteria to monitor and measure
responses to both well-established and novel therapies thereby justifying the cost and
labor required in measuring the criteria needed to formulate the MODS GI score. At
present the MODS GI score provides an objective method to measure disease severity
and assess risk of mortality. Finally, similarly to what was one of the original purposes of
severity scoring systems in people, a reliable equine MODS score could be applied across
various equine critical care units facilitating the comparison of the performance of goal-
directed therapy. This might assist equine clinicians in meeting the ultimate target of
improving outcomes in critically-ill equine patients.
In conclusion, the MODS GI score provides prognostic information in horses with
acute surgical colic when scored post-operatively. A MODS GI score of > 7 provided
good test sensitivity and specificity and was associated with the presence of SIRS. The
MODS GI score performed better at predicting six-month survival compared to the
MODS EQ score. Future studies will be necessary to test the validity of this scoring
system prospectively on critically-ill horses in different centers and with different disease
etiologies.
167
FOOTNOTES
a. McConachie EL, Giguère S, Rapoport G, Brown S, Barton MH. Assessment of
cardiovascular status in horses with naturally acquired ischemic intestinal disease.
J Vet Cardio. Submitted.
b. Sorvall Legend X1, Thermo Fischer Scientific Inc, Suwanee, GA
c. Hatachi P-module biochemical analyzer, Roche Inc., Florence, SC
d. Trinity AMAX Destiny Coagulation analyzer, Diamond Diagnostics
e. ADVIA Centaur cTnI Ultra Assay, Immulite 1000 Siemens, Deerfield, IL
f. Heska CBC-Diff, Heska Corp, Loveland, CO
g. Nova Biomedical, Critical Care Xpress, Waltham, MA.
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distress syndromes in veterinary medicine: consensus definitions: The Dorothy Russell
Haveymeyer Working Group on ALI and ARDS in Veterinary Medicine J Vet Emerg
Crit Care (San Antonio) 2007;17:333-339.
23. Dallap BL, Dolente B, Boston R. Coagulation profiles in 27 horses with large colon
volvulus. J Vet Emerg Crit Car 2003;13:215-225.
24. Welch RD, Watkins JP, Taylor TS, et al. Disseminated intravascular coagulation
associated with colic in 23 horses (1984-1989). J Vet Intern Med 1992;6:29-35.
25. Dallap Schaer BL, Epstein K. Coagulopathy of the critically ill equine patient. J Vet
Emerg Crit Care (San Antonio) 2009;19:53-65.
26. Dolente BA, Wilkins PA, Boston RC. Clinicopathologic evidence of disseminated
intravascular coagulation in horses with acute colitis. J Am Vet Med Assoc
2002;220:1034-1038.
27. Sharkey LC, DeWitt S, Stockman C. Neurologic signs and hyperammonemia in a
horse with colic. Vet Clin Pathol 2006;35:254-258.
28. Pritchett LC, Ulibarri C, Roberts MC, et al. Identification of potential physiological
and behavioral indicators of postoperative pain in horses after exploratory celiotomy for
colic. Appl Anim Behav Sci 2003;80:31-43.
29. Brewer BD, Koterba AM. Development of a scoring system for the early diagnosis
of equine neonatal sepsis. Equine Vet J 1988;20:18-22.
30. DeLong ER, DeLong DM, Clarke-Pearson DL. Comparing the areas under two or
more correlated receiver operating characteristic curves: a nonparametric approach.
Biometrics 1988;44:837-845.
171
31. Ceriani R, Mazzoni M, Bortone F, et al. Application of the sequential organ failure
assessment score to cardiac surgical patients. Chest 2003;123:1229-1239.
32. Lorente JA, Vallejo A, Galeiras R, et al. Organ dysfunction as estimated by the
sequential organ failure assessment score is related to outcome in critically ill burn
patients. Shock 2009;31:125-131.
33. Graciano AL, Balko JA, Rahn DS, et al. The Pediatric Multiple Organ Dysfunction
Score (P-MODS): development and validation of an objective scale to measure the
severity of multiple organ dysfunction in critically ill children. Crit Care Med
2005;33:1484-1491.
34. Lucas S. The Autopsy Pathology of Sepsis-Related Death, Severe Sepsis and Septic
Shock-Understanding a Serious Killer. In: Fernandez R, ed. InTech; 2012.
35. Mizock BA. The multiple organ dysfunction syndrome. Dis Mon 2009;55:476-526.
36. Serpa Neto A, Veelo DP, Peireira VG, et al. Fluid resuscitation with hydroxyethyl
starches in patients with sepsis is associated with an increased incidence of acute kidney
injury and use of renal replacement therapy: a systematic review and meta-analysis of the
literature. J Crit Care 2014;29:185 e181-187.
37. Schmidt H, Muller-Werdan U, Hoffmann T, et al. Autonomic dysfunction predicts
mortality in patients with multiple organ dysfunction syndrome of different age groups.
Crit Care Med 2005;33:1994-2002.
38. Peres Bota D, Melot C, Lopes Ferreira F, et al. The Multiple Organ Dysfunction
Score (MODS) versus the Sequential Organ Failure Assessment (SOFA) score in
outcome prediction. Intensive Care Med 2002;28:1619-1624.
172
Supplement 6.1. Modified Attitude score1
1. Pritchett LC, Ulibarri C, Roberts MC, et al. Identification of potential physiological
and behavioral indicators of postoperative pain in horses after exploratory celiotomy for
colic. Appl Anim Behav Sci 2003;80:31-43.
Criteria 1 2 3 4 Score Gross pain: (e.g. flank watching, rolling, pawing, teeth grinding)
None Occasional Continuous
Head position Above withers
At withers Below withers
Ear position Forward, frequent moving
Slightly back little movement
Location in stall
At door watching environment
Standing in middle facing door
Standing in middle facing sides of walls
Standing in middle facing back of the stall
Spontaneous locomotion
Moves freely Occasional steps
No movement
Response to open door
Moves to door
Looks at door
No response
Response to approach
Moves to observer, ears forward
Looks at observer ears forward
Moves away from observer
Does not move, ears back
Total Attitude score
173
Supplement 6.2. Rationale for MODS GI score
URL: upper reference limit; cTnI: cardiac troponin I; SVI: stroke volume index; SDNN: standard deviation of normal-to-normal intervals; CK: creatine kinase;*serum sample measured with an ultrasensitive assay; †Measured with echocardiography using the 4 chamber area-length method; ‡Measured from a 5-min artifact- and arrhythmia-free ECG recording using Kubios HRV software, γmeasured with a rapid critical care biochemical analyzer (Nova Biomedical),# the difference between two consecutive creatinine concentrations measured ≥ 24 hours apart (or at least 12 hours apart) when patient is on intravenous fluid therapy. °see Supplement 6.1
Organ system Criteria Rationale for Score criteria 0 1 2 3 Cardiovascular cTnI (ng/mL)* URL Literature review1,2 (McConachie 2015)
Delta cTnI Clinical judgment SVI (ml/kg/min)†
Literature review3 (McConachie 2015)
SDNN (ms)‡ Literature review4 Renalγ Creatinine
(mg/dL) Upper 95% CI from EC
Clinical judgment and literature review5
Delta creatinine#
Clinical judgment
Hepatic Serum bile acids (µmol/L)
URL Clinical judgment and literature review6
Respiratory PaO2/FiO2 Lower limit of 95% CI from EC
Clinical judgment, reflects PaO2 63-84 mmHg in unventilated animal breathing room air
Literature review7
Respiratory rate/effort
Clinical judgment
Musculoskeletal CK (U/L) URL Clinical judgment and literature review8 Laminitis Clinical judgment and literature review
Coagulation Platelet count (x 103 cells/µL)
Lower limit of laboratory RR
Clinical judgment and literature review9,10
Prothrombin time (sec)
Upper limit of laboratory RR
Clinical judgment and literature review10
Gastrointestinal Nasogastric reflux (L/24h)
Clinical judgment and literature review11-13
Abdominal distension
Clinical judgment
Neurologic Modified attitude score°
Clinical judgment
174
1. Nath LC, Anderson GA, Hinchcliff KW, et al. Clinicopathologic evidence of
myocardial injury in horses with acute abdominal disease. J Am Vet Med Assoc
2012;241:1202-1208.
2. Radcliffe RM, Divers TJ, Fletcher DJ, et al. Evaluation of L-lactate and cardiac
troponin I in horses undergoing emergency abdominal surgery. J Vet Emerg Crit Care
(San Antonio) 2012;22:313-319.
3. Borde L, Amory H, Grulke S, et al. Prognostic value of echocardiographic and Doppler
parameters in horses admitted for colic complicated by systemic inflammatory response
syndrome. J Vet Emerg Crit Care (San Antonio) 2014;24:302-310.
4. McConachie EG, S. Rapoport, G. Barton, M. . Heart rate variability in horses with
acute gastrointestinal disease requiring exploratory laparotomy. J Vet Emerg Crit Car
2015; In press.
5. Groover ES, Woolums AR, Cole DJ, et al. Risk factors associated with renal
insufficiency in horses with primary gastrointestinal disease: 26 cases (2000-2003). J Am
Vet Med Assoc 2006;228:572-577.
6. Underwood C, Southwood LL, Walton RM, et al. Hepatic and metabolic changes in
surgical colic patients: a pilot study. J Vet Emerg Crit Care (San Antonio) 2010;20:578-
586.
7. Wilkins PO, C. Baumgardener, J. et al. . Acute lung injury and acute respiratory
distress syndromes in veterinary medicine: consensus definitions: The Dorothy Russell
Haveymeyer Working Group on ALI and ARDS in Veterinary Medicine J Vet Emerg
Crit Care (San Antonio) 2007;17:333-339.
175
8. Krueger CR, Ruple-Czerniak A, Hackett ES. Evaluation of plasma muscle enzyme
activity as an indicator of lesion characteristics and prognosis in horses undergoing
celiotomy for acute gastrointestinal pain. BMC Vet Res 2014;10 Suppl 1:S7.
9. Dolente BA, Wilkins PA, Boston RC. Clinicopathologic evidence of disseminated
intravascular coagulation in horses with acute colitis. J Am Vet Med Assoc
2002;220:1034-1038.
10. Dallap BL, Dolente B, Boston R. Coagulation profiles in 27 horses with large colon
volvulus. J Vet Emerg Crit Car 2003;13:215-225.
11. Roussel AJ, Jr., Cohen ND, Hooper RN, et al. Risk factors associated with
development of postoperative ileus in horses. J Am Vet Med Assoc 2001;219:72-78.
12. Cohen ND, Lester GD, Sanchez LC, et al. Evaluation of risk factors associated with
development of postoperative ileus in horses. J Am Vet Med Assoc 2004;225:1070-1078.
13. Lefebvre D, Pirie RS, Handel IG, et al. Clinical features and management of equine
post operative ileus: Survey of diplomates of the European Colleges of Equine Internal
Medicine (ECEIM) and Veterinary Surgeons (ECVS). Equine Vet J 2015. Early view.
DOI: 10.1111/evj.12355
176
Table 6.1. Equine MODS GI criteria
Organ system Criteria Score criteria Organ score
0 1 2 3 Cardiovascular cTnI (ng/mL)* ≤ 0.03 0.04 - 0.14 0.15 to
0.25 > 0.25
Delta cTnI Positive Negative SVI (ml/kg/min)†
≥1.4 1.2-1.3 1.0-1.1 ≤0.9
SDNN (ms)‡ >56 40-56 26.7-39 < 26.7 Renalγ Creatinine
(mg/dL) ≤ 1.9 1.9-2.2 2.3-3 > 3
Delta creatinine# Positive or 0 (when RV <1.9) OR > 1.9 prior to fluid therapy that is within RR within 24h
0 to ≤ 0.2 (when RV 1.9 to 2.2) OR ≤ -0.3 when RV < 1.9
≤ -0.1 (when RV ≥ 1.9); OR 0 to ≤ 0.2 (when RV ≥ 2.3)
< -0.1 to OR < -0.2 OR ≤ -0.3 when RV > 2.3
Hepatic Serum bile acids (µmol/L)
≤15 16 – 30 30 - 50 > 50
Respiratory PaO2/FiO2 > 400 300 – 400 200 - 300 < 200 Respiratory rate/effort
Normal Abnormal (RR > 30
bpm, nostril flare,
increased abdominal
effort)
Musculoskeletal CK (U/L) < 343 343 – 643 644 - 943 > 943 Laminitis None Obel grade I Obel
grade II or >
Coagulation Platelet count (x 103 cells/µL)
≥ 104 88 – 103 55 - 88 < 55
Prothrombin time (sec)
< 11.6 11.6 - 13.6 13.7 - 14.3 > 14.3
Gastrointestinal Nasogastric reflux (L/24 h)
< 10 10 – 36 36 - 50 > 50
Abdominal distension
No Yes
Neurologic Attitude score [7-27]
7 - 12 13 - 18 19 - 23 24 - 27
Total Score: RV: reference value. *serum measured with an ultrasensitive assay; †Measured using the 4 chamber area-length method; ‡Measured from a 5-min artifact- and arrhythmia-free ECG (Kubios HRV software); γmeasured with a rapid critical care biochemical analyzer;# the difference between two consecutive creatinine concentrations measured ≥ 24 hours apart (or at least 12 hours apart) when patient is on intravenous fluid therapy.
177
Table 6.2. MODS EQ1 criteria
GGT: gamma glutamyl transferase; aPTT: activated partial thromboplastin time 1. Hart KA, MacKay, R. J. . Endotoxemia and Sepsis In: Smith BP, ed. Large Animal
Internal Medicine, 5th Edition. St. Louis: Mosby; 2013:684.
Organ system Criteria Organ Score
Cardiovascular (Hemodynamic)
Mean arterial pressure < 65 mm Hg after ≥ 20 mL/kg IV crystalloid fluids
Renal* Creatinine > 2 mg/dL after ≥ 20 mL/kg IV crystalloid fluids, or increase of ≥ 0.5 mg/dL since last measurement
Hepatic Bilirubin concentration >6 mg/dL; GGT > 60 U/L with no other explanation
Respiratory PaO2 < 65 mm Hg, or < 75 mm Hg with oxygen supplementation or mechanical ventilation
Musculoskeletal (Laminitis) Bounding digital pulses, sensitivity to digital pressure over the coronary band, sensitivity to hoof tester pressure over the sole, Obel grade >1
Coagulation Platelet count < 100,000/μL or aPTT > 70 seconds
Gastrointestinal Absent gut sounds, or absent motility on ultrasound examination
Neurologic Severe obtundation (stupor, semicoma, coma)
Total Score:
178
Table 6.3. Ideal score cut-off as assessed by ROC curve analysis by Day for MODS GI total score, number of organs affected and number of failed organs associated with six-month survival (P < 0.05) and corresponding odds ratios.
Score Score Sensitivity Specificity ROC Logistic regression AUC ± SE P OR (95% CI) P
Day 1 MODS GI > 8 92.3 89.8 0.94 ± 0.03 < 0.0001 105.6 (11.2 to 991.9) <0.0001 Total No. organs affected > 3 92.3 65.3 0.84 ± 0.05 < 0.0001 14.4 (1.7 to 122.9) 0.0015 Total No. failed organs > 1 69.2 91.8 0.90 ± 0.04 < 0.0001 25.3 (5.3 to 120.4) < 0.0001 Day 2 MODS GI > 6 90.0 83.7 0.94 ± 0.03 < 0.0001 46.1 (5.1 to 416.5) 0.0006 Total No. organs affected > 3 90.0 79.6 0.90 ± 0.04 < 0.0001 35.1 (4.0 to 310.4) 0.0014 Total No. failed organs ≥ 1 90.0 71.4 0.87 ± 0.07 < 0.0001 22.5 (2.6 to 194.5) 0.0047
179
Figure 6.1. Sensitivity and Specificity for the MODS GI score at various cut-points
180
Figure 6.2. Receiver operator characteristic curve analysis for MODS GI and MODS EQ
scores
181
Table 6.4. Number of horses (n) with organ systems affected according to MODS GI on Day 1 and Day 2
Organ System Time SCORE 0 1 2 3
Cardiovascular Day 1 n= 5 n= 10 n= 18 n= 29
Day 2 n= 7 n= 20 n= 15 n= 19 Renal Day 1 n= 54 n= 5 n= 0 n= 2
Day 2 n= 48 n= 8 n= 0 n= 0 Hepatic Day 1 n= 53 n= 5 n= 1 n= 0
Day 2 n= 54 n= 1 n= 1 n= 0 Respiratory Day 1 n= 50 n= 10 n= 2 n= 0
Day 2 n= 54 n= 8 n= 0 n= 0 Coagulation Day 1 n= 15 n= 32 n= 4 n= 10
Day 2 n= 26 n= 26 n= 3 n= 4 Musculoskeletal Day 1 n= 17 n= 15 n= 15 n= 12
Day 2 n= 22 n= 26 n= 4 n= 7 Neurologic Day 1 n= 28 n= 19 n= 9 n= 6
Day 2 n= 46 n= 9 n= 5 n= 0 Gastrointestinal Day 1 n= 47 n= 10 n= 0 n= 5
Day 2 n= 46 n= 7 n= 1 n= 8
182
CHAPTER 7
CONCLUSION
In previous chapters, data were presented to demonstrate the importance of colic
as a common disease entity in the horse to highlight the significant loss of use and
mortality caused by this condition.1-5 Despite the fact that acute GI disease has been the
focus of equine research for decades, substantial morbidity and mortality persists,
particularly in the post-operative period. One reason for this, similar to what previously
has been recognized in human medicine, is the occurrence of multiple organ dysfunction
and failure in the post-operative period. This phenomenon has gradually become apparent
in horses as we have improved our ability to diagnose and treat horses in the acute stages
of GI disease. These improvements in care have led to a new set of challenges in the post-
operative period related to remote and sequential organ dysfunction.6,7
The cardiovascular system was the focal point of the research presented herein for
the following key reasons: 1) cardiovascular system dysfunction and failure contributes
to the pathogenesis of MODS by promoting injury in other organs as a consequence of
reduced oxygen delivery 2) there is a significant association between cardiovascular
dysfunction, development of MODS and mortality in humans8 and 3) apart from the GI
tract itself, the cardiovascular system is perhaps the next most extensively studied organ
system in the horse due to the interest in athletic performance.9,10
Consequently, the overall aims of the studies presented herein were to describe
cardiovascular system function in horses with acute GI disease in comparison to healthy
183
adult horses and to develop a criterion based definition for MODS in horses. These goals
were achieved through a series of studies that comprised the work in this dissertation.
First, a non-invasive, 2-Dimensional echocardiographic method for CO estimation was
validated in standing adult horses. Secondly, HRV was investigated in horses with acute
GI disease and compared to healthy control horses, providing a novel approach to assess
overall cardiac health and the role of the autonomic nervous system in horses with colic.
The association between HRV, the autonomic nervous system and the cardiovascular
system, as discussed in previous chapters, is highlighted by the finding that reduced
overall HRV and increased LF power in septic humans is predictive of the development
of MODS and 28-day mortality.8,11
In the third study, the cardiovascular system was assessed comprehensively in
horses with acute GI disease by incorporation of electrocardiography, serum cTnI
concentration measurement and hemodynamic assessments including a proof of concept
measure, pressure adjusted heart rate (PAR). Finally in the fourth paper, MODS criteria
were developed and validated utilizing a group of horses with acute surgical GI disease.
Important, clinically relevant conclusions were drawn from the studies presented
herein. First, three 2-D volumetric methods for estimating CO were validated in adult
standing horses. The 4-chamber area length, the 4-chamber modified Simpson’s and the
Bullet method all had acceptable agreement with the reference method, lithium dilution.
While the Doppler method utilizing the right ventricular outflow tract was not
significantly different from the 2-D volumetric methods, the Doppler method from the
left ventricular outflow tract had a larger relative bias highlighting its inaccuracy and lack
of utility in a clinical setting. In the study herein, the use of healthy horses of different
184
breeds and ages to compare methods of CO measurement enhanced the applicability of
our results to a clinical setting in comparison to previous studies that used a specific
breed of horse, typically Standardbreds or Thoroughbreds. In addition to having a higher
degree of variability than most 2-D derived measurements, Doppler echocardiography
methods are more challenging to obtain in horses of various breeds and sizes which
becomes a factor independent of clinical proficiency. The 2-D echocardiographic
methods provide a way to recognize changes in the magnitude and direction of CO,
which is critical to the overall assessment of CV system status. Further studies will be
needed to determine the utility of non-invasive CO measures in the assessment of
common clinical practices, such as intravenous fluid administration and to define factors
that impact their accuracy and precision, such as variation over time and between
observers.
The second study highlighted a critically important difference in overall
cardiovascular health between horses with colic that required surgical exploration and
healthy horses undergoing elective surgical procedures, namely HRV. The HRV was
significantly reduced in horses with acute GI disease of any cause compared to the
healthy control horses. Furthermore, reduced HRV was associated with ischemic GI
lesions and non-survival, which suggests value for HRV in monitoring post-operative
colic cases. Specifically, the time domain method, SDNN was particularly useful when
assessed at a heart rate that was < 55 beats per minute, in which horses with an SDNN of
< 39.5 ms were 16.4 times more likely to not survive to discharge. The clinical
significance of this finding is apparent when one considers the fact that in the post-
operative period surviving horses had a median heart rate of 45 + 1.3 beats per minute in
185
contrast to non-survivors which had a median heart rate of 65 + 3.4 beats per minute.
Therefore, horses with heart rates that are in the range of 45- 55 beats per minute, that
may otherwise appear to be improving, may benefit from having HRV assessed routinely.
In such cases, when the SDNN is < 39.5 ms, further monitoring and addition or
continuation of supportive interventions in the post-operative period should be
considered. In contrast to many studies in humans, the frequency domain methods,
LF/HF ratio, LF power, and HF power were not associated with outcome. There were,
however, significant differences between horses when they were grouped according to
survival status where non-survivors had an increased LF/HF ratio, increased LF power
and reduced HF power. Taken together, these results indicate that there was concurrent
sympathetic overdrive and parasympathetic withdrawal in non-surviving horses.
Similarly, the SDNN and RMSSD variables that approximate overall HRV and
parasympathetic modulation, respectively, were reduced in horses with ischemic GI
disease and non-survivors offering further support to the proposal that autonomic
imbalance occurs in these cases. Perhaps one of the most clinically useful results of this
study was the finding that there was no significant difference between time domain
parameters when they were derived from 5- or 30-minute ECG recordings. Therefore, 5-
minute duration ECG recordings are sufficient to obtain time domain HRV indices
making this a useful clinical stall side tool.
In the third study, horses with acute GI disease had evidence of myocardial injury,
clinically significant arrhythmias, reduced stroke volume index (SVI), and reduced HRV
compared to healthy control horses. Specifically, multivariable logistic regression
analysis revealed a significant association between non-survival and both cTnI
186
concentration and low SVI. In contrast to what is observed in people, PAR was not a
useful composite measure in horses, as it was not significantly different between healthy
horses and those with acute GI disease and was not associated with outcome. However,
peak PAR, along with peak cTnI and lowest SVI were retained in a multivariable logistic
regression model that was associated with SIRS. Incremental increases in PAR are used
to define cardiovascular dysfunction in the original MODS score developed by Marshall
and colleagues.12 The PAR was initially proposed as a method to correct cardiovascular
function for physiologic support. The finding that PAR was retained as an important
explanatory variable in the SIRS multivariable logistic regression model indicates that
PAR might be a useful alternative for assessment of peripheral vascular hemodynamics
rather than measurement of MAP or CVP alone in horses. Fractional shortening, a
measure of contractility, was not different between horses with colic and control cases,
which is similar to results reported by Nath and colleagues.13 Although stroke volume
index was decreased in horses that did not survive, a single conclusion regarding the state
of left ventricular systolic function in horses with acute GI disease could not be made.
The results of this study provided a more complete understanding of the
significance of serum cTnI concentrations in horses with acute GI disease. Of note, mild
increases in cTnI are prevalent in horses that undergo exploratory laparotomy for acute
GI disease, but not in healthy horses that undergo surgery for elective procedures. The
magnitude of the cTnI increase was associated with outcome wherein a cTnI
concentration of > 0.15 ng/mL was an important explanatory variable for non-survival in
a multivariable logistic regression model. In addition, cTnI concentration was associated
with the presence of clinically significant arrhythmias and SIRS in horses with acute GI
187
disease. While non-survivors tended to have increased cTnI concentrations compared to
survivors post-operatively, there was not a significant difference between survivors and
non-survivors in the admission cTnI concentrations calling to attention that use of this
biomarker as a prognostic tool at admission would be inappropriate.
Finally, a MODS score based on equine data was developed, herein designated
the MODS GI score, and was associated with survival in horses with acute GI disease. In
addition, the MODS GI score performed equally well on both days of analysis and
performed better than a previously proposed score, designated the MODS EQ score,
which is based on organ function criteria extrapolated from human scoring systems.
Further investigation is necessary to determine if this score is significantly associated
with MODS in horses with other disease etiologies.
In summary, significant mortality is associated with dysfunction of the
cardiovascular system in horses characterized primarily by a syndrome of low SVI,
increased occurrence of clinically significant arrhythmias, reduced HRV and increased
serum cTnI concentration. The HRV was found to be a useful tool in horses with acute
GI disease and can be measured simply and rapidly with an artifact-free, 5-minute ECG
recording. Finally, a MODS GI score was developed and tested in a group of horses with
acute GI disease revealing that indeed horses with a higher total MODS GI score and
those with incrementally more organs deemed dysfunctional or failed were less likely to
survive. The criteria for the MODS GI score were based off established reference
intervals, a review of the literature and clinical judgment and the resultant score was
associated with six-month survival rather than confirmed organ failure. This is
188
appropriate as MODS is a functional, rather than a structural, syndrome which cannot be
adequately defined by pathology in many if not the majority of cases.
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