ALDRIN KENNETH REYES

ACUTE HOSPITAL ADMISSION FOR STROKE IS CHARACTERISED BY

INACTIVITY
1. Background
Inactivity is associated with a greater risk of cardiovascular disease [1] and poor functional
outcomes at three-month poststroke [2]. Physical activity is a requirement to improve and
maintain physical fitness and can also mediate the detrimental effects of prolonged inactivity [3].
Fini et al. conducted a large systematic review on physical activity after stroke, which included
103 studies that measured physical activity using different methods (i.e., behavioural mapping,
accelerometers) and at different times poststroke [4]. The results of the review showed stroke
survivors spent 78% of time sedentary regardless of time poststroke [4]. Therefore, survivors of
stroke stand to gain important beneficial effects of physical activity on cardiovascular disease
risk factors and functional capabilities [5].

In clinical practice guidelines, it is recommended that out of bed activity within a few days of
stroke should be encouraged unless otherwise contraindicated [5, 6]. However, the results of A
Very Early Rehabilitation Trial (AVERT) demonstrated that intensive, very early mobilisation
started within 24 hours of stroke and continued across the acute hospital phase could be harmful
[7]. What remains unclear is what amount of physical activity should be recommended after
stroke. Additionally, very few investigators have measured physical activity as part of their
studies conducted in the acute phase after stroke [4]. In the majority of studies, physical activity
is measured within the first weeks after stroke using observational behavioural mapping [8]. For
example, Prakash et al. investigated the amount and patterns of physical activity of stroke
survivors () admitted to a medical ward in India [9], and Astrand et al. investigated physical
activity of stroke survivors () admitted to an acute stroke ward in Sweden [10]. In both studies,
intermittent observational mapping was used where participants were observed at 10-minute
intervals during the most active part of the day only (e.g., 8 : 30 am to 6 : 00 pm) [9, 10]. This
method has disadvantages: it is labour and time intensive, and it is often limited to weekdays and
during usual work hours. Additionally, it is problematic to capture the intensity and frequency of
the activity, and behavioural mapping only provides a snapshot of activity for an individual
patient during the observation period, which is usually limited to one or two days.

An alternative to behavioural mapping is the use of monitoring devices, which are now
commonly used to objectively measure physical activity after stroke [8]. These devices are
advantageous in their capacity to measure and store data continuously over time, are minimally
intrusive, and once attached, can often remain in situ for days. Several investigators have used
accelerometer-based devices in the acute phase (≤7 days) after stroke to quantify physical
activity. In the study by Sanchez et al. [11], 23 participants who were able to independently
perform sit-to-stand were included. The researchers recorded a single day (10 : 00 am to 6 : 00 
pm) of the participants’ activity, they failed to take advantage of the monitoring device to
measure continuously over several days, and thereby providing more robust and representative
data. In the study () by Moore et al., activity of stroke survivors was recorded continuously over
ALDRIN KENNETH REYES

7 days [12]. In a larger study () by Strommen et al. of people with stroke or TIA, physical
activity was measured using five accelerometer-based devices, one placed on each limb and one
at the hip for a median of 47.0 hours (range, 2.0–167.0 hours) [13]. The output of this device is
activity counts calculated by proprietary algorithms. This output is not easy to interpret, and it is
not possible to transform the data into a clinically meaningful outcome such as step counts or
time spent active. Overall, the type of devices used, populations, and protocols vary across
studies involving participants during the acute stroke phase. This limits our ability to compare
outcomes between studies and hampers understanding of physical activity behaviour early after
stroke.

Objectively characterising activity levels, by continuously measuring activity over several days,
of patients with different levels of stroke severity in the acute inpatient setting would be
informative to further develop physical activity recommendations in the early phase of stroke
recovery. A device previously used in stroke research to measure physical activity is
ActivPAL™ (PAL Technologies Ltd©, Glasgow, UK). ActivPAL™ is able to provide data on
step count, as well as time spent inactive (resting in bed, sitting), standing, and moving
(transferring, walking, and running). It has been shown to be a valid and reliable tool to measure
step count and time spent inactive, standing, and moving in healthy people [14, 15] and in people
with stroke [16].

The aims of this study were to describe the physical activity patterns of patients with acute stroke
during hospitalisation and to examine the relationship between the physical activity behaviour of
patients with stroke and their stroke severity. We hypothesised that acute stroke patients would
be mostly inactive (i.e., lying and sitting) early after stroke. We also hypothesized that greater
levels of time spent inactive would be positively associated with (1) stroke severity and (2) age at
the time of stroke.

2. Method
This is a cross-sectional, observational study of patients with stroke admitted to an acute stroke
unit located in Geelong, Australia.

2.1. Participants
Adults over the age of 18 with a confirmed diagnosis of stroke who were admitted directly to the
stroke unit at the Geelong Hospital, Barwon Health, from the hospital emergency department
were eligible for inclusion. Participants were eligible regardless of stroke severity and were
consecutively recruited into the study, unless all available ActivPAL™ devices were in use.
Additionally, patients were eligible to participate if they were within 48 hours of admission to
the stroke unit.

Patients were excluded if they were diagnosed with subarachnoid haemorrhage and transient
ischaemic attack (TIA), as the recommended management strategies for these patients are
ALDRIN KENNETH REYES

different to those for the other types of stroke (ischaemic and nonsubarachnoid hemorrhagic
stroke). Patients were excluded if they had their stroke while in hospital for another admission
reason as this may have affected their inpatient management. If patients were allergic to
adhesives or latex and, therefore unable to wear the ActivPAL™ device, they were also
excluded.

2.2. Procedure
The admission list for the stroke unit at Geelong Hospital, Barwon Health, was screened daily
between June 2012 and December 2012 to identify eligible participants. The participants
themselves or a person responsible provided informed written consent. Ethical approval for this
study was granted by Barwon Health Human Research Ethics Committee (Approval Number
HREC/11/VICBH/38) and La Trobe University Health Science Faculty Human Research Ethics
Committee (Approval Number UHEC No. 11-065).

Physical activity was monitored using ActivPAL™, a small device worn on the upper thigh that
uses static and dynamic accelerometry data to distinguish sitting/lying, standing, and stepping.
Following enrolment, each participant was given an ActivPAL™ device to wear. Before
attaching the device to the anterior aspect of the upper 1/3 of the thigh on the paretic side, the
device was reset and reloaded and wrapped in a protective Tegaderm™ (3M, St Paul, USA)
dressing to seal the device and provide a moisture barrier. Another Tegaderm™ was used to
attach the ActivPAL™ to the paretic leg. A gauze dressing was used as a barrier between the
Tegaderm™-wrapped ActivPAL™ and the participant’s skin. Once in place, the ActivPAL™
remained in situ until the participant was discharged from the stroke unit or at 14 days after
admission (whichever was earliest). The physical activity data were categorised as (1) percentage
of time spent sitting or lying, (2) percentage of time spent standing, (3) percentage of time spent
stepping, and (4) step counts.

Participant characteristics were collected from medical records and included demographic data
and stroke characteristics.

Premorbid degree of disability was assessed using the 7-point modified Rankin Scale (mRS)
[17]. Premorbid mRS ranges from 0 = no symptoms at all to 5 = severe disability (i.e., requires
constant nursing care and attention, bedridden, incontinent). A score of 6 indicating death was
not used.

Prestroke walking ability was assessed by the attending physiotherapist in consultation with the
participant.

Stroke type was classified according to the Oxfordshire Community Stroke Program (OCSP)
classification [18]. The OCSP is used to classify stroke into five types: total anterior circulation
ALDRIN KENNETH REYES

infarct (TACI), lacunar infarct (LACI), partial anterior circulation infarct (PACI), posterior
circulation infarct (POCI), and haemorrhage.

Stroke severity was measured by a certified physiotherapist using the National Institutes of
Health Stroke Scale (NIHSS) [19]. The NIHSS is an 11 item-scale with scores ranging from 0 to
44. A higher score indicates greater stroke severity. Stroke severity was categorised into mild
(NIHSS 0-7), moderate (NIHSS 8-16), and severe () [20].

Poststroke mobility was measured by the treating physiotherapist using the Mobility Scale for
Acute Stroke (MSAS) at baseline [21, 22]. The participants were grouped into independent or
dependent ambulation categories based on an MSAS gait score of ≥6, respectively.

Adverse events were monitored throughout the study and included any event related to wearing
the device (e.g., skin rash).

2.2.1. Data Processing and Analysis

No official sample size calculation was performed for this study. Data were downloaded from
the ActivPal™ devices using ActivPal™ software. Proprietary algorithms were used to classify
the accelerometer data time spent walking, stepping, and lying down/sitting and number of steps.
Physical activity outcomes were only summarised for participants who wore the device for at
least three consecutive days, as recommended by Tinlin et al. [23] Inactivity is defined by the
time spent lying/sitting. Logic checks were performed to ensure data accuracy. A random 10%
sample of manually entered data was reentered by a second researcher and assessed for
agreement using the intraclass correlation coefficient (ICC) with 95% confidence intervals.
Descriptive statistics were used to summarise demographic and ActivPal™ data.

We expected that patients with acute stroke would be inactive in the early part of their inpatient
hospital stay. Inactivity was defined as more than 16 hrs per day (24 hrs) spent sitting or lying
down. We chose this cut-off under the assumption that on average, 8 hrs spent sleeping and
adding another 8 hours of sitting and lying (i.e., 16 hours in total per 24 hours) is equal to 50% of
the time awake spent inactive. Descriptive statistics were used to report the daily percentage of
time spent in each category, i.e., time spent inactive (time spent lying/sitting) and time spent
active (time spent upright and stepping) averaged over the three days (72 hours) of monitoring.
We also calculated the mean number of daily steps taken by using the average over three days of
monitoring during the inpatient stay. We used Spearman correlation coefficients to test the
hypothesis that greater levels of inactivity were positively associated with age and stroke
severity.
3. Results
One-hundred and thirty-one patients with acute stroke were screened for inclusion, of whom 100
were eligible for inclusion. Of these, 82 were enrolled in the study (see Figure 1). Two
participants commenced monitoring but did not tolerate wearing the device and two participants
ALDRIN KENNETH REYES

wore the device, but no data were collected due to device failure. Of the 78 participants from
whom data were collected, 54 had complete data for three days
4. Discussion
This study is one of the two large studies to date to objectively monitor physical activity of
patients admitted to an acute stroke ward. To our knowledge, it is the only study that provides
data on time spent upright, walking, and sedentary time in patients during the first few days after
a stroke. The ActivePal™ device was feasible to use in this setting, with low rates of device
failure or adverse events related to wear. None of the patients spent less than 16 hrs inactive,
with a median of 23 hrs per day spent lying and sitting. On average, we commenced recording of
patient activity within 24 hrs of admission to a stroke unit. Despite this early start, many patients
were discharged quickly from the acute stroke unit, and we were unable to gather three complete
days of physical activity data for the full sample.

The study of Strommen et al. is the only other large physical activity study in which 100 acute
patients with stroke or TIA were included [13]. The patients wore five Actical accelerometers,
one placed at each limb and one at the hip for ≤7 days which records activity counts;
consequently, we were unable to interpret or compare this outcome directly to our results. The
authors reported 16% of the day was spent inactive [13], which was less than the time spent
inactive reported here. The difference could be related to the method of measurement and their
younger study population, which had an average age of 69 years of age compared to 79 years in
our study. In a smaller study by Mattlage et al., physical activity behaviour of 32 patients in the
acute stroke unit over 4 days was measured using an ActiGraph GT3X+ accelerometer [24]. The
device records continuous 24 hrs of activity counts of participants. In this study, a cut-off value
was used to distinguish between active and inactive states. The participants in the Mattlage et al.
study were younger (average age of 55) and spent less time inactive (93% versus 98%,
respectively) [24]. Despite differences in the physical activity monitoring devices used, the
duration of physical activity recording, method of analysis, and patient clinical characteristics,
our data strengthens the overall evidence indicating patients with acute stroke are highly inactive
early after stroke.

We explored patient characteristics that might be related to physical inactivity and found a
moderate correlation between time spent inactive and stroke severity. We did not find an
association between levels of physical activity and age at stroke; however, Strommen et al.
reported higher physical activity levels in younger people and those with less severe stroke [13].
Although there seems to be a relationship between stroke severity and inactivity, it is important
to note in our study that at admission, 16% of patients were independently mobile but the
minimum time spent inactive was 20 out 24 hours. In a longitudinal study by Rand and Eng,
physical activity of patients with stroke () was monitored twice over three full days during their
inpatient rehabilitation stay (at admission and after three weeks); they found an increase in steps
taken with an increase in time poststroke [25]. Improvements in functional ability, however,
were not matched by a similar increase in activity, and activity levels in stroke survivors
ALDRIN KENNETH REYES

continued to be less than those in healthy controls [25]. Given that low physical activity levels
are a risk factor for stroke, it is likely that a large proportion of stroke survivors were inactive
before their stroke. It is therefore also likely that stroke severity is not the main factor that
impacts physical activity after stroke. With stroke survivors already having a higher risk of
recurrent stroke, it is important to focus on increasing physical activity early after stroke as it can
moderate cardiovascular disease risk including recurrent stroke.

Clinical practice guidelines continue to favour commencing out of bed activity within a few days
of stroke unless otherwise contraindicated [6, 26]. What is not clear is the amount of physical
activity that should be encouraged after stroke and, more specifically, how recommendations
may vary according to cardiovascular risk status and functional impairments to maximise patient
outcomes and prevent further stroke. Understanding who may be at a greater risk of inactivity
after stroke could help clinicians target important subgroups of patients who need more, or less,
support to recommence and sustain physical activity after having a stroke. Early after stroke,
other rehabilitation priorities, such as regaining motor function, speech, and swallowing, are
likely to take priority, and the presence of comorbid conditions, fatigue, and risk of falling may
limit opportunities to engage in physical activity for some stroke patients. Current, albeit limited,
evidence suggests a relationship between physical activity and individual characteristics. This
highlights that future research needs to consider the broad range of factors that may influence
physical activity in the acute stroke environment, including policies that may restrict or
encourage physical activity in the ward, and the built environment. The UK “End PJ paralysis”
movement (https://endpjparalysis.org/), while not targeted at people with stroke, is an example of
a policy shift that could play an important role in changing the attitudes of patients and staff
towards physical activity in the hospital environment. No objective data currently exist to
demonstrate the possible effect of this policy shift on patient behaviour, but such data would be
welcome.

This study is not without limitations. ActivPAL™ records limited details of physical activity
which are relevant for the acute stroke population. For example, ActivPAL™ does not
distinguish between lying in bed and sitting. For acute stroke survivors, therapeutic training in
sitting may be the highest level of function they are able to achieve during early rehabilitation.
The time a patient spent engaged in sitting compared to the time spent resting in bed is important
to their functional recovery and potentially also to the prevention of medical complications of
immobility. While the population in the study are representative of the stroke population in the
geographical region, the group were on average older, which might underestimate acute stroke
inpatient activity levels and therefore limit the generalisability of our results. As a single site
study, the clinical routines, policies, and processes of this unit may vary from those of other
stroke units. However, in this relatively large sample, we included stroke survivors across the
spectrum of disease severity that demonstrate many of the typical risk factors common to stroke.

5. Conclusion
ALDRIN KENNETH REYES

The findings from this study support a better understanding of physical activity practices of
patients with acute stroke and what factors influence this important care practice. There have
been few studies that have objectively measured the physical activity behaviour of people with
stroke in the inpatient hospital setting. This study highlights the inactivity of stroke survivors in
the acute inpatient setting and indicates the more severe the stroke, the less likely the stroke
patient is to be active. While there remains uncertainty around when physical activity should
commence and how much is helpful for patients with acute stroke, there can be little doubt that
the current practises of care result in high levels of inactivity. Future research should focus on
the development of interventions that promote physical activity and reduce inactivity that leads
to a sustained active lifestyle after stroke.

II. Reaction

a. Personal Standpoint / Idea

Stroke is one of the leading causes of death and long-term adult disability with a worldwide
prevalence of 15 million people per year according to the World Health Organization. A number
that is likely to increase in the near future due to aging of the population. There are two main
types of stroke, namely, hemorrhagic stroke which occurs when a blood vessel ruptures, and
ischemic stroke meaning a blood vessel becomes blocked, both leading to a disruption of blood
flow and a contralateral loss of function. Approximately 80% of the stroke patients suffer
ischemic stroke, whereas the remainder experiences hemorrhagic stroke.1 Unfortunately, current
approved stroke treatments have a very small time frame in which they can be performed,
leaving the majority of stroke patients untreated. Functional recovery over time is a common
finding in patients suffering stroke. It has been noted that intact peri-infarct as well as
contralateral brain areas are capable of adopting the lost functions, resulting in the observed
functional recovery in stroke patients.

SEPSIS: THE EVOLUTION IN DEFINITION, PATHOPHYSIOLOGY, AND

MANAGEMENT
Introduction:
ALDRIN KENNETH REYES

Sepsis is a medical emergency that describes the body’s systemic immunological response to an
infectious process that can lead to end-stage organ dysfunction and death. Despite significant
advancements in the understanding of the pathophysiology of this clinical syndrome,
advancements in hemodynamic monitoring tools, and resuscitation measures, sepsis remains one
of the major causes of morbidity and mortality in critically ill patients. 1 The annual incidence of
severe sepsis and septic shock in the United States is up to 300 cases per 100,000 people. Sepsis
is also the most expensive healthcare problem in the United States, accounting for more than $20
million (about 5.2% of the total hospital cost) in 2011 alone.2
The global epidemiological burden of sepsis is, however, difficult to ascertain. It is estimated
that more than 30 million people are affected by sepsis every year worldwide, resulting in
potentially 6 million deaths annually. Mortality rates from sepsis, as per the data from the
Surviving Sepsis Campaign 2012, were approximately 41% in Europe versus approximately
28.3% in the United States.3 This difference however disappeared when adjusted for disease
severity.3 This implies that the mortality in sepsis varies according to patient characteristics as
well. A multicenter study in Australia and New Zealand that included 101,064 critical patients
showed that the mortality rate in sepsis has decreased over the years from around 35% in 2000 to
about 20% in 2012.
Over the years, our understanding of the complex pathophysiology of sepsis has improved, and
so has our ability to define sepsis. The word sepsis is derived from the Greek word for
“decomposition” or “decay,” and its first documented use was about 2700 years ago in Homer’s
poems. It was subsequently used in the works of Hippocrates and Galen in later centuries.4 In the
1800s, the “Germ theory” of disease was conceived and there was some recognition that sepsis
originated from harmful microorganisms. The first modern definition was attempted in 1914 by
Hugo Schottmüller who wrote that “sepsis is present if a focus has developed from which
pathogenic bacteria, constantly or periodically, invade the blood stream in such a way that this
causes subjective and objective symptoms.”5 Over the course of the 20th century, numerous
experimental and clinical trials were able to demonstrate the importance of the host immune
response to the manifestations of sepsis. However, due to heterogeneity of the disease process, it
posed serious difficulties in recognizing, treating, and studying sepsis.5 Finally, at a SCCM-
ACCP conference in 1991, Roger Bone and his colleagues laid the foundation for the first
consensus definition of sepsis. There have been significant advances in the pathobiology of
sepsis in the last two decades. We have a better understanding of cell biology, biochemistry,
immunology, and morphology, as well as changes in circulation and organ function. This
understanding has led to the changes in the definition of sepsis. This has also contributed to
better management of sepsis leading to changes in the epidemiology of the sepsis.
There has been a marked evolution in our understanding of the molecular pathobiology and
immunology of sepsis. Previously it was felt that hemodynamic manifestations of sepsis were
primarily related to the hyperimmune host response to a particular pathogen.8 However, a large
body of work on the molecular basis of sepsis has revealed a far more nuanced and complex
interplay between the infectious agent and host that together produce the heterogeneous
manifestations of sepsis.
ALDRIN KENNETH REYES

Innate immunity and inflammatory mediators

The first step in the initiation of the host response to the pathogen is the activation of innate
immune cells, constituted primarily by macrophages, monocytes, neutrophils, and natural killer
cells.9 This occurs via the binding of pathogen-associated molecular patterns (PAMPs), such as
bacterial endotoxins and fungal β-glucans to specific pattern recognition receptors, on these cells.
Another source of such interaction are damage-associated molecular patterns (DAMPs) that may
be intracellular material or molecules released from dead or damaged host cells, such as ATP and
mitochondrial DNA. These bind to specific receptors on monocytes and macrophages such as
toll-like receptors (TLRs), C-type leptin receptors, NOD-like receptors (nucleotide-binding
oligomerization domain) and RIG-1 like receptors (retinoic acid inducible gene 1). This results in
the activation of intracellular signal transduction pathways that cause the transcription and
release of proinflammatory cytokines like TNFα, IL-1, and IL-6. In addition, some of the pattern
recognition receptors, such as the NOD-like receptor group, can aggregate into larger protein
complexes called inflammasomes that are involved in the production of crucial cytokines, such
as IL-1β and IL-18 as well as caspases, which are involved in programmed cell death.
Proinflammatory cytokines cause activation and proliferation of leukocytes, activation of the
complement system, upregulation of endothelial adhesion molecules and chemokine expression,
tissue factor production, and induction of hepatic acute phase reactants. In sepsis, there is an
exaggeration of the above immune response resulting in collateral damage and death of host cells
and tissues.

Dysregulation of hemostasis
In sepsis, there is an intersection between the inflammatory and hemostatic pathways, with the
simultaneous activation of both the inflammatory and the coagulation cascades. The spectrum of
this interaction can vary from mild thrombocytopenia to fulminant disseminated intravascular
coagulation (DIC). The etiology of the dysregulation of coagulation in sepsis is multifactorial.
The hypercoagulability of sepsis is thought to be driven by the release of tissue factor from
disrupted endothelial cells (other sources include monocytes and polymorphonuclear cells).10 In
fact, in vitro experimental models of endotoxemia and bacteremia have shown a complete
inhibition of inflammation-induced thrombin production with the blockade of tissue factor.11
Tissue factor then causes the systemic activation of the coagulation cascade resulting in the
production of thrombin, activation of platelets, and formation of platelet–fibrin clots. These
microthrombi can cause local perfusion defects resulting in tissue hypoxia and organ
dysfunction.

In addition to the procoagulant effect described above, there is a depression of the anticoagulant
effects of protein C and antithrombin that would normally temper the coagulation cascade.
Protein C is converted to its active form (activated protein C) by thrombomodulin which itself is
activated by thrombin. Activated protein C then exerts an anticoagulant effect by degradation of
factors Va and VIIIa acting in concert with activated protein S. It is also known to have potent
anti-inflammatory effects via the inhibition of TNFα, IL-1β, and IL-6 and limiting of neutrophil
ALDRIN KENNETH REYES

and monocyte adhesion to endothelium. In patients with severe systemic inflammation, such as
in sepsis, there are decreased plasma levels of protein C, downregulation of thrombomodulin,
and low levels of protein S thus allowing for the unregulated propagation of the coagulation
cascade.12

In addition to the hypercoagulability described above, a reduction of fibrinolysis is also observed

as a result of sepsis.13 As TNFα and IL-1β levels increase, tissue plasminogen activators are
released from vascular endothelial cells. The resultant increase in activation of plasmin is blunted
by the sustained increase in plasminogen activator inhibitor type 1 (PAI-1). The net effect is
diminished fibrinolysis and fibrin removal, which contributes to the perpetuation of
microvascular thrombosis.

Immunosuppression
Interestingly, the initial proinflammatory state of sepsis is often superseded by a prolonged state
of immunosuppression. There is a decrease in the number of T cells (helper and cytotoxic) as a
result of apoptosis and a decreased response to inflammatory cytokines.14 Postmortem studies of
ICU patients who died of sepsis demonstrated a global depletion of CD4+ and CD8+ T cells,
most notably found in the lymphoid organs such as the spleen. Studies have also demonstrated
decreased production of crucial cytokines such as IL-6 and TNF in response to endotoxin.15,16
In septic patients, neutrophils were found to have expressed fewer chemokine receptors, and
there was diminished chemotaxis in response to IL-8.17

The above findings suggest that the immune system in a septic individual is unable to stage an
effective immune response to secondary bacterial, viral, or fungal infections. Based on a study
that showed that a low lymphocyte count early in sepsis (day 4 of diagnosis) is predictive of both
28-day and 1-year mortality, it has been postulated that early lymphopenia can serve as a
biomarker for immunosuppression in sepsis.18

Cellular, tissue, and organ dysfunction

The underlying mechanism behind tissue and organ dysfunction in sepsis is the decreased
delivery to and utilization of oxygen by cells as a result of hypoperfusion. Hypoperfusion occurs
due to the cardiovascular dysfunction that is seen in sepsis.19 The incidence of septic
cardiomyopathy varies from 18% to 60% in various studies. It is thought to be related to
circulating cytokines, such as TNFα and IL-1β among others, which can cause depression of
cardiac myocytes and an interference with their mitochondrial function. The most important
feature of septic cardiomyopathy is that it is acute in onset and reversible. Second, the low left
ventricular ejection fraction is accompanied by normal or low left ventricular filling pressures
(unlike in cardiogenic shock) with increased left ventricular compliance.20 Multiple studies have
shown both systolic and diastolic dysfunction with decreased stroke volumes and increased end-
diastolic and end-systolic volumes in sepsis.21,22 A definite effect on mortality as a result of
myocardial depression, however, has not yet been established. In addition, because of the arterial
ALDRIN KENNETH REYES

and venous dilation (induced by inflammatory mediators) and consequent reduced venous return,
a state of hypotension and distributive shock is produced by sepsis. There is dilation of all three
components of the microvasculature—arterioles, venules, and capillaries. This is exacerbated by
the leakage of intravascular fluid into the interstitial space as a result of loss of endothelial
barrier function induced by alterations in endothelial cadherin and tight junctions. All the above
changes in the body’s hemodynamics in conjunction with microvascular thrombosis (described
earlier) can result in hypoperfusion of tissues and organs. Consequently, there is increased
anaerobic glycolysis in cells resulting in the production of lactic acid. In addition, the reactive
oxygen species (ROS) produced by the inflammatory response cause dysfunction of
mitochondria and a drop in ATP levels. These mechanisms cause damage at the cellular level.
The broader alterations described below that occur in the tissue and organs collectively and
cumulatively contribute to much of the morbidity and mortality of sepsis.

There are significant alterations to the endothelium with disruption of its barrier function,
vasodilation, increased leukocyte adhesion, and the creation of a procoagulant state. This results
in accumulation of edema fluid in the interstitial spaces, body cavities, and subcutaneous tissue.
In the lungs, there is disruption of the alveolar–endothelial barrier with accumulation of protein-
rich fluid in the interstitial lung spaces and alveoli. This can cause a ventilation–perfusion
mismatch, hypoxia, and decreased lung compliance producing acute respiratory distress
syndrome (ARDS) in extreme cases. In the kidneys, a combination of reduced renal perfusion,
acute tubular necrosis, and more subtle defects in the microvasculature and tubules together
produce varying degrees of acute kidney injury. In the gastrointestinal tract, the increased
permeability of the mucosal lining results both in bacterial translocation across the bowel well
and autodigestion of the bowel by luminal enzymes. In the liver, there is a suppression of
bilirubin clearance producing cholestasis. Altered mentation is commonly noted in sepsis and is
indicative of CNS dysfunction. The endothelial changes described above undermine the blood–
brain barrier, causing the entry of toxins, inflammatory cells, and cytokines. The ensuing
changes of cerebral edema, neurotransmitter disruption, oxidative stress, and white matter
damage give rise to a clinical spectrum of septic encephalopathy that varies from mild confusion
to delirium and coma. Sepsis is known to produce a catabolic state. There is a rapid and
significant breakdown of muscle to produce amino acids for gluconeogenesis that will fuel the
immune cells. In addition, increased insulin resistance can result in a state of hyperglycemia.

Management of sepsis
Before 2001, there were no evidence-based guidelines for early management of severe sepsis and
septic shock.23 Previously, clinicians targeted supraphysiological values of cardiac index and
oxygen delivery in critically ill patients with sepsis.24–26 However, Gattinoni et al.25 concluded
that such goal-oriented treatment does not reduce morbidity or mortality among critically ill
patients. Several other studies also suggested that aggressive measures to achieve higher
hemodynamic values for cardiac index and oxygen delivery did not improve patient
outcomes.27,28
ALDRIN KENNETH REYES

Beal and Cerra29 recognized that transition of sepsis to multiple organ dysfunction could be
prevented with rapid and appropriate resuscitation of shock. The idea that severe inflammatory
response syndrome (SIRS), sepsis, and severe sepsis are parts of a continuous process and that
SIRS can be limited if acted upon early formed the basis of early goal-directed therapy. Rivers et
al.,30 described the critical “golden hours” of sepsis when there is abrupt transition to serious
illness and initiation of early goal-directed therapy (EGDT). The fundamental principles of
EGDT were identification of high-risk patients, appropriate cultures, source control, and early
administration of appropriate antibiotics, which was then followed by early hemodynamic
optimization of oxygen delivery and decreasing oxygen consumption.26 The goals of initial
resuscitation for sepsis-induced hypoperfusion included central venous pressure (CVP) of 8–12
mmHg, mean arterial pressure (MAP) of 65 mmHg, urine output of 0.5 mL kg−1 h−1, and
superior vena cava oxygen saturation (ScvO2) or mixed venous saturation of 70% or 65%,
respectively.30,31 Rivers et al. concluded that EGDT instituted during the first six hours,
resulted in 15.9% absolute reduction in 28-day mortality rate when resuscitation targeted these
physiological goals in patients with severe sepsis or septic shock presenting to the emergency
department.30–32

Surviving Sepsis Campaign guidelines from 2004, thus incorporated the EGDT into the first 6-h
sepsis resuscitation bundle.33–35 Several studies done thereafter reported similar reduction in
28-day mortality with EGDT or sepsis resuscitation bundle.36,37 Other investigators remained
skeptical of the study design and treatment goals in EGDT.38 An integral element of EGDT
versus the standard care was central venous catheterization to monitor CVP and ScvO2 that
guided the use of intravenous fluid, vasopressors, packed red cell transfusions, and dobutamine
to achieve the set physiological targets.30,39 Nearly two decades after the Rivers trial,
management of sepsis has evolved, and there has been an overall decline in the mortality from
severe sepsis.40

Sepsis remains a significant burden on health systems worldwide. However, the advances made
in understanding its pathogenesis and the extensive efforts at framing guidelines for its effective
management in the last 20 years exceed anything that has been done before. There has been no
magic bullet for the management of sepsis. However, measures such as prompt use of antibiotics
and hemodynamic resuscitation, appropriate ventilator use, and judicious transfusion of blood
products have played a significant role in decreasing morbidity and mortality. The use of newer,
precision modalities like immunomodulators, while currently in a nascent stage of development,
offer a promising field of inquiry. Development of scores such as the APACHE-II and sequential
organ failure assessment (SOFA) have provided simple but useful clinical tools in the assessment
and prognostication of sepsis. The definition of sepsis continues to be a contested subject with
the latest guidelines abandoning the previously used SIRS criteria and proposing a more complex
definition based on multiorgan dysfunction and SOFA scores. It is hoped that this will improve
the accuracy of sepsis diagnosis for clinical, epidemiological, and hospital coding purposes. It
remains to be seen if there will be wider adoption and implementation of these recommendations
by healthcare facilities and providers.
ALDRIN KENNETH REYES

DISSEMINATED INTRAVASCULAR COAGULATION

Background
Disseminated intravascular coagulation (DIC) is characterized by systemic activation of blood
coagulation, which results in generation and deposition of fibrin, leading to microvascular
thrombi in various organs and contributing to multiple organ dysfunction syndrome (MODS). [1,
2] Consumption of clotting factors and platelets in DIC can result in life-threatening
hemorrhage. [3]
ALDRIN KENNETH REYES

Derangement of the fibrinolytic system further contributes to intravascular clot formation, but in
some cases, accelerated fibrinolysis may cause severe bleeding. Hence, a patient with DIC can
present with a simultaneously occurring thrombotic and bleeding problem, which obviously
complicates the proper treatment.
The subcommittee on DIC of the International Society on Thrombosis and Haemostasis has
suggested the following definition for DIC: “An acquired syndrome characterized by the
intravascular activation of coagulation with loss of localization arising from different causes. It
can originate from and cause damage to the microvasculature, which if sufficiently severe, can
produce organ dysfunction.” [4]
DIC is estimated to be present in as many as 1% of hospitalized patients. [5] DIC is not itself a
specific illness; rather, it is a complication or an effect of the progression of other illnesses. It is
always secondary to an underlying disorder and is associated with a number of clinical
conditions, generally involving activation of systemic inflammation.

NEW PATHOPHYSIOLOGICAL CONSIDERATIONS ON CEREBRAL ANEURYSMS

INTRODUCTION
A cerebral aneurysm is an outpouching of a weakened arterial wall with a prevalence that is
reported to be 2–4% in the general population [1]. Cerebral aneurysms are usually silent over
their lifetime, but they sometimes can be complicated by subarachnoid hemorrhage or mass
effect, causing substantial injury to multiple brain areas with a high fatality rate of 35% [2]. The
potential for fatal outcomes has led us to investigate the natural history of these lesions and to
provide standards for screening and giving prophylactic interventions. In Korea, screening for
ALDRIN KENNETH REYES

cerebral aneurysms is recommended for individuals who have 2 or more first-degree relatives
with cerebral aneurysm, autosomal dominant polycystic kidney disease (ADPKD), or previous
aneurysmal subarachnoid hemorrhage [3]. Screening is not recommended for those with a
negative family history and no known risk or genetic factors related to the cerebral aneurysm [4].
The decision regarding whether to treat or not should be determined by considering sufficient
patient- and aneurysm-specific factors: age, life expectancy, comorbidity, history of previous
subarachnoid hemorrhage, family history, anxiety, aneurysm size, location, multiplicity,
morphology, increasing size or morphological change during follow-up, and the assumed risk of
the treatment [3].

Despite multidisciplinary discussion according to guideline recommendations, the decision for

prophylactic treatment is often difficult in actual practice. Most current knowledge regarding
aneurysms that are high-risk for rupture has been derived from limited clinical and aneurysm
parameters. Risk factors including hypertension, smoking, and female gender are not enough to
explain the interpersonal differences in vulnerability to aneurysm rupture. We are now in search
of pathophysiology-based risk markers to better identify high-risk aneurysms. Beyond evaluating
final phenotypes shown in angiography, we need to evaluate the early pathological changes that
occur during the formation, growth, and rupture of the aneurysms. This review will address the
anatomical and embryonic origins of the cerebral artery, the mechanisms of vessel wall stress
and degeneration, and markers for high-risk aneurysms, based on new pathophysiological
considerations on cerebral aneurysms.
STRUCTURE OF THE CEREBRAL ARTERY
Sound anatomical structure ensures the functional integrity of cerebral arteries; however, its
perturbations lead to the development and progression of various cerebrovascular diseases. A
cerebral aneurysm and its complications involve structural changes in the arterial wall. A better
understanding of the anatomical and embryonic characteristics of cerebral arteries is a basis for
pathophysiological consideration of cerebral aneurysms.

Characteristics of cerebral arteries

The cerebral artery, like other systemic arteries is composed of the tunica intima, tunica media,
and the adventitia [5]. The tunica intima is the innermost layer and is lined with endothelial cells.
The tunica media consists of cellular and matrix components. The adventitia is the abluminal
layer of the vessel and is composed of fibroblasts and a collagen-rich extracellular matrix. The
internal elastic lamina partitions the tunica intima and tunica media, and the external elastic
lamina demarcates the adventitia from the tunica media. The cells and matrix in each layer
provide a structural and functional support to maintaining the integrity of the vessel wall. In
particular, smooth muscle cells and an extracellular matrix that are oriented perpendicularly to
each other in the tunica media confer contractile and regulatory functions, and thus contribute
most to the structural support of vessels [6]. The extracellular matrix includes elastin, collagen,
proteoglycans, and fibrillin, which are generated and regulated by smooth muscle cells.
Extracellular matrices are organized with each other between the lamellar layers of elastin, which
confers mechanical strength to the vessel. The turnover of smooth muscle cells and elastin is
ALDRIN KENNETH REYES

very low. The lamellar layers of elastin are constructed during the developmental period and
show either a slow proliferation or degradation rate of a half-life of approximately 40 years [7].
Therefore, the elastin layer integrity achieved during the developmental period is critical for
preserving vascular health over a lifetime.
There are some anatomical differences in the systemic vasculature. Arteries are classified as
muscular or elastic according to the composition of the tunica media. The constituents and
cellular origins of the cerebral arterial walls vary per vessel site [8,9]. Each arterial site may have
a different degree of durability and vulnerability to a variety of pathophysiological signals. The
common carotid artery is an elastic artery, and the internal carotid and intracranial arteries are
muscular arteries. The intradural and extradural portions of the intracranial arteries have different
layer structures. The adventitia in the intradural portion is thinner than that in the extradural one.
The collagen component in the adventitia is advantageous for preventing rupture in the face of
abrupt pressure changes [10]. Intradural segments also show marked attenuation of elastic fibers.
They lack the external elastic lamina that makes the intracranial artery, especially the intradural
segment, more vulnerable to aneurysm formation and rupture than other muscular arteries. The
posterior vasculature is more capable of arterial remodeling compared to the anterior vasculature
[11]. The branching site is more vulnerable to hemodynamic stress because of the deflection and
oscillation of blood flow [12], and cerebral aneurysms occur preferentially at arterial
bifurcations.
Embryonic origins of cerebral vascular smooth muscle cells
Smooth muscle cells and the extracellular matrix in the tunica media offer structural and
functional support to the cerebral artery, and thus the characteristics of these cells are important
to maintain a vascular health. Smooth muscle cells act to maintain the structural integrity of
mature vessels, which differs depending on the vessel location or the specific segment of the
same vessel, which is also related to its distinct embryonic origin [13]. There are two distinct
populations that give rise to vascular smooth muscle cells. One is the mesoderm, which forms
the dorsal aorta. The other is the neural crest cell population, which generates smooth muscle
cells in the beginning portions of the aorta, extracranial arterial trunk, and intracranial arteries
[14]. The neural crest cells migrate into the anterior and ventral head, whereas the progenitor
cells of mesodermal origin migrate into the dorsal and posterior parts of the head and neck [14].
The vascular trees of two different origins are connected and diverge at the circle of Willis. A
key function of smooth muscle cells of neural crest origin is secretion, whereas the mesodermal
cells have a contractile function. Smooth muscle cells of neural crest origin produce a higher
amount of elastin, but confer a lower contractile function compared to those of mesodermal
origin.

Aneurysmal changes can involve multiple vessels of a common embryonic origin when neural
crest cells are malpositioned or malfunction. Since the thoracic and abdominal aorta have
different embryonic origins, thoracic and abdominal aortic aneurysms have different
pathophysiological mechanisms and clinical features [15,16]. Epidemiological observations
showed that patients with thoracic aortic aneurysms have a nine-fold higher prevalence of
cerebral aneurysms than the general population [17]. It was recently found that ascending aortic
aneurysms coexisted more often with aneurysms of the anterior and middle cerebral arteries,
ALDRIN KENNETH REYES

whereas abdominal aortic aneurysms occur more often with internal carotid artery aneurysms
[18]. As the neural crest cells show high migration and differentiation properties throughout the
vessel, heart, and head and neck structures during early embryogenesis [14], perturbations in the
development of neural crest cells disrupt the integrity of the vessel walls and other head and neck
structures. There have been anecdotal reports showing that cerebral aneurysms are common
pathological features of neurocristopathy, such as bicuspid aortic valve [19], congenital heart
diseases [20], neurofibromatosis type 1 [21], fibromuscular dysplasia [22]. In line with this
concept, patients with multiple, larger aneurysms and rupture tended to have a dilated aortic root
[23].
Extracellular matrix defect and degradation
The extracellular matrix is a dynamic structure that is continuously undergoing a remodeling
process by interacting with vascular cells. Given the secretory function of smooth muscle cells in
the cerebral artery rather than contractile function, the mechanical strength of the large arteries
primarily depends on the cross-linking of elastin and collagen. The longevity of elastin generated
in early embryogenesis is similar to the human life span, and rarely experiences a wear and tear
process. Once extracellular matrix defects or degradation take place, the disease course may not
be restored. Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases that
are produced by smooth muscle cells and inflammatory cells mediate the process of extracellular
matrix degradation and remodeling. An imbalance between MMPs and their inhibitors
contributes to initiation and progression of cerebral aneurysms.

Lysyl oxidases (LOX) catalyzes the critical step in cross-linking elastin and collagen [24]. LOX
requires one tightly bound copper ion for its active role. As dietary copper amount directly
affects LOX activity [25], copper deficiency during the developmental period may attenuate
LOX activity and weaken vessel wall integrity leading to the development of aneurysms in
adulthood. It was recently demonstrated that copper deficiency in mice during the developmental
period caused complex vascular wall abnormalities involving thoracic aortic aneurysms and
cerebral aneurysms [26]. The thoracic aortae were dilated with disorganized elastic fibers, and
the fusiform and saccular aneurysms were noted in the surviving mice. Since copper deficiency
often occurs during infancy in cases of cow’s milk feeding or infant formula with low copper
content [27,28], the infancy environment and food habits may affect aneurysm prevalence and
outcome. Clinically, a variety of extracellular matrix defect have been detected in patients with
connective tissue diseases such as osteogenesis imperfecta, vascular Ehlers-Danlos syndrome,
and Marfan syndrome, which are commonly associated with cerebral aneurysms.

Hemodynamic stress
Cerebral aneurysms preferentially occur at the anterior communicating artery, the posterior
communicating artery, the middle cerebral artery bifurcation, and the basilar artery bifurcation
where local shear stress is greatest on the arterial wall [12,29]. Blood flow at the arterial
junctions, the bifurcations with wider bifurcation angles, or abrupt vascular angles are the most
turbulent, and the shear stresses in these areas are the greatest. High wall shear stress induces
endothelial cell damage, smooth muscle cell degeneration, and media thinning. Hemodynamic
ALDRIN KENNETH REYES

forces also cause endothelial cells and smooth muscle cells to release MMP-2 and MMP-9 and
subsequently to degrade the extracellular matrix, resulting in aneurysm formation. The
magnitude of local shear stress is well correlated with the degree of internal elastic lamina loss,
medial degeneration, and arterial bulging [30]. Shear stress is certainly a strong trigger for
developing aneurysms in individuals that are predisposed to them. In this regard, flow diverters
to attenuate shear stress have been recently applied to decrease the risk of aneurysm growth and
rupture [31]. On the other hand, recent investigations by computational fluid dynamics models
support the differential role of hemodynamics on development and rupture of cerebral
aneurysms. While a high wall shear stress promotes formation of aneurysms, low stress has been
associated with aneurysm rupture [32]. Moreover, the wall shear stress is significantly lower at
the rupture point that sac [33], and pooled analyses show a decreased wall shear stress could
predict aneurysm rupture [34].
CONCLUSION
Cerebral aneurysms are asymptomatic and may be found incidentally in cerebral angiographies
performed in neurology clinics or in health screening settings. It will be important to decide
whether or not to treat them, and how to continue with long-term follow-up in these patients.
Close imaging surveillance for morphological changes in the aneurysm or preventive treatment
should be provided for some patients with a profile that exhibits a high risk of rupture. However,
the majority of cerebral aneurysms require no imaging follow-up or prophylactic treatment.
Aneurysms may harbor intrinsic vessel wall deformities or acquired vessel wall degeneration
during their development, and they may have variable outcomes according to the different
pathophysiological signals. Patient- or aneurysm-derived factors can help to stratify the risk of
progression or rupture. Enriched clinical observations and advanced imaging and histological
data have enhanced our knowledge of the pathophysiology of cerebral aneurysms and provided
new patient- and/or aneurysm-specific factors for consideration (Fig. 3). Future multi-factorial
evaluations with genetic, imaging, and laboratory tests would offer the opportunity to better
identify aneurysms that have a high risk of rupture.

HEART FAILURE: DIAGNOSIS, MANAGEMENT AND UTILIZATION

1. Introduction
1.1. Background
Heart failure (HF) is a clinical syndrome caused by structural and functional defects in
myocardium resulting in impairment of ventricular filling or the ejection of blood. The most
common cause for HF is reduced left ventricular myocardial function; however, dysfunction of
ALDRIN KENNETH REYES

the pericardium, myocardium, endocardium, heart valves or great vessels alone or in

combination is also associated with HF. Some of the major pathogenic mechanisms leading to
HF are increased hemodynamic overload, ischemia-related dysfunction, ventricular remodeling,
excessive neuro-humoral stimulation, abnormal myocyte calcium cycling, excessive or
inadequate proliferation of the extracellular matrix, accelerated apoptosis and genetic mutations
[1].

1.2. Classification of HFs

Heart failure can be classified as predominantly left ventricular, right ventricular or biventricular
based on the location of the deficit. Depending on the time of onset, HF is classified as acute or
chronic. Clinically, it is typically classified into two major types based on the functional status of
heart: heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced
ejection fraction (HFrEF). In patients with HFpEF who are mostly females and older adults, EF
is usually more than 50%; the volume of the left-ventricular (LV) cavity is typically normal, but
the LV wall is thickened and stiff; hence, the ratio of LV mass/end-diastolic volume is high [2].
HFpEF is further categorized as borderline HF if the EF stays between 41% and 49% and
improved HF if EF is more than 40% [1]. In contrast, in patients with HFrEF, the LV cavity is
typically dilated, and the ratio of LV mass/end-diastolic volume is either normal or reduced. At
the cellular level, both cardiomyocyte diameter and the volume of myofibrils are higher in
HFpEF than in HFrEF [1]. As far as treatment and outcome are concerned, patients with HFrEF
respond favorably to the standard pharmacological treatment regimen and demonstrate better
prognosis. In contrast, patients with HFpEF have not been shown to respond to standard
pharmacological treatments, except for nitrates, and therefore, have a poor prognosis, especially
during the decompensated phase of HF [2,3,4]. In addition, based on cardiac output, HF is also
classified as high-output failure and low-output failure. High-output failure is an uncommon
disorder characterized by an elevated resting cardiac index of greater than 2.5–4.0 L/min/m2 and
low systemic vascular resistance. The common causes of high output failure are severe anemia,
vascular shunting, hyperthyroidism and vitamin B1 deficiency. This occurs as a result of
ineffective blood volume and pressure, which stimulate the sympathetic nervous system and
renin-angiotensin-aldosterone system (RAAS), causing the release of antidiuretic hormone
(ADH), which all together ultimately lead to ventricular enlargement, negative ventricular
remodeling and HF. Low output failure is much more common than high-output failure and is
characterized by insufficient forward cardiac output, particularly during times of increased
metabolic demand. Left ventricular dysfunction due to large MI, right ventricular dysfunction
due to an acute pulmonary embolus and biventricular dysfunction are important causes of low
output failure. More recently, exercise intolerance in HFpEF is proposed to be due to a decrease
in oxygen delivery to or impaired oxygen utilization by the exercising skeletal muscles. Oxygen
utilization is being calculated as the arterial–venous oxygen content difference (A-VO2 Diff),
rather than reduced cardiac output (CO) [5,6]. Considering the slowed down oxygen uptake
kinetics in HF along with peripheral muscle function impairment, exercise rehabilitation seems
to be a logical and essential factor in improving the inflammatory imbalance, relieving elevated
cardiac filling pressures, restoring exercise capacity, quality of life and reducing morbidity and
mortality associated with HF. Hence, exercise training, mostly high intensity as opposed to
moderate, in HFpEF patients has been significantly shown to improve rate of oxygen
consumption or VO2 without affecting endothelial function [7,8].
ALDRIN KENNETH REYES

Stage A: High risk of heart failure, but no structural heart disease or symptoms of heart failure;
Stage B: Structural heart disease, but no symptoms of heart failure;
Stage C: Structural heart disease and symptoms of heart failure;
Stage D: Refractory heart failure requiring specialized interventions.
2. Clinical Presentation of HF
The clinical presentation of HF comprises symptoms of shortness of breath (SOB)/dyspnea
(sensitivity of 84%–100%, but a specificity of 17%–34%); orthopnea/SOB on lying own
(sensitivity of 22%–50% and a specificity of 74%–77%); paroxysmal nocturnal dyspnea
(sensitivity 39%–41%, specificity from 80%–84%); fatigue/weakness/lethargy (due to HF-
induced circulation-related abnormalities in skeletal muscles); edema, abdominal distention and
right hypochondrial pain (most likely due to right-sided heart failure with sensitivity and
specificity of 23% and 80%, respectively) [9,10]. Due to compensatory mechanisms, early stages
of HF lack specific signs; however, late stages of HF demonstrate the following signs:
tachycardia (99% specificity and 7% sensitivity); pedal edema (93% specificity and 10%
sensitivity); increased jugular venous pressure (JVP) (usually > 6 cm; specificity of 92% and
sensitivity of 39%), abnormal lung sounds (crackles) (specificity of 78% and sensitivity of 60%);
S3 gallop (specificity of 99% and sensitivity of 13%). Other signs, such as hepatojugular reflux
and ascites, are not found frequently in HF, but have a specificity of 96% and 97%, while a
sensitivity of 24% and 1%, respectively [11,12]. Recent research has uncovered the
microvascular dysfunction and subsequent decrease in O2 supply or mismatch with the O2
supply vs. demand in HF patients. Therapeutic strategies to improve muscle microvascular and
oxidative function via exercise training, anti-inflammatory and antioxidant agents have been
proposed to be essential to provide better exercise tolerance and quality of life [13].

HF has primarily been recognized as a disease of the elderly population (>60 years) and is
reported to affect about 2%–3% of people in the United States. Of these include 10% of males
and 8% of females. Unfortunately, these numbers are on a gradual increase due to the on-going
prevalence of HF with increasing age. In the USA itself, about more than three million physician
visits per year have been accounted for patients with HF as the primary health issue. In 2013, the
total number of HF patients were 5.1 million, and direct costs were equal to $32 billion; and this
cost is being projected to increase by about three-fold by 2030 [14]. As of 2011, the estimated
lifetime cost of HF per individual patient was $110,000/year, with more than three-fourths of this
cost consumed by ‘in-hospital care’ [15]. Interestingly, the five-year mortality rate for HF was
reviewed to be approximately 50%, which is significantly higher than that of some cancers [16].
Among Medicare patients, 30-day all-cause, risk-standardized mortality rates for HF are 10%–
12%, while 30-day, all-cause, risk-standardized readmission rates after hospital discharge are
20%–25% [17]. There is indeed a slight decrease in HF-related mortality from 2000 to 2014. The
age-adjusted rate for HF-related mortality was 105.4 per 100,000 population in 2000 and reached
84.0 per 100,000 in 2014. Similarly, the percentage of in-hospital HF-related deaths declined
from 42.6% in 2000 to 30% in 2014 [18]. Furthermore, although in a nursing home or long-term
care facility, the percentage of deaths have been decreased from 30.1% in 2000 to 26.7% in
2014, such deaths have increased in the patients in residence and in outpatient clinics or hospice
ALDRIN KENNETH REYES

care by about 10% and 7%, respectively. Although the prognosis of other cardiac conditions,
such as acute coronary syndrome (ACS), severe hypertension, valvular and congenital heart
diseases, has improved over the past decade, the prevalence of HF has increased in a relatively
exponential manner [18]. An increase in the prevalence of co-morbid conditions and risk factors,
such as increased body mass index (BMI), metabolic syndrome, elevated apolipoprotein
B/apolipoprotein A ratio and cigarette smoking, in these populations with relatively increased
life expectancy may be some of the reasons behind the increased prevalence of HF [19].
Furthermore, available treatment options for HF only offer symptomatic relief and lack definitive
curative treatment for the affected heart. As far as hospitalization is concerned, acute
decompensated heart failure (ADHF) is the most common form of heart failure that accounts for
~80% of hospitalizations related to heart failure [19]. The common causes of ADHF include
non-adherence to medication or dietary restrictions; uncontrolled hypertension; acute coronary
syndrome/ischemia; dysrhythmia/arrhythmias and COPD exacerbation; alcohol intoxication or
excess; thyroid conditions; pregnancy; and other iatrogenic conditions, such as postoperative
fluid replacement or administration of steroids or non-steroidal anti-inflammatory drugs; all
directly or indirectly leading to the progression of the underlying disease [19].

The underlying pathogenesis of HF also involves silent inflammatory and immune-regulatory

responses, the activation of which still has not been completely understood. It has been proposed
that in HF, excessive neuroendocrine activation leads to the activation of neuro-hormones and
pro-inflammatory cytokines following an initial cardiac insult. Many of these pro-inflammatory
and anti-inflammatory cytokines and their receptors, released endotoxins, adhesion molecules,
nitric oxide and reactive oxygen species have been associated with various pathological aspects
of HF [20,21]. The pro-inflammatory cytokines include tumor necrosis factor-α (TNF-α),
sTNFR19 (soluble tumor necrosis factor receptor 1/2), soluble Fas protein, TNF-α-related
apoptosis-inducing ligand (TRAIL), interleukin 6, activin A, myeloperoxidase, pentraxin-3,
regulated on activation, normal T cell expressed and secreted (RANTES), C reactive protein,
monocyte chemotactic protein 1 (MCP1) and macrophage inflammatory protein 1-α (MIP-1-α)
[22]. Many of these inflammatory markers (such as IL-6, TNF-α, CRP) have been found to be
upregulated in HF patients, especially in the ADHF phase. In light of these findings, several
clinical trials have been designed, and drugs targeting inflammatory markers, nitric oxides and
reactive oxidative species, such as etanercept, infliximab, glucocorticoids, statins and anti-
oxidants, are being tested [21]. A newer pathological mechanism “gut hypothesis of heart
failure” has been proposed. Here, HF-associated decreased CO and alteration of systemic
circulation which lead to reduced intestinal perfusion and mucosal ischemia, thus causing
disruption in intestinal barrier, increased gut permeability, increased bacterial translocation and
increased circulating endotoxins. This in turn contributes to the elevated pro-inflammatory
response reported in patients with HF. For example, the fasting plasma trimethylamine-N-oxide
(TMAO) is reported to be elevated in HF patients and has recently been correlated to higher
long-term mortality risk independent of other HF risk factors [23]. For this reason, several
strategies have been designed to retain the normal micro-biome and maintain metabolic
homeostasis in HF patients [24].

Go to:
ALDRIN KENNETH REYES

3. Diagnosis of HF
The evaluation for HF is performed using various parameters: physical examination to determine
the presence of clinical symptoms and signs, blood tests, including complete blood count,
urinalysis, complete metabolic profile for levels of serum electrolytes (including calcium and
magnesium), blood urea nitrogen, serum creatinine, glucose, fasting lipid profile, liver function
tests and thyroid-stimulating hormone.

Other HF-specific laboratory tests (especially in patients with a high possibility of heart failure)
include brain natriuretic peptide (BNP) with 70% sensitivity and 99% specificity and N-terminal
proBNP (NT-proBNP) with 99% sensitivity and 85% specificity, the measurement which has
been recommended both in outpatient and in the hospital settings [1]. BNP is a neuro-hormone,
which is an activated form of proBNP, the 108-amino acid polypeptide precursor, stored as
secretory granules in both ventricles and, to a lesser extent, in the atria. In response to volume
expansion and pressure overload, proBNP is secreted into ventricles and breaks down into its
two cleaved forms, the 76-peptide, biologically-inert N-terminal fragment, NT-proBNP, and the
32-peptide, biologically-active hormone BNP. NT-proBNP and BNP have clinical significance
both as diagnostic and prognostic markers in the management of HF. During the diagnosis of
HF, in patients presenting with acute dyspnea, BNP levels of less than 100 pg/mL have a 90%
negative predictive value (NPV), and values of more than 500 pg/mL have an 81% positive
predictive value (PPV) [25]. The BNP level is a strong predictor of risk of death and
cardiovascular events in patients previously diagnosed with heart failure or cardiac dysfunction.
It is to be remembered that elevated BNP levels have also been associated with renal failure,
pulmonary embolism, pulmonary hypertension and chronic hypoxia while obese and overweight
individuals have relatively lower BNP levels. Furthermore, there has been no clinically
significant difference between BNP and NT-proBNP in terms of the diagnostic and prognostic
values, except for the longer half-life time of NT-proBNP (72 h) as opposed to 4 h for BNP and
that NT-pro-BNP levels are less affected by obesity [9,26]. A recent review by Simons et al.
discussed the criteria and cut off values for the diagnosis, prognosis and treatment guidance [27].
Accordingly, single measurement of natriuretic peptides (BNP ≤ 100 pg/mL or NTproBNP ≤ 300
pg/mL) rules out HF clinically, while BNP ≥ 500 pg/mL or NTproBNP ≥ 1800 pg/mL has been
proposed to have a relatively lower level of evidence in clinical settings. Nevertheless, both BNP
and NT-proBNP levels aid in decisions regarding admission/ discharge and risk stratification for
HF patients. Patients with BNP level of less than 200 pg/mL at admission have been associated
with 2% mortality rate as opposed to 9% mortality rate seen in patients with admission BNP
level of more than 200 pg/mL [28]. NT-proBNP level equal to or higher than 5000 pg/mL at
admission has been shown to be associated with in-hospital mortality rate of 22.5% and longer
length of stay in remaining surviving patients [29].

Biomarkers not only provide valuable information about the pathophysiology of the disease, but
also shed light on the severity of ongoing disease. As far as biomarkers for HF are concerned, the
National Academy of Clinical Biochemistry has set forth comparable goals in a consensus
document stating that a biomarker in HF ideally enables clinicians to: (i) identify possible
ALDRIN KENNETH REYES

underlying (and potentially reversible) causes of HF; (ii) confirm the presence or absence of the
HF syndrome; and (iii) estimate the severity of HF and the risk of disease progression.
Multiple biomarkers have been classified depending on their putative functional impact on
cardiac myocytes and the resulting pathophysiological changes in patients with HF and include
(a) myocyte stretch biomarkers; (b) myocyte necrosis biomarkers; (c) systemic inflammation
biomarkers; (d) oxidative stress biomarkers; (e) extracellular matrix turnover biomarkers; (f)
neuro-hormone biomarkers; and (g) biomarkers of extra-cardiac processes, such as renal
function. The specific biomarkers are shown in Table 1 along with the underlying mechanisms
leading to their expression in HF patients. The details of the commonly-used HF biomarkers and
other emerging biomarkers are described in other review articles authored by Ahmad et al., 2012,
Gaggin and Januzzi, 2012, and van Kimmenade et al., 2013

MANAGING ACUTE PULMONARY OEDEMA

Introduction
Acute pulmonary oedema is a medical emergency which requires immediate management.1 It is
characterised by dyspnoea and hypoxia secondary to fluid accumulation in the lungs which
impairs gas exchange and lung compliance.2
The one-year mortality rate for patients admitted to hospital with acute pulmonary oedema is up
to 40%.3 The most common causes of acute pulmonary oedema include myocardial ischaemia,
ALDRIN KENNETH REYES

arrhythmias (e.g. atrial fibrillation), acute valvular dysfunction and fluid overload. Other causes
include pulmonary embolus, anaemia and renal artery stenosis.1,4 Non-adherence to treatment
and adverse drug effects can also precipitate pulmonary oedema.
There are no current Australian data on the incidence of acute pulmonary oedema or heart
failure. However, self-reported data from 2011–12 estimated that 96 700 adults had heart failure,
with two-thirds of these being at least 65 years old.5 Most patients with chronic heart failure will
have at least one episode of acute pulmonary oedema that requires treatment in hospital.6
There are several different clinical guidelines for the management of acute pulmonary oedema.7-
15 However, these are based predominantly on low-quality evidence and expert opinion. The
goals of treatment are to provide symptomatic relief, improve oxygenation, maintain cardiac
output and perfusion of vital organs, and reduce excess extracellular fluid. Any underlying cause
should be identified when starting treatment.
The drugs used in treatment include nitrates, diuretics, morphine and inotropes. Some patients
will require ventilatory support.
Follow-up
The underlying cause of the patient’s acute pulmonary oedema should be treated. This includes
reviewing their medicines to see if any drugs, such as non-steroidal anti-inflammatory drugs,
verapamil or diltiazem, could have contributed to the problem. Additional monitoring including
daily weights, and measurements of serum electrolytes and renal function is also
recommended.15
Once the patient with cardiogenic acute pulmonary oedema has been stabilised the goal of
therapy is to improve long-term outcomes. If an echocardiogram shows a preserved left
ventricular ejection fraction, the focus is to treat any associated conditions. This includes the
management of hypertension with antihypertensive drugs, reduction of pulmonary congestion
and peripheral oedema with diuretics, and rate control for atrial fibrillation. If there is evidence
of a reduced ejection fraction and chronic heart failure then an ACE inhibitor, beta blocker and
mineralocorticoid receptor antagonist should be considered.2
ACE inhibitors are best started at 24–48 hours after admission, provided the patient is
haemodynamically stable.2 They should be used cautiously in patients with hypotension or renal
impairment, with close monitoring of blood pressure and renal function.7,9 Beta blockers, such
as bisoprolol, are commenced at low dose once the patient is euvolaemic, before discharge from
hospital. Mineralocorticoid receptor antagonist drugs, such as spironolactone, are best started
soon after discharge with careful monitoring of blood pressure, serum potassium and renal
function.2
Conclusion
Guidelines have highlighted that there is a lack of evidence to support the currently used
therapies. Additionally there are concerns regarding the efficacy and safety of these treatments
for acute pulmonary oedema. There has therefore been a shift over the last few years to favour
nitrates and non-invasive ventilation as first-line management. However, opioids and diuretics
may have a role in some patients
ALDRIN KENNETH REYES

ACUTE RESPIRATORY DISTRESS SYNDROME: AN UPDATE AND REVIEW

Introduction
Acute respiratory distress syndrome (ARDS) is an acute life threatening inflammatory lung
injury manifested by hypoxia and stiff lungs due to increased pulmonary vascular permeability
and almost always requiring mechanical ventilation support.[1] ARDS represents an acute
response to diverse provoking trigger factors and etiologies, resulting bilateral lung opacities on
radiography and hypoxemia.
ALDRIN KENNETH REYES

ARDS was first described by Ashbaugh et al. in 1967,[2] and since then there have been multiple
studies addressing the various clinical aspects of the syndrome, its pathogenesis, risk factors, and
treatment. However, despite the intense research, only few effective therapies for ARDS have
been postulated, including the lung protection strategies.

In this review article, authors will summarize the key features of ARDS, a brief overview of the
therapeutic options in the management of ARDS.

Go to:
Definition
ARDS was first defined in 1994 by the American-European Consensus Conference (AECC) as
the acute onset of hypoxemia (arterial partial pressure of oxygen to fraction of inspired oxygen
[PaO2/FIO2] ≤ 200 mm Hg) with bilateral infiltrates on frontal chest radiograph, with no
evidence of left atrial hypertension and acute lung injury (ALI) was defined using similar
criteria, but having PaO2/FIO2 ≤ 300 mm Hg.[3] Over the years, with the ongoing research on
this topic, issues regarding the validity and reliability of this definition emerged.

A panel of experts assembled in 2011 (an initiative of the European Society of Intensive Care
Medicine endorsed by the American Thoracic Society and the Society of Critical Care Medicine)
and developed the Berlin Definition of ARDS using a consensus process.[1] The Berlin
definition require all four criteria’s to be present for diagnosis of ARDS (1) Timing: Respiratory
symptoms must have begun within one week of a known clinical insult, or the patient must have
new or worsening symptoms during the past week. (2) Chest imaging: Bilateral opacities
consistent with pulmonary edema must be present on a chest radiograph or computed
tomographic scan, which is not fully explained by pleural effusions, lobar collapse, lung
collapse, or pulmonary nodules. (3) Origin of edema: The patient’s respiratory failure must not
be fully explained by cardiac failure or fluid overload. An objective assessment (e.g.,
echocardiography) to exclude hydrostatic pulmonary edema is required if no risk factors for
ARDS are present. (4) Oxygenation: A moderate to severe impairment of oxygenation must be
present, as defined by the PaO2/ FiO2 ratio.

The severity of the hypoxemia defines the severity of the ARDS: (1) Mild ARDS—The
PaO2/FiO2 is > 200 mmHg, but ≤ 300 mmHg, on a ventilator with a positive end-expiratory
pressure (PEEP) or continuous positive airway pressure ≥ 5 cm H2O. (2) Moderate ARDS—The
PaO2/ FiO2 is > 100 mmHg, but ≤ 200 mmHg, on a ventilator with a PEEP ≥ 5 cm H2O. (3)
Severe ARDS—The PaO2/ FiO2 is ≤ 100 mmHg on a ventilator with a PEEP ≥ 5 cm H2O.
ALDRIN KENNETH REYES

Compared with the AECC definition, the Berlin Definition had a better prediction for mortality
with increased percentage of mortality associated with increasing stages of ARDS: mild 27%,
moderate 32%, and severe 45% with 95% CI.[1]

Go to:
Pathophysiology and risk factors
ARDS occurs as a consequence of an alveolar injury due to various causes producing diffuse
alveolar damage. This causes the release of pro-inflammatory cytokines [tumor necrosis factor,
interleukin (IL)-1, IL-6, IL-8], which recruit neutrophils to the lungs, where they get activated
and release toxic mediators (reactive oxygen species and proteases) that damage the capillary
endothelium and alveolar epithelium leading to alveolar edema.[4] This, eventually, leads to
impairment of gas exchange, decreased lung compliance, and increased pulmonary arterial
pressure.

Pathological stages: The initial stage is the exudative stage, characterized by diffuse alveolar
damage. The second stage of proliferation develops after approximately 10–14 days,
characterized by resolution of pulmonary edema, proliferation of type II alveolar cells, squamous
metaplasia, interstitial infiltration by myofibroblasts, and early deposition of collagen. Some
patients progress to the third stage of fibrosis, characterized by obliteration of normal lung
architecture, diffuse fibrosis, and cyst formation.[5]
Current therapies
Lung-protective ventilation
Various trials have demonstrated that mechanical ventilation with lower tidal volumes (LTV)
and airway pressures (tidal volume of 4–6 ml/kg predicted body weight and maintenance of
plateau pressure between 25 and 30 cm H2O) reduces mortality in ALI and ARDS.[6] This lung-
protective ventilation preserves barrier properties of the alveolar endothelium and alveolar
epithelium by preventing alveolar overdistension, which is one of the major causes of ventilator-
induced lung injury.[6,7,8,9,10,11] The concept of open lung ventilation uses low tidal volume
with high PEEP with the rationale that LTV will minimize the damage due to overdistension
while the high PEEP will minimize the cyclic atelectasis [6], has been shown to have a beneficial
effect on the outcome of the patients. Lung-protective ventilation also down regulates
mechanosensitive pro-inflammatory pathways, resulting in reduced neutrophil accumulation in
the alveoli and lower plasma levels of IL-6, IL-8, and TNF.[7,12]

Prone ventilation
Prone ventilation showed improvement in the level of oxygenation and thus improved the
outcome in patients with ARDS having severe hypoxia.[13,14,15] This effect is due to the
reduction in the trans-pulmonary pressure gradient on making the patient prone, which helps in
recruiting the collapsed areas of the lung without causing significant increase in the airway
ALDRIN KENNETH REYES

pressures. In the study by De Jong et al. (2013), prone ventilation was found to be a significantly
effective in obese patients with ARDS than in non-obese patients.
Extracorporeal membrane oxygenation
ECMO is an advanced circulatory and ventilatory support system, which is used to salvage the
patients with refractory hypoxemia when the conventional treatment fails. The technique has
been used successfully as a rescue therapy for the severe ARDS cases as shown by the CESAR
trial in 2009 [17]. The evidence to support the use of ECMO as a primary treatment in ARDS is
lacking and needs further research.[18,19]

High-frequency oscillatory ventilation

High-frequency oscillatory ventilation (HFOV) seemed ideal for lung protection in ARDS, but
the OSCAR study concluded with no 30-day survival benefit or cost benefit in patients in whom
HFOV was used [20]. The meta-analysis of randomized control trials (RCT) by Gu et al. (2014)
also concluded that with use of HFOV, there was no improvement in survival in ARDS patients,
although it had no increase the risk of barotrauma or hypotension and also reduced the risk of
oxygenation failure.[21]
Neuromuscular blockade
Neuromuscular blocking agents (NMBAs) are commonly used in ARDS, but their use remains
controversial. In recent meta-analysis and review, the use of short term NMBAs in ARDS
patients have shown a beneficial outcome mainly by decreasing the barotrauma and ventilator-
induced lung injury.[22, 23]
Fluid-conservative therapy
In ARDS patients, due to increased alveolar vascular permeability, there is presence of alveolar
edema, which may get worsened as a consequence of fluid overload. The conservative approach
of fluid management in ARDS has been proven to be beneficial in reducing ventilator days but
doesn’t improve survival.[24]

Intravenous β-2 agonist in ARDS

The BALTI trial (2006) was a single center RCT, which showed the benefit of intravenous
infusion of Salbutamol for 7 days in patients with ARDS, by causing significant reductions in
extravascular lung water and plateau airway pressures [25]. Despite this, the recent evidence
from the BALTI 2 trial, which is a multicenter RCT, showed no benefit of intravenous β-2
agonist (Salbutamol) in patients with ARDS and concluded that this may have significant
detrimental effects with increase in mortality.[26]
Corticosteroids in ARDS
ARDS, despite being an acute lung inflammatory disease with involvement of diverse
inflammatory cells and mediators, the use of anti-inflammatory corticosteroids have not shown
improved survival. A systematic review and meta-analysis by Ruan et al. (2014), which included
ALDRIN KENNETH REYES

8 RCTs and 10 cohort studies concluded that corticosteroids may be harmful in some patients
and not to be routinely used in ARDS.[27]
Experimental trials
In experimental models of ARDS in rats, bone-marrow derived mesenchymal stem cells (MSCs)
reduce the severity of ventilator-induced lung injury by enhancing the regeneration of lung tissue
and its repair [28, 29]. Studies have shown that MSCs could be of benefit by their property to
reduce the production of inflammatory mediators, leukocyte infiltration, tissue injury, and
pulmonary failure.[30]
Conclusion
There has been considerable research on ARDS in the past decade and better understanding of its
pathogenesis. Despite this, the effective therapeutic measures to decrease mortality in ARDS
seem to be low-tidal volume mechanical ventilation, prone ventilation for severe ARDS cases;
and in life-threatening cases not responding to the conventional therapies, ECMO rescue
technology serves as a bridge to recovery.

ANENCEPHALY AND ITS ASSOCIATED MALFORMATIONS

Introduction
Failure of closure of the cranial neuropore during the fourth week of development results in the
abnormal vascularisation of the embryonic exencephalic brain [1]. The nervous tissue
subsequently undergoes degeneration and brain remains as a spongy vascular mass with some
hind brain structures [2]. Previously called as anencephaly (without brain), it is now called as
ALDRIN KENNETH REYES

Meroanencephaly as some functioning neural tissue is always present [3]. As Meroanencephaly

is a lethal malformation the research on presence of other associated malformations has largely
remained restricted. Ballantyne (1904)[4] as well as David and Illingworth [5] associated
diapharagmatic hernia with anencephaly. British Perinatal Mortality Survey [6] of 1958 first
stressed on registering the associated malformation in anencephalics. T.J.David [7] tabulated the
associated malformations and found spina bifida to be the most common. Many researchers
found that the most common associated malformations differed according to the geographical
location [8,9]. According to David TJ cardiovascular defects were common in Lancashire while
urinary tract defects were common in the Bristol [10]. Apart from CNS malformations
gastrointestinal and skeletal abnormalities were the most common according to C Pandurang [11]
in a study conducted in India.

Go to:
Materials and Methods
The study was conducted between January 2013 to March 2014 in Lokmanya Tilak Municipal
Medical College and general hospital which is a major tertiary care hospital for obstetrics in
western India. Ethical clearance was obtained by the institutional ethical committee. Twenty
anencephalic fetuses were dissected in the Anatomy department of the institute after obtaining
informed consent. The cases originated from still birth, spontaneous abortion and therapeutic
abortion. The gestational age was in the range of 16 to 34 weeks. There was no history of
diabetes, obesity and infections in the mothers. There was no exposure to any teratogenic drugs.
All mothers had received the recommended 0.5mg of folic acid supplementation. The findings
were done by external examination, photography and internal examination. Internal examination
was done for abdominal and genitourinary viscera only.
Conclusion
Anencephaly is common in females. Associated abnormalities were seen in 80% of cases in the
present study. Commonest abnormality was spina bifida. Describing the associated
malformations in anencephaly as described in present study is not only of academic and research
interest but also helpful to radiologists for correct interpretation and diagnosis. The strong
association between cleft palate and male fetus should be considered during the diagnosis. The
presence of associated abnormality like spina bifida, cleft palate, clubbed foot, clubbed hands
and gastroschisis points to the fact that anenchepaly consists of more than one aetiological entity.
Studies are required at molecular level to find its association with other anomalies.

ACUTE PANCREATITIS: CURRENT PERSPECTIVES ON DIAGNOSIS AND

MANAGEMENT

Introduction
A patient complaining of sudden onset of epigastric pain radiating to the back, associated with
nausea and vomiting, requires rapid exclusion of a wide range of life-threatening conditions
ALDRIN KENNETH REYES

involving the cardiovascular (myocardial infarction, ruptured, and/or dissecting aortic aneurysm)
and gastrointestinal (peptic ulcer disease with perforation or bleeding, acute pancreatitis)
systems. The clinician’s history and examination findings are augmented by relevant
investigations in narrowing the differential diagnoses to eventually guide the management and
treatment of a certain condition and its associated complications.

The incidence of acute pancreatitis in the UK is ~56 cases per 100,000 persons per year,1 while
in the US over 220,000 hospital admissions annually are attributed to acute pancreatitis.2 An
epidemiologic study that utilized UK and European data demonstrated an increasing incidence in
all-cause acute pancreatitis.3 The incidence of acute pancreatitis was also noted to increase with
age.3,4 The male population had an incidence that was 10%–30% higher than females.4 Despite
a reduction in the case fatality being observed over time, the population mortality has remained
largely unchanged.3 Of all hospital admissions with acute pancreatitis, ~20%–30% of patients
have a severe course,1 while severe life-threatening complications will develop in ~25% of these
patients.4 The mortality in severe acute pancreatitis can be as high as 30%,2 but the overall
mortality in acute pancreatitis is estimated to be 5%.1

Gallstones remain the most common cause for acute pancreatitis. Gallstone-related acute
pancreatitis accounts for approximately half of all UK cases, while up to 25% of acute
pancreatitis cases can be attributed to alcohol.1 Epidemiologic data have shown a linear increase
in the incidence of gallstone pancreatitis across the UK and European countries studied.
However, the UK has a much lower incidence of alcohol-induced pancreatitis compared with
European studies.3 Alcohol-induced acute pancreatitis is more common in middle-aged men.
Idiopathic acute pancreatitis accounts for 20%–34% of cases and its incidence is similar in both
men and women.3 The incidence of idiopathic acute pancreatitis depends on the extent to which
a clinician investigates a patient’s episode of acute pancreatitis for its causative etiology. Recent
advances in laboratory pathology tests and radiologic imaging techniques have contributed to a
reduction in the number of acute pancreatitis cases being labeled as idiopathic.

The incidence of gallstone-related acute pancreatitis in both men and women increases with age,
with women over the age of 60 years at higher risk.2,3 Patients with gallstones smaller than 5
mm, microlithiasis, or biliary sludge are thought to be at higher risk of gallstone pancreatitis.
Microlithiasis causes a functional obstruction at the sphincter of Oddi, which subsequently
results in bile and/or biliary-pancreatic secretion reflux that injures the pancreatic duct.5 The
common channel theory in the pathogenesis of acute gallstone pancreatitis has been refuted by
some.6 Instead, it has been postulated that acute gallstone pancreatitis is the result of pancreatic
acinar hyperstimulation secondary to ductal obstruction that triggers trypsin release, which
induces a cascade of enzyme-led pancreatic and peripancreatic inflammation.6 Others speculate
that duodenal content reflux is more causative of pancreatic ductal injury than bile reflux.7 There
are multiple theories implicated in the pathogenesis of acute pancreatitis, and all remain
controversial.
ALDRIN KENNETH REYES

Inappropriate release and activation of pancreatic enzymes induce acute pancreatitis. The key
enzyme in the activation of pancreatic zymogens has been thought to be trypsin. The
inappropriate activation of trypsinogen to trypsin and the lack of prompt pancreatic clearance of
active trypsin result in pancreatic inflammation and subsequent triggering of the inflammatory
cascade.2 Cytokines including interleukin (IL)-1, IL-6, IL-8, tumor necrosis factor a, and
platelet-activating factor are released.7 These in turn induce the hepatic synthesis of acute phase
reaction proteins such as C-reactive protein (CRP). Leukocyte migration and activation may
represent the major determining factor for both local and systemic complications.4

Go to:
Diagnosis of acute pancreatitis
In their 2005 guidelines, the UK Working Party on Acute Pancreatitis suggested that the etiology
should be determined in at least 80% of cases of acute pancreatitis. Furthermore, the
classification of cases of idiopathic acute pancreatitis should be no more than 20%.8 Therefore,
patients are subjected to extensive investigations to determine the underlying etiology.

The pretest probability of acute pancreatitis is determined by the clinician’s index of suspicion,
which is largely based on the patient’s history and clinician’s examination findings.4 The
classical teaching is that a serum amylase level that is three or four times greater than the upper
limit of normal is diagnostic of acute pancreatitis. While the measurement of serum pancreatic
enzymes such as amylase is the “gold standard” for the diagnosis of acute pancreatitis, the
measured value for the serum pancreatic enzymes should be interpreted by considering the
duration of patient’s symptoms.

In acute pancreatitis, the pancreatic enzymes amylase, lipase, elastase, and trypsin are
simultaneously released into the bloodstream. As the clearance of each of these enzymes varies,
the timing of the blood sampling from the onset of acute pancreatitis affects the test’s
sensitivity.4 Lipase has a higher diagnostic accuracy compared to amylase as the serum lipase
levels are elevated for a longer period.9 Caution should be exercised when interpreting amylase
results in patients with hypertriglyceridemia as they can have a falsely low amylase result.

During an attack of acute pancreatitis, the elevation of alanine aminotransferase to >150 IU/L is
a predictive factor for biliary cause of acute pancreatitis.10 A previous meta-analysis has
indicated that this threefold elevation in alanine aminotransferase has a positive predictive value
of 95% in diagnosing acute gallstone pancreatitis.11

The biochemical measurement of trypsinogen activation peptide (TAP) and trypsinogen-2 is

more useful as a diagnostic marker for acute pancreatitis due to their accuracy, but their
evaluation is limited by availability.9 Early elevated levels of urinary TAP have been shown to
ALDRIN KENNETH REYES

be associated with severe acute pancreatitis.4 Other markers such as IL-6 and IL-8,9 as well as
phospholipase A2 have been summarized well elsewhere,12 and are not routinely measured in
clinical practice in the UK.

Go to:
Management of acute pancreatitis
Classification of severity
Mastery of the management of acute pancreatitis is an art that can challenge experienced
clinicians at the best of times. One facet to the art of managing acute pancreatitis is classification
of the disease severity so that one can recognize, anticipate, and treat accordingly complications
of the disease. The revised 2012 Atlanta criteria for classification of the severity of acute
pancreatitis are widely accepted.13 This revised classification defines transient organ failure as
organ failure which resolves completely within 48 hours, whereas failure of resolution of organ
failure is defined as persistent. The presence of persistent organ failure, usually with one or more
local complications, indicates severe acute pancreatitis. On the other hand, the absence of organ
failure without any local or systemic complications indicates mild acute pancreatitis.
“Moderately severe acute pancreatitis”, indicated by transient organ failure and/or local or
systemic complications in the absence of persistent organ failure, is the new grade of severity
between mild and severe that was introduced in the revised classification.13 Multiple scoring
systems for the prediction of the disease severity and prognostic implications exist.12,14 The
prognostic features aid the clinician in predicting complications of acute pancreatitis.8

The Acute Physiology and Chronic Health Evaluation (APACHE) II scoring system has
demonstrated the highest accuracy for predicting severe acute pancreatitis when compared with
other scoring systems.15 Other markers of severe acute pancreatitis based on evidence from the
literature have been outlined in Box 1. The APACHE II score can be repeated daily and its trends
correlate well with clinical progress or deterioration. However, there is no significant difference
in the prognostic accuracy between the APACHE II and multiple factor scoring systems such as
Ranson, computed tomography severity index (CTSI),15,16 and the bedside index for severity in
acute pancreatitis.
The CRP is a reliable, easily accessible, single marker of assessing severity. It has demonstrated
good prognostic accuracy for severe acute pancreatitis, pancreatic necrosis, and in-hospital
mortality when measured at 48 hours following hospital admission.18,19 Another cheap and
easily obtainable parameter indicative of the severity of acute pancreatitis is the hematocrit. An
admission hematocrit ≥44% or failure of the hematocrit to decrease at 24 hours following
admission is indicative of severe acute pancreatitis in the early stage of the disease.20
Additionally, some studies have demonstrated that hemoconcentration has been associated with
the risk of developing necrotizing pancreatitis and organ failure,20,21 while others refute this
observation.22,23 The absence of hemoconcentration on admission has a high negative
predictive value for the development of necrosis.22,23 Other markers such as procalcitonin19,24
and IL-8, not used routinely in the UK, have been shown to have high predictive accuracy in
classifying the severity of necrotizing pancreatitis in the first days of the disease.
ALDRIN KENNETH REYES

The inflammatory response varies between each individual patient. The release of intrapancreatic
enzymes triggers the release of proinflammatory mediators and macrophage activation within
acinar cells resulting in local complications of acute pancreatitis, which include pancreatic
necrosis with or without infection, pancreatic pseudocyst formation, pancreatic duct disruption,
and peripancreatic vascular complications. It is unclear why in some patients the local pancreatic
inflammation triggers a systemic release of proinflammatory mediators. However, this systemic
inflammatory response manifests as organ failure, and its recognition and treatment are
important in altering the clinical course of acute pancreatitis.

Imaging
Imaging plays an important role in the diagnosis and management of acute pancreatitis. As 50%
of acute pancreatitis cases are gallstone-related, transabdominal ultrasound is the most common
initial radiologic investigation of choice. Ultrasonography has the highest sensitivity for
detection of gallbladder stones, but a poor sensitivity for choledocholithiasis (Table 1). The
retroperitoneally sited pancreas is usually difficult to visualize in acute pancreatitis during
ultrasonography, which can be further compounded by overlying bowel gas, large patient body
habitus, and abdominal pain. In the assessment of the presence or absence of gallstones, it is
recommended that at least two good quality ultrasound examinations are obtained. Where the
first exam is negative and cannot detect gallstones, the most sensitive test for diagnosis of
gallstones that may have been initially missed remains a further ultrasound examination.
Conclusion
Acute pancreatitis is frequently encountered on the emergency surgical take. Once the diagnosis
is made, clinical efforts should simultaneously concentrate on investigating for the underlying
etiology and managing the condition by anticipating its complications, which can be aided by
using any of the severity scoring systems described. Management of acute pancreatitis is largely
supportive. There is still no consensus on the ideal type and regimen of fluid for resuscitation,
but goal-directed fluid therapy is associated with better outcomes. Early enteral nutrition
modulates the inflammatory response and improves outcomes by decreasing infective
complications of acute pancreatitis. Antibiotics should be used judiciously as prophylactic
antibiotics have not shown any benefit in preventing infective complications of acute
pancreatitis. Patients with mild acute gallstone pancreatitis should be recommended to undergo a
laparoscopic cholecystectomy at the index admission, while those with severe gallstone
pancreatitis and evidence of cholangitis and/or choledocholithiasis benefit from early ERCP.
Patients with mild acute gallstone pancreatitis and concurrent choledocholithiasis benefit from
single-stage laparoscopic cholecystectomy and bile duct exploration, subject to available local
expertise. There is no difference in mortality and morbidity between the single-stage and double-
stage management of choledocholithiasis. However, the single-stage approach reduces the length
of hospital stay and need for recurrent admissions
ALDRIN KENNETH REYES

RECENT ADVANCES IN MANAGEMENT OF ACUTE LIVER FAILURE

Introduction
Acute liver failure (ALF) is a life-threatening illness, where a previously normal liver fails
within days to weeks. Sudden loss of synthetic and detoxification function of liver results in
jaundice, encephalopathy, coagulopathy, and multiorgan failure.[1,2] The incidence of ALF in
developed world is between one and six cases per million people per year.[3] Incidence may be
higher in developing world, but data are lacking.[2] The etiology of ALF varies
demographically. In India, Acute viral hepatitis is the most common cause of ALF.[4,5] The
mortality of ALF is as high as 40-50% and causes of death in ALF include brain herniation due
to raised intracranial pressure (35%) and sepsis with multiorgan failure.[2] Liver transplantation
ALDRIN KENNETH REYES

remains the only therapeutic intervention with proven survival benefit in patients with
irreversible ALF.[1]

Go to:
Definition
In 1970, Trey and Davidson defined “fulminant hepatic failure” as a severe liver injury
potentially reversible in nature and with the onset of hepatic encephalopathy within 8 weeks of
first symptoms in the absence of preexisting liver disease.[6] In 1993, O'Grady et al. based on
data from King's College subdivided ALF into hyperacute, acute, and subacute presentation
depending on the interval from onset of disease to onset of encephalopathy.[7] Hyperacute when
altered mental status occurs within 7 days of onset of jaundice, acute when altered mental state
occurs between 7 and 21 days of onset of jaundice and subacute when altered mental state occurs
between 21 days and 26 weeks of onset of jaundice.[7] The most widely accepted definition is by
American association of study of liver disease who in 2005 defined ALF as a clinical syndrome
characterized by evidence of coagulopathy (international normalised ratio [INR] >5) and any
degree of altered mental status in a patient without preexisting liver disease and duration of
illness <26 weeks.[8] Patients with Wilson's disease, vertically acquired hepatitis B, and
autoimmune hepatitis may be included in spite of possibility of underlying liver disease.[8]

Go to:
Etiology
Acute liver failure is the culmination of severe liver cell injury from a variety of causes including
viral hepatitis, toxins, metabolic disorders, and vascular insults.[9] The etiology varies with
geography. In India, viral hepatitis A and E are the most common cause for ALF.[4,5] In the
west, toxic etiologies predominate.[9] About 15-22% of ALF occur without any identifiable
cause.[10]

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Viral Hepatitis
Hepatotrophic viruses are the most common cause of ALF in developing countries.[9,10]
Hepatitis A and E viruses are transmitted via faeco-oral route and are common in India.[4,5]
ALF occurs in <1% of cases of acute hepatitis A. Hepatitis A related ALF has a better prognosis
(70% spontaneous survival) than ALF due to other causes.[11,12] Mortality usually occurs in
elderly and those with underlying chronic liver disease.[13] ALF due to hepatitis E has a worse
outcome in elderly, pregnant women, and patients with underlying chronic liver disease.[14]
Vertical transmission of hepatitis E from women with acute infection leads to ALF in 50% of
neonates.[14]
ALDRIN KENNETH REYES

Hepatitis B spreads vertically or horizontally by contact with blood or blood products of an

infected individual. ALF due to hepatitis B can occur not only from acute de novo infection but
also from flare of a chronic infection.[15,16] Flares of chronic hepatitis B can be spontaneous,
but more commonly due to treatment induced immunosuppression.[15,16] Flares of hepatitis B
have higher mortality, and early identification of patients at risk and initiation of antiviral
treatment reduces mortality. Acute hepatitis C rarely causes ALF. Other viral causes of ALF
include herpes simplex virus 1 and 2, varicella-zoster virus, cytomegalovirus, yellow fever, and
parvovirus B19.[12]

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Drugs and Toxins
Drugs are the most common cause of ALF in the west.[12,16] Drug-induced liver injury may be
dose-dependent and predictable as in Acetaminophen toxicity. ALF due to acetaminophen can
occur if a large dose (150 mg/kg) is consumed as in deliberate self-poisoning.[17] It can also
occur with substantial drug ingestion over hours to days as occurs in unintentional poisoning.[37]
Malnutrition and alcoholism are risk factors for acetaminophen-induced liver injury.[17] Other
form of drug-induced liver injury is idiosyncratic drug reaction. It is often unpredictable and
independent of dose.[18] Unlike other causes of ALF, drug-induced ALF is more common in
elderly. High mortality is seen with very high bilirubin, high aminotransferases, and advanced
age.[19] Herbal medications and dietary supplements have also been associated with ALF.

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Metabolic Causes
Wilson's disease accounts for 6-12% of cases of ALF. ALF due to Wilson disease occurs mainly
in young females. It should be suspected when patient has very high serum bilirubin and low
alkaline phosphatase at presentation.[20] Hemolysis, elevated liver enzymes, low platelet
syndrome, and acute fatty liver of pregnancy are two overlapping syndromes occurring in the
second half of pregnancy.[21] Early diagnosis and prompt delivery are critical in achieving good
outcomes.

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Vascular Causes
Acute Budd-Chiari syndrome can rarely present as ALF.[12] Early recognition and prompt
treatment can result in good recovery. Ischemic liver injury occurs in setting of cardiac arrest or
intractable hypotension. Here, the aminotransferases will be markedly elevated and responds
dramatically to stabilization of circulatory problem.[22]

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ALDRIN KENNETH REYES

Miscellaneous Causes
Acute liver failure occurs in <20% of autoimmune hepatitis. Presence of autoantibodies and a
compatible picture on biopsy helps to make a diagnosis.[23] Amanita Phalloides mushrooms,
heat stroke, and malignant infiltration of the liver are a rare causes of liver injury.[12]

Go to:
Clinical Manifestations
The diagnosis of ALF is based on the triad of Jaundice, altered metal status, and coagulopathy.
[1,2] The initial manifestation of ALF is nonspecific with anorexia, fatigue, abdominal pain, and
fever. With advancing liver injury signs of ALF emerge. Patient develops jaundice,
encephalopathy, coagulopathy, hemodynamic instability, acute renal failure, ascites, lung injury,
sepsis, and metabolic abnormalities.[25] Rarely, ALF may be confused with systemic illness that
manifest with jaundice and altered sensorium such as severe sepsis, systemic lupus
erythematosus, Thrombotic thrombocytopenic purpura and disseminated intravascular
coagulation.[26] At times, it may be difficult to differentiate severe sepsis from ALF and
measurement of factor VIII levels may help. Factor VIII levels are low in sepsis while it is
normal in patients with ALF.[26] In tropical countries like India, the differential diagnosis of
ALF should include severe infections with Plasmodium Malaria, Dengue fever, Leptospirosis,
Rickettsial infections, Enteric hepatitis, Hepatic tuberculosis, Amoebic liver abscess.[27] Early
recognition of these conditions is essential as specific therapies can cure most of these
conditions.

Go to:
Management
General consideration
Management consists of intensive care support, treatment of specific etiology if present and early
detection of candidates for liver transplantation.[1,2] Special attention should be given to coma
care, fluid management, hemodynamics, metabolic parameters, and infection control.
Coagulation parameters complete blood count, metabolic panel, and arterial blood gases should
be checked frequently.[3] Early restoration of intravascular volume and systemic perfusion can
prevent multiorgan failure.[1] In patients who continue to be hypotensive in spite of adequate
volume replacement, vasopressors should be used.[25] Patients with grade III or IV coma should
be intubated and sedated to facilitate general care and prevent aspiration pneumonia.[25] ALF is
a state of functional immunosuppression carries a high risk for sepsis. High standards of
infection control should be practiced. Frequent sputum, blood and urine culture should be done
to detect infection early. Broad spectrum antibiotics may be administered preemptively in
patients with coagulopathy, grade III or IV encephalopathy or multiorgan failure.[1,10] Overt
bleeding is uncommon in ALF. The administration of coagulation factors should be avoided
except to treat bleeding or before invasive procedures.[1]
ALDRIN KENNETH REYES

Etiology specific therapy

Depending on the etiology, specific therapies may be effective. Such treatment should be started
early in the course of the disease, and careful assessment of disease progression is necessary to
prevent delay or failure to successful liver transplantation.[1,2] N-acetyl cysteine, when
administered early, can reduce liver damage and hasten recovery in patients with acetaminophen-
induced ALF.[28] A multicenter, double-blind, randomized controlled trial has shown N-acetyl
cysteine to be effective in nonacetaminophen ALF.[29] Corticosteroids may be tried in ALF due
to autoimmune hepatitis.[30] However, patients not responding within 2 weeks should be listed
for transplantation. Antiviral therapy has shown to improve outcome in hepatitis B[31] and
herpes simplex related ALF but no randomized controlled trials are available. In patients with
Amanita phalloides ingestion, early administration of activated charcoal is recommended as it
may improve survival by binding to amatoxin.[24] Other therapies include administration of
silibinin and penicillin G.[24] ALF due to Wilson disease typically requires liver transplantation;
however, plasma exchange with fresh frozen plasma replacement may improve survival.[20]
Pregnancy-related ALF must be treated with prompt delivery of the fetus.[21]

Cerebral edema and encephalopathy

Cerebral edema is present in 25-35% of patients with grade III encephalopathy and in
approximately 75% of those with grade IV encephalopathy.[32] Cerebral edema in ALF is
caused by a combination of cytotoxic and vasogenic edema.[33,34] Excess ammonia and
glutamine alter cerebral osmolality, increase free radical production, alter glucose metabolism,
and cause calcium-mediated mitochondrial injury leading to astrocyte swelling.[33,34]
Alteration in cerebral blood flow and activation of inflammatory cytokines can aggravate
cerebral edema.[34] All patients with encephalopathy should be managed with the head end of
the bed elevated to 30°, maintenance of neck neutral position, endotracheal intubation,
minimizing painful stimuli and control of arterial hypertension.[33,34] Factors such as
hypercapnia, hyponatremia, frequent movements, neck vein compression, fluid overload, fever,
hypoxia, coughing, sneezing, seizures, and frequent endotracheal suctioning should be avoided.
[33,34] Propofol may be used for sedation and fentanyl for pain.[33] Measures to lower arterial
ammonia-like lactulose, gut decontamination and ornithine aspartate has not shown any benefit
in ALF and lactulose may aggravate the abdominal distension and bloating.[1] Seizures should
be treated with phenytoin or short-acting benzodiazepines.[1,33] There is no role for the
prophylactic phenytoin.

The aim of therapy in ALF is to maintain intracerebral pressure (ICP) <20 mm of Hg and
cerebral perfusion pressure (CPP) >60 mm of Hg.[35] ICP monitoring may be indicated in a
subset of patients.[35] However, a retrospective study on the impact of ICP monitoring did not
show any difference in the outcome in two groups. The study concluded that it might be
hazardous in the presence of severe coagulopathy.[36] In patients with ICP >20 mm of Hg
intravenous mannitol or hypertonic saline should be used to lower ICP and maintain CPP.
Therapeutic hypothermia may be used as a bridge to transplant in patients with raised ICP who
do not respond to intravenous mannitol or hypertonic saline.[39] A recent systematic review on
the use of therapeutic hypothermia in ALF patients concluded that there was limited data on
ALDRIN KENNETH REYES

safety and efficacy of moderate hypothermia for treatment of intracranial hypertension in ALF.
[37] Hyperventilation to achieve a PaCO2 between 30 and 35 mm of Hg will reduce ICP acutely
but should not be used for prolonged periods.[5] Intravenous indomethacin and barbiturates
should be used only as the last resort when all other treatments fail to reduce ICP.

Circulatory failure
High blood levels of nitric oxide and  cGMP in ALF lead to a state of high cardiac output, low
mean arterial pressure and low systemic vascular resistance.[38] This situation is further
aggravated by volume depletion due to poor oral intake, extravasation of fluid into the third
space, and rarely gastrointestinal bleed. The initial management of hemodynamic instability is
fluid resuscitation.[39] In Patients who does not respond to fluid resuscitation, norepinephrine
should be used to achieve a mean arterial pressure of 75 mm of Hg.[39] Vasopressin or its analog
terlipressin may be used as adjuvant to potentiate the effects of norepinephrine.[39] Adrenal
insufficiency should be suspected and corrected in patients who do not respond to fluid
resuscitation and vasopressors.

Renal dysfunction
About 50-80% of ALF have renal failure.[40] The etiology of renal failure in ALF is
multifactorial. Drug-induced nephrotoxicity; acute tubular necrosis; and abdominal compartment
syndrome are the main causes.[40] Every effort should be made to prevent renal failure by
improving hemodynamics, avoiding nephrotoxic drugs, and early treatment of infections. In
patients who require dialysis a continuous mode of renal replacement therapy should be used.
[41]

Infections
Acute liver failure is an immunocompromised state due to dysfunction of monocytes,
neutrophils, kupffer cells, and complement system.[42] Most common infections are bacterial
pneumonia, urinary tract infection, intravenous catheter-induced sepsis, and spontaneous
bacterial peritonitis.[42] Fungal infections occur in 30% of patients with ALF. The most
common organism is Candida Albicans. Infections are associated with hemodynamic instability,
progression of hepatic encephalopathy and renal failure. But prophylactic antibiotics or
antifungals have not been shown to improve outcomes in ALF.[42] However, empirical
antibiotics may be used in all patients with grade III or IV encephalopathy or systemic
inflammatory response syndrome. Similarly, selective gut decontamination with nonabsorbable
antibiotics has not been shown to improve survival in ALF.[42]

Coagulopathy
Decreased synthesis as well as increased consumption of fibrinolytic proteins, anticoagulant
proteins and procoagulant factors occurs in ALF. However, overt bleeding is rare in ALF.[43]
ALDRIN KENNETH REYES

Stress ulcer prophylaxis with an H2 blocker or proton pump inhibitor is to be given to all patients
with ALF. Fresh frozen plasma is indicated only for control of active bleeding or to maintain
INR <1.5 when an invasive procedure is planned.[43] Recombinant factor VIIa should be
considered when fresh frozen plasma fails to correct INR adequately. Cryoprecipitate is
recommended in patients who have hypofibrinogenemia (<1 g/L).[43] Thrombocytopenia should
be corrected if platelet count is <10,000 cells/mm3, in the presence of active bleeding or when an
invasive procedure is planned.[43]

Metabolic factors
Patients with ALF are prone to develop recurrent hypoglycemia because of glycogen depletion
and defective glycogenolysis and gluconeogenesis.[44] Hyperlactatemia can occur because of
poor systemic microcirculation as well as due to failure of liver to clear lactate. Hyperlactatemia
can aggravate hemodynamic instability and should be treated aggressively.[44] Serum levels of
phosphorus, potassium, and magnesium are usually low and should be supplemented. Early
enteral feeding should be initiated in all patients and in patients whom enteral feeding is
contraindicated parenteral nutrition should be considered.[44]

Prognostic evaluation
Early identification of patients who require liver transplantation is of great practical importance.
The two key factors determining outcome in ALF are etiology and mental status at admission.
[45] In general acetaminophen, Hepatitis A, ischemic hepatitis, and pregnancy have 60% short-
term survival whereas drug-induced liver injury; autoimmune hepatitis and indeterminate cases
have only 30% spontaneous survival.[45] Patients with early grades of encephalopathy at
presentation have a better prognosis than those presenting with an advanced coma.[45] Various
prognostic evaluation systems have been used to identify candidates for transplantation. The
most well-characterized evaluation system till date is King's College criteria [Table 1]. The
King's College criterion is used to assess the severity of ALF with a sensitivity of 68–69% and a
specificity of 82–92%.[45,46] The other prognostic criteria evaluated include the clichy criteria,
acute physiology, and chronic health evaluation-II score, model for end-stage liver disease,
sequential organ failure assessment, the ALF study group index, serum lactate, serum
phosphorus, factor V and VII/V ratio and alpha-fetoprotein levels [Table 2]. But none of these
scoring systems have the sensitivity and specificity to be used in clinical practice.[46] The
survival after ALF is multifactorial and depends on etiology, grade of coma on admission, ability
to regenerate a healthy liver, and the absence of complications.
Summary
Acute liver failure in spite of all advances remains a condition with high mortality. Early
identification of ALF and prompt intensive care management is critical improve outcome. Liver
transplant remains the only intervention with survival benefit. Liver assist devices and
hepatocyte transplant remain experimental and further advances are required. Public health
measures to control hepatitis A, B, E, and drug-induced liver injury will reduce the incidence and
mortality of ALF.
ALDRIN KENNETH REYES

IMPLICATION
Nursing Practice
This journal article will help the nurses have a deep understanding about the common cases in
ICU in terms of the risk factors, causes, and management. So that they will be able to carry out
appropriate nursing interventions in nursing practice.
Nursing Education
This journal article would help in sharing data or information about the different and common
cases in ICU. With these, the students as well as the instructors would gain additional
information about the above topics in order to be efficiently equipped in rendering nursing care
in the future.
ALDRIN KENNETH REYES

Nursing Research
This would be a great help for students who are willing to conduct journal reading activities
about the common cases in ICU, it will help them gain more information and have better
understanding about the topics.

References:
https://www.ncbi.nlm.nih.gov/pmc/articles/