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Sepsis in Older Patients: An Emerging
Concern in Critical Care
Luis A Destarac and E Wesley Ely
Department of Internal Medicine, Division of General Internal Medicine, and Center for Health Services
Research, and the Geriatric Research and Education Clinical Center of the Veterans Administration
Tennessee Valley Healthcare System, and the Division of Allergy/Pulmonary/Critical Care Medicine,
Vanderbilt University School of Medicine, Nashville, TN, USA
Severe sepsis is a very common and important cause
of morbidity and mortality in the older population,
and its incidence has increased in the last 10 years [1].
It is estimated that about 750 000 patients per year
develop severe sepsis in the US, of which nearly 60%
are >65 years-of-age [2,3]. This is also reflected in the
changing demographics of intensive care units (ICUs),
where nearly two-thirds of beds are occupied by those
>65 years old [3]. Aging patients account for 4050%
of all cases of bacteremia, and the overall case fatality
rate for older patients with bacteremia ranges from
4060%, or higher when Gram-negative organisms
are involved [4,5,6]. This segment of the population
will increase significantly over the coming years, driving
an increase in the amount of resources used on
these patients, who are thought to have a shortened
life span [7].
This review analyzes the characteristics of older
patients, discusses the unique aspects of severe sepsis
in this increasingly important segment of our society,
and provides a better understanding of the special
needs of these patients. We also outline areas of
future research that might improve outcomes in this
patient population.
Methods
We performed a Medline search of the literature from
1996 to September 2001, using the keywords sepsis,
aged, and elderly and limiting the search to human
studies and English language publications. The search
identified 3159 articles, which were reviewed initially by
title, followed by abstract to determine their relevance
for inclusion. A total of 57 articles were reviewed in
depth to determine the methodological rigor and
content, of which 42 articles were retained for inclusion
in this report.
Severe sepsis is a common problem associated with substantial mortality and a significant consumption
of healthcare resources. The number of cases per year, currently estimated at 750 000 in the US alone,
is expected to increase at a rate of 1.5% per year, and an increasingly significant proportion of these
patients will be elderly. Older persons are more prone to infections due to the effects of aging,
comorbidities, use of invasive devices, and problems associated with institutionalization. The diagnosis
of sepsis in this population can be difficult, as older patients may have atypical responses to sepsis and
may present with delirium or falls, thus delaying therapeutic interventions that may influence their
outcome. There is a tendency to treat older persons less aggressively; however, it is important to
consider criteria other than just chronological age, such as recent performance level, quality of life,
comorbidities, and patient preference, when determining the aggressiveness of care. Future studies
should focus on both short- and long-term outcomes of older patients, such as their ability to
achieve previous physiological status and social independence, in addition to their risk of mortality
after an event of severe sepsis.
ADVANCES IN SEPSIS Vol 2 No 1 2002 15
Address for correspondence: LA Destarac, Division of Allergy/
Pulmonary/Critical Care Medicine, Center for Health Services
Research, 6th Floor Medical Center East 6109, Vanderbilt University
Medical Center, Nashville, TN 37232-8300, USA. E-mail:
luis.destarac@mcmail.vanderbilt.edu
LUIS A DESTARAC AND E WESLEY ELY
ADVANCES IN SEPSIS Vol 2 No 1 2002 16
Clinical Case
A 90-year-old retired physician presented to the
emergency department with a 1-day history of
shortness of breath and cough. He denied chills or fever,
but had marked mental status changes that had begun
approximately 36 h earlier. On examination his vital
signs showed:
blood pressure of 98/65 mmHg
heart rate of 70 beats/min (paced)
respiratory rate of 32 breaths/min
temperature of 36.7C.
The patient had rhonchi at the right lung base,
anteriorly and posteriorly, with no dullness to
percussion. His white blood cell count (WBCC) was
11 800 cells/mL, and his renal function showed a blood
urea nitrogen (BUN) level of 28 mg/dL and creatinine
level of 1.6 mg/dL. His admission chest X-ray is shown
in Figure 1. The patient was begun on intravenous
antibiotics, including ceftriaxone and levofloxacin,
supplemental oxygen, and aggressive fluid resuscitation.
Despite these interventions, his condition deteriorated
requiring increased oxygen support, his WBCC rose to
23 000 cells/mL, and his BUN and creatinine levels
increased to 42 mg/dL and 2.6 mg/dL, respectively. His
chest X-ray at 72 h is shown in Figure 2. All the
patients cultures remained negative, and he completed
a 14-day course of intravenous antibiotics. The patient
eventually recovered and was discharged home
following a lengthy stay of 31 days.
As illustrated in this example, older persons often do
not present with the classical signs and symptoms of
systemic inflammatory response. Despite sepsis-induced
organ dysfunction, this patient initially had only one of
the classically defined systemic inflammatory response
syndrome criteria tachypnea. He had no fever, and
had not mounted a tachycardic response, probably
because of his pre-existing cardiac conduction disease.
He also demonstrated a delayed rise in his WBCC.
Clinicians might be misled by such a presentation,
causing a delay in disease recognition and perhaps
jeopardizing the timely administration of appropriate
therapies and, therefore, the patients ultimate
outcome. In addition, clinicians may be less inclined to
treat older persons aggressively based solely on their
age a decision that may be inappropriate for a
substantial number of older patients with a minimal
burden of comorbidity and a good premorbid state of
health and quality of life.
Figure 1. A chest X-ray on admission shows patchy
air-space disease due to community-acquired
pneumonia, predominantly in the left upper and
right lower lobes, as well as a permanent pacemaker.
Figure 2. A chest X-ray, 3 days after admission, shows,
worsening of air space disease in the upper right lobe.
This visual manifestation of disease progression,
despite appropriate antibiotics and supportive care,
demonstrates the relentless inflammatory and
coagulopathic derangements of severe sepsis.
SEPSIS IN OLDER PATIENTS: AN EMERGING CONCERN IN CRITICAL CARE
ADVANCES IN SEPSIS Vol 2 No 1 2002 17
Epidemiology of severe sepsis
Due to the varying clinical manifestations of severe
sepsis, and the vagaries of physicians chart
documentation and death certificate practices, accurate
estimates of the incidence of severe sepsis have been
difficult to establish. This is particularly evident in the
variability that exists between different studies, with
incidence estimates from past studies ranging from
73.6 per 100 000 populations, to 175.9 per 100 000
populations [1,8].
The recent observational cohort study conducted by
Angus et al. [2] reported on the incidence of severe
sepsis in seven US state hospitals, using criteria based on
the International Classification of Diseases, 9th Revision,
Clinical Modification codes, rather than the 1992
American College of Chest Physicians/Society of Critical
Care Medicine (ACCP/SCCM) guideline definitions [9];
i.e. sepsis associated with acute organ dysfunction. The
estimated incidence of severe sepsis in this study was
three cases per 1000 population. Astoundingly, the age-
specific incidence of severe sepsis increased 100-fold to
26.2 cases per 1000 population in older patients.
Mortality also steadily increased as patients aged, with a
peak of 38.4% in patients >85 years [2,3] (Fig. 3).
Many ICU patients with either preexisting infections
at ICU admission, or who develop nosocomial infections
in ICU, go on to develop sepsis. A recent international
prospective cohort study demonstrated a 21.1% crude
incidence rate of infections in ICU patients [10]. About
28% of infections were associated with sepsis, 24%
with severe sepsis, 30% with septic shock, and 18%
were not classified.
In a second prospective cohort study, Rangel-Frausto
et al. defined the epidemiology of patients with two,
three, or four systemic inflammatory response
syndrome (SIRS) criteria, sepsis, severe sepsis, and
septic shock [11]. Of the 3708 patients admitted to the
survey units, 2527 (68%) met the criteria for SIRS.
Among patients with SIRS, 649 (26%) developed
sepsis, 467 (18%) developed severe sepsis, and 110
(4%) developed septic shock. There was a stepwise
increase in mortality rates in the hierarchy from SIRS,
sepsis, severe sepsis, and septic shock: 7%, 16%, 20%,
and 46%, respectively. Of interest was that the
investigators observed equal numbers of patients who
appeared to have sepsis, severe sepsis, or septic shock,
but had negative cultures. This indicated that the
outcome of sepsis was related to the severity, reflected
Figure 3. National age-specific mortality rates for all cases of severe sepsis and for those with and without
underlying comorbidity in the USA. Comorbidity is defined as a CharlsonDeyo score >0 [23]. National estimates are
generated from the seven-state cohort using state and national age- and gender-specific population estimates from
the National Center for Health Statistics and the US census. Error bars represent 95% confidence intervals.
Reproduced with permission [2].
Age (years)
No co-morbidity
<
1
0
M
o
r
t
a
l
i
t
y

(
%
)
1

4
5

1
0

1
4
1
5

1
9
2
0

2
4
2
5

2
9
3
0

3
5

3
9

4
4
4
5

4
9
5
0

5
4
5
5

5
9
6
0

6
4
6
5

6
9
7
0

7
4
7
5

7
9
8
0

8
4
>_
8
5
5
10
15
20
25
30
35
40
45
Overall
Co-morbidity
LUIS A DESTARAC AND E WESLEY ELY
ADVANCES IN SEPSIS Vol 2 No 1 2002 18
by the degree of organ dysfunction, and not the
presence of bacteremia.
Sepsis, along with the frequent comorbid conditions of
acute lung injury necessitating mechanical ventilation, is
a major public health concern in older patients. Severe
sepsis consumes considerable healthcare resources, with
an estimated annual cost of $16.7 billion in the US in the
year 2000 [2,3]. The appropriateness of spending these
resources on older patients with this life-threatening
illness is a point of continued debate.
Pathophysiology
Infection is the most common causes of sepsis, however, in
many sepsis patients the infectious etiology is not
identified. The same biochemical and physiological
changes as those seen with infectious agents may also
present in other non-infectious conditions, such as
pancreatitis, trauma, or extensive burns. It was once
thought that the response to the initial insult or triggers
precipitated a cascade of events where interleukin-1 (IL-1),
IL-6, and tumor necrosis factor (TNF) played a central role
[6,11,12]. With our current greater understanding of the
inflammatory cascade, we now know that that sepsis is
caused by an imbalance in the normal inflammation and
coagulation responses of the patient.
On the one hand, cytokines IL-1, IL-6, and TNF-a alter
the secretion of hormones, which in turn direct an increase
in the resting energy expenditure: amino acids are
exported from the muscles to the liver, gluconeogenesis
increases, and a catabolic state is created. On the other
hand, these cytokines cause increased neutrophil
activation, and directly damage organs by activating the
coagulation cascade and inhibiting fibrinolysis [13]. This
leads to diffuse endovascular injury, and can lead to
multiorgan dysfunction and death [6].
Risk factors for the older patient
Aging is a process associated with numerous risk factors
that contribute to the increasing incidence of, and
mortality from, severe sepsis.
Performance status
A number of aging processes lead to poorer performance
status, an independent predictor of mortality [1315]:
disuse atrophy from an inactive life-style
sarcopenia from accelerated muscle loss
changes in responsiveness to trophic hormones
(growth hormones, androgens, and estrogens)
neurological alterations
altered cytokine regulation
changes in protein metabolism
changes to dietary intake.
Immune function
Older patients are often nutritionally or immunologically
impaired [16], making them an easy target for infection
and its associated complications. They are frequently
affected by comorbidities that require treatment with
foreign devices (e.g. indwelling urinary catheters,
gastrostomies, cystostomies, tracheostomies, peripherally
inserted catheters) that make patients vulnerable to
infections or complications. The natural barriers of innate
immunity are broken, providing increased access for
pathogens [13,17,18]. There is also evidence of
abnormal T and B cell function in older patients [16],
although the response to infection appears to elicit a
normal expression of proinflammatory cytokines [19].
Nutrition
One of the physiological changes of aging includes a
substantial decrease in olfactory discrimination by age
70; sweet, sour, bitter, and salty tastes are impaired [13],
which contributes to a decreased enjoyment of meals,
aggravating the anorexia of aging. An older patients
nutritional status can also be affected by [13]:
inactivity
inadequate funds or resources
mobility and transportation issues
social isolation
functional limitations
poor or restricted diets
chronic disease
dementia
depression
poor dentition
polypharmacy
alcohol or substance abuse.
Drugs
The medical community is in need of an improved
understanding of how drug absorption, hepatic
metabolism, and drug responses vary with old age. It is
evident that drug clearance from the body, particularly
through renal mechanisms, is altered in aging persons
[18]. Age-related decline in renal function predominately
underlies the decreased drug clearance. Because the
kidneys are largely responsible for the excretion of
several antibiotics, dose adjustments and monitoring of
serum drug levels may be necessary for certain drugs in
older patients. Testing only blood creatinine levels could
SEPSIS IN OLDER PATIENTS: AN EMERGING CONCERN IN CRITICAL CARE
ADVANCES IN SEPSIS Vol 2 No 1 2002 19
underestimate or overestimate the renal function of these
patients, and therefore creatinine clearance would be a
better assessment of their kidneys functional capacity.
Certain antibiotics are associated with increased side
effects in older patients (Table 1) [18]. Drug interactions
are also increased in the elderly; however, this is as a
consequence of the greater number of medications
taken, rather than age.
Social changes
Institutionalization (e.g. nursing homes) is common
amongst older people, who have to go through a period
of adjustment to their new environments. Adequate
social support should help them through the process
easily, and minimize the associated problems, such as
depression, crowding, and neglect, all of which have
impact on nutrition and immunity.
Clinical manifestations of sepsis in the older patient
The septic process is characterized by a series of signs
and symptoms that include:
fever or hypothermia
leukocytosis or leukopenia
tachycardia
tachypnea.
This SIRS, if not recognized early and treated
aggressively, can progress to a cascade of events that leads
to the development of diffuse endovascular injury,
microvascular thrombosis, organ ischemia, and death
[3,5,6,11,12,20].
Older patients pose particular challenges in the
diagnosis and early management of sepsis. Firstly,
obtaining diagnostic specimens that require patient
cooperation in the frail, debilitated, cognitively impaired,
or severely ill elderly patient can be challenging.
More importantly, the classical manifestations of the
SIRS may be minimally present, as illustrated in the
clinical case above. Healthcare professionals who are not
astute in recognizing these variations may delay
important interventions that will affect the final outcome
of these patients.
Clinical manifestations of infections in older patients
may be unusual, nonspecific, or absent, and can include
weakness, malaise, delirium, confusion, loss of appetite,
falls, or urinary incontinence [18]. Fever, a hallmark of
infection, can also be blunted or absent in infected older
patients. Although body temperature elevations in elderly
persons are an indicator for the presence of serious
infections, decreased body temperature (hypothermia)
is a more ominous sign.
The common sites of infection in the elderly are similar
to patients of other age groups, involving the respiratory,
urinary, and gastrointestinal systems, and the skin and
soft tissues [12]. The organisms found most frequently
are Gram-negative bacilli, but there has been a rapid
increase in the incidence of Gram-positive cocci infection
[1]. This increase in prevalence is probably due to the
institutionalization of aged patients, and an increased
early use of broad spectrum antibiotics, which selects for
more virulent and resistant strains.
Therapeutic options
The septic process can be altered or modified if it is
recognized early, and adequate supportive care is promptly
initiated. The most important intervention is to make a
rapid diagnosis a difficult task to achieve given the
atypical presentation of sepsis in the older patient. Once
the diagnosis has been made, appropriate antibiotics must
be administered in an attempt to halt the triggers for the
continued inflammatory cascade. Survival can be
compromised significantly if there is a delay in the use of
the antibiotics, as demonstrated in several studies [21,22].
Recent advances in the understanding of the septic
process have helped to develop new therapeutic options,
and research is promising other therapeutic options in the
coming years. Several potential targets for intervention in
the inflammatory cascade have been identified, including:
TNF [23,24]
endotoxin [25]
IL-1 [2628] and IL-6 [29]
phospholipase A
2
(a current ongoing trial)
antithrombin III (AT III) [30]
platelet-activating factor (PAF) [31]
tissue factor pathway inhibitor (unpublished data)
Activated Protein C [6].
Table 1. Antibiotics associated with increased side
effects in older patients.
Antibiotic Side effect
Aminoglycosides Renal dysfunction
Auditory nerve dysfunction
b-lactams Seizures
Skin rash
Macrolides Nausea
Abdominal cramps
Quinolones Seizures
Hallucinations
Vancomycin Renal dysfunction
LUIS A DESTARAC AND E WESLEY ELY
ADVANCES IN SEPSIS Vol 2 No 1 2002 20
The clinical trials of monoclonal anti-endotoxin antibody
and AT III replacement therapy were unable to show a
significant short-term survival improvement [2022,29].
From these and other agents currently being studied, we
hope to find interventions that will reduce the mortality of
both acute respiratory distress syndrome (ARDS) and
sepsis. For example, while clinical trials with PAF receptor
antagonists failed to show short-term survival advantage,
in a recent study designed to prevent the development of
ARDS using recombinant PAF-acetylhydrolase within 12 h
of the onset of sepsis or trauma, there was a significantly
reduced mortality in the subgroup analyses of patients
with severe sepsis [32]. These results are being validated in
a large, Phase III, multicenter trial.
Steroids, ibuprofen, and other drugs have also been
used in an attempt to halt the inflammatory response, with
an overall paucity of clinically-meaningful positive results
[33,34]. Abnormalities in adrenal cortisol production
predict a very high mortality rate in sepsis [35], and a
recent study documents that low-dose steroids might be of
benefit in some cases of refractory sepsis [36].
In March 2001, Bernard et al. [6] reported on the
Recombinant Human Activated Protein C Worldwide
Evaluation in Severe Sepsis (PROWESS) trial of drotrecogin
alfa (activated) the official generic nomenclature for
human recombinant Activated Protein C in severe sepsis.
They identified a 6% absolute risk reduction (19.4%
relative risk reduction) in the 28-day mortality of the study
group compared with the placebo group. On subgroup
analysis, drotrecogin alfa (activated) appeared at least as
effective for patients >65 years old as it was for younger
patients, with no detectable increased risk of bleeding [37].
Adequate supportive care with close monitoring,
adequate nutrition, ulcer and deep venous thrombosis
prophylaxis, and ventilatory support should be
considered essential components of the plan of care in
any aged patient with sepsis. Some authors have
suggested the use of antiseptic bonded central-line
catheters to reduce the number of catheter-related sepsis
cases, with some positive results [17].
Recent studies have documented that older patients are
treated less aggressively than their younger counterparts
[38,39], particularly those >85 years old [40], and that
race further affects the level of care provided [41]. This
may be due to the belief that the aged patients have a
significantly shorter life span, are too weak to cope with
the great physiological demands involved with surviving
the septic process, and survivors are likely to become
dependent, requiring social and economical support; by
stepping up the care, pain and suffering will be
unnecessarily increased. However, treatment decisions
based solely on age without considering other prognostic
factors (discussed below), could lead to a substantial
number of older patients who could benefit from more
aggressive treatment being under-treated.
Because new antisepsis therapies are likely to be
expensive, a better understanding of both their clinical-
effectiveness and cost-effectiveness in all patient groups
is essential. Sepsis is a disease of the elderly, therefore it is
important to consider appropriateness of care, including
the determination of patient preferences. Unfortunately,
clinical trials of antisepsis agents tend to exclude the very
elderly, as they are believed to be less likely to respond to
treatment. However, these patients form a large
proportion of the sepsis population, and their exclusion
compromises the validity of these trials and limits our
understanding of treatment options for this group.
Prognosis of severe sepsis in the older patient
Severe sepsis is a common entity with bad prognosis
across all age groups. Factors that have been used to
predict outcomes in critically ill patients include [14,15]:
pre-infectious immune or genetic status
gender
age
nosocomial events
comorbidities
severity of illness.
Although population studies have shown that older
people do have a higher mortality associated with severe
sepsis, it is important that the clinician separate the
general prognosis of a population of older patients from
that of the individual. Chronological age alone should
not be used either to predict the outcome or determine
treatment options for individual patients. Although age is
an important factor used to predict length of stay in the
ICU, the increased mortality observed in older patients
with severe sepsis is thought to be due to the increased
comorbidities among this group [38], the most important
of which are [2]:
metastatic neoplasm (43.4%)
chronic liver disease (37.1%)
non-metastatic neoplasm (36.9%)
chronic renal disease (36.7%)
chronic obstructive pulmonary disease (32.1%).
Despite the fact that older patients tend to be less
aggressively treated, aggressive care is not futile, and the
majority of older patients survive until discharge.
SEPSIS IN OLDER PATIENTS: AN EMERGING CONCERN IN CRITICAL CARE
ADVANCES IN SEPSIS Vol 2 No 1 2002 21
Unfortunately information regarding subsequent
survival and quality of life after an episode of severe
sepsis is limited, especially in the elderly. We know, for
example, that after an episode of respiratory failure, a
patient has a significantly high risk of poor quality-
adjusted survival [42]. Such data are crucial to determine
optimal healthcare policies as the population ages and
the number of cases of sepsis increases. We are unaware
of any recent studies addressing this question, but they
may be already underway.
Summary and conclusion
Sepsis is a frequently encountered problem, with
substantial mortality and a significant consumption of
healthcare resources, that predominantly affects older
persons. It is estimated that the number of cases of severe
sepsis will grow at a rate of 1.5% per year, as projected
from the US 2000 census, so that by 2020 the number of
cases will approximate 1 million per year [2], an
increasingly significant proportion of which will be aged
patients. This is expected to be a worldwide phenomenon.
Older patients are more likely to have comorbidities,
problems associated with institutionalization, or have
invasive devices, making them prone to infections. Older
patients also pose a diagnostic dilemma; they show many
atypical features of sepsis that make its early diagnosis
and management difficult. Antibiotic therapy, adequate
supportive care, and the use of newer interventions
should play a part in the survival of these patients.
Although survival is the most important outcome, the
quality of survival is also important. Given that the
aggressiveness of therapy appears to be lower in older
persons, despite representing a larger proportion of
sufferers than any other age group, further studies will
be important to justify or change current treatment
regimes. Of particular importance are those studies
looking at the short- and long-term ability of these
patients to achieve previous physiological status, social
independence, and quality of life, and their risk of
mortality after an event of severe sepsis.
With the increase in the elderly population in coming
years, understanding the extent of the problem, socially
and economically, should help us to target therapeutic
interventions in a more efficient and effective way.
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