Download Mortality Outcomes for Treating a Fever

Running head: MORTALITY OUTCOMES FOR TREATING A FEVER
Mortality Outcomes for Treating a Fever
Ashley Peczkowski
Wright State University
NUR 7203
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MORTALITY OUTCOMES FOR TREATING A FEVER
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Mortality Outcomes for Treating a Fever
Introduction
Patients admitted to the Intensive Care Units (ICU) commonly develop a febrile event during
their stay, often related to an infectious process. For many years it has become common practice to
treat these fevers with some type of antipyretic. Recently, the treatment of fevers in non-traumatic
brain injury patients has come into question related to an increase in mortality rates (Launey,
Nesseler, Malledant, & Seguin, 2011). Brain injury patients have been excluded because it has been
well researched and documented that a febrile event in a brain injury patient can often be detrimental
(Mrozek, Vardon, & Geeraerts, 2012).
Researchers have discerned a possible increase in mortality rates in septic patients who have
been treated with antipyretics, especially in the elderly. Critically ill patients are likely to develop a
fever due to an infectious or non-infectious process and there are currently no guidelines for
treatment (Ho Lee et al., 2012). By definition a fever is an up regulation of the preset hypothalamic
temperature outside of the female hormonal-induced variation and diurnal variation. While the exact
point of which the fever begins is not universally standard, many studies have developed a threshold
of ≥38.2ºC (Launey et al., 2011). In the elderly the development of a fever of unknown origin
commonly includes an infectious process or malignancy (Cunha, Hage, & Nouri, 2011).
A fever is the body’s natural defense against infection and produces many favorable effects.
An infectious or non-infectious response can trigger an up regulation of the pre-optic area of the
hypothalamus thus causing the febrile response. Activation of this area can be caused by: exogenous
pyrogens to stimulate leukocytes which produce cytokines causing secretion of prostaglandin E2 in
the organum vasculosum of the lamina propria below the hypothalamus; also IL-1β causes a
ceramide production which replaces the prostaglandin E2 causing and earlier rise in core
temperature; lastly a pathway not cytokine produced but neuronal in nature with Kupper cells
producing prostaglandin E2 after they are stimulated by lipoply saccharides and then mediated by the
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vagus nerve and nucleus tractus solitaries (Launey et al., 2011). The variety of methods to induce a
febrile response indicates how important this response is to maintaining normal body function.
Allowing the body to mount a fever below a fatal temperature (some studies suggest below 40-41ºC)
enhances the immunes’ response, reduces and slows bacterial growth, increases synthesis of
antibodies and cytokines while activating T-cells, neutrophils, and macrophages (Ho Lee et al., 2012;
Launey et al., 2011). Some studies have indicated that there is an increase in both mortality and
morbidity in infectious septic patients in the ICU when fevers were suppressed with antipyretics.
Possible causes for this are reducing the fever inhibits the beneficial effects of inhibiting bacterial
and viral activity (Carey, 2010). Other theories are that antipyretics (NSAIDS and acetaminophen)
are associated with hypotension and renal dysfunction which is often already present in a critically ill
patient thus causing further damage. Fevers are protective and the inability to produce a fever is
linked to a significantly higher mortality rate by as much as 66% in a study by Ho Lee et al. (2012).
Fever, however, also imparts extensive demand on a body. This is in addition to a body that
is already stressed from an infection, surgical event, or other medical event. Some studies have
indicated that treating the fever is more important due to a higher benefit than risk ratio. A febrile
event causes an increased metabolic demand in a compromised oxygen delivery system; reduces
myocardial function and intensifies vasodilatory shock; and finally a fever may cause additional
difficulty with oxygen exchange in lung injury patients. Treatment of fevers to prevent this
circulatory collapse has become a common practice within the ICU (Mohr & Doerschug, 2013).
Discussion of the Issue
The use of antipyretics to treat a febrile event in a critically ill septic patient has become
common practice until recently. Current studies performed on non-acute neurological injury septic
patients were showing an increase in morbidity and mortality rates when antipyretic were given.
Since this discovery, research studies specific to the effect of antipyretics in the septic patient have
been conducted. The concern is that because fevers are a beneficial defense mechanism, prevention
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of such inhibits the body’s ability to fight the infection are blunted. The question is, are healthcare
providers preventing the body from effectively killing the invasive organism or are they helping. Due
to the critical illness of the patient, many of the normal functions of the body are typically disrupted.
This raises the concern for increased risk of side effects from the use of antipyretics and is this
contributing to the increase in mortality.
Benefits to allowing permissive hyperthermia were found to have limited clinical evidence
but felt the per se argumented benefits were helpful. The main issue to debate is how fevers could
influence to outcome of septic patients. The literature reviews found the benefits to allowing
permissive febrile events to be retarded microorganism growth, with optimal pathogen growth found
between 35-37ºC temperature (Ferguson, 2007). Other studies found that increasing the temperature
inhibited parasite growth, increased activity from antimicrobial agents, and reduce the minimum
inhibitory concentration levels. Immunity and heat shock responses were also examined and found to
have reduced the severity of infection by preventing CD4 counts, B cells, and proinflammatory
cytokine TNF α from being reduced. Another study showed an increased mobility of
polymorphonuclear cells, increased phagocytosis speed, lymphocyte recruitment, T-helper
lymphocyte adherence to L-selectin, increased immunoglobulin levels and TNF α cytotoxicity. Also
important are heat shock proteins which reduce endothelial and organ damage. Data showed a heat
shock response reduced mortality and organ injury while prolonging survival time in animal trails.
Other clinical data reviewed in the study showed that patients with gram-negative bacilli bacteremia
had higher survival rates when a fever was present, morality rate were reduced in spontaneous
peritonitis when the temperature was greater than 38, and overall survival increased in spontaneous
peritonitis as the body temperature increased. In contrast elderly patients with pneumonia who failed
to develop a fever had a 29% mortality rate compared to the 4% who developed a febrile event
(Jefferies, Weatherall, Young, Eyers, & Beasley, 2012; Launey et al., 2011). Other studies were
identified in having mortality rate of 80% in hypothermic patients compared to 47% who developed a
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fever in Candida infections as did a higher incident of inflammatory response in hypothermic patients
compared to febrile patients leading to a likely protective effect of fevers. Continued re-iteration of
improved survival rates, decreased inflammatory markers, and decrease in bacterial counts were also
seen in several animal studies (Launey et al., 2011).
Disadvantages to allowing a permissive febrile event to occur include increased metabolic
demand, reduce oxygen delivery to all organs and can worsen pre-existing disease. It has been well
documented that a fever post ischemic stroke causes a secondary brain injury and increases the
morbidity and mortality rate by 20%. The heart has also shown negative effects after a fever. The
trials obtained were only in swine studies but the swine showed an increase in myocardial infarction
when a fever was induced. Other non-data supported claims to treating a fever include: patient
discomfort, febrile seizure prevention in children, and possible collateral tissues damage from
microbial consumption. Collateral damage was seen in rat studies who developed vascular
pulmonary injury and it is now thought that in a high fever over 40-41ºC the benefits do not out
weight the metabolic and inflammatory effects (Launey et al., 2011).
Finally the study looked at the side effects of antipyretic treatments and physical cooling. Concern
for antipyretic use include: delay in diagnosis and therapy for infections or side effects such as
bleeding, hypotension, hepatic and renal toxicity. A meta-analysis of eight studies on patients with
the influenza virus showed an increased mortality rate with antipyretics (odds ration= 1.34, 95%
confidence interval= 1.04 to 1.73) (Eyers, Weatherall, Shirtcliffe, Perrrin, & Beasley, 2010; Launey
et al., 2011). Other effects of antipyretic administration found were longer viral shedding, suppressed
serum-neutralizing antibody response, prolonged parasite clearance, delayed and lower antibody
response post vaccination, and increased infection rate (Walsh, 2014). These findings are indirect
data but show that antipyretic use negatively impacts the morbidity rate. Paracetamol
(acetaminophen) has had well documented hepatic necrosis with overdose due to N-acetyl-p-benzoquinoneimine metabolite which can be life threatening. Even with normal use, a critically ill patient
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may have reduced glutathione reserves (alcoholics/malnourished) which can induce a hepatitis
increasing the risk of hepatic damage. The same metabolic pathway is also implicated in nephrotic
injury and possibly playing a role in analgesic associated nephropathy. Another unclear yet
concerning finding is a threefold increase in alanine aminotransferase in healthy individuals who
took four grams for 14 days. Intravenous paracetamol has been found to inhibit platelet aggregation
along with lowering critically ill febrile patient’s blood pressure which in most cases required both
fluid boluses and/or norepinephrine administration. The latter three finding require more extensive
studies to fully appreciate their effects. In contrast, non-steroidal anti-inflammatory drugs (NSAIDS)
are known to have side effects of gastrointestinal bleeding, inhibit cyclooxygenases-1 causing the
bleeding risk, inhibit prostaglandin synthesis causing adverse effects on the kidneys, and possibly
vasospasms in patient with coronary artery disease. These side effects are seen more commonly when
higher doses are used, used in the elderly, with steroids or anticoagulants, or in short course therapy.
Lastly physical cooling data was looked at. This found that physical cooling can cause sympathetic
activation, shivering, dermal vasoconstriction, limited core cooling, elevated oxygen consumption by
up to 40%, increased catecholamine’s , rebound hypothermia, and large temperature fluctuation. The
use of a myo-relaxant medication is recommended to prevent shivering and excessive oxygen
consumption (Launey et al., 2011).
The role of the nurse practitioner in treatment of septic patients and especially elderly is
growing. Sepsis has a high mortality rate in the elderly and a leading cause of overall global
mortality. Mastering care for these individuals is complicated and requires new strategies and
knowledge. Nurse practitioners are uniquely qualified for optimizing new knowledge and use
protocols to rapidly diagnosis and treat early sepsis. This in turn reduces morbidity and mortality
outcomes in the elderly (Hans Jurgen, Seiber, Walger, Bahrmann, & Singler, 2012; Kleinpell,
Aitken, & Schorr, 2013)
Review of Literature
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In a prospective observational investigation study to evaluate if there was an independent
involvement between fever and antipyretics with mortality rate in infected critically ill patients (Ho
Lee et al., 2012). The study was performed in 25 hospitals, ten in Korea and 15 in Japan with a total
of 1,002 intensive care units (ICU) with a mean of 20 beds per ICU. Twenty of the hospitals were
tertiary and five were community hospitals. There were 1,425 adult patients included in the study
who had been in the ICU for at least 48 hours from September 2009 to November 2009. Those
excluded include “post-cardiac arrest, post craniotomy, traumatic brain injury, central nervous
system infection, subarachnoid hemorrhage, intra-cerebral hemorrhage, or stroke (Ho Lee et al.,
2012, p. 2)”. The remaining group of patients was then divided into with and without sepsis based on
identifiable organisms found. Data collected included age, sex, reason for admission, mechanical
ventilation usage, Acute Physiology and Chronic Health Evaluation (APACHE) II score, and hourly
temperature from either: pulmonary artery catheter thermistors (3%), bladder catheter thermometers
(16%), tympanic membrane thermometers (9%), or axillary thermometers (72%). Treatment data
collected was not standardized throughout the hospitals and included non-steroidal anti-inflammatory
drugs, acetaminophen, and physical cooling. Statistical analysis used to compile data was the
chisquare test, mean or median of continuous variables, Student’s t-test, or Wilcoxon rank-sum test.
The confidence interval was at 95%.
Results were: mean APACHE II score of 17, a 28 day mortality rate of 12%, median ICU
stay of seven days, median hospital stay of 26 days, and 606 patients with sepsis while 819 patients
were not septic. Results in septic patients: 28 day mortality (22.3%; P-value <0.001), Gender (male)
(63.5%), Age (67), APACHE II score 21, Mechanical ventilation (70.8%), cardiac admission
(18.0%), respiratory admission (56.6%), metabolic admission (10.0%), gastrointestinal admission
(11.2%), length of stay mean 8 days, MAX ICU <36.5 ºC (0.7%), MAX ICU 36.5-37.4 ºC (16.2%),
MAX ICU 37.5-38.4 ºC (39.1%), MAX ICU 38.5-39.4 ºC (30.5%; odds ratio 5.13 (P-value <0.007)
and 13.4 (P-value<0.001), MAX ICU ≥39.5 ºC (13.5%), NSAIDs: Given (31 patients, 5.1%),
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Acetaminophen: Given (116 patients, 19.1%), Physical Cooling: Given (307 patients, 50.7%). Non
septic patients data results included a mortality rate of 4.4%, APACHE II sore of mean 14, more
likely to be admitted for postoperative (65.7%), cardiac (53.1%), or gastrointestinal (13.1%) reasons,
lower length of stay at mean 5 days, more likely to have a MAX ICU temperature of 37.5-38.4 ºC
(52%) and more likely to be treated with NSAIDS (12.1%) (Ho Lee et al., 2012).
Limitations of the study included lack of standardized protocols; body temperature
monitoring methods were not standardized and included mostly axillary (non-core), higher severity
of illness patients were more likely to have invasive monitoring methods (core) with higher values,
and finally NSAIDs were more likely to be given in non-septic patients, acetaminophen was given
more often in septic patients, and physical cooling was used more frequently as compared to other
studies which may alter mortality rates (Ho Lee et al., 2012).
The interpretation of the results of the study concluded that there is a significantly higher 28
day mortality rate in septic patients, the use of NSAIDS or acetaminophen was associated with
higher mortality rates only in septic patients (odds ratio: NSAIDS 2.32, P=0.02; acetaminophen 2.30,
P=0.002), and it is recommended that further study be conducted to refute or confirm these finding as
it is common that septic patients develop fevers and are treated the antipyretics (Ho Lee et al., 2012).
A literature review done in 2011 set out to evaluate advantages and disadvantages of
allowing septic patient to have a fever. Also viewed were the side effects the antipyretics to evaluate
the risk/benefit ratio (Launey et al., 2011). Throughout this study the overall conclusion is that the
risk and benefits should be assessed for every patient on the need for antipyretics. While more
research is needed current recommendation are to sub stain from using antipyretics in septic patients
absent of any neurological or cardio insult. If needed, physical cooling may be useful in a select
patient subgroup. Limitations of this study were that they did not specify how many research articles
were used and the type of research reviewed (Launey et al., 2011).
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Finally a recent (2013) systematic review and meta-analysis conducted on the effects of
mortality when antipyretics are given in critically ill non-acute neurologically injured adult patients
were reviewed (Niven, Stelfox, & Laupland, 2013). Preferred Reporting Items for Systemic Reviews
and Meta-analyses (PRISMA) and Cochrane Collaboration guidelines were used for article inclusion
and data analysis. There were five articles filtered from 755 articles used and obtained from different
medical journal sites such as OVID, MEDLINE, CINAHL, EMBASE, and Cochrane. Findings
included that there have been few randomized control studies which were limited by small
populations, different types of interventions, and variable length of therapy given. They recommend
urgently performing large randomized trials to effectively study mortality rates. Limitations of this
study include the small number of randomized control studies to review and only one reported
mortality as a specific outcome (Niven et al., 2013).
Summary of Statements
Sepsis is a concerning event commonly seen in older critically ill patients in the ICU that
carry a significantly higher mortality rate. Small and limited studies have alluded to the fact the
fevers are the body’s natural defense mechanisms against infectious organisms and are better for the
patients survival. Negative findings associated with treating febrile events below fatal temperatures
with antipyretics are numerous related to both the blunting of the therapeutic effects of the fever and
also to the drugs sided effect profile. Deleterious effects of allowing the fever to continue in nonacute brain injury patients are nominal in comparison and need to be considered. Current
recommendations are to allow permissive hyperthermia below fatal temperatures in septic non-acute
brain injury patients who are able to withstand the deleterious effects of the fever itself. The use of
antipyretics and physical cooling should be kept to a minimum if possible. As more IUC’s adopt this
standard of thinking, large randomized control trials should be conducted to effectively prove this
new standard of care.
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References
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