Running head: TREATMENT OF FEVER IN SEPSIS 1

Treatment of Fever in Sepsis

Madhavi Inturi

Wright State University

TREATMENT OF FEVER IN SEPSIS 2

Treatment of Fever in Sepsis

Significance of the problem

Fever is a response to the infectious stimuli. In the clinical practice, fever is a diagnostic

sign, which helps to guide and start the treatment early through the infectious process. Fever is a

physiologic response of the body to a disease and it has benefits in fighting the infection (Roth &

Basello, 2018). Sepsis is the common cause of fever and signs of shock. Severe infection may be

caused by the spectrum of illness. Diagnosing and treating the patient early may reduce the

complications and mortality (Reifel Saltzberg, 2013). The resuscitation of the sepsis may be

complex due to the diverse physiology of the sepsis. Hemodynamic monitoring, resuscitation of

multiple clinical manifestations, and administering empirical antibiotics and approaching in an

organized way can improve the clinical outcomes of the patient. The incidence of sepsis is

increasing globally. Prompt assessment and treatment is very important in a patient with fever

and signs of shock (Reifel Saltzberg, 2013).

Fever is seen in two thirds of the patients with severe sepsis. Fever is defined as the core

body temperature above 38.3 degrees centigrade. When there is an infection, leukocytes are

activated and release the pyrogenic cytokines. Fever control measures are widely used in febrile

intensive care unit (ICU) patients. When fever is controlled the physiological effects seen are the

decrease in oxygen consumption, reduce cardiac output, increase in vascular tone, and serum

lactate clearance. Fever inhibits the growth of microorganisms and strengthens the host defense

mechanism (Schortgen et al., 2012).

Discussion of the problem

Epidemology:

Approximately fifteen percent of the elderly population and five percent of the adult

population visit the emergency department (ED) every year with fever (Dewitt, Chavez, Perkins,
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Long, & Koyfman, 2017). Sepsis and septic shock are very commonly seen diagnoses in the

intensive care units (ICU). The incidence of these diagnoses annually in the United States (U.S),

is three cases per one thousand population or 751,000 cases are seen. Most of the cases visit the

ED and get admitted from there. Fever along with the signs of shock requires immediate

treatment and management to prevent complications (Reifel Saltzberg, 2013). Each year more

than 500,000 emergency visits are comprised of the severe sepsis. Even though preventive

measures, such as vaccines and improvements in the antibiotic therapy are being used in

preventing and treating infections, the incidence of the sepsis has been increasing eight point

seven percent (8.7%) every year (Reifel Saltzberg, 2013).

In the U.S, sepsis related deaths are approximately 250,000 per year. Out of all these

deaths nine point three percent (9.3%) are due to sepsis. The mortality due to sepsis is not the

same across the country. Depending upon the state, the death rate ranges from 41 to 88 deaths

per 100,000 population every year (Reifel Saltzberg, 2013). Geographic variability is seen in the

mortality rate of the sepsis. In Australia, 24.7 percent mortality is seen in patients who are

admitted to the ICU’s with sepsis, whereas in Spain it is 37.5 percent. In Mexico, 47 percent of

the sepsis cases are due to intra- abdominal infections (Reifel Saltzberg, 2013).

Etiology:

Fever is an important sign of infection. Careful diagnostic studies are conducted to find

out the source of infection with the new onset of fever. The important elements that are

considered with the new onset of fever in ICU are: patient’s history, predisposing factors

causing fever, careful physical examination, any recent surgical wounds, venous and arterial

access sites, pressure ulcers, and any recent abdominal surgeries (Fink, 2017).
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Generally the normal body temperature is 36.8 degrees centigrade plus or minus zero

point four degrees centigrade (0.4 C). A body temperature of greater than 38.3 degrees

centigrade is considered as fever. It is concluded by a task force from the Society of the Critical

Care Medicine in 2008, that the fever could be from infectious and non-infectious reasons.

Careful clinical assessment is very important rather than ordering the laboratory and radiological

tests. When these tests are indicated, cost effective approaches are considered (Fink, 2017). The

pathogenesis of the fever is caused by the activation of the vagal afferent signals in the liver by

the pyrogenic stimuli trigger. These vagal afferent signals travel to the nucleus tractus solitarius

of the brain stem. From there, these signals travel to the hypothalamus and cause the increase in

the temperature which is mediated by the prostaglandin E2 (PGE2) through the alpha-1

adrenergic receptor- dependent pathway (Fink, 2017). A delayed or secondary rise in the

temperature is caused by the alpha-2 adrenergic dependent pathway, which causes the increase in

PGE2 due to the increase of cyclooxygenase 2 (COX2) (Fink, 2017).

Treatment issues, concerns and review of literature

Many observational studies recommend that the fever is beneficial to the patient. Fever

has a strong impact on the growth of the microorganisms. Infectious pathogen agents grow under

certain temperatures between 35 and 37 degrees centigrade. In experiments conducted with the

meningitis, it is proved that pneumococci’s growth time was increased with elevated temperature

when compared to a blunted febrile response was actuated by urethane (Launey, Nesseler,

Malledant, & Seguin, 2011). Studies conducted on plasmodium falciparum in vitro showed that

the febrile conditions had a great role and inhibited the growth of the parasites. Experiments

conducted on 432 strains of bacteria, and increased temperature from 35 to 41.5 degrees of
TREATMENT OF FEVER IN SEPSIS 5

centigrade showed an increased activity of the 17 antimicrobial agents, which were used and

reduced the minimum inhibitory concentrations (MIC) (Launey et al., 2011).

Fever is known to regulate the cellular response and induce the heat shock response.

Experiment conducted with a rat model related to peritonitis under hyper thermic conditions,

prevented the decline in the number of CD4 lymphocytes and B cells, reduced proinflammatory

cytokine tumor necrosis factor (TNF) alpha serum levels, and decrease in the severity of the

infection (Launey et al., 2011).

An observational study was conducted in 2012, in 25 hospitals, regarding the association

of mortality with fever and the use of antipyretic treatment in septic and non-septic patients

during admission to the ICUs (Lee et al., 2012). One thousand four hundred and twenty nine

(1429) critically ill patients were studied. Out of 1429 patients, 606 patients are diagnosed with

sepsis when admitted to ICU and 819 are without sepsis during admission to ICU. The

antipyretics used are acetaminophen and non-steroidal anti-inflammatory drugs (NSAIDS) (Lee

et al., 2012). This study revealed that the mortality is differently associated when antipyretics

administered in septic and non-septic patients. The possible explanations given by the study are:

1. lowering the temperature of the body using antipyretics is not desirable in septic patients, and

fever reduces the activity of the bacteria and viruses, 2. Using the NSAIDS and acetaminophen

in septic patients lowered the renal function and caused hypotension, 3. Higher mortality was

seen in septic patients who did not develop fever. The unadjusted mortality was 66 percent high

in ICU patients with temperature of less than 36.5 degrees centigrade. This finding supports that

fever is a natural protectant (Lee et al., 2012). This study concluded that the high fever greater

than 39.5 degrees centigrade in patients without sepsis is independently related to the mortality

and not associated with acetaminophen or NSAIDS administration. Whereas, in septic patients
TREATMENT OF FEVER IN SEPSIS 6

the NSAIDS and acetaminophen administration independently was related to the 28 day

mortality, also there was no association of fever with mortality (Lee et al., 2012).

A retrospective study of 218 patients with bacteremia, who had gram negative bacilli was

reported that there was a higher survival rate of patients who developed fever with bacteremia

(Launey et al., 2011). When the temperature was greater than 38 degrees centigrade, the

mortality rate was decreased in patients who are affected with bacterial peritonitis. In this

disease, it was found that with increase in temperature there was an increase in survival rate. A

higher mortality rate was seen in the elderly population who suffered from community acquired

pneumonia (CAP) and did not suffer from fever when compared to the population with the same

disease and suffered from fever. There was 29 percent of mortality seen in the patients with CAP

and lacked fever and only 4 percent mortality was seen in patients with CAP and had fever

(Launey et al., 2011).

A multicenter French AmarCand study which was conducted more recently showed that

the fever greater than 38.2 degrees centigrade plays an important role in reducing the infections

in ICU. Hypothermia and fever both had increased morbidity and mortality in the selected ICU

patients. The patients who had fever had less mortality than compared to the patients with

hypothermia (Launey et al., 2011).

Detrimental effects of fever:

Even though fever is a natural protectant and reduces the bacterial growth in the host, it

may lead to many detrimental effects related to the clinical outcomes. Fever may increase the

metabolic demand and increase the oxygen consumption of many organs in the body, such as the

brain and the heart (Launey et al., 2011). This may result in worsening of the preexisting disease.

In the patients with neurological injuries fever may contribute to the cerebral insult. In ischemic
TREATMENT OF FEVER IN SEPSIS 7

strokes fever can increase the morbidity and mortality. In neurological injured patients, fever

may lead to the worsening of the primary lesions (Launey et al., 2011).

Fever is very commonly seen in ICU patients ranging from 26 percent to 70 percent and

the frequent cause is the infection. It may increase the blood pressure, heart rate, and respiratory

rate leading to the cardiopulmonary and metabolic stress. This may be potentially harmful to the

patient (Schell-Chaple, Liu, Matthay, Sessler, & Puntillo, 2017).

Deleterious effects are seen with fever in patients with myocardial injuries. More harm is

caused due to increased oxygen consumption. A swine model of acute myocardial infarction

revealed that an elevated body temperature up to 39 degrees centigrade lead to the increase in the

infarct size (Launey et al., 2011). A study conducted in critically ill patients where the

temperature was decreased from 39 degrees centigrade to 37 degrees centigrade showed that

there was a decrease in oxygen consumption and reduced the cardio pulmonary stress. This

helped to better resuscitate the patients with limited oxygen delivery. (Launey et al., 2011).

A systematic review revealed that some randomized clinical trials found that the effects

of controlling the fever with antipyretics on critically ill patients without any neurological injury.

This study included the sample size of 100. This meta- analysis concluded that the there was no

evidence that the fever control methods influenced the mortality of the critically ill patients

without acute neurological injury (Niven, Stelfox, & Laupland, 2013).

Pharmacologic antipyretics:

These can be grouped into three categories. They are corticosteroids, aspirin and other

NSAIDS, and acetaminophen. Corticosteroids are not generally used for antipyresis. They reduce

the fever by blocking the transcription of the pyrogenic cytokines and COX (Sajadi &
TREATMENT OF FEVER IN SEPSIS 8

Mackowiak, 2015). Acetaminophen, aspirin, and other NSAIDS block COX medicated

production of the inflammatory thromboxanes and prostaglandins (Sajadi & Mackowiak, 2015).

Physical antipyresis:

These methods of antipyresis are used to cool the febrile patients. These include applying

cooling blankets, sponging, and applying ice packs. Heat loss is by conduction, convection, and

evaporation in the physical methods of antipyresis (Sajadi & Mackowiak, 2015).

Side effects of antipyretics:

Even though there is not much experimental and clinical data, clinicians treat the febrile

patients with antipyretics in ICUs. Direct cooling, use of antipyretics, such as NSAIDs and

acetaminophen are used to treat fever. When the fever is treated with antipyretics, early diagnosis

and treatment of the infections is delayed. Hypotension, hepatic toxicity, renal toxicity, and

bleeding are some of the side effects of these antipyretics (Launey et al., 2011).

External cooling method is used in ICUs for hyperthermia to decrease the temperature.

Use of cooling blankets in febrile patients in ICUs is shown to cause temperature fluctuations

and rebound hypothermia (Launey et al., 2011).

Role of Acute Care Nurse Practitioner (ACNP)

Diagnosis of sepsis depends upon the careful history taking, physical examination,

leukocytosis, and lactate level. ACNP plays an important role in careful history taking and

performing the physical examination. ACNP can order the cultures and other blood tests in a

timely and cost effective manner. Travel history of the patient is very important. ACNP should

consider the reactivation of the tuberculosis in the elderly (Leggett, 2016). ACNP should

evaluate carefully when treating fever in a critically ill patient. The clinician should carefully

investigate whether the cause of fever is infectious or from other causes. Excessive antibiotics
TREATMENT OF FEVER IN SEPSIS 9

when not warranted is considered by ACNP to prevent antibiotic resistance (Leggett, 2016). In

patients with fever and signs of shock, ACNP should act quickly and initiate the specific therapy

with antibiotics, or else delay in the proper management with antibiotics may increase the

morbidity and mortality (Leggett, 2016). Clinicians should consider antipyretics in elderly

population to reduce the mental dysfunction caused by the fever. Health care provider may give

antipyretics when there is an evidence of increased sympathetic tone, respiratory rate, respiratory

minute volume, and oxygen consumption to decrease the cardiopulmonary stress (Sajadi &

Mackowiak, 2015). Careful monitoring of the patient with new fevers is very important. When

external cooling method is used, shivering is prevented by pharmacological means, as shivering

can cause increased consumption of oxygen (Sajadi & Mackowiak, 2015). ACNP’s should

cautiously use some antipyretics such as indomethacin in patients with coronary artery disease as

it may cause vasoconstriction. Sometimes antipyretics may be administered to comfort the

patient as they also act as analgesic agents (Sajadi & Mackowiak, 2015).

Conclusion

Fever is a response caused by the infectious or non-infectious process. The benefit- to-

harm balance is complex and dependent on the severity of the infection, immune system

response, and the extent of the collateral tissue damage induced by the systemic inflammatory

response in ICU patients (Launey et al., 2011). Clinical data does not support the extensive use

of antipyretics and may be harmful specifically when the infection is progressing. Antipyretics

are introduced when there are neurological injuries, cardiac problems and or in the absence of

sepsis (Launey et al., 2011).

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References

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