FACE

In Review

Fever and Antipyretic in Critically ill patients Evaluation (FACE) Study Group.. "Association of body temperature and antipyretic treatments with mortality of critically ill patients with and without sepsis: multi-centered prospective observational study". Critical Care. 2012. 16(1):R33.
PubMed • Full text • PDF

Clinical Question

In patients admitted to the ICU with fever and receiving antipyretic treatment, are infected patients at a higher risk of death compared to non-infected patients?

Bottom Line

Temperature is not associated with mortality in the septic patient, but a higher temperature is associated with an increase in mortality in the non-infected patient

Major Points

Fever is a natural response to infection, slowing bacterial growth and promoting production of cytokines and activation of macrophages, neutrophiles, and T cells. Fever during critical illness may be detrimental by increasing metabolic rate and oxygen consumption so anti-pyretic treatment is often given.

This trial suggests that in septic patients, treatment with anti-pyretics increased 28 day mortality, not seen in non-septic patients. Physical cooling did not show increased mortality in either group. In contrast, in non-septic patients, mortality increased with temperature; the subgroup with max temperature ≥ 39.5°C had higher mortality. This was not seen in the septic patients.

Given the observational design of this trial, further randomized trials will need to be completed to confirm these findings.

Guidelines

ACCM & IDSA Critically Ill New Fever Guidelines (2008, adapted)

• Measuring Temperature
  • Axillary measurements, temporal artery estimates, and chemical dot thermometers should not be used in the ICU (level 2)
  • Rectal thermometers should be avoided in neutropenic patients (level 2)
  • New onset of temp ≥38.3°C or <36.0°C (in absence of known cause of hypothermia) is a reasonable trigger for a clinical assessment, not necessarily lab or imaging required (level 3)
  • Laboratory and imaging should be done based on clinical evaluation, no automatic based on temperature (level 2)
• Obtaining Blood Cultures
  • Obtain 3-4 blood cultures within 24hrs of ICU admission (level 2)
  • Additional cultures drawn based on clinical suspicion (level 2)
• Intravascular Catheters
  • Any expressed purulence from insertion site should be sent for C&S (level 2)
  • Any evidence of infection or septic shock, remove and replace in new site (level 2)
  • At least two blood cultures obtain, one via peripheral venipuncture (level 1)
• Non-infectious Causes of Fever
  • Consider all new medications and blood products as suspect (level 2)
  • Fever induced by drugs may take several days to resolve (level 2)

Design

• Multicenter, prospective, observational
• N=1425
  • Sepsis in first 24 hours (n=606)
  • No Sepsis in first 24 hours (n=819)
• Setting: 25 Hospitals (10 in Korea, 15 in Japan)
  • 20 academic tertiary care hospitals
  • 5 Community hospitals
• Enrollment: 1 September 2009 - 30 November 2009
• Analysis: Uni- and Mulitvariate Analysis
• Primary outcome: Mortality up to 28 days following ICU admission

Population

Inclusion Criteria

• All patients requiring ICU care >48 hours

Exclusion Criteria

• Post-cardiac arrest
• Post craniotomy
• Traumatic brain injury
• Central nervous system infection
• Subarachnoid hemorrhage
• Intracerebral hemorrhage
• Stroke

Baseline Characteristics

Presented as sepsis vs. non-sepsis; P-value

• Male: 63.5% vs 62.0%; 0.56
• Age(IRQ): 67(55,75) vs 65 (54,73); 0.015
• APACHE II (IRQ): 21 (16,25) vs 14(10,18); <0.001
• Mechanical Vent: 70.8% vs 64.5%; 0.01
• Post-op Admission: 11.2% vs 65.7%; <0.001
• Reason for Admission
  • Cardiac or vascular disease: 18.0% vs 3.1%; <0.001
  • Thoracic or respiratory disease: 56.6% vs 5.0%; <0.001
  • Renal or metabolic disease: 10.0% vs 6.6%; 0.018
  • GI disease: 11.2% vs 13.1%; 0.26
  • Other: 4.1% vs 2.1%; 0.024

Interventions

Body Temperature

• Recorded every 4 hours until ICU discharge or 28 days after admission
  • temp at start of antipyretic treatment recorded
• if more than one method of measurement used, record of most preferred by SCCM/IDSA was used

Antipyretic

• Recorded all NSAIDs, acetaminophen, physical cooling
  • NSAIDs/acetaminophen only recorded when used for fever management

Outcomes

Temperature measurement methods:

• Axillary thermometers 72%
• Bladder catheter thermistors 16%
• Tympanic membrane thermometers 9%
• Pulmonary artery catheter thermistors 3%

Primary Outcomes

Presented as Sepsis vs Non-sepsis; P-value

• 28-day mortality n(%): 135(22.3%) vs 36(4.4%); <0.001

• MAX Temp (°C, IQR): 38.3 (37.7, 39.0) vs 37.8 (37.4, 38.3); <0.001 (Difference remained statistically significant for 7 days)
  • <36.5°C: 4(0.7%) vs 2(0.2%); 0.43
  • 36.5 to 37.4°C: 98(16.2%) vs 240(29.3%); <0.001
  • 37.5 to 38.4°C: 237(39.1%) vs 425(52.0%); <0.001
  • 38.5 to 39.4°C: 185(30.5%) vs 125(15.3%); <0.001
  • ≥39.5°C: 82(13.5%) vs 27(3.3%); <0.001

Presented as Unadjusted OR(95% CI)(P-value)

• 28-day Mortality
  • <36.5°C: 2/4(50.0%) [3.08(0.41, 23.1)(P = 0.57)] vs 0/2(0%) [n.a.]
  • 36.5 to 37.4°C: 24/98(24.5%) [1(ref)] vs 4/240(1.7%) [1(ref)]
  • 37.5 to 38.4°C: 40/237(16.9%) [0.63(0.35, 1.11)(P = 0.14)] vs 17/425(4.0%) [2.46(0.82, 7.40)(P = 0.44)]
  • 38.5 to 39.4°C: 44/185(23.8%) [0.96(0.54, 1.70)(P = 0.99)] vs 10/125(8.0%) [5.13(1.58, 16.7)(P = 0.007)]
  • ≥39.5°C: 25/82(30.5%) [1.35(0.70, 2.61)(P = 0.46)] vs 5/27(18.5%) [13.4(3.35, 53.6)(P < 0.001)]

Secondary Outcomes

• Antipyretic Treatment
  • Overall 51.7% (N=1425) patients received antipyretic treatment
  • NSAIDs: 5.1% vs 12.1%; <0.001
    • Delta body temp(°C, IQR): -0.3(-0.8, 0.0) vs -0.4(-0.7, 0.0); 0.57
  • Acetaminophen: 19.1% vs 3.9%; <0.001
    • Delta body temp(°C, IQR): -0.4(-0.8, -0.2) vs -0.3(-0.7, 0.0); 0.14
  • Physical Cooling: 50.7% vs 44.4%; 0.02
    • Delta body temp(°C, IQR): -0.2(-0.5, 0.0) vs -0.1(-0.3, 0.0); <0.001
• Length of ICU stay: 8(5, 14) vs 5(4, 7); <0.001
• 28-day mortality single vs multiple episodes ≥39.5°C: NS

Univariate Analysis

Presented as Sepsis vs Non-Sepsis OR, p-value

Mortality and antipyretic treatment

• NSAIDs 2.32 p=0.02 vs 0.20 p=0.08
• Acetmainophen 2.30 p=0.002 vs 0.69 p=0.72
• Physical Cooling 1.00 p=0.99 vs 1.14 p=0.74

Multivariate Analysis

Presented as Sepsis vs Non-Sepsis Adjusted OR, p-value 28 Day Mortality

• APACHE: 1.09, p<0.001 vs 1.19, p<0.001
• Mechanical Vent Required: 1.72, p=0.045 vs 3.85, p=0.01
• Max Body Temperature (reference range 36.5°C to 37.4°C)
  • < 36.5°C: Not Reported
  • 37.5°C to 38.4°C: 0.45 p=0.014 vs 1.61 p=0.38
  • 38.5°C to 39.4°C: 0.52 p=0.09 vs 3.34 p=0.08
  • ≥ 39.5°C: 0.47 p=0.11 vs 8.14 p=0.01
• NSAIDs: 2.61 p=0.028 vs 0.22 p=0.15
• Acetaminophen: 2.05 p=0.01 vs 0.58 p=0.63
• Physical Cooling: 1.2 p=0.50 vs 0.71 p=0.44

Criticisms

Methods

• Inconsistent approach to fever in these 25 ICU. With the challenges for having an interventional study and obtaining informed concent in this population, it may be challenging to overcome this issue.
• Acetaminophen was used less often as compared to previous studies
• Excluded patients with neurologic injury due to the ethical implications through not treating fever

Temperature

• ACCM and IDSA preferred methods for temperature measurement (Table 2)
  • Most Accurate
    • Pulmonary artery thermistor
    • Urinary bladder catheter thermistor
    • Esophageal probe
    • Rectal probe
  • Other acceptable methods in order of accuracy
    • Oral probe
    • Infrared ear thermometry
  • Other methods less desirable
    • Temporal artery thermometer
    • Axillary thermometer
    • Chemical dot
• The vast majority of temperatures in the study were from axilla
• Unclear if these temperatures were corrected for comparison

Funding

The Korean Society of Critical Care Medicine and the Japanese Society of Intensive Care Medicine supported the travel expense for research committee members to JAKOICS meetings.