Fever and Hyperthermia

Normal body temperature is 37.0°C with a 0.5-1°C diurnal variation that peaks in the evening and is lowest at ~0600. Hyperthermia can either be:

Fever and hyperthermia are often used synonymously both clinically and in the literature.

However, there is some value in separating the two based on alteration of the hypothalamic set point; for the purpose of this section fever refers to ↑ body temperature due to ↑ hypothalamic set point.

This covers management of elevated body temperature. Heat injury and heat stroke are covered under Heat Injury, febrile neutropaenia and neutropaenic sepsis are covered under Febrile Neutropaenia.

True fever
↑ Temperature due to ↑ hypothalamic set point, and is defended by thermoregulatory mechanisms.
- In the critically ill is core body temperature >38.3°C
  Lower thresholds (>38.0°C) may be appropriate in certain populations:
  - Not critically unwell
  - Elderly
  - Immunocompromised
    - Neutropaenic
      Indication for empirical broad-spectrum antibiotics, independent of other clinical suspicion of infection.
  - Extracorporeal circuits
    Expect a ~0.5°C drop in body temperature on CRRT.
Non-febrile hyperthermia
↑ Temperature with a normal hypothalamic set point.
- Due to imbalance between mechanisms of heat gain and heat loss
- Causes include:
  - Exercise-induced
    Generally benign and self-limiting, though can ↑ risk of heat injury in hot and humid environments.
  - Hyperthermia due to inadequate heat dissipation
    Particularly in the unacclimatised, who do not exhibit the same degree of peripheral vasodilatation and sweating.
  - Hyperthermia due to impaired thermoregulation

Fever

Fever is a basic, adaptive evolutionary response to infection, but may be maladaptive in certain disease processes. Fever:

10% of septic patients are hypothermic and 35% are normothermic at presentation, and those that do not become febrile have a higher mortality than those who develop fever.

Often follows a variable pattern
This pattern is generally unhelpful diagnostically due to wide variability, however single fevers are unlikely to represent infection.
Magnitude gives some clue to aetiology:
- Infectious causes rarely exceed 41°C
- Non-infectious causes generally result in temperatures <39°C
Associated with rigors
Rigors are also associated with bacteraemia.

Causes of Fever
System	Infectious	Non-Infectious
Respiratory	Sinusitis Pharyngitis Dental Pneumonia	Aspiration pneumonitis ARDS
Circulatory	Endocarditis Myocarditis Line infection Mediastinitis Blood stream infection	DVT/PE Thrombophlebitis Fat emboli
Neurological	Meningitis Encephalitis Discitis Epidural abscess Ventriculitis	CVA SAH TBI Hypothalamic injury Impairment of thermoregulatory responses, giving risk of hyperthermia in a hot external environment. Anti-NMDA receptor encephalitis
Endocrine and Metabolic		Thyrotoxicosis Thyroiditis Adrenal insufficiency Ovulation
Renal	Pyelonephritis Prostatitis UTI Catheter-associated UTI.
Gastrointestinal	Oesophagitis Pancreatitis Bowel perforation Diverticulitis Colitis C. difficile colitis Perianal abscess	Mesenteric ischaemia Acalculous cholecystitis Pancreatitis GI bleed
Haematological/Oncological	Malaria	Lymphoma TLS
Integumentary	Osteomyelitis NSTI	Gout Pseudogout
Immunology		Transplant rejection Transfusion reaction Vasculitis
Toxin and Environmental		Alcohol withdrawal Drug fever
Other		Post-operative IV contrast

Non-Febrile Hyperthermia

Non-febrile hyperthermia:

May exceed 41°C
Not affected by antipyretics
Aspirin, paracetamol.
Active cooling not opposed by shivering, rigors

Causes of Non-Febrile Hyperthermia
System	Cause
Drug and Toxins	Malignant hyperthermia Serotonin syndrome NMS
Environmental	Heat injury

Pathophysiology

Hyperthermia is associated with:

↑ Metabolic rate
- ↑ Myocardial work
↓ Immune function (at high levels)

Suppression of fever is associated with:

↑ Bacterial growth
↑ Viral replication/shedding
↑ Duration of illness

Investigation

Temperature ≥38.3°C is a reasonable trigger to clinically reassess and consider cultures.

Bedside:

Temperature measurement
- Use the most accurate device available
- Axillary, temporal artery, and chemical dot thermometers should not be used in the critically ill.

Temperature should be assessed with the most accurate device available and appropriate to the clinical situation. In descending order:

Intravascular
- PAC
  Gold standard.
- Jugular bulb
  Approximates PAC except around infusion of IV fluids.
Oesophageal
Should be measured at ~T8-9.
Bladder
Relies on adequate urine output.
Nasopharyngeal
Rectal
Tympanic

Laboratory:

Blood cultures
- Strict aseptic process should be performed to minimise contamination:
  - Skin cleaning:
    - 2% chlorhexidine/70% isopropyl alcohol
    - 1-2% alcoholic iodine
  - Clean blood culture bottle with 70+% alcohol
    Avoiding cleaning with antiseptic as it may degrade the stopper.
  - Aseptic venepuncture
  - Introduction of blood into bottles can occur with the same needle
- To minimise false negative risk, take:
  - 2-3 samples from separate sites through intact skin
  - 20mL (10mL for each bottle) minimum for each draw
  - Cultures prior to antibiotics
- Culture to identify resolution of bacteraemia should occur 48-96 hours following initiation of appropriate therapy
Urine
Generally avoid unless:
- Neutropenic
- No IDC and suspicion of UTI
- Structural urological abnormality

Blood cultures should be performed when a new fever does not strongly suggest a noninfectious cause.

Culture any line in place >48 hours.

Imaging:

Other:

Specific testing:
- C. difficile
- Paracentesis
  If ascites.
- DVT/PE evaluation
- EVD CSF culture
  If in situ.
- LP
  If suggestion of meningitis.

Management

This applies to the management of fever in the general ICU patient, more aggressive temperature control is required for patients post-arrest or with hyperthermic emergencies.

Specific therapy:

Post resuscitation care is covered under Post-Resuscitation Care. Key hyperthermic emergencies are covered under Heat Injury, Serotonin Syndrome, Neuroleptic Malignant Syndrome, and Malignant Hyperthermia.

Treating with paracetamol at 39.5°C provides some leeway before the more important 40°C threshold is reached.

Pharmacological
- Antipyretics
  Treatment of ↑ temperature is generally not indicated unless:
  - Neurological injury
    - Post-cardiac arrest
  - Fever >39.5°C
  - Worsening another clinical condition
    - Delirium
    - Myocardial ischaemia
- Antibiotics
  - Suspected or confirmed infection
  - Neutropaenic fever
Procedural
- Line change
  Consider in lines >72 hours old, particularly if other features of CLABSI or sepsis.
Physical
- Cooling
  Febrile patients may require paralysis to limit shivering with active cooling.

Comparison of Cooling Therapies
Class	Method	Rate of Change (°C/hr)	Considerations
Passive	Exposure	0.5-1	Cheap Slow Cooling only
Pharmacological	Antipyretics	0.5-1	Cheap Slow Cooling only
Active External	Wet towels/ice packs	1	Cheap Wet patient Electrical safety Wound sterility Uneven cooling Frostbite risk. Cooling only
	Evaporative (fan and mist)	1-2	Cheap Risk free Cooling only
	Temperature control pad e.g. Arctic sun.	1.5-3	Effective Expensive Allows rewarming
	Cold-water Immersion	8-10	Cheap Rapid Unfeasible in large patients Wet patient Risk of overcooling
Active Internal	30-40mL/kg 4°C IV fluids	2-3	Cheap Rapid High-volume infusion Arrhythmia risk
	Intravascular catheter	2-4	Invasive Allow temperature monitoring Allows re-warming
	Body cavity lavage	3	Invasive Fluid absorption
	CPB/ECMO	10	Very invasive Expensive Limited availability
	RRT	10	Invasive May already need RRT

Key Studies

HEAT (2015)
- 700 Australasian non-pregnant adult ICU patients >38°C within 12 hours with suspected infection, on antibiotics, who did not have an acute brain disorder, were receiving TTM for cardiac arrest, or had a contraindication to paracetamol
- Multicentre (23), block-randomised, double-blind trial
- 700 patients gives 80% power for ARR of 2.2 ICU-free days
- Paracetamol vs. placebo
  - Paracetamol 1g IV Q6H
  - Placebo
  - Continued for 28 days, discharge from ICU, cessation of antibiotics, or resolution of fever
  - Rescue physical cooling permitted if >39.5°C
- No change in ICU-free days (23 vs. 22)
- Survivors had a lower ICU length of stay with paracetamol (3.5 vs. 4.3 days)
- Paracetamol group had a marginally lower peak and mean body temperature

References

Marik PE. Fever in the ICU. Chest. 2000 Mar;117(3):855–69.
Stitt JT. Fever versus hyperthermia. Fed Proc. 1979;38(1):39-43.
O’Grady NP, Barie PS, Bartlett JG, et al. Guidelines for evaluation of new fever in critically ill adult patients: 2008 update from the American College of Critical Care Medicine and the Infectious Diseases Society of America. Critical Care Medicine. 2008;36(4):1330.
Bersten, A. D., & Handy, J. M. (2018). Oh’s Intensive Care Manual. Elsevier Gezondheidszorg.