🌡️Temperature 🤒Control in Sepsis

🔥 Fever in Sepsis: Friend or Foe? 🔥

Fever is a fundamental feature of sepsis, often viewed as a double-edged sword—on one hand, it enhances immune response, but on the other, it increases metabolic demand and can lead to organ dysfunction.

⁉️ Managing temperature in sepsis has been controversial, as no definitive evidence supports fever control improving survival. However, both extreme hyperthermia (>39.5°C) and hypothermia (<36°C) are linked to poor outcomes.

Let's explore pathophysiology, clinical implications, and management strategies for temperature control in sepsis. 🚑

1️⃣ Introduction

🌡️ Fever (pyrexia) in sepsis is a well-known phenomenon, yet its optimal management remains unresolved.

🔬 Some key facts:

✅ Fever may inhibit bacterial growth and enhance immune response.

⚠️ High fever can cause metabolic stress, tachycardia, hypotension, and coagulopathy.

🔻 Hypothermia is consistently associated with worse outcomes, including increased mortality and ICU-acquired infections.

📊 Despite widespread temperature control practices in ICUs, randomized trials fail to show a mortality benefit.

So, should we treat fever in sepsis? 🤔 Let’s dive into the science!

2️⃣ Physiopathology 🧬

2.1 How Fever Works: Cellular & Molecular Changes

Our body’s thermostat, the hypothalamus, regulates temperature via an afferent-central-efferent system. Thermal receptors (mainly in the skin) sense temperature changes and trigger responses such as:

❄️ Shivering → Heat Production 🔥 Vasodilation & Sweating → Heat Dissipation

🔬 How Fever Impacts Infection

✅ Bacterial Inhibition

• Growth of Streptococcus pneumoniae & Haemophilus influenzae is impaired at high temperatures 🌡️.

• Bacteria in biofilms (Staphylococcus, Pseudomonas aeruginosa) are more susceptible to antibiotics at febrile temperatures.

✅ Enhanced Host Defense

• Heat Shock Proteins (HSPs) 🛡️ protect cells and stimulate immune activation.

• 🔥 Fever boosts NETosis, reactive oxygen species (ROS), and T-cell activation.

⚠️ But there's a catch...

• Hyperthermia (>41°C) is cytotoxic 💀—neuronal and lung epithelial damage is seen.

• Fever increases oxygen demand ⏩ tachycardia, hypotension, and coagulopathy may occur.

• Hyperthermia can accelerate clot formation 🩸 via neutrophils and histones.

2.2 Gut Microbiota’s Role 🦠

💡 Could gut microbiota influence fever patterns in sepsis? Recent research suggests YES!

📌 A study found specific bacterial taxa (Lachnospiraceae spp.) linked to lower body temperatures in sepsis.

📌 Fever in COVID-19 and neutropenic fever is associated with altered microbiota (Enterococcus faecalis, Saccharomyces cerevisiae).

📌 In a mouse model, intestinal cells released fucose 🍽️ during infection, which helped microbiota survive and improved infection tolerance.

🧐 Key Takeaway: The gut microbiota might modulate fever response in sepsis, but more research is needed.

3️⃣ The Clinical Impact & Prognostic Value of Fever in Sepsis

3.1 What We Can Learn from Non-Septic Conditions

📌 Heatstroke:

• Severe hyperthermia leads to multi-organ failure ⚠️.

📌 Malignant Hyperthermia:

• Anesthetic-induced temperature dysregulation with variable presentation.

📌 Acute Brain Injury:

• Fever worsens outcomes without proven survival benefit from cooling 🧠.

📌 Cardiac Arrest:

• Guidelines recommend active cooling (<36°C for 24h) and fever prevention (72h).

📌 ICU Patients Without Sepsis:

• 📈 High fever (>39.5°C) is linked to worse prognosis.

• 📉 Normothermia is NOT always beneficial!

3.2 Fever in Sepsis: Friend or Foe?

📊 Fever is common in ICU sepsis (~60%) 🔥, while 10–30% of septic patients present with hypothermia ❄️.

Key Findings from Meta-Analysis

✔️ Febrile (>38°C) patients: 22.2% mortality

❌ Normothermic patients: 31.2% mortality

⚠️ Hypothermic (<36°C) patients: 47.3% mortality

💡 Interpretation: Hypothermia in sepsis correlates with increased ICU-acquired infections, delayed diagnosis, and poor prognosis.

📌 Temperature Trajectories in Sepsis:

1️⃣ Rapid-resolution hyperthermia (best survival 📉)

2️⃣ Slow-resolution hyperthermia (worse outcomes ❗)

3️⃣ Normothermia

4️⃣ Hypothermia (highest mortality ❄️⚰️)

💡 Another intriguing finding: Fever patterns may predict hospital-acquired sepsis! 📊 Subtle temperature fluctuations before fever onset might be an early warning sign of impending infection. 🚨

🔥 To Treat or Not to Treat Fever in Sepsis? 🔥

4️⃣ How Do We Control Fever in Sepsis? And Should We?

🌡️ Fever control in ICU is inconsistent—some intensivists aggressively lower fever, while others allow it to run its course. But what does the evidence say? 📊

4.1 Means to Targeted Temperature Management (TTM) 🎯

4.1.1 Paracetamol (Acetaminophen) 💊

✔️ Mechanism: Lowers the hypothalamic set point, reducing fever.

✔️ Well-tolerated, but risk of hepatic injury at high doses.

📌 The HEAT Trial (700 septic patients, paracetamol vs. placebo):

❌ No reduction in ICU length of stay or mortality (RR 0.96, p=0.84).

⚠️ Limitations: Fever duration was short, and temperature differences were marginal.

💡 Bottom Line: While safe, paracetamol does not improve sepsis outcomes.

4.1.2 NSAIDs (Ibuprofen, Lornoxicam) 🩸

✔️ Mechanism: Inhibits prostaglandin synthesis (PGE2), reducing fever.

⚠️ Risks: Gastrointestinal bleeding, renal toxicity, worsened infection.

📌 Key Trials:

• Haupt et al. (29 patients, ibuprofen vs. placebo): No mortality benefit.

• Bernard et al. (455 septic patients):Ibuprofen reduced fever, tachycardia, lactate, and oxygen demand, but...❌ No survival advantage.

• Memiş et al. (40 patients, lornoxicam vs. placebo): No outcome differences.

💡 Bottom Line: NSAIDs control fever but do NOT improve survival.

4.1.3 External Cooling ❄️

✔️ Methods: Ice packs, air blankets, endovascular cooling.

⚠️ Risks: Shivering, discomfort, increased oxygen demand.

📌 Schortgen et al. Trial (200 septic shock patients, external cooling vs. control):

✅ Day 14 mortality was lower (19% vs. 34%, p=0.013).

❌ No mortality difference at day 30.

💡 Bottom Line: External cooling may have short-term benefits, but long-term survival remains unchanged.

4.2 Should We Control Hyperthermia? 🤔

🌡️ Fever is a natural response, but should we suppress it?

📌 Key Findings from Meta-Analyses:

🔹 Antipyretic therapy (drugs & cooling) does NOT improve 28-day survival (RR 0.93, 95% CI 0.77–1.13).

🔹 Patients mechanically ventilated with vasopressor support had worse outcomes with aggressive temperature control.

🚨 Extreme hyperthermia (>39.4°C) may be harmful, but there’s no clear survival benefit to aggressive fever control.

💡 Current ICU Practice:

• Treat T > 39.5°C with paracetamol 🩺.

• Use external cooling if needed, but avoid shivering! ❄️

4.3 Should We Warm Hypothermia? ❄️🔥

💀 Hypothermia (<36°C) is linked to HIGH mortality in sepsis.

✅ Hypothesis: Warming may improve perfusion, antibiotic effectiveness, and immune response.

📌 Key Studies:

• Delphi survey: Most intensivists rewarm hypothermic septic patients.

• Drewry et al. (Therapeutic hyperthermia trial):Warming afebrile septic patients to 39°C improved survival 🚀.But baseline characteristics were imbalanced, limiting conclusions.

• Ongoing Pilot Study (NCT04961151): Testing whether warming sepsis patients to 39°C improves outcomes.

💡 Bottom Line: Warming could help, but we need stronger evidence!

4.4 What Should the Bedside Doctor Do? 🏥

✅ Normothermia? No clear temperature target.

✅ Hyperthermia (>39.5°C)?

• Paracetamol recommended.

• External cooling if needed (<38.2°C target).

• Avoid shivering (sedation or neuromuscular blockade).

✅ Hypothermia?

• Gradual rewarming recommended to prevent vasoplegia.

💡 Key Takeaway: Manage extreme temperatures, but avoid unnecessary interventions.

5️⃣ Conclusion

🌡️ Fever is a carefully regulated response with both protective and harmful effects.

📊 Meta-analyses consistently show NO mortality benefit from fever control.

⚠️ Hypothermia is consistently linked to worse outcomes.

🚑 Future Research: Should we actively warm septic patients? 🤔

💡 Final Takeaway: Extreme hyperthermia (>39.5°C) and hypothermia (<36°C) should be treated, but routine fever suppression is not justified.

Reference 📖

🔗Doman M, Thy M, Dessajan J, Dlela M, Do Rego H, Cariou E, Ejzenberg M, Bouadma L, de Montmollin E, Timsit J-F. Temperature control in sepsis. Front Med. 2023;10:1292468. doi: 10.3389/fmed.2023.1292468.

💬 Discussion Time!

❓ What’s your stance on fever control in sepsis? Do you treat aggressively or let it ride? Let’s discuss! 👇🔥

📢 Tag a fellow intensivist or ICU trainee who needs to see this! 🚑💉