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Shivering During Dialysis Without Temperature Increase
Overview
Shivering (rigors) during hemodialysis in the absence of fever is a well-recognized intradialytic complication. It is physiologically distinct from the pyrogenic shivering seen in infection. Understanding why it happens requires separating two mechanisms: thermoregulatory shivering (cold-driven) and non-pyrogenic rigor (immune/inflammatory, but without a reset of the hypothalamic setpoint).
Pathophysiology
1. Thermoregulatory (Cold-Induced) Shivering - the Most Common Cause
The core mechanism:
During hemodialysis, blood is circulated outside the body through the extracorporeal circuit and dialyzer membrane. This process causes significant heat loss from the blood, leading to a drop in core body temperature. Normally, patients on standard hemodialysis lose 0.3-0.5°C in core temperature over a session, though some patients - particularly those who start with a lower baseline - lose more.
Hypothalamic shivering pathway (Guyton & Hall, Medical Physiology):
- The body's thermostat is the anterior hypothalamic-preoptic area, which sets the target temperature (~37°C)
- When blood temperature falls below this setpoint, signals reach the primary motor center for shivering in the dorsomedial portion of the posterior hypothalamus (near the 3rd ventricle wall)
- This center, normally inhibited by the heat center, becomes activated by cold signals from skin and spinal cord
- It transmits signals bilaterally down the brainstem → lateral columns of the spinal cord → anterior motor neurons
- These signals increase skeletal muscle tone throughout the body; when tone exceeds a critical threshold, shivering begins via feedback oscillation of the muscle spindle stretch reflex
- During maximum shivering, heat production can rise 4-5 times above normal
Why no fever? The hypothalamic setpoint is NOT raised (no pyrogens involved) - the body is simply responding to a genuine fall in core temperature. The shivering is a normal thermoregulatory response attempting to restore temperature to the existing setpoint, not an attempt to reach a higher one.
Contributing factors to dialysis heat loss:
- Dialysate temperature typically set at 35-37°C, which is below or near core body temperature - heat transfers from blood to dialysate
- Large blood flow rates (300-450 mL/min) amplify heat loss
- High ultrafiltration rates
- Cool room temperature
- Inadequate clothing/blankets
2. Non-Pyrogenic Immune-Mediated Rigors (No Fever Despite Inflammation)
This occurs through complement activation triggered by the dialyzer membrane, particularly with:
- Bioincompatible membranes (older cuprophane/cellulose membranes more than modern synthetic high-flux membranes)
- Endotoxin contamination of dialysate (even at low, non-pyrogenic levels - "subpyrogenic" endotoxemia)
- Dialyzer reuse reactions
- Air exposure of blood in the circuit
Mechanism:
- Blood contact with the foreign dialysis membrane activates the alternative complement pathway - releasing C3a and C5a (anaphylatoxins)
- C5a in particular causes degranulation of mast cells and basophils, releasing histamine and other mediators
- This triggers rigors and chills through direct effects on thermoregulatory centers and peripheral sensory nerves
- Importantly, the level of endotoxin/complement activation may be below the threshold needed to reset the hypothalamic setpoint (i.e., below the threshold for true fever) yet still sufficient to provoke shivering
- This is a Type B (minor) dialysis reaction - part of the broader anaphylactoid spectrum
The distinction from sepsis: in true sepsis, pyrogens (IL-1β, TNF-α, IL-6, prostaglandin E2) reset the hypothalamic thermostat upward, causing shivering as the body "races" toward the new, higher setpoint - and fever follows. In non-pyrogenic complement-mediated rigors, the cytokine release is insufficient or too localized to globally reset the setpoint.
3. Other Causes of Shivering Without Fever During Dialysis
| Cause | Mechanism |
|---|---|
| Rapid ultrafiltration | Hypovolemia → peripheral vasoconstriction + sympathetic surge → cold sensation + shivering |
| Dialysate with low Ca²⁺ or Mg²⁺ | Electrolyte shifts affect muscle membrane excitability |
| Anxiety/autonomic response | Adrenergic surge mimics cold response |
| Drug reactions (heparin, iron infusion) | Mast cell degranulation without systemic pyrogenesis |
| Hypoglycemia | Counter-regulatory catecholamine release triggers shivering |
| Iatrogenic hypothermia | Cold IV fluid, cold room, inadequate insulation |
Clinical Distinction: Shivering Without Fever vs. Shivering WITH Fever
| Feature | Shivering WITHOUT fever | Shivering WITH fever |
|---|---|---|
| Hypothalamic setpoint | Normal (not reset) | Elevated by pyrogens |
| Mechanism | Thermoregulatory or sub-pyrogenic immune | Pyrogenic cytokines (IL-1, TNF, PGE₂) |
| Temperature after shivering | Returns to normal or stays normal | Rises (fever ensues) |
| Common dialysis causes | Heat loss, membrane reaction | Bacteremia, endotoxemia, access infection |
| Clinical concern | Usually benign, correctable | Must rule out sepsis, access infection |
Treatment
Immediate / Symptomatic
- Warming measures - blankets, raising dialysate temperature to 37°C (or even 37.5°C temporarily), warming room, warm IV saline if rehydrating
- Reduce blood flow rate temporarily to decrease extracorporeal heat loss
- Reduce ultrafiltration rate if contributing to hypovolemia
Pharmacological - for Rigors Unresponsive to Warming
Meperidine (Pethidine) - historically the first-line pharmacological agent:
- Mechanism: binds μ and κ opioid receptors → lowers the shivering threshold in the hypothalamus
- Dose: 25-50 mg IV
- Caution in dialysis patients: its active metabolite normeperidine accumulates in renal failure (not well dialyzed), causing neurotoxicity - anxiety, tremors, myoclonus, and seizures. The ISMP (2007) called for avoidance in patients with renal insufficiency. If used, use the lowest effective dose for a single episode only.
Morphine - an emerging alternative to meperidine:
- Also lowers shivering threshold via μ-opioid receptor
- Less problematic metabolite accumulation than meperidine in renal failure (though morphine-6-glucuronide does accumulate - use cautiously)
- Recent evidence supports morphine for infusion-related rigors as a safer alternative
Buspirone (5-HT1A agonist):
- Lowers shivering threshold via serotonergic pathways
- Oral only - useful for prophylaxis rather than acute treatment
- Combination buspirone + meperidine has synergistic effect on shivering threshold
- May increase seizure risk in renal impairment when combined with meperidine
Dexmedetomidine (α₂ agonist):
- Reduces shivering threshold through central α₂ receptor activation
- Used mainly in ICU/post-anesthetic shivering protocols; less practical in routine dialysis
Tramadol (weak μ-agonist + serotonin/norepinephrine reuptake inhibitor):
- Used in some centers as an alternative; also has metabolite accumulation concerns in renal failure
Ondansetron (5-HT3 antagonist):
- Some evidence for reducing shivering in post-anesthetic context; occasionally used in dialysis reactions
- Generally well tolerated in renal patients
Preventive / Long-Term Measures
- Individualized dialysate temperature - lower temperature (35-36°C) paradoxically improves hemodynamic stability and is better tolerated without causing shivering in most patients; some patients who shiver need warming to 37°C
- Switch to biocompatible membrane (synthetic high-flux polysulfone) if complement-mediated reaction suspected
- Check dialysate water quality - bacterial and endotoxin testing; ensure endotoxin < 0.1 EU/mL in water, < 0.03 EU/mL for ultrapure dialysate
- Treat access infections if bacteremia is a contributing factor
- Warm clothing and blankets during sessions routinely
- Avoid pre-dialysis administration of vasodilators/antihypertensives that impair thermoregulatory vasoconstriction
Summary
Shivering during dialysis without fever is primarily driven by genuine thermoregulatory response to extracorporeal heat loss (hypothalamic cold response without setpoint change) and/or sub-pyrogenic complement/immune activation from membrane-blood contact. Unlike febrile rigors, no pyrogens reset the hypothalamic thermostat - the shivering is the body generating heat in response to a real or perceived temperature drop. Treatment centers on warming + addressing the cause, with pharmacological options (meperidine, morphine) targeting the shivering threshold at the hypothalamic level - though meperidine must be used with extreme caution in dialysis patients due to normeperidine accumulation.
Sources: Guyton & Hall Textbook of Medical Physiology (9780443111013); Rosen's Emergency Medicine (9780323757898); van der Sande et al., CJASN 2009 - PMID 18842948 (dialysate temperature and hemodynamic stability); Lucas et al., J Hematol Oncol Pharm 2024 - morphine for rigors
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