Fever and Its Types

Definition

Body Temperature Reference Ranges

Pathophysiology (How Fever Develops)

1. Trigger: Bacteria, viruses, tissue breakdown products, or other stimuli activate immune cells (macrophages, leukocytes).
2. Pyrogen release: These cells release cytokines, especially Interleukin-1 (IL-1) (also called endogenous pyrogen / leukocyte pyrogen), as well as TNF and IL-6.
3. Hypothalamic reset: IL-1 reaches the anterior hypothalamus and stimulates local synthesis of prostaglandin E2 (PGE2), which raises the hypothalamic set-point temperature.
4. Heat generation: The body activates heat-conserving and heat-generating mechanisms (vasoconstriction, shivering, piloerection = "chills") until body temperature reaches the new set point.
5. Defervescence: When the cause is removed or antipyretics (e.g., aspirin, NSAIDs - which inhibit cyclooxygenase and block PGE2 synthesis) are given, the set point falls - vasodilation and sweating occur to dissipate excess heat.

Classification by Temperature Degree

Classification by Pattern (Most Clinically Important)

1. Continuous (Sustained) Fever

• Temperature remains persistently elevated above normal throughout the day.
• Daily variation is < 1°C and the temperature does not touch normal.
• Examples: Lobar pneumonia (classical - "crisis" on day 7-10), typhoid fever (step-ladder rise then sustained), urinary tract infection, infective endocarditis.

2. Remittent Fever

• Temperature remains above normal throughout the day but fluctuates with a daily variation > 1°C.
• Temperature does not return to normal (unlike intermittent fever).
• Most common fever pattern.
• Examples: Typhoid (during active illness), bacterial pneumonia, infective endocarditis, most bacterial infections, brucellosis.

3. Intermittent Fever

• Temperature is elevated for some hours and then returns to normal (touch normal or subnormal) every day or on alternate days.
• The periodic pattern is highly diagnostically important.

Sub-types:

"Plasmodium vivax causes fever every third day, whereas fever occurs every fourth day with Plasmodium malariae."

4. Hectic (Septic) Fever

• An exaggerated form of intermittent fever with a very wide swing (> 2-3°C between peak and trough).
• Associated with drenching sweats when the temperature drops.
• Implies bacteremia or septicemia.
• Examples: Pyemia, septicemia, liver abscess, deep-seated abscesses, infective endocarditis.

5. Relapsing Fever

• Febrile episodes lasting days to weeks, separated by afebrile periods of days to weeks, then relapsing.

Key examples:

"In the Pel-Ebstein pattern, fever lasting 3-10 days is followed by afebrile periods of 3-10 days; this pattern can be classic for Hodgkin disease and other lymphomas."

6. Periodic (Recurrent) Fever Syndromes

• Febrile episodes at predictable intervals caused by autoinflammatory diseases (not infection).
• Examples:
  • Familial Mediterranean Fever (FMF): Recurrent fever + serositis (peritonitis, pleuritis)
  • TRAPS (TNF receptor-associated periodic syndrome): Prolonged fever episodes
  • Hyper-IgD syndrome: Periodic fever + lymphadenopathy
  • PFAPA (Periodic Fever, Aphthous stomatitis, Pharyngitis, Adenitis): Seen in children

7. Biphasic (Saddle-back) Fever

• Two separate waves of fever with an afebrile gap of 1-2 days in between.
• Examples: Dengue fever (classic), poliomyelitis, yellow fever, leptospirosis, Colorado tick fever.

8. Inverse Fever (Reversed Diurnal Pattern)

• Normal physiological fever is higher in the evenings. Inverse fever is higher in the mornings (reversed pattern).
• Example: Disseminated tuberculosis (miliary TB), typhoid in some stages.

Summary Table

Important Special Categories

Fever of Unknown Origin (FUO)

1. Infectious diseases
2. Autoimmune / non-infectious inflammatory disorders
3. Cancer (especially lymphomas, leukemia, renal cell carcinoma)

Temperature-Pulse Dissociation (Relative Bradycardia)

• Typhoid fever, brucellosis, leptospirosis, drug-induced fever, factitious fever

• Harrison's Principles of Internal Medicine 22E (2025), Chapters 14 & 208
• Guyton and Hall Textbook of Medical Physiology, Chapter 74
• Costanzo Physiology 7th Edition, Chapter on Temperature Regulation

Pain - Definition, Pathophysiology, and Types

Definition

"An unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage."

Pathophysiology - The Nociceptive Process (4 Steps)

1. Transduction

• A noxious stimulus (thermal, mechanical, or chemical) is converted into an electrical signal at free nerve endings called nociceptors.
• Nociceptors are distributed in skin, muscle, fascia, joints, blood vessel walls, dura, and viscera.
• Tissue injury releases sensitizing chemicals: histamine, serotonin, bradykinin, substance P, prostaglandins, cytokines, and glutamate.

2. Transmission

• The electrical signal travels via primary afferent nerve fibers toward the CNS:

• Aδ and C fibers are the nociceptors - they respond to high-threshold noxious stimuli.
• Signal travels to the dorsal horn of the spinal cord, then via the spinothalamic tract (anterolateral) to the thalamus and cortex.

3. Modulation

• Occurs primarily in the dorsal horn of the spinal cord (substantia gelatinosa).
• Ascending modulation: Wide dynamic range neurons (WDRNs) in the dorsal horn receive and integrate pain signals.
• Descending inhibition: From the periaqueductal gray (PAG), locus ceruleus, nucleus raphe magnus via the dorsolateral funiculus - using serotonin and norepinephrine.
• This system is activated by opioids, stress, placebo, acupuncture, and TENS.

4. Perception

• The final step - occurs when the signal reaches the cerebral cortex.
• This is where the subjective, emotional, and cognitive experience of pain is formed.
• Highly variable between individuals - influenced by psychology, past experience, context, and culture.

Spinal Cord Pain Tracts

Classification of Pain

A. By Duration

B. By Mechanism (IASP Classification - Most Clinically Important)

1. Nociceptive Pain

• The most common type.
• Results from injury or disease affecting somatic structures - activation of normal nociceptors by a genuine stimulus.
• Subdivided into:

• Injury to skin, muscles, bones, joints.
• Well-localized, sharp initially then throbbing/aching.
• Worsened by movements that stress the injured structure (e.g., walking worsens arthritic knee pain).
• Examples: Arthritis, fracture, myofascial pain, postoperative wound pain, connective tissue disorders.

• Originates from internal organs (hollow viscera, capsules, mesentery).
• Characteristics differ from somatic pain:
  • Poorly localized (fewer nociceptors, wide spinal cord convergence)
  • Starts as burning/throbbing, associated with autonomic activation (nausea, vomiting, sweating)
  • Often accompanied by referred pain to somatic areas
  • Notable: viscera can be cut or burned without pain - but distension or traction causes severe pain
• Examples: Angina pectoris (ischemia → left arm/jaw pain), renal colic, appendicitis (periumbilical → RLQ), pancreatitis (epigastric → back), endometriosis.

"Periumbilical pain is often associated with appendicitis - visceral afferents travel through the celiac ganglia entering at T10, sensitizing dorsal horn at T10 → pain perceived in T10 dermatome (periumbilical)." - ROSEN's Emergency Medicine, p. 93

2. Neuropathic Pain

• Caused by a lesion or disease affecting the somatosensory system (peripheral or central nervous system).
• Accounts for 15-25% of chronic pain.
• Characterized by:
  • Positive symptoms (abnormal nervous system excitability): allodynia, hyperalgesia, hyperpathia, paresthesias
  • Negative symptoms (loss of neurons): sensory loss, numbness
  • Descriptors: "shooting," "electrical," "burning," "stabbing" in a dermatomal or nerve distribution

• Allodynia: Pain from a normally non-painful stimulus (e.g., light touch)
• Hyperalgesia: Exaggerated pain response to a noxious stimulus
• Hyperpathia: Abnormally painful reaction, especially to repeated stimuli

3. Nociplastic Pain (formerly "Central Sensitization Pain")

• Arises from altered nociception without clear tissue damage, and without somatosensory system lesion.
• No biomarkers; no demonstrable structural cause.
• Typically diffuse, widespread symptoms.
• Often coexists with: fatigue, insomnia, cognitive difficulties ("brain fog"), sensitivity to light/sound, multiple chemical sensitivities.
• Examples: Fibromyalgia, irritable bowel syndrome (IBS), tension-type headache, complex regional pain syndrome type I (CRPS-I), chronic widespread pain.

4. Mixed Pain

• More than one pain mechanism operating simultaneously.
• Examples: Cancer pain (nociceptive + neuropathic), IBS (nociplastic + visceral nociceptive), headache (tension + migraine components).

C. By Anatomic Region (Selected Examples)

Referred Pain (Special Concept)

• Viscerosomatic convergence: Spinal cord neurons receive input from both visceral AND somatic sources simultaneously, so the brain misinterprets the origin of the pain.
• Visceral pain is perceived as coming from a somatic (body surface) area.

Central Sensitization

• Dorsal horn neurons show wind-up (progressive amplification with repeated stimuli)
• The NMDA receptor plays a key role
• Results in allodynia and hyperalgesia extending beyond the original injury site
• Underlies the transition from acute to chronic pain and is central to nociplastic conditions

Pain Assessment

• Visual Analogue Scale (VAS) / Numeric Rating Scale (NRS): 0-10
  • Mild: 1-3, Moderate: 4-7, Severe: > 7
• A 30% or greater reduction in pain score = clinically meaningful improvement
• For non-communicating patients: facial expression scales, behavioral scales
• Always assess: location, quality, timing, aggravating/relieving factors, associated symptoms, functional impact, psychological status

Quick Reference Summary

• Goldman-Cecil Medicine International Edition, Chapter 26 (Pain: Neuropathic, Nociceptive, Nociplastic and Mixed), p. 269-270
• Sabiston Textbook of Surgery, Chapter 20 (Mechanisms of Acute Pain), p. 352-353
• Barash Clinical Anesthesia 9e, Chapter 56 (Primary Afferents), p. 4736
• ROSEN's Emergency Medicine, Chapter 6 (Pain Transmission and Modulation), p. 92-93
• Murray & Nadel's Textbook of Respiratory Medicine, Chapter 38 (Neurobiology of Pain), p. 886

What Was Covered

Definition

Pathophysiology - 4 Steps of Nociception

1. Transduction - Noxious stimulus → electrical signal at nociceptors
2. Transmission - Via Aδ fibers (sharp/fast "first pain") and C fibers (burning/slow "second pain") → spinal cord → thalamus → cortex
3. Modulation - In the dorsal horn; descending inhibition from PAG, locus ceruleus
4. Perception - Subjective conscious experience in the cortex

Types by Duration

• Acute - Protective, resolves with healing
• Chronic - > 3 months, considered a disease itself

Types by Mechanism (IASP)

Special Concepts

• Referred pain - Visceral pain perceived at somatic surface (e.g., heart → left arm)
• Allodynia - Pain from normally non-painful stimulus
• Hyperalgesia - Exaggerated pain to a noxious stimulus
• Central sensitization - CNS hypersensitivity; drives transition to chronic pain

• Pain management / analgesic ladder
• Specific pain syndromes (migraine, neuropathic, cancer pain)
• Gate control theory
• Pain assessment tools
• Pharmacology of analgesics

Types of Pain in Surgery

I. Classification by Duration (Fundamental Surgical Distinction)

1. Acute Pain

• Pain expected to be of relatively short duration, resolving with tissue healing or withdrawal of the noxious stimulus.
• Resolves within minutes, hours, or days.
• Associated with autonomic activation: tachycardia, hypertension, tachypnea, diaphoresis.
• Has a protective/survival function - alerts to tissue injury.
• Undertreated acute pain leads to harmful pathophysiologic consequences (splinting, atelectasis, immobility, DVT, delayed recovery).
• Examples: Appendicitis pain, fracture pain, acute postoperative wound pain.

2. Chronic Pain (Persistent Surgical Pain)

• Pain persisting > 3 months beyond the expected healing period.
• Serves no useful biological function - recognized as a disease in itself.
• NOT associated with autonomic signs at rest.
• Results from peripheral sensitization, central sensitization, or nerve injury.
• Examples: Post-herniorrhaphy inguinodynia, post-mastectomy pain syndrome, phantom limb pain, failed back syndrome, chronic post-surgical pain (CPSP).

"Chronic pain serves no useful function and is now recognized as a disease itself." - Sabiston Textbook of Surgery, p. 353

II. Classification by Mechanism (Core Surgical Types)

1. Nociceptive (Somatic) Pain

• Most common type in surgery.
• Results from direct tissue injury activating nociceptors in skin, muscle, bone, fascia, and connective tissue.
• The surgical incision, dissection, and repair all cause this type.
• Quality: Initially sharp, well-localized; becomes aching/throbbing.
• Worsened by movement or stress on the anatomical structure (e.g., coughing after laparotomy, walking after hernia repair).
• Treatment: NSAIDs, paracetamol, opioids (responds well to standard analgesia).
• Examples:
  • Postoperative wound pain
  • Fracture pain
  • Musculoskeletal trauma
  • Bone metastases
  • Ligamentous/muscular injury after hernia repair

"Acute postoperative pain is generally somatic, rather than visceral or neuropathic. Tissue injury leading to somatic pain activates nociceptors activated in response to physical, chemical, or heat damage." - Fischer's Mastery of Surgery 8e, p. 481

2. Visceral Pain

• Originates from internal organs (hollow viscera, solid organ capsules, mesentery, peritoneum).
• Transmitted via autonomic (sympathetic) afferents.
• Characteristics:
  • Poorly localized, diffuse, cramping/colicky or dull/burning
  • Associated with significant autonomic features: nausea, vomiting, sweating, pallor
  • Commonly referred to somatic surface areas
  • Viscera are insensitive to cutting/burning - pain is caused by distension, traction, ischemia, or chemical irritation
• Examples:
  • Intestinal obstruction (colicky, periumbilical)
  • Biliary colic (RUQ → right shoulder)
  • Ureteric colic (loin → groin)
  • Acute appendicitis - initial periumbilical visceral pain
  • Mesenteric ischemia
  • Post-laparoscopic shoulder-tip pain (diaphragmatic irritation from CO₂)

"Visceral pain refers to pain conveyed through afferent autonomic pain fibers. It is usually poorly localized." - Schwartz's Principles of Surgery 11e, p. 1647

3. Neuropathic Pain

• Caused by direct nerve injury, entrapment, or damage during surgery or disease.
• May appear early (immediately) or late (weeks to months post-op).
• Quality: Shooting, electrical, burning, stabbing - in a nerve or dermatomal distribution.
• Features: Allodynia (pain from light touch), hyperalgesia, paresthesias, numbness.
• Treatment: Gabapentinoids (pregabalin, gabapentin), tricyclic antidepressants, SNRIs, local nerve blocks, neurectomy for refractory cases. Responds poorly to simple NSAIDs/opioids.
• Surgical examples:
  • Ilioinguinal/iliohypogastric nerve injury after inguinal hernia repair → inguinodynia
  • Intercostal nerve injury after thoracotomy → post-thoracotomy pain syndrome
  • Nerve injury after mastectomy → post-mastectomy pain syndrome
  • Phantom limb pain (after amputation)
  • Meralgia paresthetica (lateral femoral cutaneous nerve injury)
  • Post-amputation stump neuroma pain

4. Mixed Pain

• Two or more mechanisms operating simultaneously - very common in surgical oncology.
• Example: Cancer pain = nociceptive (bone/soft tissue invasion) + neuropathic (nerve compression/infiltration) + visceral (organ involvement).
• Breakthrough pain: Acute, excruciating pain superimposed on stable background cancer pain - spontaneous or triggered.

III. Specific Surgical Pain Syndromes

A. Inflammatory Pain

• Caused by tissue trauma and the release of inflammatory mediators (prostaglandins, bradykinin, histamine, substance P).
• Primary hyperalgesia: Increased sensitivity at the injury site.
• Secondary hyperalgesia: Sensitization of surrounding uninjured tissue (via central sensitization).
• Underpins the rationale for pre-emptive analgesia and multimodal analgesia.

B. Ischemic Pain / Rest Pain

• Due to tissue ischemia in peripheral vascular disease.
• Claudication: Cramping pain in muscles during walking that is relieved by rest - reproducible at a similar effort level.
• Rest pain: Constant severe pain at rest (usually in foot/toes), worsened by leg elevation, relieved by dependency - indicates critical limb ischemia (Fontaine stage III).

C. Phantom Limb Pain

• Pain perceived in a limb that has been amputated.
• Caused by neuromas (disorganized axon masses at the stump) disrupting the neural efferent-afferent loop.
• Up to 85% of amputees experience phantom pain.
• Modern treatment: Targeted Muscle Reinnervation (TMR) and Regenerative Peripheral Nerve Interface (RPNI) - surgical techniques that provide trophic targets for amputated nerves, reducing neuroma formation.

D. Cancer Pain in Surgery (WHO Analgesic Ladder)

• Oral morphine: given 4-hourly, then converted to slow-release MST every 12 hours once dose is titrated.
• Breakthrough pain: Covered with short-acting opioids (morphine/fentanyl).

IV. Chronic Post-Surgical Pain (CPSP) - Major Surgical Concern

V. Summary Table

• Sabiston Textbook of Surgery, Chapter 20 (Acute Pain Management), p. 352-353
• Fischer's Mastery of Surgery 8e, Postoperative Pain Management, p. 481
• Schwartz's Principles of Surgery 11e, Chapter on Hernia, p. 1647
• Bailey and Love's Short Practice of Surgery 28e, Cancer Pain, p. 4944
• Goldman-Cecil Medicine, Chapter 26 (Pain Classification), p. 269-270