Immune system

Immune system = detection → response → regulation → resolution

Detection

• Pattern Recognition Receptors (PRRs) detect pathogen fragments & cell injury signals)

• Toll-like receptors (TLR-4 for LPS) ignite the cytokine cascade.

First immune error in sepsis = dysregulated recognition → cytokine storm amplification.

Response

Innate immune system (seconds → minutes)

• neutrophils, macrophages, NK cells

• Complement system punches holes in bacteria

• Mechanisms: phagocytosis, cytokine release (TNF-α, IL-1, IL-6), & oxidative burst → ROS

Innate response causes early vasodilation + capillary leak.

Antigen presentation: bridging innate → adaptive

• Dendritic cells/macrophages present antigen via MHC II -> activates T helper cells

This step decides escalation vs tolerance.

Adaptive response

• T cells

  • • CD4 helper → cytokine coordination

    • CD8 cytotoxic → kill infected host cells

• B cells

  • • become plasma cells → produce antibodies

    • opsonization + neutralization

Adaptive response is slower but targeted and has memory.

Regulation/brakes on inflammation

Anti-inflammatory cytokines:

• IL-10

• TGF-β

Regulatory T cells suppress overreaction.

Failure to apply brakes → systemic inflammation → sepsis physiology.

Resolution

• remove pathogens

• clear debris

• tissue repair

• return to immune homeostasis

Persistent inflammation + immunosuppression coexist late in sepsis → secondary infections.

Immunity isn’t “strong vs weak”; it is balanced vs dysregulated.

Dysregulation patterns in sepsis:

1. Hyperinflammation: cytokine storm; vasoplegia

2. Immunoparalysis: lymphocyte apoptosis; susceptibility to fungal/secondary bacterial infections

3. Metabolic collapse: mitochondrial dysfunction; VO₂ failure

dysfunction at bedside

• rising lactate despite MAP fix → microcirculation failure

• NE escalating → NO vasoplegia

• recurrent infection in ICU → immunosuppression phase

The immune system detects danger, mounts an innate response, activates adaptive defenses, and applies brakes; in sepsis, these control loops fail, leading first to cytokine-driven vasoplegia and later to exhaustion and immunosuppression.

Steroid 

Steroid role = immune brake + receptor reset + vascular responsiveness

1. Cytokine suppression: Less cytokine signal → less iNOS activation → ↓ NO generation.

  => That’s the first brake point.

Restore vascular adrenergic responsiveness:  In sepsis, NO + cytokines causes α₁ receptor desensitisation-> impaired catecholamine response. Steroids causes

• up-regulate adrenergic receptors

• improve vasoconstrictor sensitivity

This is why the vasopressor dose drops after the steroid.

NO fate when steroids are given -> Inflammation ↓ through

→ cytokine transcription ↓

→ iNOS gene expression ↓

→ NO production ↓

→ SVR increases

→ vasoplegia improves

→ microvascular tone partially restored

→ DO₂–VO₂ coupling improves

→ lactate generation slows

After starting steroids in refractory septic shock:

• pressor requirement falls within hours

• Lactate clears faster if perfusion improves

• EF may improve as NO-mediated myocardial stunning eases

Steroids simply apply the brakes where inflammation, NO, and vasoplegia are spiralling. But steroids don’t kill microbes or rebuild glycocalyx. Thus, steroids reduce cytokine-driven iNOS induction, blunt excess nitric oxide production, restore adrenergic receptor responsiveness, and thereby tighten vascular tone—functioning as a physiologic brake in vasoplegic septic shock.

Dose: 

• Hydrocortisone 200mg/day

• ≥5 days = taper gradually (drop dose by 50 mg/day) while watching MAP and lactate. => Goal isn’t finishing steroids; goal is avoiding rebound vasoplegia.

• You can start taper when ALL are true:

  • • • off vasopressors ≥12–24 h

      • Lactate trending down

      • MAP stable without escalating fluid/pressor

      • infection controlled/improving

• Warning signs to pause taper

  • • • MAP drifting down

      • NE restarted

      • Lactate plateaus or rises

      • worsening shock physiology

• If hydrocortisone <5 days

  • • • adrenal suppression unlikely

      • No taper needed

      • just stop when shock resolves (pressor-free and MAP stable)

Use Steroid

• MAP <65 despite adequate fluid resuscitation

• vasopressors started and dose climbing

• lactate stagnant or rising → ongoing dysoxia

• Suspicion of adrenal stress insufficiency

Sepsis without shock → no routine steroids

Septic shock → steroids act as the brake

• Useful because they blunt cytokines → ↓iNOS → ↓NO → restore vascular responsiveness → reduce NE requirements.

• Steroids don’t treat sepsis. They treat the host response failure:

  • • • excessive inflammation

      • NO-mediated vasoplegia

      • adrenergic resistance

When are steroids not useful?

• uncomplicated sepsis

• early infection without shock

• mild hypotension responding to fluids

• used “just in case”

In those, steroids increase:

• • • • secondary infection risk

      • hyperglycemia

      • muscle wasting and delirium

When are they useful?

• Patient has septic shock

• fluids + vasopressors are insufficient

• Ongoing vasoplegia / rising NE dose

Because in that phase: cytokines + iNOS → excess NO → vasoplegia

Adrenergic receptors are desensitised

steroids restore tone + receptor sensitivity

Methylene blue

Methylene blue reverses NO-mediated vasodilation.

• inhibits inducible nitric oxide synthase (iNOS) → ↓ NO production

• Normally: NO → ↑ cGMP → smooth muscle relaxation. MB blocks this → ↓ cGMP → vasoconstriction restored

Use only in refractory vasoplegic shock after:

1. adequate fluids

2. NE

3. vasopressin

4. steroids

Then consider methylene blue. Typical bolus: 1–2 mg/kg IV over 20–60 min

Cautions

• Avoid in G6PD deficiency

• Interacts with serotonergic drugs → serotonin syndrome risk

• Pulse oximetry is unreliable during infusion

• can worsen pulmonary vasoconstriction if RV dysfunction is predominant

Methylene blue blocks NO-mediated vasodilation by inhibiting iNOS and guanylate cyclase, restoring vascular tone in refractory septic vasoplegia when catecholamines and vasopressin fail.

Methylene blue is not routine in ICU septic shock management. It’s a rescue therapy. Because the Evidence is limited, narrow indication, and safety caveats. It’s reserved for refractory vasoplegic shock when conventional fluids, pressors, and steroids fail.