Septic shock

Sepsis starts as a utilisation problem -> Ends as a flow problem

Sepsis begins as a problem of oxygen utilisation -> progresses to a problem of delivery -> and ends as a problem of cellular survival

MAP is just a gatekeeper, not the destination

• Early sepsis → High flow, low resistance, failed extraction

• Progressing sepsis → Flow maintained, extraction strained

• Late sepsis → Low flow, high resistance, maximal extraction

• Refractory shock → Flow + extraction both fail

MICROPERFUSION OVERRIDES EVERYTHING

If macro looks fine but the patient looks bad → believe the patient.

Use:

1. Capillary refill time

2. Mottling score (knee window)

3. Temperature gradient

4. Urine output

5. Mental status

6. Lactate trend, not number

Open pressure → restore flow → correct content → trust microperfusion

3-stage septic shock model: (based on what is failing; utilisation -> flow -> metabolism)

Through the mitochondrial frame, the stages are: Mitochondrial hibernation (high ScvO2) -> Cardiomyopathy (flow fail, low ScvO2) -> Mitochondrial damage (again high ScvO2) 

=> Sepsis begins as a utilisation disorder, becomes a flow disorder, and ends as a metabolic failure.

Basically, map ScvO₂ + CO + lactate exactly to these 3 stages

1. Early sepsis (warm shock) - Utilisation disorder/Mitochondrial hibernation/extraction failure.

In early sepsis, lactate elevation is not because tissues are hypoxic. Oxygen delivery is usually adequate or high. The problem is that oxygen reaches the tissue, but is not used properly. 

This is NOT hypoxia initially. This is adaptive metabolic throttling. 

Mechanisms: Microcirculatory shunting, Nitric oxide dysregulation, & Mitochondrial “down-regulation” (adaptive hibernation)

Here, 1. Flow looks fine, 2. BP may be fine, 3. SpO₂ is fine, and yet 4. lactate rises => Pressors don’t fix this. Inotropes don’t fix this, but Time, source control, antibiotics, and VO₂ reduction matter most

High flow + Low resistance + Failed extraction + Rising lactate

• CO ↑ / normal

• SVR ↓↓↓ (vasoplegia)

• ScvO₂ ↑ or inappropriately normal

• Lactate ↑

• Skin warm, bounding pulses, wide pulse pressure

Problem = microcirculation + mitochondria, not the pump

What is failing first? => Oxygen use, not delivery

2. Compensated sepsis (transitional phase) - Flow disorder/Progressive/ Compensated shock

What fails next? => Delivery (DO₂) can no longer match VO₂ => Septic cardiomyopathy + vasoplegia overlap

High flow · Partially restored resistance · Strained extraction · Plateauing lactate

• CO falling or insufficient for demand

• SVR improving with fluids/often due to pressors

• ScvO₂ falls or becomes “falsely normal”

• Lactate is elevated

• Macro parameters look “okay”

• Microperfusion impaired

In this phase, Sepsis is no longer just an extraction problem — it is now a true shock state (Now flow matters, Inotropes become relevant, Excess pressor becomes dangerous, & This is the most salvageable stage if recognised)

Mechanisms

• Sepsis-induced myocardial depression

• Catecholamine toxicity

• Excess afterload from vasopressors

• Capillary leak → preload inefficiency

This is where:

• Kidneys fail

• Mental status worsens

• Urine output drops

3. Late sepsis (cold shock phenotype) - Metabolic failure / REFRACTORY SHOCK

What fails finally? => ATP generation itself

Mechanisms: Structural mitochondrial damage, Loss of membrane potential, Apoptosis/necrosis, Cytopathic hypoxia becomes irreversible

Oxygen delivery no longer matters — the cell cannot use it even if perfect flow is restored

This is biological shock, not hemodynamic shock.

Low flow · High resistance · Maximal extraction · Rising lactate

• CO ↓ (septic cardiomyopathy)

• SVR ↑ (vasoconstriction, catecholamine excess)

• ScvO₂ ↓

• Lactate ↑↑

• Cold, mottled, narrow pulse pressure

• DO₂: even if improved, VO₂ cannot increase

• Multi-organ failure

Problem = pump failure + microcirculatory collapse

Mapping the stage with the help of CO + ScvO₂ + Lactate patterns

Summary:

1. Utilisation disorder (mitochondrial hibernation) => CO normal, ScvO2 ↑, Lactate ↑ 

2. Flow disorder (CO failure + afterload) => CO ↓ , ScvO2 ↓ or normal, Lactate ↑ 

3. Metabolic failure (irreversible mitochondrial dysfunction) => CO irrelevant, ScvO2 ↑, Lactate ↑ ↑ 

STAGE 1 – Utilisation disorder (early sepsis); 

Mitochondrial hibernation + microcirculatory shunt → extraction failure

delivery fine → extraction broken → lactate rises

Pitfall: “CO is good, MAP good → shock is treated.” Wrong.

Bedside clues

• Warm peripheries

• Wide pulse pressure

• ScvO₂ falsely “reassuring”

• Rising lactate without hypotension

STAGE 2 – Flow disorder (progressive septic cardiomyopathy)

Sepsis-induced myocardial depression + vasoplegia overlap

Logic; extraction intact but CO insufficient OR vasopressor clamp reduces stroke volume

Bedside clues

• Cold extremities

• Narrow pulse pressure

• ScvO₂ falls with pressor escalation

• Rising lactate despite MAP ≥65

STAGE 3 – Metabolic/cellular failure (late refractory)

Mitochondrial structural injury → irreversible cytopathic hypoxia

Logic: DO₂ is restored, yet VO₂ cannot increase

oxygen present, but cannot be used

Bedside clues

• Severe acidosis

• Unresponsive lactate

• Warm mottling or cool mottling, depending on peripheral vasomotor collapse

• Pressor/inotrope escalations do nothing

Sepsis bedside decision grid

Think: FLOW → RESISTANCE → EXTRACTION → METABOLISM

STEP 1 — Look at FLOW (CO surrogate)

Echo + pulse pressure + perfusion

• Hyperdynamic LV, wide pulse pressure → CO high

• Poor LV squeeze, small LVOT VTI, narrow pulse pressure → CO low

This decides inotrope vs not

STEP 2 — Look at RESISTANCE (SVR surrogate)

MAP + pulse pressure + vasopressor dose

• Low MAP + wide pulse pressure → Low SVR (vasoplegia)

• MAP ok / high + narrow pulse pressure → High SVR (afterload excess)

MAP alone is meaningless without pulse pressure

STEP 3 — Look at EXTRACTION

ScvO₂ (trend, not absolute)

• ScvO₂ ↑ / normal (>70%) → Extraction failure

• ScvO₂ ↓ (<65%) → Increased extraction → flow insufficient

High ScvO₂ ≠ good perfusion

STEP 4 — Look at METABOLISM

Lactate + trend

• Rising → mismatch ongoing

• Falling → system improving

• Flat high → pseudo-reassurance (esp. late shock)

Scenario 1 — Early sepsis (classic warm shock)

CO ↑ | SVR ↓ | ScvO₂ ↑ | Lactate ↑

Problem -> Vasoplegia + extraction failure

What helps

• Early norepinephrine (don’t drown with fluids)

• Source control

• Reduce VO₂: (Control fever & Adequate analgesia/sedation)

• Trust microperfusion (CRT, urine, mentation)

What won’t help:

• More fluids after preload is adequate

• Chasing ScvO₂ down

Scenario 2 — Distributive + evolving pump failure

CO ↓ | SVR ↓ | ScvO₂ ↓ | Lactate ↑

Problem -> Vasoplegia + failing myocardium

What helps

• Norepinephrine to restore SVR

• Add inotrope (dobutamine/epinephrine low dose)

• Echo-guided titration

What kills:

• Pure vasoconstriction without flow support

Scenario 3 — Late sepsis (cold shock phenotype)

CO ↓ | SVR ↑ | ScvO₂ ↓ | Lactate ↑↑

Problem -> Afterload excess + septic cardiomyopathy

What helps

• Reduce afterload if MAP is excessive

  • Inotrope > more pressor

  • Consider milrinone if SVR is very high & LV failing

Common mistake:

• Escalating norepinephrine blindly → worsens flow

Scenario 4 — Refractory septic shock

CO ↓ | SVR ↑↑ | ScvO₂ normal/high | Lactate exploding

Problem -> Terminal extraction failure + mitochondrial shutdown

What helps

• Damage control:

• Adequate MAP, not heroic

• Reduce VO₂ aggressively

• Accept permissive hypotension sometimes

• Prognosis discussion early

SEPSIS

Sepsis really is not an infection, or not a shock. Sepsis is a disorder of regulation. It loses the coordination between:

• blood flow

• vascular tone

• oxygen use

• cellular metabolism

Not just 

• infection, or

• hypotension or

• inflammation

In sepsis, delivery, distribution, and utilisation stop talking to each other.

The four pillars that collapse in sepsis: 

A. Vascular tone — uncontrolled vasodilation

• Excess NO, prostaglandins

• Vasopressin deficiency

• Smooth muscle paralysis

Result:

• ↓ SVR

• Blood pressure becomes pressure without flow

• Shunting increases

This is why MAP ≠ perfusion

B. Flow distribution — the hidden killer

Even with high CO:

• Some capillaries are overperfused

• Some are completely shut

• Some bypass tissue (shunts)

• Results:

  • • Global flow looks fine

    • Regional hypoxia exists

    • Patchy ischemia

    • This is the reason for 

      • • Kidneys fail early

        • Gut suffers silently

        • Lactate rises despite “good numbers”

C. Extraction failure — the sepsis signature

Cells cannot pull oxygen from the blood.

Mitochondrial dysfunction starts early, becomes dominant late, and is irreversible only at the end. Think of mitochondria in 3 levels

• Early sepsis → functional downregulation(reversible) - Protective “hibernation”

what happens; 

1. Inflammatory mediators inhibit electron transport chain

2. Nitric oxide competes with oxygen at cytochrome oxidase

3. Cells deliberately slow ATP production

This is the extraction failure of early sepsis => Oxygen present, mitochondria choosing not to                         use it fully.

• Progressive sepsis (partially reversible)

what happens

• Persistent hypoperfusion

• Ongoing inflammation

• Mitochondrial biogenesis can’t keep up

• ATP deficit becomes real

Now mitochondria are: Unable, not unwilling

• Late/refractory sepsis → structural mitochondrial failure (often irreversible)

what happens

• Mitochondrial membrane damage

• Loss of cristae

• mtDNA injury

• Apoptosis pathways activated

Extraction Failure Mechanisms:

• Endothelial swelling

• Capillary leak

• Mitochondrial dysfunction (Impaired electron transport chain)

Result:

• ScvO₂ ↑

• VO₂ ↓ despite adequate DO₂

Oxygen is present but unusable

This is unique to sepsis.

D. Mitochondrial shutdown — cytopathic hypoxia

This is the point of no return. 

Pyruvate can’t enter the Krebs cycle -> ATP production falls -> Cell switches to inefficient glycolysis ->  Lactate accumulates

Important: Oxygen may still be present (not hypoxia)=> This is bioenergetic failure. Cells die with oxygen around them.

WHY LACTATE RISES IN SEPSIS

Lactate in sepsis is multifactorial:

• Microcirculatory hypoxia

• Mitochondrial dysfunction

• β-adrenergic stimulation

• Accelerated glycolysis

• Impaired clearance (liver)

So; Lactate ≠ just low flow

Lactate = stress + inefficiency

That’s why:

Lactate can rise after adrenaline

Lactate may fall without a MAP change

Lactate trend > absolute value

Why ScvO₂ lies to you in sepsis

High ScvO₂ can mean:

• Not Good delivery 

• Poor extraction 

• Shunting 

• Dying mitochondria 

So: 

• High ScvO₂ + high lactate = danger

• Low ScvO₂ + high lactate = flow problem

Direction matters more than the number.

Why do fluids stop working early in sepsis?

Because:

• Endothelial glycocalyx is destroyed

• Capillary leak → third spacing

• More fluid = more edema

• Microcirculation worsens

So:

Fluids help preload only initially

After that → vasopressors + flow optimization

Sepsis is pressor-sensitive, not fluid-hungry

VO₂ manipulation — the underrated strategy

You cannot always increase DO₂. So you reduce demand.

What actually helps:

• Fever control

• Adequate analgesia

• Sedation when indicated

• Treat agitation, shivering

• Early ventilation when the work of breathing is high

Sometimes sedation saves organs more than fluids.

SEPSIS Evolution

Phase 1 — Utilisation failure

• CO ↑

• SVR ↓

• ScvO₂ ↑

• Lactate ↑

• Warm patient

Treatment target: redistribute flow, control infection, reduce VO₂

Phase 2 — Mixed failure

• CO variable

• SVR partially restored

• ScvO₂ drifting down

• Lactate plateau

Target: fine balance — pressor + inotrope

Phase 3 — Pump failure

• CO ↓

• SVR ↑

• ScvO₂ ↓

• Lactate ↑↑

• Cold shock

Target: restore flow, reduce afterload

Phase 4 — Metabolic collapse

• CO ↓↓↓

• SVR irrelevant

• ScvO₂ falsely normal

• Lactate explodes

Target: damage control, not heroics

In sepsis

Always trust:

• Mental status

• Urine output

• Skin perfusion

• Lactate trend

Not:

• MAP alone

• ScvO₂ alone

• CO alone

Sepsis begins as a utilisation disorder, becomes a flow disorder, and ends as a metabolic failure.

Sepsis starts as a problem of oxygen utilisation,

progresses to a problem of delivery,

and ends as a problem of cellular survival.

Sepsis-Induced Cardiomyopathy (SICM):

SICM develops in the context of severe sepsis, the myocardial dysfunction triggered by the systemic inflammatory response to infection, not from blocked coronary arteries or primary heart muscle inflammation.

It is a Cytokine-mediated toxicity, nitric oxide, mitochondrial dysfunction — no primary myocyte necrosis like in inflammatory conditions. 

It manifests as hemodynamic instability (hypotension, cool extremities despite fluid administration) without obvious causes of pump failure. 

It's an acute global myocardial depression — not confined to one coronary territory. May include diastolic dysfunction and RV involvement. 

Echo findings are

• ↓ EF

• LV/RV systolic dysfunction, and often dilated ventricles in a sepsis picture. 

• Global Longitudinal Strain (GLS) abnormalities on echo may detect dysfunction before LVEF drops.

• Serial echo over the first 24–72 h helps confirm evolving dysfunction and monitor reversibility.

Myocarditis is a primary inflammatory disease of the myocardium, usually viral. 

Typical presentations are

• Chest pain, arrhythmias

• Biomarker and imaging patterns are more consistent with active myocardial injury.

Key differences between SICM & Myocarditis

SCIM

• Cause -> systemic inflammation, cytokine-mediated ≠ direct inflammation of the myocardium

• Echo -> global dysfunction

• Histology -> No infiltrative inflammation

Myocarditis

• Direct myocardial inflammation (immune cells in the myocardium)

• Echo -> wall motion abnormalities

• Histology -> Lymphocytic infiltration of the myocardium (biopsy)

• Cardiac MRI -> Myocardial oedema, characteristic pattern in gadolinium enhancement

Sepsis-induced cardiomyopathy is a functional, reversible myocardial dysfunction due to systemic inflammation, best detected early with echo (especially GLS; global longitudinal strain) and serial assessments. Myocarditis is a primary inflammatory injury to the myocardium with different imaging features and a longer course. The distinction is largely clinical + imaging, not a single lab test.

NO

In sepsis, inflammatory cytokines (IL-1, TNF-α, endotoxin) switch on nitric oxide synthase (NOS) to produce NO from endothelial cells, macrophages, and smooth muscle cells, resulting

1. Vasodilator → maintains microvascular flow

2. Inhibits platelet aggregation → prevents thrombosis

3. Anti-inflammatory signaling

So basically, NO preserves microcirculatory health. 

There are different types of NOS - like eNOS (endothelial NOS), iNOS (inducible NOS)

What goes wrong in sepsis? -> In sepsis, inflammatory cytokines (IL-1, TNF-α, endotoxin) switch on iNOS, causing: 

• Excess NO

• Uncontrolled vasodilation

• Pathological smooth muscle relaxation

Consequences: 

1. Refractory hypotension: NO ↓SVR → MAP collapses

2. Vasoplegia resistant to catecholamines: because smooth muscle receptors become desensitised

3. Mitochondrial dysfunction: NO + superoxide → peroxynitrite -> damages mitochondrial complexes → ↓ATP

4. Microcirculatory shunting: capillary regulation fails -> blood flows through, but oxygen isn’t extracted

5. NO directly depresses the myocardium => Nitric oxide + septic cardiomyopathy (cytokine-induced myocyte stunning (without necrosis) & mitochondrial dysfunction reducing ATP)

This explains:

• high ScvO₂ (failed extraction)

• rising lactate despite fluids + vasopressors

NO links many features of septic shock

• ↓SVR → hypotension

• ↓response to NE → vasoplegia

• ↓ATP → organ dysfunction

• ↑ScvO₂ + lactate → microcirculatory failure

• global myocardial depression → SICM

• Why vasopressin works: vasopressin bypasses NO-blunted adrenergic receptors. constricts smooth muscle via V1 receptors, not catecholamine receptors

• Why methylene blue works in refractory vasoplegia: inhibits NO synthase + guanylate cyclase

• Why fluids alone stop helping: NO vasodilation → leakage + pooling → worsening distributive physiology

In sepsis, inflammatory activation drives uncontrolled NO production through iNOS, causing vasoplegia, mitochondrial injury, failed oxygen extraction, and reversible myocardial depression—the mechanistic core of septic shock physiology.

Bridging  NO → DO₂–VO₂ mismatch

NO excess does 3 things simultaneously:

A) Vasoplegia → ↓SVR → ↓MAP → ↓perfusion pressure → ↓DO₂ (oxygen delivery)

B) Mitochondrial inhibition; NO + superoxide → peroxynitrite -> damages electron transport chain → ↓oxidative phosphorylation → ↓VO₂ (oxygen utilization)

C) Microcirculatory shunting; arteriolar dilation uneven -> capillary recruitment chaotic → some tissues hyperperfused, some hypoxic

Even when global DO₂ looks “ok”, VO₂ falls, so DO₂–VO₂ mismatch appears—the hallmark of septic shock.

NO drives lactate kinetics

Lactate rises in sepsis not only from anaerobic metabolism.

Mechanisms directly tied to NO:

A) Mitochondrial block: ↓pyruvate entry into Krebs; pyruvate → lactate

B) Adrenergic surge: β-2 stimulation ↑of glycolysis, ↑lactate production (shows up after adding epinephrine)

C) Impaired clearance: hepatic hypoperfusion + cytokine injury → ↓lactate removal

So lactate = metabolic stress + failed extraction + impaired clearance.

NO explains treatment sequencing in septic shock

Stepwise reasoning:

Step 1 – Fluids

• NO → vasodilation + capillary leak → relative hypovolemia

• Restore stressed volume first

• but excessive fluid worsens glycocalyx injury → oedema → ↓DO₂

Stop when non-responsive.

Step 2 – Vasopressors

• NO blunts α-adrenergic smooth muscle receptors

• NE restores SVR

• vasopressin bypasses adrenergic receptors → activates V1 → resistant vasoplegia fix

Goal: restore perfusion pressure → DO₂ restoration potential.

Step 3 – Inotropes: Even with MAP restored:

• NO depresses contractility + mitochondria → ↓CO → ↓DO₂

So add inotrope (dobutamine/epi) only if perfusion markers suggest low flow, not simply for low EF.

Step 4 – Mitochondrial rescue / advanced therapy

persistent lactate + high ScvO₂ = failed VO₂ → mitochondria blocked

Possible therapies in refractory vasoplegia from NO excess:

• methylene blue (inhibits NO synthase + guanylate cyclase)

• thiamine/steroids (metabolic support/support receptor sensitivity)

Clinical interpretation at bedside

When you see:

• high lactate

• high ScvO₂

• hypotension despite NE

• fluid unresponsive

think:

• NO-mediated vasoplegia + mitochondrial dysfunction

• DO₂–VO₂ mismatch is an active process

• Lactate is a useful marker of failure and response.

Excess nitric oxide in sepsis causes vasoplegia, mitochondrial inhibition, and microvascular shunting, which disconnects oxygen delivery from utilisation, driving lactate accumulation and dictating a treatment sequence of fluids → vasopressors → inotropes → metabolic rescue.

Cytokines

Sepsis is basically a cytokine storm

Cytokines are the chemical messengers coordinating the immune response. Almost any stressed cell can release cytokines.

Cytokine classes:

• Pro-inflammatory

  • • TNF-α

    • IL-1β

    • IL-6

• Anti-inflammatory

  • • IL-10

    • TGF-β

• Chemokines – attract neutrophils/macrophages

  • • IL-8

• Interferons – antiviral signalling

(six sexy, eight attract, ten cut; proinflammatory, anti-inflammatory, & chemokines)

Cytokines are the molecular driver behind these macro/micro changes in sepsis

• massive TNF-α & IL-1 release → vasodilation

• induces nitric oxide synthase (iNOS) → excess NO

• ↑ capillary leak → oedema, ↓ preload

• myocardial suppression → septic cardiomyopathy

• altered coagulation → DIC tendency

This is why in early sepsis:

• preload tanks

• SVR collapses

• Myocardial function drops

• oxygen extraction fails

• lactate rises

Infection → Inflammation → Sepsis → Septic Shock

1. Infection

• Infection ≠ sepsis.

• Pathogen present in the body.

• Local immune response contained.

• Vitals often normal, perfusion intact.

• Example: cellulitis, UTI, pneumonia

• Most infections never enter systemic circulation.

2. Inflammation

• Inflammation is the response, not the infection itself.

• You can have inflammation without an infection (e.g., pancreatitis, trauma).

• Cellular + humoral response activated.

• Cytokines released locally: TNF-α, IL-1, IL-6.

• Vasodilation + permeability increase → redness/swelling locally.

3. Sepsis

• Definition: Life-threatening organ dysfunction caused by dysregulated host response to infection.

• SOFA ≥2 from baseline = organ dysfunction.

• Sepsis = dysfunction. Not just infection + inflammation.

• What changes physiologically: 

  • • Cytokines spill into circulation → systemic response.

    • Global vasodilation (iNOS → nitric oxide)

    • Capillary leak → relative hypovolemia

    • Microcirculatory shunting → extraction failure

    • Early stage CO often ↑ to compensate.

• Organ dysfunction markers:

  • • rising lactate

    • oliguria

    • altered mentation

    • ↑ bilirubin (stasis)

    • hypoxemia

    • thrombocytopenia

4. Septic Shock

Sepsis + cellular/metabolic dysfunction severe enough to require vasopressors to maintain MAP 65, and lactate >2 despite adequate fluids.

Mechanism:

• Refractory vasodilation → vasoplegia

• Relative hypovolemia + leaky capillaries

• Myocardial depression → fall in CO

• Mitochondrial dysfunction → ↓VO₂ extraction

• Cellular dysoxia develops even if DO₂ is “normal”.

Summary:

A. Recognise when infection becomes systemic

• Fever + tachycardia alone means nothing.

• Look for end-organ stress early.

B. A normal MAP never rules out shock

• Perfusion is flow-dependent (CO + content)

• MAP is crude; don’t anchor on 65 early

C. Lactate tells you:

• • production ↑ (anaerobic + aerobic)

  • clearance ↓ (liver hypoperfusion)

  • stress hormones ↑

D. Early sepsis paradoxes

• CO may be high but tissues starve.

• ScvO₂ may be high because extraction fails.

• Sedatives may improve perfusion by ↓VO₂.

E. Septic shock progression is biochemical

1. NO-mediated vasoplegia

2. capillary leak

3. β-receptor desensitization

4. SICM

5. mitochondrial failure

F. Why we escalate from fluids → pressor → inotrope

• fix preload first

• restore tone next

• augment pump last

• One-line summary

Infection becomes sepsis when systemic inflammation causes organ dysfunction; shock is when dysfunction threatens perfusion, requiring vasopressors + lactate rises despite fluids—reflecting cellular dysoxia and failed compensation.

Shock is failure of oxygen delivery relative to demand.

I first open pressure, then restore flow, then correct content, and finally judge success by microperfusion — not by MAP