STEPTRACKERGENERAL PRINCIPLES | PATHOLOGY + PHYSIOLOGY | HIGH-YIELD REVIEW

Hypoxia & Ischemia

Cells die when O₂ fails to arrive, fails to bind, or cannot be used — locate the break in the chain.

FOCUS ON

Separate the low PaO₂ causes from the normal PaO₂, low content causes (anemia, CO, methemoglobin) and the can't use O₂ cause (cyanide). Ischemia is worse than hypoxia alone: it also stops nutrient delivery and waste removal.

CAUSE

MECHANISM

KEY NUMBERS · SIGNS

CLASSIC SETTING

Ischemia

↓ blood flow

Arterial block, impaired venous drainage, or shock. Tissue loses O₂ and nutrients while waste builds up.

Damage fastest where supply is most distal (watershed, subendocardium)

MI, stroke, Budd-Chiari (venous), shock

Hypoxemia

↓ PaO₂

Low inspired O₂, hypoventilation, V/Q mismatch, diffusion barrier, right-to-left shunt.

Normal A–a gradient: altitude, hypoventilation. ↑ A–a: V/Q mismatch, diffusion defect, shunt.

Altitude, opioid overdose, pneumonia, fibrosis, congenital shunt

Anemia

↓ Hb

Fewer O₂ carriers; each Hb is still fully saturated.

PaO₂ and SaO₂ normal; O₂ content ↓

Any severe anemia

Carbon monoxide

blocks Hb binding

CO binds Hb ~200× more avidly than O₂ and shifts the curve left (less unloading).

PaO₂ normal; pulse oximetry falsely normal; co-oximetry shows COHb. Headache first; cherry-red skin late.

House fire, faulty heater, car exhaust → 100% or hyperbaric O₂

Methemoglobinemia

Fe³⁺ can't carry O₂

Oxidized iron (Fe³⁺) cannot bind O₂ and left-shifts the remaining sites.

PaO₂ normal; SpO₂ ~85% regardless; chocolate-brown blood; cyanosis unresponsive to O₂

Benzocaine/lidocaine sprays, dapsone, nitrites → methylene blue (needs G6PD), vitamin C

Cyanide

can't use O₂

Inhibits cytochrome c oxidase (complex IV) → oxidative phosphorylation stops.

O₂ delivered but unused → ↑ venous O₂, severe lactic acidosis, bitter-almond odor

Smoke inhalation, nitroprusside → hydroxocobalamin; nitrites + thiosulfate

Mechanism — follow the O₂ chain

AirAltitude ↓ PiO₂

→

LungHypoventilation, V/Q, diffusion, shunt

→

HemoglobinAnemia, CO, MetHb

→

FlowIschemia, shock

→

MitochondriaCyanide (complex IV)

Every break ends the same way: ↓ ATP → reversible injury → membrane damage → necrosis (pages 1.02–1.03).

The numbers that separate them

CONDITION

PaO₂

SaO₂

O₂ CONTENT

Hypoxemia

↓

Anemia

Normal

↓

CO poisoning

Normal

↓ (co-oximetry)

↓

MetHb

Normal

↓

Cyanide

Normal

Normal — unused

Most O₂-sensitive cells

Hippocampal CA1 and cerebellar Purkinje neurons, cortex layers 3, 5, 6 · subendocardium · PCT straight segment and thick ascending limb · liver zone 3

Watershed zones

Brain: ACA–MCA border · Colon: splenic flexure (SMA–IMA) and rectosigmoid

How it's tested

COMMON CONFUSIONPaO₂ is normal in anemia, CO and MetHb because PaO₂ measures dissolved O₂, not O₂ bound to Hb.

THE TRAPA fire victim with headache and lactic acidosis can have CO, cyanide, or both. A high venous O₂ saturation points to cyanide.

YOUR APPROACHWalk the chain: air → lung (A–a gradient) → Hb (saturation vs content) → flow → mitochondria (venous O₂, lactate).

If you see… think…

Whole family with headaches in winter, normal pulse ox → CO poisoning

Cyanosis after benzocaine spray, brown blood, no response to O₂ → methemoglobinemia

Smoke inhalation + lactic acidosis + bright venous blood → cyanide

Prolonged nitroprusside infusion, confusion, acidosis → cyanide toxicity

Hypotension during surgery, then proximal arm and leg weakness → ACA–MCA watershed infarct

Ischemic colitis at the splenic flexure → SMA–IMA watershed

Shock with centrilobular liver necrosis → zone 3 hypoxia ("shock liver")

Cardiac arrest survivor with memory loss → hippocampal CA1 neuron loss

Climber with low PaO₂ and normal A–a gradient → ↓ inspired O₂