Orientation
Rapid review
What you should already have
Lesson 5 — cerebral metabolism; The circulation — flow, pressure and resistance.
About 75 minutes
Plus the time it takes to redraw this lesson’s figures from memory, which is the fastest way to find out what you have not understood.
Where this shows up
Four of the figures in this lesson are drawings you should be able to reproduce from memory. It is also the physiology behind every decision you make about ventilation, blood pressure and depth in a patient with a tight brain.
Learning outcomes
By the end of this lesson you should be able to:
- State normal global, cortical and subcortical cerebral blood flow with units, and write the equation relating flow to perfusion pressure and cerebrovascular resistance.
- Outline the physiological determinants of cerebral blood flow, separating them from the pharmacological and pathological ones.
- Draw and label the autoregulation curve, state its limits in both MAP and CPP terms, and explain the myogenic mechanism.
- Draw and label the PaCO2, PaO2 and cerebral metabolic rate relationships with correct axes, units and ranges.
- Quantify carbon dioxide reactivity in three ways, and state the conditions that attenuate or abolish it.
- Explain the time course over which hyperventilation loses its effect, and the risk of abruptly restoring a normal PaCO2.
- Describe how cerebral blood flow is measured, from the Kety-Schmidt method to transcranial Doppler.
Together these settle one syllabus objective: Cerebral blood flow and its regulation. Tick it on the Physiology objective list once you can do all of the above without notes.
The minimum high-yield framework
- CBF = CPP / CVR. Not simply “flow = pressure / resistance”: name the cerebral terms.
- Normal flow about 50 mL per 100 g per minute, 12-15% of cardiac output. Grey matter receives about 80% of it, at about 4 times the flow per gram of white matter.
- CPP = MAP − ICP, or minus central venous pressure when that is higher.
- Autoregulation holds flow relatively constant across a mean arterial pressure of about 70-150 mmHg in most adults, by a myogenic mechanism. With a normal CSF pressure the lower limit is a perfusion pressure of about 60-65 mmHg, and the limits vary widely between individuals.
- Carbon dioxide: near-linear across the physiological range, attenuated at both extremes. Roughly 1-2 mL/100 g/min per mmHg.
- Oxygen: a threshold at about 60 mmHg (8 kPa), below which flow rises steeply. Above it, little effect.
- Metabolic rate: flow rises linearly with it. This is coupling, not autoregulation.
- It is cerebral blood volume, not flow, that raises intracranial pressure. They usually move together but they can move in opposite directions.
The numbers
Normal values, with units
| Variable | Value | Units |
|---|---|---|
| Global cerebral blood flow | ≈ 50 | mL / 100 g / min (12-15% of cardiac output) |
| Grey matter share of flow | 80 | % of total (white matter the remaining 20%); about 4 times the flow per gram |
| Cerebral blood volume | ≈ 5 | mL / 100 g of brain (about 10% of intracranial volume) |
| Cerebral perfusion pressure | ≈ 80 | mmHg (MAP 90 − ICP 10) |
| Lower limit of autoregulation | 70 | mmHg MAP in most adults; 60-65 mmHg expressed as CPP |
| Upper limit of autoregulation | ≈ 150 | mmHg MAP |
| Jugular venous oxygen saturation | 60-75 | % |
The relationship
The governing equation
where CBF is cerebral blood flow (mL per 100 g per minute), CPP is cerebral perfusion pressure (mmHg) and CVR is cerebral vascular resistance (mmHg per 100 g per minute per mL).
where MAP is mean arterial pressure and ICP is intracranial pressure, both in mmHg. The correct full form uses whichever of intracranial pressure and central venous pressure is higher, because the effective downstream pressure is the greater of the two, which matters whenever venous pressure is raised.
Resistance itself is described by the Hagen-Poiseuille relationship:
where η is viscosity, l is length and r is radius. Because resistance varies with the fourth power of radius, a small change in arteriolar calibre produces a large change in resistance, and so in flow. Vessel length does not change, and across the normal haematocrit range viscosity changes flow only modestly, so calibre is the variable through which the mechanisms below act.
Physiological, not pharmacological
The determinants of cerebral blood flow
| Determinant | Class of mechanism | How it acts | Note |
|---|---|---|---|
| Cerebral perfusion pressure | Myogenic | CPP = MAP − ICP (or − CVP, whichever is higher). Within the autoregulatory range, cerebrovascular resistance tracks perfusion pressure so flow is held relatively constant. | Outside the range, flow is pressure-passive. |
| Cerebral metabolic rate | Metabolic (flow-metabolism coupling) | Regional flow varies in proportion to regional metabolic rate, through local by-products of metabolism (potassium, hydrogen ion, lactate, adenosine, ATP), glutamate-driven nitric oxide release and astrocyte-derived arachidonic acid metabolites. | Raised by seizures; lowered by anaesthetic suppression of metabolism and by hypothermia. |
| Arterial carbon dioxide tension | Chemical | Carbon dioxide diffuses freely across the cerebrovascular endothelium and lowers brain extracellular pH, relaxing arteriolar smooth muscle; nitric oxide, adenosine, arachidonic acid metabolites and reactive oxygen species contribute. | Graded across the physiological range at roughly 1-2 mL/100 g/min per mmHg, and rapid in onset. |
| Arterial oxygen tension | Chemical | A threshold rather than a graded relationship. Below about 60 mmHg (8 kPa), where saturation falls rapidly, deoxyhaemoglobin releases nitric oxide and ATP and marked vasodilatation follows. | Between 60 and 300 mmHg, oxygen tension has little effect on flow. At 1 atmosphere of oxygen, flow falls by about 18%. |
| Temperature | Metabolic | Cerebral metabolic rate falls 6-7% per °C, and flow falls with it through coupling. | Between 37 and 42 °C both flow and metabolic rate rise; above 42 °C oxygen consumption falls abruptly as proteins denature. |
| Blood viscosity | Rheological | By the Hagen-Poiseuille relationship, flow varies inversely with viscosity, and haematocrit is its single most important determinant. | Across the normal haematocrit range of 33-45% the effect on flow is modest. Viscosity matters most in focal ischaemia, where vasodilatation is probably already maximal. |
| Autonomic innervation | Neurogenic | Sympathetic fibres from the superior cervical ganglion and parasympathetic fibres from the sphenopalatine ganglion innervate the cerebral vessels, with the greatest influence on the larger arteries. | At rest, MAP, PaCO₂ and metabolic rate predominate. When arterial pressure rises acutely, sympathetic activity limits the rise in downstream pressure and flow, protecting the blood-brain barrier. |
| Cardiac output | Haemodynamic | Volunteer studies suggest cardiac output contributes to flow independently of MAP: one estimate is a 10% fall in flow for a 30% fall in output. | A meta-analysis did not confirm an independent relationship, so treat it as a probable contributor, relevant when hypotension accompanies a low output. |
| Venous and intracranial pressure | Mechanical | Perfusion pressure is a gradient, so a rise in the downstream pressure, venous or intracranial, reduces it directly. | Normally both are low, and MAP serves as a surrogate for perfusion pressure. |
Two further influences belong here only as qualifications. Sympathetic stimulation raises arterial blood pressure and therefore cerebral perfusion pressure, while the sympathetic nerves to the cerebral vessels limit the resulting rise in downstream pressure and flow, protecting the blood-brain barrier during an acute pressor response. And anaesthetic drugs change flow, but they do so through metabolic rate or through direct effects on the vessels: they are pharmacological determinants, set out in section 10.
Previously examinedApril 2019 · October 2024 · April 2025 · October 2025 — the physiological determinants of cerebral blood flow, the four relationships as labelled diagrams, the behaviour of flow during a pressor response, and autoregulation after cardiac arrest. Worked answers in the library
The plateau
Cerebral autoregulation
The mechanism is principally myogenic. A rise in pressure depolarises arteriolar smooth muscle; calcium enters through voltage-gated channels and is released from intracellular stores, the muscle contracts, and cerebral vascular resistance rises. A fall in pressure lets it relax. Flow therefore stays relatively constant while pressure varies. Tone is modulated by endothelial nitric oxide, by innervation and by metabolic factors, which overlap with flow-metabolism coupling.
Rearranging the flow equation makes the logic explicit:
Holding CBF constant while CPP varies requires CVR to vary in proportion. That is all autoregulation is.
| Condition | What the vessels are doing | Flow, volume and pressure |
|---|---|---|
| MAP below the lower limit (about 70 mmHg) | Capacity to dilate exhausted | Flow becomes pressure-passive and falls; ischaemia threatens. Cerebral blood volume has risen as the vessels dilated, and rises further below the limit, so intracranial pressure is not protected either. |
| Within the plateau | Resistance tracks pressure | Flow relatively constant, with a gentle upward slope. As pressure rises the vessels constrict, so cerebral blood volume falls slightly. |
| MAP above the upper limit (about 150 mmHg) | Capacity to constrict exhausted | Flow becomes pressure-passive again and rises; volume rises with it, and the blood-brain barrier is at risk of breakthrough. |
| Chronic hypertension | Traditionally, the whole curve shifts right | Both limits move up, so a pressure normal for others may lie below this patient's lower limit. More recent studies find autoregulation preserved in hypertensive patients, treated and untreated; limiting an acute fall in MAP to 30-35% of baseline is the working compromise. |
| Neonates | The curve is shifted leftward | Both limits sit lower. |
| After traumatic brain injury | Autoregulation frequently defective | Flow follows pressure more directly, which is part of why hypotension is so damaging after a head injury. |
Matching supply to demand
Flow-metabolism coupling
Regional cerebral blood flow varies in proportion to regional cerebral metabolic rate. Plotted as flow against cerebral metabolic rate for oxygen, the relationship is a rising straight line: a CMRO₂ of about 3.3-3.5 mL per 100 g per minute corresponds to a flow of about 50 mL per 100 g per minute.
The mediators, the feedback-against-feed-forward distinction and the astrocyte’s role are set out in lesson 5. What matters here is the contrast:
| Flow-metabolism coupling | Autoregulation | |
|---|---|---|
| The question it answers | Is flow matched to demand? | Is flow protected from changes in pressure? |
| Independent variable | Cerebral metabolic rate | Arterial or cerebral perfusion pressure |
| Mechanism | Local metabolic by-products, nitric oxide and astrocytic mediators | Myogenic: arteriolar smooth muscle depolarising and contracting as pressure rises |
| Shape of the plot | A rising straight line | A gently sloped plateau with pressure-passive limbs |
| Altered by | Volatile agents: coupling persists, but at a higher flow for a given metabolic rate as the dose rises | Exceeding either limit; hypercapnia; frequently defective after traumatic brain injury |
The fast lever
Carbon dioxide reactivity
The four cerebral blood flow curves, and cerebral autoregulation
Cerebral blood flow is normally about 50 mL per 100 g of brain per minute, some 12-15% of the cardiac output, and each panel below shows what moves it. They matter here because as flow changes, cerebral blood volume changes with it, and volume drives intracranial pressure. Gas tensions are given in kPa with mmHg in brackets.
1 · Carbon dioxide
Near-linear across the physiological range, about 25-70 mmHg (3.3-9.3 kPa): roughly 1-2 mL/100 g/min for every 1 mmHg, or 2-4% per mmHg. The response is attenuated below about 25 mmHg (3.3 kPa), where further constriction is limited, and above about 75-80 mmHg (10-10.7 kPa), where the vessels are maximally dilated. The dashed curve is chronic hypercapnia: the relationship resets rightward. This is the panel behind hypercapnia raises ICP and behind hyperventilation.
2 · Oxygen
A threshold, not a gradient. From about 8 kPa (60 mmHg) to over 40 kPa (300 mmHg), oxygen tension changes cerebral blood flow very little. Below 8 kPa, where haemoglobin saturation falls rapidly, flow rises sharply, and cerebral blood volume with it: hypoxaemia is an intracranial pressure problem as well as a delivery problem. At very high tensions flow falls modestly, by about 18% at 1 atmosphere of oxygen.
3 · Mean arterial pressure: autoregulation
Autoregulation holds cerebral blood flow relatively constant across a range of arterial pressure. The traditional curve drawn here has a lower limit of 70 mmHg mean arterial pressure, a broad plateau with a gentle slope, and an upper limit of 150 mmHg; with a normal CSF pressure, 70 mmHg is a perfusion pressure of 60-65 mmHg. The mechanism is myogenic: a rise in pressure depolarises arteriolar smooth muscle, calcium enters and the vessel constricts, so cerebral vascular resistance rises with pressure and flow does not. Below the lower limit flow becomes pressure-passive and falls with pressure; above the upper limit it rises with pressure and the blood-brain barrier is at risk of breakthrough. The dashed curve is the traditional view of chronic hypertension, with both limits shifted right. The limits, width and slope of the plateau all vary between individuals.
4 · Metabolic rate: flow-metabolism coupling
Local flow is matched to local demand. Normal cerebral metabolic rate for oxygen is about 3.3-3.5 mL/100 g/min, at which flow is about 50. Raise demand, as a seizure does, and flow, blood volume and ICP rise with it; suppress demand with hypnotic agents or hypothermia and they fall. Volatile agents keep flow and metabolism linked but reset the ratio upward, giving more flow for a given metabolic rate as the dose rises.
Cerebral blood flow varies directly and near-linearly with arterial carbon dioxide tension across the physiological range, about 25-70 mmHg. Below about 25 mmHg (3.3 kPa) the response is attenuated, and above about 75-80 mmHg (10-10.7 kPa) the rise in flow is attenuated too.
Three ways to quantify it
- Absolute: flow changes by roughly 1 to 2 mL per 100 g per minute for each 1 mmHg change in PaCO₂ around the normal value.
- Proportional: about 2 to 4% per mmHg, which for a baseline flow of 50 mL/100 g/min is the same statement.
- As volume: cerebral blood volume changes by about 0.049 mL per 100 g for each 1 mmHg, some 20 mL in total across a PaCO₂ of 25-55 mmHg in an adult brain. That is the change intracranial pressure actually feels.
The mechanism
Carbon dioxide itself is not the vasodilator. It diffuses freely across the cerebrovascular endothelium; hydrogen ion does not cross the barrier. The fall in brain extracellular pH is what relaxes the arteriolar smooth muscle, with nitric oxide, adenosine, arachidonic acid metabolites and reactive oxygen species contributing.
Two consequences follow directly. An acute metabolic acidosis has little immediate effect on cerebral blood flow, because the barrier excludes hydrogen ion. And the effect of a sustained change in carbon dioxide wanes over six to eight hours as bicarbonate is extruded from the CSF and its pH returns to normal.
Three more relationships
Oxygen, temperature and viscosity
Arterial oxygen tension
Between about 60 and 300 mmHg (8-40 kPa), arterial oxygen tension has little influence on cerebral blood flow. Below about 60 mmHg (8 kPa), where haemoglobin saturation falls rapidly, flow rises rapidly and markedly. The relationship with saturation is inversely linear, which is the more informative way to state it: flow rises steadily as saturation falls.
This is a threshold, not a gradient, and that matters clinically: at high tensions flow falls only modestly (by about 18% at one atmosphere of oxygen), but a modest fall below the threshold produces a large rise in cerebral blood flow and, with it, cerebral blood volume and intracranial pressure. Hypercapnia augments the response to hypoxaemia; hypocapnia limits it.
Anaemia and hypoxaemia both reduce oxygen content and both cause vasodilatation, but hypoxaemia is by far the more potent stimulus. For an equivalent fall in arterial oxygen content, cerebral oxygen delivery is better maintained during hypoxaemia than during haemodilution.
Temperature
Cerebral metabolic rate falls 6 to 7% per degree Celsius, and flow falls with it through coupling. Between 37 and 42 °C both rise; above 42 °C oxygen consumption falls abruptly as enzymes denature: a toxic threshold, not protection. Because hypothermia reduces both the electrophysiological and the housekeeping components of metabolic rate, its effect continues below the temperature at which the electroencephalogram becomes isoelectric.
Viscosity
By Hagen-Poiseuille, flow varies inversely with viscosity, and haematocrit is the single most important determinant of blood viscosity. Across the normal haematocrit range of 33-45%, the effect on cerebral blood flow is modest. In anaemia resistance falls and flow rises, partly as a response to reduced oxygen delivery rather than to viscosity alone. Viscosity matters more in focal ischaemia, where vasodilatation is probably already maximal: reducing viscosity by haemodilution increases flow in the ischaemic territory, although manipulating viscosity has not reduced injury in acute ischaemic stroke.
How it is measured
Measuring cerebral blood flow
| Method | Principle | What it gives | Limitations |
|---|---|---|---|
| Inert tracer (Kety-Schmidt) | Wash-in or wash-out kinetics of an inert tracer, first described by Kety and Schmidt using nitrous oxide | Cerebral blood flow | Measures mainly cortical flow, so it can underestimate global flow; a snapshot rather than a continuous measure |
| Contrast perfusion imaging (CT, MRI) | First passage of intravascular contrast, with arterial inflow and venous outflow functions derived for each region | Locoregional flow, blood volume and time to peak | A snapshot in time rather than a continuous monitor; requires the scanner |
| Transcranial Doppler | Doppler shift of pulsed ultrasound reflected from red cells in a basal artery, usually the middle cerebral, through the thin temporal bone | Flow velocity, continuously: changes in velocity, emboli, vasospasm, early warning of hyperperfusion, and dynamic autoregulation | Velocity tracks flow only if vessel diameter and probe angle stay constant, and basal flow is assumed to reflect cortical flow; the temporal bone precludes an adequate study in 10-20% of patients |
| Jugular bulb oximetry | The Fick principle reversed: with haematocrit and metabolism constant, jugular venous saturation reports the balance of oxygen supply and demand | Global adequacy of supply against demand, continuously | Global, so focal hypoperfusion can leave it in the normal range; invasive; tip placement is crucial, and the dominant jugular vein drains mainly cortical blood |
| Cerebral oximetry (near-infrared) | Reflectance oximetry through the forehead; because 66-80% of cerebral blood volume is venous, it reads mainly local venous saturation | Regional oxygen saturation of frontal brain, non-invasively and continuously | Extracranial contamination; infers global adequacy from the frontal lobes; normal values are largely undefined, so trends from a baseline are used |
The Fick principle underlies jugular bulb oximetry, and is worth being able to state:
where CMRO₂ is the cerebral metabolic rate for oxygen and CaO₂ − CjvO₂ is the arteriovenous oxygen content difference across the brain. Rearranged, it says that if metabolic rate is constant, the arteriovenous difference varies inversely with flow: as flow falls, extraction rises and jugular venous saturation falls.
Anaesthetic and clinical application
What this changes in practice
| Agent | CMR | CBF | Coupling | Clinical note |
|---|---|---|---|---|
| Propofol | Decreased; about 60% at burst suppression | Decreased | Preserved | Lowers ICP, secondary to the fall in metabolic rate, flow and blood volume |
| Thiopentone | Decreased: about 30% at induction, about 50% at EEG suppression | Decreased in parallel | Preserved | No further fall in metabolic rate once the EEG is suppressed |
| Etomidate | Decreased, like the barbiturates, but mainly in the forebrain | Decreased | Preserved | Lowers ICP without lowering CPP; worsened tissue hypoxia and acidosis during temporary middle cerebral artery occlusion |
| Sevoflurane and desflurane, about 1 MAC | Decreased | Decreased against awake values (sevoflurane about 38%, desflurane about 22%) | Preserved, at a higher flow for a given metabolic rate | ICP differs little from propofol-based anaesthesia, by about 5 mmHg |
| Volatile agents, rising dose | Decreased further | Rises relative to metabolic rate by intrinsic vasodilatation; halothane far more than sevoflurane | Flow-to-metabolism ratio rises with dose | Can raise flow, blood volume and ICP |
| Nitrous oxide | Modestly increased (reports inconsistent) | Increased; blunted by intravenous agents, increased further when added to a volatile | Inconsistent | Substantial rises in ICP when given alone |
| Ketamine | Increased or unchanged (reports differ) | Increased: about 14% at subanaesthetic and 36% at anaesthetic doses | Flow exceeds metabolic need | Rise blunted by other anaesthetics; systematic reviews find no rise in ICP after head injury; avoid as the sole agent where compliance is impaired |
| Opioids | Minor decrease | Minor decrease | Inconsistent: morphine lowered metabolic rate without changing flow | Little effect on ICP by infusion; a bolus that drops MAP can raise ICP |
| Benzodiazepines | Minor at sedative doses; significant at anaesthetic doses | Decreased in parallel | Preserved | Carbon dioxide responsiveness preserved |
| Dexmedetomidine | Decreased | Decreased in proportion | Preserved | Its fall in arterial pressure matters where collateral perfusion is critical |
| Vasopressors (phenylephrine, noradrenaline) | No direct effect | Only through blood pressure | Not applicable | Raise flow when MAP is below the lower limit of autoregulation |
| Systemic vasodilators (nitroprusside, nitroglycerine, hydralazine, calcium channel blockers) | No direct effect | Cerebral vasodilatation; flow maintained or increased as pressure falls | Not applicable | Can raise cerebral blood volume as they lower blood pressure |
Two rules fall out of that table. An intravenous agent that suppresses metabolism reduces flow through preserved coupling, and with it cerebral blood volume and intracranial pressure. And a drug that dilates cerebral vessels directly can raise flow and cerebral blood volume even as it lowers blood pressure, which is why a systemic vasodilator is a poor choice for controlling hypertension in a patient with reduced intracranial compliance.
Consolidation
The lesson in one paragraph
Cerebral blood flow is about 50 mL per 100 g per minute, 12-15% of cardiac output, about four times higher per gram in grey matter than in white. CBF = CPP / CVR, where CPP = MAP − ICP, or minus central venous pressure when that is higher, and resistance follows Hagen-Poiseuille, so arteriolar radius is the controlled variable. Myogenic autoregulation holds flow relatively constant across a mean arterial pressure of about 70-150 mmHg by varying resistance with pressure; the limits vary considerably between individuals, traditionally shift right in chronic hypertension, sit lower in neonates, and are frequently defective after head injury. Flow-metabolism coupling matches regional flow to regional metabolic rate through local metabolic by-products, nitric oxide and astrocytic mediators. Chemical regulation: flow varies directly and near-linearly with PaCO₂ at about 1-2 mL/100 g/min per mmHg across about 25-70 mmHg, mediated by extracellular pH, lost with severe hypotension, and waning over six to eight hours as CSF bicarbonate adjusts; PaO₂ has little effect between 60 and 300 mmHg but causes marked vasodilatation below 60 mmHg. Rheological: viscosity changes flow only modestly across the normal haematocrit range, but matters in focal ischaemia. Neurogenic: sympathetic nerves limit the rise in flow during an acute pressor surge rather than setting flow at rest. It is cerebral blood volume, not flow, that appears in the Monro-Kellie balance, and the two can move in opposite directions.