ECMO manual

RPMs in VV ECMO

ECMO initiation: Titrate up over 1-5 minutes until the predicted blood flow (BSA*1.8 l/min/m2) is reached (calculator for body surface area: 🧮).
Subsequent titration: Titrate RPM to the minimum amount of flow that maintains adequate systemic oxygenation.
- Usually, this will initially be ~5 L/min.
- ⚠️ Increasing pump flow may increase the recirculation fraction. Thus, further increases in pump flow may not substantially improve oxygenation beyond a certain pump flow rate.

RPMs in VA ECMO

ECMO initiation: Then titrate up over 1-5 minutes until the predicted blood flow is reached (BSA* 2.4 l/min/m2, ~4 L/min).
Subsequent titration:
- Adequate MAP and systemic perfusion.
- Avoid left ventricular dilation. ⚡️

V' (ECMO blood flow)

ECMO blood flow in VV ECMO

If the native lung is not working, an ECMO flow >60-70% of the estimated cardiac output should be adequate (this will usually maintain a systemic saturation >90%). (38999360) However, if the native lung is providing some oxygenation, then less flow may be required.
Initially, flow is usually ~5 liters/min (max ~7-8 liters/min).
Safest range?
- ~3-6 L/min is generally safe (although this may vary depending on equipment and patient factors). (Red Book 6e)
- Higher flows increase the risk of hemolysis.
- Lower flows (<2-3 L/min) increase the risk of thrombosis.
Flow may be weaned off as the native lungs recover. ⚡️

ECMO blood flow in VA ECMO

Usual targets:
- LV or biventricular failure: ~80% of cardiac output (~4-5 L/min).
- Isolated RV failure: ~60-80% of cardiac output (3-5 L/min).
If low, see Low circuit flow.

Pven (venous pressure, aka P1)

This is the pressure before blood enters the pump. It reflects the suction needed to drain central venous blood through the cannula and tubing. Excessively negative pressure can cause hemolysis and damage blood vessels.
⚠️ Target a value >-100 mm. (Red book 6e) Excessively negative pressures can cause hemolysis.

causes of excessively negative Pven (aka drainage insufficiency)

Inadequate pump preload:
- Hypovolemia.
- Excessive intrathoracic pressure (evaluate for pneumothorax, reduce the mean airway pressure).
- Excessive intra-abdominal pressure (consider sedation; reposition drainage cannula above the diaphragm).
- Large variations in intrathoracic pressure:
  - Coughing.
  - Bucking the ventilator
  - (Treatment may include optimization of ventilatory synchrony, increase sweep flow to reduce respiratory drive, and opioids to suppress respiratory drive).
- VA ECMO:
  - Native cardiac recovery (the heart and ECMO circuit compete for preload).
  - Tamponade may compress the right atrium and impede venous drainage.
Venous cannula or tubing problem:
- The venous catheter is kinked.
- The catheter is malpositioned.
- Venous catheter clot (inspect the circuit for clots).
- The cannula is too small (consider the addition of a second drainage cannula).
Excessive pump speed.

management steps could include

Reduce pump speed:
- Is it possible to sufficiently support the patient with a lower ECMO flow rate?
- Sometimes, if there is excessive suction on the access site, reducing pump speed may have a neutral or positive effect on ECMO flow. (Maybauer 2022)
Assess hemodynamics and etiologies of drainage insufficiency.
Last resort: placement of an additional drainage catheter.

Pint (internal pressure, aka P2)

This is the highest pressure in the ECMO circuit.
It reflects the pressure required to push blood through the membrane, tubing, and back into the body.
The goal value is <300 mm to avoid hemolysis (although hemolysis may occur at pressures >250 mm).

Part (arterial pressure, aka post-membrane pressure, aka P3)

This is the pressure inside the arterial return tubing after leaving the membrane. It reflects the pressure required to push blood through the arterial tubing, the cannula, and into the body.
Very high Part (e.g., >300 mm) can cause hemolysis.

return obstruction (high Part, high Pint, stable deltaP)

High return cannula resistance:
- The catheter is kinked or externally compressed.
- The return cannula is incorrectly positioned (including aortic dissection in the case of VA ECMO).
- The catheter is clotted (consider increased anticoagulation).
- The catheter size is too small (consider upsizing).
Increased pressure within the vessel:
- VV ECMO: Central venous pressure is elevated due to tension pneumothorax or pericardial tamponade.
- VA ECMO: Systemic arterial hypertension (MAP >>65 mm).

management of return failure

Check the circuit for any kinks or external pressure on the cannula.
Evaluate for problems listed above.
Vascular imaging may be needed.

▵P (transmembrane pressure)

▵P = Pint – Part.
▵P is normally below ~40-50 mm. (31632747, 24977195, Schmidt 2022)
▵P >60 mm and/or consistently rising ▵P without increased circuit flow suggests membrane lung dysfunction. ⚡️
▵P >100 mm strongly suggests membrane lung dysfunction. ⚡️ (31632747)

sweep gas flow rate

basics

Typical range is 1-9 L/min. (33965970)
Sweep rate affects CO2 clearance. Sweep doesn't affect oxygenation unless the sweep is very low (e.g., <0.5 L/min).

initial sweep flow & pCO2 management

The initial sweep is usually set at ~50-100% of the ECMO flow rate. (Red Book 6e) Historically, the sweep speed was often set equal to the ECMO flow rate. However, newer membrane oxygenators are increasingly efficient, so starting the sweep flow at 50% of the ECMO flow may be better.
Indications to start at a relatively lower sweep speed include:
- [1] Baseline hypercapnia.
- [2] Situations where hypocapnia would be especially detrimental (e.g., elevated intracranial pressure).
⚠️ Among patients with baseline hypercapnia, avoid abruptly dropping the pCO2 (which is associated with neurological injury). Hypercapnia may be gradually controlled (e.g., over ~8-12 hours, depending on whether hypercapnia seems to be causing harm, such as right ventricular failure). (Red Book 6e; Maybauer 2022)
- Correct pCO2 by no more than 50% over the first 4 hours. (Bagchi 2025)

subsequent titration of sweep flow is based on:

[1] Patient comfort: For patients with high respiratory drive and ventilator dyssynchrony, increasing the sweep speed to reduce PaCO2 will reduce the respiratory drive. (Red Book 6e) This may be used to decrease opioid and sedative medication requirements.
[2] PaCO2 (e.g., targeting a safe pH). The sweep flow rate is inversely proportional to the PaCO2 level, as indicated by the below equation. (Red book 6e)
- ⚠️ For patients on lung rest settings, a low pCO2 may facilitate patient comfort and reduce the work of breathing (as discussed above). Consequently, if a patient is comfortable with a mildly low pCO2 (e.g., 30 mm), this may be fine. (Schmidt 2022) However, a normal pCO2 may be desirable to promote adequate brain perfusion in the presence of elevated intracranial pressure.

(New sweep) = (Current sweep)(Current CO2/Desired CO2)

weaning off VV ECMO

As the lungs recover, PaCO2 may start to decrease, allowing sweep flow to be reduced.
If the sweep is <1 L/min, native lungs are eliminating nearly all of the CO2.

FdO2 (fraction of delivered O2), aka FsO2 (fraction of sweep gas O2)

VV ECMO

FdO2 is generally set to 100%.

VA ECMO

Unlike VV ECMO, blood is delivered directly to the tissues. This creates a risk of tissue hyperoxia.
Adjust FdO2 to target slight hyperoxemia (PaO2 ~150 mm) after the oxygenator. (34339398)

SarO2 (arterial return saturation) & ParO2 (pO2 in arterial return)

VV ECMO

SarO2 should be ~100%.
ParO2 should be >600 mm with a new gas exchange device. ParO2 will decrease over time but should remain above ~250 mm (<150-200 mm is abnormally low; see possible causes listed below). (Schmidt 2022)

VA ECMO

SarO2 should be close to 100%, and ParO2 should be adequate but not markedly hyperoxic (see the section above regarding FdO2).
ParO2 should be >2-5 times the FdO2 (e.g., if the FdO2 is 30%, then the ParO2 should be >60-150 mm). (Red Book 6e)

causes of low SarO2 & low ParO2

FdO2 is set too low (FdO2 is discussed in the section above).
Expected limitation of the membrane lung may occur if SvdO2 is <60% and the flow rate is high (near the rated flow of the membrane lung). (Red Book 6e)
Membrane lung dysfunction. ⚡️

SvdO2 (venous drainage oxygen saturation)

SvdO2 interpretation

VV ECMO:
- Recirculation may cause rising SvdO2 with falling systemic oxygen saturation (SaO2).
  - SvdO2 >75% suggests recirculation. (Maybauer 2022)
- Shock (low DO2/VO2) may cause falling SvdO2.
  - SvdO2 <60% suggests inadequate oxygen delivery. (Red book 6e)
VA ECMO:
- SvdO2 more accurately reflects the mixed venous oxygenation in VA ECMO than in VV ECMO (since recirculation isn't possible with VA ECMO).
- SvdO2 should ideally be >65-70%. (Red book 6e; 65% Choi 2019 31364329)
- Interpretation should involve integrating the SvdO2 value with other signs of perfusion (e.g., urine output, skin perfusion).

causes of low SvdO2

Systemic hypoxemia.
Shock.
Anemia.
Increased oxygen consumption (e.g., fever, shivering).

management of low SvdO2 may include

Management of systemic hypoxemia (if present).
- Systemic desaturation in VV ECMO: ⚡️
- Systemic desaturation in VA ECMO: ⚡️
Increase systemic blood flow:
- VV ECMO: If cardiogenic shock has developed, treat it (e.g., adding an inotrope).
- VA ECMO:
  - Increase ECMO flow as able.
  - Reduce afterload if excessive.
Reduce oxygen consumption: (34339398)
- Treat fever.
- Treat shivering. 📖
- Treat agitation.
- Treat tachypnea & ventilator dyssynchrony:
  - Increasing the sweep speed may decrease PaCO2 and thereby reduce the respiratory drive. (Red Book 6e)
  - Deepen sedation (and possibly even use paralysis if necessary).
- If all other causes & therapies for hypoxemia have been exhausted, forced normothermia may be considered (e.g., 36C). (33965970)
PRBC transfusion may be considered (although efficacy is unclear; discussed further here: ⚡️).

low circuit flow & circuit flow arrest
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causes of low circuit flow

Preload inadequate (low Pven): ⚡️
Membrane failure (elevated ▵P): ⚡️
Afterload is excessive (high Part, high Pint, stable deltaP): ⚡️
Inadequate RPMs.

circuit flow arrest

[1] The clamp is still on (shortly after circuit initiation; check to ensure all clamps have been removed).
[2] Pump failure (mechanical or electrical).
[3] Catastrophic clot.
[4] Extra-luminal cannula: Chest radiograph or US to ensure the cannula is in the correct vessel without dissection.
[5] Arterial air alarm: The pump will stop if the arterial bubble detector senses air.
[6] Pump air lock: If the pump has been incompletely primed or has entrained a large amount of air, it will fail.

pump failure
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causes

Console dysfunction:
- Loss of power.
- Electronic malfunction.
Driver failure:
- Not coupled with the pump head.
Pump head failure:
- Thrombosis (noise may be heard).
- Air embolism (pump head airlock).

differential diagnosis

Flowmeter dysfunction.

clinical presentation

Abrupt loss of ECMO flow.

management

Pump head failure:
- Airlock: de-airing.
- Thrombosis: change pump or ECMO circuit.
Try a hand crank or backup console (but not for thrombosis or airlock).
VA ECMO: clamp the circuit to prevent backward flow that may cause a large arteriovenous shunt. (Schmidt 2022)
CPR may be required.

membrane lung dysfunction
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manifestations of membrane lung dysfunction may include:

[1] key finding is elevated ▵P

▵P is normally below ~40-50 mm. (31632747, 24977195)
▵P >60 mm and/or consistently rising ▵P without increased circuit flow suggests membrane lung dysfunction.
- However, the best parameter to trend is arguably the resistance of the membrane lung (▵P/ECMO blood flow).
▵P >100 mm strongly suggests membrane lung dysfunction. (31632747)
(Other findings may include: High Pint, stable Part, and reduced circuit flow.)

[2] hemolysis and/or DIC (discussed below)

[3] impaired gas exchange

Low SarO2 & low ParO2:
- This suggests membrane dysfunction, if present (discussed further: ⚡️).
- However, clots often reduce the blood flow through the membrane lung without reducing PaO2 of returning blood (similar to a central pulmonary embolism). (Maybauer 2022)
Increasing requirement for sweep speed: steadily increasing sweep flow requirements may indicate membrane dysfunction. (Schmidt 2022)
Reduced oxygen transfer rate (<100-150 ml/min) using the formula below supports the presence of membrane dysfunction. (Red Book 6e; Schmidt 2022) Other oxygenation variables should be maximized before calculation (e.g., FsO2 set to 100%). However, it's dubious how much additional insight this calculation adds beyond considering the SarO2 and ParO2. Numerous factors other than membrane lung dysfunction may also cause a reduced oxygen transfer rate (e.g., recirculation, anemia, low ECMO flow).

O2 transfer rate ~ 13.4(ECMO flow)(Hb)(▵ O2 sat)

Example: 13.4(4L/min)(10 mg/dL)(0.30) = 161 ml/min

bedside examination of membrane lung

signs of membrane lung dysfunction

Visible clots may be present on the membrane. However, this may not correlate well with membrane lung function since you see only part of the membrane.
The blood in the arterial tubing isn't bright red.
Blood leaking across the membrane into the gas exhaust line is another sign of membrane dysfunction – this requires the exchange of the membrane. Keep the gas exhaust outlet vented to the atmosphere until the membrane can be exchanged (otherwise, an air embolism may occur). (Schmidt 2022)

basic troubleshooting: ensure that

The gas source is connected and turned on.
The blender is set correctly.
Gas lines are connected and not kinked.

laboratory evaluation of membrane lung function

compare pre- and post-membrane blood gas values

⚠️ Sigh the membrane before measuring blood gas values (see below).
Oxygenation: Post-membrane O2 saturation & pO2 values are discussed here: ⚡️
Ventilation: Signs of membrane lung dysfunction may include:
- <10 mm difference in pCO2 between pre- and post-membrane blood gas despite an adequate sweep speed.
- Post-membrane pCO2 >45 mm (especially if the sweep gas flow rate is considerably higher than the ECMO flow rate).

hematologic abnormalities:

DIC: ⚡️
- Rising D-dimer.
- Falling fibrinogen level.
- Prolonged PT and PTT.
- Trends may be more important than individual values. (Maybauer 2022)
Hemolysis: ⚡️

management of membrane lung dysfunction

Sighing the lung may improve gas exchange:
- Increase sweep speed to 10-15 liters/minute for 10 seconds.
- This is an attempt to remove any moisture accumulation.
- (This won't eliminate clots in the membrane, so it won't fix an elevated ▵P).
Increasing anticoagulation levels may stabilize membrane dysfunction. (Schmidt 2022)
Replace the membrane or entire circuit.

air embolism
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definition

This refers to any air in the circuit.

causes

Entrainment: air from the atmosphere.
- [1] Circuit breech pre-pump will suck air from the environment.
- [2] Central or peripheral line near the drainage catheter that is left open or is leaking.
- [3] The drainage cannula was partially withdrawn.
- [4] Percutaneous tracheostomy with suction of air through the inferior thyroid vein.
Cavitation:
- [1] Excessively negative pressure generates microbubbles.
- [2] High sweep gas flow rate with a low blood flow rate.
Oxygenator:
- Oxygenator membrane rupture.
- Occlusion of the gas exhaust outlet. (Schmidt 2022)

manifestation

Bubble sensor alarm.
Air in the pump head may cause a distinctive sound.
A large amount of air may cause a pump airlock, with immediate loss of ECMO support.

management

Eliminate the source of air.
De-airing the circuit if possible.
Exchanging the circuit if necessary.
The patient should be placed in the Trendelenburg position so that any embolized air will be directed toward the legs. (Schmidt 2022)

circuit disruption causing blood loss
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basics

Circuit disruption downstream of the pump will cause blood loss from the circuit.

clinical presentation may include

Drainage insufficiency.
Hypotension.
Flow sensor alarm may be activated.
Blood is leaking out of the circuit.

management

Place clamps on both sides of disruption to stop ongoing blood loss.
Replace or repair the circuit.
Transfusional support to replace lost blood.

systemic desaturation in VV ECMO
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what are the saturation goals?

[1/2] Systemic arterial saturation of ~80-90% (PaO2 >~45 mm).
- Target a saturation >80% during rest settings, as long as cardiac output and hemoglobin are adequate. (ELSO guidelines)
- Arterial oxygen saturation is typically ~80-90%. (33965970)
- ⚠️ Pulse oximetry measurements may be ~3-7% too high due to elevated levels of carboxyhemoglobin. Inaccuracy appears to increase over time during an ECMO run. This may lead to occult hypoxemia in VV ECMO patients. (Taha 2024)
[2/2] Venous drainage saturation (SvdO2 ⚡️) of >~60%.
- In the absence of recirculation, SvdO2 may be utilized to assess the adequacy of systemic oxygenation.
- Targeting a SvdO2 >60% is a convenient index of adequate oxygenation. (Red Book 6e)

common causes of systemic desaturation

Basic system malfunctions (e.g., disconnection of sweep gas tubing).
Membrane lung dysfunction.
Recirculation.
ECMO flow relative insufficiency (<60% of native cardiac output).
Unusually low SvdO2 saturation.

The approach to systemic desaturation is as follows:

(#1) basic circuit check

FdO2 is set to 100%.
Sweep is functioning.
The tubing is connected correctly.

(#2) evaluate for membrane dysfunction

Consider ▵P:
- ▵P is normally below ~40-50 mm. (31632747, 24977195)
- ▵P >60 mm and/or consistently rising ▵P without increased circuit flow suggests membrane lung dysfunction.
- ▵P >100 mm strongly suggests membrane lung dysfunction. (31632747)
(Further discussion of membrane lung dysfunction: ⚡️)

(#3) evaluate for recirculation

diagnosis: signs of recirculation

Saturations:
- Increased SvdO2 >75%.
- (SpO2 – SvdO2) <10%. If this difference becomes negative (i.e., SvdO2 > SpO2), then recirculation is definitely occurring.
- Trends show a rising SvdO2 with a falling SpO2. (Taha 2024)
Visualization:
- Blood exiting and entering the patient may have a similar color (this is a visual representation of the saturation gradient discussed above).
- The drainage cannula may show flashes of bright red blood. (Schmidt 2022)
A paradoxical decrease in systemic saturation may occur with increasing ECMO flow. (33965970)
Radiography may suggest cannula malposition:
- If two cannulas are used, placement within <8 cm suggests recirculation (ideal distance may be ~8-13 cm). (Bagchi 2025)
- If a double-lumen cannula is used, placement with the arterial outflow pointing away from the right atrium may promote recirculation.

management of recirculation

Changing the ratio of circuit flow / cardiac output:
- Increasing the native cardiac output will reduce recirculation.
- Reducing pump speed will reduce the recirculation fraction (but this won't necessarily improve systemic oxygenation).
Reposition catheter(s) if malpositioned:
- With a dual lumen catheter (e.g., Avalon) – make sure the return port is oriented towards the tricuspid valve. POCUS or TEE may be helpful. (Maybauer 2022) Also, ensure that the catheter hasn't been malpositioned into the hepatic vein, which may promote recirculation. (Schmidt 2022)
- With two single-lumen catheters, target a separation distance of ~15 cm. (31632747)
Alter the ECMO circuit:
- Add another venous drainage catheter.
- Switch to a dual-lumen cannula (if feasible).

(#4) is ECMO flow inadequate?

general

Initially, ECMO flow should be >60% of cardiac output.
Causes of inadequate ECMO flow:
- Circuit dysfunction.
- Elevated cardiac output.

treatment: increase ECMO flow

See the section above on low circuit flow. ⚡️
For persistent hypoxemia, consider increasing ECMO flow to as high as ~6-7 liters/minute if possible. (31632747) However, increased ECMO flow may increase the risk of hemolysis, so this will need to be monitored more carefully at higher flow rates.

(#5) consider measures to increase SvdO2 (especially if SvdO2 is unusually low)

Some venous blood will always bypass the ECMO circuit. Consequently, improving the saturation of the venous blood (SvdO2) will improve the saturation of the systemic arterial blood. Potential interventions include the following (with further discussion above ⚡️).

Reduce systemic oxygen consumption: (34339398)
- Treat fever.
- Treat shivering. 📖
- Treat agitation.
- Treat tachypnea/ventilator dyssynchrony:
  - Increasing the sweep speed may decrease PaCO2 and thereby reduce the respiratory drive. (Red Book 6e)
  - Deepen sedation (and possibly even use paralysis if necessary).
- If all other causes & therapies for hypoxemia have been exhausted, forced normothermia may be considered (e.g., 36C). (33965970)
PRBC transfusion may be considered (although efficacy is unclear; discussed further here: ⚡️).

(#6) consider native lung deterioration

diagnosis

Chest radiograph shows pulmonary deterioration.
Impaired ventilator mechanics.

management may involve

Discontinue systemic vasodilators.
Add inhaled pulmonary vasodilators.
Increased FiO2 and potentially PEEP:
- Lung rest is ideal, but moderate increases in FiO2 (e.g., 60-70%) are likely safe.
- (With increased sweep speed and low respiratory rates, ventilator-induced lung injury and mechanical power administration to the lung may be kept at a minimum.)

ventilator optimization in VV ECMO
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rest ventilator settings (aka ultra-lung-protective ventilation)

general goals for ultra-lung-protective ventilation

PEEP: ≧10 cm is recommended (10-24 cm is an acceptable range). (33965970)
- Insufficient PEEP may lead to atelectasis. (33965970)
- Excessive PEEP could:
  - Impair venous return (into the drainage cannulae, leading to low Pven).
  - Impair right heart function.
  - Produce an excessively high plateau pressure. (33965970)
Plateau pressure: the recommended target is <25 cm (≦ 30 cm is acceptable). (33965970)
- Plateau <20 cm may be associated with less ventilator-induced lung injury and improved outcomes. (33965970)
Driving pressure ≦10 cm. (Bagchi 2025)
Tidal volume ~4 cc/kg ideal body weight.
Respiratory rate of 5-10 breaths/minute. (4-15 per ELSO 33965970)
- CO2 clearance can be easily achieved with sweep flow, so minute ventilation should be minimized to reduce mechanical power delivery to the lungs.
- 💡 Reducing the respiratory rate will cause a linear reduction in mechanical power delivered to the lungs. (34597688)
FiO2:
- FiO2 should be low enough to avoid oxygen toxicity. The level of FiO2 at which oxygen toxicity occurs is unclear but may be as low as ~60-70%. (23271823)
- FiO2 should be high enough to help somewhat with systemic oxygenation (this may reduce the required ECMO circuit flow).
- An acceptable FiO2 range might be 30-50%. (33965970)

examples of typical resting settings

Pressure Control ventilation:
- Respiratory rate 10.
- PEEP 10 cm.
- Inspiratory pressure 10 cm initially (but down-titrate to target 2-4 cc/kg tidal volume).
- FiO2 50% (range 30-50%).
Volume cycled ventilation:
- Respiratory rate 10.
- Tidal volume 4 cc/kg (target plateau ≦24 cm), PEEP ≧10 cm.
- FiO2 50% (range 30-50%).
APRV: P-Hi 15 cm, T-hi 6 seconds, T-low 0.3 seconds, FiO2 30-50%.

weaning off VV ECMO
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readiness for weaning

general signs of lung recovery

Reversal of the process that required ECMO initiation.
Improved chest radiograph.
Improved gas exchange:
- Increased etCO2, decreased PaCO2, and perhaps most importantly, decreased (etCO2 – PaCO2) gap (this gap reflects the amount of dead space).
- Improved systemic oxygen saturation.
Increased lung compliance.

rough criteria to consider when initiating a weaning trial among intubated patients

Oxygenation:
- FiO2 consistently ≦60%.
- PEEP is relatively low (e.g., ≦10 cm for non-obese patients).
- PaO2 ≧70 mm.
Ventilation:
- Tidal volume <8 ml/kg IBW.
- Respiratory rate ≦28.
- Plateau pressure ≦28 cm and driving pressure <15 cm (if the patient is sufficiently passive on the ventilator to evaluate these accurately).
- ABG/VBG shows that both pH and PaCO2 are acceptable without excessive work of breathing.
- P0.1 is <5-10 cm (discussed further: 📖)
- Minute ventilation isn't severely elevated (suggesting a manageable amount of physiological dead space).
- etCO2/paCO2 ratio >.83 (35608503)
Imaging: Chest radiograph improved.

weaning from VV ECMO

Weaning may occur over several hours to days, based on the patient's condition.

[0] Gradual increase in the level of ventilator support

During weaning, the ventilator should be gradually increased to a standard, lung-protective level of ventilator support. For example:
FiO2 may be increased to 30-60%.
Liberalize respiratory rate to a usual rate (<30 b/min).
Pressure-regulated modes of ventilation: (33965970)
- Liberalize total pressure to no more than 28 cm.
- Ensure that tidal volumes increase to 6-8 cc/kg.
Volume-regulated modes of ventilation: (33965970)
- Liberalize tidal volume by 1 cc/kg increments up to 6-8 cc/kg. (Red Book 6e)
- Plateau pressure should be kept ≦28 cm.
⚠️ Monitor for excessive work of breathing.

[1] Reduce ECMO blood flow to a moderate level

2-3 liters/min might be reasonable.
Flow should be maintained at >1 liter/minute to avoid thrombosis. (33965970)

[2] Reduce sweep gas

Stepwise reduction in sweep gas flow rate by 0.5-1 L/min to the goal of 1 L/min.
Check ABG with each decrement in the sweep gas flow rate.
Monitor saturation, pH, and work of breathing. (33965970)

[3] Off-sweep gas challenge

Turn off the sweep gas entirely for at least 2 hours (2-24 hours). (Red book 6e) The gas tubing should be clamped to prevent oxygen entrainment (analogous to apneic oxygenation). (Maybauer 2022) In a series of 192 off-sweep challenges, no significant changes were detected after two hours – so two hours may be an adequate duration. (31736407)
Oxygen within the membrane lung may be consumed within ~20 minutes, so close attention should be paid to look for delayed desaturation. (Maybauer 2022)
Pay close attention to:
- Oxygenation (saturation >88-92%; PaO2 >70-95 mm; FiO2 ≦60%).
- Ventilation (pH >7.3; pCO2 close to the patient's baseline).
- Absence of hemodynamic instability (e.g., arrhythmia, hypertension, hypotension).
- Absence of respiratory distress; p0.1 isn't very high. 📖 (33965970, Red Book 6e, Schmidt 2022)

[4] Decannulation

Confirm that off-sweep gas ABG shows PaO2 >70 mm and acceptable pH without excessive work of breathing.
The patient should be NPO (or, if a gastric tube is in situ, it should be placed on suction).
Coagulation & hematology:
- Consider coagulation status (e.g., platelet count, coagulation studies).
- Hold heparin before decannulation (guidelines recommend at least 30-60 minutes).
- The patient should have an active type-&-screen in case there is a hemorrhage.
Decannulate:
- Extreme care is required to avoid air embolism (which may occur if air is entrained through the side holes of a cannula during removal). Short-term paralysis on the ventilator may be used to ensure positive intrathoracic pressure while cannulas are removed. (Maybauer 2022)
Observe for potential complications:
- Air embolism.
- Pulmonary embolism.
- Bleeding.
- Post-decannulation SIRS.
Check for DVT after 24 hours. (33965970) The risk of DVT may be >60%. Risk factors include femoral site, larger cannula size, and less intense anticoagulation. (Red Book 6e)

RV dysfunction in VV ECMO
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basics

RV dysfunction is common in ARDS (with a rate of ~10-25%).
VV ECMO may indirectly improve RV dysfunction in several ways:
- Reduced intrathoracic pressures.
- Improved oxygenation.
- Improved pCO2 and pH.
Patients with severe, chronic pulmonary hypertension may require VA ECMO. However, patients with acute RV dysfunction due to ARDS can generally be managed with VV ECMO.

management of RV dysfunction

Other treatments for RV dysfunction:
- Pulmonary vasodilators.
- Inotropes.
- Diuretics.
VA ECMO as a last resort:
- Most RV dysfunction can be managed with VV ECMO, which typically produces fewer complications. (31632747)
- For persistent RV dysfunction, VV ECMO may be converted to VVA ECMO.

ventilator optimization in VA ECMO
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[#1/2] if the left ventricle is ejecting a significant volume of blood (most patients)

In this scenario, blood from the native lungs will supply the right arm and upper body. Blood from the ECMO circuit will supply the lower body.

ventilator settings regarding oxygenation

Adjust PEEP and FiO2 to achieve an adequate PaO2 in the right arm.
- PaO2 in the right arm should be <120 mm to reduce the risk of cerebral hyperoxia. (Red Book 6e)
PEEP:
- PEEP may help prevent left ventricular dilation and cardiogenic pulmonary edema (discussed further: ⚡️). However, high levels of PEEP may worsen right ventricular function and impair venous return (thereby reducing renal perfusion).
- Moderate PEEP is often utilized initially (e.g., 8-10 cm). (Red Book 6e)

**ventilator settings regarding ventilation (CO2)**

CO2 clearance will occur via both the membrane lung and the native lungs. This may lead to differential CO2 levels within the body (analogous to differential hypoxemia, aka north-south syndrome). However, CO2 differences between venous and arterial blood are much smaller than pO2 differences between venous and arterial blood (e.g., ▵pO2 between arterial and venous blood is often ~75 mm, whereas the ▵pCO2 may be closer to ~5 mm). Consequently, differential CO2 levels are much less consequential than differential O2 levels. An exception to this is that if blood flow through the lungs is extremely sluggish, then blood may be over-ventilated in the lungs, leading to hypocarbia in blood ejected through the aorta.
The patient's pCO2 and pH values may be optimized by adjusting the patient's minute ventilation and/or sweep speed. Predominantly clearing CO2 via the ECMO circuit may promote lung rest, as discussed next.

partial lung rest with VA ECMO

Since oxygenation of the upper body is dependent on the native lungs, it's not possible to achieve ultra-lung protective ventilation settings as utilized in VV ECMO. However, substantial lung rest is possible with VA ECMO, as follows:
[1] PEEP and FiO2 are titrated as described above.
[2] The respiratory rate is decreased to ~6-10 breaths/minute, and the tidal volume is reduced to ~6 cc/kg. Remember that reducing the respiratory rate causes a linear reduction in mechanical power delivered to the lungs. (34597688)
[3] Sweep gas speed in the ECMO circuit is increased to provide adequate CO2 clearance. Titrate the sweep gas rate to achieve a normal pCO2 in blood returning from the ECMO circuit. Most of the CO2 clearance should occur extracorporeally. (Red Book 6e)

[#2/2] if the body is being supplied primarily by the ECMO circuit (central cannulation)

This may occur in patients with central cannulation.
In this situation, oxygenation and ventilation are predominantly performed by the ECMO membrane. ECMO settings may be titrated based on the right arm's blood gas values.
Ventilator settings won't affect systemic tissues much. For patients with concomitant ARDS, it may be desirable to rest the lungs using ultra-lung-protective ventilation similar to VV ECMO (as discussed above ⚡️).

systemic desaturation in VA ECMO
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[1] Make sure FdO2 is set to 100%, and the sweep is functioning.
[2] Is there differential hypoxemia? If so, see this section: ⚡️
[3] If saturation is low everywhere, consider membrane lung dysfunction: ⚡️

hemodynamic targets in VA ECMO
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MAP goal

The optimal MAP varies between patients (there is no single optimal MAP).
- Inadequate MAP threatens to cause hypoperfusion and acute kidney injury.
- Excessive MAP may increase LV afterload, causing LV dilation. Alternatively, higher MAPs may be OK for patients with isolated RV dysfunction.
Most authors suggest targeting a normal MAP (~65-80 mm). (31219839) However, lower MAPs may be acceptable in the context of intact perfusion, especially among patients with chronic hypotension.

hypotension in VA ECMO

MAP = (Native cardiac output + ECMO flow)(SVR)

[1] Ensure perfusing rhythm.
[2] Assess volume status and hemoglobin (give fluid or blood if indicated).
[3] Attempt to increase ECMO flow (if LV distension/forward flow allows).
[4] Assess SVR (if low, then increase vasopressors).
[5] If ejection function is decreased on echocardiography, an increased dose of inotrope may be considered (this may be required in tandem with increased ECMO flow to allow the LV to continue ejecting).

Related topic: low pre-membrane oxygen saturation is discussed here ⚡️

hypertension in VA ECMO

Assess volume status; diurese if indicated.
Assess SVR; if high, then reduce vasopressor.
If improved ventricular function on echocardiography:
- Reduce inotrope dose.
- Consider reduction in ECMO flow.

LV distension
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general concept of LV distension

ECMO increases the MAP. This is good for systemic perfusion but increases afterload on the left ventricle.
If the LV is unable to eject blood against this afterload, this causes a host of problems:
- [1] The left ventricle dilates, pushing it off the Starling Curve.
- [2] Dilation increases the wall tension in the left ventricle, promoting myocardial ischemia.
- [3] Stasis promotes clot formation in LV (even despite full anticoagulation). This may be especially problematic among patients being anticoagulated with bivalirudin (bivalirudin is degraded by serum proteases, so if there is a high degree of stasis, this may lead to low local concentrations of bivalirudin).
- [4] Blood backup leads to cardiogenic pulmonary edema, leading to diffuse alveolar hemorrhage. This may also promote the development of pulmonary hypertension. (31530454)
- [6] Sluggish blood flow through the lungs may cause blood exiting the aorta to be over-ventilated (with a low pCO2 and respiratory alkalosis).
If LV distension occurs with aortic regurgitation, this can be especially problematic (with marked elevation in LV pressures).
If untreated, LV distension may prevent the LV from recovering.

risk factors for LV distension

Baseline LVEF <30%.
Mitral and/or aortic regurgitation.
VT storm.
Post-cardiac arrest.

diagnosis of LV distension

Low pulse pressure, measured via A-line in the right arm.
- The pulse pressure should ideally be >10-15 mm. (31219839)
- Pulse pressure <10 mm suggests LV distension with poor function (although low LV preload is also possible, for example, due to right ventricular failure).
- ⚠️ Pulse pressure isn't reliable if there is an IABP in place.
End-tidal CO2 <15 mm is sensitive for identifying native cardiac output <1 L/min. (32962727)
Cardiogenic pulmonary edema:
- Thoracic ultrasonography: Bilateral B-lines.
- Chest radiograph: pulmonary edema.
Echocardiography:
- [1] LV dilation with profoundly reduced ejection fraction.
- [2] The aortic valve should open at a minimum of once every three beats. Less frequent opening of the aortic valve indicates LV distension.
- [3] “Smoke” in the left ventricle indicates blood stasis & thrombosis risk.
- [4] At least moderate mitral regurgitation is usually present with LV distension. There is a bidirectional relationship between mitral regurgitation and LV dilation. Underlying mitral regurgitation promotes LV dilation, but LV dilation itself can cause functional mitral regurgitation. (Maybauer 2022)

management of LV distension

⚠️ Achieving LV ejection as soon as possible is essential to avoid thrombosis within the left ventricle.

basic initial maneuvers

Ensure a perfusing rhythm (e.g., treat VT).
Ensure adequate anticoagulation. There is a very high risk of thrombus formation in the left ventricle. Until LV distension can be resolved, ensure the patient is fully anticoagulated.

reduce ECMO flow rate

This might be the most effective noninvasive strategy for treating LV distension. (34339398)
(Further discussion of ECMO flow: ⚡️)

increase PEEP

Why this may help:
[1] PEEP may reduce LV preload, thereby decreasing pulmonary blood flow.
[2] PEEP may reduce LV afterload.
[3] PEEP may help prevent cardiogenic pulmonary edema.

vasodilators & inodilators

Vasodilator therapy (if MAP >65 mm):
- Low MAP may be acceptable if perfusion is adequate.
- If the patient is on pressors: Wean vasopressors.
- If the patient is not on pressors: Consider an arterial vasodilator or an inodilator. Afterload reduction is a desirable strategy because it reduces cardiac work (thereby decreasing myocardial ischemia).
Inodilator therapy:
- Initiate or up-titrate dobutamine or milrinone (most patients with LV failure will need this).
- (Avoid excessive inotropic treatment, as this may increase myocardial work and myocardial ischemia.)

diuresis

If hypervolemic, diuresis may be attempted.
However, diuresis is probably the least effective therapy for LV distension. (34339398)

if less invasive therapies fail: LV venting

IABP:
- This may improve ejection & coronary artery perfusion.
- Meta-analyses suggest a benefit from IABP regarding the ability to wean from ECMO. (31530454)
- ⚠️ Pulsatility may be falsely reassuring among patients who have an IABP. For such patients, aortic valve opening should be assessed with echocardiography. (Red Book 6e)
Impella: Impella may increase hemolysis (already a problem on ECMO) or limb ischemia (if both femoral arteries are cannulated). Note that LV thrombus is a contraindication to impella, as it may promote stroke in this situation.
Surgical vent: a cannula inserted to drain blood (if centrally cannulated). This is connected to the venous return cannula. Vent flow should be monitored, as there is a risk of thrombosis if flows decrease. (Bagchi 2025)
Percutaneous transseptal venting of the left atrium, or balloon atrial septostomy.

differential hypoxemia (aka north-south syndrome)
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epidemiology

Occurs in ~8% of patients on VA ECMO with peripheral cannulation.

cause

Three factors are required for differential hypoxemia:
- [1] VA ECMO with an arterial catheter in the femoral position.
- [2] Native cardiac output is sufficient to push the mixing cloud down the aorta.
- [3] Native lungs aren't working.
- (If the IVC is utilized for venous drainage, this may worsen matters by establishing dual-circuit circulation wherein blood tends to circulate within the upper body or lower body – with relatively little mixing between these areas).
The initiation of differential hypoxemia may relate to one of the following events:
- [1] Recovery of the left ventricle (in the context of ongoing lung failure).
- [2] Development of lung failure (in the context of ongoing left ventricular ejection of blood into the proximal aorta).
The net effect of these factors is that deoxygenated blood is delivered to the upper body (including the brain and coronary arteries).

diagnosis: clinical findings

[1] Saturation & PaO2 in the right upper extremity is lower than in the lower extremities.
[2] NIRS (near-infrared spectroscopy) reveals inadequate regional oxygen saturation in the brain:
- rSO2 >60% might be a therapeutic target.
- rSO2 <40% indicates cerebral desaturation & risk of brain injury.
- rSO2 asymmetry >8%.
Ventricular arrhythmias may result from perfusing the heart with deoxygenated blood. (31219839)
Venous drainage oxygen saturation (SvdO2 ⚡️) may be unusually high.
Increased pulsatility in the arterial line tracing may be seen.

treatments for differential hypoxemia

Improve the native lung function, e.g.:
- Increase the FiO2 and PEEP.
- Inhaled pulmonary vasodilators.
- Evaluate and treat any new causes of respiratory failure (e.g., VAP).
Decrease the ratio of (cardiac output)/(ECMO flow):
- [i] May decrease the power of a venting Impella.
- [ii] May decrease inotrope dose.
- [iii] Beta-blockers may be utilized to reduce endogenous cardiac output if excessive (although this raises a question of whether VA ECMO is still required). (Red Book 6e)
- [iv] May increase the ECMO flow (however, this could exacerbate cardiogenic pulmonary edema, so it's inadvisable). (Bagchi 2025)
- ⚠️ These therapies may be used as a temporizing measure to preserve oxygenation to the heart and brain. However, they will lead to left ventricular distension, so this isn't a viable long-term solution.
Switch modalities or access points:
- If the heart has recovered but the lungs continue to fail, switch to VV ECMO.
- If the patient remains dependent on VA ECMO for cardiac support, transition to V-AV ECMO:
  - Add a cannula to return oxygenated blood to the SVC.
  - This produces a combination of VV ECMO & VA ECMO.
  - Benefit: improved cerebral & coronary oxygenation.
  - Cost: reduced systemic perfusion (will reduce flow going to body), added complexity, increased likelihood of access complications. Individual flowmeters may be needed for both return catheters to avoid excessive flow return to the venous system. It may be challenging to achieve a high enough flow to perform both VV and VA ECMO simultaneously.
- The arterial return cannula may be repositioned to the axillary artery (although this carries a risk of hyperperfusion).
- Last-line intervention: convert to central cannulation of the aorta.

reverse differential hypoxemia

This rare phenomenon involves hypoxemia of the lower body, with normal saturation in the upper body.
Three factors are required simultaneously to generate this:
- [1] VA ECMO with an arterial catheter in femoral position.
- [2] The heart and lungs are working reasonably well.
- [3] Membrane failure causes the SarO2 to be low.
Management may involve either:
- [1] Replace the membrane.
- [2] Consider whether ECMO is still required. Reverse differential hypoxemia occurs only if there is some function of the native lungs and heart, so it can be a sign that ECMO can be weaned and discontinued.

VA ECMO with central cannulation
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This is essentially cardiopulmonary bypass.
Pulse pressure is generally <10 mm.
ECMO flow is titrated against a MAP goal (~65-70 mm), usually ~5 L/min.
- ECMO flow = perfusion to the body.
Nearly all patients receive an empiric LV vent.
There are no problems with differential hypoxemia.

VA ECMO in RV failure
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examples include:

Acute RV failure due to pulmonary embolism.
Long-standing pulmonary hypertension.

some unique issues encountered:

LV under-filling (rather than LV over-filling).
RV failing to eject.

LV under-filling

Clinical manifestation:
- Low pulse pressure.
- LV under-filled on echo.
Mechanism: RV failure with inadequate blood delivery to LV
Management:
- [1] Inhaled pulmonary vasodilators (to decrease RV afterload & improve flow to the LV).
- [2] Inotropes to improve RV contractility.
- [3] Decrease afterload (MAP) as clinically tolerated (e.g., with decreased vasopressors or the addition of a vasodilator).
- [4] Decreasing ECMO flow (this may increase preload on the RV, thereby improving flow through the heart).
  - Less ECMO flow is generally needed in isolated RV failure.

RV failing to eject

Failure of RV to eject is problematic:
- (a) Impairs perfusion & recovery of RV.
- (b) This may cause stasis & clots in pulmonary vascular bed. Especially in the case of massive pulmonary embolism, this may cause catastrophic clot extension.
- (c) Inability to deliver drugs to pulmonary vasculature.
Management may include:
- Inhaled pulmonary vasodilators.
- Inotropes to improve RV contractility.
- Intravenous pulmonary vasodilator may be considered.

weaning off VA ECMO
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VA ECMO increases LV afterload (which may impair LV function) and reduces RV preload. Weaning VA ECMO involves reducing ECMO support to determine how the heart will respond to increased RV preload and reduced LV afterload.

signs of recovery

cardiac recovery

Minimal vasoactive/inotropic support, which is defined as 1-2 of the following:
- Dobutamine <3 ug/kg/min.
- Milrinone <0.3 ug/kg/min.
- Norepinephrine <0.06 ug/kg/min.
- Epinephrine <0.1 ug/kg/min.
- Phenylephrine <1 ug/kg/min.
- Vasopressin <0.03 ug/kg/min. (34339398)
- (Another way to evaluate this: the Vasoactive Inotropic Score 🧮 should be <10.) (Red Book 6e)
ECMO flow decreased to 2-2.5 L/min (with adequate mixed venous or central venous oxygen saturation).
Increased pulse pressure and ejection fraction on echocardiography (further discussion of favorable echocardiographic parameters below).

pulmonary recovery

Increased SpO2 on moderate FiO2 (≦60%).
Chest radiograph improvement.
Decreased PaCO2 & decreased (PaCO2 – etCO2) gap.
- Rising etCO2 may be a reflection of increased native cardiac function with increased blood flow through the native lungs.
Increased pulmonary compliance.

weaning of VA ECMO

optimize

Ventilator settings.
Fluid balance.
Cardiac medications.
Support devices (e.g., IABP, Impella).

slowly reduce blood flow to 1 L/min

Consider intensifying anticoagulation to prevent thrombosis.
Drop the flow rate by 0.5 L/min every 10-15 minutes until reaching 1 L/min flow. (Red Book 6e)
Evaluate hemodynamic and respiratory stability (green criteria below). Ventilatory and hemodynamic support may need to be up-titrated.
⚠️ NEVER turn off the sweep flow (unlike weaning from VV-ECMO).

clamp trial

Evaluate for 3-5 minutes on no support (circuit clamped). Evaluate for the following criteria:
[1] Stable hemodynamics and perfusion, e.g.:
- MAP >60-65 mm.
- Mixed venous oxygen saturation >65%. (Schmidt 2022)
- CVP ≦10-18 cm. (34339398; Maybauer 2022)
[2] Stable oxygenation.
[3] Favorable echocardiographic parameters, such as:
- Aortic VTI >10 cm.
- Lateral mitral annulus tissue Doppler peak systolic velocity >6 cm/s.
- LVEF >~25% (ideally, the LV will increase during ECMO weaning due to reduced afterload and preserved contractile reserve). (34339398, Maybauer 2022)
- Absence of significant RV dilation.
- Absence of severe tricuspid regurgitation. (Red Book 6e)

decannulation

Prior to decannulation, increase the ECMO flow rate and hold anticoagulation (maintaining a higher ECMO flow during this period may avoid circuit thrombosis).
Once anticoagulation has worn off, decannulate.
Evaluate for complications:
- Neurovascular monitoring for arterial insufficiency.
- Ultrasound evaluation for DVT or arterial thrombus.

determining optimal anticoagulation intensity
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Anticoagulation intensity may be personalized based on the following factors. For example, anti-Xa or PTT targets may be adjusted during an ECMO run.

hemorrhage & hemostatic challenges?

Hemorrhage: Severity? Adequacy of local hemostasis?
Recent or pending surgeries/procedures?

evidence of pathological thrombosis?

History of DVT/PE?
Evidence of intracardiac thrombosis?
Fibrin or clot formation in the circuit?
Elevated ▵P?

**the net state of anticoagulation: consider all coagulopathies, including**

Medications (e.g., aspirin, P2Y12 inhibitors).
Uremic coagulopathy.
Thrombocytopenia.

VV ECMO versus VA ECMO

VV ECMO doesn't carry a risk of ischemic stroke or intracardiac thrombosis, so lower intensity of anticoagulation may be used.
- Anticoagulation can be held for prolonged periods with a flow rate maintained at >2.5-3 L/min if necessary. (Red Book 6e)
- However, access-site DVT and PE risks remain high (even despite anticoagulation).
VA ECMO patients may require more intense anticoagulation:
- [1] There is a higher risk of systemic embolization, such as ischemic stroke (especially if there is stasis of blood within the heart).
- [2] During weaning from VA ECMO, circuit flow is reduced, increasing the risk of thrombosis. (37763010)

flow rate & residence time

Higher flow rates require less anticoagulation:
- Flow rates <~2 L/min increase the risk of circuit thrombosis.
- If anticoagulation isn't safe, then high flows (e.g., 4-5 L/min) should minimize clot formation within the circuit. (31632747)
Residence time is the blood's average transit time in the circuit. One study of pediatric ECMO found that circuit lifespan may improve when the PTT/RT ratio is >2.5. (31977350) Thus, a simpler circuit with a faster flow rate may require less intense anticoagulation. (38671589)
(Further discussion of circuit flow: ⚡️)

duration of ECMO & timing

During an ECMO run, the circuit may become coated with proteins that tend to prevent thrombosis. Later on, during an ECMO run, less anticoagulation may be needed.

coagulation monitoring & targets
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core laboratory studies involved in coagulation monitoring (with targets)

Platelet count (& thrombocytopenia): ⚡️
Fibrinogen. ⚡️
INR. ⚡️
TEG. ⚡️
PTT. ⚡️
Anti-Xa level (only patients on heparin). ⚡️
Integrating anti-Xa & PTT to monitor heparin gtts. ⚡️

[1/7] platelet count

thrombocytopenia & platelet dysfunction in ECMO

Platelet count often falls to <40% normal within a few hours of ECMO initiation.
~25% of patients experience a platelet count <50,000. (Red Book 6e)
Aside from reducing platelet count, platelet dysfunction may also occur due to reduced glycoprotein (GP)Ib-alpha and GP-VI levels (receptors for vWF and collagen, respectively).
Thrombocytopenia seems to be an important risk factor for intracranial hemorrhage. (Red Book 6e)

causes of thrombocytopenia include

ECMO itself (including membrane lung dysfunction, pump head thrombosis).
DIC.
HIT.
Other causes of thrombocytopenia in the context of critical illness, e.g.:
- Sepsis.
- Major surgical procedures.
(Further discussion of causes of thrombocytopenia in ICU: 📖)

platelet transfusion threshold

Ideal platelet levels are unclear; this may depend on the overall balance of hemostasis/thrombosis and clinical context.
50 b/L is a commonly utilized transfusion threshold for nonbleeding patients (especially among patients on therapeutic anticoagulation), although some protocols have used a target of 30 b/L. (35080509, 38457000)

[2/7] fibrinogen

Generally, target >~100 mg/dL if there is no bleeding. (35080509)
Generally, target >150 mg/dL if active hemorrhage. (35080509) However, >200 mg/dL may be targeted in severe hemorrhage, especially in the context of other coagulopathies that are difficult to correct (e.g., thrombocytopenia or antiplatelet agents). (38337414)
⚠️ Fibrinogen levels may be measured to be falsely low in patients who are receiving DTIs. (32371744) TEG may be preferred in that situation (although standard TEG assays don't provide an isolated measurement of fibrinogen level 📖). (38337414)

[3/7] INR

INR correlates poorly with clinical bleeding in complex coagulopathies (e.g., DIC, cirrhosis, sepsis, ECMO).
Some sources recommend using FFP to “correct” an elevated INR, but no evidence supports this. (38457000) Consequently, usual algorithms for FFP transfusion in critically ill patients without ECMO may be applied. (38457000) TEG may be helpful to determine if enzymatic coagulation is genuinely compromised or whether there is rebalanced enzymatic coagulation.
⚠️ INR may be prolonged by DTIs (direct thrombin inhibitors). (36703184)

[4/7] TEG (thromboelastography)

basics

TEG is a whole-blood, integrative coagulation assay (discussed here: 📖).
The TEG R-time is analogous to the PTT, but it is more sensitive to endogenous anticoagulants (allowing it to detect rebalanced hemostasis). Most TEG assays utilize a contact factor activator similar to PTT. This causes the R-time to be sensitive to heparins, direct thrombin inhibitors, or deficiencies in the intrinsic coagulation system (VIII, IX, XI, and XII). (36108651)

theoretical advantages of TEG

TEG may provide a more holistic evaluation of coagulation (including a balance of clotting factors and endogenous anticoagulants, which may be depleted during ECMO).
Comparing the R-time without heparinase versus with heparinase allows for a direct evaluation of the effect of heparin on coagulation.

evidentiary basis

One small pilot RCT randomized patients to a PTT-based heparin dosing strategy or titration of heparin to target a TEG-5000 R-time of 16-24 minutes. Clinical outcomes were similar, but as a pilot study, these outcomes were underpowered. Patients in the TEG group generally had subtherapeutic anti-Xa levels of 0.1-0.2 IU/ml. Alternatively, patients in the PTT-based heparin titration group had a median R-time of 62 minutes (with 37% of patients having a “flat line” TEG tracing). Among patients with a flat-line TEG tracing, the median anti-Xa level was 0.36 IU/ml (within the therapeutic range). Overall, this study has important implications: (29340875)
- Targeting an R-time of 16-24 likely leads to subtherapeutic anticoagulation.
- TEG-5000 may be excessively sensitive to heparin (with flat-line TEG tracings occurring at therapeutic heparin levels). This casts doubt on whether TEG should be used to titrate heparin infusions.

[5/7] PTT

uses

[1] PTT is the primary laboratory test to titrate DTIs (direct thrombin inhibitors). Unfortunately, PTT may underestimate the actual anticoagulant effect of DTIs at higher drug concentrations. (35080509)
[2] PTT may be used to evaluate the level of UFH:
- PTT evaluates coagulation more globally (including the heparin effect and other coagulation factors).
- PTT might be most accurate as a global indicator of bleeding risk rather than an indicator of heparin efficacy. Supratherapeutic PTT levels correlate with clinical bleeding. (31045921)

values

Normal PTT is ~25-35 seconds.
Target in heparin anticoagulation:
- 50-70 seconds or 2-2.5 times the midpoint of the normal range is recommended by ISTH ECMO guidelines. (36700496)
- 40-60 seconds may be adequate for VV ECMO. (Red Book 6e; recommended target for VV ECMO by Rodriguez et al.; Maybauer 2022)
- >75 seconds may correlate with an increased risk of hemorrhage. (31045921)
- (Anti-Xa versus PTT to monitor heparin is discussed further in the section below. ⚡️)
Target with direct thrombin inhibitors (bivalirudin, argatroban): The same target ranges may be used as with heparin (listed above). (36700496, Maybauer 2022) For example, ISTH ECMO guidelines recommend targeting 50-70 seconds or 2-2.5 times the normal level with argatroban. (ISTH ECMO guidelines 36700496; 37763010)

[6/7] anti-Xa level

Anti-Xa level is a direct measurement of the effect of heparin on coagulation. It is utilized only to titrate unfractionated heparin.
Anti-Xa level does not represent the patient's overall hemostatic balance. (38671589)
Anti-Xa level may be the best indicator of heparin efficacy. Subtherapeutic anti-Xa levels correlate with clinical thrombosis. (31045921)
Falsely low anti-Xa occurs with: (35080509)
- Plasma-free hemoglobin >50 mg/dL. ⚡️
- Triglycerides >360-500 mg/dL. (36703184)
- Bilirubin >6 mg/dL.
Target anti-Xa level:
- 0.3-0.7 IU/ml is the usual target for therapeutic anticoagulation in general.
- 0.3-0.5 IU/ml is recommended by ISTH ECMO guidelines. (36700496)
- 0.2-0.3 IU/ml was utilized for VV ECMO in the EOLIA trial. (29791822)

[7/7] integration of anti-Xa & PTT for monitoring of heparin anticoagulation in patients on mechanical support (including ECMO & Impella)

In challenging situations, considering both anti-Xa and PTT levels is often useful. Discordance is common because these patients are highly complex, and the two assays measure different things.

disproportionately elevated PTT (blue boxes above; more common)

Clinical significance: Elevated PTT levels correlate with increased clinical bleeding risk.
Potential causes:
- Falsely low anti-Xa levels:
  - [1] Hemolysis.
  - [2] Hyperbilirubinemia.
  - [3] Hypertriglyceridemia.
- Additional causes of prolonged PTT:
  - [1] Low fibrinogen level.
  - [2] DIC. Disproportionately elevated PTT levels are associated with concomitant thrombocytopenia and INR >~1.5. (37954899, 36167522)
  - [3] FXI-FXII deficiency due to mechanical support. This causes an elevated PTT level without excess bleeding risk. In this situation, the PTT may be ignored, with ongoing heparin titration based on anti-Xa level. (35550692)
  - [4] FVIII-FIX deficiency: Causes include sepsis and cirrhosis. In this scenario, heparin titration based on APTT might be considered. (35550692)
  - [5] Lupus anticoagulant activity (rare).
Further investigation:
- Evaluate for falsely low anti-Xa levels (hemolysis, hyperbilirubinemia, hypertriglyceridemia).
- Check levels of platelets, fibrinogen, INR, FVIII, FIX, FXI, FXII.
- TEG might be helpful. If TEG demonstrates a normal or reduced R-time, this may suggest rebalanced hemostasis (e.g., due to DIC or cirrhosis). In this scenario, anticoagulation may be safe (regardless of the PTT prolongation). (37763010)
Clinical management?
- Management should ideally be tailored to specific coagulation abnormalities (e.g. if fibrinogen levels are <100 mg/dL, then cryoprecipitate may reduce PTT levels and allow heparin to be given more safely).
- Some general options that may be considered include:
  - [1] It might be reasonable to titrate heparin levels based on PTT levels. Anti-Xa levels may be monitored and ideally remain above ~0.2-0.3 IU/ml, depending on the required anticoagulation intensity. (31045921)
  - [2] Personalizing anticoagulation targets might be reasonable (e.g., targeting an anti-Xa level of 0.3-0.5 IU/ml rather than 0.3-0.7 IU/ml).

disproportionately low PTT level (tan boxes above)

Clinical significance: Thrombosis seems to correlate more closely with low anti-Xa levels (as compared to low PTT levels). Thus, patients with a therapeutic anti-Xa and low PTT levels may not be at elevated risk of clinical thrombosis.
Potential cause: Elevated acute-phase reactants (fibrinogen and factor VIII) may reduce the PTT level, masking the true heparin effect. (35080509) This generates both heparin pseudo-resistance and DTI pseudo-resistance.
Clinical management: Titration of heparin based on anti-Xa levels may be most reliable in this scenario.

Anticoagulation strategy for patients with an Impella only. This involves parallel evaluation of anti-Xa and PTT levels. pfHb = plasma free hemoglobin. (35550692)

unfractionated heparin
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unfractionated heparin basics

Heparin's mechanisms of action:
- (a) Potentiates antithrombin, which inhibits factor Xa and thrombin (IIa).
- (b) Binds heparin cofactor II, with the complex inactivating thrombin (IIa).
- (c) Increases release of tissue factor protein inhibitor (TFPI) from the endothelium, which inhibits activation of hemostasis through TF-VIIa
Clearance: Independent of organ function.
Half-life: ~60-90 minutes. (35080509)

dosing

Loading bolus: Generally 75-100 U/kg up to a maximum of 5,000 units. (Red book 6e)
Maintenance infusion:
- Start the infusion at ~20-25 U/kg/hr initially.
- Range: ~10-70 U/kg/hr (upper limit is discussed in the section below on heparin resistance).
- Infusions should be titrated based on a local heparin protocol.

heparin resistance
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definition of heparin resistance?

Definitions of heparin resistance are arbitrary and variable in the literature. (37619694)
Heparin resistance might be defined as the inability to reach therapeutic anticoagulation with a heparin dose of roughly >30 U/kg/hr. (28898902, 37619694)

causes of heparin resistance

[1] Heparin pseudo-resistance:
- This is a laboratory artifact whereby high fibrinogen and/or Factor VIII levels artificially reduce the PTT level.
- In heparin pseudo-resistance, anti-Xa levels should remain accurate.
[2] Heparin level is truly low: This may occur as a response to inflammation, with elevated levels of heparin-binding proteins. Heparin may also bind to the ECMO circuit.
[3] Antithrombin-III deficiency, which may be caused by:
- DIC.
- Acute thrombosis (e.g., PE, DVT).
- Sepsis.
- Surgery or trauma (antithrombin III levels often nadir ~3 days postoperatively). (29915655)
- ECMO itself, hemodialysis, and possibly IABP. (35927191) ECMO-related AT-III deficiency is frequently seen upon ECMO initiation. (38337414)
- Cirrhosis.
- Unfractionated heparin itself reduces antithrombin levels over time.
[4] Multifactorial: ECMO patients often have many of the above causes of heparin resistance.

investigation of heparin resistance: laboratory studies to obtain

Three assays of heparin activity should ideally be obtained:
- [1] Anti-Xa level should always be obtained (if it hasn't been already).
- [2] PTT.
- [3] TEG (with and without heparinase).
Antithrombin-III level (<40% suggests antithrombin-III deficiency may contribute to heparin resistance).
INR.
Fibrinogen and Factor VIII levels (especially if considering transition to direct thrombin inhibitor).
(PTT with exogenous heparinase: This eliminates the effect of heparin, thereby revealing the baseline PTT value. The exact utility of this test remains unclear, but it might be beneficial in situations where TEG and anti-Xa levels are unavailable.)

management of heparin resistance

**step #1: If anti-Xa & PTT levels are discordant, consider personalizing the anticoagulation target**

Anti-Xa and PTT levels are frequently discordant.
Evaluation and management of anti-Xa/PTT discordance is discussed above. ⚡️

step #2: Consider simply increasing the heparin dose

If anti-Xa and PTT levels are both low, this suggests that it's safe to increase the heparin dose.
Increasing the heparin dose may be a simple and inexpensive approach to overcoming heparin resistance. The maximal rate of heparin infusion is unknown. Heparin doses of ~40-70 IU/kg/hr may be needed for some patients. (28898902)
Escalating the heparin dose is especially reasonable if antithrombin-III levels are >40% (implying that the true heparin concentration is low). Alternatively, if antithrombin-III levels are extremely low (<<40%), that may predict a failure of heparin to achieve adequate anticoagulation (in which case transitioning to a direct thrombin inhibitor could be more rapidly effective).

step #3: Consider switching to a DTI (direct thrombin inhibitor)

Rationale:
- Using a direct thrombin inhibitor avoids issues relating to heparin resistance due to heparin adsorption to proteins or antithrombin-III deficiency.
- Numerous studies that demonstrate excellent outcomes (mostly with bivalirudin) support direct thrombin inhibitor use in ECMO.
- ISTH guidelines recommend switching from heparin to a DTI in patients with treatment failure on heparin. (36700496)
⚠️ Caution: DTIs may be subject to pseudo-resistance with PTT monitoring (similar to heparin). An unexpectedly low PTT level may foreshadow problems here (especially if there are markedly elevated fibrinogen and/or Factor VIII levels). Unfortunately, there is no simple solution to monitoring direct thrombin inhibitors in pseudo-resistance. Please note that patients with heparin pseudo-resistance using PTT are best managed by continuing a heparin infusion and transitioning to dosing based on anti-Xa levels. (Further discussion of DTI pseudo-resistance is here: 📖)

(generally not preferred: supplementation of antithrombin-III levels)

One potential treatment for patients with low antithrombin-III levels is administering antithrombin-III concentrate. However, this is often not a preferred strategy for the following reasons:
[#1] There is little evidence to support using antithrombin-III supplementation for heparin resistance in the ICU (reports are mainly limited to case studies).
[#2] Antithrombin-III is extremely expensive. (24391399)
[#3] Dosing of antithrombin-III and heparin can be tricky. Heparin and antithrombin-III interact synergistically, so they must be combined carefully. Especially in ECMO patients, hemostasis is unbalanced and the effect of exogenous AT is unpredictable. (38747332)
[#4] Antithrombin-III supplementation may increase the risk of acute kidney injury. (36853953, 35877927)
[#5] Many critically ill patients may have multifactorial heparin resistance. Administration of antithrombin-III won't resolve this situation. This may explain a recent RCT demonstrating that antithrombin supplementation in VV ECMO didn't affect the heparin dose. (32947474)
[#6] ISTH guidelines don't recommend antithrombin-III supplementation. (36700496)

direct thrombin inhibitors (bivalirudin & argatroban)
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pharmacokinetics

bivalirudin

Clearance:
- 80% is cleared via proteolytic enzymes in the serum.
- 20% is cleared by the kidneys. (38671589)
Half-life: 25 minutes with normal renal function (compared to 60-90 minutes for heparin). (35080509) However, in severe renal failure, the half-life may increase to an hour.

argatroban

Clearance: Hepatic (no dose adjustment is needed for renal failure).
Half-life: ~45 minutes (but may increase to 3 hours in patients with severe hepatic dysfunction or critical illness).

advantages, disadvantages, indications, selection

advantages of DTIs

[1] There are no issues with heparin resistance.
[2] There are no problems with HIT.
[3] Pharmacokinetics and pharmacodynamics are often more predictable than heparin (due to the absence of interaction with antithrombin-III or adsorption to various proteins/surfaces).
[4] DTIs cause inhibition of both circulating and fibrin-bound thrombin (unlike heparin, which acts only on circulating fibrin). (38671589) This may allow some activity against preformed thrombus. (Maybauer 2022)
[5] DTIs may cause less thrombocytopenia than heparin (even among patients who don't have HIT, heparin often causes non-immune mediated thrombocytopenia). (30461625)
[6] Small, retrospective studies suggest that bivalirudin use is associated with reduced risk of bleeding, thrombosis, and in-hospital mortality as compared to heparin (less evidence is available regarding argatroban). (38671589) This is low-quality data, but it does suggest that direct thrombin inhibitor use is safe and effective (whether bivalirudin is genuinely superior to heparin remains unknown).

disadvantages of DTIs

[1] No reversal agent (but this is generally unnecessary, given the short half-life of these agents).
[2] DTIs impair testing of underlying coagulation abnormalities (e.g., DTIs cause abnormalities in the measurement of fibrinogen, INR, and PTT levels).
[3] Monitoring can be challenging since this is based entirely on PTT values:
- Patients with elevated fibrinogen and Factor VIII levels may have artificially low PTT levels, causing DTI pseudo-resistance. 📖
- Patients with elevated baseline PTT (e.g., due to cirrhosis or DIC) are at risk of under-dosing if a fixed PTT value is targeted.
[4] Bivalirudin is metabolized by localized proteolysis. This may lead to subtherapeutic levels in areas of blood stasis (where anticoagulation is most important). This may be especially relevant in the following situations:
- VA ECMO with left ventricular dilation and stasis. (35080509)
- VA ECMO during a clamp trial.
- VA ECMO leg reperfusion cannulas. (37763010)
[5] DTIs often have a higher drug acquisition cost as compared to heparin. However, this may be defrayed by reducing other costs (e.g., avoidance of supplemental antithrombin-III, fewer circuit changes). Additionally, patients on ECMO often require low doses of DTIs, so dispensing smaller aliquots of the drug at a time may reduce drug costs (by avoiding throwing away wasted drug when medication bags dispensed to the ICU expire).

indications for DTIs

[1] HIT (either suspected or known).
[2] Heparin resistance.
[3] Some centers use bivalirudin as a front-line anticoagulant for all ECMO patients.

selection of bivalirudin versus argatroban

Overall, bivalirudin has the advantage of a shorter half-life, which allows it to be more easily discontinued for procedures or hemorrhage. However, bivalirudin levels decrease in areas of stagnant blood flow, which may be a problem (especially with VA ECMO). The choice of bivalirudin versus argatroban will often depend on local practice patterns.
Severe renal failure: Argatroban may be preferred (bivalirudin loses its advantage of a short half-life).
Severe hepatic failure: Bivalirudin may be substantially preferred (the half-life of argatroban may extend to 2-3 hours, which makes titration and discontinuation a significant problem).

dosing & monitoring

monitoring of DTIs:

DTIs may be monitored based on PTT values.
The target PTT levels for DTIs are generally the same as those used with heparin. However, the target may be personalized based on the risk of thrombosis, bleeding, and type of ECMO.
(Target PTT level in various scenarios is discussed above: ⚡️)

bivalirudin: one dose-titration protocol

Initial dose:
- GFR < 10: 0.02 mg/kg/hr & discuss with pharmacy.
- CRRT: 0.04 mg/kg/hr.
- GFR 10-29: 0.07 mg/kg/hr.
- GFR 30-60: 0.1 mg/kg/hr.
- GFR >60: 0.15 mg/kg/hr.
Adjustment based on PTT levels:
- PTT >20 s low: Increase 20%, repeat in 6 hours.
- PTT 10-20 s low: Increase 10%, repeat in 6 hours.
- PTT at target: Repeat in 12 hours.
- PTT 10-20 s high: Decrease 10%, repeat in 6 hours.
- PTT >20 s high: Hold 1 hour, decrease 20%, repeat in 6 hours.

argatroban: one dose-titration protocol

Initial dose:
- The initial dose in ECMO is much lower than the usual doses utilized for HIT (e.g., 0.2-0.3 mcg/kg/min). (31364329, 36700496)
- Start at 0.3 mcg/kg/min, based on total body weight.
Adjust based on PTT levels:
- PTT >20 seconds low: Increase by 0.2 mcg/kg/min, repeat in 3 hours.
- PTT 11-20 seconds low: Increase by 0.15 mcg/kg/min, repeat in 3 hours.
- PTT 1-10 seconds low: Increase by 0.1 mcg/kg/min, repeat in 3 hours.
- PTT at goal: Repeat in 3 hours, then 6 hours, then q12 hours.
- PTT 1-10 seconds high: Decrease by 0.1 mcg/kg/min, repeat in 3 hours.
- PTT 11-20 seconds high: Hold infusion for 1 hour and decrease by 0.15 mcg/kg/min; repeat in 3 hours.
- PTT >20 seconds high: Hold infusion for 1 hour and decrease by 0.2 mcg/kg/min; repeat in 3 hours. (based on Maybauer 2022)

DIC
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common causes of DIC in ECMO patients

Sepsis.
Thrombosis within the circuit (e.g., membrane lung dysfunction ⚡️)
Other potential causes of DIC are explored here: 📖

diagnosis of DIC

The ISTH DIC score may be utilized. 📖
Utilization of D-dimer?
- Elevation of D-dimer is nonspecific, but markedly elevated values have greater significance.
- Elevation of D-dimer levels may reflect DIC or clot formation in the pump or oxygenator (suggested by steady increases in D-dimer). (36703184)

treatment of DIC

[1] Manage the cause if possible:
- If membrane thrombosis is causative, exchange the membrane or the entire circuit. In the absence of an alternative cause, rising D-dimer predicts the need for circuit exchange. (Maybauer 2022)
- If caused by sepsis, treat the sepsis.
[2] Supportive management with factor replacement as needed (e.g., for active bleeding).
(Further discussion of the management of DIC: 📖)

acquired von Willebrand syndrome (AVWS)
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pathophysiology of vWF

Normal functions of von Willebrand factor include:
- [1] A bridge between damaged blood vessels and activated platelets (through the GPIb receptor).
- [2] Carrier for factor VIII (significantly increasing the half-life of factor VIII). (Maybauer 2022)
High shear forces in ECMO deplete high molecular-weight von Willebrand factor multimers. (28898902, Red Book 6e) This is an example of type 2A acquired von Willebrand syndrome.

epidemiology

Almost all ECMO patients develop partial or complete loss of vWF high-molecular-weight multimers within a few hours of ECMO initiation. (38925492)

clinical manifestations may include

Diffuse hemorrhage.
Sudden mucosal bleeding. (38747332)
Unexpected bleeding after minor surgery. (Maybauer 2022)

laboratory analysis

AVWS doesn't affect most coagulation studies (e.g., conventional coagulation tests, TEG).
The diagnosis can be made based on a reduced ratio of vWF activity relative to vWF antigen level. However, this is largely impossible to measure in practice (due to delayed turnaround time).
PFA (platelet function analyzer) is highly sensitive but not specific to the loss of vWF high molecular-weight multimers. 📖 Additionally, the PFA is not valid if the platelet count is <80,000/uL or the hematocrit is <30% – conditions frequently encountered among ECMO patients. (15982339)
Epidemiological studies show that AVWS occurs in nearly all patients on ECMO. Consequently, it's unclear whether laboratory testing is necessary. (38925492)

treatment

Treatment may be considered in the face of persistent or life-threatening bleeding (based on the assumption that AVWS may be contributing to the net state of anticoagulation). However, there is no high-quality evidence to support this. Unfortunately, any strategy to deliver vWF will be limited by ongoing vWF consumption.
DDAVP may cause a transient increase in vWF levels. This was found to be ineffective in one study involving COVID-19 patients. However, the generalizability of this study may be limited due to endothelial vWF depletion seen in COVID. (38925492)
Cryoprecipitate can be used to replete vWF and VIII levels. This hasn't been studied as a specific therapy for AVWD in ECMO patients. However, it might be a theoretical argument to favor the use of cryoprecipitate over fibrinogen concentrates as a therapy for hypofibrinogenemia among bleeding ECMO patients.
Antifibrinolytics (e.g., tranexamic acid or aminocaproic acid) have demonstrated efficacy for other etiologies of von Willebrand Disease 2A, but this hasn't been evaluated in ECMO patients. This could be considered for refractory, life-threatening bleeding in the absence of better options. (39133377)
vWF levels recover quickly after discontinuation of ECMO. (Red Book 6e)

HIT (heparin induced thrombocytopenia)
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epidemiology

The incidence might be ~5%. This is an uncommon but real complication. (Red Book 6e)

diagnosis

Diagnosis is challenging because both thrombocytopenia and thrombosis are common in ECMO.
Clues to a diagnosis of HIT may include falling platelet counts and circuit thrombosis. (38747332)
The 4T score 📖 appears to have adequate sensitivity (with a score of 0-3 excluding HIT). However, the 4T score may have impaired specificity. (32232501)
Definitive diagnosis relies upon detecting platelet-factor-4 antibodies and serotonin release assay (diagnostic algorithm discussed further here: 📖).

treatment for probable/definite HIT

If there is a significant clinical concern about HIT, anticoagulation should be transitioned to a non-heparin agent (bivalirudin or argatroban) while the evaluation is ongoing.
Platelet transfusion should be avoided (as this may aggravate thrombosis).
Heparin-coating of the ECMO circuit doesn't appear to cause or perpetuate thrombocytopenia or thrombosis. (31632747) However, weakly heparin-bonded coating should be avoided if possible. (Red book 6e)
(Further discussion about the treatment of HIT: 📖).

bleeding
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common sites of bleeding

Cannulation sites are the most common. (Taha 2024)
Other procedural/surgical site (e.g., post-cardiothoracic surgery).
Lungs, including hemoptysis related to suctioning (6%).
Gastrointestinal bleeding (~5%). (36703184)
Intracranial hemorrhage (~3%).
Retroperitoneal hemorrhage.
Hemothorax.

pathophysiology of hemorrhage in ECMO

ECMO patients often accumulate a variety of coagulopathies over time:

Anticoagulation (e.g., heparin or bivalirudin).
DIC causes consumptive coagulopathy (e.g., hypofibrinogenemia).
Thrombocytopenia.
Platelet dysfunction:
- [1] Uremic platelet dysfunction.
- [2] Medication-related (e.g., aspirin, P2Y12 inhibitors).
- [3] Platelet dysfunction is caused by the loss of glycoproteins Iba and VI receptors on platelets due to exposure to high shear stress in the ECMO circuit. (37519116)
Acquired von Willebrand syndrome ⚡️

hemorrhage management

evaluation of coagulation status

Complete blood count.
Fibrinogen level.
INR, PTT.
Anti-Xa level (for patients on heparin).
TEG.
Ionized calcium (if undergoing massive transfusion or dialysis with a citrate anticoagulant).

potential interventions

Hemorrhage source control. Local hemostatic control is ideal (e.g., packing, surgical control, angiographic embolization). Topical hemostatic agents may be helpful for superficial bleeding.
PRBC transfusion to replace blood losses.
Adjust the target level of anticoagulation:
- Temporarily holding anticoagulation may be required for severe hemorrhage (e.g., intracranial hemorrhage).
- For catastrophic bleeding, heparin reversal with protamine may be considered (but this carries a high risk of membrane lung clot formation). 📖 (Maybauer 2022)
- For moderate bleeding, reducing the target level of anticoagulation intensity may be a reasonable compromise.
- Consider increasing the ECMO flow to reduce the risk of circuit thrombosis.
Address other coagulopathies:
- Platelet transfusion for target >50-100 b/L.
- Cryoprecipitate to target fibrinogen levels >150-200 mg/dL.
- FFP may be considered (especially if TEG reveals a prolonged R-time).
- Desmopressin (DDAVP) may be a rational therapy for improving platelet function and alleviating acquired von Willebrand syndrome, but no evidence supports its use.
- Calcium administration for hypocalcemia.
- Uncontrollable, life-threatening bleeding has been treated successfully with antifibrinolytics (aminocaproic acid or tranexamic acid). However, due to the risk of circuit thrombosis, this should be utilized only for refractory hemorrhage. (Schmidt 2022)

hemolysis
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causes of hemolysis

Excessive circuit pressures:
- Pven <-100 mm ⚡️; tubing chatter.
- Part >250 mm. ⚡️
- High circuit flow rates. ⚡️
- Kinked or intentionally split tubing. (Schmidt 2022)
Clot in the circuit:
- Pump head thrombosis (occurs in <4% of cases but may cause sudden and massive hemolysis). (34339398)
- Membrane lung dysfunction. ⚡️
The heat exchanger that is malfunctioning.
Venting Impella (if present).

diagnosis of significant hemolysis

Plasma free hemoglobin:
- Generally, free hemoglobin is <10 mg/dL. (Maybauer 2022)
- 50-100 mg/dL indicates moderate hemolysis (occurs in ~3% of patients). This should prompt an evaluation of the cause of hemolysis. (Maybauer 2022) Without an alternative explanation, it is concerning for circuit-derived hemolysis. (Schmidt 2022)
- >100 mg/dL indicates severe hemolysis that should prompt immediate action. (Red Book 6e)
- Other causes of elevated plasma-free hemoglobin may include blood transfusion, surgery, and laboratory artifact due to hemolysis within the blood tube.
Hemolysis index (HI):
- This index is routinely measured by the chemistry laboratory to evaluate specimens for hemolysis. It is calculated by performing spectrophotometry on plasma, so it is fundamentally a measurement of plasma-free hemoglobin.
- The hemolysis index correlates linearly with plasma-free hemoglobin, with values that might be ~1.5 times higher than the plasma-free hemoglobin (figure below).
- Many centers lack immediate access to plasma-free hemoglobin measurement so that they may use the hemolysis index instead.
Urine examination & evaluation:
- Pink urine may occur in severe hemolysis (but this is nonspecific since it may also happen with minor Foley trauma). For anuric patients on dialysis, the dialysis effluent may turn pink. (Taha 2024)
- Urinalysis may be chemically positive for “heme” without erythrocytes being seen in the sediment.
Other indices that are less specific:
- LDH >2,000 U/L suggests hemolysis (but LDH correlates poorly with plasma-free hemoglobin).
- Falling hemoglobin.

Correlation between hemolysis index (HI) and plasma-free hemoglobin. (Zapletal B et al. PMID 38611592)

consequences of hemolysis

[1] Acute kidney injury.
[2] Thrombosis (activates platelets).
[3] Nitrogen oxide depletion increases vascular tone.
(It also interferes with colorimetric anti-Xa assay. ⚡️)

epidemiology

One series found that plasma-free hemoglobin >50 mg/dL in 4% of survivors and 16% of nonsurvivors among a mixed population of VV ECMO and VA ECMO. (25902047)
Hemolysis may be more common in VA ECMO than in VV ECMO. (Red Book 6e)

management

Circuit pressures & tubing chatter must be decreased:
- If possible, reduce the circuit flow rate.
- Remove any kinks in the tubing.
- Further discussion on the management of Pven: ⚡️
- Further discussion on the management of Part: ⚡️
If clots are present in the circuit and/or membrane:
- Circuit components may need to be changed (e.g., the membrane lung or the entire circuit).
- Anticoagulation should be optimized to avoid ongoing thrombosis.
Replace the heat exchanger if it malfunctions. (Schmidt 2022)
Anemia may require PRBC transfusion (discussion of target hemoglobin: ⚡️).

optimal hemoglobin
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Hemoglobin >7 g/dL is adequate for most patients. (38999360)
Hemoglobin >8 g/dL is a reasonable target with active myocardial ischemia.
Blood transfusion to target a hemoglobin of 10 g/dL may occasionally be used to improve oxygen delivery (DO2). However, this should ideally be avoided, given evidence that a restrictive transfusion strategy may improve outcomes. (28704244) Several drawbacks of a higher hemoglobin level should be considered:
- [1] Higher hemoglobin increases blood viscosity – which may impair flow through the circuit and the body.
- [2] Higher hematocrit will increase the tendency of blood to clot.
- [3] Blood transfusion has numerous potential risks (including exacerbation of ARDS, volume overload, infection, immunosuppression, and alloimmunization). Alloimmunization may be especially problematic for patients who require organ transplantation.
- [4] It's unclear whether transfused blood truly improves oxygen delivery to the tissues. (Schmidt 2022)

pulmonary complications
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common complications include:

Pneumonia (including ventilator-associated pneumonia).
Pulmonary edema and diffuse alveolar hemorrhage (especially with LV dilation in VA ECMO: ⚡️)
Neuromuscular weakness causing diaphragm dysfunction.
Pneumothorax.
Pleural effusion (including hemothorax).
Pulmonary embolism (discussed further below).

pulmonary embolism (& venous thromboembolic disease)

Causes of PE:
- [1] Thrombosis at the site of venous cannula.
- [2] Embolization of clots formed within the circuit (VV ECMO).
Epidemiology: The risk of PE is high (often in the 10-15% range).
Diagnosis:
- Ultrasonography is the test of choice for evaluating DVT. A routine DVT study should be performed following decannulation.
- CT angiography may be utilized to evaluate for PE (but this can be challenging due to abnormal contrast flow dynamics).
- Transesophageal echocardiography may identify large, central pulmonary emboli.
Treatment:
- Anticoagulation is indicated (including potentially an adjustment in anticoagulation intensity).
- For submassive/massive PE, tPA is generally contraindicated in the context of ECMO (based on the underlying complex coagulopathy). Large, central PE may be treated with mechanical thrombectomy. (Further discussion: 📖)

gastrointestinal issues
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nutritional support

Nutritional support is generally similar to that of other critically ill patients.
Orogastric tube access may be preferred to nasogastric tube access to avoid epistaxis.
VA ECMO was historically considered a contraindication to enteral nutrition due to concerns about mesenteric ischemia. However, recent evidence has allayed these fears, suggesting instead that enteral nutrition might reduce the risk of mesenteric ischemia. (33609105, 30030574) Following initial resuscitation and stabilization on VA ECMO, enteral nutrition appears to be safe and beneficial.
Indirect calorimetry isn't possible on ECMO because the membrane lung removes CO2. Consequently, caloric needs should be estimated based on weight (e.g., 25 kCal/kg). (Taha 2024)
Total parenteral nutrition may cause problems due to infused lipid accumulating in the membrane lung. Enteral nutrition is preferred whenever feasible.
(Further discussion of critical care nutrition is here: 📖)

stress ulcer prophylaxis

Stress ulcer prophylaxis is generally indicated for patients undergoing ECMO. Patients are critically ill, often mechanically ventilated, and often quite coagulopathic.
There is no clear evidence regarding the optimal stress ulcer prophylaxis among ECMO patients.
Proton pump inhibitors (PPIs) have the advantage of being more effective than H2-blockers (0.5% absolute reduction in clinically significant gastrointestinal hemorrhage based on the PEPTIC trial). (31950977)

AKI (acute kidney injury)
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epidemiology

Renal failure requiring dialysis occurs in ~40% of patients on ECMO. This is an enormous problem that increases mortality and may interfere with other therapies (e.g., cardiac transplantation). (Red Book 6e)

causes of AKI include:

Renal hypoperfusion (and lack of pulsatile blood in VA ECMO).
Hemolysis.
Microemboli to the renal vasculature.
Nephrotoxic medications (list: 📖).
Congestive nephropathy.
Inflammatory effects of blood exposure to the circuit and membrane. (Red Book 6e)
(For a more complete list of the causes of AKI: 📖).

prevention of AKI:

Minimizing hemolysis:
- Avoid hemolysis by using safe flow rates and pressures.
- Respond rapidly to evidence of hemolysis.
- Avoid insertion of a venting Impella, if possible.
Avoid nephrotoxins as much as possible (e.g., vancomycin, NSAIDs).
Target a euvolemic volume status.

investigation of AKI may involve:

Urinalysis, including sediment analysis.
Measurement of creatinine kinase level.
Evaluation for hemolysis. ⚡️
Relevant drug levels (e.g., vancomycin, aminoglycoside, tacrolimus).
Renal ultrasound.

management

General supportive care for AKI as discussed here: 📖.
Hemodialysis may be performed via a separate access site or via accessing the ECMO circuit. When possible, it might be preferable to keep hemodialysis separate from the ECMO circuit in order to keep the ECMO circuit as simple as possible and to facilitate troubleshooting the ECMO circuit.

neurological complications
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hypoxic-ischemic brain injury (aka global brain ischemia)

epidemiology and causes

Hypoxic-ischemic brain injury is a common complication of ECMO, occurring in 14-61% of patients. (31599814)
Causes include:
- [1] CNS hypoperfusion prior to cannulation (most common cause).
- [2] Differential hypoxemia. ⚡️
- [3] Cardiac arrest.
- [4] CO2 dysregulation and cerebral vasoconstriction. (31599814)

management

[1] Post-arrest treatment involves standard resuscitative pathways (including targeted temperature management). The ECMO circuit may be utilized to control temperature, eliminating the need for other temperature control devices. 📖
[2] Avoid any long-acting sedatives or opioids that may interfere with neuroprognostication.

ischemic stroke

epidemiology & causes

Incidence may be ~5-10%.
Causes include:
- Embolic stroke is most common (especially with VA-ECMO, but paradoxical embolism may occur with VV-ECMO).
- Septic emboli.
- Cerebral sinus vein thrombosis (risk may be increased with jugular vein cannulation).

diagnosis

CT scan is a cornerstone study:
- CT angiography may help evaluate for large vessel occlusion (LVO).
- CT venography is recommended in VV-ECMO patients to exclude cerebral vein sinus thrombosis. (31599814)
- CT perfusion may be considered while the patient is at the scanner (given how difficult it is to mobilize ECMO patients to CT scan).

management

Revascularization options: 📖
- IV alteplase is contraindicated in ECMO. (31599814, 39620302)
- Mechanical thrombectomy may be performed for large vessel occlusion.
Anticoagulation & investigation of the cause of the stroke:
- In VA ECMO, check the circuit for thrombosis and may consider circuit exchange.
- Consider the optimal anticoagulation intensity. This may be very complicated since anticoagulation in the context of a large stroke can increase the risk of hemorrhagic transformation. For moderate to large strokes, holding anticoagulation for a few days may be considered. (31599814)
Blood pressure: In general, patients with new acute ischemic stroke without intervention should be allowed to have permissive hypertension up to 220/120 mm to promote perfusion of the ischemic prenumbra.
- VA ECMO: Cardiac function often cannot tolerate excessive afterload, so very high blood pressures cannot be tolerated. (39620302)

cerebral air embolism

Symptoms may include:
- Alarms indicating air within the ECMO circuit.
- Hemodynamic instability.
- Acute neurologic symptoms (which may include coma, seizure, focal deficits, headache, and/or encephalopathy).
CT brain should be obtained to evaluate for alternative pathologies. (31599814)
Treatment is supportive. Maximizing the FiO2 to decrease the nitrogen content of the blood may accelerate the reabsorption of emboli (treatment is discussed further here: 📖).

ICH (intracranial hemorrhage)

epidemiology

The risk is ~4%. (33814895)
Most ICHs seem to be present shortly after ECMO cannulation. (33814895)
Risk relates largely to anticoagulation and/or consumptive coagulopathies. Specific risk factors include:
- Thrombocytopenia, in particular, is a risk factor.
- Anticoagulant and antiplatelet use.
- Bloodstream infections.
- Rapid reduction of pCO2 (which may cause an ischemic area with subsequent hemorrhagic transformation).
- Renal failure, dialysis. (31599814, 33814895)
Types of intracranial hemorrhage:
- [1] Intraparenchymal hemorrhage.
- [2] Subarachnoid hemorrhage.
- [3] Subdural hematoma.

investigation

CT scan with CT angiography +/- CT venography is the test of choice.

management

Anticoagulation must be held and potentially reversed (although reversal may carry high risks of membrane lung thrombosis). ECMO circuit flow may be increased to reduce the risk of circuit thrombosis. The duration of holding anticoagulation may depend on patient specifics. Close monitoring for any evidence of thrombosis may help guide management as well (e.g., visual inspection for thrombi and circuit pressures). (33814895)
Platelets should be maintained at least >50,000. (Red Book 6e)
Blood pressure control to reduce hematoma expansion.
- Further discussion regarding hematologic investigation and management for bleeding on ECMO is here: ⚡️
- General management strategies for intracranial hemorrhage: 📖

CVST (cerebral venous sinus thrombosis)

CVST may be associated with large-bore jugular cannulas, which cause venous hypertension.
Manifestations are various (e.g., headache, seizure, encephalopathy).
Diagnosis is based on CT venography.
Management:
- Anticoagulation (which patients are on anyway).
- Acetazolamide may be considered to reduce intracranial pressure.
- Endovascular mechanical thrombectomy may be considered. (39620302)
- (More on CVST management: 📖)

seizures

Seizures are reported in 1-6% of ECMO patients. (31599814)
Treatment:
- Propofol and benzodiazepines are likely to be sequestered by the ECMO circuit, so higher doses may be required than usual.
- Levetiracetam isn't sequestered substantially (<10% protein binding, LogP -0.6). (31599814)

limb ischemia
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risk factors for limb ischemia

Type of ECMO:
- ~1% rate in VV ECMO.
- ~5% rate in VA ECMO.
Larger bore cannula.
Peripheral arterial disease.
Cannulation in the superficial femoral artery.
Arterial dissection.
Impaired venous drainage leads to compartment syndrome.

common causes of limb ischemia

Thrombus formation with distal embolization to the limb.
Vessel occlusion from the cannula itself. (Red Book 6e)

monitoring & diagnosis of limb perfusion may involve:

Clinical examination (mottling, temperature, pulses).
NIRS (near-infrared spectroscopy) may be helpful. A sustained rSO2 <50% indicates inadequate limb perfusion. A rSO2 differential >15% between legs also supports regional hypoperfusion. (29848162) NIRS can reveal tissue oxygenation even in the absence of pulsatile blood flow.
Ultrasound evaluation (spectral Doppler ultrasound may evaluate blood flow, compared to the contralateral limb, to account for changes in left ventricular ejection). (25296619)
CT angiography with runoff can be definitive.

management

Distal perfusion catheter for VA ECMO (some centers insert routinely, others selectively).
Wean vasopressors as able.
Other therapies may include:
- Revascularization strategies (e.g., vascular surgery or interventional radiology).
- Compartment syndrome may require fasciotomy.
- If all else fails, amputation may be needed.
- Rhabdomyolysis may require medical management.

approach to infection in an ECMO patient
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diagnosis of infection is challenging

ECMO itself triggers a systemic inflammatory response.
The heater/cooler system prevents fever or hypothermia (common signs of infection).
CRP or procalcitonin are nonspecific and not usually recommended for patients on ECMO. (Red Book 6e, 38442737)
Microbial culture data is often essential (however, sorting out infection versus colonization may remain confounding).
It's frequently unknown how precisely to define infections among patients on ECMO. (38442737)

common sites of infection

Pre-existing infection before ECMO initiation (e.g., community-acquired pneumonia).
VAP (ventilator-associated pneumonia) is the most common infection among patients on VV ECMO. (38442737)
Line infection (including cannula sites).
- The risk of cannula insertion site infection was 14% in the EOLIA trial. (29791822) Risk increases linearly related to the duration of therapy. (35326801)
- Directly accessing the circuit for cultures isn't recommended as this may risk contaminating the circuit. (38442737)
- Treatment:
  - Initial therapy involves antibiotics. Follow blood cultures to determine if the blood can be sterilized. If positive blood cultures persist, replacing the ECMO circuit may be necessary. (Taha 2024) Additional investigation for endocarditis and other device/line infections may also be appropriate.
  - If infection is persistent and uncontrolled, removing the ECMO cannulae and inserting fresh cannulae at different sites may be necessary.
  - Antibiotics generally need to be continued until after decannulation. (38442737)
Surgical site infection.
Urinary tract infection (although it's often difficult to differentiate infection from colonization; discussed further here: 📖).
C. difficile. (38442737)

pathogenic organisms often reflect nosocomial pathogens

Most common:
- Gram-positive organisms, including MRSA, coagulase-negative staphylococci, and Enterococcus species.
- Gram-negative organisms, including Pseudomonas aeruginosa or Enterobacteriaceae.
Candida species may be involved, especially among patients repeatedly exposed to broad-spectrum antibiotics.

(Further discussion about the investigation & treatment of infection in the ICU: 📖)

antimicrobial pharmacology in ECMO
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Below are antibiotics that are more useful for patients on ECMO. Hydrophilic antibiotics have the most predictable pharmacokinetics, although these will have an increased volume of distribution (due to the volume of the ECMO circuit).

general approach for determining the risk of ECMO circuit sequestration ⚡️

Protein binding <30% (low):
- LogP <1 & Vd <1 L/kg: Low risk.
- LogP 1-2 & Vd 1-5 L/kg: Low to moderate risk.
- LogP >2 & Vd >5 L/kg: Moderate risk (consider increasing dose/frequency).
Protein binding 30-60% (moderate):
- LogP <1 & Vd <1 L/kg: Low-to-moderate risk.
- LogP 1-2 & Vd 1-5 L/kg: Moderate risk (consider increasing dose/frequency).
- LogP >2 & Vd >5 L/kg: Moderate-to-high risk (use higher loading and/or maintenance doses and/or increase frequency)
Protein binding >60% (high):
- LogP <1 & Vd <1 L/kg: Moderate risk (consider increasing dose/frequency).
- LogP 1-2 & Vd 1-5 L/kg: Moderate-to-high risk (use higher loading and/or maintenance doses and/or increase frequency)
- LogP >1 & Vd >5 L/kg: High risk (avoid if possible; if required, use higher loading doses and/or maintenance doses and increased frequency if appropriate; follow medication levels if available). (Red Book 6e)

beta-lactams

Ampicillin 🟢 💉 (20% protein binding; Vd 0.25 L/kg; LogP -1.1). The higher end of standard dosage appears to achieve therapeutic targets, but available clinical data is sparse. (37243488)
Nafcillin 🟠 💉 (90% protein binding; LogP 2.9). It may be sequestered by the ECMO circuit. Dose on the higher end of the normal dosing range. (39367501)
Cefazolin 🟡 💉 (80% protein binding; Vd 0.2 L/kg; LogP -0.6) Standard dosing is probably adequate, but some in vitro data suggests ~20% loss to the circuit. Dose on the aggressive side of the standard dosing range. (31610538, 35326801, 39367501)
Ceftazidime 🟢 💉 (15% protein binding; Vd 0.3 L/kg; LogP -1.6). Pharmacokinetics are unaffected by ECMO. (35326801)
Ceftriaxone 🟢 💉 (90% protein binding; Vd 0.2 L/kg; LogP -1.7). Standard dosing appears to achieve therapeutic targets. In a prospective study involving 14 patients, ECMO didn't influence ceftriaxone pharmacokinetics. (35253107) Dose on the higher end of the normal dosing range. (35253107; 29732181, 39367501)
Cefepime 🟢 💉 (20% protein binding, Vd 0.3 L/kg; LogP -0.1). It is unlikely to be affected by ECMO, with validation in patient PK samples. (39367501)
Ceftaroline 🟢 💉 (20% protein binding; Vd 0.3 L/kg; LogP -0.8 to 2.3). It is unlikely to be affected by ECMO, but little data exists regarding clinical use. Kim et al. suggest increasing the dose to 600 mg q8hr. (39367501)
Piperacillin-tazobactam 🟡 💉 (30% protein binding; Vd 0.3 L/kg; LogP 0.5). Data is somewhat conflicting. Dose on the higher end of a normal dosing range (ideally with extended infusion). (29732181, 34460303, 33569597, 39367501)
Ertapenem: 🔴 💉 (90% protein bound, LogP 0.3). Data is lacking; use meropenem instead. (39367501)
Meropenem 🟢 💉 (2% protein binding; Vd 0.35 L/kg; LogP -0.7). Dosing is similar to other critically ill patients, with several studies showing no change in pharmacokinetics due to ECMO. (29732181, 35326801, 34460303)

other antibiotics

Azithromycin 🟢 💉 (7-51% protein bound; LogP 3-4): Use standard doses. A case series demonstrated minimal effect on pharmacokinetics. (39367501)
Doxycycline 🟡 💉 (80% protein binding; Vd 0.75 L/kg; LogP 0.6). Data is limited, but one case report found adequate pharmacokinetics. (Mehta et al.) Kim et al. recommend using standard doses. (39367501)
Linezolid 🟠 💉 (30% protein binding; Vd 0.6 L/kg; LogP 0.7). Despite hydrophilicity, some case reports describe inadequate levels when using linezolid. (32426841, 35326801, 33239110, 23453617) Ceftaroline might be preferable for the therapy of MRSA pneumonia. Kim et al. recommend considering a dose of 600 q8hr or an alternative agent for severe infection or if a suboptimal response is noted. (39367501)
Daptomycin 🟢 💉 (90% protein bound; LogP -5). Data suggest minimal effects on PK (including a prospective study with 36 patients). (38814793) Standard doses may be used. (39367501)
Metronidazole 🟢 💉 (20% protein binding; Vd 0.7 L/kg; LogP -0.18). Unlikely to be affected by ECMO.
Trimethoprim-Sulfamethoxazole 🟠 💉 (Sulfamethoxazole is 70% protein bound with LogP of 0.9; trimethoprim is 44% protein bound with LogP of 0.9). Little data is available (a single case report showed adequate pharmacokinetics). (39367501) The dose of trimethoprim-sulfamethoxazole is controversial, with traditional doses being unnecessarily high (e.g., 15 mg/kg/day for Pneumocystis). As such, using a traditional dose is likely to achieve adequate levels.
Fluoroquinolones 🟢 💉
- Ciprofloxacin (30% protein binding; Vd 2.5 L/kg; LogP -1.1).
- Levofloxacin (30% protein binding; Vd 1.1 L/kg; LogP -0.4).
- Fluoroquinolone concentrations remain therapeutic with standard dosing, but fluoroquinolones aren't usually preferred in the ICU. (29732181, 35326801)

nephrotoxic antibiotics with potential therapeutic dose monitoring

Vancomycin 💉 (50% protein binding; Vd 0.7 L/kg; LogP -3.1). Dosing similar to other critically ill patients (e.g., loading dose of 25-30 mg/kg followed by 30-40 mg/kg/day). (35326801) Careful monitoring of levels is required. (29732181) Vancomycin use should be avoided, if possible, to reduce the risk of renal failure.
Aminoglycosides 💉 (<30% protein binding; LogP <0). The volume of distribution is often increased, but the circuit doesn't adsorb aminoglycosides. Close monitoring should be utilized. The primary drawbacks are nephrotoxicity and limited penetration of some tissues.

antifungal therapies

Fluconazole 💉 (10% protein binding; Vd 0.7 L/kg; LogP 0.4). Minimal sequestration seems to occur with the ECMO circuit. (35326801) Kim et al. recommend using a loading dose of 12 mg/kg or double the usual treatment dose followed by standard treatment doses. (39367501)
Voriconazole 💉 (60% protein binding; LogP 1.5). Significant drug adsorption to the circuit seems to occur (71% circuit drug loss in one report). (29732181) Kim et al. suggest increasing the loading dose duration (e.g., 6 mg/kg q12 for two days) and then reducing the dose to 3-4 mg/kg. Drug levels should also be followed. (39367501)
Caspofungin 💉 (95% protein binding; Vd 0.3-2 L/kg; LogP -3.8). Usual doses are likely adequate, although studies are conflicting. (32816724, 37300631)
Micafungin 💉 (>99% protein binding; Vd 0.2 L/kg; LogP -1.6). Studies are limited, with some suggesting no difference, but the EMPIRICUS study suggests a 23% reduction in area under the curve. (37300631) A dose escalation to ~150 mg/day is likely adequate. (39367501)

ECMO pharmacology
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general approach for determining the risk of ECMO circuit sequestration

Protein binding <30% (low):
- LogP <1 & Vd <1 L/kg: Low risk.
- LogP 1-2 & Vd 1-5 L/kg: Low to moderate risk.
- LogP >2 & Vd >5 L/kg: Moderate risk (consider increasing dose/frequency).
Protein binding 30-60% (moderate):
- LogP <1 & Vd <1 L/kg: Low-to-moderate risk.
- LogP 1-2 & Vd 1-5 L/kg: Moderate risk (consider increasing dose/frequency).
- LogP >2 & Vd >5 L/kg: Moderate-to-high risk (use higher loading and/or maintenance doses and/or increase frequency)
Protein binding >60% (high):
- LogP <1 & Vd <1 L/kg: Moderate risk (consider increasing dose/frequency).
- LogP 1-2 & Vd 1-5 L/kg: Moderate-to-high risk (use higher loading and/or maintenance doses and/or increase frequency)
- LogP >1 & Vd >5 L/kg: High risk (avoid if possible; if required, use higher loading doses and/or maintenance doses and increased frequency if appropriate; follow medication levels if available). (Red Book 6e)
(Log P is the octanol-water partition coefficient. High Log P values indicate greater lipophilicity.)
⚠️ When possible, pharmacokinetic data should be sought regarding individual medications. The above approach is a rough guide for medications whose ECMO pharmacology hasn't been well investigated.

major pharmacologic issues in ECMO

[1] Increased volume of distribution (affects hydrophilic medications with a low Vd):
- This results from the additional volume of blood in the circuit.
[2] Sequestration (primarily affects highly lipophilic and protein-bound drugs):
- Drugs adhere to the plastic of the circuit.
- Initially, sequestration may decrease drug levels.
- Later on, reabsorption of drugs from the circuit may lead to toxicity.
- Sequestration may be greatest with newly primed circuits. (Red Book 6e)
[3] Low albumin levels (affects highly protein-bound drugs):
- Albumin levels may decrease due to the adsorption of protein onto the circuit.
- Lower albumin levels may increase free drug levels.

general strategies for optimizing pharmacokinetics

Select a more hydrophilic drug, if possible.
If possible, select medications with a wider therapeutic index (which are more forgiving pharmacokinetically).
Titrate drugs to level or effect:
- [1] If drug level can be checked (e.g., vancomycin, phenobarbital), follow this carefully.
- [2] For sedatives/analgesics, administration in boluses PRN may allow dose personalization while avoiding drug accumulation (which may result from infusions that aren't continuously and aggressively weaned down).

antibiotic pharmacology: ⚡️

analgesia & sedation

Most neuroactive medications are lipophilic (since this is required to penetrate the brain). This causes many sedatives and analgesics to have relatively high adsorption to the ECMO circuit. However, since many of these drugs are titrated to effect, they may still be used effectively – albeit with higher doses and closer attention to dose titration.

nonpharmacologic therapies to improve comfort

Adequate CO2 clearance: For patients with tachypnea or ventilator dyssynchrony, increasing the sweep speed may reduce the pCO2 and thereby blunt the respiratory drive. (More on sweep gas titration: ⚡️)
Treat hypernatremia since this may promote thirst and agitation. 📖

acetaminophen 💉

Acetaminophen has favorable pharmacokinetics in ECMO (20% protein binding; LogP 0.5).
Scheduled acetaminophen may provide a mild amount of analgesia with minimal toxicity. Efficacy is low and gradual-onset, so it's generally optimal to give this on a scheduled basis (rather than PRN).

opioids

Pharmacokinetic summary:
- 🏆 Hydromorphone: 10% protein binding; LogP 0.9 (Taha 2024)
- Fentanyl: 80-85% protein binding; LogP 4.1
- Morphine: 30-40% protein binding; LogP 0.9
Hydromorphone:
- Low lipophilicity and protein binding.
- Generally, it is a preferred opioid for ECMO patients. (Taha 2024)
- Hydromorphone has a relatively long half-life so that it may be dosed in a PRN fashion.
- Some studies suggest that the use of hydromorphone correlates with reduced opioid requirements and improved days alive without delirium or coma, as compared to fentanyl. (38999360)
Fentanyl may be useful for very brief analgesia (e.g., for procedures). It is the most sequestered of all three commonly utilized opioids. (Taha 2024)
Morphine: Pharmacokinetically, morphine is reasonably good. However, histamine release and accumulation of active metabolites in renal failure limit its use. (Taha 2024)

propofol

Pharmacokinetics: 95-99% protein binding; LogP 3.8.
Propofol is safe to use with current membrane oxygenators. However, it will be substantially sequestered within the ECMO circuit so that higher doses may be required. It is unclear how to balance the need for higher doses with the minimization of propofol infusion syndrome.
Propofol may remain useful for procedural sedation and short-term sedation. (Taha 2024)

central alpha-2 agonists

Dexmedetomidine infusion: 💉
- Pharmacokinetics: 94-97% protein binding; LogP 3.39 (Taha 2024)
- The circuit will substantially adsorb dexmedetomidine. Higher doses may be required, especially if there is a circuit change. (Red Book 6e)
Enteral guanfacine: 💉
- Pharmacokinetics: 70% protein binding; LogP ~1.7 (PubChem).
- Guanfacine is likely to be sequestered in the ECMO circuit, but high doses could be trialed.

ketamine

Pharmacokinetics: ~35-47% protein binding; Log P ~3.
The circuit may adsorb ketamine, leading to lower drug levels. However, numerous studies describe the successful use of ketamine among patients on ECMO.

benzodiazepines

Pharmacokinetics:
- Midazolam: 97% protein binding; LogP 3.9
- Lorazepam: 85% protein binding; LogP 2.2
- Diazepam: 98% protein binding; LogP 2.8
Benzodiazepines will have a reduced duration of effect due to clearance by the ECMO circuit.
Midazolam could be helpful for procedural sedation.
Benzodiazepines are not generally preferred agents in the ICU due to the increased risk of ICU delirium.

antipsychotics

Pharmacokinetics:
- Haloperidol: 90% protein binding; LogP 4.3
- Quetiapine: 80% protein binding; LogP 2.8
- Olanzapine: 93% protein binding; LogP 4
- Lurasidone: 99% protein binding; LogP 5.6
- Chlorpromazine: >90% protein binding; LogP 5.4
Overall, antipsychotics are likely to be substantially sequestered by the ECMO circuit. IV haloperidol could be utilized for behavioral emergencies. However, ongoing use of adjunctive atypical antipsychotics seems unlikely to achieve pharmacokinetic targets. There is also a risk that once the circuit is saturated with the drug, levels could accumulate, leading to oversedation.

valproic acid 💉

Pharmacokinetics: 90-95% protein binding; LogP 2.8
Valproic acid has mood-stabilizing properties that may be useful for the management of some patients with persistent agitated delirium that is refractory to more commonly utilized agents.
Valproic acid has been used successfully in ECMO patients for seizure management. (33198577) It could be considered for refractory agitation. An advantage of valproic acid is the ability to measure drug levels (however, caution is required when measuring total valproate level since the free level may be proportionally higher among patients with hypoalbuminemia).

phenobarbital

Pharmacokinetics: 50% protein binding; LogP 1.5
Extremely slow metabolism and the ability to check phenobarbital levels facilitate safe titration of phenobarbital to effect.
Phenobarbital may be a helpful agent for adjunctive sedation in the context of ECMO. (Curran et al.)
A significant limitation of phenobarbital is that it induces cytochrome P450 enzymes with numerous drug-drug interactions. This could further complicate the pharmacokinetics, especially among patients on a wide variety of medications. Thus, phenobarbital might be more helpful toward the end of an ECMO run when patients are on fewer medications.

paralytics

Pharmacokinetics:
- Cisatracurium: LogP -3.73, 38% protein binding.
- Rocuronium: LogP -1.68, 46% protein binding.
- Vecuronium: LogP -0.75, 70% protein binding. (Taha 2024)
Cisatracurium is the best agent for ongoing paralytic infusions. Its clearance isn't affected by renal or hepatic dysfunction, which is common among patients on ECMO. Cisatracurium has lower lipophilicity than rocuronium or vecuronium, so it likely has lower ECMO sequestration. Cisatracurium may also have a lower rate of neuromuscular complications than aminosteroid paralytics (rocuronium, vecuronium).
Paralysis should be closely monitored using a train-of-four and titrated to effect.

ECMO radiology
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There are innumerable possible ECMO configurations. The following discussion refers to the most common ones.

VV ECMO with two cannulas

The distance between the two cannulas should ideally be >10-15 cm to avoid recirculation. (33272724)

femorojugular configuration

Venous drainage cannula: The distal tip is below the IVC/RA junction, near the hepatic vein.
Arterial return cannula: Distal tip at the SVC/RA junction.

(femorofemoral configuration; less common)

Venous drainage cannula: Distal tip in the lower IVC, 5-10 cm below the RA/IVC junction, above the bifurcation of the iliac veins. (33272724)
Arterial return cannula: Distal tip in the right atrium.

VV ECMO with a single catheter

Avalon catheter (bicaval dual lumen catheter)

The return port is within the RA, pointed toward the tricuspid valve. If the arterial outflow points away from the tricuspid valve, this may promote recirculation.

ProtekDuo catheter (veno-pulmonary artery ECMO)

This is a single, dual-lumen cannula positioned similarly to a Swan-Ganz catheter, with the tip of the catheter sitting in the main pulmonary artery.
Drainage ports should project over the right atrium. (33272724)

peripheral VA ECMO

Venous drainage cannula:
- Often at the junction of IVC and right atrium (a few cm above the diaphragm).
- Sometimes, it may be inserted through the right atrium, with the distal tip at the SVC/RA junction. (Shepard 2019)
Arterial return cannula:
- Usually in the common iliac artery or distal aorta.
- (Doesn't require daily radiograph.)

ECMO in pregnancy
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indications

Indications are similar to non-pregnant populations.
The fetus is an end-organ so that fetal distress may indicate inadequate systemic perfusion or gas exchange.
More common indications include:
- ARDS.
- Pulmonary embolism.
- Amniotic fluid embolism.
- Pulmonary hypertensive crisis.
- Peripartum cardiomyopathy.

gas exchange targets

Oxygenation target is often a PaO2 ≧70 mm and oxygen saturation ≧95% to ensure fetal oxygenation.
PaCO2 is normally ~27-32 mm in pregnancy, so mild respiratory alkalosis should usually be targeted.
(Further discussion of normal blood gas parameters in pregnancy: 📖).

medications

Anticoagulation: Either heparin or DTIs may be used (similarly to other ECMO patients). (Red Book 6e)
Steroid: dexamethasone or betamethasone have higher fetal uptake (discussed further: 📖)

candidacy for ECMO
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patient selection for VV ECMO

VV ECMO is a bridge to either:

Recovery of native lungs (most patients).
Lung transplant. (33965970)

contraindications to VV ECMO

[1] Irreversible lung injury plus ineligible for transplant (absolute contraindication).
[2] CNS pathology:
- Central nervous system hemorrhage.
- Irreversible and incapacitating central nervous system pathology.
[3] Non-correctable coagulopathy/bleeding:
- Contraindication to anticoagulation (e.g., severe coagulopathy).
[4] Mechanical ventilation for >7 days with Pplat >30 cm and FiO2 >90%. (33965970)
[5] Global considerations:
- Severe, acute multiorgan failure (especially if respiratory failure is unlikely to drive the overall outcome).
- Pre-existing life-limiting disease (e.g., advanced malignancy).
- Age >75 years old, especially with declining baseline functional status (increasing risk of death with increasing age; no strict cutoff threshold is established).
- Severe immunosuppression.

general indications for VV ECMO

Hypoxemic respiratory failure:
- General indication: P/F <80 mm after optimal medical management, including a trial of prone positioning (if possible).
- EOLIA trial criteria include the following (despite optimization including measures such as paralysis, proning, and inhaled pulmonary vasodilators). (38999360)
  - P/F <50 for >3 hours, on FiO2 >0.8%.
  - P/F <80 for >6 hours, on FiO2 >0.8%.
Hypercapnic respiratory failure:
- pH <7.20-7.25 with PaCO2 >60 mm despite optimal conventional mechanical ventilation (respiratory rate 35 b/m and plateau pressure ≦30-32 cm).
Lung transplantation: Support as a bridge to lung transplantation or primary graft dysfunction following lung transplantation. (33965970)

situations where VV ECMO may be beneficial

Common indications:
- ARDS, including various etiologies such as:
  - Severe pneumonia.
  - Aspiration.
  - Thoracic trauma (e.g., traumatic lung injury and severe pulmonary contusion).
  - Acute eosinophilic pneumonia.
- Status asthmaticus.
- Massive air leak syndromes (e.g., large bronchopleural fistula). (38999360)
- Severe inhalational injury.
Other indications may include:
- Pulmonary hemorrhage (including diffuse alveolar hemorrhage). Anticoagulation may be omitted or utilized at a reduced intensity while accepting an increased risk of device-related complications. (Red Book 6e)
- Peri-lung transplant (e.g., primary lung graft dysfunction and bridge to transplant). (33965970)
- Complex airway management.

scoring systems

The RESP score may be utilized to predict mortality. 🧮

patient selection for VA ECMO

VA ECMO is a bridge to:

[1] Recovery of native heart, e.g.:
- Time to recover (e.g., viral myocarditis).
- Bridge to procedure (e.g., revascularization, pulmonary embolectomy).
[2] Durable LVAD.
[3] Heart or heart-lung transplantation.

contraindications to VA ECMO

Cardiac recovery is unlikely and not a candidate for heart transplant or durable LVAD.
Poor life expectancy (e.g., end-stage peripheral organ diseases, advanced malignancy, chemotherapy-induced chronic cardiomyopathy).
Severe vascular disease (including axillary arteries).
Acute Type A or B aortic dissection with extensive aortic branches involved.
Severe aortic regurgitation.
Severe neurological impairment (e.g., prolonged anoxic brain injury, extensive trauma, or hemorrhage).
Severe immunosuppression.
Contraindication to anticoagulation (e.g., severe coagulopathy).
Cirrhosis (Child-Pugh class B and C; online calculator here 🧮).
Older age (higher risk of mortality; no threshold is established). (34339398, Red Book 6e)

common situations where VA ECMO may be beneficial

Fulminant myocarditis.
Acute MI.
Intoxication with cardiotoxic drugs.
Hypothermia with refractory cardiocirculatory instability.
Massive pulmonary embolism.

considerations

VA ECMO should be considered for cardiogenic shock within 6 hours of its occurrence, refractory to conventional pharmacology and fluid therapy, in patients with reversible cardiocirculatory collapse or those eligible for LVADs or transplant. (34339398)
Prognostic scores may be used to provide information regarding decision-making before ECMO.
- SAVE score predicts survival after VA ECMO (MDCalc: 🧮).

questions & discussion
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To keep this page small and fast, questions & discussion about this post can be found on another page here.

Acknowledgement: Thanks to Dr. Scott Weingart (@emcrit) for thoughtful comments on this chapter.

References

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Books

MacLaren, G. (2022). Extracorporeal Life support: The ELSO Red Book 6th Edition.
Maybauer, M. O. (2022). Extracorporeal membrane oxygenation: An Interdisciplinary Problem-Based Learning Approach. Oxford University Press.
Schmidt, G. A. (2022). Extracorporeal membrane oxygenation for adults. Springer Nature.
Taha, A. R. (2024). ECMO: A practical guide to management. Springer. 38747332

CONTENTS

basic management issues

management unique to VV ECMO

management unique to VA ECMO

hematology of ECMO

other topics

circuit parameters(back to contents)

circuit parameters

pump speed (RPM)

RPMs in VV ECMO

RPMs in VA ECMO

V' (ECMO blood flow)

ECMO blood flow in VV ECMO

ECMO blood flow in VA ECMO

Pven (venous pressure, aka P1)

causes of excessively negative Pven (aka drainage insufficiency)

management steps could include

Pint (internal pressure, aka P2)

Part (arterial pressure, aka post-membrane pressure, aka P3)

return obstruction (high Part, high Pint, stable deltaP)

management of return failure

▵P (transmembrane pressure)

sweep gas flow rate

basics

initial sweep flow & pCO2 management

subsequent titration of sweep flow is based on:

weaning off VV ECMO

FdO2 (fraction of delivered O2), aka FsO2 (fraction of sweep gas O2)

VV ECMO

VA ECMO

SarO2 (arterial return saturation) & ParO2 (pO2 in arterial return)

VV ECMO

VA ECMO

causes of low SarO2 & low ParO2

SvdO2 (venous drainage oxygen saturation)

SvdO2 interpretation

causes of low SvdO2

management of low SvdO2 may include

low circuit flow & circuit flow arrest(back to contents)

low circuit flow & circuit flow arrest

causes of low circuit flow

circuit flow arrest

pump failure(back to contents)

pump failure

causes

differential diagnosis

clinical presentation

management

membrane lung dysfunction(back to contents)

membrane lung dysfunction

manifestations of membrane lung dysfunction may include:

[1] key finding is elevated ▵P

[2] hemolysis and/or DIC (discussed below)

[3] impaired gas exchange

bedside examination of membrane lung

signs of membrane lung dysfunction

basic troubleshooting: ensure that

laboratory evaluation of membrane lung function

compare pre- and post-membrane blood gas values

hematologic abnormalities:

management of membrane lung dysfunction

air embolism(back to contents)

air embolism

definition

causes

manifestation

management

circuit disruption causing blood loss(back to contents)

circuit disruption causing blood loss

basics

clinical presentation may include

management

systemic desaturation in VV ECMO(back to contents)

systemic desaturation in VV ECMO

what are the saturation goals?

common causes of systemic desaturation

(#1) basic circuit check

(#2) evaluate for membrane dysfunction

(#3) evaluate for recirculation

diagnosis: signs of recirculation

circuit parameters
(back to contents)

low circuit flow & circuit flow arrest
(back to contents)

pump failure
(back to contents)

membrane lung dysfunction
(back to contents)

air embolism
(back to contents)

circuit disruption causing blood loss
(back to contents)

systemic desaturation in VV ECMO
(back to contents)

ventilator optimization in VV ECMO
(back to contents)

weaning off VV ECMO
(back to contents)

RV dysfunction in VV ECMO
(back to contents)

ventilator optimization in VA ECMO
(back to contents)

**ventilator settings regarding ventilation (CO2)**

systemic desaturation in VA ECMO
(back to contents)

hemodynamic targets in VA ECMO
(back to contents)

LV distension
(back to contents)

differential hypoxemia (aka north-south syndrome)
(back to contents)

VA ECMO with central cannulation
(back to contents)

VA ECMO in RV failure
(back to contents)