Ion Channel Dysfunction During
Critical Illness
Mark Rich MD/PhD
Wright State University
Case History- Weakness and coma
in the ICU
A 22 year old male developed pneumonia, sepsis. He was
intubated and treated with neuromuscular blocking agents
for two weeks. He gradually improved and the blocking
agents were discontinued, but he remained unresponsive with
no movement of the limbs for 1 week. At this point neurology
was consulted to determine why he was paralyzed and
unresponsive.
Common causes of Weakness in ICU Patients
1) Critical Illness Polyneuropathy- A problem in
peripheral nerves. Patients have severe weakness that
persists for weeks to months after the acute illness has
resolved. It is thought that axons die-the cause is
unknown.
2) Critical Illness Myopathy- A muscle disease that causes
severe weakness that persists for weeks to months after
the acute illness has resolved.
Case study- Nerve conduction results
1) Absent sensory responses in the arms and legs.
2) Absent motor responses in the legs, small responses in the arms.
3) Direct muscle stimulation showed that muscle was inexcitable.
Direct muscle stimulation
Neuropathy
Myopathy
Summary- Case study
1) The patient had inexcitable skeletal muscle as is found
in critical illness myopathy.
2) The absent sensory responses suggest he also had
critical illness polyneuropathy.
3) The patient also had low ECG amplitude and poor
contractility of the heart.
4) The cause of coma remained a mystery.
In the rat model of critical illness
myopathy muscle becomes less
excitable.
The cause of reduced muscle excitability
is a sodium channelopathy
Depolarization
Closed
Open
Continued
Depolarization
Repolarization
Inactivated
The cause of reduced muscle
excitability is a sodium channelopathy
Control RP
Control Inactivation
Excitable Inactivation
Inexcitable Inactivation
Normalized Current (%)
100
80
13.5 mV
60
Excitable RP
40
20
Inexcitable RP
0
-100
-90
-80
Voltage (mV)
-70
-60
-50
Case study re-interpreted in light of channelopathy
1) The patient likely had a sodium channelopathy
making muscle inexcitable.
2) What if absent sensory responses are due to sodium
channel dysfunction in nerve?
3) Could sodium channelopathy account for the
abnormalities in the heart?
4) Could his coma be due to sodium channelopathy?
Reduced nerve excitability in critically ill rats
is consistent with a sodium channelopathy
ECG Changes in a critically ill patient suggest reduced cardiac excitability
Changes in cardiac action potentials suggest a selective
reduction in sodium current during critical illness
Reduction in motor neuron excitability during critical illness
suggests that neurons in the central nervous system are
also affected
Summary
1) We hypothesize that during critical illness, sodium
channelopathy affects skeletal muscle, peripheral nerve,
heart and the central nervous system.
2) This channelopathy could account for weakness,
cardiac failure and coma.
3) It is possible that correcting the defect in sodium
channels will correct much of multi-system organ failure
in critically ill patients.
4) The patient woke up and recovered completely.