Neostigmine-induced increase in EEG activity following severe traumatic brain injury.

To JNA Readership: Neostigmine, a competitive inhibitor of the enzyme acetylcholinesterase, is used clinically to stimulate bowel movement, shorten the effects of nondepolarizing muscle relaxants, and reverse the central anticholinergic syndrome by increasing extracellular acetylcholine concentrations. In addition, acetylcholinesterase inhibitors activate cholinergic pathways within the central nervous system, thereby inducing neuronal excitation and decreasing depth of anesthesia. Under conditions of disturbed balance between excitatory and inhibitory pathways with a posttraumatic shift toward increased release of excitatory transmitters, an additional increase in extracellular acetylcholine due to inhibited enzymatic degradation with subsequent neuronal activation could contribute to secondary tissue damage. A 45-year-old male patient suffering from severe isolated traumatic brain injury (TBI) with intracranial pressure (ICP) values exceeding 30mm Hg required high-dose thiopental that decreased ICP below 20mm Hg. After stopping thiopental infusion the patient received fentanyl and midazolam at a dosage of 0.4 and 40mg/h, respectively. Electroencephalographic (EEG) activity remained depressed resulting in an isoelectric line. To overcome thiopental-induced paralytic ileus, continuous slow neostigmine infusion (3mg over 6 h) was begun. Within 8 minutes, EEG activity was significantly increased (Fig. 1). Subsequent bolus injection and increase in fentanyl and midazolam dosage as well as stopping continuous neostigmine infusion abolished the increased EEG activity and restored the previous isoelectric line. The patient remained hemodynamically stable with unchanged ICP and cerebral perfusion pressure values. Cholinesterase inhibitors, as for example, neostigmine dose-dependently influence the autonomic nervous system by inducing acetylcholine-mediated activation of muscarinergic and nicotinergic receptors due to inhibited enzymatic degradation of acetylcholine. Apart from systemic effects (eg, nausea, vomitus, diarrhea, sustained bronchial secretions and bronchospasm, dysrhythmias, and hypotension) increased acetylcholine concentrations within the extracellular space and synaptic cleft stimulate nicotinergic receptors which increases neuronal activity and enhances synchronized cortical interneuronal activity, lowers the seizure threshold, thereby resulting in convulsions. The presently described increase in EEG activity upon neostigmine administration is in line with recently published findings obtained during elective anesthesia settings in which neostigmine-mediated antagonism of neuromuscular blockade during propofol-remifentanil anesthesia increased BIS values and enhanced recovery from anesthesia. The worrisome finding in this patient is that neostigmine was associated with a significant increase in EEG activity despite a pharmacologically induced cortical isoelectric line. This could reflect inadequate inhibition of subcortical circuits as the input of ascending adrenergic and cholinergic pathways cannot be differentiated by conventional EEG recordings using superficial electrodes. The fact that this observed neostigmine-induced increase in EEG activity could be controlled by increasing the dose of fentanyl and midazolam suggests that cortical responsiveness to ascending activation can be manipulated pharmacologically. Nevertheless, during the early phase after severe TBI, administration of neostigmine should be considered with extreme caution to avoid uncontrolled neuronal activity that might induce secondary brain damage related to sustained energy and oxygen consumption in face of locally compromised structural and functional integrity.