Table 2.

Summary of clinical CMD studies.

Studies	Summary of main results	Clinical utility	Reference
Observational studies
Glycemic control	Tight (4–6 mM) vs. moderate (6.1–8 mM) glycemic control is associated with more episodes of low glucoseCMD	Management of insulin	(11, 12, 26–31)
Cerebral perfusion	Cerebral hypoperfusion is associated with increased cerebral metabolic distress (high L/PCMD/low glucCMD)	Early ischemia detection	(37, 42, 43)
		Targeted CPP therapy
Hemoglobin level	Anemia (Hgb <9 g/dL) is associated with increased cerebral metabolic distress	Management of RBCT	(46, 47, 50, 51)
Oxygen therapy	NBHO (2–4 h) is associated with improved LPRCMD	Targeted management of PaO2/FiO2	(57–59)
	NBHO benefit mostly when baseline lactateCMD >3.5 mM
	HBOT is associated with improved L/PCMD
Interventional studies
NOS inhibitors	NOS inhibition (i.v.) does not affect cerebral metabolism	Potential for CMD biomarkers to be used as surrogate efficacy endpoints in phase II clinical trials	(61)
rh IL-1 ra	rh IL-1ra (i.v.) does not affect cerebral metabolism		(62)
Hypertonic lactate	Hypertonic lactate (i.v.) is associated with glucoseCMD increase		(66, 67)
Succinate	Succinate (i.c.) is associated with reduced cerebral metabolic distress		(65)
Mechanistic studies
Seizures	Electrographic seizures are associated with increased cerebral metabolic distress	Monitoring and testing the efficacy of future interventions targeted at reducing seizure and CSD	(84)
CSD	CSD are associated with low glucoseCMD		(86, 87)
Brain edema	Cellular edema is associated with increased ${\text{Na}}_{\text{CMD}}^{+}$, ${\text{K}}_{\text{CMD}}^{+}$, and taurineCMD	Targeted therapy of brain edema based on disease pathology	(90–92, 96, 97)
	Vasogenic edema is associated with increased MMPCMD
Neuroinflammation	Identification of several cytokines (including IL-1ra, IL-6, IL-8, and TNF-α) involved in the complex inflammatory cascade following acute brain injury	Development of therapeutics targeted at attenuating the inflammatory cascade	(106, 107)
Neurodegeneration	Relationship of tau and NfL with MRI axonal degeneration and patient outcome	Characterization of disease neuropathology	(108, 109)
		Patient selection for interventional studies targeted at reducing neurodegeneration

CMD, cerebral microdialysis; CPP, cerebral perfusion pressure; CSD, cortical spreading depression; FiO₂, fraction of inspired oxygen; HBOT, hyperbaric oxygen therapy; Hgb, hemoglobin; i.c., intracerebral; IL, interleukin; i.v., intravascular; L/P lactate/pyruvate ratio; MMP, matrix metalloproteases; MRI, magnetic resonance imaging; NBHO, normobaric hyperoxia; NfL, neurofilament light chain; NOS, nitric oxide synthase; PaO₂, arterial partial pressure of oxygen; ra, receptor antagonist; RBCT, red blood cell transfusion; rh, recombinant human; TNF, tumor necrosis factor.