TABLE 1.

SD-Guided ICU Care Protocol

Tier	Target thresholds and treatments	Escalation	De-escalation
1	SBP >120 mm Hg, or CPP >70 mm Hga	To Tier 2 as soon as 3 SDs occur in a 24-h period	Return to standard care targets if no SDs occur for 48 h:
	ETCO2 to goal PaCO2 ≥35 mm Hg as tolerated by ICPa,b		• SBP >110 or CPP >60
	Core temperature <38.5°C		• ETCO2 ≥35 mm Hg
	ICP < 22 mm Hga		• Core temperature <38.5°C
	PbtO2 >20 mm Hga		• Serum glucose >80 mg/dL
	Serum glucose concentrations 140-180 mg/dL		• ICP, PbtO2: no change
2	Continue Tier 1 goals for SBP/CPP, ICP, glucose, and PbtO2	To Tier 3 as soon as 3 SDs occur in a 24-h period	Return to Tier 1 if no SDs occur for 24 h
	ETCO2 to goal PaCO2 ≥ 40 mm Hg as tolerated by ICPa,b
	Core temperature < 37.0°C
	Initiate ketamine at 1 mg/kg/h (16.67 mcg/kg/min)
	• Lower dosing may be used as per clinical judgment
	• Fentanyl and either midazolam or propofol should be used concurrently for analgosedation
3	Continue Tier 2 goals	N.A.	Return to Tier 2 if no SDs occur for 12 h
	Increase ketamine to 2-4 mg/kg/h (33.33-66.67 mcg/kg/min)
	• Start at 2 mg/kg/h (33.33 mcg/kg/min). Increase dose by 0.5 mg/kg/h (8.33 mcg/kg/min) if SD occurs >15 min after previous dose start. Titrate up to 4 mg/kg/h maximum dose, as needed
	• Ensure protected airway before initiation of Tier 3 intervention
	• Fentanyl and either midazolam or propofol should be used concurrently for analgosedation

CPP, cerebral perfusion pressure; E_TCO₂, end-tidal concentration of expired carbon dioxide; ICP, intracranial pressure; ICU, intensive care unit; P_aCO₂, partial pressure of arterial carbon dioxide; P_btO₂, Brain tissue oxygen; N.A., not applicable; SD, spreading depolarization; SBP, systolic blood pressure.

^aOnly applicable to patients undergoing intracranial neuromonitoring as part of clinical care.

^bArterial blood gases will be drawn every 6 h and correlated with E_TCO₂.

Note: Tier 3 includes ketamine treatment at 2 to 4 mg/kg/h, a dose that requires ventilatory assistance. Thus, patients at Tier 1 can be extubated when clinically indicated, and Tier 2 will be the maximum for patients who are breathing spontaneously. For intubated patients at Tiers 2-3, mechanical ventilation will be continued until criteria are met for de-escalation to Tier 1. Extubation and de-escalation of such patients who have not met these criteria are allowed per clinical judgment but will be recorded as a protocol violation. Mechanical ventilation will not be extended because of SD considerations for longer than 7 days total.

Bold indicates the difference compared with standard care.