Table 2.

Sedation Treatment and Cerebrovascular Response: Summary of Study Details

References	medication and dose	CBF/Cerebrovascular response	Limitations	Conclusions
Human studies
Lee et al.28	Propofol: 1 mg/kg	Metabolic reactivity was induced through propofol burst suppression -CPP increase by 5% (p < 0.01) -SjvO2 increase by 3% (p < 0.01) -MAP was constant -MCAv in most models decrease by 30%, CBF also demonstrated a decrease but was not significant -Trend to deteriorate vasoreactivity with 20% of patients having reduced response PCO2 and PO2 levels were controlled through ventilation	MAP during burst suppression was maintained with phenylephrine, which may interfere with CBF	Propofol through metabolic suppression decreased CBFv
Steiner et al.10	Propofol: 3-4 mg/kg/h	Propofol -Higher doses decreased MCAv by 8% -Little change to CPP or AVDO2 -MAP remained relatively constant -Static rate of autoregulation on average decreased from 56 ± 36 to 28 ± 35% but increased in some patients PCO2 and PO2 levels were controlled through ventilation	MAP was maintained with norepinephrine, which may interfere with CBF	Propofol decreases MCAv, which is a surrogate measure of CBFv
James et al.34	Propofol: 25.5 μg/kg/min Dexmedetomine: 0.54 μg/kg/h	Propofol -Slight decrease in ICP and no change in PbtO2 although both lacked statistical significance -CPP increased during and fell after injection by about 6% -Lactate/Pyruvate ratio increased drastically after injection -CBF had minimal changes, based on limited response in ICP and PO2 Dexmedetomine -A slight increase in ICP with no change in PbtO2 though both lacked statistical significance -CPP fell slightly by 2% -Lactate/Pyruvate ratio increased drastically after injection -CBF had minimal changes, based on limited response in ICP and PO2 PCO2 and PO2 levels were controlled through ventilation From ICP and CPP, MAP can be assumed to be near constant	Based on limited number of patients	Propofol demonstrated little to no effect on CBF derived from the ICP/PO2 comparison
Johnston et al.23	Propofol: 3-4 mg/kg/h	Propofol -AVDO2, ICP, and PCO2 all slightly decreased as compared with baseline values -PO2 and PbtO2 slightly increased -CPP and lactate/pyruvate ratio had little variation -All changes were not significant	ICP, CPP, and MAP can be assumed to be near constant	Propofol demonstrates a slight non-significant increase to CBF in the setting of TBI
Pinaud et al.27	Propofol: 2 mg/kg then 150 μg/kg/min (3-5 μg/mL)	Propofol -rCBF decrease by 25% (p < 0.01) -ICP decreased by 18% (p < 0.001), this decrease was then inverted after propofol infusion ceased -CPP dropped by28% (p < 0.001) -AVDO2 decreased by (6%) but was not significant -CVR increased then decrease as a result from propofol although this was not significant apart from 1 patient -PCO2 remained constant at 33 ± 2 mm Hg	Large variation within individual patients was not accounted for	Propofol caused a varying decrease in rCBF in all patients; this was associated with a decrease in ICP and CPP This indicates that rCBF drop is caused by MAP decrease
Tanguy et al.33	Propofol: 1 mg/kg/h and increased by same increment with 5 mg/kg/h being max Midazolam: 0.03 mg/kg/h and increased by 0.01 mg/kg/h	Propofol -ICP of 19 ± 12 mm Hg -PO2 of 97 ± 2% -PCO2 of 38 ± 7 mm Hg -CPP of 73 ± 11 mm Hg -MAP of 91 ± 11 mm Hg -CBF had minimal changes, based on limited response in CPP and PO2 Midazolam -ICP of 20 ± 12 mm Hg -PO2 of 98 ± 1% -PCO2 of 35 ± 10 mm Hg -CPP of 73 ± 11 mm Hg -MAP of 100 ± 16 mm Hg -CBF had minimal changes, based on limited response in CPP and PO2 PCO2 and PO2 levels were controlled through ventilation No difference was seen in the lactate/pyruvate ratio was seen	MAP was maintained with catecholamines, which may interfere with CBF Therapeutic goals and sedation levels were independent from microdialysis biomarkers	Using the CPP/PO2 to find CBF, it is indicated that propofol and midazolam are near identical in CBF effect, both demonstrating no significant response
Albanèse et al.24	Sufentanil: 1 μg/kg then 0.005 μg/kg/min Alfentanil: 100 μg/kg then 0.7 μg/kg/min Fentanyl: 10 μg/kg then 0.075 μg/kg/min	Sufentanil, alfentanil, and fentanyl -Initial increase ICP (25%) then after 60 min ICP returned to baseline -CPP decreased by 41% (p < 0.05) -SvjO2 remained relatively unchanged -Based on CPP/ SvjO2, CBF was indicated to increase -Based on CMRO2/AVDO2, CBF slightly decreased PCO2 levels were maintained between 32 and 35 torr and CPP stayed between 27 to 37 mm Hg PCO2 and PO2 levels were controlled through ventilation No changes in lactate-oxygen index or MAP	Based on limited number of patients	Sufentanil, alfentanil, and fentanyl had a slight increase and decrease to CBF found through the surrogate measure of CPP/SvjO2 and CMRO2/AVDO2 although it was not maintained or significant
de Nadal et al.26	Morphine: 0.2 mg/kg Fentanyl: 2 μg/kg	Morphine -Slight increase in CBF (10%) with no change in MCAv -When comparing autoregulation there was little difference in MCAv; however for CBF, impaired autoregulation demonstrated lower overall response (7%) then intact autoregulation (13%) Fentanyl -Slight increase in CBF (10%) and a slight decrease in CBFv (10%) -There was little difference in impaired vs. intact autoregulation in CBF and CBFv response All changing in AVDO2 were adjusted for PCO2 levels MAP remained relatively constant in all groups Slight decrease in CPP associated with ICP then increase to baseline	CBF was approximated or found from the MCA MAP was maintained with phenylephrine, which may interfere with CBF	Fentanyl showed little change in CBF in any group whether with intact or impaired autoregulation although the direct measurement by CBFv and 1/AVDO2 contradicted in response Morphine showed a slight increase in CBF with no significant change in CBFv. Intact autoregulation had a higher response then impaired autoregulation in any group whether intact or impaired autoregulation although the direct measurement by CBFv and 1/AVDO2 contradicted in response
de Nadal et al.25	Fentanyl: 2 μg/kg	Fentanyl -ICP: Increased then slowly decreased in both the group with intact and impaired autoregulation -CPP: Moderately decreased by 6% -AVDO2 initially decreased (11%) then returned to the baseline at 60 min but was not significant MAP showed a similar decrease as CPP All changing in AVDO2 were adjusted for PCO2 levels		Fentanyl showed a decrease in CPP with a small increase in 1/AVDO2 as a surrogate measure for CBF; this was a small and nonsignificant increase Fentanyl had little influence on autoregulation based on limited differences
Papazian et al.32	Midazolam: 0.15 mg/kg	Midazolam -Reduced CPP by 26% (p < 0.0001) -Non-significant change to ICP >18 mm Hg before TBI, when ICP <18 mm Hg before TBI an increase in ICP was observed (20%) -CBF had little change apart from mentioned ICP <18 mm Hg in which case midazolam caused a slight increase in CBF (10%) PCO2 and PO2 were measured and maintained	CBF assumed through CMRO2 coupling	CBF had little change apart from the mentioned ICP <18 mm Hg, in which case midazolam caused a slight increase in CBF Midazolam was assumed to have limited influence on autoregulation due to limited difference in ICP groups
Animal studies
Feuerstein et al.29	Isoflurane at 2% Propofol: 33 to 53 mg/kg/h	Isoflurane -rCBF increased initially with injection then returned to baseline after 1 min (19.8 ± 27.2%) Propofol -rCBF increased initially with injection then returned to baseline after 1 min (27.5 ± 38.2%) -Atrial diameter decrease of 50% where isoflurane had no response Blood gasses were maintained through ventilation MAP had little change in each group	Limited number of subjects	There was little response in rCBF in both groups, with propofol demonstrating a constriction of cerebral pial vessels
Kahveci et al.31	Propofol: 12 mg/kg/h Isoflurane: 0.9 ± 0.04%	Propofol -Decrease ICP from 50% (p < 0.01) -CPP increased by 10% -No significant change to PO2, CBFv, or MAP Isoflurane -No significant effect on CBFv, ICP, or PO2 -MAP and CPP decrease over time by 30% Blood gasses were maintained through ventilation	Subjects were also in a hypothermic state, which influences CBF	Despite the limited result, it was indicated that propofol is the better choice in hypothermic conditions, with no response in CBFv The limited CBF effects of isoflurane are exaggerated by hypothermia indicating that isoflurane either caused no change or an increase in CBF
Bedell et al.30	Isoflurane: 1-1.5% Fentanyl: 50 μg/kg/h	Isoflurane -ICP increased -CPP decreased by 7% then returned to baseline -MAP, CBF, and CVR remain relatively constant Fentanyl -ICP decreased then slightly increased -CPP decrease by 30% -MAP decreased from 30% -CBF decreased by 22% at 75 min then increased to baseline -CVR decreased by 28% EEG, ICP, PCO2, PO2, pH, and temperature were similar between groups	Surgery may influence CBF	In the presence of hypotension fentanyl demonstrated a prevention of CBF indicating the fentanyl may increase CBF; along with this there was a decrease in CVR indicating an vasoconstrictive effect Isoflurane had little influence on cerebral vasculature
Statler et al.36	Isoflurane at 4% then reduced to 1% Fentanyl: 50 μg/mL then 50 μg/kg/h	Fentanyl MAP was higher than isoflurane; however during infusion the MAP and CPP remained constant throughout the experiment CPP after 4 h was greater in fentanyl than isoflurane group by10%, but both constant CBF was 2 to 3 times higher in isoflurane then fentanyl group PO2 and PCO2were controlled by ventilation	Subjects also sedated with nitrous oxide	The increase in CPP by isoflurane indicates that CBF is increased in contrast to the fentanyl demonstrating only minor change in CPP and therefor demonstrated little effect to CBF

AVDO₂, arterio-jugular venous oxygen differences; CBF, cerebral blood flow; CBFv, cerebral blood flow velocity; CMRO₂, cerebral metabolic rate of oxygen; CPP, cerebral perfusion pressure; CVR, cerebrovascular resistance; EEG, electroencephalogram; h, hour; ICP, intracranial pressure; MAP, mean arterial pressure; MCA, middle cerebral artery; MCAv, middle cerebral artery velocity; min, minute; mm Hg, millimeters of mercury; PbtO₂, brain tissue oxygen tension; PCO₂, partial pressure of carbon dioxide; PO₂, partial pressure of oxygen; rCBF, regional cerebral blood flow; sec, second; SvjO₂, jugular venous oxygen saturation; TBI, traumatic brain injury.