Table 2.

Efficacy evaluation of norepinephrine.

Reference	Participants and dosing regimen	BP	HR	Non-invasive hemodynamic	Drug consumption	Performance error
Hasanin et al., 2018 [2]	Group NE1 (n=95), 0.025 μg/kg/min; NE2 (n=93), 0.05 μg/kg/min; NE3 (n=96), 0.75 μg/kg/min; followed with an initial bolus of NE 5 μg given post spinal anesthesia	SBP was higher with NE2/NE3 compared to NE1∗  Frequency of post-spinal hypotension: NE1 > NE2/NE3, 42.1%, 24.7%, and 26.0%, respectively∗  Frequency of severe hypotension, intraoperative hypertension, and postdelivery hypotension: ns	HR was lower in NE2/NE3 compared to NE1∗  Frequency of bradycardia requiring atropine, ns	N/A	Ephedrine requirements: NE1 > NE2/NE3, 7 ± 10, 5 ± 9, and 5 ± 9 mg, respectively∗	N/A
Sharkey et al., 2018 [10]	Group NE (n=56) and group PE (n=56), NE bolus 6 μg vs. PE 100 μg whenever SBP lower than baseline, ephedrine 10 mg is given when SBP < 80% baseline + HR < 60bpm or SBP < 80% baseline for 2 consecutive readings	Incidence of hypotension, hypertension, and tachycardia: ns Need for NE and PE bolus: ns Need for rescue ephedrine bolus: 7.2% vs. 21.4%∗	Incidence of bradycardia: group NE < group PE, 6 (10.9%) vs 21 (37.5%)∗  Incidence of > 2 episodes of bradycardia: group NE < group PE, 2(3.6%) vs 11(19.6%)∗	N/A	Proportion of need for ephedrine: group NE < group PE, 7.2% vs. 21.4%∗  Vasopressor bolus required: 9 [6-14] for NE vs. 8 [5.5-10.5] for PE, ns	N/A
Ngan Kee et al., 2018 [3]	Group NE1 (n=53), manually controlled variable rate infusion, 0-5 μg/min for SBP near baseline Group NE2 (n=54), bolus 5 μg whenever SBP < 80% baseline	Incidence of hypotension: group NE1 < NE2, 9 (17%) vs 35 (66%)∗  AUC of SBP over time: group NE1 > NE2, 110.9 ± 8.3 vs 101.9 ± 9.4 mmHg∗	Incidence of bradycardia: 4 (7.5%) vs 4 (7.4%), ns AUC of HR over time: group NE1 < NE2, 82.2 ± 10.4 vs 88.2 ± 12.1 mmHg∗	CO: 6.85 ± 1.37 for group NE1 vs 6.42 ± 1.31 L/min for group NE2, ns	Total dose: group NE1 > NE2, 61.0 (47.0-72.5) vs 5.0 (0-18.1) μg Median rate: group NE1 > NE2, 2.22 (1.87-2.57) vs 0.28 (1.87-2.57) μg/min	MDPE: group NE1 < NE2, -2.99 (-6.36 to 0.29) vs -11.15 (-14.77 to -7.65)∗  MDAPE: group NE1 < NE2, 4.97 (3.81 to 6.74) vs 11.33 (7.86 to 14.99)∗  Wobble, 3.13 (2.51 to 3.76) vs 3.32 (2.45 to 5.00), ns
Chen D et al., 2018 [4]	Group NE1 (n=29), 5 μg/kg/h; NE2 (n=30), 10 μg/kg/h; NE3 (n=28), 15 μg/kg/h; control group (n=30), saline infusion; rescue bolus 10 μg for SBP < 80 % baseline or < 90 mmHg	Incidence of hypotension: control group > NE1, NE2, NE3, 86.7, 37.9, 20, 25%, respectively∗  Incidence of hypertension: control group < NE1/NE2 < NE3, 10, 41.4, 36.6, and 75%, respectively∗	Incidence of bradycardia: 0, 3.4, 3.3, 10.7 %, ns HR: ns among groups	CO, SVR: ns	Total dose: control group < NE1 < NE2, NE3, 23 ± 20, 186.9 ± 79.6, 375.8 ± 137.3, 479.1 ± 243.8μg, respectively∗	N/A
Vallejo M et al., 2017 [7]	Group NE (n=43), 0.05 μg/kg/min; group PE (n=38), 0.1 μg/kg/min; for SBP with 100-120% of baseline, rescue bolus PE 100 μg for hypotension (SBP < baseline) or rescue ephedrine 5 mg for hypotension + bradycardia (HR < 60 bpm)	Proportion of vasopressor requirement: 21 (48.8%) for group NE and 25 (65.8%) for group PE, ns Requirement for PE rescue bolus: 20 (46.5%) for group NE and 20 (52.6%) for group PE, ns Requirement for ephedrine rescue bolus: group NE < PE, 1 (2.3%), 9 (23.7%)∗  Incidence of hypertension: 1 (2.6%) vs 2 (4.7%), ns	Incidence of bradycardia: 8 (18.6%) for group NE and 9 (23.7%) for group PE, ns	CO, CI, SV, SVR: ns	Median total rescue PE dose: 100 [0-700] for group NE and 50 [0-1000]μg for group PE, ns Median total rescue ephedrine dose: 0 [0-30] for group NE and 0 [0-85] mg for group PE, ns	N/A
Onwochei et al., 2017 [5]	Bolus NE 3 (n=6), 4 (n=2), 5 (n=9), 6 (n=20), 7 μg (n=3) to rescue first episode of hypotension	ED90 of NE 5.49 μg (95%CI 5.15-5.83) using truncated Dixon and Mood method; 5.80 μg (95% CI 5.01-6.59) using the isotonic regression method Hypotension incidence: 6 (15%), of which 5 (83.3%) with NE < 6μg; Incidence of hypertension: 4 (10%)	Incidence of bradycardia: 3 (7.3%)	N/A	Cumulative NE dose: 6 to 78 μg	N/A
Ngan Kee et al., 2017 [6]	NE bolus 4, 5, 6, 8, 10, 12 μg vs. PE 60, 80, 100, 120, 160, 200 μg (n=15 for each dose group) for first episode of hypotension	ED50 for NE and PE is 10 μg (95%CI, 6-17μg), 137 μg (95% CI, 79 -236μg) ED90 for NE and PE is 18 μg (95%CI, 5-63μg), 239 μg (95% CI, 66-869μg) Potency ratio of NE compared to PE: 13.1 (95% CI, 10.4- 15.8)	HR decrease: NE< PE∗	N/A	N/A	N/A
Ngan Kee et al., 2017 [8]	NE 0-5 μg/min (n=49) vs. PE 0-100μg/min (n=52) for SBP near baseline with computer designed algorithm	Incidence of hypotension: 4(8.2%) for group NE, 4(7.7%) for group PE, ns Incidence of hypertension: 4 (8.2%) for group NE, 9 (17.3%) for group PE, ns	Incidence of bradycardia: 9 (18.4%) for group NE, 29 (55.8%) for group PE∗	N/A	Total vasopressor volume: 10.4 [9.5-14.1], 14.3 [9.9-16.9] ml, ns	MDPE (%): group NE < PE, 0.75 [-1.56 to 2.52] vs. 2.61 [0.83 to 4.57]∗  MDAPE (%): group NE < PE, 3.79 [2.82 to 5.17] vs. 4.70 [3.23 to 6.57]∗  Wobble (%): 2.85 [2.07 to 3.92] vs. 3.39 [2.62 to 4.90]∗  Divergence (% /min): ns
Ngan Kee et al., 2015 [9]	NE 0-5 μg/min (n=49) vs. PE 0-100μg/min (n=52) for SBP near baseline with computer designed algorithm	AUC of SBP over time: ns	AUC of HR over time: group NE > PE∗	AUC of CO: group NE > PE∗  AUC of SV: ns AUC of SVR: group NE < PE∗	N/A	N/A

NE: norepinephrine; PE: phenylephrine; MDPE: median performance error; MDAPE: median absolute performance error; SBP: systolic blood pressure; HR: heart rate; CO: cardiac output; CI: cardiac index; SV: stroke volume; SVR: systemic vascular resistance; AUC: area under the curve; Values are mean (standard deviation), median [interquartile range], or number (%);^∗P <0.05; ns: no statistical significance between groups; N/A: not available.