The Efficacy and Safety of Norepinephrine and Its Feasibility as a Replacement for Phenylephrine to Manage Maternal Hypotension during Elective Cesarean Delivery under Spinal Anesthesia

Table 1

Characteristics of enrolled studies.

Reference	Study design	Participants	Anesthesia	Dosing regimen	Intervention	Observational-end point	Primary outcome variables
Hasanin et al., 2018 [2]	Double-blind RCT	284 healthy women	Spinal anesthesia with bupivacaine 10 mg + fentanyl 20 μg, rapid crystalloid coloading to 1500 ml starting at subarachnoid block, left tilt supine position	Fixed rate infusion	NE infusion 0.025, 0.05, or 0.075 μg/kg/min for SBP maintenance after an initial bolus of NE 5 μg given post spinal anesthesia, ephedrine 9 mg is given when SBP < 80% baseline or SBP < 80% baseline + bradycardia (HR<55 bpm), ephedrine 15 mg is given for severe hypotension (SBP < 60% baseline), atropine 0.5mg for bradycardia persisted after the previous measure	Immediately post spinal anesthesia until 5 min post delivery	Frequency of post-spinal hypotension (SBP < 80% baseline)
Sharkey et al., 2018 [10]	Double-blind RCT	112 healthy women	Spinal anesthesia with bupivacaine 13.5 mg + fentanyl 10 μg+ morphine 100 μg, rapid hydration for 10ml/kg immediately preceding intrathecal injection, left tilt supine position	Intermittent bolus	NE bolus 6 μg vs. PE 100 μg whenever SBP lower than baseline, ephedrine 10 mg is given when SBP < 80% baseline + HR < 60 bpm or SBP < 80% baseline for 2 consecutive readings	Immediately post spinal anesthesia until delivery	Incidence of bradycardia (HR < 50 bpm) in the predelivery period
Ngan Kee et al., 2018 [3]	Double-blind RCT	107 healthy women	Spinal anesthesia with bupivacaine 11 mg + fentanyl 15 μg, rapid hydration for 2 L post spinal anesthesia, left tilt supine position, suprasternal Doppler (USCOM) for hemodynamic monitor	Manually controlled variable rate infusion vs. intermittent bolus	NE infusion 0-5 μg/min for SBP near baseline vs. NE bolus 5 μg whenever SBP < 80% baseline	Immediately post spinal anesthesia until delivery	Incidence of hypotension (SBP < 80% baseline), and overall stability of SBP control compared with performance error (MDAPE, MDPE, Wobble)
Chen D et al., 2018 [4]	Double-blind RCT	117 healthy women	Spinal anesthesia with ropivacaine 11-12.5 mg + morphine 0.1 mg, preloading with LR 10 ml/kg, left tilt supine position, noninvasive monitoring (LIDCO) for CO and SVR	Fixed rate infusion	NE infusion 5, 10, or 15 μg/kg/h vs. saline for SBP maintenance, NE rescue bolus 10 μg for SBP < 80% baseline or < 90 mmHg	Immediately post spinal anesthesia until the end of surgery	Proportion of hypotension participants (SBP < 80% baseline or < 90mmHg)
Vallejo M et al., 2017 [7]	Open label RCT	81 healthy women	Spinal anesthesia with bupivacaine 12-15 mg + fentanyl 20 μg + morphine 0.2 mg, preloading with LR 500 ml, left tilt supine position, noninvasive monitoring (Nexfin) for CO, CI, SV, SVR	Fixed rate infusion	NE 0.05 vs. PE 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)	Immediately post spinal anesthesia until the patient care transferred to the labor and delivery nurse postoperatively	Number and type of rescue bolus intervention needed to maintain SBP
Onwochei et al., 2017 [5]	Double-blind up-down sequential allocation dose-finding study	40 pregnant women	Spinal anesthesia with bupivacaine 13.5 mg + fentanyl 10 μg + morphine 0.1 mg, rapid hydration for 10ml/kg immediately preceding intrathecal injection, left tilt supine position	Intermittent bolus	NE bolus 3, 4, 5, 6, 7, or 8 μg whenever SBP < 100% baseline	Immediately post spinal anesthesia until delivery	Success of NE regimen to maintain SBP at or above 80% of baseline
Ngan Kee et al., 2017 [6]	Random allocation-graded dose-response study	180 healthy women	Spinal anesthesia with bupivacaine 11 mg + fentanyl 15 μg, rapid cohydration with Plasma-Lyte-A 2L, left tilt supine position	Intermittent bolus	NE bolus 4, 5, 6, 8, 10, 12 μg vs. PE 60, 80, 100, 120, 160, 200 μg for first episode of hypotension (SBP < 80% baseline)	Post spinal anesthesia until completion of each response measurement	Dose response curve
Ngan Kee et al., 2017 [8]	Two-arm parallel, double-blind RCT	101 healthy women	Spinal anesthesia with bupivacaine 11 mg + fentanyl 15 μg, rapid cohydration with LR to maximal 2L just after intrathecal injection, left tilt supine position	Closed-loop feedback computer-controlled infusion	NE 0-5 μg/min vs. PE 0-100 μg/min for SBP near baseline with computer designed algorithm	Immediately post spinal anesthesia until delivery	MDAPE)
Ngan Kee et al., 2015 [9]	Two-arm parallel, double-blind RCT	101 healthy women	Spinal anesthesia with bupivacaine 11 mg + fentanyl 15 μg, rapid cohydration with LR to maximal 2 L just after intrathecal injection, left tilt supine position, suprasternal Doppler (USCOM) for CO monitor	Closed-loop feedback computer-controlled infusion	NE 0-5 μg/min vs. PE 0-100 μg/min for SBP near baseline with computer designed algorithm	Immediately post spinal anesthesia until delivery	CO

RCT: randomized controlled trial; NE: norepinephrine; PE: phenylephrine; SBP: systolic blood pressure; HR: heart rate; LR: lactated ringers’ solution; CO: cardiac output; CI: cardiac index; SV: stroke volume; SVR: systemic vascular resistance; MDAPE: median absolute performance error; MDPE: median performance error; Wobble: a measure of the variability of performance error around MDPE for each patient.