Spinal anesthesia is commonly used for cesarean delivery

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1 Society for Obstetric Anesthesia and Perinatology Section Editor: Cynthia A. Wong REVIEW ARTICLE A Review of the Impact of Phenylephrine Adistration on Maternal Hemodynamics and Maternal and Neonatal Outcomes in Women Undergoing Cesarean Delivery Under Spinal Anesthesia Ashraf S. Habib, MBBCh, MSc, MHS, FRCA Phenylephrine is effective for the management of spinal anesthesia-induced hypotension in parturients undergoing cesarean delivery under spinal anesthesia. While ephedrine was previously considered the vasopressor of choice in obstetric patients, phenylephrine is increasingly being used. This is largely due to studies suggesting improved fetal acid-base status with the use of phenylephrine as well as the low incidence of hypotension and its related side effects with prophylactic phenylephrine regimens. This review highlights the effects of phenylephrine compared with ephedrine on maternal hemodynamics (arterial blood pressure, heart rate, and cardiac output), and occurrence of intraoperative nausea and vomiting. The impact of the adistration of phenylephrine as a bolus for the treatment of established hypotension compared with its adistration as a prophylactic infusion is discussed. This article also reviews the impact of phenylephrine compared with ephedrine on uteroplacental perfusion, and fetal outcomes such as neonatal acid-base status and Apgar scores. The optimum dosing regimen for phenylephrine adistration is also discussed. (Anesth Analg 2012;114:377 90) Spinal anesthesia is commonly used for cesarean delivery because it avoids the risks of general anesthesia related to difficult intubation and aspiration of gastric contents. It is frequently associated with hypotension, which can have detrimental effects on the mother and neonate, including nausea, vomiting, and dizziness in the mother, as well as decreased uteroplacental bloodflow resulting in impaired fetal oxygenation and fetal acidosis. Whether the mode of anesthesia affects neonatal outcomes is controversial. A meta-analysis reported that umbilical artery ph may be lower with spinal anesthesia than with general or epidural anesthesia. 1 A large retrospective study also suggested an association between type of anesthesia and neonatal mortality of very preterm infants, with spinal anesthesia being associated with an increased risk of neonatal mortality compared with general or epidural anesthesia. 2 On the basis of better preservation of uteroplacental circulation in animal models, ephedrine was historically From the Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina. Accepted for publication September 7, Funding: Departmental. The author declares no conflict of interest. Reprints will not be available from the author. Address correspondence to Ashraf S. Habib, MBBCh, MSc, MHS, FRCA, Department of Anesthesiology, Duke University Medical Center, Box 3094, Durham, NC Address to habib001@mc.duke.edu. Copyright 2012 International Anesthesia Research Society DOI: /ANE.0b013e a3e considered the gold standard vasopressor for the management of spinal anesthesia-induced hypotension. 3,4 However, studies over the last 2 decades have suggested that fetal acid-base status might be improved if phenylephrine or other -adrenergic agonists are used during cesarean delivery instead of ephedrine. 5 Consequently, the use of phenylephrine for arterial blood pressure management during cesarean delivery under spinal anesthesia has increased. In 2001, a United Kingdom survey of the Obstetric Anesthetists Association consultant members found that 95% of respondents used ephedrine as the first-choice vasopressor, 6 whereas in 2006, 51% indicated that phenylephrine is their first-line vasopressor. a In 2007 a survey of the members of the Society of Obstetric Anesthesia and Perinatology reported that 32% used ephedrine for treating spinal-induced hypotension, 23% used phenylephrine, and 41% used either drug on the basis of heart rate. 7 However, there is still significant variation in practice regarding the choice, dosing, and method of adistration of vasopressors during cesarean delivery. 7 This article will review the impact of phenylephrine adistration on maternal hemodynamics, intraoperative nausea and vomiting (IONV), and neonatal outcomes including Apgar scores and acidbase status. The optimum dose and method of adistration of phenylephrine will also be discussed. a McGlennan A, Patel N, Sujith B, Bell R. A survey of pre-loading and vasopressor use during regional anaesthesia for caesarean section. Int J Obstet Anesth 2007;16:S27. February 2012 Volume 114 Number

2 REVIEW ARTICLE INTRAOPERATIVE BLOOD PRESSURE, NAUSEA, AND VOMITING Hypotension is one of the most important causes of IONV, 8 particularly in the initial period after initiation of spinal anesthesia. Hypotension may lead to cerebral hypoperfusion and brainstem ischemia, which is thought to activate the vomiting center. 9 It has also been suggested that hypotension results in gut hypoperfusion with the subsequent release of emetogenic substances such as serotonin. 10 Prevention of hypotension significantly reduces the incidence of IONV. Optimum use of vasopressors has therefore a significant impact on the incidence of IONV, with some studies suggesting that IONV might be affected by the choice and method of adistration of the vasopressor. A description of studies included in this review is shown in Table 1. Studies of IV phenylephrine adistration reporting on IONV are summarized in Table 2. A few details are important to consider when interpreting the reported incidence of IONV in these studies. First, the duration of data collection was different among studies, with some studies stopping at uterine incision or delivery, and therefore not including postdelivery IONV episodes (likely induced by uterine exteriorization and visceral manipulation). Second, many studies relied on self-reporting of nausea by patients, and so might have missed some episodes of nausea. 11,12 Third, studies might not have compared equipotent doses of phenylephrine and ephedrine. There has been some controversy regarding the vasopressor potency ratio, with some published studies using ratios varying from 20:1 to 250:1. A dose response study of prophylactic infusions using an up down sequential allocation technique found a potency ratio of 83:1. 13 Finally, most of the studies did not have IONV as a primary endpoint and were therefore not powered to report statistically significant differences in this outcome despite reporting clinically relevant differences. Ephedrine Versus Phenylephrine Boluses The use of phenylephrine boluses of 100 g for the treatment of hypotension was associated with a lower incidence of IONV than was ephedrine 6 to 10 mg despite a similar incidence and frequency of hypotension. 14,15 The lower incidence of IONV with the use of phenylephrine might be related to the faster onset of pressor effect compared with ephedrine (mean onset 61 seconds vs 89 seconds), 16 leading to more rapid correction of hypotension. The use of lower doses of phenylephrine of 40 to 80 g, however, failed to reduce the incidence of IONV compared with ephedrine 5 to 10 mg, 17,18 with the 40- g dose being associated with a higher incidence of hypotension than ephedrine 5 mg. 18 Similarly, the addition of 20 g of phenylephrine to a 5-mg ephedrine bolus for the treatment of hypotension was not effective in reducing the incidence of hypotension or IONV compared to ephedrine alone. 19 Ephedrine Versus Phenylephrine Infusions In contrast to treating established hypotension, the use of a prophylactic vasopressor infusion might be more effective in reducing the incidence of hypotension and IONV. The use of prophylactic phenylephrine infusions ranging from 33 to 100 g/ has been more effective in reducing the incidence of hypotension and IONV than prophylactic ephedrine infusions 1 to 8 mg/. 12,20,21 However, the use of a lower infusion rate of phenylephrine at 10 g/ was not better than ephedrine 1 to 2 mg/ in reducing the incidence of hypotension or IONV. 22 Reactive hypertension has been reported with the use of prophylactic vasopressor infusions 11,12,20,23 26 ; however, this is usually transient and responds quickly to stopping the infusion. Combined Ephedrine and Phenylephrine Infusions The addition of phenylephrine 10 g/ to an ephedrine infusion at 2 mg/ resulted in a significantly lower incidence of hypotension and IONV than did ephedrine alone. 25 In contrast, the addition of ephedrine to a phenylephrine infusion did not result in any extra benefit over phenylephrine alone in terms of lower incidence of hypotension or IONV, 12,21 with 1 study reporting the incidence of IONV increasing from 17% with phenylephrine alone to 55% when ephedrine was added to phenylephrine, despite similar arterial blood pressure control. 21 Cooper et al. suggested that this might be secondary to phenylephrineinduced venoconstriction, reducing preload and avoiding excessive -adrenergic stimulation. 21 This in turn decreases the risk of increased vagal tone that might lead to IONV with spinal anesthesia. Furthermore, another study comparing various combinations of phenylephrine and ephedrine infusions reported that as the proportion of phenylephrine decreased and the proportion of ephedrine increased, hemodynamic control worsened and the incidence of IONV increased. 12 In this study, the groups contained the proportional potency equivalent of 100%, 75%, 50%, 25%, or 0% of phenylephrine and 0%, 25%, 50%, 75%, or 100%, respectively, of ephedrine, assug 100 g phenylephrine to be equipotent to 8 mg ephedrine. Phenylephrine Bolus Versus Phenylephrine infusion Adistration of phenylephrine as a prophylactic infusion was associated with an incidence of hypotension of 13% 23% compared to an incidence of 85% 88% when phenylephrine boluses of 100 g were used to treat a 20% decrease in arterial blood pressure. 11,27 Infusions compared to bolus adistration were also associated with a lower incidence of IONV. 11 Allen et al., 26 however, did not find a reduction in the incidence of IONV with the use of prophylactic phenylephrine infusions at 25, 50, 75, and 100 g/ compared to treatment of hypotension with 100 g phenylephrine boluses, despite a significantly lower incidence of hypotension with the infusion regimens. Data collection in this latter study continued for 10 utes after delivery, and therefore exteriorization of the uterus, visceral manipulation, and adistration of oxytocin might have contributed to a higher overall incidence of nausea in all groups. In another study, the adistration of a single prophylactic phenylephrine bolus of 50 g was less effective than a prophylactic infusion in reducing the incidence of hypotension and IONV ANESTHESIA & ANALGESIA

3 Impact of Phenylephrine on Maternal and Neonatal Outcomes Table 1. Studies Comparing Ephedrine to Phenylephrine: Anesthetic Technique and Hemodynamic Management Groups N Spinal drugs Fluid management BP goal BP management regimen Ngan Kee 14 PE bolus 100 g 102 Bup mg No preload, coload E bolus 10 mg 102 Fent 15 g with up to 2LLR Prakash 15 PE bolus 100 g 30 Bup 10 mg 10 ml/kg LR E bolus 6 mg 30 preload over utes Moran 17 PE bolus 80 g for initial 2 SBP of 5 mmhg followed by g to keep SBP 100 E bolus 10 mg followed by 5 10 mg as in PE group Magalhaes 18 PE 80 g prophylactic bolus followed by 40 g for 2 BP E 10 mg prophylactic bolus followed by 5 mg for 2 BP Loughrey 19 E10mg PE 40 g prophylactic bolus followed by E5mg PE 20 g for 2 BP E 10 mg prophylactic bolus followed by E 5 mg for 2 BP 31 Bup mg according to height Bup 10 mg Sufent 3 g Bup 12 mg Fent 10 g morphine 0.2 mg Ngan Kee 20 PE 100 g/ 52 Bup 10 mg E 8 mg/ 52 Fentanyl 15 g Ngan Kee 12 PE 100 g/ PE 75 g/ E 2 mg/ Bup 10 mg Fentanyl 15 g PE 50 g/ E 4 mg/ 25 PE 25 g/ E 6 mg/ 24 E 8 mg/ Preload 2LLR utes before spinal Bradycardia definition Anticholinergic indication SBP 100 Bolus for SBP bpm HR 50 bpm and 2 BP SBP 80% of 2 L LR after spinal SBP 80% of Preload LR 10 ml/kg Bolus for SBP 80% 60 bpm HR 60 bpm and SBP 100% or HR 45 bpm End of study (if specified) Uterine Incision SBP 100 Bolus for SBP bpm Delivery SBP 80% of or 100 No preload First 2 utes: SBP 20% of, then between and 80% of No preload, coload with up to 2 L LR First 2 utes: SBP 20% of, then between and 80% of Bolus for SBP 80% 50 bpm HR 50 bpm and2 BP Bolus for SBP 80% or 100 First 2 utes: infusion stopped if SBP 120%, then infusion continued if SBP 100%, stopped if SBP 100%, 100 g PE bolus if SBP 80% for 2 utes First 2 utes: infusion stopped if SBP 120%, then infusion continued if SBP 100%, stopped if SBP 100%, 100 g PE bolus if SBP 80% for 2 utes 50 bpm HR 50 bpm and 2 BP 50 bpm HR 50 bpm and 2 BP Delivery Uterine Incision Uterine incision (Continued) February 2012 Volume 114 Number

4 REVIEW ARTICLE Table 1. (Continued) Groups N Spinal drugs Fluid management BP goal BP management regimen Cooper 21 PE 33 g/ 48 4 techniques Preload 10 ml/kg SBP 25% of LR E 1 mg/ 50 Bup 12.5 Fent 20 g PE 16.5 g/ E 0.5 mg/ Hall 22 PE 20 g bolus followed by 10 g/ E 6 mg bolus followed by 2 mg/ E 6 mg bolus followed by 1 mg/ Mercier 25 E 2 mg/ PE 10 g/ 49 Levo 10 mg Fent 20 g Levo 10 mg Fent 10 g Levo 12.5 mg Fent 10 g 10 Bup 15 mg (13.75 mg if height 9 10 E 2 mg/ cm) 19 Bup 11 mg Sufent 2.5 g morphine 0.1 mg Ngan Kee 11 PE 100 g/ infusion 26 Bup 10 mg Fent PE 100 g bolus g Das PE 0.15 g/kg/ 40 Bup 10 mg Neves PE 50 g prophylactic bolus after spinal PE bolus 50 g for 20% drop in SBP or DBP morphine 0.1 mg Allen 26 PE Bolus 100 g 20 Bup 12 mg Fent 40 PE 25 g/ 20 PE 50 g/ 20 PE 75 g/ 19 PE 100 g/ 22 Ngan Kee 23 PE 100 g/ PE 100 g/ g morphine 0.15 mg Bup 10 mg Fent 15 g Preload LR 20 ml/kg Preload LR 15 ml/kg No preload, LR at 5 ml/ LR 10 ml/kg after spinal SBP 20% of SBP 20% of After 3 utes: between and 80% of. 2 L LR Coload SBP 20% of or 90 mm hg Coload up to 2L LR LR at imal rate Infusion stopped if SBP 125%, restarted at half rate when SBP 125%. Infusion doubled and 1 ml bolus given if SBP 75% Infusion stopped if SBP 120% for 3 utes; 2 ml of study drug (PE 20 g ore 6 mg) if SBP 80% Infusion halved if SBP 105% 120%, stopped if SBP 120%, restarted at initial rate if SBP decreased back to 90% 105% and double initial rate if 90%, rate doubled if SBP 80% 90%, E 6 mg bolus if SBP 80% or 100 Infusion for 3 utes, then stopped if SBP 100%, continued or restarted if SBP 100%, 1 ml 100 g PE if SBP 80% 20% of Infusion stopped for BP 120%, PE bolus 30 g every 2 utes for SBP or DBP 80% First 2 utes: SBP 20% of, then between and 80% of Infusion stopped for SBP 120%, restarted when SBP 120%, permanently discontinued if stopped 3 times, PE bolus 100 g for SBP 80% or 90 First 2 utes: infusion stopped if SBP 120%, then infusion continued if SBP 100%, stopped if SBP 100%, 100 g PE bolus if SBP 80% for 3 utes Bradycardia definition Anticholinergic indication HR 60 bpm and SBP 75%, or HR 50 bpm and SBP 100%, or HR 45 bpm 40 bpm HR 40 bpm End of study (if specified) Delivery Delivery 50 bpm HR 50 bpm and 2 BP Uterine incision 50 bpm HR 50 bpm and 2 BP 50 bpm HR 50 bpm 10 utes after delivery 50 bpm HR 50 bpm and 2 BP Uterine incision (Continued) ANESTHESIA & ANALGESIA

5 Impact of Phenylephrine on Maternal and Neonatal Outcomes Table 1. (Continued) Ngan Kee 24 PE 100 g/ to maintain SBP at 100% PE 100 g/ to Groups N Spinal drugs Fluid management BP goal BP management regimen maintain SBP at 90% PE 100 g/ to maintain SBP at 80% 24 Bup 10 mg Fent 15 g Stewart 28,50 PE 25 g/ 25 Bup 11 mg Fent PE 50 g/ g PE 100 g/ 25 Pierce 52 PE 40 g bolus 13 Bup mg E 5 mg bolus 13 Fent 10 g Dyer 16 PE 80 g bolus 20 Bup 10 mg Fent E 10 mg bolus g No preload, LR at imal rate Preload 500 ml LR After 2 utes, SBP at 100%, 90%, and 80% of in 100%, 90%, and 80% groups, respectively SBP between and 80% of Preload 2LLR SBP 100 and within 90% of 20 ml/kg LR coload MBP 80% of Infusion for 2 utes, then continued if SBP 100%, 90% or 80%, and turned off if SBP 100%, 90%, or 80%. PE 100 g given if SBP 100%, 90%, or 80% for 3 utes. Infusion stopped if SBP 100%, PE 100 g if SBP 80% for 2 utes, E 6 mg if SBP still 80% after 2 more utes PE g or E 5 10 mg to keep SBP 100 and within 90% of Bolus for MBP 80%, repeat same vasopressor if MBP continues to decrease to 60%, if MBP still 80% other vasopressor is used Thomas 30 PE 100 g bolus 19 Bup 12.5 mg Preload 1500 ml SBP 90% of Bolus for SBP 90% E 5 mg bolus 19 LaPorta 45 PE 40 g bolus 20 Bup mg Preload L SBP 100 Bolus for SBP 100 E 5 mg bolus 20 based on height LR Cooper 47 PE 100 g bolus or infusion E 6 mg bolus or infusion No vasopressor 148 (51 bolus, 97 infusion) 122 (110 bolus, 20 infusion) 115 Cooper 53 PE 33 g/ 27 Coload with 10 E 1.5 mg/ 27 ml/kg LR SBP 20% of or 90 Infusion doubled or halved and boluses given to achieve target according to predefined algorithm Retrospective study. Guidelines for PE infusion: 33 g/ titrated to SBP 100%, doubled, or halved, as required, maximum rate 67 g /, 100 g bolus for 2 BP despite the infusion. No guidelines for E infusion. Bradycardia definition Anticholinergic indication 50 bpm 50 bpm and SBP 100% 50 bpm 50 bpm and SBP 100% HR 60 bpm and SBP 80% or 90 or HR 45 bpm End of study (if specified) Uterine incision Delivery 90 utes after spinal or end of surgery BP blood pressure; SBP systolic blood pressure; DBP diastolic blood pressure; MBP mean blood pressure; bpm beats per ute; PE phenylephrine; E ephedrine; Bup bupivacaine; Levo levobupivacaine; Fent fentanyl; sufent sufentanil; Diamorh diamorphine; LR lactated Ringer s; HR heart rate; 2 BP hypotension; 2 HR bradycardia. Percentages in blood pressure management regimen column are percentages of. February 2012 Volume 114 Number

6 REVIEW ARTICLE Table 2. Intraoperative Nausea and Vomiting and Hemodynamic Changes Associated with Phenylephrine and Ephedrine Adistration Study Groups prophylactic antiemetics Hypotension ION IOV IONV Bradycardia Anticholinergic use Reactive hypertension Ngan Kee 14 PE bolus 100 g 74/102 (73) 4/102 (4) 0/102 (0) E bolus 10 mg 74/102 (73) 13/102 (13)* 0/102 (0) Prakash 15 PE bolus 100 g All patients 0/30 (0) 0/30 (0) 5/30 (17) 3/30 (10) 0/30 (0) E bolus 6 mg All patients 4/30 (13) 1/30 (3) 0/30 (0) 0/30 (0) 0/30 (0) Moran 17 PE bolus 80 g for initial 2 SBP of 5 followed by g to keep SBP 100 E bolus 10 mg followed by 5 10 mg as in PE group Magalhaes 18 PE 80 g prophylactic bolus followed by 40 g for 2 BP E 10 mg prophylactic bolus followed by 5 mg for 2 BP Loughrey 19 E10mg PE 40 g prophylactic bolus followed by E5mg PE 20 g for 2 BP E 10 mg prophylactic bolus followed by E 5 mg for 2 BP - metoclopramide 10 mg to patients in both groups All patients had 2 BP, SBP 100 : 0 (0) All patients had 2 BP, SBP 100 : 1 (3) 8/31 (25) 0/31 (0) 8/29 (28) 0/29 (0) 28/30 (93) 10 episodes 6 episodes 1/30 (3) 1/30 (3) 4 episodes 21/30 (70)* 7 episodes 4 episodes 0/30 (0) 0/30 (0) 5 episodes 19/20 (95) 1/20 (5) 0/20 (0) 16/20 (80) 2/20 (10) 0/20 (0) Ngan Kee 20 PE infusion 100 g/ 2/52 (4) 1/52 (2) 6/52 (12) 0/52 (0) 21/52 (41) E infusion 8 mg/ 13/52 (25)* 18/52 (35)* 0/52 (0)* 0/52 (0) 24/52 (47) Ngan Kee 12 PE 100 g/ 1/24 (4) 0/24 (0) 3/24 (13) 0/24 (0) 12/24 (50) PE 75 g/ E 2 mg/ 3/24 (13) 4/24 (17) 1/24 (4) 0/24 (0) 13/24 (54) PE 50 g/ E 4 mg/ 3/25 (12) 0/25 (0) 1/25 (4) 0/25 (0) 9/25 (36) PE 25 g/ E 6 mg/ 2/24 (8) 5/24 (21) 0/24 (0) 0/24 (0) 8/24 (33) E 8 mg/ 8/25 (32) 10/25 (40)# 1/25 (4) 0/25 (0) 15/25 (60) Cooper 21 PE 33 g/ 23/48 (48) 8/48 (17) 0/48 (0) 8/48 (17) 2/48 (4) E 1 mg/ 34/50 (68) 15/50 (30) 18/50 (36) 33/50 (66) 5/50 (10) PE 16.5 g/ E 0.5 mg/ 28/49 (57) 18/49 (37) 9/49 (18) 27/49 (55)# 1/49 (2) Hall 22 PE 20 g bolus followed by 10 g/ 8/10 (90) 5/10 (50) 2/10 (20) 2/10 (20) 0/10 (0) E 6 mg bolus followed by 2 mg/ 4/9 (44) 0/9 (0) 0/9 (0) 0/9 (0) 1/9 (11) E 6 mg bolus followed by 1 mg/ 9/10 (80) 4/10 (40) 0/10 (0) 0/10 (0) 0/10 (0) Mercier 25 E 2 mg/ PE 10 g/ 7/19 (37) 8/19 (41) 3/19 (16) E 2 mg/ 15/20 (75)* 14/20 (70)* 5/20 (25) Ngan Kee 11 PE 100 g/ 6/26 (23) 1/26 (4) 2/26 (8) 0/26 (0) 10/26 (38) PE 100 g bolus 21/24 (88)* 5/24 (21) 0/24 (0) 0/24 (0) 2/24 (8)* Das Neves 27 PE 0.15 g/kg/ 7/40 (18) 4/40 (10) 0/40 (0) 0/40 (0) 0/40 (0) 1/40 (3) PE 50 g prophylactic bolus after spinal 13/40 (33) 6/40 (15) 3/40 (8) 1/40 (3) 0/40 (0) 0/40 (0) PE bolus 50 g for 20% drop in SBP or DBP 34/40 (85)# 16/40 (40)# 5/50 (13) 0/40 (0) 0/40 (0) 0/40 (0) (Continued) ANESTHESIA & ANALGESIA

7 Impact of Phenylephrine on Maternal and Neonatal Outcomes Table 2. (Continued) Anticholinergic use Reactive hypertension Study Groups prophylactic antiemetics Hypotension ION IOV IONV Bradycardia Allen 26 Pre/post delivery Pre/post delivery PE bolus 100 g 16/20 (80)/ 9/20 (45) 7/20 (35) 2/20 (10) 1/20 (5) 1/20 (5) 2/20 (10)/ 0/20 (0) PE 25 g/ 6/20 (30)/ 5/20 (25) 8/20 (40) 2/20 (10) 3/20 (15) 3/20 (15) 5/20 (25)/ 0/20 (0) PE 50 g/ 3/20 (15)/ 1/20 (5) 8/20 (40) 0/20 (0) 0/20 (0) 0/20 (0) 8/20 (40)/ 5/20 (25) PE 75 g/ 2/19 (11)/ 4/19 (21) 6/19 (32) 1/19 (5) 6/19 (32) 2/19 (11) 14/19 (74)/ 2/19 (11) PE 100 g/ 0/22 (0)#/ 2/22 (9) 7/22 (32) 1/22 (5) 7/22 (32) 7/22 (32) 18/22 (82) # / 8/22 (36) Ngan Kee 23 PE 100 g/ 2L LR coload 1/53 (2) 2/53 (4) 1/53 (2) 9/53 (17) 0/53 (0) 25/53 (47) PE 100 g/ LR at imal rate 15/53 (28)* 2/53 (4) 1/53 (2) 13/53 (25) 0/53 (0) 25/53 (47) 7/24 (29) 1/24 (4) 3/24 (8) 0/24 (0) 5/24 (21) Ngan Kee 24 PE 100 g/ to maintain SBP at 100% PE 100 g/ to maintain SBP at 90% 18/25 (72) 4/25 (16) 8/25 (32) 1/25 (4) 4/25 (16) PE 100 g/ to maintain SBP at 80 % 24/25 (96)# 10/25 (40)# 5/25 (20) 1/25 (4) 6/25 (24) Stewart 28,50 PE 25 g/ 10/25 (40) 6/25 (24) 2/25 (8) 6/25 (24) PE 50 g/ 5/25 (20) 1/24 (4) 0/25 (0) 10/25 (40) PE 100 g/ 3/25 (12)# 0/25 (0)# 0/25 (0) 9/25 (36) Data are presented as n/n (percentage). BP blood pressure; DBP diastolic blood pressure; SBP systolic blood pressure; ION intraoperative nausea; IOV intraoperative vomiting; IONV intraoperative nausea and vomiting; PE phenylephrine; E ephedrine; 2 BP hypotension. Reactive hypertension is SBP 120% of. *Statistically significant difference between 2 groups. #Overall statistically significant difference among the groups for studies with more than 2 groups. Comparison of Different Phenylephrine Infusion Regimens A phenylephrine infusion at 100 g/ combined with a 2-L crystalloid coload was associated with a lower incidence of hypotension, compared to a similar regimen with fluid adistered at a imal rate (1.9% vs 23.8%). 23 The incidence of IONV was low and not different between the groups. In another study by the same group of investigators, a similar phenylephrine infusion regimen initiated at 100 g/ was titrated to maintain systolic blood pressure at 80%, 90%, or 100% of. 24 The incidence of IONV was lowest in the group with the blood pressure goal of 100% of. Stewart et al. reported a dose-related reduction in the incidence of IONV as the infusion rate increased from phenylephrine 25 g/ (25% incidence) to 50 g/ (4%) and 100 g/ (0%). There was also a significant dose-related increase in systolic blood pressure in this study. 28 These studies stopped data collection at delivery or uterine incision. 23,24,28 Allen et al. however collected data up to 10 utes after delivery and reported a higher incidence of IONV, ranging from 32% to 40%, with phenylephrine infusions of 25, 50, 75, and 100 g/; there was no significant difference among groups. 26 Although the incidence of hypotension was higher in the lower-infusion-rate groups, the differences were not statistically significant, and the study was not powered for this endpoint. INTRAOPERATIVE HEART RATE AND CARDIAC OUTPUT Heart Rate Changes Phenylephrine has both direct and indirect sympathomimetic effects; it primarily functions as an -adrenergic receptor agonist. The indirect effect results from norepinephrine release from nerve terals storage sites. 29 Unlike ephedrine, it lacks direct inotropic or chronotropic effects. Phenylephrine adistration is associated with reflex bradycardia. Studies have consistently reported a slower heart rate with phenylephrine than with ephedrine. 12,14 17,20,21,30 Use of prophylactic phenylephrine infusions is associated with an overall slower heart rate compared to treatment of hypotension with phenylephrine boluses. 11,31 Comparison of different phenylephrine infusion rates demonstrate dose-related reductions in heart rate. 24,28 Bradycardia occurring during adistration of a prophylactic phenylephrine infusion should be managed by reducing the rate or stopping the infusion, unless accompanied by hypotension. Adistration of an anticholinergic to treat bradycardia in the absence of hypotension results in significant hypertension. 26,32 Cardiac Output Changes Initiation of spinal anesthesia is associated with changes in cardiac output. Robson et al. used intermittent suprasternal Doppler flow measurements at 5, 10, and 15 utes after spinal anesthesia with 10 to 12.5 mg hyperbaric bupivacaine in 16 women receiving a prophylactic ephedrine infusion. 33 Stroke volume was significantly decreased in 16 patients, and cardiac output was reduced in 12; the decrease in cardiac output exceeded 1 L/ in 9 subjects. More recently, Langesaeter et al. measured cardiac output February 2012 Volume 114 Number

8 REVIEW ARTICLE continuously using pulse waveform analysis after spinal anesthesia using bupivacaine 7 to 10 mg with or without a phenylephrine infusion at 0.25 g/kg/, and reported an initial decrease in systemic vascular resistance together with a concomitant increase in cardiac output after the initiation of spinal anesthesia 31 ; such an increase may be missed in studies using intermittent measurements starting several utes after initiation of the spinal anesthetic. Studies investigating cardiac output changes associated with phenylephrine suggest that heart rate changes parallel changes in cardiac output. An earlier study using intermittent suprasternal Doppler for 15 utes after intrathecal injection reported no overall changes in cardiac output with ephedrine 5 mg compared to phenylephrine 100 g for the treatment of hypotension. 30 This study, however, did not specifically report cardiac output changes immediately after vasopressor adistration. Furthermore, atropine was used in 58% of patients who received phenylephrine. More recently, Dyer et al. measured cardiac output continuously using pulse waveform analysis and thoracic bioimpedance. In patients who required a vasopressor to treat a 20% decrease in mean arterial blood pressure, there was a 35% decrease in systemic vascular resistance compared to, accompanied by a 12% increase in heart rate, 9% increase in stroke volume, and 23% increase in cardiac output before vasopressor adistration. Cardiac output and heart rate were significantly lower during the 150 seconds after adistration of a phenylephrine bolus of 80 g compared to ephedrine 10 mg for the treatment of hypotension, but cardiac output values after phenylephrine adistration [mean sd ( L/)] were still numerically higher than values ( L/). 16 In comparison with prevasopressor values, cardiac output increased by 5% with ephedrine and decreased by 14% with phenylephrine. Stroke volume was not different between the groups. Heart rate was slower in patients receiving phenylephrine and strongly correlated with cardiac output. The authors suggested that maintaining heart rate at might therefore be a surrogate for maintaining cardiac output. In women receiving phenylephrine infusions at 25, 50, and 100 g/ after spinal anesthesia with 11 mg hyperbaric bupivacaine, there were significant dose-related and time-related reductions in heart rate and cardiac output measured using suprasternal Doppler for 20 utes after intrathecal injection. 28 Stroke volume remained stable with no significant differences among the groups, suggesting that cardiac output changes were mainly due to heart rate reduction. In another study using lower doses of intrathecal bupivacaine (7 and 10 mg), Langesaeter et al. randomized patients to receive a prophylactic low-dose phenylephrine infusion (0.25 g/kg/, equivalent to about 20 g/) or placebo. Hypotension was treated with phenylephrine boluses of 30 g. The investigators reported that heart rate and cardiac output were also significantly lower in patients receiving the phenylephrine infusion. 31 The initial increase in cardiac output seen after initiation of spinal anesthesia was obtunded with phenylephrine. Similar to other studies, stroke volume was not different between groups. Cardiac Output Changes in Women with Pre-Eclampsia Tihtonen et al. measured cardiac output using bioimpedance in 10 pre-eclamptic women undergoing cesarean delivery under spinal anesthesia and compared hemodynamic variables with those of healthy parturients. 34 At, mean arterial blood pressure and systemic vascular resistance index were higher, while stroke index and cardiac index were lower in pre-eclamptic women. Systemic vascular resistance index and mean arterial blood pressure decreased in both groups after spinal anesthesia, while cardiac index and stroke index were not changed. Hypotension, defined as a decrease in systolic arterial blood pressure to 80% of or 100, occurred in 3 patients with pre-eclampsia and was treated with ephedrine, which increased both mean arterial blood pressure and systemic vascular resistance index. In another observational study involving 15 women with severe preeclampsia undergoing cesarean delivery under spinal anesthesia, 35 Dyer et al. reported that cardiac output was higher than when women were placed supine before lateral tilt immediately after spinal placement, and then was not different from until it increased after delivery and oxytocin adistration. In this study, 10 patients received phenylephrine 50 g boluses for the treatment of a 20% decrease in mean arterial blood pressure. Phenylephrine adistration was associated with a significant decrease in heart rate, a trend toward a reduction in cardiac output, and no change in stroke volume. NEONATAL OUTCOMES Assessments of Uteroplacental Perfusion A few studies compared the effects of ephedrine to phenylephrine and other -agonists on uteroplacental circulation using ultrasound measurements. These studies reported on the pulsatility index in maternal and fetal vessels, which is calculated as the difference between the peak systolic and end-diastolic flow velocity divided by the average flow velocity. 36 Alahuhta et al. adistered a bolus of ephedrine 5 mg or phenylephrine 100 g followed by an infusion of ephedrine 50 mg/h or phenylephrine 1000 g/h when the level of spinal block reached T5. 36 The investigators reported that compared to, mean maternal uterine and placental arcuate arteries pulsatility index values were increased in patients receiving phenylephrine but not those receiving ephedrine, suggesting an increase in vascular resistance with phenylephrine. In contrast, the pulsatility index in fetal renal arteries decreased with phenylephrine. There was no change in fetal umbilical artery pulsatility in either group. In another study in which hypotension was treated with boluses of ephedrine 5 mg or phenylephrine 100 g, 30 there was also no difference in umbilical artery pulsatility index measured at and 15 utes after initiation of spinal anesthesia. Similarly, Ngan Kee et al. reported no difference in uterine artery pulsatility index in parturients who received a prophylactic ephedrine or metaraol infusion initiated immediately after induction of spinal anesthesia. 37 Apgar Scores and Umbilical Cord Blood Gases Neonatal assessments were performed in most studies using Apgar scores and umbilical cord blood gas and ph ANESTHESIA & ANALGESIA

9 Impact of Phenylephrine on Maternal and Neonatal Outcomes analysis, with the latter commonly being the primary outcome of the study. While Apgar scoring is widely used in clinical practice, and provides a useful assessment of the condition of the infant in the first utes after birth, its usefulness as a predictor of neonatal outcome continues to be debated. For instance, low Apgar scores alone are not sufficient evidence of hypoxia that might cause neurological damage. 38 Poor correlation between Apgar scores and umbilical cord ph has been observed. 39 On the other hand, umbilical cord blood gas and ph provide an indication of the fetal condition immediately before delivery, and might therefore be more useful than Apgar scores when assessing perfusion and the impact of vasopressors on the fetus. While ph is most commonly quoted, the scale is logarithmic. Therefore, the base excess, which is also adjusted for Pco 2, provides a more linear measure of metabolic acid accumulation. Low arterial cord ph may be associated with clinically significant neonatal outcomes. 40 While umbilical artery ph of 7.2 was historically considered the lower limit of normal, 41 the use of this threshold value has been challenged. It has been suggested that ph values of 7.02 to 7.18 represent the lower limit of normal umbilical artery ph. 42 In fact, a ph 7.0 seems to be a better threshold value since significant adverse outcomes in the neonate are rare with umbilical artery ph 7.0 or base excess 12 mmol/l. 43 Studies exaing Apgar scores and fetal acid-base status have consistently reported no difference in Apgar scores, but a higher umbilical artery ph and base excess with IV phenylephrine compared with ephedrine in lowrisk parturients undergoing elective cesarean delivery (Table 3). This result has been reported whether the vasopressors were adistered as a bolus for the treatment of established hypotension or as a prophylactic infusion. The higher fetal ph has been attributed to a greater placental transfer of ephedrine compared to phenylephrine (median umbilical vein/maternal artery concentration ratio of 1.13 compared with 0.17) and less early metabolism or redistribution in the fetus of the more lipid soluble ephedrine. 20 In turn, fetal ephedrine stimulates fetal -adrenergic receptors, therefore increasing metabolic activity, 20,21,44 and resulting in higher umbilical artery and vein Pco 2, lower fetal ph, and increased fetal concentrations of lactate, glucose, epinephrine, and norepinephrine. 20,21,45 The difference in ph is usually in the range of 0.01 to 0.08 ph units. It is unclear whether this difference is clinically relevant in low-risk pregnancies. Some studies have reported a lower umbilical artery and umbilical vein Po 2 with phenylephrine compared with ephedrine, possibly related to greater vasoconstriction of the uteroplacental circulation with resultant reduced flow and increased oxygen extraction. 12,14,20 This does not appear to have a detrimental effect on the neonate. Sheep studies suggest that this lack of adverse effect is due to greater uterine blood flow relative to what is required to meet fetal oxygen demand under normal physiologic conditions. 46 All the above studies were conducted in women with low-risk pregnancies undergoing elective cesarean delivery. In women undergoing nonelective cesarean delivery, there was no difference in acid-base status when hypotension was treated with ephedrine or phenylephrine boluses, but fetal lactate concentrations were higher with ephedrine. 14 Similarly, in a retrospective study, Cooper et al. reported no difference in umbilical artery ph with the use of ephedrine or phenylephrine for arterial blood pressure control in high-risk cesarean deliveries. 47 When comparing different regimens of phenylephrine adistration, there was no difference in neonatal acidbase status when phenylephrine was adistered as a bolus for the treatment of hypotension or as a prophylactic infusion, despite a lower incidence of maternal hypotension with the infusion. 11,26 This is probably due to prompt treatment and short duration of hypotension. However, infusions titrated to maintain maternal systolic blood pressure at were associated with a small (0.02 ph unit difference) but statistically significantly higher umbilical artery ph compared to infusion rates titrated to maintain blood pressure at 80% or 90% of. 24 Optimum Dosing and Adistration Regimen of Phenylephrine The optimal adistration regimen for phenylephrine is unknown. Treatment of established hypotension by bolus adistration is simple but associated with more hypotension and more IONV than prophylactic infusions. 11,26 Conversely, prophylactic adistration is associated with a higher incidence of reactive hypertension and bradycardia. Studies have generally used phenylephrine bolus doses ranging from 40 to 100 g. Doses of 40 to 80 g were associated with a higher incidence of hypotension and failed to reduce the incidence of IONV compared with ephedrine in some studies. 17,18 Furthermore, 2 recent dosefinding studies using an up down sequential allocation methodology suggested that a dose of phenylephrine higher than what is routinely used in practice and in previous studies may be needed for bolus adistration. Tanaka et al. reported that the ED95 of a prophylactic bolus dose of phenylephrine to prevent hypotension or nausea, when given immediately after intrathecal injection of 12 mg hyperbaric bupivacaine, was 159 g (95% confidence interval: 122 to 371 g). 48 For the treatment of established hypotension after intrathecal adistration of a similar dose of bupivacaine, George et al. estimated that the ED90 of a bolus dose of phenylephrine was 147 g (95% confidence interval: 98 to 222 g). 49 It is important to note that both studies estimated the dose needed early after intrathecal injection when the sympathectomy was evolving; this might differ from the dose required to treat hypotension later, once the block has stabilized. When given as a prophylactic infusion, phenylephrine doses ranging from 10 to 100 g/ have been used; however, the 10 g/ dose was ineffective with a 90% incidence of hypotension. 22 Two recent dose response studies investigated fixed phenylephrine infusion doses ranging from 25 to 100 g/. 26,28 Both groups of investigators recommended the use of lower infusion rates of 25 to 50 g/ because these were associated with less reactive hypertension, 26 bradycardia, 28 and reduction in cardiac output 28 compared to higher-dose infusions. The 50 g/ rate was also associated with the fewest number of February 2012 Volume 114 Number

10 REVIEW ARTICLE Table 3. Umbilical Cord Gas Data and Apgar Scores Study Groups ph (A) ph (V) PCO 2 (A), PCO 2 (V), PO 2 (A), PO 2 (V), Base excess (A), mmol/l Base excess (V), mmol/l ph <7.2 Lactate (A), mmol/l Lactate (V), mmol/l Apgar <7 Apgar <7 1 ute 5 utes Ngan Kee 14 PE bolus 100 g /102 (0) (ph 7 reported) /102 (0) 0/102 (0) E bolus 10 mg * 30.8* /102 (2) 2.7* 2.6* 1/102 (0) 1/102 (0) Prakash 15 PE bolus 100 g /30 (0) 0/30 (0) 0/30 (0) E bolus 6 mg 7.29* 7.34* * 1.9* 0/30 (0) 0/30 (0) 0/30 (0) Pierce 52 PE 40 g bolus E 5 mg bolus Dyer 16 PE 80 g bolus E 10 mg bolus * 4.75* Thomas 30 PE 100 g bolus /19 (0) 0/19 (0) 0/19 (0) E 5 mg bolus 7.27* /19 (5) 0/19 (0) 0/19 (0) LaPorta 45 PE 40 g bolus /20 (0) 0/20 (0) E 5 mg bolus 7.28* * * 2.0* 0/20 (0) 0/20 (0) Moran 17 PE bolus 80 g for initial 2 SBP of 5 mmhg followed by g to keep SBP 100 E bolus 10 mg followed by 5 10 mg as in PE group Magalhaes 18 PE 80 g prophylactic bolus followed by 40 g for 2 BP E 10 mg prophylactic bolus followed by 5 mg for 2 BP Loughrey 19 E10mg PE 40 g prophylactic bolus followed by E 5mg PE 20 g for 2 BP E 10 mg prophylactic bolus followed by E 5mg for 2 BP /31 (0) 0/31 (0) 7.28* * * 1.54* 1/29 (3) 0/29 (0) /30 (0) 0/30 (0) 7.22* /30 (0) 0/30 (0) /20 (0) 0/20 (0) /20 (0) 0/20 (0) Ngan Kee 20 PE 100 g/ /52 (2) 0/52 (0) E 8 mg/ 7.25* 7.31* 56* * 4.8* 4.3* 4.2* 3.4* 0/52 (0) 0/52 (0) Ngan Kee 12 PE 100 g/ /24 (0) 0/24 (0) 0/24 (0) PE 75 g/ E 2 mg/ /24 (13) 0/24 (0) 0/24 (0) PE 50 g/ E 4 mg/ PE 25 g/ E 6 mg/ /25 (24) 0/25 (0) 0/25 (0) /24 (29) 0/24 (0) 0/24 (0) E 8 mg/ 7.21# 7.30# 62# 45 14# 32# 5.1# 4.9# 12/25 (48)# 0/25 (0) 0/25 (0) (Continued) ANESTHESIA & ANALGESIA

11 Impact of Phenylephrine on Maternal and Neonatal Outcomes Table 3. (Continued) Study Groups ph (A) ph (V) PCO 2 (A), PCO 2 (V), PO 2 (A), PO 2 (V), Base excess (A), mmol/l Base excess (V), mmol/l ph <7.2 Lactate (A), mmol/l Lactate (V), mmol/l Apgar <7 Apgar <7 1 ute 5 utes Cooper 21 PE 33 g/ /48 (2) 0/48 (0) 0/48 (0) E 1 mg/ /48 (21) 0/50 (0) 0/50 (0) PE 16.5 g/ E 0.5 mg/ 7.31# 7.37# 54# /47 (2)# 0/49 (0) 0/49 (0) Hall 22 PE 20 g bolus followed by 10 g/ E 6 mg bolus followed by 2 mg/ E 6 mg bolus followed by 1 mg/ Mercier 25 E 2 mg/ PE 10 g/ /10 (0) 0/10 (0) /9 (0) 0/9 (0) /10 (0) 0/10 (0) /19 (31) 0/19 (0) 0/19 (0) E 2 mg/ 7.19* 7.28* 13/20 (63) 0/20 (0) 0/20 (0) Ngan Kee 11 PE 100 g/ /26 (4) 2/26 (8) 0/26 (0) PE 100 g bolus /24 (4) 0/24 (0) 0/24 (0) Allen 26 PE bolus 100 g /19 (11) PE 25 g/ /18 (0) PE 50 g/ /18 (0) PE 75 g/ /18 (11) PE 100 g/ /17 (0) Ngan Kee 23 PE 100 g/ 2LLR coload PE 100 g/ LR at imal rate Ngan Kee 24 PE 100 g/ to maintain SBP at 100% PE 100 g/ to maintain SBP at 90% PE 100 g/ to maintain SBP at 80% /53 (2) 0/53 (0) /53 (2) 0/53 (0) /24 (0) 1/24 (4) 0/24 (0) /25 (0) 0/25 (0) 0/25 (0) 7.30# /25 (0) 0/25 (0) 0/25 (0) Stewart 28 PE 25 g/ PE 50 g/ PE 100 g/ Cooper 47 PE (retrospective) /148 (15) 6/148 (4) E (retrospective) /122 (20) 0/122 (0) No vasopressor # /115 (23) 3/115 (3) Cooper 53 PE 33 g/ /23 (9) E 1.5 mg/ 7.20* 7.28* 62* 47* * 4.2* 13/26 (50)* Data are means, medians, or number (percentage). A/V umbilical arterial/venous; BP blood pressure; PE phenylephrine; E ephedrine; SBP systolic blood pressure; 2 BP hypotension. *Statistically significant difference between the 2 groups. #Overall statistically significant difference among the groups for studies with more than 2 groups. February 2012 Volume 114 Number

12 REVIEW ARTICLE physician interventions needed to maintain arterial blood pressure within the target range and had the lowest degree of inaccuracy of systolic blood pressure control compared to the 25, 75, and 100 g/ rates; the differences were, however, only statistically significant when compared to the 100 g/ group. 26 The choice of a starting infusion rate balances the risk of hypotension versus reactive hypertension. For instance, the 25 g/ rate has been associated with an incidence of hypotension of 30% 40%, compared to 15% 20% with 50 g/. 26,28 However, the incidence of reactive hypertension was 40% and 25% with the 50 and 25 g/ doses, respectively. 26,50 With the exception of the study by Cooper at al, 21 most of the published studies to date have investigated a fixedrate infusion regimen that is switched on and off based on blood pressure response. 11,12,20,22 24,26,28 While this technique is simple, a variable rate infusion titrated to blood pressure changes may allow more accurate blood pressure control. Recently, Ngan Kee et al. reported that a closedloop variable rate algorithm provided tighter and more accurate blood pressure control compared to the manual on/off technique, but with no difference in other maternal or neonatal outcomes. 51 More studies investigating variable rate phenylephrine infusions are needed. An additional difficulty is that studies have used different goals for blood pressure control with a prophylactic phenylephrine infusion. For instance, while some studies have switched the infusion off when the blood pressure exceeded, 28 others have used the same target but allowed a 20% blood pressure increase in the first 2 to 3 utes, 11,12,20,23 or allowed a 20% 25% increase in blood pressure from throughout the duration of the infusion. 21,22,26 Allowing an increase in blood pressure from increased the incidence of reactive hypertension with higher infusion rates of 100 g/, but not with rates of 25 and 50 g/. 26,50 It is not clear, however, if different targets have an impact on the occurrence of hypotension, IONV, or need to make frequent adjustments to the infusion rate. Most studies have also allowed a 20% decrease in blood pressure. A study by Ngan Kee et al., however, reported that the incidence of IONV is lowest and fetal ph highest when blood pressure is maintained at 100% of compared to allowing a 10% 20% decrease in blood pressure. 24 Fluid adistration regimens also varied among the studies. This should be considered when comparing the results of different studies to detere the optimum adistration regimen for phenylephrine. For instance, in women receiving a prophylactic phenylephrine infusion, adistering a2lcrystalloid coload was associated with a lower incidence of hypotension and reduced phenylephrine requirements compared with adistering fluids at a imal rate. 23 The optimum duration of phenylephrine infusion is also not known. Most studies have stopped the infusion at uterine incision, 11,12,20,21,23,28 while Allen at al. 26 continued the infusion for 10 utes after delivery to counteract oxytocin induced hypotension. CONCLUSION Both ephedrine and phenylephrine are effective in managing spinal anesthesia-induced hypotension. Phenylephrine may be associated with a lower incidence of IONV, and higher umbilical artery ph and base excess compared with ephedrine. However, the difference in ph is small and unlikely to be clinically relevant in low-risk deliveries. Adistration of phenylephrine as a prophylactic infusion is more effective in reducing the incidence of hypotension and IONV compared with bolus adistration. However, phenylephrine use is associated with a decrease in maternal cardiac output. The clinical significance of this reduction in healthy low-risk parturients is unclear. Studies suggest that such changes do not appear to have any consequences in healthy mothers. The optimum phenylephrine adistration regimen is unclear. Studies addressing the use of phenylephrine in high-risk pregnancies, such as those complicated by placental insufficiency, preeclampsia, and growth restriction, are needed. DISCLOSURES Name: Ashraf S. Habib, MBBCh, MSc, MHS, FRCA. Contribution: This author helped analyze the data and write the manuscript. Attestation: Ashraf S. Habib approved the final manuscript. This manuscript was handled by: Cynthia A. Wong, MD. REFERENCES 1. Reynolds F, Seed PT. Anaesthesia for Caesarean section and neonatal acid-base status: a meta-analysis. Anaesthesia 2005; 60: Laudenbach V, Mercier FJ, Roze JC, Larroque B, Ancel PY, Kaski M, Breart G, Diemunsch P, Subtil D, Lejus C, Fresson J, Arnaud C, Rachet B, Burguet A, Cambonie G. Anaesthesia mode for caesarean section and mortality in very preterm infants: an epidemiologic study in the EPIPAGE cohort. Int J Obstet Anesth 2009;18: Ralston DH, Shnider SM, DeLorimier AA. 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13 Impact of Phenylephrine on Maternal and Neonatal Outcomes 12. Ngan Kee WD, Lee A, Khaw KS, Ng FF, Karmakar MK, Gin T. A randomized double-blinded comparison of phenylephrine and ephedrine infusion combinations to maintain blood pressure during spinal anesthesia for cesarean delivery: the effects on fetal acid-base status and hemodynamic control. Anesth Analg 2008;107: Saravanan S, Kocarev M, Wilson RC, Watkins E, Columb MO, Lyons G. Equivalent dose of ephedrine and phenylephrine in the prevention of post-spinal hypotension in Caesarean section. Br J Anaesth 2006;96: Ngan Kee WD, Khaw KS, Lau TK, Ng FF, Chui K, Ng KL. Randomised double-blinded comparison of phenylephrine vs ephedrine for maintaining blood pressure during spinal anaesthesia for non-elective Caesarean section. Anaesthesia 2008;63: Prakash S, Pramanik V, Chellani H, Salhan S, Gogia AR. 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14 REVIEW ARTICLE 47. Cooper DW, Sharma S, Orakkan P, Gurung S. Retrospective study of association between choice of vasopressor given during spinal anaesthesia for high-risk caesarean delivery and fetal ph. Int J Obstet Anesth 2010;19: Tanaka M, Balki M, Parkes RK, Carvalho JC. ED95 of phenylephrine to prevent spinal-induced hypotension and/or nausea at elective cesarean delivery. Int J Obstet Anesth 2009;18: George RB, McKeen D, Columb MO, Habib AS. Up down deteration of the 90% effective dose of phenylephrine for the treatment of spinal anesthesia-induced hypotension in parturients undergoing cesarean delivery. Anesth Analg 2010;110: Stewart A, Fernando R, McDonald S, Hignett R, Jones T, Columb M. Can phenylephrine infusions cause reactive hypertension during elective caesarean section? Int J Obstet Anesth 2011;20:S7 51. Ngan Kee WD, Khaw KS, Tam YH, Ng FF. Comparison of closed-loop feedback computer-controlled and manualcontrolled phenylephrine infusions during spinal anesthesia for cesarean section. Int J Obstet Anesth 2011;20:S Pierce ET, Carr DB, Datta S. Effects of ephedrine and phenylephrine on maternal and fetal atrial natriuretic peptide levels during elective cesarean section. Acta Anaesthesiol Scand 1994;38: Cooper DW, Gibb SC, Meek T, Owen S, Kokri MS, Malik AT, Koneti KK. Effect of intravenous vasopressor on spread of spinal anaesthesia and fetal acid-base equilibrium. Br J Anaesth 2007;98: Residual Neuromuscular Block: Lessons Unlearned. Part II: Methods to Reduce the Risk of Residual Weakness: Erratum Figures 1A and 1B in a recent manuscript on residual weakness were graciously provided by Dr. Douglas Eleveld, Department of Anesthesiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. We apologize that the appropriate credit was unintentionally omitted and extend our appreciation to Dr. Eleveld for providing the images. Reference: Residual neuromuscular block: lessons unlearned. Part II: Methods to reduce the risk of residual weakness. Anesth Analg 2010;111: ANESTHESIA & ANALGESIA