Prevention of Hypotension During Cesarean Section (NOR-PHEN)

• ClinicalTrials.gov Identifier: NCT03842046
• Recruitment Status: Completed
• First Posted: February 15, 2019
• Last Update Posted: May 26, 2020
• Sponsor: Aretaieion University Hospital
• Collaborator: Alexandra Hospital, Athens, Greece
• Information provided by (Responsible Party): Dr Kassiani Theodoraki, Aretaieion University Hospital

Tracking Information

• First Submitted Date: February 13, 2019
• First Posted Date: February 15, 2019
• Last Update Posted Date: May 26, 2020
• Actual Study Start Date: February 16, 2019
• Actual Primary Completion Date: August 31, 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 21, 2020)

incidence of bradycardia [ Time Frame: intraoperative ]

any incidence of heart rate<60/min will be recorded

• Original Primary Outcome Measures (submitted: February 13, 2019): incidence of hypotension [ Time Frame: intraoperative ]

Current Secondary Outcome Measures (submitted: May 21, 2020)

• need for vasoconstrictor [ Time Frame: intraoperative ]
  parturient needed or not vasoconstrictor during the operation
• type of vasoconstrictor administered [ Time Frame: intraoperative ]
  phenylephrine verus ephedrine
• number of bolus doses of vasoconstrictor administered [ Time Frame: intraoperative ]
  number of provided interventions to maintain systolic blood pressure within the set limits will be recorded
• total dose of vasoconstrictor administered [ Time Frame: intraoperative ]
  total dose in mg for ephedrine or μg for phenylephrine
• incidence of hypotension [ Time Frame: intraoperative ]
  any occurrence of hypotension throughout the operation will be recorded (systolic arterial pressure<80% of baseline throughout the operation)
• incidence of hypertension [ Time Frame: intraoperative ]
  any incidence of systolic blood pressure >120% of baseline will be recorded
• incidence of nausea/vomiting [ Time Frame: intraoperative ]
  incidence of nausea and vomiting throughout the operation
• neonatal Apgar score at 1 min [ Time Frame: 1 min post delivery ]
  neonatal Apgar score will be recorded at 1 min after delivery. The Apgar score is determined by evaluating the newborn baby on five simple criteria on a scale from zero to two, then summing up the five values thus obtained. The resulting Apgar score ranges from zero to 10. Scores 7 and above are generally normal; 4 to 6, fairly low; and 3 and below are generally regarded as critically low and cause for immediate resuscitative efforts.
• neonatal Apgar score at 5 min [ Time Frame: 5 min post delivery ]
  neonatal Apgar score will be recorded at 5 min after delivery. The Apgar score is determined by evaluating the newborn baby on five simple criteria on a scale from zero to two, then summing up the five values thus obtained. The resulting Apgar score ranges from zero to 10. Scores 7 and above are generally normal; 4 to 6, fairly low; and 3 and below are generally regarded as critically low and cause for immediate resuscitative efforts.
• neonatal blood gases [ Time Frame: 1 min post delivery ]
  fetal cord blood analysis will be performed immediately post-delivery
• glucose in neonatal blood [ Time Frame: 1 min post delivery ]
  glucose will be measured in the cord blood gas sample taken immediately post-delivery

Original Secondary Outcome Measures (submitted: February 13, 2019)

• time of first hypotensive event [ Time Frame: intraoperative ]
• need for vasoconstrictor [ Time Frame: intraoperative ]
• type of vasoconstrictor administered [ Time Frame: intraoperative ]
• number of bolus doses of vasoconstrictor administered [ Time Frame: intraoperative ]
• total dose of vasoconstrictor administered [ Time Frame: intraoperative ]
• incidence of bradycardia [ Time Frame: intraoperative ]
• incidence of hypertension [ Time Frame: intraoperative ]
• incidence of nausea/vomiting [ Time Frame: intraoperative ]
• neonatal Apgar score [ Time Frame: 1 min, 5 min post delivery ]
• neonatal blood gases [ Time Frame: 1 min post delivery ]
• glucose in neonatal blood [ Time Frame: 1 min post delivery5 ]
• adrenaline in neonatal blood [ Time Frame: 5 min post delivery ]
• noradrenaline in neonatal blood [ Time Frame: 5 min post delivery ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Prevention of Hypotension During Cesarean Section
• Official Title: Comparison of Continuous Infusion of Noradrenaline Versus Phenylephrine During Cesarean Section Under Spinal Anesthesia. A Randomized Controlled Trial
• Brief Summary: The aim of this double-blind randomized study will be to compare a fixed-rate prophylactic noradrenaline infusion to a fixed-rate prophylactic phenylephrine infusion during elective cesarean section under combined spinal-epidural anesthesia

Detailed Description

• Spinal anesthesia is the anesthetic technique of choice for elective cesarean section.
• Spinal anesthesia can be complicated by hypotension, with incidence exceeding 80% occasionally. Hypotension can lead to nausea, emesis and a subjective feeling of discomfort due to cerebral hypoperfusion. If left untreated, severe or sustained hypotension can lead to decreased uteroplacental flow and fetal distress of premature or compromised fetuses while severe complications to the parturient might ensue, such as loss of consciousness, aspiration, apnea or cardiac arrest
• One of the standard techniques to avoid maternal hypotension is the administration of a continuous phenylephrine infusion while studies have demonstrated its superiority as compared to rescue bolus phenylephrine administration. Additionally, as compared to ephedrine, phenylephrine is associated with less neonatal acidosis and better maintenance of uteroplacental blood flow. However, phenylephrine can lead to baroreceptor-mediated reflex bradycardia, with untoward consequences for maternal cardiac output.
• Recently, noradrenaline has been shown to be effective in maintaining blood pressure in obstetric patients. Noradrenaline is a strong-alpha agonist with weak beta-action, too. Therefore, it might prove superior in maintaining cardiac output as compared to phenylephrine. There have been a few studies examining the use of noradrenaline as a continuous infusion in this context but the optimal dose and safety and efficacy profile of noradrenaline continuous infusion in obstetrics is yet to be determined
• In all parturients, standard hemodynamic monitoring will be applied. Baseline systolic arterial pressure will be considered the average of three consecutive measurements that will not differ more than 10% among them. All parturients will have a peripheral intravenous catheter placed in the upper extremity after baseline hemodynamic measurements are recorded and will be infused 5 mL/kg of hydroxyethylstarch (pre-loading) before the regional procedure.
• Study group allocation will taker place according to a computer-generated sequence of random numbers. A standard spinal anesthetic consisting of ropivacaine 0.75% 1.8 mL plus fentanyl 10 μg will be administered in the left lateraL position at the L3-4 or L4-5 vertebral interspace. The study infusion medication (either phenylephrine or norepinephrine, depending on group allocation) will be started at the same time cerebrospinal fluid is obtained, immediately before injection of spinal medications. After the intrathecal injection, patients will placed in the supine position with a left lateral tilt of the table to provide left uterine displacement and to prevent aortocaval compression. The spinal sensory level will be tested bilaterally by pinprick to ensure a T4 dermatomal level before surgical incision.
• Hemodynamic parameters (systolic arterial blood pressure, diastolic arterial blood pressure, mean arterial blood pressure and heart rate) will be measured and recorded at discrete timepoints throughout the operation (baseline, start of vasoactive agent administration, parturient at supine position, sympathetic block at T4, knife-to-skin, neonatal delivery, start of oxytocin administration, start of skin closure, end of operation.
• During the operation, a rescue dose of phenylephrine 50 μg will be administered when systolic arterial pressure drops below 80% of baseline in combination with heart rate>80 bpm. Ephedrine 5 mg will be administered when there is hypotension (systolic arterial pressure <80% of baseline) in combination with heart rate less than 80 bpm. Hypertensive episodes (systolic blood pressure >120% of baseline) will be treated with halving the infusion while when systolic arterial pressure increases above 130% of baseline the infusion will be discontinued and will be restarted when systolic blood pressure decreases below the upper limit of the target range (120% of baseline value).

• Study Type: Interventional
• Study Phase: Not Applicable
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Prevention

Condition

• Hypotension Symptomatic
• Obstetric Anesthesia Problems
• Cesarean Section Complications
• Vasoconstriction

Intervention

• Procedure: phenylephrine infusion
  In parturients allocated to the phenylephrine group, a phenylephrine infusion will be initiated as soon as spinal anesthesia is established
• Procedure: norepinephrine infusion
  In parturients allocated to the norepinephrine group group, a phenylephrine infusion will be initiated as soon as spinal anesthesia is established

Study Arms

• Active Comparator: phenylephrine infusion
  phenylephrine infusion (30 mL/h corresponding to 50 μg/min)
  Intervention: Procedure: phenylephrine infusion
• Active Comparator: norepinephrine infusion
  norepinephrine infusion (30 mL/h corresponding to 4 μg/min)
  Intervention: Procedure: norepinephrine infusion

Publications *

• Afolabi BB, Lesi FE. Regional versus general anaesthesia for caesarean section. Cochrane Database Syst Rev. 2012 Oct 17;10:CD004350. doi: 10.1002/14651858.CD004350.pub3.
• Klohr S, Roth R, Hofmann T, Rossaint R, Heesen M. Definitions of hypotension after spinal anaesthesia for caesarean section: literature search and application to parturients. Acta Anaesthesiol Scand. 2010 Sep;54(8):909-21. doi: 10.1111/j.1399-6576.2010.02239.x. Epub 2010 Apr 23.
• Maayan-Metzger A, Schushan-Eisen I, Todris L, Etchin A, Kuint J. Maternal hypotension during elective cesarean section and short-term neonatal outcome. Am J Obstet Gynecol. 2010 Jan;202(1):56.e1-5. doi: 10.1016/j.ajog.2009.07.012. Epub 2009 Aug 28.
• Ngan Kee WD. Prevention of maternal hypotension after regional anaesthesia for caesarean section. Curr Opin Anaesthesiol. 2010 Jun;23(3):304-9. doi: 10.1097/ACO.0b013e328337ffc6.
• Laudenbach V, Mercier FJ, Roze JC, Larroque B, Ancel PY, Kaminski M, Breart G, Diemunsch P, Subtil D, Lejus C, Fresson J, Arnaud C, Rachet B, Burguet A, Cambonie G; Epipage Study Group. Anaesthesia mode for caesarean section and mortality in very preterm infants: an epidemiologic study in the EPIPAGE cohort. Int J Obstet Anesth. 2009 Apr;18(2):142-9. doi: 10.1016/j.ijoa.2008.11.005. Epub 2009 Feb 4.
• Ngan Kee WD, Khaw KS, Ng FF, Lee BB. Prophylactic phenylephrine infusion for preventing hypotension during spinal anesthesia for cesarean delivery. Anesth Analg. 2004 Mar;98(3):815-21, table of contents. doi: 10.1213/01.ane.0000099782.78002.30.
• Ngan Kee WD, Khaw KS, Ng FF. Comparison of phenylephrine infusion regimens for maintaining maternal blood pressure during spinal anaesthesia for Caesarean section. Br J Anaesth. 2004 Apr;92(4):469-74. doi: 10.1093/bja/aeh088. Epub 2004 Feb 20.
• Siddik-Sayyid SM, Taha SK, Kanazi GE, Aouad MT. A randomized controlled trial of variable rate phenylephrine infusion with rescue phenylephrine boluses versus rescue boluses alone on physician interventions during spinal anesthesia for elective cesarean delivery. Anesth Analg. 2014 Mar;118(3):611-8. doi: 10.1213/01.ane.0000437731.60260.ce.
• Lee A, Ngan Kee WD, Gin T. A quantitative, systematic review of randomized controlled trials of ephedrine versus phenylephrine for the management of hypotension during spinal anesthesia for cesarean delivery. Anesth Analg. 2002 Apr;94(4):920-6, table of contents. doi: 10.1097/00000539-200204000-00028.
• 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 Dec;63(12):1319-26. doi: 10.1111/j.1365-2044.2008.05635.x.
• Cooper DW, Carpenter M, Mowbray P, Desira WR, Ryall DM, Kokri MS. Fetal and maternal effects of phenylephrine and ephedrine during spinal anesthesia for cesarean delivery. Anesthesiology. 2002 Dec;97(6):1582-90. doi: 10.1097/00000542-200212000-00034.
• Stewart A, Fernando R, McDonald S, Hignett R, Jones T, Columb M. The dose-dependent effects of phenylephrine for elective cesarean delivery under spinal anesthesia. Anesth Analg. 2010 Nov;111(5):1230-7. doi: 10.1213/ANE.0b013e3181f2eae1. Epub 2010 Sep 14.
• Ngan Kee WD, Lee SW, Ng FF, Tan PE, Khaw KS. Randomized double-blinded comparison of norepinephrine and phenylephrine for maintenance of blood pressure during spinal anesthesia for cesarean delivery. Anesthesiology. 2015 Apr;122(4):736-45. doi: 10.1097/ALN.0000000000000601.
• Vallejo MC, Attaallah AF, Elzamzamy OM, Cifarelli DT, Phelps AL, Hobbs GR, Shapiro RE, Ranganathan P. An open-label randomized controlled clinical trial for comparison of continuous phenylephrine versus norepinephrine infusion in prevention of spinal hypotension during cesarean delivery. Int J Obstet Anesth. 2017 Feb;29:18-25. doi: 10.1016/j.ijoa.2016.08.005. Epub 2016 Aug 28.
• Carvalho B, Dyer RA. Norepinephrine for Spinal Hypotension during Cesarean Delivery: Another Paradigm Shift? Anesthesiology. 2015 Apr;122(4):728-30. doi: 10.1097/ALN.0000000000000602. No abstract available.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: May 20, 2020): 82
• Original Estimated Enrollment (submitted: February 13, 2019): 80
• Actual Study Completion Date: August 31, 2019
• Actual Primary Completion Date: August 31, 2019 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• adult parturients, American Society of Anesthesiologists (ASA) I-II, singleton gestation>37 weeks
• elective cesarean section

Exclusion Criteria:

• Body Mass Index (BMI) >40 kg/m2
• Body weight <50 kg
• Body weight>100 kg
• height<150 cm
• height>180 cm
• multiple gestation
• fetal abnormality
• fetal distress
• active labor
• cardiac disease
• pregnancy-induced hypertension
• thrombocytopenia
• coagulation abnormalities
• use of antihypertensive medication during pregnancy
• communication or language barriers
• lack of informed consent
• contraindication for regional anesthesia

Sex/Gender

• Sexes Eligible for Study: Female

• Ages: 18 Years to 48 Years (Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Greece

Administrative Information

• NCT Number: NCT03842046
• Other Study ID Numbers: NOR-PHEN
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Dr Kassiani Theodoraki, Aretaieion University Hospital
• Original Responsible Party: Same as current
• Current Study Sponsor: Aretaieion University Hospital
• Original Study Sponsor: Same as current
• Collaborators: Alexandra Hospital, Athens, Greece

Investigators

• Principal Investigator: Kassiani Theodoraki, PhD; Aretaieion University Hospital
• Principal Investigator: Emmanouil Stamatakis, PhD; Alexandra General Hospital of Athens
• Principal Investigator: Dimitrios Valsamidis, PhD; Alexandra General Hospital of Athens
• Principal Investigator: Sofia Chatzilia, PhD; Alexandra General Hospital of Athens

• PRS Account: Aretaieion University Hospital
• Verification Date: May 2020