Perineal Local Infiltration Study
Perineal Local Infiltration Study
The prevalence of birth canal lacerations is more than 70% of all deliveries in Canada. The
 repair of such lacerations is usually done using a pre-existing epidural analgesia. Once the
 analgesic effect of the epidural analgesia fades, the laceration may cause intolerable pain,
 and result in emotional stress, difficulties in ambulation and breastfeeding, and more.

 The research team hypothesis is that adding a locally injected analgesic, which will take
 effect once the epidural analgesia fades, may alleviate perineal pain, prevent such
 difficulties, and improve women's overall well-being and satisfaction.

 The proposed trial is a two-arm, single-masked, randomized trial. Women with a working
 epidural analgesia, and a laceration will be invited to participate. Women in the local
 anesthesia (LA) arm will get a LA injected to the laceration and women in the sham arm will
 get no injection. The differences in perineal pain between the groups will be evaluated at 6
 hours after last epidural dose.
1. The Need for the Trial

 1.1. Background

 Perineal trauma during delivery may be iatrogenic (episiotomy) or spontaneous (perineal
 tear). First-degree injury involves the perineal skin only, while a 2nd-degree perineal
 tear (2PT) involves perineal muscles as well1,2. A 3rd-degree tear involves the anal
 sphincter, and a 4th-degree tear involves the entire anal sphincter complex (external
 and internal anal sphincters) and the anal epithelium1,2. An episiotomy (Epi) is usually
 performed in a mediolateral or lateral manner, and is considered a 2nd degree laceration
 by definition. The morbidity associated with obstetrical anal sphincter injury (3rd or
 4th degree perineal tear) is considerably higher than in 1st or 2nd degree tear1,2.

 The repair of a perineal tear may be done using the epidural anesthesia that was used
 during delivery, with no additional analgesia. If the patient is delivered without an
 epidural anesthesia, a short-acting local anesthetic agent, such as lidocaine, may be
 infiltrated to the edges of the wound prior to suturing.

 Scope of the problem The annual number of deliveries in Canada approaches 390,000, of
 which more than 145,000 are anticipated to take place in Ontario3. It has been reported
 that approximately 70% of deliveries in Ontario are vaginal deliveries4. Episiotomies
 occur in approximately 20% of vaginal deliveries, with 50% a 1st or 2nd degree perineal
 tear occur, and 3.2% of vaginal deliveries are complicated by a 3rd or 4th degree
 perineal tear4,5.

 Pain and morbidity associated with perineal lacerations Numerous studies have addressed
 the short- and long-term pain and morbidity associated with perineal lacerations. While
 numbers vary according to local practices and cultural and ethnical differences, most
 agree that perineal trauma is a major source of pain and morbidity6-12. Most studies
 reported Numeric Rating Scale (NRS) or Visual Analog Scale (VAS) scores in which pain is
 ranked by the patient verbally (from 0 to 10) or on a 10-cm ruler13, respectively. Some
 of the studies have reported VAS scores associated with 2PT/Epi of more than 5, and up
 to 8.5, in the first postpartum day7,9,12. Moreover, it has been shown that perineal
 lacerations, iatrogenic or spontaneous, are associated with interference with daily
 activities such as sitting, ambulation, urination and bowel movements14-19. Some have
 reported that more than 55% of women with 2PT/Epi experienced interference with at least
 one daily activity that was attributed to perineal pain7, and others have shown that
 between 45-75% of women with 2PT/Epi complained of at least moderate pain while sitting
 or moving10. Perineal pain associated with 2PT/Epi was also found to interfere with
 breastfeeding, and proper analgesia was found to have a beneficial effect on this
 matter14-16. Furthermore, acute pain during the immediate postpartum period was found to
 be associated with a higher risk of persistent pain 8 weeks postpartum, as well as with
 the development of postpartum depression7. The authors hypothesized that the severity of
 acute pain is not just a marker for the development of persistent pain, but also plays a
 role in the plasticity pathophysiology of acute-to-chronic pain transition.

 Pain relief - current practice

 As stated, perineal tear is usually repaired and sutured using the pre-existing epidural
 anesthesia that was used for delivery. Once the epidural anesthesia fades, the women
 will likely experience some perineal pain, mainly during the first 24 hours postpartum.
 Several studies have examined the benefits of different analgesic regimens, including
 oral or rectal analgesics, non-pharmacological methods, and topical anesthetics20-25. In
 most institutions, oral analgesics are provided, whether in a pre-scheduled analgesic
 plan or as per patient request.

 Despite efforts to alleviate perineal pain, current acceptable pain management protocols
 have several limitations. First, the use of systematic medications in order to treat
 local pain may induce side effects, and fail to target the specific pain on the other.
 Second, many women have concerns regarding the use of systemic medications along with
 breastfeeding, despite reassurance from medical staff. Topically applied anesthetics
 were not proven to alleviate postpartum perineal tear, and rectal analgesia was only
 studied as a single agent compared to placebo, and not as an adjunct to commonly used
 pain management protocols, thus no superiority was shown.

 At Sunnybrook Health Sciences Centre), a per-patient-request protocol is instituted,
 which includes acetaminophen (oral, 1000mg every 6 hours, PRN) and naproxen (oral, 400mg
 every 6 hours, PRN). Additionally, patients may ask for topical lidocaine 4% solution
 and oral oxycodone 5-10 mg every 4 hours (up to 40 mg/day in breastfeeding mothers).

 1.2. Hypothesis

 Injecting a long-acting local anesthetic into the edges of 2PT/Epi, before suturing, in
 women who had a vaginal delivery with an epidural anesthesia, will provide longer and
 more efficient pain relief compared with the common practice of not using local
 anesthetics.

 1.3. Research questions

 1.3.1. Primary research question

 Using the PICOT technique, the primary research question addresses five main aspects of
 the trial: population, intervention, comparison, outcome, and time.

 P: In women who have had a vaginal delivery under an epidural anesthesia and have
 experienced an episiotomy or a 2nd degree perineal tear, I: Does the local injection of
 bupivacaine to the edges of 2PT/Epi C: compared to a current practice of no analgesic O:
 increase or decrease perineal pain T: 6 hours after last epidural bolus?

 1.3.2. Other research questions

 In women who have had a vaginal delivery under an epidural anesthesia and have
 experienced an episiotomy or a 2nd degree tear, does the local injection of bupivacaine
 to the edges of 2PT/Epi compared to no analgesic increase or decrease -

 -  Time to first ambulation (getting out of bed for any activity).

 -  Time to first analgesic administration.

 -  Number of analgesics administrations during the 24 hours after last epidural bolus.

 -  Perineal pain at 12 and 24 hours (±30 minutes) after last epidural bolus.

 -  Most severe perineal pain in rest during the first 12 and 24 hours after last
 epidural bolus.

 -  Most severe perineal pain while sitting during the first 12 and 24 hours after last
 epidural bolus.

 -  Most severe perineal pain during walking and breastfeeding during the first 12 and
 24 hours after last epidural bolus.

 -  Most severe perineal pain during breastfeeding during the first 12 and 24 hours
 after last epidural bolus.

 -  Most severe perineal pain in rest, sitting, walking and breastfeeding during the
 first 12 and 24 hours after last epidural bolus.

 1.4. Supporting evidence for the hypothesis

 Potential intervention - local infiltration of surgical wound with local anesthetics

 Local anesthetics have been used in multimodal anesthesia regimens in order to reduce
 the need for post-operative analgesia, mainly opioids26. Several reports have
 demonstrated the efficacy of local infiltration of anesthetics in surgical wounds. Some
 have found reductions in both post-operative analgesia use and VAS scores, while some
 reported more modest outcomes27-33.

 Local infiltration of perineal lacerations with local anesthesia agent or saline

 Two studies have examined infiltration of perineal laceration as a preventative measure
 to provide longer-acting pain relief once the epidural anesthesia fades.

 The first, by Khan and Lilford, dates back to 198734. In their study, they compared
 three groups of women with episiotomies (50 women in each group): group 1 had an
 epidural anesthesia, group 2 had an epidural anesthesia and local infiltration of
 saline, and group 3 did not have epidural anesthesia, and received lignocaine prior to
 suture of the episiotomy. They excluded women with large perineal tears, extended
 episiotomies or third degree perineal tears. They have found that both group 2 and 3 had
 lower pain scores on day 1 postpartum, and that group 2 (epidural + saline) had the
 lowest pain scores. They concluded that the artificial swelling induced by the
 infiltrated agents (regardless of which agent) accommodates the inflammatory edematous
 response, thus preventing the compression of the tissue by the sutures, and preventing
 the pain resulting from it. This study had some limitations in that it was not blinded,
 it excluded perineal tears, was performed three decades ago when practices were
 different, and did not control for different confounders.

 The second report is more recent, yet only patients with episiotomies were included35.
 In this double-blind randomized prospective study, infiltration with 15 mL of 0.75%
 ropivacaine, 1% lidocaine, or saline was performed immediately before initiating the
 perineal repair. A total of 154 patients were included. The authors did not find any
 differences between time to first oral analgesic request or pain scores during the first
 24 hours postpartum. Yet, while this study employed a more adequate methodology, it did
 not compare patients to common practice (which is to infiltrate no agent), it included
 only women with episiotomies and excluded women with operative vaginal deliveries, and
 did not report the power of the study.

 Bupivacaine

 Bupivacaine Hydrochloride is 2-Piperidinecarboxamide,
 1-butyl-N-(2,6-dimethylphenyl)-monohydrochloride, monohydrate, a white crystalline
 powder that is freely soluble in 95 percent ethanol, soluble in water, and slightly
 soluble in chloroform or acetone. It is available in sterile isotonic solutions with and
 without epinephrine (as bitartrate) 1:200,000 for injection via local infiltration,
 peripheral nerve block, and caudal and lumbar epidural blocks. It is related chemically
 and pharmacologically to the aminoacyl local anesthetics, and is chemically related to
 lidocaine.

 The onset of action with Bupivacaine Hydrochloride is rapid and anesthesia is long
 lasting. The duration of anesthesia is significantly longer with Bupivacaine
 Hydrochloride than with any other commonly used local anesthetic. It has also been noted
 that there is a period of analgesia that persists after the return of sensation, during
 which time the need for strong analgesics is reduced. The half-life of Bupivacaine
 Hydrochloride in adults is 2.7 hours36. Bupivacaine was chosen for the purpose of this
 study since it is long-acting37 and likely to provide pain relief once the epidural
 analgesia has subsided.

 How will the information from the study be used? If the proposed hypothesis will be
 proven, better pain management could be offerred to women, and improve the quality of
 postpartum care. In addition, alleviation of postpartum perineal pain will enable women
 to take better care of their offspring.

 2. The Proposed Trial

 2.1. Proposed Trial design

 The proposed trial will be a two-armed, randomized, single-masked, controlled trial

 2.2. Planned interventions

 2.2.1. Randomization

 Once a woman has consented to be considered for the trial, eligibility must be
 confirmed. Once eligibility has been confirmed, the women will be randomized into the
 study using computer-generated sequence and sealed envelopes to one of three study arms:
 Bupivacaine injection or sham injection to reflect current care.

 2.2.2. All study participants

 Prior to injection of the intervention drug, the patient will be asked to press the
 bolus button of the epidural analgesia; the time of this occurs will be recorded. The
 length of the 2PT/Epi will be measured in centimeters and documented. The laceration
 will be sutured using 2-0 Caprosyn suture. Subcuticular sutures will be used for skin
 closure.

 2.2.3. Bupivacaine arm

 The edges of the 2PT/Epi will be infiltrated with 10ml of Bupivacaine 0.5%+Epinephrine
 50mcg prior to suture placement.

 2.2.4. Control arm

 Sham injection will be done using a syringe filled with 10ml of NaCl 0.9%, but the fluid
 will not be injected to the edges of the laceration but discarded. The sham injection
 will last no less than 10 seconds.

 2.3. Methods of protecting against bias

 The randomization will be done using a computer software. The patients and their
 companions will be asked not to observe the injection process. The physician performing
 the perineal repair will prepare the injection outside the patient's room. The nursing
 staff who will be directly involved with the care of the patients will be masked to the
 assigned arm.

 2.4. Planned inclusion/exclusion criteria

 2.4.1. Inclusion criteria

 -  Maternal age > 18 years of age

 -  Gestational age≥34 weeks of gestation

 -  Vaginal delivery

 -  Perineal laceration (2PT/Epi)

 -  Effective epidural anesthesia

 -  No known hypersensitivity to bupivacaine or amino-amide anesthetics

 2.4.2. Exclusion criteria

 -  Medical history of a chronic pain syndrome

 -  Intrapartum morphine use

 2.5. Duration of treatment period The treatment will be given as a single dose.
 Follow-up will take place for 24 hours after the last bolus dose.

 2.6. Primary outcome and other outcomes

 2.6.1. Primary outcome

 The primary outcome will be the proportion of women in the bupivacaine arm and the no
 analgesic arm who have a Numeric Rating Scale (NRS) score≤4 at 6-hours (±30 minutes)
 after last epidural bolus.

 Numeric Rating Scale (NRS)

 The NRS for pain is a unidimensional measure of pain intensity in adults. It is a
 segmented numeric version of the visual analog scale (VAS) in which a respondent selects
 a whole number (0-10 integers) that best reflects the intensity of their pain. The NRS
 is anchored by terms describing pain severity extremes, with 0 representing one pain
 extreme (e.g., "no pain") and 10 representing the other pain extreme (e.g., "pain as bad
 as you can imagine" and "worst pain imaginable"). The number that the respondent
 indicates on the scale to rate their pain intensity is recorded. Scores range from 0
 -1013.

 Visual Analog Scale (VAS)

 The pain VAS is a continuous scale comprised of a horizontal or vertical line, usually
 10 centimeters (100 mm) in length, anchored by 2 verbal descriptors, one for each
 symptom extreme. The respondent is asked to place a line perpendicular to the VAS line
 at the point that represents their pain intensity. The score is determined by measuring
 the distance (mm) on the 10-cm line between the "no pain" anchor and the patient's mark,
 providing a range of scores from 0-100 (mm) or 0-10 (cm). A higher score indicates
 greater pain intensity. Based on the distribution of pain VAS scores in postsurgical
 patients, the following cut points on the pain VAS have been recommended: no pain (0-4
 mm), mild pain (5-44 mm), moderate pain (45-74 mm), and severe pain (75- 100 mm). No
 training is required other than the ability to use a ruler to measure distance to
 determine a score13.

 2.6.3. Other outcomes

 The following are the other outcomes which will be compared among the three intervention
 arms:

 -  Time to first ambulation (getting out of bed).

 -  Time to first analgesic administration.

 -  Number of administration of additional analgesics in the first 24 hours after last
 epidural bolus.

 -  NRS at 12 and 24 hours (±30 minutes) after last epidural bolus.

 -  Highest NRS while in rest during the first 12 and 24 hours after last epidural
 bolus.

 -  Highest NRS while sitting during the first 12 and 24 hours after last epidural
 bolus.

 -  Highest NRS while walking during the first 12 and 24 hours after last epidural
 bolus.

 -  Highest NRS while breastfeeding during the first 12 and 24 hours after last
 epidural bolus.

 2.7. Sample size and planned Recruitment Rate

 Group sample sizes of 323 in group one and 323 in group two achieve 80% power to detect
 a difference between the group proportions of -0.0990 (30% reduction). The proportion in
 group one (the treatment group) is assumed to be 0.3300 under the null hypothesis and
 0.2310 under the alternative hypothesis. The proportion in group two (the control group)
 is 0.3300. The test statistic used is the two-sided Z test with pooled variance. The
 significance level of the test was targeted at 0.0500.

 To account for 10% loss to follow-up the sample size will be inflated to 355 per group.
 This will result in a total sample size of 710 for the 2 arms. The calculation was
 carried out using PASS Version 12 (Hintze, J. (2014). NCSS, LLC. Kaysville, Utah.).

 2.8. Analysis plan

 2.8.1. Interim Analysis

 An interim analysis of efficacy (the primary outcome) is planned when 50% of the total
 subjects have outcome data available. The group sequential method of Lan and DeMets will
 be used to characterize the rate at which the type I error is spent where the spending
 function is the O'Brien-Fleming boundary. The nominal alpha level at the interim
 analysis (50% of participants) is 0.0031 and at the final analysis (100%) is 0.049. In
 addition, a futility analysis will be conducted whereby the probability of finding a
 significant result at the end of the study will be calculated based on the current trend
 in the data, the null and alternative hypotheses.

 2.8.2. Final Analysis

 Descriptive statistics will be calculated for all variables of interest. Continuous
 measures such as age will be summarized using means and standard deviations whereas
 categorical measures will be summarized using counts and percentages.

 The primary outcome, proportion of women with NRS≥4 , will be compared between arms
 using tests of proportions.

 The secondary outcome, will be compared between arms using chi-square tests (or Fisher's
 exact tests in the case of low expected cell counts).

 The remaining outcome measures, such as Time to first ambulation, are continuous or
 interval measures. These will be assessed using t-tests or Wilcoxon rank sum tests in
 the case of non-normally distributed data.

 All analyses will be carried out using SAS Version 9.4 (SAS Institute, Cary, NC, USA).
Inclusion Criteria:

 -  Maternal age > 18 years of age

 -  Gestational age≥34 weeks of gestation

 -  Vaginal delivery

 -  Perineal laceration (2PT/Epi)

 -  Effective epidural anesthesia

 -  No known hypersensitivity to bupivacaine or amino-amide anesthetics

 Exclusion Criteria:

 -  Medical history of a chronic pain syndrome

 -  Intrapartum morphine use