This is a prospective, randomized, double-blinded sham controlled (preservative free normal saline) regional anesthetic (supra-orbital and infra-orbital nerve (SION)) study to compare the systemic post-operative pain medication requirements in patients having trans-sphenoidal endoscopic, endo-nasal pituitary surgery under general anesthesia. The study protocol is performed in accordance with the relevant guidelines and is included in detail below. The primary endpoint was the systemic morphine sulfate PCA (patient-controlled analgesia) opioid consumption by the 2 groups during the first 6 hours post-operatively (regional + general anesthesia vs. general anesthesia alone). The secondary endpoints included: (1) incidence of PONV, (2) time to eligibility for PACU discharge, and (3) length of hospital stay/discharge. To our knowledge, this is the first published clinical trial examining the use of SION block to control postoperative pain after endonasal pituitary surgery. The results from the two groups were compared using unpaired student t-test. P< 0.05 was considered to indicate a statistically significant difference.
Following Institutional Review Board approval at the University of California, San Francisco, USA (UCSF) study enrollment was offered to adult patients (male and female) (aged 18-65), having an ASA (American Society of Anesthesiologists) physical status I or II scheduled for same day admit endo-scopic endo-nasal trans-sphenoidal hypophysectomy to be performed by a single surgeon (SK). Additional inclusion criteria were: (1) elective pituitary surgery for tumors less than or equal to 2 cm diameter within the sella turcica and without cavernous sinus invasion, (2) both male or female patients, (3) English speaking patients providing informed consent, (4) not on chronic pre-op pain medications (non-narcotics) in the last week prior to surgery per patient report, (5) no opioid pain medications pre-op in the last month before surgery per patient report, (6) no abuse of recreational drugs (cocaine, methamphetamines, marijuana, opioids, heroin etc.…) per patient report and (7) no herbal medications for pain in the last 1 month prior to surgery per patient report. Urine or blood testing was not used to confirm opioid use pre-operatively. Exclusion criteria included: (1) patients less than 18 yo, (2) non-English speaking and unable to consent, (3) known allergy to ropivacaine, (4) chronic pain conditions, including idiopathic migraine as defined by the ICHD (International Classification of Headache Disorders) II criteria, requiring the use of pain medications or (5) inability to comprehend or adhere to the study protocol (Chart 1).
Inclusion Criteria
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1.
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Elective pituitary surgery for tumors less than or equal to 2 cm diameter volume within the Sella Turcica and without cavernous sinus invasion
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2.
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Male or female patients
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3.
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English speaking patients providing informed consent
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4.
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Not on chronic pre-op pain medications (non-narcotics) in the last week prior to surgery per patient report
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5.
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No opioid pain medications pre-op in the last month before surgery per patient report
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6.
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No abuse of recreational drugs (cocaine, methamphetamines, marijuana, opioids, heroin etc.) per patient report
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7.
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No herbal medications for pain in the last 1 month prior to surgery
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Exclusion Criteria
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1.
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Patients less than 18 years old
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2.
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Non-English speaking and unable to consent
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3.
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Allergy to ropivacaine
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4.
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Chronic pain conditions, including idiopathic migraine as defined by the ICHD (International Classification of Headache Disorders) II criteria, requiring the use of pain medication
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5.
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Inability to comprehend or adhere to the study protocol
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After written informed consent, the subjects were randomly assigned to 1 of 2 groups using randomization envelopes in 3 blocks of 20. A “triple mask design” was used: the subjects, healthcare providers (including the anesthesiologist in the operating room, anesthesiologist administering the SION blocks), randomization consent nurse and data collection nurse as well as the statistician were all blinded to the treatment groups assigned.
Intra-operative Block Protocol:
The subjects assigned to Block group (B) would receive the SION blocks with 0.5% ropivacaine with epinephrine 1:200 000 following induction of general anesthesia and the Placebo group (P) would receive the same volume SION blocks using sterile, preservative free normal saline. Following general anesthetic induction and endo-tracheal intubation, supra-orbital and infra-orbital (SION) injections with study medication were performed. Supra-orbital nerve blocks were performed bilaterally using 3 cc (on each side for a total of 6 cc) of the study solution. A percutaneous technique was used to block both bilateral supra-orbital and supra-trochlear nerves. A 27 gauge, 1.5 in needle, attached to a 10-cc syringe was used. Then, the infra-orbital nerves were blocked intra-orally following retraction of the upper lip and using a 27-gauge, 2.54 cm needle attached to a 10-cc syringe inserted anterior to the ipsi-lateral canine tooth that runs along the maxilla. Here, 3 cc of study drug was placed bilaterally for a total of 6 cc. The needles were directed superiorly toward the infra-orbital foramen on the ipsi-lateral side as was described in the “Lynch” method.8 Correct needle placement was confirmed by palpation of the needle tip near the infra-orbital foramen and by negative aspiration for blood. A wheel of study drug was palpated next to the nose under the inferior orbital rim. As mentioned earlier, the study drug was prepared by an independent physician who was not involved in the data acquisition, operating room care of the patient, or placement of the block. Thus, a total of 12 cc of the study solution was placed per patient in the distribution of the supra-orbital branches of V1 (Trigeminal sensory nerve) and infra-orbital nerve V2 (Trigeminal sensory nerve).
Intra-Operative Anesthetic:
Following a pre-medication with midazolam 1-2 mg IV, anesthesia was induced with lidocaine 1 mg/kg IV, propofol 1-2 mg/kg IV, fentanyl 1 mcg/kg IV, and rocuronium 0.6 mg/kg IV.
The surgeons then administered standard topical intra-nasal anesthesia with lidocaine and epi soaked pledgets on the inner nasal mucosa. Less than 10 cc of 1% lidocaine with epi 1:200 000 was used to ensure hemostasis. Exposure of the pituitary gland was obtained trans-nasally with an endoscope via the sphenoid sinus and then via the sellar floor. Following removal of the sellar floor, the dura was opened, and the pituitary tumor was resected using a series of micro-dissectors and curettes. CSF leaks were then repaired, and fat was placed in the free intra-sellar space. The sellar floor was repaired and the sphenoid sinus and nostrils packed temporarily to close the sellar space. We removed the nasal packings just prior to extubation.
Following induction of anesthesia, the local injection study block drug/placebo was administered, and the patients were maintained with a balanced anesthetic technique using intra-venous agents, inhaled gas and a neuro-muscular relaxant. Desflurane in O2/Air mixture with 80% inspired O2 was administered to provide anesthesia and to maintain the blood pressure within 20% of baseline. Fentanyl was infused at 1 mcg/kg/hr from induction of anesthesia to end of surgery. Dexamethasone 10 mg IV or Hydrocortisone 100 mg IV was administered at the beginning of surgery as directed by the surgeon. An end-tidal CO2 of 30-35 mmHg was maintained. The patients were relaxed with rocuronium as needed to maintain 1-2 twitches by a NMT (neuro-muscular twitch) monitor. On emergence from anesthesia, ondansetron 4 mg IV was administered, and residual muscle relaxation was reversed with neostigmine 0.07 mg/kg and glycopyrrolate 0.01 mg/kg IV.
Post-operatively, a morphine PCA (1mg IV every 6 min lock out time) to a max of 10 mg IV morphine sulfate per hour, without a basal rate was administered. For pain ranked at >4/10, rescue pain medicine of morphine 1 mg IV was administered by the PACU recovery room nurses every 5-10 min until the pain was < 4/10 or acceptable to the patient. Blood pressure was maintained with a systolic BP< 140 mmHg using (labetalol, esmolol, nicardipine). Following intra-operative treatment of nausea with ondansetron and dexamethasone/hydrocortisone, the following escalating rescue algorithm was used for PONV:
- Additional ondansetron 4 mg IV for 1 dose, then
- prochlorperazine 5-10 mg IV, then
- scopolamine patch 1.5 mg topical.9
The primary outcome of the study was to compare the total amount of morphine (in mg) used post-operatively (for 6 hours) in the 2 study groups from T0-T6 time from PACU entry (T0) to 6 hours post PACU entry (T6). Study data was collected for 5 data time points: T0 (PACU entry), T1, T2, T4, T6 (1,2,4,6 hours after PACU entry, respectively). Pain scores (P0-P6) were collected using the Wong-Baker FACES Pain Rating Scale at times T0-T6 in the scale (0-10/10) with 10/10 being the worst imaginable pain. Nausea score N0-N6 was collected using the Baxter retching faces (BARF) nausea scale (0-10/10) with 10/10 being the worst nausea imaginable with or without vomiting. Other secondary data collected included Tr (total time in PACU from admission to “eligibility” for PACU discharge (using the UCSF Modified Aldrete Score), Th (total time from surgery start to eligibility for home discharge), Tn (time from surgery start to last dose of narcotic). Modified UCSF Aldrete PACU score in PACU incorporates individual scores for vital signs, activity, mental status, pain, nausea, bleeding and intake/output. At one-week post-op, patients were contacted by phone and asked about potential study complications.
A research assistant collected all the study data and was blinded to the assigned treatment group.
ClinicalTrials.gov NCT04670614, Date of Registration 17/12/2020
Statistics
From Jan 1, 2017 through Dec 31, 2018, 175 patients were screened for the study using the inclusion and exclusion criteria. (Chart 1) Based on clinical experience, we considered an effect size 0.5 to be clinically significant. With this assumption, 64 patients randomized into two equal groups should have provided a statistical power of 0.8 for the main outcome. Of those, 49 patients were enrolled and randomized into the study. Although the original sample size was estimated at 64 patients, study enrollment was stopped after 49 subjects for administrative reasons.
Demographics and opioid consumption results are presented as means with 95% confidence intervals. Comparisons between groups were performed with unpaired t-tests, Mann-Whitney u-tests and Fisher’s exact test as appropriate. Parametric data are presented as means (95% confidence interval [95%CI]), while non-parametric data are presented as medians (95%CI). Opioid consumption, pain exposure, and nausea exposure over time were analyzed with a repeated measures mixed effects model. Groups were compared post-hoc at each time point, correcting for multiple comparisons using the two-stage linear step-up procedure of Benjamini, Krieger and Yekutieli to control the false discovery rate. Results with a p < 0.05 or a false discovery rate q < 0.05 were considered statistically significant. All analyses were performed using Prism 8.4.2 for MacOS (GraphPad Software, Inc, La Jolla, CA, USA).