Abstract: Background and Objective: Minimal invasive parathyroidectomy under local anesthesia with sedation has the same cure rates as the general anesthesia but has better postoperative complications control. The objective of the study was to justify the hypothesis that levobupivacaine infiltration and midazolam sedation technique is effective in minimally invasive parathyroidectomy. Materials and Methods: Total, 248 patients who had clinically confirmed primary hyperparathyroidism were included in a trial. Patients had received intravenous propofol (PI group, n = 124) or infiltrated preoperatively by levobupivacaine with midazolam sedation (LM group, n = 124) followed image-guided minimal invasive parathyroidectomy by an ENT surgeon. Postoperative pain, anesthesia-emergent adverse effects, surgical cure and length of hospital stay were recorded. Results: Cure rate was equal in both groups (96 vs. 95%). Hospitalization was fewer in patients of LM group (1.81±0.11 days) than those of PI group (2.36±0.21 days, p<0.0001, q = 40.59). Overall satisfaction of patients was strongly in favor of levobupivacaine infiltration with midazolam sedation than propofol-based general anesthesia (VAS score 3.11±0.41 vs. 5.46±1.12, p<0.0001, q = 37.87). Patients of PI group had required higher intravenous pain medication (32.12±4.15 mg vs. 19.11±2.12 mg morphine/morphine equivalent, p<0.0001, q = 36.712) and more numbers of anti-emetic doses than LM group. Conclusion: Preoperative levobupivacaine infiltration with midazolam sedation technique was effective and had high advantages in minimally invasive parathyroidectomy.
INTRODUCTION
Primary hyperparathyroidism (PHT) is an endocrinopathy condition with hypercalcemia1. It had a higher level of parathyroid hormone2 due to parathyroid hormone-secreting adenomas or carcinomas (rare cases)3. There are limited data available for manifestations of PHT4. The biochemical and clinical features of PHT in Chinese patients are still traditional but the disease becomes a more asymptomatic type. Moreover, biochemical abnormalities of Chinese patients are different from those reported in the United States5.
There are several surgical procedures available for PHT, e.g., four-gland bilateral neck exploration, minimal invasive parathyroidectomy (MIP)6 and video-assisted minimal invasive parathyroidectomy7. Among this four-gland bilateral neck, exploration is considered as ‘gold standard’ surgical procedure for PHT8. The MIP is preferred for the removal of the unwanted parathyroid gland with a small incision9. It has benefits of better cosmetic results and less post-operative pain. It could be done under cervical blockage, local anesthesia with sedation and general anesthesia9. The MIP under local anesthesia with sedation has better postoperative pain control than general anesthesia. Moreover, cure rates and complication rates are as equal as under propofol. General anesthesia leads to more postoperative nausea and vomiting than local anesthesia10. Moreover, the surgical procedure under general anesthesia is complicated and risky for co-morbid patients and increased financial burden on patients too. However, MIP under cervical blockage, local anesthesia is successful for patients with single adenoma only9.
The primary aim of the study was to achieve surgical cure by performing MIP under propofol-based general anesthesia or preoperatively levobupivacaine infiltration with midazolam sedation in clinically confirmed PHT patients. The secondary endpoint of the trial was a comparison of postoperative pain, anesthetic-emergent adverse effects, length of the hospital stay, the requirement of intravenous pain medication and cost of the surgeries under both types of anesthetic techniques at level 2b of evidence without conflict of interest.
MATERIALS AND METHODS
Anesthetics and chemicals: Levobupivacaine (Chirocaine) was purchased from Abbott Laboratories, China. Midazolam (Dormicum) was purchased from Shanghai Roche Pharmaceuticals Ltd, China. Propofol (Recofol) was purchased from Bayer (China) Limited, Hong Kong, China. Oxygen was purchased from Guangzhou Maya Medical Equipment Co., Ltd., Guangzhou, China. Normal saline was purchased from Baxter, USA. Technetium Tc 99 m sestamibi was purchased from Cardinal Health, USA.
Ethical consideration and consent to participate: The study had been registered in research registry (www.researchregistry.com), UID No. research registry 4086 dated 16 January 2015. The protocol (CL/AN/HU/14/15, dated 12 January 2015) had been granted by the China-Japan Union Hospital review board. The study had adhered to Consolidated Standards of Reporting Trials (CONSORT) guideline, 2013 Declarations of Helsinki11 and the law of China. The work has been reported in line with the Strengthening the Reporting of Cohort Studies in Surgery (STROCSS) criteria12. An informed consent form regarding pathology, anesthesia, surgeries and publication of the study in all formats (electronic and hard) irrespective of time and language had been signed by all enrolled patients or their relatives (legally authorized person).
Inclusion criteria: All patients admitted to the Department of Endocrinology of the hospital from 18 January 2015-2 June 2017 who had clinically confirmed PHT (by at least one clinical test: hypercalcemia and/or high level of parathyroid hormone) were included in the trial. Patients who had provided informed consent form and age 18 years and above were included in the study. The demographic parameters of the enrolled patients are present in Table 1 (There were no discriminations for demographic parameters between groups, p>0.01 for all).
Exclusion criteria: Patients who had coexistent thyroid disease, multiglandular disease, uniglandular disease, extra-cervical parathyroid localizations were excluded from the trial. Patients who had a contraindication to propofol and female patients with pregnancy were excluded from the general anesthetic group (PI group). Patients who had sleep apnea syndrome, excessive wariness and non-cooperative patients were excluded from local anesthesia with sedation group (LM group).
Design of the study: Total, 248 patients were subjected to randomized trial (simple randomization). CONSORT flow diagram of the study is presented in Fig. 1.
| Table 1: | The demographic characters of the enrolled patients |
| Constant data were represented as a number (percentage) and continuous data were represented as Mean±SD, Chi-square independence test and Unpaired t-test were performed for constant data and continuous data respectively between groups, A p<0.01 was considered significant. All patients have PR China origin | |
Sample size calculation: Power calculation for randomized clinical trial was preferred. The prior sample size was calculated using OpenEpi 3.01-Chinese (Open Source Epidemiologic Statistics for Public Health, USA) and it was found to be 124. The other factors as population size (for finite population correction factor (N) was 248, outcome percentage in both groups was 95%, risk ratio detected was 1 and normal approximation was 1.073% at 5% primary cut-off value (α = 0.05).
Anesthetic technique: The options of general or local anesthesia with sedation were provided to the enrolled patients before surgeries. Patients of LM group were infiltrated before half an hour of the start of the surgery with 0.5% of levobupivacaine injection in normal saline at posterior and anterior sides of the sternocleidomastoid muscle13. Patients were subjected to administration of oxygen supplementation, application of standard monitoring and 1.5 mg of slow intravenous midazolam in normal saline14. Patients of PI group were received 1 mg kg–1 bolus propofol followed by propofol perfusion 0.5 mg kg–1/4 min (maintenance dose)15. Anesthesiologist(s) were continuously monitored vital signs of patients and depth of sedation at every minute during surgery. A supraglottic system with a displacement of the larynx was used for management of the airway.
| Fig. 1: | CONSORT flow diagram of the study |
| Population size: 248, 95% outcome in both groups, risk ratio: 1 and normal approximation: 1.073% at 5% primary cut-off value (α = 0.05) | |
In case of ineffective anesthesia high doses of anesthesia were given but up to safe level (however, no any patient was reported with ineffective anesthesia for surgery making).
MIP: About 10 mCi of Technetium Tc 99m sestamibi was injected to the enrolled patients, scintigraphy imaging was obtained by dual-phase technique and then the patient was operated on within 3 h from the radiotracer injection. Background counts were determined with help of an 11 mm collimated gamma probe (Neoprobe 2000; Ethicon, USA). In the operating room, the probe was put on the thyroid isthmus. After a surgical cut, localize abnormal parathyroid glands were detected by intra-operative scanning whose had radionuclide counts more than the background. Parathyroid hormone level was checked at 5, 10 and 15 min after parathyroidectomy. If Parathyroid hormone level had failed, the neck was explored for the other adenomas resection under levobupivacaine local infiltration16.
Postoperative pain measurement: When patients had become conscious (Aldrete Score for the conscious level), postoperative pain was recorded on Visual Analog Scale (VAS) scoring method by nursing staff who had blinded regarding anesthetic technique. No pain was coded as 0 and 10 was considered the worst possible pain17. When patients had complained of pain, intravenous pain medication (morphine, fentanyl, etc.) were administered. Intravenous pain medication was converted to morphine equivalent. Patient’s satisfaction regarding anesthetic and surgical procedure was considered on VAS score8.
Anesthesia emergent adverse effects: Data related to vomiting and/or nausea and anti-emetic usage were recorded by nursing staff who had blinded regarding anesthetic technique.
Surgical cure: During 6 months after surgeries, if serum calcium was less than 10.5 mg dL–1, it was considered as a surgical cure. If serum calcium was exceeded 10.5 mg dL–1 in consecutive samples, it was considered as recurrence of PHT and if serum calcium was greater than 10.5 mg dL–1, it was considered as persistent PHT. The weight of resected tumor was also carried out by digital balance (BL-220H, Shimadzu Corp. Japan)10.
Cost analysis: Costs of operating room, operating charges of surgeon and anesthesiologist (consultant charges), hospital stay charges (ward/room charges, meal, other expenses), preoperative and postoperative diagnostic tests (chest X-ray, laboratory tests, ECG, other medical examinations) and medication charges (anesthetic(s), anti-emetic(s) and intravenous pain medication used) were counted for each patient8.
Length of hospital stay: From admission of the hospital to the discharge (a decision of surgeon and experts) was considered as the length of hospital stay18.
All primary and secondary outcome measures were evaluated at level 2b of evidence19.
Statistical analysis: Chi-square independence test3 and one-way ANOVA (analysis of variance)5 or Unpaired Student’s t-test20 were performed for constant data and continuous data respectively between groups. Tukey test (considering critical value (q) >3.328) was performed for post hoc analysis. Preoperative and postoperative results were considered significant at 99 and 95% of confidence levels, respectively. Statistical analysis was performed with InStat (GraphPad, USA). Intention-to-treat analysis method was adopted.
RESULTS
Lengths of stays in Post- Anesthesia Care Unit for patients were 162±22 and 151±18 min for PI and LM groups. Resected glands had the same weight in both groups (p = 0.152). Both groups had the same postoperative parathyroid hormone (p = 0.095) and calcium (p = 0.077) levels. The cure rate was equal in both groups (96 vs. 95%). Two patients of the LM group had suffered from transient recurrent laryngeal nerve palsy, which was subjected to resolve. Three patients from PI group had suffered from hypocalcemia, who was put on an oral calcium supplement. Co-incidentally, more numbers of patients who had gland localized in deeper to the trachea-esophageal groove were enrolled in PI group than LM group (73 vs. 66; Table 2).
Operating room charges for LM group patients (985±45 $) was lower than PI group patients (1015±61 $, p<0.0001, q>21.879). Consultant charges (126±19 $ vs. 129±9 $, p = 0.113) and diagnostic tests charges (1261±139 $ vs. 1289±80 $, p = 0.053) were the same for both groups patients. Hospital stays charges were higher for PI group patients (515±67 $) than LM group patients (345±27 $, p<0.0001, q = 42.518). However, choice of room, meal and the other expenses may affect total hospital stays charges.
| Table 2: | Post-operative parameters |
| Constant data were represented as a number (percentage) and continuous data were represented as Mean±SD, Chi-square independence test and Unpaired t-test were performed for constant data and continuous data respectively between groups, A p<0.05 was considered significant, Surgical cure: Serum calcium<10.5 mg dL–1, Recurrence: Serum calcium>10.5 mg dL–1 in consecutive samples, Persistent: Serum calcium>10.5 mg dL–1 | |
| Table 3: | Impact of anesthetic techniques on different levels of cost of minimally invasive parathyroidectomy |
| Data were represented as Mean±SD of all, n = 124, One-way ANOVA following Tukey post hoc test was used for statistical analysis, A p<0.05 and q>3.328 were considered as significant, *Operation room charge was considered in terms of $/h, N/A: Not applicable, 1 $ = 6 ¥ | |
| Table 4: | Secondary outcomes of the trial |
| Constant data were represented as a number (percentage) and continuous data were represented as Mean±SD, Chi-square independence test and Unpaired t-test were performed for constant data and continuous data respectively between groups, Tukey test was used for post hoc analysis, A p<0.05 and q>3.328 were considered as significant, *Score method was used for assessment. 0: No pain, 10: The worst possible pain, ¶Assumed that no anti-emetic dose was required after surgery for comparison purpose, ¥Assumed that only single dose of 10 mg morphine injection (or equivalent) was necessary for postoperative pain for comparison purpose | |
Medication charges for LM group patients (215±13 $) were lower than PI group patients (415±35 $, p<0.0001, q = 103.32, Table 3). Overall propofol-based general anesthesia was increased financial burden over patients than levobupivacaine infiltration with midazolam sedation for MIP (2500±125 $ vs. 2000±100 $, p<0.0001, q = 51.093).
Hospital stay was fewer for patients LM group (1.81±0.11 days) than PI group (2.36±0.21 days, p<0.0001, q = 40.59).
Overall satisfaction of patients was more strongly in favor of levobupivacaine infiltration with midazolam than propofol-based anesthesia (VAS score 3.11±0.41 vs. 5.46±1.12, p<0.0001, q = 37.87).
The PI group had more numbers of patients with postoperative nausea (59 vs. 22, p<0.0001, q = 9.116) and vomiting (32 vs. 7, p<0.0001, q = 7.829) than LM group.
Patients of PI group (32.12±4.15 mg morphine/morphine equivalent) had required higher intravenous pain medication during hospital stay than those of LM group (19.11±2.12 mg, p<0.0001, q = 36.712).
There is no standard equivalent measurement method available for anti-emetic drugs and different anti-emetics (e.g., metoclopramide 10 mg, domperidone 10 mg, ondansetron 4/8 mg) were used after surgeries. Propofol (6.12±1.14 total numbers of anti-emetic doses required) was successfully stimulated the vestibular system, which leads to requiring more numbers of anti-emetic doses than levobupivacaine and midazolam (2.12±0.51 total numbers of anti-emetic doses required, p<0.0001, q = 61.578).
All secondary outcomes of the trial are presented in Table 4.
DISCUSSION
In the study, endocrinologists (with ENT surgeons) were adopted scintigraphy imaging-guided MIP with intraoperative parathyroid assay under propofol-based anesthesia or preoperative levobupivacaine infiltration with midazolam sedation for removal of an unwanted parathyroid tissue. The MIP is safe and effective surgical technique than four-gland bilateral neck exploration10. The MIP is less expensive than video-assisted minimal invasive parathyroidectomy8. Four-gland bilateral neck exploration has a risk of cosmesis21, hypocalcemia10, failure of surgeries22 and also required a larger incision (minimum 3 mm) to perform surgery23. With respect to risk factors and costs required for surgeries, endocrinologists were adopted an optimal technique to treat PHT for trial.
Trial with level 2b of evidence reported that patients who had faced MIP under preoperative levobupivacaine infiltration with midazolam sedation had less (1.81±0.11 days) hospital stays, high procedural satisfaction, 96% of cure rate and 2000±100 $ total cost of hospitalization. Cervical blockage, local anesthesia technique is efficacious, safe and cheap than four-gland bilateral neck exploration surgery to treat PHT6,24. However, unlike, levobupivacaine infiltration with midazolam, propofol is primarily some sedative hypnotics without analgesic drugs, any stimulation can cause patient move during operation and this will affect the operation of surgeons25. The load and maintenance dose of propofol-based general anesthesia have associated risk for respiration, patients need intubation and the chances of ineffective anesthesia15. The results of the study were in the shoulder to shoulder with available studies6,10. In respect to the results of the trial, MIP under preoperative levobupivacaine infiltration with midazolam sedation has no associated risk for management of PHT.
Patients who had faced MIP under propofol-based general anesthesia had competitive 2.36±0.21 days of hospital stays and 95% of cure rate. MIP under propofol-based general anesthesia is succeeded to manage PHT with deeply localized gland (through an incision of 2-3 cm)6. In respect to the results of the study, MIP under propofol-based general anesthesia is a good option when the gland is localized deeper into the trachea-esophageal groove.
Patients underwent preoperative levobupivacaine infiltration with midazolam sedation had less postoperative pain (VAS scoring, p<0.0001, q = 37.87), nausea, vomiting episodes, required fewer doses of intravenous pain medication and oral anti-emetic medications than those underwent propofol-based general anesthesia. Propofol has no effect on postoperative pain, it can reduce anxiety and depression26. However, levobupivacaine blocks the conduction and the generation of nerve impulses at the site of infiltration27. These results were not in line with an available study28 but in line with some available research report10. Preoperative local infiltration with levobupivacaine for the postoperative management in parathyroidectomy seems worthy to investigate in future trials.
In limitations of the study, for examples, some of the patients were not randomized for the choice of anesthesia. These were assigned to the particular type of anesthesia by consultants themselves only. Age and anatomical features of the patients may have effects on the threshold of pain and anesthesia-emergent adverse effects. These parameters were not addressed in the study. The experience of surgeons makes difference in the postoperative results of surgeries irrespective of technologies used during surgeries17. However, no specific criteria regarding the experience of ENT surgeons who performed MIP were maintained. The study was not blind to the surgeon because both interventions had a unique technique for applications. The blind study may give accurate postoperative results. Different drugs were used for postoperative pain treatment.
CONCLUSION
Levobupivacaine infiltration with midazolam sedation and propofol-based general anesthesia have no effect on the cure rate. Propofol is an intravenous anesthetic with a short half-life and long-term infusion does not significantly prolong waking time, nor does it affect hospital days. However, preoperative levobupivacaine infiltration with midazolam sedation was efficacious, safe and cheap anesthetic technique for image-guided minimal invasive parathyroidectomy under intraoperative parathyroid assay.
SIGNIFICANCE STATEMENT
A randomized controlled trial on patients with clinically confirmed primary hyperparathyroidism concluded that preoperative infiltration of levobupivacaine with midazolam sedation was effective and had high advantages in minimally invasive parathyroidectomy. The finding will help the endocrinologist to uncover the critical areas of surgical procedures available for primary hyperparathyroidism that many anesthesiologists are not able to explore.
ACKNOWLEDGMENTS
Authors are thankful for anesthetic, the surgical, medical and non-medical staff of China-Japan Union Hospital of Jilin University, Changchun, Jilin, China.