The effect of ketorolac on posterior minimally invasive transforaminal lumbar interbody fusion: an interim analysis from a randomized, double-blinded, placebo-controlled trial.

BACKGROUND CONTEXT: Postoperative pain control following posterior lumbar fusion continues to be challenging and often requires high doses of opioids for pain relief. The use of ketorolac in spinal fusion is limited due to the risk of pseudarthrosis. However, recent literature suggests it may not affect fusion rates with short-term use and low doses. PURPOSE: We sought to demonstrate noninferiority regarding fusion rates in patients who received ketorolac after undergoing minimally invasive (MIS) posterior lumbar interbody fusion. Additionally, we sought to demonstrate ketorolac's opioid-sparing effect on analgesia in the immediate postoperative period. STUDY DESIGN/SETTING: This is a prospective, randomized, double-blinded, placebo-controlled trial. We are reporting our interim analysis. PATIENT SAMPLE: Adults with degenerative spinal conditions eligible to undergo a one to three-level MIS transforaminal lumbar interbody fusion (TLIF). OUTCOME MEASURES: Six-month and 1-year radiographic fusion as determined by Suk criteria, postoperative opioid consumption as measured by intravenous milligram morphine equivalent, length of stay, and drug-related complications. Self-reported and functional measures include validated visual analog scale, short-form 12, and Oswestry Disability Index. METHODS: A double-blinded, randomized placebo-controlled, noninferiority trial of patients undergoing 1- to 3-level MIS TLIF was performed with bone morphogenetic protein (BMP). Patients were randomized to receive a 48-hour scheduled treatment of either intravenous ketorolac (15 mg every 6 hours) or saline in addition to a standardized pain regimen. The primary outcome was fusion. Secondary outcomes included 48-hour and total postoperative opioid use demonstrated as milligram morphine equivalence, pain scores, length of stay (LOS), and quality-of-life outcomes. Univariate analyses were performed. The present study provides results from a planned interim analysis. RESULTS: Two hundred and forty-six patients were analyzed per protocol. Patient characteristics were comparable between the groups. There was no significant difference in 1-year fusion rates between the two treatments (p=.53). The difference in proportion of solid fusion between the ketorolac and placebo groups did not reach inferiority (p=.072, 95% confidence interval, -.07 to .21). There was a significant reduction in total/48-hour mean opioid consumption (p<.001) and LOS (p=.001) for the ketorolac group while demonstrating equivalent mean pain scores in 48 hours postoperative (p=.20). There was no significant difference in rates of perioperative complications. CONCLUSIONS: Short-term use of low-dose ketorolac in patients who have undergone MIS TLIF with BMP demonstrated noninferior fusion rates. Ketorolac safely demonstrated a significant reduction in postoperative opioid use and LOS while maintaining equivalent postoperative pain control.

Using aneurysm clips for repair of cisterna chyli injury during posterior spinal fusion.

BACKGROUND: Injury to the cisterna chyli (CC) is a rare surgical complication with a lack of literature describing its repair. Aneurysm clips have been successfully used to repair durotomies. Its usage in lymphatic injury has never been described. We sought to demonstrate the use of aneurysm clips for the repair of lymphatic vessels. CASE DESCRIPTION: A 60-year-old male retired physician with Parkinson's disease underwent a lumbosacral instrumented fusion with pelvic fixation (L1-pelvis) in 2011. He returned 5 months postoperatively after a fall and was ambulatory with a cane upon admission. CT demonstrated worsening kyphosis with pedicular and superior endplate fracture at the fusion apex. MRI revealed spinal cord compression at the failed level. Extension thoracolumbar fusion was performed (T3-L1) with intraoperative violation of the anterior longitudinal ligament (ALL) during T12/L1 discectomy. CC laceration was suspected. The ALL was dissected from the CC and aorta, allowing visualization of the injury. Three curved aneurysm clips were applied to the lacerated CC, which was visually inspected to ensure a patent lumen. The disk space was filled with poly-methyl-methacrylate cement in place of an interbody cage, preventing migration of the clips. The patient underwent rehabilitation in an inpatient facility with improved ambulation. He has had regular clinic follow-up and was last seen in 2020 with no evidence of lymphedema noted. CONCLUSION: CC injury is rare, and usage of aneurysm clips in its repair has never been described. We demonstrate the safe use of aneurysm clips to repair CC injury with long-term favorable clinical outcomes.

Reconstruction of a Thoracic Spine Epithelioid Hemangioendothelioma with Antibiotic Impregnated Poly-methyl Methacrylate: A Case Report.

A 58-year-old female presented to the hospital with respiratory distress several days after a right hallux amputation. A new lytic lesion within the fourth thoracic (T4) vertebral body and mediastinal lymphadenopathy was noted on chest computed tomography scan. A bone biopsy was performed, revealing bone and collagenous fragments only. Two months later, new imaging revealed approximately 60% lytic destruction of the T4 vertebral body with new right pedicle involvement. Surgical treatment was offered. Intraoperative frozen pathology indicated a hemangioma. An intralesional debulking and stabilization was performed. The right T4 nerve was sacrificed to gain access to the entire vertebral body. Curettage was then used to push the tumor away from the spinal canal into the vertebral body. The spine was reconstructed with 5-10mm beads of Simplex P bone cement (Stryker®, Kalamazoo, MI) which contained 40 grams of poly-methyl methacrylate and 1 gram of tobramycin. Five months after resection, the patient presented with computed tomography and magnetic resonance imaging findings of recurrent disease at T4 and spread to the adjacent T5 vertebral body with lytic changes. At 18 months following her second debulking surgery and radiation treatment, the patient was doing well with no pain or numbness. Long-term imaging compared to the patient's preoperative imaging displayed improvement in spinal debulking with minimal residual enhancement of tumor despite significant artifact.

Repair of Postoperative Cervical Pseudomeningocele with the Use of Bone Morphogenetic Protein.

Recurrent cerebrospinal fluid (CSF) leak carries significant morbidity and mortality. A 25-year-old Caucasian male developed a symptomatic pseudomeningocele eight days after surgical resection of a cervical schwannoma. With no improvement after lumbar drain placement, the dural sleeve defect over the left C3 nerve root was repaired with suturable DuraGen® (Integra LifeSciences, Plainsboro, NJ, USA). Muscle and fat graft were then laid over the repair site and covered by Tisseel® (Baxter Healthcare, Deerfield, IL, USA). Recombinant human bone morphogenetic protein-2 (rhBMP-2) was applied via extra-small sponge laid over the graft. At 15-month clinical and 16-month radiographic follow-up, the patient had complete resolution of symptoms without any evidence of infection, ectopic bone formation, excessive inflammation, neoplasm, or recurrent CSF leak. This case demonstrates the successful use of BMP in the treatment of recurrent symptomatic cervical pseudomeningocele after tumor resection. We believe that the pro-inflammatory effects of rhBMP-2 lead to early scarring of dural defect and resolution of CSF leak.

Repair of encephalocele and cerebrospinal fluid leak with the use of bone morphogenetic protein: A case report.

BACKGROUND: Encephaloceles are rare phenomena which occur when brain parenchyma herniates through a skull defect which, if left untreated, may lead to significant issues such as cerebrospinal fluid (CSF) fistulas, meningitis, and intractable seizures. Due to the rarity and variety in size and location of encephaloceles, no standard technique has been established for the resultant defect. Herein, we demonstrate the safe and effective use of bone morphogenetic protein (BMP) in the repair of CSF leak caused by encephalocele. CASE DESCRIPTION: A retrospective chart review was conducted on a 50-year-old female who presented with sudden onset spontaneous right nostril CSF leak due to the right lateral sphenoid sinus recess encephalocele, for which she underwent surgical repair. After resecting the encephalocele, cadaver crushed bone was used to fill the skull base defect. Following, an absorbable sponge from the extra-small BMP kit was cut in half and soaked with recombinant human BMP-2 (rhBMP-2) before being laid over the bony defect. On postoperative clinic visits at 2 weeks and at 3 months, the patient demonstrated good recovery without evidence of recurrent CSF leak. On follow-up computed tomography imaging at 9 months' postsurgery, there was no evidence of recurrent CSF leak or encephalocele, infection, ectopic bone formation, excessive inflammation, or neoplasm. CONCLUSION: In this case, we demonstrate the successful use of BMP for the repair of CSF leak due to encephalocele. It is our extrapolation that the pro-inflammatory properties of rhBMP-2 lead to the prevention of recurrent CSF leak.

Bone Morphogenetic Protein in the Repair of Cerebrospinal Fluid Leak after Transsphenoidal Surgery.

BACKGROUND: Recurrent cerebrospinal fluid (CSF) leak carries significant morbidity. We sought to demonstrate that bone morphogenetic protein (BMP) use is effective and safe for the repair of recurrent CSF leak after a transsphenoidal pituitary tumor resection (TSPTR). MATERIALS AND METHODS: We reviewed charts and radiographic data of consecutive patients who underwent BMP repair of recurrent CSF leak after TSPTR from January 2010 to June 2015 and who failed previous multilayer closure. We detailed the technique for constructing and placing a BMP-DuraGen patch for the repair. The primary variables include postoperative computed tomography/magnetic resonance imaging (CT/MRI) evidence of ectopic bone growth or inflammation, newly diagnosed systemic neoplasm within 1 year, and recurrent CSF leak. Secondary outcome is the length of stay after BMP repair. All patients were followed up radiographically and through phone interview. RESULTS: Four patients underwent BMP repair of recurrent CSF leak after TSPTR. The average postoperative CT/MRI interval was 22 months. Postoperative CT/MRI revealed no ectopic bone formation or inflammatory changes around the site of BMP application. There was no recurrence of CSF leak or newly diagnosed neoplasm from both chart review and phone interview. CONCLUSIONS: We demonstrate that the use of BMP is a safe and an effective treatment in the repair of recurrent CSF leaks after TSPTR.

Minimally Effective Dose of Bone Morphogenetic Protein in Minimally Invasive Lumbar Interbody Fusions: Six Hundred Ninety Patients in a Dose-Finding Longitudinal Cohort Study.

STUDY DESIGN: Retrospective longitudinal cohort. OBJECTIVE: We sought to demonstrate the minimally effective bone morphogenetic protein (BMP) dose to achieve fusion in minimally invasive transforaminal lumbar interbody fusions. SUMMARY OF BACKGROUND DATA: Multiple studies have been conducted, which used a wide range of BMP doses for lumbar fusions highlighting associated risks and benefits. There is, however, a paucity in the literature in determining the minimally effective dose. METHODS: Consecutive patients who underwent transforaminal lumbar interbody fusion from 2009 to 2014 were reviewed. Fusion was determined by a combination of computed tomography and dynamic x-ray by independent radiologists. We used backward stepwise multiple logistic regression with fusion as the dependent variable to determine whether BMP dose/level was a significant predictor for fusion. To determine the minimally effective dose of BMP/level, separate logistic regressions for different BMP dose ranges and sensitivity analyses were used. A P value ≤0.025 was considered significant. RESULTS: There were 1102 interspaces among 690 patients. Average BMP dose was 1.28 mg/level. Overall fusion was 95.2% with a mean follow-up of 19 months. BMP dose/level was a significant predictor for fusion. Odds of fusion increased by 2.02 when BMP dose range was increased from (0.16-1 mg/level) to (1.0-2 mg/level), but fusion odds did not increase when BMP dose increased to more than 2 mg/level. CONCLUSION: BMP dose/level was a significant predictor for fusion. There was a significant increase in odds of fusion when BMP dose increased from 0.16 to 1 mg/level to 1.0 to 2 mg/level. No benefit from increasing the dose more than 2 mg/level was found, suggesting 1.0 mg/level to be the minimally effective BMP dose. LEVEL OF EVIDENCE: 3.

The effect of ketorolac on posterior thoracolumbar spinal fusions: a prospective double-blinded randomised placebo-controlled trial protocol.

INTRODUCTION: Ketorolac has been shown to provide quality postoperative pain control and decrease opioid requirement with minimal side effects following spinal surgery. However, the literature addressing its use in spinal fusions is highly variable in both its effectiveness and complications, such as pseudarthrosis. Recent literature postulates that ketorolac may not affect fusion rates and large randomised controlled trials are needed to demonstrate ketorolac as a safe and effective adjuvant treatment to opioids for postoperative pain control. METHODS AND ANALYSIS: This is a multihospital, prospective, double-blinded, randomised placebo-controlled trial. Data concerning fusion rates, postoperative opioid use, pain scores, length of stay will be recorded with the aim of demonstrating that the use of ketorolac does not decrease thoracolumbar spinal fusion rates while identifying possible adverse events related to short-term minimal effective dose compared with placebo. Additionally, this investigation aims to demonstrate a decrease in postoperative opioid use demonstrated by a decrease in morphine equivalence while showing equivalent postoperative pain control and decrease the average length of stay. ETHICS AND DISSEMINATION: Ethical approval was obtained at all participating hospitals by the institutional review board. The results of this study will be submitted for publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT03278691.

Comparison of Substrate Specificity of Escherichia Coli p-Aminobenzoyl-Glutamate Hydrolase with Pseudomonas Carboxypeptidase G.

Reduced folic acid derivatives support biosynthesis of DNA, RNA and amino acids in bacteria as well as in eukaryotes, including humans. While the genes and steps for bacterial folic acid synthesis are known, those associated with folic acid catabolism are not well understood. A folate catabolite found in both humans and bacteria is p-aminobenzoyl-glutamate (PABA-GLU). The enzyme p-aminobenzoyl-glutamate hydrolase (PGH) breaks down PABA-GLU and is part of an apparent operon, the abg region, in E. coli. The subunits of PGH possess sequence and catalytic similarities to carboxypeptidase enzymes from Pseudomonas species. A comparison of the subunit sequences and activity of PGH, relative to carboxypeptidase enzymes, may lead to a better understanding of bacterial physiology and pathway evolution. We first compared the amino acid sequences of AbgA, AbgB and carboxypeptidase G2 from Pseudomonas sp. RS-16, which has been crystallized. Then we compared the enzyme activities of E. coli PGH and commercially available Pseudomonas carboxypeptidase G using spectrophotometric assays measuring cleavage of PABA-GLU, folate, aminopterin, methotrexate, 5-formyltetrahydrofolate, and 5-methyltetrahydrofolate. The Km and Vmax values for the folate and anti-folate substrates of PGH could not be determined, because the instrument reached its limit before the enzyme was saturated. Therefore, activity of PGH was compared to the activity of CPG, or normalized to PABA-GLU (nmole/min/µg). Relative to its activity with 10 µM PABA-GLU (100%), PGH cleaved glutamate from methotrexate (48%), aminopterin (45%) and folate (9%). Reduced folates leucovorin (5-formyltetrahydrofolate) and 5-methyltetrahydrofolate were not cleaved by PGH. Our data suggest that E. coli PGH is specific for PABA-GLU as its activity with natural folates (folate, 5-methyltetrahydrofolate, and leucovorin) was very poor. It does, however, have some ability to cleave anti-folates which may have clinical applications in treatment of chemotherapy overdose.