Intravenous Ketorolac Substantially Reduces Opioid Use and Length of Stay After Lumbar Fusion: A Randomized Controlled Trial.

STUDY DESIGN: A randomized, double-blinded, placebo-controlled trial. OBJECTIVE: To examine the effect of intravenous ketorolac (IV-K) on hospital opioid use compared with IV-placebo (IV-P) and IV acetaminophen (IV-A). SUMMARY OF BACKGROUND DATA: Controlling postoperative pain while minimizing opioid use after lumbar spinal fusion is an important area of study. PATIENTS AND METHODS: Patients aged 18 to 75 years undergoing 1 to 2 level lumbar fusions between April 2016 and December 2019 were included. Patients with chronic opioid use, smokers, and those on systemic glucocorticoids or contraindications to study medications were excluded. A block randomization scheme was used, and study personnel, hospital staff, and subjects were blinded to the assignment. Patients were randomized postoperatively. The IV-K group received 15 mg (age > 65) or 30 mg (age < 65) every six hours (q6h) for 48 hours, IV-A received 1000 mg q6h, and IV-P received normal saline q6h for 48 hours. Demographic and surgical details, opioid use in morphine milliequivalents, opioid-related adverse events, and length of stay (LOS) were recorded. The primary outcome was in-hospital opioid use up to 72 hours. RESULTS: A total of 171 patients were included (58 IV-K, 55 IV-A, and 58 IV-P) in the intent-to-treat (ITT) analysis, with a mean age of 57.1 years. The IV-K group had lower opioid use at 72 hours (173 ± 157 mg) versus IV-A (255 ± 179 mg) and IV-P (299 ± 179 mg; P = 0.000). In terms of opiate use, IV-K was superior to IV-A ( P = 0.025) and IV-P ( P = 0.000) on ITT analysis, although on per-protocol analysis, the difference with IV-A did not reach significance ( P = 0.063). When compared with IV-P, IV-K patients reported significantly lower worst ( P = 0.004), best ( P = 0.001), average ( P = 0.001), and current pain ( P = 0.002) on postoperative day 1, and significantly shorter LOS ( P = 0.009) on ITT analysis. There were no differences in opioid-related adverse events, drain output, clinical outcomes, transfusion rates, or fusion rates. CONCLUSIONS: By reducing opioid use, improving pain control on postoperative day 1, and decreasing LOS without increases in complications or pseudarthrosis, IV-K may be an important component of "enhanced recovery after surgery" protocols.

Differences in imaging and clinical characteristics are associated with higher rates of decompression-fusion versus decompression-alone in women compared to men for lumbar degenerative spondylolisthesis.

PURPOSE: The goals were to ascertain if differences in imaging/clinical characteristics between women and men were associated with differences in fusion for lumbar degenerative spondylolisthesis. METHODS: Patients had preoperative standing radiographs, CT scans, and intraoperative fluoroscopic images. Symptoms and comorbidity were obtained from patients; procedure (fusion-surgery or decompression-alone) was obtained from intraoperative records. With fusion surgery as the dependent variable, men and women were compared in multivariable logistic regression models with clinical/imaging characteristics as independent variables. The sample was dichotomized, and analyses were repeated with separate models for men and women. RESULTS: For 380 patients (mean age 67, 61% women), women had greater translation, listhesis angle, lordosis, and pelvic incidence, and less diastasis and disc height (all p ≤ 0.03). The rate of fusion was higher for women (78% vs. 65%; OR 1.9, p = 0.008). Clinical/imaging variables were associated with fusion in separate models for men and women. Among women, in the final multivariable model, less comorbidity (OR 0.5, p = 0.05), greater diastasis (OR 1.6, p = 0.03), and less anterior disc height (OR 0.8, p = 0.0007) were associated with fusion. Among men, in the final multivariable model, opioid use (OR 4.1, p = 0.02), greater translation (OR 1.4, p = 0.0003), and greater diastasis (OR 2.4, p = 0.0002) were associated with fusion. CONCLUSIONS: There were differences in imaging characteristics between men and women, and women were more likely to undergo fusion. Differences in fusion within groups indicate that decisions for fusion were based on composite assessments of clinical and imaging characteristics that varied between men and women.

Anion-Dependent Reactivity of Mono- and Dinuclear Boron Cations.

The dinuclear bis(N-heterocyclic carbene) borane adduct 2 rapidly reacts with tritylium salts at room temperature but the outcome is strongly impacted by the respective counter-ion. Using tritylium tetrakis(perfluoro-tert-butoxy)aluminate affords - depending on the solvent - either the bis(boronium) ion 4 or the hydride-bridged dication 5. In case of tritylium hexafluorophosphate, however, H/F exchange occurs between boron and phosphorus yielding the dinuclear BF3 adduct 3 along with phosphorus dihydride trifluoride. H/F exchange also takes place when using the mononuclear N-heterocyclic carbene BH3 adduct 6 and hence provides a facile route to PH2 F3 , which is usually synthesized in more complex reaction sequences regularly involving toxic hydrogen fluoride. DFT calculations shed light on the H/F exchange between the borenium ion and the [PF6 ]- counter-ion and the computed mechanism features only small barriers in line with the experimental observations.

Emerging Need for PROMs to Measure the Impact of Spine Disorders on Overall Health and Well-being: Measuring Expectations as an Example for Lumbar Degenerative Spondylolisthesis.

Background: Assessing the impact of spine disorders such as lumbar degenerative spondylolisthesis (LDS) on overall health is a component of quality of care that may not be comprehensively captured by spine-specific and single-attribute patient-reported outcome measures (PROMs). Purpose: We sought to compare PROMs to the Lumbar Surgery Expectations Survey ("Expectations Survey"), which addresses multiple aspects of health and well-being, and to compare the relevance of surgeon-selected versus survey-selected Patient-Reported Outcomes Measurement Information System (PROMIS) items to LDS. Methods: In a cross-sectional study, 379 patients with LDS preoperatively completed the Expectations Survey, Numerical Rating Pain Scales, Oswestry Disability Index (ODI), and PROMIS computer-adaptive physical function, pain, and mental health surveys. Expectations Survey scores were compared to PROMs with correlation coefficients (indicating strengths of relationships) and probability values (indicating associations by chance). Surgeons reviewed physical function questions to identify those particularly relevant to LDS. Results: Patients' mean age was 67 years, 64% were women, and 83% had single-level and 17% had multiple-level LDS. Probability values between the Expectations Survey and PROMs were reliable, but strengths of relationships were only mild to moderate, indicating PROMs did not comprehensively capture the impact of LDS. None of the surgeon-selected PROMIS physical function questions were posed to patients. Conclusion: This cross-sectional study found PROMs to be reliably associated but not strongly correlated with the Expectations Survey, which addresses the whole-patient impact of LDS. New measures that complement PROMIS and ODI should be developed to capture the whole-person effects of LDS and permit attribution of LDS treatments to overall health.

Instability Missed by Flexion-Extension Radiographs Subsequently Identified by Alternate Imaging in L4-L5 Lumbar Degenerative Spondylolisthesis.

STUDY DESIGN: Cross-sectional preoperative and intraoperative imaging study of L4-L5 lumbar degenerative spondylolisthesis (LDS). OBJECTIVE: To determine if alternate imaging modalities would identify LDS instability that did not meet the criteria for instability based on comparison of flexion and extension radiographs. SUMMARY OF BACKGROUND DATA: Pain may limit full flexion and extension maneuvers and thereby lead to underreporting of true dynamic translation and angulation in LDS. Alternate imaging pairs may identify instability missed by flexion-extension. MATERIALS AND METHODS: Consecutive patients scheduled for surgery for single-level L4-L5 LDS had preoperative standing radiographs in the lateral, flexion, and extension positions, supine computed tomography (CT) scans, and intraoperative fluoroscopic images in the supine and prone positions after anesthesia but before incision. Instability was defined as translation ≥3.5 mm or angulation ≥11° between the following pairs of images: (1) flexion-extension; (2) CT-lateral; (3) lateral-intraoperative supine; (4) lateral-intraoperative prone; and (5) intraoperative supine-prone. RESULTS: Of 240 patients (mean age 68 y, 54% women) 15 (6%) met the criteria for instability by flexion-extension, and 225 were classified as stable. Of these 225, another 84 patients (35% of total enrollment) were reclassified as unstable by comparison of CT-lateral images (21 patients) and by lateral-intraoperative images (63 patients). Nine of the 15 patients diagnosed with instability by flexion-extension had fusion (60%), and 68 of the 84 patients reclassified as unstable by other imaging pairs had fusion (81%) ( P =0.07). The 84 reclassified patients were more likely to undergo fusion compared with the 141 patients who persistently remained classified as stable (odds ratio=2.6, 95% CI: 1.4-4.9, P =0.004). CONCLUSIONS: Our study provides evidence that flexion and extension radiographs underreport the dynamic extent of LDS and therefore should not be solely relied upon to ascertain instability. These findings have implications for how instability should be established and the extent of surgery that is indicated.

Quantitative CT for Preoperative Assessment of Lumbar Degenerative Spondylolisthesis: The Unique Impact of L4 Bone Mineral Density on Single-Level Disease.

Background: Quantitative computed tomography (qCT) efficiently measures 3-dimensional vertebral bone mineral density (BMD), but its utility in measuring BMD at various vertebral levels in patients with lumbar degenerative spondylolisthesis (LDS) is unclear. Purpose: We sought to determine whether qCT could differentiate BMD at different levels of LDS, particularly at L4-L5, the most common single level for LDS. In addition, we sought to describe patterns of BMD for single-level and multiple-level LDS. Methods: We conducted a study of patients undergoing surgery for LDS who were part of a larger longitudinal study comparing preoperative and intraoperative images. Preoperative patients were grouped as single-level or multiple-level LDS, and qCT BMD was obtained for L1-S1 vertebrae. Mean BMD was compared with literature reports; in multivariable analyses, BMD of each vertebra was assessed according to the level of LDS, controlling for covariates and for BMD of other vertebrae. Results: Of 250 patients (mean age: 67 years, 64% women), 22 had LDS at L3-L4 only, 170 at L4-L5 only, 13 at L5-S1 only, and 45 at multiple levels. Compared with other disorders reported in the literature, BMD in our sample similarly decreased from L1 to L3 then increased from L4 to S1, but mean BMD per vertebra in our sample was lower. Nearly half of our sample met criteria for osteopenia. In multivariable analysis controlling for BMD at other vertebrae, lower L4 BMD was associated with LDS at L4-L5, greater pelvic incidence minus lumbar lordosis, and not having diabetes. In contrast, in similar multivariable analysis, greater L4 BMD was associated with LDS at L3-L4. Bone mineral density of L3 and L5 was not associated with LDS levels. Conclusion: In our sample of preoperative patients with LDS, we observed lower BMD for LDS than for other lumbar disorders. L4 BMD varied according to the level of LDS after controlling for covariates and BMD of other vertebrae. Given that BMD can be obtained from routine imaging, our findings suggest that qCT data may be useful in the comprehensive assessment of and strategy for LDS surgery. More research is needed to elucidate the cause-effect relationships among spinopelvic alignment, LDS, and BMD.

Acute development of spinal lumbar synovial facet cyst within 1 week after lumbar decompression: illustrative case.

BACKGROUND: Synovial facet cysts can sometimes develop in patients with lumbar spinal stenosis after decompressive laminectomy. The etiology of spinal lumbar synovial cysts is still unclear, but their formation is associated with underlying spinal instability, facet joint arthropathy, and degenerative spondylolisthesis. OBSERVATIONS: A 61-year-old-male patient presented with neurogenic claudication due to lumbar spinal stenosis. Radiographic studies showed grade I spondylolisthesis and radiological predictors of delayed spinal instability. He underwent lumbar decompression and shortly thereafter developed spinal instability and recurrent symptoms, with formation of a new spinal lumbar synovial facet cyst. He required revisional decompression, cyst excision, and posterolateral spinal fusion for definitive treatment. LESSONS: The literature reports postoperative spinal instability in up to one-third of patients with lumbar spinal stenosis and stable degenerative spondylolisthesis who undergo decompressive laminectomy. Close radiographic monitoring and early advanced imaging may be prudent in this patient population if they develop new postoperative neurological symptoms and show radiographic predictors of instability on preoperative imaging. Posterolateral spinal fusion with instrumentation should be considered in addition to lumbar decompression in this select group of patients who demonstrate radiographic predictors of delayed spinal instability if they are medically capable of tolerating a spinal fusion procedure.

Impact of the Novel Z-Acceptor Ligand Bis{(ortho-diphenylphosphino)phenyl}zinc (ZnPhos) on the Formation and Reactivity of Low-Coordinate Ru(0) Centers.

The preparation and reactivity with H2 of two Ru complexes of the novel ZnPhos ligand (ZnPhos = Zn(o-C6H4PPh2)2) are described. Ru(ZnPhos)(CO)3 (2) and Ru(ZnPhos)(IMe4)2 (4; IMe4 = 1,3,4,5-tetramethylimidazol-2-ylidene) are formed directly from the reaction of Ru(PPh3)(C6H4PPh2)2(ZnMe)2 (1) or Ru(PPh3)3HCl/LiCH2TMS/ZnMe2 with CO and IMe4, respectively. Structural and electronic structure analyses characterize both 2 and 4 as Ru(0) species in which Ru donates to the Z-type Zn center of the ZnPhos ligand; in 2, Ru adopts an octahedral coordination, while 4 displays square-pyramidal coordination with Zn in the axial position. Under photolytic conditions, 2 loses CO to give Ru(ZnPhos)(CO)2 that then adds H2 over the Ru-Zn bond to form Ru(ZnPhos)(CO)2(µ-H)2 (3). In contrast, 4 reacts directly with H2 to set up an equilibrium with Ru(ZnPhos)(IMe4)2H2 (5), the product of oxidative addition at the Ru center. DFT calculations rationalize these different outcomes in terms of the energies of the square-pyramidal Ru(ZnPhos)L2 intermediates in which Zn sits in a basal site: for L = CO, this is readily accessed and allows H2 to add across the Ru-Zn bond, but for L = IMe4, this species is kinetically inaccessible and reaction can only occur at the Ru center. This difference is related to the strong π-acceptor ability of CO compared to IMe4. Steric effects associated with the larger IMe4 ligands are not significant. Species 4 can be considered as a Ru(0)L4 species that is stabilized by the Ru→Zn interaction. As such, it is a rare example of a stable Ru(0)L4 species devoid of strong π-acceptor ligands.

The effect of omega-3 fatty-acid supplements on perioperative bleeding following posterior spinal arthrodesis.

PURPOSE: To investigate the effect of omega-3 fatty-acid supplements (n-3FA) on bleeding during posterior spinal arthrodesis. METHODS: We reviewed all one- or two-level posterolateral lumbar decompression/fusions with or without interbody fusion by five surgeons within 3 years. Patients taking n-3FA preoperatively were matched 1:2 with controls based on procedure, surgeon and operative time. Patients with abnormal coagulation parameters, known bleeding disorders or other medications that could affect surgical blood loss were excluded. RESULTS: Twenty-eight patients met inclusion criteria. The n-3FA and control groups were similar with respect to gender, age, body mass index, operative time, and preoperative use of non-steroidal anti-inflammatory drugs. The n-3FAs were stopped an average of 5.2 days before surgery (range 1-10). Mean estimated blood loss (EBL) was 697 ml in the n-3FA group and 771 ml in the control group (p = 0.36). Mean transfused volume of Cell Saver (CS) was 282 ml in the n-3FA group and 321 ml in the control group (p = 0.30). A post hoc power analysis showed that the study was powered to detect a minimum difference of 105 ml for EBL and 50 ml for CS. The multivariate generalized estimating equation did not show a significant difference between groups for EBL or CS (p = 0.35 and p = 0.29, respectively). Secondary outcomes including drop in postoperative hemoglobin, transfusion requirement, complications and surgical drain output were similar between the two groups. CONCLUSIONS: The n-3FA use did not contribute to higher perioperative blood loss during spinal arthrodesis.

A novel method for the quantitative evaluation of lumbar spinal stenosis.

STUDY DESIGN: A retrospective study of computed tomography (CT) myelographic images in patients with degenerative lumbar spinal stenosis (LSS). OBJECTIVES: To introduce a new technique for the quantitative evaluation of LSS. BACKGROUND: Advances in hardware and software technology now permit inexpensive digitalization of radiological images, and enable methodologies for quantifying space available for neural elements in spinal canal. However, a valid method with quantitative evaluation of spinal stenosis in living patients has not been developed yet. METHODS AND MATERIALS: Preoperative CT myelographic scans of 50 patients with degenerative LSS were collected for retrospective investigation. The patients subsequently underwent lumbar decompressive surgery. They included scans from thoracic vertebra 12 (T12) to sacrum (S1), in which each segment was scanned through both the vertebral body and disk. All CT scan films were digitized using a high-resolution digital camera. ImageTool software was used to measure three parameters: cross-sectional area of dural sac at disk level (A), cross-sectional area of spinal canal at midpedicular level (B), and cross-sectional area of vertebral body (C). The dural sac canal ratio (DSCR) was calculated as A/B x 100%. Low DSCR implied severe dural sac compression with a high degree of stenosis. The spinal canal vertebral ratio (CVR) was also calculated as B/C x 100%. Low CVR implied a low baseline of canal capacity for neural elements. They were calculated from T12 to S1. RESULTS: The study consisted of 26 male and 24 female patients, with an average age of 68.4 (35-97) years. A total of 295 segments were evaluated, of which 118 (40%) were surgically decompressed. There were wide ranges of canal cross-sectional areas (140-475 mm(2)) and dural sac cross-sectional area (54-435 mm(2)). Male patients had a slightly larger canal cross-sectional area than female patients at each level. The mean CVR was found decreased from T12 (26.1%) to L4 (18.3%). This was higher in female than in male patients, especially from T12 to L2 (P < 0.01). There were significant correlations between spinal canal and dural sac cross-sectional area (r = 0.55, P < 0.001), and also between CVR and DSCR (r = 0.31, P < 0.001). Of the levels decompressed, 82% was performed from the level L2 to L5, in which there was no significant difference in canal cross-sectional area and CVR between decompression and nondecompression (P > 0.05). There was a good correspondence between decreasing mean DSCR and increasing percentile of levels decompressed. CONCLUSION: DSCR represents a useful method for the quantitative diagnosis of lumbar spinal canal stenosis. ImageTool software is a useful tool in measuring spinal morphometry.

Molecular signaling in intervertebral disk development.

The purpose of this investigation is to identify and study the expression pattern of pertinent molecular factors involved in the differentiation of the intervertebral disk (IVD). It is likely that hedgehog genes and the BMP inhibitors are key factors involved in spinal joint formation. Radioactive in situ hybridization with mRNA probes for pax-1, SHH, IHH and Noggin gene was performed on mouse embryo and adult tissue. Immunohistochemistry was performed to localize hedgehog receptor, "patched" (ptc). From 14.5 dpc until birth pax-1 mRNA was expressed in the developing anulus fibrosus (AF). During the same developmental period Noggin mRNA is highly expressed throughout the spine, in the developing AF, while ptc protein and SHH mRNA were expressed in the developing nucleus pulposus (NP). IHH mRNA was expressed by condensing chondrocytes of the vertebral bodies and later becomes confined to the vertebral endplate. We show for the first time that pax-1 is expressed in the adult intervertebral disk. Ptc expression in the NP is an indicator of hedgehog protein signaling in the developing IVD. The expression pattern of the BMP inhibitor Noggin appears to be important for the normal formation of the IVD and may prove to play a role in its segmental pattern formation.

Discography-induced acute lumbar disc herniation: a report of five cases.

The reported complication rate of provocative lumbar discography is low, ranging from 0-2.5%. We report five cases of acute lumbar disc herniation precipitated by discography, a previously unreported complication. The cases reported comprise of four men and one woman with ages ranging from 23-45 years. All developed an acute exacerbation of radicular leg pain following multilevel provocative lumbar discography. One patient developed an acute foot drop. Comparison of lumbar MRI scans before and after discography demonstrated either a new herniated disc fragment or an increase in size of a preexisting herniation in all cases. On review of each discogram study and pre-discogram MRI an annular tear or small disc herniation was noted in all cases. In each case the patients' symptoms failed to resolve necessitating surgical intervention in all cases. In conclusion, annular deficiency is an obvious predisposing factor to discogram related disc herniation. New onset or a persistent exacerbation of radicular symptoms following provocative discography merits further investigation.

Gene therapy for spinal applications.

Gene therapy is a promising drug delivery mechanism for the treatment of spinal disorders. Currently, the technique has been most useful in enhancing growth factor therapy for spinal fusion, intervertebral disc regeneration, and spinal cord injury healing. Gene therapy allows for the high-level local production of growth factors, obviating the need for slow release carriers or continuous infusion pumps that are otherwise necessary because of the short half-lives of most peptide growth factors. Although continuous expression is desirable, growth factor therapy is usually intended to be transient. The typical expression profile of Ad vectors--at a high level over 2 weeks or so--has been ideal, leading to its widespread use in these applications. Despite the ability of Ad to deliver genes directly in vivo, however, the cell-based ex vivo approach has been used widely in spinal applications. In spinal cord injury, cells such as peripheral nerve or Schwann cells may provide a permissive substrate for axonal growth [51]. For spinal fusion and IVD regeneration, ex vivo manipulation of cells facilitates gene transfer, because bone and IVD tissue are too dense to be penetrated by injection of Ad or other vectors. The use of cells may be advantageous in these applications in which new tissue formation is the goal. Finally, the use of genetically modified cells may decrease the inflammatory reaction induced by Ad vectors. Although gene therapy for spinal disorders has been centered around Ad-mediated transfer of single growth factor genes, the options for candidate genes and vectors are growing rapidly. Ad vectors are being improved by decreasing their immunogenicity and altering their tropism [2]. Vectors based on other viruses (such as herpes, adeno-associated virus, and lentivirus) are being developed, also with lower immunogenicity and with longer durations of expression [26,67]. Regulated expression, such as with the tetracycline regulated promoter, is being developed so that genes can be turned on or off as needed. Such regulation may be sensitive even to physiologic cues in the future [68,69]. Finally, the high throughput technologies, such as the gene chip, are elucidating thousands of genes that may be good candidates for the enhancement of bone healing and IVD and spinal cord regeneration. Genes whose products not only support bone, fibrocartilage, or axon growth but also neutralize natural inhibitors or promote tissue remodeling and maturation may be good future candidates. In the future, a series of vectors with multiple genes that are regulated by physiologic cues might be used to enhance spinal fusion, restore IVD tissue, or support spinal cord healing.