Tropine exacerbates the ventilatory depressant actions of fentanyl in freely-moving rats.

Our lab is investigating the efficacy profiles of tropine analogs against opioid-induced respiratory depression. The companion manuscript reports that the cell-permeant tropeine, tropine ester (Ibutropin), produces a rapid and sustained reversal of the deleterious actions of fentanyl on breathing, alveolar-arterial (A-a) gradient (i.e., index of alveolar gas exchange), and arterial blood-gas (ABG) chemistry in freely-moving male Sprague Dawley rats, while not compromising fentanyl analgesia. We report here that in contrast to Ibutropin, the injection of the parent molecule, tropine (200 µmol/kg, IV), worsens the adverse actions of fentanyl (75 µg/kg, IV) on ventilatory parameters (e.g., frequency of breathing, tidal volume, minute ventilation, peak inspiratory and expiratory flows, and inspiratory and expiratory drives), A-a gradient, ABG chemistry (e.g., pH, pCO2, pO2, and sO2), and sedation (i.e., the righting reflex), while not affecting fentanyl antinociception (i.e., the tail-flick latency) in freely-moving male Sprague Dawley rats. These data suggest that tropine augments opioid receptor-induced signaling events that mediate the actions of fentanyl on breathing and alveolar gas exchange. The opposite effects of Ibutropin and tropine may result from the ability of Ibutropin to readily enter peripheral and central cells. Of direct relevance is that tropine, resulting from the hydrolysis of Ibutropin, would combat the Ibutropin-induced reversal of the adverse effects of fentanyl. Because numerous drug classes, such as cocaine, atropine, and neuromuscular blocking drugs contain a tropine moiety, it is possible that their hydrolysis to tropine has unexpected/unintended consequences. Indeed, others have found that tropine exerts the same behavioral profile as cocaine upon central administration. Together, these data add valuable information about the pharmacological properties of tropine.

Direct Photobiomodulation Therapy on the Sciatic Nerve Significantly Attenuates Acute Nociceptive Sensitivity Without Affecting Motor Output.

OBJECTIVES: Pharmacologic pain treatments lack specific targeting and often produce unwanted side effects (eg, addiction, additional hyperalgesia). We previously established that the direct application of laser irradiation (direct photobiomodulation [PBM]) of the sural nerve reduces thermal hypersensitivity in a rodent model of chronic pain, but not mechanical hypersensitivity. These observations were consistent with a selective reduction in the small-diameter fiber contribution to electrophysiologically measured evoked response after direct PBM of a sensory nerve (saphenous). However, to our knowledge, direct application of laser irradiation has never been performed in an animal model of acute nociceptive pain or on a mixed nerve in which sensory and motor outcomes can be observed. MATERIALS AND METHODS: In this study, we describe the effects of direct application of laser irradiation (808 nm, 60 mW, 4 minutes) on a mixed nerve (sciatic nerve) in an acute nociceptive pain model (intradermal capsaicin injection) in rats over the course of two weeks. To investigate whether laser irradiation of a mixed nerve alters motor function, in separate experiments, we applied laser irradiation to the sciatic nerve (using the same parameters as in the chronic pain experiments), and force generation of the gastrocnemius was measured. RESULTS: Capsaicin-induced hypersensitivities to mechanical (pin prick) and thermal (Hargreaves) noxious stimuli, associated with Aδ- and C-fibers, showed a maximal reduction of 70% and 56.2%, respectively, by direct PBM, when compared with a control group (vehicle injection, no PBM) on the same day. This reduction was determined to be significant using a mixed-design analysis of variance with a p value < 0.05. Force generation remained unchanged for up to 120 minutes after laser irradiation. In summary, direct PBM selectively inhibits C- and Aδ-fiber transmission while leaving Aɑ-, Aß-, and motor-fiber activity intact. CONCLUSIONS: These results, in conjunction with our previous analyses of laser irradiation effects on the sural nerve in a chronic spared nerve injury pain model, suggest that direct PBM is a promising candidate for treating pain induced by small-diameter fiber activity.

Restoring L4-S1 Lordosis Shape in Severe Sagittal Deformity: Impact of Correction Techniques on Alignment and Complication Profile.

BACKGROUND: Severe sagittal plane deformity with loss of L4-S1 lordosis is disabling and can be improved through various surgical techniques. However, data are limited on the differing ability of anterior lumbar interbody fusion (ALIF), pedicle subtraction osteotomy (PSO), and transforaminal lumbar interbody fusion (TLIF) to achieve alignment goals in severely malaligned patients. METHODS: Severe adult spinal deformity patients with preoperative PI-LL >20°, L4-S1 lordosis <30°, and full body radiographs and PROMs at baseline and 6-week postoperative visit were included. Patients were grouped into ALIF (1-2 level ALIF at L4-S1), PSO (L4/L5 PSO), and TLIF (1-2 level TLIF at L4-S1). Comparative analyses were performed on demographics, radiographic spinopelvic parameters, complications, and PROMs. RESULTS: Among the 96 included patients, 40 underwent ALIF, 27 underwent PSO, and 29 underwent TLIF. At baseline, cohorts had comparable age, sex, race, Edmonton frailty scores, and radiographic spinopelvic parameters (P > 0.05). However, PSO was performed more often in revision cases (P < 0.001). Following surgery, L4-S1 lordosis correction (P = 0.001) was comparable among ALIF and PSO patients and caudal lordotic apex migration (P = 0.044) was highest among ALIF patients. PSO patients had higher intraoperative estimated blood loss (P < 0.001) and motor deficits (P = 0.049), and in-hospital ICU admission (P = 0.022) and blood products given (P = 0.004), but were otherwise comparable in terms of length of stay, blood transfusion given, and postoperative admission to rehab. Likewise, 90-day postoperative complication profiles and 6-week PROMs were comparable as well. CONCLUSIONS: ALIF can restore L4-S1 sagittal alignment as powerfully as PSO, with fewer intraoperative and in-hospital complications. When feasible, ALIF is a suitable alternative to PSO and likely superior to TLIF for correcting L4-S1 lordosis among patients with severe sagittal malalignment.

Distal Lumbar Lordosis is Associated With Reoperation for Adjacent Segment Disease After Lumbar Fusion for Degenerative Conditions.

STUDY DESIGN: A single centre retrospective review. OBJECTIVE: Recent studies have suggested that distal lordosis (L4-S1, DL) remains constant across all pelvic incidence (PI) subgroups, whilst proximal lordosis (L1-L4, PL) varies. We sought to investigate the impact of post-operative DL on adjacent segment disease (ASD) requiring reoperation in patients undergoing lumbar fusion for degenerative conditions. METHODS: Patients undergoing 1-3 level lumbar fusion with the two senior authors between 2007-16 were included. Demographic and radiographic data were recorded. Univariate, multivariate binary logistic regression, and Kaplan Meier survivorship analyses were performed. RESULTS: 335 patients were included in the final analysis. Most had single (67%) or two (31%) level fusions. The mean follow-up was 64-month. Fifty-seven patients (17%) underwent reoperation for ASD at an average of 78-month post-operatively (R group). The R group had a significantly lower mean post-operative DL (27.3 vs 31.1 deg, P < .001) and mean PI (55.5 vs 59.2 deg, P < .05). On univariate analysis, patients with a post-operative DL of <35 deg had higher odds of reoperation for ASD than those with a post-operative DL of ≥35 deg (OR 2.7, P = .016). In the multivariate model, post-operative DL, low/average PI, and spondylolisthesis were all significantly associated with reoperation for ASD. CONCLUSION: This study provides preliminary support to an association between post-operative distal lumbar lordosis and risk of reoperation for ASD in patients undergoing fusions for degenerative conditions. Further multicentre prospective study is needed to independently confirm this association and identify the impact of restoration of physiological distal lumbar lordosis on long term patient outcomes.

Wound Closure and Wound Dressings in Adult Spinal Deformity Surgery From the AO Spine Surveillance of Post-Operative Management.

STUDY DESIGN: An e-mail-based online survey for adult spinal deformity (ASD) surgeons. OBJECTIVE: Wound closure and dressing techniques may vary according to the discretion of the surgeon as well as geographical location. However, there are no reports on most common methods. The purpose of this study is to clarify the consensus. METHODS: An online survey was distributed via email to AO Spine members. Responses from 164 ASD surgeons were surveyed. The regions were divided into 5 regions: Europe and South Africa (ESA), North America (NA), Asia Pacific (AP), Latin America (LA), and Middle East and North Africa (MENA). Wound closure methods were evaluated by glue(G), staples(S), external non-absorbable sutures (ENS), tapes(T), and only subcuticular absorbable suture (SAS). Wound Dressings consisted of dry dressing (D), plastic occlusive dressing (PO), G, Dermabond Prineo (DP). RESULTS: The number of respondents were 57 in ESA, 33 in NA, 36 in AP, 22 in LA, and 16 in MENA. S (36.4%) was the most used wound closure method. This was followed by ENS (26.2%), SAS (14.4%), G (11.8%), and T (11.3%). S use was highest in ESA (44.3%), NA (28.6%), AP (31.7%), and MENA (58.8%). D was used by 50% of surgeons postoperatively. AP were most likely to use PO (36%). 21% of NA used DP, while between 0%-9% of surgeons used it in the rest of the world. CONCLUSION: Wound closure and dressings methods differ in the region. There are no current guidelines with these choices. Future studies should seek to standardize these choices.

Opioid Use Prior to Adult Spine Deformity Correction Surgery is Associated With Worse Pre- and Postoperative Back Pain and Prolonged Opioid Demands.

STUDY DESIGN: Prospective multicenter database post-hoc analysis. OBJECTIVES: Opioids are frequently prescribed for painful spinal conditions to provide pain relief and to allow for functional improvement, both before and after spine surgery. Amidst a current opioid epidemic, it is important for providers to understand the impact of opioid use and its relationship with patient-reported outcomes. The purpose of this study was to evaluate pre-/postoperative opioid consumption surrounding ASD and assess patient-reported pain outcomes in older patients undergoing surgery for spinal deformity. METHODS: Patients ≥60 years of age from 12 international centers undergoing spinal fusion of at least 5 levels and a minimum 2-year follow-up were included. Patient-reported outcome scores were collected using the Numeric Rating Scale for back and leg pain (NRS-B; NRS-L) at baseline and at 2 years following surgery. Opioid use, defined based on a specific question on case report forms and question 11 from the SRS-22r questionnaire, was assessed at baseline and at 2-year follow-up. RESULT: Of the 219 patients who met inclusion criteria, 179 (81.7%) had 2-year data on opioid use. The percentages of patients reporting opioid use at baseline (n = 75, 34.2%) and 2 years after surgery (n = 55, 30.7%) were similar (P = .23). However, at last follow-up 39% of baseline opioid users (Opi) were no longer taking opioids, while 14% of initial non-users (No-Opi) reported opioid use. Regional pre- and postoperative opioid use was 5.8% and 7.7% in the Asian population, 58.3% and 53.1% in the European, and 50.5% and 40.2% in North American patients, respectively. Baseline opioid users reported more preoperative back pain than the No-Opi group (7.0 vs 5.7, P = .001), while NRS-Leg pain scores were comparable (4.8 vs 4, P = .159). Similarly, at last follow-up, patients in the Opi group had greater NRS-B scores than Non-Opi patients (3.2 vs 2.3, P = .012), but no differences in NRS-Leg pain scores (2.2 vs 2.4, P = .632) were observed. CONCLUSIONS: In this study, almost one-third of surgical ASD patients were consuming opioids both pre- and postoperatively world-wide. There were marked international variations, with patients from Asia having a much lower usage rate, suggesting a cultural influence. Despite both opioid users and nonusers benefitting from surgery, preoperative opioid use was strongly associated with significantly more back pain at baseline that persisted at 2-year follow up, as well as persistent postoperative opioid needs.

Fentanyl activates opposing opioid and non-opioid receptor systems that control breathing.

Fentanyl elicits profound disturbances in ventilatory control processes in humans and experimental animals. The traditional viewpoint with respect to fentanyl-induced respiratory depression is that once the effects on the frequency of breathing (Freq), tidal volume (TV), and minute ventilation (MV = Freq × TV) are resolved, then depression of breathing is no longer a concern. The results of the present study challenge this concept with findings, as they reveal that while the apparent inhibitory effects of fentanyl (75 µg/kg, IV) on Freq, TV, and MV in adult male rats were fully resolved within 15 min, many other fentanyl-induced responses were in full effect, including opposing effects on respiratory timing parameters. For example, although the effects on Freq were resolved at 15 min, inspiratory duration (Ti) and end inspiratory pause (EIP) were elevated, whereas expiratory duration (Te) and end expiratory pause (EEP) were diminished. Since the effects of fentanyl on TV had subsided fully at 15 min, it would be expected that the administration of an opioid receptor (OR) antagonist would have minimal effects if the effects of fentanyl on this and other parameters had resolved. We now report that the intravenous injection of a 1.0 mg/kg dose of the peripherally restricted OR antagonist, methyl-naloxone (naloxone methiodide, NLXmi), did not elicit arousal but elicited some relatively minor changes in Freq, TV, MV, Te, and EEP but pronounced changes in Ti and EIP. In contrast, the injection of a 2.5 mg/kg dose of NLXmi elicited pronounced arousal and dramatic changes in many variables, including Freq, TV, and MV, which were not associated with increases in non-apneic breathing events such as apneas. The two compelling conclusions from this study are as follows: 1) the blockade of central ORs produced by the 2.5 mg/kg dose of NLXmi elicits pronounced increases in Freq, TV, and MV in rats in which the effects of fentanyl had apparently resolved, and 2) it is apparent that fentanyl had induced the activation of two systems with counter-balancing effects on Freq and TV: one being an opioid receptor inhibitory system and the other being a non-OR excitatory system.

Identification and characterization of calcium binding protein, spermatid-associated 1 (CABS1)# in selected human tissues and fluids.

Calcium binding protein, spermatid associated 1 (CABS1) is a protein most widely studied in spermatogenesis. However, mRNA for CABS1 has been found in numerous tissues, albeit with little information about the protein. Previously, we identified CABS1 mRNA and protein in human salivary glands and provided evidence that in humans CABS1 contains a heptapeptide near its carboxyl terminus that has anti-inflammatory activities. Moreover, levels of an immunoreactive form of CABS1 were elevated in psychological stress. To more fully characterize human CABS1 we developed additional polyclonal and monoclonal antibodies to different sections of the protein and used these antibodies to characterize CABS1 in an overexpression cell lysate, human salivary glands, saliva, serum and testes using western blot, immunohistochemistry and bioinformatics approaches exploiting the Gene Expression Omnibus (GEO) database. CABS1 appears to have multiple molecular weight forms, consistent with its recognition as a structurally disordered protein, a protein with structural plasticity. Interestingly, in human testes, its cellular distribution differs from that in rodents and pigs, and includes Leydig cells, primary spermatogonia, Sertoli cells and developing spermatocytes and spermatids, Geodata suggests that CABS1 is much more widely distributed than previously recognized, including in the urogenital, gastrointestinal and respiratory tracts, as well as in the nervous system, immune system and other tissues. Much remains to be learned about this intriguing protein.

The Effect of Anaemia on Intra-operative Neuromonitoring Following Correction of Large Scoliosis Curves: Two Case Reports.

The correction of anemia is important in reversing significant intraoperative bilateral motor-evoked potential (MEP) loss following rod placement for correction of large scoliosis curves. This article presents a retrospective review of intraoperative neuromonitoring (IONM) data, anesthesia records, and medical charts of two patients with significant bilateral MEP changes associated with posterior spinal surgery for deformity correction. A 70 kg 12-year-old and a 44 kg 16-year-old female with main thoracic curves underwent a posterior scoliosis correction with multilevel posterior column osteotomies. Following rod insertion, significant reduction in the bilateral lower extremity MEP occurred in both cases despite mean arterial pressure exceeding 70 mmHg, which was presumed to be due to the scale of the correction attempted in the setting of haemorrhage which rendered the patient acutely anaemic, thus compromising cord vasculature and oxygen delivery. The rods were removed and packed red blood cell transfusions were administered in response to acute anaemia as a result of haemorrhage in both cases. Neither was noted to be anaemic preoperatively. Once the MEP signals improved, the rods were reinserted and correction was attempted, limited by neuromonitoring signals and resistance of the bony anchors to pullout. At closure, the MEPs were near baseline in the first case and >50% of baseline in the second. There were no changes in the somatosensory evoked potential signals in either case. Post-operative neurological function was normal in both patients. Correcting the circulating haemoglobin concentration through blood product resuscitation allowed for safe correction of spinal deformity in two cases with significant bilateral MEP loss following the initial placement of rods.

L-NAC and L-NAC methyl ester prevent and overcome physical dependence to fentanyl in male rats.

N-acetyl-L-cysteine (L-NAC) is a proposed therapeutic for opioid use disorder. This study determined whether co-injections of L-NAC (500 µmol/kg, IV) or its highly cell-penetrant analogue, L-NAC methyl ester (L-NACme, 500 µmol/kg, IV), prevent acquisition of acute physical dependence induced by twice-daily injections of fentanyl (125 µg/kg, IV), and overcome acquired dependence to these injections in freely-moving male Sprague Dawley rats. The injection of the opioid receptor antagonist, naloxone HCl (NLX; 1.5 mg/kg, IV), elicited a series of withdrawal phenomena (i.e. behavioral and cardiorespiratory responses, hypothermia and body weight loss) in rats that received 5 or 10 injections of fentanyl and similar numbers of vehicle co-injections. With respect to the development of dependence, the NLX-precipitated withdrawal phenomena were reduced in rats that received had co-injections of L-NAC, and more greatly reduced in rats that received co-injections of L-NACme. In regard to overcoming established dependence, the NLX-precipitated withdrawal phenomena in rats that had received 10 injections of fentanyl (125 µg/kg, IV) were reduced in rats that had received co-injections of L-NAC, and more greatly reduced in rats that received co-injections of L-NACme beginning with injection 6 of fentanyl. This study provides compelling evidence that co-injections of L-NAC and L-NACme prevent the acquisition of physical dependence and overcome acquired dependence to fentanyl in male rats. The higher efficacy of L-NACme is likely due to its greater cell penetrability in brain regions mediating dependence to fentanyl and interaction with intracellular signaling cascades, including redox-dependent processes, responsible for the acquisition of physical dependence to fentanyl.

Post-operative bracing following adult spine deformity surgery: Results from the AO Spine surveillance of post-operative management of patients with adult spine deformity.

STUDY DESIGN: Cross-sectional international survey with a literature review. OBJECTIVES: While some surgeons favor spine bracing after surgery for adult spine deformity (ASD) to help prevent mechanical failures, there is a lack of evidence. The objective of the present study was to better understand the current trend in the use of bracing following ASD surgery based on an international survey. METHODS: An e-mail-based online survey was conducted among over 6000 international AO Spine members regarding the post-operative management of patients with ASD. The details of brace prescription, indications and influencing factors were solicited. Descriptive data were summarized based on different demographic groups and fusion levels for the responding surgeons who annually perform at least 10 long-segment fusions of >5 levels extending to the pelvis. RESULTS: A total of 116 responses were received, including 71 surgeons (61%) who used post-operative bracing for >5 levels of long fusion. The most common reason for bracing was pain management (55%) and bone quality was the strongest influencing factor (69%). Asia-Pacific surgeons had the highest rate of bracing (88%), while North American surgeons had the lowest (45%). The most common type of brace used were TLSO for cases with an uppermost instrumented vertebra (UIV) in the low- or mid-thoracic spine and a cervical brace for UIV at T1-3. The majority (56%) used bracing for 6-12 weeks after surgery. CONCLUSIONS: The present survey demonstrated significant interest in bracing following ASD surgery, however, there is substantial variability in post-operative bracing practice. A formal study on the role of bracing in ASD surgery is needed.

The Reducing Agent Dithiothreitol Modulates the Ventilatory Responses That Occur in Freely Moving Rats during and following a Hypoxic-Hypercapnic Challenge.

The present study examined the hypothesis that changes in the oxidation-reduction state of thiol residues in functional proteins play a major role in the expression of the ventilatory responses in conscious rats that occur during a hypoxic-hypercapnic (HH) gas challenge and upon return to room air. A HH gas challenge in vehicle-treated rats elicited robust and sustained increases in minute volume (via increases in frequency of breathing and tidal volume), peak inspiratory and expiratory flows, and inspiratory and expiratory drives while minimally affecting the non-eupneic breathing index (NEBI). The HH-induced increases in these parameters, except for frequency of breathing, were substantially diminished in rats pre-treated with the potent and lipophilic disulfide-reducing agent, L,D-dithiothreitol (100 µmol/kg, IV). The ventilatory responses that occurred upon return to room air were also substantially different in dithiothreitol-treated rats. In contrast, pre-treatment with a substantially higher dose (500 µmol/kg, IV) of the lipophilic congener of the monosulfide, N-acetyl-L-cysteine methyl ester (L-NACme), only minimally affected the expression of the above-mentioned ventilatory responses that occurred during the HH gas challenge or upon return to room air. The effectiveness of dithiothreitol suggests that the oxidation of thiol residues occurs during exposure to a HH gas challenge and that this process plays an essential role in allowing for the expression of the post-HH excitatory phase in breathing. However, this interpretation is contradicted by the lack of effects of L-NACme. This apparent conundrum may be explained by the disulfide structure affording unique functional properties to dithiothreitol in comparison to monosulfides. More specifically, the disulfide structure may give dithiothreitol the ability to alter the conformational state of functional proteins while transferring electrons. It is also possible that dithiothreitol is simply a more efficient reducing agent following systemic injection, although one interpretation of the data is that the effects of dithiothreitol are not due to its reducing ability.

Surgeon Preference Regarding Wound Dressing Management in Lumbar Fusion Surgery: An AO Spine Global Cross-Sectional Study.

OBJECTIVE: To evaluate the global practice pattern of wound dressing use after lumbar fusion for degenerative conditions. METHODS: A survey issued by AO Spine Knowledge Forums Deformity and Degenerative was sent out to AO Spine members. The type of postoperative dressing employed, timing of initial dressing removal, and type of subsequent dressing applied were investigated. Differences in the type of surgery and regional distribution of surgeons' preferences were analyzed. RESULTS: Right following surgery, 60.6% utilized a dry dressing, 23.2% a plastic occlusive dressing, 5.7% glue, 6% a combination of glue and polyester mesh, 2.6% a wound vacuum, and 1.2% other dressings. The initial dressing was removed on postoperative day 1 (11.6%), 2 (39.2%), 3 (20.3%), 4 (1.7%), 5 (4.3%), 6 (0.4%), 7 or later (12.5%), or depending on drain removal (9.9%). Following initial dressing removal, 75.9% applied a dry dressing, 17.7% a plastic occlusive dressing, and 1.3% glue, while 12.1% used no dressing. The use of no additional coverage after initial dressing removal was significantly associated with a later dressing change (p < 0.001). Significant differences emerged after comparing dressing management among different AO Spine regions (p < 0.001). CONCLUSION: Most spine surgeons utilized a dry or plastic occlusive dressing initially applied after surgery. The first dressing was more frequently changed during the first 3 postoperative days and replaced with the same type of dressing. While dressing policies tended not to vary according to the type of surgery, regional differences suggest that actual practice may be based on personal experience rather than available evidence.

Stronger association of objective physical metrics with baseline patient-reported outcome measures than preoperative standing sagittal parameters for adult spinal deformity patients.

OBJECTIVE: Sagittal alignment measured on standing radiography remains a fundamental component of surgical planning for adult spinal deformity (ASD). However, the relationship between classic sagittal alignment parameters and objective metrics, such as walking time (WT) and grip strength (GS), remains unknown. The objective of this work was to determine if ASD patients with worse baseline sagittal malalignment have worse objective physical metrics and if those metrics have a stronger relationship to patient-reported outcome metrics (PROMs) than standing alignment. METHODS: The authors conducted a retrospective review of a multicenter ASD cohort. ASD patients underwent baseline testing with the timed up-and-go 6-m walk test (seconds) and for GS (pounds). Baseline PROMs were surveyed, including Oswestry Disability Index (ODI), Patient-Reported Outcomes Measurement Information System (PROMIS), Scoliosis Research Society (SRS)-22r, and Veterans RAND 12 (VR-12) scores. Standard spinopelvic measurements were obtained (sagittal vertical axis [SVA], pelvic tilt [PT], and mismatch between pelvic incidence and lumbar lordosis [PI-LL], and SRS-Schwab ASD classification). Univariate and multivariable linear regression modeling was performed to interrogate associations between objective physical metrics, sagittal parameters, and PROMs. RESULTS: In total, 494 patients were included, with mean ± SD age 61 ± 14 years, and 68% were female. Average WT was 11.2 ± 6.1 seconds and average GS was 56.6 ± 24.9 lbs. With increasing PT, PI-LL, and SVA quartiles, WT significantly increased (p < 0.05). SRS-Schwab type N patients demonstrated a significantly longer average WT (12.5 ± 6.2 seconds), and type T patients had a significantly shorter WT time (7.9 ± 2.7 seconds, p = 0.03). With increasing PT quartiles, GS significantly decreased (p < 0.05). SRS-Schwab type T patients had a significantly higher average GS (68.8 ± 27.8 lbs), and type L patients had a significantly lower average GS (51.6 ± 20.4 lbs, p = 0.03). In the frailty-adjusted multivariable linear regression analyses, WT was more strongly associated with PROMs than sagittal parameters. GS was more strongly associated with ODI and PROMIS Physical Function scores. CONCLUSIONS: The authors observed that increasing baseline sagittal malalignment is associated with slower WT, and possibly weaker GS, in ASD patients. WT has a stronger relationship to PROMs than standing alignment parameters. Objective physical metrics likely offer added value to standard spinopelvic measurements in ASD evaluation and surgical planning.

Factors Associated with the Maintenance of Cost-Effectiveness at 5 Years in Adult Spinal Deformity Corrective Surgery.

STUDY DESIGN: Retrospective cohort. OBJECTIVE: To evaluate factors associated with the long-term durability of cost-effectiveness (CE) in ASD patients. BACKGROUND: A substantial increase in costs associated with the surgical treatment for adult spinal deformity (ASD) has given precedence to scrutinize the value and utility it provides. METHODS: We included 327 operative ASD patients with 5-year (5 Y) follow-up. Published methods were used to determine costs based on CMS.gov definitions and were based on the average DRG reimbursement rates. Utility was calculated using quality-adjusted life-years (QALY) utilizing the Oswestry Disability Index (ODI) converted to Short-Form Six-Dimension (SF-6D), with a 3% discount applied for its decline with life expectancy. The CE threshold of $150,000 was used for primary analysis. RESULTS: Major and minor complication rates were 11% and 47% respectively, with 26% undergoing reoperation by 5 Y. The mean cost associated with surgery was $91,095±$47,003, with a utility gain of 0.091±0.086 at 1Y, QALY gained at 2 Y of 0.171±0.183, and at 5 Y of 0.42±0.43. The cost per QALY at 2 Y was $414,885, which decreased to $142,058 at 5 Y.With the threshold of $150,000 for CE, 19% met CE at 2 Y and 56% at 5 Y. In those in which revision was avoided, 87% met cumulative CE till life expectancy. Controlling analysis depicted higher baseline CCI and pelvic tilt (PT) to be the strongest predictors for not maintaining durable CE to 5 Y (CCI OR: 1.821 [1.159-2.862], P=0.009) (PT OR: 1.079 [1.007-1.155], P=0.030). CONCLUSIONS: Most patients achieved cost-effectiveness after four years postoperatively, with 56% meeting at five years postoperatively. When revision was avoided, 87% of patients met cumulative cost-effectiveness till life expectancy. Mechanical complications were predictive of failure to achieve cost-effectiveness at 2 Y, while comorbidity burden and medical complications were at 5 Y.

Analysis of tranexamic acid usage in adult spinal deformity patients with relative contraindications: does it increase the risk of complications?

OBJECTIVE: Complex spinal deformity surgeries may involve significant blood loss. The use of antifibrinolytic agents such as tranexamic acid (TXA) has been proven to reduce perioperative blood loss. However, for patients with a history of thromboembolic events, there is concern of increased risk when TXA is used during these surgeries. This study aimed to assess whether TXA use in patients undergoing complex spinal deformity correction surgeries increases the risk of thromboembolic complications based on preexisting thromboembolic risk factors. METHODS: Data were analyzed for adult patients who received TXA during surgical correction for spinal deformity at 21 North American centers between August 2018 and October 2022. Patients with preexisting thromboembolic events and other risk factors (history of deep venous thrombosis [DVT], pulmonary embolism [PE], myocardial infarction [MI], stroke, peripheral vascular disease, or cancer) were identified. Thromboembolic complication rates were assessed during the postoperative 90 days. Univariate and multivariate analyses were performed to assess thromboembolic outcomes in high-risk and low-risk patients who received intravenous TXA. RESULTS: Among 411 consecutive patients who underwent complex spinal deformity surgery and received TXA intraoperatively, 130 (31.6%) were considered high-risk patients. There was no significant difference in thromboembolic complications between patients with and those without preexisting thromboembolic risk factors in univariate analysis (high-risk group vs low-risk group: 8.5% vs 2.8%, p = 0.45). Specifically, there were no significant differences between groups regarding the 90-day postoperative rates of DVT (high-risk group vs low-risk group: 1.5% vs 1.4%, p = 0.98), PE (2.3% vs 1.8%, p = 0.71), acute MI (1.5% vs 0%, p = 0.19), or stroke (0.8% vs 1.1%, p > 0.99). On multivariate analysis, high-risk status was not a significant independent predictor for any of the thromboembolic complications. CONCLUSIONS: Administration of intravenous TXA during the correction procedure did not change rates of thromboembolic events, acute MI, or stroke in this cohort of adult spinal deformity surgery patients.

Impact of Hip and Knee Osteoarthritis on Full Body Sagittal Alignment and Compensation for Sagittal Spinal Deformity.

STUDY DESIGN: Retrospective review of prospectively collected data. OBJECTIVE: To investigate the effect of lower extremity osteoarthritis on sagittal alignment and compensatory mechanisms in adult spinal deformity (ASD). BACKGROUND: Spine, hip, and knee pathologies often overlap in ASD patients. Limited data exists on how lower extremity osteoarthritis impacts sagittal alignment and compensatory mechanisms in ASD. PATIENTS AND METHODS: In total, 527 preoperative ASD patients with full body radiographs were included. Patients were grouped by Kellgren-Lawrence grade of bilateral hips and knees and stratified by quartile of T1-Pelvic Angle (T1PA) severity into low-, mid-, high-, and severe-T1PA. Full-body alignment and compensation were compared across quartiles. Regression analysis examined the incremental impact of hip and knee osteoarthritis severity on compensation. RESULTS: The mean T1PA for low-, mid-, high-, and severe-T1PA groups was 7.3°, 19.5°, 27.8°, and 41.6°, respectively. Mid-T1PA patients with severe hip osteoarthritis had an increased sagittal vertical axis and global sagittal alignment ( P <0.001). Increasing hip osteoarthritis severity resulted in decreased pelvic tilt ( P =0.001) and sacrofemoral angle ( P <0.001), but increased knee flexion ( P =0.012). Regression analysis revealed that with increasing T1PA, pelvic tilt correlated inversely with hip osteoarthritis and positively with knee osteoarthritis ( r2 =0.812). Hip osteoarthritis decreased compensation through sacrofemoral angle (ß-coefficient=-0.206). Knee and hip osteoarthritis contributed to greater knee flexion (ß-coefficients=0.215, 0.101; respectively). For pelvic shift, only hip osteoarthritis significantly contributed to the model (ß-coefficient=0.100). CONCLUSIONS: For the same magnitude of spinal deformity, increased hip osteoarthritis severity was associated with worse truncal and full body alignment with posterior translation of the pelvis. Patients with severe hip and knee osteoarthritis exhibited decreased hip extension and pelvic tilt but increased knee flexion. This examines sagittal alignment and compensation in ASD patients with hip and knee arthritis and may help delineate whether hip and knee flexion is due to spinal deformity compensation or lower extremity osteoarthritis.

Selective neural inhibition via photobiomodulation alleviates behavioral hypersensitivity associated with small sensory fiber activation.

OBJECTIVE: Photobiomodulation at higher irradiances has great potential as a pain-alleviating method that selectively inhibits small diameter nerve fibers and corresponding sensory experiences, such as nociception and heat sensation. The longevity and magnitude of these effects as a function of laser irradiation parameters at the nerve was explored. METHODS: In a rodent chronic pain model (spared nerve injury-SNI), light was applied directly at the sural nerve with four delivery schemes: two irradiance levels (7.64 and 2.55 W/cm2 ) for two durations each, corresponding to either 4.8 or 14.4 J total energy, and the effect on sensory hypersensitivities was evaluated. RESULTS: At emitter irradiances of 7.64 W/cm2 (for 240 s), 2.55 W/cm2 (for 720 s), and 7.64 W/cm2 (for 80 s) the heat hypersensitivity was relieved the day following photobiomodulation (PBM) treatment by 37 ± 8.1% (statistically significant, p < 0.001), 26% ± 6% (p = 0.072), and 28 ± 6.1% (statistically significant, p = 0.032), respectively, and all three treatments reduced the hypersensitivity over the course of the experiment (13 days) at a statistically significant level (mixed-design analysis of variance, p < 0.05). The increases in tissue temperature (5.3 ± 1.0 and 1.3 ± 0.4°C from 33.3°C for the higher and lower power densities, respectively) at the neural target were well below those typically associated with permanent action potential disruption. CONCLUSIONS: The data from this study support the use of direct PBM on nerves of interest to reduce sensitivities associated with small-diameter fiber activity.

L-cysteine ethylester reverses the adverse effects of morphine on breathing and arterial blood-gas chemistry while minimally affecting antinociception in unanesthetized rats.

L-cysteine ethylester (L-CYSee) is a membrane-permeable analogue of L-cysteine with a variety of pharmacological effects. The purpose of this study was to determine the effects of L-CYSee on morphine-induced changes in ventilation, arterial-blood gas (ABG) chemistry, Alveolar-arterial (A-a) gradient (i.e., a measure of the index of alveolar gas-exchange), antinociception and sedation in male Sprague Dawley rats. An injection of morphine (10 mg/kg, IV) produced adverse effects on breathing, including sustained decreases in minute ventilation. L-CYSee (500 µmol/kg, IV) given 15 min later immediately reversed the actions of morphine. Another injection of L-CYSee (500 µmol/kg, IV) after 15 min elicited more pronounced excitatory ventilatory responses. L-CYSee (250 or 500 µmol/kg, IV) elicited a rapid and prolonged reversal of the actions of morphine (10 mg/kg, IV) on ABG chemistry (pH, pCO2, pO2, sO2) and A-a gradient. L-serine ethylester (an oxygen atom replaces the sulfur; 500 µmol/kg, IV), was ineffective in all studies. L-CYSee (500 µmol/kg, IV) did not alter morphine (10 mg/kg, IV)-induced sedation, but slightly reduced the overall duration of morphine (5 or 10 mg/kg, IV)-induced analgesia. In summary, L-CYSee rapidly overcame the effects of morphine on breathing and alveolar gas-exchange, while not affecting morphine sedation or early-stage analgesia. The mechanisms by which L-CYSee modulates morphine depression of breathing are unknown, but appear to require thiol-dependent processes.

The Case for Operative Efficiency in Adult Spinal Deformity Surgery: Impact of Operative Time on Complications, Length of Stay, Alignment, Fusion Rates, and Patient-Reported Outcomes.

STUDY DESIGN: Retrospective review of prospectively collected data. OBJECTIVE: To analyze the impact of operative room (OR) time in adult spinal deformity (ASD) surgery on patient outcomes. BACKGROUND: It is currently unknown if OR time in ASD patients matched for deformity severity and surgical invasiveness is associated with patient outcomes. MATERIALS AND METHODS: ASD patients with baseline and two-year postoperative radiographic and patient-reported outcome measures (PROM) data, undergoing a posterior-only approach for long fusion (>L1-Ilium) were included. Patients were grouped into short OR time (<40th percentile: <359 min) and long OR time (>60th percentile: >421 min). Groups were matched by age, baseline deformity severity, and surgical invasiveness. Demographics, radiographic, PROM data, fusion rate, and complications were compared between groups at baseline and two years follow-up. RESULTS: In total, 270 patients were included for analysis: the mean OR time was 286 minutes in the short OR group versus 510 minutes in the long OR group ( P <0.001). Age, gender, percent of revision cases, surgical invasiveness, pelvic incidence minus lumbar lordosis, sagittal vertical axis, and pelvic tilt were comparable between groups ( P >0.05). Short OR had a slightly lower body mass index than the short OR group ( P <0.001) and decompression was more prevalent in the long OR time ( P =0.042). Patients in the long group had greater hospital length of stay ( P =0.02); blood loss ( P <0.001); proportion requiring intensive care unit ( P =0.003); higher minor complication rate ( P =0.001); with no significant differences for major complications or revision procedures ( P >0.5). Both groups had comparable radiographic fusion rates ( P =0.152) and achieved improvement in sagittal alignment measures, Oswestry disability index, and Short Form-36 ( P <0.001). CONCLUSION: Shorter OR time for ASD correction is associated with a lower minor complication rate, a lower estimated blood loss, fewer intensive care unit admissions, and a shorter hospital length of stay without sacrificing alignment correction or PROMs. Maximizing operative efficiency by minimizing OR time in ASD surgery has the potential to benefit patients, surgeons, and hospital systems.