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Nitrous Oxide for the Treatment of Chronic Low Back Pain

Turan, Alparslan MD*; Sarwar, Sheryar MD*; Atim, Abdulkadir MD*; Deogaonkar, Anupa MD; Yousef, Hani F. MD, PhD*; Katyal, Sumit MD†‡; Liu, Jinbo MD*; You, Jing MS*; Leizman, Daniel MD; Mekhail, Nagy MD, PhD; Sessler, Daniel I. MD*

doi: 10.1213/ANE.0000000000000951
Pain Medicine: Research Report

BACKGROUND: Neuropathic back pain is mediated, at least partially, by N-methyl-D-aspartate (NMDA) receptors. Nitrous oxide (N2O) is an NMDA receptor antagonist. We therefore tested the primary hypothesis that patients receiving N2O have lower pain scores after epidural steroid injection than patients not receiving N2O.

METHODS: Patients with recurrent low back pain scheduled for epidural steroid blocks were randomly assigned to receive either oxygen (O2, n = 39) or the combination of 50% O2 and 50% N2O during and after each block (N2O, n = 39). Before each injection and at a 3-month follow-up visit, patients completed questionnaires: Oswestry survey, 12-Item Short Form Health Survey questionnaire, Leeds Assessment of Neuropathic Symptoms and Signs pain scale, and Visual Analog Scale. Total opioid use per 24 hours was recorded. The serum samples for tumor necrosis factor-α, interleukin (IL)-6, interferon-γ, IL-10, IL-17A, and IL-1β assays were collected at every visit and evaluated. Standard descriptive statistics were used to compare the randomized groups on baseline variables. Any imbalanced covariates with an absolute standardized difference >0.44 were adjusted for in both primary and secondary analyses. Both modified intention-to-treat and per-protocol analyses were conducted for our outcomes. Our secondary analyses were per protocol.

RESULTS: in patients given N2O (mean [SD], −1.6 [3.0] cm) and O2 (−1.2 [2.6] cm), with difference −0.13 (95% confidence interval: −1.43, 1.17), N2O − O2; P = 0.84. No difference was found between the 2 randomized groups on changes in Leeds Assessment of Neuropathic Symptoms and Signs pain score, Oswestry score, or 12-Item Short Form Health Survey from baseline, or in satisfaction with the procedure, satisfaction with pain treatment, or use of opioid overtime. Overall, no significant differences on any cytokine were found between the 2 groups. The estimated odds ratios of taking opioid was 0.46 (0.12, 1.84) (N2O versus O2; P = 0.12).

CONCLUSIONS: N2O administration did not improve pain or psychological or physical aspects of health-related quality of life. N2O does not appear to be an effective treatment for chronic neuropathic back pain.

From the *Department of Outcomes Research, Cleveland Clinic; Cleveland Clinic; and Department of Pain, Anesthesiology Institute, Cleveland Clinic, Cleveland, Ohio.

Sheryar Sarwar, MD, is currently affiliated with University Hospitals of Cleveland, Cleveland, Ohio.

Abdulkadir Atim, MD, is currently affiliated with Gulhane Military Medical Academy, Ankara, Turkey.

Anupa Deogaonkar, MD, is currently affiliated with Ohio State University, Columbus, Ohio.

Sumit Katyal, MD, is currently affiliated with Texas Pain Relief Group, Plano, Texas.

Jinbo Liu, MD, is currently affiliated with Case Western Reserve University, Cleveland, Ohio.

Accepted for publication June 23, 2015.

Funding: Institutional and/or departmental.

The authors declare no conflicts of interest.

Reprints will not be available from the authors.

Address correspondence to Alparslan Turan, MD, Cleveland Clinic, 9500 Euclid Ave., P-77, Cleveland, OH 44195. Address e-mail to turana@ccf.org; www.OR.org.

Low back pain is the fifth most common presenting complaint for physician office visits in United States; furthermore, it is the most common disorder requiring invasive treatment.1 Low back pain is associated with reduced functional performance, psychological stress, and diminished quality of life. The pathophysiology of low back pain is complex and includes both nociceptive and neuropathic components,2 but neuropathic pain is thought to be the primary cause.3 Chronic low back pain is associated with elevated plasma and cerebrospinal fluid concentrations of interleukin (IL)-1β, IL-2, IL-6, interferon (IFN)-γ, and tumor necrosis factor-α (TNF-α), which suggests an inflammatory component.4–9

N-Methyl-D-aspartate (NMDA) receptors (NMDARs) are ionotropic glutamate receptors with multiple subunits that are believed to be involved in the onset and maintenance of neuropathic pain.10 In chronic pain states, NMDARs promote central sensitization and “windup” in the dorsal horn of spinal cord.11,12 Short-term NMDAR blocks may, in fact, downregulate the central sensitization, resulting in a long-lasting antiallodynic effect.13 Similarly, pain relief with NMDAR antagonists far exceeds the duration of meaningful drug quantities at the receptor, suggesting an indirect mechanism for neuropathic analgesia.14–17 Even short exposures to NMDAR antagonists can thus have long-lasting analgesic effects.

Nitrous oxide (N2O), an NMDAR antagonist,18,19 produces moderate analgesia at subanesthetic concentrations. N2O promotes the release of opioid peptides in the periaqueductal brainstem, activating descending noradrenergic inhibitory pathways via γ-aminobutyric acid—thus reducing nociception at spinal cord level.20 N2O exposure is also associated with reduced persistent surgical pain that is thought to have a substantial neuropathic component.21 However, in this study, the surgical insult at the time of N2O inhalation is much less intense (and might even be a nonissue). Furthermore, a single exposure to N2O facilitates postinjury pain management and rehabilitation and ameliorates even severe neuropathic pain.22 Few studies, however, focus on patients with preexisting chronic neuropathic pain.

N2O may thus ameliorate chronic back pain by blocking NMDARs and/or reducing inflammation and consequent cytokine release. However, whether exposure produces a clinically important benefit remains unknown. We therefore tested the primary hypothesis that patients receiving N2O have lower pain scores after epidural steroid injection than patients not receiving N2O. Our secondary hypotheses were that patients given N2O have fewer neuropathic symptoms and signs, use less opioid analgesic, have lower blood concentrations of inflammatory biomarkers, and have better functional capacity than patients not receiving N2O.

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METHODS

With approval of the Institutional Ethics Committee (Cleveland Clinic, Cleveland) and written consent from participating patients, we studied 78 adults with recurrent low back pain and radicular pain scheduled for lumbar epidural steroid block. The trial was registered at ClinicalTrials.gov (NCT01172600).

Patients eligible for participation were between 18 and 80 years old and had a history of low back pain lasting at least 6 months due to radiculopathy, symptomatic spinal canal stenosis, disk prolapse, or postlaminectomy syndrome. They had minimal evidence of facet joint pathology and Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) scores >12.23

Patients were excluded if they had a known allergy to steroids, sensitivity to N2O, or contraindications to epidural injection or steroids. Patients were also excluded if they had received epidural blocks in the previous year, active workers’ compensation claims, or fluctuating or substantial opioid use (≥400 mg of morphine equivalents daily), psychiatric disorders, drug or alcohol abuse within 6 months, severe medical illness that could interfere with the interpretation of study outcomes, myocardial infarction (MI) within 6 months, or pregnancy.

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Protocol

A Web-based randomization system was used to assign patients 1:1 without stratification to either inhaled N2O and O2 or O2 alone during their epidural injections and continuing thereafter for a total of 2 exposure hours. The Web system was activated after written consent had been obtained and shortly before each procedure, thus concealing allocation as long as practical. A combination of N2O (50%) and O2 or O2 alone was given via a Food and Drug Administration–approved mask breathing circuit (MXR Flowmeter, Porter, Hatfield, PA). Patients and study personnel following the patient were blinded to N2O or O2 allocation. An unblinded investigator, otherwise uninvolved in data collection, adjusted the machine and covered it to mask clinicians and patients.

Patients were given 1 to 4 mg of midazolam for anxiolysis and positioned prone. If needed, 50 to 100 µg IV fentanyl was also given. Epidural steroid injections were completed under fluoroscopy, and radiopaque contrast was used to confirm proper positioning of the epidural needle. Steroids and local anesthetics were then injected at the discretion of the blinded physician performing the block. Thereafter, inhalation of the study drug continued for a total of 2 hours. After a suitable period of monitored recovery, patients were discharged home with standard instructions for back exercises.

Epidural injections were repeated up to 3 times at the discretion of blinded pain physician, typically at 1-month intervals. When patients returned for follow-up treatments, the original allocation to N2O and O2 or O2 alone was maintained, again with 2-hour exposures to the study gas.

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Measurements

Before each epidural steroid injection, and at a 3-month follow-up visit, patients completed a set of questionnaires that included (1) modified Oswestry for evaluating functional disability24; (2) 12-Item Short Form Health Survey (SF-12) questionnaire for functional health and well-being; (3) LANSS pain scale23; and (4) 10-cm-long Visual Analog Scale. Potential side effects of N2O were monitored and recorded, including nausea, vomiting, desaturation, sedation, and dizziness.

Opioids were converted to IV morphine equivalents, with the amount of each drug being reduced by its route-dependent bioavailability. The total amount of opioid drug use in a 24-hour period for the last week was recorded. Total amounts of nonsteroidal antiinflammatory drugs and muscle relaxants for back pain were also recorded. Patients were questioned at each visit about their satisfaction with the procedure and pain treatment.

The serum samples from patients were stored at −80°C. Twenty-five microliters of serum from each patient was used for the 6 types of cytokine (TNF-α, IL-6, IFN-γ, IL-10, IL-17A and IL-1β) analysis according to the MILLIPLEX protocol by human multiple cytokine kits (EMD Millipore Co, Billerica, MA). The cytokine assay method itself is >90% accurate.

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Statistical Analysis

Standard descriptive statistics of baseline variables were reported. Absolute standardized difference (ASD) was used to compare the randomized groups on baseline variables. Any imbalanced covariates with an ASD >0.44 (i.e.,

CV

CV

) were adjusted for in both primary and secondary analyses. Both intention-to-treat and per-protocol analyses were conducted for our primary outcome. In the intention-to-treat analysis, all participants who were randomly assigned were included in the final analysis, regardless of withdrawals or lost to follow-up. While in the per-protocol analysis, only patients who completed follow-up assessments were analyzed. Our secondary analyses were per-protocol.

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Primary Aims

We compared the randomized groups on change in Verbal Analog Scale (VAS) pain score (range, 0 no pain to 10 worst pain imaginable) from baseline (before the first epidural) to 3-month follow-up after the final block, while adjusting for VAS at the baseline, number of epidural blocks received, and imbalanced baseline variables as covariates in an analysis of covariance (ANCOVA). The primary analysis was on an intention-to-treat basis. For patients missing the 3-month follow-up, we assigned the outcome as follows: for patients who had second or the third epidural block, we assigned the last VAS observation (i.e., from VAS before second or third block to 3-month follow-up); and for patients who only had the first epidural block, we assigned the worst value (i.e., 10) for the N2O patients and the best value (i.e., 0) for the O2 patients. In addition, we conducted a per-protocol analysis, which was restricted to patients who received the intervention and had all outcome assessments.

As a secondary analysis, we compared N2O patients and O2 patients on change in VAS pain sore over time: from baseline (before the first epidural block) to second epidural block, from baseline to third epidural block, and from baseline to 3-month follow-up after last block, using ANCOVA with repeated measures. VAS pain score at the baseline and imbalanced baseline variables was adjusted for in the analysis. P < 0.017 was considered statistically significant (i.e., 0.05/3, Bonferroni correction).

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Secondary Aims

Our secondary outcomes include LANSS pain score, percentage of disability and pain intensity of Oswestry score, SF-12, use of opioids, satisfaction with procedure, satisfaction with pain treatment, and proinflammatory cytokines related to the pathogenesis of chronic low back pain. The overall significance level was 0.006 for each outcome (i.e., 0.05/8, Bonferroni correction); further corrections were made appropriately for multiple comparisons for different assessment times within each outcome.

The treatment effect on change in LANSS pain scale score, Oswestry score, and SF-12 over time was assessed, using ANCOVA with repeated measures with adjustment for the corresponding measurement at the baseline and imbalanced baseline variables as covariates. The global treatment effect over time on 3 binary outcomes (satisfaction with procedure and with pain treatment and usage of opioids) was assessed using a generalized estimating equation model with compound symmetry covariance matrix.

We compared the 2 randomized groups on change in proinflammatory cytokines over time (after logarithm transformation), including IL-1β, IL-6, IL-10, IL-17A, IFN-γ, and TNF-α, using ANCOVA with repeated measures accounting for within-subject correlation, adjusting for the corresponding baseline cytokine value and any imbalanced baseline variables. P < 0.008 was considered significant for each comparison (i.e., 0.01/6 = 0.0017; Bonferroni correction). Next, we estimated the Pearson correlations between each of the 6 cytokines and VAS pain score at baseline.

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Sample Size Considerations

The sample size was based on being able to detect differences of 1.5 cm or more in the mean VAS of the N2O and no N2O groups using ANCOVA on the outcomes at the follow-up before the second epidural (previous publications reported 1.324 cm difference in VAS as minimum clinically significant change and combined with our experience we chose a more conservative number). Using an SD estimate of 2 cm for VAS (based on experience and literature) with standard type I and type II error rates (a = 0.05, b = 0.10), 39 patients per group were needed (total sample size of 78 patients). SAS 9.3 software (SAS Institute, Cary, NC) was used for all analyses and graphics.

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RESULTS

We enrolled 78 patients with recurrent low back pain and radicular pain who were scheduled for lumbar epidural injections. Seventy-four percent of patients in nitrous oxide group (29 out of 39) returned for a second injection and 46% (18 out of 39) returned for third. Among the 21 patients who did not complete 3 injections, 3 patients were lost at follow-up, 8 patients were satisfied with the pain treatment from the last block treatment, and 10 patients were not satisfied. In the oxygen group, 72% (28/39) returned for a second injection, and 33% (13/39) returned for a third epidural steroid injection. Twenty-six patients did not complete 3 injections, including 2 lost follow-ups, 2 withdraws, 12 patients who were satisfied with the pain treatment from the last block treatment, and 10 patients who were not satisfied.

Table 1

Table 1

Patients randomized to N2O and O2 were well balanced, with ASD < 0.44 on most of the baseline characteristics (Table 1), except for ASA physical status (ASD = 0.55) and previous MI (ASD = 0.54). We therefore adjusted for each covariable in our between-group comparisons.

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Intention-to-Treat Analysis

Table 2

Table 2

Three patients withdrew and 7 were lost to follow-up (5 patients in each group). Among these 10 patients with missing VAS at the 3-month follow-up, we assigned the last observed VAS pain score to 5 patients, a VAS of 10 to 2 N2O patients and a VAS of 0 to 3 O2 patients. No difference was found in the change of VAS pain score from baseline to the 3-month period after the final epidural injection between the 2 groups (P = 0.84), after adjusting for baseline VAS pain score, number of epidural blocks, ASA physical status, and MI. The estimated mean difference in the change in VAS was −0.13 (95% confidence interval [CI]: −1.43, 1.17; N2O − O2; Table 2).

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Per-Protocol Analysis

Among the 68 patients who completed follow-up assessments, the estimated mean change in VAS pain score from baseline to 3 months after the final epidural injection was −1.4 (SD, 2.8) cm. No difference was found in the change in VAS between patients given N2O (mean [SD]: −1.6 [3.0] cm) and O2 alone (−1.2 [2.6] cm), after the same covariable adjustment (difference: −1.03 [95% CI: −2.34, 0.28], N2O − O2; P = 0.12; Table 2). Furthermore, the between-group differences on treatment effect on controlling pain (i.e., change in VAS pain score from baseline) were consistent over time (time-by-group interaction: P = 0.53; Fig. 1). On average, VAS pain scores changed less from baseline in N2O patients than in those given O2: 0.71 lower (95% CI: 1.68 lower, 0.27 higher, P = 0.15; Table 2).

Figure 1

Figure 1

Based on 68 patients with follow-up assessment, the estimated mean change from baseline to 3 months after the final epidural injection was −2.3 (SD, 5.7) for the LANSS pain score, −8% (20%) for the Oswestry score (percent of disability), −0.74 (1.8) for the Oswestry score (pain intensity), 4.7 (12.5) for the physical component of SF-12, and 5.6 (13.1) for the mental component of the SF-12.

No difference was found between the 2 randomized groups on the change in LANSS pain score (P = 0.40), Oswestry score (percentage of disability, P = 0.40 and pain intensity, P = 0.29), or SF-12 (physical component, P = 0.14 and mental component, P = 0.11) from baseline overtime or satisfaction with procedure (P = 0.02), satisfaction with pain treatment (P = 0.55), or usage of opioid overtime (P = 0.12) (Table 3; Fig. 2). The estimated average change over time was −0.92 (99.4% CI: −4.04, 2.19) in LANSS pain score in the N2O group (versus O2 group), −3.15 (−13.7, 7.38) in percentage of disability of Oswestry score, 0.34 (–0.56, 1.24) in pain intensity of Oswestry score, 2.83 (−3.05, 8.70) in physical component of SF-12, and 3.12 (−3.07, 9.31) in mental component of SF-12 (Table 3).

Table 3

Table 3

Figure 2

Figure 2

The estimated odds ratios of satisfying with previous procedure and previous pain treatment were 4.11 (0.83, 20.5) and 1.29 (0.41, 4.06) (N2O versus O2 patients), respectively. The estimated odds ratios of taking opioid were 0.46 (0.12, 1.84) for N2O patients compared with O2 patients (Table 3). The between-group difference in change of any of these outcomes from baseline was consistent over time (minimum time-by-group interaction P = 0.33; Fig. 2).

The between-group difference in any of those cytokines from measurement to measurement (at the follow-up before the second and third blocks) was consistent (all time-by-group interaction P > 0.27; Fig. 3). Overall, no significant difference on any cytokine was found between the 2 groups after adjusting for the corresponding baseline cytokine value, ASA physical status, and previous MI (Table 4). Furthermore, VAS pain scores were not significantly correlated with any of the proinflammatory cytokines evaluated at baseline in our study (all P > 0.05; Table 5). The estimated Pearson correlations were all weak, ranging from −0.11 to −0.23 (Table 5).

Table 4

Table 4

Table 5

Table 5

Figure 3

Figure 3

No N2O/O2 side effects were reported. None of the patients experienced nausea and vomiting, desaturation, sedation, or dizziness.

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DISCUSSION

Our main findings are that N2O, given as an adjunct to epidural steroid injections, did not decrease pain, improve functional capacity, or reduce neuropathic symptoms and signs.

Independent of randomized allocation, VAS pain scores were reduced by an average of 1.4 ± 2.8 cm 3 months after the final epidural steroid injection. This result suggests that only a decrease of 1.4 from a starting VAS of 6 suggests minimal efficacy, especially as that small reduction may well have occurred without treatment in these spinal stenosis patients. This is consistent with a recent study by Friedly et al.25 demonstrating that epidural injections offered minimal or no benefit in the treatment of lumbar spinal stenosis. The small improvement we observed in both groups might be because of a minor therapeutic effect of the injections but might equally well have resulted from placebo effect or resolution of back problems.

N2O alleviates long-term pain in animal and human studies.22,26,27 Pain scores were nonetheless similar 3 months after the final epidural injections in both our groups. Lack of efficacy in our model of treatment for chronic pain differs from an ancillary study of the ENIGMA 1 trial in which Chan et al.21 demonstrated that N2O reduces the risk of developing persistent incisional pain by a factor-of-2. Important differences between the studies are that we used N2O as a treatment for established pain rather than to prevent development of persistent pain and that we used only 50% N2O rather than 75%.

The Oswestry Disability Index is the most commonly used quantification of low back pain intensity and functional impairment.24 There was 11% decrease in disability from baseline in N2O patients and 6% decrease in O2 patients, a difference that was neither statistically significant nor clinically important. The pain component of Oswestry also did not differ. SF-12 and LANSS scores were also comparable, further supporting our primary result. N2O patients were, by a factor-of-4, more satisfied with the combination of previous procedures and 29% more likely to be satisfied with the combination of previous pain treatment compared with O2 patients. This result was surprising because N2O did not have a favorable effect on pain and functional outcomes. Enhanced satisfaction with N2O may have been because of the drug’s well-established anxiolytic effect.28

Although statistically insignificant, N2O administration decreased opioid requirements; a result that is unsurprising because animal studies clearly show that N2O is an NMDA antagonist.29 Central sensitization plays an important role in neuropathic pain, and NMDAR antagonists reduce sensitization.11,12 Ketamine, like N2O, is also an NMDAR antagonist and has been found to decrease pain and opioid consumption postoperatively in opiate-dependent patients.30 N2O is also antinociceptive via activation of supraspinal opioid receptors, as well as dopaminergic and noradrenergic neurons.29,31,32 N2O also inhibits voltage-dependent calcium channels.33 The effect on opioid use may result from a direct antagonist effect on NMDARs, previously mentioned mechanisms, and/or from potentiating other analgesic drugs used to treat the neuropathic component of low back pain. Future adequately powered studies for opioid consumption are warranted in neuropathic pain models.

Low back pain has been associated with an imbalance in immune inflammatory environment.34,35 For example, disk degeneration, angiogenesis, and nerve in growth in animal models of low back pain are associated with increased cytokine concentrations, particularly TNF-α, IL-1, and IL-6.34–37 As one might thus expect, chronic back pain is relieved both by local injections of steroids and systemic nonsteroidal antiinflammatory medications. However, we were unable to show any association between baseline proinflammatory cytokines and VAS pain score. The most obvious explanation is that local inflammation is prominent and is poorly reflected by systemic cytokine concentrations. Another possible explanation might be that inflammatory cytokines may not be prominent in chronic conditions when compared with acute events. There were also no significant differences in proinflammatory cytokines between N2O and O2 group, although previous studies in surgical patients have demonstrated that inflammatory cytokines decrease after N2O exposure. The absence of difference observed in our study may have resulted from different dosing or application times, and there was much less surgical trauma in our study.

Although N2O can cause side effects, we did not observe any. This is consistent with a previous randomized clinical trial showing that 50% N2O does not predispose parturient to desaturation, nausea, or vomiting.38 For practical reasons, each N2O exposure was restricted to 50% for 2 hours; higher concentrations and/or longer exposure may prove more effective. For example, ketamine, which is a more potent NMDA antagonist, is effective for both acute surgical and chronic neuropathic pain.39–41

In summary, N2O is an NMDAR antagonist and has other actions likely to ameliorate chronic neuropathic pain. Nonetheless, 2 hours of N2O exposure during and after 1, 2, or 3 epidural injections for chronic low back pain did not significantly reduce pain scores, improve functional capacity, or reduce neuropathic symptoms and signs. Opioid use was halved by N2O, but it seems unlikely that reduced opioid intake alone justifies the effort and expense of N2O administration.

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DISCLOSURES

Name: Alparslan Turan, MD.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Attestation: Alparslan Turan has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Sheryar Sarwar, MD.

Contribution: This author helped conduct the study and write the manuscript.

Attestation: Sheryar Sarwar has seen the original study data and approved the final manuscript.

Name: Abdulkadir Atim, MD.

Contribution: This author helped conduct the study and write the manuscript.

Attestation: Abdulkadir Atim has seen the original study data and approved the final manuscript.

Name: Anupa Deogaonkar, MD.

Contribution: This author helped conduct the study.

Attestation: Anupa Deogaonkar has seen the original study data and approved the final manuscript.

Name: Hani F. Yousef, MD, PhD.

Contribution: This author helped conduct the study and write the manuscript.

Attestation: Hani F. Yousef has seen the original study data and approved the final manuscript.

Name: Sumit Katyal, MD.

Contribution: This author helped design the study, conduct the study, and write the manuscript.

Attestation: Sumit Katyal has seen the original study data and approved the final manuscript.

Name: Jinbo Liu, MD.

Contribution: This author helped conduct the study and write the manuscript.

Attestation: Jinbo Liu has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Jing You, MS.

Contribution: This author helped design the study, analyze the data, and write the manuscript.

Attestation: Jing You has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.

Name: Daniel Leizman, MD.

Contribution: This author helped design the study, conduct the study, and write the manuscript.

Attestation: Daniel Leizman has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Nagy Mekhail, MD, PhD.

Contribution: This author helped design the study, conduct the study, and write the manuscript.

Attestation: Nagy Mekhail has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Daniel I. Sessler, MD.

Contribution: This author helped design the study, analyze the data, and write the manuscript.

Attestation: Daniel I. Sessler has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

This manuscript was handled by: Spencer S. Liu, MD.

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