Risk factors for early mortality in elderly patients with unstable isolated C2 odontoid fracture treated with halo-vest or surgery

The aim of this study was to compare in-hospital mortality of three procedures –halo-vest immobilization, anterior spinal fixation (ASF), and posterior spinal fixation (PSF)– in the treatment of elderly patients with isolated C2 odontoid fracture. We extracted data for elderly patients who were admitted with C2 odontoid fracture and treated with at least one of the three procedures (halo-vest immobilization, ASF, or PSF) during hospitalization. We conducted a generalized propensity score-based matching weight analysis to compare in-hospital mortality among the three procedures. We further investigated independent risk factors for in-hospital death. The study involved 891 patients (halo-vest, n = 463; ASF, n = 74; and PSF, n = 354) with a mean age of 78 years. In-hospital death occurred in 45 (5.1%) patients. Treatment type was not significantly associated with in-hospital mortality. Male sex (odds ratio 2.98; 95% confidence interval 1.32–6.73; p = 0.009) and a Charlson comorbidity index of ≥ 3 (odds ratio 9.18; 95% confidence interval 3.25–25.92; p < 0.001) were independent risk factors for in-hospital mortality. In conclusion, treatment type was not significantly associated with in-hospital mortality in elderly patients with isolated C2 odontoid fracture. Halo-vest immobilization can help to avoid adverse events in patients with C2 odontoid fracture who are considered less suitable for surgical treatment.

The incidence of C2 odontoid fracture in elderly patients has increased during the past two decades because of expansion of the geriatric population worldwide 1 .In elderly patients, C2 odontoid fracture mostly results from low-energy impacts such as falls 2 .With this increase in the number of elderly patients sustaining C2 odontoid fracture, the number of conservative treatments has increased by two to three times in the last decade 3 .Because most elderly patients have comorbidities and high baseline mortality, optimal management of odontoid fracture has long been a major concern.
We previously reported that most patients with C2 odontoid fracture were elderly and treated conservatively without halo-vest 4 .However, when the fracture is unstable and conservative treatment with a cervical collar is insufficient, we should consider external immobilization using a halo-vest or surgical treatment involving anterior spinal fixation (ASF) or posterior spinal fixation (PSF) 5 .Although a halo-vest is widely used for conservative treatment, several studies showed that halo-vest immobilization had worse survival outcomes than surgery 6 .The mortality rate of elderly people treated with halo-vest ranged from 16 to 42%; thus, halo-vest was considered less suitable for elderly patients than young patients 7 .In contrast, several other studies showed no association between the treatment type and clinical outcome 2,8 .This controversy makes it difficult for clinicians to select the optimal treatment for patients with unstable odontoid fracture, especially in elderly patients who are likely to have several comorbidities.

Patient selection
From July 2010 to March 2017, we screened all patients who were admitted with C2 fracture (ICD-10 code: S12.1) and further identified odontoid fracture using Japanese disease codes.The inclusion criteria were age of ≥ 65 years and admission for treatment of odontoid fracture by at least one of three procedures (halo-vest immobilization (K1444), ASF(K142-1), or PSF (K142-2)) during hospitalization.We excluded patients with multiple fractures (any fractures other than odontoid fractures), with severe consciousness disturbance at admission, who underwent combined surgery (both ASF and PSF), or who died within 2 days of admission.The patients who were treated with halo-vest before or after ASF or PSF were included in the surgery group.
The primary endpoint was overall in-hospital mortality.The secondary endpoints were at least one complication after admission, post-treatment length of stay (PLOS), and total hospitalization cost in US dollars (USD).We identified complications after admission from the diagnoses recorded after admission using the following ICD-10 codes and defined at least one complication as at least one of the following complications during hospitalization: sepsis (A40-A41), pulmonary embolism (I26), respiratory complications [pneumonia (J12-J18, J69), respiratory failure (J96), respiratory disorders (J95)], acute coronary syndrome (I21-I24), heart failure (I50), stroke (I60-I64), urinary tract infection (N30, N34, N36-N37, N39), and renal failure (N17-N19).PLOS was defined as the length of stay from the day treated with halo-vest, ASF, or PSF to discharge (or death).Total hospitalization cost includes item-by-item prices for surgical, pharmaceutical, laboratory, nursing care, and other inpatient services, that are offered by universal health care in Japan.The currency exchange rate was set at 100 Japanese yen per USD to account for the average rate of the study period.

Statistical analysis
We used a propensity score-based method to account for differences in observed factors that might affect either the treatment assignment or outcome 16 .The propensity score was defined as the probability of a patient undergoing halo-vest immobilization, ASF, or PSF based on the patient's baseline covariates.Covariate selection was prespecified by using both potential confounding factors and variables that can serve as proxies for unknown or unmeasured confounding variables.The propensity score was estimated using a multinomial logistic model with the procedure received as the dependent variable and the following baseline factors as independent variables 17 : age; sex; BMI category; smoking status; ambulance use; emergency admission; admission to intensive care unit before treatment; oxygenation therapy before treatment; use of urinary catheter; pre-existence of diabetes mellitus, hypertension, or chronic lung disease; history of cerebrovascular disease, cardiac disease, hepatic disease, dementia, or osteoporosis; at least one comorbidity; Japan Coma Scale score category; Barthel index; and CCI category on admission.
To balance the patients' baseline characteristics among the three procedures, a matching weight approach was applied 18 .Matching weights is recommended for comparing outcomes across multiple treatment groups when the covariates' overlaps are relatively limited, outcomes are rare, or exposure distributions are unequal 19 .Each patient was weighted by the inverse probability with the lower propensity score of the three procedures as the numerator 19 .The patients would receive each of the treatments among halo-vest immobilization, ASF, or PSF, allowing average treatment effects to be estimated.Baseline covariate balance was checked after weighting, using a p value of > 0.05 calculated by analysis of variance or the chi-squared test among the three treatments.
We compared the following outcomes among the three groups (halo-vest immobilization, ASF, and PSF) using analysis of variance and the chi-square test in the matching weighted cohort: overall in-hospital death, complications after admission, PLOS, total hospitalization costs, and Barthel index at discharge.We further conducted logistic regression analyses to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) for overall in-hospital death and at least one complication after admission.We also conducted a linear regression analysis to estimate the regression coefficient and 95% CI for the PLOS.Moreover, we conducted a multivariable logistic regression analysis with adjustment for age, sex, BMI category, smoking status, and CCI category in the non-weighted and weighted cohorts to identify risk factors for in-hospital death.The following sensitivity analyses were undertaken to assess the robustness of the results.We combined the ASF and PSF groups as the surgery group and compared halo-vest immobilization with the surgery group using propensity score-matching analysis and matching weight analysis to balance the baseline variables.
Statistical analyses were performed using Stata/MP version 15 software (StataCorp, College Station, TX, USA).A two-tailed significance level of p < 0.05 and 95% CIs were used in the analyses.

Ethical approval
The study design was approved by the Institutional Review Board of The University of Tokyo.

Consent to participate
The requirement for informed consent was waived because of the anonymous nature of the data.

Results
We finally included 891 patients (halo-vest, n = 463; ASF, n = 74; and PSF, n = 354) with isolated C2 odontoid fracture (Fig. 1).More than half of the patients underwent halo-vest immobilization.Table 1 shows the patients' baseline characteristics before and after matching weight.Overall, 366 patients (41%) were male, and their mean age was 78 ± 7.5 years.Navigation was used in 115 patients among the surgical groups (ASF: 8/74, 11%; PSF: 107/354, 30%).Despite significant differences in emergency admission, ambulance use, urinary catheter use on admission, and Barthel index on admission, the weighted cohort became well balanced for the recorded baseline variables.
Table 2 shows the clinical outcomes among the treatments before and after weighting.Overall and 30-day in-hospital death occurred in 45 (5.1%) and 10 (1.1%) patients, respectively.The proportion of patients with at least one complication was 15%, and the most common complications after admission were respiratory complications (7.4%).The halo-vest group had a significantly longer PLOS than the ASF and PSF groups and significantly lower total costs than the PSF group.Univariable analysis in the weighted cohort showed that (i) in-hospital death was higher in the halo-vest group (6.6%) than the ASF (4.1%) and PSF (4.7%) groups with no significant difference, (ii) at least one complication was not significantly different among the treatments, and (iii) the PLOS was significantly longer in the halo-vest group than in the ASF or PSF group.Regarding complications after admission in the weighted cohort, the proportion of respiratory complications, cardiac events, and stroke were lower in the halo-vest group than in the ASF or PSF group.
Table 3 shows the results of logistic regression and linear regression analyses of the main outcomes before and after matching weight.In the weighted cohort, there was no significant difference in overall in-hospital death between the halo-vest group and the ASF group (OR 0.60; 95% CI 0.17-2.07;p = 0.42) or PSF group (OR 0.70; 95% CI 0.35-1.44;p = 0.34).Although there was no significant difference in patients who developed at least one complication among the procedures, halo-vest immobilization was significantly associated with a longer PLOS than ASF (regression coefficient, − 25 days; 95% CI − 32.9 to − 17.5; p < 0.001) and PSF (regression coefficient, − 25 days; 95% CI − 29.6 to − 19.7; p < 0.001).
Figure 2 shows the results of the multivariable logistic regression analysis for in-hospital death before and after weighting.Male sex and a higher CCI category were independent risk factors for in-hospital mortality (male sex: OR 3.02; 95% CI 1.47-6.22;p = 0.003; CCI category 2: OR 3.61; 95% CI 1.65-7.92;p = 0.001; CCI of ≥ 3: OR 9.18; 95% CI 3.25-25.92;p < 0.001).The results of the sensitivity analyses were similar to those of the main analyses (Appendix Tables S1-S6).

Discussion
We used a nationwide database and conducted a propensity score-based matching weight analysis to compare clinical outcomes of halo-vest immobilization, ASF, and PSF for elderly patients with isolated C2 odontoid fracture.In-hospital mortality and the development of at least one complication were not significantly different among the three procedures, whereas the PLOS was longer in the halo-vest group than in the surgery groups.Male sex and a higher CCI were independent risk factors for in-hospital mortality.
Halo-vest has been considered to be associated with higher mortality than surgical treatment in patients with C2 odontoid fracture, especially elderly patients 7,20 .Furthermore, in the latest meta-analysis, conservative treatment showed a trend toward higher mortality than surgical treatment 21 .The present study also showed relatively higher mortality in the halo-vest group than in the ASF or PSF group.However, halo-vest immobilization was not an independent risk factor for in-hospital death.One reason for higher mortality with conservative treatment may be selection bias due to limited settings of the target population.Most previous studies may have www.nature.com/scientificreports/included critically ill patients with C2 fracture who could not be treated surgically.Furthermore, the sample sizes were small, even in the meta-analysis 1,2,7 .According to our results, the difference in in-hospital mortality between halo-vest immobilization and surgery may be slight.Halo-vest immobilization can be an option for C2 odontoid fracture if the patient cannot be treated surgically even when the fracture should be initially stabilized with surgery.
Respiratory complications are a cause of increased mortality of elderly patients who undergo halo-vest immobilization, and surgical treatment can reportedly decrease the incidence of pneumonia, cardiac arrest, and respiratory failure 6 .However, several studies showed no significant difference in complications between conservative and surgical treatment 6,8 .In the present study, complications including pneumonia, heart failure, and stroke were less common in the halo-vest group than in the ASF and PSF groups.Respiratory and cardiac complications can also occur as a result of surgery or general anesthesia, especially in elderly patients, who tend to have higher comorbidities and lower cardiac function 22 .Because surgical treatment may have more complications than halo-vest immobilization in elderly patients, careful attention is needed to avoid adverse events after surgical treatment of C2 odontoid fracture.
Optimal treatment for odontoid fracture has been discussed over the years.Previous studies have revealed that surgical treatment is more effective than conservative treatment for inducing bony fusion 23 .However, fibrous fusion is a more acceptable outcome than morbidity or mortality associated with surgery 23 .Thus, osseous union is not a prerequisite to obtaining satisfactory clinical outcomes in elderly patients.Additionally, the association between bony fusion and mortality remains inconsistent if neurological complications are absent 23 .In the present study, male sex and a higher CCI were strongly associated with in-hospital death in patients with isolated C2 odontoid fracture.Among elderly patients, pre-existing comorbidities themselves can be associated with mortality 24 .A comprehensive decision is necessary regardless of treatment type for C2 odontoid fracture, especially in terms of age, sex, and comorbidities.
This study has several limitations.First, we could not obtain data on the type of fracture, severity of instability, degree of dislocation, or surgical techniques details from the database.Second, despite using propensity score-based analysis, unmeasured confounding may not have been completely removed.The above-mentioned We screened all patients who were admitted with C2 fracture (ICD-10 code: S12.1) and further identified odontoid fracture with the Japanese disease code.After excluding patients who were treated conservatively without halo-vest and who were aged < 65 years, we further excluded patients who had severe consciousness disturbance, had multiple injuries, and died within 2 days after admission to exclude critically ill patients.Finally, 891 patients with isolated C2 odontoid fracture were identified (halo-vest, n = 463; ASF, n = 74; PSF, n = 354).ICD-10, International Classification of Diseases, 10th revision; ASF, anterior spinal fixation; PSF, posterior spinal fixation.

Figure 2 .
Figure 2. Risk factors for in-hospital death.Non-weighted and weighted ORs for each subgroup are shown.ORs and 95% CIs were obtained by multivariable logistic regression analysis adjusted by procedure, age category, sex, BMI category, smoking status, and CCI category.The square and horizontal bars represent the mean difference and 95% CI, respectively.OR, odds ratio; CI, confidence interval; ASF, anterior spinal fixation; PSF, posterior spinal fixation; BMI, body mass index; CCI, Charlson comorbidity index.

Table 1 .
Baseline characteristics of patients with isolated C2 odontoid fracture before and after matching weight.Data are presented as n (%), mean ± standard deviation, or median (interquartile range).ASF, anterior spinal fixation; PSF, posterior spinal fixation; BMI, body mass index; ICU, intensive care unit; JCS, Japan Coma Scale; CCI, Charlson comorbidity index.

Table 2 .
Clinical outcomes of patients before and after inverse probability treatment weighting.Data are presented as n (%), mean ± standard deviation, or median (interquartile range).ASF, anterior spinal fixation; PSF, posterior spinal fixation.

Table 3 .
Logistic regression and multiple linear regression models of main outcomes before and after weighting.ASF, anterior spinal fixation; PSF, posterior spinal fixation; SE, standard error.