Identi cation of Risk Factors For Mortality and Delayed Oral Dietary Intake In Patients With Open Drainage Due To Deep Neck Infections: A Nationwide Study Using A Japanese Inpatient Database

Hiroshi Hidaka (  zay00015@nifty.com ) Kansai Medical Unversity https://orcid.org/0000-0001-5214-3159 Kunio Tarasawa Department of Health Administration and Polocy, Tohoku University Graduate School of Medicine Kenji Fujimori Department of Health Administration and Policy, Tohoku University Graduate School of Medicine Taku Obara Tohoku Medical Megabank Organization Kiyohide Fushimi Department of Health Policy and Informatics, Tokyo Medical and Dental University Graduate School of Medicine Masafumi Sakagami Dep. of Otolaryngology-HNS, Kansai Medical University Masao Yagi Dep. of Otolaryngology-HNS, Kansai Medical University Hiroshi Iwai Dep. of Otolaryngology-HNS, Kansai Medical University


Background
A deep neck infection (DNI) is a serious disorder that often spreads to other organs and sometimes proves fatal. The most crucial initial treatment strategy in the management of deep neck infections is prompt assessment and selection of patients requiring surgical intervention for drainage. Descending necrotizing mediastinitis (DNM) originating from a deep neck infection is a relatively rare, but rapidly progressive, destructive disease that is often fatal (1)(2)(3)(4). Despite improvements in diagnostic methods, surgical technique, and intensive care protocols, DNM has been reported to be a life-threatening condition with mortality rates up to 40% (5)(6)(7). Although the aetiology and clinical outcomes of treating DNI and/or DNM have been extensively reported, no study, other than a few sporadic case reports published in the Japanese language, has addressed dysphagia after surgical treatment (8)(9)(10). We thus recently reported a logistic regression analysis addressing risk factors related to swallowing recovery after surgical intervention for DNI in a retrospective cohort of 123 patients (11). However, these studies have several limitations attributed to their relatively small sample size from a single medical centre. Moreover, the infrequency of DNM has been one reason for the di culties in prospective investigations of these patients; no precise therapeutic schema has been proposed, and the optimal treatment for DNM is still debated.
The present study used a nationwide inpatient database in Japan to investigate the factors associated with mortality and delayed recovery of oral dietary intake in patients who underwent drainage surgery for DNI, including DNM.

Data source
Data were extracted from the Diagnostic Procedure Combination (DPC) database, a national inpatient database in Japan. The details of the DPC database have been described previously (12,13). Brie y, the DPC database includes administrative claims data and detailed medical data, collected for all inpatients discharged from participating hospitals. The number of hospitals that participated in the DPC projects included more than 80% of acute inpatient care in Japan (12)(13)(14)(15)(16). To optimize the accuracy of recorded diagnoses, responsible physicians are obligated to record the diagnosis with reference to the medical charts. The dates of hospital admission, surgery, discharge, bedside procedures, and drugs administered are recorded using a uniform data submission format (13).
All patient identi ers were removed from this database. Because of the anonymous nature of the data, the need for informed consent was waived. Study approval was obtained from the Institutional Review Board of the Tokyo Medical and Dental University (protocol Number: M2000-788-15).

Patient Selection And Characteristics
From the 38.2 million inpatients in the DPC database over a total of 5 years (between April 2012 and March 2017), patients satisfying the following inclusion criteria according to surgical interventions encoded with original Japanese codes (17,18) were selected: 1) underwent incisional drainage for deep neck infection (Japanese code: K384-2) or retropharyngeal abscess (Japanese code: K387, corresponding to intra-pharyngeal drainage for DNI) and 2) underwent mediastinotomy (Japanese code: K502).
According to the World Health Organization and previous reports using the DPC database (17,18), BMI was classi ed as underweight (< 18.5 kg/m 2 ), normal (18.5 ≤ to < 30 kg/m 2 ), and obese (≥ 30 kg/m 2 ). In addition to these groups, the 774 cases with missing values for calculation of BMI were categorized into the "missing" group. There were also missing values for smoking status (337 cases), and patients were thus subdivided into the following 3 groups: smoking, non-smoking, and missing.

Outcome Measurement
The primary outcome was survival at discharge. Regarding the subgroup analysis focusing on patients who were alive at discharge, the secondary outcome was the interval between admission and presumed full recovery of oral intake without nutrition from tube feeding or intravenous hydration, according to our previous retrospective, cohort study (11).

Statistical Analysis
Differences in continuous variables and frequencies between the groups were determined using the Kruskal-Wallis test and the χ 2 test, respectively. Multiple logistic regression analysis was performed to identify risk factors associated with survival at discharge (primary outcome) and delayed recovery of postoperative swallowing (secondary outcome). In terms of the secondary outcome, patients were divided into two groups according to median duration (9 days) of recovering oral intake without support of tube feeding or intravenous hydration. Inclusion of independent variables in the model was based on earlier research and existing knowledge (19) in terms of the following risk factors for aggravation of DNI (11,(20)(21)(22)(23): age, sex, obesity, smoking habits, DNM, comorbid DM and sepsis, repeated surgical interventions, undergoing tracheotomy and/or mechanical ventilation, and duration of empirical antibiotic therapy. A p value < 0.05 was considered signi cant. All statistical analyses were conducted using EZR software (24).

Demographic Data
A total of 6,405 cases were identi ed, as shown in Fig. 1. Of the 6,040 patients who underwent drainage for a deep neck infection and/or retropharyngeal abscess, 13 and 1,232 cases were excluded because their surgeries were attributed to an injury or foreign body and related to resection of pharyngeal tumour or haemostasis after laryngopharyngeal surgeries, respectively. Of the 365 patients who underwent mediastinotomy, 154 patients were selected after excluding 108 patients who underwent surgery for resection of a mediastinal tumour, 6 patients with mediastinitis attributed to injury or a foreign body, and 97 patients whose mediastinitis was attributed to a thoracic lesion including the oesophagus, because ICD-10 codes addressing acute infections in the head and neck region were lacking. Finally, 4,949 patients from 635 hospitals were selected.
Of all of the 4,949 patients, the 4,791 patients who were alive at discharge were divided into 2 groups according to the median interval (9 days) between admission and full recovery of oral intake without nutrition from tube feeding or intravenous hydration. Namely, group A and group B included the cases with intervals less than < 10 days and ≥ 10 days, respectively. Another 158 patients who died in hospital were assigned to group C. Table 1 summarizes the baseline characteristics of each group of patients. The patients were categorized into three groups according to the clinical outcome, as follows: A) alive at discharge undergoing nutritional support for 9 days after admission; B) alive at discharge undergoing nutritional support for more than 10 days after the rst operation; and C) died in hospital. The median ages of groups A, B, and C were 56, 66, and 73 years, respectively. Group C showed a signi cantly higher interquartile range for age  years) than the other groups (p < 0.001, Kruskal-Wallis test). Conversely, both the male to female ratios and obesity evaluated by the BMI of the three groups were not signi cantly different. Smoking status was also not signi cantly different. Patients were categorized into three groups according to outcomes related to survival at discharge and prolonged interval for achieving oral intake, as follows: A) alive at discharge undergoing nutrition support for 9 days after admission; B) alive at discharge undergoing nutrition support for more than 10 days after the rst operation; and C) died in hospital.
#Chi-squared test, conducted for other than unknown cases for each characteristic. Patients were categorized into three groups according to outcomes related to survival at discharge and prolonged interval for achieving oral intake, as follows: A) alive at discharge undergoing nutrition support for 9 days after admission; B) alive at discharge undergoing nutrition support for more than 10 days after the rst operation; and C) died in hospital.
#Chi-squared test, conducted for other than unknown cases for each characteristic.

Group
Interquartile range 7-12 13-28 9.25-37.5 Patients were categorized into three groups according to outcomes related to survival at discharge and prolonged interval for achieving oral intake, as follows: A) alive at discharge undergoing nutrition support for 9 days after admission; B) alive at discharge undergoing nutrition support for more than 10 days after the rst operation; and C) died in hospital.
#Chi-squared test, conducted for other than unknown cases for each characteristic.
Concerning disease comorbidity, the prevalence of DM was higher in group C (69.6%) than in group A (20.7%) and group B (40.0%) (p < 0.001). In addition, comorbid sepsis was signi cantly higher in group C (51.3%) than in group A (5.2%) and group B (19.7%) (p < 0.001). In terms of the presence of DNM, the prevalence was higher in group C (29.1%) than in group A (3.6%) and group B (18.1%) (p < 0.001).
Regarding surgical interventions, the prevalence of repeated surgical interventions (more than one surgical drainage) was higher in both group B (13.5%) and group C (11.4%) than in group A (1.8%) (p < 0.001). The prevalence of subsequent tracheotomy was greater than 40% in both group B and group C, signi cantly higher than in group A (18.9%) (p < 0.001). Moreover, there was a signi cant difference in patients undergoing mechanical ventilation and/or intensive care unit (ICU) therapy among the groups (p < 0.001).
As for postoperative care, the prevalence of receiving rehabilitation therapy for oral dietary intake was lower in group A than in group B (p < 0.001). Regarding the duration of antibiotic therapy, the mean durations of groups A, B, and C were 9, 18, and 20 days, respectively (p < 0.001, Kruskal-Wallis test).

Risk Factors Contributing To In-hospital Mortality
Logistic regression analysis showed that the following factors were signi cant (with crude odds ratios (ORs  Interval Between Admission And Achievement Of Oral Intake Table 3 shows the distribution of intervals between admission and achievement of oral intake in 4,791 patients who were alive at discharge (groups A and B in Table 1) categorized by DNM, which represents subgroup analyses without group C. More than half of the 4,287 patients without DNM (56.2%) achieved oral dietary intake < 10 days after admission. Conversely, the rate was only 17.9% in the 504 patients with DNM. In addition, 57.7% of the patients with DNM could not achieve oral dietary intake in 20 days. In addition, logistic regression analysis showed that sex, obesity, and smoking did not differ according to the delay in oral dietary intake (

Discussion
In this study, a total of 4,949 patients throughout Japan who underwent drainage surgery for DNIs were investigated using a Japanese nationwide inpatient database. To the best of our knowledge, this is the rst study to investigate the factors affecting mortality and delay in oral dietary intake in patients with DNIs, including DNM, in a nationwide clinical setting. The present study was also unique in that it compared these two outcomes by logistic regression analysis using the same clinical risk factors as independent variables. Interestingly, a few factors were associated with both in-hospital mortality and delay in oral dietary intake. Comorbid DM and sepsis were signi cantly associated only with in-hospital mortality. Conversely, several factors (DNM, repeated surgical interventions, ICU admission, and rehabilitation for oral dietary intake) were found to be signi cantly related only to delayed oral dietary intake.
Advanced age has been reported to be a risk factor for developing DNIs (25,26). The present study showed that age ≥ 75 years was signi cantly associated with both mortality (adjusted OR 5.57, 95%CI 2.8-11.1) and longer recovery of oral dietary intake (adjusted OR 1.89, 95%CI 1.48-2.41). The presence of systemic disease was the most important predisposing factor for the severity of DNI. Of them, comorbid DM is a well-known risk factor. The present study showed that DM was correlated with mortality, with an adjusted OR of 2.47 (95%CI 1.69-3.62). These results are consistent with a recent systematic review and meta-analysis, showing that DM was associated with a higher prevalence of multispace spread of infection, complications, and failure to identify pathogens, with risk ratios of 1.96, 2.42, and 1.29, respectively (22). Conversely, DM was not a signi cant factor related to delay in oral dietary intake, with an adjusted OR of 0.97 (95%CI 0.82-1. 16). No background mechanisms have been con rmed to explain this inconsistency. One hypothesis is that this factor was adjusted by other variables, because the crude OR of this factor was 2.60 (95%CI 2.29-2.95).
Similar to sex, obesity evaluated by BMI was relatively uniform among the three groups. Speci cally, the prevalence of patients with obesity (BMI ≥ 30 kg/m 2 ) was 4-5% in all groups, and it was not a risk factor for either mortality or delay in oral dietary intake. Although the relationship between the severity of DNIs and obesity has yet to be determined, a previous report showed that obesity (BMI ≥ 30 kg/m 2 ) was correlated with longer hospitalization (27). The DPC database has missing data for evaluating BMI in 7% (337/4949) of cases. In the DPC data, the codes corresponding to each surgery, clinical procedure, and medication are almost complete because they are compulsory items for reimbursement of healthcare costs de ned in a central system in Japan to check the adequacy of the data (All-Japan Federation of the National Health Insurance Organization). However, other information submitted with claims that is not directly related to charges may be missing, such as height/weight and smoking index (28). These less accurate data may also be responsible for the failure to identify obesity and smoking as risk factors for both mortality and delay in oral dietary intake in the present study. The smoking index was missing in 15% (754/4791) of cases in the DPC data, similar to the previous study (28).
The mortality rate for all patients with DNIs was 3% (158/4949), and that for patients with DNM was 8% (46/550). The latter rate is consistent with recent meta-analyses (6, 7) demonstrating mortality of 9-10% for the combined cervical and transthoracic approach compared to mortality of 47-50% for cervical drainage only in cases of infection to the inferior mediastinum. Interestingly, comorbidity with DNM was not found to be a signi cant factor for mortality. These results could be attributed to the spreading of strategies in Japan for transthoracic drainage in patients with DNM with extension below the tracheal bifurcation (11,29). In the present cohort, 22% (158/550) of the patients with DNM underwent transthoracic drainage. In contrast to the results for mortality, the present study showed that DNM was a signi cant factor for the delay in oral dietary intake, with an adjusted OR of 1.41 (95%CI 1.04-1.92). In addition to severe infection, systematic debridement and broad opening of the involved fascial planes are considered to contribute to limited laryngeal elevation and/or severe scar contraction speci cally around the cricopharyngeal muscle (11). Therefore, patients with DNM should receive postoperative care with careful attention to the risk of delayed recovery of oral intake.
Of the systemic diseases contributing to mortality, several previous reports addressed death due to complications with sepsis (25,(30)(31)(32)(33). In contrast to the outcome related to DNM, the present study showed that sepsis was a signi cant factor only for mortality, with an adjusted OR of 3.32 (95%CI 2.29-4.82), not for a delay in oral dietary intake, with an adjusted OR of 1.15 (95%CI 0.88-1.51). Therefore, sepsis, rather than DNM, should be considered a risk factor for mortality in treating DNIs and DNM.
In the present study, tracheotomy contributed only to a delay in oral dietary intake, with an adjusted OR of 1.70 (95%CI 1.44-2.00), which was similar to the result for DNM. Previous reports advocated tracheotomy for DNI cases with severe airway obstruction and/or presumed di cult re-intubation speci cally managed by otolaryngologists (6,(34)(35)(36)(37). These results are consistent with our previous study and imply that a disturbance in swallowing function may be encountered after tracheotomy, presumably resulting from desensitization of the larynx after diversion of the air passage or xation of the larynx (11,38).
It is plausible that undergoing repeated surgery is related to a delay in oral dietary intake, with an adjusted OR of 1.70 (95%CI 1. 16-2.48). Interestingly, this factor was opposite to the risk for mortality, with an adjusted OR of 0.45 (95%CI 0.23-2.07). Singhal (39) reported that CT imaging of the neck and chest should be performed with any clinical deterioration of the patient or empirically 48-72 hours after an operative drainage procedure to identify any progression of the infection. Because initial drainage is often inadequate in patients speci cally with DNM, the present results suggest surgical interventions with repeat drainage. However, these patients should receive postoperative care with careful attention to the risk of delay for recovering oral intake.
Postoperative care has been reported to play a critical role in patients with DNIs and DNM (5, 31, 40).
Appropriate and careful selection of patients for ICU admission is sometimes fundamental for these patients to manage severe sepsis and/or septic shock and every possible complication, both at the beginning and after surgery (31,40). In the present study, ICU admission was not found to be a crucial factor related to mortality. One hypothesis for these results is that the above-mentioned critical care might contribute to the survival of patients with severe morbidities.
In contrast to the above-mentioned risk factor, mechanical ventilation was a signi cant risk factor for both mortality and delay in oral dietary intake, with adjusted ORs of 3.96 (95%CI 2.51-6.23) and 1.92 (95%CI 1.53-2.41), respectively. One background hypothesis is that the deteriorated conditions of the patients led to endotracheal intubation in the rst place. According to the previous support, most cases with DNM showed whole body deterioration and received support from an arti cial respirator for an extended period (2, 40). Similar to the results for mechanical ventilation, the duration of empirical antibiotic therapy (days) was also a signi cant risk factor for both mortality and delay in oral dietary intake, with adjusted ORs of 1.00 (95%CI 1.00-1.02) and 1.18 (95%CI 1.17-1.19), respectively. Along with surgical drainage, high-dose intravenous antibiotics are the mainstay for the management of DNIs. These results correspond to the longer intravenous antibiotic therapy in more critically ill patients with infection.
Finally, if patients can recover from their severely ill condition, rehabilitation for dysphagia might be indicated. Although only a few reports have addressed rehabilitation for DNIs or DNM because of the absence of detailed swallowing evaluation (11,41), the present nationwide study showed that approximately 10% of patients with DNIs received rehabilitation therapy. This was a signi cant factor for a delay in oral dietary intake, with an adjusted OR of 2.05 (95%CI 1.44-2.92). These results correspond to the situation where the right person (suffering from dysphagia) is in the right place (undergoing rehabilitation).
Several limitations of this study need to be acknowledged. First, this study was based on a retrospective cohort study using a national Japanese database, and generalization of the results outside Japan may not be appropriate. Second, comorbidities are less accurately recorded in administrative claims databases than in planned prospective studies. Third, the absence of records on vital signs, blood tests, and blood and bacteriological cultures in the DPC database precluded a more rigorous de nition of septic shock, as discussed in the previous report (13). Moreover, DPC data come from an inpatient database, and it is di cult to evaluate the delay from onset to intervention.
Within these limitations, the current study with the largest retrospective cohort using a nationwide database has several advantages. It was found that clinical risk factors differed between mortality and delay in oral dietary intake other than age ≥ 75 years, sepsis, mechanical ventilation, and duration of empirical antibiotic therapy. Other than these factors, DM contributed only to mortality. Conversely, DNM, repeated surgery, tracheostomy, and intensive care unit admission contributed to a delay in oral dietary intake, but not mortality. Further research including multicentre prospective studies of DNM and DNI is necessary to establish precise therapeutic approaches for managing DNIs and the optimal treatment for DNM.

Conclusions
In this study using a large nationwide inpatient database, a few factors (advanced age, mechanical ventilation, and duration of empirical antibiotic therapy) were associated with both mortality and delay in oral dietary intake in patients with DNIs including DNM. Comorbid DM and sepsis were signi cantly associated only with mortality. Conversely, several factors (DNM, repeated surgical interventions, ICU admission, and rehabilitation for oral dietary intake) were found to be signi cantly related only to delayed oral dietary intake. Although DNM was not necessarily related to mortality, patients with DNM should receive postoperative care with careful attention to avoid a delay in oral dietary intake.  Figure 1 Schematic of patient selection. DPC, Diagnostic Procedure Combination.