Balance dysfunction the most significant cause of in-hospital falls in patients taking hypnotic drugs: A retrospective study.

PURPOSE: Preventing falls in patients is one of the most important concerns in acute hospitals. Balance disorder and hypnotic drugs lead to falls. The Standing Test for Imbalance and Disequilibrium (SIDE) is developed for the evaluation of static standing balance ability. There have been no reports of a comprehensive assessment of falls risk including hypnotic drugs and SIDE. The purpose of this study was to investigate the fall rate of each patient who took the hypnotic drug and the factor associated with falls.
METHODS: Fall rates for each hypnotic drug were calculated as follows (number of patients who fell/number of patients prescribed hypnotic drug x 100). We investigated the hypnotic drugs as follows; benzodiazepine drugs, Z-drugs, melatonin receptor agonists, and orexin receptor antagonists. Hypnotic drug fall rate was analyzed using Pearson's chi-square test. Decision tree analysis is the method we used to discover the most influential factors associated with falls.
RESULTS: This study included 2840 patients taking hypnotic drugs. Accidents involving falls were reported for 211 of inpatients taking hypnotic drugs. Z-drug recipients had the lowest fall rate among the hypnotic drugs. We analyzed to identify independent factors for falls, a decision tree algorithm was created using two divergence variables. The SIDE levels indicating balance disorder were the initial divergence variable. The rate of falls in patients at SIDE level ≦ 2a was 14.7%. On the other hand, the rate of falls in patients at SIDE level ≧ 2b was 2.9%. Gender was the variable for the second classification. In this analysis, drugs weren't identified as divergence variables for falls.
CONCLUSION: The SIDE balance assessment was the initial divergence variable by decision tree analysis. In order to prevent falls, it seems important not only to select appropriate hypnotic drugs but also to assess patients for balance and implement preventive measures.

Introduction

Falls and related injuries are important problems in acute hospitals. About 2% of hospitalized patients experience falls during their hospital stay [1]. In one study, among the hospitalized patients who experienced falls, 30% experienced mild injuries and 5% experienced severe injuries [2]. Hip fracture is considered one of the most severe injuries caused by in-hospital falls, due to complications reducing quality of life, increasing required staff hours, and incurring unnecessary social cost [3]. The patients with a hospital-acquired hip fracture are already in poor condition physically and mentally and have an especially poor outcome [4]. Thus, patients with a hospital-acquired hip fracture have worse outcomes including death and discharging to nursing care facilities than patients who fall outside of the hospital [5]. Moreover, falls in the hospital are detrimental to the patient and can result in medical lawsuits. Therefore, preventing falls in patients is one of the important concerns in acute hospitals.

Falls have multiple causes. Compromised physical function, including balance disorder and gait disorder, lead to falls as well as hypnotic drugs [6]. Standing balance is important in predicting a patient’s risk of falling. The Standing Test for Imbalance and Disequilibrium (SIDE) has been developed for the evaluation of static standing balance ability [7]. SIDE classifies the patients into six grades, the classification of patients based on their abilities would facilitate communication between medical staff and the development of fall-prevention programs. We have started using SIDE in assessing hospitalized patients to prevent falls.

Some kinds of medications including hypnotics, antidepressants, anti-hypertensive drugs, and diuretics cause falls [8]. Among them, hypnotics are often ordered as a single-use solution for insomnia because insomnia is a common symptom in hospitalized patients. Benzodiazepines have been widely prescribed for treating insomnia, however, they have severe side effects such as rebound insomnia, delirium, dementia, and falls [9, 10]. To avoid these severe side effects, benzodiazepines aren’t recommended to be prescribed for elderly patients [3], and melatonin receptor agonists and orexin receptor antagonists have been developed [11, 12]. However, in one study, even zolpidem and suvorexant resulted in impaired balance ability versus a placebo [12]. Therefore, it is crucial to take into account the patient’s balance ability and prevent falls when prescribing hypnotic drugs. To the best of our knowledge, there is no study to investigate the relationship between balance ability and falls in hospital patients who took hypnotic drugs.

The purpose of this study was to investigate the fall rate of each patient who took the hypnotic drug and the factor associated with falls.

Methods

Ethics

This study protocol conformed to the ethics guidelines of the Declaration of Helsinki, as reflected in prior approval given by the institutional review board of Kurume University Hospital (approval ID:20167). Informed consent from patients was obtained using an opt-out approach.

Patients

We did a retrospective study and enrolled all hospitalized patients who were taking hypnotic drugs from July to December 2020 at Kurume University Hospital. Our hospital has 1,018 beds in 23 medical departments. We summarized inclusion and exclusion criteria in Fig 1. We obtained data of falls from incident and accident reports submitted by medical personnel.

Fig 1

Diagram of patient’s inclusion and exclusion criteria in this study.

All patients admitted to our hospital from July to December 2020 who were prescribed hypnotic drugs were included in the study. Finally, 2840 patients were included in the analysis.

Drugs

We investigated the top 6 hypnotic drugs that were often prescribed as follows; benzodiazepine drugs (brotizolam), Z-drugs (eszopiclone, zolpidem), melatonin receptor agonists (ramelteon), and orexin receptor antagonists (lemborexant, suvorexant). We extracted patient data from prescription records of inpatient hypnotic drugs. Therefore, the number of patients is the total number of patients. We also investigated the dosage of each patient.

We investigated other drugs as follows, angiotensin converting enzyme inhibitors, alpha blockers, beta blockers, alpha beta blockers, loop diuretics, and selective serotonin reuptake inhibitors which were previously reported to be the cause of falls [8, 13]. We defined polypharmacy as patients who were taking three or more drugs [14].

Evaluation of balance

The SIDE is useful to assess balance ability at the bedside by various medical personnel (Fig 2). The accuracy of SIDE is validated by comparing the results with another functional balance scale; the Berg Balance Scale [7]. We defined patients who were unable to do tandem standing as having balance disorder (SIDE level 0, 1, and 2a).

Fig 2

Standing Test for Imbalance and Disequilibrium (SIDE).

The patients perform the static balance test in the following order, standing with feet apart, standing with feet together, tandem standing, and standing on one foot. After checking which movements are possible or impossible for the patient, the medical staff assesses the patients into six levels: Level 0, 1, 2a, 2b, 3, and 4. Level 0: The patient can’t stand with feet apart without assistance. Level 1: The patient can stand with feet apart without assistance. However, the patients can’t stand with feet together for more than 5 s. Level 2a: The patient can stand with feet together for more than 5 s. However, the patients can’t stand in a tandem position with either foot forward. Level 2b: The patient can stand tandem with one but not the other foot in the leading position for more than 5 s. Level 3: The patient can stand tandem standing with each foot forward for more than 5 s. However, the patient can’t stand on one foot more than 30 s. Level 4: The patient can stand on one foot more than 30 s with either foot.

Statistical analysis

Fall rates for each hypnotic drug were calculated as follows (number of patients who fell/number of patients prescribed a hypnotic drug x 100).　Each hypnotic drug fall rate, age, and balance disorder were analyzed using Pearson’s chi-square test. Logistic regression analysis was conducted to investigate falls in each hypnotic drug. Decision tree analysis is a data mining technique that identifies high-priority factors [15]. Decision tree analysis reveals factors even if no a priori hypothesis is imposed. Therefore, decision tree analysis helps to discover the most influential factors associated with falls. This approach is useful to discover hidden factors that cannot be identified by logistic regression analysis. Decision tree analysis can identify the combinations of factors that constitute the highest risk for a condition of interest [16]. Therefore, a decision-tree algorithm was constructed to reveal profiles associated with falls. Subjects were classified according to the indicated cut-off values of the variable. A p-value <0.05 was considered statistically significant.

Results

Characteristics of patients and falls rates

This study included 3489 patients, 649 patients were excluded because they couldn’t be assessed by SIDE or data was missing. Finally, 2840 patients were involved in this study. Median age of patients was 70.5 (59–77.9) years-old. Gender ratio of patients was male/female (55% / 45%). Falls incidents occurred in 27 departments, and the most prevalent department was Respiratory M edicine (13.1%) (Table 1). The drugs prescribed to the patients were as follows: benzodiazepine drugs; 276 (9.7%), Z-drugs; 722 (50.3%), melatonin receptor agonists; 413 (14.6%) and orexin receptor antagonists; 722 (25.4%). The SIDE levels of patients were level 0 (n = 352, 12.4%), level 1 (n = 186, 6.5%), level 2a (n = 542, 19.1%), level 2b (n = 543, 19.1%), level 3 (n = 510, 18.0%), and level 4 (n = 707, 24.9%). The number of patients who were assessed by SIDE to have a balance disorder was 1080 (38.0%).

Table 1

Prevalence by department.

	%	n
Respiratory Medicine	13.10	372
Neuropsychiatry	9.79	278
Orthopedic Surgery	9.44	268
Digestive Surgery	8.20	233
Cardiovascular Surgery	7.78	221
Cardiovascular Medicine	6.23	177
Otolaryngology	6.16	175
Urology	4.82	137
Neurosurgery	4.30	122
Gastroenterology	3.59	102
Gynecology	2.99	85
Nephrology	2.99	85
Hematology	2.82	80
Ophthalmology	2.71	77
Dermatology	2.32	66
Palliative care	2.04	58
Internal medicine of endocrinology and metabolism	1.69	48
Respiratory Surgery	1.62	46
Medical Oncology	1.48	42
Radiology	1.41	40
Emergency Medicine	1.34	38
Plastic Surgery	1.30	37
Oral Surgery	1.20	34
Breast Surgery	0.49	14
Pediatric Surgery	0.11	3
Pediatrics	0.07	2

Fall rates for each hypnotic drug

Fall accidents were reported for 211 (7.4%) of 2860 inpatients taking hypnotic drugs. The fall rate for each hypnotic drug was as follows: Z-drug (5.5%); melatonin receptor agonist (7.5%); benzodiazepine drugs (8.7%) and orexin receptor antagonists (10.7%) (Fig 3). The fall rate for z-drugs was significantly lower than for benzodiazepine drugs, and orexin receptor antagonists (p = 0.0432, p < .0001). However, there was no significant difference in the fall rate between z-drugs and melatonin receptor agonists (p = 0.1352).

Fig 3

Fall rate for each hypnotic drug.

Fall rate for z-drugs was significantly lower than those for benzodiazepine drugs and orexin receptor antagonists. *: means statistically significant.

Age, and balance disorder in each hypnotic drug

Patients who were prescribed melatonin receptor agonists and orexin receptor antagonists were significantly older than those receiving z-drugs (p < .0001, p < .0001). There was no significant difference in age between patients who were prescribed z-drugs and benzodiazepines drugs (p = 0.1831) (Fig 4A).

Fig 4

Age and ratio of balance disorder and each patient who was prescribed hypnotic drugs.

The patients taking z-drugs were significantly younger than those taking melatonin receptor agonists and orexin receptor antagonists. The ratio balance disorder in the patients taking z-drugs was significantly smaller than that of melatonin receptor agonists and orexin receptor antagonists. *: means statistically significant.

Ratio of balance disorder in each hypnotic drug were shown in Fig 4B. Ratio of balance disorder in melatonin receptor agonists and orexin receptor antagonists were significantly higher than those of z-drugs (p < .0001, p < .0001). There was no significant difference in balance disorder ratio between z-drugs and benzodiazepine drugs (p = 0.3819) (Fig 4B).

Cox regression analysis for falls

Z-drugs were significantly associated with a decreased odds ratio of falls in the univariate analysis (p < .0001). Orexin receptor antagonists were significantly associated with an increased odds ratio of falls in the univariate analysis (p = 0.0002). Benzodiazepines drugs and melatonin receptor agonists were not significantly associated with an increased odds ratio of falls in the univariate analysis (p = 0.4024, p = 0.9541) (Table 2).

Table 2

Cox regression analysis for fall.

Factors	Univariate analysis for fall odds ratio (95% Confidence interval, P-value)	Multivariate analysis for fall odds ratio (95% Confidence interval, P-value)
Benzodiazepines drugs	1.21	1.50
	(0.76–1.89, 0.4024)	(0.94–2.39, 0.089)
Z-drugs	0.57	0.69
	(0.42–0.75, < .0001)	(0.52–0.93, 0.0135)
Melatonin receptor agonists	1.01	0.78
	(0.68–1.50, 0.9541)	(0.52–1.18, 0.24)
Orexin receptor antagonists	1.76	1.28
	(1.31–2.37, 0.0002)	(0.94–1.74, 0.1128)

The multivariate regression analysis was done with variables related to falls; age, sex, dosage, SIDE levels, the use of multiple drugs, angiotensin-converting enzyme inhibitors, alpha-blockers, beta-blockers, alpha beta-blockers, loop diuretics, and selective serotonin reuptake inhibitors. Z-drugs were significantly associated with a decreased odds ratio of falls in the multivariate analysis (p = 0.0135). Melatonin receptor agonists were not significantly associated with a decreased odds ratio of falls in the multivariate analysis (p = 0.24). Benzodiazepine drugs and melatonin receptor agonists were not significantly associated with an increased odds ratio of falls in the multivariate analysis (p = 0.089, p = 0.1128) (Table 2).

Decision-tree algorithm for falls

Decision-tree algorithm was done with variables related to falls; age, gender, dosage, SIDE levels, the use of multiple drugs, and hypnotic drugs, angiotensin converting enzyme inhibitors, alpha blockers, beta blockers, alpha beta blockers, loop diuretics, and selective serotonin reuptake inhibitors. To clarify the profiles associated with falls, a decision tree algorithm was created using two divergence variables and classifying the patients into three groups (Fig 5). The SIDE levels were the initial divergence variable. Falls were seen in 2.9% of patients with normal balance ability (the SIDE levels 2b, 3, and 4). Among the patients with balance disorders (the SIDE level 0, 1, and 2a), gender was the variable for the second classification. Falls were seen in 11.4% of female patients. On the other hand, falls were seen in 17.8% of male patients. In this analysis, drugs weren’t identified as divergence variables for falls.

Fig 5

Decision-tree algorithm for falls in hospitalized patients taking hypnotic drugs.

The pie indicates the proportion of patients with falls (black) and without falls (white). The falls rate in patients at SIDE level 2a or lower was five times the falls rate in patients at SIDE level 2b or higher. In addition, the falls rate in males was higher than in females for SIDE level 2a or lower.

Discussion

Hypnotic drugs and balance are two causes of falls. In this study, we investigated the relationship between hypnotic drugs, balance and falls in hospitalized patients. Accidents involving falls were reported for 211 (7.4%) of 2860 inpatients during hospitalization. Z-drug recipients had the lowest fall rate among the hypnotic drugs. We analyzed to identify independent factors for falls. However, hypnotic drugs weren’t independent factors of falls using the decision-tree algorithm. The SIDE balance assessment was the initial divergence variable. In order to prevent falls, it seems important not only to select appropriate hypnotic drugs but also to assess patients for balance and implement preventive measures.

The relationship between falls rate and hypnotic drugs

Z-drugs were developed to overcome disadvantages of benzodiazepine drugs, including confusion, dependence, and abuse [17]. Z-drugs are safer and better as a first-line choice for treatment of insomnia than benzodiazepine drugs [18]. The falls rate for z-drugs was significantly lower than for benzodiazepine drugs in this study. Z-drugs were significantly associated with a decreased odds ratio of falls in the multivariate analysis. On the other hand, Ishibashi et al. have been reported that Z-drugs have a higher fall risk than benzodiazepines [19]. It remains unclear why these results are different. However, there are two possible reasons. First, our patients were younger than those of Ishibashi et al. In particular, the age of our patients who were taking oral z-drugs was 64.1 years which was younger than that of the patients of Ishibashi et al. Second, the study by Ishibashi et al. is a case-control study, with age- and gender-adjusted patients. They compared the results in age- and gender-adjusted patients. Their study included 44.3% and 67.9% of patients in the fall and control groups who were not taking hypnotic drugs. On the other hand, our study included only patients taking hypnotic drugs. These two differences may be related to the results regarding z-drugs. In this study, z-drugs resulted in the lowest fall rate, however, since all hypnotic drugs had some effect on falls in this study, the physician should consider the risk of falls when prescribing z-drugs as well.

Orexin receptor antagonists cause less postural instability than other hypnotic drugs, and do not impair alertness [20]. Orexin receptor antagonists are reported to be safe and effective hypnotic drugs for older patients in a systematic review [21]. Although the fall rate for orexin receptor antagonists was significantly higher than for z-drugs in this study, the causes remain unclear. Possible reasons include the following. Patients receiving orexin receptor antagonists were significantly older than those receiving z-drugs. Moreover, the ratio of balance disorder was higher in patients with orexin receptor antagonists than with z-drugs. This trend has been reported in other studies. Ishibashi et al. [19] demonstrated that orexin receptor antagonists were associated with falls and were often prescribed to elderly patients. Our hospital recommends that physicians prescribe melatonin receptor agonists and orexin receptor antagonists, not benzodiazepines, to prevent falls. Therefore, clinicians may have prescribed orexin receptor antagonists to older patients with balance disorders when prescribing drugs for insomnia. Orexin receptor antagonists are safe drugs, but the risk of falls should be considered when prescribing them to elderly patients with a balance disorder.

The independent causes of falls

In this study, we investigated the independent causes of falls. Balance disorders assessed using SIDE in decision tree analysis was an independent factor for causes of falls. The independent factor resulting in falls showed to be the SIDE level rather than the types of hypnotic drug in this analysis. This result may indicate that balance disorders need to be considered in addition to the choice of hypnotic drugs in order to prevent falls. The SIDE is a method devised to identify and assess the ability to maintain balance in a static standing position, allowing a simple assessment of patients immediately after admission to the ward [7]. Balance disorder was the initial divergence variable. The rate of falls in patients at SIDE level ≦ 2a was 14.7%. On the other hand, the rate of falls in patients at SIDE level≧2b was 2.9%. This result indicates the patients who can stand in a tandem position rarely fall. Furthermore, Teranishi et al. reported that no falls had been observed in patients at a SIDE level of 2b or higher in a rehabilitation hospital in a previous study [22]. This aligns with our findings. The SIDE may be a useful tool for assessing risk of falls in acute phase hospitals. Based on these results, while it is important to select hypnotics that have fewer side effects such as falls, it is also important to implement fall prevention in clinical practice by identifying high risk patients using balance assessment.

Limitation

This study has several limitations. First, our study evaluated balance function in patients who took the hypnotic drug. We assessed patients’ balance ability at admission in this study. On the other hand, the timing of hypnotic prescriptions varies. Some patients had begun taking hypnotics before being admitted, while others started them during hospitalization. This is a limitation of this retrospective study. A prospective randomized controlled trial is needed to resolve this issue. Second, we assessed only balance function and were unable to assess other risk factors such as the patient’s muscle strength, walking, visible impairment, and previous falls.

Conclusions

This study investigated the fall ratio of patients who took the hypnotic drug. The fall ratio for z-drugs was significantly lower than for benzodiazepine drugs, and orexin receptor antagonists. Moreover, we also investigated the factors associated with falls. Balance disorder was an independent factor for falls using decision-tree analysis. Therefore, a physician should consider not only the choice of drugs but also balance functions in inpatients.

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18 Apr 2022

The manuscript needs to be more detailed to clarify the study design, study gap and  clinical importance of using decision trees .

I would also recommend proofreading the manuscript before submission for spellings and grammar.

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Reviewer #1: Although I believe that this study is based on good research question, several critical problems and questions exist.

1. it is not clear why the analysis was conducted using decision trees; if the goal is to evaluate SIDE and sleeping pills, why not just include SIDE and sleeping pills at the same time in the multivariate regression analysis? (in case-control study or cross sectional study)

It may be necessary to clarify the clinical importance of using decision trees in the background and discussion.

2. Are there any reasons for limiting the study participants who have been prescribed hypnotic drugs?

When examining the effects of SIDE and hypnotic drugs, limiting the study to those who took hypnotic drugs not only reduces the external validity of this study, but also causes selection bias.

Reasonable rationale for the selection of study subjects is necessary.

3. Isn't it necessary to consider age in the presentation of results?

I consider that it is necessary to take age into account when comparing the ability of balance between patients prescribing hypnotic drugs.

In general, melatonin receptor agonists tend to be used in elderly patients in Japan.

This may lead to more balance problems in patients who prescribing melatonin receptor agonists.

Is the decision tree adjusted for age?

If so, it is necessary to specify in what form the variable is included (continuous or category like more than 65 years old or not).

4. Z-drug users had the lowest fall rate among the hypnotics, but is there any effect of age or other factors?

In general, Z-drugs have been reported to have a higher fall risk than benzodiazepines (Ishibashi, Y. et al. PloS one, 15(9), e0238723. Brandt, J., & Leong, C. (2017). Drugs in R & D, 17(4), 493-507.)

Differences from previous studies should be described in the discussion.

5. It needs to be clearly stated how the study dealt with patients who took multiple hypnotic drugs.

The authors stated, "We investigated the top 6 hypnotic drugs that were often prescribed as follows,". Only the most commonly prescribed drugs in patients were used as variables, and the others were ignored? This needs to be described in methods.

It should be stated whether the dosage was also taken into account.

6. It is necessary to clarify whether the high risk of falling at orexin receptors is due to age or to low balance ability.

According to previous study (Ishibashi, Y. et al. PloS one, 15(9), e0238723), orexin receptors are reported to have a higher risk of falls.

However, they are more likely to be administered to the elderly in Japan, and people with frail may be administered them.

7. More details are needed on the timing of SIDE assessment.

Was the SIDE taken prior to admission?

Was the patient taking medication internally at that time?

It needs to be clarified whether the SIDE represents a loss of balance due to medication or whether it represents the patient's original degree of frailty.

Was the SIDE assessed on admission, followed by the start of drug medication and the assessment of falls?

Related to the above, the timing of the collection of the patient's exposure of oral medications also needs to be described.

Are the medications taken into account when the fall occurred? Or are you considering oral medication upon admission? Do you take into account the medication at discharge?

Do you need to consider the possibility that the medication may change due to falls?

Differences in the timing of medication prescribing between patients who have fallen and those who have not fallen may be a source of bias.

Reviewer #2: Thank you for your interesting paper.

- Abstract:

o Concise and readable.

- Introduction:

o Please describe that why patients with a hospital-acquired hip fracture have higher complication rate than those who fall outside of the hospital.

o The study gap is not clearly stated in the introduction section. The authors can highlight the components of the standing balance postural controls in elderly subjects.

- Methods

o There is a discrepancy in duration of data gathering. In line 122, the authors stated that data gathering was conducted from July to December 2021. However, in line 128 (for figure legend), it was reported as July to December 2020. Please check that which one is correct.

o In introduction section, the authors stated that in their hospital benzodiazepine in not prescribed for patients. However, in method section the benzodiazepine is one of the hypnotic drugs that prescribed to the patients.

o Line 204: please report the p-value for fall ratio between z-drugs and melatonin receptor agonists.

- Discussion:

o Please compare the results of this study with related articles that published previously.

o In limitation section, please describe that why retrospective nature of the study design is one of limitation of the study.

- Conclusion:

o Relevant to the main findings.

- General point:

o There is some grammatical error in the text that should be revised by a native fluent reviewer.

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Reviewer #1: Yes: Yoshiki Ishibashi

Reviewer #2: Yes: Taher Babaee

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3 Jun 2022

Responses to REVIEWER 1:

Thank you for your comments regarding our manuscript (PONE-D-22-02308). We appreciate your comments, which have helped us to improve our manuscript. In line with your comments, please find below our point-by-point responses.

Specific comments

Introduction

Comment 1:

it is not clear why the analysis was conducted using decision trees; if the goal is to evaluate SIDE and sleeping pills, why not just include SIDE and sleeping pills at the same time in the multivariate regression analysis? (in case-control study or cross-sectional study) It may be necessary to clarify the clinical importance of using decision trees in the background and discussion.

Answer: We appreciate your valuable advice to improve our research. We added some sentences about decision tree analysis in the statistical analysis section. We used decision tree analysis to identify the most influential factors associated with falls and the combinations of factors for falls. We also conducted a cox regression analysis. The multivariate regression analysis was done with variables related to falls; age, sex, dosage, Standing Test for Imbalance and Disequilibrium levels, the use of multiple drugs, angiotensin-converting enzyme inhibitors, alpha-blockers, beta-blockers, alpha beta-blockers, loop diuretics, and selective serotonin reuptake inhibitors were significant factors for falling. We added these results in the result section and the discussion section.

(Page7, line183-184) (Page10, line241-257)

Table2. Cox regression analysis for fall

Factors Univariate analysis for fall OR

(95% Confidence interval, P-value) Multivariate analysis for fall OR

(95% Confidence interval, P-value)

Benzodiazepines drugs 1.21

(0.76-1.89, 0.4024) 1.50

(0.94-2.39, 0.089)

Z-drugs 0.57

(0.42-0.75, <.0001) 0.69

(0.52-0.93, 0.0135)

Melatonin receptor agonists 1.01

(0.68–1.50, 0.9541) 0.78

(0.52-1.18, 0.24)

Orexin receptor antagonists 1.76

(1.31–2.37, 0.0002) 1.28

(0.94-1.74, 0.1128)

Comment 2: Are there any reasons for limiting the study participants who have been prescribed hypnotic drugs? When examining the effects of SIDE and hypnotic drugs, limiting the study to those who took hypnotic drugs not only reduces the external validity of this study, but also causes selection bias. Reasonable rationale for the selection of study subjects is necessary.

Answer: We appreciate your valuable comment. Hypnotic drugs impair balance ability [1]. Therefore, we need to pay attention to the balance function of patients taking hypnotic drugs. There was no study focused on investigating falls with patients taking hypnotic drugs. For this reason, the title stated that the patient was taking hypnotic drugs internally. However, as you pointed out, the introduction was inadequately written and did not provide enough background regarding the fact that the study subjects were patients taking hypnotic drugs. We revised the introduction to clarify this study's aim.

(Page4, line76 – Page5, line114)

Comment 3: Isn't it necessary to consider age in the presentation of results?

I consider that it is necessary to take age into account when comparing the ability of balance between patients prescribing hypnotic drugs. In general, melatonin receptor agonists tend to be used in elderly patients in Japan.　This may lead to more balance problems in patients who prescribing melatonin receptor agonists. Is the decision tree adjusted for age? If so, it is necessary to specify in what form the variable is included (continuous or category like more than 65 years old or not).

Answer:

We apologize for our unclear description. The age of patients taking melatonin receptor agonists was higher than that of other patients (Figure 4A). Moreover, the ratio of balance disorder in patients taking melatonin receptor agonists was higher than that of patients taking other drugs (Figure4B). As you noted, aging impairs balance functions, so we thought we should adjust for the effects of age as well. Decision-tree algorithm was done with variables related to falls; age, sex, SIDE levels, the use of multiple drugs, hypnotic drugs, angiotensin-converting enzyme inhibitors, alpha-blockers, beta-blockers, alpha beta-blockers, loop diuretics, and selective serotonin reuptake inhibitors. Age was not a significant factor in falls in the decision tree analysis. (Page11, line 263-266)

Moreover, we have added the results of the Cox regression analysis. The melatonin receptor agonists were not significantly associated with an increased odds ratio of falls in cox regression analysis. We added these results in the main texts. Thank you for your advice.

(Page10, line 253-255)

Comment 4: Z-drug users had the lowest fall rate among the hypnotics, but is there any effect of age or other factors? In general, Z-drugs have been reported to have a higher fall risk than benzodiazepines (Ishibashi, Y. et al. PloS one, 15(9), e0238723. Brandt, J., & Leong, C. (2017). Drugs in R & D, 17(4), 493-507.) Differences from previous studies should be described in the discussion.

Answer:

Thank you for your valuable comments. As you pointed out, there are some reports using z-drug-caused falls [2, 3]. However, the muscle-relaxant effect of z-drugs is weaker than benzodiazepines; the risk of falls with z-drugs is low [4]. Thus, we consider that no certain conclusion has been reached regarding the relationship between z-drugs and falls. Comparing the present study and results with those reported by Ishibashi et al. [5], the two points are different. First, our patients were younger than those of Ishibashi et al. In particular, the age of our patients who were taking oral z-drugs was 64.1 years which was younger than that of the patients of Ishibashi et al. In this study, attending physicians may have prescribed an orexin receptor agonist to elderly patients with impaired balance function (Figure 4 A, B). Second, the study by Ishibashi et al. is a case-control study, with age- and gender-adjusted patients. They compared the results in age- and gender-adjusted patients. Their study included 44.3% and 67.9% of patients in the fall and control groups who were not taking hypnotic medication. On the other hand, our study included only patients taking hypnotic medication. These two differences may be related to the results regarding z-drugs. We added these sentences in the discussion sections.

(Page12, line296 - Page13, line315)

Comment 5: It is necessary to clarify whether the high risk of falling at orexin receptors is due to age or to low balance ability. According to previous study (Ishibashi, Y. et al. PloS one, 15(9), e0238723), orexin receptors are reported to have a higher risk of falls. However, they are more likely to be administered to the elderly in Japan, and people with frail may be administered them.

Answer: We fully agree with you. The patients who took orexin receptor antagonists were elderly and had compromised balance (Figure 4 A, B). We performed an additional multivariate analysis on patients taking oral orexin receptor antagonists. These patients' falls were associated with a balance disorder. Please see the supplemental table below. In a systematic review, orexin receptor antagonists are reported to be safe and effective hypnotic drugs for older patients [6]. However, Ishibashi et al. [5] demonstrated that orexin receptor antagonists were associated with falls and were often prescribed to elderly patients. Taken together, orexin receptor antagonists are safe drugs, but the risk of falls should be considered when prescribing them to elderly patients with a balance disorder. We added this point in the discussion section. Thank you for your advice.

(Page13, line 325-327)

Supplementally table1: Cox regression analysis for falls in patients who took orexin receptor antagonists

Factors OR

(95% Confidence interval, P-value)

age 1.01

(0.10–1.03, 0.1198)

Balance disorder 5.41

(2.87–10.19, <.0001)

Multiple logistic regression adjusted age, standing test for Imbalance and disequilibrium levels

Comment 6: It needs to be clearly stated how the study dealt with patients who took multiple hypnotic drugs. The authors stated, "We investigated the top 6 hypnotic drugs that were often prescribed as follows,". Only the most commonly prescribed drugs in patients were used as variables, and the others were ignored? This needs to be described in methods. It should be stated whether the dosage was also taken into account.

Answer: We apologize for the inadequate description of our methodology. We extracted patient data from inpatient prescription records of hypnotic drugs. Therefore, the number of patients is the total number of patients. We also investigated the dosage of each patient. We also included dosage as a variable in the multivariate analysis. We have added sentences in the methods section.

(Page6, line141-143)

Comment 7: More details are needed on the timing of SIDE assessment. Was the SIDE taken prior to admission?　Was the patient taking medication internally at that time?　It needs to be clarified whether the SIDE represents a loss of balance due to medication or whether it represents the patient's original degree of frailty. Was the SIDE assessed on admission, followed by the start of drug medication and the assessment of falls?　Related to the above, the timing of the collection of the patient's exposure of oral medications also needs to be described.　Are the medications taken into account when the fall occurred? Or are you considering oral medication upon admission? Do you take into account the medication at discharge?　Do you need to consider the possibility that the medication may change due to falls?　Differences in the timing of medication prescribing between patients who have fallen and those who have not fallen may be a source of bias.

Answer: We assessed the patient's balance ability when they were admitted. On the other hand, the timing of the prescription of the hypnotic drug is different. Some patients who are admitted to the hospital have already been taking some hypnotic drugs, while others start during their hospital stay. Regarding the timing of falling and medication, as you pointed out, we were not able to take into account the timing when the fall occurred. As you pointed out, this point is a limitation of this retrospective study. A prospective randomized control study is needed to solve this problem. We added this point in the limitation section. Thank you for your advice.

(Page14, line356-364)

1. Bland H, Li X, Mangin E, Yee KL, Lines C, Herring WJ, et al. Effects of Bedtime Dosing With Suvorexant and Zolpidem on Balance and Psychomotor Performance in Healthy Elderly Participants During the Night and in the Morning. J Clin Psychopharmacol. 2021;41(4):414-20. Epub 2021/06/29. doi: 10.1097/JCP.0000000000001439. PubMed PMID: 34181362.

2. Bellazzi R, Zupan B. Predictive data mining in clinical medicine: current issues and guidelines. Int J Med Inform. 2008;77(2):81-97. Epub 2006/12/26. doi: 10.1016/j.ijmedinf.2006.11.006. PubMed PMID: 17188928.

3. Kolla BP, Lovely JK, Mansukhani MP, Morgenthaler TI. Zolpidem is independently associated with increased risk of inpatient falls. J Hosp Med. 2013;8(1):1-6. Epub 2012/11/21. doi: 10.1002/jhm.1985. PubMed PMID: 23165956.

4. Obayashi K, Araki T, Nakamura K, Kurabayashi M, Nojima Y, Hara K, et al. Risk of falling and hypnotic drugs: retrospective study of inpatients. Drugs R D. 2013;13(2):159-64. Epub 2013/06/14. doi: 10.1007/s40268-013-0019-3. PubMed PMID: 23760758; PubMed Central PMCID: PMCPMC3689908.

5. Ishibashi Y, Nishitani R, Shimura A, Takeuchi A, Touko M, Kato T, et al. Non-GABA sleep medications, suvorexant as risk factors for falls: Case-control and case-crossover study. PLoS One. 2020;15(9):e0238723. Epub 2020/09/12. doi: 10.1371/journal.pone.0238723. PubMed PMID: 32916693; PubMed Central PMCID: PMCPMC7486134 Chiba, Keiko Ashidate, Tomoyasu Ichijo, Takanori Shirai, Nobuo Ishiwata, Masataka Sasabe. declares that they have no conflicts of interest. Yoshiki Ishibashi, reports personal fees from Children and Future co., Ltd. Akiyoshi Shimura reports personal fees from Dainippon Sumitomo Pharma, Yoshitomiyakuhin, and Meiji Seika Pharma. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

6. Sys J, Van Cleynenbreugel S, Deschodt M, Van der Linden L, Tournoy J. Efficacy and safety of non-benzodiazepine and non-Z-drug hypnotic medication for insomnia in older people: a systematic literature review. Eur J Clin Pharmacol. 2020;76(3):363-81. Epub 2019/12/16. doi: 10.1007/s00228-019-02812-z. PubMed PMID: 31838549.

Responses to REVIEWER 2:

Thank you for your comments regarding our manuscript (PONE-D-22-02308). We appreciate your comments, which have helped us to improve our manuscript. In line with your comments, please find below our point-by-point responses.

Specific comments

Introduction

Comment 1:

Please describe that why patients with a hospital-acquired hip fracture have higher complication rate than those who fall outside of the hospital.

Answer: We fully agree with your comment. We added the reason why the patients with a hospital-acquired hip fracture have a poor prognosis. The patients with a hospital-acquired hip fracture are already in poor condition physically and mentally and have an especially poor outcome [1]. We added this sentence in the introduction sections. Thank you for your advice.

(Page4, line83-85)

Comment 2: The study gap is not clearly stated in the introduction section. The authors can highlight the components of the standing balance postural controls in elderly subjects.

Answer: We apologize for our unclear description. We should have clarified the study gap in the introduction section. Hypnotic drugs, including z-drug and orexin receptor antagonists, affect balance ability [2]. Therefore, we need to pay attention to the balance function of patients taking hypnotic drugs. We revised the introduction section to clarify this study’s aim in the introduction sections.

(Page5, line111-114)

Comment 3: o There is a discrepancy in the duration of data gathering. In line 122, the authors stated that data gathering was conducted from July to December 2021. However, in line 128 (for figure legend), it was reported as July to December 2020. Please check that which one is correct.

Answer: We apologize for the typo. I wrote the following sentence. Thank you for your careful reading. We did a retrospective study and enrolled all hospitalized patients who were taking hypnotic drugs from July to December 2020 at Kurume University Hospital.

(Page5, line126-128)

Comment 4: In introduction section, the authors stated that in their hospital benzodiazepine in not prescribed for patients. However, in method section the benzodiazepine is one of the hypnotic drugs that prescribed to the patients.

Answer: Thank you for pointing out the unclear points in our sentences. Our hospital recommends that physicians not prescribe benzodiazepines in case of insomnia. However, there were patients who had been taking benzodiazepines before they were admitted to our hospital in this study. As you point out, the introduction section seems misleading. We removed this sentence and revised the introduction sentences.

Comment 5: Line 204: please report the p-value for fall ratio between z-drugs and melatonin receptor agonists.

Answer: Thank you for your careful reading. As you suggested, we wrote the p-value for fall ratio between z-drugs and melatonin receptor agonists. We added the following sentence in the results sections.

However, there was no significant difference in the fall ratio between z-drugs and melatonin receptor agonists (p=0.1352).

(Page9, line213-214)

Comment 6: Please compare the results of this study with related articles that published previously.

Answer: Thank you for your advice. We compared the results of each drug fall rate in this study with the previous study in the discussion section. I appreciate your valuable comments.

(Page12, line300- Page13, line315)

Comment 7: In limitation section, please describe that why retrospective nature of the study design is one of limitation of the study.

Answer: Thank you for pointing this out. Our study evaluated balance function in patients who took the hypnotic drug. We assessed patients' balance ability at admission in this study. On the other hand, the timing of hypnotic prescriptions varies. Some patients had begun taking hypnotics before being admitted, while others started them during hospitalization. This is a limitation of this retrospective study. A prospective randomized controlled trial is needed to resolve this issue. We have added this point to the limitations section.

(Page14, line356-364)

Comment 8: - Conclusion: Relevant to the main findings.

Answer: We appreciate your comments. As you pointed out, the conclusion was inadequate. We modified the conclusion according to the results as follows.

This study investigated the ratio of patients who took the hypnotic drug. The falls ratio for z-drugs was significantly lower than for benzodiazepine drugs, and orexin receptor antagonists. Moreover, we also investigated the factors associated with falls. Balance disorder was an independent factor for falls using decision-tree analysis. Therefore, a physician should consider not only the choice of drugs but also balancing functions in inpatients.

(Page14, line368-373)

Comment 9: General point: There is some grammatical error in the text that should be revised by a native fluent reviewer.

Answer: Thank you for your advice. A native speaker had checked this manuscript before submission. We asked her to recheck this manuscript after revision. We consider that this manuscript's grammar has improved.

1. Foss NB, Palm H, Kehlet H. In-hospital hip fractures: prevalence, risk factors and outcome. Age Ageing. 2005;34(6):642-5. Epub 2005/11/04. doi: 10.1093/ageing/afi198. PubMed PMID: 16267194.

2. Bland H, Li X, Mangin E, Yee KL, Lines C, Herring WJ, et al. Effects of Bedtime Dosing With Suvorexant and Zolpidem on Balance and Psychomotor Performance in Healthy Elderly Participants During the Night and in the Morning. J Clin Psychopharmacol. 2021;41(4):414-20. Epub 2021/06/29. doi: 10.1097/JCP.0000000000001439. PubMed PMID: 34181362.

Submitted filename: PLOS one SIDE Responses to REVIEWER 2 final.docx

Click here for additional data file.

7 Jul 2022

9 Jul 2022

Responses to REVIEWER 3:

Thank you for your comments regarding our manuscript (PONE-D-22-02308R1). We appreciate your comments, which have helped us to improve our manuscript. In line with your comments, please find below our point-by-point responses.

Specific comments

Comment 1:

All the reviewers’ comments are addressed. However, I would like to ask about figure 6 is balance disorder " no" when the level of SIDE is:2a,1,0?

Answer: I apologize for my miswriting in figure 6. We defined patients who were unable to do tandem standing as having balance disorder (SIDE levels 0, 1, and 2a) (Page6, line153-155). We revised figure 6, thank you for your careful reading.

Comment 2: Also, the aim of work in abstract: The aim of this study was to investigate the cause of falls in hospitalized patients taking hypnotic drugs, while, in the introduction section, The purpose of this study was to investigate the fall rate of each patient who took the hypnotic drug and the factor associated with falls. In the conclusion section, "This study investigated the ratio of patients who took the hypnotic drug" is this accurate as regards the results?.

Answer: As you pointed out, the aim in the abstract and introduction was not appropriate. I revised the aim in the abstract section as follows. “The purpose of this study was to investigate the fall rate of each patient who took the hypnotic drug and the factor associated with falls.” (Page3, line51-53) Moreover, I miswrote the conclusion in the main text. I revised the conclusion as follows.” This study investigated the fall ratio of patients who took the hypnotic drug. The fall ratio for z-drugs was significantly lower than for benzodiazepine drugs, and orexin receptor antagonists. Moreover, we also investigated the factors associated with falls. Balance disorder was an independent factor for falls using decision-tree analysis. Therefore, a physician should consider not only the choice of drugs but also balance functions in inpatients.” (Page14, line369-374) I appreciate your valuable comments.

Submitted filename: PLOS one SIDE Responses to REVIEWER 3.docx

Click here for additional data file.

28 Jul 2022

Balance dysfunction the most significant cause of in-hospital falls in patients taking hypnotic drugs: A retrospective study

PONE-D-22-02308R2

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23 Aug 2022

PONE-D-22-02308R2

Balance dysfunction the most significant cause of in-hospital falls in patients taking hypnotic drugs: A retrospective study

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