Specific anxiety disorders and suicidal behaviors
\\n\\n
IntechOpen Book Series will also publish a program of research-driven Thematic Edited Volumes that focus on specific areas and allow for a more in-depth overview of a particular subject.
\\n\\nIntechOpen Book Series will be launching regularly to offer our authors and editors exciting opportunities to publish their research Open Access. We will begin by relaunching some of our existing Book Series in this innovative book format, and will expand in 2022 into rapidly growing research fields that are driving and advancing society.
\\n\\nLaunching 2021
\\n\\nArtificial Intelligence, ISSN 2633-1403
\\n\\nVeterinary Medicine and Science, ISSN 2632-0517
\\n\\nBiochemistry, ISSN 2632-0983
\\n\\nBiomedical Engineering, ISSN 2631-5343
\\n\\nInfectious Diseases, ISSN 2631-6188
\\n\\nPhysiology (Coming Soon)
\\n\\nDentistry (Coming Soon)
\\n\\nWe invite you to explore our IntechOpen Book Series, find the right publishing program for you and reach your desired audience in record time.
\\n\\nNote: Edited in October 2021
\\n"}]',published:!0,mainMedia:{caption:"",originalUrl:"/media/original/132"}},components:[{type:"htmlEditorComponent",content:'With the desire to make book publishing more relevant for the digital age and offer innovative Open Access publishing options, we are thrilled to announce the launch of our new publishing format: IntechOpen Book Series.
\n\nDesigned to cover fast-moving research fields in rapidly expanding areas, our Book Series feature a Topic structure allowing us to present the most relevant sub-disciplines. Book Series are headed by Series Editors, and a team of Topic Editors supported by international Editorial Board members. Topics are always open for submissions, with an Annual Volume published each calendar year.
\n\nAfter a robust peer-review process, accepted works are published quickly, thanks to Online First, ensuring research is made available to the scientific community without delay.
\n\nOur innovative Book Series format brings you:
\n\nIntechOpen Book Series will also publish a program of research-driven Thematic Edited Volumes that focus on specific areas and allow for a more in-depth overview of a particular subject.
\n\nIntechOpen Book Series will be launching regularly to offer our authors and editors exciting opportunities to publish their research Open Access. We will begin by relaunching some of our existing Book Series in this innovative book format, and will expand in 2022 into rapidly growing research fields that are driving and advancing society.
\n\nLaunching 2021
\n\nArtificial Intelligence, ISSN 2633-1403
\n\nVeterinary Medicine and Science, ISSN 2632-0517
\n\nBiochemistry, ISSN 2632-0983
\n\nBiomedical Engineering, ISSN 2631-5343
\n\nInfectious Diseases, ISSN 2631-6188
\n\nPhysiology (Coming Soon)
\n\nDentistry (Coming Soon)
\n\nWe invite you to explore our IntechOpen Book Series, find the right publishing program for you and reach your desired audience in record time.
\n\nNote: Edited in October 2021
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Only a small percentage of the proposed drug candidates receive government approval and reach the market place. Unfavorable pharmacokinetic properties, poor bioavailability and efficacy, low solubility, adverse side effects and toxicity concerns account for many of the drug failures encountered in the pharmaceutical industry. 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Suicide is undoubtedly the most tragic event in human life. Globally speaking, around one million people commit suicide each year. Suicide is possibly witnessed among a wide range of population extending from normal individuals reacting differently to stress-triggering life conditions to people diagnosed with a mental disorder. Mental disorders as suicide causes have been studied in numerous researches and the correlation between depression and suicide has been particularly emphasized because major depression disorder comes first among the mental disorders that are related to both completed suicide and also suicidal ideation and attempt. The relation between anxiety disorders and suicidal behavior has been examined in limited numbers of studies with differing results. Some studies posited that there might be a relation between anxiety disorder and suicidal behavior, while in other studies it was posited that anxiety disorders on their own cannot be effective in triggering suicidal behavior. Anxiety disorders often cooccur with depression, and this may be masking a risk of suicidal behavior specifically related to anxiety. This higher likelihood was seen despite controlling for current depression, highlighting the importance of clinicians considering suicidal risk when working with anxiety patients who do not necessarily also have a diagnosis of depression. Although anxiety has been proposed to be a potentially modifiable risk factor for suicide, research examining the relationship between anxiety and suicidal behaviors has demonstrated mixed results. Until recently, anxiety disorders were not regarded as an independent risk factor for suicidal behavior which in turn limited the number of studies focusing on the significant relation between anxiety disorder and suicidal behavior. In a different saying, suicidal ideation in anxiety-diagnosed patients went unnoticed. Strong evidences have been gathered proving that panic disorder is an independent risk factor for suicide. There are uncertain findings about the possibility that specific anxiety disorders such as generalized anxiety disorder, obsessive-compulsive disorder, and posttrauma stress disorder may be independent risk factors for suicide. There are, however, stronger evidences that when anxiety disorder is codiagnosed with comorbid depression, bipolar disorder, schizophrenia, drug use, and personality disorders the risk may be substantially higher. In other words, controversy exists whether anxiety disorders are independently associated (i.e., after adjusting for comorbid mental disorders) with suicidal ideation and suicide attempts. Despite the existence of literature studies providing nonhomogenous findings, it is of great importance that clinicians focus more eagerly and attentively on suicide behavior in patients with anxiety disorder – particularly in patients codiagnosed with mental-disorder – to provide assistance to suicide prevention attempts. In this chapter, the relation between suicidal behavior and the anxiety disorder will be discussed.
Anxiety disorders belong to the most frequent mental disorders and are often characterized by an early onset and a progressive, persistent/chronic, or recurrent course. Several individual, familial, and environmental risk factors for adverse course characteristics of anxiety disorders (including higher persistence, lower probability of remission, and increased risk of recurrence) have been identified, and previous research suggests that clinical features of anxiety (e.g., higher severity, duration, and avoidance) as well as comorbid other mental disorders are particularly useful for predicting an unfavorable course of anxiety disorders [1]. The literature reviewed here is consistent in showing that anxiety disorders are common psychiatric disorders that typically has an early age of onset, a chronic course, and a high degree of comorbidity with mood disorders and other psychiatric disorders [2]. Anxiety disorders are one of the most prevalent of all psychiatric disorders in the general population [3-5]. Phobias are the most common with the highest rates for simple phobia (SP) and agoraphobia. For example, SP is the most common anxiety disorder, with up to 49% of people reporting an unreasonably strong fear. Among general population, prevalence of social anxiety disorder (SAD) meeting DSM-IV diagnosis criteria is circa 13%. Among general population, prevalence of posttraumatic stress disorder (PTSD) is 7.8%; however among particular groups (war veterans with 20%, domestic violence victim women 12%), higher prevalence of PTSD has been reported [6]. Panic disorder (PD) and obsessive-compulsive disorder (OCD) are less frequent, and there are discordant results for SAD and generalized anxiety disorder [7]. The epidemiological studies have shown that anxiety disorders are highly prevalent and important causes of functional impairment [2, 8]. However, due to their methodic differences, epidemiologic studies fail to adequately explain the effects of anxiety disorders on functionality since the high frequency of confusing sociodemographic variables (gender, age, race, ethnic structure, education, and marital status) can play different roles in the symptom severity and course of anxiety disorders [7]. Agoraphobia, SP, and generalized anxiety disorder (GAD) are more common in female, while there is no gender difference for SAD, PD, and OCD [6]. Anxiety disorders are more common among separated, divorced, or widowed people between ages 25 and 44. Anxiety disorders are rare among age 65 and above. Start age for anxiety disorders however varies for specific anxiety disorders. For instance, phobic disorders start at early age, while panic disorder is witnessed during early adulthood stage. Rather than epidemiological studies, stressful life events, childhood experiences, and familial factors as risk factors have been examined in clinical researches. Anxiety disorders are usually chronic and persistent and are generally accompanied with other psychiatric disorders such as other anxiety disorders, depressive disorders, personality disorders, and drug use. These codiagnosed conditions may negatively affect functionality and life quality. Further study is needed to better understand the comorbidity between anxiety disorders, the consistently higher rates of anxiety disorders, and the differential effects of socioeconomic and cultural factors on anxiety disorders.
The currently accepted nomenclature of suicide-related behaviors identifies suicide, nonfatal suicide attempts, and suicidal ideation [9]. Suicidal ideation is verbally expressing one’s ideas about killing himself/herself. Suicide attempt is performing behaviors with the intention of killing oneself not ending with death but potentially causing major injuries. Completed suicide is dying as a result of the behavior performed to kill oneself. It is a requirement to make such classification for suicidal behaviors since for three different groups risk factors and clinical presentations vary. Hence this classification is needed in the prevention of suicides likewise. Global estimates suggest that each year there are 10–20 million suicide attempts and one million completed suicides [10]. Suicide attempts are costly in terms of occupational and interpersonal disruption [11]. Moreover, substantial financial costs are associated with the intensive psychiatric resources devoted to these patients [12]. Suicide is a multivariate phenomenon occurring with the combined effect of a multitude of factors such as psychological, sociological, economical, and cultural. That explains the reason why suicide can be witnessed among a vast sampling group ranging from normal individuals to patients with severe mental disorders. Mood disorders and personality disorders (borderline personality disorder in particular) are psychiatric problems most frequently associated with suicide. Besides, there have been striking findings recently that point to the increasing effect of anxiety disorders on suicide. On that account this relation should definitely be analyzed in the prevention of suicide, which is a crucial public health problem. In cases with anxiety disorder, analyzing suicidal ideation and suicide attempt may prevent completed suicides hence lower the ratios of completed suicide; because suicidal ideation and preattempted suicide are the biggest risk factors for a completed suicide [10, 13, 14]. Studying such thoughts and behaviors, therefore, may increase our understanding of who is likely to attempt or complete suicide, potentially informing suicide risk management and prevention efforts. Psychiatric disorders are one the primary risk factors for suicidality, with up to 95% of suicides committed by individuals with one or more disorders.
Patients with anxiety disorders are at high risk for suicidal ideation, regardless of whether the suicidal ideation is due to anxiety disorders itself or to cooccurring conditions. In evaluating the literature, it is necessary to review general requirements for establishing anxiety as a risk factor for suicidal behaviors [9]. In addition to establishing a meaningful and consistent interrelation of anxiety with suicidal behavior, the other requirement is the absence of a third variance (mixing factor) between suicidal behaviors and anxiety. Besides, anxiety must have existed before suicidal behavior and in suicidal behaviors anxiety must act as the independent risk factor. Psychiatric disorders are one of the primary risk factors for suicidality, with up to 95% of suicides committed by individuals with one or more disorder [15]. In particular, the mood and anxiety disorders are associated with suicide ideation and attempts [16-19]. The relationship between anxiety disorders and suicide-related behaviors has received a modest amount of attention. However, research has also accumulated over the past several years indicating that anxiety disorders confer unique risk of suicide [20, 21]. The presence of current or lifetime anxiety disorders, including panic disorder, social phobia, generalized anxiety disorder, and posttraumatic stress disorder, are associated with increased suicide risk [10, 18, 22, 23]. Individuals with anxiety disorders demonstrate increased suicidal ideation and rates of self injury and more frequent suicide attempts than those without mental health disorders [10, 16, 17]. For this reason, it is of vital importance to comprehend and manage the risk factors for suicide among individuals with anxiety disorders. Despite the prevalence of high risk for suicide within cases with anxiety disorder, the determinants of suicide risk in this group have not yet been clearly established. In other words, anxiety disorders are very common and increase risk for suicide attempts. Little is known about predictors of increased risk specifically among individuals with anxiety disorders [19]. Studies of individuals with specific anxiety disorders including panic disorder, social phobia, and posttraumatic stress disorder indicate that the additional presence of depression and substance use disorders increases suicide risk [10, 24]. Severity and aspects of functional impairment are also related to suicide risk in patients with anxiety disorders. For example, anxiety symptom severity is associated with increased suicidal ideation and attempts in patients with PD and patients with PTSD [10, 25, 26]. Associations between suicide risk and impairment in general functioning in PTSD and social functioning in both PTSD and PD are also documented [27, 28]. Twelve-month prevalence rates of suicidal ideation in patients with obsessive-compulsive disorder (OCD, 27.3%), the prevalence rate of suicide attempts in panic disorder (3.6%) and the prevalence rate of suicide attempts in OCD (3.3%) were the highest [21]. The overall 12-month and lifetime prevalence of GAD was 0.8% and 1.2%, respectively. Being older than 25 years and female, lower education level, unemployed status, and lower monthly income were associated with increased risk of GAD in China [29]. It remains unclear whether certain anxiety disorders are risk factors for suicide. For instance, Uebelacker et al. [19] have reported that PTSD, major depressive disorder (MDD), intermittent depressive disorder, epilepsy, pain and low social functionality are, according to univariate analysis, predictors of suicide attempt. In the same study, the findings of multivariate analysis showed that, even when the suicide attempts of the past are controlled, MDD and intermittent depressive disorder are independent risk factors in current attempts for suicide. However, it was concluded in this research that except panic disorder, no other specific anxiety disorder constituted an independent risk factor for suicide attempt. Mood disorders and past history of suicide attempts are the most powerful predictors of a future suicide attempt. Particularly, the patients with comorbid major depressive disorder anxiety are at higher risk for suicide. Thereby primary care health service doctors, emergency and mental health professionals, and clinicians who frequently come across with anxiety disordered cases should be alerted and attentive against potential suicidal ideation and suicide attempts among these patients.
The presence of anxiety disorder is frequently associated with suicide ideation and behaviors. Considering the high costs of suicidal behaviors for the individuals and also the society, it is a foremost priority to prevent suicide. Grasping the factors related to increased risk for suicide among people with anxiety disorders may be contributive to suicide prevention attempts [10]. Anxiety disorders are independent risk factors for suicide attempts and underscore the importance of anxiety disorders as a serious public health problem [17]. The relationship between anxiety disorders and completed suicide is not known exactly. There are a limited number of studies on this subject [30, 31]. It is unclear whether clinical and behavioral suicide risk factors, identified primarily among men, can be extended to women. Personality variants and gender differences among suicide completers with psychopathological autopsy method were investigated. Among women, the ratio of completed suicides is lower than men. Impulsivity and alcohol use are risk factors for completed suicides. It is less common among women to see lifelong alcohol consumption, and among women with alcohol addiction, there is less prevalence of comorbid depression when compared to men. There exists a correlation between alcohol consumption and impulsivity. The low ratio of impulsivity among women triggers alcohol consumption as well. Furthermore, when the relation between impulsivity and applied suicide method is examined, it surfaces that among cases with high ratio of impulsivity, the tendency to apply violence methods is more common. It is argued that women prefer nonviolent suicide methods less pain causing but regardless of their sex, cases with anxiety disorder apply to nonviolent methods more frequently. On the other hand, when high ratio of impulsivity is combined with alcohol consumption, there may occur an elevated risk of suicide for both sexes [30].
The relationship between anxiety disorders and racial and ethnic differences has been studied in several research. For instance, Vanderwerker et al. [32] examined in their study covering 131 adults from different ethnic and racial origins (more than half of the cases with African American roots) the differences of risk factors for suicidal ideation and suicide attempts. They have detected that among young white adults, anxiety disorder (not depression) has an independent relation with suicide tendency, while there is no such relationship for African-Americans among whom there is a significant relation between suicidal behavior and social support could be identified. These findings clearly prove that suicide risk factors vary among races and ethnicities [32]. The results suggest that race/ethnicity-specific risk profiles may improve the detection of suicidality in vulnerable populations. But, Beautrais et al. [33] were found no ethnic differences in suicidal ideation. Risks of suicidal ideation, plan, and attempt were associated with mood disorder, substance use disorder, and anxiety disorder. Major depression was the specific disorder most strongly associated with suicidal ideation, plan, and attempt [33]. In a different study based on society sampling, a number of variables (demographic, work status, mental and physical health condition, personality features, stressful life experiences, and social environment) impacting the suicide-attempt speed in cases with suicidal ideation have been examined. Among age groups between 20–24 and 40–44 having committed suicide attempt, it has been seen that there was a higher ratio of suicidal ideation with respect to age-matched groups and higher levels of anxiety and depression. Upon checking the remaining variables, it has been reported that in cases between ages 20–24, rather than suicidal ideation but anxiety itself constituted a risk factor for suicide attempt. Particularly among men between ages 40–44, physical diseases and unemployment, rather than anxiety and depression, posed greater risks for suicide attempt. In a different saying, Fairweather et al. [34] found that ideators and attempters experience comparable levels of depression and anxiety. Rates of self-harm and associations between self-harm and suicidal behaviors, anxiety, hostility, and paranoid ideas were reported by Fliege et al. [35]. Although there has been significant interest in whether anxiety disorders are risk factors for suicidal behavior, this remains a controversial area. Cross-sectional community and clinical studies have repeatedly demonstrated in univariate models that anxiety disorders are associated with suicidal ideation, attempted suicide, and completed suicides. In multivariate models, it has been questioned whether panic disorder is associated with suicidal behavior after adjusting for other anxiety and psychiatric disorders. Because anxiety disorders are highly comorbid with other anxiety disorders and tend to cluster together, it is important to address whether anxiety disorders as a group of psychiatric disorders have an impact on suicidal behavior after adjusting for other types of other psychiatric disorders (especially mood and substance use disorders) [16].
The relationship between anxiety disorders and suicidal behaviors has not received sufficient amount of interest till present age. Literature review shows that when there is a definite result for a single anxiety disorder, anxiety disorders in general have high frequency relation with suicidal ideation; however its relationship with suicide attempt is not definite [9, 18, 36]. General tendency indicates that for each anxiety disorder there is a similar risk for suicide primarily obsessive-compulsive disorder, generalized anxiety disorder, and social anxiety disorder are associated with suicide ideation. The only specific anxiety disorder related most with suicide attempt is panic disorder [37]. In addition, a clear relationship was reported between PTSD and suicidal thoughts and behaviors, irrespective of the type of trauma experienced. It has been suggested that PTSD has a strong association with suicidality, predicting subsequent suicidal attempts [28, 38].
Suicidal behaviors are multifactorial behaviors. While, historically, anxiety has been regarded as an important risk factor in suicidal behaviors, epidemiological studies carried out on general population or panic patients have evidenced the possible links between suicidal behaviors and the occurrence of panic attacks [39, 40]. Both panic attacks and panic disorders are, in the society and primary health care service, independently related with the increased suicide attempt risk. In epidemiologic samplings, panic disorder is, like major depressive disorder, a risk factor for lifelong suicide ideation and suicide attempt [40-42]. For example, an association between panic and suicidal ideation has been reported by Goodwin and Roy-Byrne [43]. Epidemiologic catchment area (ECA) studies indicate that, when contrasted with other psychiatric disorders, panic disorder is associated with increased suicide ideation and suicide attempt risk [40]. Additionally, epidemiologic data show that when panic disorder is codiagnosed with major depression, alcohol addiction, personality disorders, and cocaine use, there is higher risk for suicide attempt [44, 45]. For instance, Goodwin and Roy-Byrne report that despite the vital role comorbid depression and drug abuse play, attempts for the last one year (not lifelong) are independently related to panic disorder [43]. It has been suggested that panic disorder may not increase past suicide attempt systematically but may climb the suicide attempt in the future. In a vast majority of the monitoring studies of patients with anxiety disorder, there was 20% ratio of suicide caused deaths like the results in major depressive disorder. Similarly, the ratios in suicide attempts have been similar to major depressive disorder and panic disorder [40, 46]. Existing findings are quite remarkable. Patients who suffered from major depressive disorder with related panic disorder were given to more impulsive suicide attempts, even if the difference with depressed patients without panic disorder was statistically insignificant [39]. Primary care patients with PD are at high risk for suicidal ideation, and patients with PD and cooccurring MDD are at especially high risk. Patients with PD in primary care thus should be assessed routinely for suicidal ideation and depression [42]. Although in society-based studies it is indicated that there is a strong relation between PD and suicide ideation, in many other studies with clinic sampling (receiving psychiatric treatment and hospitalized in psychiatry clinic or hospital), no statistically significant relation between PD and suicidal ideation could be detected [24, 47]. For example, Warshaw et al. [24] reported that there was no association between PD and suicidal ideation after controlling for common comorbid psychiatric disorders. In another study, it was revealed that suicidal behavior risk in panic disorder is not higher than the risk in major depressive disorder [42]. Dammen et al. [47] could not find any difference in terms of suicidal ideation between patients with or without panic disorder. Several mental disorders, such as personality disorders, and life events that that have been associated with suicidality, e.g., early childhood abuse, were not assessed and may account partially for the observed association between PD and suicidal ideation [48, 49]. In some clinical studies, patients with PD and borderline personality disorder were at significantly higher risk of suicidal behavior than were PD patients with panic disorder alone [24]. To sum up, there is still an ongoing discussion about the relation between panic disorder and suicide behavior. It is not yet identified if panic disorder singly or when comorbid with other mental disorders like major depressive disorder is effective in suicidal behavior [24, 40, 50]. Thus, the data indicate that the risk of suicide in panic disorder is substantial. As a consequence, clinicians should alert themselves to this preventable outcome and approach treatment with added caution.
Posttraumatic stress disorder (PTSD) is frequently associated with suicidal ideation and suicide attempts. Suicide is an important cause of death in veterans, and the risk for intentional death continues to be high many years after service [51]. Suicidal behavior is a critical problem in war veterans. Combat veterans are not only more likely to have suicidal ideation, often associated with PTSD and depression, but they are more likely to act on a suicidal plan [52]. Citizen soldiers (National Guard and Reserves) represent approximately 40% of the two million armed forces deployed to Afghanistan and Iraq. Twenty-five to forty percent of them develop PTSD, clinical depression, sleep disturbances, or suicidal thoughts [53]. Veterans reporting subthreshold PTSD were three times more likely to endorse these markers of elevated suicide risk relative to the veterans without PTSD [54]. They found no significant differences in likelihood of endorsing hopelessness or suicidal ideation comparing subthreshold and threshold PTSD groups, although the subthreshold PTSD group was less likely to report prior mental health treatment [54]. Major depressive disorder cooccurs frequently with PTSD, and both disorders are linked to suicidal ideation. For the war veterans with depression symptoms, there is a strong relation between PTSD symptoms and suicidal ideation. According to these findings, when analyzing PTSD-diagnosed war veterans, depression symptoms of suicidal ideation must be taken into account [55]. Of those veterans diagnosed with PTSD, many have comorbid psychiatric disorders, typically major depressive disorder, substance use disorders, and other anxiety disorders [56]. Veterans with PTSD are also more likely to have social, occupational, and functional difficulties, including social isolation, frequent interpersonal altercations, and suicidal ideation [28]. PTSD and MDD occur together frequently, and both disorders have been separately linked to the increased risk of suicidal ideation [57, 58]. It is unclear, however, whether the combination of comorbid MDD and PTSD confers an increased risk for suicidal ideation beyond the risk presented by either diagnosis alone. Several studies of veteran samples have found that the combination of PTSD and MDD did not place individuals at greater risk for suicidal ideation than did a single diagnosis [54, 55, 59]. Conversely, Oquendo et al. [60] found that individuals with current MDD and comorbid PTSD were more likely to endorse suicidal ideation compared to those without a current PTSD diagnosis. In a different study, it was determined that among veterans with schizophrenia and schizoaffective disorder, there is an independent relation between comorbid PTSD suicidal ideation risk but no such risk could be detected for suicide attempt [61]. Suicide has huge effect on public health but despite efficient interventions, a great number of people with suicide risk cannot benefit from these interventions and lose their lives. Until now, a huge number of programs and strategies named as “suicide prevention” have been developed. Recent interventions about exercise give hope in the prevention of suicide thanks to its ease of application because exercise mitigates depression symptoms. Alleviating depression symptoms may provide lessened suicidal ideation and attempt but no study has so far indicated a direct relation between exercise and suicidal behavior. Davidson et al. [62] analyzed in veteran sampling a number of variables (sleep disorders, PTSD, and depression) that might be associated with suicidal risk. In this study, it has been emphasized that there may exist an indirect relation between exercise and suicide. It has also been suggested that exercise is also connected with low depression symptoms and a better sleep pattern, which might in effect lead to lower suicidal risk. A high prevalence of all types of violence is associated with the highest prevalence of depression and PTSD [63]. It is well established that intimate male partner violence (IPV) has a high impact on women’s mental health. Compared to women in control group, among women subjected to physical and psychological IPV, there is higher ratio of depression and anxiety disorders, PTSD, and suicidal ideation. Among women exposed to sexual abuse and sexual violence, there is high ratio of depression symptoms, physical/psychological abuse, and suicide attempt. In reality, PTSD on its own is quite hard to see. Depression symptoms are present either singly or codiagnosed with PTSD. Anxiety ratios are higher among women with comorbidite or abused women with depression symptoms. This may explain the high ratio of suicide attempts and anxiety among physically/psychologically abused women [64, 65]. Recovery from depressive symptoms, state anxiety, and posttraumatic stress disorder in women exposed to physical and psychological but not to psychological intimate partner violence alone. A metaanalysis with 50-article examining the relation among PTSD and past and present suicidal ideation and behavior has been conducted. There is no evidence showing that among PTSD patients there is a risk for completed suicide risk. A relation has been found among presuicide attempt and past and present suicidal ideation. Upon checking other psychiatric disorders (including depression), the relation between PTSD and suicide attempt has been examined but no sufficient data could be detected, but it was also reported that comorbidity depression and pretraumatic psychiatric state may have been a mediator. It is seen that a relation exists among various factors and PTSD and suicidal tendency [66]. In a different study, it was seen that among women patients with comorbid PTSD and drug addiction, suicide behavior varies according to drug addiction type and presence of preventive factors (for instance, worries about kids, will to live, and coping skill) [67]. Clinicians should be attentive to suicide risk in returned veterans and in women exposed to physical/psychological and psychological IPV. For future studies, assessing suicide risk in PTSD and identifying risk factors shall assist in better understanding the topic and preventing suicidal behavior.
Suicidal thoughts and behaviors, also known as suicidality, are a fairly neglected area of study in patients with obsessive-compulsive disorder. Patients with obsessive-compulsive disorder (OCD) have historically been considered at low risk for suicide, but recent studies are controversial. Torres et al. [68] found thirty-six percent of the patients reported lifetime suicidal thoughts, 20% had made suicidal plans, 11% had already attempted suicide, and 10% presented current suicidal thoughts. The sexual/religious dimension and comorbid substance use disorders remained associated with suicidal thoughts and plans, while impulse-control disorders were associated with current suicidal thoughts and with suicide plans and attempts [68]. The risk of suicidal behaviors must be carefully investigated in OCD patients, particularly those with symptoms of the sexual/religious dimension and comorbid major depressive disorder, PTSD, substance use disorders, and impulse-control disorders [69]. Lester and Abdel-Khalek [70] reported that there is no relation between OCD and suicidal ideation but a relation between OCD and suicide attempt. However, there are certain limits such as the smallness of sampling group and failure to control depression. In a different study conducted with same research group in 2002, it was reported that there is a significant relation between OCD and suicidal ideation but again depression was not controlled in another study [71]. Obsessive-compulsive personality disorder is a factor increasing risk for nonfatal suicidal behavior independently of risk conferred by depressive disorders. For example, Diaconu and Turecki [72] reported that the comorbid obsessive-compulsive personality disorder depression group presented increased current and lifetime suicide ideation compared to the groups with depression alone or without depression, or personality disorders they also had increased history of suicide attempts which were often multiple attempts. OCD is associated with a high risk for suicidal behavior. Depression and hopelessness are the major correlates of suicidal behavior [73]. Suicidal behavior is not a common phenomenon in OCD, but among single patients in particular, accompanying depression, symmetry/order obsession, and compulsions are high risk factors for suicide [74]. In patients with OCD, risk factors for suicidal behavior have been left ignored when compared to other anxiety disorders. However, a high ratio as 10–27% was reported for suicidal behavior. This condition shows that OCD patients may commit suicide attempt at least once in their life [16]. Besides as in OCD assistance-seeking ratio is comparatively lower than assistance search in comorbid OCD, it becomes evident that in OCD patients assistance-seeking methods should be increased in suicide prevention strategies. Suicidality has been underestimated in OCD and should be investigated in every patient, so that appropriate preventive measures can be taken.
Generalized anxiety disorder (GAD) is a chronic general disease among adult population but it is comparatively a less understood clinical state. Clinicians may have knowledge about the characteristics of GAD such as over anxiety, anxiety, and hypervigilance, but such symptoms may fall short in distinguishing GAD from other psychiatric disorders, because in the course of several mental diseases these symptoms are frequently observed. Interestingly enough, despite the changes in diagnosis criteria, prevalence predictions for GAD are quite consistent among epidemiologic studies. It is predicted that among general population, lifelong prevalence is 5% (DSM-III and/or DSM-IV-R criteria). GAD is common in different levels among gender, ethnics, and social groups. Among age 40 and above women, in addition to high ratio as 10%, in the cases applying to primary care service, GAD is 8%. Again in the first primary care service, GAD is the most widely diagnosed anxiety disorder. GAD’s age of onset is different than other anxiety disorders. Prevalence ratios are low among teenagers and young adults but age is a remarkably triggering effect. Women are, compared to men, at higher risk. GAD is more frequent among unemployed housewives with chronic medical diseases [75]. GAD is frequently associated with accompanying depression, other anxiety, and somatoform disorders [76]. Weak family relations, codiagnosed C group personality disorders in stressful life events and codiagnosed Axis 1 disorders, are the increasing factors of GAD’s effects [77]. GAD is quite prevalent all over the world but the relation between GAD and suicidal behavior has not been investigated. There are a limited number of studies on this topic. In another study, it was detected that there is a relation between impairment and suicidal ideation and GAD [29]. Zimmerman and Chelminski [78] found that depressed patients with GAD had higher levels of suicidal ideation when compared to patients with depression only. In future studies, analyzing the impact of GAD on suicidal behavior may be illuminating on the potential risk factors.
Life-long prevalence of social anxiety disorder is 13%, which is a quite high ratio among general public. Not only it leads to a major loss of ability but it is often associated with increased suicide ratios and codiagnosed drug abuse; but the relation between social anxiety disorder and suicidal behaviors has not been analyzed adequately so far. The characteristics of patients with social anxiety disorder are that they unrealistically fear that others will constantly and persistently criticize their acts. Social anxiety disorder usually springs up during puberty and it really emerges for the first time after age 25 [79]. Rates of social anxiety disorder were highest among women and persons who were younger, less educated, single, and of lower socioeconomic class. SAD is a common illness often followed by comorbid MDD and alcohol dependence. SAD with comorbid MDD predicts a substantially elevated risk of alcohol dependence and suicide-related symptoms, stressing the need for early SAD detection [80]. It has been reported that despite the high frequency of suicidal ideation among patients with anxiety disorder, the level of suicide attempt is low. Furthermore, the data show that in social anxiety disordered cases, the ratio of lifelong suicide attempt is 12–18% but this condition is associated with codiagnosed depression symptoms [81]. It is also reported that 69% of patients with social anxiety disorder are afflicted with other lifelong comorbid mental disorders and with the occurrence of social anxiety usually, they are added into clinical picture. Once contrasted with people having no mental disorder, uncomplicated social anxiety disorder is found to be connected with increased suicidal ideation, financial dependency, and having sought medical treatment. Nonetheless, no connection was established between social anxiety disorder and suicide attempt and psychiatric treatment. It has been reported that in social anxiety disorder there is elevated suicide attempts, but these cases are surprisingly comorbid cases. In the absence of comorbidity, social anxiety disorder is still a problem that spoils the functionality, but patients rarely seek psychiatric treatment; hence large numbers of cases cannot be examined well by the clinicians [82]. The effect of anxiety disorder alone on suicide behavior has not yet been established but when social anxiety disorder’s chronic course and adverse impact on functionality are considered, particular attention needs to be paid in the assessment of patients in this group.
Comparison of the suicidal behaviors of the specific anxiety disorders is given in Table 1.
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t
Panic disorder | \n\t\t\t++++ | \n\t\t\t++++ | \n\t\t\t? | \n\t\t
Posttraumatic stress disorder | \n\t\t\t+++ | \n\t\t\t+++ | \n\t\t\t? | \n\t\t
Obsessive-compulsive disorder | \n\t\t\t+/? | \n\t\t\t? | \n\t\t\t? | \n\t\t
Social anxiety disorder | \n\t\t\t? | \n\t\t\t? | \n\t\t\t? | \n\t\t
Generalized anxiety disorder | \n\t\t\t? | \n\t\t\t? | \n\t\t\t? | \n\t\t
Simple phobia | \n\t\t\t? | \n\t\t\t? | \n\t\t\t? | \n\t\t
Specific anxiety disorders and suicidal behaviors
Strong evidence: ++++, Evidence: +++, No clear evidence +/?, No data: ?
Anxiety disorders, when accompanied with other comorbid mental disorders, may affect the course and treatment of disease. Comorbid conditions may occasionally lead to diagnostic ambiguity, and in a number of cases, multiple comorbid mental disorder may accompany the present clinical picture. In a research conducted by Sanderson et al. [83], it was reported that among 70% of patients with anxiety disorder, there is minimum one additional Axis 1 diagnosis. In present study, the highness of comorbidity ratio draws attention. However, once considered that current diagnosis systems are largely consisting of joint symptom clusters, these ratios appear to be exaggerated predictions. Nevertheless, mental disorder comorbidity is considered negative for the natural course of illness by implying additional kinds of dysfunction depending on whether it is a disorder of mood, substance abuse, or personality [84, 85]. These three are the most common comorbid disorders.
The potential association between anxiety disorders and suicidal ideation rendered mixed results. In the researches, positive findings between anxiety and suicidal ideation may be connected to accompanying depression. In patients diagnosed with anxiety disorder not positing mood disorder story, there was no increased risk for suicidal ideation. On the other hand, in a recent study, it has been reported that among anxiety disordered cases not accompanied with mood disorder, there is an increased risk for suicidal ideation [86]. Nonetheless, in current research, subsyndromic depression symptoms have not been excluded, which puts the findings of research open to discussion. Traditionally, research on suicide has emphasized relationships with mood disorders, psychotic disorders, and some personality disorders. Although certain features of anxiety have been incorporated into models of suicide, anxiety-related conditions such as severe psychic anxiety, agitation, and panic have typically been examined as predictors of suicidal behaviors only to the extent that they overlap with mood disorders. Sareen et al. [16] in their 3-year long monitoring studies probed into the relation between anxiety and mood disorder–diagnosed cases and lifelong suicide ideation and suicide attempt, and they found out that in the presence of an anxiety disorder not positing a mood disorder story, there is a significant relation between lifelong suicidal ideation and suicide attempt. However, the main limitation of their study is that while analyzing particular anxiety disorders, probable mixing factors (syndromal depressive symptoms, etc.) have not been excluded. Despite this, there is fairly strong evidence that even subthreshold depressive symptoms are associated with increased psychosocial impairment, higher rates of comorbid substance use problems, and greater risk for future syndromal depressive episodes [87]. Further, studies provide strong evidence for an additive and interactive relative risk conveyed by cooccurring anxiety and depression. Consequently, comprehensive suicide assessment plans are strongly recommended when evaluating or treating individuals with an anxiety disorder, and especially individuals with comorbid anxiety and depressive disorders [88].
Clinical and epidemiological studies have provided convincing evidence that comorbid anxiety disorders are relatively prevalent among patients with bipolar disorder (BD), found in up to 65% of cases [89]. Henry et al. [90] studied 318 inpatients including bipolar I and found that 24% had at least one lifetime anxiety disorder and 11% of the patients had more than one such disorder. Comorbidity of anxiety disorders may be associated with greater suicidality, substance abuse, resistance to pharmacological treatment, and poor outcome [91-93]. Altındag et al. [94] studied 70 outpatients including bipolar I and found that 27.1% had at least one lifetime anxiety disorder, and most common anxiety disorders in this sample were obsessive-compulsive disorder (12.8%) and specific phobia (12.8%), followed by panic disorder (5.7%). Anxiety disorder comorbidity appears to be associated with greater number of hospitalizations, psychotic symptoms, and suicide attempts in patients with bipolar disorder type I. Bipolar subjects with anxiety disorders were younger, had earlier age at onset of illness, and were overrepresented by female subjects and those with earlier onset illness compared to those without anxiety disorder [95]. Panic disorder, which also confers an independent risk of suicide and psychiatric comorbidity, in general has been found to amplify suicidality in mood-disordered patients [96]. The presence of comorbid panic disorder in individuals with bipolar disorder may confer an increased risk of suicide risk. Some papers’ reviewed have conflicting conclusions but the majority of papers support an increased risk. Future research should study specific bipolar subgroups, focus on anxiety and panic symptoms rather than diagnosis, and look at the role of specific pharmacological treatment in patients with comorbid mood and anxiety disorders. Among anxiety disorders, only social phobia (SP) was significantly associated with history of suicide attempt in BD. In other words, SP is an important risk factor for suicidal behavior in BD [97]. Suicide takes significantly different forms within different stages of behavioral bipolar disorder. Suicide attempts and suicidal ideation have been found to be most closely connected to the depressive periods of disease. Severity of despair and depression are the key indicators of risk for all stages [98]. Previous studies have shown a significant relationship between suicide ideation and mixed depression. The rates of mixed depression among bipolar and nonbipolar depressive suicide attempters were much higher than previously reported among nonsuicidal bipolar II and unipolar depressive outpatients, suggesting that suicide attempters come mainly from mixed depressives with predominantly bipolar II base. Irritability and psychomotor agitation were the strongest predictors of suicide attempt [99]. Although anxiety may be a modifiable suicide risk factor among bipolar patients, anxiety disorder comorbidity has not been highlighted as critical in identification of high-risk individuals nor has its treatment been integrated into suicide prevention strategies. Although lifelong anxiety disorders are related to past suicide attempts, current comorbid anxiety disorders are found to be connected to suicidal ideation. In anxiety disordered individuals, suicidal ideation is a risk factor for suicide behaviors in future. The early onset of polar disorder and frequent appearance of rapid cycling and mixed periods constitute great risk for suicidal behavior. All in all, both bipolar disorder and anxiety disorder bear risks for suicidal behavior. In the presence of comorbid anxiety disorders, suicide behavior risk may gain even further impetus in bipolar disorder cases. To put differently, anxiety disorders (social anxiety disorder at most) may play active role in developing suicidal ideation and suicide attempt among bipolar disordered cases [100]. In the presence of comorbid anxiety disorders in bipolar disordered cases, patients must be attentively monitored against suicidal risk. Further studies shall contribute to better comprehending suicide behavior in bipolar disorder patients with anxiety disorder.
The high prevalence of comorbid drug abuse in anxiety disorders is attributed to patients’ relief seeking in alcohol and/or drugs for alleviating the emotional stress they cope with (self-medication). Regardless of the high ratios of alcohol and drug use in anxiety disorders, self-medication has been discussed in limited numbers of studies. Likewise although in mood disorders there is high frequency of alcohol and drug abuse, there is a limited body of research on this domain. The use of alcohol and drugs to relieve affective symptoms is common among individuals with mood disorders in the general population [101]. Comorbid specific mood and anxiety disorders and specific drug use are widely common in American society. Among women in particular comorbid psychiatric disorders may lead to critical use of illegal drugs. In present study, it was reported that among female cases diagnosed with comorbid mood and anxiety disorder, in comparison to postdrug-alcohol addicted men, medical prognosis of disease is affected more negatively [102]. Among cases with anxiety disorder self-medication has been associated with accompanying mood disorders, drug abuse, anxiety, suicidal ideation, and increased risk for suicide attempt. Even after controlling sociodemographic and psychiatric variances self-medication remained to be related to suicidal ideation and increased risk for suicide attempt. Bolton et al. [103] reported that individuals with anxiety disorders who self-medicate their symptoms with alcohol or drugs may be at increased risk for mood and substance use disorders and suicidal behavior. In this study covering a wide sampling of society, self-medication prevalence varied between 7.9% (social phobia and speech subtype) and 35.6% (GAD). Multivariate analyses put forth that self-medication is independently related to lifelong suicidal ideation and attempts and also to an increased comorbid mood disorder and drug abuse tendency. Alcohol use disorders and suicidal ideation cooccur, yet few studies have investigated the risk and protective factors that influence their comorbidity. The comorbidity between alcohol use disorders and suicidal ideation is characterized in young women by cooccurring psychopathology, drinking to cope, and negative life events [104].
Among schizophrenic patients, there is a considerably high ratio of suicidal behavior. It is particularly noteworthy that among schizophrenic cases with suicide attempt story and suicidal ideation in the past, there is also comorbid OCD. Also the ones with suicide story are significantly higher in patients with OCD-schizophrenia than in patients with non-OCD schizophrenia. Compulsive symptoms were significant predictors of suicide attempt among patients with schizophrenia [105]. The obsessive-compulsive symptoms may account for the emergence of suicidality in patients with OCD-schizophrenia. In schizophrenia suicidal ideation has been auspicated with depressive mood, anxiety, low self esteem, negative disease perceptions, negative assessments of the self and others, and daily alcohol consumption. The frequency of coping with audio hallucinations and delusions has no connection with suicidal ideation but distress caused by positive symptoms was found to be related to suicidal ideation [106]. Affective dysfunction, including distress in response to hallucinations and delusions, was a key factor associated with suicidal ideation in individuals with psychotic relapse.
In elderly persons with major depressive disorder, coexisting generalized anxiety disorder or panic disorder is associated with more severe symptoms and poorer short-term treatment outcomes. De Luca et al. [107] found evidence that comorbid generalized anxiety disorder or panic disorder is associated with a greater decline in memory in late-life MDD and suicidal ideation. The clinical correlates of comorbid anxiety and depression in a sample of older patients with major depression. In elderly patients with anxious depression, psychosocial support and suicidal ideation should be assessed [108]. Anxiety symptoms are the frequent comorbids of old-age depression; hence MDB comorbid with subsyndromal anxiety symptoms is termed as “anxious depression.” In reality, MDD is generally comorbid with specific anxiety disorders but there is no definite information on the frequency, diagnosis, clinical course, and treatment approaches for anxiety disorders among elderly group. It is acknowledged that specific anxiety disorders, anxiety disorders comorbid with MDD, are less common among the elderly. Still, in aged people with anxious depression, particularly in complex cases comorbid with chronic physical disease, there is a heightened risk for suicidal ideation, disability, and poor prognosis. Standard pharmacotherapy could be sufficient for depression but among many older people with anxious depression. Standard pharmacotherapy on its own may fail to be sufficient. There are a number of psychosocial treatments but they are not specific for old-age anxious depression. However, psychosocial interventions may be a major constituent in the treatment of these patients [109]. In the elderly group, ratios of completed suicide are significantly higher than the other age groups, thus in preventing old-age suicides, the elderly cases diagnosed with “anxious depression” must be studied attentively.
Suicidal ideation and behavior have been associated with a variety of neurological illnesses. There are important linkages between suicidal ideation and behavior and neurological conditions, including epilepsy, multiple sclerosis, and amyotrophic lateral sclerosis [110]. Anxiety disorders are common in patients with multiple sclerosis, but are frequently overlooked and undertreated. Korostil and Feinstein [111] studied 140 outpatients including multiple sclerosis and found that 35.7% had at least one lifetime anxiety disorder, and most common anxiety disorders in this sample were panic disorder (10%) and obsessive-compulsive disorder (8.6%), followed by generalized anxiety disorder (18.6%). Subjects with an anxiety disorder were more likely to be female, have a history of depression, drink to excess, report higher social stress, and have contemplated suicide. Risk factors include being female, a comorbid diagnosis of depression, and limited social support. Clinicians should evaluate all multiple sclerosis subjects for anxiety disorders, as they represent a treatable cause of disability in multiple sclerosis. The studies have observed a strong relationship between coronary artery disease (CAD) and psychiatric disorder, notably depression, anxiety, and panic attacks. A significant positive relation was observed between CAD and lifelong prevalence of suicide attempts. Suicide attempts were found to be connected with major depression and comorbid anxiety disorder but no relation was detected between suicide attempts and anxiety singly. At the end of logistic regression analysis, the relation between suicide attempt and CAD continued after making correction for depression and anxiety. In a different saying, CAD is an independent risk factor more powerful than depression for suicide behavior [112]. Acne is a common disease in adolescence with female preponderance. It could cause poor self-esteem and social phobia. Previous studies based on questionnaires from several thousands of adolescents showed that acne is associated with major depression and suicide [113, 114]. However, the gender- and age-specific risk of depression and suicide in patients with acne remain largely unknown. The risk is additive in women with acne. Similar additive risk of suicide was noticed in women with acne. In recently, Yang et al. [115] reported that acne and gender, independently and jointly, were associated with major depression and suicide. Special medical support should be warranted in females with acne for the risk of major depression and suicide. It has been demonstrated that a correlation exists between an extensive scope of physical diseases and increased ratios of suicide. As the studies on particular topic are examined, it surfaces that medical diagnoses alone are not sufficient causes to lead a person to suicide. Comorbid mental disorders are equally responsible in the development of suicide. It is thus important to train the clinicians on identifying not only physical symptoms but mental symptoms too and the ways to determine their effects on the treatment and the course of disease. To have a lifesaving effect, particular attention to crisis periods, stages of physical illness, and postdischarge period should be monitored attentively on accounts of being risk-posing periods for suicide behavior. It is thus obviously crucial to monitor physically sick patients to stay alert against suicide behavior.
A comprehensive metaanalysis to identify the proportions of comorbid personality disorders (PD) across the major subtypes of anxiety disorders has not previously been published. Friborg et al. [85] reported that the rate of any comorbid PD was high across all anxiety disorders. The findings reveal that Group C personality disorders are two times more common compared to Group A and B personality disorders, and within Group C personality disorders, the highest ratio was seen in avoidant PD, followed alternately by obsessive-compulsive and the dependent personality disorder. In cases where personality disorders are codiagnosed with anxiety disorders, the course and treatment response of the disease may alter. It has, for instance, been reported that in social anxiety disorder where PTSD provides a heterogeneous clinical picture, there is a high ratio of comorbid with avoidant PD. Except early onset, avoidant PD rendered insignificant or minor impacts on social anxiety disorder. No relation could be established between gender or length of anxiety disorder and personality disorder comorbidity. Patients with social phobia (61%) and generalized anxiety disorder (49%) were most often diagnosed with a personality disorder. Patients with simple phobia were rarely diagnosed with a personality disorder (12%) [83]. In a different study, it has been illustrated that present or lifelong panic disorders are related with borderline, avoidant, and dependent personality disorders; social anxiety disorder connected with avoidant personality disorder; and obsessive-compulsive disorder associated with obsessive-compulsive and avoidant personality disorders. In anxiety disorders comorbid with personality disorders, unlike anxiety disorders with no personality disorder, there has been a more chronic course, increased suicidal behavior, and low level of functionality [116]. The relationship between cooccurring personality disorders and anxiety disorders (panic disorder with or without agoraphobia, social phobia, and generalized anxiety disorder) was examined, taking into account the effect of major depression. Generalized anxiety disorder, social phobia, and major depression were positively associated with the occurrence of one or more personality disorders, whereas panic disorder with agoraphobia was not associated [117]. The effect of comorbid personality disorders in obsessive-compulsive disorder is unclear. Baer and Jenike [118] in their research covering 96 OCD adult patients detected that in patients with mixed personality disorder, the length of OCD is longer compared to the ones with no OCD. The authors argued that the impacts of personality disorders on behavior and life style can be secondary OCD. The studies indicate that most individuals with OCD have comorbid personality disorders (PDs), particularly from the anxious cluster. However, the nature and strength of this association remains unclear, as the majority of previous studies have relied heavily on clinical populations. Personality pathology is highly prevalent among people with OCD who are living in the community and should be routinely assessed, as it may affect help-seeking behavior and response to treatment [119]. Latas and Milovanovic [120] in a recent study proved that in anxiety disorder cases, personality disorders exhibit quite a high prevalence as 35% in posttraumatic stress disorder, 47% in panic disorder with agoraphobia and generalized anxiety disorder, 48% in social phobia, and 52% in OCD. In anxiety disorder cases, the highest ratio (39%) was found in Group C personality disorders. Also in samplings with personality disorders, high ratio of anxiety was detected particularly among borderline personality disorder cases. It is agreed that borderline personality disorder is a high risk factor for recurrent suicidal behavior. Personality disorders comorbid with anxiety disorder display a number of clinical outcomes such as suicide risk and more severe and less treatable anxiety disorders, thereby clinicians should place particular emphasis on identifying potential personality disorders in patients with anxiety disorder. Further studies should focus on the causes and risk factors for suicidal behavior particularly in patients with anxiety disorders comorbid with personality disorders.
The basic principles of treatment of anxiety disorders in major depression involve longer treatment and higher doses than are usually required for major depression. The impact of psychosocial disability and severity of depressive symptoms can be ameliorated with appropriate treatment. Screening for depressive symptoms as well as administering an appropriate therapy seems the best way to prevent suicide attempts [121]. Newer treatments, such as the combination of psychotherapy and pharmacotherapy, may prove to be of greatest benefit for individuals with comorbidity of anxiety disorders in psychiatric disorders [122]. For the recent 25 years, much progress has been made in the treatment of five specific anxiety disorders such as social phobia, obsessive-compulsive disorder, generalized anxiety disorder, and posttraumatic stress disorder. Placebo-controlled evidences suggest that pharmacological and psychological treatments offer substantially effective solutions [21, 123]. Treatment of anxiety disorders involve antidepressants (selective serotonin reuptake inhibitors (SSRI) mostly) and cognitive behavioral therapy. Among patients diagnosed with mood disorder and comorbid anxiety disorders, it is advisable to administer higher doses of SSRI [124]. Besides, a long-term discussion has been going on about the use of SSRIs (paroxetine, fluoxetine, and citalopram) which, as some argue, may have a triggering/stipulating effect on adult suicides since 1991 and children since 2002. Apter et al. [125] stated that paroxetine taking adult patients with major depression are at higher risk for suicidal ideation and behavior, and the same authors also claimed that there was no attempt in OCD and social phobia cases. In sync with this finding, the benefits of sertraline outweigh its potential risks in suicidal behavior among OCD patients, and OCD’s effects are, in contrast to its effects in major depression, further positive [126]. In younger patients diagnosed with major depression, the risk of suicidal behavior uncovered with treatment is even higher. It is suggested that the rise in suicidal ideation and attempt parallel to the use of antidepressants is more risky for children and teenagers [21, 123]. Rickels et al. [127] in their two randomized controlled studies reported the positive effects of long-released venlafaxine on GAD. Among children and teenagers major depression and in GAD patients with venlafaxine, there might be a stage between suicidal behaviors and hostile behaviors. Antidepressant drugs play a vital role in the treatment of anxiety disorders and preventing suicidal behaviors among adult patients. Selective serotonin reuptake inhibitors are the first-line pharmacological treatment for these disorders, and that newer serotonin and norepinephrine reuptake inhibitors show significant promise, especially for comorbid cases. In the treatment of anxiety disorders, cognitive behavior therapy (CBT) can be applied in combination with pharmacotherapy or independently. For instance, in the treatment of panic disorder, CBT aims to control agoraphobic symptoms in panic disorders comorbid with agoraphobia, to inhibit adverse effect of medicine deduction and treatment and prevention of panic attacks. Not much study has been made on the effects of CBT applications in anxiety disorders on suicidal behavior, but when anxiety disorder cases are successfully treated with CBT there is likelihood to witness fewer ratios of suicide [128]. When anxiety disorders are comorbid with depression, disease symptoms are likely to be more severe; hence symptom severity should be taken into account while making treatment plan. Particularly speaking, patients diagnosed with panic disorder, PTSD, and comorbidity of anxiety disorders in major depression bear higher risks for suicide. The cases bearing potential risks for suicide should be kept and monitored under strict scrutiny by clinicians. In order to assess and monitor these patients, there is a need for relevant measurement tools of which reliability and validity tests have been confirmed. In suicide behavior treatment studies among anxiety disorders, ethic limitations have restricted the participation of individuals with acute suicidal tendency. In relevant studies, the lowness of suicidal behavior and restricted volume of samplings inhibited a precise detection of the real effect of treatments. As we consider the fact that various factors interact in the emergence of suicidal behavior, it is probable that drug effect may be regulated in the same way with the interactions among such factors. The fact that no treatment study manages to equally control the risk factors among treatment groups makes it hard to identify the causal factors in suicide-relevant cases. Furthermore, in the analysis of SSRIs, short-term risks alone were examined; hence it is a requirement to detect long-term risks and create future-oriented study designs with wider databases and closer monitoring procedures. There is a need for more research to develop a guideline/protocol exclusively for suicide prevention in patients with anxiety disorders.
Traditionally, anxiety disorders have not been viewed as independent risk factors for suicidal behavior, and therefore assessment of anxiety disorders has not been particularly emphasized in clinical enquiries, and suicide screening tools specific anxiety disorders (e.g., generalized anxiety disorder, panic disorder, and obsessive-compulsive disorder) may be independently associated with suicidality, to which they particularly contribute when they are comorbid with bipolar disorder, personality disorders, depression, schizophrenia, and substance use disorders. Despite methodological issues, these findings should prompt clinicians to evaluate more specifically the impact of anxiety disorders on suicidal behavior, particularly when they are comorbid. Further research into treatment of anxiety disorders in relation to preventing suicide is required.
I offer thanks to our team for suggesting that we write a book about anxiety disorders and suicide.
Bronchopleural fistula (BPF) is defined as a central fistulous connection of inspired air between trachea, major, lobar, or segmental bronchus into the pleural space [1, 2]. Or a BPF can occur peripherally when there are connections between the distal segmental bronchus or lung parenchyma and the pleural space [1, 2]. Although rare, managing a BPF is challenging and represents a high morbidity and mortality.
After an anatomical lung resection, a BPF is rare but severe complications can occur and may be fatal. The BPF incidence after a pneumonectomy for lung cancer is between 4.5% and 20% and 0.5–1% after a lobectomy [1, 3, 4]. The mortality rate after a pneumonectomy is estimated to be 18–71% with a much lower rate for lobectomy [2, 4]. The pleural space is exposed to the endobronchial bacterial flora with the pleural effusion leaking into the major airway and into the peripheral alveolar space. The main cause of death is aspiration pneumonia, empyema, and subsequent respiratory distress [4, 5]. Treatment for BPF after surgery requires emergency treatment due to patient’s lung volume loss and short-term poor respiratory function with surgical damage to the respiratory muscles [5].
The less common causes of BPF include suppurative lung processes such as septic pulmonary emboli, infected pulmonary infarctions, or tuberculosis [6]. Neoplasms with tumor invasion into the pleural space may also lead to BPF. Iatrogenic etiologies due to complications with chest tube insertion, thoracentesis or lung biopsies may result in BPF [6].
When considering different surgical approaches and incidence of BPF, one study evaluated the Society of Thoracic Surgeons and General Thoracic Surgery Database (STS-GTD) to compare outcomes of video-assisted thoracoscopic surgery (VATS) and robotic-assisted lobectomy (RATS) for primary clinical stage I or II non-small cell lung cancer (NSCLC) at high volume centers from 2009 to 2013. This study identified 1,220 RATS and 12,378 VATS patients. The incidence of BPF between these two groups was not statistically significant (0.6% vs. 0.3%, p = 0.08) [7]. Another study that included 737 cases of VATS lobectomies and 748 cases of open lobectomies for the surgical treatment of resectable non-small cell lung cancer showed no statistical difference in incidence of BPF postoperatively [8].
Certain anatomic, technical, and patient factors lead to increased risk for BPF (Table 1). Generally, right-sided pneumonectomy is associated with high risk of BPF. Devascularization of the bronchial stump, diabetes, malnutrition, steroids, neoadjuvant chemoradiotherapy, stump closure, residual carcinomatous tissue, presence of empyema and postoperative mechanical ventilation all lead to increased risk of bronchial stump dehiscence [9, 10].
Right pneumonectomy Devascularization of bronchial stump Long bronchial stump Stump closure Residual carcinoma at bronchial margin Preoperative radiotherapy Presence of empyema Postoperative mechanical ventilation Diabetes Chronic Steroid Use Nutritional status |
Risk factors for bronchopleural fistula after pulmonary resection.
Generally, right-side pneumonectomy and right lower lobectomy are associated with high risk of BPF and are multifactorial. The right upper pulmonary artery is made up of the apical, anterior, and posterior ascending branches [11]. The apical and anterior branches are located in the front of the hilum and the posterior is located at the posterior segment of the horizontal fissure [11]. The right lower pulmonary artery is divided into the dorsal and basilar segment and is located at the corresponding position of the posterior ascending branch in the horizontal fissure [11]. This single bronchial artery supplies the entire right mainstem bronchus whereas the left mainstem bronchus has a vascular supply by two bronchial arteries [9]. During lymphadenectomy if the single artery of the right bronchus is damaged, the bronchial stump becomes ischemic [4].
After a right pneumonectomy, the risk for BPF increases due to the diversion of the entire cardiac output going through the smaller left lung and increased load on the right ventricle [12]. This compensation results in decreasing circulating blood volume, pulmonary hypertension, increased pulmonary pressures, increased pulmonary vascular resistance and right ventricular failure [12, 13]. Loss of the larger right lung may compromise pulmonary function resulting in respiratory failure predisposing the patient to the postpneumonectomy edema syndrome [12, 14, 15]. Larger perioperative fluid resuscitation causes overload of the pulmonary circulation and right ventricle and has been reported to be a poor outcome predictor [14, 15].
Anatomical differences in the right bronchus versus the left are significant factors in increased risk of BPF. The right main bronchus is more vertical and wider than the left increasing the accumulation of secretions in the bronchial stump [4]. The right mainstem bronchus is not naturally buttressed by mediastinal tissue coverage and therefore likely to be exposed to the thoracic pleural free space [9, 15]. The left main bronchial stump tends to be protected and covered by the aortic arch with its surrounding vascularized mediastinal tissue [9, 15]. The left bronchial stump retracts within that tissue under the aortic arch after dissection giving protection from the pleural free space.
The surgical approach to mediastinal lymph node dissection at the time of pulmonary resection for NSCLC has been a subject of interest for several decades. Accurate pathologic lymph node examination offers the most accurate staging and survival benefit and provides the most significant prognostic factor [16]. Accurate nodal staging increases survival by improved risk categorization, increased detection of candidates for adjuvant therapy and possibly resection of oligometastatic disease [17]. Staging NSCLC may have lymph node metastases even after appearing localized by imaging which makes the extent of mediastinal lymph node removal controversial [18]. Patients with negative nodes by systematic lymph node dissection with early stage NSCLC did not have improved survival with complete mediastinal lymph node dissection [17, 18, 19]. Intraoperative lymph node sampling is removal of one or more lymph nodes decided by preoperative or intraoperative findings and is determined by the surgeon [19]. Systematic nodal dissection contains all mediastinal tissue containing lymph nodes and is removed systematically within anatomical landmarks. To meet minimal recommendations, for right-sided cancers, mediastinal lymphadenectomy should contain stations 2R, 4R, 7, 8, and 9. Left side stations 4 L, 5, 6, 7, 8 and 9 should be included [17, 18, 19]. Patients should have N1 and N2 node resection with a minimum of N2 stations sampled [17, 18, 19]. Some argue that systematic mediastinal lymph node sampling versus mediastinal lymph node dissection is adequate for staging and that complete dissection does not provide survival advantage as most patients with N2 disease die from systemic disease [18, 19].
Lymph node dissection removes tissue from adjacent organs and skeletonization of intrathoracic structures. It includes enblock removal of tissues with cancer cells that includes lymph nodes and fatty tissue within bronchus, trachea, superior vena cava, aorta, pulmonary vessels, and pericardium [17, 20].
Healing of the bronchial stump is delayed due to decreased post-operative blood supply after lymph node dissection. Superior and inferior mediastinal lymph node dissection for NSCLC is widely performed adjunct to pulmonary resection [21]. Vascular supply to the suture line is watershed from the descending thoracic aorta across the mediastinum and is decreased after mediastinal lymph node dissection [11]. Ischemic bronchitis after lymph node dissection due to decreased bronchial microvascularization negatively influences bronchial stump healing [11, 21]. Lymph node sampling rather than complete lymphadenectomy leading to devascularization of the bronchial stump can permit adequate blood flow to the bronchial stump [21]. Meticulous technique while dissecting around the bronchus is necessary. Preventing devascularization of the bronchus during lymph node dissection can decrease the incidence of fistulization [9, 21].
The Sweet principles on bronchial closure, emphasized in 1945 are still followed today. Trauma to the end of the bronchus should be minimized and the blood supply must be preserved all the way to the end cut of the bronchus [22]. The cut edges of the bronchus should be carefully approximated [22]. Tissue reinforcement of the bronchial closure should be provided. Clamps should not be used on the proximal bronchus [22]. The major change to Sweet’s original description has been leaving the posterior membranous wall longer when cutting the bronchus so it can be used as a flap to decrease tension on the closure [22].
Typically, when the bronchus is pulled to place a stapler, an abrupt onset of vagal-induced atrial fibrillation or bradycardia may occur, along with hypotension that leads to releasing the bronchus [23]. There is a natural tendency with the next attempt to reduce bronchial traction allowing for a longer stump. Using a Roticulator linear stapler is useful to suture and clip the main bronchus close to the carina [23]. To avoid pooling of secretions within the bronchial stump, the stump should be resected back to its origin and for a pneumonectomy divided as close to the level of the carina as possible [9, 24]. This is critical to avoid secretions pooling resulting in infection and stump breakdown.
When closing a very proximal right bronchial stump or thickened bronchial wall, attention must be directed to ensure there is no closure under tension [25]. Closure under tension can be implicated in right sided BPFs at the point of transection of the right mainstem bronchus as it is generally larger than the left [25]. By the Law of LaPlace, the tension on the curved cartilaginous membranes and the fluid within the crenelated surface is higher in the larger orifice of the right bronchial stump [18, 26, 27]. Elimination of the stump diverticulum may reduce surgical line tension [18, 26, 27]. The cartilaginous ring at the origin of the right mainstem bronchus tends to keep the bronchus open and closure should be parallel to the bifurcation spur of the resected bronchus [21, 28]. This decreases the intraluminal deformity of the remaining bronchi with the straightened angle of the longitudinal axes [21, 28].
The surgical technique of bronchial closure remains controversial and has been studied extensively. The preferred technique of pulmonary hilum vessel ligation and bronchial stump closure has troubled thoracic surgeons for years. In 1909, regarding bronchial stump closure, Meyer advised his inversion technique [29]. In 1945, Sweet described the longitudinal, single interrupted silk suture closure [29, 30]. Dr. Mark Ravitch started using staplers in the United States in 1964 after having observed their early development in Russia [29]. In 1970, Kirksey reported 147 patients who underwent pulmonary resection with disposable and plastic American staplers called Thoraco-Abdominal (TA) [29]. Reluctance to use vascular staplers due to fear of fatal hemorrhage because of malfunction continued the debate concerning pulmonary hilum vessel manual ligation versus stapled division for many decades [29]. The cessation of the alarm resulted after Asamura et al., in 2002 published results of 842 vascular divisions using endoscopic staples with 0.1% incidence of stapling failure and Yano et al., in 2013 reported 3393 pulmonary vein and artery stapling uses with a failure rate of only 0.27% [29].
It is decided by the surgeon perioperatively to use either manual suturing or stapling methods [31]. None of these have proven superiority in reducing the incidence of BPF and around a 4% rate of BPF has been reported for mechanical stapling and suture technique [31, 32]. Ucvet et al., 2011 reported the weakest part of the line are the end points of the stapler and it may incompletely close the tissue [31]. The staple line that exceeded the length of the bronchus caused a detachment in this end site creating a microfistula. These microfistulas can lead to large BPF along with infections [31]. To provide stump safety, lateral suturing to the weak and risky stump end points was required [31].
Endoscopic staplers have 2 differences compared to conventional TA type staplers: proximal and distal ends can be closed, both division and stapling can be performed simultaneously in one firing motion [31, 33]. The advantages of using endostaplers during a pulmonary resection are: (1) Time required for closure can be reduced, compared to the TA stapler when closure of the distal end of the bronchus and division are required; (2) Both proximal and distal ends of the bronchi are simultaneously and tightly closed without purulent or contaminated discharge which minimizes contamination of the operative field; (3) By selecting the appropriate cartridges, endostaplers can be used safely in vascular division [31, 33].
Suture closure is considered when the bronchial wall is hardened due to calcification [10, 21, 33]. Suture closure is also used with position difficulty due to hilar adenopathy or when the tumor is close to the pulmonary hilum due to a more extensive proximal dissection or a technically difficult bronchial stump [10, 21, 33]. Manual suturing may have the advantage of allowing inspection and assessment of the bronchial mucosa quality. Tumor fragments may also be recovered after the main bronchus is clamped [34].
Generally, wound healing has three phases: (1) inflammatory phase (2) proliferation phase (3) remodeling phase [35]. The inflammatory phase is marked by the aggregation of platelets, infiltration with leukocytes and coagulation. This phase begins soon after injury and is followed by the proliferation phase. The proliferation phase is characterized by reepithelialization, fibroplasia, angiogenesis, and wound contraction. Persistent inflammation can last about 2 weeks and likely causes robust adhesion. The remodeling phase takes place over months when the epithelium produces collagen and matrix proteins responding to the injury [35]. The phase of wound healing needs to be considered when deciding which type of bronchial closure is used.
Several options are available for coverage of bronchial closure. To reduce the incidence of postpneumonectomy BPF with soft tissue buttressing after bronchial closure has been debated. Many suggest stump reinforcement in patients with increased risk factors for BPF [36]. Cerfolio et al., 2005 suggests the best way to treat postoperative complications is to prevent it [37]. Local soft tissue coverage may provide vascular ingrowth to promote stump healing and effectively contain a small bronchial stump dehiscence [38]. Algar et al. 2001, found that the absence of bronchial stump tissue coverage was an independent predictor of BPF in the final multivariable model (p = 0.039) [32].
The intercostal muscle flap causes no functional disability, is easy to harvest, has adequate length to reach most sites, has adequate vascularity and is harvested through the same thoracotomy incision [39]. Sfyridis et al., discovered the group that received an intercostal muscle flap had a lower incidence of development of BPF (0% versus 8.8%;
In a retrospective study, Taghavi et al., found 93 patients who underwent pneumonectomy for primary lung cancer, identified no BPF during follow up after using a pedicled pericardial flap for bronchial stump coverage [41]. A pericardial fat pad is harvested from the anterolateral pericardium, pedicled at its cranial part, avoiding inclusion or injury to the phrenic nerve [9, 42]. A wide based pedicle should be used to assure vascularity of the flap. Careful attention should be used to avoid twisting the pedicle. The flap is attached caplike over the bronchial stump with numerous single mattress stitches to avoid devascularization when tied down over the four corners of the bronchial stump. The defect in the pericardium is then reconstructed with mesh [9, 42].
Bronchopleural fistula is exceedingly rare when a pedicled muscle flap is used to buttress the lobar bronchus, even after preoperative radiation doses of 60Gy or higher are administered [43]. To provide sufficient protection after preoperative radiation, using omental or serratus as a prophylactic buttress for the highly irradiated right main stem bronchus after a right pneumonectomy is recommended [43].
If the patient is believed to be at extraordinary risk of stump complications, larger muscle or omental flaps are used. The serratus anterior flap and omental flap are also used to treat a postoperative bronchopleural fistula to close the fistula [43, 44].
The serratus anterior muscle, one of the workhorse flaps is easily harvested, reliable, often preserved during the initial pneumonectomy due to its utility in dealing with potential complications [44]. The vascular pedicle that runs on the lateral undersurface of the scapula is where the serratus anterior muscle is based [25]. This muscle is mobilized and placed between the ribs in the second or third interspace where it will reach the hilum without tension. The thoracodorsal vascular pedicle is protected throughout the dissection [44]. With tight interspaces, compromising the vascular supply of the flap, a segment of the third rib can be removed to allow the flap to enter the pleural space easily [25]. The serratus anterior flap is secured with interrupted absorbable sutures to the mediastinal areolar or peribronchial tissue [25] (Figure 1). This tissue helps with infection control and healing due to its blood supply emanating from regions beyond the inflamed field [25]. The flap is placed over the bronchial stump with uninterrupted suture to secure the closure [9, 25, 44].
The serratus anterior muscle is harvested and mobilized into the chest between the ribs in the second or third interspace with rib segmentation. (Sugarbaker D, Bueno R, Burt B, et al, editors. Adult chest surgery. 3rd edition. New York: McGraw-Hill Education; 2020; with permission).
The omentum has superior blood supply and plasticity which allows for a very safe and easy bronchus closure even in the presence of fibrotic tissue or infection [45]. The omentum with a rich blood supply assures adequate antibiotic and oxygen delivery [46]. Delivering potent angiogenic factors, the omentum improves neovascularization of the bronchial suture lines in experimental models. Omental transposition does not impair muscle function or produce chest wall deformities seen with major muscle flaps [46].
The disadvantage of tradition omental flap transposition extends the surgical procedure into the abdomen, requiring laparotomic access. Usually the omentum is mobilized through the upper midline abdominal incision, transposed into the chest via a substernal or anterior transdiaphragmatic route [46]. This description applies a transdiaphragmatic harvesting technique of the greater omentum performed through the standard thoracotomy [46].
The five centimeter incision in the diaphragm is performed radially between its anterior insertion and central tendon through the standard thoracotomy [46, 47]. Oval forceps are used to slide through the diaphragm into the abdominal cavity. Once confirmation the omentum is free of adhesions, the greater omentum gently can be retracted through the diaphragm into the chest. The omental insertion of the transverse colon is identified and divided as extensively as possible. The most distal omental extremity is identified in the chest cavity by gentle traction and subsequently isolated carefully inspecting its vascular supply. After confirming the omental flap has no traction on the stomach or colon, the omentum is sutured to the bronchial stump in the usual fashion. The diaphragmatic incision is closed leaving a large enough opening to avoid strangulation of the omentum. The omental flap is sutured with interrupted sutures to the diaphragmatic opening to further relieve any tension. This technique is appropriate to reinforce the bronchial stump and can be large enough to fill the pleural space [46, 47].
Residual disease is characterized by residual carcinomatous tissue within the margin of resection either under visible inspection or under microscopy [48]. Residual disease at the bronchial stump may cause poor prognosis with the increased risk of lung cancer recurrence both distantly and locally [48]. It may also decrease the bronchial stump anastomosis which can lead to a fatal bronchopleural fistula or empyema [48, 49]. In all pulmonary resections, the estimated incidence of residual disease left at the bronchial stump is 4–5% [49]. Asamura et al. reported in 2359 patients that the most important risk factor for a BPF was resection type, followed by presence of residual microscopic tumor at the resection margin (p < 0.01) [28]. Survival is worse in patients with bronchial margin residual disease; 1 and 5 year survivals range between 20 and 50% and 0–20% respectively [48]. Mediastinal lymph node involvement is associated with the poor survival in 75–85% of patients with residual bronchial margin disease [48]. Radiotherapy or reoperation may be considered in these patients [48, 49].
Neoadjuvant chemoradiotherapy is a crucial strategy in multidisciplinary treatments to improve the survival rate and resectability for patients with lung cancer [50]. Especially for patients with advanced lung cancer, chemoradiotherapy can eliminate or reduce the micro-metastasis. Previously published randomized control trials have been integrated with recent systematic reviews and have concluded that neoadjuvant chemoradiotherapy can significantly benefit the survival outcomes in operable patients [50]. Relative to other pulmonary resections, pneumonectomy has been associated with increased morbidity and mortality. The mortality for a pneumonectomy after neoadjuvant therapy has reports with very low mortality (<5%) countered by other reports with alarmingly high mortality (>20%) [51]. For the patient with N2 disease who requires a pneumonectomy, the correct approach can be unclear with the postoperative and intraoperative complications remaining a debate [50, 51]. Bronchial mucosa ischemia is induced by radiotherapy but the mucosal blood flow can recover in eight to ten days after completion of therapy. Early effects of radiation can cause mucosal edema and inhibit capillary angiogenesis [52]. Late effects of radiation cause fibrotic small vessel disease through radiation vasculopathy [52]. Radiation pneumonitis, poor wound healing, and fibrosis can occur in previously irradiated bronchial tissue with a higher perioperative and postoperative complication leading to a bronchopleural fistula [53, 54]. Induction therapy may cause injury to the bronchial microvascularization predisposing to airway complications but published literature does not support the notion that all pneumonectomies after therapy are associated with postoperative mortalities [51, 55].
Empyema is the presence of purulent fluid in the postpneumonectomy pleural space. Postpneumonectomy empyema occurs in 2–16% of patients and can be life threatening [55]. This postoperative complication is associated with BPF which can further increase morbidity and mortality [56]. Most BPFs associated with empyema is monomicribial with most pathogens being Streptococcus or Staphylococcus species and occur within 10 to 14 days of surgery [52, 57]. A late empyema can occur more than three months to 40 years after a pneumonectomy and is most often acquired via a hematogenous route [52, 57]. After a pneumonectomy, to avoid spillage of infected fluid into contralateral lung the patient should be kept upright at least 45 degrees [52]. An early empyema withing 10 to 14 days after surgery presents with expectoration of purulent sputum and fever [57]. Radiographic findings show a shift of the mediastinum away from the postpneumonectomy space, development of a new or sudden change in the existing air-fluid level, and failure of the mediastinum to shift normally in the immediate postoperative period [57]. Empyema diagnosis is confirmed by fluid sample in the postpneumonectomy space [57].
Mechanical ventilation in patients after a pneumonectomy, subjects the bronchial stump line to increased wall tension and continuous barotrauma [1]. Positive pressure ventilation can be challenging in these patients and the aim is to prevent further lung injury by keeping the airway pressure below the critical opening pressure of the fistula, optimizing pleural suction pressures and provide adequate alveolar ventilation of sufficient gas exchange [58, 59]. To decrease the flow across a BPF, reducing the proportion of minute ventilation provided by the ventilator, minimal levels of positive end expiratory pressure (PEEP), low tidal volumes and respiratory rate are helpful [1, 59]. Adverse effects in mechanically ventilated patients with BPF include loss of effective tidal volume, incomplete lung expansion, inability to remove carbon dioxide and prolonged ventilatory support [59]. The majority of reported studies report a significant relationship between the occurrence of BFP and mechanical ventilation after pneumonectomy [60].
Typically, surgeons consider diabetes mellitus in patients requiring surgical intervention an important contributor to some fatal adverse events [61]. Diabetic microangiopathy alters the vascular bed causing small vessel ischemia impairing proper wound healing [40]. This decreases the oxygen diffusion capacity and the bronchial stump circulation is particularly prone to poor wound healing [52, 61]. The largest retrospective analysis reported by Asamura et al. in 1992, showed statistical results from both univariate and multivariate analysis indicating significantly increased risk of postoperative BPF in patients with diabetes [28].
Preoperative use of corticosteroids is believed to contribute to several postoperative complications which include impaired bronchial healing [62]. In a study by Algar et al. 2001, patients with preoperative steroid therapy were associated with higher risk of BPF (p < 0.001) [32]. This same study found hypoalbuminemia to also be related to higher risk of BPF (p < 0.017) [32]. Hypoalbuminemia has a negative effect on the healing process, and in order to decrease the BPF risk, an albumin level above 3.5 mg/dl is the goal [63]. Patients requiring a pneumonectomy are usually very catabolic and nutritional assessment is essential in their management [1]. Metabolic alterations induced by the lung cancer tumor affects the nutrition in these patients [64]. These alterations lead to cachexia syndrome with higher levels of the proinflammatory cytokines interleukin-6 and tumor necrosis factor and lower levels of albumin [64]. Malnutrition increases the risk of 90-day mortality rate, postoperative infection and length of hospital stay after a pneumonectomy and a thorough preoperative evaluation is crucial [64].
An early BPF has a peak incidence within 8 to 12 days after surgery but can occur at any time in the postoperative period [59]. Surgical closure of the BPF is the cornerstone of management. If a BPF is seen within the first 4 days after surgery, it requires exploration as it is likely due to a mechanical failure of the bronchial stump [59]. Early BPFs are normally approached urgently through the previous thoracotomy incision. An acute BPF can be life-threatening due to asphyxiation from pulmonary flooding or tension pneumothorax due to a massive air leak [59, 65, 66] (Figure 2). Acute BPF should be suspected in patients who present with fever, dyspnea, subcutaneous emphysema, excessively productive cough of purulent fluid, hypotension, trachea or mediastinal shift, disappearance, or reduction of pleural effusion on the chest radiograph or persistent air leak [25, 59, 65]. Chest radiography monitors the efficacy of BPF therapy and plays an essential role in evaluating the possibility of a BPF after a lung resection [2]. These symptoms appearing should raise the index of suspicion and quick and accurate diagnosis must be made before there is an overwhelming amount of aspiration into the remaining lung [25].
Axial lung window after right pneumonectomy with large pneumothorax with evidence suggesting communication of the bronchial stump and pleural space. Case courtesy of Radswiki, Radiopaedia.org, rID: 11262.
Late bronchopleural fistula present in the postoperative period more than 14 days [59]. The subacute and chronic forms present with more insidious symptoms and is characterized by fever, malaise, wasting, minimally productive cough, dullness to percussion on the affected side and reduced air entry with progressive clinical deterioration and varying levels of respiratory compromise [2, 59, 65]. A late BPF is often seen in debilitated or immunocompromised patients with many comorbidities [59]. In the chronic form that is associated with empyema, there is fibrosis of the mediastinum and pleural space preventing the mediastinal shift [59, 65].
Causes of late BPF include foreign body aspiration, refractory infection, chemotherapy and radiotherapy, and blunt chest trauma [67]. The time of interval is 2 months to 20 years between the surgery, therapy or injury and the onset of the late BPF [67].
In late BPF, due to the relatively stable mediastinal structures, conservative treatment is accepted by many investigators as the first step. Closure of the bronchial fistula with endoscopic treatment should be considered [67]. Proper antimicrobial coverage is mandatory along with proper nutrition with patients frequently requiring parenteral or enteral feeding [65]. Aggressive nutritional support and physical rehabilitation should be started early to optimize patients and enhance their recovery [65]. If surgery is indicated for a late BPF, the previous transthoracic approach may be unsafe due to fibrosis with associated inflammation with risk of bleeding and injury to vital structures [68, 69]. With a median sternotomy, approaching well vascularized, healthy, virgin tissues to reach the carina and bronchi may be preferrable and necessary. The advantages to the transsternal approach for BPF closure are avoidance of an inflamed operative field, scarring and adhesions in previous surgical fields and deformities of the thorax with thoracoplasty [68, 69]. The disadvantage of this approach is the infected empyema space is not managed at the time of closure. Previous cardiac surgery is not recommended for this type of approach [68, 69].
Once a BPF is suspected, a Computerized Tomography (CT) Scan with intravenous contrast to map the vasculature and better define the air-fluid levels and the peripheral rind enhancement is necessary [70]. This scan will identify the fistulous tract and will allow evaluation of the potential causes of BPF (i.e. recurrent tumor, staple line dehiscence, pneumonia, abscess, devascularized stump). It will also be simultaneously used to define the anatomic relationship of the adjacent mediastinal structures, vasculature, and diaphragm. A large fistulous tract can be clearly identified and a vigilant search must take place to look for subtle signs of a small BPF such as a change in the appearance of pre-existing pleural air-fluid levels and extraluminal air bubbles adjacent to the bronchial stump. Care must be taken to ensure while the patient is lying flat during the scan that they do not aspirate the pleural fluid through the BPF to the healthy lung [70].
All patients should undergo diagnostic bronchoscopy whether the BPF diagnosis is apparent radiographically or clinically [25]. A large fistula can be visualized but smaller 1 to 2 mm fistulas may be difficult to recognize [25]. Bronchoscopy provides information about the tissue at the level of the stump and condition of the remaining bronchial stump and can assist in deciding definitive repair [25].
Management varies according to the individual patient, but the importance of addressing the risk of contralateral aspiration pneumonia and tension pneumothorax by drainage of the pleural space at time of diagnosis has to be emphasized [69]. The most important action when an acute BPF is suspected is protecting the contralateral lung from spillage of pleural fluid [2]. The primary principle is drainage of the pleural space by chest tube thoracostomy and care should be taken to place the chest tube above the previous thoracotomy incision as the diaphragm will be elevated with the normal thoracic remodeling that occurs after pneumonectomy [25, 59, 71, 72]. Pleural fluid should be sent for total protein, complete blood cell count, glucose, cytology, lactate dehydrogenase, triglycerides, gram stain and culture to evaluate for pleural infection [59]. Although integral for drainage, the chest tube can predispose the pleural space to infection and function as a foreign body [59]. Connecting the chest tube to a digital chest drainage system allows for more accurate and objective assessment of air flow and larger flow values and trend evaluation would provide more detailed information about the size and severity of the BPF [73]. For patients who are mechanically ventilated, the chest tube can be used for occlusion during the inspiratory phase or to add positive intrapleural pressure during the expiratory phase [59]. These interventions decrease BPF during inspiration and decrease air leak during expiration to maintain positive end-expiratory pressure (PEEP) [59].
Acute failure of the bronchial stump is usually due to bronchial stump dehiscence and expeditious surgical repair with this single-staged intervention is recommended once clinical stabilization is achieved [71, 74, 75]. Given the relative integrity of the tissue, early stage of the infectious process, minimal pleural contamination and no problematic residual space, early reoperation is warranted to reestablish an airtight stump [25, 71, 74, 75]. Exploration with surgical revision by posterolateral thoracotomy with selective intubation and lung isolation of the contralateral mainstem bronchus to prevent further spillage of the remaining lung is recommended [25, 71, 75]. The fistula, if not readily visible can be identified with the assistance of positive pressure ventilation while covering the bronchial stump with irrigation [25]. The pleural space should be completely debrided and irrigated to remove all necrotic tissue [25]. The bronchial stump is refashioned and carefully dissected to decrease trauma to the blood supply [25, 71]. Measured from the carina, all efforts are made to made for the final stump to be less than 1 cm in length [25] (Figure 3). The stump may be reclosed with a stapler if their remains sufficient length on initial exploration. In cases where there is too much inflammation to allow stapling, the bronchial stump is mobilized and reclosed with interrupted monofilament sutures [25, 71]. A balance between avoiding too much exposure that may damage blood supply and exposing enough bronchus to avoid tension on the closure much be achieved [25].
A. The bronchial stump should be less than 1 cm. After inspection, if there is enough length on the stump, it can be closed with a stapling device. B. With too much inflammation, the stump may need to be sutured closed. (Sugarbaker D, Bueno R, Burt B, et al, editors. Adult chest surgery. 3rd edition. New York: McGraw-Hill Education; 2020; with permission).
Using a vascularized tissue to reinforce the suture line is the most important aspect of closure [25, 76]. Stump coverage was previously discussed as a preventive measure for BPF. The objective in treating a BPF with vascularized tissue is to obliterate the postpneumonectomy pleural space [25, 71, 75, 77]. Deciding which muscle flap to use depends on which muscle was preserved or damaged from the previous thoracotomy and the amount of space to be filled [71, 75, 77]. The most common muscles used in the pleural space to treat a BPF are serratus anterior, pectoralis major, pectoralis minor, latissimus dorsi, and intercostal muscles [25, 71, 75, 77, 78]. The latissimus dorsi is the most reliable and largest muscle but may not be sufficient to obliterate the postpneumonectomy cavity if it was already divided in the original thoracotomy [77, 78]. The greater omentum consists of a large fold of peritoneum with excellent blood supply and antibacterial effect, lymphoid tissue, and fat [76, 78]. Using large muscles as the latissimus dorsi, greater omentum and serratus anterior has the advantage to contribute bulk to fill some of the dead postpneumonectomy space sugar [76, 77, 78]. In a study by Mazzella et al. 2017, fourteen patients with early BPF were treated with surgical repair of the bronchial stump via thoracoscopy (2) or thoracotomy (12) with omentum and fibrin glue (2) parietal pleural (3), intercostal muscle (1) or pericardial patch (2) with no recurrence of BPF after surgery [79].
Treating a BPF with empyema and sepsis may require an Eloesser flap for patients too debilitated or too ill for a decortication or prolonged procedure involving muscle flaps [25, 80, 81]. The difference between the Clagett open-window thoracostomy (OWT) procedure and Eloesser flap is that the Clagett procedure is larger than the Eloesser flap and the Clagett window is temporary to allow complete drainage of purulent drainage in the pleural space [80] (Figure 4). The Eloesser flap creates a permanent drainage window in the pleural space [80].
(A) Clagett window and (B) Eloesser flap. (Sugarbaker D, Bueno R, Colson Y, et al, editors. Adult chest surgery. 2nd edition. New York: McGraw-Hill Education; 2015; with permission).
In 1963, Clagett and Geraci described a technique as a two-step procedure for the management of postpneumonectomy empyema [81, 82]. This procedure combined an open-window thoracostomy pleural drainage with repetitive irrigation of the infected cavity with obliteration of the space with antibiotic fluid without direct fistula closure [2, 25, 81, 82, 83, 84]. The procedure resulted in recurrences of fistulization and prolonged hospitalization and significant mortality. This technique is rarely used and has been modified with initial bronchial stump closure with muscle transposition described earlier [2, 25, 80, 81, 82, 83, 84].
Once the BPF is closed and buttressed with muscle transposition, diluted wet povidone-iodine (Betadine) dressings are placed in the thorax and changed every 48 hours in the operating room [81, 83, 84]. This is done for approximately 4 to 6 days until the muscle flap is adherent to the bronchial stump and adjacent mediastinum [81, 83, 84]. Then the pack is changed in the patient’s room 3 to 4 times a day. When health granulation is present in the pleural space, the entire cavity is filled with antibiotic solution selected to tailor culture and sensitivity results [25, 81, 83, 84]. In multiple layers to avoid leakage of fluid, the chest is then closed [25, 81, 83, 84].
The modified Clagett procedure involves daily intracavitary dressing changes, lasting for a long period of time and may not allow chest closure. Other ways to accelerate wound healing process were investigated [85]. Wound vacuum-assisted closure (VAC) therapy has recently been evaluated and used in patients with complex infected wounds without the OWT [86]. Bacterial proteinases are microorganisms and play a pathogenic role in an infected wound by consuming oxygen and nutrients that are required for tissue repair [87]. Reducing the bacterial proteinase load in a wound would allow the body to heal [87]. The VAC allows topical solutions to be cyclically flushed into the foam dressing before removal under negative pressure that irrigates, cleans, and removes infectious material from the pleural space [85, 87]. This is done without OWT, decreasing postoperative pain [88]. Recent studies show that as an adjunct to standard therapy, the VAC can decrease pain, hospital length of stay and morbidity in patients with complicated postoperative empyema [85, 88].
The Eloesser Flap OWT continues to evolve. A “H” or “U” shaped incision is made above the previous incision over the dependent portion of the space [25, 80]. A segmentary resection of one or two ribs are removed to obtain a window and limit the tendency of the opening to contract and close [25, 79, 80]. Necrotic tissue is debrided and edges of the flap are sutured directly to the parietal pleura with absorbable interrupted sutures to create an epithelized tract which encourages healing and maintains window patency [25, 79, 80]. The window should be not too far inferiorly which may interfere with the diaphragm and not too posterior that would be difficult for the patient to manage [25, 79, 80]. Using moistened gauze, dressing changes are performed until the cavity is decontaminated. Care is taken to prevent cardiac tamponade by excessive gauze inserted in the cavity [25, 79, 80]. The thoracostomy is closed with a thoracomyoplasty when clinical conditions suggest correct timing. In the chest cavity, healthy granulation tissue, improved clinical condition, closure of the bronchial stump and negative cultures of the chest cavity all suggest proper timing [25, 79, 80].
Many different biological glues for endoscopic BPF closure are available. Fibrin-based, albumin-glutaraldehyde tissue adhesive, and cyanoacrylate-based glues are the most common [2, 83]. Application technique is performed by a catheter inserted through the flexible bronchoscope and placed above the fistula [2, 83]. The glue is injected into the fistula and creates a plug after a few seconds that occludes the fistula with instantaneous cessation of air leak expected [2, 83]. Some prefer glue injection with a 21G needle due to less glue displacement and more effective closing of the BPF. This procedure may need to be repeated and endoscopic surveillance and close clinical monitoring is important for signs of failure [2, 83].
Cardillo et al. 2015, reported patients with BPF sized 1 cm or less with a viable bronchial stump were treated endoscopically [89]. The cure rate with endoscopic treatment was 92.3% in very small fistulas <2 mm with mechanical abrasion of the fistula. Cure rate was 71.4% in small fistulas >2 mm and < 3 mm with submucosal injection of 0.5 to 2 mL polidocanolhydroxypolyethoxydodecane at the fistula. This liquid surfactant causes endothelial cell lysis. It induces sclerosis and acts on the venous endothelium via interferences with cell membrane lipids. Cure rate with intermediate fistulas >3 mm and < 6 mm was 80%. Treatment was with n-butyl cyanoacrylate glue injected into the fistula. This mechanically occludes the fistula causing proliferation of the bronchial mucosa and a local inflammatory reaction. Morbidity and mortality rates were 5.8% [89].
Endobronchial valves (EBV) have been available since 2003 and were originally developed for the reduction of lung volume in patients with emphysema [90, 91]. They were first described by Snell et al., 2005 for BPF [92]. Introduced through a flexible bronchoscope, EBV have a unidirectional valve to prevent airflow into the fistula and will result in atelectasis and collapse of the fistula [90, 91, 93]. This results in decreased or absent air leak. The process of recovery would lead to resolution of the shunt, fibrosis, and eventual extraction of the EBV [90, 91, 93]. Complete elimination of air flow through the BPF does not always occur and does not mean the EBV is unsuccessful. Decreased flows may bring the rate below critical rate flows and allow for fistula healing [91].
Many small fistulas (<3 mm) spontaneously heal or heal with glue placed endoscopically [94, 95]. Treatment for BPF endoscopically can bridge to control infection until a patient is able to able to undergo surgical repair [90, 92] (Figure 5). Amplatzer device is normally used for transcatheter closure of atrial septal defects. This device can contribute to intrabronchial granulation tissue and has good biocompatibility [94, 95]. The tissue growth reduces the risk of displacement. The waist of the Amplatzer device is placed inside the fistula and the two discs are placed at the distal and proximal ends of the fistula [94, 95]. Fruehter et al. 2011 treated nine patients with Amplazter device with BPF and the fistula was successfully closed [96]. After nine months, the results were maintained [96].
Amplatzer Muscular VSD Occluder 8mm x 7mm placed to occlude the right mainstem bronchopleural fistula. Image courtesy of Dr. Tarek Dammad, Orlando, Florida.
Improvements in thoracic surgery have decreased the incidence of BPF but mortality remains high. Proactive approaches to risk management and mitigating potential causes for increased chance for BPF preoperatively and intraoperatively are essential to improved outcomes. Expeditious surgical repair for acute BPF, along with new therapies with wound vacuum-assisted closure (VAC) therapy and endoscopic options for small fistulas may all expedite closure of BPF and improve survival.
The author declares no conflict of interest.
To my colleagues: Dr. Joseph Boyer, Dr. Nayer Khouzam, Dr. George Palmer and Dr. Marcello DaSilva at AdventHealth Orlando, Florida, U.S.A. and to Dr. Steve Talbert at the University of Central Florida. You all have taught me so much, for so many years, and I sincerely thank you.
This is a brief overview of the main steps involved in publishing with IntechOpen Compacts, Monographs and Edited Books. Once you submit your proposal you will be appointed a Author Service Manager who will be your single point of contact and lead you through all the described steps below.
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Experimentation is an application of treatments applied to experimental units and is then part of a scientific method based on the measurement of one or more responses. It is necessary to observe the process and the operation of the system well. For this reason, in order to obtain a final result, an experimenter must plan and design experiments and analyzes the results. One of the most commonly used experimental designs for optimization is the response surface methodology (RSM). Because it allows evaluating the effects of multiple factors and their interactions on one or more response variables it is a useful method. In this section, recent studies have been compiled which aim to extraction of plant material in high yield and quality and determine optimum conditions for this extraction process.",book:{id:"5856",slug:"statistical-approaches-with-emphasis-on-design-of-experiments-applied-to-chemical-processes",title:"Statistical Approaches With Emphasis on Design of Experiments Applied to Chemical Processes",fullTitle:"Statistical Approaches With Emphasis on Design of Experiments Applied to Chemical Processes"},signatures:"Alev Yüksel Aydar",authors:[{id:"218870",title:"Dr.",name:"Alev Yüksel",middleName:null,surname:"Aydar",slug:"alev-yuksel-aydar",fullName:"Alev Yüksel Aydar"}]},{id:"56460",doi:"10.5772/intechopen.69501",title:"Application of Taguchi-Based Design of Experiments for Industrial Chemical Processes",slug:"application-of-taguchi-based-design-of-experiments-for-industrial-chemical-processes",totalDownloads:3223,totalCrossrefCites:27,totalDimensionsCites:54,abstract:"Design of experiment is the method, which is used at a very large scale to study the experimentations of industrial processes. It is a statically approach where we develop the mathematical models through experimental trial runs to predict the possible output on the basis of the given input data or parameters. The aim of this chapter is to stimulate the engineering community to apply Taguchi technique to experimentation, the design of experiments, and to tackle quality problems in industrial chemical processes that they deal with. Based on years of research and applications, Dr. G. Taguchi has standardized the methods for each of these DOE application steps. Thus, DOE using Taguchi approach has become a much more attractive tool to practicing engineers and scientists. And since the last four decades, there were limitations when conventional experimental design techniques were applied to industrial experimentation. And Taguchi, also known as orthogonal array design, adds a new dimension to conventional experimental design. Taguchi method is a broadly accepted method of DOE, which has proven in producing high-quality products at subsequently low cost.",book:{id:"5856",slug:"statistical-approaches-with-emphasis-on-design-of-experiments-applied-to-chemical-processes",title:"Statistical Approaches With Emphasis on Design of Experiments Applied to Chemical Processes",fullTitle:"Statistical Approaches With Emphasis on Design of Experiments Applied to Chemical Processes"},signatures:"Rahul Davis and Pretesh John",authors:[{id:"199438",title:"Mr.",name:"Rahul",middleName:null,surname:"Davis",slug:"rahul-davis",fullName:"Rahul Davis"}]},{id:"14634",doi:"10.5772/15998",title:"The Application of FT-IR Spectroscopy in Waste Management",slug:"the-application-of-ft-ir-spectroscopy-in-waste-management",totalDownloads:6651,totalCrossrefCites:18,totalDimensionsCites:34,abstract:null,book:{id:"1574",slug:"fourier-transforms-new-analytical-approaches-and-ftir-strategies",title:"Fourier Transforms",fullTitle:"Fourier Transforms - New Analytical Approaches and FTIR Strategies"},signatures:"Ena Smidt, Katharina Böhm and Manfred Schwanninger",authors:[{id:"20376",title:"Dr.",name:"Katharina",middleName:null,surname:"Böhm",slug:"katharina-bohm",fullName:"Katharina Böhm"},{id:"22840",title:"Dr.",name:"Ena",middleName:null,surname:"Smidt",slug:"ena-smidt",fullName:"Ena Smidt"},{id:"22915",title:"Dr.",name:"Manfred",middleName:null,surname:"Schwanninger",slug:"manfred-schwanninger",fullName:"Manfred Schwanninger"}]},{id:"15157",doi:"10.5772/15959",title:"Fourier Transform Mass Spectrometry for the Molecular Level Characterization of Natural Organic Matter: Instrument Capabilities, Applications, and Limitations",slug:"fourier-transform-mass-spectrometry-for-the-molecular-level-characterization-of-natural-organic-matt",totalDownloads:4347,totalCrossrefCites:6,totalDimensionsCites:34,abstract:null,book:{id:"122",slug:"fourier-transforms-approach-to-scientific-principles",title:"Fourier Transforms",fullTitle:"Fourier Transforms - Approach to Scientific Principles"},signatures:"Rachel L. 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In this paper, the basic concepts of robust optimization are developed, the different types of robustness are defined in detail, the main areas in which it has been applied are described and finally, the future lines of research that appear in this area are included.",book:{id:"6587",slug:"nature-inspired-methods-for-stochastic-robust-and-dynamic-optimization",title:"Nature-inspired Methods for Stochastic, Robust and Dynamic Optimization",fullTitle:"Nature-inspired Methods for Stochastic, Robust and Dynamic Optimization"},signatures:"José García and Alvaro Peña",authors:[{id:"227809",title:"Ph.D.",name:"Jose",middleName:null,surname:"Garcia",slug:"jose-garcia",fullName:"Jose Garcia"},{id:"240407",title:"Dr.",name:"Alvaro",middleName:null,surname:"Peña",slug:"alvaro-pena",fullName:"Alvaro Peña"}]}],mostDownloadedChaptersLast30Days:[{id:"59209",title:"Utilization of Response Surface Methodology in Optimization of Extraction of Plant Materials",slug:"utilization-of-response-surface-methodology-in-optimization-of-extraction-of-plant-materials",totalDownloads:5469,totalCrossrefCites:64,totalDimensionsCites:97,abstract:"Experimental design plays an important role in several areas of science and industry. Experimentation is an application of treatments applied to experimental units and is then part of a scientific method based on the measurement of one or more responses. It is necessary to observe the process and the operation of the system well. For this reason, in order to obtain a final result, an experimenter must plan and design experiments and analyzes the results. One of the most commonly used experimental designs for optimization is the response surface methodology (RSM). Because it allows evaluating the effects of multiple factors and their interactions on one or more response variables it is a useful method. In this section, recent studies have been compiled which aim to extraction of plant material in high yield and quality and determine optimum conditions for this extraction process.",book:{id:"5856",slug:"statistical-approaches-with-emphasis-on-design-of-experiments-applied-to-chemical-processes",title:"Statistical Approaches With Emphasis on Design of Experiments Applied to Chemical Processes",fullTitle:"Statistical Approaches With Emphasis on Design of Experiments Applied to Chemical Processes"},signatures:"Alev Yüksel Aydar",authors:[{id:"218870",title:"Dr.",name:"Alev Yüksel",middleName:null,surname:"Aydar",slug:"alev-yuksel-aydar",fullName:"Alev Yüksel Aydar"}]},{id:"74096",title:"Time Frequency Analysis of Wavelet and Fourier Transform",slug:"time-frequency-analysis-of-wavelet-and-fourier-transform",totalDownloads:1283,totalCrossrefCites:6,totalDimensionsCites:8,abstract:"Signal processing has long been dominated by the Fourier transform. However, there is an alternate transform that has gained popularity recently and that is the wavelet transform. The wavelet transform has a long history starting in 1910 when Alfred Haar created it as an alternative to the Fourier transform. In 1940 Norman Ricker created the first continuous wavelet and proposed the term wavelet. Work in the field has proceeded in fits and starts across many different disciplines, until the 1990’s when the discrete wavelet transform was developed by Ingrid Daubechies. 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In all cases, cyclical ups and downs depend not only on internal system cyclical processes and their factors in countries but also on the consequences of intercountry interaction. The ability to measure and predict business cycles, taking into account their mutual influence, is a prerequisite for the development of an adequate business policy of countries and their associations.",book:{id:"6703",slug:"statistics-growing-data-sets-and-growing-demand-for-statistics",title:"Statistics",fullTitle:"Statistics - Growing Data Sets and Growing Demand for Statistics"},signatures:"Elena Zarova",authors:null},{id:"54366",title:"Solution of Differential Equations with Applications to Engineering Problems",slug:"solution-of-differential-equations-with-applications-to-engineering-problems",totalDownloads:6866,totalCrossrefCites:5,totalDimensionsCites:8,abstract:"Over the last hundred years, many techniques have been developed for the solution of ordinary differential equations and partial differential equations. While quite a major portion of the techniques is only useful for academic purposes, there are some which are important in the solution of real problems arising from science and engineering. In this chapter, only very limited techniques for solving ordinary differential and partial differential equations are discussed, as it is impossible to cover all the available techniques even in a book form. The readers are then suggested to pursue further studies on this issue if necessary. After that, the readers are introduced to two major numerical methods commonly used by the engineers for the solution of real engineering problems.",book:{id:"5513",slug:"dynamical-systems-analytical-and-computational-techniques",title:"Dynamical Systems",fullTitle:"Dynamical Systems - Analytical and Computational Techniques"},signatures:"Cheng Yung Ming",authors:[{id:"191017",title:"Dr.",name:"Cheng",middleName:null,surname:"Y.M.",slug:"cheng-y.m.",fullName:"Cheng Y.M."}]},{id:"56538",title:"Stochastic Resonance and Related Topics",slug:"stochastic-resonance-and-related-topics",totalDownloads:1718,totalCrossrefCites:1,totalDimensionsCites:1,abstract:"The stochastic resonance (SR) is the phenomenon which can emerge in nonlinear dynamic systems. In general, it is related with a bistable nonlinear system of Duffing type under additive excitation combining deterministic periodic force and Gaussian white noise. It manifests as a stable quasiperiodic interwell hopping between both stable states with a small random perturbation. Classical definition and basic features of SR are regarded. The most important methods of investigation outlined are: analytical, semi-analytical, and numerical procedures of governing physical systems or relevant Fokker-Planck equation. Stochastic simulation is mentioned and experimental way of results verification is recommended. Some areas in Engineering Dynamics related with SR are presented together with a particular demonstration observed in the aeroelastic stability. Interaction of stationary and quasiperiodic parts of the response is discussed. Some nonconventional definitions are outlined concerning alternative operators and driving processes are highlighted. The chapter shows a large potential of specific basic, applied and industrial research in SR. This strategy enables to formulate new ideas for both development of nonconventional measures for vibration damping and employment of SR in branches, where it represents an operating mode of the system itself. Weaknesses and empty areas where the research effort of SR should be oriented are indicated.",book:{id:"6128",slug:"resonance",title:"Resonance",fullTitle:"Resonance"},signatures:"Jiří Náprstek and Cyril Fischer",authors:[{id:"207472",title:"Dr.",name:"Jiri",middleName:null,surname:"Naprstek",slug:"jiri-naprstek",fullName:"Jiri Naprstek"},{id:"213311",title:"Dr.",name:"Cyril",middleName:null,surname:"Fischer",slug:"cyril-fischer",fullName:"Cyril Fischer"}]}],onlineFirstChaptersFilter:{topicId:"15",limit:6,offset:0},onlineFirstChaptersCollection:[{id:"83034",title:"Optimal N-of-1 Clinical Trials for Individualized Patient Care and Aggregated N-of-1 Designs",slug:"optimal-n-of-1-clinical-trials-for-individualized-patient-care-and-aggregated-n-of-1-designs",totalDownloads:2,totalDimensionsCites:0,doi:"10.5772/intechopen.106352",abstract:"Precision medicine typically refers to the use of genomic signatures of patients to assign more effective therapies to treat patients, or, for improved diagnosis of the early onset of a disease so that interventions can be delivered to prevent or delay the disease progression. Because the aim is to provide individualized patient treatment, such single-person trials are called N-of-1 trials. This chapter reviews fundamental ideas, models, and construction of optimal designs for N-of-1 trials, which are invariably constructed from crossover trials, where each patient receives a random sequence of trial treatments over time. We construct examples of universally optimal N-of-1 designs for comparing two treatments under various correlation structure assumptions and discuss how N-of-1 trials may be combined to form optimal aggregated N-of-1 trials for assessing average treatment effects for two or more treatments.",book:{id:"10678",title:"Biostatistics",coverURL:"https://cdn.intechopen.com/books/images_new/10678.jpg"},signatures:"Yin Li, Weng Kee Wong and Keumhee Chough Carriere"},{id:"83029",title:"Quasi Conformally Flat Quasi Einstein-Weyl Manifolds",slug:"quasi-conformally-flat-quasi-einstein-weyl-manifolds",totalDownloads:3,totalDimensionsCites:0,doi:"10.5772/intechopen.105683",abstract:"The aim of this work is to study on quasi conformally flat quasi Einstein-Weyl manifolds. In this book chapter, firstly, an interesting relationship between complementary vector field and generator of the quasi Einstein-Weyl manifold is obtained and supported by an example. Then, it is investigated that quasi conformally flat quasi Einstein-Weyl manifolds are of quasi constant curvature, recurrent and semi-symmetric under which conditions after obtaining the expression of the curvature tensor of the quasi conformally flat quasi Einstein-Weyl manifold. Furthermore, some equivalences are obtained between to be of quasi constant curvature and to be semi-symmetric in quasi conformally flat quasi Einstein-Weyl manifolds.",book:{id:"11502",title:"Manifolds - Recent Developments and Applications",coverURL:"https://cdn.intechopen.com/books/images_new/11502.jpg"},signatures:"Fusun Nurcan"},{id:"82970",title:"Probability to be Involved in a Road Accident: Transport User Socioeconomic Approach",slug:"probability-to-be-involved-in-a-road-accident-transport-user-socioeconomic-approach",totalDownloads:4,totalDimensionsCites:0,doi:"10.5772/intechopen.106325",abstract:"Road education is one of the most relevant issues focused to reduce traffic accidents, so it is important to analyze the driver’s behavior on the roads. International research has found evidence for a relationship between socioeconomic characteristics and traffic accidents. In this sense, the chapter shows a methodology to estimate the probability to be involved in a road accident, considering the road education and the socioeconomic characteristics of the population of a specific region, taking the Santiago de Querétaro city (in México) as a study case. Through a logit model estimation and a survey applied to pedestrian, cyclist, motorcyclist, car driver, and freight driver allow us to determine which socioeconomic variables and road education are significant to determine the probability of being involved in a road accident.",book:{id:"12021",title:"Applied Probability Theory - New Perspectives, Recent Advances and Trends",coverURL:"https://cdn.intechopen.com/books/images_new/12021.jpg"},signatures:"Saúl Antonio, Obregón Biosca, José Luis Reyes Araiza and Miguel Angel Pérez Lara y Hernández"},{id:"82947",title:"Some Tauberian Theorems under Triple Statistically Nörlund-Cesáro Summability Method",slug:"some-tauberian-theorems-under-triple-statistically-n-rlund-ces-ro-summability-method",totalDownloads:2,totalDimensionsCites:0,doi:"10.5772/intechopen.106141",abstract:"In this paper, we extend the notion presented by Braha (2020) in a higher dimension, we introduce the notion of Np,qn,m,gCn,m,g1,1,1-statistically convergence and show necessity and sufficiency conditions under which the existence of the limit st-limn,m,g→∞xn,m,g=L follows from that st-limn,m,g→∞Np,qn,m,gCn,m,g1,1,1=L. These conditions are one-sided or two-sided if xn,m,g is a sequence of real or complex numbers, respectively.",book:{id:"11503",title:"Functional Calculus - Recent Advances and Development",coverURL:"https://cdn.intechopen.com/books/images_new/11503.jpg"},signatures:"Carlos Granados"},{id:"82847",title:"A Chaos Auto-Associative Model with Chebyshev Activation Function",slug:"a-chaos-auto-associative-model-with-chebyshev-activation-function",totalDownloads:5,totalDimensionsCites:0,doi:"10.5772/intechopen.106147",abstract:"In this work, we shall put forward a novel chaos memory retrieval model with a Chebyshev-type activation function as an artificial chaos neuron. According to certain numerical analyses of the present association model with autocorrelation connection matrix between neurons, the dependence of memory retrieval properties on the initial Hamming distance between the input pattern and a target pattern to be retrieved among the embedded patterns will be presented to examine the retrieval abilities, i.e. the memory capacity of the associative memory.",book:{id:"12019",title:"Chaos Theory - Recent Advances, New Perspectives and Applications",coverURL:"https://cdn.intechopen.com/books/images_new/12019.jpg"},signatures:"Masahiro Nakagawa"},{id:"82826",title:"A Brief Look at the Calderón and Hilbert Operators",slug:"a-brief-look-at-the-calder-n-and-hilbert-operators",totalDownloads:2,totalDimensionsCites:0,doi:"10.5772/intechopen.106027",abstract:"The Calderón operator is the sum of the Hardy averaging operator and its adjoint, and plays an important role in the theory of real interpolation. On the other hand, the Hilbert operator arises from the continuous version of Hilbert’s inequality. Both operators appear in different contexts and have numerous applications within harmonic analysis. In this chapter we will briefly review the Calderón and Hilbert operators, showing some of the most relevant results within functional analysis and finally we will present recent results on these operators within Fourier analysis.",book:{id:"11503",title:"Functional Calculus - Recent Advances and Development",coverURL:"https://cdn.intechopen.com/books/images_new/11503.jpg"},signatures:"Guillermo J. 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Gharieb",profilePictureURL:"https://mts.intechopen.com/storage/users/225387/images/system/225387.jpg",institutionString:"Assiut University",institution:{name:"Assiut University",institutionURL:null,country:{name:"Egypt"}}}]},{id:"8",title:"Bioinspired Technology and Biomechanics",keywords:"Bioinspired Systems, Biomechanics, Assistive Technology, Rehabilitation",scope:'Bioinspired technologies take advantage of understanding the actual biological system to provide solutions to problems in several areas. Recently, bioinspired systems have been successfully employing biomechanics to develop and improve assistive technology and rehabilitation devices. The research topic "Bioinspired Technology and Biomechanics" welcomes studies reporting recent advances in bioinspired technologies that contribute to individuals\' health, inclusion, and rehabilitation. Possible contributions can address (but are not limited to) the following research topics: Bioinspired design and control of exoskeletons, orthoses, and prostheses; Experimental evaluation of the effect of assistive devices (e.g., influence on gait, balance, and neuromuscular system); Bioinspired technologies for rehabilitation, including clinical studies reporting evaluations; Application of neuromuscular and biomechanical models to the development of bioinspired technology.',annualVolume:11404,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/8.jpg",editor:{id:"144937",title:"Prof.",name:"Adriano",middleName:"De Oliveira",surname:"Andrade",fullName:"Adriano Andrade",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRC8QQAW/Profile_Picture_1625219101815",institutionString:null,institution:{name:"Federal University of Uberlândia",institutionURL:null,country:{name:"Brazil"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"49517",title:"Prof.",name:"Hitoshi",middleName:null,surname:"Tsunashima",fullName:"Hitoshi Tsunashima",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYTP4QAO/Profile_Picture_1625819726528",institutionString:null,institution:{name:"Nihon University",institutionURL:null,country:{name:"Japan"}}},{id:"425354",title:"Dr.",name:"Marcus",middleName:"Fraga",surname:"Vieira",fullName:"Marcus Vieira",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003BJSgIQAX/Profile_Picture_1627904687309",institutionString:null,institution:{name:"Universidade Federal de Goiás",institutionURL:null,country:{name:"Brazil"}}},{id:"196746",title:"Dr.",name:"Ramana",middleName:null,surname:"Vinjamuri",fullName:"Ramana Vinjamuri",profilePictureURL:"https://mts.intechopen.com/storage/users/196746/images/system/196746.jpeg",institutionString:"University of Maryland, Baltimore County",institution:{name:"University of Maryland, Baltimore County",institutionURL:null,country:{name:"United States of America"}}}]},{id:"9",title:"Biotechnology - Biosensors, Biomaterials and Tissue Engineering",keywords:"Biotechnology, Biosensors, Biomaterials, Tissue Engineering",scope:"The Biotechnology - Biosensors, Biomaterials and Tissue Engineering topic within the Biomedical Engineering Series aims to rapidly publish contributions on all aspects of biotechnology, biosensors, biomaterial and tissue engineering. We encourage the submission of manuscripts that provide novel and mechanistic insights that report significant advances in the fields. Topics can include but are not limited to: Biotechnology such as biotechnological products and process engineering; Biotechnologically relevant enzymes and proteins; Bioenergy and biofuels; Applied genetics and molecular biotechnology; Genomics, transcriptomics, proteomics; Applied microbial and cell physiology; Environmental biotechnology; Methods and protocols. Moreover, topics in biosensor technology, like sensors that incorporate enzymes, antibodies, nucleic acids, whole cells, tissues and organelles, and other biological or biologically inspired components will be considered, and topics exploring transducers, including those based on electrochemical and optical piezoelectric, thermal, magnetic, and micromechanical elements. Chapters exploring biomaterial approaches such as polymer synthesis and characterization, drug and gene vector design, biocompatibility, immunology and toxicology, and self-assembly at the nanoscale, are welcome. Finally, the tissue engineering subcategory will support topics such as the fundamentals of stem cells and progenitor cells and their proliferation, differentiation, bioreactors for three-dimensional culture and studies of phenotypic changes, stem and progenitor cells, both short and long term, ex vivo and in vivo implantation both in preclinical models and also in clinical trials.",annualVolume:11405,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/9.jpg",editor:{id:"126286",title:"Dr.",name:"Luis",middleName:"Jesús",surname:"Villarreal-Gómez",fullName:"Luis Villarreal-Gómez",profilePictureURL:"https://mts.intechopen.com/storage/users/126286/images/system/126286.jpg",institutionString:null,institution:{name:"Autonomous University of Baja California",institutionURL:null,country:{name:"Mexico"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"35539",title:"Dr.",name:"Cecilia",middleName:null,surname:"Cristea",fullName:"Cecilia Cristea",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYQ65QAG/Profile_Picture_1621007741527",institutionString:null,institution:{name:"Iuliu Hațieganu University of Medicine and Pharmacy",institutionURL:null,country:{name:"Romania"}}},{id:"40735",title:"Dr.",name:"Gil",middleName:"Alberto Batista",surname:"Gonçalves",fullName:"Gil Gonçalves",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYRLGQA4/Profile_Picture_1628492612759",institutionString:null,institution:{name:"University of Aveiro",institutionURL:null,country:{name:"Portugal"}}},{id:"211725",title:"Associate Prof.",name:"Johann F.",middleName:null,surname:"Osma",fullName:"Johann F. 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