Effect of intensity of care on mortality and withdrawal of life-sustaining therapies in severe traumatic brain injury patients : a post-hoc analysis of a multicenter cohort study

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Effect of intensity of care on mortality and

withdrawal of life-sustaining therapies in severe

traumatic brain injury patients:

A post-hoc analysis of a multicenter cohort study

Mémoire

Peter Raouf Aziz Gerges

Maîtrise en épidémiologie - épidémiologie clinique

Maître ès sciences (M. Sc.)

Québec, Canada

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Effect of intensity of care on mortality and

withdrawal of life-sustaining therapies in severe

traumatic brain injury patients:

A post-hoc analysis of a multicenter cohort study

Mémoire

Peter Raouf Aziz Gerges

Sous la direction de:

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Résumé

Introduction et objectifs

Le traumatisme craniocérébral (TCC) est un problème de santé majeur dans le monde. Chez les patients ayant subi un TCC grave, une amélioration de la mortalité a été observée dans les centres de traumatologie offrant une intensité de traitement élevée et un monitorage intensif. Cependant, la mortalité ainsi que l’incidence du retrait du maintien des fonctions vitales varient entre les différents centres de traumatologie. Notre étude visait à évaluer l’association en l’effet de l'intensité des soins sur l’incidence du retrait du maintien des fonctions vitales et de mortalité chez les patients ayant subi un TCC grave.

Méthodes

Notre étude est une analyse post-hoc d’une étude cohorte rétrospective multicentrique de patients ayant subi un TCC grave (n = 720). Nous avons défini l’intensité des soins en utilisant le type d’interventions effectuées à l’'unité de soins intensifs. Les interventions ont été classées en fonction de leur spécificité par rapport au TCC et en fonction de leur nature : 1) médicale, 2) chirurgicale, et 3) diagnostique. L’effet de l'intensité des soins, sur la mortalité et le retrait du maintien des fonctions vitales, a été évalué en utilisant des modèles à risques proportionnels de Cox ajustés.

Résultats

L’intensité des soins a été associée à une diminution de la mortalité (HR 0,69, IC à 95% 0,63 à 0,74, p <0,0001) et du retrait du maintien des fonctions vitales (HR 0,73, IC à 95% 0,67 à 0,79, p <0,0001). Les associations ont été significatives pour l'intensité des interventions spécifiques et non-spécifiques au TCC et pour les interventions médicales et diagnostiques, mais non significatives pour les interventions chirurgicales.

Conclusion

Nous avons observé une association significative entre l'intensité globale des soins sur la mortalité et sur l'incidence du retrait du maintien des fonctions vitales suivant un TCC grave. Cette association était significative avec les interventions spécifiques et non-spécifiques au TCC, ainsi qu’avec les interventions médicales et diagnostiques.

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Abstract

Introduction and objectives

Traumatic brain injury (TBI) is a major health problem. In severe TBI, better outcomes and reduced mortality were shown in trauma centers providing high intensity of treatment and monitoring. Mortality as well as incidence of withdrawal of life-sustaining therapies were found to vary among different trauma centers. Our study aimed to evaluate the effect of intensity of care for severe TBI on the incidence of withdrawal of life-sustaining therapy and mortality.

Methods

Our study is post-hoc analysis of a Canadian multicenter retrospective cohort study of patients with severe TBI (n = 720). We defined the intensity of care using interventions performed in ICU. They were categorized into 1) TBI related interventions, 2) interventions non-specific to TBI, and according to type of interventions: 1) medical, 2) surgical, and 3) diagnostic interventions. The effect of intensity of care, on mortality and the withdrawal of life-sustaining therapies, was evaluated with adjusted Cox proportional-hazards regression analyses of time-to-event data.

Results

The intensity of care was associated with decreased mortality (HR 0.69, 95% CI 0.63–0.74, p<0.0001) and decreased withdrawal of life support (HR 0.73, 95% CI 0.67–0.79, p<0.0001). The associations with outcomes were also significant for both the intensity of interventions specific to TBI and general ICU interventions. The associations with outcomes also maintained their significance with medical and diagnostic components of care but were not significant with surgical component of care.

Conclusion

We observed a significant association between the overall intensity of care, defined by the different interventions commonly used, on mortality and on the incidence of withdrawal of life-sustaining therapies in severe TBI. This association was present whether interventions were specific or not specific to TBI, as well as whether they were medical or diagnostic interventions.

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Je suis l’auteur principal de cette recherche et Dr Alexis Turgeon, mon directeur de recherche, a supervisé chaque étape de son développement. J’ai effectué la revue de littérature et ai rédigé le premier jet du protocole de recherche. J’ai fait les analyses statistiques des données avec l’aide du Dr Alexis Turgeon et de Xavier Neveu, biostatisticien de l’équipe de recherche. Finalement, j'ai fait l’interprétation des données aidé du Dr Alexis Turgeon et ai écrit le premier jet du manuscrit avec l’aide du Dr Turgeon et de Mme Caroline Léger.

Cet article sera soumis pour publication sous peu. Le manuscrit de l’article inclus dans le présent document a respecté les exigences éditoriales pour publication, cependant il n’est pas définitivement la version qui sera publiée.

Je tiens à remercier sincèrement Dr Alexis Turgeon pour son mentorat, son appui et en sa qualité de directeur de recherche.

Je remercie les coauteurs pour leur aide à réaliser les étapes de ce projet; surtout Dr Lynne Moore pour son expérience en biostatistiques, Dr François Lauzier pour son expertise clinique en soins intensifs, et Dr Ryan Zarychanski pour les mêmes raisons. J'apprécie beaucoup l'aide à effectuer ce projet et la collaboration de Caroline Léger, gestionnaire de l’équipe de recherche en soins intensifs, Michèle Shemilt, assistante de recherche, et Xavier Neveu, biostatisticien de l’équipe de recherche.

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1 Chapter one: Introduction

1.1 Definition of traumatic brain injury

Although the term "traumatic brain injury" appears self-explanatory, clear-cut terminology and unambiguous definition are prerequisites for epidemiology and clinical research. The early literature about our population of interest often used the terms "head injury" and "traumatic brain injury" synonymously. This interchangeable use of terms took place in many studies in spite of the fact that the head may sustain an injury, for example to the scalp, without affecting the brain and the brain may be injured by a mechanical mechanism not apparently affecting the other parts of the head. That is why the neurotraumatology community has been evolving consensus, over the past five decades, about what falls under the specific term "traumatic brain injury"; including different injury mechanisms and pathophysiology (See section 1.2 for more details about TBI pathophysiology).

This evolution ultimately led to a recommendation of clear distinction between the two terms, the general term "head injury" and the more precise term "traumatic brain injury", by a consensus conference sponsored in 1992 by the National Institute of Disability and Rehabilitation Research in the USA (1). This change in nomenclature led many organizations, related to this clinical field, to change their names to include the term "brain injury" instead of "head injury" (for example National Brain Injury Association in the USA).

However, various definitions have been proposed in the literature to the increasingly used term "traumatic brain injury". The diagnostic ambiguity and the variability in TBI case definition, among different epidemiological studies, could confound precise TBI epidemiologic description and therefore create difficulties in comparing findings. Thus, the continuous cumulative efforts, exerted to standardize the epidemiological TBI case definition, led to a widely-accepted definition posed by the Centers for Disease control and Prevention (CDC) in the USA. It defines TBI as an « injury to the head (arising

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2 from blunt or penetrating trauma, or from acceleration/deceleration forces) that is associated with any of these symptoms attributable to the injury: decreased level of consciousness, amnesia, other neurologic or neuropsychologic abnormalities, skull fracture, diagnosed intracranial lesions, or death »(2-5). This definition corresponds to codes of the International Classification of Diseases (ICD- 10) for intracranial injury (codes S06.0; S06.0–S06.9; Appendix A) (6, 7). ICD-10 codes are commonly used in epidemiological studies to identify TBI patients. Our study is a post-hoc analysis of a retrospective cohort study that used ICD-10 codes to identify TBI patients.

Another TBI definition that corresponds to ICD-10 codes was proposed in 2010 by an international interagency working group (8). It defines TBI as an “alteration in brain function or other evidence of brain pathology, caused by an external force”. This definition was adopted in 2011 by Brain Injury Association of America (9), because, although being concise, it consists of conclusive and precise elements for establishing a TBI diagnosis (see Appendix B). The different elements of TBI’s definition will be clearer in the light of TBI pathophysiological background discussed in the next section.

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1.2 Pathophysiology of traumatic brain injury

Traumatic brain injury has a complex pathophysiology. Although primary TBI insults are caused by a single acute event, exerting an external force on the brain, a cascade of pathophysiological processes subsequently takes place causing secondary TBI insults (10). The following subsections illustrate the mechanism of brain injury, followed by the pathophysiology of primary and secondary TBI insults.

1.2.1 Mechanism of traumatic brain injury

By definition, traumatic brain injury results from external force (see section 1.1 and Appendix A). The nature, intensity and duration of this external force determine the pattern of brain damage as well as its extent (11). The more intense and durable the external force, the more damage it causes to the brain. The intensity of the external force affects the severity as well as the depth of brain injury; deeper brain structures are injured as the intensity of the force increases (12, 13). As for the nature of external force causing TBI, it can be one of two main types; penetrating or blunt.

Penetrating TBI, also called open TBI, occurs when the skull and membrane lining of the central nervous system are pierced by an object (i.e. a weapon), thereby causing the brain tissue to be exposed to the external environment. This exposure of the brain tissue may explain why penetrating TBI has much higher early mortality than blunt TBI (14). The biological pathways of primary and secondary TBI insults are less understood in penetrating than blunt TBIs (14). We are interested in blunt TBI since its estimated incidence is 100:6, compared to penetrating TBI (15).

Blunt TBI, also called closed TBI, occurs when the brain is moved violently, by the effect of an external mechanical force, without exposure of brain tissue to the external environment. The most common blunt mechanical mechanisms of TBI include acceleration-deceleration injuries and rotational injuries, which are frequently resulting from motor vehicle accidents and shaking injuries (16). Acceleration-deceleration

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4 injury occurs when the moving head rapidly decelerated. On the other hand, rotational injury takes place when the brain is exposed to a rotational movement within the skull. Both injury mechanisms, if of high enough intensity, may cause twisting or shearing of neural fibers (i.e. diffuse axonal injury).

If the primary injury occurs mainly adjacent to site of impact, it is known as coup injury, with minimal, little, or no injury to the opposite side of the brain (17, 18) (Appendix C). Whereas, Coup-contrecoup injury occurs when both the site of the impact and the opposite side of the brain are injured (Appendix C).

The above mentioned different trauma mechanisms cause primary brain insult followed by development of secondary brain insults as complications of the original injury (See Appendix D). The following two subsections will discuss, in more details, the primary and secondary TBI insults, respectively.

1.2.2 Primary traumatic brain injury

The primary insults are those directly caused by the trauma mechanism. They occur immediately at the time of the trauma and will develop over the following hours, and can be in the form of focal lesions; cerebral contusions and intracranial hematomas, and/or diffuse axonal injury (11, 19-22) (See Appendix D). To better understand the primary TBI pathology, brief descriptions of the most common types of primary TBI insults are presented below.

Cerebral contusions

Cerebral contusions are “bruises” or hemorrhagic lesions on the brain surface. The site is determined by the impact of the brain on the skull; either on the side of the blow (coup injury) and/or on the opposite side (countercoup injury) (17, 18) (Appendix C).

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5 Intracranial hematomas

Intracranial hematomas, localized collections of blood outside the blood vessels, result from intracranial bleeding (hemorrhage) due to tearing of blood vessels by the traumatic external force. There are three types of hematomas, according to their site; epidural (between the skull and dura), subdural (between the dura and the brain) or intracerebral (in the brain) (Appendix F).

Diffuse axonal injury

Diffuse axonal injury is a widespread microscopic severing of the brain axons. Axons are the neural fibers connecting neurons with each other, and form a main constituent of the brain white matter. Diffuse axonal injury is caused by mechanical shearing following rapid deceleration, rotational or shaking movement of the head (23). The axonal injury occurs when the stationary brain lags behind a rapid movement of the skull, in high energy mechanical traumas like motor vehicle accidents, causing brain axons to tear. This stretch of the axons causes both physical disruptions of the cystoskeleton as well as its biodegradation through enzymes activated by the injury. Therefore, this may ultimately cause separation of the axon and cell death (24).

1.2.3 Secondary traumatic brain injuries

Following the initial brain injury, a cascade of pathophysiological events takes place at the systemic and local levels. During this period, the injured brain remains fragile and is susceptible to any new insult that may generate changes in brain oxygen delivery. As an example, episodes of hypotension or hypoxemia may generate new lesions due to loss of the normal autoregulation of cerebral blood flow. The local pathophysiological cascade of events may include cellular changes within the brain parenchyma (25). This cascade of events may lead to secondary brain injuries generating new injuries and worsening the prognosis.

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6 Most interventions provided during the acute phase of severe TBI management aim to prevent the development of secondary brain injuries or minimize their effects (26) (See section 1.6.3). The mechanisms responsible for these secondary brain injuries include the progression of brain edema, increased intracranial pressure (ICP), decreased cerebral perfusion pressure and the generation of cerebral ischemia (27, 28) (Appendix D).

Brain edema

Edema is extracellular fluid accumulation. By definition, there are two mechanisms of edema formation: vasogenic and cytotoxic mechanisms (20). The vasogenic edema is produced by the increased permeability of blood vessels and the cytotoxic edema by the cell damage caused by the primary injury. Significant neural damage leads to diffuse brain edema, which constitutes an important secondary brain injury mechanism in severe TBI (29). The diffuse edema leads to another secondary brain injury mechanism: increased intracranial pressure.

Increased intracranial pressure

The increased intracranial pressure is an important secondary TBI injury mechanism. It is caused by several factors including diffuse brain edema and swelling, formation of intracranial hematomas, blockage of cerebrospinal fluid, and loss of the normal autoregulation of cerebral blood flow. The increased intracranial pressure leads to a decrease in cerebral perfusion pressure (CPP), and therefore may lead to brain ischemia (12).

Brain ischemia

The most significant factor in secondary brain damage is ischemia. It is caused by increased intracranial pressure and inadequate blood flow (decreased CPP) (12). Brain ischemia causes a cascade of inflammatory and cytotoxic mechanisms which may lead to tissue damage and cell death (28).

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1.3 Classification of traumatic brain injury severity

The previous section discussed, among others, the classification of TBI by the mechanism of injury; into blunt and penetrating TBIs. Traumatic brain injury is also traditionally classified by the degree of the neurological injury severity, i.e. into mild, moderate or severe TBI, based on the level of consciousness (See Appendix G). The three different levels of TBI severity show variation in epidemiology, clinical recovery and prognosis (30).

Disturbed consciousness is one of the immediate sequelae of most traumatic brain injuries. However, the degree of disturbance in consciousness varies from a slight reduction in alertness to deep coma. Therefore, severity of TBI can be inferred by measuring the alteration of the patient's neurological responsiveness. Thus, in the literature, TBI severity is traditionally evaluated, and classified, by a clinical index of neurological responsiveness, which may be the duration of loss of consciousness (LOC), duration of post-traumatic amnesia (PTA) or depth of coma measured by the Glasgow Coma Scale (GCS) score (30) (See Appendix G). Among these tools, the GCS score is the most widely used to classify TBI severity (31). These clinical indices will be described, in more details, in the following subsections respectively.

1.3.1 Loss of consciousness

The presence and duration of loss of consciousness (LOC) has been historically a main method to categorize TBI severity. In a TBI patient, if the consciousness is altered or lost for less than 30 minutes, this corresponds to mild TBI (32). If the LOC is for more than 30 minutes but less than 24 hours, moderate TBI will be the appropriate degree of severity. If the LOC persists for ≥ 24 hours, TBI is classified as severe. Thus, a disadvantage of this method is that 24 hours of LOC must be reported before confirming that the TBI is severe and not moderate (33, 34) (See Appendix G).

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8 1.3.2 Post-traumatic amnesia

Assessment of the duration of post-traumatic amnesia (PTA) is another possible method for classifying TBI severity (35). Post-traumatic amnesia was defined as the period following head injury during which the patient is unable to store information about ongoing events (36). Therefore, by definition, PTA includes the period of coma, if exists, and extends until the patient regains continuous memory; also called the anterograde memory (37, 38).

In their original study on PTA , it was defined at less than one hour after the trauma as mild degree, one to 24 hours as moderate degree and more than 24 hours as severe degree (36). Some authors used these cut-offs of PTA duration, among other tools, for categorization of TBI severity (39, 40). However, according to the recommendations of Mild Traumatic Brain Injury Committee of the American Congress of Rehabilitation Medicine,, in 1993, the cut-off of PTA in mild and moderate TBI was modified to 24 hours and that for severe TBI is placed at 7 days (41, 42) (see Appendix G). Therefore, a total duration of one week is needed before being able to classify TBI, using PTA, as severe. On the other hand, standardized PTA evaluation is recommended for assisting the diagnosis and classification of mild TBI as well as its monitoring, early management and prognostic evaluation (41, 42). Standardized PTA evaluation of the suspected cases of mild TBI, can be performed by the Abbreviated Westmead Post Traumatic Amnesia Scale (A-WPTAS) (43, 44). A-WPTAS is a validated tool (45-49) that uses picture identification in evaluating the patient's new continuous memory on an hourly basis.

1.3.2 Glasgow Coma Scale

The above-mentioned two methods used to stratify TBI severity, namely loss of consciousness and post-traumatic amnesia are based on the quantitative assessment of the duration of altered consciousness and amnesia respectively (50). For severe TBI,

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9 the clinical evaluation using these first two tools cannot be completed, by definition, before the first 24 hours, since severe TBI patient's LOC often exceeds this duration. On the other hand, initial GCS assessment of TBI is typically measured in the acute setting following the stabilization of the patient's condition. The level of consciousness of the patient is inferred, by the GCS assessment, from the extent of alterations of the patient's responsiveness to stimuli (51, 52) (See Appendix G).

For several decades, the most widely used clinical TBI severity scale has been the GCS, proposed in 1974 to generally assess the level of consciousness or depth of coma (51, 52). The GCS is an observational instrument which separately assesses eye opening, motor and verbal responsiveness to stimuli (51, 53) (See Appendix H). This separation in the assessment of three evaluated parameters is appropriate conceptually, as each response may vary independently. This distinction is also convenient in clinical practice, which may have partially contributed to the wide use of the GCS approach in the acute setting. The scores of the three different components are summated into an overall coma score ranging from 3 to 15 (52, 54). The GCS minimum score of 3 is assigned to patients lacking any response to painful stimuli. On the other hand, the maximum score of 15 is assigned to the fully alert and oriented patients.

A TBI patient with GCS score of 13-15 is classified to have mild TBI (55), whereas GCS score of 9-12 corresponds to moderate TBI (56). The widely used definition for severe TBI is that with a GCS of 3-8 (55) (see Appendix G). This definition was originally derived from the international studies coordinated from the Institute of Neurological Sciences at Glasgow - Scotland (57, 58), in which severe TBI is defined as the patient in a coma for six hours. Coma was defined, in these original studies, as the state of not obeying commands, absence of eye opening and absence of comprehensible verbal response (57, 58); which translates using GCS into a score of 8 or less, hence the adoption of this score range (53) (see Appendix G and Appendix H). Nevertheless, the six hour duration, in the original definition, has become difficult to apply because severe TBI acute management includes sedation, intubation, and ventilation (26), and hence the GCS is un-assessable for at least several hours after

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10 admission. Thus, the initial GCS and TBI severity are usually assessed by the clinical findings on admission.

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1.4 Epidemiology of traumatic brain injury

Although TBI is known to be a major public health problem, the available epidemiological data may partially fail to show its full extent. It is believed that the incidence and prevalence of TBI may be underestimated. This is, at least in part, due to the possibility of missing a significant proportion of mild TBI cases, undiagnosed in the primary care settings (59-61). Added to that is the possibility of under-reporting of traumatic brain injury sustained as part of multi-traumas (62).

1.4.1 Traumatic brain injury incidence and prevalence

Traumatic brain injury is estimated to affect 10 million individuals worldwide every year (62, 63). The country-based estimates of the TBI incidence vary from 108 to 332 new cases per 100,000 population admitted in hospital every year (64). Nevertheless, these estimates of TBI often include only patients admitted to hospitals (65), with the possibility of missing a significant proportion of the medically unattended patients, misdiagnosed cases and milder cases not admitted to inpatient care (59-61, 65). Hence, these incidence rates, as previously mentioned, may be underestimated.

Traumatic brain injury in the United States

Traumatic brain injuries were estimated to account for 3% of all injuries in the USA in 2000 (66). In the period 2002-2006, the rate of total TBI-related emergency department (ED) visits, hospitalizations and deaths was 577 per 100,000 population per year (67) (See Appendix K and appendix L for further details).

The most recent estimates, by Centers for Disease Control and Prevention (CDC) in 2010, suggest that every year TBIs account for approximately 2.5 million ED visits, hospitalizations, and deaths in the USA; (31). From 2007 to 2010, the total annual rate

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12 for TBI-related ED visits, hospitalizations and deaths increased by 45%; (31, 68). This increase is mainly driven by a notable increase in the rate of TBI-related ED visits by 56% (31, 68) (See Appendix M and Appendix N).

Traumatic brain injury in Canada

The incidence and prevalence data of traumatic brain injuries in Canada are not as readily available as for the USA. Nonetheless, Canadian estimates have been proposed, based on USA data (69) (See Appendix O). The Canadian Institute for Health Information (CIHI) reported 15,298 hospitalizations resulting from TBI in the fiscal 2003-2004; equating to more than 41 admissions per day (70). A decreasing trend has shown in the inpatient-admissions over time in Canada (71). This may be, at least in part, due to improvement in emergency medical systems which leads to a shift of TBI management to emergency department with a decreased need of hospital admissions; especially for mild TBI and for younger ages (72) (See Appendix P and appendix Q).

1.4.2 Traumatic brain injury contributory factors

Certain patient characteristics have been reported to contribute to the risk of sustaining a TBI. These possible contributory factors include age, sex, socioeconomic status and patient history. These factors are presented in more details in the next three subsections.

Age

Early childhood, late adolescence and elderly have shown the highest TBI estimated incidence rates in population-based studies on TBI-related episodes of care (31, 62, 67). This may be related to the higher risk to falls, among young children and elderly, and to motor vehicle accidents among older adolescents (See section 1.4.3) (67,

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73-13 75). In severe TBI, patients older than 55 years were observed to more likely die than younger patients (76-78).

Sex

The literature presents varying differences in the incidence of TBI in terms of sex. For instance, the ratio of TBI incidence in males to that in females, across thirteen North American studies, ranges from 1.6:1 and 2.8:1 (79). A wider range was shown by a review of 20 studies to be from 1.5:1 to 3:1 (80). In Canada, the incidence of severe TBI, our population of interest, was shown to be higher for males at all age groups than their female counterparts (81).

Although the TBI incidence is generally higher in males than females across all age groups (72, 82), the difference is more pronounced in young adults (67). Hence, the highest incidence of TBI, in terms of sex and age combined, is in males aged 16 - 24 years (83).

This pattern of incidence may be attributed to differences in exposure to motor vehicle accidents, occupational hazards, and risk-taking behavior as participation in contact sports and interpersonal violence; which may be higher in men especially of younger age (84).

Socio-economic status and patient history

Overall, the socio-demographic variables can influence the TBI epidemiology. A higher incidence of TBI has been shown to occur among individuals living in lower socio-economic regions (65, 85). Lower socioeconomic status has shown an association with higher incidences of traumatic brain injuries (86) especially with

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14 regards to more severe injuries (87). In Canada, among Toronto’s homeless population, more than half were estimated to have sustained traumatic brain injuries (88).

The higher TBI risk in lower socioeconomic population may be due in part to a higher incidence of substance abuse and risk-taking behavior that leads to higher TBI risk. Alcohol and drugs abuse are overrepresented among traumatic brain injury patients (21, 89-91). This can be further explained by the fact that intoxication is considered a contributory factor to road traffic accidents especially among those including pedestrians and cyclists (92).

In general TBI risks may also increase in the presence of a personal history of behavioral problems and psychiatric disorders (93). Another important contributory factor to increased TBI risks has shown to be exposure to sports and recreational activities (94).

1.4.3 Causes of traumatic brain injuries

The leading causes of traumatic brain injuries in the USA and Canada are estimated to be falls, road accidents and being struck by or against an object (31, 67, 72) (See Appendix R and Appendix S). In general, road accidents and falls were among the 20 leading causes of death worldwide in 2015 and among the 20-leading global burden of disease and injury in 2012 (See Appendices T and U respectively).

Falls dominate as cause of TBI with the highest rates among children aged 0-4 years and elderly aged ≥75 years (62, 67). The high TBI incidence among young children and the elderly may be attributed to falls (74, 75) (See Section 1.4.2). A Canadian study showed that, among older adults, as the age increases the contribution of falls as a cause of TBI increases (95).

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15 Road accidents are the leading cause of TBI-related deaths and their highest rates are among adults aged 20-24 years (67). Road accidents are the most common cause contributing to severe TBI (35).

1.4.4 Consequences of traumatic brain injuries

In addition to its high mortality, TBI has serious health implications that may cause long-term disability. Therefore, TBI is a major public health problem that causes the society a substantial economic burden. In the following subsections, TBI economic burden, morbidity and mortality will be discussed respectively in more details.

Economic burden

Injuries, including TBI, pose their economic burden to societies in the form of direct medicalcosts and indirect societal costs (96). In the following subsections, the direct, indirect and total costs of TBI will be respectively discussed.

Direct costs

The direct medical costs of TBI include the initial costs, in the form of acute care and hospitalization costs, in addition to the long-term care and rehabilitation costs. The costs of TBI hospitalization, in the USA acute-care setting were estimated to range from $8,189 for a moderate TBI patient to $33,537 for a critical TBI case (in 2002 US dollars (97); or from $10,826 to $44,338 when inflated to 2015 US dollars (98)). Inpatient rehabilitation costs were estimated at $16,686 per rehabilitation hospital admission for TBI (99, 100).

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16 The lifetime medical costs were estimated at $9.2 billion per year in the USA (101) ($13.1 billion in 2013 dollars (102) or $13.4 billion when inflated to 2015 dollars (98) - See Appendix V for further details on estimated lifetime TBI costs). Therefore, TBIs, although accounting for 3% of all injuries in 2000, were estimated to account for 11% of the injury-attributable lifetime medical costs (101).

In Canada, a study estimated the mean medical costs to be $32,132 per TBI patient for the first yearpost-injury in Ontario (103). The total medical costs, for all Ontario TBI patients in their first post-injury year, are estimated to be $120.7 million annually (103). Assuming a similar incidence of TBI in Canada, the total medical costs in Canada for first-year management of TBI patients were estimated accordingly at $331.1 million (103).

Indirect costs

The indirect costs of TBI, also called productivity losses, are shown to be substantial (104). This is, at least in part, due to the disabilities TBI may causeand the young age of those most often involved (See Section 1.4.2). The TBI survivors who sustained their injury at a young age can be expected to live 35-60 years, which shows the scale of productivity losses (105). The mean lifetime productivity losses of a TBI case were estimated at $38,126 (104). Accordingly, the lifetime productivity losses, of the USA TBIs in the year 2000, were estimated at $51.2 billion annually (104) ($64.7 billion in 2013 dollars (102); $66.1 billion in 2015 dollars (98); see Appendix V).

Total costs

The sum of the above-mentioned direct medical and indirect societal costs of TBI gives its total lifetime costs. In the USA, the average of total lifetime costs of a TBI case in the year 2000 was estimated at $44,986 (106). The total lifetime costs of all TBI cases

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17 in the year 2000 were estimated to be $60.4 billion annually (106) ($82.87 billion in 2015 dollars (98), See Appendix V). Based on these USA estimates, a study estimated the total lifetime costs of TBI in Canada at $6.79 billion in 2010 and projected them to be $8.6 billion in 2036 (69) (these estimated amounts were expressed in US dollars; see Appendix O).

1.4.5 Morbidity and disability of traumatic brain injuries

Traumatic brain injuries can adversely affect the patient's quality of life in several ways. The health effects of TBI may negatively impact the patient's whole pattern of life including social, interpersonal and occupational functioning. The health effects of TBI may vary according to the injury location and severity and the patient's medical history prior to the injury (107, 108). However, these health effects can broadly be grouped into cognitive, behavioral/emotional, motor, sensory, and somatic symptoms (109-115) (See Appendix W for further details).These health effects associated with TBI can persist and therefore may lead to long-term impairment, functional limitations and potential disability (109, 110) that may affect the patient's capacity to work (116, 117).

TBI-related long-term disability was estimated, using Functional Independence Measures (FIM), to range from 35% (4) to 43.3% (100) of hospitalized TBI survivors in the USA (See Appendix X for further details on FIM). This corresponds to an annual incidence ranging from 80,000–90,000 (4) to 124,626 (100) new cases of TBI-related long-term disability; estimated for the years 1996 and 2003 respectively. The prevalence of TBI-related long-term disability ranges from 3.17 million people estimated in 2005 (118), to 5.3 million estimated in 1999 (4); corresponding to a range of 1.1% to 2% of the USA population, respectively.

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18 In Canada, based on the USA estimates and the Canadian population statistics, the prevalence of Canadians living with TBI disabilities is estimated to be 648,375 in 2010 and extrapolated to grow to 826,128 in 2036 (69)(See Appendix O).

1.4.6 Mortality in traumatic brain injury

TBI contribute to 30 % of all injury-related deaths in the USA; either as a direct or indirect cause of death (31, 67). In the period 1997-2007, the USA had an average of 53,000 annual deaths related to TBI; at an average rate of 18.4 per 100,000 individuals (119). However, during this time period, death rates slightly decreased from 19.3 to 17.8 per 100,000 population (119). This slight decrease can be plausibly explained by the reduction in road accidents (31).

In Canada, TBI is a major cause of death for young adults (120, 121). Based on the USA data and the Canadian population statistics, Canada was estimated to have 5,819 deaths in 2010, which was extrapolated to grow to 7,414 annually in 2036 (69) (See appendix O). In one decade, from 1994-1995 to 2003-2004, the proportion of older Canadians who died as a result of TBI, after admission to hospital, has increased by 35% (70). In 2003-2004, deaths in hospitalized patients due to traumatic head injuries accounted for 20% of all trauma deaths. The majority of deaths occurred in the elderly (59%) (70). Most deaths following TBI are caused by severe TBI; with an average mortality of 39% (122). Despite the development of research and quality of care in the last decades, substantial improvements in mortality have not been achieved since 1970s (See Appendix Y). Most deaths (70 %) among severe traumatic brain injured patients are shown to be subsequent to withdrawal of life-sustaining therapies, and no patient or very few survive this process (123). Hence, the next section is dedicated to discuss life-sustaining therapies in more details.

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19

1.5 Withdrawal of life-sustaining therapies in traumatic brain-injured patients

Withdrawal of life-sustaining therapies means discontinuation of treatments that have previously been implemented to sustain life; these include endotracheal intubation, mechanical ventilation, intravenous fluids, massive blood transfusion, vasopressor infusion, renal replacement therapy and cardiopulmonary resuscitation (124). A study showed that 70% of hospital mortality among severe traumatic brain-injured patients occurred following withdrawal of life-sustaining therapies, with no patient surviving the withdrawal of therapies (123).

1.5.1 Variability in withdrawal of life-sustaining therapies

There is a wide variability in the incidence of withdrawal of life-sustaining therapies. A systematic review of studies on adult ICU patients has shown this variability worldwide as well as within the same country. The variability exists between different countries, different regions of same country, different ICUs of same region, and between different physicians within the same ICU (125). In Canada, a significant variation has been shown between six trauma centers in withdrawal of life-sustaining therapies among severe traumatic brain-injured patients (123).

This wide variation in the incidence can be explained, at least in part, by specific factors contributing to withdrawal of life-sustaining therapies. Therefore, several studies sought to detect the possible contributing factors in the general critical care context (126-139). However, some of these possible factors do not apply for traumatic brain-injured patients, being generally younger in age and having fewer or no prior comorbidities as compared to the general critical care patient population (123, 139-142). Therefore, some studies have assessed factors associated with withdrawal of life-sustaining therapies in this specific traumatic population (123, 139-141).

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20 1.5.2 Factors associated with the withdrawal of life-sustaining therapies in traumatic brain-injured patient

Making the decision to withdraw life-sustaining therapies is a complex process in which the patient’s condition, the family, and the caregiver are involved (143). Hence, this critical decision is most probably multi-factorial (128, 135, 144, 145). For traumatic critical care patients, the institution type has been shown to be an independent predicator of withdrawal of life-sustaining therapies. Being cared for in a trauma center, versus non-trauma center, has shown to be associated with higher rate of withdrawal of life-sustaining therapies (144). This may be, at least in part, because these facilities and clinical providers have more experience in managing end-of-life traumatic patients, and therefore are more capable to provide guidance to families concerning making end-of-life decisions (144).

At the patient level, namely for traumatic critical care patients, factors associated with withdrawal of life-sustaining therapies included comorbidity and advanced age; most prominently the age group from 75 to 84 years (144). The injury severity and the initial GCS motor score were also associated with the withdrawal of life-sustaining therapies (144). In TBI population, brain herniation on the initial head CT scan is associated with increased odds of withdrawal of life-sustaining therapies (139). On the other hand, epidural hematoma is associated with fewer odds of withdrawal of life-sustaining therapies compared to the other initial CT findings (139). Lower odds to withdraw life-sustaining therapies, in severe TBIs, are also associated with the different surgical interventions common in this patients’ population. These surgical interventions include decompressive craniectomy, laparotomy, thoracotomy, sternotomy and open reduction of internal fracture. Two surgical procedures have not shown a significant association with withdrawal of life-sustaining therapies; namely tracheotomy and percutaneous endoscopic gastrostomy (PEG) tube insertion (139).

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21 At the level of the caregivers; some physicians have shown to be reticent about the decision to withdraw life-sustaining therapies (146, 147). The most reported common reason for withdrawal of life-sustaining therapies in severe traumatic brain-injured patients has been having poor chance of survival; according to the medical team evaluation (123). The second most common reason has been that the prognosis is incompatible with the patient’s wishes, as indicated by the next of kin. While a poor long-term prognosis, as indicated by the medical team, was the third common reported reason for withdrawal of life-sustaining therapy in severe traumatic brain-injured patients. In order to better understand withdrawal of life-sustaining therapy in the context of trauma critical care, further research and investigation has been recommended (144).

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22

1.6 Intensity of care

The overall care provided to a patient can be defined by two determinants; its quality as well as its quantity; or more precisely its intensity. In the critical care field, including traumatic brain-injured patients, the quality of care provided has much improved with the technological and research development in recent decades. However, there has been limited research dedicated to the quantification of the intensity of care and its association with outcomes in severe traumatic brain-injured patients; our population of interest. A greater knowledge of the contribution of intensity of care to outcome can help making insightful decisions in the management of the severe traumatic brain-injured patients. This improved knowledge can also aid the standardization of care provided to this population aiming to better outcome.

Although no study has quantified the intensity of care for traumatic brain-injured patients, there have been studies suggesting a possible association between more intense care and favorable outcomes. The results of these studies are presented in more details below after presenting the definition of intensity of care. Components of care for severe traumatic brain-injured patients are also presented in this section.

1.6.1 Definition of intensity of care

The current literature has not yet offered a standard definition of the expression intensity of care. This may be due, in part, to the relative paucity of research specifically dedicated to this topic, and may also because it varies according to the different health care conditions. The intensity is defined, by Merriam-Webster online dictionary, as "the magnitude of a quantity (as force or energy) per unit (as of area, charge, mass, or time)" (148). In the case of intensity of care, our exposure variable of interest, the quantification of care provided to a patient can be plausibly assessed per unit of time. Hence, based on the above-mentioned definition of intensity, the definition of intensity

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23 of care would be: "the magnitude of the quantified care per unit time". Time factor is evidently and plausibly vital in the management and care for patients.

1.6.2 Intensity of care for traumatic brain-injured patients

In a systematic review and meta-analysis, it was suggested that the increased mortality observed in patients admitted to an intensive care unit (ICU) over the weekend may be accounted for by the lower intensity of care provided during these off-hours (149). This proposed hypothesis was based on results of a meta-analysis, of data pooled from ten eligible studies, assessing the association between the time of admission to the ICU and mortality. The results demonstrated that patients admitted to the ICUs over the weekends had significant increased mortality. However, these results did not apply for those admitted in nighttime shifts; which were not associated with mortality. Hence, this higher mortality in week-ends was attributed by the authors to be possibly due to lower intensity of care. Although, this meta-analysis included general ICU patients, not specifically traumatic brain-injured, its findings give an indication of the possible variation of mortality, among the critical care patients, with the variation of the intensity of care provided to them.

Another relevant study evaluates the effect of age on mortality among traumatic brain injured adults (142). The results of the study demonstrated a higher mortality among the elderly. The authors suggested the decreased intensity of care provided to the elderly population as the possible cause for this higher mortality among them. Although the study did not quantify the intensity of care as one continuous variable, it measured separately indices of high intensity of care, as the use of relatively aggressive intervention or the number of surgical or medical consultations. Unadjusted for the severity of the traumatic brain injury, the percentage distributions of most of these indices were least in the elderly. Hence, the authors proposed their hypothesis

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24 explaining the higher mortality in older severe traumatic brain-injured patients by the possible lower intensity of care provided to them.

A systematic review and meta-analyses studied the association between high-intensity trauma centers and outcomes for severe traumatic brain-injured patients (150). The meta-analysis showed that, from 1970 to 2009, the centers categorized as providing high intensity of care, had lower mortality rates and better outcomes than their time-matched low-intensity centers. However, the intensity of care at the patient level could not be assessed in this study. Moreover, the intensity of care of the centers was not quantified and assessed as a continuous variable, but dichotomized into either high or low intensity centers. For the studies before 1996, the centers classified into high-intensity group are those provided intracranial pressure monitoring for at least 50% of severe traumatic brain injured patients. For the studies after 1996, the centers are classified as high-intensity based on whether the Guidelines of Brain Trauma Foundation were followed (151), as judged by two of the reviewers.

Another study evaluated the cost-effect of high intensity of care; also called aggressive care by its authors (152). The indicators for the aggressive versus routine care were defined as the use of intracranial pressure monitoring for at least 50% of severe traumatic brain-injured patient and decompressive craniotomy, as indicated. This study did not quantify the intensity of care but used indicators to dichotomize the care into aggressive and routine care. The study suggested that the aggressive care was associated with better outcome as well as being less costly on the long-term; taking in consideration long-term medical and rehabilitation costs and the indirect costs caused by the loss of productivity.

However, one major limitation in all these studies is that none of them targeted the specific patient population of critically ill traumatic brain injury patients. More so, most are small, single center, and/or biased by indication.

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25 1.6.3 Components of care for severe traumatic-brain injured patients

To describe the intensity of care in the management of critically ill patients, we can define three main types of interventions; medical, surgical and diagnostic interventions (See Appendix Z). These types of interventions also correlate with the care of critically ill patients with traumatic brain injury.

Medical component of care

There are several medical interventions that may be indicated for severe traumatic brain- injured patients. In general, much of the medical practice in the management of these patients is based on the guidelines of the Brain Trauma Foundation (26).

Mechanical ventilation

Hypoxemia was shown to occur in 22.4% of severe traumatic brain-injured patients (26, 153, 154). A significant association was shown between hypoxemia and mortality in this patient population (26, 153, 154). Moreover, the duration of hypoxemia (defined as O2 saturation ≤ 90%; median duration from 11.5 to 20 min) was found to independently predict mortality in severe TBI (26, 155). This can be explained by the fact that systemic hypoxemia may result in cerebral hypoxia and therefore may cause secondary brain injuries (26) (See Section 1.2.3).

One of the goals of the management of severe TBI is to prevent or correct cerebral hypoxia, defined as PaO2 < 60 mm Hg or O2 saturation < 90%, as this may subsequently lead to secondary brain damage (26, 156). Thus, severe traumatic brain-injured patients are usually mechanically ventilated since coma, or GCS score < 8, is

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26 an indication for mechanical ventilation in this population in order to prevent or correct hypoxia (157).

Jugular Venous Saturation Monitoring

Jugular venous saturation measures cerebral oxygenation and is an indicator of adequate cerebral perfusion (26, 157). In severe traumatic brain-injured patients, episodes of jugular venous desaturation (< 50-55%) were shown to be associated with poor outcome (26, 158, 159). Therefore, the use of jugular venous saturation monitoring is recommended in severe TBI management, with jugular venous saturation < 50% as a threshold for treatment (26, 157).

Sedatives and analgesics

In severe traumatic brain-injured patients, there are many potential causes of pain in addition to the trauma. These include, among others, endotracheal intubation, mechanical ventilation, surgical interventions, ICU procedures and nursing care (157). Therefore, the use of pharmacological agents has been advocated in severe TBI to decrease the pain and agitation (160).This has been thought to be particularly beneficial since painful stimuli and agitation may contribute to elevations in intracranial pressure, in blood pressure, and in body temperature as well as to resistance to ventilation (160). In the following subsections, these pharmacological agents will be discussed in more details.

Opioids

Morphine is the most widely used opioid in the acute setting (160).Although morphine has shown a high level of efficacy and safety as analgesic in the acute setting, its

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27 sedative effect has shown to be minimal (160). Morphine commonly needs a dose escalation during its use and a prolonged withdrawal period when discontinued (160). Opioids also include synthetic narcotics, as fentanyl and sufentanyl, which are more rapidly metabolized and therefore have more brief duration of action (160).

Propofol

Propofol is sedative-hypnotic anesthetic agent that is a widely used in neuro-sedation of severe TBI because of its rapid onset as well as short duration of action (157, 160, 161). In addition, it may have a neuroprotective effect as it has been shown to suppress cerebral oxygen consumption and metabolism (160). However, the use of propofol has not shown significant differences in mortality or neurotically outcome from the use of morphine in severe traumatic brain-injured patients (162).

Benzodiazepines

Benzodiazepines, such as midazolam and lorazepam, are tranquilizers that can be administered in ICU setting as intermittent bolus or continuous infusion (157, 160). Midazolam is a widely used in neurosurgical intensive care units, especially to decrease agitation in mechanically ventilated patients (160). Before starting a continuous infusion of midozolam, a test bolus can be administered to ascertain its systemic response and efficacy (160).

Barbiturates

Barbiturates, such as pentobarbital, are central nervous system depressants that have shown intracranial pressure-lowering effect especially in high doses (160). They did not show a significant association with improvement in outcome, when used as prophylaxis to prevent intracranial hypertension in severe TBI (160, 163, 164).

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28 However, high-dose barbiturates may be considered in hemodynamically stable severe traumatic brain-injured patients having intractable intracranial hypertension (157, 160). Barbiturate use can result in control of intracranial pressure in severe TBI when other medical and surgical therapies have failed (157, 160)

Neuromuscular blocking agents

Neuromuscular blocking agents, also called muscle paralyzing agents, are commonly considered in traumatic brain-injured patients with increased intracranial pressure (165-167). Since there has been a lack of satisfactory evidence about the effect of neuromuscular blocking agents on TBI long-term outcome (165), their use presently relies mostly on clinician’s preference (165, 167, 168). The potential benefits of their use in severe TBI include facilitation of mechanical ventilation management (165).

Neuromuscular blockers have also shown their ability to limit cough and related fluctuations in intracranial pressure (165, 169, 170). They may also help to decrease the energy expenditure and oxygen consumption by respiratory muscles of severe traumatic brain-injured patients (165, 171). Neuromuscular blockers can also decrease oxygen consumption and metabolic rate by preventing shivering in febrile traumatic brain-injured patients (165, 172).

Anticonvulsants

Anticonvulsants, such as phenytoin, are used to control seizures. There is a relatively high incidence of posttraumatic seizures in severe traumatic brain-injured patients (173-175) Posttraumatic seizures (PTS), following TBI, are classified into early and late PTS (173-175). Early PTS occur within 7 days of the injury and late PTS occur after 7 days following injury (173-175). The prophylactic use of anticonvulsants has not been shown to significantly reduce the incidence of late PTS (173, 176). However,

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29 incidence of early PTS has been shown to be significantly reduced with the use of phenytoin (173, 176).

Hyperosmolar agents

Hyperosmolar agents are used to control increased intracranial pressure in severe traumatic brain-injured patients (177). Mannitol and hypertonic saline are the two hyperosmolar agents currently used for this patient population (161, 177). Administration of mannitol is common in severe TBI management to control a suspected or actual high intracranial pressure (177). Its effectiveness in reducing intracranial pressure and its beneficial short-term effect on neurological outcome have been widely accepted (177).

Although not being strong enough to provide a firm conclusion, current evidence suggests that hypertonic saline may be an effective alternative or adjuvant to mannitol in controlling intracranial hypertension (177, 178). In hypotensive traumatic brain-injured patients, administration of hypertonic saline as the initial resuscitation fluid has shown to significantly raise blood pressure and decrease fluid requirements (179).

Induced hypothermia

Hypothermia has often been induced on admission to prevent or control high intracranial pressure in severe traumatic brain-injured patients (180). Prophylactic hypothermia was shown to be significantly associated with better neurological outcome compared to normothermia (180-183). Although prophylactic hypothermia was not associated with a significant decrease in mortality, preliminary results suggested that a lower mortality risk was observed when hypothermia was maintained for > 48 hours in traumatic brain-injured patients (181, 184, 185).

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30

Vasopressors

Vasopressors include phenylephrine, norepinephrine, epinephrine, dopamine and vasopressin (186). They are a group of agents used to pharmacologically increase vascular tone in critically ill patients with hemodynamic impairment (187). Pharmacologic control of hypotension, defined as systolic blood pressure <90 mmHg (186, 188), is frequently used in severe TBI to maintain cerebral perfusion pressure between 50 and 70 mmHg and prevent or treat resulting cerebral ischemia (186, 187, 189).

Glycemic control

Insulin administration in severe traumatic brain-injured patients is used to control hyperglycemia which is common in this patient population (190-192). Hyperglycemia is a frequent component of the stress response to TBI (190, 193) which may be due, at least in part, to post-traumatic increase of catecholamines levels (194). In addition, the injured brain cells may be unable to normally metabolize glucose through oxidative pathway (194) which may lead to brain tissue acidosis (194). Control of hyperglycemia in severe traumatic brain-injured patients, using insulin administration, should be guided by blood glucose levels to avoid hypoglycemia (195, 196).

Venous thromboembolism prophylaxis

Prevention of thromboembolic events in severe TBI can be effectively achieved by administration of heparin (either the unfractionated or low-molecular-weight heparin) (26). In the absence of prophylaxis, the risk of developing thromboembolic events after severe TBI is significantly high, which may be due to post-traumatic inflammatory

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31 response, clotting cascade activation and prolonged immobilization (26, 157, 197, 198).

Thromboembolic events such as deep venous thrombosis and pulmonary embolism are common after severe TBI (26) and occur in up to 20% in the absence of prophylaxis (26, 199). The prevention of deep venous thrombosis is critical since pulmonary emboli may result from the thrombi affecting the proximal leg veins (26). Pulmonary emboli are associated with high rates of mortality and morbidity (26, 200).

Surgical component of care

Different surgical procedures may be indicated in caring for traumatic brain-injured patients and these can be divided in two broad categories: TBI-directly related procedures and procedures non-specific to TBI. TBI directly related procedures include intracranial pressure monitoring and surgical decompression. Procedures non-specific to TBI include tracheostomy, percutaneous endoscopic gastrostomy tube insertion and other general surgical procedures. These procedures will be respectively discussed in more details.

Intracranial pressure monitoring

The use of intracranial pressure monitoring is recommended in severe traumatic brain-injured patients with abnormal CT scan, because they are considered at a high risk of intracranial hypertension (201, 202). A head CT scan is considered abnormal if it reveals swelling, herniation, contusions, hematomas, or compressed basal cisterns (201, 202).

Intracranial pressure monitoring is also indicated in patients who have normal CT scan if they have two or more of the following characteristics at the time of admission: are

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32 over 40 years, there is unilateral or bilateral motor posturing, or their systolic blood pressure (BP) is < 90 mm (201, 202). Having two of these characteristics put the severe traumatic brain-injured patients at risk of intracranial hypertension similar to those patients with abnormal CT scans (201, 202).

Intracranial pressure monitoring provides data used to calculate and manage cerebral perfusion pressure (201), and to guide intracranial pressure lowering therapies (203). It can also be the first indicator of an evolving intracranial pathology or surgical mass lesion (26, 203).

Surgical decompression

In severe traumatic brain-injured patients, intractable intracranial hypertension not responding to medical treatment can be corrected effectively by surgical decompression (204, 205). Surgical decompression can be performed primarily to reduce the intractably high intracranial pressure (204-206) or in the context of evacuation of intracranial lesions as subdural hematomas (204, 207, 208).

Surgical opening of the cranial vault decompresses the intracranial contents by increasing the volume available to them and (207, 209) therefore reduces the intracranial pressure (206, 209, 210). This also improves the cerebral compliance (206, 209, 211) and helps to prevent herniation (207). The surgical procedure is called either craniectomy if the opened bone flap is removed or craniotomy if the bone flap is replaced (212).

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33 Mechanically ventilated patients may require tracheostomy to facilitate weaning (213). Tracheostomy provides a relatively well tolerated and stable airway that allows access for pulmonary toilet, permits oral feeding and earlier ambulation (214, 215). Tracheostomy is recommended in severe brain injured-patients as an early alternative to protect airways and decrease the duration and complications of mechanical ventilation (26, 214).

Percutaneous endoscopic gastrostomy

Nutrition of severe traumatic brain-injured patients should aim to attain full caloric replacement by 7 days after the injury (26). To achieve this goal, nutritional replacement should begin no later than 72 h post-injury (26). Percutaneous endoscopic gastrostomy can be used to provide enteral nutrition in patients with impaired swallowing (26, 216, 217). Percutaneous endoscopic gastrostomy tube insertion is safe, effective and well tolerated in severe traumatic brain-injured patients (26, 218, 219).

Other general surgical procedures

Other general surgical procedures may be performed for severe traumatic brain-injured patients, according to the other body organs affected. These include, for example, open reduction of internal fracture (220, 221), laparotomy (222-224), thoracotomy and sternotomy (225, 226). Early management of associated injuries may improve outcome in severe TBI patients (225).

Diagnostic component of care

Diagnostic interventions are by definition useful to follow up and evaluate the patients’ current condition as well as their overall clinical course. Hence, diagnostic procedures,

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34 along with the clinical evaluations can be useful in the estimation of probable prognosis. However, in comatose patients or patients with altered consciousness, where the efficient clinical evaluation could be limited, the role of the intensity of diagnostic procedures becomes more evident in evaluating patient condition and therefore in guiding treatment.

Diagnostic procedures performed for severe TBI include radiological imaging and electrophysiological tests. Radiological imaging procedures used in severe TBI are head computed tomography scan and brain magnetic resonance imaging. Electrophysiological tests used in this patient population include electroencephalography and somatosensory evoked potential. These procedures will be respectively discussed in more details.

Computed tomography scan

Head computed tomography (CT) scan is recommended to be performed in all severe traumatic brain-injured patients (26, 161). Localization of the lesion and determination of its extent and etiology can be done using head CT, which is vital in managing the lesion and its effects (26, 161). In addition to this direct therapeutic implication, the information provided by head CT may also help early estimation of the prognosis (26, 161, 227). Severe traumatic brain-injured patients should be considered at high risk of intracranial hypertension if their head CTs shows swelling, herniation, hematomas, contusions or compressed basal cisterns. Therefore, these patients should be monitored and managed accordingly (26, 202).

Magnetic resonance imaging

Brain magnetic resonance imaging (MRI) provides sensitive information on the neuroanatomy of brain tissue and blood vessels, the extent of brain injury and its

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35 secondary effects as edema, intracranial bleeding, and brain tissue degeneration (228). In severe traumatic brain-injured patients, brain MRI is useful in detection of parenchymal brain lesions, cortical contusions and brain stem lesions (227, 229-231). Brain MRI is also sensitive in diagnosis of diffuse brain injuries as diffuse axonal injury (227, 229-231)resulting from damage of axons caused by shearing, rotational or acceleration-declaration forces on the brain (232, 233).

Somatosensory evoked potentials

Somatosensory evoked potentials (SSEPs) provide an assessment of the neural conduction integrity and functionality of peripheral and central pathways (234). Therefore, SSEPs are used in TBI to provide information about the impact of the trauma on the integrity of sensory and cognitive processing pathways (234). Moreover, SSEPs serve as a prognostic tool for neurological outcome of severe traumatic brain-injured patients, because bilateral absence of SSEPs has been shown to be associated with unfavorable neurological prognosis and outcome for this patient population (234-238).

Electroencephalography

In severe traumatic brain-injured patients, the brain undergoes several

electrophysiological changes and therefore there is a relatively high incidence of posttraumatic seizures (26, 174, 175, 239). Thus, electroencephalogram (EEG) is useful to evaluate these electrophysiological changes and detect the presence of even subclinical non-convulsive seizure activity (239). It can also detect seizures masked by the administration of neuromuscular blocking agents and monitor their treatment (157, 239, 240). In barbiturate administration for severe traumatic brain-injured patients, EEG monitoring can also be used to titrate doses to the lowest possible dose to achieve a specific EEG pattern, called burst-suppression (241, 242).

Effect of intensity of care on mortality and withdrawal of life-sustaining therapies in severe traumatic brain injury patients : a post-hoc analysis of a multicenter cohort study

Effect of intensity of care on mortality and

withdrawal of life-sustaining therapies in severe

traumatic brain injury patients:

A post-hoc analysis of a multicenter cohort study

Mémoire

Peter Raouf Aziz Gerges

Maîtrise en épidémiologie - épidémiologie clinique

Maître ès sciences (M. Sc.)

Québec, Canada

Effect of intensity of care on mortality and

withdrawal of life-sustaining therapies in severe

traumatic brain injury patients:

A post-hoc analysis of a multicenter cohort study

Mémoire

Peter Raouf Aziz Gerges

Sous la direction de:

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