**Brain Death in Children**

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CCM.0000045182.90302.B3

114 Intensive Care

DOI: 10.7326/0003-4819-73-4-523

Eleni Athanasios Volakli, Peristera‐Eleni Mantzafleri, Serafeia Kalamitsou, Asimina Violaki, Elpis Chochliourou, Menelaos Svirkos, Athanasios Kasimis and Maria Sdougka

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.68468

#### **Abstract**

Brain death (BD) is a distinct mode of death in pediatric intensive care units, accounting for 16–23% of deaths. Coma, absent brainstem reflexes, and apnea in a patient with acute irreversible neurological insult should alarm the attending physician to start the appro‐ priate actions to establish or refute the diagnosis for BD. BD diagnosis is clinical, starting with the preconditions that should be met, and based on the examination of all brain‐ stem reflexes, including the apnea test. Apnea testing should be conducted according to standard criteria to demonstrate the absence of spontaneous respirations, in the case of an intense ventilatory stimulus, setting at increased PaCO<sup>2</sup> levels ≥60 and ≥20 mm Hg, compared to baseline. When elements of clinical examination and/or apnea test cannot be performed, ancillary studies to demonstrate the presence/absence of electrocerebral silence and/or cerebral blood flow are guaranteed. Two clinical examinations by qualified physicians at set intervals are required. Time of death is the time of second examination and ventilator support should stop at that time, except for organ donation. The use of check list in documentation of BD helps in the uniformity of diagnosis and fosters further trust from medical, family, and community personnel.

**Keywords:** brain death, pediatric intensive care unit, apnea testing, brainstem reflexes, coma

### **1. Introduction**

The evolution of intensive care has led to circumstances that a human being could be artificially maintained in life through technological advancements even in the presence of

© 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

an irreversible neurological damage. Brain death (BD) in most instances occurs when an acute insult to the brain causes a neuropathologic viscious cycle of brain edema, increases intracranial pressure (ICP), and decreases cerebral blood flow that compromise blood supply to the brain and results in ischemia, a situation which resembles to "total brain infarction" according to Swedish Committee on defining death [1]. Severe traumatic head injury, infections, tumors, cerebral vascular accidents, or acute global anoxic/ischemic injury following severe respiratory failure, shock, or cardiac arrest are the main causes of BD in children [2]. Rarely, acute toxic neuronal injury as happened in fulminant hepatic failure or other metabolic diseases are the reasons, or cellular dysoxia, which prevents extraction or utilization of oxygen, as is the case in cyanide poisoning.

Brain death is a distinct mode of death both in adult and pediatric population; it is estimated that BD accounts for approximately 16–23% of deaths in the pediatric intensive care unit (PICU), while the corresponding values for adults are quite similar and depending on the nature of the unit, rising from 15% in multidisciplinary units up to 30% in neurocritical units [3–6]. Most research about BD involves adults; however, not all principles regarding BD could be transferred to children. The pediatric brain is immature; the development, plasticity, and maturation of cen‐ tral nervous system (CNS) ends by the 2 years of age according to the majority οf researchers, while others believe to continue beyond the first decade of life [7]. Moreover, resilience to cer‐ tain forms of injury could be found, due to the open fontanelles in infancy and the presence of certain forms of diseases that result in hydranencephalia and cerebral atrophy, and/or wide craniectomy, that could hasten the progress of intracranial hypertension. The above should be considered when interpreting diagnosis and confirming BD in infants and children [8].

The first effort to define BD as a new criterion for death was made in 1968 by a consensus report of the Ad Hoc Committee of the Harvard Medical School, without specific recommendations with respect to age [9]. Irreversible coma was defined as unresponsiveness to external stimuli, absent movements or breathing, absent reflexes, and a flat electroencephalograph (EEG).Later on, in 1975, on a review of the Harvard criteria by the American Academy of Neurology (AAN), they question the applicability of the consensus criteria to children stating that the above cri‐ teria may be inapplicable for children under 5 years of age since there are indications that the immature nervous system can survive significant periods of electrocerebral silence. In an effort to set a standard national definition on BD, in 1981, in the USA, the Uniform Determination of Death Act was adopted as part of the President's Commission [10]. Death was determined in accordance with accepted medical standards either as an irreversible cessation of circulatory and respiratory functions of a person, or irreversible cessation of all functions of the entire brain, including the brain stem. Age‐specific guidelines were again not provided and medical standards were not described, and the commission recommended caution in applying neuro‐ logical criteria to determine death in children younger than 5 years.

In 1995, the Quality Standards Subcommittee of the AAN published the practice parameters for determining brain death in adults to delineate the medical standards for the determination of BD in patients older than 18 years. The document emphasized the three cardinal clinical findings necessary to confirm irreversible cessation of all functions of the entire brain, includ‐ ing the brainstem: *coma or unresponsiveness* (with known cause), *absence of brainstem reflexes*, and *apnea*. Future research in apnea testing, and the need for validation of confirmatory tests was recommended [11]. However, despite the published parameters, considerable practice variations were recorded, which led to the 2010 update that sought to use evidence‐based methods to answer questions historically related to variations in BD determination, to pro‐ mote uniformity in diagnosis [12].

an irreversible neurological damage. Brain death (BD) in most instances occurs when an acute insult to the brain causes a neuropathologic viscious cycle of brain edema, increases intracranial pressure (ICP), and decreases cerebral blood flow that compromise blood supply to the brain and results in ischemia, a situation which resembles to "total brain infarction" according to Swedish Committee on defining death [1]. Severe traumatic head injury, infections, tumors, cerebral vascular accidents, or acute global anoxic/ischemic injury following severe respiratory failure, shock, or cardiac arrest are the main causes of BD in children [2]. Rarely, acute toxic neuronal injury as happened in fulminant hepatic failure or other metabolic diseases are the reasons, or cellular dysoxia, which prevents

Brain death is a distinct mode of death both in adult and pediatric population; it is estimated that BD accounts for approximately 16–23% of deaths in the pediatric intensive care unit (PICU), while the corresponding values for adults are quite similar and depending on the nature of the unit, rising from 15% in multidisciplinary units up to 30% in neurocritical units [3–6]. Most research about BD involves adults; however, not all principles regarding BD could be transferred to children. The pediatric brain is immature; the development, plasticity, and maturation of cen‐ tral nervous system (CNS) ends by the 2 years of age according to the majority οf researchers, while others believe to continue beyond the first decade of life [7]. Moreover, resilience to cer‐ tain forms of injury could be found, due to the open fontanelles in infancy and the presence of certain forms of diseases that result in hydranencephalia and cerebral atrophy, and/or wide craniectomy, that could hasten the progress of intracranial hypertension. The above should be

considered when interpreting diagnosis and confirming BD in infants and children [8].

logical criteria to determine death in children younger than 5 years.

The first effort to define BD as a new criterion for death was made in 1968 by a consensus report of the Ad Hoc Committee of the Harvard Medical School, without specific recommendations with respect to age [9]. Irreversible coma was defined as unresponsiveness to external stimuli, absent movements or breathing, absent reflexes, and a flat electroencephalograph (EEG).Later on, in 1975, on a review of the Harvard criteria by the American Academy of Neurology (AAN), they question the applicability of the consensus criteria to children stating that the above cri‐ teria may be inapplicable for children under 5 years of age since there are indications that the immature nervous system can survive significant periods of electrocerebral silence. In an effort to set a standard national definition on BD, in 1981, in the USA, the Uniform Determination of Death Act was adopted as part of the President's Commission [10]. Death was determined in accordance with accepted medical standards either as an irreversible cessation of circulatory and respiratory functions of a person, or irreversible cessation of all functions of the entire brain, including the brain stem. Age‐specific guidelines were again not provided and medical standards were not described, and the commission recommended caution in applying neuro‐

In 1995, the Quality Standards Subcommittee of the AAN published the practice parameters for determining brain death in adults to delineate the medical standards for the determination of BD in patients older than 18 years. The document emphasized the three cardinal clinical findings necessary to confirm irreversible cessation of all functions of the entire brain, includ‐ ing the brainstem: *coma or unresponsiveness* (with known cause), *absence of brainstem reflexes*,

extraction or utilization of oxygen, as is the case in cyanide poisoning.

116 Intensive Care

The irreversible cessations of all functions of brain, including the brainstem, are not uni‐ versally accepted; the definition of BD in each nation depends on jurisdiction. In the USA, Australia, and New Zealand for example, a whole brain death definition is accepted. On the contrary, in the UK, India, and Canada a brainstem‐based definition of death is in place and the term "death by neurological criteria" (DNC) is adopted [13–16]. In the UK, the most recent definition for DNC was published in 2008 by the Academy of Medical Royal Colleges (AoMRC) in the code of practice for the diagnosis and confirmation of death. Consciousness and breathing capacity were recognized as essential characteristics of life and the irrevers‐ ible loss of them were regarded equal to death [13]. The applicability of the criteria in infants younger than 2 months were questioned, in agreement with a report presented by the British Paediatric Association (BPA) in 1991, which stated also that the criteria of DNC cannot be applied in infants younger than 37 weeks of gestation [17]. Caution was relieved by the guide‐ lines issued in 2015 by the Royal College of Paediatrics and Child Health (RCCHD) consider‐ ing the diagnosis of DNC in infants from 37 weeks corrected gestation (postmenstrual) to 2 months (postterm) of age. RCCHD stated that the 2008 criteria of death could be applied to this population with precautionary measures regarding the apnea test due to immaturity of the newborn infant's respiratory system [18].

The first specific pediatric guidelines on BD were issued in 1987 by the American Academy of Pediatrics (AAP) to solve questions and give answers for this special topic. These guidelines were a consensus opinion regarding necessary clinical history, physical examination criteria, observation periods, and ancillary laboratory tests required to determine brain death in chil‐ dren[19]. An update followed in 2011, with emphasis given to two different age populations: the one from newborn 37 weeks gestation to 30 days of life and the other from 31 days of life to 18 years [20]. These guidelines could serve as a basis for the development of national guide‐ lines at each nation, taking into account legal, cultural, and religious differences, and will be analyzed in this chapter, enriched by the experience of a single centre and the discussion of relevant references.

BD in most occasions is intertwined to organ harvesting and transplantation, and much research in the field has been done through national organ procurement databases [21, 22]. Nevertheless, the declaration of BD should be done by the patient physicians only, according to local national and institutional guidelines, irrespective from the transplantation team [23, 24]. The priority of the medical system is to save lives rather than to obtain organs and the public must feel confident that they would become organ donors only after all reasonable attempts to save their lives have failed. Maintenance of public trust is essential for the functioning of organ transplantation systems around the world [24]. BD is still a controversial issue for some physicians, and civilians as well, who deny the conceptual basis for equating an irreversibly nonfunctioning brain with a dead human being [25]. Though, the ethical, psychosocial, and philosophical approach of BD is beyond the scope of this chapter which will concentrate on the biological and clinical approach only of pediatric patients dying from BD.

### **2. Dying from BD in the PICU**

Regardless some terminology differences between the most widely USA definition of BD as the death of the whole brain, and the UK definition of death by DNC as the death of the brain‐ stem, the concept that is universally accepted is that *the patient dying from BD suffered an acute irreversible CNS insult that resulted to coma, absent brainstem reflexes, and apnea* [7]. Although cases of confirmation of BD in children have been described outside the PICU, the proper place where the patients should be treated and diagnosis takes place is the PICU [22–24]. Frequently, the first indication by the bedside nurse is the lack of spontaneous awakening periods, the absence of cough during suctioning, and the fixed dilated pupils, which should alarm the attending physician that the patient deteriorates, and may be is going to BD. All sedative medications, including antiepileptic drugs and neuromuscular blocking agents, should stop at that time, the patient should continue to receive the maximum supportive intensive care treatment to preserve homeostasis, and the preparations should begin to estab‐ lish or refute the diagnosis of BD. The diagnosis of BD is confirmed by clinical examination criteria only, based on the absence of neurologic function with a known irreversible cause of coma. Ancillary studies are not required except in cases where the clinical examination and apnea test cannot be completed [13, 14, 20].

### **3. Management of critically ill children dying from BD**

For the better understanding of the evolution to BD in children, we will present the sequence of the events that happen in pediatric patients treated in a PICU after a severe neurological insult, step by step, in a timely manner. Our data were obtained from a retrospective study regarding all deaths that occurred between January 2011 and April 2016, in a multidisci‐ plinary eight‐bed PICU of Northern Greece. Among 275 deaths, 44 (16%) were defined as BD. The incidence was higher in boys (28/44 patients, 63.6%). Mean age was 68.75 ± 44.04 months (range 2 months to 13 years) and mean severity of illness as estimated with the pediatric risk of mortality (PRISM III‐24 h) score at admission was 21.67 ± 9.98. Head injury was the most frequent cause of BD (29.41%) followed by CNS infection (23.52%), hypoxic/ischemic insults (23.52%), CNS tumors (11.76%), and intracranial bleeding (11.76%).

The management of the patients was done under the relevant for the diagnosis international protocols, under sedation, mechanical ventilation, chemoprophylaxis, gastric ulcer prophy‐ laxis, and artificial nutrition. At admission, 88.6% of patients were already on mechanical ventilation and almost half of them (52.3%) were in shock. Central venous catheters and arte‐ rial lines were inserted in all patients. Nine patients (20.5%) had intracranial pressure (ICP) monitoring. Almost all received osmotherapy with either NaCl 3% (37 patients, 84.1%) and/ or mannitol 20% (36 patients, 81.8%). Sedation was achieved with midazolam at mean max dose of 0.93 ± 0.56 mg/kg/h and remifantanil at max dose of 0.09 ± 0.05 mcg/kg/min. Cis‐attra‐ curium was administered for neuromuscular blocking at a bolus dose of 0.2 mg/kg, as needed before interventions, e.g., suctioning to avoid inadvertent increase in ICP. Sodium thiopental at a max dose of 5 mg/kg/h was administered in 18 patients (40.9%) and four patients (9.1%) were treated with craniectomy, as a third tier therapy to refractory intracranial hypertention [26]. Diabetes insipidus was recorded in 33 patients (75%), and high sugar levels needed insu‐ lin therapy in 19 patients (43.2%). The higher serum Na and sugar levels that were recorded were 165 ± 15.39 mmol/l and 281 ± 159.07 mg/dl, respectively. During their stay, the majority of the patients (79.5%) needed inotropic and/or vasopressor support to preserve an acceptable hemodynamic status.

philosophical approach of BD is beyond the scope of this chapter which will concentrate on the

Regardless some terminology differences between the most widely USA definition of BD as the death of the whole brain, and the UK definition of death by DNC as the death of the brain‐ stem, the concept that is universally accepted is that *the patient dying from BD suffered an acute irreversible CNS insult that resulted to coma, absent brainstem reflexes, and apnea* [7]. Although cases of confirmation of BD in children have been described outside the PICU, the proper place where the patients should be treated and diagnosis takes place is the PICU [22–24]. Frequently, the first indication by the bedside nurse is the lack of spontaneous awakening periods, the absence of cough during suctioning, and the fixed dilated pupils, which should alarm the attending physician that the patient deteriorates, and may be is going to BD. All sedative medications, including antiepileptic drugs and neuromuscular blocking agents, should stop at that time, the patient should continue to receive the maximum supportive intensive care treatment to preserve homeostasis, and the preparations should begin to estab‐ lish or refute the diagnosis of BD. The diagnosis of BD is confirmed by clinical examination criteria only, based on the absence of neurologic function with a known irreversible cause of coma. Ancillary studies are not required except in cases where the clinical examination and

For the better understanding of the evolution to BD in children, we will present the sequence of the events that happen in pediatric patients treated in a PICU after a severe neurological insult, step by step, in a timely manner. Our data were obtained from a retrospective study regarding all deaths that occurred between January 2011 and April 2016, in a multidisci‐ plinary eight‐bed PICU of Northern Greece. Among 275 deaths, 44 (16%) were defined as BD. The incidence was higher in boys (28/44 patients, 63.6%). Mean age was 68.75 ± 44.04 months (range 2 months to 13 years) and mean severity of illness as estimated with the pediatric risk of mortality (PRISM III‐24 h) score at admission was 21.67 ± 9.98. Head injury was the most frequent cause of BD (29.41%) followed by CNS infection (23.52%), hypoxic/ischemic insults

The management of the patients was done under the relevant for the diagnosis international protocols, under sedation, mechanical ventilation, chemoprophylaxis, gastric ulcer prophy‐ laxis, and artificial nutrition. At admission, 88.6% of patients were already on mechanical ventilation and almost half of them (52.3%) were in shock. Central venous catheters and arte‐ rial lines were inserted in all patients. Nine patients (20.5%) had intracranial pressure (ICP) monitoring. Almost all received osmotherapy with either NaCl 3% (37 patients, 84.1%) and/ or mannitol 20% (36 patients, 81.8%). Sedation was achieved with midazolam at mean max

biological and clinical approach only of pediatric patients dying from BD.

**2. Dying from BD in the PICU**

118 Intensive Care

apnea test cannot be completed [13, 14, 20].

**3. Management of critically ill children dying from BD**

(23.52%), CNS tumors (11.76%), and intracranial bleeding (11.76%).

The clinical suspicion on BD was set on 3.59 ± 5.46 day through dilated unreacted pupils. Mean pupil size at admission was 4.07 ± 2.06 mm which was increased to the final size of 6.28 ± 1.13 mm. Following that all the prerequisites of BD were fulfilled, two clinical examina‐ tions were performed by a panel of three doctors registered for at least 2 years; one anesthetist, one neurologist or neurosurgeon, and the attending physician (pediatrician or pediatric sur‐ geon), according to the Greek law. Mean sedation time was 4.02 ± 3.03 days. The first tests were done in 9.88 ± 6.50 days after admission and the second in 11.28 ± 6.53 days. Mean time between tests was 27.54 ± 11.80 h. Apnea testing was prepared according to national BD protocol, with preoxygenation with 100% oxygen for at least 10 min, and baseline mechanical ventilation aimed at 40 mmHg of PaCO<sup>2</sup> [11]. Oxygenation during apnea was done through a catheter tai‐ lored to endotracheal tube (ETT) size (size in CH doubled the ID size of ETT in mm), inserted in the endotracheal tube at a length corresponded to tracheal carina, with a flow of 1 l/min/age in years, initially, according to acute pediatric life support (APLS) recommendation for apneic oxygenation [27]. If oxygenation was inadequate, a gradually increase in O<sup>2</sup> flow in increments of 1 l/min up to max 12 l/min was performed [12]. For this purpose, we used a simple suction catheter of appropriate size as described above, with the valve occluded, and connected to an oxygen flow source, preferably a low pressure one (capable of giving oxygen at driving pres‐ sure of 1–2 bar). In the case of acute respiratory distress syndrome (ARDS), hypoxia, and need for high positive end expiratory pressure (PEEP), apnea testing was performed on continuous positive airway pressure (CPAP) modality. Duration of apnea was 10 min if feasible, or earlier if signs of hypoxia and/or hypotension appeared. Apnea testing was considered positive for BD if no spontaneous respiration occurred when the PaCO<sup>2</sup> level was >60 and *>*20 mmHg com‐ pared to baseline, in accordance with international guidelines [11, 12, 14].

A total of 88 apnea tests were recorded. Incomplete data concerning the way of oxygenation during the apnea test were revealed in 50% of the tests, probably due to the retrospective data analysis and incomplete recordings. Thirty‐six patients (81.81%) completed the test successfully. Eleven apnea tests (12.5%) were aborted, mainly due to hypoxia (8/11, 72.72%) and to a lesser degree due to shock (3/11, 27.27%). In detail, four patients did not manage to complete the first apnea test (three hypoxia, one shock), while seven patients aborted the second test (five hypoxia, two shock). The data of apnea testing are presented in **Table 1**. Ancillary study with magnetic resonance angiography (MRA) was carried out in eight patients (18.18%). Patients died 54.58 ± 59.64 h after the completion of the second apnea test. Three families (6.81%) gave consent for organ donation.


IPPV, intermittent postitive pressure ventilation; PRVC, pressure regulated volume control; SIMV‐PS, synchronized intermittend mandatory ventilation‐pressure support; CPAP, continuous positive airway pressure; Tracheal O<sup>2</sup> , tracheal insufflation of oxygen at age‐related flows of 1 l/min/age (max 12 l/min); NA, not applicable (lack of data).

**Table 1.** Data of apnea testing (*n* = 77) in pediatric BD patients (*n* = 44).

### **4. Guidelines for the determination of BD in infants and children**

### **4.1. Definition of BD**

In 2011, a multidisciplinary committee was formed by the Society of Critical Care Medicine (SCCM) and the AAP to update the 1987 Task Force Recommendations for the diagnosis of pediatric BD [12, 14, 20]. According to guidelines, *BD is a clinical diagnosis based on the absence of neurologic function with a known diagnosis that has resulted in irreversible coma.* Coma and apnea must coexist to diagnose DB. A complete neurologic examination is mandatory to determine BD with all components appropriately documented. An algorithm for the diagnosis of BD in children adapted from Ref. [20] is provided in Appendix 1.

#### **4.2. Age definition**

Two age definitions were set with an impact on the timing of first exam and the observation period between tests.


Because of insufficient data in the literature, recommendations for preterm infants less than 37 weeks gestational age were not included in this guideline.

### **4.3. Timing of first exam**


It is reasonable to defer neurologic examination to determine brain death for longer than 24 h, if dictated by clinical judgment of the treating physician. Neonates who probably suffered from hypoxic/ischemic insult during the neonatal period and had been put in therapeutic hypothermia deserve a longer observation time before the first examination. Hypothermia not only could interfere with brainstem reflexes interpretation but hastens drug metabolism as well. In addition, the first examination should be postponed beyond 24 h if residual drug effect is suspected. In general, the first examination cannot be performed unless all the pre‐ conditions of diagnosing BD are met.

### **4.4. Irreversible and identifiable cause of coma**

A known and irreversible cause of coma should be established before the diagnosis of BD. In most instances, the evolution of a brain damage to BD is depicted with computed tomog‐ raphy (CT) or magnetic resonance imaging (MRI). Sometimes, neuroimaging if performed early enough in the course of the disease is without significant findings. Serial examinations in such occasions are helpful. CT and MRI are introductory studies and should not be relied on to make the determination of brain death. Additional data such as results from cerebrospi‐ nal fluid (CSF) analysis and/or other microbiological data are supportive [12]. In 2011 AAP guidelines, three major causes of coma were recognized: traumatic brain injury, anoxic brain injury, and known metabolic disorder. In cases that the cause of coma is not identifiable, the physician should specify the cause of coma as "Other." It is advisable to keep these major causes when recording BD, which will enable international comparisons, if needed.

### **4.5. Preconditions**

**4. Guidelines for the determination of BD in infants and children**

insufflation of oxygen at age‐related flows of 1 l/min/age (max 12 l/min); NA, not applicable (lack of data).

children adapted from Ref. [20] is provided in Appendix 1.

**Mechanical ventilation mode FiO2**

(29.6%)

(25%)

**Table 1.** Data of apnea testing (*n* = 77) in pediatric BD patients (*n* = 44).

PRVC (22.5%) SIMV‐PS (9.1%)

120 Intensive Care

Tracheal O<sup>2</sup>

NA (50%)

Tracheal O<sup>2</sup>

NA (52.3%)

37 weeks gestational age were not included in this guideline.

• Newborns 37 weeks gestation to 30 days of life.

• Infants 31 days of life to 18 years.

In 2011, a multidisciplinary committee was formed by the Society of Critical Care Medicine (SCCM) and the AAP to update the 1987 Task Force Recommendations for the diagnosis of pediatric BD [12, 14, 20]. According to guidelines, *BD is a clinical diagnosis based on the absence of neurologic function with a known diagnosis that has resulted in irreversible coma.* Coma and apnea must coexist to diagnose DB. A complete neurologic examination is mandatory to determine BD with all components appropriately documented. An algorithm for the diagnosis of BD in

IPPV, intermittent postitive pressure ventilation; PRVC, pressure regulated volume control; SIMV‐PS, synchronized intermittend mandatory ventilation‐pressure support; CPAP, continuous positive airway pressure; Tracheal O<sup>2</sup>

**% pH PaO2**

Baseline IPPV (68.4%) 50.8 ± 20.6 7.44 ± 0.062 133.88 ± 33.90 33.36 ± 4.60

A. prep. 100 7.33 ± 0.084 382 ± 97.59 45.46 ± 4.18 A. Apnea test CPAP (20.4%) 100 7.10 ± 0.063 235 ± 107.18 84.15 ± 10.53

B. Prep. 100 7.33 ± 0.073 354 ± 127 45.21 ± 5.20 B. Apnea test CPAP (22.7%) 100 7.11 ± 0.063 223 ± 129.72 84.79 ± 13.99

 **(mmHg) PaCO2**

 **(mmHg)**

, tracheal

Two age definitions were set with an impact on the timing of first exam and the observation

Because of insufficient data in the literature, recommendations for preterm infants less than

**4.1. Definition of BD**

**4.2. Age definition**

period between tests.

The interpretation and validity of the clinical neurological examination and the apnea testing should not leave any space for concern. All the potentially influencing factors must be cor‐ rected in advance and the subsequent undeniable preconditions must be met:

• *Cardiovascular stability.* Mean or arterial systolic pressure should be normal for age (no less than two standard deviations from the mean age responding values). Inotropic and vasomotor support may be necessary for the treatment of shock. Direct arterial pressure measurement is strongly recommended, not only for the monitoring but for blood gases analysis and PaCO<sup>2</sup> evaluation as well, which is an integral part of the apnea testing that follow.


#### **4.6. Physical examination: coma**

The neurologic examination BD criteria in pediatrics have been adapted from 2010 American Academy of Neurology criteria for BD determination in adults [12]. Patients must exhibit complete loss of consciousness, vocalization, and volitional activity and should be in a pro‐ found state of coma. Flaccid tone is confirmed by passive range of motion in extremities given there are no limitations to performing such an examination, e.g., previous trauma, and the patient is observed for any spontaneous or induced movements. Noxious stimuli in the cra‐ nial nerve distribution (deep supraorbital and/or condylomandibular pressure) and all four limbs (deep bed nail pressure), and trunk (sternal rub) should be applied and the responses, if any, should be carefully evaluated. Central (in the territory of cranial nerves, e.g., facial area) responsiveness to central and peripheral (outside the territory of cranial nerves) noxious stimuli must be absent, apart from spinally mediated reflexes. Complete absence of motion would equate a Clasgow Coma Scale (GCS) of 3. Observations such as decerebrate or decor‐ ticate posturing, true extensor or flexor motor responses to painful stimuli and seizures are not compatible with BD. Any motor response within the cranial nerve distribution, or any response in the limbs in response to cranial nerve stimulation, *precludes determination of brain death*. Spinal reflexes should be suspected in cases of motor responses in a somatic distribu‐ tion after noncranial, e.g., peripheral nerve stimulus and not after stimulus in the cranial nerve territory [14].

### **4.7. Brainstem reflexes**

• *Normothermia.* Therapeutic hypothermia is increasingly used as an adjunctive therapy of the insulted brain and the physician should be aware of the potential hypothermia impact on the diagnosis of brain death. Hypothermia is a depressant to central nervous system activity and may lead to a false diagnosis of brain death. Metabolism and clearance of medications are retarded, which can interfere with brain death examination. Achieving normothermia with a core body temperature of 35°C (95°F) before the first exam and main‐

• *Hοmeostasis.* The most common metabolic disturbance during BD is hypernatremia due to diabetes insipidus that should be corrected with the administration of antidiouretic hor‐ mone or desmopressin. Hyperglygemia is common too, and close monitoring of glucose levels and treatment with insulin when necessary is indicated. Hyponatremia, hypogly‐ cemia, hypothyroidism, severe pH disturbances, severe hepatic or renal dysfunction or inborn errors of metabolism may also occur and cause a potentially reversible coma in pe‐ diatric patients. All the above should be excluded before moving on diagnostic tests for BD. A high index of clinical suspicion for metabolic disturbances should be especially raised in situations where the clinical history alone does not provide a reasonable explanation for

• *Neuromuscular blocking (NMB) agents*. Adequate clearance of these agents should be con‐ firmed. In case there is a doubt for residual NMB action, a nerve stimulator with documenta‐ tion of neuromuscular junction activity and twitch response should be used to demonstrate

• *Drug intoxications.* Barbiturates, opioids, sedative and anesthetic agents, antiepileptic agents, and alcohols should be discontinued. Adequate clearance (based on the age of the child, presence of organ dysfunction, total amount of medication administered, elimina‐ tion half‐life of the drug and any active metabolites) should be allowed before the neuro‐ logic examination. Recommendations of time intervals before brain death evaluation for many of the commonly used medications administered to critically ill neonates and chil‐ dren are listed in Appendix 2 of 2011 AAP guidelines. Laboratory testing of drug levels should be performed if there is a concern regarding residual drug effect. Although there is evidence that therapeutic and subtherapeutic barbiturate levels (phenobarbital and pento‐ barbital at 15–40 ug/ml) did not interfere with the reliability of BD diagnosis, it is advised these drugs to be at the low to mid therapeutic range before neurological examination [28]. Unusual causes of coma such as neurotoxins and chemical exposure, e.g., organophos‐ phates and carbamates, should be occluded in rare cases where an etiology for coma has

The neurologic examination BD criteria in pediatrics have been adapted from 2010 American Academy of Neurology criteria for BD determination in adults [12]. Patients must exhibit complete loss of consciousness, vocalization, and volitional activity and should be in a pro‐ found state of coma. Flaccid tone is confirmed by passive range of motion in extremities given

good neuromuscular activity with 4/4 responds in "train of four" testing [12, 23].

taining it throughout the observation period is essential.

the evolution of BD.

122 Intensive Care

not been established.

**4.6. Physical examination: coma**

The absence of all brain stem reflexes must be confirmed by the physical examination. Afferent and efferent pathways of cranial nerves are given in parentheses:


#### **4.8. Apnea test**

Only if all the above reflexes are absent, proceed with testing for apnea. The apnea test should be conducted last so that a high PaCO<sup>2</sup> does not confound the testing of the other cranial nerves [14]. Apnea testing is the cornerstone for the diagnosis of BD both in adults and chil‐ dren and is conducted similar to adults. However, despite the consensus criteria published for adults and pediatrics, considerable variation has been described in performing the apnea test in both populations [2, 21, 22, 29]. In 1987 Task Force guidelines for pediatric BD is reported that apnea testing using standardized methods can be performed, but this is ordinarily done only after other examination criteria are met. Yet, the standardized methods are not described and the two associated references reported different ways of performing the apnea test. The former, by Outwaker and Rockoff, described apnea testing in 10 children aged 10 months to 13 years who met the conventional criteria for BD. In their study, oxygen 100% was provided for 5 min before the test, the ventilator rate was set to zero, and a continuous flow of oxygen was provided through the ETT. Arterial blood gases (ABG) were drawn at 0, 1, 2, 3, and 5 min. All patients completed the test successfully; mean PaCO<sup>2</sup> was 39.4 ± 7.4 mm Hg at the begin‐ ning and 59.5 ± 10.2 at the end of the test, with a mean rise of 4.0 ± 0.9 mm Hg/min [30]. The latter, by Rowland and coworkers, in 9 children aged 4 months to 13 years, mentioned that PCO<sup>2</sup> rise was faster than adults, and faster in the beginning of apnea test (4.4 ± 1.6, 3.4 ± 1.3 and 2.6 ± 1.2 mm Hg/min at 5, 10, and 15 min, respectively). PaCO<sup>2</sup> ranged from 60 to 116 mm Hg after 15 min of apnea. All apnea tests were accomplished uneventfully and no spontane‐ ous respirations were observed in any of the patients after 15 min of apnea. The authors rec‐ ommended that prevention of hypoxia can be reliably achieved with administration of 100% oxygen for 10 min before discontinuing ventilator support, and continuing oxygen (6 l/min) through a catheter into the length of the ETT for the duration of the test. An initial apnea test of 10 min was proposed, and if the desired levels of PCO<sup>2</sup> failed to achieve, then a repeated test with a longer duration of 15 min was advised. The study concluded that apneic oxygen‐ ation can be safely conducted in children as a component of the clinical evaluation of BD [31].

The above studies performed apnea testing differently. Even in the recent guidelines, there are no accurate instructions on how to perform a safe apnea test in children. Questions such as how much time is necessary for the preoxygenation period, which is the optimum base‐ line PCO<sup>2</sup> level, which is the best way for apneic oxygenation, how to prevent hypoxia and/ or hypotention during the apnea test, which is the exact duration of apnea testing, remain blurred and left to the resolution of the attending physician. Physicians should always remember that *apnea testing is the last element in clinical diagnosis of BD in suspected BD children*. There are references of prospective, retrospective studies, and case reports, in suspected BD children, mentioning that occasionally patients developed spontaneous breathing during apnea testing [2, 32–35]. These references not at all blunt the validity of apnea; on the con‐ trary they confirm the value of the test on establishing pediatric BD. Not all parts of pediatric brain die simultaneously, especially in patients with preexisting neurologic disease. In cases that apnea is not positive for BD the patient is returned back to full support, until a following apnea test can be performed or an auxiliary test is pursued to establish or refute the diag‐ nosis. It is worth mentioning that almost in all the aforementioned reports, most children died ultimately shortly afterwards, by a second apnea test that confirmed BD diagnosis or spontaneous cardiac arrest. One patient, who never fulfilled apnea testing, and therefore BD, remained in severe neurological impairment, keeping in life technology dependent, through tracheostomy, home mechanical ventilation, and gastrostomy [34]. Brain recovery of children that met all adult BD criteria based on neurologic examination has not been con‐ firmed so far. The apparent reversibility of brain death reported by some authors through spontaneous respirations during apnea testing is questionable; further review of these cases would reveal that those children could not had fulfilled strict brain death criteria by cur‐ rently accepted medical standards. There is no documented case of a person who *fulfils the preconditions and criteria for brain death* ever subsequently developing any return of brain function [8, 14, 18, 20, 23].

#### **4.9. Performing apnea testing**

• *Gag reflex (afferent IX, efferent X).* The pharyngeal or gag reflex is tested after stimulation of the posterior pharynx using a tongue blade or suction device. The sucking and rooting

• *Cough—tracheal reflex (afferent X).* The tracheal reflex is most reliably tested by examining the cough response to tracheal suctioning. The catheter should be inserted into the trachea and advanced to the level of the carina followed by one or two suctioning passes. The effer‐ ent limbs for this reflex are the phrenic nerve and the thoracic and abdominal musculature.

Only if all the above reflexes are absent, proceed with testing for apnea. The apnea test should

nerves [14]. Apnea testing is the cornerstone for the diagnosis of BD both in adults and chil‐ dren and is conducted similar to adults. However, despite the consensus criteria published for adults and pediatrics, considerable variation has been described in performing the apnea test in both populations [2, 21, 22, 29]. In 1987 Task Force guidelines for pediatric BD is reported that apnea testing using standardized methods can be performed, but this is ordinarily done only after other examination criteria are met. Yet, the standardized methods are not described and the two associated references reported different ways of performing the apnea test. The former, by Outwaker and Rockoff, described apnea testing in 10 children aged 10 months to 13 years who met the conventional criteria for BD. In their study, oxygen 100% was provided for 5 min before the test, the ventilator rate was set to zero, and a continuous flow of oxygen was provided through the ETT. Arterial blood gases (ABG) were drawn at 0, 1, 2, 3, and 5 min.

ning and 59.5 ± 10.2 at the end of the test, with a mean rise of 4.0 ± 0.9 mm Hg/min [30]. The latter, by Rowland and coworkers, in 9 children aged 4 months to 13 years, mentioned that

Hg after 15 min of apnea. All apnea tests were accomplished uneventfully and no spontane‐ ous respirations were observed in any of the patients after 15 min of apnea. The authors rec‐ ommended that prevention of hypoxia can be reliably achieved with administration of 100% oxygen for 10 min before discontinuing ventilator support, and continuing oxygen (6 l/min) through a catheter into the length of the ETT for the duration of the test. An initial apnea test

test with a longer duration of 15 min was advised. The study concluded that apneic oxygen‐ ation can be safely conducted in children as a component of the clinical evaluation of BD [31]. The above studies performed apnea testing differently. Even in the recent guidelines, there are no accurate instructions on how to perform a safe apnea test in children. Questions such as how much time is necessary for the preoxygenation period, which is the optimum base‐

or hypotention during the apnea test, which is the exact duration of apnea testing, remain blurred and left to the resolution of the attending physician. Physicians should always

level, which is the best way for apneic oxygenation, how to prevent hypoxia and/

rise was faster than adults, and faster in the beginning of apnea test (4.4 ± 1.6, 3.4 ± 1.3

does not confound the testing of the other cranial

was 39.4 ± 7.4 mm Hg at the begin‐

failed to achieve, then a repeated

ranged from 60 to 116 mm

Therefore, it cannot be assessed in patients with high cervical cord injury [12].

reflexes are sought in neonates and infants [20].

be conducted last so that a high PaCO<sup>2</sup>

All patients completed the test successfully; mean PaCO<sup>2</sup>

of 10 min was proposed, and if the desired levels of PCO<sup>2</sup>

and 2.6 ± 1.2 mm Hg/min at 5, 10, and 15 min, respectively). PaCO<sup>2</sup>

**4.8. Apnea test**

124 Intensive Care

PCO<sup>2</sup>

line PCO<sup>2</sup>

The rationale behind the apnea test is that an intense ventilator stimulus, such as hypercap‐ nia/respiratory acidosis is needed, to stimulate respiratory drive centers in the medulla to start respiratory efforts. During this procedure, concomitant hypoxemia should be avoided by the administration of 100% O<sup>2</sup> . The levels of PCO<sup>2</sup> sufficient to stimulate the respiratory drive (PCO<sup>2</sup> threshold) was set at 60 mm Hg, based on the study of Scafer and Caronna, which report that three comatose, apparently BD adults, started to breath at PCO<sup>2</sup> levels of 44–56 mmHg [36]. According to AAP 2011 guidelines, if no respiratory effort is observed from the initiation of the apnea test to the time the measured PaCO<sup>2</sup> is ≥60 and ≥20 mm Hg above the baseline, the apnea test is consistent with brain death. Patients with chronic respiratory disease and chronic hypercapnia may need a higher respiratory stimulus, and in this case, the limit of ≥20 mm Hg above baseline is more appropriate.

Apnea testing should not pose risk in the patients tested; it should be safe, accurate, and reproducible [29]. In the literature, there is evidence that approximately 10% of all apnea tests are aborted (12.5% in our study), mainly due to hypoxia and to a lesser degree due to hypotension [22]. A preparation period is necessary; a fluid bolus, e.g., R/L 20 ml/kg (iv), may be helpful in the case of volume depletion in the context of diabetes insipidus that may be present; and inotropes and vasopressors should be ready and connected in line, even if they are not needed before apnea testing. The effects of raised PCO<sup>2</sup> levels in the circulatory sys‐ tem can vary. There could be an increase in heart rate and blood pressure due to sympathetic stimulation, or blood pressure may start falling due to the vasodilatation caused by the rising PCO<sup>2</sup> levels and the myocardial depression caused by the acidosis; arterial line is necessary for a beat to beat evaluation of blood pressure and drug titration. Oxygenation is mostly maintained by the preoxygenation with 100% O<sup>2</sup> for 10 min, and through the apneic oxygen‐ ation during the test with the oxygen‐diffusion technique, e.g., with tracheal insufflation of oxygen at a rate suitable for the age of the child (as described previously in our study). The catheter administrating oxygen should not be cut, the size should be appropriate to permit escaping for the excess oxygen through the ETT and prevent air trapping, and the oxygen rate should be appropriate; if these precautions are not met, there is a risk for inadvertent high oxygen pressures. Cases of barotrauma with pneumothoraces and/or pneumomediasti‐ num have been described during apnea testing and should be avoided [37, 38]. In the case of hypoxia, CPAP could be applied through the application of the suitable valve in the T‐piece. A Mapleson anesthesia bag attached to the ETT could also be used. There are reports of suc‐ cessfully performing the apnea test through a T‐piece attached to the ET only; however, a question is arising if oxygen flowing simply at the end of ETT is capable of reaching the tra‐ chea to diffuse in the alveoli. Accomplishing apnea testing with the patient connected to ven‐ tilator should be avoided because all modern ventilators have built in apnea back up modes that do not allow zeroing the respiratory rate for a long time. Moreover, cardiac beating could trigger the ventilator if strong enough, and a false indication of spontaneous respiratory effort may appear. Maintenance of the homeostasis is of paramount importance for the safe and successful performance of the apnea test:


possibilities for a positive apnea test. AAP 2011 guidelines suggest serial follow up ABG to monitor the rise in PaCO<sup>2</sup> while the patient remains disconnected from mechanical ventilation [20].


### **4.10. Inability to perform elements of clinical examination and/or apnea**

Clinical neurological examination and/or apnea test cannot be performed under some circum‐ stances, especially during trauma. Ocular trauma, severe maxilofascial injuries, skull base fractures that are running through the external ear canal, and ear drum rupture limit the ability to perform and evaluate many of the brainstem reflexes. Cervical spinal trauma with possible participation of phrenic nerve limits the spontaneous breathing ability during apnea testing. Flaccid tone in patients with high spinal cord injury or neuromuscular diseases poses further concerns about the validity of clinical examination.

Furthermore, apnea testing cannot be performed in cases of severe hypoxia, e.g., in ARDS patients even under CPAP conditions, and/or in patients with severe hemodynamic insta‐ bility. When concerns about the potentials and validity of elements of clinical examination and/or apnea testing are arisen, then continued observation is recommended. A valid neu‐ rologic evaluation and apnea test could be performed at a later time, as soon as all issues are resolved. If this is not possible, then an ancillary study is indicated to establish BD diagnosis.

### **4.11. Ancillary studies**

PCO<sup>2</sup>

126 Intensive Care

maintained by the preoxygenation with 100% O<sup>2</sup>

successful performance of the apnea test:

levels for a positive apnea testing [11, 12, 14].

muscles) throughout the entire procedure [14].

• If the patient is well oxygenated (SpO<sup>2</sup>

PaCO<sup>2</sup>

baseline PCO<sup>2</sup>

genated and a normal PaCO<sup>2</sup>

 levels and the myocardial depression caused by the acidosis; arterial line is necessary for a beat to beat evaluation of blood pressure and drug titration. Oxygenation is mostly

ation during the test with the oxygen‐diffusion technique, e.g., with tracheal insufflation of oxygen at a rate suitable for the age of the child (as described previously in our study). The catheter administrating oxygen should not be cut, the size should be appropriate to permit escaping for the excess oxygen through the ETT and prevent air trapping, and the oxygen rate should be appropriate; if these precautions are not met, there is a risk for inadvertent high oxygen pressures. Cases of barotrauma with pneumothoraces and/or pneumomediasti‐ num have been described during apnea testing and should be avoided [37, 38]. In the case of hypoxia, CPAP could be applied through the application of the suitable valve in the T‐piece. A Mapleson anesthesia bag attached to the ETT could also be used. There are reports of suc‐ cessfully performing the apnea test through a T‐piece attached to the ET only; however, a question is arising if oxygen flowing simply at the end of ETT is capable of reaching the tra‐ chea to diffuse in the alveoli. Accomplishing apnea testing with the patient connected to ven‐ tilator should be avoided because all modern ventilators have built in apnea back up modes that do not allow zeroing the respiratory rate for a long time. Moreover, cardiac beating could trigger the ventilator if strong enough, and a false indication of spontaneous respiratory effort may appear. Maintenance of the homeostasis is of paramount importance for the safe and

• Regular arterial blood gas (ABG) analysis should ensure normalization of the pH and

• Preoxygenation using 100% oxygen, aiming at nitrogen removal and oxygen enrichment, should be applied for at least 10 min [12]. Mechanical ventilation parameters could be mod‐ ified as well at the same time, it is advisable to keep tidal volume and PEEP at the same level to avoid derecruitment and decrease only the respiratory rate aimed at eucapnia with

level of 35–45 mm Hg. This could facilitate the rise in PaCO<sup>2</sup>

• Intermittent mandatory mechanical ventilation is discontinued once the patient is well oxy‐

• Cardiac beating, blood pressure, and oxygen saturation should be continuously moni‐ tored while observing carefully for spontaneous respiratory effort (any respiratory muscle activity that results in abdominal or chest excursions or activity of accessory respiratory

tion to 10 min and then draw ABG for analysis. The longer the apnea times the more the

such as a Mapleson circuit connected to the ETT, or CPAP in cases of hypoxemia.

accomplished with the apneic oxygenation method through the ETT as described earlier. The patient could also be changed to a T‐piece attached to the ETT, or a self‐inflating bag

around 40 mm Hg has been achieved. Oxygenation should be

> 85%) and hemodynamic stable, keep apnea dura‐

line for immediate hemodynamic support, in case hypotension occurs.

; maintenance of core temperature above 35°C and normotension for age should be confirmed, even through dose adjustment of inotropic and vasopressor agents. Still in hemodynamic stable patients before the test, these drugs should be ready and connected to

for 10 min, and through the apneic oxygen‐

to the desired

The 2011 AAP BD guidelines recommends that ancillary studies (electroencephalogram and radionuclide cerebral blood flow) are not required to establish brain death and are not a sub‐ stitute for the neurologic examination. The term "ancillary study" is preferred to "confir‐ matory study" since these tests assist the clinician in making the clinical diagnosis of brain death. Ancillary studies are not common in places where the DNC concept, as the death of the brainstem, is accepted; on the contrary they are more common where the whole concept of BD, including the death of the brainstem, is acknowledged. Nevertheless, apart the above mentioned reasons that question the potential and safety of clinical examination, ancillary studies are sought also in suspected drug intoxication and to reduce the inter‐examination observation period.

Before the use of ancillary studies, all the preconditions of BD that could be applied, and all parts of clinical examination, including apnea test, that could be performed, should be recorded. When an ancillary study supports the diagnosis of BD, a second clinical examina‐ tion and apnea test must be done and components that can be completed must remain con‐ sistent with brain death. In this instance, the inter‐examination observation interval may be shortened and the second clinical evaluation and apnea test (or all components that can be completed safely) can be performed and documented at any time thereafter for children of all ages [20].

#### *4.11.1. EEG*

Electroencephalograph (EEG) has been extensively studied in 485 suspected BD pediatric patients where signs of electrocerebral silence (ECS) were sought. In their first study, 76% of patients had ECS, which elevated to 89% in subsequent, if any, studies. Sixty‐six patients had a second study that confirmed the ECS of the first study in 64/66 patients (97%). The two patients who showed EEG activity, in retrospect in depth analysis, would not have met the recent criteria for BD due to pharmacological agents present at the time of examination (a newborn with high phenobarbital levels of 30 μg/ml and a 5 years head trauma boy that received pentobarbital and pancuronium at the time of testing). In case that the first study showed EEG activity (85 patients), the second study showed ECS in 47/85 (55%) of patients. The rest 38/45 patients (45%), either did not have a second examination, or an ECG activity, as expected, were confirmed. It is worth mentioning that all the examined patients died (spon‐ taneously or by withdrawal of support). Only one patient survived with severe neurological impairment from this entire group of 485 patients, the above‐mentioned neonate with an elevated phenobarbital level, whose first EEG showed photic response [20].

#### *4.11.2. CBF*

Four‐vessel cerebral angiography is the gold standard for determining the absence of cerebral blood flow (CBF). However, the technique is not always available, is very invasive and dif‐ ficult to perform in young infants, and carry all the risk of transferring a potentially unstable patient outside the PICU. Thus, use of radionuclide CBF determinations to document the absence of CBF, with portable scanners where feasible, remains the most widely used meth‐ ods to support the clinical diagnosis of brain death in infants and children. Evidence suggests that radionuclide CBF study can be used in patients with high dose barbiturate or other drugs therapy to demonstrate the absence of CBF. The classical appearance in a CBF scanning study positive for BD is the "hollow skull phenomenon" or "hot nose sign" due to the absence of circulation in the brain with relatively increased nasal region perfusion due to preserved external carotid artery flow [12, 20].

An extended study of CBF in 681 suspected BD patients showed that 86% of patients who met clinical BD criteria had absent CBF on first examination, a percentage that rose to 89% in case they had a following test. Among them, 26 patients had a second examination that con‐ firm the absence of CBF in 24/26 patients (92%). The two exceptions with no flow in the first study that revealed some flow in the second study were two newborns. The first newborn had minimal flow on the second study and ventilator support was discontinued. The other newborn developed flow on the second study and had some spontaneous respirations and activity, and survived with severe neurologic impairment. Along with the 34 patients that had present flow in first study, 9/34 (26%) had no flow on the subsequent study, due to evo‐ lution to BD. The remaining 25/34 (74%) either had preserved flow or no further CBF studies were done, and all died (either spontaneously or by withdrawal of support). Interestingly, only one patient survived from this entire group (the one mentioned earlier) with severe neurologic deficit [20].

### *4.11.3. ECG versus CBF*

the brainstem, is accepted; on the contrary they are more common where the whole concept of BD, including the death of the brainstem, is acknowledged. Nevertheless, apart the above mentioned reasons that question the potential and safety of clinical examination, ancillary studies are sought also in suspected drug intoxication and to reduce the inter‐examination

Before the use of ancillary studies, all the preconditions of BD that could be applied, and all parts of clinical examination, including apnea test, that could be performed, should be recorded. When an ancillary study supports the diagnosis of BD, a second clinical examina‐ tion and apnea test must be done and components that can be completed must remain con‐ sistent with brain death. In this instance, the inter‐examination observation interval may be shortened and the second clinical evaluation and apnea test (or all components that can be completed safely) can be performed and documented at any time thereafter for children of

Electroencephalograph (EEG) has been extensively studied in 485 suspected BD pediatric patients where signs of electrocerebral silence (ECS) were sought. In their first study, 76% of patients had ECS, which elevated to 89% in subsequent, if any, studies. Sixty‐six patients had a second study that confirmed the ECS of the first study in 64/66 patients (97%). The two patients who showed EEG activity, in retrospect in depth analysis, would not have met the recent criteria for BD due to pharmacological agents present at the time of examination (a newborn with high phenobarbital levels of 30 μg/ml and a 5 years head trauma boy that received pentobarbital and pancuronium at the time of testing). In case that the first study showed EEG activity (85 patients), the second study showed ECS in 47/85 (55%) of patients. The rest 38/45 patients (45%), either did not have a second examination, or an ECG activity, as expected, were confirmed. It is worth mentioning that all the examined patients died (spon‐ taneously or by withdrawal of support). Only one patient survived with severe neurological impairment from this entire group of 485 patients, the above‐mentioned neonate with an

Four‐vessel cerebral angiography is the gold standard for determining the absence of cerebral blood flow (CBF). However, the technique is not always available, is very invasive and dif‐ ficult to perform in young infants, and carry all the risk of transferring a potentially unstable patient outside the PICU. Thus, use of radionuclide CBF determinations to document the absence of CBF, with portable scanners where feasible, remains the most widely used meth‐ ods to support the clinical diagnosis of brain death in infants and children. Evidence suggests that radionuclide CBF study can be used in patients with high dose barbiturate or other drugs therapy to demonstrate the absence of CBF. The classical appearance in a CBF scanning study positive for BD is the "hollow skull phenomenon" or "hot nose sign" due to the absence of circulation in the brain with relatively increased nasal region perfusion due to preserved

elevated phenobarbital level, whose first EEG showed photic response [20].

observation period.

128 Intensive Care

all ages [20].

*4.11.1. EEG*

*4.11.2. CBF*

external carotid artery flow [12, 20].

There are 12 studies in the literature examining 149 suspected BD patients of any age with both initial EEG and CBF studies, which present special interest to compare one to another for their diagnostic yield. Data were stratified by three age groups: (i) all children (*n* = 149); (ii) newborns (<1 month of age, *n* = 30); and (iii) children aged >1 month to 18 years (*n =* 119). In the first EEG study, ECS was found in 70% in the whole cohort, 40% in newborns and 78% in older children. Similarly, the absence of flow in the first CBF study was documented in the same proportion in all age groups (70%), though performance was better in infants with absent flow in 63%, whereas in older children remained the same with absent flow in 71% of patients. Both studies were compatible with BD in 58% of all patients, only in 26% of newborns and 66% of older children. It seemed that for newborns, EEG with ECS was less sensitive (40%) than the absence of CBF (63%) when confirming the diagnosis of brain death, but even in the CBF group the yield was low. Performance was better for children older than 1 month of age and both of these ancillary studies remain accepted tests to assist with deter‐ mination of brain death and are of similar confirmatory value. Radionuclide CBF techniques are increasingly being used in many institutions replacing EEG [20].

If the results of the ancillary study are equivocal, the patient cannot be pronounced BD. Observation under maximum supportive care is continued until a valid clinical examination and apnea testing is possible, or a subsequent ancillary study with definite results can be per‐ formed. A waiting period of 24 h is recommended before further radionuclide CBF study is performed, to allow for adequate clearance of Tc‐99m. A waiting period of 24 h is reasonable and recommended before repeating EEG ancillary study as well.

There are reports of other newer ancillary studies performed in adults and children with suspected BD. Concerning the adult population, Transcranial Doppler is not included in adult AAN 2010 guidelines, whereas it is reported as a screening only test in ANZICS 2013 guidelines [12,14]. MRA angiography, CT angiography, somatosensory evoked potentials, and bispectral index are mentioned in adult 2010 guidelines but are not recommended due to insufficient evidence [12]. Correspondingly, pediatric AAP 2011 guidelines cannot recommend any of the above studies as ancillary studies to assist with the determination of BD in children [20].

### **4.12. Number of examinations**

Two examinations, including apnea testing with each examination, separated by an obser‐ vation period, are required. The examinations should be performed by different attending physicians involved in the care of the child, or as specified by national law. The first examina‐ tion determines the child has met neurologic examination criteria for brain death. The second examination, performed by a different attending physician, confirms brain death, based on an unchanged and irreversible condition.

### **4.13. Number of examiners**

According to AAP 2011 guidelines, two physicians (one each time) must perform two indepen‐ dent examinations separated by specific intervals. Apnea testing, as an objective test, could be performed by the same physician, preferably the attending physician who is managing ventila‐ tor care of the child. The committee recommends that these examinations be performed by dif‐ ferent attending physicians involved in the care of the child. Physicians should have experience with neonates, infants, and children and have specific training in neurocritical care. They must be competent to perform the clinical examination and interpret results from ancillary studies. Pediatric intensivists and neonatologists, pediatric neurologists and neurosurgeons, pediat‐ ric trauma surgeons, and pediatric anesthesiologists with critical care training could serve as examiners for BD diagnosis in children. Adult specialists should have the appropriate neuro‐ logic and critical care training to diagnose brain death in children. Junior doctors, residents, and fellows should be encouraged to learn how to properly perform brain death testing by observ‐ ing and participating in BD diagnosis performed by senior experienced attending physicians.

The exact number, specialty, and the required qualifications of the examiners vary according to national law; e.g., in Greece, three physicians (anesthetist, neurologist/neurosurgeon, and attending physician such as pediatrician/pediatric surgeon), who should be board registered for their specialty at least for 2 years, are required. The same panel of doctors is mandatory to perform the second examination at the set observation period. No one must be potentially involved in the organ donation and transplantation team.

### **4.14. Observation period**

The recommended observation periods are as follows:


Observation period could be shortened in case of an ancillary study compatible with BD. On this occasion, the second neurologic examination and apnea test (or all components that can be completed safely) can be performed and documented at any time thereafter for children of all ages [20].

### **5. Special considerations for term newborns (37 weeks gestation to 30 days of age) by AAP 2011 guidelines**

recommend any of the above studies as ancillary studies to assist with the determination

Two examinations, including apnea testing with each examination, separated by an obser‐ vation period, are required. The examinations should be performed by different attending physicians involved in the care of the child, or as specified by national law. The first examina‐ tion determines the child has met neurologic examination criteria for brain death. The second examination, performed by a different attending physician, confirms brain death, based on an

According to AAP 2011 guidelines, two physicians (one each time) must perform two indepen‐ dent examinations separated by specific intervals. Apnea testing, as an objective test, could be performed by the same physician, preferably the attending physician who is managing ventila‐ tor care of the child. The committee recommends that these examinations be performed by dif‐ ferent attending physicians involved in the care of the child. Physicians should have experience with neonates, infants, and children and have specific training in neurocritical care. They must be competent to perform the clinical examination and interpret results from ancillary studies. Pediatric intensivists and neonatologists, pediatric neurologists and neurosurgeons, pediat‐ ric trauma surgeons, and pediatric anesthesiologists with critical care training could serve as examiners for BD diagnosis in children. Adult specialists should have the appropriate neuro‐ logic and critical care training to diagnose brain death in children. Junior doctors, residents, and fellows should be encouraged to learn how to properly perform brain death testing by observ‐ ing and participating in BD diagnosis performed by senior experienced attending physicians. The exact number, specialty, and the required qualifications of the examiners vary according to national law; e.g., in Greece, three physicians (anesthetist, neurologist/neurosurgeon, and attending physician such as pediatrician/pediatric surgeon), who should be board registered for their specialty at least for 2 years, are required. The same panel of doctors is mandatory to perform the second examination at the set observation period. No one must be potentially

of BD in children [20].

130 Intensive Care

**4.12. Number of examinations**

unchanged and irreversible condition.

involved in the organ donation and transplantation team.

The recommended observation periods are as follows:

• 12 h for infants and children (>30 days to 18 years).

• 24 h for neonates (37 weeks gestation to term infants 30 days of age).

Observation period could be shortened in case of an ancillary study compatible with BD. On this occasion, the second neurologic examination and apnea test (or all components that can be completed safely) can be performed and documented at any time thereafter for children

**4.13. Number of examiners**

**4.14. Observation period**

of all ages [20].

The younger the patient the greater the challenge of diagnosing BD in pediatric patients; the younger the patient the longer the observation period, unless clinical BD diagnosis is supported with ancillary studies whereas the observation period could be shortened [20]. Interestingly, the performances of ancillary studies which are supposed to help in the diagno‐ sis are less accurate in very young infants. These reservations were recorded for the first time in AAP 1987 guidelines and are listed below for historical reasons [19]. Different diagnostic criteria were defined in those guidelines according three age categories starting from the 7th day of life; no recommendation was done then for neonates younger than 7 days of life due to insufficient data. Ancillary studies, especially EEG, were regarded an essential component of the diagnosis and were mandatory with different observation periods across age:


In AAP 2011 guidelines, although some of the above precautions were revised, especially about the necessity of ancillary studies, there are still special considerations about the term newborns (37 weeks gestation to 30 days of life) in:


when ancillary tests are present and compatible with BD, the inter‐examination interval could be shortened at the same way as happened to older children.

Similar recommendations for patients younger than 36 weeks to 1 month of age were issued by the ANZICS 2013 guidelines as well, stating that the initial evaluation for BD should defer for 48 h, with an interval of 24 h between the two tests [14].

### **6. Special considerations in patients younger than 2 months by RCCHD 2015 guidelines**

Due to uncertainty about the validity of the 2008 AoMRC code of practice DNC criteria in young infants, in the UK, the RCCHD examined literature evidence for BD in very young patients from 37 weeks corrected gestation (postmenstrual) to 2 months postterm [18]. According to their guidelines, DNC is a clinical diagnosis with certain preconditions, and ancillary tests do not help in this diagnosis. They recommended that DNC for this age group should be made taking into account the following:


### **7. Special considerations for premature newborns**

Brainstem reflexes are not fully developed in premature babies, for example the pupillary response to light appears at 30 weeks, but is only consistently present at 32–35 weeks of gestation, and the central respiratory response to CO<sup>2</sup> is relatively poorly developed below 33 weeks of ges‐ tation. Due to the uncertainty surrounding this issue, there are not any international guidelines to address BD diagnosis in premature babies below 36–37 weeks postconceptual age [14, 20].

### **8. Declaration of death: documentation**

when ancillary tests are present and compatible with BD, the inter‐examination interval

Similar recommendations for patients younger than 36 weeks to 1 month of age were issued by the ANZICS 2013 guidelines as well, stating that the initial evaluation for BD should defer

**6. Special considerations in patients younger than 2 months by RCCHD** 

Due to uncertainty about the validity of the 2008 AoMRC code of practice DNC criteria in young infants, in the UK, the RCCHD examined literature evidence for BD in very young patients from 37 weeks corrected gestation (postmenstrual) to 2 months postterm [18]. According to their guidelines, DNC is a clinical diagnosis with certain preconditions, and ancillary tests do not help in this diagnosis. They recommended that DNC for this age group

• *Preconditions:* The same preconditions are recommended as those detailed in the 2008 AoM‐ RC code of practice and in the 1991 BPA report, with an additional prerequisite about the first clinical examination. Postasphyxiated infants or those receiving intensive care after resuscitation, having or not being treated with therapeutic hypothermia, should have a period of at least 24 h of observation. This observation period could be extended in the case

• *Clinical diagnosis of DNC:* The same DNC clinical criteria are recommended as those used in the 2008 AoMRC code of practice for adults, children, and older infants, with special considerations on apnea. A stronger hypercarbic stimulus is used to establish respirato‐

(>20 mm Hg) *above a baseline of at least 5.3 kPa (40 mm Hg)* to >8.0 kPa (60 mm Hg) with no respiratory response at that level. Two clinical examinations are required with the same

• *Ancillary tests:* Ancillary tests were not found sufficiently robust to help confidently diagnose DNC in infants. They are required only in cases where a clinical diagnosis of DNC is not pos‐ sible (for example because of extensive faciomaxillary injuries, or high cervical cord injury). • *Examiners:* Two qualified pediatricians who have been registered for more than 5 years and are competent in the procedure are required. At least one should be a consultant. They

Brainstem reflexes are not fully developed in premature babies, for example the pupillary response to light appears at 30 weeks, but is only consistently present at 32–35 weeks of gestation,

levels of >2.7 kPa

ry unresponsiveness. Specifically, there should be a clear rise in PaCO<sup>2</sup>

could be shortened at the same way as happened to older children.

for 48 h, with an interval of 24 h between the two tests [14].

should be made taking into account the following:

of suspected residual drug‐induced sedation.

interval as in 2008 AoMRC code of practice.

should perform successfully two tests, including apnea.

**7. Special considerations for premature newborns**

**2015 guidelines**

132 Intensive Care

Death is declared after the second neurologic examination and apnea test confirms an unchanged and irreversible condition. When there is a concern about the validity of the first clinical examination and ancillary studies are used, documentation of components from the second clinical examination that can be completed, including a second apnea test, must remain consistent with brain death. Documentation at each step of diagnosis is necessary, starting from the preconditions that should be met and finishing with the exact time of death, accompanied by the well written names and signatures of the responsible physicians. The use of a checklist provides standardized documentation to determine brain death ensuring that no step is missing and is highly recommended [20, 21, 24]. A checklist outlining essential examination and testing components is provided in Appendix 2.

The law, almost worldwide, recognizes that after DB declaration, preservation of technol‐ ogy‐dependent life in modern ICUs is of no use, unless the patient is going to be an organ donor, whereas all the necessary actions should be undertaken. Time of clinical death after BD varies in different references according to national social, cultural, and religious preferences. In a preliminary announcement of our study, this time was approximately 2.74 days after the completion of the second apnea test, mainly attributed to the high emotional stress of the parents and the time needed by the family to accept the reality of BD for their children [39]. In one of the first relevant studies in children, it is reported that among 171 BD pediatric patients 47% had their ventilatory support withdrawn an average of 1.7 days after the diagnosis of BD, whereas in 46% support was continued until a cardiac arrest that happened an average of 22.7 days later [40]. The shorter period of 8.52 h is reported in Canada [2] and the longer period up to 4 years is recorded in Japan [7].

### **9. Parental support**

The loss of a child is the most powerful emotional stress for a family. Moreover, there is evi‐ dence that parents cannot understand the concept of the brain death in a child that is appar‐ ently alive, connecting to ventilator with its heart beating. Good communication between the family and the medical team is necessary to make clear that, despite everything had been made for the recovery of their children, they will have a dismal outcome. The role of the bed‐ side nurse who spent more time with the patients and the parents is fundamental in creating the trust to accept the reality of BD. From the very beginning of the admission of their child at the PICU, the parents should be fully informed of the disease, the treatments and the unfavor‐ able prognosis. When parents are not well informed, they will take longer to understand the evolution to BD and accept the death of their child [7, 23].

Communication with families must be clear and concise, yet using a simple language with‐ out pompous medical terminology that they could not understand. Apart medical and nurs‐ ing team, other medical workers could help families cope with the apparent death as well. The clerk and psychotherapists/psychologists may help them to take difficult end‐of‐life decisions and parents should be offered this possibility. The presence of family during the tests is questionable. Some families may find it helpful and relieving to see each diagnostic step and the complete loss of responsiveness, but a danger of severe emotional embarrass‐ ment lurks in case spinal reflexes are elicited [7]. The family must understand that after the confirmation of BD, their child meets legal criteria for death and continuation of medi‐ cal therapies, including ventilator support, is no longer an option unless organ donation is planned [20].

### **10. Conclusions**

Diagnosing BD in children is a challenging task and despite the existence of pediatric guide‐ lines since 1987, great variation has been recorded. Strict adherence to published guidelines and medical standards for determining brain death is the minimum requirement for main‐ taining public trust. The neurological criteria, as outlined above, represent international practice in which the medical profession and the public can have complete confidence [16]. The use of checklist promotes the necessary documentation of each part of declaration of BD and is strongly recommended [2, 21, 24]. International guidelines should form a basis where national guidelines could be established, taking into account legal, ethical, cultural, and reli‐ gious differences. Diagnosing BD is a medical duty and should be faced with the appropriate knowledge and responsibility.

Although it becomes more and more clear that BD is a clinical diagnosis, there are circum‐ stances where ancillary studies are still necessary. Technology is rapidly evolving and newer methods assessing brain function are developed. Newer methods to assess CBF and neuro‐ physiologic function comparing them to traditional ancillary studies is a forthcoming need, and they will be probably included in future guidelines to assist with determination of brain death in children. Additional information or studies are required to determine if a single neu‐ rologic examination is sufficient for neonates, infants, and children to determine brain death as currently recommended for adults over 18 years of age, by the 2010 AAN adult guidelines on BD [12, 20].

### **Appendices**

**Appendix 1.** Brain death diagnosis algorithm (adapted from Ref. [20])

**Appendix 2.** Check list for determination of brain death (adapted from Ref. [20])

Communication with families must be clear and concise, yet using a simple language with‐ out pompous medical terminology that they could not understand. Apart medical and nurs‐ ing team, other medical workers could help families cope with the apparent death as well. The clerk and psychotherapists/psychologists may help them to take difficult end‐of‐life decisions and parents should be offered this possibility. The presence of family during the tests is questionable. Some families may find it helpful and relieving to see each diagnostic step and the complete loss of responsiveness, but a danger of severe emotional embarrass‐ ment lurks in case spinal reflexes are elicited [7]. The family must understand that after the confirmation of BD, their child meets legal criteria for death and continuation of medi‐ cal therapies, including ventilator support, is no longer an option unless organ donation is

Diagnosing BD in children is a challenging task and despite the existence of pediatric guide‐ lines since 1987, great variation has been recorded. Strict adherence to published guidelines and medical standards for determining brain death is the minimum requirement for main‐ taining public trust. The neurological criteria, as outlined above, represent international practice in which the medical profession and the public can have complete confidence [16]. The use of checklist promotes the necessary documentation of each part of declaration of BD and is strongly recommended [2, 21, 24]. International guidelines should form a basis where national guidelines could be established, taking into account legal, ethical, cultural, and reli‐ gious differences. Diagnosing BD is a medical duty and should be faced with the appropriate

Although it becomes more and more clear that BD is a clinical diagnosis, there are circum‐ stances where ancillary studies are still necessary. Technology is rapidly evolving and newer methods assessing brain function are developed. Newer methods to assess CBF and neuro‐ physiologic function comparing them to traditional ancillary studies is a forthcoming need, and they will be probably included in future guidelines to assist with determination of brain death in children. Additional information or studies are required to determine if a single neu‐ rologic examination is sufficient for neonates, infants, and children to determine brain death as currently recommended for adults over 18 years of age, by the 2010 AAN adult guidelines

**Appendix 1.** Brain death diagnosis algorithm (adapted from Ref. [20])

**Appendix 2.** Check list for determination of brain death (adapted from Ref. [20])

planned [20].

**10. Conclusions**

knowledge and responsibility.

on BD [12, 20].

**Appendices**


### **Author details**

136 Intensive Care

Eleni Athanasios Volakli\*, Peristera‐Eleni Mantzafleri, Serafeia Kalamitsou, Asimina Violaki, Elpis Chochliourou, Menelaos Svirkos, Athanasios Kasimis and Maria Sdougka

\*Address all correspondence to: elenavolakli@gmail.com

Pediatric Intensive Care Unit, Hippokration General Hospital, Thessaloniki, Greece

### **References**


[24] Shore PM. Following guidelines for brain death examinations: A matter of trust. Pediatric Critical Care Medicine. 2013;**14**:98‐99. DOI: 10.1097/PCC.0b013e31826775bb

[11] Wijdicks FME. Determining brain death in adults. Neurology. 1995;**45**:1003‐1011

Determining brain death in adults. Neurology. 2010;**74**:1911‐1918

and Organ Donation (Edition 3.2). Melbourne: ANZICS; 2013

potential. Canadian Medical Association Journal. 2006;**174**:S13

children. Archives of Neurology. 1987;**44**(6):587‐588

Force recommendations. Pediatrics. 2011;**128**:e720‐e740

practice and safety of the apnea test. Neurology. 2008;**71**:1240

[Accessed: January 20, 2017]

138 Intensive Care

Party Report; 1991

2008;**121**:988

2005;**15**:301‐307

[12] Wijdicks EFM, Varelas NP, Gronseth SG, Greer MD. Evidence‐based guideline update:

[13] Academy of Medical Royal Colleges. A Code of Practice for the Diagnosis and Confirmation of Death [Internet]. 2008. Available from: http://www.aomrc.org. uk/doc\_details/42‐a‐code‐ofpractice‐for‐the‐diagnosis‐and‐confirmation‐of‐death

[14] Australian and New Zealand Intensive Care Society. The ANZICS Statement on Death

[15] Shemie SD, Ross H, Pagliarello J, et al. Brain arrest: The neurological determination of death and organ donor management in Canada: Organ donor management in Canada: Recommendations of the forum on medical management to optimize donor organ

[16] Gardiner D, Shemie S, Manar A, Opdam H. International perspective on the diagnosis of death. British Journal of Anaesthesia. 2012;**108**(S1):i14‐i28. DOI: 10.1093/bja/aer397

[17] British Paediatric Association. Diagnosis of brain stem death in children. A Working

[18] Marikar D. The diagnosis of death by neurological criteria in infants less than 2 months old: RCPCH guideline 2015. Archives of Disease in Childhood Education and Practice Edition. 2016;**101**(4):186. DOI: 10.1136/archdischild‐2015‐309706. Epub 2016 Mar 9

[19] Task Force for the Determination of Brain Death in Children. Guidelines for the deter‐ mination of brain death in children. Task force for the determination of brain death in

[20] Thomas A. Nakagawa, Stephen Ashwal, Mudit Mathur, Mohan Mysore, and the society of critical care medicine, section on critical care and section on neurology of the ameri‐ can academy of pediatrics, and the child neurology society. Clinical report—Guidelines for the determination of brain death in infants and children: An update of the 1987 Task

[21] Mathur M, Petersen LC, Stadtler M, Rose C, Ejike JC, Petersen F, et al. Variability in pedi‐ atric brain death determination and documentation in Southern California. Pediatrics.

[22] Wijdicks EFM, Rabinstein AA, Manno ME, et al. Pronouncing brain death: Contemporary

[23] Paul B. Diagnosis and management of brain death in children. Current Paediatrics.


### **Chapter 7**

## **Fat Embolism Syndrome**

Syed Abdul Rahman, Arif Valliani and

Arshad Chanda

[37] Bar‐Joseph G, Bar‐Lavie Y, Zonis Z. Tension pneumothorax during apnea testing for the

[38] Burns JD, Russell JA. Tension pneumothorax complicating apnea testing during brain

[39] Mantzafleri PE, Volakli E, Violakli A, Chochliourou E, Svirkos M, Kasimis A, et al. Incidence and management of brain death in a Greek PICU. European Journal of Pedia‐

[40] Ashwal S, Schneider S. Brain death in children: Part I. Pediatric Neurology. 1987;**3**(1):5‐11

determination of brain death. Anesthesiology. 1998;**89**(5):1250‐1251

death evaluation. Journal of Clinical Neuroscience. 2008;**15**(5):580‐582

trics. 2016;**175**(11):1393‐1880:E‐poster 1105

140 Intensive Care

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.69815

#### **Abstract**

Fat embolism syndrome (FES) is a clinical syndrome characterized by signs and symptoms resulting from fat emboli and typically occurs after trauma, orthopaedic surgeries and non-traumatic conditions like acute pancreatitis. Literature reports an incidence of FES of up to 19% in prospective studies. Fat embolism refers to the presence of fat globules in pulmonary microcirculation and is often asymptomatic. The clinical syndrome of FES is characterized by systemic manifestations resulting from fat emboli which may manifest with a triad of lung, brain, and skin involvement in about 24–72 hours of asymptomatic period. The pathophysiology of fat embolism syndrome remains unclear. Two theories have been hypothesized: mechanical(disruptive) and biochemical(production of toxic metabolites). Universal agreement on the definition of FES is lacking. FES presents with nonspecific signs and symptoms;common to other critical illnesses and is often a diagnosis of exclusion. The clinical criteria proposed by Gurd and Wilson are popular. Biochemical tests and imaging may be of value in supporting the diagnosis. Treatment for FES is essentially supportive care in ICU. Principles of treatment include maintenance of adequate oxygenation, ventilation, hemodynamics, and organ perfusion. It may be prevented by early fixation of large bone fractures.

**Keywords:** fat embolism syndrome (FES), long bone fractures, clinical criteria, imaging studies, supportive care, early fixation

### **1. Introduction**

The term "fat embolism" (FE) is often loosely used to describe both fat embolization (of insignificant clinical relevance) and the clinical syndrome of fat embolism syndrome (FES) [1].

© 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

The term "fat embolism" may be defined as the presence of fat globules in the pulmonary microcirculation irrespective of its clinical relevance, while the clinical syndrome of FES is characterized by the clinical signs and symptoms (systemic manifestations) resulting from fat emboli [2] and must be differentiated from the pathophysiological phenomenon of fat embolization [3].

### **2. History**

Fat embolism was described as early as 1862 by Zenker. Warthin [4] opined that fat embolism from traumatic lipemia was not rare and the most frequent cause of death following long bone fractures in the absence of infection.

More data on FES came forth in the early twenty‐first century from wounded soldiers involved in armed conflict across the world. A series of 1000 combats injured in the World War II reported the incidence of FES to be 0.8%. In Vietnam, cases of arterial hypoxemia among wounded soldiers were attributed to FES and also reported a few classic presentations of FES [3].

### **3. Pathophysiology**

The pathophysiology of development of fat embolism syndrome is still unclear. However, two theories were hypothesized for its mechanism: mechanical and biochemical. Either the disrupted fat globules from bone marrow or adipose tissues enter into the bloodstreams (mechanical) or any sequel that leads to the production of toxic metabolites in the blood (biochemical) can give rise to a conundrum of clinical features that characterize the fat embolism syndrome. It is also likely that either the mechanisms exist in tandem or one gives rise to the other in the production of FES.

### **3.1. Mechanical theory**

In the twentieth century, it was suggested that following a trauma, fat particles from the bone marrow and adipose tissues enter into the disrupted venules and travel to the pulmonary circulation or enter into the systemic circuit via arteriovenous shunts. The echocardiographic finding of echogenic material passing into the right heart during an orthopedic procedure contributed to this mechanical theory [5].

### **3.2. Biochemical theory**

However, the mechanical theory does not explain the development of FES after a delay of 2–3 days postinjury. There are many biochemical mechanisms involved in the progression of fat embolism syndrome; the most widely accepted is the release of free fatty acids into the plasma following trauma, sepsis, and/or systemic inflammation. Acute phase reactants, like C-reactive proteins, lead to lipid agglutination that tend to cause Acute respiratory distress syndrome (ARDS) in animal models, dysfunction of cardiac contractility and increase in plasma lipase concentration, which are the features of FES. These free fatty acids migrate to other organs, causing multiorgan failure [6]. This theory also helps in understanding the development of nontraumatic fat embolism syndrome.

### **4. Incidence**

The term "fat embolism" may be defined as the presence of fat globules in the pulmonary microcirculation irrespective of its clinical relevance, while the clinical syndrome of FES is characterized by the clinical signs and symptoms (systemic manifestations) resulting from fat emboli [2] and must be differentiated from the pathophysiological phenomenon of fat

Fat embolism was described as early as 1862 by Zenker. Warthin [4] opined that fat embolism from traumatic lipemia was not rare and the most frequent cause of death following long

More data on FES came forth in the early twenty‐first century from wounded soldiers involved in armed conflict across the world. A series of 1000 combats injured in the World War II reported the incidence of FES to be 0.8%. In Vietnam, cases of arterial hypoxemia among wounded soldiers were attributed to FES and also reported a few classic presentations of

The pathophysiology of development of fat embolism syndrome is still unclear. However, two theories were hypothesized for its mechanism: mechanical and biochemical. Either the disrupted fat globules from bone marrow or adipose tissues enter into the bloodstreams (mechanical) or any sequel that leads to the production of toxic metabolites in the blood (biochemical) can give rise to a conundrum of clinical features that characterize the fat embolism syndrome. It is also likely that either the mechanisms exist in tandem or one gives rise to the

In the twentieth century, it was suggested that following a trauma, fat particles from the bone marrow and adipose tissues enter into the disrupted venules and travel to the pulmonary circulation or enter into the systemic circuit via arteriovenous shunts. The echocardiographic finding of echogenic material passing into the right heart during an orthopedic procedure

However, the mechanical theory does not explain the development of FES after a delay of 2–3 days postinjury. There are many biochemical mechanisms involved in the progression of fat embolism syndrome; the most widely accepted is the release of free fatty acids into the plasma following trauma, sepsis, and/or systemic inflammation. Acute phase reactants,

embolization [3].

bone fractures in the absence of infection.

**2. History**

142 Intensive Care

FES [3].

**3. Pathophysiology**

other in the production of FES.

contributed to this mechanical theory [5].

**3.1. Mechanical theory**

**3.2. Biochemical theory**

Fat Embolism is common in trauma patients, particularly those with pelvic or long bone fractures [3]. Most literature reporting incidence of FES involves orthopedic or trauma patients with retrospective studies reporting an incidence of below 1%, while prospective studies have reported a much higher incidence of 11–19% [7]. Autopsy studies reported a much higher incidence of Fat embolism. One study demonstrated pulmonary fat emboli in 82% of trauma patients at autopsy [8]. Up to 67% of trauma patients without clinical features of fat embolism syndrome were shown to have circulating fat globules [3].

Fat emboli with a diameter of more than 20 µm have been shown to occur in up to 90% of patients with long bone fractures. Another study concluded that more than 90% of patients with long bone fractures had embolism with fat droplets more than 20 µm in diameter [9].

Gurd proposed that the clinical syndrome of fat embolism can be differentiated from a mere presence of fat emboli at autopsy in patients with no prior clinical features. Gurd suggested that a distinction can be made between the clinical syndrome of fat embolism and demonstration of fat embolism on autopsy with no prior clinical features of the syndrome [10].

Bulger et al. studied the incidence of FES at a level I trauma center over a 10‐year period, reporting an incidence of 0.9% among patients with long bone fractures [11]. More recent data from the National Hospital Discharge Survey in USA looking at 21,538,000 patients with long bones and pelvic fractures reported a diagnosis of FES in 0.12% of the patients [12].

### **5. Etiology and risk factor**

The development of FES is frequently associated following an orthopedic trauma, with highest occurrence in closed and/or multiple long bone fractures, particularly of lower limb bones like femur. Aggressive nailing of the medullary canal poses increased risk of FES. Vigorous nailing of medullary cavity during intramedullary nailing and increase in gap between nail and cortical bone puts the patient at high risk of developing FES [6].

Furthermore, younger populations of 10–40 years and men more often than women are at high risk. Fat embolism has been reported in other nontraumatic conditions like pancreatitis, liposuction, bone marrow transplant, sickle cell disease, and liver disease. Nontraumatic causes of fat embolism syndrome include bone marrow transplant, pancreatitis, liposuction, alcoholic liver disease, and sickle cell crisis [13].

### **6. Clinical features**

The phenomenon of fat embolism (fat droplets in circulation) is often undiagnosed in clinical practice. The clinical syndrome of FES tends to present with signs and symptoms similar to other critical illness and is mostly a diagnosis of exclusion. Fat embolism, which is a mere presence of fat emboli in circulation, may frequently go undiagnosed [10], while fat embolism syndrome presents with nonspecific clinical features common to other critical illnesses and is often a diagnosis of exclusion.

The fulminating form may present with sudden cardiovascular collapse and right ventricular failure subsequent to pulmonary and systemic fat embolization. More often, it is characterized by a more gradual onset of hypoxemia, neurological symptoms and a petechial rash about 12–36 hours after an injury [7].

Fat emboli could travel through the systemic vasculature resulting in a multiorgan disease involving lungs, brain, skin, retina, kidneys, liver, and heart.

The most common manifestations among patients with FES are of pulmonary system. Pumonary manifestations though of varying severity are the most common finding in patient with fat embolism syndrome. Bulger et al. reported hypoxemia in 96% of the cases, and 44% of the patients with FES required mechanical ventilation [11]. Patients may develop dyspnea and tachypnea and a more severe syndrome indistinguishable from Acute respiratory distress syndrome (ARDS) may develop.

Nonspecific neurological symptoms including lethargy, restlessness or a decrease in Glasgow Coma Scale (GCS) may suggest cerebral edema subsequent to FES [14]. Severe neurological deterioration with cerebral edema has been reported with FES [15].

Skin involvement characterized by a petechial rash manifests in up to 60% of patients and usually affects oral mucous membranes, neck and axilla skin folds and conjunctiva. Dermal manifestations with a petechial rash pathogonomic of FES usually involves the conjunctiva, oral mucous membranes and skin folds of the neck and axillae and occuring in up to 60% of patients with FES [7].

### **7. Diagnosis**

### **7.1. Gurd's and Wilson's criteria**

Universal agreement on a standard definition of FES is lacking. There is a lack of universally accepted definition of FES [3]. The major and minor criteria proposed by Gurd and Wilson (**Table 1**) in 1970 are still popular [10]. It required one major criterion plus four minor criteria's in addition to fat macroglobulinemia for a diagnosis of FES.

### **7.2. Schonfeld's criteria**

**6. Clinical features**

144 Intensive Care

often a diagnosis of exclusion.

about 12–36 hours after an injury [7].

syndrome (ARDS) may develop.

patients with FES [7].

**7.1. Gurd's and Wilson's criteria**

**7. Diagnosis**

involving lungs, brain, skin, retina, kidneys, liver, and heart.

deterioration with cerebral edema has been reported with FES [15].

in addition to fat macroglobulinemia for a diagnosis of FES.

The phenomenon of fat embolism (fat droplets in circulation) is often undiagnosed in clinical practice. The clinical syndrome of FES tends to present with signs and symptoms similar to other critical illness and is mostly a diagnosis of exclusion. Fat embolism, which is a mere presence of fat emboli in circulation, may frequently go undiagnosed [10], while fat embolism syndrome presents with nonspecific clinical features common to other critical illnesses and is

The fulminating form may present with sudden cardiovascular collapse and right ventricular failure subsequent to pulmonary and systemic fat embolization. More often, it is characterized by a more gradual onset of hypoxemia, neurological symptoms and a petechial rash

Fat emboli could travel through the systemic vasculature resulting in a multiorgan disease

The most common manifestations among patients with FES are of pulmonary system. Pumonary manifestations though of varying severity are the most common finding in patient with fat embolism syndrome. Bulger et al. reported hypoxemia in 96% of the cases, and 44% of the patients with FES required mechanical ventilation [11]. Patients may develop dyspnea and tachypnea and a more severe syndrome indistinguishable from Acute respiratory distress

Nonspecific neurological symptoms including lethargy, restlessness or a decrease in Glasgow Coma Scale (GCS) may suggest cerebral edema subsequent to FES [14]. Severe neurological

Skin involvement characterized by a petechial rash manifests in up to 60% of patients and usually affects oral mucous membranes, neck and axilla skin folds and conjunctiva. Dermal manifestations with a petechial rash pathogonomic of FES usually involves the conjunctiva, oral mucous membranes and skin folds of the neck and axillae and occuring in up to 60% of

Universal agreement on a standard definition of FES is lacking. There is a lack of universally accepted definition of FES [3]. The major and minor criteria proposed by Gurd and Wilson (**Table 1**) in 1970 are still popular [10]. It required one major criterion plus four minor criteria's Other authors later adapted these criteria and proposed the combinations of major and minor features needed for a diagnosis. Schonfeld et al. proposed (**Table 3**) a quantitative measure to diagnose FES; a score of more than 5 is required to diagnose FES [3].

#### **7.3. Lindeque's criteria**

Lindeque proposed criteria for diagnosis of fat embolism syndrome based on respiratory changes alone [16]. A positive diagnosis of FES was proposed if atleast one of the criteria are met (**Table 2**).



**Table 2.** Lindeque's criteria (with permission from Dr. Nissar Shaikh) [6].


**Table 3.** Schonfeld's criteria (with permission from Dr. Nissar Shaikh) [6].

### **8. Investigations**

Diagnosis must be made on the basis of clinical findings but biochemical changes may be of value to support in diagnosis.

In the initial stages, a blood gas analysis is imperative, which will show hypoxia with paO2 of less than 60 mmHg and hypocapnia within the first 24–48 hours. Also, there will be an unexplained increase in the pulmonary shunt fraction and an alveolar to arterial oxygen tension difference. These are highly suggestive of a diagnosis of FES.

Nonspecific findings include anemia, thrombocytopenia, hypofibrinogenemia and high erythrocytes sedimentation rate. Cytological examination of urine, blood, sputum, and pulmonary capillary blood may detect fat globules in patients with FES; however, these tests are rarely done in the immediate period as they lack sensitivity and their absence does not rule out fat embolism [6].

#### **8.1. Imaging studies**

#### *8.1.1. Chest X‐ray*

Various nonspecific findings have been reported on chest X‐ray though none of them is diagnostic. Numerous radiological findings have been described but none is diagnostic of fat embolism syndrome. The chest X-ray is often normal initially but in some patients bilateral fluffy shadows can be seen with worsening respiratory insufficiency (**Figure 1**).

**Figure 1.** AP radiograph of the chest showing bilateral basal air space‐filling lesions (consolidation in a patient of FES) (with permission from Dr. Nissar Shaikh) [6].

### *8.1.2. Ventilation – perfusion scan (V/Q)*

**8. Investigations**

Sustained pO2

146 Intensive Care

Sustained pCO2

**Schonfeld's criteria**

Hypoxaemia (Pao2 < 9.3 kPa) 3

Tachycardia (>120 beats min−1) 1

Cumulative score >5 required for diagnosis

Tachypnoea (>30 bpm) 1

Petechiae 5

Fever (>38°C) 1

< 8 kpa

> 7.3 kpa

Sustained respiratory rate > 35 per min, in spite of sedation Increase work of breathing, dyspnea, tachycardia, anxiety

Chest X‐ray changes (diffuse alveolar infiltrates) 4

embolism [6].

**8.1. Imaging studies**

*8.1.1. Chest X‐ray*

value to support in diagnosis.

Diagnosis must be made on the basis of clinical findings but biochemical changes may be of

of

In the initial stages, a blood gas analysis is imperative, which will show hypoxia with paO2

difference. These are highly suggestive of a diagnosis of FES.

**Table 3.** Schonfeld's criteria (with permission from Dr. Nissar Shaikh) [6].

less than 60 mmHg and hypocapnia within the first 24–48 hours. Also, there will be an unexplained increase in the pulmonary shunt fraction and an alveolar to arterial oxygen tension

Nonspecific findings include anemia, thrombocytopenia, hypofibrinogenemia and high erythrocytes sedimentation rate. Cytological examination of urine, blood, sputum, and pulmonary capillary blood may detect fat globules in patients with FES; however, these tests are rarely done in the immediate period as they lack sensitivity and their absence does not rule out fat

Various nonspecific findings have been reported on chest X‐ray though none of them is diagnostic. Numerous radiological findings have been described but none is diagnostic of fat embolism syndrome. The chest X-ray is often normal initially but in some patients bilateral

fluffy shadows can be seen with worsening respiratory insufficiency (**Figure 1**).

V/Q scans may demonstrate a mottled pattern of subsegmental perfusion defects with a normal ventilatory pattern.

### *8.1.3. CT – computerized tomography chest and head*

Spiral CT scan of the chest may show focal areas of ground glass opacification with interlobular septal thickening. Normal findings or diffuse petechial hemorrhages of white matter may be seen on CT scan of brain. CT Head may be normal or reveal diffuse white‐matter petechial hemorrhages consistent with microvascular injury. This will also rule out other causes for deterioration in consciousness level (**Figure 2**).

**Figure 2.** CT image showing minimal hypodense changes in periventricular region, which are more evident in MRI DWI and T2WI as areas of high signals (with permission from Dr. Nissar Shaikh) [6]. (Produced with permission) Constellation of findings along with clinical data is characteristic for FES.

#### *8.1.4. MRI of brain*

It may reveal high-intensity T2 signal which correlates with the degree of neurological impairment found clinically.

### **9. Treatment**

Treatment is largely supportive care in a unit equipped with intensive care capabilities. Maintaining adequate oxygenation, ventilation, and organ perfusion are the essential goals of treatment. Principles of treatment include maintenance of adequate oxygenation and ventilation, hemodynamics, and perfusion. Correction of hypoxemia to maintain normal oxygen tension may require simple measures like oxygen supplementation or mechanical ventilation and Positive end expiratory pressure (PEEP) depending on the clinical context. Shock in patients with FES can worsen the lung injury and hence restoration of intravascular volume with balanced salt solutions or albumin is often required. Albumin administration not only expands the intravascular volume but may also mitigate the extent of lung injury as a result of its binding with fatty acids. Vasopressors to maintain the hemodynamics may be required. It has been proposed that heparin by enhancing lipase activity may augment the clearance of lipids from blood circulation. Treatment modalities including corticosteroids and anticoagulation have unfortunately not been shown to improve the morbidity or mortality. Other medications including alcohol and dextran have also been shown to be ineffective [2, 6].

### **10. Prognosis**

Fat embolism occur in around 90% of all trauma patient, but FES accounts for less than 5% of patients having long bone fracture [17, 18]. The unstable form of FES presents as acute respiratory failure, cor pulmonale, and/or embolic event, leading to death within a few hours of injury. This is seen more often among high‐risk patients and those with a background of multiple comorbidities.

It is hard to predict the extent of FES as it is often subclinical and the outcome of patients are generally favorable [6]. Mortality rate is less than 10% at present as there have been significant improvements in supportive care. Neurological deficits and pulmonary manifestations usually resolve completely over time [18].

### **11. Prevention**

Studies have shown early fixation of fractures involving long bones is important in decreasing the incidence of fat embolism syndrome and may prevent it [6, 19, 20]. Preventing significant increase in intraosseous pressure in orthopedic surgeries may reduce embolization of fat droplets and thereby reduce the incidence of FES. It has been suggested that plate fixation and external fixation results in less emboli and less severity of lung injury than surgical fixation with intramedullary nailing [6]. Prophylactic use of corticosteroids may have a beneficial effect in preventing fat embolism syndrome [21]. Wong et al. suggested monitoring with continuous pulse oximetry in patients with long bone fractures for early identification of desaturation [22]. This would allow early initiation of appropriate oxygen supplementation and other measures, possibly reducing the systemic complications of fat embolism syndrome [6].

### **Author details**

*8.1.4. MRI of brain*

148 Intensive Care

**9. Treatment**

ineffective [2, 6].

**10. Prognosis**

multiple comorbidities.

**11. Prevention**

ally resolve completely over time [18].

ment found clinically.

It may reveal high-intensity T2 signal which correlates with the degree of neurological impair-

Treatment is largely supportive care in a unit equipped with intensive care capabilities. Maintaining adequate oxygenation, ventilation, and organ perfusion are the essential goals of treatment. Principles of treatment include maintenance of adequate oxygenation and ventilation, hemodynamics, and perfusion. Correction of hypoxemia to maintain normal oxygen tension may require simple measures like oxygen supplementation or mechanical ventilation and Positive end expiratory pressure (PEEP) depending on the clinical context. Shock in patients with FES can worsen the lung injury and hence restoration of intravascular volume with balanced salt solutions or albumin is often required. Albumin administration not only expands the intravascular volume but may also mitigate the extent of lung injury as a result of its binding with fatty acids. Vasopressors to maintain the hemodynamics may be required. It has been proposed that heparin by enhancing lipase activity may augment the clearance of lipids from blood circulation. Treatment modalities including corticosteroids and anticoagulation have unfortunately not been shown to improve the morbidity or mortality. Other medications including alcohol and dextran have also been shown to be

Fat embolism occur in around 90% of all trauma patient, but FES accounts for less than 5% of patients having long bone fracture [17, 18]. The unstable form of FES presents as acute respiratory failure, cor pulmonale, and/or embolic event, leading to death within a few hours of injury. This is seen more often among high‐risk patients and those with a background of

It is hard to predict the extent of FES as it is often subclinical and the outcome of patients are generally favorable [6]. Mortality rate is less than 10% at present as there have been significant improvements in supportive care. Neurological deficits and pulmonary manifestations usu-

Studies have shown early fixation of fractures involving long bones is important in decreasing the incidence of fat embolism syndrome and may prevent it [6, 19, 20]. Preventing significant increase in intraosseous pressure in orthopedic surgeries may reduce embolization Syed Abdul Rahman, Arif Valliani and Arshad Chanda\*

\*Address all correspondence to: drarshadchanda@yahoo.com

Surgical Intensive Care Unit, Hamad Medical Corporation, Doha, Qatar

### **References**

