J Endocrinol Invest (2014) 37:143–148 DOI 10.1007/s40618-013-0020-2
ORIGINAL ARTICLE
Is routine endocrine evaluation necessary after paediatric traumatic brain injury? M. A. Salomo´n-Este´banez • G. Grau • A. Vela • A. Rodrı´guez • E. Morteruel L. Castan˜o • I. Rica
•
Received: 22 July 2013 / Accepted: 17 November 2013 / Published online: 9 January 2014 Ó Italian Society of Endocrinology (SIE) 2013
Abstract Background Traumatic brain injury (TBI) is a common event in childhood. It is a recognised cause of hypopituitarism both in adult and paediatric patients. Routine endocrine evaluation has been proposed for adult TBIsurvivors; nevertheless, incongruous data have been reported in children. Aim The goal of this study was to describe the prevalence of pituitary dysfunction after TBI in a cohort of children. Material/subjects and methods This is a cross-sectional study comprising retrospective medical record review and prospective testing. Children with brain injury discharged from the Paediatric Intensive Care Unit from year 2004 to 2009 were recruited. Height and weight were recorded, systemic examination was performed and baseline pituitary function tests were undertaken. Provocative tests were performed only if abnormal basal levels were detected. M. A. Salomo´n-Este´banez G. Grau A. Vela A. Rodrı´guez I. Rica (&) Department of Paediatric Endocrinology, Cruces University Hospital, Plaza de Cruces s/n, 48903 Barakaldo, Biscay, Spain e-mail: [email protected] A. Vela L. Castan˜o CIBERER: Centre for Biomedical Network Research on Rare Diseases, Valencia, Spain
Results Thirty-six patients were collected; the mean age at assessment was 7.2 years and the mean interval since injury 3.3 years. All patients had skull fracture or intracranial haemorrhage; 36.6 % of them had moderate to severe TBI. No abnormalities were found on examination. Low serum IGF 1 levels were detected in four patients and two patients had low serum cortisol levels with inappropriately normal plasma ACTH concentrations. No evidence of pituitary dysfunction was observed in these patients after clinical follow-up, repeated baseline hormone levels or dynamic function tests. Conclusions No endocrine sequelae have been detected in this population. The routine endocrine evaluation in children with mild to moderate TBI might not be justified, according to our findings. Keywords Hypopituitarism Traumatic brain injury Children Pituitary gland Endocrine investigations Abbreviations TBI Traumatic brain injury PICU Paediatric Intensive Care Unit GHD Growth hormone deficiency CT Computed tomography GCS Glasgow Coma Scale SDS Standard deviation score
E. Morteruel Paediatric Intensive Care Unit, Cruces University Hospital, Barakaldo, Biscay, Spain L. Castan˜o Endocrinology and Diabetes Research Group, Cruces University Hospital, Barakaldo, Biscay, Spain L. Castan˜o I. Rica CIBERDEM: Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders, Barcelona, Spain
Introduction Hypopituitarism after traumatic brain injury (TBI) was first described in 1918 [1]. In 1942, Escamilla et al. [2] reported that head trauma accounted for pituitary dysfunction in 4 of 595 patients (0.7 %). By 1986 only 53 cases of TBI-
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induced endocrinopathies had been published [3]. In 2000, Benvenga et al. [4] collected 367 cases of hypopituitarism following TBI from the international literature and since then brain trauma has been considered as one of the major causes of pituitary dysfunction. In adults, pituitary abnormalities in at least one axis have been reported in 15–90 % of TBI survivors [5–16], not only in the acute phase but also as a long-term complication. Growth hormone deficiency (GHD) appears to be the most common disorder [5, 6, 11, 12]. Follow-up and endocrine assessment have been proposed after head trauma in adult patients [17] and, although TBI is a recognised cause of childhood pituitary dysfunction, there is currently scarce evidence to support such approach in paediatric population. Several studies have been carried out in children [18–24], with a variable prevalence of pituitary abnormalities (5–61 %). The results of these publications differ depending on the population studied, the severity of the head injury, the time interval between head injury and assessment and the testing methods used to assess the endocrine function. Einaudi et al. [18] studied pituitary function both retrospectively and prospectively in 48 survivors of childhood TBI and demonstrated 10 % hypothalamic—pituitary dysfunction at 12 months. Niederland et al. [19] did cross-sectional study of 26 patients at 30 ± 8 months after head trauma and detected pituitary disorders in 61 %; most of them had insufficient growth hormone (GH) response to stimulation tests. Poomthavorn et al. [20] included 54 patients in their cross-sectional study and reported pituitary dysfunction in 17 % of patients. Norwood et al. [21] retrospectively recruited 32 patients and found GHD in 16 % of their participants. These four studies support the use of routine endocrine evaluation of children following TBI. However, in 2010, two cross-sectional studies reported no clinically significant endocrinopathy amongst childhood TBI survivors [22, 23]. The prospective study by Kaulfers et al. showed that many of the pituitary abnormalities found in the first months after TBI were transient. They evaluated 31 children; the incidence of pituitary dysfunction was 15 % at 1 month, 75 % at 6 months and 29 % at 12 months after injury [24]. In view of these highly variable results, we aimed to evaluate the prevalence of pituitary dysfunction among a cohort of paediatric TBI survivors and also to investigate any relationship between severity of TBI and endocrine involvement.
Patients and methods Patients The study population comprised patients with TBI admitted to the Paediatric Intensive Care Unit (PICU) at the
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Cruces University Hospital (Biscay, Spain) between January 2004 and December 2009. Subjects were identified from the PICU admissions database. Inclusion criteria were evidence of skull fracture or brain injury in the cranial computed tomography (CT), age \14 years old at the time of the study and having been discharged alive from hospital.
Methods Eligible patients’ families were contacted by telephone; patients and parents were informed about the study and were invited to participate. After agreeing to take part in the study, informed consent was obtained. The following information was extracted from the patients’ medical records: date of birth, date of injury, sex, mechanism of injury, first documented Glasgow Coma Scale (GSS) score, CT findings, duration of PICU admission, need for inotropic support, mechanical ventilation, neurosurgical intervention or barbiturate-induced coma. Mild, moderate or severe TBI were defined, respectively, as head trauma with GCS scores of 13–15, 9–12 and \9. The functional outcome and disabilities after TBI were evaluated at the time of the study using the Glasgow Outcome Scale (GOS) that is a 5-level score: 5, capacity to resume normal activity; 4, moderate disability but the ability to live independently; 3, severe disability requiring assistance with activities of daily living; 2, vegetative state; 1, death. Subjects were assessed in the Paediatric Endocrinology Outpatient Department. A medical history was taken, children and their families were asked about symptoms related to pituitary dysfunction and a full clinical examination was performed evaluating weight, height and pubertal development. Anthropometric data were expressed as standard deviation scores (SDS) for age and sex using the local growth charts [25], and pubertal staging was assessed according to Tanner’s criteria [26]. Pre-injury height and weight were obtained from record review or primary care charts. Precocious puberty was considered if there were signs of pubertal development before age 8 in girls and age 9 in boys. Basal serum hormone levels were analysed to determine free thyroxine (fT4), thyroid stimulating hormone (TSH), prolactin, cortisol, oestradiol (female patients), testosterone (male patients), luteinizing hormone (LH), follicle-stimulating hormone (FSH), insulin-like growth factor-1 (IGF 1) and insulin-like growth factor binding protein-3 (IGF BP3). Adrenocorticotropic hormone (ACTH) levels were analysed in plasma. Serum electrolytes were analysed as well as urine and serum osmolality. Blood samples were collected in the morning, as early as possible.
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Provocative tests were performed in patients with endocrine symptoms or in those whose basal hormone levels were abnormal. All hormone assays were performed using chemiluminescent immunometric methods. FSH, LH, TSH, fT4, prolactin, oestradiol and testosterone were measured by the ADVIA Centaur analyzer (Siemens Medical Diagnostics). ACTH and cortisol were measured using LiaisonÒ DiaSorin’s automated assay. IGF 1 and IGF BP3 were determined by the IMMULITE 2000 analyzer. IGF 1 and IGF BP3 levels were interpreted according to the age reference ranges determined for the IMMULITE IGF I and IGF BP3 assays [27].
Results Seventy-four children with TBI were admitted to PICU during the years 2004–2009 and 58 of them met the eligible criteria. Twenty-two subjects were not contactable or declined to participate. Thirty-six patients agreed to enter the study (61.1 % male). The mean age at injury was 3.8 years and the mean time interval between head trauma and endocrine assessment was 3.3 years. Falls were the leading cause of TBI,
the majority of the brain injuries were mild and the head CT scan showed lesions in all cases. Further clinical details are summarised in Table 1. We did not find any statistically significant differences between recruited and nonrecruited patients in terms of age, severity, duration of PICU admission and CT findings. No abnormalities were found in the physical examination: the mean height SDS was -0.18 ± 0.9 and the mean weight SDS 0.1 ± 1.2. No precocious puberty was observed. Pituitary function results are shown in Table 2. There was no clinical evidence of posterior pituitary dysfunction. Serum basal prolactin levels were within the reference range in all patients. Thirty-five children had serum free T4 and TSH concentrations within the reference ranges. One of 36 patients was diagnosed of autoimmune hypothyroidism. Serum basal oestradiol or testosterone, LH and FSH were appropriate for age, sex and pubertal stage in all subjects. Six children required further investigation to exclude adrenal or somatotropic axes dysfunction. In four of them, serum IGF 1 levels were below the 2.5th centile, not Table 2 Pituitary function results Mean (SD)
Table 1 Clinical characteristics of participants
Posterior pituitary function, lactotropic and thyroid axes
Patients Age at injury, years (mean [range])
3.8 [0.1–12.7]
Age at study, years (mean [range])
7.2 [2.7–15.1a]
Mechanism of injury (n) Falls
24
Traffic accidents Impacts (struck by objects)
7 3
Sport injuries
2
TBI severity (mild/moderate/severe)
Intracerebral haemorrhages or contusion
4.5 (0.5)
Plasma osmolality (mOsm/l)
283 (5.5)
Urine osmolality (mOsm/l)
888 (217)
Prolactin (ng/ml)
9.8 (6.6)
Free T4 (ng/dl)
1.2 (0.15)
TSH (mU/ml)
3.7 (4.3) Pre-puertal (n = 27) Mean (SD)
Pubertal (n = 9) Mean (SD)
Gonadal axis
10
Testosterone (ng/dl)
8
Oestradiol (pg/ml)
19.4 (2.8)
59 (34.2)
LH (mU/ml)
0.97 (0.6)
4.2 (2)
FSH (mU/ml)
1.7 (1)
Skull fracture/sinking
6
Subarachnoid haemorrhages
6
Subdural haemorrhages
138.8 (2)
Plasma potasium (mEq/l)
23/5/8
CT Findings (n) Epidural haematoma
Plasma sodium (mEq/l)
7.7 (6.3)
421 (30.4)
4.2 (2.3)
6
Inotropic support (yes/no)
5/31
Mechanical ventilation (yes/no)
14/22
Neurosurgical intervention (yes/no)b
9/27
Induced-coma (yes/no)
2/34
GOS (5/4/3)c
31/3/2
a
The child older than 15 was a diabetic patient previously controlled in our department
b
Reconstructive surgery is not included
c
5, good recovery; 4, moderate disability; 3, severe disability
% Normal levels Somatotropic axis IGF-1 (ng/ml) (normal levels: [2.5th centile)
88.9 %
IGF-BP3 (lg/ml) (normal levels: [5th centile)
100 %
Mean (SD) Adrenal axis Basal cortisol (lg/dl)
12.03 (5.2)
ACTH (pg/ml)
22.37 (14.52)
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attributed to other causes (malnutrition, liver disease, diabetes or hypothyroidism). IGF BP3 levels were within the normal range. These patients were reassessed 1 year later and they all showed spontaneous increase of IGF 1 levels, normal height velocity (above the 25th centile) and bone age similar to chronological age. Insulin tolerance test was undertaken on two asymptomatic patients who had low morning cortisol levels with inappropriately normal ACTH concentrations. One of them had a suboptimal cortisol response to hypoglycaemia. Unfortunately, he was receiving inhaled corticosteroids at that moment; for that reason the test was probably inaccurate. Once he was off treatment, basal levels of cortisol and ACTH were both within the reference ranges, which makes adrenal insufficiency unlikely.
Discussion We did not observe any TBI-related endocrine disorder in our cohort. This result differs from some previously published studies in children and adults that report variable frequency of TBI-induced endocrinopathies [5–16, 18–21]. Below, we analyse the factors that may affect these different results, including the study design, the type and severity of TBI or the variations in testing methods and cut off diagnostic criteria. Most of the studies published are retrospective or crosssectional; ours was a cross-sectional study with a time range from injury to assessment of 1.3–5.8 years. Longitudinal studies in children and adults have demonstrated that most pituitary abnormalities resolve by 1 year [24] or between 1 and 3 years after TBI [11]. Norwood et al. observed GHD in 16 % of patients, but the interval between injury and testing in this group was significantly lower than in patients without GHD; therefore, these disorders might be transient. Lorenzo et al. [28] proposed screening of pituitary function at least 1 year post-TBI, especially for hormones that do not need to be urgently replaced (GH, sexual hormones). With regard to our study, the minimum time interval since injury was 1.3 years; hence we may have missed some transient hormone deficiency. However, all of our children were asymptomatic, had normal height and none of them showed growth impairment after TBI assessed by comparison between height at assessment and pre-injury height. The association between TBI severity and pituitary dysfunction has been observed in some studies [5, 14]. However, it has not been confirmed in the paediatric population [18, 19, 21, 23, 24]. Our selection criteria did not include GCS score but admission to PICU and abnormal CT scan. The GCS score has some limitations as the
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time between injury and GCS grading is highly variable, inter observer reliability is weak and is poorly applicable in young children [29, 30]. The fact that teenagers aged over 14 years were not included in our cohort may have had some influence on the results as this population is at higher risk of head injury, usually caused by contact sports or traffic accidents [31]. Traffic accidents are frequently associated with polytrauma [32] and with higher risk of hypovolemic shock and impairment of cerebral blood flow. The disparities between paediatric and adult outcomes may also be due to a greater neuroplasticity in children during recovery from injury and to the differences in the cerebral flow regulatory mechanisms. It is possible that pituitary gland in children is less vulnerable to injury because of a more accurate auto-regulation of the cerebral blood flow and a less susceptibility to cerebral blood flow oscillations [33]. In contrast to other paediatric studies [19, 21, 23, 24], we did not perform stimulation tests unless there was a low baseline hormone level or clinical findings suggestive of endocrine dysfunction, according to the consensus guidelines on the assessment of pituitary function following TBI in adults [17]. Interestingly, higher prevalence of hypopituitarism, even if not always clinically relevant, was observed in those studies in which provocative tests were performed in all subjects [19, 21, 23, 24]. Similarly to our study, Moon et al. did not perform dynamic tests routinely and found just one case of possible delayed puberty. In our study, all the patients’ heights were within the normal range and there was no evidence of growth impairment after TBI. Only four of our patients had initial low serum basal IGF 1 levels with IGF BP3 levels within the normal range. Instead of performing provocative tests directly, we decided to monitor their growth, repeat the IGF 1 levels and evaluate their bone age. No GH stimulation tests were performed in these patients as the height velocity and IGF 1 levels were subsequently within the normal ranges. The methodological variations between the different studies make it difficult to compare the results. TBI-related GHD has been the most frequently reported endocrine dysfunction in adults and children [5, 6, 11, 12, 18, 19]. Various different tests have been used to assess the somatotropic axis in paediatric studies and with different cut off values for diagnosis [19–21, 23]. A variety of stimuli has also been used to assess the adrenal function in the paediatric population. Glucagon and low-dose ACTH tests are known to cause false-positive results and should, therefore, be followed by additional tests. Insulin tolerance test is considered to be the gold standard test [34]. We did not find any evidence of adrenal insufficiency or precocious puberty in our cohort. As the majority of
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children were pre-pubertal (80 %), we advised families to pay special attention to their pubertal development. In conclusion, no TBI-related endocrine disorder was identified in our cohort. Therefore, the routine evaluation of pituitary function after mild to moderated head trauma in children might not be justified according to our findings. It is reassuring that in the short-middle term after such a life-threatening event, we have not found any endocrine sequelae amongst participants. However, we consider that general paediatricians and primary care health workers should be aware of this potential complication and monitor thoroughly and systematically the growth and pubertal development in this group of patients. We believe that the invasive and expensive tests required to assess the pituitary function are not routinely justified in these patients. However, they should be prospectively followed up as symptoms of pituitary deficiencies may be non-specific and could overlap with the sequelae after TBI. Acknowledgments The authors thank Paloma Jime´nez for her excellent technical assistance, Dr Maria Angeles Aniel-Quiroga for her technical support and advice and Dr Pedro Martul for his expertise and very helpful comments on the manuscript. Conflict of interest The authors M.A. Salomo´n-Este´banez, G. Grau, A. Vela, A. Rodrı´guez, E. Morteruel, L. Castan˜o, and I. Rica declare that they have no conflict of interest.
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ORIGINAL ARTICLE
Is routine endocrine evaluation necessary after paediatric traumatic brain injury? M. A. Salomo´n-Este´banez • G. Grau • A. Vela • A. Rodrı´guez • E. Morteruel L. Castan˜o • I. Rica
•
Received: 22 July 2013 / Accepted: 17 November 2013 / Published online: 9 January 2014 Ó Italian Society of Endocrinology (SIE) 2013
Abstract Background Traumatic brain injury (TBI) is a common event in childhood. It is a recognised cause of hypopituitarism both in adult and paediatric patients. Routine endocrine evaluation has been proposed for adult TBIsurvivors; nevertheless, incongruous data have been reported in children. Aim The goal of this study was to describe the prevalence of pituitary dysfunction after TBI in a cohort of children. Material/subjects and methods This is a cross-sectional study comprising retrospective medical record review and prospective testing. Children with brain injury discharged from the Paediatric Intensive Care Unit from year 2004 to 2009 were recruited. Height and weight were recorded, systemic examination was performed and baseline pituitary function tests were undertaken. Provocative tests were performed only if abnormal basal levels were detected. M. A. Salomo´n-Este´banez G. Grau A. Vela A. Rodrı´guez I. Rica (&) Department of Paediatric Endocrinology, Cruces University Hospital, Plaza de Cruces s/n, 48903 Barakaldo, Biscay, Spain e-mail: [email protected] A. Vela L. Castan˜o CIBERER: Centre for Biomedical Network Research on Rare Diseases, Valencia, Spain
Results Thirty-six patients were collected; the mean age at assessment was 7.2 years and the mean interval since injury 3.3 years. All patients had skull fracture or intracranial haemorrhage; 36.6 % of them had moderate to severe TBI. No abnormalities were found on examination. Low serum IGF 1 levels were detected in four patients and two patients had low serum cortisol levels with inappropriately normal plasma ACTH concentrations. No evidence of pituitary dysfunction was observed in these patients after clinical follow-up, repeated baseline hormone levels or dynamic function tests. Conclusions No endocrine sequelae have been detected in this population. The routine endocrine evaluation in children with mild to moderate TBI might not be justified, according to our findings. Keywords Hypopituitarism Traumatic brain injury Children Pituitary gland Endocrine investigations Abbreviations TBI Traumatic brain injury PICU Paediatric Intensive Care Unit GHD Growth hormone deficiency CT Computed tomography GCS Glasgow Coma Scale SDS Standard deviation score
E. Morteruel Paediatric Intensive Care Unit, Cruces University Hospital, Barakaldo, Biscay, Spain L. Castan˜o Endocrinology and Diabetes Research Group, Cruces University Hospital, Barakaldo, Biscay, Spain L. Castan˜o I. Rica CIBERDEM: Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders, Barcelona, Spain
Introduction Hypopituitarism after traumatic brain injury (TBI) was first described in 1918 [1]. In 1942, Escamilla et al. [2] reported that head trauma accounted for pituitary dysfunction in 4 of 595 patients (0.7 %). By 1986 only 53 cases of TBI-
123
144
induced endocrinopathies had been published [3]. In 2000, Benvenga et al. [4] collected 367 cases of hypopituitarism following TBI from the international literature and since then brain trauma has been considered as one of the major causes of pituitary dysfunction. In adults, pituitary abnormalities in at least one axis have been reported in 15–90 % of TBI survivors [5–16], not only in the acute phase but also as a long-term complication. Growth hormone deficiency (GHD) appears to be the most common disorder [5, 6, 11, 12]. Follow-up and endocrine assessment have been proposed after head trauma in adult patients [17] and, although TBI is a recognised cause of childhood pituitary dysfunction, there is currently scarce evidence to support such approach in paediatric population. Several studies have been carried out in children [18–24], with a variable prevalence of pituitary abnormalities (5–61 %). The results of these publications differ depending on the population studied, the severity of the head injury, the time interval between head injury and assessment and the testing methods used to assess the endocrine function. Einaudi et al. [18] studied pituitary function both retrospectively and prospectively in 48 survivors of childhood TBI and demonstrated 10 % hypothalamic—pituitary dysfunction at 12 months. Niederland et al. [19] did cross-sectional study of 26 patients at 30 ± 8 months after head trauma and detected pituitary disorders in 61 %; most of them had insufficient growth hormone (GH) response to stimulation tests. Poomthavorn et al. [20] included 54 patients in their cross-sectional study and reported pituitary dysfunction in 17 % of patients. Norwood et al. [21] retrospectively recruited 32 patients and found GHD in 16 % of their participants. These four studies support the use of routine endocrine evaluation of children following TBI. However, in 2010, two cross-sectional studies reported no clinically significant endocrinopathy amongst childhood TBI survivors [22, 23]. The prospective study by Kaulfers et al. showed that many of the pituitary abnormalities found in the first months after TBI were transient. They evaluated 31 children; the incidence of pituitary dysfunction was 15 % at 1 month, 75 % at 6 months and 29 % at 12 months after injury [24]. In view of these highly variable results, we aimed to evaluate the prevalence of pituitary dysfunction among a cohort of paediatric TBI survivors and also to investigate any relationship between severity of TBI and endocrine involvement.
Patients and methods Patients The study population comprised patients with TBI admitted to the Paediatric Intensive Care Unit (PICU) at the
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J Endocrinol Invest (2014) 37:143–148
Cruces University Hospital (Biscay, Spain) between January 2004 and December 2009. Subjects were identified from the PICU admissions database. Inclusion criteria were evidence of skull fracture or brain injury in the cranial computed tomography (CT), age \14 years old at the time of the study and having been discharged alive from hospital.
Methods Eligible patients’ families were contacted by telephone; patients and parents were informed about the study and were invited to participate. After agreeing to take part in the study, informed consent was obtained. The following information was extracted from the patients’ medical records: date of birth, date of injury, sex, mechanism of injury, first documented Glasgow Coma Scale (GSS) score, CT findings, duration of PICU admission, need for inotropic support, mechanical ventilation, neurosurgical intervention or barbiturate-induced coma. Mild, moderate or severe TBI were defined, respectively, as head trauma with GCS scores of 13–15, 9–12 and \9. The functional outcome and disabilities after TBI were evaluated at the time of the study using the Glasgow Outcome Scale (GOS) that is a 5-level score: 5, capacity to resume normal activity; 4, moderate disability but the ability to live independently; 3, severe disability requiring assistance with activities of daily living; 2, vegetative state; 1, death. Subjects were assessed in the Paediatric Endocrinology Outpatient Department. A medical history was taken, children and their families were asked about symptoms related to pituitary dysfunction and a full clinical examination was performed evaluating weight, height and pubertal development. Anthropometric data were expressed as standard deviation scores (SDS) for age and sex using the local growth charts [25], and pubertal staging was assessed according to Tanner’s criteria [26]. Pre-injury height and weight were obtained from record review or primary care charts. Precocious puberty was considered if there were signs of pubertal development before age 8 in girls and age 9 in boys. Basal serum hormone levels were analysed to determine free thyroxine (fT4), thyroid stimulating hormone (TSH), prolactin, cortisol, oestradiol (female patients), testosterone (male patients), luteinizing hormone (LH), follicle-stimulating hormone (FSH), insulin-like growth factor-1 (IGF 1) and insulin-like growth factor binding protein-3 (IGF BP3). Adrenocorticotropic hormone (ACTH) levels were analysed in plasma. Serum electrolytes were analysed as well as urine and serum osmolality. Blood samples were collected in the morning, as early as possible.
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Provocative tests were performed in patients with endocrine symptoms or in those whose basal hormone levels were abnormal. All hormone assays were performed using chemiluminescent immunometric methods. FSH, LH, TSH, fT4, prolactin, oestradiol and testosterone were measured by the ADVIA Centaur analyzer (Siemens Medical Diagnostics). ACTH and cortisol were measured using LiaisonÒ DiaSorin’s automated assay. IGF 1 and IGF BP3 were determined by the IMMULITE 2000 analyzer. IGF 1 and IGF BP3 levels were interpreted according to the age reference ranges determined for the IMMULITE IGF I and IGF BP3 assays [27].
Results Seventy-four children with TBI were admitted to PICU during the years 2004–2009 and 58 of them met the eligible criteria. Twenty-two subjects were not contactable or declined to participate. Thirty-six patients agreed to enter the study (61.1 % male). The mean age at injury was 3.8 years and the mean time interval between head trauma and endocrine assessment was 3.3 years. Falls were the leading cause of TBI,
the majority of the brain injuries were mild and the head CT scan showed lesions in all cases. Further clinical details are summarised in Table 1. We did not find any statistically significant differences between recruited and nonrecruited patients in terms of age, severity, duration of PICU admission and CT findings. No abnormalities were found in the physical examination: the mean height SDS was -0.18 ± 0.9 and the mean weight SDS 0.1 ± 1.2. No precocious puberty was observed. Pituitary function results are shown in Table 2. There was no clinical evidence of posterior pituitary dysfunction. Serum basal prolactin levels were within the reference range in all patients. Thirty-five children had serum free T4 and TSH concentrations within the reference ranges. One of 36 patients was diagnosed of autoimmune hypothyroidism. Serum basal oestradiol or testosterone, LH and FSH were appropriate for age, sex and pubertal stage in all subjects. Six children required further investigation to exclude adrenal or somatotropic axes dysfunction. In four of them, serum IGF 1 levels were below the 2.5th centile, not Table 2 Pituitary function results Mean (SD)
Table 1 Clinical characteristics of participants
Posterior pituitary function, lactotropic and thyroid axes
Patients Age at injury, years (mean [range])
3.8 [0.1–12.7]
Age at study, years (mean [range])
7.2 [2.7–15.1a]
Mechanism of injury (n) Falls
24
Traffic accidents Impacts (struck by objects)
7 3
Sport injuries
2
TBI severity (mild/moderate/severe)
Intracerebral haemorrhages or contusion
4.5 (0.5)
Plasma osmolality (mOsm/l)
283 (5.5)
Urine osmolality (mOsm/l)
888 (217)
Prolactin (ng/ml)
9.8 (6.6)
Free T4 (ng/dl)
1.2 (0.15)
TSH (mU/ml)
3.7 (4.3) Pre-puertal (n = 27) Mean (SD)
Pubertal (n = 9) Mean (SD)
Gonadal axis
10
Testosterone (ng/dl)
8
Oestradiol (pg/ml)
19.4 (2.8)
59 (34.2)
LH (mU/ml)
0.97 (0.6)
4.2 (2)
FSH (mU/ml)
1.7 (1)
Skull fracture/sinking
6
Subarachnoid haemorrhages
6
Subdural haemorrhages
138.8 (2)
Plasma potasium (mEq/l)
23/5/8
CT Findings (n) Epidural haematoma
Plasma sodium (mEq/l)
7.7 (6.3)
421 (30.4)
4.2 (2.3)
6
Inotropic support (yes/no)
5/31
Mechanical ventilation (yes/no)
14/22
Neurosurgical intervention (yes/no)b
9/27
Induced-coma (yes/no)
2/34
GOS (5/4/3)c
31/3/2
a
The child older than 15 was a diabetic patient previously controlled in our department
b
Reconstructive surgery is not included
c
5, good recovery; 4, moderate disability; 3, severe disability
% Normal levels Somatotropic axis IGF-1 (ng/ml) (normal levels: [2.5th centile)
88.9 %
IGF-BP3 (lg/ml) (normal levels: [5th centile)
100 %
Mean (SD) Adrenal axis Basal cortisol (lg/dl)
12.03 (5.2)
ACTH (pg/ml)
22.37 (14.52)
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attributed to other causes (malnutrition, liver disease, diabetes or hypothyroidism). IGF BP3 levels were within the normal range. These patients were reassessed 1 year later and they all showed spontaneous increase of IGF 1 levels, normal height velocity (above the 25th centile) and bone age similar to chronological age. Insulin tolerance test was undertaken on two asymptomatic patients who had low morning cortisol levels with inappropriately normal ACTH concentrations. One of them had a suboptimal cortisol response to hypoglycaemia. Unfortunately, he was receiving inhaled corticosteroids at that moment; for that reason the test was probably inaccurate. Once he was off treatment, basal levels of cortisol and ACTH were both within the reference ranges, which makes adrenal insufficiency unlikely.
Discussion We did not observe any TBI-related endocrine disorder in our cohort. This result differs from some previously published studies in children and adults that report variable frequency of TBI-induced endocrinopathies [5–16, 18–21]. Below, we analyse the factors that may affect these different results, including the study design, the type and severity of TBI or the variations in testing methods and cut off diagnostic criteria. Most of the studies published are retrospective or crosssectional; ours was a cross-sectional study with a time range from injury to assessment of 1.3–5.8 years. Longitudinal studies in children and adults have demonstrated that most pituitary abnormalities resolve by 1 year [24] or between 1 and 3 years after TBI [11]. Norwood et al. observed GHD in 16 % of patients, but the interval between injury and testing in this group was significantly lower than in patients without GHD; therefore, these disorders might be transient. Lorenzo et al. [28] proposed screening of pituitary function at least 1 year post-TBI, especially for hormones that do not need to be urgently replaced (GH, sexual hormones). With regard to our study, the minimum time interval since injury was 1.3 years; hence we may have missed some transient hormone deficiency. However, all of our children were asymptomatic, had normal height and none of them showed growth impairment after TBI assessed by comparison between height at assessment and pre-injury height. The association between TBI severity and pituitary dysfunction has been observed in some studies [5, 14]. However, it has not been confirmed in the paediatric population [18, 19, 21, 23, 24]. Our selection criteria did not include GCS score but admission to PICU and abnormal CT scan. The GCS score has some limitations as the
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time between injury and GCS grading is highly variable, inter observer reliability is weak and is poorly applicable in young children [29, 30]. The fact that teenagers aged over 14 years were not included in our cohort may have had some influence on the results as this population is at higher risk of head injury, usually caused by contact sports or traffic accidents [31]. Traffic accidents are frequently associated with polytrauma [32] and with higher risk of hypovolemic shock and impairment of cerebral blood flow. The disparities between paediatric and adult outcomes may also be due to a greater neuroplasticity in children during recovery from injury and to the differences in the cerebral flow regulatory mechanisms. It is possible that pituitary gland in children is less vulnerable to injury because of a more accurate auto-regulation of the cerebral blood flow and a less susceptibility to cerebral blood flow oscillations [33]. In contrast to other paediatric studies [19, 21, 23, 24], we did not perform stimulation tests unless there was a low baseline hormone level or clinical findings suggestive of endocrine dysfunction, according to the consensus guidelines on the assessment of pituitary function following TBI in adults [17]. Interestingly, higher prevalence of hypopituitarism, even if not always clinically relevant, was observed in those studies in which provocative tests were performed in all subjects [19, 21, 23, 24]. Similarly to our study, Moon et al. did not perform dynamic tests routinely and found just one case of possible delayed puberty. In our study, all the patients’ heights were within the normal range and there was no evidence of growth impairment after TBI. Only four of our patients had initial low serum basal IGF 1 levels with IGF BP3 levels within the normal range. Instead of performing provocative tests directly, we decided to monitor their growth, repeat the IGF 1 levels and evaluate their bone age. No GH stimulation tests were performed in these patients as the height velocity and IGF 1 levels were subsequently within the normal ranges. The methodological variations between the different studies make it difficult to compare the results. TBI-related GHD has been the most frequently reported endocrine dysfunction in adults and children [5, 6, 11, 12, 18, 19]. Various different tests have been used to assess the somatotropic axis in paediatric studies and with different cut off values for diagnosis [19–21, 23]. A variety of stimuli has also been used to assess the adrenal function in the paediatric population. Glucagon and low-dose ACTH tests are known to cause false-positive results and should, therefore, be followed by additional tests. Insulin tolerance test is considered to be the gold standard test [34]. We did not find any evidence of adrenal insufficiency or precocious puberty in our cohort. As the majority of
J Endocrinol Invest (2014) 37:143–148
children were pre-pubertal (80 %), we advised families to pay special attention to their pubertal development. In conclusion, no TBI-related endocrine disorder was identified in our cohort. Therefore, the routine evaluation of pituitary function after mild to moderated head trauma in children might not be justified according to our findings. It is reassuring that in the short-middle term after such a life-threatening event, we have not found any endocrine sequelae amongst participants. However, we consider that general paediatricians and primary care health workers should be aware of this potential complication and monitor thoroughly and systematically the growth and pubertal development in this group of patients. We believe that the invasive and expensive tests required to assess the pituitary function are not routinely justified in these patients. However, they should be prospectively followed up as symptoms of pituitary deficiencies may be non-specific and could overlap with the sequelae after TBI. Acknowledgments The authors thank Paloma Jime´nez for her excellent technical assistance, Dr Maria Angeles Aniel-Quiroga for her technical support and advice and Dr Pedro Martul for his expertise and very helpful comments on the manuscript. Conflict of interest The authors M.A. Salomo´n-Este´banez, G. Grau, A. Vela, A. Rodrı´guez, E. Morteruel, L. Castan˜o, and I. Rica declare that they have no conflict of interest.
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