Clinical Endocrinology (2015) 82, 115–121
doi: 10.1111/cen.12533
ORIGINAL ARTICLE
Chronic hypopituitarism is uncommon in survivors of aneurysmal subarachnoid haemorrhage M. J. Hannon*, L. A. Behan*, M. M. O’Brien*, W. Tormey†, M. Javadpour‡, M. Sherlock*,§ and C. J. Thompson* *Academic Department of Endocrinology, Beaumont Hospital/RCSI Medical School, †Academic Department of Chemical Pathology, Beaumont Hospital/RCSI Medical School, ‡The National Neurosurgical Centre, Beaumont Hospital/RCSI Medical School and §Department of Endocrinology, Adelaide and Meath Hospital/Trinity College Dublin Medical School, Dublin, Ireland
Summary Objective The incidence of hypopituitarism after aneurysmal subarachnoid haemorrhage (SAH) is unclear from the conflicting reports in the literature. As routine neuroendocrine screening for hypopituitarism for all patients would be costly and logistically difficult, there is a need for precise data on the frequency of hypopituitarism and on factors which might predict the later development of pituitary dysfunction. We aimed to: (i) Establish the incidence of long-term hypopituitarism in patients with aneurysmal SAH. (ii) Determine whether data from patients’ acute admission with SAH could predict the occurrence of long-term hypopituitarism. Design One hundred patients were studied prospectively from the time of presentation with acute SAH. Plasma cortisol, plasma sodium and a variety of clinical and haemodynamic parameters were sequentially measured for the first 12 days of their acute admission. Forty-one patients then underwent dynamic pituitary testing at median 15 months following SAH (range 7–30 months), with insulin tolerance test (ITT) or, if contraindicated, a glucagon stimulation test (GST) plus short synacthen test (SST). If symptoms of cranial diabetes insipidus (CDI) were present, a water deprivation test was also performed. Results Forty-one patients attended for follow-up dynamic pituitary testing. Although 14 of 100 had acute glucocorticoid deficiency immediately following SAH, only two of 41 had longterm adrenocorticotrophic hormone (ACTH) deficiency and four of 41 had growth hormone (GH) deficiency. None were hypothyroid or gonadotrophin deficient. None had chronic CDI or hyponatraemia. There was no association between acute glucocorticoid deficiency, acute CDI or acute hyponatraemia and long-term pituitary dysfunction. Conclusion Both anterior and posterior hypopituitarism are very uncommon following SAH and are not predicted by acute clinical, haemodynamic or endocrinological parameters. Routine neuroendocrine screening is not justified in SAH patients. Correspondence: Mark J. Hannon, Academic Department of Endocrinology, Beaumont Hospital, Beaumont Road, Dublin 9, Ireland. Tel.: +353 (1) 8092377; E-mail: [email protected] © 2014 John Wiley & Sons Ltd
(Received 11 April 2014; returned for revision 4 June 2014; finally revised 11 June 2014; accepted 19 June 2014)
Introduction Subarachnoid haemorrhage (SAH) is known to cause long-term hypopituitarism.1,2 However, the rates of long-term hypopituitarism reported following SAH vary widely between the six major studies performed to date.2–7 Over the last 5 years, a growing evidence base has emerged to show that pituitary dysfunction may occur acutely following cerebral insult.2,8,9 Data from our own group have revealed a high incidence of hyponatraemia following SAH, with a lower incidence of acute glucocorticoid insufficiency and cranial diabetes insipidus (CDI).10 However, there are very few studies to date linking the presence of acute pituitary dysfunction to the development of long-term hypopituitarism. The only large study to examine a cohort with SAH both acutely and chronically following SAH found little evidence of chronic hypopituitarism, even in those with previous acute pituitary insufficiency.2 Given that long-standing hypopituitarism can have adverse effects on patient morbidity and mortality,11,12 hormone replacement therapy may improve the patient’s clinical course. However, previous research has emphasized that the time of onset of hypopituitarism and the number of deficits in pituitary function detected are highly variable following insults such as traumatic brain injury (TBI);5,13–15 if this were also the case following SAH, it would effectively mean that permanent hormonal changes may only be identified by systematic screening 4–6 months after insult, which has significant economic implications. Also, screening for permanent hypopituitarism following SAH is logistically difficult as patient numbers are very large, and there are no guidelines in the existing literature which accurately predict those at high risk of development of long-term pituitary insufficiencies. Furthermore, although studies on TBI patients have suggested that follow-up dynamic pituitary testing be performed on those patients with acute hypocortisolaemia,16 acute CDI,16 more severe TBI, basal skull fracture or diffuse axonal injury,17–19 no 115
116 M. J. Hannon et al. such evidence base exists for SAH. On the basis of clinical observations, we hypothesized that the true incidence of long-term hypopituitarism following SAH is lower than that for TBI. We also hypothesized that sequential endocrinological, clinical and haemodynamic data from patients with acute SAH10 may help to predict those who will develop chronic hypopituitarism and therefore, make selective screening for post-SAH hypopituitarism logistically and economically viable. To investigate these hypotheses, we aimed to: • Establish the true incidence of long-term anterior and posterior hypopituitarism in a cohort of survivors of acute aneurysmal SAH. • Determine the clinical and endocrinological data from the patients’ acute admissions which could be used to predict the incidence of long-term hypopituitarism.
Methods One hundred patients with acute aneurysmal SAH were recruited on admission to hospital. The details of the study design have been previously described.10 Our centre is the national referral centre for neurosurgical disease in Ireland, with a catchment area of 458 million people. Aneurysmal SAH was confirmed by the presence of blood on computerized tomography (CT) scan of brain or on cerebrospinal fluid (CSF) analysis, with the presence of a cerebral aneurysm on CT angiography or catheter cerebral angiography. Those patients aged under 18, pregnant and lactating females, those hyponatraemic on admission, those with a history of arteriovenous malformation, previous intracerebral insult or endocrinopathy were excluded. Those currently on corticosteroids and those on corticosteroids at any time in the 3 months preceding admission were excluded. Patients on medications known to cause hyponatraemia, such as thiazide diuretics or selective serotonin reuptake inhibitors (SSRIs) were not excluded, once sodium level was normal on admission. The precise methods utilized to examine patients’ acute anterior and posterior pituitary function following admission are outlined in our previous publication of these data.10 Those with persistent glucocorticoid insufficiency or CDI following SAH were discharged on hydrocortisone therapy or dDAVP therapy, respectively, as outlined in our group’s previous publication.10 All patients with SAH who survived to discharge from our centre were invited for dynamic anterior pituitary testing at least 6 months following their admission with SAH. Similar exclusion criteria applied to the follow-up study as the acute study. Detailed history and clinical examination were performed when patients returned for dynamic pituitary testing. Baseline blood tests including plasma sodium were obtained. Our first line dynamic pituitary test was the insulin tolerance test,20 which involves the measurement of serum cortisol and serum growth hormone (GH) before and at 15, 30, 45, 60, 90 and 120 min after the intravenous administration of 01–015 U/kg of actrapid insulin (Novo Nordisk, Bagsvaerd, Denmark), to induce a plasma glucose nadir of
doi: 10.1111/cen.12533
ORIGINAL ARTICLE
Chronic hypopituitarism is uncommon in survivors of aneurysmal subarachnoid haemorrhage M. J. Hannon*, L. A. Behan*, M. M. O’Brien*, W. Tormey†, M. Javadpour‡, M. Sherlock*,§ and C. J. Thompson* *Academic Department of Endocrinology, Beaumont Hospital/RCSI Medical School, †Academic Department of Chemical Pathology, Beaumont Hospital/RCSI Medical School, ‡The National Neurosurgical Centre, Beaumont Hospital/RCSI Medical School and §Department of Endocrinology, Adelaide and Meath Hospital/Trinity College Dublin Medical School, Dublin, Ireland
Summary Objective The incidence of hypopituitarism after aneurysmal subarachnoid haemorrhage (SAH) is unclear from the conflicting reports in the literature. As routine neuroendocrine screening for hypopituitarism for all patients would be costly and logistically difficult, there is a need for precise data on the frequency of hypopituitarism and on factors which might predict the later development of pituitary dysfunction. We aimed to: (i) Establish the incidence of long-term hypopituitarism in patients with aneurysmal SAH. (ii) Determine whether data from patients’ acute admission with SAH could predict the occurrence of long-term hypopituitarism. Design One hundred patients were studied prospectively from the time of presentation with acute SAH. Plasma cortisol, plasma sodium and a variety of clinical and haemodynamic parameters were sequentially measured for the first 12 days of their acute admission. Forty-one patients then underwent dynamic pituitary testing at median 15 months following SAH (range 7–30 months), with insulin tolerance test (ITT) or, if contraindicated, a glucagon stimulation test (GST) plus short synacthen test (SST). If symptoms of cranial diabetes insipidus (CDI) were present, a water deprivation test was also performed. Results Forty-one patients attended for follow-up dynamic pituitary testing. Although 14 of 100 had acute glucocorticoid deficiency immediately following SAH, only two of 41 had longterm adrenocorticotrophic hormone (ACTH) deficiency and four of 41 had growth hormone (GH) deficiency. None were hypothyroid or gonadotrophin deficient. None had chronic CDI or hyponatraemia. There was no association between acute glucocorticoid deficiency, acute CDI or acute hyponatraemia and long-term pituitary dysfunction. Conclusion Both anterior and posterior hypopituitarism are very uncommon following SAH and are not predicted by acute clinical, haemodynamic or endocrinological parameters. Routine neuroendocrine screening is not justified in SAH patients. Correspondence: Mark J. Hannon, Academic Department of Endocrinology, Beaumont Hospital, Beaumont Road, Dublin 9, Ireland. Tel.: +353 (1) 8092377; E-mail: [email protected] © 2014 John Wiley & Sons Ltd
(Received 11 April 2014; returned for revision 4 June 2014; finally revised 11 June 2014; accepted 19 June 2014)
Introduction Subarachnoid haemorrhage (SAH) is known to cause long-term hypopituitarism.1,2 However, the rates of long-term hypopituitarism reported following SAH vary widely between the six major studies performed to date.2–7 Over the last 5 years, a growing evidence base has emerged to show that pituitary dysfunction may occur acutely following cerebral insult.2,8,9 Data from our own group have revealed a high incidence of hyponatraemia following SAH, with a lower incidence of acute glucocorticoid insufficiency and cranial diabetes insipidus (CDI).10 However, there are very few studies to date linking the presence of acute pituitary dysfunction to the development of long-term hypopituitarism. The only large study to examine a cohort with SAH both acutely and chronically following SAH found little evidence of chronic hypopituitarism, even in those with previous acute pituitary insufficiency.2 Given that long-standing hypopituitarism can have adverse effects on patient morbidity and mortality,11,12 hormone replacement therapy may improve the patient’s clinical course. However, previous research has emphasized that the time of onset of hypopituitarism and the number of deficits in pituitary function detected are highly variable following insults such as traumatic brain injury (TBI);5,13–15 if this were also the case following SAH, it would effectively mean that permanent hormonal changes may only be identified by systematic screening 4–6 months after insult, which has significant economic implications. Also, screening for permanent hypopituitarism following SAH is logistically difficult as patient numbers are very large, and there are no guidelines in the existing literature which accurately predict those at high risk of development of long-term pituitary insufficiencies. Furthermore, although studies on TBI patients have suggested that follow-up dynamic pituitary testing be performed on those patients with acute hypocortisolaemia,16 acute CDI,16 more severe TBI, basal skull fracture or diffuse axonal injury,17–19 no 115
116 M. J. Hannon et al. such evidence base exists for SAH. On the basis of clinical observations, we hypothesized that the true incidence of long-term hypopituitarism following SAH is lower than that for TBI. We also hypothesized that sequential endocrinological, clinical and haemodynamic data from patients with acute SAH10 may help to predict those who will develop chronic hypopituitarism and therefore, make selective screening for post-SAH hypopituitarism logistically and economically viable. To investigate these hypotheses, we aimed to: • Establish the true incidence of long-term anterior and posterior hypopituitarism in a cohort of survivors of acute aneurysmal SAH. • Determine the clinical and endocrinological data from the patients’ acute admissions which could be used to predict the incidence of long-term hypopituitarism.
Methods One hundred patients with acute aneurysmal SAH were recruited on admission to hospital. The details of the study design have been previously described.10 Our centre is the national referral centre for neurosurgical disease in Ireland, with a catchment area of 458 million people. Aneurysmal SAH was confirmed by the presence of blood on computerized tomography (CT) scan of brain or on cerebrospinal fluid (CSF) analysis, with the presence of a cerebral aneurysm on CT angiography or catheter cerebral angiography. Those patients aged under 18, pregnant and lactating females, those hyponatraemic on admission, those with a history of arteriovenous malformation, previous intracerebral insult or endocrinopathy were excluded. Those currently on corticosteroids and those on corticosteroids at any time in the 3 months preceding admission were excluded. Patients on medications known to cause hyponatraemia, such as thiazide diuretics or selective serotonin reuptake inhibitors (SSRIs) were not excluded, once sodium level was normal on admission. The precise methods utilized to examine patients’ acute anterior and posterior pituitary function following admission are outlined in our previous publication of these data.10 Those with persistent glucocorticoid insufficiency or CDI following SAH were discharged on hydrocortisone therapy or dDAVP therapy, respectively, as outlined in our group’s previous publication.10 All patients with SAH who survived to discharge from our centre were invited for dynamic anterior pituitary testing at least 6 months following their admission with SAH. Similar exclusion criteria applied to the follow-up study as the acute study. Detailed history and clinical examination were performed when patients returned for dynamic pituitary testing. Baseline blood tests including plasma sodium were obtained. Our first line dynamic pituitary test was the insulin tolerance test,20 which involves the measurement of serum cortisol and serum growth hormone (GH) before and at 15, 30, 45, 60, 90 and 120 min after the intravenous administration of 01–015 U/kg of actrapid insulin (Novo Nordisk, Bagsvaerd, Denmark), to induce a plasma glucose nadir of
