Neuropeptides 48 (2014) 91–96

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Vasopressin and oxytocin in CSF and plasma of patients with aneurysmal subarachnoid haemorrhage Jan Martin a,⇑, Simone M. Kagerbauer a, Tibor Schuster b, Manfred Blobner a, Eberhard F. Kochs a, Rainer Landgraf c a b c

Klinik für Anaesthesiologie, Technische Universität München, Klinikum rechts der Isar, Ismaninger Strasse 22, 81675 München, Germany Institut für Medizinische Statistik und Epidemiologie, Technische Universität München, Klinikum rechts der Isar, Ismaninger Strasse 22, 81675 München, Germany Max-Planck-Institut für Psychiatrie, Kraepelinstrasse 2, 80804 München, Germany

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Article history: Received 23 May 2013 Accepted 23 December 2013 Available online 3 January 2014 Keywords: Vasopressin Oxytocin CSF Plasma Aneurysmal Subarachnoid Haemorrhage

a b s t r a c t Objective: Clinicopathological studies on patients succumbing to subarachnoid haemorrhage (SAH) demonstrated hypothalamic lesions. The implication of the hypothalamic neuropeptides arginine-vasopressin (AVP) and oxytocin (OXT) has not been linked to aneurysmal SAH yet. This study investigates AVP and OXT in CSF and plasma of patients with spontaneous aneurysmal SAH and their association with outcome. Methods: CSF and plasma samples of 12 patients with aneurysmal SAH were prospectively studied for 2 weeks. AVP and OXT were measured by radioimmunoassay. Outcome was assessed on Glasgow-Outcome-Scale. Twenty-nine patients without neuropsychiatric disturbances served as controls. Differences in neuropeptide concentration time courses were assessed by regression models. Group comparisons were performed by Kruskal–Wallis and correlations by Spearman tests. Results: Regression of CSF levels between patients with poor and good outcome revealed significantly lower levels of AVP in patients with poor outcome (p = 0.012) while OXT showed a trend towards lower levels (p = 0.063). In plasma, no significant differences between outcome groups were found. Group comparisons between poor outcome patients and controls revealed significant differences in CSF for AVP (p = 0.001) and OXT (p = 0.015). In plasma, AVP yielded significantly different results while OXT did not. No differences were found between the good outcome group and controls. Plasma and CSF concentrations showed no significant correlation. Conclusion: Patients with poor outcome after aneurysmal SAH have lower AVP and OXT levels in CSF than patients with good outcome while neuropeptide levels in plasma failed to reflect differences in outcome. The data indicate hypothalamic damage as an aetiologic factor for outcome after aneurysmal SAH. Ó 2014 Elsevier Ltd. All rights reserved.

1. Introduction The incidence of subarachnoid haemorrhage (SAH) is approximately six to seven per 100,000 person-years in most populations (van Gijn et al., 2007; Linn et al., 1996). Ruptured cerebral aneurysms are the cause in 85% of patients (van Gijn et al., 2007). Half the patients are younger than 55 years at the time of haemorrhage, thus producing a large burden of premature morbidity and mortality (Johnston et al., 1998; van Gijn et al., 2007). Despite improved methods of microsurgery, interventional neuroradiology and treatment in specialized intensive care units, the neurological outcome after aneurysmal SAH often remains disappointing (Hackett and Anderson, 2000; Mayer et al., 2002). The initial neurological status of the patient after the ictus seems to have a crucial impact on the ⇑ Corresponding author. Tel.: +49 89 41405471; fax: +49 89 41404886. E-mail address: [email protected] (J. Martin). 0143-4179/$ - see front matter Ó 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.npep.2013.12.004

outcome while the precise pathogenesis of a possibly evolving delayed neurological deterioration and its causal links to the initial neurological condition remain unclear (Macdonald et al., 2007; Giraldo et al., 2012; Rosengart et al., 2007). Early clinicopathological studies of patients succumbing to SAH demonstrated hypothalamic lesions in histological examinations (Doshi and Neil-Dwyer, 1980; Neil-Dwyer et al., 1994; Crompton, 1963). Since disturbances in sodium metabolism and osmolality were frequently reported in patients with SAH, the implication of the hypothalamic neuropeptides arginine-vasopressin (AVP) and oxytocin (OXT) was assessed in clinical studies focusing on electrolyte-water balance, cerebral vasospasm and diurnal concentration changes in cerebrospinal fluid (CSF) (Mather et al., 1981; Kuboyama et al., 1988). In a rather small study, Kuboyama et al. analysed AVP and OXT in CSF of 4 patients for 2 days in the second week after aneurysmal SAH and found a preserved diurnal pattern but all patients were without neurological deficit (Kuboyama et al.,

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1988). Mather et al. suggested a relation between increased AVP concentrations, cerebral oedema and worsening of the neurological status (Mather et al., 1981). Neither, however, did these authors investigate the concentration course during the 2 weeks of sub-acute illness after the onset of SAH nor was OXT measured in conjunction with AVP. The latter is of particular interest, as both neuropeptides have been shown to cross-react, due to the high extent of receptor homology (Sala et al., 2011). Since cerebral vasospasm received growing attention as a possible cause for neurological deterioration, the involvement of AVP in the development of cerebral vasospasm was suggested in rodent subarachnoid haemorrhage models (Nishihashi et al., 2005; Trandafir et al., 2004; Delgado et al., 1988). At present, the hypothalamic neuropeptides OXT and AVP are subjected to ongoing research, in particular their functional implication in promoting diverse aspects of socio-emotional behaviours including social preference and cognition, pair-bonding, aggression and anxiety (Lukas et al., 2011; Bosch and Neumann, 2008; Donaldson and Young, 2008; Jarcho et al., 2011; Gabor et al., 2012; Bielsky and Young, 2004; Gossen et al., 2012; Neumann and Landgraf, 2012) but have not been linked to aneurysmal SAH yet. As the hypothalamus constitutes a possible focus of damage in aneurysmal SAH (Neil-Dwyer et al., 1994; Doshi and Neil-Dwyer, 1980; Mather et al., 1981), alterations in neuropeptide concentrations merit further attention. AVP and OXT are released centrally and peripherally (Landgraf and Neumann, 2004; Neumann and Landgraf, 2012) with no correlative concentrations in both compartments as recently shown in humans (Kagerbauer et al., 2013). The present study thus investigates the levels of the neuropeptides AVP and OXT in both CSF and plasma of patients with spontaneous aneurysmal SAH during the 2 weeks of sub-acute illness after the initial bleed. The association with the patients’ functional outcome is evaluated.

2. Materials and methods The study was approved by the Institutional Review Board of the Medical Faculty of the Technische Universität München. We prospectively studied 12 patients (average age 55.1 years, range 21–71) with aneurysmal SAH (Table 1). No patients with a history of intracranial illness were included in the study. The patients’ preoperative clinical condition was assessed by the grading scale of the World Federation of Neurological Surgeons (WFNS) and the system of Hunt and Hess (HH) (Hunt and Hess, 1968; Teasdale et al., 1988). Computed tomographic classification was based on the method of Fisher et al. (1980). Transcranial Doppler (TCD) was performed daily to measure blood flow velocities in the anterior, middle and posterior cerebral arteries. Cerebral infarction was diagnosed by computer tomography (CT). Cranial CT scans were performed on hospital admission, on neurological deterioration, before ICU dismissal and in comatose patients approximately twice a week during the first 2 weeks of sub-acute illness. Patient outcome was assessed on the Glasgow Outcome Scale (GOS) 3 months after the ictus (Jennett and Bond, 1975). A GOS of 1–3 (death, vegetative state, severe disability) was considered as poor outcome, whereas a GOS of 4–5 (moderate disability, good recovery) was considered as good outcome. A cohort of 29 patients (15 female, 14 male patients; average age 52.8 years, range 19–81) without neuropsychiatric disturbances served as control group. CSF and plasma samples were obtained concomitantly during spinal anaesthesia for elective minor orthopaedic or urological surgery. Samples of CSF and plasma were collected daily or every other day via the arterial line and the external ventricular drainage for 2 weeks after the onset of SAH (mean sampling period 12 days,

range 10–14 days). Per patient, eight to nine paired CSF and plasma samples were drawn resulting in a total of 194 samples for analysis of AVP and OXT in each sample. All samples were collected in prechilled plastic EDTA tubes and centrifuged for 10 min at 1300g at 4 °C immediately after sampling. CSF and plasma samples were analysed identically, i.e., extracted and assayed in the same batch at the same time. Briefly, samples (0.5 ml) were kept at 20 °C until extraction using LiChroprepÒ Si60 (Merck) heat-activated at 700 °C for 3 h. Twenty milligram of LiChroprepÒ Si60 in 1 ml distilled water were added to the sample, mixed for 30 min, washed twice with distilled water and 0.01 N HCl and eluded with 60% acetone. The lyophilized extract was divided to assay both neuropeptides in highly sensitive and specific radioimmunoassays (RIAgnosis, Munich, Germany). Assay sensitivities were in the 0.5 pg range, cross-reactivities with related peptides

Vasopressin and oxytocin in CSF and plasma of patients with aneurysmal subarachnoid haemorrhage.

Clinicopathological studies on patients succumbing to subarachnoid haemorrhage (SAH) demonstrated hypothalamic lesions. The implication of the hypotha...
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