In our patient collective of neurocritical care patients, we found only weak correlations of AVP concentrations in the central and peripheral compartments. A significant correlation between central or peripheral AVP and hematocrit and sodium concentrations in blood could not be demonstrated either. The picture is different in postmenopausal women: Here, a significant positive correlation between AVP in plasma and CSF could be detected. Furthermore, we found moderate inverse correlations between AVP in CSF and sodium and AVP in CSF and hematocrit in this subgroup with the correlation between AVP CSF and sodium being statistically significant. Outcome was not significantly related to either central or peripheral AVP concentrations.
The nonapeptide AVP exerts multiple functions. AVP secretion within the central nervous system is considered crucial for maintaining a mental balance, and disturbances in the central neuropeptide system, in which AVP plays an important role, may contribute to the development of psychiatric issues like post-traumatic stress disorder [5]. Especially in brain trauma, intracerebral AVP is said to exert proinflammatory effects [18].
In the periphery, AVP mediates the maintenance of blood pressure and water and electrolyte homeostasis; additionally, it is involved in the endocrine stress response [7]. Stimuli for AVP secretion are fever, pain and psychological stress. Therefore, blood AVP concentrations are considered a potential biomarker for poor psychological and physical outcome of intensive care patients [19]. Due to these facts, AVP is of increasing interest in critical care medicine. In the context of the Covid-pandemic it has been shown that arginine-vasopressin is increased in patients with fever and dehydration and associated with hyponatremia and inflammatory disorders. Therefore, it might contribute to the development of complications [19]. Already some years before, it was found that hyponatremia and resulting elevated AVP blood concentrations are correlated with poor outcome and mortality in patients with community acquired pneumonia [20].
AVP is detectable in various body fluids such as blood, saliva, urine and cerebrospinal fluid. However, the majority of studies do not distinguish between central and peripheral AVP concentrations. As data on CSF are rare, blood concentrations are mostly used as a surrogate and the exact relationship between the concentrations of the nonapeptide within the CNS and in the periphery is still unclear. Although separate central and peripheral secretion mechanisms are assumed, blood or saliva are used for many questions due to their ease of extraction.
In a previous work on a comparable—not identical—patient population, our group could already show for oxytocin, which is closely related to AVP, that blood concentrations correlate only weakly with CSF concentrations [11]. In the case of oxytocin, however, there was a moderate to strong correlation between saliva and CSF values, which we were unable to reproduce here in a new patient population for AVP. Restrictively, it must be said that saliva values in ICU patients are fundamentally difficult to interpret because many of the drugs administered either cause dry mouth and make extraction difficult or cause hypersalivation which leads to dilution effects [21].
Another issue is the time of sample collection, which is assumed to influence hypothalamic neuropeptide concentrations especially in the central compartment [22]. However, studies on neurocritical care patients which mainly examined patients with aneurysmal subarachnoid hemorrhage, showed that AVP secretion neither in the blood nor in the CSF follows a diurnal rhythm [23, 24]. In our study on a more heterogenous patient collective, samples were obtained only during day shifts, where a steady level of light and noise prevailed at the ward to minimize potential external influences on AVP secretion.
The limited number of human studies using a wide variety of body fluids complicates the analysis of AVP concentrations. Moreover, AVP is elaborately and costly to analyze, which is the reason that some authors used the equimolar secreted copeptin as a surrogate for blood concentrations in their studies [25, 26]. This use of a further surrogate contributes even more to the heterogenous data situation. These circumstances prompted us to investigate AVP in the intensive care context in more detail.
The primary objective of our study was to examine AVP concentrations in the blood, CSF, and saliva compartments for any correlations to determine whether CNS concentrations in critically ill patients can be estimated by blood or saliva concentrations.
Our primary findings were only very weak to weak correlations between central and peripheral compartments in the entire patient collective. This confirms previous statements in the literature that central and peripheral secretion of neuropeptides are not necessarily coupled and that the blood–brain barrier is largely impermeable to endogenous neuropeptides [3].
The subgroup of postmenopausal women differed from the overall collective in showing a moderate positive correlation of AVP in plasma and CSF. This may have several causes: On the one hand, the coupling of central and peripheral AVP secretion mechanisms could differ between sexes. A rodent study for example showed that AVP plasma values increased in male and female rats with heart failure whereas mRNA levels were lower in females than in males [27]. Another reason might be that the permeability of the blood–brain-barrier is influenced by sex. Especially in the post-menopause, blood–brain-barrier function decreases due to a fall in estrogen levels whereas older men continue to produce estrogen from testosterone [28]. In the patient population we considered, we have to assume that all patients had a more or less compromised blood–brain barrier due to their underlying disease. However, a difference in disease severity between males and females cannot be suspected, because there was no significant difference in neurologic outcome.
In the second part of our study, we attempted to capture, at least roughly, the relationship between AVP and volume and electrolyte status. We chose serum sodium and hematocrit as two parameters from the routine laboratory that seemed suitable for this purpose. This choice based on the fact that sodium concentrations account for a large part of serum osmolality [29], and an older study by Murton and coworkers found significant correlations between AVP and sodium as well as hematocrit in critically ill patients with burns [30]. Hematocrit can be used in a common formula to calculate plasma volume [31].
Regarding the whole patient collective, only very weak to weak correlations could be shown between AVP concentrations in CSF, plasma, and saliva and sodium and hematocrit. This somehow reflects the findings of a historical study, where a rise in plasma AVP only after an acute salt load has been shown whereas 90 min after the salt load, no correlation could be found between plasma osmolality and AVP concentration [32]. Our patients did not have acute changes in osmolality and hematocrit, as patients with large volume shifts and acute blood loss were not included in the study.
Again, the subgroup of postmenopausal females differed from the whole collective. Postmenopausal women showed moderate inverse relations of AVP in CSF and serum sodium and hematocrit, where the correlation with sodium was statistically significant. This finding may be a hint to sex differences in volume and electrolyte regulation. At least in animal studies, plasma AVP response to hemorrhage was higher in female rats whereas pituitary AVP content was lower [10]. A human study showed that osmotic AVP release threshold is influenced by estrogen, and osmotic induced AVP release is reduced by sex hormones [33].
In rats with liver cirrhosis, differences between males and females in AVP release were also detected which provided an explanation for females not developing hyponatremia in that study [34].
Regarding outcome, no significant differences in AVP concentrations of the three compartments blood, CSF and saliva were found according to the Glasgow Outcome Scale (GOS) at discharge from ICU. However, our patient collective included only few patients with good neurological outcome, and the vast majority was GOS 3 which means severe disability and dependency in daily life [35]. Therefore, our patient collective was too small and imbalanced to draw conclusions. However, patients with good neurological status are often not in need of an extraventricular drain and are therefore not amenable to CSF sampling.