Oxytocin levels in response to pituitary provocation tests in healthy volunteers

Objective: Oxytocin, secreted into circulation through the posterior pituitary, regulates lactation, weight, and socio-behavioral functioning. Oxytocin deficiency has been suggested in patients with hypopituitarism, however, diagnostic testing for oxytocin deficiency has not been developed. The aim of this study was to investigate known pituitary provocation tests to stimulate plasma oxytocin. Design: 65 healthy volunteers underwent either the hypertonic saline or arginine infusion test, known to stimulate copeptin, or the oral macimorelin test, known to stimulate growth hormone. Plasma oxytocin was measured before and once plasma sodium ≥150mmol/l for the hypertonic saline, after 60 minutes for the arginine infusion and after 45 minutes for the oral macimorelin test (expected peak of copeptin and growth hormone levels, respectively). Primary outcome was change from basal to stimulated oxytocin levels using paired t-tests. Results: As expected, copeptin increased in response to hypertonic saline and arginine infusion (p<0.001), and growth hormone increased to oral macimorelin (p<0.001). Oxytocin increased in response to hypertonic saline infusion from 0.4pg/mL (0.2) to 0.6pg/mL (0.3) (p=0.003) but with a high variance. There was no change to arginine infusion (p=0.4), and a trend to lower stimulated levels to oral macimorelin (p=0.05). Conclusion: Neither the arginine infusion nor the oral macimorelin test stimulate plasma oxytocin levels, whereas there was an increase with high variance upon hypertonic saline infusion. As a predictable rise in most participants is required for a reliable pituitary provocation test, none of the investigated pituitary provocation tests can be recommended diagnostically to identify patients with an oxytocin deficiency.

Oxytocin Levels in Response to Pituitary Provocation Tests in Healthy Volunteers

Background: Oxytocin, secreted into the circulation through the posterior pituitary, regulates lactation, weight, and socio-behavioral functioning. Oxytocin deficiency has been suggested in patients with hypopituitarism, however, diagnostic testing for oxytocin deficiency has not been developed. Known stimuli used in the diagnosis of pituitary deficiencies - the hypertonic saline and arginine infusion tests stimulating copeptin levels, and the oral macimorelin test stimulating growth hormone levels - have also been shown to stimulate oxytocin secretion in animal models. We hypothesized that these provocation tests would stimulate plasma oxytocin levels in humans. Methods: Basal plasma oxytocin levels were measured for all three tests. Stimulated plasma oxytocin was measured once plasma sodium &gt;150 mmol/l for the hypertonic saline and after 45 minutes for the arginine infusion and the oral macimorelin test, expected peak of copeptin and growth hormone levels, respectively. Primary outcome was change between basal and stimulated oxytocin levels using a paired t-test. Results: Median (IQR) age of all participants was 24 years (22, 28), 51% were female. As expected, copeptin increased in response to hypertonic saline from 4.0 pmol/L [3.3, 6.7] to 34.2 pmol/L [23.2, 45.4] (p-value &lt;0.001) and in response to arginine infusion from 4.6 pmol/L [3.2, 6.2] to 8.3 pmol/L [6.4, 10.8] (p-value &lt;0.001). Growth hormone increased in response to oral macimorelin from 1.6 ng/mL [0.3, 17.2] to 106.0 ng/mL [73.3, 127.2] (p-value &lt;0.001). Oxytocin levels increased in response to hypertonic saline infusion from 0.3 pg/mL [0.3, 0.5] to 0.6 pg/mL [0.4, 0.7] (p-value 0.007), while there was no change in response to arginine infusion (basal 0.4 pg/mL [0.4, 0.6], stimulated 0.4 pg/mL [0.3, 0.6], p-value 0.6), nor to oral macimorelin (basal 38.7 pg/mL [31.1, 66.9], stimulated 34.2 pg/mL [31.2, 48.2], p-value 0.3). Conclusion: We found that hypertonic saline infusion results in doubling of oxytocin levels. Further research will be important to determine whether this test could be used diagnostically to identify patients with oxytocin deficiency. In contrast to animal data, arginine and macimorelin did not stimulate oxytocin.

Medullary Noradrenergic Neurons Mediate Hemodynamic Responses to Osmotic and Volume Challenges

Despite being involved in homeostatic control and hydro-electrolyte balance, the contribution of medullary (A1 and A2) noradrenergic neurons to the hypertonic saline infusion (HSI)-induced cardiovascular response after hypotensive hemorrhage (HH) remains to be clarified. Hence, the present study sought to determine the role of noradrenergic neurons in HSI-induced hemodynamic recovery in male Wistar rats (290–320 g) with HH. Medullary catecholaminergic neurons were lesioned by nanoinjection of antidopamine-β-hydroxylase–saporin (0.105 ng·nl−1) into A1, A2, or both (LES A1; LES A2; or LES A1+A2, respectively). Sham rats received nanoinjections of free saporin in the same regions (SHAM A1; SHAM A2; or SHAM A1+A2, respectively). After 15 days, rats were anesthetized and instrumented for cardiovascular recordings. Following 10 min of stabilization, HH was performed by withdrawing arterial blood until mean arterial pressure (MAP) reaches 60 mmHg. Subsequently, HSI was performed (NaCl 3 M; 1.8 ml·kg−1, i.v.). The HH procedure caused hypotension and bradycardia and reduced renal, aortic, and hind limb blood flows (RBF, ABF, and HBF). The HSI restored MAP, heart rate (HR), and RBF to baseline values in the SHAM, LES A1, and LES A2 groups. However, concomitant A1 and A2 lesions impaired this recovery, as demonstrated by the abolishment of MAP, RBF, and ABF responses. Although lesioning of only a group of neurons (A1 or A2) was unable to prevent HSI-induced recovery of cardiovascular parameters after hemorrhage, lesions of both A1 and A2 made this response unfeasible. These findings show that together the A1 and A2 neurons are essential to HSI-induced cardiovascular recovery in hypovolemia. By implication, simultaneous A1 and A2 dysfunctions could impair the efficacy of HSI-induced recovery during hemorrhage.

Lidocaine coinfusion alleviates vascular pain induced by hypertonic saline infusion: a randomized, placebo-controlled trial

Background Hypertonic saline solution has been frequently utilized in clinical practice. However, due to the nonphysiological osmolality, hypertonic saline infusion usually induces local vascular pain. We conducted this study to evaluate the effect of lidocaine coinfusion for alleviating vascular pain induced by hypertonic saline. Methods One hundred and six patients undergoing hypertonic saline volume preloading prior to spinal anesthesia were randomly allocated to two groups of 53 each. Group L received a 1 mg/kg lidocaine bolus followed by infusion of 2 mg/kg/h through the same IV line during hypertonic saline infusion; Group C received a bolus and infusion of normal saline of equivalent volume. Visual analogue scale (VAS) scores of vascular pain were recorded every 4 min. Results The vascular pain severity in Group L was significantly lower than that in Group C for each time slot (P < 0.05). The overall incidence of vascular pain during hypertonic saline infusion in Group L was 48.0%, which was significantly lower than the incidence (79.6%) in Group C (P < 0.05). Conclusion Lidocaine coinfusion could effectively alleviate vascular pain induced by hypertonic saline infusion. Trial registration Chinese Clinical Trial Registry, number: ChiCTR1900023753. Registered on 10 June 2019.

Effects of oral macimorelin on copeptin and anterior pituitary hormones in healthy volunteers

Purpose The test with the highest diagnostic accuracy for diabetes insipidus is copeptin measurement after hypertonic saline infusion. However, the procedure is cumbersome and unpleasant due to rapid sodium increase. An oral stimulation test would be highly desirable. Macimorelin, an oral ghrelin agonist, is a newly approved diagnostic test for growth hormone (GH) deficiency, but its effects on copeptin/vasopressin are unknown and the effects on other pituitary hormones only scarcely investigated. Methods In this prospective, interventional, proof-of-concept study Copeptin and anterior pituitary hormones were measured in 28 healthy volunteers on two test days at baseline, 30, 45, 60, 90 and 120 min after a single dose of macimorelin (first visit: 0.5 mg/kg, second visit: 0.75 mg/kg). Results Baseline copeptin levels were 5.26 pmol/L [1.57, 6.81] and did not change after macimorelin intake (0.5 mg/kg: maximal median change 0.40 [− 0.49, 0.65] pmol/L, p = 0.442; 0.75 mg/kg: − 0.13 [− 0.45, 0.17] pmol/L, p = 0.442. Median GH levels increased from 3.67 mU/L with a maximal median change of 94.66 [IQR 56.5; 110.96] mU/L, p < 0.001. No effect was seen on cortisol, ACTH, LH and FSH levels. Prolactin (max. median change 100 [2.5; 146.5] mU/L, p = 0.004) and free thyroxine (fT4) (0.5 [0.2; 0.8] pmol/L, p < 0.001) increased, whereas TSH decreased (− 0.18 [− 0.22, − 0.09] mU/L, p < 0.001). Conclusion We confirm an increase of GH upon macimorelin in healthy volunteers. However, macimorelin did not stimulate copeptin and therefore does not provide an oral test alternative for the diagnosis of diabetes insipidus. Additionally, a stimulatory effect was seen for prolactin and fT4, but not for ACTH and gonadotropic hormones. Registration The trial was registered on ClinicalTrials.gov (NCT03844217) on February 18, 2019.

Association of Hyperchloremia and Acute Kidney Injury in Patients With Traumatic Brain Injury

Introduction: Hypertonic saline is often used to treat patients with traumatic brain injury. It carries the undesired side effect of hyperchloremia, which has been linked to acute kidney injury (AKI). We sought to evaluate the relationship of hyperchloremia and AKI in this population and whether the absolute exposure to hyperchloremia, including maximal hyperchloremia and duration of hyperchloremia were associated with AKI. Methods: A retrospective study of severe traumatic brain injury patients who received hypertonic saline at a single academic institution. Demographics, head abbreviated injury scale, development of hyperchloremia (Cl ≥ 115), duration of hyperchloremia, highest chloride level, duration of hypertonic saline use, admission GFR, and administration of nephrotoxic medications were abstracted. The outcome of interest was the association between renal function and hyperchloremia. Results: A total of 123 patients were included in the study. Multivariable logistic regression analysis demonstrated that only duration of hyperchloremia ( p = 0.014) and GFR on admission ( p = 0.004) were independently associated with development of AKI. The number of days of hypertonic saline infusion ( p = 0.79) without the persistence of hyperchloremia and highest serum chloride levels ( p = 0.23) were not predictive of AKI development. Discussion: In patients with traumatic brain injury, admission GFR and prolonged hyperchloremia rather than the highest chloride level or the duration of hypertonic saline infusion were associated with the development of AKI.