Primary polydipsia in the medical and psychiatric patients

Background: Primary polydipsia is characterized by increased fluid intake and consistent excretion of profound quantities of diluted urine. It has mainly been described in psychiatric patients but with the current lifestyle-trend and believe that fluid intake is healthy, it is speculated to be increasing in the general population. One of the main and most severe complications of primary polydipsia is hyponatremia, which occurs when free water intake exceeds free water excretion. Despite the increasing prevalence, consistent clinical data on patients with primary polydipsia is lacking. Most of the existing data stems from case reports and retrospective studies within the psychiatric setting, particularly from patients with a schizophrenia spectrum disorder. Pathophysiological understanding and the risk for hyponatremia in non-psychiatric patients remains unclear. Treatment options for patients with primary polydipsia are scarce and have mainly been studied in the psychiatric setting. Objective: This MD-PhD thesis aims at contributing to improving the pathophysiological understanding of, to characterize complications in, and to find treatment options for patients with primary polydipsia. Methods: To reach the aspired aim, I first performed a secondary analysis of a prospective observational study to characterize patients with primary polydipsia hospitalized with profound hyponatremia. Second, I investigated the association of hyponatremia and outdoor temperature in patients with and without primary polydipsia in three distinct cohorts. Third, I was involved in a randomized, placebo-controlled cross-over trial evaluating glucagon-like peptide-1 receptor agonists, medications used to treat type 2 diabetes mellitus and obesity, as a treatment option for patients with primary polydipsia. Results: First, primary polydipsia’s main complication, i.e. hyponatremia, also occurs in medical patients also without psychiatric comorbidities. Second, the risk of profound hyponatremia increases in all polydisic patients in the presence of contributing factors impairing the renal excretory capacity: low solute intake or increased arginine vasopressin. Primary polydipsia in association with profound hyponatremia is furthermore associated with a poor outcome, e.g. hyponatremia recurrence, rehospitalization, and death. Third, hyponatremia shows a season dependent effect with increased hyponatremia prevalence during summer months in correlation with increased outdoor temperature. Fourth, glucagon-like peptide-1 receptor agonists reduce fluid intake in patients with primary polydipsia. Conclusion: Primary polydipsia has mainly been described in the psychiatric setting, but it seems to be also common in the general population. Special attention should be paid in patients with primary polydipsia to reduce hyponatremia inducing factors and prevent hyponatremia. Glucagon-like peptide- 1 receptor agonists are a promising new treatment option for patients with primary polydipsia

FGF-21 levels in polyuria-polydipsia syndrome

The pathomechanism of primary polydipsia is poorly understood. Recent animal data reported a connection between fibroblast growth factor 21 (FGF-21) and elevated fluid intake independently of hormonal control by the hormone arginine-vasopressin (AVP) and osmotic stimulation. We therefore compared circulating FGF-21 levels in patients with primary polydipsia to patients with AVP deficiency (central diabetes insipidus) and healthy volunteers. In this prospective cohort study, we analyzed FGF-21 levels of 20 patients with primary polydipsia, 20 patients with central diabetes insipidus and 20 healthy volunteers before and after stimulation with hypertonic saline infusion targeting a plasma sodium level ≥150 mmol/L. The primary outcome was the difference in FGF-21 levels between the three groups. Baseline characteristics were similar between the groups except for patients with central diabetes insipidus being heavier. There was no difference in baseline FGF-21 levels between patients with primary polydipsia and healthy volunteers (122 pg/mL (52,277) vs 193 pg/mL (48,301), but higher levels in patients with central diabetes insipidus were observed (306 pg/mL (114,484); P = 0.037). However, this was not confirmed in a multivariate linear regression analysis after adjusting for age, sex, BMI and smoking status. Osmotic stimulation did not affect FGF-21 levels in either group (difference to baseline: primary polydipsia −23 pg/mL (−43, 22); central diabetes insipidus 17 pg/mL (−76, 88); healthy volunteers −6 pg/mL (−68, 22); P = 0.45). To conclude, FGF-21 levels are not increased in patients with primary polydipsia as compared to central diabetes insipidus or healthy volunteers. FGF-21 therefore does not seem to be causal of elevated fluid intake in these patients

FGF-21 levels in polyuria-polydipsia syndrome

The pathomechanism of primary polydipsia is poorly understood. Recent animal data reported a connection between fibroblast growth factor 21 (FGF-21) and elevated fluid intake independently of hormonal control by the hormone arginine-vasopressin (AVP) and osmotic stimulation. We therefore compared circulating FGF-21 levels in patients with primary polydipsia to patients with AVP deficiency (central diabetes insipidus) and healthy volunteers. In this prospective cohort study, we analyzed FGF-21 levels of 20 patients with primary polydipsia, 20 patients with central diabetes insipidus and 20 healthy volunteers before and after stimulation with hypertonic saline infusion targeting a plasma sodium level >= 150 mmol/L. The primary outcome was the difference in FGF-21 levels between the three groups. Baseline characteristics were similar between the groups except for patients with central diabetes insipidus being heavier. There was no difference in baseline FGF-21 levels between patients with primary polydipsia and healthy volunteers (122 pg/mL (52,277) vs 193 pg/mL (48,301), but higher levels in patients with central diabetes insipidus were observed (306 pg/mL (114,484);P=0.037). However, this was not confirmed in a multivariate linear regression analysis after adjusting for age, sex, BMI and smoking status. Osmotic stimulation did not affect FGF-21 levels in either group (difference to baseline: primary polydipsia -23 pg/mL (-43, 22);central diabetes insipidus 17 pg/mL (-76, 88);healthy volunteers -6 pg/mL (-68, 22);P=0.45). To conclude, FGF-21 levels are not increased in patients with primary polydipsia as compared to central diabetes insipidus or healthy volunteers. FGF-21 therefore does not seem to be causal of elevated fluid intake in these patients

Fluid Overload Is Associated With Late Poor Outcomes in Neonates Following Cardiac Surgery*

Hyperosmolality, osmotic stimulus or stress results in vasopressin release. Animal and human in vitro studies have shown that inflammatory parameters such as interleukin-8 (IL-8) and tumour necrosis factor-α (TNF-α) increase in parallel in the central nervous system and bronchial, corneal or intestinal epithelial cell lines in response to osmotic stimulus. Whether osmotic stimulus directly causes a systemic inflammatory response in humans is unknown. We therefore investigated the influence of osmotic stimulus on circulatory markers of systemic inflammation in healthy volunteers. In this prospective cohort study, 44 healthy volunteers underwent a standardized test protocol with an osmotic stimulus leading into the hyperosmotic/hypernatremic range (serum sodium ≥150mmol/l) by hypertonic-saline infusion. Copeptin (a marker indicating vasopressin activity), serum sodium and osmolality, plasma IL-8 and TNF-α were measured at baseline and directly after osmotic stimulus. Median (range) serum sodium increased from 141 mmol/l (136, 147) to 151 mmol/l (145, 154) (p-value <0.01), serum osmolality increased from 295 mmol/l (281, 306) to 315 mmol/l (304, 325) (p-value <0.01). Median (range) copeptin increased from 4.3 pg/l (1.1, 21.4) to 28.8 pg/l (19.9, 43.4) (p-value <0.01). Median (range) IL-8 levels showed a trend to decrease from 0.79 pg/ml (0.37, 1.6) to 0.7 pg/ml (0.4, 1.9) (p-value 0.09) and TNF-α levels decreased from 0.53 pg/ml (0.11, 1.1) to 0.45 pg/ml (0.12, 0.97) (p-value 0.036). Contrary to data obtained in vitro, circulating proinflammatory cytokines tend to or decrease in human plasma after osmotic stimulus. Osmotic stress does not to stimulate circulating markers of systemic inflammation

Examinations and assessments in patients with a newly acquired spinal cord injury – retrospective chart analysis as part of a quality improvement project

AIMS OF THE STUDY Examinations and assessments can be used to ensure good quality rehabilitation. Within the framework of a quality improvement project, the aims of the current analysis were: first, to analyse the time points of selected examinations and assessments in the rehabilitation process of patients with a newly acquired spinal cord injury. Second, to identify differences between the subgroups with different aetiologies, levels and completeness of spinal cord injuries. And third, to compare the examinations and assessments performed with the guideline recommendations and to use discrepancies as a starting point for a quality improvement project. METHODS In this retrospective chart analysis, adult patients with a newly acquired spinal cord injury who were admitted to a single specialised acute care and rehabilitation clinic for their first rehabilitation between December 2013 and December 2014 were included and assessed until discharge. The main objective was to assess the time to examinations or assessments after injury or hospital admission in comparison to the respective recommendations. Analyses were done using time-to-event analysis and represented graphically using Kaplan-Meier plots. RESULTS Of the 105 patients included in this study (median age 58 years, 29% female), 61% had a traumatic and 39% a non-traumatic spinal cord injury; 39% were paraplegic and 61% were quadriplegic; and 59% had a motor complete and 41% a sensor-motor incomplete spinal cord injury. The percentage of patients for whom the respective assessment or examination was performed and the percentage of these patients for whom it performed within the recommended time were: 90% and 71% for magnetic resonance imaging; 85% and 90% for computed tomography; 87% and 79% for the manual muscle test; 95% and 59% for the International Standards for Neurological Classification of Spinal Cord (ISNCSCI); 84% and 50% for electrophysiological assessment; 73% and 90% for urodynamic testing; and 49% and 53% for lung function testing. CONCLUSIONS Our data suggest a relevant gap between recommendations and clinical routine for time to some assessments after spinal cord injury. Within the framework of a quality improvement project, the next steps should be to build a national and international consensus on specific time frames for examinations and assessments in patients with a newly acquired spinal cord injury and thereafter, to develop an institutional implementation strategy

The challenges of sodium measurements - indirect versus direct ion selective method

Diagnosis and treatment of dysnatremia is challenging and further complicated by the pitfalls of different sodium measurement methods. Routinely used sodium measurements are the indirect (plasma/serum) and direct (whole blood) ion selective electrode (ISE) method, showing discrepant results especially in the setting of acute illness. Few clinicians are aware of differences between the methods in clinically stable patients or healthy volunteers.; Data of 140 patients and 91 healthy volunteers undergoing osmotic stimulation with hypertonic saline infusion were analyzed. Sodium levels were measured simultaneously by indirect and direct ISE method before and at different time points during osmotic stimulation up to a sodium threshold of ≥150 mmol/l. The primary outcome was the difference in sodium levels between the indirect and the direct ISE method.; 878 sodium measurements were analyzed. Mean (SD) sodium levels ranged from 141mmol/l (2.9) to 151mmol/ (2.1) by the indirect ISE compared to 140mmol/l (3) to 149mmol/l (2.8) by the direct ISE method. The interclass correlation coefficient between the two methods was 0.844 (95%-CI 0.823, 0.863). On average, measurements by the indirect ISE were 1.9mmol/l (95%-CI limits -3.2; 6.9) higher than by the direct ISE method (p<0.001). The tendency of the indirect ISE method resulting in higher levels increased with increasing sodium levels.; Intra-individual sodium levels differ significantly between the indirect and direct ISE method also in the absence of acute illness. It is therefore crucial to adhere to the same method in critical situations to avoid false decisions due to measurement differences