University of Groningen
The multifactorial aetiology of ICU-acquired hypernatremia
IJzendoorn, Marianne
DOI:
10.33612/diss.109636342
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The multifactorial aetiology of
ICU-acquired hypernatremia
M.C.O. (Marjolein) van IJzendoorn
The multifactorial aetiology of ICU-acquired hypernatremia
PhD thesis University of Groningen, with a summary in Dutch
ISBN: 978-94-034-2300-5 (printed version)
ISBN: 978-94-034-2301-2 (electronic version)
Copyright © Marjolein van IJzendoorn
No part of this thesis may be reproduced, stored, or transmitted in any
form or by any means, without permission from the author.
Cover design: Christien van IJzendoorn, www.carrotent.com
Layout: Marjolein van IJzendoorn
Printed by: Ipskamp Printing, Enschede, www.ipskampprinting.nl
The publication of this thesis was financially supported by:
Rijksuniversiteit Groningen
The multifactorial aetiology of
ICU-acquired hypernatremia
Proefschrift
ter verkrijging van de graad van doctor aan de
Rijksuniversiteit Groningen
op gezag van de
rector magnificus prof. Dr. C. Wijmenga
en volgens besluit van het College voor Promoties.
De openbare verdediging zal plaatsvinden op
woensdag 8 januari 2020 om 11:00
door
Marianne Cornelia Ottolina Slabbekoorn
geboren op 16 maart 1987
te Rotterdam
Promotor
Prof. dr. G.J. Navis
Co-promotores
Dr. E.C. Boerma
Dr. H. Buter
Beoordelingscommissie
Prof. dr. C.A. Stegeman
Prof. dr. R.P. Pickkers
Prof. dr. P. Honoré
Contents
Chapter I: Introduction & thesis outline
9
Chapter II: The development of intensive care unit acquired
hypernatremia is not explained by sodium overload or water deficit: a
retrospective cohort study on water balance and sodium handling.
Crit Care Res Pract 2016; 2016:9571583 23
Chapter III: Hydrochlorothiazide in intensive care unit-acquired
hypernatremia: a randomized controlled trial.
J Crit Care 2017 Apr; 38:225-230 43
Chapter IV: Is furosemide eenmaal daags wel zinvol?
Ned Tijdschr Geneeskd 2017;161(0):D1083 67
Chapter V: Renal function is a major determinant of ICU-acquired
hypernatremia; a balance study on sodium handling
Submitted 83
Chapter VI: An observational study on intracutaneous sodium storage
in intensive care patients and controls
PLoS One, 2019 Oct;14(10):e0223100 127
Chapter VII
155
I. Summary & future perspectives
II. Nederlandse samenvatting
Dankwoord
179
Biography
Bibliography
Abbreviations and acronyms
ADH Antidiuretic hormone AKI Acute kidney injuryAPACHE Acute physiology and chronic health evaluation AVP Arginine vasopressin
BIA Bioelectrical impedance analysis BMI Body mass index
CCL2 Chemokine ligand 2 cDNA Complementary DNA CI Confidence interval CVP Central venous pressure ECF Extracellular fluid
EFWC Electrolyte free water clearance eGFR Estimated glomerular filtration rate FEna Fractional sodium excretion
Feurea Fractional urea excretion
FWC Free water clearance HCT Hydrochlorothiazide
IAH ICU-acquired hypernatremia
IAH 143 ICU-acquired hypernatremia, defnied as a serum sodium concentration of ≥ 143mmol/l
IAH 145 ICU-acquired hypernatremia, defnied as a serum sodium concentration of ≥ 145mmol/l
ICF Intracellular fluid ICU Intensive care unit IQR Interquartile range
K Potassium
LOS Length of stay
MCL Medical Centre Leeuwarden MPS Mononuclear phagocyte system MV Mechanical ventilation
N Nitrogen
Na Sodium
OR Odds ratio
PDMS Patient data management system PDPN Podoplanin
POCT Point-of-care-testing
qRT-PCR Quantitative real time polymerase chain reaction
R Resistance
r Spearman's rank correlation coefficient RAAS Renine-angiotensine-aldosteron-systeem RRT Renal replacement therapy
RTPO Regionale toetsingscommissie patiëntgebonden onderzoek SCC Sodium chloride cotransporter
sCreat Serum creatinine concentration sNa Serum sodium concentration SOFA Sequential organ failure assessment SPSS Statistical package for the social sciences TIH Thiazide induced hyponatremia
uCreat Urine creatinine concentration uK Urine potassium concentration uNa Urine sodium concentration
VEGFC Vascular endothelial growth factor C Xc Reactance
Chapter I
General introduction
Solving a problem starts with defining it. In the case of ICU-acquired hypernatremia (IAH) this seems quite simple. ‘ICU-acquired’ indicates anything which occurs during an intensive care unit (ICU) admission. This something is hypernatremia. The ‘natr’ part yields that sodium is involved and ‘-emie’ stems from the Greek word (haima), which means blood. This said sodium in the bloodstream is higher than considered normal, therefore it’s called ‘hyper’natremia. Unfortunately, simplicity ends with this assessment of ‘higher than considered normal’. To begin with, what exactly is deemed normal? The usual cut-off value for hypernatremia is a serum sodium
concentration (sNa) of 146mmol/l, because in 97.5% of healthy adults sNa is below this concentration1,2. When sNa rises above normal values, symptoms
can occur3,4. Moreover, previous research in ICU-patients has shown that
patients with borderline hypernatremia (sNa of 143 mmol/l or above) already tended to have worse outcomes (Fig. 1) 5. Before things get overly
complicated, however, let us first go back to the basics of water and sodium homeostasis.
Fig. 1: Hazard ratio for mortality of elevated serum sodium concentration (adapted from Darmon et al.5)
0 1 2 3 4 5
No dysnatremia sNa 142-145 sNa 146-150 sNa 151-155 sNa >155 Unadjusted Adjusted
Water and sodium homeostasis
Sodium concentration in human blood is regulated between the relatively narrow limits of 135 to 145mmol/l2,6. Under physiological conditions
osmoregulation, by its effects on water balance, is the main determinant of serum sodium concentration (sNa). The linkage between sodium and water balance is quite complex, as illustrated by Patel (Fig. 2)7.
Fig. 2: Major regulatory mechanisms of sodium and water homeostasis7
Fig. 2 illustrates the complexity of sodium and water interplay. Explaining all parts of these regulatory mechanisms is beyond the scope of this thesis. We will focus on the derangements of serum sodium regulations in ICU patients from a clinical perspective, i.e. primarily analysing parameters that are routinely collected in these patients (e.g. electrolytes, renal function, fluid balances). The link between sNa and sodium and water content of the body can be summarized in the Edelman equation8:
[Na+] =(Total exchangeable Na++ total exchangeable K+)
Total body water
Sodium is the main solute in extracellular fluid (ECF), potassium is the main solute in intracellular fluid (ICF), and water moves freely between these compartments (Fig. 3)9. Under physiological conditions alterations in sNa are
corrected by osmoregulation. Alterations in sNa are detected by the osmosensor in the hypothalamus, which responds to alterations in plasma osmolality. Elevated sNa leads to a rise in plasma osmolality, which induces thirst and stimulates the release of antidiuretic hormone (ADH). ADH prompts the kidneys to retain water and thereby to dilute sNa, leading sNa to return to baseline levels. Conversely, when sNa decreases, ADH-release is inhibited, and accordingly urine becomes more dilute. Eventually, the kidneys restore sodium balance of the body by retention or excretion of additional sodium. Development of dysnatremias can easily be explained using the
aforementioned equation by Edelman: excess sodium intake or water deficit leads to hypernatremia, sodium deficit or excess water intake leads to hyponatremia. Both hyper- and hyponatremia have negative effects on the outcome of ICU-patients5. However, in ICU-admitted patients, development of
hypernatremia is far more common than development of hyponatremia10.
Therefore, the focus of this thesis is on hypernatremia.
The assumption underlying the Edelman equation is that all sodium and all water in the body are subject to the osmotic exchange. This assumption has been challenged by several findings in experimental animals, as well as in humans. Accurate long-term studies on sodium balance revealed
discrepancies between sodium and water balance, as well as sNa, which could not be accounted for by the parameters in the Edelman equation. Moreover, studies have shown that following a sodium load, healthy subjects are very efficient in handling excess sodium intake. After a sodium load in healthy subjects, sNa rises only slightly or not at all, with very rapid correction to normonatremia and little or no water accumulation11-17. This was not only
explained by increased renal sodium excretion but also by the existence of a third compartment (Fig. 3), where sodium can be non-osmotically stored18.
This compartment consists of cartilage, muscle, and skin19-21. The skin was
found to play a fundamental role in sodium homeostasis by harbouring a sodium reservoir where sodium is stored by way of binding to subcutaneous glycosaminoglycans22,23. Storage and release are governed by regulatory
Fig. 3: Relation of sodium and water in different body compartments in A) normonatremia, B) hypernatremia by water loss, C) hypernatremia by sodium overload and D) with the third compartment
ECF: Extracellular fluid, ICF: Intracellular fluid, *: sodium molecules, +: potassium molecules, ←: direction of water shift
A: Distribution of sodium and water in ECF and ICF under steady state physiological conditions. B: When hypernatremia occurs because of loss of extracellular fluid, this is compensated by an osmotical shift of water from ICF to ECF. C: When hypernatremia occurs because of sodium overload, water shifts also osmotically from ICF to ECF, in this case resulting in expansion of ECF. D: With non-osmotical storage of sodium no changes occur in ECF or ICF.
A
B
C
Hypernatremia
Despite all physiological mechanisms, at some point homeostasis is no longer sufficient to maintain normonatremia and hypernatremia occurs. About 2% of hospitalized patients develop hypernatremia24. In these patients
hypernatremia is mostly due to increased water loss and / or decreased water intake3,25. Water loss is not exclusively renal, but can also result from
gastro-intestinal losses or by excessive sweating26. Examples of situations with
insufficient fluid intake are patients with diminished sense of thirst (elderly) or patients with no or limited access to water (intubated or otherwise immobilized patients)27. Main symptoms of hypernatremia are neurologic.
Symptoms and their severity depend on the severity of hypernatremia, the period in which it developed, and on how fast these alterations are corrected. With rising sNa, fluid shifts from the intracellular to the extracellular space (Fig. 3). This leads to shrinkage of cells, also intracerebral, and thereby to neurological symptoms as altered consciousness and weakness 9,28. In cases
with very rapid increase of sNa, the concomitant rapid shrinkage of brain cells can even lead to vascular damage by traction with possible coma or death as a result. Also the onset of osmotic demyelinisation is possible. Rapid correction of chronic hypernatremia on the other hand can lead to cerebral edema. Other possible complications are elevated peripheral insulin resistance, decreased contractility of the left ventricle, higher blood viscosity with increased risk of deep venous thrombosis, and in cases of severe hypernatremia
ICU-acquired hypernatremia
Reported incidence of hypernatremia in patients admitted to the ICU is 2-9%33,34. Development of hypernatremia during ICU stay (ICU-acquired
hypernatremia, IAH) is even more common. Because the development of IAH is considered mainly iatrogenic, prevention and/or treatment seems simple: avoid interventions that induce IAH. However, during the past decades incidence of IAH even increased35. Depending on the chosen subgroup of
ICU-patients and cut-off value for hypernatremia about 3-17% of ICU ICU-patients develops IAH10,34,36. Hypernatremia is associated with morbidity and mortality
and a prolonged length of stay in the ICU36-38. Commonly a sNa of 145 mmol/l
is used as cut-off value for hypernatremia. However, as described above also borderline hypernatremia (sNa ≥ 143mmol/l) is associated with worse outcomes in ICU-patients (Fig. 1)5.
In the current paradigm two iatrogenic factors are considered accountable for the development of IAH. First and in contrast to hypernatremia in
non-critically ill patients (in which excessive sodium intake is a rather rare origin of hypernatremia) sodium overload is considered a major causative factor for IAH. The second factor that is considered important is water depletion, either by inadequate fluid administration or excessive fluid loss due to use of diuretics3,4,30,39-42. A few years ago in our ICU a shift in policy was made
towards resuscitation fluids containing less sodium43. After this intervention
mean sodium concentration in the total ICU-population decreased from 139 mmol/l to 138mmol/l, but the incidence of sNa ≥ 145mmol/l did not change. These finding supports the assumption that other factors such as impaired renal cation excretion could play a role in the development of IAH44. However,
current literature about other contributing factors in the development of IAH is scarce and no systematic assessment of determinants is available.
Aim of this thesis
The hitherto only partially explained aetiology of IAH makes it difficult to initiate optimal treatment for this condition. The persistent incidence of IAH and its known complications warrant research in this topic. Primary aim of this thesis, therefore, is to investigate whether the current paradigm of ‘too much salt and too little water’ is sufficient to explain the development of IAH. And if not, to investigate which other factors play a role in this sodium derangement in critically ill patients.
Thesis outline
As a first exploration we designed a case-control retrospective study. Primary aim of this study was to investigate prevalence and severity of IAH and make a first attempt to identify the determinants of IAH in our ICU. Secondary aim of this study was to investigate renal sodium excretion in patients with IAH. Results of this study are described in chapter II.
Even without exact data on prevalence and severity, in daily practice it was clear that IAH is a tenacious condition that occurs commonly. Previous literature suggested that impaired renal sodium excretion was a contributing factor to IAH that probably could be treated with thiazides44. Based on the idea
that hydrochlorothiazide (HCT) enhances renal sodium excretion, in our ICU this drug was prescribed routinely in patients with IAH. This practice however was based on very scarce literature. In chapter III we describe a randomized controlled trial that compared HCT and placebo in the treatment of IAH. In chapter IV we describe the effects of another commonly prescribed diuretic, of a different diuretic class, i.e. furosemide.
As the aetiology of IAH is still partly a ‘black box’ we conducted a prospective case-control study in which we compare ICU-patients with and without IAH. In this study we explore a number of factors that potentially contribute to the development of IAH. Besides these factors we investigated again, and this time prospectively, the applicability of the current ‘too much salt, too little water’-paradigm. This study is described in chapter V.
To identify the relevant components of the ‘black box’, we were also interested in hitherto unknown factors that may contribute to the development of IAH. In this search the relatively recently discovered third compartment had our particular interest. Previous studies on sodium storage in the third compartment, more specifically in skin, were executed in animals, healthy controls or non-critically ill patients. Many processes get deranged in the presence of critically illness. So before it can become clear which role
cutaneous sodium storages plays in the development of IAH, sodium storage in itself had to be explored in critically ill patients. The results of this
exploration can be found in chapter VI.
In chapter VII, finally, we summarize our findings and give our view on future perspectives for further research on and management of IAH.
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21. Wahlgren V. Über die Bedeutung der Gewebe als Chlordepots. Archiv für experimentelle Pathologie und Pharmakologie. 1909;61(2):97-112.
22. Titze J, Machnik A. Sodium sensing in the interstitium and relationship to hypertension. Curr Opin Nephrol Hypertens. 2010;19(4):385-92.
23. Titze J, Shakibaei M, Schafflhuber M, Schulze-Tanzil G, Porst M, Schwind KH et al. Glycosaminoglycan polymerization may enable osmotically inactive Na+ storage in the skin. Am J Physiol Heart Circ Physiol. 2004;287(1):H203-8.
24. Palevsky PM, Bhagrath R, Greenberg A. Hypernatremia in hospitalized patients. Ann Intern Med. 1996;124(2):197-203.
25. Nederlandse Internisten Vereniging. Richtlijn elektrolytstoornissen NIV 2012.
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27. Sam R, Feizi I. Understanding hypernatremia. Am J Nephrol. 2012;36(1):97-104.
28. Sterns RH. Disorders of plasma sodium--causes, consequences, and correction. N Engl J Med. 2015;372(1):55-65.
29. Sakr Y, Rother S, Ferreira AMP, Ewald C, Dünisch P, Riedemmann N et al. Fluctuations in serum sodium level are associated with an increased risk of death in surgical ICU patients. Crit Care Med. 2013;41(1):133-42.
30. Lindner G, Funk GC. Hypernatremia in critically ill patients. J Crit Care. 2013;28(2):216.e11-20.
31. Incecik F, Herguner MO, Yildizdas D, Ozcan K, Altunbasak S. Rhabdomyolysis caused by hypernatremia. Indian J Pediatr. 2006;73(12):1124-6.
32. Bihari S, Ou J, Holt AW, Bersten AD. Inadvertent sodium loading in critically ill patients. Crit Care Resusc. 2012;14(1):33-7.
33. Polderman KH, Schreuder WO, Strack van Schijndel RJ, Thijs LG.
Hypernatremia in the intensive care unit: an indicator of quality of care? Crit Care Med. 1999;27(6):1105-8.
34. Lindner G, Funk GC, Schwarz C, Kneidinger N, Kaider A, Schneeweiss B et al. Hypernatremia in the critically ill is an independent risk factor for
mortality. Am J Kidney Dis. 2007;50(6):952-7.
35. Oude Lansink-Hartgring A, Hessels L, Weigel J, de Smet AMGA, Gommers D, Panday PVN et al. Long-term changes in dysnatremia incidence in the ICU: a shift from hyponatremia to hypernatremia. Ann Intensive Care. 2016;6(1):22. 36. Darmon M, Timsit JF, Francais A, Nguile-Makao M, Adrie C, Cohen Y et al. Association between hypernatraemia acquired in the ICU and mortality: a cohort study. Nephrology Dialysis Transplantation. 2010;25(8):2510-5.
37. Waite MD, Fuhrman SA, Badawi O, Zuckerman IH, Franey CS. Intensive care unit-acquired hypernatremia is an independent predictor of increased mortality and length of stay. J Crit Care. 2013;28(4):405-12.
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39. Arora SK. Hypernatremic disorders in the intensive care unit. J Intensive Care Med. 2013;28(1):37-45.
40. Hoorn EJ, Betjes MG, Weigel J, Zietse R. Hypernatraemia in critically ill patients: too little water and too much salt. Nephrology Dialysis
Transplantation. 2008;23(5):1562-8.
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43. Koopmans M, Egbers P, Boerma E. The influence of a switch from NaCl based colloids to sodium acetate-based colloids on teh incidence of hypernatremia on the ICU. .
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Chapter II
The development of intensive care unit acquired
hypernatremia is not explained by sodium overload or water
deficit: a retrospective cohort study on water balance and
sodium handling.
Het ontstaan van hypernatriëmie bij intensive care patiënten
kan niet verklaard worden door overmatige zoutintake of
watertekort: een retrospectieve cohortstudie naar
vochtbalans en natriumhantering
Marjolein M.C.O. van IJzendoorn
Hanneke Buter
W. Peter Kingma
Gerjan Navis
E. Christiaan Boerma
Published in: Critical Care Research and Practice 2016 (online), Article ID
Abstract
The development of ICU-acquired hypernatremia (IAH) is mainly considered an iatrogenic complication, induced by sodium overload and water deficit. However, in daily practice doubts arose about the completeness of this explanation. The main goal of this exploratory retrospective cohort study was twofold. Firstly, we were interested if the development of IAH indeed can be explained by sodium intake and water balance. Second focus of interest was if renal cation excretion can explain the development of IAH. Therefore two retrospective studies were conducted: a balance study in 97 ICU-patients with and without IAH and a survey on renal cation excretion in 115 patients with IAH. Sodium intake was high in both groups, but no differences between patients that did and did not develop IAH were found. Fluid balances were positive in both groups and did also not differ between patients that did and did not develop IAH. In the majority of patients with IAH from which a spot urine sample was collected total urine cation excretion was lower than the serum sodium concentration. Beside this findings, severity of illness was the only independent variable predicting the development of IAH.
Samenvatting
Het ontstaan van hypernatriëmie bij intensive care patiënten (ICU-acquired hypernatremia, IAH) wordt vaak gezien als een iatrogene complicatie door het geven van teveel zout en te weinig water. In de praktijk ontstond echter de vraag of dit het ontstaan van IAH volledig verklaart. Het belangrijkste doel van deze exploratieve retrospectieve cohortstudie was tweeledig. Allereerst wilden we onderzoeken of het ontstaan van IAH inderdaad verklaard kan worden door natriuminname en vochtbalans. Daarnaast waren we benieuwd of renale kationexcretie het ontstaan van IAH kan verklaren. Daarom werden twee retrospectieve studies uitgevoerd. Namelijk: een balansstudie in 97 intensive care patiënten met en zonder IAH en een onderzoek naar renale kationexcretie in 115 patiënten met IAH. De natriuminname was hoog bij zowel patiënten met als zonder IAH, maar tussen deze groepen was geen verschil. De vochtbalans was positief in beide groepen en er was geen verschil tussen patiënten die wel en geen IAH ontwikkelden. De totale kationexcretie in de urinemonsters van de meeste patiënten met IAH bleek lager dan de serumnatriumconcentratie. Daarnaast vonden we dat de ernst van ziekte de enige onafhankelijke voorspellende variabele was voor het ontstaan van IAH.
Introduction
ICU-acquired hypernatremia (IAH), defined as a serum sodium concentration (sNa) of more than 145mmol/l, is a regularly occurring condition in a large variety of intensive care patients1. In previous publications the incidence of
IAH varies from 3 to 17%2-5. We previously reported an incidence of IAH
between 6 and 9%6. In several studies IAH was associated with higher
morbidity and mortality and a prolonged length of stay in the ICU4,5,7-9.
Moreover, recent observations by Darmon et al. confirmed the association between IAH and mortality with an even lower cut off value for sNa ≥ 143mmol/l7.
Under normal circumstances, sNa is maintained within relatively narrow limits by osmo- and volume-regulation. A change in sodium balance is
associated with only subtle changes in sNa10,11. Theoretically, hypernatremia is
caused by a disturbance in water homeostasis and sodium content12-16. These
mechanisms are derived from the Edelman equation, which in simplified form is as follows17:
[Na+] =(Total exchangeable Na
++ total exchangeable K+)
Total body water
In the past decades IAH is mainly seen as an iatrogenic complication. On the one hand excessive sodium intake during critical illness, attributed to the infusion of sodium-rich fluids may play a role12,14,18-20. On the other hand
decrease in total body water, caused by renal or extra renal water loss, or insufficient water intake may enhance the rise in sNa. ICU-patients are either incapable of swallowing or have limited access to free water whilst being sedated during mechanical ventilation7,14. Excessive water loss can be due to
diabetes insipidus, the use of diuretics, osmotic diuresis (for example in case of high urea excretion), electrolyte disorders, increased or non-replenished insensible loss, nasogastric suction or fluid loss via tubes or drains12,19.
Healthy individuals, subject to intravenous sodium loading, display increased renal sodium excretion to maintain homeostasis21-23. In critically ill patients an
impaired ability to excrete cations has been reported, independently of their volume status14,15. This is in line with our own observations that consistent
fluids, did not seem to change the overall incidence of IAH in our own ICU department6.
As a first step to unravel the aetiology of IAH we performed two
complementary observational studies to answer the following questions: First, can the development of IAH be (fully) explained by parameters of sodium intake and water balance? Or could it be explained by renal cation excretion? Methods
Patients and setting
This study consisted of two complementary parts; one balance study and a study on renal cation excretion. The balance study was a single-centre retrospective cohort analysis in patients admitted to the ICU from September 2013 until February 2014. The ICU is a 22-bed combined medical and surgical unit in a tertiary teaching hospital. All patients with a length of stay (LOS) in the ICU ≥ 48 hours were included. Exclusion criteria were sNa ≥ 143mmol/l on admission and renal replacement therapy. Patients were divided into two subgroups: one group of patients that developed a sNa ≥ 143mmol/l and one group that did not. An alternative sNa ≥ 145mmol/l cut-off value was also predefined for secondary analysis.
Simultaneously a single-centre cohort analysis on renal cation excretion was performed. As a by-product of an ongoing trial spot urine samples were available in patients with IAH. These samples were obtained as soon as possible after the occurrence of IAH. Inclusion criteria for this study were IAH and a LOS ICU ≥ 48 hours. Exclusion criteria were sNa ≥ 143mmol/l on admission and renal replacement therapy. Spot urine samples were collected in the period between September 2013 and April 2015 and retrospectively analysed. Groups were classified on the assumption that in non-hypovolemic patients a total renal excretion of sodium and potassium lower than sNa implies impaired ability of the kidney to excrete cations15. In group 1 total
renal cation excretion (urine (uNa) + urine potassium (uK)) was < sNa. In group 2 total renal cation was ≥ sNa.
Data collection
Data were extracted from the patient data management system (PDMS). The following patient characteristics were identified: gender, age, Acute
daily Sequential Organ Failure Assessment (SOFA) scores25, reason for
admission and length of ICU stay. Routine daily collected measurements of sNa, serum creatinine concentration and serum urea concentration were used. sNa was measured with point-of-care-testing (POCT, ABL800 AutoCheck®, Radiometer Pacific Pty. Ltd., Australia and New Zealand). In addition
registration of total sodium intake (including enteral and parenteral feeding, administered fluids, sodium content of administered drugs and their solvents), fluid balance (derived from PDMS minus 500 ml anticipated insensible
loss/day), diuresis and administration of diuretics were part of daily routine. Urine cation excretion was calculated as the sum of urine sodium and
potassium concentrations, derived from a spot urine sample. A local ethics board (Regionale Toetsingscommissie Patiëntgebonden Onderzoek, Leeuwarden, the Netherlands) waived the need for informed consent, according to applicable laws.
Statistical analysis
Data were collected in and analysed with SPSS 20 (IBM, New York, USA). Distribution of data was evaluated by histograms and Shapiro-Wilk testing. Data are expressed as median with interquartile range (IQR) or as a number with the corresponding percentage.
In the balance study sNa was used as a dichotomous variable to determine the difference in total sodium intake and fluid balance between groups after 24 and 48 hours. Applicable tests for independent variables were conducted to compare groups. Outcomes were considered significant at p ≤ 0.05. Backwards multivariate logistic regression analysis was performed, including all variables with a p-value ≤ 0.25 in the univariate analysis. In case of categorical variables the first category served as reference. Probability for stepwise entry and removal were set at 0.05. Outcomes are expressed as odds ratio (OR) with a confidence interval (CI) of 95%.
Results
Balance study
During the study period 97 patients were eligible for inclusion. 47 Patients were included in the IAH-group (sNa ≥ 143mmol/l), 50 patients in the non-IAH group (sNa <143mmol/l).
Baseline characteristics are presented in Table 1. Apart from severity of illness scores, which were higher in patients developing IAH, there was no significant difference between groups at baseline.
Median number of days until fulfilment of the IAH-criterion was 3 [2-4]; median duration of sNa ≥ 143mmol/l was 3 days [1-9]. Total sodium intake after 48 hours was 12.5 [9.3-17.5] gram in the non-IAH group versus 15.8 [9-21.9] gram in the IAH-group, p = 0.13. Fluid balances were positive in both groups and did not differ between groups at 24 and 48 hours after admission. Central venous pressure, as an indirect parameter of volume status, did not differ between groups (Table 2 and 3, Fig. 1). Spot urine samples were available from 22 patients with IAH. Median amount of sodium in these samples was 45mmol/l [10-94].
Table 1: Baseline characteristics balance study s[Na] < 143mmol/l s[Na] ≥ 143mmol/l P-value Number of patients, n (%) Male gender, n (%) Age, years APACHE IV-score SOFA-score on admission Reason for admission, n (%) Cardiovascular surgery Sepsis Elective surgery Emergency surgery Cardiopulmonary resuscitation Miscellaneous
Serum sodium on admission, mmol/l Serum creatinine on admission, µmol/l Serum urea on admission, mmol/l
50 (51) 34 (68) 66 [61-73] 58 [44-77] 6 [4-8] 25 (50) 4 (8) 3 (6) 10 (20) 4 (8) 4 (8) 138 [136-140] 93 [71-117] 7 [5-7] 47 (49) 29 (62) 67 [57-77] 68 [56-101] 7 [4-10] 14 (30) 7 (15) 2 (4) 5 (11) 8 (17) 11 (23) 138 [136-140] 85 [69-113] 6 [5-8] 0.53 0.57 0.01 0.16 0.25 0.55 0.44
sNa: Serum sodium concentration, APACHE: Acute Physiology And Chronic Health evaluation, SOFA: Sequential Organ Failure Assessment. Data are presented as median [IQR] or as absolute numbers (%).
Table 2: Main results balance study s[Na] < 143mmol/l s[Na] ≥ 143mmol/l P-value
Length of stay, days SOFA-score after 24 hours SOFA-score after 48 hours Fluid intake after 24 hours, L Fluid intake after 48 hours, L Fluid balance after 24 hours, L1
Fluid balance after 48 hours, L1
Sodium intake after 24 hours, grams Sodium intake after 48 hours, grams Serum creatinine after 24 hours, µmol/l Serum creatinine after 48 hours, µmol/l Serum urea after 24 hours, mmol/l Serum urea after 48 hours, mmol/l No of patients on furosemide after 24h Total dose furosemide after 24h, mg No of patients on furosemide after 48 h Total dose furosemide after 48h, mg
4 [3-5] 6 [4-7] 5 [3-6] 4.4 [3.7-5.6] 7.5 [6-9.2] 2 [1-2.8] 2.3 [1-3.7] 9.6 [6.9-11.8] 12.5 [9.3-17.5] 87 [66-130] 79 [60-116] 8 [6-10] 8 [6-12] 5 20 [20-60] 18 30 [20-60] 7 [4-15] 8 [5-10] 7 [4-10] 3.8 [2.9-6.3] 6.9[5.3-9.2] 1.6 [0.6-3.7] 2.5 [0.8-4.2] 9.7 [5.9-15.8] 15.8 [9-21.9] 81 [65-110] 77 [61-121] 7 [5-11] 9 [5-13] 4 60 [25-400] 15 40 [20-60] <0.001 0.02 <0.001 0.54 0.59 0.78 0.77 0.70 0.13 0.40 0.91 0.47 0.71 1 0.29 0.83 0.19
sNa: serum sodium concentration, SOFA: Sequential Organ Failure Assessment. 1 Fluid balances are as extracted from
the patient data management system, minus 500ml of expected insensible loss per day of admission. Data are presented as median [IQR] or as absolute numbers (%).
Table 3: Central venous pressure
s[Na] <
143mmol/l s[Na] ≥ 143mmol/l P-value CVP admission, mmHg MV (n = 70) 10 [8-11] 11 [9-12] 0.05 No MV (n = 7) n = 2 n = 5 NA CVP 24 hours, mmHg MV (n = 45) No MV (n = 32) 8 [5-11] 6 [4-9] 9 [5-12] 5 [2-8] 0.78 0.20 CVP 48 hours, mmHg MV (n = 30) No MV (n = 47) 7 [3-11] 5 [2-8] 9 [6-12] 6 [2-9] 0.40 0.58 CVP: Central venous pressure, MV: mechanical ventilation, NA: Not applicable
Fig. 1: Total sodium intake and fluid balance 48 hours after admission in patients with and without developing IAH
sNa: serum sodium concentration
Length of stay of patients with IAH was significantly longer in comparison to the control group (4 [3-5] versus 6 [4-12], p < 0.001, Table 2). In a
multivariate logistic regression analysis severity of illness, defined by APACHE IV-scores, remained as the only significant factor in the development of IAH (OR 1.020, (CI 1.004-1.035), p = 0.01). Analysing data with sNa ≥ 145mmol/l as an alternative cut-off value for IAH are did not significantly change
outcomes.
Renal cation excretion study
Renal cation excretion was measured in 115 patients with IAH. 99 Patients were included in the group with low cation excretion (uNa + uK < sNa), 16 patients in the group with high cation excretion (uNa + uK ≥ sNa). Baseline characteristics are provided in Table 4. At the time of urine analysis median sNa in group 1 was 144 [143-147]mmol/l versus 145 [143-146] mmol/l in group 2 (p = 0.85). Median sodium concentration in spot urine samples was 38 [15-67]mmol/l in group 1 and 133 [104-152]mmol/l in group 2 (p < 0.001). Potassium concentration was also significantly lower in group 1 (36mmol/l versus 45mmol/l, p < 0.001). In a multivariate logistic regression model APACHE IV remained the only significant independent predictive variable for low urine cation excretion.
Table 4: Baseline characteristics renal cation excretion study Group 1 (uNa + uK < sNa) Group 2 (uNa + uK ≥ sNa) P-value Number of patients, n (%) Male gender, n (%) Age, years APACHE IV-score SOFA-score on admission Reason for admission, n (%) Cardiovascular surgery Sepsis Elective surgery Emergency surgery Cardiopulmonary resuscitation Miscellaneous
Serum sodium on admission, mmol/l Serum creatinine on admission, µmol/l Serum urea on admission, mmol/l
99 (86) 74 (75) 67 [57-74] 88 [68-116] 8 [7-11] 18 (18) 33 (34) 6 (6) 5 (5) 12 (12) 25 (25) 137 [135-139] 94 [79-129] 8 [6-12] 16 (14) 9 (56) 63 [42-70] 62 [51-80] 7 [5-9] 2 (12) 6 (38) 3 (19) 0 (0) 0 (0) 5 (31) 139 [136-141] 78 [72-105] 7 [5-8] 0.14 0.44 0.02 0.26 0.16 0.22 0.05
uNa: urine sodium concentration, uK: urine potassium concentration, sNa: serum sodium concentration, APACHE: Acute Physiology And Chronic Health evaluation, SOFA: Sequential Organ Failure Assessment. Data are presented as median [IQR] or as absolute numbers (%).
Discussion
The balance study showed that development of IAH is not fully explained by differences in sodium intake or fluid balance. Our data do not seem to be completely in line with previous literature and with the equation as described by Edelman. Over the last decades the common opinion has been that IAH is a primary iatrogenic problem caused by either sodium overload, lack of
adequate water intake or a combination1,12,14,16,18-20,26-28. However original data
on the differences in sodium intake and fluid balance between ICU-patients with and without IAH seem to be scarce. In addition some authors have focused on specific sources of sodium intake, such as resuscitation fluids or line flushing18. Our PDMS provided us the opportunity to incorporate all
sources of sodium intake, including tube feeding and medication. In addition populations investigated in previous publications were considerably smaller than in our study20,26. Lastly, an important difference between this study and
previous publications is the cut-off value for IAH. We deliberately chose 143mmol/l as cut-off value since Darmon et al. demonstrated the potential detrimental effects of even mildly elevated sNa in critically ill patients7. In
previous studies a cut-off value of 145mmol/l or even 150mmol/l was not uncommon1,12,14,18-20,26-28.
This not only reflects the change in mind set with respect to the relevance of IAH, but also the focus on the reduction of excessive sodium intake due to fluid overload and fluid composition in comparison to previous literature. It is conceivable that in previous publications the widespread use of ‘isotonic’ saline in combination with more liberal infusion triggers has been a
contributing factor in the development of IAH12. However, even in our setting,
with tight infusion triggers and lower sodium content of resuscitation fluids, median sodium intake is far beyond the recommended daily amount of 2.6g sodium and a specific group of ICU-patients still develops IAH6. This suggests
both differences in sodium handling between patients that do and do not develop hypernatremia and the potential for other contributing factors in the development of IAH not yet identified.
The study on renal cation excretion revealed that most patients with IAH seem to have an impairment in renal cation excretion. Such inability to excrete cations was previously suggested by others as a contributing factor in the aetiology of IAH14-16,26-27. Indeed, in our study on renal cation excretion, the
vast majority of patients with IAH displayed a total renal cation excretion below serum sodium concentration. This is unlikely due to a water deficit, since fluid balances were clearly positive. Strictly, this does not rule out an absolute water deficit, but makes it unlikely to be the only contributing factor. Suggested mechanisms are tubular dysfunction in the cause of acute renal failure or osmotic diuresis as a result of enhanced urea excretion16,26,29.
Although we did not measure urea excretion, the positive fluid balances in our patients make excessive renal water loss by osmotic diuresis as a cause of IAH unlikely.
If IAH cannot be explained by sodium intake or fluid balance, the issue of an alternative explanation arises. The fact that the APACHE IV-score, as markers of severity of illness, was independently associated as risk factor for
respectively IAH in the balance study and for low renal cation excretion fuels the idea of a more complex aetiology of IAH. Such alternative explanation could be found in a third compartment for storage of sodium. Already in 1910 Padtberg mentioned this compartment30. Storage of osmotically inactive
sodium in (extremely) high concentrations has been reported in cartilage, muscle, bone and skin31-33. In healthy volunteers water-free sodium storage
has been described32. In recent papers attention to this compartment was
renewed with focus on hypertension and its treatment34-36. In animal and
in-vitro models differences in sodium storage capacity were found and appeared to be related with the development of hypertension34,36. Binding of sodium to
proteoglycans seems to be the major mechanism for intra-cutaneous non-osmotic sodium storage and thereby serve as a conceivable third
compartment. Altered configuration with consequent changes in electrical binding capacity has been suggested during inflammation37. Our observation
that IAH was related to severity of illness, independent of sodium intake and fluid balance, may be in line with an inflammation mediated pathway. Further investigations on these mechanisms in relation to IAH should be initiated. Due to the retrospective single centre design this study has its limitations. Full fluid and sodium balances were not performed; sodium and water content in sweat and stool were left out of the equation. In this study insensible loss of 500 ml per day was estimated38,39. Urine analysis was limited to spot urine
samples and was restricted to patients with IAH. ADH-concentrations, urine urea concentrations and urine osmolality were not measured. Mentioned fluid balances did not include fluid administration prior to ICU admission. Due to
diurnal variation in renal sodium excretion spot urine samples are not optimal in evaluating urine sodium excretion.
Conclusion
In spite of the current opinion development of IAH is not (fully) explained by sodium intake or fluid balance. This lack of association between IAH and sodium intake and/or fluid balance suggests other factors unaccounted for in the current paradigm. Thereby IAH does not seem to be a primary iatrogenic complication. Severity of illness as an independent risk factor for both IAH and low renal sodium excretion may reflect other contributing factors, including sodium handling in the third compartment, not yet identified. Therefore prospective studies concerning handling and distribution of sodium and sodium balance, including hormone activity, to unravel the complex aetiology of IAH are needed.
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28. Lansink AO, Fahrentholz S, Nijsten MW. Risk of severe hypernatremia depends on underlying cause in critically ill patients. J Crit Care.
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29. Lindner G, Schwarz C, Funk GC. Osmotic diuresis due to urea as the cause of hypernatraemia in critically ill patients. Nephrology Dialysis
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30. Padtberg J. Über die Bedeutung der Haut als Chlordepot. Archiv für experimentelle Pathologie und Pharmakologie. 1910;63(1):60-79. 31. Cannon. Organization for physiological homeostasis. Physiol Rev. 1929;IX(3):399-431.
32. Titze J, Maillet A, Lang R, Gunga HC, Johannes B, Gauquelin-Koch G et al. Long-term sodium balance in humans in a terrestrial space station simulation study. Am J Kidney Dis. 2002;40(3):508-16.
33. Titze J, Lang R, Ilies C, Schwind KH, Kirsch KA, Dietsch P et al. Osmotically inactive skin Na+ storage in rats. Am J Physiol Renal Physiol.
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34. Titze J, Krause H, Hecht H, Dietsch P, Rittweger J, Lang R et al. Reduced osmotically inactive Na storage capacity and hypertension in the Dahl model. Am J Physiol Renal Physiol. 2002;283(1):F134-41.
35. Machnik A, Neuhofer W, Jantsch J, Dahlmann A, Tammela T, Machura K et al. Macrophages regulate salt-dependent volume and blood pressure by a vascular endothelial growth factor-C-dependent buffering mechanism. Nat Med. 2009;15(5):545-52.
36. Titze J, Bauer K, Schafflhuber M, Dietsch P, Lang R, Schwind KH et al. Internal sodium balance in DOCA-salt rats: a body composition study. Am J Physiol Renal Physiol. 2005;289(4):F793-802.
37. Zaferani A, Talsma DT, Yazdani S, Celie JWAM, Aikio M, Heljasvaara R et al. Basement membrane zone collagens XV and XVIII/proteoglycans mediate leukocyte influx in renal ischemia/reperfusion. PloS one. 2014;9(9):e106732. 38. Kerry Brandis. Insensible water loss [Internet]. [cited 01.06.2015].
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Chapter III
Hydrochlorothiazide in intensive care unit-acquired
hypernatremia: a randomized controlled trial.
Hydrochloorthiazide bij op de intensive care ontstane
hypernatriëmie: een gerandomiseerde studie
Marjolein M.C.O. van IJzendoorn
Hanneke Buter
W. Peter Kingma
Matty Koopmans
Gerjan Navis
E. Christiaan Boerma
Abstract
Impaired renal cation excretion seems to play a role in the aetiology of ICU-acquired hypernatremia (IAH). Therefore enhancing renal cation excretion seems to be a rational treatment for IAH. It was previously suggested to use thiazides for this purpose. We investigated the effect of hydrochlorothiazide (HCT) on IAH. Primary aim of the study was reducing sNa in patients with IAH with HCT in comparison to placebo. Secondary endpoints were a difference in urine sodium concentration (uNa) and duration of severe IAH. Therefore a monocentric, double-blind placebo-controlled trial was conducted in 50 patients with IAH and a low cation excretion. This low cation excretion was defined as a serum sodium concentration (sNa) lower than the sum of urine potassium and uNa in a spot urine sample. Eligible patients were randomized to HCT 25mg or placebo 1qd for maximal 7 days. Patients on renal
replacement therapy, on medication inducing diabetes insipidus or with recent use of diuretics were excluded. IAH was defined as sNa ≥ 143mmol/l. At baseline sNa and uNa were comparable between groups. During the study period sNa decreased significantly in both groups. No significant differences were found between groups. Median uNa increased significantly in both groups, with no difference between groups. Median duration of more severe IAH (sNa ≥ 145 mmol/l) was the same in both groups. All these findings led to the conclusion that HCT 25mg 1qd did not significantly affect sNa nor uNa in patients with IAH.
Samenvatting
Verminderde renale kationexcretie lijkt een rol te spelen bij het ontstaan van hypernatriëmie bij intensive care patiënten (ICU acquired hypernatremia, IAH). Daarom leek het rationeel om IAH te behandelen door het verhogen van renale kationexcretie. In eerdere literatuur werd gesuggereerd om voor dit doel een thiazidediureticum te gebruiken. Wij hebben het effect van
hydrochloorthiazide (HCT) op IAH onderzocht. Het primaire doel van deze studie was het verlagen van de serumnatriumconcentratie (sNa) bij patiënten met IAH ten opzichte van patiënten zonder IAH. Secundaire eindpunten waren het verschil in urinenatriumconcentratie (uNa) en de duur van ernstigere IAH. Hiervoor voerden wij een monocentrische dubbelblinde
placebogecontroleerde studie uit bij 50 patiënten met IAH en een lage
kationexcretie. Lage kationexcretie was gedefinieerd als een sNa lager dan het totaal van natrium en kalium in een urinemonster. Geschikte patiënten
werden gerandomiseerd naar 25mg HCT of placebo eenmaal daags gedurende maximaal 7 dagen. Patiënten met nierfunctievervangende therapie, medicatie die diabetes insipidus zou kunnen veroorzaken of recent diureticumgebruik werden uitgesloten van deelname aan de studie. IAH werd gedefinieerd als een sNa ≥ 143mmol/l. Bij het starten van de studie was er geen verschil tussen patiënten met en zonder IAH in sNa en uNa. Gedurende de studieperiode daalde de sNa in beide groepen significant, maar tussen de groepen werd geen verschil gevonden. De mediane uNa steeg significant in beide groepen, maar ook voor deze variabele was er geen verschil tussen patiënten die wel en geen IAH ontwikkelden. Ook de mediane duur van ernstigere hypernatriëmie (gedefinieerd als sNa ≥ 145 mmol/l) was hetzelfde in beide groepen. Al deze uitkomsten leidden tot de conclusie dat eenmaaldaags 25mg HCT geen significant effect heeft op sNa of uNa bij patiënten met IAH.
Introduction
ICU-acquired hypernatremia (IAH) is a common finding with a reported incidence between 3 and 17% 1-8. IAH has clinical significance, because it is
associated with prolonged length of stay (LOS) in the ICU and higher
morbidity and mortality6-8. IAH is supposed to stem mainly from disturbances
in water and sodium homeostasis, including salt overloading and inadequate water administration9-15. As such, the traditional approach to reduce serum
sodium concentration (sNa) in hypernatraemic ICU-patients is to reduce sodium intake and enhance (par)enteral water suppletion. Although this strategy is effective to some extent, it is of note that a systematic reduction in parenteral sodium intake was not associated with a reduction in incidence of IAH2. Moreover, water suppletion reduces sNa, but does not interfere with
potential other underlying mechanisms.
Impairment in renal excretion of cations was identified as one of the
contributing factors leading to IAH15. To enhance sodium excretion treatment
with hydrochlorothiazide (HCT) has been suggested9,15. The expected rise in
sodium excretion is due to inhibition of sodium reabsorption in the distal tubule and reduced free water clearance16. However, data on the effectiveness
of HCT in the specific setting of IAH seems to be missing. To evaluate the effect of HCT treatment on sNa in IAH a prospective randomized placebo-controlled clinical trial was conducted.
Materials and Methods
Design and setting
This single centre prospective double blind randomized placebo-controlled trial was conducted in a 20-bed mixed medical and surgical ICU in a tertiary teaching hospital. The primary aim of the study was to detect in patients with IAH a difference in reduction of sNa of at least 3mmol/l after treatment with HCT in comparison to placebo. Secondary endpoints were the difference in renal sodium excretion, the duration of sNa ≥ 145mmol/l and fractional sodium excretion (FEna).
Patients were included between September 2013 and April 2015. This trial consisted of two study arms. HCT (25mg) or placebo were administered once daily via a nasogastric tube. HCT is not labelled for the use of lowering sNa, but hyponatremia is a well-known side effect of this drug. Patients were
randomized by a list, generated by a dedicated pharmaceutical trial assistant, in blocks of 6 patients each to distribute patients on HCT or placebo equally during the study period. This randomization list was only available to the pharmaceutical staff, responsible for the preparation of the study medication. Criteria for in- and exclusion are presented in Table 1. In this study IAH was defined as a sNa of ≥ 143mmol/l. This cut-off value was chosen because of the association with adverse outcome of even mild IAH as observed by Darmon et al.7. The outcome ‘prevalence of more severe IAH (sNa ≥ 145mmol/l)’ was
added to investigate if HCT could be beneficial in preventing IAH from
becoming more severe compared to placebo. Patients were screened for their eligibility to be enrolled in the study by spot urine samples. Patients were considered eligible in case urine sodium concentration (uNa) plus urine potassium concentration (uK) did not exceed sNa. Informed consent was obtained from the patient or next of kin in compliance with applicable laws. The study protocol was approved by the local ethic board and registered at clinicaltrials.gov (NTC01974739) and Eudract (2013-002165-19).
Table 1: In- and exclusion criteria
Inclusion Exclusion
ICU-acquired serum sodium concentration ≥143mmol/l Expected ICU-stay >24 hours 18 years of age or above
Indication of incapacity for renal sodium excretion: urine sodium + urine potassium < serum sodium concentration
Informed consent
Serum sodium concentration on ICU- admission ≥143mmol/l
Central or nephrogenic diabetes insipidus
Severe hypokalaemia Administration of lithium,
amphotericine B or agents affecting vasopressine receptors
(Anticipation of) renal replacement therapy
Diuresis < 400ml/day
Use of HCT <48 hours previous to urine screen
Use of loop diuretics <12 hours previous to urine screen Intolerance to thiazides Pregnancy
HCT: Hydrochlorothiazide
Collected baseline parameters included demographic data, diagnosis and severity of illness on admission, serum electrolyte concentrations and data concerning renal excretion. Study medication was administered at 6 PM, after which collection of 24 hours urine started for the duration of the study period. During the study period electrolytes were measured routinely four times a day by point-of-care testing (POCT, ABL800 AutoCheck®, Radiometer Pacific Pty. Ltd., Australia and New Zealand). Serum creatinine and urea concentrations were routinely measured once daily. FEna was calculated according to
Equation 1. Additionally collected data included fluid balances, dose and kind of administered diuretics, gastric retentions and severity of illness. All patients with gastric retention > 150ml per six hours over a period >24h were
equipped with a duodenal feeding tube. By protocol administration of study medication was limited to a maximum of 7 days. Other reasons to end the administration of study medication were a sNa <139mmol/l, the need for (unanticipated) renal replacement therapy, administration of >120mg furosemide per day and ICU discharge. A certain administered dose of furosemide was allowed to investigate the effect of HCT on IAH in common daily ICU practice. In this daily practice prescription of other diuretics is very rare. In case sNa exceeded 149mmol/l, glucose 5% was administered
intravenously until sNa returned to ≤149mmol/l. Hypokalaemia (<
3.5mmol/l) was corrected by a nurse-driven potassium suppletion protocol. All clinical data were automatically stored in a patient data management system (PDMS) from which they were extracted into an anonymised database. No funding was received.
Statistical analysis
The power analysis was based on data previously collected in patients with sNa ≥ 143mmol/l in our ICU. Main goal was to detect a difference of 3mmol/l in reduction in sNa between both groups with a power of 80% and α of 5%. Including correction for 2 drop-outs per group 25 patients were needed in both groups. Data were collected and analysed in SPSS version 19 and 20 (IBM, New York, USA), based on an intention-to-treat principle. Since the majority of variables was not normally distributed, data are expressed as median [IQR]. Analyses were conducted using Mann-Whitney-U testing for independent variables, Wilcoxon Signed Rank test for dependent variables and Fisher’s exact test to compare percentages. Outcomes were considered significant at p ≤ 0.05. Effect sizes were calculated according to Equation 2. Equation 1: Fractional sodium excretion (FEna)
𝐹𝐸𝑛𝑎 (%) =𝑢𝑁𝑎 𝑠𝑁𝑎𝑥
𝑠𝐶𝑟𝑒𝑎𝑡 𝑥 0.001 𝑢𝐶𝑟𝑒𝑎𝑡 𝑥 100
FEna: Fractional sodium excretion, uNa: urine sodium excretion in mmol/l, sNa: serum sodium concentration in mmol/l, sCreat: serum creatinine concentration in µmol/l, uCreat: urine creatinine concentration in mmol/l Equation 2: Effect size
𝑍/√𝑛 Z: Z-score, n = number of observations
Results
Baseline characteristics
In the inclusion period 2321 patients were admitted of which 299 patients developed IAH (Fig. 1). Urine screening was performed in 116 patients. Main reason not to perform a screening spot urine sample was an expected LOS ICU <24 hours. Baseline characteristics did not differ significantly between groups (Table 2). In both groups the study was terminated prematurely in 1 patient: One patient because of hypercalcaemia, which was considered a
contraindication of HCT; the other because of the development of diabetes insipidus. Serum creatinine according to laboratory reference values for men and women was elevated in 13 patients in the HCT-group and 8 patients in the placebo group (p = 0.25)17.
Primary and secondary endpoints
Main results are shown in Table 3 and 4 and Figure 2 and 3. On the last day of the study median sNa in patients treated with HCT was 141 [137-147] mmol/l and in patients treated with placebo 144 [139-146] mmol/l (p = 0.30). In comparison to baseline median sNa decreased significantly over time with 4mmol/l in both groups (p < 0.01). However the decrease in sNa over time, which was the primary endpoint, was not different between groups (p = 0.47). If groups were divided into quartiles based on their sNa at study start
(<144mmol/l, 144-145mmol, 146-147mmol/l or >147mmol/l) still no differences in decrease of sNa occur. Median uNa at the end of the study was 110 [70-124] mmol/l in the HCT-group and 84 [52-126] mmol/l in the placebo group (p = 0.40). In comparison to baseline median uNa increased significantly over time by 46 [26-86] mmol/l in patients treated with HCT and 36 [9-78] mmol/l in patients on placebo (p < 0.01). However, this increase did not differ between groups (p = 0.70). Median duration of sNa ≥ 145 mmol/l was 3 days in both groups (p = 0.91).
IAH = ICU-acquired hypernatremia (defined as serum sodium concentration ≥ 143 mmol/l), sNa = serum sodium concentration in mmol/l, uNa = urine sodium concentration in mmol/l, uK = urine potassium concentration in mmol/l, HCT = hydrochlorothiazide, CVVH = continuous veno-venous hemofiltration
