University of Groningen
The multifactorial aetiology of ICU-acquired hypernatremia
IJzendoorn, Marianne
DOI:
10.33612/diss.109636342
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Publication date: 2020
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IJzendoorn, M. (2020). The multifactorial aetiology of ICU-acquired hypernatremia. Rijksuniversiteit Groningen. https://doi.org/10.33612/diss.109636342
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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 processes still incompletely understood in both health and disease.
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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