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CJASN May 2019, 14 (5) 656-663; DOI: https://doi.org/10.2215/CJN.10640918
Rate of Correction of Hypernatremia and Health Outcomes in Critically Ill Patients.
Hypernatremia (serum sodium concentration >145 mEq/L) is a common electrolyte disorder and is especially common among elderly institutionalized individuals. Hypernatremia can also be seen among hospitalized patients, especially intubated patients in the intensive care unit without access to water. Upon admission to the ICU, approximately 2% of patients are already hypernatremic and another 7% develop hypernatremia during the hospitalization. It is associated with increased length of stay and mortality.
Though hypernatremia is defined and named after sodium, it is not a sodium disorder, it is a water disorder. Hypernatremia develops when there is loss of water that is not compensated for either by an adequate ingestion of water or by an adequate generation of electrolyte free water by the kidney. Additionally, gain of sodium can cause hypernatremia if the increased sodium load is not adequately matched with water ingestion and generation of electrolyte free water by the kidney. Hypernatremia is thus the convergence of too little water and/or too much salt.
Since hypernatremia that occurs during hospitalization is typically iatrogenic and treatable, It has been suggested as a quality of care indicator. But since there is no compelling data showing improved outcomes from the treatment of hypernatremia, some have questioned this metric.
The clinical approach to the patient with hypernatremia is to first deal with emergencies, and then to anticipate and prevent dangers induced by therapy.
Damned if you do
“The double edged sword in dysnatremias on brainy issues.”
Acute hypernatremia (<48hrs) may induce lethargy, weakness, seizures or even coma, and should be immediately corrected. For patients with chronic hypernatremia (>48hrs), where an osmotic brain adaptation has occurred but not less symptomatic, expert opinion favors a slower rate of correction to avoid cerebral edema.
Damned if you don’t (apologies to Tomas Berl)
On the other hand, slow correction prolongs hypernatremia and its associated morbidity. In retrospective analysis, slow correction is associated with both a failure to correct the sodium at all, and with an increased hospital mortality. This has been reported in two studies: in patients who presented with hypernatremia to the emergency and in a single-center study of US veterans who developed hypernatremia during hospitalization. In both studies, most patients were still hypernatremic three days after presenting with or developing hypernatremia.
In contrast to hyponatremia, where speed limits for sodium correction have been extensively studied, there is little evidence of morbidity from rapid correction of hypernatremia. The experts Adrogue and Sterns suggested a slower reduction rate of no more than 0.5 mmol/L per hour, with an absolute change of 10 mmol/L per day to avoid cerebral edema, seizure, and permanent neurologic damage from rapid correction. This recommendation is founded on data from a case-control study of age matched infants with and without seizures during fluid resuscitation for hypernatremic dehydration secondary to acute gastroenteritis. The cases (seizures, group I) had higher BUN than the controls.
The authors focused on the rate of fluid resuscitation and the drop in sodium to differentiate the cases from the controls:
Note that the controls had an average sodium decrease faster than the 0.5 mmol/L/hr recommendation. Adrogue has a second reference to support the slow rehydration. This had 18 infants who had no seizures and an average sodium lowering rate of 0.3 mmol/L/hr, and found that with oral rehydration achieving a mean sodium decrease of 0.32 mmol/L/h, no seizures were observed. Sterns’ reference, a retrospective study from a NICU is also probably not applicable to an internal medicine cohort with univariate risk factors including, first time mom and maternal age being younger. Additionally the seizure group (group 2 here) is quite a bit sicker:
Though to his credit, Sterns walks away from the data to inject a bit of rationality in the discussion:
Limiting correction of chronic hypernatremia so that the plasma sodium concentration is decreased by less than 0.5 mmol per liter per hour reduces the risk of cerebral edema and seizures associated with rehydration. However, the fear of these complications, which have been reported only in young children, should not deter the aggressive rehydration of adults with acute hypernatremia to avoid brain hemorrhage or osmotic demyelination (Table 2). In contrast to the risk of inadvertent overcorrection in patients with hyponatremia, there is little risk of inadvertent overcorrection in patients with hypernatremia, and adults with hypernatremia are often undertreated.
In children with DKA, about 1% develop cerebral edema which has a mortality rate of 50-80%. There is some data that aggressive glucose lowering may cause an osmotic cerebral edema. However the data is far from conclusive.
The bottom line is that there is theoretical risk of cerebral edema from the rapid correction of hypernatremia but hard data, especially for adults, is scant. In fact there is some data that under treating hypernatremia may put patients at risk. This is the environment that this week’s NephJC article wanders into: is there risk of seizures, poor neurologic outcome, or death from the rapid treatment of hypernatremia, or can we safely ignore this dogma?
Is there an association between the rate of correction of hypernatremia and adverse patient outcomes?
A retrospective observational study from a single-center tertiary care hospital (Beth Israel Deaconess Medical Center in Boston, MA) from 2001 to 2012.
The data was abstracted from from the Medical Information Mart for Intensive Care-III (MIMIC-III) database.
Serum sodium > 155 mmol/L during an inpatient stay
Over 18 years old
No serum sodium value after peak
Chronic Hypernatremia: either admission with a serum sodium over 155 or a serum sodium > 145 mmol/L for > 48 hours in the hospital.
Formula for correction:
Slow correction ≤ 0.5 mmol/hr (ie 12 mmol/24 hours)
Rapid correction > 0.5 mmol/hr
In addition to this grouping of rapid and slow, the authors also used a few other grouping by performing several subanalysis with varying hypernatremia correction rates of:
> 8 mmol/L per 24 hours
> 10 mmol/L per 24 hours
> 12 mmol/L per 24 hours
The main outcomes of interest were
the incidence of neurologic outcomes (cerebral edema, seizures, alteration of consciousness)
Both of these were measured at 30 days. ICD 9 codes were used for the neurological complications, and imaging reports, and discharge summaries were manually reviewed by two independent clinicians to identify the cause of cerebral edema and to determine whether it was attributable to rapid hypernatremia correction.
The primary analysis was conducted to explore differences between patients who experienced slow versus rapid correction stratified by two groups: admission hypernatremia and hospital-acquired hypernatremia. They further divided categories into those who achieved a normal sodium (< 145 mmol/L) versus those that never achieved it.
A Kaplan–Meier survival curve was used to assess diference in mortality between groups. Logistic regression was used to determine the rate of correction’s influence on mortality over time, with adjustment for age, sex, DNR status, and Charlson comorbidity index included in the model. A subgroup analysis looking at patients with in-hospital sodium over 145 mmol/L for 48 hours as having chronic hypernatremia was also done.
Research reported in this publication was supported by the NIDDK (National Institute of Diabetes and Digestive and Kidney Diseases) of the National Institutes of Health.
Over the period of the study, from 2001 – 2012, the authors included 449 patients from the 41, 149 patients with sodium values in the MIMICS II database.
See more details of those 449 patients came from, and the rates of correction below:
Table 1 below describes the baseline characteristics by correction rates in both groups. The slower correction rate in both groups were sicker patients.
Patients with rapid sodium correction with hypernatremia on admission were more likely to be female, have depression, and were less likely to have CKD. Patients with rapid sodium correction with hospital-acquired-hypernatremia had lower serum bicarbonate, lower prevalence of stroke, and shorter hospital stay.
And the business end of table 1.
Table 2 Describes the Distribution of the sodium level, difference, and correction time. The peak serum sodium was higher in Admission-Hypernatremia group.
The time to correction to serum sodium <145 in the Hospital-Acquired group was 14.7hr from peak sodium, with a higher median rate of correction (0.9mmol/hr) vs 18 hr from peak to <145 and median rate of correction (0.7mmol/hr) in the Admission group.
Association of Serum Sodium Correction Rate with in-hospital Mortality
There was no difference in mortality between patients on rapid vs slow correction in both groups, not even on the multivariable analysis.
In the categorial analysis with different cut-offs correction values at 24 hours. There was a trend for lower mortality in the admission hypernatremia with rapid correction rate.
Rapid correction and Neurological Sequelae
Among both groups of patients, the manual review found no patients that had documented worsening mental status, seizures, or generalized cerebral edema that could be attributed to correction of serum sodium
There were patients who did have these complications, but they were attributed to intracerebral hemorrhage, stroke, epilepsy, brain tumors, and brain trauma.
This is the largest adult cohort study focusing on the neurologic complications and mortality after hypernatremia correction in critically ill adults.
There wasn’t any evidence that rapid correction of hypernatremia was associated with a higher risk for mortality, or neurological sequelae (seizure, alteration of consciousness, and/or cerebral edema) in critically ill adult patients with either admission or hospital-acquired hypernatremia. The latter result is based on a the manual review performed by the authors.
This retrospective study adds to the existing literature which has consistently been unable to show any reduction in adverse neurologic (or other) outcomes with slow correction of hypernatremia. In addition, as seen in two prior studies, there was a trend towards harm with slow correction. It is contrast to the study done in neonates which did report a higher risk of death and convulsions with rapid correction. The authors speculate that this could be due to the difference in brain volume: cranial vault size which is maximal at 6 years, and could limit adaptation in neonates and children, more than in adults.
The study design is a retrospective chart review, and not a prospective study or a clinical trial.
The attribution of the neurological sequelae was done by two of the investigators and not by a blinded adjudication committee (as in done in trials); and actual progress notes were available only for 47 patients - in other cases the judgment was made on the basis of the imaging reports. Nevertheless, this was performed independently by the two authors.
The authors point out in their discussion of the limitations some additional potential issues:
They had limited information about the intravenous fluids used for correction, and whether those could be confounding, however little or no data exist on the role of different fluid regimens on these outcomes.
The study included critically ill patients, and not patients with milder levels of hypernatremia and those who were not critically ill, so caution should be exercised in extrapolating the results to these patients. On the other hand, one could argue that if no adverse effects were seen in sicker patients, there are no adverse effects that should be expected in less sick patients.
One concern is the high rate of hospice and dementia in the cohort, this of course is the very population that is prone to hypernatremia but this population may also mask subtle neurologic changes and caution may be warranted in aggressive sodium lowering in otherwise neurologically intact and younger adults.
These studies have all been retrospective chart reviews so it is wise to be skeptical but it is increasingly looking like the treatment of hypernatremia is unique from the development of acute hyponatremia and is well tolerated in older adults.
Summary by Aldo Rodrigo Jimenez Vega, Mexico City, Mexico