Neurocrit Care DOI 10.1007/s12028-014-0067-8
ORIGINAL ARTICLE
Hypernatremia is a Significant Risk Factor for Acute Kidney Injury After Subarachnoid Hemorrhage: A Retrospective Analysis Avinash B. Kumar • Yaping Shi • Matthew S. Shotwell Justin Richards • Jesse M. Ehrenfeld
•
Ó Springer Science+Business Media New York 2014
A. B. Kumar (&) Department of Anesthesiology, Division of Critical Care Medicine, Vanderbilt University, 1211 21st Avenue, S, 526 MAB, Nashville, TN 37212, USA e-mail: [email protected]
72 h and 14 days following admission. A Cox proportional hazards survival model with multiple time varying covariates was developed to evaluate the effect of maximum sodium exposure on the risk of AKI. Sodium exposure was captured as the running maximum of daily maximum serum sodium concentration (mEq/L). Sodium exposure was used as a surrogate for hypertonic saline therapy. Results The final cohort of patients included 736 patients admitted to the neuro intensive care unit between 2006 and 2012. The number of patients who developed AKI was 64 (9 %). These patients had an increased length of stay (15.6 ± 9.4 vs. 12.5 ± 8.7 days). The odds of death were more than two fold greater among patients who developed AKI (odds ratio 2.33 95 % CI 1.27, 4.3). Sodium exposure was significantly associated with the hazard of developing AKI, adjusting for age, sex, preexisting renal disease, diabetes mellitus, radiocontrast exposure, number of days on mechanical ventilation, and admission Glasgow Coma Scale score. For each 1 mEq/L increase in the running maximum daily serum sodium, the hazard of developing AKI was increased by 5.4 % (95 % CI 1.4, 9.7). Conclusion The maximum daily sodium is a significant risk factor for developing AKI in patients with SAH.
Y. Shi M. S. Shotwell Department of Biostatistics, Vanderbilt University, 1211 21st Avenue, S, 526 MAB, Nashville, TN 37212, USA e-mail: [email protected]
Keywords Hypernatremia Acute kidney injury Subarachnoid hemorrhage Hyperosmolar therapy Hypertonic saline Serum sodium
Abstract Background Hypertonic saline therapy is often used in critically ill subarachnoid hemorrhage (SAH) patients for indications ranging from control of intracranial hypertension to managing symptomatic hyponatremia. The risk factors for developing acute kidney injury (AKI) in this patient population are not well defined. Specific Aim To study the role of serum sodium in developing AKI (based on the AKIN definition) in the SAH population admitted to a large academic neurocritical care unit. Methods This is an IRB-approved, retrospective cohort study of patients admitted to a tertiary neuro intensive care unit. We included adult (age C18 years) SAH patients admitted to the neuro intensive care unit for at least 72 h. Development of AKI after admission to the ICU was defined using the AKIN serum creatinine criteria between
M. S. Shotwell e-mail: [email protected] J. Richards J. M. Ehrenfeld Department of Anesthesiology, Vanderbilt University, 1211 21st Avenue, S, 526 MAB, Nashville, TN 37212, USA e-mail: [email protected] J. M. Ehrenfeld e-mail: [email protected]
Introduction Subarachnoid hemorrhage (SAH) accounts for only about 5 % of all strokes but remains a devastating disease with mortality approaching 50 % and with less than 1 in 2 survivors reaching functional independence [1]. The
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neurocritical care course of these patients is frequently complicated by non-neurologic complications including cardiorespiratory complications including the development of acute kidney injury or AKI [2]. The intensive care course of this patient population deviates from other ICU encounters (e.g. patients with septic shock or heart failure) due to exposure to specific interventions and management strategies. These include potential repeated exposure to IV contrast media, hyperosmolar agents, and euvolemic fluid management strategies as well as development of hyponatremia, and high urine output states. Prior studies of renal dysfunction following neurologic injury have been challenging due to the lack of a consistent, validated and reproducible definition of acute renal failure. This has largely been overcome with the changes in the definition and criteria for diagnosis of acute renal failure. Currently, acute kidney injury has replaced the term acute renal failure and has been validated in various patient populations by the RIFLE and AKIN criteria [3]. However, little is known about the specific risk factors for AKI in the SAH patient population and its subsequent impact on outcomes [4]. Specific Aim In this retrospective analysis, we seek to study the incidence, risk factors, and outcomes following development of new onset acute kidney injury (based on the new validated definition) following SAH (SAHAKI) population admitted to a large academic neuro intensive care unit.
Materials and Methods Our retrospective study was approved by the Vanderbilt University Institutional Review Board. We set out to analyze all patients admitted to the Vanderbilt neuroscience intensive care unit with the diagnosis of SAH (aneurysmal and non-aneurysmal) between 2006 and 2012. Traumatic brain injury patients were not in the dataset since at our institution, their primary location of admission is a different ICU. We excluded patients who did not survive the first 24 h of admission, and patients on renal replacement therapy (RRT). We also excluded patients whose primary source of intracranial blood was not a SAH (e.g. a large intraparenchymal bleed with some subarachnoid blood was excluded). Data Collection and Definitions Preoperative data points included age, sex, height, weight, BMI, current smoking status, diabetes mellitus, hypertension, preoperative kidney function (defined as the latest available serum creatinine prior to admission), admission
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neurologic exam, admission Glasgow coma score, Hunt and Hess class of SAH, and location of bleed and aneurysm (if applicable). Intensive care variables included duration of mechanical ventilation, intracranial hypertension, hyperosmolar therapy (mannitol and hypertonic saline), daily fluid balances, and transfusion support (including use of packed red blood cells, fresh frozen plasma, cryoprecipitate, and recombinant Factor 7). Laboratory values assessed included daily maximum and minimum serum sodium, minimum and maximum serum osmolality. All variables were followed for 14 days post ICU admission. The primary outcome was development of AKI based on the acute kidney injury network (AKIN) serum creatinine (sCr) criteria. The secondary outcomes were intensive care length of stay (LOS) and 28day mortality. Data were obtained from the Vanderbilt Perioperative Data Warehouse, an IRB-approved data registry containing case and outcomes information on all surgical and ICU patients cared for at our institution. The AKIN criteria has been utilized and validated in prospective studies in patients with AKI after cardiac surgery, septic shock, ARDS, and mixed ICU populations [3]. Stage 1 in the AKIN classification includes patients with an increase in sCr of at least 0.3 mg/dl over baseline, since there is accumulating evidence that even minor increments in serum creatinine are associated with adverse outcomes. Stage 2 is defined as an increase of 2–3 fold over the baseline sCr. Any patient treated with RRT, irrespective of urine output or sCr, or with a C3 fold rise in sCr is categorized as stage 3 in the AKIN system. The AKIN classification uses a 48-hour time window for assessment of renal function based on the evidence that adverse outcomes were reported when the creatinine elevation occurred within 24–48 h of hospitalization [5]. In the AKIN definitions, the thresholds for urine flow for the definition of AKI have been derived empirically and are less well substantiated than the thresholds for increase in SCr. Urine output has traditionally been a bellwether of renal dysfunction in the general ICU patient population. The SAH patient population is frequently complicated by high output renal states such as cerebral salt wasting, and the AKIN urine output criteria have not been validated in this patient population. We chose to use the creatinine-based definition of AKI, with the most recent serum creatinine including upto day of admission being considered the baseline value. Preoperative renal insufficiency was defined as a baseline serum Cr C1.2 mg/dl. The decision to initiate RRT was at the discretion of the attending consultant nephrologist. Although hypertonic saline is used in varying strengths from 3 % solution (513 mmol/L), 7.5 % solution (1283 mmol/L), or in a 23.4 % solution (4008 mmol/L), in our study hypertonic saline was limited to 3 % NaCl. We followed the patients for development of SAHAKI for a period of 14 days. We focused on this time frame since this is considered the highest risk period for clinically
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significant vasospasm and subsequent exposure to multiple interventions. Statistical Analysis Patient demographics and clinical data were summarized using the 25th percentile, median, and 75th percentile for continuous variables, and with percentages for categorical variables. Unadjusted comparisons between those who did and did not develop AKI on demographic and clinical data were conducted using the Wilcoxon rank sum test for continuous variables and the Pearson Chi square test for categorical variables. The AKI incidence and mortality rate were estimated and reported with 95 % confidence intervals using a nonparametric bootstrap method. Unadjusted AKI free survival was depicted using a Kaplan–Meier curve. Serum creatinine was measured daily from ICU admission (day 1) to discharge or day 14 whichever was the earlier. The primary outcome was indicated when serum creatinine increased by more than 0.3 mg/dl within a 48hour period. Patients were removed from the at-risk pool once AKI had been observed. Patients who did not develop AKI during their ICU stay were censored at the time of ICU discharge or at 14 days, whichever came earlier. A Cox proportional hazards model with time varying covariates was used to identify risk factors for developing AKI during the ICU stay. The fixed risk factors included patient age at hospital admission, sex, diabetes mellitus, preexisting renal disease, and Glasgow coma score. The time varying risk factors included the cumulative count of radiocontrast exposure in days, the cumulative count of days on mechanical ventilation, and the running maximum of daily maximum serum sodium concentration. All analyses were implemented using R 3.0.2 (R Foundation for Statistical Computing, Vienna, Austria). A significance level of 0.05 was used for statistical inference.
Results Our study included 736 consecutive adult SAH patients with an overall AKISAH incidence of 9.0 % (64 out of 736). Patients who developed AKI had an increased length of ICU stay (15.6 ± 9.4 vs. 12.5 ± 8.7 days, p = 0.002). The overall mortality in the AKI cohort was 0.25 (95 % CI 0.16, 0.36) and 0.12 (95 % CI 0.10, 0.15) in non-AKI patients. The unadjusted odds of death were more than two fold greater among patients who developed AKI during their clinical ICU course (odds ratio 2.33 95 % CI 1.27, 4.3). Among the 64 patients in the AKI cohort, 58 (90.6 %) patients had a change in serum Cr 300 % putting them in the AKI-Class III category. Of the 736 patients in our final cohort, the majority patients were female (59 %). The median age at time of hospital admission was 55 ± 15 Y. Among those who developed AKI, 19 and 14 % of the patients had diabetes mellitus and preexisting renal disease respectively, compared to 12 and 6 % of patients who did not develop AKI. There was a difference in the baseline count of patients with diabetes mellitus (p = 0.016) and exposure to packed red cell transfusion (p = 0.054) in the AKI versus no-AKI group (Table 1). However, there was no statistically significant difference between cohorts with regard to admission Glasgow coma score [11.3 ± 4.9 in the AKI cohort and 11.7 ± 4.6 in nonAKI cohort, (p = 0.69)]. Mechanical ventilation was initiated on admission in 35 % (22/63) of patients in the AKI cohort compared to 29 % (194/669) in the No AKI cohort. However, there was no statistically significant difference between the cohorts regarding endotracheal intubation and mechanical ventilation on admission (p = 0.32). There was no significant unadjusted difference between cohorts with respect to exposure to hypertonic saline, mannitol, IV contrast, or baseline levels of serum sodium on admission. A Cox proportional hazards regression with multiple time varying covariates was implemented to evaluate the effect of specific risk factors and development of AKISAH. We utilized previously published independent risk factors as predictors of AKISAH [6]. These independent risk factors included age, sex, preexisting kidney disease, and DM. The SAH centric risk factors for AKI that we explored included packed red blood cell transfusions, exposure to contrast, and location of bleed, etiology of SAH (aneurysmal vs. non-aneurysmal), Glasgow coma score on presentation, mechanical ventilation, highest serum sodium every 24 h, 24 h fluid balances, and BMI. The results are shown in Table 2. There was insufficient evidence associating the development of AKI with age, sex, diabetes mellitus, preexisting renal disease, GCS, and cumulative count of radiocontrast exposure or cumulative count of days on mechanical ventilation. The Kaplan–Meier (K–M) curve for the unadjusted time to development of AKISAH is illustrated in Fig. 1. The first peak of AKI developed around day 3 followed by a second smaller peak by day 7. An estimated six percent of patients developed early AKISAH by day 3, rising to 12 % at 14 days. Intravenous contrast media is a known risk factor for development of acute kidney injury. We explored the temporal exposure patterns of patients to IV contrast over a period of 14 days. The exposure to IV contrast exposure is shown in Fig. 2 (contrast exposure). The highest exposure was on day 1 (39.3 % of all patients) as anticipated, due to
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Neurocrit Care Table 1 Patient demographics and baseline characteristics
Age
AKI (N = 64)
No AKI (N = 672)
Combined (N = 736)
p
49, 56, 73
45, 55, 65
45, 55, 65
0.17
(55 ± 15)
(59 ± 16)
(55 ± 15)
Female
53 % (34/64)
60 % (402/672)
59 % (436/736)
0.3
BMI
23.0, 26.6, 31.3
23.1, 25.9, 30.4
23.1, 26.0, 30.4
0.94
(28.2 ± 8.3)
(28.1 ± 11.1)
(28.1 ± 10.9)
Diabetes mellitus-type II (%)
19 % (12/64)
12 % (84/672)
13 % (96/736)
0.16
Preexisting renal disease (%) Glasgow coma score
14 % (8/64) 7.0, 15.0, 15.0
6 % (40/672) 8.0, 15.0, 15.0
7 % (51/736) 7.0, 15.0, 15.0
0.07 0.69
(11.3 ± 4.9)
(11.7 ± 4.6)
(11.6 ± 4.7)
Contrast exposure(%)
44 % (28/64)
39 % (261/672)
39 % (289/736)
0.44
Mannitol (%)
6 % (4/64)
3 % (20/672)
3 % (26/736)
0.23
Sodium
0, 137, 140
0, 137, 140
0, 137, 140
0.39
(100 ± 64)
(93 ± 65)
(94 ± 65)
Osmolality RBC transfusion
296, 308, 320
298, 304, 314
298, 305, 317
(303 ± 25)
(308 ± 18)
(308 ± 19)
4.5 % (3/64)
1 % (7/672)
1.3 % (10/736)
0.94 0.054
Summary statistics are shown as the 25th, 50th, 75th percentile (mean ± SD) for continuous variables, percentage for categorical variables. p values were calculated using the Wilcoxon rank sum test for continuous variables and the Pearson Chi-square test for categorical variables Table 2 Effect estimate (95 % CI) calculated from the time varying Cox proportional hazard model Variable
HR (95 % CI)
p
Age
1.02 (0.99, 1.04) 0.16
Female
0.74 (0.42, 1.30) 0.29
Diabetes mellitus
1.55 (0.82, 2.94) 0.18
Preexisting renal disease
1.45 (0.55, 3.81) 0.45
Glasgow coma score
1.02 (0.96, 1.09) 0.47
Cumulative maximum sodium
1.06 (1.01, 1.10) 0.008
Cumulative count of radiocontrast exposure 1.09 (0.78, 1.53) 0.62 Cumulative count of days on mechanical 1.04 (0.96, 1.12) 0.36 ventilation
concentration (mEq/L). The distribution of daily maximum sodium is shown in Fig. 3. Hypernatremia (secondary to the use of hypertonic saline) and even small increments of daily serum sodium was a significant risk factor for AKISAH after adjusting for other risk factors. The strongest risk factor associated with development of AKI in the SAH patient population was the daily maximum serum sodium. For each 1 mEq/L increase in the running maximum of daily maximum serum sodium, the hazard of developing AKI was increased by 5.5 % (95 % CI 1.4, 9.7, p value = 0.008).
Discussion the nature of the diagnostic workup of a SAH. This exposure was reduced significantly by day 3 (about 3.5 % of patients being exposed) and continued to be low at about 5 % until day 8 and 9. There was a second peak of contrast exposure on day 8 and 9 (10.4 and 17 % respectively). However, based on our Cox proportional hazards regression model, in spite of significant exposure, there was insufficient evidence that the running count of IV contrast exposure events was a significant risk factor for AKISAH in our patient population. After adjusting for other covariates including sodium exposure, HR for AKI was 1.09 (0.78, 1.53); p = 0.62. Sodium exposure was used as a surrogate for hypertonic saline therapy in our analysis and was captured as the running maximum of daily maximum serum sodium
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Significant strides have been made in the neurologic management of SAH in the past decade. The focus now rests on minimizing the non-neurologic complications associated with this disease that still has a high morbidity and mortality [7]. Identification of patient and procedural risk factors may therefore allow for improvements in longterm outcome by affecting changes in perioperative management and disease prevention. In our analysis, the overall incidence of AKI was 9 %, which is lower compared to reported AKI rates in post cardiac surgical and general post surgical intensive care units, where rates as high as 47 % have been reported [8]. Hypernatremia secondary to the use of hypertonic saline was the strongest risk factor for developing AKISAH in our
Neurocrit Care Fig. 1 Kaplan–Meier curve showing the timeline to develop AKI in the ICU in the SAH patient population
Fig. 2 Temporal trend of IV contrast exposure in all patients showing the proportion of patients (%) exposed to I.V. contrast between ICU day 1 and ICU day 14
patient population. Interestingly, the traditional risk factors for AKI in mixed ICU populations such as diabetes mellitus, preexisting kidney disease, advanced age were not significant risk factors for developing AKI in our SAH population. Contrast-induced nephropathy was not a significant event in our patient population in spite of increasing frequency of contrast exposure each year of the study in the SAH patient population. Patients who developed new onset AKI had an increased length of stay and were at an increased risk of in-hospital mortality. Raised intracranial pressure (ICP) is an independent predictor of poor neurologic outcome following SAH. Intracranial hypertension and cerebral edema are cardinal manifestations of severe brain injury resulting from diverse
insults ranging from traumatic brain injury to SAH. Early and aggressive management of intracranial hypertension is a key to a good outcome. Hyperosmolar therapy with mannitol and hypertonic saline has been the cornerstone in the management of intracranial hypertension [9]. Recent studies including a metaanalysis showed HS to be more effective with controlling ICP compared to mannitol [10]. The intensivist preferences of using mannitol versus hypertonic saline are evenly divided based on a recent national survey [11]. In the same survey, interestingly the major reason for the preference for using hypertonic saline was the perceived ‘‘decreased risk of renal dysfunction’’ compared to mannitol [11]. As our experience with the use of hypertonic saline in various concentrations grows, we will gather a better renal risk profile of hypertonic saline. Dominguez et al. reported the increased risk of renal dysfunction in pediatric patients who were maintained in a hyperosmolar state at 160 mEq/L in severe traumatic brain injury [12]. It is thought that hypernatremia can lead to renal dysfunction through the mechanism of intravascular dehydration and vasoconstriction either directly or through a tubuloglomerular feedback mechanism [13]. Animal studies have shown a reduction of renal blood flow, glomerular filtration rate, and an inhibition of renin secretion when the sodium level in the renal artery is increased rapidly [14]. These findings can be explained by the fact that the kidney, in contrast to other organs, responds with vasoconstriction to a hypernatremic state. HTS is not without potential major adverse effects. While relatively rare, serious electrolyte
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Fig. 3 Sodium max on ICU day 1 through day 14. The panel on the top shows sodium max data for patients who developed AKI, and the panel on the bottom shows the cohort with no AKI
disturbances may be induced central pontine myelinolysis in malnourished patients with an acute hypernatremic state following rapid serum sodium correction [15, 16]. Hyperchloremic acidosis and acute hemolysis are further consequences of HTS administration. Hyperosmolar therapy is also known to induce rapid intravascular volume expansion and subsequent cardiac overload with pulmonary edema. Further worsening of cerebral swelling and increased ICP maybe indicative of a disrupted blood brain barrier and a ‘‘reverse osmosis’’ phenomenon (1). In addition, renal complications due to HTS therapy are an real concern [15, 17]. The therapeutic management of SAH has undergone significant changes in the past decade for SAH with the advent of neurovascular interventions such as stenting and endovascular coiling of aneurysms [18]. These procedures frequently require contrast angiography to define the anatomy, and during the therapeutic intervention as well. Thus, with a change in the management paradigm for SAH, patients today have a higher potential for multiple exposures to IV contrast media secondary to both diagnostic and
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therapeutic interventions during their ICU course [19]. This increases the risk of contrast-induced nephropathy in this patient population. In the general patient population, hypovolemia, volume of contrast used, preexisting kidney disease, diabetes mellitus, advanced age, and decreased left ventricular function are established risk factors for contrast-induced nephropathy. Rate of contrast-induced nephropathy has been reported to be as high as 20–25 % in high-risk patients (e.g. cardiac ICU patient population) [20]. Interestingly, although there has been conflicting data on the rates of CIN in the SAH population, the overall incidence is lower than the general mixed ICU patient population [21, 22]. This reflects the finding in our study as well that exposure to IV contrast was not associated with an increased risk of AKI SAH in our patient population over a time course of 14 days. The precise reasons for this are unclear at this time. We speculate that the aggressive avoidance of hypovolemia, higher blood pressure goals, and modified augmented cardiac index management of cerebral vasospasm may have contributed to maintaining effective renal perfusion and the overall increased vigilance to the risks of contrast exposures maybe a contributing factor as well. SAH patients pose a relatively unique set of challenges to the intensivists compared to other non-neurologic ICU patients. The liberal fluid management strategies (i.e. post aneurysm intervention), sedation management, hemodynamic management (e.g. augmented cardiac index therapy) often seem counterintuitive to other traditional ICU patients with diseases such as ARDS and septic shock. The overall incidence of AKI following SAH is lower compared to the incidence following other high mortality diagnoses such as septic shock or ARDS [23]. The precise reasons are unclear at this time. The predominant pathophysiologic model of AKI in general ICU patients is the ischemia–reperfusion model frequently triggered by perturbations in hemodynamics leading to the development and worsening of AKI in septic shock and ARDS [24, 25]. This clinical scenario tends to be less frequent in the SAH patient population especially with the institution of augmented cardiac index therapy or the comparable version of triple-H therapy in these patients. In fact, the MAP and cardiac output may be at a higher than baseline level in the post intervention period and during the active management of cerebral vasospasm [26, 27]. The increasing use of statins in patients with patients with SAH for their pleiotropic immune modulating effects (non-cholesterol lowering effects) may further confound the picture. Investigations have been exploring the role of statins in the perioperative period to prevent or decrease the severity of AKI and need for RRT [28]. Statins have been tried as a prophylactic agent for CIN especially in the patients undergoing coronary angiography with limited success in
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smaller studies [29, 30]. The results of numerous trials have been conflicting and there is insufficient data at this time to support the routine use of statins in all SAH patients for the prevention of AKI [31, 32]. The current definitions and risk stratification of acute kidney injury has helped better define and study the problem of kidney dysfunction across various pathophysiologic spectra include SAH. The diagnosis of AKI using the AKIN (Acute Kidney Injury Network) or RIFLE (Risk, Injury, Failure, Loss, End-stage kidney disease) criteria is currently limited as SCr and UO can only indirectly reflect that kidney damage has occurred. There are however continuing limitations with the current AKIN system as well. Serum creatinine remains the most frequently used parameter in the diagnosis of AKI. sCr is an insensitive and unreliable biomarker during short-term changes in kidney function because it lags behind the decline and recovery in glomerular filtration rate by days. Moreover, sCr is affected by age, race, muscle mass, volume of distribution, medications, and protein intake; it does not discriminate the nature of renal insult (e.g., ischemic vs. prerenal insult). A change in serum creatinine does not indicate the site of kidney injury (i.e. glomerular versus tubular etc.) but rather provides an overall index of function [33]. Therefore, there is a need for more sensitive and specific biomarkers that can diagnose AKI earlier, possibly indicate the cause, and rapidly measure the response to therapy. The use of the next generation of biomarkers for acute kidney injury such as NGAL (neutrophil gelatinase associate lipocalin), Kidney injury molecule-1 (KIM-1) are becoming more widely available. They may play a role in the future to further determine the patients at risk or allow early detection of AKI and in turn may provide a window of opportunity for early therapeutic interventions. Robust data on the use of biomarkers in AKI following SAH are anticipated in the near future. The strength of our analysis is that the data spans multiple years and multiple providers were involved with the care of patients. The large cohort of consecutive patients with SAH and the robustness of the data collected add strength to our study. Certain limitations of this current study deserve mention. This is a single center retrospective study and the known inherent limitations of this kind of analysis apply to this study as well. The variability of clinical practice including fluid management, blood pressure management strategies may have had an impact on the final outcomes. We also did not have any biomarker specific data for AKI in this patient population. Additional studies are warranted to study the pathophysiologic processes and interventions to prevent the development of AKI in his high mortality patient population. We anticipate future studies to shed more light on this important nonneurologic complication following SAH.
Conclusion Hypernatremia is independently associated with an increased risk of development of AKI in the SAH patient population. Patients who developed AKI had an increased length of stay and a significantly increased 28-day mortality. Understanding the risk posed by hypernatremia in the pathogenesis of AKI after SAH may help us develop management strategies to minimize harm to the kidneys in this high mortality disease. Conflict of interest conflict of interest. Funding
All the author declared that they have no
Departmental funds only.
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early phase of shock: a prospective, explorative cohort study. Crit Care. 2011;15(3):R135. Dunser MW, Takala J, Ulmer H, Mayr VD, Luckner G, Jochberger S, Daudel F, Lepper P, Hasibeder WR, Jakob SM. Arterial blood pressure during early sepsis and outcome. Intensive Care Med. 2009;35(7):1225–33. Joseph M, Ziadi S, Nates J, Dannenbaum M, Malkoff M. Increases in cardiac output can reverse flow deficits from vasospasm independent of blood pressure: a study using xenon computed tomographic measurement of cerebral blood flow. Neurosurgery. 2003;53(5):1044–51 discussion 1051-1042. Muench E, Horn P, Bauhuf C, Roth H, Philipps M, Hermann P, Quintel M, Schmiedek P, Vajkoczy P. Effects of hypervolemia and hypertension on regional cerebral blood flow, intracranial pressure, and brain tissue oxygenation after subarachnoid hemorrhage. Crit Care Med. 2007;35(8):1844–51 quiz 1852. Coleman MD, Shaefi S, Sladen RN. Preventing acute kidney injury after cardiac surgery. Curr Opin Anaesthesiol. 2011;24(1):70–6. Leoncini M, Toso A, Maioli M, Tropeano F, Villani S, Bellandi F. Early high-dose rosuvastatin for contrast-induced nephropathy prevention in acute coronary syndrome: Results from the PRATO-ACS Study (Protective Effect of Rosuvastatin and Antiplatelet Therapy On contrast-induced acute kidney injury and myocardial damage in patients with Acute Coronary Syndrome). J Am Coll Cardiol. 2014;63(1):71–9. Layton JB, Brookhart MA, Funk Jonsson M, Simpson RJ Jr, Pate V, Sturmer T, Kshirsagar AV. Acute kidney injury in statin initiators. Pharmacoepidemiol Drug Saf. 2013;22(10):1061–70. Murugan R, Weissfeld L, Yende S, Singbartl K, Angus DC, Kellum JA, Genetic, Inflammatory Markers of Sepsis Investigators. Association of statin use with risk and outcome of acute kidney injury in community-acquired pneumonia. Clin J Am Soc Nephrol. 2012;7(6):895–905. Argalious MY, Dalton JE, Sreenivasalu T, O’Hara J, Sessler DI. The association of preoperative statin use and acute kidney injury after noncardiac surgery. Anesth Analg. 2013;117(4):916–23. Kumar AB, Suneja M. Cardiopulmonary bypass-associated acute kidney injury. Anesthesiology. 2011;114(4):964–70.
ORIGINAL ARTICLE
Hypernatremia is a Significant Risk Factor for Acute Kidney Injury After Subarachnoid Hemorrhage: A Retrospective Analysis Avinash B. Kumar • Yaping Shi • Matthew S. Shotwell Justin Richards • Jesse M. Ehrenfeld
•
Ó Springer Science+Business Media New York 2014
A. B. Kumar (&) Department of Anesthesiology, Division of Critical Care Medicine, Vanderbilt University, 1211 21st Avenue, S, 526 MAB, Nashville, TN 37212, USA e-mail: [email protected]
72 h and 14 days following admission. A Cox proportional hazards survival model with multiple time varying covariates was developed to evaluate the effect of maximum sodium exposure on the risk of AKI. Sodium exposure was captured as the running maximum of daily maximum serum sodium concentration (mEq/L). Sodium exposure was used as a surrogate for hypertonic saline therapy. Results The final cohort of patients included 736 patients admitted to the neuro intensive care unit between 2006 and 2012. The number of patients who developed AKI was 64 (9 %). These patients had an increased length of stay (15.6 ± 9.4 vs. 12.5 ± 8.7 days). The odds of death were more than two fold greater among patients who developed AKI (odds ratio 2.33 95 % CI 1.27, 4.3). Sodium exposure was significantly associated with the hazard of developing AKI, adjusting for age, sex, preexisting renal disease, diabetes mellitus, radiocontrast exposure, number of days on mechanical ventilation, and admission Glasgow Coma Scale score. For each 1 mEq/L increase in the running maximum daily serum sodium, the hazard of developing AKI was increased by 5.4 % (95 % CI 1.4, 9.7). Conclusion The maximum daily sodium is a significant risk factor for developing AKI in patients with SAH.
Y. Shi M. S. Shotwell Department of Biostatistics, Vanderbilt University, 1211 21st Avenue, S, 526 MAB, Nashville, TN 37212, USA e-mail: [email protected]
Keywords Hypernatremia Acute kidney injury Subarachnoid hemorrhage Hyperosmolar therapy Hypertonic saline Serum sodium
Abstract Background Hypertonic saline therapy is often used in critically ill subarachnoid hemorrhage (SAH) patients for indications ranging from control of intracranial hypertension to managing symptomatic hyponatremia. The risk factors for developing acute kidney injury (AKI) in this patient population are not well defined. Specific Aim To study the role of serum sodium in developing AKI (based on the AKIN definition) in the SAH population admitted to a large academic neurocritical care unit. Methods This is an IRB-approved, retrospective cohort study of patients admitted to a tertiary neuro intensive care unit. We included adult (age C18 years) SAH patients admitted to the neuro intensive care unit for at least 72 h. Development of AKI after admission to the ICU was defined using the AKIN serum creatinine criteria between
M. S. Shotwell e-mail: [email protected] J. Richards J. M. Ehrenfeld Department of Anesthesiology, Vanderbilt University, 1211 21st Avenue, S, 526 MAB, Nashville, TN 37212, USA e-mail: [email protected] J. M. Ehrenfeld e-mail: [email protected]
Introduction Subarachnoid hemorrhage (SAH) accounts for only about 5 % of all strokes but remains a devastating disease with mortality approaching 50 % and with less than 1 in 2 survivors reaching functional independence [1]. The
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neurocritical care course of these patients is frequently complicated by non-neurologic complications including cardiorespiratory complications including the development of acute kidney injury or AKI [2]. The intensive care course of this patient population deviates from other ICU encounters (e.g. patients with septic shock or heart failure) due to exposure to specific interventions and management strategies. These include potential repeated exposure to IV contrast media, hyperosmolar agents, and euvolemic fluid management strategies as well as development of hyponatremia, and high urine output states. Prior studies of renal dysfunction following neurologic injury have been challenging due to the lack of a consistent, validated and reproducible definition of acute renal failure. This has largely been overcome with the changes in the definition and criteria for diagnosis of acute renal failure. Currently, acute kidney injury has replaced the term acute renal failure and has been validated in various patient populations by the RIFLE and AKIN criteria [3]. However, little is known about the specific risk factors for AKI in the SAH patient population and its subsequent impact on outcomes [4]. Specific Aim In this retrospective analysis, we seek to study the incidence, risk factors, and outcomes following development of new onset acute kidney injury (based on the new validated definition) following SAH (SAHAKI) population admitted to a large academic neuro intensive care unit.
Materials and Methods Our retrospective study was approved by the Vanderbilt University Institutional Review Board. We set out to analyze all patients admitted to the Vanderbilt neuroscience intensive care unit with the diagnosis of SAH (aneurysmal and non-aneurysmal) between 2006 and 2012. Traumatic brain injury patients were not in the dataset since at our institution, their primary location of admission is a different ICU. We excluded patients who did not survive the first 24 h of admission, and patients on renal replacement therapy (RRT). We also excluded patients whose primary source of intracranial blood was not a SAH (e.g. a large intraparenchymal bleed with some subarachnoid blood was excluded). Data Collection and Definitions Preoperative data points included age, sex, height, weight, BMI, current smoking status, diabetes mellitus, hypertension, preoperative kidney function (defined as the latest available serum creatinine prior to admission), admission
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neurologic exam, admission Glasgow coma score, Hunt and Hess class of SAH, and location of bleed and aneurysm (if applicable). Intensive care variables included duration of mechanical ventilation, intracranial hypertension, hyperosmolar therapy (mannitol and hypertonic saline), daily fluid balances, and transfusion support (including use of packed red blood cells, fresh frozen plasma, cryoprecipitate, and recombinant Factor 7). Laboratory values assessed included daily maximum and minimum serum sodium, minimum and maximum serum osmolality. All variables were followed for 14 days post ICU admission. The primary outcome was development of AKI based on the acute kidney injury network (AKIN) serum creatinine (sCr) criteria. The secondary outcomes were intensive care length of stay (LOS) and 28day mortality. Data were obtained from the Vanderbilt Perioperative Data Warehouse, an IRB-approved data registry containing case and outcomes information on all surgical and ICU patients cared for at our institution. The AKIN criteria has been utilized and validated in prospective studies in patients with AKI after cardiac surgery, septic shock, ARDS, and mixed ICU populations [3]. Stage 1 in the AKIN classification includes patients with an increase in sCr of at least 0.3 mg/dl over baseline, since there is accumulating evidence that even minor increments in serum creatinine are associated with adverse outcomes. Stage 2 is defined as an increase of 2–3 fold over the baseline sCr. Any patient treated with RRT, irrespective of urine output or sCr, or with a C3 fold rise in sCr is categorized as stage 3 in the AKIN system. The AKIN classification uses a 48-hour time window for assessment of renal function based on the evidence that adverse outcomes were reported when the creatinine elevation occurred within 24–48 h of hospitalization [5]. In the AKIN definitions, the thresholds for urine flow for the definition of AKI have been derived empirically and are less well substantiated than the thresholds for increase in SCr. Urine output has traditionally been a bellwether of renal dysfunction in the general ICU patient population. The SAH patient population is frequently complicated by high output renal states such as cerebral salt wasting, and the AKIN urine output criteria have not been validated in this patient population. We chose to use the creatinine-based definition of AKI, with the most recent serum creatinine including upto day of admission being considered the baseline value. Preoperative renal insufficiency was defined as a baseline serum Cr C1.2 mg/dl. The decision to initiate RRT was at the discretion of the attending consultant nephrologist. Although hypertonic saline is used in varying strengths from 3 % solution (513 mmol/L), 7.5 % solution (1283 mmol/L), or in a 23.4 % solution (4008 mmol/L), in our study hypertonic saline was limited to 3 % NaCl. We followed the patients for development of SAHAKI for a period of 14 days. We focused on this time frame since this is considered the highest risk period for clinically
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significant vasospasm and subsequent exposure to multiple interventions. Statistical Analysis Patient demographics and clinical data were summarized using the 25th percentile, median, and 75th percentile for continuous variables, and with percentages for categorical variables. Unadjusted comparisons between those who did and did not develop AKI on demographic and clinical data were conducted using the Wilcoxon rank sum test for continuous variables and the Pearson Chi square test for categorical variables. The AKI incidence and mortality rate were estimated and reported with 95 % confidence intervals using a nonparametric bootstrap method. Unadjusted AKI free survival was depicted using a Kaplan–Meier curve. Serum creatinine was measured daily from ICU admission (day 1) to discharge or day 14 whichever was the earlier. The primary outcome was indicated when serum creatinine increased by more than 0.3 mg/dl within a 48hour period. Patients were removed from the at-risk pool once AKI had been observed. Patients who did not develop AKI during their ICU stay were censored at the time of ICU discharge or at 14 days, whichever came earlier. A Cox proportional hazards model with time varying covariates was used to identify risk factors for developing AKI during the ICU stay. The fixed risk factors included patient age at hospital admission, sex, diabetes mellitus, preexisting renal disease, and Glasgow coma score. The time varying risk factors included the cumulative count of radiocontrast exposure in days, the cumulative count of days on mechanical ventilation, and the running maximum of daily maximum serum sodium concentration. All analyses were implemented using R 3.0.2 (R Foundation for Statistical Computing, Vienna, Austria). A significance level of 0.05 was used for statistical inference.
Results Our study included 736 consecutive adult SAH patients with an overall AKISAH incidence of 9.0 % (64 out of 736). Patients who developed AKI had an increased length of ICU stay (15.6 ± 9.4 vs. 12.5 ± 8.7 days, p = 0.002). The overall mortality in the AKI cohort was 0.25 (95 % CI 0.16, 0.36) and 0.12 (95 % CI 0.10, 0.15) in non-AKI patients. The unadjusted odds of death were more than two fold greater among patients who developed AKI during their clinical ICU course (odds ratio 2.33 95 % CI 1.27, 4.3). Among the 64 patients in the AKI cohort, 58 (90.6 %) patients had a change in serum Cr 300 % putting them in the AKI-Class III category. Of the 736 patients in our final cohort, the majority patients were female (59 %). The median age at time of hospital admission was 55 ± 15 Y. Among those who developed AKI, 19 and 14 % of the patients had diabetes mellitus and preexisting renal disease respectively, compared to 12 and 6 % of patients who did not develop AKI. There was a difference in the baseline count of patients with diabetes mellitus (p = 0.016) and exposure to packed red cell transfusion (p = 0.054) in the AKI versus no-AKI group (Table 1). However, there was no statistically significant difference between cohorts with regard to admission Glasgow coma score [11.3 ± 4.9 in the AKI cohort and 11.7 ± 4.6 in nonAKI cohort, (p = 0.69)]. Mechanical ventilation was initiated on admission in 35 % (22/63) of patients in the AKI cohort compared to 29 % (194/669) in the No AKI cohort. However, there was no statistically significant difference between the cohorts regarding endotracheal intubation and mechanical ventilation on admission (p = 0.32). There was no significant unadjusted difference between cohorts with respect to exposure to hypertonic saline, mannitol, IV contrast, or baseline levels of serum sodium on admission. A Cox proportional hazards regression with multiple time varying covariates was implemented to evaluate the effect of specific risk factors and development of AKISAH. We utilized previously published independent risk factors as predictors of AKISAH [6]. These independent risk factors included age, sex, preexisting kidney disease, and DM. The SAH centric risk factors for AKI that we explored included packed red blood cell transfusions, exposure to contrast, and location of bleed, etiology of SAH (aneurysmal vs. non-aneurysmal), Glasgow coma score on presentation, mechanical ventilation, highest serum sodium every 24 h, 24 h fluid balances, and BMI. The results are shown in Table 2. There was insufficient evidence associating the development of AKI with age, sex, diabetes mellitus, preexisting renal disease, GCS, and cumulative count of radiocontrast exposure or cumulative count of days on mechanical ventilation. The Kaplan–Meier (K–M) curve for the unadjusted time to development of AKISAH is illustrated in Fig. 1. The first peak of AKI developed around day 3 followed by a second smaller peak by day 7. An estimated six percent of patients developed early AKISAH by day 3, rising to 12 % at 14 days. Intravenous contrast media is a known risk factor for development of acute kidney injury. We explored the temporal exposure patterns of patients to IV contrast over a period of 14 days. The exposure to IV contrast exposure is shown in Fig. 2 (contrast exposure). The highest exposure was on day 1 (39.3 % of all patients) as anticipated, due to
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Neurocrit Care Table 1 Patient demographics and baseline characteristics
Age
AKI (N = 64)
No AKI (N = 672)
Combined (N = 736)
p
49, 56, 73
45, 55, 65
45, 55, 65
0.17
(55 ± 15)
(59 ± 16)
(55 ± 15)
Female
53 % (34/64)
60 % (402/672)
59 % (436/736)
0.3
BMI
23.0, 26.6, 31.3
23.1, 25.9, 30.4
23.1, 26.0, 30.4
0.94
(28.2 ± 8.3)
(28.1 ± 11.1)
(28.1 ± 10.9)
Diabetes mellitus-type II (%)
19 % (12/64)
12 % (84/672)
13 % (96/736)
0.16
Preexisting renal disease (%) Glasgow coma score
14 % (8/64) 7.0, 15.0, 15.0
6 % (40/672) 8.0, 15.0, 15.0
7 % (51/736) 7.0, 15.0, 15.0
0.07 0.69
(11.3 ± 4.9)
(11.7 ± 4.6)
(11.6 ± 4.7)
Contrast exposure(%)
44 % (28/64)
39 % (261/672)
39 % (289/736)
0.44
Mannitol (%)
6 % (4/64)
3 % (20/672)
3 % (26/736)
0.23
Sodium
0, 137, 140
0, 137, 140
0, 137, 140
0.39
(100 ± 64)
(93 ± 65)
(94 ± 65)
Osmolality RBC transfusion
296, 308, 320
298, 304, 314
298, 305, 317
(303 ± 25)
(308 ± 18)
(308 ± 19)
4.5 % (3/64)
1 % (7/672)
1.3 % (10/736)
0.94 0.054
Summary statistics are shown as the 25th, 50th, 75th percentile (mean ± SD) for continuous variables, percentage for categorical variables. p values were calculated using the Wilcoxon rank sum test for continuous variables and the Pearson Chi-square test for categorical variables Table 2 Effect estimate (95 % CI) calculated from the time varying Cox proportional hazard model Variable
HR (95 % CI)
p
Age
1.02 (0.99, 1.04) 0.16
Female
0.74 (0.42, 1.30) 0.29
Diabetes mellitus
1.55 (0.82, 2.94) 0.18
Preexisting renal disease
1.45 (0.55, 3.81) 0.45
Glasgow coma score
1.02 (0.96, 1.09) 0.47
Cumulative maximum sodium
1.06 (1.01, 1.10) 0.008
Cumulative count of radiocontrast exposure 1.09 (0.78, 1.53) 0.62 Cumulative count of days on mechanical 1.04 (0.96, 1.12) 0.36 ventilation
concentration (mEq/L). The distribution of daily maximum sodium is shown in Fig. 3. Hypernatremia (secondary to the use of hypertonic saline) and even small increments of daily serum sodium was a significant risk factor for AKISAH after adjusting for other risk factors. The strongest risk factor associated with development of AKI in the SAH patient population was the daily maximum serum sodium. For each 1 mEq/L increase in the running maximum of daily maximum serum sodium, the hazard of developing AKI was increased by 5.5 % (95 % CI 1.4, 9.7, p value = 0.008).
Discussion the nature of the diagnostic workup of a SAH. This exposure was reduced significantly by day 3 (about 3.5 % of patients being exposed) and continued to be low at about 5 % until day 8 and 9. There was a second peak of contrast exposure on day 8 and 9 (10.4 and 17 % respectively). However, based on our Cox proportional hazards regression model, in spite of significant exposure, there was insufficient evidence that the running count of IV contrast exposure events was a significant risk factor for AKISAH in our patient population. After adjusting for other covariates including sodium exposure, HR for AKI was 1.09 (0.78, 1.53); p = 0.62. Sodium exposure was used as a surrogate for hypertonic saline therapy in our analysis and was captured as the running maximum of daily maximum serum sodium
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Significant strides have been made in the neurologic management of SAH in the past decade. The focus now rests on minimizing the non-neurologic complications associated with this disease that still has a high morbidity and mortality [7]. Identification of patient and procedural risk factors may therefore allow for improvements in longterm outcome by affecting changes in perioperative management and disease prevention. In our analysis, the overall incidence of AKI was 9 %, which is lower compared to reported AKI rates in post cardiac surgical and general post surgical intensive care units, where rates as high as 47 % have been reported [8]. Hypernatremia secondary to the use of hypertonic saline was the strongest risk factor for developing AKISAH in our
Neurocrit Care Fig. 1 Kaplan–Meier curve showing the timeline to develop AKI in the ICU in the SAH patient population
Fig. 2 Temporal trend of IV contrast exposure in all patients showing the proportion of patients (%) exposed to I.V. contrast between ICU day 1 and ICU day 14
patient population. Interestingly, the traditional risk factors for AKI in mixed ICU populations such as diabetes mellitus, preexisting kidney disease, advanced age were not significant risk factors for developing AKI in our SAH population. Contrast-induced nephropathy was not a significant event in our patient population in spite of increasing frequency of contrast exposure each year of the study in the SAH patient population. Patients who developed new onset AKI had an increased length of stay and were at an increased risk of in-hospital mortality. Raised intracranial pressure (ICP) is an independent predictor of poor neurologic outcome following SAH. Intracranial hypertension and cerebral edema are cardinal manifestations of severe brain injury resulting from diverse
insults ranging from traumatic brain injury to SAH. Early and aggressive management of intracranial hypertension is a key to a good outcome. Hyperosmolar therapy with mannitol and hypertonic saline has been the cornerstone in the management of intracranial hypertension [9]. Recent studies including a metaanalysis showed HS to be more effective with controlling ICP compared to mannitol [10]. The intensivist preferences of using mannitol versus hypertonic saline are evenly divided based on a recent national survey [11]. In the same survey, interestingly the major reason for the preference for using hypertonic saline was the perceived ‘‘decreased risk of renal dysfunction’’ compared to mannitol [11]. As our experience with the use of hypertonic saline in various concentrations grows, we will gather a better renal risk profile of hypertonic saline. Dominguez et al. reported the increased risk of renal dysfunction in pediatric patients who were maintained in a hyperosmolar state at 160 mEq/L in severe traumatic brain injury [12]. It is thought that hypernatremia can lead to renal dysfunction through the mechanism of intravascular dehydration and vasoconstriction either directly or through a tubuloglomerular feedback mechanism [13]. Animal studies have shown a reduction of renal blood flow, glomerular filtration rate, and an inhibition of renin secretion when the sodium level in the renal artery is increased rapidly [14]. These findings can be explained by the fact that the kidney, in contrast to other organs, responds with vasoconstriction to a hypernatremic state. HTS is not without potential major adverse effects. While relatively rare, serious electrolyte
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Fig. 3 Sodium max on ICU day 1 through day 14. The panel on the top shows sodium max data for patients who developed AKI, and the panel on the bottom shows the cohort with no AKI
disturbances may be induced central pontine myelinolysis in malnourished patients with an acute hypernatremic state following rapid serum sodium correction [15, 16]. Hyperchloremic acidosis and acute hemolysis are further consequences of HTS administration. Hyperosmolar therapy is also known to induce rapid intravascular volume expansion and subsequent cardiac overload with pulmonary edema. Further worsening of cerebral swelling and increased ICP maybe indicative of a disrupted blood brain barrier and a ‘‘reverse osmosis’’ phenomenon (1). In addition, renal complications due to HTS therapy are an real concern [15, 17]. The therapeutic management of SAH has undergone significant changes in the past decade for SAH with the advent of neurovascular interventions such as stenting and endovascular coiling of aneurysms [18]. These procedures frequently require contrast angiography to define the anatomy, and during the therapeutic intervention as well. Thus, with a change in the management paradigm for SAH, patients today have a higher potential for multiple exposures to IV contrast media secondary to both diagnostic and
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therapeutic interventions during their ICU course [19]. This increases the risk of contrast-induced nephropathy in this patient population. In the general patient population, hypovolemia, volume of contrast used, preexisting kidney disease, diabetes mellitus, advanced age, and decreased left ventricular function are established risk factors for contrast-induced nephropathy. Rate of contrast-induced nephropathy has been reported to be as high as 20–25 % in high-risk patients (e.g. cardiac ICU patient population) [20]. Interestingly, although there has been conflicting data on the rates of CIN in the SAH population, the overall incidence is lower than the general mixed ICU patient population [21, 22]. This reflects the finding in our study as well that exposure to IV contrast was not associated with an increased risk of AKI SAH in our patient population over a time course of 14 days. The precise reasons for this are unclear at this time. We speculate that the aggressive avoidance of hypovolemia, higher blood pressure goals, and modified augmented cardiac index management of cerebral vasospasm may have contributed to maintaining effective renal perfusion and the overall increased vigilance to the risks of contrast exposures maybe a contributing factor as well. SAH patients pose a relatively unique set of challenges to the intensivists compared to other non-neurologic ICU patients. The liberal fluid management strategies (i.e. post aneurysm intervention), sedation management, hemodynamic management (e.g. augmented cardiac index therapy) often seem counterintuitive to other traditional ICU patients with diseases such as ARDS and septic shock. The overall incidence of AKI following SAH is lower compared to the incidence following other high mortality diagnoses such as septic shock or ARDS [23]. The precise reasons are unclear at this time. The predominant pathophysiologic model of AKI in general ICU patients is the ischemia–reperfusion model frequently triggered by perturbations in hemodynamics leading to the development and worsening of AKI in septic shock and ARDS [24, 25]. This clinical scenario tends to be less frequent in the SAH patient population especially with the institution of augmented cardiac index therapy or the comparable version of triple-H therapy in these patients. In fact, the MAP and cardiac output may be at a higher than baseline level in the post intervention period and during the active management of cerebral vasospasm [26, 27]. The increasing use of statins in patients with patients with SAH for their pleiotropic immune modulating effects (non-cholesterol lowering effects) may further confound the picture. Investigations have been exploring the role of statins in the perioperative period to prevent or decrease the severity of AKI and need for RRT [28]. Statins have been tried as a prophylactic agent for CIN especially in the patients undergoing coronary angiography with limited success in
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smaller studies [29, 30]. The results of numerous trials have been conflicting and there is insufficient data at this time to support the routine use of statins in all SAH patients for the prevention of AKI [31, 32]. The current definitions and risk stratification of acute kidney injury has helped better define and study the problem of kidney dysfunction across various pathophysiologic spectra include SAH. The diagnosis of AKI using the AKIN (Acute Kidney Injury Network) or RIFLE (Risk, Injury, Failure, Loss, End-stage kidney disease) criteria is currently limited as SCr and UO can only indirectly reflect that kidney damage has occurred. There are however continuing limitations with the current AKIN system as well. Serum creatinine remains the most frequently used parameter in the diagnosis of AKI. sCr is an insensitive and unreliable biomarker during short-term changes in kidney function because it lags behind the decline and recovery in glomerular filtration rate by days. Moreover, sCr is affected by age, race, muscle mass, volume of distribution, medications, and protein intake; it does not discriminate the nature of renal insult (e.g., ischemic vs. prerenal insult). A change in serum creatinine does not indicate the site of kidney injury (i.e. glomerular versus tubular etc.) but rather provides an overall index of function [33]. Therefore, there is a need for more sensitive and specific biomarkers that can diagnose AKI earlier, possibly indicate the cause, and rapidly measure the response to therapy. The use of the next generation of biomarkers for acute kidney injury such as NGAL (neutrophil gelatinase associate lipocalin), Kidney injury molecule-1 (KIM-1) are becoming more widely available. They may play a role in the future to further determine the patients at risk or allow early detection of AKI and in turn may provide a window of opportunity for early therapeutic interventions. Robust data on the use of biomarkers in AKI following SAH are anticipated in the near future. The strength of our analysis is that the data spans multiple years and multiple providers were involved with the care of patients. The large cohort of consecutive patients with SAH and the robustness of the data collected add strength to our study. Certain limitations of this current study deserve mention. This is a single center retrospective study and the known inherent limitations of this kind of analysis apply to this study as well. The variability of clinical practice including fluid management, blood pressure management strategies may have had an impact on the final outcomes. We also did not have any biomarker specific data for AKI in this patient population. Additional studies are warranted to study the pathophysiologic processes and interventions to prevent the development of AKI in his high mortality patient population. We anticipate future studies to shed more light on this important nonneurologic complication following SAH.
Conclusion Hypernatremia is independently associated with an increased risk of development of AKI in the SAH patient population. Patients who developed AKI had an increased length of stay and a significantly increased 28-day mortality. Understanding the risk posed by hypernatremia in the pathogenesis of AKI after SAH may help us develop management strategies to minimize harm to the kidneys in this high mortality disease. Conflict of interest conflict of interest. Funding
All the author declared that they have no
Departmental funds only.
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