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Hyponatremia in Patients with Traumatic Brain Injury: Etiology, Incidence, and Severity Correlation
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Hyponatremia in Patients with Traumatic Brain Injury: Etiology, Incidence, and Severity Correlation Subash Lohani and Upendra Prasad Devkota
Key words 䡲 Cerebral salt wasting syndrome 䡲 Fractional excretion of uric acid 䡲 Hyponatremia 䡲 Syndrome of inappropriate antidiuretic hormone 䡲 Traumatic brain injury
䡲 BACKGROUND: Hyponatremia is common in patients with traumatic brain injury (TBI). This study aims at ascertaining the incidence of hyponatremia in TBI with its etiologic diagnosis, biochemical confirmation, and severity correlation with initial Glasgow Coma Scale (GCS) score and computed tomography (CT) abnormality.
Abbreviations and Acronyms CSWS: Cerebral salt wasting syndrome CT: Computed tomography CVP: Central venous pressure FEUA: Fractional excretion of uric acid GCS: Glasgow Coma Scale GOS: Glasgow Outcome Scale SIADH: Syndrome of inappropriate antidiuretic hormone TBI: Traumatic brain injury
䡲 METHODS: All patients more than 20 years old with severe and moderate TBI and the mild ones with CT abnormality were included. Daily sodium level was monitored for 14 days. Central venous pressure (CVP) was measured for assessment of volume status. Fractional excretion of uric acid (FEUA) was measured in all patients with hyponatremia, both before and after its correction.
Department of Neurosurgery, National Institute of Neurological and Allied Sciences, Bansbari, Kathmandu, Nepal To whom correspondence should be addressed: Subash Lohani, M.B.B.S. [E-mail: [email protected]] Citation: World Neurosurg. (2011) 76, 3/4:355-360. DOI: 10.1016/j.wneu.2011.03.042 Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com 1878-8750/$ - see front matter © 2011 Elsevier Inc. All rights reserved.
INTRODUCTION Traumatic brain injury (TBI) results in a range of neurological and cognitive impairment to personality, behavioral changes, and lifestyle consequences (12). Posttraumatic endocrine complications also pose a great challenge in the management of TBI. Early recognition of these subtle problems can produce a significant impact on outcome (3, 4). Hyponatremia is a common electrolyte disorder in the setting of central nervous system disease including TBI (9). Two common etiologies, namely the syndrome of inappropriate antidiuretic hormone (SIADH) (10, 13) and cerebral salt wasting syndrome (CSWS) (5, 14, 19) are primarily responsible. Differentiation among the two conditions is based on the volume status of the patient (20). Given a
䡲 RESULTS: Of 40 consecutive patients, 33 remained for analysis. Hyponatremia was seen in 9 (27.2%) patients, of whom 6 developed it within the first week. Mean duration of hyponatremia was 1.78 days. We found that 5 patients had an elevated CVP consistent with the syndrome of inappropriate antidiuretic hormone (SIADH), whereas 3 had low CVP consistent with cerebral salt wasting syndrome (CSWS) and 1 had an equivocal reading. Measurement of FEUA did not show consistent pattern to suggest a biochemical distinction. There were 33.3% each of mild and moderate, and 16.6% of severe TBI among hyponatremic patients. Hyponatremia was seen in Rotterdam CT scores I to IV in increasing incidence (r ⴝ 0.983, P ⴝ 0.017), whereas it had no significant correlation with initial GCS (r ⴝ 0.756, P ⴝ 0.455). 䡲 CONCLUSIONS: Hyponatremia due to SIADH is more common in TBI. FEUA measurement is not consistent enough to make a distinction between SIADH and CSWS. CT scoring of severity is more predictive of hyponatremia than initial GCS.
typical case scenario, distinction might not appear difficult. Yet, an exceeding number of cases have a borderline picture with diagnostic confusion and impediment in therapeutic intervention. Researchers are thus making an attempt in differentiating the two conditions based on biochemical alterations, especially that of the fractional excretion of uric acid (FEUA) (15). This study primarily aims at identifying the etiology, incidence, and timing of hyponatremia in patients with TBI, including its correlation with initial severity and final outcome. Severity correlation is done with both the clinical and radiological severity status.
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METHODS Study Design This is a prospective, descriptive, and analytical study conducted at the National Institute of Neurological and Allied Sciences, Bansbari, Kathmandu. Patients admitted with the diagnosis of TBI were the target population. All patients presenting from April to September 2008 who fulfilled the inclusion criteria were enrolled in the study. Study variables were age distribution, sex distribution, Glasgow Coma Scale (GCS) at the time of presentation, Rotterdam computed tomography (CT) score (Table 1) (17), mechanism of head injury, and associated comorbidity. Theses independent variables
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TOOLS AND TECHNIQUES
Table 1. Rotterdam CT Score CT Characteristics Basal cistern
Category
Score
Normal
0
Compressed
1
Absent
2
Midline shift
No or ⱕ5 mm
0
⬎5 mm
1
Mass lesion
Epidural
0
Nonepidural
1
Absent
0
IVH or tSAH
Present
1 ⫹1*
Sum score
CT, computed tomography; IVH, intraventricular hemorrhage; tSAH, traumatic subarachnoid hemorrhage. *⫹1 is added to the sum score to make the grading numerically consistent with Marshall CT grading and the motor score of the Glasgow Coma Scale.
were used to calculate dependent variables such as incidence of hyponatremia/SIADH/ CSWS, timing of hyponatremia, duration of hospital stay, and Glasgow Outcome Scale (GOS) (11) at discharge. Associated comorbidity and medication-induced hyponatremia were the confounding variables. Inclusion and exclusion criteria were defined as follows.
Inclusion Criteria
y Patients 20 years and older irrespective of their gender, because until the age of 20 years, FEUA levels can be variable (6).
y Patients attending to this hospital up to 3 days post-TBI; since this is a referral center for patients from all over Nepal, a delay of 3 days had to be considered.
Exclusion Criteria
y Patients with established renal, thyroid, or adrenal diseases prior to the TBI because they have a profound effect on fluid and electrolyte balance (4).
y Patients presenting beyond 3 days postTBI.
y Patients younger than 20 years old (6). y Cases with associated spinal cord injuries, because they alone have been reported to cause CSWS (1).
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Pertinent information was prospectively gathered during admission. Consent was obtained from patients at the time of admission as far as possible. Preformed structured formats were used to make pertinent clinical, radiological, and laboratory documentation. Severity of TBI was classified as mild, moderate, or severe based on GCS 13 to 15, 9 to 11, and 3 to 8, respectively (22). CT scan was performed in all patients, and CT grading was noted. Baseline investigations were done in all patients. This included hemoglobin, random blood sugar, serum albumin, sodium (Na), potassium (K), urea, and creatinine. Sodium levels were checked daily for 14 days or until the patient was discharged, whichever was earlier. A CVP catheter was inserted in all patients who underwent surgical intervention. In those with conservative management, a catheter was inserted after the development of hyponatremia. After every insertion of a CVP, proper catheter positioning was confirmed with a chest X-ray, with radiopaque dye if needed. CVP of 6 to 10 cm was considered a normal measurement (20). A sodium level below 130 mEq/L was considered hyponatremia (8, 21). On the diagnosis of hyponatremia, further investigation was performed with the aim of differentiating SIADH and CSWS (15). These included serum/urinary creatinine, serum/urinary uric acid, serum albumin, and serum urea. In addition, some baseline investigations were repeated, per the requirement for management. Regarding the treatment of hyponatremia, fluid restriction in patients with head injury was avoided, irrespective of the diagnosis. All patients were treated with oral salt supplementation and intravenous normal saline after detection of hyponatremia. If the patient did not respond to this therapy and had high CVP, then moderate fluid restriction up to 1500 mL/d was done. In patients with low CVP, fludrocortisone was used if initial therapy did not correct hyponatremia.
RESULTS A total of 40 patients were enrolled in the study, of whom 7 were excluded because they had a hospital stay of less than 1 week for various reasons such as early mortality, transfer to other centers, or associated
medical ailments that could produce hyponatremia. Of 33 patients who remained for analysis, hyponatremia was seen in 9 patients within the period of 2 weeks.
Age Distribution The mean age was 37.42 (19 to 70) years with a standard deviation (SD) of 15.33. Age groups of 20 to 30 and 31 to 50 had 42.4% and 39.4% patients, with least being 18.2% in the age group of ⬎50. Among the hyponatremic patients, the mean age was 38.44 (23 to 69) years with SD 16.4.
Sex Distribution There were a total of 26 male and 7 female patients. The male-to-female ratio was 3.7:1. Among hyponatremic patients, 7 were male and 2 were female. The male-tofemale ratio was 3.5:1.
Severity Based on GCS at the Time of Presentation There were 12 cases each of mild and severe head injury, whereas moderate head injury was found in 9 (Figure 1). Among hyponatremic patients, there were 4 (33.33%) with mild, 3 with moderate (33.33%), and 2 (16.66%) with severe head injury.
Site of Intracranial Lesion Ten patients had lesions at more than one site. Frontal lesion in 21 patients was the most common, followed by temporal lesion in 14. One patient had a small hematoma in the brainstem. Among hyponatremic patients, 3 had lesion at more than one site. Frontal lesion was again the most common, followed by temporal lesion; 6 and 4, respectively.
Type of Intracranial Lesion Eight patients had an epidural lesion, whereas 4 had a subdural lesion. There were total of 22 patients with intraparenchymal lesions, but none of them had an intraventricular extension. Three patients also had pneumocephalus. Traumatic subarachnoid hemorrhage was seen in 5 patients. Nine patients had more than one type of lesion. Among the hyponatremic patients, intraparenchymal lesion, seen in 8 patients, was
WORLD NEUROSURGERY, DOI:10.1016/j.wneu.2011.03.042
PEER-REVIEW REPORTS SUBASH LOHANI AND UPENDRA PRASAD DEVKOTA
HYPONATREMIA IN PATIENTS WITH TRAUMATIC BRAIN INJURY
CT Scoring: Rotterdam CT Grade Most of the patients had Rotterdam scores 2, 3, and 4; 33.3%, 24.2%, and 27.3%, respectively (Figure 2). Hyponatremia was seen in scores 2, 3, and 4 in increasing incidence, 22.2%, 33.3%, and 44.4% respectively (Pearson correlation coefficient 0.983, P ⫽ 0.017; grades 1 to 4 considered for the analysis) (Table 2). None of the patients with score 5, however, developed hyponatremia. While considering GCS for the correlation with development of hyponatremia, no significant correlation was seen (Pearson correlation coefficient 0.756, P ⫽ 0.454 ) (Table 2). Figure 1. Bar diagram showing the severity of traumatic brain injury and occurrence of hyponatremia.
Surgical Intervention Nineteen (57.6%) patients had their hematoma surgically evacuated. The remaining 14 patients were conservatively managed.
Figure 2. Bar diagram showing Rotterdam computed tomography grade among total and hyponatremic patients.
Table 2. Correlation of GCS, Rotterdam CT Score, and Incidence of Hyponatremia Variables Dependent Variable
Pearson Correlation
Significance (2-Tailed)
GCS category
Incidence of hyponatremia
.756
0.454
Rotterdam CT grade
Incidence of hyponatremia
.983*
0.017
Independent Variable
CT, computed tomography; GCS, Glasgow Coma Scale. *Correlation is significant at the 0.05 level (2-tailed).
the most common lesion. None of the subdural lesions were associated with hyponatremia. Epidural lesion, pneumocephalus, and traumatic subarachnoid hemorrhage were seen in 3, 2, and 1 patients, respectively. Three patients had more than one type of lesion.
Side of Intracranial Lesions Unilateral lesions predominated, with 72.7% over bilateral lesions (24.2%). Leftsided lesions (39.4%) were more common than right ones. Among hyponatremic patients, unilateral, bilateral, and midline lesions were observed in equal incidence, 33.33% each.
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Hyponatremia Hyponatremia occurred in 9 (27.27%) patients. Six of the patients had hyponatremia within the first week of injury (Figure 3). Clustering of cases was seen late in the first week and early in the second week (Figure 4). The mean duration of hyponatremia was 1.78 (1 to 3) days, SD 0.83 (Figure 5). The minimum level of hyponatremia observed was 113 mEq/L. One other patient had hyponatremia down to 120 mEq/L. The remaining 7 patients had sodium levels above 125 mEq/L. All patients recovered well with oral salt supplementation and intravenous normal saline. One patient’s sodium level dropped to 113 mEq/L despite oral and intravenous supplementation, thus requiring fludrocortisone in addition. One other patient who went into hyponatremia of 120 mEq/L on the first postoperative day with a frank picture of SIADH had to be kept on moderate fluid restriction. Two patients (22.2%) had recurrence of hyponatremia, at day 11 in one and day 12 in the other.
Etiology of Hyponatremia Based on CVP measurement at the time of development of hyponatremia, the etiology was ascertained. Five patients were considered to have a diagnosis consistent with SIADH, and 3 with CSWS. Because 1 patient did not manifest any CVP variation, a diagnosis could not be assigned.
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first instance. In 3, the FEUA level decreased relative to the previous level, but remained elevated above normal. In 2, however, the FEUA level further increased after correction of hyponatremia. Among 3 patients with a CSWS-consistent diagnosis, 1 had normal FEUA at the beginning of hyponatremia. In all, however, FEUA remained persistently elevated compared with the previous level. In 1 of the hyponatremic patients, however, CVP remained within the normal range, making it difficult to assign a diagnosis. FEUA was elevated and remained persistently elevated even after correction of hyponatremia. Figure 3. Bar diagram showing the timing of hyponatremia.
Hospital Stay Overall, the mean hospital stay was 26.73 (7 to 90) days, SD 19.4. Among the hyponatremic patients, the mean hospital stay was 24.67 (15 to 51) days, SD 13.4. No significant difference in means (P ⫽ 0.83) was shown by independent sample t test (Table 4).
Figure 4. Graph showing the day of occurrence of hyponatremia.
GOS at Discharge Overall, the mean GOS at discharge was 3, SD 1.25. Among hyponatremic patients, the mean GOS was 3.22, SD 1.09. No significant difference in means (P ⫽ 0.553) was seen on independent sample t test (Table 4).
DISCUSSION
Figure 5. Bar diagram showing duration of hyponatremia.
Hyponatremia and FEUA FEUA was calculated using the following formula: Urinary uric acid ⫻ Serum creatinine Urinary creatinine ⫻ Serum uric acid
358
⫻ 100%
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Contrary to expectations, FEUA as measured after detection of hyponatremia and after the correction of hyponatremia showed bizarre findings (Table 3). Among 5 patients with an SIADH-consistent diagnosis, all had elevated FEUA at the
To begin with demographics, mean age and sex ratio of overall and hyponatremic patients are comparable. The incidence of hyponatremia was 27.27%, which is comparable to that described by Moro et al. (18) among the subgroup of head injury patients who had intracranial bleeding. Hyponatremia has been shown to have an association with the severity of brain injury (9). However, both mild and moderate head injuries had 33.33% hyponatremia, whereas with increasing severity, incidence decreased to 16.66%. Similar types of observations were made in the study by Doczi et al. (7), in which hyponatremia was seen more in moderate head injury rather than severe. Thus it seems that the occurrence of hyponatremia does not correlate well with GCS at admission. As seen in our study as well,
WORLD NEUROSURGERY, DOI:10.1016/j.wneu.2011.03.042
PEER-REVIEW REPORTS SUBASH LOHANI AND UPENDRA PRASAD DEVKOTA
HYPONATREMIA IN PATIENTS WITH TRAUMATIC BRAIN INJURY
Table 3. CVP Measurements, Consistent Diagnosis, and FEUA Measurements Among Hyponatremic Patients Patient
CVP (Normal 6 to 10 cm)
Consistent Diagnosis
Before FEUA (%)
After FEUA (%)
1
High/20 cm
SIADH
90.90
30.25
2
High/20 cm
SIADH
34.37
33.92
3
High/21 cm
SIADH
28.20
21.09
4
High/18 cm
SIADH
8.40
9.84
5
High/25 cm
SIADH
33.50
41.41
6
Normal/7 cm
—
12.39
17.42
7
Low/0 cm
CSWS
7.77
20.40
8
Low/3 cm
CSWS
11.25
29.72
9
Low/4 cm
CSWS
16.66
31.42
CSWS, cerebral salt wasting syndrome; CVP, central venous pressure; FEUA, fractional excretion of uric acid; SIADH, syndrome of inappropriate antidiuretic hormone.
36.36% of cases had mild head injury based on GCS score alone, whereas all of them had one or the other CT abnormality, requiring intervention in many instances. There was no statistical correlation between GCS at initial presentation and occurrence of hyponatremia. Interestingly, however, observing the trend in Rotterdam CT scores, with increasing grades from 2 to 4, incidence of hyponatremia also increased. Although there were no instances of hyponatremia in score 5, the pattern seems convincing that a CT grading might be a more important determinant of severity and hence occurrence of hyponatremia. With the exclusion of score 5, for which no hyponatremia was seen, a significant statistical correlation was also established. A higher rate of surgical intervention was
due to the inclusion of high-risk trauma patients in the study; mild head injuries with normal CT scans were excluded. Because most of the patients underwent surgical evacuation, Marshall CT grade 5 (16) would be the most common if classified accordingly. As the proportion of patients who underwent surgical intervention was proportionate among total and hyponatremic patients, here again it seems plausible that CT scoring based on individual CT characteristics such as of Rotterdam CT score would be more consistent with the severity and consequent events. Frontal location of the lesion was most common, be it among overall patients or hyponatremic patients. Similarly, intraparenchymal lesion was the most common type. In contrast to the findings of Moro et al. (18), in which chronic subdural lesions
Table 4. The t Test for the Equality of Means (Duration of Hospital Stay and Glasgow Outcome Score at Discharge) t Test for Equality of Means 95% Confidence Interval of the Difference
t
Significance (2-Tailed)
Mean Difference
Standard Error Difference
Lower
Upper
Duration of hospital stay
⫺.217
.830
⫺1.62
7.459
⫺16.830
13.595
Glasgow outcome at discharge
⫺.600
.553
⫺.29
.478
⫺1.262
.689
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were associated with 15.9% hyponatremia, none of the acute subdural lesions in our series had hyponatremia. Right, left, and bilateral lesions were all associated with an equal incidence of hyponatremia. Management of hyponatremia depends on the level of sodium, clinical state, volume status, and tonicity (2). Because the policy of our institution is to avoid fluid restriction in patients with head injury, irrespective of the diagnosis, all patients were treated with oral salt supplementation and intravenous normal saline after hyponatremia was observed. Hyponatremia corrected in almost all instances with this treatment strategy, probably because most of the cases were mild. In one instance, the patient went into frank SIADH on the first postoperative day with significantly decreased urine output. The following day, the patient had an excess urine output leading to spontaneous correction of hyponatremia, and it never recurred again. This particular instance suggests that an over-zealous attempt at correction might lead to a toorapid correction of hyponatremia, which should always be avoided. Two-thirds of hyponatremic cases occurred during the first week. This was noticed in days 1, 3, 6, and 7, contrary to what was described by Moro et al. (18). They described a peak of hyponatremia in the first week within the first 3 days. In our finding, clustering of cases was seen late in the first week and early in the second week. Given a typical case scenario, differentiation of SIADH and CSWS might not sound difficult. Yet in clinical practice, confusion still persists. In trying to solve this confusion, Maesaka et al. (15) suggested that FEUA increases in both conditions at the onset of hyponatremia, whereas after correction, it persists at a higher level in CSWS and normalizes in SIADH. In this study, FEUA was measured in all cases that developed hyponatremia both before and after the correction of hyponatremia. Contrary to the presumed findings, FEUA measurement failed to display consistent findings. The mean hospital stay and mean GOS at discharge were comparable among overall, hyponatremic, and nonhyponatremic patients. There was no significant difference in means for both variables, suggesting that with prompt identification and appropriate
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treatment, hyponatremia does not confer any additional morbidity.
CONCLUSION AND RECOMMENDATIONS Hyponatremia is common in TBI, with an incidence of 27.27% among high-risk patients. Most of them can be attributed to SIADH, although CSWS also occurs in a few. CT scoring of injury has a better correlation with its occurrence than does initial GCS. With prompt identification and treatment, hyponatremia does not result in prolonged hospital stay or any undue morbidity and mortality. Measurement of FEUA does not seem consistent enough for the differentiation of SIADH or CSWS. Because early identification of hyponatremia allows prompt treatment and avoids undue prolongation of morbidity, it seems plausible that daily sodium level measurement at least for the initial 10 days should be routinely done, especially in high-risk TBIs. Because this study has its limitation in terms of small population, further studies will be necessary to build on the findings generated.
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HYPONATREMIA IN PATIENTS WITH TRAUMATIC BRAIN INJURY
ter traumatic brain injury. J Clin Endocrinol Metab 89:5987-5992, 2004. 4. Bondanelli M, Ambrosio MR, Zatelli MC, Marinis LD, Ubertiet EC. Hypopituitarism after traumatic brain injury. Eur J Endocrinol 152:679-691, 2005. 5. Born JD, Hans P, Smitz SJ, Legros J, Kay S. Syndrome of inappropriate secretion of antidiuretic hormone after severe head injury. Surg Neurol 23: 383-387, 1985. 6. Davison C, Grunfeld K, Ritz W. Uric acid and kidney. In: Davison AM, ed. Oxford Textbook of Clinical Nephrology, 2nd Edition. Oxford: Oxford University Press, 1998:1156-1173.
17. Maas A, Hukkelhoven CW, Marshall LF, Steyerberg EW. Prediction of outcome in traumatic brain injury with computed tomographic characteristics: a comparison between the computed tomographic classification and combinations of computed tomographic predictors. Neurosurgery 57:1173-1182, 2005. 18. Moro N, Katayama Y, Igarashi T, Mori T, Kawamata T, Kojima J. Hyponatremia in patients with traumatic brain injury: incidence, mechanism, and response to sodium supplementation or retention therapy with hydrocortisone. Surg Neurol 68:387393, 2007.
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14. Kawajiri K, Matsuoka Y, Kan M. Cerebral salt wasting syndrome secondary to head injury: a case report. No Shinkei Geka 20:1003-1007, 1992.
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16. Marshall LF, Marshall SB, Klauber MR, Clark MvB, Eisenberg HM, Jane JA, Luerssen TG, Marmarou A, Foulkes MA. A new classification of head injury based on computerized tomography. J Neurosurg 75:S14-S20, 1991.
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Conflict of interest statement: National Health Research Council (NHRC) Nepal provided support for laboratory investigations. received 5 October 2010; accepted 29 March 2011 Citation: World Neurosurg. (2011) 76, 3/4:355-360. DOI: 10.1016/j.wneu.2011.03.042 Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com 1878-8750/$ - see front matter © 2011 Elsevier Inc. All rights reserved.
WORLD NEUROSURGERY, DOI:10.1016/j.wneu.2011.03.042
Hyponatremia in Patients with Traumatic Brain Injury: Etiology, Incidence, and Severity Correlation Subash Lohani and Upendra Prasad Devkota
Key words 䡲 Cerebral salt wasting syndrome 䡲 Fractional excretion of uric acid 䡲 Hyponatremia 䡲 Syndrome of inappropriate antidiuretic hormone 䡲 Traumatic brain injury
䡲 BACKGROUND: Hyponatremia is common in patients with traumatic brain injury (TBI). This study aims at ascertaining the incidence of hyponatremia in TBI with its etiologic diagnosis, biochemical confirmation, and severity correlation with initial Glasgow Coma Scale (GCS) score and computed tomography (CT) abnormality.
Abbreviations and Acronyms CSWS: Cerebral salt wasting syndrome CT: Computed tomography CVP: Central venous pressure FEUA: Fractional excretion of uric acid GCS: Glasgow Coma Scale GOS: Glasgow Outcome Scale SIADH: Syndrome of inappropriate antidiuretic hormone TBI: Traumatic brain injury
䡲 METHODS: All patients more than 20 years old with severe and moderate TBI and the mild ones with CT abnormality were included. Daily sodium level was monitored for 14 days. Central venous pressure (CVP) was measured for assessment of volume status. Fractional excretion of uric acid (FEUA) was measured in all patients with hyponatremia, both before and after its correction.
Department of Neurosurgery, National Institute of Neurological and Allied Sciences, Bansbari, Kathmandu, Nepal To whom correspondence should be addressed: Subash Lohani, M.B.B.S. [E-mail: [email protected]] Citation: World Neurosurg. (2011) 76, 3/4:355-360. DOI: 10.1016/j.wneu.2011.03.042 Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com 1878-8750/$ - see front matter © 2011 Elsevier Inc. All rights reserved.
INTRODUCTION Traumatic brain injury (TBI) results in a range of neurological and cognitive impairment to personality, behavioral changes, and lifestyle consequences (12). Posttraumatic endocrine complications also pose a great challenge in the management of TBI. Early recognition of these subtle problems can produce a significant impact on outcome (3, 4). Hyponatremia is a common electrolyte disorder in the setting of central nervous system disease including TBI (9). Two common etiologies, namely the syndrome of inappropriate antidiuretic hormone (SIADH) (10, 13) and cerebral salt wasting syndrome (CSWS) (5, 14, 19) are primarily responsible. Differentiation among the two conditions is based on the volume status of the patient (20). Given a
䡲 RESULTS: Of 40 consecutive patients, 33 remained for analysis. Hyponatremia was seen in 9 (27.2%) patients, of whom 6 developed it within the first week. Mean duration of hyponatremia was 1.78 days. We found that 5 patients had an elevated CVP consistent with the syndrome of inappropriate antidiuretic hormone (SIADH), whereas 3 had low CVP consistent with cerebral salt wasting syndrome (CSWS) and 1 had an equivocal reading. Measurement of FEUA did not show consistent pattern to suggest a biochemical distinction. There were 33.3% each of mild and moderate, and 16.6% of severe TBI among hyponatremic patients. Hyponatremia was seen in Rotterdam CT scores I to IV in increasing incidence (r ⴝ 0.983, P ⴝ 0.017), whereas it had no significant correlation with initial GCS (r ⴝ 0.756, P ⴝ 0.455). 䡲 CONCLUSIONS: Hyponatremia due to SIADH is more common in TBI. FEUA measurement is not consistent enough to make a distinction between SIADH and CSWS. CT scoring of severity is more predictive of hyponatremia than initial GCS.
typical case scenario, distinction might not appear difficult. Yet, an exceeding number of cases have a borderline picture with diagnostic confusion and impediment in therapeutic intervention. Researchers are thus making an attempt in differentiating the two conditions based on biochemical alterations, especially that of the fractional excretion of uric acid (FEUA) (15). This study primarily aims at identifying the etiology, incidence, and timing of hyponatremia in patients with TBI, including its correlation with initial severity and final outcome. Severity correlation is done with both the clinical and radiological severity status.
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METHODS Study Design This is a prospective, descriptive, and analytical study conducted at the National Institute of Neurological and Allied Sciences, Bansbari, Kathmandu. Patients admitted with the diagnosis of TBI were the target population. All patients presenting from April to September 2008 who fulfilled the inclusion criteria were enrolled in the study. Study variables were age distribution, sex distribution, Glasgow Coma Scale (GCS) at the time of presentation, Rotterdam computed tomography (CT) score (Table 1) (17), mechanism of head injury, and associated comorbidity. Theses independent variables
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TOOLS AND TECHNIQUES
Table 1. Rotterdam CT Score CT Characteristics Basal cistern
Category
Score
Normal
0
Compressed
1
Absent
2
Midline shift
No or ⱕ5 mm
0
⬎5 mm
1
Mass lesion
Epidural
0
Nonepidural
1
Absent
0
IVH or tSAH
Present
1 ⫹1*
Sum score
CT, computed tomography; IVH, intraventricular hemorrhage; tSAH, traumatic subarachnoid hemorrhage. *⫹1 is added to the sum score to make the grading numerically consistent with Marshall CT grading and the motor score of the Glasgow Coma Scale.
were used to calculate dependent variables such as incidence of hyponatremia/SIADH/ CSWS, timing of hyponatremia, duration of hospital stay, and Glasgow Outcome Scale (GOS) (11) at discharge. Associated comorbidity and medication-induced hyponatremia were the confounding variables. Inclusion and exclusion criteria were defined as follows.
Inclusion Criteria
y Patients 20 years and older irrespective of their gender, because until the age of 20 years, FEUA levels can be variable (6).
y Patients attending to this hospital up to 3 days post-TBI; since this is a referral center for patients from all over Nepal, a delay of 3 days had to be considered.
Exclusion Criteria
y Patients with established renal, thyroid, or adrenal diseases prior to the TBI because they have a profound effect on fluid and electrolyte balance (4).
y Patients presenting beyond 3 days postTBI.
y Patients younger than 20 years old (6). y Cases with associated spinal cord injuries, because they alone have been reported to cause CSWS (1).
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Pertinent information was prospectively gathered during admission. Consent was obtained from patients at the time of admission as far as possible. Preformed structured formats were used to make pertinent clinical, radiological, and laboratory documentation. Severity of TBI was classified as mild, moderate, or severe based on GCS 13 to 15, 9 to 11, and 3 to 8, respectively (22). CT scan was performed in all patients, and CT grading was noted. Baseline investigations were done in all patients. This included hemoglobin, random blood sugar, serum albumin, sodium (Na), potassium (K), urea, and creatinine. Sodium levels were checked daily for 14 days or until the patient was discharged, whichever was earlier. A CVP catheter was inserted in all patients who underwent surgical intervention. In those with conservative management, a catheter was inserted after the development of hyponatremia. After every insertion of a CVP, proper catheter positioning was confirmed with a chest X-ray, with radiopaque dye if needed. CVP of 6 to 10 cm was considered a normal measurement (20). A sodium level below 130 mEq/L was considered hyponatremia (8, 21). On the diagnosis of hyponatremia, further investigation was performed with the aim of differentiating SIADH and CSWS (15). These included serum/urinary creatinine, serum/urinary uric acid, serum albumin, and serum urea. In addition, some baseline investigations were repeated, per the requirement for management. Regarding the treatment of hyponatremia, fluid restriction in patients with head injury was avoided, irrespective of the diagnosis. All patients were treated with oral salt supplementation and intravenous normal saline after detection of hyponatremia. If the patient did not respond to this therapy and had high CVP, then moderate fluid restriction up to 1500 mL/d was done. In patients with low CVP, fludrocortisone was used if initial therapy did not correct hyponatremia.
RESULTS A total of 40 patients were enrolled in the study, of whom 7 were excluded because they had a hospital stay of less than 1 week for various reasons such as early mortality, transfer to other centers, or associated
medical ailments that could produce hyponatremia. Of 33 patients who remained for analysis, hyponatremia was seen in 9 patients within the period of 2 weeks.
Age Distribution The mean age was 37.42 (19 to 70) years with a standard deviation (SD) of 15.33. Age groups of 20 to 30 and 31 to 50 had 42.4% and 39.4% patients, with least being 18.2% in the age group of ⬎50. Among the hyponatremic patients, the mean age was 38.44 (23 to 69) years with SD 16.4.
Sex Distribution There were a total of 26 male and 7 female patients. The male-to-female ratio was 3.7:1. Among hyponatremic patients, 7 were male and 2 were female. The male-tofemale ratio was 3.5:1.
Severity Based on GCS at the Time of Presentation There were 12 cases each of mild and severe head injury, whereas moderate head injury was found in 9 (Figure 1). Among hyponatremic patients, there were 4 (33.33%) with mild, 3 with moderate (33.33%), and 2 (16.66%) with severe head injury.
Site of Intracranial Lesion Ten patients had lesions at more than one site. Frontal lesion in 21 patients was the most common, followed by temporal lesion in 14. One patient had a small hematoma in the brainstem. Among hyponatremic patients, 3 had lesion at more than one site. Frontal lesion was again the most common, followed by temporal lesion; 6 and 4, respectively.
Type of Intracranial Lesion Eight patients had an epidural lesion, whereas 4 had a subdural lesion. There were total of 22 patients with intraparenchymal lesions, but none of them had an intraventricular extension. Three patients also had pneumocephalus. Traumatic subarachnoid hemorrhage was seen in 5 patients. Nine patients had more than one type of lesion. Among the hyponatremic patients, intraparenchymal lesion, seen in 8 patients, was
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PEER-REVIEW REPORTS SUBASH LOHANI AND UPENDRA PRASAD DEVKOTA
HYPONATREMIA IN PATIENTS WITH TRAUMATIC BRAIN INJURY
CT Scoring: Rotterdam CT Grade Most of the patients had Rotterdam scores 2, 3, and 4; 33.3%, 24.2%, and 27.3%, respectively (Figure 2). Hyponatremia was seen in scores 2, 3, and 4 in increasing incidence, 22.2%, 33.3%, and 44.4% respectively (Pearson correlation coefficient 0.983, P ⫽ 0.017; grades 1 to 4 considered for the analysis) (Table 2). None of the patients with score 5, however, developed hyponatremia. While considering GCS for the correlation with development of hyponatremia, no significant correlation was seen (Pearson correlation coefficient 0.756, P ⫽ 0.454 ) (Table 2). Figure 1. Bar diagram showing the severity of traumatic brain injury and occurrence of hyponatremia.
Surgical Intervention Nineteen (57.6%) patients had their hematoma surgically evacuated. The remaining 14 patients were conservatively managed.
Figure 2. Bar diagram showing Rotterdam computed tomography grade among total and hyponatremic patients.
Table 2. Correlation of GCS, Rotterdam CT Score, and Incidence of Hyponatremia Variables Dependent Variable
Pearson Correlation
Significance (2-Tailed)
GCS category
Incidence of hyponatremia
.756
0.454
Rotterdam CT grade
Incidence of hyponatremia
.983*
0.017
Independent Variable
CT, computed tomography; GCS, Glasgow Coma Scale. *Correlation is significant at the 0.05 level (2-tailed).
the most common lesion. None of the subdural lesions were associated with hyponatremia. Epidural lesion, pneumocephalus, and traumatic subarachnoid hemorrhage were seen in 3, 2, and 1 patients, respectively. Three patients had more than one type of lesion.
Side of Intracranial Lesions Unilateral lesions predominated, with 72.7% over bilateral lesions (24.2%). Leftsided lesions (39.4%) were more common than right ones. Among hyponatremic patients, unilateral, bilateral, and midline lesions were observed in equal incidence, 33.33% each.
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Hyponatremia Hyponatremia occurred in 9 (27.27%) patients. Six of the patients had hyponatremia within the first week of injury (Figure 3). Clustering of cases was seen late in the first week and early in the second week (Figure 4). The mean duration of hyponatremia was 1.78 (1 to 3) days, SD 0.83 (Figure 5). The minimum level of hyponatremia observed was 113 mEq/L. One other patient had hyponatremia down to 120 mEq/L. The remaining 7 patients had sodium levels above 125 mEq/L. All patients recovered well with oral salt supplementation and intravenous normal saline. One patient’s sodium level dropped to 113 mEq/L despite oral and intravenous supplementation, thus requiring fludrocortisone in addition. One other patient who went into hyponatremia of 120 mEq/L on the first postoperative day with a frank picture of SIADH had to be kept on moderate fluid restriction. Two patients (22.2%) had recurrence of hyponatremia, at day 11 in one and day 12 in the other.
Etiology of Hyponatremia Based on CVP measurement at the time of development of hyponatremia, the etiology was ascertained. Five patients were considered to have a diagnosis consistent with SIADH, and 3 with CSWS. Because 1 patient did not manifest any CVP variation, a diagnosis could not be assigned.
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first instance. In 3, the FEUA level decreased relative to the previous level, but remained elevated above normal. In 2, however, the FEUA level further increased after correction of hyponatremia. Among 3 patients with a CSWS-consistent diagnosis, 1 had normal FEUA at the beginning of hyponatremia. In all, however, FEUA remained persistently elevated compared with the previous level. In 1 of the hyponatremic patients, however, CVP remained within the normal range, making it difficult to assign a diagnosis. FEUA was elevated and remained persistently elevated even after correction of hyponatremia. Figure 3. Bar diagram showing the timing of hyponatremia.
Hospital Stay Overall, the mean hospital stay was 26.73 (7 to 90) days, SD 19.4. Among the hyponatremic patients, the mean hospital stay was 24.67 (15 to 51) days, SD 13.4. No significant difference in means (P ⫽ 0.83) was shown by independent sample t test (Table 4).
Figure 4. Graph showing the day of occurrence of hyponatremia.
GOS at Discharge Overall, the mean GOS at discharge was 3, SD 1.25. Among hyponatremic patients, the mean GOS was 3.22, SD 1.09. No significant difference in means (P ⫽ 0.553) was seen on independent sample t test (Table 4).
DISCUSSION
Figure 5. Bar diagram showing duration of hyponatremia.
Hyponatremia and FEUA FEUA was calculated using the following formula: Urinary uric acid ⫻ Serum creatinine Urinary creatinine ⫻ Serum uric acid
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⫻ 100%
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Contrary to expectations, FEUA as measured after detection of hyponatremia and after the correction of hyponatremia showed bizarre findings (Table 3). Among 5 patients with an SIADH-consistent diagnosis, all had elevated FEUA at the
To begin with demographics, mean age and sex ratio of overall and hyponatremic patients are comparable. The incidence of hyponatremia was 27.27%, which is comparable to that described by Moro et al. (18) among the subgroup of head injury patients who had intracranial bleeding. Hyponatremia has been shown to have an association with the severity of brain injury (9). However, both mild and moderate head injuries had 33.33% hyponatremia, whereas with increasing severity, incidence decreased to 16.66%. Similar types of observations were made in the study by Doczi et al. (7), in which hyponatremia was seen more in moderate head injury rather than severe. Thus it seems that the occurrence of hyponatremia does not correlate well with GCS at admission. As seen in our study as well,
WORLD NEUROSURGERY, DOI:10.1016/j.wneu.2011.03.042
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HYPONATREMIA IN PATIENTS WITH TRAUMATIC BRAIN INJURY
Table 3. CVP Measurements, Consistent Diagnosis, and FEUA Measurements Among Hyponatremic Patients Patient
CVP (Normal 6 to 10 cm)
Consistent Diagnosis
Before FEUA (%)
After FEUA (%)
1
High/20 cm
SIADH
90.90
30.25
2
High/20 cm
SIADH
34.37
33.92
3
High/21 cm
SIADH
28.20
21.09
4
High/18 cm
SIADH
8.40
9.84
5
High/25 cm
SIADH
33.50
41.41
6
Normal/7 cm
—
12.39
17.42
7
Low/0 cm
CSWS
7.77
20.40
8
Low/3 cm
CSWS
11.25
29.72
9
Low/4 cm
CSWS
16.66
31.42
CSWS, cerebral salt wasting syndrome; CVP, central venous pressure; FEUA, fractional excretion of uric acid; SIADH, syndrome of inappropriate antidiuretic hormone.
36.36% of cases had mild head injury based on GCS score alone, whereas all of them had one or the other CT abnormality, requiring intervention in many instances. There was no statistical correlation between GCS at initial presentation and occurrence of hyponatremia. Interestingly, however, observing the trend in Rotterdam CT scores, with increasing grades from 2 to 4, incidence of hyponatremia also increased. Although there were no instances of hyponatremia in score 5, the pattern seems convincing that a CT grading might be a more important determinant of severity and hence occurrence of hyponatremia. With the exclusion of score 5, for which no hyponatremia was seen, a significant statistical correlation was also established. A higher rate of surgical intervention was
due to the inclusion of high-risk trauma patients in the study; mild head injuries with normal CT scans were excluded. Because most of the patients underwent surgical evacuation, Marshall CT grade 5 (16) would be the most common if classified accordingly. As the proportion of patients who underwent surgical intervention was proportionate among total and hyponatremic patients, here again it seems plausible that CT scoring based on individual CT characteristics such as of Rotterdam CT score would be more consistent with the severity and consequent events. Frontal location of the lesion was most common, be it among overall patients or hyponatremic patients. Similarly, intraparenchymal lesion was the most common type. In contrast to the findings of Moro et al. (18), in which chronic subdural lesions
Table 4. The t Test for the Equality of Means (Duration of Hospital Stay and Glasgow Outcome Score at Discharge) t Test for Equality of Means 95% Confidence Interval of the Difference
t
Significance (2-Tailed)
Mean Difference
Standard Error Difference
Lower
Upper
Duration of hospital stay
⫺.217
.830
⫺1.62
7.459
⫺16.830
13.595
Glasgow outcome at discharge
⫺.600
.553
⫺.29
.478
⫺1.262
.689
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were associated with 15.9% hyponatremia, none of the acute subdural lesions in our series had hyponatremia. Right, left, and bilateral lesions were all associated with an equal incidence of hyponatremia. Management of hyponatremia depends on the level of sodium, clinical state, volume status, and tonicity (2). Because the policy of our institution is to avoid fluid restriction in patients with head injury, irrespective of the diagnosis, all patients were treated with oral salt supplementation and intravenous normal saline after hyponatremia was observed. Hyponatremia corrected in almost all instances with this treatment strategy, probably because most of the cases were mild. In one instance, the patient went into frank SIADH on the first postoperative day with significantly decreased urine output. The following day, the patient had an excess urine output leading to spontaneous correction of hyponatremia, and it never recurred again. This particular instance suggests that an over-zealous attempt at correction might lead to a toorapid correction of hyponatremia, which should always be avoided. Two-thirds of hyponatremic cases occurred during the first week. This was noticed in days 1, 3, 6, and 7, contrary to what was described by Moro et al. (18). They described a peak of hyponatremia in the first week within the first 3 days. In our finding, clustering of cases was seen late in the first week and early in the second week. Given a typical case scenario, differentiation of SIADH and CSWS might not sound difficult. Yet in clinical practice, confusion still persists. In trying to solve this confusion, Maesaka et al. (15) suggested that FEUA increases in both conditions at the onset of hyponatremia, whereas after correction, it persists at a higher level in CSWS and normalizes in SIADH. In this study, FEUA was measured in all cases that developed hyponatremia both before and after the correction of hyponatremia. Contrary to the presumed findings, FEUA measurement failed to display consistent findings. The mean hospital stay and mean GOS at discharge were comparable among overall, hyponatremic, and nonhyponatremic patients. There was no significant difference in means for both variables, suggesting that with prompt identification and appropriate
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treatment, hyponatremia does not confer any additional morbidity.
CONCLUSION AND RECOMMENDATIONS Hyponatremia is common in TBI, with an incidence of 27.27% among high-risk patients. Most of them can be attributed to SIADH, although CSWS also occurs in a few. CT scoring of injury has a better correlation with its occurrence than does initial GCS. With prompt identification and treatment, hyponatremia does not result in prolonged hospital stay or any undue morbidity and mortality. Measurement of FEUA does not seem consistent enough for the differentiation of SIADH or CSWS. Because early identification of hyponatremia allows prompt treatment and avoids undue prolongation of morbidity, it seems plausible that daily sodium level measurement at least for the initial 10 days should be routinely done, especially in high-risk TBIs. Because this study has its limitation in terms of small population, further studies will be necessary to build on the findings generated.
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Conflict of interest statement: National Health Research Council (NHRC) Nepal provided support for laboratory investigations. received 5 October 2010; accepted 29 March 2011 Citation: World Neurosurg. (2011) 76, 3/4:355-360. DOI: 10.1016/j.wneu.2011.03.042 Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com 1878-8750/$ - see front matter © 2011 Elsevier Inc. All rights reserved.
WORLD NEUROSURGERY, DOI:10.1016/j.wneu.2011.03.042