Increased intracranial pressure is associated with ...

Increased intracranial pressure is associated with elevated cerebrospinal fluid ADH levels in closed-head injury Marsha A. Widmayer1–4, Jeffrey L. Browning3–5, Shankar P. Gopinath1,3, Claudia S. Robertson1,3, David S. Baskin1–6 1

Department of Neurosurgery, The Methodist Hospital, Houston, TX, USA, 2The Methodist Hospital Research Institute, Houston, TX, USA, 3Department of Neurosurgery, Baylor College of Medicine, Houston, TX, USA, 4Veteran’s Affairs Medical Center, Houston, TX, USA, 5The Center of Excellence for Research on Returning War Veterans, Central Texas Veterans Health Care System and Department of Psychiatry and Behavioral Sciences, Texas A&M Health Science Center, Temple, TX 76504, 6Department of Neurosurgery, Weill Cornell Medical College, New York, USA

Objectives: Head injury frequently results in increased intracranial pressure and brain edema. Investigators have demonstrated that ischemic injury causes an increase in cerebrospinal fluid (CSF) levels of antidiuretic hormone (ADH); increased CSF ADH levels exacerbate cerebral edema, and inhibition of the ADH system with specific ADH antagonists reduces cerebral edema. The current study was designed to test the hypothesis that elevated levels of ADH are present in the CSF of subjects with head injury. Methods: Ventricular CSF and blood samples were taken from 11 subjects with head injury and 12 subjects with no known head trauma or injury. ADH levels were analyzed using radioimmunoassay. Severity of increased intracranial pressure (ICP) was rated in head-injured subjects using a four-point ordinal scale, based on which treatments were necessary to reduce ICP. Results: Subjects with head injury had higher CSF (3.2 versus 1.2 pg/ml; P,0.02) and plasma (4.1 versus 1.4 pg/ml; P,0.02) levels of ADH than did control subjects. In head-injured subjects, CSF ADH levels positively correlated with severity of ICP. Discussion: The results of this study suggest that ADH plays a role in brain edema associated with closed head injury. Keywords: Head injury, Trauma, Antidiuretic hormone, Vasopressin, Intracranial pressure

Introduction The consequences of closed head injury are frequently severe, and can be fatal. Following human head injury regional and global reductions in cerebral blood flow can occur, resulting in secondary cerebral ischemia.1,2 A further dangerous consequence of closed head injury is cerebral edema, which typically results in elevated intracranial pressure.3,4 Despite its frequent occurrence and deleterious consequences, cerebral edema remains a difficult problem to treat.3,5 The medical treatment for severe head injury with intractable brain edema includes techniques that compensate for the reduced amount of available oxygen, by reducing the amount of cerebral oxygen consumed.6,7 This is accomplished by administering anesthetics, paralytics or even instituting pharmacologic coma. Administration of hyperosmotics, such as Correspondence to: David S. Baskin, Department of Neurosurgery, The Methodist Hospital, 6560 Fannin, Suite 944, Houston, TX 77030, USA. Email: [email protected]

ß W. S. Maney & Son Ltd 2010 DOI 10.1179/016164110X12714125204155

mannitol or lasix is also used, although the results of this treatment may, at times, be harmful.8–10 In some cases, surgical procedures such as a decompressive craniectomy are performed. Although this procedure has many proponents, it also has many opponents.11–13 Investigation of effective treatment for cerebral edema should include a consideration of the endogenous system that controls water balance.14 It has been shown that the retention or excretion of water both in the extracellular and intracellular compartments can be altered in animals by either increasing or decreasing release of antidiuretic hormone [ADH, arginine vasopressin (AVP)].15,16 Indeed, the ADH system is frequently disrupted following damage to the brain. Following head injury, the syndrome of inappropriate antidiuretic hormone secretion is common17 and may occur in as many as 33% of patients.18 Furthermore, cerebral ischemia, often seen after closed head injury, results in increases in both cerebrospinal fluid and plasma levels of ADH in patients.19,20

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Intracranial pressure is associated with ADH levels

Increased secretion of ADH following brain damage is likely deleterious, as central and peripheral administration of ADH have been shown to exacerbate cerebral edema in animal studies.21–23 In addition, ADH release inhibitors such as the kappa opioid agonists Dynorphin 1–13, RU 51599 (niravoline) and U-50,488 reduce brain edema following experimental cerebral ischemia.24–27 Furthermore, ADH receptor antagonists also reduce experimental brain edema.28–31 The present study was designed to evaluate the relationship between ADH levels and brain edema [as indicated by intracranial pressure (ICP)] following traumatic brain injury.

Materials and methods All procedures were approved by the Baylor College of Medicine Institutional Review Board. Each subject or his representative signed an Informed Consent Form. Eleven patients with head injury were entered into the study. The patients presented at Ben Taub General Hospital and were diagnosed with moderate to severe head injury. All patients entered into the study were male. The average age was 40 years (Table 1). Ventricular catheters were placed in each patient and cerebrospinal fluid (CSF) was withdrawn, as necessary, until the ICP was stable. Blood samples were taken immediately following CSF sampling. ICP was continuously measured, and was recorded once every hour. For purposes of data analysis, subjects were organized into one of four groups depending on the level of treatment needed to reduce their ICP (Table 2). Contemporaneous control ventricular CSF and blood were obtained from 12 subjects with no known head trauma or ischemic injury. The average age of the control patients was 50 years. These patients had

received ventriculoperitoneal shunts for hydrocephalus at least 2 days prior to CSF sampling, and all had normal ICP and neurological examinations at the time of sampling. One patient each had aqueductal stenosis and hemorrhage-induced hydrocephalus. Six patients had obstructive hydrocephalus, and four patients had idiopathic hydrocephalus. Plasma and CSF AVP levels were determined via radioimmunoassay using a kit provided by Nichols Institute (San Mateo, CA, USA). Specimens were placed on ice immediately following collection, were centrifuged at 4uC and the plasma or CSF was stored at 280uC until thawed for assay. Following a standard ethanol extraction and drying, the samples were reconstituted and assayed in duplicate. Antivasopressin was added and the samples were incubated at 4uC for 24 hours. 125I vasopressin was then added and the samples incubated at 4uC for an additional 24 hours. The unbound vasopressin was precipitated and decanted, and the antibody-bound radiolabeled vasopressin was counted for 2 minutes in a gamma counter. A standard curve was generated using vasopressin standards provided in the kit. Statistical comparisons of ADH levels in control and head-injured subjects were performed using the Mann–Whitney U rank sum test. The relationship between CSF ADH levels and ICP rating or Glasgow Coma Scale (GCS) was analyzed using the Spearman rank order correlation (for ordinal data). Care was taken to exclude GCS that were influenced by paralytics. The relationship between mean CSF ADH levels and highest Neurointensive Care Unit (NICU) ICP, percent of NICU time that ICP>25 mm Hg, pupil size or number of days in the NICU were analyzed using the Pearson correlation (for interval data). Data from subjects who died

Table 1 Subject information Mean CSF Elapsed hours Subject Age ADH in NICU at no. (years) (pg/ml) CSF draws 1

36

0.8

2

41

1.0

3 4 5 6 7 8 9 10 11

70 8 33 54 29 25 46 29 46

1.6 1.8 2.9 3.2 3.2 3.9 4.6 7.5 8.3

Max. % time ICP in ICP >25 ICP Pupil Days in 6-month NICU* mm Hg* score* GCS* size* NICU out-come

223, 238, 260, 284, 308, 333, 355, 374 43, 55, 78, 102, 125, 173, 266 20, 44, 68, 93 173 99, 125, 147, 166, 240 55, 75 72 146, 151 8, 29, 43, 73, 98 11, 22, 38 22, 33, 49

38

1.7

2

9

4

25

24

0

0

3

6

2

14 35 46 21 43 45 67 48 59

0 0.2 12.8 0 10.6 10.2 53.4 21.7 30.3

0 1 3 1 2 2 3 3 3

6 3 8 7 4 8 9 12{ 14

6 6 7 n/a 8 8 10 10 8

26 17 37 13 34 29 13 42 11

MD

Injury EDH

Died in NICU GSW SD MD SD{ SD SD MD Died in NICU MD Died in NICU

DWM SDH Contusion Contusion SDH Contusion, SAH Contusion, SDH Contusion, EDH Contusion

Notes: ICP score per Table 2. % time ICP>25 mm Hg refers to percent of NICU stay only. Pupil size is sum of millimeter diameter of both eyes. Subject number six’s pupil size n/a due to injury. CSF, cerebrospinal fluid; ADH, antidiuretic hormone; NICU, Neurointensive Care Unit; GCS, Glasgow Coma Scale score in the emergency room; MD, moderate disability; SD, severe disability; EDH, epidural hemotoma; SDH, subdural hemotoma; SAH, subarachnoid hemorrhage; DWM, diffuse white matter; GSW, gunshot wound. *Significant positive correlation with CSF ADH, P,0.05. {GCS from field assessment, as patient was given paralytic upon ER admittance. {1-month follow-up only.

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Figure 1 Mean CSF and plasma ADH levels in head-injured and control subjects. The mean ADH level was calculated for each subject for CSF or plasma. Subjects with head injury (n511) had significantly elevated levels of ADH in both CSF (*P,0.02) and plasma (*P,0.01) compared to control subjects (n512); Mann–Whitney U.

Figure 2 Relationship between highest ICP measured in the NICU and CSF ADH in head-injured subjects. The mean CSF ADH level was calculated for each subject with head injury (n511). A Pearson product–moment correlation was then performed for mean CSF ADH levels and the highest ICP. A significant positive relationship was demonstrated (correlation coefficient50.66, P,0.03).

in the NICU were excluded from analysis of number of days in the NICU. Comparisons were considered to be statistically significant at an alpha of (0.05.

pressure, jugular venous oxygen saturation, the length of time the subject was in a coma, subject outcome, or total number of days the subject was in the NICU. Total number of days in the NICU did, however, correlate with severity of ICP (Spearman correlation coefficient50.79, P,0.05; Table 1). CSF ADH levels had a tendency to decrease over time (4.7 versus 2.6 pg/ml), but the difference did not reach statistical significance (paired t-test, t52.19, P(0.06).

Results Subjects with head injury had higher plasma and CSF levels of ADH than did control subjects (P,0.02, each; Fig. 1). Mean CSF and plasma levels showed very little positive correlation (Pearson correlation coefficient50.23). This lack of correlation was due almost entirely to one subject who had a mismatch between plasma and CSF ADH levels at three time points. In subjects with head injury, mean CSF ADH levels positively correlated with three indicators of ICP, highest ICP measured in the NICU (Pearson correlation coefficient50.66, P,0.03, Fig. 2), percent of time in NICU that ICP was >25 mm Hg (Pearson correlation coefficient50.66, P,0.03, Fig. 3) and severity of ICP (Spearman correlation coefficient50.70, P,0.02; Fig. 4). Mean CSF ADH levels also positively correlated with entry GCS (Spearman correlation coefficient50.62, P,0.05; Table 1) and emergency room pupil size (Pearson correlation coefficient50.77, P,0.01, Table 1). No significant correlation was seen between CSF ADH and cerebral perfusion pressure, mean arterial Table 2 Assessment of ICP Severity of ICP

Treatment necessary to reduce ICP

0 1

No treatment Sedation No paralysis No mannitol Sedation Paralysis Minimal mannitol (,1500 mg/kg total) Sedation Paralysis Maximal mannitol (.1500 mg/kg total)

2

3

Discussion The ability to consistently reduce cerebral edema would be a powerful tool for the treatment of head injury and stroke.3,5,32 Current usage of osmotic diuretics is problematic and is complicated by hypotension and subsequent secondary brain injury33 and the need to administer fluids and/or vasopressors for blood pressure maintenance and to maintain normovolemia.7,33 In the present study, we demonstrated that head injury is associated with an elevation in CSF levels of ADH, and that increased CSF ADH directly correlates with increased ICP. Studies performed in the early to mid-1980s demonstrated a positive relationship between ICP and CSF ADH levels in patients with various neurological diseases including pseudotumor cerebri, intracranial tumor, spinocerebellar degeneration, and peripheral neuropathy.20,34–37 In these early studies, however, much or all of the ICP data was gathered from lumbar puncture, whereas in this study, all CSF was obtained from the ventricular system. The control CSF in the present study was drawn from patients undergoing ventriculostomy for hydrocephalus. Because the head injury and control patients were from somewhat different populations, it is possible that the control levels do not fully reflect adequate control values for the head injury subjects. In support of our data, however, are published


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Figure 3 Relationship between percent of time in the NICU that ICP was >25 mm Hg and CSF ADH in head-injured subjects. The mean CSF ADH level was calculated for each subject with head injury (n511). A Pearson product–moment correlation was then performed for mean CSF ADH levels and the percent of time in the NICU that the subject’s ICP was >25 mm Hg. A significant positive relationship was demonstrated (correlation coefficient50.66, P,0.03).

reports of control AVP in human CSF which directly match the levels seen in the present study.38,39 Although one patient had a mismatch between CSF and plasma AVP levels, recent research has demonstrated that it is not uncommon for large gradients to exist between CSF and plasma levels of hormones as well as poor correlation between the two.40 There is currently evidence that ADH levels are increased in humans following ischemia19,20,41 and that higher ADH levels are associated with larger lesions and worse outcomes.19 It is possible that the increased ADH levels in the current study are an indicator of irreversible ischemic damage rather than reversible cerebral edema and therefore, would not be a potential target for treatment. However, studies using animal models of neurological disorders have demonstrated that both vasopressin and vasopressin receptors are upregulated following traumatic brain injury.42 Animal studies have also confirmed that increased CSF ADH exacerbates cerebral edema, whereas inhibition of the ADH system successfully reduces cerebral edema.22,29,30,43,44 ADH increases brain water permeability and exacerbates experimental injury-induced brain edema.22,38,45 Animals which are deficient in central ADH receptors, such as the Brattleboro rat, do not experience the increase in cerebral edema typically seen following stroke23,46 or subarachnoid hemorrhage.47 Intracerebro-ventricular administration of ADH,46 or peripheral administration of dDAVP23 normalizes the development of ischemia-induced cerebral edema in the ADH deficient rats. Compounds which block ADH-induced brain edema would, therefore, likely be promising neuroprotective candidates. Indeed, studies of V1 and V2 vasopressin receptor antagonists have independently demonstrated neuroprotection. In animal studies of traumatic brain injury, V1 antagonists have been

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Figure 4 Relationship between severity of ICP and CSF ADH in head-injured subjects. The mean CSF ADH level was calculated for each subject with head injury (n511). A Spearman rank correlation was then performed for mean CSF ADH levels and the ordinal data indicating severity of ICP. A significant positive relationship was demonstrated (correlation coefficient50.74, P,0.01).

shown to significantly reduce brain water content, ICP, contusion expansion and motor deficit.48 V2 antagonists have been shown to effectively reduced brain edema in experimental models of global ischemia,28 subarachnoid hemorrhage,30 and water intoxication.49 Ikeda and colleagues showed that the AVP release inhibitor, niravoline (RU51599) reduced both coldinjury and ischemia-induced cerebral edema in the rat.27 Interestingly, niravoline was first developed as a kappa opioid agonist and only later became to be better known for its AVP actions.27 It is now generally believed that AVP inhibition is provided by kappa opioids.50 The endogenous kappa ligand, dynorphin, exerts a tonic inhibition on the secretion of ADH.51–53 This tonic inhibition is disrupted following injury to the brain if there is a concomitant decrease in levels of dynorphin. Therefore, compounds that provide replacement kappa receptor activation can reinstate the tonic inhibition of ADH thereby also reducing brain edema.50,51 The results of this study provide confirmatory support for the hypothesis that ADH plays an important role in brain edema. While this study provides only correlative data, other experimental data suggests that elevated CSF ADH levels indeed produce cerebral edema.22,41,54 These results suggest that inhibition and/or modulation of the ADH system may be a promising treatment for some forms of CNS edema.

Acknowledgements This research was supported in part, by R01 CA78912 from the National Cancer Institute, National Institutes of Health, by 004949-054 from the Texas Higher Education Coordinating Board, and by grants from the VA Merit Review Board, The American Heart Association, Texas Affiliate, The

Widmayer et al.

Taub Foundation, The Henry J. N. Taub Fund for Neurosurgical Research, The Blanche Greene Estate Fund of the Pauline Sterne Wolff Memorial Foundation, The George A. Robinson, IV Foundation, and The Koppelman Fund of the Neurological Research Foundation.

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