Update: L-Carnitine

L-Carnitine

Forty patients with severe traumatic brain injury were randomized into 2 groups. The l-carnitine (LCA-) group received standard treatment with placebo while the (LCA+) group received l-Carnitine 2g/day for one week. Neuron specific enolase (NSE) was measured on days 1, 3 and 7 after the initiation of the study. Neurocognitive and neurobehavioral disorders were recorded on the first and third months.

Neurocognitive function and NSE significantly improved within one week in both groups. Patient mortality was similar in LCA+ and LCA- groups (P value: 0.76). Brain edema was present in 7 patients in LCA+ group and 13 patients in LCA-group (P value: 0.044). While there was no difference in NSE levels between the two groups. Neurological function was preserved in the LCA+ group with an exception of attention deficit, which was frequent in the LCA+ group.

Mahmoodpoor et al. concluded that despite improvements in neurobehavioral function and the degree of cerebral edema, 7-days of treatment with l-Carnitine failed to reduce serum NSE levels or improve mortality rate at 90days in patients with TBI 1).


There is evidence in the literature for mitochondrial dysfunction in Parkinson’s disease as well as fatty acid beta-oxidation, involving l-carnitine.

Gill et al. investigated l-carnitine in the context of microglial activation, suggesting a potential new strategy of supplementation for PD patients. Preliminary results from this studies suggest that the treatment of activated microglia with the endogenous antioxidant l-carnitine can reverse the effects of detrimental neuroinflammation in vitro 2).

1)

Mahmoodpoor A, Shokouhi G, Hamishehkar H, Soleimanpour H, Sanaie S, Porhomayon J, Rasouli F, Nader ND. A pilot trial of l-carnitine in patients with traumatic brain injury: Effects on biomarkers of injury. J Crit Care. 2018 Feb 9;45:128-132. doi: 10.1016/j.jcrc.2018.01.029. [Epub ahead of print] PubMed PMID: 29454227.
2)

Gill EL, Raman S, Yost RA, Garrett TJ, Vedam-Mai V. l-Carnitine Inhibits Lipopolysaccharide-Induced Nitric Oxide Production of SIM-A9 Microglia Cells. ACS Chem Neurosci. 2018 Jan 31. doi: 10.1021/acschemneuro.7b00468. [Epub ahead of print] PubMed PMID: 29370524.

Update: Abciximab

Abciximab

Abciximab is made from the Fab fragments of an immunoglobulin that targets the glycoprotein IIbIIIa receptor on the platelet membrane.

Abciximab (previously known as c7E3 Fab), a glycoprotein IIb/IIIa receptor antagonist manufactured by Janssen Biologics BV and distributed by Eli Lilly under the trade name ReoPro, is a platelet aggregation inhibitor mainly used during and after coronary artery procedures like angioplasty to prevent platelets from sticking together and causing thrombus (blood clot) formation within the coronary artery. It is a glycoprotein IIb/IIIa inhibitor.

While abciximab has a short plasma half-life, due to its strong affinity for its receptor on the platelets, it may occupy some receptors for weeks. In practice, platelet aggregation gradually returns to normal about 96 to 120 hours after discontinuation of the drug 1).

Rx: 0.25 mg/kg IV bolus over at least 1 min, 10-60 min before start of PCI, THEN

0.125 mcg/kg/min IV continuous infusion for 12 hr; not to exceed infusion rate of 10 mcg/min


Patel et al. evaluated the efficacy of treatment of acute thrombus formation with abciximab, as well as the results of pre-procedure platelet inhibition testing.

Acute thrombus formation was encountered in five patients following PED placement (5%). Early angiographic signs were present in all cases and included progressive stagnation of blood flow in covered side branches, occlusion of covered side branches, excessive stagnation of blood flow in the target aneurysm, as well as occlusion of the target aneurysm. These sequelae completely resolved following abciximab treatment in all five cases, with no permanent neurological morbidity or mortality. Four of the five patients had a pre-procedure P2Y12 value >200 (range 201-227).

Progressive stagnation or occlusion of covered side branches or target aneurysm are early angiographic signs of acute thrombus formation following PED placement and should prompt immediate treatment with a glycoprotein IIb/IIIa inhibitor. Platelet inhibition testing may help identify those patients who are at an increased risk for this complication 2).


A review provides a comprehensive evaluation of the current published literature pertaining to the use of all available GP IIb/IIIa inhibitors for thromboembolic complications, providing recommendations for dosing and administration of abciximab, eptifibatide, and tirofiban based on previously published rates of efficacy and intracranial hemorrhage 3).


Abciximab produces a high rate of angiographic improvement and a low incidence of postprocedural infarct in neuroendovascular procedures complicated by thromboemboli. IA abciximab produces greater angiographic improvement than IV treatment. Postprocedural infarction is less common in patients with complete angiographic response than in those with partial or no response 4).


In acute ICA-MCA/distal ICA occlusions, extracranial stenting followed by intracranial IA Abciximab and thrombectomy appears feasible, effective, and safe. Further evaluation of this treatment strategy is warranted 5).


There was no statistically significant difference in the rate of ischemic stroke or postprocedural hemorrhage with the use of abciximab compared with the use of eptifibatide in treatment of intraprocedural thrombosis 6).

1)

Tanguay, J.F., Eur Heart J 1999; 1 (suppl E): E27-E35
2)

Patel A, Miller TR, Shivashankar R, Jindal G, Gandhi D. Early angiographic signs of acute thrombus formation following cerebral aneurysm treatment with the Pipeline embolization device. J Neurointerv Surg. 2017 Nov;9(11):1125-1130. doi: 10.1136/neurintsurg-2016-012701. Epub 2016 Oct 21. PubMed PMID: 27770038.
3)

Dornbos D 3rd, Katz JS, Youssef P, Powers CJ, Nimjee SM. Glycoprotein IIb/IIIa Inhibitors in Prevention and Rescue Treatment of Thromboembolic Complications During Endovascular Embolization of Intracranial Aneurysms. Neurosurgery. 2017 May 3. doi: 10.1093/neuros/nyx170. [Epub ahead of print] PubMed PMID: 28472526.
4)

Kansagra AP, McEachern JD, Madaelil TP, Wallace AN, Cross DT 3rd, Moran CJ, Derdeyn CP. Intra-arterial versus intravenous abciximab therapy for thromboembolic complications of neuroendovascular procedures: case review and meta-analysis. J Neurointerv Surg. 2017 Feb;9(2):131-136. doi: 10.1136/neurintsurg-2016-012587. Epub 2016 Aug 18. PubMed PMID: 27540089.
5)

Al-Mufti F, Amuluru K, Manning NW, Khan I, Peeling L, Gandhi CD, Prestigiacomo CJ, Pushchinska G, Fiorella D, Woo HH. Emergent carotid stenting and intra-arterial abciximab in acute ischemic stroke due to tandem occlusion. Br J Neurosurg. 2017 Oct;31(5):573-579. doi: 10.1080/02688697.2017.1297377. Epub 2017 Mar 15. PubMed PMID: 28298139.
6)

Adeeb N, Griessenauer CJ, Moore JM, Foreman PM, Shallwani H, Motiei-Langroudi R, Gupta R, Baccin CE, Alturki A, Harrigan MR, Siddiqui AH, Levy EI, Ogilvy CS, Thomas AJ. Ischemic Stroke After Treatment of Intraprocedural Thrombosis During Stent-Assisted Coiling and Flow Diversion. Stroke. 2017 Apr;48(4):1098-1100. doi: 10.1161/STROKEAHA.116.016521. Epub 2017 Feb 28. PubMed PMID: 28246277.

Update: Tirilazad

Tirilazad

U74006F (U-74006F) is a member of steroid drugs called 21 aminosteroids, which are potent inhibitors of lipid peroxidation with little or no glucocorticoid or mineralocorticoid activity 1).


Alotaibi et al. performed a post-hoc analysis of 3567 patients who underwent clipping of ruptured intracranial aneurysms in the randomized trials of tirilazad mesylate from 1990 to 1997. These trials included 162 centers and 156 surgeons from 21 countries. Primary and secondary outcomes were: Glasgow outcome scale score and mortality, respectively. Total publications, H-index, and graduate degrees were used as academic indicators for each surgeon. The association between outcomes and academic factors were assessed using a hierarchical logistic regression analysis, adjusting for patient covariates.

Academic profiles were available for 147 surgeons, treating a total of 3307 patients. Most surgeons were from the USA (62, 42%), Canada (18, 12%), and Germany (15, 10%). On univariate analysis, the H-index correlated with better functional outcomes and lower mortality rates. In the multivariate model, patients under the care of surgeons with higher H-indices demonstrated improved neurological outcomes (p = 0.01) compared to surgeons with lower H-indices, without any significant difference in mortality. None of the other academic indicators were significantly associated with outcomes.

Although prognostication following surgery for ruptured intracranial aneurysms primarily depends on clinical and radiological factors, the academic impact of the operating neurosurgeon may explain some heterogeneity in surgical outcomes 2).


The multicenter Tirilazad database (3551 patients) was used to create this clinical outcome prediction model in order to elucidate significant brain-body associations. Traditional binary logistic regression models were used.

Binary logistic regression main effects model included four statistically significant single prognostic variables, namely, neurological grade, age, stroke, and time to surgery. Logistic regression models demonstrated the significance of hypertension and liver disease in development of brain swelling, as well as the negative consequences of seizures in patients with a history of myocardial infarction and post-admission fever worsening neurological outcome.

Using the aforementioned results generated from binary logistic regression models, we can identify potential patients who are in the high risk group of neurological deterioration. Specific therapies can be tailored to prevent these detriments, including treatment of hypertension, seizures, early detection and treatment of myocardial infarction, and prevention of hepatic encephalopathy 3).


Data were extracted from two concurrently conducted randomized clinical trials of the drug tirilazad; the designs of these studies were similar. The studies included 1701 patients with severe and 476 patients with moderate TBI. Differences were primarily investigated between studies performed in Europe and North America, but also among European regions and between Canada and the United States. Associations among regions and outcomes (6-month mortality rate and Glasgow Outcome Scale scores) were studied using multivariable logistic regression analysis. Comparisons between continents and among regions within Europe showed differences in the distribution of patient ages, causes of injury, and several clinical characteristics (motor score, pupillary reactivity, hypoxia, hypotension, intracranial pressure [ICP]). and findings on computerized tomography scans. Secondary referrals occurred 2.5 times more frequently in Europe. Within Europe secondary referral was mainly associated with an increased proportion of patients with mass lesions (46% in the European Study compared with 40% in the North American Study). Therapy for lowering ICP was more frequently applied in North America. After adjustments for case mix and management, mortality and unfavorable outcomes were significantly higher in Europe (odds ratios = 1.58 and 1.46, respectively). Significant differences in outcome between regions within Europe or within North America were not observed.

Despite the use of a strict study protocol, considerable differences in patient characteristics and case management exist between continents and among countries, reflecting variations in social, cultural, and organizational aspects. Outcomes of TBI may be worse in Europe compared with North America, but this finding requires further study 4).


Striking problems with imbalance concerning basic prognostic variables were observed in spite of the large population studied. These imbalances concerned pretreatment hypotension, pretreatment hypoxia, and the incidence of epidural hematomas. In future trials of pharmacological therapy for severe head injury, serious consideration must be given to alternative randomization strategies. Given the heterogeneous nature of head injury and the identification of populations that do relatively well with standard therapy, target populations with a higher risk for mortality and morbidity may be more suitable for clinical trials of such agents 5).


The efficacy of U74006F in reducing cerebral infarct size was investigated in a rabbit model of thromboembolic stroke. Each animal received either U74006F (3.0 mg/kg immediately before and 2 hr after embolization, n = 8) or vehicle control (n = 10). Hematocrit, mean arterial pressure, PCO2, PO2, and pH were measured and controlled both before and after the administration of an autologous clot into one internal carotid artery. Regional cerebral blood flow (in ml/100 g/min, mean +/- SEM) measured by hydrogen clearance was similar in both groups, being reduced from 68.2 +/- 9.6 to 5.2 +/- 1.9 in the control group immediately after clot embolization and from 73.3 +/- 14.9 to 7.0 +/- 1.7 in the U74006F group. Four hours after embolization the brain was harvested and cerebral infarct size was determined using the triphenyl-tetrazolium chloride technique (% hemisphere, mean +/- SEM). In the U74006F-treated group, the infarct size was significantly reduced (P < 0.05) to 14.8 +/- 6.4 from a control value of 36.0 +/- 6.4. Additionally, cerebral blood flow values after embolization were consistently higher in the U74006F group, although the differences were not statistically significant. This data suggests that the 21-aminosteroid U74006F may have a protective effect in cerebral ischemia 6).


The ability of a non-glucocorticoid 21 aminosteroid U74006F to inhibit lipid peroxidation of central nervous system tissue in vitro and to enhance the early neurological recovery and survival of mice after a severe concussive head injury is described. In the in vitro studies, U74006F was found to be an extremely potent inhibitor of lipid peroxidation in an assay system where the glucocorticoid steroid methylprednisolone and the non-glucocortoid steroids U72099E and U75718A were almost completely ineffective. In the head-injury studies, unanesthetized male CF-1 mice were subjected to a 900 gm-cm closed head injury produced by a 50-gm weight being dropped 18 cm. This concussive injury resulted in immediate unconsciousness (loss of righting reflex) in all animals and death in approximately 30%. Survivors received a tail vein injection of either vehicle or U74006F (0.001 to 30 mg/kg) within 5 minutes postinjury. Their neurological status was evaluated 1 hour later using a grip test. The grip-test score indicated that intravenous administration of a single dose of U74006F resulted in a significant improvement by as much as 168.6% in the neurological status 1 hour postinjury over a broad dose range (0.003 to 30 mg/kg). A 1-mg/kg dose given intravenously within 5 minutes and again at 1 1/2 hours after a severe injury, in addition to improving early recovery, also increased the 1-week survival rate to 78.6% compared to 27.3% in vehicle-treated mice (p less than 0.02). The compound was also effective in enhancing early recovery after a more moderate injury. This study demonstrates that early treatment after severe concussive head injury with a potent inhibitor of iron-dependent lipid peroxidation can significantly benefit the injured brain in mice and promote both early neurological recovery and long-term survival 7).


In a study it was tested for effects on brain edema and metabolites after impact injury to the closed skull. Anesthetized cats were blindly treated with U-74006F or vehicle at 30 min (1 mg/kg) and 2.5 hr (0.5 mg/kg) after head or sham injury. They were sacrificed 4 hr after injury by in situ fixation of the brain. Head-injured cats were selected for unilateral (left) cerebral contusion. Metabolites (enzyme fluorometry) and edema (specific gravity) were measured in the cerebral cortex and white matter bilaterally. Cerebral hemisphere, contusion, and vasogenic edema volumes were morphometrically measured. Magnitude of edema and metabolites in tissue with vasogenic edema was similar in vehicle- and drug-treated cats. By contrast, the cortex and nonedematous white matter neighboring contusion in drug-treated cats had lactate, glucose, and glycogen levels that suggested an improved metabolic state over vehicle treatment. Most metabolites were not affected by trauma or treatment in the uncontused hemisphere. These results suggest that postinjury treatment with the nonglucocorticoid steroid U-74006F may benefit the metabolism of nonedematous tissue adjacent to contusion 8).


The present study evaluated the effect on the development of regional cerebral edema after lateral fluid-percussion (FP) brain injury. Male Sprague-Dawley rats (n = 40) were anesthetized and subjected to FP brain injury of moderate severity centered over the left parietal cortex (2.5-2.6 atms). Fifteen minutes after brain injury, animals randomly received an i.v. bolus of either U74006F (3 mg/kg, n = 21) followed by a second bolus (3 mg/kg) at 3 hr or buffered sodium citrate vehicle (equal volume, n = 15). An additional group of 12 surgically prepared but uninjured animals served as preinjury controls. At 48 hr after injury, animals were sacrificed and brain tissue assayed for water content and regional cation concentrations. With the use of specific gravimetric techniques, no significant differences were observed in posttraumatic cerebral edema between drug- and control-treated animals. However, using wet weight/dry weight methodology, we found that administration of U74006F significantly reduced water content in the right hippocampus (contralateral to the site of injury) compared to saline-treated animals (p less than 0.05). U74006F also significantly prevented the postinjury increase in sodium concentrations in the ipsilateral hippocampus (p less than 0.05) and thalamus (p less than 0.03). Regional concentrations of potassium were unaltered after drug treatment. Administration of U74006F significantly reduced postinjury mortality, from 28% in control animals to zero in treated animals (p = 0.01). These results suggest that lipid peroxidation may be involved in the pathophysiological sequelae of brain injury and that 21-aminosteroids may be beneficial in the treatment of brain injury 9).


The effects of 5 days of pretreatment with the 21-aminosteroid anti-oxidant U74006F have been examined on the rate of functional degeneration of cat soleus motor nerve terminals after axon section. Female cats were dosed for 5 days with either 7.7, 13.0 or 30.0 mg/kg (average doses) of U74006F p.o. twice daily followed by unilateral sciatic nerve section at the hip level on day 5. On day 7, the bilateral in vivo soleus nerve muscle prep. was set up to assess the neuromuscular functional status of the 48 h degenerating soleus nerve terminals in comparison to the contralateral non-sectioned preparation. In untreated cats, the ratio of the nerve-evoked (0.4 Hz) contractile tension of the 48 h nerve-sectioned to that of the contralateral non-sectioned was only 52 +/- 8%. U74006F pretreatment produced a dose-related improvement with the 13.0 mg/kg dose having the best effect; the ratio was 86 +/- 5% (P less than 0.01 vs untreated). The maintenance of tetanic tension during a 10 s period of 100 Hz nerve stimulation was also improved by the 13.0 mg/kg dose from only 54.0 +/- 5.2% in untreated animals to 72.2 +/- 5.7 (P less than 0.02). These results show a preservation of motor nerve function during early degeneration by the anti-oxidant U74006F thus providing further evidence for a free radical-mediated process in anterograde degeneration 10).


Vollmer et al. performed a work to establish whether the nonglucocorticoid, 21-aminosteroid, U74006F, could prevent the development of delayed cerebral vasospasm after experimental subarachnoid hemorrhage. The subarachnoid hemorrhage was produced by percutaneous injection of 4.5 mL of nonheparinized autologous blood into the cisterna magna of rabbits. U74006F (1 mg/kg) or placebo was injected intraperitoneally every 12 hours starting 12 hours prior to induction of hemorrhage for a total of six doses. The animals were sacrificed by perfusion fixation. The basilar artery was removed on day 2 and processed for morphometric analysis. Control/placebo and subarachnoid hemorrhage/placebo basilar artery diameters were 651.2 +/- 25.4 and 366.3 +/- 34.2 mu, respectively. Control/U74006F basilar artery diameters (669.8 +/- 21.8 mu) were not significantly different from that of the control/placebo group. U74006F treatment greatly minimized subarachnoid hemorrhage-induced reduction in mean luminal diameter (563.7 +/- 48.2 mu) (p less than 0.001). These results demonstrate considerable therapeutic promise for U74006F in the prevention of cerebral vasospasm 11).


Young et al. investigated the effects of U74006F on the early ionic edema produced by middle cerebral artery occlusion in rats. Intravenous doses of 3 mg/kg U74006F were given 10 minutes and 3 hours after occlusion. Tissue concentrations of Na+, K+, and water at and around the infarct site were measured by atomic absorption spectroscopy and by wet-dry weight measurements 24 hours after occlusion. Compared with vehicle treatment, U74006F treatment reduced brain water entry, Na+ accumulation, K+ loss, and net ion shift by 25-50% in most brain areas sampled in the frontal and parietal cortex. However, reductions of ionic edema were most prominent and reached significance (p less than 0.005, unpaired two-tailed t test) mostly in the frontoparietal and parietal cortex areas adjacent to the infarct site. Our findings suggest that a steroid drug without glucocorticoid or mineralocorticoid activity can reduce edema in cerebral ischemia but that the effects are largely limited to tissues in which collateral blood flow may be present 12).

Studies in experimental models of ischemic stroke had suggested that tirilazad had neuroprotective properties. As a result, clinical studies were undertaken to assess the safety and efficacy of tirilazad in the treatment of acute ischemic stroke.


Marshall et al., prospectively studied the efficacy of tirilazad mesylate, a novel aminosteroid, in humans with head injuries.

A cohort of 1120 head-injured patients received at least one dose of study medication (tirilazad or placebo). Eighty-five percent (957) of the patients had suffered a severe head injury (Glasgow Coma Scale [GCS] score 4-8) and 15% (163) had sustained a moderate head injury (GCS score 9-12). Six-month outcomes for the tirilazad- and placebo-treated groups for the Glasgow Outcome Scale categories of both good recovery and death showed no significant difference (good recovery in the tirilazad-treated group was 39% compared with the placebo group in which it was 42% [p=0.461]; death in the tirilazad-treated group occurred in 26% of patients compared with the placebo group, in which it occurred in 25% [p=0.750]). Subgroup analysis suggested that tirilazad mesylate may be effective in reducing mortality rates in males suffering from severe head injury with accompanying traumatic subarachnoid hemorrhage (death in the tirilazad-treated group occurred in 34% of patients; in the placebo group it occurred in 43% [p=0.026]). No significant differences in frequency or types of serious adverse events were shown between the treatment and placebo groups.

Striking problems with imbalance concerning basic prognostic variables were observed in spite of the large population studied. These imbalances concerned pretreatment hypotension, pretreatment hypoxia, and the incidence of epidural hematomas. In future trials of pharmacological therapy for severe head injury, serious consideration must be given to alternative randomization strategies. Given the heterogeneous nature of head injury and the identification of populations that do relatively well with standard therapy, target populations with a higher risk for mortality and morbidity may be more suitable for clinical trials of such agents 13).

Trials

Trials of tirilazad were identified from searches of the Cochrane Library and communication with the Pharmacia & Upjohn company, the manufacturer of tirilazad. Data relating to early and end-of-trial case fatality, disability (Barthel Index and Glasgow Outcome Scale), phlebitis, and corrected QT interval were extracted by treatment group from published data and company reports and analyzed by using the Cochrane Collaboration meta-analysis software REVMAN.

Six trials (4 published, 2 unpublished) assessing tirilazad in 1757 patients with presumed acute ischemic stroke were identified; all were double-blind and placebo controlled in design. Tirilazad did not alter early case fatality (odds ratio [OR] 1.11, 95% confidence interval [CI] 0.79 to 1.56) or end-of-trial case fatality (OR 1.12, 95% CI 0.88 to 1.44). A just-significant increase in death and disability, assessed as either the expanded Barthel Index (OR 1.23, 95% CI 1.01 to 1.51) or Glasgow Outcome Scale (OR 1. 23, 95% CI 1.01 to 1.50) was observed. Tirilazad significantly increased the rate of infusion site phlebitis (OR 2.81, 95% CI 2.14 to 3.69). Functional outcome (expanded Barthel Index) was significantly worse in prespecified subgroups of patients: females (OR 1.46, 95% CI 1.08 to 1.98) and subjects receiving low-dose tirilazad (OR 1.31, 95% CI 1.03 to 1.67); a nonsignificant worse outcome was also seen in patients with mild to moderate stroke (OR 1. 40, 95% CI 0.99 to 1.98).

Tirilazad mesylate increases death and disability by about one fifth when given to patients with acute ischemic stroke. Although further trials of tirilazad are now unwarranted, analysis of individual patient data from the trials may help elucidate why tirilazad appears to worsen outcome in acute ischemic stroke 14).

1) , 6)

Wilson JT, Bednar MM, McAuliffe TL, Raymond S, Gross CE. The effect of the 21-aminosteroid U74006F in a rabbit model of thromboembolic stroke. Neurosurgery. 1992 Nov;31(5):929-33; discussion 933-4. PubMed PMID: 1436419.
2)

Alotaibi NM, Ibrahim GM, Wang J, Guha D, Mamdani M, Schweizer TA, Macdonald RL. Neurosurgeon academic impact is associated with clinical outcomes after clipping of ruptured intracranial aneurysms. PLoS One. 2017 Jul 20;12(7):e0181521. doi: 10.1371/journal.pone.0181521. eCollection 2017. PubMed PMID: 28727832; PubMed Central PMCID: PMC5519166.
3)

Lo BW, Fukuda H, Angle M, Teitelbaum J, Macdonald RL, Farrokhyar F, Thabane L, Levine MA. Clinical outcome prediction in aneurysmal subarachnoid hemorrhage – Alterations in brain-body interface. Surg Neurol Int. 2016 Aug 1;7(Suppl 18):S527-37. doi: 10.4103/2152-7806.187496. eCollection 2016. PubMed PMID: 27583179; PubMed Central PMCID: PMC4982352.
4)

Hukkelhoven CW, Steyerberg EW, Farace E, Habbema JD, Marshall LF, Maas AI. Regional differences in patient characteristics, case management, and outcomes in traumatic brain injury: experience from the tirilazad trials. J Neurosurg. 2002 Sep;97(3):549-57. PubMed PMID: 12296638.
5) , 13)

Marshall LF, Maas AI, Marshall SB, Bricolo A, Fearnside M, Iannotti F, Klauber MR, Lagarrigue J, Lobato R, Persson L, Pickard JD, Piek J, Servadei F, Wellis GN, Morris GF, Means ED, Musch B. A multicenter trial on the efficacy of using tirilazad mesylate in cases of head injury. J Neurosurg. 1998 Oct;89(4):519-25. PubMed PMID: 9761043.
7)

Hall ED, Yonkers PA, McCall JM, Braughler JM. Effects of the 21-aminosteroid U74006F on experimental head injury in mice. J Neurosurg. 1988 Mar;68(3):456-61. PubMed PMID: 3343616.
8)

Dimlich RV, Tornheim PA, Kindel RM, Hall ED, Braughler JM, McCall JM. Effects of a 21-aminosteroid (U-74006F) on cerebral metabolites and edema after severe experimental head trauma. Adv Neurol. 1990;52:365-75. PubMed PMID: 2396533.
9)

McIntosh TK, Thomas M, Smith D, Banbury M. The novel 21-aminosteroid U74006F attenuates cerebral edema and improves survival after brain injury in the rat. J Neurotrauma. 1992 Spring;9(1):33-46. PubMed PMID: 1619674.
10)

Hall ED, Yonkers PA. Preservation of motor nerve function during early degeneration by the 21-aminosteroid anti-oxidant U74006F. Brain Res. 1990 Apr 16;513(2):244-7. PubMed PMID: 2350694.
11)

Vollmer DG, Kassell NF, Hongo K, Ogawa H, Tsukahara T. Effect of the nonglucocorticoid 21-aminosteroid U74006F experimental cerebral vasospasm. Surg Neurol. 1989 Mar;31(3):190-4. PubMed PMID: 2922661.
12)

Young W, Wojak JC, DeCrescito V. 21-Aminosteroid reduces ion shifts and edema in the rat middle cerebral artery occlusion model of regional ischemia. Stroke. 1988 Aug;19(8):1013-9. PubMed PMID: 3400099.
14)

Tirilazad mesylate in acute ischemic stroke: A systematic review. Tirilazad International Steering Committee. Stroke. 2000 Sep;31(9):2257-65. Erratum in: Stroke 2001 Jan;32(1):279. PubMed PMID: 10978061.

Update: Hypertonic saline

Hypertonic saline

Hypertonic saline emerged as an alternative to mannitol 1) , and gained increasing clinical interest due to its reported efficacy in treating cerebral edema and elevated intracranial pressure 2) 3).

Early data suggest that indications for each agent may ultimately depend on ICP etiology 4).

Hypertonic saline avoids the diuretic effect of mannitol while still being effective at reducing brain water. After administration, cerebral perfusion may actually be increased 5).

Mannitol and hypertonic saline are routinely employed as hyperosmolar therapy in North America. Specific circumstances may prompt selection of a specific agent. Hypertonic saline administration may be hazardous in hyponatremia 6).

Serum sodium values did not significantly change more than 10h after infusion of HS. Further studies are needed to determine the optimal frequency of routine sodium checks to increase the quality of care and decrease healthcare costs 7).

Bolus dosing of hypertonic saline was first studied and documented 1919 by Weed and McKibben 8).

Various concentrations are clinically used, with as much as 30 mL boluses of 23.4% saline in a single dose. Rapid increases in serum sodium in this setting do not appear to cause the neurological complications that may be encountered in the context of rapid correction of hyponatremia 9).

Hypertonic saline has attributes beyond those expected for a simple osmotherapeutic agent. It affects the vasoregulatory, immunomodulatory, and neurochemical environment of the brain and the blood–brain barrier in ways that may benefit different categories of brain injury 10) 11) 12).

Hypertonic saline (HTS) provides better brain relaxation than mannitol during elective intracranial tumor surgery 13).

Case series

2003

Twenty consecutive patients with head trauma and persistent coma who required infusions of an osmotic agent to treat episodes of intracranial hypertension resistant to well-conducted standard modes of therapy were studied. Intracranial hypertension was considered refractory when it persisted despite deep sedation, optimal hemodynamic status, and, in some patients, drainage of cerebral spinal fluid.

INTERVENTIONS: Patients were randomly assigned to receive isovolume infusions of either 7.5% hypertonic saline solution (2400 mOsm/kg/H(2)O) or 20% mannitol (1160 mOsm/kg/H(2)O). The patients were given 2 mL/kg (body weight) of either solution, i.e., 361 +/- 13 mOsm of saline or 175 +/- 12 mOsm of mannitol per injection.

MEASUREMENTS AND MAIN RESULTS: The main variables studied were the number and the duration of episodes of intracranial hypertension per day during the study period, which was stopped after the last episode of intracranial hypertension was recorded from intracranial pressure monitoring or after the allocated treatment failure. Patients in the HHS group were monitored for 7 +/- 5 days and those in the mannitol group for 7 +/- 6 days (not significant). The rate of failure for each treatment was also evaluated. Failure was defined as the persistence of intracranial hypertension despite two successive infusions of the same osmotic agent. The mean number of osmotic solute infusions was 3.7 +/- 5.3 in the mannitol group and 3.3 +/- 4.1 in the hypertonic saline solution group (not significant). The mean number (6.9 +/- 5.6 vs. 13.3 +/- 14.6 episodes) of intracranial hypertension episodes per day and the daily duration (67 +/- 85 vs. 131 +/- 123 min) of intracranial hypertension episodes were significantly lower in the hypertonic saline solution group (p <.01). The rate of clinical failure was also significantly lower in the hypertonic saline solution group: 1 of 10 patients vs. 7 of 10 patients (p <.01).

In this study, when a hypertonic solute was required for the treatment of refractory intracranial hypertension episodes in patients with severe head trauma, increasing the osmotic load by giving 2 mL/kg (body weight) of 7.5% saline (361 +/- 13 mOsm) was more effective than giving 2 mL/kg (body weight) of 20% mannitol (175 +/- 12 mOsm). Within the limitations of the present study, these data suggest that giving 2 mL/kg hypertonic saline solution (approximately 480 mOsm/70 kg body weight) is an effective and safe initial treatment for intracranial hypertension episodes in head-trauma patients when osmotherapy is indicated 14).

1999

Qureshi et al. performed a retrospective chart review of all patients admitted with severe head injury, defined as admission Glasgow Coma Scale score of 8 or less, in the neurocritical care unit of a University hospital. Intravenous infusion of 2% or 3% saline/acetate for treatment of cerebral edema was introduced in the unit in April of 1993. The clinical characteristics, interventions required, and outcomes in patients who received HS were compared with patients who received 0.9% saline infusion only. Multivariate analyses were used to evaluate the impact of HS use on in-hospital mortality and Glasgow Outcome Scale score at discharge.

Thirty-six patients with cerebral edema caused by head trauma received infusion of HS initiated within 48 hours of admission for a mean period of 72 +/- 85 hours. Compared with 46 patients who did not receive HS, there were no differences observed in age and admission Glasgow Coma Scale scores. Patients who received HS were more likely to have a penetrating injury (p = 0.07) and a mass lesion on initial computed tomographic scan (p = 0.07). There was no difference between frequency of use of hyperventilation, mannitol, cerebrospinal fluid drainage, and vasopressors between the two groups. The requirement for pentobarbital coma was higher in HS group (n = 7 patients) versus control group (n = 2,p = 0.04). After adjusting for differences between both groups, infusion of HS was associated with higher in-hospital mortality (OR, 3.1; 95% CI, 1.1-10.2).

HS administration as prolonged infusion does not seem to favorably impact on requirement for other interventions and in-hospital mortality in our experience. Further efforts should be directed toward use of HS as bolus administrations or short infusions 15).

1998

Thirty-four patients were enrolled and were similar in age and Injury Severity Score. HTS patients had a lower admission Glasgow Coma Scale score (HTS: 4.7+/-0.7; LRS: 6.7+/-0.7; p = 0.057), a higher initial ICP (HTS: 16+/-2; LRS: 11+/-2; p = 0.06), and a higher initial mean maximum ICP (HTS: 31+/-3; LRS: 18+/-2; p < 0.01). Treatment effectively lowered ICP in both groups, and there was no significant difference between the groups in ICP at any time after entry. HTS patients required significantly more interventions (HTS: 31+/-4; LRS: 11+/-3; p < 0.01). During the study, the change in maximum ICP was positive in the LRS group but negative in the HTS group (LRS: +2+/-3; HTS: -9+/-4; p < 0.05).

As a group, HTS patients had more severe head injuries. HTS and LRS used with other therapies effectively controlled the ICP. The widely held conviction that sodium administration will lead to a sustained increase in ICP is not supported by this work 16).

Metaanalysis

A wealth of evidence from randomized controlled trials (RCTs) has indicated that hypertonic saline (HS) is at least as effective as, if not better than, mannitol in the treatment of increased intracranial pressure (ICP). However, there is little known about the effects of HS in patients during neurosurgery. Thus, a meta-analysis was performed to compare the intraoperative effects of HS with mannitol in patients undergoing craniotomy.

PUBMED, EMBASE and Cochrane Central Register of Controlled Trials, internet-based clinical trial registries and conference proceedings were searched.

The outcomes included intraoperative brain relaxation, intraoperative ICP, total volume of fluid required, diuresis, hemodynamic parameters, electrolyte level, mortality or dependence and adverse events.

Seven RCTs with 468 participants were included. The quality of the included trials was acceptable. HS could significantly increase the odds of satisfactory intraoperative brain relaxation (OR: 2.25, 95% CI: 1.32-3.81; P = 0.003) and decrease the mean difference (MD) of maximal ICP (MD: -2.51mmHg, 95% CI: -3.39-1.93mmHg; P<0.00001) in comparison with mannitol with no significant heterogeneity among the study results. Compared with HS, mannitol had a more prominent diuretic effect. And patients treated with HS had significantly higher serum sodium than mannitol-treated patients.

Considering that robust outcome measures are absent because brain relaxation and ICP can be influenced by several factors except for the hyperosmotic agents, the results of present meta-analysis should be interpreted with cautions. Well-designed RCTs in the future are needed to further test the present results, identify the impact of HS on the clinically relevant outcomes and explore the potential mechanisms of HS 17).

Hypertonic saline for aneurysmal subarachnoid hemorrhage

1)

Doyle JA, Davis DP, Hoyt DB. The use of hypertonic saline in the treatment of traumatic brain injury. J Trauma. 2001 Feb;50(2):367-83. Review. PubMed PMID: 11242309.

2)

Ware ML, Nemani VM, Meeker M, Lee C, Morabito DJ, Manley GT. Effects of 23.4% sodium chloride solution in reducing intracranial pressure in patients with traumatic brain injury: a preliminary study. Neurosurgery. 2005;57:727–736. doi: 10.1227/01.NEU.0000175726.08903.0A.

3)

Kerwin AJ, Schinco MA, Tepas JJ3, Renfro WH, Vitarbo EA, Muehlberger M. The use of 23.4% hypertonic saline for the management of elevated intracranial pressure in patients with severe traumatic brain injury: a pilot study. J Trauma. 2009;67:277–282. doi: 10.1097/TA.0b013e3181acc726.

4)

Ogden AT, Mayer SA, Connolly ES Jr. Hyperosmolar agents in neurosurgical practice: the evolving role of hypertonic saline. Neurosurgery. 2005 Aug;57(2):207-15; discussion 207-15. Review. PubMed PMID: 16094147.

5)

Qureshi AI, Suarez JI. Use of hypertonic saline solutions in treatment of cerebral edema and intracranial hypertension. Crit Care Med. 2000;28:3301–3313. doi: 10.1097/00003246-200009000-00032.

6)

Brain Trauma Foundation; American Association of Neurological Surgeons; Congress of Neurological Surgeons; Joint Section on Neurotrauma and Critical Care, AANS/CNS, Bratton SL, Chestnut RM, Ghajar J, McConnell Hammond FF, Harris OA, Hartl R, Manley GT, Nemecek A, Newell DW, Rosenthal G, Schouten J, Shutter L, Timmons SD, Ullman JS, Videtta W, Wilberger JE, Wright DW. Guidelines for the management of severe traumatic brain injury. II. Hyperosmolar therapy. J Neurotrauma. 2007;24 Suppl 1:S14-20. Erratum in: J Neurotrauma. 2008 Mar;25(3):276-8. multiple author names added. PubMed PMID: 17511539.

7)

Tucker AM, Lee SJ, Chung LK, Barnette NE, Voth BL, Lagman C, Nagasawa DT, Yang I. Analyzing the efficacy of frequent sodium checks during hypertonic saline infusion after elective brain tumor surgery. Clin Neurol Neurosurg. 2017 May;156:24-28. doi: 10.1016/j.clineuro.2017.02.011. Epub 2017 Feb 22. PubMed PMID: 28288395.

8)

Weed LH, McKibben PS. Experimental alteration of brain bulk. Am J Physiol – Legacy Content. 1919;48:531–558.

9)

Koenig MA, Bryan M, Lewin JL, Mirski MA, Geocadin RG, Stevens RD. Reversal of transtentorial herniation with hypertonic saline. Neurology. 2008;70:1023–1029. doi: 10.1212/01.wnl.0000304042.05557.60.

10)

Zeynalov E, Chen C, Froehner SC, et al. The perivascular pool of aquaporin-4 mediates the effect of osmotherapy in postischemic cerebral edema. Crit Care Med. 2008;36:2634–2640. doi: 10.1097/CCM.0b013e3181847853.

11)

Gundersen Y, Ruud TE, Krohn CD, Sveen O, Lyngstadaas SP, Aasen AO. Impact of hypertonic saline on the release of selected cytokines after stimulation with LPS or peptidoglycan in ex vivo whole blood from healthy humans. Shock. 2010;34:450–454. doi: 10.1097/SHK.0b013e3181e68649.

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Jin QH, Ueda Y, Ishizuka Y, Kunitake T, Kannan H. Cardiovascular changes induced by central hypertonic saline are accompanied by glutamate release in awake rats. Am J Physiol Regul Integr Comp Physiol. 2001;281:R1224–R1231.

13)

Dostal P, Dostalova V, Schreiberova J, Tyll T, Habalova J, Rehak S, Cesak T. A Comparison of Equivolume, Equiosmolar Solutions of Hypertonic Saline and Mannitol for Brain Relaxation in Patients Undergoing Elective Intracranial Tumor Surgery: A Randomized Clinical Trial. J Neurosurg Anesthesiol. 2014 Jul 17. [Epub ahead of print] PubMed PMID: 25036870.

14)

Vialet R, Albanèse J, Thomachot L, Antonini F, Bourgouin A, Alliez B, Martin C. Isovolume hypertonic solutes (sodium chloride or mannitol) in the treatment of refractory posttraumatic intracranial hypertension: 2 mL/kg 7.5% saline is more effective than 2 mL/kg 20% mannitol. Crit Care Med. 2003 Jun;31(6):1683-7. PubMed PMID: 12794404.

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Qureshi AI, Suarez JI, Castro A, Bhardwaj A. Use of hypertonic saline/acetate infusion in treatment of cerebral edema in patients with head trauma: experience at a single center. J Trauma. 1999 Oct;47(4):659-65. PubMed PMID: 10528599.

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Shackford SR, Bourguignon PR, Wald SL, Rogers FB, Osler TM, Clark DE. Hypertonic saline resuscitation of patients with head injury: a prospective, randomized clinical trial. J Trauma. 1998 Jan;44(1):50-8. PubMed PMID: 9464749.

17)

Shao L, Hong F, Zou Y, Hao X, Hou H, Tian M. Hypertonic Saline for Brain Relaxation and Intracranial Pressure in Patients Undergoing Neurosurgical Procedures: A Meta-Analysis of Randomized Controlled Trials. PLoS One. 2015 Jan 30;10(1):e0117314. doi: 10.1371/journal.pone.0117314. eCollection 2015. PubMed PMID: 25635862.

Progesterone for acute traumatic brain injury

Systematic reviews

2016

Ma et al., updated the searches of the following databases: the Cochrane Injuries Group’s Specialised Register (30 September 2016), the Cochrane Central Register of Controlled Trials (CENTRAL; Issue 9, 2016), MEDLINE (Ovid; 1950 to 30 September 2016), Embase (Ovid; 1980 to 30 September 2016), Web of Science Core Collection: Conference Proceedings Citation Index-Science (CPCI-S; 1990 to 30 September 2016); and trials registries: Clinicaltrials.gov (30 September 2016) and the World Health Organization (WHO) International Clinical Trials Registry Platform (30 September 2016).

They included randomised controlled trials (RCTs) of progesterone versus no progesterone (or placebo) for the treatment of people with acute TBI.

Two review authors screened search results independently to identify potentially relevant studies for inclusion. Independently, two review authors selected trials that met the inclusion criteria from the results of the screened searches, with no disagreement.

They included five RCTs in the review, with a total of 2392 participants. We assessed one trial to be at low risk of bias; two at unclear risk of bias (in one multicentred trial the possibility of centre effects was unclear, whilst the other trial was stopped early), and two at high risk of bias, due to issues with blinding and selective reporting of outcome data.All included studies reported the effects of progesterone on mortality and disability. Low quality evidence revealed no evidence of a difference in overall mortality between the progesterone group and placebo group (RR 0.91, 95% CI 0.65 to 1.28, I² = 62%; 5 studies, 2392 participants, 2376 pooled for analysis). Using the GRADE criteria, we assessed the quality of the evidence as low, due to the substantial inconsistency across studies.There was also no evidence of a difference in disability (unfavourable outcomes as assessed by the Glasgow Outcome Score) between the progesterone group and placebo group (RR 0.98, 95% CI 0.89 to 1.06, I² = 37%; 4 studies; 2336 participants, 2260 pooled for analysis). We assessed the quality of this evidence to be moderate, due to inconsistency across studies.Data were not available for meta-analysis for the outcomes of mean intracranial pressure, blood pressure, body temperature or adverse events. However, data from three studies showed no difference in mean intracranial pressure between the groups. Data from another study showed no evidence of a difference in blood pressure or body temperature between the progesterone and placebo groups, although there was evidence that intravenous progesterone infusion increased the frequency of phlebitis (882 participants). There was no evidence of a difference in the rate of other adverse events between progesterone treatment and placebo in the other three studies that reported on adverse events.

This updated review did not find evidence that progesterone could reduce mortality or disability in patients with TBI. However, concerns regarding inconsistency (heterogeneity among participants and the intervention used) across included studies reduce our confidence in these results.There is no evidence from the available data that progesterone therapy results in more adverse events than placebo, aside from evidence from a single study of an increase in phlebitis (in the case of intravascular progesterone).There were not enough data on the effects of progesterone therapy for our other outcomes of interest (intracranial pressure, blood pressure, body temperature) for us to be able to draw firm conclusions.Future trials would benefit from a more precise classification of TBI and attempts to optimise progesterone dosage and scheduling 1).

2012

Ma et al., searched: the Cochrane Injuries Group’s Specialised Register (13 July 2012), Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 7, 2012), MEDLINE (Ovid) (1950 to August week 1, 2012), EMBASE (Ovid) (1980 to week 32 2012), LILACS (12 August 2012), Zetoc (13 July 2012), Clinicaltrials.gov (12 August 2012), Controlled-trials.com (12 August 2012). SELECTION CRITERIA: We included published and unpublished randomised controlled trials (RCTs) of progesterone versus no progesterone (or placebo) for the treatment of people with acute TBI. DATA COLLECTION AND ANALYSIS: Two review authors independently screened search results to identify the full texts of potentially relevant studies for inclusion. From the results of the screened searches two review authors independently selected trials meeting the inclusion criteria, with no disagreement. MAIN RESULTS: Three studies were included with a total of 315 people. Two included studies were of high methodological quality, with low risk of bias in allocation concealment, blinding and incomplete outcome data. One study did not use blinding and had unclear risk of bias in allocation concealment and incomplete outcome data. All three studies reported the effects of progesterone on mortality. The pooled risk ratio (RR) for mortality at end of follow-up was 0.61, 95% confidence interval (CI) 0.40 to 0.93. Three studies measured disability and found the RR of death or severe disability in patients treated with progesterone to be 0.77, 95% CI 0.62 to 0.96. Data from two studies showed no difference in mean intracranial pressure or the rate of adverse and serious adverse events among people in either group. One study presented blood pressure and temperature data, and there were no differences between the people in the progesterone or control groups. There was no substantial evidence for the presence of heterogeneity.

Current clinical evidence from three small RCTs indicates progesterone may improve the neurologic outcome of patients suffering TBI. This evidence is still insufficient and further multicentre randomised controlled trials are required 2).

2011

Junpeng et al., searched: the Cochrane Injuries Group’s Specialised Register (to April 2010), Cochrane Central Register of Controlled Trials 2010, Issue 1 (The Cochrane Library), MEDLINE (Ovid) (1950 to April week 1 2010), EMBASE (Ovid) (1980 to week 14 2010), LILACS (to 17 April 2010 ), Zetoc (to 21 April 2010), Clinicaltrials.gov (17 April 2010 ), Controlled-trials.com (17 April 2010).

They included published and unpublished randomised controlled trials (RCTs) of progesterone versus no progesterone (or placebo) for the treatment of acute TBI.

Two authors independently screened search results to identify the full texts of potentially relevant studies for inclusion. From the results of the screened searches two authors independently selected trials meeting the inclusion criteria, with no disagreement.

Three studies were included with 315 patients. All three studies reported the effects of progesterone on mortality. The pooled relative risk (RR) for mortality at end of follow-up is 0.61, 95% confidence interval (CI) 0.40 to 0.93. Three studies measured disability and found the RR of death or severe disability in patients treated with progesterone was 0.77, 95% confidence interval (CI) 0.62 to 0.96. Two studies presented data on intracranial pressure and adverse events. One study presented blood pressure and temperature data. There was no substantial evidence for the presence of heterogeneity.

Current clinical evidence from three small RCTs indicates progesterone may improve the neurologic outcome of patients suffering TBI. This evidence is still insufficient and further multicentre randomised controlled trials are required 3).


Progesterone has been associated with robust positive effects in animal models of traumatic brain injury (TBI) and with clinical benefits in two phase 2 randomized controlled trials. Skolnick et al, investigated the efficacy and safety of progesterone in a large, prospective, phase 3 randomized controlled trial.

A multinational placebo controlled study, in which 1195 patients, 16 to 70 years of age, with severe traumatic brain injury TBI (Glasgow Coma Scale score, ≤8 (on a scale of 3 to 15, with lower scores indicating a reduced level of consciousness and at least one reactive pupil) were randomly assigned to receive progesterone or placebo. Dosing began within 8 hours after injury and continued for 120 hours. The primary efficacy end point was the Glasgow Outcome Scale score at 6 months after the injury.

Proportional-odds analysis with covariate adjustment showed no treatment effect of progesterone as compared with placebo (odds ratio, 0.96; confidence interval, 0.77 to 1.18). The proportion of patients with a favorable outcome on the Glasgow Outcome Scale (good recovery or moderate disability) was 50.4% with progesterone, as compared with 50.5% with placebo. Mortality was similar in the two groups. No relevant safety differences were noted between progesterone and placebo.

Primary and secondary efficacy analyses showed no clinical benefit of progesterone in patients with severe TBI. These data stand in contrast to the robust preclinical data and results of early single-center trials that provided the impetus to initiate phase 3 trials. (Funded by BHR Pharma; SYNAPSE ClinicalTrials.gov number, NCT01143064 .) 4).

There was no significant difference between the progesterone group and the placebo group in the proportion of patients with a favorable outcome (relative benefit of progesterone, 0.95; 95% confidence interval [CI], 0.85 to 1.06; P=0.35). Phlebitis or thrombophlebitis was more frequent in the progesterone group than in the placebo group (relative risk, 3.03; CI, 1.96 to 4.66). There were no significant differences in the other prespecified safety outcomes. Conclusions This clinical trial did not show a benefit of progesterone over placebo in the improvement of outcomes in patients with acute TBI. (Funded by the National Institute of Neurological Disorders and Stroke and others; PROTECT III ClinicalTrials.gov number, NCT00822900 .) 5).


There is significant theoretical evidence for the potential role of estrogen and progesterone use in altering the pathogenesis of SAH. Nevertheless, this has received mixed reviews in both case controlled studies and cohort analysis within the literature 6)


1) Ma J, Huang S, Qin S, You C, Zeng Y. Progesterone for acute traumatic brain injury. Cochrane Database Syst Rev. 2016 Dec 22;12:CD008409. doi: 10.1002/14651858.CD008409.pub4. [Epub ahead of print] Review. PubMed PMID: 28005271.
2) Ma J, Huang S, Qin S, You C. Progesterone for acute traumatic brain injury. Cochrane Database Syst Rev. 2012 Oct 17;10:CD008409. doi: 10.1002/14651858.CD008409.pub3. Review. PubMed PMID: 23076947.
3) Junpeng M, Huang S, Qin S. Progesterone for acute traumatic brain injury. Cochrane Database Syst Rev. 2011 Jan 19;(1):CD008409. doi: 10.1002/14651858.CD008409.pub2. Review. Update in: Cochrane Database Syst Rev. 2012;10:CD008409. PubMed PMID: 21249708.
4) Skolnick BE, Maas AI, Narayan RK, van der Hoop RG, MacAllister T, Ward JD, Nelson NR, Stocchetti N; the SYNAPSE Trial Investigators. A Clinical Trial of Progesterone for Severe Traumatic Brain Injury. N Engl J Med. 2014 Dec 10. [Epub ahead of print] PubMed PMID: 25493978.
5) Wright DW, Yeatts SD, Silbergleit R, Palesch YY, Hertzberg VS, Frankel M, Goldstein FC, Caveney AF, Howlett-Smith H, Bengelink EM, Manley GT, Merck LH, Janis LS, Barsan WG; the NETT Investigators. Very Early Administration of Progesterone for Acute Traumatic Brain Injury. N Engl J Med. 2014 Dec 10. [Epub ahead of print] PubMed PMID: 25493974.
6) Young AM, Karri SK, Ogilvy CS. Exploring the use of estrogen & progesterone replacement therapy in subarachnoid hemorrhage. Curr Drug Saf. 2012 Jul;7(3):202-6. Review. PubMed PMID: 22950381.

Levetiracetam for hemifacial spasm

Levetiracetam proved its effectiveness and safety in the treatment of a case of HFS.Nevertheless, there is a need for further controlled studies with larger samples 1).


Kuroda et al., experienced two elderly hemifacial spasm (HFS) patients who exhibited a marked response to levetiracetam (LEV) without side effects. Although the exact underlying pharmacological mechanism remains unknown, we assume anti-kindling effect as one of the important pharmacological mechanism underlying the effect of LEV against HFS. Moreover, LEV is considered to be suitable for use in elderly patients because of its good tolerability. In addition, the lack of hepatic induction or inhibition makes it an easy and safe drug when used in addition to other anticonvulsants. Although the long-term benefit remains unknown, LEV may represent an alternative treatment for elderly HFS patients who are unable to undergo or decline surgical intervention and/or botulinum toxin injections or are intolerant to other anticonvulsants 2).


1) Biagio Carrieri P, Petracca M, Montella S. Efficacy of levetiracetam in hemifacial spasm: a case report. Clin Neuropharmacol. 2008 May-Jun;31(3):187-8. doi: 10.1097/WNF.0b013e3180ed44c8. PubMed PMID: 18520988.
2) Kuroda T, Saito Y, Fujita K, Yano S, Ishigaki S, Kato H, Murakami H, Ono K. Efficacy of levetiracetam in primary hemifacial spasm. J Clin Neurosci. 2016 Dec;34:213-215. doi: 10.1016/j.jocn.2016.05.025. PubMed PMID: 27460515.

Spontaneous intracranial epidural hematoma during rivaroxaban treatment

Rivaroxaban (BAY 59-7939) is an oral anticoagulant invented and manufactured by Bayer; in a number of countries it is marketed as Xarelto. In the United States, it is marketed by Janssen Pharmaceutica.

It is the first available orally active direct factor Xa inhibitor. Rivaroxaban is well absorbed from the gut and maximum inhibition of factor Xa occurs four hours after a dose. The effects last approximately 8–12 hours, but factor Xa activity does not return to normal within 24 hours so once-daily dosing is possible 1).

Thrombolysis and/or endovascular thrombectomy might be safe for patients treated with the new anticoagulant rivaroxaban 2).

Complications

Direct factor Xa inhibitors rivaroxaban and apixaban are efficacious alternatives to warfarin and confer a lower risk of spontaneous intracranial hemorrhage (ICH).

Despite several advantages rivaroxaban compared with vitamin K antagonists (VKA), its lack of specific antidotes to reverse anticoagulant effects may increase the risk profile of patients with bleeding complications.

There are few studies in the literature regarding the presence of intracerebral hemorrhage and the volume and prognosis of bleeding associated with rivaroxaban 3).

The results suggest that rivaroxaban may exacerbate intracranial haemorrhage in patients with mild traumatic brain injury (TBI)4).

Case series

A total of 70 patients with traumatic intracranial hemorrhage (tICH) after mild traumatic brain injury (TBI) were included in a retrospective analysis and were categorized into three groups: group A (no antithrombotics n=37), group B (antiplatelet medication n=22, VKA=5), and group C (rivaroxaban n=6). Medical charts were reviewed for baseline characteristics, laboratory values, intracranial haemorrhage, repeated computed tomography (CT) scans, re-haemorrhage, Glasgow Coma Scale (GCS) scores and in-hospital mortality.

No significant differences were observed for baseline characteristics. The rate of re-haemorrhage was significantly higher in group C (50%) than in group A (11%) (p<0.05). Two patients died and both had been treated with rivaroxaban which resulted in a significantly higher mortality rate of 33% in group C compared with groups A (0%) and B (0%). No significant differences were observed for GCS at discharge and length of hospital stay between survivors of groups A-C.

Despite major limitations of retrospective design and small patient numbers, the results suggest that rivaroxaban may exacerbate intracranial hemorrhage in patients with mild TBI. Further studies are needed to characterize the risk profile of this drug in patients with tICH 5).

Case reports

2016

First case described in the literature of spontaneous intracranial epidural hematoma secondary to the use of Xareltor. Spontaneous intracranial epidural hematomas are rarely described in the literature. They are associated with infectious diseases of the skull, coagulation disorders, vascular malformations of the dura mater and metastasis to the skull. Long-term post-marketing monitoring and independent reports will probably detect the full spectrum of hemorrhagic complications of the use of rivaroxaban 6).

2015

The clinical and radiologic findings and follow-up of an 80-year-old male patient with intracerebral hemorrhage who uses rivaroxaban for anticoagulation are presented in the article of Çalışkan et al. 7).

2014

Ishihara et al. report an acute stroke patient taking rivaroxaban who received intravenous thrombolysis with recombinant tissue plasminogen activator (rt-PA). An 80-year-old man with a history of nonvalvular atrial fibrillation, who had been receiving 10 mg of rivaroxaban showed abrupt onset of aphasia and right hemiparesis. National Institutes of Health Stroke Scale score was 10. Onset of neurologic deficits occurred 4 hours after the last dose of rivaroxaban. Clinical data on admission were as follows: blood pressure, 170/90 mm Hg; prothrombin time (PT), 22.6 seconds (control, 12.9 seconds); international normalized ratio, 2.03; activated partial thromboplastin time, 46 seconds (normal, 23-32 seconds); and creatinine level, 1.11 mg/dL. Magnetic resonance angiography revealed occlusion of the superior trunk of the left middle cerebral artery. Intravenous infusion of .6 mg/kg of rt-PA (total dose, 36 mg) was performed 6 hours after the last rivaroxaban administration with informed consent. The neurologic deficit improved during infusion of rt-PA. Repeat brain computed tomography showed left frontal cortical infarction without hemorrhagic changes. In the case of rivaroxaban, it is difficult to accurately determine the drug activity. As the anticoagulant activity of rivaroxaban can be estimated from its pharmacokinetics and PT, it is clinically important to obtain accurate information about the timing of medication and blood sampling 8).


A 83-year-old woman had a medical history with ischemic stroke due to paroxysmal atrial fibrillation and was then administered 10 mg of rivaroxaban daily. Although she took rivaroxaban in the morning, ischemic stroke recurred at midnight of that day. Soon after transferring to the hospital, Kimura et al. confirmed right middle cerebral artery (MCA) occlusion in the patient and then initiated treatment with intravenous rt-PA. Although no hemorrhagic complication occurred, recovery of her symptoms was not seen, and endovascular thrombectomy was performed. Although the inferior branch of the MCA was recanalized, an infarct was seen in her left frontal lobe. Hemorrhagic transformation was not observed during or after these combined treatments 9).


1) Komotar RJ, Starke RM, Connolly ES Jr. Orally administered factor xa inhibitor, rivaroxaban: a novel thromboembolic prophylaxis agent. Neurosurgery. 2008 Oct;63(4):N10-1. doi: 10.1227/01.NEU.0000339454.55968.F0. PubMed PMID: 18981864.
2) , 9) Kimura S, Ogata T, Fukae J, Okawa M, Higashi T, Iwaasa M, Inoue T, Tsuboi Y. Revascularization for acute ischemic stroke is safe for rivaroxaban users. J Stroke Cerebrovasc Dis. 2014 Oct;23(9):e427-31. doi: 10.1016/j.jstrokecerebrovasdis.2014.05.015. Epub 2014 Aug 20. PubMed PMID:25149204.
3) , 7) Çalışkan F, Akdemir HU, Nurata H, Akdemir N, Başara G, Yavuz Y.Rıvaroxaban-induced severe diffuse ıntracerebral hemorrhage. Am J Emerg Med. 2015 Mar;33(3):475.e1-5. doi: 10.1016/j.ajem.2014.08.028. Epub 2014 Aug 21. PubMed PMID: 25218622.
4) , 5) Beynon C, Potzy A, Sakowitz OW, Unterberg AW. Rivaroxaban and intracranial haemorrhage after mild traumatic brain injury: A dangerous combination? Clin Neurol Neurosurg. 2015 May 30;136:73-78. doi: 10.1016/j.clineuro.2015.05.035. [Epub ahead of print] PubMed PMID: 26070116.
6) Ruschel LG, Rego FM, Milano JB, Jung GS, Silva LF Jr, Ramina R. Spontaneous intracranial epidural hematoma during rivaroxaban treatment. Rev Assoc Med Bras (1992). 2016 Nov;62(8):721-724. doi: 10.1590/1806-9282.62.08.721. PubMed PMID: 27992010.
8) Ishihara H, Torii H, Imoto H, Oka F, Sadahiro H, Suzuki M. Intravenous thrombolysis with recombinant tissue plasminogen activator in a stroke patient treated with rivaroxaban. J Stroke Cerebrovasc Dis. 2014 Nov-Dec;23(10):e457-9. doi: 10.1016/j.jstrokecerebrovasdis.2014.07.008. Epub 2014 Oct 3. PubMed PMID: 25280819.