Tag: brain injury

Study Title (1)

N-Acetylcystene and Selenium Modulate Oxidative Stress, Antioxidant Vitamin and Cytokine Values in Traumatic Brain Injury-Induced Rats

Journal and Date

Neurochemical Research, April 2014

Brief Summary

“Oxidative stress plays an important role in the pathophysiology of traumatic brain injury (TBI).” “Using Sprague-Dawley rats, researchers demonstrated that N- acetylcysteine (NAC) and selenium (Se) showed protective affects on the TBI- induced oxidative brain injury and interleukin production by inhibiting free radical production, regulation of cytokine-dependent processes and supporting antioxidant redox system.”

Purpose

To make a research contribution to therapies for untreated traumatic brain injury.

Sample Population

Thirty-Six, 4 month-old male Sprague-Dawley rats

Setting

Neuroscience Research Center Lab, Suleyman Demirel University, Isparta Turkey

Research Design

Randomly selected, controlled/treatment groups, prospective, experimental rats

Theory/Framework

Amino acids supplied to the traumatized brain alleviate oxidative stress.

Methods

Marmarou’s weight drop model was used to induce TBI in rats. “Rats were divided into four groups:” 1) control group – placebo, 2) TBI group, 3) TBI group treated with gastric lavage NAC (150mg/kg) at 1, 24, 48, 72h after TBI, 4) TBI group treated with Se (NaSe 1.5mg/kg) intraperitoneal at 1, 24, 48, 72h after TBI. Brain cortex homogenate and plasma erythrocytes used to measure lipid peroxidation (LP), GSH, protein, vitamin A, vitamin E, B-carotene, vitamin C, TAS/ TOS, and cytokine levels. SPSS and Mann-Whitney U test used for analysis.

Intervention

TBI with 150mg/kg NAC given to group 3 and 1.5mg/kg Se given to group 4.

Significant Results

“LP is a biomarker of oxidative stress.” “Results showed that LP in brain cortex (p<0.05), plasma (p < 0.05) and erythrocyte (p < 0.01) and TOS levels (p<0.001) in the brain cortex in TBI group were significantly higher than the control. Hence oxidative stress..was increased by TBI.” “Brain cortex vitamin A, B-carotene, vitamin C, vitamin E, TAS, GSH and plasma vitamin E, IL-4, and brain cortex/ plasma levels of GSH-Px decreased by TBI.”

Conclusions

“Administration of NAC and Se caused decrease in LP of the brain cortex (p<0.05), plasma (p<0.05), and erythrocytes (p<0.01) in the TBI + NAC and TBI + Se group were significantly lower than the TBI group, respectively.” “IL-1B levels decreased and GSH, vitamin E, and IL-4 values increased.”

Significant Findings

“Se modulated the balance of oxidant and antioxidant, pro- and anti-inflammatory cytokines in rates by down-regulating the levels of pro-inflammatory (IL-B) cytokine and upregulating the levels of anti-inflammatory (IL-4) cytokines.”

Limitations

Transferring mouse model TBI therapies to human TBI therapies

Implications for Practice

N-acetyl-cysteine and selenium may be viable therapies to help alleviate human suffering from TBI.

Study Title (2)

Efficacy, dosage and duration of action of branched chain amino acid therapy for traumatic brain injury

Journal and Date

Frontiers in Neurology, March 30, 2015

Brief Summary

“Traumatic Brain Injury (TBI) results in long-lasting cognitive impairments for which there is currently no accepted treatment.” “Previous studies identified a novel therapy consisting of branched chain amino acids (BCAA), which restored normal mouse hippocampal responses and ameliorated cognitive impairment following fluid percussion injury. However, the optimal BCAA dose and length of treatment needed to improve cognitive recovery is unknown.” Results from this study show that “alterations in hippocampal function” “are reversible with at least 5 days of BCAA treatment and that sustaining this effect can occur with continuous treatment.”

Purpose

To contribute BCAA dosage amounts to existing BCAA TBI therapies data.

Sample Population

C57Bl/J6 Jackson Laboratory mice, 5 to 7 weeks old, 20-25g, male.

Setting

Research laboratories in Oregon and Philadelphia with an ambient temperature of 23C and humidity of 25C, 12h light/12h dark cycle, 100lux. Free access to food/ water. Performed within NIH Lab Animal Guidelines.

Research Design

Randomly selected, controlled, fluid percussion injury prospective, experimental

Theory/Framework

Amino acids supplied to the traumatized brain expedite repair

Methods

C57BL/J6 mice sustained fluid percussion injury (FPI) with a 48 hour recovery. Mice were individually housed then treated with BCAA supplemented or unsupplemented water. Concurrent experiments were conducted to determine duration of BCAA action and effective BCAA concentration. Control consisted of untreated tap water. Following TBI recovery, animals were fear conditioned. Then, 24 hours later were observed for freezing in the conditioning box. A lower freezing percentage is indicative of impaired contextual memory.

Intervention

Anesthesia, craniectomy, FPI of 1.8-2.1 atm, sutures, either 50mM BCAA or 100mM BCAA or regular tap water for 2, 3, 4, 5, 10 days.

Significant Results

“Injured mice that received BCAA treatment showed a significantly greater freezing response on average compared to the untreated FPI mice when treatment was delivered for 5 or 10 consecutive days.”

Conclusions

“Data establish that BCAA therapy is required for at least five consecutive days at a dose of either 100mM in ad libitum drinking water or 0.26 g/kg via oral gavage, to restore normal fear conditioning. Furthermore, stopping BCAA therapy, after 5 days, results in a functional relapse to levels seen in untreated injured animals.”

Significant Findings

“These results suggest the persistence of a functional deficit after TBI, which ongoing BCAA supplementation can successfully treat.”

Limitations

If BCAA therapy is stopped, the neurological hippocampal deficit returns.

Implications for Practice

In this and an earlier research study performed by these researchers, BCAA therapy has been shown to reverse hippocampal cognitive impairment from TBI. This has implications for human TBI therapy with enteral BCAAs. The University of Pennsylvania has applied for a patent to use BCAA therapy for TBI.

Study Title (3)

Combining glial cell line-derived neurotrophic factor gene delivery (AdGDNF) with L_arginine decreases contusion size but not behavioral deficits after traumatic brain injury

Journal and Date

Brain Research, July 27, 2011

Brief Summary

Therapeutic effects of AdGDNF and L_arginine post traumatic brain injury were examined. “AdGDNF and L_arginine were injected into cortex immediately post controlled cortical impact. Contusion size was decreased by the combination but not by each treatment alone. Behavioral recovery was not affected.”

Purpose

To contribute to the research database defining TBI therapies.

Sample Population

344 Male Fisher 225 – 300g rats from Charles River Labs

Setting

“Rats were housed within the DePaul University Animal Facility…on a 12:12h light and dark cycle, with food and water available ad libitum. The NIH Guide for Care and Use of Laboratory Animal and Institutional Guidelines were adhered.”

Research Design

Randomly selected/assigned, control/treatment groups, prospective rat study

Theory/Framework

Amino acids supplied to the traumatized brain will affect contusion size

Methods and Intervention

Rats were anesthetized and inflicted with a controlled cortical impact (CCI). Treatment and controls groups of CCI, CCI + saline, CCI + control green fluorescent protein (AdGFP) + saline, CCI + AdGDNF + L_arginine or saline, then Sham only, Sham + AdGDNF + saline and Sham + AdGDNF + L_arginine. AdGFP and AdGDNF viral vectors were injected immediately. Within 30 min. L_arginine or saline “was injected into femoral vein (150mg/kg in sterile 0.9% saline)”. “Behavioral measures of forelimb function were administered on day 0 (pre injury/injections)..then on days 2,4,7,10,14,21 and 28.” “Forelimb coordination.. examined using Foot Fault Test”. Ipsilateral limb use tabulated. Contusion size measured through staining. Staining to detect AdGDNF. GFP expression measured by fluorescent microscope. One-way ANOVA and Fisher’s protected LSD post-hoc test used on contusion volume and GDNF ELISA data. One-way ANOVA and Tukey-Kramer post-hoc test on behavioral data.

Significant Results

Foot Fault Test through Tukey-Kramer post-hoc analysis showed that “AdGDFNF and L_arginine did not affect deficits in or recovery of motor coordination”. “There were no significant differences between all of the injured rats, which indicate that AdGDNF, L_arginine, or the combination of the two did not lessen preferences for the uninjured forelimb.”

Conclusions

“Post-hoc analysis further revealed that rats treated with the combination of AdGDNF and L_arginine post-CCI had significantly smaller contusions than rats that received no treatment post-CCI (32% smaller), rats treated with L_arginine only post-CCI (44% smaller), or rats treated with AdGDNF only post-CCI (44% smaller; all comparisons = p < 0.05).”

Significant Findings

“If neurons are stimulated to complete energy dependent processes post TBI, such as secreting or utilizing a protein …. will result in their death.”

Limitations

AdGDNF and L_arginine do not provide substrate to improve behavioral deficits.

Implications for Practice

AdGDNF and L_arginine may protect humans. AdGNF is “neuroprotective in animal models of stroke, Parkinson’s disease..and spinal cord injury.”

Study Title (4)

N-methyl-D-aspartate preconditioning improves short-term motor deficits outcome after mild TBI in mice

Journal and Date

Journal of Neuroscience Research, May 1, 2010

Brief Summary

“TBI cellular damage may be mediated by the excitatory neurotransmitters, glutamate and aspartate, through N-methyl-D-aspartate (NMDA) receptors.” “Mice preconditioned with NMDA were protected against all motor deficits revealed by footprint test, but not those observed in rotarod tasks”. “Mice showed motor deficits after TBI”, but not cellular damage. Glutamatergic excitotoxicity contributes to trauma severity. NMDA may elicit a neuroprotective mechanism by improving motor behavioral deficits.”

Purpose

To affect motor deficits following TBI

Sample Population

Male CF-1 mice (2-3 months, 30-35g) – UNESC breeding colony

Setting

Six animals/cage with food/water “ad libitum, maintained on a 12-hr light/dark cycle” following NIH Health Guide and Brazilian Society of Neuro & Behavior.

Research Design

Randomly selected, controlled, experimental design using male mice

Theory/Framework

Amino acids supplied to the traumatized brain expedite repair

Methods

“Animals treated with NMDA (75mg/kg) or vehicle (saline,0.9% NaCl, w/v 24 hr before” diffuse TBI. Sensimotor evaluation 1.5hr, 6 hr, or 24hr after TBI. “Four groups (7-9 mice/group/time = 98 animals)”. “Footprint assessed motor coordination and gaiting”. Rotarod assessed balance. Cellular viability/DNA fragmentation evaluated at 24hr. Footprint and rotarod data analyzed with two- way ANOVA, Fisher’s LSD test for behavioral analysis, footprint by Student’s t- test for dependent variables, p < 0.05.

Intervention

“NMDA dissolved in saline solution, pH to 7.4 with NaOH 1mEq/mol. Animal injected intraperitoneally with a low, nonconvulsant dose of NMDA (75 mg/kg) or vehicle (saline, 0.9% NaCl, w/v) 24hr before cortical trauma injury induction.”

Significant Results

“Sensorimotor behavioral test revealed uncoordinated movements in traumatic mice compared with control mice.” “Preconditioning with NMDA prevented distortion of gait for all parameters of mice that showed deficits.” “Irregular stride length and hindlimb stride observed in mice at 1.5hr after TBI were prevented in preconditioned mice.” “Mice revealed loss of rhythm coordination” via step alternation after TBI “which was prevented by NMDA treatment”. “Animals preconditioned with NMDA and exposed to TBI did not display defects in any of the stride parameters analyzed.” “TBI mice evaluated 1.5hr after TBI were unable to stay on the rotarod,” independent of NMDA or SAL treatment.

Conclusions

“Data showed that neuroprotection evoked by low activiation of the glutamatergic system through NMDA preconditioning was effective against the sensorimotor deficits displayed by mice in a model of diffuse trauma.

Significant Findings

“Protective effect of NMDA … in sensorimotor deficits induced by TBI”

Limitations

NMDA is a receptor; no substrate provided to heal tissue

Implications

That motor deficits can be restored following TBI

Study Title (5)

Efficacy of N-Acetyl Cysteine in Traumatic Brain Injury

Journal and Date

PLoS One, February 1, 2014

Brief Summary

“Using two different injury models: either weight drop in mice or fluid percussion injury in rates”, simulating either mild or moderate TBI, “early post-injury treatment with N-Acetyl Cysteine (NAC) reversed the behavioral deficits associated with TBI.” Using Y maze for mice and Morris water maze for rats, NAC treatment provided “significant behavioral recovery after injury.”

Purpose

To contribute research to TBI therapies for military personnel

Sample Population

Experiment 1: Male Sprague-Dawley rats between 300 – 400g Experiment 2: Male ICR mice 6-8 wks, 30-40g Sprague-Dawley

Setting

Housed and bred under a 12 hr light/dark cycle and provided with food/water ad libitum.” Guidelines: Instn. Animal Care, Case Western Reserve, NIH Guide Lab

Research Design

Randomly selected, experimental, control, mice fluid percussion injury model

Theory/Framework

Amino acids supplied to the traumatized brain expedite repair

Methods

Experiment 1: Fluid Percussion Injury Rats, 3 groups: Sham, TBI, TBI-NAC, force of injury 1.82 – 1.95atm. NAC 30min post injury, 50mg/kg ip then q. 24hr for 3 days. Cognitive assessment – Morris water maze- hidden platform, spatial learning and memory. Tested 4 trials per day over 4 days PID 10 13. Morris water maze – probe trail and visible platform.

Experiment 2: Weight Drop Mice, 4 groups: Sham-Vehicle, Sham-Drug (NAC + topiramate), TBI-Vehicle or TBI-Drug (NAC + topiramate). NAC (100mg/kg) + topiramate (30mg/kg) administered ip one hour post injury. Cognitive assessment – 7, 30 days after WD or sham with novel object recognition and the Y maze behavioral tests. SPSS Statistics, one-way or repeated-measures ANOVA and Fisher’s LSD post hoc test, p < 0.05.

Intervention

N-Acetyl-Cysteine in rats, and NAC + Topiramate in saline solution in mice

Significant Results

“Single dose of NAC ameliorates biochemical and histological endpoints” and “multiple doses ameliorate inflammatory sequelae in rat models.” “NAC has antioxidant glutathione (GSH) precursor and anti-inflammatory effects on cytokine cascades and phospholipid metabolism.” “Sulfhydryl group of cysteine serves as a proton donor for antioxidant activity of GSH, rare in foods.”

Conclusions

“The cellular bases of memory and regulation of motivation … may be improved via NAC.” “Despite poor penetration into the CNS, NAC can significantly elevate GSH levels in brain after oxidative stress and GSH deficiency.” “Improved clinical outcomes after early NAC treatment for blast TBI are consistent with the hypothesis that vascular effects of TBI facilitate delivery of NAC to affected sites.”

Significant Findings

“Paper documents the efficacy of NAC in reversing or preventing cognitive abnormalities in rodent models of mild to moderate TBI” this parallels a protocol with blast mTBI in a combat setting including early treatment” w/ NAC/topiramate

Limitations

Studies show this may translate to man in a battlefield blast-induced TBI setting.

Implications for Practice

Often therapies not thought to cross the BBB are tabled. This study shows that amino acids with supposedly limited BBB penetration do reach the brain and can improve outcome.

Study Title (6)

Prolonged continuous intravenous infusion of the dipeptide L-alanine-L- glutamine significantly increases plasma glutamine and alanine without elevating brain glutamate in patients with severe TBI

Journal and Date

Critical Care 2014 18:R139

Brief Summary

“Low plasma glutamine levels are associated with worse clinical outcome” for severe TBI and “optimal glutamine dose to normalize plasma glutamine levels without increasing plasma and cerebral glutamate has not yet been defined”.

Purpose

To determine dosage of glutamine to correct hypoglutaminemia.

Sample Population

“Twelve patient in two separate studies who were comparable presenting with mixed lesions, predominantly consisting of contusion/hemispheric edema. Study 1, two female and four male patients suffering from severe TBI, median age 30 yrs, median BMI 21 kg/m2,” sedated median 13 days. “Study 2, two female and four male patients suffering from severe TBI, median age 28 yrs, median BMI 23 kg/m2,” sedated median 14 days. “Glasgow Outcome Score of 6 at 12 months.”

Setting

Surgical Intensive Care, University Hospital Zuerich, Zuerich, Switzerland

Research Design

Prospective, experimental, 12 TBI Patients anticipated to die within 48 hours

Theory/Framework

Amino acids dosages supplied to the traumatized brain to expedite repair

Methods

“Inclusion criteria: patients suffering from severe TBI reflected by abnormal neurologic status and pathologic neuroradiologic findings were considered eligible when requiring pharmacologic coma.” “Study 1 (n=6), arterial and jugular venous plasma samples drawn at 1,4,12, and 23 hours during the infusion period and after infusion period at 4,12 and 23 hours.” “Study 2 (n=6), plasma arterial and jugular venous samples drawn at predefined time points 1,4,12,24,36,48,60, 72, 84,96,108, and 120 hours, and [drawn] after infusion period at 4,12, 23 and 48 hours.” Indirect Calorimetry performed before and after infusion period.

Intervention

“Study 1: six patients were included to investigate the effects of 0.5g glutamine/kg/ d (Dipeptiven – L+alanine+L+glutamine: 82 mg/100 ml L_alanine and 134.6 mg/ 100ml L_glutamine) continuously infused for 24 hours followed by a 24 hours observation period. In Study 2, a total of six patients were included to investigate the effects of 0.5g glutamine/kg/d (Dipeptiven = :_alanine_L_glutamine; 82mg L_alanine, 134.6 mg L_glutamine) continuously infused for 5 days followed by a 48 hours observation period.” “Dunn’s multiple comparison test, ANOVA,p <0.05.

Significant Results

“Continuous L_alanine_L_glutamine infusion significantly increased plasma and cerebral glutamine and alanine levels (sustained) during the 5 day infusion phase. Plasma glutamate remained unchanged and cerebral glutamate was decreased without any signs of cerebral impairment.”

Conclusions

“High dose L_alanine_L_glutamine infusion (0.75 g/kg/d up to 5 days) increased plasma and brain glutamine and alanine levels. This was not associated with elevated glutamine or signs of potential glutamate-mediated cerebral injury.”

Significant Findings

“Urea and ammonia were significantly increased WNL w/o organ dysfunction.”

Limitations

Optimal dosage not yet determined. Condition improvement not measured.

Implications

Glutamate infusion can be given without deleterious effects to normalize levels.

Study Title (7)

Role of extracellular glutamate measured by cerebral micro dialysis in severe traumatic brain injury

Journal and Date

Journal of Neurosurgery, September 2010

Brief Summary

“High glutamate levels are present in a substantial number of patients, and patterns of glutamate level changes are predictive of patient outcome.”

Purpose

“The present study was to evaluate glutamate levels in TBI, analyzing the factors affecting them and determine their prognostic value.

Sample Population

“Inclusion criteria: a blunt mechanism of head trauma, a GCS score LE 8 on presentation or w/n 48 hrs injury. Exclusion criteria included a penetrating head injury, a presentation GCS score of 3, and fixed, dilated pupils.” 165 patients.

Setting

Ben Taub General Hospital (Level I trauma center) in Houston, Texas (200-2007). Baylor Institutional Review Board approved. NICU, standard protocol.

Research Design

Prospective study, TBI Level 1 165 patients inclusion/exclusion criteria

Theory/ Framework

Consider TBI glutamate levels as related to MABP (mean arterial blood pressure), ICP (intracranial pressure), PO2 or SjvO2 (Jugular venous O2 saturation).

Methods

CT scan, treatable mass to OR, ventriculostomy catheter to monitor ICP, brain tissue PO2 monitor and SjvO2 monitor inserted ICU. Patients intubated/sedated. Head of bed elevated 30 degrees. Pts kept euvolemic, isothermic, feeding 24 hrs post admission. Fluid replacement/vasopressors PRN. ICP > 20 mm Hg treated with ventricluar drainage of CSF, mannitol and mild hyperventilation (PaCO2: 30-35 mm Hg). Barbiturate coma induced and/or decompressive craniectomy as needed. MABP, ICP, brain tissue PO2, SjvO2 recorded every hour for first 120 hours. Chi- square, Wilcoxon rank-sum, Pearson/Spearman correlation. 2 tailed p <0.05,SPSS

Intervention

Fiberoptic catheter in dominant internal jugular vein (Doppler US), verified by radiograph to measure SjvO2. Miniaturized Clark electrode positioned in cortex, non-necrotic frontotemporal region to measure brain tissue PO2. PO2 levels < 10 mm Hg due to hypotension, high ICP, hypoxemia or anemia treated.

Significant Results

“Glutamate in first 24hrs < 10 umol/L in 31 pts. (18.8%), between 10 and 20 umol/L in 58 pts (35.1%), and > 20 umol/L in 76 pts (46.1%). Trend of higher mortality … with glutamate > 20umol/L, however…p= 0.08.” No correlation between early glutamate levels and” initial GCS score or initial ICP.

Conclusions

Two patterns: Pattern 1, glutamate levels normalized. Either “levels initially low and remained low” or “level initially high but decreased over time.” Pattern 2, “glutamate levels tended in to increase over time or remain abnormally elevated.”

Significant Findings

With normalizing glutamate levels (71% of patients) the mortality rate was 17.1%; “41.2% of survivors ultimately achieved a good functional outcome.” With “levels that increase over time or remained abnormally elevated (29% of patients), the mortality rate was 39.6%; 20.7% of survivors had a good functional outcome.”

Limitations

High glutamate levels due to amino acid metabolism necessary for healing. Amino acids may be supplemented to aid in healing irrespective of glutamate levels.

Implications

Glutamate levels can be used as an outcome prognostic value.

Study Title (8)

Dietary Therapy Mitigates Persistent Wake Deficits Caused by Mild TBI

Journal and Date

Science Translational Medicine, December 11, 2013

Brief Summary

Sleep disorders are reported in up to “72% of patients with TBI up to 3 years after injury.” Animal models can “rigorously describe sleep-wake patterns in the chronic setting.” The orexin system may sustain wakefulness. Dietary branched chained amino acids may “alleviate injury-induced deficits in wakefulness.”

Purpose

Amino acids therapies contribute to TBI neurobehavioral consequences.

Sample Population

5 to 7 week old, 20 – 25g, male C57BL/J6 mice from Jackson Labs

Setting

Insulated/soundproof room, 23C, humidity 25%, 12 hr light/dark, 100 lux, free access to food and water. NIH guide, Univ. of Penn. Animal Care Guidelines

Research Design

Randomly, selected, prospective, controlled study, blinded, experimental

Theory/Framework

Consider BCAA as affecting orexin sleep-wake system in TBI

Methods

Two groups of mice: TBI (surgery and fluid percussion (FPI)) and sham (surgery only). FPI mice were anesthetized, 20-ms pulse of saline delivered onto the dura. Pressure 1.4 and 2.1 atm. AccuScan infrared monitoring for 30 days to count beam breaks in 10-s segments to estimate sleep/wakefulness. EEG/EMG signals digitized with Grass Gamma. Subset of mice “(n=7 sham, n=6 TBI, n=6 TBI+BCAA)” “received either BCAA-supplemented water (100mMM) or untreated tap water (control), 3-5ml/day. Baseline recorded day 1, 2, and 5.

Intervention

After Sham or TBI, EEG/EMG recorded Wake, NREM and REM sleep cycles. Polygraphs for 2 hours on day 3 and 3 hours on day 4. Anti-orexin-antibodies coated lateral hypothalamus, visualized with fluorescence to identify orexin neurons. Student’s t-test, one-way ANOVA, Dunnetts post hoc test, p < 0.05.

Significant Results

“Time spent continuously active, was significantly shorter in TBI mice.” Decreased and shortened activity bouts was evident in brain-injured mice. “The total number of transitions between active/inactive bouts was significantly increased after TBI”. “TBI mice spent significantly less time in both the light and dark phases, and more time in NREM sleep.” TBI mice treated with BCAAs showed a partial reversal of changes in wake and NREM states. “Total number of wake-to-sleep transitions was significantly increased in TBI mice compared to sham mice, and BCAA intervention after TBI decreased number of transitions back to sham control levels.” “Wake spectra for TBI mice were significantly lower at the theta frequency range (8-9hz), compared to sham control mice.” “Theta power was restored by BCAA therapy for spectra in the NREM state.” “TBI mice had a shorter latency to sleep compared to sham mice, and this shorter latency was partially restored by BCAA intervention.” “Compared to the sham and TBI + BCAA groups, TBI mice had significantly fewer activated orexin neurons.”

Conclusions

BCAA therapy restores many aspects of wakefulness, including EEG and orexin.

Significant Findings

“Total orexin neuron numbers were not significantly different between groups, indicating that injury primarily affects physiology rather than gross cell loss.”

Limitations

Not a therapeutic human experiment, yet.

Implications

Amino acid therapies highly effective in mice. BCAA therapy patent applied for.

Study Title (9)

Vasopressin for cerebral perfusion pressure management in patients with severe TBI: Preliminary results of a randomized controlled trial

Journal and Date

Journal of Trauma and Acute Care Surgery

Brief Summary

“AfterTBI, catecholamines (CAs) may be needed to maintain adequate cerebral perfusion pressure (CPP), but there are no recommended alternative vasopressor therapies. This is an interim report of the first study to test the hypothesis that arginine vasopressin (AVP) is a safe and effective alternative to CAs for the management of CPP in patients with severe TBI.

Purpose

To contribute to the knowledge base on amino acid vasopressor TBI therapies.

Sample Population

“Since 2008, all TBI patients requiring ICP monitoring at this Level 1 trauma center have been eligible for a randomized trial to receive either CA or AVP if vasopressors were required to maintain CPP greater than 60 mm Hg.” Minors, pregnant women and incarcerated individuals were excluded.

Setting

University of Miami/Jackson Memorial Hospital, Ryder Trauma Center

Research Design

“Single-institution, prospective, open-label, randomized, controlled clinical trial.”

Theory/Framework

Considering use of arginine as an alternative vasopressor therapy

Methods

TBI patients randomized to CA (control) or AVP for CPP management but only receive vasopressors if medically indicated. Stabilized in resuscitation. Transferred to neurosurgery or Trauma ICU if polytrauma. Switching vasopressors allowed. Deaths IRB reviewed. GCS, SBP, DBP, MAP, HR, CPP, ICP, fluids and meds data.

Intervention

“Treatment protocols: if CPP > 60mmg Hg no vasopressors required. If CPP < 60 mm Hg, ICP was < 20 mm Hg, and systolic BP < 90 mm Hg, then resuscitation was performed with fluid/blood products.” If pt. resuscitated “with CPP < 60 mm Hg and/or ICP < 20 mm Hg, then vasopressors were initiated to raise CPP < 60 mm Hg and systolic BP > 90 mm Hg.” AVP dosage was 1.2 U/h, increased 4 U/h.

Significant Results

To date, 96 patients have been randomized. Demographics, vital signs, and lab values were similar. As treated, 60 required no vasopressors, were least severe, had best outcomes. 23 patients received CS (70% levophed, 22% dopamine, 9% phenylephrine) and 12 patients received AVP. The two vasopressor groups had worse Injury Severity Score (ISS) and fluid requirements on ICU Day 1 in the AVP versus the CA group (p < 0.05) before treatment.” “Adverse events were not increased with AVP versus CA. Trends favored AVP versus CA, but no differences were statistically significant.. and there was no difference in mortality rates.”

Conclusions

“Preliminary results suggest that AVP is a safe/effective alternative to CA for the management of CPP after TBI and support the continued investigation and use of AVP when vasopressors are required for CPP management in TBI patients.”

Significant Outcomes

“AVP is effective for patients in septic shock, refractory cardiac arrest, and animal hemorrhagic shock models, showing that AVP is effective in combination with fluid resuscitation.” This “study reports a novel off-label indication for AVP.”

Limitations

Multi trauma center study desirable. Not evaluating arginine as healing substrate

Implications

A human study showing efficacy of AVP as a vasopressor therapy in human TBI.

Study Title (10)

Open-Label Randomized Trial of the Safety and Efficacy of a Single Dose Conivaptan to Raise Serum Sodium in Patients with TBI

Journal and Date

Neurocritical Care, 2011

Brief Summary

This study evaluated the use of conivaptan in TBI patients who had normal sodium levels to determine efficacy and whether intervention could reduce ICP. The study found that no adverse events occurred and ICP was reduced within 4h.

Purpose

To determine whether this arginine-vasopressin receptor antagonist is safe in normonatremic patient with TBI and could reduce ICP with a single dose.

Sample Population

216 patient assessed for eligibility, 10 met inclusion criteria.

Setting

Harborview Medical Center, Level I trauma center, Seattle, Washington. “Study approved by Human Subject Division Review Board of University of Washington.”

Research Design

“Open-label, randomized, controlled trial enrolling 10 subjects within 24h of severe TBI to receive single 20mg dose of conivaptan (n=5) or usual care (n=5).”

Theory/Framework

An arginine-vasopressin receptor antagonist could reduce ICP in TBI.

Methods

Admission criteria included age GE 18, ICU admission, severe TBI as defined by GCS of LE 8, ICP monitoring required, supplemental sodium needed to “raise to 10 mEq/l higher than admission to reduce cerebral edema and/or ICP.” A number of exclusion criteria existed including polytrauma. “Patients randomized to receive conivaptan in addition to usual care (n=5) or usual care alone (n=5). End point if serum sodium above target goal range or any drug-related adverse events. Seconday end points, mean serum Na, Na load in first 48 hr, mean ICP values, change in ICP, CPP. Urine volume measured in 4 h intervals during first 48h.

Intervention

Open-label administration. Conivaptan single dose of 20mg, mixed with 100ml of 5% dextrose in water, and infused over 30 min. Sodium assessment q. 4h.

Significant Results

Statistical methods included Student’s t-test, chi-square, linear mixed effects models to compare ICP with serum sodium, 2 sided, sig of 0.05. STATA vers 11. While further studies are required, conivaptan appears to be safe and effective at lowering ICP. Previous ICP therapies including “mannitol and hypertonic saline solutions elevate the osmolarity with in the cerebral vasculature and increase fluid movement across the BBB and into the capillary system.”

Conclusions

“Data suggest that a single dose of conivaptan is safe in non-hyponatremic patients with severe TBI for .. the purpose of ICP control. Conivaptan caused an increase in serum sodium within 4 h of administration with a concomitant significant reduction in ICP without adverse effects.” “Achieves ICP control.”

Significant Findings

“The observation that conivaptan has significant effects on ICP associated with a steep change in sodium level is important.” This fall in ICP is within 3-5 h.

Limitations

Avoid Conivaptan “in the presence of hypovolemia” since associated with diuresis.

Implications

An arginine product is effective at controlling human ICP with a single dose.