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Pharmacologic management of Traumatic Brain Injury in the

Critically Ill Patient

Kristen Ditch, PharmD, BCPS, BCCCP

Clinical Pharmacy Specialist Neuro-Trauma Intensive Care UnitUmass Memorial Medical Center

Objectives

• Compare the mechanism of action of osmotic agents and corresponding monitoring parameters

• Evaluate optimal fluid management strategies in traumatic brain injury

• Recommend pharmacologic regimens during hypo- and/or normothermia for intracranial hypertension

TBI statistics 2001 to 2010

• ED visits: 420 to 715 per 100,000

• Death: 18.5 to 17 per 100,000

• Major risk factors for TBI in the US

• Age: extremes of age (<10 or > 74)

• Gender

• Low socioeconomic status

• Leading cause of TBI

• Falls

• Motor vehicle accident

• Americans living with TBI-associated disability: 3.2 million

Centers for Disease Control and Prevention website https://www.cdc.gov/traumaticbraininjury/data/index.html Accessed August 2016

J Head Trauma Rehabil 2010;25(2):72-80

Mechanisms causing increased ICP

Condition Mass effect Edema Impaired CSF circulation

TBI + +

Subarachnoid hemorrhage + + +

Ischemic stroke +

Brain tumor + +

Spontaneous intracerebralhematoma

+ +

Abscess or meningitis + +

Acute liver encephalopathy +

Hypertensive encephalopathy

+

N Engl J Med 2014;370:2121-30

Cerebral Perfusion Pressure

CPP = MAP - ICP Monroe Kellie Doctrine

• Total volume in within the skull remains constant

• CSF + blood + brain tissue

• If cerebrovascularautoregulation is intact:

• Compensatory mechanisms occur to maintain ICP WNL

J Neurotrauma 2007;42:S55-S58J Intensive Care Med 2002;17:55-67

• CPP goal > 60-70

• ICP goal < 20 mm Hg

• CPP 50-150 mm Hg:cerebral blood flow can autoregulate

High ICP can lead to herniation

N Engl J Med 2014;370:2121-30

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Secondary injury

• Reduced from mitochondrial dysfunction

• Excitotoxicity

• Oxidative stress – Glutamate, reactive O2 species

• Inflammation – Cytokines, Chemokines

• Necrosis vs Apoptosis

• Microvascular occlusion

Secondary injury: Simple, right?

With permission,Dr. Carandang

Approach to treatment of increased ICP

Intubation and sedation

Hyperosmolartherapy and CSF drainage

Temperature modulation and/or metabolic suppression

N Engl J Med 2015;372:55-65

Hyperosmolar therapy comparison

Mannitol 20% 23.4 % NaCl 3% NaCl

Osmolarity 1098 mOsm/L 8008 mOsm/L 1027 mOsm/L

Typical dose range

0.25 – 1 gm/kg 15- 30 mL 2.5-5 mL/kg

Infusion volume 250 mL-500 mL 15- 30 mL Bolus: ~100-250 mL

Infusion instructions

Infused over 15 minutes (0.2 micron filter). Central line preferred.

Infused over 15-30 minutes via syringe pump. Central line.

Infused over 15-30 minutes. Central line preferred.

Hyperosmolar therapy comparison

Mannitol HTS

Monitoring parameters

Urine output (net fluid balance)Serum electrolytesSCrOsmolar gap (goal < 20)

Serum osmolalitySerum Na, K, ClInfusion site

Adverseeffects

HypokalemiaHypovolemiaRenal failure (ATN)↑↓ SodiumRebound cerebral edema

HypernatremiaHypokalemiaHyperchloremicmetabolic acidosisCentral pontinemyelinolysis (rare)Disruption of BBB

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Osmolar gap: an estimate of mannitol concentration

Osmolar gap = Actual serum osmolarity – Calculated serum osmolarity

Crit Care Med 2004;32:986-991

Sodium: how high is too high?

• N= 339 neuro ICU patients with Na > 150 mEq/L + mannitol

• Only Na > 160 mEq/L independently associated with increased mortality

• Not clear risk/benefit of lowering sodium to achieve 160 mEq/L vsrebound cerebral edema

J Critical Care 2006(21);163-172

2015 Meta-analysisReference Study Design Patients Intervention

Cottenceau(2011)

RCT TBI Mannitol 20% vs HTS 7.5%

Sakellaridis (2011)

RCT Severe brain injury

Mannitol 20% vs HTS 15%

Oddo(2009)

Retrospective TBI Mannitol 25% vs HTS 7.5%

Francony(2008)

RCT Severe brain injury

Mannitol 20% vs HTS 7.45%

Harutjunyan(2005)

RCT Neuronal damage

Mannitol 15% vs HTS 7.2% + HES

Battison(2005)

RCT Brain injury Mannitol 20% vs HTS 7.5% + 6% dextran-70

Vialet(2003)

RCT Head trauma and coma

Mannitol 20% vs HTS 7.5%

Medicine 2015;94(17):e668

2015 Meta-analysis: ICP at different times

0 - 30 minutes

0 - 60 minutes

0 - 120 minutes

Overall difference in means of ICP

reduction

Favors HTS Favors MannitolMedicine 2015;94(17):e668

03:00 06:00 09:00 12:00 15:00 18:00 21:00

Time (hr)

seru

m o

smo

lari

ty(m

Osm

/L)

300

320

24:00

mannitol

23.4% NaClIntravenous fluid (IVF)

management in TBI

No hypotonic fluids!

J Neurotrauma 2007;42:S12-S20

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IVF and acid-base status

Chloride-restrictive

fluids

Chloride-rich fluids

JAMA 2012;308(15):1566-1572

JAMA 2012;308(15):1566-1572

Sodium acetate IVF

Sodium Acetate strength

(equivalent Na strength)

mEq/L mOsmol/L PIV vs CIV?

1.26% sodium acetate

(0.9% NaCl)

154 308 Either

2.1 % sodium acetate

(1.5% NaCl)

256 513 Either

4.2% sodium acetate

(3% NaCl)

513 1027 Either (CIV preferred)

Approach to treatment of increased ICP

Intubation and sedation

Hyperosmolartherapy and CSF drainage

Temperature modulation and/or metabolic suppression

Possible protective effects of hypothermia

• Prevention of apoptosis

• Reduced mitochondrial dysfunction

• Reduced free radical production

• Reduced permeability of the BBB

• Improved ion homoeostasis

• Decreased pro-inflammatory reactions

• Suppress seizure activity

• Control intracranial hypertension

Lancet 2008;371:1955-69

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Eurotherm3235 Trial

Does hypothermia to reduce ICP after TBI improve outcomes?

Eurotherm3235 Pilot Trial

Pilot phase designed to assess cooling TBI patients

Standardized protocol, inclusion criteria, power calculation

Early studies support hypothermia to lower ICP

Small numbers, differences in protocols, lack of outcomes

Effective at lowering ICP

Trials 2013;14:277N Engl J Med 2015;373:2403-12

Eurotherm3235 Trial

Stage 1: Mechanical ventilation and sedation management. If ICP > 20 mm Hg, then randomization occurred

Stage 2: Osmotherapy for ICP control and inotropes to maintain CPP ≥ 60 mm Hg

Stage 3: Barbiturates with EEG monitoring and decompressivecraniectomy if required and if failed hypothermia and all other stage 2 treatments

N Engl J Med 2015;373:2403-12

Eurotherm3235 Trial: Results

• Trial stopped early (after 5 years) after interim dataanalysis suggested increasing harm to hypothermia group

• Increase in the adjusted odds of an unfavorable outcomein hypothermia group

• OR 1.53 (1.02 to 2.30; p = 0.04)

• Increase in the odds of death at 6 months in thehypothermia group

• HR 1.45 (1.01 to 2.10; p = 0.047)

N Engl J Med 2015;373:2403-12

Targeted temperature management

• Adverse effects of cooling:

• Electrolyte disorders

• Cardiac changes

• Impaired coagulation cascade

• Insulin resistance

• Infection risk

• Shivering

Crit Care Med 2009;37:1101-1120

Bedside Shivering Assessment Scale

Score Term Description

0 No Absence of shivering

1 Mild Localized to the neck and/or thorax

2 Moderate Involvement of the upper extremities with or without neck or pectoralismuscles

3 Severe Generalized, whole-body involvement

Crit Care Med 2009;37[Suppl.]:S250-S257 Neuro Crit Care 2011;14(3):389-394

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Columbia study

Patients

• Acute brain injury + [cardiac arrest or ↑ICP or refractory fever]

Interven-tion

• Method and duration of cooling at discretion of the neurointensivist

• Normothermia 36 to 37 C; Hypothermia 33 to 35.5 C

Goal

• Using a protocol, achieve no-to-minimal shivering

• BSAS score ≤ 1

Neuro Crit Care 2011;14(3):389-394

Columbia anti-shivering protocol

Neuro Crit Care 2011;14(3):389-394

Columbia protocol: Results

Step Protocol All patients Hypothermia Normothermia

Interventions N (%)

0 39 (18) 22 (25) 17 (14)

1 61 (29) 23 (26) 38 (31)

2 74 (35) 28 (31) 46 (37)

3 34 (15) 12 (13) 22 (18)

4 5 (2.4) 4 (4.5) 1 (1)

Neuro Crit Care 2011;14(3):389-394

Conclusions

• Hyperosmolar therapy is effective at lowering ICP and requires knowledge of key monitoring parameters to minimize adverse effects

• Isotonic fluids that contain a sodium content of at least 154 mEq/L are the mainstay in managing a TBI patient

• Although TTM is beneficial in lowering ICP, it’s impact on clinical outcomes remains undetermined

• Anti-shivering agents that do not compromise the neuro-exam are preferred

What are the best daily monitoring parameters for

mannitol?

Urine output, serum electrolytes, osmol gap

Net fluid status, osmol gap, serum electrolytes

Serum osmolarity, serum creatinine, urine output

Hypteronic saline has been shown to be superior to mannitol in lowering ICP

True

False

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The Bedside Shivering Assessment Scale (BSAS) score went from 0 to 1 on a patient

cooled to 36◦C (normothermia goals).

What would be the best pharmacologic intervention to achieve your goal BSAS score?

Meperidine 12.5 mg IV x 1

Cisatracurium 10 mg IV x 1

Buspirone 30 mg enteral q8hr

Key Takeaways

• Key Takeaway #1• Standardizing the key monitoring parameters for hyperosmolar

therapy (e.g., checking osmolar gaps q6-12hr while on mannitol) can minimize adverse effects of these high risk agents

• Key Takeaway #2• Standardized IVF can be created by working with the IV room

and the needs of neuro-ICU population in order to safely and efficiently dispense iso- or hyper-tonic solutions

• Key Takeaway #3• Knowledge of the various anti-shivering agents specific to the

neuro-ICU population can minimize use of sedation and/or paralytics during prolonged periods of normo- or hypo- thermia

Acknowledgements

• Dr. Jeffrey Fong, PharmD, BCPS, Associate Professor of Pharmacy Practice, MCPHS University

• Dr. Wiley Hall, MD, Director Neuro-Intensive Care Unit

• Dr. Susanne Muehlschlegel, MD, MPH, FNCS, FCCM; Neurocritical Care, Associate Professor of Neurology, Anesthesia/Critical Care and Surgery, University of Massachusetts Medical School

• Dr. Raphael Carandang, MD Program Director Neurology Residency Program; Assistant Professor Departments of Neurology, Anesthesiology and Surgery; University of Massachusetts Medical School