DEXAMETHASONE (DECADRON): An examination of single dose decadron: the basic pharmacodynamics and role as an adjuvant to regional anesthesia.

By Devon Boyd NAR

OBJECTIVES Briefly discuss:

The mechanism of action of corticosteroids -- specifically decadron.

Current uses Antiemetic Anti-inflammatory

Discuss new revelations about how decadron can enhance our anesthetics.

Explore the use of decadron as an adjuvant to regional anesthesia. Decrease block onset time Double the length of motor block Double the length of analgesia

DECADRON AS AN ANTIEMETIC Decadron’s role as an

antiemetic is related to its ability to reduce the cellular production of serotonin (5-HT3) through the inhibition of the production of tryptophan hydroxylase the enzyme that converts tryptophan to serotonin (Allen, 2007).

DECADRON AS AN ANTIEMETIC 5-HT3 released from the gut during surgery

is a contributor to postoperative nausea and vomiting.When given in combination with

Zofran, a (5-HT3) receptor antagonist, this combination is highly effective against nausea (Allen,2007).

GENERAL STATEMENTS ABOUT DECADRON

Decadron is a synthetic glucocorticoid with minimal mineralocorticoid activity. Single dose – no disruption of the patient’s

electrolyte or fluid balance (Allen, 2007). Potent anti-inflammatory

25-50 times the potency of hydrocortisone 16 times the potency of prednisone (Allen, 2007).

WHAT IS THE PROVEN MECHANISM OF ACTION OF DECADRON?

Glucocorticoid-receptor complexes cross the nuclear membrane and modulates gene mediated protein production (Tasker, 2005).

This requires 45 min – 1 hour for full effect

This is why decadron is more effective at treating nausea if it is given right after induction of general anesthesia

CELL NUCLEUS GENE MODULATION -- ROLE IN REDUCTION OF INFLAMMATORY AND CHEMOTAXIC MEDIATORS Decreased production of proteins includes the decreased production of:

Bradykinin Decreases both the cell mRNA expression and the response to Bradykinin binding

COX-2 Prostaglandin

Tryptophan Hydroxylase Serotonin (5-HT3)

Interlukin-1 Interlukin-2 Interlukin-6 (Allen, 2007) Substance P Nitric oxide Tumor Necrosis Factor

Indirectly histamine release Histamine is released from mast cells in response to

Substance p Kinins Interlukin-1 (Kelly, 2001)

The effect of this steroid is to reduce the production of excitatory neurotransmitters. Reduction of the above chemical mediators is very important

MECHANISM OF ACTION OF DECADRON CONTINUED Binding of decadron to cellular DNA results in

changes in metabolism of: Carbohydrates

Increases gluconeogenesis Increases blood glucose levels (Allen,2007).

Fats Corticosteroids increase the production of HMG CoA

Allows cells to make more of their own cholesterol Increases circulation of Low Density Lipoproteins (LDL)

Chronic use results in: Increased serum cholesterol Deposition of fat Results in Cushing’s Syndrome with chronic use (Allen,2007)

Proteins Decreases the production of proteins (Allen, 2007)

• This is one of the BIG features of interest in the perioperative and postoperative setting!!

REDU

CES THE CH

EMICALS TH

AT MED

IATE PAIN

This illustration represents a C-fiber nociceptor.

The production of these mediators is inhibited by decadron. These are the chemicals responsible for “wind-up” pain.

C Fiber Nociceptor

EFFECT ON POSTOPERATIVE PAIN --- SINGLE PREOPERATIVE OR PERIOPERATIVE DOSE OF DECADRON TO A GENERAL SURGERY PATIENT Two meta-analysis’ conducted by De Oliviera

et al. (2011) and Waldron et al. (2013) suggest that decadron can: Modestly decrease postoperative opioid

requirements for patients having open abdominal surgery: 16.8% during the first 24 hours

De Oliviera et al. showed a statistically significant decrease in time to discharge: 5.5 hour on average

THE MOST BANG FOR THE BUCK The suggested dose of

single dose decadron is 0.1-0.2 mg/kg with a plateau effect at doses >10mg (De Oliveira, 2011).

This dose is effective as an antiemetic while also being effective at reducing pro-inflammatory and pain inducing proteins (Allen,

2007).

AS AN ADJUVANT FOR REGIONAL ANESTHESIA Preservative free

decadron 8mg-10mg administered as an adjuvant to local anesthetic for neuraxial and peripheral nerve blocks dramatically increases the length of analgesia (by 100% to 180%)(Cummings III, 2011).

It is safe for use in both neuraxial and peripheral nerve blocks (cummings III, 2011).

RANDOMIZED, CONTROLLED, DOUBLE-BLIND TEST RESULTS This is from the British Journal of Anesthesia June

2011 K.C. Cummings III et al. Researchers sought to determine the effect of

adding 8ml of preservative free decadron to 0.5% Bupivacaine and 0.5% Ropivacaine used for interscalene blocks Results:

Length of analgesia Plain 0.5% Ropivacaine -- 11.8 hours 0.5% Ropivacaine with 8mg decadron --22.2 hours

Plain 0.5% Bupivacaine-- 14.8 hours 0.5% Bupivacaine with 8mg decadron-- 22.4 hours

RANDOMIZED, CONTROLLED, DOUBLE-BLIND TEST RESULTS CONTINUED This is from the Indian Journal of Anesthesia April 2013 P.A Biradar et al. Researchers sought to determine the effect of the

addition of 8mg of preservative free decadron to 1.5% lidocaine (7mg/kg) with epinephrine (1:200,000)to a supraclavicular brachial plexus block.

Results Onset of sensory blockade:

Lido ĉ Epi. – 16.0 + 2.3 min. Lido ĉ Epi and 8mg decadron – 13.4 + 2.8 min.

Onset of motor blockade Lido ĉ Epi – 18.7 + 2.8 min. Lido ĉ Epi and 8mg decadron – 16.0 + 2.7 min.

Duration of sensory blockade Lido ĉ Epi – 159 + 20.1 Min Lido ĉ and 8mg decadron – 326 + 58.6 min.

Duration of motor block Lido ĉ Epi. – 135.5 + 20.3 min. Lido ĉ and 8mg decadron – 290.6 + 52.7 min.

RANDOMIZED, CONTROLLED, DOUBLE-BLIND TEST RESULTS CONTINUED This is from the

Saudi Journal of Anesthesia 2011

Bani-hashem et al. Sought to determine

the effect of the addition of 8mg of decadron to a 0.5% bupivacaine spinal.

YOU CAN GIVE DECADRON I.V. WITH THE SAME EFFECT New research shows

that I.V. decadron administered 45min-1hour before regional anesthesia has the same analgesia extending effect as decadron administered perineurally (Desmet, 2013)! To avoid perineal

itching administer in 50ml-100ml 0.9% NaCl over 10 minutes.

TWO RANDOMIZED, CONTROLLED, AND DOUBLE-BLINDED TRIALS SUGGEST THAT I.V. DECADRON CAN HAVE THE SAME EFFECT AS PERINEURALLY ADMINISTERED DECADRON Egyptian Journal of

Anesthesia March 2011 Abdelmonem et al. Sought to determine if

perianal injection of 0.5% bupivacaine and decadron was equivalent to perianal injection of 0.5%bupivacaine after I.V. decadron 8mg for hemorrhoidectomy patients.

RESULTS FROM ABDELMON ET AL. Onset of sensory blockade:

0.5% bupivacaine 20ml alone – 5.5 + 1.2 minutes 0.5% bupivacaine 20ml ĉ 8mg decadron -- 3.8 + 0.7 minutes 0.5% bupivacaine 20ml ĉ 8mg I.V. decadron-- 3.8 + 0.9 minutes

Onset of motor blockade: 0.5% bupivacaine 20ml alone – 6.5 + 1.1 minutes 0.5% bupivacaine 20ml ĉ 8mg decadron -- 4.0 + 0.7 minutes 0.5% bupivacaine 20ml ĉ 8mg I.V. decadron-- 3.8 + 0.9 minutes

Duration of analgesia: 0.5% bupivacaine 20ml alone – 162.0 + 16.9 minutes 0.5% bupivacaine 20ml ĉ 8mg decadron – 287.7 + 21.0 minutes 0.5% bupivacaine 20ml ĉ 8mg I.V. decadron-- 286.3 + 16.9 minutes

I.V. DECADRON CAN HAVE THE SAME EFFECT AS PERINEURALLY ADMINISTERED DECADRON British Journal of

Anesthesia April 2013 Desmet et al. Sought to determine if

0.5% ropivacaine with decadron 10mg injected to perform an interscalene nerve block was equivalent to 0.5% ropivacaine injected interscalene after an I.V. infusion of decadron 10mg.

RESULTS FROM DESMET ET AL.

Length of analgesia: 0.5% bupivacaine alone – 757 minutes 0.5% bupivacaine ĉ 10mg decadron -- 1405 minutes 0.5% bupivacaine ĉ 10mg I.V. decadron-- 1275 minutes

Increase in postoperative blood glucose: 0.5% bupivacaine alone – 0 mg / dl 0.5% bupivacaine ĉ 10mg decadron -- 38 mg / dl 0.5% bupivacaine ĉ 10mg I.V. decadron-- 51 mg / dl

RAPID ACTION SEEN WITH PERINEURAL INJECTION There is a decrease in

onset time of regional anesthesia when decadron is used as an adjuvant to local anesthetics.

This cannot be explained through the known action of glucocorticoids.

The fact is – there is not a definitive explanation for why decadron decreases the onset time of regional anesthesia (Abdelmonem, 2011).

RAPID ACTION SEEN WITH PERINEURAL INJECTION There are many proposed mechanisms of

immediate action of decadron Upregulation of K+ channels leading to neural

hyperpolarization of C fibers (Attardi, 1993).

Intraneural acidification - leading to increased and sustained ionization of local anesthetic (Kapacz, 2003).

Vasoconstriction – reducing local anesthetic absorption (Kapacz, 2003).

G-protein mediated retrograde endocannabinoid suppression of presynaptic glutamate (Tasker, 2005).

PROPOSED MECHANISM FOR RAPID ACTION G-protein

mediated retrograde endocannabinoid suppression of presynaptic glutamate (Tasker, 2005).

EFFECT OF A SINGLE DOSE OF DECADRON ON BLOOD GLUCOSE

Desmet et al. 2013

Decadron perineural injection 10mg Caused patient blood

glucose to rise by a mean of 38mg/dl for 24 hours

Decadron I.V. injection 10mg Caused patient blood

glucose to rise by 51 mg/dl for 24 hours

EFFECT OF A SINGLE DOSE OF DECADRON ON WOUND HEALING A single dose of IV decadron is out of the

circulatory system within 3 hours (Allen, 2007).

The single dose is completely metabolized within 24 hours (Allen, 2007).

There is no difference in wound healing at two week and six week intervals between decadron and a control group (De Oliviera, 2011).

WHY IS IT SAFE TO INJECT DECADRON INTO THE NEURAXIAL SPACE Decadron is

frequently used as an anti-inflammatory in pain control

Metabolized and excreted within 24 hours

Not an ester Does not have to

undergo ester hydrolysis in order to be metabolized

DECADRON AS AN ADJUVANT TO REGIONAL ANESTHETICS, INCLUDING SPINALS AND EPIDURALS Particulate size of

corticosteroids commonly injected in the neuraxial space: Methylprednisolone –Large

particulate size Betamethasone – Medium

particulate size Dexamethasone – no

particulates

No potential for embolic infarction after particulate corticosteroid injection into an arterial vessel (MacMahon, 2009)

REFERENCES Abdelmonem, A., & Rizk, S. (2011). Comparative study between

intravenous and local dexamethasone as adjuvant to bupivacaine in perianal block. Egyptian Journal of Anesthesia, 27, 163-168.

Allen, K. (2007). Dexamethasone: an all purpose agent? Australian Anaesthesia, 65-70.

Attardi, B., Takimoto, K., Grealy, R., Severns, C., & Levatitan, E. (1993). Glucocorticoid induced up-regulation of a pituitary K+ channel mRNA in vitro and in vivo. Receptors Channels, 1, 287-

293. Bani-hashem, N., Hassan-nasab, B., & Jabbari, A. (2011, October-

December). Addition of intrathecal dexamethasone to bupivacaine for spinal anesthesia in orthopedic surgery. Saudi journal of anesthesia, 5(4), 382-386.

Biradar, P., Kaimar, P., & Gopalakrishna, K. (2013). Effect of dexamethasone added to lidocaine in supraclavicular brachial plexus block: a prospective, randomised, double-blind study. Indian Journal of Anesthesia, 57(2), 180-184.

Chapman, R., Tuckett, R., & Song, C. (2008). Pain and stress in a systems perspective: reciprocal neural, endocrine and immune interactions. Journal of Pain, 9(2), 122-145.

REFERENCES CONTINUED Cummings III, K., Napierkowski, D., Parra-Sanchez, I., Kurz, A.,

Dalton, J., Brems, J., & Sessler, D. (2011). Effect of dexamethasone on the duration of interscalene nerve blocks

with ropivacaine or bupivacaine. British Journal of Anesthesia, 107(3), 446-453.

De Oliveira, G., Almeida, M., Benzon, H., & McCarthy, R. (2011). Perioperative single dose systemic dexamethasone for postoperative pain. Anesthesiology, 115(3), 575-588.

Desmet, M., Braems, H., Reynvoet, M., Plasschaert, S., Van Cauwelaert, J., Pottel, H., . . . Van de Velde, M. (2013). I.V. and perineural dexamethasone are equivalent in increasing the analgesic duration of a single-shot interscalene block with ropivacaine for shoulder surgery: a prospective, randomized, placebo-controlled study. British Journal of Anesthesia, 1-8.

Elston, M., Conaglen, H., Hughes, C., Tametea , J., Meyer-Rochow, G., & Conaglen, J. (2013). Duration ofcortisol suppression

following a single dose of dexamethasone in healthy volunteers: a randomised double-blind placebo-controlled trial. Anesthesia Intensive Care, 41(5), 596-601.

REFERENCES CONTINUED Islam, S., Hossain, M., & Maruf, A. (2011). Effect of addition of

dexamethasone to local anesthetics in supraclavicular brachial plexus block. JAFMC Bangladesh, 7(1), 11-14.

Kapacz, D., Lacouture, P., Wu, D., Nandy, P., Swanton, R., & Landau, C. (2003). The dose response and effects of dexamethasone on bupivacaine microcapsules for intercostal blockade (T9 to T11) in healthy volunteers. Anesthesia and Analgesia, 96, 576- 582.

Kelly, D., & Ahmad, M. (2001). Preemptive analgesia I: physiological pathways and pharmacological modalities. Canadian J ournal of Anesthesia, 1000-1010.

Tasker, J., Di, S., & Malcher-Loez, R. (2005). Rapid Central Corticosteroid Effects: Evidence for Membrane Glucocorticoid Receptors in the Brain. Integrative and Comparative Biology, 45(4), 665-671.

Ullian, M. (1999). The role of corticosteroids in the regulation of vascular tone. Cardiovascular Research, 41, 55-64.

Waldron, N., Jones, C., Gan, T., Allen, T., & Habib, A. (2013). Impact of perioperative dexamethasone on postoperative analgesia and side-effects. British Journal of Anesthesia, 1(2), 191-200.