pharmacy critical care

CRITICAL CARE PHARMACY HANDBOOK

2010

CLINICAL PHARMACY WORKING COMMITTEE (CRITICAL CARE SUBSPECIALTY)

PHARMACEUTICAL SERVICES DIVISION, MINISTRY OF HEALTH

LIST OF CONTENTS

Page

CHAPTER 1 : THE ROLE OF PHARMACIST IN CRITICAL CARE Datin Fadilah

CHAPTER 2 : PROTOCOLS

2.1 Dilution Protocols Masrahayu, Rahela, Maznuraini

2.2 DVT Prophylaxis Thong

2.3 Stress Ulcer Prophylaxis Ros Sakinah

2.4 Antibiotic Guidelines for Infections in Intensive Care Unit

2.5 Neuromuscular Blocking Agents in Critically Ill Patients Martina

2.6 Sedative Agents in Critically Ill Patients Azrina

2.7 Fluid Management in Critically Ill Patients Pn Rohana

2.8 Medication Administration through Enteral Feeding TubesNgua

2.9 Prokinetic Agents Ngua : Pls get the doc from Pn. Siti Hir and add into this file

CHAPTER 3 : DOSING

3.1 Renal Dosing Pn Nik Mah, Pn Nurdita

3.2 Liver Dosing Shafie

3.3 Special Dosing in Obese Patients Siti Hir

CHAPTER 4 : NUTRITION

4.2 Parenteral Nutrition in Critically Ill Patients Mazni

CHAPTER 5 : OTHERS

5.1 Drug Causing Haematological Disorder Irma

5.2 Poisoning Hasni

APPENDICES:

Appendix 1: Drugs that may unmask/exacerbate Myasthenia Gravis- Ain

Appendix 2: Categories of Safe & Unsafe Drugs in the Acute Porphyrias- Ain

Appendix 3: Drugs and Chemicals in Glucose-6-Phosphate Dehydrogenase Deficiency

Appendix 4 : Drug-Disease Interactions Pn Yam (Appendix 3 & 4)

2

CHAPTER 1

THE ROLE OF PHARMACIST IN CRITICAL CARE

CHAPTER 2

3

PROTOCOLS

2.1 Dilution Protocols

2.1.1 Antiarrhythmic Agents

DRUG a. Digoxin b. Adenosine

STRENGTH/UNIT 500mcg/2ml ( Lanoxin ) 6mg/2ml ( Adenocor )

STORAGE Below 25˚C, Protect from lightBelow 25ºC ( Do not

refrigerate )RECONSTITUITION Already in solution Already in solution.

STABILITY AFTER RECONSTITUITION

Immediate use is recommended NA

DILUENTS FOR INFUSION

D5%

NA

NSFor direct IV injection can be administered undiluted or diluted with a 4 fold or greater

volume of diluents. The use of less than a 4 fold volume of diluents could lead to precipitation of

digoxin.

( eg. 2ml ampoule with 500mcg in 500ml of diluents for infusion)

METHOD OF ADMINISTRATION

IV infusion (over 10-20 mins or longer-Product Information Lanoxin Injection). ( To be given at

least 2 hours - BNF) IV bolus (2 seconds )

REMARKS

Intramuscular route are not recommended. The IM route is painful and associate with muscle

necrosis.

IV bolus into central or large peripheral vein.

Rapid injection is not recommended; it may cause systemic and coronary arteriolar

constriction.

If given into an IV line, it should be injected as proximally as possible, and followed by a

rapid saline flush (5ml of NS ).

Mixing digoxin with other drugs in the same container or simultaneous administration in the

same intravenous line is not recommended.

Administer with cardiac monitoring.

REFERENCES:

1. Product information ( Lanoxin Injection). 2. Micromedex Healthcare series. 3. Pocket Guide to Injectable Drugs. Companion

to the handbook on Injectable Drugs.13 th edition. Lawrence A. Trissel. 2005.

4. British National Formulary (BNF). 55 edition. March 2008.

1. Product information Adenocor.2. Micromedex Healthcare series.3. Lexi-Comp's Drug

Information Handbook, 13th Edition, Charles F, Lacy, et al.2005

4. BNF 50, September 2005.

DRUG c. Amiodarone d. Isoproterenol Hydrochloride

4

STRENGTH/UNIT 150mg/3ml ( Cordarone ) 1mg/5ml ( Isuprel )

STORAGE Below 25ºC. 20ºC - 25ºC. Protect from light.

RECONSTITUITION Already in solution. Already in solution.


NA NA


D5%NS ( for IV bolus only )

D5% ( for IV bolus and IV infusion )


IV ( Central line )

Loading Dose : Dilute 300mg in 50 mL D5%, run over 1 hour.

Maintenance Dose : Dilute 600mg in 500mL D5% run over 23 hours.

IV bolus : dilute 0.2mg ( 1ml ) to 10 ml NS or D5%.

IV infusion : dilute 2mg ( 10ml ) in 500 ml D5%.

IM : use undiluted ( 0.2mg )

SC : use undiluted ( 0.2mg )

Intracardiac : use undiluted ( 0.02mg )

REMARKS

Do not use concentrations of less than 2 ampoules ( 300mg) in 500 ml.

Incompatible with NS.Do not add any other products to the

infusion solution.

Must be administered via the central venous route.

Concentration up to 10 times greater have been used when limitation of

volume is essential

Rate over 30mcg/min have been used in advanced stages of shock.

If heart rate exceed 110 beats /min,decrease or temporarily

discontinue the infusion.

Do not use if is pinkish or darker than slightly yellow or contain precipitate.

REFERENCES:

1. Product information Cordarone. 2. Micromedex Healthcare series. 3. Lexi-Comp's Drug Information Handbook, 13th Edition, Charles F, Lacy, et al.20054. BNF 50, September 2005.

1. Product information Isuprel.2. Micromedex Healthcare series.3. Lexi-Comp's Drug Information

Handbook, 13th Edition, Charles F, Lacy, et al.2005


DRUG a. Streptokinase

STRENGTH/UNIT 1 500 000 IU ( Streptase )

STORAGE 2ºC - 25ºC.

RECONSTITUITION 5ml NS.


24 hours at 2ºC - 8ºC.


NS

D5%


IV infusion : dilute up to 20 - 250mL NS or D5% over 60 mins.

REMARKS Avoid IM use.

REFERENCES: 1. Product information Streptase.2. Micromedex Healthcare series.3. Lexi-Comp's Drug Information Handbook, 13th

Edition, Charles F, Lacy, et al.20054. BNF 50, September 2005.

5

2.1.2 Antibiotics

DRUG a. Amikacin b. Ampicilin c. Azithromycin

6

STRENGTH/UNIT250mg/2ml

500mg/2ml

500mg 500mg (Zithromax)

STORAGEBelow 25˚C, Protect from light,

Do not freezeBelow 25˚C 15ºC - 30ºC

RECONSTITUITION Already in solution 5ml Water for Injection 4.8ml Water for Injection


NAuse within 1 hour

24 hours at room temperature

1 week in refrigerator


D5% NS

D5% 1/2 NS D5% 1/4 NS

Lactated Ringer's Injection

NSInfusion concentration

should not exceed 30mg/ml.

NS1/2NSD5%

Lactated Ringer's InjectionInfusion

concentration: 1mg/ml - 2mg/ml


IV infusion : Adults and paed over 30 to 60 minutes. Infant over

1 to 2 hours.

IM injection in large muscle mass.

IV Bolus : 3 - 5 min

IV Infusion : 30 - 60 min

IM (Dissolve 500mg in 1.8ml Water for

Injection)

IV infusion 1mg/ml over 3 hours

IV infusion 2mg/ml over 1 hour

REMARKS

Amikacin should not be mixed with other antibiotics in the same

solution and must be administered separately.

Rapid infusion may cause seizures.

Should not be given as IV bolus or IM

REFERENCES

1. Product information Amikozit.2. Micromedex Healthcare

series.3. Lexi-Comp's Drug Information



1. Product information Pamecil.

2. Micromedex Healthcare series.


1. Product information Zithromax.


3. Lexi-Comp's Drug Information Handbook, 13th Edition, Charles F, Lacy, et al.2005


DRUGd. Cefepime e. Cefotaxime f. Ceftazidime

7

STRENGTH/UNIT1gm (Maxipime) 1gm 1gm , 2gm ( Fortum )

STORAGE 15ºC - 30ºC15ºC - 30ºC , Protect

from lightBelow 25ºC, Protect

from light

RECONSTITUITION10ml Water for Injection, D5%,

NS

10ml Water for Injection 10ml Water for Injection ( both 1gm

and 2gm)




Not to be stored above 25ºC

Not longer than 24 hours

18 hours at below 25ºC



NS

D5%

Infusion concentration: 1mg/ml - 40mg/ml

NS

D5%

NS

D5%


IV infusion over 30 minutes

IM ( Dissolve 1gm in 3ml Water for Injection, D5%, 1%

Lidocaine )

IV bolus over 3-5 minutes.

IV infusion: 100ml over 50 - 60 minutes.

IM ( Dissolve 1gm in 4ml Water for Injection )


IV infusion: diluent up to 50ml over 30

minutes.

IM ( Dissolve 1gm in 3ml Water for Injection

)

REMARKSIV preferable for patient with

severe or life-threatening infection.

IV preferable for dose exceed 1gm

IV preferable for dose exceeds1gm.

May be used in peritoneal dialysis and

CAPD.

Concentration : 125 - 250mg for 2L of

dialysis fluid

REFERENCES

1. Product information Maxipime.




1. Product information Rekaxime.




1. Product information Fortum.




8

DRUGg. Ceftriaxone h. Cefuroxime i. Ciprofloxacin

STRENGTH/UNIT 500mg ( Rocephin )750mg, 1.5gm (Zinacef ) 100mg/50ml, 200mg/

100ml ( Ciprobay )

STORAGE Below 30ºC25ºC Below 25ºC, Do not

freeze

RECONSTITUITION 5ml of solvent

6ml Water for Injection for 750mg

15ml Water for Injection for 1.5gm

Already in solution



24 hours in refrigerator



NA


NS

D5%

NS

0.45%NS

D5%

NS

D5%

Ringer lactate



IV infusion: 50 to 100ml over at least 30 minutes.

IM ( Dissolve 500mg in 2ml 1% Lidocaine )


IV infusion : 50 to 100ml over 30 minutes.

IM ( Dissolve 750mg in 3ml Water for

Injection )

IV Infusion over 60 minutes

REMARKS

Neonates : IV infusion should at least 60 minutes.

Dose exceed 1gm not be given by IM.

Only use Calcium-free infusion solutions.

Slow infusion into a large vein minimize

local IV site reactions

Ciprofloxacin solution can be infused directly or mixing with compatible infusion diluents.

REFERENCES

1. Product information Rocephin.




1. Product information Zinacef.




1. Product information Ciprobay




9

DRUGj. Amoxicillin and Clavulanate Potassium

k. Cloxacillin l. Sulfamethoxazole and Trimethoprim

STRENGTH/UNIT1.2gm 500mg 480mg/5ml

STORAGE Below 25ºC.Below 25ºC. Below 30ºC, Do not

refrigerate. Protect from light.

RECONSTITUITION WFI10ml Water for

Injection.Already in solution


Solution should be made up to full infusion volume,

immediately after reconstitution.

30 minutes after reconstitution.

NA


WFI

NS

NS

D5%

NS

D5%


IV Infusion: 50-100ml over 30-40 minutes

IV Infusion complete within 4 hours of reconstitution.


IV Infusion over 20-30 minutes

IM ( Dissolve 500mg in 2.5ml Water for

Injection )

IV Infusion over 60-90 minutes

REMARKSLess stable in infusions

containing glucose, dextran or bicarbonate.

1 amp(5ml) to 125ml, 2amp(10ml) to 250ml, 3amp(15ml) to 500ml

diluent.

Fluid restriction required, 1amp(5ml) to 75ml diluent.

Infusion commenced within 30 minutes after

preparation.

Duration of infusion not exceed 1.5 hours.

REFERENCES

1. Product information Moxied-CLV

2. 2. BNF 50, September 2005.

1. Product information Monoclox

1. Product information DBL2. Micromedex Healthcare

series.3. Lexi-Comp's Drug



10

DRUGm. Fusidic Acid n. Gentamicin o. Imipenem with cilastatin

STRENGTH/UNIT500mg ( Fucidin) 80mg/2ml 500mg

STORAGE 15 - 20ºC Below 25ºC 15 - 30ºC

RECONSTITUITION10ml of buffer solution

provided.

Already in solution. 10ml of diluent for infusion


NA

NA 4 hours at room temperature



NS

D5% **

NS

D5%

NS

D5%

D10%

D5%NS

Mannitol 5% and 10%


IV Infusion: 250 -500ml over 2-4 hours

IV infusion : 100-200ml over 30 minutes.

IV infusion : 500mg in 100m diluent for infusion. Rate depend

on dose.

Dose ≤ 500mg over 20 - 30 minutes , ≥ 500mg over 40 -60

minutes.

REMARKS

Give through central venous line to minimize venospams

and thrombophlebitis.

If superficial vein used, infusion over 6 hours.

Never be injected undiluted.

Must not be given intramuscularly or subcutaneously.

** Precipitation may occur in infusion solution pH below 7.4

( more acidic samples of dextrose 5% )

For extended-interval doses, an infusion period of 60 minutes recommended.

Administer other antibiotic at least 1 hour before or after gentamycin.

Must use the same diluent for reconstitution and as infusion

solution.

Reconstitution of Tienam : add ≈ 10 ml of appropriate infusion

solution to vial. Shake well and transfer the suspension to infusion solution container. Repeat with additional 10ml infusion solution to ensure

complete transfer of vial contents to infusion solution. Resulting

mixture should be agitated until clear.

REFERENCES

1. Product information Fucidin.



1. Product information Garasent.




1. Product information Tienam.

2. 2. Micromedex Healthcare series.



DRUGp. Meropenem q. Metronidazole r. Linezolid

STRENGTH/UNIT 500mg , 1gm ( Meronem ) 500mg/100ml 600mg/300ml ( Zyvox)

11

STORAGE Below 30ºC15 - 30ºC. Protect from light 15 - 30ºC. Protect from

light.Keep in overwrap until ready to use.

RECONSTITUITION500mg - 10ml , 1gm - 20ml of

NS or D5%

Already in solution Already in solution


NS : 2 hours at RT, 18 hours in refrigerator.

D5% : 1 hours at RT, 8 hours in refrigerator.

NA NA


NS

D5%

NA NA


IV bolus : 10ml of WFI per 500mg over 5 minutes.

IV infusion : 50-200ml over 15 - 30 minutes.

IV infusion : 100ml over 20 - 30 minutes.

IV infusion : 30 -120 minutes.

REMARKSRecommended to use freshly

prepared solution of Meropenem.

Avoid contact between drug and aluminium in infusion set.

Do not mix or infuse with other medications.

Yellow color of the injection may intensify over time without

affecting potency.

REFERENCES

1. Product information Meronem.




1. Product information .2. Micromedex

Healthcare series.3. Lexi-Comp's Drug




DRUGs. Polymixin B t. Sulbactam

Sodium/Ampicilin u. Sulbactam

Sodium/Cefoperazone

12

Sodium Sodium

STRENGTH/UNIT500,000 units 1.5gm 1gm ( Sulperazon)

STORAGE 15 - 30ºC Below 25ºC Below 25ºC

RECONSTITUITION500mg - 10ml , 1gm - 20ml of

NS or D5%

3.2ml Water for Injection 3.4ml Water for Injection, NS, D5%


72 hours in refrigerator.

Stability at 25ºC and 4ºC depends on concentration of

solution prepared. For IM administration, used within 1

hour of reconstitution.

Stability at 25ºC and 4ºC depends on concentration of

solution prepared. For IM administration, used within 1

hour of reconstitution.


D5% Water for Injection

NS

D5%

Lactated ringer

Water for InjectionNS

D5%



IM : 2ml Water for Injection, NS, 1% procaine solution.

Intrathecal : 10ml physiological solution

IV bolus : slowly over 10 -15 minutes


IM : 3.2ml Water for Injection or 2% Lidocaine

IV bolus : over minimum 3 minutes

IV infusion : 20ml over 15 - 60 minutes.

IM : 3.2ml Water for Injection, and further diluted with 2%

Lidocaine.

REMARKS

Intrathecal is for meningeal infection.

May cause extravasation. Monitor the IV site, rotate infusion site frequently.

IV infusion : dilute using diluents (NS,Water for Injection, Lactated ringer) to a maximum concentration of 45mg/ml.

IV infusion : dilute using D5% to a maximum concentration of 30mg/ml. Administer within 2 hours.

Must use the same diluent for reconstitution and as infusion

solution.

REFERENCES



1. Product information Easyn.



1. Product information Easyn.2. Micromedex Healthcare

series

DRUGv. Piperacillin / Tazobactam w. Vancomycin

13

STRENGTH/UNIT4.5gm ( Tazocin ) 500mg

STORAGE Below 25ºC Below 25ºC. Protect from light.

RECONSTITUITION 20ml of Water for Injection, NS10ml Water for Injection.




Freshly prepared prior to use.


Water for Injection

NS

D5%

NS

D5%


Slow Iv injection : 3 - 5 mins

IV Infusion :- 50 ml - 150ml for 20 - 30 mins.

IM : 2.25g with 4ml WFI

IV Infusion : dilute with infusion fluid up to 5mg/ml over 1 hour.

REMARKS

IV infusion : maximum infusion volume with WFI is 50ml.

During IV infusion, discontinue primary infusion solution.

IV infusion concentration can increased to 10mg/ml in fluid restriction, but increased risk of infusion-related effects.

Rate of administration not exceed 10mg/min for doses over 500mg.

Use continuous infusion if intermittent not feasible.

If Red-man syndrome appears, slow infusion rate to 1½ - 2 hours and increase dilution volume.

REFERENCES

1. Product information Tazocin.2. Micromedex Healthcare series.3. Lexi-Comp's Drug Information



1. Product information Vancotex.2. Micromedex Healthcare series.3. Lexi-Comp's Drug Information


4. BNF 50, September 2005

2.1.3 Antifungal

14

DRUGa. Amphotericin B b. Fluconazole c. Voriconazole

STRENGTH/UNIT500mg ( Fungizone) 100mg/50ml ( Diflucan ) 200mg ( Vfend)

STORAGE

Stored in refrigerator

Protected against exposure to light

Below 30ºC, Do not refrigerate.

15-30ºC

RECONSTITUITION 10ml Water for InjectionAlready in solution 19ml Water for Injection.




NA 24 hours at 2- 8ºC


D5%

Infusion concentration is 0.1mg/ml

NS

Ringer's Solution

Hartmann's solution

D20%

NS

D5%

Compound Sodium Lactate


Slow Intravenous infusion : 2 - 6 hours

IV Infusion over 1-2 hours IV infusion: dilute to concentration of 0.5-5mg/ml

over 1 -2 hours.

REMARKS

Test dose : 1mg in 20ml D5% , administer over 20-30 minutes

Do not reconstitute with NS

Begin infusion immediately after dilution and protect from light.

Infusion rate do not exceed 200mg/hr

Fluconazole is formulated in 0.9% sodium

chloride solution, each 100mg containing 7.5mmol

of sodium.

Patient requiring sodium or fluid restriction, consideration given to rate

of fluid administration.

Maximum rate :3mg/kg/hour.

REFERENCES

1. Product information Fungizone.




1. Product information Diflucan.




1. Product information Vfend.

2. 2. Micromedex Healthcare series.



2.1.4 Antiviral

15

DRUG Acyclovir

STRENGTH/UNIT250mg

STORAGE Below 25˚C, Protect from light

RECONSTITUITION 10ml Water for Injection

STABILITY AFTER RECONSTITUITION12 hours at room temperature

Do not refrigerate


D5%

NS

Infusion concentration should be approximately 7mg/ml or less.


IV infusion (over 1 hour)

REMARKS

Should not be given intramuscularly, subcutaneously, locally or intra-ocularly.

Rapid infusion is not recommended to avoid possible renal tubular damage.

REFERENCES

1. Product information Klovireks-L.2. Micromedex Healthcare series.3. Lexi-Comp's Drug Information Handbook, 13th Edition,

Charles F, Lacy, et al.20054. BNF 50, September 2005.

2.1.5 Anticoagulants

16

DRUGHeparin Fondaparinux ( Arixtra ) Enoxaparin Sodium

( Clexane )

STRENGTH/UNIT1000 IU/ml , 5000 IU/ml.

2.5mg/0.5ml 40mg/0.4ml , 60mg/0.6ml

STORAGE15ºC - 30 ºC. Protect from

light.

Below 25ºC. Do not freeze. Below 25ºC.

RECONSTITUITION Already in solution.Already in solution. Already in solution.


NA NANA


NS

D5%

NA NA


IV infusion : minimum volume 250ml D5%.

Subcutaneous.

Subcutaneous. Subcutaneous.

REMARKS

Should be avoided in children below 2 years old and not

used in neonates.

Do not administer IM due to pain, irritation and hematoma

formation.

Must not be administered by IM.

Do not mix with other injections or infusions.

Prefilled syringe is designed with an automatic needle protection system to

prevent needle stick injuries.

Do not administer by IM route.

Pre-filled syringes are ready-to-use.

REFERENCES

1. Product information Heparinol.




1. Product information Arixtra.




1. Product information Clexane.




2.1.6 Antiepileptics

17

DRUGa. Phenytoin b. Phenobarbitone c. Sodium Valproate

STRENGTH/UNIT250mg/ Dilantin 200mg/ml 400mg (Epilim)

STORAGEBetween 15°C to 30°C (Do not

freeze)

Protect from light Below 25°C

RECONSTITUITION Already in solutionAlready in solution Reconstitute with solvent

provided


NA NA24 hours at 2°C to 8°C


NS

Dilute with 50-100ml NS to make a 1mg/ml solution. Max

concentration is 10mg/ml.

NS

D5%

IV infusion: Dilute with at least an equal volume of

fluid.

NS

D5%

Dilute with at least 50ml of NS or D5%


IV: Rate not exceeding 50mg/minute. Sensitive patient eg. Elderly with cardiovascular condition should receive more

slowly (eg. 20mg/minute)

Recommended to give through a 0.22-0.5 micron in-line filter

due to high potential of precipitation.

Finish infusion within 1 hour after mixing the solution.

IV: Over 3 to 5 minutes. Not to exceed 60mg/min.

IV infusion: eg. Emergency in status epilepticus

IM

S/C

IV infusion: Administer as 60 minutes infusion. Not to

exceed 20mg/min

IV: (Loading dose) single doses up to 15mg/kg has

been administered as rapid infusion over 5-10 minutes.

REMARKS

IM administration is approved but not recommended due to

erratic absorption

The solution is vesicant. Avoid extravasation.

Avoid intra-arterial injection Divide total daily dose if exceeds 250 mg/day

REFERENCES

1. Product information (Dilantin Injection).2. Micromedex Healthcare

series.3. Britisn National Formulary

564. Lexi-Comp's Drug


1. Product information (Phenobarbital Sodium Injection).



1. Product information (Epilim Injection).



DRUGd. Diazepam e. Thiopentone (Thiopental)

18

STRENGTH/UNIT10mg/2ml (Valium) 500 mg (Pentotex)

STORAGE Room temperatureBelow 25°C

RECONSTITUITION Already in solution


NA

Use immediately. Discard any unused portion after 24 hours.


Recommended to give alone

But stable in NS, D5%. Use immediately after mixing.

Dilute 10 mg with 200-250ml NS or D5%

WFI

NS

D5%


IM

IV injection: Rate not exceeding 5mg/min

IV infusion: Rate not exceeding 5mg/min

IV slow: Over 20 to 40 seconds of 2.5% solution. (occasionally as 0.5%

solution)

IV infusion: as 0.2-0.4% solution.

REMARKS

Infusion rate exceeding 5mg/ min may cause apnea, venous thrombosis,

thrombophlebitis and hypotension. Avoid extravasation.

Thiopental sodium preparation may be given rectally as solution or

suspension

REFERENCES

1. Product information ( Diazepam Injection).

2. Micromedex Healthcare series.3. Britisn National Formulary 564. Lexi-Comp's Drug Information


1. Product information ( Pentotex Injection).

2. Micromedex Healthcare series.3. Lexi-Comp's Drug Information


2.1.7 Antihypertensive

19

DRUGa. Frusemide b. Isosorbide Dinitrate

STRENGTH/UNIT20mg/2ml 10mg/10ml

STORAGE

Below 25˚C. Protect from light. Do not use if solutions yellow in colour. Refrigeration

may result in precipitation. However, resolubilization at room temperature or

warming may be performed without affecting the stability of frusemide.

Below 30˚C.

RECONSTITUITION Already in solutionAlready in solution


24 hours. Protect from light.24 hours.


NSLactated Ringer's

D5%

.

NS

D5%

Recommended concentration: 0.1mg/ml ( 10mg/amp in 100 ml

diluents for infusion) OR 0.2 mg/ml ( 10mg/amp in 50 ml diluents for

infusion).


IM

Direct IV injection (slowly over 1-2 mins)- for doses<120mg

IV infusion or continuous IV infusion: rate of infusion should not exceed 4mg/min.

Continuous IV infusion.

It should always be administered as an intravenous admixture and should

never be injected directly.

1-10mg/hr

REMARKS

Unstable in acidic media but very stable in basic media.

Isosorbide dinitrate adsorbed to some extent by PVC infusion containers.

Preferably use glass or polyethylene container.

REFERENCES

1. Micromedex Healthcare series.2. Pocket Guide to Injectable Drugs.

Companion to the handbook on Injectable Drugs.


4. Drug Information Handbook. 13th edition. 2005-2006. Lexi-comps.

5. Product information Frusemide Injection - AKOSET®. (Duopharma).

1. Micromedex Healthcare series.2. British National Formulary (BNF).

55 edition. March 2008.3. Product information Isosorbide

Injection - Isoket®. (Schwardz Pharma).

DRUGc. Labetalol d. Hydralazine

STRENGTH/UNIT 25mg/5ml 20mg

20

STORAGE Below 30˚C. Protected from light.Below 30˚C. Protected from light.

RECONSTITUITION Already in solutionDissolve with 1ml water for injection


Within 24 hours.

Within 24 hours.


NS

D5%

Recommended concentration: 1mg/ml. Suggested volume: 200ml (200mg/40ml

labetalol injection into 160ml of compatible diluent )

Slow IV Injection: 10ml NS

IV Infusion: 500ml NS or Ringer's solution


IV bolus injection - slowly over 2 minutes. May repeat 40-80mg at 10 min intervals, up

to 300mg total dose.

Continuous IV infusion - initial rate of 2mg/min, titrate to response up to 300mg

total dose.

IM, Slow IV Injection over 1 min. 10-20mg 4-6 hours as needed.

IV Infusion: Initially 200mcg-300mcg/min; maintenance 50-

150mcg/min

REMARKS

Incompatible with Sodium Bicarbonate and alkaline solution. Precipitation may occur.

D5% decrease stability of Hydralazine

REFERENCES


Companion to the handbook on Injectable Drugs.


4. Product information Labetalol Injection (Trandate®).

5. Drug Information Handbook. 13th edition. 2005-2006. Lexi-comps.

1. Micromedex Healthcare series.2. British National Formulary (BNF).

55 edition. March 2008.3. Product information Hydralazine

Injection (Apresoline®).4. Drug Information Handbook. 13th

edition. 2005-2006. Lexi-comps.

2.1.8 Gastrointestinal

21

DRUG a. Ranitidine b. Esomeprazole

STRENGTH/UNIT50mg/2ml

STORAGEBelow 30˚C, Protect from light. Solution is a clear,

colorless to yellow solution; slight darkening does not affect potency.

Below 30˚C. Protect from light. However, can be stored exposed to normal in door light outside the box for up to 24 hours.

RECONSTITUITION Already in solution

5ml of NS (The degradation of reconstituted solution is highly pH

dependent. It must only be reconstituted in the specified volume of NS).


Within 48 hours at room temperature.

Reconstituted solution for injection: With 5ml of NS and store within 12 hours at room temperature. Refrigeration is not

required.

Reconstitution solution for infusion: With 5ml of NS, Lactate Ringer's, D5% then

further dilute to final volume of 50ml solution. Storage for 6hours (D5%) and 12 hours (NS and Lactate Ringer's) in room

temperature. Refrigeration is not required.


- D5%- NS- Intermittent bolus injection: dilute to maximum

of 2.5mg/ml- Intermittent infusion: dilute to maximum of

0.5mg/ml

- NS- Lactate Ringer's- D5%


- IM: Injection is administered undiluted.- IV: must be diluted. May be administered IVP or

IVPB or continuous IV infusion.- Direct IV injection/IVP: 50mg diluted to a total of 20

ml with compatible infusion solution and given over at least 5 mins. (Administration not greater than 4ml/min.)

- Intermittent infusion/ IV PB : 50mg added to 100ml of compatible solution and administer over 15-20 mins. (Administration not greater than 5-7ml/min).

- Continuous IV infusion: 150mg diluted in 250ml of compatible IV solution and infused at 6.25mg/hr for 24hrs

IV injection: over a period of at least 3 mins.

IV infusion: over a period of 10-30 mins.

REMARKS

The stability of esomeprazole in aqueous solution is strongly dependent upon pH. The rate of degradation increase in response of decreasing pH.

REFERENCES

1. Product information Gastril Injection. (Duopharma).2. Micromedex Healthcare series3. Pocket Guide to Injectable Drugs. Companion to

the handbook on Injectable Drugs. 13 th edition. Lawrence A. Trissel. 2005.

4. Drug Information Handbook. 13th edition. 2005-2006. Lexi-comps


1. Product information Nexium Injection. (AstraZeneca).

2. Micromedex Healthcare series.3. British National Formulary (BNF). 55

edition. March 2008.

2.1.9 Inotropes

22

DRUG a. Adrenaline b. Dobutamine

STRENGTH/UNIT1.8mg/1ml 250mg/20ml

STORAGE 15˚C - 30˚C. Protect from light.Below 25˚C, Protect from light



Within 24hrs at room temperature and refrigerate. Oxidation turns drug pink, then a brown color; solution should not be used if they are discoloured or contain a

precipitate.

Within 24 hours. A pink discoloration may form due to slight oxidation of the drug but

no significant drug loss within recommended times. If refrigerated,

solution can be stored up to 48 hours.


IV: NSIV:D5%

Recommended: IV infusion: 1mg in 250ml of NS

Intratracheal: dilute in NS or WFI. Absorption is greater with distilled water, but causes

more adverse effects on PaO2.

D5%NS

Must be diluted to a concentration of not more than 5mg/ml before use. If higher

concentration is used eg 500mg dobutamine in 50 cc diluents of infusion. It

should be protected from light.

Recommended: ( eg. 250mg-500mg of dobutamine in 500 cc diluents of infusion)


SC, IM, slow IV injection, IV infusion, intracardiac injection, intratracheal injection.

IM injection into the buttocks should be avoided.

IV infusion (mcg/min): 1-10mcg/min

IV infusion (mcg/kg/min)

REMARKS

Central line administration if IV infusion. Avoid extravasation.

Incompatible with bicarbonate solution and other alkaline solutions.

Do not add to 5% sodium bicarbonate or other strongly alkaline solution.

Should not be used in conjunction with other agents or diluent containing sodium

bisulphites and ethanol.

REFERENCES

1. Product information Adrenaline Injection BP. (Duopharma)

2. Micromedex Healthcare series.3. Pocket Guide to Injectable Drugs. Companion to

the handbook on Injectable Drugs. 13 th edition. Lawrence A. Trissel. 2005.



1. Product information Mobitil Injection. (Duopharma)


Companion to the handbook on Injectable Drugs. 13 th edition. Lawrence A. Trissel. 2005.



23

DRUG c. Dopamine d. Noradrenaline

STRENGTH/UNIT200mg/5ml 4mg/4ml

STORAGE Below 25˚C. Protected from lightBelow 25˚C, Protect from light



Within 24 hours. Do not use the injection if it is darker than slightly yellow or discoloured in any

other way.

Within 24 hours with protection from light. Solution gradually darkens with exposure to light or air. Do not use if it is discoloured or

contains a precipitate.


D5%

NS

Injection should be diluted before administration.

Recommended: 200mg or 400mg of dopamine in 250ml or 500ml diluents for infusion. (Micromedex, Handbook of Injectable Drugs). Max concentration:

3.2mg/ml (BNF)

D5%

D5%in NS

NS alone is not recommended.(Product Information Levophed Injection). (Lack of

oxidation protection).

Must be diluted before infusion. Recommended:

a. 4-8mg in 250-1000ml of diluents for infusion. ( Micromedex). (Handbook of

Injectable drugs). b. 4mg in 50ml of diluents for infusion. (BNF)



Do not add dopamine in any alkaline solution. It is inactivated in alkaline solution. Incompatible with

bicarbonate


REMARKS

It is also sensitive to oxidizing agent and iron salts.

Avoid extravasation. Administer into the large vein.

IV infusion must be given into a large vein. Avoid extravasation.

Avoid contact with iron salts, alkalis, or oxidizing agents.(Product Information

Levophed).

Incompatible with bicarbonate solution.

REFERENCES

1. Product information Loxin Injection (Duopharma)

2. Micromedex Healthcare series.3. Pocket Guide to Injectable Drugs. Companion

to the handbook on Injectable Drugs. 13 th edition. Lawrence A. Trissel. 2005.



1. Product information Loxin Injection (Duopharma)


Companion to the handbook on Injectable Drugs. 13 th edition. Lawrence A. Trissel. 2005.



2.1.10 Miscellaneous

24

DRUGa. Parentrovite b. Potassium chloride c. Pralidoxime

STRENGTH/UNIT5ml x 2 ampoules (1 pair)

(P-Trovite)10% W/V, 10ml 500mg/20ml (Pampara)

STORAGEProtect from light Below 25˚C Below 28˚C, Protect

from light,

RECONSTITUITIONAlready in solution Already in solution Already in solution


N/A NA NA


Compatible with commonly used

intravenous solutions

NS (for the treatment of hypokalemia)

Maximum concentration recommended for peripheral

line is 6g/L. (can dilute up to 3 gm KCL in 500ml NS).

For fluid restricted patient with central line, maximum

concentration recommended is 11g/L.

For IV intermittent: as 5% to 10% solution (the

product is 2.5% in strenght, so can be

readily administered)

For IV infusion: Dilute in 100ml NS


The content of each ampoule (No 1 and No 2) should be mixed prior to

injection.

Although compatible with commonly used

intravenous solutions, it is recommended

parentrovite is given by slow injection



IV intermittent : over 5 to 10 minutes.

IIV infusion: over 15 to 30 minutes

S/C

IM

REMARKS

Use with caution in patients with cardiac disease

Maximum recommended daily

dose is 12 gm

REFERENCES

Product information (P-trovitel).

1. Product information (Potassium chloride 10%

W/v 10ml).2. Micromedex Healthcare

series.3. British National

Formulary 56.4. Lexi-Comp's Drug


1. Product information (Pampara injection).


3. British National Formulary 56.


DRUGd. N-Acetylcysteine e. Piracetam f. Desmopressin

25

STRENGTH/UNIT

2gm/10ml

5gm/25ml

1gm/5ml 4mcg/ml (Minirin)

STORAGEBelow 25˚C, 15°C to 25°C 2°C to 8°C

RECONSTITUITIONAlready in solution Already in solution Already in solution


NA NA NA


D5% (Preferable)

NS

PCM poisoning: 150mg/kg in 200ml, then 50mg/kg in

500ml followed by 100mg/kg in 1000ml.

NS

IV infusion: Dilute in 50ml NS


PCM poisoning: IV infusion of 150mg/kg over 15 to 60 minutes, then IV infusion of

50mg/kg over 4 hours followed by IV infusion of 100mg/kg over 16 hours.

Prevention of radiocontrast-induced renal dysfunction

(unlabeled use): IV infusion

S/C

IM

IV infusion over 15 to 30 minutes

REMARKS

For PCM poisoning patient less than 40kg and those

requiring fluid restriction, the volume of diluent could be

adjusted as needed to avoid fluid overload.

NA

REFERENCES

1. Product information (Hidonac N-Acetylcysteine).


3. Britisn National Formulary 56


1. Product information (Nootropil Injection).


1. Product information ( Minirin injection).


3. Micromedex Healthcare series


DRUGg. Haloperidol h. Calcium gluconate i. Dantrolene

STRENGTH/UNIT 5mg/ml 10ml 20 mg (Dantrium)

26

STORAGEBelow 25°C. Protect from

light.Below 30°C. Below 30 °C. Do not

refrigerate. Protect from light.

RECONSTITUITIONAlready in solution Already in solution

60ml WFI (shake until solution is clear)

If necessary transfer individual vials into a

larger volume sterile IV plastic bag. Do not transfer into glass

bottle. Precipitation may occur.


NA NA Use within 6 hours at room temperature.


D5%

IV infusion : Dose of 0.5mg-100mg in 50ml-100ml D5%

D5%

NS

IV infusion: Dilute to a maximum concentration of 50mg/ml (eg. 1gm in 20ml)

NOT to be mixed with other intravenous

infusions.


IM

IV bolus

IV infusion of 50ml-100ml diluted solution with the rate

of 3-25mg/hour

IV slow bolus: Maximum rate of 50mg/minute

IV infusion: The diluted solution of 50mg/ml to be

infused over 1 hour

IV push: In malignant hyperthemia crisis

IV infusion: Over 1 hour in prevention of

malignant hyperthemia

REMARKS

Decanoate form should never be administered IV

(IM only)

Has rarely been given by IM and S/C, but not

recommended because the risk of tissue necrosis.

Solution is high pH and there is possibility for tissue necrosis, avoid

extravasation.

REFERENCES

1. Product information (Manace injection 5mg)




1. Product information (Calcium gluconate injection)




1. Product information (Dantrium Intravenous)


3. Lexi-Comp's Drug Information Handbook,

DRUGj. Mannitol k. Potassium dihydrogen

phosphatel. Human Normal

Immunoglobulin

27

STRENGTH/UNIT20% (100gm/500ml) 10mmol/10ml (1.361g) Intragam 3g (50ml)

STORAGEBetween 15°C to 30°C. Do

not freeze.

Below 25°C. 2°C to 8°C. Do not freeze. Once removed from

refrigeration, store below 25°C and use within 3

months

RECONSTITUITIONAlready in solution. Already in solution Already in solution


NA NA NA


NA

D5%

NS

Must be diluted before use

IV doses should be incorporated into patient's

maintenance IV fluid. Intermittent IV infusion should

be reserved for severe depletion patient under ECG

monitoring.

Can be administered undiluted

Or can be diluted with up to 2 parts of NS or D5%


Test dose (to assess adequate renal function): IV

over 3-5 minutes

IV infusion (eg. Cerebral edema or increased

intraocular pressure): over more than 30 minutes

IV infusion, slow: administer over 6 to 12 hours. Minimum

infusion time is 4 hours.

IV infusion: can be given undiluted. Start infusion at the

rate of 1ml/minute. After 15 minutes, the rate can be gradually increased to a

maximum of 3 to 4ml/minute. Reducing the rate in elderly

and in patients with pre-existing renal disease should

be considered.

REMARKS

Use a filter when infuse mannitol solution of

concentration of 20% or more.

Incompatible with calcium or magnesium containing

solutions.

Infusion which is too rapid may cause flushing and

changes in heart rate and blood pressure. Prolonged

administration (over 6 hours) using larger dose (greater than 0.4g/kg) may result in

thrombophlebitis at the infusion site.

REFERENCES



1. Product information (Potassium Dihydrogen Phosphate injection)


Product information (Intragam).

28

DRUGm. Hydrocortisone n. Methylprednisolone o. Dexamethasone sodium

phosphate

STRENGTH/UNIT

100mg 1gm (Solu-Medrol) 8mg/2ml

STORAGEBelow 25˚C Below 25°C Below 25˚C, Protect from light.

RECONSTITUITION

2ml WFI Reconstitute with the diluent (15.6ml

WFI+ Benzyl alcohol) providedAlready in solution

STABILITY AFTER RECON-

STITUITION

Use immediately after reconstitute

48 hours at temperature below 25°CNA


D5%

NS

IV infusion: Reconstituted solution is then further

diluted to 1mg/ml

D5%

NS

D5%

NS

IV infusion: Dilute content of vial with 50-100ml of diluents

Diluted solution is stable for 24 hours in room temperature or 2

days in fridge

METHOD OF ADMINISTRATI

ON

IM

IV injection: Over 30 seconds to several

minutes depending on the dose

IV infusion: Over 20 to 30 minutes

IM

IV bolus: The reconstitued solution can be given undiluted. Preferred for

emergency. Only for low dose (<125mg) - over 5 to 15 minutes and moderate dose (below 250mg) - over

15 to 30 minutes. Maximum concentration: 125mg/ml

IV infusion : Dilute the reconstitued solution with D5% or NS. For high dose (more than 250mg) - over at

least 30 minutes. Dose of more than 1 gm - over 1 hour

Special notes: For acute spinal cord injury, start with IV bolus. After 45

minutes pause, followed by IV infusion of 5.4mg/kg/hour for 23

hours.

IM

IV injection: Administer as IV bolus over 5-10 minutes or can be administered through tubing

IV infusion: Of diluted solution

REMARKS none Rapid IV bolus injection is associated with high incidence of

perianal discomfort

REFERENCES

1.Product information ( Stricort 100mg)

2.Lexi-Comp's Drug Information Handbook, 12th Edition, Charles F, Lacy, et al.2003

3.British National Formulary 56

1. Product information (Solumedrol)2. Lexi-Comp's Drug Information


3. Britisn National Formulary 564. Micromedex Healthcare series.

1. Product information (Penatone Injection).2. British National Formulary 563. Micromedex Healthcare series.4. Lexi-Comp's Drug Information


29

DRUGp. Vitamin K (Phytomenadione)

q. Tranexamic acid r. Sodium bicarbonate

STRENGTH/UNIT10mg/ml (Kisan) 1g/10ml 8.4% (10mmol/10ml)

STORAGEBelow 25˚C. Protect from light. Between 15˚C to 30˚C. Protect

from light.Below 25˚C. Protect from

light.

RECONSTITUITIONAiready in solution Aiready in solution

Aiready in solution


NA NA NA


NS

D5%

NS

D5%

WFI

NS

D5%

S/C: Dilute to isotonicity (1.5%) by adding 1ml of 8.4% solution into 4.6ml WFI or NS

or D5%


IM

Slow IV: Reserved for potentially fatal haemorrhage. Maximum per dose-20 mg and maximum total doses - 40mg.

IV injection at rate not exceeding 1mg/minute.

IV infusion

S/C

Slow IV: Do not inject more rapidly than 1ml/min

IV continous infusion: eg. Local fibrinolysis - 25 to 50mg/kg over 24 hours or post operation on heart -1mg/kg/hour for 5 to 6

hours.

IV: of undiluted solution. Rate not exceeding 10mEq/minute (equivalent to 10ml/minute)

IV: of diluted solution

S/C: Of diluted to 1.5% solution.

REMARKS

Injectable solution may be given orally, undiluted.

Sodium bicarbonate solution 8.4% contains 1 mEq/ml

bicarbonate (and sodium)

REFERENCES

1. Product information ( Kisan 10mg/ml)

2. British National Formulary 56



1. Product information ( Tren Injection)

2. British National Formulary 563. Lexi-Comp's Drug Information


4. Micromedex Healthcare series5. Martindale 32nd Edition

1. Product information ( Sodium Bicarbonate 8.4% injection)



30

DRUGs. Magnesium Sulphate t. Nimodipine

STRENGTH/UNIT2.465 g/ 5ml 10mg/50ml (Nimotop)

STORAGEBelow 25˚C. Below 30˚C.

RECONSTITUITIONAiready in solution Already in solution


NA N/A


NS

D5%

Lactated Ringer

IV: 1 ampoule (5ml) diluted with at least 7.5ml of compatible solution

IM: dilution is not required but each ampoule (5ml) can be diluted with 5ml of

compatible solution.

Solution is for direct infusion. See Method Of Administration


IM: of undiluted or diluted solution.

IV bolus: of diluted solution at rate not exceeding 150mg/minute

IV infusion: rate not exceeding 2g/hour

500mg MgSO4 = 4.06 mEq Mg = 49.3 mg elemental Magnesium

IV infusion: administer as continous IV infusion via CENTRAL catheter using infusion pump. It

should be given via three-way stopcock together with 40ml/hr of either NS or D5% or

Lactated Ringer.

Solution must not be added to an infusion bag or bottle.

Nimodipine is absorbed by PVC so the PE tube provided must be used.

REMARKS

Mannitol, human albumin or blood are suitable for co-infusion

REFERENCES

1. Product information ( Magnesium Sulphate Concentrated Injection)



4. Micromedex Healthcare series5. Martindale 32nd Edition

1. Product information (Nimotop)2. British National Formulary 56.

31

2.1.11 Muscle Relaxant

DRUGa. Suxamethonium b. Rocuronium c. Pancuronium

STRENGTH/UNIT100mg/ 2ml

25mg/ 2.5 ml (Esmeron)

50mg/ 5ml

4mg/ 2ml (Pavulon)

STORAGE

Between 2°C to 8°C. Protect from light

Multiple-dose vial solution are stable at room temperature for 14

days

Between 2°C to 8°C. Protect from light.

Between 2°C to 8°C.


Already in solution.


NA NA N/A


NS

D5%

Normally prepared as 1-2mg/ ml solution

NS

D5%

WFI

Dilute to a concentration of 0.5mg/ ml or 2mg/ml. Up to

5mg/ml.

NS

D5%


IM: Total dose not exceeding 150mg

IV injection: over 10 to 30 seconds. Without dilution

IV infusion: Ranged from 0.5 mg-10mg/ minute. Normally at the rate

of 2.5-4.3mg/ minute.

IV bolus: of indiluted

IV infusion

IV bolus: of the undiluted solution.

Can be administered through the line of a

running infusion.

IV infusion.

REMARKS

Suxamethonium Chloride = Succinylcholine chloride

If stored at room temperature, rocuronium should be used

within 60 days

REFERENCES

1. Product information ( Suxamethonium Chloride - Fresinius Injection).




1. Product information (Rocuronium bromide

Injection - Esmeron).2. British National

Formulary 563. Lexi-Comp's Drug



1. Product information (Pavulon).



32

DRUGd. Atracurium e. Vecuronium

STRENGTH/UNIT

25mg/ 2.5ml

50mg/ 5ml

4mg (Norcuron)

10mg

STORAGEBetween 2°C to 8°C. Protect from light. Below 25°C. Protect from light.

RECONSTITUITIONAlready in solution

Norcuron 4mg: with 1ml WFI (to make 4mg/ml solution) or with 4ml WFI (to

make1mg/ml solution)

Norcuron 10mg: with 5ml WFI (to make 2mg/ml solution) or with 10ml WFI (to make

1mg/ml solution)


NA12 hours at 15°C to 25°C. But product

leaflet recommends to discard any unused portion.


NS

D5%

Solution may be prepared in a range of 0.2mg/ml to 5mg/ml. Common as 0.2mg/ml

and 0.5mg/ml.

Stability: 24 hrs in NS, 8 hrs in D5% at 30°C

D5%

NS

Dilute reconstituted vial to 0.1-0.2mg/ml.


IV injection: of indiluted

IV infusion

IV bolus: of reconstituted solution

IV infusion: of diluted solution. Concentration of 1mg/ml may be used for

IV infusion in fluid-restricted patient

REMARKS

Not for IM due to tissue irritation.

REFERENCES

1. Product information ( Atralex Injection).2. British National Formulary 563. Lexi-Comp's Drug Information



1. Product information (Norcuron).2. British National Formulary 563. Lexi-Comp's Drug Information


33

2.1.12 Respiratory

DRUGa. Potassium chloride b. Pralidoxime c. Salbutamol

STRENGTH/UNIT10% W/V, 10ml

500mg/20ml (Pampara) 0.5mg/ml

5mg/5ml

STORAGEBelow 25˚C

Below 28˚C, Protect from light,Below 30˚C, Protect

form light


Already in solution


NA NA NA


NS (for the treatment of hypokalemia)

Maximum concentration recommended for peripheral

line is 6g/L. (can dilute up to 3 gm KCL in 500ml NS).



For IV intermittent: as 5% to 10% solution (the product is 2.5% in strenght, so can be

readily administered)

For IV infusion: Dilute in 100ml NS

NS

D5%

WFI

WFI can be used to dilute Ventolin 0.5mg/ml

to facilitate injection

IV infusion: Dilute 5mg/5ml salbutamol in 500ml Ns or D5% to produce 10mcg/ml

solution.


IV infusion (Maximum rate is 3 gm/hour)

IV intermittent : over 5 to 10 minutes.

IIV infusion: over 15 to 30 minutes

S/C

IM

S/C

IM

IV slow bolus

IV infusion

REMARKSUse with caution in patients

with cardiac diseaseMaximum recommended daily

dose is 12 gm

REFERENCES

1. Product information ( Potassium chloride 10% W/v 10ml).




1. Product information (Pampara injection).




1. Product information (Ventolin injection).



34

DRUGd. Terbutaline e. Aminophylline

STRENGTH/UNIT0.5mg/ml

250mg/5ml

STORAGEBelow 25°C

Below 25°C



N/A NA


D5%

NS

For premature labour: Dilute in D5% to a concentration 100mcg/ml and give

via syringe pump. If pump not available, dilute to a concentration of

10mcg/ml.

NS

D5%

Dilute with NS to a concentration of 1mg/ml. Max concentration is 25mg/ml


S/C: For bronchodilation.

IV infusion: For tocolysis acute (unlabeled used), duration of infusion is

at least 12 hours.

IV slow injection

IV infusion: LD: Over 20-30 minutes. Rate not exceeding 25mg/minute.

REMARKS

Dose of aminophylline = dose of theophylline/ 0.8

REFERENCES

1. Product information (Terbutaline injection- Baltic).


3. British National Formulary 56.4. Lexi-Comp's Drug Information


1. Product information (Aminophyllin IV-Fresenius injection).

2. Micromedex Healthcare series.3. British National Formulary 56.4. Lexi-Comp's Drug Information


35

2.1.13 Sedative

DRUGa. Fentanyl b. Dexmedetomidine

Hydrochloridec. Propofol

STRENGTH/UNIT0.1mg/2ml

200mg/2ml (Precedex) 200mg/20ml (Fresofol 1% emulsion)

STORAGE

Below 25°C. Protect from light.

Between 15°C to 30°C . Below 25°C. Do not freeze. Shake before use.


Already in solution


NAAfter dilution, store at 2-8°C

and use within 24 hours.NA


NS

D5%

NS

Must be diluted before use for both LD and maintenance

dose. Dilution is the same for LD and MD: 2ml of

dexmedetomidine add into 48ml NS.

NS

D5%

Minimum concentration is 2mg propofol /1ml diluent. Do not dilute less than 2mg/ml. Dilute in glass bottle. Shake

before use

Also compatible with lidocaine 1% (not exceeding

20mg lidocaine /200mg propofol)


IV slow over 1-2 minutes

IV infusion

IM

IV infusion (using a controlled infusion device)

LD: 1mcg/kg over 10 minutes followed by infusion of 0.2-

0.7mcg/kg/hr (titrate accordingly)

IV bolus

IV infusion

For IV infusion, both diluted or undiluted solution can be

used.

REMARKS

Muscle rigidity may occur with rapid IV

administration

Contious infusion not to exceed 24 hours. Safety and effectiveness have not been

evaluated in infusions over 24 hours.

Duration of administration must not exceed 7 days.

REFERENCES

1. Product information (Fentanyl Citrate Injection).




1. Product information (Precedex)



1. Product information (Fresofol 1% MCT/LCT emulsion).



36

DRUGd. Midazolam e. Morphine

STRENGTH/UNIT5mg/ml , 15mg/3ml (Dormicum)

10mg/ml

STORAGERoom temperature

Below 25°C. Protect from light.

RECONSTITUITIONAlready in solution Already in solution.


NA NA


NS

D5%

Concentration of dilution: 15mg midazolam per 100-1000ml diluent (source: Dormicum product insert)

Concentration of dilution: The 5mg/ml formulation should be

diluted to a concentration 0.5mg/ml (source: Micromedex)

D5%

Usual concentration for IV infusion is 0.1-1mg/ml

For IV slow, a strenght of 2.5 to 15mg may be diluted in 4-5ml WFI


IV bolus (at a rate of 1mg over 30 seconds. Elderly: dose of 2-2.5mg

over 5-10 minutes)

IV infusion

IM

IV slow (over 2-5 minutes)

IV infusion

IM

S/C

REMARKS

None Rapid S/C administration may cause local tissue irritation

REFERENCES

1. Product information (Dormicum).2. Britisn National Formulary 523. Micromedex Healthcare series.4. Lexi-Comp's Drug Information


1. Product information (Dormicum).2. Britisn National Formulary 523. Micromedex Healthcare series.4. Lexi-Comp's Drug Information


37

2.2 Deep Vein Thrombosis Prophylaxis

2.2.1 INTRODUCTION

The occurrence of deep vein thrombosis in hospitalised patients is depending upon various risk factors. In orthopaedic patients undergoing surgery, up to 76.5% incidence of DVT has been reported.1 Meanwhile approximately 10 to 40% among medical or general surgical patients and 40 to 60% of patients having major orthopedic surgery, and was not placed on DVT prophylaxis are confirmed as having hospital-acquired DVT.2 One quarter to one third of these thrombi involve the proximal deep veins, and these thrombi are much more likely to produce symptoms and result in pulmonary embolism (PE). 3In a study of 51,645 hospitalized patients, the prevalence of acute PE was 1%, and PE was believed to have caused or contributed to death in 37% of these cases4.

To prevent the occurrence of DVT and subsequent pulmonary embolism which can be fatal, thromboprophylaxis is recommended. The 2 methods of prophylaxis are either pharmacological or mechanical and are described under methods of prophylaxis.

2.2.2 DEFINITIONS

Deep vein thrombosis (DVT) is defined as a clot that occurs in the deep veins of the extremities. Further subclassifications include symptomatic versus asymptomatic and proximal (above the knee) versus distal (below the knee). 5

Pulmonary embolism is defined as being a clot usually originating from a DVT that travels to the pulmonary vasculature where it becomes an embolism and thereby impedes gas exchange distal to embolism. 5

Venous thromboembolism (VTE) is defined as an event due to thrombosis of a vein and includes DVT or PE. 5

Thrombophlebitis is the inflammation of a vein around which a DVT has occurred. This condition can be painful and chronic. This term is synonymous with postphlebitic or postthrombotic syndrome. 5

Immobilized : restricted to bed or chair with no instruction or ability to ambulate. 5

2.2.3 INDICATIONS FOR PROPHYLAXIS

38

All adult inpatients will be assessed for their risk of VTE that include the background history and acute or subacute precipitating factors which are shown in table 1. Clinicians will need to use their own judgment in addition to the guideline to determine the best method of reducing the risk of VTE in each individual patient. It is the combined responsibility of the physician and other healthcare staff including the clinical pharmacist and nursing staff to ensure all patients at risk for VTE have received appropriate prophylaxis when needed.1

Table 1 : Venous Thromboembolism – Risk Factors 6

Background Factors Age

Marked obesity ( BMI >30 )

Immobility ( bed rest longer than 4 days. )

Pregnancy

Puerperium

High dose estrogens

Previous DVT or PE

Thrombophilia - Deficiency of antithrombin, protein-C or protein-S - activated protein-C resistance - antiphospholipid antibody or

Lupus anticoagulant.

Precipitating Factors Trauma or surgery, especially of pelvis, hip, lower limb.

Malignancy , especially pelvic , abdominal , metastatic

Heart failure

Recent myocardial infarction

Paralysis of lower limb(s)

Severe infection

Inflammatory bowel disease

Nephrotic syndrome

Polycythemia

Paraproteinemia

Paroxysmal nocturnal hemoglobinurea

39

Bechet’s disease.

Burns

a. Low-risk groups 1

patients with minor trauma or minor medical illness at any age, in the absence of thrombophilia, previous DVT or PE.

patients undergoing minor surgery (duration under 30 minutes) at any age, in the absence of other risk factors.

patients undergoing major surgery (duration over 30 minutes) who are aged under 40 years and have no additional risk factors.

b. Moderate risk groups 1

patients undergoing major general, urological, gynaecological, cardiothoracic, vascular, or neurological surgery who are aged > 39 years or with other risk factors.

patients immobilised with acute medical illness. major trauma minor surgery or trauma or illness in patients with previous deep

vein thrombosis, pulmonary embolism, or thrombophilia.

c. High-risk groups1

fracture or major orthopaedic surgery of pelvis, hip, or lower limb. major pelvic or abdominal surgery for cancer. major surgery, trauma, or illness in patients with previous deep vein

thrombosis, pulmonary embolism, or thrombophilia. lower limb paralysis (for example, hemiplegic stroke, paraplegia). critical lower limb ischaemia or major lower limb amputation.

2.2.4 METHODS OF PROPHYLAXIS

There are two method of prophylaxis of DVT, which are 1

a. Pharmacological methods :

40

- Standard heparin (usually in low dosage)- Low molecular weight heparins- Oral anticoagulant such as warfarin- Aspirin

b. Mechanical methods - increase venous outflow and/or reduce stasis within the leg veins :

- Graduated compression stockings (GCS) - Intermittent pneumatic compression (IPC) devices - Venous foot pump (VFP)

* Below is a summary table for recommendation of method prophylaxis regarding the type of risk and procedure.

Table 2: Recommended DVT prophylaxis for surgical procedures and medical conditions 8

Surgery/Condition Recommended Prophylaxis

Comments

General Surgery—low-risk: minor procedures, <40 years old, no additional risks

None Early ambulation

General Surgery—moderate risk: minor procedure but with risk factor, nonmajor surgery age 40-60 with no risks, or major surgery <40 years with no risks

Heparin , LMWH , ES, or IPC

Heparin 5000 – 7500 iu bd

OR

LMWH (daily dose according to manufacturer) with IPC or ES.

* LMWH and heparin has comparable efficacy for DVT prophylaxis.8,9 The clinical advantages of LMWH over LDUH is its once-daily administration and the lower risk of heparin-induced thrombocytopenia (HIT), BUT LMWH is more costly.10

General Surgery—high risk: non-major surgery over age 60 or over age 40 with risks.

Heparin , LMWH Heparin 5000 – 7500 iu tds

OR

LMWH (daily dose according to manufacturer)

41


Comments

*In high-risk general surgery patients, higher doses of LMWH provide greater protection than lower doses.3

General Surgery—very high risk: major surgery over age 40 plus prior VTE, cancer or hypercoagulable state

LMWH combined with ES or IPC

LMWH (daily dose according to manufacturer

*May consider post discharge LMWH or perioperative warfarin

Elective Hip Replacement

LMWH or warfarin May combine with ES or IPC; start LMWH 12 hours before surgery, 12-24 hours after surgery, or 4-6 hours after surgery at half the dose for initial dose for at least 10 days. Start warfarin preoperatively or immediately after surgery, target INR 2. 0-3. 0. Extended prophylaxis is recommended for up to 28 to 35 days after surgery. 8

Elective Knee Replacement

LMWH or warfarin Both LMWH and warfarin resulted in significantly fewer proximal DVTs compared with LDUH or IPC (p<0.006 for each comparison).11 Pooled data from 5 trials that directly compared LMWH with warfarin showed rates of proximal DVT of 3.4% and 4.8%, respectively.8

Hip Fracture Surgery LMWH or warfarin

Neurosurgery IPC, LDUH or LMWH

Start LMWH post-surgery

Trauma LMWH with ES or IPC

If high risk of bleeding, may use ES and/or IPC alone.

Acute Spinal Cord Injury

LMWH Continue LMWH during rehabilitation or convert to warfarin (target INR 2.5)

Ischemic Stroke LDUH, LMWH If contraindication to anticoagulant, use ES or IPC.

Two studies directly comparing LDUH (5000 U three times daily) to LMWH (enoxaparin 40 mg once daily), using venography for diagnosis, found greater reduction in DVT with LMWH.8

A meta-analysis of studies of hospitalized patients with conditions other than myocardial infarction or ischemic stroke given VTE prophylaxis with unfractionated or low molecular weight heparin

42


Comments

showed no significant difference was found between LMWH and LDUH in incidence of DVT, PE, or mortality; however, major hemorrhage was lower with LMWH than with LDUH (RR 0.48, 95% CI: 0.23-1.00).12

ES : elastic stockings LDUH: low-dose unfractionated heparin

INR : international normalized ratio LMWH: low molecular weight heparin

IPC : intermittent pneumatic compression VTE : venous thromboembolis.

* warfarin is hardly use in critical care due to administration problem, thus it is not recommended as first line

43

Table 3: MEDICATIONS USED TO PREVENT DVT

Medication Class Unfractionated heparin

Low molecular weight heparin

Medication Heparin Enoxaparin Fondaparinux

Dosage Moderate risk

SC Heparin 5000units twice daily

High risk

SC Heparin 5000units 8 hourly

20 mg SC daily

(moderate risk surgery) OR

40 mg SC daily

(can go up to 30 mg SC q12h for high risk general surgery, major trauma or acute spinal cord injury) 14

Morbid obese (> 150 kg): can increase to SC 60 mg 12 hourly 13

Dose renal adjustment ( CrCL < 30 ml/min )14

Prophylaxis dose :

SC 20 mg daily

Therapeutic dose : 1 mg/kg daily

Adult (>50 kg)

2.5 mg SC once daily

Initiate dose after hemostasis has been established, 6 – 8 hours postoperatively. 16

Duration 5 days OR until hospital discharge if this is earlier than 5 days.

Surgical case14

7 – 10 days or longer if there is a risk of DVT and until patient ambulatory.

Medical case14

6 – 14 days

Orthopedic and abdominal surgery15

5 – 9 days after surgery.

In patient undergoing hip fracture surgery 9 – 24 days ( consider the risk )

Medical patients with DVT risk

Duration of 6 to 14 days .

Monitoring Platelet count

Recommendation : the platelet count is monitored in patients receiving heparin for more than five days,

Platelet count

Risk of thrombocytopenia (happen between 5th and the 21st day following the beginning of enoxaparin therapy.) If it significant decrease (30 to 50% of initial count),

Full blood count, serum creatinine, and occult blood testing of stools are recommended. PT and APTT are insensitive measures. 16




and that heparin is stopped immediately if thrombocytopenia occurs.

the treatment should be discontinued and switch to other alternative.

Contraindication16 - bleeding disorders - a history of allergy either to enoxaparin, heparin or other low molecular

weight heparin 1

- Hypersensitivity to fondaparinux

- severe renal impairment (CLCr < 30 mL/min)

- body weight < 50 kg (prophylaxis)

- active major bleeding

- bacterial endocarditis

- thrombocytopenia

Precaution16 Hypersensitivity to drug.

May cause thrombocytopenia. Discontinue and consider alternative if platelet are < 100,000/mm3 or /and thrombosis develop.

In neonate suggest use preservative free as some preparation content large amount benzyl alcohol (> 100 mg/kg/day) that can cause fatal toxicity (gasping syndrome).

Recent or anticipated neuraxial anesthesia (epidural or spinal anesthesia) are at risk of spinal or epidural hematoma and subsequent paralysis. Consider risk versus benefit.

Risk of thrombocytopenia

Caution in patient with renal failure; dosage adjustment need for ClCr < 30 mL/min.

Same with enoxaparin

Not to be use interchangeable (unit-for-unit) with heparin, LMWH or heparinoids.

Use caution in patient with moderate renal dysfunction

Patient with severe hepatic impairment with elevation in prothrombin time.

Not recommended prior to and during percutaneous coronary prevention (PCI) for reperfusion in STEMI patients, due to




increasesd risk for guiding catheter thrombosis.

Avoid administration 24 hours before and 48 hours after coronary artery bypass graft (CABG) surgery.

Side effect Thrombocytopenia occurs in about 3-4% of patients given prophylactic heparin.

Allergic reactions (including skin necrosis), raised serum transaminase concentrations, and osteoporosis with long term use (especially in pregnancy) 1

1 to 10% risk16

CNS : fever, confusion, pain

Dermatology : erythema, bruising, hematoma at site of injection

GI : nausea, diarrhea

Hematologic : hemorrhage, thrombocytopenia

Hepatic : ALT/ALP increase

> 10%

- Fever, nausea, anemia16

1- 10%

Edema, hypotension, insomnia, dizziness, headache, confusion, rash, purpura, bullous eruption, hypokalemia, constipation, vomiting, diarrhea, dyspepsia, moderate thrombocytopenia, increase in liver enzyme. 16

Drug interaction Increased effect/toxicity if use with anticoagulant, thrombolytics, dextran and drug affect platelet function ( eg aspirin, NSAIDs, dipyridamole, ticlopidine, clopidogrel), cephalosporins which contain MTT chain and parenteral penicillins (may inhibit platelet aggregation). 16

Decreased effect if use with Nitroglycerin (IV) that may occur in high dosages. 16

Increased effect/toxicity if use with anticoagulant, thrombolytics, dextran and drug affect platelet function ( eg aspirin, NSAIDs, dipyridamole, ticlopidine, clopidogrel), cephalosporins which conatain MTT chain and parenteral penicillins (may inhibit platelet aggregation). 16

Increased effect/toxicity if use with anicoagulants, antiplatelet agents, drotecogin alfa, NSAIDs, salicylates and thrombolytic agents. 16




Special instruction

There is an increased risk of wound haematomas, which can be minimised by avoiding injections close to wounds. 1

To avoid loss of medicinal product when using prefill syringe do not expel the air bubble from the syringe before the injection. 15

IV administration (first dose in STEMI patients only) either directly or use small volume (25-50 ml) 0.9% saline minibag and administer through existing IV line over 1 -2 minute. Then flush with saline after injection to ensure all medicinal product is administered.15

References

1. College of surgeons Malaysia. 1999 . Consensus On Prophylaxis Of Venous Thromboembolism. Academy of medicine Malaysia.

2. Wiig, JN, Solhaug, JH, Bilberg, T, et al 1995. Prophylaxis of venographically diagnosed deep vein thrombosis in gastrointestinal surgery: multicentre trials 20 mg and 40 mg enoxaparin versus dextran. Eur J Surg 161,663-668

3. Geerts WH, GP, Pineo Heit JA, Bergqvist D, Lassen MR, Colwell CW, & Ray JGl. 2009. Prevention of venous thromboembolism. Chest seventh ACCP Consensus Conference on Antithrombotic Therapy.

4. Stein PD, Henry JW. 1995. Prevalence of acute pulmonary embolism among patients in a general hospital and at autopsy. Chest 108,978-981

5. Thambi M, Galanter B. 2006. VTE/Deep vein thrombosis prophylaxis. University of Illinios Medical Centre.

6. Thromboembolic Risk Factors ( THRIFT ) Consensus Group. Risk of and prophylaxis for venous thromboembolism in hospital patients. BMJ 1992; 305: 567 - 74.

7. Kleinbart J, Williams MV and Rask KR. Chapter 31. Prevention of Venous Thromboembolism Emory University Schools of Medicine and Public Health. www.ahrg.gov.

8. Geerts WH, Heit JA, Clagett GP, Pineo GF, Colwell CW, Anderson FA, et al. 2001. Prevention of venous thromboembolism. 156S-158S. Chest Sixth ACCP Consensus Conference on Antithrombotic Therapy.

9. Palmer AJ, Schramm W, Kirchhof B, Bergemann R. 1997.Low molecular weight heparin and unfractionated heparin for prevention of thrombo-embolism in general surgery: a meta-analysis of randomised clinical trials. Haemostasis 27:65-74.

10. Warkentin, TE, Levine, MN, Hirsh, J, et al 1995 Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin. N Engl J Med 332,1330-1335

11. Freedman KB, Brookenthal KR, Fitzgerald RH, Jr. , Williams S, Lonner JH. 2000. A meta-analysis of thromboembolic prophylaxis following elective total hip arthroplasty. J Bone Joint Surg 82-A:929-938.

12. Mismetti P, Laporte-Simitsidis S, Tardy B, Cucherat M, Buchmuller A, Juillard-Delsart D, et al. 2000. Prevention of venous thromboembolism in internal medicine with unfractionated or low-molecular-weight heparins: a meta-analysis of randomised clinical trials. Thromb Haemost 83:14-19.

13. Duplaga BA, Rivers CW, Nutescu E. 2001. Dosing and monitoring of low-molecular-weight heparins in special populations. Pharmacotherapy 21:218-34.

14. Enoxaparin (Clexane) product leaflet, Sanofi-Aventis15. Fondaparinux (Arixtra) product leaflet, GloxiSmithKline16. Drug Information Handbook 17th Edition. 2008. Lexi Comp. United States

Author

1. Dr Arbayah Rais, Head of Dept Anesthetist, Selayang Hospital2. Fadilah Othman, Chief Pharmacist (Senior Clinical Pharmacist), Pharmacy Dept. Selayang Hospital3. Dr Haslinda Anesthetist ICU, Selayang Hospital4. Norliza Mat Ariffin, Pharmacist, Pharmacy Dept. Selayang Hospital5. Masrahayu Moydin, Clinical Pharmacist, Pharmacy Dept. Selayang Hospital

2.3 STRESS ULCER PROPHYLAXIS

2.3.1 INTRODUCTION

Stress-related mucosal disease (SRMD) is an acute condition which erosion of the gastric mucosa occur secondary to a physiologic stress.1 It can be manifestation by bleeding which can be considered equivalent to overt gastroduodenal bleeding that result in hemodynamic instability (measured through a drop in blood pressure or an increase in heart rate) and subsequent need for red blood cell transfusions or surgical intervention of the gastric ulcers.2,

(I suggest this sentence be rephrase cos it is too long and as a reader I cannot grasp its full meaning comment from MartinaRos Sakinah please look into it). 2, 3

The etiology of stress-related mucosal disease (SRMD) or stress related ulcer is multifactorial and complex. Patients with head injury or burns represent those at highest risk of SRMD, likely due to gastric acid secretion resulting from vagal stimulation. Other critically ill patients appear to develop SRMD as a result of diminishes mucosal defenses and hypoperfusion. 4 The longer the gastric pH remains below 4 the greater the risk of hemorrhage. Clinical trials have estimates clinically important bleeding occur in 3% to 6% of intensive care unit (ICU) patients with the most common risk factors ( ie those who are ventilated or have coagulopathy). 5, 6 Work by Cook and colleagues ascribed the risk of overt bleeding to be 4.4 % and clinically significant bleeding to be 1.5%.5 There is a strong relationship between duration of mechanical ventilation, duration of intensive care stay and incidence of ulceration: patient without coagulopathy and mechanical ventilation had an incidence of bleeding of 0.1%. 5

2.3.2 INDICATION OF PROPHYLAXIS

a. High risk patient - All patients to receive prophylaxis- mechanical ventilation > 48 hours- coagulopathy- History of previous GI hemorrhage- Current outpatient PUD treatment or prophylaxis- Central nervous system (CNS) injury ( subarachnoid hemorrhage (SAH) /

cardiovascular attack (CVA) – hemorrhagic or ischemic)- Sepsis with or without organ dysfunction- Vasopressor/inotropic prescription

b. Moderate risk patient - consider prophylaxis- Chronic non steroidal antiinflamatory drug (NSAID) or aspirin use- High dose prolonged steroid treatment- ICU stay > 10 days

c. Low risk patient or tolerating per oral diet/Full gastric enteral feeds – No prophylaxis or discontinue prophylaxis

2.3.3 NUTRITIONAL GUIDELINE AND STRESS ULCERS

The administration of gastric nutrition reduces, but does not eliminate the risk of GI hemorrhage. Any patient predicted to be mechanically ventilated > 48 hours and without a contraindication to gastric enteral nutrition, is encouraged to have nasogastric nutrition initiated within 72 hours of admission when a nasoenteric tube is in situ.

2.3.4 PROPHYLAXIS SMRD AGENT

Many agents are available for use in patients at risk for stress-related mucosal disease. These agents include histamine type 2 receptor antagonists (H2RAs), proton pump inhibitors (PPIs), sucralfate, antacids, and prostaglandin analogs. Common products, usual dosage ranges, and considerations are shown in the Table 1.

Current studies reveal that histamine type 2 receptor antagonists are the most widely used first-line agents; however proton pump inhibitors are widely used and their diverse routes of administration and favorable side effect profile are desirable features.13

The largest randomized controlled trial to date involved 1200 mechanically ventilated patients has determined that ranitidine was significantly better than sucralfate in reducing clinically important SRMD bleeding (odds ratio [ OR]: 0.44; 95% confidence interval [CI] : 0.21-0.92). 7

Multiple studies have examined the effects of proton inhibitors (PPIs) in ICU patients, but all have been small and many measured intermediate endpoints. 7

Some studies have been observational with PPI therapy alone, whereas others have compared PPI therapy with placebo or histamine-2 receptor antagonist (H2RA) therapy. Conclusions that can be gathered currently are that acid suppression achieved with PPI therapy is, on average, superior to that achieved with H2RAs, and that the clinical benefit of PPIs for reducing SRMD bleeding appears to be at least similar to that achieved with H2RAs. Current trends indicate increasing awareness and use of acid suppression in the population, with H2RAs representing first-line agents and PPIs gaining use.

The most common complication of stress ulcer prophylaxis is pneumonia. 10 The hypothesis is based upon the concept that higher pH relates to overgrowth of gastric microbes and leads to upper tracheal colonization. This concept partnered with microspiration of intubated patients lying supine may increase the nosocomial pneumonia rate. The ability to reliably maintain a pH < 4 will

decrease the rate of pneumonia. Several studies comparing the pneumonia rate when comparing sucralfate, antacids and H2RA show ether improvement or insignificant trends toward decreasing rate with sucralfate. 10 However, due to the current incidence of outpatient ulcer and reflux reduction therapy and the complexity of administering sucralfate, overall benefit appears to be small.

Table 1: MEDICATION USED TO PREVENT SRMD 14

Medication class Histamine Type 2 Receptor

Antagonists

Proton pump inhibitors

Medication Ranitidine Esomeprazole Omeprazole Pantoprazole

Dosage Adult

Oral : 150 mg bd

IV : 50 mg Q8H

Adjust for creatinine clearance

(CrCl) < 50 ml/min.

Oral : 150 mg every 24 hour

IV : 50 mg every 18-24 hours; adjust dose cautiously if needed

Hemodialysis : Adjust dosing schedule so that dose coincides with the end of hemodialysis.

40 mg daily (IV, nasogastric tube, PO)

20-40 mg daily (PO, nasogastric/jejunal, duodenal tube)

40 mg daily (IV,nasogastric tube, PO)

Patient who develops significant GI hemorrhage receiving prophylaxis :

IV Omeprazole / Pantoprazole / Esomeprazole

80 mg loading dose followed by 8 mg/hr for 3 days

- consider endoscopic evaluation

- When no evidence of bleeding for 24 hours, convert to intermittent dosing schedule.

*Defined as bleeding that requires transfusion, causes hemodynamic changes and/or decrease in Hmeoglobin (Hgb) ≥ 1 gram

The result of 16 randomized, controlled trials involving a total of > 3,800 patients (1,892 receiving PPIs and 1,911 controls) suggest that bolus administration plus continuous infusion of PPIs is a more effective pharmacotherapy than bolus infusion alone in decreasing both rebleeding and the need for surgery. 11


Antagonists



Monitoring AST, ALT, serum creatinine, sign and symptoms of PUD, occult blood with GI bleeding, renal function

Hypersecretory disorders

Contraindication Hypersensitivity to the component of the formulation

Precaution Use in caution in patient with hepatic impairment and renal impairment

Severe liver dysfunction may require dose adjustment

Bioavailability may increase in the elderly, Asian population, and with hepatic dysfunction

IV preparation contain edentate sodium (EDTA); use caution in patient who are at risk for zinc deficiency if other EDTA containing solution are co-administered

Side effect Arrythmias, dizziness, headache, mental confusion, rash, anemia, thrombocytopenia, leucopenia, hepatic failure and pneumonia

Headache, hypertension, pain, dizziness, flatulence, diarrhesa, constipation, urinary tract infection, anemia, pneumonia

Headache, dizziness, diarrhea, abdominal pain, pneumonia

Headache, diarrhea, flatulence, abdominal pain, abnormal liver function test


Antagonists



Drug interaction CYP450 effect

Increase the effect : Cyclosporine

Decrease effect

Warfarin, ketoconazole, itraconazole, cephalosporin, cycanocobalamin

CYP450 effect

Increase the effect : HMG-CoA reductase inhibitor, methotrexate, benzodiazepine, phenytoin

Decrease effect

ketoconazole, itraconazole,

CYP450 effect

Increase the effect :

HMG-CoA reductase inhibitor, Montelukast, phenytoin, warfarin, methotrexate

Decrease effect

ketoconazole, itraconazole,

Special instruction

First line in treatment of SRMD

If patient on PPI for chronic disease (PUD treatment or prophylaxis) requiring this medication

Stability of PPIs after reconstitution

After reconstitution with 10 ml of isotonic sodium chloride solution, intravenous omeprazole / pantoprazole can be administered as a rapid injection over 2 minutes or it can be stores for up to 2 hours at room temperature.

Intravenous admixtures of pantoprazole can be prepared by mixing with 100 ml of isotonic sodium chloride solution, 5% dextrose in water, or lactated Ringer’s solution to achieve a final concentration of 0.4 mg/ml. This solution can be stored for up to 24 hours at room temperature. This admixture can be administered over 15 minutes. 12

References

1. Sesler JM. Stress-related mucosal disease in the intensive care unit: an update on prophylaxis. AACN Adv Crit Care. 2007; 18:119-126.

2. Cook DJ, Fuller HD, Guyatt GH, et al. Risk factors for gastrointestinal bleeding in critically ill patients. Canadian Critical Care Trials Group. N Engl J Med. 1994; 330:377-381.

3. ASHP Therapeutic Guidelines on Stress Ulcer Prophylaxis. ASHP Commission on Therapeutics and approved by the ASHP Board of Directors on November 14, 1998. Am J Health Syst Pharm. 1999; 56:347-379.

4. Cho CH, Koo MWL, Garg GP, et al. Stress-induced gastric ulceration: Its aetiology and clinical implications, Scand J Gastroenterol. 1992;27:257-262.

5. Cook DJ, Fuller HD, Guyatt GH, et al. Risk factors for gastrointestinal bleeding in critically ill patients. N Eng J Med. 1994;330:337-381.

6. Brown RB, Klar J, Teres D, et al. Prospective study of clinical bleeding in intensive care unit patients. Crit Care Med. 1988;16:1171-1176.

7. Cook DJ, Guyatt G, Marshall J et al. A comparison of sucralfate and ranitidine for the prevention of upper gastrointestinal bleeding in patients requiring mechanical ventilation.

8. Jung R, Maclaren R. Proton pump inhibitor for stress ulcer prophylaxis in critically ill patients. Ann Pharmacother. 2002;36:1929-1937.

9. Redbuck JA, Welage LS et al. Prevention of stress ulceration: current trends in critical care. Crit care Med. 2004;32: 2008-2013.

10. Messori A, Trippoli S, Vaiani M, Gorini M, Corrado A. Bleeding and pneumonia in intensive care patients given ranitidine and sucralfate for prevention of stress ulcer : meta analysis of randomized controlled trials. BMJ 2202;321(7269):1103-1106.

11. Morgan D. Crit care Med. 2002;30:S369-S37212. Wyeth Pharmaceutical [package insert]. Philadelphia, Pa: Wyeth laboratories;200413. Daley RJ, Rebuck JA, Welage LS, Rogers FB. Prevention of stress ulceration: current trends in

critical care. Crit Care Med. 2004; 32:2008-2013.14. Drug Information Handbook 17th Edition. 2008. Lexi Comp. United States

Author

6. Dr Anselm Suresh Rao, Intensivist ICU, Selayang Hospital7. Wong Kok Thong, Chief Pharmacist, Pharmacy Dept. Selayang Hospital8. Fadilah Othman, Clinical Pharmacist, Pharmacy Dept. Selayang Hospital9. Zainon Abudin, Pharmacist, Pharmacy Dept. Selayang Hospital10. Siti Hajar Abdul Jalil, Pharmacist, Pharmacy Dept. Selayang Hospital11. Masrahayu Moydin, Clinical Pharmacist, Pharmacy Dept. Selayang Hospital

2.4 ANTIBIOTIC GUIDELINE FROM INFECTIONS IN INTENSIVE CARE UNITS – Adapted from National Antibiotic Guideline 2008, MOH Malaysia

Infection/ condition & Likely Organism

Suggested Treatment Comments

Preferred Alternative

A. Severe Sepsis or Septic Shock Where Site Of Infection Is Not IdentifiedSevere sepsis or septic shock

(site of infection is unknown)

Gram-negative bacilli

Gram-positive cocci

Methicillin-resistant S.aureus

Penicillin-resistant

S. pneumoniae

Ampicillin-resistant Enterococci

Candida

Cefepime 2g IV q12h;

ORPiperacillin/Tazobactam 4.5g IV q8h

PLUS OPTIONALVancomycin1 1g IV q12h

PLUS OPTIONALFluconazole 400 - 800mg IV q24h

Meropenem 1g IV q8h;

ORImipenem 500mg IV q6h

PLUS OPTIONALAmphotericin B 0.6 -1.0mg/kg IV q24h

Current evidence suggests that carbapenems, 4th generation cephalosporins or Piperacillin/ Tazobactam are equally effective in treatment of septic shock.

If melioidosis cannot be ruled out, carbapenem should be used as the empirical agent.

Empirical use of Vancomycin1 is only justified in areas with high endemic levels of MRSA or high levels of penicillin-resistant S.pneumoniae

Empirical antifungal agents should not be used on a routine basis.

Reference 1,2

B. Severe Community-Acquired Pneumonia Requiring Mechanical Ventilation




Severe community-acquired pneumonia requiring mechanical ventilation

S. pneumoniae

H. influenzae

S. aureus

K. pneumoniae

M. pneumoniae

L. pneumophilia

C. pneumoniae

*B.pseudomallei

3rd gen. Cephalosporins, e.g;

Ceftriaxone 2g IV q24h

PLUSErythromycin 500mg IV q6h

ORAzithromycin 500mg IV q24h

* If risk factors present, consider Ceftazidime (Please Refer to Page 95(LRTI))

-lactam/-lactamase inhibitors, eg;

Amoxycillin/Clavulanate 1.2g IV q8h

PLUSErythromycin 500mg IV q6h

ORAzithromycin 500mg IV q24h

Reference 3,4,5

C. Severe Nosocomial Pneumonia Requiring Mechanical Ventilation (Including Ventilator-Associated Pneumonia)

Nosocomial pneumonia requiring mechanical ventilation (including VAP)

Low risk for infection with multi-drug resistant (MDR) organisms - < 5 days

S. pneumoniae H. influenzae

S. aureus E. coli

K. pneumoniae Enterobacter spp. Proteus spp. Serratia marcescens

3rd gen. Cephalosporins, e.g;

Ceftriaxone 2g IV q24h;

OR


Ampicillin/Sulbactam 1.5g IV q6h


Amoxycillin/Clavulanate 1.2g IV q8h

S. aureus is more common in diabetes mellitus, head trauma.

Monotherapy is recommended for early onset HAP/VAP/HCAP.

Reference 6,7




High risk for infection with multi-drug resistant (MDR) organisms

P. aeruginosa

Acinetobacter spp.

K. pneumoniae (ESBL)

Methicillin-Resistant S. aureus

Piperacillin/Tazobactam 4.5g IV q6h OR Cefepime 2g IV q12h

PLUSAmikacin1 15mg/kg/24h IV ORCiprofloxacin 400mg IV q8h

Cefoperazone/Sulbactam 2g IV q12h

Meropenem 1g IV q8hORImipenem 500mg IV q6h

PLUS(if MRSA is suspected)Vancomycin1 1g IV q12h

Imipenem 500mg IV q6h ORMeropenem 1g IV q8h

PLUS

Amikacin1 15mg/kg/24h IV ORCiprofloxacin 400mg IV q8h

-lactam/-lactamase inhibitors, eg; Ampicillin/Sulbactam 1.5g IV q6h

Use combination therapy if MDR pathogen is suspected.

Aminoglycoside can be stopped after 5-7 days in patients on combination therapy who are responding to treatment.

1Refer Appendix 1 (Clinical Pharmacokinetic Guidelines: Aminoglycosides & Vancomycin)

References:

1. Crit Care Med 2003; 31:1250-1256 3. Am J Respir Crit Care Med 2002, 166:717-723 6. Am J Respir Crit Care Med. 2005;171:388-4162. Crit Care Med 2004; 32(11)S495 S512 4. Clin Infect Dis 2003;37:1405-33 Curr Anaes and 7. Crit Care 2005;16:209-219 5. Curr Opin Crit Care 2004; 10:59-64

2.5 NEUROMUSCULAR BLOCKING AGENTS IN CRITICALLY ILL PATIENTS

2.5.1 INTRODUCTION

The use of neuromuscular blocking agents in the ICU remains a problematic issue, especially since the indications for the pharmacologic paralysis of ICU patients are unclear. The current recommendations are that muscle relaxants be used to facilitate mechanical ventilation in patients whom sedation alone is inadequate in providing effective mechanical ventilation. The decision to treat a patient in the ICU with neuromuscular blocking agents is a difficult one that is guided more commonly by individual practitioner preference than by standards based on evidence-based medicine.1

2.5.2 NEUROMUSCULAR TRANSMISSION AND BLOCKADE2

The neuromuscular junction consists of the nerve terminal, the synaptic cleft, and the motor endplate. Acetylcholine (ACh) is released into the synaptic cleft when nerve impulses reach the nerve terminal and diffuses across the synaptic cleft to the motor endplate. Attachment of Ach to the nicotinic (not muscarinic) receptors on skeletal muscle causes a conformational change in the receptor that increases myocyte cell membrane permeability to sodium, potassium, chloride and calcium ions and releases calcium from the sarcoplasmic reticulum, leading to transmission of an action potential. Depolarization terminates when Ach unbinds from the receptor. Ach either diffuses back into the nerve terminal or is broken down by acetylcholinesterase.

Neuromuscular blocking agents are structurally related to Ach and act by interfering with the binding of Ach to the motor endplate. They are divided into depolarizing or nondepolarizing agents based upon their mechanism of action.

Depolarizing NMBAs bind to cholinergic receptors on the motor endplate, causing initial depolarization on the endplate membrane followed by blockade of neuromuscular transmission. Because calcium is not resequestered in the sarcoplasmic reticulum, muscles are refractory to repeat depolarization until depolarizing NMBAs diffuse from the receptor to the circulation and are hydrolyzed by plasma pseudocholinesterase.

Nondepolarizing NMBAs competitively inhibit the Ach receptor on the motor endplate. Drug binding to the Ach receptor either prevents the conformational change in the receptor or physically obstructs the ion channels so that an endplate potential is not generated.

2.5.3 NEUROMUSCULAR BLOCKING AGENTS

Atracurium

Atracurium is an intermediate acting NMBA with minimal cardiovascular adverse effects and is associated with histamine release at higher doses. Atracurium has been administered to various critically ill populations, including those with liver failure, brain injury or multiple organ dysfunction syndrome (MODS), to facilitate mechanical ventilation. Recovery of normal neuromuscular activity usually occurred within one to two hours after stopping the infusions and is independent of organ function. Long term infusions have been associated with the development of tolerance, necessitating significant dose increases or conversion to other NMBAs. Atracurium has been associated with persistent neuromuscular weakness as have other NMBAs.1

Pancuronium

Pancuronium is a long acting, nondepolarizing compound which has vagolytic effects (more than 90% of ICU patients will have an increase in heart rate of ≥10 beats/min), which limits its use in patients who cannot tolerate an increase in heart rate. In patients with renal failure or cirrhosis, neuromuscular blocking effects of pancuronium are prolonged because of its increased elimination half-life and the decreased clearance of its 3-hydroxypancuronium metabolite that has one-third to one-half the activity of pancuronium.1

Rocuronium

Rocuronium is a nondepolarizing NMBA with a monoquaternary steroidal chemistry that has an intermediate duration of action and has a very rapid onset of action, with maximum neuromuscular blockade within 4 minutes. The metabolite of rocuronium which is 17-des-acetylrocuronium has only 5 - 10% activity compared with the parent compound1 and rocuronium is metabolized minimally in the liver.3

Vecuronium

Vecuronium is an intermediate acting NMBA that has a structural analogue of pancuronium and is not vagolytic. Because of up to 35% of a dose is renally excreted, patients with renal failure will have decreased dose requirements. Similarly, because up to 50% of an injected dose is excreted in bile, patients with hepatic insufficiency will also have decreased drug requirements to maintain adequate blockade. The 3-desacetylvecuronium metabolite has 50% of the pharmacologic activity of the parent compound, patients with organ dysfunction may have increased plasma concentrations of both the parent compound and the active metabolite, which contributes to the prolongation of blockade if the dose is not adjusted. Vecuronium has

been reported to be more commonly associated with prolonged blockade once discontinued, compared with other NMBAs and therefore it is being used with decreased frequency in ICU.3

Table 1: Neuromuscular Blocking Agents

Atracurium Rocuronium Pancuronium

Dose 1.Adjunct to general anaesthesia (for surgery or intubation)

Initial :

IV injection : 0.3 – 0.6 mg/kg 4,5

Maintenance :

IV injection : 0.1 – 0.2 mg/kg 4,5 OR

IV infusion : 5 – 10 mcg/kg/min (300 – 600 mcg/kg/hr) 4,5

2.Intensive care

Initial :

IV injection : 0.3 – 0.6 mg/kg 4,5

Maintenance :

IV infusion : 4.5 – 29.5 mcg/kg/min (usual : 11 – 13 mcg/kg/min) 4,5

1.Surgery procedures (Intubation)

Initial :

IV injection : 0.6 mg/kg 4,6

Maintenance :

IV injection : 0.15 mg/kg (Elderly : 0.075 – 0.1 mg/kg)4,6

OR

IV infusion : 0.3 – 0.6 mg/kg/h (Elderly : 0.4 mg/kg/h) 4,6

2.Intensive care

Initial :

IV injection : 0.6 mg/kg 4,6

Maintenance :

IV infusion : 0.3 – 0.6 mg/kg/h for first hour then adjusted according to response 4,6

1.Neuromuscular blockade

Initial :

IV injection : 0.06 – 0.1 mg/kg or 0.05 mg/kg after initial dose of succinylcholine for intubation 3

Maintenance :

IV injection 0.01 mg/kg 60 – 100 min after initial dose, then 0.01 mg/kg every 25 – 60 min 3

2.Intensive care

IV injection : 0.05 – 0.1 mg/kg bolus followed by 0.8 – 1.7 mcg/kg/min once recovery from bolus seen or 0.1 – 0.2 mg/kg every 1-3 hours 3

Onset 2 – 3 min 3 1 – 2 min (within 4 min) 3 2 – 3 min 3

Duration 20 – 35 min 3 ~ 30 min 3 60 – 100 min 3

Monitoring Vital signs (heart rate, blood pressure, respiratory rate); renal function and

Peripheral nerve stimulator measuring twitch response; heart rate, blood pressure,

Heart rate, blood pressure, assisted ventilation status 3


liver function 3 assisted ventilation status 3

Contraindications Hypersensitivity to atracurium besylate or any component of the formulation 3

Hypersensitivity to rocuronium or any component of the formulation 3

Hypersensitivity to pancuronium or any component of the formulation 3

Precautions Reduce initial dose and inject slowly over 1 – 2 min in patients in whom substantial histamine release will be potentially hazardous (patients with clinically important cardiovascular disease) 3

Increased sensitivity in patients with myasthenia gravis and Eaton-Lambert syndrome 3

Use with caution in patients with valvular heart disease, pulmonary disease, hepatic impairment; ventilation must be supported during neuromuscular blockade 3


Ventilation must be supported during neuromuscular blockade 3

Use with caution in patients with renal and/or hepatic impairment (adjust dose appropriately) 3


Side effects 1 – 10% :

Cardiovascular : Bradycardia, flushing, hypotension, tachycardia3

<1% :

Broncheal secretions, erythema, itching, urticaria, wheezing 3

>1% :

Cardiovascular : Transient hypertension and hypotension 3

<1% (Limited to important or life-threatening):

Abnormal ECG, anaphylaxis, arrhythmia, bronchospasm, edema, hiccups, nausea, rash, rhonchi, shock, tachycardia, wheezing, vomiting 3

Frequency not defined :

Cardiovascular : elevation in pulse rate, elevated blood pressure and cardiac output, tachycardia, edema, skin flushing, circulatory collapse3

Dermatologic : Rash, itching, erythema, burning sensation along the vein3

Gastrointestinal : excessive salivation3

Neuromuscular & skeletal : profound muscle weakness3

Respiratory : wheezing, bronchospasm3


Drug interaction Increased effect :

Aminoglycosides, beta blocker, calcium channel blocker, clindamycin, imipenem, quinolones, tetracycline, vancomycin, macrolides, loop diuretics (frusemide), ketamine, magnesium sulphate, procainamide, quinidine. May increase risk of myopathy when used with high-dose corticosteroids for extended periods3

Decreased effect :

Carbamazepine (chronic use), phenytoin (chronic use), theophylline, sympathomimetics 3

References :

o ASHP Therapeutic Guidelines for sustained neuromuscular blockade in the adult critically

ill patient. Approved by the ASHP Board of Directors on November 17, 2001. Am J Health Syst Pharm. 2002; 59:179-195.

o Hanson, CW. Pharmacology of neuromuscular blocking agents in the intensive care unit. Crit Care Clin 1994; 10:779

o Drug Information Handbook 14th International Edition. 2006 - 2007. Lexi Comp. United

States

o British National Formularies 54th Edition. September 2007. United Kingdom

o GlaxoSmithKline [TracriumTM package insert]. GlaxoSmithKline Manufacturing S.p.A.,

Parma, Italy ;2005

o Organon [Esmeron ® package insert]. N.V. Organon, Oss, Holland ;2002

2.6 SEDATIVE AGENTS IN CRITICALLY ILL PATIENTS

2.6.1 INTRODUCTION

Sedatives and analgesics are often used to facilitate patient tolerance of invasive mechanical ventilation.1 Patients undergoing mechanical ventilation experience significant stress superimposed on their acute medical problem, ranging from anxiety about their surroundings and condition to distress with potential pain from necessary nursing care and procedures. 3 The goals of sedation and analgesia in this context include decreasing pain and anxiety, reducing the stress response, and facilitating nursing care. Recent evidence indicates that the choice of sedating agents, frequency of administration and regular assessment of sedation contribute to patient outcomes2 such as length of stay in the ICU, days of mechanical ventilation, and rate of self-extubation.1 Titrating the dose of sedative medication based on a sedation scale will help prevent over-sedation and treat under-sedation. Under-sedated patients may become agitated and distressed and are at risk of adverse events such as extubation4 while over-sedation can contribute to hypotension, venous thrombosis, prolonged ventilation, an increased risk of pneumonia and a prolonged stay in ICU.2

Improving sedation management through sedation protocols and interventions such as daily interruption of sedation is an increasing focus of quality improvement initiatives in critical care.4 In 2000, Kress and co-workers showed that daily withholding of sedative agents led to reduced length of ICU stay, less ventilator time, fewer ICU complications and fewer neurological investigations. Subsequent studies by the same group demonstrated daily sedation withholding to be safe in patients with ischaemic heart disease and that it reduces the psychological sequelae of critical illness. Sedation withholding is now part of the ‘Ventilator Care Bundle’, as outlined by the UK Department of Health and recommended by the Surviving Sepsis Campaign.2

Assessment of sedation level is carried out mainly by nurses or critical care physicians by assessing patient responses to simple stimuli.2 Sedation-agitation scales can be used to identify and quantify agitation, and to grade the depth of sedation.5 Sedation scales such as the Revised Riker Sedation and Agitation Scale, Ramsay Scale or the Richmond Agitated-Sedation Scale are widely used.2

The Malaysian Ministry of Health ICU Management Protocol suggested that patients are to be assessed for sedation and agitation based on the revised Riker Sedation and Agitation Scale every 4 hours and titrate the sedative infusion rate with the aim of keeping the sedation score between -1 to +1.6

Exceptions to keeping the sedation score between -1 and +16 :

Head injured on cerebral protection : sedation score -3

Severe sepsis on high inotropic support : sedation score of at least -1

ARDS on high ventilatory support : sedation score of at least -2

Tetanus : sedation score of at least -2

Revised Riker Sedation Agitation Scale6

Score Description Definition

+3 Agitated and restless When awaken or otherwise, pulling at ETT, trying to remove catheters or requires physical restraints

+2 Awake but mildly agitated Anxious but mildly agitated. Attempts to sit up but calms down with verbal instructions

+1 Awake and calm Awake, calm and easily follows commands

0 Aroused by voice and remains calm

Awakens easily to verbal stimuli. Remains awake, calm and easily follows command

-1 Aroused by movement Awakens to loud verbal stimuli or gentle shaking. Has eye contact for at least 10 seconds but drifts off to sleep

OR

Awakens to loud verbal stimuli or gentle shaking and follows simple commands

-2 Aroused by painful stimuli Localising or flexion to pain. Does not communicate or follow commands

-3 Unarousable Extension, minimal or no response to painful stimuli

2.6.2 SEDATIVE AGENTS

Benzodiazepines7

Benzodiazepines binds to a specific receptor site of the GABA receptor, and thus the degree of modulation is limited, which explains the ceiling effect of their CNS depression. It has been suggested that a benzodiazepine receptor occupancy of 20% provides anxiolysis, whereas an occupancy of 30% to 50% is associated with sedation, and 60% is required for hypnosis.

Midazolam is the most commonly used benzodiazepine for ICU sedation. It is a short acting, water soluble benzodiazepine that undergoes

extensive oxidation in the liver to form water soluble hydroxylated metabolites, which are excreted in urine. However, the primary metabolite, namely 1-hydroxymethylmidazolam, has mild CNS depressant activity and may accumulate in the critically ill patient especially in the case of kidney failure. Medications that interfere with the cytochrome P450 enzyme will decrease metabolization of midazolam. During short term infusions, midazolam is generally safe and effective sedative agent. However, during continuous infusions, accumulation of midazolam can occur because of the large volume distribution and its high lipophilicity. It was shown that older patients require much lower plasma concentrations of benzodiazepine to achieve level of sedation comparable to those in younger patients

Propofol7

Propofol is a unique sedative-hypnotic agentwith a rapid onset and offset action. Like the benzodiazepines, propofol acts on the GABA receptor, although the site of action on this receptor is different.

It is available for intravenous administration dissolved in fat emulsion has extremely rapid distribution and metabolization (by hepatic conjugation) responsible for promptly patient arousal after a single dose or interruption of drug infusion. Its metabolites are excreted by kidneys. Its formulation causes a transiently elevation on triglyceride level and has some allergic properties. It has respiratory and cardiovascular depressant effects, with minimal influence on heart rate, and is still very expensive what limits its routine use in ICU. Hepatic and renal diseases have little impact on the pharmacokinetics of propofol.

Propofol infusion syndrome is a rare but serious and potentially fatal adverse effect, typically seen with infusion rates >5 mg/kg/h for more than 48 hours. This syndrome is characterized by dysrythmias, heart failure, metabolic acidosis, hyperkalemia and rhabdomyolisis, and it carries a mortality rate of up to 85%. In order to minimize the risk of this syndrome, propofol dosage should be under 4 mg/kg/h for a maximum of 7 days.

Dexmedetomidine7

Dexmedetomidine is a centrally acting α2-agonist with sedative and analgesic properties. The sedative properties are facilitated through the locus coeruleus site in the CNS and the analgesic effects may occur via activation of the α2 receptors by accentuating the action of opioids. It causes no significant effect on respiratory drive, even when used with opioids.

Most studies involving dexmedetomidine have evaluated postoperative ICU patients and demonstrated efficacy for short-term sedation and analgesic sparing. Although dexmedetomidine is labeled in some countries only for sedation of less than 24 hours, the drug has not been extensively studied as an agent for long-term administration to critically ill, mechanically ventilated patients.

Table 1: Drug doses

Midazolam Propofol Dexmedetomidine

Dose Initial dose :

0.01 - 0.05 mg/kg (~0.5 - 4 mg for a typical adult)9

Maintenance dose :

0.02 – 0.1 mg/kg/h or 1 – 7 mg/h9

1) Monitored anaesthesia care sedation (healthy adults <55 y.o)(dih & mdx)

Initial dose :

100 – 150 mcg/kg/min (6 – 9 mg/kg/h) IV infusion or 0.5 mg/kg slow IV injection for 3 – 5 min9,10

Maintenance dose :

25 – 75 mcg/kg/min (1.5 – 4.5 mg/kg/h) IV infusion or 10 – 20 mg incremental IV bolus doses9,10

2) Sedation for mechanically ventilated ICU patient

Initial dose :

5 mcg/kg/min (0.3 mg/kg/h) IV infusion for 5 min then titrate in 5 – 10 mcg/kg/min (0.3 – 0.6 mg/kg/h)

Initial dose :

1 mcg/kg over 10 mins9,10

Maintenance dose :

0.2 – 0.7 mcg/kg/h for a maximum of 24 hours9,10


increments to achieve desired sedation level9,10

Maintenance dose :

5 – 50 mcg/kg/min (0.3 – 3 mg/kg/h) or higher9,10

Onset 1- 5 min9 9-51 sec (average 30 sec)9

Rapid9

Duration 15 – 30 min9 3 – 10 min (dose and rate dependent)9

Cardiac effects Minimal depressant effect9,10

Important depressant effect9,10


Respiratory effects Important depressant effect9,10


Minimal depressant effect9,10

Analgesia None9 None 9 Yes 9

Monitoring Respiratory and cardiovascular status, blood pressure9

Anaphylactic reactions, cardiorespiratory depression, fever, propofol infusion syndrome, increased intracranial pressure or impaired cerebral circulation especially in neurosurgical patients10

Level of sedation, heart rate, respiration, rhythm9

Contraindication Hypersensitivity to midazolam and its components including benzyl alcohol (cross-sensitivity with other benzodiazepines may exist)9

Narrow-angle glaucoma and pregnancy9

Hypersensitivity to propofol, fospropofol or its components9

Allergy to eggs, egg products, soybeans or soy products10

Hypersensitivity to dexmedetomidine and its components9

Use outside of intensive care setting10


Precaution May cause severe respiratory depression, respiratory arrest or apnea9

May cause hypotension – hemodynamic events are more common in paediatric patients or patients with hemodynamic instability9

Hypotension and/or respiratory depression may occur frequently in patients who have received narcotic analgesics9

Use slower rate of induction in elderly9

Do not administer with blood or blood products through the same IV catheter9

Abrupt discontinuation can result in rapid awakening, anxiety, agitation and resistance to mechanical ventilation9

Use cautiously in elderly patients; hypotension and/or bradycardia may be more pronounced10

Use caution in patients with heart block, severe ventricular dysfunction, hypovolemia, diabetes and chronic hypertension9

Side effects COMMON10

Gastrointestinal : Nausea & vomiting

Neurologic : Excessive somnolence, headache

Respiratory : Cough

Other : Hiccoughs

SERIOUS10

Cardiovascular : Cardiac arrest, usually in combination with CNS depressant drug; hypotensive episode

Endocrine metabolic : Desaturation of blood in paediatric patients

COMMON10

Gastrointestinal : Nausea & vomiting

Musculoskeletal : Involuntary movement

SERIOUS10

Cardiovascular : Bradyarrhythmia, heart failure

Gastrointestinal : Pancreatitis

Immunologic : Anaphylaxis

Neurologic : Seizure

Respiratory : Apnea,

COMMON10

Gastrointestinal : Nausea, xerostomia

SERIOUS10

Cardiovascular : Atrial fibrillation, bradyarrythmia, cardiac dysrythmia, hypertension, hypotension, tachycardia

Respiratory :

Apnea, bronchospasm, dyspnea, hypercapnia, hypoventilation, pleural effusion, pulmonary congestion, respiratory


Neurologic : Involuntary movement

Psychiatric : Agitation

Respiratory : Apnea, respiratory arrest with CNS depressant drug, respiratory depression, respiratory obstruction

respiratory acidosis acidosis

Drug Interaction10 Atazanavir (contraindicated, theoretical)

Carbamazepine (moderate, probable)

Clarithromycin (moderate, probable)

Codeine (major, probable)

Dantrolene (major, theoretical)

Diltiazem (moderate, probable)

Efavirenz (contraindicated, theoretical)

Fluconazole (moderate, established)

Theophylline (moderate, probable)

Voriconazole (moderate, established)

Bupivacaine (major, probable)

Lidocaine (major, probable)

Succinylcholine (moderate, probable)

Tapentadol (major, theoretical)

References :

1. Arroliga A, Frutos-Viva F, Hall J, Esteban A, Apezteguia C, Soto L,Anzueto A. 2005. Use of sedatives and neuromuscular blockers in a cohort of patients receiving mechanical ventilation. Chest 128:496 – 506

2. Reschreiter H, Maiden M, Kapila A. 2008. Sedation practice in the intensive care unit: a UK national survey. Critical Care 12:R125

3. Schweickert WD, Kress JP. 2008. Strategies to optimize analgesia and sedation. Critical Care 12(Suppl 3):S6

4. Jackson DL, Proudfoot CW, Cann KF, Walsh TS. 2009. The incidence of sub-optimal sedation in the ICU: a systematic review. Critical Care 13:R204

5. Sessler CN, Grap MJ, Ramsay MAE. 2008. Evaluating and monitoring analgesia and sedation in the intensive care unit. Critical Care 12(Suppl 3):S2

6. Management Protocols in ICU. 2006. Program Anestesia & Cawangan Kualiti Penjagaan Kesihatan, Bahagian Perkembangan Perubatan, Kementerian Kesihatan Malaysia.

7. Gommerz D, Bakker J. 2008. Medications for analgesia and sedation in the intensive care unit: an overview. Critical Care 12(Suppl 3):S4

8. Sessler CN, Wilhelm W. 2008. Analgesia and sedation in the intensive care unit: an overview of the issues. Critical Care 12(Suppl 3):S1

9. Drug Information Handbook 14th International Edition. 2006-2007. Lexi Comp. United States

10. MICROMEDEX® Healthcare Series Vol. 143. 2010 Thomson Reuters. United States

2.7 MANAGEMENT OF ELECTROLYTES IMBALANCE IN CRITICALLY ILL PATIENTS

2.7.1 POTASSIUM (3.5 – 4.5 mmol/L )

Potassium is one of the body's major ions. Nearly 98% of the body's potassium is intracellular. The ratio of intracellular to extracellular potassium is important in determining the cellular membrane potential. Small changes in the extracellular

potassium level can have profound effects on the function of the cardiovascular and neuromuscular systems.

a. Hypokalemia

i) Sign and Symptoms of Hypokalemia (usually present when K<2.5mmol/L)

► Malaise, fatigue

► Neuromuscular disturbances: Weakness, hyporeflexia, paraesthesias,

cramps, restlessness leg syndrome, rhabdomylysis, paralysis.

► Gastrointestinal: Constipation, ileus

► Polyuria, polydipsia, metabolic alkalosis

► ECG changes: small or inverted T waves, prominent U wave,

depressed ST segments, prolonged PR interval.

► Arrhytmias: First and second degree heart block, atrial fibrillation,

ventricular tachycardia, ventricular fibrillation.

ii) Correction of Hypokalemia

If K+ <2.5 mmol/L or <3mmol/L if on digoxin or presence of life-threatening symptoms

Give KCL 2G diluted to 100 mls N/S through a central line over an hour.

Max. rate 0.4 mmol/kg/hour (20-30 mmol/hour)

(1G KCL= 13.3mmol K+ )

If no life threatening symptoms, K+ <3.5 mmol/L

Give KCL 1G diluted to 50mls N/S over an hour or oral/NG KCl 20-40 mmol q6h

iii) Potassium Correction Formula

= (4.5 – Current K + ) x 0.4 + Body Weight + 1 x Body Weight

13.4 13.4 = g KCL

b. Hyperkalemia

i) Sign And Symptoms of Hyperkalemia (Hyperkalemia is an emergency. The first sign of hyperkalemia may be death. Usually occur when K>6.5 mmol/L)

► Neuromuscular manisfestations : Bradycardia, prolongation of AV conduction, complete heart block, wide complex tachycardia, ventricular fibrillation and asystole.

► Urgent 12-lead ECG; possible changes are: Tall tented T waves, small P waves, depressed ST segments, widened QRS complexes, sine wave (biphasic waves, pre-cardiac arrest)

► ECG has limitation in predicting cardiac toxicity. Thus, patient should be treated even in the absence of ECG changes

ii) Correction of Hyperkalemia

If K+ > 6 mmol/L

with ECG abnormalities

Give Calcium Gluconate 10% 20 ml IV over 3 min (may be repeated in 5 min)

5-10 units Actrapid in 100 ml 50% dextrose IV over 30-60 min.

IV Frusemide 20mg to increase urine output.

Resonium 15G q8h oral/N/G or 30G q8h enema/rectal.

IV NaHCO3 50-100 mmol over 5-10 min (not to be given after calcium as Ca2+ bind HCO3.

Lastly dialysis.

2.7.2 SODIUM ( 135 – 145 mmol/L)

Serum sodium concentration and serum osmolarity normally are maintained under precise control by homeostatic mechanisms involving stimulation of thirst, secretion of antidiuretic hormone (ADH), and renal handling of filtered sodium. Clinically significant hyponatremia is relatively uncommon and is nonspecific in its

presentation; therefore, the physician must consider the diagnosis in patients presenting with vague constitutional symptoms or with altered level of consciousness. Irreparable harm can befall the patient when abnormal serum sodium levels are corrected too quickly or too slowly. The physician must have a thorough understanding of the pathophysiology of hyponatremia to initiate safe and effective corrective therapy. The patient's fluid status must be accurately assessed upon presentation, as it guides the approach to correction.

a. Hyponatremia

i) Sign and Symptoms of Hyponatremia

The clinical features of acute hyponatremia are related to osmotic water shifted that leads to increased ICF volume and brain cells swelling. Mild hyponatremia is usually asymptomatic.

Serum Na of about 120 mmol/L may be associated with disturbed mental state, restlessness, confusion and irritability.

As the Na approaches 110 mmol/L, seizures and coma may occur.

ii) Correction of Hyponatremia

b.

Hypernatremia

i) Sign and Synptoms of Hypernatremia

► Definition Na > 145mmol/L

► Features are tremulousness, irritability, ataxia, spasticity, mental confusion and coma

ii) Correction of Hypernatremia

Free H2O replacement

Water deficit (L) = 0.6 x BW in kg x ( measured Na - 1)

Total Na+ deficit (mmol)

= (130 –current Na+) x 60% of body weight in kg.

Volume (ml) required to replace total Na+ deficit using 0.9% N/S

= Total Na + deficit (mmol) x 1000

154 (mmol /L)

Volume (ml) required to replace total Na deficit using 3% N/S


513 (mmol /L)

Volume (ml) required to replace total Na deficit using 20 % N/S


3400 (mmol/L)

The volume calculated should be given within the calculated no. of hours

= (130 –current Na + )

0.5

The rate of rise in plasma Na should not exceed 0.5 mmol/L/ hour and the final plasma Na+ concentration should not exceed 130mmol/L.

140

To be given over 48-72 hours

Use Dextrose 5%.

2.7.3 MAGNESIUM ( 0.7 – 1 mmol/L)

Magnesium plays an important role in neuromuscular function. Only 1 % is in ECF, 60% are found in bones and reminder in cells. Therefore, serum magnesium may not reflect total body magnesium content.

a. Hypomagnesemia

i) Sign & Symptoms of Hypomagnesemia

► Symptomatic magnesium depletion is associated with refractory

hypokalemia, hypocalcemia and metabolic alkalosis.

► Features are : - Tremors, muscle twitching.

- Positive Trousseau’s and Chvostek’s signs

- Generalized weakness, confusion, ataxia

- Vertical nystagmus

- Tetany, seizures

- ECG Mild to moderate: prolongation of QT or QU

intervals, bifid T waves, U wave, supraventricular and

ventricular ectopics. Severe: PSVT, R-on-T phenomena,

torsades de pointes, VT

- Hypomagnesaemia facilitates development of digoxin

cardiotaxicity.

ii) Correction of Hypomagnesemia

50% MgSo4 solution has osmolarity of 4000 mOsm/L, dilute to 10-20% solution before IV use.

1mg MgSo4 =4 mmol (8mEq) elemental Mg

1 ml 50% MgSo4 =0.5G=2 mmol (4 mEq) Mg2+

Without symptoms IV 0.125G/kg MgSo4 x24h then 0.0625G/kg MgSo4 daily x3-5 days

IV Mg SO4 20mmol in 40ml NS OVER 2 hours

IV Mg SO4 10mmol in 20ml NS OVER ½ hour

If Mg2+ <0.6 mmol/L with cardiac abnormalities/ asthma/ eclampsia/ tetanus/ pulmonary hypertension

IV 0.05-0.07G/kg MgSo4 over 20 min then 0.03-0.05G/kg/h

Keep serum Mg2+ 2.0-3.5 mmol/L

c. Hypermagnesemia

i) Sign and Symptoms of Hypermagnesemia

► Magnesium levels of 2-4 mEq/L are associated with the following:

o Nauseao Vomiting

o Skin flushing

o Weakness

o Lightheadedness

► High magnesium levels are associated with depressed levels of consciousness, respiratory depression, and cardiac arrest.

ii) Correction of Hypermagnesemia

Only in patients with impaired renal failure

IV Calcium Gluconate 10% 30 mls over 3 minutes

Diuresis if possible

Dialysis

2.7.4 CALCIUM ( 2.1 – 2.65 mmol/L)

Calcium regulation is critical for normal cell function, neural transmission, membrane stability, bone structure, blood coagulation, and intracellular signaling. The essential functions of this divalent cation continue to be elucidated, particularly in head injury/stroke and cardiopulmonary effects. Depending on the cause, unrecognized or poorly treated hypocalcemic emergencies can lead to significant morbidity or death

a. Hypocalcemia

i) Sign and Symptoms of Hypocalcemia

► Paraesthesia

► Circumoral numbness

► Cramp

► Tetany

► Dystonia

► Convulsion

► Psychosis

► Chvostek’s sign – gentle tapping over facial nerve cause twitching of

facial muscles.

► Trousseau’s sign – inflation of sphygmomanometer cuff above diastolic

pressure for 5 min causes carpopaedal spasm.

► Papilloedema (severe)

► Prolonged Q-T interval on ECG

► Long-standing hypocalcemia may result in dry skin, coarse hair,

alopecia, brittle nails and hypoplastic teeth.

ii) Correction of Hypocalcemia

10 mls 10% CaCl2 (to be given through central line) contains 272 mg elemental calcium

10 mls 10% Ca gluconate (can be given through peripheral line) contains

90 mg elemental calcium

Treatment directed at underlying cause:

If symptomatic (muscle spasm, laryngeal spasms or cardiac involvement)

If ionised Ca2+ <0.65 mmol/L or corrected Ca2+ <2.0 mmol/L

i) IV 10-20mls 10% Ca gluconate over 10 min followed by 1-2 mg/kg/h x6-12h i.e. 30 mls 10% Ca gluconate diluted to 100 mls N/S run at 25-40ml/h x6-12h

ii) Give Mg if deficientiii) Daily maintenance dose of Ca 2-4G orally

b. Hypercalcemia

i) Sign and Symptoms of Hypercalcemia

► Neurology :- Depression, proximal myopathy, fatigue, confusion,

stupor and coma.

► Renal :- Hypertension, renal colic (nephrolithiasis), polyuria and

nocturia (nephrogenic diabetes insipidus), dehydration.

► Bones:- Pain, pathological fractures – osteitis fibrosa cystics in

hyperthyroidism (subperiosteal resorption, bone cysts).

► Abdominal:- Nausea, vomiting, constipation, abdominal colic, peptic

ulcer disease, pancreatitis.

► General:- Soft tissue and corneal calcification (band keratopathy)

► ECG changes:- Shortened QT intervals.

ii) Correction of Hypercalcemia

2.7.5 PHOSPHATE ( 0.8 – 1.5 mmol/L)

Phosphate is the most abundant intracellular anion and is essential for membrane structure, energy storage, and transport in all cells. In particular, phosphate is necessary to produce ATP, which provides energy for nearly all cell functions. Phosphate is an essential component of DNA and RNA. Phosphate is also necessary in red blood cells for production of 2,3-diphosphoglycerate (2,3-DPG), which facilitates release of oxygen from hemoglobin.

Approximately 85% of the body's phosphorus is in bone as hydroxyapatite, while most of the remainder (15%) is present in soft tissue. Only 0.1% of phosphorus is present in extracellular fluid, and it is this fraction that is measured with a serum phosphorus level.

a. Hypophosphatemiai) Sign and Symptoms of Hypophosphatemia

► Weakness is the most common symptom suggesting hypophosphatemia and may involve any muscular system to any extent.

o Diplopiao Dysarthria

o Dysphagia

o Weakness of trunk or extremities, particularly the large muscle groups

► Symptoms of respiratory insufficiency or myocardial depression may indicate hypophosphatemia.

► Neurologic symptoms may vary, ranging from simple paresthesias to profound alterations in mental status.

N/S or 1/2N/S at 250-500 ml/h to correct hypovolaemia

Frusemide 40-80 mg I/V every 2 hours to maintain urine output 100-

200mls/hr.

ii) Correction of Hypophosphatemia

Add 2 ampuoles of KH2PO4 in 1 pint IVD

OR

IV KH2PO4 20mmol/L in 100ml NS OVER 6 hours

OR

IV KH2PO4 10mmol/L in 100ml NS OVER 4 hours

2.7.6 FLUID/IV DRIP SUMMARY

Na+

(mmol/L)

Cl-

(mmol/L)

K+

(mmol/L)

Ca2+

(mmol/L)

Osmolarity (mOsmol)

pH Others

D5% (500ml) - - - - 252 3.2-6.5 Dextrose 50g170 Kcal

Dextrose 5% Saline 0.9% (500ml) 154 154 - - 560 Dextrose 50g

170 Kcal

0.9% NaCl (500ml) 154 154 - - 308 5.0 -

0.45% NaCl (500ml) 77 77 - - 154 5.0 -

3% NaCl (500ml) 513 513 - - 1026 5.0 -

Hartmann’s (500ml) 130 109 4 3 273 6.0-7.5 Lactate 28mEq/L

Gelafundin (500ml) 154 120 - - 274 7.1-7.7 Gelatin 40g/L

HES 6% 154 154 - - 310 4.0-7.0 Starch 60g/L

Voluven (100ml) 154 154 - - 308 5.5 Hydroxyethyl Starch 130/0.4 6g

Venofundin (1000ml) 154 154 - - 309 4.0-6.5Poly(O-2-

hydroxyethyl)starch (HES) 60g

Sterofundin (1000ml) 140 140 4 2.5

2.8 MEDICATION ADMINISTRATION THROUGH ENTERAL FEEDING TUBES

2.8.1 Medication plan

Temporarily discontinue medications that are not immediately necessary Consider giving medications by an alternate route such as transdermal,

rectal, inhaled, intramuscular, subcutaneous, buccal, sublingual or intravenous whichever possible

2.8.2 . Enteral administration of medications

Evaluate tube type, tube location in the GI tract, site of drug action and absorption and effects of food on drug absorption (e.g. sucralfate is not suitable for intestinal feeding tubes administration as it acts on the stomach)

Drug that require administration on empty stomach, feeding should be stopped 30 minutes before and after dosing

Liquid dosage forms is preferred whenever possible Tablets that could be crushed into fine powder and the contents of capsules

can be mixed to a slurry in water and given through large-bore feeding tubes Feeding tubes should be flushed with at least 30 ml of water before and after

administration of medication via the tube Medication should not be added to enteral formula to reduce the risk of

microbial contamination and to avoid drug-nutrient incompatibilities

2.8.3 Medications that should not be crushed

2.8.4 Consideration with Liquid Medications

Medication dosage or frequency may need adjustment when switching from solid to liquid preparations (e.g. extended-release phenytoin capsules may be given once daily, however phenytoin suspension is an immediate-release product that need to be dosed 2 to 4 times daily)

Osmolality

Formulation Reason

Sustained-release Crushing destroys the sustained-release tablets and microencapsulated drugs, resulting in erratic blood levels

Enteric-coated Do not crush well but break into small chunks that bond together when moist and clogging the tube

Decreased the efficacy of the medication Increased stomach irritation

Teratogenic, carcinogenic or cytotoxic medication

Aerosolized particles may be harmful to the health-care provider

- Many commercial liquids have osmolalities over 1000 mOsm/kg, the osmolality of GI secretions ranges from 100 to 400 mOsm/kg

- Diarrhea, cramping, abdominal distension and vomiting may occur after administration of hyperosmolar products through the feeding tube – the effects may be reduced by diluting medication with 10-30 ml of sterile water before administration

- Osmolality of diluted mixture = (osmolality of drug / volume of drug) / total volume of mixture

Contents of sorbitol

- many sweeteners including mannitol, lactose, saccharin and sucrose may cause or worsen diarrhea, the most likely excipient to cause GI problems is sorbitol

- sorbitol may cause gas and bloating at total daily doses of 10 gram, cramping and diarrhea may occur a total daily dose of 20 gram

2.8.5 Drug interaction and incompatibility and special consideration

Interaction / Incompatibility Recommended intervention (s)

Syrups and other acidic medication (pH less than 4) may clump when mixed with enteral feeding formulas

Stopping the enteral feeding for 1 to 2 hours before and 2 hours after drug administration

To avoid nutritional status compromise:- minimize the time of feeding interruption by

using once daily or twice daily dosing regimen

Phenytoin absorption decreases by 50% to 75% when given with enteral feeding

Stopping the enteral feeding for 2 hours before and after each dose

Flushing the tube before and after each phenytoin dose

Phenytoin suspension given through feeding tube may be diluted with 20-60 ml of water

Close monitoring of serum concentrations is warranted

Carbamezepine absorption may decrease with enteral feeding

Carbamazepine suspension may be diluted with an equal volume of sterile water or normal saline

Close monitoring of serum concentrations is warranted

Warfarin effects may be decrease in patients receiving enteral feeding due to reduce absorption and vitamin K antagonism

Consider increasing the warfarin dose or using alternative anticoagulants

Monitor prothrombin time Consider vitamin K contents in enteral

formulas – vitamin K may directly block warfarin’s effects in doses of 140-500 mcg.day

Interaction / Incompatibility Recommended intervention (s)

Fluroquinolones antibtiotics may have an erratically changes in its pharmacokinetics in patients receiving enteral feeds

Fluroquinoloes should not be given within 2 hours before or 4 hours after enteral formulas

Avoid giving via enteral feeding tubes or concomitantly with enteral formulas – parenteral route is preferred

If to be given via entral tube – crush tablets and mix in 20 to 60 ml sterile water immediately before administration

Proton-pump inhibitors – these medications are acid labile and inactivated by gastric acid, specially formulated to maintain the acidity until it delivers to alkaline pH of the duodenum for absorption

Omeprazole and lansoprazole capsules (delayed-release) through large-bore nasogastric or gastrostomy tubes- may be mixed with juices (apple, orange)- mixing with water may cause clumping and

lead to occlusion Omeprazole and lansoprazole capsules

(delayed-release) through small-bore jejunostomy or gastrostomy tubes- Dissolve in sodium bicarbonate 8.4%

solution Esomeprazole granules (delayed-release)

should be mixed with water Commercial immediate-release omperazole

with sodium bicarbonate- Should only be mixed with water- Continuous enteral feeding should be held

for 3 hours before and 1 hour after medication administration

Lansoprazole disintegrating tablet (delayed-release)- Dissolves on tongue or may be mixed with

small amount of water in an oral syringe and injected through the NG tube

- Should not be given through feeding tube – increased viscosity, tube occlusion

Continuous enteral feeding should be held for 3 hours before and 1 hour after medication administration

Laxatives Bulk forming laxatives (e.g. methycellulose) - Should not be given via feeding tubes- Form semisolid mass that may occlude

feeding tube when mixed with less than 250 ml fluid (still potentially block feeding tube when mixed properly)

- Consider using fiber-containing enteral nutrition

References:

1. Silberman H. Parenteral and Enteral Nutrition. 2nd ed. Norwalk, CT: Appleton & Lange; 1989, 117–58.

2. Estoup M. Approaches and limitations of medication delivery in patients with enteral feeding tubes. Crit Care Nurse. 1994;14:68–72,79.

3. Gora ML, et al. Considerations of drug therapy in patients receiving enteral nutrition. Nutr Clin Pract. 1989; 4:105–10.

4. Thomson F.C., Naysmith, M.R. & Lindsay, A. Managing drug therapy in patients receiving enteral and parenteral nutrition. Hosp Pharmacist. 2000;7:155–64.

5. Gilbar PJ. A guide to enteral drug administration in palliative care. J Pain Symptom Manage. 1999;17:197–207.

6. Rombeau JL, Caldwell MD, eds. Clinical Nutrition: Enteral and Tube Feeding. 3rd ed. Philadelphia, PA: WB Saunders; 1997.

7. Janson DD, Chessman KH. Enteral nutrition. In: DiPiro JT et al, eds. Pharmacotherapy: A Pathophysiologic Approach. 5th ed. New York, NY: McGraw-Hill; 2002, 2495–517.

8. Mitchell JF. Oral dosage forms that should not be crushed or chewed. Hosp Pharm. 2002; 37:213–14.

9. Dickerson RN, Melnik G. Osmolality of oral drug solutions & suspensions. Am J Hosp Pharm. 1988;45:832–34.

10. Jew RK, et al. Osmolality of commonly used medications and formulas in the neonatal intensive care unit. Nutr Clin Pract. 1997;12:158–63.

11. Lutomski DM, et al. Sorbitol content of selected oral liquids. Ann Pharmacother. 1993;27:269–74.

12. Burns PE, et al. Physical compatibility of enteral formulas with various common medications. J Am Diet Assoc. 1988;88:1094–6.

13. Cutie AJ, et al. Compatibility of enteral products with commonly employed drug additives. JPEN J Parenter Enter Nutr. 1983;7:186–91.

14. Healy DP, et al. Ciprofloxacin absorption is impaired in patients given enteral feedings orally and via gastrostomy and jejunostomy tubes. Antimicrob Agents Chemother. 1996;40:6–10.

15. de Marie S, et al. Bioavailability of ciprofloxacin after multiple enteral and intravenous doses in ICU patients with severe gram-negative intra-abdominal infections. Intensive Care Med. 1998;24:343–6.

16. Wright DH, et al. Decreased in vitro fluoroquinolone concentrations after admixture with an enteral feeding formulation. JPEN J Parenter Enter Nutr. 2000;24:42–8.

17. Cohn SM, et al. Enteric absorption of ciprofloxacin during tube feeding in the critically ill. J Antimicrob Chemother. 1996;38:871–6.

18. Mueller BA, et al. Effect of enteral feeding with Ensure on oral bioavailabilities of ofloxacin and ciprofloxacin. Antimicrob Agents Chemother. 1994;38:2101–5.

19. Mimoz O, et al. Pharmacokinetics and absolute bioavailability of ciprofloxacin administered through a nasogastric tube with continuous enteral feeding to critically ill patients. Intensive Care Med. 1998;24:1047–51.

20. Cacek, A.T., DeVito, J.M. & Koonce, J.R. 1986. In vitro evaluation of nasogastric administration methods for phenytoin. Am. J. Hosp. Pharm. 43: 689-692.

21. Clark-Schmidt, A.L., Garnett, W.R., Lowe, DR et al. 1990. Loss of carbamazepine suspension through nasogastric feeding tubes. Am. J. Hosp. Pharm. 47: 2034-2037.

22. Williams, N.E. 2008. Medication administration through enteral feeding tubes. Am. J. Hosp. Pharm. 65(24): 2347-2357.

23. Beckwith, M.C., Feddema, S.S., Barton, R.G. & Graves, C. 2004. A guide to drug therapy in patients with enteral feeding tubes: dosage form selection and administration method. Hospital Pharmacy. 39(3): 225-237.

CHAPTER 3: DOSING

3.1 RENAL DOSING

Acute renal failure is common in critical care situations and is associated with significant morbidity and mortality. Rapid assessment of renal function is important in critical care for the following reasons:

Emergency angiography (coronary or otherwise) Emergency dosing of drugs with narrow therapeutic window Severe CHF or volume overload condition Severe hyperkalemia

Investigations have to be carried on in order to determine renal status or renal injury. Measurements included:

Estimation of GFR Assessment of Proteinuria or other urine markers of renal injury Functional assessment of renal function (e.g. Fractional excretion of sodium) Urine volume

Acute Renal Failure characterized by deterioration of renal function over a period of hours to days. The mortality rate for patients in the intensive care unit (ICU) is lower in those who have ARF, especially when ARF is severe enough to require dialysis treatment. In addition, evidence suggests that the relative risk of death is 4.9 in patients in the ICU who have renal failure that is not severe enough to require dialysis. The mortality rate in postoperative renal failure is 24 - 100% and about 50 - 70% in intensive care who require dialysis. Mortality rate has not decreased significantly over the past 50 years.

A prospective multicenter observational study (Beginning and Supportive Therapy for the Kidney (BEST) Study) had discovered the incidence of ARF among 29,269 subjects of critically ill ICU patients was 5.7% and 2/3 required dialysis. 30% of the total subjects studied already had pre-existing renal dysfunction. Overall mortality associated with ARF was 60.3%. The most common contributing factor is septic shock. This study defined ARF as oliguria and/or BUN > 84mg/dl (>30mmol/L).JAMA 294:813;2005

Cockcroft Gault Equation is most common method being used in estimating GFR:

RIFLE criteria are one type of classification to determine the progression of renal damage. A study done on 5,383 intensive care unit patients, 67% developed acute renal injury. 12% of patient with R classification had mortality rate of 8.8%, 27% patient with I classification had mortality rate of 11.4% and 28% patient with F classification had

(140-Age)xWeight (kg) x (0.85 if female)

72xSCr

mortality rate of 26.3%. More than 50% patients progressed from ‘‘R’’to ‘‘I’’or ‘‘F’’ had worse outcomes than non-progressed. (Hosteet al. Critical Care 10:R73, 2006et 2006)

RIFLE Criteria - adopted from Bellomo et al Crit Care 8:R204; 2004

Standard guideline

Agent Usual Dosage Renal Dosing

AMPICILLIN Mild to moderate infection: 500mg to 2g ivpb q6h. Severe infection: 2g ivpb q4h (150-200mg/kg/day)

>50/ q6h || 10-50/ q6-12h || <10/ q12-24 hours || Hemodialysis: Dose after dialysis || PD: 250mg q12h.

AMPICILLIN (Oral) Usual dose: 250mg to 1g po q6h (50-100mg/kg/ day).

>50/ no changes || 10-50/ q6-12h || <10/ q12h

AMPICILLIN - SULBACTAM (UNASYN)

Usual dose: 1.5 to 3g ivpb q6h >30/ q6-8h || 15-29/ q12h || 5-14/ q24h

AUGMENTIN (Oral) Usual dose: 875mg po q12h or 250-500mg po q8h

>30/ no change || 10-30/ 250-500mg q12h || <10/ 250-500mg po q24h

AZACTAM Mild infection (i.e. UTI): 500mg to 1g ivpb q8-12h. Usual dose: 1-2g ivpb q8-12h. Severe or life threatening: 2g ivpb q6-8h. Max 8g/day

>30/ no change || 10-30/ 50% of usual dose q6-8h || <10/ 25% of usual dose q6-8h || HD/PD: see <10 guidelines. (HD: 500mg AD) Give loading dose of 1-2g before starting regimens above.

AZITHROMYCIN (ZITHROMAX)

Usual oral dose: 500mg x 1, then 250mg po qd x 4 days. Chlamydia: 1gram po x 1. MAC prevention: 1200mg qwk or 500mg po TTW. PID or CAP: 500mg ivpb qd x 2 days or more than 500mg po qd. Uncomplicated gonococcal infection: 2 grams orally x1 *(see comments)

No adjustments required in renal failure. Cannot be given IM. *Because of the high incidence of gastric upset with the 2 gram dose--this is the least preferred regimen for treatment of uncomplicated gonococcal infections.

BACTRIM IV: Usual dose: 8-10mg/kg/day divided q6h, q8h or q12h. PCP: 15-20mg/kg/day in 3 or 4 divided doses. Oral: UTI: 1 DS tab (160mg TMP/800mg SMX) po q12h.

>30/ no change || 15-30/ 50% of usual dose q12h-alternatively: 8-10mg/kg/day divided q12h x 1-2 days, then 4-6mg/kg q24h. || <15/ not recommended by manufacturer. Alternatively: 8-10mg/kg/dose q48h or 4-6 mg/kg/day.

CEFAZOLIN Usual: 500mg to 1g ivpb 8h. Severe: 1.5g ivpb q6h. Life threatening: 6-12g/day.

>55/q6-8h || 35-54/q8h || 11-34/ 50% usual dose q12h || <10 ml/min/ 50% to full dose q24-48h. || Hemodialysis: 0.5-1 gram after dialysis

CEFEPIME (MAXIPIME)

Mild to moderate infection: 500mg to 2g ivpb q12h. Severe: 2g ivpb q8h.

>60/ 0.5-2g q12h || 30-60/ 0.5g-2g q24h || 11-29/ 0.5g-1g q24h || <10/ 250-500mg q24h or 0.5-2g q48h. || HD: 1g AD || PD: 1-2 grams q48h


CEFOTETAN (IV) Usual dose: 1g ivpb q12h. Severe: 2-3g ivpb q12h. (Max 6g/day)

>30/ Usual dose || 10-30/ 50% of dose q12h || <10/ 25% of dose q12h.|| Hemodialysis or PD: 50% of usual dose q24h

CEFOXITIN (IV) Mild infection: 1g ivpb q6-8h Moderate-severe: 1g ivpb q4h or 2g ivpb q6-8h. Life-threatening: 2g ivpb q4h or 3g ivpb q6h.

10-50/ q8-12h || <10/ q24-48h || HD: give 1g after Dialysis: e.g. Give Cefoxitin 1g ivpb M-W-F after dialysis + a supplemental dose on Sunday.

CEFOTAXIME (IV) Mild infection: 1-2g ivpb q12h. Moderate: 1-2g ivpb q8h; Severe: 2g ivpb q6-8h; Life threatening: 2g ivpb q4h (Max dose/day= 12g)

>50/ Usual dose || 10-50/ q8-12h || <10/ q24h || HD: 0.5 to 2g ivpb q24h AD. || PD: 1g ivpb q24h.

CEFUROXIME (IV) Usual: 750mg to 1.5g ivpb q8h. Severe: 1.5g ivpb q6-8h.

>20/q8h || 10-20/ q12h || <10/ 750mg q24h. || Hemodialysis: Give single dose after dialysis or give 750mg q12h. || PD: 750mg-1.5g q24h

CEFTIN (ORAL) Usual dose: 250-500mg po q12h No changes req'd (usual oral doses are not significant).

CEFTRIAXONE (IV) Usual dose: 1-2g ivpb q24h. Severe: 2g ivpb q12h

No dosage adjustments req'd in renal failure. PD: 750mg ivpb q12h

CEFTAZIDIME (IV) Usual dose: 1g ivpb q8-12h. Severe: 2g ivpb q8-12h. (Max dose/day= 6 grams).

Crcl 30-50/ q12h || 10-30/ q24h || <10/ q48h

CEPHALEXIN KEFLEX/VELOSEF

Usual dose: 250-500mg po q6h; 500mg-1g q12h.

Keflex: 10-50/ q6-12h || <10/ q12-24h . Velosef: >20/ no change || 5-20/ 250mg q6h || < 5/ 250mg q12h

CIPROFLOXACIN (CIPRO)

Oral dosing: 250-750mg po q12h; cystic fibrosis: 750mg po q8h. IV dosing: 200-400mg ivpb q12h. Febrile neutrapenic pt: 400mg ivpb q8h

>50/ no change || 10-50/ 50-75% of usual dose q12h || <10/50% of usual dose q12. Alternatives: [200mg ivpb or 250mg po q12h] or [400 mg ivpb or 500mg po q24h]. || HD/PD: 250-500mg po or 200-400mg ivpb q24h AD or 200mg ivpb or 250mg po q12h.

CLARITHROMYCIN (BIAXIN)

Usual dose: 250-500mg orally q12h. Severe (Legionella): 500-1000 mg po q12h. Helicobacter: 500mg po tid.

Severe renal dysfunction: decrease dose or increase interval. [crcl < 30 ml/min: 500mg loading dose, then 250 mg once or twice daily.]

CLINDAMYCIN (IV/PO)

Usual oral dose: 150-400mg po q6h. Usual IV dose: 600mg ivpb

No dosage adjustments required for renal


q6-8h or 900mg ivpb q8h. Maximum daily dose= 4800mg

failure

DICLOXACILLIN (Oral)

Usual dose: 250-500mg po q6h No changes required for renal insufficiency.

DOXYCYCLINE (VIBRAMYCIN)

Usual dose: 100mg po bid x1 f/b 100mg qd or divided bid (if severe: 100mg po bid) or 100-200mg ivpb qd or divided doses q12h.

No dosage adjustments required for renal failure

ERYTHROMYCIN Usual oral dose: 500mg to 1g po q12h or 250mg to 1g po q6h. Usual IV dose: 250mg to 1g q6h. Max 4 g/day.

>10/ No change || <10/ 50-75% of usual dose. Max 2 grams/day. || Hemo: no supplement.

IMIPENEM (PRIMAXIN)

Mild to moderate infection: 250-500mg ivpb q6-8h. Severe infection: 500mg to 1g ivpb q6-8h. Max dose/day= 50mg/kg/day or 4g/day

31-70/ 500mg q6-8h || 21-30/ 500mg q8-12h max || 0-20/ 250-500mg q12h max. || HD: 250 mg AD + q12h. || PD: max dose= 1gram/day i.e. 500mg ivpb q12h.

LEVOFLOXACIN (LEVAQUIN)

Usual dose: 500mg po or ivpb q24h. UTI or pyelonephritis: 250mg po/ivpb q24h.

>50/ no change || 20-49/ 500mg x 1 then 250mg q24h || <19/HD/PD: 500mg x 1 then 250mg q48h

METRONIDAZOLE (FLAGYL)

IV: 1 gram or 15 mg/kg load IV, then 500mg or 7.5 mg/kg q6h (range: q6-12h --long T ½ ). Oral: 250-750mg po tid. (occasionally bid). Max 4g/day.

> 10/ no change || <10/ 500mg ivpb q12h.

NAFCILLIN Mild to moderate infection: 500mg to 1g ivpb q4h or 1-2g ivpb q6h. Severe: 1-2g ivpb q4h

No dosage changes req'd for renal failure. || Renal + Hepatic dysfcn: decrease dose by 50%.

OFLOXACIN (FLOXIN)

Usual dose: 200-400mg po/IV q12h.

>50/ no change || 10-50/ usual dose q24h || <10/ 100-200mg q24h

PENICILLIN G (Aqueous)

Usual dose: 0.5 to 4 mu q4-6h. Severe infection: Dosing interval q2-3h (i.e. 3mu q3h). Max dose per day: up to 30 million units

>50/ Usual dose || 10-50/ 75% of usual dose || <10/ 20-50% of usual dose. || Hemo/PD: 20-50% of dose usually q6h. Max dose in ESRD: 6 mu/day.

PEN VK (Oral) Usual dose: 250-500mg po q6h >10/ No Changes || <10/ 250-500mg po q8h

PENICILLIN G Group A strept URI: 1.2 mu IM x Administer by deep IM in the upper outer


BENZATHINE Peak: 12-24hrs Duration: 1-4 wks.

1. Prophylaxis of recurrent rheumatic fever: 1.2mu q3-4wks. Early syphilis: 2.4mu x 1 (in 2 injection sites). Late syphilis (> 1yr): 2.4 mu (in 2 sites) qwk x 3.

quadrant of the buttock. Not indicated as single drug tx of neurosyphilis, but may be given 1 time/wk x 3 weeks following IV tx. Levels: (time to peak): 12-24hrs. Levels are detectable for 1-4 wks. Higher doses increase duration not peak. Use a PCN-procaine/benzathine combination (bicillin) to achieve early peak levels in acute infections. [Supplied: 600,000 u/ml (1ml., 2ml, 4ml)

PENICILLIN G PROCAINE

Peak: 1-4 hrs Duration: 15-24 hours

Dosing: 0.6 to 4.8 mu/day in 1-2 dd. Uncomplicated gonorrhea: 1g probenecid f/b 4.8mu divided into 2 inj sites 30min later. Endocarditis (strept): 1.2 mu q6h x 2-4wks. Neurosyphilis: 2-4 mu/day + 500mg probenecid qid x 10-14days(Note: IV Pcn is D.O.C)

Time to peak: 1-4 hrs. Duration: 15 to 24 hours. Supplied: 600,000 u/ml (1 ml, 2ml, 4ml). 300,000u/ml-10ml vial.

PIPERACILLIN Mild infection: 3-4g ivpb q6-8h Serious infection: 3-4g ivpb q4-6h (200-300mg/kg/day) Max 24g/day

>40/ No change || 20-40/ 4g q8h || <20/ 4g q12h || HD/PD: 2g q8h. || Alternatively: >50/q4-6h || 10-50/ q6-8h || <10/ q8h

PIPERACILLIN-TAZOBACTAM (ZOSYN)

Mild infection: 3.375g ivpb q6h Moderate to severe: 3.375g ivpb q4h

>40/ 3.375g q6h || 20-40/ 2.25g q6h || <20/ 2.25g q8h || HD: Max 2.25g q8h. 0.75g AD. || PD: 2.25g q8h

SYNERCID 7.5 mg/kg ivpb q8-12h (usually q8h). Dilute dose in 250ml D5W and infuse over 1 hour.

TETRACYCLINE Usual dose: 250-500mg po/iv q6h.

50-90/ q8-12h || 10-50/ q12-24h || <10/ q24h (use not recommended)

TIMENTIN Usual dose: 3.1g ivpb q4-6h >60/ 3.1g q4-6h || 30-60/q8-12h || 10-30/ q12-24h or 2g ivpb q8h || <10/ 2g q12h or 3.1g q24-48h || <10 + hepatic dysfcn/ 2g q24h || PD: 3.1g q12h || Hemodialysis: 2g q12h + 3.1g after dialysis.

ANTIFUNGALS

AMPHOTERICIN B Test dose: (optional): 1 mg/20-50 ml D5W over 10-30 min. Monitor temp, pulse, RR and BP q30min x 4 hours. Do not give premeds with test dose. Maintenance dose: Initially give 0.25-0.3 mg/kg/day. Increase as tolerated by an equivalent amountqd. Usual daily dose: 0.5-1 mg/kg/day or up to 1.5 mg/kg qod. For life-


threatening infection may give full dose the first day (usually 0.6-0.7 mg/kg IBW on Day # 1). Premedication: Prevention of fever/chills: Tylenol 650mg PO/PR + Benadryl 25-50mg PO/IVP 60min prior to maintenance infusion. May also add: Hydrocortisone 25-50mg IV/IM +/- Demerol 50mg IV. Renal dosing: <10/ q24-36h. During therapy if the BUN increases above 40 mg/dl or the serum creatinine exceeds 2.5-3 mg/dl, Hold Ampho B until renal function improves, then restart at a reduced dose or change to QOD dosing until Serum creatinine/BUN improve. Bladder irrigation: Add 30-50mg Ampho B to 1000ml (or less) sterile H2O administered intermittently or continuously for 2 to 14 days. (Note: use of D5W for Bladder irrigations is not recommended because of the possibility of enhancing microbial and fungal growth in the bladder).

FLUCONAZOLE (DIFLUCAN)

Oral: Oropharyngeal candidiasis: 200mg po x 1, f/b 100mg po qd. Esophageal candidiasis: 100-200 mg po qd (up to 400mg/day). Cryptococcal meningitis: 400mg po x 1, f/b 200mg po qd x 10-12 weeks (Suppression: 50-200mg po qd). Onychomycosis: 200-300mg qweek or 100-200mg po qod (further studies needed). IV: since oral absorbtion is rapid and essentially complete-IV dose=oral dose.

>50/ no change || <50 / 50% of usual dose. || Alternatively: 20 to 50/ give normal dose q48h. || <20 / 50% of usual dose q48h. || Hemodialysis: give 100-200mg after each dialysis. || CAPD: give 50% of usual dose at usual interval.

FLUCYTOSINE (ANCOBON

Dosing: 12.5 to 37.5 mg/kg po q6h (50 to 150mg/kg/day). Doses up to 250 mg/kg/day have been used in severe infections. Capsules should be taken a few at a time over 15 min to minimize N&V.

>50 / no change || 10 to 50/ q12-24 hrs || <10 / q24-48 hrs. || Hemodialysis: Single doses after dialysis || CAPD: 500mg to 1 gram q24h

ITRACONAZOLE (SPORANOX)

Systemic mycosis: 200mg po qd with food (up to max of 400mg/day if unsatisfactory clinical response with lower dose). Doses >200mg are given in 2 divided doses. Onychomycosis: 200mg po bid for 1 week each month x 2 months (fingernails); x 3-4 months (toenails). Oropharyngeal candidiasis: 200mg (20ml)-oral solution-swish vigorously then swallow once daily x 1-2 weeks. Esophageal candidiasis: 100mg

No adjustments necessary in renal insufficiency.Duration of therapy: Oral candidiasis, Tinea Corporis, and Tinea Cruris: 15 days. Tinea Pedis: 30 days. Tinea Capitis: 4-8 weeks.[100mg capsule; 10 mg/ml oral soln]


(10ml) oral soln-swish and swallow qd x 3 weeks. May increase to 200mg/day. Life-threatening infections: Loading dose: 200mg po tid should be given for the first 3 days of therapy, then 200-400mg/day.

TERBINAFINE (LAMISIL)

Superficial mycoses(tinea corporus, cruris, pedis, capitis; cutaneous candidiasis): 250 mg po qd. Onychomycosis: (fingernails) 250mg po qd x 6 weeks or pulse dosing: 500mg po qd for 1st week of month x 2 months. (Toenails): 250mg po qd x 12 weeks or pulse dosing: 500mg po qd for 1st week of month x 4 months. Systemic mycosis: 250-500mg po qd.

Specific guidelines are not available for renal or hepatic insufficiency. [250mg tab]

ANTIVIRALS

ACYCLOVIR (ZOVIRAX)

Mucocutaneous herpes simplex: IV: 5 mg/kg/dose q8h x 5-10 days. Encephalitis: 10mg/kg/dose IV q8h. Primary HSV infection-genital (Oral tx): 200mg q4h while awake (5x/day) or 400mg po tid x 10 days. Recurrent genital: 400mg po tid x 5 days. Herpes Zoster: 800mg po q4h while awake (5x/day) x 7 days. If severe give 10-12 mg/kg IV q8h x 7-14 days. Chronic suppression (genital herpes): 400mg po bid. Zovirax ointment: apply ½" q3h (6 x/day).

50 - 90/ 5 to 12.4 mg/kg q8h || 10-50 / 5-12.4 mg/kg q12-24h || <10 / 2.5 to 6 mg/kg q24h. Alternatively: (Oral): 10-25 / dose q8h || <10 / dose q12h. (IV): 25-50/ 5-10mg/kg q12h || 10-25/ 5-10mg/kg q24h || <10/ 2.5 to 5mg/kg IV q24h. || HD: dose after dialysis || CAPD: see < 10.

FAMCICLOVIR (FAMVIR)

Herpes Zoster: 500mg po q8h x 7 days. Recurrent herpes simplex(genital): 125 mg po bid x 5 days. Primary Genital herpes simplex: 250 mg po tid x 5-10 days. Genital-chronic suppression: 250 mg po bid. [125mg, 250mg, 500mg tablet]

>60/ no change || 40-59/ 500mg q12h || 11-39/ 500mg q24h || <10/ 250 mg q48h || HD: 250mg after dialysis.


VALACYCLOVIR (VALTREX)

Herpes zoster: 1000mg po tid x 7 days. Primary genital herpes: 1000mg po bid x 10 days. Recurrent genital: 500mg po bid x 5 days. Genital-chronic suppression: 500mg po qd [500mg caplet]

>50/ no change || 30-49/ 1 gram q12h || 10-29/ 1 gram q24h || <10/ 500mg q24h. || HD: dose after dialysis. || CAPD: 500mg q24h.

AMANTADINE (SYMMETREL

Parkinsons dx: 100mg po bid. Influenza A viral infection: 200mg/day in 1-2 divided doses.

50-60/ 200mg alternating c 100mg po qd || 30-50/ 100mg qd || 20-30/ 200mg twice weekly || 10-20/ 100mg 3x/week || <10/ 200 mg alternating c 100mg q7 days. || HD/PD: No supplemental dose req'd.

RIMANTADINE (FLUMADINE)

Prophylaxis and treatment of influenza A virus. Dosing: 100mg po bid. [100mg tab; 50mg/5ml syrup]

> 10/ no change || <10/ 100mg po qd

H2 Antagonists

Cimetidine (Tagamet)

Active ulcer: Oral: 800 mg orally at bedtime or 300mg orally four times daily or 400 mg orally twice daily. IM/IV: 300mg every 6 hours or 37.5 mg/hr continuous infusion. Active bleed: 37.5 mg/hr continuous IV (maximum 2400mg/day). Maintanance (duodenal ulcer prophylaxis): 400mg orally at bedtime. Gastric hypersecretory conditions: 300-600mg every 6 hours.

CRCL (> 40ml/min) / 300mg q6-8h ; (20-40 ml/min) / 300 mg q8h ; (5-20ml/min) /200-300mg q12h; (< 5ml/min) / 200mg q12h.

Famotidine (Pepcid) Usual dose (Acute): 40mg orally at bedtime or 20mg orally twice daily. Maintenance: 20 mg orally at bedtime. Hypersecretory conditions: 20mg orally every 6 hours. May increase up to 160mg orally every 6 hours

CRCL > 50 ml/min: No changes (40mg IV/PO qd or 20mg q12h.) || CRCL < 50 ml/min: Oral: 20mg qd or 40mg qod. IV: 20mg q24h. [Since CNS adverse effects have been reported in patients with moderate and severe renal insufficiency, to avoid excess accumulation of the drug in patients with moderate or severe renal insufficiency, the dose of PEPCID may be reduced to half the dose or the dosing interval may be prolonged to 36-48 hours as indicated by the patient's clinical response.]

Nizatidine (Axid) Usual: 300mg orally at bedtime or CRCL > 50 ml/min: Usual dose || CRCL


150 mg orally twice daily. Maintenance: 150mg orally at bedtime. Supplied: [150, 300mg capsule]

20-49 ml/min: 150mg qd. || CRCL < 20 ml/min: 150mg qod.

Ranitidine (Zantac) Usual dose: 150mg orally twice daily or 300mg orally at bedtime. Maintenance: 150mg orally at bedtime. Gastric hypersecretory conditions: 150mg orally 2 to 4 times daily. IVPB: 50mg every 6 to 8 hours (Maximum: 400mg/day) Continuous infusion: (preferred in actively bleeding patients): 6.25 mg/hr titrated to gastric pH >4 for prophylaxis or >7.0 for treatment.

CRCL (ml/min) >50/ no change; 10-50: Administer at 75% of normal dose or administer 50mg IV or 150mg orally every 18-24 hours. CRCL <10 mL/minute: Administer at 50% of normal dose or administer 50mg IV every 18-24 hours or 150mg orally q24h. || Hemodialysis: Slightly dialyzable (5% to 20%). Give dose at end of dialysis session.

References

1. American Hospital Formulary Service. Drug Information. Bethesda, MD: ASHP, 1997.

2. Bartlett JG.1998 Pocket Book of Infectious Disease Therapy., Ninth Edition. Baltimore,MD: Williams&Wikins,1998.

3. Bennett, WM, Aronoff, GR et. al. Drug Prescribing in Renal Failure: Dosing Guidelines for Adults. Fourth Edition, 1999.

4. Drug Information Handbook, 5th Ed. 1997, Lexi-Comp inc.

5. Gilbert DN, Moellering RC, Sande MA. The Sanford Guide to Antimicrobial Therapy 2000. 30th ed. Hyde Park,VT: Antimicrobial Therapy, Inc.; 2000.

ANTIBIOTIC DOSING IN RENAL IMPAIRMENT

DRUG NAME USUAL DOSE (Normal renal function)

CrCl (ml/min)

DOSAGE ADJUSTMENT (in renal insufficiency)

ABACAVIR 300 mg PO q12h no change no change ACYCLOVIR 5 - 10 mg/kg IV q8h > 50 5 - 10 mg/kg IV q8h

25-50 5-10 mg/kg IV q12h 24-10 5 - 10 mg/kg IV q24h 0-9 2.5 -5 mg/kg IV q24h HD 2.5 - 5 mg/kg IV q24h (give dose after

dialysis on dialysis days) 200 mg PO q4h (5x daily)

> 10 no adjustment necessary


CrCl (ml/min)


0-10 200 mg PO q12h 400 mg PO q4 (5x daily) - 12h

>10 no adjustment necessary

0-10 200 - 400 mg PO q12h 800 mg PO q4 (5x daily) - 12h

> 25 no adjustment necessary

24-10 800 mg PO q8 - 12h 0-9 400 - 800 mg PO q12h HD 800 mg PO q12h (give dose after dialysis

on dialysis days) AMOXICILLIN 500 mg - 1 gm PO

q12h > 30 no dose adjustment necessary 24-10 250 - 875 mg PO q12h <10 250 - 875 mg PO q24h HD 250 - 875 mg PO q24h + 250 - 500 mg

after each HD AMOXICILLIN + CLAVULANATE

500 - 875 mg PO q12h >15 normal dose and interval 15-5 500 - 875 mg q24h < 5 250 - 500 mg q24h HD 250 - 500 mg q24h + 250 - 500mg after

each HD AMPHOTERICIN B 0.25 - 1.5 mg/kg/day *

not to exceed total daily dose of 1.5 mg/kg

no dose change necessary

AMPICILLIN 250 mg - 2 gm IV q4-6h

> 30 no dose adjustment necessary 30-10 normal dose q6 - 8h < 10 normal dose q8h HD normal dose q8h + supplemental dose

after each HD AMPICILLIN / SULBACTAM

1.5 - 3 gms IV q6h > 30 normal dose IV q6h 15-30 normal dose IV q12h < 15 normal dose IV q24h HD normal dose q24h + supplemental dose

after each HD AMPRENAVIR 1200 mg PO q12h no change no change AZITHROMYCIN 500 mg IV/PO once

daily for 3 days no change no change

AZTREONAM 1 - 2 gms IV q8h > 30 normal dose 30-10 load with 1-2 gm, then 500 mg - 1 gm IV

q8h <10 load with 1-2 gm, then 250 - 500 mg IV

q8h HD dose for CrCl < 10 + supplemental dose

after HD CEFAZOLIN 500 mg - 1 gm IV q8h > 35 no dose adjustment necessary

35-10 500 mg - 1 gm q12h < 10 500 mg - 1 gm q24h


CrCl (ml/min)


HD 2 gm after each HD CEFEPIME 1 - 2 gm IV q12h > 60 no dose adjustment necessary

30 - 60 1 - 2 gm q 24h 29-10 500 mg - 1 gm q24h < 11 250 - 500 mg q24h HD dose for CrCl < 11 + 250 - 500 mg after

each HD 2 gm IV q8h (meningitis)

> 60 no dose adjustment necessary

30-60 2 gm IV q12h 29-10 2 gm IV q24h < 10 1 gm IV q24h HD dose for CrCl < 11 + 1 gm after each HD

1 gm IV q8h (neutropenic fever)

> 60 no dose adjustment necessary 30 - 60 1 gm IV q12h 29-10 1 gm IV q24h < 11 500 mg IV q24h HD dose for CrCl < 11 + 500 mg after each

HD CEFTRIAXONE 1 - 2 gms IV q24h no change * adults with both renal and hepatic

failure should not receive more than 2 gm/day

* max. dose = 4 gm/day

CEFUROXIME AXETIL

250 - 500 mg PO q12h > 10 normal dose < 10 250 mg PO q24h

CEFOTAXIME 500 mg - 1 gm IV q8h > 35 no dose adjustment necessary 35-10 1 gm q12h < 10 1 gm q24h

CLARITHROMYCIN 250 - 500 mg PO q12h > 30 normal dose < 30 If normal dose is 500 mg PO q12h: give

load of 500 mg then 250 mg q12h If normal dose is 250 mg PO q12h, give 250 mg q24h

CLINDAMYCIN 600 mg IV q8h OR 150 - 450 mg PO q6h

no change no change

DICLOXACILLIN 125 - 500 mg PO q6h no change no change DIDANOSINE (ddI) > 60 kg: 200 mg PO

q12h OR 400 mg PO q24h (tablets) <60kg: 125 mg PO q12h 250 mg PO q24h (tablets) OR

50 > 60 kg: normal dose < 60 kg: normal dose

26 - 49 > 60 kg: 100 mg PO q12h or 200 mg PO q24h (tablets) < 60 kg: 75 mg PO q12h or 150 mg PO q24h (tablets)

25-10 > 60 kg: 150 mg PO q24h (tablet) < 60 kg: 100 mg PO q24h (tablet)

< 10 > 60 kg: 100 mg PO q24h (tablet) < 60 kg: 75 mg PO q24h (tablet)


CrCl (ml/min)


HD dose for CrCl < 10 DOXYCYCLINE 100 mg IV/PO q12h no change no change EFAVIRENZ 600 mg PO q24h no change no change ERYTHROMYCIN 250 - 500 mg PO q6 -

12h OR 15 - 20 mg/kg/day IV divided q6h

no change no change

ETHAMBUTOL 15 - 25 mg/kg/day > 50 normal dose 10-50 normal dose q24 -36h < 10 normal dose q48h HD normal dose after each HD

FLUCONAZOLE Loading Dose: 100 - 800 mg PO/IV q24h Maintenance Dose: 50 - 800 mg PO/IV q24h

> 50 normal dose

< 50 (no HD)

50% normal dose q24h

HD load with 100 - 400 mg, then normal dose after each HD

FLUCYTOSINE(5-FC)

50 - 150 mg/kg/day PO divided q6h

> 40 normal dose 20 - 40 12.5 - 37.5 mg/kg q12h 20-10 12.5 - 37.5 mg/kg q24h < 10 12.5 - 37.5 mg/kg q24 - 48h HD If receiving HD q 48 - 72h then 20 - 50

mg/kg immediately after each HD GANCICLOVIR IV Induction: 5 mg/kg IV

q12h x 14 - 21 days >70 5 mg/kg q12h 50-69 2.5 mg/kg q12h 25-49 2.5 mg/kg q24h <25 1.25 mg/kg q24h HD 1.25 mg/kg 3x/week with doses given

after HD Maintenance: 5 mg/kg IV q24h

>70 5 mg/kg q24h 50-69 2.5 mg/kg q24h 25-49 1.25 mg/kg q24h <25 0.625 mg/kg q24h HD 0.625 mg/kg 3x/week with doses given

after HD IMIPENEM (Refer to product information for complete prescribing information for patients requiring different total daily doses)

500 mg IV q6h (2 g/day) [Note that meningitis dose is higher (up to 1g q 6h, depending on renal function- consult ID)]

> 71 > 70 kg: 500 mg q6h 60 - 69 kg: 500 mg q8h 50 - 59 kg: 250 mg q6h 40 - 49 kg: 250 mg q6h 30 - 39 kg: 250 mg q8h

41 - 70 > 70 kg: 500 mg q8h 60 - 69 kg: 250 mg q6h 50 - 59 kg: 250 mg q6h 40 - 49 kg: 250 mg q8h

21 - 40 > 70 kg: 250 mg q6h **In patients undergoing hemodialysis or with a Clcr of 6-20 ml/min, the 500mg IV q 12 hour dose should be reserved for treatment of severe infections. Patients with Clcr < 5 ml/min should not receive imipenem/cilastatin unless dialysis is going to be instituted within 48


CrCl (ml/min)


hours. These patients may be at an increased risk of seizures.

INDINAVIR 800 mg PO q 8h no change no change ISONIAZID 300 mg PO daily no change no change ITRACONAZOLE 100 - 200 mg PO

(capsule / solution) q12h OR 200 mg IV q12h x 4 doses, then 200 mg IV q24h ***IV use NOT TO EXCEED 14 days***

PO: no change

PO: no change

IV: > 30 normal dose IV: < 30 not recommended due to injectable

excipient

LAMIVUDINE 150 mg po q 12h > 50 150 mg PO q12h

30-49 150 mg PO q24h

15-29 150 mg x 1,then 100 mg PO q24h

14-May 150 mg x 1, then 50 mg PO q24h

< 5 150 mg x 1, then 25 mg PO q24h

HD 150 mg x 1, then 25 - 50 mg PO q24h

LAMIVUDINE/ZIDOVUDINE (COMBIVIR)

1 tablet PO q12h not recommended in fixed combination for Clcr < 50 ml/min

LEVOFLOXACIN If normal dose 250 mg IV/PO q24h

> 20 250 mg q24h < 20 and HD

250 mg q48h

If normal dose 500 mg IV/PO q24h

> 50 500 mg q24h 20 - 49 500 mg q48h < 20 and HD

500 mg x 1, then 250 mg q48h

CVVHD 500 mg q 48h If normal dose 750 mg IV/POq24 h (note that the 500 mg q 24h dosage schedule shown above should be used if the levofloxacin MIC is <0.5 ug/ml)

> 50 750 mg q24h 20 - 49 750 mg q48h < 20 and HD

750 mg X 1, then 500 mg q48h

CVVHD 750 mg q 48h

LINEZOLID 600 mg IV/PO q12h no change no change MEROPENEM 1 gm IV q 8h - (note

that meningitis dose is higher, 2g q 8h, with normal renal function)

>50 normal dose 26-50 normal dose q12h 25-Oct 50% normal dose q12h <10 50% normal dose q24h HD 50% normal dose q24h + 50% normal

dose after each HD


CrCl (ml/min)


METRONIDAZOLE 500 mg IV/PO q12h no change no change 500 mg IV/PO q8h (C. difficile diarrhea)

no change no change

NAFCILLIN 2 gm IV q4-6h no change no change NELFINAVIR 1250 mg PO q12h no change no change NEVIRAPINE 200 mg PO q12h no change no change NITROFURANTION 50-100 mg PO q12h > 40 normal dose

< 40 avoid use: therapeutic levels not attained in the urine

NORFLOXACIN 400 mg PO q12h > 30 normal dose < 30 normal dose PO q24h

PENICILLIN G 2.0 - 4.0 million units IV q4h

> 125 3.0 - 4.0 million units q4h 60 - 124 1.8 - 2.0 million units q4h 40 - 59 1.3 - 1.5 million units q4h 20 - 39 800,000 - 1.0 million units q4h 19-Oct 800,000 - 1.0 million units q6h < 10 & HD 500,000 - 800,000 units q6h < 10 & ESLD

500,000 units q8h

PENTAMIDINE 4 mg/kg IV or IM q24h > 50 normal dose Oct-50 normal dose q24-36h < 10 normal dose q48h HD dose for CrCL < 10 ml/min

PIPERACILLIN/TAZOBACTAM

Mild to Moderate Infections: 3.375 gm IV q6h

>40 normal dose 20-40 2.25 gm q6h <20 2.25 gm q8h HD 2.25 gm q8h + 1.125 gm supplemental

dose after each HD Severe/life threatening infections: 4.5 gm IV q6h


dose after each HD Pseudomonas aeruginosa infections*: 3.375 gm IV q4h. * Combination therapy with an aminoglycoside may be indicated, depending on piperacillin MIC and site of infection. Treatment of uncomplicated UTIs can be with "mild to


dose after each HD


CrCl (ml/min)


moderate infection" dosages

QUINUPRISTIN/DALFOPRISTIN

7.5 mg/kg IV q8h no change no change

PYRAZINAMIDE 15-30 mg/kg/d (maximum 2 gm/day)

> 10 normal dose <10 25-30 mg/kg three times weekly HD 25-30 mg/kg three times weekly, post-

dialysis PYRIMETHAMINE 25 - 75 mg PO q24h no change no change RIFABUTIN 300 mg PO q24h no change no change RIFAMPIN 600 mg IV/PO q12 -

24h no change no change

RITONAVIR 600 mg PO q12h no change no change SAQUINAVIR 600 mg PO q8h no change no change STAVUDINE > 60kg: 40 mg PO

q12h < 60kg: 30 mg PO q12h

> 50 normal dose 26-49 normal dose q24h < 25 and HD

50% normal dose q24h

STREPTOMYCIN 15 mg/kg/day IM > 80 normal dose 50-80 1 gram loading dose, then 7.5 mg/kg

q24h Oct-49 1 gram loading dose, then 7.5 mg/kg

q24-72h < 10 7.5 mg/kg q72-96h HD give 50-75% of loading dose after each

HD < 10 normal dose q24h

TMP/SMX (Bactrim, Septra) 1SS tablet = 80 mg TMP; 1DS tablet =160 mg TMP; 1 ampule(5 ml) = 80 mg TMP

Urinary Tract Infections: 5 mg/kg/day of trimethoprim component given in divided doses Serious Systemic Infections: 8-10 mg/kg/day of trimethoprim component given in divided doses (q 6 -12hr) Pneumocystis carinii Pneumonia 15-20 mg/kg/day of trimethoprim component given q 6-8hr

> 30 normal dose

15 - 30 normal dose divided q12h x 48-72h then 50% of normal daily dose given q24h

< 15 NOT ADVISED

HD NOT ADVISED-

VALACYCLOVIR Primary Genital Herpes Simplex 1 gm PO q12hrs

> 30 normal dose 29-Oct 1 g q24 hrs

<10 500 mg q24 hrs


CrCl (ml/min)


HD 500 mg q24 hrs dosed post-dialysis Recurrent Herpes Simplex (genital) 500 mg PO q12h

> 30 normal dose < 29 500 mg PO q24h HD dose for Clcr < 29, given after HD

Herpes zoster: 1 gm PO q8h

> 50 normal dose 30-49 1 gm PO q12h 29-Oct 1 gm PO q24h <10 500 mg PO q24h HD dose for Clcr < 10, given after HD

VALGANCICLOVIR 900 mg po q12h INDUCTION

MAINTENANCE

> 60 900 mg po q12h

900 mg po q24h

40 - 59 450 mg po q12h

450 mg po q24h

25 - 39 450 mg po q24h

450 mg po q2days

24-Oct 450 mg po q2days

450 mg po twice weekly

HD do not use in patients on hemodialysis ZALCITABINE (ddC)

0.75 mg PO Q8H > 50 normal dose Oct-49 0.75 mg q12h < 10 and HD

0.75 mg q24h

ZIDOVUDINE 200 mg PO q8h > 26 normal dose < 25 and HD

100 mg q8h

Ali Olyaei PharmD, 2005

REFERRENCES

Joshi MC. Dose Adjustment- An Important Issue in Critical Care. Internet Journal of Medical Update Vol1, No1, Jan-jun 2006

Mahendra Agraharkar, MD, FACP. Acute Renal Failure

http://www.emedicine.com/cgi-bin/foxweb.exe/screen@d:/em/ga?book=med&authorid=2256&topicid=1595

3.2 LIVER DOSING

DRUGS DOSAGE ADJUSTMENT

Acyclovir No adjustment

Adenosine No adjustment

Adrenaline No adjustment

Alprazolam Reduce dose by 50 % to 60% or avoid in cirrhosis. May

precipitate coma in liver disease.

Amikacin No adjustment

Aminophylline Adjusted according to serum level measurement during

the first 12 to 24 hours. Use with caution.

Amiodarone Dosage adjustment should be considered, drug extensively

metabolised by liver.

Amitryptylline Increase sedative effect; avoid or use with caution in liver

disease.

Amlodipine Required dosage adjustment; 2.5mg od for hypertension,

5 mg od for angina.

Amoxycillin-Clavulanate

(Augmentin)

No adjustment

Ampicillin + Sulbactam

(Unasyn)

No adjustment

Amphotericin B No adjustment

Aspirin Avoid use in severe liver disease; may increase risk of

gastrointestinal bleeding.

Atenolol No adjustment

Atracurium No adjustment

Atropine No adjustment

Atorvastatin Contraindicated in active liver disease and increase in

serum transaminase

Azithromycin Not necessary; use with caution due to potential

hepatotoxicity (rare). Specific dosing guidelines for

hepatic impairment have not been established.

Baclofen No adjustment

Budesonide Reduced dose in moderate to severe case

Bupivacaine Reduced dose in severe case; use with caution

Calcium Polystyrene Sulfonate

Powder (Kalimate)

No adjustment as drug not absorbed systematically.

Carbamazepine Avoided if aggravated liver dysfunction or active liver

disease

Caspofungin Mild case: no adjustment necessary

Moderate case: 35mg/day; initial 70mg loading dose

should still be administered in treatment of invasive

infections; Esophageal candidiasis: 35mg/day

Severe case: no clinical experience

Cefepime No adjustment

Cefoperazone-Sulbactam

(Sulperazone)

Reduce dose by 50 % in patient with advanced liver

cirrhosis, maximum daily dose: 4 g.

Cefotaxime Moderate dosage reduction is recommended in severe

liver disease.

Ceftazidime No adjustment

Ceftriaxone Decrease dose and monitor plasma concentration if both

hepatic and severe renal impairment.

Cefuroxime No adjustment

Celecoxib ↓ 50% in moderate case. Avoided in severe case.

Ciprofloxacin No adjustment

Clarithromycin No need if renal function normal. Elderly : age related

reduction in renal function; monitor and adjust dose if

necessary.

Clindamycin Reduced dose (adjustment recommanded in severe

hepatic diseases).

Cloxacillin No adjustment

Clopidogrel Caution (risk of bleeding); avoid in severe hepatic

impairment. Reduced in moderate case.

Dantrolene Chronic therapy contraindicated in active liver disease;

has potential for hepatotoxicity

Dexamethasone No adjustment

Dexmedetomidine Dose reduction may need to be considered (↓ clearence)

Diazepam Use with caution. Reduced by 50%.

Digoxin No specific dosage adjustment is necessary

Diltiazem ↓ dose. Safe in cirrhosis up to 90mg/day.

Dobutamin No adjustment

Dopamin No adjustment

Doxycycline No adjustment

Enalapril No adjustment

Enoxaparine Use with caution in hepatic impairment

Erythromycin May cause idiosyncratic hepatotoxicity. Decrease dose in

moderate and severe cases.

Esmolol No adjustment

Esomeprazole Severe hepatic disease dose should not exceed 20mg. Mild

to moderate- no adjustment.

Felodipine Begin at dose of 2.5mg/day. Dose above 10mg/day should

not be used as incidence and severity of adverse event

outweighs additional hypotensive effects.

Fentanyl No adjustment.

Fondaparinux No adjustment.

Frusemide Hepatic disease: 20-120mg/day; used as adjunct to

spirinolactone and other measures.

Fucidic acid Not excrete renally. Patient with hyperbilirubinemia prior

to fucidic acid therapy have experienced an elevation of

bilirubin levels during therapy which returned to

pretreatment levels with discontinuation. Drug should be

avoided in these patient. Patient with cholestasis : 500mg

intravenously.

Gemfibrozil No adjustment

Gentamicin No adjustment

Glycopyrrolate No adjustment

Griseofulvin Avoid in severe liver disease

Haloperidol No adjustment

Heparin No adjustment

Hydralazine No adjustment

Hydrocortisone Dosage adjustment may be necessary.

Imipenem-Cilastatin (Tienam) No adjustment.

Ipratropium No adjustment.

Isoniazid Use with caution; monitor liver function regularly in the

first 2 months. Dose should be reduced in severe liver

disease.

Itraconazole Use only if benefit outweighs risk; dose reduction may be

necessary.

Isoflurane No adjustment

Ketoconazole Specific adjusment not described. Dose reduction in

severe liver disease.

Ketorolac Use with caution, may cause elevation of liver enzyme.

Hepatic dose may prolong elimination half life.

Labetalol Chronic liver disease → ↓ metabolism of labetalol. Dosage

reduction is required to avoid decrease in heart rate and

supine blood pressure.

Lactulose No adjustment.

Lamotrigine Moderate →severe : initial escalation & maintenance

doses should ↓ by 25%.

Severe & ascites: initial escalation & maintenance should

↓ by 50%.

Lansoprazole Dose should not > 30mg od in severe liver disease.

Levetiracetam Mild to moderate no need adjustment;

Severe: ↓ dose by 50 %.

Levobupivacaine Caution in liver disease.

Levofloxacin No adjustment.

Lignocaine ↓ dose in acute hepatitis & cirrhosis by 50%.

Linezolid Mild to moderate hepatic impairment : no dosage

adjusment neccessary. Use in severe not been adequately

evaluated.

Lorazepam No dose adjusment needed. The administration with the

lowest , effective dose is recommended.

Losartan ↓initial dose to 25mg/day.

Lovastatin Use with caution in patient with past history of liver

disease; active liver disease is contraindicated.

Mannitol No adjustment.

Meloxicam Mild to moderate: no adjustment necessary.

Severe : not been adequately studied

Meropenem No dosage adjustment .

Metformin Risk factor for lactic acidosis, should be avoided in

patients with hepatic insufficiency.

Methyldopa No adjustment.

Methylprednisolone No adjustment

Metoclopramide Dosage adjustment necessary, 10 mg tds effective and safe

for treatment of nausea and heartburn.

Metoprolol Dosage adjustment may be required; reduce dose slightly.

Metronidazole Mild : no need adjusment

Severe: ↓ dose; maximum 500mg iv suggested.

Midazolam Reduced midazolam clearance in patients with cirrhosis.

Dose reduction is necessary.

Morphine Mild: unchange but avoid in severe.

Excessive sedation may occur in cirrhosis.

Duration of action prolonged, dosage should be adjusted.

Dosing interval suggested to be increased 1.5 to 2 times

normal dose.

Nalbuphine Administrated with caution in reduced doses

Naproxene Suggested that dose of naproxene↓ at least 50%.

Nifedipine ↓ dose in severe liver disease

Noradrenaline No adjustment.

Omeprazole Not > 20mg od in liver disease

Pantoprazole Maximum 20mg od in severe liver disease & cirrhosis

→monitor liver function ( discontinue if deterioration)

Paracetamol Dose related toxicity – avoid large doses

Safely administered in therapeutic dose in stable hepatic

disease, t ½ ↑ in patient with acetaminophene induced

liver disease.

Parecoxib Mild →no adjustment

Halve dose in moderate case (max: 40mg od)

Severe hepatic impairment – no data; not recommended

Perindopril No adjustment

Pethidine ↓ initial dose in severe hepatic impairment; use with

caution.

Phenobarbital use with caution; initial dose should be reduced.

Phenytoin Mild : safe in usual dose

Reduced dose in moderate to severe.

Phytomenadione (Vit K) No adjustment

Piracetam Cirrhosis : clearance ↓; dose adjustment necessary

Piperacillin-tazobactam

(Tazocin)

No adjustment.

Polymyxin B No adjustment.

Prazosin Initially 0.5mg od; increased with caution.

Prednisolone No adjustment.

Propofol No adjustment.

Propranolol Marked slowing of heart rate may occur during cirrhosis

with conventional dose ; low initial dose required.

Pyrazinamide Monitor hepatic function ; idiosyncratic hepatoxicity

more common

Specific dosage recommendation not provided.

Ranitidine No adjustment.

Ramipril No adjustment.

Rifampicin Avoid or do not exceed 8mg/kg od. Discontinue treatment

if symptom such as nausea, vomiting, malaise or jaundice

develop.

Rocuronium Routine dose adjustment not necessary.

Ropivacaine ↓ dose or avoid.

Salbutamol No adjustment.

Sevoflurane Use with caution in patient with underlying hepatic

condition.

Simvastatin Contraindicated in active liver disease.

Sodium bicarbonate In patient with fluid retention, avoid those contain large

amount of sodium.

Sodium polystyrene sulfonate

powder (Resonium)

No adjustment as drug not absorbed systematically.

Sulfamethoxazole &

trimethoprim (Bactrim)

No adjustment.

Suxamethonium Prolonged apnoe may occur in severe liver disease due to

reduced hepatic synthesis of pseudocholinesterase. May

↓dose.

Telmisartan 20-40mg od in mild / moderate impairment, avoid in

severe.

Terbutaline No adjustment.

Theophylline Monitor serum level and ↓ dose.

Thiopental No adjustment.

Tigecycline No adjustment.

Topiramate Use with caution in hepatic impairment;

May decrease clearance but no specific dosing.

Tramadol Cirrhosis: 50mg bd.

Valpraote (valproic acid) Avoid if possible, hepatotoxicity & hepatic failure may

occur (usually in first 6 month)

Valsartan Mild to moderate ≤ 80mg/day; avoid if severe.

Vancomycin No adjustment

Vecuronium Not recommended; if must be used, lowest effective dose

must is recommended.

Verapamil ↓ dose by 20% to 50% of normal dose ; patient should be

monitored for abnormal prolongation of the PR interval.

Voriconazole Mild to moderate : follow standard loading dose, ↓

maintenance dose by 50% .

Severe : used only if benefit outweighs risk.

Warfarin Avoid in severe liver disease especially if protrombin time

already prolonged.

Respond to oral anticoagulant may be enhance in

obstuctive jaundice (due to ↓ vit K absorption), hepatitis

and cirrhosis (due to ↓ production of vit K dependent

clotting factor)

Zolpidem ↓ dose to 5mg od.

References:

1. Micromedex (R) Healthcare Series. Vol 141

2. British Formulary 56, September 2008.

3. Drug Information Handbook. 15th Edition 2003.

4. Infectious Disease Handbook; Antimicrobial Therapy & Diagnostic test/Procedure. 5th Edition. Lexi-Comp.2003.

5. Anesthesiology & Critical Care Drug Handbook. 6th Edition.2005. Lexi-Com

6. Medical Toxicology. Richard C. Dart. .2004.pg 1914. Dantrolene.

7. www.rxlist.com/mevacor-drug.htm. Lovastatin Drug Information: Used, Side effect, Drug Dosage.

8. Dexmedetomidine: a novel sedative-analgesic agentRalph Gertler, MD, 1 H. Cleighton Brown, MD,1 Donald H. Mitchell, MD,1 and Erin N. Silvius, MD1

2001.

3.3 SPECIAL DOSING IN OBESE PATIENTS

Obesity is defined by the CDC as a BMI of >30kg/m2, and morbid obesity is defined as a BMI of >40kg/m2.

3.3.1 Physiological changes in obesity

Can alter pharmacodynamic and pharmacokinetic of a drug which includes:

Dramatically increased adipose tissue Slightly increased lean tissue mass Increased cardiac output Increased glomerular filtration rate Fatty infiltration of liver

A higher proportion of body tissue can influence drug with lipophilic properties whereas increased organ mass, lean body mass, and blood volume in obesity can affect hydrophilic medications.

Failure to adjust doses in obesity may result either in sub therapeutic failure or increased toxicity.

3.3.2 Reported dosing adjustment in obesity

Drugs Suggested dosing weight Additional dosing recommendation

AntimicrobialsAcyclovir IBW1

Aminoglycosides IBW + 0.4(ABW-IBW)1

Amphotericin B ABW for conventional preparation; IBW for lipid preparation1

Beta-lactams IBW + 0.3(ABW-IBW)2

Ciprofloxacin IBW + 0.45(ABW-IBW)2

Erythromycin IBW1

Fluconazole Consider higher doses in obese patient1

Ganciclovir ABW3

Mycobacterial antibiotics IBW2

Vancomycin ABW2

Muscle relaxantSuxamethonium IBW3

Atracurium IBW3

Pancuronium IBW3

SedativePropofol ABW5

ABW = actual body weight IBW = ideal body weight

Calculations:-IBW (Ideal body weight):Male IBW (kg) = 50 kg + 2.3 (height in inches over 60 inches)Female IBW (kg) = 45.5 kg + 2.3 (height in inches over 60 inches)

3.3.3 Creatinine clearance in obese patient4

Overestimation or underestimation of clearance can occur in obesity when considering actual body weight versus ideal body weight, respectively. The Cockcroft-Gault equation is commonly used to calculate glomerular filtration rate (GFR) in lean patients, however its use in obesity is questionable due to the disparity between muscle mass and body weight ratio observed in obesity.

The Salazar-Corcoran equation takes into account multiple factors to provide a better estimation of ClCr in obesity including serum creatinine, gender, actual weight, age, and height.

Salazar-Corcoran Equation 4 :

ClCr(Male) = (137-age)x[(0.285xWt)+(12.1xHt 2 )] (51xSCr)

ClCr(Female) = (146-age)x[(0.287xWt)+(9.74xHt 2 )] (60xSCr)

Wt= actual body weight in kgHt= height in metersSCr=serum creatinine in mg/dl

Although some drugs have established dosing adjustments for obesity, it remains unknown for the majority of drugs if dosing adjustment is warranted.

References:

1. Optimal antibiotic dosing for obese patients a challenge for clinicians by Elizabeth Dodds Ashley, PharmD, BCPS Infectious Disease News June 2007

2. Antimicrobial Dosing in Obesity Rebecca Wurtz, GailItokazu, and Keith Rodvold Clinical Infectious Diseases1997;25:112C

3. Uptodate 17.1

4. Pharmacokinetics Alterations in Obesity By Jane B. Lee, PharmD; P. Shane Winstead, PharmD;Aaron M. Cook, PharmD ORTHOPEDICS 2006; 29:984

5. MICROMEDEX(R) Healthcare Series Vol. 143

CHAPTER 4: NUTRITION

4.1 PARENTERAL NUTRITION IN CRITICALLY ILL PATIENTS

ESPEN Guidelines on Parenteral Nutrition: Intensive Care (Adapted from Singer et al., 2009)

Recommendations Grade

Indications

Starvation and underfeeding in ICU patients is aasociated with increased morbidity and mortality

Parenteral Nutrition (PN) should be initiated within 24 to 48 hours in all patients who are not expected to be on normal nutrition within 3 days when enteral nutrition (EN) is not feasible

All patients receiving less than their targeted enteral feeding after 2 days should be considered for supplementary PN

C

C

C

Requirements

A complete PN formulation should be given to ICU patients to cover their needs fully

The aim in acute illness is to provide energy as close as possible to the measured energy expenditure (to reduce negative energy balance)

ICU patients should receive 25 kcal/kg/day increasing to target over the next 2-3 days (in the absence of indirect calorimetry)

C

B

C

Carbohydrates

The minimal amount required is about 2g/kg of glucose per day Hyperglycemia (glucose >10 mmol/L) contributes to death in critically ill

patient and should be avoided to prevent infectious complications

B

B

Lipids

Lipids should be an integral part of PN for energy and to ensure essential fatty acid provision in long term ICU patients

Intravenous lipid emulsions can be administered safely at a rate of 0.7 g/kg up to 1.5 g/kg over 12 to 24 hours

The tolerance of mixed LCT/MCT lipid emulsions in standard use is sufficiently documented

Olive oil-based PN is well tolerated in critically ill patients EPA and DHA containing lipid emulsions had demonstrable effects on cell

membranes and inflammatory process. Fish oil-enriched lipid emulsions probably decrease length of stay in crtitically ill patients

B

B

C

B

B

Amino Acids

A balanced amino acid mixture should be infused at approximately 1.3-1.5 g/kg of ideal body weight per day in conjunction with an adequate energy supply

B

Recommendations Grade

In critically ill patients indicated for PN, the amino acid solution should contain 0.2-0.4 g/kg/day of L-glutamine (e.g. 0.3-0.6 g/kg/day alanyl-glutamine dipeptide) A

Micronutrients

All PN prescriptions should include a daily dose of multivitamins and of trace elements

C

Route

A central venous access is required to administer the high osmolarity PN mixture

Peripheral venous access may be considered for low osmolarity PN mixture (<850 mOsm/L)

If peripherally administered PN does not allow full provision of the patient’s need, then PN should be administered via the central venous access

C

C

C

Mode

PN admixtures should be administered as a complete all-in-one bag B

Reference:

Singer, P., Berger, M.M., Van den Berghe, G., Biolo, G., Calder, P., Forbes, A., Griffiths, R., Kreyman, G., Leverve, X. & Pichard, C. 2009. ESPEN guidelines on parenteral nutrition: intensive care. Clinical Nutrition. (28). 387-400.

CHAPTER 5: OTHERS

5.1 DRUG CAUSING HAEMATOLOGICAL DISORDER

Drugs may produce hematologic toxicity by one of three general mechanisms:

direct drug (or a metabolite) toxicity

toxicity due to a drug effect on a genetic abnormality in the bone marrow

toxicity involving immune mechanisms.

The four major blood dyscrasias attributable to drugs are:

agranulocytosis or leukopenia (loss of the white blood cells)

aplastic anemia (loss of all the formed elements of the blood)

thrombocytopenia (loss of the platelets)

hemolytic anemia (loss of the red blood cells).

The incidence of these adverse hematologic drug reactions, the relative importance of various etiologic chemicals, and their resultant morbidity and mortality vary.

5.1.1 Drugs Suspected of Inducing Agranulocytosis (Leukopenia)

Drug-induced agranulocytosis is classified as Type 1 (due to an immune mechanism) and Type II (drug effect on bone marrow DNA synthesis). In Type I reactions, blood immunoglobins are directed against drug-related antigens located on circulating leukocytes.

Allopurinol*

Aminopyrine

Chloramphenicol

Chlordiazepoxide

Chloroquine

Chlorpromazine

Indomethacin

Mefenamic acid

Penicillamine

Anticonvulsants

Antimalarials

Aspirin

Captopril

Cephalosporins

Chlorthalidone

Cimetidine

Clindamycin

Diazepam

Isotretinoin

L-dopa

Mercurial diuretics

Methyldopa

Naproxyn

Nitrofurantoin

Penicillins

Phenothiazines

Piroxicam

Phenylbutazone

Phenytoin

Quinidine

Rifampicin

Sulfonamides

Thiazides

Acetaminophen §

Acetazolamide

Diflunisal

Doxycycline

Fenoprofen

Gentamicin

Griseofulvin

Hydralazine

Ibuprofen

Isoniazid

Procainamide

Propranolol

Spironolactone

Streptomycin

Sulfonylureas

Sulindac

Tolmetin

Vancomycin

* Underlined drugs are most significant

§ Many of these other drugs have been implicated in only one or a few case reports

5.1.2 Drugs Suspected of Inducing Aplastic Anemia

Aplastic anemia is an unexpected peripheral-blood pancytopenia with variable bone marrow hypocellularity in the absence of underlying malignant or myeloproliferative disease.

Severe aplastic anemia is seen with a bone marrow of less than 25% of normal cellularity or a bone marrow of less than 50% of normal cellularity with less than 30% of the hematopoietic cells and at least two of the following peripheral blood values:

Granulocytes fewer than 500/mm3

Platelets fewer than 20,000/mm3

Anemia with reticulocytes fewer than 1%. 15 About 65% of people with aplastic anemia die within 4 months of diagnosis; few die after this 4-month period.'

Allopurinol*

Aminopyrine

Chloramphenicol

Sulfonamides

Acetaminophen §

Aspirin

Naproxyn

Organic solvents

Phenytoin

Chloroquine

Gold salts

Indomethacin

Mefenamic acid

Phenylbutazone

Propylthiouracil

Benzene

Captopril

Chlordiazepoxide

Chlorpromazine

Fenoprofen

Indoprofen

Piroxicam

Sulfonylureas

Sulindac

Thiazides

Thiocyanate

*Underlined drugs are most significant


5.1.3 Drugs Suspected of Inducing Thrombocytopenia

Drug-induced immune thrombocytopenia is characterized by acute purpura, confluent petechiae or ecchy-moses- particularly after mild trauma-and gastrointestinal, central nervous system, or urinary tract bleeding,all associated with a mild or severe lack of blood platelets.

Drugs may induce marrow hypoplasia, destroy platelets directly, or be responsible for an immune reaction. Thrombocytopenia may be associated with several disease states (acute leukemia, Gaucher's disease, systemic lupus erythematosus, sarcoidosis); drug-induced thrombocytopenia usually remits 1 to 2 weeks after drug discontinuance.

Gold salts*

Indomethacin

Mefenamic acid

Quinidine

Quinine

Thiazides

Acetaminophen §

Aminopyrine

Aspirin

Codeine

Danazol

Diclofenac

Digitoxin

Fenoprofen

Heparin

Ibuprofen

Isotretinoin

Para-aminosalicyclic acid

Phenytoin

Piroxicam

Ranitidine

Sulindac

Tolmetin

Amiodarone

*Underlined drugs are most significant


5.1.4 Drugs Suspected of Inducing Hemolytic Anemia

Aminopyrine*

Methyldopa

Quinidine

Acetaminophen §

Aspirin

Cephalosporins

Chlorpromazine

Phenytoin

Diclofenac

Ibuprofen

L-dopa

Mefenamic acid

Naproxyn

Penicillins

Phenylbutazone

Quinine

Rifampicin

Sulfonamides

Sulindac

Tetracyclines

Thiopental

Volatile nitrites

*Underlined drugs are most significant.

§ Many of these other drugs have been implicated in only one or a few case reports.

5.2 POISONING

Treatment Option Dose & Duration Dilution Side Effects Contraindications Monitoring

Organophosphate Poisoning

1. Prevention of absorption

- Activated Charcoal

Adult : 25 – 100 gm

Child : 25 – 50 gm

< 1 yr : 0.5 – 1 gm/kg

Tx : Cont until pt clinical condition improve.

Dilute 30 gm in 240 ml Impaired intestinal motility

Absence of bowel sounds, GI perforation, intestinal obstruction, recent surgery, GI haemorrhage

Serum electrolyes, ECG, serum amylase

2. Treatment- Atropine

Adult :

2 mg q5-10 min

(IV) until atropinised

Child :

0.05 mg/kg (IV),

then 0.02-0.05

mg/kg q15-60 min

until atropinised

Tx : cont for 12 – 24 H

Commnet from Martina Want to include the infusion dose?

Given undiluted

I/Tracheal : Dilute dose in 1-2 ml of NS

Antimuscarinic effect e.g dry skin, dilated pupil, flushing, urinary retention,↓bronchial secretion, constipation, bradycardia etc

Hypersensivity, Myasthenia Gravis, paralytic ileus, pyloric stenosis and prostatic enlargement

Pulse rate, EKG, urine output, GI motility

- Pralidoxime Adult : 30mg/kg (bolus),repeat at 4-6 H, Inf : 8mg/kg/H(Max : 12 gm/day)Child : 20 – 50 mg/kg, 10 – 20 mg/kg/H(Max : 2gm/dose)

Dilute up to 20 mg/ml with WFI for IV inj. given over 5-10 min

Inf : dilute in 100ml NS over 15-30 min

Blurred vision, diplopis, dizziness, drowsiness,↑BP

headache,transient ↑ LFT, impaired accommodation, N, tachycardia,

Hypersensitvity to any component of the product

GIVE only after patient is adequately atropinised

Vital signs, ECG, urine output

Note : administer as soon as possible after exposure, however pt presenting late (2-6 days post exposure) may


Tx : until pt clinical condition improve

laryngospasm still benefit

Paraquat Poisoning

Prevention of absorption


- Fdbck from Martina: Fuller’s earth?

Adult : 25 – 100 gm

Child : 25 – 50 gm

< 1 yr : 0.5 – 1 gm/kg

Tx : Cont until pt clinical condition improve




Opiods Poisoning

1. Overdosage

- Naloxone

Adult :

0.4 – 2 mg q 2-3 min (bolus) (Max : 10 mg)

Child :

0.01 mg/kg, then 0.1 mg/kg if no response

Tx : up to 48H

Maybe given undiluted

Infusion :

4mg in 500ml in NS, D5 discrd inf after 24H

Hyperyension, N, V, sweating, tachycardia, elevated PTT

Hypersensitivity to naloxone

Vital Signs

2. Reversal of Opiod induced resp distress


- Naloxone 1.5 – 3 µg/kg (IV), if needed increment of 0.1mg q2min, further dose IM after 1-2H prn

Benzodiazepines Poisoning

1. Prevention of absorption- Activated

Charcoal

Adult : 25 – 100 gm

Child : 25 – 50 gm

< 1 yr : 0.5 – 1 gm/kg





2. Treatment- Flumazenil

Adult :

0.2 mg (15 sec), then 0.1mg q1min prn, usual 0.3-0.6mg (Slow IV),

Inf : 0.1-0.4 mg/H (Max : 2 mg)

Child :

5µg/kg every 60 sec, max 40 µg/kg

Given undiluted or further dilute with D5,NS,½ NS

Discard solution after 24H

N, V, Flushing, agitation, anxiety, transient ↑BP, HR

Life threatening condition controlled by BDZ (e.g ↑ intracranial pressure, status epilepticus)

Airway, breathing, circulation, vital signs, ECG


then 2-10 µ/kg/H

Tx : until desired level of consciousness with max dose achieved

Heparin and Derivatives Poisoning

Severe Haemorrhage- Protamine Sulfate

Adult :

1mg /100U hep,

(Max : 100 mg)

Child :

1mg/100U hep, 0.5mg/100U hep. If > 1H (slow IVstat), subs dose1mg/kg (Max : 50 mg)

Tx : any dose over 100mg in 2H should be justified by coagulation studies

Undiluted over 10 min

Maybe further dilute with NS or D5.Rate <5mg/min inf over 2-3H

Hypotension, bradycardia and dyspnoea

None when use as indicated

Airway, breathing, circulation, vital signs, Coagulation Profile, FBC

Warfarin Overdosage


- Activated

Adult : 25 – 100 gm

Child : 25 – 50 gm


Absence of bowel sounds, GI perforation, intestinal obstruction, recent surgery, GI



Charcoal < 1 yr : 0.5 – 1 gm/kg


haemorrhage

2. Treatment- Vitamin K

Adult : 10 mg

(Max : 25 – 50 mg)

Child : 1-5 mg

(Max : 0.6 mg/kg)

Tx : may repeat in 6-8H if initial response is not adequate

Dilute 10mg in 50ml D5 over 30 min or into Y site of fast running D5

Max 40mg over 24H

Venous irritation, phlebitis, anaphylaxis

Hypersensitivity to components

Airway, breathing, circulation, vital signs, Coagulation Profile, FBC, INR

Paracetamol Poisoning



Adult : 25 – 100 gm

Child : 25 – 50 gm

< 1 yr : 0.5 – 1 gm/kg






2. Treatment

- N-Acetylcysteine Adult :

150mg/kg over 15min, then 50mg/kg over 4H, then 100mg/kg over 16H

Child : Same as adult

Tx : usually total infusion time is 21H

Adult :

Initial dilute in 200ml D5% given over 15min, then in 500ml over 4H, then in 1L over 16 H

Child (<12y) :

Dilution ½ of adult given at the same rate of adult dose.

Child (<20 kg) :

Initial dilute as 3ml/kg over 15 min, then 7ml/kg over 4H, then 14/kg over 16H.

Rash, anaphylaxis, bronchospasm, hypocalcaemia and ECG changes

From Martina: Want to add what to do if these happens. Stop or not to stop NAC?

Hypersensitivity to acetylcysteine or any of its component

Airway, breathing, circulation, vital signs, Ca2+ level, LFT, ECG

Notes : NAC therapy should begin within 8H of ingestion if possible. NAC efficacy decrease progressively from 8-16H post ingestion

References :

1. BNF 51, March 2006

2. Drug Doses, 13th Ed 2005, Frank Shann3. Intravenous Medication 2008, 24th Ed, Betty LG, Adrienne RN4. Micromedex (R) Healthcare Series Vol. 13

APPENDICES

APPENDIX 1: DRUGS THAT MAY UNMASK/EXACERBATE MYASTHENIA GRAVIS

Anesthetic agentsChloroprocaine Diazepam Ether Halothane Ketamine Lidocaine

Neuromuscular blocking agents Propanidid Procaine

Antibiotics Aminoglycosides Amikacin Gentamicin Kanamycin Neomycin Netilmicin Paromomycin Spectinomycin Streptomycin Tobramycin

Fluoroquinolones Ciprofloxacin Levofloxacin Norfloxacin

Others Ampicillin Clarithromycin Clindamycin Colistin Erythromycin Lincomycin Quinine Telithromycin Tetracyclines Anticonvulsants Gabapentin Phenytoin Trimethadione

Antipsychotics Chlorpromazine

Lithium Phenothiazines

Antirheumatic drugs Chloroquine Penicillamine

Cardiovascular drugs Beta blockers Bretylium Procainamide Propafenone Quinidine Verapamil and calcium channel blockers

Glucocorticoids Corticotropin Methylprednisolone Prednisone

Neuromuscular blockers and muscle relaxants Botulinum toxin Magnesium sulfate and magnesium salts Methocarbamol

Ophthalmologic drugs Betaxolol Echothiophate Timolol Tropicamide Proparacaine

Other drugs Anticholinergics Carnitine Cholinesterase inhibitors Deferoxamine Diuretics Emetine (Ipecac syrup) Interferon alpha Iodinated contrast agents Narcotics Oral contraceptives Oxytocin Ritonavir and antiretroviral protease inhibitors Statins Thyroxine

* Drugs listed here should be used with caution in patients with myasthenia gravis. Aminoglycosides should be used only if absolutely necessary with close monitoring. Please refer to the text for further information.

Ref: Uptodate 17.1

APPENDIX 2: CATEGORIES OF SAFE & UNSAFE DRUGS IN THE ACUTE PORYPHYRIAS

Categories of safe drugs in the Acute Porphyrias

Drugs Which are SAFE to use: Drugs which are PROBABLY SAFE to use:

Drugs which are PROBABLY SAFE to use: (cont.)

Acetaminophen Acetazolamide Allopurinol Amiloridine Aspirin Atropine Bethanidine Bromides Bumetanide Chloral hydrate Cimetidine Corticosteroids Coumarins Fluoxetine Gabapentin Gentamycin Guanethidine Insulin Narcotic analgesics Ofloxacin Paracetamol Penicillins Phenothiazines Propranalol Streptomycin Succinylcholine Tetracycline

Adrenaline Amitriptyline Azathioprine Chloramphenicol Cisapride Colchicine Cyclosporin Cytarabine Dicumarol Chloroquine Digoxin Daunorubicin Doxazosin Estrogens (natural/endogenous) Ibuprophen Imipramine Indomethacin Labetalol Lithium Losartan

Methenamine Methylphenidate Naproxen Neostigmine Nortriptyline Nitrous oxide Penicillamine Procaine Propanidid Propofol Propoxyphene Rauwolfia alkaloids 6-Thioguanine Thiouracils Thyroxine Tricyclic antidepressants Tubocurarine Vigabatrin Vitamin B Vitamin C

This list is NOT comprehensive and does not reflect all information and opinions about drug safety in the acute porphyrias. There is considerable evidence for classification of drugs in the "Safe" category, but much less evidence, or conflicting evidence, for drugs in the "Probably Safe" category. Additional information concerning safe and unsafe drugs can be found in the text, including available websites. Reproduced with permission from Anderson, KE, et al. Disorders of heme synthesis: X-linked sidero-blastic anemia and the porphyrias. In: The metabolic and molecular bases of inherited disease (Scriver, CR, Beaudet, AL, Sly, WS, Valle, D, eds). McGraw-Hill Medical Publishing Division, New York. p 2991. Copyright © 2000 The McGraw-Hill Companies.

Categories of Unsafe drugs in the Acute Porphyrias

Drugs which are UNSAFE

Drugs which are UNSAFE (cont.)

Drugs which are POTENTIALLY UNSAFE

Drugs which are POTENTIALLY UNSAFE (cont.)

ACE inhibitors Antipyrine Aminopyrine (amidopyrine) Aminoglutethamide Barbiturates (all) N-butylscopolammonium bromide Calcium channel blockers Carbamazepine Chlorpropamide Danazol Dapsone Diclofenac Enalapril Diphenylhydantoin Ethosuximide Ergot preparations Ethchlorvynol Ethinamate Felbamate Glutethimide Griseofulvin Ketoconazole Lamotrigine

Mephenytoin Metoclopramide Meprobamate Methyprylon Nefazadone Nifedipine Novobiocin Phenazone Phenylbutazone Primidone Pargyline Progesterone (progestins) Rifampin Succinimides Sulfasalazine Sulfonamide antibiotics Sulfonmethane (sulfonal) Sulfonethylmethane (trional) Sulfonylureas Trimethadione Valproic acid Tranylcypromine

Alfadolone acetate Alfaxolone Alkylating agents* Altretamine (hexamethylmelamine) Benzodiazepines Busulfan Captopril Cephalosporins Chlorambucil Chlordiazepoxide Clonidine Cyclophosphamide Dacarbazine Deferoxamine Diazepam Diltiazem Colistin Dacarbazine Diphenhydramine EDTA Etomidate Estrogens (synthetic) Erythromycin 5-Fluorouracil Gold compounds Fluroxene

Heavy metals (eg, Gold) Hydralazine Hyoscine Ketamine Lisinopril Mefenamic acid Melphalan Mifepristone Methyldopa Metyrapone Nalidixic acid Nikethamide Nitrazepam Nitrofurantoin o,p'-DDD Pentazocine Phenoxybenzamine Procarbazine Pyrazinamide Spironolactone Theophylline Tiagabine Tramadol Tricyclic antidepressants Troglitazone

This list is NOT comprehensive and does not reflect all information and opinions about drug safety in the acute porphyrias. There is considerable evidence for classification of drugs in the "Unsafe" category, but much less evidence, or conflicting evidence, for drugs in the "Probably Unsafe" category. Additional information concerning safe and unsafe drugs can be found in the text, including available websites.

* Chlorambucil and Melphalan may be safer than the other alkylating agents listed here.

Reproduced with permission from Anderson, KE, et al. Disorders of heme synthesis: X-linked sidero-blastic anemia and the porphyrias. In: The metabolic and molecular bases of inherited disease (Scriver, CR, Beaudet, AL, Sly, WS, Valle, D, eds). McGraw-Hill Medical Publishing Division, New York. p 2991. Copyright © 2000 The McGraw-Hill Companies.

Ref: Uptodate 17.1

APPENDIX 3: DRUGS AND CHEMICALS IN GLUCOSE-6-PHOSPHATE DEHYDROGENASE

Unsafe for class I, II, and III variants Safe for class II and III variants*

Acetanilid Dapsone Furazolidone Methylene blue Nalidixic acid Naphthalene (mothballs, henna) Niridazole Nitrofurantoin Phenazopyridine Phenylhydrazine Primaquine Sulfacetamide Sulfamethoxazole Sulfanilamide Sulfapyridine Thiazosulfone Toluidine blue Trinitrotoluene

Acetaminophen Aminopyrine Ascorbic acid (except in very high doses) Aspirin Chloramphenicol Chloroquine Colchicine Diphenhydramine Isoniazid L-DOPA Menadione Paraaminobenzoic acid Phenacetin Phenytoin Probenecid Procainamide Pyrimethamine Quinidine Quinine Streptomycin Sulfamethoxpyridazine Sulfisoxazole Trimethoprim Tripelennamine Vitamin K

* Safety for class I variants is usually not known.

Data from Beutler, E, Blood 1994; 84:3613.

Reference: Uptodate 17.1

APPENDIX 4: DRUG-DISEASE INTERACTIONS

Drug Disease Remarks Management Ref

1 Aminoglycosides Myasthenia Gravis

Cause significant increase in weakness, respiratory depression. Aminoglycoside-related postoperative respiratory depression caused the greatest frequency of drug-induced neuromuscular blockade

Avoid or use only if absolutely necessary with close monitoring

www.uptodate.com

2 Androgens (testosterone)

HF Edema Endocrine Society Guideline (US) recommend not to use in NYHA III, IV

Uptodate vs 17.1

3 Amiodarone Thyroid disorders

the iodine-rich amiodarone affects the thyroid gland, causing overt hypothyroidism or thyrotoxicosis in 14%-18% of cases.

Thyroid function to be monitored.

Complex Drug-Drug-Disease Interactions Between Amiodarone, Warfarin, and the Thyroid GlandKurnik, Daniel MD; Loebstein, Ronen MD; Farfel, Zvi MD; Ezra, David MD; Halkin, Hillel MD; Olchovsky, David MD

4 Antiarrhythmic (sotalol, ibutilide)

HF Negative inotropic, precipitate HF, proarrhythmic

Amiodarone is the preferred choice in arrhythmias in HF

Uptodate vs 17.1

5 ACE inhibitors gold salts and interferon .

Psoriasis Occasional triggers of a psoriatic flare Use Cautiously Skin Therapy Letter • Editor: Dr. Stuart Maddin • Vol. 4 No. 3

6 Antimalarials Psoriasis Exacerbate Not contraindicated. Skin Therapy Letter • Editor: Dr. Stuart Maddin • Vol. 4 No. 3

7 Antipsychotics Parkinson’s disease

Parkinsonism Use with caution Neurology, Vol 66, Issue 6, March 2006


8 Beta Blockers COPD, Asthma Non selective beta blockers prevents bronchodilatation

-All beta blockers are contraindicated in severe disease

-Non selective ones to be avoided in mild to moderate disease. Selective or combined alpha/beta to be used cautiously at low dose

Uptodate vs 17.1

9 Beta Blockers Diabetes Facilitation of hypoglycaemia Use cautiously Uptodate vs 17.1

10 Beta Blockers Peripheral Vascular Disease, Raynaud’s phenomenon

Non selective beta blockers implicated. Reduction in cardiac output and blockade of beta-2-receptor-mediated skeletal muscle vasodilation contribute to the vascular insufficiency [

Selective agents can be used cautiously

Uptodate vs 17.1

11 Beta blockers Bradycardia, heart block

-ve Chronotropic effect.

-maintenance of cardiac output depends on sympathetic drive

Use cautiously Uptodate vs 17.1

12 Beta Blockers Psoriasis May aggravate existing disease Not contraindicated in psoriasis. However,

when there is a clear relationship between the exacerbation of

the psoriasis and the intake of a beta blocker, it sometimes help to switch from a non-cardioselective beta 2 blocker to

Skin Therapy Letter • Editor: Dr. Stuart Maddin • Vol. 4 No. 3


a cardioselective beta 1 blocker.

13 Beta Blockers Myasthenia gravis

Exacerbate Use with caution Uptodate vs 17.1

14 Chemotherapeutic agents (cyclophospha-mide, traztuzumab, bevacizumab, anthracycline-like chemo agents

HF Cardiotoxic Altenative administration schedule. Baseline and periodic monitoring of ECG and LVEF (with either ECHO) is recommended.

Uptodate vs 17.1

15 CNS depressants, opioids, muscle relaxants

Myasthenia Gravis

Increase symptoms when used together or at high doses

Use cautiously Uptodate vs 17.1

16 Corticosteroids Psoriasis Rebound that invariably follows their

use. The flare-up may be even worse than the original attack.

Avoid Skin Therapy Letter • Editor: Dr. Stuart Maddin • Vol. 4 No. 3


17 COX-2 selective inhibitosr

HF Exacerbation of HF Use with caution Uptodate vs17.1

18 Calcium Channel Blockers

CHF Negative Inotropic, increase sympathetic activity by short acting dihydropyridines. Longer acting ones appears safe

Avoid use of shorter acting dihydropyridines

Efficacy and safety of calcium channel blockers in heart failure: focus on recent trials with second-generation dihydropyridines.

AU de Vries RJ; van Veldhuisen DJ; Dunselman PH

SO Am Heart J 2000 Feb;139(2 Pt 1):185-94.

19 Calcium channel blockers (short acting –verapamil, diltiazem, nifedipine)

2nd-3rd degree heart block

Negative Inotropic. Avoid use of shorter acting dihydropyridines

20 Fluoroquinolones Myasthenia gravis

Exacerbate Use with caution Uptodate vs17.1

21 Lithium Psoriasis Well recognised cause of exacerbation.

It may even cause pustular or erythrodermic psoriasis in a significant proportion of

affected patients.

Lithium does not aggravate a pre-existing

psoriasis in all cases, and therefore is not contraindicated

Skin Therapy Letter • Editor: Dr. Stuart Maddin • Vol. 4 No. 3


in all patients with psoriasis.

22 Lignocaine and procaine may cause worsening if given iv

Myasthenia Gravis

Uptodate vs 17.1

23 Magnesium Sulfate Myasthenia Gravis

Relatively contraindicated since it has inhibitory effect on acetylcholine release

Relative contraindication Uptodate vs 17.1

24 Metformin HF Increased risk of lactic acidosis Use with caution Uptodate vs 17.1

25 NSAIDs, Aspirin Peptic Ulcers Gastrotoxicity Use with caution Uptodate vs 17.1

26 NSAIDs, Aspirin Asthma Acute exacerbation of airway inflammation. Less likely with COX-2 inhibitors

Avoid in aspirin sensitive asthma. Use with caution in others

Uptodate vs 17.1

27 NSAIDs HF Exacerbation and impaired response to ACE-I

Use with caution Uptodate vs 17.1

28 NSAIDs Psoriasis Anecdotal reports suggest adversely affecting psoriasis

Consider discontinuing a NSAID if the patient’s psoriasis worsened on starting, and

improved after stopping that drug

Uptodate vs 17.1

29 Neuromuscular Myasthenia Unmask or exacerbate MG Titrate judiciously Uptodate version 17.1


Blocking Agents Gravis

30 High Dose Prednisolone, glucocorticoids in high doses

Myasthenia Gravis

Exacerbation during early stages of treatment

During crisis, use only if patient’s airway is protected

Uptodate version 17.1

31 Penicillamine Myasthenia Gravis

Induces autoimmune Myasthenic syndrome. Reversible

Avoid Uptodate version 17.1

32 Phenytoin, Gabapentin

Myasthenia Gravis

Rare cases of exacerbation Use cautiously Uptodate version 17.1

33 Procainamide, quinidine, quinine,

List is comprehensive-Refer Appendix 1

Myasthenia Gravis

Cause significant increase in weakness Avoid Uptodate version 17.1

34 PDE-3 (Cilostazol) HF Increased mortality Contraindicated Uptodate vs 17.1

35 PDE-4 (Anagrelide) HF +inotropic, vasodilatory, leading to fluid retention and heart failure

Avoid Uptodate vs 17.1

36 PDE-5 (sildenafil, vardenafil, tadalafil)

HF Potentially hazardous in patients with HF with borderline BP. Avoid in IHD

Use with caution Lexicomp

37 Statins Myasthenia Gravis

Unmasking subclinical MG due to myotoxicity, new and worsening MG

Use cautiously Uptodate version 17.1

38 Sildenafil CHD Safety and efficacy has not been Use with caution Lexicomp Drugs


studied in these patients

39 Sulfonamide Antibiotics, Penicillin (but not the semi synthetic ones)

SLE Exacerbate SLE Avoid Uptodate vs 17.1

40 Theophylline Cardiac disease Can reduce theophylline clearance by as much as 50%

Monitor level closely Shannon: Haddad and Winchester's Clinical Management of Poisoning and Drug Overdose, 4th ed. Ch 65

41 Theophylline Primary Hepatic Disease

Can reduce theophylline clearance by as much as 50%

Monitor level closely Shannon: Haddad and Winchester's Clinical Management of Poisoning and Drug Overdose, 4th ed. Ch 65

42 Theophylline Cystic Fibrosis, Hyperthyroi-dism

Increase clearance May need to increase dose Shannon: Haddad and Winchester's Clinical Management of Poisoning and Drug Overdose, 4th ed. Ch 65

43 TNF blockers HF New onset or worsening pre-existing HF Use with caution in patients with HF or decreased left ventricular function; worsening and new-onset HF has been reported." In addition, infliximab is contraindicated at doses

Drug labels


higher than 5 mg/kg in patients with moderate or severe HF (NYHA class III/IV)

44 TNF blockers Psoriasis Possibility of emergence or worsening of psoriasis during treatment with TNF blockers, particularly pustular and palmoplantar forms of psoriasis.

Monitor FDA ALERT [8/4/2009]

45 Telithromycin Myasthenia Gravis

Black box warning on possibility of exacerbating or unmasking MG. Should not use.

Uptodate version 17.1

46 Warfarin Thyroid disorders

thyroid disorders may affect warfarin sensitivity, with hypothyroidism and thyrotoxicosis resulting in increased or decreased warfarin requirements, respectively

Thyroid function should be tested in any patient with otherwise unexplained changes in warfarin dose requirements, particularly if concomitantly treated with amiodarone.

Complex Drug-Drug-Disease Interactions Between Amiodarone, Warfarin, and the Thyroid GlandKurnik, Daniel MD; Loebstein, Ronen MD; Farfel, Zvi MD; Ezra, David MD; Halkin, Hillel MD; Olchovsky, David MD

47 Inexhaustive list (see Appendix 2)

Acute Intermittent Porphyria

Can exacerbate disease Refer to Appendix 2 Uptodate 17.1

48 Inexhaustive list (see Appendix 3)

G6PD deficiency

Can cause hemolysis Refer to Appendix 3 Uptodate 17.1

pharmacy critical care

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